treatment guidelines

Treatment Guidelinesfor Medicine and PrimaryCare2004 Edition

New NMS Practice Parameters

Paul D. Chan, MDMargaret T. Johnson, MD

Current Clinical Strategies Pub-lishing

www.ccspublishing.com/ccs

Copyright © 2004 by Current Clinical Strategies Publish-ing. All rights reserved. This book, or any parts thereof,may not be reproduced or stored in an informationretrieval network without the permission of the publisher.Current Clinical Strategies is a registered trademark ofCurrent Clinical Strategies Publishing Inc. The reader isadvised to consult the drug package insert and otherreferences before using any therapeutic agent. Nowarranty exists, expressed or implied, for errors andomissions in this text.

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Cardiovascular Disorders

Acute Coronary Syndromes(Acute Myocardial Infarction andUnstable Angina)

Acute myocardial infarction (AMI) and unstable anginaare part of a spectrum known as the acute coronarysyndromes (ACS), which have in common a rupturedatheromatous plaque. These syndromes include unstableangina, non–Q-wave MI, and Q-wave MI. The ECGpresentation of ACS includes ST-segment elevationinfarction, ST-segment depression (including non–Q-wave MI and unstable angina), and nondiagnostic ST-segment and T-wave abnormalities. Patients with ST-segment elevation will usually develop Q-wave MI.Patients with ischemic chest discomfort who do not haveST-segment elevation will develop Q-wave MI andnon–Q-wave MI or unstable angina.

I. Clinical evaluation of chest pain and acute coro-nary syndromesA. History. Chest pain is present in 69% of patients

with AMI. The pain may be characterized as aconstricting or squeezing sensation in the chest.Pain can radiate to the upper abdomen, back,either arm, either shoulder, neck, or jaw. Atypicalpain presentations in AMI include pleuritic, sharpor burning chest pain. Dyspnea, nausea, vomiting,palpitations, or syncope may be the only com-plaints.

B. Cardiac Risk factors include hypertension,hyperlipidemia, diabetes, smoking, and a strongfamily history (coronary artery disease in early or

mid-adulthood in a first-degree relative).C. Physical examination may reveal tachycardia or

bradycardia, hyper- or hypotension, or tachypnea.Inspiratory rales and an S3 gallop are associatedwith left-sided failure. Jugulovenous distention(JVD), hepatojugular reflux, and peripheral edemasuggest right-sided failure. A systolic murmur mayindicate ischemic mitral regurgitation or ventricularseptal defect.

II. Laboratory evaluation of chest pain and acutecoronary syndromesA. Electrocardiogram (ECG)

1. The hallmark of Q-wave infarction is acuteST-segment elevation in association with severechest pain. Significant ST-segment elevation isdefined as 0.10 mV or more measured 0.02second after the J point in two contiguous leads,from the following combinations: (1) leads II, III,or aVF (inferior infarction), (2) leads V1 throughV6 (anterior or anterolateral infarction), or (3)leads I and aVL (lateral infarction). Abnormal Qwaves usually develop within 8 to 12 up to 24 to48 hours after the onset of symptoms. AbnormalQ waves are at least 30 msec wide and 0.20 mVdeep in at least two leads.

2. Complete left bundle branch block with acute,severe chest pain should be managed as acutemyocardial infarction pending cardiac markeranalysis. It is usually not possible to definitivelydiagnose acute myocardial infarction by theECG alone in the setting of left bundle branchblock.

B. Laboratory markers1. Creatine phosphokinase (CPK) enzyme is

found in the brain, muscle, and heart. Thecardiac-specific dimer, CK-MB, however, ispresent almost exclusively in myocardium.

Common Markers for Acute Myocardial Infarc-tion

Marker InitialEleva-tion Af-ter MI

MeanTime toPeakEleva-tions

Time toReturnto Base-line

Myoglobin 1-4 h 6-7 h 18-24 h

CTnl 3-12 h 10-24 h 3-10 d

CTnT 3-12 h 12-48 h 5-14 d

CKMB 4-12 h 10-24 h 48-72 h

CKMBiso 2-6 h 12 h 38 h

CTnI, CTnT = troponins of cardiac myofibrils; CPK-MB, MM= tissue isoforms of creatine kinase.

2. CK-MB subunits. Subunits of CK, CK-MB, -MM, and -BB, are markers associated with arelease into the blood from damaged cells.Elevated CK-MB enzyme levels are observedin the serum 2-6 hours after MI, but may not bedetected until up to 12 hours after the onset ofsymptoms.

3. Cardiac-specific troponin T (cTnT) is aqualitative assay and cardiac troponin I (cTnI)is a quantitative assay. The cTnT level remainselevated in serum up to 14 days and cTnI for 3-7 days after infarction.

4. Myoglobin is the first cardiac enzyme to bereleased. It appears earlier but is less specificfor MI than other markers. Myoglobin is mostuseful for ruling out myocardial infarction in thefirst few hours.

Differential diagnosis of severe or prolongedchest pain

Myocardial infarctionUnstable anginaAortic dissectionGastrointestinal disease (esophagitis, esophageal spasm,peptic ulcer disease, biliary colic, pancreatitis)PericarditisChest-wall pain (musculoskeletal or neurologic)Pulmonary disease (pulmonary embolism, pneumonia,pleurisy, pneumothorax)Psychogenic hyperventilation syndrome

III. Initial treatment of acute coronary syndromesA. Continuous cardiac monitoring and IV access

should be initiated. Morphine, oxygen, nitroglyc-erin, and aspirin ("MONA") should be adminis-tered to patients with ischemic-type chest painunless contraindicated.

B. Morphine is indicated for continuing pain unre-sponsive to nitrates. Morphine reduces ventricularpreload and oxygen requirements by venodilation.Administer morphine sulfate 2-4 mg IV every 5-10minutes prn for pain or anxiety.

C. Oxygen should be administered to all patients withischemic-type chest discomfort and suspectedACS for at least 2 to 3 hours.

D. Nitroglycerin1. Nitroglycerin is an analgesic for ischemic-type

chest discomfort. Nitroglycerin is indicated forthe initial management of pain and ischemiaunless contraindicated by hypotension (SBP<90 mm Hg) or RV infarction. Continued use ofnitroglycerin beyond 48 hours is only indicatedfor recurrent angina or pulmonary congestion.

2. Initially, give up to three doses of 0.4 mgsublingual NTG every five minutes or nitroglyc-erine aerosol, 1 spray sublingually every 5minutes. An infusion of intravenous NTG maybe started at 10-20 mcg/min, titrating upwardby 5-10 mcg/min every 5-10 minutes (maxi-mum, 3 mcg/kg/min). Titrate to decrease themean arterial pressure by 10% in normotensivepatients and by 30% in those with hyperten-sion. Slow or stop the infusion if the SBP dropsbelow 100 mm Hg.

E. Aspirin1. Aspirin should be given as soon as possible to

all patients with suspected ACS unless thepatient is allergic to it. Aspirin therapy reducesmortality after MI by 25%.

2. A dose of 325 mg of aspirin should be chewedand swallowed on day 1 and continued POdaily thereafter at a dose of 80 to 325 mg.Clopidogrel (Plavix) may be used in patientswho are allergic to aspirin as an initial dose of75 to 300 mg, followed by a daily dose of 75mg.

Therapy for acute coronary syndromes

Treatment Recommendations

Antiplateletagent Aspirin, 325 mg (chewable)

Nitrates

Sublingual nitroglycerin (Nitrostat), onetablet every 5 min for total of three

tablets ini-tially, fol-lowed by IVform (Ni-tro-Bid IV,Tridil) ifneeded

Beta-blocker

IV therapy optional for prompt response,followed by oral therapy:Metoprolol (Lopressor), 5 mg IV every 5min for three dosesPropranolol (Inderal), 1 mg IV; may re-peat every 5 min for total of 5 mgEsmolol (Brevibloc), initial IV dose of 50micrograms/kg/min and adjust up to200-300 micrograms/kg/min

Heparin 60 U/kg IVP, followed by 12 U/kg/hr.Goal: aPTT, 1.5-2.5 X control

Enoxaparin(Lovenox)

1 mg/kg IV, followed by 1 mg/kg subcu-taneously bid

GlycoproteinIIb/IIIa inhibi-tors

Abciximab (ReoPro), eptifibatide(Integrilin), or tirofiban (Aggrastat) forpatients with high-risk features in whoman early invasive approach is planned

Adenosinediphosphatereceptor-in-hibitor

Consider clopidogrel (Plavix) therapy

Cardiaccatheteriza-tion

Consideration of early invasive ap-proach in patients at

intermediate to high risk and those inwhom conservative managementfails

IV. Risk stratification, initial therapy, and evaluationfor reperfusion in the emergency department

Risk Stratification with the First 12-Lead ECG

Use the 12-lead ECG to triage patients into 1 of 3groups:

1. ST-segment elevation

2. ST-segment depression(>1 mm)

3. Nondiagnostic or normal ECG

A. Patients with ischemic-type chest pain and ST-segment elevation >1 mm in 2 contiguous leadshave acute myocardial infarction. Reperfusiontherapy with thrombolytics or angioplasty is recom-mended.

B. Patients with ischemic-type pain but normal ornondiagnostic ECGs or ECGs consistent withischemia (ST-segment depression only) usually donot have AMI. These patients should not be givenfibrinolytic therapy.

C. Patients with normal or nondiagnostic ECGs usu-ally do not have AMI, and they should be evaluatedwith serial cardiac enzymes and additional tests todetermine the cause of their symptoms.

V. Management of ST-segment elevation myocardialinfarctionA. Patients with ST-segment elevation have AMI

should receive reperfusion therapy with fibrinolyticsor percutaneous coronary intervention.

B. Reperfusion therapy: Fibrinolytics1.Patients who present with ischemic pain and ST-

segment elevation (>1 mm in >2 contiguousleads) within 12 hours of onset of persistent painshould receive fibrinolytic therapy unless contra-indicated. Patients with a new bundle branchblock (obscuring ST-segment analysis) andhistory suggesting acute MI should also receivefibrinolytics or angioplasty.

Treatment Recommendations for AMI

Supportive Care for Chest Pain• All patients should receive supplemental oxygen, 2 L/min

by nasal canula, for a minimum of three hours• Two large-bore IVs should be placed

Aspirin:

Inclusion Clinical symptoms or suspicion of AMI

Exclusion Aspirin allergy, active GI bleeding

Recommen-dation

Chew and swallow one dose of160-325mg, then orally qd

Thrombolytics:

Inclusion All patients with ischemic pain and ST-seg-ment elevation (>1 mm in >2 contiguousleads) within 12 hours of onset of persis-tent pain, age <75 years.All patients with a new bundle branch blockand history suggesting acute MI.

Exclusion Active internal bleeding; history ofcerebrovascular accident; recentintracranial or intraspinal surgery ortrauma; intracranial neoplasm,arteriovenous malformation, or aneurysm;known bleeding diathesis; severe uncon-trolled hypertension

Recommen-dation

Reteplase (Retavase) 10 U IVP over 2min x 2. Give second dose of 10 U 30 minafter first dose ORTenecteplase (TNKase): <60 kg: 30 mgIVP; 60-69 kg: 35 mg IVP; 70-79 kg: 40 mgIVP; 80-89 kg: 45 mg IVP; >90 kg: 50 mgIVP ORt-PA (Alteplase, Activase) 15 mg IV over2 minutes, then 0.75 mg/kg (max 50 mg)IV over 30 min, followed by 0.5 mg/kg(max 35 mg) IV over 30 min.

Heparin:

Inclusion Administer concurrently withthrombolysis

Exclusion Active internal or CNS bleeding

Recommen-dation

Heparin 60 U/kg IVP, followed by 12U/kg/hr continuous IV infusion x 48 hours.Maintain aPTT 50-70 seconds

Beta-Blockade:

Inclusion All patients with the diagnosis of AMI.Within 12 hours of diagnosis of AMI

Exclusion Severe COPD, hypotension, bradycardia,AV block, pulmonary edema, cardiogenicshock

Recommen-dation

Metoprolol (Lopressor), 5 mg IV push ev-ery 5 minutes for three doses; followed by25 mg PO bid. Titrate up to 100 mg PO bidORAtenolol (Tenormin), 5 mg IV, repeated in5 minutes, followed by 50-100 mg PO qd.

Nitrates:

Inclusion All patients with ischemic-type chest pain

Exclusion Nitrate allergy; sildenafil (Viagra) withinprior 24 hours; hypotension; caution inright ventricular infarction

Recommen-dation

0.4 mg NTG initially q 5 minutes, up to 3doses or nitroglycerine aerosol, 1 spraysublingually every 5 minutes. IV infusion ofNTG at 10-20 mcg/min, titrating upward by5-10 mcg/min q 5-10 minutes (max 3mcg/kg/min). Slow or stop infusion if sys-tolic BP <90 mm Hg

ACE Inhibitors:

Inclusion All patients with the diagnosis of AMI. Initi-ate treatment within 24 hours after AMI

Exclusion Bilateral renal artery stenosis, angioedemacaused by previous treatment

Recommen-dation

Lisinopril (Prinivil) 2.5-5 mg qd, titrate to10-20 mg qd. Maintain systolic BP >100mm hg

C. Thrombolytics1. ECG criteria for thrombolysis

a. ST Elevation (>1 mm in two or more contig-uous leads), time to therapy 12 hours orless, age younger than 75 years.

b. A new bundle branch block (obscuring ST-segment analysis) and history suggestingacute MI.

2. Alteplase (t-PA, tissue plasminogen activa-tor, Activase) and Reteplase (Retavase)convert plasminogen to plasmin. Both agentsare clot-specific and bind to new thrombus.Activase is superior to streptokinase. The

alteplase thirty-day mortality rate of 6.3% is thelowest of the fibrinolytics, compared with 7.3%for streptokinase. Alteplase provides theearliest and most complete reperfusion.

3. Streptokinase (SK, Streptase) providesgreater benefit in older patients with a smalleramount of myocardium at risk who presentlater and those with a greater risk of ICH. Thedose of IV SK is 1.5 million units given over 60minutes.

D. Reperfusion therapy: Percutaneous coronaryintervention1. PCI is preferable to thrombolytic therapy if

performed in a timely fashion by individualsskilled in the procedure. Coronary angioplastyprovides higher rates of flow thanthrombolytics and is associated with lowerrates of reocclusion and postinfarctionischemia than fibrinolytic therapy.

2. Patients at high risk for mortality or severe LVdysfunction with signs of shock, pulmonarycongestion, heart rate >100 bpm, and SBP<100 mm Hg should be sent to facilities capa-ble of performing cardiac catheterization andrapid revascularization. When available within90 minutes, PCI is recommended for all pa-tients, particularly those who have a high riskof bleeding with fibrinolytic therapy.

E. Heparin is recommended in patients receivings e l e c t i v e f i b r i n o l y t i c a g e n t s(tPA/Reteplase/tenectaplase). A bolus dose of 60U/kg should be followed by infusion at a rate of 12U/kg/hour (a maximum bolus of 4000 U/kg andinfusion of 1000 U/h for patients weighing <70kg). An aPTT of 50 to 70 seconds is optimal.

F. Beta-blockade use during and after AMI reducesmortality by 36%. Contraindications to beta-blockers include severe LV failure and pulmonaryedema, bradycardia (heart rate <60 bpm),hypotension (SBP <100 mm Hg), signs of poorperipheral perfusion, second- or third-degreeheart block.1. Metoprolol (Lopressor), 5 mg IV push every

5 minutes for three doses; followed by 25 mgPO bid. Titrate up to 100 mg PO bid OR

2. Atenolol (Tenormin), 5 mg IV, repeated in 5minutes, followed by 50-100 mg PO qd.

G. ACE-inhibitors increase survival in patients withAMI. ACE-inhibitors should be started between 6to 24 hours after AMI and continued for 4-6weeks, and indefinitely if ejection fraction <40%.1. Captopril (Capoten) is given as a 6.25 mg

initial dose and titrated up to 50 mg po bid, or2. Lisinopril (Prinivil) may be given as 2.5-5 mg

qd, titrate to 10-20 mg qd. VI. Management Non–Q-wave MI and high-risk

unstable angina with ST-segment depression(Non-ST-Segment Elevation Syndromes)

A. Anti-ischemic therapy 1. Once unstable angina or non-ST-segment

elevation MI has been identified, standardanti-ischemic treatments should be initiated.

2. Oxygen is indicated for patients withhypoxemia, cyanosis, or respiratory distress.Oxygen should be administered for at leastthe initial acute phase in all patients andlonger in patients with congestive heartfailure or a documented oxygen saturation ofless than 92%.

3. Nitrates. Patients with ongoing chest painshould be given a 0.4-mg tablet of nitroglyc-erin (NitroQuick, Nitrostat) sublingually every5 minutes for a total of three tablets in 15minutes. If angina persists, continuous intra-venous infusion of nitroglycerin starting at 10micrograms/min should be instituted. Adjust-ments to 100 to 150 micrograms/min may bemade as needed for pain if blood pressurepermits. Tolerance to continuous nitroglyc-erin administration can develop after 24hours.

4. Morphine. Intravenous morphine sulfatemay be administered when ischemic chestpain is not relieved with nitroglycerin or whenacute pulmonary congestion or severe agita-tion is noted.

5. Beta-Blockersa. Beta-blockade remains an important

mainstay of therapy for unstable anginaand non-ST-segment elevation MI. Ithelps reduce cardiac workload and myo-cardial oxygen demand as well as im-prove blood flow in coronary arteries.Unless contraindicated, beta-blockersshould always be given to patients pre-senting with an unstable coronary syn-drome.

b. Intravenous therapy should be adminis-tered even when patients are alreadytaking oral beta-blockers. Options includemetoprolol (Lopressor), 5 mg given intra-venously every 5 minutes for a total of 15mg, and propranolol (Inderal), 1 mg givenintravenously every 5 minutes for up to 5mg. Esmolol (Brevibloc) infusion startingat 50 micrograms/kg per minute for amaximum dose of 200 to 300 micro-grams/kg per minute can also be used.The target heart rate with beta-blockadeis less than 60 beats per minute.

6. Angiotensin-converting enzyme (ACE)inhibitors should be given early on in patientswith left ventricular dysfunction or evidenceof congestive heart failure.

7. Intra-aortic balloon pump may be consid-ered in patients with severe ischemia refrac-tory to intensive medical therapy or inhemodynamically unstable patients before orafter coronary angiography.

B. Anticoagulant therapy1. Low-molecular-weight heparins

a. The low-molecular-weight heparins havea longer half-life than unfractionated hep-arin and thus allow subcutaneous injec-tions to be given once or twice daily. Inaddition, these agents do not requireserial monitoring or frequent dose adjust-ments. Heparin-induced thrombo-cytopenia is less common withlow-molecular-weight heparins than withunfractionated heparin.

b. Enoxaparin (Lovenox) use in patientswith non-ST-segment elevation acutecoronary syndromes significantly reducesthe risk of point of death, MI, recurrentangina, and need for urgentrevascular izat ion compared tounfractionated heparin. Enoxaparin(Lovenox) should be considered as areplacement for unfractionated heparin innon-ST-segment elevation acute coronarysyndromes. Enoxaparin (Lovenox) 1.0mg/kg SQ q12h.

Heparin and ST-Segment Depression andNon–Q-Wave MI/Unstable Angina

! IV heparin therapy for 3 to 5 days is standard for high-riskand some intermediate-risk patients. Treat for 48 hours,then individualized therapy.

! LMWH is an acceptable alternative to IV unfractionatedheparin.

-Enoxaparin (Lovenox) 1.0 mg/kg SQ q12h OR-Dalteparin (Fragmin) 120 IU/kg (max 10,000 U) SQq12h.

2. Statin therapy. Use of 3-hydr-oxy-3-methylglutaryl coenzyme A reductaseinhibitors (“statins”) as part of an early, aggres-sive lipid-lowering approach results in improvedendothelial function, vasodilation, decreasedplatelet aggregation, and plaque stabilization.

C. Antiplatelet therapy1. Antiplatelet drug therapy is a crucial component

of management of acute coronary syndromes.The risk of death or nonfatal MI can be reducedwith early antiplatelet therapy in patients withunstable angina or non-ST-segment elevationMI.

2. Aspirina. Aspirin exerts its antiplatelet effect by irre-

versibly inhibiting the platelet enzymecyclooxygenase-1; this inhibition preventsformation of thromboxane A2, a potentvasoconstrictor and activator of platelet ag-gregation. Aspirin decreases rates of mortalityand cardiac events. In addition, aspirin incombination with heparin further reduces therisk of these adverse outcomes.

b. Aspirin should be administered as soon aspossible after presentation of an acute coro-nary syndrome and continued indefinitely.Patients not previously given aspirin shouldchew the initial dose to rapidly achieve highblood levels. Aspirin therapy should be con-tinued at a daily dose of 325 mg.

3. Clopidogrel (Plavix) is a thienopyridine deriva-tive that exerts an antiplatelet effect by blockingadenosine diphosphate-dependent plateletactivation. Clopidogrel should be added toaspirin therapy as part of the antiplatelet regi-men in acute coronary syndromes at a dailydose of 75 mg for nine to 12 months.

4. Glycoprotein IIb-IIIa receptor antagonists

a. The GpIIb-IIIa receptor on the platelet surfaceserves as the final common pathway forplatelet-platelet interaction and thrombusformation. Three GpIIb-IIIa inhibitor drugs arecommercially available: abciximab (ReoPro),eptifibatide (Integrilin), and tirofiban(Aggrastat). The various GpIIb-IIIa receptorantagonists have been approved for treat-ment of medically refractory unstable angina.However, abciximab is not currently approvedwithout planned percutaneous coronaryintervention or cardiac catheterization.

b. Bleeding remains the most frequent compli-cation of GpIIb-IIIa inhibitors. Severethrombocytopenia (platelets, <50 X103/microliters) occurs in 0.1% to 0.7% ofcases. Cont ra ind ica t ions inc ludecerebrovascular accident or neurosurgicalintervention within less than 6 months, sur-gery or gastrointestinal hemorrhage withinless than 6 weeks, intracranial malignancy,and platelet count less than 100 X103/microliters. Eptifibatide and tirofibanrequire dose adjustments with a serumcreatinine level of more than 2 mg/dL.

c. Because of the significant risk of bleedingwith use of GpIIb-IIIa antagonists (which aregiven in conjunction with other antiplateletand anticoagulation treatment), routine sur-veillance for mucocutaneous bleeding, bleed-ing at the vascular access site, and spontane-ous bleeding is important. Hemoglobin leveland platelet counts should be measured daily.

d. GpIIb-IIIa antagonist therapy should bestrongly considered for patients who havehigh-risk features, such as elevated levels ofcardiac markers, dynamic ST-segmentchanges, and refractory chest pain and inwhom early angiography and percutaneouscoronary intervention are planned.

e. Intravenous GP blocker dosages(1) Abciximab (ReoPro), 0.25 mg/kg IVP

over 2 min, then 0.125 mcg/kg/min (max10 mcg/min) for 12 hours.

(2) Eptifibatide (Integrilin), 180 mcg/kg IVPover 2 min, then 2 mcg/kg/min for 24-72hours. Use 0.5 mcg/kg/min if creatinine is>2.0 mg/dL.

(3) Tirofiban (Aggrastat), 0.4 mcg/kg/minfor 30 min, then 0.1 mcg/kg/min IV infu-sion for 24-72 hours. Reduce dosage by50% if the creatine clearance is <30mL/min.

VII.Conservative versus early invasive approachA. Early invasive approach. An early invasive ap-

proach was most beneficial in patients with interme-diate- or high-risk factors. Such factors include anelevated troponin level, ST-segment changes, agegreater than 65 years, diabetes, and an elevatedTIMI risk score. In low-risk patients, a routine earlyinvasive approach provided no benefit and tendedto increase the adverse event rate.

TIMI risk score* for unstable angina andnon-ST-segment elevation myocardial infarc-tion

1. Age >65 yr2. Three risk factors for coronary artery disease3. Previous coronary stenosis of 50%4. ST-segment deviation on electrocardiography5. Use of aspirin in previous 7 days6. Elevated serum cardiac markers7. At least two anginal events in previous 24 hr*One point per risk factor. Low risk, 0 to 2 points;intermediate risk, 3 to 4 points; high risk, 5 to 7points.

B. An early invasive approach is most beneficial for

patients presenting with elevated levels of cardiacmarkers, significant ST-segment changes, recurrentangina at a low level of activity despite medicaltherapy, recurrent angina and symptoms of heartfailure, marked abnormalities on noninvasive stresstesting, sustained ventricular tachycardia, recentpercutaneous coronary intervention, or prior CABG.

C. Patients who are not appropriate candidates forrevascularization because of significant or exten-sive comorbidities should undergo conservativemanagement.

VIII. Management of patients with a nondiagnosticECG

A. Patients with a nondiagnostic ECG who have anindeterminate or a low risk of MI should receiveaspirin while undergoing serial cardiac enzymestudies and repeat ECGs.

References, see page 282.

Chronic Stable AnginaAngina pectoris is a symptom complex caused bymyocardial ischemia. Stable angina refers to chestdiscomfort that occurs predictably and reproducibly at acertain level of exertion and is relieved with rest ornitroglycerin. Unstable angina includes new onset ofchest pain, progressing effort angina, rest angina,post-myocardial infarction angina, and angina afterrevascularization.

I. Clinical evaluationA. Important points include the following:

1. History of previous heart disease2. Possible non-atheromatous causes of angina

(eg, aortic stenosis)3. Symptoms of systemic atherosclerosis (eg,

claudication)4. Severity and pattern of symptoms of angina 5. Risk factors for coronary heart disease, include

smoking, inappropriate activity level, stress,hyperlipidemia, obesity, hypertension, and di-abetes mellitus.

B. Physical examination should include a cardiovas-cular examination, evaluation for hyperlipidemia,hypertension, peripheral vascular disease, conges-tive heart failure, anemia, and thyroid disease.

C. Laboratory studies should include an electro-cardiogram and a fasting lipid profile. Furtherstudies may include chest films, hemoglobin, andtests for diabetes, thyroid function, and renal func-tion.

D. Exercise electrocardiography. An exercise testshould be obtained for prognostic information.1. Sensitivity of exercise electrocardiography may

be reduced for patients unable to reach the levelof exercise required for near maximal effort, suchas:a. Patients taking beta blockersb. Patients in whom fatigue, dyspnea, or

claudication symptoms developc. Patients who cannot perform leg exercises

2. Reduced specificity may be seen in patients withabnormalities on baseline electrocardiograms,such as those taking digoxin or with left ventricu-lar hypertrophy or left bundle branch block.

E. Noninvasive imaging, such as myocardial perfu-sion scintigraphy or stress echocardiography, maybe indicated in patients unable to complete exerciseelectrocardiography.

II. Management of stable angina pectorisA. Nonpharmacologic measures

1. Underlying medical conditions that mightaggravate myocardial ischemia, such as hyper-tension, fever, tachycardia thyrotoxicosis, ane-mia, or hypoxemia should be treated.

2. Regular aerobic exercise should be encour-aged.

3. Risk factor reduction includes treatment ofhypertension, cessation of smoking, and correc-tion of hyperlipidemia. Weight reduction andstress reduction should be encouraged.

III.Treatment recommendationsA. Aspirin. All patients should be treated with aspirin.

The dose is 81 mg (one baby aspirin) per day.B. Lipid-lowering. In patients with hypercholesterol-

emia with coronary disease, the goal serum LDLcholesterol for secondary prevention is less than100 mg/dL. Lipid-lowering therapy begins withdietary modification and a statin, such asatorvastatin (Lipitor)10-40 mg PO qhs.

C. Low- and intermediate-risk patients should betreated with medical therapy in an effort to controlsymptoms.

D. Sublingual nitroglycerin should be used asnecessary for anginal episodes and prophylacti-cally before activities known to precipitate angina.A dose of 0.3 mg should be initiated. A seconddose can be taken if symptoms persist after threeto five minutes.

E. Long-acting antianginal therapy. A beta-blockershould be initiated in patients with more frequentangina unless contraindicated because of overtheart failure, advanced AV block, markedbradycardia, or obstructive lung disease.

F. Atenolol or metoprolol (cardioselective agent) isrecommended. The starting dose of atenolol(Tenormin) is 25 mg once daily, which can beincreased as tolerated to a maximum of 200 mgonce a day until the resting heart rate is 50 to 60beats/min and does not exceed 100 beats/min.The starting dose of metoprolol (Lopressor) is 25

mg BID, which can be increased to 200 mg BID astolerated.

G. Diltiazem (Cardizem) is an alternative if thepatient has a contraindication or intolerance tobeta-blockers. A dose of 30 mg QID should beinitiated and increased to 90 mg QID as needed.The patient can be switched to a diltiazem CD(Cardizem CD);120-360 mg qd.

H. Angina that persists with monotherapy. Additionof a second drug is indicated if angina persists withmonotherapy. If the patient is already taking abeta-blocker, a long-acting nitrate can be started.Options for nitrate therapy may include isosorbidedinitrate (starting at 10 mg TID and increasing to40 mg TID as necessary, given at 8 a.m., 1 p.m.,and 6 p.m.), transdermal nitropatch (starting at 5mg/24 hr and increasing to 15 mg/24 hr at 8 a.m.with removal of the patch at 8 p.m.), orisosorbide-5-mononitrate (20 mg twice daily at 8a.m. and 4 p.m.).

I. Nitrates act as venodilators, coronary vasodilators,and modest arteriolar dilators.1. Sublingual nitroglycerin is the therapy of

choice for acute anginal episodes and prophy-lactically for activities that elicit angina. Allpatients with stable angina should be givensublingual nitroglycerin (tablets or spray).a. Nitroglycerin SL (Nitrostat), 0.3-0.6 mg SL

q5min prn pain [0.15, 0.3, 0.4, 0.6 mg].b. Nitroglycerin oral spray (Nitrolingual) 1-2

sprays prn pain.c. The major side effects associated with nitrate

use are headache, lightheadedness, andflushing. However, a 12- to 14-hour ni-trate-free interval must be observed in orderto avoid tolerance.

Nitrate Preparations

Preparation Route of Ad-ministration

Dosage

Nitroglycerine(Nitrostat)

Sublingual tab 0.15-0.9 mg

Nitroglycerine(Nitrolingual)

Sublingual spray 0.4 mg

Nitroglycerine(Transderm-Ni-tro)

Transdermal 0.2-0.8 mg/h

Isosorbidedinitrate (IsordilSR)

Oral 10-40 mg tid

Isosorbidemononitrate(ISMN)

Oral 20-40 mg bid

ISMN, extendedrelease (Imdur)

Oral 30-120 mg oncedaily

d. Isosorbide dinitrate (ISDN, Isordil SR,Dilatrate-SR, Isordil Tembids) is the mostcommonly used oral nitrate preparation.Tolerance limits usefulness. A dosingschedule of 8 a.m., 1 p.m., and 6 p.m. isrecommended, which results in a 14-hournitrate dose-free interval. The initial doseshould be 10 mg three times daily, advanc-ing to 30 mg three times daily as needed.Alternatively, isosorbide dinitrate can betaken twice daily at 8 a.m. and 4 p.m.

e. Isosorbide mononitrate (ISMN). Theusual starting dose is 20 mg twice daily;however 40 mg twice daily may be neces-sary in some patients. Tolerance is a prob-lem. The extended-release preparation ofisosorbide mononitrate (Imdur) is recom-mended.

f. Transdermal nitroglycerin. The usualdose is 0.2 to 0.8 mg/hr. The patient mustremember to remove the patch for 12 to 14hours to prevent tolerance. The patchshould be applied at 8 a.m. and removed at8 p.m [0.2, 0.4, 0.6, 0.8 mg/h patches].

2. Beta-blockers are well tolerated and ex-tremely effective in reducing anginal episodesand improving exercise tolerance. Beta-blockers are the only antianginal drugs provento prevent reinfarction and to improve survivalin patients who have sustained a myocardialinfarction.

Adverse Effects of Beta-blockers

Bradycardia, decreased contractility, AV node conductiondelay

Bronchoconstriction can be induced by nonselective agentsand high doses of cardioselective agents.

Worsening of symptoms of peripheral vascular disease orRaynaud's phenomenon.

Fatigue may be due to the reduction in cardiac output or todirect effects on the central nervous system.

Central side effects include depression, nightmares, insom-nia, and hallucinations.

Impotence is often a problem.

Beta-blockers

Class Drugname

Startingdose

Maximaldose

Cardiosel-ective

Atenolol(Tenormin)

25 mg QD 100 mg QD

Cardiosel-ective

Metoprolol(Lopressor)

25 mg BID 100 mg BID

Nonselec-tive

NadoIol(Corgard)

25 mg QD 240 mg QD

Nonselec-tive

Propranolol(Inderal)

40 mg BID 120 mg BID

Intrinsicsympatho-mimetic

PindoIoI(Visken)

5 mg BID 30 mg BID

Alphablocker

Labetalol(Normodyne)

100 mgBID

600 mg BID

a. Nonselective agents. Propranolol (Inderal)is the most widely used beta-blocker.

b. Cardioselective beta-blockers offer theadvantage of not interfering withb r o n c h o d i l a ta t i o n o r pe r i p h e r a lvasodilatation.(1) Atenolol (Tenormin). The starting dose

is 25 mg once daily, which can be in-creased as tolerated to a maximum of100 mg once a day.

(2) Metoprolol (Lopressor). The startingdose of metoprolol (Lopressor) is 25 mgBID, which can be increased to 100 mgBID as tolerated.

J. Calcium channel blockers reduce anginal symp-toms and increase exercise tolerance.1. Verapamil is a negative inotrope that also slows

sinus rate and decreases AV conduction. Sideeffects include symptomatic bradycardia, heartblock, worsening congestive heart failure, andconstipation. The dihydropyridines (nifedipine,nicardipine, felodipine, amlodipine) are potentvasodilators with less effect on contractility andAV conduction.

2. Diltiazem (Cardiazem) has intermediate effects,being a modest negative inotropic agent andvasodilator with a low incidence of side effects.Diltiazem is a good alternative if beta-blockersare contraindicated.

K. Indications for coronary arteriography followedby revascularization:1. Angina which significantly interferes with a

patient's lifestyle despite maximal tolerablemedical therapy.

2. In patients with single vessel disease, espe-cially those with good left ventricular function,PTCA should be considered if symptoms arerefractory to medical therapy or if there is alarge amount of ischemic myocardium.


Heart Failure Caused by SystolicDysfunctionApproximately 5 million Americans have heart failure,and an additional 400,000 develop heart failure annually.Coronary artery disease producing ischemiccardiomyopathy is the most frequent cause of left ventric-ular systolic dysfunction.

I. Diagnosis A. Left ventricular systolic dysfunction is defined as

an ejection fraction of less than 40 percent. Theejection fraction should be measured to determinewhether the symptoms are due to systolic dysfunc-tion or another cause.

B. Presenting Signs and Symptoms

1. Heart failure often presents initially as dyspneawith exertion or recumbency. Patients alsocommonly have dependent edema, rapid fa-tigue, cough and early satiety. Arrhythmiascausing palpitations, dizziness or aborted sud-den death may also be initial manifestations.

Classification of Patients with Heart FailureCaused by Left Ventricular Dysfunction

New classifica-tion based onsymptoms

Corresponding NYHA class

Asymptomatic NYHA class I

Symptomatic NYHA class II/III

Symptomatic withrecent history ofdyspnea at rest

NYHA class IIIb

Symptomatic withdyspnea at rest

NYHA class IV

Precipitants of Congestive Heart Failure

• Myocardial ischemia orinfarction

• Atrial fibrillation • Worsening valvular dis-

ease• Pulmonary embolism• Hypoxia• Severe, uncontrolled

hypertension• Thyroid disease

• Pregnancy• Anemia• Infection• Tachycardia or

bradycardia• Alcohol abuse• Medication or dietary

noncompliance

C. Diagnostic Studies1. Electrocardiography. Standard 12-lead elec-

trocardiography should be used to determinewhether ischemic heart disease or rhythmabnormalities are present.

2. Transthoracic echocardiography confirmssystolic dysfunction by measurement of the leftventricular ejection fraction and provides infor-mation about ventricular function, chamber sizeand shape, wall thickness and valvular function.

3. Exercise stress testing is useful for evaluatingactive and significant concomitant coronaryartery disease.

4. Other Studies. Serum levels of atrial natriureticpeptide (ANP), brain natriuretic peptide (BNP)are elevated in patients with heart failure. ANPand BNP levels may predict prognosis and areused to monitor patients with heart failure.

Laboratory Workup for Suspected Heart Failure

Blood urea nitrogenCardiac enzymes (CK-MB,troponin) Complete blood cell count Creatinine ElectrolytesLiver function testsMagnesium

Thyroid-stimulating hor-mone Urinalysis Echocardiogram ElectrocardiographyImpedance cardiographyAtrial natriuretic peptide(ANP)Brain natriuretic peptide(BNP)

II. Treatment of heart failureA. Lifestyle modification

1. Cessation of smoking and avoidance of morethan moderate alcohol ingestion.

2. Salt restriction to 2 to 3 g of sodium per day tominimize fluid accumulation.

3. Water restriction in patients who are alsohyponatremic.

4. Weight reduction in obese subjects.5. Cardiac rehabilitation program for all stable

patients.B. Improvement in symptoms can be achieved by

digoxin, diuretics, beta-blockers, ACE inhibitors,and ARBs. Prolongation of survival has beendocumented with ACE inhibitors, beta-blockers,and, in advanced disease, spironolactone. Initialmanagement with triple therapy (digoxin, ACEinhibitor, and diuretics) is recommended in agree-ment with the ACC/AHA task force guidelines.

C. ACE inhibitors and other vasodilators. Allpatients with asymptomatic or symptomatic leftventricular dysfunction should be started on anACE inhibitor. Beginning therapy with low doses(eg, 2.5 mg of enalapril BID or 6.25 mg of captoprilTID) will reduce the likelihood of hypotension. Ifinitial therapy is tolerated, the dose is then gradu-ally increased to a maintenance dose of 10 mg BID

of enalapril, 50 mg TID of captopril, or up to 40mg/day of lisinopril or quinapril. Angiotensin IIreceptor blockers appear to be as effective as ACEinhibitors and are primarily given to patients whocannot tolerate ACE inhibitors, generally due tochronic cough or angioedema.

D. Beta-blockers. Beta-blockers, particularlycarvedilol, metoprolol, bisoprolol, improve survivalin patients with New York Heart Association(NYHA) class II to III HF and probably in class IVHF. Carvedilol, metoprolol, or bisoprolol is recom-mended for symptomatic HF, unless contraindi-cated.1. Relative contraindications to beta-blockers:

a. Heart rate <60 bpm.b. Systolic arterial pressure <100 mm Hg.c. Signs of peripheral hypoperfusion.d. PR interval >0.24 sec.e. Second- or third-degree atrioventricular block.f. Severe chronic obstructive pulmonary dis-

ease.g. History of asthma.h. Severe peripheral vascular disease.

2. In the absence of a contraindication, carvedilol,metoprolol, or bisoprolol should be offered topatients with NYHA class II, III and IV HF due tosystolic dysfunction.

3. Initiation of therapy. Therapy should be begunin very low doses and the dose doubled (everytwo to three weeks) until the target dose isreached or symptoms become limiting.a. Carvedilol (Coreg), initial dose 3.125 mg

BID; target dose 25 to 50 mg BID.b. Metoprolol (Lopressor), initial dose 6.25

mg BID; target dose 50 to 75 mg BID, and forextended-release metoprolol (Toprol XL),initial dose 12.5 or 25 mg daily, and targetdose 200 mg/day.

c. Bisoprolol (Zebeta), initial dose 1.25 mg QD;target dose 5 to 10 mg QD.

E. Digoxin (Lanoxin) is given to patients with HF andsystolic dysfunction to control fatigue, dyspnea,and exercise intolerance and, in patients with atrialfibrillation, to control the ventricular rate. Digoxintherapy is associated with a significant reduction inhospitalization but has no effect on survival.1. Digoxin should be started in patients with left

ventricular systolic dysfunction and NYHAfunctional class II, III and IV heart failure. Theusual daily dose is 0.125 to 0.25 mg, basedupon renal function. The serum digoxin is main-tained between 0.7 to 1.2 ng/mL.

2. Digoxin is not indicated as primary therapy forthe stabilization of patients with acutelydecompensated HF. Such patients should firstreceive appropriate treatment for HF, usuallywith intravenous medications.

F. Diuretics1. A loop diuretic should be given to control pulmo-

nary and/or peripheral edema. The usual start-ing dose in outpatients with HF is 20 to 40 mg offurosemide (Lasix). Subsequent dosing is deter-mined with goal weight reduction of 0.5 to 1.0kg/day. If a patient does not respond, the doseshould be increased. In patients with a relativelynormal glomerular filtration rate, the maximumsingle doses are 40 to 80 mg of furosemide.

G. Spironolactone. A low dose of spironolactone (25to 50 mg/day) is recommended in patients withsymptoms at rest (despite therapy with the abovemedications), a serum creatinine concentrationless than 2.5 mg/dL (221 :mol/L), and a serumpotassium less than 5 meq/L.

Treatment Classification of Patients with HeartFailure Caused by Left Ventricular SystolicDysfunction

Symptoms Pharmacology

Asymptomatic ACE inhibitorBeta blocker

Symptomatic ACE inhibitorBeta blockerDiuretic If symptoms persist:digoxin (Lanoxin)

Symptomatic with recenthistory of dyspnea at rest

DiureticACE inhibitor Spironolactone (Aldactone) Beta blocker Digoxin

Symptoms Pharmacology

Symptomatic with dyspneaat rest

DiureticACE inhibitor Spironolactone (Aldactone) Digoxin

Dosages of Primary Drugs Used in the Treat-ment of Heart Failure

Drug Starting Dosage Target Dosage

Drugs that decrease mortality and improve symptoms

ACE inhibitorsCaptopril(Capoten)

6.25 mg threetimes daily(one-half tablet)

12.5 to 50 mgthree times daily

Enalapril(Vasotec)

2.5 mg twice daily 10 mg twice daily

Lisinopril (Zestril) 5 mg daily 10 to 20 mg dailyRamipril (Altace) 1.25 mg twice

daily5 mg twice daily

Trandolapril(Mavik)

1 mg daily 4 mg daily

Aldosterone antagonistSpironolactone(Aldactone)

25 mg daily 25 mg daily

Beta blockersBisoprolol(Zebeta)

1.25 mg daily(one-fourth tablet)

10 mg daily

Carvedilol(Coreg)

3.125 mg twicedaily

25 to 50 mg twicedaily

Metoprololtartrate(Lopressor)

12.5 mg twicedaily (one-fourthtablet)

50 to 75 mg twicedaily

Metoprololsuccinate(Toprol-XL)

12.5 mg daily(one-half tablet)

200 mg daily

Drugs that treat symptomsThiazide diureticsHydrochlorothia-zide (Esidrex)

25 mg daily 25 to 100 mgdaily

Metolazone(Zaroxolyn)

2.5 mg daily 2.5 to 10 mg daily

Loop diureticsBumetanide(Bumex)

1 mg daily 1 to 10 mg onceto three timesdaily

Ethacrynic acid(Edecrin)

25 mg daily 25 to 200 mgonce or twicedaily

Furosemide(Lasix)

40mg daily 40 to 400 mgonce to threetimes daily

Torsemide(Demadex)

20 mg daily 20 to 200 mgonce or twicedaily

InotropeDigoxin (Lanoxin) 0.125 mg daily 0.125 to 0.375

mg daily

Angiotensin Receptor Blockers for Heart Fail-ure

Candesartan (Atacand) – start 4-8 mg qd bid, target 8-16mg qd-bidEprosartan (Teveten) – start 400-800 mg qd, target 800mg/dIrbesartan (Avapro) – start 75-150 mg qd, target 150-300mg qdLosartan (Cozaar) – start 25-50 mg qd, target 50 mg bidValsartan (Diovan) – start 80 mg qd, target 160-320 mg qd

H. Management of refractory HF1. Inotropic agents other than digoxin. Patients

with decompensated HF are often treated withan intravenous infusion of a positive inotropicagent, such as dobutamine, dopamine,milrinone, or amrinone.

2. Symptomatic improvement has been demon-strated in patients after treatment with a contin-uous infusion of dobutamine (at a rate of 5 to7.5 :g/kg per min) for three to five days. Thebenefit can last for 30 days or more. Use ofintravenous dobutamine is limited to the inpa-tient management of patients with severedecompensated heart failure.

3. Natriuretic peptidesa. Atrial and brain natriuretic peptides regulate

cardiovascular homeostasis and fluid vol-ume.

b. Nesiritide (Natrecor) is structurally similarto atrial natriuretic peptide. It has natriuretic,diuretic, vasodilatory, smooth-muscle relax-

ant properties, and inhibits the renin-angio-tensin system. Nesiritide is indicated for thetreatment of moderate-to-severe heart fail-ure. The initial dose of is 0.015 mcg/kg/minIV infusion, max 0.03 mcg/kg/min.

4. Pacemakers. Indications for pacemakers inpatients with HF include symptomaticbradycardia, chronic AF, or AV nodal ablation.Patients with refractory HF and severe symp-toms may benefit from long-term dual-chamberpacing.

5. Hemofiltration. Extracorporeal ultrafiltrationvia hemofiltration removes intravascular fluid; itis an effective treatment for patients with refrac-tory HF.

6. Mechanical circulatory support. Circulatoryassist devices are used for refractory HF. Thereare three major types of devices:a. Counterpulsation devices (intraaortic balloon

pump and noninvasive counterpulsation).b. Cardiopulmonary assist devices.c. Left ventricular assist devices.

7. Indications for cardiac transplantationa. Repeated hospitalizations for HF.b. Escalation in the intensity of medical ther-

apy.c. A reproducible peak oxygen of less than 14

mL/kg per min.d. Other absolute indications for cardiac trans-

plantation, recommended:(1) Refractory cardiogenic shock.(2) Continued dependence on intravenous

inotropes.(3) Severe symptoms of ischemia that limit

routine activity and are not amenable torevascularization or recurrent unstableangina not amenable to other interven-tion.

(4) Recurrent symptomatic ventriculararrhythmias refractory to all therapies.

Treatment of Acute Heart Failure/PulmonaryEdema

• Oxygen therapy, 2 L/min by nasal canula• Furosemide (Lasix) 20-80 mg IV• Nitroglycerine start at 10-20 mcg/min and titrate to BP

(use with caution if inferior/right ventricular infarctionsuspected)

• Sublingual nitroglycerin 0.4 mg• Morphine sulfate 2-4 mg IV. Avoid if inferior wall MI

suspected or if hypotensive or presence of tenuousairway

• Potassium supplementation prn


Atrial FibrillationAtrial fibrillation (AF) is the most common cardiac rhythmdisturbance. Hemodynamic impairment andthromboembolic events result in significant morbidity andmortality.

I. PathophysiologyA. Atrial fibrillation (AF) is characterized by impaired

atrial mechanical function. The ECG is character-ized by the replacement of consistent P waves byrapid oscillations or fibrillatory waves that vary insize, shape, and timing, associated with an irregu-lar ventricular response.

B. The prevalence of AF is 0.4%, increasing with age.It occurs in more than 6% of those over 80 years ofage. The rate of ischemic stroke among patientswith nonrheumatic AF averages 5% per year.

II. Causes and Associated ConditionsA. Acute Causes of AF. AF can be related to exces-

sive alcohol intake, surgery, electrocution,myocarditis, pulmonary embolism, andhyperthyroidism.

B. AF Without Associated Cardiovascular Dis-ease. In younger patients, 20% to 25% of cases ofAF occur as lone AF.

C. AF With Associated Cardiovascular Disease.Cardiovascular conditions associated with AFinclude valvular heart disease (most often mitral),coronary artery disease (CAD), and hypertension.

III.Clinical ManifestationsA. AF can be symptomatic or asymptomatic. Patients

with AF may complain of palpitations, chest pain,dyspnea, fatigue, lightheadedness, or polyuria.Syncope is uncommon.

B. Evaluation of the Patient With Atrial Fibrillation1. The initial evaluation of a patient with suspected

or proven AF includes characterizing the patternof the arrhythmia as paroxysmal or persistent,

determining its cause, and defining associatedcardiac and factors.

2. The physical examination may reveal an irregu-lar pulse, irregular jugular venous pulsations,and variation in the loudness of the first heartsound. Examination may disclose valvular heartdisease, myocardial abnormalities, or heartfailure.

3. Investigations. The diagnosis of AF requiresECG documentation. If episodes areintermittant, then a 24-h Holter monitor can beused. Additional investigation may includetransesophageal echocardiography.

IV. Management of Atrial FibrillationA. In patients with persistent AF, the dysrhythmia may

be managed by restoration of sinus rhythm, or AFmay be allowed to continue while the ventricularrate is controlled.

B. Cardioversion1. Cardioversion is often performed electively to

restore sinus rhythm. The need for cardioversioncan be immediate when the arrhythmia causesacute HF, hypotension, or angina pectoris.Cardioversion carries a risk of thromboembolismunless anticoagulation prophylaxis is initiatedbefore the procedure; this risk is greatest whenthe arrhythmia has been present more than 48hours.

2. Methods of Cardioversion. Cardioversion canbe achieved by drugs or electrical shocks. Thedevelopment of new drugs has increased thepopularity of pharmacological cardioversion.Pharmacological cardioversion is most effec-tive when initiated within seven days after theonset of AF. Direct-current cardioversioninvolves a synchronized electrical shock. Car-dioversion is performed with the patient havingfasted and under anesthesia. An initial energy of200 J or greater is recommended.

C. Maintenance of Sinus Rhythm1. Maintenance of sinus rhythm is relevant in

patients with paroxysmal AF and persistent AF(in whom cardioversion is necessary to restoresinus rhythm).

2. Approach to Antiarrhythmic Drug Therapya. Prophylactic drug treatment is seldom indi-

cated after the first-detected episode of AFand can be avoided in patients with infre-quent and well-tolerated paroxysmal AF.

b. Beta-blockers can be effective in patientswho develop AF only during exercise.

c. In patients with lone AF, a beta-blockermay be tried first, but flecainide,propafenone, and sotalol are particularlyeffective. Amiodarone and dofetilide arerecommended as alternative therapy.Quinidine, procainamide, and disopyramideare not favored unless amiodarone fails or iscontraindicated.

d. The anticholinergic activity of long-actingdisopyramide makes it a relatively attractivechoice for patients with vagally induced AF.

Drugs Used to Maintain Sinus Rhythm in AtrialFibrillation

Drug DailyDosage

Potential Adverse Effects

Amiodarone

100–400mg

Photosensitivity, pulmonarytoxicity, polyneuropathy, GIupset, bradycardia, torsadede pointes (rare), hepatic tox-icity, thyroid dysfunction

Disopyramide

400–750mg

Torsade de pointes, HF,glaucoma, urinary retention,dry mouth

Dofetilide 500–1000mcg

Torsade de pointes

Flecainide 200–300mg

Ventricular tachycardia, con-gestive HF, conversion toatrial flutter

Procainamide

1000–4000 mg

Torsade de pointes, lupus-like syndrome, GI symptoms

Propafenone

450–900mg

Ventricular tachycardia, con-gestive HF, conversion toatrial flutter

Quinidine 600–1500mg

Torsade de pointes, GI up-set, conversion to atrial flutter

Sotalol 240–320mg

Torsade de pointes, conges-tive HF, bradycardia, exacer-bation of chronic obstructiveor bronchospastic lung dis-ease

3.Nonpharmacological Correction of AFa. A surgical procedure (maze operation)

controls AF in more than 90% of selectedpatients.

b. Catheter ablation eliminates or reducesthe frequency of recurrent AF in more than60% of patients, but the risk of recurrent AFis 30% to 50%. This procedure has notbeen widely applied.

D. Rate Control During Atrial Fibrillation1.Pharmacological Approach. An alternative

to maintenance of sinus rhythm in patientswith paroxysmal or persistent AF is control ofthe ventricular rate. The rate is controlledwhen the ventricular response is between 60and 80 bpm at rest and between 90 to 115bpm during moderate exercise.a. Anticoagulation is recommended for 3 to 4

weeks before and after cardioversion forpatients with AF of unknown duration orthat has lasted more than 48 h. Whenacute AF produces hemodynamic instabil-ity, immediate cardioversion should not bedelayed, but intravenous heparin or low-molecular-weight heparin should be admin-istered first.

Intravenous Agents for Heart Rate Control inAtrial Fibrillation

Drug Load-ingDose

On-set

Mainte-nanceDose

Major SideEffects

Diltiazem

0.25mg/kgIV over2 min

2–7min

5–15 mgper hourinfusion

Hypotension,heart block,HF

Esmolol

0.5mg/kgover

1min

0.05–0.2mg/kg/min

Hypotension,heart block,bradycardia,asthma, HF

Metoprolol

2.5–5mg IVbolusover 2min upto 3doses

5min

NA Hypotension,heart block,bradycardia,asthma, HF

Propranolol

0.15mg/kgIV

5min


Verapamil

0.075–0.15mg/kgIV over2 min

3–5min

Hypotension,heart block,HF

Digoxin

0.25 mgIV each2 h, upto 1.5mg

2 h 0.125–0.25 mgdaily

Digitalis toxic-ity, heartblock, brady-cardia

Oral Agents for Heart Rate Control

Drug LoadingDose

UsualMainte-nanceDose

Major Side Ef-fects

Digoxin

0.25 mgPO each2 h ; up to1.5 mg

0.125–0.375 mgdaily

Digitalis toxicity,heart block,bradycardia

Diltiazem

NA 120–360mg dailyin divideddoses;slow re-leaseavailable

Hypotension,heart block, HF

Metoprolol

NA 25–100mg BID


Propranolol

NA 80–240mg dailyin divideddoses


Verapamil

NA 120–360mg dailyin divideddoses;slow re-leaseavailable

Hypotension,heart block, HF,digoxininteraction

Amiodarone

800 mgdaily for 1wk600 mgdaily for 1wk400 mgdaily for4–6 wk

200 mgdaily

Pulmonary toxic-ity, skin discolor-ation, hypo-thyroidism, cor-neal deposits,optic neuropathy,warfarin interac-tion, proarrhyth-mia

V. Prevention of Thromboembolic ComplicationsA. Atrial fibrillation is the underlying cause of 30,000

to 40,000 embolic strokes per year. The incidenceof these strokes increases with age, rising from1.5 percent in patients aged 50 to 59 years to 23.5percent in patients aged 80 to 89 years.

B. Risk factors for stroke in patients with atrial fibrilla-tion include a history of transient iscemic attack orischemic stroke, age greater than 65 years, ahistory of hypertension, the presence of a pros-thetic heart valve, rheumatic heart disease, leftventricular systolic dysfunction, or diabetes.

VI. Anticoagulant drugsA. Heparin

1. Heparin is the preferred agent for initialanticoagulation. The drug should be given asan intravenous infusion, with the dose titratedto achieve an activated partial thromboplastintime of 1.5 to 2.5. Heparin 80 U/kg load, 18U/kg/hr drip.

2. Heparin should not be used in patients withsigns of active bleeding. Its use in patients withacute embolic stroke should be guided by theresults of transesophageal echocardiography todetect atrial thrombi.

3. In patients with atrial fibrillation that has per-sisted for more than 48 hours, heparin can beused to reduce the risk of thrombus formationand embolization until the warfarin level istherapeutic or cardioversion is performed.

B. Warfarin (Coumadin). Chronic warfarin therapyis commonly used to prevent thromboemboliccomplications in patients with atrial fibrillation.Warfarin therapy is monitored using the Interna-tional Normalized Ratio (INR), which is derivedfrom the prothrombin time. Risk factors for majorbleeding include poorly controlled hypertension,propensity for falling, dietary factors, interactionswith concomitant medications, and patient non-compliance. The INR should be kept between 2.0and 3.0.

C. Aspirin. If bleeding risk prohibits the use ofwarfarin, aspirin is an alternative. Aspirin inhibitsplatelet aggregation and thrombus formation.Aspirin is slightly less effective than warfarin inpreventing stroke in patients with atrial fibrillation,but it is safer in patients at high risk for bleeding.

VII.Anticoagulation during cardioversionA. Early cardioversion

1. Early medical or electrical cardioversion maybe instituted without prior anticoagulationtherapy when atrial fibrillation has been presentfor less than 48 hours. However, heparin isroutinely used.

2. If the duration of atrial fibrillation exceeds 48hours or is unknown, transesophagealechocardiography (to rule out atrial thrombi)followed by early cardioversion is recom-mended. Heparin therapy should be institutedduring transesophageal echocardiography. Ifno atrial thrombi are observed, cardioversioncan be performed. If atrial thrombi are de-tected, cardioversion should be delayed andanticoagulation continued. To decrease the riskof thrombus extension, heparin should becontinued, and warfarin therapy should beinitiated. Once the INR is above 2.0, heparincan be discontinued, but warfarin should becontinued for four weeks.

3. If cardioversion is unsuccessful and patientsremain in atrial fibrillation, warfarin or aspirinmay be considered for long-term prevention ofstroke.

B. Elective Cardioversion1. Warfarin (Coumadin) should be given for

three weeks before elective electrical cardio-version is performed. The initial dose is 5 to 10mg per day. After successful cardioversion,warfarin should be continued for four weeks todecrease the risk of new thrombus formation.

2. If atrial fibrillation recurs or patients are at highrisk for recurrent atrial fibrillation, warfarin maybe continued indefinitely, or aspirin therapymay be considered. Factors that increase therisk of recurrent atrial fibrillation include anenlarged left atrium and left ventricular dysfunc-tion.

Antithrombotic Therapy in Cardioversion forAtrial Fibrillation

Timing of cardiover-sion Anticoagulation

Early cardioversion in pa-tients with atrial fibrillationfor less than 48 hours

Heparin during cardiover-sion period to achieve PTTof 1.5 to 2.5. Heparin 80U/kg load, 18 U/kg/hr drip.

Early cardioversion in pa-tients with atrial fibrillationfor more than 48 hours oran unknown duration, butwithout documented atrialthrombi

Heparin during cardiover-sion period to achieve PTTof 1.5 to 2.5 Warfarin (Coumadin) for 4weeks after cardioversionto achieve target INR of 2.5(range: 2.0 to 3.0)

Elective cardioversion inpatients with atrial fibrilla-tion for more than 48 hoursor an unknown duration

Warfarin for 3 weeks be-fore and 4 weeks after car-dioversion to achieve tar-get INR of 2.5 (range: 2.0to 3.0)

VIII.Long-Term AnticoagulationA. Long-term anticoagulation therapy should be

considered in patients with persistent atrialfibrillation who have failed cardioversion and inpatients who are not candidates for medical orelectrical cardioversion. Patients with a signifi-cant risk of falling, a history of noncompliance,active bleeding, or poorly controlled hyperten-sion should not receive long-termanticoagulation therapy.

B. Factors that significantly increase the risk forstroke include previous stroke, previous tansientcerebral ischemia or systemic embolus, hyper-tension, poor left ventricular systolic function,age greater than 75 years, prosthetic heartvalve, and history of rheumatic mitral valvedisease. With persistent atrial fibrillation, pa-tients older than 65 years and those with diabe-tes are also at increased risk. The lowest risk forstroke is in patients with atrial fibrillation who areless than 65 years of age and have no history ofcardiovascular disease, diabetes, or hyperten-sion.

C. Warfarin therapy has been shown to reduce theabsolute risk of stroke by 0.8 percent per year,compared with aspirin. In patients with a historyof stroke, warfarin reduces the absolute risk ofstroke by 7 percent per year.

Recommendations for Anticoagulation in AtrialFibrillation

Heparin therapy should be considered in hospitalizedpatients with atrial fibrillation persisting beyond 48 hoursand in patients undergoing medical (pharmacologic) orelectrical cardioversion. Heparin 80 U/kg load, 18 U/kg/hrdrip.

Antithrombotic therapy using warfarin (Coumadin) shouldbe given for 3 weeks before cardioversion and 4 weeksafter successful cardioversion. The initial dose is 5 to 10mg per day, with the daily dose then adjusted according tothe INR.

Patients with persistent or recurrent atrial fibrillation afterattempted cardioversion should be given chronic warfarinor aspirin therapy for stroke prevention.

Warfarin is the preferred agent in patients at high riskfor stroke because of previous stroke, age over 75years, and/or poor left ventricular function.

Aspirin is the preferred agent in patients at low riskfor stroke and in patients with a risk of falling, historyof noncompliance, active bleeding, and/or poorlycontrolled hypertension.


HypertensionHigh blood pressure is defined as a systolic bloodpressure of 140 mm Hg or greater or a diastolic pressureof 90 mm Hg or greater. Hypertension is a major riskfactor for coronary artery disease (CAD), heart failure,stroke, and renal failure. Approximately 50 millionAmericans have hypertension.

I. Clinical evaluation of the hypertensive patientA. Evaluation of hypertension should include an

assessment of missed doses of maintenanceantihypertensive therapy, use of nonsteroidal anti-inflammatory drugs, decongestants, diet medica-tions, cocaine, or amphetamines.

B. History should assess the presence of coronaryheart disease (chest pain), hyperlipidemia, diabe-tes, or smoking.

Classification of blood pressure for adults

Category Systolic (mm Hg) Diastolic (mmHg)

Optimal <120 <80

Normal <130 <85

High-normal 130-139 85-89

Hypertension

Stage 1 140-159 90-99

Stage 2 160-179 100-109

Stage 3 >180 >110

The sixth report of the Joint National Committee on Preven-tion, Detection, Evaluation, and Treatment of High BloodPressure.

C. Physical examination. The diagnosis of hyperten-sion requires three separate readings of at least140/90. The physical exam should search for retinalhemorrhages, carotid bruits, left ventricular en-largement, coarctation of the aorta, aortic aneu-rysm, and absence of a peripheral pulse in anextremity.

Target organ damage associated with hyperten-sion

Heart diseaseLeft ventricular hypertrophyCoronary artery disease, myocardial infarctionHeart failure

Cerebrovascular diseaseStrokeTransient ischemic attack

Peripheral vascular diseaseAortic aneurysmPeripheral occlusive disease

Nephropathy, renal failureRetinopathy

II. Initial diagnostic evaluation of hypertensionA. 12 lead electrocardiography may document

evidence of ischemic heart disease, rhythm andconduction disturbances, or left ventricular hyper-trophy.

B. Screening labs include a complete blood count,glucose, potassium, calcium, creatinine, BUN, anda fasting lipid panel.

C. Urinalysis. Dipstick testing should include glucose,protein, and hemoglobin.

D. Selected patients may require plasma renin activity,24 hour urine catecholamines, or renal functiontesting (glomerular filtration rate and blood flow).

III. Secondary hypertensionA. Only 1-2% of all hypertensive patients will prove to

have a secondary cause of hypertension. Age ofonset greater than 60 years, age of onset less than20 in African-American patients, or less than 30 inwhite patients suggests a secondary cause. Bloodpressure that is does not respond to a three-drugregimen or a sudden acceleration of blood pressuresuggests secondary hypertension.

B. Hypokalemia (potassium <3.5 mEq/L) suggestsprimary aldosteronism. Cushingoid features sug-gests Cushing’s disease. Spells of anxiety, sweat-ing, or headache suggests pheochromocytoma.

C. Aortic coarctation is suggested by a femoral pulsedelayed later than the radial pulse, or by posteriorsystolic bruits below the ribs. Renovascular steno-sis is suggested by paraumbilical abdominal bruits.

D. Pyelonephritis is suggested by persistent urinarytract infections or costovertebral angle tenderness.Renal parenchymal disease is suggested by anincreased serum creatinine >1.5 mg/dL andproteinuria.

Evaluation of Secondary Hypertension

RenovascularHypertension

Captopril test: Plasma renin level be-fore and 1 hr after captopril 25mg. A greater than 150% in-crease in renin is positive

Captopril renography: Renal scanbefore and after 25 mg

MRI angiography Arteriography (DSA)

Hyperaldosteronism

Serum potassiumSerum aldosterone and plasma reninactivityCT scan of adrenals

Pheochromocytoma

24 hr urine catecholaminesCT scanNuclear MIBG scan

Cushing's Syn-drome

Plasma cortisolDexamethasone suppression test

Hyperparathyroidism

Serum calciumSerum parathyroid hormone

IV. Treatment of hypertensionA. Treatment should begin with an aggressive

lifestyle modification program. Some patients canbring blood pressure down to normal with lifestylemodification alone.

Lifestyle modifications for prevention andmanagement of hypertension

Lose weight if over ideal body weight Limit alcohol intake to no more than 1 oz of ethanol perday Increase aerobic physical activity Reduce sodium intake to no more than 2.4 g sodium perday Maintain adequate intake of dietary potassium, calcium,and magnesium Stop smoking Reduce intake of saturated fat and cholesterol

B. Diuretics1. Diuretics are recommended as the initial treat-

ment for patients with uncomplicated hyperten-sion. Hydrochlorothiazide is the most widelyused diuretic; it is easy to use, effective, andinexpensive.

2. Most of the blood-pressure-lowering effect ofdiuretics is achieved at low doses (ie, 12.5 mgof hydrochlorothiazide). Little further benefitaccrues at higher doses. A number of drugscombine hydrochlorothiazide with other agents.

3. Side effects of diuretics include dehydrationand orthostatic hypotension, which may lead tofalls. Hypokalemia and hypomagnesemia arealso possible side effects of diuretics, whichcan precipitate life-threatening arrhythmias.Gout and leg cramps are common.

Thiazide Diuretics

Drug Usual dose

Hydrochlorothiazide (HCTZ,Hydrodiuril)

12.5-50 mg qd

Chlorthalidone (Hygroton) 12.5-25 mg qd

Chlorothiazide (Diuril) 125-500 mg qd

Indapamide (Lozol) 1.25 mg qd

Metolazone (Zaroxolyn) 1.25-5 mg qd

C. Beta-blockers1. Beta-blockers are effective at reducing the

incidence of fatal and nonfatal stroke. The JointNational Committee recommends beta blockersas first-line therapy for treatment of hyperten-sion if no contraindications are evident.

2. These drugs should be the first choice forhypertension in myocardial infarction survivors.Even patients with lung disease tolerate betablockers well if no active bronchospasm ispresent.

3. Beta-blockers may provide substantial benefitfor patients with systolic heart failure. Carvedilol(Coreg), a nonselective beta blocker withalpha-blocking activity, reduces the risk ofdeath in patients with heart failure.

Beta-blockers

Drug Usual dose Maximum dose

Acebutolol(Sectral)

200-800 mg/d (qdor bid)

1.2 g/d (bid)

Atenolol(Tenormin)

50-100 mg qd 100 mg qd

Betaxolol(Kerlone)

10 mg qd 20 mg qd

Drug Usual dose Maximum dose

Bisoprolol(Zebeta)

5 mg qd 20 mg qd

Carteolol(Cartrol)

2.5 mg qd 10 mg qd

Carvedilol(Coreg)

6.26-25 mg bid 100 mg/d

Labetalol(Normodyne,Trandate)

100-600 mg bid 1200 mg/d

Metoprolol(Toprol XL)

100-200 mg qd 400 mg qd

Metoprolol(Lopressor)

100-200 mg/d (qdor bid)

450 mg/d (qd orbid)

Nadolol(Corgard)

40 mg qd 320 mg/d

Penbutolol(Levatol)

20 mg qd NA

Pindolol (Visken) 5 mg bid 60 mg/d

Propranolol(Inderal, InderalLA)

120-160 mg qd(LA 640 mg/d)

Timolol(Blocadren)

10-20 mg bid 60 mg/d (bid)

D. Angiotensinogen-converting enzyme inhibitors1. ACE inhibitors are the drugs of choice for

treating heart failure. The ACE inhibitorenalapril maleate (Vasotec) improves overallsurvival and quality of life for patients withsevere heart failure. Patients with asymptom-atic left ventricular dysfunction also benefit fromACE inhibition.

2. ACE inhibitors are also beneficial after myocar-dial infarction. Overall mortality and the inci-dence of fatal and nonfatal myocardial infarc-tion are significantly reduced.

3. Patients with diabetes-induced renal diseasemay also benefit from treatment with ACEinhibitors because these drugs prevent pro-gression from microalbuminuria to proteinuriaand offer protection against deterioration ofrenal function. Serum potassium levels shouldbe monitored in patients with chronic renalfailure treated with ACE inhibitors, and thedrugs should be stopped if potassium levelsincrease to 6 mEq/L.

Angiotensin-converting enzyme inhibitors

Drug Usual doses Maximum dose

Benazepril(Lotensin)

10-40 mg qd ordivided bid

80 mg/d

Captopril(Capoten)

50 mg bid-qid 450 mg/d

Enalapril(Vasotec,Vasotec IV)


40 mg/d

Fosinopril(Monopril)


80 mg/d

Lisinopril (Prinivil,Zestril)

20-40 mg qd 40 mg/d

Moexipril(Univasc)

15-30 mg qd 30 mg/d

Quinapril(Accupril)


80 mg/d

Ramipril (AItace) 5-20 mg qd ordivided bid

20 mg/d

Trandolapril(Mavik)

1-4 mg qd 8 mg/d

Perindopril(Aceon)

4-8 mg qd-bid 8 mg/d

E. Angiotensin II receptor blockers1. These antihypertensive agents block the action

of angiotensin II. They effectively lower bloodpressure and bring about the samehemodynamic changes that occur with ACEinhibitors. Patients are less likely to have thedry cough that sometimes occurs with use ofACE inhibitors.

2. The angiotensin II receptor blockers used fortreatment of hypertension are losartan(Cozaar), valsartan (Diovan), irbesartan(Avapro), and candesartan (Atacand). Angio-tensin II receptor blockers are often substitutedfor ACE inhibitors in patients who experiencechronic cough.

Angiotensin II Receptor Blockers

Drug Usual dose Maximumdose

Losartan (Cozaar) 50 mg qd 100 mg/d

Candesartan (Atacand) 4-8 mg qd 16 mg/d

Eprosartan (Teveten) 400-800 mgqd

800 mg/d

Irbesartan (Avapro) 150-300 mgqd

300 mg/d

Telmisartan (Micardis) 40-80 mgqd

80 mg/d

Valsartan (Diovan) 80 mg qd 320 mg/d

F. Calcium channel blockers1. Calcium channel blockers are very effective

antianginal agents and are often used in combi-nation with beta blockers and nitrates for treat-ment of ischemic heart disease. Thedihydropyridine calcium channel blockers areoften used in difficult cases.

2. The first-generation calcium channel blockersare all negative inotropic drugs and can worsenheart failure. New long-acting calcium channelblockers are safer to use in patients with leftventricular dysfunction.

Calcium channel blockers

Drug Dosage

Diltiazem extended-re-lease (Cardizem SR)

120-360 mg in 2 doses

Diltiazem CD (CardizemCD)

120-360 mg in 1 dose

Diltiazem XR (Dilacor XR) 120-480 mg in 1 dose

Verapamil (Calan) 120-480 mg in 2 or 3doses

Verapamil extended-re-lease (Calan SR)

120-480 mg in 1 or 2doses

Verapamil HS (Covera-HS) 180-480 mg in 1 dose

Dihydropyridines

Amlodipine (Norvasc) 2.5-10 mg in 1 dose

Felodipine (Plendil) 2.5-10 mg in 1 dose

Isradipine (DynaCirc) 5-10 mg in 2 doses

Isradipine extended-re-lease (DynaCirc CR)

5-10 mg in 1 dose

Nicardipine (Cardene) 60-120 mg in 3 doses

Nicardipine extended-re-lease (Cardene SR)

60-120 mg in 2 doses

Nifedipine extended-re-lease (Adalat CC,Procardia XL)

30-90 mg in 1 dose

Nisoldipine (Sular) 10-60 mg in 1 dose

Combination Agents for Hypertension

Drug Initial dose Comments

Beta-Blocker/Diuretic

Atenolol/chlorthalidone (Tenoretic)

50 mg/25 mg, 1tab qd

Additivevasodilation

Bisoprolol/HCTZ(Ziac)

2.5 mg/6.25 mg, 1tab qd

Metoprolol/HCTZ(Lopressor HCTZ)


Nadolol/HCTZ(Corzide)

40 mg/5 mg, 1 tabqd

Propranolol/HCTZ(Inderide LA)


Timolol/HCTZ(Timolide)


ACE inhibitor/Diuretic

Benazepril/HCTZ(Lotensin HCT)

5 mg/6.25 mg, 1tab qd

ACE inhibitorconserves po-tassium andmagnesium;combinationbeneficial forCHF patientswith HTN

Captopril/HCTZ(Capozide)


Enalapril/HCTZ(Vaseretic)


Lisinopril/HCTZ(Zestoretic,Prinzide)


Moexipril/HCTZ(Uniretic)

7.5 mg/12.5 mg, 1tab qd

ACE inhibitor/Calcium-channel blocker

Benazepril/amlodipine (Lotrel)

2.5 mg/10 mg, 1tab qd

Enalapril/felodipine (Lexxel)

5 mg/5 mg, 1 tabqd

Enalapril/diltiazem(Teczem)


Trandolapril/verapamil (Tarka)


Angiotensin II receptor blocker/Diuretic

Losartan/HCTZ(Hyzaar)


Valsartan/HCTZ(Diovan HCT)


Alpha-1-Blocker/Diuretic

Prazosin/polythiazide (Minizide)

1 mg/0.5 mg, 1cap bid

Synergisticvasodilation

K+-sparing diuretic/Thiazide

Amiloride/HCTZ

(Moduretic)5 mg/50 mg, 1 tabqd

Electrolyte-sparing effect

Triamterene/HCTZ(Dyazide,Maxzide)

37.5 mg/25 mg, ½tab qd

Consideration of Concomitant Conditions in theTreatment of Hypertension

Compelling indications

Heart failure ACE inhibitor, diuretic

Isolated systolic hy-pertension

Diuretic (first choice), long-actingcalcium-channel blocker (secondchoice)

Post acute myocar-dial infarction

$-blocker (non-ISA); ACE inhibi-tor (in systolic dysfunction)

Type 1 diabetesmellitus

ACE inhibitor

Likely to be beneficial to patients with comorbidity

Angina $-blocker, calcium-channelblocker

Atrial fibrillation $-blocker, calcium-channelblocker

Heart failure Carvedilol, ACE inhibitor

Diabetes mellitus ACE inhibitor


Hypertensive EmergencySevere hypertension is defined as an elevation indiastolic blood pressure (BP) higher than 130 mm Hg.

I. Clinical evaluation of severe hypertensionA. Hypertensive emergency is defined by a diastolic

blood pressure >120 mm Hg associated with ongo-ing vascular damage. Symptoms or signs of neuro-logic, cardiac, renal, or retinal dysfunction arepresent. Hypertensive emergencies include severehypertension in the following settings:1. Aortic dissection2. Acute left ventricular failure and pulmonary

edema3. Acute renal failure or worsening of chronic renal

failure4. Hypertensive encephalopathy 5. Focal neurologic damage indicating thrombotic

or hemorrhagic stroke6. Pheochromocytoma, cocaine overdose, or other

hyperadrenergic states7. Unstable angina or myocardial infarction8. Eclampsia

B. Hypertensive urgency is defined as diastolic bloodpressure >130 mm Hg without evidence of vasculardamage; the disorder is asymptomatic and noretinal lesions are present.

C. Causes of secondary hypertension includerenovascular hypertension, pheochromocytoma,cocaine use, withdrawal from alpha-2 stimulants,clonidine, beta-blockers or alcohol, and noncompli-ance with antihypertensive medications.

II. Initial assessment of severe hypertensionA. When severe hypertension is noted, the measure-

ment should be repeated in both arms to detect anysignificant differences. Peripheral pulses should beassessed for absence or delay, which suggestsdissecting aortic dissection. Evidence of pulmonaryedema should be sought.

B. Target organ damage is suggested by chest pain,neurologic signs, altered mental status, profoundheadache, dyspnea, abdominal pain, hematuria,focal neurologic signs (paralysis or paresthesia), orhypertensive retinopathy.

C. Prescription drug use should be assessed, includ-ing missed doses of antihypertensives. History ofrecent cocaine or amphetamine use should besought.

D. If focal neurologic signs are present, a CT scanmay be required to differentiate hypertensiveencephalopathy from a stroke syndrome.

III. Laboratory evaluation A. Complete blood cell count, urinalysis for protein,

glucose, and blood; urine sediment examination;chemistry panel (SMA-18).

B. If chest pain is present, cardiac enzymes areobtained.

C. If the history suggests a hyperadrenergic state, thepossibility of a pheochromocytoma should beexcluded with a 24-hour urine for catecholamines.A urine drug screen may be necessary to excludeillicit drug use.

D. Electrocardiogram should be completed.E. Suspected primary aldosteronism can be excluded

with a 24-hour urine potassium and an assessmentof plasma renin activity. Renal artery stenosis can

be excluded with captopril renography and intrave-nous pyelography.

IV. Management of hypertensive urgenciesA. The initial goal in patients with severe asymptom-

atic hypertension should be a reduction in bloodpressure to 160/110 over several hours with con-ventional oral therapy.

B. If the patient is not volume depleted, furosemide(Lasix) is given in a dosage of 20 mg if renal func-tion is normal, and higher if renal insufficiency ispresent. A calcium channel blocker (isradipine([DynaCirc], 5 mg or felodipine [Plendil], 5 mg)should be added. A dose of captopril(Capoten)(12.5 mg) can be added if the responseis not adequate. This regimen should lower theblood pressure to a safe level over three to sixhours and the patient can be discharged on aregimen of once-a-day medications.

V.Management of hypertensive emergenciesA. The patient should be hospitalized for intravenous

access, continuous intra-arterial blood pressuremonitoring, and electrocardiographic monitoring.Volume status and urinary output should be moni-tored. Rapid, uncontrolled reductions in bloodpressure should be avoided because coma, stroke,myocardial infarction, acute renal failure, or deathmay result.

B. The goal of initial therapy is to terminate ongoingtarget organ damage. The mean arterial pressureshould be lowered not more than 20-25%, or to adiastolic blood pressure of 100 mm Hg over 15 to30 minutes.

VI. Parenteral antihypertensive agents A. Nitroprusside (Nipride)

1. Nitroprusside is the drug of choice in almost allhypertensive emergencies (except myocardialischemia or renal impairment). It dilates both ar-teries and veins, and it reduces afterload andpreload. Onset of action is nearly instantaneous,and the effects disappear 1-2 minutes afterdiscontinuation.

2. The starting dosage is 0.25-0.5 mcg/kg/min bycontinuous infusion with a range of 0.25-8.0mcg/kg/min. Titrate dose to gradually reduceblood pressure over minutes to hours.

3. When treatment is prolonged or when renalinsufficiency is present, the risk of cyanide andthiocyanate toxicity is increased. Signs ofthiocyanate toxicity include anorexia, disorienta-tion, fatigue, hallucinations, nausea, toxic psy-chosis, and seizures.

B. Nitroglycerin1. Nitroglycerin is the drug of choice for hyperten-

sive emergencies with coronary ischemia. Itshould not be used with hypertensiveencephalopathy because it increases intracranialpressure.

2. Nitroglycerin increases venous capacitance,decreases venous return and left ventricularfilling pressure. It has a rapid onset of action of2-5 minutes. Tolerance may occur within 24-48hours.

3. The starting dose is 15 mcg IV bolus, then 5-10mcg/min (50 mg in 250 mL D5W). Titrate by in-creasing the dose at 3- to 5-minute intervals upto max 1.0 mcg/kg/min.

C. Labetalol IV (Normodyne) 1. Labetalol is a good choice if BP elevation is

associated with hyperadrenergic activity, aorticdissection, an aneurysm, or postoperative hyper-tension.

2. Labetalol is administered as 20 mg slow IV over2 min. Additional doses of 20-80 mg may beadministered q5-10min, then q3-4h prn or 0.5-2.0 mg/min IV infusion. Labetalol is contraindi-cated in obstructive pulmonary disease, CHF, orheart block greater than first degree.

D. Enalaprilat IV (Vasotec)1. Enalaprilat is an ACE-inhibitor with a rapid onset

of action (15 min) and long duration of action (11hours). It is ideal for patients with heart failure oraccelerated-malignant hypertension.

2. Initial dose, 1.25 mg IVP (over 2-5 min) q6h, thenincrease up to 5 mg q6h. Reduce dose inazotemic patients. Contraindicated in bilateralrenal artery stenosis.

E. Esmolol (Brevibloc) is a non-selective beta-blocker with a 1-2 min onset of action and shortduration of 10 min. The dose is 500 mcg/kg/min x1 min, then 50 mcg/kg/min; max 300 mcg/kg/min IVinfusion.

F. Hydralazine is a preload and afterload reducingagent. It is ideal in hypertension due to eclampsia.Reflex tachycardia is common. The dose is 20 mgIV/IM q4-6h.

G. Nicardipine (Cardene IV) is a calcium channelblocker. It is contraindicated in presence of CHF.

Tachycardia and headache are common. The onsetof action is 10 min, and the duration is 2-4 hours.The dose is 5 mg/hr continuous infusion, up to 15mg/hr.

H. Fenoldopam (Corlopam) is a vasodilator. It maycause reflex tachycardia and headaches. The onsetof action is 2-3 min, and the duration is 30 min. Thedose is 0.01 mcg/kg/min IV infustion titrated, up to0.3 mcg/kg/min.

I. Phentolamine (Regitine) is an intravenous alpha-adrenergic antagonist used in excessc a t e c h o l a m i n e s t a t e s , s u c h a spheochromocytomas, rebound hypertension due towithdrawal of clonidine, and drug ingestions. Thedose is 2-5 mg IV every 5 to 10 minutes.

J. Trimethaphan (Arfonad) is a ganglionic-blockingagent. It is useful in dissecting aortic aneurysmwhen beta-blockers are contraindicated; however,it is rarely used because most physicians are morefamiliar with nitroprusside. The dosage oftrimethoprim is 0.3-3 mg/min IV infusion.


SyncopeSyncope is defined as a sudden, transient loss of con-sciousness characterized by unresponsiveness and lossof postural tone. The prognosis for most persons withsyncopal episodes is good; however, persons withsyncope caused by a cardiac disorder have a one-yearmortality rate of 20-30%. Hospitalization is generally notnecessary, unless a cardiac etiology or a significantinjury during the syncopal event is suspected.

I. PathophysiologyA. Vasovagal attacks, cardiac disorders and pulmo-

nary outflow obstruction produce syncope becauseof a reduction of cerebral blood flow. Hypoxia,hyperventilation and hypoglycemia, increasedintracranial pressure, seizures and hysteria cancause syncope.

B. Cardiac syncope is caused by inadequate outputfrom the left ventricle. Mechanical causes of car-diac syncope include aortic stenosis, hypertrophiccardiomyopathy, myocardial infarction and pulmo-nary embolus. Tachyarrhythmias, especially ven-tricular tachycardia, account for most of thearrhythmias that result in cardiac syncope. Syn-cope of cardiac origin results in markedly in-creased rates of mortality and sudden death. Thecause of syncope can not be determined in 38-47% of patients.

II. Clinical evaluationA. The history and physical examination can identify

potential causes of syncope in 50-85% of cases inwhich a successful diagnosis is made. A young,healthy patient with a history compatible withvasovagal syncope probably needs no furtherdiagnostic testing.

B. A complete description of the syncopal episode,prodromal circumstances and symptoms followingthe syncopal episode should be obtained. Therelationship of fainting to micturition, defecation,cough, swallowing or postural change may reveala cause.

