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1 AJH 1998;11: Little Effect of Ordinary Antihypertensive Therapy on Nocturnal High Blood Pressure in Patients with Sleep Disordered Breathing Lisa H. Pelttari, Eino K. Hietanen, Tiina T. Salo, Matti J. Kataja, and Ilkka M. Kantola The antihypertensive effects of four different antihypertensive medications ( -blocking agent, atenolol 50 mg; calcium-antagonist, isradipine SRO [slow release] 2.5 mg; diuretic, hydrochlorothiazide [HCTZ] 25 mg; and angiotension converting enzyme-inhibitor, spirapril 6 mg) on obese patients with sleep disordered breathing and hypertension were compared by the ambulatory blood pressure measurement (ABPM). Eighteen patients were randomized in a doubleblind, crossover fashion to receive each of the four different medications for 8 weeks. ABPM was performed at baseline and after an 8-week treatment with these medications. A 2- to 3-week washout period occurred both at baseline and between each of the four medications. Three patients were omitted from statistical analysis because of technical problems of ABPM. Atenolol, isradipine SRO, and spirapril decreased significantly (P <.01) the mean 24-h systolic blood pressure, whereas HCTZ did not. The mean 24-h diastolic blood pressure decreased significantly after all four medications: 12 (SD 14) mm Hg with atenolol, 7 (SD 10) mm Hg with isradipine SRO, 3 mm Hg (SD 14) with HCTZ, and 6 (SD 15) mm Hg with spirapril (P <.01). During nighttime none of the medications reduced the mean diastolic or systolic blood pressure significantly. According to the 24-h blood pressure curve the influence of these four medications during the whole measurement period was not similar. Atenolol and spirapril lost their antihypertensive effect during the early morning hours. The antihypertensive effect of HCTZ varied markedly from hour to hour. The trough-to-peak ratio of no medication was >0.50. Negative correlation was observed between the apnea time and the mean systolic 24-h (r 0.604, P NS) and the mean systolic nocturnal blood pressure change (r 0.590, P NS). Our study revealed that the daytime high blood pressure was quite easily controlled by the ordinary monotherapy in these patients with partial upper airway obstruction and hypertension. Instead none of the medications used decreased nocturnal high blood pressure markedly. Am J Hypertens 1998;11: American Journal of Hypertension, Ltd. KEY WORDS: Ambulatory blood pressure measurement, atenolol, hydrochlorothiazide, hypertension, isradipine, sleep apnea, spirapril. Received May 15, Accepted September 29, From the Department of Medicine (LHP, TTS, IMK); Department of Clinical Physiology (EKH), Turku University Central Hospital, Turku; and National Public Health Institute (MJK), Helsinki, Finland. Address correspondence and reprint requests to Lisa Pelttari, MD, Vakka-Suomen sairaala, Terveystie 2, FIN Uusikaupunki, Finland; lisa.pelttari@pp.fimnet.fi 1998 by the American Journal of Hypertension, Ltd /98/$19.00 Published by Elsevier Science, Inc. PII S (97)00469-X

2 AJH MARCH 1998 VOL. 11, NO. 3, PART 1 ANTIHYPERTENSIVE MEDICATION IN OSA 273 Patients with obstructive sleep apnea (OSA) are often hypertensive. 1 4 Epidemiologic studies have suggested that one-third of the patients with hypertension suffer from sleep apnea. 5 7 However, evidence confirming a causal association between obstructive sleep apnea and daytime hypertension is still lacking. Confounding factors such as obesity and alcohol consumption have been suggested to explain the association. The increased mortality of the sleep apneic patients has been explained by the cardiovascular consequences. 