Cardiac Arrhythmias and Sudden Death in Subarachnoid Hemorrhage BY BRUNO V. ESTANOL, M.D., AND OSCAR S. M. MARIN, M.D. Abstract:
Cardiac Arrhythmias and Sudden Death in Subarachnoid Hemorrhage
• Life-threatening cardiac arrhythmias can occur in patients with subarachnoid hemorrhage secondary to rupture of intracranial aneurysms. The arrhythmias are secondary to acute dysfunction of the central nervous system and possibly to sudden increase in intracranial pressure. The autonomic nervous system is the mediator in the production of these disorders. The clinical significance of these rhythm disorders is discussed, particularly in regard to the sudden, unexpected death seen in this type of patient. The possible mechanisms of production are analyzed and their therapeutic implications are stressed. Additional Key Words intracranial aneurysms electrocardiographical abnormalities
D The functional relationship between heart and brain is an ancient topic.1'2 It has been known since 19473 that primary, spontaneous subarachnoid hemorrhage (SAH) and other acute intracranial events can precipitate dramatic changes in the morphology of the waves of the electrocardiogram (ECG). A wealth of literature has been published since that time on this subject. Distinctive electrocardiographical abnormalities associated with this intracranial event include a prolonged QT interval (the importance of this change will be discussed later), large upright or deeply inverted T waves, elevation or depression of ST segments, prominent U waves and a marked increase in the amplitude of the U waves in postextrasystolic beats.3'18 The time course of these abnormalities has not been adequately documented.10 These ECG changes may closely resemble an acute myocardial infarction.6' n'13> 16 The most widely accepted view is that they represent disturbances of ventricular repolarization. It is likely that the ECG changes are secondary to a derangement in the autonomic control of the heart. A large body of experimental and clinical evidence exists to support this view.10- " Many of the patients who had abnormal ECGs and who died of central nervous system lesions had normal hearts at autopsy.10 On the other hand, there is experimental and clinical evidence that shows that many of these patients have acute structural changes in the myocardium, and furthermore that this myocardial damage appears to be secondary to brain lesions.1822 Connor 19 -" demonstrated structural changes of the myocardium in patients dying with a variety of diseases of the brain. These changes consisted of focal myocytolysis, myofibrillar degeneration, lipofuscin pigment deposition in the myofibrils Department of Neurology, Baltimore City Hospitals and Johns Hopkins University School of Medicine, Baltimore, Maryland 21224.
autonomic
nervous
system
and sparse collections of histiocytes in the area of necrosis. The mechanism responsible for the pathological myocardial changes produced by intracranial lesions is not known. However, it appears that the autonomic nervous system and its various chemical mediators play a role in its pathogenesis.9 In contradistinction to the abundance of information concerning ECG changes in SAH, there is hardly any mention of disturbances of cardiac rhythm in the neurological and cardiological literature. Scattered reports on this subject have been published;23'28 nevertheless, there is a dearth of information concerning the incidence, time of appearance, clinical importance and methods of prevention and treatment of these feared events. No mention of arrhythmias is made in the standard textbooks of neurology and the condition is merely regarded as a curiosity at best. However, the presence of these disorders of the heart beat is likely to have great clinical importance, particularly as it pertains to the distressingly common, sudden and now somewhat expected death so unfortunately frequent in these patients. Moreover, when there is a concomitant impairment of consciousness and no clinical history, the disturbance of the cardiac rhythm may appear to be the primary illness of these patients.23 Parizel24 described two cases of spontaneous SAH, both of which developed several different arrhythmias within a short period of time: supraventricular tachycardia, short bursts of ventricular premature beats, multifocal ventricular tachycardia, ventricular flutter and ventricular fibrillation necessitating D.C. countershock and intravenous antiarrhythmic drugs. Both patients survived. His comments are enlightening: "Life-threatening arrhythmias can occur in patients with subarachnoid hemorrhage. Our two patients would undoubtedly have died without the prompt resuscitative measures made possible by their admission to a coronary care unit. Their death would have been attributed to their
382
Stroke, Vol. 6, July-August 1975
Downloaded from http://stroke.ahajournals.org/ by guest on June 25, 2016
CARDIAC ARRHYTHMIAS AND SUDDEN DEATH IN SAH
nervous system disease." Prior to this report the seriousness of these events had not been emphasized. Plum and Posner23 described a 44-year-old man who presented with arrhythmias of various sorts: 2:1 block, sino-atrial block, sinus arrhythmia, intermittent complete atrioventricular block, supraventricular tachycardia and finally ventricular tachycardia. This patient was mistakenly diagnosed as having a myocardial infarction, but postmortem examination showed a massive SAH from rupture of an aneurysm of the anterior communicating artery. No mention was made of the state of the heart. The transient nature of these disorders and the fact that many of these patients are not under careful cardiac monitoring during the acute illness are also additional factors in the poor documentation of these arrhythmias. A prospective study of electrocardiographical changes associated with SAH does not mention the presence of cardiac arrhythmias.29 We have recently seen two cases of acute SAH secondary to rupture of intracranial aneurysms in whom life-threatening cardiac arrhythmias were present. In only one case was it possible to obtain full documentation of the disorder.