Medications Associated with Syncope

Antihypertensives/anti-anginals

Adrenergic antagonists

Calcium channelblockers DiureticsNitrates Vasodilators

AntidepressantsTricyclic antidepres-sants Phenothiazines

Antiarrhythmics DigoxinQuinidine

InsulinDrugs of abuse

Alcohol Cocaine Marijuana

Differential Diagnosis of Syncope

Non-cardiovascular Cardiovascular

MetabolicHyperventilation Hypoglycemia Hypoxia

NeurologicCerebrovascular insuffi-ciency Normal pressure hydro-cephalus SeizureSubclavian steal syn-drome

Increased intracranialpressure

PsychiatricHysteriaMajor depression

Reflex syncope (heartstructurally normal) VasovagalSituationalCough Defecation Micturition Postprandial Sneeze Swallow Carotid sinus syncope

Orthostatic hypotensionDrug-inducedCardiac

Obstructive Aortic dissectionAortic stenosis Cardiac tamponade Hypertrophiccardiomyopathy Left ventricular dysfunc-tion Myocardial infarction MyxomaPulmonary embolism Pulmonary hyperten-sion Pulmonary stenosisArrhythmias

Bradyarrhythmias Sick sinus syn-drome Pacemaker fail-ure

Supraventricular andventriculartachyarrhythmias

Clues to the Etiology of Syncope

Associated Feature Etiology

CoughMicturitionDefecationSwallowing

Situational syncope

Post-syncopal disori-entationUrinary or fecal in-continence

Seizure

Syncope with armexercise

Subclavian steal syndrome

Syncope with shav-ing

Carotid sinus syncope

Prodromal symp-toms (nausea,diaphoresis)

Vasovagal syncope

Abrupt onset Cardiac syncope

Syncope with exer-tion

Aortic stenosis, hypertrophiccardiomyopathy, arrhythmias

Syncope withchange of position

Orthostatic hypotension

Blood pres-sure/pulse differen-tial

Aortic dissection, subclaviansteal syndrome

Abnormal posturalvital signs

Orthostatic hypotension

Cardiac mur-murs/rhythms

Aortic stenosis, hypertrophiccardiomyopathy, arrhythmias,pulmonary hypertension

Carotid bruit Cerebrovascular insufficiency

C. Vasovagal syncope is usually preceded by nausea,diaphoresis, pallor and light-headedness, com-monly occurring after a stressful or frightful situa-tion.

D. Syncope that has an abrupt onset, without warning,suggests a cardiac arrhythmia, especially in aperson known to have cardiac disease.

E. Syncope that occurs with exertion is indicative ofaortic stenosis, hypertrophic cardiomyopathy, leftventricular dysfunction, or a cardiac arrhythmia.

F. Activities that involve stretching the neck, such asshaving or looking back over one's shoulder, cancause carotid sinus syncope. The relationship ofsyncope to meals or alcohol or drug ingestionshould be determined.

G.Rapid return to alertness usually follows a syncopalepisode; however, a period of postictal confusionusually follows a seizure (Todd’s paralysis).Prodromal auras and fecal and urinary inconti-

nence are suggestive of a seizure.III. Physical examination

A. Orthostatic blood pressure and pulse mea-surements, taken with the patient standing fortwo minutes after a supine period of at least fiveminutes, can be used to detect orthostatichypotension.

B. A difference in pulse intensity or blood pres-sure of more than 20 mm Hg between the twoarms may indicate aortic dissection or subclaviansteal syndrome.

C. Carotid or subclavian bruits can be indicators ofvascular disease.

D. Cardiac examination may reveal aortic stenosis,idiopathic hypertrophic subaortic stenosis, mitralvalve prolapse, or pulmonary hypertension.

E. Carotid sinus pressure can be applied duringelectrocardiographic monitoring to assess poten-tial vascular flow abnormalities. Because ventricu-lar fibrillation and prolonged asystole are potentialcomplications, intravenous access should beestablished before carotid massage is performed.Severe cerebrovascular disease is a relativecontraindication to carotid massage.

F. Neurologic examination should then be per-formed to exclude focal deficits, and stool shouldbe tested for occult blood.

IV. Laboratory testsA. Blood tests may be helpful in confirming anemia,

hypoglycemia, hypoxia, electrolyte abnormality orrenal failure. An associated seizure disorder mayexplain a low bicarbonate level obtained soonafter a syncopal event. Cardiac enzyme determi-nations can be of value if myocardial infarction issuspected.

B. Computed tomographic (CT) scans of the headare unlikely to reveal useful information unlessfocal neurologic findings or a head injury arepresent.

C. Electroencephalogram (EEG) should be ob-tained if a seizure disorder is suspected.

D. Noninvasive cardiac evaluation1. Electrocardiography is the most useful test

when a cardiac source of syncope is sus-pected. The likelihood is low that arrhythmiasare a cause of syncope in persons with anormal ECG.

2. Echocardiography may be valuable in theevaluation of patients with suspected structuralheart disease.

3. Ambulatory electrocardiographic monitor-ing frequently shows arrhythmia. Only 2 per-cent of patients developed arrhythmia-relatedsymptoms during monitoring.

E. Electrophysiologic studies are sometimeshelpful in the evaluation of patients withsyncope.Use in the evaluation of patients withsyncope should be limited to patients with signifi-cant structural heart disease and recurrent syn-cope.

F. Tilt table test can be used in the evaluation ofrecurrent syncope. The table is tilted in an effort toinduce a vasovagal-like reaction.


HypercholesterolemiaThe Third Report of the Expert Panel on Detection,Evaluation and Treatment of High Blood Cholesterol inAdults (Adult Treatment Panel III, or ATP III) summarizesthe current management of high serum cholesterol.

I. Identification of patients at riskA. The ATP III recommendations that treatment of

hypercholesterolemia be based upon theLDL-cholesterol fraction and influenced by thecoexistence of CHD and the number of cardiac riskfactors.

Step 1. The first step in determining patient risk is toobtain a fasting lipid profile.

Classification of LDL, Total, and HDL Cholesterol(mg/dL)

LDL Cholesterol

<100 Optimal

100-129 Near optimal/above optimal

130-159 Borderline high

160-189 High

>190 Very high

Total Cholesterol

<200 Desirable

200-239 Borderline high

>240 High

HDL Cholesterol

<40 Low

>60 High

Step 2. CHD equivalents, risk factors that place thepatient at similar risk for CHD events as ahistory of CHD itself, should be identified instep 2:

1. Diabetes mellitus2. Symptomatic carotid artery disease3. Peripheral arterial disease4. Abdominal aortic aneurysm

Step 3. Major CHD factors other than LDL are identifiedin step 3:1. Cigarette smoking2. Hypertension (BP 140/90 or antihypertensive

medication)3. Low HDL cholesterol (<40 mg/dL)4. Family history of premature CHD (in male first

degree relatives <55 years, in female first degreerelatives <65 years)

5. Age (men 45 years, women 55 years)6. HDL cholesterol 60 mg/dL counts as a "negative"

risk factor; its presence removes one risk factorfrom the total count.

Step 4. If two or more risk factors other than LDL (asdefined in step 3) are present in a patient withoutCHD or a CHD equivalent (as defined in step 2), the10-year risk of CHD is assessed using Framinghamrisk tables.

Step 5.The last step in risk assessment is to determinethe risk category that establishes the LDL goal,when to initiate therapeutic lifestyle changes, andwhen to consider drug therapy.

LDL Cholesterol Goals for Therapeutic LifestyleChanges (TLC) and Drug Therapy in Different RiskCategories.

Risk Cate-gory

LDL-CGoal

LDL Level atWhich to Initi-ate Therapeu-tic LifestyleChanges

LDL Level atWhich to Con-sider DrugTherapy

CHD <100mg/dL

>100 mg/dL >130 mg/dL(100-129mg/dL: drugoptional)

2+ Risk Fac-tors

<130mg/dL

>130 mg/dL 10-year risk 10-20%:>130mg/dL

10-year risk<10%:>160mg/dL

0-1 Risk Fac-tor

<160mg/dL

>160 mg/dL >190 mg/dL(160-189mg/dL: LDL-lowering drugoptional)

II. TreatmentA. Cardiovascular benefits of cholesterol lowering

with statin drugs have been demonstrated in thefollowing groups:1. Patients with CHD, with or without

hyperlipidemia2. Men with hyperlipidemia but no known CHD3. Men and women with average total and LDL

cholesterol levels and no known CHDB. Secondary prevention. In patients who already

have CHD, a goal LDL-cholesterol value of lessthan 100 mg/dL is recommended for secondaryprevention. Dietary modification should be em-ployed in any patient with CHD and anLDL-cholesterol exceeding 100 mg/dL, and drugtherapy should be considered if theLDL-cholesterol remains above 130 mg/dL.

C. Primary prevention. The serum LDL-cholesterolconcentration and risk factor status determinethe suggested approach:1. Individuals with desirable serum

LDL-cholesterol values may be reevaluated infive years, while those with borderline high-riskvalues and less than two cardiac risk factorsshould be reevaluated in one year (one riskfactor is subtracted if the serum HDL is 60mg/dL).

2. A cholesterol lowering diet is indicated in pa-tients with a high-risk serum LDL-cholesterolconcentration and in those with borderlinehigh-risk values plus two or more cardiac riskfactors.

3. Drug therapy with a statin should be consideredif, after a trial of dietary modification, serumLDL-cholesterol remains above 190 mg/dL inany patient or above 160 mg/dL in a patientwith two or more CHD risk factors.

4. The goal serum LDL-cholesterol concentrationshould be below 160 mg/dL in patients with lessthan two CHD risk factors. A lower value of 130mg/dL is recommended in patients with two ormore CHD risk factors.

D. Patients with low HDL. Therapy aimed at raisingHDL levels into the normal range has been advo-cated in patients with overt CHD and those at highrisk because of a strong family history. Low HDLcholesterol is defined as <40 mg/dL.

E. Hypertriglyceridemia should be treated in pa-tients who also have hypercholesterolemia. Possi-ble indications for treatment of isolatedhypertriglyceridemia include overt CHD, a strongfamily history of CHD, multiple coexisting cardiacrisk factors, and very high triglyceride levels(>1000 mg/dL).

F. Lifestyle modifications include reductions indietary fat, weight loss in overweight patients, andaerobic exercise. All patients with high LDL choles-terol should undergo lifestyle modifications. Manywill not reach the goal level of cholesterol and willrequire drug therapy.

G. Drug therapy1. Statins are commonly used in the treatment of

hypercholesterolemia. They are the most pow-erful drugs for lowering LDL cholesterol, withreductions of 20 to 60%. Fluvastatin (Lescol) issomewhat less potent, decreasing LDL by 20-25%. Atorvastatin is the most potent, reducingLDL by 29-61%. An additional benefit ofatorvastatin is more effective triglyceride lower-ing (14 to 33%). Adverse reactions occur lessfrequently with the statins than with otherlipid-lowering agents.

2. Cholesterol absorption inhibitors -Ezetimibe (Zetia) modestly lowers the LDLcholesterol when used alone, but may have itsgreatest use in combination with statins. It doesnot have the gastrointestinal effects of the bileacid sequestrants. It is more effective in lower-ing LDL cholesterol than doubling the dose ofthe statin.

Dose, Side Effects, and Drug Interactions ofLipid-Lowering Drugs

Drug class Dose Dosing Major sideeffects anddrug interac-tions

HMG CoA reductase inhibitors

Atorvastatin(Lipitor) Lovastatin(generic,Mevacor)Extended-releaselovastatin(Altocor)Pravastatin(Pravachol)Simvastatin(Zocor)Fluvastatin(Lescol,Lescol XL)

10-40mg/day 20-80mg/day

10-60mg/day

10-40mg/day

5-40mg/day10-40mg/day

Take atbed-time.TakeBID ifdose>20mg/day.

Headache;nausea; sleepdisturbance;elevations inliver enzymesand alkalinephosphatase.Myositis andrhabdomyo-lysis.Lovastatin andsimvastatinpotentiate war-farin and in-crease digoxinlevels

Cholesterol absorption inhibitors

Ezetimibe(Zetia)

10mg/day

10 mgqd

Increasedtransaminasesin combinationwith statins

Drug class Dose Dosing Major sideeffects anddrug interac-tions

Bile acid sequestrants

Cholestyramine(Questran,QuestranLite)Colestipol(Colestid)Colesevelam(Welchol)

4-24g/day

5-30g/day3.75 gmonce ordividedBID

Takewithin30 minof meal.A dou-bledosewithdinnerpro-ducessameeffectas BIDdosing

Nausea, bloat-ing, cramping,constipation;elevations inhepatic trans-aminases andalkalinephosphatase.Impaired ab-sorption of fatsoluble vita-mins, digoxin,warfarin,thiazides, beta-blockers, thy-roxine, pheno-barbital.

Nicotinicacid

1-12g/day

Givenwithmeals.Startwith100 mgBID and titrate to500 mgTID.After 6weeks,checklipids,glu-cose,liverfunc-tion,and uricacid.

Prostaglandin-mediated cuta-neous flushing,headache, pru-ritus; hyper-pigmentation;acanthosisnigricans; dryskin; nausea;diarrhea; myo-sitis.

Fibrates

Gemfibrozil(Lopid)

600 mgBID

50 to 60min be-foremeals.

Potentiateswarfarin. Ab-sorption ofgemfibrozil di-minished bybile acidsequestrants.

Fenofibrate(Lipidil)

201mg/day

3 cap-sules(67 mgeach)withbreak-fast.Uselowerdoseswithrenalinsuffi-ciency

Skin rash, nau-sea, bloating,cramping,myalgia; lowerscyclosporinlevels; nephro-toxic incyclosporin-treated pa-tients.

Clofibrate(Atromid-5)

500 mgfourtimesdaily

Nausea, skinrash

Probucol 500 mgBID

Loose stools;eosinophilia;QT prolonga-tion;angioneuroticedema.

Extended-release nia-cin plus(immediate-release)lovastatin(Advicor)

1000mg/40mg/day

1000mg + 40mgh.s.3

markedly low-ersLDL and tri-glycerides andraises HDL

Average Reduction in LDL Levels with StatinDrugs

Statin1 0 - m gdosage

2 0 - m gdosage

4 0 - m gdosage

8 0 - m gdosage

Atorvastatin(Lipitor)

38% 46% 51% 54%

Simvastatin(Zocor)

28% 35% 40% 48%

Lovastatin(Mevacor,generic)

-- 29% 31% 48%

Cerivastatin(Baycol)

0.2-mgdosage:25%

0.3-mgdosage:30%

0.4-mgdosage:36%

0.8-mgdosage:44%

Pravastatin(Pravachol)

19% 24% 34% 40%

Fluvastatin(Lescol)

-- 17% 23% 33%

3. Fibrates (gemfibrozil, clofibrate, fenofibrate)primarily lower plasma triglyceride and raiseHDL levels. They are effective for the treat-ment of hypertriglyceridemia and combinedhyperlipidemia.

4. Bile acid sequestrants are effective inpatients with mild to moderate elevations ofLDL cholesterol. Bile acid sequestrants arealso effective when used with a statin ornicotinic acid. Use is often limited by sideeffects.

5. Nicotinic acid is effective in patients withhypercholesterolemia and in combinedhyperlipidemia associated with normal andlow levels of HDL cholesterol. Use is oftenlimited by poor tolerability.

6. Probucol modestly lowers LDL cholesterol,but more prominently reduces HDL choles-terol. Probucol should be limited to refractoryhypercholesterolemia or familial hypercho-lesterolemia and xanthomas.


Pulmonary Disorders

AsthmaAsthma is the most common chronic disease amongchildren. Asthma triggers include viral infections; environ-mental pollutants, such as tobacco smoke; aspirin,nonsteroidal anti-inflammatory drugs, and sustainedexercise, particularly in cold environments.

I. DiagnosisA. Symptoms of asthma may include episodic com-

plaints of breathing difficulties, seasonal or night-time cough, prolonged shortness of breath after arespiratory infection, or difficulty sustaining exer-cise.

B. Wheezing does not always represent asthma.Wheezing may persist for weeks after an acutebronchitis episode. Patients with chronic obstructivepulmonary disease may have a reversible compo-nent superimposed on their fixed obstruction.Etiologic clues include a personal history of allergicdisease, such as rhinitis or atopic dermatitis, and afamily history of allergic disease.

C. The frequency of daytime and nighttime symptoms,duration of exacerbations and asthma triggersshould be assessed.

D. Physical examination. Hyperventilation, use ofaccessory muscles of respiration, audible wheez-ing, and a prolonged expiratory phase are common.Increased nasal secretions or congestion, polyps,and eczema may be present.

E. Measurement of lung function. An increase in theforced expiratory volume in one second (FEV1) of12% after treatment with an inhaled beta2 agonist issufficient to make the diagnosis of asthma. A 12%change in peak expiratory flow rate (PEFR) mea-sured on a peak-flow meter is also diagnostic.

II. Treatment of asthmaA. Beta2 agonists

1. Inhaled short-acting beta2-adrenergic agonistsare the most effective drugs available for treat-ment of acute bronchospasm and for preventionof exercise-induced asthma. Levalbuterol(Xopenex), the R-isomer of racemic albuterol,offers no significant advantage over racemicalbuterol.

2. Salmeterol (Serevent), a long-acting beta2agonist, has a relatively slow onset of action anda prolonged effect. a. Salmeterol should not be used in the treat-

ment of acute bronchospasm. Patients takingsalmeterol should use a short-acting beta2agonist as needed to control acute symptoms.Twice-daily inhalation of salmeterol has beeneffective for maintenance treatment in combi-nation with inhaled corticosteroids.

b. Fluticasone/Salmeterol (Advair Diskus) is along-acting beta agonist and corticosteroidcombination; dry-powder inhaler [100, 250 or500 :g/puff],1 puff q12h.

3. Formoterol (Foradil) is a long-acting beta2agonist like salmeterol. It should only be used inpatients who already take an inhaledcorticosteroid. Patients taking formoterol shoulduse a short-acting beta2 agonist as needed tocontrol acute symptoms. For maintenance treat-ment of asthma in adults and children at least 5years old, the recommended dosage is 1 puff bid.

4. Adverse effects of beta2 agonists. Tachycar-dia, palpitations, tremor and paradoxicalbronchospasm can occur. High doses can causehypokalemia.

Drugs for Asthma

Drug Formulation Dosage

Inhaled beta2-adrenergic agonists, short-acting

AlbuterolProventilProventil-HFAVentolinVentolinRotacaps

metered-doseinhaler (90:g/puff)

dry-powder in-haler (200:g/inhalation)

2 puffs q4-6hPRN

1-2 capsules q4-6h PRN

AlbuterolProventil

multi-dosevials

Ventolin NebulesVentolin

nebulized 2.5 mg q4-6hPRN

Levalbuterol -Xopenex

nebulized 0.63-1.25 mg q6-8h PRN

Inhaled beta2-adrenergic agonist, long-acting

Formoterol -Foradil

dry-powder in-haler (12 :g/puff)

1 puff bid.

SalmeterolSereventSerevent Diskus

metered-doseinhaler (21:g/puff)dry-powder in-haler (50:g/inhalation)

2 puffs q12h

1 inhalation q12h

Fluticasone/Salmeterol AdvairDiskus

dry-powder in-haler (100, 250or 500 :g/puff)

1 puff q12h

Inhaled Corticosteroids

BeclomethasonedipropionateBecloventVancerilVanceril Double-Strength

metered-doseinhaler (42:g/puff) (84:g/puff)

4-8 puffs bid

2-4 puffs bid

BudesonidePulmicortTurbuhaler

dry-powder in-haler (200:g/inhalation)

1-2 inhalationsbid

Flunisolide -AeroBid

metered-doseinhaler

(250 :g/puff)

2-4 puffs bid

FluticasoneFlovent

Flovent Rotadisk

metered-doseinhaler(44, 110 or 220:g/puff)dry-powder in-haler (50, 100 or250:g/inhalation)

2-4 puffs bid(44 :g/puff)1 inhalation bid(100:g/inhalation)

TriamcinoloneacetonideAzmacort


2 puffs tid-qid or4 puffs bid

Leukotriene Modifiers

Montelukast -Singulair

tablets 10 mg qhs

Zafirlukast -Accolate

tablets 20 mg bid

Zileuton - Zyflo tablets 600 mg qid

Mast Cell Stabilizers

Cromolyn Intal


2-4 puffs tid-qid

Nedocromil Tilade

metered-doseinhaler (1.75mg/puff)

2-4 puffs bid-qid

Phosphodiesterase Inhibitor

Theophylline Slo-BidGyrocaps, Theo-Dur, Unidur

extended-releasecapsules or tab-lets

100-300 mg bid

B. Inhaled corticosteroids1. Regular use of an inhaled corticosteroid can

suppress inflammation, decrease bronchialhyperresponsiveness and decrease symptoms.Inhaled corticosteroids are recommended formost patients.

2. Adverse effects. Inhaled corticosteroids areusually free of toxicity. Dose-dependent slow-

ing of linear growth may occur within 6-12weeks in some children. Decreased bonedensity, glaucoma and cataract formation havebeen reported. Churg-Strauss vasculitis hasbeen reported rarely. Dysphonia and oralcandidiasis can occur. The use of a spacerdevice and rinsing the mouth after inhalationdecreases the incidence of candidiasis.

C. Leukotriene modifiers1. Leukotrienes increase production of mucus

and edema of the airway wall, and may causebronchoconstriction. Montelukast andzafirlukast are leukotriene receptor antago-nists. Zileuton inhibits synthesis ofleukotrienes.

2. Montelukast (Singulair) is modestly effectivefor maintenance treatment of intermittent orpersistent asthma. It is taken once daily in theevening. It is less effective than inhaledcorticosteroids, but addition of montelukastmay permit a reduction in corticosteroid dos-age. Montelukast added to oral or inhaledcorticosteroids can improve symptoms.

3. Zafirlukast (Accolate) is modestly effective formaintenance treatment of mild-to-moderateasthma It is less effective than inhaledcorticosteroids. Taking zafirlukast with foodmarkedly decreases its bioavailability.Theophylline can decrease its effect.Zafirlukast increases serum concentrations oforal anticoagulants and may cause bleeding.Infrequent adverse effects include mild head-ache, gastrointestinal disturbances and in-creased serum aminotransferase activity.Drug-induced lupus and Churg-Straussvasculitis have been reported.

4. Zileuton (Zyflo) is modestly effective for main-tenance treatment, but it is taken four times aday and patients must be monitored for hepatictoxicity.

D. Cromolyn (Intal) and nedocromil (Tilade) 1. Cromolyn sodium, an inhibitor of mast cell

degranulation, can decrease airwayhyperresponsiveness in some patients withasthma. The drug has no bronchodilatingactivity and is useful only for prophylaxis.Cromolyn has virtually no systemic toxicity.

2. Nedocromil has similar effects as cromolyn.Both cromolyn and nedocromil are much lesseffective than inhaled corticosteroids.

E. Theophylline1. Oral theophylline has a slower onset of action

than inhaled beta2 agonists and has limitedusefulness for treatment of acute symptoms. Itcan, however, reduce the frequency and sever-ity of symptoms, especially in nocturnalasthma, and can decrease inhaledcorticosteroid requirements.

2. When theophylline is used alone, serum con-centrations between 8-12 mcg/mL provide amodest improvement is FEV1. Serum levels of15-20 mcg/mL are only minimally more effec-tive and are associated with a higher incidenceof cardiovascular adverse events.

F. Oral corticosteroids are the most effective drugsavailable for acute exacerbations of asthmaunresponsive to bronchodilators. 1. Oral corticosteroids decrease symptoms and

may prevent an early relapse. Chronic use oforal corticosteroids can cause glucose intoler-ance, weight gain, increased blood pressure,osteoporosis, cataracts, immunosuppressionand decreased growth in children. Alternate-day use of corticosteroids can decrease theincidence of adverse effects, but not of osteo-porosis.

2. P r e d n i s o n e , p r e d n i s o l o n e o rmethylprednisolone (Solu-Medrol), 40-60 mgqd; for children, 1-2 mg/kg/day to a maximumof 60 mg/day. Therapy is continued for 3-10days. The oral steroid dosage does not need tobe tapered after short-course “burst” therapy ifthe patient is receiving inhaled steroid therapy.

Pharmacotherapy for Asthma Based on DiseaseClassification

Classifi-cation

Long-term controlmedications

Quick-relief medi-cations

Mild in-termittent

Short-acting beta2agonist as needed

Mild per-sistent

Low-dose inhaledcorticosteroid orcromolyn sodium (In-tal) or nedocromil(Tilade)


Moder-ate per-sistent

Medium-dose inhaledcorticosteroid plus along-actingbronchodilator (long-acting beta2 agonist)


Severepersis-tent

High-dose inhaledcorticosteroid plus along-actingbronchodilator andsystemic corticosteroid


III. Management of acute exacerbationsA. High-dose, short-acting beta2 agonists delivered

by a metered-dose inhaler with a volume spacer orvia a nebulizer remains the mainstay of urgenttreatment.

B. Most patients require therapy with systemiccorticosteroids to resolve symptoms and preventrelapse. Hospitalization should be considered ifthe PEFR remains less than 70% of predicted.Patients with a PEFR less than 50% of predictedwho exhibit an increasing pCO2 level and decliningmental status are candidates for intubation.

C. Non-invasive ventilation with bilevel positive airwaypressure (BIPAP) may be used to relieve the work-of-breathing while awaiting the effects of acutetreatment, provided that consciousness and theability to protect the airway have not been compro-mised.


Chronic Obstructive PulmonaryDiseaseChronic obstructive pulmonary disease (COPD) ischaracterized by the presence of persistent airflowlimitation, arising usually after many years of tobaccosmoking. This disease affects at least 6% of men and 3%of women.

I. Characteristics of COPDA. Chronic bronchitis is characterized by a cough

that produces sputum and that lasts at least 3months per year for at least 2 consecutive years.Emphysema refers to enlargement and destructionof the air spaces in the lungs. The term “COPD”describes any combination of chronic bronchitisand emphysema.

B. Causes. The principal risk factor for developmentof COPD is smoking. About 15% of smokersdevelop COPD.

C. Clinical clues to COPD include history of smokinggreater than 20 pack-years, older age at onset ofsymptoms (usually >60 years), a negative allergyhistory, no family history of asthma, and a slowlyprogressive rate of disease.

Classification of acute exacerbations of COPD

Type I One of three cardinal symptoms:1. Worsening dyspnea2. Increase in sputum purulence3. Increase in sputum volume and One of the following:Upper respiratory tract infection in the past 5 daysFever without other apparent causeIncreased wheezingIncreased coughIncrease in respiratory or heart rate by 20% above baseline

Type IITwo of three cardinal symptoms

Type IIIAll three cardinal symptoms

II. Diagnostic testingA. Pulse oximetry is an inexpensive, noninvasive

procedure for assessing oxygen saturation.B. Arterial blood gases. Both hypercarbia and

hypoxemia occur when pulmonary function falls tobelow 25-30% of the predicted normal value.

C. Pulmonary function testing is a useful means forassessing ventilatory function. Irreversible airflowlimitation, or the reduced ratio of forced expiratoryvolume in 1 second (FEV1) to forced vital capacity(FVC), is the hallmark of COPD. Emphysemamanifests as low carbon monoxide diffusion capac-ity with hyperinflation (increased total lung capac-ity) and increased residual volume. Peak-flowmeters are available that can provide a quickassessment of expiratory function.

D. Chest radiography will permit identification ofpatients with COPD with pneumonia,pneumothorax, and decompensated CHF.

E. An ECG may be useful in patients who have ahistory of chest pain, syncope, and palpitations.

F. Labs: Complete blood count (CBC) is useful inpatients with acute exacerbation of COPD if pneu-monia is suspected. The hematocrit is frequentlyelevated as a result of chronic hypoxemia.

III. Treatment

Stepwise treatment of chronic obstructive pul-monary disease

Indication Intervention

Known diagnosis Smoking cessation, vaccinationsNicotine replacement therapy orbupropion (Zyban)

Mild, intermittentsymptoms

Short-acting anticholinergic or beta2agonist prn

Regular symp-toms

Regular use of ipratropium (Atrovent),2-4 inhalations tid to qid prn, oralbuterol, 2-4 inhalations tid to qid prnThe ipratropium (Atrovent) inhalationdose is 500 mcg/2.5 mL solutionnebulized 3-4 times daily.

Symptoms con-tinue or are noc-turnal

Add salmeterol (Serevent), 25 micro-grams/dose, 2 inhalations bid. Not tobe used for rescue

Symptoms con-tinue

Sustained-release theophylline 400-800 mg/day. Low therapeuticlevel (ie, 55-85 micromoles/L)

Symptoms con-tinue

Fluticasone (Flovent), 2 puffs bid. Only if objective improvement after2-wk course of oral corticosteroids

Moderate to se-vere disease

Oxygen therapy 24 hr/day. If PO2<55 mm Hg or <60 mm Hg with evi-dence of cor pulmonale,polycythemia, or nocturnal orexertional desaturation

A. Bronchodilators improve the airway obstruction ofCOPD and decrease breathlessness. Short-actingbronchodilators include anticholinergic agents (eg,ipratropium bromide [Atrovent]) and beta2 agonists(eg, albuterol, terbutaline sulfate [Brethaire,Brethine, Bricanyl]).

B. While beta2 agonists are the bronchodilators ofchoice in asthma, elderly patients with COPD tendto have a greater response to anticholinergicdrugs. A combination of both agents has greaterbronchodilator benefit than single-agent therapy.COPD patients are likely to require larger doses ofbronchodilating drugs than are asthma patients. Atypical effective regimen is ipratropium, 4 puffsadministered with a spacer four times a day.

C. Longer-acting beta2 agonists (eg, formoterol[Foradil], salmeterol [Serevent]) may be of benefitto selected COPD patients.

D. A minority of the COPD population (10% to 20%)benefits from inhaled corticosteroids, as deter-mined by FEV1 response to a 2-week trial of oralprednisone, 0.5 mg/kg/day. Patients who respondshould be treated with fluticasone.1. Fluticasone (Flovent) 2 puffs bid; inhaler: 44,

110, 220 mcg/puff. Diskus inh: 50, 100, 250mcg.

2. Triamcinolone (Azmacort) MDI 2-4 puffs bid.3. Flunisolide (AeroBid, AeroBid-M) MDI 2-4

puffs bid. 4. Beclomethasone (Beclovent) MDI 2-4 puffs

bid.5. Budesonide (Pulmicort) MDI 2 puffs bid.

E. Theophylline is not widely used because of thepotential toxicity of the drug. However, theophyllinecan be effective at lower doses and serum levels of55 to 85 micromoles/L. It is most useful in symp-tomatic patients who have not responded well tothe first- and second-line agents. The dosage oflong-acting theophylline (Slo-bid, Theo-Dur) is 200-300 mg bid. Theophylline preparations with 24-hour action may be administered once a day in theearly evening. Theo-24, 100-400 mg qd [100, 200,300, 400 mg].

F. Pneumococcal and influenza vaccination arerecommended for all COPD patients. Both vac-cines can be given at the same time at differentsites.

G. Treatment of exacerbations1. Oxygen. Patients in respiratory distress should

receive supplemental oxygen therapy. Oxygentherapy usually is initiated by nasal cannula tomaintain an O2 saturation greater than 90%.Patients with hypercarbia may require controlledoxygen therapy using a Venturi mask.

2. Antibiotics are indicated when two of threetypical symptoms are present: (1) increasedsputum volume, (2) increased sputum puru-lence, and (3) increased dyspnea. Between 25%and 50% of exacerbations are caused by vi-ruses, and the remainder are caused by bacte-ria. The primary bacterial pathogens areHaemophilus influenzae, Streptococcuspneumoniae, and Moraxella catarrhalis.

3. Amoxicillin-resistant, beta-lactamase-pro-ducing H. influenzae are common.Azithromycin has an appropriate spectrum ofcoverage. Levofloxacin is advantageous whengram-negative bacteria or atypical organismspredominate. Amoxicillin-clavulanate has activityagainst beta-lactamase-producing H. influenzaeand M. catarrhalis.

4. Patients with severe underlying lung dis-ease. Use of second-line agents (ie, amoxicillinand clavulanate [Augmentin], ciprofloxacin[Cipro], azithromycin [Zithromax]) significantlyreduces the treatment failure rate and increasestime between exacerbations.

5. Seven to 10 days of antibiotic therapy should besufficient in the absence of pneumonia.

Choice of empirical antibiotic therapy for COPDexacerbation

First-line treatment Dosage*

Amoxicillin (Amoxil,Trimox, Wymox) 500 mg tid

Trimethoprim-sulfamethoxazole (Bactrim, Cotrim,Septra)

1 tablet (80/400 mg) bid

Doxycycline 100 mg bid

Erythromycin 250-500 mg qid

Second-line treatment**

Amoxicillin and clavulanate(Augmentin) 500-875 mg bid

Second- or third-generationcephalosporin (eg,cefuroxime [Ceftin])

250-500 mg bid

Macrolides

Clarithromycin (Biaxin) 250-500 mg bid

Azithromycin (Zithromax) 500 mg on day 1, then 250mg qd X 4 days

Quinolones

Ciprofloxacin (Cipro) 500-750 mg bid

Levofloxacin (Levaquin)*** 500 mg qd

*May need adjustment in patients with renal or hepaticinsufficiency. **For patients in whom first-line therapy has failed andthose with moderate to severe disease or resistant orgram-negative pathogens. ***Although the newer quinolones have better activityagainst Streptococcus pneumoniae, ciprofloxacin may bepreferable in patients with gram-negative organisms.

H. Methylprednisolone (Solumedrol), 125 mg IVevery 6 hours for 3 days, followed by prednisonetapered over 2 weeks results in a shortened hospi-tal stay (1 day) and lower rates of treatment failure.Prednisone at a dosage of 40 mg per day for 10days or less is recommended. Hyperglycemia isthe most common adverse effect associated withcor t icostero id adminis trat ion . Inhaledcorticosteroids are not beneficial in acute exacer-bations of COPD.

I. Management of acute respiratory failure1. Acute respiratory failure is manifested by an

arterial PO2 of less than 50 mm Hg while breath-ing room air or a PCO2 of more than 50 mm Hgwith a pH of less than 7.35, or both. Oxygen isthe cornerstone of therapy in hypoxemic pa-tients. Excessive supplemental oxygen mayresult in hypercapnia due to suppression of thehypoxic ventilatory drive.

2. Arterial blood gases should be monitored inpatients given supplemental oxygen for acuteexacerbation. Oxygen should be administeredby Venturi mask at a concentration of 24-28% orby nasal cannula at low flow rates (1 to 2 L/min)to achieve an arterial PO2 of 60 mm Hg with anoxygen saturation of 90-92%.

3. Indications for mechanical ventilation in patientswith exacerbations of COPD include laboredbreathing with respiratory rates of more than 30breaths per minute, moderate to severe respira-tory acidosis (pH <7.25-7.30), decreased levelof consciousness, respiratory arrest, and com-plicating comorbid conditions (eg, shock, sep-sis, metabolic abnormalities).

4. Noninvasive positive pressure ventilation(NIPPV), administered by tight-fitting mask, ishighly effective. NIPPV should not be used inpatients who have respiratory arrest, impairedmental status, or copious secretions or thosewho are at high risk for aspiration.

5. Invasive mechanical ventilation is indicated inpatients in whom NIPPV fails and in those withobtundation, an inability to clear copious secre-tions, life-threatening acidosis, or cardiovascularinstability.

J. Surgery. Lung volume reduction surgery restoreschest wall mechanics, improves lung elastic recoiland airflow, and improves oxygen levels. Trans-plantation may be considered when other thera-peutic options have been exhausted, the FEV1 isless than 25% of predicted.

K. Supplemental oxygen is recommended for

patients with either a resting PO2 of 55 mm Hg ora resting PO2 of less than 60 mm Hg and evidenceof cor pulmonale or polycythemia.


Acute BronchitisAcute bronchitis is one of the most common diagnosesin ambulatory care medicine, accounting for 2.5 millionphysician visits per year. This condition is one of the top10 diagnoses for which patients seek medical care.Acute bronchitis is one of the most common diagnosesmade by primary care physicians. Viruses are the mostcommon cause of acute bronchitis in otherwise healthyadults. Only a small portion of acute bronchitis infectionsare caused by nonviral agents, with the most commonorganisms being Mycoplasma pneumoniae andChlamydia pneumoniae.

I. DiagnosisA. The cough in acute bronchitis may produce either

clear or purulent sputum. This cough generally lastsseven to 10 days. Approximately 50 percent ofpatients with acute bronchitis have a cough thatlasts up to three weeks, and 25 percent of patientshave a cough that persists for over a month.

B. Physical examination. Wheezing, rhonchi, or aprolonged expiratory phase may be present.

C. Diagnostic studies1. The appearance of sputum is not predictive of

whether a bacterial infection is present. Purulentsputum is most often caused by viral infections.Microscopic examination or culture of sputumgenerally is not helpful. Since most cases ofacute bronchitis are caused by viruses, culturesare usually negative or exhibit normal respiratoryflora. M. pneumoniae or C. pneumoniae infectionare not detectable on routine sputum culture.

2. Acute bronchitis can cause transient pulmonaryfunction abnormalities which resemble asthma.Therefore, to diagnose asthma, changes thatpersist after the acute phase of the illness mustbe documented. When pneumonia is suspected,chest radiographs and pulse oximetry may behelpful.

II. Pathophysiology

Selected Triggers of Acute Bronchitis

Viruses: adenovirus, coronavirus, coxsackievirus,enterovirus, influenza virus, parainfluenza virus, respiratorysyncytial virus, rhinovirus Bacteria: Bordetella pertussis, Bordetella parapertussis,Branhamella catarrhalis, Haemophilus influenzae, Strepto-coccus pneumoniae, atypical bacteria (eg, Mycoplasma pneumoniae, Chlamydia pneumoniae,Legionella species) Yeast and fungi: Blastomyces dermatitidis, Candidaalbicans, Candida tropicalis, Coccidioides immitis,Cryptococcus neoformans, Histoplasma capsulatum Noninfectious triggers: asthma, air pollutants, ammonia,cannabis, tobacco, trace metals, others

A. Acute bronchitis is usually caused by a viral infec-tion. In patients younger than one year, respiratorysyncytial virus, parainfluenza virus, and coronavirusare the most common isolates. In patients one to10 years of age, parainfluenza virus, enterovirus,respiratory syncytial virus, and rhinovirus predomi-nate. In patients older than 10 years, influenzavirus, respiratory syncytial virus, and adenovirusare most frequent.

B. Parainfluenza virus, enterovirus, and rhinovirusinfections most commonly occur in the fall. Influ-enza virus, respiratory syncytial virus, andcoronavirus infections are most frequent in thewinter and spring.

III. Signs and symptomsA. Cough is the most commonly observed symptom of

acute bronchitis. The cough begins within two daysof infection in. Most patients have a cough for lessthan two weeks; however, 26 percent are stillcoughing after two weeks, and a few cough for sixto eight weeks.

B. Other signs and symptoms may include sputumproduction, dyspnea, wheezing, chest pain, fever,hoarseness, malaise, rhonchi, and rales. Sputummay be clear, white, yellow, green, or tinged withblood. Color alone should not be considered indica-tive of bacterial infection.

IV. Physical examination and diagnostic studiesA. The physical examination should focus on fever,

tachypnea, wheezing, rhonchi, and prolongedexpiration. Evidence of consolidation is absent.Fever may be present in some patients with acutebronchitis. However, high fever should prompt

consideration of pneumonia or influenza.B. Chest radiography should be reserved for patients

with possible pneumonia, heart failure, advancedage, chronic obstructive pulmonary disease, malig-nancy, tuberculosis, or immunocompromised ordebilitated status.

V.Differential diagnosisA. Acute bronchitis or pneumonia can present with

fever, constitutional symptoms and a productivecough. Patients with pneumonia often have rales.When pneumonia is suspected on the basis of thepresence of a high fever, constitutional symptomsor severe dyspnea, a chest radiograph should beobtained.

Differential Diagnosis of Acute Bronchitis

Diseaseprocess

Signs and symptoms

Asthma Evidence of reversible airway obstructioneven when not infected

Allergicaspergillosis

Transient pulmonary infiltrates Eosinophilia in sputum and peripheral bloodsmear

Occupa-tional expo-sures

Symptoms worse during the work week buttend to improve during weekends, holidaysand vacations

Chronicbronchitis

Chronic cough with sputum production on adaily basis for a minimum of three months Typically occurs in smokers

Sinusitis Tenderness over the sinuses, postnasaldrainage

Commoncold

Upper airway inflammation and no evidenceof bronchial wheezing

Pneumonia Evidence of infiltrate on the chest radio-graph

Congestiveheart failure

Basilar rales, orthopnea Cardiomegaly Evidence of increased interstitial or alveolarfluid on the chest radiograph S3 gallop, tachycardia

Refluxesophagitis

Intermittent symptoms worse when lyingdown Heartburn

Bronchogenic tumor

Constitutional signs often present Cough chronic, sometimes with hemoptysis

Aspirationsyndromes

Usually related to a precipitating event, suchas smoke inhalation Vomiting Decreased level of consciousness

B. Asthma should be considered in patients withrepetitive episodes of acute bronchitis. Patientswho repeatedly present with cough and wheezingcan be given spirometric testing withbronchodilation to help differentiate asthma fromrecurrent bronchitis.

C. Congestive heart failure may cause cough,shortness of breath and wheezing in older patients.Reflux esophagitis with chronic aspiration cancause bronchial inflammation with cough andwheezing. Bronchogenic tumors may produce acough and obstructive symptoms.

VI. Treatment A. Protussives and antitussives

1. Because acute bronchitis is most often causedby a viral infection, usually only symptomatictreatment is required. Treatment can focus onpreventing or controlling the cough (antitussivetherapy).

2. Antitussive therapy is indicated if cough is creat-ing significant discomfort. Studies have reportedsuccess rates ranging from 68 to 98 percent.Nonspecific antitussives, such as hydrocodone(Hycodan), dextromethorphan (Delsym), codeine(Robitussin A-C), carbetapentane (Rynatuss),and benzonatate (Tessalon), simply suppresscough.

Selected Nonspecific Antitussive Agents

Preparation Dosage Side effects

Hydromorphone-guaifenesin(Hycotuss)

5 mg per 100mg per 5 mL(one teaspoon)

Sedation, nau-sea, vomiting,respiratory de-pression

Dextromethorphan (Delsym)

30 mg every 12hours

Rarely, gastroin-testinal upset orsedation

Hydrocodone(Hycodan syrupor tablets)

5 mg every 4 to6 hours

Gastrointestinalupset, nausea,drowsiness,constipation

Codeine(Robitussin A-C)

10 to 20 mg ev-ery 4 to 6 hours

Gastrointestinalupset, nausea,drowsiness,constipation

Carbetapentane(Rynatuss)

60 to 120 mgevery 12 hours

Drowsiness,gastrointestinalupset

Benzonatate(Tessalon)

100 to 200 mgthree times daily

Hypersensitivity,gastrointestinalupset, sedation

B. Bronchodilators. Patients with acute bronchitis

who used an albuterol metered-dose inhaler areless likely to be coughing at one week, comparedwith those who received placebo.

C. Antibiotics. Physicians often treat acute bronchitiswith antibiotics, even though scant evidence existsthat antibiotics offer any significant advantage overplacebo. Antibiotic therapy is beneficial in patientswith exacerbations of chronic bronchitis.

Oral Antibiotic Regimens for Bronchitis

Drug Recommended regimen

Azithromycin (Zithromax) 500 mg; then 250 mg qd

Erythromycin 250-500 mg q6h

Clarithromycin (Biaxin) 500 mg bid

Levofloxacin (Levaquin) 500 mg qd

Trovafloxacin (Trovan) 200 mg qd

Trimethoprim/sulfamethoxazole (Bactrim, Septra)

1 DS tablet bid

Doxycycline 100 mg bid

D. Bronchodilators. Significant relief of symptomsoccurs with inhaled albuterol (two puffs four timesdaily). When productive cough and wheezing arepresent, bronchodilator therapy may be useful.


Infectious Disorders

PneumoniaCommunity-acquired pneumonia is the leading infectiouscause of death and is the sixth-leading cause of deathoverall.

I. Clinical diagnosisA. Symptoms of pneumonia may include fever, chills,

malaise and cough. Patients also may have pleu-risy, dyspnea, or hemoptysis. Eighty percent ofpatients are febrile.

B. Physical exam findings may include tachypnea,tachycardia, rales, rhonchi, bronchial breathsounds, and dullness to percussion over the in-volved area of lung.

C. Chest radiograph usually shows infiltrates. Thechest radiograph may reveal multilobar infiltrates,volume loss, or pleural effusion. The chest radio-graph may be negative very early in the illnessbecause of dehydration or severe neutropenia.

D. Additional testing may include a complete bloodcount, pulse oximetry or arterial blood gas analysis.

II. Laboratory evaluationA. Sputum for Gram stain and culture should be

obtained in hospitalized patients. In a patient whohas had no prior antibiotic therapy, a high-qualityspecimen (>25 white blood cells and <5 epithelialcells/hpf) may help to direct initial therapy.

B. Blood cultures are positive in 11% of cases, andcultures may identify a specific etiologic agent.

C. Serologic testing for HIV is recommended inhospitalized patients between the ages of 15 and54 years. Urine antigen testing for legionella isindicated in endemic areas for patients with seriouspneumonia.

III. Indications for hospitalizationA. Age >65yearsB. Unstable vital signs (heart rate >140 beats per

minute, systolic blood pressure <90 mm Hg, respi-ratory rate >30 beats per minute)

C. Altered mental statusD. Hypoxemia (PO2 <60 mm Hg)E. Severe underlying disease (lung disease, diabetes

mellitus, liver disease, heart failure, renal failure)F. Immune compromise (HIV infection, cancer,

corticosteroid use)G. Complicated pneumonia (extrapulmonary infection,

meningitis, cavitation, multilobar involvement,sepsis, abscess, empyema, pleural effusion)

H. Severe electrolyte, hematologic or metabolicabnormality (ie, sodium <130 mEq/L, hematocrit<30%, absolute neutrophil count <1,000/mm3,serum creatinine > 2.5 mg/dL)

I. Failure to respond to outpatient treatment within 48to 72 hours.

Pathogens Causing Community-AcquiredPneumonia

More Common Less Common

Streptococcus pneumoniaeHaemophilus influenzaeMoraxella catarrhalisMycoplasma pneumoniaeChlamydia pneumoniaeLegionella speciesVirusesAnaerobes (especially withaspiration)

Staphylococcus aureusGram-negative bacilliPneumocystis cariniiMycobacterium tuberculo-sis

IV. Treatment of community-acquired pneumonia

Recommended Empiric Drug Therapy for Pa-tients with Community-Acquired Pneumonia

Clinical Situa-tion

PrimaryTreatment

Alternative(s)

Younger (<60yr) outpatientswithout under-lying disease

Macrolide anti-biotics(azithromycin,clarithromycin,dirithromycin,orerythromycin)

Levofloxacin ordoxycycline

Clinical Situa-tion

PrimaryTreatment

Alternative(s)

Older (>60 yr)outpatientswith underlyingdisease

Levofloxacinor cefuroximeorTrimethoprim-sulfa-methoxazoleAddvancomycin insevere, life-threateningpneumonias

Beta-lactamaseinhibitor (withmacrolide iflegionella infectionsuspected)

Gross aspira-tion suspected

Clindamycin IV Cefotetan,ampicillin/sulbactam

A. Younger, otherwise healthy outpatients1. The most commonly identified organisms in this

group are S pneumoniae, M pneumoniae, Cpneumoniae, and respiratory viruses.

2. Erythromycin has excellent activity against mostof the causal organisms in this group except Hinfluenzae.

3. The newer macrolides, active against Hinfluenzae (azithromycin [Zithromax] andclarithromycin [Biaxin]), are effective as empiri-cal monotherapy for younger adults withoutunderlying disease.

B. Older outpatients with underlying disease1. The most common pathogens in this group are

S pneumoniae, H influenzae, respiratory viruses,aerobic gram-negative bacilli, and S aureus.Agents such as M pneumoniae and Cpneumoniae are not usually found in this group.Pseudomonas aeruginosa is rarely identified.

2. A second-generation cephalosporin (eg,cefuroxime [Ceftin]) is recommended for initialempi r ica l t rea tment . T r imethopr im-sulfamethoxazole is an inexpensive alternativewhere pneumococcal resistance to not preva-lent.

3. When legionella infection is suspected, initialtherapy should include treatment with amacrolide antibiotic in addition to a beta-lactam/beta-lactamase inhibitor (amoxicillinclavulanate).

C. Moderately ill, hospitalized patients1. In addition to S pneumoniae and H influenzae,

more virulent pathogens, such as S aureus,Legionella species, aerobic gram-negative bacilli(including P aeruginosa, and anaerobes), shouldbe considered in patients requiring hospitaliza-tion.

2. Hospitalized patients should receive an intrave-nous cephalosporin active against Spneumoniae and anaerobes (eg, cefuroxime,ceftriaxone [Rocephin], cefotaxime [Claforan]),or a beta-lactam/beta-lactamase inhibitor.

3. Nosocomial pneumonia should be suspectedin patients with recent hospitalization or nursinghome status. Nosocomial pneumonia is mostcommonly caused by Pseudomonas or Staphaureus. Empiric therapy should consist ofvancomycin and double pseudomonal coveragewith a beta-lactam (cefepime, Zosyn, imipenem,ticarcillin, ceftazidime, cefoperazone) and anaminoglycoside (amikacin, gentamicin,tobramycin) or a quinolone (ciprofloxacin).

4. When legionella is suspected (in endemic areas,cardiopulmonary disease, immune compromise),a macrolide should be added to the regimen. Iflegionella pneumonia is confirmed, rifampin(Rifadin) should be added to the macrolide.

Common Antimicrobial Agents for Community-Acquired Pneumonia in Adults

Type Agent Dosage

Oral therapy

Macrolides ErythromycinClarithromycin(Biaxin)Azithromycin(Zithromax)

500 mg PO qid500 mg PO bid500 mg PO onday 1, then 250mg qd x 4 days

Beta-lactam/beta-lactamaseinhibitor

Amoxicillin-clavulanate(Augmentin)Augmentin XR

500 mg tid or 875mg PO bid

2 tabs q12h

Quinolones Ciprofloxacin(Cipro)Levofloxacin(Levaquin)Ofloxacin (Floxin)

500 mg PO bid500 mg PO qd400 mg PO bid

Type Agent Dosage

Tetracycline Doxycycline 100 m g PO bid

Sulfonamide Trimethoprim-sulfamethoxazole

160 mg/800 mg(DS) PO bid

Intravenous Therapy

Cephalosporins

Second-generation

Third-gen-eration(anti-Pseu-domonasaeruginosa)

Cefuroxime(Kefurox,Zinacef)Ceftizoxime(Cefizox)Ceftazidime(Fortaz)Cefoperazone(Cefobid)

0.75-1.5 g IV q8h

1-2 g IV q8h1-2 g IV q8h1-2 g IV q8h

Beta-lactam/beta-lactamaseinhibitors

Ampicillin-sulbactam(Unasyn)Piperacillin/tazobactam (Zosyn)Ticarcillin-clavulanate(Timentin)

1.5 g IV q6h

3.375 g IV q6h

3.1 g IV q6h

Quinolones Ciprofloxacin(Cipro)Levofloxacin(Levaquin)Ofloxacin (Floxin)

400 mg IV q12h500 mg IV q24h400 mg IV q12h

Aminoglycosides

GentamicinAmikacin

Load 2.0 mg/kgIV, then 1.5mg/kg q8h

Vancomycin Vancomycin 1 gm IV q12h

D. Critically ill patients1. S pneumoniae and Legionella species are the

most commonly isolated pathogens, and aero-bic gram-negative bacilli are identified withincreasing frequency. M pneumoniae, respira-tory viruses, and H influenzae are less com-monly identified.

2. Erythromycin should be used along with anantipseudomonal agent (ceftazidime,imipenem-cilastatin [Primaxin], or ciprofloxacin[Cipro]). An aminoglycoside should be addedfor additional antipseudomonal activity untilculture results are known.

3. Severe life-threatening community-acquiredpneumonias should be treated withvancomycin empirically until culture results areknown. Twenty-five percent of S. pneumoniaeisolates are no longer susceptible to penicillin,and 9% are no longer susceptible to extended-spectrum cephalosporins.

4. Pneumonia caused by penicillin-resistantstrains of S. pneumoniae should be treatedwith high-dose penicillin G (2-3 MU IV q4h), orcefotaxime (2 gm IV q8h), or ceftriaxone (2 gmIV q12h), or meropenem (Merrem) (500-1000mg IV q8h), or vancomycin (Vancocin) (1 gm IVq12h).

5. H. influenzae and Moraxella catarrhalis oftenproduce beta-lactamase enzymes, makingthese organisms resistant to penicillin andampicillin. Infection with these pathogens istreated with a second-generation cephalo-sporin, beta-lactam/beta-lactamase inhibitorcombination such as amoxicillin-clavulanate,azithromycin, or trimethoprim-sulfameth-oxazole.

6. Most bacterial infections can be adequatelytreated with 10-14 days of antibiotic therapy. Ashorter treatment course of 3-5 days is possi-ble with azithromycin because of its long half-life. M pneumoniae and C pneumoniae infec-tions require treatment for up to 14 days.Legionella infections should be treated for aminimum of 14 days; immunocompromisedpatients require 21 days of therapy.


TuberculosisBeginning in 1986, an unexpected resurgence of tuber-culosis occurred in the United States, with the incidenceof the disease rising to 10.5 cases per 100,000 popula-tion.

I. Screening for Tuberculosis

A. Tuberculin testing generally should be performed inpersons who belong to at least one of the high-riskgroups. Screening should be performed using theMantoux test (intracutaneous tuberculin test).

B. Purified protein derivative (PPD) tuberculin 0.1 mL(5 units) injected intracutaneously, raising a wheal6 to 10 mm in diameter. After 48 to 72 hours, thetest should be “read.”

II. Treatment of Latent Tuberculosis InfectionA. Before initiating treatment of latent tuberculosis

infection, physicians must ensure that active dis-ease is not present.

B. The usual dosage of isoniazid is 5 mg per kg perday to a maximum of 300 mg per day. Anine-month regimen is recommended. Atwice-weekly dosing regimen is acceptable whencompliance is in question, but isoniazid should beadministered only as directly observed therapy.

C. A nine-month course of isoniazid is recommendedin children. To reduce the risk of drug-relatedperipheral neuropathy with isoniazid therapy,pyridoxine (Hexa-Betalin), in a dosage of 10 to 50mg per day, is coadministered in all children sixyears of age and older. Pyridoxine should also bestrongly considered in patients who have conditionsin which neuropathy is common (eg, diabetes,alcoholism and malnutrition), pregnant women andpatients who are also taking anticonvulsant drugs.

Groups at High Risk for Tuberculosis

Persons with recent Mycobacterium tuberculosis infection(within the past 2 years) or a history of inadequatelytreated tuberculosis

Close contacts of persons known or suspected to havetuberculosis

Persons infected with the human immunodeficiency virusPersons who inject illicit drugs or use other locally identified

high-risk substances (eg crack cocaine)Residents and employees of high-risk congregate settings

(eg correctional institutions, nursing homes, mentalinstitutions or shelters for the homeless)

Health-care workers who serve high-risk clientsForeign-born persons including children who have recently

arrived (within 5 years) from countries that have a highincidence or prevalence of tuberculosis (Africa Asiaand Latin America)

Some medically underserved low-income populationsHigh-risk racial or ethnic minority populations as definedlocallyElderly personsChildren less than 4 years of age or infants children and

adolescents who have been exposed to adults inhigh-risk categories

Persons with medical conditions known to increase the riskof tuberculosis: Chest radiograph findings suggestive of previous tu-

berculosis in a person who received inadequatetreatment or no treatment

Diabetes mellitusSilicosisOrgan transplantationProlonged corticosteroid therapy (eg prednisone in a

15 mg or more per day for 1 monthOther immunosuppressive therapyCancer of the head and neckHematologic and reticuloendothelial diseases (eg leu-

kemia and lymphoma)End-stage renal diseaseIntestinal bypass or gastrectomyChronic malabsorption syndromesWeight that is 10 percent or more below ideal body

weight

Interpretation of the Purified Protein DerivativeTuberculin Skin Test

I. An induration of 5 mm or more is classified as positivein persons with any of the following:

A. Human immunodeficiency virus infectionB. Recent close contact with persons who have

active tuberculosisC. Chest radiographs showing fibrosis (consistent

with healed tuberculosis) II. An induration of 10 mm or more is classified as positive

in all persons who do not meet any of the criteria insection I but have other risk factors for tuberculosis

III. An induration of 15 mm or more is positive in personswho do not meet any of the criteria from sections I or II.

IV. Recent tuberculin skin test conversion is defined as anincrease in induration of 10 mm or more within atwo-year period, regardless of age.

V. In health-care workers, the recommendations in sec-tions I, II and III generally should be followed. In facili-ties where tuberculosis patients frequently receive care,the optimal cut-off point for health-care workers with noother risk factors may be an induration of 10 mm orgreater.

D. Monthly clinical assessments are mandatory inpatients taking isoniazid for latent tuberculosis. Ateach monthly visit, patients should be evaluatedfor hepatitis, anemia and neurotoxicity.

E. Measuring baseline liver enzyme levels before theinitiation of isoniazid therapy is recommended onlyin patients with pregnancy, postpartum status,human immunodeficiency virus infection, alcohol-ism or chronic hepatitis.

F. Isoniazid should be discontinued if transaminaselevels are more than three times higher than theupper limit of normal in symptomatic patients orfive times higher than the upper limit of normal inasymptomatic patients.

G. Regimens for patients exposed tomultidrug-resistant tuberculosis generally consistof two drugs to which the infecting organism islikely to be susceptible.

III. Diagnosis of Active TuberculosisA. Symptoms of pulmonary tuberculosis, particularly

reactivation disease, include cough, fever, sweats,chills, anorexia, weight loss and malaise. Signs ofactive disease included upper-zone disease onthe chest radiograph, fever, night sweats andweight loss, along with a CD4 count of less than200 cells per mm3 in HIV-infected patients.

B. Extrapulmonary tuberculosis may be associatedwith altered mental status (central nervous systeminvolvement), back pain (spinal disease) andabdominal pain (peritoneal disease). The mostcommon types of extrapulmonary tuberculosis arepleural, lymphatic, bone and joint disease, genito-urinary tract and miliary disease, meningitis andperitonitis.

C. Although a PPD test should always be performed,it may be negative in 10 to 25 percent of patientswith active disease.

D. When pulmonary tuberculosis is suspected, chestradiographs should be obtained. In primary pulmo-nary tuberculosis, numerous abnormalities can beobserved, including atelectasis, parenchymalconsolidation, lymphadenopathy, pleural effusionand a miliary pattern. Any lung lobe may be af-fected, although lower-lobe involvement may besomewhat more common. In contrast, reactivationtuberculosis has a predilection for upper-lobeinvolvement, and cavitation occurs in approxi-mately 50 percent of patients.

E. In all patients with suspected active disease, threesputum samples for mycobacterial acid-fast stainexamination and Mycobacterium tuberculosiscultures should be collected on each of threeconsecutive days. Acid-fast smears are usuallycomplete within 24 hours.

IV. Treatment of Active TuberculosisA. A four-drug regimen should be initiated in all

adults with confirmed or suspected active tubercu-losis, and pyridoxine in a dosage of 50 mg per dayshould be administered with regimens containingisoniazid to help prevent neurotoxicity.

B. After two months of a four-drug regimen to whichthe initial isolates were sensitive, patients continuetreatment with isoniazid and rifampin alone ifrepeat sputum cultures are negative and thepatient has improved clinically. Patients continuethis dual regimen for another four months, atwhich time treatment may be discontinued ifsputum cultures remain negative. Monthly evalua-tions, including sputum acid-fast smears andcultures, should be performed throughout treat-ment.

Treatment of Active Tuberculosis: First-LineMedications

Drug Dailydosing

Twice-weekly dos-ing

Thrice-weeklydosing

Adversereac-tions

Isoniazid (INH)

Children:10 mgper kgPO or IMAdults:300 mgPO or IMMax: 300mg Chil-dren: 20-40 mg/kgPO/IM

Adults: 15mg per kgPO or IMMaxi-mum: 300mg Chil-dren: 20to 40 mgper kg POor IM

Adults:15 mgper kgPO or IMMaxi-mum:300 mg

Elevationofhepaticenzymelevels,hepatitis,neuropa-thy, cen-tral ner-vous sys-tem ef-fects

Rifampin(Rifadin)

Children:10 to 20mg perkg PO orIVAdults:10 mgper kgPO or IVMaxi-mum:600 mgChildren:10 to 20mg perkg PO orIV

Adults: 10mg per kgPO or IVMaxi-mum: 600mg Chil-dren: 10to 20 mgper kg POor IV

Adults:10 mgper kgPO or IVMaxi-mum:600 mg

Orangediscolor-ation ofsecre-tions andurine,gastroin-testinaltract up-set, hep-atitis,bleedingprob-lems,flu-likesymp-toms,drug in-teractions, rash

Pyrazinamide

Children:20 to 30mg perkg POAdults:25 mgper kgPO

Maxi-mum: 2 gChildren:50 to 70mg per kgPOAdults: 50to 70 mgper kg PO

Maxi-mum: 4 gChildren:50 to 70mg perkg POAdults:50 to 70mg perkg PO Maxi-mum: 3 g

Gastroin-testinaltract up-set, hep-atitis,hyperuricemia,arthralgias

Ethambutol(Myambutol)

Childrenandadults:15 to 25mg perkg PO

Childrenandadults: 50mg per kgPO

Childrenandadults:25 to 30mg perkg PO

Opticneuritis

Preferred Initial Treatment of Children andAdults

Option 1(dailytreat-ment)

Administer isoniazid (INH), rifampin (Rifadin),pyrazinamide and ethambutol (Myambutol)daily for 2 months; then administer isoniazidand rifampin daily or two to three times aweek (only by directly observed therapy) forsusceptible isolates.

Option 2(twice-weeklytreat-ment)

Administer isoniazid, rifampin, pyrazinamideand ethambutol daily for 2 weeks; then ad-minister the same drugs two times a week for6 weeks (only by directly observed therapy);subsequently administer isoniazid andrifampin two times a week for 4 months (onlyby directly observed therapy) for susceptibleisolates.

Option 3(thrice-weeklytreat-ment)

Administer isoniazid, rifampin, pyrazinamideand ethambutol three times a week for 6months (only by directly observed therapy).

Selected Regimens for Single-Drug Resistance

Drug to whichinfection is re-sistant

Treatment regi-men

Duration of ther-apy

Isoniazid (INH) RifampinEthambutolPyrazinamide

6 to 9 months

Rifampin (Rifadin) IsoniazidEthambutol

18 months

Ethambutol(Myambutol),pyrazinamide orstreptomycin

IsoniazidRifampin

6 to 9 months


TonsillopharyngitisIn about a quarter of patients with a sore throat, thedisorder is caused by group A beta-hemolytic streptococ-cus. Treatment of streptococcal tonsillopharyngitisreduces the occurrence of subsequent rheumatic fever,an inflammatory disease that affects the joints and heart,skin, central nervous system, and subcutaneous tissues.

I. Prevalence of pharyngitisA. Group A beta-hemolytic streptococcus (GABHS)

typically occurs in patients 5-11 years of age, andit is uncommon in children under 3 years old. Mostcases of GABHS occur in late winter and earlyspring.

B. Etiologic causes of sore throat1. Viral. Rhinoviruses, influenza, Epstein-Barr

virus2. Bacterial. GABHS (Streptococcus pyogenes),

Streptococcus pneumoniae, Haemophilusinfluenzae, Moraxella catarrhalis, Staphylococ-cus aureus, anaerobes, Mycoplasmapneumoniae, Candida albicans.

C. In patients who present with pharyngitis, the majorgoal is to detect GABHS infection because rheu-matic fever may result. Severe GABHS infectionsmay also cause a toxic-shock-like illness (toxicstrep syndrome), bacteremia, streptococcal deeptissue infections (necrotizing fascitis), and strepto-coccal cellulitis.

II. Clinical evaluation of sore throatA. GABHS infection is characterized by sudden onset

of sore throat, fever and tender swollen anteriorcervical lymph nodes, typically in a child 5-11years of age. Headache, nausea and vomiting mayoccur.

B. Cough, rhinorrhea and hoarseness are generallyabsent.

III. Physical examinationA. Streptococcal infection is suggested by erythema

and swelling of the pharynx, enlarged anderythematous tonsils, tonsillar exudate, or palatalpetechiae. The clinical diagnosis of GABHS infec-tion is correct in only 50-75% of cases when basedon clinical criteria alone.

B. Unilateral inflammation and swelling of the pharynxsuggests peritonsillar abscess. Distortion of theposterior pharyngeal wall suggests aretropharyngeal abscess. Corynebacteriumdiphtheriae is indicated by a dull membrane whichbleeds on manipulation. Viral infections may causeoral vesicular eruptions.

C. The tympanic membranes should be examined forerythema or a middle ear effusion.

D. The lungs should be auscultated because viralinfection occasionally causes pneumonia.

IV.Diagnostic testingA. Rapid streptococcal testing has a specificity of

90% and a sensitivity of 80%. A dry swab shouldbe used to sample both the posterior wall and thetonsillar fossae, especially erythematous orexudative areas.

B. Throat culture is the most accurate test availablefor the diagnosis of GABHS pharyngitis.

C. Diagnostic approach1. Patients presenting with an acute episode of

pharyngitis should receive a rapid streptococcalantigen test. If the rapid test is negative, aculture should be done.

2. If the rapid test is positive, treatment with anantibiotic should be initiated for 10 days. Thepresence of physical and historical findingssuggesting GABHS infection may also promptthe initiation of antibiotic therapy despite anegative rapid strep test.

3. After throat culture, presumptive therapy shouldbe initiated. If the culture is positive for GABHS,a 10-day course of therapy should be com-pleted. If the culture is negative, antibiotics maybe discontinued.

V. Antibiotic therapyA. Starting antibiotic therapy within the first 24-48

hours of illness decreases the duration of sorethroat, fever and adenopathy by 12-24 hours.Treatment also minimizes risk of transmission andof rheumatic fever.

B. Penicillin VK is the antibiotic of choice forGABHS; 250 mg PO qid or 500 mg PO bid x 10days [250, 500 mg]. A 10-day regimen is recom-mended. Penicillin G benzathine (Bicillin LA) maybe used as one-time therapy when compliance isa concern; 1.2 million units IM x 1 dose.

C. Azithromycin (Zithromax) offers the advantage ofonce-a-day dosing for just 5 days; 500 mg x 1,then 250 mg qd x 4 days [6 pack].

D. Clarithromycin (Biaxin), 500 mg PO bid; bacteri-ologic efficacy is similar to that of penicillin VK, andit may be taken twice a day.

E. Erythromycin is also effective; 250 mg PO qid; orenteric coated delayed release tablet (PCE) 333mg PO tid or 500 mg PO bid [250, 333, 500 mg].Erythromycin ethyl succinate (EES) 400 PO qidor 800 mg PO bid [400 mg]. Gastrointestinal upsetis common.

VI.Treatment of recurrent GABHS pharyngitisA. When patient compliance is an issue, an injection

of penicillin G benzathine may be appropriate.When patient compliance is not an issue, therapyshould be changed to a broader spectrum agent.1. Cephalexin (Keflex) 250-500 mg tid x 5 days

[250, 500 mg]2. Cefadroxil (Duricef) 500 mg bid x 5 days [500

mg]3. Loracarbef (Lorabid) 200-400 mg bid x 5 days

[200, 400 mg]4. Cefixime (Suprax) 400 mg qd x 5 days [200,

400 mg]5. Ceftibuten (Cedax) 400 mg qd x 5 days [400

mg]6. Cefuroxime axetil (Ceftin) 250-500 mg bid x 5

days [125, 250, 500 mg]B. Amoxicillin/clavulanate (Augmentin) has dem-

onstrated superior results in comparison with peni-cillin; 250-500 mg tid or 875 mg bid [250, 500, 875mg].

C. Sulfonamides, trimethoprim, and the tetracyclinesare not effective for the treatment of GABHSpharyngitis.


SinusitisSinusitis affects 12% of adults and complicates 0.5% ofviral upper respiratory infections. Symptoms that havebeen present for less than 1 month are indicative ofacute sinusitis, while symptoms of longer duration reflectchronic sinusitis.

I. PathophysiologyA. Factors that predispose to sinus infection include

anatomic abnormalities, viral URIs, allergies,overuse of topical decongestants, asthma, andimmune deficiencies.

B. Acute sinusitis is associated with the samebacteria as otitis media. Streptococcuspneumoniae, Haemophilus influenzae, and

Moraxella catarrhalis are the most commonlyencountered pathogens. Thirty-five percent of Hinfluenzae and 75% of M catarrhalis strains pro-duce beta-lactamases, making them resistant topenicillin antibiotics.

C. Chronic sinusitis is associated with Staphylococ-cus aureus and anaerobes.

II. Clinical evaluationA. Symptoms of acute sinusitis include facial pain or

tenderness, nasal congestion, purulent nasal andpostnasal discharge, headache, maxillary toothpain, malodorous breath, fever, and eye swelling.Pain or pressure in the cheeks and deep nasalrecesses is common.

B. If symptoms have lasted for less than 7 to 10 daysand the patient is recovering, a self-limited viralURI is the most likely cause. However, worseningsymptoms or symptoms that persist for more than7 days are more likely to be caused by sinusitis.

C. High fever and signs of acute toxicity are unusualexcept in the most severe cases. Purulent drain-age in the patient's nose or throat may sometimesbe seen.

D. The nasal mucosa is often erythematous andswollen. The presence of mucopus in the externalnares or posterior pharynx is highly suggestive ofsinusitis. Facial tenderness, elicited by percussion,is an unreliable sign of sinusitis.

III. Laboratory evaluationA. Imaging. Plain films are usually unnecessary for

evaluating acute sinusitis because of the high costand relative insensitivity.

B. CT scanning is useful if the diagnosis remainsuncertain or if orbital or intracranial complicationsare suspected. CT scanning is nonspecific andmay demonstrate sinus abnormalities in 87% ofpatients with colds.

C. MRI is useful when fungal infections or tumors area possibility.

D. Sinus aspiration is an invasive procedure, and isonly indicated for complicated sinusitis,immunocompromise, failure to respond to multiplecourses of empiric antibiotic therapy, or severesymptoms.

E. Cultures of nasal secretions correlate poorly withresults of sinus aspiration.

IV.Management of sinusitisA. Antibiotic therapy for sinusitis

1. First-line agentsa. Amoxicillin (Amoxil): Adults, 500 mg tid PO

for 14 days. Children, 40 mg/kg/d in 3 divideddoses.

b. Trimethoprim/sulfamethoxazole (Bactrim,Septra): Adults, 1 DS tab (160/800 mg) bid.Children, 8/40 mg/kg/d bid.

c. Erythromycin/sulfisoxazole (Pediazole):Children, 50/150 mg/kg/d qid.

2. A 10- to 14-day course of therapy is recom-mended; however, if the patient is improved butstill symptomatic at the end of the course, themedication should be continued for an addi-tional 5 to 7 days after symptoms subside.

3. Broader-spectrum agentsa. If the initial response to antibiotics is unsatis-

factory, beta-lactamase-producing bacteriaare likely to be present, and broad-spectrumtherapy is required.

b. Amoxicillin/clavulanate (Augmentin): adults,250 mg tid or 875 mg bid; children, 40mg/kg/d in 3 divided doses.

c. Amoxicillin/clavulanate extended-release(Augmentin XR), 1000 mg tabs; 2 tabs q12h

d. Azithromycin (Zithromax): 500 mg as a singledose on day 1, then 250 mg qd.

e. Clarithromycin (Biaxin): 500 mg bid.f. Cefuroxime axetil (Ceftin): adults, 250 mg

bid; children, 125 mg bid.g. Cefixime (Suprax): adults, 200 mg bid; chil-

dren, 8 mg/kg/d bid.h. Cefpodoxime (Vantin) 200 mg bidi. Cefprozil (Cefzil) 250-500 mg qd-bidj. Loracarbef (Lorabid) 400 mg bid.k. Levofloxacin (Levaquin) 500 mg qd.

4. Penicillin-resistant S. Pneumoniae result frombacterial alterations in penicillin-binding pro-teins. Highly resistant strains are resistant topenicillin, trimethoprim/sulfamethoxazole( T MP / S MX) , a n d t h i r d - g e n e r a t i o ncephalosporins. The prevalence of multiple-drugresistant S. pneumoniae is 20-35%. High doseamoxicillin (80 mg/kg/d), or amoxicillin plusamoxicillin/clavulanate, or clindamycin areoptions.

B. Chronic sinusitis is commonly caused by anaero-bic organisms. 3-4 weeks of therapy or longer isrequired.

C. Ancillary treatments1. Steam and saline improves drainage of mucus.

Spray saline (NaSal) or a bulb syringe with asaline solution (1 tsp of salt in 1 quart of warmwater) may be used.

2. Decongestantsa. Topical or systemic decongestants may be

used in acute or chronic sinusitis.Phenylephrine (Neo-Synephrine) oroxymetazoline (Afrin) nasal drops or spraysare commonly used.

b. Oral decongestants, such as phenylephrineor pseudoephedrine, are active in areas notreached by topical agents.


Infectious ConjunctivitisInfectious conjunctivitis is one of the most commoncauses of red eye. The clinical term "red eye" is appliedto a variety of infectious or inflammatory diseases of theeye. Conjunctivitis is most frequently caused by abacterial or viral infection. Sexually transmitted diseasessuch as chlamydial and gonorrhea are less commoncauses of conjunctivitis. Ocular allergy is a major causeof chronic conjunctivitis.

I. Clinical evaluation of conjunctivitisA. The history should establish whether the condition

is acute, subacute, chronic or recurrent, andwhether it is unilateral or bilateral.

B. Discharge1. Serous discharge (watery) is most commonly

associated with viral or allergic ocular conditions.2. Mucoid discharge (stringy or ropy) is highly

characteristic of allergy or dry eyes.3. Mucopurulent or purulent discharge, often

associated with morning crusting and difficultyopening the eyelids, strongly suggests a bacte-rial infection. The possibility of Neisseriagonorrhoeae infection should be consideredwhen the discharge is copiously purulent.

C. Itching is highly suggestive of allergic conjunctivitis.A history of recurrent itching or a personal or familyhistory of hay fever, allergic rhinitis, asthma oratopic dermatitis is also consistent with ocularallergy.

D. Bilateral conjunctivitis suggests allergic conjuncti-vitis. Unilateral conjunctivitis suggests infectionscaused by viruses and bacteria.

E. Pain and photophobia do not usually occur withconjunctivitis, and these findings suggest an ocularor orbital disease processes, including uveitis,keratitis, acute glaucoma or orbital cellulitis. Blurredvision is not characteristic of conjunctivitis and isindicative of corneal or intraocular pathology.

F. Recent contact with an individual with an upperrespiratory tract infection suggests adenoviralconjunctivitis. Chlamydial or gonococcal infectionmay be suggested by the sexual history, includinga history of urethral discharge.

Differential Diagnosis of Red Eye

ConjunctivitisInfectious

ViralBacterial (eg, staphy-lococcus, Chlamydia)

NoninfectiousAllergic conjunctivitisDry eyeToxic or chemical reactionContact lens useForeign bodyFactitious conjuncti-vitis

KeratitisInfectious. Bacterial,viral, fungalNoninfectious. Recur-rent epithelial erosion,foreign body

UveitisEpiscleritis/scleritisAcute glaucomaEyelid abnormalitiesOrbital disorders

Preseptal and orbital cellulitisIdiopathic orbital inflam-mation (pseudotumor)

II. Examination of the eyeA. Visual acuity should be tested before the examina-

tion. Regional lymphadenopathy should be soughtand the face and eyelids examined. Viral orchlamydial inclusion conjunctivitis typically presentswith a tender, preauricular or submandibular lymphnode. Palpable adenopathy is rare in acute bacte-rial conjunctivitis. Herpes labialis or a dermatomalvesicular eruption (shingles) is indicative of aherpetic conjunctivitis.

B. Purulent discharge suggests a bacterial infection.Stringy mucoid discharge suggests allergy. Clearwatery discharge suggests viral infection.

III.Cultures and Gram stain usually are not required inpatients with mild conjunctivitis of suspected viral,bacterial or allergic origin. However, bacterial cultures

should be obtained in patients who have severeconjunctivitis.

IV. Treatment of bacterial conjunctivitisA. Acute bacterial conjunctivitis typically presents with

burning, irritation, tearing and a mucopurulent orpurulent discharge. The three most common patho-gens in bacterial conjunctivitis are Streptococcuspneumoniae, Haemophilus influenzae and Staphy-lococcus aureus.

B. Topical broad-spectrum antibiotics such aserythromycin ointment and bacitracin-polymyxin Bointment as well as combination solutions such astrimethoprim-polymyxin B provide excellent cover-age for most pathogens. Ointments are bettertolerated by young children. Solutions are preferredby adults.1. Erythromycin ophthalmic ointment, apply to

affected eye(s) q3-4h.2. Bacitracin-polymyxin B (Polysporin) ophthal-

mic ointment or solution, apply to affected eye(s)q3-4h.

3. Trimethoprim-polymyxin B (Polytrim), oint-ment or solution, apply to affected eye(s) q3-4h.

C. Conjunctivitis due to H. influenzae, N.gonorrhoeae, and N. meningitidis requiressystemic antibiotic therapy in addition to topicaltreatment. Gonococcal conjunctivitis may be treatedwith ceftriaxone (Rocephin) 1 g IM and topicalerythromycin.

D. Chlamydial conjunctivitis can be present innewborns, sexually active teenagers, and adults.Diagnosis is by antibody staining of ocular samples.Treatment includes oral tetracycline, doxycycline(Vibramycin) or erythromycin for two weeks.

V. Viral conjunctivitisA. Adenovirus is the most common cause of viral

conjunctivitis. Viral conjunctivitis often occurs inepidemics, typically presenting with an acutely redeye, watery discharge, conjunctival swelling, atender preauricular node, photophobia and aforeign-body sensation. Some patients have anassociated upper respiratory tract infection.

B. Treatment consists of cold compresses and topicalvasoconstrictors (Vasocon-A, Naphcon-A). Patientsshould avoid direct contact with other persons for atleast one week after the onset of symptoms.

C. Ocular herpes simplex and herpes zoster ismanaged with topical agents, including trifluridine(Viroptic) and systemic acyclovir, famciclovir orvalacyclovir.


Bacterial MeningitisThe age group at greatest risk for acute bacterial menin-gitis (ABM) includes children between 1 and 24 monthsof age. Adults older than 60 years old account for 50% ofall deaths related to meningitis.

I. Clinical presentationA. Eighty-five percent of patients with bacterial menin-

gitis present with fever, headache, meningismus ornuchal rigidity, and altered mental status. Othercommon signs and symptoms includephotophobia, vomiting, back pain, myalgias,diaphoresis, and malaise. Generalized seizurescan occur in up to 40% of patients with ABM.

B. Kernig's sign (resistance to extension of the legwhile the hip is flexed) and Brudzinski's sign(involuntary flexion of the hip and knee when thepatient's neck is abruptly flexed while laying su-pine) are observed in up to 50% of patients.

C. About 50% of patients with N. meningitidis maypresent with an erythematous macular rash, whichprogresses to petechiae and purpura.

II. Patient evaluationA. Computerized tomography (CT). Patients who

require CT prior to LP include those with focalneurologic findings, papilledema, focal seizures, orabnormalities on exam that suggest increasedintracranial pressure. If bacterial meningitis is astrong consideration, and the decision is made toperform a CT prior to LP, two sets of blood cul-tures should be obtained and antibiotics should beadministered before sending the patient forneuroimaging. Urine cultures may be helpful in thevery young and very old.

B. Blood cultures followed by antibiotic administrationwithin 30 minutes of presentation is mandatory inall patients suspected of having bacterial meningi-tis.

C. Interpretation of lumbar puncture. Examinationof the CSF is mandatory for evaluation of meningi-tis.

D. CSF, Gram’s stain, and culture are positive in 70-

85% of patients with ABM.

Cerebrospinal Fluid Parameters in Meningitis

Nor-mal

Bac-terial

Viral

Fun-gal

TB

Para-men-ingealFo-cusorAb-scess

WBCcount(WBC/:L)

0-5 >1000

100-1000

100-500

100-500

10-1000

%PMN

0-15 90 <50

<50 <50

<50

%lymph

>50 >50

>80

Glu-cose(mg/dL)

45-65

<40 45-65

30-45

30-45

45-65

CSF:bloodglu-coseratio

0.6 <0.4 0.6

<0.4 <0.4

0.6

Pro-tein(mg/dL)

20-45

>150 50-100

100-500

100-500

>50

Openingpressure(cmH20)

6-20 >180mmH20

NLor+

>180mmH20

>180mmH20

N/A

E. If the CSF parameters are nondiagnostic, or thepatient has been treated with prior oral antibiotics,and, therefore, the Gram's stain and/or cultureare likely to be negative, then latex agglutination(LA) may be helpful. The test has a variablesensitivity rate, ranging between 50-100%, andhigh specificity. Latex agglutination tests areavailable for H. influenza, Streptococcuspneumoniae, N. meningitidis, Escherichia coli K1,and S. agalactiae (Group B strep). CSFCryptococcal antigen and India ink stain shouldbe considered in patients who have HIV diseaseor HIV risk factors.

III. Treatment of acute bacterial meningitis

Antibiotic Choice Based on Age and ComorbidMedical Illness

Age Organism Antibiotic

Neonate E. coli, Group Bstrep, Listeriamonocytogenes

Ampicillin andceftriaxone orcefotaxime

1-3 months S. pneumoniae,N. meningitidis,H. influenzae, S.agalactiae, Liste-ria, E. coli

Ceftriaxone orcefotaxime andvancomycin

3 months to18 years

N. meningitidis,S. pneumoniae,H. influenzae


18-50 years S. pneumoniae,N. meningitidis


Older than 50years

N. meningitidis,S. pneumoniae Gram-negativebacilli, Listeria,Group B strep

Ampicillin andceftriaxone orcefotaxime andvancomycin

Age Organism Antibiotic

Neurosur-gery/head in-jury

S. aureus, S.epidermidisDiphtheroids,Gram-negativebacilli

Vancomycin andCeftazidime

Immunosuppression

Listeria, Gram-negative bacilli,S. pneumoniae,N. meningitidis

Ampicillin andCeftazidime (con-sider addingVancomycin)

CSF shunt S. aureus, Gram-negative bacilli

Vancomycin andCeftazidime

Antibiotic Choice Based on Gram’s Stain

Stain Results Organism Antibiotic

Gram's (+)cocci

S. pneumoniaeS. aureus, S.agalactiae(Group B)

Vancomycin andceftriaxone orcefotaxime

Gram's (-)cocci

N. meningitidis Penicillin G orchloramphenicol

Gram's (-)coccobacilli

H. influenzae Third-generationcephalosporin

Gram's (+)bacilli

Listeriamonocytogenes

Ampicillin, Peni-cillin G + IVGentamicin ±intrathecalgentamicin

Gram's (-)bacilli

E. coli, KlebsiellaSerratia, Pseudo-monas

Ceftazidime +/-aminoglycoside

Recommended Dosages of Antibiotics

Antibiotic Dosage

Ampicillin 2 g IV q4h

Cefotaxime 2 g IV q4-6h

Ceftazidime 2 g IV q8h

Ceftriaxone 2 g IV q12h

Chloramphenicol 0.5-1.0 gm IV q6h

Gentamicin Load 2.0 mg/kg IV, then 1.5mg/kg q8h

Nafcillin/Oxacillin 2 g IV q4h

Penicillin G 4 million units IV q4h

Rifampin 600 mg PO q24h

Trimethoprim-sulfamethoxazole

15 mg/kg IV q6h

Vancomycin 1.0-1.5 g IV q12h

A. In areas characterized by high resistance topenicillin, vancomycin plus a third-generationcephalosporin should be the first-line therapy. H.influenzae is usually adequately covered by athird-generation cephalosporin. The drug ofchoice for N. meningitidis is penicillin orampicillin. Chloramphenicol should be used if thepatient is allergic to penicillin. Aztreonam may beused for gram-negative bacilli, and trimethoprim-sulfamethoxazole may be used for Listeria.

