Abstract
Background and objectives
Obstructive sleep apnea is associated with significantly increased cardiovascular morbidity and mortality. Fluid overload may promote obstructive sleep apnea in patients with ESRD through an overnight fluid shift from the legs to the neck soft tissues. Body fluid shift and severity of obstructive sleep apnea before and after hemodialysis were compared in patients with ESRD.
Design, setting, participants, & measurements
Seventeen patients with hemodialysis and moderate to severe obstructive sleep apnea were included. Polysomnographies were performed the night before and after hemodialysis to assess obstructive sleep apnea, and bioimpedance was used to measure fluid overload and leg fluid volume.
Results
The mean overnight rostral fluid shift was 1.27±0.41 L prehemodialysis; it correlated positively with fluid overload volume (r=0.39; P=0.02) and was significantly lower posthemodialysis (0.78±0.38 L; P<0.001). There was no significant difference in the mean obstructive apnea-hypopnea index before and after hemodialysis (46.8±22.0 versus 42.1±18.6 per hour; P=0.21), but obstructive apnea-hypopnea index was significantly lower posthemodialysis (−10.1±10.8 per hour) in the group of 12 patients, with a concomitant reduction of fluid overload compared with participants without change in fluid overload (obstructive apnea-hypopnea index +8.2±16.1 per hour; P<0.01). A lower fluid overload after hemodialysis was significantly correlated (r=0.49; P=0.04) with a lower obstructive apnea-hypopnea index. Fluid overload—assessed by bioimpedance—was the best predictor of the change in obstructive apnea-hypopnea index observed after hemodialysis (standardized r=−0.68; P=0.01) in multivariate regression analysis.
Conclusions
Fluid overload influences overnight rostral fluid shift and obstructive sleep apnea severity in patients with ESRD undergoing intermittent hemodialysis. Although no benefit of hemodialysis on obstructive sleep apnea severity was observed in the whole group, the change in obstructive apnea-hypopnea index was significantly correlated with the change in fluid overload after hemodialysis. Moreover, the subgroup with lower fluid overload posthemodialysis showed a significantly lower obstructive sleep apnea severity, which provides a strong incentive to further study whether optimizing fluid status in patients with obstructive sleep apnea and ESRD will improve the obstructive apnea-hypopnea index.
Keywords: ESRD, hemodialysis, nocturnal hypoxemia, ultrafiltration, water-electrolyte balance
Introduction
Obstructive sleep apnea (OSA) is a severe chronic condition caused by repeated upper airway collapse during sleep, resulting in recurrent nocturnal asphyxia, fragmented sleep, major fluctuations in BP and heart rate, and increased sympathetic activity (1). Furthermore, patients with untreated OSA are at increased risk of hypertension, stroke, heart failure, and premature death (2–7). Two recent studies investigated the occurrence of OSA in patients with different degrees of CKD. In the hemodialysis subgroup, a 57% prevalence of moderate to severe sleep apnea and a 26% prevalence of severe sleep apnea were reported (8,9), which is notably higher than the 5%–17% prevalence of OSA in the middle-aged general population (10–12).
According to current understanding, OSA is a heterogeneous disorder with multiple underlying pathophysiologic mechanisms and varying phenotypes in different patient populations (13,14). A better understanding of the underlying mechanisms of OSA is, therefore, important to tailor the treatment according to the specific causes of OSA in a given population.
In recent years, the overnight rostral fluid shift (i.e., fluid displacement occurring overnight from the legs to the neck soft tissues) emerged as a new concept in the pathophysiology of sleep apnea. The studies performed by the group of Bradley and coworkers (15–17) highlighted this phenomenon using antishock trousers to apply lower body positive pressure in healthy individuals. The same mechanism was subsequently confirmed in patients with congestive heart failure (18) and venous insufficiency of the lower limbs (19).
