Case 37-2005 — A 35-Year-Old Man with Cardiac Arrest while Sleeping
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《新英格兰医药杂志》
Presentation of Case
Dr. Alex Manini (Emergency Medicine): A 35-year-old man was brought to the emergency department of this hospital by ambulance after a cardiac arrest while sleeping.
According to his partner and his brother, the patient had been in good health. His partner reported being awakened from sleep by a scream from the patient, who groaned once and then became unresponsive, with agonal breathing and a bluish skin color. The patient's partner called 911 and initiated mouth-to-mouth "rescue" breathing, but not chest compressions. Personnel from emergency medical services arrived at the scene 6 to 8 minutes later, approximately 11 minutes after the onset of the event. The technicians found that the patient was in ventricular fibrillation. Electrical defibrillation was performed eight times with an automated external defibrillator, with two doses (1 mg each) of intravenously administered epinephrine, resulting in a return of spontaneous circulation. During the resuscitation, the patient was orotracheally intubated without premedication. During transport to the emergency department, a wide-complex tachycardia (140 beats per minute) developed, and a continuous intravenously administered lidocaine drip (2 mg per minute, with a 100-mg bolus) was initiated.
In the emergency department, the endotracheal tube was verified to be in the correct position by qualitative assessment of end-tidal carbon dioxide (in which a portable device is attached to the endotracheal tube, with a yellow color change indicating that the tube is in the trachea) and auscultation. Bilateral breathing sounds and peripheral pulses were present and normal. The blood pressure was 110/60 mm Hg, the heart rate was 75 beats per minute, the oxygen saturation was 100 percent while the patient was being ventilated with 100 percent oxygen, and the temperature was 35.5°C.
A physical examination revealed that the patient had a score on the Glasgow Coma Scale of 5-T: eyes, 1 (no opening); verbal, T (could not be evaluated because of tracheal intubation); and motor, 4 (withdrawal from pain). The scale ranges from 3 to 15, with a score of 8 or less indicating coma. The pupils were equal, round, and reactive to light (constricting from 4 to 2 mm). The results of an examination of the head and face were normal, without evidence of trauma. There was no jugular venous distention or carotid bruits. The chest was clear; examination of the heart revealed a regular rate and rhythm, without murmurs, rubs, or gallops. The abdomen was soft and not distended, with normal bowel sounds. A rectal examination yielded guaiac-negative stool. The arms and legs were well perfused, with normal peripheral pulses.
On neurologic examination, the patient did not follow commands or visually track the examiner. His corneal reflexes were absent. His face was symmetric. Tone in both arms was slightly increased, and both legs were rigid. He spontaneously moved and withdrew both arms in response to noxious stimuli. His legs were extended, and he did not withdraw them in response to noxious stimuli. His toes were turned down bilaterally.
An electrocardiogram (Figure 1) revealed sinus rhythm, with normal intervals and 3-mm ST-segment elevations in the inferior leads (II, III, and aVF) as well as 1-mm ST-segment elevations in the lateral leads (V5 and V6). Another electrocardiogram with right-sided leads revealed no ST-segment elevation in lead V4R.
Figure 1. Electrocardiogram Obtained on Admission to the Emergency Department.
There is sinus rhythm (Panel A), with normal intervals and 3-mm ST-segment elevations in the inferior leads (II, III, and aVF) as well as 1-mm ST-segment elevations in the lateral leads (V5 and V6) (arrows). An electrocardiogram with right-sided leads (Panel B) shows no ST-segment elevation in lead V4R (arrowhead).
An orogastric tube was placed, and minimal gastric contents, which appeared normal, were manually suctioned. Portable chest radiography revealed that the endotracheal and orogastric tubes were in appropriate positions and there was no evidence of acute cardiopulmonary disease. Computed tomography (CT) of the head showed diffuse cerebral swelling with loss or blurring of the junction of gray matter with white matter, with no evidence of intracranial hemorrhage. The results of a complete blood count and measurements of prothrombin time, renal function, and levels of electrolytes, calcium, phosphorus, magnesium, creatine kinase, and troponin T were normal, and a urine toxicology screening was negative for cocaine and amphetamine metabolites. A serum toxicology screening revealed the presence of pseudoephedrine but was otherwise negative.
Shortly after the patient's arrival, his partner arrived at the emergency department and provided the information that the patient had a history of bipolar disorder and his only medication was divalproex sodium (1 g per day). He had no known drug allergies. He drank alcohol occasionally, did not smoke, and did not use illicit drugs. There was no family history of sudden death or coronary artery disease.
Aspirin (325 mg) was administered rectally. Metoprolol (5-mg bolus) was given intravenously. Unfractionated heparin was given as a 4000-U bolus and then as a continuous infusion at a rate of 1000 U per hour. A bolus of eptifibatide, 13.5 mg (180 μg per kilogram of body weight), was delivered, and a continuous infusion was established at a rate of 150 μg per minute (2 μg per kilogram per minute). The lidocaine drip was discontinued. A bolus of amiodarone (150 mg) was administered over the course of 10 minutes, followed by a continuous infusion at a rate of 1 mg per minute.
After 20 minutes in the emergency department, the patient remained hypotensive despite the administration of normal saline (2 liters). Ultrasonography, performed at the bedside by the chief resident in emergency medicine, was interpreted as showing no pericardial effusion. A continuous intravenous infusion of dopamine was initiated to maintain adequate blood pressures.
The cardiology service was consulted, and the patient was transferred to the cardiac catheterization laboratory. Coronary angiography revealed normal coronary arteries. Left ventriculography showed an ejection fraction of 50 percent.
A diagnostic test was performed.
Differential Diagnosis
Dr. Keith A. Marill: This previously healthy young man had a cardiac arrest while sleeping; his partner had witnessed the event and had administered rescue breathing without chest compressions; despite a response to defibrillation, the patient remained hypotensive and did not regain consciousness. The issues raised by this case include the management of out-of-hospital cardiac arrest due to ventricular fibrillation both at the scene and in the emergency department and the differential diagnosis of cardiac arrest in a young patient.