Casel A 61-year-old white man was brought to the emergency room of the Baltimore City Hospitals in a stuporous state. Cardiac examination disclosed a very fast apical rate with a varying first sound. ECG revealed ventricular flutter at a rate of 250 per minute (fig. 1) that spontaneously reverted to normal sinus rhythm in about 30 seconds. Over the next few minutes he had multiple premature atrial contractions (PACs), intermittent 2:1 block, multifocal premature ventricular contractions (PVCs), and short episodes of
-ri 4i-4rr+rfflIfr mfiFfllrftT-r, h ; rlr
bigeminal rhythm. Fifty milligrams of intravenous xylocaine were given with restoration of normal sinus rhythm. Following these events the patient was lethargic, but easily arousable, and oriented. He complained of a severe headache. He related that he was standing on the street when he suddenly became dizzy and then "blacked out." He did not recall falling or having a headache prior to losing consciousness. The next memory he had was that of waking up in the ambulance with a severe headache; he remembered he suddenly lost consciousness again upon entering the emergency room. His past medical history was unremarkable except for mild hypertension of ten years' duration, for which he had been treated intermittently with 50 mg of hydrochlorothiazide daily. An ECG taken one year prior to his admission was within normal limits and a chest x-ray taken at the same time was normal as well. He denied any history of heart disease. He denied angina or symptoms of congestive heart failure. He did not smoke or drink, and stated that his general health prior to this incident had been excellent. Physical examination on admission revealed a man in acute distress complaining of a severe headache. He was lethargic but easily arousable and oriented. Blood pressure when the patient was in normal sinus rhythm was 200/120 mm Hg, respiratory rate was 25 per minute and regular, and pulse 110 per minute and regular. Rectal temperature was 101°. General physical examination showed no evidence of jugular venous distention, the lungs were clear, the heart sounds were normal with no gallops or murmurs, and the heart was not enlarged. There was grade 1 hypertensive retinal changes (Keith-Wagener classification) and normal peripheral pulses. Neurological examination revealed slight neck stiffness and the presence of an incomplete left third nerve palsy, with 50% palpebral ptosis, and a left pupil which was 2 mm larger than the right and sluggishly reactive to light. There was paresis of left medial rectus, inferior oblique and superior rectus. There were no hemipareses, sensory deficits or visual field defects. A lumbar puncture showed an opening pressure higher than 300 mm H 2 O. The CSF was grossly bloody with a xanthochromic supernatant and a hematocrit of 6%. The urine showed no protein or sugar and the sediment contained no red or white cells. An ECG taken one hour after admission revealed a sinus rhythm of 85 per minute, first degree AV block, left axis deviation (-15°), and a QT interval of 0.44 second. There were no U waves but the T waves were slightly depressed over the precordial leads. There was no evidence of a myocardial infarction in the ECG. A blood count showed leukocytosis with a shift to the left. Two hours after admission the electrolytes were normal, including potassium. Continuous monitoring over the next 48 hours did not reveal the presence of a serious cardiac arrhythmia. The ECG remained unchanged. Serial arterial blood gases were normal. An arteriogram revealed a left posterior communicating artery aneurysm at the point of junction with the left internal carotid artery.
Case 2 FIGURE 1
Trace A shows ventricular flutter at a rale of 250 per minute. No P waves are discernible in this tracing. B and C show multifocal premature ventricular contractions (PVCs).
A 29-year-old black man was admitted to the Johns Hopkins Hospital because of sudden onset of severe, generalized headache that developed while the patient was having intercourse. His previous health had been good and his family history was negative for neurological or cardiac diseases. His general physical examination on admission was negative. Neurological examination showed moderate
Stroke. Vol. 6, July-August 1975
383
Downloaded from http://stroke.ahajournals.org/ by guest on June 25, 2016
ESTANOL, MARIN
neck stiffness and a Kernig sign, but was otherwise negative. While he was being examined by the house staff he suddenly developed multifocal PVCs and runs of ventricular tachycardia each lasting a few seconds. These arrhythmias were directly observed on the cardiac monitor. They subsided spontaneously after a few minutes and no therapy was given. At no time was there evidence of shock or decreased cerebral perfusion. Electrolytes, arterial blood gases, chest x-ray and an ECG taken one hour after this episode were within normal limits. Lumbar puncture showed an opening pressure of 400 mm of CSF and was grossly bloody with a xanthochromic supernatant. Cerebral angiography proved the presence of a right posterior communicating artery aneurysm, again at the point of junction with the internal carotid artery.
Discussion PATHOPHYSIOLOGY
The neural mechanisms by which these arrhythmias are produced are not clearly understood. However, in recent years some physiological information has accumulated which sheds some light upon this subject.30"36 An excellent review of this somewhat confusing topic was made recently by Mauck.32 In the experimental animal, cardiac arrhythmias can be induced by electrical stimulation of several cortical and subcortical areas. These include the frontal lobes, the limbic system, the amygdaloid nuclei, the hypothalamus, the mesencephalon and other areas in the brain stem.30 These arrhythmias are in all likelihood mediated through the autonomic nervous system.32 In another study, Hockman et al.34 induced a spectrum of ectopic ventricular rhythms by electrical stimulation of some areas of the mesencephalon and diencephalon. Observed in sequence were ventricular tachycardia, both unifocal and multifocal, ventricular premature contractions in bigeminal pattern, and final return to sinus rhythm. Bilateral vagotomy had no effect on the response; however, it was completely abolished by beta-adrenergic blockage with propranolol. They concluded that the type of arrhythmia observed was directly related to the intensity of the sympathetic discharge and that all abnormal ventricular complexes observed in the clinic could be elicited experimentally. On the other hand, Smith and Ray33 were able to provoke various cardiac arrhythmias in anesthetized dogs by rapid increase in intracranial pressure or by instantaneous release of previously elevated intracranial pressure. Both the administration of atropine and vagotomy eliminated or prevented the arrhythmias. These animals also developed cardiac arrhythmias after injections of isoproterenol. More recently it has been shown35 that if hypoxia is present the frequency of these problems is increased. Thus, the experimental evidence appears to indicate that both the sympathetic and the parasympathetic systems are implicated in the production of these rhythm disturbances. That sudden increase of intracranial pressure can precipitate cardiac arrhythmias is of particular clinical interest. Wong
