1992; 1 : 2 19-222

Circadian Rhythm of Blood Pressure in Patients with Obstructive Sleep Apnea IAN WILCOX,’-3 RONALD R. GRUNSTEIN,’.’ FIONA L. COLLINS,’JEAN M. DOYLE,’ DAVID T. KELLY’.3and COLIN E. SULLIVAN From the ‘Department of Medicine, University of Sydney and the ’Sleep Disorders Centre and ’Department of Cardiology, Royal Prince Alfred Hospital, Sydney, N S W 2050, Australia

Wilcox I, Grunstein RR, Collins FL, Doyle JM, Kelly DT, Sullivan CE. Circadian rhythm


blood pressure in pafients with

obstructive sleep apnea. Blood Pressure 1992; 1: 219-222.

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Aims: The aims of this study were to examine the circadian variation in blood pressure (BP) in obstructive sleep apnea (OSA) and to compare this between normotensive and hypertensive subjects. Merhods: We measured 24-hour ambulatory BP (ABP) in 72 men (mean age 51 & 8 years), with OSA diagnosed on overnight sleep study. Measurements of BP were made at 15 min intervals for 24 h using either an Oxford Medilog ABP or Spacelabs 90207 recorder. All recordings were performed after 2 3 week washout of anti-hypertensive drugs. The day-time monitoring period was defined as 07:OO hrs to 22:OO and night-time 22:OO to 07:OO. The ratio of night:day systolic and diastolic BP was calculated. Results: The patients were obese (mean body mass index 3 3 + 5 kg/m*) with a central pattern of obesity (waist:hip ratio 0.99 & 0.14, normal < 0.94). The mean 24-h ABP (systolic/diastolic) was 138 k 18/88 & 12 mmHg. The mean daytime ABP was 143k 18/93+ 12 and night-time ABP 128*20/80& 12 Hg. The night:day BP ratio was 0.90k0.07 (systolic) and 0.87+0.09 (diastolic) indicating that average BP was lower during the night. This pattern was similar in normotensive and hypertensive subjects. In contrast there was a significant relationship between increasing BMI and night:day blood pressure ratio (r =0.56, p lO/h of sleep) for inclusion in the study. We excluded patients with a high current alcohol intake (> 80 g/day), morbid obesity (weight > 150% ideal), patients whom the largest blood pressure cuff did not fit correctly and those with significant lung disease. Patients on anti-hypertensive drugs were weaned off these medications for a minimum of 3 weeks before the blood pressure recording. None of the patients were shift workers. Polysomnographic recordings All patients had detailed overnight polysomnographic recordings in one of three affiliated sleep laboratories. The studies were performed after patients had been withdrawn from antihypertensive medications for a minimum of 3 weeks. Polysomnographic studies were


I. Wilcox et al.



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12 Time (hrs)




Fig. 1. Circadian variation in ambulatory blood pressure and heart rate (- - - -) in OSA.


performed between 22:OO and 06:OO in all patients. The study included electroencephalography (EEG), extraocular muscle, submental, diaphragm electromyography (EMG) and air flow measurements. Respiratory movement was measured using chest and abdominal strain gauge transducers (Respitrace, Ambulatory monitoring, Ardsley, New York). Arterial oxygen saturation (SaOz) was measured using apulse oximeter with an ear probe and set to its fastest response (Biox 3700E, Ohmeda). All data were recorded on a polygraph recorder (Model 78D, Grass Instruments, Quincy, Massachussetts). Sleep staging was performed according to standard criteria [lo]. An apnea was defined as 10 seconds or more of absent airflow in the presence of chest or abdominal wall motion and a hypopnea defined as greater than 50% reduction in amplitude of the respitrace signal for more than 10 s. The respiratory disturbance index (RDI) was defined as the number of apneas or hypopneas/hour of sleep. Obstructive sleep apnea was considered present if an average of 10 or more respiratory events per hour of sleep were detected. Ambulatory blood pressure recordings A 24-h ambulatory blood pressure recording was performed, after a 3 week washout of anti-hypertensive medications, during the patients’ usual activities out of hospital. The recording was not performed during the overnight polysomnographic study. An appropriately sized cuff was chosen and placed on the non-dominant arm. Two different types of recorders were used, either the Oxford Medilog ABP (Oxford Medilog ABP, Oxford Medical Systems, Abingdon, UK) or the Spacelabs 90207 (Spacelabs Inc, Redmond, Washington, USA) recorder. Blood pressure measurements were performed at 15min intervals throughout the 24-h monitoring period. Patients were asked to keep their

