Effects of cilazapril on hypertension, sleep, and apnea

I

I

Effects of Cilazapril on Hypertension, Sleep, and Apnea JORGHERMANNPETER,M.D., PH.D., WERNERGASSEL,JORGENMAYER,M.D., BETrlNAHERRER-MAYER,THOMASPENZEL, HAR'rMUTSCHNEIDER,ULRIKEWEICHLER,KATJAWEBER,PETERYONWICHERT,M.D. Marbum,FederalRepublic of Germany

Epidemioiogic studies revealed that up to 10 percent of middle-aged men show more than 10 cessations of'breathing of more than 10 seconds' duration. In these patients, increased morbidity and mortality rates have been proved. More than 50 percent of apnea patients exhibit arterial hypertension, and up to 50 percent of hypertensive patients experience sleep apnea. Patients with sleep apnea and essential hypertension need special attention paid to their antihypertensive therapy because the following side effects of drugs have to be avoided: increases of cardiac insufficiency, hyperviscosity of the blood, intensification of the hypersomnia by central sedation, intensification of a pre-existing tendency towards arrhythmias, and deprivation of deep and rapid eye movement sleep. In this study, the effects of angiotensin-converting enzyme inhibitors in patients with sleep apnea and hypertension are examined. An interim evaluation of six patients (aged 50 to 57) yielded the following results: Average Broca index, 124; average blood pressure before therapy, 159/102 mm Hg; average blood pressure after therapy, 132/78; a decrease of the apnea and hypopnea index from x = 31 (range, 12 to 77) to x = 20 (range, two to 54). Therapy did not influence sleep structure: before therapy, an average of 19 percent of sleep episodes were of the rapid eye movement type (range, 11 to 32 percent); after therapy, 23 percent were of this type on average (range, 21 to 25 percent). A final evaluation will be carried out after the second study phase for 12 patients who have been treated in a double-blind scheme with metropolol versus cilazapril.

Fromthe MedizinischeUniversitats-Poliklinik,Zeitreihenlabor, Baldingerstrasse,3550 Marburg.Federal Republic of Germany. Requestsfor reprints should be addressed to Dr. J. H.Peter, MedizinischeUniversit~ts-Poliklinik,Baldingerstrasse,D-3550 Marburg. Federal Republic of Germany. 6B-72S

E

pidemiologic studies have indicated a high prevalence of the sleep-related breathing disorders (SRBD) "sleep apnea" and "obstructive snoring" [17]. There is an obvious statistical coincidence between both forms of SRBD and arterial hypertension. According to numerous studies, more than 50 percent of patients with sleep apnea have arterial hypertension. In 50 percent of patients who had hypertension for periods of years, a higher sleep apnea activity was found [8-12]. It is necessary therefore to consider not only possible pathophysiologic correlations but also the consequences of therapy. During nocturnal respiratory therapy with nasal continuous positive airway pressure, daytime blood pressure also generally normalizes [13], provided that therapy effectively eliminates cessations of breathing and snoring. Up to now, there have been no detailed studies of the effects of specific antihypertensive drugs on sleep apnea and/or snoring. These are of special importance with respect to preliminary analyses of correlations between age, sleep apnea, and hypertension indicating that arterial hypertension is an early effect of SRBD [14]. The data are of practical relevance for numerous, mostly younger, patients who require therapy for hypel~ension associated with only a slight degree of SRBD, for which nasal continuous positive airway pressure therapy is not indicated according to current thinking. The drug therapy of hypertension in patients with sleep apnea should be chosen so that the medication does not reinforce existing or potential symptoms and secondary diseases of SRBD. First results of a study with the angiotensinconverting enzyme inhibitor cilazapril are reported here. SRBD AND ARTERIAL HYPERTENSION

