u
REVIEW
Sleep Apnea and Systemic Hypertension: A Causal Association Review VICTORHOFFSTEIN,M.D.,CHARLESK.CHAN,M.D.,ARTHURS.SLUTSKY,M.D., Toronto,
Ontario,
Canada
OELJJZCTLVE: To critically examine the causal association between sleep apnea syndrome and hypertension. METHODS: A retrospective systematic critique of five epidemiologic studies published in the English literature during 1978 to 1989 identified on Medline and manual literature searches. The evidence was evaluated using the standard observational criteria for causation strength of association, consistency, dose-response relationship, temporal sequence, specificity, and biologic plausibility. RESULTS: We found evidence to support a causal association between sleep apnea syndrome and hypertension in consistency and specificity and some evidence to suggest a dose-response relationship. Review of the data dealing with the mechanisms important in the pathogenesis of sleep apnea and hypertension allowed us to advance several theories to provide support for biologic plausibility. CONCLUSION: We concluded that there is a positive association-relative risk estimate between 1.3 and IO--for sleep apnea syndrome and hypertension, but the risk association is uustable. Thus, we believe that there is insufficient data to justify doing polysomnography as part of the routine diagnostic work-up for patients with hypertension.
From the Divisions of Respiratory Medicine, Departments of Medicine, St. Michael’s (VH), Wellesley &KC). and Mount Sinai Hospitals (ASS), University of Toronto, Toronto, Ontario, Canada. Requests for reprints should be addressed to Charles K. Chan, M.D., 160 Wellesley Street East, Suite 242, Toronto, Ontario, Canada M4Y lJ3. Manuscript submitted November 7. 1990, and accepted in revised form April 22, 1991.
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H
ypertension affects 20% of the adult population and is a major risk factor for the development of cardiac and cerebral events. Although our understanding of the mechanisms producing hypertension has increased greatly over the past 20 years, in the majority of cases no underlying etiology is identified [l]. One of the diseases that has been associated with systemic hypertension is the sleep apnea syndrome (SAS) [2-lo]. A number of prospective studies involving patients with severe sleep apnea [2,3] have clearly demonstrated significant hemodynamic changes during apneic episodes. Thus, it is widely believed that significant cardiovascular end-organ damage and systemic hypertension result when sleep apnea is not recognized and thus is untreated. The exact incidence of SAS is unclear, but it has been estimated to be present in more than 1% of the adult population [4]. One can argue that if SAS has an important causal association with systemic hypertension, then it may be necessary to include appropriate investigations for the presence of sleep apnea in the routine work-up of patients with systemic hypertension. This approach obviously has significant implications for the health care delivery system because diagnostic work-ups using polysomnographic sleep studies are very expensive, in contrast to the usual screening investigations used in the routine assessment of patients with systemic hypertension. The mere fact that systemic hypertension is a very prevalent disease in North America means that any additional expensive diagnostic work-up will not be readily accepted by most patients, physicians, or third-party insurance carriers unless a firm causal association can be established. Although hypertension is known to be a prevalent co-morbid disease in patients with SAS [2], systematic investigations of the causality between SAS and systemic hypertension have not gained a great deal of attention in the last two decades. Given the availability of effective therapy for obstructive sleep apnea, it becomes necessary to address the question of causal association between SAS and systemic hypertension in order to determine if screening for SAS should be done routinely in the hypertensive population. The purpose of this critique is to appraise the available epidemiologic evi-
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dence for a causal association systemic hypertension.
between
d
SAS and
Summary of Studies Used to Exammethe RelatIonshIpBetween Sleep
MATERIALS AND METHODS Literature Search Computerized and manual literature searches were conducted and we identified five epidemiologic studies published in the English literature during 1978 to 1989 that addressed the causal association between SAS and systemic hypertension [5-91. The literature search was conducted using Grateful Med software applied to the National Library of Science MEDLINE database.
Reference
Epidemiologic Studies of Sleep Apnea and Systemic Hypertension A case-control approach using hypertensive patients as the cases and normotensive patients as the controls was the study design used in four of the investigations [5-81. The other study [9] employed a cross-sectional design aimed at estimating the prevalence of SAS among patients with essential hypertension. Four of the studies were done in the United States [5-81 and one was done in Israel [9]. The hypertensive patients or cases in these studies were primarily recruited from hypertensive clinics. The control subjects were normotensive patients who were referred to the sleep laboratory for various investigations or patients who were admitted to other services in the hospital. All the cases and controls were studied using polysomnographic sleep studies. One of the difficulties encountered in attempting to use the aforementioned studies to examine the association between sleep apnea and hypertension is the lack of a uniform definition of sleep apnea. Williams et al [8] used an apnea index (defined as the number of apneic events per hour) greater than 5 to define sleep apnea. Lavie et al [9] used an apnea index greater than 10 to separate apneic from nonapneic patients. Hirshkowitz et al [5] presented their data using several apneic cutoffs (5, 10, and 15). Kales et al [6] divided their hypertensive and normotensive patients into groups based on the total number of apneic episodes per night, rather than on the apnea index. Fletcher et al [7] used an apnea index greater than 10 as the apnea cutoff. Consistent analysis of these studies requires the adoption of a uniform definition of sleep apnea. We selected two commonly used apnea indices (5 and 10) to divide the population into apneic and nonapneic groups. With these definitions, the studies of Hirshkovitz et al [5] and Lavie et al [9] could be used directly. The data of Williams and co-workers [8], Fletcher et al [7], and Kales and colleagues [6] could not be used directly, because these authors
n
Hypertensives Al >5 Al>10
n
Normotensives Al>5 Al>10
defined sleep apnea based on apnea indices of 5 [8] or 10 [7] or on the total number of apneic events per night [6]. However, all of the authors assumed a normal distribution of the apnea indices and summarized their data by reporting means, standard deviations, or standard errors. We used the normality distribution of the raw data to re-classify the number of subjects likely to have apnea indices greater than our pre-selected cutoffs of 5 and 10. Table I summarizes the five studies, indicating the number of hypertensive and normotensive subjects with apnea indices greater than 5 and greater than 10. Unlike the explicit criteria that were chosen for the diagnosis of SAS in all five studies, the definition of hypertension was not only variable but not stated in two studies [6,8]. Hypertension was defined as a diastolic blood pressure of greater than 90 mm Hg or a systolic pressure greater than 160 mm Hg by Hirshkowitz et al [5], diastolic greater than 95 mm Hg and systolic greater than 160 mm Hg by Lavie and co-workers [9], and diastolic greater than 90 mm Hg or systolic greater than 140 mm Hg for men under the age of 45 years and diastolic above 95 mm Hg for men over 45 years by Fletcher et al [7]. The data presented in each study were insufficient to stratify the study groups into normotensive and hypertensive subgroups using a uniform criterion. Since the patients included in the five studies are primarily men and the racial representation is poorly distributed, we cannot address the interesting issues regarding gender and race on the causal association between SAS and hypertension. Criteria for a Causal Association The five investigations being reviewed are clinical epidemiologic studies, which are different from experimental investigations, and thus we cannot use the conventional experimental criteria for causation (Henle-Koch postulates) to establish causality. An acceptable substitute would be to apply six observational or epidemiologic criteria for causation. These criteria are: (1) strength of association,
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range from 1.3 to 23 (Table II). Similarly, using a more conservative and perhaps more appropriate cutoff of more than 10, the strength of the association is also quite variable; results of the four studies show odds ratios from 1.5 to 40 (Table II). The cross-sectional study by Lavie et al [9] did not have any control subjects but nevertheless found a prevalence of 26% using an apnea index greater than 5, and 22% using an apnea index greater than 10, among the group of 50 patients with hypertension. This prevalence is substantially higher than the 1.26% of men older than 21 who are estimated to have SAS [ll].