Management of Cardiac Arrest Due to Ventricular Fibrillation
Although mortality continues to be high, the continuum of the management of sudden death from cardiac causes from cardiopulmonary resuscitation by bystanders to the care provided by emergency medical services, emergency departments, and intensive care units continues to evolve with numerous incremental scientific advances. This patient was in ventricular fibrillation when first seen by emergency-medical-services personnel. Ventricular fibrillation is the most common cause of sudden cardiac arrest and is the initial rhythm found in the majority of people who survive cardiac arrest. Ventricular fibrillation initially generates a coarse pattern on an electrocardiographic tracing because of quasiperiodic ventricular excitation. If the condition is left untreated, this pattern of ventricular fibrillation is usually followed by a predictable and inexorable decay to a more disorganized state, with energy dissolution and eventual asystole (Figure 2).1,2 This decay is revealed on the surface electrocardiogram by progression from a coarse pattern to fine deflections and increasing smoothness.
Figure 2. Electrophysiology of Ventricular Fibrillation.
A computer-generated two-dimensional model in four segments (Panel A) shows a cardiac scroll wave (arrow), which degenerates over time into smaller wavelets (arrowheads). This phenomenon is associated with an initial coarse tracing of ventricular fibrillation on a representative rhythm strip at 60 seconds after the onset of arrest (Panel B, top), which later becomes finer, over a period of 600 seconds (Panel B, bottom). (Panel A is reprinted with permission from Weiss et al.,1 and Panel B is reprinted with permission from Angelos et al.2)
Care by bystanders is the first link in the chain of survival as described by the American Heart Association. The most important initial action for a bystander is to call for help from emergency medical services, as was done in this case. The next action is to begin cardiopulmonary resuscitation (CPR), which consists of chest compressions and artificial respirations. CPR slows the rate of decay from coarse to fine ventricular fibrillation and improves survival.3 Chest compressions are more important than artificial respirations. Instruction of laypersons in both types of intervention can cause confusion, and the interruption of chest compressions to perform excessive artificial respirations may be detrimental.4,5 This case exemplifies the tragic potential for confusion by a layperson: the patient received respirations but not chest compressions. If available, an automatic external defibrillator should be applied by trained bystanders. One of the primary challenges of the use of an automatic external defibrillator in the community is determining the optimal placement of the units. As in this case, the majority of cardiac arrests occur at home, often in patients with no history of cardiac disease; routine installation of automatic external defibrillators in homes is clearly not practical. The accurate identification of the majority of patients at risk for sudden death from cardiac causes and the reliable prediction of serious adverse events continue to elude physicians.
Personnel in emergency medical services have the capability to perform defibrillation, but immediate defibrillation, which was presumably done in this case, may not always be the best choice. If the patient has been in ventricular fibrillation for more than four to five minutes, "priming the cardiac pump" with a period of cardiopulmonary resuscitation before defibrillation is likely to be beneficial.6 The rationale for this is a partial repletion of myocardial oxygen tension and metabolic substrates, allowing the resumption of organized contractions after defibrillation. The optimal duration of cardiopulmonary resuscitation before defibrillation remains uncertain. Electronic analysis of the smoothness of the ventricular-fibrillation waveform in animals has been shown to predict the effectiveness of immediate defibrillation with an external defibrillator, as compared with performing cardiopulmonary resuscitation before defibrillation — an analysis that could be of use in the future to direct therapy in humans when the onset time of arrest is unknown.7
A patient such as the patient under discussion with cardiac arrest associated with ventricular fibrillation will usually require definitive airway control with endotracheal intubation in the field or on arrival to the emergency department; this procedure was performed in the field in this case. Patients who have no response to initial defibrillation attempts may benefit from vasopressor agents such as epinephrine or vasopressin, or both; epinephrine was used in this case when initial shocks were unsuccessful. Although they have not been proved to reduce mortality, these agents may improve coronary-perfusion pressure, and their benefit may be synergistic.8 The efficacy of antidysrhythmic agents in improving outcomes by altering repolarization or other electrophysiological characteristics remains uncertain. Amiodarone may improve the return of spontaneous circulation with defibrillation, but it has not been proved to increase the likelihood of survival to hospital discharge.9,10 The results of trials of other agents that delay repolarization and prolong the myocardial cellular refractory period, such as bretylium and sotalol, have been disappointing.11,12 In this patient, lidocaine was used in the field to treat tachycardia with a wide QRS complex, and amiodarone was substituted when he arrived in the emergency department.
Patients such as this who remain comatose after cardiac arrest may benefit from hypothermic therapy to improve the neurologic outcome.13,14 Techniques to induce rapid hypothermia include chemical paralysis to prevent shivering, external cooling, and internal cooling with endovascular devices or the infusion of cold saline or other solutions.15
Differential Diagnosis of Ventricular Fibrillation–Induced Arrest
Although I am aware of the diagnosis in this case, the differential diagnosis in a patient such as this man, who presented to the emergency department with ventricular fibrillation, is broad and includes noncardiac disease and both primary nondysrhythmic and dysrhythmic cardiac disease (Table 1).
Table 1. Causes of Ventricular Fibrillation–Induced Cardiac Arrest.
Noncardiac Causes of Ventricular Fibrillation
Respiratory causes including bronchospasm, aspiration, or both should be considered, but these seem unlikely to be the causes in this patient, who had no history of dyspnea. Sleep apnea is associated with nocturnal cardiac arrest, but the patient had no known history of sleep disorder. Primary pulmonary hypertension may lead to sudden death from cardiac causes, but generally only after the development of advanced congestive heart failure. Metabolic derangements of potassium, magnesium, calcium, or glucose should be considered, and these values should be checked. Seizure must be considered, particularly in this patient, who groaned at the onset of the event; however, there was no supporting historical or physical evidence of seizure, including acute or prior tonic–clonic activity, lateral tongue laceration, or incontinence. An underlying neurovascular event is possible, but a finding of symmetry on neurologic examination and the absence of a lesion on CT scanning of the head reduce the likelihood.
Toxic exposures must always be considered. This patient was taking divalproex sodium, a dimer of valproic acid, and had evidence of the decongestant pseudoephedrine in his serum. Divalproex sodium would not be expected to cause cardiac arrest, but pseudoephedrine ingestion, coupled with exercise, has been associated with supraventricular tachycardia.16 The patient was noted to have a "bluish" hue, which raises the slight possibility of methemoglobinemia or sulfhemoglobinemia, which could be caused by a number of medications. The possibility of an overdose of a cyclic antidepressant drug should always be explored, particularly in a patient with a history of psychiatric illness. An overdose of stimulants such as cocaine or amphetamine is possible. Patients who have had an overdose of narcotic drugs or a benzodiazepine generally present with depression of respirations and mental status as the primary features. Exposure to an environmental toxin, such as carbon monoxide, is also possible; however, the patient's partner had no medical symptoms.