Sleep apnea is defined as the cessation of airflow for more than 10 seconds' duration during sleep. A central pattern of sleep apnea refers to a disturbance in the activation of all sets of muscles usually involved in breathing. An obstructive pattern of apnea involves normal activation of the so-called respiratory pump (diaphragm and chest muscles), but impairment of active opening of the oropharynx causes complete oropharyngeal occlusion. In contrast, obstructiv.e snoring indicates an incomplete obstruction of the upper airways. Although it does not impede but only disturbs inspiration, it can be accompanied by pronounced increases of blood pressure (Figure 1). There is epidemiologic evidence for an association between an average of more than 10 apnea phases per hour of sleep time (apnea index greater than 10) and daytime arterial hypertension [8-12]. Epidemiologic examinations of snorers have not included a quantification of snoring but were based on questionnaire

December26, 1989 The AmericanJournal of Medicine Volume87 (suppl 6B)

SYMPOSIUM ON ACE INHIBITORS IN CARDIOVASCULARTHERAPY / PETER ET AL ,-I--

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the Finapress; RC = respiratory chest movements; Abd = respiratory movements of the abdomen.

studies. Probably statements about the occurrence of loud and irregular snoring also cover postapneic snoring of patients, but heavy-snoring patients also constitute a well-recognized group. They are mostly young men, still without a high apnea index, but who nonetheless experience periods during which distinct obstructive snoring and hypertension occur simultaneously. In more than 95 percent of our internal patients with pathologic apnea index values, the pattern of mixed apnea is found. The breathing cessations begin with a short-lived central pattern phase followed by an obstructive phase. Subsequent to apnea, hypoxemia occurs. In relation to long apneas, hypercapnia and acidosis also arise, especially when they are not followed by sufficiently intermittent hyperventilation but instead coincide with hypoventilation. Blood gas level changes can lead to an increase of pulmonary arterial and arterial pressure. A further important causal mechanism may lead to variations of pressure that can alter the blood volume reaching the heart [16]. First studies of the correlation between intrathoracic variations of pressure influenced by apnea and atrial natriuretic peptide concentration in the right atrium reveal an increased release of atrial natriuretic peptide at night in apnea patients. Precise ideas about the correlation of acute blood pressure changes at night and increased releases of atrial natriuretic peptide with the causation of arterial hypertension are still the subjects of discussion. One possible cause is the exhaustion of the atrial natriuretic peptide mechanism and/or the interaction of atrial natriuretic peptide with other blood pressure-regulating hormones [17,18]. The influence of catecholamine release and increased sympathetic tone that occurs in relation to

the fragmentation of sleep seems to be an eventual cause [19]. Apnea phases and obstructive snoring may be terminated by central alarm reactions that produce so-called micro-arousals in the frame of a central nervous activating reaction allowing blood gases to be balanced again by intermittent hyperventilation. At the same time, however, repeated arousals mean a disturbance of the physiologic sleep structure. It seems plausible that this permanent sleep disturbance contributes to the development of hypertension in patients with SRBD [20]. Table ! illustrates the pathophysiologic correlations that are relevant for sleep apnea and snoring to the TABLE I Most Important Predisposing Factors for SRBD, Modifying Factors, and Pathomechanisms of Sleep Apnea and Consequences Predisposingfactors Predispositionfor SRBD(genetic?degenerative?hormones,etc.)

Modifyingfactors Anatomical

Pharmacologic Behavioral

Pathomechanismsinsleepapnea Oropharyngealobstruction Hypoventilation Arousal

Consequences Arterialhypertension Increasedpulmonaryarterialpressure Noctomatcardiacard'~hmias

Snoring

December 26, 1989 The American Journal of Medicine Volume87 (suppl 6B)

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SYMPOSIUM ON ACE INHIBITORS IN CARDIOVASCULAR THERAPY / PETER ET AL

dromes are therefore just the tip of the iceberg. Patients with a less distinct apnea usually do not take the trouble to seek nocturnal respiratory therapy. Moreover, when such treatment is necessary in cases of slight to moderate severity is not clearly defined. In our outpatient department, we are treating one third of the cases with nocturnal home ventilation and two thirds with advice on behavior and drug therapy relating to hypertension. The only specific respiratory drug therapy we are using is theophylline. Antihypertensive agents given should not enhance the common unwanted effects associated with sleep apnea listed in Table II.

