Download - Pulmonary HTN
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Pulmonary
Hypertension
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How Common is It?
Pulmonary Hypertension Relatively CommonPulmonary Arterial
Hypertension RelativelyUncommon
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What is the Difference?
Pulmonary Hypertension = A general term used todescribe elevated pressure in the pulmonary vascularbed, not describing where the
lesion
is.
Pulmonary Arterial Hypertension = A term thatdescribes elevated pressure in the pulmonary
vasculature, limited to the arteries/arterioles, and due toan intrinsic abnormality in the pulmonary arterial bed.
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Definition of PAH by WHO
Required:Mean PAP 25 mm Hg at rest or 35 mmHg
with exercisePCWP 15 mm Hg
Should be present:PVR 3 Wood Units (240 dynes.sec.cm -5)
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A Word about Hemodynamics
The right heart catheterization is crucial.Diagnosis and/or treatment choices shouldalmost never be made based uponechocardiography alone, it is a screening tool.Useful calculations:
mPAP = 1/3 sPAP + 2/3 dPAPPVR = mPAP PCWP / C.O.
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PAH The term PAH represents truepulmonary ateriopathy,
characterized by:In situ microthrombosisPlexiform lesion formation
Leads to progressive increase inpulmonary vascular resistance andculminates in right heart failure and
death Three key pathogeneses:Relative decrease inbioavailability of NORelative increase in serumendothelin-1
Relative deficieny ofPGI2/excess of thromboxane
A2 The term PH represents increasedPAP but not due to intrinsic
vascular disease
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Classification of PH
The current classification system groupstogether forms of pulmonary hypertensionbased on similarities in their pathophysiologiesand responses to treatment.Important to classify patients correctly to ensuretherapeutic choices are appropriate.Current classification system revised in 2003,
with recent update pending (2/2008).
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Group 1 -- PAHIPAHFamilial
Associated with PAHConnective Tissue Disease (Scleroderma, SLE, MCTD, DM/PM, RA)Congenital Heart DiseasePortal hypertension (5-7% of patients)HIV (0.5% of patients)Drugs/toxins (aminorex-, dexfenfluramine-, or fenfluramine-containing products, cocaine, methamphetamine)Other: thyroid disorders, glycogen storage disease, Gaucher
s disease,hereditary hemorrhagic telangiectasia, hemoglobinopathies,
myeloproliferative disorders, splenectomy Associated with venous/capillary involvement
Pulmonary veno-occlusive disease (elevated mPAP, normal PCWP,evidence of pulmonary vascular congestion)Pulmonary capillary hemangiomatosis
PPHN
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Groups 2-5 -- PHGroup 2: Pulmonary hypertension with left heart disease
Left-sided ventricular or atrial diseaseLeft-sided valvular disease
Group 3: Pulmonary hypertension associated with lung disease and/orhypoxemia
Chronic obstructive lung diseaseInterstitial lung diseaseSleep-disordered breathing
Alveolar hypoventilation disordersChronic exposure to high altitudeDevelopmental abnormalities
Group 4: Pulmonary hypertension due to chronic thrombotic and/or embolicdisease
Thromboembolic obstruction of proximal pulmonary arteries Thromboembolic obstruction of distal pulmonary arteries
Group 5: MiscellaneousSarcoidosis, histiocytosis X, lymphangiomyomatosis, compression of
pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)
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Symptoms of PAH
Dyspnea 60%Fatigue 19%Near syncope/syncope 13%Chest pain 7%Palpitations 5%LE edema 3%
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Reasons to Suspect PAH
Unexplained dyspnea despite multiplediagnostic tests
Typical symptoms (look for Raynaud
s)Comorbid conditons:
CREST, liver disease, HIV, sickle cell
Family history of PAHHistory of stimulant/anorexigen use
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Why is it missed?
Young patients with non-specific sxs with nlCXR and EKGs often attributed to
somatization and treated with reassuranceLack of therapies in earlier era lead to attitudeof indifference with regard to aggressive
workupComorbid conditions with similar sxs
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Physical exam clues TelengectasiasCalcinosisRaynaud
s
Palmar erythema/stigmata of liver dz JVDRV heaveMurmur TR, VSD/ASDLoud P2 (can hear 2nd heart sound clearly atapex)Clubbing
LE edema
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Diagnostic Work-up
Labs Autoimmune serologiesMarkers of liver synthetic function
HIV serologies when dictated by historyEKG
Not sensitive enough to be a screen but can help guide dx workup
RVH 87% of PHRAD 79% of PHRAE: p wave > 2.5 mm in II, III, aVF
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Diagnostic Work-up
Chest x-rayNot sensitive enough to screen
Attenuated
motheaten
peripheral vasculatureEnlarged PAs (especially right)
EchocardiogramOrder for screening when clinical suspicion existsOrder for standard interval screening in selected groups:
Family of those with IPAH or with known BMPR2 mutationScleroderma spectrumCHD ptsPre-liver transplant
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Always Rule out CTEPH
Must be excluded in every case of PAHPotentially surgically remediable
1 center with most experience = UCSD V/Q scan is preferred screening test, not PE protocolCT (this is best for acute emboli).In chronic thromboembolic disease, at least one (andmore commonly, several) segmental or largermismatched ventilation-perfusion defects are present.Formal angiography will be done before surgicalprocedure if V/Q positive
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Right Heart Cath
Essential for firm diagnosis:Helps to not dx people with PAH that do not haveit!
