Published ahead of print on November 14, 2008, doi:10.1164/rccm.200807-1076OC
© 2009 American Thoracic Society doi: 10.1164/rccm.200807-1076OC
Relationship between Overnight Rostral Fluid Shift and Obstructive Sleep Apnea in Nonobese Men1 Sleep Research Laboratory of the Toronto Rehabilitation Institute; 2 Centre for Sleep Medicine and Circadian Biology, University of Toronto; and 3 Department of Medicine, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada Correspondence and requests for reprints should be addressed to T. Douglas Bradley, M.D., Toronto General Hospital of the University Health Network, 9N-943, 200 Elizabeth Street, Toronto, ON, M5G 2C4 Canada. E-mail: douglas.bradley{at}utoronto.ca
Rationale: The cause of increased pharyngeal collapsibility in patients with obstructive sleep apnea is incompletely understood. In awake healthy subjects, we showed that fluid displacement from the legs into the neck induced by lower body positive pressure reduces upper airway size and increases its collapsibility. Prolonged sitting leads to dependent fluid accumulation in the legs. Objectives: To test the hypotheses that the apnea–hypopnea index (AHI) during sleep will be related to the amount of fluid spontaneously displaced from the legs overnight, and that this will, in turn, be related to the time spent sitting the previous day. Methods: In 23 nonobese healthy men referred for sleep studies for suspected obstructive sleep apnea, we assessed the changes in leg fluid volume and in neck circumference from the beginning to the end of the night, and the time spent sitting during the previous day. Measurements and Main Results: The overnight change in leg fluid volume correlated strongly with the AHI (r = –0.773, P < 0.001), the change in neck circumference (r = –0.792, P < 0.001), and the time spent sitting (r = –0.588, P = 0.003). Multivariate analysis showed that the only significant independent correlates of the AHI were the overnight changes in leg fluid volume and neck circumference, which together explained 68% of the variability in the AHI among subjects. Conclusions: These novel findings suggest that overnight rostral fluid displacement from the legs, related to prolonged sitting, may play a previously unrecognized role in the pathogenesis of obstructive sleep apnea in nonobese men that is independent of body weight.
Key Words: pathophysiology • inactivity • fluid distribution
Obstructive sleep apnea (OSA) is a common disorder with significant morbidity that affects approximately 9% of men and 4% of women (1). Although the key pathological feature of OSA is repetitive collapse of the upper airway during sleep, the cause of upper airway collapse is not completely understood. In addition, although continuous positive airway pressure alleviates OSA, many patients find it difficult to tolerate (2). Accordingly, a better understanding of the pathogenesis of OSA might lead to new and better treatments. Although obesity is a risk factor for OSA, a large epidemiologic study reported that approximately 60% of patients with OSA in the community are not obese (3). Hence, in such patients factors other than obesity must play a role in the pathogenesis of upper airway obstruction. The observation that OSA is more prevalent in patients with edematous states, such as heart and renal failure, than in the general population, despite lower body weight (1, 4, 5), raises the possibility that fluid retention may increase the risk of developing OSA. For example, fluid that has accumulated in the lower extremities while upright during the day could shift rostrally into the neck on assuming the recumbent position during sleep. Such fluid displacement might cause distension of the great veins and/or edema of the peripharyngeal soft tissue and predispose to upper airway obstruction. In previous studies, we induced displacement of approximately 160 to 190 ml of fluid from each leg by the application of lower body positive pressure, using medical antishock trousers in healthy, nonobese subjects while awake. This caused a significant increase in neck circumference in association with a reduction in upper airway caliber and an increase in its collapsibility (6–8), indicating that a portion of the fluid displaced from the legs reached the neck and altered the properties of the upper airway. Nevertheless, the possibility that such rostral fluid displacement could occur spontaneously overnight and predispose to upper airway obstruction during sleep has not been assessed. Humans have evolved a bipedal upright stance that predisposes to gravitational fluid accumulation in the legs. This is counteracted by contraction of the calf muscles during physical activity, particularly walking (9–12). However, in more recent years, the introduction of modern technologies into the workplace has greatly reduced the need for physical activity and increased the number of jobs requiring prolonged sitting, during which absence of contraction of the calf muscles leads to dependent fluid accumulation in the legs that is proportional to the time spent in this position (9, 10, 13, 14). When assuming the recumbent position at bedtime, the fluid retained in the legs during the day is redistributed to the upper body (15). It is therefore plausible that some of this displaced fluid might reach the neck and predispose to upper airway obstruction. We therefore undertook the present study to test the hypotheses that the greater the amount of fluid displaced from the legs overnight, the greater will be the increase in neck circumference and severity of OSA as assessed by the frequency of apneas and hypopneas per hour of sleep (i.e., the apnea–hypopnea index [AHI]), and that the amount of fluid displaced from the legs overnight will be proportional to the time spent sitting the previous day. Some of the data reported herein have been published in abstract form (16).
