- Email: [email protected]
Circadian blood pressure variation after acute stroke
Journal of Clinical Neuroscience 13 (2006) 558–562 www.elsevier.com/locate/jocn
Clinical study
Circadian blood pressure variation after acute stroke Jeyaraj D. Pandian a,*, Andrew A. Wong a, Douglas J. Lincoln b, James P. Davis a, Robert D. Henderson a, John D. O’ Sullivan a, Stephen J. Read a a
Stroke Unit, Department of Neurology, Level 7, Ned Hanlon Building, Royal Brisbane and Women’s Hospital, Herston Road, Brisbane, Queensland 4029, Australia b Royal Brisbane and Women’s Hospital Research Foundation, Herston Road, Brisbane 4029, Australia Received 9 June 2005; accepted 8 September 2005
Abstract We aimed to characterise the patterns of circadian blood pressure (BP) variation after acute stroke and determine whether any relationship exists between these patterns and stroke outcome. BP was recorded manually every 4 h for 48 h following acute stroke. Patients were classified according to the percentage fall in mean systolic BP (SBP) at night compared to during the day as: dippers (fall P 10– <20%); extreme dippers (P20%); non–dippers (P0–<10%); and reverse dippers (<0%, that is, a rise in mean nocturnal SBP compared to mean daytime SBP). One hundred and seventy-three stroke patients were included in the study (83 men, 90 women; mean age 74.3 years). Four patients (2.3%) were extreme dippers, 25 (14.5%) dippers, 80 (46.2%) non-dippers and 64 (36.9%) reverse dippers. There was a non-significant trend in the proportion of patients who were dead or dependent at 3 months in the extreme dipper (p = 0.59) and reverse dipper (p = 0.35) groups. Non-dipping and reverse-dipping were relatively common patterns of circadian BP variation seen in acute stroke patients. These patterns were not clearly associated with outcome. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Circadian variations; Blood pressure; Diurnal; Acute stroke
1. Introduction In normal subjects the mean nocturnal systolic blood pressure (SBP) is 10–20% lower than mean daytime SBP, so-called dipping.1 Abnormal patterns of circadian BP variation have also been described in which the nocturnal fall of BP may be increased (P20%, extreme dippers), reduced (<10%, non-dippers) or even reversed (reverse dippers).1 In comparison to normal dipping, patients exhibiting these abnormal patterns are more likely to suffer occult and overt cerebrovascular disease.2,3 Extreme dippers and non-dippers appear to have an increased risk of silent cerebral infarction, periventricular white matter hyperintensities and overt stroke, while a higher risk of intracerebral haemorrhage has been reported in reverse dippers.1,3
*
Corresponding author. Tel.: +61 7 36367096; fax: +61 7 3636 7675. E-mail address: [email protected] (J.D. Pandian).
0967-5868/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2005.09.003
It is unclear how frequently each of these abnormal patterns occur following acute stroke. Previous studies of abnormal BP variability patterns in acute stroke looked at only one dipping pattern, either non-dipping or reverse dipping.4–8 Previous researchers have also tried to link changes in circadian BP variability with different stroke subtypes, although results have been conflicting. For example, in different studies non-dipping has been shown to be associated with ischaemic stroke, haemorrhage, and to show no association with stroke type.4–7 The influence of abnormal circadian BP patterns on stroke outcome is also unclear. Some studies have found poor outcome among reverse dippers9 and non-dippers,10 while others have noted no association between the different patterns of circadian BP variation and outcome.7 We undertook this study to examine the patterns of circadian BP variation, to determine their frequency during the first 48 h after acute stroke, and to assess whether any relationship exists between these patterns and stroke outcome.
