Sudden Cardiac Arrest BRUGADA SYNDROMECarlo Francisco S. Gochuico, M.D.

August 14, 2008

OBJECTIVESTo present a case of sudden cardiac arrest in a young maleTo discuss the approach and management of Brugada syndrome

General DataJ.D.28 year oldMaleFilipino

Chief ComplaintLoss of consciousness

History of Present IllnessOne hour PTAFound unconsciousSeen with upward rolling of eyeballs, stiffening of extremities, and salivary poolingLasted 3 to 5 minutes Regained full consciousness with no recollection of the incidentWas able to drink, sit on a chair, and talk with parentsNo slurring of speech, no extremity weakness, no chest pain

History of Present IllnessFive minutes after Recurrence of stiffening of extremities and upward rolling of eyeballsRushed to MMC ERDuring transit, he remained unconscious

Events at ERQuicklook showed cyanosisBP 0 HR 0GCS 3 E1V1M1 Initial tracing at ER at 1:42 AMChest compressions and bag mask ventilationDefibrillation at 200 joulesEpinephrine 1mg IVIntubated and advised ICU admissionCXRAY, stat5 and ABG

12 L EKG 8-1-08 2:16 AM post defibrillation CRBBB PR interval 0.16 sec QT interval 0.36 sec

Events at ER2:33 AM at ERSystolic BP170Pulse 80s regularPost CP arrest

Events at ER2:47 AM Episode of stiffening of extremitieschest compression and defibrillation at 200 joules

Events at ER2:52 AM Post defibrillationBP 120/80Pulse 80sAmiodarone drip startedCardiac enzymesReferred to neurologyAdmitted to ICU

Review of SystemsGeneral: no fever, fatigue, weight lossSkin: no rashes, jaundice, ecchymoses, petechiaeHead: no recent head injury, headache, dizzinessEyes: no blurring of vision, redness, painEars: no tinnitus, vertigo, earache, discharge

Review of SystemsNose: no colds, nasal congestion, dischargeMouth: no sore throat, hoarsenessNeck: no pain, lumps, mass, stiffnessRespiratory: no cough, dyspnea, wheezing, hemoptysisCardiac: no chest pain, palpitations, orthopnea, PND, edema, recent chest trauma

Review of SystemsGastrointestinal: no nausea, vomiting, regurgitation, dysphagia, hematemesis, abdominal pain, change in frequency and characteristic of stoolsUrinary: no hematuria, dysuria, oliguria, polyuria, urgency, hesitancyVascular: no claudication, varicose veins, leg crampsMusculoskeletal: no myalgia, arthralgia, and swelling

Review of SystemsHematologic: no anemia, pallor, easy bruising or bleedingEndocrine: no heat or cold intolerance, no excessive thirst or hungerPsychiatric: no depression, nervousness

Past Medical HistoryNo history of HPN, DM, and BAPTB, treated for 6 monthsNo previous seizure disorder, no known neurologic and cardiac problemsHad a history of syncope during early childhood and another one a year ago, no work-ups were done

Family History(+) HPN in paternal side(-) DM, BA, stroke, cancerNo seizure disorder

Personal and Social HistoryOccasional smokerOccasional alcoholic beverage drinkerDenies illicit drug use

PHYSICAL EXAMINATIONConscious, restless, intubatedBP 120/80 HR 80 regular RR 20 assisted afebrileWarm moist skin, no active dermatoses, no jaundiceAnicteric sclerae, pink palpebral conjunctivae, pupils 2-3 mm ERTL OUNo visible anterior neck mass, no neck vein distention, no carotid bruitNo cervical lymphadenopathies

PHYSICAL EXAMINATIONEqual chest expansion, no retractions, no rales, wheezes, cracklesAdynamic precordium, AB at 5th LICS MCL, regular rhythm, S1>S2 at base, S2>S1 at apex, no extra heart sounds, no murmursAbdomen flabby, normoactive bowel sounds, soft, no guarding, no direct and rebound tenderness, no hepatosplenomegalyNo costovertebral angle tendernessNo pedal edemaPulses full and equal

PHYSICAL EXAMINATIONGCS 11 E4V1 (intubated) M6No papilledemaFull and equal EOMNo facial asymmetryIntact dolls eye movement, gag and corneal reflexesDirect tendon reflexes normalMotor and Sensory: intactLocalizes to pain and temperatureNo babinski, kernigs, and brudzinski

