Roberts, James R. MD
Learning Objectives: After reading this article, the physician should be able to:
1. Discuss the EKG changes of Brugada syndrome.
2. Describe the clinical characteristics of Brugada syndrome.
3. Summarize the complications of Brugada syndrome.
Release Date: July 2009
Emergency physicians read numerous EKGs per day, some with a furtive glance, some with a modicum of analysis, still others with intense scrutiny. Computer readings have helped the clinician's diagnostic acumen, particularly when ****ACUTE MI appears in the printout. There are a few EKG findings that portend significant morbidity, even mortality. One cannot expect EPs always to consider the nuances of the ST segment or T wave peccadilloes, and certainly there are some subtle yet serious EKG findings that escape even a seasoned cardiologist.
I discussed the unusual but potentially arrhythmogenic QTC prolongation in a patient overdosed with methadone last month, especially its propensity for Torsades de pointes. The prescient clinician might consider the ramifications of such subtle EKG findings in someone with syncope or palpitations when there is methadone in the serum.
This month's EKG contender, Brugada syndrome (BS), is one of those findings that will elude many if not most EPs. This is a relatively new and rare entity, but one that is currently the object of much interest to the erudite cardiologists who study such things. This syndrome is not an expected pickup by ED clinicians, at least not yet, but if you're perceptive enough to spot it, you will certainly look like a star.
Brugada Syndrome: Report of the Second Consensus Conference: Endorsed by the Heart Rhythm Society and the European Heart Rhythm Association
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Antzelevitch C, et al
This is an alarming article dealing with a topic that has received little attention in the emergency medicine literature. BS, as an extant clinical entity, has only existed since the early 1990s, long after many of us graduated medical school and distanced ourselves from EKG Conference. Once considered a rare syndrome, the authors of this consensus report contend that it is second only to automobile accidents as a cause of death among young adults in some countries. This is a rather sobering statement, but I'm not sure I'm buying it just yet.
Essentially, BS is a clandestine EKG abnormality that can be a harbinger of sudden death in young and otherwise healthy adults. In fact, it is characteristically asymptomatic until a cardiac disaster arises. BS has a variety of associated clinical, genetic, cellular, ionic, and molecular aspects, many inscrutable to the average physician. Only recently highlighted, primarily in the cardiology literature, the diagnostic criteria are listed in Table 1.
The salient clinical features of BS include an RBBB pattern with ST segment elevation in the right precordial EKG leads in the presence of an otherwise structurally normal heart. There are a number of subtypes that have somewhat similar EKG findings. Probably a congenital abnormality, the syndrome manifests itself during adulthood, with a mean age of sudden death being a mere 41 years (+/-15) years. The syndrome has been diagnosed, however, in a 2-month-old and an 84-year-old.
A remarkable statistic is that BS is said to be responsible for at least 20 percent of sudden death in patients with structurally normal hearts. I find this difficult to believe. Hopefully, medical examiners are clued in when positing a cause of death in a patient who had contact with a clinician and always review prior EKGs (fat chance of this) before signing off on a cause of death.
It is distressing to note that the EKG pattern varies over time. It can be dynamic or concealed so the true incidence of BS in the general population is difficult to predict. It appears much more commonly in Asian populations, as frequently as in 12 of 10,000 people in Japan. The incidence is much lower in Europe and the United States, although Asian immigrants in this country appear to have the same risk. In U.S. Caucasians and Hispanics, the prevalence is very rare, about 0.1 percent to 0.2 percent. (Am Heart Hosp J 2008;6:48.) Sudden unexplained nocturnal death is a classic manifestation. One wonders about the role of this enigma in sudden infant death syndrome when the autopsy is anatomically normal.
About 20 percent of patients with BS will develop an SVT, including atrial fibrillation, re-entrant tachycardia, or WPW syndrome. These rhythms may be a marker for BS, but probably are not a lethal complication. An implantable cardiodefibrillator (ICD) can be lifesaving if ventricular dysrhythmias occur, but would be placed only if the nefarious and surreptitious condition is diagnosed prior to sudden death.
The EKG shown demonstrates three types of Brugada syndrome. At first glance, they are not grossly abnormal enough to sound an alarm to many clinicians. When found incidentally, RBBB is considered a benign condition in most. The criteria for definitive diagnosis of BS include a RBBB pattern with ST segment elevation in V1 to V3, but only when coupled with a documented case of VF or VT, a family history of sudden death at a young age, the ability to induce VT with electrical stimulation (EPS), syncope, or nocturnal apnea.