and Cooper27 published a case of SAH with atrial fibrillation and ventricular slowing in which a lumbar puncture, presumably by decreasing the increased intracranial pressure, abolished the cardiac arrhythmia. Also, the prolongation of the QT interval so frequently seen in these patients has been associated with sudden death.36 According to James,36 "Prolongation of the QT interval represents delayed ventricular repolarization and an increase in the duration of the vulnerable period with greater susceptibility to the development of a ventricular dysrhythmia. In a patient with a prolonged QT interval, therefore, it is particularly important to prevent the occurrence of premature ventricular beats or supraventricular dysrhythmias." Smith25 published a case of SAH associated with a prolonged QT interval and ventricular bigeminy and quadrigeminy. He stated that the cardiac arrhythmias were clearly related to a prolonged QT interval. The prolonged QT interval appears to be secondary to a non-uniformity in the rate of repolarization of these cells.37'38 Intracellular studies of the sino-auricular node39 (SA node) have shown that the firing rate of the SA node is modified by both sympathetic and parasympathetic nervous systems. It is well established that the rate of depolarization of the SA node is greatly influenced by neural mechanisms.39 For example, vagal discharges depress the pacemaker by slowing the rate of depolarization; on the other hand, an increase in sympathetic discharge increases the slope of depolarization. By reciprocal effects on the rate of depolarization in the transmitter tissue, conduction through the atrioventricular node (AV node) is either increased or decreased. Sudden changes in discharges of either vagal or sympathetic systems could produce a number of cardiac arrhythmias. In addition to the aforementioned neural factors, pre-existent heart disease, changes in electrolytes, and pH of the blood or Pao, may be of significance in the production of these arrhythmias. However, neither abnormalities in the above-mentioned factors nor an increase in circulating catecholamines has been found to be consistently associated with the electrocardiographical abnormalities of SAH.40 The role of the myocardial lesions secondary to acute brain lesions in the genesis of these problems is not known.41 RELATION OF ARRHYTHMIAS TO THE SUDDEN UNEXPECTED DEATH SYNDROME
An important point that naturally arises is the possible relationship between the cardiac arrhythmias and the sudden unexpected death of some patients with primary SAH. It has been estimated that as many as 15% of the patients with spontaneous SAH die before reaching the nearest hospital.42 Twenty percent more will die within 48 hours after the onset of symptoms.42 Hamman43 found that 8% of all patients who died suddenly had some sort of cerebral hemorrhage. Others44 have found SAH to be responsible for 4.7%
384
Stroke, Vol. 6, July-August 1975
Downloaded from http://stroke.ahajournals.org/ by guest on June 25, 2016
CARDIAC ARRHYTHMIAS AND SUDDEN DEATH IN SAH
of all sudden deaths. In a remarkable study SecherHansen39 analyzed 115 cases of autopsy-proved spontaneous subarachnoid hemorrhage, all of which fulfilled the criterion for sudden unexpected death (all deaths ranging from "instantaneous" to the first 24 hours) and found that 75% of his cases had died instantaneously! The mechanisms of death in these patients are not entirely clear and are doubtless multiple. Acute destruction or compression of vital centers operates in some cases.45-te According to Helpern et al.44 the most common postmortem finding is a diffuse subarachnoid hemorrhage covering the base of the brain. Also, Crompton47 has shown that blood may rapidly distend the basal cisterns, stretching perforating arteries which pass into the brain, causing spasm of these vessels and resultant diencephalic ischemia. This can bring as a consequence impairment of vegetative functions. It is entirely possible that the incidence of cardiac arrhythmias is greater when an aneurysm ruptures in the base of the brain, but there is not enough clinical information to decide upon this point. There is no satisfactory explanation for the initial loss of consciousness that usually accompanies SAH. There is no evidence that extravasation of blood in the subarachnoid space can, by itself, cause unconsciousness.48 Hemorrhage into the brain, infarction or arterial spasm have been incriminated, but the clinical fact that many patients recover consciousness with intact nervous system function militates against this thesis. Some of these patients may have seizures, albeit the incidence of seizures at the time the aneurysm ruptures is not known. It should be stressed that patients with SAH should have cardiac monitoring in a place in which proper treatment is available. In regard to the treatment of these disorders, the few arrhythmias reported in the literature responded well to the standard methods of treatment for arrhythmias of other causes.24 However, chemical blockage of the sympathetic and parasympathetic systems with atropine and propranolol has been advocated for the prevention of myocardial damage in patients with intracranial hemorrhage.22'49> 50 It is probably significant that these patients and three others reported in the literature2325 had bizarre atrial and ventricular arrhythmias similar to those reported in the experimental animal by Hockman et al.34 Also, from the cases isolated from the literature in which the location of the aneurysm was known, two cases23'27 had aneurysms of the anterior communicating artery, and at least three cases23 (and those reported here) had aneurysms of the posterior communicating in the junction with the internal carotid. The fact that these aneurysms were located in the base of the brain may imply an important relationship between the location of an intracranial hemorrhage and its potential pathogenicity; however, more studies are needed to clarify this point and many others in this important medical problem.