B. In patients who are at risk for Listeria meningitis,ampicillin must be added to the regimen. S.agalactiae (Group B) is covered by ampicillin, andadding an aminoglycoside provides synergy.Pseudomonas and other Gram-negative bacillishould be treated with a broad spectrum third-generation cephalosporin (ceftazidime) plus anaminoglycoside. S. aureus may be covered bynafcillin or oxacillin. High-dose vancomycin (peak35-40 mcg/mL) may be needed if the patient is atrisk for methicillin-resistant S. aureus.

C. Corticosteroids. Audiologic and neurologicalsequelae in infants older than two months of ageare markedly reduced by early administration ofdexamethasone in patients with H. influenzaemeningitis. Dexamethasone should be given at adose of 0.15 mg/kg q6h IV for 2-4 days to childrenwith suspected H. influenzae or pneumococcalmeningitis. The dose should be given just prior toor with the initiation of antibiotics.


SepsisAbout 400,000 cases of sepsis, 200,000 cases of septicshock, and 100,000 deaths from both occur each year.

I. Pathophysiology A. Sepsis is defined as the systemic response to

infection. In the absence of infection, it is calledsystemic inflammatory response syndrome and ischaracterized by at least two of the following:temperature greater than 38/C or less than 36/C;heart rate greater than 90 beats per minute; respi-ratory rate more than 20/minute or PaCO2 less than32 mm Hg; and an alteration in white blood cellcount (>12,000/mm3 or <4,000/mm3).

B. Septic shock is defined as sepsis-inducedhypotension that persists despite fluid resuscitationand is associated with tissue hypoperfusion.

C. The initial cardiovascular response to sepsisincludes decreased systemic vascular resistanceand depressed ventricular function. Low systemicvascular resistance occurs. If this initial cardiovas-cular response is uncompensated, generalizedtissue hypoperfusion results. Aggressive fluidresuscitation may improve cardiac output andsystemic blood pressure, resulting in the typicalhemodynamic pattern of septic shock (ie, highcardiac index and low systemic vascular resis-tance).

D. Although gram-negative bacteremia is commonlyfound in patients with sepsis, gram-positive infec-tion may affect 30-40% of patients. Fungal, viraland parasitic infections are usually encountered inimmunocompromised patients.

Defining sepsis and related disorders

Term Definition

Systemicinflammatoryresponse syn-drome (SIRS)

The systemic inflammatory response toa severe clinical insult manifested by >2of the following conditions: Temperature>38°C or <36°C, heart rate >90beats/min, respiratory rate >20breaths/min or PaCO2 <32 mm Hg,white blood cell count >12,000cells/mm3 , <4000 cells/mm3 , or >10%band cells

Sepsis The presence of SIRS caused by aninfectious process; sepsis is consideredsevere if hypotension or systemic mani-festations of hypoperfusion (lactic acido-sis, oliguria, change in mental status) ispresent.

Septic shock Sepsis-induced hypotension despiteadequate fluid resuscitation, along withthe presence of perfusion abnormalitiesthat may induce lactic acidosis, oliguria,or an alteration in mental status.

Multiple organdysfunctionsyndrome(MODS)

The presence of altered organ functionin an acutely ill patient such that homeo-stasis cannot be maintained without in-tervention

E. Sources of bacteremia leading to sepsis includethe urinary, respiratory and GI tracts, and skin andsoft tissues (including catheter sites). The sourceof bacteremia is unknown in 30% of patients.

F. Escherichia coli is the most frequently encounteredgram-negative organism, followed by Klebsiella,Enterobacter, Serratia, Pseudomonas, Proteus,Providencia, and Bacteroides species. Up to 16%of sepsis cases are polymicrobic.

G. Gram-positive organisms, including Staphylococ-cus aureus and Staphylococcus epidermidis, areassociated with catheter or line-related infections.

II. DiagnosisA. A patient who is hypotensive and in shock should

be evaluated to identify the site of infection, andmonitor for end-organ dysfunction. History shouldbe obtained and a physical examination per-formed.

B. The early phases of septic shock may produceevidence of volume depletion, such as dry mucousmembranes, and cool, clammy skin. After resusci-tation with fluids, however, the clinical pictureresembles hyperdynamic shock, including tachy-cardia, bounding pulses with a widened pulsepressure, a hyperdynamic precordium on palpa-tion, and warm extremities.

C. Signs of infection include fever, localized ery-thema or tenderness, consolidation on chestexamination, abdominal tenderness, andmeningismus. Signs of end-organ hypoperfusioninclude tachypnea, oliguria, cyanosis, mottling ofthe skin, digital ischemia, abdominal tenderness,and altered mental status.

D. Laboratory studies should include of arterialblood gases, lactic acid level, electrolytes, renalfunction, liver enzyme levels, and chest radio-graph. Cultures of blood, urine, and sputum shouldbe obtained before antibiotics are administered.Cultures of pleural, peritoneal, and cerebrospinalfluid may be appropriate. If thrombocytopenia orbleeding is present, tests for disseminatedintravascular coagulation should includefibrinogen, d-dimer assay, platelet count, periph-eral smear for schistocytes, prothrombin time, andpartial thromboplastin time.

Manifestations of Sepsis

Clinical featuresTemperature instabilityTachypneaHyperventilationAltered mental statusOliguriaTachycardiaPeripheral vasodilation

Laboratory findingsRespiratory alkalosesHypoxemiaIncreased serum lactatelevelsLeukocytosis and in-creased neutrophil concen-trationEosinopeniaThrombocytopeniaAnemiaProteinuriaMildly elevated serum bili-rubin levels

III. Treatment of septic shockA. Early management of septic shock is aimed at

restoring mean arterial pressure to 65 to 75 mmHg to improve organ perfusion. Clinical clues toadequate tissue perfusion include skin tempera-

ture, mental status, and urine output. Urine outputshould be maintained at >20 to 30 mL/hr. Lacticacid levels should decrease within 24 hours iftherapy is effective.

B. Intravenous access and monitoring1. Intravenous access is most rapidly obtained

through peripheral sites with two 16- to18-gauge catheters. More stable access can beachieved later with central intravenous access.Placement of a large-bore introducer catheter inthe right internal jugular or left subclavian veinallows the most rapid rate of infusion.

2. Arterial lines should be placed to allow for morereliable monitoring of blood pressure. Pulmo-nary artery catheters measure cardiac output,systemic vascular resistance, pulmonary arterywedge pressure, and mixed venous oxygensaturation. These data are useful in providingrapid assessment of response to various thera-pies.

C. Fluids1. Aggressive volume resuscitation is essential in

treatment of septic shock. Most patients require4 to 8 L of crystalloid. Fluid should be adminis-tered as a bolus. The mean arterial pressureshould be increased to 65 to 75 mm Hg andorgan perfusion should be improved within 1hour of the onset of hypotension.

2. Repeated boluses of crystalloid (isotonic so-dium chloride solution or lactated Ringer'sinjection), 500 to 1,000 mL, should be givenintravenously over 5 to 10 minutes, until meanarterial pressure and tissue perfusion areadequate (about 4 to 8 L total over 24 hours forthe typical patient). Boluses of 250 mL areappropriate for patients who are elderly or whohave heart disease or suspected pulmonaryedema. Red blood cells should be reserved forpatients with a hemoglobin value of less than10 g/dL and either evidence of decreasedoxygen delivery or significant risk from anemia(eg, coronary artery disease).

D. Vasoactive agents1. Patients who do not respond to fluid therapy

should receive vasoactive agents. The primarygoal is to increase mean arterial pressure to 65to 75 mm Hg.

2. Dopamine (Intropin) traditionally has beenused as the initial therapy in hypotension,primarily because it is thought to increasesystemic blood pressure. However, dopamine isa relatively weak vasoconstrictor in septicshock.

3. Norepinephrine (Levophed) is superior todopamine in the treatment of hypotensionassociated with septic shock. Norepinephrine isthe agent of choice for treatment of hypotensionrelated to septic shock. Dobutamine (Dobutrex)should be reserved for patients with a persis-tently low cardiac index or underlying left ven-tricular dysfunction.

Hemodynamic effects of vasoactive agents

Agent Dose Effect

CO MAP SVR

Dopamine(Inotropin)

5-20mcg/kg/min

2+ 1+ 1+

Norepin-ephrine(Levophed)

0.05-5mcg/kg/min

-/0/+ 2+ 2+

Dobutamine(Dobutrex)

5-20mcg/kg/min

2+ -/0/+ -

Epineph-rine

0.05-2mcg/kg/min

2+ 2+ 2+

Phenylephrine(Neo-Synephrine)

2-10mcg/kg/min

-/0 2+ 2+

E. Antibiotics should be administered within 2 hoursof the recognition of sepsis. Use of vancomycinshould be restricted to settings in which the caus-ative agent is most likely resistant Enterococcus,methicillin-resistant Staphylococcus aureus, orhigh-level penicillin-resistant Streptococcus

pneumoniae.

Recommended Antibiotics in Septic Shock

Suspectedsource Recommended antibiotics

Pneumonia Second- or third-generation cephalosporin(cefuroxime, ceftazidime, cefotaxime,ceftizoxime) plus macrolide(antipseudomonal beta lactam plusaminoglycoside if hospital-acquired)

Urinary tract Ampicillin plus gentamicin (Garamycin) orthird-generation cephalosporin(ceftazidime, cefotaxime, ceftizoxime)

Skin or softtissue

Nafcillin (add metronidazole [Flagyl, MetroIV, Protostat] or clindamycin if anaerobicinfection suspected)

Meningitis Third-generation cephalosporin(ceftazidime, cefotaxime, ceftizoxime)

Intra-abdominal

Third-generation cephalosporin(ceftazidime, cefotaxime, ceftizoxime) plusmetronidazole or clindamycin

Primarybacteremia

Ticarcillin/clavulanate (Timentin) orpiperacillin/tazobactam(Zosyn)

Dosages of Antibiotics Used in Sepsis

Agent Dosage

Ceftizoxime (Cefizox) 2 gm IV q8h

Ceftazidime (Fortaz) 2 g IV q8h

Cefotaxime (Claforan) 2 gm q4-6h

Cefuroxime (Kefurox,Zinacef)

1.5 g IV q8h

Cefoxitin (Mefoxin) 2 gm q6h

Cefotetan (Cefotan) 2 gm IV q12h

Piperacillin/tazobactam(Zosyn)

3.375-4.5 gm IV q6h

Ticarcillin/clavulanate(Timentin)

3.1 gm IV q4-6h (200-300mg/kg/d)

Ampicillin 1-3.0 gm IV q6h

Ampicillin/sulbactam(Unasyn)

3.0 gm IV q6h

Nafcillin (Nafcil) 2 gm IV q4-6h

Piperacillin, ticarcillin,mezlocillin

3 gm IV q4-6h

Meropenem (Merrem) 1 gm IV q8h

Imipenem/cilastatin(Primaxin)

1.0 gm IV q6h

Gentamicin ortobramycin

2 mg/kg IV loading dose, then1.7 mg/kg IV q8h

Amikacin (Amikin) 7.5 mg/kg IV loading dose,then 5 mg/kg IV q8h

Vancomycin 1 gm IV q12h

Metronidazole (Flagyl) 500 mg IV q6-8h

Clindamycin (Cleocin) 600-900 mg IV q8h

Linezolid (Zyvox) 600 mg IV/PO q12h

Quinupristin/dalfopristin (Synercid)

7.5 mg/kg IV q8h

1. Initial treatment of life-threatening sepsis

usually consists of a third-generationcephalosporin (ceftazidime, cefotaxime,ceftizoxime) or piperacillin/tazobactam (Zosyn).An aminoglycoside (gentamicin, tobramycin, oramikacin) should also be included.Antipseudomonal coverage is important forhospital- or institutional-acquired infections.A p p r o p r i a t e c h o i c e s i n c l u d e a nantipseudomonal penicillin, cephalosporin, oran aminoglycoside.

2. Methicillin-resistant staphylococci. If linesepsis or an infected implanted device is apossibility, vancomycin should be added to theregimen to cover for methicillin-resistant Staphaureus and methicillin-resistant Staph epider-midis.

3. Vancomycin-resistant enterococcus (VRE):An increasing number of enterococcal strainsare resistant to ampicillin and gentamicin. Theinc idence of vancomycin- res is tantenterococcus (VRE) is rapidly increasing.a. Linezolid (Zyvox) is an oral or parenteral

agent active against vancomycin-resistantenterococci, including E. faecium and E.faecalis. Linezolid is also active againstmethicillin-resistant staphylococcus aureus.

b. Quinupristin/dalfopristin (Synercid) is aparenteral agent active against strains ofvancomycin-resistant enterococcus faecium,but not enterococcus faecalis. Most strainsof VRE are enterococcus faecium.

F. Other therapies1. Hydrocortisone (100 mg every 8 hours) in

patients with refractory shock significantlyimproves hemodynamics and survival rates.Corticosteroids may be beneficial in patientswith refractory shock.

2. Activated protein C (drotrecogin alfa[Xigris]) has antithrombotic, profibrinolytic, andanti-inflammatory properties. Activated proteinC reduces the risk of death by 20%. Activatedprotein C is approved for treatment of patientswith severe sepsis who are at high risk of

death. Drotrecogin alfa is administered as 24mcg/kg/hr for 96 hours. There is a small risk ofb l e e d i n g . C o n t r a i n d i c a t i o n s a r ethrombocytopenia, coagulopathy, recent sur-gery or recent hemorrhage.


DiverticulitisBy age 50, one-third of adults have diverticulosis coli;two-thirds have diverticulosis by age 80. Diverticulitis ordiverticular hemorrhage occurs in 10-20% of patientswith diverticulosis. Causes of diverticulosis include aging,elevation of colonic intraluminal pressure, and decreaseddietary fiber. Eighty-five percent are found in the sigmoidcolon.

I. Clinical presentation of diverticulitisA. Diverticulitis is characterized by the abrupt onset of

unremitting left-lower quadrant abdominal pain,fever, and an alteration in bowel pattern. Diverticu-litis of the transverse colon may simulate ulcerpain; diverticulitis of the cecum and redundantsigmoid may resemble appendicitis.

B. Physical exam. Left-lower quadrant tenderness ischaracteristic. Abdominal examination is oftendeceptively unremarkable in the elderly and inpersons taking corticosteroids.

Differential Diagnosis of Diverticulitis

Elderly Middle Aged andYoung

Ischemic colitisCarcinomaVolvulusColonic ObstructionPenetrating ulcerNephrolithiasis/urosepsis

AppendicitisSalpingitisInflammatory bowel diseasePenetrating ulcerUrosepsis

II. Diagnostic evaluationA. Plain X-rays may show ileus, obstruction, mass

effect, ischemia, or perforation. B. CT scan with contrast is the test of choice to

evaluate acute diverticulitis. The CT scan can beused for detecting complications and ruling outother diseases.

C. Contrast enema. Water soluble contrast is safeand useful in mild-to-moderate cases of diverticuli-tis when the diagnosis is in doubt.

D. Endoscopy. Acute diverticulitis is a relative con-traindication to endoscopy; perforation should beexcluded first. Endoscopy is indicated when thediagnosis is in doubt to exclude the possibility ofischemic bowel, Crohn's disease, or carcinoma.

E. Complete blood count may show leukocytosis.III. Treatment

A. Outpatient treatment1. Clear liquid diet 2. Oral antibiotics

a. Ciprofloxacin (Cipro) 500 mg PO bid ANDb. Metronidazole (Flagyl) 500 mg PO qid.

B. Inpatient treatment1. Severe cases require hospitalization for gastro-

intestinal tract rest (NPO), intravenous fluidhydration, and antibiotics. Nasogastric suctionis initiated if the patient is vomiting or if there isabdominal distention.

2. Antibiotic coverage should include entericgram-negative and anaerobic organismsa. Ampicillin 1-2 gm IV q4-6h ANDb. Gentamicin or tobramycin 100-120 mg IV

(1.5-2 mg/kg), then 80 mg IV q8h (5mg/kg/d) AND

c. Metronidazole (Flagyl) 500 mg IV q6-8h (15-30 mg/kg/d) OR

d. Cefoxitin (Mefoxin) 2 gm IV q6h ORe. Piperacillin-tazobactam (Zosyn) 3.375-4.5

gm IV q6h.C. Failure to improve or deterioration are indications

for reevaluation and consideration of surgery.Analgesics should be avoided because they maymask acute deterioration, and they may obscurethe need for urgent operation.

D. Oral antibiotics should be continued for 1-2 weeksafter resolution of the acute attack. Ciprofloxacin,500 mg PO bid.

E. After the acute attack has resolved, clear liquidsshould be initiated, followed by a low residue dietfor 1-2 weeks, followed by a high-fiber diet withpsyllium.

IV.Surgical therapyA. An emergency sigmoid colectomy with proximal

colostomy is indicated for attacks of diverticulitisassociated with sepsis, peritonitis, obstruction, orperforation.

B. Elective sigmoid resection is indicated for secondor subsequent attacks of diverticulitis, or for at-tacks with complications managed nonoperatively(eg, percutaneous CT-guided drainage of anabscess), or carcinoma.

C. Operative procedures1. Single-stage procedure. This procedure is

usually performed as an elective procedureafter resolution of the acute attack of diverticuli-tis. The segment containing inflamed diverticu-lum (usually sigmoid colon) is resected withprimary anastomosis. A bowel prep is required.

2. Two-stage procedure. This procedure isindicated for acute diverticulitis with obstructionor perforation with an unprepared bowel. Thefirst stage consists of resection of the involvedsegment of colon with end colostomy and eithera mucous fistula or a Hartmann rectal pouch.The second stage consists of a colostomy take-down and reanastomosis after 2-3 months.


Urinary Tract InfectionUrinary tract infections (UTIs) are a leading cause ofmorbidity in persons of all ages. Sexually active youngwomen, elderly persons and those undergoing genitouri-nary instrumentation or catheterization are at risk.

I. Acute uncomplicated cystitis in young womenA. Sexually active young women are most at risk for

UTIs.B. Approximately 90 percent of uncomplicated cystitis

episodes are caused by Escherichia coli, 10 to 20percent are caused by coagulase-negative Staphy-lococcus saprophyticus and 5 percent or less arecaused by other Enterobacteriaceae organisms orenterococci. Up to one-third of uropathogens areresistant to ampicillin and, but the majority aresusceptible to trimethoprim-sulfamethoxazole (85to 95 percent) and fluoroquinolones (95 percent).

C. Patients should be evaluated for pyuria by urinaly-sis (wet mount examination of spun urine) or adipstick test for leukocyte esterase.

Urinary Tract Infections in Adults

Category Diagnosticcriteria

First-linetherapy

Comments

Acute un-compli-cated cys-titis

Urinalysisfor pyuriaand hema-turia (culturenot re-quired)

TMP-SMXDS(Bactrim,Septra)Trimethoprim(Proloprim)Ciprofloxacin (Cipro)Ofloxacin(Floxin)

Three-daycourse is bestQuinolonesmay be usedin areas ofTMP-SMXresistance orin patientswho cannottolerateTMP-SMX

Recurrentcystitis inyoungwomen

Symptomsand a urineculture witha bacterialcount ofmore than100 CFUper mL ofurine

If the patienthas morethan threecystitis epi-sodes peryear, treatprophylacti-cally withpostcoital,patient- di-rected orcontinuousdaily ther-apy

Repeat ther-apy for sevento 10 daysbased on cul-ture resultsand then useprophylactictherapy

Acute cys-titis inyoungmen

Urine cul-ture with abacterialcount of1,000 to10,000 CFUper mL ofurine

Same as foracute un-complicatedcystitis

Treat forseven to 10days

Acute un-compli-catedpyelo-nephritis

Urine cul-ture with abacterialcount of100,000CFU per mLof urine

Ifgram-negative organ-ism, oralfluoroquinolone Ifgram-positive organism,amoxicillin If parenteraladministra-tion is re-quired,ceftriaxone(Rocephin)or afluoroquino-loneIfEnterococcus species,add oral orIVamoxicillin

Switch from IVto oral admin-istration whenthe patient isable to takemedication bymouth; com-plete a 14-daycourse

Compli-cated uri-nary tractinfection

Urine cul-ture with abacterialcount ofmore than10,000 CFUper mL ofurine

Ifgram-negative organ-ism, oralfluoroquinoloneIfEnterococcus species,ampicillin oramoxicillinwith or with-out gent-amicin(Garamycin)

Treat for 10 to14 days

Catheter-associatedurinarytract infec-tion

Symptomsand a urineculture witha bacterialcount ofmore than100 CFUper mL ofurine

Ifgram-negative organ-ism, afluoro-quinoloneIfgram-positive organism,ampicillin oramoxicillinplus genta-micin

Remove cath-eter if possi-ble, and treatfor seven to10 daysFor patientswith long-termcatheters andsymptoms,treat for five toseven days

Antibiotic Therapy for Urinary Tract Infections

Diagnos-tic group

Dura-tionofther-apy

Empiric options

Acute un-compli-cated uri-nary tractinfectionsin women

Threedays

Trimethoprim-sulfamethoxazole(Bactrim DS), one dou-ble-strength tablet PO twicedaily

Trimethoprim (Proloprim), 100 mgPO twice daily

Norfloxacin (Noroxin), 400 mgtwice daily

Ciprofloxacin (Cipro), 250 mgtwice daily

Lomefloxacin (Maxaquin), 400 mgper day

Ofloxacin (Floxin), 200 mg twicedaily

Enoxacin (Penetrex), 200 mgtwice daily

Sparfloxacin (Zagam), 400 mg asinitial dose, then 200 mg per day

Levofloxacin (Levaquin), 250 mgper day

Nitrofurantoin (Macrodantin), 100mg four times daily

Cefpodoxime (Vantin), 100 mgtwice daily

Cefixime (Suprax), 400 mg perday

Amoxicillin-clavulanate(Augmentin), 500 mg twice daily

Acute un-compli-catedpyelonephritis

14days

Trimethoprim-sulfamethoxazoleDS, one double-strength tabletPO twice daily


Levofloxacin (Maxaquin), 250 mgper dayEnoxacin (Penetrex), 400 mgtwice dailySparfloxacin (Zagam) 400 mg ini-

tial dose, then 200 mg per day 104.50

Ofloxacin (Floxin), 400 mg twicedailyCefpodoxime (Vantin), 200 mgtwice dailyCefixime (Suprax), 400 mg perday

Up to3 days

Trimethoprim-sulfamethoxazole(Bactrim) 160/800 IV twice daily

Ceftriaxone (Rocephin), 1 g IV perday


Ofloxacin (Floxin), 400 mg twicedailyLevofloxacin (Penetrex), 250 mg

per dayAztreonam (Azactam), 1 g three

times dailyGentamicin (Garamycin), 3 mg

per kg per day in 3 divideddoses every 8 hours

Compli-cated uri-nary tractinfections

14days

Fluoroquinolones PO

Up to3 days

Ampicillin, 1 g IV every six hours,and gentamicin, 3 mg per kg perday

Urinarytract infec-tions inyoung men

Sevendays

Trimethoprim-sulfamethoxazole,one double-strength tablet POtwice daily

Fluoroquinolones

D. Treatment of acute uncomplicated cystitis inyoung women1. Three-day regimens appear to offer the optimal

combination of convenience, low cost and anefficacy comparable to that of seven-day orlonger regimens.

2. Trimethoprim-sulfamethoxazole is the mostcost-effective treatment. Three-day regimens ofciprofloxacin (Cipro), 250 mg twice daily, andofloxacin (Floxin), 200 mg twice daily, producebetter cure rates with less toxicity.

3. Quinolones that are useful in treating compli-cated and uncomplicated cystitis includeciprofloxacin, norfloxacin, ofloxacin, enoxacin(Penetrex), lomefloxacin (Maxaquin),sparfloxacin (Zagam) and levofloxacin(Levaquin).

4. Trimethoprim-sulfamethoxazole remains theantibiotic of choice in the treatment of uncompli-cated UTIs in young women. Fluoroquinolonesare recommended for patients who cannottolerate sulfonamides or trimethoprim or who

have a high frequency of antibiotic resistance.Three days is the optimal duration of treatmentfor uncomplicated cystitis. A seven-day courseshould be considered in pregnant women,diabetic women and women who have hadsymptoms for more than one week.

II. Recurrent cystitis in young womenA. Up to 20 percent of young women with acute

cystitis develop recurrent UTIs. The causativeorganism should be identified by urine culture.

B. Women who have more than three UTI recur-rences within one year can be managed using oneof three preventive strategies.1. Acute self-treatment with a three-day course of

standard therapy. 2. Postcoital prophylaxis with one-half of a

trimethoprim-sulfamethoxazole double-strengthtablet (40/200 mg).

3. Continuous daily prophylaxis for six months withtrimethoprim-sulfamethoxazole, one-half tabletper day (40/200 mg); nitrofurantoin, 50 to 100mg per day; norfloxacin (Noroxin), 200 mg perday; cephalexin (Keflex), 250 mg per day; ortrimethoprim (Proloprim), 100 mg per day.

III. Complicated UTI A. A complicated UTI is one that occurs because of

enlargement of the prostate gland, blockages, orthe presence of resistant bacteria.

B. Accurate urine culture and susceptibility are nec-essary. Treatment consists of an oralfluoroquinolone. In patients who require hospital-ization, parenteral administration of ceftazidime(Fortaz) or cefoperazone (Cefobid), cefepime(Maxipime), aztreonam (Azactam), imipenem-cila-statin (Primaxin) or the combination of anantipseudomonal penicillin (ticarcillin [Ticar],mezlocillin [Mezlin], piperacillin [Pipracil]) with anaminoglycoside.

C. Enterococci are frequently encountereduropathogens in complicated UTIs. In areas inwhich vancomycin-resistant Enterococcus faeciumis prevalent, quinupristin-dalfopristin (Synercid)may be useful.

D. Patients with complicated UTIs require at least a10- to 14-day course of therapy. Follow-up urinecultures should be performed within 10 to 14 daysafter treatment.

IV.Uncomplicated pyelonephritis A. Women with acute uncomplicated pyelonephritis

may present with a mild cystitis-like illness andflank pain; fever, chills, nausea, vomiting,leukocytosis and abdominal pain; or a seriousgram-negative bacteremia. Uncomplicatedpyelonephritis is usually caused by E. coli.

B. The diagnosis should be confirmed by urinalysisand by urine culture. Urine cultures demonstratemore than 100,000 CFU per mL of urine in 80percent of women with pyelonephritis. Bloodcultures are positive in up to 20 percent of womenwho have this infection.

C. Empiric therapy using an oral fluoroquinolone isrecommended in women with mild to moderatesymptoms. Patients who are too ill to take oralantibiotics should initially be treated with aparenterally third-generation cephalosporin,aztreonam, a broad-spectrum penicillin, aquinolone or an aminoglycoside.

D. The total duration of therapy is usually 14 days.Patients with persistent symptoms after three daysof antimicrobial therapy should be evaluated byrenal ultrasonography for evidence of urinaryobstruction or abscess.


SyphilisSyphilis, an infection caused by Treponema pallidum, isusually sexually transmitted and is characterized byepisodes of active disease interrupted by periods oflatency.

I. Clinical evaluationA. Primary syphilis

1. The incubation period for syphilis is 10-90 days;21 days is average. The lesion begins as apainless, solitary nodule that becomes anindurated ulceration (chancre) with a ham-colored, eroded surface, and a serous dischargefound on or near the genitalia. Atypical lesionsare frequent and may take the form of smallmultiple lesions.

2. The chancre is usually accompanied by pain-less, enlarged regional lymph nodes. Untreatedlesions heal in 1-5 weeks.

3. The diagnosis is made by the clinical appear-

ance and a positive darkfield examination; theserologic test (VDRL, RPR) is often negative inthe first 4-6 weeks after infection.

B. Secondary syphilis1. Twenty-five percent of untreated patients prog-

ress to secondary syphilis 2-6 months afterexposure. Secondary syphilis lasts for 4-6weeks.

2. Bilateral, symmetrical, macular, papular, orpapulosquamous skin lesions become wide-spread. The lesions are non-pruritic and fre-quently involve the palms, soles, face, trunk andextremities. Condyloma lata consists of rash andmoist lesions. Secondary syphilis is highlyinfectious. Mucous membranes are often in-volved, appearing as white patches in themouth, nose, vagina, and rectum.

3. Generalized nontender lymphadenopathy andpatchy alopecia sometimes occur. A smallpercentage of patients have iritis, hepatitis,meningitis, fever, and headache.

4. The serologic test (VDRL, RPR) is positive in>99% of cases; the test may be falsely negativebecause of the prozone phenomenon caused byhigh antigen titers. Retesting of a diluted bloodsample may be positive. No culture test is avail-able.

C. Latent syphilis consists of the interval betweensecondary syphilis and late syphilis. Patients haveno signs or symptoms, only positive serologicaltests.

D. Late syphilis is characterized by destruction oftissue, organs, and organ systems.1. Late benign syphilis. Gummas occur in skin or

bone.2. Cardiovascular syphilis. Medial necrosis of the

aorta may lead to aortic insufficiency or aorticaneurysms.

3. Neurosyphilisa. Spinal fluid shows elevated WBCs, increased

total protein, and positive serology. b. Pupillary changes are common; the Argyll

Robertson pupil accommodates but does notreact to light.

c. Neurosyphilis may cause general paresis ortabes dorsalis--degeneration of the sensoryneurons in the posterior columns of thespinal cord.

II. SerologyA. Nontreponemal tests

1. Complement fixation tests (VDRL or RPR) areused for screening; they become positive 4-6weeks after infection. The tests start in low titerand, over several weeks, may reach 1:32 orhigher. After adequate treatment of primarysyphilis, the titer becomes nonreactive within 9-18 months.

2. False-positive tests occur in hepatitis, mononu-cleosis, viral pneumonia, malaria, varicella,autoimmune diseases, diseases associated withincreased globulins, narcotic addicts, leprosy,and old age.

B. Treponemal tests1. Treponemal tests include the FTA-ABS test, TPI

test, and microhemagglutination assay for T.pallidum (MHA-TP). A treponemal test should beused to confirm a positive VDRL or RPR.

2. Treponemal tests are specific to treponemaantibodies and will remain positive after treat-ment. All patients with syphilis should be testedfor HIV.

III. Treatment of primary or secondary syphilis A. Primary or secondary syphilis. Benzathine

penicillin G, 2.4 million units IM in a single dose.B. Patients who have syphilis and who also have

symptoms or signs suggesting neurologic disease(meningitis) or ophthalmic disease (uveitis) shouldbe evaluated for neurosyphilis and syphilitic eyedisease (CSF analysis and ocular slit-lamp exami-nation).

C. Penicillin allergic patients. Doxycycline 100 mgPO 2 times a day for 2 weeks.

D. Follow-up and retreatment1. Early syphilis--repeat VDRL at 3, 6, and 12

months to ensure that titers are declining.2. Syphilis >1 year--also repeat VDRL at 24

months.3. Neurosyphilis-- also repeat VDRL for 3 years.4. Indications for retreatment

a. Clinical signs or symptoms persist or recur. b. Four-fold increase in the titer of a

nontreponemal test (VDRL).c. Failure of an initially high titer nontreponemal

test (VDRL) to show a 4-fold decrease withina year.

5. Sex partners should be evaluated and treated.IV. Treatment of latent syphilis

A. Patients who have latent syphilis who have ac-quired syphilis within the preceding year are classi-fied as having early latent syphilis. Latent syphilisof unknown duration should be managed as latelatent syphilis.

B. Treatment of early latent syphilis. Benzathinepenicillin G, 2.4 million units IM in a single dose.

C. Treatment of late latent syphilis or latent syphi-lis of unknown duration. Benzathine penicillin G2.4 million units IM each week x 3 weeks.

D. All patients should be evaluated clinically forevidence of late syphilis (aortitis, neurosyphilis,gumma, iritis).

E. Indications for CSF examination before treat-ment1. Neurologic or ophthalmic signs or symptoms2. Other evidence of active syphilis (aortitis,

gumma, iritis)3. Treatment failure 4. HIV infection5. Serum nontreponemal titer >1:32, unless dura-

tion of infection is known to be <1 year6. Nonpenicillin therapy planned, unless duration

of infection is known to be <1 year.F. CSF examination includes cell count, protein, and

CSF-VDRL. If a CSF examination is performed andthe results are abnormal, the patient should betreated for neurosyphilis.

V. Treatment of late syphilisA. Benzathine penicillin G 2.4 million units IM weekly

x 3 weeks. Penicillin allergic patients are treatedwith doxycycline, 100 mg PO bid x 4 weeks.

B. Patients with late syphilis should undergo CSFexamination before therapy.

VI. Treatment of neurosyphilisA. Central nervous system disease can occur during

any stage of syphilis. Evidence of neurologicinvolvement (eg, ophthalmic or auditory symptoms,cranial nerve palsies) warrants a CSF examination.Patients with CSF abnormalities should havefollow-up CSF examinations to assess response totreatment.

B. Treatment of neurosyphilis. Penicillin G 2-4million units IV q4h for 10-14 days. Alternatively,penicillin G procaine 2.4 million units IM daily plusprobenecid 500 mg PO qid, both for 10-14 days,can be used.

C. Follow-up. If CSF pleocytosis was present initially,CSF examination should be repeated every 6months until the cell count is normal.


Gastrointestinal Disorders

Helicobacter Pylori Infection andPeptic Ulcer DiseaseThe spiral-shaped, gram-negative bacteriumHelicobacter pylori is found in gastric mucosa or adher-ent to the lining of the stomach. Acute infection is mostcommonly asymptomatic but may be associated withepigastric burning, abdominal distention or bloating,belching, nausea, flatulence, and halitosis. H. pyloriinfection can lead to ulceration of the gastric mucosa andduodenum and is associated with malignancies of thestomach. The prevalence of H. pylori infection is as highas 52 percent.

I. PathophysiologyA. Helicobacter pylori (HP), a spiral-shaped, flagel-

lated organism, is the most frequent cause ofpeptic ulcer disease (PUD). Nonsteroidal anti-inflammatory drugs (NSAIDs) and pathologicallyhigh acid-secreting states (Zollinger-Ellison syn-drome) are less common causes. More than 90%of ulcers are associated with H. pylori. Eradicationof the organism cures and prevents relapses ofgastroduodenal ulcers.

B. Complications of peptic ulcer disease includebleeding, duodenal or gastric perforation, andgastric outlet obstruction (due to inflammation orstrictures).

II. Clinical evaluationA. Symptoms of PUD include recurrent upper ab-

dominal pain and discomfort. The pain of duodenalulceration is often relieved by food and antacidsand worsened when the stomach is empty (eg, atnighttime). In gastric ulceration, the pain may beexacerbated by eating.

B. Nausea and vomiting are common in PUD.Hematemesis (“coffee ground” emesis) or melena(black tarry stools) are indicative of bleeding.

C. Physical examination. Tenderness to deeppalpation is often present in the epigastrium, andthe stool is often guaiac-positive.

Presentation of Uncomplicated Peptic UlcerDisease

Epigastric pain (burning, vague abdominal discomfort, nau-sea)

Often nocturnal Occurs with hunger or hours after meals Usually temporarily relieved by meals or antacidsPersistence or recurrence over months to years History of self-medication and intermittent relief

D. NSAID-related gastrointestinal complications.NSAID use and H pylori infection are independentrisk factors for peptic ulcer disease. The risk is 5 to20 times higher in persons who use NSAIDs thanin the general population. Misoprostol (Cytotec)has been shown to prevent both NSAID ulcers andrelated complications. The minimum effectivedosage is 200 micrograms twice daily; total dailydoses of 600 micrograms or 800 micrograms aresignificantly more effective.

III. When to test and treatA. In the absence of alarm symptoms for cancer or

complicated ulcer disease, the approach to testingin patients with dyspepsia can be divided into fourclinical scenarios: (1) known peptic ulcer disease,currently or previously documented; (2) knownnonulcer dyspepsia; (3) undifferentiated dyspep-sia, and (4) gastroesophageal reflux disease(GERD).

B. Peptic ulcer disease. Treatment of H. pyloriinfection in patients with ulcers almost alwayscures the disease and reduces the risk for perfora-tion or bleeding.

C. Nonulcer disease. There is no convincing evi-dence that empiric eradication of H. pylori inpatients with nonulcer dyspepsia improves symp-toms.

D. Undifferentiated dyspepsia. A test-and-treatstrategy is recommended in which patients withdyspepsia are tested for the presence of H. pyloriwith serology and treated with eradication therapyif the results are positive. Endoscopy is reservedfor use in patients with alarm signs or those withpersistent symptoms despite empiric therapy.

Alarm Signs for Risk of Gastric Cancer of Com-plicated Ulcer Disease

Older Than 45 years Rectal bleeding or melenaWeight los of >10 percentof body weightAnemiaDysphagia

Abdominal massJaundiceFamily history of gastriccancerPrevious history of pepticulcerAnorexia/early satiety

Evaluation for Helicobacter pylori-Related Dis-ease

Clinical scenario Recommended test

Dyspepsia in patient withalarm symptoms for canceror complicated ulcer (eg,bleeding, perforation)

Promptly refer to agastroenterologist for en-doscopy.

Known PUD, uncompli-cated

Serology antibody test;treat if result is positive.

Dyspepsia in patient withprevious history of PUD notpreviously treated witheradication therapy


Dyspepsia in patient withPUD previously treated forH. pylori

Stool antigen or ureabreath test; if positive, treatwith regimen different fromthe one previously used;retest to confirm eradica-tion. Consider endoscopy.

Undifferentiated dyspepsia(without endoscopy)


Documented nonulcer dys-pepsia (after endoscopy)

Unnecessary

GERD Unnecessary

Asymptomatic with historyof documented PUD notpreviously treated witheradication therapy


Asymptomatic Screening unnecessary

E. Gastroesophageal Reflux Disease. H. pyloriinfection does not increase the risk of GERD.Eradication therapy does not eliminate GERDsymptoms (sensation of burning and regurgitation.

IV.Helicobacter pylori TestsA. Once testing and eradication are chosen, several

diagnostic tests are available. Unless endoscopy isplanned, a practical approach is to use serology toidentify initial infection, and use the stool antigentest or urea breath test to determine cure, if indi-cated.

Noninvasive Testing Options for DetectingHelicobacter pylori

Test

Whatdoesitmea-sure?

Sensitivity

Test ofcure?

Com-ments

Serol-ogy:labora-tory-basedELISA

IgG 90 to93

No Accurate;convenientfor initial in-fection; titersmay remainpositive afterone year

Wholeblood:of-fice-basedELISA

IgG 50 to85

No Less accu-rate but fast,convenient

Stool:HpSA

H. pylorianti-gens

95 to98

Yes Relativelyconvenientand available

Ureabreathtest

Ureaseactivity

95 to100

Yes Sensitivityreduced byacid sup-pression

B. Endoscopy and Biopsy. Alarm symptoms forcancer or ulcer complication warrant promptendoscopic evaluation. A gastric antral biopsyspecimens is considered the gold standard for

detecting the presence of H. pylori. Cultures ofbiopsy specimens obtained during endoscopy canbe tested for antimicrobial resistance in cases oftreatment failure.

C. Serology/ELISA. When endoscopy is not per-formed, the most commonly used diagnosticapproach is the laboratory-based serologic anti-body test. This enzyme-linked immunosorbentassay (ELISA) detects IgG antibodies to H. pylori,indicating current or past infection. A positiveserologic test suggests active infection in patientswho have not undergone eradication therapy. Theserologic test results may not revert to negativeonce the organism is eradicated; therefore, the testis not used to identify persistent infection.

D. Stool testing with enzyme-linked immunoassayfor H. pylori antigen in stool specimens is highlysensitive and specific, the stool antigen test revertsto negative from five days to a few months aftereradication of the organism, with 90 percent speci-ficity. This test is useful in confirming eradication,and, because it is office-based, is less costly andmore convenient than the urea breath test.False-positive results may occur even four weeksfollowing eradication therapy.

E. Urea Breath Test. The urea breath test is areliable test for cure and can detect the presenceor absence of active H. pylori infection with greateraccuracy than the serologic test. It is usuallyadministered in the hospital outpatient settingbecause it requires time and special equipment.

V. Principles of treatmentA. Antimicrobial resistance and incomplete treatment

are major reasons for treatment failure. Continuedtherapy for 14 days is the most reliable and effec-tive regimen.

Triple Therapy Regimens for Helicobacterpylori Infection

Treatment (10 to 14 days oftherapy recommended)

Conve-niencefactor Tolera

bility

1. Omeprazole (Prilosec), 20 mgtwo times dailyor Lansoprazole (Prevacid), 30 mgtwo times daily plus Metronidazole (Flagyl), 500 mgtwo times daily or Amoxicillin, 1 g two times daily plus Clarithromycin (Biaxin), 500 mgtwo times daily Prepackaged triple-ther-apy(Prevpac): taken bid for 14days; consists of 30 mglansoprazole, 1 g amoxicillin, and500 mg clarithromycin.

Twice-dailydosing

Fewersignifi-cantsideeffects,butmoreabnor-maltasteversusotherregi-mens

2. Ranitidine bismuth citrate(Tritec), 400 mg twice daily plusClarithromycin, 500 mg twice daily

or Metronidazole, 500 mg twice daily

plus Tetracycline, 500 mg twice daily or Amoxicillin, 1 g twice daily 92(RMA)

Twice-dailydosing

In-creased diar-rheaversusotherregi-mens

B. Triple and quadruple therapies have eradication

rates approaching 90 percent or more.C. Post-Treatment Followup

1. Routine laboratory testing for cure is not re-quired in patients whose symptoms respond toeradication therapy.

2. Routine, noninvasive follow-up testing also canbe considered in patients who have persistentsymptoms following eradication therapy. Inthese patients, the stool antigen test, performedfour weeks following therapy, is a convenientmethod. Patients with a history of ulcer compli-cations, gastric mucosa-associated lymphoidtissue (MALT), or early gastric cancer shouldundergo a routine post-treatment urea breathtest or endoscopy to ensure successful eradica-tion.

D. Treatment of NSAID-related ulcers1. When the ulcer is caused by NSAID use, heal-

ing of the ulcer is greatly facilitated by discon-tinuing the NSAID. Acid antisecretory therapywith an H2-blocker or proton pump inhibitorspeeds ulcer healing. Proton pump inhibitors

are more effective in inhibiting gastric acidproduction and are often used to heal ulcers inpatients who require continuing NSAID treat-ment.

2. If serologic or endoscopic testing for H pylori ispositive, antibiotic treatment is necessary.

3. Acute H2-blocker therapya. Ranitidine (Zantac), 150 mg bid or 300 mg

qhs.b. Famotidine (Pepcid), 20 mg bid or 40 mg

qhs.c. Nizatidine (Axid Pulvules), 150 mg bid or

300 mg qhs.d. Cimetidine (Tagamet), 400 mg bid or 800

mg qhs.4. Proton pump inhibitors

a. Omeprazole (Prilosec), 20 mg qd.b. Lansoprazole (Prevacid), 15 mg before

breakfast qd. c. Esomeprazole (Nexium) 20-40 mg qd.d. Pantoprazole (Protonix) 40 mg PO, 20

minuted before the first meal of the day or IVonce daily.

e. Rabeprazole (Aciphex) 20 mg/day, 20 to 30minutes before the first meal of the day.

VI.Surgical treatment of peptic ulcer diseaseA. Indications for surgery include exsanguinating

hemorrhage, >5 units transfusion in 24 hours,rebleeding during same hospitalization, intractabil-ity, perforation, gastric outlet obstruction, andendoscopic signs of rebleeding.

B. Unstable patients should receive a truncalvagotomy, oversewing of bleeding ulcer bed, andpyloroplasty.


Gastroesophageal Reflux DiseaseGastroesophageal reflux disease is caused by thecombination of excess reflux of gastric juice and impairedclearance of this refluxate from the esophagus. GERD isdefined as symptoms or tissue damage caused by refluxof gastric contents with or without esophageal inflamma-tion.

I. Clinical manifestations A. Typical symptoms of GERD are heartburn and

regurgitation; atypical symptoms includeodynophagia, dysphagia, chest pain, cough, andreactive airway disease. Up to half of the generalpopulation has monthly heartburn or regurgitation.

B. Heartburn, the most common symptom of GERD,is a substernal burning sensation that rises fromthe upper abdomen into the chest and neck.Dysphagia, the sensation that swallowed materialis lodged in the chest, may be caused by esopha-geal inflammation or impaired motility. Esophagealcancer also is an important differential diagnosticconsideration when dysphagia is the presentingcomplaint.

Symptoms of GERD

Heartburn (pyrosis)RegurgitationDysphagiaWater brashGlobusOdynophagiaHoarseness

Chronic coughNocturnal coughAsthmaDyspepsiaHiccupsChest painNausea

C. Chest pain due to GERD can mimic angina.Extraesophageal manifestations of GERD includeasthma, chronic cough, sinusitis, pneumonitis,laryngitis, hoarseness, hiccups, and dental disease.Complications of long-standing GERD includeesophageal stricture and Barrett's esophagus.

Differential diagnostic considerations in GERD

Esophageal neoplasmInfectious esophagitisCaustic esophagitisPill esophagitisGastritisPeptic ulcer disease

Nonulcer dyspepsiaCoronary artery diseaseHepatobiliary diseaseEsophageal motility disordersCholelithiasis

II. DiagnosisA. Diagnosis of GERD is often based on clinical

findings and confirmed by the response to therapy.Diagnostic evaluation should be pursued if symp-toms are chronic or refractory to therapy or ifesophageal or extra-esophageal complications aresuspected.

Indications for esophageal endoscopy in pa-tients with GERD

Dysphagia or odynophagiaPersistent or progressive symptoms despite therapyEsophageal symptoms in an immunocompromised patientMass, stricture, or ulcer on upper gastrointestinal barium studyGastrointestinal bleeding or iron deficiency anemiaAt least 10 years of GERD symptoms (screen for Barrett'sesophagus)

B. Ambulatory esophageal pH monitoring is per-formed by placing a pH electrode just above thelower esophageal sphincter. This test has a sensi-tivity of 60-100%.

C. Short PPI trials are useful for diagnosis of GERDand have a sensitivity of 70 to 90% and specificityof 55 to 85%.

III. Treatment options A. Lifestyle modification. Strategies include eleva-

tion of the head of the bed 6 to 8 in; reducedconsumption of fatty foods, chocolate, alcohol,colas, red wine, citrus juices, and tomato products;avoidance of the supine position after meals; noteating within 3 hours of bedtime; avoidance oftight-fitting clothing; weight loss if obese; andsmoking cessation.

B. Although H2-blockers are less expensive than PPIs,PPIs provide superior acid suppression, healingrates and symptom relief. Therefore, PPIs may bemore cost-effective than H2-blockers, especially inpatients with more severe acid-peptic disorders,because of their lower and less frequent dosingrequirements and their comparatively shorterduration of required therapy.

C. Histamine2-blockers are used extensively. Thefour available agents, cimetidine (Tagamet),famotidine (Pepcid), nizatidine (Axid), andranitidine (Zantac), are equivalent. Dosage must bereduced in patients with renal failure. In general,doses of H2 blockers required to control GERDsymptoms and heal esophagitis are two to threetimes higher than those needed for treatment ofpeptic ulcer disease. Rates of symptom control andhealing are about 50%.1. Cimetidine (Tagamet), 800 mg twice daily;

ranitidine (Zantac), 150 mg four times daily;famotidine (Pepcid), 40 mg twice daily; andnizatidine (Axid), 150 mg twice daily.

D. Proton pump inhibitors (PPIs) irreversibly bindand inhibit the proton pump.1. The five available PPIs, esomeprazole (Nexium),

lansoprazole (Prevacid), omeprazole (Prilosec),pantoprazole (Protonix), and rabeprazole(Aciphex), have similar pharmacologic activities.PPIs should be taken 20 to 30 minutes beforethe first meal of the day. PPIs are more effectivethan are H2 blockers.

2. In contrast to the other Proton Pump Inhibitors(PPIs), rabeprazole (Aciphex) forms a partiallyreversible bond with the proton pump. Therefore,it may have a more sustained acid-suppressingeffect than the other PPIs. Rabeprazole andpantoprazole, seem to have fewer drug interac-tions. Pantoprazole is the least expensive.

Proton Pump Inhibitors

Drug Dosage

Esomeprazole -Nexium

20 mg or 40 mg, 20 to 30 min-utes before the first meal of theday

Lansoprazole -Prevacid

30 mg, 20 to 30 minutes beforethe first meal of the day

Omeprazole -Prilosec, generic

20 mg/day, 20 to 30 minutesbefore the first meal of the day

Pantoprazole -Protonix

40 mg PO, 20 minuted beforethe first meal of the day or IVonce daily

Rabeprazole -Aciphex

20 mg/day, 20 to 30 minutesbefore the first meal of the day

E. Surgical treatment. The most common of theantireflux procedures used to treat GERD is theNissen fundoplication, which is a laparoscopicprocedure. A portion of the stomach is wrappedaround the distal esophagus. Indications includepatient preference for surgical treatment overprolonged medical therapy, incomplete controldespite medical therapy, and refractory manifesta-tions of reflux (eg, pneumonia, laryngitis, asthma).

IV. Management considerationsA. Patients with frequent or unrelenting symptoms or

esophagitis, or both, should be treated from theoutset with a PPI once or twice daily as appropri-ate.

B. Refractory GERD. Increasing the dosage of PPIsoften can control GERD in patients receiving asingle daily dose. Sometimes switching to a differ-ent PPI can improve symptoms. Antireflux surgicaltreatment is an alternative.

Alternative diagnoses in patients with refrac-tory GERD

Esophageal hypersensitiv-ity (visceral hyperalgesia)AchalasiaDistal esophageal cancerStricture NSAID-induced symptomsInfection (eg, Candida,herpes, cytomegalovirusesophagitis)

Caustic exposureImpaired gastric emptyingEosinophilic gastroenteritisBile acid refluxNonulcer dyspepsiaPill esophagitis


Viral HepatitisAcute viral hepatitis consists of hepatocellular necrosisand inflammation caused by hepatitis A virus (HAV),hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitisD virus (HDV), or hepatitis E virus (HEV). Chronic viralhepatitis is seen with HBV, HCV, and HDV infection.Hepatitis A and hepatitis E virus do not cause a chroniccarrier state or chronic liver disease.

I. Clinical manifestations of viral hepatitisA. Acute viral hepatitis

1. Symptoms of acute hepatitis include anorexia,fatigue, myalgias and nausea, developing 1-2weeks prior to the onset of jaundice. Weight lossand distaste for food and cigarettes may occur,followed by headaches, arthralgias, vomiting, andright upper quadrant tenderness.

2. Symptoms of hepatitis A, B and C are indistin-guishable, except that patients with hepatitis Aare more frequently febrile. Five to 10% of pa-tients will develop a serum-sickness syndromefollowing infection with HBV, characterized byfever, rash, and arthralgias.

3. Physical examination. Jaundice occurs in lessthan one-half of hepatitis patients. Jaundice canbe observed when the bilirubin is greater than2.5 mg/dL and is most easily observed under thetongue or in the sclerae. Hepatomegaly and/orsplenomegaly may also occur.

B. Chronic hepatitis1. Chronic hepatitis most frequently presents as

fatigue in patients with HBV, HCV, or HDV infec-tion; jaundice is rarely present. The major differ-ence between chronic hepatitis caused by HBV,compared to HCV, is a higher rate of cirrhosisthat develops with HCV.

2. In both hepatitis B and hepatitis C, evidence ofchronic liver disease may include amenorrhea,muscle wasting, gynecomastia, and spider

angiomata. As the disease progresses, asterixis,ascites, hepatic encephalopathy, peripheraledema, easy bruisability, testicular atrophy,bleeding, and esophageal varices may develop.

3. Chronic hepatitis requires a liver biopsy to con-firm the diagnosis and to assess severity so as todetermine whether treatment is needed. A majorcomplication of chronic hepatitis is hepatocellularcarcinoma.

II.Diagnosis of acute hepatitisA. Laboratory findings in acute hepatitis

1. Aspartate aminotransferase (AST) and alanineaminotransferase (ALT) enzymes increaseduring the prodromal phase of hepatitis and mayreach 20 times normal. The peak usually occurswhen the patients are jaundiced, then rapidly fallsduring recovery.

2. In icteric patients, the bilirubin continues toincrease as the aminotransferases decline andmay reach 20 mg/dL. There are equal propor-tions of direct and indirect bilirubin.

3. The international normalized ratio is usuallynormal in acute hepatitis, but it can become pro-longed in patients with severe hepatitis. The INRis a marker of prognosis.

4. If acute viral hepatitis is suspected, serologictests should include IgM anti-HAV, IgM anti-HBc,HBsAg, and anti-HCV. In patients with fulminanthepatic failure or known previous infection withHBV, an anti-HDV should also be ordered.

Hepatitis Panels and Tests

Panel Marker Detected

Acute hepati-tis panel

IgM anti-HAV, IgM anti-HBc, HBsAg,anti-HCV

To monitorHBV

HBsAg, HBeAg, anti-HBe, HBsAg,HBeAg, total anti-HBc

HBV immu-nity panel

Anti-HBs, total anti-HBc

IndividualTests

Marker Detected

Immunity toHBV

Anti-HBs (post-vaccination)

Immunity toHAV

Anti-HAV

To screen forHBV infection

HBsAg for pregnant women

To monitorHCV infection

Anti-HCV

B. Clinical evaluation of acute hepatitis1. Initially, patients should be evaluated for other

etiologies of liver disease that can cause elevatedliver enzymes.

2. Common causes of elevated aminotransferaselevelsa. Infection. Pneumococcal bacteremia, sepsis,

Epstein-Barr virus, cytomegalovirus, herpessimplex virus, Varicella-zoster virus, syphilis,tuberculosis, mycobacterium avium complex.

b. Drugs and toxins. Acetaminophen, benzenes,carbon tetrachloride, halothane, isoniazid,ketoconazole, 6-mercaptopurine, phenytoin,propylthiouracil, rifampin.

c. Vascular anoxia. Budd-Chiari syndrome,congestive heart failure, veno-occlusive dis-ease.

d. Metabolic. Alpha-1-anti-trypsin deficiency,hemochromatosis, Wilson's disease.

e. Others. A lcoho l ic l i ver d isease,choledocholithiasis, nonalcoholic steatohep-atitis, malignancy, shock.

f. Autoimmune hepatitis occurs primarily inyoung women with systemic manifestations ofautoimmune phenomena. These patients havepositive tests for antinuclear antibody and anti-Sm antibody.

g. Wilson's disease is an autosomal recessivecondition that results in toxic copper accumula-tion in the liver as well as other organs. Diagno-sis can be made by identifying Kayser-Fleischerrings in the eyes, an elevated urinary copper, orlow serum ceruloplasmin.

Blood Studies for Evaluating Elevations of Se-rum Liver Enzymes

Disease to be RuledOut

Suggested Blood Test

Alpha1 -antitrypsindeficiency

Alpha-1-antitrypsin

Autoimmune chronichepatitis

ANA, anti-Sm antibody

Hemochromatosis Serum iron, TIBC, ferritin

Hepatitis B HBsAg, HBeAg, anti-HBc

Hepatitis C Anti-HCV

Primary biliary cirrhosis Anti-mitochondrial antibody

Wilson's disease Ceruloplasmin

III. Hepatitis A virus (HAV)A. Hepatitis A is usually an acute, self-limited infec-

tion, which does not result in a chronic carrierstate. Low-grade fever (<101° F) is common at theonset, with malaise, anorexia, dark urine, and palestools. Fulminant hepatic failure resulting inencephalopathy or death is rare.

B. Transmission is by the fecal-oral route, and hepati-tis A should be suspected if infection occurs follow-ing ingestion of contaminated food or shellfish, ininstitutionalized persons, children in day carecenters, or if travel to an endemic area.

C. The diagnosis is confirmed by the presence of IgManti-HAV. The IgM anti-HAV titer decreases overseveral months. The IgG anti-HAV rises andpersists indefinitely and affords immunity to subse-quent HAV exposure.

D. Treatment of acute hepatitis A infection consistsof antipyretics. Ninety-nine percent of acute hepati-tis A will resolve without sequelae.

IV.Hepatitis B virus (HBV)A. The hepatitis B virus is composed of a double-

stranded DNA molecule, core antigens and surfaceantigens. Incubation is 45-160 days. Transmissionis parenteral or sexual, with serum, semen andsaliva shown to be contagious.

B. Hepatitis B is difficult to distinguish from hepatitisA, but it usually has a more protracted course. Thediagnosis of acute hepatitis B is made by thedemonstration of HBsAg in the serum and IgMantibody to hepatitis B core antigen (anti-HBc IgM),which appears at the same time as symptoms.Anti-HBc IgM gradually declines during recovery.

C. In children born to women positive for HBsAg, thetransmission rate is 10-40%. In homosexual males,the prevalence rate is 70%. Transmission amongadolescents is primarily through sexual inter-course. Asymptomatic acute illness accounts for40-50% of all infections.

D. Laboratory diagnosis of hepatitis B1. Antibody to HBsAg (anti-HBs) develops after

active infection and serves as an indicator ofimmunity. Anti-HBs alone is also detectable inthe serum of individuals who have been vacci-nated against HBV or who have been givenhepatitis B immune globulin (HBIG).

2. IgM anti-HBc indicates recent HBV infectionwithin the preceding 4-6 months.

3. Presence of HBeAg indicates active viral repli-cation and high infectivity. Antibody to HBeAg(anti-HBe) develops in most people infectedwith HBV.

4. The persistence of HBsAg for six months afterthe diagnosis of acute HBV indicates progres-sion to chronic hepatitis B.

E. Prognosis1. Over 90% of adult patients with acute hepatitis

B recover uneventfully. The mortality rate fromacute hepatitis B is 1-2%.

2. Chronic hepatitis will develop in 6-10%, mani-fest by persistent HBsAg positivity.

3. Fulminant hepatic failure occurs in <1%, andit is characterized by prolongation of the INR,hyperbilirubinemia, and encephalopathy.

F. Management of acute hepatitis B1. Indications for hospitalization include inability

to maintain intake of nutrition and fluid,encephalopathy, bleeding, or INR >2.0.

2. Bed rest is not mandatory in uncomplicatedcases. Diet should be free of fried or fatty foods.

G. Management of chronic hepatitis B

Indications for antiviral therapy in chronic hep-atitis B virus (HBV) infection

Seropositivity for hepatitis B surface antigen for longer than6 monthsSeropositivity for hepatitis B e antigenMeasurable HBV DNA in serumElevated serum alanine aminotransferase levelCompensated liver disease (If interferon alfa therapy isbeing considered)

Contraindications to antiviral therapy forchronic hepatitis B

No findings of hepatitis B e antigenDecompensated cirrhosis*Psychiatric disorder*Severe comorbid condition*Normal serum alanine aminotransferase level*If interferon therapy is being considered.

V. Chronic HBV infectionA. Patients with chronic HBV infection are at in-

creased risk of cirrhosis, hepatocellular carcinoma,and liver failure. The relative risk of primary livercancer in infected patients is 223 times higher.

B. Chronic HBV infection is suggested by persistenceof hepatitis B surface antigen (HBsAg) 6 monthsafter acute infection. In addition, there may beserologic evidence of ongoing viral replication,consisting of detectable hepatitis B e antigen(HBeAg) or HBV DNA on quantitative assays or thepresence of biochemical markers (eg, an elevatedalanine aminotransferase [ALT] level). ChronicHBsAg carriers who have active viral replicationand an elevated ALT value should be evaluated forpossible antiviral therapy.

C. Combination therapy for chronic hepatitis Bvirus infection. Lamivudine plus interferon.Combination of Peg-IFN and lamivudine hassuperior anti-viral effect to lamivudine monotherapyin the treatment of chronic hepatitis B infection.Pegasys (at 90 mcg, 180 mcg or 270 mcg) onceweekly for a 24-week-period. And Lamivudine(Epivir). Lamivudine has few adverse effects, andsafety among patients with advanced liver disease.100 mg po qd.

VI. Hepatitis C A. Anti-HCV antibody is positive in 70-90% of pa-

tients with hepatitis C, although there is a pro-longed interval between onset of illness andseroconversion. The test does not distinguishacute from chronic infection.

B. Clinical features of acute hepatitis C are indistin-guishable from those of other viral hepatitides.Clinically recognized acute hepatitis C infectionoccurs less commonly than with HAV or HBV,and the majority of patients are asymptomatic.

C. Multiple transfusions, injection drug use, or high-risk sexual activity increase the index of suspicionfor HCV. Perinatal transmission can occur in the3rd trimester; in HCV-infected mothers, theoffspring are infected 50% of the time.

D. Heterosexual or household contacts have a 1-14% prevalence of anti-HCV. Between homosex-uals, the attack rate is 2.9% per year.

E. Prognosis. Fifty percent of patients with acutehepatitis C will progress to chronic liver disease,and 20% of these will develop cirrhosis. Patientswith chronic hepatitis C are at risk forhepatocellular carcinoma.

F. Treatment of Hepatitis C Virus Infection1. Treatment of Acute hepatitis C

a. The majority of patients who are acutelyinfected with HCV are asymptomatic andhave a clinically mild course; jaundice ispresent in fewer than 25 percent, andfulminant hepatic failure due to acute HCVinfection is rare. After an acute episode ofhepatitis C, 80 to 100 percent of patientsremain HCV RNA positive, and 60 to 80percent have persistently elevated serumaminotransferases.

b. Treatment with pegylated interferon alfa forat least six months is reasonable. Innonresponding patients at 12 weeks,ribavirin may be added.

2. Treatment of chronic hepatitis Ca. General measures in chronic HCV

(1) Diet. Alcohol promotes the progressionof chronic HCV; therefore, alcohol con-sumption should be avoided.Supplementation with vitamin E impairsfibrogenesis.

(2) Fatigue. Many patients complain offatigue. Ondansetron (4 mg BID) ishelpful.

(3) Vaccination. Patients with chronic HCVinfection should be vaccinated againsthepatitis A if they lack hepatitis A anti-body. Patients who lack antibodies tohepatitis B virus should be vaccinatedagainst hepatitis B. Pneumococcal vac-cine and yearly influenza vaccinationshould be considered in cirrhosis.

(4) Screening for varices andhepatocellular carcinoma. Patientswith cirrhosis should be screened foresophageal varices by upper endoscopyand should be screened forhepatocellular carcinoma with a rightupper quadrant ultrasound and serumalfa fetoprotein every six months.

(5) Role of liver biopsy. Liver biopsy priorto treatment of chronic HCV infection isuseful for predicting the stage and prog-nosis of the disease.

b. NIH guidelines(1) All patients with chronic hepatitis C

should be considered as potential candi-dates for antiviral therapy. Treatmentshould be recommended for patientswith measurable HCV, a liver biopsyshowing portal or bridging fibrosis, andat least moderate inflammation andnecrosis; the majority of these patientshave persistently elevated serum ALT.Treatment in other patient populationsshould be determined on an individualbasis.

(2) Mild liver disease. Patients who havepersistent elevation in serum ALT but donot have fibrosis and have minimalnecroinflammatory changes are likely tohave only slow disease progression.Such patients can be monitored periodi-cally.

(3) Advanced liver disease. The responseis lower than in patients without cirrho-sis. The main treatment option for suchpatients is liver transplantation.

(4) Cautions. Interferon monotherapy withribavirin may be contraindicated withsignificant cytopenia, pregnancy, severedepression or other psychiatric condi-tions, cardiac diseases, poorly con-trolled diabetes, seizure disorders, andautoimmune or potentially im-mune-mediated diseases.

c. Recommendations for initial therapy(1) Combination therapy with pegylated

interferon plus ribavirin is superior tointerferon monotherapy and to standardinterferon/ribavirin combination therapy.Combination therapy should be adminis-tered for 48 weeks.

(2) Ribavirin-and-interferon combinationtherapy (Rebetron)

(a) Attachment of interferon to polyethyl-ene glycol (PEG) prolongs the drug'shalf-life and allows for a sus-t a i n e d - r e l e a s e p r e p a r a t i o n .“Pegylated” interferon delivers a sig-nificantly higher amount of interferonalfa and that response rates arehigher than with the standardthree-times-weekly dosing regimen.

(b) Ribavirin (Rebetol) combined withinterferon alfa-2b (CoPegus) wasfound to be more effective than inter-feron alfa monotherapy for chronicHCV infection. Combination therapyresulted in a sustained-response rateof 49% when used for relapse duringinterferon alfa therapy and up to 39%when used as initial therapy. 180 mcgonce/week SC; 1000 mg(75 kg)-1200mg (>75 kg) daily PO x 48 weeks.

Indications for antiviral therapy in chronic viralhepatitis C

Seropositivity for HCV antibodies for longer than 6 monthsSeropositivity for HCV RNAElevated serum alanine aminotransferase levelCompensated liver disease

Contraindications to antiviral therapy forchronic hepatitis C

No findings of hepatitis C virus RNADecompensated cirrhosis*Psychiatric disorder*Severe comorbid condition*Normal serum alanine aminotransferase level*If interferon therapy is being considered.

d. Liver transplantation for treatment of hepa-titis C is now common, although 19% ofpatients develop cirrhosis following trans-plantation.

VII. Hepatitis DA. Hepatitis D develops in patients who are

coinfected with both HBV and HDV. Drug addictsand hemophiliacs are frequently affected, andinfection can result in acute or chronic hepatitis.

B. The clinical manifestations of HDV infection areindistinguishable from HBV alone; however,coinfected patients are at higher risk for fulminanthepatic failure. Cirrhosis may develop in up to70%.

C. An anti-HDV test should be ordered in patientswith fulminant hepatitis or in patients known to beHBsAg positive who suffer a clinical deterioration.

D. Treatment of hepatitis D. Interferon alfa may beadministered as 10 million units three times perweek for at least 12 months. Results have notbeen encouraging, and any durable response mayrequire treatment for life.

VIII. Hepatitis EA. No tests are available for diagnosis of hepatitis E.

The clinical course is self-limited and similar to thatof HAV. This infection should be suspected inindividuals recently returning from India, SoutheastAsia, Middle East, North Africa, and Mexico.

B. The incubation period is 30-40 days, and treatmentconsists of supportive care.

IX. Hepatitis G is a parenterally transmitted virus. Itshares about 25 percent of its viral genome with thehepatitis C virus and may also cause chronic infec-tion. Persistent infection with hepatitis G virus iscommon but does not seem to lead to chronic dis-ease.

X. Prevention of hepatitisA. Prevention of hepatitis A

1. Employees of child care facilities and travelersto third world countries should be vaccinatedagainst hepatitis A, and they should avoiduncooked shellfish, fruits, vegetables orcontaminated water.

2. Vaccination is given 2 weeks prior to exposure,with a booster dose anytime between 6 and 12months. Children and adults exposed to hepati-tis A at home or in child care facilities shouldreceive immune globulin (0.02 mg/kg).

B. Prophylactic therapy for hepatitis B1. Passive immunization with hepatitis B im-

mune globulin (HBIG) is recommended for:a. Accidental needlestick or mucosal exposure

to HBsAg.b. Accidental transfusion of HBSAG-positive

blood products.c. Spouses and/or sexual contacts of acute

cases.d. Infants born to HBsAg-positive mothers.

2. Recommendations for active immunizationa. Pre-exposure. Infants, children, adoles-

cents, health care workers, hemodialysispatients, homosexual males, illicit drugabusers, recipients of multiple blood prod-ucts, sexual and household contacts of HBVcarriers, prison inmates, heterosexuallyactive persons with multiple partners, travel-ers to HBV-endemic areas.

b. Post-exposure (in conjunction withHBIG). Infants born to HBsAg positive moth-ers; sexual contacts of acute hepatitis Bcases; needlestick exposure to HBV; vaccinerecipients with inadequate anti-HBs andneedlestick exposure.

3. There are two hepatitis B vaccines available,Recombivax HB and Engerix-B. Vaccination atzero, one and two months appears to result inprotective antibody against HBV occurs in 90-95% of vaccinated individuals.

4. Infants born to HBsAg-positive womenshould receive HBIG (0.5 mL) and hepatitis Bvaccine.

5. Postexposure prophylaxis following sexualexposure to HBV consists of HBIG and simul-taneous hepatitis B vaccination with completionof the vaccine series at 1 and 6 months.

C. Hepatitis C. There is no immune globulin prepara-tion or vaccine available.


Acute PancreatitisThe incidence of acute pancreatitis ranges from 54 to238 episodes per 1 million per year. Patients with mildpancreatitis respond well to conservative therapy, butthose with severe pancreatitis may have a progressivelydownhill course to respiratory failure, sepsis, and death(less than 10%).

I. EtiologyA. Alcohol-induced pancreatitis. Consumption of

large quantities of alcohol may cause acute pan-creatitis.

B. Cholelithiasis. Common bile duct or pancreaticduct obstruction by a stone may cause acutepancreatitis. (90% of all cases of pancreatitis occursecondary to alcohol consumption orcholelithiasis).

C. Idiopathic pancreatitis. The cause of pancreatitiscannot be determined in 10 percent of patients.

D. Hypertriglyceridemia. Elevation of serum triglycer-ides (>l,000mg/dL) has been linked with acutepancreatitis.

E. Pancreatic duct disruption. In younger patients,a malformation of the pancreatic ducts (eg, pancre-atic divisum) with subsequent obstruction is oftenthe cause of pancreatitis. In older patients withoutan apparent underlying etiology, cancerous lesionsof the ampulla of Vater, pancreas or duodenummust be ruled out as possible causes of obstructivepancreatitis.

F. Iatrogenic pancreatitis. Radiocontrast studies ofthe hepatobiliary system (eg, cholangiogram,ERCP) can cause acute pancreatitis in 2-3% ofpatients undergoing studies.

G. Trauma. Blunt or penetrating trauma of any kind tothe peri-pancreatic or peri-hepatic regions mayinduce acute pancreatitis. Extensive surgicalmanipulation can also induce pancreatitis duringlaparotomy.

Causes of Acute Pancreatitis

AlcoholismCholelithiasisDrugsHypertriglyceridemiaIdiopathic causes

InfectionsMicrolithiasisPancreas divisumTrauma

Medications Associated with Acute Pancreatitis

Asparaginase (Elspar)Azathioprine (Imuran)Didanosine (Videx)EstrogensEthacrynic acid (Edecrin)Furosemide (Lasix)

Mercaptopurine(Purinethol)PentamidineSulfonamidesTetracyclinesThiazide diureticsValproic acid (Depakote)

II. Pathophysiology. Acute pancreatitis results when aninitiating event causes the extrusion of zymogengranules, from pancreatic acinar cells, into theinterstitium of the pancreas. Zymogen particles causethe activation of trypsinogen into trypsin. Trypsincauses auto-digestion of pancreatic tissues.

III. Clinical presentationA. Signs and symptoms. Pancreatitis usually pres-

ents with mid-epigastric pain that radiates to theback, associated with nausea and vomiting. Thepain is sudden in onset, progressively increases inintensity, and becomes constant. The severity ofpain often causes the patient to move continuouslyin search of a more comfortable position.

B. Physical examination1. Patients with acute pancreatitis often appear

very ill. Findings that suggest severe pancreati-tis include hypotension and tachypnea withdecreased basilar breath sounds. Flankecchymoses (Grey Tuner's Sign) orperiumbilical ecchymoses (Cullen's sign) maybe indicative of hemorrhagic pancreatitis.

2. Abdominal distension and tenderness in theepigastrium are common. Fever and tachycar-dia are often present. Guarding, rebound ten-

derness, and hypoactive or absent bowelsounds indicate peritoneal irritation. Deeppalpation of abdominal organs should beavoided in the setting of suspected pancreatitis.

IV.Laboratory testingA. Leukocytosis. An elevated WBC with a left shift

and e levated hematocr i t ( ind icat inghemoconcentration) and hyperglycemia are com-mon. Pre-renal azotemia may result from dehydra-tion. Hypoalbuminemia, hypertriglyceridemia,hypocalcemia, hyperbilirubinemia, and mild eleva-tions of transaminases and alkaline phosphataseare common.

B. Elevated amylase. An elevated amylase leveloften confirms the clinical diagnosis of pancreatitis.

C. Elevated lipase. Lipase measurements are morespecific for pancreatitis than amylase levels, butless sensitive. Hyperlipasemia may also occur inpatients with renal failure, perforated ulcer dis-ease, bowel infarction and bowel obstruction.

D. Abdominal Radiographs may reveal non-specificfindings of pancreatitis, such as "sentinel loops"(dilated loops of small bowel in the vicinity of thepancreas), ileus and, pancreatic calcifications.

E. Ultrasonography demonstrates the entire pan-creas in only 20 percent of patients with acutepancreatitis. Its greatest utility is in evaluation ofpatients with possible gallstone disease.

F. Helical high resolution computed tomographyis the imaging modality of choice in acute pancre-atitis. CT findings will be normal in 14-29% ofpatients with mild pancreatitis. Pancreatic necro-sis, pseudocysts and abscesses are readily de-tected by CT.

Selected Conditions Other Than PancreatitisAssociated with Amylase Elevation

Carcinoma of the pan-creas Common bile duct ob-struction Post-ERCPMesenteric infarction Pancreatic traumaPerforated viscusRenal failure

Acute alcoholismDiabetic ketoacidosisLung cancerOvarian neoplasmRenal failureRuptured ectopic preg-nancySalivary gland infectionMacroamylasemia

V. Prognosis. Ranson's criteria is used to determineprognosis in acute pancreatitis. Patients with two orfewer risk factors have a mortality rate of less than 1percent, those with three or four risk-factors a mortal-ity rate of 16 percent, five or six risk factors, a mortal-ity rate of 40 percent, and seven or eight risk factors,a mortality rate approaching 100 percent.

Ranson's Criteria for Acute Pancreatitis

At admission During initial 48 hours

1. Age >55 years2. WBC >16,000/mm3

3. Blood glucose >200mg/dL4. Serum LDH >350IU/L5. AST >250 U/L

1. Hematocrit drop >10%2. BUN rise >5 mg/dL3. Arterial pO2 <60 mm Hg4. Base deficit >4 mEq/L5. Serum calcium <8.0 mg/dL6. Estimated fluid sequestra-tion >6 L

VI. Treatment of pancreatitisA. Expectant management. Most cases of acute

pancreatitis will improve within three to sevendays. Management consists of prevention ofcomplications of severe pancreatitis.

B. NPO and bowel rest. Patients should take noth-ing by mouth. Total parenteral nutrition should beinstituted for those patients fasting for more thanfive days. A nasogastric tube is warranted ifvomiting or ileus.

C. IV fluid resuscitation. Vigorous intravenoushydration is necessary. A decrease in urine outputto less than 30 mL per hour is an indication ofinadequate fluid replacement.

D. Pain control. Morphine is discouraged becauseit may cause Oddi's sphincter spasm, which mayexacerbate the pancreatitis. Meperidine(Demerol), 25-100 mg IV/IM q4-6h, is favored.Ketorolac (Toradol), 60 mg IM/IV, then 15-30 mgIM/IV q6h, is also used.

E. Antibiotics. Routine use of antibiotics is notrecommended in most cases of acute pancreatitis.In cases of infectious pancreatitis, treatment withcefoxitin (1-2 g IV q6h), cefotetan (1-2 g IV q12h),imipenem (1.0 gm IV q6h), or ampicillin/sulbactam(1.5-3.0 g IV q6h) may be appropriate.

F. Alcohol withdrawal prophylaxis. Alcoholics mayrequire alcohol withdrawal prophylaxis withlorazepam (Ativan) 1-2mg IM/IV q4-6h as needed

x 3 days, thiamine 100mg IM/IV qd x 3 days, folicacid 1 mg IM/IV qd x 3 days, multivitamin qd.

G. Octreotide. Somatostatin is also a potent inhibitorof pancreatic exocrine secretion. Octreotide is asomatostatin analogue, which has been effectivein reducing mortality from bile-induced pancreati-tis. Clinical trials, however, have failed to docu-ment a significant reduction in mortality

H. Blood sugar monitoring and insulin adminis-tration. Serum glucose levels should be moni-tored.

VII.ComplicationsA. Chronic pancreatitisB. Severe hemorrhagic pancreatitisC. Pancreatic pseudocystsD. Infectious pancreatitis with development of sepsis

(occurs in up to 5% of all patients with pancreati-tis)

E. Portal vein thrombosis


Lower Gastrointestinal BleedingThe spontaneous remission rates for lower gastrointesti-nal bleeding is 80 percent. No source of bleeding can beidentified in 12 percent of patients, and bleeding isrecurrent in 25 percent. Bleeding has usually ceased bythe time the patient presents to the emergency room.

I. Clinical evaluationA. The severity of blood loss and hemodynamic status

should be assessed immediately. Initial manage-ment consists of resuscitation with crystalloidsolutions (lactated Ringers) and blood products ifnecessary.

B. The duration and quantity of bleeding should beassessed; however, the duration of bleeding isoften underestimated.

C. Risk factors that may have contributed to thebleeding include nonsteroidal anti-inflammatorydrugs, anticoagulants, colonic diverticulitis, renalfailure, coagulopathy, colonic polyps, and hemor-rhoids. Patients may have a prior history of hemor-rhoids, diverticulosis, inflammatory bowel disease,peptic ulcer, gastritis, cirrhosis, or esophagealvarices.

D. Hematochezia. Bright red or maroon output perrectum suggests a lower GI source; however, 12 to20% of patients with an upper GI bleed may havehematochezia as a result of rapid blood loss.

E. Melena. Sticky, black, foul-smelling stools suggesta source proximal to the ligament of Treitz, butMelena can also result from bleeding in the smallintestine or proximal colon.

F. Clinical findings1. Abdominal pain may result from ischemic

bowel, inflammatory bowel disease, or a rup-tured aneurysm.

2. Painless massive bleeding suggests vascularbleeding from diverticula, angiodysplasia, orhemorrhoids.

3. Bloody diarrhea suggests inflammatory boweldisease or an infectious origin.

4. Bleeding with rectal pain is seen with analfissures, hemorrhoids, and rectal ulcers.

5. Chronic constipation suggests hemorrhoidalbleeding. New onset of constipation or thinstools suggests a left sided colonic malignancy.

6. Blood on the toilet paper or dripping into thetoilet water suggests a perianal source of bleed-ing, such as hemorrhoids or an anal fissure.

7. Blood coating the outside of stools suggests alesion in the anal canal.

8. Blood streaking or mixed in with the stool mayresults from polyps or a malignancy in thedescending colon.

9. Maroon colored stools often indicate smallbowel and proximal colon bleeding.

II. Physical examinationA. Postural hypotension indicates a 20% blood

volume loss, whereas, overt signs of shock (pallor,hypotension, tachycardia) indicates a 30 to 40percent blood loss.

B. The skin may be cool and pale with delayed refill ifbleeding has been significant.

C. Stigmata of liver disease, including jaundice,caput medusae, gynecomastia and palmar ery-thema, should be sought because patients withthese findings frequently have GI bleeding.

III. Differential diagnosis of lower GI bleedingA. Angiodysplasia and diverticular disease of the

right colon accounts for the vast majority of epi-sodes of acute lower GI bleeding. Most acute lowerGI bleeding originates from the colon however 15

to 20 percent of episodes arise from the smallintestine and the upper GI tract.

B. Elderly patients. Diverticulosis and angiodysplasiaare the most common causes of lower GI bleeding.

C. Younger patients. Hemorrhoids, anal fissures andinflammatory bowel disease are most commoncauses of lower GI bleeding.

Clinical Indicators of Gastrointestinal Bleedingand Probable Source

Clinical Indicator

Probability ofUpper Gastroin-testinal source

Probability ofLower Gastroin-testinal Source

Hematemesis Almost certain Rare

Melena Probable Possible

Hematochezia Possible Probable

Blood-streakedstool

Rare Almost certain

Occult blood instool

Possible Possible

IV. Diagnosis and management of lower gastroin-testinal bleeding

A. Rapid clinical evaluation and resuscitationshould precede diagnostic studies. Intravenousfluids (1 to 2 liters) should be infused over 10- 20minutes to restore intravascular volume, and bloodshould be transfused if there is rapid ongoing bloodloss or if hypotension or tachycardia are present.Coagulopathy is corrected with fresh frozenplasma, platelets, and cryoprecipitate.

B. When small amounts of bright red blood arepassed per rectum, then lower GI tract can beassumed to be the source. In patients with largevolume maroon stools, nasogastric tube aspirationshould be performed to exclude massive uppergastrointestinal hemorrhage.

C. If the nasogastric aspirate contains no blood thenanoscopy and sigmoidoscopy should be performedto determine weather a colonic mucosal abnormal-ity (ischemic or infectious colitis) or hemorrhoidsmight be the cause of bleeding.

D. Colonoscopy in a patient with massive lower GIbleeding is often nondiagnostic, but it can detectulcerative colitis, antibiotic-associated colitis, orischemic colon.

E. Polyethylene glycol-electrolyte solution (CoLyteor GoLytely) should be administered by means ofa nasogastric tube (Four liters of solution is givenover a 2-3 hour period), allowing for diagnostic andtherapeutic colonoscopy.

V. Definitive management of lower gastrointestinalbleedingA. Colonoscopy

1. Colonoscopy is the procedure of choice fordiagnosing colonic causes of GI bleeding. Itshould be performed after adequate preparationof the bowel. If the bowel cannot be adequatelyprepared because of persistent, acute bleeding,a bleeding scan or angiography is preferable.

2. If colonoscopy fails to reveal the source of thebleeding, the patient should be observed be-cause, in 80% of cases, bleeding ceases spon-taneously.

B. Radionuclide scan or bleeding scan.Technetium- labeled (tagged) red blood cell bleed-ing scans can detect bleeding sites when bleedingis intermittent. Localization may not he a preciseenough to allow segmental colon resection.

C. Angiography. Selective mesenteric angiographydetects arterial bleeding that occurs at rates of 0.5mL/per minute or faster. Diverticular bleedingcauses pooling of contrast medium within a diver-ticulum. Bleeding angiodysplastic lesions appearas abnormal vasculature. When active bleeding isseen with diverticular disease or angiodysplasia,selective arterial infusion of vasopressin may beeffective.

D. Surgery1. If bleeding continues and no source can be

found, surgical intervention is usually warranted.Surgical resection may be indicated for patientswith recurrent diverticular bleeding, or for pa-tients who have had persistent bleeding fromcolonic angiodysplasia and have required bloodtransfusions.

2. Surgical management of lower gastrointestinalbleeding is ideally undertaken with a secureknowledge of the location and cause of thebleeding lesion. A segmental bowel resection toinclude the lesion and followed by a primaryanastomosis is usually safe and appropriate in

all but the most unstable patients.VI. Diverticulosis

A. Diverticulosis of the colon is present in more than50% of the population by age 60 years. Bleedingfrom diverticula is relatively rare, affecting only 4%to 17% of patients at risk.

