pii: jc- 00452-15
http://dx.doi.org/10.5664/jcsm.6190
S CI E NT IF IC IN VES TIGATIONS
Relationship of Fluid Accumulation in the Neck to Sleep Structure in Men during Daytime Sleep Azadeh Yadollahi, PhD1,2, Daniel Vena, MSc2; Owen D. Lyons, MBBCh1,3,4; T. Douglas Bradley, MD1,3,4 Toronto Rehabilitation Institute-University Health Network , Toronto, Canada; 2Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada; Centre for Sleep Medicine and Circadian Biology, University of Toronto, Toronto, Canada; 4Department of Medicine, University Health Network, Toronto General Hospital, Toronto, Canada 1 3
Study Objectives: Induction of fluid overload during sleep in older men causes fluid accumulation in the neck, worsens obstructive sleep apnea (OSA), and reduces sleep efficiency and slow wave sleep. However, it is not clear whether disrupted sleep structure was related to age, fluid accumulation, or to OSA severity as assessed by the apnea-hypopnea index (AHI). We hypothesize that fluid accumulation in the neck is a significant contributor to the sleep structure. Methods: Twenty non-obese men, 46 ± 11 years, underwent a daytime sleep study following a night of sleep deprivation. Before and after sleep, neck circumference (NC), upper airway cross-sectional area, and neck fluid volume (NFV) were assessed. Stepwise regression analyses were used to determine factors that contributed to sleep structure, AHI, and arousal frequency. Independent factors were age, NC, ΔNC, ΔNFV, and AHI (excluded for AHI and arousal). Results: Subjects slept for 145 ± 44 minutes with a mean AHI of 26 ± 25. After sleep, NC and NFV increased and the upper airway narrowed (all: p < 0.001). ΔNC and ΔNFV correlated directly with %N2 and inversely with %N3 sleep. Regression analyses revealed that only ΔNC correlated directly with %N2 sleep (r2 = 0.44, p = 0.001). ΔNC, ΔNFV, and pre-sleep NC correlated inversely with %N3 sleep (r 2 = 0.76, p < 0.001). Pre-sleep NC and ΔNC correlated directly with AHI and arousal frequency. Conclusions: Fluid accumulation in the neck and larger neck circumference are related to impaired sleep structure with reduced %N3 sleep. Fluid accumulation in the neck had stronger contribution to sleep structure than AHI or age. Keywords: neck fluid volume, obstructive sleep apnea, rostral fluid shift, sleep structure Citation: Yadollahi A, Vena D, Lyons OD, Bradley TD. Relationship of fluid accumulation in the neck to sleep structure in men during daytime sleep. J Clin Sleep Med 2016;12(10):1365–1371.
I N T RO D U C T I O N
BRIEF SUMMARY
Sleep has significant effects on physiological and psychological function. Poor sleep quality characterized by sleep fragmentation and insufficient sleep are associated with increased daytime sleepiness as well as increased risk of car and workrelated accidents, poor work performance, neurocognitive disorders, and several chronic diseases.1–6 Various factors such as total sleep time, sleep efficiency, absolute and percentage time spent in each sleep stage, degree of sleep fragmentation, and sleep latency may be assessed by polysomnography for the objective assessment of sleep quality and structure. Increasing age, male sex, and obstructive sleep apnea (OSA) are associated with reduced sleep efficiency, decreased proportion of slow wave (N3) sleep, and increased sleep fragmentation.7,8 OSA occurs due to recurrent upper airway collapse during sleep.9 While several factors contribute to the pathophysiology of OSA, we showed that its severity, assessed by the frequency of apneas and hypopneas per hour of sleep (apnea-hypopnea index [AHI]), is directly related to the amount of fluid displaced from the legs to the neck overnight while recumbent.10 Such displacement of fluid into the neck can narrow the upper airway,10–13 increase its resistance14,15 and collapsibility16; all of which could contribute to the worsening of OSA.17,18 1365
Current Knowledge/Study Rationale: While it is known that age and sleep apnea severity worsen sleep structure, our previous studies show a strong association between total body water and sleep structure. We hypothesized that fluid accumulation in the neck is a significant contributor to the sleep structure. Study Impact: This is the first study to show that compared to sleep apnea severity or age, fluid accumulation in the neck had a stronger contribution to impair sleep structure and reduce slow wave sleep.
Interventions that reduce fluid accumulation in the legs during the day and rostral fluid shift into the neck at night can reduce severity of OSA. For example, Kasai et al. showed that intensified diuretic therapy in drug-resistant hypertensive patients reduced total body water, the amount of fluid displaced from the legs overnight, the degree of the overnight increase in neck circumference (NC), the AHI and frequency of arousals from sleep.19 In end-stage renal disease patients, fluid removal by ultrafiltration reduced AHI and improved sleep structure.20,21 In addition, wearing compression stockings during the day for two weeks reduced leg fluid volume, overnight fluid shift out of the legs, and the AHI, both in the general OSA population and in OSA patients with venous insufficiency.22,23 Conversely, we showed that inducing fluid overload via an intravenous saline infusion of approximately 2L during sleep, led to an increase Journal of Clinical Sleep Medicine, Vol. 12, No. 10, 2016
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in fluid accumulation in the neck, induction or worsening of OSA, and a reduction in sleep efficiency and N3 sleep time.24 Also, these effects were more pronounced in older men than younger men.24 Similarly, patients with fluid retaining conditions, such as heart failure and renal failure, have poor sleep quality compared to the general population.25–28 While these observations suggest that fluid accumulation in the neck at night could have adverse effects on sleep structure, it is not clear whether such effects are related to fluid accumulation per se, to age, to the worsening of OSA, or all. A recent study showed that after controlling for age, AHI, sex, BMI, arousal index, and diabetes, the presence of endstage renal disease is independently associated with reduced total and REM sleep.29 The authors concluded that fluid overload, uremia, or both could contribute to the reduced sleep time. While the underlying mechanisms are not investigated, it is possible that increases in upper airway mucosal edema may, in the absence of increased AHI or elevated upper airway resistance, narrow the upper airway, increase inspiratory flow limitation, negatively impair sleep structure and lead to more fragmented sleep. Several studies have shown an association between fluid volume status and sleep structure in fluid overloaded patients20,21,29; however, the potential contribution of fluid accumulation in the neck on sleep structure in the general population has not been investigated. Accordingly, the objective of this study was to test the hypothesis that fluid accumulation in the neck could negatively alter sleep structure. METHODS
Subjects
Subjects were recruited by advertisement. Inclusion criteria were non-obese men (body mass index < 30 kg/m2), aged 18–70 years, and a blood pressure of ≤ 140/90 mm Hg. Since our previous studies showed that men are more susceptible to the adverse effects of rostral fluid shift than women,11,13,30 only men were included in this study. Exclusion criteria were a history of cardiovascular, renal, neurological or respiratory diseases, taking any prescribed medication for these disorders or any over-the-counter medication that might influence fluid retention, a previous diagnosis of OSA, taking any treatment for sleep apnea, or having less than one hour of sleep during the protocol. Subjects with central dominant sleep apnea (> 50% of apneas and hypopneas were central) were excluded from the study.
Sleep Studies
For the convenience of subjects and the research personnel to conduct the protocol, daytime polysomnography was performed. To facilitate daytime sleep, subjects underwent voluntary sleep restriction to less than 4 hours the night before the study to induce sleepiness. Standard techniques and criteria were used for scoring sleep stages and arousals. Thoracoabdominal motion was monitored by respiratory inductance plethysmography, nasal pressure by nasal cannula and arterial oxyhemoglobin saturation (SpO2 ) by oximetry.31 Apneas were defined as > 90% reduction in tidal volume lasting ≥ 10 sec. Journal of Clinical Sleep Medicine, Vol. 12, No. 10, 2016
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Hypopneas were defined as 50% to 90% reduction in tidal volume, lasting ≥ 10 sec, and being associated with arousals or minimum 3% reductions in SpO2. Apneas and hypopneas were classified as obstructive if there was out-of-phase thoracoabdominal motion or flow limitation on the nasal pressure tracing; otherwise, they were classified as central.32 Sleep studies were scored by personnel blind to the fluid measurements and vice versa.