Salient Features28 M FilipinoLoss of consciouness at night during sleep2 episodes of stiffening of extremitiesPost CP arrest 2x (VFib)No fever, headache, chest pain, weakness

History of syncope 2xPositive family history of cardiac diseaseNo illicit drug use

Differential Diagnosis

Differential Diagnosis

Differential Diagnosis

Differential DiagnosisStructural heart diseasesIschemic heart diseaseNon-ischemic cardiomyopathiesValvular heart diseasesArrhythmogenic right ventricular dysplasiaPrimary electrophysiologic abnormalitiesLong QT syndromeBrugada syndrome

IschemiaCardiac arrest due to ventricular arrhythmias may be due to chronic scar or to acute MI/ischemia. A chronic infarct scar can serve as the focus for reentrant ventricular tachyarrhythmias

Non-ischemic cardiomyopathiesrepresent the second largest group of patients who experience SCD Dilated cardiomyopathy is usually characterized by ventricular dilatation, initially usually of the left ventricle (LV), with myocyte hypertrophy and diminished systolic function

Hypertrophic cardiomyopathy (HCM)an autosomal-dominant, incompletely penetrant genetic disorder resulting from a mutation in one of the many (>45) genes encoding proteins of the cardiac muscle sarcomere

Echo of HCMSmall LV cavity due to marked hypertrophy of the myocardium and encroachment into the LV cavity Reduced septal motion and thickening during systole, particularly of the upper septum, due to the disarray of the myofibrillar architecture and abnormal contractile function Reduced rate of closure of the mitral valve in mid diastole due to a decrease in LV compliance Left atrial enlargement

Course in the Ward1st Hospital day in the ICU (1230 PM)Repeat 12L EKG doneRsr patternST elevation in lead V1-V3

2D echo N LVD EF69% Normal LA and RA dimensionsNormal MV, TV, AV, PVMild MR, TRNormal left ventricular diastolic function indices

FIo2 adjusted to 0.35

Course in the WardICU at 1500HT-piece placed and repeat ABG doneReferred to cardiology EPSThyroid function test requestedQuinidine bisulfate started

Course in the WardICU at 1750 HPatient extubated

4th Hospital dayTransferred to regular roomQuinidine 200mg/tab adjusted to 1 tablets in the morning and evening, and 1 tablet at lunchtime

Course in the Ward5th hospital dayRepeat 12 L EKGNormal

Discharged on 6th hospital dayFollow-up after 1 week

CXRAY Aug 1, 2008Lungs are clearHeart is magnifiedET in place with tip at carina

Cranial CT Scan Aug 1, 08Normal non-contrast CT of the brain

EEGNormal

2D ECHOCARDIOGRAPHYAugust 1, 2008Normal left ventricular dimension with normal wall motion and contractility.Computed LV EF 69%Normal left and right atrial dimensionsNormal mitral, aortic, tricuspid, and pulmonic valvesMild MR, TRNormal left ventricular diastolic function indices

Repeat 12 L EKG 8-1-08 12:30 PM IRBBBPR interval 0.16 secQT interval 0.40 sec

Laboratory Results and Ancillary ProceduresCBCHgb 16.8Hct 50.2WBC 14.21seg54 lymph36 eos4 mono5 Baso1Platelet 204000Stat 5Na 137K 2.7Hgb 16.7Hct 49Glucose (random) 245 mg/dL

Laboratory Results and Ancillary Procedures

PTTpatient 27.3control 27.6

PTpatient 11.1control 11.7activity 115.6%INR 0.94Cardiac enzymesCK total 165 U/LCPK MB 1.4 ng/mLTroponin I 0 ng/mL

Laboratory Results and Ancillary Procedures

glucose 120 CPK 506 LDH 262ALT 185 AST 82 alkaline phosphatase 148

SPEC 23Na 137 K 3.6 Cl 103 calcium 9.78 BUN 13 creatinine 1.1HDL 46 trig 119 LDL 166 cholesterol 245

