Sleep Apnea and Hypertension-What a Mess!

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1 Sleep, 20(9): American Sleep Disorders Association and Sleep Research Society Controversies In Sleep Medicine: Hypertension Editorial One of the widespread beliefs in the sleep medicine field is that sleep apnea is associated with arterial hypertension, and the arterial hypertension, in tum, may be responsible for some of the cardiovascular morbidities in this disorder. Even recently, whether or not hypertension is an important issue in obstructive sleep apnea has been questioned. Does sleep apnea cause arterial hypertension? Is sleep apnea simply associated with hypertension because both disorders are found in people with similar demographics? Is it an issue that the sleep medicine community needs to be concerned about? In this Controversies section, there are contributions that examine this issue in depth. It was not easy to find an author who would be willing to present the point of view that hypertension is not necessarily a problem in sleep apnea, and I thank Dr. John Stradling, who in the tradition of an Oxford debater, presents a very persuasive article. The readers are encouraged to read all three articles, which approach the topic from different points of view, to reach their own conclusions. -Meir H. Kryger, Section Editor Sleep, 20(9): American Sleep Disorders Association and Sleep Research Society Sleep Apnea and Hypertension-What a Mess! J. Stradling and R. J. O. Davies Osler Chest Unit, Churchill Hospital, Oxford, U.K. Summary: It is unarguable that obstructive sleep apnea (OSA) causes pulsatile hypertension during sleep, but whether there is significant carryover of hypertension into waking hours is far from clear. It is perhaps more useful to consider whether OSA is related to the consequences of hypertension (e,g. stroke), since both nocturnal and daytime hypertension could be responsible for these. Furthermore, the effects of nasal continuous positive airway pressure (CPAP) on hypertension (or its consequences) must be assessed by randomized controlled studies, in exactly the same way as trials on hypotensive drugs would be carried out, before treatment is prescribed for OSA in the absence of any daytime symptoms. Key words: Hypertension-Apnea. Many recent reviews have looked at the relationship between obstructive sleep apnea (OSA) and diurnal hypertension (1-10). All have essentially concluded that there are tantalizing data to suggest that sleep ap- Accepted for publication February Address correspondence and reprint requests to Dr. J. Stradling, Osler Chest Unit, Churchill Hospital, Oxford OX3 7LJ, U.K. 789 nea might be a significant independent risk factor for diurnal hypertension, but that confounding variables such as obesity (and its pattern of distribution), alcohol consumption, age, and levels of exercise make this link extremely hard to prove (6). The more the study is carefully controlled for confounding variables, the harder it is to prove a true independent relationship. It

2 STRADLING AND R. 1. O. DA VIES is important to rigorously prove any such relationship, because a strong relationship might suggest that occult OSA, a common phenomenon (11), is a significant vascular risk within the community. In this short review, we shall concentrate on whether the more recent studies have helped resolve this debate. The first issue is to separate nighttime from daytime blood pressure changes. It is certain that OSA produces recurrent nocturnal rises in blood pressure (12,13), which elevate the mean sleeping blood pressure (14). The transient postapneic rises (13) (sometimes as much as 100 mmhg with every apnea) are probably the consequence of repetitive arousal from sleep (15-17). In passing, it is worth noting that this marked blood pressure lability makes the interpretation of nighttime blood pressure recordings in patients with OSA using inflating cuff techniques of doubtful veracity. In addition to disturbing sleep and raising the blood pressure (18), these techniques react far too slowly to quantify such an extremely labile pressure profile. The unarguable nighttime blood pressure (BP) changes of OSA seem to make a heated debate about subtle daytime changes slightly pointless. The crux issue is actually the cardiovascular complications of a rise in blood pressure (stroke, myocardial infarction, renal damage, etc.), and because nocturnal BP changes alone may cause these sequelae, efforts would perhaps be better directed toward assessing these outcome measures. There is ample opportunity for work in this area, because the available data on sleep apnea and possible cardiovascular complications are even more confusing than those on hypertension and suffer from all the same methodological problems. In addressing daytime blood pressure, the problem of confounding variables is almost insurmountable. Because of the intimate relationship between blood pressure, obesity, and sleep apnea, disentangling cause and effect in epidemiological studies is very difficult. Increasing obesity is associated with a rise in blood pressure (19). This relationship is particularly associated with an upper body pattern of fat deposition (19), which itself is associated with OSA (20). In addition, if part of the well-established relationship between blood pressure and obesity was actually due to sleep apnea (rather than the conventional way round), then routinely allowing for obesity in regression analysis would wipe out any opportunity for sleep apnea to exert any independent effect. Conversely, if hypertension actually led to sleep apnea, as has been suggested (21), then disentanglement