TABLE II Strength of Associationand ConsistencyBetween Sleep Apnea and Hypertension Reference [51
StudyDesign Case-control
n
Al
285
>5 >lO >5 >lO
[61
Case-control
100
[71
Case-control
80
[81
Case-control
[91
Case-series
31 50
Odds Ratio 1.3 1.5 :i
>5
1.8
>I0
4.5
95% Cl 0.8-2.1 0.8-2.8
4.9-108 6.3-255 0.7-4.5 1.3-16
>5
15.6
1.4-170
>lO
13.2
1.2-152
26%, no control 22%, no control
>5
>lO
= apnea index; 95% Cl = 95% confidence interval of the odds ratio.
TABLE Ill Severityof Sleep Apnea Syndrome Correlateswith the Severity of Hypertension 161 Numberof ApneicEvents 30-99 loo-380
n
MeanArterial Blood Pressure(mm tlg)
z
129.4 * 7.4 162.0 + 8.3
(2) consistency, (3) dose-response relationship, (4) temporal sequence, (5) specificity, and (6) biologic plausibility. Findings of the five epidemiologic studies of SAS and systemic hypertension will be presented in accordance with these six criteria for causation.
RESULTS Strength of Association The study design, the estimates of relative risk, and the odds ratios for the five studies are summarized in Table II, using two different apnea cutoffs. Relative risk is defined as the incidence of hypertension in the sleep apnea group divided by the incidence of hypertension in the non-apneic group. The odds ratio is defined as the odds in favor of hypertension in the apnea group divided by the odds in favor of hypertension in the non-apneic group. Obviously, the lower the cutoff in terms of the apnea index, the higher the prevalence of SAS in the study population. Using a lower cutoff may increase the chance of finding an association between SAS and hypertension but that association may not be specific, i.e., it may reflect common causative factors for both SAS and hypertension such as obesity [lo], rather than indicating causality between SAS and hypertension. Using an apnea index greater than 5, the odds ratios of the four studies [5-91 192
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Consistency Perfect consistency would include all studies having an odds ratio greater than 1, with all the corresponding confidence intervals excluding 1. Unfortunately, due to the small sample sizes in most studies, not all the reported 95% confidence intervals are considered statistically significant (Table II). Despite the wide range of odds ratios, five of the eight relative risk estimates are statistically significant at a p = 0.05 level (Table II). Depending on the choice of the apnea index cutoffs and variable sample sizes, the 95% confidence interval may not necessarily avoid 1. Although three of the odds ratios were not significant [5,7], it should be emphasized that all odds ratios reported to date, irrespective of the choice of apnea index cutoffs, are more than 1. Therefore, all five studies on the association between SAS and systemic hypertension are consistent. Dose-Response Relationship No specific epidemiologic study was designed to address the issue of a dose-response relationship between SAS and systemic hypertension. Nevertheless, based on the available evidence, one can gain some insight into such a possible relationship. One approach to investigating a dose-response relationship is to evaluate a group of patients with SAS and to classify their apnea as mild, moderate, or severe, based on clinical, laboratory, and polysomnographic data. If there is indeed a causal association between SAS and systemic hypertension, one would expect to show that the more severe the sleep apnea, the more prevalent and perhaps severe would be the hypertension and vice versa. Analysis of the data collected by Kales et al [6] (Table III) shows that patients with 30 to 99 apneic events per night (apnea index between 5 and 15) had a mean arterial blood pressure of 129 mm Hg, which was significantly lower than the 162 mm Hg observed in patients with more than 100 apneic events per night (apnea index greater than 15).
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An alternative approach to assessing the doseresponse relationship is to compare the odds ratio in the controlled hypertensive population versus that in the refractory hypertensive population. If SAS is responsible for the difficulties in the control of hypertension in some patients, then one would hypothesize that the refractory group of patients should show a higher prevalence of sleep apnea and thus have a higher odds ratio. The data provided by Hirshkowitz et al [5] does show such a relationship. In the hypertensive group in which the blood pressure was well controlled, the odds ratio was 0.9, in contrast to the refractory hypertensive group where the odds ratio was 2.2 (Table IV). Using a higher cutoff, an apnea index greater than 10, the controlled hypertensive group had an odds ratio of 1.8, and the refractory group had an odds ratio of 3.2. A similar conclusion can be drawn from the data of Fletcher and co-workers [7] in Table II. However, the dose-response pattern was by no means consistent in all five studies [5-g], with contradictory data from two of them [8,9]. It is prudent to point out that the evidence discussed is very preliminary. Although the overall data seem to support an argument for the existence of a dose-response relationship between SAS and systemic hypertension, they by no means establish a relationship. Temporal Sequence Thus far, no prospective or longitudinal followup study of cohorts of patients with and without SAS is available; thus, there is no evidence to support a temporal sequence argument for either SAS causing hypertension or hypertension eventually resulting in SAS. Such a natural history study to demonstrate the temporal sequence may become increasingly difficult to do because almost all hypertensive patients will be treated, and with the availability of continuous positive airway pressure for the treatment of obstructive sleep apnea, it becomes more difficult to assemble a meaningful cohort of patients with mild-to-moderate obstructive sleep apnea who will simply be followed with repeated polysomnographic and hemodynamic studies over a period of years to document the development of systemic hypertension with untreated SAS. Thus, the epidemiologic evidence to support a temporal sequence argument may be dependent on creative retrospective-prospective studies. A recent example of such an investigation is the retrospectively assembled but prospective follow-up study of 198 patients with obstructive sleep apnea by Partinen and Guilleminault [12]. That study provided some clues to the natural history of SAS because there were 127 conservatively treated patients with
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ET AL
TABLE IV RefractoryHypertensive Patients Are More Likely to Have Sleep Apnea Syndrome Al >5 Controlled Refractory
0.9 (0.3-2.4)* 2.2 (1.0-4.5)
Al >lO 1.8 (0.6-5.1) 3.2 (0.4-7.0)
Al = apnea index. *Ninety-five percent confidence interval of the odds ratio.