Measurements Upper Airway Cross-Sectional Area and Neck Circumference With subjects supine, prior to sleep, upper airway crosssectional area (UA-XSA) was measured by acoustic pharyngometry,33 and NC was assessed by a tape measure above the cricothyroid cartilage. A line was drawn at this level to ensure that measurements after sleep were made at the same level. Both measurements were repeated immediately after waking up from sleep.12 Neck Fluid Volume Previously, we developed a method to measure fluid volumes in various body segments using bioelectrical impedance.13 Bioelectrical impedance of a tissue is inversely related to its fluid content. In this study, we used MP150 Biopac System and EBI100C module to measure bioelectrical impedance and estimate neck fluid volume (NFV). Two electrodes injected a low amplitude (400 μA) current at 50 kHz, and 2 electrodes measured voltage to calculate bioelectrical impedance.34 The voltage recording electrodes were placed on the right side of the neck below the right ear and at the base of the neck, and the injecting electrodes were placed one inch from the sensing electrodes, as described before.13 The electrodes were secured to the skin with adhesive tape. Considering the effects of length and circumference of the neck, its fluid volume can be estimated as35:
ρ 2 L5 C 2 V= 4π R 2
1/3
(1)
where C is the neck circumference, ρ is the resistivity, R is the measured impedance, and L is neck length measured as the distance between voltage electrodes on the neck. Neck length was measured before sleep and measurements of NC before and after sleep were used to estimate NFV in the evening and morning, respectively. In a study of 73 healthy subjects ρ was estimated to be 47 Ωcm.34
Protocol
This study was part of a randomized, double crossover protocol to investigate the effects of fluid overloading by saline infusion on OSA severity in men.24 For purposes of the present study, we used data from the control arm of the original protocol. In this arm of the protocol, subjects had an intravenous cannula inserted with a very negligible amount of normal saline infused just sufficient to keep the vein open (approximately 100 mL), as opposed to the intervention arm in which 22 mL/kg body weight (approximately 2,000 mL) was infused as a bolus just after sleep onset. The saline solution was
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Figure 1—Schematic of the study protocol.
Table 1—Baseline characteristics and sleep data of the 20 subjects.
warmed to body temperature by placing the bag containing the solution in warm water at 37°C, prior to use so as not to induce coolness, and possibly arousals in the arm being infused. Subjects arrived in the sleep laboratory at noon following a night of sleep deprivation and were instrumented for sleep studies. Subjects were randomized after they were set up to start the experiment into a control or intervention arm using a computer-generated randomization table with unequal blocks of 2 and 4. Although subjects were blind to the intervention, experimenters were of necessity not blinded. However, personnel analyzing the results were kept blind to randomization. Subjects slept supine on a single pillow for the entire study period to eliminate any potential effect of postural changes on AHI and other variables. Two small sandbags were placed beside the head to limit the head movement and facilitate supine sleep. In the rare occasions that subjects changed their posture, the technician would enter the room and correct their position to supine. Before sleep, baseline measurements including UAXSA, NC, and NFV, were made with subjects supine. Once subjects woke up, baseline measurements were repeated (Figure 1). One week after the initial session, subjects crossed over to the other arm of the study. The protocol was approved by the Research Ethics Board of Toronto Rehabilitation Institute, and all subjects provided written consent prior to participation.24
Data Analysis
Changes (Δ) in NC, UA-XSA, and NFV from pre- to post-sleep were calculated and their statistical significance were assessed by pairwise comparison using paired t-test or Wilcoxon ranksum test for normally and non-normally distributed data, respectively. Correlations between sleep structure (% of time spent in different sleep stages) and age, pre-sleep NC, ΔNC, ΔUA-XSA, ΔNFV, and AHI were investigated by Pearson or Spearman rank functions. Step-wise regression models were used to determine factors that contributed to the variations in sleep structure, 1367
Age, years Height, cm Weight, kg BMI, kg/m2 NC, cm UA-XSA, cm2 Neck length, cm NFV, mL Total sleep time, min N1 sleep, % of TST N2 sleep, % of TST N3 sleep, % of TST REM sleep, % of TST Sleep efficiency, % Total AHI, events/h Obstructive AHI, events/h Central AHI, events/h non-REM AHI, events/h REM AHI, events/h Arousal index, arousals/h Mean SpO2
45.8 ± 11.1 176.2 ± 6.5 79.2 ± 10.5 25.7 ± 3.0 42.0 ± 2.9 2.6 ± 0.6 11.4 ± 1.6 265.3 ± 47.6 144.7 ± 44.1 20.0 ± 11.5 58.9 ± 13.7 11.7 ± 13.5 9.4 ± 8.5 71.8 ± 16.8 26.3 ± 24.8 24.7 ± 24.7 3.3 ± 6.8 26.6 ± 27.3 36.0 ± 21.3 29.1 ± 17.1 90.9 ± 4.4
Data are expressed as mean ± standard deviation. AHI, apneahypopnea index; BMI, body mass index; NC, neck circumference; NFV, neck fluid volume; REM, rapid eye movement; TST, total sleep time; UAXSA, upper airway cross-sectional area.
AHI, and arousal index (arousals per hour of sleep). The models for %N1, %N2, %N3, and % rapid-eye movement (REM) sleep stages included age, pre-sleep NC, ΔNC, ΔNFV, and total AHI. The models for AHI and arousal index included age, presleep NC, ΔNC, and ΔNFV. Statistical analyses were performed by SAS 9.3 and a two-sided p value < 0.05 was considered significant. Data are presented as mean ± standard devaiation. R ES U LT S Of the 26 men who participated in this study, one was excluded because he could not fall asleep and 5 were excluded because they had central dominant sleep apnea. The baseline characteristics of 20 men who completed the study are presented in Table 1. The amount of intravenous saline infused to keep vein open during the study was 98 ± 11 mL. Participants slept for an average of 145 ± 44 min (Table 1), with an average sleep latency of 3.1 ± 3.4 minutes. All participants had NREM sleep and 16 of them had REM sleep. Although we advertised for participants with no history of sleep apnea and excluded those with clinical diagnosis of sleep apnea or taking any treatment for sleep apnea, the participants had a wide range of AHIs, between 0.7 and 86.2. Eleven subjects had moderate to severe sleep apnea (AHI ≥ 15), with an average AHI of 42.4 ± 24.3. Nine subjects had no or mild sleep apnea (AHI < 15) with an average AHI of 6.9 ± 4.4 events/h. Journal of Clinical Sleep Medicine, Vol. 12, No. 10, 2016
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Pairwise comparisons revealed that from before to after sleep, there were significant increases in NC and NFV and a significant decrease in UA-XSA (∆NC: 0.6 ± 0.4cm, ∆NFV: 17.8 ± 7.5ml, ∆UA-XSA: −0.3 ± 0.3cm2, p < 0.001 for all variables). Correlation analysis showed that the increase in NFV correlated significantly with the reduction in UA-XSA (Figure 2). Age was associated with a significant increase in NC (r = 0.56, p = 0.009), which was independent of pre-sleep NC (p > 0.15). Increased
Figure 2—The relationship between the changes in neck fluid volume (NFV) and upper airway cross-sectional area (UA-XSA) after sleep.