J.D. Pandian et al. / Journal of Clinical Neuroscience 13 (2006) 558–562
2. Methods All patients presenting between June 2002 and March 2003 with a diagnosis of stroke were eligible for inclusion. Patients with a diagnosis of transient ischaemic attack, subarachnoid haemorrhage or bleeding due to trauma were excluded. All patients were enrolled within 24 h of stroke. Blood pressure was recorded using a standard aneroid sphygmomanometer every 4 h for 48 h after stroke. In each subject, the mean nocturnal SBP was taken as the mean of the BP recordings between 22.00 h and 6.00 h and mean daytime SBP as the mean of BP readings between 6.00 h and 22.00 h. The percentage difference between mean nocturnal SBP and mean daytime SBP was calculated using the formula: %difference ¼ 1 ðmean nocturnal SBP=mean daytime SBPÞ 100:1 Patients were classified according to the percentage difference as: extreme dippers (% difference P 20%), dippers (P10%–<20%), non-dippers (P0%–<10%), and reverse dippers (<0%, that is, a rise in mean nocturnal SBP over the daytime mean SBP).1 The mean daytime and the nocturnal SBP, diastolic BP (DBP) and mean arterial pressure (MAP) were compared between the dippers and each of the other three groups, and also between ischaemic and haemorrhagic stroke cohorts. Demographic variables (age, gender), risk factors, type of stroke (ischaemic and haemorrhagic) and stroke severity (National Institute of Health Stroke Scale [NIHSS]) were compared between the dippers and each of the other three groups. Past history of hypertension and the use of current antihypertensive medications were also compared between the dippers and the other three groups. Functional capacity was measured using the modified Rankin Scale (mRS) at 3 months post-stroke. The primary outcomes of death, and the combined outcome of death or
559
dependency (defined as an mRS P 3) at 3 months were compared between the dipper and each of the other groups. Statistical analysis was done using SAS software version 8.02 (SAS Institute Inc, Cary, NC, USA). Demographic and clinical characteristics of the patients were compared across the four groups using standard univariate analyses. Statistical comparisons across all groups simultaneously were made using the F-test and Pearson’s chi-squared test. Kruskall-Wallis test was used to compare the baseline NIHSS values across the four groups. Statistical comparisons between the dipper group and each of the other groups were made using the unpaired t-test, Pearson’s chi-squared test and Fisher’s exact test, with significance levels adjusted for multiple comparisons using the Bonferroni method.11 A p-value of <0.017 was considered significant. The hospital Human Research Ethics Committee approved this study. Written informed consent was obtained from patients or from their next of kin where patients were unable to do so themselves. 3. Results Two hundred and twenty-patients were screened at admission. Forty-seven patients were ineligible to participate, refused consent, withdrew from the study, had insufficient BP data or had diagnosis other than stroke, leaving 173 patients for analysis. There were 83 (48%) men and 90 (52%) women. The mean age was 74.3 years. The frequencies of the patterns of circadian BP variation in the study patients are shown in Table 1. Comparison is made with data from the study by Kario et al.1 We observed more non-dippers and reverse dippers after stroke than in their elderly hypertensive cohort without a history of stroke. Table 2 shows the BP characteristics of patients with the various patterns. Compared to dippers, non-dippers and reverse dippers had a significantly higher mean nocturnal
Table 1 Pattern of circadian BP variation between acute stroke patients and elderly hypertensive cohort (Kario et al.)1
Acute stroke present study (n = 173) Elderly hypertensive cohort (n = 575)1
Extreme dipper
Dipper
Non-dipper
Reverse dipper
4 (2.3%) 97 (17%)
25 (14.5%) 230 (40%)
80 (46.2%) 185 (32%)
64 (36.9%) 63 (11%)
Table 2 Blood pressure characteristics in different groups compared with dippers Dipper (n = 25) Mean SBP Day 149.1 Night 128.6 Mean DBP Day 75.4 Night 68.4 Mean MAP Day 99.9 Night 88.5
Extreme dipper (n = 4)
p-value
Non-dipper (n = 80)
p-value
Reverse dipper (n = 64)
p-value
164.2 127.7
0.24 0.93
151.8 144.9
0.59 0.001
143.9 153.9
0.33 0.001
82.4 70.7
0.16 0.63
77.5 75.4
0.39 0.006
74.3 76.1
0.68 0.004
109.7 89.7
0.16 0.84
102.3 98.5
0.43 0.0008
97.5 102.0
0.44 0.001
[SBP-systolic blood pressure (mm Hg), DBP-diastolic blood pressure (mm Hg), MAP-mean arterial blood pressure (mm Hg)].
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J.D. Pandian et al. / Journal of Clinical Neuroscience 13 (2006) 558–562
Table 3 Demographic variables, stroke risk factors and stroke severity between different groups compared with dippers
Age Men Women Diabetes Dyslipidemia Hypertension Anti-hypertensive medication Smoking Atrial fibrillation
Dipper (n = 25) n (%)
Extreme dipper (n = 4) n (%)
p-value
Non-dipper (n = 80) n (%)
p-value
Reverse dipper (n = 64) n (%)
p-value
74.9 14 (56) 11 (44) 4 (16) 4 (16) 13 (52) 14 (56) 8 (32) 6 (24)
77.5 3 (75) 1 (25) 1 (25) 1 (25) 2 (50) 2 (50) – –
0.65 0.31
69.6 34 (43) 46 (57) 18 (23) 28 (35) 47 (59) 35 (44) 28 (35) 22 (28)
0.14 1.0
75.9 35 (55) 29 (45) 8 (13) 23 (36) 49 (77) 38 (59) 20 (31) 17 (27)
0.56 0.48
0.53 0.53 1.0 1.0 0.26 0.55
SBP, mean nocturnal DBP and mean nocturnal MAP (all p-values <0.006). The extreme dippers had a higher mean daytime SBP, mean daytime DBP, and mean daytime MAP than the dippers, but the number of extreme dippers was small and not statistically significant. Patients with a haemorrhagic stroke had a raised mean daytime SBP (155.1 mm Hg) and mean nocturnal SBP (147.6 mmHg) compared to the ischaemic stroke group (mean daytime SBP 147.6 mmHg and mean nocturnal SBP 145.1 mmHg), but this was not significant (p = 0.13 and p = 0.62, respectively). Forty-nine out of 64 (77%) subjects with a reverse dipping pattern had a history of hypertension, compared to 13 out of 25 (52%) patients with a normal dipping pattern (p = 0.02) (Table 3). There were no significant differences in age, gender, and other stroke risk factors such as diabetes, dyslipidaemia, anti-hypertensive medications, current smoking and atrial fibrillation between the dippers and the other three groups (Table 3). 100
Death
90
Death and Dependency
Percentage of patients
80
75
70 59
60 46
50
43
40 31 30
26
25 20
20 10 0 Extreme dipper (n=4)
Dipper (n=25)
Non-dipper (n=80)
Reverse dipper (n=64)
Fig. 1. Outcome by pattern of circadian BP variation.