TABLE II Symptoms and Findings in Patients with Sleep Apnea that Should Not Be Reinforced by Antihypertensive Drugs . Oifflcoltiesin maintainingconcentration,daytimesleepiness * Myocardialinsufficiency , Cardiacarrhythmiasandblocks * Lipometabolicdisorders o Hemoconcentration

same extent and supposedly contribute to the development of arterial hypertension in patients with these disorders. Of special importance are oropharyngeal obstruction, hypoventilation, and arousals. Conduct of life, drugs, and anatomical conditions can have modifying effects on single pathophysiologic factors. Complex clinical pictures that are causally correlated with sleep apnea are called sleep apnea syndromes. In case of sufficiently early diagnosis and therapy (e.g., nasal continuous positive airway pressure therapy [21]) all symptoms and secondary diseases are completely reversible. This is also the case with arterial hypertension [22]. Psychic changes seen during the daytime after sleep is disturbed chronically by breathing disorders are commonly reported. They appear as depressive disposition, decrease in vitality, intolerance towards monotony, irritation, lack of concentration, daytime tiredness to the extent of compulsion to sleep, headache in the morning, or impotence. In addition, objective signs of arterial hypertension can often be manifested: mostly nocturnal cardiac arrhythmias, pulmonary arterial hypertension, shortened sleep latency, loud and irregular snoring, nocturnal sweating, overweight, metabolic disorders, and, rarely, polycythemia. The individual symptoms and findings can occur in different combinations. Distinct sleep apnea syn-

PATIENTS

AND

METHODS

This study attempted to investigate the suitability of the angiotensin-converting enzyme inhibitor cilazapril for antihypertensive treatment of patients who have hypertension and sleep apnea concomitantly. We planned to perform a double-blind study in 24 patients with sleep apnea and essential hypertension using 2.5 mg cilazapril or 100 mg metoprolol with respect to blood pressure, breathing, and sleep. When the results became available for the first 12 patients entered in the trial, the code was broken with respect to the subjects. We present here results from the first six patients treated with cilazapril. This interim evaluation was intended to help us to decide whether to continue the study. The subjects were six men aged 43 to 66 years (Table III). The average age was 53 years; the Broca index lay between 106 and 167 with a mean of 124. The apnea index in two ambulatory measurements without therapy was greater than 10 on each occasion; the diastolic blood pressure values were 95 to 108 mm Hg in repeated measurements. The patients were monitored for two nights in the sleep laboratory while receiving no therapy. Six days of hospitalized treatment with a morning dose of 2.5 mg cilazapril followed.

TABLE III Blood Pressure (indirect), Respiration, and Sleep before and after Therapy with 2.5 mg Cilazapril Blood Pressure (mm Hg) RR Systolic

RR Diastolic

RDI/Hour

Sleep

Average

Range

Average

Range

Average

Range

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159

138-210

95-108 60-94

31

12-77 2-54

19

] ]3-163

102 78

360

132

314

23

Before After

20

% REM

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Non-Rapid Eye Movement Sleep

Rapid Eye Movement Sleep

Average

Range

Average

Range

Average

Range

154

132-181

133-177 143-115

138-180

119-150

149 127

151

130

133

118-152

92

83-103

75

62-92

90 77

85-100 64--97

92 82

83-104 6%105

Systolic

Before After Diastolic Before After *All valuesare in mm Hg. 6B-74S

December 26, 1989 The American Journal of Medicine Volume 87 (suppl 6B)