age showed a nonsignificant tendency for higher AHI (r = 0.43, p = 0.06) and arousal index (r = 0.42, p = 0.07). Correlation analysis demonstrated that the percentage of N1 sleep was greater in subjects with higher AHIs (r = 0.55, p = 0.010) and arousal indices (r = 0.71, p < 0.001). Percentage of N2 sleep correlated directly with age (r = 0.62, p = 0.003) and increases in NC and NFV after sleep (Figure 3). Percentage of N3 sleep had significant inverse correlations with age (r = −0.75, p < 0.001) and %ΔNC (Figure 3), and a borderline significant inverse correlation with %ΔNFV (Figure 3). Furthermore, lower %N3 sleep correlated with higher AHIs and arousal indices (AHI: r = −0.50, p = 0.021, arousal index: r = −0.59, p = 0.005). There was no significant relationship between %REM sleep and ΔNC, ΔUA-XSA, or ΔNFV. Table 2 shows the results of stepwise regression analysis to predict the factors that could contribute to the variations in the sleep structure. The only significant factor related to %N1 sleep was the AHI (Table 2). The only factor that contributed directly to %N2 sleep was the ΔNC after sleep (Table 2). Three factors that contributed inversely and independently to %N3 sleep were ΔNC, ΔNFV, and pre-sleep NC (Table 2). Together, these factors accounted for 76% of the variability in %N3 sleep (p < 0.0001). Only AHI contributed significantly to the percentage of REM sleep (Table 2). Pre-sleep NC and ΔNC after sleep significantly contributed to both AHI (r2 = 0.56, p = 0.001) and arousal index (r2 = 0.57, p = 0.001). D I SCUS S I O N The most important and novel finding of our study was that increased fluid accumulation in the neck during supine sleep was associated with worsening of sleep structure in men. We found
The reduction in UA-XSA correlated directly with the increase in NFV.
Figure 3—The relationship between percentages of N2 and N3 sleep and changes in (A) neck circumference (NC) and (B) neck fluid volume (NFV) after sleep.
AB
The percentage of N2 sleep correlated directly with changes in NC and NFV after sleep. The percentage of N3 sleep correlated inversely with the change in NC. There was also a borderline significant inverse correlation between percentage N3 sleep and NFV after sleep.
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Table 2—Results of stepwise regression analysis to predict the factors that could contribute to the variations in the sleep structure. The models for N1, N2 and N3 included age (years), NC (cm), ΔNC (cm), ΔNFV (mL), and total AHI (events/h). Dependent Variable N1, %
Step 1
Variable entered AHI
N2, %
1
ΔNC, cm
N3, %
1 2 3
REM, %
1
Estimate 0.19
Partial R2 0.23
Model R2 0.23
p value in the final model 0.032
25.42
0.44
0.44
0.001
ΔNC, cm ΔNFV, mL NC, cm
−23.19 −0.96 −2.13
0.42 0.16 0.18
0.42 0.58 0.76
0.001 0.017 0.002
AHI
−0.15
0.22
0.22
0.04
AHI, apnea-hypopnea index; NC, neck circumference; NFV, neck fluid volume; REM, rapid eye movement.
that the greater the increase in NC during sleep, the greater the arousal index and percentage of N2 sleep and the lower the percentage of N3 sleep. While age and total AHI correlated inversely with percentage of N3 sleep, neither age nor AHI contributed significantly to the variations in the percentage of N3 sleep when the model included NC, ΔNC, and ΔNFV. While fluid accumulation in the neck during sleep could negatively alter sleep structure by increasing AHI and arousals, these results suggest that the correlation between sleep structure and fluid accumulation in the neck is stronger than those with AHI or age. We also found that older men had a greater increase in NC after sleep. Therefore, we may conclude that one of the mechanisms through which aging could contribute to the variations in sleep structure is by facilitating more fluid accumulation in the neck during sleep. Our results suggest that baseline NC and fluid accumulation in the neck during sleep affect sleep structure. We found that the percentage of N3 sleep correlated inversely with the increase in NC and NFV after sleep. On the other hand, the percentage of time spent in N2 sleep correlated significantly with the increase in NC after sleep independent of other factors. Furthermore, subjects with larger pre-sleep NC and greater increases in NC during sleep had more sleep fragmentation, as assessed by arousal index. Our findings are the first to suggest that changes in NC or NFV during sleep could negatively alter sleep structure by increasing sleep fragmentation. Arousal is directly related to the pressure generated by the pharyngeal muscles to open the airways.36 Patients with poor passive anatomy of the upper airway or lower upper airway gain are more likely to have an arousal before pharyngeal muscles could open the airways.37 As previously shown, we found that NC increased from pre- to post-sleep.24 However, we have extended this previous observation by demonstrating that this increase in NC was associated with an increase in NFV and a reduction in UA-XSA. Accordingly, increased pharyngeal tissue pressure resulting from an increase in fluid volume of the internal jugular veins and/or peripharyngeal soft tissue likely contributed to this narrowing of the upper airway.9,38 The observed increases in NC and NFV in association with a decrease in UA-XSA could increase upper airway resistance and collapsibility14,16,30 during sleep. Together, these changes could impair the passive anatomy of the upper airway, impair upper airway gain, and increase the likelihood of arousals.9,39 Indeed our results show that pre-sleep NC and
change in NC after sleep were the significant factors that increased arousal index. It has been shown previously that OSA severity is a factor that negatively alters sleep structure.8,9,40,41 Previous studies from our group show that fluid overloading by intravenous saline infusion of about 2 liters during sleep increased NC and AHI, and decreased the proportion of N3 sleep in older men.24 Conversely, in patients with end stage renal disease and sleep apnea, who were on hemodialysis thrice-weekly, the removal of an additional 2L of fluid by ultrafiltration was associated with a reduction in the AHI and an increase in N3 sleep.20 While these studies show the effects of fluid accumulation on sleep structure and sleep apnea severity, our current results are unique in demonstrating a model that represents the effects of fluid accumulation in the neck on sleep structure and sleep apnea severity. More importantly, this model shows that the contribution of fluid accumulation in the neck on sleep structure is more significant than those due to the AHI. Furthermore, in the present study, there was no significant relationship between the proportion of REM sleep and either ΔNC, ΔUAXSA, or ΔNFV, in keeping with our previous findings that fluid accumulation in the neck is associated with a reduction in N3, but not REM sleep.24 In a cross-sectional study of 2,685 participants aged 37 to 92 years, Redline et al. demonstrated that aging was associated with a decreased percentage of N3 and REM sleep, and a higher arousal index in men, independent of BMI and sleep disordered breathing.8 Similar to these studies, our results show that with aging, the proportion of N3 sleep decreases, and there is a tendency for increased AHI and arousal index. However, when we included ∆NC, ∆NFV in the stepwise regression models, neither age nor AHI contributed significantly to the variations in percentages of N2 or N3 sleep. This observation raises the possibility that aging could contribute to the changes in sleep structure by facilitating more fluid accumulation in the neck. Indeed, in our previous study in which we infused a bolus of saline into younger and older men during sleep, we found a greater accumulation of fluid in the neck of the subjects older than 40 years old than in those aged 40 years or less.24 Similarly, Redolfi et al. showed that in 23 non-obese men, age was a significant independent predictor of the overnight accumulation of fluid in the neck as assessed by change in NC, and was in turn strongly related to the amount of fluid moving out of the legs overnight.12 Despite the evidence, however, it is still