Recently, Elias et al. (20) have described a positive association between the volume of overnight rostral fluid shift and the severity of sleep apnea in 26 patients with ESRD and OSA. Intuitively, the overhydration state typically seen in patients with ESRD should accentuate the phenomenon of overnight rostral fluid shift. Chronic fluid overload might, therefore, partly explain the higher prevalence of OSA in patients with ESRD, and the fluid withdrawal obtained by a hemodialysis session should—in theory—temporarily reduce the severity of OSA.
In a previous study, nocturnal hemodialysis was found to be effective in improving OSA; however, the underlying mechanism was not investigated (21). There is, to date, no study on the effectiveness of volume subtraction obtained during hemodialysis on OSA severity.
The aim of this study was to assess the effect of changes in the magnitude of fluid overload on the severity of OSA in patients with ESRD with established sleep disordered breathing. We hypothesized that a lower fluid overload after hemodialysis would result in a lower nocturnal shift volume and hence, a lower severity of OSA.
Materials and Methods
Participants and Study Protocol
Participants were recruited in three Swiss hemodialysis centers from patients suspected to have OSA on the basis of a screening test (Apnealink Plus; ResMed Corporation, San Diego, CA). Inclusion criteria were (1) age ≥18 years old, (2) ESRD on chronic intermittent hemodialysis, and (3) confirmed OSA with an apnea-hypopnea index (AHI) ≥15/h on polysomnography (PSG; see below). Exclusion criteria were (1) decompensated congestive left heart failure (clinically evaluated before each nocturnal recording), (2) use of a pacemaker, (3) active psychiatric disease, and (4) amputation of a lower limb proximal to the ankle.
Each participant underwent two consecutive PSGs performed on two consecutive nights, including the night after the midweek hemodialysis session. Prescription of the hemodialysis session was not influenced by the study, and the volume of fluid withdrawal was left to the discretion of the treating nephrologist.
The sequence of the two PSGs with respect to hemodialysis was randomized (Figure 1) to minimize the first night effect on sleep (22,23). We assessed leg fluid volume by multifrequency electrical bioimpedance (see below) and measured neck circumference at the beginning and the end of each PSG. Fluid overload was assessed by multifrequency electrical bioimpedance before each sleep recording.
Figure 1.
Study protocol: the sequence of the two polysomnographies with respect to hemodialysis was randomized. AHI, apnea-hypopnea index; HD, outpatient hemodialysis session; PSG 0, prehemodialysis polysomnography; PSG 1, posthemodialysis polysomnography.
The study complied with the Declaration of Helsinki and was approved by the local institutional ethics committee (Commission Cantonale d’Ethique de la Recherche sur l’Etre Humain, Lausanne, number 157/12). All participants provided written informed consent.
Measurements and Equipment
Attended PSGs were recorded with a digital system device (Embla N7000; Embla Systems, Reykjavik, Iceland) in Lausanne University Sleep Laboratory. PSG recordings were manually scored using Somnologica software (Version 5.1.1; Embla, Reykjavik, Iceland). Sleep stages and arousals were scored according to the American Association of Sleep Medicine (AASM) 2007 criteria (24–26).
Chest and abdominal motion bands, finger pulse oximetry, and a nasal pressure cannula were applied to analyze respiration. Respiratory events were scored according to the AASM consensus criteria (27) by two physicians of the sleep center (A.O. and A.M.) blinded to the randomization group, the timing of the PSG in relation to the hemodialysis, and the anthropometric measures. Special care was taken to avoid overscoring hypopnea during periodic legs movement (PLM) periods by scoring them only when they were associated with an oxygen desaturation. The obstructive apnea-hypopnea index (OAHI)—calculated as an index of obstructive apneas and hypopneas per hour of sleep—was chosen as the primary outcome measure.
The fluid volume of each leg was measured by multifrequency bioelectrical impedance (Body Composition Monitor; Fresenius Medical Care, Bad Homburg, Germany). Impedance to electric current between two pairs of electrodes placed at the level of the greater trochanter and the ipsilateral ankle was used to assess the fluid content of the body segment as previously described and validated (15–17,28–30). Marks were drawn on the skin to position electrodes for the subsequent measurements. The sum of the results of both legs was used in the analysis.