8 The information about the effect of antihypertensive medication on obstructive sleep apnea is still scant. Kantola et al 9 observed in snorers that the calcium antagonist isradipine influenced breathing disturbances during sleep less than the -blocking agent metoprolol, although both drugs lowered blood pressure equally. In a study by Mayer et al, 10 although both metoprolol and the angiotensin converting enzyme inhibitor cilazapril reduced blood pressure in patients with sleep apnea, only cilazapril reduced blood pressure during rapid eye movement (REM) sleep. Weichler et al 11 showed that both metoprolol and cilazapril treatment reduced sleep apnea activity in hypertensive patients. The intermittent nocturnal blood pressure elevations have been suggested to cause the cardiovascular complications seen in sleep apnea. 12 Ambulatory blood pressure measurement (ABPM) provides a valuable method to monitor nocturnal blood pressure elevations, to detect the duration of the antihypertensive effect, 13 and to compare agents with different pharmacokinetic properties. 14 In this study we studied the effect of four different antihypertensive agents on patients with sleep disordered breathing and hypertension by using ABPM. PATIENTS AND METHODS Study Protocol Eighteen hypertensive (diastolic blood pressure [DBP] 95 to 115 mm Hg after washout period) patients with sleep disordered breathing according to the former Static Charge-Sensitive Bed (SCSB) method (described below) results were randomized to receive once a day at 7 am each of the four antihypertensive medications (the -blocking agent atenolol 50 mg; the diuretic, hydrochlorothiazide (HCTZ) 25 mg; the calcium antagonist isradipine SRO (slow release) 2.5 mg; or the angiotensin converting enzyme (ACE) inhibitor spirapril 6 mg) in a doubleblind crossover schedule. To be included the patients had to have sleep disordered breathing at least 10% of the time in bed according to the SCSB method performed 4 to 8 weeks before the start of the study. Patients received each medication for 8 weeks with a 2- to 3-week washout period between the medications. ABPM and SCSB were performed to all of the patients at the beginning of the study at baseline after a 3-week washout period and at 8 weeks during each medication. Also, SCSB was performed at the end of each washout period. The patients visited the study center before each active treatment period (control visit) and at 4 and 8 weeks during the active therapy in the morning. Heart rate, body weight, and office blood pressure were measured during all control visits. Patients Eighteen patients with sleep disordered breathing and hypertension were selected from a larger group of patients who had been sent to the Department of Medicine at Turku University Central Hospital for sleep recordings. Three patients were excluded from the statistical analyses because of the technical problems of ABPM, which was performed successfully on 15 patients. The mean age of the patients was (SD) 52 6 years (range, 41 to 62 years) and the body mass index (BMI) 32 kg/m 2 ( 4) (range, 26 to 41 kg/m 2 ). The characteristics of the patients who participated in the study are shown in Table 1. The severity of their sleep apnea varied significantly. The patient with the apnea time of 0 had increased respiratory resistance 5.1% of the time in bed. The patients were healthy except for sleep disordered breathing and hypertension. No treatment for sleep apnea was given during the study and BMI (32 kg/m 2 ) remained unchanged. The mean (SD) office systolic blood pressure (SBP) was mm Hg and DBP mm Hg at the beginning of the first treatment period. TABLE 1. CHARACTERISTICS OF THE PATIENTS (N 15) WHO PARTICIPATED IN THE STUDY Patient No. BMI (kg/m 2 ) Apnea Time (% of TIB) Dippers v Nondippers (1.2) Dipper (5.3) Dipper Nondipper (6.9) Dipper (3.2) Dipper (9.0) Nondipper (11.5) Nondipper (15.3) Dipper (6.2) Dipper (17.9) Nondipper (28.4) Dipper (2.5) Dipper (23.8) Dipper Nondipper Dipper Apnea time expressed as the addition of obstructive periodic breathing type 2 and 3 measured by using the static charge sensitive bed. Apnea time is the mean (SD) of the four measurements performed at the end of each washout period in 13 patients, in 2 patients according to a single prestudy SCSB recording. Dipper is a patient with at least a 10 mm Hg nighttime diastolic blood pressure decrease. BMI, body mass index; TIB, time in bed.