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possible that aging is independently associated with both increased fluid shift into the neck and reduced percentage of N3 sleep through other mechanisms. As such, the design of this study, while suggestive, does not prove a causal link between fluid shift and percentage of N3 sleep. Our study is subject to some limitations. To avoid the potential confounding effects of obesity on obstructive sleep apnea and fluid retention, we limited our study to non-obese subjects (BMI < 30). Our study was confined to men because previous studies showed that men accumulate more fluid in their necks than women while recumbent, and are more susceptible to the adverse effects of rostral fluid shift on upper airway physiology than women.11,30 Thus the present findings may not apply to women. Further studies will be required to determine if fluid accumulation in the neck in women influences sleep structure. For reasons of feasibility, sleep studies were performed during the day. While our subjects had an average sleep time of 145 minutes and 80% of them had at least one full sleep cycle including REM sleep, these findings may not be fully applicable to nocturnal sleep. We restricted sleeping position to supine to minimize the effects of posture on AHI variability and sleep structure. Therefore, our findings may not apply to the nonsupine positions. In this study, we investigated the relationship between fluid accumulation in the neck and AHI; however, AHI alone may not properly reflect severity of the upper airway narrowing during sleep. Future studies should investigate the relationship between fluid accumulation in the neck and other features such as percentage of inspiratory flow limitation, presence, and severity of snoring sounds. Lastly, while the study findings suggest an association between neck fluid accumulation and sleep structure, it is not possible to deduce causality given the observational nature of the study design. In conclusion, our findings indicate that fluid accumulation in the neck while recumbent could be a mechanism contributing to variations in sleep structure in men. While age is a well-known contributor to variations in sleep structure, our results suggest that those contributions may be due to the differing effects of aging on patterns of fluid redistribution, particularly into the neck, while recumbent during sleep. Further investigations will be required to determine why more fluid accumulates in the neck with aging, how fluid accumulation in the neck influences sleep structure, and whether alterations in upper airway anatomy and physiology play a role in this effect. The present findings, along with those of our previous studies, provide a strong rationale for testing the effects of reducing nocturnal rostral fluid shift and fluid accumulation in the neck on sleep structure in men. R E FE R E N CES 1. Johnson KD, Patel SR, Baur DM, et al. Association of sleep habits with accidents and near misses in United States transportation operators. J Occup Environ Med 2014;56:510–5. 2. Swanson LM, Arnedt JT, Rosekind MR, Belenky G, Balkin TJ, Drake C. Sleep disorders and work performance: findings from the 2008 National Sleep Foundation Sleep in America poll. J Sleep Res 2011;20:487–94. 3. Franzen PL, Siegle GJ, Buysse DJ. Relationships between affect, vigilance, and sleepiness following sleep deprivation. J Sleep Res 2008;17:34–41.
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4. Torelli F, Moscufo N, Garreffa G, et al. Cognitive profile and brain morphological changes in obstructive sleep apnea. NeuroImage 2011;54:787–93. 5. Morselli LL, Guyon A, Spiegel K. Sleep and metabolic function. Eur J Physiol 2012;463:139–60. 6. van Leeuwen WM, Lehto M, Karisola P, et al. Sleep restriction increases the risk of developing cardiovascular diseases by augmenting proinflammatory responses through IL-17 and CRP. PloS One 2009;4:e4589. 7. Moraes W, Piovezan R, Poyares D, Bittencourt LR, Santos-Silva R, Tufik S. Effects of aging on sleep structure throughout adulthood: a population-based study. Sleep Med 2014;15:401–9. 8. Redline S, Kirchner HL, Quan SF, Gottlieb DJ, Kapur V, Newman. A The effects of age, sex, ethnicity, and sleep-disordered breathing on sleep architecture. Arch Intern Med 2004;164:406–18. 9. Jordan AS, McSharry DG, Malhotra A. Adult obstructive sleep apnoea. Lancet 2014;383:736–47. 10. Shiota S, Ryan CM, Chiu KL, et al. Alterations in upper airway cross-sectional area in response to lower body positive pressure in healthy subjects. Thorax 2007;62:868–72. 11. Kasai T, Motwani SS, Yumino D, Mak S, Newton GE, Bradley TD. Differing relationship of nocturnal fluid shifts to sleep apnea in men and women with heart failure. Circulation. Heart Fail 2012;5:467–74. 12. Redolfi S, Yumino D, Ruttanaumpawan P, et al. Relationship between overnight rostral fluid shift and Obstructive Sleep Apnea in nonobese men. Am J Respir Crit Care Med 2009;179:241–6. 13. Yadollahi A, Singh B, Bradley TD. Differences in supine fluid redistribution within multiple body segments between men and women. Ann Biomed Eng 2015;43:2131–42. 14. Chiu KL, Ryan CM, Shiota S, et al. Fluid shift by lower body positive pressure increases pharyngeal resistance in healthy subjects. Am J Respir Crit Care Med 2006;174:1378–83. 15. Kasai T, Motwani SS, Yumino D, et al. Contrasting effects of lower body positive pressure on upper airways resistance and partial pressure of carbon dioxide in men with heart failure and obstructive or central sleep apnea. J Am Coll Cardiol 2013;61:1157–66. 16. Su MC, Chiu KL, Ruttanaumpawan P, et al. Lower body positive pressure increases upper airway collapsibility in healthy subjects. Respir Physiol Neurobiol 2008;161:306–12. 17. Schwab RJ, Pasirstein M, Pierson R, et al. Identification of upper airway anatomic risk factors for obstructive sleep apnea with volumetric magnetic resonance imaging. Am J Respir Crit Care Med 2003;168:522–30. 18. White LH, Bradley TD. Role of nocturnal rostral fluid shift in the pathogenesis of obstructive and central sleep apnoea. J Physiol 2013;591:1179–93. 19. Kasai T, Bradley TD, Friedman O, Logan AG. Effect of intensified diuretic therapy on overnight rostral fluid shift and obstructive sleep apnoea in patients with uncontrolled hypertension. J Hypertens 2014;32:673–80. 20. Lyons OD, Chan CT, Yadollahi A, Bradley TD. Effect of ultrafiltration on sleep apnea and sleep structure in patients with end stage renal disease. Am J Respir Crit Care Med 2015;191:1287–94. 21. Hanly PJ, Pierratos A. Improvement of sleep apnea in patients with chronic renal failure who undergo nocturnal hemodialysis. New Eng J Med 2001;344:102–7. 22. White LH, Lyons OD, Yadollahi A, Ryan CM, Bradley TD. Effect of belowthe-knee compression stockings on severity of obstructive sleep apnea: a randomized trial. Sleep Med 2015;16:258–64. 23. Redolfi S, Arnulf I, Pottier M, et al. Attenuation of obstructive sleep apnea by compression stockings in subjects with venous insufficiency. Am J Respir Crit Care Med 2011;184:1062–6. 24. Yadollahi A, Gabriel JM, White LH, Montemurro LT, Kasai T, Bradley TD. A Randomized, double cross-over study to investigate the influence of saline infusion on sleep apnea severity in men. Sleep 2014;37:1699–705. 25. Arzt M, Young T, Finn L, et al. Sleepiness and sleep in patients with both systolic heart failure and obstructive sleep apnea. Arch Intern Med 2006;166:1716–22. 26. Murtagh FE, Addington-Hall J, Higginson IJ The prevalence of symptoms in end-stage renal disease: a systematic review. Adv Chronic Kidney Dis 2007;14:82–99.
