TY - JOUR
AU1 - , de Melo, Camila M
AU2 - Taranto-Montemurro,, Luigi
AU3 - Butler, James, P
AU4 - White, David, P
AU5 - Loring, Stephen, H
AU6 - Azarbarzin,, Ali
AU7 - Marques,, Melania
AU8 - Berger, Philip, J
AU9 - Wellman,, Andrew
AU1 - Sands, Scott, A
AB - Abstract Study objectives In principle, if metabolic rate were to fall during sleep in a patient with obstructive sleep apnea (OSA), ventilatory requirements could be met without increased respiratory effort thereby favoring stable breathing. Indeed, most patients achieve periods of stable flow-limited breathing without respiratory events for periods during the night for reasons that are unclear. Thus, we tested the hypothesis that in patients with OSA, periods of stable breathing occur when metabolic rate (VO2) declines. Methods Twelve OSA patients (apnea–hypopnea index >15 events/h) completed overnight polysomnography including measurements of VO2 (using ventilation and intranasal PO2) and respiratory effort (esophageal pressure). Results Contrary to our hypothesis, VO2 did not differ between stable and unstable breathing periods in non-REM stage 2 (208 ± 20 vs. 213 ± 18 mL/min), despite elevated respiratory effort during stable breathing (26 ± 2 versus 23 ± 2 cmH2O, p = .03). However, VO2 was lowered during deeper sleep (244 to 179 mL/min from non-REM stages 1 to 3, p = .04) in conjunction with more stable breathing. Further analysis revealed that airflow obstruction curtailed metabolism in both stable and unstable periods, since CPAP increased VO2 by 14% in both cases (p = .02, .03, respectively). Patients whose VO2 fell most during sleep avoided an increase in PCO2 and respiratory effort. Conclusions OSA patients typically convert from unstable to stable breathing without lowering metabolic rate. During sleep, OSA patients labor with increased respiratory effort but fail to satisfy metabolic demand even in the absence of overt respiratory events. OSA, stable breathing, metabolic rate, respiratory effort, deep sleep Statement of Significance We tested the theory-based hypothesis that stable breathing occurs overnight in OSA patients when metabolic rate declines. Surprisingly, we found no difference in metabolic rate between stable and unstable breathing periods, indicating that spontaneous OSA resolution must result from other changes. For the first time, we show in both unstable and stable flow-limited periods that metabolic rate increases when airflow obstruction is ameliorated with CPAP, revealing the existence of a latent metabolic demand during upper airway obstruction, whether or not patients exhibit frank obstructive events. We also show that patients who substantially lower their metabolic rate are protected from sequelae including increased PCO2 and respiratory effort. These new findings suggest that nocturnal metabolic rate could influence the outcomes of OSA. INTRODUCTION Obstructive sleep apnea (OSA) is characterized by upper airway narrowing during sleep, causing a reduction in ventilation below levels consistent with maintenance of sleep.1,2 Based on a ventilatory insufficiency model, if ventilation is reduced substantially during OSA,2–4 oxygen levels fall and carbon dioxide rises, yielding increased respiratory effort (ie, intrathoracic pressure) until a threshold is reached that results in arousal. Yet most individuals with OSA exhibit stable periods of breathing without respiratory events over the course of the night.1,5 The mechanisms responsible for the spontaneous development of stable breathing overnight remain unclear; such insight might point to novel therapeutic strategies for OSA. Metabolic rate is an important putative determinant of OSA that has not been sufficiently explored. In principle, for a given severity of pharyngeal airflow obstruction, a lower metabolic rate would minimize the severity of hypoxia/hypercapnia and the reflex rise in respiratory effort, and could potentially enable respiratory effort to remain below the threshold that triggers arousal from sleep (Figure 1). Thus, the elevated metabolic rate in patients with OSA, both in the daytime6–8 and during sleep,9 is—at least in principle—a key pathophysiological trait predisposing to OSA. In addition, the reduced metabolic rate of slow wave sleep10 might explain the substantial improvement in OSA severity in that state,11,12 a phenomenon that remains unresolved. Metabolic rate may also fall “in response” to the hypoventilation that accompanies airflow obstruction, perhaps via oxygen-conserving mechanisms akin to the diving reflex.13–15 Indeed, in physiological studies, some patients have been found to tolerate profound and sustained reductions in ventilation during stable flow-limited breathing, to as low as 50% of their prior eupneic levels without arousal from sleep3,16: If metabolic rate does not decline in conjunction with airflow obstruction, then alveolar and arterial carbon dioxide tension (PCO2) would rise toward an intolerable 80 mmHg17; thus, metabolic rate appears to be reduced at such times. Figure 1 Open in new tabDownload slide Hypothesis: lowered metabolic rate facilitates stable breathing. An illustrative ventilatory control diagram showing ventilation versus respiratory effort. At a higher metabolic rate (open circles, dashed blue line), partial collapse of the upper airway leads to an increase in respiratory effort (via rising PCO2) to a level that is higher than the threshold for arousal (i). Thus, stable breathing during sleep is not possible. However, if