0.58 0.08 0.49 0.79 0.79 0.80
1.0 0.07 0.02 0.81 0.79 1.0
The baseline median NIHSS scores were as follows: dippers 6.0 (mean, 9.7 ± 8.8, interquartile 2–16); non-dippers 6.0 (mean 9.3 ± 8.5, interquartile 3–15); extreme dippers 13.5 (mean 14.7 ± 12, interquartile 5.5–24); and reverse dippers six (mean 8.6 ± 7.6, interquartile 3–12). There was no significant difference across the groups. There appeared to be a slightly higher proportion of patients who were dead or dependent at 3 months in patients exhibiting extreme dipper and reverse dipper patterns compared to dippers, but this was not significant (p = 0.59 and p = 0.35, respectively) (Fig. 1). No difference in mortality was seen across the groups. 4. Discussion In acute stroke patients we found more non-dippers and reverse dippers, and fewer extreme dippers and normal dippers, than has been reported among elderly hypertensive patients without a prior history of stroke.1 To our knowledge, our study is the first to look at the four different diurnal BP patterns in patients after stroke. Previous studies in stroke patients that concentrated on the rise in nocturnal BP found similar proportions of non-dippers and reverse dippers to that seen in our cohort.7,8 The predominant trend in our study appeared to be a rise in nocturnal blood pressure, with a loss of the normal nocturnal fall in BP. In our patients who exhibited either a non-dipper or reverse dipper pattern, there were increases in the mean nocturnal SBP, DBP and MAP compared to dippers, with consequent loss of the normal nocturnal fall in BP. Conversely, extreme dippers exhibited higher daytime blood pressures with a preserved nocturnal fall to similar BP levels as normal dippers. The loss of nocturnal fall has been reported previously in acute stroke, and has been seen in both ischaemic and haemorrhagic stroke.4–8 The normal nocturnal fall in BP is, in part, determined by changes in sympathetic activity.1 The loss of nocturnal fall and the rise in nocturnal BP has been associated with an increase in plasma norepinephrine levels, indicating an alteration in modulation of the sympathetic nervous system.8 This increased level of sympathetic activity in the night may determine the dipping status in non-dippers and reverse dippers.12,13
J.D. Pandian et al. / Journal of Clinical Neuroscience 13 (2006) 558–562
Some previous studies have suggested an association between the loss of nocturnal fall in BP and poor outcome.9,10 However, Jain et al. did not find any association between the different circadian BP patterns and outcome.7 Our data suggested a slightly worse prognosis in the reverse dipper and extreme dipper groups, with a slightly higher proportion of patients who were dead or dependent at 3 months. However, the numbers of patients in our study, especially with the extreme dipper pattern, are small, and further data is needed to clarify this finding. The method of classification of circadian BP patterns varies between published studies. Both absolute2 and relative6,8 differences between daytime and nighttime SBP have been used, and some have used diurnal changes in DBP5 or MAP7 rather than SBP. These varied definitions may result in the dipping status of individual patients being classified differently.14 Moreover, there is no consensus regarding which definition is the most valid or clinically important.15 We adapted the classification method used by Kario et al., which has been shown to have a good reproducibility.1,16 One potential criticism of our study is that we used manual BP measurements, taken by different individuals and not by a single observer. We cannot exclude problems related to observer bias and inter-observer error in the recording of BP in our study. Other investigators have used 24-h ambulatory blood pressure monitoring (ABPM) to avoid some of these problems, as it reduces the measurement variability and observer bias when compared to casually recorded BP. An ABPM system may also avoid any ‘white coat’ effect contributing to a rise in recorded BP.17,18 However, the use of manual BP recordings reflects routine clinical practice, and it is upon such readings that management decisions are generally made. Despite the recognised limitations, many researchers continue to use manual BP measurements to study the influence of BP on stroke outcome.19–21 One problem shared by both manual and ABPM is in the measurement of BP during sleep. Transient auditory and tactile stimuli associated with cuff inflation during sleep can cause a transient rise in BP and is an inherent limitation in all studies using either manual BP or ABPM.22 It is unclear how much arousal from sleep during BP measurement has affected the results of this study or other similar studies. Another limitation of the present study is that we did not have an age and gender matched control arm, of either hospitalised patients without stroke, or healthy volunteers. This study is observational because of the lack of a true control group, but it provides new information about the patterns of circadian BP variation after acute stroke. In conclusion, we observed more non-dippers and reverse dippers in the first 48 h after stroke than in published cohorts of elderly hypertensive patients.1 No clear association between patterns of BP variation and outcome was observed. Further clinical studies in a larger cohort of patients, perhaps using ABPM to reduce measurement variability, are required to clarify the relationship of these abnormal circadian BP patterns and stroke outcome.