A Yadollahi, D Vena, OD Lyons et al. Fluid Shift and Sleep Structure 27. Unruh ML, Hartunian MG, Chapman MM, Jaber BL. Sleep quality and clinical correlates in patients on maintenance dialysis. Clin Nephrol 2003;59:280–8. 28. Hanly PJ, Gabor JY, Chan C, Pierratos A. Daytime sleepiness in patients with CRF: impact of nocturnal hemodialysis. Am J Kidney Dis 2003;41:403–10. 29. Elias RM, Chan CT, Bradley TD. Altered sleep structure in patients with endstage renal disease. Sleep Med 2016;20:67–71. 30. Su MC, Chiu KL, Ruttanaumpawan P, et al. Difference in upper airway collapsibility during wakefulness between men and women in response to lower-body positive pressure. Clin Sci (Lond) 2009;116:713–20. 31. Clark SA, Wilson CR, Satoh M, Pegelow D, Dempsey JA. Assessment of inspiratory flow limitation invasively and noninvasively during sleep. Am J Respir Crit Care Med 1998;158:713–22. 32. Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 2012;8:597–619. 33. Fredberg JJ, Wohl ME, Glass GM, Dorkin HL. Airway area by acoustic reflections measured at the mouth. J Appl Physiol Respir Environ Exerc Physiol 1980;48:749–58. 34. De Lorenzo A, Andreoli A, Matthie J, Withers P. Predicting body cell mass with bioimpedance by using theoretical methods: a technological review. J Appl Physiol 1997;82:1542–58. 35. Fenech M, Jaffrin MY Extracellular and intracellular volume variations during postural change measured by segmental and wrist-ankle bioimpedance spectroscopy. IEEE Trans Biomed Eng 2004;51:166–75. 36. Kimoff RJ, Cheong TH, Olha AE, et al. Mechanisms of apnea termination in obstructive sleep apnea. Role of chemoreceptor and mechanoreceptor stimuli. Am J Respir Crit Care Med 1994;149:707–14. 37. Joosten SA, Edwards BA, Wellman A, et al. The effect of body position on physiological factors that contribute to obstructive sleep apnea. Sleep 2015;38:1469–78. 38. Elias RM, Chan CT, Paul N, et al. Relationship of pharyngeal water content and jugular volume with severity of obstructive sleep apnea in renal failure. Nephrol Dial Transplant 2013;28:937–44.
39. Edwards BA, Wellman A, Sands SA, et al. Obstructive sleep apnea in older adults is a distinctly different physiological phenotype. Sleep 2014;37:1227–36. 40. Edwards BA, O’Driscoll DM, Ali A, Jordan AS, Trinder J, Malhotra A. Aging and sleep: physiology and pathophysiology. Semin Respir Crit Care Med 2010;31:618–33. 41. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. New Engl J Med 1993;328:1230–5.
SUBM I SSI O N & CO R R ESPO NDENCE I NFO R M ATI O N Submitted for publication October, 2015 Submitted in final revised form May, 2016 Accepted for publication May, 2016 Address correspondence to: T. Douglas Bradley, MD, University Health Network Toronto General Hospital, 9N-943, 200 Elizabeth Street, Toronto, ON., M5G 2C4, Canada; Tel: (416) 340-4719; Fax: (416) 340-4197; Email: douglas.bradley@ utoronto.ca
D I SCLO S U R E S TAT E M E N T This was not an industry supported study. This study was supported by a Canadian Institutes of Health Research (CIHR) operating grant MOP-82731. Dr. Yadollahi was supported by Fellowships from the Mitacs Elevate program and a CIHR Training Grant in Sleep and Biological Rhythms. Daniel Vena was supported by a Fellowship from the NSERC CREATE Academic Rehabilitation Engineering (CARE) training program. Dr. Lyons was supported by the Peter Macklem European Respiratory Society/Canadian Thoracic Society Joint Research Fellowship and the Joseph M. West Family Memorial Fund Postgraduate Research Award. Dr. Bradley was supported by the Clifford Nordal Chair in Sleep Apnea and Rehabilitation Research. Dr. Bradley has received research support from Philips Respironics and has financial interest in BresoTec Inc. The other authors have indicated no financial conflicts of interest. This research was performed at the Sleep Laboratory, Toronto Rehabilitation Institute.
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http://dx.doi.org/10.5664/jcsm.6190
S CI E NT IF IC IN VES TIGATIONS
Relationship of Fluid Accumulation in the Neck to Sleep Structure in Men during Daytime Sleep Azadeh Yadollahi, PhD1,2, Daniel Vena, MSc2; Owen D. Lyons, MBBCh1,3,4; T. Douglas Bradley, MD1,3,4 Toronto Rehabilitation Institute-University Health Network , Toronto, Canada; 2Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada; Centre for Sleep Medicine and Circadian Biology, University of Toronto, Toronto, Canada; 4Department of Medicine, University Health Network, Toronto General Hospital, Toronto, Canada 1 3
Study Objectives: Induction of fluid overload during sleep in older men causes fluid accumulation in the neck, worsens obstructive sleep apnea (OSA), and reduces sleep efficiency and slow wave sleep. However, it is not clear whether disrupted sleep structure was related to age, fluid accumulation, or to OSA severity as assessed by the apnea-hypopnea index (AHI). We hypothesize that fluid accumulation in the neck is a significant contributor to the sleep structure. Methods: Twenty non-obese men, 46 ± 11 years, underwent a daytime sleep study following a night of sleep deprivation. Before and after sleep, neck circumference (NC), upper airway cross-sectional area, and neck fluid volume (NFV) were assessed. Stepwise regression analyses were used to determine factors that contributed to sleep structure, AHI, and arousal frequency. Independent factors were age, NC, ΔNC, ΔNFV, and AHI (excluded for AHI and arousal). Results: Subjects slept for 145 ± 44 minutes with a mean AHI of 26 ± 25. After sleep, NC and NFV increased and the upper airway narrowed (all: p < 0.001). ΔNC and ΔNFV correlated directly with %N2 and inversely with %N3 sleep. Regression analyses revealed that only ΔNC correlated directly with %N2 sleep (r2 = 0.44, p = 0.001). ΔNC, ΔNFV, and pre-sleep NC correlated inversely with %N3 sleep (r 2 = 0.76, p < 0.001). Pre-sleep NC and ΔNC correlated directly with AHI and arousal frequency. Conclusions: Fluid accumulation in the neck and larger neck circumference are related to impaired sleep structure with reduced %N3 sleep. Fluid accumulation in the neck had stronger contribution to sleep structure than AHI or age. Keywords: neck fluid volume, obstructive sleep apnea, rostral fluid shift, sleep structure Citation: Yadollahi A, Vena D, Lyons OD, Bradley TD. Relationship of fluid accumulation in the neck to sleep structure in men during daytime sleep. J Clin Sleep Med 2016;12(10):1365–1371.
I N T RO D U C T I O N
BRIEF SUMMARY
Sleep has significant effects on physiological and psychological function. Poor sleep quality characterized by sleep fragmentation and insufficient sleep are associated with increased daytime sleepiness as well as increased risk of car and workrelated accidents, poor work performance, neurocognitive disorders, and several chronic diseases.1–6 Various factors such as total sleep time, sleep efficiency, absolute and percentage time spent in each sleep stage, degree of sleep fragmentation, and sleep latency may be assessed by polysomnography for the objective assessment of sleep quality and structure. Increasing age, male sex, and obstructive sleep apnea (OSA) are associated with reduced sleep efficiency, decreased proportion of slow wave (N3) sleep, and increased sleep fragmentation.7,8 OSA occurs due to recurrent upper airway collapse during sleep.9 While several factors contribute to the pathophysiology of OSA, we showed that its severity, assessed by the frequency of apneas and hypopneas per hour of sleep (apnea-hypopnea index [AHI]), is directly related to the amount of fluid displaced from the legs to the neck overnight while recumbent.10 Such displacement of fluid into the neck can narrow the upper airway,10–13 increase its resistance14,15 and collapsibility16; all of which could contribute to the worsening of OSA.17,18 1365
Current Knowledge/Study Rationale: While it is known that age and sleep apnea severity worsen sleep structure, our previous studies show a strong association between total body water and sleep structure. We hypothesized that fluid accumulation in the neck is a significant contributor to the sleep structure. Study Impact: This is the first study to show that compared to sleep apnea severity or age, fluid accumulation in the neck had a stronger contribution to impair sleep structure and reduce slow wave sleep.