References 1. Cannon WB: "Voodoo" death. Amer Anthropologist (new series) 44:169-181, 1942 2. Wolf S: The end of the rope: The role of the brain in cardiac death. Canad Med Assoc J 97:1022-1025 (Oct 21) 1967 3. Byer E, Ashman R, Toth LA: Electrocardiograms with large, upright T waves and long Q-T intervals. Amer Heart J 33:796-806, 1947 4. Burch GE, Phillips JH: The large upright T wave as an electrocardiographic manifestation of intracranial disease. Southern Med J 61:331-336 (Apr) 1968 5. Srivastava SC, Robson AO: Electrocardiographs abnormalities associated with subarachnoid haemorrhage. Lancet 2:431-433 (Aug 29) 1964 6. Cropp GJ, Manning GW: Electrocardiographic changes simulating myocardial ischemia and infarction associated with spontaneous intracranial hemorrhage. Circulation 22:25-38 (July) 1960 7. Fentz V, Gormsen J: Electrocardiographs patterns in patients with cerebrovascular accidents. Circulation 25:2228 (Jan) 1962 8. Hersch C: Electrocardiographs changes in subarachnoid haemorrhage, meningitis, and intracranial space-occupying lesions. Brit Heart J 26:785-793, 1964 9. Burch GE, Colcolough H, Giles T: Intracranial lesions and the heart. Amer Heart J 80:574-575 (Oct) 1970 10. Abildskov JA, Millar K, Burgess MJ, et ah The electrocardiogram and the central nervous system. Prog Cardiovasc Dis 13:210-216, 1970 11. Belief S: Brain and heart relationships. In Belief S: Clinical Disorders of the Heart Beat. Philadelphia, Lea & Febiger, p 840-852, 1971 12. Burch GE, Meyers R, Abildskov JA: A new electrocardiographs pattern observed in cerebrovascular accidents. Circulation 9:719-723 (May) 1954 13. Menon IS: Electrocardiographic changes simulating myocardial infarction in cerebrovascular accident. Lancet 2:433434 (Aug 29) 1964 14. Hugenholtz PG: Electrocardiographs abnormalities in cerebral disorders. Report of six cases and review of the literature. Amer Heart J 63:451-461 (Apr) 1962 15. Kreus K-E, Kemild SJ, Takala JK: Electrocardiographic changes in cerebrovascular accidents. Acta Med Scand 185:327-334, 1969 16. Shuster S: Electrocardiogram in subarachnoid haemorrhage. Brit Heart J 22:316-320, 1960 17. Abildskov JA, Burgess MJ: Neurogenic abnormalities of ventricular repolarization. J Electrocardiol 4:87-90, 1971 18. Koskelo P, Punsar S, Sipild W: Subendocardial haemorrhage and ECG changes in intracranial bleeding. Brit Med J 1:1479-1480 (June 6) 1964 19. Connor RCR: Myocardial damage secondary to brain lesions. Amer Heart J 78:145-148 (Aug) 1969 20. Burch GE, Sun SC, Colcolough HL, et al: Acute myocardial lesions. Following experimentally-induced intracranial hemorrhage in mice: A histological and histochemical study. Arch Path 84:517-521 (Nov) 1967 21. Groover ME Jr, Stout G Neurogenic myocardial necrosis. Angiology 16:180-186, 1965 22. Connor RCR: Fuchsinophilic degeneration of myocardium in patients with intracranial lesions. Brit Heart J 32:81-84, 1970 23. Plum F, Posner JB: Diagnosis of Stupor and Coma. Philadelphia, FA Davis Co, 1970 385
Stroke, Vol. 6. July-August 1975
Downloaded from http://stroke.ahajournals.org/ by guest on June 25, 2016
ESTANOL, MARIN 24. Parizel G: Life-threatening arrhythmias in subarachnoid hemorrhage. Angiology 24:17-21 (Jan) 1973 25. Smith M: Ventricular bigeminy and quadrigeminy occurring in a case of subarachnoid hemorrhage. J Electrocardiol 5:78-85, 1972 26. Reinstein L, Gracey JG, Kline JA, et ah Cardiac monitoring of the acute stroke patient. Arch Phys Med Rehab 53:311-314 (July) 1972 27. Wong TC, Cooper ES: Atrial fibrillation with ventricular slowing in a patient with spontaneous subarachnoid hemorrhage. Amer J Cardiol 23:473-477 (Mar) 1969 28. Cooper ES, West JW: Cardiac arrhythmias, cerebral function, and stroke. Curr Concepts Cerebrovascular Dis Stroke 5:53-58 (Nov-Dec) 1970 29. Galloon S, Rees GAD, Briscoe CE, et ah Prospective study of electrocardiographic changes associated with subarachnoid haemorrhage. Brit J Anaesth 44:511-516, 1972 30. Mauck HP Jr, Hockman CH: Central nervous system mechanisms mediating cardiac rate and rhythm. Amer Heart J 74:96-109 (July) 1967 31. Hoffman BF, Cranefield PF: The physiological basis of cardiac arrhythmias. Amer J Med 37:670-684 (Nov) 1964 32. Mauck HP Jr: Autonomic control of cardiovascular function. In Frohlich ED (ed): Pathophysiology. Altered Regulatory Mechanisms in Disease. Philadelphia, JB Lippincott, p 599614, 1972 33. Smith M, Ray CT: Cardiac arrhythmias, increased intracranial pressure and the autonomic nervous system. Chest 6 1 (Suppl): 125-133 (Feb) 1972 34. Hockman CH, Mauck HP Jr, Hoff EC: ECG changes resulting from cerebral stimulation. II. A spectrum of ventricular arrhythmias of sympathetic origin. Amer Heart J 71:695700 (May) 1966 35. Mauck HP Jr, Szumski AJ, Fu T-C, et ah The effect of acute hypoxia on cardiac dysrhythmias induced by mesencephalic stimulation. Amer Heart J 87:197-202 (Feb) 1974 36. James TN: QT prolongation and sudden death. Mod Concepts Cardiovasc Dis 38:35-37 (July) 1969 37. Han J, Moe GK: Nonuniform recovery of excitability in ven-
tricular muscle. Circulation Research 14:44-60 (Jan) 1964 38. Han J, Millet D, Chizzonitti B, et ah Temporal dispersion of recovery of excitability in atrium and ventricle as a function of heart rate. Amer Heart J 71:481-487 (Apr) 1966 39. Secher-Hansen E: Subarachnoidal haemorrhage and sudden unexpected death. Acta Neurol Scand 40:115-130, 1964 40. Eisalo A, Perasalo J, Halonen PI: Electrocardiographic abnormalities and some laboratory findings in patients with subarachnoid haemorrhage. Brit Heart J 34:217-226 (Mar) 1972 41. Greenhoot JH, Reichenbach DD: Cardiac injury and subarachnoid hemorrhage. A clinical, pathological and physiological correlation. J Neurosurg 30:521-531 (May) 1969 42. Locksley HB: Natural history of subarachnoid hemorrhage, intracranial aneurysms, and arteriovenous malformations. Based on 6,368 cases in the cooperative study. Parts 1 and 2. In Sahs AL, Perret GE, Locksley HB, et al (eds): Intracranial Aneurysms and Subarachnoid Hemorrhage. Philadelphia, JB Lippincott, p 37-108, 1969 43. Hamman L: Sudden death. Bull Johns Hopkins Hosp 55:387415, 1934 44. Helpern M, Rabson SM: Sudden and unexpected natural death — general considerations and statistics. NY State J Med 45:1197-1201 (June 1) 1945 45. Dinning TAR, Falconer MA: Sudden or unexpected natural death due to ruptured intracranial aneurysms. Survey of 250 forensic cases. Lancet 2:799-801 (Oct 17) 1953 46. Berkheiser SW: Intracranial aneurysm and sudden death. Aerospace Med 43:331-332 (Mar) 1972 47. Crompton MR: The pathology of subarachnoid haemorrhage. J R Coll Physicians Lond 7:235-238 (Apr) 1973 48. Elliot FA: Clinical Neurology. Philadelphia, WB Sounders Co, p 389, 1971 49. Valero A: Treatment of severe physostigmine poisoning. Lancet 2:459-460 (Aug 24) 1968 50. Weintraub BM, McHenry LC Jr: Cardiac abnormalities in subarachnoid hemorrhage: A resume. Stroke 5:384-392 (May-June) 1974