metabolic rate is lowered (see arrow; closed circles, solid blue line), the same partial upper airway collapse is better tolerated, and a steady state (closed circle) becomes possible at a value of effort that is below the threshold for arousal (ii). If this mechanism explains why OSA is spontaneously resolved, then we would expect a reduced metabolic rate to be observed in stable versus unstable periods. Blue lines describe the ventilatory demand, ie, the level of respiratory effort in response to changes to ventilation. Figure 1 Open in new tabDownload slide Hypothesis: lowered metabolic rate facilitates stable breathing. An illustrative ventilatory control diagram showing ventilation versus respiratory effort. At a higher metabolic rate (open circles, dashed blue line), partial collapse of the upper airway leads to an increase in respiratory effort (via rising PCO2) to a level that is higher than the threshold for arousal (i). Thus, stable breathing during sleep is not possible. However, if metabolic rate is lowered (see arrow; closed circles, solid blue line), the same partial upper airway collapse is better tolerated, and a steady state (closed circle) becomes possible at a value of effort that is below the threshold for arousal (ii). If this mechanism explains why OSA is spontaneously resolved, then we would expect a reduced metabolic rate to be observed in stable versus unstable periods. Blue lines describe the ventilatory demand, ie, the level of respiratory effort in response to changes to ventilation. Accordingly, the current study aimed to investigate metabolic rate—quantified as oxygen uptake, VO2—during sleep in periods of stable breathing compared with periods of unstable breathing (respiratory events, ie, obstructive apneas/hypopneas). We tested the primary hypothesis that periods of stable breathing during sleep are associated with lowered metabolic rate. We also tested secondary hypotheses that (1) more stable breathing with deeper sleep is accompanied by lowered metabolic rate, (2) that relief of airflow obstruction with intervention (continuous positive airway pressure, CPAP) increases metabolic rate, and (3) that patients with the greatest reduction in metabolic rate exhibit the least severe disturbance to alveolar gases and respiratory effort with airflow obstruction. METHODS Participants Seventeen individuals with diagnosed OSA were recruited from our sleep clinics and the general community. Written, informed consent was obtained before participation in the study, which was approved by the Human Research Committee at Brigham and Women’s Hospital. Participants attended a preliminary overnight polysomnographic study to confirm the presence of moderate-to-severe OSA (defined as an apnea–hypopnea index, AHI >15 events/h). Twelve patients with moderate-to-severe OSA on the night of investigation contributed data for analysis; five participants were excluded because of the absence of OSA on the research sleep study night (AHI <15 events/h). Among the 12 patients included, the AHI on the preliminary study was 46.6 ± 6.8 events/h. Experimental Setup Participants completed an overnight research polysomnography with additional physiological measurements. A sealed mask enabled measurement of ventilation (pneumotachometer model 3700A; Hans-Rudolph, Kansas City, MO). Esophageal pressure was recorded using a balloon catheter advanced nasally to sit in the lower third of the esophagus. Intranasal PO2 and PCO2 were recorded (O2 analyzer/capnograph, Vacumed, Ventura, CA; response time ~0.15 s) to provide measurements of metabolic rate and end-tidal PO2/PCO2. Oxygen uptake (VO2) was calculated using the breath-by-breath method15,16 based on the ventilatory flow and PO2 waveforms (see below); mean oxygen uptake was used to measure metabolic rate. Procedure Participants were asked to sleep supine for as long as possible overnight. For a period in the middle third of the night (34 ± 10% of the total sleep time), subjects were placed on a therapeutic level of CPAP (a pressure level required to resolve apneas/hypopneas, snoring, and inspiratory flow limitation; Pcrit 3000, Philips Respironics, Murrysville, PA) in order to assess metabolic rate under eupneic conditions during sleep. This period was also used to perform CPAP dial-downs for assessing OSA phenotypes (data not shown).3 Data Selection Selection of Breathing Patterns During the Night The night was manually divided up into periods of quiet wakefulness, unstable breathing (recurrent respiratory events) during sleep, stable breathing during sleep, and eupneic breathing on therapeutic CPAP during sleep. Long consecutive periods of data within the same category were broken up into 3-min epochs. Periods of stable breathing were selected based on the absence of respiratory events and arousals, and on the constancy of ventilation (no trend toward increasing or decreasing ventilation for ≥1 minute). Periods of respiratory events were selected based on clinically scored obstructive apneas and hypopneas (≥30% reduction in airflow with 3% desaturation or arousal); breaths within arousals were not excluded from analysis as necessary to infer metabolic rate from oxygen uptake. Periods of unstable sleep (eg, arousals without respiratory events at sleep onset) were excluded from analysis. Periods with reduced PO2 signal integrity (eg, accompanying mouth breathing) were excluded. We note that stable breathing was universally flow-limited in our group of patients with