Interventions that reduce fluid accumulation in the legs during the day and rostral fluid shift into the neck at night can reduce severity of OSA. For example, Kasai et al. showed that intensified diuretic therapy in drug-resistant hypertensive patients reduced total body water, the amount of fluid displaced from the legs overnight, the degree of the overnight increase in neck circumference (NC), the AHI and frequency of arousals from sleep.19 In end-stage renal disease patients, fluid removal by ultrafiltration reduced AHI and improved sleep structure.20,21 In addition, wearing compression stockings during the day for two weeks reduced leg fluid volume, overnight fluid shift out of the legs, and the AHI, both in the general OSA population and in OSA patients with venous insufficiency.22,23 Conversely, we showed that inducing fluid overload via an intravenous saline infusion of approximately 2L during sleep, led to an increase Journal of Clinical Sleep Medicine, Vol. 12, No. 10, 2016
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in fluid accumulation in the neck, induction or worsening of OSA, and a reduction in sleep efficiency and N3 sleep time.24 Also, these effects were more pronounced in older men than younger men.24 Similarly, patients with fluid retaining conditions, such as heart failure and renal failure, have poor sleep quality compared to the general population.25–28 While these observations suggest that fluid accumulation in the neck at night could have adverse effects on sleep structure, it is not clear whether such effects are related to fluid accumulation per se, to age, to the worsening of OSA, or all. A recent study showed that after controlling for age, AHI, sex, BMI, arousal index, and diabetes, the presence of endstage renal disease is independently associated with reduced total and REM sleep.29 The authors concluded that fluid overload, uremia, or both could contribute to the reduced sleep time. While the underlying mechanisms are not investigated, it is possible that increases in upper airway mucosal edema may, in the absence of increased AHI or elevated upper airway resistance, narrow the upper airway, increase inspiratory flow limitation, negatively impair sleep structure and lead to more fragmented sleep. Several studies have shown an association between fluid volume status and sleep structure in fluid overloaded patients20,21,29; however, the potential contribution of fluid accumulation in the neck on sleep structure in the general population has not been investigated. Accordingly, the objective of this study was to test the hypothesis that fluid accumulation in the neck could negatively alter sleep structure. METHODS
Subjects
Subjects were recruited by advertisement. Inclusion criteria were non-obese men (body mass index < 30 kg/m2), aged 18–70 years, and a blood pressure of ≤ 140/90 mm Hg. Since our previous studies showed that men are more susceptible to the adverse effects of rostral fluid shift than women,11,13,30 only men were included in this study. Exclusion criteria were a history of cardiovascular, renal, neurological or respiratory diseases, taking any prescribed medication for these disorders or any over-the-counter medication that might influence fluid retention, a previous diagnosis of OSA, taking any treatment for sleep apnea, or having less than one hour of sleep during the protocol. Subjects with central dominant sleep apnea (> 50% of apneas and hypopneas were central) were excluded from the study.
Sleep Studies
For the convenience of subjects and the research personnel to conduct the protocol, daytime polysomnography was performed. To facilitate daytime sleep, subjects underwent voluntary sleep restriction to less than 4 hours the night before the study to induce sleepiness. Standard techniques and criteria were used for scoring sleep stages and arousals. Thoracoabdominal motion was monitored by respiratory inductance plethysmography, nasal pressure by nasal cannula and arterial oxyhemoglobin saturation (SpO2 ) by oximetry.31 Apneas were defined as > 90% reduction in tidal volume lasting ≥ 10 sec. Journal of Clinical Sleep Medicine, Vol. 12, No. 10, 2016
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Hypopneas were defined as 50% to 90% reduction in tidal volume, lasting ≥ 10 sec, and being associated with arousals or minimum 3% reductions in SpO2. Apneas and hypopneas were classified as obstructive if there was out-of-phase thoracoabdominal motion or flow limitation on the nasal pressure tracing; otherwise, they were classified as central.32 Sleep studies were scored by personnel blind to the fluid measurements and vice versa.
Measurements Upper Airway Cross-Sectional Area and Neck Circumference With subjects supine, prior to sleep, upper airway crosssectional area (UA-XSA) was measured by acoustic pharyngometry,33 and NC was assessed by a tape measure above the cricothyroid cartilage. A line was drawn at this level to ensure that measurements after sleep were made at the same level. Both measurements were repeated immediately after waking up from sleep.12 Neck Fluid Volume Previously, we developed a method to measure fluid volumes in various body segments using bioelectrical impedance.13 Bioelectrical impedance of a tissue is inversely related to its fluid content. In this study, we used MP150 Biopac System and EBI100C module to measure bioelectrical impedance and estimate neck fluid volume (NFV). Two electrodes injected a low amplitude (400 μA) current at 50 kHz, and 2 electrodes measured voltage to calculate bioelectrical impedance.34 The voltage recording electrodes were placed on the right side of the neck below the right ear and at the base of the neck, and the injecting electrodes were placed one inch from the sensing electrodes, as described before.13 The electrodes were secured to the skin with adhesive tape. Considering the effects of length and circumference of the neck, its fluid volume can be estimated as35:
ρ 2 L5 C 2 V= 4π R 2
1/3
(1)
where C is the neck circumference, ρ is the resistivity, R is the measured impedance, and L is neck length measured as the distance between voltage electrodes on the neck. Neck length was measured before sleep and measurements of NC before and after sleep were used to estimate NFV in the evening and morning, respectively. In a study of 73 healthy subjects ρ was estimated to be 47 Ωcm.34
Protocol
This study was part of a randomized, double crossover protocol to investigate the effects of fluid overloading by saline infusion on OSA severity in men.24 For purposes of the present study, we used data from the control arm of the original protocol. In this arm of the protocol, subjects had an intravenous cannula inserted with a very negligible amount of normal saline infused just sufficient to keep the vein open (approximately 100 mL), as opposed to the intervention arm in which 22 mL/kg body weight (approximately 2,000 mL) was infused as a bolus just after sleep onset. The saline solution was
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Figure 1—Schematic of the study protocol.
Table 1—Baseline characteristics and sleep data of the 20 subjects.