Subjects The protocol was approved by the local research ethics board, and all subjects provided written informed consent before participation. We studied consecutive nonobese (body mass index [BMI] < 30 kg/m2) men at least18 years of age, referred to the sleep laboratory because of snoring or suspected OSA. Exclusion criteria included tonsillar hypertrophy, present smoking, alcohol abuse, history of hypertension or other chronic disease, use of prescribed medications, and previously diagnosed OSA. Subjects refrained from alcohol, sedative medications and caffeine for 12 hours before sleep studies. The evening of the sleep study, subjects were examined for tonsillar hypertrophy and pitting edema of the legs.
Sleep Studies
Weight, Leg Fluid Volume, and Neck and Calf Circumferences
Assessment of Sitting during the Day
Statistical Analysis
We studied 23 subjects whose characteristics are displayed in Table 1. Insensible fluid loss led to a 0.3% overnight reduction in body weight (see Table 1). As shown in Figure 1, we found that the variable that correlated best with the AHI was the overnight change in LFV, such that the more fluid was displaced from the leg at night, the greater the AHI. This relationship was best described by an exponential curve (r2 = 0.643, P < 0.001; see Figure 1), although the linear relationship was also significant (r2 = 0.597, P < 0.001). None of the subjects had pitting edema of either leg. There were also significant linear correlations between the AHI and the overnight change in neck circumference (P = 0.035), the sitting time (P = 0.008), and the out-of-bed time (P = 0.044), but not with age, BMI, or neck circumference before or after sleep (Table 2). The multivariate analysis showed that the only significant independent correlates of the AHI were the overnight change in LFV and change in neck circumference (P < 0.001 and P = 0.039, respectively), which together accounted for 67.7% (r2 = 0.677) of the variability in the AHI (Table 3).
The only significant independent correlate of the change in neck circumference was the overnight change in LFV (r2 = 0.627, P < 0.001; Figure 2): the more fluid that shifted out of the leg, the greater the increase in neck circumference. The strongest correlate of the overnight change in LFV was the time spent sitting: the longer the sitting time, the more fluid shifted rostrally overnight (r2 = 0.346, P = 0.003; Figure 3). The change in LFV also correlated significantly with age and out-of-bed time but not with height or BMI (Table 4). Multivariate analysis revealed that both sitting time and age correlated significantly and independently with the change in LFV (P = 0.006 and P = 0.026, respectively) and, together, accounted for 49.4% (r2 = 0.494) of its variability among subjects (Table 5).