B. In most cases, bleeding ceases spontaneously, butin 10% to 20% of cases, the bleeding continues.The risk of rebleeding after an episode of bleedingis 25%. Right-sided colonic diverticula occur lessfrequently than left-sided or sigmoid diverticula butare responsible for a disproportionate incidence ofdiverticular bleeding.

C. Operative management of diverticular bleeding isindicated when bleeding continues and is notamenable to angiographic or endoscopic therapy.It also should be considered in patients with recur-rent bleeding in the same colonic segment. Theoperation usually consists of a segmental bowelresection (usually a right colectomy or sigmoidcolectomy) followed by a primary anastomosis.

VII. Arteriovenous malformationsA. AVMs or angiodysplasias are vascular lesions that

occur primarily in the distal ileum, cecum, andascending colon of elderly patients. Thearteriographic criteria for identification of an AVMinclude a cluster of small arteries, visualization of avascular tuft, and early and prolonged filling of thedraining vein.

B. The typical pattern of bleeding of an AVM is recur-rent and episodic, with most individual bleedingepisodes being self-limited. Anemia is frequent,and continued massive bleeding is distinctly un-common. After nondiagnostic colonoscopy,enteroscopy should be considered.

C. Endoscopic therapy for AVMs may include heaterprobe, laser, bipolar electrocoagulation, or argonbeam coagulation. Operative management isusually reserved for patients with continued bleed-ing, anemia, repetitive transfusion requirements,and failure of endoscopic management. Surgicalmanagement consists of segmental bowel resec-tion with primary anastomosis.

VIII. Inflammatory bowel diseaseA. Ulcerative colitis and, less frequently, Crohn's

colitis or enteritis may present with major or mas-sive lower gastrointestinal bleeding. Infectiouscolitis can also manifest with bleeding, although itis rarely massive.

B. When the bleeding is minor to moderate, therapydirected at the inflammatory condition is appropri-ate. When the bleeding is major and causeshemodynamic instability, surgical intervention isusually required. When operative intervention isindicated, the patient is explored through a midlinelaparotomy, and a total abdominal colectomy withend ileostomy and oversewing of the distal rectalstump is the preferred procedure.

IX. Tumors of the colon and rectumA. Colon and rectal tumors account for 5% to 10% of

all hospitalizations for lower gastrointestinal bleed-ing. Visible bleeding from a benign colonic or rectalpolyp is distinctly unusual. Major or massive hemor-rhage rarely is caused by a colorectal neoplasm;however, chronic bleeding is common. When theneoplasm is in the right colon, bleeding is oftenoccult and manifests as weakness or anemia.

B. More distal neoplasms are often initially confusedwith hemorrhoidal bleeding. For this reason, thetreatment of hemorrhoids should always be pre-ceded by flexible sigmoidoscopy in patients olderthan age 40 or 50 years. In younger patients,treatment of hemorrhoids without further investiga-tion may be appropriate if there are no risk factorsfor neoplasm, there is a consistent clinical history,and there is anoscopic evidence of recent bleedingfrom enlarged internal hemorrhoids.

X. Anorectal diseaseA. When bleeding occurs only with bowel movements

and is visible on the toilet tissue or the surface ofthe stool, it is designated outlet bleeding. Outletbleeding is most often associated with internalhemorrhoids or anal fissures.

B. Anal fissures are most commonly seen in youngpatients and are associated with severe pain duringand after defecation. Other benign anorectalbleeding sources are proctitis secondary to inflam-matory bowel disease, infection, or radiation injury.Additionally, stercoral ulcers can develop in pa-tients with chronic constipation.

C. Surgery for anorectal problems is typically under-taken only after failure of conservative medicaltherapy with high-fiber diets, stool softeners, and/orhemorrhoidectomy.

XI. Ischemic colitisA. Ischemic colitis is seen in elderly patients with

known vascular disease. The abdomen pain may

be postprandial and associated with bloody diar-rhea or rectal bleeding. Severe blood loss is un-usual but can occur.

B. Abdominal films may reveal "thumb-printing"caused by submucosal edema. Colonoscopyreveals a well-demarcated area of hyperemia,edema and mucosal ulcerations. The splenicflexure and descending colon are the most com-mon sites. Most episodes resolve spontaneously,however, vascular bypass or resection may berequired.


Acute DiarrheaAcute diarrhea is defined as diarrheal disease of rapidonset, often with nausea, vomiting, fever, and abdominalpain. Most episodes of acute gastroenteritis will resolvewithin 3 to 7 days.

I. Clinical evaluation of acute diarrheaA. The nature of onset, duration, frequency, and

timing of the diarrheal episodes should be as-sessed. The appearance of the stool, buoyancy,presence of blood or mucus, vomiting, or painshould be determined.

B. Contact with a potential source of infectious diar-rhea should be sought.

C. Drugs that may cause diarrhea include laxatives,magnesium-containing compounds, sulfa-drugs,and antibiotics.

II. Physical examinationA. Assessment of volume status. Dehydration is

suggested by dry mucous membranes, orthostatichypotension, tachycardia, mental status changes,and acute weight loss.

B. Abdominal tenderness, mild distention andhyperactive bowel sounds are common in acuteinfectious diarrhea. The presence of reboundtenderness or rigidity suggests toxic megacolon orperforation.

C. Evidence of systemic atherosclerosis suggestsischemia. Lower extremity edema suggestsmalabsorption or protein loss.

III. Acute infectious diarrheaA. Infectious diarrhea is classified as

noninflammatory or inflammatory, depending onwhether the infectious organism has invaded theintestinal mucosa.

B. Noninflammatory infectious diarrhea is caused byorganisms that produce a toxin (enterotoxigenic Ecoli strains, Vibrio cholerae). Noninflammatory,infectious diarrhea is usually self-limiting and lastsless than 3 days.

C. Blood or mucus in the stool suggests inflam-matory disease, usually caused by bacterial inva-sion of the mucosa (enteroinvasive E coli, Shigella,Salmonella, Campylobacter). Patients usually havea septic appearance and fever; some have abdom-inal rigidity and severe abdominal pain.

D. Vomiting out of proportion to diarrhea is usuallyrelated to a neuroenterotoxin-mediated foodpoisoning from Staphylococcus aureus or Bacilluscereus, or rotavirus (in an infant), or Norwalk virus(in older children or adults). The incubation periodfor neuroenterotoxin food poisoning is less than 4hours, while that of a viral agent is more than 8hours.

E. Traveler's diarrhea is a common acute diarrhea.Three or four unformed stools are passed/per 24hours, usually starting on the third day of travel andlasting 2-3 days. Anorexia, nausea, vomiting,abdominal cramps, abdominal bloating, and flatu-lence may also be present.

F. Antibiotic-related diarrhea1. Antibiotic-related diarrhea ranges from mild

illness to life-threatening pseudomembranouscolitis. Overgrowth of Clostridium difficilecauses pseudomembranous colitis. Amoxicillin,cephalosporins and clindamycin have beenimplicated most often, but any antibiotic can bethe cause.

2. Patients with pseudomembranous colitis havehigh fever, cramping, leukocytosis, and severe,watery diarrhea. Latex agglutination testing forC difficile toxin can provide results in 30 min-utes.

3. Enterotoxigenic E colia. The enterotoxigenic E coli include the E coli

serotype 0157:H7. Grossly bloody diarrhea ismost often caused by E. coli 0157:H7, caus-ing 8% of grossly bloody stools.

b. Enterotoxigenic E coli can cause hemolyticu r e m i c s y n d r o m e , t h r o m b o t i cthrombocytopenic purpura, intestinal perfora-

tion, sepsis, and rectal prolapse.IV.Diagnostic approach to acute infectious diarrhea

A. An attempt should be made to obtain a pathologicdiagnosis in patients who give a history of recentingestion of seafood (Vibrio parahaemolyticus),travel or camping, antibiotic use, homosexualactivity, or who complain of fever and abdominalpain.

B. Blood or mucus in the stools indicates the pres-ence of Shigella, Salmonella, Campylobacterjejuni, enteroinvasive E. coli, C. difficile, or Yersiniaenterocolitica.

C. Most cases of mild diarrheal disease do not requirelaboratory studies to determine the etiology. Inmoderate to severe diarrhea with fever or pus, astool culture for bacterial pathogens (Salmonella,Shigella, Campylobacter) is submitted. If antibioticswere used recently, stool should be sent forClostridium difficile toxin.

V. Laboratory evaluation of acute diarrheaA. Fecal leukocytes is a screening test which should

be obtained if moderate to severe diarrhea ispresent. Numerous leukocytes indicate Shigella,Salmonella, or Campylobacter jejuni.

B. Stool cultures for bacterial pathogens should beobtained if high fever, severe or persistent (>14 d)diarrhea, bloody stools, or leukocytes is present.

C. Examination for ova and parasites is indicatedfor persistent diarrhea (>14 d), travel to a high-riskregion, gay males, infants in day care, or dysen-tery.

D. Blood cultures should be obtained prior to start-ing antibiotics if severe diarrhea and high fever ispresent.

E. E coli 0157:H7 cultures. Enterotoxigenic E colishould be suspected if there are bloody stools withminimal fever, when diarrhea follows hamburgerconsumption, or when hemolytic uremic syndromeis diagnosed.

F. Clostridium difficile cytotoxin should be ob-tained if diarrhea follows use of an antimicrobialagent.

G. Rotavirus antigen test (Rotazyme) is indicatedfor hospitalized children <2 years old withgastroenteritis. The finding of rotavirus eliminatesthe need for antibiotics.

VI.Treatment of acute diarrheaA. Fluid and electrolyte resuscitation

1. Oral rehydration. For cases of mild to moder-ate diarrhea in children, Pedialyte or Ricelyteshould be administered. For adults with diar-rhea, flavored soft drinks with saltine crackersare usually adequate.

2. Intravenous hydration should be used if oralrehydration is not possible.

B. Diet. Fatty foods should be avoided. Well-toleratedfoods include complex carbohydrates (rice, wheat,potatoes, bread, and cereals), lean meats, yogurt,fruits, and vegetables. Diarrhea often is associatedwith a reduction in intestinal lactase. A lactose-freemilk preparation may be substituted if lactoseintolerance becomes apparent.

VII. Empiric antimicrobial treatment of acute diar-rhea

A. Febrile dysenteric syndrome1. If diarrhea is associated with high fever and

stools containing mucus and blood, empiricantibacterial therapy should be given forShigella or Campylobacter jejuni.

2. Norfloxacin (Noroxin) 400 mg bid OR3. Ciprofloxacin (Cipro) 500 mg bid.

B. Travelers' diarrhea. Adults are treated withnorfloxacin 400 mg bid, ciprofloxacin 500 mg bid,or ofloxacin 300 mg bid for 3 days.


Chronic DiarrheaDiarrhea is considered chronic if it lasts longer than 2weeks.

I. Clinical evaluation of chronic diarrheaA. Initial evaluation should determine the characteris-

tics of the diarrhea, including volume, mucus,blood, flatus, cramps, tenesmus, duration, fre-quency, effect of fasting, stress, and the effect ofspecific foods (eg, dairy products, wheat, laxatives,fruits).

B. Secretory diarrhea1. Secretory diarrhea is characterized by large

stool volumes (>1 L/day), no decrease withfasting, and a fecal osmotic gap <40.

2. Evaluation of secretory diarrhea consists of agiardia antigen, Entamoeba histolytica antibody,

Yersinia culture, fasting serum glucose, thyroidfunction tests, and a cholestyramine (Cholybar,Questran) trial.

C. Osmotic diarrhea1. Osmotic diarrhea is characterized by small stool

volumes, a decrease with fasting, and a fecalosmotic gap >40. Postprandial diarrhea withbloating or flatus also suggests osmotic diar-rhea. Ingestion of an osmotically active laxativemay be inadvertent (sugarless gum containingsorbitol) or covert (with eating disorders).

2. Evaluation of osmotic diarrheaa. Trial of lactose withdrawal.b. Trial of an antibiotic (metronidazole) for small-

bowel bacterial overgrowth.c. Screening for celiac disease (anti-endomysial

antibody, antigliadin antibody).d. Fecal fat measurement (72 hr) for pancreatic

insufficiency.e. Trial of fructose avoidance.f. Stool test for phenolphthalein and magne-

sium if laxative abuse is suspected.g. Hydrogen breath analysis to identify

disaccharidase deficiency or bacterial over-growth.

D. Exudative diarrhea1. Exudative diarrhea is characterized by bloody

stools, tenesmus, urgency, cramping pain, andnocturnal occurrence. It is most often caused byinflammatory bowel disease, which may besuggested by anemia, hypoalbuminemia, and anincreased sedimentation rate.

2. Evaluation of exudative diarrhea consists of acomplete blood cell count, serum albumin, totalprotein, erythrocyte sedimentation rate, electro-lyte measurement, Entamoeba histolytica anti-body titers, stool culture, Clostridium difficileantigen test, ova and parasite testing, andflexible sigmoidoscopy and biopsies.


Inflammatory Bowel DiseaseUlcerative colitis is limited to the rectum and colon.Crohn's disease may involve both the small and the largebowel, but 15% to 25% of cases are isolated to thecolon. Both Crohn's disease and ulcerative colitis canfollow an active and remitting course and have a highlyvariable response to therapy.

I. Clinical presentationA. Crohn’s disease is a chronic, transmural,

granulomatous disorder that can involve anysegment of gastrointestinal tract from the mouth tothe anus. In the bowel it may affect multiple distinctsegments, with normal intervening bowel. Crohn’sdisease also may be complicated by intestinalstrictures, fistulas, and perianal fistulas. The clini-cal presentation of Crohn’s disease ranges fromintestinal obstruction, to bloody or nonbloodydiarrhea, to malabsorption.

B. Ulcerative colitis is a nongranulomatous inflam-matory condition that always starts in the rectumand extends proximally throughout the colon in acontinuous and confluent fashion, never involvingthe small bowel. The clinical presentation of ulcer-ative colitis is more uniform than that of Crohn’sdisease and includes rectal bleeding or bloodydiarrhea. In addition to gastrointestinal symptoms,extraintestinal manifestations can occur and mayinvolve the skin (eg, erythema nodosum, pyodermagangrenosum), joints (sacroiliitis, ankylosingspondylitis, and peripheral arthritis), eyes (iritis anduveitis), and liver (sclerosing cholangitis).Extraintestinal manifestations are due to the re-lease of bacterial antigens from the colonic lumen.

C. Differential diagnosis. In patients with new-onsetbloody diarrhea and abdominal cramps, an infec-tious cause must first be ruled out. In addition toroutine cultures, cultures for Clostridium difficile,ova and parasites, and hemorrhagic Escherichiacoli should be done. Colonic ischemia presentswith symptoms similar to those of IBD--abdominalcramps, rectal bleeding, and diarrhea--and shouldbe a consideration in older patients. Nonsteroidalanti-inflammatory drugs can also cause coloniculcerations that mimic colonic Crohn’s disease.

II. Induction therapyA. Mild-to-moderate Crohn’s disease

1. Patients with mild to moderate colonic Crohn’sdisease may be managed successfully with5-ASA products, such as sulfasalazine(Azulfidine), 1 g two to four times daily, whichproduces remission in about 50%.

2. Sulfasalazine is composed of a sulfapyridine

moiety attached to 5-ASA. It is activated in thecolon by colonic bacteria that releasessulfapyridine, which is then absorbed. The5-ASA remains in the colon. Side effects includenausea, gastrointestinal upset, rash, headache,and reversible male infertility. Rare hypersensi-tivity reactions include hemolytic anemia,neutropenia, and hepatitis.

3. For patients with colonic Crohn’s disease whoare unable to tolerate sulfasalazine or who areallergic to sulfa drugs, sulfa-free 5-ASA prod-ucts have been developed. Olsalazine(Dipentum), 500 mg two or three times daily,and balsalazide (Colazal), 2.25 g three timesdaily, work exclusively in the colon, whereas themesalamine preparations--Asacol, 800 to 1,600mg three or four times daily, and Pentasa, 1 gfour times daily--are released in the small boweland the colon.

4. Antibiotics also have been used in the treatmentof colonic Crohn’s disease. Metronidazole(Flagyl), 250 to 500 mg three times daily, hasbeen shown to be beneficial in colonic Crohn’sdisease as well as in Crohn’s in patients withperianal abscesses and fistulas. Ciprofloxacin(Cipro) has been used as an alternative tometronidazole for both colonic and perianalCrohn’s disease.

B. Mild-to-moderate ulcerative colitis1. Ulcerative colitis with fewer than six loose

bowel movements per day, with or withoutblood, and without significant weight loss oranemia is considered to be mild-to-moderatedisease. In this setting, 5-ASA drugs such assulfasalazine or Asacol are often used as pri-mary therapy. Onset of action is usually within 1week, but peak effect is not reached for 3 to 6weeks.

2. For patients with isolated proctitis, corticosteroid(Anusol) or mesalamine (Canasa) suppositorygiven once or twice a day is usually sufficienttherapy. When ulcerative colitis extends beyondthe rectum, corticosteroid foam (Cortifoam,ProctoFoam) or enema (Cortenema) ormesalamine enema (Rowasa) may be usednightly.

C. Moderate-to-severe Crohn’s disease1. Patients with moderate to severe Crohn’s dis-

ease often present with severe abdominal pain,diarrhea, weight loss, fever, and symptoms ofobstruction.

2. Budesonide (Entocort), 9 mg once daily, isapproved for the treatment of ileal and ileocecalCrohn’s disease. Although prednisone andbudesonide are equally efficacious,budesonide’s extensive first-pass metabolismthrough the liver and high affinity for theglucocorticoid receptor in the small bowel.

3. Another novel therapy for Crohn’s disease isinfliximab (Remicade), which is approved forinduction of remission. Infliximab is amonoclonal antibody to tumor necrosis factoralpha and is given intravenously. A singleoutpatient infusion of infliximab yielded a clinicalresponse in up to 80%.

4. Methotrexate, 25 mg intramuscularly, has beenshown to be efficacious in a subgroup of ste-roid-dependent patients.

D. Moderate-to-severe ulcerative colitis1. Patients presenting with moderate to severe

ulcerative colitis usually have more than sixloose to watery bowel movements per day, oftencontaining blood, along with abdominal cramps,weight loss, and anemia. Patients with ulcer-ative colitis may be treated with oral prednisoneor intravenous therapy.If a severely ill patientfails to respond within 7 to 10 days, intravenouscyclosporine or colectomy should be consid-ered.

2. Cyclosporine. In a trial of patients with ulcer-ative colitis refractory to corticosteroids, 83%responded to cyclosporine. Cyclosporine shouldbe used as a transitional agent or bridge tolonger-term therapy with an immunomodulatingdrug or to elective colectomy.

III. Maintenance therapy A. Most of the drugs used for induction of remission

also may be used for maintenance therapy. Treat-ments include 5-ASA products, immunomodulators(6-mercaptopurine [Purinethol] and azathioprine[Imuran]), and infliximab. Corticosteroids, however,should almost never be used for long-term therapy.

B. For patients with Crohn’s disease or ulcerativecolitis refractory to prednisone therapy or whobecome prednisone-dependent, use ofimmunomodu la t i ng agen ts such as6-mercaptopurine, 1.5 to 2 mg/kg per day, and its

prodrug azathioprine, 2 to 2.5 mg/kg per day, hasproved beneficial. Infliximab has recently beenshown to be efficacious in the maintenance ofremission for Crohn’s disease.


Neurologic Disorders

Ischemic StrokeIschemic stroke is the third leading cause of death in theUnited States and the most common cause of neurologicdisability in adults. Approximately 85 percent of strokesare ischemic in nature.

I. Clinical evaluation of the stroke patientA. A rapid evaluation should determine the time when

symptoms started. Other diseases that may mimica stroke, such as seizure disorders, metabolicabnormalities, hypoglycemia, complex migraine,dysrhythmia or syncope, infection, should beexcluded.

B. Markers of vascular disease such as diabetes,angina pectoris and intermittent claudication, aresuggestive of ischemic stroke. A history of atrialfibrillation or MI suggests a cardiac embolic stroke.

C. The most difficult cases involve patients with focalsigns and altered level of consciousness. It isimportant to ask whether the patient takes insulinor oral hypoglycemic agents, has a history of aseizure disorder or drug overdose or abuse, medi-cations on admission, or recent trauma.

Acute Stroke Differential Diagnosis

MigraineIntracerebraI hemorrhageHead traumaBrain tumorTodd's palsy (paresis, aphasia, neglect, etc. after a seizureepisode) Functional deficit (conversion reaction) Systemic infectionToxic-metabolic disturbances (hypoglycemia, acute renalfailure, hepatic insufficiency, exogenous drug intoxication)

II. Physical examinationA. Assessment should determine whether the pa-

tient's condition is acutely deteriorating or relativelystable. Airway and circulatory stabilization takeprecedence over diagnostic and therapeutic inter-ventions.

B. Blood pressure. The mean arterial blood pressure(MAP) is usually elevated in patients with an acutestroke. This may be due to chronic hypertension,which is a major risk factor for ischemic stroke.However, in many cases the acutely elevated bloodpressure is necessary to maintain brain perfusion.Measuring ICP directly allows blood pressure to bereduced as low as possible while still maintainingthe CPP above 60 mm Hg.

C. Neurologic exam. Evaluation should include thelevel of consciousness, orientation; ability to speakand understand language; cranial nerve function,especially eye movements, pupil reflexes and facialparesis; neglect, gaze preference, arm and legstrength, sensation, and walking ability. A semicon-scious or unconscious patient probably has ahemorrhage. A patient with an ischemic stroke maybe drowsy but is unlikely to lose consciousnessunless the infarcted area is large.

D. Neck and retroorbital regions should be evalu-ated for vascular bruits, and palpation of pulses inthe neck, arms, and legs to assess for their ab-sence, asymmetry, or irregular rate. The heartshould be auscultated for murmurs.

E. Skin should be examined for cholesterol emboli,purpura, or ecchymoses. The funduscopic exami-nation may reveal cholesterol emboli orpapilledema. The head should be examined forsigns of trauma. A tongue laceration may occurwith tongue biting during a seizure.

III. CT scanning and diagnostic studiesA. Imaging studies. In the evaluation of the acute

stroke patient, imaging studies are used to ex-clude hemorrhage, to assess the degree of braininjury, and to identify the vascular lesion responsi-ble for the ischemic deficit.1. Computed tomography

a. The main advantages of computed tomogra-phy (CT) are widespread access and speedof acquisition. In the hyperacute phase, anoncontrast CT scan is usually ordered toexclude or confirm hemorrhage; it is highlysensitive.

b. Using new generation CT scanners, a subtlelow density lesion is a specific indicator ofinfarction in almost 50 percent of patientswithin six hours of a stroke. Early signs ofinfarction include subtle parenchymalhypodensity can be detected in 45 to 85percent of cases, especially in the basalganglia and insular cortex area. Early focalbrain swelling is present in up to 40 percentof patients and also has been adverselyrelated to outcome.

c. Early CT changes include effacement ofsulci or ventricles, blurring of the basalganglia, mass effect, and loss of the normalgray-white junction in the insula.

2. CT angiography. Spiral (helical) CT scansoffer angiographic capabilities. CT angiography(CTA) can be performed immediately afterconventional CT scanning, requires only fiveminutes of additional examination time, andprovides a look at the perfusion status of thebrain parenchyma.

3. Magnetic resonance imaging. Diffusionweighted imaging (DWI) can detect abnormali-ties due to ischemia within 15 to 30 minutes ofonset, with three seconds of imaging time.

4. Transcranial Doppler ultrasound (TCD) usessound to penetrate bony windows and visualizeintracranial vessels of the circle of Willis. It hasgained wide acceptance as a noninvasivemeans of assessing the patency of intracranialvessels.

5. Carotid duplex ultrasound is a noninvasiveexamination to evaluate extracranialatherosclerotic disease. It may help to establishthe source of an embolic stroke, but is rarelyused acutely for this purpose.

6. Other studies. Electrocardiography detectschronic arrhythmias which predispose to em-bolic events (eg, atrial fibrillation).Transthoracic and transesophagealechocardiography adequately detect cardio-genic and aortic sources for cerebral embolism.

B. Complete blood count including platelets,international normalized ratio, activated partialthromboplastin time, serum electrolytes, and arapid blood glucose should be obtained. ECG,and chest x-ray should be ordered. Arterial bloodgas and lumbar puncture should be obtainedwhen indicated.

Laboratory studies

Complete blood count and erythrocyte sedimentation rateElectrolytes, urea nitrogen, creatinine, glucoseLiver function testsProthrombin time and partial thromboplastin timeToxicology screenBlood for type and cross matchUrine human chorionic gonadotropin in women ofchild-bearing potentialConsider evaluation for hypercoagulable state in youngpatients without apparent stroke risk factors

Criteria for thrombolysis in acute ischemicstroke using tissue plasminogen activator

Inclusion criteriaAge greater than 18 yearsClinical diagnosis of ischemic stroke, with onset of symp-toms within three hours of initiation of treatmentNoncontrast CT scan with no evidence of hemorrhage

Exclusion criteria History Stroke or head trauma in previous three months History of intracranial hemorrhage that may increase riskof recurrent hemorrhageMajor surgery or other serious trauma in previous 14 daysGastrointestinal or genitourinary bleeding in previous 21daysArterial puncture in previous seven days Pregnant or lactating patientClinical findingsRapidly improving stroke symptomsSeizure at onset of strokeSymptoms suggestive of subarachnoid hemorrhage, evenif CT scan is normalPersistent systolic pressure greater than 185 mm Hg ordiastolic pressure greater than 110 mm Hg, or patient isrequiring aggressive therapy to control blood pressureClinical presentation consistent with acute myocardialinfarction or postmyocardial infarction pericarditis requirescardiologic evaluation before treatmentImaging resultsCT scan with evidence of hemorrhageCT scan with evidence of hypodensity and/or effacementof cerebral sulci in more than one-third of middle cerebralartery territoryLaboratory findings Glucose level less than 50 mg per dL or greater than 400mg per dLPlatelet count less than 100,000 per mm3

Warfarin therapy with an international normalized ratio>1.7Patient has received heparin within 48 hours, and partialthromboplastin time is increased

IV. Management of ischemic strokeA. Thrombolytic therapy

1. Intravenous thrombolysisa. Thrombolytic therapy administered within

three hours of the onset of symptoms re-duces disability, but at the expense of anincrease in deaths within the first seven toten days and an increase in the risk ofintracranial hemorrhage. Administration ofalteplase within three hours of symptomonset will result in one more independentsurvivor for every ten patients treated, onefewer death for every 100 patients treated,and one additional symptomatic hemor-rhage for every 14 patients treated. Thebenefits of treatment outweigh the riskswithin three hours of symptom onset.

b. Alteplase is administered in a dose of 0.9mg/kg (max 90 mg), with 10 percent of thetotal dose given as an initial bolus and theremainder infused over 60 minutes, pro-vided that treatment is initiated within threehours of symptom onset.

Initial management of acute stroke

Determine whether stroke is ischemic or hemorrhagic bycomputed tomography

Consider administration of t-PA if less than three hoursfrom stroke onset

General management:• Blood pressure (avoid hypotension)• Assure adequate oxygenation • Administer intravenous glucose • Take dysphagia/aspiration precautions • Consider prophylaxis for venous thrombosis if the pa-

tient is unable to walk • Suppress fever, if present • Assess stroke mechanism (eg, atrial fibrillation, hyper-

tension) • Consider aspirin or clopidogrel (Plavix) therapy if

ischemic stroke and no contraindications (begin 24hours after t-PA).

c. Treatment of patients not eligible fort h r o m b o l y s i s . H e p a r i n ,low-molecular-weight heparin, and aspirinmay be considered in the majority of patientswho, because of time (ie, more than threehours from symptom onset) or medical rea-sons, are not eligible for intravenousalteplase.

(1) Full-dose anticoagulation is not recom-mended for treatment of ischemic strokebecause of limited efficacy and an in-creased risk of bleeding complications.Early anticoagulation should be avoidedwhen potential contraindications toanticoagulation are present, such as alarge infarction, uncontrolled hypertension,or other bleeding conditions.

(2) Early anticoagulation may be warrantedfor treatment of acute cardioembolic andlarge-artery ischemic strokes and forprogressing stroke when the suspectedmechanism is ongoing thromboembolism

In the selected patients who receive hepa-rin in the acute stroke setting, a bolus isnot administered. A weight-basednomogram for heparin infusion should beused.

B.Antiplatelet agents1. Aspirin therapy in acute ischemic stroke leads to

a reduction of 11 nonfatal strokes or deaths per1000 patients in the first few weeks.

2. Aspirin therapy (160 to 325 mg/day) should begiven to patients with ischemic stroke who arenot receiving alteplase, intravenous heparin, ororal anticoagulants. Aspirin should be givenwithin 48 hours of stroke onset and may also beused in combination with subcutaneous heparinfor deep vein thrombosis prophylaxis.

3. Aspirin, clopidogrel (Plavix) (75 mg/day), andthe combination of extended-releasedipyridamole and aspirin (25/200 mg twice daily)are all acceptable options. However, initialtherapy with aspirin (50 to 325 mg per day) isrecommended. Clopidogrel or ticlopidine (Ticlid)are alternatives for patients intolerant to aspirin.

Antiplatelet Agents for Prevention of IschemicStoke

• Enteric-coated aspirin (Ecotrin) 325 mg PO qd• Clopidogrel (Plavix) 75 mg PO qd• Extended-release aspirin 25 mg with dipyridamole 200

mg (Aggrenox) one tab PO qd


Transient Ischemic AttackTransient ischemic attack (transient cerebral ischemia,TIA) is a temporary focal neurologic deficit caused by thebrief interruption of local cerebral blood flow. The preva-lence of TIAs 1.6-4.1 percent. Stroke occurs in one-thirdof patients who have a TIA. The duration of a focalneurologic deficit that leads to cerebral infarction hasarbitrarily been determined to be 24 hours or greater.

I. Pathophysiology. The most frequent mechanism ofTIA is embolization by a thrombus from anatherosclerotic plaque in a large vessel (stenoticcarotid artery). TIAs may also occur as manifestationsof intracranial atherosclerotic disease (lacunar TIAs)or large-vessel occlusion. In addition, they can beassociated with atrial fibrillation or mitral valve pro-lapse, carotid or vertebral dissection, andhypercoagulable states (antiphospholipid antibodysyndrome).

II. Evaluation of TIA symptoms A. The primary objective when evaluating a patient

with a transient ischemic attack (TIA) is to deter-mine whether the ischemic insult has occurred inthe anterior or posterior circulation.

B. Anterior circulation ischemia causes motor orsensory deficits of the extremities or face,amaurosis fugax, aphasia, and/or homonymoushemianopia.

C. Posterior circulation ischemia causes motor orsensory dysfunction in association with diplopia,dysphasia, dysarthria, ataxia, and/or vertigo.

D. Assessment should determine the activity in whichthe patient was engaged and the patient's physicalposition at the onset of the attack. A description ofthe specific symptoms of the attack should beobtained, including the speed with which theydeveloped, whether they were bilateral or unilat-eral, and their duration.

E. History of hypertension, diabetes, cardiac disease,previous TIA or stroke, cigarette smoking, or useof street drugs should be sought.

F. Differentiating TIAs from other entities1. Seizures almost always involve a change in the

level of consciousness or awareness, excessivemotor activity and confusion, none of whichcharacterizes a TIA.

2. Syncope. Changes in cardiac output producegeneralized, rather than focal, cerebralischemia, characterized by loss of conscious-ness and a rapid heartbeat (often due to anarrhythmia).

3. Benign positional vertigo. Recurrent waves ofdizziness, which last 2-10 seconds and arerelated to movement (standing up or sittingdown), are characteristic.

G. Physical examination1. Heart rate and rhythm and the blood pressure

in both arms, peripheral pulses, skin lesions(petechiae of embolic origin), and skinmanifestations of connective tissue disease

should be assessed.2. Carotid bruits may suggest carotid stenosis.

Ophthalmoscopic examination can detectarterial or venous occlusion and emboli.

3. Neurologic examinationa. The neurologic examination should be nor-

mal in TIA patients unless the patient hashad a previous stroke or is currently experi-encing a TIA or stroke.

b. Evaluation should include the level of con-sciousness, orientation, ability to speak andunderstand language; cranial nerve function,especially eye movements and pupil reflexesand facial paresis. Neglect, gaze preference,arm and leg strength, sensation, and walkingability should be assessed.

III. Differential diagnosis and symptoms

Common Clinical Findings Associated withIschemia in Various Arterial Distributions Anterior cerebral arteryWeakness incontralateral legSensory loss incontralateral leg, with orwithout weakness ornumbness in proximalcontralateral armMiddle cerebral arteryContralateral hemiparesisDeviation of head andeyes toward side of lesionContralateral hemianesthesiaContralateral hemianopiaAphasia (if dominanthemisphere is affected)Unawareness of stroke (ifnondominant hemisphereis affected)

Lenticulostriate arteriesPure motor hemiparesis(lacunar syndrome)Posterior cerebral arteryVisual field disturbanceContralateral sensory lossAmnesiaVertebrobasilar arteriesVertigoNausea and vomitingAtaxiaNystagmus

IV. Laboratory studies

Initial Evaluation of a Patient with TransientIschemic Attack

Complete blood cell count with platelet countChemistry profile (including cholesterol and glucose levels)Prothrombin time and activated partial thromboplastin timeErythrocyte sedimentation rateSyphilis serologyElectrocardiographyCranial computed tomography (particularly with hemi-spheric transient ischemic attack)Noninvasive arterial imaging (ultrasonography, magneticresonance angiography)

A. Complete blood count with differential rules outprofound anemia, polycythemia, leukocytosis,thrombocytopenia and thrombocytosis. The chem-istry profile may demonstrate hypoglycemia thatcan present with focal neurologic deficits orhyperglycemia that can worsen the outcome afterstroke.

B. Prothrombin time and an activated partialthromboplastin time are needed to rule outcoagulopathies. The erythrocyte sedimentationrate serves as a screening test for autoimmunedisorders. Syphilis serology screens forneurosyphilis.

C. Electrocardiogram (ECG) is used to detectarrhythmias (eg, atrial fibrillation) as the cause ofischemia. Computed tomographic (CT) scanningof the head is necessary to rule out intracranialbleeding or tumors. CT may reveal the vasculardistribution of previous ischemic events.

D. Carotid duplex studies are recommended in allpatients with TIA symptoms. These tests (eg,Doppler plus B-mode imaging) detect extracranialcarotid disease.

E. Echocardiography may be helpful in identifyingatrial thrombus in patients with atrial fibrillation.Transcranial Doppler ultrasonography can revealintracranial stenosis of the middle cerebral orposterior cerebral arteries.

F. Magnetic resonance angiography is used todetect stenosis in extracranial or intracranialcerebral arteries. Arteriography is reserved forsuspected intracranial vasculitis or arterial dissec-tion.

G. Special testing for hypercoagulable states(antiphospholipid antibodies) protein C and S,antithrombin III should be reserved for use inpatients less than 50 years of age, patients with ahistory of thrombotic disease and patients in whomno other cause of TIA is found. Holter monitoringis recommended for use in patients who hadpalpitations.

H. Lumbar puncture may be warranted if centralnervous system infection is suspected or the

presenting symptoms suggest subarachnoidhemorrhage but the CT scan is negative.

V. TreatmentA. Reduction of risk factors

1. Aggressive treatment of chronic hypertensionshould maintain the systolic blood pressurebelow 140 mm Hg and the diastolic bloodpressure below 90 mm Hg.

2. Cigarette smoking and consumption of three ormore alcohol drinks per day should be discour-aged.

3. Atrial fibrillation is one of the strongest inde-pendent risk factors for stroke. Warfarin(Coumadin) or aspirin is effective for strokeprevention in patients with atrial fibrillation.

B. Carotid endarterectomy guidelines1. Surgery is recommended in symptomatic pa-

tients with 70 percent carotid stenosis.2. Surgery may be considered in symptomatic

patients with carotid stenosis of 50 to 69 per-cent. The risks and benefits of surgery shouldbe carefully considered in these patients.

3. Surgery should not be considered in patientswith carotid stenosis of less than 50 percent.

C. Stroke prevention, antithrombotic therapy1. Aspirin. Because aspirin inactivates

cyclooxygenase activity for the life of platelets,thromboxane A2 cannot be produced. Aspirin ina dosage of 75 to 325 mg per day is recom-mended for all TIA patients for stroke preven-tion. Clopidogrel or ticlopidine are alternativesfor patients who cannot tolerate aspirin.

2. Clopidogrel (Plavix), 75 mg qd, is recom-mended for patients who can not tolerateaspirin. Clopidogrel has fewer side effects thanticlopidine.

3. Ticlopidine (Ticlid) inhibits platelet aggrega-tion and is recommended for patients who cannot tolerate aspirin. The dosage is 250 mg PObid. Adverse events include neutropenia,thrombocytopenia, diarrhea, rash, abnormalliver function tests and elevated cholesterollevels. Close monitoring of complete bloodcount is required for the first three months.

4. Aggrenox Cap ER (Aspirin 25 mg,Dipyridamole 200 mg) is an alternative forpatients who have an event while on aspirinalone. 1 cap bid. Side effects include GI bleed-ing, headache, diarrhea.


Alzheimer's DiseaseAlzheimer's disease currently affects about 4 millionpeople in the United States. This neurodegenerativedisease causes selective neuronal loss in brain regionsinvolved in memory, language, personality, and cogni-tion. The earliest symptom of Alzheimer's disease isusually the insidious onset and progression of memoryloss. Initially, this memory loss can be difficult to differen-tiate from common age-associated benign forgetfulness.However, patients with age-associated benign forgetful-ness are aware of the deficit and their activities of dailyliving are minimally impaired.

I. PathogenesisA. Age is the major risk factor for development of

Alzheimer's disease. The incidence of Alzheimer'sdisease increases with age, doubling every 5 yearsbetween ages 60 and 85. Limited education and ahistory of head trauma may also be factors indevelopment of disease.

B. The presenilin 1 gene is the most common site ofmutations responsible for early-onset Alzheimer'sdisease. Genetic testing should be restricted topatients with early-onset Alzheimer's disease anda strong family history of dementia.

C. Onset of dementia symptoms after age 60 occursin about 90% of patients with Alzheimer's disease.

II. Diagnosis

Criteria for diagnosis of Alzheimer's disease

Dementia established by clinical examination and docu-mented by the Mini-Mental State Examination or similarexamination Deficits in two or more areas of cognition (ie, language,memory, perception) Progressive worsening of memory and other cognitivefunction; as disease progresses, patient experiencesimpairment in activities of daily living and altered behav-ioral patterns No disturbance of consciousness Onset between ages 40 and 90, but most often after age65 Absence of other systemic disorder or brain disease thatmay account for deficits in memory and cognition

A. Computed tomographic scanning and magneticresonance imaging often show generalized andhippocampal atrophy in patients with Alzheimer'sdisease. These tests are not sensitive enough toestablish a diagnosis. Imaging is useful in exclud-ing a diagnosis of stroke, tumor, or hydrocephalus.

B. Delirium should be excluded and coexisting condi-tions that worsen dementia by reviewing medica-tions, screening for depression, and ruling outnutritional deficiencies, diabetes mellitus, uremia,alterations in electrolytes and thyroid disease.

III. Treatment of Cognitive Deficits in Alzheimer'sDiseaseA. Cholinesterase Inhibitors. Treatment with

cholinesterase inhibitors can provide modestimprovement of symptoms, temporary stabilizationof cognition, or reduction in the rate of cognitivedecline in mild to moderate Alzheimer's disease.Approximately 20 to 35 percent exhibit aseven-point improvement on neuropsychologictests (5 to 15 percent benefit). These agents raiseacetylcholine levels in the brain by inhibitingacetylcholinesterase.

Cholinesterase Inhibitors for the Treatment ofMild-to-Moderate Alzheimer's Disease

Drug Dosage Side effects Specificcautions

Donepezil (Aricept)

Initial dos-age is 5 mgonce daily; ifnecessary,dosage canbe in-creased to10 mg oncedaily after 4to 6 weeks.

Mild side ef-fects, includingnausea, vomit-ing, and diar-rhea; effectscan be re-duced by tak-ing with food.Initial increaseof agitation insome; agita-tion subsidesafter a fewweeks.

Possible in-teractionswithcimetidine(Tagamet),theophylline,warfarin(Coumadin),and digoxin(Lanoxin)

Rivastigmine(Exelon)

Initial dos-age of 1.5mg bid (3mg per day)is well toler-ated; dos-age can beincreased astolerated tomaximum of6 mg twicedaily (12 mgper day).

Nausea, vomit-ing, diarrhea,headaches,dizziness, ab-dominal pain,fatigue, mal-aise, anxiety,and agitation;these effectscan be re-duced by tak-ingrivastigminewith food.

Weight lossInteractingdrugs includeamino-glycosidesandprocainamide(Procanbid).

Galantamine(Reminyl)

Initial dos-age is 4 mgbid (8 mgper day) for4 weeks;dosage isthen in-creased to 8mg twicedaily (16 mgper day) forat least 4weeks. Anincrease to12 mg twicedaily (24 mgper day)should beconsidered.

Mild side ef-fects, includingnausea, vomit-ing, and diar-rhea; theseeffects can bereduced bytakinggalantaminewith food.No apparentassociationwith sleep dis-turbances(which canoccur withothercholinergictreatments)

Contraindi-cated for usein patientswith hepaticor renal im-pairment

Tacrine(Cognex)

Initial dos-age is 10mg fourtimes daily(40 mg perday) for 4weeks.

High incidenceof side effects,including gas-trointestinalproblems.

Hepatotoxicity is a prob-lem; hence,liver testsshould beperformed.

1. Donepezil (Aricept) is given once daily, begin-ning with a dosage of 5 mg per day, which canbe increased to 10 mg per day (max) after fourweeks. Donepezil is not hepatotoxic. Adverseeffects are mild (eg, nausea, vomiting, anddiarrhea) and are reduced when taken withfood. An initial increase in agitation may occur,which subsides after the first few weeks.Donepezil produces improvements of cognitiveand global function with mild-to-moderateAlzheimer's disease.

2. Rivastigmine (Exelon) is initiated in a dosageof 1.5 mg twice daily. The dosage is increasedby 1.5 mg twice daily (3 mg per day) as toler-ated, every four weeks, to a maximum of 6 to12 mg per day. No laboratory monitoring isrequired. Adverse effects include nausea,vomiting, diarrhea, weight loss, headaches,dizziness, abdominal pain, fatigue, malaise,anxiety, and agitation. Rivastigmine has beenis effective in temporarily slowing cognitivedecline, improving function, and reducingbehavioral and psychopathologic symptoms inmild-to-moderate Alzheimer's disease.

3. Galantamine (Reminyl) starting dosage is 4mg twice daily, taken with morning and eveningmeals. After four weeks, the dosage is in-creased to 8 mg twice daily. An increase to 12mg twice daily may be considered. The mostcommon side effects are nausea, vomiting, anddiarrhea, which can be minimized by titratingthe dosage gradually and taking the medicationwith meals. Improvement of cognitive andfunctional outcomes and behavioral symptomshas been demonstrated.

4. Tacrine (Cognex) is a second-line agentbecause, unlike the newer cholinesteraseinhibitors, tacrine causes elevation of liverenzyme levels; thus, biweekly liver tests arenecessary.

5. Beneficial response to a cholinesterase inhibi-tor can be determined from the physician'sglobal assessment of the patient, the primarycaregiver's report, a neuropsychologic assess-ment or mental status questionnaire, or evi-dence of behavioral or functional changes.Observation for six to 12 months is usuallynecessary to assess potential benefit.

B. Vitamin E intake of 2,000 IU daily of may slow theprogression of functional symptoms.

C. N-methyl-D-aspartate (NMDA) receptor antago-nists1. Glutamate is the principle excitatory amino acid

neurotransmitter in cortical and hippocampalneurons. One of the receptors activated byglutamate is the N-methyl-D-aspartate (NMDA)receptor, which is involved in learning andmemory.

2. Memantine (Axura, Ebixa) is an NMDA recep-tor antagonist. In patients with mild-to-moder-ate vascular dementia (mini mental statusexamination scores 12 to 20), memantinesignificantly improves cognitive abilities. Therewere no serious side effects with therapy. Thismay represent a promising avenue for thetreatment of vascular dementia.

IV.Comorbid conditions. Depression is common inolder adults, including those with Alzheimer's disease.Selective serotonin reuptake inhibitors, such ascitalopram (Celexa) and sertraline (Zoloft), appear tobe effective and have few side effects; thus, they arethe agents of choice for the treatment of depression.


Seizure Disorders and EpilepsyEpilepsy is a disorder that consists of recurrent seizures.Epilepsy occurs in 1 to 2 percent of the general popula-tion. The incidence of epilepsy is highest in infancy. Itdecreases during childhood and is lowest in adoles-cence. The incidence markedly increases in elderlypatients.

I. Clinical evaluationA. Epileptic seizures are behavioral changes resulting

from paroxysmal, excessive electrical dischargesfrom the brain. Not all jerks, shakes, and episodicbehaviors are seizures. For example, tics, tremors,dystonia, and attention-deficit disorder can imitateepileptic seizures.

B. Once a paroxysmal behavioral event is identified asa seizure, the next step is to determine whether it isepilepsy or a secondary effect of hypoxia,hypoglycemia, infection, fever, and toxic substanceabuse (eg, alcohol withdrawal, cocaine use).

Epilepsy is characterized by recurrent seizures (ie,at least two seizures are needed for diagnosis).

C. Epilepsy can result from either inherited or acquiredfactors. Head injury, stroke, brain tumor, corticaldysplasia, and infection are common causes ofboth seizures. In many cases, the cause of epilepsyremains unknown.

Nonepileptic paroxysmal disorders that canmimic epileptic seizure

Syncope ! Reflex (vasovagal, carotid sinus, glossopharyngeal,

cough) ! Decreased cardiac output ! Decreased left ventricular filling (hypovolemia,

orthostatic hypotension, pulmonary embolism) ! Cardiac arrhythmia

Migraine with auras, basilar migraine, confusional migraine Transient ischemic attackPeriodic paralysis Sleep disorders (parasomnias, daytime amnestic episodes) Gastrointestinal disorders (reflux, motility disorders) Movement disorders (tics, Tourette's syndrome,nonepileptic myoclonus, paroxysmal choreoathetosis,shuddering attacks) Psychiatric disorders (panic, somatization, dissociation,conversion [nonepileptic psychogenic seizures]) Drug toxicity and substance abuse Breath-holding spells

II. Features of epileptic seizuresA. Epileptic seizures are divided into two broad cate-

gories--generalized and partial. Generalized sei-zures arise from both sides of the brain simulta-neously. Partial (ie, focal) seizures occur within oneor more restricted regions of the brain.

Classification of epileptic seizures

Generalized Partial

AbsenceMyoclonicTonicAtonicClonicTonic-clonic (grand malseizure)

Simple partial (conscious-ness not impaired)Complex partial (con-sciousness impaired)Partial with secondary gen-eralization (can betonic-clonic, tonic, orclonic)

B. Partial seizures are further classified as simple,complex, or secondarily generalized. Simple partialseizures alter behavior but do not impair conscious-ness. Complex partial seizures alter conscious-ness. Partial seizures can also become secondarilygeneralized, causing tonic and clonic movements.

C. History of the event. A witnessed, 90-secondepisode that involved loss of consciousness,stiffening, and jerking of the extremities followed bymuscle soreness, headache, and the need to sleepfor several hours afterwards strongly suggests atonic-clonic seizure.

History of a suspected seizure

Before the eventUnusual stress (eg, severe emotional trauma)Sleep deprivationRecent illnessUnusual stimuli (eg, flickering lights)Use of medicationsand drugsActivity immediately before event (eg, change in posture,exercise)

During the eventSymptoms at onset (eg, aura)Temporal mode of onset: gradual versus suddenDuration: brief (ictal phase <5 min) versus prolongedStereotypy: duration and features of episodes nearly identi-cal versus frequently changingTime of day: related to sleep or occurring on awakeningAbility to talk and respond appropriatelyAbility to comprehendAbility to recall events during the seizureAbnormal movements of the eyes, mouth, face, head,arms, and legsBowel or bladder incontinenceBodily injury

After the eventConfusionLethargyAbnormal speechFocal weakness or sensory loss (ie, Todd's paralysis)Headache, muscle soreness, or physical injury

D. A witness should answer the following ques-tions:1. What was the patient doing at the onset? Did the

event begin with arrested speech, odd behavior,

or repetitive actions? Evidence of any focalrhythmic behavior of the face or extremities atthe onset suggests partial epilepsy.

2. What was the patient doing during the event?Signs may include: tonic movements or postur-ing seen as stiffening, most often of the extremi-ties or axial body; clonic movements; a rhythmicflexion-extension movement of the extremities;loss of consciousness; incontinence; and tonguebiting.

3. What was the duration of the ictal event? Thisinformation can differentiate true seizure frompsychogenic events, which often last longer.

4. What was the patient doing after the ictal event?Focal deficits and Todd's paralysis are commonfindings. The presence of postictal confusionmay help differentiate between seizure andsyncope.

III.Past medical historyA. Meningitis, encephalitis, head trauma, cancer, or

cerebrovascular disease suggests the cause ofepilepsy focus. In diabetic patients, hypoglycemia(glucose less than 40 mg/dL) or hyperglycemia(glucose higher than 300 mg/dL) may precipitateseizures. Hyponatremia, hypocalcemia, hypomag-nesemia, hypoparathyroidism, hypothyroidism alsomay cause seizures.

B. Medications. Theophylline, meperidine (Demerol),isoniazid, antipsychotic drugs (clozapine [Clozaril],phenothiazines), radiocontrast dyes, alkylatingagents, and ß-lactam antibiotics are among themost commonly implicated medications in seizure.Other medications include lidocaine, anesthetics,tricyclic antidepressants, selective serotoninreuptake inhibitors, bupropion (Wellbutrin),acyclovir (Zovirax), ß-blockers, and decongestants(eg, phenylpropanolamine). Seizures can beprovoked by alcohol withdrawal, cocaine,phencyclidine (PCP), and 3,4-methylenedioxy-methamphetamine (MDMA, "ecstasy").

IV. Physical examinationA. Findings may include trauma, infection, malig-

nancy, congenital anomalies, and focal weaknessor spasticity suggesting previous stroke.

B. Vital signs should be measured and a generalmedical examination performed.1. Examine the patient for injuries from the seizure

or fall.2. Check oxygen saturation and auscultate the

chest for aspiration.3. Measure heart rhythm and rate, blood pressure,

and orthostatic changes for assessment ofsyncope.

4. Auscultate for carotid murmurs or carotid bruitsand sources of embolic stroke.

5. Check for rapid pulses, which are often presentafter seizure and may help in evaluation ofpsychogenic seizures.

C. Neurologic examination1. Patients should be observed for fluency of

language, facial asymmetry, gaze preferences,and pupillary asymmetry. The last presents inpatients who have herniation from brain swellingcaused by parenchymal or epidural bleeding andin those who have a rapidly growing brain tumor.

2. Sensory deficits suggest parietal lobe dysfunc-tion. An extensor plantar response may be notedafter a seizure and is not necessarily a patho-logic finding.

V. Diagnostic testingA. Measurement of glucose, calcium, magnesium,

thyroid hormone, liver enzyme levels, and toxicol-ogy screening (including blood alcohol levels) mayreveal common medical causes of seizures. Acomplete blood cell count may suggest infection,anemia, or sickle cell disease.

B. Lumbar puncture should be performed in patientssuspected to have had an infection or a fever afterassessment of the possible risks of the procedure(eg, coagulopathy, mass lesion). Patients who areimmunocompromised because of corticosteroiduse, recent transplantation or HIV infection shouldundergo cerebrospinal fluid evaluation to detectpossible fungal, bacterial, or viral infection.

C. Computed tomography can detect the presenceof bleeding or gross structural lesions immediatelyafter a seizure. However, magnetic resonanceimaging is the study of choice because it is moresensitive and specific for evaluating structurallesions.

D. Electroencephalogram (EEG) can help establishthe presence and type of epilepsy, although itsvalue is limited. An estimated 0.4% of adults and2.8% of children who have never had a seizuremay have interictal epileptiform discharges. Anormal EEG does not refute the diagnosis ofepilepsy. The initial EEG reveals epileptiform

activity in only 40% of the patients with probableepilepsy. The yield of the test is enhanced by usingsleep deprivation, hyperventilation, and photicstimulation.

E. Ambulatory 24-hour EEG recordings can beuseful for patients in whom epileptic seizure is arelatively strong possibility when the standard EEGis normal.

VI. Treatment of epilepsyA. After a single tonic-clonic seizure, recurrence rates

are 15 to 60%. After two tonic-clonic seizures, therisk of a third seizure is 85%.

B. Treatment should be started with one drug andthen increase the dose gradually until the patient isseizure-free or experiences significant side effects.

Initial treatment for partial and generalizedepilepsies

Type ofepilepsy

First-lineagents

Second-lineagents

Partial

Carbamazepine,oxcarbazepine(Trileptal),phenytoin (Dilan-tin)

Divalproex(Depakote),felbamate (Felbatol),gabapentin (Neurontin),lamotrigine(Lamictal),levetiracetam(Keppra), tiagabine(Gabitril Filmtabs),topiramate(Topamax),valproate(Depakene),zonisamide(Zonegran)

Generalized

Absenceseizures

Ethosuximide(Zarontin),valproate

Lamotrigine,levetiracetam

Idiopathic Lamotrigine,valproate

Topiramate,zonisamide

Symptom-atic

Lamotrigine,topiramate,valproate,zonisamide

Barbiturates,benzodiazepines

VII. Therapy for localization-related partial epilepsyA. About 70% of adult patients with epilepsy have

partial-onset seizures, which encompass simplepartial, complex partial, and secondarily general-ized tonic-clonic seizures. About 50% of patientshave both partial seizures and secondarily general-ized tonic-clonic seizures.

B. For the majority of patients with newly diagnosedpartial epilepsy, initial treatment consists ofcarbamazepine (Tegretol), oxcarbazepine(Trileptal), or phenytoin (Dilantin). Alternativechoices include divalproex (Depakote), felbamate(Felbatol), gabapentin (Neurontin), lamotrigine(Lamictal), levetiracetam (Keppra), tiagabine(Gabitril), topiramate (Topamax), and zonisamide(Zonegran).

Antiepileptic Drugs

Adult dos-age

Children(per kg ofbodyweight)

Dosingintervals

Carbamazepine(Tegretol)

600 to1,600 mg

20 to 40mg

Three orfour timesper day

Ethosuximide(Zarontin)

750 to1,5000 mg

4 to 5 mg Twice perday

Gabapentin(Neurontin)

900 mg upto 6,000mg


Lamotrigine(Lamictal)

200 to 800mg

Twice perday

Levetiracetam(Keppra).

500 and1500 mg

Once ortwice perday

Phenobar-bital(Solfoton)

1 to 4 mgper kg

2 to 5 mg Once ortwice perday

Adult dos-age

Children(per kg ofbodyweight)

Dosingintervals

Phenytoin(Dilantin)

200 to 500mg

5 mg up toa maxi-mum of300 mg

Once ortwice perday

Primidone(Mysoline)

500 to1,000 mg

10 to 20mg


Tiagabine(GabitrilFilmtabs)

32 to 56mg


Topiramate(Topamax)

400 to 800mg

Twice perday

Valproicacid(Depakene,Depakote)

15 to 60mg per kg

15 to 60mg


Zonisamide(Zonegran)

100 and600 mg perday

Once perday

C. Carbamazepine (Tegretol) usual starting dose is200 mg twice per day, with weekly increases of 200mg per day and a usual daily maintenance dose of600 to 1,200 mg. The long-acting formulations ofcarbamazepine improve compliance because theycan be taken twice daily and are better tolerated.Carbamazepine is a strong inducer of some ofhepatic cytochrome P-450 and is associated with anumber of significant drug-drug interactions. Inaddition, carbamazepine induces its own metabo-lism. The usual therapeutic range for serumcarbamazepine levels is 6 to 12 mg/L.

D. Oxcarbazepine (Trileptal) is approved for initialmonotherapy. This drug has significant efficacy asmonotherapy in patients newly diagnosed as havingpartial epilepsy as well as patients whose conditionis refractory. Oxcarbazepine is more tolerable andassociated with less frequent rashes thancarbamazepine. Oxcarbazepine is initiated at 150mg twice a day, with weekly increments of 300 mgper day and a target dose of 900 to 1,200 mg.Compared with carbamazepine, oxcarbazepine isassociated with substantially fewer drug-druginteractions and does not undergo autoinduction.

E. Phenytoin (Dilantin), the usual starting dose is300 mg daily (4 to 5 mg/kg per day), with a mainte-nance dose of 200 to 500 mg per day. A loadingdose of phenytoin at 18 to 20 mg/kg can be givenorally or intravenously. Phenytoin can be givenonce daily, although it is often administered two orthree times per day to minimize side effects. Thetherapeutic serum range of phenytoin is 10 to 20mg/L. Phenytoin is a strong hepatic enzyme in-ducer and is prone to drug-drug interactions.

F. Divalproex (Depakote) is usually started at 250 to500 mg twice daily (10 to 15 mg/kg per day), withweekly increments of 250 to 500 mg per day (5 to10 mg/kg per day) and a range in daily dose from1,000 to 3,000 mg. An intravenous formulation isavailable. The therapeutic serum range is 50 to 150mg/L.

G. Monotherapy versus polytherapy1. About 47% of patients with newly diagnosed

epilepsy became seizure-free during treatmentwith their first AED and 14% became sei-zure-free during treatment with a second or thirddrug.

2. Felbamate (Felbatol) is an effective drug, but itsuse has been severely restricted because of itsassociation with life-threatening aplastic anemiaand fulminant hepatic failure. It should not beused as first-line therapy.

3. Gabapentin (Neurontin) has the advantages ofsafety, tolerability, favorable pharmacokineticprofile, and ease of use. It has been used mostlyas adjunctive therapy in patients with refractoryseizures but is an attractive agent asmonotherapy in patients with severe hepaticdisease, cutaneous allergies, porphyria, oracquired immunodeficiency disease and inelderly patients who take a number of medica-tions. The effective dose is 900 to 4,800 mg perday, divided into three doses.

4. Lamotrigine (Lamictal) is approved as adjunc-tive therapy and as second-line monotherapy. Itis sometimes used as initial monotherapy be-cause it has a similar efficacy as phenytoin orcarbamazepine and is better tolerated thancarbamazepine.

5. Tiagabine (Gabitril) exerts its effect by inhibitingthe reuptake of g-aminobutyric acid. It has

efficacy two times daily or four times daily. Thisdrug is used as adjunctive therapy, with a usualstarting dose of 4 mg per day, weekly incrementsof 4 mg per day, and a target daily dose between32 and 64 mg.

6. Topiramate (Topamax) has significant efficacywhen used as adjunctive therapy. Because ofpotential adverse cognitive events, it should bestarted at a low dose, with gradual adjustment.Starting dose is 25 or 50 mg per day with weeklyincrements of 25 to 50 mg per day. The usualtarget dose for adjunctive therapy is 400 mgtaken twice daily, with a dose range between 100and 1,000 mg per day.

7. Levetiracetam (Keppra) is an attractive AEDbecause of tolerability and ease of use. Thestarting dose is 500 mg at bedtime, with weeklyincrements of 500 mg and a total target dailydose between 1,000 and 3,000 mg divided intotwo doses. It can be used in monotherapy.

8. Zonisamide (Zonegran) is approved as adjunc-tive therapy. It should be avoided in patients withsulfa allergies. Zonisamide can be associatedwith a rash in 3%; rare cases ofStevens-Johnson syndrome and toxic epidermalnecrolysis, can occur. The recommended start-ing dose is 100 mg taken once a day, with incre-ments of 100 mg every 2 weeks if needed, witha target dose between 100 and 600 mg per day.

VIII. Therapy for generalized epilepsiesA. For patients who have multiple seizure types, it is

necessary to choose a broad-spectrumanticonvulsant with efficacy against multiple seizuretypes.

B. Valproate remains a mainstay treatment for thesepatients, but lamotrigine, topiramate, andzonisamide, are also efficacious against multipleseizure types and can be considered as alternativeagents. Because of its tolerability, some physiciansselect lamotrigine rather than valproate as the initialdrug of choice.

IX. Discontinuation of therapy. Patients who remainseizure-free for at least 2 years should be consid-ered candidates for tapering and discontinuing AEDtreatment. About two-thirds of patients remainseizure-free following discontinuation of treatment.


Migraine HeadacheMigraine affects 15% to 17% of women and 6% of men.Headaches can generally be grouped into three majorcategories: migraine, tension-type, and organic.

I. Clinical evaluationA. Migraine headaches are usually unilateral, and

the acute attack typically lasts from 4 to 24 hours.Migraine headaches can occur with an aura orwithout an aura. The aura may consist of focalneurologic symptoms starting 5 to 30 minutesbefore onset of an acute headache attack.

B. The most common aura symptoms associated withmigraine include scotomata (blind spots),teichopsia (fortification spectra, or the sensation ofa luminous appearance before the eyes),photopsia (flashing lights), and paresthesias, aswell as visual and auditory hallucinations, diplopia,ataxia, vertigo, syncope, and hyperosmia.

C. Tension-type headache is characterized bysteady, aching pain of mild to moderate intensity,often as a band-like pain around the head. Gastro-intestinal and neurologic signs and symptomsusually do not occur.

D. Physical examination should assess the fundusof the eye, neck rigidity, and identify infectiousprocesses of the nose and throat. The temporalartery may appear dilated and pulsating. Neuro-logic symptoms should be evaluated with com-puted tomographic scanning.

Features of Migraine Headache and HeadacheCaused by Underlying Disease

Migraine headache Headache caused by seri-ous underlying disease

History

• Chronic headache pat-tern similar from attackto attack

• Gastrointestinal symp-toms

• Aura, especially visual• Prodrome

• Onset before puberty orafter age 50 (tumor)

• "Worst headache ever"(subarachnoid hemor-rhage)

• Headache occurring afterexertion, sex, or bowelmovement (subarachnoidhemorrhage)

• Headache on rising in themorning (increasedintracranial pressure, tu-mor)

• Personality changes, sei-zures, alteration of con-sciousness (tumor)

• Pain localized to temporalarteries or sudden loss ofvision (giant cell arteritis)

• Very localized headache(tumor, subarachnoidhemorrhage, giant cellarteritis)

Physical examination

• No signs of toxicity• Normal vital signs• Normal neurologic ex-

amination

• Signs of toxicity (infection,hemorrhage)

• Fever (sinusitis, meningi-tis, or other infection)

• Meningismus (meningitis)• Tenderness of temporal

arteries (giant cell arteritis)• Focal neurologic deficits

(tumor, meningitis, hemor-rhage)

• Papilledema (tumor)

Laboratory tests and neuroimaging

• Normal results • Erythrocyte sedimentationrate >50 mm/hr (giant cellarteritis)

• Abnormalities on lumbarpuncture (meningitis, hem-orrhage)

• Abnormalities on CT orMRI (tumor, hemorrhage,aneurysm)

II.Pathophysiology of migraineA. Migraine headache is probably generated by a

nucleus in the brainstem. The central generator isthe contralateral dorsal raphe nucleus of themidbrain. After the dorsal raphe central generatorturns on, there is an activation of thetrigeminovascular system. This system connectsthe generator to the meningeal blood vessels,which dilate and become inflamed, a processreferred to as neurogenic inflammation.

B. Two key serotonin (5-HT) receptors, 5-HT1B and 5-HT1D , reverse the migraine processes. The 5-HT1Dreceptors are vasoconstrictive and are located inthe lumen of the meningeal vessels.

III. Treatment of migraineA. 5-HT1D receptor agonists ("Triptans")

1. Rizatriptan (Maxalt)a. Rizatriptan (Maxalt) is a high-efficacy, quick-

onset triptan, like sumatriptan andzolmitriptan. Oral bioavailability is more than40%.

b. Rizatriptan has two doses, 5 and 10 mg, andtwo forms, traditional tablet and mint-fla-vored, orally dissolvable tablet or melt. Two-hour headache response for the optimaldose (10 mg) is 67-77%. Recurrence rate is30-47%.

c. The melt is not absorbed through the buccalmucosa, but rather dissolves on the tongue,is swallowed, and then is absorbed in thegastrointestinal tract. Its efficacy is the sameas the traditional tablet, with a two-hourheadache response of 66-74%. Adverseevents for rizatriptan are similar to thoseseen with sumatriptan and zolmitriptantablets.

d. Propranolol raises the circulating rizatriptanlevel, so patients on propranolol should begiven the 5-mg rizatriptan dose. Othersshould take the 10-mg dose. The maximumrizatriptan dose is 30 mg per 24 hours, but15 mg per 24 hours for patients onpropranolol.

2. Almotriptan (Axert)

a. Almotriptan works as well as sumatriptan;however, it is better tolerated. Almotriptancauses less chest pain than sumatriptan;however, it remains contraindicated in pa-tients with ischemic heart disease or uncon-trolled hypertension as are all triptans. Itcomes in 6.25 and 12.5 mg tablets.

b. Most patients should take 12.5 mg at theonset of a migraine. Patients with hepatic orrenal impairment should start with 6.25 mg.Patients should not take more than 2 dosesin 24 hours.

3. Sumatriptan (Imitrex)a. Sumatriptan (Imitrex) is available in three

forms: subcutaneous injection, nasal spray,and oral tablet. Injectable sumatriptan co-mes as a 6 mg dose for use with anautoinjector. Subcutaneous sumatriptan isthe most effective triptan. It works extremelyquickly with 50% headache response at 30minutes, a one-hour headache response of77%, and more than 80% at two hours.Recurrence of migraine within 24 hours aftera headache response with injectablesumatriptan is 34-38%. Recurrence with thespray and tablet is 35-40%.

b. Nasal spray sumatriptan. 20 mg is theoptimal dose, with a two-hour headacheresponse of 64%. Almost 40% have head-ache response at 30 minutes. The spraycomes in a single-use device. When sniffed,it causes a terrible taste in the back of thethroat; therefore, patients should spray itonce in one nostril and not sniff in.

c. The sumatriptan oral tablet has abioavailability of 14%. The optimal startingdose is 50 mg, with a 61% headache re-sponse at two hours.

d. Maximum sumatriptan dosages are two 6-mg subcutaneous doses, two 20-mg nasalsprays, or four 50-mg tablets per 24 hours.However, if a patient needs to switch, shecan use one injection or one spray plus twotablets in the same day, or one injection plusone spray in 24 hours.

e. All triptans can cause subjective "triptansensations," which include heat feelings andflushing, numbness, paresthesias, tirednessand tightening, and heaviness of neck, jaw,and chest. Triptans can narrow coronaryarteries. These drugs are contraindicated incoronary artery disease, vascular disease,uncontrolled hypertension, basilar orhemiplegic migraine or within 24 hours ofanother triptan or ergot.

f. Sumatriptan is the most used triptan. Theinjection has the fastest onset for a triptan,and the highest overall efficacy.

4. Zolmitriptan (Zomig)a. Zolmitriptan has an oral bioavailability of

40%. Zolmitriptan is contraindicated withMAO-A inhibitors. The optimal dose is 2.5mg. The maximum dose is 10 mg per 24hours. Two-hour headache response is 62-65%. Recurrence rate averages about 30%.Adverse events are triptan sensations,similar to sumatriptan tablets.

b. Zolmitriptan is superior to oral sumatriptan(50 mg) for headache response at twohours, 67.1% vs. 63.8%, respectively.Zolmitriptan has a longer duration of actionthan sumatriptan.

5. Naratriptan (Amerge) has good oralbioavailability (63-74%) and a longer T 1/2 (6hours) than sumatriptan. It works more slowly,and in a lower percentage of patients, than theother three triptans. Two-hour headache re-sponse for the optimal dose of 2.5 mg is 48%.The maximum dose is 5 mg per 24 hours.Naratriptan should not be used in patients withrapid onset migraine or who wake up withmigraine. Naratriptan should only be selectedfor those patients who are sensitive to sideeffects.

6. Frovatriptan (Frova) has the longest half-life(26 hours compared to 6 hours or less for theothers). It has a slow onset and is less effectivethan the other triptans. Frova comes in 2.5 mgtablets. Patients start with one tablet and canrepeat after 2 hours if the headache recurs;maximum 3 tabs in 24 hours.

7. Eletriptan (Relpax) appears to be at least aseffective as oral sumatriptan for acute treat-ment of migraine. Eletriptan interacts withCYP3A4 inhibitors, including verapamil, whichis used for migraine prophylaxis. Initial dosageis 20 or 40 mg, which can be repeated after 2

hours if headache improves and then recurs.The maximum dosage is 80 mg in 24 hours.

8. Triptan selectiona. Patients with migraine should receive a

triptan as the first-line medication. If theyhave significant nausea, an oral drug is notrecommended. Rather, a parenteral or nasalspray sumatriptan should be used.

b. Most patients should initially be treated withrizatriptan (Maxalt) or almotriptan (Axert).Other agents may be used if the patientrequires a faster onset, longer duration, orfewer side effects.

c. Sumatriptan provides the greatest versatilityin multiple forms to allow a patient variousmodes of treatment. The 6-mg subcutane-ous injection offers the greatest speed andthe highest efficacy of any triptan.

d. Rizatriptan (Maxalt) tends to be faster andmore effective than oral sumatriptan with asimilar incidence of adverse effects.

e. Almotriptan (Axert) seems to work aboutas well as sumatriptan, but it’s better toler-ated.

f. Zolmitriptan (Zomig) has similar efficacyand tolerability compared to sumatriptan.

g. Naratriptan (Amerge) has a slower onsetand is less effective, but this agent is bettertolerated.

h. Frovatriptan (Frova) has the longest half-life (26 hours compared to 6 hours or lessfor the others). It has a slow onset and isless effective than the other triptans.

Drugs for Treatment of Migraine and TensionHeadache

Drug Dosage

5-HT1 Receptor Agonists ("Triptans")

Rizatriptan (Maxalt) 5- or 10-mg tablet or wafer(MLT); can be repeated in 2hours; max 100 mg/day,5 mg/day in patients onpropranolol

Almotriptan (Axert) 12.5 mg at the onset of a mi-graine. Patients with hepatic orrenal impairment should start with6.25 mg. Max 2 doses per day.

Sumatriptan (Imitrex) 6 mg SC; can be repeated in 1hour; max 2 injections/day50 mg PO; can be repeated in 2hours; max 100 mg20 mg intranasally; can be re-peated after 2 hours; max 40mg/dayMax in combination: two injec-tions or sprays; or one of eitherplus two tablets

Naratriptan(Amerge)

2.5-mg tablet, can be repeated 4hours later; max 5 mg/day

Zolmitriptan (Zomig) 2.5 mg PO; can be repeated in 2hours; max 10 mg/day

Frovatriptan (Frova) 2.5 mg PO, repeat after 2 hours ifthe headache recurs; max 3 tabsin 24 hours. Longest half-life,slow onset, less effective

Eletriptan (Relpax) 20 or 40 mg, repeated after 2hours if headache recurs; max 80mg in 24 hours.

NSAIDs

Ibuprofen (Motrin) 400-800 mg, repeat as needed in4 hr

Naproxen sodium(Anaprox DS)

550-825 mg, repeat as needed in4 hr

Ergot Alkaloids

DihydroergotamineDHE 45

Migranal NasalSpray

1 mg IM; can be repeated twiceat 1-hour intervals (max 3mg/attack)1 spray (0.5 mg)/nostril, repeated15 minutes later (2 mg/dose; max3 mg/24 hours)

Ergotamine 1mg/caffeine 100 mg

(Ercaf,Gotamine,Wigraine)

2 tablets PO, then 1 q30min, x 4PRN (max 6 tabs/attack)

Butalbital combinations

Aspirin 325 mg, caf-feine 40 mg,butalbital 50 mg(Fiorinal)

2 tablets, followed by 1 tablet q4-6h as needed

Isometheptene combination

Isometheptene 65mg, acetaminophen325 mg, dichloral-phenazone 100 mg(Midrin)

2 tablets, followed by 1 tablet asneeded q4-6h prn

Opioid Analgesics

Butorphanol (StadolNS)

One spray in one nostril; can berepeated in the other nostril in60-90 minutes; the same two-dose sequence can be repeatedin 3 to 5 hours

B. Prophylaxis against migraine 1. Patients with frequent or severe migraine

headaches or those refractory to symptomatictreatment may benefit from prophylaxis. Men-strual or other predictable migraine attacks maysometimes be prevented by a brief course ofan NSAID, taken for several days before andduring menstruation.

2. Beta-adrenergic blocking agents are usedmost commonly for continuous prophylaxis.Propranolol, timolol, metoprolol (Lopressor),nadolol (Corgard) and atenolol (Tenormin)have been effective.

3. Tricyclic antidepressants can prevent mi-graine and may be given with other prophylac-

tic agents. Amitriptyline (Elavil) in a dosageranging from 10 to 50 mg qhs is commonlyused.

4. Valproate (Depakote), an anticonvulsant, hasbeen effective in decreasing migraine fre-quency. Its effectiveness is equal to that ofpropranolol. Adverse effects include nausea,weight gain and fatigue.

Drugs for Prevention of Migraine

Drug Dosage

Propranolol (Inderal) 80 to 240 mg/day, divided bid,tid or qid

Timolol (Blocadren) 10 to 15 mg bid

Divalproex (Depakote) 250 mg bid

Amitriptyline (Elavil) 25-50 mg qhs


VertigoThe clinical evaluation of vertigo begins with the patient'sdescription of symptoms and the circumstances in whichthey occur. Many drugs can cause dizziness. Commonnonvestibular causes (eg, hyperventilation, orthostatichypotension, panic disorder) are often diagnosed.

I. History and physical examinationA. Patients may use the term "dizziness" to describe

one or more different sensations. These sensa-tions include vertigo (spinning), light-headedness,unsteadiness and motion intolerance. The onset ofsymptoms, whether the sensation is constant orepisodic, how often episodes occur and the dura-tion of episodes should be assessed. Activities ormovements that provoke or worsen a patient'sdizziness should be sought as well as activitiesthat minimize symptoms. Rotational vertigo whenrolling over in bed is highly suggestive of BPPV.

B. Vertigo is a sensation of movement of the self or ofone's surroundings. Patients may describe vertigoas a sensation of floating, giddiness or disorienta-tion. The duration of vertiginous symptoms andwhether head movement provokes symptoms(positional vertigo) or if attacks occur withoutprovocation (spontaneous vertigo) should beassessed.

C. Hearing loss, tinnitus and aural fullness should besought. Vision, strength and sensation, coordina-tion, speech and swallowing should be evaluated.Double vision or hemiplegia strongly suggest acentral nervous system lesion rather than a periph-eral vestibular disorder. History for cardiac dis-ease, migraine, cerebrovascular disease, thyroiddisease and diabetes should be sought.

Drugs Associated with Dizziness

Class of drug Type of dizzi-ness

Mechanism

Alcohol Positional vertigo Specific-gravitydifference inendolymph vscupula

Intoxication CNS depression DisequilibriumCerebellar dys-function

Tranquilizers Intoxication CNS depression

Anticonvulsants IntoxicationDisequilibrium

CNS depression Cerebellar dys-function

Antihypertensives Near faint Posturalhypotension

Aminoglycosides Vertigo DisequilibriumOscillopsia

Asymmetrichair-cell loss Vestibulospinalreflex loss Vestibulo-ocularreflex loss

D. Physical examination should evaluate orthostaticblood pressure changes followed by a completehead and neck examination as well as otologic andneurologic examinations. A pneumatic otoscopeshould be used to confirm normal tympanic mem-brane mobility. Balance, gait, cerebellar andcranial nerve function, and nystagmus should beevaluated.

E. Nystagmus consists of involuntary eye move-ments caused by asymmetry of signals from theright and left vestibular systems. Nystagmus ofperipheral vestibular origin is usually horizontalwith a slight or dramatic rotary component. Nystag-mus of central origin is usually predominantlyvertical.

F. The Dix-Hallpike test is particularly helpful to elicitnystagmus associated with BPPV. This maneuverstimulates the posterior semicircular canal, whichis the semicircular canal most commonly involvedin BPPV.

G. An audiogram should be performed if a specificcause of dizziness cannot be found after a thor-ough history and physical examination. Additionaltesting may include electronystagmography,auditory evoked brainstem response testing,radiologic imaging of the brain, brainstem andtemporal bone and selected blood tests. Auditoryevoked brainstem response testing measures theintegrity of the auditory system and is useful toscreen for acoustic tumors. Magnetic resonanceimaging (MRI) should be reserved for patients withunilateral otologic symptoms or neurologic symp-toms or those in whom dizziness persists despiteappropriate treatment.

II. Benign paroxysmal positional vertigoA. The most common cause of peripheral vestibular

vertigo is BPPV. This condition is characterized bysudden, brief and sometimes violent vertigo aftera change in head position. The sensation of vertigousually lasts for only a few seconds. This form ofvertigo is often noticed when a patient lies down,arises or turns over in bed. BPPV does not causehearing loss, ear fullness or tinnitus. BPPV canoccur at any age but is most commonly seen inelderly persons. Although usually unilateral, bilat-eral BPPV occurs in up to 15 percent of patients.Nystagmus is characteristic of BPPV.

B. BPPV is caused by displacement of otoconia fromthe utricle or saccule into the posterior semicircularcanal. Therefore, when a patient moves the headinto a provocative position, the otoconia provokemovement of the endolymphatic fluid inside thesemicircular canal, creating a sensation of vertigo.

C. Treatment of BPPV. In-office physical therapy,known as repositioning maneuvers, redirectsdisplaced otoconia into the utricle. This form oftreatment is effective in 85 to 90 percent of pa-tients. Another type of exercise that is performed athome also attempts to redirect displaced otoconiaand is effective in 60 to 70 percent of patients.

D. During these exercises, the patient initially sitsupright on the edge of a bed or couch. Then thepatient rapidly lies down on his side with the af-fected ear down. Vertigo usually occurs. After thevertigo subsides (or after one minute if no vertigooccurs), the patient rapidly turns in a smooth arc tothe opposite side. After vertigo associated with thismovement subsides (or after one minute if novertigo occurs), the patient slowly sits upright. The

entire maneuver is repeated five times twice perday until the patient no longer experiences vertigofor two successive days. Surgical treatment isreserved for the 2 to 5 percent of cases that fail torespond to nonsurgical treatment.

III.Vestibular neuronitisA. Vestibular neuronitis is characterized by acute

onset of intense vertigo associated with nauseaand vomiting that is unaccompanied by any neuro-logic or audiologic symptoms. The symptomsusually reach their peak within 24 hours and thengradually subside. During the first 24 to 48 hours ofa vertiginous episode, severe truncal unsteadinessand imbalance are present.

B. Vestibular neuronitis is presumed to have a viraletiology because it is often associated with arecent history of a flu-like illness. Management ofthe initial stage of vestibular neuronitis includesbed rest and the use of antiemetics (eg,promethazine [Phenergan]) and vestibular sup-pressants (eg, diazepam [Valium]). After thepatient is able to stand, the brain begins compen-sating for the acute loss of unilateral vestibularfunction. The compensation process may beenhanced by performance of vestibular exercisestwice per day for eight to 10 weeks.

IV. Meniere's diseaseA. Meniere's disease is characterized by fluctuating

hearing loss, tinnitus, episodic vertigo and, occa-sionally, a sensation of fullness or pressure in theear. Vertigo rapidly follows and is typically severe,with episodes occurring abruptly and withoutwarning. The duration of vertigo is usually severalminutes to hours. Unsteadiness and dizziness maypersist for days after the episode of vertigo.

B. Diseases with similar symptoms include syphilis,acoustic neuroma and migraine. Isolated episodesof hearing loss or vertigo may precede the charac-teristic combination of symptoms by months oryears.

C. Meniere's disease results from excessive accumu-lation of endolymphatic fluid (endolymphatichydrops). As inner-ear fluid pressure increases,symptoms of Meniere's disease develop.

D. Diuretics (eg, triamterene-hydrochlorothiazide[Dyazide, Maxzide]) and a low-salt diet are themainstays of treatment. This combined regimenreduces endolymphatic fluid pressure. Otherpreventive measures include use of vasodilatorsand avoidance of caffeine and nicotine. Acutevertiginous episodes may be treated with oral orintravenous diazepam. Promethazine orglycopyrrolate (Robinul) is effective in the treat-ment of nausea.

E. Surgical treatments are an option when appropri-ate prophylactic measures fail to prevent recurrentepisodes of vertigo. Surgical procedures used inthe treatment of Meniere's disease range fromdraining excess endolymphatic fluid from the innerear (endolymphatic shunt) to severing the vestibu-lar nerve (with hearing preservation). In selectedcases, a chemical labyrinthectomy may be per-formed. Chemical labyrinthectomy involves theinjection of a vestibulotoxic gentamicin(Garamycin) solution into the middle ear.

Antivertiginous and Antiemetic Drugs

Classes andagents

Dosage Comments

Antihistamines

Dimenhydrinate (Benadryl)

50 mg POq4-6h or100-mg supp.q8h

Available without pre-scription, mild sedation,minimal side effects

Meclizine(Antivert)

25-50 mg POq4-6h

Mild sedation, minimalside effects

Promethazine(Phenergan)

25-50 mg PO,IM, or supposi-tory q4-6h

Good for nausea, ver-tigo, more sedation,extrapyramidal effects

Monoaminergic agents

Amphetamine 5 or 10 mg POq4-6h

Stimulant, can counter-act sedation of antihis-tamines, anxiety

Ephedrine 25 mg POq4-6h

Available without pre-scription

Benzodiazepine

Diazepam(Valium)

5 or 10 mg POq6-8h

Sedation, little effect onnausea

Phenothiazine

Prochlorperazine(Compazine)

5-25 mg PO,IM, or supposi-tory q4-6h

Good antiemetic;extrapyramidal sideeffects, particularly inyoung patients


Chronic Fatigue SyndromeChronic fatigue is relatively common, but criteria-basedchronic fatigue syndrome (CFS) is rare. Fatigue isdefined as severe mental and physical exhaustion thatdiffers from somnolence or lack of motivation and is notattributable to exertion or diagnosable disease. Chronicfatigue is defined as persistent or relapsing fatiguelasting 6 or more consecutive months. CFS is character-ized by severe disabling fatigue lasting more than 6months and symptoms that feature impairments inconcentration and short-term memory, sleep distur-bances, and musculoskeletal pain. About 24% of pa-tients complain of fatigue.

I. Common causes of chronic fatigueA. The differential diagnosis of fatigue includes many

infections, malignancies, endocrinopathies, andconnective tissue disease. The psychiatric ill-nesses include depression, anxiety, bipolar dis-ease, and somatoform and psychotic disorders.Depression is one of the most common underlyingdiagnoses when fatigue is a primary complaint.

B. Anxiety. Both depression and anxiety tend to beaccompanied by sleep disturbance symptoms.Anemia characteristically will cause a more gener-alized physical fatigue without sleep disturbances.Asthma and other lung diseases are commoncauses of fatigue.