OSA, based on the presence of a nonrounded (eg, flattened/scooped/irregular) flow trace and elevated respiratory effort compared with wakefulness. Periods of eupneic breathing on CPAP were selected using a level of CPAP that resolved flow limitation. Data Analysis Metabolic Rate (VO2) The average oxygen uptake at the nose/mouth measured over time is equivalent to the average oxygen utilization occurring in the cell. That is, in the steady-state, external respiration equals internal respiration. The measurement of oxygen uptake—and thus metabolic rate—is based on the physical principle that the volume of oxygen consumed is equal to the difference between the volume of oxygen inspired and the volume of oxygen expired. Oxygen uptake is therefore calculated by summing the expired oxygen volume (ie, FO2 × expired ventilation) and subtracting this from the inspired oxygen volume at each time step (Δt, 0.008 s) throughout each expiratory period: ie, VO2 = sum[(inspired FO2 − expired FO2) × expired ventilation × Δt] × respiratory rate.18 Sampled gases were dried via Nafion tubing, and FO2 waveforms were corrected for delays before analysis. VO2 data are expressed as STPD (standard temperature and pressure, dry). We report data for oxygen uptake rather than carbon dioxide excretion (VCO2) because changes in VCO2 at the nose/mouth can occur with changes in ventilation independent of metabolic CO2 excretion, ie, via loading/unloading of the body’s substantial tissue CO2 stores, an issue that is less of a concern with the use of VO2.19,20 Respiratory Effort Esophageal pressure swings were assessed breath-by-breath by measuring the difference between the nadir value and the prior end-expiratory (zero-flow baseline) value. Of note, greater esophageal pressure swings indicate a greater oxygen cost of breathing.21 Alveolar Gases End-tidal PO2 and PCO2 values were measured as a surrogate for alveolar and arterial levels to indicate blood gas disturbances. For breaths when end-tidal values were not available, due to apneas/hypopneas, a single compartment model (fit to the available data across the full window) provided estimates of the alveolar PO2 and PCO2 levels,22 avoiding the potential bias associated with failure to capture the magnitude of hypercapnia due to airway occlusion (see Supplementary Figure S1). Mean values of breath-by-breath variables (oxygen uptake, ventilation, respiratory effort, alveolar PO2/PCO2) were obtained for each epoch (weighted mean using breath duration). Median values from multiple epochs of data were taken to yield a single value for each participant for each category (eg, stable non-REM 2, unstable non-REM 2). To avoid trivial changes in pharyngeal collapsibility affecting our results, analyses were performed using data taken exclusively in the supine position. Care was taken to maintain consistent neck position (flexion/rotation) throughout the night, to the extent possible via live video without objective measurement. Primary comparisons were made using data exclusively from non-REM stage 2, the most common stage, to control for potential state effects. Statistical Analysis All variables were tested for normality (Komolgorov–Smirnov test). Student t-tests (paired) compared metabolic rate (and other variables) during stable versus unstable breathing. Our study was powered to detect a 1 SD difference in VO2 between stable and unstable breathing conditions (88% power, alpha = 0.05 for N = 12). General linear models were used to assess the impact of CPAP on metabolic rate (and other variables), using wakefulness values and subject (binary dummy variables) as covariates; interaction terms were not tested. The same approach was used to examine sleep state effects, where non-REM sleep depth was included as a single variable (non-REM 1, 2, 3 were denoted by −1, 0, 1, respectively). Subgroup analyses compared values of metabolic rate (relative to wakefulness data) between groups using unpaired Student’s t-tests. SigmaPlot (Systat Software, San Jose, CA) was used for statistical analysis. Values are presented as mean ± SEM unless specified otherwise. P <.05 was considered significant. No corrections were made for multiple comparisons. RESULTS Summary characteristics including polysomnographic data for the 12 patients with OSA are shown in Table 1. On average, participants were overweight/obese and had severe OSA. Figure 2 demonstrates example breathing patterns in one patient. Table 1 Participant characteristics. Characteristic Value Demographics  Gender (M:F) 9:3  Age (years) 56.2 ± 6.4  Body mass index (kg/m2) 31.9 ± 5.7 Polysomnography  Total sleep time (min) 358 ± 120  Apnea–hypopnea index, total (events/h) 41.3 ± 18.4  Apnea–hypopnea index, non-REM supine (events/h) 40.9 ± 17.3  Stable breathinga (%total sleep time) 27.3 ± 20.1  Arousalb (%) 19.6 ± 9.0 Characteristic Value Demographics  Gender (M:F) 9:3  Age (years) 56.2 ± 6.4  Body mass index (kg/m2) 31.9 ± 5.7 Polysomnography  Total sleep time (min) 358 ± 120  Apnea–hypopnea index, total (events/h) 41.3 ± 18.4  Apnea–hypopnea index, non-REM supine (events/h) 40.9 ± 17.3  Stable breathinga (%total sleep time) 27.3 ± 20.1  Arousalb (%) 19.6 ± 9.0 Data from research polysomnography are shown (mean ± SD). SD = standard deviation. aPercentage of sleep without respiratory events or arousals (at least 1 min). bProportion of sleep time in arousals (sum of arousal durations/total sleep time). Open in new tab Table 1 Participant characteristics. Characteristic