Overwhelming sepsis, such as with streptococcal infection, can lead to cardiac arrest and persistent hypotension, even in a formerly healthy person. Conditions that obstruct blood flow, such as spontaneous pneumothorax with secondary elevated intrathoracic tension, and pulmonary embolism more typically lead to pulseless electrical activity rather than ventricular fibrillation. There was no evidence of external hemorrhage, but the possibility of an internal vascular catastrophe such as rupture of the aorta or other major vessel should be investigated. This would be of particular concern in a young adult patient if the physical features suggest the presence of Marfan's syndrome.
Cardiac Causes of Ventricular Fibrillation
A primarily nondysrhythmic cardiac event such as acute myocardial infarction can lead to abrupt pump failure, secondary ventricular fibrillation, or both. This patient's initial electrocardiogram was suggestive of inferolateral myocardial infarction, with ST-segment elevation in the inferior limb and lateral chest leads and reciprocal ST-segment depression in the septal chest leads V1 and V2. Cardiac arrest due to acute valvular failure would be an unlikely cause of ventricular fibrillation, unless it was associated with ascending aortic dissection or acute myocardial infarction. Cardiologic causes of obstruction to blood flow include cardiac tamponade, aortic stenosis, and hypertrophic obstructive cardiomyopathy. Traumatic pericardial tamponade is more likely than nontraumatic pericardial tamponade to cause cardiac arrest because of the rapid accumulation of blood in the pericardial sac. This patient had no known history of trauma. Aortic stenosis and hypertrophic obstructive cardiomyopathy usually cause symptoms including dyspnea, chest pain, and sudden death on exertion rather than at rest. Sudden death in patients with hypertrophic obstructive cardiomyopathy is primarily due to an increased risk of ventricular fibrillation, not obstruction of flow, but this typically occurs during exertion. Patients with a congenital anatomical heart disease, such as tetralogy of Fallot, or those in whom such a defect has been repaired, may be at increased risk for sudden death from cardiac causes. This patient's arrest occurred while he was sleeping, and he had no history of congenital heart disease.
Primary dysrhythmic causes of sudden death from cardiac causes may or may not be associated with structural cardiac disease. Coronary artery disease is the most important structural cause of ventricular fibrillation and may lead to this condition as a result of acute plaque rupture, localized ischemia, and myocardial infarction. Myocardial scar formation owing to prior myocardial infarction causes sustained ventricular tachycardia, which can degenerate to ventricular fibrillation. Dilated cardiomyopathy from any cause increases the risk of ventricular fibrillation and ventricular tachycardia, including bundle-branch reentry. Patients with myocardial diseases such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia are at increased risk for ventricular fibrillation–induced arrest. Cardiac catheterization of this patient revealed no evidence of coronary artery disease and an unremarkable left ventriculogram, although the results of right ventriculography were not described.
There are a variety of exercise-induced nonstructural conditions associated with ventricular tachydysrhythmias and possible sudden death, including right ventricular outflow tract ventricular tachycardia, catecholaminergic polymorphic ventricular tachycardia, and commotio cordis, or blunt chest-wall trauma. Since this patient's arrest occurred during sleep, conditions unrelated to exercise are probably more important in understanding his event.
Patients with viral myocarditis can present with ventricular fibrillation and elevations of the ST segment and enzyme levels despite having normal coronary arteries. However, this patient had no preceding symptoms of viral infection or chest pain. Ventricular fibrillation may be caused by a variety of other infections, including bacterial endocarditis and Chagas' disease, which is associated with right bundle-branch block. In this case, there was no history of injection-drug use, recent dental manipulation, valvular heart disease, fevers, or travel to suggest the presence of bacterial endocarditis or Chagas' disease. The Wolff–Parkinson–White syndrome is associated with atrial fibrillation and potentially unstable high-frequency ventricular excitation through conduction by the accessory pathway. The PR interval and QRS upstroke on this patient's electrocardiogram were normal and not suggestive of the presence of the Wolff–Parkinson–White syndrome and ventricular preexcitation. Polymorphic ventricular tachycardia in association with a prolonged QT interval during sinus rhythm, termed "torsades de pointes," can occur in young adults as a result of either congenital or acquired derangements. The QT interval in this patient was normal.
The understanding of cardiac ion-channel diseases is advancing rapidly, and diseases of the sodium, potassium, and calcium channels can lead to syndromes associated with short and long QT intervals and to sudden death.17,18,19 Fatal dysrhythmias may occur with activity (long-QT syndrome, variant 1) or rest (long-QT syndrome, variant 3), depending on the disease variant. The Brugada syndrome, a disease ascribed primarily to the cardiac sodium channel, causes sudden death, often nocturnal, in young men with no structural heart disease. The electrocardiographic pattern in patients with this syndrome is characterized by complete or incomplete right bundle-branch block, with downsloping, early ST-segment elevation in the anterior precordial electrocardiographic leads. This patient's initial electrocardiogram did not show the typical features; however, the right-sided electrocardiogram is suggestive of the presence of the Brugada syndrome. With the Brugada syndrome as with other abnormalities of conduction, such as the long-QT syndromes and the Wolff–Parkinson–White syndrome, manifestations of the conduction abnormality can vary considerably on the resting electrocardiogram as a function of the autonomic and physiologic milieu.
The Brugada Syndrome
The Brugada syndrome is an autosomal dominant disease caused by a variety of mutations of the cardiac sodium-channel genes. Different defects of the same gene, SCN5A, are also responsible for long-QT syndrome, variant 3. Although there are many remaining questions, substantial progress has been made in understanding the structure and function of the sodium channel protein resulting from this gene (Figure 3).20,21 Defects associated with the Brugada syndrome lead to premature inactivation and other loss-of-function abnormalities of the cardiac sodium channel. Differential manifestation of a specific conducting defect within and between the ventricular epicardium and endocardium leads to heterogeneous cellular repolarization across the myocardium and the potential for reentrant ventricular tachydysrhythmias such as polymorphic ventricular tachycardia and ventricular fibrillation.22 The disease appears to be prevalent in Southeast Asian populations and is at least partly responsible for the nocturnal sudden death described as "lai tai" (death during sleep) in Thailand, "bangungut" (to rise and moan during sleep and then die) in the Philippines, and "pokkuri" (unexpected sudden death from cardiac causes at night) in Japan.23 The clinical manifestations are nine times as common among men as among women, often first occurring in the third or fourth decade of life and in patients at rest or during sleep.