Common causes of fatigue

Diagnosis Frequency inprimary care

Fatigued pa-tients (%)

Depression Very common 18

Environment (life-style)

Very common 17

Anxiety, anemia,asthma

Very common 14

Diabetes Very common 11

Infections Common 10

Thyroid, tumors Common 7

Rheumatologic Common 5

Endocarditis, car-diovascular

Common 8

Drugs Common 5

C. Diabetes should be considered in the obesepatient with fatigue. Hypothyroidism andhyperthyroidism are easily treatable causes offatigue. Tumors and other malignancies may causetiredness. Many infections cause fatigue, includingviruses, tuberculosis, Lyme disease, and HIVinfection.

D. Rheumatologic disorders, including rheumatoidarthritis, systemic lupus erythematosus andfibromyalgia, are common causes of fatigue.

E. Endocarditis is a very rare cause of fatigue asso-ciated with valvular and other cardiovasculardiseases.

F. Drugs that may cause fatigue including analgesics,psychotropics, antihypertensives, and antihista-mines. Over-the-counter medications and sub-stance abuse (caffeine, alcohol, and illicit drugs)may cause fatigue.

II. Clinical evaluationA. Evaluation of chronic fatigue should exclude

diseases associated with fatigue. The time of onsetof symptoms and the nature of the fatigue shouldbe determined. Chronic fatigue syndrome is char-acterized by fatigue that is typically presentthroughout the day (even upon awakening), wors-ens with exercise, and is not improved with rest.

B. Fever, chills, night sweats, weight loss or anorexiamay be seen in chronic fatigue syndrome; how-ever, infectious disease or malignancy should alsobe considered. Confusion and cognitive difficultiesare reported by nearly all chronic fatigue syndromepatients.

C. Headaches, myalgias, arthralgias, and painfuladenopathy are common complaints in chronicfatigue syndrome, although the presence of arthri-tis may also suggest connective tissue diseases.Anhedonia is suggestive of depression.

D. Recent travel, insect bites, tick exposure, skinrashes, and use of prescription and over-the-counter drugs should be sought.

E. Physical examination. Specific physical findingss u c h a s n o n e xu d a t i ve p h a ryn g i t i s ,lymphadenopathy, skin rashes, muscle tendernessand orthostatic hypotension are often seen inchronic fatigue syndrome patients. The Rombergtest and tandem gait test may be abnormal in up to20% of chronic fatigue syndrome patients.

Criteria for chronic fatigue syndrome

Clinically evaluated, unexplained, persistent or relapsingchronic fatigue of new or definite onset; not the result ofongoing exertion; not substantially alleviated by rest; andcauses substantial reduction in previous levels of occupa-tional, educational, social, or personal activities; and

Occurs concomitantly with four or more of the followingsymptoms, all of which must have persisted or recurredduring 6 or more consecutive months of illness and mustnot have predated the fatigue:

Short-term memory or concentration impairmentSore throatTender cervical or axillary lymph nodesMuscle pain or multijoint pain without joint swelling orrednessHeadaches of a new type, pattern, or severityUnrefreshing sleepPostexertional malaise lasting more than 24 hours

Laboratory evaluation of chronic fatigue

For all patientsComplete blood cell count with differentialErythrocyte sedimentation rateUrinalysis

Other tests based on findingsThyroid stimulating hormoneBlood Chemistry levels:

Alanine aminotransferaseAspartate aminotransferaseBlood urea nitrogenElectrolytesGlucose

Heterophil antibody test (Monospot)Serologic studies for Lyme or HIV antibody titers

III. Management of the fatigued patientA. Regular exercise will improve functional capacity,

mood, and sleep. Regular sleep habits should beadvised. In those complaining of depressivesymptoms or sleep disturbance, an antidepres-sant or sleep hypnotic is indicated. A sedatingantidepressant, such as amitriptyline (Elavil) 25mg qhs, may be helpful for complaints of insom-nia or restlessness. If the primary complaints arehypersomnia and psychomotor retardation, aselective serotonin reuptake inhibitor is indicated.

B. For physical symptoms such as headaches,myalgias, or arthralgias, nonsteroidal anti-inflam-matory agents may be helpful. Therapies forwhich no effectiveness has been demonstrated inCFS include vitamins, acyclovir, gamma globulin,folic acid, cyanocobalamin, and magnesium.

C. Antidepressants1. Selective serotonin reuptake inhibitors (SSRIs)

are the drugs of choice. Fluoxetine (Prozac),paroxetine (Paxil), sertraline (Zoloft), andfluvoxamine (LuVox) are effective in reducingfatigue, myalgia, sleep disturbance, and de-pression.

2. For the patient who has significant difficultywith insomnia or with pain, paroxetine at bed-time is recommended because it is mildlysedating. Fluoxetine is useful in patients whocomplain of lack of energy because it hasactivating properties. Fluoxetine often im-proves cognitive functioning, especially con-centrating ability.

3. Initial dosage should be low because manyCFS patients are sensitive to side effects.a. Fluoxetine (Prozac) 20 mg PO qAM; 20-40

mg/d [20 mg].b. Paroxetine (Paxil) 10 mg qAM; increase as

needed to max of 40 mg/d. [10, 20, 30, 40mg].

c. Fluvoxamine (LuVox) 50-100 mg qhs; max300 mg/d [50, 100 mg]

d. Sertraline (Zoloft) 50-100 mg PO qAM [50,100 mg].

D. Omega-3 and omega-6 fatty acids, in the formof fish oil supplements, may bring some improve-ment.

IV. Prognosis. CFS is a chronic illness, but 40-60% ofpatients improve within1-3 years after diagnosis. Themean duration of illness prior to diagnosis is 52.6months.


Dermatologic and AllergicDisorders

Herpes Simplex Virus Infections

Herpes simplex virus (HSV) affects more than one-thirdof the world's population. Ninety percent of infectionscaused by HSV-2 are genital, and 90 percent of thosecaused by HSV-1 are oral.

I. DiagnosisA. The diagnosis of genital HSV infection may be

made clinically, but laboratory confirmation isrecommended in patients presenting with primaryor suspected recurrent infection. The gold standardof diagnosis is viral isolation by tissue culture,although this process can take as long as four tofive days, and the sensitivity rate is 70 to 80 per-cent.

B. Antigen detection tests have lower sensitivity rates(50 to 70 percent) than viral culture.

II. Genital HerpesA. Genital HSV infection is usually transmitted

through sexual contact. About 22 percent of adultshave serologic evidence of HSV-2 infection.

B. Clinical Presentation1. Primary genital herpes has an incubation period

of two to 12 days, followed by a prodrome ofitching, burning or erythema. Multiple transient,painful vesicles then appear on the penis,perineum, vulva, vagina or cervix, and tenderinguinal lymphadenopathy may follow. Theinitial ulceration crusts and heals by 14 to 21days. Fever, headache, malaise, abdominalpain and myalgia are common in primary dis-ease. Recurrences are usually less severe andshorter in duration.

2. Women with established genital HSV-2 infectionhave asymptomatic shedding 1 to 5 percent ofdays.

C. Treatment of Primary Infection1. Antiviral therapy is recommended for the initial

genital herpes outbreak. Oral acyclovir is effec-tive in reducing symptoms. Topical acyclovirreduces the length of time before all lesionsbecome crusted but is much less effective thanoral acyclovir.

2. The oral acyclovir dosage for treatment ofprimary or initial nonprimary genital herpes is200 mg five times daily for 10 days.

3. Valacyclovir, given twice daily, is effective forthe treatment of primary genital herpes butcosts more than acyclovir. Famciclovir, giventhree times daily, is as effective as acyclovir,although it may be twice as expensive.

Dosage and Cost of Treatment Regimens forPrimary Genital Herpes Infection

Drug Dosage

Acyclovir (Zovirax) 200 mg five times daily for 10 days

Famciclovir(Famvir)

250 mg three times daily for 10days

Valacyclovir(Valtrex)

1 g twice daily for 10 days

D. Treatment of Recurrent Infection1. Drug therapy to prevent recurrences is effective;

it is prescribed for use in patients who havemore than six outbreaks per year.

2. Acyclovir has been used to suppress recur-rences of genital herpes, decreasing the fre-quency by 80 percent and preventing recurrenceby 45 percent.

3. Famciclovir and valacyclovir are as effective asacyclovir in suppressing recurrent genital her-pes. Valacyclovir has the advantage ofonce-daily dosing. Famciclovir must be giventwice daily.

Dosages and Characteristics of Chronic Sup-pressive Treatment Regimens for RecurrentGenital Herpes Infection

Drug Dosage Decreasein recur-rence rate(percent-age)

Use in pa-tients with>6 recur-rences peryear

Acyclovir(Zovirax)

400 mgtwice daily

78 to 79 Yes

Famciclovir(Famvir)

250 mgtwice daily

79 Yes


1 g oncedaily

78 to 79 Yes

250 mgtwice daily

78 to 79 Yes

500 mgonce daily

71 No

250 mgonce daily

54 No

E. Episodic Therapy. Acyclovir, taken hours after theprodrome of recurrence begins, exerts a benefit inrecurrent genital herpes. Famciclovir andvalacyclovir are slightly more effective thanacyclovir for the treatment of recurrent infections.

Dosages of Antiviral Agents for Treatment ofEpisodic Genital Herpes

Drug Dosage

Acyclovir (Zovirax) 200 mg 5 times daily for 5days 800 mg twice daily for 5days

Famciclovir (Famvir) 125 mg twice daily for 5days

Valacyclovir (Valtrex) 500 mg twice daily for 5days

III.Orolabial HerpesA. Orolabial herpes (gingivostomatitis) is the most

prevalent form of herpes infection; 35 to 60 per-cent of persons show serologic evidence of havingbeen infected by HSV-1.

B. Primary herpetic gingivostomatitis usually affectschildren under the age of five. It appears aspainful vesicles and ulcerative erosions on thetongue, palate, gingiva, buccal mucosa and lips.

C. Systemic symptoms are often present, includingfever (38.4 to 40/C), malaise and myalgia. Theduration of the illness is two to three weeks, andoral shedding of virus may continue for a 23 days.

D. Recurrences typically occur two or three times ayear. The duration is shorter and the discomfortless severe than in primary infections, and thevesicles heal completely by eight to 10 days.

E. Treatment of Primary Infection1. Topical medication for HSV infection is not

highly effective. Topical penciclovir, appliedevery two hours for four days, reduces healingtime by only about one day.

2. Oral acyclovir, in a dosage of 200 mg five timesdaily for five days, accelerates loss of crusts byone day (seven versus eight days) and canreduce the duration of pain by 36 percent

F. Treatment of Recurrent Infection1. Oral acyclovir, in dosages ranging from 400 to

1,000 mg daily, is effective in reducing by 50 to78 percent the frequency of herpes labialisfollowing UV light exposure. Oral acyclovir maylessen the severity of lesions. Short-term pro-phylactic therapy with acyclovir may be desir-able in some patients who anticipate intenseexposure to UV light (eg, skiers).

2. Early treatment of recurrent orolabial HSVinfection with high dosages of antiviral medica-tion markedly decreases the size and durationof lesions. Famciclovir, in a dosage of 250 mgthree times daily for five days decreases lesionsurface area by 50 percent and accelerateshealing time.


Herpes Zoster and Postherpetic

NeuralgiaHerpes zoster (shingles) results from reactivation of thevaricella-zoster virus. Herpes zoster has a lifetimeincidence of 10 to 20 percent. The incidence of herpeszoster increases sharply with advancing age, doubling ineach decade past the age of 50 years.

I. Clinical evaluationA. Herpes zoster typically presents with a prodrome

consisting of hyperesthesia, paresthesias, burningdysesthesias or pruritus along the affecteddermatome(s). The prodrome generally lasts one totwo days.

B. The prodromal phase is followed by developmentof a maculopapular rash that follows a dermatomaldistribution. The maculopapular rash evolves intovesicles with an erythematous base. The vesiclesare painful, and their development is often associ-ated with flu-like symptoms.

C. Although any vertebral dermatome may be in-volved, T5 and T6 are most commonly affected.The most frequently involved cranial nervedermatome is the ophthalmic division of thetrigeminal nerve.

D. The most common chronic complication of herpeszoster is postherpetic neuralgia. Pain that persistsfor longer than one to three months after resolutionof the rash is a sign of postherpetic neuralgia.Affected patients usually report constant burning,lancinating pain. Symptoms tend to abate overtime. Less than one-quarter of patients still experi-ence pain at six months after the herpes zostereruption, and fewer than one in 20 has pain at oneyear.

II. Treatment of herpes zosterA. Antiviral agents

1. Antiviral agents have been shown to decreasethe duration of herpes zoster rash and theseverity of pain in patients who receive antiviralagents within 72 hours after the onset of rash.

2. Acyclovir (Zovirax), valacyclovir (Valtrex) andfamciclovir (Famvir) therapy appear to producea moderate reduction in the development ofpostherpetic neuralgia. Major drawbacks oforally administered acyclovir include its lowerbioavailability compared with other agents andits dosing frequency (five times daily).

3. Valacyclovir (Valtrex) is administered threetimes daily. Compared with acyclovir,valacyclovir may be slightly better at decreasingthe severity of pain and the duration ofpostherpetic neuralgia.

4. Famciclovir (Famvir). The advantages offamciclovir are its dosing schedule (three timesdaily), its longer intracellular half-life comparedwith acyclovir and its better bioavailability com-pared with acyclovir and valacyclovir.

Treatment Options for Herpes Zoster

Medication Dosage

Acyclovir(Zovirax)

800 mg orally five times daily for 7 to 10days 10 mg per kg IV every 8 hours for 7 to10 days

Famciclovir(Famvir)

500 mg orally three times daily for 7days


1,000 mg orally three times daily for 7days

Prednisone(Deltasone)

30 mg orally twice daily on days 1through 7; then 15 mg twice daily ondays 8 through 14; then 7.5 mg twicedaily on days 15 through 21 2 (2 to 4)for days 1 through 72 (1 to 3) for days 8 through 141 (1 to 2) for days 15 to 21

B. Corticosteroids. Prednisone used in conjunctionwith acyclovir has been shown to reduce the painassociated with herpes zoster. Prednisone maydecrease the incidence of postherpetic neuralgia. Itshould be used only in patients more than 50 yearsof age because they are at greater risk of develop-ing postherpetic neuralgia.

C. Analgesics. Mild to moderate pain may respond toover-the-counter analgesics. More severe pain mayrequire a narcotic. Lotions containing calamine (eg,Caladryl) may be used on open lesions to reducepain and pruritus. Once the lesions have crustedover, capsaicin cream (Zostrix) may be applied.Topical lidocaine (Xylocaine) and nerve blocks havealso been reported to be effective in reducing pain.

D. Ocular involvement. Ocular herpes zoster istreated with oral antiviral agents and corticosteroids.Ophthalmologic consultation is recommended.

III. Treatment of postherpetic neuralgiaA. Although postherpetic neuralgia is generally a

self-limited condition, it can last indefinitely.

Treatment Options for Postherpetic Neuralgia

Medication Dosage

Topical agents

Capsaicin cream(Zostrix)

Apply to affected area three to fivetimes daily.

Lidocaine(Xylocaine)patch

Apply to affected area every 4 to 12hours as needed.

Tricyclic antidepressants

Amitriptyline(Elavil)

0 to 25 mg orally at bedtime; increasedosage by 25 mg every 2 to 4 weeksuntil response is adequate, or to maxi-mum dosage of 150 mg per day.

Nortriptyline(Pamelor)

0 to 25 mg orally at bedtime; increasedosage by 25 mg every 2 to 4 weeksuntil response is adequate, or to maxi-mum dosage of 125 mg per day.

Imipramine(Tofranil)

25 mg orally at bedtime; increase dos-age by 25 mg every 2 to 4 weeks untilresponse is adequate, or to maximumdosage of 150 mg per day.

Desipramine(Norpramin)

25 mg orally at bedtime; increase dos-age by 25 mg every 2 to 4 weeks untilresponse is adequate, or to maximumdosage of 150 mg per day.

Anticonvulsants

Phenytoin (Di-lantin)

100 to 300 mg orally at bedtime; in-crease dosage until response is ade-quate or blood drug level is 10 to 20 :gper mL (40 to 80 :mol per L).

Carbamazepine(Tegretol)

100 mg orally at bedtime; increase dos-age by 100 mg every 3 days until dos-age is 200 mg three times daily, re-sponse is adequate or blood drug levelis 6 to12 :g per mL (25.4 to 50.8 :molper L).

Gabapentin(Neurontin)

100 to 300 mg orally at bedtime; in-crease dosage by 100 to 300 mg every3 days until dosage is 300 to 900 mgthree times daily or response is ade-quate.

B. Analgesics1. Capsaicin is more efficacious than placebo but

must be applied to the affected area three to fivetimes daily. Pain will likely increase during thefirst few days to a week after capsaicin therapy isinitiated.

2. Lidocaine patches reduce pain intensity, withminimal systemic absorption. The effect lastsonly four to 12 hours with each application.

3. A c e t a m i n o p h e n a n d n o n s te r o i d a lanti-inflammatory drugs are useful for potentiat-ing the pain-relieving effects of narcotics.

C. Tricyclic Antidepressants1. Tricyclic antidepressants can be effective ad-

juncts in reducing pain. Tricyclic antidepressantscommonly used in the treatment of postherpeticneuralgia include amitriptyline (Elavil),nortriptyline (Pamelor), imipramine (Tofranil) anddesipramine (Norpramin).

2. The tricyclic antidepressants may cause seda-tion, dry mouth, postural hypotension, blurredvision and urinary retention. Nortriptyline is bettertolerated.

D. Gabapentin is effective in treating the pain ofpostherpetic neuralgia. The dosages required foranalgesia are often lower than those used in thetreatment of epilepsy.

E. Transcutaneous electric nerve stimulation(TENS), biofeedback and nerve blocks are alsosometimes used.

Atopic Dermatitis and EczemaAtopic dermatitis is a chronic inflammation of the skinthat occurs in persons of all ages but is more common inchildren. Atopic dermatitis affects 10 percent of children.The symptoms of atopic dermatitis resolve by adoles-cence in 50 percent of affected children.

I. Diagnosis

A. Exposure to aeroallergens, irritating chemicals,foods and emotional stress may worsen the rash.

B. Acute lesions are papules and vesicles on a back-ground of erythema. Subacute lesions may developscales and lichenification. Chronically involvedareas become thick and fibrotic. Lesions candevelop secondary infections with crusting andweeping. Xerosis (dry skin) is characteristic.

Diagnostic Features of Atopic Dermatitis

Major features Pruritus Chronic or relapsing dermatitis Personal or family history of atopic disease Typical distribution and morphology of atopic dermatitisrash: Facial and extensor surfaces in infants and young children Flexure lichenification in older children and adults

Minor features Eyes Cataracts (anteriorsubcapsular) Keratoconus Infraorbital folds affected

Facial pallorPalmar hyperlinearity Xerosis Pityriasis alba White dermatographism Ichthyosis Keratosis pilaris Nonspecific dermatitis of thehands and feet

Nipple eczema Positive type I hypersensitiv-ity skin tests Propensity for cutaneousinfections Elevated serum IgE level Food intolerance Impaired cell-mediated im-munity Erythroderma Early age of onset

C. In infants and young children, pruritus commonly ispresent on the scalp, face (cheeks and chin) andextensor surfaces of the extremities. Older childrenand adults typically have involvement of the flexorsurfaces (antecubital and popliteal fossa), neck,wrists and ankles.

D. Exposure to pollens, molds, mites and animaldander may be important in some patients.

II.TreatmentA. Bathing and moisturizers. Bathing should occur

once daily with warm water for five to 10 minutes.Soap should not be used unless it is needed forthe removal of dirt. A mild cleanser (eg, Dove,Basis, Kiss My Face or Cetaphil) may be used.After bathing, patients should apply a moisturizerliberally (eg, Vaseline, Aquaphor, Eucerin,Moisturel, mineral oil or baby oil). Ointments aresuperior to creams. Lotions are least effectivebecause of their alcohol content. To avoid injury tothe skin from scratching, fingernails should be cutshort, and cotton gloves can be worn at night.

B. Pruritus that is refractory to moisturizers andconservative measures can be treated with sedat-ing agents such as hydroxyzine (Atarax) anddiphenhydramine (Benadryl). Tricyclic antidepres-sants such as doxepin (Sinequan) and amitriptyline(Elavil) also induce sleep and reduce pruritus.

C. Systemic corticosteroids should be reserved foruse in patients with severe treatment-resistantatopic dermatitis.

D. It is reasonable to use a mild topical steroid initiallyin infants and for intertriginous areas in patients ofany age. If the dermatitis is severe, a more potentsteroid is needed.

Commonly Used Topical Corticosteroids

Preparation Size

Low-Potency Agents

Hydrocortisone ointment, cream, 1, 2.5% (Hytone) 30 g

Mild-Potency Agents

Alclometasone dipropionate cream, ointment,0.05% (Aclovate)

60 g

Triamcinolone acetonide cream, 0.1% (Aristocort) 60 g

Fluocinolone acetonide cream, 0.01% (Synalar) 60 g

Medium-Potency Agents

Triamcinolone acetonide ointment (Aristocort A),0.1%

60 g

Betamethasone dipropionate cream (Diprosone),0.05%

45 g

Mometasone cream 0.1% (Elocon) 45 g

Fluocinolone acetonide ointment, 0.025% (Synalar) 60 g

Betamethasone valerate cream, 0.1% (Valisone) 45 g

Hydrocortisone valerate cream, ointment, 0.2%(Westcort)

60 g

E. Immunosuppressants and antineoplastics1. Pimecrolimus (Elidel) is a non-steroid cream

for the treatment of mild to moderate eczema.Pimecrolimus has anti-inflammatory activity. Itdoes not cause skin atrophy. Topical applicationis comparable to that of a potent topical steroid.1% pimecrolimus cream is applied twice daily.It may be used in children >2 years old.

2. Tacrolimus (Protopic) is more potent thanpimecrolimus in the treatment of severe orrefractory atopic dermatitis, with few adverseeffects. Tacrolimus is available in 0.1% and0.03%. The lower strength may be used inchildren >2 years old.

3. Cyclosporine (Sandimmune) has been effec-tive in patients with refractory atopic dermatitis.The condition returns after the cessation oftherapy, although not always at the original levelof severity.


Acne VulgarisAcne vulgaris is a polymorphous skin disorder of thesebaceous follicles that begins around the time ofpuberty and peaks during the teenage years. Prevalenceexceeds 85% in teenagers and then declines to about8% in 25-to 34-year olds and to 3% in 35- to 44-year-olds. More adolescent boys than girls are afflicted.

I. Pathophysiology of acneA. Acne is a disease of the pilosebaceous follicle,

most commonly on the face, neck, and uppertrunk. Acne vulgaris arises from increased sebumproduction. Androgenic hormones produced duringthe pubertal period enlarge sebaceous glands,causing increased sebum production.

B. Proliferation of Propionibacterium acnes is felt toplay a pivotal role in the pathogenesis of inflamma-tory acne lesions.

II. Clinical evaluation. Acne vulgaris occurs primarily onthe face and (to a varying degree) the neck, upperback, chest, and shoulders. Classification is based onthe number and predominant type of lesions and onthe affected sites. The three distinct types are ob-structive acne, inflammatory ache, and acne scars.

III. Treatment of acneA. Topical agents are generally preferred for

comedonal lesions and for superficial inflammatoryacne without scarring. Cream is the vehicle ofchoice in patients with dry or sensitive skin. Topicalgels and solutions contain alcohol and are pre-ferred by those with excessively oily skin.

B. Topical comedolytic agents reduce the formation ofthe microcomedo by reversing abnormalkeratinization process duct. These agents are thecornerstone of obstructive acne treatment and animportant adjunct in all patients with inflammatoryacne.1. Topical tretinoin (Retin-A), a vitamin A deriva-

tive, promotes the drainage of preexistingcomedones and reduces the formation of newones. The full cosmetic benefit may not beapparent for 6-12 weeks. Tretinoin should be

applied lightly every night at bedtime. Skinirritation (dryness, erythema, and peeling) iscommon. Patients should avoid excessive sunexposure or should use a protective sunscreen.

2. Tretinoin (Retin-A) is available in creams(0.025%, 0.05%, 0.1%), gels (0.01%, 0.025%),liquid (0.05%), and a microsphere (Retin-AMicro 0.1%). The liquid is the most irritating.Patients with fair or sensitive skin should beginby using the 0.025% cream every other day andgradually increase to daily use at a higherconcentration as tolerated. The microspherereduces the potential for irritation.

3. Adapalene (Differin 0.1% gel), a naphthoicacid derivative with retinoid activity, is compara-ble to tretinoin, it appears to be less irritating,and it has anti-inflammatory activity. Adapaleneis applied as a thin film daily at bedtime. Atherapeutic effect is typically seen within 8-12weeks. Skin irritation occurs in 10-40% of pa-tients. Users should minimize exposure tosunlight.

4. Tazarotene (Tazorac, 0.05% and 0.1% gel), asynthetic acetylenic retinoid with comedolyticproperties, is FDA-approved for topical treat-ment of mild-to-moderate facial acne. It isapplied every evening. Tazarotene is associ-ated with skin irritation. Tazarotene does notoffer any significant advantages over tretinoin oradapalene.

C. Topical antibiotics inhibit the growth and activityof P acnes. Choices include clindamycin (Cleocin-T1% solution, lotion, or gel), erythromycin (A/T/S 2%gel or solution, Erygel 2% gel, Akne-Mycin 2%ointment, T-Stat 2% solution and pads),sulfacetamide (Klaron 10% lotion), and a 3%erythromycin and 5% benzoyl peroxide gel(Benzamycin). Topical antibiotics are applied twicedaily. Skin dryness and irritation are the mostcommon side effects. Antibiotic resistance ispossible. Resistance is less likely with theerythromycin and benzoyl peroxide combination,making it an option for patients who have devel-oped resistance to other agents.

D. Benzoyl peroxide is an antibacterial, agent thatmay also have mild comedolytic properties. It isavailable over-the-counter and in prescriptionformulations (2.5%, 5%, and 10% lotions, creams,and gels). Benzoyl peroxide is typically applied asa thin film, once or twice daily. Mild redness andscaling are common during the first few weeks.

E. Azelaic acid (Azelex 20% cream), a dicarboxylicacid with combined antimicrobial and comedolyticproperties, is FDA-approved for mild-to-moderateinflammatory acne. It is massaged in twice daily.Mild skin irritation occurs in 5-10% of patients.Because azelaic acid does not causephotosensitivity, it is an alternative comedolyticagent for patients who are reluctant to refrain fromactivities that involve significant exposure to thesun. Hypopigmentation is a rare adverse reaction.

F. Systemic agents1. Oral antibiotics are the foundation of moderate-

to-severe inflammatory acne treatment becausethey reduce ductal concentrations of P acnes.Improvement can generally be seen within 2-3weeks.

2. Tetracycline is favored because of its bettertolerability and lower incidence of P acnesresistance. It is initiated at a dose of 1-2 g/d in2-4 divided doses. Tetracycline should be takenon an empty stomach. Many individuals whoseacne is controlled can be weaned off oral antibi-otics after 6 months of therapy, and then topicalantimicrobial therapy can be continued formaintenance.

3. Long-term use is considered safe; the mostcommon side effects are gastrointestinal upsetand vulvovaginal candidiasis. Gram-negativefolliculitis may occur, typically manifested by thesudden appearance of superficial pustular orcystic acne lesions around the nares and flaringout over the cheeks.

4. M i n o c y c l i n e ( M i n o c i n ) a n dtrimethoprim/sulfamethoxazole (TMP/SMX[Bactrim, Septra]) have a place in treating somerefractory cases. Minocycline can be particularlyvaluable for patients with treatment-resistantinflammatory acne. Minocycline, like alltetracyclines, is contraindicated in pregnantwomen and in children younger than 9 years ofage because of potential adverse effects ondeveloping bones and teeth.

5. TMP/SMX is prescribed at a dose of 1 regular-strength tablet, qd or bid. Hematologic anddermatologic side effects have restricted its useto patients with severe acne refractory to otherantibiotics and to those who develop gram-

negative folliculitis secondary to long-termantibiotic therapy.

G. Hormone therapy improves acne by suppressingsebum production. A triphasic oral contraceptivepill containing ethinyl estradiol, 35 :g, andnorgestimate (Ortho Tri-Cyclen) has been shownto reduce inflammatory acne lesions by 40%.

H. Oral isotretinoin (13-cis-retinoic acid [Accutane])is the only available agent with the potential to cureacne. Most patients are started at 0.5-1 mg/kg qdor bid, typically for 15-20 weeks. Adverse reactionsinclude cheilitis, nose bleeds, dry skin and mucousmembranes, and photosensitivity. Less commonare arthralgias myalgias, headache, nyctalopia,and, in rare cases, pseudotumor cerebri.Isotretinoin can induce abnormalities in liver,hematologic, and lipid functions. Isotretinoin is ateratogen. Contraception must be ensured.

I. Comedone extraction is an office procedure usedto disimpact obstructive acne lesions. The ob-structing plug can usually be expressed afterenlarging the pore with a 25-gauge needle.

J. Intralesional corticosteroid injection can rapidly(within 48-72 hours) resolve large or recalcitrantinflammatory acne lesions and reduce the risk forscarring. A 30-gauge needle is used to inject 0.05-0.3 mL of a solution containing triamcinoloneacetonide through the pore of the lesion.


Superficial Fungal Infections of theSkinSuperficial fungal infections can be divided intodermatophytic infections, tinea versicolor, and cutaneouscandidiasis. Up to 20% of the US population is infectedwith dermatophytes.

I. Tinea pedisA. Tinea pedis is the most common dermatophytosis

and may affect up to 70% of adults. Also referred toas athlete's foot, it involves the plantar surface andinterdigital spaces of the foot.

B. Trichophyton rubrum accounts for mostdermatophytic foot infections. The three most com-mon clinical forms of tinea pedis are interdigital,moccasin type, and vesiculobullous. Interdigitalinfection often presents as white, macerated skinbetween the fourth and fifth toes, but it may appearin any web space.

C. Moccasin-type, or hyperkeratotic, tinea pedis usuallypresents as silvery white scales on a red, thickenedbase on the sole, heel, and sides of the foot. Occa-sionally, a single hand may also be involved.Onychomycosis often is present. Vesiculobulloustinea pedis usually presents as vesicles or pustuleson the sole. With each flare of infection, the solebecomes thicker, and maceration, itching, or sec-ondary infection can develop.

D. Most cases of tinea pedis respond to topical agents,such as econazole (Spectazole), ketoconazole(Nizoral), and terbinafine (Lamisil). Recurrence iscommon.

II. Tinea corporisA. Tinea corporis is dermatophytosis of the skin of the

trunk and extremities. Commonly referred to asringworm, this infection consists of a round, scalypatch that has a prominent, enlarging border and aclear central portion. The prominent edge oftencontains pustules or follicular papules, and multiplelesions can be present. A deep form of tineacorporis known as Majocchi's granuloma can de-velop. It typically develops after inappropriate topicalcorticosteroid therapy.

B. Conditions that may appear similar to the infectioninclude nummular eczema, plaque psoriasis, contactdermatitis, granuloma annulare, and erythemanodosum. Tinea corporis usually responds to topicaltherapy.

III. Tinea crurisA. Tinea cruris is dermatophytosis of the proximal

medial thigh and buttock. Also known as jock itch, itis more common in the summer and in persons whowear tight-fitting clothing. Tinea cruris is foundprimarily in young men.

B. The lesion on the leading edge of the thigh is promi-nent, with follicular papules and pustules. A ringedlesion typically extends from the crural fold over theadjacent upper inner thigh.

C. Differential diagnosis includes chafing, which oftenhas sharp demarcation from the normal skin and noscaling in the center of the lesion. Candidiasis canbe differentiated from tinea cruris by its irregularborder with satellite lesions and scrotal involvement.Tinea cruris often responds to topical therapy.

IV. Tinea versicolor

A. Tinea versicolor is common, in young and mid-dle-aged adults. The condition is caused by thelipophilic yeasts, Pityrosporum orbiculare andPityrosporum ovale. P orbiculare is known asMalassezia furfur. Tinea versicolor is also referred toas pityriasis versicolor.

B. Tinea versicolor is typically found on the upper trunk,neck, and arms. The characteristic finding is skindepigmentation, but lesions can range from red tohypopigmented to hyperpigmented.

C. Tinea versicolor usually does not clear spontane-ously and may persist for many years. “Spotty body”often presents in adolescence and is associatedwith itching. Tinea versicolor has a high rate ofrecurrence, and periodic retreatment may beneeded.

D. Differential diagnosis includes vitiligo, tinea corporis,pityriasis rosea, pityriasis alba, and secondarysyphilis.

E. Tinea versicolor responds to topical therapies, suchas terbinafine, econazole, ketoconazole, and sele-nium sulfide lotion or shampoo (Exsel, Head &Shoulders, Selsun). Recurrences may be lessfrequent if a short course of oral itraconazole(Sporanox) or ketoconazole (Nizoral) is instituted.

V. Tinea capitisA. Tinea capitis is a dermatophytic infection of the head

and scalp, usually found in infants, children, andyoung adolescents. Most infections occur in pre-school-aged children in African-American or His-panic populations. Infection can be spread fromchild to child or from animals to humans.

B. As the inflammatory response to infection increases,inflammatory alopecia may develop. Breakage ofhairs at the roots may result in “black-dot” alopecia.Scaling that resembles seborrheic dermatitis mayoccur on the scalp. Nodular, boggy swellings knownas kerions may develop.

C. Tinea capitis should be considered in anyprepubertal child over the age of 6 months who hasscalp scaling. Cervical lymphadenopathy is commonin symptomatic children. Fungal culture usually candifferentiate tinea capitis from other conditions.Differential diagnosis of tinea capitis includesseborrheic dermatitis, dandruff, scalp psoriasis,atopic dermatitis, bacterial furunculosis,trichotillomania, and alopecia areata.

D. Treatment requires an oral agent, such asgriseofulvin. Other oral antifungal agents have beenused successfully. Ketoconazole cream and sham-poo can be added as adjunctive therapy.

VI. Tinea facieiA. Tinea faciei is a dermatophytosis of the nonbearded

areas of the face. The condition may present asitchy, red skin without a discernible border, or it mayhave a raised border.

B. Differential diagnosis of tinea faciei includes discoidlupus erythematosus, lymphocytic infiltration,seborrheic dermatitis, rosacea, and contact dermati-tis. The infection often responds to topical therapy.

VII. Tinea manuumA. Tinea manuum is an unusual dermatophytic infec-

tion of the interdigital and palmar surfaces. It maycoexist with other fungal infections, such as tineapedis. The palmar surface often has diffuse areas ofdry, hyperkeratotic skin. Differential diagnosis shouldinclude pompholyx, eczema, secondary syphilis, andcallus formation.

B. The condition often responds to topical therapy.VIII. Cutaneous candidiasis

A. Cutaneous candidiasis is caused by C albicans.Other candidiasis infections include angular cheilitis(perlèche), erosio interdigitalis blastomycetica,candidal intertrigo, balanitis, vaginitis, andparonychia. Involvement of the skinfolds is mostcommon, but any area of the skin with increasedmoisture is susceptible.

B. Wearing of occlusive clothing, obesity or disordersaffecting the immune system (eg, diabetes, AIDS)may increase susceptibility to candidal infection.

C. Candidal skin infection often presents with ery-thema, cracking, or maceration. When macerationdevelops in the web spaces of the fingers, the skincan become soft and white. Candidal skin infectionis characterized by irregular (serrated) edges, tissueerythema, and satellite lesions.

D. In patients with normal immunity, candidiasis is mostoften treated with topical therapy. Commonly usedtopical agents include nystatin (Mycostatin),ketoconazole, miconazole, and clotrimazole. Ther-apy with oral fluconazole (Diflucan) is highly effec-tive.

IX. Topical agentsA. Topical treatment alone may be sufficient for

noninflammatory tinea corporis, tinea cruris, tineafaciei, tinea manuum, and tinea pedis.

B. Imidazoles1. Ketoconazole (Nizoral) 2% is indicated for treat-

ment of tinea corporis, tinea cruris, and tineapedis. It also is effective for tinea versicolor,

cutaneous candidiasis, and seborrheic dermatitis.C. Allylamines are effective in treatment of

dermatophytes and Candida, but they have noantibacterial properties. Terbinafine (Lamisil) 1% isapproved for treatment of tinea pedis, tinea cruris,and tinea corporis. Terbinafine seems to be morepotent than naftifine (Naftin) in eliminatingdermatophytosis.

D. Polyenes are useful in topical treatment ofcandidiasis, but they have no efficacy againstdermatophytes. Nystatin powder (eg, Pedi-Dri)provides drying as well as antifungal action againstcandidiasis in intertriginous areas (eg, perineum,under breasts). The efficacy of nystatin is similar tothat of clotrimazole.

E. Ciclopirox(Loprox) is effective against cutaneouscandidiasis, tinea versicolor, tinea pedis, and tineacruris.

X. Systemic agentsA. Systemic therapy is indicated for treatment of tinea

capitis, onychomycoses, and recalcitrant cutaneousmycoses. Systemic therapy often is needed intreatment of moccasin-type tinea pedis.

B. Griseofulvin1. This agent is active against Trichophyton,

Epidermophyton, and Microsporum species butineffective against yeasts and nondermatophytes.Griseofulvin is first-line therapy for tinea capitis. Adosage of 15 to 25 mg/kg daily of the liquidmicrosized formula (Grifulvin V) is recommended.

2. Common side effects are rash, hives, headache,nausea, vomiting, arthralgia, peripheral neuritis,confusion, insomnia, and memory lapse.

C. Ketoconazole (Nizoral)1. This agent is effective against dermatophytes,

yeasts, and some systemic mycoses. A dosageof 200 mg once daily for 2 to 4 weeks is ofteneffective for tinea cruris, tinea capitis, and tineapedis. In addition, oral ketoconazole therapy for1 week may eradicate tinea versicolor.

2. Use of oral ketoconazole is limited by the poten-tial for hepatotoxicity. Other potential side effectsinclude nausea, vomiting, abdominal pain, diar-rhea, headache, pruritus, insomnia, leukopenia,hemolytic anemia, decreased libido, and impo-tence.

D. Itraconazole (Sporanox)1. Itraconazole has the broadest spectrum of activity

of all the oral antifungal agents. It is effectiveagainst dermatophytes, Candida, some molds,and P ovale. It is effective in treatment of tineacorporis, tinea cruris, tinea pedis, tinea manuum,and onychomycoses.

2. Possible side effects include diarrhea, headache,rhinitis, dyspepsia, nausea, dry skin, rash, weak-ness, pruritus, dizziness, hypertension, and lossof libido. Itraconazole has interactions with medi-cations metabolized by cytochrome P-450, suchas astemizole (Hismanal), triazolam (Halcion),and midazolam (Versed).

E. Terbinafine (Lamisil)1. Oral terbinafine has shown efficacy in tinea pedis,

tinea cruris, tinea corporis, and onychomycoses.A dosage of 250 mg daily for 6 weeks for finger-nail onychomycosis and 12 weeks for toenailonychomycosis is highly effective. Terbinafine isnot effective for cutaneous candidiasis or tineaversicolor.

2. Common side effects include diarrhea, pruritus,dyspepsia, rash, taste disturbance, abdominalpain, and toxic effects on the liver.

F. Fluconazole (Diflucan)1. This agent is beneficial in superficial fungal

infections at a dosage of 50 to 200 mg daily for 1to 4 weeks. It also has been used for treatment ofonychomycoses caused by dermatophytes.

2. Fluconazole has significant drug interactions withastemizole, oral hypoglycemic agents, coumadin,phenytoin (Dilantin), cyclosporine (Sandimmune),theophylline, and cisapride (Propulsid). Sideeffects include nausea, headache, rash, vomiting,diarrhea, and hepatotoxicity.


Common Skin DiseasesI. Alopecia Areata

A. Alopecia areata is characterized by asymptomatic,noninflammatory, non-scarring areas of completehair loss, most commonly involving the scalp, butthe disorder may involve any area of hair-bearingskin.

B. Auto-antibodies to hair follicles are the most likelycause. Emotional stress is sometimes a precipitat-ing factor. The younger the patient and the morewidespread the disease, and the poorer the prog-

nosis.C. Regrowth of hair after the first attack takes place in

6 months in 30% of cases, with 50% regrowingwithin 1 year, and 80% regrowing within 5 years.Ten to 30% of patients will not regrow hair; 5%progress to total hair loss.

D. Lesions are well defined, single or multiple roundor oval areas of total hair loss. Typical “exclama-tion point” hairs (3-10 mm in size with a tapered,less pigmented proximal shaft) are seen at themargins.

E. Differential diagnosis includes tinea capitis,trichotillomania, secondary syphilis, and lupuserythematosus.

F. A VDRL or RPR test for syphilis should be ob-tained. A CBC, SMAC, sedimentary rate, thyroidfunction tests, and antinuclear antibody should becompleted to screen for pernicious anemia,chronic active hepatitis, thyroid disease, lupuserythematosus, and Addison's disease.

G. Therapy. Topical steroids, intralesional steroids,and topical minoxidil may be somewhat effective.1. Intralesional glucocorticoid injection is the most

common therapy for limited involvement. Triam-cinolone in a dosage of 10 mg per mL, is thepreferred agent.

2. Topical therapy may be beneficial when it iscombined with minoxidil, anthralin or injectedsteroids.

3. Topical minoxidil, 5 percent solution, is 40%effective in stimulating hair growth on the scalp,eyebrows and beard area. Minoxidil solution isapplied twice daily and stimulates hair growthwithin 12 weeks.

4. Anthralin cream is commonly used in children.New hair growth may occur within two to threemonths after initiation of topical anthralin ther-apy. In one study, 25 percent of patients hadcosmetically acceptable results by six months.Side effects of anthralin include redness, itchingand scaling. Removal of the cream after appli-cation for 20 to 60 minutes is often recom-mended. However, overnight application hasbeen shown to be well tolerated by some pa-tients.

5. The investigational technique called topicalimmunotherapy, or contact sensitization, maybe effective.

II. ScabiesA. Scabies is an extremely pruritic eruption usually

accentuated in the groin, axillae, navel, breastsand finger webs, with sparing the head.

B. Scabies is spread by skin to skin contact. Thediagnosis is established by finding the mite, ova, orfeces in scrapings of the skin, usually of the fingerwebs or genitalia.

C. Treatment of choice for nonpregnant adults andchildren is lindane (Kwell), applied for 12 hours,then washed off.

D. Elimite, a 5% permethrin cream, applied liberallyhead to toe and rinsed off in 12 hours, is moreeffective but more expensive than lindane (Kwell).

E. Treatment should be given to all members of aninfected household simultaneously. Clothing andsheets must be washed on the day of treatment.

III. Acne RosaceaA. This condition commonly presents in fair-skinned

individuals and is characterized by papules, ery-thema, and telangiectasias.

B. Initial treatment consists of doxycycline or tetracy-cline. Once there has been some clearing, topicalmetronidazole gel (Metro-gel) can prevent remis-sion. Sunblock should be used because sunlightcan exacerbate the condition.

IV.Drug EruptionsA. Drug eruptions may be type I, type II, type III, or

type IV immunologic reactions. Cutaneous drugreactions may start within 7 days of initiation of thedrug or within 4-7 days after the offending drughas been stopped.

B. The cutaneous lesions usually become moresevere and widespread over the following severaldays to 1 week and then clear over the next 7-14days.

C. Lesions most often start first and clear first fromthe head and upper extremities to the trunk andlower legs. Palms, soles, and mucous membranesmay be involved.

D. Most drug reactions appear as a typicalmaculopapular drug reaction. Tetracycline isassociated with a fixed drug eruption. Thiazidediuretics have a tendency for photosensitivityeruptions.

E. Treatment of drug eruptions1. Oral antihistamines are very useful.

Diphenhydramine (Benadryl), 25-50 mg q4-6h.Soothing, tepid water baths in Aveeno or corn

starch or cool compresses are useful.2. Severe signs and symptoms. A 2-week

course of systemic steroids (prednisone startingat 60 mg/day and then tapering) will usuallystop the symptoms.

F. Erythema Multiforme1. Erythema multiforme presents as dull red

macules or papules on the back of hands,palms, wrists, feet, elbows and knees. Theperiphery is red and the center becomes blue ordarker red, hence the characteristic target or irislesion.

2. The rash is most commonly a drug reactioncaused by sulfa medications or phenytoin(Dilantin). It is also seen as a reaction to herpessimplex virus infections, mycoplasma, andHepatitis B.

3. Erythema multiforme major or Steven’s John-son syndrome is diagnosed when mucousmembrane or eye involvement is present.

4. Prednisone 30-60 mg/day is often given with a2-4 week taper.

5. For HSV-driven erythema multiforme, acyclovirmay be helpful. Ophthalmologic consultation isobtained for ocular involvement.

V. Pityriasis RoseaA. Pityriasis rosea is an acute inflammatory dermatitis

characterized by self-limited lesions distributed onthe trunk and extremities. A viral cause is hypothe-sized. It is most common between the ages of 10and 35.

B. Clinical manifestations1. The initial lesion, called the "herald patch," can

appear anywhere on the body, and is 2-6 cm insize, and begins a few days to several weeksbefore the generalized eruption. The hands,face, and feet are usually spared.

2. The lesions are oval, and the long axes followthe lines of cleavage. Lesions are 2 cm or less,pink, tan, or light brown. The borders of thelesions have a loose rim of scales, peelingperipherally, called the "collarette." Pruritus isusually minimal.

C. Differential diagnosis. Secondary syphilis (aVDRL is indicated for atypical rashes), drug erup-tions, viral exanthems, acute papular psoriasis,tinea corporis.

D. Treatment. Topical antipruritic emollients(Caladryl) relieve itching. Ultraviolet therapy maybe used. The disease usually resolves in 2-14weeks and recurrences are unusual.


Bacterial Infections of the SkinBacterial skin infections most commonly include cellulitis,impetigo, and folliculitis.

I. CellulitisA. Cellulitis is a painful, erythematous infection of the

dermis and subcutaneous tissues that is character-ized by warmth, edema, and advancing borders.Cellulitis commonly occurs near breaks in the skin,such as surgical wounds, trauma, tinea infections,or ulcerations. Patients may have a fever and anelevated white blood cell count. The most commonsites of cellulitis are the legs and digits, followed bythe face, feet, hands, torso, neck, and buttocks.

B. In otherwise healthy adults, isolation of an etiologicagent is difficult and unrewarding. If the patient hasdiabetes, an immunocompromising disease, orpersistent inflammation, blood cultures or aspira-tion of the area of maximal inflammation may beuseful.

C. Empiric treatment of infection in patients with-out diabetes:1. Penic i l l inase-res is tant penic i l l in :

Dicloxacillin (Pathocil) 40 mg/kg/day in 4divided doses for 7-12 days; adults: 500 mg qidor

2. First-generation cephalosporin: Cephalexin(Keflex) 50 mg/kg/day PO in 4 divided dosesfor 7-10 days; adults: 500 mg PO qid or

3. Amoxicillin/clavulanate (Augmentin) 500 mgtid or 875 mg bid for 7-10 days.

4. Azithromycin (Zithromax) 500 mg on day 1,then 250 mg PO qd for 4 days.

5. Erythromycin ethylsuccinate 40 mg/kg/day in3 divided doses for 7-10 days; adults: 250-500mg qid.

6. Limited disease can be treated orally, but moreextensive disease requires parenteral therapy.Marking the margins of erythema with ink ishelpful in following the progression or regressionof cellulitis.

7. Outpatient therapy with injected ceftriaxone(Rocephin) provides 24 hours of parenteralcoverage and may be an option for some pa-tients.

Descriptions of Bacterial Skin Infections

Disease Description

Carbuncle A network of furuncles connected by sinustracts

Cellulitis Painful, erythematous infection of deepskin with poorly demarcated borders

Erysipelas Fiery red, painful infection of superficialskin with sharply demarcated borders

Folliculitis Papular or pustular inflammation of hairfollicles

Furuncle Painful, firm or fluctuant abscess originat-ing from a hair follicle

Impetigo Large vesicles and/or honey-crusted sores

D. Antibiotics should be maintained for at least threedays after the resolution of acute inflammation.Adjunctive therapy includes cool compresses;appropriate analgesics for pain; tetanus immuniza-tion; and immobilization and elevation of theaffected extremity.

E. A parenteral second- or third-generationcephalosporin (with or without an aminoglycoside)should be considered in patients who have diabe-tes, immunocompromised patients, those withunresponsive infections, or in young children. Thepatient may also require a plain radiograph of thearea or surgical debridement to evaluate for gasgangrene, osteomyelitis, or necrotizing fasciitis.

F. Periorbital cellulitis is caused by the same organ-isms that cause other forms of cellulitis and istreated with warm soaks, oral antibiotics, and closefollow-up. Children with periorbital or orbitalcellulitis often have underlying sinusitis. If the childis febrile and appears toxic, blood cultures shouldbe performed and lumbar puncture considered.

G. Orbital cellulitis occurs when the infection passesthe orbital septum and is manifested by proptosis,orbital pain, restricted eye movement, visualdisturbances, and concomitant sinusitis. Thisocular emergency requires intravenous antibiotics,otorhinolaryngology, and ophthalmologic consulta-tion.

II. ErysipelasA. Erysipelas usually presents as an intensely

erythematous infection with clearly demarcatedraised margins and lymphatic streaking. Commonsites are the legs and face.

B. Erysipelas is caused almost exclusively bybeta-hemolytic streptococcus and thus can betreated with oral or intravenous penicillin, or thisinfection may be treated the same as cellulitis.Adjunctive treatment and complications are thesame as for cellulitis.

III. ImpetigoA. Impetigo is most commonly seen in children aged

two to five years and is classified as bullous ornonbullous. The nonbullous type predominatesand presents with an erosion (sore), cluster oferosions, or small vesicles or pustules that have ahoney-yellow crust. Impetigo usually appears inareas where there is a break in the skin, such as awound, herpes simplex infection, or angularcheilitis.

B. The bullous form of impetigo presents as a largethin-walled bulla (2 to 5 cm) containing serousyellow fluid. It often ruptures leaving a denudedarea. Both forms of impetigo are primarily causedby S. aureus with Streptococcus usually beinginvolved in the nonbullous form.

C. An oral antibiotic with activity against S. aureusand group A beta-hemolytic streptococcus iswarranted in nonlocalized cases.1. Azithromycin (Zithromax) for five days and

cephalexin (Keflex) for 10 days have beenshown to be effective and well-tolerated.

2. Dicloxacillin (Pathocil), 500 mg PO qid for 2weeks.

3. Oxacillin (Prostaphlin) 1-2 gm IV q4-6h.4. Cephalexin (Keflex) 250-500 mg PO qid.5. Amoxicillin/clavulanate (Augmentin) 500 mg tid

or 875 mg bid for 7-10 days.6. Broad-spectrum fluoroquinolones have also

been shown to be effective for treating skin andsoft tissue infections. These medications haveexcellent skin penetration and good

bioavailability.IV.Folliculitis

A. The most common form is superficial folliculitis thatmanifests as a tender or painless pustule thatheals without scarring. Multiple or single lesionscan appear on any skin bearing hair including thehead, neck, trunk, buttocks, and extremities. S.aureus is the most likely pathogen. Topical therapywith erythromycin, clindamycin (Cleocin T gel),mupirocin (Bactroban), or benzoyl peroxide can beadministered to accelerate the healing process.

B. Staphylococci will occasionally invade the deeperportion of the follicle, causing swelling and ery-thema. These lesions are painful and may scar.This inflammation of the entire follicle or thedeeper portion of the hair follicle is called deepfolliculitis. Oral antibiotics are usually used andinclude first-generation cephalosporins,penicillinase-resistant penicillins, macrolides, andfluoroquinolones.

C. Gram-negative folliculitis usually involves the faceand affects patients with a history of long-termantibiotic therapy for acne. Pathogens includeKlebsiella, Enterobacter, and Proteus species. Itcan be treated as severe acne with isotretinoin(Accutane).

V. Furuncles and CarbunclesA. Furuncles and carbuncles occur as a follicular

infection progresses deeper and extends out fromthe follicle. Commonly known as an abscess orboil, a furuncle is a tender, erythematous, firm orfluctuant mass of walled-off purulent material,arising from the hair follicle. The pathogen isusually S. aureus. Typically, the furuncle willdevelop into a fluctuant mass and eventually opento the skin surface.

B. Carbuncles are an aggregate of infected hairfollicles that form broad, swollen, erythematous,deep, and painful masses that usually open anddrain through multiple tracts. Fever and malaise,are commonly associated with these lesions. Withboth of these lesions, gentle incision and drainageis indicated when lesions “point” (fluctuant). Thewound may be packed (usually with iodoformgauze) to encourage further drainage. In severecases, parenteral antibiotics such as cloxacillin(Tegopen), or a first-generation cephalosporin,such as cefazolin (Ancef), are required.


PsoriasisPsoriasis affects about 2 percent of the U.S. population.

I. DiagnosisA. Psoriasis is characterized by well-demarcated

erythematous plaques with a silvery scale. Psoria-sis is symmetrically distributed, with lesions on theears, elbows, knees, umbilicus, gluteal cleft andgenitalia. The joints, nails and scalp may also beaffected. Itching is the most common symptom.

B. Guttate psoriasis is characterized by numeroussmall, oval (teardrop-shaped) lesions that developafter an acute upper respiratory tract infection.Guttate psoriasis must be differentiated frompityriasis rosea, another condition characterized bythe sudden outbreak of red scaly lesions. Com-pared with pityriasis rosea, psoriatic lesions arethicker and scalier, and the lesions are not usuallydistributed along skin creases.

Types of Psoriasis, Associated Findings andTreatment Options

Type ofpsoriasis

Clinicalfeatures

Differentialdiagnosis

Treatmentoptions

Plaque-type psoriasis

Red, thick,scaly le-sions withsilvery scale

Atopic der-matitis, irri-tant dermati-tis, cutane-ous T-celllymphoma,pityriasisrubra pilaris,seborrheicdermatitis

Localized:topical ther-apy with cort-icosteroids,calcipotriene(Dovonex),coal tars,anthralin(Anthra-Derm)or tazarotene(Tazorac).Generalized:phototherapy,systemicagents, com-bination ther-apy

Type ofpsoriasis

Clinicalfeatures

Differentialdiagnosis

Treatmentoptions

Guttatepsoriasis

Teardrop-shaped, pinkto salmon,scalyplaques;usually onthe trunk,with sparingof palmsand soles

Pityriasisrosea, sec-ondarysyphilis,drug erup-tion

Ultraviolet Bphototherapy,natural sun-light

Pustularpsoriasis,localized

Erythematous papulesor plaquesstuddedwith pus-tules; usu-ally onpalms orsoles(palmoplantar pustularpsoriasis)

Pustulardrug erup-tion,dyshidroticeczema,subcornealpustulardermatosis

Same as forplaque-typepsoriasis

Pustularpsoriasis,general-ized

Same aslocalizedwith a moregeneral in-volvement;may be as-sociatedwith sys-temic symp-toms suchas fever,malaise anddiarrhea

Pustulardrug erup-tion,subcornealpustulardermatosis

Systemic ther-apy and/orhospitalizationusually re-quired

Erythrodermic psoria-sis

Severe, in-tense, gen-eralized ery-thema andscaling cov-ering entirebody; oftenassociatedwith sys-temic symp-toms; mayor may nothave hadpreexistingpsoriasis

Drug erup-tion, eczem-atous der-matitis,mycosisfungoides,pityriasisrubra pilaris

Systemic ther-apy and/orhospitalizationusually re-quired

II. Topical TherapyA. Treatment of Localized Psoriasis

1. Topical Corticosteroidsa. Topical corticosteroids are the most com-

monly prescribed treatment for psoriasis.Treatment is initiated with a me-dium-strength agent, and high-potencyagents are reserved for thick plaques.

b. Side effects from corticosteroids may in-clude cutaneous atrophy, telangiectasia,striae, acne, glaucoma, hypothalamus-pit-uitary-adrenal axis suppression and growthretardation. Topical calcipotriene is oftenused in combination with topical cortico-steroids.

2. Calcipotrienea. Calcipotriene is a vitamin D3 analog. It

inhibits epidermal cell proliferation. Effectsmay not be noticeable for up to six to eightweeks.

b. Maximal benefits are achieved whencalcipotriene is used in combination withpotent topical corticosteroids. Treatmentcould be initiated with twice-daily applica-tions of a topical corticosteroid andcalcipotriene until the lesions are flat.

3. Coal Tar. Coal tar is a black viscous fluidthought to suppress epidermal DNA synthesis.Coal tar is available as an ointment, cream,lotion, shampoo, bath oil and soap. Coal tar iseffective when it is combined with topicalcorticosteroids.

4. Anthralina. If good control of psoriasis is not achieved

with topical corticosteroids, considerationshould be given to the addition of anthralin ortazarotene therapy.

b. Anthralin is available in 0.1 percent to 1percent ointments, creams and solutions.Anthralin can be combined with ultravioletphototherapy.

5. Tazarotene is a topical retinoid, which helps tonormalize the proliferation of keratinocytes.Once-daily application of tazarotene gel, 0.05percent or 0.1 percent concentration, has beenshown to be effective.a. Tazarotene should usually be used in combi-

nation with corticosteroids.6. Sunlight and Tanning-Bed Treatment. Sun

exposure in addition to topical therapy may bebeneficial when multiple areas are affected withpsoriasis.

7. Intralesional Injections, Phototherapy andSystemic Therapya. Psoriatic plaques that fail to respond to

topical therapy may be improved by triamcin-olone (Kenalog) injected directly into thedermis. The concentration is generally 3 to10 mg per mL.

b. The patient with refractory lesions may bene-fit from phototherapy and systemic therapywith oral retinoids, methotrexate orcyclosporine.

c. Alefacept (Amevive), the first biologic agentfor treatment of psoriasis, is fairly effective inmoderate to severe disease. Alefacept mustbe given parenterally (once a week).


Allergic Rhinitis and ConjunctivitisAllergic rhinitis and allergic conjunctivitis are character-ized by inflammation of the nasal mucosa, rhinorrhea,nasal congestion, sneezing, and conjunctival injection.The disorder is episodic, seasonal or perennial. Inhaled,ingested or injected allergens encounter IgE that isbound to mast cell membranes, resulting in mast celldegranulation and symptoms.

I. DiagnosisA. Allergic rhinitis presents with nasal congestion,

rhinorrhea, sneezing, nasal or ocular pruritus,excessive lacrimation, and postnasal drip withresulting sore throat and cough. Patients oftenhave asthma or atopic dermatitis in their personalor family history.

B. Physical examination 1. Conjunctivae may be injected, and profuse

tearing may be present. Some patients presentwith swollen eyelids and boggy sclera. Thenasal mucosa may be congested with a profuseclear discharge.

2. Patients may exhibit “allergic shiners” (darkenedcircles under the eyes caused by venous pool-ing) and a crease across the bridge of the nosecaused by the “allergic salute” (upward rubbingof the nose).

C. Laboratory testing1. Nasal smear. Infectious rhinitis demonstrates a

predominance of neutrophils, and allergicdisease shows a predominance of eosinophils.

2. Allergy testing is useful to identify patients withallergic disease that does not display a clearseasonal pattern.

II. Treatment

Drugs for Allergic Rhinitis

Drug Tradename

Dose

Corticosteroid Nasal Sprays

Beclomethasone BeconaseVancenaseBeconaseAQVancenaseAQ

One spray two to qidOne spray bid-qidOne to two sprays bidOne to two sprays bid

Triamcinolone Nasacort Two to four sprays qd

Budesonide Rhinocort Two to four sprays bid

Flunisolide Nasalide Two sprays bid

Fluticasone Flonase Two sprays/day or onespray bid

Mometasone Nasonex Two sprays qd

Oral H1-receptor Blockers

Citrizine Zyrtec 5 or 10 mg once/d

Desloratadine Clarinex 5 mg once/d

Fexofenadine Allegra 60 mg bid or 180 mgonce/d

Loratadine ClaritinClaritinReditabsAlavert

10 mg once/d

Drug Tradename

Dose

Leukotriene Modifier

Montelukast Singulair 10 mg once/d

A. Allergen avoidance is accomplished throughhaving patients stay indoors as much as possibleduring times when the offending allergen is at itsseasonal peak. Other measures include enclosingmattresses or pillows with allergen-proof casings,and eliminating carpeting.

B. Intranasal steroids are useful in relieving itching,rhinorrhea and congestion, and they are moreeffective than antihistamines. The most commonside effects are headache and local irritation.Occasionally, patients develop intranasalcandidiasis.

C. Oral antihistamines are less effective thantopical nasal steroids and are an alternativetherapy. Second generation antihistamines foracute symptoms and combination second genera-tion antihistamine-decongestants (eg, loratadinepseudoephedrine [Claritin] or fexofenadinepseudoephedrine [Allegra]) for chronic symptomsmay be preferable in patients with mild symptoms.

D. Montelukast (Singulair) might be as effective asan oral antihistamine for treatment of seasonalallergic rhinitis, but it is less effective than anintranasal corticosteroid, and more expensivethan either.

E. Azelastine nasal spray (Astelin) is an intranasal,topical antihistamine, which may cause somno-lence; 2 sprays in each nostril bid.

F. Ophthalmic therapy1. Ocular corticosteroids are very effective.

Dexamethasone (Decadron) 0.1% ophthalmicsoln, 1-2 drops q4-8h. Because these drugsmay elevate intraocular pressure and worseninfections, they should be administered withcaution.

2. Antihistamine-vasoconstrictor prepara-tions. Vasocon-A (naphazoline/antazoline)and Naphcon-A (naphazoline/pheniramine) areover-the-counter antihistamine-decongestants;1-2 drops q2h as needed; up to 4 times a day.Rebound congestion can occur with long-termuse.

3. Cromolyn (Crolom), a mast cell stabilizer, ishighly effective for the treatment of allergicconjunctivitis; 1-2 drops in each eye q4-6h.

4. Lodoxamide (Alomide), a mast cell stabilizer,is more potent than cromolyn; 1-2 drops qid.

5. Levocabastine (Livostin), a histamine H1antagonist, provides relief within a few min-utes.

6. Ketorolac (Acular) is a topical NSAID; 1 dropqid is effective for seasonal allergic conjunctivi-tis.

III. Immunotherapy. Allergen immunotherapy is effec-tive in patients with allergic rhinitis, and it may beconsidered if other measures fail.


Renal Disorders

Acute Renal FailureAcute renal failure is defined as a sudden decrease inrenal function sufficient to increase the concentration ofnitrogenous wastes in the blood. It is characterized by anincreasing BUN and creatinine.

I. Clinical presentation of acute renal failureA. Oliguria is a common indicator of acute renal

failure, and it is marked by a decrease in urineoutput to less than 30 mL/h. Acute renal failure maybe oliguric (<500 L/day) or nonoliguric (>30 mL/h).Anuria (<100 mL/day) does not usually occur inrenal failure, and its presence suggests obstructionor a vascular cause.

B. Acute renal failure may also be manifest byencephalopathy, volume overload, pericarditis,bleeding, anemia, hyperkalemia, hyperphos-phatemia, hypocalcemia, and metabolic acidemia.

II. Clinical causes of renal failureA. Prerenal insult

1. Prerenal insult is the most common cause ofacute renal failure, accounting for 70% of cases.Prerenal failure is usually caused by reducedrenal perfusion secondary to extracellular fluidloss (diarrhea, diuresis, GI hemorrhage) orsecondary to extracellular fluid sequestration(pancreatitis, sepsis), inadequate cardiac output,renal vasoconstriction (sepsis, liver disease,drugs), or inadequate fluid intake or replace-ment.

2. Most patients with prerenal azotemia haveoliguria, a history of large fluid losses (vomiting,diarrhea, burns), and evidence of intravascularvolume depletion (thirst, weight loss, orthostatichypotension, tachycardia, flat neck veins, drymucous membranes). Patients with congestiveheart failure may have total body volume excess(distended neck veins, pulmonary and pedaledema) but still have compromised renal perfu-sion and prerenal azotemia because of dimin-ished cardiac output.

3. Causes of prerenal failure are usually reversibleif recognized and treated early; otherwise,prolonged renal hypoperfusion can lead to acutetubular necrosis and permanent renal insuffi-ciency.

B. Intrarenal insult1. Acute tubular necrosis (ATN) is the most

common intrinsic renal disease leading to ARF.a. Prolonged renal hypoperfusion is the most

common cause of ATN.b. Nephrotoxic agents (aminoglycosides,

heavy metals, radiocontrast media, ethyleneglycol) represent exogenous nephrotoxins.ATN may also occur as a result of endoge-nous nephrotoxins, such as intratubularpigments (hemoglobinuria), intratubularproteins (myeloma), and intratubular crystals(uric acid).

2. Acute interstitial nephritis (AIN) is an allergicreaction secondary to drugs (NSAIDs, $-lac-tams).

3. Arteriolar injury occurs secondary to hyperten-sion, vasculitis, microangiopathic disorders.

4. Glomerulonephritis secondary to immunologi-cally mediated inflammation may causeintrarenal damage.

C. Postrenal insult results from obstruction of urineflow. Postrenal insult is the least common cause ofacute renal failure, accounting for 10%. Postrenalinsult may be caused by obstruction secondary toprostate cancer, benign prostatic hypertrophy, orrenal calculi. Postrenal insult may be caused byamyloidosis, uric acid crystals, multiple myeloma,methotrexate, or acyclovir.

III.Clinical evaluation of acute renal failureA. Initial evaluation of renal failure should determine

whether the cause is decreased renal perfusion,obstructed urine flow, or disorders of the renalparenchyma. Volume status (orthostatic pulse,blood pressure, fluid intake and output, dailyweights, hemodynamic parameters), nephrotoxicmedications, and pattern of urine output should beassessed.

B. Prerenal azotemia is likely when there is a historyof heart failure or extracellular fluid volume loss ordepletion.

C. Postrenal azotemia is suggested by a history ofdecreased size or force of the urine stream, anuria,flank pain, hematuria or pyuria, or cancer of thebladder, prostate or pelvis.

D. Intrarenal insult is suggested by a history of

prolonged volume depletion (often post-surgical),pigmenturia, hemolysis, rhabdomyolysis, ornephrotoxins. Intrarenal insult is suggested byrecent radiocontrast, aminoglycoside use, orvascular catheterization. Interstitial nephritis maybe implicated by a history of medication rash, fever,or arthralgias.

E. Chronic renal failure is suggested by diabetesmellitus, normochromic normocytic anemia,hypercalcemia, and hyperphosphatemia.

IV. Physical examinationA. Cardiac output, volume status, bladder size, and

systemic disease manifestations should be as-sessed.

B. Prerenal azotemia is suggested by impairedcardiac output (neck vein distention, pulmonaryrales, pedal edema). Volume depletion is sug-gested by orthostatic blood pressure changes,weight loss, low urine output, or diuretic use.

C. Flank, suprapubic, or abdominal masses mayindicate an obstructive cause.

D. Skin rash suggests drug-induced interstitial nephri-tis; palpable purpura suggests vasculitis;nonpalpable purpura suggests thromboticthrombocytopenic purpura or hemolytic-uremic syn-drome.

E. Bladder catheterization is useful to rule outsuspected bladder outlet obstruction. A residualvolume of more than 100 mL suggests bladderoutlet obstruction.

F. Central venous monitoring is used to measurecardiac output and left ventricular filling pressure ifprerenal failure is suspected.

V. Laboratory evaluationA. Spot urine sodium concentration

1. Spot urine sodium can help distinguish betweenprerenal azotemia and acute tubular necrosis.

2. Prerenal failure causes increased reabsorptionof salt and water and will manifest as a low spoturine sodium concentration <20 mEq/L and alow fractional sodium excretion <1%, and aurine/plasma creatinine ration of >40. Fractionalexcretion of sodium (%) = ([urine sodium/plasmasodium] ÷ [urine creatinine/plasma creatinine] x100).

3. If tubular necrosis is the cause, the spot urineconcentration will be >40 mEq/L, and fractionalexcretion of sodium will be >1%.

B. Urinalysis1. Normal urine sediment is a strong indicator of

prerenal azotemia or may be an indicator ofobstructive uropathy.

2. Hematuria, pyuria, or crystals may be asso-ciated with postrenal obstructive azotemia.

3. Abundant cells, casts, or protein suggests anintrarenal disorder.

4. Red cells alone may indicate vascular disor-ders. RBC casts and abundant protein suggestglomerular disease (glomerulonephritis).

5. White cell casts and eosinophilic castsindicate interstitial nephritis.

6. Renal epithelial cell casts and pigmentedgranular casts are associated with acute tubu-lar necrosis.

C. Ultrasound is useful for evaluation of suspectedpostrenal obstruction (nephrolithiasis). The pres-ence of small (<10 cm in length), scarred kidneysis diagnostic of chronic renal insufficiency.

VI. Management of acute renal failureA. Reversible disorders, such as obstruction, should

be excluded, and hypovolemia should be correctedwith volume replacement. Cardiac output should bemaintained. In critically ill patients, a pulmonaryartery catheter should be used for evaluation andmonitoring.

B. Extracellular fluid volume expansion. Infusion ofa 1-2 liter crystalloid fluid bolus may confirm sus-pected volume depletion.

C. If the patient remains oliguric despite euvolemia, IVdiuretics may be administered. A large single doseof furosemide (100-200 mg) may be administeredintravenously to promote diuresis. If urine flow isnot improved, the dose of furosemide may bedoubled. Furosemide may be repeated in 2 hours,or a continuous IV infusion of 10-40 mg/hr (max1000 mg/day) may be used.

D. The dosage or dosing intervals of renally excreteddrugs should be modified.

E. Hyperkalemia is the most immediately life-threat-ening complication of renal failure. Serum potas-sium values greater than 6.5 mEq/L may lead toarrhythmias and cardiac arrest. Potassium shouldbe removed from IV solutions. Hyperkalemia maybe treated with sodium polystyrene sulfonate(Kayexalate), 30-60 gm PO/PR every 4-6 hours.

F. Hyperphosphatemia can be controlled with alu-minum hydroxide antacids (eg, Amphojel or

Basaljel), 15-30 ml or one to three capsules POwith meals, should be used.

G. Fluids. After normal volume has been restored,fluid intake should be reduced to an amount equalto urinary and other losses plus insensible lossesof 300-500 mL/day. In oliguric patients, daily fluidintake may need to be restricted to less than 1 L.

H. Nutritional therapy. A renal diet consisting of dailyhigh biologic value protein intake of 0.5 gm/kg/d,sodium 2 g, potassium 40-60 mg/day, and at least35 kcal/kg of nonprotein calories is recommended.Phosphorus should be restricted to 800 mg/day

I. Dialysis. Indications for dialysis include uremicpericarditis, severe hyperkalemia, pulmonaryedema, persistent severe metabolic acidosis (pHless than 7.2), and symptomatic uremia.


HematuriaHematuria may be a sign of urinary tract malignancy orrenal parenchymal disease. Up to 18% of normal per-sons excrete red blood cells into the urine, averaging 2RBCs per high-power field (HPF).

I. Clinical evaluation of hematuriaA. Dipstick testing detects hemoglobin and myoglobin;

therefore, microscopic examination of the urinarysediment is required before a diagnosis ofhematuria can be made.

B. The patient should be asked about frequency,dysuria, pain, colic, fever, fatigue, anorexia, abdom-inal, flank, or perineal pain. Exercise, jogging,menstruation, or a history of kidney stones shouldbe sought.

C. The patient should be examined for hypertension,edema, rash, heart murmurs, or abdominal masses(renal tumor, hydronephrosis from obstruction).Costovertebral-angle tenderness may be a sign ofrenal calculus or pyelonephritis.

D. Genitourinary examination may reveal a foreignbody in the penile urethra or cervical carcinomainvading the urinary tract. Prostatitis, carcinoma, orbenign prostatic hyperplasia may be found.

II.Laboratory evaluationA. At least one of the following criteria should be met

before initiating a workup for hematuria.1. More than 3 RBCs/HPF on two of three properly

collected clean-catch specimens (abstain fromexercise for 48 hours before sampling; notduring menses).

2. One episode of gross hematuria.3. One episode of high-grade microhematuria

(>100 RBCs HPF).B. A properly collected, freshly voided specimen

should be examined for red blood cell morphology;the character of the sediment and the presence ofproteinuria should be determined.

C. RBC casts are pathognomonic ofglomerulonephritis. WBC casts and granular castsare indicative of pyelonephritis.

D. Urine culture should be completed to rule outurinary tract infection, which may cause hematuria.

E. Serum blood urea nitrogen and creatinine levelsshould be evaluated to rule out renal failure. Im-paired renal function is seen more commonly withmedical causes of hematuria.

F. Fasting blood glucose levels should be obtained torule out diabetes; a complete blood count should beobtained to assess severity of blood loss.

G. Serum coagulation parameters should be mea-sured to screen for coagulopathy. A skin test fortuberculosis should be completed if risk factors arepresent. A sickle cell prep is recommended for allAfrican-American patients.

III. Classification of hematuriaA. Medical hematuria is caused by a glomerular

lesion. Plasma proteins are present in the urine outof proportion to the amount of hematuria. Medicalhematuria is characterized by glomerular RBCs,which are distorted with crenated membranes andan uneven hemoglobin distribution. Microscopichematuria and a urine dipstick test of 2+ protein ismore likely to have a medical cause.

B. Urologic hematuria is caused by urologic lesions,such as urolithiasis or bladder cancer. It is charac-terized by minimal proteinuria. Non-glomerularRBCs (disk shaped) and an absence of casts arecharacteristic.

IV. Diagnostic evaluation of medical hematuriaA. Renal ultrasound is used to evaluate kidney size

and rule out hydronephrosis or cystic disease.B. 24-hour urine. Creatinine, creatinine clearance and

protein should be measured to assess renal failure.C. Immunologic studies that may suggest a diagno-

sis include third and fourth complement compo-nents, antinuclear antibodies, cryoglobulins, anti-basement membrane antibodies; serum and urineprotein electrophoresis (to rule out IgAnephropathy).

D. Audiogram should be obtained if there is a familyhistory of Alport syndrome.

E. Skin biopsy can reveal dermal capillary deposits ofIgA in 80% of patients with Berger's disease (IgAnephropathy), which is the most common cause ofmicrohematuria in young adults.

V. Diagnostic evaluation of urologic hematuria A. Intravenous pyelography is the best screening

test for upper tract lesions if the serum creatinineis normal. It is usually contraindicated in renalinsufficiency. If renal insufficiency is present, renalultrasound and cystoscopy with retrogradepyelogram should be used to search for stones ormalignancy. If the IVP Is normal, cystoscopy withwashings for cytology may reveal the cause ofbleeding.

B. Other tests. Lesions in the kidney visualized onIVP can be evaluated by renal ultrasound to as-sess cystic or solid character. CT-guided aspirationof cysts may be considered. Filling defects in theureter should be evaluated by retrogradepyelogram and ureteral washings.

VI.Idiopathic hematuria A. Idiopathic hematuria is a diagnosis of exclusion.

Five to 10% of patients with significant hematuriawill have no diagnosis. Suspected urologichematuria with a negative initial workup should befollowed every 6-12 months with a urinalysis andurine cytology. An IVP should be done every 2-3years.

B. Renal function and proteinuria should be moni-tored. If renal function declines or if proteinuriaexceeds 1 gm/day, renal biopsy is indicated.


HyperkalemiaBody potassium is 98% intracellular. Only 2% of totalbody potassium, about 70 mEq, is in the extracellularfluid, with the normal concentration of 3.5-5 mEq/L.

I. Pathophysiology of potassium homeostasisA. The normal upper limit of plasma K is 5-5.5 mEq/L,

with a mean K level of 4.3.B. External potassium balance. Normal dietary K

intake is 1-1.5 mEq/kg in the form of vegetablesand meats. The kidney is the primary organ forpreserving external K balance, excreting 90% ofthe daily K burden.

C. Internal potassium balance. Potassium transferto and from tissues, is affected by insulin, acid-base status, catecholamines, aldosterone, plasmaosmolality, cellular necrosis, and glucagon.

II. Clinical disorders of external potassium balanceA. Chronic renal failure. The kidney is able to

excrete the dietary intake of potassium until theglomerular filtration rate falls below 10 cc/minute oruntil urine output falls below 1 L/day. Renal failureis advanced before hyperkalemia occurs.

B. Impaired renal tubular function. Renal diseasesmay cause hyperkalemia, and the renal tubularacidosis caused by these conditions may worsenhyperkalemia.

C. Primary adrenal insufficiency (Addison's dis-ease) is now a rare cause of hyperkalemia. Diag-nosis is indicated by the combination ofhyperkalemia and hyponatremia and is confirmedby a low aldosterone and a low plasma cortisollevel that does not respond to adrenocorticotropichormone treatment.

D. Drugs that may cause hyperkalemia includenonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, cyclosporine, andpotassium-sparing diuretics. Hyperkalemia isespecially common when these drugs are given topatients at risk for hyperkalemia (diabetics, renalfailure, advanced age).

E. Excessive potassium intake 1. Long-term potassium supplementation results in

hyperkalemia most often when an underlyingimpairment in renal excretion already exists.

2. Intravenous administration of 0.5 mEq/kg over1 hour increases serum levels by 0.6 mEq/L.Hyperkalemia often results when infusions ofgreater than 40 mEq/hour are given.

III. Clinical disorders of internal potassium balanceA. Diabetic patients are at particular risk for severe

hyperkalemia because of renal insufficiency andhyporeninemic hypoaldosteronism.

B. Systemic acidosis reduces renal excretion of

potassium and moves potassium out of cells,resulting in hyperkalemia.

C. Endogenous potassium release from muscleinjury, tumor lysis, or chemotherapy may elevateserum potassium.

IV.Manifestations of hyperkalemiaA. Hyperkalemia, unless severe, is usually asymp-

tomatic. The effect of hyperkalemia on the heartbecomes significant above 6 mEq/L. As levelsincrease, the initial ECG change is tall peaked Twaves. The QT interval is normal or diminished.

B. As K levels rise further, the PR interval becomesprolonged, then the P wave amplitude decreases.The QRS complex eventually widens into a sinewave pattern, with subsequent cardiac standstill.

C. At serum K is >7 mEq/L, muscle weakness maylead to a flaccid paralysis. Sensory abnormalities,impaired speech and respiratory arrest may follow.

V. Pseudohyperkalemia A. Potassium may be falsely elevated by hemolysis

during phlebotomy, when K is released fromischemic muscle distal to a tourniquet, and be-cause of erythrocyte fragility disorders.

B. Falsely high laboratory measurement of serumpotassium may occur with markedly elevatedplatelet counts (>106 platelet/mm3) or white bloodcell counts (>50,000/mm3).

VI.Diagnostic approach to hyperkalemiaA. The serum K level should be repeat tested to rule

out laboratory error. If significant thrombocytosis orleukocytosis is present, a plasma potassium levelshould be determined.

B. The 24-hour urine output, urinary K excretion,blood urea nitrogen, and serum creatinine shouldbe measured. Renal K retention is diagnosedwhen urinary K excretion is less than 20 mEq/day.

C. High urinary K, excretion of >20 mEq/day, isindicative of excessive K intake as the cause.

VII. Renal hyperkalemia A. If urinary K excretion is low and urine output is in

the oliguric range, and creatinine clearance islower than 20 cc/minute, renal failure is the proba-ble cause. Prerenal azotemia resulting from vol-ume depletion must be ruled out because thehyperkalemia will respond to volume restoration.

B. When urinary K excretion is low, yet blood ureanitrogen and creatinine levels are not elevated andurine volume is at least 1 L daily and renal sodiumexcretion is adequate (about 20 mEq/day), theneither a defect in the secretion of renin oraldosterone or tubular resistance to aldosterone islikely. Low plasma renin and aldosterone levels,will confirm the diagnosis of hyporeninemichypoaldosteronism. Addison's disease is sug-gested by a low serum cortisol, and the diagnosisis confirmed with a ACTH (Cortrosyn) stimulationtest.

C. When inadequate K excretion is not caused byhypoaldosteronism, a tubular defect in K clearanceis suggested. Urinary tract obstruction, renaltransplant, lupus, or a medication should beconsidered.

VIII. Extrarenal hyperkalemiaA. When hyperkalemia occurs along with high urinary

K excretion of >20 mEq/day, excessive intake of Kis the cause. Potassium excess in IV fluids, diet, ormedication should be sought. A concomitantunderlying renal defect in K excretion is also likelyto be present.

B. Blood sugar should be measured to rule out insulindeficiency; blood pH and serum bicarbonateshould be measured to rule out acidosis.

C. Endogenous sources of K, such as tissue necro-sis, hypercatabolism, hematoma, gastrointestinalbleeding, or intravascular hemolysis should beexcluded.

IX.Management of hyperkalemia A. Acute treatment of hyperkalemia

1. Calciuma. If the electrocardiogram shows loss of P

waves or widening of QRS complexes,calcium should be given IV; calcium reducesthe cell membrane threshold potential.

b. Calcium chloride (10%) 2-3 g should begiven over 5 minutes. In patients with circu-latory compromise, 1 g of calcium chloride IVshould be given over 3 minutes.

c. If the serum K level is greater than 7 mEq/L,calcium should be given. If digitalis intoxica-tion is suspected, calcium must be givencautiously. Coexisting hyponatremia shouldbe treated with hypertonic saline.

2. Insulin: If the only ECG abnormalities arepeaked T waves and the serum level is under 7mEq/L, treatment should begin with insulin(regular insulin, 5-10 U by IV push) with 50%dextrose water (D50W) 50 mL IV push. Re-

peated insulin doses of 10 U and glucose canbe given every 15 minutes for maximal effect.

3. Sodium bicarbonate promotes cellular uptakeof K. It should be given as 1-2 vials (50-mEq/vials) IV push.

4. Potassium elimination measures a. Sodium polystyrene sulfonate (Kayexalate)

is a cation exchange resin which binds topotassium in the lower GI tract. Dosage is30-60 gm premixed with sorbitol 20%PO/PR.

b. Furosemide (Lasix) 100 mg IV should begiven to promote kaliuresis.

c. Emergent hemodialysis for hyperkalemia israrely necessary except when refractorymetabolic acidosis is present.


HypokalemiaHypokalemia is characterized by a serum potassiumconcentration of less than 3.5 mEq/L. Ninety-eightpercent of K is intracellular.

I. Pathophysiology of hypokalemiaA. Cellular redistribution of potassium.

Hypokalemia may result from the intracellular shiftof potassium by insulin, beta-2 agonist drugs,stress induced catecholamine release, thyrotoxicperiodic paralysis, and alkalosis-induced shift(metabolic or respiratory).

B. Nonrenal potassium loss1. Gastrointestinal loss can be caused by diar-

rhea, laxative abuse, villous adenoma, biliarydrainage, enteric fistula, clay ingestion, potas-sium binding resin ingestion, or nasogastricsuction.

2. Sweating, prolonged low-potassium diet,hemodialysis and peritoneal dialysis may alsocause nonrenal potassium loss.

C. Renal potassium loss1. Hypertensive high renin states. Malignant

hypertension, renal artery stenosis, renin-pro-ducing tumors.

2. Hypertensive low renin, high aldosteronestates. Primary hyperaldosteronism (adenomaor hyperplasia).

3. Hypertensive low renin, low aldosteronestates. Congenital adrenal hyperplasia (11 or17 hydroxylase deficiency), Cushing's syn-d r o m e o r d i s e a s e , e x o g e n o u smineralocorticoids (Florinef, licorice, chewingtobacco), Liddle's syndrome.

