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(Stroke. 1995;26:1805-1810.)
© 1995 American Heart Association, Inc.

Articles

Is Blood Pressure Really a Triggerfor the Circadian Rhythm of Subarachnoid Hemorrhage?

Günther Kleinpeter, MD; Roland Schatzer, MD Fritz Böck, MD

From Neurochirurgische Abteilung, Donauspital (G.K., R.S.) and Rudolfstiftung (F.B.), Vienna, Austria.

Correspondence to Dr Günther Kleinpeter, Neurochirurgische Abteilung, Donauspital, Langobardenstraße 122, A-1220 Vienna, Austria.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Circadian blood pressure changes are not infrequently cited as a trigger for the onset of subarachnoid hemorrhage (SAH). Our purpose was to determine the reliability of this chronorisk and study the variability and consequences of it as it occurs in hypertensive and normotensive individuals.

Methods Of 273 consecutive patients with proven SAH of aneurysmal origin seen between January 1990 and December 1993, we studied 120 (44%) for whom the exact time of hemorrhage could be reliably determined. Beyond the recognition of a circadian rhythm for this collective, the patients were then sorted by blood pressure, yielding one group each of 80 normotensive (group N, 66.7%) and hypertensive (group H, 33.3%) individuals. The differential chronorisk of these two groups was studied.

Results A circadian rhythm with a definitive characteristic acrophase was observed for the entire group, occurring between 9 AM and 10 AM (² test, P<.0005) with a possible secondary peak in the afternoon hours. The separation into two blood pressure groups somewhat surprisingly revealed a different curve for each group (² test, P=.01). Statistical analysis of each group's separate chronorisk revealed that this acrophase only holds true for hypertensive individuals, whereas normotensive patients not only lack a morning peak, but an apparent elevation in the afternoon is statistically irrelevant, leading to the impression that SAH in normotensive persons seems to be subject to no circadian rhythm at all.

Conclusions The incidence of SAH conforms to circadian blood pressure variation in hypertensive patients, similar to the diurnal rhythms observed with strokes and myocardial infarctions. This leads to the hypothesis that blood pressure elevation is a trigger for the onset of bleeding in this group. In clear contrast, normotensive individuals with cerebrovascular aneurysms seem to have a random 24-hour distribution of SAH onset times, thus leaving the nature of a possible trigger mechanism unresolved.

Key Words: blood pressure • circadian rhythm • subarachnoid hemorrhage

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Circadian periodicity is a phenomenon common to most biological processes. Such periodicity therefore accompanies many pathophysiological mechanisms as well. A study of this aspect of disturbance could well lead to a deeper understanding of the disease process itself, which might in turn lead to an enrichment of therapeutic strategies. In this light, cerebrovascular events have been studied,^{1 2 3 4 5} and various "Zeitgebers" (see below) have been postulated as risk factors for a particular time of day.

Within this area, the specific entity of subarachnoid hemorrhage (SAH) has been studied, usually in association with ischemic and thromboembolic incidents.^{6 7 8} While methodologically and epidemiologically justified, this association neglects the specific and fundamental differences in the pathophysiology of aneurysmal bleedings.

We have attempted to establish a presumptive chronorisk for cases of SAH specifically due to ruptured cerebral aneurysm in the hope that such knowledge could lead to a more finely honed treatment strategy. The work of Tsementzis et al,⁶ Wroe et al,⁷ and Sloan et al⁸ has demonstrated a characteristic daily periodicity, for which at least two peaks of incidence have been observed. A first morning acrophase (peak of incidence) occurs between 8 AM and noon. This is variously explained on the basis of blood pressure (Tsementzis) or physical activity (Wroe). A second broader, later, and less clearly defined peak has been observed for which a transparent explanation has yet to be found.