Our study has given rise to several novel findings that provide insights into the pathogenesis of OSA, and suggest new approaches to its prevention and therapy. First, and most importantly, we found in nonobese, otherwise healthy men with no clinically detectable edema that the frequency of obstructive apneas and hypopneas during sleep (i.e., the AHI) was strongly and independently related to the amount of fluid spontaneously displaced from the legs overnight. Second, our observation that the overnight change in neck circumference was also strongly related to the overnight change in LFV indicates that a portion of the fluid displaced from the legs via the abdomen was redistributed into the neck. Indeed, the overnight changes in LFV and neck circumference were the only independent correlates of the AHI, and together accounted for 68% of its variability among subjects. Third, we found that the overnight change in LFV was proportional to the time spent sitting the previous day. Therefore, an important implication of our observations is that sedentary living may predispose to OSA not only by promoting obesity, but also by causing dependent fluid accumulation in the legs, which can shift rostrally into the neck overnight. Manipulation of this fluid displacement may therefore provide a novel approach to prevention and therapy of OSA in some nonobese subjects. In previous studies, we showed that the displacement of approximately 160 to 190 ml of fluid from each leg by application of lower body positive pressure caused an increase in neck circumference, a decrease in upper airway caliber (6), as well as increases in upper airway resistance (7) and collapsibility (8) in healthy, nonobese subjects while awake. In keeping with those findings, the present study demonstrates that such fluid displacement from the legs into the neck can occur spontaneously during sleep and is strongly and independently related to the AHI. Hence, accumulation of fluid in the neck, whether in the blood vessels or the interstitial space, may increase extralumenal tissue pressure, narrow the upper airway, and predispose to its collapse during sleep. The exponential relationship between change in AHI and LFV may be related to the fact that the resistance to airflow increases to the fourth power of the reduction in radius of the upper airway lumen. In contrast, there was no significant relationship between the AHI and either BMI or baseline neck circumference. Even among the general population, including obese subjects, BMI and neck circumference, the most widely used variables to describe adiposity in relation to OSA, together account for only approximately one third of the variability in AHI (21, 22). Taken together, these data suggest that in nonobese subjects, overnight rostral fluid displacement can participate in the pathogenesis of OSA. Whether the same applies to obese subjects remains to be tested. Body fluid distribution is influenced by body posture. During sitting or motionless standing, the height of the venous blood column to the level of the heart is higher than in the supine position. This greater gravitational force sequesters blood in the capacitance vessels of the legs. The consequent higher capillary hydrostatic pressure results in higher transcapillary fluid filtration into the interstitial tissue spaces of the legs in accordance with Starling's equation (23, 24). The activation of the muscular leg pump during walking decreases the venous blood pressure and is the principal mechanism preventing fluid accumulation in the legs (9–12). Accordingly, the amount of fluid accumulated in the lower extremities at the end of the day is proportional to the amount of time spent in the sitting position during the day (9, 10, 13, 14) and is associated with an increase in total body water (14). When subjects assume the recumbent position, the interstitial fluid accumulated in the legs is reabsorbed into the intravascular compartment (23) and is redistributed into the upper body in relation to gravitational forces (15, 24, 25). Consistent with these principles, we found that an important determinant of the overnight change in LFV was the time spent sitting the previous day. This suggests that one mechanism, other than weight gain, by which sedentary living could contribute to the development of OSA is through daytime accumulation of fluid in the legs, which is redistributed rostrally at bedtime. In keeping with these considerations, an inverse relationship between the amount of exercise during the week, and the severity of OSA that is independent of BMI has been reported (26, 27). It is possible that the time our subjects spent sitting was also a marker of level of physical activity and cardiovascular fitness, but we did not assess cardiovascular fitness in our subjects. Moreover, a reduction in OSA severity has been described after an exercise intervention without concomitant change in body weight (28). Hence, exercise may protect against, or reduce severity of, OSA apart from any effect on body weight, but the underlying mechanism for this effect remains unknown. Our results suggest that one mechanism by which exercise can attenuate OSA is by prevention of fluid accumulation in the legs, and a consequent reduction in fluid displacement into the neck during sleep. This hypothesis merits testing. Older age might also contribute to fluid accumulation in the legs as suggested by the observation that age correlated independently with the amount of fluid shifting rostrally overnight (see Tables 4 and 5). Dependent fluid accumulation in the legs is more likely to occur in the elderly because of reduced activity and compromised function of the venous valves of the legs that allow gravitational fluid accumulation (29). Indeed, other investigators have reported that OSA prevalence increases progressively with age (1). However, in our study, we found that once the overnight change in LFV was taken into account in multivariable analysis, there was no significant influence of age on AHI (see Tables 2 and 3). These observations support the possibility that if older age is related to the severity of OSA, it may be so partly through its effect on dependent fluid retention in the legs. To avoid the potentially confounding influence of obesity on the AHI, we confined our study to nonobese subjects. In this population, we found no significant relationship