obstructive sleep apnea in the cohort. One of the conservatively treated patients with obstructive sleep apnea developed hypertension after 7 years of follow-up. The incidence is obviously low, and since there was no concurrent control group, the evidence is insufficient to support a temporal sequence argument. Specificity If SAS causes systemic hypertension, then successful treatment of the sleep apnea should lead to normalization of the blood pressure without any other interventions. Among the five epidemiologic studies reviewed, the one that has provided data to support the specificity argument is that by Fletcher et al [7]. In a selected subgroup of eight patients with significant obstructive sleep apnea, with apnea indices ranging from 13.6 to 91.1 and a mean of 32.5 at the time of diagnosis, therapy for sleep apnea was given and these patients were re-evaluated after treatment. The mean arterial blood pressure at the time of diagnosis but prior to any specific therapy given for apnea was 149/95 mm Hg. Therapy consisted of protriptyline in seven and uvulopalatopharyngoplasty in the remaining patient. All eight patients were restudied using polysomnography after 2 months of therapy or surgery. The apnea index was substantially reduced to a mean of 7.4, and the mean arterial blood pressure decreased to 139/90 mm Hg. Although the sample size was small, these results were statistically significant using a paired t-test analysis. With the widespread availability of nasal continous positive airway pressure therapy for obstructive sleep apnea, this type of study in patients with obstructive sleep apnea and hypertension can be readily repeated. Therefore, one should expect more definitive evidence on the specificity of this causal association in the very near future. Biologic Plausibility Based on the current studies [2,13,14] of hemodynamic changes in patients with obstructive sleep apnea, it is possible to advance several theories and hypotheses to link SAS with hypertension. These
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biologic plausibilities include: (1) essential hypertension causes sleep apnea, (2) sleep apnea causes essential hypertension, and (3) both diseases are caused by some common underlying mechanism(s). ESSENTIALHYPERTENSIONCAUSESSLEEPAPNEA:
One hypothesis to explain the pathophysiology of obstructive sleep apnea is that it is due to instability of the respiratory control system. Within the context of this hypothesis, increased drive from arterial chemoreceptors in patients with essential hypertension causes instability in the respiratory control system, thus leading to repeated apneic episodes [15]. Although this is an attractive hypothesis, it does present some difficulties in explaining why treatment of sleep apnea normalizes blood pressure [7], while treatment of essential hypertension does not usually result in the resolution of the sleep apnea [5]. However, such data cannot be used to reject the hypothesis conclusively because abnormal respiratory control may cause both hypertension and sleep apnea. The latter, in turn, may lead to a further elevation of blood pressure; therefore, treatment of sleep apnea may result in partial normalization of the blood pressure. On the other hand, treatment of hypertension may not improve sleep apnea because pharmacologic normalization of the blood pressure may not necessarily alter the abnormality in respiratory control. An alternative hypothesis is that drugs used to treat hypertension can cause sleep apnea because a number of medications, usually sedating medications, can worsen sleep apnea. However, this seems unlikely to be the major factor since many patients who present with SAS are not taking antihypertensive medications at the time of presentation, and medical treatment of hypertension does not seem to increase the severity of sleep apnea. SLEEPAPNEACAUSESHYPERTENSION: Therearea number of theoretic mechanisms by which SAS can produce systemic hypertension. One obvious factor is the recurrent episodes of hypoxemia [14]. Apneic periods are often associated with a significant drop in oxygen saturation that can be profound, reaching levels of saturation below 60% (representing arterial oxygen tension below 30 mm Hg); these episodes of oxygen desaturation can occur hundreds of times per night. In addition to hypoxemia, apneic events are accompanied by a rise in the arterial partial pressure of carbon dioxide. This combination of hypoxemia and hypercapnia would lead to excitation of the arterial chemoreceptors, causing increased sympathetic discharge and resulting in increased pulmonary and systemic pressures [X-18]. Cardiac contractility and heart rate are also stimulated and increased. In accordance with this hypothesis, re-
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cent observations that hypertensive patients with sleep apnea have double the hypoxic ventilatory response compared with normotensive sleep apnea patients are interesting supportive evidence [18]. Furthermore, increased sympathetic activity and elevated catecholamine levels seen during apneic events may also contribute to hypertension [19-221. There is no doubt that clear-cut episodes of pulmonary and systemic hypertension frequently occur during apneic events in patients with severe sleep apnea [2,3]. It is possible that repeated stimulation of the arterial chemoreceptors during hypertensive periods produces sympathetic discharges that prolong the peripheral effect into the daytime. In accord with this hypothesis is a study showing that hypertensive patients with sleep apnea have elevated daytime levels of epinephrine, as well as an absence of diurnal variation in the level of urinary catecholamines, which suggests that these patients have increased sympathetic activity while they are awake and during sleep [22]. These abnormalities disappear after correction of sleep apnea by tracheostomy [22]. A further mechanism linking hypertension with SAS may be abnormal renal function. Nephrotic syndrome, proteinuria, and increased urinary sodium excretion have been observed in patients with SAS [23-261. Furthermore, a recent international multicenter study showed that urinary sodium levels are directly related to elevations in blood pressure [27]. Thus, impairment in renal function resulting from sleep apnea may account for the elevated blood pressure found in some patients. Although the precise factors that cause termination of apneic episodes are not known with certainty, many episodes terminate coincidentally with arousal from sleep. Thus, patients with severe obstructive sleep apnea can have hundreds of arousals every night. Possibly, the sequelae of these arousal events may be sustained daytime hypertension, perhaps also via a sympathetic mechanism. COMMONUNDERLYINGMECHANISMS: One of the common factors accounting for the association between SAS and essential hypertension may be obesity [lo]. Although not all patients with idiopathic obstructive sleep apnea are obese, a high percentage of patients with severe obstructive sleep apnea have markedly elevated body mass indices. Several studies have demonstrated that body mass index is an independent determinant of sleep apnea [lo]. Similarly, obesity is associated with hypertension, perhaps via an abnormality in insulin metabolism [28]. It is thus possible that the association between SAS and essential hypertension may very well be confounded by the fact that obese patients are more
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likely than non-obese patients to have both of these relatively common conditions. To elucidate the relationship between obesity, sleep apnea, and hypertension, further careful measurements of blood pressure in apneic and non-apneic subjects matched for weight and body mass index are required. A recent study by Escourrou et al [29] indicates that hypertension in patients with sleep apnea is not directly related to weight or body mass index. If SAS and hypertension are linked, and since hypertension is a well-known risk factor for increased mortality, we might expect that SAS would also be associated with higher mortality. Although prospective epidemiologic studies demonstrating an increased mortality rate in SAS are still lacking, there is evidence suggesting the existence of a direct relationship between the apnea-hypopnea index and mortality [13].