3 274 PELTTARI ET AL AJH MARCH 1998 VOL. 11, NO. 3, PART 1 FIGURE 1. Periodic breathing type 1 (P-1) is characterized by few if any gross body movements on the wide frequency band (WFB), 1periodically waxing and waning respiratory amplitudes that form symmetric spindle shapes with stable and undisturbed rate of breathing on the low frequency band (LFB), and stable ballistocardiographic activity with normal respiratory variation, without high frequency spikes on the high frequency band (HFB). 2SaO 2 may slightly fluctuate. Obstructive periodic breathing type 1 (OP-1) is characterized by few if any gross body movements on the WFB, 1periodically waxing and waning respiratory amplitudes that form symmetric spindle shapes with stable and undisturbed rate of breathing on the LFB, and 2high frequency spikes on the HFB. 3SaO 2 may slightly fluctuate. Obstructive periodic breathing type 2 (OP-2) is characterized by 1recurrent gross body movements on the WFB, 2periodically waxing and waning respiratory amplitudes that form nonsymmetric spindle shapes on the LFB, and 3few, if any, high frequency spikes on the HFB. 4SaO 2 is slightly fluctuating. Obstructive periodic breathing type 3 (OP-3) is characterized by 1recurrent body movements on the WFB, 2periodically waxing and waning respiratory amplitudes that form nonsymmetric spindle shapes on the LFB, and 3high frequency spiking with increasing amplitude on the HFB. 4SaO 2 shows recurrent episodes of severe hypoxia. Increased respiratory resistance (IRR) episode is characterized by 1a terminating body movement on the WFB, 2progressively increasing respiratory amplitude on the LFB, and 3progressively increasing high frequency spiking on the HFB. 4SaO 2 may slightly decrease during the episode. No correlation was seen between BMI, apnea time, and the dipper status. Ambulatory Blood Pressure Measurement ABPM (Novacor Diasys, Novacor S.A. Rueil-Malmaison, France) 15 was performed at the end of the washout period at baseline and after each 8-week medication period. The ABPM device was installed by an experienced nurse and the readings by the device were compared to mercury sphygmomanometer by using a T-piece. The comparison was made in standing, sitting, and supine positions, both at the time of the installation and removal of the device. The values of the ABPM monitor should not differ more than 5 mm Hg from the auscultatory values. Blood pressure was measured every 20 min during daytime and every 60 min at night. The minimum valid SBP was preset at 60 mm Hg and the maximum valid SBP at 261 mm Hg and the minimum valid DBP at 40 mm Hg and the maximum valid DBP at 151 mm Hg. If a reading was outside these limits, it was not considered valid and was eliminated automatically. The study protocol was approved by the ethics committee of Turku University Central Hospital. Sleep Studies The severity of obstructive sleep apnea was determined by using the SCSB (Bio-Matt, Biorec, Turku; Finland) method. 16,17 The SCSB record-

4 AJH MARCH 1998 VOL. 11, NO. 3, PART 1 ANTIHYPERTENSIVE MEDICATION IN OSA 275 TABLE 2. THE MEAN AMBULATORY DAY AND NIGHTTIME BLOOD PRESSURE VALUES AT BASELINE AND AFTER 8 WEEKS OF THERAPY WITH 50 mg ATENOLOL, 2.5 mg ISRADIPINE SRO, 25 mg HYDROCHLOROTHIAZIDE, AND 6 mg SPIRAPRIL ABPM Baseline (mm Hg) Atenolol (mm Hg) Isradipine SRO (mm Hg) HCTZ (mm Hg) Spirapril (mm Hg) Mean SD Mean SD Mean SD Mean SD Mean SD SBP daytime * * DBP daytime * * * 98 14* SBP nighttime DBP nighttime *P.01 compared to baseline. SBP, systolic blood pressure; DBP, diastolic blood pressure; ABPM, ambulatory blood pressure measurement; SD, standard deviation. ings were performed 1 to 2 months before the beginning of the study (for the inclusion criteria) and repeated after all washout periods before starting the antihypertensive medication and at 8 weeks during each medication. The method and its application for monitoring nocturnal breathing disturbances have previously been reported in detail The SCSB consists of a movement sensor placed under a regular foam plastic mattress. The sensor forms a kind of capacitor, the charge of which is modified by moving static-charge layers. Before sending off to the recorder, the original movement signal is preamplified and filtered into three separate frequency bands: low frequency band (LFB, 0.25 to 0.9 Hz) to display the respiratory movements, high frequency band (HFB, 6 to 16 Hz) to display the ballistocardiogram, and wide frequency band (WFB, 0.25 to 16 Hz) to display gross body movements. The three-channel SCSB recordings were visually analyzed according to previously described criteria. 