386
Stroke. Vol. 6, July August 1975
Downloaded from http://stroke.ahajournals.org/ by guest on June 25, 2016
Cardiac Arrhythmias and Sudden Death in Subarachnoid Hemorrhage BRUNO V. ESTANOL and OSCAR S. M.MARIN Stroke. 1975;6:382-386 doi: 10.1161/01.STR.6.4.382 Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1975 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://stroke.ahajournals.org/content/6/4/382
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Stroke is online at: http://stroke.ahajournals.org//subscriptions/
Downloaded from http://stroke.ahajournals.org/ by guest on June 25, 2016
Cardiac Arrhythmias and Sudden Death in Subarachnoid Hemorrhage
• Life-threatening cardiac arrhythmias can occur in patients with subarachnoid hemorrhage secondary to rupture of intracranial aneurysms. The arrhythmias are secondary to acute dysfunction of the central nervous system and possibly to sudden increase in intracranial pressure. The autonomic nervous system is the mediator in the production of these disorders. The clinical significance of these rhythm disorders is discussed, particularly in regard to the sudden, unexpected death seen in this type of patient. The possible mechanisms of production are analyzed and their therapeutic implications are stressed. Additional Key Words intracranial aneurysms electrocardiographical abnormalities
D The functional relationship between heart and brain is an ancient topic.1'2 It has been known since 19473 that primary, spontaneous subarachnoid hemorrhage (SAH) and other acute intracranial events can precipitate dramatic changes in the morphology of the waves of the electrocardiogram (ECG). A wealth of literature has been published since that time on this subject. Distinctive electrocardiographical abnormalities associated with this intracranial event include a prolonged QT interval (the importance of this change will be discussed later), large upright or deeply inverted T waves, elevation or depression of ST segments, prominent U waves and a marked increase in the amplitude of the U waves in postextrasystolic beats.3'18 The time course of these abnormalities has not been adequately documented.10 These ECG changes may closely resemble an acute myocardial infarction.6' n'13> 16 The most widely accepted view is that they represent disturbances of ventricular repolarization. It is likely that the ECG changes are secondary to a derangement in the autonomic control of the heart. A large body of experimental and clinical evidence exists to support this view.10- " Many of the patients who had abnormal ECGs and who died of central nervous system lesions had normal hearts at autopsy.10 On the other hand, there is experimental and clinical evidence that shows that many of these patients have acute structural changes in the myocardium, and furthermore that this myocardial damage appears to be secondary to brain lesions.1822 Connor 19 -" demonstrated structural changes of the myocardium in patients dying with a variety of diseases of the brain. These changes consisted of focal myocytolysis, myofibrillar degeneration, lipofuscin pigment deposition in the myofibrils Department of Neurology, Baltimore City Hospitals and Johns Hopkins University School of Medicine, Baltimore, Maryland 21224.
autonomic
nervous
system
and sparse collections of histiocytes in the area of necrosis. The mechanism responsible for the pathological myocardial changes produced by intracranial lesions is not known. However, it appears that the autonomic nervous system and its various chemical mediators play a role in its pathogenesis.9 In contradistinction to the abundance of information concerning ECG changes in SAH, there is hardly any mention of disturbances of cardiac rhythm in the neurological and cardiological literature. Scattered reports on this subject have been published;23'28 nevertheless, there is a dearth of information concerning the incidence, time of appearance, clinical importance and methods of prevention and treatment of these feared events. No mention of arrhythmias is made in the standard textbooks of neurology and the condition is merely regarded as a curiosity at best. However, the presence of these disorders of the heart beat is likely to have great clinical importance, particularly as it pertains to the distressingly common, sudden and now somewhat expected death so unfortunately frequent in these patients. Moreover, when there is a concomitant impairment of consciousness and no clinical history, the disturbance of the cardiac rhythm may appear to be the primary illness of these patients.23 Parizel24 described two cases of spontaneous SAH, both of which developed several different arrhythmias within a short period of time: supraventricular tachycardia, short bursts of ventricular premature beats, multifocal ventricular tachycardia, ventricular flutter and ventricular fibrillation necessitating D.C. countershock and intravenous antiarrhythmic drugs. Both patients survived. His comments are enlightening: "Life-threatening arrhythmias can occur in patients with subarachnoid hemorrhage. Our two patients would undoubtedly have died without the prompt resuscitative measures made possible by their admission to a coronary care unit. Their death would have been attributed to their
382
Stroke, Vol. 6, July-August 1975
Downloaded from http://stroke.ahajournals.org/ by guest on June 25, 2016
CARDIAC ARRHYTHMIAS AND SUDDEN DEATH IN SAH
nervous system disease." Prior to this report the seriousness of these events had not been emphasized. Plum and Posner23 described a 44-year-old man who presented with arrhythmias of various sorts: 2:1 block, sino-atrial block, sinus arrhythmia, intermittent complete atrioventricular block, supraventricular tachycardia and finally ventricular tachycardia. This patient was mistakenly diagnosed as having a myocardial infarction, but postmortem examination showed a massive SAH from rupture of an aneurysm of the anterior communicating artery. No mention was made of the state of the heart. The transient nature of these disorders and the fact that many of these patients are not under careful cardiac monitoring during the acute illness are also additional factors in the poor documentation of these arrhythmias. A prospective study of electrocardiographical changes associated with SAH does not mention the presence of cardiac arrhythmias.29 We have recently seen two cases of acute SAH secondary to rupture of intracranial aneurysms in whom life-threatening cardiac arrhythmias were present. In only one case was it possible to obtain full documentation of the disorder.