Fluid overload was assessed just before the sleep study by bioimpedance. The fluid overload volume is directly provided by the Body Composition Monitor device according to a factory-set algorithm comparing the measured extracellular water with the expected extracellular water, which is estimated assuming normal hydration of the measured lean tissue and adipose mass. This technique has been validated against the respective gold standards in healthy individuals and patients on hemodialysis (31,32), and it has shown excellent reproducibility (coefficient of variation =0.15%–0.64% for the estimation of total body water) (33). The validity of the calculated fluid overload volume has further been shown by clinical assessment and comparison with the withdrawn ultrafiltration volume in several hundred patients on hemodialysis (31).
Neck circumference was measured with a nonstretchable tape above the cricothyroid membrane immediately before measuring leg fluid volume (19,28,34).
The hemodialysis efficacy was assessed using urea kinetic modeling and expressed as equilibrated Kt/V according to the international Kidney Disease Outcomes Quality Initiative recommendations (35).
Venous blood samples were taken at the beginning and the end of the hemodialysis session. Laboratory analyses were performed at the reference chemical laboratory of each hemodialysis center using standard methods and stringent internal quality controls. Bicarbonates were calculated by the chemical laboratory on basis of pH and pCO2 of the blood sample.
Statistical Analyses
Statistical analysis was conducted using Stata 11.0 for Windows (Stata Corp LP). Mean and SD were used to describe continuous variables, and percentages were used to describe dichotomous or categorical variables. We used a paired t test or McNemar test to compare the measurements performed before and after hemodialysis. Associations between continuous variables were assessed by linear regression. We conducted univariate linear regressions to explore the factors associated with the severity of OSA. Significant factors were then entered into a multivariate model. To further investigate the association between OSA and fluid overload, we also compared the characteristics of participants in whom hemodialysis effectively reduced fluid overload in a post hoc analysis, empirically defining a volume of 0.5 L as a clinically significant cutoff, with those in whom it did not using chi-squared and t tests. Statistical significance was established at P value <0.05.
Results
Study Population and Sleep Characteristics
Twenty patients participated in the study. Three of them were excluded because of having an AHI<15/h. Fifteen men and two women were included in the analysis (Figure 1).
Mean (SD) age of the patients was 63.4 (14.9) years, and mean body mass index (BMI) was 28.1 (3.5) kg/m2. They had been on RRT for a median (interquartile range) of 7.1 (1.0–11.4) years. Diabetes, hypertension, and coronary heart disease were prevalent comorbid conditions. Demographic, anthropometric, relevant medical, and hemodialysis data are detailed in Table 1.
Table 1.
Characteristics of the study population
| Characteristic | Mean (SD) or N (%) | Range |
|---|---|---|
| Age (yr) | 63.4 (14.9) | 36–89 |
| Men, N (%) | 15 (88) | |
| Body mass index (kg/m2) | 28.1 (3.5) | 22.8–34.4 |
| Diabetes, N (%) | 9 (53) | |
| Hypertension, N (%) | 16 (94) | |
| Coronary heart disease, N (%) | 7 (41) | |
| Active smoking, N (%) | 9 (53) | |
| Nephropathy, N (%) | ||
| Diabetic | 7 (41) | |
| Hypertensive | 3 (18) | |
| GN | 1 (6) | |
| Other/unknown | 6 (35) | |
| HD vintage (yr), median [interquartile range] | 7.1 [1.0–11.4] | 0.3–35.4 |
| Residual diuresis (ml/24 h) | 398 (471) | 0–1350 |
| HD characteristics | ||
| Duration of the HD session (min)a | 231 (14) | 210–240 |
| HD access, N (%) | ||
| Fistula | 12 (71) | |
| Catheter | 5 (29) | |
| Morning HD shift, N (%) | 12 (71) | |
| Type of HD membrane, N (%) | ||
| Synthetic,b high flux | 16 (94) | |
| Synthetic,b low flux | 1 (6) | |
| Surface area of the membrane (m2) | 2.2 (0.1) | 2.1–2.5 |
| Blood flow rate (ml/min) | 401 (64) | 300–500 |
| Dialysate flow rate (ml/min) | 700 (140) | 500–850 |
| Ultrafiltration volume (L) | 2.31 (1.02) | 0.60–4.00 |
| eKt/V | 1.52 (0.25) | 1.19–2.04 |
| Urea reduction ratio (%) | 76.3 (5.2) | 68–85 |
| Dialysate bicarbonate concentration (mEq/L) | 32.5 (0.9) | 32–34 |
| Dialysate sodium concentration (mEq/L)c | 137.7 (0.9) | 135–138 |
| Dialysate calcium concentration (mEq/L) | 2.60 (0.30) | 2.25–3.50 |
HD, hemodialysis; eKt/V, hemodialysis efficacy assessed using urea kinetic modeling.