Vasoreactivity testingNO, Flolan, Adenosine drop in mPAP by 10 mmHg to
value < 40 mmHgPredicts CCB response
Evaluate for septal defectsShed light on the issue of diastolic dysfunctionInterpret data in context of patient
s volume status
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How do we Treat Them?
General measures: Avoid pregnancy
Contraception imperativeMaternal mortality 30%
Immunizations for respiratory illnessesInfluenza & pneumonia vaccinations
Minimize valsalva maneuvers increase risk ofsyncopeCough, constipation, heavy lifting, etc
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Classes of therapyMedical
DiureticsCoumadin (IPAH, Anorexigen)OxygenPAH specific therapy
Surgical therapy Atrial septostomyLung transplantation
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Diuretics
Principally to treat edema from right heartfailure
Ventricular interdependence ensure LV outputpreserved.May need to combine classes-Thiazide and loop diuretics
Careful to avoid too much pre-load reductionPatients often require large doses of diuretics
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Coumadin
Studies only show benefit in IPAH patients,based on improved survival.Other PAH groups not as clear, use in themconsidered expert opinion.Generally, keep INR 2.0-2.5.
Thought to lessen in-situ thrombosis
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Oxygen
Formal assessment of nocturnal and exertionaloxygenation needs.Minimize added insult of hypoxic vasoconstriction
Keep oxygen saturation 90% May be impossible with large right to left shunt
Exclude nocturnal desaturation
Overnight oximetryRule out concomitant obstructive sleep apnea andhypoventilation syndromes
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WHO functional classification
PAHClass I: No limitation in physical activity. Ordinaryphysical activity does not cause undue dyspnea or fatigue,chest pain or near syncope.Class II: Slight limitation in physical activity. Ordinaryphysical activity causes undue dyspnea or fatigue, chestpain or near syncope.Class III: Marked limitation in physical activity. Less than
ordinary physical activity causes undue dyspnea or fatigue,chest pain or near syncope.Class IV: Inability to perform any physical activity
without symptoms. Signs of right heart failure. Dyspneaand/or fatigue may be present at rest. Syncope.
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PAH-Specific Therapies
Calcium channel blockersEndothelin receptor antagonists (ERAs) bosentan , sitaxsentan, ambrisentanPhosphodiesterase (type 5) inhibitors (PDE 5-I)--sildenafilProstanoids epoprostenol , treprostinil,iloprost
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Calcium Channel Blockers
Use only when demonstrated vasoreactivity inRHC (about 10% or less of patients)Diltiazem or nifedipine preferred.
Titrate up to maximum tolerated dose.Systemic hypotension may prohibit useOnly 50% of patients maintain response toCCB.Not in FC IV patients or severe right heartfailure
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Endothelin Receptor Antagonists(ETRA)
Targets relative excess of endothelin-1 by blockingreceptors on endothelium and vascular smooth muscleBosentan (Tracleer, 5 yrs) and ambrisentan (Letairis, 1
yr) Ambrisentan is ET-A selective.Both show improvement in 6MWD and time to clinical
worsening.Monthly transaminase monitoring required for both Annual cost about $40,000
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Bosentan (Tracleer)
215 patients
70% IPAH92% Class III Week 16: 36 meterImprovement44 meter
treatmenteffect
1Adapted from Rubin LJ et al. N Engl J Med 2002;346:896-903
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Bosentan (Tracleer)Improved Hemodynamics
Adapted from Channick, et al. Lancet 2001
C h a n g
e f r o m
b a s e
l i n e
( % )
TracleerPlacebo
-30%
-20%
-10%
0%
10%
20%
30%
40%
50%
PAP - 6.7 mm Hg
(p
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Bosentan (Tracleer)Potential for serious liver injury (including very rare cases of unexplained hepatic
cirrhosis after prolonged treatment)
Tracleer causes at least a 3-fold increase in aminotransferases (ALT and AST) in
about 11% of patients and may be accompanied by an elevation of bilirubin in a
small number of cases Teratogenic and lowers sperm Significant drug interactions Glyburide inhibits bosentan metabolism Bosentan induces metabolism of oral
contraceptives, warfarin, and statins Calcineurin inhibitors (cyclosporin A,tacrolimus), protease inhibitors, amiodarone, ketoconozole
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Bosentan (Tracleer)
Oral dosingInitiate at 62.5 mg BID for first 4 weeksIncrease to maintenance dose of 125 mg BID thereafterInitiation and maintenance dose of 62.5 mg BIDrecommended for patients >12 years of age with body
weight
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Ambrisentan (Letairis)
5 or 10 mg once dailyMuch less risk of transaminase elevation (about1%), but monthly monitoring still requiredNo dose adjustment of coumadin needed
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PDE-5 inhibitors
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
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Sildenafil (Revatio)
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
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Sildenafil (Revatio)
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
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Sildenafil (Revatio)
SafetySide effects: headaches, epistaxis, and hypotension(transient)
Sudden hearing lossDrug interaction with nitratesFDA approved dose is 20 mg tid
Higher doses often used given hemodynamic findings.
