Triggers of Subarachnoid Hemorrhage

Transcription

1 Triggers of Subarachnoid Hemorrhage Role of Physical Exertion, Smoking, and Alcohol in the Australasian Cooperative Research on Subarachnoid Hemorrhage Study (ACROSS) Craig Anderson, PhD, FAFPHM, FRACP; Cliona Ni Mhurchu, BSc(Hons), PhD; David Scott, BA(Hons), PhD; Derrick Bennett, MSc, PhD; Konrad Jamrozik, DPhil, FAFPHM; Graeme Hankey, MD, FRCP, FRACP; for the Australasian Cooperative Research on Subarachnoid Hemorrhage Study Group Background and Purpose Unaccustomed strenuous physical exertion can trigger myocardial infarction, but little is known about the mechanisms precipitating subarachnoid hemorrhage (SAH). Methods We identified all cases of first-ever SAH among the combined populations (2.8 million) of 4 urban centers in Australia and New Zealand. Information on the type, time, and intensity of exposures in the 26 hours before the onset of SAH was ascertained by structured interviews. We used the case-crossover technique to assess the risk of SAH associated with transient exposures of moderate to extreme physical exertion, heavy cigarette smoking, and binge alcohol consumption. Results We registered 432 first-ever cases of SAH (62% women; mean age, 56.5 years). A definite time of onset of SAH was established for 393 patients (91%), and information on the levels of physical activity in the preceding 26 hours was obtained in 338 (78%). Of these patients, 19% engaged in moderate to extreme exertion ( 5 metabolic equivalents) in the 2 hours before SAH, which was associated with a tripling in the risk of SAH (odds ratio [OR], 2.7; 95% CI, 1.6 to 4.6). There was no evidence of any association between heavy cigarette smoking or binge drinking and risk of SAH in the subsequent 2 hours (OR, 1.1; 95% CI, 0.4 to 3.7; and OR, 0.41; 95% CI, to 5.3). Habitual exercise did not appear to alter the risk of SAH associated with moderate to extreme exertion. Conclusions Moderate to extreme physical exertion tripled the risk of SAH, but there was no association between transient heavy smoking or binge drinking and risk of SAH. These data suggest that heavy physical activity may trigger SAH. (Stroke. 2003;34: ) Key Words: crossover studies epidemiology physical activity risk factors subarachnoid hemorrhage Despite advances in medical and surgical treatments, subarachnoid hemorrhage (SAH) remains a serious disease, with most deaths resulting from the initial severe hemorrhage. Apart from cigarette smoking, 1 knowledge about predisposing risk factors for SAH is limited, 2 and the pathophysiological events that lead to the rupture of intracerebral aneurysms, the major cause of SAH, are poorly understood. 3 The health benefits of regular exercise 4,5 are offset by the hazard of strenuous exertion, which is associated with a temporary increase in the risk of acute myocardial infarction, particularly among inactive individuals. 6,7 A similar effect of physical exertion may hold for SAH 8 because it is commonly held that the acute event is often precipitated by a transient rise in blood pressure associated with sneezing, coitus, micturition or defecation, extreme physical activity, or a sudden emotional shock. 8,9 However, this perception is based mainly on anecdotal reports and studies of selected series of patients in which issues of bias and confounding have not always been addressed. Although a recent population-based study found the relative risk of sustaining SAH during vigorous activity to be 11.6 and 15.0 in case-control and case-crossover analyses, respectively, the small number of cases and complexities of analysis raise uncertainty about the estimates. 10 To date, no other study has quantified the association between physical exertion (including sexual activity) and SAH or examined other factors that might trigger such an event, including heavy alcohol consumption or cigarette smoking. 11 The Australasian Cooperative Research on Subarachnoid Hemorrhage Study (ACROSS) was a large, prospective, Received October 10, 2002; final revision received January 27, 2003; accepted February 5, From the Clinical Trials Research Unit (C.A., C.N.M., D.B.) and Department of Statistics (D.S.), University of Auckland, Auckland, New Zealand; Department of Primary Health Care and General Practice, Imperial College of Science, Technology and Medicine, London, and Department of Public Health, University of Western Australia, Crawley, Australia (K.J.); and Stroke Unit, Royal Perth Hospital, Perth, Australia (G.H.). Correspondence to Professor Craig Anderson, Clinical Trials Research Unit, University of Auckland, Private Bag 92019, Auckland, New Zealand. c.anderson@ctru.auckland.ad.nz 2003 American Heart Association, Inc. Stroke is available at DOI: /01.STR A7 1771