All patients on three times per week HD.
Polysulfone or polyethersulfone.
Sodium modeling was not used in any of the patients.
Sleep characteristics did not differ between the two study nights, except for a longer mean duration of rapid eye movement sleep and a lower incidence of PLM during the night after hemodialysis (Table 2). In particular, there were no differences in sleep time spent in supine position, which could have influenced the change in OAHI.
Table 2.
Sleep characteristics on pre- and posthemodialysis nights
| Characteristic | Prehemodialysis Polysomnography | Posthemodialysis Polysomnography | P Value |
|---|---|---|---|
| Total sleep time (min) | 347 (72) | 365 (92) | 0.35 |
| Sleep efficiency (%) | 77 (17) | 79 (15) | 0.50 |
| Light sleep, stages 1 and 2 (%) | 69 (14) | 61 (12) | 0.11 |
| Deep sleep, stage 3 (%) | 7 (9) | 9 (7) | 0.38 |
| REM sleep (%) | 15 (9) | 20 (10) | 0.04 |
| Supine sleep time (%) | 48 (28) | 36 (23) | 0.10 |
| AHI (no./h) | 56.1 (22.6) | 53.7 (22.3) | 0.60 |
| OAHI (no./h) | 46.8 (22.0) | 42.1 (18.6) | 0.21 |
| Central apneas (no./h) | 5.3 (7.9) | 7.2 (9.8) | 0.17 |
| AHI in supine position (no./h) | 70.8 (27.5) | 66.2 (26.5) | 0.39 |
| AHI in nonsupine position (no./h) | 46.1 (23.4) | 50.3 (25.6) | 0.42 |
| AHI in REM sleep (no./h) | 40.6 (21.4) | 40.0 (19.4) | 0.88 |
| AHI in NREM sleep (no./h) | 57.2 (25.2) | 55.5 (27.0) | 0.73 |
| Mean SaO2 (%) | 93.0 (1.6) | 93.0 (1.9) | 0.78 |
| ODI (no./h) | 51.2 (22.7) | 51.9 (22.1) | 0.88 |
| Periodic leg movements (no./h) | 47.9 (42.9) | 34.4 (31.4) | 0.03 |
Values are expressed as means (SDs); P value is by paired t test. REM, rapid eye movement; AHI, index of apneas and hypopneas per hour of sleep; OAHI, index of obstructive apneas and hypopneas per hour of sleep; NREM, non-REM; SaO2, oxygen saturation; ODI, oxygen desaturation index (index of desaturations per hour of sleep).
Sleep Disordered Breathing
The main pre- and posthemodialysis PSG results are displayed in Table 2. There was no significant difference in the mean OAHI before and after hemodialysis (46.8±22.0/h versus 42.1±18.6/h; P=0.21). Central apneas represented 8.7% of the respiratory events without significant change between the two nights. On both nights, AHI was significantly higher in the supine than the nonsupine position.
Overnight Rostral Fluid Shift
On the night before hemodialysis, total leg fluid volume decreased from 10.68 (±1.91) L in the evening to 9.41 (±1.86) L the next morning (P<0.001); a concomitant increase occurred in the neck circumference of 0.6 (±1.1) cm (P=0.04). A similar fluid shift of smaller magnitude was present on the postdialysis night.