COMMENTS Studies reporting a causal association between SAS and hypertension may all be challenged on several grounds including possible assembly bias in the selection of patients from hypertensive clinics, inappropriate choices of apnea indices for the definition of SAS, poor or absent criteria for the definition of hypertension, and a lack of adequate matching for weight or body mass index [5-g]. A fastidious approach would be to criticize the evidence accumulated to date and maintain the position that the causal association cannot be addressed based on the currently available evidence. This approach was chosen in two prior epidemiologic reviews on the association between snoring and vascular disease [30] and the co-morbidity between sleep apnea and hypertension [31]. Our pragmatic approach is to review the best available evidence and interpret the results using the generally accepted epidemiologic criteria for a causal association. Subanalysis of the available data also allowed us to provide evidence under most of these different criteria. It is evident based on the available data that there is at least a modest association between SAS and essential hypertension. If one were to choose an apnea index cutoff of 30, which is considered clinically significant by all workers in this field, one may very well find a higher odds ratio but a much larger sample of hypertensive patients would have to be included in the study. Using a conventional apnea cutoff of 10, the relative risk estimates from the studies range from 1.5 to 40. Although statistical significance is not necessarily achieved in all the reported studies, the consistency of the association is clearly established among the various centers.
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/ HOFFSTEIN
ET AL
Due to the lack of prospective or longitudinal data, temporal sequence cannot be addressed based on the current evidence. Nevertheless, specificity suggesting that SAS causes hypertension is nicely supported by subanalysis of the data available from some of these studies. There are certainly numerous theories to provide support for biologic plausibility for the causal association between SAS and hypertension. This is clearly the area where further work is required if elucidation of the mechanism(s) of the association is to be made. At the present time, it would seem that the most likely link is SAS causing systemic hypertension, or SAS and essential hypertension are both caused by one or more common mechanism(s). In the current era of the availability of continuous positive airway pressure for treating patients with moderate-to-severe obstructive sleep apnea, we may be losing the opportunity to investigate the temporal sequence and natural history of SAS. On the other hand, if careful attention is paid to the clinical course of those patients who are receiving this therapy and careful longitudinal epidemiologic studies are designed to collect prospective data on those patients, one might be able to highlight the sequence of events that occur as a result of successful treatment of sleep apnea, i.e., provide more evidence for specificity. This would help to elucidate whether SAS causes hypertension. In our view, existing epidemiologic evidence would support at least a modest causal association between obstructive SAS and essential hypertension. However, the true magnitude of the risk association is unclear and thus we do not believe that it is cost-effective to perform polysomnography on all patients with hypertension. Rather, clinicians should be more aware of the association between SAS and hypertension. There is clearly a need for prospective longitudinal studies that define the changes in blood pressure from the recognition of SAS through treatment and follow-up. Until more epidemiologic data become available, simple clinical assessments such as inquiry into snoring, hypersomnolence, and morning tiredness should be part of the routine clinical evaluation of hypertensive patients; in suspected cases, polysomnography can be performed to diagnose SAS. We caution that the validity of this clinical screening strategy has yet to be demonstrated by careful prospective research.
ACKNOWLEDGMENT We wish to thank
Fehmida Nurmohamed
for preparing
the manuscript
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SLEEP APNEA AND SYSTEMIC HYPERTENSION / HOFFSTEIN ET AL (SUPPI 1): 1-106-l-10. 2. Tilkian AG, Guilleminault C. Schroeder JS. Lehrman KL. Simmons FB, Dement WC. Hemodynamics in sleep-induced apnea. Ann Intern Med 1976; 85: 714-9. 3. Podszus T. Mayer J. Penzel T, Peter JH, van Wichert P. Nocturnal hemodynamics in patients with sleep apnea. Eur J Respir Dis 1986; 69: 435-42. 4. Lavie P. Incidence of sleep apnea in a presumably healthy working population: a significant relationship wrth excessive daytime sleeprness. Sleep 1983; 6: 312-8. 5. Hirshkowitz M, Karacan I, Gurakar A, Williams RL. Hypertension, erectile dysfunction, and occult sleep apnea. Sleep 1989; 12: 223-32. 6. Kales A, Bixler EO. Cadieux RJ. et a/. Sleep apnea in a hypertensive population. Lancet 1984; 2: 1005-8. 7. Fletcher EC, DeBenke RD, Lovoi MS, Gorin AB. Undiagnosed sleep apnea in patients with essential hypertension. Ann Intern Med 1985; 103: 190-5. 6. Williams Al, Houston D, Finberg S. eta/. Sleep apnea syndrome and essential hypertension. Am J Cardiol 1985; 55: 1019-22. 9. Lavie P, Ben-Yosef R. Rubin AE. Prevalence of sleep apnea syndrome among patients with essential hypertension. Am Heart J 1984; 108: 373-6. 10. Smith PL. Gold AR, Meyers AA, Haponik F. Bleecker ER. Weight loss in mildly to moderately obese patients with obstructive sleep apnea. Ann Intern Med 1985: 103: 850-5. 11. Block JA, Boysen PG. Wynne JW. Hunt LA. Sleep apnea, hypopnea and oxygen desaturation in normal subjects. N Engl J Med 1979; 300: 513-7. 12. Partinen M. Guilleminault C. Daytime sleepiness and vascular morbidity at seven-year follow-up in obstructive sleep apnea patients. Chest 1990; 97: 27-32. 13. He J, Kryger MH, Zorick FJ. Conway W, Roth T. Mortality and apnea index In obstructive sleep apnea: experience in 385 male patients. Chest 1988; 94: 9-14. 14. Shepard JW Jr, Garrison M. Grither D, et a/. Hemodynamic responses to oxygen desaturation in obstructive sleep apnea [abstract]. Am Rev Respir Dis 1985; 131: A106. 15. Przybylski J. Sabbah HN. Stein PD. Why do patients with essential hypertension experience sleep apnea syndrome? Medical Hypothesis 1986; 20: 1737. 16. Somers VK. Mark AL, Abboud FM. Potentiation of sympathetic nerve response to hypoxia in borderline hypertensive subjects. Hypertension 1988; 11: 608-12. 17. Somers VK, Mark AL, Abboud FM. Sympathetic activation by hypoxia and
