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(Stroke. 1997;28:805-808.)
© 1997 American Heart Association, Inc.
Articles |
Circadian Fluctuations in Onset of Subarachnoid Hemorrhage
New Data on Aneurysmal and Perimesencephalic Hemorrhage and a Systematic Review
From the University Department of Neurology Utrecht, The Netherlands.
Correspondence to Gabriel J.E. Rinkel, MD, University Department of Neurology, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. E-mail g.j.e.rinkel{at}neuro.azu.nl
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Background and Purpose Several studies have found a morning peak in onset of stroke. A similar peak has been suggested for subarachnoid hemorrhage (SAH), which seems in contradiction with the physical activities associated with aneurysmal rupture. Most studies included only a few patients with SAH. We analyzed time of onset of aneurysmal SAH in our patients and in data pooled from previous studies. We also studied time of onset in patients with perimesencephalic hemorrhage, which is believed to have a nonaneurysmal venous origin.
Methods Of all 468 patients registered from 1989 through 1995, 385 fulfilled the criteria for aneurysmal SAH and 37 the criteria for perimesencephalic hemorrhage. Time of onset was categorized in 2-hour and 6-hour intervals. We did a Medline search to find previous studies on time of onset of SAH and pooled the data in 2-hour, 3-hour, and 6-hour intervals. Analysis of all intervals was performed by calculating rate ratios with 95% confidence intervals by means of Poisson methods.
Results The risk of aneurysmal rupture was lower at night (from 12 PM to 6 AM) in our series and in the pooled-data series. Risk remained high throughout the day and evening, with a nadir around noon. For perimesencephalic hemorrhage, we found the same fluctuation in onset but without a nadir around noon.
Conclusions The risk of aneurysmal SAH is low during the night and at noon and high during working hours. This circadian fluctuation parallels that of blood pressure and suggests that an increase in blood pressure is a risk factor for aneurysmal rupture.
Key Words: blood pressure • circadian rhythm • perimesencephalic hemorrhage • subarachnoid hemorrhage
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Many studies have found a peak in onset of ischemic stroke, acute myocardial infarction, and sudden cardiac death in the morning.1 2 3 4 This peak has tentatively been linked to the circadian rhythm of blood pressure.5 A similar peak has been suggested for SAH,6 7 but such a peak seems in contradiction with the physical activities commonly associated with aneurysmal rupture, such as defecation, sexual intercourse, or heavy lifting.7 8 Because most previous studies on the circadian rhythm of aneurysmal rupture included only a small number of patients, we studied the time of onset in our own series of patients with ASAH and in pooled data from the previous studies.
PMH is a benign subset of SAH, characterized by a typical pattern of hemorrhage on CT scan and the absence of an aneurysm.9 The cause of PMH is still unknown, but there are indications for a venous rather than arterial source of hemorrhage.10 Because the rupture of a vein might be less related to changes in arterial blood pressure than is rupture of an aneurysm, we also studied time of onset of PMH.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We studied all 468 patients registered from 1989 through 1995 in the SAH database of the Utrecht University Hospital. The diagnosis of SAH was based on positive CT scan or, if the CT was negative, on xanthochromia of cerebrospinal fluid. ASAH was diagnosed if an aneurysm was seen on angiography or, in patients without angiography, if CT showed a typical aneurysmal pattern of hemorrhage. PMH was diagnosed in patients with a perimesencephalic pattern of hemorrhage on CT and normal four-vessel angiography.9 Patients with other or unknown causes of the hemorrhage were excluded.
Day and time of onset are registered in the SAH database. If there was a history of previous bouts of sudden headache, we used the day and time of onset of the headache that had led to admission. Patients were asked about the exact time of onset; in cases of depressed level of consciousness, a relative or eyewitness was asked. The time of day recorded in the database was categorized into 12 2-hour intervals. If the exact time of onset was unknown, as was the case in many patients who had been found unconscious, we categorized the time in four intervals, namely, night (12 PM to 6 AM), morning (6 to 12 AM), afternoon (12 AM to 6 PM), and evening (6 to 12 PM). In the absence of data on the time of onset, we used only the day of onset. In cases in which even the latter was ambiguous, the patient was excluded from this study.