2 1772 Stroke July 2003 multicenter, population-based study of the incidence, risk factors, and outcome of SAH. 12 We report here results of the nested case-crossover study, which aimed to estimate the relative risk of SAH after strenuous physical exertion, cigarette smoking, and binge (alcohol) drinking compared with periods free of, or only light, exposure to these factors. Patients and Methods Study Population The design of ACROSS has been described elsewhere. 12 Briefly, ACROSS involved population-based registers of SAH in 4 major urban centers in Australia and New Zealand in 1995 to The total study population (age, 15 years) was 2.8 million according the 1996 census for each city. SAH was defined according to standard criteria as an abrupt onset of severe headache and/or loss of consciousness with or without focal neurological signs for which CT, necropsy, or lumbar puncture revealed focal or generalized blood in the subarachnoid space. 13 Patients whose hemorrhage was found to originate from sources other than an intracranial aneurysm were excluded, but patients with proven hemorrhage in whom an aneurysm could not be identified either by cerebral angiography or at necropsy were included. Institutional ethics committees in each study center approved the protocol, and all participants (or next of kin for case subjects who were severely ill, unconscious, or deceased) provided written, informed consent. Ascertainment of Exposure ACROSS had a nested case-crossover study, an epidemiological technique used to assess the short-term effects of transient exposures on the risk of onset of acute events. 6,7,14 16 With this method, each subject serves as his or her own control, with bias and confounding resulting from age, sex, medical history, and other stable withinperson factors thereby eliminated. Given that some patients may experience a warning headache 17 resulting from early bleeding, we defined the time of onset of SAH as the time of the most severe symptoms. As soon as possible after notification, the study nurses undertook face-to-face interviews with subjects or the partner or next of kin if the subject was deceased or disabled. A structured questionnaire was used to obtain information regarding demographics; clinical, medical, and family histories; and exposures of interest. Data were obtained on the intensity and timing of key exposures physical activity, alcohol consumption, and cigarette smoking over the 26 hours before the onset of SAH (ie, for the 2-hour hazard period immediately before and the preceding 24 hours). In the first year of the study, information on exposure was collected for each 6-hour interval in the preceding 26 hours, including the 2-hour hazard period immediately before the SAH. However, the questionnaire was refined for the second year of the study to allow the exposures to be recorded more precisely for each of the 2-hour intervals over the 26 hours before the SAH. Subjects were shown examples of types of physical activity on a card and asked to estimate the total minutes they spent engaged at various levels for a given type of activity. Physical activity was then assessed on a scale between 1 and 3 metabolic equivalents (METs) using generally accepted MET values 6 and categorized as follows: sleeping (1 MET), sitting (2 MET), light exertion (3 to 4 MET), moderate exertion (5 MET), and extreme exertion (6 to 8 MET). Subjects were asked whether they smoked cigarettes or drank alcohol before the SAH; for each prespecified hazard period, data were recorded on the number of cigarettes smoked and the number of standard drinks of alcohol consumed in the preceding 26 hours. In addition, subjects were asked questions to ascertain their usual frequency of low-intensity and high-intensity (moderate to extreme) physical activity during the 2 weeks preceding the event: (1) During the course of your work, activities around the house, or recreational activities, did you have periods of 15 minutes or more in which you found yourself continuously walking or on the move, and (2) during the course of your work, activities around the house, or Case-crossover techniques. A indicates pair-matched interval method of the case-crossover technique (model 1; one 2-hour control period at the same time on the previous day); B, nonparametric multiple intervals method of the case-crossover technique (model 2; multiple 2-hour control periods over the previous 24 hours). recreational activities, did you have periods of 15 minutes or more in which you found yourself sweating, and puffing and panting, as a result of your activity? These questions were adapted from those used in health surveys conducted by the Australian Bureau of Statistics. 18 Subjects were thus categorized as sedentary or active (on the basis of either high- or low-intensity activities at least 1 time per week). They were also questioned about their lifetime use of tobacco (never, current, or ex-smoker 12 months) and about their usual weekly use of alcohol in the previous year (number of standard drinks per week). Statistical Analyses The hypotheses to be tested were that the following exposures in the predefined 2-hour hazard interval were each associated with an increased risk of SAH: (1) a peak exertion estimated to be at least 6 MET (a level that is routinely used in studies of coronary events), (2) consumption of 4 standard drinks (ie, 40 g ethanol), or (3) smoking 4 cigarettes. In regard to physical exertion, however, too few cases had undertaken activities at 6 MET to allow meaningful statistical analysis, so the exposure level was subsequently changed to moderate to extreme, defined as from 5 to 8 MET. The primary statistical analysis used the pair-matched interval method of the case-crossover technique (model 1) 14,15 in which each person s exposure in the defined 2-hour hazard period immediately before the SAH was contrasted with