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hypercapnia-implications for sleep apnea. Clin Exp Hypertens 1988; 10: 413-22. 18. Daskalapoulou VE. Sandhagen B. Gislason T. St. Alenheim G. High ventilatory response to hypoxia in hypertensive patients with sleep apnea. Ups J Med Sci 1989; 94: 89-94. 19. Hedner J, Ejnell H. Sellgren J. Hedner T. Wallin G. Is high and fluctuating muscle nerve sympathebc activity in sleep apnea syndrome of pathogenetic importance for the development of hypertension? J Hypertens 1988; 6(suppl 4): s529-31. 20. Clark RW. Boudonias H, Schaal SF, Schmidt HS. Adrenergic hyperactivity and cardiac abnormality In primary disorders of sleep. Neurology 1980; 30: 113-9. 21. Wildschiodtz G, Clemmersen PH. Hammerberg PE, Pedersen H. Nocturnal urinary excretion of catecholamines in obstructwe sleep apnea [abstract]. Sleep Res 1983; 12: 295. 22. Fletcher EC, Miller J, Schaaf JW, Fletch JG. Urinary catecholamines before and after tracheostomy in patients with obstructive sleep apnea and hypertension. Sleep 1987; 10: 35-44. 23. Sklar AH, Chaudhary BA. Harp R. Nocturnal urinary protein excretion rates in patients with sleep apnea. Nephron 1989: 51: 35-8. 24. Krieger J, lmbs JL. Schmidt M. Kurtz D. Renal function in patients with obstructive sleep apnea: effects of nasal continuous positive airway pressure. Arch Intern Med 1988; 148: 1337-40. 25. Warley ARH, Stradling JR. Abnormal diurnal variation in salt and water excretion in patients with obstructive sleep apnea. Clin Sci 1988; 74: 183-5. 26. Chaudhary BA, Sklar AH, Chaudhary TK. Kolbeck RC, Speir WA Jr. Sleep apnea, proteinuria. and nephrotic syndrome. Sleep 1988; 11: 69-74. 27. Intersalt Cooperative Research Group. Intersalt: an international study of electrolyte excretion and blood pressure. Results for 24 hour urinary sodium and potassium excretion. Br Med J 1988; 297: 319-28. 26. Modan M, Kalkin t-l, Almog S. et al. Hyperinsulinemia: a link between hypertension, obesity, and glucose intolerance. J Clin Invest 1985; 75: 809-17. 29. Escourrou P, Jirani A, Nedelcoux H. Duroux P, Gaultier C. Systemic hypertension in sleep apnea syndrome. Chest 1990; 98: 1362-5. 30. Wailer PC, Bhopal RS. Is snoring a cause of vascular disease? An epidemiological review. Lancet 1989: 1: 143-6. 31. Jeong DU. Dimsdale JE. Sleep apnea and essential hypertension: a critical review of the epidemrological evidence for co-morbtdity. Clin Exper Hypertens 1989: All: 1301-23.
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REVIEW
Sleep Apnea and Systemic Hypertension: A Causal Association Review VICTORHOFFSTEIN,M.D.,CHARLESK.CHAN,M.D.,ARTHURS.SLUTSKY,M.D., Toronto,
Ontario,
Canada
OELJJZCTLVE: To critically examine the causal association between sleep apnea syndrome and hypertension. METHODS: A retrospective systematic critique of five epidemiologic studies published in the English literature during 1978 to 1989 identified on Medline and manual literature searches. The evidence was evaluated using the standard observational criteria for causation strength of association, consistency, dose-response relationship, temporal sequence, specificity, and biologic plausibility. RESULTS: We found evidence to support a causal association between sleep apnea syndrome and hypertension in consistency and specificity and some evidence to suggest a dose-response relationship. Review of the data dealing with the mechanisms important in the pathogenesis of sleep apnea and hypertension allowed us to advance several theories to provide support for biologic plausibility. CONCLUSION: We concluded that there is a positive association-relative risk estimate between 1.3 and IO--for sleep apnea syndrome and hypertension, but the risk association is uustable. Thus, we believe that there is insufficient data to justify doing polysomnography as part of the routine diagnostic work-up for patients with hypertension.
From the Divisions of Respiratory Medicine, Departments of Medicine, St. Michael’s (VH), Wellesley &KC). and Mount Sinai Hospitals (ASS), University of Toronto, Toronto, Ontario, Canada. Requests for reprints should be addressed to Charles K. Chan, M.D., 160 Wellesley Street East, Suite 242, Toronto, Ontario, Canada M4Y lJ3. Manuscript submitted November 7. 1990, and accepted in revised form April 22, 1991.
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H
ypertension affects 20% of the adult population and is a major risk factor for the development of cardiac and cerebral events. Although our understanding of the mechanisms producing hypertension has increased greatly over the past 20 years, in the majority of cases no underlying etiology is identified [l]. One of the diseases that has been associated with systemic hypertension is the sleep apnea syndrome (SAS) [2-lo]. A number of prospective studies involving patients with severe sleep apnea [2,3] have clearly demonstrated significant hemodynamic changes during apneic episodes. Thus, it is widely believed that significant cardiovascular end-organ damage and systemic hypertension result when sleep apnea is not recognized and thus is untreated. The exact incidence of SAS is unclear, but it has been estimated to be present in more than 1% of the adult population [4]. One can argue that if SAS has an important causal association with systemic hypertension, then it may be necessary to include appropriate investigations for the presence of sleep apnea in the routine work-up of patients with systemic hypertension. This approach obviously has significant implications for the health care delivery system because diagnostic work-ups using polysomnographic sleep studies are very expensive, in contrast to the usual screening investigations used in the routine assessment of patients with systemic hypertension. The mere fact that systemic hypertension is a very prevalent disease in North America means that any additional expensive diagnostic work-up will not be readily accepted by most patients, physicians, or third-party insurance carriers unless a firm causal association can be established. Although hypertension is known to be a prevalent co-morbid disease in patients with SAS [2], systematic investigations of the causality between SAS and systemic hypertension have not gained a great deal of attention in the last two decades. Given the availability of effective therapy for obstructive sleep apnea, it becomes necessary to address the question of causal association between SAS and systemic hypertension in order to determine if screening for SAS should be done routinely in the hypertensive population. The purpose of this critique is to appraise the available epidemiologic evi-
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dence for a causal association systemic hypertension.
between
d
SAS and
Summary of Studies Used to Exammethe RelatIonshIpBetween Sleep
MATERIALS AND METHODS Literature Search Computerized and manual literature searches were conducted and we identified five epidemiologic studies published in the English literature during 1978 to 1989 that addressed the causal association between SAS and systemic hypertension [5-91. The literature search was conducted using Grateful Med software applied to the National Library of Science MEDLINE database.