4. Normotensive statesa. Metabolic acidosis. Renal tubular acidosis

(type I or II)b. Metabolic alkalosis (urine chloride <10

mEq/day). Vomitingc. Metabolic alkalosis (urine chloride >10

mEq/day). Bartter's syndrome, diuretics,magnesium depletion, normotensive hyper-aldosteronism

5. Drugs associated with potassium loss includeamphotericin B, ticarcillin, piperacillin, and loopdiuretics.

II. Clinical effects of hypokalemiaA. Cardiac effects. The most lethal consequence of

hypoka lemia is card iac ar rhythmia .Electrocardiographic effects include a depressedST segment, decreased T-wave amplitude, Uwaves, and a prolonged QT-U interval.

B. Musculoskeletal effects. The initial manifestationof K depletion is muscle weakness, which can leadto paralysis. In severe cases, respiratory muscleparalysis may occur.

C. Gastrointestinal effects. Nausea, vomiting,constipation, and paralytic ileus may develop.

III. Diagnostic evaluationA. The 24-hour urinary potassium excretion should

be measured. If >20 mEq/day, excessive urinaryK loss is the cause. If <20 mEq/d, low K intake, ornon-urinary K loss is the cause.

B. In patients with excessive renal K loss and hyper-tension, plasma renin and aldosterone should bemeasured to differentiate adrenal from non-adre-nal causes of hyperaldosteronism.

C. If hypertension is absent and serum pH is acidotic,renal tubular acidosis should be considered. Ifhypertension is absent and serum pH is normal toalkalotic, a high urine chloride (>10 mEq/d) sug-gests hypokalemia secondary to diuretics orBartter's syndrome. A low urine chloride (<10mEq/d) suggests vomiting.

IV. Emergency treatment of hypokalemiaA. Indications for urgent replacement.

Electrocardiographic abnormalities, myocardialinfarction, hypoxia, digitalis intoxication, markedmuscle weakness, or respiratory muscle paralysis.

B. Intravenous potassium therapy1. Intravenous KCL is usually used unless con-

comitant hypophosphatemia is present, wherepotassium phosphate is indicated.

2. The maximal rate of intravenous K replacementis 30 mEq/hour. The K concentration of IV fluidsshould be 80 mEq/L or less if given via a pe-ripheral vein. Frequent monitoring of serum Kand constant electrocardiographic monitoring isrecommended when potassium levels are beingreplaced.

V. Non-emergent treatment of hypokalemiaA. Attempts should be made to normalize K levels if

<3.5 mEq/L.B. Oral supplementation is significantly safer than IV.

Liquid formulations are preferred due to rapid oralabsorption, compared to sustained release formu-lations, which are absorbed over several hours.1. KCL elixir 20-40 mEq qd-tid PO after meals.2. Micro-K, 10 mEq tabs, 2-3 tabs tid PO after

meals (40-100 mEq/d).


HypermagnesemiaSerum magnesium has a normal range of 0.8-1.2mmol/L. Magnesium homeostasis is regulated by renaland gastrointestinal mechanisms. Hypermagnesemia isusually iatrogenic and is frequently seen in conjunctionwith renal insufficiency.

I. Clinical evaluation of hypermagnesemiaA. Causes of hypermagnesemia

1. Renal. Creatinine clearance <30 mL/minute.2. Nonrenal. Excessive use of magnesium cathar-

tics, especially with renal failure; iatrogenicovertreatment with magnesium sulfate.

B. Card iovascu la r man i festa t ions ofhypermagnesemia1. Hypermagnesemia <10 mEq/L. Delayed

interventricular conduction, first-degree heartblock, prolongation of the Q-T interval.

2. Levels greater than 10 mEq/L. Low-gradeheart block progressing to complete heart blockand asystole occurs at levels greater than 12.5mmol/L (>6.25 mmol/L).

C. Neuromuscular effects1. Hyporeflexia occurs at a magnesium level >4

mEq/L (>2 mmol/L); diminution of deep tendonreflexes is an early sign of magnesium toxicity.

2. Respiratory depression due to respiratorymuscle paralysis, somnolence and coma occurat levels >13 mEq/L (6.5 mmol/L).

3. Hypermagnesemia should always be consid-ered when these symptoms occur in patientswith renal failure, in those receiving therapeuticmagnesium, and in laxative abuse.

II. Treatment of hypermagnesemiaA. Asymptomatic, hemodynamically stable pa-

tients. Moderate hypermagnesemia can be man-aged by elimination of intake.

B. Severe hypermagnesemia 1. Furosemide 20-40 mg IV q3-4h should be given

as needed. Saline diuresis should be initiatedwith 0.9% saline, infused at 120 cc/h to replaceurine loss.

2. If ECG abnormalities (peaked T waves, loss ofP waves, or widened QRS complexes) or ifrespiratory depression is present, IV calciumgluconate should be given as 1-3 ampules(10% solution, 1 gm per 10 mL amp), added tosaline infusate. Calcium gluconate can beinfused to reverse acute cardiovascular toxicityor respiratory failure as 15 mg/kg over a 4-hourperiod.

3. Parenteral insulin and glucose can be given toshift magnesium into cells. Dialysis is necessaryf o r p a t i e n t s w h o h a v e s e v e r ehypermagnesemia.


HypomagnesemiaMagnesium deficiency occurs in up to 11% of hospital-ized patients. The normal range of serum magnesium is1.5 to 2.0 mEq/L, which is maintained by the kidney,intestine, and bone.

I. PathophysiologyA. Decreased magnesium intake. Protein-calorie

malnutrition, prolonged parenteral fluid administra-tion, and catabolic illness are common causes ofhypomagnesemia.

B. Gastrointestinal losses of magnesium mayresult from prolonged nasogastric suction, laxativeabuse, and pancreatitis.

C. Renal losses of magnesium1. Renal loss of magnesium may occur secondary

to renal tubular acidosis, glomerulonephritis,interstitial nephritis, or acute tubular necrosis.

2. Hyperthyroidism, hypercalcemia, andhypophosphatemia may cause magnesium loss.

3. Agents that enhance renal magnesiumexcretion include alcohol, loop and thiazidediuretics, amphotericin B, aminoglycosides,cisplatin, and pentamidine.

D. Alterations in magnesium distribution1. Redistribution of circulating magnesium occurs

by extracellular to intracellular shifts, sequestra-tion, hungry bone syndrome, or by acute admin-istration of glucose, insulin, or amino acids.

2. Magnesium depletion can be caused by largequantities of parenteral fluids and pancreatitis-induced sequestration of magnesium.

II. Clinical manifestations of hypomagnesemiaA. Neuromuscular findings may include positive

Chvostek's and Trousseau's signs, tremors,myoclonic jerks, seizures, and coma.

B. Cardiovascular. Ventricular tachycardia, ventricu-lar fibrillation, atrial fibrillation, multifocal atrialtachycardia, ventricular ectopic beats, hyperten-sion, enhancement of digoxin-induceddysrhythmias, and cardiomyopathies.

C. ECG changes include ventricular arrhythmias(extrasystoles, tachycardia) and atrial arrhythmias(atrial fibrillation, supraventricular tachycardia,torsades de Pointes). Prolonged PR and QTintervals, ST segment depression, T-wave inver-sions, wide QRS complexes, and tall T-waves mayoccur.

III. Clinical evaluationA. Hypomagnesemia is diagnosed when the serum

magnesium is less than 0.7-0.8 mmol/L. Symptomsof magnesium deficiency occur when the serummagnesium concentration is less than 0.5 mmol/L.A 24-hour urine collection for magnesium is thefirst step in the evaluation of hypomagnesemia.Hypomagnesia caused by renal magnesium loss isassociated with magnesium excretion that exceeds24 mg/day.

B. Low urinary magnesium excretion (<1 mmol/day),with concomitant serum hypomagnesemia, sug-gests magnesium deficiency due to decreasedintake, nonrenal losses, or redistribution of magne-sium.

IV.Treatment of hypomagnesemiaA. Asymptomatic magnesium deficiency

1. In hospitalized patients, the daily magnesiumrequirements can be provided through either abalanced diet, as oral magnesium supplements(0.36-0.46 mEq/kg/day), or 16-30 mEq/day in aparenteral nutrition formulation.

2. Magnesium oxide is better absorbed and lesslikely to cause diarrhea than magnesium sul-fate. Magnesium oxide preparations includeMag-Ox 400 (240 mg elemental magnesium per400 mg tablet), Uro-Mag (84 mg elementalmagnesium per 400 mg tablet), and magnesiumchloride (Slo-Mag) 64 mg/tab, 1-2 tabs bid.

B. Symptomatic magnesium deficiency1. Serum magnesium <0.5 mmol/L requires IV

magnesium repletion with electrocardiographicand respiratory monitoring.

2. Magnesium sulfate 1-6 gm in 500 mL of D5Wcan be infused IV at 1 gm/hr. An additional 6-9gm of MgSO4 should be given by continuousinfusion over the next 24 hours.


Disorders of Water and SodiumBalanceI. Pathophysiology of water and sodium balance

A. Volitional intake of water is regulated by thirst.Maintenance intake of water is the amount of watersufficient to offset obligatory losses.

B. Maintenance water needs= 100 mL/kg for first 10 kg of body weight+ 50 mL/kg for next 10 kg+ 20 mL/kg for weight greater than 20 kg

C. Clinical signs of hyponatremia. Confusion,agitation, lethargy, seizures, and coma.

D. Pseudohyponatremia1. Elevation of blood glucose may creates an

osmotic gradient that pulls water from cells intothe extracellular fluid, diluting the extracellularsodium. The contribution of hyperglycemia tohyponatremia can be estimated using thefollowing formula: Expected change in serum sodium = (serumglucose - 100) x 0.016

2. Marked elevation of plasma lipids or protein canalso result in erroneous hyponatremia becauseof laboratory inaccuracy. The percentage ofplasma water can be estimated with the follow-ing formula: % plasma water = 100 - [0.01 x lipids (mg/dL)] -[0.73 x protein (g/dL)]

II. Diagnostic evaluation of hyponatremia A. Pseudohyponatremia should be excluded by

repeat testing. The cause of the hyponatremiashould be determined based on history, physicalexam, urine osmolality, serum osmolality, urinesodium and chloride. An assessment of volumestatus should determine if the patient is volumecontracted, normal volume, or volume expanded.

B. Classification of hyponatremic patients basedon urine osmolality1. Low-urine osmolality (50-180 mOsm/L)

indicates primary excessive water intake (psy-chogenic water drinking).

2. High-urine osmolality (urine osmolality>serum osmolality)a. High-urine sodium (>40 mEq/L) and vol-

ume contraction indicates a renal source ofsodium loss and fluid loss (excessive diureticuse, salt-wasting nephropathy, Addison'sdisease, osmotic diuresis).

b. High-urine sodium (>40 mEq/L) and nor-mal volume is most likely caused by waterretention due to a drug effect,hypothyroidism, or the syndrome of inappro-priate antidiuretic hormone secretion. InSIADH, the urine sodium level is usuallyhigh. SIADH is found in the presence of amalignant tumor or a disorder of the pulmo-nary or central nervous system.

c. Low-urine sodium (<20 mEq/L) and vol-ume contraction, dry mucous membranes,decreased skin turgor, and orthostatichypotension indicate an extrarenal source offluid loss (gastrointestinal disease, burns).

d. Low-urine sodium (<20 mEq/L) andvolume-expansion, and edema is causedby congestive heart failure, cirrhosis withascites, or nephrotic syndrome. Effectivearterial blood volume is decreased. De-creased renal perfusion causes increasedreabsorption of water.

Drugs Associated with SIADH

Acetaminophen BarbituratesCarbamazepineChlorpropamideClofibrate CyclophosphamideIndomethacin

IsoproterenolProstaglandin E1 Meperidine Nicotine TolbutamideVincristine

III. Treatment of water excess hyponatremiaA. Determine the volume of water excess

Water excess = total body water x([140/measured sodium] -1)

B. Treatment of asymptomatic hyponatremia.Water intake should be restricted to 1,000 mL/day.Food alone in the diet contains this much water, sono liquids should be consumed. If an intravenoussolution is needed, an isotonic solution of 0.9%sodium chloride (normal saline) should be used.Dextrose should not be used in the infusion be-cause the dextrose is metabolized into water.

C. Treatment of symptomatic hyponatremia 1. If neurologic symptoms of hyponatremia are

present, the serum sodium level should becorrected with hypertonic saline. Excessivelyrapid correction of sodium may result in a syn-drome of central pontine demyelination.

2. The serum sodium should be raised at a rate of1 mEq/L per hour. If hyponatremia has beenchronic, the rate should be limited to 0.5 mEq/Lper hour. The goal of initial therapy is a serumsodium of 125-130 mEq/L, then water restrictionshould be continued until the level normalizes.

3. The amount of hypertonic saline needed isestimated using the following formula: Sodium needed (mEq) = 0.6 x wt in kg x (desiredsodium - measured sodium)

4. Hypertonic 3% sodium chloride contains 513

mEq/L of sodium. The calculated volume re-quired should be administered over the periodrequired to raise the serum sodium level at arate of 0.5-1 mEq/L per hour. Concomitantadministration of furosemide may be required tolessen the risk of fluid overload.

IV.HypernatremiaA. Clinical manifestations of hypernatremia:

Clinical manifestations include tremulousness,irritability, ataxia, spasticity, mental confusion,seizures, and coma.

B. Causes of hypernatremia1. Net sodium gain or net water loss will cause

hypernatremia2. Failure to replace obligate water losses may

cause hypernatremia, as in patients unable toobtain water because of an altered mentalstatus or severe debilitating disease.

3. Diabetes insipidus: If urine volume is high buturine osmolality is low, diabetes insipidus is themost likely cause.

Drugs Associated with Diabetes Insipidus

EthanolPhenytoinChlorpromazineLithium

GlyburideAmphotericin BColchicineVinblastine

C. Diagnosis of hypernatremia1. Assessment of urine volume and osmolality are

essential in the evaluation of hyperosmolality.The usual renal response to hypernatremia isthe excretion of the minimum volume (<500mL/day) of maximally concentrated urine (urineosmolality >800 mOsm/kg). These findingssuggest extrarenal water loss.

2. Diabetes insipidus generally presents withpolyuria and hypotonic urine (urine osmolality<250 mOsm/kg).

V. Management of hypernatremiaA. If there is evidence of hemodynamic compromise

(eg, orthostatic hypotension, marked oliguria), fluiddeficits should be corrected initially with isotonicsaline. Once hemodynamic stability is achieved,the remaining free water deficit should be cor-rected with 5% dextrose water or 0.45% NaCl.

B. The water deficit can be estimated using thefollowing formula:

Water deficit = 0.6 x wt in kg x (1 - [140/mea-sured sodium]).

C. The change in sodium concentration should notexceed 1 mEq/liter/hour. One-half of the calculatedwater deficit can be administered in the first 24hours, followed by correction of the remainingdeficit over the next 1-2 days. The serum sodiumconcentration and ECF volume status should beevaluated every 6 hours. Excessively rapid correc-tion of hypernatremia may lead to lethargy andseizures secondary to cerebral edema.

D. Maintenance fluid needs from ongoing renal andinsensible losses must also be provided. If thepatient is conscious and able to drink, water shouldbe given orally or by nasogastric tube.

E. Treatment of diabetes insipidus1. Vasopressin (Pitressin) 5-10 U IV/SQ q6h;

fast onset of action with short duration.2. Desmopressin (DDAVP) 2-4 mcg IV/SQ q12h;

slow onset of action with long duration of effect.VI.Mixed disorders

A. Water excess and saline deficit occurs whensevere vomiting and diarrhea occur in a patientwho is given only water. Clinical signs of volumecontraction and a low serum sodium are present.Saline deficit is replaced and free water intakerestricted until the serum sodium level has normal-ized.

B. Water and saline excess often occurs with heartfailure, manifesting as edema and a low serumsodium. An increase in the extracellular fluidvolume, as evidenced by edema, is a saline ex-cess. A marked excess of free water expands theextracellular fluid volume, causing apparent hypo-natremia. However, the important derangement inedema is an excess of sodium. Sodium and waterrestriction and use of furosemide are usuallyindicated in addition to treatment of the underlyingdisorder.

C. Water and saline deficit is frequently caused byvomiting and high fever and is characterized bysigns of volume contraction and an elevated serumsodium. Saline and free water should be replacedin addition to maintenance amounts of water.


Endocrinologic Disorders

Diabetic KetoacidosisDiabetic ketoacidosis is defined by hyperglycemia,metabolic acidosis, andketosis.

I. Clinical presentationA. Diabetes is newly diagnosed in 20% of cases of

diabetic ketoacidosis. In patients with known diabe-tes, precipitating factors include infection, noncom-pliance with insulin, myocardial infarction, andgastrointestinal bleeding.

B. Symptoms of DKA include polyuria, polydipsia,fatigue, nausea, and vomiting, developing over 1 to2 days. Abdominal pain is prominent in 25%.

C. Physical examination1. Patients are typically flushed, tachycardic,

tachypneic, and volume depleted with dry mu-cous membranes. Kussmaul's respiration (rapid,deep breathing and air hunger) occurs when theserum pH is between 7.0 and 7.24.

2. A fruity odor on the breath indicates the pres-ence of acetone, a byproduct of diabeticketoacidosis.

3. Fever, although seldom present, indicatesinfection. Eighty percent of patients with diabeticketoacidosis have altered mental status. Mostare awake but confused; 10% are comatose.

D. Laboratory findings1. Serum glucose level >300 mg/dL2. pH <7.35, pCO2 <40 mm Hg3. Bicarbonate level below normal with an elevated

anion gap4. Presence of ketones in the serum

II. Differential diagnosisA. Differential diagnosis of ketosis-causing condi-

tions1. Alcoholic ketoacidosis occurs with heavy

drinking and vomiting. It does not cause anelevated glucose.

2. Starvation ketosis occurs after 24 hours withoutfood and is not usually confused with DKA be-cause glucose and serum pH are normal.

B. Differential diagnosis of acidosis-causingconditions1. Metabolic acidoses are divided into increased

anion gap (>14 mEq/L) and normal anion gap;anion gap = sodium - (CI- + HCO3-).

2. Anion gap acidoses can be caused byketoacidoses, lactic acidosis, uremia, salicylate,methanol, ethanol, or ethylene glycol poisoning.

3. Non-anion gap acidoses are associated with anormal glucose level and absent serum ketones.Causes of non-anion gap acidoses include renalor gastrointestinal bicarbonate loss.

C. Hyperglycemia caused by hyperosmolarnonketotic coma occurs in patients with type 2diabetes with severe hyperglycemia. Patients areusually elderly and have a precipitating illness.Glucose level is markedly elevated (>600 mg/dL),osmolarity is increased, and ketosis is minimal.

III. Treatment of diabetic ketoacidosisA. Fluid resuscitation

1. Fluid deficits average 5 liters or 50 mL/kg. Re-suscitation consists of 1 liter of normal salineover the first hour and a second liter over thesecond and third hours. Thereafter, ½ normalsaline should be infused at 100-120 mL/hr.

2. When the glucose level decreases to 250 mg/dL,5% dextrose should be added to the replace-ment fluids to prevent hypoglycemia. If theglucose level declines rapidly, 10% dextroseshould be infused along with regular insulin untilthe anion gap normalizes.

B. Insulin1. An initial loading dose consists of 0.1 U/kg IV

bolus. Insulin is then infused at 0.1 U/kg perhour. The biologic half-life of IV insulin is lessthan 20 minutes. The insulin infusion should beadjusted each hour so that the glucose declinedoes not exceed 100 mg/dL per hour.

2. The insulin infusion rate may be decreased whenthe bicarbonate level is greater than 20 mEq/L,the anion gap is less than 16 mEq/L, or theglucose is <250 mg/dL.

C. Potassium1. The most common preventable cause of death in

patients with DKA is hypokalemia. The typicaldeficit is between 300 and 500 mEq.

2. Potassium chloride should be started when fluidtherapy is started. In most patients, the initial rateof potassium replacement is 20 mEq/h, but

hypokalemia requires more aggressive replace-ment (40 mEq/h).

3. All patients should receive potassium replace-ment, except for those with renal failure, no urineoutput, or an initial serum potassium levelgreater than 6.0 mEq/L.

D. Sodium. For every 100 mg/dL that glucose iselevated, the sodium level should be assumed tobe higher than the measured value by 1.6 mEq/L.

E. Phosphate. Diabetic ketoacidosis depletes phos-phate stores. Serum phosphate level should bechecked after 4 hours of treatment. If it is below 1.5mg/dL, potassium phosphate should be added tothe IV solution in place of KCl.

F. Bicarbonate therapy is not required unless thearterial pH value is <7.0. For a pH of <7.0, add 50mEq of sodium bicarbonate to the first liter of IVfluid.

G. Magnesium. The usual magnesium deficit is 2-3gm. If the patient's magnesium level is less than 1.8mEq/L or if tetany is present, magnesium sulfate isgiven as 5g in 500 mL of 0.45% normal saline over5 hours.

H. Additional therapies 1. A nasogastric tube should be inserted in semi-

conscious patients to protect against aspiration.2. Deep vein thrombosis prophylaxis with subcu-

taneous heparin should be provided for patientswho are elderly, unconscious, or severelyhyperosmolar (5,000 U every 12 hours).

IV. Monitoring of therapyA. Serum bicarbonate level and anion gap should

be monitored to determine the effectiveness ofinsulin therapy.

B. Glucose levels should be checked at 1-2 hourintervals during IV insulin administration.

C. Electrolyte levels should be assessed every 2hours for the first 6-8 hours, and then q8h. Phos-phorus and magnesium levels should be checkedafter 4 hours of treatment.

D. Plasma and urine ketones are helpful in diagnos-ing diabetic ketoacidosis, but are not necessaryduring therapy.

V.Determining the underlying causeA. Infection is the underlying cause of diabetic

ketoacidosis in 50% of cases. Infection of theurinary tract, respiratory tract, skin, sinuses, ears,or teeth should be sought. Fever is unusual indiabetic ketoacidosis and indicates infection whenpresent. If infection is suspected, antibiotics shouldbe promptly initiated.

B. Omission of insulin doses is often a precipitatingfactor. Myocardial infarction, ischemic stroke, andabdominal catastrophes may precipitate DKA.

VI. Initiation of subcutaneous insulinA. When the serum bicarbonate and anion gap levels

are normal, subcutaneous regular insulin can bestarted.

B. Intravenous and subcutaneous administration ofinsulin should overlap to avoid redevelopment ofketoacidosis. The intravenous infusion may bestopped 1 hour after the first subcutaneous injec-tion of insulin.

C. Estimation of subcutaneous insulin require-ments 1. Multiply the final insulin infusion rate times 24

hours. Two-thirds of the total dose is given in themorning as two-thirds NPH and one-third regularinsulin. The remaining one-third of the total doseis given before supper as one-half NPH and one-half regular insulin.

2. Subsequent doses should be adjusted accordingto the patient's blood glucose response.


DiabetesUp to 4 percent of Americans have diabetes. Vasculardisease accounts for over 70 percent of deaths in adultswith diabetes.

I. Classification and pathophysiologyA. Type 1 diabetes mellitus primarily occurs in

children and adolescents. Patients with type 1diabetes have an absolute deficiency of endoge-nous insulin and require exogenous insulin forsurvival.

B. Type 2 diabetes accounts for 90% of individualswith diabetes mellitus, and the incidence increasesin frequency with age, obesity and physical inactiv-ity. The initial problem in type 2 diabetes is resis-tance to the action of insulin at the cellular level.

II. ScreeningA. All adults should be screened for diabetes at

regular intervals. Factors that confer an increasedrisk for development of diabetes include impairedglucose tolerance, hypertension, lipid disorders,coronary artery disease, obesity, and physicalinactivity.

B. A fasting plasma glucose test is recommended forscreening. A level of 110 to 125 mg/dL is consid-ered “impaired fasting glucose,” and a value ofgreater than or equal to 126 mg/dL, if confirmed onrepeat testing, establishes the diagnosis of diabe-tes. If a patient is found to have a random plasmaglucose level over 160 mg/dL, more formal testingwith a fasting plasma glucose should be consid-ered.

Criteria for Diagnosis of Diabetes inNonpregnant Adults

Fasting plasma glucose 126 mg/dL or higherorRandom plasma glucose 200 mg/dL or higher with symp-

toms of diabetes (fatigue, weight loss, polyuria,polyphagia, polydipsia)

orAbnormal two-hour 75-g oral glucose tolerance test result,

with glucose 200 mg/dL or higher at two hoursAny abnormal test result must be repeated on a subse-

quent occasion to establish the diagnosis

III. Screening for microvascular complications indiabeticsA. Retinopathy. Diabetic retinopathy and macular

degeneration are the leading causes of blindnessin diabetes. Adults with diabetes should receiveannual dilated retinal examinations beginning atthe time of diagnosis.

B. Nephropathy. Diabetes-related nephropathyaffects 40% of patients with type 1 disease and 10-20% of those with type 2 disease.Microalbuminuria can be detected with annualurine screening for albumin/creatinine ratio.

C. Peripheral neuropathy affects many patients withdiabetes and causes nocturnal or constant pain,tingling and numbness. The feet should be evalu-ated regularly for sensation, pulses and sores.

D. Autonomic neuropathy is found in many patientswith long-standing diabetes, resulting in diarrhea,constipation, gastroparesis, vomiting, orthostatichypotension, and erectile or ejaculatory dysfunc-tion.

Routine Diabetes Care

HistoryReview physical activity, diet, self-monitored blood glucosereadings, medications Assess for symptoms of coronary heart diseaseEvaluate smoking status, latest eye examination results,foot care

Physical examinationWeightBlood pressureFoot examinationPulseSores or callusMonofilament test for sensationInsulin injection sitesRefer for dilated retinal examination annually

Laboratory studiesHbA1c every three to six monthsAnnual fasting lipid panelAnnual urine albumin/creatinine ratioAnnual serum creatinine

IV. Treatment of type 2 diabetes mellitusA. The patient should monitor his fasting blood glu-

cose. Some readings should also be obtained aftermeals and at other times during the day, and whenhypoglycemia is suspected.

American Diabetes Association goals for thetreatment of diabetes

Preprandial blood glucoselevel

80 to 120 mg/dL

Bedtime blood glucoselevel

100 to 140 mg/dL

Normal hemoglobin A1c(HbA1c) level

4% to 6%

Target HbA1c level <7%

“Take action” HbA1c level >8%

V. SulfonylureasA. Sulfonylureas promote increased pancreatic

insulin secretion. Sulfonylureas can lead tohypoglycemia and weight gain. All members of thisdrug class appear to be equally efficacious, with adecrease in fasting plasma glucose concentrationof 60 to 70 mg/dL and a drop in HbA1c levels ofabout 1.5% to 2%.

B. Most patients who are of normal weight or onlymoderately obese should initially take asulfonylurea. A typical initial sulfonylurea regimenconsists of 2.5 mg of glipizide (Glucotrol) orglyburide (Micronase) taken before breakfast. Ifadequate glycemic control is not attained in thenext two to four weeks, the dose can be increasedto 5 mg and then 10 mg.

VI. MeglitinidesA. The mechanism of action of the meglitinides is

similar to that of the sulfonylureas. Unlikesulfonylureas, however, meglitinides have a “quickon-quick off” action that offers improved postpran-dial control and reduces the incidence of latepostprandial hypoglycemia.

B. The efficacy of the meglitinides is similar to that ofthe sulfonylureas, leading to a decrease in thefasting plasma glucose level of 60 mg/dL and inHbA1c of 1.7% to 1.9%. The main disadvantages ofthe meglitinides are their frequent dosing require-ments and the risk for hypoglycemia and hyper-insulinemia, which is the same as with thesulfonylureas.

C. Repaglinide (Prandin) is taken shortly beforeeach meal in doses ranging from 0.5 to 4 mg, upto three or four times a day. It may benefit patientswith unpredictable meal schedules or large post-prandial glucose excursions.

D. Nateglinide (Starlix) is a derivative ofphenylalanine. Nateglinide appears to have afaster onset and disappearance of action thanrepaglinide but a somewhat reduced efficacy. 60-120 mg tid before meals.

VII. BiguanidesA. Metformin (Glucophage), a biguanide, decreases

hepatic glucose production. Gastrointestinaldistress is common (eg, abdominal pain, nausea,diarrhea), most prominent during initiation oftherapy. The incidence of lactic acidosis frommetformin is only 0.03 per 1,000 patient-years.

B. Metformin lowers fasting plasma glucose levels by60 to 70 mg/dL and HbA1c by 1.5% to 2.0%. It isequally efficacious in non-obese patients. It is anappropriate first-line therapy for patients of anyweight.

Contraindications to metformin therapy

Renal dysfunctionSerum creatinine level >1.5 mg/dL in men, >1.4 mg/dLin womenMetformin should be temporarily discontinued in pa-tients undergoing radiologic studies involvingintravascular administration of iodinated contrast mate-rials. Treatment may be restarted 48 hours after theprocedure when normal renal function is documented. Treatment should be carefully initiated in patients >80years of age after measurement ofcreatinine clearance demonstrates that renal function isnot reduced.

Congestive heart failure that requires pharmacologic ther-apyHepatic dysfunctionDehydrationAcute or chronic metabolic acidosis (diabetic ketoacidosis)Known hypersensitivity to metformin

VIII. Alpha-glucosidase inhibitorsA. The alpha-glucosidase inhibitors slow the rate of

absorption of carbohydrates. The use ofacarbose (Precose) and miglitol (Glyset) islimited by both their relatively mild efficacy andthe high frequency of gastrointestinal distress.These drugs may be suitable for mild diabetes

or for those taking other oral agents who con-tinue to have large postprandial blood glucoseincreases. They must be taken with each mealto reduce the rise of postprandial plasma glu-cose levels.

B. Alpha-glucosidase inhibitors decrease postpran-dial plasma glucose levels by 40 to 60 mg/dL,fasting plasma glucose levels by 20 to 30 mg/dL,and HbA1c levels by 0.5% to 1.0%. Many patientsexperience abdominal bloating, cramping, andflatulence during initial therapy.

C. Acarbose (Precose) is available as 50 and 100mg tablets which should be taken with the firstbite of each meal; 50 mg three times daily.

D. Miglitol (Glyset) may be started at 50 mg tidwith the first bite of each meal.

IX. ThiazolidinedionesA. Thiazolidinediones increase insulin sensitivity in

muscle resulting in lower circulating glucoseconcen t ra t ions . Th iazo l i d i ned iones ,rosiglitazone (Avandia) and pioglitazone(Actos), decrease fasting plasma glucose by 30to 60 mg/dL and decrease HbA1c level by 1% to1.5%. Pioglitazone is given once daily androsiglitazone once or twice daily. Rosiglitazoneand pioglitazone may be used for monotherapyor in combination with metformin or asulfonylurea or insulin. Thiazolidinediones areno more effective than metformin, and theyshould be used only in patients who have con-traindications to metformin.

B. Adverse effects of thiazolidinedione therapyinclude weight gain and peripheral edema.Expansion of the extracellular fluid space canoccur, and anemia is occasionally seen. Ther-apy is contraindicated in advanced congestiveheart failure.

X. Choice of agentA. Diet, weight loss, and exercise remain the

most important initial steps in the managementof type 2 diabetes. Pharmacologic therapy ismandatory for patients who are unable toachieve glycemic control with lifestyle modifica-tions or who have significant symptoms.

B. Lean patients with type 2 diabetes usually haveinsulin deficiency as the predominant feature,and a sulfonylurea is recommended in thissubgroup. If control remains suboptimal,metformin or an alpha-glucosidase inhibitor maybe added. First-line therapy with metformin isalso reasonable, especially if glucose levels areonly mildly elevated, because risk ofhypoglycemia in these patients is increased withsulfonylurea therapy.

C. Overweight patients. Metformin should beconsidered the first-line agent because of theweight loss and lack of hypoglycemia. If controlis suboptimal with metformin, the addition of athiazolidinedione may be beneficial. If adequatecontrol cannot be achieved with two drugs, theaddition of a third oral agent should be consid-ered. Alternatively, insulin could be added orsubstituted entirely (a patient who is 20 percentabove ideal body weight and has a fasting bloodglucose of 180 mg/dL should be started on atotal dose of 21 units per day).

Pharmacotherapy of Type 2 Diabetes

Agent Startingdose

Maximumdose

Comments

Sulfonylureas

Glipizide(Glucotrol)Glyburide(DiaBeta,Micronase)Glimepiride(Amaryl)

5 mg daily

2.5 mgdaily

1 mg daily

20 mg twicedaily

10 mg twicedaily

8 mg daily

May causehypoglycemia,weight gain.Maximumdose shouldbe used onlyin combinationwith insulintherapy

Biguanide Metformin(Glucophage)

500 mgdaily

850 mgthree timesdaily

Do not use ifserumcreatinine isgreater than1.4 mg/dL inwomen or 1.5mg/dL in menor in the pres-ence of heartfailure, chronicobstructivepulmonarydisease orliver disease;may causelactic acidosis

Glyburide/metformin(Glucovance)

25 mg/250mg; 2.5mg/500mg; 5mg/500mg

1 tab qAM-bid

Thiazolidinediones

Pioglitazone(Actos)Rosiglitazone(Avandia)

15 mgdaily

4 mg daily

45 mg perday

4 mg twicedaily

Should beused only inpatients whohave contrain-dications tometformin

Alpha-glucosi-dase inhibi-tor

Acarbose(Precose)Miglitol(Glyset)

50 mg tid

50 mg tid

100 mgthree timesdaily100 mgthree timesdaily

Flatulence;start at lowdose to mini-mize side ef-fects; take atmealtimes

Meglita-mide

Repaglinide(Prandin)Nateglinide (Starlix)

0.5 mgbeforemeals120 mg tidbeforemeals or60 mg tidbeforemeals

4 mg tid-qid

120 mg tid

Take at meal-times

XI.Treatment of type 1 diabetes mellitus

Goals of intensive diabetes treatment

Premealblood glu-cose level

Postpran-dial (ie,mealtime)glucoselevel

Bedtimeglucoselevel

Hemoglo-bin A1c

(HbA1c)level

90 to 130mg/dL

120 to 180mg/dL

110 to 150mg/dL

Less than6.5%

A. Basics of insulin use1. Tighter control is recommended for pregnant

women. Looser control may be appropriate inyoung children; elderly patients with activecardiac, cognitive, or visual disorders; andpatients who (1) have hypoglycemic unaware-ness or recurrent severe hypoglycemia, (2)abuse alcohol or drugs, (3) have poor socialsupport, or (4) have diabetes resulting fromcombined exocrine and endocrine pancreaticfailure. Looser control is also indicated in pa-tients in whom a hypoglycemic event might putthem or others in danger (eg, bus drivers).

2. Starting insulin dose in otherwise healthypatients in whom type 1 diabetes was recentlydiagnosed, during the “honeymoon period” istypically 10 to 15 U/day (or 0.2 to 0.6 U/kg perday). Two-thirds of the total dose of intermedi-ate-acting isophane insulin suspension (NPH,or N) is given in the morning and one-third atdinnertime. Short-acting regular insulin or amore rapid-acting insulin, such as lispro (LP) or

aspart (as insulin analogue), is given withbreakfast and dinner.

3. Over time, patients who have type 1 diabeteswithout intercurrent illness typically need 0.5 to1 U/kg per day. Higher doses may be requiredduring pregnancy and the adolescent growthspurt. If the patient's condition is unstablebecause of diabetic ketoacidosis, the insulinrequirements may rise in the short term to 1 to1.5 U/kg per day or higher.

Initiating Insulin Therapy in a Patient withNewly Diagnosed Type 1 Diabetes

The total daily insulin dosage is 0.3 unit per kg of bodyweight.Two-thirds of the total daily insulin dose may be given 20 to

30 minutes before breakfast and one-third of the dosemay be given 20 to 30 minutes before the eveningmeal.

NPH insulin and regular insulin can be given in a 2:1 ratiofor the breakfast dose and a 1:1 ratio for the eve-ning-meal dose.

As more complete insulin deficiency develops this regimenbecomes less effective.

Pharmacokinetic properties of types of insulin

Type ofinsulin Onset Peak

effect

Du-ra-tionofac-tion

Dosinginterval

Mealtime Insulin

Lispro(Humalog)(rapid-acting)

5-15min

30min-1.5hr

2 to 4hours

Meal-time

Aspart(Novolog)(rapid-acting)

5-15min 1-2 hr Meal-

time

Regular(HumulinR)(short-acting)

30-60min 2-4 hr 5 to 8

hours

20-45min be-foremeals

Background Insulin

Isophaneinsulin sus-pension(NPH)(HumulinN) (inter-medi-ate-acting)

45min-3hr

4.5-7 hr18 to28hours

Twicedaily

Lente(HumulinL) (inter-medi-ate-acting)

1-3 hr 6-8 hr13 to20hours

Twicedaily

Glargine (Lantus)(long-acting)

1.5-2hr

Nopeak

13 to18hours

Oncedaily

4. In patients with type 2 diabetes in whom oralagents have failed, the starting dose of N insulinis 0.15 U/kg at bedtime (when oral agents arecontinued) or a total multidose regimen of 0.3 to0.7 U/kg per day (when all oral agents arediscontinued). The total insulin dose required inobese patients with type 2 diabetes averages1.2 U/kg per day.

5. Lispro insulin is superior to regular insulin incontrolling postprandial glucose spikes whengiven in addition to a background insulin. Otheradvantages of lispro insulin are that it can beinjected anytime from 15 minutes before toshortly after the meal, and it carries less risk ofhypoglycemia and weight gain.

6. Glargine insulin is a human insulin that isslowly released, resulting in a relatively constantconcentration over 24 hours with no pro-nounced peak. When patients are switched toglargine from twice-daily N insulin, it is sug-gested that 10% to 20% less glargine be giventhan the previous daily total dose of N insulin.Patients require regular, lispro, or aspart insulinboluses with each meal. Because of its consis-tency and prolonged action, glargine is a supe-

rior background insulin. Other peaklesslong-acting analogues (eg, Determir) will beavailable soon.

B. Multiple-dose strategies1. Near-normoglycemia usually requires two to

four daily injections or use of the insulin pump.2. The most physiologic ratio of mealtime insulin to

background insulin is 50:50. However, someactive adolescents do best on a 60:40 ratio,whereas more sedentary adults might need a40:60 ratio.

Conventional and intensive insulin regimes

No. ofinjec-tions

Regi-men 8AM/Noon/6PM/10PM

Morningdose

Noondose

Din-nerdose

Bedtimedose

Two injections

40%meal-time

N+R/0/N+R/0or

20%R orLP

- 20%R orLP

-

60%back-ground

N+LP/0/N+LP/0

40%N - 20%

N -

Three injections

40%meal-time

N+LP/0/LP/Nor

20%LP orR

-20%LPor R

-

60%back-ground

N+R/0/R/N

40%N - - 20%

N

Three injections

50%meal-time

U+R/R/U+R/0or

15%R orLP

15%R orLP

20%R orLP

-

50%back-ground

U+LP/LP/U+LP/0

20%U - 30% -


HypothyroidismHypothyroidism is second only to diabetes mellitus as themost common endocrine disorder, and its prevalencemay be as high as 18 cases per 1,000 persons in thegeneral population. The disorder becomes increasinglycommon with advancing age, affecting about 2 to 3percent of older women.

I. EtiologyA. Primary hypothyroidism

1. The most common cause of hypothyroidism isHashimoto's (chronic lymphocytic) thyroiditis.Most patients who have Hashimoto's thyroiditishave symmetrical thyroid enlargement, althoughmany older patients with the disease haveatrophy of the gland. Anti-thyroid peroxidase(TPO) antibodies are present in almost allpatients. Some patients have blocking antibod-ies to the thyroid-stimulating hormone (TSH)receptor.

2. Hypothyroidism also occurs after treatment ofhyperthyroidism by either surgical removal orradioiodine ablation. Less common causes ofhypo thyro id ism inc lude congen i ta ldyshormonogenesis, external radiotherapy,infiltrative diseases, such as amyloidosis, andperipheral resistance to thyroid hormone action.

B. Secondary and central hypothyroidism. Pituitaryand hypothalamic dysfunction can lead tohypothyroidism. Pituitary adenomas, cranio-pharyngiomas, pinealomas, sarcoidosis,histiocytosis X, metastatic disease, primary centralnervous system (CNS) neoplasms (eg, menin-gioma), and head trauma all may causehypothyroidism.

C. Transient hypothyroidism. Subacute thyroiditis isfrequently associated with a hyperthyroid phase of4 to 12 weeks' duration; a 2- to 16-week hypothy-roid phase follows, before recovery of thyroidfunction. Subacute granulomatous (de Quervain's)thyroiditis and subacute lymphocytic (painless)thyroiditis are viral and autoimmune disorders,respectively; the latter condition may occur postpartum.

II. DiagnosisA. Symptoms and signs of hypothyroidism include

fatigue, weight gain, muscle weakness andcramps, fluid retention, constipation, and neuropa-thy (eg, carpal tunnel syndrome). Severehypothyroidism may be associated withcarotenemia, loss of the lateral aspect of theeyebrows, sleep apnea, hypoventilation,bradycardia, pericardial effusion, anemia,hyponatremia, hyperprolactinemia, hypercholester-olemia, hypothermia, and coma.

B. In patients with primary hypothyroidism, the thy-roid-stimulating hormone (TSH) level is elevated,and free thyroid hormone levels are depressed. Incontrast, patients with secondary hypothyroidismhave a low or undetectable TSH level.

C. TSH results have to be interpreted in light of thepatient's clinical condition. A low TSH level shouldnot be misinterpreted as hyperthyroidism in thepatient with clinical manifestations ofhypothyroidism. When symptoms are nonspecific,a follow-up assessment of the free thyroxine (T4)level can help distinguish between primary andsecondary hypothyroidism.

Laboratory Values in Hypothyroidism

TSH level

FreeT4level

FreeT3level Likely diagnosis

High Low Low Primaryhypothyroidism

High (>10 :Uper mL)

Nor-mal

Nor-mal

Subclinicalhypothyroidism withhigh risk for futuredevelopment ofovert hypothyroidism

High (6 to 10:U per mL)

Nor-mal

Nor-mal

Subclinicalhypothyroidism withlow risk for futuredevelopment ofovert hypothyroidism

High High Low Congenital absenceof T4-T3nconvertingenzyme; amio-darone (Cordarone)effect on T4-T3 con-version

High High High Peripheral thyroidhormone resistance

Low Low Low Pituitary thyroid defi-ciency or recentwithdrawal of thyrox-ine after excessivereplacement therapy

Causes of Hypothyroidism

Primary hypothyroidism (95% of cases) Idiopathic hypothyroidismHashimoto's thyroiditis Irradiation of the thyroid subsequent to Graves' diseaseSurgical removal of the thyroid Late-stage invasive fibrous thyroiditis Iodine deficiency Drug therapy (eg, lithium, interferon) Infiltrative diseases (eg, sarcoidosis, amyloidosis,scleroderma, hemochromatosis)

Secondary hypothyroidism (5% of cases) Pituitary or hypothalamic neoplasms Congenital hypopituitarism Pituitary necrosis (Sheehan's syndrome)

III. Treatment of hypothyroidism A. Initiating thyroid hormone replacement

1. Most otherwise healthy adult patients withhypothyroidism require thyroid hormone re-placement in a dosage of 1.7 mcg per kg perday, with requirements falling to 1 mcg per kgper day in the elderly. Thus, (Synthroid) in adosage of 0.10 to 0.15 mg per day is needed toachieve euthyroid status. For full replacement,children may require up to 4 mcg per kg perday.

2. In young patients without risk factors for cardio-vascular disease, thyroid hormone replacementcan start close to the target goal. In mosthealthy young adults, replacement is initiatedusing levothyroxine in a dosage of 0.075 mgper day, with the dosage increased slowly asindicated by continued elevation of the TSHlevel.

3. Levothyroxine (Synthroid) should be initiated ina low dosage in older patients and those at riskfor cardiovascular compromise; the usualstarting dosage is 0.025 mg per day, increasedin increments of 0.025 to 0.050 mg every fourto six weeks until the TSH level returns tonormal.

Commonly Prescribed Thyroid Hormone Prepa-rations

GenericName

BrandName(s)

Approxi-mateEquivalentDose

Prepara-tions

Levothyroxine

SynthroidLevothroidLevoxylEltroxin

100 mcg Tablets: 25,50, 75, 88,100, 112,125, 137,150, 175,200, 300mcg

IV. Monitoring thyroid functionA. In patients with an intact hypothalamic-pituitary

axis, the adequacy of thyroid hormone replace-ment can be followed with serial TSH assess-ments. The TSH level should be evaluated noearlier than four weeks after an adjustment in thelevothyroxine dosage. The full effects of thyroidhormone replacement on the TSH level may notbecome apparent until after eight weeks of ther-apy.

B. In patients with pituitary insufficiency, measure-ments of free T4 and T3 levels can be performed todetermine whether patients remain euthyroid. TSHor free T4 levels are monitored annually in mostpatients with hypothyroidism.

V. Subclinical HypothyroidismA. The TSH level can be mildly elevated when the

free T4 and T3 levels are normal, a situation thatoccurs most often in women and becomes in-creasingly common with advancing age. Thiscondition has been termed “subclinicalhypothyroidism.”

B. In patients at higher risk for osteoporosis orfractures, the deleterious effects of excessivethyroid hormone can be avoided by withholdingreplacement until the free T4 and T3 levels dropbelow normal.


ObesityObesity is a risk factor for many medical illnesses, and amodest reduction of 5% to 10% of body weight canmodify risk factors for heart disease, including lipidlevels, glycemic control, and blood pressure. Obesity isdefined as a body mass index (BMI) of 30 kg per m2 ormore. Overweight is defined as a BMI of 25 to 29.9 kgper m2.

I. Diagnosis of obesity begins with the determinationof BMI. The BMI can be ascertained by measuring thepatient's height and weight and then using a BMI tableto find the BMI value. The distribution of fat based onthe waist circumference or the waist-to-hip circumfer-ence ratio (WHR) and investigations for comorbidconditions such as diabetes mellitus, dyslipidemia,hypertension, and heart disease should be deter-mined.

II. ManagementA. For most patients, the initial weight loss objective

should be a 10 percent reduction from baselinebody weight over a period of about four to sixmonths. After six months, the rate of weight lossoften stabilizes or slows.

B. An overweight individual with a BMI of less than 30kg per m2 and no health risk factors should have atarget, six-month BMI in the range of 20 to 27. Adecrease of 300 to 500 kcal per day will produceweight losses of 0.5 to 1 lb per week (10 percentreduction at six months).

C. Nutrition therapy1. A meal plan that creates an energy deficit of 500

to 1,000 kcal per day less than the individual's

average daily intake will usually be suitable forweight reduction. Along with caloric reduction, areduction in total fat consumption should berecommended. Caloric restrictions for the treat-ment of overweight and obesity can be classifiedas follows:a. Moderate deficit diet (all health risk groups).

Women: 1200+ kcal per day; men: 1400+kcal per day

b. Low-calorie diet (moderate to extremely highhealth risk groups). Women: 800 to 1200 kcalper day; men: 800 to 1400+ kcal per day

c. Very low-calorie diet (high to extremely high-health risk groups). Less than 800 kcal perday.

2. Among patients treated with a moderate deficitdiet, weight losses average about 1 lb (0.45 kg)per week.

D. Physical activity. Although most weight loss isachieved through decreased caloric intake, physi-cal activity is the primary factor responsible forincreased caloric expenditure. The long-termphysical activity goal of most adults should be toperform 30 or more minutes of physical activityeach day.

III.Treatment of obesityA. Obesity is a chronic condition requiring long-term

therapy. If obesity is not treated for the duration ofthe patient's life, obesity re-emerges as a potentcomorbid risk factor for disability or prematuredeath.

B. Candidates for use of weight loss drugs are pa-tients who have failed to lose weight with diet andexercise therapy, have a body mass index greaterthan 27 to 30, or have risk factors or medicalconditions caused by obesity. Weight loss medica-tions should not be used by pregnant or lactatingwomen. Any medical condition (eg, cardiovasculardisease) should be stable before these drugs areprescribed. Anorexiants are contraindicated inpatients with glaucoma.

C. Goals of therapy. Weight loss should exceed 2 kgduring the first month of drug therapy, fall morethan 5 percent below baseline by three to sixmonths, and remain at this level to be consideredeffective. Weight loss of 10 to 15 percent is consid-ered a good response and loss exceeding 15percent is considered an excellent response.Weight loss may lower blood pressure and serumlipid concentrations, increase insulin sensitivity, andreduce hyperglycemia.

Anorectic Medication for Obesity Treatment

Medica-tion

Schedule

TradeName(s)

Dos-age(mg)

Common Use

Phentermine

IV 8, 15,30

Initial dose: 8-15mg/d Higher dose: 15mg bid or 30 mgq AM

Adipex-P

37.5 Initial dose: 1/2tablet/dHigher dose: 1/2tablet bid or 37.5-mg tablet q AM

Fastin 30 1 capsule q AM

Phentermineresin

IV Ionamin

15, 30 Initial dose: 15mg/d Higher dose: 15mg bid or 30 mgq AM

Diethylpropion

IV TenuateTenuateDospan(sustained-re-leaseform)

2575

25 mg tid 75 mg qd

Sibutramine

IV Meridia 5, 10,15

Initial dose: 5-10mg/dHigher dose: 15-25 mg/d

Orlistat IV Xenical 120 Initial dose: 1capsule with afatty meal qd;bid; or tid

D. Anorexiant therapy1. Anorexiants that have low potential for abuse

are phentermine (eg, Adipex-P, Fastin,Ionamin), mazindol (Mazanor, Sanorex), anddiethylpropion (Tenuate).

2. Anorexiants may cause patients to feel nervousor experience insomnia and dry mouth. Patientsshould expect to lose about 0.5 lb per week.

E. Orlistat (Xenical) therapy1. Orlistat inhibits gastrointestinal lipases. Minor

gastrointestinal side effects of steatorrhea, oilyspotting, and fecal urgency usually resolve withcontinued use. One-fourth to one-half of moti-vated patients have success with orlistat therapyin that it prevents weight regain after dieting orit decreases weight by 5% to 10%.

2. Orlistat should be prescribed as 120 mg threetimes daily with meals, along with a diet re-stricted to 30% of calories obtained from fat. Amultivitamin should be taken daily.

F. Sibutramine (Meridia, Reductil) therapy1. Sibutramine is a serotonin and

norepinephrine-uptake inhibitor that increasesenergy expenditure and satiety. Treatment with10 to 15 mg/day of sibutramine results in weightloss between 10.6 to 13.4 lb. Sibutramine alsohas been shown to maintain weight loss attainedby dieting.

2. Side effects include insomnia, dizziness, consti-pation, and dry mouth. Sibutramine increasesheart rate 4 or 5 beats per minute and bloodpressure by 1 to 3 mm Hg. Pre-existing hyper-tension should be controlled before sibutramineis prescribed.

G. Metformin (Glucophage) has been used forweight loss in patients who are overweight withoutdiabetes. Women who combine metformin with alow-calorie and reduced carbohydrate diet can lose20 to 30 pounds in one year. Metformin helpsmaintain weight loss. Initial dose is 500 mg BIDwith meals, increasing to 1500 mg/day.

IV. Surgical therapyA. Surgical therapy should be considered in patients

with severe obesity meeting the following criteria:1. A BMI of 40 kg per m2 or more and have failed in

attempts at medical treatment, or2. A BMI of 35 kg per m2 or more with coexisting

morbidities or other complicating risk factors.

Rheumatic andHematologic Disorders

OsteoarthritisApproximately 40 million Americans of all ages areaffected by osteoarthritis and 70 to 90 percent of Ameri-cans older than 75 years have at least one involved joint.The prevalence of osteoarthritis ranges from 30 to 90percent.

Clinical Features of Osteoarthritis

SymptomsJoint painMorning stiffness lastingless than 30 minutesJoint instability or bucklingLoss of function

Pattern of joint involve-mentAxial: cervical and lumbarspinePeripheral: distalinterphalangeal joint proxi-mal interphalangeal jointfirst carpometacarpaljoints,

knees, hips

SignsBony enlargement at af-fected jointsLimitation of range of mo-tionCrepitus on motionPain with motionMalalignment and/or jointdeformity

I. Clinical evaluationA. Pathogenesis. Osteoarthritis is caused by a

combination of mechanical, cellular, and biochemi-cal processes leading to changes in the composi-tion and mechanical properties of the articularcartilage and degenerative changes and an abnor-mal repair response.

B. The typical patient with osteoarthritis is mid-dle-aged or elderly and complains of pain in theknee, hip, hand or spine. The usual presentingsymptom is pain involving one or only a few joints.Joint involvement is usually symmetric. The patientusually has pain, stiffness, and some limitation offunction. Pain typically worsens with use of theaffected joint and is alleviated with rest. Morningstiffness lasting less than 30 minutes is common.(morning stiffness in rheumatoid arthritis lastslonger than 45 minutes.)

C. Patients with osteoarthritis of the hip may complainof pain in the buttock, groin, thigh or knee. Hipstiffness is common, particularly after inactivity.Involvement of the apophyseal or facet joints of thelower cervical spine may cause neck symptoms,and involvement of the lumbar spine may causepain in the lower back. Patients may have radicularsymptoms, including pain, weakness and numb-ness.

D. The physical examination should include an as-sessment of the affected joints, surrounding softtissue and bursal areas. Joint enlargement maybecome evident. Crepitus, or a grating sensation inthe joint, is a late manifestation.

E. Laboratory work may include erythrocyte sedimen-tation rate and rheumatoid factor. Synovial fluidanalysis may be conducted to help exclude otherdiagnoses.

F. Radiographic findings consistent with osteoarthritisinclude presence of joint space narrowing,osteophyte formation, pseudocyst in subchondralbone, and increased density of subchondral bone.The absence of radiographic changes does notexclude the diagnosis of osteoarthritis. Radio-graphs are recommended for patients with trauma,joint pain at night, progressive joint pain, significantfamily history of inflammatory arthritis, and childrenyounger than 18 years.

II. Treatment of osteoarthritisA. Exercise. The goals of an exercise program are to

maintain range of motion, muscle strength andgeneral health.

Management of Osteoarthritis of the Knee

1. Patient education, exercise, weight loss, joint protection2. Acetaminophen (Tylenol), up to 4 g per day.3. Add topical capsaicin cream (eg ArthriCare) applied four

times daily if needed.4. If joint effusion is present consider aspiration and

intra-articular injection of triamcinolone (Aristocort) 40mg.

5. If more pain or symptom control is needed add anNSAID, 400 mg of ibuprofen (eg Advil) taken four timesdaily or a nonacetylated salicylate such as choline mag-nesium trisalicylate (Trilisate), 500-1500 mg bid, orsalsalate (Disalcid), 500-1000 mg tid.

6. If more pain or symptom control is needed use the fulldosage of an NSAID plus misoprostol (Cytotec) or aproton pump inhibitor if the patient is at risk for uppergastrointestinal tract bleeding or ulcer disease, or sub-stitute a cyclo-oxygenase-2 inhibitor for the NSAID;some patients may benefit from intra-articular injectionsof a hyaluronic acid-like product.

7. If the response is inadequate, consider joint lavage,arthroscopic debridement osteotomy, or joint replace-ment.

Risk Factors for Ulcer Complications Inducedby Nonsteroidal Anti-inflammatory Drugs

Definite risk factorsPatient older than 65 yearsof agePrevious ulcer disease orupper gastrointestinal tractbleedingUse of a high dosage ofone of these drugsConcomitant oralcorticosteroid therapyConcomitant anticoagulanttherapyDuration of therapy (risk ishigher in first three monthsof treatment)

Possible risk factorsFemale genderSmokingAlcohol consumptionHelicobacter pylori infec-tion

B. The risk of NSAID-induced renal and hepatictoxicity is increased in older patients and in pa-tients with preexisting renal or hepatic insuffi-ciency. Thus, it is important to monitor renal andliver function. Choline magnesium trisalicylate(Trilisate) and salsalate (Disalcid) cause less renaltoxicity. Liver function tests and serum hemoglo-bin, creatinine and potassium measurementsshould be performed before NSAID therapy isinitiated and again after six months of treatment.

C. Cyclooxygenase-2 (COX-2) inhibitors1.Celecoxib (Celebrex) is a COX-2 inhibitor

labeled for treatment of osteoarthritis and rheu-matoid arthritis. Celecoxib effectively alleviatespain and reduces inflammation, but it does notcause gastric ulcers or affect platelet function(two toxic effects associated with COX-1 inhibi-tors). The most common side effects ofcelecoxib are dyspepsia, diarrhea and abdomi-nal pain. The FDA has labeled celecoxib, 100mg twice daily and 200 mg once daily, for thetreatment of osteoarthritis. This drug is alsolabeled, in a dosage of 100 to 200 mg twicedaily, for the treatment of rheumatoid arthritis inadults.

2.Rofecoxib (Vioxx) is also given once daily forthe treatment of osteoarthritis and acute pain.The FDA has labeled rofecoxib for the treatmentof primary dysmenorrhea, acute pain, andosteoarthritis. For osteoarthritis, the recom-mended dosage of rofecoxib is 12.5 to 25 mgonce daily. For acute pain and primarydysmenorrhea, the dosage is 50 mg once daily.

3.Meloxicam (Mobic) has been labeled by theFDA for the treatment of osteoarthritis. Thestarting and maintenance dosage is 7.5 mg perday.

4.Valdecoxib (Bextra) is an COX-2 inhibitor fortreating arthritis and menstrual pain.

Costs of Some Common NonsteroidalAnti-inflammatory Drugs

Drug Usual dosagefor adults

Formulations

Acetic acids

Diclofenac po-tassium(Cataflam)

100 to 200 mgdaily

50 mg

Diclofenac so-dium Immedi-ate-release(Voltaren)

100 to 200 mgdaily

25, 50, 75 mg

De-layed-release(Voltaren XR)

100 to 200 mgdaily

100 mg

Withmisoprostol(Arthrotec)

50 mg threetimes daily

50 mg three orfour times dailyfor rheumatoidarthritis

50 mg diclofenacsodium with 200:g misoprostol75 mg diclofenacsodium with 200:g misoprostol

Etodolac Immedi-ate-release(Lodine)

600 to 1,000 mgdaily given intwo divideddoses

200 mg300 mg400 mg500 mg

Ex-tended-release(Lodine XL)

400 to 1,000 mgdaily

400 mg500 mg600 mg

Sulindac(Clinoril)

150 mg twicedaily (maximumdosage: 400 mgdaily)

150, 200 mg

Propionic acids

Flurbiprofen(Ansaid)

200 to 300 mgdaily given intwo to four di-vided doses

50, 100 mg

Ibuprofen(Motrin)

400 to 800 mgthree or fourtimes daily(maximum dos-age: 3,200 mgdaily)

200 mg 400 mg600 mg800 mg

Ketoprofen Immedi-ate-release(Orudis)

150 to 300 mgdaily given inthree to four di-vided doses

25 mg50 mg75 mg

Ex-tended-release(Oruvail)

150 to 300 mgdaily given inthree or fourdivided doses

100 mg150 mg200 mg

Over-the-counter (Orudis KT)

12.5 mg every 4to 6 hours

12.5 mg

Naproxen Im-medi-ate-release(Naprosyn)

250 to 500 mgtwice daily

250 mg375 mg500 mg

De-layed-release(EC Naprosyn)

750 or 1,000 mgdaily

375 mg500 mg

Naproxen so-dium Immedi-ate-release(Anaprox,Anaprox DS)

275 or 550 mgtwice daily

275 mg550 mg

Ex-tended-release(Naprelan)

750 or 1,000 mgdaily

375 mg500 mg

Over-the-counter (Aleve)

220 mg every 8to 12 hours

220 mg

Oxaprozin(Daypro)

1,200 mg daily 600 mg

Nonacidic agents

Nabumetone(Relafen)

1,000 to 2,000mg given oncedaily or twicedaily in divideddoses

500 mg750 mg

Drug Usual dosagefor adults

Formulations

Cyclooxygenase-2 inhibitors

Celecoxib(Celebrex)

100 mg twicedaily or 200 mgdaily forosteoarthritis 100 to 200 mgtwice daily forrheumatoid ar-thritis

100 mg200 mg

Rofecoxib(Vioxx)

12.5 to 25 mgdaily forosteoarthritis 50 mg daily forprimarydysmenorrheaand acute pain

12.5 mg25 mg50 mg 12.5 or 25 mg in5-mL susp

Meloxicam(Mobic)

7.5 mg per day. 7.5 mg

Valdecoxib(Bextra)

10-20 mg oncedaily

10 mg20 mg

D. Local analgesics. Capsaicin (eg, ArthriCare) hasbeen shown to be better than placebo inosteoarthritis. Capsaicin cream is available overthe counter in concentrations of 0.025, 0.075 and0.25 percent.

E. Intra-articular corticosteroid injections. Patientswith a painful flare of osteoarthritis of the knee maybenefit from intra-articular injection of triamcino-lone (Aristocort) or prednisone 8-20 mg.Intra-articular steroid injections should not beadministered more than three to four times peryear. Knee injections significantly reduce pain forup to four weeks.

F. Intra-articular injections of hyaluronic acid-likeproducts. Hyaluronate (Hyalgan) and hylan G-F20 (Synvisc) injections are useful for the treatmentof osteoarthritis of the knee. Hylan G-F 20 injec-tions are at least as effective as continuous NSAIDtherapy.

G. Surgery. Patients whose symptoms are not ade-quately controlled with medical therapy and whohave moderate to severe pain and functionalimpairment are candidates for surgery.Osteoarthritis of the knee may be treated witharthroscopic debridement or joint lavage.


Low Back PainApproximately 90 percent of adults experience back painat some time in life, and 50 percent of persons in theworking population have back pain every year.

I. Evaluation of low back painA. A comprehensive history and physical examination

can identify the small percentage of patients withserious conditions such as infection, malignancy,rheumatologic diseases and neurologic disorders.

B. The history and review of systems include patientage, constitutional symptoms and the presence ofnight pain, bone pain or morning stiffness. Thepatient should be asked about the occurrence ofvisceral pain, claudication, numbness, weakness,radiating pain, and bowel and bladder dysfunction.

History and Physical Examination in the Pa-tient with Acute Low Back Pain

HistoryOnset of pain (eg, time of day, activity)Location of pain (eg, specific site, radiation of pain)Type and character of pain (sharp, dull)Aggravating and relieving factorsMedical history, including previous injuriesPsychosocial stressors at home or work"Red flags": age greater than 50 years, fever, weight lossIncontinence, constipation Physical examinationInformal observation (eg, patient's posture, expressions,pain behavior)Physical examination, with attention to specific areas asindicated by the historyNeurologic evaluationBack examination

PalpationRange of motion or painful arcStanceGaitMobility (test by having the patient sit, lie down andstand up)Straight leg raise test

C. Specific characteristics and severity of the pain, a

history of trauma, previous therapy and its efficacy,and the functional impact of the pain on the pa-tient's work and activities of daily living should beassessed.

D. The most common levels for a herniated disc areL4-5 and L5-S1. The onset of symptoms is charac-terized by a sharp, burning, stabbing pain radiatingdown the posterior or lateral aspect of the leg, tobelow the knee. Pain is generally superficial andlocalized, and is often associated with numbnessor tingling. In more advanced cases, motor deficit,diminished reflexes or weakness may occur.

E. If a disc herniation is responsible for the backpain, the patient can usually recall the time of onsetand contributing factors, whereas if the pain is of agradual onset, other degenerative diseases aremore probable than disc herniation.

F. Rheumatoid arthritis often begins in theappendicular skeleton before progressing to thespine. Inflammatory arthritides, such as ankylosingspondylitis, cause generalized pain and stiffnessthat are worse in the morning and relieved some-what throughout the day.

G. Cauda equina syndrome. Only the relativelyuncommon central disc herniation provokes lowback pain and saddle pain in the S1 and S2 distri-butions. A central herniated disc may also com-press nerve roots of the cauda equina, resulting indifficult urination, incontinence or impotence. Ifbowel or bladder dysfunction is present, immediatereferral to a specialist is required for emergencysurgery to prevent permanent loss of function.

II. Physical and neurologic examination of the lumbarspine A. External manifestations of pain, including an

abnormal stance, should be noted. The patient'sposture and gait should be examined for sciatic list,which is indicative of disc herniation. The spinousprocesses and interspinous ligaments should bepalpated for tenderness.

B. Range of motion should be evaluated. Pain duringlumbar flexion suggests discogenic pain, while painon lumbar extension suggests facet disease.Ligamentous or muscular strain can cause painwhen the patient bends contralaterally.

C. Motor, sensory and reflex function should beassessed to determine the affected nerve rootlevel. Muscle strength is graded from zero (noevidence of contractility) to 5 (motion againstresistance).

D. Specific movements and positions that repro-duce the symptoms should be documented. Theupper lumbar region (L1, L2 and L3) controls theiliopsoas muscles, which can be evaluated bytesting resistance to hip flexion. While seated, thepatient should attempt to raise each thigh while thephysician's hands are placed on the leg to createresistance. Pain and weakness are indicative ofupper lumbar nerve root involvement. The L2, L3and L4 nerve roots control the quadriceps muscle,which can be evaluated by manually trying to flexthe actively extended knee. The L4 nerve root alsocontrols the tibialis anterior muscle, which can betested by heel walking.

E. The L5 nerve root controls the extensor hallucislongus, which can be tested with the patient seatedand moving both great toes in a dorsiflexed posi-tion against resistance. The L5 nerve root alsoinnervates the hip abductors, which are evaluatedby the Trendelenburg test. This test requires thepatient to stand on one leg; the physician standsbehind the patient and puts his or her hands on thepatient's hips. A positive test is characterized byany drop in the pelvis and suggests L5 nerve rootpathology.

Differential Diagnosis of Acute Low Back Pain

Disease orcondition

Patient age(years)

Location ofpain Quality of pain

Aggravating or reliev-ing factors

Signs

Back strain 20 to 40 Low back, but-tock, posteriorthigh

Ache, spasm Increased with activityor bending

Local tenderness,limited spinal motion

Acute discherniation

30 to 50 Low back tolower leg

Sharp, shooting orburning pain,paresthesia in leg

Decreased with stand-ing; increased withbending or sitting

Positive straight legraise test, weakness,asymmetric reflexes

Osteoarthritisor spinal steno-sis

>50 Low back tolower leg; of-ten bilateral

Ache, shootingpain, "pins andneedles" sensation

Increased with walking,especially up an incline;decreased with sitting

Mild decrease in ex-tension of spine; mayhave weakness orasymmetric reflexes

Spondy-lolisthesis

Any age Back, poste-rior thigh

Ache Increased with activityor bending

Exaggeration of thelumbar curve, palpa-ble "step off" (defectbetween spinous pro-cesses), tight ham-strings

Ankylosingspondylitis

15 to 40 Sacroiliacjoints, lumbarspine

Ache Morning stiffness Decreased back mo-tion, tenderness oversacroiliac joints

Infection Any age Lumbar spine,sacrum

Sharp pain, ache Varies Fever, percussivetenderness; mayhave neurologic ab-normalities or de-creased motion

Malignancy >50 Affectedbone(s)

Dull ache, throb-bing pain; slowlyprogressive

Increased with recum-bency or cough

May have localizedtenderness, neuro-logic signs or fever

F. Cauda equina syndrome can be identified byunexpected laxity of the anal sphincter, perianal orperineal sensory loss, or major motor loss in thelower extremities.

G. Nerve root tension signs are evaluated with thestraight-leg raising test in the supine position. Thephysician raises the patient's legs to 90 degrees.If nerve root compression is present, this testcauses severe pain in the back of the affected legand can reveal a disorder of the L5 or S1 nerveroot.

H. The most common sites for a herniated lumbardisc are L4-5 and L5-S1, resulting in back painand pain radiating down the posterior and lateralleg, to below the knee.

I. A crossed straight-leg raising test may suggestnerve root compression. In this test, straight-legraising of the contralateral limb reproduces morespecific but less intense pain on the affected side.In addition, the femoral stretch test can be used toevaluate the reproducibility of pain. The patientlies in either the prone or the lateral decubitusposition, and the thigh is extended at the hip, andthe knee is flexed. Reproduction of pain suggestsupper nerve root (L2, L3 and L4) disorders.

Indications for Radiographs in the Patient withAcute Low Back Pain

History of significant traumaNeurologic deficitsSystemic symptomsTemperature greater than 38°C (100.4°F)Unexplained weight lossMedical history

CancerCorticosteroid useDrug or alcohol abuse

Ankylosing spondylitis suspected

Waddell Signs: Nonorganic Signs Indicatingthe Presence of a Functional Component ofBack Pain

Superficial, nonanatomic tendernessPain with simulated testing (eg, axial loading or pelvicrotation)Inconsistent responses with distraction (eg, straight legraises while the patient is sitting)Nonorganic regional disturbances (eg, nondermatomalsensory loss)Overreaction

Location of Pain and Motor Deficits in Associa-tion with Nerve Root Involvement

Disclevel

Location of pain Motor deficit

T12-L1 Pain in inguinal re-gion and medialthigh

None

L1-2 Pain in anterior andmedial aspect ofupper thigh

Slight weakness inquadriceps; slightlydiminished supra-patellar reflex

L2-3 Pain inanterolateral thigh

Weakenedquadriceps; dimin-ished patellar orsuprapatellar reflex

L3-4 Pain inposterolateral thighand anterior tibialarea

Weakenedquadriceps; dimin-ished patellar reflex

L4-5 Pain in dorsum offoot

Extensor weaknessof big toe and foot

L5-S1 Pain in lateral as-pect of foot

Diminished or ab-sent Achilles reflex

J. Laboratory tests1. Evaluation may include a complete blood count,

determination of erythrocyte sedimentation rate.2. Radiographic evaluation. Plain-film radiogra-

phy is rarely useful in the initial evaluation ofpatients with acute-onset low back pain. Plain-film radiographs are normal or equivocal inmore than 75 percent of patients with low backpain. Views of the spine uncover useful informa-tion in fewer than 3 percent of patients.Anteroposterior and lateral radiographs shouldbe considered in patients who have a history oftrauma, neurologic deficits, or systemic symp-

toms.3. Magnetic resonance imaging and computed

tomographic scanninga.Magnetic resonance imaging (MRI) and com-

puted tomographic (CT) scanning often dem-onstrate abnormalities in "normal" asymptom-atic people. Thus, positive findings in patientswith back pain are frequently of questionableclinical significance.

b.MRI is better at imaging soft tissue (eg, herni-ated discs, tumors). CT scanning providesbetter imaging of bone (eg, osteoarthritis).MRI has the ability to demonstrate disc dam-age. MRI or CT studies should be consideredin patients with worsening neurologic deficitsor a suspected systemic cause of back painsuch as infection or neoplasm.

4. Bone scintigraphy or bone scanning, can beuseful when radiographs of the spine are nor-mal, but the clinical findings are suspicious forosteomyelitis, bony neoplasm or occult fracture.

5. Physiologic assessment. Electrodiagnosticassessments such as needle electromyographyand nerve conduction studies are useful indifferentiating peripheral neuropathy fromradiculopathy or myopathy.

III. Management of acute low back painA. Pharmacologic therapy

1. The mainstay of pharmacologic therapy foracute low back pain is acetaminophen or anonsteroidal anti-inflammatory drug (NSAID). Ifno medical contraindications are present, a two-to four-week course of medication at anti-inflam-matory levels is suggested.

2. Naproxen (Naprosyn) 500 mg, followed by 250mg PO tid-qid prn [250, 375,500 mg].

3. Naproxen sodium (Aleve) 200 mg PO tid prn.4. Naproxen sodium (Anaprox) 550 mg, followed

by 275 mg PO tid-qid prn.5. Ibuprofen (Motrin, Advil) 800 mg, then 400 mg

PO q4-6h prn.6. Diclofenac (Voltaren) 50 mg bid-tid or 75 mg

bid.7. Gastrointestinal prophylaxis, using a histamine

H2 antagonist or misoprostol (Cytotec), shouldbe prescribed for patients who are at risk forpeptic ulcer disease.

8. Rofecoxib (Vioxx) and celecoxib (Celebrex) areNSAIDs with selective cyclo-oxygenase-2 inhibi-tion. These agents have fewer gastrointestinalside effects.

9. Celecoxib (Celebrex) is given as 200 mg qd or100 mg bid.

10. Rofecoxib (Vioxx) is given as 25-50 mg qd.11. For relief of acute pain, short-term use of a

narcotic may be considered. B. Rest. Two to three days of bed rest in a supine

position may be recommended for patients withacute radiculopathy.

C. Physical therapy modalities1. Superficial heat, ultrasound (deep heat), cold

packs and massage are useful for relievingsymptoms in the acute phase after the onset oflow back pain.

2. No convincing evidence has demonstrated thelong-term effectiveness of lumbar traction andtranscutaneous electrical stimulation.

D. Aerobic exercise has been reported to improve orprevent back pain. Exercise programs that facilitateweight loss, trunk strengthening and the stretchingof musculotendinous structures appear to be mosthelpful. Exercises should promote the strengthen-ing of muscles that support the spine.

E. Trigger point injections can provide extendedrelief for localized pain sources. An injection of 1 to2 mL of 1 percent lidocaine (Xylocaine) withoutepinephrine is usually administered. Epiduralsteroid injection therapy has been reported to beeffective in patients with lumbar disc herniation.

F. Indications for herniated disc surgery. Mostpatients with a herniated disc may be effectivelytreated conservatively. Indications for referralinclude the following: (1) cauda equina syndrome,(2) progressive neurologic deficit, (3) profoundneurologic deficit and (4) severe and disabling painrefractory to four to six weeks of conservativetreatment.


Gout

Gout comprises a heterogeneous group of disorderscharacterized by deposition of uric acid crystals in thejoints and tendons. Gout has a prevalence of 5.0 to 6.6cases per 1,000 men and 1.0 to 3.0 cases per 1,000women.

I. Clinical featuresA. Asymptomatic hyperuricemia is defined as an

abnormally high serum urate level, without goutyarthritis or nephrolithiasis. Hyperuricemia is definedas a serum urate concentration greater than 7mg/dL. Hyperuricemia predisposes patients to bothgout and nephrolithiasis, but therapy is generallynot warranted in the asymptomatic patient.

B. Acute gout is characterized by the sudden onsetof pain, erythema, limited range of motion andswelling of the involved joint. The peak incidence ofacute gout occurs between 30 and 50 years of age.First attacks are monoarticular in 90 percent. Inmore than one-half of patients, the firstmetatarsophalangeal joint is the initial joint in-volved, a condition known as podagra. Joint in-volvement includes the metatarsophalangeal joint,the instep/forefoot, the ankle, the knee, the wristand the fingers.

C. Intercritical gout consists of the asymptomaticphase of the disease following recovery from acutegouty arthritis.

D. Recurrent gouty arthritis. Approximately 60percent of patients have a second attack within thefirst year, and 78 percent have a second attackwithin two years.

E. Chronic tophaceous gout. Tophi are deposits ofsodium urate that are large enough to be seen onradiographs and may occur at virtually any site.Common sites include the joints of the hands orfeet, the helix of the ear, the olecranon bursa, andthe Achilles tendon.

II. DiagnosisA. Definitive diagnosis of gout requires aspiration and

examination of synovial fluid for monosodium uratecrystals. Monosodium urate crystals are identifiedby polarized light microscopy.

B. If a polarizing microscope is not available, thecharacteristic needle shape of the monosodiumurate crystals, especially when found within whiteblood cells, can be identified with conventional lightmicroscopy. The appearance resembles a tooth-pick piercing an olive.

III. Treatment of gout A. Asymptomatic hyperuricemia. Urate-lowering

drugs should not be used to treat patients withasymptomatic hyperuricemia. If hyperuricemia isidentified, associated factors such as obesity,hypercholesterolemia, alcohol consumption andhypertension should be addressed.

B. Acute gout1. NSAIDs are the preferred therapy for the treat-

ment of acute gout. Indomethacin (Indocin),ibuprofen (Motrin), naproxen (Naprosyn),sulindac (Clinoril), piroxicam (Feldene) andketoprofen (Orudis) are effective. More than 90percent of patients have a resolution of theattack within five to eight days.

Drugs Used in the Management of Acute Gout

Drug Dosage Side effects/com-ments

NSAIDS

Indomethacin(Indocin)

Naproxen(Naprosyn)Ibuprofen(Motrin)Sulindac(Clinoril)Ketoprofen(Orudis)

25 to 50 mgfour times daily500 mg twotimes daily800 mg fourtimes daily 200 mg twotimes daily75 mg fourtimes daily

Contraindicatedwith peptic ulcerdisease or systemicanticoagulation;side effects includegastropathy,nephropathy, liverdysfunction, andreversible plateletdysfunction; maycause fluid overloadin patients withheart failure

Drug Dosage Side effects/com-ments

Corticosteroids

Oral Prednisone,0.5 mg per kgon day 1, taperby 5.0 mg eachday thereafter

Fluid retention; im-paired wound heal-ing

Intramuscular Triamcinoloneacetonide(Kenalog), 60mg intramuscu-larly, repeat in24 hours ifnecessary

May require repeatinjections; risk ofsoft tissue atrophy

Intra-articular Large joints: 10to 40 mgSmall joints: 5to 20 mg

Preferable route formonoarticular in-volvement

ACTH 40 to 80 IUintramuscu-larly; repeatevery 8 hoursas necessary

Repeat injectionsare commonlyneeded; requiresintact pitu-itary-adrenal axis;stimulation ofmineralocorticoidrelease may causevolume overload

Colchicine 0.5 to 0.6 mgPO every houruntil relief orside effectsoccur, or until amaximum dos-age of 6 mg isreached

Dose-dependentgastrointestinal sideeffects; improperintravenous dosinghas caused bonemarrow suppres-sion, renal failureand death

2. Corticosteroidsa. Intra-articular, intravenous, intramuscular

or oral corticosteroids are effective in acutegout. In cases where one or two joints areinvolved, intra-articular injection ofcorticosteroid can be used.

b. Intramuscular triamcinolone acetonide (60mg) is as effective as indomethacin in reliev-ing acute gouty arthritis. Triamcinoloneacetonide is especially useful in patients withcontraindications to NSAIDs.

c. Oral prednisone is an option when repeatdosing is anticipated. Prednisone, 0.5 mg perkg on day 1 and tapered by 5 mg each day isvery effective.

3. Colchicine is effective in treating acute gout;however, 80 percent of patients experiencegastrointestinal side effects, including nausea,vomiting and diarrhea. Intravenous colchicine isavailable but is highly toxic and not recom-mended.

C. Treatment of intercritical gout1. Prophylactic colchicine (from 0.6 mg to 1.2 mg)

should be administered at the same timeurate-lowering drug therapy is initiate.Colchicine should be used for prophylaxis onlywith concurrent use of urate-lowering agents.Colchicine is used for prophylaxis until theserum urate concentration is at the desired leveland the patient has been free from acute goutyattacks for three to six months.

2. Urate-lowering agentsa. After the acute gouty attack is treated and

prophylactic therapy is initiated, sources ofhyperuricemia should be eliminated to lowerthe serum urate level without the use ofmedication.

b. Medications that may aggravate the patient'scondition (eg, diuretics) should be discontin-ued; purine-rich foods and alcohol consump-tion should be curtailed, and the patientshould gradually lose weight, if obese.

Purine Content of Foods and Beverages

High Avoid: Liver, kidney, anchovies, sardines, herring, mus-sels, bacon, codfish, scallops, trout, haddock, veal, veni-son, turkey, alcoholic beverages

Moderate May eat occasionally: Asparagus, beef, bouillon,chicken, crab, duck, ham, kidney beans, lentils, limabeans, mushrooms, lobster, oysters, pork, shrimp, spinach

3. 24-hour urine uric acid excretion measure-

ment is essential to identify the most appropri-ate urate-lowering medication and to check forsignificant preexisting renal insufficiency.a. Uricosuric agents should be used in most

patients with gout because most are"underexcretors" of uric acid. Inhibitors of uricacid synthesis are more toxic and should bereserved for use in "overproducers" of urate(urine excretion >800 mg in 24 hours).

b. Urate-lowering therapy should not be initiateduntil the acute attack has resolved, since theymay exacerbate the attack.

Urate-Lowering Drugs for the Treatment of Goutand Hyperuricemia

Drug Dosage Indica-tions

Side ef-fects/comments

Probenecid(Bene-mid)

Begin with250 mgtwice daily,graduallytitratingupwarduntil theserumurate levelis <6 mgper dL;maximum:3 g perday

Recurrentgout maybe com-bined withallopurinolin resis-tanthyperuricemia

Uricosuric agent;creatinine clearancemust be >60 mL perminute; therapeuticeffect reversed byaspirin therapy; avoidconcurrent daily aspi-rin use; contraindi-cated in urolithiasis;may precipitate goutyattack at start of ther-apy; rash or gastroin-testinal side effectsmay occur

Allopurinol(Zyloprim)

Begin with50 to 100mg daily,graduallytitratingupwarduntil theserumurate levelis <6 mgper dL;typicaldosage:200 to 300mg daily

Chronicgouty ar-thritis;second-ary hyper-uricemiarelated tothe use ofcytolyticsin thetreatmentofhematologic malig-nancies;gout com-plicatedby renaldiseaseor renalcalculi

Inhibits uric acid syn-thesis; side effectsinclude rash, gastro-intestinal symptoms,headache, urticariaand interstitial nephri-tis; rare, potentiallyfatal hypersensitivitysyndrome

4. Probenecid (Benemid) is the most frequentlyused uricosuric medication. Candidates forprobenecid therapy must have hyperuricemiaattributed to undersecretion of urate (ie, <800mg in 24 hours), a creatinine clearance of >60mL/minute and no history of nephrolithiasis.Probenecid should be initiated at a dosage of250 mg twice daily and increased as needed, upto 3 g per day, to achieve a serum urate level ofless than 6 mg per dL. Side effects includeprecipitation of an acute gouty attack, renalcalculi, rash, and gastrointestinal problems.

5. Allopurinol (Zyloprim) is an inhibitor of uricacid synthesis. Allopurinol is initiated at a dos-age of 100 mg per day and increased in incre-ments of 50 to 100 mg per day every two weeksuntil the urate level is <6 mg per dL. Side effectsinclude rash, gastrointestinal problems, head-ache, urticaria and interstitial nephritis. A hyper-sensitivity syndrome associated with fever, bonemarrow suppression, hepatic toxicity, renalfailure and a systemic hypersensitivity vasculitisis rare.


Rheumatoid ArthritisRheumatoid arthritis (RA) is a chronic, polyarticular,symmetric, inflammatory disease that affects about 2.5million people in the United States. The disease has apredilection for small proximal joints, although virtuallyevery peripheral joint in the body can be involved. RAstrikes women, usually of childbearing age, three timesmore often than it does men. This process causes theimmune system to attack the synovium of various joints,leading to synovitis.

I. Clinical manifestationsA. RA is a chronic, symmetric polyarthritis. The

polyarthritis is often deforming. About 80% ofpatients describe a slowly progressive onset overweeks or months.

B. Inflammatory features 1. The joints in RA are swollen, tender, slightly

warm, and stiff. Synovial fluid is cloudy and hasan increased number of inflammatory whiteblood cells.

2. Patients with RA usually have profound andprolonged morning stiffness. Fatigue, anemia ofchronic disease, fever, vasculitis, pericarditis,and myocarditis, are common.

C. Joint involvement. RA may begin in one or twojoints, but it almost invariably progresses to affect20 or more. In some cases, joint involvement isnearly symmetric. Initially, the disease typicallyinvolves the metacarpophalangeal, proximalinterphalangeal, wrist, and metatarsophalangealjoints, either alone or in combination with others.