561
Acknowledgements and funding The authors thank the staff of the RBWH Stroke Unit for their support and assistance in performing this study. The Royal Brisbane and Women’s Hospital Research Foundation provided funding support to Dr. Wong. References 1. Kario K, Pickering TG, Matsuo T, Hoshide S, Schwartz JE, Shimada K. Stroke prognosis and abnormal nocturnal blood pressure falls in older hypertensives. Hypertension 2001;38:852–7. 2. Shimada K, Kawamoto A, Matsubayashi K, Nishinaga M, Kimura S, Ozawa T. Diurnal blood pressure variations and silent cerebrovascular damage in elderly patients with hypertension. J Hypertens 1992;10:875–8. 3. Kario K, Matsuo T, Kobayashi H, Imiya M, Matsuo M, Shimada K. Nocturnal fall of blood pressure and silent cerebrovascular damage in elderly hypertensive patients. Advanced silent cerebrovascular damage in extreme dippers. Hypertension 1996;27:130–5. 4. Dawson SL, Evans SN, Manktelow BN, Fotherby MD, Robinson JF, Potter JF. Diurnal blood pressure changes varies with stroke subtype in the acute phase. Stroke 1998;29:1519–24. 5. Yamamoto Y, Akiguchi I, Oiwa K, Satoi H, Kimura J. Diminished nocturnal blood pressure decline and lesion site in cerebrovascular disease. Stroke 1995;26:829–33. 6. Lip GY, Zarifis J, Farooqi IS, Page A, Sagar G, Beevers DG. Ambulatory blood pressure monitoring in acute stroke: The West Birmingham Stroke Project. Stroke 1997;28:31–5. 7. Jain S, Namboodri KK, Kumari S, Prabhakar S. Loss of circadian rhythm of blood pressure following acute stroke. BMC Neurology 2004;4:1. 8. Sander D, Klingelhofer J. Changes of circadian blood pressure patterns after hemodynamic and thromboembolic brain infarction. Stroke 1994;25:1730–7. 9. Panayiotou BN, Taub NA, Fotherby MD. Twenty four hour blood pressure profiles following stroke. Blood Press Monit 1996;1:409–14. 10. Bhalla A, Wolfe CD, Rudd AG. The effect of 24 h blood pressure levels on early neurological recovery after stroke. J Intern Med 2001;250:121–30. 11. Bland JM, Altman DG. Multiple significance tests: the Bonferroni method. BMJ 1995;310:170. 12. Kohara K, Nishida W, Maguchi M, Hiwada K. Autonomic nervous function in nondipper essential hypertensive subjects: Evaluation by power spectral analysis of heart rate variability. Hypertension 1995;26:808–14. 13. Kario K, Motai K, Mitsuhashi T, et al. Autonomic nervous system dysfunction in elderly hypertensive patients with abnormal diurnal blood pressure variation: relation to silent cerebrovascular disease. Hypertension 1997;30:1504–10. 14. Butkevich A, Phillips RA, Sheinart KF, Tuhrim S. The effects of various definitions of dipping and daytime and nighttime on classification of the 24-h profiles of blood pressure. Blood Press Monit 2000;5:19–22. 15. Phillips RA, Butkevich A, Sheinart KF, Tuhrim S. Dipping is superior to cusums analysis in assessment of the risk of stroke in a case-control study. Am J Hypertens 2001;14:649–52. 16. Kario K, Shimada K. Differential effects of amlodipine on ambulatory blood pressure in elderly hypertensive patients with different nocturnal reductions in blood pressure. Am J Hypertens 1997;10:261–8. 17. Harper G, Fotherby MD, Panayiotou BJ, Castleden CM, Potter JF. The changes in blood pressure after acute stroke: abolishing the ‘white coat effect’ with 24 h ambulatory monitoring. J Intern Med 1994;235:343–6. 18. Parati G, de Leeuw P, Illyes M, et al. 2001 Consensus conference of ambulatory blood pressure monitoring participants. Blood pressure measurement in research. Blood Press Monit 2002;7:83–7.
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19. Christensen H, Meden P, Overgaard K, Boysen G. The course of blood pressure in acute stroke is related to the severity of the neurological deficits. Acta Neurol Scand 2002;106:142–7. 20. Oliveira-Filho J, Silva SC, Trabuco CC, Pedreira BB, Sousa EU, Bacellar A. Detrimental effect of blood pressure reduction in the first 24 h of acute stroke onset. Neurology 2003;61:1047–51.