We did a Medline search from 1966 onward using the key words "aneurysm," "subarachnoid hemorrhage," "circadian rhythm," and "stroke onset" to identify studies on the circadian fluctuations in onset of ASAH between 1966 and 1995. In addition, we searched in the reference lists of all publications for other relevant studies. We checked, in turn, the reference lists of the latter studies. We continued cross-checking until no further publications could be found. We excluded studies if in fewer than 90% of patients the diagnosis of SAH had been confirmed by means of CT scanning, angiography, direct surgery, or autopsy. Confirmation is important because clinical diagnosis combined with a xanthochromic spinal fluid is erroneous in 20% of patients, even if all patients with focal signs are excluded.11
We divided the total number of patients by a current estimate of the overall incidence of SAH (6 per 100 000 person-years)12 to estimate the total number of patient-years from which the patients with SAH originated. The number of patient-years was thereafter equally distributed over the time intervals studied. The number of patients within each time interval was divided by this distributed number of patient-years, resulting in an incidence per time interval. Finally, we calculated rate ratios that may be interpreted as RRs with corresponding 95% CIs for each time interval by means of univariate Poisson regression, using the first afternoon interval as reference. We used Monday as reference in the analysis of the daily intervals.
We pooled our own data and all data from the literature on the onset of ASAH and separately analyzed the data that could be categorized in 2-hour, 3-hour, and 6-hour intervals.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Patient Series
We excluded 4 of the 468 patients registered in the Utrecht University Hospital SAH database because the day of hemorrhage was uncertain and another 42 because they did not fulfill the criteria of either ASAH or PMH. Of the remaining 422 patients, 385 patients (91%) met the criteria for ASAH, and 37 patients (9%) did so for PMH.
The exact time of onset was known for 222 of the 385 patients with ASAH, the 6-hour interval of onset for 137 additional patients, and only the day of onset for 26 patients. The exact time of onset was available for 26 of the 37 patients with PMH, the 6-hour interval for another 10 patients, and only the day of onset for 1.
None of the 2-hour intervals showed an increased risk for onset of ASAH
in comparison with the 12 AM to 2 PM interval
(Fig 1A
). The risk was lower in two intervals: from 2 to
4 AM (RR, 0.25; 95% CI, 0.09 to 0.67) and from 4 to 6
AM (RR, 0.35; 95% CI, 0.15 to 0.83). An analysis
based on 6-hour intervals showed a reduced risk (RR, 0.40; 95% CI,
0.28 to 0.57) during night hours (12 PM to 6
AM), but mornings and evenings showed no higher risks than
afternoons. ASAH occurrence was spread evenly over the days of the week
(Fig 1B).
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The number of patients with PMH was too small to allow for a
calculation by 2-hour intervals. Using 6-hour intervals, risks during
any particular interval were not higher or lower than during the
afternoon interval (Fig 2). Because the number of
patients was too small to allow a day-by-day analysis, we
compared the average weekend incidence to the average incidence during
working days. We found PMH to occur nearly as often during the weekends
(RR, 0.96; 95% CI, 0.77 to 1.2) as during the working days.
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Pooled Data
We identified 10 studies on the time of onset of SAH that
fulfilled the inclusion criteria (see
Table).6 7 13 14 15 16 17 18 19 20 We excluded the study of
Kelly-Hayes et al,21 since their data on SAH were not
separated from other stroke subtypes. The study of Ricci et
al22 was not included because in 5 of 15 patients the
diagnosis of SAH was based only on clinical grounds.
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The 10 included studies and our own study resulted in a total of 2778 patients. Data of eight studies, comprising 2074 patients, could be categorized into 2-hour intervals. Six studies, including 2059 patients, allowed for categorization into 3-hour intervals. We could combine the data of all studies into 6-hour intervals.
Two consecutive 2-hour intervals showed a lower risk than the
reference interval of 12 AM to 2 PM (RR; 95%
CI): from 12 PM to 2 AM (0.54; 0.42 to 0.70)
and 2 to 4 AM (0.36; 0.27 to 0.49) (Fig 3A).