Patients with a higher fluid overload in the evening showed a greater change in their leg fluid volume overnight (r=0.39; P=0.02). The overnight leg fluid volume shift was significantly lower the night after hemodialysis (Figure 2, Table 3).
Figure 2.
Overnight change in leg fluid volume during the prehemodialysis and posthemodialysis nights. Thin lines represent the individual measurements, and thick lines represent the mean (±SD) values. Delta, change from the evening to the morning.
Table 3.
Anthropometric measures, fluid distribution, and metabolic parameters
| Parameter | Prehemodialysis Night | Posthemodialysis Night | P Value |
|---|---|---|---|
| Body weight (kg) | 80.3 (8.0) | 78.8 (7.7) | <0.001 |
| Neck circumference in the evening (cm) | 41.8 (2.9) | 41.1 (2.9) | 0.001 |
| Morning systolic BP (mmHg) | 153 (13) | 142 (21) | 0.02 |
| Morning diastolic BP (mmHg) | 78 (13) | 78 (12) | 0.77 |
| Heart rate (bpm) | 70.1 (11.4) | 69.5 (8.4) | 0.73 |
| Total body water (L) | 40.0 (4.6) | 37.8 (4.3) | <0.001 |
| Fluid overload (L) | 1.98 (1.56) | 1.05 (1.13) | <0.01 |
| Leg fluid volume (L) | 10.7 (1.9) | 9.9 (1.9) | <0.001 |
| Overnight rostral fluid shift (L) | 1.27 (0.41) | 0.78 (0.38) | <0.001 |
| Overnight urine volume (L) | 0.11 (0.25) | 0.02 (0.05) | 0.14 |
| Overnight fluid intake (L) | 0.10 (0.10) | 0.09 (0.09) | 0.54 |
| pH | 7.35 (0.07) | 7.44 (0.06) | <0.001 |
| Bicarbonates (mEq/L) | 22.2 (2.1) | 27.0 (2.4) | <0.001 |
| BUN (mg/dl) | 54.3 (17.1) | 14.0 (4.2) | <0.001 |
Values are expressed as means (SDs); P value is by paired t test.
Fluid Overload and OSA
The change in fluid overload observed after hemodialysis was significantly correlated with the difference in OAHI (r=0.49; P=0.04) (Figure 3). Three patients presented a higher OAHI after hemodialysis, despite a lower fluid overload volume (Figure 3, upper left quadrant). These three patients had a higher BMI (32.5±2.1 versus 27.2±3.0 kg/m2; P=0.02) than the remaining participants, comprising three of four patients who were obese (BMI≥30 kg/m2) in the study population.
Figure 3.
Correlation of the change in fluid overload after hemodialysis (delta fluid overload measured by bioimpedance) with the change in the severity of obstructive sleep apnea (delta OAHI). OAHI, obstructive apnea-hypopnea index.
The OAHI change after hemodialysis was significantly associated with the fluid overload volume before hemodialysis, the reduction in overnight leg fluid volume shift posthemodialysis, and the severity of OSA at baseline. No association was found with demographic and anthropometric characteristics or hemodialysis and laboratory variables (Table 4). As such, the ultrafiltration volume obtained during hemodialysis was not significantly associated with the change in OAHI; in the meantime, ultrafiltration volume and difference in fluid overload volume (measured in the evening) were significantly correlated but not identical (r=0.62; P<0.01). Bicarbonates were significantly lower before (22.2±2.1 mEq/L) than after hemodialysis (27.0±2.4 mEq/L; P<0.001), and pH increased accordingly (Table 3); neither bicarbonates nor pH were associated with the change in OSA severity in the regression analysis (Table 4).
Table 4.