21. Castillo J, Leira R, Garcia MM, Serena J, Blanco M, Davalos A. Blood pressure decrease during the acute phase of ischemic stroke is associated with brain injury and poor stroke outcome. Stroke 2004;35:520–6. 22. Davies RJ, Belt PJ, Roberts SJ, Ali NJ, Stradling JR. Arterial blood pressure responses to graded transient arousal from sleep in normal humans. J Appl Physiol 1993;74:1123–30.
Clinical study
Circadian blood pressure variation after acute stroke Jeyaraj D. Pandian a,*, Andrew A. Wong a, Douglas J. Lincoln b, James P. Davis a, Robert D. Henderson a, John D. O’ Sullivan a, Stephen J. Read a a
Stroke Unit, Department of Neurology, Level 7, Ned Hanlon Building, Royal Brisbane and Women’s Hospital, Herston Road, Brisbane, Queensland 4029, Australia b Royal Brisbane and Women’s Hospital Research Foundation, Herston Road, Brisbane 4029, Australia Received 9 June 2005; accepted 8 September 2005
Abstract We aimed to characterise the patterns of circadian blood pressure (BP) variation after acute stroke and determine whether any relationship exists between these patterns and stroke outcome. BP was recorded manually every 4 h for 48 h following acute stroke. Patients were classified according to the percentage fall in mean systolic BP (SBP) at night compared to during the day as: dippers (fall P 10– <20%); extreme dippers (P20%); non–dippers (P0–<10%); and reverse dippers (<0%, that is, a rise in mean nocturnal SBP compared to mean daytime SBP). One hundred and seventy-three stroke patients were included in the study (83 men, 90 women; mean age 74.3 years). Four patients (2.3%) were extreme dippers, 25 (14.5%) dippers, 80 (46.2%) non-dippers and 64 (36.9%) reverse dippers. There was a non-significant trend in the proportion of patients who were dead or dependent at 3 months in the extreme dipper (p = 0.59) and reverse dipper (p = 0.35) groups. Non-dipping and reverse-dipping were relatively common patterns of circadian BP variation seen in acute stroke patients. These patterns were not clearly associated with outcome. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Circadian variations; Blood pressure; Diurnal; Acute stroke
1. Introduction In normal subjects the mean nocturnal systolic blood pressure (SBP) is 10–20% lower than mean daytime SBP, so-called dipping.1 Abnormal patterns of circadian BP variation have also been described in which the nocturnal fall of BP may be increased (P20%, extreme dippers), reduced (<10%, non-dippers) or even reversed (reverse dippers).1 In comparison to normal dipping, patients exhibiting these abnormal patterns are more likely to suffer occult and overt cerebrovascular disease.2,3 Extreme dippers and non-dippers appear to have an increased risk of silent cerebral infarction, periventricular white matter hyperintensities and overt stroke, while a higher risk of intracerebral haemorrhage has been reported in reverse dippers.1,3
*
Corresponding author. Tel.: +61 7 36367096; fax: +61 7 3636 7675. E-mail address: [email protected] (J.D. Pandian).
0967-5868/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2005.09.003
It is unclear how frequently each of these abnormal patterns occur following acute stroke. Previous studies of abnormal BP variability patterns in acute stroke looked at only one dipping pattern, either non-dipping or reverse dipping.4–8 Previous researchers have also tried to link changes in circadian BP variability with different stroke subtypes, although results have been conflicting. For example, in different studies non-dipping has been shown to be associated with ischaemic stroke, haemorrhage, and to show no association with stroke type.4–7 The influence of abnormal circadian BP patterns on stroke outcome is also unclear. Some studies have found poor outcome among reverse dippers9 and non-dippers,10 while others have noted no association between the different patterns of circadian BP variation and outcome.7 We undertook this study to examine the patterns of circadian BP variation, to determine their frequency during the first 48 h after acute stroke, and to assess whether any relationship exists between these patterns and stroke outcome.