D. Proliferative/erosive features. The inflamedsynovial tissue evolves into a thickened, boggymass known as a pannus. Pannus can eat throughjoint cartilage and into adjacent bone.

E. Joint deformity. Deformities of RA are more likelyto be the result of damage to ligaments, tendons,and joint capsule.

II. DiagnosisA. RA is a clinical diagnosis. The presence of arthritis

excludes the many forms of soft tissue rheumatism(eg, tendinitis, bursitis). The degree of inflamma-tion excludes osteoarthritis and traumatic arthritis.Polyarticular involvement of the appropriate jointsmakes the spondyloarthropathies unlikely. Thepannus is often palpable as a rubbery mass oftissue around a joint.

B. Rheumatoid factor testing helps to confirm thediagnosis of RA. Rheumatoid factor serves as amarker for RA, but it is not reliable because 1-2%of the normal population have rheumatoid factor.Chronic infections, other inflammatory conditionsand malignancies may trigger formation of rheuma-toid factor. Conversely, 15% of patients with RAare seronegative for rheumatoid factor.

C. Radiography. Typical erosions around joint mar-gins help confirm the diagnosis of RA.

III. Treatment of rheumatoid arthritisA. Nonsteroidal anti-inflammatory drugs (NSAIDs) do

not alter the course of the disease and have beenshown to be as toxic as many of the slow-actingantirheumatic agents that modify disease. There-fore, combination therapy early in the course of RAhas become the standard approach.

B. Hydroxychloroquine (Plaquenil) sulfate andsulfasalazine (Azulfidine EN-tabs) are often usedin combination with methotrexate (RheumatrexDose Pack) and cytotoxic agents.

Antirheumatic drugs used in treatment of rheu-matoid arthritis

Drug Deliv-ery

Dose Side effects

Methotrex-ate(Rheumatrex DosePack)

PO orSC

5-20mg/wk

Marrow suppression,mucositis,hepatotoxicity, pulmo-nary disease, suscepti-bility to infection

Cyclospor-ine (Neoral)

PO 2-4mg/kgdaily

Marrow suppression,renal toxicity,hyperuricemia, suscep-tibility to infection

Azathio-prine(Imuran)

PO 50-250mg/day

Marrow suppression, GIintolerance,hepatotoxicity, tumors,susceptibility to infec-tion

Chloram-bucil(Leukeran)

PO 2-8mg/day

Marrow suppression(particularlythrombocytopenia), tu-mors, susceptibility toinfection

Cyclophos-phamide(Cytoxan,Neosar)

PO 25-150mg/day

Marrow suppression,hemorrhagic cystitis,transitional cell carci-noma and other tumors,susceptibility to infec-tion

Drug Deliv-ery

Dose Side effects

Leflunomide (Arava)

PO 100mg/dayfor 3days,then 20mg/day

Diarrhea, dyspepsia,rash, alopecia,hepatotoxicity, marrowsuppression

Infliximab(Remicade)

IV 10mg/kginfu-sionssporad-ically

Susceptibility to infec-tion, autoimmune phe-nomenon, diarrhea,rash, infusion reactions

Etanercept(Enbrel)

SC 25 mgtwice/wk

Injection site reactions,upper respiratory tractinfections; theoretically,sepsis or tumors

Adalimumab (Humira)

SC 40 mg,everyotherweek

Injection site reactions,upper respiratory tractinfections; theoretically,sepsis or tumors

C. Methotrexate is the "gold standard" of RA ther-apy. In addition to being efficacious, methotrexateis surprisingly well tolerated. Potential toxic effectsof methotrexate include bone marrow suppres-sion, hepatotoxicity, interstitial pneumonitis, pul-monary fibrosis, increased susceptibility to infec-tion, and pseudo-sun sensitivity.

D. Cytotoxic agents. Azathioprine (Imuran),chlorambucil (Leukeran), and cyclophosphamide(Cytoxan, Neosar) have been found to be helpfulin treatment of recalcitrant RA. However, theusefulness of these agents is limited by toxic sideeffects.

E. Leflunomide (Arava) is the first antipyrimidineagent to be used in treatment of RA. Because thedrug is teratogenic in animals, its use is contraindi-cated in pregnant women and women of child-bearing age who are not using contraception.Efficacy is 60%. Leflunomide is an oral alternativefor patients who do not respond to methotrexate.

F. Inhibitors of TNF-alpha 1. The inflammatory and destructive processes

characteristic of RA are mediated, in part, byTNF-alpha cytokines released frommacrophages and lymphocytes..

2. Infliximab (Remicade). Patients with RA haveshown definite clinical improvement after intra-venous administration of this agent, whichcontains chimeric (mouse/human) monoclonalantibodies to TNF-alpha. These antibodies bindcirculating TNF-alpha. Joint swelling and ten-derness, grip strength, duration of morningstiffness improve significantly.

3. Etanercept (Enbrel) is the first efficaciousbiologic antirheumatic therapeutic agent. Jointswelling and tenderness, morning stiffness,erythrocyte sedimentation rate, general painlevel, and assessments of disease activityimprove significantly. Etanercept combined withmethotrexate produces a synergistic effect.

4. Adalimumab (Humira), a tumor necrosis factoralpha inhibitor is effective in moderate to se-vere rheumatoid arthritis refractory tomethotrexate, either as a single agent or inaddition to methotrexate. Adalimumab appearsto be about as effective as etanercept (Enbrel)or infliximab (Remicade).


Deep Venous ThrombosisDeep venous thrombosis (DVT) has an incidence of 1case per 1,000 persons. Fifty percent of venous thrombiof the lower extremity will embolize to the lung if nottreated.

I. Risk factors for deep venous thrombosisA. Venous stasis risk factors include prolonged

immobilization, stroke, myocardial infarction, heartfailure, obesity, varicose veins, anesthesia, andage >65 years old.

B. Endothelial injury risk factors include surgery,trauma, central venous access catheters, pace-maker wires, previous thromboembolic event.

C. Hypercoagulable state risk factors include malig-

nant disease and high estrogen level (pregnancy,oral contraceptives).

D. Hematologic disorders. Polycythemia,leukocytosis, thrombocytosis, antithrombin IIIdeficiency, protein C deficiency, protein S defi-ciency, antiphospholipid syndrome, and inflamma-tory bowel disease.

II. Signs and symptoms of deep venous thrombosisA. The disorder may be asymptomatic or the patient

may complain of pain, swelling, "heaviness,"aching, or the sudden appearance of varicoseveins. Risk factors for DVT may be absent.

B. DVT may manifest as a unilaterally edematouslimb with a erythrocyanotic appearance, dilatedsuperficial veins, elevated skin temperature, ortenderness in the thigh or calf. Absence of clinicalsigns does not preclude the diagnosis.

C. A swollen, tender leg with a palpable venous "cord"in the popliteal fossa strongly suggests poplitealDVT. Marked discrepancy in limb circumferencesupports the diagnosis of DVT, but most patientsdo not have measurable swelling. The clinicaldiagnosis of DVT is correct only 50% of the time;therefore, diagnostic testing is mandatory whenDVT is suspected.

III. Diagnostic testingA. Ultrasonography. Color-flow Duplex scanning is

the imaging test of choice for patients with sus-pected DVT. This test is noninvasive and widelyavailable. The Doppler component evaluates bloodflow for proximal obstruction, and the addition ofcolor flow technology provides accurate images.The color-flow duplex scan can detect 95-99% ofacute thrombi above the knee. Ultrasound can alsodistinguish other causes of leg swelling, such astumor, popliteal cyst, abscess, aneurysm, orhematoma. Pain, edema, dyspnea, and a history ofDVT are most predictive of positive scans.

B. When results of duplex scanning are positive,these techniques are adequately specific to diag-nose DVT. Results that do not support the clinicalimpression should be investigated withvenography.

C. Contrast venography. When ultrasound tech-niques fail to demonstrate a thrombus, venographyis the diagnostic "gold standard" for patients athigh clinical risk. The test is negative if contrastmedium is seen throughout the deep venous sys-tem. Venography can cause iatrogenic venousthrombosis in 4%, and allergic contrast reactionsoccur in 3% of patients.

D. MRI may have an accuracy comparable to that ofcontrast venography, and it may soon replacecontrast venography as the "gold standard" ofvenous imaging.

IV.Treatment of Deep Vein ThrombosisA. Low-molecular-weight heparin. Low-molecular-

weight (LMW) derivatives of commercial heparinhave a mean molecular weight of 4000 to 6000daltons.1. Advantages of low-molecular-weight heparin

a. They have greater bioavailability when givenby subcutaneous injection.

b. The duration of the anticoagulant effect isgreater, permitting once or twice daily admin-istration.

c. The anticoagulant response (anti-Xa activity)is highly correlated with body weight, permit-ting administration of a fixed dose.

d. Laboratory monitoring is not necessary.e. There is a lesser risk of thrombocytopenia.

2. Subcutaneous, unmonitored, LMW heparingiven once or twice daily, is at least as effectiveand safe as unfractionated heparin in patientswith proximal venous thrombosis and may beassociated with greater inhibition of in vivothrombin generation, higher rates of thrombusregression, and lower rates of recurrent venousthromboembolism, major bleeding, and mortal-ity.

3. LMW heparin is associated with a lower rate ofboth recurrent DVT (2.7 versus 7.0 percent) andmajor bleeding (0.9 versus 3.2 percent) thanunfractionated heparin.

B. Outpatient use. Patients with proximal DVT canbe safely treated with LMW heparin in the outpa-tient setting without loss of efficacy.

Management of Deep Venous Thrombosis

Superficial Venous Thrombosis• Use duplex scan to screen for involvement of deep

system• Elevation, nonsteroidal anti-inflammatory drugs

Deep Venous Thrombosis• Begin warfarin on the first hospital day• Low-molecular-weight heparin--more effective and

safer than standard heparin

Phlegmasia Dolens• Enoxaparin 1.0 mg/kg SQ q12h• Heparin 80 U/kg load, 18 U/kg/hr drip• Thrombolysis for severe disease in young adults• Vena cava filter if thrombosis in presence of adequate

anticoagulation

Exclusions for Home Treatment for DVT

Medical ExclusionsConcurrent Pulmonary Embolism (PE)Serious co-morbid conditionCancer, infection, strokePrior DVT or PEContraindications to anticoagulationFamilial bleeding disorderKnown deficiency of Antithrombin Ill, Protein C, Protein SPregnancy

Social ExclusionsNo phoneLives far from hospitalUnable to understand instructions or comply with follow-upFamily or patient resistance to home therapy

Low Molecular Weight Heparin Protocol

Subcutaneous enoxaparin 1 mg/kg q12hours for a mini-mum of five days and achieving INR of 2-3 (from warfarintherapy)Warfarin to be started on first day of therapyINR should be monitored during outpatient treatmentWarn patients to return immediately for shortness ofbreath, hemorrhage, or clinical decomposition

1. Because LMWH primarily inhibits factor X-a andhas little effect on thrombin or platelet aggrega-tion, there are fewer hemorrhagic complications.LMWH usually does not elevate the PTT. LMWHis valued for its antithrombotic effect and lack ofanticoagulant effect.

2. Enoxaparin (Lovenox) is the only LMWHcurrently approved for treatment of DVT. Thedose of enoxaparin for inpatient treatment ofDVT, with or without PE is 1 mg/kg q12hours SQor 1.5 mg/kg SQ qd. The dose of enoxaparin foroutpatient therapy of deep venous thrombosiswithout pulmonary embolism is 1 mg/kgq12hours SQ.

3. Enoxaparin should be administered for at leastfive days, and warfarin can be started on thesame day as the LMWH or the day after. Bloodshould be drawn daily to monitor theprothrombin time for the first few days; theInternational Normalized Ration (INR) should bebetween 2.0 and 3.0 for two consecutive daysbefore the LMWH is stopped.

C. Heparin. Anticoagulant response is monitoredusing either the activated partial thromboplastintime (aPTT) or heparin levels, and the dose istitrated to the individual patient.

D. Anticoagulation goals. The efficacy of heparintherapy depends upon achieving a critical therapeu-tic level of heparin within the first 24 hours of treat-ment, via a continuous heparin infusion. The criticaltherapeutic level of heparin (as measured by theaPTT) is 1.5 times the mean of the control value orthe upper limit of the normal aPTT range.

E. The level of anticoagulation described above (aPTTratio 1.5 to 2.5) corresponds to a heparin bloodlevel of 0.2 to 0.4 U/mL by the protamine sulfatetitration assay and 0.3 to 0.6 U/mL by the amidolyticanti-factor Xa assay.

F. Heparin is usually given simultaneously with warfa-rin. Heparin is overlapped with warfarin for a mini-mum of four to five days until the InternationalNormalized Ratio (INR) has been within the thera-peutic range (2.0 to 3.0) for two consecutive days.When combined with early administration of warfa-rin, four to five days of heparin therapy is adequate.

G. Method of heparin administration andanticoagulation adequacy

Weight-Based Nomogram for Intravenous HeparinInfusions

Initial dose 80 U/kg bolus, then 18U/kg per hour

aPTT <35 sec (<1 .2 xcontrol)

80 U/kg bolus, then in-crease infusion rate by 4U/kg per hour

aPTT 35-45 sec (1 .2-1 .5x control)

40 U/kg bolus, then in-crease infusion rate by 2U/kg per hour

aPTT 46-70 sec (1.5-2.3 xcontrol)

No change

aPTT 71-90 sec (2.3-3.0 xcontrol)

Decrease infusion rate by2 U/kg per hour

aPTT >90 sec (>3.0 x con-trol)

Hold infusion 1 hour, thendecrease infusion rate by 3U/kg per hour

1. Patients treated with the weight-adjusted regi-men receive a starting bolus dose of 80 units/kgfollowed by an 18 units/kg per hour infusion. Theheparin dose is adjusted to maintain an APTT of1.5 to 2.3 times control.

2. Complications. The major side effects of hepa-rin therapy are bleeding and thrombocytopenia,which is often associated with thrombosis.

H. Inferior vena caval interruption. Insertion of aninferior vena caval (IVC) filter is generally indicatedin patients with acute venous thromboembolismwho have an absolute contraindication to anticoag-ulant therapy (recent surgery, hemorrhagic stroke,ac t i ve b leed ing , hepar in assoc ia tedthrombocytopenia), who have recurrent venoust h r o m b o e m b o l i s m d e s p i t e a d e q u a t eanticoagulation, or who have such limited pulmo-nary vascular reserve that they may not surviveadditional thromboemboli.

I. Warfarin (Coumadin). Treatment with heparin isusually followed by at least a three to six monthperiod of anticoagulation to prevent recurrentdisease. Warfarin therapy is preferred in mostpatients. Heparin and warfarin treatment shouldoverlap by four to five days when warfarin is initi-ated in patients with thrombotic disease.1. Dose and therapeutic range. Warfarin is ad-

ministered in an initial dose of 5 to 10 mg perday for the first two days, with the daily dosethen adjusted according to the INR. Heparin isdiscontinued on the fourth or fifth day followinginitiation of warfarin therapy, provided the INR isprolonged to an INR 2.0 to 3.0 for two consecu-tive days. Once the patient’s warfarin doserequirements are stable, the INR should bemonitored every one to two weeks. Once warfa-rin/heparin have been started and the patient’ssymptoms (ie, pain, swelling) are under control,the patient is encouraged to ambulate.

2. Patients without an identifiable risk factor, whoare more likely to have a recurrent event, shouldgenerally be treated for six months. Treatmentwith oral warfarin is recommended for at least 12months after a second episode of venousthromboembolism. Indefinite anticoagulation isrecommended for patients with three or moreepisodes of venous thromboembolism. In thosepatients with a continuing risk factor that ispotentially reversible (eg, prolonged bed rest),long-term therapy should be continued until therisk factor is reversed.

3. Patients with a first thromboembolic event in thecontext of a reversible or time-limited risk factorshould be treated for at least three months,whereas those with an idiopathic firstthromboembolic event should be treated for atleast six months. Patients with recurrent idio-pathic VTE or a continuing risk factor (eg, can-cer, antithrombin deficiency, anticardiolipinantibody syndrome) should be treated for 12months or longer.


Pulmonary EmbolismPulmonary embolism (PE) is responsible for approxi-mately 150,000 to 200,000 deaths per year in the UnitedStates and is one of the most common causes of pre-ventable death in the hospital. Untreated PE is associ-

ated with a mortality rate of 30 percent. Most patientscurrently are treated with intravenous heparin followed byoral warfarin.

I. Diagnosis of pulmonary embolism A. Pulmonary embolism should be suspected in any

patient with new cardiopulmonary symptoms orsigns and significant risk factors. If no other satis-factory explanation can be found in a patient withfindings suggestive of pulmonary embolism, theworkup for PE must be pursued to completion.

B. Signs and symptoms of pulmonary embolism.Pleuritic chest pain, unexplained shortness ofbreath, tachycardia, hypoxemia, hypotension,hemoptysis, cough, syncope. The classic triad ofdyspnea, chest pain, and hemoptysis is seen inonly 20% of patients. The majority of patients haveonly a few subtle symptoms or are asymptomatic.

C. Massive pulmonary emboli may cause the suddenonset of precordial pain, dyspnea, syncope, orshock. Other findings include distended neck veins,cyanosis, diaphoresis, pre-cordial heave, a loudpulmonic valve component of the second heartsound. Right ventricular S3, and a tricuspid insuffi-ciency.

D. Deep venous thrombosis may manifest as anedematous limb with an erythrocyanotic appear-ance, dilated superficial veins, and elevated skintemperature.

Frequency of Symptoms and Signs in Pulmo-nary Embolism

Symptoms Freq-uency(%)

Signs Freq-uency(%)

DyspneaPleuritic chestpain Apprehension Cough Hemoptysis SweatingNon-pleuriticchest pain

84745953302714

Tachypnea(>16/min)RalesAccentuatedS2TachycardiaFever(>37.8°C)DiaphoresisS3 or S4 gal-lopThrombophlebitis

92 58534443363432

II.Risk factors for pulmonary embolismA. Venous stasis. Prolonged immobilization, hip

surgery, stroke, myocardial infarction, heart failure,obesity, varicose veins, anesthesia, age >65 yearsold.

B. Endothelial injury. Surgery, trauma, centralvenous access catheters, pacemaker wires, previ-ous thromboembolic event.

C. Hypercoagulable state. Malignant disease, highestrogen level (oral contraceptives).

D. Hematologic disorders. Polycythemia,leukocytosis, thrombocytosis, antithrombin IIIdeficiency, protein C deficiency, protein S defi-ciency, antiphospholipid syndrome, inflammatorybowel disease, factor 5 Leiden defect.

III. Diagnostic evaluationA. Chest radiographs are nonspecific and insensi-

tive, and findings are normal in up to 40 percent ofpatients with pulmonary embolism. Abnormalitiesmay include an elevated hemidiaphragm, focalinfiltrates, atelectasis, and small pleural effusions.

B. Electrocardiography is nonspecific and oftennormal. The most common abnormality is sinustachycardia. Other findings may include ST-seg-ment or T-wave changes. Occasionally, acute rightventricular strain causes tall peaked P waves inlead II, right axis deviation, right bundle branchblock, or atrial fibrillation.

C. Blood gas studies. There is no level of arterialoxygen that can rule out pulmonary embolism.Most patients with pulmonary embolism have anormal arterial oxygen.

D. Ventilation-perfusion scan1. Patients with a clearly normal perfusion scan do

not have a pulmonary embolism, and less than5 percent of patients with near-normal scanhave a pulmonary embolism. A high-probabilityscan has a 90 percent probability of a pulmo-nary embolism.

2. A low-probability V/Q scan can exclude thediagnosis of pulmonary embolism only if thepatient has a clinically low probability of pulmo-nary embolism.

3. Intermediate V/Q scans are not diagnostic and

usually indicate the need for further diagnostictesting. One-third of patients with intermediatescans have a pulmonary embolism and shouldhave a follow-up chest CT or pulmonaryangiography.

E. Venous imaging1. If the V/Q scan is nondiagnostic, a workup for

deep venous thrombosis (DVT) should bepursued using duplex ultrasound. The identifica-tion of DVT in a patient with signs and symp-toms suggesting pulmonary embolism provesthe diagnosis of pulmonary embolism. A deepvenous thrombosis can be found in 80% ofcases of pulmonary emboli.

2. Inability to demonstrate the existence of a DVTdoes not significantly lower the likelihood of pul-monary embolism because clinically asymptom-atic DVT may not be detectable.

3. Patients with a nondiagnostic V/Q scan and nodemonstrable site of DVT should proceed tochest CT or pulmonary angiography.

F. Chest CT may be used in place of pulmonaryangiography in patients with abnormal chest x-rayin whom V/Q scan is nondiagnostic, or in presenceof an intermediate probability of PE on V/Q scan.Chest CT is associated with fewer complicationsthan pulmonary angiography. However, chest CToffers a more limited view of this pulmonary fieldand does not allow for measurement of pulmonaryartery pressure.

G. Angiography. Contrast pulmonary arteriography isthe “gold standard” for the diagnosis of pulmonaryembolism. False-negative results occur in 2-10%of patients. Angiography carries a low risk ofcomplications (minor 5%, major nonfatal 1%, fatal0.5%).

IV. Management of acute pulmonary embolismA. Oxygen should be initiated for all patients.B. Heparin therapy

1. Heparin (unfractionated) and oral warfarinshould be initiated simultaneously in all patientswho are medically stable. Exceptions includeunstable patients who require immediate medi-cal or surgical intervention, such asthrombolysis or insertion of a vena cava filter,and patients at very high risk for bleeding.Heparin therapy should be started as soon asthe diagnosis of pulmonary embolism is sus-pected. Full-dose heparin can be given immedi-ately after major surgery.

2. Therapeutic level of heparin (as measuredby the APTT) is at least 1.5 times the controlvalue. This level of anticoagulation (APTT ratio1.5 to 2.5) corresponds to a heparin blood levelof 0.2 to 0.4 units/mL by the protamine sulfatetitration assay and 0.3 to 0.6 by the amidolyticanti-factor Xa assay.

3. Side effects of heparin therapy include bleed-ing, thrombocytopenia (which is often associ-ated with thrombosis), and osteoporosis.Platelet count should be monitored duringheparin therapy; thrombocytopenia develops in5% of patients after 3-7 days of therapy. Hepa-rin may rarely induce hyperkalemia, whichresolves spontaneously upon discontinuation.

4. Heparin therapy is overlapped with warfarinfor a minimum of 5 days and continued until theInternational Normalized Ratio (INR) has beenwithin the therapeutic range (2.0 to 3.0) for twoconsecutive days.

5. Dose titration and monitoring

Weight-Based Nomogram for Intravenous HeparinInfusions

Initial dose 80 U/kg bolus, then 18 U/kgper hour

aPTT* <35 sec (<1 .2 xcontrol)

80 U/kg bolus, then increaseinfusion rate by 4 U/kg perhour

aPTT 35-45 sec (1 .2-1 .5x control)

40 U/kg bolus, then increaseinfusion rate by 2 U/kg perhour

aPTT 46-70 sec (1.5-2.3x control)

No change

aPTT 71-90 sec (2.3-3.0x control)

Decrease infusion rate by 2U/kg per hour

aPTT >90 sec (>3.0 xcontrol)

Hold infusion 1 hour, thendecrease infusion rate by 3U/kg per hour

a. Patients treated with the weight-adjustedregimen received a starting bolus dose of 80units/kg followed by an 18 units/kg per hourinfusion. The aPTT should be obtained in 6hours. The heparin dose was adjusted tomaintain an APTT of 1.5 to 2.3 times control.

6. Dose and therapeutic range. Warfarin isadministered in an initial dose of 5 to 10 mg perday for the first two days, with the daily dosethen adjusted according to the INR. Heparin isdiscontinued on the fourth or fifth day followinginitiation of warfarin therapy, provided the INRis prolonged into the recommended therapeuticrange for venous thromboembolism (INR 2.0 to3.0) for two consecutive days. Once the antico-agulant effect and patient's warfarin dose re-quirements are stable, the INR should be moni-tored every one to two weeks.

C. Thrombolytic therapy1. Unstable patients (systolic <90 mm Hg) with

proven pulmonary embolism require immediateclot lysis by thrombolytic therapy. Tissueplasminogen activator (Activase) is recom-mended because it is the fastest-acting throm-bolytic agent.

2. Contraindications to thrombolyticsa. Absolute contraindications. Active bleed-

ing, cerebrovascular accident or surgerywithin the past 2 months, intracranialneoplasms.

b. Relative contraindications. Recent gastro-intestinal bleeding, uncontrolled hyperten-sion, recent trauma (cardiopulmonary resus-citation), pregnancy.

3. Alteplase (tPA, Activase). 100 mg by periph-eral IV infusion over 2 hr. Heparin therapyshould be initiated after cessation of the throm-bolytic infusion. Heparin is started without aloading dose at 18 U/kg/hr when the aPTT is1.5 times control rate.

D. Fluid and pharmacologic management. In acutecor pulmonale, gentle pharmacologic preloadreduction with furosemide unloads the congestedpulmonary circuit and reduces right ventricularpressures. Hydralazine, isoproterenol, ornorepinephrine may be required. Pulmonary arterypressure monitoring may be helpful.

E. Emergency thoracotomy. Emergency surgicalremoval of embolized thrombus is reserved forinstances when there is an absolute contraindica-tion to thrombolysis or when the patient's conditionhas failed to improve after thrombolysis. Cardiacarrest from pulmonary embolism is an indicationfor immediate thoracotomy.

F. Inferior vena cava filter placement is recom-mended when anticoagulation is contraindicated orwith recurrent thromboembolism despite adequateanticoagulation, chronic recurrent embolism withpulmonary hypertension, situations with a high-riskof recurrent embolization, and in conjunction withthe performance of pulmonary embolectomy orendarterectomy.

V. Long-term treatment of venous thromboembolismA. First thromboembolic event. It is recommended

that patients with a first thromboembolic eventoccurring in the setting of reversible or time-limitedrisk factors (eg, immobilization, surgery, trauma,estrogen use) should receive warfarin therapy forthree to six months. Patients with idiopathic firstthromboembolic events should be treated for atleast six months. Patients with a first

thromboembolic event occurring in the setting ofanticardiolipin antibody, antithrombin deficiency, ormalignancy should be anticoagulated for at least12 months, and possibly for life.

B. Recurrent thromboembolism. Warfarin treatmentfor more than 12 months is indicated in patientswith recurrent venous thromboembolism in thesetting of thrombophilia or when a second idio-pathic event occurs.


Gynecologic Disorders

OsteoporosisOver 1.3 million osteoporotic fractures occur each yearin the United States. The risk of all fractures increaseswith age; among persons who survive until age 90, 33percent of women will have a hip fracture. The lifetimerisk of hip fracture for white women at age 50 is 16percent. Osteoporosis is characterized by low bonemass, microarchitectural disruption, and increasedskeletal fragility.

Risk Factors for Osteoporotic Fractures

Personal history of fractureas an adult History of fracture in a first-degree relativeCurrent cigarette smoking Low body weight (less than58 kg [127 lb]) Female sex Estrogen deficiency(menopause before age 45years or bilateralovariectomy, prolongedpremenopausalamenorrhea [greater thanone year])

White raceAdvanced ageLifelong low calcium intakeAlcoholismInadequate physical activ-ityRecurrent fallsDementiaImpaired eyesight despiteadequate correctionPoor health/frailty

I. Screening for osteoporosis and osteopeniaA. Normal bone density is defined as a bone mineral

density (BMD) value within one standard deviationof the mean value in young adults of the same sexand race.

B. Osteopenia is defined as a BMD between 1 and2.5 standard deviations below the mean.

C. Osteoporosis is defined as a value more than 2.5standard deviations below the mean; this level isthe fracture threshold. These values are referred toas T-scores (number of standard deviations aboveor below the mean value).

D. Dual x-ray absorptiometry. In dual x-rayabsorptiometry (DXA), two photons are emittedfrom an x-ray tube. DXA is the most commonlyused method for measuring bone density becauseit gives very precise measurements with minimalradiation. DXA measurements of the spine and hipare recommended.

E. Biochemical markers of bone turnover. Urinarydeoxypyridinoline (DPD) and urinary alpha-1 toalpha-2 N-telopeptide of collagen (NTX) are themost specific and clinically useful markers of boneresorption. Biochemical markers are not useful forthe screening or diagnosis of osteoporosis be-cause the values in normal and osteoporosisoverlap substantially.

II. Recommendations for screening for osteoporosisof the National Osteoporosis FoundationA. All women should be counseled about the risk

factors for osteoporosis, especially smoking cessa-tion and limiting alcohol. All women should beencouraged to participate in regular weight-bearingand exercise.

B. Measurement of BMD is recommended for allwomen 65 years and older regardless of riskfactors. BMD should also be measured in allwomen under the age of 65 years who have one ormore risk factors for osteoporosis (in addition tomenopause). The hip is the recommended site ofmeasurement.

C. All adults should be advised to consume at least1,200 mg of calcium per day and 400 to 800 IU ofvitamin D per day. A daily multivitamin (whichprovides 400 IU) is recommended. In patients withdocumented vitamin D deficiency, osteoporosis, orprevious fracture, two multivitamins may be rea-sonable, particularly if dietary intake is inadequateand access to sunlight is poor.

D. Treatment is recommended for women without riskfactors who have a BMD that is 2 SD below themean for young women, and in women with riskfactors who have a BMD that is 1.5 SD below themean.

III. Nonpharmacologic therapy of osteoporosis inwomenA. Diet. An optimal diet for treatment (or prevention)

of osteoporosis includes an adequate intake ofcalories (to avoid malnutrition), calcium, andvitamin D.

B. Calcium. Postmenopausal women should beadvised to take 1000 to 1500 mg/day of elemental

calcium, in divided doses, with meals.C. Vitamin D total of 800 IU daily should be taken.D. Exercise. Women should exercise for at least 30

minutes three times per week. Any weight-bearingexercise regimen, including walking, is acceptable.

E. Cessation of smoking is recommended for allwomen because smoking cigarettes acceleratesbone loss.

IV. Drug therapy of osteoporosis in womenA. Selected postmenopausal women with osteoporo-

sis or at high risk for the disease should be consid-ered for drug therapy. Particular attention shouldbe paid to treating women with a recent fragilityfracture, including hip fracture, because they are athigh risk for a second fracture.

B. Candidates for drug therapy are women whoalready have postmenopausal osteoporosis (lessthan -2.5) and women with osteopenia (T score -1to -2.5) soon after menopause.

C. Bisphosphonates1. Alendronate (Fosamax) (10 mg/day or 70 mg

once weekly) or risedronate (Actonel) (5mg/day or 35 mg once weekly) are goodchoices for the treatment of osteoporosis.Bisphosphonate therapy increases bone massand reduces the incidence of vertebral andnonvertebral fractures.

2. Alendronate (5 mg/day or 35 mg once weekly)and risedronate (5 mg/day of 35 mg onceweekly) have been approved for prevention ofosteoporosis.

3. Alendronate or risedronate should be taken witha full glass of water 30 minutes before the firstmeal or beverage of the day. Patients shouldnot lie down for at least 30 minutes after takingthe dose to avoid the unusual complication ofpill-induced esophagitis.

4. Alendronate is well tolerated and effective for atleast seven years.

5. The bisphosphonates (alendronate orrisedronate) and raloxifene are first-line treat-ments for prevention of osteoporosis. Thebisphosphonates are first-line therapy for treat-ment of osteoporosis. Bisphosphonates arepreferred for prevention and treatment of osteo-porosis because they increase bone mineraldensity more than raloxifene.

D. Selective estrogen receptor modulators1. Raloxifene (Evista) (5 mg daily or a once-a-

week preparation) is a selective estrogen recep-tor modulator (SERM) for prevention and treat-ment of osteoporosis. It increases bone mineraldensity and reduces serum total and low-density-lipoprotein (LDL) cholesterol. It alsoappears to reduce the incidence of vertebralfractures and is one of the first-line drugs forprevention of osteoporosis.

2. Raloxifene is somewhat less effective than thebisphosphonates for the prevention and treat-ment of osteoporosis. Venous thrombo-embolism is a risk.

Treatment Guidelines for Osteoporosis

Calcium supplements with or without vitamin D supple-ments or calcium-rich diet Weight-bearing exercise Avoidance of alcohol tobacco productsAlendronate (Fosamax) Risedronate (Actonel)Raloxifene (Evista)

Agents for Treating Osteoporosis

Medication Dosage Route

Calcium 1,000 to 1,500 mg per day Oral

Vitamin D 400 IU per day (800 IU perday in winter in northern lati-tudes)

Oral

Alendronate(Fosamax)

Prevention: 5 mg per day or35 mg once-a-weekTreatment: 10 mg per day or70 mg once-a-week

Oral

Risedronate(Actonel)

5 mg daily or 35 mg onceweekly

Oral

Raloxifene(Evista)

60 mg per day Oral

Conjugatedestrogens

0.3 mg per day Oral

E. Monitoring the response to therapy1. Bone mineral density and a marker of bone

turnover should be measured at baseline,followed by a repeat measurement of themarker in three months.

2. If the marker falls appropriately, the drug ishaving the desired effect, and therapy shouldbe continued for two years, at which time bonemineral density can be measured again. Theanticipated three-month decline in markers is50 percent with alendronate.

F. Estrogen/progestin therapy1. Estrogen-progestin therapy is no longer a first-

line approach for the treatment of osteoporosisin postmenopausal women because of in-creases in the risk of breast cancer, stroke,venous thromboembolism, and coronary dis-ease.

2. Indications for estrogen-progestin inpostmenopausal women include persistentmenopausal symptoms and patients with anindication for antiresorptive therapy who cannottolerate the other drugs.


Management of the AbnormalPapanicolaou SmearThe Papanicolaou smear is a screening test for abnor-malities that increases the risk of cervical cancer. Treat-ment decisions are based upon the results ofcolposcopically directed biopsies of the cervix.Papanicolaou smear reports are classified using theBethesda System, which was revised in 2001.

I. Pap Smear Report

Bethesda 2001 Pap Smear Report

Interpretation ResultNegative for intraepithelial lesion or malignancy (whenthere is no cellular evidence of neoplasia, state this in theGeneral Categorization above and/or in the Interpreta-tion/Result section of the report, whether there are organ-isms or other non-neoplastic findings)Infection (Trichomonas vaginalis, Candida spp., shift in

flora suggestive of bacterial vaginosis, Actinomycesspp., cellular changes consistent with Herpes simplexvirus)

Other Non-neoplastic Findings (Optional to report; listnot inclusive):

Reactive cellular changes associated with inflammation(includes typical repair) radiation, intrauterine contra-ceptive device (IUD)

Glandular cells status post-hysterectomy Atrophy

OtherEndometrial cells (in a woman >40 years of age) (spec-

ify if "negative for squamous intraepithelial lesion")Epithelial Cell Abnormalities

Squamous CellAtypical squamous cells

-of undetermined significance (ASC-US)-cannot exclude HSIL (ASC-H)

Low-grade squamous intraepithelial lesion (LSIL)encompassing: HPV/mild dysplasia/CIN 1

High-grade squamous intraepithelial lesion (HSIL)encompassing: moderate and severe dysplasia,CIS/CIN 2 and CIN 3 with features suspicious forinvasion (if invasion is suspected)

Squamous cell carcinomaGlandular Cell

Atypical-Endocervical cells (not otherwise specified orspecify in comments)-Glandular Cell (not otherwise specified or spec-ify in comments)-Endometrial cells (not otherwise specified orspecify in comments)-Glandular cells (not otherwise specified or spec-ify in comments)

Atypical-Endocervical cells, favor neoplastic-Glandular cells, favor neoplastic

Endocervical adenocarcinoma in situAdenocarcinoma (endocervical, endometrial,extrauterine, not otherwise specified (not otherwisespecified)

Other Malignant Neoplasms (specify)

II. Screening for cervical cancerA. Regular Pap smears are recommended for all

women who are or have been sexually active andwho have a cervix.

B. Testing should begin when the woman first en-gages in sexual intercourse. Adolescents whosesexual history is thought to be unreliable should bepresumed to be sexually active at age 18.

C. Pap smears should be performed at least every 1to 3 years. Testing is usually discontinued afterage 65 in women who have had regular normalscreening tests. Women who have had a hysterec-tomy, including removal of the cervix for reasonsother than cervical cancer or its precursors, do notrequire Pap testing.

III. Techniques used in evaluation of the abnormalpap smear A. Colposcopy allows examination of the lower

genital tract to identify epithelial changes. Abnor-mal areas should be targeted for biopsy to deter-mine a pathologic diagnosis.

B. Human papillomavirus testing1. HPV infection is the leading etiologic agent in

the development of premalignant and malignantlower genital tract disease. Premenopausalwomen who test positive for certain types ofHPV are at higher risk of cervical dysplasia(HPV positive), while those who are HPV nega-tive or have types of HPV DNA of lowoncogenic potential are at low risk.

2. The most commonly used HPV test is theHybrid Capture ll HPV DNA Assay (HC ll), whichtests for high-risk HPV types 16, 18, 31, 33, 35,39, 45, 51, 52, 56, 58, 59, and 68. High-riskHPV types 16 and 18 are the viruses mostfrequently isolated in cervical cancer tissue.

IV. Atypical squamous cellsA. Atypical squamous cells of undetermined signif-

icance (ASCUS) is further divided into ASC-US,which are qualified as "of undetermined signifi-cance," and ASC-H, in which a high-gradesquamous intraepithelial lesion (HSIL) cannot beexcluded.

B. ASC requires further evaluation. This cytologicdiagnosis is common and frequently associated with

spontaneously resolving, self-limited disease.However, 5 to 17 percent of patients with ASC and24 to 94 percent of those with ASC-H will have CINII or III at biopsy.

C. Women with ASC-US1. Management of minimally abnormal cervical

cytology smears (ASC-US):a. If liquid-based cytology is used, reflex testing

for HPV should be performed, alternativelycocollection for HPV DNA testing can be doneat the time of a conventional cervical cytologysmear.

b. Colposcopy should performed if humanpapillomavirus testing is positive. Thirty to 60percent of women with ASC will test positivefor high-risk HPV types and require immedi-ate colposcopy.

2. Patients with a positive high-risk type HPV DNAtest should be evaluated by colposcopy; thosewith a negative test may be triaged to repeatcytologic evaluation in 12 months. Managementof women who test positive for high-risk HPVtypes, but have no CIN consists of either 1)cytological testing repeated in six and 12 monthswith colposcopic evaluation of ASC-US orgreater or 2) HPV testing repeated in 12 monthswith colposcopy if HPV results are positive.

V. Special circumstancesA. When an infectious organism is identified, the

patient should be contacted to determine if she issymptomatic. Antibiotic therapy is indicated forsymptomatic infection.

B. Reactive changes due to inflammation areusually not associated with an organism on the Papsmear. The Pap smear does not need to be re-peated unless the patient is HIV positive, in whichcase it should be repeated in four to six months.

C. Atrophic epithelium is a normal finding inpostmenopausal women.1. Administration of estrogen causes atypical

atrophic, but not dysplastic, epithelium to matureinto normal squamous epithelium.

2. Hormonal therapy given for vaginal atrophyshould be followed by repeat cervical cytologyone week after completing treatment. If negative,cytology should be repeated again in four to sixmonths. If both tests are negative, the womancan return to routine screening intervals, but ifeither test is positive for ASC-US or greater, sheshould be evaluated with colposcopy.

D. Immunosuppressed women, including all womenwho are HIV positive, with ASC-US should bereferred for immediate colposcopy, instead of HPVtesting.

E. ASC-US with absence of CIN on biopsy. Ifcolposcopic examination does not show CIN, thenfollow-up cytological testing should be performed in12 months.

F. ASC-US with biopsy proven CIN. Since spontane-ous regression is observed in approximately 60percent of CIN l, expectant management with serialcytologic smears at three to four month intervals isreasonable for the reliable patient.

G. Women with ASC-H. All women with ASC-H oncytological examination should receive colposcopy.If repeat of cytology confirms ASC-H but biopsy isnegative for CIN, follow-up cytology in six and 12months or HPV DNA testing in 12 months is recom-mended. Colposcopy should be repeated for ASCor greater on cytology or a positive test for high riskHPV DNA. Biopsy proven CIN is treated, as appro-priate.

VI. Low- and high-grade intraepithelial neoplasiaA. Low-grade squamous intraepithelial lesions

(LSIL) may also be referred to as CIN I or milddysplasia. Immediate referral for colposcopy is therecommended management for LSIL. Endocervicalsampling should be done in nonpregnant women inwhom the transformation zone cannot be fullyvisualized or a lesion extends into the endocervicalcanal. Endocervical sampling also should be donein nonpregnant women when no lesion is identifiedon colposcopy.1. If no CIN is identified following satisfactory or

unsatisfactory colposcopy and biopsies, thenoptions for follow-up include either:a. Repeat cytology testing at six and 12 months,

or b. HPV DNA testing at 12 months

2. Referral for repeat colposcopy is required ifcytology yields ASC or greater or HPV DNA ispositive for a high-risk type.

3. Women with histologically confirmed CIN I LSILmay be treated with ablation or excision or

followed with serial cytologic smears every threeto six months if the entire lesion and limits of thetransformation zone are completely visualized.LSIL confined to the endocervical canal may befollowed with repeat smears obtained with acytobrush and with ECC.

4. Postmenopausal women. Postmenopausalwomen may be managed by serial cytology atsix and 12 months or HPV DNA testing at 12months with referral to colposcopy for positiveresults. Women with atrophy are treated withintravaginal estrogen followed by repeat cytologyseven days after completion of therapy, withreferral to colposcopy if an abnormality persists.If repeat cytology is normal, then another cytol-ogy test should be obtained in four to sixmonths. The woman can return to routine sur-veillance if both tests are normal, but should bereferred for colposcopy if either test is positive.

5. Adolescents. Initial colposcopy may be deferredin adolescents. Instead, they may be managedwith serial cytology at six and 12 months or HPVDNA testing at 12 months with referral tocolposcopy for positive results.

6. Pregnant women. Colposcopy should be per-formed, with biopsy and endocervical curettageperformed for any lesion suspicious for HSIL ormore severe disease.

B. High-grade squamous intraepithelial lesions1. A high-grade squamous intraepithelial lesion

(HSIL) may also be referred to as CIN II or III,severe dysplasia, or carcinoma in situ (CIS).One to two percent of women with HSIL on acytologic smear have invasive cancer at the timeof further evaluation and 20 percent of womenwith biopsy-proven CIS will develop an invasivecancer if left untreated. All women with HSILshould be referred for colposcopy andendocervical sampling.

C. Follow-up evaluation. Pap smears are recom-mended every three to four months for the first yearafter treatment for dysplasia. Women with cervicaldysplasia present at the LEEP or cone margin or inthe concomitant ECC also need a follow-upcolposcopy with endocervical curettage every sixmonths for one year. Routine surveillance can beresumed if there is no recurrence after the first year.Surveillance consists of Pap smears on a yearlybasis for most women, and on a twice-yearly basisfor high-risk women (ie, HIV positive).

VII. Abnormal glandular cellsA. A report of atypical glandular cells (AGC) indicates

the presence of glandular cells that could be comingfrom the endocervical or endometrial region. TheBethesda 2001 system classifies AGC into twosubcategories:1. AGC endocervical, endometrial, or not otherwise

specified (NOS)2. AGC favor neoplasia, endocervical or NOS

B. Additional categories for glandular cell abnormali-ties are:1. Endocervical adenocarcinoma in situ (AIS)2. Adenocarcinoma

C. Evaluation of AGC or AIS on cervical cytology:These women should be referred for colposcopyand sampling of the endocervical canal. Womenover age 35 and younger women with AGC andunexplained vaginal bleeding also need anendometrial biopsy. Women with only atypicalendometrial cells on cytology can be initially evalu-ated with endometrial biopsy.

D. Endometrial cells in women >40 years of age:Endometrial biopsy should be performed.


Sexually Transmissible InfectionsApproximately 12 million patients are diagnosed with asexually transmissible infection (STI) annually in theUnited States. Sequella of STIs include infertility, chronicpelvic pain, ectopic pregnancy, and other adversepregnancy outcomes.

Diagnosis and Treatment of Bacterial SexuallyTransmissible Infections

Organ-ism

Diagnos-tic Meth-ods

RecommendedTreatment

Alternative

Chlamydiatracho-matis

Direct flu-orescentantibody,enzymeimmuno-assay,DNAprobe, cellculture,DNA am-plification

Doxycycline 100mg PO 2 times aday for 7 days or Azithromycin(Zithromax) 1 gPO

Ofloxacin (Floxin)300 mg PO 2 timesa day for 7 days

Neisseriagonor-rhoeae

CultureDNAprobe

Ceftriaxone(Rocephin) 125mg IM orCefixime 400 mgPO orCiprofloxacin(Cipro) 500 mgPO orOfloxacin(Floxin) 400 mgPOplus Doxycycline100 mg 2 timesa day for 7 daysor azithromycin 1g PO

Levofloxacin(Levaquin) 250 mgPO once Spectinomycin 2 gIM once

Trepo-nemapalli-dum

Clinicalappear-ance Dark-fieldmicros-copyNontreponemal test:rapidplasmareagin,VDRLTreponemal test:MHA-TP,FTA-ABS

Primary and sec-ondary syphilisand early latentsyphilis (<1 yearduration):benzathine peni-cillin G 2.4 mil-lion units IM in asingle dose.

Penicillin allergy inpatients with pri-mary, secondary,or early latentsyphilis (<1 year ofduration):doxycycline 100mg PO 2 times aday for 2 weeks.

Diagnosis and Treatment of Viral Sexually Trans-missible Infections

Organ-ism

DiagnosticMethods

Recommended Treatment Regi-mens

Herpessimplexvirus

Clinical ap-pearanceCell cultureconfirmation

First episode: Acyclovir (Zovirax)400 mg PO 5 times a day for 7-10days, or famciclovir (Famvir) 250mg PO 3 times a day for 7-10 days,or valacyclovir (Valtrex) 1 g PO 2times a day for 7-10 days.Recurrent episodes: acyclovir 400mg PO 3 times a day for 5 days, or800 mg PO 2 times a day for 5days or famciclovir 125 mg PO 2times a day for 5 days, orvalacyclovir 500 mg PO 2 times aday for 5 days Daily suppressive therapy:acyclovir 400 mg PO 2 times a day,or famciclovir 250 mg PO 2 times aday, or valacyclovir 250 mg PO 2times a day, 500 mg PO 1 time aday, or 1000 mg PO 1 time a day

Humanpapillomavirus

Clinical ap-pearance ofcondylomapapulesCytology

External warts: Patient may applypodofilox 0.5% solution or gel 2times a day for 3 days, followed by4 days of no therapy, for a total ofup to 4 cycles, or imiquimod 5%cream at bedtime 3 times a weekfor up to 16 weeks. Cryotherapywith liquid nitrogen or cryoprobe,repeat every 1-2 weeks; orpodophyllin, repeat weekly; or TCA80-90%, repeat weekly; or surgicalremoval.Vaginal warts: cryotherapy withliquid nitrogen, or TCA 80-90%, orpodophyllin 10-25%

Humanimmuno-defi-ciencyvirus

Enzymeimmunoassay Western blot(for confirma-tion)Polymerasechain reac-tion

Antiretroviral agents

Treatment of Pelvic Inflammatory Disease

Regimen

Inpatient Outpatient

A Cefotetan (Cefotan) 2 gIV q12h; or cefoxitin(Mefoxin) 2 g IV q6hplus doxycycline 100mg IV or PO q12h.

Ofloxacin (Floxin) 400mg PO bid for 14 daysplus metronidazole 500mg PO bid for 14 days.

B Clindamycin 900 mg IVq8h plus gentamicinloading dose IV or IM (2mg/kg of body weight),followed by a mainte-nance dose (1.5 mg/kg)q8h.

Ceftriaxone (Rocephin)250 mg IM once; orcefoxitin 2 g IM plusprobenecid 1 g PO; orother parenteral third-generation cephalosporin(eg, ceftizoxime,cefotaxime) plusdoxycycline 100 mg PObid for 14 days.

I. Chlamydia TrachomatisA. Chlamydia trachomatis is the most prevalent STI in

the United States. Chlamydial infections are mostcommon in women age 15-19 years.

B. Routine screening of asymptomatic, sexually activeadolescent females undergoing pelvic examinationis recommended. Annual screening should bedone for women age 20-24 years who are eitherinconsistent users of barrier contraceptives or whoacquired a new sex partner or had more than onesexual partner in the past 3 months.

II. Gonorrhea. Gonorrhea has an incidence of 800,000cases annually. Routine screening for gonorrhea isrecommended among women at high risk of infection,including prostitutes, women with a history of repeatedepisodes of gonorrhea, women under age 25 yearswith two or more sex partners in the past year, andwomen with mucopurulent cervicitis.

III.SyphilisA. Syphilis has an incidence of 100,000 cases annu-

ally. The rates are highest in the South, amongAfrican Americans, and among those in the 20- to24-year-old age group.

B. Prostitutes, persons with other STIs, and sexualcontacts of persons with active syphilis should bescreened.

IV.Herpes simplex virus and human papillomavirusA. An estimated 200,000-500,000 new cases of

herpes simplex occur annually in the United States.New infections are most common in adolescentsand young adults.

B. Human papillomavirus affects about 30% of young,sexually active individuals.


VaginitisVaginitis is the most common gynecologic problemencountered by primary care physicians. It may resultfrom bacterial infections, fungal infection, protozoaninfection, contact dermatitis, atrophic vaginitis, or allergicreaction.

I. Clinical evaluation of vaginal symptomsA. The type and extent of symptoms, such as itching,

discharge, odor, or pelvic pain should be deter-mined. A change in sexual partners or sexualactivity, changes in contraception method, medica-tions (antibiotics), and history of prior genital infec-tions should be sought.

B. Physical examination1. Evaluation of the vagina should include close

inspection of the external genitalia for excoria-tions, ulcerations, blisters, papillary structures,erythema, edema, mucosal thinning, or mucosalpallor.

2. The color, texture, and odor of vaginal or cervicaldischarge should be noted.

C. Vaginal fluid pH can be determined by immersingpH paper in the vaginal discharge. A pH levelgreater than 4.5 indicates the presence of bacterialvaginosis or Trichomonas vaginalis.

D. Saline wet mount1. One swab should be used to obtain a sample

from the posterior vaginal fornix, obtaining a"clump" of discharge. Place the sample on aslide, add one drop of normal saline, and applya coverslip.

2. Coccoid bacteria and clue cells (bacteria-coated,stippled, epithelial cells) are characteristic ofbacterial vaginosis.

3. Trichomoniasis is confirmed by identification oftrichomonads – mobile, oval flagellates. Whiteblood cells are prevalent.

E. Potassium hydroxide (KOH) preparation1. Place a second sample on a slide, apply one

drop of 10% potassium hydroxide (KOH) and acoverslip. A pungent, fishy odor upon addition ofKOH – a positive whiff test – strongly indicatesbacterial vaginosis.

2. The KOH prep may reveal Candida in the form ofthread-like hyphae and budding yeast.

F. Screening for STDs. Testing for gonorrhea andchlamydial infection should be completed forwomen with a new sexual partner, purulent cervicaldischarge, or cervical motion tenderness.

II. Differential diagnosisA. The most common cause of vaginitis is bacterial

vaginosis, followed by Candida albicans. Theprevalence of trichomoniasis has declined in recentyears.

B. Common nonvaginal etiologies include contactdermatitis from spermicidal creams, latex in con-doms, or douching. Any STD can produce vaginaldischarge.

Clinical Manifestations of Vaginitis

Candidal Vagi-nitis

Nonmalodorous, thick, white, "cottagecheese-like" discharge that adheres tovaginal walls

Hyphal forms or budding yeast cells onwet-mountPruritusNormal pH (<4.5)

BacterialVaginosis

Thin, dark or dull grey, homogeneous,malodorous discharge that adheres tothe vaginal walls

Elevated pH level (>4.5) Positive KOH (whiff test) Clue cells on wet-mount microscopic

evaluation

TrichomonasVaginalis

Copious, yellow-gray or green, homoge-neous or frothy, malodorous discharge

Elevated pH level (>4.5)Mobile, flagellated organisms and leuko-

cytes on wet-mount microscopic eval-uation

Vulvovaginal irritation, dysuria

Atrophic Vagi-nitis

Vaginal dryness or burning

III. Yeast vaginitisA. Half of all women have had at least one episode

of yeast vaginitis. Candida albicans accounts for80% of yeast infections. The remaining 20% arecaused by Candida glabrata or Candida tropicalis.Pregnancy, oral contraceptives, antibiotics,diabetes and HIV infection are contributing fac-tors.

B. Diagnosis1. Typical symptoms are pruritus, thick vaginal

discharge, and genital irritation. Discharge isodorless and cottage cheese-like. Women maycomplain of dysuria.

2. Physical examination may reveal vulvar ery-thema and fissuring.

3. Laboratory evaluation of vaginal fluid reveals apH of less than 4.5 and the presence ofhyphae on 10% potassium hydroxide (KOH)wet mount. Elevations in pH also occur in thepresence of semen or blood.

4. Microscopy will reveal hyphae. The sensitivityof the KOH wet mount is only 50% to 70%.Therefore, treatment should be instituted evenwhen hyphae are absent but the clinical im-pression is otherwise consistent.

5. Culture should be considered if the diagnosisis in doubt or in recurrent cases. Dermatophytetest medium is sensitive yeast.

C. Treatment1. Uncomplicated vaginitis. These episodes can

be treated with any nonprescriptionshort-course (up to 7-day) preparation, sinceall are equally effective.

Treatment regimens for yeast vaginitis*

1-day regimensClotrimazole vaginal tablets (Mycelex G), 500 mg hs**Fluconazole tablets (Diflucan), 150 mg POItraconazole capsules (Sporanox), 200 mg PO bidTioconazole 6.5% vaginal ointment (Vagistat-1), 4.6 g hs**[5 g]

3-day regimensButoconazole nitrate 2% vaginal cream (Femstat 3), 5 g hs [28 g]Clotrimazole vaginal inserts (Gyne-Lotrimin 3), 200 mg hs**Miconazole vaginal suppositories (Monistat 3), 200 mg hs**Terconazole 0.8% vaginal cream (Terazol 3), 5 g hsTerconazole vaginal suppositories (Terazol 3), 80 mg hsItraconazole capsules (Sporanox), 200 mg PO qd (4)

5-day regimenKetoconazole tablets (Nizoral), 400 mg PO bid (4)

7-day regimensClotrimazole 1% cream (Gyne-Lotrimin, Mycelex-7,Sweet'n Fresh Clotrimazole-7), 5 g hs**Clotrimazole vaginal tablets (Gyne-Lotrimin, Mycelex-7,Sweet'n Fresh Clotrimazole-7), 100 mg hs**Miconazole 2% vaginal cream (Femizol-M, Monistat 7), 5 ghs**Miconazole vaginal suppositories (Monistat 7), 100 mg hs**Terconazole 0.4% vaginal cream (Terazol 7), 5 g hs

14-day regimensNystatin vaginal tablets (Mycostatin), 100,000 U hsBoric acid No. 0 gelatin vaginal suppositories, 600 mg bid(2)

*Suppositories can be used if inflammation is predomi-nantly vaginal; creams if vulvar; a combination if both.Cream-suppository combination packs available:clotrimazole (Gyne-Lotrimin, Mycelex); miconazole(Monistat, M-Zole). If diagnosis is in doubt, consider oraltherapy to avoid amelioration of symptoms with use ofcreams. Use 1-day or 3-day regimen if compliance is anissue. Miconazole nitrate may be used during pregnancy.

**Nonprescription formulation. If nonprescription therapiesfail, use terconazole 0.4% cream or 80-mg suppositories atbedtime for 7 days.

2. Complicated infections are more severe andcure is more difficult. With use of nonprescrip-tion preparations, the treatment course shouldbe longer (10 to 14 days). Since Candida spe-cies other than albicans may be more likely incomplicated infections, treatment withterconazole (Terazol) should be considered.Single-dose oral fluconazole should be avoided.

Management options for complicated or recur-rent yeast vaginitis

Extend any 7-day regimen to 10 to 14 daysEliminate use of nylon or tight-fitting clothing Consider discontinuing oral contraceptivesConsider eating 8 oz yogurt (with Lactobacillus acidophilus

culture) per day Improve glycemic control in diabetic patients For long-term suppression of recurrent vaginitis, use

ketoconazole, 100 mg (½ of 200-mg tablet) qd for 6months

D. Recurrent infection is defined as more than fourepisodes per year. Suppressive therapy for 6months is recommended after completion of 10 to14 days of a standard regimen. Oral ketoconazole,100 mg daily for 6 months, has been shown toreduce the recurrence rate to 5%. If the sexualpartner has balanitis, topical therapy should beprescribed.

IV. TrichomoniasisA. Trichomoniasis is responsible for less than 25% of

vaginal infections. The infection is caused byTrichomonas vaginalis, which is a sexually trans-mitted disease. Most men are asymptomatic.

B. Diagnosis1. A copious, watery discharge is common, and

some patients may notice an odor. Often fewsymptoms are present. Usually, the vulva andvaginal mucosa are free of signs of inflamma-tion. The discharge is thin and characterized byan elevated pH, usually 6 to 7. Occasionally,small punctate cervical hemorrhages withulcerations (strawberry cervix) are found.

2. Microscopic examination of vaginal fluid mixedwith saline solution (“wet prep”) shows anincreased number of leukocytes and motiletrichomonads. Microscopy has a sensitivity ofonly 50% to 70%. Trichomonads are some-times reported on Pap smears, butfalse-positive results are common.

3. Culture for identification of T vaginalis has asensitivity of 95% and should be performedwhen the clinical findings are consistent withtrichomoniasis but motile organisms are ab-sent. A rapid DNA probe test, which has asensitivity of 90% and a specificity of 99.8%,can also be used.

C. Treatment. Oral metronidazole (Flagyl, Protostat)is recommended. Treatment of male sexualpartners is recommended. Metronidazole gel(MetroGel-Vaginal) is less efficacious than oralantiinfective therapy. The single 2-g dose of oralmetronidazole can be used safely in any trimesterof pregnancy.

Treatment options for trichomoniasis

Initial measuresMetronidazole (Flagyl, Protostat), 2 g PO in a single dose,or metronidazole, 500 mg PO bid X 7 days, ormetronidazole, 375 mg PO bid X 7 daysTreat male sexual partners

Measures for treatment failureTreatment sexual contacts Re-treat with metronidazole, 500 mg PO bid X 7 days If infection persists, confirm with culture and re-treat withmetronidazole, 2-4 g PO qd X 3-10 days

V. Bacterial Vaginosis A. Bacterial vaginosis is a polymicrobial infection

caused by an overgrowth of anaerobic organisms.It is the most common cause of vaginitis, account-ing for 50% of cases. Gardnerella vaginalis hasbeen identified as one of the key organisms inbacterial vaginosis.

B. Diagnosis1. Most have vaginal discharge (90%) and foul

odor (70%). Typically there is a homogeneousvaginal discharge, pH higher than 4.5, “cluecells” (epithelial cells studded with coccobacillion microscopic examination, and a positive“whiff” test.

2. A specimen of vaginal discharge is obtained byspeculum, and the pH is determined before thespecimen is diluted. Next, the “whiff” test isperformed by adding several drops of 10%KOH to the specimen. The test is positive whena fishy odor is detected. Finally, the specimenis viewed by wet-mount microscopy.

C. Treatment consists of oral metronidazole, 500mg twice a day for 7 days. Common side effectsof metronidazole include nausea, anorexia,abdominal cramps, and a metallic taste. Alcoholmay cause a disulfiram-like reaction. Use ofsingle-dose metronidazole may result in a higherrecurrence rate and an increase in gastrointesti-nal side effects. Topical clindamycin is an option,but the cream may weaken latex condoms anddiaphragms.

VI. Other diagnoses causing vaginal symptomsA. One-third of patients with vaginal symptoms will

not have laboratory evidence of bacterialvaginosis, Candida, or Trichomonas. Othercauses of the vaginal symptoms include cervicitis,allergic reactions, and vulvodynia.

B. Atrophic vaginitis should be considered inpostmenopausal patients if the mucosa appearspale and thin and wet-mount findings are nega-tive.1. Oral estrogen (Premarin) 0.3 mg qd should

provide relief. 2. Vaginal ring estradiol (Estring), a silastic

ring impregnated with estradiol, is the pre-ferred means of delivering estrogen to thevagina. The silastic ring delivers 6 to 9 µg ofestradiol to the vagina daily. The rings arechanged once every three months. Concomi-tant progestin therapy is not necessary.

3. Conjugated estrogens (Premarin), 0.5 gm ofcream, or one-eighth of an applicatorful dailyinto the vagina for three weeks, followed bytwice weekly thereafter. Concomitant progestintherapy is not necessary.

4. Estrace cream (estradiol) can also by givenby vaginal applicator at a dose of one-eighth ofan applicator or 0.5 g (which contains 50 µg ofestradiol) daily into the vagina for three weeks,followed by twice weekly thereafter. Concomi-tant progestin therapy is not necessary.

C. Allergy and chemical irritation1. Patients should be questioned about use of

substances that cause allergic or chemicalirritation, such as deodorant soaps, laundry

detergent, vaginal contraceptives, bath oils,perfumed or dyed toilet paper, hot tub orswimming pool chemicals, and synthetic cloth-ing.

2. Topical steroids and systemic antihistaminescan help alleviate the symptoms.


Breast Cancer Screening and Diag-nosis Breast cancer is the second most commonly diagnosedcancer among women, after skin cancer. Approximately182,800 new cases of invasive breast cancer are diag-nosed in the United States per year. The incidence ofbreast cancer increases with age. White women aremore likely to develop breast cancer than black women.The incidence of breast cancer in white women is about113 cases per 100,000 women and in black women, 100cases per 100,000.

I. Risk factors

Risk Factors for Breast Cancer

Age greater than 50 yearsPrior history of breastcancerFamily historyEarly menarche, beforeage 12Late menopause, afterage 50Nulliparity

Age greater than 30 atfirst birthObesityHigh socioeconomic sta-tusAtypical hyperplasia onbiopsyIonizing radiation expo-sure

A. Family history is highly significant in a first-degreerelative (ie, mother, sister, daughter), especially ifthe cancer has been diagnosed premenopausally.Women who have premenopausal first-degreerelatives with breast cancer have a three- tofourfold increased risk of breast cancer. Havingseveral second-degree relatives with breast can-cer may further increase the risk of breast cancer.Most women with breast cancer have no identifi-able risk factors.

B. Approximately 8 percent of all cases of breastcancer are hereditary. About one-half of thesecases are attributed to mutations in the BRCA1and BRCA2 genes. Hereditary breast cancercommonly occurs in premenopausal women.Screening tests are available that detect BRCAmutations.

II. Diagnosis and evaluationA. Clinical evaluation of a breast mass should

assess duration of the lesion, associated pain,relationship to the menstrual cycle or exogenoushormone use, and change in size since discovery.The presence of nipple discharge and its character(bloody or tea-colored, unilateral or bilateral,spontaneous or expressed) should be assessed.

B. Menstrual history. The date of last menstrualperiod, age of menarche, age of menopause orsurgical removal of the ovaries, previous pregnan-cies should be determined.

C. History of previous breast biopsies, cyst aspira-tion, dates and results of previous mammogramsshould be determined.

D. Family history should document breast cancer inrelatives and the age at which family memberswere diagnosed.

III. Physical examinationA. The breasts should be inspected for asymmetry,

deformity, skin retraction, erythema, peau d'orange(breast edema), and nipple retraction, discolor-ation, or inversion.

B. Palpation1. The breasts should be palpated while the

patient is sitting and then supine with theipsilateral arm extended. The entire breastshould be palpated systematically. The massshould be evaluated for size, shape, texture,tenderness, fixation to skin or chest wall.

2. A mass that is suspicious for breast cancer isusually solitary, discrete and hard. In someinstances, it is fixed to the skin or the muscle.A suspicious mass is usually unilateral andnontender. Sometimes, an area of thickeningmay represent cancer. Breast cancer is rarelybilateral. The nipples should be expressed fordischarge.

3. The axillae should be palpated for adenopathy,with an assessment of size of the lymph nodes,number, and fixation.

IV. Mammography. Screening mammograms are recom-mended every year for asymptomatic women 40 yearsand older. Unfortunately, only 60 percent of cancersare diagnosed at a local stage.

Screening for Breast Cancer in Women

Age American Cancer Society guide-lines

20 to 39 years Clinical breast examination everythree yearsMonthly self-examination of breasts

Age 40 yearsand older

Annual mammogramAnnual clinical breast examinationMonthly self-examination of breasts

V. Methods of breast biopsyA. Palpable masses. Fine-needle aspiration bi-

opsy (FNAB) has a sensitivity ranging from 90-98%. Nondiagnostic aspirates require surgicalbiopsy.1. The skin is prepped with alcohol and the lesion

is immobilized with the nonoperating hand. A10 mL syringe, with a 14 gauge needle, isintroduced in to the central portion of the massat a 90° angle. When the needle enters themass, suction is applied by retracting theplunger, and the needle is advanced. Theneedle is directed into different areas of themass while maintaining suction on the syringe.

2. Suction is slowly released before the needle iswithdrawn from the mass. The contents of theneedle are placed onto glass slides for patho-logic examination.

3. Excisional biopsy is done when needle biopsiesare negative but the mass is clinically sus-pected of malignancy.

B. Stereotactic core needle biopsy. Using acomputer-driven stereotactic unit, the lesion islocalized in three dimensions, and an automatedbiopsy needle obtains samples. The sensitivity andspecificity of this technique are 95-100% and 94-98%, respectively.

C. Nonpalpable lesions1. Needle localized biopsy

a. Under mammographic guidance, a needleand hookwire are placed into the breastparenchyma adjacent to the lesion. Thepatient is taken to the operating room alongwith mammograms for an excisional breastbiopsy.

b.The skin and underlying tissues are infil-trated with 1% lidocaine with epinephrine.For lesions located within 5 cm of the nipple,a periareolar incision may be used or use acurved incision located over the mass andparallel to the areola. Incise the skin andsubcutaneous fat, then palpate the lesionand excise the mass.

c. After removal of the specimen, a specimenx-ray is performed to confirm that the lesionhas been removed. The specimen can thenbe sent fresh for pathologic analysis.

d.Close the subcutaneous tissues with a 4-0chromic catgut suture, and close the skinwith 4-0 subcuticular suture.

D. Ultrasonography. Screening is useful to differenti-ate between solid and cystic breast masses whena palpable mass is not well seen on amammogram. Ultrasonography is especiallyhelpful in young women with dense breast tissuewhen a palpable mass is not visualized on amammogram. Ultrasonography is not used forroutine screening because microcalcifications arenot visualized and the yield of carcinomas isnegligible.


Secondary AmenorrheaAmenorrhea (absence of menses) can be a transient,intermittent, or permanent condition resulting fromdysfunction of the hypothalamus, pituitary, ovaries,uterus, or vagina. Amenorrhea is classified as eitherprimary (absence of menarche by age 16 years) orsecondary (absence of menses for more than three

cycles or six months in women who previously hadmenses). Pregnancy is the most common cause ofsecondary amenorrhea.

I. Diagnosis of secondary amenorhea A. Step 1: Rule out pregnancy. A pregnancy test is

the first step in evaluating secondary amenorrhea.Measurement of serum beta subunit of hCG is themost sensitive test.

B. Step 2: Assess the history1. Recent stress; change in weight, diet or exercise

habits; or illnesses that might result in hypotha-lamic amenorrhea should be sought.

2. Drugs associated with amenorrhea, systemicillnesses that can cause hypothalamicamenorrhea, recent initiation or discontinuationof an oral contraceptive, androgenic drugs(danazol) or high-dose progestin, andantipsychotic drugs should be evaluated.

3. Headaches, visual field defects, fatigue, orpolyuria and polydipsia may suggesthypothalamic-pituitary disease.

4. Symptoms of estrogen deficiency include hotflashes, vaginal dryness, poor sleep, or de-creased libido.

5. G a l a c t o r r h e a i s s u g g e s t i v e o fhyperprolactinemia. Hirsutism, acne, and ahistory of irregular menses are suggestive ofhyperandrogenism.

6. A history of obstetrical catastrophe, severebleeding, dilatation and curettage, orendometritis or other infection that might havecaused scarring of the endometrial lining sug-gests Asherman's syndrome.

Causes of Primary and Secondary Amenorrhea

Abnormality Causes

Pregnancy

Anatomic abnormalities

Congenital abnormalityin Mullerian develop-ment

Isolated defectTesticular feminization syn-drome5-Alpha-reductase defi-ciencyVanishing testes syndromeDefect in testis determiningfactor

Congenital defect ofurogenital sinus devel-opment

Agenesis of lower vaginaImperforate hymen

Acquired ablation orscarring of theendometrium

Asherman’s syndromeTuberculosis

Disorders ofhypothalamic-pituitaryovarian axis

Hypothalamic dysfunc-tionPituitary dysfunctionOvarian dysfunction

Causes of Amenorrhea due to Abnormalities inthe Hypothalamic-Pituitary-Ovarian Axis

Abnormality Causes

Hypothalamic dys-function

Functional hypothalamicamenorrhea

Weight loss, eating disordersExerciseStressSevere or prolonged illness

Congenital gonadotropin-releas-ing hormone deficiencyInflammatory or infiltrative dis-easesBrain tumors - eg,craniopharyngiomaPituitary stalk dissection or com-pressionCranial irradiationBrain injury - trauma, hemor-rhage, hydrocephalusOther syndromes - Prader-Willi,Laurence-Moon-Biedl

Pituitary dysfunction HyperprolactinemiaOther pituitary tumors-acromegaly, corticotrophadenomas (Cushing's disease)Other tumors - meningioma,germinoma, gliomaEmpty sella syndromePituitary infarct or apoplexy

Ovarian dysfunction Ovarian failure (menopause)SpontaneousPremature (before age 40years)Surgical

Other HyperthyroidismHypothyroidismDiabetes mellitusExogenous androgen use

Drugs Associated with Amenorrhea

Drugs that In-crease Prolactin

AntipsychoticsTricyclic antidepressantsCalcium channel blockers

Drugs with Estro-genic Activity

Digoxin, marijuana, oral contra-ceptives

Drugs with OvarianToxicity

Chemotherapeutic agents

C. Step 3: Physical examination. Measurements ofheight and weight, signs of other illnesses, andevidence of cachexia should be assessed. Theskin, breasts, and genital tissues should be evalu-ated for estrogen deficiency. The breasts shouldbe palpated, including an attempt to expressgalactorrhea. The skin should be examined forhirsutism, acne, striae, acanthosis nigricans,vitiligo, thickness or thinness, and easy bruisability.

D. Step 4: Basic laboratory testing. In addition tomeasurement of serum hCG to rule out pregnancy,minimal laboratory testing should include measure-ments of serum prolactin, thyrotropin, and FSH torule out hyperprolactinemia, thyroid disease, andovarian failure (high serum FSH). If there ishirsutism, acne or irregular menses, serumdehydroepiandrosterone sulfate (DHEA-S) andtestosterone should be measured.

E. Step 5: Follow-up laboratory evaluation1. High serum prolactin concentration.

Prolactin secretion can be transiently increasedby stress or eating. Therefore, serum prolactinshould be measured at least twice before cra-nial imaging is obtained, particularly in thosewomen with small elevations (<50 ng/mL).These women should be screened for thyroiddisease with a TSH and free T4 becausehypothyroidism can cause hyperprolactinemia.

2. Women with verified high serum prolactinvalues should have a cranial MRI unless a veryclear explanation is found for the elevation (eg,antipsychotics). Imaging should rule out ahypothalamic or pituitary tumor.

3. High serum FSH concentration. A high serumFSH concentration indicates the presence ofovarian failure. This test should be repeatedmonthly on three occasions to confirm. Akaryotype should be considered in most womenwith secondary amenorrhea age 30 years oryounger.

4. High serum androgen concentrations. A highserum androgen value may suggest the diagno-sis of polycystic ovary syndrome or may suggestan androgen-secreting tumor of the ovary oradrenal gland. Further testing for a tumor mightinclude a 24-hour urine collection for cortisoland 17-ketosteroids, determination of serum 17-hydroxyprogesterone after intravenous injectionof corticotropin (ACTH), and a dexamethasonesuppression test. Elevation of 17-ketosteroids,DHEA-S, or 17-hydroxyprogesterone is moreconsistent with an adrenal, rather than ovarian,source of excess androgen.

5. Normal or low serum gonadotropin concen-trations and all other tests normal a. This result is one of the most common out-

comes of laboratory testing in women withamenorrhea. Women with hypothalamicamenorrhea (caused by marked exercise orweight loss to more than 10 percent belowthe expected weight) have normal to lowserum FSH values. Cranial MRI is indicatedin all women without an a clear explanationfor hypogonadotropic hypogonadism and inmost women who have visual field defects orheadaches. No further testing is required ifthe onset of amenorrhea is recent or is easilyexplained (eg, weight loss, excessive exer-cise) and there are no symptoms suggestiveof other disease.

b. High serum transferrin saturation may indi-cate hemochromatosis, high serumangiotensin-converting enzyme values sug-gest sarcoidosis, and high fasting bloodglucose or hemoglobin A1c values indicatediabetes mellitus.

6. Normal serum prolactin and FSH concentra-tions with history of uterine instrumentationpreceding amenorrheaa. Evaluation for Asherman's syndrome should

be completed. A progestin challenge shouldbe performed (medroxyprogesterone acetate10 mg for 10 days). If withdrawal bleedingoccurs, an outflow tract disorder has beenruled out. If bleeding does not occur, estro-gen and progestin should be administered.

b. Oral conjugated estrogens (0.625 to 2.5 mgdaily for 35 days) with medroxyprogesteroneadded (10 mg daily for days 26 to 35); failureto bleed upon cessation of this therapystrongly suggests endometrial scarring. Inthis situation, a hysterosalpingogram orhysteroscopy can confirm the diagnosis ofAsherman syndrome.

II. Treatment A. Athletic women should be counseled on the need

for increased caloric intake or reduced exercise.Resumption of menses usually occurs.

B. Nonathletic women who are underweightshould receive nutritional counseling and treatmentof eating disorders.

C. Hyperprolactinemia is treated with a dopamineagonist. Cabergoline (Dostinex) or bromocriptine(Parlodel) are used for most adenomas. Ovulation,regular menstrual cycles, and pregnancy mayusually result.

D. Ovarian failure should be treated with hormonereplacement therapy.

E. Hyperandrogenism is treated with measures toreduce hirsutism, resume menses, and fertility andpreventing endometrial hyperplasia, obesity, andmetabolic defects.

F. Asherman's syndrome is treated withhysteroscopic lysis of adhesions followed by long-term estrogen administration to stimulate regrowthof endometrial tissue.


Abnormal Vaginal BleedingMenorrhagia (excessive bleeding) is most commonlycaused by anovulatory menstrual cycles. Occasionally itis caused by thyroid dysfunction, infections or cancer.

I. Pathophysiology of normal menstruationA. In response to gonadotropin-releasing hormone

from the hypothalamus, the pituitary gland synthe-sizes follicle-stimulating hormone (FSH) andluteinizing hormone (LH), which induce the ovariesto produce estrogen and progesterone.

B. During the follicular phase, estrogen stimulationcauses an increase in endometrial thickness. After

ovulation, progesterone causes endometrial matu-ration. Menstruation is caused by estrogen andprogesterone withdrawal.

C. Abnormal bleeding is defined as bleeding thatoccurs at intervals of less than 21 days, more than36 days, lasting longer than 7 days, or blood lossgreater than 80 mL.

II. Clinical evaluation of abnormal vaginal bleedingA. A menstrual and reproductive history should in-

clude last menstrual period, regularity, duration,frequency; the number of pads used per day, andintermenstrual bleeding.

B. Stress, exercise, weight changes and systemicdiseases, particularly thyroid, renal or hepaticdiseases or coagulopathies, should be sought. Themethod of birth control should be determined.

C. Pregnancy complications, such as spontaneousabortion, ectopic pregnancy, placenta previa andabruptio placentae, can cause heavy bleeding.Pregnancy should always be considered as apossible cause of abnormal vaginal bleeding.

III. Puberty and adolescence--menarche to age 16A. Irregularity is normal during the first few months of

menstruation; however, soaking more than 25 padsor 30 tampons during a menstrual period is abnor-mal.

B. Absence of premenstrual symptoms (breast tender-ness, bloating, cramping) is associated withanovulatory cycles.

C. Fever, particularly in association with pelvic orabdominal pain may, indicate pelvic inflammatorydisease. A history of easy bruising suggests acoagulation defect. Headaches and visual changessuggest a pituitary tumor.

D. Physical findings1. Pallor not associated with tachycardia or signs

of hypovolemia suggests chronic excessiveblood loss secondary to anovulatory bleeding,adenomyosis, uterine myomas, or blooddyscrasia.

2. Fever, leukocytosis, and pelvic tendernesssuggests PID.

3. Signs of impending shock indicate that theblood loss is related to pregnancy (includingectopic), trauma, sepsis, or neoplasia.

4. Pelvic masses may represent pregnancy, uter-ine or ovarian neoplasia, or a pelvic abscess orhematoma.

5. Fine, thinning hair, and hypoactive reflexessuggest hypothyroidism.

6. Ecchymoses or multiple bruises may indicatetrauma, coagulation defects, medication use, ordietary extremes.

E. Laboratory tests1. CBC and platelet count and a urine or serum

pregnancy test should be obtained.2. Screening for sexually transmitted diseases,

thyroid function, and coagulation disorders(partial thromboplastin time, INR, bleeding time)should be completed.

3. Endometrial sampling is rarely necessary forthose under age 20.

F. Treatment of infrequent bleeding1. Therapy should be directed at the underlying

cause when possible. If the CBC and otherinitial laboratory tests are normal and the historyand physical examination are normal, reassur-ance is usually all that is necessary.

2. Ferrous gluconate, 325 mg bid-tid, should beprescribed.

G. Treatment of frequent or heavy bleeding1. Treatment with nonsteroidal anti-inflammatory

drugs (NSAIDs) improves platelet aggregationand increases uterine vasoconstriction. NSAIDsare the first choice in the treatment ofmenorrhagia because they are well toleratedand do not have the hormonal effects of oralcontraceptives.a. Mefenamic acid (Ponstel) 500 mg tid during

the menstrual period.b. Naproxen (Anaprox, Naprosyn) 500 mg

loading dose, then 250 mg tid during themenstrual period.

c. Ibuprofen (Motrin, Nuprin) 400 mg tidduring the menstrual period.

d. Gastrointestinal distress is common. NSAIDsare contraindicated in renal failure and pepticulcer disease.

2. Iron should also be added as ferrous gluconate325 mg tid.

H. Patients with hypovolemia or a hemoglobinlevel below 7 g/dL should be hospitalized forhormonal therapy and iron replacement.

1. Hormonal therapy consists of estrogen(Premarin) 25 mg IV q6h until bleeding stops.Thereafter, oral contraceptive pills should beadministered q6h x 7 days, then taper slowly toone pill qd.

2. If bleeding continues, IV vasopressin (DDAVP)should be administered. Hysteroscopy may benecessary, and dilation and curettage is a lastresort. Transfusion may be indicated in severehemorrhage.


IV. Primary childbearing years – ages 16 to early40s

A. Contraceptive complications and pregnancy are themost common causes of abnormal bleeding in thisage group. Anovulation accounts for 20% of cases.

B. Adenomyosis, endometriosis, and fibroids increasein frequency as a woman ages, as do endometrialhyperplasia and endometrial polyps. Pelvic inflam-matory disease and endocrine dysfunction mayalso occur.

C. Laboratory tests1. CBC and platelet count, Pap smear, and preg-

nancy test.2. Screening for sexually transmitted diseases,

thyroid-stimulating hormone, and coagulationdisorders (partial thromboplastin time, INR,bleeding time).

3. If a non-pregnant woman has a pelvic mass,ultrasonography or hysterosonography (withuterine saline infusion) is required.

D. Endometrial sampling1. Long-term unopposed estrogen stimulation in

anovulatory patients can result in endometrialhyperplasia, which can progress to adeno-carcinoma; therefore, in perimenopausal pa-tients who have been anovulatory for an ex-tended interval, the endometrium should bebiopsied.

2. Biopsy is also recommended before initiation ofhormonal therapy for women over age 30 andfor those over age 20 who have had prolongedbleeding.

3. Hysteroscopy and endometrial biopsy with aPipelle aspirator should be done on the first dayof menstruation (to avoid an unexpected preg-nancy) or anytime if bleeding is continuous.

E. Treatment1. Medical protocols for anovulatory bleeding

(dysfunctional uterine bleeding) are similar tothose described above for adolescents.

2. Hormonal therapya. In women who do not desire immediate

fertility, hormonal therapy may be used totreat menorrhagia.

b. A 21-day package of oral contraceptives isused. The patient should take one pill threetimes a day for 7 days. During the 7 days oftherapy, bleeding should subside, and,following treatment, heavy flow will occur.After 7 days off the hormones, another 21-day package is initiated, taking one pill eachday for 21 days, then no pills for 7 days.

c. Alternatively, medroxyprogesterone(Provera), 10-20 mg per day for days 16through 25 of each month, will result in areduction of menstrual blood loss. Pregnancywill not be prevented.

d. Patients with severe bleeding may havehypotension and tachycardia. These patientsrequire hospitalization, and estrogen(Premarin) should be administered IV as 25mg q4-6h until bleeding slows (up to a maxi-mum of four doses). Oral contraceptivesshould be initiated concurrently as describedabove.


4. Surgical treatment can be considered if child-bearing is completed and medical managementfails to provide relief.

V. Premenopausal, perimenopausal, andpostmenopausal years--age 40 and overA. Anovulatory bleeding accounts for about 90% of

abnormal vaginal bleeding in this age group.However, bleeding should be considered to befrom cancer until proven otherwise.

B. History, physical examination and laboratorytesting are indicated as described above. Meno-pausal symptoms, personal or family history ofmalignancy and use of estrogen should be

sought. A pelvic mass requires an evaluation withultrasonography.

C. Endometrial carcinoma1. In a perimenopausal or postmenopausal wom-

an, amenorrhea preceding abnormal bleedingsuggests endometrial cancer. Endometrialevaluation is necessary before treatment ofabnormal vaginal bleeding.

2. Before endometrial sampling, determination ofendometrial thickness by transvaginalultrasonography is useful because biopsy isoften not required when the endometrium isless than 5 mm thick.

D. Treatment1. Cystic hyperplasia or endometrial hyperplasia

without cytologic atypia is treated with depo-medroxyprogesterone, 200 mg IM, then 100 to200 mg IM every 3 to 4 weeks for 6 to 12months. Endometrial hyperplasia requiresrepeat endometrial biopsy every 3 to 6 months.

2. Atypical hyperplasia requires fractional dilationand curettage, followed by progestin therapy orhysterectomy.

3. If the patient's endometrium is normal (oratrophic) and contraception is a concern, a low-dose oral contraceptive may be used. If contra-ception is not needed, estrogen and progester-one therapy should be prescribed.

4. Surgical managementa. Vaginal or abdominal hysterectomy is the

most absolute curative treatment.b. Dilatation and curettage can be used as a

temporizing measure to stop bleeding.c. Endometrial ablation and resection by

laser, electrodiathermy “rollerball,” orexcisional resection are alternatives tohysterectomy.