Five of the 2-hour intervals showed an increased risk: from 6 to 8
AM (1.3; 1.0 to 1.5), 8 to 10 AM (1.3; 1.0 to
1.6), 2 to 4 PM (1.3; 1.1 to 1.6), 4 to 6 PM
(1.3; 1.0 to 1.6), and 6 to 8 PM (1.2; 1.0 to 1.5). In the
analysis of 3-hour intervals, we found that risks were lower
from 12 PM to 3 AM (0.44; 0.36 to 0.55) and 3
to 6 AM (0.61; 0.50 to 0.74) and that risks were higher
from 6 to 9 AM (1.3; 1.1 to 1.5), 3 to 6 PM
(1.2; 1.0 to 1.4), and 6 to 9 PM (1.2; 1.0 to 1.4) than
during the afternoon interval (Fig 3B). We found a nadir in occurrence
during the 6-hour interval between 12 PM and 6
AM (0.46; 0.41 to 0.52) and a peak between 6 and 12
AM (1.2; 1.1 to 1.3) (Fig 3C).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Our study shows that the risk of aneurysmal rupture is low during the night, starts to rise in the early morning, remains high during the day with a small nadir around noon, and decreases in the evening. A recent study showed this circadian nadir during the night again.23 In contrast with cerebral ischemia or intracerebral hemorrhage, there is no pronounced morning peak. The circadian fluctuation of the risk of aneurysmal rupture is similar to that of plasma concentrations of noradrenalin and blood pressure.24 25 26 This similarity to blood pressure variations includes the nadir around noon, which may be associated with afternoon naps.27 The close resemblance of the circadian fluctuations of blood pressure and risk of aneurysmal rupture suggests that an increase in blood pressure is a risk factor for rupture of an intracranial aneurysm. This suggestion is further corroborated by the steep increase in blood pressure during sexual intercourse,28 which is a frequent precipitant of aneurysmal rupture.
We did not find a preferred day of the week for onset of ASAH; this is similar to the findings of Lejeune et al18 but in contrast with the study of Kelly-Hayes et al21 and that of Juvela et al,29 in which over 30% of the patients had their hemorrhage on weekends or holidays. For PMH, the risk is slightly less during the weekends. The risk of PMH is higher during working hours, but since we examined only 37 patients, this result, although statistically significant, needs further corroboration.
Our study was hospital- and not population-based, along with nine other studies.6 7 13 14 16 17 18 19 20 We do not think, however, that this introduced a bias because it seems unlikely that the time of onset of the hemorrhage influences the admission pattern. Meta-analysis in general is prone to publication bias; regarding this topic, studies without apparent circadian fluctuations might be less likely to be published than studies with circadian fluctuations. In our review, two studies had not found a peak or nadir in occurrence but still were published. We therefore do not think that publication bias has influenced our results in an important way. Six studies restricted inclusion to patients in whom the aneurysm was proven by angiography, surgery, or autopsy. Patients with poor clinical condition or early death without autopsy were excluded from these studies, which results in selection toward patients in good clinical condition. We do not think this selection has biased our results, since it is unlikely that the severity of the bleeding is related to the time of onset.
Our study is the first that distinguishes ASAH from PMH. The studies that included patients with SAH without proof of an aneurysm might have included patients with PMH in the ASAH series, but since PMH only counts for 10% of all SAH, inclusion of patients with this type of hemorrhage probably did not lead to gross imprecision in these studies.
In conclusion, the risk of onset of ASAH, as well as PMH, is higher during the working hours. However, there is no early morning peak, such as there is for primary intracerebral hemorrhage, cerebral infarction, and ischemic heart disease. The higher risk during working hours indicates that blood pressure variations may be an important factor in aneurysmal rupture.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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We would like to thank Frits Rosendaal, MD, for advice on data analysis and Fleur Bominaar for help in preparing the figures.
Received November 18, 1996; revision received January 23, 1997; accepted January 27, 1997.
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References |
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