J.D. Pandian et al. / Journal of Clinical Neuroscience 13 (2006) 558–562
2. Methods All patients presenting between June 2002 and March 2003 with a diagnosis of stroke were eligible for inclusion. Patients with a diagnosis of transient ischaemic attack, subarachnoid haemorrhage or bleeding due to trauma were excluded. All patients were enrolled within 24 h of stroke. Blood pressure was recorded using a standard aneroid sphygmomanometer every 4 h for 48 h after stroke. In each subject, the mean nocturnal SBP was taken as the mean of the BP recordings between 22.00 h and 6.00 h and mean daytime SBP as the mean of BP readings between 6.00 h and 22.00 h. The percentage difference between mean nocturnal SBP and mean daytime SBP was calculated using the formula: %difference ¼ 1 ðmean nocturnal SBP=mean daytime SBPÞ 100:1 Patients were classified according to the percentage difference as: extreme dippers (% difference P 20%), dippers (P10%–<20%), non-dippers (P0%–<10%), and reverse dippers (<0%, that is, a rise in mean nocturnal SBP over the daytime mean SBP).1 The mean daytime and the nocturnal SBP, diastolic BP (DBP) and mean arterial pressure (MAP) were compared between the dippers and each of the other three groups, and also between ischaemic and haemorrhagic stroke cohorts. Demographic variables (age, gender), risk factors, type of stroke (ischaemic and haemorrhagic) and stroke severity (National Institute of Health Stroke Scale [NIHSS]) were compared between the dippers and each of the other three groups. Past history of hypertension and the use of current antihypertensive medications were also compared between the dippers and the other three groups. Functional capacity was measured using the modified Rankin Scale (mRS) at 3 months post-stroke. The primary outcomes of death, and the combined outcome of death or
559
dependency (defined as an mRS P 3) at 3 months were compared between the dipper and each of the other groups. Statistical analysis was done using SAS software version 8.02 (SAS Institute Inc, Cary, NC, USA). Demographic and clinical characteristics of the patients were compared across the four groups using standard univariate analyses. Statistical comparisons across all groups simultaneously were made using the F-test and Pearson’s chi-squared test. Kruskall-Wallis test was used to compare the baseline NIHSS values across the four groups. Statistical comparisons between the dipper group and each of the other groups were made using the unpaired t-test, Pearson’s chi-squared test and Fisher’s exact test, with significance levels adjusted for multiple comparisons using the Bonferroni method.11 A p-value of <0.017 was considered significant. The hospital Human Research Ethics Committee approved this study. Written informed consent was obtained from patients or from their next of kin where patients were unable to do so themselves. 3. Results Two hundred and twenty-patients were screened at admission. Forty-seven patients were ineligible to participate, refused consent, withdrew from the study, had insufficient BP data or had diagnosis other than stroke, leaving 173 patients for analysis. There were 83 (48%) men and 90 (52%) women. The mean age was 74.3 years. The frequencies of the patterns of circadian BP variation in the study patients are shown in Table 1. Comparison is made with data from the study by Kario et al.1 We observed more non-dippers and reverse dippers after stroke than in their elderly hypertensive cohort without a history of stroke. Table 2 shows the BP characteristics of patients with the various patterns. Compared to dippers, non-dippers and reverse dippers had a significantly higher mean nocturnal
Table 1 Pattern of circadian BP variation between acute stroke patients and elderly hypertensive cohort (Kario et al.)1
Acute stroke present study (n = 173) Elderly hypertensive cohort (n = 575)1
Extreme dipper
Dipper
Non-dipper
Reverse dipper
4 (2.3%) 97 (17%)
25 (14.5%) 230 (40%)
80 (46.2%) 185 (32%)
64 (36.9%) 63 (11%)
Table 2 Blood pressure characteristics in different groups compared with dippers Dipper (n = 25) Mean SBP Day 149.1 Night 128.6 Mean DBP Day 75.4 Night 68.4 Mean MAP Day 99.9 Night 88.5
Extreme dipper (n = 4)
p-value
Non-dipper (n = 80)
p-value
Reverse dipper (n = 64)
p-value
164.2 127.7
0.24 0.93
151.8 144.9
0.59 0.001
143.9 153.9
0.33 0.001
82.4 70.7
0.16 0.63
77.5 75.4
0.39 0.006
74.3 76.1
0.68 0.004
109.7 89.7
0.16 0.84
102.3 98.5
0.43 0.0008
97.5 102.0
0.44 0.001
[SBP-systolic blood pressure (mm Hg), DBP-diastolic blood pressure (mm Hg), MAP-mean arterial blood pressure (mm Hg)].
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J.D. Pandian et al. / Journal of Clinical Neuroscience 13 (2006) 558–562
Table 3 Demographic variables, stroke risk factors and stroke severity between different groups compared with dippers
Age Men Women Diabetes Dyslipidemia Hypertension Anti-hypertensive medication Smoking Atrial fibrillation
Dipper (n = 25) n (%)
Extreme dipper (n = 4) n (%)
p-value
Non-dipper (n = 80) n (%)
p-value
Reverse dipper (n = 64) n (%)
p-value
74.9 14 (56) 11 (44) 4 (16) 4 (16) 13 (52) 14 (56) 8 (32) 6 (24)
77.5 3 (75) 1 (25) 1 (25) 1 (25) 2 (50) 2 (50) – –
0.65 0.31
69.6 34 (43) 46 (57) 18 (23) 28 (35) 47 (59) 35 (44) 28 (35) 22 (28)
0.14 1.0
75.9 35 (55) 29 (45) 8 (13) 23 (36) 49 (77) 38 (59) 20 (31) 17 (27)
0.56 0.48
0.53 0.53 1.0 1.0 0.26 0.55
SBP, mean nocturnal DBP and mean nocturnal MAP (all p-values <0.006). The extreme dippers had a higher mean daytime SBP, mean daytime DBP, and mean daytime MAP than the dippers, but the number of extreme dippers was small and not statistically significant. Patients with a haemorrhagic stroke had a raised mean daytime SBP (155.1 mm Hg) and mean nocturnal SBP (147.6 mmHg) compared to the ischaemic stroke group (mean daytime SBP 147.6 mmHg and mean nocturnal SBP 145.1 mmHg), but this was not significant (p = 0.13 and p = 0.62, respectively). Forty-nine out of 64 (77%) subjects with a reverse dipping pattern had a history of hypertension, compared to 13 out of 25 (52%) patients with a normal dipping pattern (p = 0.02) (Table 3). There were no significant differences in age, gender, and other stroke risk factors such as diabetes, dyslipidaemia, anti-hypertensive medications, current smoking and atrial fibrillation between the dippers and the other three groups (Table 3). 100
Death
90
Death and Dependency
Percentage of patients
80
75
70 59
60 46
50
43
40 31 30
26
25 20
20 10 0 Extreme dipper (n=4)
Dipper (n=25)
Non-dipper (n=80)
Reverse dipper (n=64)
Fig. 1. Outcome by pattern of circadian BP variation.