Figure 3. The Cardiac Sodium Channel with Some Sites of Mutations Associated with the Brugada Syndrome and the Long-QT Syndrome.
Panel A shows the three-dimensional configuration of the cardiac sodium-channel pore. Panel B shows an active and an inactive sodium channel. A linear map of the protein (Panel C) shows the four transmembrane domains (I, II, III, and IV) and the sites of common mutations. Protein mutations associated with the Brugada syndrome are shown in purple; those causing the long-QT syndrome are in red, and yellow is associated with both the long-QT syndrome, variant 3 (LQT3), and the Brugada syndrome. The S4 segments of each domain are colored pink to signify their overall positive charge and instrumental role in sensing the transmembrane voltage.
The diagnosis of the Brugada syndrome is made on the basis of the electrocardiographic characteristics of a pattern of right bundle-branch block and an elevation at the J point that is greater than 2 mm, with a slowly descending ST segment in conjunction with flat or negative T waves in the right precordial leads V1, V2, or V3. In addition, there would be a history of syncope, inducible polymorphic ventricular tachycardia or ventricular fibrillation, or sudden death from cardiac causes in the patient or a family member and no obvious structural cause of sudden death.24,25 The electrocardiographic morphology associated with the Brugada syndrome varies in individual patients, decreasing in prominence with sympathetic stimulation and exercise and increasing with body temperature and the administration of class I antidysrhythmic agents, which variably decrease sodium-channel conduction.26,27 Thus, the diagnostic test in this case should be a repeated electrocardiogram.
Dr. Keith Marill's Diagnosis
The Brugada syndrome.
Diagnostic Discussion
Dr. Manini: A second electrocardiogram was obtained (Figure 4), which demonstrated downsloping ST-segment elevations in leads V1 and V2 with a pattern of partial right bundle-branch block. Straight down sloping of the ST segment in V1 and a saddle appearance of the ST segment in V2 were suggestive of known variants of the Brugada syndrome pattern.
Figure 4. Additional Electrocardiograms.
An electrocardiogram obtained approximately seven hours after the first (Panel A) shows a pattern of incomplete right bundle-branch block and downsloping ST-segment elevation in the anterior septal leads V1 and V2, consistent with patterns associated with the Brugada syndrome. Classically, in the Brugada syndrome, the ST segment in these leads is "coved," showing upward concavity. This patient's electrocardiogram shows two common variants of ST-segment morphology: a straight downward ST segment in lead V1 (arrow) and a saddle-shaped ST segment in lead V2 (arrowhead). An electrocardiogram obtained the next day (Panel B), 31 hours after the initial tracing, shows more classic coving of the ST segment in lead V2 (arrow).
On the basis of the electrocardiographic findings, in concert with the clinical circumstances, a diagnosis of the Brugada syndrome was made.
Discussion of Management
Dr. Marill: This patient did not have a family history of cardiac dysrhythmias or sudden death but had a ventricular fibrillation–induced cardiac arrest, no evident structural cause, and on a repeated electrocardiogram, findings characteristic of the Brugada syndrome. If he recovers from this episode, what are the prognosis and management options?
The likelihood of sudden death from cardiac causes in patients with the Brugada syndrome increases with a history of syncope or cardiac arrest, a spontaneous — as opposed to drug-inducible — abnormality on electrocardiography, male sex, and probably, the potential to induce ventricular tachydysrhythmias with programmed electrical stimulation.28,29,30 This patient's history clearly puts him at high risk for a recurrence. Primary therapy for all symptomatic patients with the Brugada syndrome is an automatic implantable cardioverter–defibrillator. His family members should be evaluated for evidence of the Brugada syndrome. Testing involves electrocardiography, followed by repeated electrocardiography in the electrophysiology laboratory after challenge with a sodium-channel–blocking agent such as procainamide if the initial tracing is normal; programmed electrical stimulation may be helpful for diagnosis and assessment of the risk of tachydysrhythmia if the electrocardiogram shows abnormalities. The approach to an asymptomatic patient remains challenging.28,29,30
Dr. Manini: The patient was transferred to the cardiac intensive care unit in critical condition. The placement of an automatic implantable cardioverter–defibrillator was deferred until the extent of his neurologic recovery could be determined. Induction of hypothermia was considered by a neurology consultant, but it was deferred because the patient had purposeful movements and was not unequivocally comatose and because the procedure carries some risk. A cooling blanket and acetaminophen were used to maintain euthermia. Follow-up brain magnetic resonance imaging revealed changes consistent with the presence of anoxic brain injury. On the second hospital day, bloody diarrhea occurred and an abdominal CT performed with contrast material showed changes consistent with the presence of ischemic colitis. On the third day, the patient remained comatose and did not respond to stimuli; the prognosis for a neurologic recovery was thought to be poor. After the clinicians consulted with the patient's family, life support was withdrawn and the patient died. An autopsy was not performed.
Dr. Patrick T. Ellinor: It was recommended that all the patient's first-degree relatives be screened for the Brugada syndrome. The patient's 32-year-old brother had no cardiac symptoms. His evaluation, which included the results of a stress test performed a few months earlier for atypical chest pain, a resting electrocardiogram, and an echocardiogram, was normal. There were no inducible ST-segment abnormalities present after the infusion of procainamide. To my knowledge, the parents have not been evaluated. The only identified cause of the Brugada syndrome is an abnormality in the cardiac sodium channel; however, mutations in this gene appear to account for only one third of the cases. Testing for mutations in this gene is commercially available, but a negative result would not be helpful. As part of a research protocol in our laboratory, the cardiac sodium channel SCN5A was analyzed and no mutation was identified in this patient.
Dr. Marill reports owning equity in Medtronic and in Johnson & Johnson/Guidant.
We are indebted to Dr. David F. Brown for his assistance with this discussion and to Drs. Josep Brugada and William Catterall for their generous contributions to the manuscript figures.
Source Information
From the Department of Emergency Medicine (K.A.M.) and the Cardiology Division (P.T.E.), Massachusetts General Hospital; and the Division of Emergency Medicine (K.A.M.) and the Department of Medicine (P.T.E.), Harvard Medical School — both in Boston.