The EKG manifestations can be fleeting, and vary with a number of physiologic states. The EKG abnormality may be unmasked by sodium channel blocking drugs but also by a febrile state or a vagotonic stimulus. One can precipitate an arrhythmia with a variety of antiarrhythmics that block the sodium channel. Some intended therapeutic antiarrhythmics are termed proarrhythmic. I wonder if there's a connection here.
Syncope is a red flag that prompts one to consider BS. Table 2 lists confounding factors that could account for a similar EKG tracing as well as common and uncommon causes of syncope. Occasionally a Brugada-like EKG appears after direct current cardioversion or is evident following resuscitation from cardiac arrest. The list of drugs that can produce Brugada-like ST segment elevation is likewise prodigious.
BS can be suspected from a standard EKG, but if one shifts the right precordial leads to the second and third intercostal space, type 1 Brugada EKG findings may be unmasked. The rather unusual syndrome of arrhythmogenic right ventricular cardiomyopathy (a new diagnosis for me) displays a characteristic BS pattern, and produces similar morbidity and mortality. The vast majority of patients with BS, however, possess a structurally normal heart, suggesting that BS is primarily an electrical malfunction.
A genetic link has been postulated (in about 50% of familial cases), but information is minimal. Inheritance seems to follow an autosomal dominant mode of transmission. The condition is 10 times more common in men than women. BS has been linked to mutations in the cardiac sodium channel gene (SCN5A). Why vagaries and vicissitudes of the sodium channel cause ST segment elevation is a puzzle so far.
EKG manifestations also can be unmasked or exacerbated by alpha-adrenergic agents, beta-blockers, tricyclic antidepressants, cocaine toxicity, alcohol, and disorders of potassium and calcium. One wonders how many cases of sudden death from cocaine use are actually an underlying clandestine BS unmasked by adrenergic stress. So much for TASER, positional asphyxia, or police brutality causing death in excited delirium police custody cases.
Ventricular fibrillation and sudden death from this process usually occur at night or at rest when there is more vagal tone or bradycardia. It is postulated that bradycardia in well trained athletes may precipitate this event, possibly accounting for sudden death in young sports figures. Strangely, the peak incidence of death is between 10 p.m. and 3 a.m., and this event is infrequent during the early morning.
In one report of 547 individuals diagnosed with BS and no prior cardiac arrest, 124 abnormal EKGs were identified only after an episode of syncope. In the remainder, the abnormal EKG findings surfaced during routine screening because family members exhibited the syndrome.
Once this obtuse and puzzling diagnosis is made, therapeutic recommendations are less straightforward. Unfortunately, there is no proven pharmacological intervention for preventing sudden cardiac death in patients with BS. The only established effective therapy is AICD placement. Ablation, pacemaker, amiodarone, beta-blockers, and a variety of other exotic antiarrhythmics are either contraindicated or of no value. (See also: Circulation 2002;106:2514.)
Comment: This is one scary syndrome. Since I first heard about it a few years ago, I have been looking for a case. There have been a few false alarms, but I (and my interrogated colleagues) have not come across a bona fide BS case yet in clinical practice. Many cardiologists have only a smattering of knowledge about Brugada syndrome, but their literature and database are growing. It's best, however, to put this syndrome into perspective. Despite the hoopla, consensus statements, and admonitions about the potential to kill, this has to be a very unusual and rare syndrome in denizens of U.S. EDs. Nonetheless, the pendulum has swung so far to the paranoia side one would think that patients are dropping like flies because uninitiated ED clinicians are sending young men with undiagnosed Brugada Syndrome to the great beyond after discharge from the ED when the workup fails to find a cause of syncope.