0.58 0.08 0.49 0.79 0.79 0.80
1.0 0.07 0.02 0.81 0.79 1.0
The baseline median NIHSS scores were as follows: dippers 6.0 (mean, 9.7 ± 8.8, interquartile 2–16); non-dippers 6.0 (mean 9.3 ± 8.5, interquartile 3–15); extreme dippers 13.5 (mean 14.7 ± 12, interquartile 5.5–24); and reverse dippers six (mean 8.6 ± 7.6, interquartile 3–12). There was no significant difference across the groups. There appeared to be a slightly higher proportion of patients who were dead or dependent at 3 months in patients exhibiting extreme dipper and reverse dipper patterns compared to dippers, but this was not significant (p = 0.59 and p = 0.35, respectively) (Fig. 1). No difference in mortality was seen across the groups. 4. Discussion In acute stroke patients we found more non-dippers and reverse dippers, and fewer extreme dippers and normal dippers, than has been reported among elderly hypertensive patients without a prior history of stroke.1 To our knowledge, our study is the first to look at the four different diurnal BP patterns in patients after stroke. Previous studies in stroke patients that concentrated on the rise in nocturnal BP found similar proportions of non-dippers and reverse dippers to that seen in our cohort.7,8 The predominant trend in our study appeared to be a rise in nocturnal blood pressure, with a loss of the normal nocturnal fall in BP. In our patients who exhibited either a non-dipper or reverse dipper pattern, there were increases in the mean nocturnal SBP, DBP and MAP compared to dippers, with consequent loss of the normal nocturnal fall in BP. Conversely, extreme dippers exhibited higher daytime blood pressures with a preserved nocturnal fall to similar BP levels as normal dippers. The loss of nocturnal fall has been reported previously in acute stroke, and has been seen in both ischaemic and haemorrhagic stroke.4–8 The normal nocturnal fall in BP is, in part, determined by changes in sympathetic activity.1 The loss of nocturnal fall and the rise in nocturnal BP has been associated with an increase in plasma norepinephrine levels, indicating an alteration in modulation of the sympathetic nervous system.8 This increased level of sympathetic activity in the night may determine the dipping status in non-dippers and reverse dippers.12,13
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Some previous studies have suggested an association between the loss of nocturnal fall in BP and poor outcome.9,10 However, Jain et al. did not find any association between the different circadian BP patterns and outcome.7 Our data suggested a slightly worse prognosis in the reverse dipper and extreme dipper groups, with a slightly higher proportion of patients who were dead or dependent at 3 months. However, the numbers of patients in our study, especially with the extreme dipper pattern, are small, and further data is needed to clarify this finding. The method of classification of circadian BP patterns varies between published studies. Both absolute2 and relative6,8 differences between daytime and nighttime SBP have been used, and some have used diurnal changes in DBP5 or MAP7 rather than SBP. These varied definitions may result in the dipping status of individual patients being classified differently.14 Moreover, there is no consensus regarding which definition is the most valid or clinically important.15 We adapted the classification method used by Kario et al., which has been shown to have a good reproducibility.1,16 One potential criticism of our study is that we used manual BP measurements, taken by different individuals and not by a single observer. We cannot exclude problems related to observer bias and inter-observer error in the recording of BP in our study. Other investigators have used 24-h ambulatory blood pressure monitoring (ABPM) to avoid some of these problems, as it reduces the measurement variability and observer bias when compared to casually recorded BP. An ABPM system may also avoid any ‘white coat’ effect contributing to a rise in recorded BP.17,18 However, the use of manual BP recordings reflects routine clinical practice, and it is upon such readings that management decisions are generally made. Despite the recognised limitations, many researchers continue to use manual BP measurements to study the influence of BP on stroke outcome.19–21 One problem shared by both manual and ABPM is in the measurement of BP during sleep. Transient auditory and tactile stimuli associated with cuff inflation during sleep can cause a transient rise in BP and is an inherent limitation in all studies using either manual BP or ABPM.22 It is unclear how much arousal from sleep during BP measurement has affected the results of this study or other similar studies. Another limitation of the present study is that we did not have an age and gender matched control arm, of either hospitalised patients without stroke, or healthy volunteers. This study is observational because of the lack of a true control group, but it provides new information about the patterns of circadian BP variation after acute stroke. In conclusion, we observed more non-dippers and reverse dippers in the first 48 h after stroke than in published cohorts of elderly hypertensive patients.1 No clear association between patterns of BP variation and outcome was observed. Further clinical studies in a larger cohort of patients, perhaps using ABPM to reduce measurement variability, are required to clarify the relationship of these abnormal circadian BP patterns and stroke outcome.
