Torsade de pointes as a complication of subarachnoid hemorrhage: A critical reappraisal

Journal of Electrocardiology Vol. 30 No. 1 1997

Torsade d e P o i n t e s as a C o m p l i c a t i o n of Subarachnoid Hemorrhage A Critical Reappraisal

Christian Machado,

MD, John

Joel Reinoehl,

J. B a g & M D , R a y m o n d

M D , R u s s e l l T. S t e i n m a n ,

Michael

H. Lehmann,

Kawasaki,

MD,

MD, and

MD

Abstract: Subarachnoid hemorrhage is widely accepted as a potential cause of torsade de pointes (TdP), yet this putative etiologic relationship has never been systematically evaluated. We therefore undertook a MEDLINE search from 1966 through 1993, with relevant back referencing, and identified 20 cases of TdP in the setting of subarachnoid hemorrhage. It was impossible in any of these cases (usually because of insufficient data) to completely exclude one or more alternative explanations for TdP, including congenital long QT syndrome, hypokalemia, hypomagnesemia, or drug-induced QT prolongation. Furthermore, of a total of 1,139 patients in 16 prospective series of subarachnoid hemorrhage with electrographic analyses, there were only five reported cases of TdP, all in patients with hypokalemia. Thus, extremely limited scientific data exist to support the notion that subarachnoid hemorrhage .:an be a distinct cause of TdP. Until more definitive evidence is available, the development of TdP in patients with subarachnoid hemorrhage is probably better characterized as a multifactorial phenomenon occurring in an acute, typically intensive care, setting. Key words: torsade de pointes, QT interval, subarachnoid hemorrhage, sudden death, ventricular arrhythmias.

Torsade de pointes (TdP) is k n o w n to occur u n d e r a wide variety of conditions that prolong the QT interval (1,2). This potentially lethal tachy a r r h y t h m i a has also b e e n described in patients suffering f r o m s u b a r a c h n o i d h e m o r r h a g e (3-21). In light of these reports, s u b a r a c h n o i d h e m o r r h a g e has b e e n frequently listed (explicitly, or implicitly u n d e r "central n e r v o u s system injury [or disorder]") a m o n g the factors t h a t can give rise to

acquired long QT s y n d r o m e a n d TdP (1, 22-26). Recently, however, s o m e investigators h a v e voiced skepticism regarding the actual existence of this association (21, 27, 28). Yet no study to date has systematically evaluated the evidence purporting to d e m o n s t r a t e that TdP can be caused by subarachnoid h e m o r r h a g e . Given the growing interest in the p a t h o p h y s i o l o g y of this potentially lethal a r r h y t h m i a a n d the n e e d to clearly identify risk factors for its occurrence (1, 29), we u n d e r t o o k a critical review of the relevant literature to evaluate the extent of scientific evidence implicating subarachnoid h e m o r r h a g e as a distinct predisposing factor for TdP.

From the Arrhythmia Center, Division of Cardiology~Department of Internal Medicine, Sinai Hospital, Detroit, Michigan.

Reprint requests: Michael H. Lehmann, MD, 14800 West McNichols, Suite 314, Detroit, MI 48235.

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Journal of Electrocardiology Vol. 30 No. 1 January 1997

Materials and Methods Literature A MEDLINE search for relevant articles, with at least an abstract or summary written in English, tor the period 1996-1993 was undertaken. We searched for articles pertaining to the association of subarachnoid hemorrhage and TdP, using the following key words: ventricular arrhythmias, dysrhythmias, ventricular tachycardia (VT), ventricular flutter/fibrillation, (VF), TdP, atypical ventricular tachycardia, polymorphic VT, subarachnoid hemorrhage, and cerebrovascular accidents. The search was supplemented by pertinent references from the reviewed articles. Bibliographies from all articles were studied to uncover further cases that might have been reported before 1966. Personal communication with one investigator who had reported cases of unspecified "ventricular arrhythmias" in subarachnoid hemorrhage (30) yielded additional information regarding these cases.