SYMPOSIUM ON ACE INHIBITORS IN CARDIOVASCULAR THERAPY/PETER ET AL

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Then two nights of control measurements in the sleep laboratory were undergone, during which time cilazapril was given in the evening. In addition to polysomnographic measurements made dining the nights, 2A-hour blood pressure profiles, derived invasively, were recorded during the two following days. We used a portable invasive blood pressure measurement system developed by the Brunel Institute of Technology in cooperation with Oxford Medicine Technique. It is the size of one and a half packages of cigarettes and is equipped with a pressure receiver connected to the liquid column of a catheter. The system is able to transform pressure changes into electlic signals. An integral liquid reservoir together with a pump allows constant rinsing of the small catheter (1-mm diameter and 100-mm length). The catheter, using a sterile technique, is inserted in the nondomi-

nant arm proximal to the bend of the elbow as far as possible into the arteria brachialis. The measuring and rinsing unit contained in a cloth bag is tied around the patient's neck and also fixed around the abdomen. The pressure receiver lies on a level with the right atrium. The receiving unit consists of an Oxford Medilog Recorder 4:24 and is equipped with a commercial C120 tape cassette. Every 12 hours the functional ability is controlled and adjusted. The receiver registers blood pressure 2 mm/second and enables continuous registration for 24 hours. On a second channel, an electrocardiogram is recorded. Dining the night, the following additional measurements were obtained under polysomnographic aspects: electroencephalogram, electrooculogram, electromyogram, two-channelbreathing derivation by inductive plethysmography,

December 26, 1989 The American Journal of Medicine Volume 87 (suppl 6B)

61]-758

SYMPOSIUM ON ACE INHIBEORS IN CARDIOVASCULAR THERAPY/PETER ET AL

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December 26, 1989 The American Joumal of Medicine Volume 87 (suppl 6B)

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Figure 5. Sleep stage and electroencephalogram Fourier Transformation (alpha, delta, and sigma) in comparison with arterial blood pressure of a patient with distinct sleep apnea. Before therapy with 2.5 mg cUazaprU for six days, frequent increases of systolic blood pressure (BP sys) of more than 160 mm Hg occurred during the second part of the night. (A mean value of 15 seconds of blood pressure and heart rate [HR] measurements was calculated.) BP mean = mean blood pressure; BP dias = diastolic blood pressure.

SYMPOSIUM ON ACE INHIBITORS IN CARDIOVASCULAR THERAPY / PETER ET AL

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Figure 6. Sleep stage and electroencephalogram Fourier Transformation (alpha, delta, and sigma) in comparison with arterial blood pressure of the same patient whose data is illustrated in Figure 5. After therapy with 2.5 mg cilazapril for six d,~ys, arterial blood pressure remained below ]60 mm Hg. (A mean value of 15 seconds of blood pressure and heart [HR] measurements was calculated.) BP sys= systolic blood pressure; BP mean = mean blood pressure; BP dies = diastolic blood pressure.

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transcutaneous oxygen saturation, and heart rate. Sleep stages were evaluated according to Rechtschaffen and Kales [23]. Blood pressure values are related to sleep stages per minute. The mean value per stage was calculated. The electroencephalogram was also analyzed continuously in relation to the following spectral components: alpha-band, delta-band, and sigma-band [24]. The power in the single electroencephalogram bands, the sleep stages derived according to Rechtschaffen and Kales [23], blood pressure, and heart rate in 15second intervals are depicted for sleep stages on one plot. RESULTS The results are summarized in Table III and Table IV. Indirect blood pressure measurement revealed a decrease in the systolic blood pressure of 27 mm Hg and in the diastolic blood pressure of 24 mm Hg. Direct blood pressure measurement in the night indicated a less distinct average decrease of blood pressure under therapy with 2.5 mg cilazapril: systolic blood pressure was reduced 24 mm Hg in the waking stage, 22 mm Hg in non-rapid eye movement sleep, and 18 mm Hg in rapid eye movement sleep. Diastolically, blood pressure was reduced 17 mm Hg in the waking stage, 13 mm Hg in non-rapid eye movement sleep, and 10 mm Hg in rapid eye movement sleep. Figure 2 shows a continuous analogue recording example of respiration and blood pressure before therapy. Nocturnal systolic blood pressure increases to