warmed to body temperature by placing the bag containing the solution in warm water at 37°C, prior to use so as not to induce coolness, and possibly arousals in the arm being infused. Subjects arrived in the sleep laboratory at noon following a night of sleep deprivation and were instrumented for sleep studies. Subjects were randomized after they were set up to start the experiment into a control or intervention arm using a computer-generated randomization table with unequal blocks of 2 and 4. Although subjects were blind to the intervention, experimenters were of necessity not blinded. However, personnel analyzing the results were kept blind to randomization. Subjects slept supine on a single pillow for the entire study period to eliminate any potential effect of postural changes on AHI and other variables. Two small sandbags were placed beside the head to limit the head movement and facilitate supine sleep. In the rare occasions that subjects changed their posture, the technician would enter the room and correct their position to supine. Before sleep, baseline measurements including UAXSA, NC, and NFV, were made with subjects supine. Once subjects woke up, baseline measurements were repeated (Figure 1). One week after the initial session, subjects crossed over to the other arm of the study. The protocol was approved by the Research Ethics Board of Toronto Rehabilitation Institute, and all subjects provided written consent prior to participation.24
Data Analysis
Changes (Δ) in NC, UA-XSA, and NFV from pre- to post-sleep were calculated and their statistical significance were assessed by pairwise comparison using paired t-test or Wilcoxon ranksum test for normally and non-normally distributed data, respectively. Correlations between sleep structure (% of time spent in different sleep stages) and age, pre-sleep NC, ΔNC, ΔUA-XSA, ΔNFV, and AHI were investigated by Pearson or Spearman rank functions. Step-wise regression models were used to determine factors that contributed to the variations in sleep structure, 1367
Age, years Height, cm Weight, kg BMI, kg/m2 NC, cm UA-XSA, cm2 Neck length, cm NFV, mL Total sleep time, min N1 sleep, % of TST N2 sleep, % of TST N3 sleep, % of TST REM sleep, % of TST Sleep efficiency, % Total AHI, events/h Obstructive AHI, events/h Central AHI, events/h non-REM AHI, events/h REM AHI, events/h Arousal index, arousals/h Mean SpO2
45.8 ± 11.1 176.2 ± 6.5 79.2 ± 10.5 25.7 ± 3.0 42.0 ± 2.9 2.6 ± 0.6 11.4 ± 1.6 265.3 ± 47.6 144.7 ± 44.1 20.0 ± 11.5 58.9 ± 13.7 11.7 ± 13.5 9.4 ± 8.5 71.8 ± 16.8 26.3 ± 24.8 24.7 ± 24.7 3.3 ± 6.8 26.6 ± 27.3 36.0 ± 21.3 29.1 ± 17.1 90.9 ± 4.4
Data are expressed as mean ± standard deviation. AHI, apneahypopnea index; BMI, body mass index; NC, neck circumference; NFV, neck fluid volume; REM, rapid eye movement; TST, total sleep time; UAXSA, upper airway cross-sectional area.
AHI, and arousal index (arousals per hour of sleep). The models for %N1, %N2, %N3, and % rapid-eye movement (REM) sleep stages included age, pre-sleep NC, ΔNC, ΔNFV, and total AHI. The models for AHI and arousal index included age, presleep NC, ΔNC, and ΔNFV. Statistical analyses were performed by SAS 9.3 and a two-sided p value < 0.05 was considered significant. Data are presented as mean ± standard devaiation. R ES U LT S Of the 26 men who participated in this study, one was excluded because he could not fall asleep and 5 were excluded because they had central dominant sleep apnea. The baseline characteristics of 20 men who completed the study are presented in Table 1. The amount of intravenous saline infused to keep vein open during the study was 98 ± 11 mL. Participants slept for an average of 145 ± 44 min (Table 1), with an average sleep latency of 3.1 ± 3.4 minutes. All participants had NREM sleep and 16 of them had REM sleep. Although we advertised for participants with no history of sleep apnea and excluded those with clinical diagnosis of sleep apnea or taking any treatment for sleep apnea, the participants had a wide range of AHIs, between 0.7 and 86.2. Eleven subjects had moderate to severe sleep apnea (AHI ≥ 15), with an average AHI of 42.4 ± 24.3. Nine subjects had no or mild sleep apnea (AHI < 15) with an average AHI of 6.9 ± 4.4 events/h. Journal of Clinical Sleep Medicine, Vol. 12, No. 10, 2016
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Pairwise comparisons revealed that from before to after sleep, there were significant increases in NC and NFV and a significant decrease in UA-XSA (∆NC: 0.6 ± 0.4cm, ∆NFV: 17.8 ± 7.5ml, ∆UA-XSA: −0.3 ± 0.3cm2, p < 0.001 for all variables). Correlation analysis showed that the increase in NFV correlated significantly with the reduction in UA-XSA (Figure 2). Age was associated with a significant increase in NC (r = 0.56, p = 0.009), which was independent of pre-sleep NC (p > 0.15). Increased
Figure 2—The relationship between the changes in neck fluid volume (NFV) and upper airway cross-sectional area (UA-XSA) after sleep.
age showed a nonsignificant tendency for higher AHI (r = 0.43, p = 0.06) and arousal index (r = 0.42, p = 0.07). Correlation analysis demonstrated that the percentage of N1 sleep was greater in subjects with higher AHIs (r = 0.55, p = 0.010) and arousal indices (r = 0.71, p < 0.001). Percentage of N2 sleep correlated directly with age (r = 0.62, p = 0.003) and increases in NC and NFV after sleep (Figure 3). Percentage of N3 sleep had significant inverse correlations with age (r = −0.75, p < 0.001) and %ΔNC (Figure 3), and a borderline significant inverse correlation with %ΔNFV (Figure 3). Furthermore, lower %N3 sleep correlated with higher AHIs and arousal indices (AHI: r = −0.50, p = 0.021, arousal index: r = −0.59, p = 0.005). There was no significant relationship between %REM sleep and ΔNC, ΔUA-XSA, or ΔNFV. Table 2 shows the results of stepwise regression analysis to predict the factors that could contribute to the variations in the sleep structure. The only significant factor related to %N1 sleep was the AHI (Table 2). The only factor that contributed directly to %N2 sleep was the ΔNC after sleep (Table 2). Three factors that contributed inversely and independently to %N3 sleep were ΔNC, ΔNFV, and pre-sleep NC (Table 2). Together, these factors accounted for 76% of the variability in %N3 sleep (p < 0.0001). Only AHI contributed significantly to the percentage of REM sleep (Table 2). Pre-sleep NC and ΔNC after sleep significantly contributed to both AHI (r2 = 0.56, p = 0.001) and arousal index (r2 = 0.57, p = 0.001). D I SCUS S I O N The most important and novel finding of our study was that increased fluid accumulation in the neck during supine sleep was associated with worsening of sleep structure in men. We found
The reduction in UA-XSA correlated directly with the increase in NFV.
Figure 3—The relationship between percentages of N2 and N3 sleep and changes in (A) neck circumference (NC) and (B) neck fluid volume (NFV) after sleep.
AB
The percentage of N2 sleep correlated directly with changes in NC and NFV after sleep. The percentage of N3 sleep correlated inversely with the change in NC. There was also a borderline significant inverse correlation between percentage N3 sleep and NFV after sleep.
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Table 2—Results of stepwise regression analysis to predict the factors that could contribute to the variations in the sleep structure. The models for N1, N2 and N3 included age (years), NC (cm), ΔNC (cm), ΔNFV (mL), and total AHI (events/h). Dependent Variable N1, %
Step 1
Variable entered AHI
N2, %
1
ΔNC, cm
N3, %
1 2 3
REM, %
1
Estimate 0.19
Partial R2 0.23
Model R2 0.23
p value in the final model 0.032
25.42
0.44
0.44
0.001
ΔNC, cm ΔNFV, mL NC, cm
−23.19 −0.96 −2.13
0.42 0.16 0.18
0.42 0.58 0.76
0.001 0.017 0.002
AHI
−0.15
0.22
0.22
0.04
AHI, apnea-hypopnea index; NC, neck circumference; NFV, neck fluid volume; REM, rapid eye movement.