Laboratory Results and Ancillary ProceduresRoutine urinalysisYellow hazy PH 6 spgr 1.020 +3 protein trace sugar negative ketones, nitrites, leucocyte esterase +1 blood rbc 2/hpf wbc 2/hpf epith 10/hpfBact 15/hpfThyroid Function TestTSH 0.037 (0.27-3.75)FT3 4.419 (4.2-12)FT4 17.815 (8.8-33)

Laboratory Results and Ancillary ProceduresABGPost intubation PO2 426.2 PH 7.34 PCO2 41 HCO3 22.1 O2 sat 99.8 AC mode 100% FiO2 VT 420

Laboratory Results and Ancillary ProceduresABG

5 PM PO2 169.1 PH 7.39 PCO2 37.3 HCO3 22.5 O2 sat 99.1 inline neb via T piece 35% FiO2

Repeat 12 L EKG 8-6-08 9:54 AM NormalPR interval 0.20 secQT interval 0.44 sec

DISCUSSIONSudden cardiac death (SCD) is an unexpected death due to cardiac causes, heralded by loss of consciousness occurring in a short time period (generally within 1 hour of symptom onset)Most cases are due to cardiac arrhythmias such as VF or VT which is responsible for 50-80% of cases

Sudden Cardiac DeathMost cases of SCD occur in patients with structural abnormalities in the heart, related to either a prior MI, coronary artery disease, cardiomyopathiesValvular diseases such as aortic stenosis are associated with increased risk of SCDAcute inflammatory and infiltrative disorders, such as myocarditis, provide a sustained risk of SCD

Sudden Cardiac DeathLess commonly, SCD happens in patients who may not have apparent structural diseaseThese conditions are usually inherited arrhythmia syndromes or primary electrophysiologic abnormalities

Primary Electrophysiologic AbnormalitiesThis generally represents a group of abnormalities in which patients have no apparent structural heart disease but have a primary electrophysiologic abnormality that predisposes them to VF or VTBrugada syndrome, Long QT syndrome

Brugada SyndromeA cardiac disease caused by an inherited ion channelopathy associated with a propensity to develop ventricular fibrillation (VF)Reported as early as 1953 but was first described as a distinct clinical entity associated with a high risk of sudden cardiac death in 1992

Brugada SyndromeIn the 1980s, the Centers for Disease Control and Prevention reported a high incidence of sudden death in young immigrants from Southeast Asia.For natives, it is known as lai tai (death during sleep) in Thailand, bangungut (sudden death during sleep) in the Philippines, and pokkuri (unexpected sudden death at night) in Japan

Brugada SyndromeFamilial disease with an autosomal dominant mode of transmission, with incomplete penetrance and an incidence ranging between 5 and 66 per 10 000In Southeast Asia where it is endemic, it is distinguished by a male predominance (8:1 male:female ratio) and the appearance of arrhythmic events at an average age of 40 years (range: 1 to 77 years)

Brugada SyndromeThe syndrome typically manifests during adulthood, with a mean age of sudden death of 41 +/- 15 years. The youngest patient clinically diagnosed with the syndrome is 2 days old and the oldest is 84 years oldBrugada Syndrome: Report of the Second Consensus Conference Circulation 2005

Brugada SyndromeIt is thought that it may cause 4 to 10 sudden deaths per 10,000 inhabitants in Southeast Asia annually, making it the second most common cause of natural death in men aged younger than 40 yearsIn endemic countries, it has been estimated to cause at least 4% of all sudden deaths and at least 20% of all sudden cardiac deaths in patients with structurally normal hearts.Orphanet Journal of Rare Diseases 2006

Brugada SyndromeThe prevalence of BrS in the general population is unknown. The suggested prevalence ranges from 5/1,000 (Caucasians) to 14/1,000 (Japanese)In Laos, it causes an estimated 1 sudden death per 1000 inhabitants per year, and in Thailand, unexpected sudden death is the most common cause of natural death in young people

Brugada SyndromeIt has been linked to a genetic mutation located on the SCN5A gene on chromosome 3 p21-23, which codes for the subunit of the cardiomyocyte sodium ion channelsThis mutation leads to either complete loss of channel function or an accelerated recovery from activationThis can generate heterogeneity of repolarization and increase the chance of intramyocardial re-entry circuits, which may induce ventricular tachyarrhythmias