in epidemiological studies would become quite impossible. Besides these complexities, there are neglected methodological questions that further complicate the results of epidemiological studies of OSA and blood pressure. The considerable variation in sleep apnea severity, which occurs night to night (and possibly Over a longer time course), means that sleep apnea severity is not accurately quantified by a single night's sleep study. This inevitably weakens the apparent univariate relationship between sleep apnea severity and blood pressure in community studies through regression dilution bias (22), and also indicates that as an independent predictor of blood pressure in multiple regression analyses, it will always be at a disadvantage compared to body mass index (BMI), for which measurement is easy and accurate and in which there is little shortterm variation (which means a single estimate is a good guide to "usual" levels). Thus, it is entirely possible to falsely lose a real independent relationship between blood pressure and sleep apnea by allowing for obesity first, simply because the severity of sleep apnea has been poorly measured. Against this complex background, have recent studies produced data that have clarified the daytime blood pressure debate? Hla et al. (23) studied 147 men and women in one of the most recent population-based attempts to explore the relationship between sleep apnea (defined by conventional polysomnography) and hypertension (by 24-hour monitoring). Such a relationship was found, even when a nonobese (BMI < 27) subgroup was analyzed. Hypertension was dichotomized [hypertension being defined as a systolic BP (SBP) >140 mmhg or a diastolic BP (DBP) >90 mm Hg], and therefore a multiple linear regression analysis was not reported using continuous measures of the apnea/hypopnea index (AHI), obesity, and age as independent predictors. It was also not clear, even within the nonobese group, whether there might have been a blood pressure dependence on BM!. In addition, so far there has been no published reanalysis with allowance for upper body obesity (e.g. waist circumference/ height) and alcohol; these are factors that might confound this relationship (24-28). Finally, without a multiple linear regression analysis and confidence intervals, it is difficult to get a feel for the clinical relevance of the statistical relationships. The dichotomized logistic regression that was presented showed that an AHI between 5 and 25 (compared to an AHI of less than 5), produced an odds ratio for hypertension of only 2:5. This would probably explain somewhat less than 5% (and probably less than 2%) of the variance in blood pressure. A more recent and larger epidemiological study (441 subjects) from Australia (29) looked at the association between blood pressure (previously diagnosed, on antihypertensives, SBP > 105 mmhg or DBP > 90 mmhg) and sleep apnea (limited monitoring using tracheal microphone and rib cage and abdominal movements). Although the presence of sleep-disordered breathing (respiratory disturbance in-

3 SLEEP APNEA AND HYPERTENSION 791 dex > 15) produced a significant odds ratio for hypertension (3.8, 95% confidence interval 1.9:7.5), this became nonsignificant (1.5, 0.7:3.3) once adjustment had been made for age, sex, BMI, akohol consumption, and smoking. Only the relationship with the AHI has so far been reported from either of the above studies, although oximetry data were collected. Further analysis using the nocturnal hypoxemia data would be interesting, because the results of both of these studies actually seem potentially similar to the larger, earlier Oxford study which used oximetry rather than AHI in 748 men from the community (30). Whether apneas, arousals, or hypoxemic dips should be used in these kinds of studies is unclear. Arousal itself produces a rise in nighttime BP (see above). However, multiple arousal disorders such as periodic movements of the legs (without any hypoxemia) cause transient BP rises (31), but there is no evidence that they are responsible for diurnal hypertension. For this reason and others, nocturnal hypoxemia is advanced as the probable cause of any sustained rise in daytime blood pressure (5) in OSA. However, in most of the epidemiological studies of blood pressure and OSA, the OSA is mild and produces trivial hypoxemia compared to many clinic patients. Furthermore, other causes of more severe nocturnal hypoxemia such as altitude, congenital heart disease, and other nocturnal hypoventilation disorders, do not seem to be a risk factor for hypertension (32). Perhaps both a decrease in oxygen saturation and recurrent arousals may be needed to provoke a sustained daytime blood pressure change (if such exists). Alternatively, another aspect of sleep apnea may be important, such as increased inspiratory efforts for long periods of the night. A different statistical technique to dissect confounding variables is to use carefully matched control subjects. Davies et al. (33) carefully matched 18 severe OSA male patients with 18 control subjects without OS A, but with similar obesity indices, waist to hip ratios, smoking histories, and alcohol consumption. Twenty-four-hour BP monitoring (and left ventricular mass) in the two groups showed no difference, and this study excluded in the OSA patients an SBP elevation of >0.2 mmhg (DBP >3.8 nimhg) with a confidence interval of 95%. Such was the problem of the obesity/os A interaction that the medical records of more than 3,000 normal subjects had to be reviewed to find 18 controls matched for age, obesity, alcohol, and cigarette consumption, who also did not have sleep apnea. If neither