Factors associated with change in the index of obstructive apneas and hypopneas per hour of sleep between the two study nights
| Factor | Univariate Linear Regression | Multivariate Linear Regression | ||
|---|---|---|---|---|
| Change in OAHI (no./h) β (95% CI) | P Value | Change in OAHI (no./h) β (95% CI) | P Value | |
| OAHI pre-HD (no./h) | 0.4 (0.1 to 0.7) | 0.02 | 0.3 (0.0 to 0.5) | 0.05 |
| Fluid overload pre-HD (L) | 6.9 (3.3 to 10.5) | <0.001 | 6.5 (1.6 to 11.4) | 0.01 |
| ΔFluid overload (L) | 6.7 (0.2 to 13.3) | 0.04 | 2.1 (−5.1 to 9.2) | 0.54 |
| ΔNocturnal rostral fluid shift (L) | 20.1 (0.5 to 39.6) | 0.04 | 3.1 (−15.3 to 21.6) | 0.72 |
| Age (yr) | 0.3 (−0.2 to 0.8) | 0.21 | ||
| Sex (men) | 3.1 (−21.4 to 27.5) | 0.79 | ||
| Body mass index (kg/m2) | 1.7 (−0.5 to 3.8) | 0.11 | ||
| Neck circumference in evening (cm) | 0.5 (−2.3 to 3.2) | 0.71 | ||
| Time on RRT (yr) | 0.2 (−1.0 to 0.6) | 0.53 | ||
| Residual diuresis (ml) | 3.3 (−14.7 to 21.3) | 0.70 | ||
| Ultrafiltration volume (ml) | 4.0 (−3.7 to 11.7) | 0.28 | ||
| ΔpH | −6.6 (−23.1 to 9.8) | 0.39 | ||
| ΔBicarbonates (mEq/L) | −0.8 (−4.1 to 2.4) | 0.58 | ||
| ΔBUN (mg/dl) | 1.2 (−3.4 to 5.8) | 0.59 | ||
| eKt/V | 9.9 (−16.8 to 36.6) | 0.44 | ||
r2 of the multivariate model=0.68. It should be noted that multicolinearity between the factors limits the interpretation of the coefficients associated with the individual variables. OAHI, index of obstructive apneas and hypopneas per hour of sleep; 95% CI, 95% confidence interval; HD, hemodialysis; delta, change from prehemodialysis to posthemodialysis; eKt/V, hemodialysis efficacy assessed using urea kinetic modeling.
A multivariate linear model including the four significant characteristics reported above explained 68% of the difference in OAHI observed after hemodialysis. Prehemodialysis fluid overload volume was the best predictor of the reduction in OAHI observed after hemodialysis, but the significant correlation between the factors (multicolinearity) prevented additional detailed interpretation of the model (Figure 4, Table 4).
Figure 4.
Association between predialysis fluid overload (measured by bioimpedance) and change in the severity of obstructive sleep apnea after hemodialysis (delta OAHI). OAHI, obstructive apnea-hypopnea index.
Fluid Removal and No Fluid Removal Groups
In 12 of 17 patients (fluid removal group), fluid overload was effectively lower after hemodialysis (mean change =−1.43 [±0.77] L; P<0.001). In these patients, we observed a significantly lower mean OAHI after hemodialysis (42.2±19.2/h versus 52.3±20.7/h; P<0.01). This was associated with a lower (−0.58±0.34 L) overnight rostral fluid shift volume. In the remaining five patients, neither OAHI nor overnight rostral fluid shift volume was significantly different after hemodialysis. The two groups differed only in the fluid overload parameters and their change after hemodialysis, whereas demographic factors, anthropometric parameters, and hemodialysis characteristics were not discriminatory (Table 5, Supplemental Table 1). Although metabolic parameters, such as pH, bicarbonates, and BUN, were significantly modified by hemodialysis, their variation was not significantly different between the fluid-removal group and the no-fluid-removal group.
Table 5.