In fact, the vast majority of cases of sudden cardiac arrest (SCA) are due to physical abnormalities of the heart, especially coronary artery disease and hypertrophic cardiomyopathies, including the recently described arrhythmogenic right ventricular cardiomyopathy (ARVC). SCA in the face of a (properly done) normal postmortem analysis of the heart congers up prolonged QT syndrome from a plethora of sources: pre-excitation, a blow to the precordium (commotion cordis), or even a drug not tested for. Drug overdose aside, only about five percent of SCA autopsies fail to find structural heart abnormalities. (Circulation 2000;102:649.) Of course, BS is unlikely to be diagnosed or even considered in cardiac arrest cases where other more popular causes are considered culprit. It seems prudent, however, to remember to look for the characteristic EKG findings when evaluating the ED patient with syncope. The fact that a vagotonic state can precipitate BS certainly makes the conclusion of vasovagal syncope one to ponder carefully. To make things even more difficult, EKG changes can be transient (Circulation 2004;110:3023), and fluctuating EKG patterns may be common with BS.
One of my keen interests - excited delirium and sudden death - congers up a possible relationship to BS, but I have not seen it in the literature. Myriad cardiac factors probably play roles in excited delirium deaths, and it's been established that submission positions (hogtying, chokeholds), restraints, mace, and even the much loathed TASER are unlikely to be lethal. Most of those young healthy delirious patients who succumb to sudden death in custody don't have their prior EKGs scrutinized by the medical examiner for BS. After reading this paper, one wonders about the role of BS in such patients. Because cocaine is a sodium channel blocker itself and death from BS is an example of a sodium channelopathy, the observation that cocaine use is linked to BS is not surprising.
Some have postulated subtle structural or microscopic abnormalities, fibrosis, or inflammation, especially in the right ventricle. The bevy of inpatient tests often used in the workup for syncope (labs, echocardiogram, stress testing, and even cardiac MRI) will be normal. It seems that cardiologists can't yet agree on the role of electrophysiological study in patients with known or suspected BS. The study does not appear to be recommended in asymptomatic patients with only EKG findings. When performed, electrophysiological studies have less than stellar sensitivity and specificity (66% and 34%, respectively).
What to do then? When evaluating a patient for syncope, an EKG is almost always warranted, even when you think it's a simple faint because of bad news or emotional stress. Young patients in particular need an EKG now that BS has hit the airwaves. One always looks for common EKG nuances, such as new onset atrial fibrillation, Wolff-Parkinson-White syndrome, left ventricular hypertrophy, and prolonged QT interval in patients with syncope. Now add to the list particular attention to V1 through V3. Most will probably glance at an EKG of a healthy 30-year-old who has fainted, and interpret BS as an incidental incomplete right bundle branch block. I'm sure the computer on the EKG machine will concur. Syncope, albeit a risk factor for subsequent arrhythmias, was only about 36% sensitive for BS in one study so most patients with syncope will not have this disorder, and should not routinely be investigated for it. (Circulation 2002;105:1342).
Current consensus is that isolated EKG findings are termed Brugada pattern, and one must manifest other criteria to garner the moniker of a bona fide Brugada syndrome. The pathology in BS seems to be polymorphic VT that degenerates into VT or cardiac arrest. VT would be obvious, but BS can be silent unless provoked. The chance of sudden death or VF within two years of diagnosing BS, especially if the patient has syncope or inducible VT-VF with electrophysiological study, is about two to eight percent.
The illustrious Dr. Amal Mattu (University of Maryland) is one of the few who has highlighted BS for EPs (listen to EM:RAP March 2008; Mel Herbert, MD, editor; http://prod2.ccme.org/emrap/), but most front-line EPs have never heard of it, let alone seen it. Hoping to impress the cardiologist last month, I immediately latched onto a diagnosis of BS for a pristinely healthy 40-year-old man who had fainted the prior day. I even talked the consultant into believing that the EKG could be a Brugada variant, but it was simply a garden-variety incomplete right bundle branch block. We were both a bit flummoxed by this syndrome. On careful analysis, the EKG lacked specific criteria. The cardiologist asked me to perform a procainamide stress test in the ER. It almost drew me in, but my colleagues thought it more prudent to leave that one to the inpatient team. (It was never done.)
There appears to be a resurgence of using procainamide to treat new onset of atrial fibrillation in the ED. Up-to-Date says one can challenge potential BS patients with 10 mg/kg procainamide IV over 10 minutes. (www.uptodate.com.) That's a 700 mg dose in a 70 kg patient, a boatload of procainamide to be given in the ED over 10 minutes. In Canada it's very common to infuse one gram of procainamide over an hour in an attempt to convert new onset AF. Curiously, AF can be related to BS. One wonders if the syndrome is first ruled out prior to this seemingly reasonable ED intervention.