Value Demographics  Gender (M:F) 9:3  Age (years) 56.2 ± 6.4  Body mass index (kg/m2) 31.9 ± 5.7 Polysomnography  Total sleep time (min) 358 ± 120  Apnea–hypopnea index, total (events/h) 41.3 ± 18.4  Apnea–hypopnea index, non-REM supine (events/h) 40.9 ± 17.3  Stable breathinga (%total sleep time) 27.3 ± 20.1  Arousalb (%) 19.6 ± 9.0 Characteristic Value Demographics  Gender (M:F) 9:3  Age (years) 56.2 ± 6.4  Body mass index (kg/m2) 31.9 ± 5.7 Polysomnography  Total sleep time (min) 358 ± 120  Apnea–hypopnea index, total (events/h) 41.3 ± 18.4  Apnea–hypopnea index, non-REM supine (events/h) 40.9 ± 17.3  Stable breathinga (%total sleep time) 27.3 ± 20.1  Arousalb (%) 19.6 ± 9.0 Data from research polysomnography are shown (mean ± SD). SD = standard deviation. aPercentage of sleep without respiratory events or arousals (at least 1 min). bProportion of sleep time in arousals (sum of arousal durations/total sleep time). Open in new tab Figure 2 Open in new tabDownload slide Example traces of the different breathing patterns selected during the night. In this illustrative example, note that metabolic rate (dashed blue line; mean of breath-by-breath oxygen uptake) was reduced in both unstable and stable breathing patterns compared with wakefulness and CPAP (black line). However, stable breathing periods are associated with greater esophageal pressure swings (effort) than unstable periods; CPAP normalized effort but also increased metabolic rate. PO2 = end-tidal oxygen tension; SpO2 = oxygen saturation level. Figure 2 Open in new tabDownload slide Example traces of the different breathing patterns selected during the night. In this illustrative example, note that metabolic rate (dashed blue line; mean of breath-by-breath oxygen uptake) was reduced in both unstable and stable breathing patterns compared with wakefulness and CPAP (black line). However, stable breathing periods are associated with greater esophageal pressure swings (effort) than unstable periods; CPAP normalized effort but also increased metabolic rate. PO2 = end-tidal oxygen tension; SpO2 = oxygen saturation level. On average, we analyzed 42 ± 4 min of data per patient during unstable breathing, 24 ± 7 min during stable breathing, 32 ± 7 min during wake, and 10 ± 3 min on therapeutic CPAP. Stable Versus Unstable Breathing Contrary to our primary hypothesis, we found no significant difference in metabolic rate between stable and unstable breathing periods in the same sleep state (non-REM 2, see Table 2; Figure 3A–B). Instead, stable breathing is accompanied by a reduction in ventilation (−8%), a trend toward reduced alveolar PO2 and increased alveolar PCO2, and an increased respiratory effort (esophageal pressure swings, +3 cmH2O). Table 2 Effect of stable versus unstable breathing. Characteristic Unstable Stable Stable vs unstable Metabolic rate, VO2 (mL/min) 213.1 ± 18.0 208.3 ± 20.7 p = .5 Ventilation (L/min) 6.3 ± 0.4 5.8 ± 0.4 p = .004 Esophageal pressure (cmH2O) 22.9 ± 2.2 25.7 ± 2.6 p = .033 Alveolar PO2 (mmHg) 98.3 ± 1.7 97.1 ± 2.2 p = .076 Alveolar PCO2 (mmHg) 39.8 ± 1.2 40.3 ± 1.3 p = .078 Characteristic Unstable Stable Stable vs unstable Metabolic rate, VO2 (mL/min) 213.1 ± 18.0 208.3 ± 20.7 p = .5 Ventilation (L/min) 6.3 ± 0.4 5.8 ± 0.4 p = .004 Esophageal pressure (cmH2O) 22.9 ± 2.2 25.7 ± 2.6 p = .033 Alveolar PO2 (mmHg) 98.3 ± 1.7 97.1 ± 2.2 p = .076 Alveolar PCO2 (mmHg) 39.8 ± 1.2 40.3 ± 1.3 p = .078 Data presented as mean ± SEM. Alveolar PO2/PCO2 refers to mean end-tidal PO2/PCO2 with corrections for periods of apnea/hypopnea as appropriate. Data for non-REM stage 2 are shown. Statistics: Paired Student t-test. SEM = standard error of mean. Open in new tab Table 2 Effect of stable versus unstable breathing. Characteristic Unstable Stable Stable vs unstable Metabolic rate, VO2 (mL/min) 213.1 ± 18.0 208.3 ± 20.7 p = .5 Ventilation (L/min) 6.3 ± 0.4 5.8 ± 0.4 p = .004 Esophageal pressure (cmH2O) 22.9 ± 2.2 25.7 ± 2.6 p = .033 Alveolar PO2 (mmHg) 98.3 ± 1.7 97.1 ± 2.2 p = .076 Alveolar PCO2 (mmHg) 39.8 ± 1.2 40.3 ± 1.3 p = .078 Characteristic Unstable Stable Stable vs unstable Metabolic rate, VO2 (mL/min) 213.1 ± 18.0 208.3 ± 20.7 p = .5 Ventilation (L/min) 6.3 ± 0.4 5.8 ± 0.4 p = .004 Esophageal pressure (cmH2O) 22.9 ± 2.2 25.7 ± 2.6 p = .033 Alveolar PO2 (mmHg) 98.3 ± 1.7 97.1 ± 2.2 p = .076 Alveolar PCO2 (mmHg) 39.8 ± 1.2 40.3 ± 1.3 p = .078 Data presented as mean ± SEM. Alveolar PO2/PCO2 refers to mean end-tidal PO2/PCO2 with corrections for periods of apnea/hypopnea as appropriate. Data for non-REM stage 2 are shown. Statistics: Paired Student t-test. SEM = standard error of mean. Open in new tab Figure 3 Open in new tabDownload slide Individual data for metabolic rate (top) and respiratory effort (bottom). Metabolic rate falls from wake to sleep (A) by similar amounts in stable and unstable stable breathing periods; CPAP raises metabolic rate. Respiratory effort (esophageal pressure swings, (B) is greater in stable versus unstable breathing, and is reduced with CPAP. With deeper sleep (non-REM 1 to 3), metabolic rate falls (C) and respiratory effort increases (D). Mean values are indicated by the horizontal bars. Values are shown as percentage of wakefulness to facilitate visual comparisons. The patients shown in green (N = 5) are those who lowered their metabolic rate by more than 30% from wake to sleep. See text and Tables for statistical analyses. CPAP = continuous positive airway pressure; NREM = non-rapid eye movement sleep. Figure 3 