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Prostacyclin analogues
Epoprostenol, treprostinil, iloprostBenefits
VasodilationPlatelet inhibition
Anti-proliferative effectsInotropic effects
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Epoprostenol (Flolan)
First PAH specific therapy available in the mid1990
sLack of acute vasodilator response does notcorrelate well with epoprostenolunresponsiveness.
Very short half life = 2 minutesDelivered via continuous infusionCost about $100,000/year
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Epoprostenol (Flolan)
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
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Epoprostenol (Flolan)
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
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Epoprostenol (Flolan)
Side effects: headache, jaw pain, flushing,diarrhea, nausea and vomiting, flu-likesymptoms, and anxiety/nervousnessComplex daily preparation
Individualized dosingCatheter complications
Dislodgement/malfunctionCatastrophic deteriorationEmbolization
Infection (3% deaths)
1 Flolan Flolan[package [package insert]. Research Triangle Park, NC:GlaxoSmithKline;2002 insert].Research Triangle Park, NC:GlaxoSmithKline;20022Rich S et al. Rich S et al. J Am College J Am College Cardiol Cardiol 1999;34:1184 1999;34:1184-87 87McLaughlin V et al. McLaughlin V et al. Circulation Circulation 2002;106:1477 2002;106:1477-82 82
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Treprostinil (Remodulin)
Continuous subcutaneousinfusion or IV infusionLonger t1/2 than flolan = 4hours
Less risk of rapid fataldeterioriation if infusion stops
Significant site pain at infusionsite limits use
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
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Treprostinil (Remodulin)
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
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Treprostinil (Remodulin)
Intravenous treprostinilHemodynamic improvements and 6MWDimprovements 1
No site painRisk of catheter related bloodstream infection andembolic phenomenonRecent concerns about increased gram-negativebloodstream infections (CDC MMWR March 2,2007 / 56(08);170-172)
1Tapson VF et al. Chest 2006;129:683-88
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Iloprost (Ventavis)
Inhaled prostacyclin Administered 6-9 timesdaily via special nebulizer
Reported risk ofmorning syncope
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Iloprost (Ventavis)
Improvements in 6MW, functional class and hemodynamicsobserved
Olschewski H et al. N Engl J Med 2002;347:322-29
Safety and side effectsPotential for increased hypotensive effect
with antihypertensivesIncreased risk of bleeding, especially with
co-administration of anticoagulantsFlushing, increased cough, headache, insomniaNausea, vomiting, flu-like syndromeIncreased liver enzymes
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ACCP 2007 Treatment Guidelines
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Following Response to Therapy
Six minute walk testEchocardiogramRight heart catheterizationBNPFunctional class
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Acute Decompensations
Patients with advanced PAH may present acutely with volume overload, marginal blood pressure, and, attimes, elevated creatinine, related either to an acuteprocess or simply worsening RV failure.
In the decompensated patient, elevated RV volumeleads to septal shift, with reduced left ventricular end-diastolic volume and low cardiac output.
Treatment of the acutely ill patient with PAH shouldinclude careful evaluation for secondary causes ofdecompensation such as a low-grade line infection (forthose on an intravenous therapy) or pulmonarythromboembolism.
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Acute Decompensations
Many patients are volume overloaded at presentation,and diuresis, even in the setting of marginal cardiacoutput and low blood pressure, may be required.
In some cases, support with inotropes or pressors isnecessary: animal data suggest a better hemodynamicresponse with sympathomimetic agents such asdobutamine, norepinephrine, and dopamine rather than
vasopressin or phenylephrine; milrinone also hasfavorable effects on cardiac output but may lead toexcessive hypotension.
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Summary
Make sure to differentiate PAH from PHDetermine etiology of PAH as best as possibleRefer early to specialist if you find itDon
t treat without a RHC Treat agressively, don
t settle for
stability