Genetic mutations detected so far in the Brugada syndrome result in defective myocardial sodium channels that reduce sodium inflow currents, resulting in shorter-than-normal action potentials

Brugada SyndromeIt can also present atrial fibrillation, which is present in 10% to 20% of casesPotential clinical manifestations dizziness, palpitations, syncope, and sudden cardiac deathECG abnormalities constitute the hallmark of Brugada syndrome

Circadian patternVF and sudden death in Brugada syndrome usually occur at rest and at night

Modulating and precipitating factorsThe ECG manifestations of congenital Brugada syndrome are often concealed but can be unmasked or modulated by:Sodium channel blockers, a febrile state, vagotonic agents, alpha and beta adrenergic agonists, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin, hyperkalemia, hypokalemia, hypercalcemia, and alcohol and cocaine toxicity

Brugada Syndrome Electrocardiographic CharacteristicsThe J wave is a deflection that appears in the ECG as a late delta wave following the QRS or as a small secondary R wave (R'). Also referred to as the Osborn wave

Brugada Syndrome Electrocardiographic CharacteristicsType1 is characterized by a prominent coved ST-segment elevation displaying J wave amplitude or ST-segment elevation 2 mm or 0.2 mV at its peak followed by a negative T-wave, with little or no isoelectric separationProposed Diagnostic Criteria for the Brugada Syndrome: Consensus Report Circulation 2002

Brugada Syndrome

Brugada Syndrome Electrocardiographic CharacteristicsType 2 also has a high take-off STsegment elevation, but in this case, J wave amplitude (2 mm) gives rise to a gradually descending ST-segment elevation (remaining 1 mm above the baseline), followed by a positive or biphasic T-wave that results in a saddle back configurationProposed Diagnostic Criteria for the Brugada Syndrome: Consensus ReportCirculation 2002

Brugada Syndrome Electrocardiographic CharacteristicsType 3 is a right precordial ST-segment elevation of 1 mm of saddle back type, coved type, or bothProposed Diagnostic Criteria for the Brugada Syndrome: Consensus ReportCirculation 2002

Brugada SyndromeProposed Diagnostic Criteria for the Brugada Syndrome: Consensus ReportCirculation 2002

Brugada Syndrome: Report of the Second Consensus Conference Circulation 2002It can be established in the presence of:ST-segment elevation (type 1) in more than one right precordial lead (V1 to V3), and one of the following:Documented ventricular fibrillation; self terminating polymorphic ventricular tachycardia; a family history of sudden cardiac death (

Brugada Syndrome: Report of the Second Consensus ConferenceAppearance of type 2 ST-segment elevation ("saddleback type") in more than one right precordial lead upon challenge with a sodium channel blocker. A drug-induced ST-segment elevation to a value >2 mm should raise the possibility of Brugada syndrome when one or more clinical criteria are present

Brugada Syndrome: Report of the Second Consensus ConferenceAppearance of type 3 ST segment elevation in more than one lead under baseline conditions with conversion to type 1 after challenge with a sodium channel blocker is considered equivalent to case 1 aboveDrug-induced conversion of type 3 to type 2 is not considered diagnosticCharacteristic EKG morphologies recorded within the first few hours after resuscitation cannot be taken as diagnostic

Drug ChallengeDrug challenge should be performed while the patient is continuously monitored and with defibrillator and advanced coronary life support facilities close at handDrug administration should be stopped when the test is positive and/or when ventricular arrhythmias, including ventricular premature complexes, are evident, or when significant QRS widening (30%) is observed

Type 2 and type 3 ECGs, the test is recommended to clarify the diagnosis. Conversion of a type 2 or 3 ECG to a type 1 is considered positiveProposed Diagnostic Criteria for the Brugada Syndrome: Consensus Report Circulation 2002

Differential DiagnosisAcute myocardial ischemiaAcute myocarditisTricyclic antidepressant overdoseCocaine intoxicationArrhythmogenic right ventricular dysplasiaLong QT syndrome

Arrhythmogenic right ventricular dysplasiaDiscrimination between BrS and ARVC may be particularly difficult because ARVC may at times mimic BrS Before the diagnosis Brugada syndrome is made, a serious attempt should be taken to exclude ARVC.Drug challenge with sodium channel blockers may be useful in discriminating between these 2 disease