Open in new tabDownload slide Individual data for metabolic rate (top) and respiratory effort (bottom). Metabolic rate falls from wake to sleep (A) by similar amounts in stable and unstable stable breathing periods; CPAP raises metabolic rate. Respiratory effort (esophageal pressure swings, (B) is greater in stable versus unstable breathing, and is reduced with CPAP. With deeper sleep (non-REM 1 to 3), metabolic rate falls (C) and respiratory effort increases (D). Mean values are indicated by the horizontal bars. Values are shown as percentage of wakefulness to facilitate visual comparisons. The patients shown in green (N = 5) are those who lowered their metabolic rate by more than 30% from wake to sleep. See text and Tables for statistical analyses. CPAP = continuous positive airway pressure; NREM = non-rapid eye movement sleep. Sleep Stage Effects As expected, the progression from lighter to deeper non-REM sleep (stage 1 to 3) was accompanied by a profound and progressive improvement in OSA severity and likelihood of stable breathing (Table 3, stable and unstable data pooled; Figure 3C–D; for unpooled data see Supplementary Table S1). Concurrently, we observed a progressive ~27% reduction in metabolic rate from stages 1 to 3, with progressively lowered ventilation, no change in alveolar gases, but increased respiratory effort (+8 cmH2O). Metabolic rate and ventilation in REM was similar to non-REM 2, but respiratory effort was reduced. Table 3 Effect of sleep stage on metabolic rate. Characteristic Wake NREM 1 NREM 2 NREM 3 REM Deeper vs lighter NREM NREM 2 vs wake REM vs NREM 2 Apnea–hypopnea index (events/h) 48.8 ± 7.1 34.8 ± 4.2 13.2 ± 4.0 49.0 ± 8.3 p < .001 p = .031 Stable breathing (%) 7.0 ± 2.5 34.6 ± 6.3 90.9 ± 9.1 18.3 ± 16.4 p < .001 p = .034 Arousal (%) 29.3 ± 2.4 15.1 ± 2.7 0.5 ± 0.5 19.3 ± 6.6 p < .001 p = .068 Metabolic rate, VO2 (mL/min) 294 ± 19 244 ± 22 214 ± 19 179 ± 12 213 ± 22 p = .039 p < .001 Ventilation (L/min) 8.6 ± 0.6 6.7 ± 0.6 6.1 ± 0.4 5.8 ± 0.3 6.1 ± 0.5 p = .068 p < .001 Esophageal pressure (cmH2O) 14.1 ± 1.7 20.0 ± 2.3 23.9 ± 2.4 27.7 ± 3.3 17.5 ± 2.6 p = .005 p < .001 p = .025 Alveolar PO2 (mmHg) 102.6 ± 1.4 98.2 ± 1.5 98.7 ± 1.6 98.7 ± 1.8 96.7 ± 1.7 p < .001 p = .018 Alveolar PCO2 (mmHg) 39.5 ± 1.0 40.0 ± 1.0 40.1 ± 1.2 39.7 ± 1.0 40.6 ± 1.1 p = .1 Characteristic Wake NREM 1 NREM 2 NREM 3 REM Deeper vs lighter NREM NREM 2 vs wake REM vs NREM 2 Apnea–hypopnea index (events/h) 48.8 ± 7.1 34.8 ± 4.2 13.2 ± 4.0 49.0 ± 8.3 p < .001 p = .031 Stable breathing (%) 7.0 ± 2.5 34.6 ± 6.3 90.9 ± 9.1 18.3 ± 16.4 p < .001 p = .034 Arousal (%) 29.3 ± 2.4 15.1 ± 2.7 0.5 ± 0.5 19.3 ± 6.6 p < .001 p = .068 Metabolic rate, VO2 (mL/min) 294 ± 19 244 ± 22 214 ± 19 179 ± 12 213 ± 22 p = .039 p < .001 Ventilation (L/min) 8.6 ± 0.6 6.7 ± 0.6 6.1 ± 0.4 5.8 ± 0.3 6.1 ± 0.5 p = .068 p < .001 Esophageal pressure (cmH2O) 14.1 ± 1.7 20.0 ± 2.3 23.9 ± 2.4 27.7 ± 3.3 17.5 ± 2.6 p = .005 p < .001 p = .025 Alveolar PO2 (mmHg) 102.6 ± 1.4 98.2 ± 1.5 98.7 ± 1.6 98.7 ± 1.8 96.7 ± 1.7 p < .001 p = .018 Alveolar PCO2 (mmHg) 39.5 ± 1.0 40.0 ± 1.0 40.1 ± 1.2 39.7 ± 1.0 40.6 ± 1.1 p = .1 Values are reported as mean ± SEM. General linear model: Y = β0 + β1 × SleepDepth + β2 × wake + β3 × REM + Σβpatient × patient, where SleepDepth = −1, 0, 1 for non-REM 1, 2, 3, respectively. An effect of deeper versus lighter NREM is revealed by β1 being significantly greater or less than zero. N = 11/12 patients provided data for NREM 1, N = 4/12 for NREM 3, and N = 7/12 for REM. p values above .2 are not shown. All data shown are off CPAP. Stable and unstable periods were pooled for analysis. NREM = non-REM; REM = rapid eye movement sleep. Open in new tab Table 3 Effect of sleep stage on metabolic rate. Characteristic Wake NREM 1 NREM 2 NREM 3 REM Deeper vs lighter NREM NREM 2 vs wake REM vs NREM 2 Apnea–hypopnea index (events/h) 48.8 ± 7.1 34.8 ± 4.2 13.2 ± 4.0 49.0 ± 8.3 p < .001 p = .031 Stable breathing (%) 7.0 ± 2.5 34.6 ± 6.3 90.9 ± 9.1 18.3 ± 16.4 p < .001 p = .034 Arousal (%) 29.3 ± 2.4 15.1 ± 2.7 0.5 ± 0.5 19.3 ± 6.6 p < .001 p = .068 Metabolic rate, VO2 (mL/min) 294 ± 19 244 ± 22 214 ± 19 179 ± 12 213 ± 22 p = .039 p < .001 Ventilation (L/min) 8.6 ± 0.6 6.7 ± 0.6 6.1 ± 0.4 5.8 ± 0.3 6.1 ± 0.5 p = .068 p < .001 Esophageal pressure (cmH2O) 14.1 ± 1.7 20.0 ± 2.3 23.9 ± 2.4 27.7 ± 3.3 17.5 ± 2.6 p = .005 p < .001 p = .025 Alveolar PO2 (mmHg) 102.6 ± 1.4 98.2 ± 1.5 98.7 ± 1.6 98.7 ± 1.8 96.7 ± 1.7 p < .001 p = .018 Alveolar PCO2 (mmHg) 39.5 ± 1.0 40.0 ± 1.0 40.1 ± 1.2 39.7 ± 1.0 40.6 ± 1.1 p = .1 Characteristic Wake NREM 1 NREM 2 NREM 3 REM Deeper vs lighter NREM NREM 2 vs wake REM vs NREM 2 Apnea–hypopnea index (events/h) 48.8 ± 7.1 34.8 ± 4.2 13.2 ± 4.0 49.0 ± 8.3 p < .001 p = .031 Stable breathing (%) 7.0 ± 2.5 34.6 ± 6.3 90.9 ± 9.1 18.3 ± 16.4 p < .001 p = .034 Arousal (%) 29.3 ± 2.4 15.1 ± 2.7 0.5 ± 0.5 19.3 ± 6.6 p < .001 p = .068 Metabolic rate, VO2 (mL/min) 294 ± 19 244 ± 22 214 ± 19 179 ± 12 213 ± 22 p = .039 p < .001 Ventilation (L/min) 8.6 ± 0.6 6.7 ± 0.6 6.1 ± 0.4 5.8 ± 0.3 6.1 ± 0.5 p = .068 p < .001 Esophageal pressure (cmH2O) 14.1 ± 1.7 20.0 ± 2.3 23.9 ± 2.4 27.7 ± 3.3 17.5 ± 2.6 p = .005 p < .001 p = .025 Alveolar PO2 (mmHg) 102.6 ± 1.4 98.2 ± 1.5 98.7 ± 1.6 98.7 ± 1.8 96.7 ± 1.7 p < .001 p = .018 Alveolar PCO2 (mmHg) 39.5 ± 1.0 40.0 ± 1.0 40.1 ± 1.2 39.7 ± 1.0 40.6 ± 1.1 p = .1 Values are reported as mean ± SEM. General linear model: Y = β0 + β1 × SleepDepth + β2 × wake + β3 × REM + Σβpatient × patient, where SleepDepth = −1, 0, 1 for non-REM 1, 2, 3, respectively. An effect of deeper versus lighter NREM is revealed by β1 being significantly greater or less than zero. N = 11/12 patients provided data for NREM 1, N = 4/12 for NREM 3, and N = 7/12 for REM. p values above .2 are not shown. All data shown are off CPAP. Stable and unstable periods were pooled for analysis. NREM = non-REM; REM = rapid eye movement sleep. Open in new tab Effect of Resolving Airflow Obstruction With CPAP To determine the effect of airflow obstruction on metabolic rate, we examined the influence of therapeutic CPAP during non-REM stage 2 (Table 4, stable and unstable data pooled; Figure 3A and B). Resolving airflow obstruction with CPAP increased metabolic rate by 14%. In addition, ventilation and alveolar PO2 increased, and esophageal pressure swings returned to wakefulness levels. The statistical effects of CPAP were upheld when compared exclusively to stable breathing (p = .029) and to unstable breathing separately (p = .017), see Supplementary Table S2. Table 4 Effect of CPAP on metabolic rate. Characteristic Wake NREM 2 off CPAP NREM 2 on CPAP Effect of CPAP Metabolic rate, VO2 (mL/min) 294 ± 19* 214 ± 19 244 ± 18 p = .034 Ventilation (L/min) 8.6 ± 0.6* 6.1 ± 0.4 7.2 ± 0.5 p = .007 Esophageal pressure (cmH2O) 14.1 ± 1.7* 23.9 ± 2.5 10.8 ± 1.5 p < .001 Alveolar PO2 (mmHg) 102.2 ± 1.4* 97.8 ± 1.9 102.7 ± 1.8 p < .001 Alveolar PCO2 (mmHg) 39.5 ± 1.0 40.1 ± 1.3 39.8 ± 1.1 p > .2 Characteristic Wake NREM 2 off CPAP NREM 2 on CPAP Effect of CPAP Metabolic rate, VO2 (mL/min) 294 ± 19* 214 ± 19 244 ± 18 p = .034 Ventilation (L/min) 8.6 ± 0.6* 6.1 ± 0.4 7.2 ± 0.5 p = .007 Esophageal pressure (cmH2O) 14.1 ± 1.7* 23.9 ± 2.5 10.8 ± 1.5 p < .001 Alveolar PO2 (mmHg) 102.2 ± 1.4* 97.8 ± 1.9 102.7 ± 1.8 p < .001 Alveolar PCO2 (mmHg) 39.5 ± 1.0 40.1 ± 1.3 39.8 ± 1.1 p > .2 General linear model: Y = β0 + β1 × CPAP + β2 × wake + Σβpatient × patient. Stable and unstable periods off CPAP were pooled (separate analysis yields similar findings). NREM 2 = non-rapid eye movement stage 2. *p < .05 wake vs sleep (off CPAP). Open in new tab Table 4 Effect of CPAP on metabolic rate. Characteristic Wake NREM 2 off CPAP NREM 2 on CPAP Effect of CPAP Metabolic rate, VO2 (mL/min) 294 ± 19* 214 ± 19 244 ± 18 p = .034 Ventilation (L/min) 8.6 ± 0.6* 6.1 ± 0.4 7.2 ± 0.5 p = .007 Esophageal pressure (cmH2O) 14.1 ± 1.7* 23.9 ± 2.5 10.8 ± 1.5 p < .001 Alveolar PO2 (mmHg) 102.2 ± 1.4* 97.8 ± 1.9 102.7 ± 1.8 p < .001 Alveolar PCO2 (mmHg) 39.5 ± 1.0 40.1 ± 1.3 39.8 ± 1.1 p > .2 Characteristic Wake NREM 2 off CPAP NREM 2 on CPAP Effect of CPAP Metabolic rate, VO2 (mL/min) 294 ± 19* 214 ± 19 244 ± 18 p = .034 Ventilation (L/min) 8.6 ± 0.6* 6.1 ± 0.4 7.2 ± 0.5 p = .007 Esophageal pressure (cmH2O) 14.1 ± 1.7* 23.9 ± 2.5 10.8 ± 1.5 p < .001 Alveolar PO2 (mmHg) 102.2 ± 1.4* 97.8 ± 1.9 102.7 ± 1.8 p < .001 Alveolar PCO2 (mmHg) 39.5 ± 1.0 40.1 ± 1.3 39.8 ± 1.1 p > .2 General linear model: Y = β0 + β1 × CPAP + β2 × wake + Σβpatient × patient. Stable and unstable periods off CPAP were pooled (separate analysis yields similar findings). NREM 2 = non-rapid eye movement stage 2. *p < .05 wake vs sleep (off CPAP). Open in new tab Subgroup Analysis To examine associations with lowered metabolic rate during sleep, we divided patients into two groups based on whether they lowered metabolic rate by more than or less than 30% in non-REM 2 compared to wakefulness (Table 5, stable and unstable data pooled; for unpooled data see Supplementary Table S3). Patients with a lowered metabolic rate (N = 5), were the same patients with a >30% reduction in ventilation. Interestingly, patients with reduced metabolic rate exhibited minimal changes in alveolar PCO2/PO2 and respiratory effort from wake to sleep (see Figure 3A and B and Table 5). By contrast, those with a lesser fall in metabolic rate (N = 7) exhibited an increase in alveolar PCO2 (+1.5 mmHg), reduction in alveolar PO2 (−6 mmHg) and a substantial increase in esophageal pressure (+130%) from wake to sleep (Figure 3A and B and Table 5). Table 5 Subgroup analysis. Variable Reduced VO2 (N = 5)a Preserved VO2 (N = 7) pb Apnea–hypopnea index (events/h) 43 ± 7 29 ± 6 .12 Stable breathing (%) 25 ± 10 41 ± 8 >.2 Arousal (%) 18 ± 4 13 ± 4 >.2 Metabolic rate, VO2 (mL/min) 174 ± 10 242 ± 21  Change from wake (%) −41 ± 5c −16 ± 2c <.0001 Ventilation (L/min) 5.7 ± 0.4 6.5 ± 0.4  Change from wake (%) −37 ± 1c −21 ± 2c <.0001 Esophageal pressure (cmH2O) 22.3 ± 2.8 25.0 ± 2.3  Change from wake (%) +31 ± 45 +130 ± 38c .09 Alveolar PO2 (mmHg) 101.6 ± 2.1 95.1 ± 2.5  Change from wake (mmHg) −2.0 ± 1.6 −6.4 ± 1.4c .047 Alveolar PCO2 (mmHg) 36.9 ± 2.0 42.5 ± 1.0  Change from wake (mmHg) −0.6 ± 0.8 +1.5 ± 0.6c .031 Variable Reduced VO2 (N = 5)a Preserved VO2 (N = 7) pb Apnea–hypopnea index (events/h) 43 ± 7 29 ± 6 .12 Stable breathing (%) 25 ± 10 41 ± 8 >.2 Arousal (%) 18 ± 4 13 ± 4 >.2 Metabolic rate, VO2 (mL/min) 174 ± 10 242 ± 21  Change from wake (%) −41 ± 5c −16 ± 2c <.0001 Ventilation (L/min) 5.7 ± 0.4 6.5 ± 0.4  Change from wake (%) −37 ± 1c −21 ± 2c <.0001 Esophageal pressure (cmH2O) 22.3 ± 2.8 25.0 ± 2.3  Change from wake (%) +31 ± 45 +130 ± 38c .09 Alveolar PO2 (mmHg) 101.6 ± 2.1 95.1 ± 2.5  Change from wake (mmHg) −2.0 ± 1.6 −6.4 ± 1.4c .047 Alveolar PCO2 (mmHg) 36.9 ± 2.0 42.5 ± 1.0  Change from wake (mmHg) −0.6 ± 0.8 +1.5 ± 0.6c .031 Data presented in mean ± SEM. SEM = standard error of mean. aThe reduced metabolic rate (VO2) subgroup is defined by a reduction in VO2 in