20 The four types of periodic breathing patterns: periodic breathing type 1 (P-1), obstructive periodic breathing type 1 (OP-1), obstructive periodic breathing type 2 (OP-2), obstructive periodic breathing type 3 (OP-3), and the increased respiratory resistance (IRR) pattern were quantified in 3-minute epochs and expressed as TABLE 3. PERCENTAGE OF PATIENTS WITH 24-H MEAN SYSTOLIC BP < 140 mm Hg OR 24-H MEAN DIASTOLIC BP < 90 mm Hg AFTER 8-WEEK THERAPY WITH 50 mg ATENOLOL, 2.5 mg ISRADIPINE SRO, 25 mg HYDROCHLOROTHIAZIDE (HCTZ), AND 6 mg SPIRAPRIL Therapy SBP <140 mm Hg (%) DBP <90 mm Hg (%) Atenolol Isradipine SRO HCTZ 36 8 Spirapril percentage of time in bed (TIB) with the motor active wakefulness excluded (Figure 1). Apnea time was counted as an addition of obstructive periodic breathing type 2 and 3, which have been suggested to represent obstructive apneas. 20 SCSB was not performed during the study on two patients because one worked abroad and the other had undergone uvulopalatopharyngoplasty just before the study. The rest of the patients underwent on average nine SCSB recordings during the study. Arterial oxyhemoglobin saturation (SaO 2 ) was measured through a finger probe with Biox II oximeter (BOC Group Inc, Louisville, CO). Statistical Methods Statistical analyses were performed by using two-way analysis of variance and paired Student s t test. The results are expressed as means and standard deviation (SD). The results of the baseline recordings were used as reference values to the recording during active treatment. Comparisons were performed by Tukey s Honestly Significant Difference test. Daytime was defined as the period between 10:30 am and going to bed and nighttime between going to bed and getting up. The daytime was defined to begin at 10:30 am in statistical analyses, because the time between 8 and 10 am was not constantly recorded because of variations in the installation time. The circadian blood pressure curves are smoothed by applying the three-point moving medians to them (in each place the middle one in size order of the three consecutive measurements is taken). The advantage of the moving median is the removing of all large single deviations. The relationship between BMI, apnea time, the dipper status, and the drug-induced changes in SBP and DBP were analyzed by the use of linear regression (Systat Inc., Evanston, IL). The trough-to-peak ratio of the different medications was counted from the mean blood pressure values, not from the individual values.

5 276 PELTTARI ET AL AJH MARCH 1998 VOL. 11, NO. 3, PART 1 TABLE 4. REDUCTION OF THE 24-H MEAN SYSTOLIC AND DIASTOLIC BLOOD PRESSURE AFTER 8 WEEKS OF THERAPY WITH 50 mg ATENOLOL, 2.5 mg ISRADIPINE SRO, 25 mg HYDROCHLOROTHIAZIDE (HCTZ), AND 6 mg SPIRAPRIL Therapy SBP (mm Hg) DBP (mm Hg) Mean SD P Mean SD P Atenolol Isradipine SRO HCTZ 2 20 NS Spirapril Mean values and standard deviation (SD) and the statistically significant differences from the pretreatment values are shown. SBP, systolic blood pressure; DBP, diastolic blood pressure. Paired t-test. RESULTS Ambulatory Blood Pressure Measurements After the washout period at baseline the mean (SD) daytime SBP by ABPM was mm Hg and the DBP mm Hg. The mean nighttime SBP before treatment was mm Hg, and the DBP was mm Hg. The mean 24-h SBP before treatment was mm Hg and the DBP mm Hg. Ten of the patients were dippers (at least 10 mm Hg nocturnal blood pressure decrease) and 5 nondippers (Table 1) according to the baseline 24-h circadian curve. Atenolol, isradipine SRO, and spirapril decreased daytime SBP significantly (P.01) unlike HCTZ. During daytime all four medications decreased DBP (P.01), but no significant reduction of SBP or DBP was seen during nighttime (Table 2). The percentage of the patients with the mean 24-h SBP 140 mm Hg or DBP 90 mm Hg after 8 weeks of therapy is seen in Table 3. Atenolol reduced the mean 24-h SBP more effectively than the other medications (P.05 compared to isradipine and P.01 compared to HCTZ and spirapril), also isradipine and spirapril reduced SBP more than HCTZ (P.01). Exactly the same pattern was observed with the mean 24-h DBP (atenolol v all other medications, P.01; isradipine v HCTZ, P.01 and spirapril v HCTZ, P.05) (Table 4). The 24-h profiles of SBP and DBP after washout pe- FIGURE 2. The 24-h curve of the blood pressure at baseline after a 2- to 3-week washout period in 15 patients with sleep apnea. The curves are smoothed. Systolic blood pressure ( ) and diastolic blood pressure ( ).