Patient Selection and Data Collection The articles identified by literature search were reviewed to determine their relevance for the study

on the basis of prospectively defined indusion and exclusion criteria. An article was included if (1) at least the abstract or summary was written in English, and (2) it contained at least one case of TdP or polymorphic VT occurring in association with QT or rate-corrected QT (QTc) prolongation (_> 0.45 second 1/2) in the setting of subarachnoid hemorrhage. Within a given article, individual patients were excluded if only one or more of the following applied: (1) they did not have polymorphic VT as evident from the report or personal communication; (2) they had polymorphic VT without manifest QTc prolongation; or (3) their reports had already been included in other series. When available, the following data were collected for each patient: age, sex, baseline QTc, structural heart disease, need for cardioversion/defibrillation, heart rate before the onset of TdP, acute QT and QTc (as defined below), serum potassium, serum magnesium, and thyroid tunction tests. In order to obtain an estimate of TdP prevalence in patients with subarachnoid hemorrhage, an additional search was made of the neurosurgical and cardiology literature from 1973 (when the association of TdP and subarachnoid hemorrhage was first made (3), through 1993, looking for prospective series of subarachnoid hemorrhage that also mentioned assodated electrocardiographic (ECG) findings.

Table 1. Summary of Clinical and ECG Findings in 20 Reported Clinical Characteristics

Author Parizel (3) Beaufils et al, (4) Beaufils et al.(4) Grossman (5) Ranquin and Parizel(6) Carruth and Silverman(7) Keren et al.(8) Pinciroli et al.(9) Sen et al.(10) Sen et al. (10) Hust et al. (11) Yoshido and Inui(12) Advani et al. (13) Tobias et al. (14) Amagasa et al. (15) DiPasquale et al. (16) DiPasquale et al. (16) DiPasquale et al. (16) DiPasquale et al. (16) DiPasquale et al. (16)

Age/Sex

Structural Heart Disease

66/F 23/M 38/M 56/F Unk/F 51IF Unk 58/F 44/F 52/F 73/F 51/F 35/M 58/F 54/F 49/M 44/M 68/F 67/F 46/M

Unk None None Unk Unk Unk Unk None None None None Unk None Unk Unk EVIl None None LVH None

ECG Features*

Defib Required

Baseline QTc (s m)

HR Before TdP Onset (beats/rain)

Acute QT (s)

Acute QTc (s 1/2)

Yes Yes Yes No Yes No Unk Yes Yes No No Yes Yes Unk Unk No Yes No No No

Unk Unk Unk 0.55 Unk 0.40 0.40 Unk Unk Unk Unk Unk Unk Unk 0.45 Unk Unk Unk Unk Unk

140 90 65 Unk Unk 68 64 46 Unk Unk 60 90 160 180 60 110 80 70 116 70

q" .50 1" Unk 1" 0.56 0.60 0.68 Unk Unk 0.86 0.55 $ 1" 0.76 .48 .48 .52 .43 .63

Unk 0.61 Unk 0.65 Unk 0.60 0.62 0.60 0.67 0.60 0.86 0.67 1" "]" 0.76 0.65 0.56 0.56 0.60 0.69

*Rate-corrected QT (QTc) values calculated by the Bazzett formula (QT supraventricular tachycardia; TDE torsade de pointes; Unk, u n k n o w n .

+

RR1/2), Defib, defibrillation; HR, h e a r t rate; LVH, left

Torsade de Pointes and Subarachnoid Hemorrhage

Definitions Torsade de pointes: For t h e p u r p o s e of this study, TdP wets d e f i n e d as p o l y m o r p h i c VT occurring in the setting of a p r o l o n g e d QT i n t e r v a l ( 1, 31-34); this d e f i n i t i o n is in accord w i t h the g e n e r a l l y a c c e p t e d c o n c e p t t h a t p o l y m o r p h i c VT w i t h o u t QT p r o l o n g a t i o n is a p a t h o p h y s i o l o g i c a l l y distinct e n t i t y (35, 36). Acute QT a n d r a t e - c o r r e c t e d QT: These are t h e QT a n d QTc values (specified or calculated) i m m e d i a t e l y before or after an episode of TdR Baseline r a t e - c o r r e c t e d QT: This is t h e QTc value r e p o r t e d by t h e a u t h o r as baseline, w h e n available; o t h e r w i s e t h e value o b t a i n e d f r o m the first available ECG tracing prior to suba r a c h n o i d h e m o r r h a g e or the value m e a s u r e d on an ECG after r e c o v e r y f r o m s u b a r a c h n o i d hemorrhage.