Proposed Diagnostic Criteria for the Brugada Syndrome: Consensus Report Circulation 2002

Long QT syndromeThere is an alteration in the function of a myocellular channel protein that regulates the potassium flux during electrical repolarizationClinical course is variable, some remain aymptomatic and some develop syncope and sudden deathRisk is impacted by factors such as hypokalemia, emotional extremes, and vigorous physical activity

Long QT syndromeinvolve an abnormal repolarization of the heart causes differences in the "refractoriness" of the myocytes leading to re-entrant ventricular arrhythmias

Long QT syndromeA commonly used criterion to diagnose LQTS is the LQTS "diagnostic score. Its based on several criteria giving points to each. With 4 or more points the probability is high for LQTS, and with 1 or less point the probability is low. Two or 3 points indicates intermediate probability.

Long QT syndromeQTc (Defined as QT interval / square root of RR interval) >= 480 msec - 3 points 460-470 msec - 2 points 450 msec and male gender - 1 point Torsade de Pointes ventricular tachycardia - 2 points T wave alternans - 1 point Notched T wave in at least 3 leads - 1 point Low heart rate for age (children) - 0.5 points Syncope (one cannot receive points both for syncope and Torsades de pointes) With stress - 2 points Without stress - 1 point Congenital deafness - 0.5 points Family history (the same family member cannot be counted for LQTS and sudden death) Other family members with definite LQTS - 1 point Sudden death in immediate family (members before the age 30) - 0.5 points

Long QT syndrome

Long QT syndromeBeta blockers are the first choice in treating Long QT syndromeThe only effective form of arrhythmia termination in individuals with LQTS is placement of an implantable cardioverter-defibrillator (ICD). ICD are commonly used in patients with syncopes despite beta blocker therapy, and in patients who have experienced a cardiac arrest.

Brugada: Risk stratificationBrugada et al found that patients initially presenting with aborted sudden death are at the highest risk for a recurrence (69%)Those presenting with syncope and a spontaneously appearing type 1 ECG have a recurrence rate of 19%Men had a 5.5-fold higher risk of sudden death than did women

Brugada SyndromeIndication for ICD implantationBrugada Syndrome Report of the Second Consensus ConferenceEndorsed by the Heart Rhythm Society and the European Heart Rhythm Association

Brugada SyndromeIndication for ICD implantationBrugada Syndrome Report of the Second Consensus ConferenceEndorsed by the Heart Rhythm Society and the European Heart Rhythm Association

Outcome After Implantation of a Cardioverter-Defibrillator in Patients With Brugada SyndromeA Multicenter Study Circulation 2006In this large Brugada syndrome population, a low incidence of arrhythmic events was found, with an annual event rate of 2.6% during a follow-up of 3 yearsDevice-related complications (8.9%/year). Inappropriate shocks were 2.5 times more frequent than appropriate ones

Efficacy of Quinidine in High-Risk Patients WithBrugada SyndromeBernard Belhassen, MD; Aharon Glick, MD; Sami Viskin, MDCirculation 2004Quinidine depresses Ito current, which may play an important role in the arrhythmogenesis of this diseaseIt prevented VF induction in 22 of the 25 patients (88%)The effective quinidine serum blood levels rangedfrom 1.29 to 5.2 mg/L (meanSD, 2.650.99 mg/L)

QuinidineMay exert its beneficial effects in Brugada syndrome by inhibiting Ito, thereby restoring electrical homogeneityIn addition, quinidine prolongs ventricular refractorinessFinally, the anticholinergic effect of quinidine might contribute to its antiarrhythmic efficacy in the Brugada syndromeDespite these hypotheses, the basis for quinidine efficacy in this setting remains to be elucidated

Study shows the following:First, quinidine is highly effective (88% success rate) for preventing VF induction in patients with inducible VFSecond, it also appears to be effective in preventing spontaneous VF, with no arrhythmic events observed during a mean SD follow-up of 56-67 months

Third, the drug could be chronically tolerated with therapeutic effectiveness in 16 study patients (64%)Fourth, no proarrhythmic event occurred in any treated patient despite QT prolongation. Finally, although quinidine related side effects (thrombocytopenia, diarrhea, esophagitis, allergic reaction, aggravation of sinus node dysfunction) were common, they were always transient and invariably resolved after drug discontinuation

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