between BMI and AHI. Because approximately 60% of subjects with OSA in the community are nonobese (4), our findings may be relevant to a large proportion of individuals with OSA. However, our finding may not be applicable to obese patients. Nevertheless, because obesity is frequently associated with inactivity, and salt and fluid retention (30), the possibility that rostral fluid redistribution at bedtime might also be a factor predisposing obese subjects to OSA warrants testing. Because we also confined our study subjects to men to avoid the potentially confounding influence of sex on susceptibility to OSA (1), our results may not be applicable to women. It would therefore be important to compare overnight LFV shifts in men and women to see whether this relates to differing susceptibility to OSA between the sexes. As important as dependent fluid accumulation and overnight rostral fluid redistribution may be in predisposing to OSA in otherwise healthy subjects, such a mechanism may play an even more important role in patients with fluid-retaining states, such as heart and renal failure. The potential for them to experience greater rostral fluid shift overnight might, in part, explain the higher prevalence of OSA in these patients than in the general population, despite lower BMI (31). Two observations favor this possibility. First, in a nonrandomized, uncontrolled study involving patients with diastolic heart failure and OSA, intensive diuresis was accompanied by attenuation of OSA in association with an increase in pharyngeal caliber (32). Second, in patients with end-stage renal failure, after conversion from nocturnal peritoneal dialysis to continuous peritoneal dialysis the severity of OSA increased in association with a reduction in the amount of fluid removed during the night (33). In the present study we did not analyze the time course of the overnight rostral fluid shift because contraction of the leg muscles, knee flexion, and contact between the two legs, which invariably occurred during sleep, interfere with the accuracy of the LFV measurement (20). However, in a previous study, two phases of the rostral fluid displacement were identified on the transition from the standing to the supine position. Initially, there was a shift of intravascular fluid from the lower extremities to the upper body within a few seconds, followed by displacement of extravascular fluid over the next several hours, most of which occurred within 30–60 minutes (25). This suggests that rostral fluid displacement from the legs while recumbent occurs fairly rapidly. The bioelectrical impedance technique is accurate in euvolemic and hypervolemic subjects, but may be less so in those who are anorexic or severely malnourished (34). It is also most accurate in subjects under the age of 80 years (35). Accuracy is also greatest at ambient temperatures of 22.3 to 27.7°C (36). Because our subjects were all euvolemic, were not malnourished, were all under the age of 80 years, and were studied at room temperatures of 22 to 25°C, measurements of LFV should not have been subject to artifacts related to these factors. Because this study was observational in nature, the results do not prove a cause–effect relationship between overnight rostral fluid shift and OSA. Nevertheless, the finding that the degree of this fluid shift was proportional to the time spent sitting suggests that this fluid shift is contributing to the severity of OSA, rather than the opposite. One limitation of our study was that assessment of sitting time was by self-report. However, by providing an hour-by-hour schedule for the subjects to fill in on a working day immediately before they arrived in the sleep laboratory that evening, we aimed to facilitate the recollection of their activities on a routine working day, making computation of the time sitting, standing, and laying down simple and easy. Notwithstanding this limitation, the novelty of these findings does create a strong rationale to undertake randomized trials to determine whether reducing such fluid shift reduces the severity of OSA. For example, one could test the effects of raising the head of the bed to prevent fluid displacement into the neck during sleep, or using diuretics or an exercise intervention to reduce dependent fluid accumulation during the day, and thereby reduce rostral fluid displacement during the night. In conclusion, our findings may have important implications for the pathogenesis and therapy of OSA in nonobese men. The observation of a strong relationship between the amount of fluid displaced from the legs into the neck overnight and the AHI, that is independent of BMI, suggests that such fluid displacement can contribute to the pathogenesis of OSA. The degree of fluid displacement overnight was in turn related to the amount of time spent sitting, suggesting that a sedentary way of life may predispose to OSA independently of any effect of adiposity. Thus sedentary living and dependent fluid accumulation may be modifiable risk factors that could be therapeutic targets in the management of some patients with OSA. Testing this hypothesis will require further studies to determine whether preventing leg fluid accumulation during the day, or rostral fluid shift overnight, reduces the AHI in patients with OSA.
Supported by operating grant MOP-82731 from the Canadian Institutes of Health Research. S. Redolfi was supported by research fellowships from the University of Brescia, Italy and the Toronto Rehabilitation Institute; D. Yumino by an unrestricted research fellowship from Fuji Respironics Inc.; P. Ruttanaumpawan by research fellowships from Siriraj Hospital, Bangkok, Thailand and the Toronto Rehabilitation Institute; and M.-C. Su by a research fellowship from Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan. Originally Published in Press as DOI: 10.1164/rccm.200807-1076OC on November 14, 2008 Conflict of Interest Statement: S.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.Y. received an unrestricted research grant from Fuji-Respironics Inc. P.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. B.Y. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M-C.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. T.D.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form July 13, 2008; accepted in final form November 10, 2008
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