The influence of the hypothalamus on SAH has yet to be addressed.^{9 10 11 12} Circadian periodicity is fundamentally governed by the activity of the hypothalamus and is a genetically determined function of complex life-forms. This is a classic example of phylogenetic adaptation to the environment. Under natural circumstances, circadian periodicity is synchronized with day-night variation over 24 hours. The periodic environmental factors responsible for this synchronization (in the case of light or darkness) are called "Zeitgeber."¹³ "The circadian system is a composite timing system comprised of an endogenous neural pacemaker and a photoreceptive system for interfacing with synchronizing signals from the light-dark cycle of the environment."¹⁴ The neural pacemakers are the suprachiasmatic nuclei in the ventral hypothalamus.^{15 16 17 18 19} Peptide-mediated input arrives from the retina,^{20 21} the corpus geniculatum,²² and the nuclei of the mesencephalic raphe.^{23 24} Output is mediated via melatonin^{25 26} and somatostatin.²⁷

The present article addresses the significance of other periodic factors, including synchronous endorhythms with respect to the onset of SAH, a largely unclarified question.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The database for this study consisted of the records of all patients with proven SAH undergoing surgery at our service from 1990 through 1993. There were only two centers available for such surgery for a catchment population of 2.5 million during that period, and all other facilities referred patients directly to either center within a few hours. Patients with an unknown source of bleeding were excluded, as were those who died before panangiography could be performed. A total of 273 patients were included (Table 1).

View this table: [in this window] [in a new window]   Table 1. Major Characteristics of Entire Patient Group (n=273) Including Raw Data of Subarachnoid Hemorrhage Incidence, Determined for Each of the 12 Months of the Year

The exact time of hemorrhage could be established exactly for only 120 patients (44%). Patients in good condition (Hunt-Hess stages I or II) were interviewed; history for the remaining patients was provided by other persons present at the time of occurrence. We excluded 153 patients (56%) whose onset of bleeding could not be positively pinpointed within (15 minutes.

The selected 120 patients comprised 66 women (55%) and 54 men (45%). Average age was 47.5 years, ranging from 21 to 76 years. The location of the ruptured aneurysm generally corresponded to the usual distribution: 46% anterior communicating artery (n=55); 17% middle cerebral artery (n=21); 15% internal carotid artery (n=18); and 10% posterior communicating artery (n=13). Rarer findings were aneurysms of the basilar tip (n=6) and pericallosal artery (n=4) and, in 1 patient each, at the anterior cerebral artery, posterior inferior cerebellar artery, and vertebral artery. Angiography revealed that 15 patients (12%) had additional aneurysms in addition to the one that had ruptured. The distribution of the patients' condition immediately before surgery according to the Hunt-Hess classification²⁸ (in contrast to their condition at hemorrhage) was 36 patients at stage I, 44 at stage II, and 16 at stage III. Twenty-four patients (20%) were in stages IV and V (15 in stage IV and 9 in stage V).

With respect to blood pressure, the patients were divided into two groups. We classified patients as hypertensive when a documented history of hypertension and the need for antihypertensive drugs before this admission could be established or such a situation was revealed during the hospitalization. All others (those whose systolic blood pressure did not regularly exceed 160 mm Hg) were judged normotensive. (Blood pressure elevations immediately after SAH are unrelated to premorbid blood pressure history, thus the readings at admission did not influence this classification.) The selected 120 patients were thus subdivided into group N (normal pressure; n=80, 66%) and group H (hypertensive; n=40, 33%) (Table 2). Groups N and H were also studied separately with regard to their chronorisk.

View this table: [in this window] [in a new window]   Table 2. Baseline Data of Entire Group (n=273) and Study Group (n=120) Comparing Normotensive and Hypertensive Subgroups

History was collected regarding the patients' activity at the onset of bleeding. In 31 patients (26%), the hemorrhage occurred during physical activity. Among those, the following were somewhat more frequent: sexual intercourse (n=6), strenuous sports (n=6), and defecation (n=4). However, there was no correlation between activity risk and blood pressure: roughly one third of the 31 were hypertensive and two thirds normotensive. In 89 patients there was either no or mild physical activity, and seven hemorrhages occurred during sleep.