excess of 30% from wake to sleep (NREM 2). bp values in the table compare between groups (unpaired Student’s t-test). Data from NREM stage 2 are shown. Stable and unstable periods off CPAP were pooled. cSignificant change from wakefulness. Open in new tab Table 5 Subgroup analysis. Variable Reduced VO2 (N = 5)a Preserved VO2 (N = 7) pb Apnea–hypopnea index (events/h) 43 ± 7 29 ± 6 .12 Stable breathing (%) 25 ± 10 41 ± 8 >.2 Arousal (%) 18 ± 4 13 ± 4 >.2 Metabolic rate, VO2 (mL/min) 174 ± 10 242 ± 21  Change from wake (%) −41 ± 5c −16 ± 2c <.0001 Ventilation (L/min) 5.7 ± 0.4 6.5 ± 0.4  Change from wake (%) −37 ± 1c −21 ± 2c <.0001 Esophageal pressure (cmH2O) 22.3 ± 2.8 25.0 ± 2.3  Change from wake (%) +31 ± 45 +130 ± 38c .09 Alveolar PO2 (mmHg) 101.6 ± 2.1 95.1 ± 2.5  Change from wake (mmHg) −2.0 ± 1.6 −6.4 ± 1.4c .047 Alveolar PCO2 (mmHg) 36.9 ± 2.0 42.5 ± 1.0  Change from wake (mmHg) −0.6 ± 0.8 +1.5 ± 0.6c .031 Variable Reduced VO2 (N = 5)a Preserved VO2 (N = 7) pb Apnea–hypopnea index (events/h) 43 ± 7 29 ± 6 .12 Stable breathing (%) 25 ± 10 41 ± 8 >.2 Arousal (%) 18 ± 4 13 ± 4 >.2 Metabolic rate, VO2 (mL/min) 174 ± 10 242 ± 21  Change from wake (%) −41 ± 5c −16 ± 2c <.0001 Ventilation (L/min) 5.7 ± 0.4 6.5 ± 0.4  Change from wake (%) −37 ± 1c −21 ± 2c <.0001 Esophageal pressure (cmH2O) 22.3 ± 2.8 25.0 ± 2.3  Change from wake (%) +31 ± 45 +130 ± 38c .09 Alveolar PO2 (mmHg) 101.6 ± 2.1 95.1 ± 2.5  Change from wake (mmHg) −2.0 ± 1.6 −6.4 ± 1.4c .047 Alveolar PCO2 (mmHg) 36.9 ± 2.0 42.5 ± 1.0  Change from wake (mmHg) −0.6 ± 0.8 +1.5 ± 0.6c .031 Data presented in mean ± SEM. SEM = standard error of mean. aThe reduced metabolic rate (VO2) subgroup is defined by a reduction in VO2 in excess of 30% from wake to sleep (NREM 2). bp values in the table compare between groups (unpaired Student’s t-test). Data from NREM stage 2 are shown. Stable and unstable periods off CPAP were pooled. cSignificant change from wakefulness. Open in new tab DISCUSSION The current study is the first to explore changes in metabolic rate as a potential determinant of OSA across the course of a night. Contrary to our primary hypothesis (Figure 1), we demonstrated that the spontaneous conversion from unstable to stable breathing is not accompanied by a reduction in metabolic rate. Rather stable breathing was characterized by elevated respiratory effort compared with unstable breathing. However, we found that deeper sleep is accompanied by a lowered metabolic rate, a factor which may facilitate the observed disappearance of OSA with more established sleep. We also found that relief of airflow obstruction with CPAP raises metabolic rate, demonstrating that obstructive sleep disordered breathing—observed either as overt respiratory events or stable flow-limited breathing—acutely lowers nocturnal metabolic rate. Thus, obstructed breathing has implications for restorative metabolic processes that normally occur during sleep. We also showed that patients with the greatest decline in metabolic rate during sleep experience the smallest disturbances to PCO2 levels and respiratory effort, which may explain differences in metabolic, neurocognitive, and cardiovascular outcomes across patients. Physiological Insights Stable Versus Unstable Breathing Our finding that metabolic rate is similarly reduced in stable breathing versus unstable breathing periods, in the same position and sleep state, illustrates that other factors are typically responsible for the spontaneous development of stable breathing. Such factors likely include: (1) spontaneous improvements in upper airway physiology via increased dilator muscle activity5,23,24; (2) improvements in arousability from sleep,25 consistent with our observation of increased effort during stable breathing. A third possibility is that there are no distinct physiological changes per se that occur between stable and unstable breathing conditions. For example, a stable equilibrium may exist but a perturbation still initiates cyclic events,26–28 ie, one event promotes the likelihood of another via reflex ventilatory overshoot/undershoot perpetuation of oscillations. Although metabolic rate was not reduced during stable breathing, it remains possible that interventions that lower metabolic rate (and thus ventilatory demand) may help improve sleep apnea in some individuals. Increased Respiratory Effort During Stable Breathing in Patients With Sleep Apnea Our study demonstrates for the first time (to our knowledge) that respiratory effort, as revealed by esophageal pressure, is greater in periods of stable versus unstable breathing in patients with sleep apnea. This finding is consistent with a previous report that the largest epiglottic pressure swings during obstructive events are similar in magnitude to the average swings seen during stable breathing.5 On the surface, these findings might appear paradoxical: If sleep apnea spontaneously resolves through an improvement in airway collapsibility—whether via passive mechanics or dilator muscle activity—one would expect a reduction in effort accompanying a shift to stable breathing. Reducing loop gain (ie, a diminished chemoreflex increase in respiratory effort in response to lowered ventilation) would also tend to lower ventilatory effort. However, if sleep apnea resolves through an increased arousal threshold, we would expect an increase in ventilatory effort to accompany stable breathing, consistent with our findings. Presumably, the sustained higher level of respiratory