Clinical characteristics and main polysomnography results for fluid removal and no fluid removal groups
| Characteristic | Fluid Removal Group | No Fluid Removal Group | P Value |
|---|---|---|---|
| N | 12 | 5 | |
| Age (yr) | 62.3 (15.4) | 66.0 (15.0) | 0.66 |
| Body mass index (kg/m2) | 27.8 (3.6) | 28.7 (3.5) | 0.64 |
| Waist-to-hip ratio | 1.00 (0.08) | 1.03 (0.03) | 0.33 |
| Neck circumference in evening (cm) | 42.0 (3.0) | 41.4 (3.0) | 0.72 |
| Time on RRT (yr) | 10.4 (11.3) | 5.1 (6.1) | 0.34 |
| Residual diuresis (ml/24 h) | 383 (459) | 430 (552) | 0.86 |
| HD duration (min) | 233 (13) | 228 (16) | 0.52 |
| Ultrafiltration volume (L) | 2.58 (1.03) | 1.64 (0.66) | 0.08 |
| eKt/V | 1.48 (0.22) | 1.64 (0.37) | 0.34 |
| ΔpH | 0.11 (0.07) | 0.09 (0.04) | 0.63 |
| ΔBicarbonates (mEq/L) | 5.1 (2.7) | 4.0 (2.0) | 0.42 |
| ΔBUN (mg/dl) | −38.9 (14.3) | −44.5 (11.5) | 0.52 |
| Interdialytic weight gain (kg) | 2.49 (1.04) | 1.30 (0.46) | 0.03 |
| Fluid overload volume (L) | 2.59 (1.35) | 0.50 (0.90) | <0.01 |
| ΔFluid overload volume (L) | −1.43 (0.77) | 0.30 (0.60) | <0.001 |
| ΔOvernight rostral fluid shift (L) | −0.58 (0.34) | −0.26 (0.34) | 0.10 |
| ΔOAHI (no./h) | −10.1 (10.8) | 8.2 (16.1) | 0.01 |
| ΔAHI (no./h) | −8.4 (13.2) | 12.0 (23.2) | 0.03 |
Values are expressed as means (SDs). P value represents the difference between groups by t test. HD, hemodialysis; eKt/V, hemodialysis efficacy assessed using urea kinetic modeling; delta, change from prehemodialysis to posthemodialysis; OAHI, index of obstructive apneas and hypopneas per hour of sleep; AHI, index of apneas and hypopneas per hour of sleep.
Discussion
To the best of our knowledge, this is the first study providing direct evidence for a role of rostral fluid shift and fluid overload in the severity of OSA in patients with ESRD. Despite the observed overall lack of benefit of hemodialysis on OSA severity, our results suggest that a reduction in fluid overload may decrease nocturnal rostral fluid shift and severity of sleep disordered breathing in patients with ESRD and OSA.
OSA has a remarkably high prevalence in patients on hemodialysis (8,9), suggesting the existence of additional pathophysiologic mechanisms specific to this population on top of classic risk factors, such as upper airway collapsibility and anatomic traits. The significant correlation that we found between the difference in fluid overload volume observed in the evening after hemodialysis and the concomitant change in the severity of OSA confirms the contribution of fluid overload in the pathogenesis of OSA in this population.
In recent years, the overnight rostral fluid shift emerged as a new concept in the pathophysiology of sleep apnea. During daytime, while in an upright position, fluid tends to accumulate in the legs by gravity. When lying supine at night, water redistributes to the upper part of the body, including the soft tissues of the neck, narrowing upper airways and thus, increasing the risk of OSA. This phenomenon has been described in otherwise healthy nonobese individuals (28), nonobese sedentary men (36), and patients with drug-resistant hypertension (34) and is supported by physiology and imaging studies (15–17,37).
The observation of an overnight rostral fluid shift contributing to OSA severity in patients with congestive heart failure (18) and venous insufficiency of the lower limbs (19) suggests that the same phenomenon could occur in populations sharing the presence of fluid overload, such as patients with ESRD. So far, only cross-sectional observational data had suggested a role of rostral fluid shift in the pathogenesis of OSA in patients with ESRD. As such, Beecroft et al. (38) recently described a reduced pharyngeal cross-sectional area in patients with ESRD and OSA compared with individuals with normal kidney function. In addition, Elias et al. (20) described an association between the volume of fluid displaced from the legs overnight and the apnea-hypopnea time in patients with ESRD. However, the lack of intervention on fluid overload did not allow its causative role on the severity of sleep apnea in patients with ESRD to be ascertained.