their exposure during the comparable 2-hour period at the same time on the day before the event (the Figure). These data were checked for robustness with a supplementary approach to the case-crossover technique that uses an alternative source of control data. In the nonparametric multiple intervals method (model 2), exposure in the hazard period was contrasted with each of the 2-hour control periods in the 26 hours preceding the SAH (the Figure). This model takes into account circadian variation in SAH 19 and includes time of day as a potential confounding variable. However, this method was used only for the subset of the study population that had complete data on all 2-hour control periods in the 26 hours preceding the SAH. The sample size of 432 provided 80% power and 2-tailed significance ( 0.05 for detecting relative risks of 2.0 attendant on exposures in 20% of the population). Analyses were undertaken with SAS 6.12, 20 S-PLUS, 21 and LogXact software. 22 Differences between groups were examined with the 2 test for categorical variables and independent-sample t tests for continuous variables. Odds ratios (ORs) as estimates of relative risks and 95% confidence intervals (CIs) were calculated with the Mantel-Haenszel approach 23 and conditional logistic regression analysis. 24 Modifications of risks

3 Anderson et al Triggers of Subarachnoid Hemorrhage 1773 were assessed by comparing different subgroups, with particular attention given to known risk factors for SAH. Populationattributable risk, 25 a measure of the proportion of total cases of SAH associated with a risk factor in the total population, and corresponding 95% CIs 26 were also calculated. Results Study Population Table 1 gives the characteristics of the 432 patients with first-ever SAH (62% women; mean SD age, years) registered in ACROSS. SAH was verified by CT in 390 (90%) or necropsy alone in 39 (9%), and 330 patients (76%) had an aneurysmal origin of the SAH diagnosed by angiography, surgery, or autopsy. Interviews were completed for patients or proxies (in 63% of cases) at a median of 9 (interquartile range, 4 to 34) days after onset of SAH. Proxies were interviewed for patients who experience sudden or early death or disability; these patients had a significantly worse prognosis, were older, and were more likely to be married, to be more physically active, and less likely to drink alcohol than patients who survived and were able to be interviewed. However, there was no difference between the groups (directversus proxy-interviewed patients) in regard to the type of SAH (aneurysmal versus nonaneurysmal) or smoking status. Proxies were a spouse, partner, or other close relative such as a parent, child, or sibling in 79% of cases. Although the information obtained was cross-checked for accuracy against medical records, the research nurses rated the reliability of interview as good or high quality in 98% and judged the person to have no difficulty responding to the questions in 73% of cases. Use of medical records alone for exposure data occurred in only 12% of cases. Physical Exertion A definite time of onset of SAH was established for 393 patients (91%), and information on the levels of physical activity around this time was obtained for 338 (78%). Table 2 shows the level of activity reported by these 338 patients, categorized as sleeping (13%), sitting (36%), light activity (31%), and moderate to extreme (strenuous) exertion (19%). In the primary pair-matched interval analysis (model 1), there were 304 patients (70%) for whom information was available on activities in the 2 relevant time periods. Of these patients, 58 (19%) reported moderate to extreme exertion only during the 2-hour period before onset compared with 27 (9%) who reported such exertion only during the control period (the same 2-hour period on the previous day) and 10 (3%) who reported moderate to extreme exertion at both times. This analysis yielded almost a tripling in risk of SAH for those who engaged in moderate to extreme exertion during the hazard period (OR, 2.7; 95% CI, 1.6 to 4.6). The alternative nonparametric multiple intervals method of analysis (model 2) was restricted to the 158 patients for whom we had information on activities over the full 26 hours before the onset of SAH. In this analysis, adjusted for time of day, moderate to extreme exertion within the 2-hour hazard period was associated with a similar risk of SAH (OR, 2.7; 95% CI, 1.2, 4.6). TABLE 1. Characteristics of 432 Cases of First-Ever SAH Characteristic % City Adelaide 35 Auckland 22 Hobart 8 Perth 35 Sex M 38 F 62 Age,* y Type of SAH Confirmed aneurysmal 76 Negative investigations 19 Uncertain 6 Source of information Proxy 63 Patient 37 Marital status Never married 11 Currently married 59 Previously married 29 Missing 2 Highest level of education High school 65 High school 27 Missing 8 Risk factors Cigarette smoking Never 32 Past 20 Current 20 cigarettes/d 19 Current 20 cigarettes/d 20 Missing 9 Alcohol, 10 g units/wk Missing 14 Regular vigorous physical activity Yes 26 No 61 Missing 13 History of hypertension Yes 44 No 49 Missing 7 History of heart disease Yes 13 No 82 Missing 5 History of diabetes mellitus Yes 4 No 90 Missing 6 *Mean ( SD) age, y. Vigorous physical activity was defined as periods of 15 minutes of sweating or puffing.