arms as still as possible during the inflation: deflation cycle of the recorders and to keep a diary of activities throughout the recording period. The 24-h period was divided into 2 separate periods with night-time defined as 22:OO to 07:OO h and daytime from 07:OO to 22:OO h [l 11. For hourly blood pressure values the averages of all recorded values in a given hour was used. In comparing day and night differences in blood pressure, all recorded values were used for data analysis. Statistics All values are expressed as mean k standard deviation. Comparison between groups were performed using unpaired t-tests. A two-tailed p value of 160/95). None of the patients had previously had a cause of secondary hypertension documented and none had a prior history of stroke.


Ambulatory blood pressure recordings The average 24-h blood pressure (systolic/diastolic) was 139k 18/88 12 mmHg. The mean daytime blood pressure was 144+ 18/94+ 12 and mean night-time blood pressure 130f 20/82 f 12 mmHg. (Fig. 1) Using


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24-hour ambulatory blood pressure in sleep apnea

a daytime ambulatory blood pressure of 134/84 mmHg (1 1) as the upper limit of normal blood pressure, 44 of 72 patients (61 %) had day-time hypertension. The average night: day blood pressure ratio was 0.90 f0.07 (systolic) and 0.87 0.09 (diastolic), indicating that night-time blood pressure was lower than day-time blood pressure. Using a value of < 10% fall in systolic and diastolic blood pressure at night to define ‘nondippers’ (2), 21 of 72 patients (29%)were ‘non-dippers’. Only 10/72 patients (14%)had no fall in systolic blood pressure (night :day ratio 2 1 .O), only 3/72 (4%)had no fall in diastolic blood pressure at night. A similar pattern of nocturnal fall in blood pressure was noted in both normotensive and hypertensive subjects, although there was a trend towards a smaller fall in nocturnal blood pressure in hypertensive patients with sleep apnea: the night :day systolic blood pressure ratio was 0.89 0.07 compared to 0.92 f0.07 (normotensive vs hypertensive, p = NS) and the night-day diastolic blood pressure ratio was 0.85 f0.1 compared to 0.89 fO.09 (normotensive vs hypertensive, p =NS).


Heart rate changes

The diurnal changes in heart rate were similar to those demonstrated for blood pressure. The average 24-h heart rate was 80+ 1 1 beats/min with a normal fall in heart rate during the night: day-time heart rate 84 f 12 beats/min, night-time heart rate 71 5 11 beats/min, night: day ratio 0.85 & 0.09. This pattern was similar in both normotensive and hypertensive subjects for both day-time (85 f 10 compared with 83 f 14 beats/min, p = NS), night-time (72 f 10 compared with 7 1 f 13 beats/min, p = NS), and night: day heart rate ratio: 0.86 f0.1 and 0.84 f0.08 ( p = NS). Circadian blood pressure and obesity

Most of the patients were obese with 75% having a BMI > 28 kg/m2. Lean patients (BMI < 28 kg/m2)with OSA had a trend to a lower 24-h ambulatory blood pressure compared to obese patients (1 33 f20/87 11 mm Hg compared to 141 & 18/89 13 mm Hg) but this was not significant. However there was relationship between increasing BMI and night: day blood pressure ratio for both systolic (r= 0.56, p < 0.001) and diastolic blood pressure (r = 0.33,p < 0.02). Thus with increasing obesity there was a progressive reduction in the nighttime fall in blood pressure. Obesity explained 28% of the variance in night: day systolic blood pressure ratio and 10% of the variance in night:day diastolic blood pressure ratio. In multiple linear regression analysis, BMI was the only independent predictor of night: day blood pressure ratio when 24-h blood pressure, RDI, and BMI were included in the model.