epidemiological surveys nor cross sectional studies on clinic patients can be relied on to provide unequivocal data, can the response to continuous positive airway pressure (CPAP) be used where subjects act as their own controls? All but one of the studies on the effect of CPAP on BP have lacked proper controls (34-40). No one looking at an antihypertensive drug would think of leaving out a control group, because there are many reasons why blood pressure measured on two occasions may be lower on the second (for example, regression to the mean). Par~ tial cohtrolling can be attempted by using those patients not using their CPAp, but such noncompliers are never proper matches for compliers. A study of 19 patients receiving CPAP for OSA showed decreases in BP at 8 weeks, but only in those complying with the treatment (35). However, a similar study over a 20-month period on 12 patients receiving CPAP showed no decrease in 24-hour BP or left ventricular mass, despite significant decreases in markers of adrenergic activity (34). Although there were no objective compliance data, the decrease in adrenergic activity presumably suggests significant change. A study from Austria found a small decrease in BP following CPAp, but controlling for weight changes removed significance (37). The only controlled study of the effect of CPAP on BP comes from Edinburgh, U.K. (41). In 13 patients who received 3 weeks of CPAP (average use 4.3 hours per night) or placebo tablets in a crossover trial, there was no significant decrease in 24-hour BP. The only evidence for any blood pressure decrease was in the tiny subgroup of five patients who, while taking the placebo, did not experience a decrease in BP during the night (quantified with an inflating cuff method, with all its attendant problems). In these subjects there was a small significant drop in mean daytime arterial BP (4 mmhg). However, there was no difference in the BP at 3 weeks between good and poor compliers. Recent evidence has suggested that there may be some carryover of the higher BP at night during OSA into the first hours of the morning (20,42,43), but the effect may be gone by the afternoon or evening. Thus, the timing of BP measurements is important in this sort of work and may explain some of the differences between studies. The difficulties experienced with human work has led to the development of animal models to explore the effect of OSA on diurnal hypertension. Fletcher's group has performed extensive work in rats showing that intermittent severe hypoxia can lead to a sustained rise in BP within 35 days (44). However, this response is dependent on the strain of rat studied and is therefore probably under genetic control (45). An extraordinarily sophisticated animal model of OSA has been developed by Brooks et al. in Toronto (46). They have automatically linked recurrent tracheal occlusions to electroencephalograph (EEG) sleep stage using telemetric devices and on-line computer systems to simulate OSA in free living dogs. They can produce apnea

4 STRADLING AND R DA VIES index values of 60 or so at will for 8 hours per 24 hours. They have shown in four dogs that this abrupt onset of OSA raises diurnal BP by about 15 mmhg over a period of approximately 100 days. Following cessation of the OSA, the elevated BP resolved within 7 days in two dogs but took longer in the other two. More recent studies have shown that equivalent sleep fragmentation alone does not similarly raise diurnal blood pressure. This is powerful evidence for a direct link between OSA and sustained hypertension, particularly if it can be reproduced in a few more dogs. There are, however, important differences in human OSA. First, human OSA characteristically evolves over many years during which compensatory mechanisms may come into play. It is possible that, with time, the dogs' daytime BP values might return toward normal, or not increase at all if the OSA is introduced gradually. Second, of course, species differences may be important, as implied by the inconsistent responses of the two genetically different rat strains. In conclusion, no convincing evidence yet exists that OSA is a significant independent risk factor for sustained daytime hypertension in humans. Although there is good evidence that treating OSA with adequate CPAP produces profound nocturnal cardiovascular changes, a sustained reduction in daytime blood pressure has not been convincingly demonstrated. What is needed is a large, placebo-controlled trial of the effects of CPAP on BP in patients with a range of OSA severity, of similar quality to that demanded for new antihypertensive agents. It seems possible that eventually it will be shown that clinical OSA is a small independent risk factor for daytime hypertension and, perhaps, its adverse complications such as stroke. As yet, even in large retrospective sleep laboratory surveys (1,620 patients), the diagnosis of OSA does not seem to be an independent adverse risk factor for mortality when confounders are adequately considered (47). Thus, any link is unlikely to provide adequate justification for treating prophylactically hundreds of thousands of asymptomatic individuals with OSA. They would be extremely unlikely to comply with a treatment such as nasal CPAP anyway, in the absence of daytime symptoms, particularly if the only perceived benefits were some minor and distant reduction in an already low risk of stroke or myocardial infarction. It might justify a yet more aggressive approach to weight loss in obese individuals who snore, for whom the benefits of such action are already established. 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