6 AJH MARCH 1998 VOL. 11, NO. 3, PART 1 ANTIHYPERTENSIVE MEDICATION IN OSA 277 FIGURE 3. The 24-h ABPM smoothed curves showing the differences in the systolic and diastolic blood pressures (mm Hg) compared to baseline after 8 weeks of treatment with 50 mg atenolol, 2.5 mg isradipine SRO, 25 mg HCTZ, or 6 mg spirapril. Systolic blood pressure ( ) and diastolic blood pressure ( ). riod and the 8-week treatment with atenolol, isradipine, HCTZ, and spirapril are shown in Figures 2 and 3. All four medications showed a different influence on the 24-h blood pressure variation. Although atenolol decreased both the mean 24-h SBP and DBP most effectively, it seemed to lose part of its efficacy during the early morning hours. Also spirapril lost its antihypertensive effect during nighttime. The antihypertensive effect of HCTZ varied significantly during the 24-h measurement. None of the the medications decreased nocturnal blood pressure significantly (Table 5). The trough-to-peak ratio of the different medications is shown in Table 6. A negative correlation was seen between the apnea time and the mean (all four medications) nocturnal SBP change (r 0.590, P NS)and the mean 24-h SBP change (r 0.604, P NS). Also a negative correlation (r 0.590, P NS) was seen between the dipper status and the mean nocturnal DBP change. SCSB Recording According to the SCSB nocturnal breathing abnormalities (increased respiratory resistance and obstructive apneas) occurred on average 49% 30% of the TIB. Partial upper airway obstruction was the predominant finding on sleep recordings. OP-1 with partial upper airway obstruction occurred 24% 24% of the TIB, P-1 only 1.7% 2.5% of the TIB, OP-2 OP-3 15% 15% of the TIB, and the IRR pattern 9% 7% of the TIB. The mean blood oxygen saturation during sleep recording was 93% 2%. The mean minimum blood oxygen saturation was 77% 8%. As seen from Table 1, the SCSB recordings during the four washout periods varied so much that no statistical analyses were possible. DISCUSSION The aim of this study was to investigate the effect of four different antihypertensive medications (atenolol, isradipine SRO, HCTZ, and spirapril) on patients with

7 278 PELTTARI ET AL AJH MARCH 1998 VOL. 11, NO. 3, PART 1 TABLE 5. REDUCTION OF THE NIGHTTIME MEAN SYSTOLIC (SBP) AND DIASTOLIC (DBP) BLOOD PRESSURE AFTER 8 WEEKS OF THERAPY WITH 50 mg ATENOLOL, 2.5 mg ISRADIPINE SRO, 25 mg HYDROCHLOROTHIAZIDE (HCTZ), AND 6 mg SPIRAPRIL Therapy SBP (mm Hg) DBP (mm Hg) Mean SD Mean SD Atenolol Isradipine SRO HCTZ Spirapril Mean values and standard deviation (SD) are shown. sleep disordered breathing and hypertension. Our results showed that the effect of the different medications used were not equal and varied markedly during daytime and nighttime. The -blocking agent atenolol reduced both the SBP and DBP most effectively. Also, the calcium-antagonist isradipine and the ACE inhibitor spirapril reduced both daytime SBP and DBP. HCTZ had the least effect on blood pressure, and only DBP was reduced significantly. During nighttime none of the medications reduced SBP or DBP effectively. Also atenolol, which otherwise reduced blood pressure most effectively, lost its effect in the early morning hours. It is possible that the weak antihypertensive effect of atenolol during the early morning hours is attributable to the insufficient duration of its antihypertensive effect. Unfortunately we did not have a control group without sleep apnea that could have clarified whether the morning hour blood pressure increase was attributable to sleep apnea, obesity, or the insufficient duration of the antihypertensive effect of atenolol. According to the trough-to-peak ratio the effect of the medications did not last 24 h. Our patients were quite heterogeneous especially concerning sleep disordered breathing but we have to remember that the true variation of the degree of the sleep disordered breathing is also wide among the subjects selected from the population register. 