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more than 200 mm Hg and the diastolic blood pressure to more than 120 mm Hg during distinct apnea phases in rapid eye movement sleep. Figure 3 shows the directly measured arterial blood pressure and momentary heart rate in the same patient after morning intake of 2.5 mg cilazapril. Figure 4 shows the directly measured arterial blood pressure and heart rate of the same patient after evening intake of 2.5 mg cilazapril. In neither case (morning and evening intake) does the nocturnal blood pressure increase occur after therapy. Figure 5 shows for the same patient the relation between blood pressure and sleep (top) and blood pressure and heart rate (bottom). The recordings show clearly on the one hand the disturbed sleep structure in the electroencephalogram analysis, and on the other hand the blood pressure increases and variations, especially in rapid eye movement sleep in the second half of the night. This patient rarely shows deep sleep at stages 3 and 4. Figure 6 shows the equivalent recordings for the same patient after morning intake of 2.5 mg cilazapril. Despite extended rapid eye movement sleep.phases and ongoing blood pressure variations caused by sleep apnea, the increases of hypertension in the second half of the night have ceased. COMMENTS Adequate blood pressure lowering was achieved by the intake of 2.5 mg cilazapril in the six patients with concomitant hypertension and sleep apnea. Total sleep

December 26, 1989 The American Journal of Medicine Volume 87 (suppl 6B)

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SYMPOSIUM ON ACE INHIBITORS IN CARDIOVASCULAR THERAPY/PETER ET AL

time decreased by about 44 minutes. The results might have been due to the unspecific effects of hospitalization. The same explanation might apply to the • decrease in apnea index from 31 to 20. The relative share of rapid eye movement sleep increased from 19 to 23 percent. Therefore, sleep structure was not influenced adversely by the angiotensin-convhrting enzyme inhibitor. In one case of extended sleep apnea, we have demonstrated the therapeutic effect of 2.5 mg cilazapril on the nocturnal increase of blood pressure occurring under apnea even after morning intake of cilazapril. This interim evaluation supports continuation of the double-blind study. Questions to be considered at the final evaluation include: what specific differences are there between the profiles of cilazapril and metoprolol, and what effects such as, for example, the reduction of total sleep time or the decrease of the apnea index are due to unspecific factors like hospitalization?

REFERENCES 1. Lugaresi E, Cirignotta F, Montagna P: A clinical approach to heavy snorers disease and other Sleep related respiratory disorders. In: Peter JH, Podszus T, von Wichert P, eds. Sleep related disorders and internal diseases. Berlin: Springer, 1987; 201-210. 2. Peter JH, Hess U, Hirnmelmann H, eta/: Sleep apnea activity and general morbidity in a held study. In: Peter JH, Podszus T, von Wichert P, eds. Sleep related disorders and internal diseases. Berlin: Springer, 1987; 248-253. 3. Schmidt-Nowara WW, Wiggins CL, Walsh JK: Prevalence of sleepiness in an adult population. In: Peter JH, Penzel T, Podszos T, yon Wichert P, eds. Sleep and health risk. Berlin: Springer, 1989 (in press). 4. Cirignotta F, D'Allesandro RD, Partinen M, eta/: Prevalence of every night snoring and sleep apneas among 30-69 year old men of Bologna, Italy. In: Peter JH, Penzel T, Podszus T, von Wichert P, eds. Sleep and health risk Berlin: Springer, t989 (in press). 5. Gislason T, Bj6rnsson J, Benadildsdottir B. Gudrnundsson J, Kristbjamarson H, Thorleifsdottir B: Prevalence of sleep complaints among middle aged women. In: Peter JH, Penzel T, Podszus T, von Wichert P, eds. Sleep and health risk. Berlin: Springer, 1989 (in press). 6. Stradling JR, Thomas G, Freeland A: Daytime hypoxaemia, sleep disturbance, nocturnal hypoxaemia and retarded growth in young children who snore (before and after adenotonsillectomy) compared to control children. In: Peter JH, Penzel T, Podszus T, yon Wichert P, eds. Sleep and health risk. Berlin: Springer, 1989 (in press). 7. Lugaresi E, Cirignotta F, Coccagna G, Piana C: Some epidemiological data on snoring