Reference
Epidemiologic Studies of Sleep Apnea and Systemic Hypertension A case-control approach using hypertensive patients as the cases and normotensive patients as the controls was the study design used in four of the investigations [5-81. The other study [9] employed a cross-sectional design aimed at estimating the prevalence of SAS among patients with essential hypertension. Four of the studies were done in the United States [5-81 and one was done in Israel [9]. The hypertensive patients or cases in these studies were primarily recruited from hypertensive clinics. The control subjects were normotensive patients who were referred to the sleep laboratory for various investigations or patients who were admitted to other services in the hospital. All the cases and controls were studied using polysomnographic sleep studies. One of the difficulties encountered in attempting to use the aforementioned studies to examine the association between sleep apnea and hypertension is the lack of a uniform definition of sleep apnea. Williams et al [8] used an apnea index (defined as the number of apneic events per hour) greater than 5 to define sleep apnea. Lavie et al [9] used an apnea index greater than 10 to separate apneic from nonapneic patients. Hirshkowitz et al [5] presented their data using several apneic cutoffs (5, 10, and 15). Kales et al [6] divided their hypertensive and normotensive patients into groups based on the total number of apneic episodes per night, rather than on the apnea index. Fletcher et al [7] used an apnea index greater than 10 as the apnea cutoff. Consistent analysis of these studies requires the adoption of a uniform definition of sleep apnea. We selected two commonly used apnea indices (5 and 10) to divide the population into apneic and nonapneic groups. With these definitions, the studies of Hirshkovitz et al [5] and Lavie et al [9] could be used directly. The data of Williams and co-workers [8], Fletcher et al [7], and Kales and colleagues [6] could not be used directly, because these authors
n
Hypertensives Al >5 Al>10
n
Normotensives Al>5 Al>10
defined sleep apnea based on apnea indices of 5 [8] or 10 [7] or on the total number of apneic events per night [6]. However, all of the authors assumed a normal distribution of the apnea indices and summarized their data by reporting means, standard deviations, or standard errors. We used the normality distribution of the raw data to re-classify the number of subjects likely to have apnea indices greater than our pre-selected cutoffs of 5 and 10. Table I summarizes the five studies, indicating the number of hypertensive and normotensive subjects with apnea indices greater than 5 and greater than 10. Unlike the explicit criteria that were chosen for the diagnosis of SAS in all five studies, the definition of hypertension was not only variable but not stated in two studies [6,8]. Hypertension was defined as a diastolic blood pressure of greater than 90 mm Hg or a systolic pressure greater than 160 mm Hg by Hirshkowitz et al [5], diastolic greater than 95 mm Hg and systolic greater than 160 mm Hg by Lavie and co-workers [9], and diastolic greater than 90 mm Hg or systolic greater than 140 mm Hg for men under the age of 45 years and diastolic above 95 mm Hg for men over 45 years by Fletcher et al [7]. The data presented in each study were insufficient to stratify the study groups into normotensive and hypertensive subgroups using a uniform criterion. Since the patients included in the five studies are primarily men and the racial representation is poorly distributed, we cannot address the interesting issues regarding gender and race on the causal association between SAS and hypertension. Criteria for a Causal Association The five investigations being reviewed are clinical epidemiologic studies, which are different from experimental investigations, and thus we cannot use the conventional experimental criteria for causation (Henle-Koch postulates) to establish causality. An acceptable substitute would be to apply six observational or epidemiologic criteria for causation. These criteria are: (1) strength of association,
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range from 1.3 to 23 (Table II). Similarly, using a more conservative and perhaps more appropriate cutoff of more than 10, the strength of the association is also quite variable; results of the four studies show odds ratios from 1.5 to 40 (Table II). The cross-sectional study by Lavie et al [9] did not have any control subjects but nevertheless found a prevalence of 26% using an apnea index greater than 5, and 22% using an apnea index greater than 10, among the group of 50 patients with hypertension. This prevalence is substantially higher than the 1.26% of men older than 21 who are estimated to have SAS [ll].
TABLE II Strength of Associationand ConsistencyBetween Sleep Apnea and Hypertension Reference [51
StudyDesign Case-control
n
Al
285
>5 >lO >5 >lO
[61
Case-control
100
[71
Case-control
80
[81
Case-control
[91
Case-series
31 50
Odds Ratio 1.3 1.5 :i
>5
1.8
>I0
4.5
95% Cl 0.8-2.1 0.8-2.8
4.9-108 6.3-255 0.7-4.5 1.3-16
>5
15.6
1.4-170
>lO
13.2
1.2-152
26%, no control 22%, no control
>5
>lO
= apnea index; 95% Cl = 95% confidence interval of the odds ratio.
TABLE Ill Severityof Sleep Apnea Syndrome Correlateswith the Severity of Hypertension 161 Numberof ApneicEvents 30-99 loo-380
n
MeanArterial Blood Pressure(mm tlg)
z
129.4 * 7.4 162.0 + 8.3
(2) consistency, (3) dose-response relationship, (4) temporal sequence, (5) specificity, and (6) biologic plausibility. Findings of the five epidemiologic studies of SAS and systemic hypertension will be presented in accordance with these six criteria for causation.
RESULTS Strength of Association The study design, the estimates of relative risk, and the odds ratios for the five studies are summarized in Table II, using two different apnea cutoffs. Relative risk is defined as the incidence of hypertension in the sleep apnea group divided by the incidence of hypertension in the non-apneic group. The odds ratio is defined as the odds in favor of hypertension in the apnea group divided by the odds in favor of hypertension in the non-apneic group. Obviously, the lower the cutoff in terms of the apnea index, the higher the prevalence of SAS in the study population. Using a lower cutoff may increase the chance of finding an association between SAS and hypertension but that association may not be specific, i.e., it may reflect common causative factors for both SAS and hypertension such as obesity [lo], rather than indicating causality between SAS and hypertension. Using an apnea index greater than 5, the odds ratios of the four studies [5-91 192
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Consistency Perfect consistency would include all studies having an odds ratio greater than 1, with all the corresponding confidence intervals excluding 1. Unfortunately, due to the small sample sizes in most studies, not all the reported 95% confidence intervals are considered statistically significant (Table II). Despite the wide range of odds ratios, five of the eight relative risk estimates are statistically significant at a p = 0.05 level (Table II). Depending on the choice of the apnea index cutoffs and variable sample sizes, the 95% confidence interval may not necessarily avoid 1. Although three of the odds ratios were not significant [5,7], it should be emphasized that all odds ratios reported to date, irrespective of the choice of apnea index cutoffs, are more than 1. Therefore, all five studies on the association between SAS and systemic hypertension are consistent. Dose-Response Relationship No specific epidemiologic study was designed to address the issue of a dose-response relationship between SAS and systemic hypertension. Nevertheless, based on the available evidence, one can gain some insight into such a possible relationship. One approach to investigating a dose-response relationship is to evaluate a group of patients with SAS and to classify their apnea as mild, moderate, or severe, based on clinical, laboratory, and polysomnographic data. If there is indeed a causal association between SAS and systemic hypertension, one would expect to show that the more severe the sleep apnea, the more prevalent and perhaps severe would be the hypertension and vice versa. Analysis of the data collected by Kales et al [6] (Table III) shows that patients with 30 to 99 apneic events per night (apnea index between 5 and 15) had a mean arterial blood pressure of 129 mm Hg, which was significantly lower than the 162 mm Hg observed in patients with more than 100 apneic events per night (apnea index greater than 15).