In this study, we compared pre- and posthemodialysis PSGs and found a significant correlation between the change in fluid overload volume observed after hemodialysis and the change in OSA severity. A significant difference in mean OAHI was not observed in the whole population but only in those showing lower fluid overload volume after hemodialysis as assessed by bioimpedance in the evening. This tends to confirm the role of fluid shift and fluid overload, because the difference between the two groups was explained by neither an effect of the hemodialysis on the metabolic parameters, such as change in pH, BUN, and bicarbonates, nor a difference in the hemodialysis efficacy between the two groups. Changes in the acid-base status occurring after hemodialysis may have an effect on the respiratory drive and thus, the severity of OSA, but this effect seems not to have a major impact in our population, because we found no significant association between the difference in bicarbonates or pH and the change in OSA severity. To further assess the influence of the acid-base status on OSA, we analyzed the association between bicarbonate level and OSA severity but found no significant correlation (data not shown). We observed, as expected, a lower PLM index during the night after hemodialysis compared with the night before hemodialysis, but this aspect is beyond the scope of this article.
Our study adds a new paradigm to the current understanding of the pathophysiologic mechanisms of OSA in patients with ESRD, suggesting that a focused fluid management strategy could be used to reduce the disease’s severity in this population. It should be underlined that our observations focused on fluid overload volume measured in the evening just before sleep recording. This assessment takes into account not only the ultrafiltration volume during hemodialysis but also, the possible weight gain during the time elapsed between the end of the hemodialysis session and the recording night, being thus representative of the hydration state during sleep. This provides the rationale for additional research exploring the efficacy of specific fluid management strategies aiming at reducing fluid overload as much as possible in patients with OSA. Furthermore, our data suggest that bioimpedance parameters, such as fluid overload volume, could predict the effect of volume depletion on the severity of OSA. The use of bioimpedance to optimize fluid balance in patients on hemodialysis has been validated and is proposed as an objective method to adapt the ultrafiltration volume during hemodialysis sessions (31,32,39,40). Our results suggest a potential application of this technique in patients with ESRD and OSA to reduce the severity of their sleep breathing disorder by optimizing their hydration status. In this context, bioimpedance could serve as a readily available estimator of the magnitude of overnight rostral fluid shift, which cannot routinely be measured in the clinical practice.
There are also limitations in our study that need to be considered. First, we did not use fluid status to select participants and let the treating nephrologist decide on the hemodialysis protocol. As a consequence, variable fluid overload differences were observed before and after dialysis, which allowed us to evidence a correlation between the change in fluid overload volume and the severity of OSA, with a significant change in OAHI limited to participants with a difference in fluid overload.
Second, the number of participants was rather low, and our data need confirmation in larger studies; however, the randomized order of the nights ensures that the observed results cannot be explained by differences in the sleep architecture of the patients caused by a first-night effect.
In conclusion, our findings provide a proof of concept that fluid overload contributes to the severity of sleep disordered breathing in patients on intermittent hemodialysis with OSA apparently through an increased overnight rostral fluid shift. A reduction in fluid overload seems to be associated with a decrease in the overnight rostral fluid shift in overhydrated patients and an attenuation of OSA severity. This provides a strong incentive to optimize the management of fluid balance in patients with ESRD and OSA and suggests that bioimpedance could be a valuable tool in the clinical practice to identify patients who could benefit from additional fluid removal. The therapeutic potential of this novel strategy warrants additional prospective investigation on a larger population.
Disclosures
None.
Supplementary Material
Acknowledgments
This study was supported by unrestricted research grants from the Swiss Kidney Foundation (Schweizerische Nierenstiftung) and the Pulmonary League of Canton Vaud (Ligue Pulmonaire Vaudoise).
The Center for Investigation and Research in Sleep and the Nephrology Department of Lausanne University Hospital provided logistic support.
The results were presented in the form of a poster at the American Thoracic Society 2014 International Conference in San Diego, CA (May 16–21, 2014).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Footnotes
A.O. and V.F.O. contributed equally to this work.
Published online ahead of print. Publication date available at www.cjasn.org.
This article contains supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.08760914/-/DCSupplemental.
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