4 1774 Stroke July 2003 TABLE 2. Activities Undertaken by Patients in the 2 Hours Preceding the Onset of SAH All Patients (n 338) Level of Activity n % Sleeping Sitting Light activity Moderate exertion* Heavy exertion* *Activities included sexual intercourse (n 15), sports or exercise (n 13), working (n 10), gardening (n 6), housework (n 6), shopping (n 3), and other (including defecation, singing, and anger, n 12). Table 3 shows that according to model 1, the risks of SAH associated with moderate to extreme exertion were consistent among subgroups of patients with different characteristics. Older patients and those with a history of hypertension were at a somewhat higher risk when engaged in moderate to extreme exertion, although the associations were not significant. Usual level of activity did not significantly alter the risk associated with acute moderate to extreme exertion. Similarly consistent results were derived with the second approach. However, the number of cases who reported engaging in moderate to extreme activity on a regular basis (activities involving puffing undertaken 3 times per week in the previous 2-week period) was only 17%. Thus, the point prevalence of involvement in such activity in any single 2-hour period is only 0.1%, and the corresponding population-attributable risk is only 2% (95% CI, 4.9 to 8.4). Information on cigarette smoking was available for 348 patients in the 2 relevant time periods (model 1). Overall, 15 patients (4%) had smoked 4 cigarettes over the 2-hour hazard period, and 14 (4%) had smoked a similar amount during the same period on the day before onset. This analysis yielded an OR of 1.1 (95% CI, 0.4 to 3.7). There were 340 patients for whom information was available on alcohol intake in the 2 relevant time periods (model 1). Three patients (1%) had drunk 4 standard drinks of alcohol during the hazard period, and 5 (1%) had drunk a similar amount during the same period on the day before onset, yielding an OR of 0.4 (95% CI, to 5.3). Discussion We found that moderate to extreme physical exertion was associated with a tripling of the risk of SAH in the subsequent 2 hours compared with periods of light or no activity and that usual levels of activity did not alter this transient risk association. Heavy cigarette smoking and binge drinking were not associated with an increased risk of SAH, but these analyses suffered from the problem of sparse data in a subset of the population. The strengths this study include the prospective ascertainment of cases from a large population base (limiting referral bias), uniform and strict diagnostic criteria (limiting misclassification of SAH), and use of the case-crossover design. However, the study did have several limitations, including the use of proxy respondents to obtain information on exposures TABLE 3. Risk of SAH Within 2 Hours of Moderate to Extreme Exertion according to Characteristics of Patients Using the Pair-Matched Intervals Analysis and Exact Conditional Logistic Regression Patients, n Total (Exposed in Case Periods, Characteristic Control Periods) OR (95% CI) All patients 304 (58, 27) 2.7 ( ) Age, y (10, 6) 2.3 ( ) (25, 12) 2.2 ( ) (20, 8) 5.0 ( ) (3, 1) 3.0 ( ) Sex M 114 (29, 13) 3.0 ( ) F 190 (29, 14) 2.5 ( ) Cerebral aneurysm, confirmed* Yes 240 (51, 24) 2.7 ( ) No 64 (7, 3) 3.0 ( ) Source of information Proxy 170 (28, 13) 3.1 ( ) Patient 134 (30, 14) 2.5 ( ) Medical history Hypertension Yes 128 (23, 7) 4.2 ( ) No 168 (34, 20) 2.1 ( ) Ever smoked Yes 203 (43, 24) 2.2 ( ) No 101 (15, 3) 7.0 ( ) Ever consumed alcohol Yes 218 (51, 22) 3.2 ( ) No 86 (7, 5) 1.4 ( ) Usual level of activity Sedentary 87 (14, 8) 2.2 ( ) Active 216 (43, 19) 2.8 ( ) *SAH caused by cerebral aneurysm refers to diagnosis made by cerebral angiography or autopsy. Sedentary activity was defined as light activity at work or home 3 times per week. in a high proportion of the cases who were unable to be interviewed because of early death or disability, but this situation is not uncommon in epidemiological studies of SAH. 11,27 Even though studies have reported a high level of agreement between index and proxy respondents in regard to personal habits and medical conditions 28,29 such as those considered in these analyses, it is possible that some of our cases may have underreported exposures such as recent alcohol intake, whereas proxies might have overestimated them, leading to a bias. To some extent, though, any such error is likely to be nondifferential because the case-crossover design permits a self-matched analysis in a subject who serves as his or her own control. On the other hand, differential error resulting from missing information is hard