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An alternative approach to assessing the doseresponse relationship is to compare the odds ratio in the controlled hypertensive population versus that in the refractory hypertensive population. If SAS is responsible for the difficulties in the control of hypertension in some patients, then one would hypothesize that the refractory group of patients should show a higher prevalence of sleep apnea and thus have a higher odds ratio. The data provided by Hirshkowitz et al [5] does show such a relationship. In the hypertensive group in which the blood pressure was well controlled, the odds ratio was 0.9, in contrast to the refractory hypertensive group where the odds ratio was 2.2 (Table IV). Using a higher cutoff, an apnea index greater than 10, the controlled hypertensive group had an odds ratio of 1.8, and the refractory group had an odds ratio of 3.2. A similar conclusion can be drawn from the data of Fletcher and co-workers [7] in Table II. However, the dose-response pattern was by no means consistent in all five studies [5-g], with contradictory data from two of them [8,9]. It is prudent to point out that the evidence discussed is very preliminary. Although the overall data seem to support an argument for the existence of a dose-response relationship between SAS and systemic hypertension, they by no means establish a relationship. Temporal Sequence Thus far, no prospective or longitudinal followup study of cohorts of patients with and without SAS is available; thus, there is no evidence to support a temporal sequence argument for either SAS causing hypertension or hypertension eventually resulting in SAS. Such a natural history study to demonstrate the temporal sequence may become increasingly difficult to do because almost all hypertensive patients will be treated, and with the availability of continuous positive airway pressure for the treatment of obstructive sleep apnea, it becomes more difficult to assemble a meaningful cohort of patients with mild-to-moderate obstructive sleep apnea who will simply be followed with repeated polysomnographic and hemodynamic studies over a period of years to document the development of systemic hypertension with untreated SAS. Thus, the epidemiologic evidence to support a temporal sequence argument may be dependent on creative retrospective-prospective studies. A recent example of such an investigation is the retrospectively assembled but prospective follow-up study of 198 patients with obstructive sleep apnea by Partinen and Guilleminault [12]. That study provided some clues to the natural history of SAS because there were 127 conservatively treated patients with
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TABLE IV RefractoryHypertensive Patients Are More Likely to Have Sleep Apnea Syndrome Al >5 Controlled Refractory
0.9 (0.3-2.4)* 2.2 (1.0-4.5)
Al >lO 1.8 (0.6-5.1) 3.2 (0.4-7.0)
Al = apnea index. *Ninety-five percent confidence interval of the odds ratio.
obstructive sleep apnea in the cohort. One of the conservatively treated patients with obstructive sleep apnea developed hypertension after 7 years of follow-up. The incidence is obviously low, and since there was no concurrent control group, the evidence is insufficient to support a temporal sequence argument. Specificity If SAS causes systemic hypertension, then successful treatment of the sleep apnea should lead to normalization of the blood pressure without any other interventions. Among the five epidemiologic studies reviewed, the one that has provided data to support the specificity argument is that by Fletcher et al [7]. In a selected subgroup of eight patients with significant obstructive sleep apnea, with apnea indices ranging from 13.6 to 91.1 and a mean of 32.5 at the time of diagnosis, therapy for sleep apnea was given and these patients were re-evaluated after treatment. The mean arterial blood pressure at the time of diagnosis but prior to any specific therapy given for apnea was 149/95 mm Hg. Therapy consisted of protriptyline in seven and uvulopalatopharyngoplasty in the remaining patient. All eight patients were restudied using polysomnography after 2 months of therapy or surgery. The apnea index was substantially reduced to a mean of 7.4, and the mean arterial blood pressure decreased to 139/90 mm Hg. Although the sample size was small, these results were statistically significant using a paired t-test analysis. With the widespread availability of nasal continous positive airway pressure therapy for obstructive sleep apnea, this type of study in patients with obstructive sleep apnea and hypertension can be readily repeated. Therefore, one should expect more definitive evidence on the specificity of this causal association in the very near future. Biologic Plausibility Based on the current studies [2,13,14] of hemodynamic changes in patients with obstructive sleep apnea, it is possible to advance several theories and hypotheses to link SAS with hypertension. These
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biologic plausibilities include: (1) essential hypertension causes sleep apnea, (2) sleep apnea causes essential hypertension, and (3) both diseases are caused by some common underlying mechanism(s). ESSENTIALHYPERTENSIONCAUSESSLEEPAPNEA:
One hypothesis to explain the pathophysiology of obstructive sleep apnea is that it is due to instability of the respiratory control system. Within the context of this hypothesis, increased drive from arterial chemoreceptors in patients with essential hypertension causes instability in the respiratory control system, thus leading to repeated apneic episodes [15]. Although this is an attractive hypothesis, it does present some difficulties in explaining why treatment of sleep apnea normalizes blood pressure [7], while treatment of essential hypertension does not usually result in the resolution of the sleep apnea [5]. However, such data cannot be used to reject the hypothesis conclusively because abnormal respiratory control may cause both hypertension and sleep apnea. The latter, in turn, may lead to a further elevation of blood pressure; therefore, treatment of sleep apnea may result in partial normalization of the blood pressure. On the other hand, treatment of hypertension may not improve sleep apnea because pharmacologic normalization of the blood pressure may not necessarily alter the abnormality in respiratory control. An alternative hypothesis is that drugs used to treat hypertension can cause sleep apnea because a number of medications, usually sedating medications, can worsen sleep apnea. However, this seems unlikely to be the major factor since many patients who present with SAS are not taking antihypertensive medications at the time of presentation, and medical treatment of hypertension does not seem to increase the severity of sleep apnea. SLEEPAPNEACAUSESHYPERTENSION: Therearea number of theoretic mechanisms by which SAS can produce systemic hypertension. One obvious factor is the recurrent episodes of hypoxemia [14]. Apneic periods are often associated with a significant drop in oxygen saturation that can be profound, reaching levels of saturation below 60% (representing arterial oxygen tension below 30 mm Hg); these episodes of oxygen desaturation can occur hundreds of times per night. In addition to hypoxemia, apneic events are accompanied by a rise in the arterial partial pressure of carbon dioxide. This combination of hypoxemia and hypercapnia would lead to excitation of the arterial chemoreceptors, causing increased sympathetic discharge and resulting in increased pulmonary and systemic pressures [X-18]. Cardiac contractility and heart rate are also stimulated and increased. In accordance with this hypothesis, re-