Results Patient Selection N i n e t e e n articles (3-21) m e t the i n c l u s i o n criteria. Patients described in these articles w e r e t h e n subjected[ to e x c l u s i o n criteria. Of t h e total of 31

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Machado et al.

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p a t i e n t s r e p o r t e d , I1 w e r e o m i t t e d after application of the p r o s p e c t i v e l y d e f i n e d e x c l u s i o n criteria; of these cases 8 w e r e r e p o r t e d m o r e t h a n once a n d 3 h a d s u s t a i n e d m o n o m o r p h i c VT, v e n t r i c u l a r fibrillation, or v e n t r i c u l a r flutter w i t h o u t d o c u m e n t a t i o n (or e v e n m e n t i o n e d ) of TdP (3,17-21). The r e m a i n i n g 20 cases of TdP in the setting of suba r a c h n o i d h e m o r r h a g e f o r m the basis of this r e p o r t a n d are listed in Table 1 .

Clinical and ECG Characteristics of Included Patients The m e a n age was 52 years, 13 (65%) w e r e w o m e n , a n d s t r u c t u r a l h e a r t disease was a b s e n t in 9 of 12 p a t i e n t s for w h o m its p r e s e n c e or absence was specified. Defibrillation was r e q u i r e d for m a n a g e m e n t of TdP in 9 (53%) of 17 cases for w h i c h r e l e v a n t i n f o r m a t i o n was p r o v i d e d . The r e p o r t e d h e a r t rates p r i o r to onset of TdP v a r i e d f r o m 46 to 180 b e a t s / m i n , w i t h a m e a n of 92 b e a t s / m i n . The r a t e - c o r r e c t e d QT i n t e r v a l was p r o l o n g e d (range, 0 . 5 6 - 0 . 8 6 secondsl/2) in all i 5 cases for w h i c h acute v a l u e s w e r e available. Of the 12 p a t i e n t s w i t h r e p o r t e d acute absolute QT intervals, QT was > 0.50 s e c o n d I/2 or l o n g e r (up to 0.86 secondU2) in 9.

Cases of Torsade de Pointes Occurring in the Setting of Subarachnoid Hemorrhage Potentially Confounding Factors

Medications Unk Unk Unk Alomet Unk Unk None Unk Unk Unk None Unk Unk Unk Unk Unk Unk Unk Unk Unspecified diuretic

K+ (mEq/L)

Mg2+ (mEq/L)

Thyroid Function

Unk 4.5 Unk 3.6 Unk N1 Unk N1 Unk Unk N1 4.4 4.8 Unk Unk 3.3 3.3 3.5 3.3 2.5

Unk Unk Unk Unk Unk N1 Unk Unk Unk Unk Unk 1.9 Unk Unk Unk Unk Unk Unk Unk Unk

Unk Unk Unk Unk Unk Unk Unk Unk Unk Unk Unk Unk Unk Unk Unk Unk Unk Unk Unk Unk

....

Comments

Procainamide 200 mg IV 1 h prior to TdP History of hypothyroidism and alcohol abuse

Alcohol intoxication; rhythm not specified Rhythm prior to TdP was SVT

ventricular hypertrophy; Nl, reported to be normal without actual value specified; I", "prolonged" but exact interval not provided; SVT,

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Journal of Electrocardiology Vol. 30 No. 1 January 1997

Potentially Confounding Factors

Preexisting QT Prolongation. Of four reported baseline QTc intervals, three were 0.45 second 1/2 or less and only one was prolonged (0.55 second1/2). As this interval was not reported in the remainder of cases, it was impossible in most patients to exclude preexisting (congenital or acquired) long QT s y n d r o m e as the basis for TdR Drug-induced QT Prolongation. The one patient with a prolonged baseline QTc (0.55 seconds 1/2) had received a QT prolonging drug (procainamide) prior to the episode of TdP. In only two cases were the patients explicitly reported not to be taking medication that might prolong QTc. No pertinent data were available in the remaining cases. Thus, the possibility of drug-induced TdP could not be excluded in the majority of patients. Electrolytes a n d T h y r o i d Status. Serum potassium values were available for only 12 patients (60%); a normal serum potassium was d o c u m e n t e d in 7 (58%) of these 12 cases, whereas hypokalemia (range 2.5-3.5 retool/L) was present in five (42%). Information on serum magnesium was available for only two patients (normal levels in both). Thyroid function tests were not provided in any case, although a history of hypothyroidism was mentioned in one report (7). This frequent lack of data on electrolytes and thyroid status made it impossible to systematically rule out hypokalemia, hypomagnesemia, or hypothyroidism (1,37), as factors that m a y have contributed to TdP. It should be noted that