21 No conclusions concerning the effect of the medications on sleep disordered breathing could be drawn because already the reference value was obscure as can be seen from the standard deviations in Table 1. It seems to be difficult to get patients with even sleep apnea because the severity of sleep disordered breathing varies so much from night to night. Sleep apnea is quite often associated with obesity. 22 Our patients were obese but no correlation was seen between the severity of sleep disordered breathing and obesity. It has been suggested that hypertensive pateints with sleep apnea are nondippers. 23 We could not observe that in our study. Only one-third of our patients were nondippers and no correlation was seen between the dipping status and sleep disordered breathing (r 0.075). One explanation may be the large night-tonight variability of sleep disordered breathing of our patients. None of the four medications changed the mean dipping profile markedly. Frequent arousals with apneic periods produce a unique cyclic pattern of pulmonary and systemic arterial blood pressure changes. 24 We measured blood pressure only at every 60 min at nighttime. Because breathing abnormalities occurred on average about half of the TIB, it was probable that we did not capture all nocturnal variation of the blood pressure. Nocturnal waking levels of blood pressure differ only little from those seen in daytime. 25 It does not explain our results because the nighttime blood pressure in our study was clearly lower than the daytime. One explanation for the low nocturnal antihypertensive effect of these medications might be the insufficient dosage that did not last 24 h in these obese patients. Altogether it seems that the nocturnal blood pressure of these obese patients with sleep disturbances and frequent arousals is difficult to control with the ordinary antihypertensive therapy. We saw a negative correlation between the change in 24-h and nocturnal SBP and the apnea time. Although the correlation coefficient was quite high, the correlation was not significant because of the small number of patients. According to our results it seems that it is more difficult to decrease blood pressure in the patients with the most severe nocturnal breathing disorder. Probably the most effective way to handle their high blood pressure would be the treatment (operative, nasal continuous positive airway pressure) of their sleep apnea. Because we measured blood pressure during nighttime only once an hour no conclusions can be made using our ABPM results of the nocturnal blood pressure variability of these patients. Although the pathophysiology of blood pressure in OSA is very complicated, we know that sympathetic nerve activity and plasma norepinephrine levels are TABLE 6. THE TROUGH-TO-PEAK RATIO OF 50 mg ATENOLOL, 2.5 mg ISRADIPINE SRO, 25 mg HYDROCHLOROTHIAZIDE (HCTZ), AND 6 mg SPIRAPRIL COUNTED FROM THE MEAN BLOOD PRESSURE (BP) VALUES Therapy Systolic BP Diastolic BP Atenolol Isradipine SRO HCTZ Spirapril 0 0

8 AJH MARCH 1998 VOL. 11, NO. 3, PART 1 ANTIHYPERTENSIVE MEDICATION IN OSA 279 elevated in these patients, 26 which may explain the superior effect of the -blocking agent atenolol on the 24-h mean blood pressure. The sympathetic activity may be especially high during nighttime because of the frequent repetitive arousals induced by obstructive breathing, 27 which may explain the poor nocturnal blood pressure control achieved by all four medications. In conclusion it seems that daytime high blood pressure of the patients with partial upper airway obstruction was ordinarily controlled by the antihypertensive monotherapy used by us. In contrast nighttime high blood pressure could not be managed with ordinary monotherapy probably both because of sleep disturbances and also due to the obesity of these patients. REFERENCES 1. Tilkian AG, Guilleminault C, Schroeder JS, et al: Haemodynamics in sleep-induced apnoea: studies during wakefulness and sleep. Ann Intern Med 1976;85: Lugaresi E, Coccagna G, Cirignotta F: Snoring and its implications, in Guilleminault C, Dement WC (eds): Sleep Apnea Syndrome. Alan R. Liss, New York, 1978, pp Guilleminault C, van den Hoed J, Mitler MM: Clinical overview of the sleep apnea syndromes, in Guilleminault C, Dement WC (eds): Sleep Apnea Syndrome. Alan R. Liss, New York, 1978, pp Millman RP, Redline S, Carlisle CC, et al: Daytime hypertension in obstructive sleep apnea. Prevalence and contributing risk factors. Chest 1991;99: Lavie P, Ben-Yosef R, Rubin AE: Prevalence of sleep apnea syndrome among patients with essential hypertension. Am Heart J 1984;108: Fletcher EC, DeBehnke RD, Lovoi BA, et al: Undiagnosed sleep apnea in patients with essential hypertension. Ann Intern Med 1985;103: Williams AJ, Houston D, Finberg S: Sleep apnea syndrome and essential hypertension. Am J Cardiol 1985; 55: Partinen M, Jamieson A, Guilleminault C: Long term outcome for obstructive sleep apnea syndrome patients: mortality. Chest 1988;94: Kantola I, Rauhala E, Erkinjuntti M, et al: Sleep disturbances in hypertension: a double-blind study between isradipine and metoprolol. J Cardiovasc Pharmacol 1991;18(suppl 3):S41 S Mayer J, Weichler U, Herres-Mayer B, et al: Influence of metoprolol and cilizapril on blood pressure and on sleep apnea activity. J Cardiovasc Pharmacol 1990;16: Weichler V, Herres-Mayer B, Mayer J, et al: Influence of antihypertensive drugs therapy on sleep pattern and sleep apnea activity. Cardiology 1991;78: Carlson J, Davies R, Ehlenz K, et al: Obstructive sleep apnea and blood pressure elevation: what is the relationship? Blood Pressure 1995;2: Weber MA, Tonkon MJ, Klein ZC: Blood pressure monitoring for assessing the duration of action of antihypertensive treatment. J Clin Pharmacol 1987;28: Floras JS, Jones JV, Hassan MO, et al: Ambulatory blood pressure during once-daily randomised doubleblind administration of atenolol, metoprolol, pindolol and slow-release propranolol. Br Med J 1982;285: Bartehelemy JC, Geyssant A, Auboyer C, et al: Accuracy of ambulatory blood pressure determination: a comparative study. Scand J Clin Lab Invest 1991;51: Alihanka J, Vaahtoranta K: A static charge sensitive bed, a new method for recording body movements during sleep. Electro-encephalogr Clin Neurophysiol 1979;46: Alihanka J, Vaahtoranta J, Saarikivi I: A new method for long-term monitoring of the ballistocardiogram, heart rate and respiration. Am J Physiol 1981;240: Alihanka J: Basic principles for analyzing and scoring Bio-Matt (SCSB) recordings. Annales Universitatis Turkuensis 1987;D26: Salmi T, Telakivi T, Partinen M: Evaluation of automatic analysis of SCSB, airflow and oxygen saturation signals in patients with sleep related apneas. Chest 1989;96: Polo O: Partial upper airway obstruction during sleep. Studies with the Static Charge-sensitive bed (SCSB). Acta Physiol Scand 1992;145(suppl 606): Pelttari L, Rauhala E, Polo O, et al: Upper airway obstruction in hypothyroidism. J Intern Med 1994;236: Guilleminault C, Dement W: Sleep apnea syndromes and related disorders. in Williams R, Karacan I, Moore C (eds.): Sleep Disorders: Diagnosis and Treatment. Wiley, New York, 1988, pp Noda A, Okada T, Hayashi H, et al: 24-hour ambulatory blood pressure variability in obstructive sleep apnea syndrome. Chest 1993;103: Coccagna G, Mantovani M, Brignani F, et al: Continous recording of the pulmonary and systemic blood pressure during sleep in syndromes of hypersomnia with periodic sleeping. Bull Eur Physiopath Resp 1972;8: Kasting GA, Elfberg DL, Fritch JM, et al: Continuous resetting on the human carotid baroreceptor-cardiac reflex. J Physiol 1987;252:R Carlson J, Hedner JA, Elam M, et al: Augmented resting sympathetic activity in awake patients with obstructive sleep apnea. Chest 1993;103: Hedner J, Ejnell H, Sellgren J, et al: Is high and fluctuating muscle nerve sympathetic activity in the sleep apnea syndrome of pathogenesis importance for the development of hypertension? J Hypertens 1988;6: S