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DISCUSSION We have shown that most patients with obstructive sleep apnea have a normal circadian rhythm of blood pressure with lower night-time than day-time blood pressure despite repetitive episodes of apnea during sleep. Although there was a trend to a reduction in the normal fall in blood pressure during the night in hypertensive subjects, this was not significant. These findings differ from previous reports which have shown a loss of the normal nocturnal fall in blood pressure in patients with sleep apnea [7-91. An important difference between this study and previously published data is that nocturnal and day-time blood pressures were compared but not differences in supine blood pressure between wakefulness and sleep. The intermittent measurements of blood pressure obtained using non-invasive ambulatory BP recording devices do not adequately measure the increased blood pressure variability which is well known to occur during apneic episodes when blood pressure is measured continuously [8]. However the blood pressure measurements, which were taken at the same intervals through both day and night, showed that average blood pressure levels were lower during the night than during the day. The mechanism of the normal nocturnal decline in blood pressure is not clearly understood [12]. Peripheral sympathetic activity is decreased during sleep in normal subjects but patients with OSA have increased peripheral sympathetic nerve activity with further cyclical increases associated with apneas [ 131 which would tend to oppose any tendency for blood pressure to fall during sleep. In contrast, the changes in plasma volume regulating systems in OSA would favour a decrease in nocturnal blood pressure. The RenalAngiotensin-Aldosterone (RAA) system is suppressed in OSA [ 141 and plasma levels of atrial natriuretic factor (ANF) are increased [15]. Thus, similar to normal subjects, the reason for the relatively preserved circadian blood pressure rhythm in OSA remains unknown. The relationship between obesity and reduction in the night-time fall in blood pressure as indicated by increasing night :day blood pressure with increasing obesity has not to our knowledge been reported previously. It does not appear to be related to the severity of sleep disordered breathing but this finding should be interpreted with caution since most of the patients had at least moderate OSA and no control patients without OSA were included in the study. Hypertension was common in these patients as has been reported previously [17-191. The high proportion of patients with hypertension in the present study, whether based on a prior history of hypertension, office blood pressure measurements or ambulatory record-

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I . wilcox et a / .

ings, is consistent with previously published d a t a [3-61. However, patients in this study were not selected a t random and a selection bias favouring hypertensive patients cannot be excluded. Epidemiological d a t a linking daytime hypertension with obstructive sleep apnea is potentially confounded by other factors such as age, obesity and alcohol consumption [6]. We have reported that morning blood pressure in subjects with suspected sleep apnea is related t o severity of sleep disordered breathing independently of the effects of age or obesity [20]. In addition, effective treatment of obstructive sleep apnea is associated with a fall in office [8, 2 I , 221 and ambulatory blood pressure [23]. Thus, there is increasing evidence that OSA influences blood pressure and the relatively normal circadian pattern blood pressure suggests that OSA affects blood pressure throughout the 24-h period.

ACKNOWLEDGEMENTS We thank nursing and technical staff, of the Hornsby and Camperdown Sleep Disorders Centres and the Sleep Disorders Laboratory, Royal Prince Alfred Hospital, for assistance with polysomnographic recordings. This study was supported by a Project Grant from the National Health and Medical Research Council of Australia and by a Cardiovascular Research Grant from the Australian Mutual Provident Society. REFERENCES I . Khatri IM, Freis ED. Hemodynamic changes during sleep. J Appl Physiol 1967; 22: 867-73. 2. Verdecchia P, Schillaci G, Guerrieri M, et al. Circadian blood pressure changes and left ventricular hypertrophy in essential hypertension. Circulation 1990; 81: 528-36. 3. Guilleminault C, Tillkan A, Dement W. The sleep apnea syndromes. Ann Rev Med 1976; 27: 465-84. 4. Millman RP, Redline S, Carlisle CC, Assaf A, Levinson PD. Daytime hypertension in obstructive sleep apnea. Prevalence and contributing risk factors. Chest 1991; 99: 86 1-6. 5. Williams AJ, Houston D, Finberg S, Lam C, Kinney JL, Santiago S. Sleep apnea syndrome and essential hypertension. Am J Cardiol 1985; 55: 1019-22. 6. Stradling JR. Sleep apnoea and systemic hypertension. Thorax 1989; 44: 984-9. 7. Tilkian AG, Guilleminault C, Schroeder JS, Lehrman KL, Simmons FB, Dement W. Haemodynamics in sleepinduced apnea: studies in wakefulness and sleep. Ann Int Med 1976; 85: 714-19. 8. Mayer J, Becker H, Brandenburg U, Penzel T, Peter JH, Wichert P von. Blood pressure and sleep apnea: results of long-term nasal continuous positive airways pressure therapy. Cardiology 1991; 79: 84-92. 9. Jennum P, Wildschadtz G, Christensen NJ, Schwartz T. Blood pressure, catecholamines and pancreatic polypeptide in obstructive sleep apnea with and without nasal continuous positive airway pressure (nCPAP) treatment. Am J Hypertens 1989; 2: 847-52. 10. Rechtschaffen A, Kales A, eds. A manual ofstandardized