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Dr. Alex Manini (Emergency Medicine): A 35-year-old man was brought to the emergency department of this hospital by ambulance after a cardiac arrest while sleeping.
According to his partner and his brother, the patient had been in good health. His partner reported being awakened from sleep by a scream from the patient, who groaned once and then became unresponsive, with agonal breathing and a bluish skin color. The patient's partner called 911 and initiated mouth-to-mouth "rescue" breathing, but not chest compressions. Personnel from emergency medical services arrived at the scene 6 to 8 minutes later, approximately 11 minutes after the onset of the event. The technicians found that the patient was in ventricular fibrillation. Electrical defibrillation was performed eight times with an automated external defibrillator, with two doses (1 mg each) of intravenously administered epinephrine, resulting in a return of spontaneous circulation. During the resuscitation, the patient was orotracheally intubated without premedication. During transport to the emergency department, a wide-complex tachycardia (140 beats per minute) developed, and a continuous intravenously administered lidocaine drip (2 mg per minute, with a 100-mg bolus) was initiated.
In the emergency department, the endotracheal tube was verified to be in the correct position by qualitative assessment of end-tidal carbon dioxide (in which a portable device is attached to the endotracheal tube, with a yellow color change indicating that the tube is in the trachea) and auscultation. Bilateral breathing sounds and peripheral pulses were present and normal. The blood pressure was 110/60 mm Hg, the heart rate was 75 beats per minute, the oxygen saturation was 100 percent while the patient was being ventilated with 100 percent oxygen, and the temperature was 35.5°C.
A physical examination revealed that the patient had a score on the Glasgow Coma Scale of 5-T: eyes, 1 (no opening); verbal, T (could not be evaluated because of tracheal intubation); and motor, 4 (withdrawal from pain). The scale ranges from 3 to 15, with a score of 8 or less indicating coma. The pupils were equal, round, and reactive to light (constricting from 4 to 2 mm). The results of an examination of the head and face were normal, without evidence of trauma. There was no jugular venous distention or carotid bruits. The chest was clear; examination of the heart revealed a regular rate and rhythm, without murmurs, rubs, or gallops. The abdomen was soft and not distended, with normal bowel sounds. A rectal examination yielded guaiac-negative stool. The arms and legs were well perfused, with normal peripheral pulses.
On neurologic examination, the patient did not follow commands or visually track the examiner. His corneal reflexes were absent. His face was symmetric. Tone in both arms was slightly increased, and both legs were rigid. He spontaneously moved and withdrew both arms in response to noxious stimuli. His legs were extended, and he did not withdraw them in response to noxious stimuli. His toes were turned down bilaterally.
An electrocardiogram (Figure 1) revealed sinus rhythm, with normal intervals and 3-mm ST-segment elevations in the inferior leads (II, III, and aVF) as well as 1-mm ST-segment elevations in the lateral leads (V5 and V6). Another electrocardiogram with right-sided leads revealed no ST-segment elevation in lead V4R.
Figure 1. Electrocardiogram Obtained on Admission to the Emergency Department.
There is sinus rhythm (Panel A), with normal intervals and 3-mm ST-segment elevations in the inferior leads (II, III, and aVF) as well as 1-mm ST-segment elevations in the lateral leads (V5 and V6) (arrows). An electrocardiogram with right-sided leads (Panel B) shows no ST-segment elevation in lead V4R (arrowhead).
An orogastric tube was placed, and minimal gastric contents, which appeared normal, were manually suctioned. Portable chest radiography revealed that the endotracheal and orogastric tubes were in appropriate positions and there was no evidence of acute cardiopulmonary disease. Computed tomography (CT) of the head showed diffuse cerebral swelling with loss or blurring of the junction of gray matter with white matter, with no evidence of intracranial hemorrhage. The results of a complete blood count and measurements of prothrombin time, renal function, and levels of electrolytes, calcium, phosphorus, magnesium, creatine kinase, and troponin T were normal, and a urine toxicology screening was negative for cocaine and amphetamine metabolites. A serum toxicology screening revealed the presence of pseudoephedrine but was otherwise negative.
Shortly after the patient's arrival, his partner arrived at the emergency department and provided the information that the patient had a history of bipolar disorder and his only medication was divalproex sodium (1 g per day). He had no known drug allergies. He drank alcohol occasionally, did not smoke, and did not use illicit drugs. There was no family history of sudden death or coronary artery disease.
Aspirin (325 mg) was administered rectally. Metoprolol (5-mg bolus) was given intravenously. Unfractionated heparin was given as a 4000-U bolus and then as a continuous infusion at a rate of 1000 U per hour. A bolus of eptifibatide, 13.5 mg (180 μg per kilogram of body weight), was delivered, and a continuous infusion was established at a rate of 150 μg per minute (2 μg per kilogram per minute). The lidocaine drip was discontinued. A bolus of amiodarone (150 mg) was administered over the course of 10 minutes, followed by a continuous infusion at a rate of 1 mg per minute.
After 20 minutes in the emergency department, the patient remained hypotensive despite the administration of normal saline (2 liters). Ultrasonography, performed at the bedside by the chief resident in emergency medicine, was interpreted as showing no pericardial effusion. A continuous intravenous infusion of dopamine was initiated to maintain adequate blood pressures.
The cardiology service was consulted, and the patient was transferred to the cardiac catheterization laboratory. Coronary angiography revealed normal coronary arteries. Left ventriculography showed an ejection fraction of 50 percent.
A diagnostic test was performed.
Differential Diagnosis
Dr. Keith A. Marill: This previously healthy young man had a cardiac arrest while sleeping; his partner had witnessed the event and had administered rescue breathing without chest compressions; despite a response to defibrillation, the patient remained hypotensive and did not regain consciousness. The issues raised by this case include the management of out-of-hospital cardiac arrest due to ventricular fibrillation both at the scene and in the emergency department and the differential diagnosis of cardiac arrest in a young patient.