that the greater the increase in NC during sleep, the greater the arousal index and percentage of N2 sleep and the lower the percentage of N3 sleep. While age and total AHI correlated inversely with percentage of N3 sleep, neither age nor AHI contributed significantly to the variations in the percentage of N3 sleep when the model included NC, ΔNC, and ΔNFV. While fluid accumulation in the neck during sleep could negatively alter sleep structure by increasing AHI and arousals, these results suggest that the correlation between sleep structure and fluid accumulation in the neck is stronger than those with AHI or age. We also found that older men had a greater increase in NC after sleep. Therefore, we may conclude that one of the mechanisms through which aging could contribute to the variations in sleep structure is by facilitating more fluid accumulation in the neck during sleep. Our results suggest that baseline NC and fluid accumulation in the neck during sleep affect sleep structure. We found that the percentage of N3 sleep correlated inversely with the increase in NC and NFV after sleep. On the other hand, the percentage of time spent in N2 sleep correlated significantly with the increase in NC after sleep independent of other factors. Furthermore, subjects with larger pre-sleep NC and greater increases in NC during sleep had more sleep fragmentation, as assessed by arousal index. Our findings are the first to suggest that changes in NC or NFV during sleep could negatively alter sleep structure by increasing sleep fragmentation. Arousal is directly related to the pressure generated by the pharyngeal muscles to open the airways.36 Patients with poor passive anatomy of the upper airway or lower upper airway gain are more likely to have an arousal before pharyngeal muscles could open the airways.37 As previously shown, we found that NC increased from pre- to post-sleep.24 However, we have extended this previous observation by demonstrating that this increase in NC was associated with an increase in NFV and a reduction in UA-XSA. Accordingly, increased pharyngeal tissue pressure resulting from an increase in fluid volume of the internal jugular veins and/or peripharyngeal soft tissue likely contributed to this narrowing of the upper airway.9,38 The observed increases in NC and NFV in association with a decrease in UA-XSA could increase upper airway resistance and collapsibility14,16,30 during sleep. Together, these changes could impair the passive anatomy of the upper airway, impair upper airway gain, and increase the likelihood of arousals.9,39 Indeed our results show that pre-sleep NC and
change in NC after sleep were the significant factors that increased arousal index. It has been shown previously that OSA severity is a factor that negatively alters sleep structure.8,9,40,41 Previous studies from our group show that fluid overloading by intravenous saline infusion of about 2 liters during sleep increased NC and AHI, and decreased the proportion of N3 sleep in older men.24 Conversely, in patients with end stage renal disease and sleep apnea, who were on hemodialysis thrice-weekly, the removal of an additional 2L of fluid by ultrafiltration was associated with a reduction in the AHI and an increase in N3 sleep.20 While these studies show the effects of fluid accumulation on sleep structure and sleep apnea severity, our current results are unique in demonstrating a model that represents the effects of fluid accumulation in the neck on sleep structure and sleep apnea severity. More importantly, this model shows that the contribution of fluid accumulation in the neck on sleep structure is more significant than those due to the AHI. Furthermore, in the present study, there was no significant relationship between the proportion of REM sleep and either ΔNC, ΔUAXSA, or ΔNFV, in keeping with our previous findings that fluid accumulation in the neck is associated with a reduction in N3, but not REM sleep.24 In a cross-sectional study of 2,685 participants aged 37 to 92 years, Redline et al. demonstrated that aging was associated with a decreased percentage of N3 and REM sleep, and a higher arousal index in men, independent of BMI and sleep disordered breathing.8 Similar to these studies, our results show that with aging, the proportion of N3 sleep decreases, and there is a tendency for increased AHI and arousal index. However, when we included ∆NC, ∆NFV in the stepwise regression models, neither age nor AHI contributed significantly to the variations in percentages of N2 or N3 sleep. This observation raises the possibility that aging could contribute to the changes in sleep structure by facilitating more fluid accumulation in the neck. Indeed, in our previous study in which we infused a bolus of saline into younger and older men during sleep, we found a greater accumulation of fluid in the neck of the subjects older than 40 years old than in those aged 40 years or less.24 Similarly, Redolfi et al. showed that in 23 non-obese men, age was a significant independent predictor of the overnight accumulation of fluid in the neck as assessed by change in NC, and was in turn strongly related to the amount of fluid moving out of the legs overnight.12 Despite the evidence, however, it is still
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possible that aging is independently associated with both increased fluid shift into the neck and reduced percentage of N3 sleep through other mechanisms. As such, the design of this study, while suggestive, does not prove a causal link between fluid shift and percentage of N3 sleep. Our study is subject to some limitations. To avoid the potential confounding effects of obesity on obstructive sleep apnea and fluid retention, we limited our study to non-obese subjects (BMI < 30). Our study was confined to men because previous studies showed that men accumulate more fluid in their necks than women while recumbent, and are more susceptible to the adverse effects of rostral fluid shift on upper airway physiology than women.11,30 Thus the present findings may not apply to women. Further studies will be required to determine if fluid accumulation in the neck in women influences sleep structure. For reasons of feasibility, sleep studies were performed during the day. While our subjects had an average sleep time of 145 minutes and 80% of them had at least one full sleep cycle including REM sleep, these findings may not be fully applicable to nocturnal sleep. We restricted sleeping position to supine to minimize the effects of posture on AHI variability and sleep structure. Therefore, our findings may not apply to the nonsupine positions. In this study, we investigated the relationship between fluid accumulation in the neck and AHI; however, AHI alone may not properly reflect severity of the upper airway narrowing during sleep. Future studies should investigate the relationship between fluid accumulation in the neck and other features such as percentage of inspiratory flow limitation, presence, and severity of snoring sounds. Lastly, while the study findings suggest an association between neck fluid accumulation and sleep structure, it is not possible to deduce causality given the observational nature of the study design. In conclusion, our findings indicate that fluid accumulation in the neck while recumbent could be a mechanism contributing to variations in sleep structure in men. While age is a well-known contributor to variations in sleep structure, our results suggest that those contributions may be due to the differing effects of aging on patterns of fluid redistribution, particularly into the neck, while recumbent during sleep. Further investigations will be required to determine why more fluid accumulates in the neck with aging, how fluid accumulation in the neck influences sleep structure, and whether alterations in upper airway anatomy and physiology play a role in this effect. The present findings, along with those of our previous studies, provide a strong rationale for testing the effects of reducing nocturnal rostral fluid shift and fluid accumulation in the neck on sleep structure in men. R E FE R E N CES 1. Johnson KD, Patel SR, Baur DM, et al. Association of sleep habits with accidents and near misses in United States transportation operators. J Occup Environ Med 2014;56:510–5. 2. Swanson LM, Arnedt JT, Rosekind MR, Belenky G, Balkin TJ, Drake C. Sleep disorders and work performance: findings from the 2008 National Sleep Foundation Sleep in America poll. J Sleep Res 2011;20:487–94. 3. Franzen PL, Siegle GJ, Buysse DJ. Relationships between affect, vigilance, and sleepiness following sleep deprivation. J Sleep Res 2008;17:34–41.
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SUBM I SSI O N & CO R R ESPO NDENCE I NFO R M ATI O N Submitted for publication October, 2015 Submitted in final revised form May, 2016 Accepted for publication May, 2016 Address correspondence to: T. Douglas Bradley, MD, University Health Network Toronto General Hospital, 9N-943, 200 Elizabeth Street, Toronto, ON., M5G 2C4, Canada; Tel: (416) 340-4719; Fax: (416) 340-4197; Email: douglas.bradley@ utoronto.ca
D I SCLO S U R E S TAT E M E N T This was not an industry supported study. This study was supported by a Canadian Institutes of Health Research (CIHR) operating grant MOP-82731. Dr. Yadollahi was supported by Fellowships from the Mitacs Elevate program and a CIHR Training Grant in Sleep and Biological Rhythms. Daniel Vena was supported by a Fellowship from the NSERC CREATE Academic Rehabilitation Engineering (CARE) training program. Dr. Lyons was supported by the Peter Macklem European Respiratory Society/Canadian Thoracic Society Joint Research Fellowship and the Joseph M. West Family Memorial Fund Postgraduate Research Award. Dr. Bradley was supported by the Clifford Nordal Chair in Sleep Apnea and Rehabilitation Research. Dr. Bradley has received research support from Philips Respironics and has financial interest in BresoTec Inc. The other authors have indicated no financial conflicts of interest. This research was performed at the Sleep Laboratory, Toronto Rehabilitation Institute.
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