terminology. Technics and scoring systems for sleep stages of normal subjects. Bethesda: National Institutes of Health, 1968 (Publication no 204). 11. Consensus document on non-invasive ambulatory blood pressure monitoring. J Hypertens 1990; 8: 135-40. 12. Staessen JA, Fagard RH, Lijnen PJ, Lutgarde T, Van Hoof R, Amery AK. Mean and range of the ambulatory pressure in normotensive subjects from a meta-analysis of 23 studies. Am J Cardiol 1991; 67: 723-7. 13. Pickering TG, O’Brien E. Second international consensus meeting on twenty-four-hour ambulatory blood pressure measurement: consensus and conclusions. J Hypertens 1991, ~(SUPPI 8): S2-6. 14. Hedner JA, Ejnell H, Sellgren J, Hedner T, Wallin G. Is high and fluctuating muscle sympathetic nerve activity in the sleep apnea syndrome, of pathogenetic importance for the development of hypertension? J Hypertens 1988; 6: 529-31. 15. Brandenberger G, Follenius M, Muzet A. Nocturnal oscillations in plasma renin activity and REM-NREM sleep cycles in humans: a common regulatory mechanism. Sleep 1988; 11: 242-50. 16. Krieger J, Laks L, Wilcox I, et at. Atrial natriuretic peptide release during sleep in patients with obstructive sleep apnea before and during treatment with nasal continuous positive airway pressure. Clin Sci 1989; 77: 407-11. 17. Lavie P, Rachamim B-Y, Rubin A-HE. Prevalence of sleep apnea syndrome among patients with essential hypertension. Am Heart J 1984; 108: 373-6. 18. Kales A, Bixler EO, Cadieux RJ, et al. Sleep apnoea in a hypertensive population. Lancet 1984; ii: 1005-22. 19. Fletcher EC, DeBehnke RD, Lovoi MS, Gorin AB. Undiagnosed sleep apnea in patients with essential hypertension. Ann Int Med 1985; 103: 190-5. 20. Grunstein RR, Wilcox I, Yang TS, Hedner JA, Could Y, Dodd MJ. Sleep apnoea: a confounding factor in the relationship between pattern of obesity and systemic hypertension? (Abstract) Journal of Sleep Research 1992; 1 (Suppl 1): 87. 21. Burack B, Pollack C, Borowiecki B, Weitzman E. The hypersomnia-sleep apnea syndrome: a reversible major cardiovascular hazard. (Abstract) Circulation 1977; 56: 17. 22. Guilleminault C, Simmons FB, Motta J, Cumminskey J, Schroeder JS, Dement WC. Obstructive sleep apnea syndrome and tracheostomy. Long-term follow-up experience. Ann Int Med 1981; 141: 985-8. 23. Wilcox I, Hedner JA, Grunstein RR, Doyle JM, Kelly DT, Fletcher PJ, Sullivan CE. Non-pharmacological reduction of systemic blood pressure in patients with sleep apnea by treatment with nasal continuous positive airway pressure. (Abstract) Circulation 1991; 84: 11-480. Submitted August 10, 1992; accepted September 18, 1992 Address f o r correspondence: Ian Wilcox David Read Laboratory Department of Medicine, Building DO6 University of Sydney Sydney, NSW 2006 Australia Fax: 61 2 550 3851

Circadian rhythm of blood pressure in patients with obstructive sleep apnea.

The aims of this study were to examine the circadian variation in blood pressure (BP) in obstructive sleep apnea (OSA) and to compare this between nor...
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