Management of Cardiac Arrest Due to Ventricular Fibrillation
Although mortality continues to be high, the continuum of the management of sudden death from cardiac causes from cardiopulmonary resuscitation by bystanders to the care provided by emergency medical services, emergency departments, and intensive care units continues to evolve with numerous incremental scientific advances. This patient was in ventricular fibrillation when first seen by emergency-medical-services personnel. Ventricular fibrillation is the most common cause of sudden cardiac arrest and is the initial rhythm found in the majority of people who survive cardiac arrest. Ventricular fibrillation initially generates a coarse pattern on an electrocardiographic tracing because of quasiperiodic ventricular excitation. If the condition is left untreated, this pattern of ventricular fibrillation is usually followed by a predictable and inexorable decay to a more disorganized state, with energy dissolution and eventual asystole (Figure 2).1,2 This decay is revealed on the surface electrocardiogram by progression from a coarse pattern to fine deflections and increasing smoothness.
Figure 2. Electrophysiology of Ventricular Fibrillation.
A computer-generated two-dimensional model in four segments (Panel A) shows a cardiac scroll wave (arrow), which degenerates over time into smaller wavelets (arrowheads). This phenomenon is associated with an initial coarse tracing of ventricular fibrillation on a representative rhythm strip at 60 seconds after the onset of arrest (Panel B, top), which later becomes finer, over a period of 600 seconds (Panel B, bottom). (Panel A is reprinted with permission from Weiss et al.,1 and Panel B is reprinted with permission from Angelos et al.2)
Care by bystanders is the first link in the chain of survival as described by the American Heart Association. The most important initial action for a bystander is to call for help from emergency medical services, as was done in this case. The next action is to begin cardiopulmonary resuscitation (CPR), which consists of chest compressions and artificial respirations. CPR slows the rate of decay from coarse to fine ventricular fibrillation and improves survival.3 Chest compressions are more important than artificial respirations. Instruction of laypersons in both types of intervention can cause confusion, and the interruption of chest compressions to perform excessive artificial respirations may be detrimental.4,5 This case exemplifies the tragic potential for confusion by a layperson: the patient received respirations but not chest compressions. If available, an automatic external defibrillator should be applied by trained bystanders. One of the primary challenges of the use of an automatic external defibrillator in the community is determining the optimal placement of the units. As in this case, the majority of cardiac arrests occur at home, often in patients with no history of cardiac disease; routine installation of automatic external defibrillators in homes is clearly not practical. The accurate identification of the majority of patients at risk for sudden death from cardiac causes and the reliable prediction of serious adverse events continue to elude physicians.
Personnel in emergency medical services have the capability to perform defibrillation, but immediate defibrillation, which was presumably done in this case, may not always be the best choice. If the patient has been in ventricular fibrillation for more than four to five minutes, "priming the cardiac pump" with a period of cardiopulmonary resuscitation before defibrillation is likely to be beneficial.6 The rationale for this is a partial repletion of myocardial oxygen tension and metabolic substrates, allowing the resumption of organized contractions after defibrillation. The optimal duration of cardiopulmonary resuscitation before defibrillation remains uncertain. Electronic analysis of the smoothness of the ventricular-fibrillation waveform in animals has been shown to predict the effectiveness of immediate defibrillation with an external defibrillator, as compared with performing cardiopulmonary resuscitation before defibrillation — an analysis that could be of use in the future to direct therapy in humans when the onset time of arrest is unknown.7
A patient such as the patient under discussion with cardiac arrest associated with ventricular fibrillation will usually require definitive airway control with endotracheal intubation in the field or on arrival to the emergency department; this procedure was performed in the field in this case. Patients who have no response to initial defibrillation attempts may benefit from vasopressor agents such as epinephrine or vasopressin, or both; epinephrine was used in this case when initial shocks were unsuccessful. Although they have not been proved to reduce mortality, these agents may improve coronary-perfusion pressure, and their benefit may be synergistic.8 The efficacy of antidysrhythmic agents in improving outcomes by altering repolarization or other electrophysiological characteristics remains uncertain. Amiodarone may improve the return of spontaneous circulation with defibrillation, but it has not been proved to increase the likelihood of survival to hospital discharge.9,10 The results of trials of other agents that delay repolarization and prolong the myocardial cellular refractory period, such as bretylium and sotalol, have been disappointing.11,12 In this patient, lidocaine was used in the field to treat tachycardia with a wide QRS complex, and amiodarone was substituted when he arrived in the emergency department.
Patients such as this who remain comatose after cardiac arrest may benefit from hypothermic therapy to improve the neurologic outcome.13,14 Techniques to induce rapid hypothermia include chemical paralysis to prevent shivering, external cooling, and internal cooling with endovascular devices or the infusion of cold saline or other solutions.15
Differential Diagnosis of Ventricular Fibrillation–Induced Arrest
Although I am aware of the diagnosis in this case, the differential diagnosis in a patient such as this man, who presented to the emergency department with ventricular fibrillation, is broad and includes noncardiac disease and both primary nondysrhythmic and dysrhythmic cardiac disease (Table 1).
Table 1. Causes of Ventricular Fibrillation–Induced Cardiac Arrest.
Noncardiac Causes of Ventricular Fibrillation
Respiratory causes including bronchospasm, aspiration, or both should be considered, but these seem unlikely to be the causes in this patient, who had no history of dyspnea. Sleep apnea is associated with nocturnal cardiac arrest, but the patient had no known history of sleep disorder. Primary pulmonary hypertension may lead to sudden death from cardiac causes, but generally only after the development of advanced congestive heart failure. Metabolic derangements of potassium, magnesium, calcium, or glucose should be considered, and these values should be checked. Seizure must be considered, particularly in this patient, who groaned at the onset of the event; however, there was no supporting historical or physical evidence of seizure, including acute or prior tonic–clonic activity, lateral tongue laceration, or incontinence. An underlying neurovascular event is possible, but a finding of symmetry on neurologic examination and the absence of a lesion on CT scanning of the head reduce the likelihood.
Toxic exposures must always be considered. This patient was taking divalproex sodium, a dimer of valproic acid, and had evidence of the decongestant pseudoephedrine in his serum. Divalproex sodium would not be expected to cause cardiac arrest, but pseudoephedrine ingestion, coupled with exercise, has been associated with supraventricular tachycardia.16 The patient was noted to have a "bluish" hue, which raises the slight possibility of methemoglobinemia or sulfhemoglobinemia, which could be caused by a number of medications. The possibility of an overdose of a cyclic antidepressant drug should always be explored, particularly in a patient with a history of psychiatric illness. An overdose of stimulants such as cocaine or amphetamine is possible. Patients who have had an overdose of narcotic drugs or a benzodiazepine generally present with depression of respirations and mental status as the primary features. Exposure to an environmental toxin, such as carbon monoxide, is also possible; however, the patient's partner had no medical symptoms.