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Acknowledgements and funding The authors thank the staff of the RBWH Stroke Unit for their support and assistance in performing this study. The Royal Brisbane and Women’s Hospital Research Foundation provided funding support to Dr. Wong. References 1. Kario K, Pickering TG, Matsuo T, Hoshide S, Schwartz JE, Shimada K. Stroke prognosis and abnormal nocturnal blood pressure falls in older hypertensives. Hypertension 2001;38:852–7. 2. Shimada K, Kawamoto A, Matsubayashi K, Nishinaga M, Kimura S, Ozawa T. Diurnal blood pressure variations and silent cerebrovascular damage in elderly patients with hypertension. J Hypertens 1992;10:875–8. 3. Kario K, Matsuo T, Kobayashi H, Imiya M, Matsuo M, Shimada K. Nocturnal fall of blood pressure and silent cerebrovascular damage in elderly hypertensive patients. Advanced silent cerebrovascular damage in extreme dippers. Hypertension 1996;27:130–5. 4. Dawson SL, Evans SN, Manktelow BN, Fotherby MD, Robinson JF, Potter JF. Diurnal blood pressure changes varies with stroke subtype in the acute phase. Stroke 1998;29:1519–24. 5. Yamamoto Y, Akiguchi I, Oiwa K, Satoi H, Kimura J. Diminished nocturnal blood pressure decline and lesion site in cerebrovascular disease. Stroke 1995;26:829–33. 6. Lip GY, Zarifis J, Farooqi IS, Page A, Sagar G, Beevers DG. Ambulatory blood pressure monitoring in acute stroke: The West Birmingham Stroke Project. Stroke 1997;28:31–5. 7. Jain S, Namboodri KK, Kumari S, Prabhakar S. Loss of circadian rhythm of blood pressure following acute stroke. BMC Neurology 2004;4:1. 8. Sander D, Klingelhofer J. Changes of circadian blood pressure patterns after hemodynamic and thromboembolic brain infarction. Stroke 1994;25:1730–7. 9. Panayiotou BN, Taub NA, Fotherby MD. Twenty four hour blood pressure profiles following stroke. Blood Press Monit 1996;1:409–14. 10. Bhalla A, Wolfe CD, Rudd AG. The effect of 24 h blood pressure levels on early neurological recovery after stroke. J Intern Med 2001;250:121–30. 11. Bland JM, Altman DG. Multiple significance tests: the Bonferroni method. BMJ 1995;310:170. 12. Kohara K, Nishida W, Maguchi M, Hiwada K. Autonomic nervous function in nondipper essential hypertensive subjects: Evaluation by power spectral analysis of heart rate variability. Hypertension 1995;26:808–14. 13. Kario K, Motai K, Mitsuhashi T, et al. Autonomic nervous system dysfunction in elderly hypertensive patients with abnormal diurnal blood pressure variation: relation to silent cerebrovascular disease. Hypertension 1997;30:1504–10. 14. Butkevich A, Phillips RA, Sheinart KF, Tuhrim S. The effects of various definitions of dipping and daytime and nighttime on classification of the 24-h profiles of blood pressure. Blood Press Monit 2000;5:19–22. 15. Phillips RA, Butkevich A, Sheinart KF, Tuhrim S. Dipping is superior to cusums analysis in assessment of the risk of stroke in a case-control study. Am J Hypertens 2001;14:649–52. 16. Kario K, Shimada K. Differential effects of amlodipine on ambulatory blood pressure in elderly hypertensive patients with different nocturnal reductions in blood pressure. Am J Hypertens 1997;10:261–8. 17. Harper G, Fotherby MD, Panayiotou BJ, Castleden CM, Potter JF. The changes in blood pressure after acute stroke: abolishing the ‘white coat effect’ with 24 h ambulatory monitoring. J Intern Med 1994;235:343–6. 18. Parati G, de Leeuw P, Illyes M, et al. 2001 Consensus conference of ambulatory blood pressure monitoring participants. Blood pressure measurement in research. Blood Press Monit 2002;7:83–7.
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