Casel A 61-year-old white man was brought to the emergency room of the Baltimore City Hospitals in a stuporous state. Cardiac examination disclosed a very fast apical rate with a varying first sound. ECG revealed ventricular flutter at a rate of 250 per minute (fig. 1) that spontaneously reverted to normal sinus rhythm in about 30 seconds. Over the next few minutes he had multiple premature atrial contractions (PACs), intermittent 2:1 block, multifocal premature ventricular contractions (PVCs), and short episodes of
-ri 4i-4rr+rfflIfr mfiFfllrftT-r, h ; rlr
bigeminal rhythm. Fifty milligrams of intravenous xylocaine were given with restoration of normal sinus rhythm. Following these events the patient was lethargic, but easily arousable, and oriented. He complained of a severe headache. He related that he was standing on the street when he suddenly became dizzy and then "blacked out." He did not recall falling or having a headache prior to losing consciousness. The next memory he had was that of waking up in the ambulance with a severe headache; he remembered he suddenly lost consciousness again upon entering the emergency room. His past medical history was unremarkable except for mild hypertension of ten years' duration, for which he had been treated intermittently with 50 mg of hydrochlorothiazide daily. An ECG taken one year prior to his admission was within normal limits and a chest x-ray taken at the same time was normal as well. He denied any history of heart disease. He denied angina or symptoms of congestive heart failure. He did not smoke or drink, and stated that his general health prior to this incident had been excellent. Physical examination on admission revealed a man in acute distress complaining of a severe headache. He was lethargic but easily arousable and oriented. Blood pressure when the patient was in normal sinus rhythm was 200/120 mm Hg, respiratory rate was 25 per minute and regular, and pulse 110 per minute and regular. Rectal temperature was 101°. General physical examination showed no evidence of jugular venous distention, the lungs were clear, the heart sounds were normal with no gallops or murmurs, and the heart was not enlarged. There was grade 1 hypertensive retinal changes (Keith-Wagener classification) and normal peripheral pulses. Neurological examination revealed slight neck stiffness and the presence of an incomplete left third nerve palsy, with 50% palpebral ptosis, and a left pupil which was 2 mm larger than the right and sluggishly reactive to light. There was paresis of left medial rectus, inferior oblique and superior rectus. There were no hemipareses, sensory deficits or visual field defects. A lumbar puncture showed an opening pressure higher than 300 mm H 2 O. The CSF was grossly bloody with a xanthochromic supernatant and a hematocrit of 6%. The urine showed no protein or sugar and the sediment contained no red or white cells. An ECG taken one hour after admission revealed a sinus rhythm of 85 per minute, first degree AV block, left axis deviation (-15°), and a QT interval of 0.44 second. There were no U waves but the T waves were slightly depressed over the precordial leads. There was no evidence of a myocardial infarction in the ECG. A blood count showed leukocytosis with a shift to the left. Two hours after admission the electrolytes were normal, including potassium. Continuous monitoring over the next 48 hours did not reveal the presence of a serious cardiac arrhythmia. The ECG remained unchanged. Serial arterial blood gases were normal. An arteriogram revealed a left posterior communicating artery aneurysm at the point of junction with the left internal carotid artery.
Case 2 FIGURE 1
Trace A shows ventricular flutter at a rale of 250 per minute. No P waves are discernible in this tracing. B and C show multifocal premature ventricular contractions (PVCs).
A 29-year-old black man was admitted to the Johns Hopkins Hospital because of sudden onset of severe, generalized headache that developed while the patient was having intercourse. His previous health had been good and his family history was negative for neurological or cardiac diseases. His general physical examination on admission was negative. Neurological examination showed moderate
Stroke. Vol. 6, July-August 1975
383
Downloaded from http://stroke.ahajournals.org/ by guest on June 25, 2016
ESTANOL, MARIN
neck stiffness and a Kernig sign, but was otherwise negative. While he was being examined by the house staff he suddenly developed multifocal PVCs and runs of ventricular tachycardia each lasting a few seconds. These arrhythmias were directly observed on the cardiac monitor. They subsided spontaneously after a few minutes and no therapy was given. At no time was there evidence of shock or decreased cerebral perfusion. Electrolytes, arterial blood gases, chest x-ray and an ECG taken one hour after this episode were within normal limits. Lumbar puncture showed an opening pressure of 400 mm of CSF and was grossly bloody with a xanthochromic supernatant. Cerebral angiography proved the presence of a right posterior communicating artery aneurysm, again at the point of junction with the internal carotid artery.
Discussion PATHOPHYSIOLOGY
The neural mechanisms by which these arrhythmias are produced are not clearly understood. However, in recent years some physiological information has accumulated which sheds some light upon this subject.30"36 An excellent review of this somewhat confusing topic was made recently by Mauck.32 In the experimental animal, cardiac arrhythmias can be induced by electrical stimulation of several cortical and subcortical areas. These include the frontal lobes, the limbic system, the amygdaloid nuclei, the hypothalamus, the mesencephalon and other areas in the brain stem.30 These arrhythmias are in all likelihood mediated through the autonomic nervous system.32 In another study, Hockman et al.34 induced a spectrum of ectopic ventricular rhythms by electrical stimulation of some areas of the mesencephalon and diencephalon. Observed in sequence were ventricular tachycardia, both unifocal and multifocal, ventricular premature contractions in bigeminal pattern, and final return to sinus rhythm. Bilateral vagotomy had no effect on the response; however, it was completely abolished by beta-adrenergic blockage with propranolol. They concluded that the type of arrhythmia observed was directly related to the intensity of the sympathetic discharge and that all abnormal ventricular complexes observed in the clinic could be elicited experimentally. On the other hand, Smith and Ray33 were able to provoke various cardiac arrhythmias in anesthetized dogs by rapid increase in intracranial pressure or by instantaneous release of previously elevated intracranial pressure. Both the administration of atropine and vagotomy eliminated or prevented the arrhythmias. These animals also developed cardiac arrhythmias after injections of isoproterenol. More recently it has been shown35 that if hypoxia is present the frequency of these problems is increased. Thus, the experimental evidence appears to indicate that both the sympathetic and the parasympathetic systems are implicated in the production of these rhythm disturbances. That sudden increase of intracranial pressure can precipitate cardiac arrhythmias is of particular clinical interest. Wong