Overwhelming sepsis, such as with streptococcal infection, can lead to cardiac arrest and persistent hypotension, even in a formerly healthy person. Conditions that obstruct blood flow, such as spontaneous pneumothorax with secondary elevated intrathoracic tension, and pulmonary embolism more typically lead to pulseless electrical activity rather than ventricular fibrillation. There was no evidence of external hemorrhage, but the possibility of an internal vascular catastrophe such as rupture of the aorta or other major vessel should be investigated. This would be of particular concern in a young adult patient if the physical features suggest the presence of Marfan's syndrome.
Cardiac Causes of Ventricular Fibrillation
A primarily nondysrhythmic cardiac event such as acute myocardial infarction can lead to abrupt pump failure, secondary ventricular fibrillation, or both. This patient's initial electrocardiogram was suggestive of inferolateral myocardial infarction, with ST-segment elevation in the inferior limb and lateral chest leads and reciprocal ST-segment depression in the septal chest leads V1 and V2. Cardiac arrest due to acute valvular failure would be an unlikely cause of ventricular fibrillation, unless it was associated with ascending aortic dissection or acute myocardial infarction. Cardiologic causes of obstruction to blood flow include cardiac tamponade, aortic stenosis, and hypertrophic obstructive cardiomyopathy. Traumatic pericardial tamponade is more likely than nontraumatic pericardial tamponade to cause cardiac arrest because of the rapid accumulation of blood in the pericardial sac. This patient had no known history of trauma. Aortic stenosis and hypertrophic obstructive cardiomyopathy usually cause symptoms including dyspnea, chest pain, and sudden death on exertion rather than at rest. Sudden death in patients with hypertrophic obstructive cardiomyopathy is primarily due to an increased risk of ventricular fibrillation, not obstruction of flow, but this typically occurs during exertion. Patients with a congenital anatomical heart disease, such as tetralogy of Fallot, or those in whom such a defect has been repaired, may be at increased risk for sudden death from cardiac causes. This patient's arrest occurred while he was sleeping, and he had no history of congenital heart disease.
Primary dysrhythmic causes of sudden death from cardiac causes may or may not be associated with structural cardiac disease. Coronary artery disease is the most important structural cause of ventricular fibrillation and may lead to this condition as a result of acute plaque rupture, localized ischemia, and myocardial infarction. Myocardial scar formation owing to prior myocardial infarction causes sustained ventricular tachycardia, which can degenerate to ventricular fibrillation. Dilated cardiomyopathy from any cause increases the risk of ventricular fibrillation and ventricular tachycardia, including bundle-branch reentry. Patients with myocardial diseases such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia are at increased risk for ventricular fibrillation–induced arrest. Cardiac catheterization of this patient revealed no evidence of coronary artery disease and an unremarkable left ventriculogram, although the results of right ventriculography were not described.
There are a variety of exercise-induced nonstructural conditions associated with ventricular tachydysrhythmias and possible sudden death, including right ventricular outflow tract ventricular tachycardia, catecholaminergic polymorphic ventricular tachycardia, and commotio cordis, or blunt chest-wall trauma. Since this patient's arrest occurred during sleep, conditions unrelated to exercise are probably more important in understanding his event.
Patients with viral myocarditis can present with ventricular fibrillation and elevations of the ST segment and enzyme levels despite having normal coronary arteries. However, this patient had no preceding symptoms of viral infection or chest pain. Ventricular fibrillation may be caused by a variety of other infections, including bacterial endocarditis and Chagas' disease, which is associated with right bundle-branch block. In this case, there was no history of injection-drug use, recent dental manipulation, valvular heart disease, fevers, or travel to suggest the presence of bacterial endocarditis or Chagas' disease. The Wolff–Parkinson–White syndrome is associated with atrial fibrillation and potentially unstable high-frequency ventricular excitation through conduction by the accessory pathway. The PR interval and QRS upstroke on this patient's electrocardiogram were normal and not suggestive of the presence of the Wolff–Parkinson–White syndrome and ventricular preexcitation. Polymorphic ventricular tachycardia in association with a prolonged QT interval during sinus rhythm, termed "torsades de pointes," can occur in young adults as a result of either congenital or acquired derangements. The QT interval in this patient was normal.
The understanding of cardiac ion-channel diseases is advancing rapidly, and diseases of the sodium, potassium, and calcium channels can lead to syndromes associated with short and long QT intervals and to sudden death.17,18,19 Fatal dysrhythmias may occur with activity (long-QT syndrome, variant 1) or rest (long-QT syndrome, variant 3), depending on the disease variant. The Brugada syndrome, a disease ascribed primarily to the cardiac sodium channel, causes sudden death, often nocturnal, in young men with no structural heart disease. The electrocardiographic pattern in patients with this syndrome is characterized by complete or incomplete right bundle-branch block, with downsloping, early ST-segment elevation in the anterior precordial electrocardiographic leads. This patient's initial electrocardiogram did not show the typical features; however, the right-sided electrocardiogram is suggestive of the presence of the Brugada syndrome. With the Brugada syndrome as with other abnormalities of conduction, such as the long-QT syndromes and the Wolff–Parkinson–White syndrome, manifestations of the conduction abnormality can vary considerably on the resting electrocardiogram as a function of the autonomic and physiologic milieu.
The Brugada Syndrome
The Brugada syndrome is an autosomal dominant disease caused by a variety of mutations of the cardiac sodium-channel genes. Different defects of the same gene, SCN5A, are also responsible for long-QT syndrome, variant 3. Although there are many remaining questions, substantial progress has been made in understanding the structure and function of the sodium channel protein resulting from this gene (Figure 3).20,21 Defects associated with the Brugada syndrome lead to premature inactivation and other loss-of-function abnormalities of the cardiac sodium channel. Differential manifestation of a specific conducting defect within and between the ventricular epicardium and endocardium leads to heterogeneous cellular repolarization across the myocardium and the potential for reentrant ventricular tachydysrhythmias such as polymorphic ventricular tachycardia and ventricular fibrillation.22 The disease appears to be prevalent in Southeast Asian populations and is at least partly responsible for the nocturnal sudden death described as "lai tai" (death during sleep) in Thailand, "bangungut" (to rise and moan during sleep and then die) in the Philippines, and "pokkuri" (unexpected sudden death from cardiac causes at night) in Japan.23 The clinical manifestations are nine times as common among men as among women, often first occurring in the third or fourth decade of life and in patients at rest or during sleep.