At follow-up at least 1 year after surgery, according to the Clinical Outcome Scale²⁹ 69 patients (57%) were classified as grade 1 (excellent), 13 (10%) as grade 2 (good), and 5 (4%) as grade 3 (fair). This group with more or less favorable outcome contrasts with 7 patients (6%) of grade 4 (poor) and 26 (21%) deaths (grade 5).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The day was divided into 24-hour periods, and the time of day that hemorrhage occurred was assigned for each of the 120 patients. First, the incidence deviation during each period was subjected to ² analysis compared with incidence of deviation during the remainder of the day. Then, the periodicity observed for the hypertensive group was compared with that of the normotensive group with the ² permutation test (STATEXACT, CYTEL Software Corp, 1992). Finally, time/incidence and phase graphs were charted for each of the three cohort groups (all subjects, hypertensive, normotensive); monthly incidence was also graphed for the "all-subjects" cohort to visualize a possible circa-annual rhythm.

The raw data (Table 3) and the simple time/incidence diagram of all subjects (Fig 1) show the presence of an acrophase in the 9 to 10 AM period (² test, P<.0005). Fig 1 reveals three distinct deviations from the mean (5 incidents per hour): a nighttime "zero-incidence" period (3 to 4 AM; ² test, P<.025), the aforementioned morning acrophase at 9 to 10 AM, and a second, smaller afternoon peak at 5 to 6 PM. Decreased incidence is noted during the night, leaving the impression that incidents occur even during sleep.

View this table: [in this window] [in a new window]   Table 3. Raw Data of Incidence of Subarachnoid Hemorrhage for the Study Group (n=120), Determined for Each of the 24 Hours of the Day

View larger version (12K): [in this window] [in a new window]   Figure 1. Graph shows the incidence of subarachnoid hemorrhage for the study group (n=120) determined for each of the 24 hours of the day.

Fig 2 shows a distinct phase difference when comparing 80 normotensive (group N) with 40 hypertensive (group H) patients, which is apparently most pronounced for the time between noon and midnight. ² permutation analysis reveals a statistically significant difference (P=.01) between the two groups over 24 hours. This difference is even more visible in a phase diagram (Fig 3) calculated on the basis of 2-hour periods (simply amplifying the number of incidents per period). The significant peak for group H at 8 to 10 AM is responsible for the observed day maximum during the morning. In contrast to expectations derived from observations based on all subjects, the interval from 2 to 10 PM for hypertensive individuals contains far fewer incidents overall and no afternoon peak. In other words, hypertensive patients not only do not conform to the "two-peak rule," they seem to have an absolute dearth of incidents in the evening. A third possible finding emerges from this table in that hypertensive patients are at greater risk during the night (from 10 PM to 6 AM) than are normotensive patients.

View larger version (18K): [in this window] [in a new window]   Figure 2. Graph shows the comparative incidence of subarachnoid hemorrhage for each blood pressure subgroup determined for each of the 24 hours of the day. N indicates normotensive; H, hypertensive.

View larger version (30K): [in this window] [in a new window]   Figure 3. Graph shows comparative phases for normotensive (N) and hypertensive (H) groups. The percentage of deviation from the period mean (five bleeding episodes) is determined for each group for each of the 12 2-hour periods of the day.

The incidences of the 80 normotensive patients are distributed differently. Deviations in excess of 50% of mean incidence occurred twice during the day. A valley occurs once in the interval from midnight to 6 AM when, compared with hypertensives, these patients also had far fewer episodes overall. A peak can be seen to center on the 4 to 6 PM period. The most impressive difference between the two groups is that normotensive patients have no peak of cerebrovascular episodic activity during the commonly described 8 to 10 AM acrophase.