even in the three e x d u d e d patients with sustained ventricular tachyarrhythmias (monomorphic tachycardia, fibrillation, or flutter), no documentation of actual TdP or serum potassium and magnesium levels was provided; moreover, baseline QTc was prolonged in one and not reported in the other two. Overall, the data in Table 1 indicate that, even if the question of occult h y p o t h y r o i d i s m is put aside, findings suggesting other etiologies for TdP were evident or information needed to exclude such etiologies was lacking for at least one potentially contributory factor in all 20 cases, for two or more factors in 19 cases (95%), and for three or more tactors in 13 cases (65%).

Prevalence of Torsade de Pointes Among Patients With Subarachnoid Hemorrhage Sixteen prospective series (16, 30, 3 8 - 5 0 ) i n c l u d ing a combined total of 1,139 patients with subarachnoid hemorrhage and ECG analyses were identified (Table 2). Aside trom five patients reported by DiPasquale et al. (16), all of w h o m had hypokalemia (Table 1), no additional cases of TdP were identified. Of note, the detailed series of Brouwers et al. (30) reported nine cases of "ventricular arrhythmias," but n o n e of these were TdP or other types of VT (Brouwers P JAM, personal communication). In 10 other cases, "nonsustained VT" was mentioned in the article, with the description of "polymorphic VT" in only one case; however, in none of the 10 was QT or QTc interval data provided (42, 44, 50). Thus, there were no cases of unequivo-

Table 2. Prevalence of Torsade de Pointes Among 1,139 Cases of Subarachnoid Hemorrhage Reported in 1972-1991 Author

No. of Patients

Casesof TdP

20 40 10 50 15

0 0 0 0 0

Goldstein (43) Britton et al. (44)

28 100

0 0

Melin and Fogelholm(45) Singh et al. (46) Rudehill et a1.(47) Stober and Kunze(48) DiPasquale et al.(16) Brouwers et al. (30) Davies et a1.(49) Grad et al.(50)

146 20 406 52 132 61 19 40

0 0 0 0 5 0 0 0

Eisalo et a1.(38) Cruickshank et a1.(39) Dimant and Grob(40) Noya et al.(41) Estanol-Vidal et al. (42)

Comments 13 cases of unspecified "tachycardia," defined as HR > 100 3 cases of unspecified "nonsustained VT," of which ECG tracing resembling polymorphic VT but with unmeasurable QT is shown for 1 case 1 case of "nonsustained VT,"without reported QT or QTc; 13% of patients had hypokalemia

All 5 cases clearly associated with hypokalemia (Table 1) 9 cases of "ventricular arrhythmia," none of which was VT* 6 cases of "nonsustained VT,"but no examples given and QT intervals unknown

*Brouwers, PJAM, personal communication, HR heart rate; TdP, torsade de pointes; VT, ventricular tachycardia; QTc, rate-corrected QT.

Torsade de Pointes and Subarachnoid Hemorrhage

cal TdP as a direct complication of subarachnoid hemorrhage among 1,139 patients, excluding the five patients with ]known hypokalemia; this corresponds to a 95% confidence interval of 0.0-0.3%. If the five cases of TdP with hypokalemia; are counted, the prevalence of TdP would be 0.4% (95% confidence interval, 0.1-1.0%); and if the 10 cases of nonsustained VT are also included, the most liberal estimate of TdP prevalence would be I5/1139, or 1.3% (95% confidence interval, 0.7-2.2%).