Figure 3. The Cardiac Sodium Channel with Some Sites of Mutations Associated with the Brugada Syndrome and the Long-QT Syndrome.
Panel A shows the three-dimensional configuration of the cardiac sodium-channel pore. Panel B shows an active and an inactive sodium channel. A linear map of the protein (Panel C) shows the four transmembrane domains (I, II, III, and IV) and the sites of common mutations. Protein mutations associated with the Brugada syndrome are shown in purple; those causing the long-QT syndrome are in red, and yellow is associated with both the long-QT syndrome, variant 3 (LQT3), and the Brugada syndrome. The S4 segments of each domain are colored pink to signify their overall positive charge and instrumental role in sensing the transmembrane voltage.
The diagnosis of the Brugada syndrome is made on the basis of the electrocardiographic characteristics of a pattern of right bundle-branch block and an elevation at the J point that is greater than 2 mm, with a slowly descending ST segment in conjunction with flat or negative T waves in the right precordial leads V1, V2, or V3. In addition, there would be a history of syncope, inducible polymorphic ventricular tachycardia or ventricular fibrillation, or sudden death from cardiac causes in the patient or a family member and no obvious structural cause of sudden death.24,25 The electrocardiographic morphology associated with the Brugada syndrome varies in individual patients, decreasing in prominence with sympathetic stimulation and exercise and increasing with body temperature and the administration of class I antidysrhythmic agents, which variably decrease sodium-channel conduction.26,27 Thus, the diagnostic test in this case should be a repeated electrocardiogram.
Dr. Keith Marill's Diagnosis
The Brugada syndrome.
Diagnostic Discussion
Dr. Manini: A second electrocardiogram was obtained (Figure 4), which demonstrated downsloping ST-segment elevations in leads V1 and V2 with a pattern of partial right bundle-branch block. Straight down sloping of the ST segment in V1 and a saddle appearance of the ST segment in V2 were suggestive of known variants of the Brugada syndrome pattern.
Figure 4. Additional Electrocardiograms.
An electrocardiogram obtained approximately seven hours after the first (Panel A) shows a pattern of incomplete right bundle-branch block and downsloping ST-segment elevation in the anterior septal leads V1 and V2, consistent with patterns associated with the Brugada syndrome. Classically, in the Brugada syndrome, the ST segment in these leads is "coved," showing upward concavity. This patient's electrocardiogram shows two common variants of ST-segment morphology: a straight downward ST segment in lead V1 (arrow) and a saddle-shaped ST segment in lead V2 (arrowhead). An electrocardiogram obtained the next day (Panel B), 31 hours after the initial tracing, shows more classic coving of the ST segment in lead V2 (arrow).
On the basis of the electrocardiographic findings, in concert with the clinical circumstances, a diagnosis of the Brugada syndrome was made.
Discussion of Management
Dr. Marill: This patient did not have a family history of cardiac dysrhythmias or sudden death but had a ventricular fibrillation–induced cardiac arrest, no evident structural cause, and on a repeated electrocardiogram, findings characteristic of the Brugada syndrome. If he recovers from this episode, what are the prognosis and management options?
The likelihood of sudden death from cardiac causes in patients with the Brugada syndrome increases with a history of syncope or cardiac arrest, a spontaneous — as opposed to drug-inducible — abnormality on electrocardiography, male sex, and probably, the potential to induce ventricular tachydysrhythmias with programmed electrical stimulation.28,29,30 This patient's history clearly puts him at high risk for a recurrence. Primary therapy for all symptomatic patients with the Brugada syndrome is an automatic implantable cardioverter–defibrillator. His family members should be evaluated for evidence of the Brugada syndrome. Testing involves electrocardiography, followed by repeated electrocardiography in the electrophysiology laboratory after challenge with a sodium-channel–blocking agent such as procainamide if the initial tracing is normal; programmed electrical stimulation may be helpful for diagnosis and assessment of the risk of tachydysrhythmia if the electrocardiogram shows abnormalities. The approach to an asymptomatic patient remains challenging.28,29,30
Dr. Manini: The patient was transferred to the cardiac intensive care unit in critical condition. The placement of an automatic implantable cardioverter–defibrillator was deferred until the extent of his neurologic recovery could be determined. Induction of hypothermia was considered by a neurology consultant, but it was deferred because the patient had purposeful movements and was not unequivocally comatose and because the procedure carries some risk. A cooling blanket and acetaminophen were used to maintain euthermia. Follow-up brain magnetic resonance imaging revealed changes consistent with the presence of anoxic brain injury. On the second hospital day, bloody diarrhea occurred and an abdominal CT performed with contrast material showed changes consistent with the presence of ischemic colitis. On the third day, the patient remained comatose and did not respond to stimuli; the prognosis for a neurologic recovery was thought to be poor. After the clinicians consulted with the patient's family, life support was withdrawn and the patient died. An autopsy was not performed.
Dr. Patrick T. Ellinor: It was recommended that all the patient's first-degree relatives be screened for the Brugada syndrome. The patient's 32-year-old brother had no cardiac symptoms. His evaluation, which included the results of a stress test performed a few months earlier for atypical chest pain, a resting electrocardiogram, and an echocardiogram, was normal. There were no inducible ST-segment abnormalities present after the infusion of procainamide. To my knowledge, the parents have not been evaluated. The only identified cause of the Brugada syndrome is an abnormality in the cardiac sodium channel; however, mutations in this gene appear to account for only one third of the cases. Testing for mutations in this gene is commercially available, but a negative result would not be helpful. As part of a research protocol in our laboratory, the cardiac sodium channel SCN5A was analyzed and no mutation was identified in this patient.
Dr. Marill reports owning equity in Medtronic and in Johnson & Johnson/Guidant.
We are indebted to Dr. David F. Brown for his assistance with this discussion and to Drs. Josep Brugada and William Catterall for their generous contributions to the manuscript figures.
Source Information
From the Department of Emergency Medicine (K.A.M.) and the Cardiology Division (P.T.E.), Massachusetts General Hospital; and the Division of Emergency Medicine (K.A.M.) and the Department of Medicine (P.T.E.), Harvard Medical School — both in Boston.
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