As I said, I don't like this syndrome, and it doesn't seem fair game to qualify for common emergency medicine knowledge just yet. One might conclude it's omnipresent, if not ubiquitous, in fainting young men if you read the cardiology journals. Reviewing the overall scenario, I wonder how many I have missed. Resuscitation from cardiac arrest should raise one's antennae to this condition. One would hope the inpatient team would pick it up, but I doubt it. Medicare and other payors are pushing us to discharge patients with syncope of unknown cause after ED perusal, or at least not pay for the admission. It's an outpatient workup, say the bureaucrats. The payor's fantasy is that an outpatient workup for syncope is easy, proximate, and quite acceptable. In light of the delayed or impossible to obtain outpatient workup we all face, I shudder at the thought of missing one of these cases.
Here's an even scarier conundrum. In an e-Medicine chapter, electrophysiologists write that a drug challenge with a sodium channel blocker should be considered in each patient with syncope in whom no obvious cause is found. (http://emedicine.medscape.com/article/163751-followup.) That's outright lunacy! What was e-Medicine thinking when promulgating that outrageous stance, under the paragraph Medicolegal Pitfalls no less. Clearly this is not standard care in any ED at this stage. Such statements by electrophysiologists who don't see ED patients show how confused and paranoid the current literature is on this subject. The sensitivity and specificity of such drug testing is totally unknown; it need not be done if type 1 BS is evident (no more information is gained), and this can cause a ventricular arrhythmia. Even the use of electrophysiological studies themselves is debated, not a proven predictor of outcome.
The recent uproar about atypical antipsychotic drugs causing sudden cardiac death (New Engl J Med 2009; 360:225) and prior deaths in patients on typical antipsychotics opens up a whole new area of investigation into this subject. I'm surprised no one has picked up on it in the general medical literature. Perhaps such patients had a clandestine, undiagnosable, underlying cardiac problem first described by the brothers Brugada (J Am Coll Cardiol 1992;20:139), and precipitated by well intentioned psychiatric pharmaceuticals.
BS is a potentially important but not yet well defined entity that should be on the ED radar, but confirming the diagnosis is difficult. Most of the literature regarding this abnormality surfaced within the past seven years or so, making it a new syndrome. Brugada syndrome is one zebra that most EPs have never heard about, don't look for, and like the rest of the world, don't currently understand. Perhaps the takeaway message is to look specifically for an atypical right bundle branch block on the cardiogram, coupled with curiously elevated ST segment in V1-V3, in someone with syncope, palpitations, supraventricular arrhythmias, or after surviving cardiac arrest. If fortuitously noted in the ED, punt to someone else to fine-tune the issues. All in all, we don't know much about BS; it's a work in progress.
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Dear Dr. Roberts: Having to address the letter in your May column (EMN 2009;31:12) from Wayne Pasanen, MD, a physician who basically agrees with methadone clinics, is certainly not a difficult task. I have worked in emergency medicine for more than 14 years. I have seen patients coming from methadone clinics on high doses of methadone, OxyContin, and Percocet. These patients are on so much methadone, as high as 180-200 mg a day, that they can't function.
If you and Dr. Pasanen truly believe that there is a biochemical abnormality in the brain, I am sure you can make this same argument with cocaine, marijuana, and other addictive drugs. I think we need to start treating the problem instead of creating another huge problem by providing free methadone to people who are already on narcotics. If your argument truly holds, then we should legalize all forms of drug addiction and give out free drugs.
We should work hard for the better of society to get people off narcotics, not create long-term addiction. - Marcus Ma, MD, Temperance, MI
Dr. Roberts responds: The widely disparate opinions of Drs. Ma and Pasanen highlight the emotion, confusion, and compassion and contempt physicians have regarding methadone maintenance and drug addiction. I did not, however, make up the concept of altered CNS receptor function of chronic opioid (and cocaine) use. Of course, everyone would be delighted if we could get addicts off opioids (and getting the clueless American public off cigarettes, alcohol, and Quarter Pounders with cheese), but other than to lament the plight, I eagerly await anyone's solution to these woes of society. Many have tried, but no one has yet succeeded; maybe Dr. Ma has the answer, and I hope he will share it. I intuit that Dr. Ma is not signing up for California Gov. Arnold Schwarzenegger's task force that is investigating the legalization of marijuana.
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