MenopauseMenopause is defined as the cessation of menstrualperiods in women. The average age of menopause is 51years, with a range of 41-55. The diagnosis of meno-pause is made by the presence of amenorrhea for six totwelve months, together with the occurrence of hotflashes. If the diagnosis is in doubt, menopause isindicated by an elevated follicle-stimulating hormone(FSH) level greater than 40 mlU/mL.

I. Perimenopausal transition is defined as the two toeight years preceding menopause and the one yearafter the last menstrual period. It is characterized bynormal ovulatory cycles interspersed with anovulatory(estrogen-only) cycles. As a result, menses becomeirregular, and heavy breakthrough bleeding, termeddysfunctional uterine bleeding, can occur duringlonger periods of anovulation.

II. Effects of estrogen deficiency after menopauseA. Hot flashes. The most common acute change

during menopause is the hot flash, which occurs in75 percent of women. About 50 to 75 percent ofwomen have cessation of hot flashes within fiveyears. Hot flashes typically begin as a suddensensation of heat centered on the face and upperchest that rapidly becomes generalized. Thesensation lasts from two to four minutes and isoften associated with profuse perspiration. Hotflashes occur several times per day.

B. Sexual function. Estrogen deficiency leads to adecrease in blood flow to the vagina and vulva.This decrease is a major cause of decreasedvaginal lubrication, dyspareunia, and decreasedsexual function in menopausal women.

C. Urinary incontinence. Menopause results inatrophy of the urethral epithelium with subsequentatrophic urethritis and irritation; these changespredispose to both stress and urge urinary inconti-nence.

D. Osteoporosis. A long-term consequence of estro-gen deficiency is the development of osteoporosisand fractures. Bone loss exceeds bone reforma-tion. Between 1 and 5 percent of the skeletal masscan be lost per year in the first several years afterthe menopause. Osteoporosis may occur in as littleas ten years.

E. Cardiovascular disease. The incidence of myo-cardial infarction in women, although lower than inmen, increases dramatically after the menopause.

III.Estrogen replacement therapyA. Data from the WHI and the HERS trials has deter-

mined that continuous estrogen-progestin therapy

does not appear to protect against cardiovasculardisease and increases the risk of breast cancer,coronary heart disease, stroke, and venousthromboembolism over an average follow-up of 5.2years. As a result, the primary indication for estro-gen therapy is for control of menopausal symp-toms, such as hot flashes.

IV. Prevention and treatment of osteoporosisA. Screening for osteoporosis. Measurement of

BMD is recommended for all women 65 years andolder regardless of risk factors. BMD should alsobe measured in all women under the age of 65years who have one or more risk factors for osteo-porosis (in addition to menopause). The hip is therecommended site of measurement.

B. Bisphosphonates1. Alendronate (Fosamax) has effects compara-

ble to those of estrogen for both the treatmentof osteoporosis (10 mg/day or 70 mg once aweek) and for its prevention (5 mg/day).Alendronate (in a dose of 5 mg/day or 35mg/week) can also prevent osteoporosis inpostmenopausal women.

2. Risedronate (Actonel), a bisphosphonate, hasbeen approved for prevention and treatment ofosteoporosis at doses of 5 mg/day or 35 mgonce per week. Its efficacy and side effectprofile are similar to those of alendronate.

C. Raloxifene (Evista) is a selective estrogen recep-tor modulator. It is available for prevention andtreatment of osteoporosis. At a dose of 60 mg/day,bone density increases by 2.4 percent in the lum-bar spine and hip over a two year period. Thiseffect is slightly less than with bisphosphonates.

D. Calcium. Maintaining a positive calcium balance inpostmenopausal women requires a daily intake of1500 mg of elemental calcium; to meet this mostwomen require a supplement of 1000 mg daily.

E. Vitamin D. All postmenopausal women should takea multivitamin containing at least 400 IU vitamin Ddaily.

F. Exercise for at least 20 minutes daily reduces therate of bone loss. Weight bearing exercises arepreferable.

V. Treatment of hot flashes and vasomotor instabilityA. The manifestations of vasomotor instability are hot

flashes, sleep disturbances, headache, and irritabil-ity. Most women with severe vasomotor instabilityaccept short-term estrogen therapy for thesesymptoms.

B. Short-term estrogen therapy for relief of vaso-motor instability and hot flashes1. Short-term estrogen therapy remains the best

treatment for relief of menopausal symptoms,and therefore is recommended for mostpostmenopausal women, with the exception ofthose with a history of breast cancer, CHD, aprevious venous thromboembolic event orstroke, or those at high risk for these complica-tions. Short-term therapy is continued for sixmonths to four or five years. Administration ofestrogen short-term is not associated with anincreased risk of breast cancer.

2. Low dose estrogen is recommended (eg, 0.3mg conjugated estrogens [Premarin] daily or 0.5mg estradiol [Estrace] daily). These doses areadequate for symptom management and pre-vention of bone loss.

3. Endometrial hyperplasia and cancer can occurafter as little as six months of unopposed estro-gen therapy; as a result, a progestin must beadded in those women who have not had ahysterectomy. Medroxyprogesterone (Provera),2.5 mg, is usually given every day of the month.

4. After the planned treatment interval, the estro-gen should be discontinued gradually to mini-mize recurrence of the menopausal symptoms,for example, by omitting one pill per week (6pills per week, 5 pills per week, 4 pills perweek).

C. Treatment of vasomotor instability in womennot taking estrogen1. Selective serotonin reuptake inhibitors

(SSRIs) also relieve the symptoms of vasomotorinstability. a. Venlafaxine (Effexor), at doses of 75 mg

daily, reduces hot flashes by 61 percent.Mouth dryness, anorexia, nausea, and con-stipation are common.

b. Paroxetine (Zoloft), 50 mg per day, relievesvasomotor instability.

c. Fluoxetine (Prozac) 20 mg per day also hasbeneficial effects of a lesser magnitude.

2. Clonidine (Catapres) relieves hot flashes in80%. In a woman with hypertension, clonidinemight be considered as initial therapy. It isusually given as a patch containing 2.5 mg perweek. Clonidine also may be given orally indoses of 0.1 to 0.4 mg daily. Side effects oftenlimit the use and include dry mouth, dizziness,constipation, and sedation.

3. Megestrol acetate (Megace) is a syntheticprogestin which decreases the frequency of hotflashes by 85 percent at a dose of 40 to 80 mgPO daily. Weight gain is the major side effect.

VI. Treatment of urogenital atrophyA. Loss of estrogen causes atrophy of the vaginal

epithelium and results in vaginal irritation anddryness, dyspareunia, and an increase in vaginalinfections. Systemic estrogen therapy results inrelief of symptoms.

B. Treatment of urogenital atrophy in women nottaking systemic estrogen1. Moisturizers and lubricants. Regular use of a

vaginal moisturizing agent (Replens) and lubri-cants during intercourse are helpful. Watersoluble lubricants such as Astroglide are moreeffective than lubricants that become moreviscous after application such as K-Y jelly. Amore effective treatment is vaginal estrogentherapy.

2. Low-dose vaginal estrogena. Vaginal ring estradiol (Estring), a silastic

ring impregnated with estradiol, is the pre-ferred means of delivering estrogen to thevagina. The silastic ring delivers 6 to 9 µg ofestradiol to the vagina daily for a period ofthree months. The rings are changed onceevery three months by the patient. Concomi-tant progestin therapy is not necessary.

b. Conjugated estrogens (Premarin), 0.5 gmof cream, or one-eighth of an applicatorfuldaily into the vagina for three weeks, fol-lowed by twice weekly thereafter. Concomi-tant progestin therapy is not necessary.

c. Estrace cream (estradiol) can also bygiven by vaginal applicator at a dose of one-eighth of an applicator or 0.5 g (which con-tains 50 µg of estradiol) daily into the vaginafor three weeks, followed by twice weeklythereafter. Concomitant progestin therapy isnot necessary.

d. Estradiol (Vagifem). A tablet containing 25micrograms of estradiol is available and isinserted into the vagina twice per week.Concomitant progestin therapy is not neces-sary.


Urologic Disorders

Erectile DysfunctionErectile dysfunction is defined as the persistent inabilityto achieve or maintain penile erection sufficient forsexual intercourse. Between the ages of 40 and 70years, the probability of complete erectile dysfunctiontriples from 5.1 percent to 15 percent.

I. Physiology of erectionA. Penile erection is mediated by the parasympathetic

nervous system, which when stimulated causesarterial dilation and relaxation of the cavernosalsmooth muscle. The increased blood flow into thecorpora cavernosa in association with reducedvenous outflow results in penile rigidity.

B. Nitric oxide is a chemical mediator of erection. Thissubstance is released from nerve endings andvascular endothelium, causing smooth musclerelaxation, resulting in venous engorgement andpenile tumescence.

Causes of Erectile Dysfunction and DiagnosticClues

Cause History

PhysicalExamina-tion

Possible lab-oratory find-ings

Vas-cular

Coronary ar-tery disease;hypertension;claudication;dyslipidemia;smoking

Decreasedpulses;bruits; ele-vated bloodpressure;cool extremi-ties

Abnormallipid profileAbnormalpenile-brachial pres-sure index

Dia-betesmellitus

Diabetes;polyuria;polydipsia;polyphagia

Peripheralneuropathy;retinopathy;obesity

Abnormalfasting bloodglucoseElevatedglycosylatedhemoglobinProteinuriaGlycosuriaHypertriglyceridemia

Hypogonad-ism

Decreasedlibido; fatigue

Bilateraltesticularatrophy;scant bodyhair;gynecomastia

Decreasedfree testoster-oneIncreased LHIncreasedFSH

Hyperpro-lactinemia

Decreasedlibido;galactorrhea;visual com-plaints; head-ache

Bitemporalhemianopsia

ElevatedprolactinAbnormal CTor MRI scansof pituitarygland

Hypothy-roidism

Fatigue; coldintolerance

Goiter;myxedema;dry skin;coarse hair

Increased TSHDecreasedfree T4

Hyperthy-roid-ism

Heat intoler-ance; weightloss;diaphoresis;palpitations

Lid lag;exophthalmos;hyperreflexia; tremor;tachycardia

Decreased TSHIncreasedfree T4

Cush-ing'ssyn-drome

Easy bruising;weight gain;corticosteroiduse

Truncal obe-sity; "moonface"; "buf-falo hump";striae

Elevatedovernightdexametha-sone sup-pression test

Alco-holism

Excessivealcohol use;social, eco-nomic or oc-cupationalconsequencesof alcoholabuse; with-drawal symp-toms

Positivescreen; thinbodyhabitus; pal-mar ery-thema; spi-dertelangiectasias;gynecomastia; tremor

AbnormalhepatictransaminasesDecreasedalbuminMacrocyticanemia

Cause History

PhysicalExamina-tion

Possible lab-oratory find-ings

Neu-rologic

Spinal cordinjury; nerveinjury (pros-tate surgery);stroke; periph-eral neuropa-thy; inconti-nence; multi-ple sclerosis;Parkinson'sdisease

Motor orsensory defi-cits; aphasia;gait abnor-mality; ab-normalbulbocaver-nosus reflex;tremor

Me-chanical

Genitaltrauma or sur-gery; Peyro-nie's disease;congenitalabnormalities

Fibrouspenileplaques orchordae

None

Psychogenic

Nocturnalerections;sudden onset;history of de-pression;anhedonia;poor relation-ship with part-ner; anxiety;life crisis

Sad or with-drawn affect;tearful; psy-chomotorretardation;depression

Nocturnalpenile tumes-cence (stamptest; Snap-Gauge)

Pharmacologic

Inquire aboutall prescriptionand nonpre-scription drugs

II. History and physical examinationA. The history should include the frequency and

duration of symptoms, the presence or absence ofmorning erections, and the quality of the relation-ship with the sexual partner. The sudden onset oferectile dysfunction in association with normalmorning erections or a poor relationship suggestspsychogenic impotence. Chronic disease such asatherosclerosis, hypertension or diabetes mellitusshould be sought. Decreased libido and symptomsof hypothyroidism should be evaluated.

B. Common pharmacologic causes of erectile dys-function include antihypertensive drugs, mostnotably the centrally acting agents, beta-blockersand diuretics. Antipsychotic and antidepressantdrugs are also frequently implicated. Excessivealcohol intake, heroin use and cigarette smokingare common causes.

C. Physical examination. Signs of hypogonadism,such as gynecomastia or the loss of axillary andpubic hair, should be noted. The size and consis-tency of the testes should be noted. The penisshould be examined for fibrosis and plaquesindicative of Peyronie's disease. Thebulbocavernosus and cremasteric reflexes shouldbe assessed. The bulbocavernosus reflex iselicited by squeezing the glans penis while observ-ing for contraction of the external anal sphincter.

Agents That May Cause Erectile Dysfunction

Antidepressants Monoamine oxidaseinhibitors Selective serotoninreuptake inhibitors Tricyclic antidepres-sants

Antihypertensives Beta blockers Centrally acting alphaagonists Diuretics

Antipsychotics Anxiolytics

Miscellaneous Cimetidine (Tagamet) Corticosteroids Finasteride (Proscar) Gemfibrozil (Lopid)

Drugs of abuse Alcohol Anabolic steroids Heroin Marijuana

III. Laboratory testsA. A urinalysis, complete blood count and basic

chemistry panel will help to rule out most meta-bolic and renal diseases. In elderly men, thyroid-stimulating hormone level should be measured torule out thyroid dysfunction. A free testosteronelevel should be obtained in all men aged 50 andolder and in those younger than 50 who havesymptoms or signs of hypogonadism (eg, de-creased libido, testicular atrophy, reduced amountof body hair).

B. The prolactin level should be measured if the freetestosterone level is low, the patient has a sub-stantial loss of libido, or if a prolactinoma is sus-

pected on the basis of a history of headache withvisual field cuts. Luteinizing hormone level isreserved for use in distinguishing primary fromsecondary hypogonadism in men with low testos-terone levels.

IV. Treatment strategies

Newer Pharmacologic Agents for Erectile Dys-function

Drug Ease of use Side ef-fects

Comment

Sildenafil(Viagra)

Taken orallyone hour be-fore antici-pated inter-course

Headache;flushing;dyspepsia

Avoid usewith nitrates

Transurethralalprostadil(MUSE)

Inserted intourethradoses of 500:g

Penile pain Method ofdeliverymay limitcompliance

Intracavernosal alpros-tadil (Caver-ject)

Injected intopenis

Penile pain;hematoma;priapism

Method ofdeliverymay limitcompliance

A. Transurethral alprostadil provides the samesignificant improvement in erectile function asinjectable alprostadil with a better tolerated methodof delivery. Successful and satisfactory intercourseoccurs in 65%. Dosage is initially 125 to 250 µg,with adjustment up or down as indicated. Fewpatients respond to less than 500 mg. The drug isavailable in 125-, 250-, 500- and 1,000-µg suppos-itories. Transurethral alprostadil should not beused during sexual intercourse with a pregnantwoman.

B. Sildenafil (Viagra) inhibits the conversion ofcGMP to guanosine monophosphate in thecorpus cavernosum.1. The most common side effects of sildenafil are

headache, flushing and dyspepsia. A smallpercentage of patients report an alteration incolor perception. Sildenafil is contraindicatedin patients taking nitrates because of thepotential for sudden severe hypotension.

2. Erection appropriate for intercourse is attainedin 72-85%. Sildenafil should initially be pre-scribed at 50 mg to be taken one hour beforeanticipated intercourse. The dose can beincreased to 100 mg if needed. Sildenafilshould not be used more than once a day.

C. Intracavernosal alprostadil (Caverject) hassuccess rates of 67 to 85 percent. When injecteddirectly into the corpus cavernosum, alprostadil(prostaglandin E1) produces an erection withinseveral minutes. The usual dose is between 5and 40 µg per injection. Patients usually start at2.5 µg and titrate up.

D. Testosterone cypionate (200 mg IM q 2 weeks)or testosterone patches may be beneficial if theserum-free testosterone is low (<9 ng/dL). Oldermales (>50 years) are at risk for development ofprostate cancer. A careful rectal examination andPSA testing is recommended prior to institutionof, and during, testosterone therapy.

E. Vacuum constriction devices (VCD) are aneffective treatment alternative for erectile dys-function. The design involves a plastic cylinderthat is placed on the penis with negative pressurecreated. A constriction band is placed at the baseof the penis.

F. Surgical treatment of erectile dysfunction con-sists of placement of a penile prosthesis. Devicesavailable include semirigid or inflatable prosthe-ses. An occasionally indicated treatment option isvascular surgery.


Benign Prostatic HyperplasiaMore than 80 percent of men older than 80 years havebenign prostatic hyperplasia (BPH). When symptoms ofurinary obstruction interfere with quality of life, treatmentis warranted. Sequelae of BPH include urinary retention,detrusor instability, infection, stone formation, bladderdiverticula, and upper tract dilation with renal insuffi-ciency.

I. Clinical evaluationA. Obstructive symptoms, such as nocturia, a slow

urine stream, intermittency, and double voiding, aregenerally evaluated through focused history taking,and a digital rectal examination, with or withoutserum PSA testing.

B. Symptoms of BPH may be obstructive, which aresecondary to bladder outlet obstruction or impairedbladder contractility, or irritative, which result fromdecreased vesicle compliance and increasedbladder instability. Obstructive symptoms include aweak stream, hesitancy, abdominal straining,terminal dribbling, an intermittent stream, andretention; irritative symptoms are frequency,nocturia, urgency, and pain during urination.

C. Physical examination should include a digitalrectal examination, and a focused neurologicexamination to rule out a neurologic cause ofsymptoms.

D. Laboratory assessment1. Urinalysis and a serum creatinine assay are

useful to ascertain there is no infection,hematuria, or decreased renal function.

2. Prostate-specific antigen (PSA) testing may beoffered to patients at risk for prostate cancer whoprefer to be screened for the malignancy. PSAtesting and rectal examination should be offeredannually to men 50 years of age and older if theyare expected to live at least 10 more years. Blackmen and men who have a first-degree relativewith prostate cancer are at high risk for prostatecancer. These men should be offered screeningat 45 years of age.

BPH Symptom Score

For each question, circle the answer that best describes your situation.Add the circled number together to get your total score. See the keyat the bottom of this form to determine the overall rating of yoursymptoms.

Notat all

Lessthanonein fivetimes

Lessthanhalf ofthetime

About halfofthetime

Morethanhalf ofthetime

Al-mostal-ways

In the pastmonth, howoften haveyou had asensation ofnot emptyingyour bladdercompletelyafter you fin-ished void-ing? 0 1 2 3 4 5

In the pastmonth, howoften haveyou had tourinate againless than 2hours afteryou finishedurinating be-fore? 0 1 2 3 4 5

In the pastmonth, howoften haveyou found youstopped andstarted againseveral timeswhen you uri-nated? 0 1 2 3 4 5

In the pastmonth, howoften haveyou found itdifficult topostpone uri-nation? 0 1 2 3 4 5

In the pastmonth, howoften haveyou had aweak urinarystream? 0 1 2 3 4 5

In the pastmonth, howoften haveyou had topush or strainto begin uri-nation? 0 1 2 3 4 5

In the pastmonth, howmany timesdid you typi-cally get up tourinate fromthe time youwent to beduntil youarose in themorning? 0 1 2 3 4 5

II. Treatment optionsA. Watchful Waiting is appropriate in patients with a

low AUA symptom score (zero to seven) becausestudies have shown that medications are notsignificantly more effective than placebo in thesepatients.

B. Medical treatments1. Nonselective alpha-blockers

a. Doxazosin (Cardura), prazosin (Minipress),and terazosin (Hytrin) reduce prostaticsmooth muscle tone and, thus, have animmediate effect on urinary flow. Thesemedications quickly improve BPH symptoms.

b. Side effects such as dizziness, posturalhypotension, fatigue, and asthenia affect from7 to 9 percent of patients treated withnonselective alpha blockers. Side effects canbe minimized by bedtime administration andslow titration of the dosage. Alpha-blockerscan be used with other therapies as needed.Prazosin has the cost advantage of genericavailability; however, unlike doxazosin andterazosin, it is not available in a once-dailyformulation.

c. Therapy for BPH with terazosin (Hytrin) isusually begun with a daily dosage of 1 mg hs.Dosage is raised to 2 mg, 5 mg, and 10 mg.Clinical response may not be seen for 4-6weeks, even at the 10-mg dosage. Doxazosin

(Cardura) is usually given at dosages of 1-4mg qd.

Starting dosages of alpha-blocking agents formanaging benign prostatic hypertrophy

Drug Starting dosage

Tamsulosin (Flomax) 0.4 mg qd

Terazosin (Hytrin) 1 mg qd, adjusted up to 5mg qd

Doxazosin mesylate(Cardura)

1 mg qd, adjusted up to 4mg qd

2. Selective alpha-blocker. Tamsulosin( F l o m a x ) i s a h i g h l y s e l e c t i vealpha1A-adrenergic antagonist that was devel-oped to avoid the side effects of nonselectiveagents. Some patients who do not respond tononselective alpha-blockers may respond totamsulosin and, because of the selectivity, mayhave fewer side effects, including hypotension.Tamsulosin is initiated in a dosage of 0.4 mgonce daily, with a maximum of 0.8 mg per day.Tamsulosin has no antihypertensive effect.

3. 5a-Reductase inhibitorsa. Finasteride (Proscan) slowly induces an 80

to 90 percent reduction in the serumdihydrotestosterone level. As a result, pros-tatic volume decreases by about 20 percentover three to six months. Improvements withfinasteride are significantly less than thosewith any alpha-blocker or surgery. Finasteridemay work best in men with a large gland,whereas alpha-blockers are effective acrossthe range of prostate sizes. Side effects withfinasteride are similar to that with placebo,and include decreased libido, ejaculatorydisorder, and impotence. The daily dosage is5 mg.

b. Dutasteride (Duagen), 0.5-mg capsule qd, isapproved for the treatment of BPH (labelingfor male-pattern baldness is pending). Thisdrug has a distinct mechanism of action, inthat it blocks both types 1 and 25a-reductase. Sexual side effects are similarto those of finasteride.

C. Surgical treatments1. Surgery should be considered in patients who

fail medical treatment, have refractory urinaryretention, fail catheter removal, or have recur-rent urinary tract infections, persistenthematuria, bladder stones, or renal insufficiency.Surgery can also be the initial treatment inpatients with high AUA symptom scores whowant surgical treatment and are good candi-dates for surgery.

2. Transurethral resection of the prostate(TURP). The most commonly employed surgicalprocedure for BPH, TURP reduces symptoms in88 percent of patients. The most frequent com-plications of the procedure are inability to void,clot retention, and secondary infection. Bleedingoccurs in only 1 percent of patients. Long-termcomplications include retrograde ejaculation(70%), impotence (14%), partial incontinence(6%), and total incontinence (1%).


Acute EpididymoorchitisI. Clinical evaluation of testicular pain

A. Epididymoorchitis is indicated by a unilateral painfultesticle and a history of unprotected intercourse,new sexual partner, urinary tract infection, dysuria,or discharge. Symptoms may occur following acutelifting or straining.

B. The epididymis and testicle are painful, swollen, andtender. The scrotum may be erythematosus andwarm, with associated spermatic cord thickening orpenile discharge.

C. Differential diagnosis of painful scrotal swelling1. Epididymitis, testicular torsion, testicular tumor,

hernia.2. Torsion is characterized by sudden onset, age

<20, an elevated testicle, and previous episodesof scrotal pain. The epididymis is usually locatedanteriorly on either side, and there is an absenceof evidence of urethritis and UTI.

3. Epididymitis is characterized by fever, laboratoryevidence of urethritis or cystitis, and increasedscrotal warmth.

II. Laboratory evaluation of epididymoorchitisA. Epididymoorchitis is indicated by leukocytosis with

a left shift; UA shows pyuria and bacteriuria. Mid-stream urine culture will reveal gram negativebacilli. Chlamydia and Neisseria cultures should beobtained.

B. Common pathogens1. Younger men. Epididymoorchitis is usually

associated with sexually transmitted organismssuch as Chlamydia and gonorrhea.

2. Older men. Epididymoorchitis is usually associ-ated with a concomitant urinary tract infection orprostatitis caused by E. coli, proteus, Klebsiella,Enterobacter, or Pseudomonas.

III. Treatment of epididymoorchitisA. Bed rest, scrotal elevation with athletic supporter,

an ice pack, analgesics, and antipyretics are pre-scribed. Sexual and physical activity should beavoided.

B. Sexually transmitted epididymitis in sexuallyactive males1. Ceftriaxone (Rocephin) 250 mg IM x 1 dose AND

doxycycline 100 mg PO bid x 10 days OR2. Ofloxacin (Floxin) 300 mg bid x 10 days.3. Treat sexual partners

C. Epididymitis secondary to urinary tract infection1. TMP/SMX DS bid for 10 days OR2. Ofloxacin (Floxin) 300 mg PO bid for 10 days.


Prostatitis Prostatitis is a common condition, with a 5 percentlifetime prevalence to 9 percent. Prostatitis is divided intothree subtypes: acute, chronic bacterial prostatitis andchronic nonbacterial prostatitis/chronic pelvic painsyndrome (CNP/CPPS).

I. Acute Bacterial ProstatitisA. Acute bacterial prostatitis (ABP) should be consid-

ered a urinary tract infection. The most commoncause is Escherichia coli. Other species frequentlyfound include Klebsiella, Proteus, Enterococci andPseudomonas. On occasion, cultures grow Staphy-lococcus aureus, Streptococcus faecalis,Chlamydia or Bacteroides species.

B. Patients may present with fever, chills, low backpain, perineal or ejaculatory pain, dysuria, urinaryfrequency, urgency, myalgias and obstruction. Theprostate gland is tender and may be warm, swol-len, firm and irregular. Vigorous digital examinationof the prostate should be avoided because it mayinduce bacteremia.

C. The infecting organism can often be identified byurine culturing.

D. T r e a t m e n t c o n s i s t s o ftrimethoprim-sulfamethoxazole (TMP-SMX[Bactrim, Septra]), a quinolone or tetracycline. Menat increased risk for sexually transmitted diseaserequire antibiotic coverage for Chlamydia.

Common Antibiotic Regimens for Acute Bacte-rial Prostatitis

Medication Standard dosage

Trimethoprim-sulfamethoxazole (Bactrim, Septra)

1 DS tablet (160/800 mg)twice a day

Doxycycline (Vibramycin) 100 mg twice a day

Ciprofloxacin (Cipro) 500 mg twice a day

Norfloxacin (Noroxin) 400 mg twice a day

Ofloxacin (Floxin) 400 mg twice a day

E. Antibiotic therapy should be continued for three to

four weeks. Extremely ill patients should be hospi-talized to receive a parenteral broad-spectrumcephalosporin and an aminoglycoside.

II. Chronic Bacterial ProstatitisA. Chronic bacterial prostatitis (CBP) is a common

cause of recurrent urinary tract infections in men.Men experience irritative voiding symptoms, pain inthe back, testes, epididymis or penis, low-gradefever, arthralgias and myalgias. Signs may includeurethral discharge, hemospermia and secondary

epididymo-orchitis. Often the prostate is normal onrectal examination.

B. CBP presents with negative premassage urineculture results, and greater than 10 to 20 whiteblood cells per high-power field in the pre- and thepostmassage urine specimen. Significantbacteriuria in the postmassage urine specimensuggests chronic bacterial prostatitis.

C. TMP-SMX is the first-line antibiotic for CBP.Norfloxacin (Noroxin) taken twice a day for 28 daysachieves a cure rate in 64 percent. Ofloxacin(Floxin) is also highly effective. Some men requirelong-term antibiotic suppression with TMP-SMX ornitrofurantoin.

III.Chronic Nonbacterial Prostatitis/Chronic PelvicPain Syndrome (Prostatodynia)A. Patients with CNP/CPPS have painful ejaculation

pain in the penis, testicles or scrotum, low backpain, rectal or perineal pain, and/or inner thighpain. They often have irritative or obstructiveurinary symptoms and decreased libido or impo-tence. The physical examination is usually unre-markable, but patients may have a tender prostate.

B. No bacteria will grow on culture, but leukocytosismay be found in the prostatic secretions.

C. Treatment begins with 100 mg of doxycycline(Vibramycin) or minocycline (Minocin) twice dailyfor 14 days. Other therapies may includeAllopurinol (Zyloprim), thrice-weekly prostatemassage or transurethra l microwavethermotherapy.

D. Hot sitz baths and nonsteroidal anti-inflammatorydrugs (NSAIDs) may provide some relief. Somemen may notice aggravation of symptoms withalcohol or spicy foods and should avoid them.Anticholinergic agents (oxybutynin [Ditropan]) oralpha-blocking agents (doxazosin [Cardura],tamsulosin [Flomax] or terazosin [Hytrin]) may bebeneficial.


Psychiatric Disorders

DepressionThe lifetime prevalence of major depression in the UnitedStates is 17 percent. In primary care, depression has aprevalence rate of 4.8 to 8.6 percent.

I. DiagnosisA. The Diagnostic and Statistical Manual of Mental

Disorders (DSM-IV) includes nine symptoms in thediagnosis of major depression.

B. These nine symptoms can be divided into twoclusters: (1) physical or neurovegetative symptomsand (2) psychologic or psychosocial symptoms. Thenine symptoms are: depressed mood plus sleepdisturbance; interest/pleasure reduction; guiltfeelings or thoughts of worthlessness; energychanges/fatigue; concentration/attention impair-ment; appetite/weight changes; psychomotordisturbances, and suicidal thoughts.

Diagnostic Criteria for Major Depression, DSMIV

Cluster 1: Physical or neurovegetative symptomsSleep disturbanceAppetite/weight changesAttention/concentration problemEnergy-level change/fatiguePsychomotor disturbance

Cluster 2: Psychologic or psychosocial symptomsDepressed mood and/orInterest/pleasure reductionGuilt feelingsSuicidal thoughts

Note: Diagnosis of major depression requires at least oneof the first two symptoms under cluster 2 and four of theremaining symptoms to be present for at least two weeks.Symptoms should not be accounted for by bereavement.

II.Drug Therapy

Characteristics of Common Antidepressants

Drug RecommendedDosage

Comments

Selective Serotonin Reuptake Inhibitors (SSRIs)

Citalopram(Celexa)

Initially 20 mg qd;maximum 40 mg/d

Minimal sedation, activa-tion, or inhibition of hepatic enzymes, nau-sea, anorgasmia, head-ache

Fluoxetine(Prozac)

10-20 mg qd ini-tially, taken in AM

Anxiety, insomnia, agita-tion, nausea,anorgasmia, erectiledysfunction, headache,anorexia.

Fluvoxamine(LuVox)

50-100 mg qhs;max 300 mg/d [50,100 mg]

Headache, nausea, se-dation, diarrhea

Paroxetine (Paxil)

20 mg/d initially,given in AM; in-crease in 10-mg/dincrements asneeded to max of50 mg/d. [10, 20,30, 40 mg]

Headache, nausea,somnolence, dizziness,insomnia, abnormalejaculation, anxiety, diar-rhea, dry mouth.

Sertraline(Zoloft)

50 mg/d, increasingas needed to max of200 mg/d [50, 100mg]

Insomnia, agitation, drymouth, headache, nau-sea, anorexia, sexualdysfunction.

Secondary Amine Tricyclic Antidepressants

Desipramine(Norpramin,generics)

100-200 mg/d, grad-ually increasing to300 mg/d as toler-ated.[10, 25, 50, 75,100, 150 mg]

No sedation; may havestimulant effect; besttaken in morning toavoid insomnia.

Nortriptyline(Pamelor)

25 mg tid-qid, max150 mg/d. [10, 25,50, 75 mg]

Sedating

Tertiary Amine Tricyclics

Amitriptyline (Elavil,generics)

75 mg/d qhs-bid,increasing to 150-200 mg/d. [25, 50,75, 100, 150 mg]

Sedative effect precedesantidepressant effect.High anticholinergic ac-tivity.

CIomipramine(Anafranil)

25 mg/d, increasinggradually to 100mg/d; max 250mg/d; may be givenonce qhs [25, 50, 75mg].

Relatively high sedation,anticholinergic activity,and seizure risk.

Protriptyline(Vivactil)

5-10 mg PO tid-qid;15-60 mg/d [5, 10mg]

Useful in anxious de-pression; nonsedating

Doxepin(Sinequan,generics)

50-75 mg/d, in-creasing up to 150-300 mg/d asneeded [10, 25, 50,75, 100, 150 mg]

Sedating. Also indicatedfor anxiety. Contraindi-cated in patients withglaucoma or urinary re-tention.

Imipramine(Tofranil,generics)

75 mg/d in a singledose qhs, increas-ing to 150 mg/d;300 mg/d. [10, 25,50 mg]

High sedation andanticholinergic activity.Use caution in cardio-vascular disease.

Miscellaneous

Bupropion(Wellbutrin,Wellbutrin SR)

100 mg bid; in-crease to 100 mg tid[75, 100 mg]Sustained release:100-200 mg bid[100, 150 mg]

Agitation, dry mouth,insomnia, headache,nausea, constipation,tremor. Good choice forpatients with sexual sideeffects from otheragents; contraindicatedin seizure disorders.

Venlafaxine(Effexor)

75 mg/d in 2-3 di-vided doses withfood; increase to225 mg/d asneeded. [25, 37.5,50, 75, 100 mg].Extended-release:initially 37.5 mgqAM. The dosagecan be increased by75 mg every fourdays to a max of225 mg qd [37.5,75, 100, 150 mg].

Inhibits norepinephrineand serotonin. Hyperten-sion, nausea, insomnia,dizziness, abnormalejaculation, headache,dry mouth, anxiety.

Drug RecommendedDosage

Comments

Maprotiline(Ludiomil)

75 to 225 in singleor divided doses[25, 50, 75 mg].

Delays cardiac conduc-tion; high anticholinergicactivity; contraindicatedin seizure disorders.

Mirtazapine(Remeron)

15 to 45 PO qd [15,30 mg]

High anticholinergic ac-tivity; contraindicated inseizure disorders.

Nefazodone(Serzone)

Start at 100 mg PObid, increase to 150-300 mg PO bid asneeded [100, 150,200, 250 mg].

Headache, somnolence,dry mouth, blurred vi-sion. Posturalhypotension, impotence.

Reboxetine(Vestra)

5 mg bid Selective norepinephrinereuptake inhibitor. Drymouth, insomnia, consti-pation, increased sweat-ing

Trazodone(Desyrel,generics)

150 mg/d, increas-ing by 50 mg/d ev-ery 3-4 d 400 mg/din divided doses[50, 100, 150, 300mg]

Rarely associated withpriapism. Orthostatichypotension in elderly.Sedating.

A.Selective Serotonin Reuptake Inhibitors1. The selective serotonin reuptake inhibitors

(SSRIs) all share the property of blocking theaction of serotonin reuptake pump. The antide-pressant effects of SSRIs may not appear forthree to six weeks.

2. Fluoxetine (Prozac). a. The half-life (t 1/2) of fluoxetine is four to six

days. Fluoxetine is a potent inhibitor ofCYP2D6. Drugs metabolized by hepaticCYP2D6 (tricyclics, antiarrhythmics) must beused cautiously when coadministered withfluoxetine.

b. The usual effective dose of fluoxetine is 20mg QD. The dosage can be increased by 10to 20 mg as tolerated up to 80 mg QD.

c. Once weekly fluoxetine (Prozac) can beadministered for patients who have re-sponded to the daily fluoxetine preparation.Patients should wait seven days after the lastdaily dose of fluoxetine before beginning theonce weekly formulation.

d. Initial side effects of fluoxetine are nausea,insomnia, and anxiety. These effects usuallyresolve over one to two weeks. Decreasedlibido, erectile dysfunction, and delayedejaculation or anorgasmia are common.Addition of bupropion (BuSpar [75 to 150mg/day in divided doses]) or buspirone(Wellbutrin [10 to 20 mg twice daily]) mayalleviate decreased libido, diminished sexualarousal, or impaired orgasm.

3. Sertraline (Zoloft) has a low likelihood ofinteractions with coadministered medications.a. Sertraline is usually started at 50 mg QD; the

effective maintenance dose is 50 to 100 mgQD, although doses up to 200 mg QD arenecessary in some cases.

b. Common initial side effects of sertralineinclude nausea, diarrhea, insomnia, andsexual dysfunction. It may be more likely thanthe other SSRIs to cause nausea.

4. Paroxetine (Paxil)a. Paroxetine substantially inhibits the liver

enzyme CYP2D6 and must be used cau-tiously when coadministered with other drugsmetabolized by this enzyme. Paroxetine cancause more anticholinergic side effects thanthe other SSRIs.

b. The usual starting and maintenance dose ofparoxetine is 20 mg QD, but can be raised to40 mg QD if necessary. Paroxetine has atendency to be mildly sedating. Other sideeffects include nausea, dry mouth, and sex-ual dysfunction.

5. Fluvoxamine (Luvox)a. Fluvoxamine is a potent inhibitor of the liver

enzyme p450 1A2 and has the potential tointeract with clozapine and theophylline.

b. The usual starting dose of fluvoxamine is 50mg QD; the therapeutic dose tends to be inthe range of 150 to 250 mg. Its side effectprofile is similar to the other SSRIs, althoughit may be more likely to cause nausea.

6. Citalopram (Celexa)

a. Citalopram has significantly less p450 inter-actions than other SSRIs, making it an ap-pealing choice in patients who are on othermedications. Citalopram may cause lesssexual dysfunction than other SSRIs.Citalopram may have fewer side effects thansertraline. In addition, anxiety symptomssignificantly improve.

b. The usual starting dose of citalopram is 20mg QD. The therapeutic dose range tends tobe 20 to 40 mg QD in a single morning dose.

B.Heterocyclic Antidepressants. The cyclic antide-pressants are less commonly used as first-lineantidepressants with the development of the SSRIsand other newer antidepressants. This is mainlydue to the less benign side-effect profile of thecyclic antidepressants. In contrast to the SSRIs,the cyclic antidepressants can be fatal in doses aslittle as five times the therapeutic dose.

C.Other Antidepressants1. Bupropion (Wellbutrin). Bupropion is an

aminoketone. The rate of seizures caused bybupropion is 0.4 percent, slightly higher thanother antidepressants. A slow-release (SR)formulation of bupropion allows for lower peakblood levels and is associated with a seizureincidence of 0.1 percent.a. Because of its mildly stimulating properties,

bupropion is often prescribed to depressedpatients who have fatigue and poor concen-tration. It does not have anxiolytic properties.

b. The immediate-release form of bupropion isusually started at 100 mg bid and increasedto a usual maintenance dose of 200 to 300mg in 2 or 3 divided doses. The SR allows fortwice- or once-daily dosing at 100-150 mgqd-bid.

c. The side-effect profile of bupropion is rela-tively benign. Some patients notice a stimu-lant-like effect. It is unique among antidepres-sants in that it does not cause sexual dys-function. It tends to have a mild appe-tite-suppressing effect, and may cause mildweight loss.

2. Venlafaxine (Effexor) is a phenylethylamine. Itis a potent inhibitor of serotonin andnorepinephrine reuptake, and a mild inhibitor ofdopamine reuptake. It has a benign side-effectprofile.a. Dosing for the immediate-release form of

venlafaxine typically begins at 37.5 mg bid. Ifnecessary, the medication can be increasedby 75 mg every four days to a maximum doseof 375 mg daily in three divided doses.

b. For the extended-release form of venlafaxine,dosing frequently begins as a single morningdose of 37.5 mg. The dosage can be in-creased by 75 mg every four days to a maxi-mum of 225 mg qd in a single daily dose.

c. Side effects include nausea, dizziness, in-somnia, sedation, and constipation. It canalso induce sweating. Venlafaxine may causeblood pressure increases of 3 percent.

3. Nefazodone (Serzone). Nefazodone is uniquein that it may increase REM sleep. It also maycause less sexual dysfunction than other antide-pressants.a. Dosing is usually begun at 100 mg bid. The

dose can be increased to 150 mg bid afterone week and increased further if necessaryto the therapeutic dose range of 300 to 600mg qd.

b. Side effects include dry mouth, constipation,nausea, sedation, and dizziness. Nefazodoneincreases the blood level of alprazolam andtriazolam.

4. Mirtazapine (Remeron) is a tetracyclic com-pound, but is unrelated to TCAs.a. Mirtazapine may possess anxiolytic effects. It

can be particularly helpful in depressedpatients with insomnia because of sedativeproperties.

b. Dosing is most frequently started at 15 mgqhs, and can be increased to 30 mg or 45 mgqd as needed in one to two week intervals.

c. The most notable side effects are sedation,weight gain, and dry mouth. Mirtazapine mayhave relatively less propensity to causesexual dysfunction than the SSRIs. Agranulo-cytosis and neutropenia may rarely occur.Mild transaminase elevations have beennoted.

5. Reboxetine (Vestra)

a. Reboxetine is the first selectivenorepinephrine reuptake inhibitor (NRI). Itmay be an appealing treatment option forpatients who do not respond to SSRIs.Reboxetine may be more effective thanSSRIs in improving social functioning.

b. The recommended starting dose is 4 mg BID,with increases after three weeks to 5 mg BID.Reboxetine is fairly well tolerated. The mostcommonly reported side effects are drymouth, hypotension, insomnia, decreasedsweating, and blurred vision.

III. Electroconvulsive Therapy (ECT) is highly effectivein patients with delusional depression and with severemelancholic depression on maximum medical ther-apy. The often quick response and low side-effectprofile make ECT one of the most effective ways toaddress the symptoms of major depression.


Generalized Anxiety Disorder

Generalized anxiety disorder (GAD) is characterized byexcessive worry and anxiety that are difficult to controland cause significant distress and impairment. Com-monly patients develop symptoms of GAD secondary toother DSM-IV diagnoses such as panic disorder, majordepression, alcohol abuse, or an axis II personalitydisorder.

I. Epidemiology. GAD is a common anxiety disorder.The prevalence is estimated to be 5 percent in theprimary care setting. Twice as many women as menhave the disorder. GAD may also be associated withsubstance abuse, post-traumatic stress disorder, andobsessive compulsive disorder. Between 35 and 50percent of individuals with major depression meetcriteria for GAD.

II. Clinical manifestations and diagnosisA. The diagnostic criteria for GAD suggest that

patients experience excessive anxiety and worryabout a number of events or activities, occurringmore days than not for at least six months, that areout of proportion to the likelihood or impact offeared events. Affected patients also present withsomatic symptoms, including fatigue, muscletension, memory loss, and insomnia, and otherpsychiatric disorders.

DSM-IV-PC Diagnostic Criteria for GeneralizedAnxiety Disorder

1. Excessive anxiety and worry about a number of eventsor activities, occurring more days than not for at leastsix months, that are out of proportion to the likelihoodor impact of feared events.

2. The worry is pervasive and difficult to control.3. The anxiety and worry are associated with three (or

more) of the following six symptoms (with at leastsome symptoms present for more days than not forthe past six months):Restlessness or feeling keyed up or on edgeBeing easily fatiguedDifficulty concentrating or mind going blankIrritabilityMuscle tensionSleep disturbance (difficulty falling or staying asleep,

or restless unsatisfying sleep)4. The anxiety, worry, or physical symptoms cause clini-

cally significant distress or impairment in social, occu-pational, or other important areas of functioning.

B. Comorbid psychiatric disorders and an organicetiology for anxiety must be excluded by carefulhistory taking, a complete physical examination,and appropriate laboratory studies. The medicalhistory should focus upon current medical disor-ders, medication side effects, or substance abuseto anxiety (or panic) symptoms.

C. Psychosocial history should screen for majordepression and agoraphobia, stressful life events,family psychiatric history, current social history,substance abuse history (including caffeine,nicotine, and alcohol), and past sexual, physicaland emotional abuse, or emotional neglect.

D. Laboratory studies include a complete bloodcount, chemistry panel, serum thyrotropin (TSH)and urinalysis. Urine or serum toxicology measure-ments or drug levels can be obtained for drugs ormedications suspected in the etiology of anxiety.

Physical Causes of Anxiety-Like Symptoms

CardiovascularAngina pectoris, arrhythmias, congestive heart failure,hypertension, hypovolemia, myocardial infarction, syncope(multiple causes), valvular disease, vascular collapse(shock)DietaryCaffeine, monosodium glutamate (Chinese restaurantsyndrome), vitamin-deficiency diseasesDrug-relatedAkathisia (secondary to antipsychotic drugs),anticholinergic toxicity, digitalis toxicity, hallucinogens,hypotensive agents, stimulants (amphetamines, cocaine,related drugs), withdrawal syndromes (alcohol, sedative-hypnotics), bronchodilators (theophylline,sympathomimetics)Hematologic AnemiasImmunologicAnaphylaxis, systemic lupus erythematosusMetabolicHyperadrenaIism (Cushing's disease), hyperkalemia,hyperthermia, hyperthyroidism, hypocalcemia,hypoglycemia, hyponatremia, hypothyroidism, menopause,porphyria (acute intermittent)NeurologicEncephalopathies (infectious, metabolic, toxic), essentialtremor, intracranial mass lesions, postconcussive syn-drome, seizure disorders (especially of the temporal lobe),vertigoRespiratoryAsthma, chronic obstructive pulmonary disease, pneumo-nia, pneumothorax, pulmonary edema, pulmonary embo-lismSecreting tumorsCarcinoid, insulinoma, pheochromocytoma

III. TreatmentA. Drug therapy. While benzodiazepines have been

the most traditionally used drug treatments forGAD, selective serotonin reuptake inhibitors(SSRIs), selective serotonin and norepinephrinereuptake inhibitors (SNRIs, eg venlafaxine), andbuspirone are also effective, and because of theirlower side effect profiles and lower risk for toler-ance are becoming first-line treatment.

B. Antidepressants1. Venlafaxine SR (Effexor) may be a particularly

good choice for patients with coexisting psychi-atric illness, such as panic disorder, majordepression, or social phobia, or when it is not

clear if the patient has GAD, depression, orboth. Venlafaxine can be started as venlafaxineXR 37.5 mg daily, with dose increases in incre-ments of 37.5 mg every one to two weeks untila dose of 150 mg to 300 mg is attained.

C. Tricyclic antidepressants, SSRIs, or SNRIs may beassociated with side effects such as restlessnessand insomnia. These adverse effects can beminimized by starting at lower doses and graduallytitrating to full doses as tolerated. 1. Selective serotonin reuptake inhibitors

a. Paroxetine (Paxil) 5 to 10 mg qd, increasingto 20 to 40 mg.

b. Sertraline (Zoloft) 12.5 to 25 mg qd, increas-ing to 50 to 200 mg.

c. Fluvoxamine (Luvox) 25 mg qd, increasing to100 to 300 mg.

d. Fluoxetine (Prozac) 5 mg qd, increasing to20 to 40 mg.

e. Citalopram (Celexa) 10 mg qd, increasing to20 to 40 mg.

f. Side effects of SSRIs include agitation,headache, gastrointestinal symptoms (diar-rhea and nausea), and insomnia. About 20to 35 percent of patients develop sexual sideeffects after several weeks or months ofSSRI therapy, especially a decreased abilityto have an orgasm. Addition of bupropion(75 to 150 mg/day in divided doses) orbuspirone (10 to 20 mg twice daily) mayalleviate decreased libido, diminished sexualarousal, or impaired orgasm.

2. Imipramine (Tofranil), a starting dose of 10 to20 mg po at night can be gradually titrated up to75 to 300 mg each night. Imipramine hasanticholinergic and antiadrenergic side effects.Desipramine (Norpramin), 25-200 mg qhs, andnortriptyline (Pamelor), 25 mg tid-qid, can beused as alternatives.

3. Trazodone (Desyrel) is a serotonergic agent,but because of its side effects (sedation andpriapism), it is not an ideal first-line agent. Dailydosages of 200 to 400 mg are helpful in pa-tients who have not responded to other agents.

4. Nefazodone (Serzone) has a similar pharma-cologic profile to trazodone, but it is bettertolerated and is a good alternative; 100 mg bid;increase to 200-300 mg bid.

D. Buspirone (BuSpar) appears to be as effective asthe benzodiazepines for the treatment of GAD.However, the onset of action can be severalweeks, and there are occasional gastrointestinalside effects. Advantages of using buspirone in-stead of benzodiazepines include the lack ofabuse potential, physical dependence, or with-drawal, and lack of potentiation of alcohol or othersedative-hypnotics. Most patients need to betitrated to doses of 30 to 60 mg per day given intwo or three divided doses.

E. Benzodiazepines. Several controlled studies havedemonstrated the efficacy of benzodiazepines (eg,chlordiazepoxide, diazepam, alprazolam) in thetreatment of GAD.1. Many anxious patients who start on

benzodiazepines have difficulty stopping them,particularly since rebound anxiety and with-drawal symptoms can be moderate to severe.Methods of facilitating withdrawal and decreas-ing rebound symptoms include tapering themedication slowly, converting short-actingbenzodiazepines to a long-acting preparation(eg, clonazepam) prior to tapering, and treatingthe patient with an antidepressant before at-tempting to taper.

2. Symptoms of anxiety can be alleviated in mostcases of GAD with clonazepam (Klonopin) 0.25to 0.5 mg po bid titrated up to 1 mg bid or tid, orlorazepam (Ativan) 0.5 to 1.0 mg po tid titratedup to 1 mg po tid or qid. Often an antidepres-sant is prescribed concomitantly. After six toeight weeks, when the antidepressant begins tohave its optimal effects, the benzodiazepineusually should be tapered over months, achiev-ing roughly a 10 percent dose reduction perweek.

Benzodiazepines Commonly Prescribed for Anx-iety Disorders

Name Half-life(hours)

Dosagerange (perday)

Initial dos-age

Alprazolam(Xanax)

14 1 to 4 mg 0.25 to 0.5mg fourtimes daily

Chlordiazepoxide (Librium)

20 15 to 40 mg 5 to 10 mgthree timesdaily

Clonazepam(Klonopin)

50 0.5 to 4.0mg

0.5 to 1.0mg twicedaily

Clorazepate(Tranxene)

60 15 to 60 mg 7.5 to 15.0mg twicedaily

Diazepam (Val-ium)


Lorazepam(Ativan)

14 1 to 6 mg 0.5 to 1.0mg threetimes daily

Oxazepam(Serax)


F. Agents with short half-lives, such as oxazepam(Serax), do not cause excessive sedation. Theseagents should be used in the elderly and in pa-tients with liver disease. They are also suitable foruse on an “as-needed” basis. Agents with longhalf-lives, such as clonazepam (Klonopin), shouldbe used in younger patients who do not haveconcomitant medical problems. The longer-actingagents can be taken less frequently during the day,patients are less likely to experience anxietybetween doses and withdrawal symptoms are lesssevere.


Panic DisorderPanic disorder is characterized by the occurrence ofpanic attacks--sudden, unexpected periods of intensefear or discomfort. About 15% of the general populationexperiences panic attacks; 1.6-3.2% of women and0.4%-1.7% of men have panic disorder.

DSM-IV Criteria for panic attack

A discrete period of intense fear or discomfort in which fouror more of the following symptoms developed abruptly andreached a peak within 10 minutes.

Chest pain or discomfortChokingDepersonalization or derealizationDizziness, faintness, or unsteadinessFear of "going crazy" or being out of controlFear of dyingFlushes or chillsNausea or gastrointestinal distressPalpitations or tachycardiaParesthesiasShortness of breath (or feelings of smothering)SweatingTrembling or shaking

Diagnostic criteria for panic disorder withoutagoraphobia

Recurrent, unexpected panic attacksAndAt least one attack has been followed by at least 1 monthof one (or more) of the following:Persistent concern about experiencing more attacksWorry about the meaning of the attack or its consequences(fear of losing control, having a heart attack, or "goingcrazy")A significant behavioral change related to the attacksAndAbsence of agoraphobiaAndDirect physiological effects of a substance (drug abuse ormedication) or general medical condition has been ruledout as a cause of the attacksAndThe panic attacks cannot be better accounted for by an-other mental disorder

I. Clinical evaluationA. Panic attacks are manifested by the sudden onset

of an overwhelming fear, accompanied by feelingsof impending doom, for no apparent reason.

B. The essential criterion for panic attack is the pres-ence of 4 of 13 cardiac, neurologic, gastrointestinal,or respiratory symptoms that develop abruptly andreach a peak within 10 minutes. The physicalsymptoms include shortness of breath, dizziness orfaintness, palpitations, accelerated heart rate, andsweating. Trembling, choking, nausea, numbness,flushes, chills, or chest discomfort are also com-mon, as are cognitive symptoms such as fear ofdying or losing control.

C. One third of patients develop agoraphobia, or afear of places where escape may be difficult, suchas bridges, trains, buses, or crowded areas. Medi-cations, substance abuse, and general medicalconditions such as hyperthyroidism must be ruledout as a cause of the patient's symptoms.

D. The history should include details of the panicattack, its onset and course, history of panic, andany treatment. Questioning about a family history ofpanic disorder, agoraphobia, hypochondriasis, ordepression is important. Because panic disordermay be triggered by marijuana or stimulants suchas cocaine, a history of substance abuse must beidentified. A medication history, including prescrip-tion, over-the-counter, and herbal preparations, isessential.

E. The patient should be asked about stressful lifeevents or problems in daily life that may havepreceded onset of the disorder. The extent of anyavoidance behavior that has developed or suicidalideation, self-medication, or exacerbation of anexisting medical disorder should be assessed.

II. ManagementA. Patients should reduce or eliminate caffeine con-

sumption, including coffee and tea, cold medica-tions, analgesics, and beverages with addedcaffeine. Alcohol use is a particularly insidiousproblem because patients may use drinking toalleviate the panic.

Pharmacologic treatment of panic disorder

Dosage range (mg/d)

Drug Initial Therapeutic

SSRIsFluoxetine(Prozac)Fluvoxamine(LuVox)Paroxetine (Paxil)Sertraline (Zoloft)Citalopram(Celexa)

5-1025-5010-2025-5010-20 mg qd

10-6025-30020-5050-20020-40

BenzodiazepinesAlprazolam(Xanax)Alprazolam XR(Xanax XR)

Clonazepam(Klonopin)Diazepam (Val-ium)Lorazepam(Ativan)

0.5 In divideddoses, tid-qid0.5 to 1 mg/daygiven once in themorning.0.5 In divideddoses, bid-tid2.0 In divideddoses, bid-tid0.5 In divideddoses, bid-tid

1-4 In divideddoses, tid-qid3-6 mg qAM

1-4 In divideddoses, bid-tid2-20 In divideddoses, bid1-4 In divideddoses, bid-tid

TCAsAmitriptyline(Elavil)Clomipramine(Anafranil)Desipramine(Norpramin) Imipramine(Tofranil)Nortriptyline(Pamelor)

1025101010

10-30025-30010-30010-30010-300

MAOIsPhenelzine(Nardil)Tranylcypromine(Parnate)

1510

15-9010-30

B. Selective serotonin reuptake inhibitors(SSRIs) are an effective, well-tolerated alternativeto benzodiazepines and TCAs. SSRIs are supe-rior to either imipramine or alprazolam. They lackthe cardiac toxicity and anticholinergic effects ofTCAs. Fluoxetine (Prozac), fluvoxamine (LuVox),paroxetine (Paxil), sertraline (Zoloft), andcitalopram (Celexa) have shown efficacy for thetreatment of panic disorder.

C. Tricyclic antidepressants (TCAs) have demon-strated efficacy in treating panic. They are, how-ever, associated with a delayed onset of actionand side effects--particularly orthostatichypotension, anticholinergic effects, weight gain,and cardiac toxicity.

D. Benzodiazepines1. Clonazepam (Klonopin), alprazolam (Xanax),

and lorazepam (Ativan), are effective in block-ing panic attacks. Advantages include a rapidonset of therapeutic effect and a safe, favor-able, side-effect profile. Among the drawbacksare the potential for abuse and dependency,worsening of depressive symptoms, withdrawalsymptoms on abrupt discontinuation,anterograde amnesia, early relapse on discon-tinuation, and inter-dose rebound anxiety.

2. Benzodiazepines are an appropriate first-linetreatment only when rapid symptom relief isneeded. The most common use forbenzodiazepines is to stabilize severe initialsymptoms until another treatment (eg, an SSRIor cognitive behavioral therapy) becomeseffective.

3. The starting dose of alprazolam is 0.5 mg bid.Approximately 70% of patients will experiencea discontinuance reaction characterized byincreased anxiety, agitation, and insomniawhen alprazolam is tapered. Clonazepam'slong duration of effect diminishes the need for

multiple daily dosing. Initial symptoms of seda-tion and ataxia are usually transient.

E. Monoamine oxidase inhibitors (MAOIs). MAOIssuch phenelzine sulfate (Nardil) may be the mosteffective agents for blocking panic attacks and forrelieving the depression and concomitant socialanxiety of panic disorder. Recommended dosesrange from 45-90 mg/d. MAOI use is limited byadverse effects such as orthostatic hypotension,weight gain, insomnia, risk of hypertensive crisis,and the need for dietary monitoring. MAOIs areoften reserved for patients who do not respond tosafer drugs.

F. Beta-blockers are useful in moderating heart rateand decreasing dry mouth and tremor; they areless effective in relieving subjective anxiety.


InsomniaInsomnia is the perception by patients that their sleep isinadequate or abnormal. Insomnia may affect as manyas 69% of adult primary care patients. The incidence ofsleep problems increases with age. Younger persons areapt to have trouble falling asleep, whereas older personstend to have prolonged awakenings during the night.

I. Causes of insomniaA. Situational stress concerning job loss or prob-

lems often disrupt sleep. Patients under stress mayexperience interference with sleep onset and earlymorning awakening. Attempting to sleep in a newplace, changes in time zones, or changing bed-times due to shift work may interfere with sleep.

B. Drugs associated with insomnia includeantihypertensives, caffeine, diuretics, oral contra-ceptives, phenytoin, selective serotonin reuptakeinhibitors, protriptyline, corticosteroids, stimulants,theophylline, and thyroid hormone.

C. Psychiatric disorders. Depression is a commoncause of poor sleep, often characterized by earlymorning awakening. Associated findings includehopelessness, sadness, loss of appetite, andreduced enjoyment of formerly pleasurable ac-tivities. Anxiety disorders and substance abusemay cause insomnia.

D. Medical disorders. Prostatism, peptic ulcer,congestive heart failure, and chronic obstructivepulmonary disease may cause insomnia. Pain,nausea, dyspnea, cough, and gastroesophagealreflux may interfere with sleep.

E. Obstructive sleep apnea syndrome1. This sleep disorder occurs in 5-15% of adults. It

is characterized by recurrent discontinuation ofbreathing during sleep for at least 10 seconds.Abnormal oxygen saturation and sleep patternsresult in excessive daytime fatigue and drowsi-ness. Loud snoring is typical. Overweight,middle-aged men are particularly predisposed.Weight loss can be helpful in obese patients.

2. Diagnosis is by polysomnography. Use of hyp-notic agents is contraindicated since they in-crease the frequency and the severity of apneicepisodes.

II. Clinical evaluation of insomniaA. Acute personal and medical problems should be

sought, and the duration and pattern of symptomsand use of any psychoactive agents should beinvestigated. Substance abuse, leg movements,sleep apnea, loud snoring, nocturia, and daytimenapping or fatigue should be sought.

B. Consumption of caffeinated beverages, prescribeddrugs, over-the-counter medications, and illegalsubstances should be sought.

III. Pharmacologic managementA. Hypnotics are the primary drugs used in the man-

agement of insomnia. These drugs include thebenzodiazepines and the benzodiazepine receptoragonis ts in the im idazopyr id ine orpyrazolopyrimidine classes.

Recommended dosages of hypnotic medica-tions (elderly dosages are in parentheses)

Benzodiaz-epinehypnotics

Recom-mended

dose, mg

Tmax Elimina-tionhalf-life

Re-ceptorse-

lectivity

Benzodiazepine receptor agonists

Zolpidem(Ambien)

5-10 (5) 1.6 2.6 Yes

Zaleplon (So-nata)

5-10 (5) 1 1 Yes

Hypnotic Medications

Estazolam(ProSom)

1-2 (0.5-1)

2.7 17.1 No

Flurazepam(Dalmane)

15-30(15)

1 47.0-100

No

Triazolam(Halcion)

0.250(0.125)

1.2 2.6 No

Temazepam(Restoril)

7.5-60(7.5-20)

0.8 8.4 No

Quazepam(Doral)

7.5-15.0(7.5)

2 73 No

B. Zolpidem (Ambien) and zaleplon (Sonata) havethe advantage of achieving hypnotic effects withless tolerance and fewer adverse effects.

C. The safety profile of these benzodiazepines andbenzodiazepine receptor agonists is good; lethaloverdose is rare, except when benzodiazepinesare taken with alcohol. Sedative effects may beenhanced when benzodiazepines are used inconjunction with other central nervous systemdepressants.

D. Zolpidem (Ambien) is a benzodiazepine agonistwith a short elimination half-life that is effective ininducing sleep onset and promoting sleep main-tenance. Zolpidem may be associated withgreater residual impairment in memory andpsychomotor performance than zaleplon.

E. Zaleplon (Sonata) is a benzodiazepine receptoragonist that is rapidly absorbed (TMAX = 1 hour)and has a short elimination half-life of 1 hour.Zaleplon does not impair memory or psychomotorfunctioning at as early as 2 hours after adminis-tration, or on morning awakening. Zaleplon doesnot cause residual impairment when the drug isgiven in the middle of the night. Zaleplon can beused at bedtime or after the patient has tried tofall asleep naturally.

F. Benzodiazepines with long half-lives, such asflurazepam (Dalmane), may be effective in pro-moting sleep onset and sustaining sleep. Thesedrugs may have effects that extend beyond thedesired sleep period, however, resulting in day-time sedation or functional impairment. Patientswith daytime anxiety may benefit from the resid-ual anxiolytic effect of a long-acting benzodiaz-epine administered at bedtime. Benzodiazepineswith intermediate half-lives, such as temazepam(Restoril), facilitate sleep onset and maintenancewith less risk of daytime residual effects.

G. Benzodiazepines with short half-lives, such astriazolam (Halcion), are effective in promoting theinitiation of sleep but may not contribute to sleepmaintenance.

H. Sedating antidepressants are sometimes usedas an alternative to benzodiazepines or benzo-diazepine receptor agonists. Amitriptyline (Elavil),25-50 mg at bedtime, or trazodone (Desyrel), 50-100 mg, are common choices.


Nicotine DependenceSmoking causes approximately 430,000 smoking deathseach year, accounting for 19.5% of all deaths. Daily useof nicotine for several weeks results in physical depend-ence. Abrupt discontinuation of smoking leads to nicotinewithdrawal within 24 hours. The symptoms includecraving for nicotine, irritability, frustration, anger, anxiety,restlessness, difficulty in concentrating, and moodswings. Symptoms usually last about 4 weeks.

I. Drugs for treatment of nicotine dependanceA. Treatment with nicotine is the only method that

produces significant withdrawal rates. Nicotinereplacement comes in three forms: nicotinepolacrilex gum (Nicorette), nicotine transdermalpatches (Habitrol, Nicoderm, Nicotrol), and nicotinenasal spray (Nicotrol NS) and inhaler (Nicotrol).Nicotine patches provide steady-state nicotinelevels, but do not provide a bolus of nicotine ondemand as do sprays and gum.

B. Bupropion (Zyban) is an antidepressant shown tobe effective in treating the craving for nicotine. Thesymptoms of nicotine craving and withdrawal arereduced with the use of bupropion, making it auseful adjunct to nicotine replacement systems.

Treatments for nicotine dependence

Drug Dosage Comments

Nicotine gum(Nicorette)

2- or 4-mgpiece/30 min

Available OTC;poor compliance

Nicotinepatch(Habitrol,NicodermCQ)

1 patch/d for 6-12 wk, thentaper for 4 wk

Available OTC; lo-cal skin reactions

Nicotine na-sal spray(Nicotrol NS)

1-2 doses/h for6-8 wk

Rapid nicotine de-livery; nasal irrita-tion initially

Nicotine in-haler(NicotrolInhaler)

6-16 car-tridges/d for 12wk

Mimics smokingbehavior;provides low dosesof nicotine

Bupropion(Zyban)

150 mg/day for3 d, then titrateto 300 mg

Treatment initiated1 wk before quitday; contraindi-cated with seizures,anorexia, heavyalcohol use

C. Nicotine polacrilex (Nicorette) is available OTC.The patient should use 1-2 pieces per hour. A 2-mg dose is recommended for those who smokefewer than 25 cigarettes per day, and 4 mg forheavier smokers. It is used for 6 weeks, followedby 6 weeks of tapering. Nicotine gum improvessmoking cessation rates by about 40%-60%.Drawbacks include poor compliance and unpleas-ant taste.

D. Transdermal nicotine (Habitrol, Nicoderm,Nicotrol) doubles abstinence rates compared withplacebo, The patch is available OTC and is easierto use than the gum. It provides a plateau level ofnicotine at about half that of what a pack-a-daysmoker would normally obtain. The higher doseshould be used for 6-12 weeks followed by 4weeks of tapering.

E. Nicotine nasal spray (Nicotrol NS) is availableby prescription and is a good choice for patientswho have not been able to quit with the gum orpatch or for heavy smokers. It delivers a high levelof nicotine, similar to smoking. Nicotine nasalspray doubles the rates of sustained abstinence.The spray is used 6-8 weeks, at 1-2 doses perhour (one puff in each nostril). Tapering overabout 6 weeks. Side effects include nasal andthroat irritation, headache, and eye watering.

F. Nicotine inhaler (Nicotrol Inhaler) deliversnicotine orally via inhalation from a plastic tube. Itis available by prescription and has a success rateof 28%, similar to nicotine gum. The inhaler hasthe advantage of avoiding some of the adverseeffects of nicotine gum, and its mode of deliverymore closely resembles the act of smoking.

G. Bupropion (Zyban) 1. Bupropion is appropriate for patients who have

been unsuccessful using nicotine replacement.Bupropion reduces withdrawal symptoms andcan be used in conjunction with nicotine re-placement therapy. The treatment is associatedwith reduced weight gain. Bupropion is contra-indicated with a history of seizures, anorexia,heavy alcohol use, or head trauma.

2. Bupropion is started at a dose of 150 mg dailyfor 3 days and then increased to 300 mg dailyfor 2 weeks before the patient stops smoking.Bupropion is then continued for 3 months.When a nicotine patch is added to this regi-men, the abstinence rates increase to 50%compared with 32% when only the patch isused.


Alcohol and Drug AddictionThe prevalence of alcohol disorders is 16-28%, and theprevalence of drug disorders is 7-9%. Alcoholism ischaracterized by impaired control over drinking, preoccu-pation with alcohol, use of alcohol despite adverseconsequences, and distortions in thinking (denial).Substance abuse is a pattern of misuse during which thepatient maintains control. Addiction or substance de-pendence is a pattern of misuse during which the patienthas lost control.

I. Clinical assessment of alcohol use and abuseA. The amount and frequency of alcohol use and

other drug use in the past month, week, and dayshould be determined. Whether the patient everconsumes five or more drinks at a time (bingedrinking) and previous abuse of alcohol or otherdrugs should be assessed.

B. Effects of the alcohol or drug use on the patient'slife may include problems with health, family, job orfinancial status or with the legal system. History ofblackouts, motor vehicle crashes, and the effect ofalcohol use on family members or friends shouldbe evaluated.

Clinical Clues to Alcohol and Drug Disorders

Social historyArrest for driving under theinfluenceLoss of job or sent homefrom work for alcohol- ordrug-related reasonsDomestic violenceChild abuse/neglect

Family instability (divorce,separation)Frequent, unplanned ab-sencesPersonal isolationProblems at work/schoolMood swings

Medical historyHistory of addiction to anydrugWithdrawal syndromeDepressionAnxiety disorderRecurrent pancreatitisRecurrent hepatitisHepatomegalyPeripheral neuropathyMyocardial infarction atless than age 30 (cocaine)Blood alcohol level greaterthan 300 mg per dL orgreater than 100 mg per dL

Alcohol smell on breath orintoxicated during officevisitTremorMild hypertensionEstrogen-mediated signs(telangiectasias, spiderangiomas, palmar ery-thema, muscle atrophy)Gastrointestinal complaintsSleep disturbancesEating disordersSexual dysfunction

DSM-IV Diagnostic Criteria for Substance De-pendence

A maladaptive pattern of substance use leading to clinicallysignificant impairment or distress as manifested by 3 ormore of the following occurring at any time during the same12-month period.

Tolerance, as defined by one of the following:• A need for markedly increased amounts of the sub-

stance to achieve intoxication of the desired effect.• Markedly diminished effect with continued use of the

same amount of the substance.

Withdrawal, as manifested by one of the following:• The characteristic withdrawal syndrome for the sub-

stance.• The same, or a closely related, substance is taken to

relieve or avoid withdrawal symptoms.• The substance is often taken in larger amounts or

over a longer period than was intended.• There is a persistent desire or unsuccessful efforts to

cut down or control substance use.• A great deal of time is spent in activities necessary to

obtain the substance, use the substance, or recoverfrom its effects.

• Important social, occupational, or recreational activi-ties are given up or reduced because of substanceuse.

• Substance use is continued despite knowledge ofhaving a persistent or recurrent physical or psycho-logic problem that is likely caused or exacerbated bythe substance.

II. Laboratory screeningA. Mean corpuscular volume. An elevated mean

corpuscular volume (MCV) level may result fromfolic acid deficiency, advanced alcoholic liverdisease, or the toxic effect of alcohol on red bloodcells. MCV has poor sensitivity for predictingaddiction.

B. Gamma-glutamyltransferase. The sensitivity ofGGT for predicting alcohol addiction is higher thanthat of MCV, but its specificity is low.

C. Other liver function test results may be elevatedbecause of heavy alcohol consumption, includingaspartate aminotransferase (AST) and alanineaminotransferase (ALT). These markers have lowsensitivity and specificity. An AST/ALT ratiogreater than 2:1 is highly suggestive of alcohol-related liver disease.

D. Carbohydrate-deficient transferrin (CDT).Consumption of 4 to 7 drinks daily for at least 1week results in a decrease in the carbohydratecontent of transferrin. The sensitivity and specificityof CDT are high.

III. Alcohol intoxication. Support is the main treatmentfor alcohol intoxication. Respiratory depression isfrequently the most serious outcome. Unconsciouspatients should receive thiamine intravenously beforereceiving glucose.

IV. Alcohol withdrawal. Treatment consists of fourdoses of chlordiazepoxide (Librium), 50 mg every 6hours, followed by 3 doses of 50 mg every 8 hours,followed by 2 doses of 50 mg every 12 hours, andfinally 1 dose of 50 mg at bedtime.

Signs and Symptoms of Alcohol Withdrawal

Withdrawal is characterized by the development of a com-bination of any of the following signs and symptoms sev-eral hours after stopping a prolonged period of heavydrinking:

1. Autonomic hyperactivity: diaphoresis, tachycardia, ele-vated blood pressure2. Tremor3. Insomnia4. Nausea or vomiting5. Transient visual, tactile, or auditory hallucinations orillusions6. Psychomotor agitation7. Anxiety8. Generalized seizure activity

Management of Alcohol Withdrawal

ClinicalDisorder

Mild/Moderate AWS, ableto take oral

Mild/Moderate AWS,unable totake oral

SevereAWS

AdrenergicHyperactiv-ity

Lorazepam(Ativan) 2 mgpo q2h orChlordiaz-epoxide (Libri-um) 25-100mg po q6h

Lorazepam1-2 mgIM/IV q1-2h asneeded

Lorazepam1-2 mg IV q5-10 min

Dehydration Water or juicepo

NS 1 literbolus, thenD5NS 150-200 mL/h

Aggressivehydrationwith NS/D5NS

NutritionalDeficiency

Thiamine 100mg poMultivitaminsFolate 1 mgpo

Thiamine100 mg IVMultivita-mins 1amp in firstliter of IVfluidsFolate 1mg IV infirst liter ofIV fluids

Thiamine100 mg IVMultivita-mins 1 ampin first liter ofIV fluidsFolate 1 mgIV in firstliter of IVfluids

Hypoglycemia

High fructosesolution po

25 mL D50IV (repeatas neces-sary)

25 mL D50IV (repeatas neces-sary)

Hyperthermia

Coolingblankets

Seizures Lorazepam(Ativan) 2 mgIV

Lorazepam2 mg IV

Lorazepam2 mg IV

V. Sedative-hypnotic withdrawal. Establishment ofphysical dependence usually requires daily use oftherapeutic doses of these drugs for 6 months orhigher doses for 3 months. Treatment of withdrawalfrom sedative-hypnotics is similar to that of withdrawalfrom alcohol; chlordiazepoxide (Librium) andlorazepam (Ativan) are the drugs of choice.

VI.Maintenance treatmentA. Twelve-step programs make a significant contri-

bution to recovery. Alcoholics Anonymous (AA) isthe root of 12-step programs.

B. Drugs for treatment of alcohol addiction1. Disulfiram inhibits aldehyde dehydrogenase.

On ingesting alcohol, patients taking disulfiramexperience flushing of the skin, palpitations,decreased blood pressure, nausea, vomiting,shortness of breath, blurred vision, and confu-sion. Death has been reported. Side effectsinclude drowsiness, lethargy, peripheral neurop-athy, hepatotoxicity, and hypertension. Theusual dose is 250 to 500 mg daily.

2. Naltrexone, an opioid antagonist, reducesdrinking. It has diminished effectiveness overtime and does not reduce relapse rates.

3. Serotonergic drugs reduce drinking in heavy-drinking, nondepressed alcoholic patients, butonly 15% to 20% from pretreatment levels.

4. Acamprosate (calcium acetylhomotaurinate)reduces the craving for alcohol. Acamprosateappears to result in more frequent and longer-lasting periods of abstinence than doesnaltrexone.

VII. Opiates

Signs and Symptoms of Opiate Withdrawal

1. Mild elevation of pulse and respiratory rates, bloodpressure, and temperature2. Piloerection (gooseflesh)3. Dysphoric mood and drug craving4. Lacrimation and/or rhinorrhea5. Mydriasis, yawning, and diaphoresis6. Anorexia, abdominal cramps, vomiting, and diarrhea7. Insomnia8. Weakness

Agents Used to Treat Opiate Withdrawal

Methadone (Dolophine) is a pure opioid agonist restrictedto inpatient treatment or specialized outpatient drug treat-ment programs. Treatment is a 15- to 20-mg daily dose for2 to 3 days, followed by a 10 to 15 percent reduction indaily dose.

Clonidine (Catapres) is an alpha-adrenergic blocker. One0.2-mg dose every 4 hours to relieve symptoms of with-drawal may be effective. It may be continued for 10 to 14days, followed by tapering.

Buprenorphine (Buprenex) is a partial mu-receptor ago-nist which can be administered sublingually in doses of 2,4, or 8 mg every 4 hours for the management of opiatewithdrawal symptoms.

Naltrexone (ReVia, Trexan)/clonidine involves pretreat-ment with 0.2 to 0.3 mg of clonidine, followed by 12.5 mgof naltrexone (a pure opioid antagonist). Naltrexone isincreased to 25 mg on day 2, 50 mg on day 3, and 100 mgon day 4, with clonidine doses of 0.1 to 0.3 mg 3 timesdaily.

VIII. Stimulant Drugs

Signs and Symptoms of Cocaine or StimulantWithdrawal

1. Dysphoric mood2. Fatigue, malaise3. Vivid, unpleasant dreams4. Sleep disturbance5. Increased appetite6. Psychomotor retardation or agitation

A. Stimulant withdrawal is treated with bromocriptine(Parlodel). This drug reduces stimulant craving andwithdrawal symptoms. Bromocriptine dosage is0.625 to 2.5 mg taken orally three times daily.

B.An alternative protocol uses desipramine to reducethe stimulant craving and postwithdrawal symp-toms. Desipramine may be used alone or withbromocriptine. The initial dosage of desipramine is50 mg per day taken orally. This dosage is in-creased until a dosage of 150 to 200 mg isachieved. Paranoia or combativeness is treatedwith lorazepam, 2-mg IM.


Anorexia NervosaAnorexia nervosa is a psychologic illness characterizedby marked weight loss, an intense fear of gaining weighteven though the patient is underweight, a distorted bodyimage and amenorrhea. Anorexia primarily affectsadolescent girls and occurs in approximately 0.2 to 1.3percent of the general population.

I. Diagnosis and Clinical FeaturesA. The typical patient with anorexia nervosa is an

adolescent female who is a high achiever. Sheusually has successful parents and feels compelledto excel. She is a perfectionist and a good student,involved in many school and community activities.

DSM-IV Diagnostic Criteria for AnorexiaNervosa

• Refusal to maintain body weight at or above a minimallynormal weight for age and height (eg, weight loss lead-ing to maintenance of body weight less than 85 percentof that expected; or failure to make expected weightgain during a period of growth, leading to body weightless than 85 percent of that expected).

• Intense fear of gaining weight or becoming fat, eventhough underweight.

• Disturbance in the way in which one's body weight orshape is experienced, undue influence of body weightor shape on self-evaluation, or denial of the serious-ness of the current low body weight.

• In postmenarchal females, amenorrhea, ie, the absenceof at least three consecutive menstrual cycles. (Awoman is considered to have amenorrhea if her periodsoccur only following hormone, eg, estrogen, administra-tion.)

Specify type:• Restricting type: During the current episode of anorexia

nervosa, the person has not regularly engaged in binge-eating or purging behavior (ie, self-induced vomiting orthe misuse of laxatives, diuretics or enemas).

• Binge-eating/purging type: During the current episodeof anorexia nervosa, the person has regularly engagedin binge-eating or purging behavior (ie, self-inducedvomiting or the misuse of laxatives, diuretics or ene-mas).

B. Persons with anorexia nervosa have a disturbedperception of their own weight and body shape.Individuals perceive themselves as overweighteven though they are emaciated.

Features Associated with Anorexia Nervosa

Bulimic episodesPreparation of elaboratemeals for others but self-limitation to a narrow selec-tion of low-calorie foodsObsessive-compulsive, be-haviorsDenial or minimization ofillness Delayed psychosexual de-velopment Hypothermia Bradycardia Hypotension

Edema Lanugo Overactivity, exercise Early satiety Constipation Skin dryness Hypercarotenemia Hair loss Dehydration

II. TreatmentA. A trial of outpatient treatment may be attempted if

the patient is not severely emaciated, has had theillness for less than six months, has no seriousmedical complications, is accepting her illness andis motivated to change, and has supportive andcooperative family and friends.

B. The first step in the treatment of anorexia nervosais correction of the starvation state. A goal weightshould be set and the patient's weight should bemonitored once or twice a week in the office. Acaloric intake to provide a weight gain of 1 to 3 lbper week should be instituted. Initially, weight gain

should be gradual to prevent gastric dilation, pedaledema and congestive heart failure. Often, anutritional supplement is added to the regimen toaugment dietary intake.

C. During the process of refeeding, weight gain aswell as electrolyte levels should be strictly moni-tored. The disturbed eating behavior must beaddressed in specific counseling sessions.

D. Inpatient treatment is indicated if weight lossexceeds 30 percent of ideal weight; patient ishaving suicidal thoughts; patient is abusing laxa-tives, diuretics or diet pills, or outpatient treatmenthas failed.

E. The drug of choice for the treatment of anorexianervosa is food. In cases of depression refractoryto proper nutrition, an antidepressant may behelpful. The use of serotonin-specific reuptakeinhibitors (SSRIs) is common and has proved toalleviate the depressed mood and moderateobsessive-compulsive behaviors. Fluoxetine(Prozac) has been used successfully in the therapyof anorexia and bulimia; 20-40 mg PO qAM.


Bulimia NervosaBulimia nervosa is characterized by binge eating andinappropriate vomiting, fasting, excessive exercise andthe misuse of diuretics, laxatives or enemas. Bulimianervosa is 10 times more common in females than inmales and affects up to 3 percent of young women. Thecondition usually becomes symptomatic between theages of 13 and 20 years.

I. Diagnostic criteriaA. The diagnostic criteria for bulimia nervosa now

include subtypes to distinguish patients who com-pensate for binge eating by purging (vomitingand/or the abuse of laxatives and diuretics) fromthose who use nonpurging behaviors (eg, fasting orexcessive exercising).

II. Patient evaluationA. Physical examination should include vital signs and

an evaluation of height and weight relative to age.Hair loss, lanugo, abdominal tenderness,acrocyanosis (cyanosis of the extremities), jaun-dice, edema, parotid gland tenderness or enlarge-ment, and scars on the dorsum of the hand shouldbe sought.

B. Laboratory tests include a complete blood countwith differential, serum chemistry and thyroidprofiles, and urine chemistry microscopy testing. Achest radiograph and electrocardiogram may beindicated in some cases.

C. Psychiatric assessment1. Standardized testing should document the

patient's general personality features,characterologic disturbance and attitudes abouteating, body size and weight.

2. A complete history should document the pa-tient's body weight, eating patterns and at-tempts at weight loss, including typical dailyfood intake, methods of purging and perceivedideal weight.

3. The patient's interpersonal history and function-ing, including family dynamics, peer relation-ships, and present or past physical, sexual oremotional abuse should be assessed. Anevaluation of medical and psychiatriccomorbidity, as well as documentation of previ-ous attempts at treatment.

DSM IV Diagnostic Criteria for Bulimia Nervosa

• Recurrent episodes of binge eating. An episode ofbinge eating is characterized by both of the following:

• Eating, in a discrete period of time (eg, within a two-hour period), an amount of food that is definitely largerthan most people would eat during a similar period oftime and under similar circumstances.

• A sense of lack of control over eating during the epi-sode (eg, a feeling that one cannot stop eating or con-trol what or how much one is eating).

• Recurrent inappropriate compensatory behavior inorder to prevent weight gain, such as self-inducedvomiting; misuse of laxatives, diuretics, enemas, orother medications; fasting or excessive exercise.

• The binge eating and inappropriate compensatorybehaviors both occur, on average, at least twice aweek for three months.

• Self-evaluation is unduly influenced by body shape andweight.

• The disturbance does not occur exclusively duringepisodes of anorexia nervosa.

Specify type:• Purging type: during the current episode of bulimia

nervosa, the person has regularly engaged in self-induced vomiting or the misuse of laxatives, diuretics,or enemas.

• Nonpurging type: during the current episode ofbulimia nervosa, the person has used other inappropri-ate compensatory behaviors, such as fasting or exces-sive exercise, but has not regularly engaged in self-induced vomiting or the misuse of laxatives, diuretics,or enemas.

III. TreatmentA. Tricyclic antidepressants. Desipramine, 150 to

300 mg per day, is superior to placebo in thetreatment of bulimia nervosa. Imipramine, 176 to300 mg per day, is also beneficial. Amitriptyline,150 mg per day, is effective in reducing bingeeating (72 percent).

B. Selective serotonin reuptake inhibitors.Fluoxetine (Prozac), 20-mg dosage, results in a 45percent reduction in binge eating. Fluoxetine in adosage of 60 mg per day produces the best treat-ment response, demonstrating a 67 percent reduc-tion in binge eating.

C. Psychotherapy. Cognitive-behavioral therapy hasresulted in the most significant reductions of bingeeating and/or purging. Cognitive-behavioral ther-apy principally involves interventions aimed ataddressing preoccupation with body, weight andfood, perfectionism, dichotomous thinking and lowself-esteem. The initial goal of cognitive-behavioraltherapy is to restore control over dietary intake.

References

References are available at www.ccspublishing.com.

treatment guidelines

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