and Cooper27 published a case of SAH with atrial fibrillation and ventricular slowing in which a lumbar puncture, presumably by decreasing the increased intracranial pressure, abolished the cardiac arrhythmia. Also, the prolongation of the QT interval so frequently seen in these patients has been associated with sudden death.36 According to James,36 "Prolongation of the QT interval represents delayed ventricular repolarization and an increase in the duration of the vulnerable period with greater susceptibility to the development of a ventricular dysrhythmia. In a patient with a prolonged QT interval, therefore, it is particularly important to prevent the occurrence of premature ventricular beats or supraventricular dysrhythmias." Smith25 published a case of SAH associated with a prolonged QT interval and ventricular bigeminy and quadrigeminy. He stated that the cardiac arrhythmias were clearly related to a prolonged QT interval. The prolonged QT interval appears to be secondary to a non-uniformity in the rate of repolarization of these cells.37'38 Intracellular studies of the sino-auricular node39 (SA node) have shown that the firing rate of the SA node is modified by both sympathetic and parasympathetic nervous systems. It is well established that the rate of depolarization of the SA node is greatly influenced by neural mechanisms.39 For example, vagal discharges depress the pacemaker by slowing the rate of depolarization; on the other hand, an increase in sympathetic discharge increases the slope of depolarization. By reciprocal effects on the rate of depolarization in the transmitter tissue, conduction through the atrioventricular node (AV node) is either increased or decreased. Sudden changes in discharges of either vagal or sympathetic systems could produce a number of cardiac arrhythmias. In addition to the aforementioned neural factors, pre-existent heart disease, changes in electrolytes, and pH of the blood or Pao, may be of significance in the production of these arrhythmias. However, neither abnormalities in the above-mentioned factors nor an increase in circulating catecholamines has been found to be consistently associated with the electrocardiographical abnormalities of SAH.40 The role of the myocardial lesions secondary to acute brain lesions in the genesis of these problems is not known.41 RELATION OF ARRHYTHMIAS TO THE SUDDEN UNEXPECTED DEATH SYNDROME
An important point that naturally arises is the possible relationship between the cardiac arrhythmias and the sudden unexpected death of some patients with primary SAH. It has been estimated that as many as 15% of the patients with spontaneous SAH die before reaching the nearest hospital.42 Twenty percent more will die within 48 hours after the onset of symptoms.42 Hamman43 found that 8% of all patients who died suddenly had some sort of cerebral hemorrhage. Others44 have found SAH to be responsible for 4.7%
384
Stroke, Vol. 6, July-August 1975
Downloaded from http://stroke.ahajournals.org/ by guest on June 25, 2016
CARDIAC ARRHYTHMIAS AND SUDDEN DEATH IN SAH
of all sudden deaths. In a remarkable study SecherHansen39 analyzed 115 cases of autopsy-proved spontaneous subarachnoid hemorrhage, all of which fulfilled the criterion for sudden unexpected death (all deaths ranging from "instantaneous" to the first 24 hours) and found that 75% of his cases had died instantaneously! The mechanisms of death in these patients are not entirely clear and are doubtless multiple. Acute destruction or compression of vital centers operates in some cases.45-te According to Helpern et al.44 the most common postmortem finding is a diffuse subarachnoid hemorrhage covering the base of the brain. Also, Crompton47 has shown that blood may rapidly distend the basal cisterns, stretching perforating arteries which pass into the brain, causing spasm of these vessels and resultant diencephalic ischemia. This can bring as a consequence impairment of vegetative functions. It is entirely possible that the incidence of cardiac arrhythmias is greater when an aneurysm ruptures in the base of the brain, but there is not enough clinical information to decide upon this point. There is no satisfactory explanation for the initial loss of consciousness that usually accompanies SAH. There is no evidence that extravasation of blood in the subarachnoid space can, by itself, cause unconsciousness.48 Hemorrhage into the brain, infarction or arterial spasm have been incriminated, but the clinical fact that many patients recover consciousness with intact nervous system function militates against this thesis. Some of these patients may have seizures, albeit the incidence of seizures at the time the aneurysm ruptures is not known. It should be stressed that patients with SAH should have cardiac monitoring in a place in which proper treatment is available. In regard to the treatment of these disorders, the few arrhythmias reported in the literature responded well to the standard methods of treatment for arrhythmias of other causes.24 However, chemical blockage of the sympathetic and parasympathetic systems with atropine and propranolol has been advocated for the prevention of myocardial damage in patients with intracranial hemorrhage.22'49> 50 It is probably significant that these patients and three others reported in the literature2325 had bizarre atrial and ventricular arrhythmias similar to those reported in the experimental animal by Hockman et al.34 Also, from the cases isolated from the literature in which the location of the aneurysm was known, two cases23'27 had aneurysms of the anterior communicating artery, and at least three cases23 (and those reported here) had aneurysms of the posterior communicating in the junction with the internal carotid. The fact that these aneurysms were located in the base of the brain may imply an important relationship between the location of an intracranial hemorrhage and its potential pathogenicity; however, more studies are needed to clarify this point and many others in this important medical problem.