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and cardiovasculatory disturbances. Sleep 1980; 3: 22]-224. 8. Retcher EC, DeBehnke RD, Lovoi MS, Gorin AG: Undiagnosed sleep apnea in patients with essential hypertension. Ann Intern Med 1985; 103: 190-195. 9. Kales A, Cadieux P-J, Shaw LC III, eta/: Sleep apnoea in a hypertensive population. Lancet 1984; I1: 1005-]008. 10. Lavie P, Ben-Yosef R, Rubin A: Prevalence of sleep apnea syndrome among patients with essential hypertension. Am Heart J ]984; ]08: 373-376. 11. Peter JH, Bolm-Audorff U, 8ecker E, et al: Schlafapnoe und essentielle Hypertonie. Verh Dtsch Ges Inn Med, 1983; 89:. ] 132-1135. 12. Peter JH: Hat leder dritte Patient mit essentieller Hypertonie ein undiagnostiziertes Schlafapnoe-Syndrom? Dtsch Med Wochenschr 1986; ] 11: 556-559. 13. Mayer J, 8ecker H, Brandenburg U, et al: Hemodynamic changes in patients with sleep apnea after therapy with nCPAP (nasal continuous positive airway pressure) (abstr). Sleep Res 1988; 17: 216. 14. Peter JH: Sleep apnaa and cardiovascular diseases. In: Guilleminault C, Partinene M, eds. Diagnosis and treatment of the sleep apnea syndromes. New York Raven, 1989 (in press). 15. Penzel T, Peter JH, Schneider H, Stott FD: The use of a mobile sleep laboratory in diagnosing sleep related breathing disorders. J Med Eng Technol 1989; 13: 100-103. 16. Podszus T: Pulmonale Hypertonie be] AtemregulationsstOrungen. Internist 1988; 29: 681-687. 17. Ehlenz K, Peter JH, Podszus T, eta/: Changes in volume and pressure regulating hormone systems during nasal CPAP therapy in patients with obstructivesleep apnea syndrome. In: Peter JH, Penzel T, Podszus T. yon Wichert P, eds. Sleep and health risk Berlin: Springer, 1989 (in press). 18. Kneger J, Barthelmebs M, Slorza E, Imbs JL, Lehr L, Kurtz D: Hormonal factors in volume regulation in obstructive sleep apnea patients. In: Peter JH, Penzel T, Podszus T, yon Wichert P, eds: Sleep and health risk. Berlin: Springer, 1989 (in press). 19. Ehlenz K, Kohler U, Mayer J, Peter JH, von Wichert P, Kaffarnik H: Plasma levels of catecholaminas and cardiovascular parameters during sleep in patients with sleep apnea. In: Peter JH, Podszus T, von Wichert P, eds. Sleep related disorders and internal diseases. Berlin: Springer, 1987; 32]-325. 20. Siegdst J: Sleep disturbances and cardiovascular risk: a biopsychosocial approach. In: Peter JH, Podszus T, von Wichert P, eds. Sleep related disorders and internal diseases. Berlin: Springer, 1987; 173-182. 21. Becker H, Koehler U, Peter JH, Steinberg M, yon Wichert P: Effectiveness and sideeffects of nasal continuous positive airway pressure therapy in 66 patients with sleep apnea. In: Karczewski WA, Gdeb P, Kulesza J, 8onsignore G, eds. Control of breathing dudng sleep and anaesthesia. Warschau: Plenum, ]988; 39-42. 22. Mayer J, Herres-Mayer B, We]chief U, eta/: Sleep, sleep related breathing disorders and arterial hypertension. In: Peter JH, Penzel T, Podszus T, von Wichert P, eds, Sleep and health risk Berlin: Springer, 1989 (in press). 23. Rechtschaffen A, Kales A: A manual of standardized terminology, techniques and scodng system for sleep stages of human subjects. (Public Health Service Publication 204.) Washington, D.C.: United States Government Printing Office, ]968. 24. Penzel T, Petzold J: A new method for the classification of subvigil stages using the fourier transform and its applications to sleep apnea. Comput Biol Med 1989; 19: 7-34.

Volume 87 (suppl 6B)