Given the fact that reliable global numbers are unavailable, it is at best a questionable endeavor to postulate an annual SAH rhythmicity. We have performed an analysis of data collected over 3 years for all 273 patients based on the "month of the event" information (Table 1). Peaks are noted in March and early winter, with a nadir during the month of June. Nevertheless, useful epidemiological data would not only have to embrace the entire population but also the exact determination of factors such as seasonal fluctuations in occupational and tourist migration.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In agreement with three recent major studies,^{6 7 8} the graph of diurnal activity derived from our data shows similar peaks. The acrophase is generally found to range from 8 AM to noon; our data define it as occurring at 9 to 10 AM. This configuration, so in parallel with the acrophase for blood pressure, has prompted investigators to conclude a causal relationship of blood pressure not only with strokes in general but also with SAH.^{6 7} Our data, which differentiate between hypertensive and normotensive individuals, reveal that only the hypertensive patients display this parallel with statistical significance. Normotensive patients, who are known to have a blood pressure acrophase in the morning hours too,³⁰ do not have a statistically significant acrophase for SAH, nor do they have it at any other time throughout the day.

All graphs seem to demonstrate somewhat variable second acrophases in the afternoon and evening hours (6 PM to midnight,⁶ 6 to 8 PM,⁷ and 2 to 4 PM⁸ ), the significance of which is less agreed on than that of the morning peak. In our data, one such peak occurs in the 5 to 6 PM period, which is not statistically significant. Since there is no blood pressure acrophase between noon and 5 AM, a causal connection between pressure and hemorrhage is not just "more difficult to explain"⁶ but is simply untenable. A comparison of the diurnal variations of SAH of normotensive and hypertensive subjects in our cohort reveals a second peak for normotensive patients only. Hypertensive patients had a decreased incidence of bleeding mostly during this period (2 to 10 PM). We did in fact register another small, statistically irrelevant peak of SAH for hypertensive patients at 10 PM to midnight, uncorrelated to blood pressure. On the whole, the diurnal curves for SAH and blood pressure are fairly synchronous for hypertensive patients. For normotensive patients who present with SAH, the analysis of our data allows for no interpretation of causality regarding specific trigger mechanisms or overall association with other chronorhythms. Finally, despite reports of a putative annual rhythmicity,^{31 32} for reasons already discussed our data suggest no connection beyond mere chance.

An increasing number of parameters have been investigated for their potential as Zeitgebers with regard to grave cerebrovascular disturbances, among them blood pressure levels,^{5 30 33 34 35 36 37} cortisol levels,^{38 39} plasma viscosity,^{38 40 41} hematocrit levels,⁴¹ plasma protein concentration,⁴¹ catecholamine concentrations,^{38 42 43 44} platelet aggregability,^{41 45 46} fibrinogen concentration,^{41 47} fibrinolytic activity,^{45 48} sympathetic nervous activity,^{41 49} and levels of blood plasminogen activators and inhibitors.^{50 51} Coincidences and parallels have frequently been noted with typical ischemic strokes, but the general risk profile of those patients differs from that of patients stricken with SAH. Still, it is likely that these other multiple risk factors are applicable to SAH, too.

In summary, our data seem to support the existence of a blood pressure–sensitive late-morning chronorisk for SAH among hypertensive persons with cerebral aneurysms. Only this hypertensive subgroup is comparable to patients studied in consideration of stroke due to other causes. Normotensive people are quite different in that their hemorrhages seem to occur independent of blood pressure, and our data suggest no correlation with any known circadian rhythm. The mean deviation of the incidence of bleedings in any single hour of the day, as matched with the incidence of the remaining 23 hours, is statistically irrelevant and therefore coincidental. However, we must allow for the possibility that a larger study might strengthen our preliminary impression that normotensive patients with SAH have a late-afternoon/early-morning rhythmicity. If this is true, it could lead to the development of a causal model for this subgroup as well.

	Acknowledgments

 
We wish to thank Professor Dr P. Bauer (Institut für Medizinische Statistik der Universität Wien) for performing the statistical analysis and Dr G. Brownstone for help with the translation.

Received March 27, 1995; revision received May 30, 1995; accepted June 29, 1995.

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