References 1. Cannon WB: "Voodoo" death. Amer Anthropologist (new series) 44:169-181, 1942 2. Wolf S: The end of the rope: The role of the brain in cardiac death. Canad Med Assoc J 97:1022-1025 (Oct 21) 1967 3. Byer E, Ashman R, Toth LA: Electrocardiograms with large, upright T waves and long Q-T intervals. Amer Heart J 33:796-806, 1947 4. Burch GE, Phillips JH: The large upright T wave as an electrocardiographic manifestation of intracranial disease. Southern Med J 61:331-336 (Apr) 1968 5. Srivastava SC, Robson AO: Electrocardiographs abnormalities associated with subarachnoid haemorrhage. Lancet 2:431-433 (Aug 29) 1964 6. Cropp GJ, Manning GW: Electrocardiographic changes simulating myocardial ischemia and infarction associated with spontaneous intracranial hemorrhage. Circulation 22:25-38 (July) 1960 7. Fentz V, Gormsen J: Electrocardiographs patterns in patients with cerebrovascular accidents. Circulation 25:2228 (Jan) 1962 8. Hersch C: Electrocardiographs changes in subarachnoid haemorrhage, meningitis, and intracranial space-occupying lesions. Brit Heart J 26:785-793, 1964 9. Burch GE, Colcolough H, Giles T: Intracranial lesions and the heart. Amer Heart J 80:574-575 (Oct) 1970 10. Abildskov JA, Millar K, Burgess MJ, et ah The electrocardiogram and the central nervous system. Prog Cardiovasc Dis 13:210-216, 1970 11. Belief S: Brain and heart relationships. In Belief S: Clinical Disorders of the Heart Beat. Philadelphia, Lea & Febiger, p 840-852, 1971 12. Burch GE, Meyers R, Abildskov JA: A new electrocardiographs pattern observed in cerebrovascular accidents. Circulation 9:719-723 (May) 1954 13. Menon IS: Electrocardiographic changes simulating myocardial infarction in cerebrovascular accident. Lancet 2:433434 (Aug 29) 1964 14. Hugenholtz PG: Electrocardiographs abnormalities in cerebral disorders. Report of six cases and review of the literature. Amer Heart J 63:451-461 (Apr) 1962 15. Kreus K-E, Kemild SJ, Takala JK: Electrocardiographic changes in cerebrovascular accidents. Acta Med Scand 185:327-334, 1969 16. Shuster S: Electrocardiogram in subarachnoid haemorrhage. Brit Heart J 22:316-320, 1960 17. Abildskov JA, Burgess MJ: Neurogenic abnormalities of ventricular repolarization. J Electrocardiol 4:87-90, 1971 18. Koskelo P, Punsar S, Sipild W: Subendocardial haemorrhage and ECG changes in intracranial bleeding. Brit Med J 1:1479-1480 (June 6) 1964 19. Connor RCR: Myocardial damage secondary to brain lesions. Amer Heart J 78:145-148 (Aug) 1969 20. Burch GE, Sun SC, Colcolough HL, et al: Acute myocardial lesions. Following experimentally-induced intracranial hemorrhage in mice: A histological and histochemical study. Arch Path 84:517-521 (Nov) 1967 21. Groover ME Jr, Stout G Neurogenic myocardial necrosis. Angiology 16:180-186, 1965 22. Connor RCR: Fuchsinophilic degeneration of myocardium in patients with intracranial lesions. Brit Heart J 32:81-84, 1970 23. Plum F, Posner JB: Diagnosis of Stupor and Coma. Philadelphia, FA Davis Co, 1970 385
Stroke, Vol. 6. July-August 1975
Downloaded from http://stroke.ahajournals.org/ by guest on June 25, 2016
ESTANOL, MARIN 24. Parizel G: Life-threatening arrhythmias in subarachnoid hemorrhage. Angiology 24:17-21 (Jan) 1973 25. Smith M: Ventricular bigeminy and quadrigeminy occurring in a case of subarachnoid hemorrhage. J Electrocardiol 5:78-85, 1972 26. Reinstein L, Gracey JG, Kline JA, et ah Cardiac monitoring of the acute stroke patient. Arch Phys Med Rehab 53:311-314 (July) 1972 27. Wong TC, Cooper ES: Atrial fibrillation with ventricular slowing in a patient with spontaneous subarachnoid hemorrhage. Amer J Cardiol 23:473-477 (Mar) 1969 28. Cooper ES, West JW: Cardiac arrhythmias, cerebral function, and stroke. Curr Concepts Cerebrovascular Dis Stroke 5:53-58 (Nov-Dec) 1970 29. Galloon S, Rees GAD, Briscoe CE, et ah Prospective study of electrocardiographic changes associated with subarachnoid haemorrhage. Brit J Anaesth 44:511-516, 1972 30. Mauck HP Jr, Hockman CH: Central nervous system mechanisms mediating cardiac rate and rhythm. Amer Heart J 74:96-109 (July) 1967 31. Hoffman BF, Cranefield PF: The physiological basis of cardiac arrhythmias. Amer J Med 37:670-684 (Nov) 1964 32. Mauck HP Jr: Autonomic control of cardiovascular function. In Frohlich ED (ed): Pathophysiology. Altered Regulatory Mechanisms in Disease. Philadelphia, JB Lippincott, p 599614, 1972 33. Smith M, Ray CT: Cardiac arrhythmias, increased intracranial pressure and the autonomic nervous system. Chest 6 1 (Suppl): 125-133 (Feb) 1972 34. Hockman CH, Mauck HP Jr, Hoff EC: ECG changes resulting from cerebral stimulation. II. A spectrum of ventricular arrhythmias of sympathetic origin. Amer Heart J 71:695700 (May) 1966 35. Mauck HP Jr, Szumski AJ, Fu T-C, et ah The effect of acute hypoxia on cardiac dysrhythmias induced by mesencephalic stimulation. Amer Heart J 87:197-202 (Feb) 1974 36. James TN: QT prolongation and sudden death. Mod Concepts Cardiovasc Dis 38:35-37 (July) 1969 37. Han J, Moe GK: Nonuniform recovery of excitability in ven-
tricular muscle. Circulation Research 14:44-60 (Jan) 1964 38. Han J, Millet D, Chizzonitti B, et ah Temporal dispersion of recovery of excitability in atrium and ventricle as a function of heart rate. Amer Heart J 71:481-487 (Apr) 1966 39. Secher-Hansen E: Subarachnoidal haemorrhage and sudden unexpected death. Acta Neurol Scand 40:115-130, 1964 40. Eisalo A, Perasalo J, Halonen PI: Electrocardiographic abnormalities and some laboratory findings in patients with subarachnoid haemorrhage. Brit Heart J 34:217-226 (Mar) 1972 41. Greenhoot JH, Reichenbach DD: Cardiac injury and subarachnoid hemorrhage. A clinical, pathological and physiological correlation. J Neurosurg 30:521-531 (May) 1969 42. Locksley HB: Natural history of subarachnoid hemorrhage, intracranial aneurysms, and arteriovenous malformations. Based on 6,368 cases in the cooperative study. Parts 1 and 2. In Sahs AL, Perret GE, Locksley HB, et al (eds): Intracranial Aneurysms and Subarachnoid Hemorrhage. Philadelphia, JB Lippincott, p 37-108, 1969 43. Hamman L: Sudden death. Bull Johns Hopkins Hosp 55:387415, 1934 44. Helpern M, Rabson SM: Sudden and unexpected natural death — general considerations and statistics. NY State J Med 45:1197-1201 (June 1) 1945 45. Dinning TAR, Falconer MA: Sudden or unexpected natural death due to ruptured intracranial aneurysms. Survey of 250 forensic cases. Lancet 2:799-801 (Oct 17) 1953 46. Berkheiser SW: Intracranial aneurysm and sudden death. Aerospace Med 43:331-332 (Mar) 1972 47. Crompton MR: The pathology of subarachnoid haemorrhage. J R Coll Physicians Lond 7:235-238 (Apr) 1973 48. Elliot FA: Clinical Neurology. Philadelphia, WB Sounders Co, p 389, 1971 49. Valero A: Treatment of severe physostigmine poisoning. Lancet 2:459-460 (Aug 24) 1968 50. Weintraub BM, McHenry LC Jr: Cardiac abnormalities in subarachnoid hemorrhage: A resume. Stroke 5:384-392 (May-June) 1974
386
Stroke. Vol. 6, July August 1975
Downloaded from http://stroke.ahajournals.org/ by guest on June 25, 2016
Cardiac Arrhythmias and Sudden Death in Subarachnoid Hemorrhage BRUNO V. ESTANOL and OSCAR S. M.MARIN Stroke. 1975;6:382-386 doi: 10.1161/01.STR.6.4.382 Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1975 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://stroke.ahajournals.org/content/6/4/382
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Stroke is online at: http://stroke.ahajournals.org//subscriptions/
Downloaded from http://stroke.ahajournals.org/ by guest on June 25, 2016