5 Anderson et al Triggers of Subarachnoid Hemorrhage 1775 to avoid in studies of SAH because of its high mortality and morbidity. It is possible, therefore, that the lifestyle patterns of survivors were different from those of patients who died early, leading to bias. Another problem is that the measure of physical exertion was limited compared with other more objective measures of physical activity. Moreover, the questionnaire was updated during the course of the study, and the prespecified criteria for heavy exertion, often used in studies of coronary artery disease, were not appropriate for this analysis because of sparse data in this category. For all these reasons, the magnitude of the relative risks associated with the transient exposures investigated should be viewed as estimates. The role of physical activity in the etiology of SAH has not been clearly defined, 2 although surveys of activities preceding aneurysmal SAH have shown that it is common for patients to be engaged in at least moderate activity before the event. 8,9 The 1 previous case-crossover 10 investigation suggested that vigorous physical activity increased the risk of SAH 15-fold. However, this study was based on a small series of patients, and the methods used for the case-crossover analysis were not standard because assumptions were made about patterns of exertion in the reference period. Our results suggest that moderate to extreme physical exertion ( 5 MET) can trigger the onset of SAH, which mirrors the results of case-crossover analyses of triggers of myocardial infarction 6,7,30 and sudden death. 31 It is important to note, however, that our study differs from other case-crossover investigations of physical activity because, for reasons given earlier, the cutoff point used for exertion here was 5 MET, whereas most of the other studies in cardiac patients have used a cutoff of 6 MET. Transient elevations in blood pressure would seem to be an obvious explanatory mechanism linking physical activity to SAH. This hypothesis is supported by the circadian pattern in the incidence of SAH, 32 intracerebral hemorrhage, 33 and stroke in general, 34 being highest in the morning when elevations in blood pressure and heart rate occur in parallel with the commencement of activity. Case-crossover studies have identified strenuous physical exertion as a trigger for myocardial infarction, particularly among sedentary people, 6,7 whereas we found no association between habitual exercise habits and risk of SAH. There are several potential explanations for this difference. First, chronic exposures, including physical activity, may be less relevant to SAH and/or the formation and rupture of cerebral aneurysms. Second, regular dynamic recreational exercise may produce only modest reductions in 24-hour levels of blood pressure, 35 so levels achieved during moderate to extreme exertion may remain independently high enough to precipitate SAH. Third, usual activity levels may have been incorrectly estimated or misclassified, producing a null effect. In conclusion, if the relationship between moderate to extreme physical exertion and SAH were determined to be causal, this finding should not deter people from being physically active because the absolute number of cases of SAH caused by this activity is extremely low. Acknowledgments This study was supported by grants from the National Health and Medical Research Council of Australia, the Health Research Council of New Zealand, and the Sylvia and Charles Viertel Charitable Foundation of Queensland, Australia. Dr Ni Mhurchu holds a fellowship from the National Heart Foundation of New Zealand. We thank the following people and organizations for their help: the study investigators and coordinators; the ACROSS Study Manager, Janet Bennett; the Coroner s Department in each center; the Australian Bureau of Statistics and Statistics New Zealand; and the nursing, administration, and medical records staff of the clinical centers. 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