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cent observations that hypertensive patients with sleep apnea have double the hypoxic ventilatory response compared with normotensive sleep apnea patients are interesting supportive evidence [18]. Furthermore, increased sympathetic activity and elevated catecholamine levels seen during apneic events may also contribute to hypertension [19-221. There is no doubt that clear-cut episodes of pulmonary and systemic hypertension frequently occur during apneic events in patients with severe sleep apnea [2,3]. It is possible that repeated stimulation of the arterial chemoreceptors during hypertensive periods produces sympathetic discharges that prolong the peripheral effect into the daytime. In accord with this hypothesis is a study showing that hypertensive patients with sleep apnea have elevated daytime levels of epinephrine, as well as an absence of diurnal variation in the level of urinary catecholamines, which suggests that these patients have increased sympathetic activity while they are awake and during sleep [22]. These abnormalities disappear after correction of sleep apnea by tracheostomy [22]. A further mechanism linking hypertension with SAS may be abnormal renal function. Nephrotic syndrome, proteinuria, and increased urinary sodium excretion have been observed in patients with SAS [23-261. Furthermore, a recent international multicenter study showed that urinary sodium levels are directly related to elevations in blood pressure [27]. Thus, impairment in renal function resulting from sleep apnea may account for the elevated blood pressure found in some patients. Although the precise factors that cause termination of apneic episodes are not known with certainty, many episodes terminate coincidentally with arousal from sleep. Thus, patients with severe obstructive sleep apnea can have hundreds of arousals every night. Possibly, the sequelae of these arousal events may be sustained daytime hypertension, perhaps also via a sympathetic mechanism. COMMONUNDERLYINGMECHANISMS: One of the common factors accounting for the association between SAS and essential hypertension may be obesity [lo]. Although not all patients with idiopathic obstructive sleep apnea are obese, a high percentage of patients with severe obstructive sleep apnea have markedly elevated body mass indices. Several studies have demonstrated that body mass index is an independent determinant of sleep apnea [lo]. Similarly, obesity is associated with hypertension, perhaps via an abnormality in insulin metabolism [28]. It is thus possible that the association between SAS and essential hypertension may very well be confounded by the fact that obese patients are more
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likely than non-obese patients to have both of these relatively common conditions. To elucidate the relationship between obesity, sleep apnea, and hypertension, further careful measurements of blood pressure in apneic and non-apneic subjects matched for weight and body mass index are required. A recent study by Escourrou et al [29] indicates that hypertension in patients with sleep apnea is not directly related to weight or body mass index. If SAS and hypertension are linked, and since hypertension is a well-known risk factor for increased mortality, we might expect that SAS would also be associated with higher mortality. Although prospective epidemiologic studies demonstrating an increased mortality rate in SAS are still lacking, there is evidence suggesting the existence of a direct relationship between the apnea-hypopnea index and mortality [13].
COMMENTS Studies reporting a causal association between SAS and hypertension may all be challenged on several grounds including possible assembly bias in the selection of patients from hypertensive clinics, inappropriate choices of apnea indices for the definition of SAS, poor or absent criteria for the definition of hypertension, and a lack of adequate matching for weight or body mass index [5-g]. A fastidious approach would be to criticize the evidence accumulated to date and maintain the position that the causal association cannot be addressed based on the currently available evidence. This approach was chosen in two prior epidemiologic reviews on the association between snoring and vascular disease [30] and the co-morbidity between sleep apnea and hypertension [31]. Our pragmatic approach is to review the best available evidence and interpret the results using the generally accepted epidemiologic criteria for a causal association. Subanalysis of the available data also allowed us to provide evidence under most of these different criteria. It is evident based on the available data that there is at least a modest association between SAS and essential hypertension. If one were to choose an apnea index cutoff of 30, which is considered clinically significant by all workers in this field, one may very well find a higher odds ratio but a much larger sample of hypertensive patients would have to be included in the study. Using a conventional apnea cutoff of 10, the relative risk estimates from the studies range from 1.5 to 40. Although statistical significance is not necessarily achieved in all the reported studies, the consistency of the association is clearly established among the various centers.
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Due to the lack of prospective or longitudinal data, temporal sequence cannot be addressed based on the current evidence. Nevertheless, specificity suggesting that SAS causes hypertension is nicely supported by subanalysis of the data available from some of these studies. There are certainly numerous theories to provide support for biologic plausibility for the causal association between SAS and hypertension. This is clearly the area where further work is required if elucidation of the mechanism(s) of the association is to be made. At the present time, it would seem that the most likely link is SAS causing systemic hypertension, or SAS and essential hypertension are both caused by one or more common mechanism(s). In the current era of the availability of continuous positive airway pressure for treating patients with moderate-to-severe obstructive sleep apnea, we may be losing the opportunity to investigate the temporal sequence and natural history of SAS. On the other hand, if careful attention is paid to the clinical course of those patients who are receiving this therapy and careful longitudinal epidemiologic studies are designed to collect prospective data on those patients, one might be able to highlight the sequence of events that occur as a result of successful treatment of sleep apnea, i.e., provide more evidence for specificity. This would help to elucidate whether SAS causes hypertension. In our view, existing epidemiologic evidence would support at least a modest causal association between obstructive SAS and essential hypertension. However, the true magnitude of the risk association is unclear and thus we do not believe that it is cost-effective to perform polysomnography on all patients with hypertension. Rather, clinicians should be more aware of the association between SAS and hypertension. There is clearly a need for prospective longitudinal studies that define the changes in blood pressure from the recognition of SAS through treatment and follow-up. Until more epidemiologic data become available, simple clinical assessments such as inquiry into snoring, hypersomnolence, and morning tiredness should be part of the routine clinical evaluation of hypertensive patients; in suspected cases, polysomnography can be performed to diagnose SAS. We caution that the validity of this clinical screening strategy has yet to be demonstrated by careful prospective research.
ACKNOWLEDGMENT We wish to thank
Fehmida Nurmohamed
for preparing
the manuscript
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