Discussion Acquired long QT syndrome with TdP results primarily from exogenous agents or electrolyte derangements that prolong cardiac repolarization (1, 2, 29). The fact that subarachnoid hemorrhage has long been considered a potential etiology for TdP has been of particular interest precisely because, if true, it would represent a unique clinical model of TdP, one related to a primary central nervous system disorder. The plausibility of such an association has certainly been bolstered by observations of QT prolongation and T wave abnormalities in subarachnoid hemorrhage (38, 43, 47, 51, 52) and by experimental observations involving the presumed mechanism, namely, sympathetic tone-mediated alternations in cardiac repolarization (53-57). This study is the first to systematically evaluate the scientific evidence in the literature purporting to establish an association between subarachnoid hemorrhage and TdR Our findings show that, contrary to widely held belief, a cause and effect relationship between subarachnoid hemorrhage and TdP has not been convincingly documented. In 20 reported cases of TdP in patients with subarachnoid hemorrhage, identified from articles published over a 15-year period, it was impossible to exclude completely one or, very often, two or more alternative explanations for TdP, including congenital long QT syndrome, hypokalemia, hypomagnesemia, or drug-induced QT prolongation; moreover, the possibility of hypothyroidism was suggested by history in one case and was not ruled out in any of the reports. In most cases, these factors capable of promoting TdP could not be excluded, simply because the necessary data were not provided. In six cases (30%), potentially contributory factors were clear][y identifiable, chief among these being hypokalemia. The presence of hypokalemia in 5 of the 12 TdP cases (42%) in which there was information about serum potassium values in the setting of subarachnoid hemorrhage represents a somewhat higher

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prevalence than the 18-29% prevalence of this electrolyte derangement observed in cases of TdP associated with QT-prolonging drugs (1, 29). Interestingly, in the large prospective series of DiPasquale et al. (16), hypokalemia was documented in all five reported cases of TdP associated with subarachnoid hemorrhage. It is conceivable that the hyperadrenergic state associated with subarachnoid hemorrhage (50, 53) could via a cellular effect of catecholamines on potassium transport (58, 59), cause hypokalemia, which might secondarily precipitate TdR In patients with subarachnoid hemorrhage, however, many other factors could contribute to hypokalemia, including diuretics, hypercorticism (53), exogenously administered conticosteroids, and ventilator-induced respiratory alkalosis. These various factors would have to be systematically excluded and evidence of increased sympathetic activity demonstrated before one could conclude that hypokalemia in a particular patient is directly attributable to subarachnoid hemorrhage. In a parallel attempt to assess the alleged association between subarachnoid hemorrhage and TdP, we estimated the prevalence of this arrhythmia from a large number of prospective series of subarachnoid hemorrhage cases, which included an analysis of ECG changes in over 1,000 patients. Based on the upper 95% confidence interval limit, it could be estimated that the prevalence of TdP in patients with snbarachnoid hemorrhage is no higher than 0.3% (or at most 2.2%, if all ambiguous cases of TdP or "nonsustained VT" are counted as unequivocal cases of TdP secondary to subarachnoid hemorrhage). Such a prevalence is lower than the 2.4-8.5% of patients who develop TdP following exposure to antiarrhythmic drugs that prolong the QT interval (60-64). Thus, even in the unlikely circumstance that subarachnoid hemorrhage may independently precipitate TdP, such a complication must be considered quite rare.

Conclusion From the available data in the literature, there is little scientific evidence to support the notion that subarachnoid hemorrhage, in the absence of other predisposing factors, is capable of causing TdP. Definitive confirmation of a cause and effect relationship will require prospective studies that analyze (and exclude) other factors potentially contributing to the occurrence of TdP, complemented ideally by rigorous investigations in experimental models. On the basis of our current level of knowledge, however, TdP in patients with subarachnoid

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Journal of Electrocardiology Vol. 30 No. 1 January 1997

h e m o r r h a g e is m o s t l i k e l y to r e p r e s e n t a m u l t i f a c t o rial p h e n o m e n o n t h a t is e x p e c t e d in a n a c u t e ( o f t e n i n t e n s i v e care) setting. As in all cases of TdE clinical a t t e n t i o n n e e d s to b e f o c u s e d o n i m m e d i a t e t h e r a p e u t i c m e a s u r e s a n d c o r r e c t i o n of r e v e r s i b l e causes.

15.

16.

Acknowledgment The authors thank Karen Beal for excellent secretarial assistance in the preparation of the manuscript.

17.

18.

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