effort observed provides a stimulus for the known increase in dilator muscle activity at this time.5 Thus, we consider stable breathing in OSA to be a state of elevated drive. By contrast, when breathing is unstable, the airway is recurrently reopened to allow respiratory effort to return transiently toward normal levels (see Figure 1), albeit at the cost of fluctuating blood gases and sleep fragmentation. Thus, it is important to consider that OSA interventions that promote a switch from unstable to stable flow-limited breathing may not always be advantageous given the links between negative intrathoracic pressure and risk of adverse cardiovascular outcomes.29–31 Changes in Metabolic Rate Caused by Airflow Obstruction Importantly, our study found that patients with OSA exhibit reduced metabolic rate as a consequence of airflow obstruction, as illustrated by the finding that acute CPAP application raises metabolic rate. Thus, despite elevated work of breathing and the presumed increase in oxygen utilization by inspiratory muscles (ie, diaphragm), whole body metabolic rate is actually lower than it would be if the OSA patient had a normal airway. We note that the metabolic cost of breathing is relatively small compared with whole body metabolism, normally representing roughly 1–3% of total body VO2 at rest32–34; thus, a doubled work of breathing alone (Table 4) may be expected to raise whole body VO2 by approximately 1–3%. (This estimate might be larger in morbidly obese.34) The concept that obstructive sleep disordered breathing (cyclic apneas or hypoventilation with increased effort) reduces metabolic rate is supported by evidence that breath-holding reduces metabolic rate in animal13,14 and human studies (eg, volitional 30-s breath holds lower cerebral metabolic O2 consumption),15 and that hypoventilation consequent to increased respiratory resistance (added respiratory loads) in neonates causes a reduced metabolic rate.35 There is also evidence that metabolic rate is lowered with meditation in conjunction with hypoventilation (reduced respiratory rate).36 In an apparent contrast, experimental human adult studies have found increased metabolic rate with added respiratory loads (designed to increase respiratory effort) during wakefulness. However, these studies have either kept ventilation constant or changes in ventilation were not reported37,38; thus, we suspect that a reduction in ventilation is essential for the observed reduction in metabolic rate in our study. The specific mechanism by which metabolic rate falls with reduced ventilation is not clear, but we speculate that this phenomenon is likely to be driven by reflex oxygen sparing mechanisms39,40 rather than direct effects of arterial hypoxemia per se given that changes in O2 were minimal and that there is evidence that hypoxia can raise metabolic rate (eg, via sympathetic excitation).41 The finding that airflow obstruction lowers metabolic rate appears to contradict the observations that patients with OSA typically have an increased metabolic rate: Resting metabolic rate is higher in OSA patients versus controls,6–8 at rest during wakefulness and overnight,17,18 a difference which holds up when correcting for obesity.6,8 In particular, Lin et al.9 recently measured metabolic oxygen uptake via indirect calorimetry (canopy method) in 25 moderate-to-severe OSA and 15 control participants and found a higher overnight metabolic rate in OSA versus controls. Our work demonstrates that the greater metabolic rate in OSA patients cannot be the direct consequence of airflow obstruction, since acute CPAP treatment actually increases rather than decreases metabolic rate. Taken together, the available data illustrates that the higher metabolic demand in OSA may be an inherent trait—potentially contributing to OSA—or an indirect consequence of sleep disordered breathing. Our findings therefore shed light on the controversial effects of CPAP on metabolic rate.8,42,43 For many years, CPAP was thought to potentially assist in weight loss through improving daytime function and exercise habits in sleep apnea patients.44,45 More recently, it was discovered that, over time, CPAP use led to a small gain in weight.46,47 This weight gain was postulated to be consequent to a reduced work of breathing.48 Indeed, chronic CPAP treatment lowered resting (daytime) metabolic rate in sleep apnea patients42 (although perhaps less clear when assessing 24-h metabolic rate43). In contrast, acute effects of CPAP indicate that CPAP raises metabolic rate in OSA: One study using daytime measurements found an overnight fall in metabolic rate in patients with OSA, but not in controls,8 consistent with our results. Importantly, this reduction in metabolic rate was prevented with a single night of CPAP.8 Our results show that acute application of CPAP during sleep directly increases metabolic rate by 10–20% while reducing respiratory effort. Thus, the weight gain effects of CPAP cannot be attributed to CPAP’s direct effects on resolving airflow obstruction and lowering work of breathing. Impact of Sleep Depth Our study is the first to our knowledge to examine the impact of sleep depth on metabolic rate in patients with sleep apnea. Studies of effects of sleep stage on metabolic rate in healthy controls have found inconsistent results. While there is a consistent reduction in metabolic rate from wake to sleep in controls,10,49–53 as confirmed by our study in sleep apnea, only two of six studies found reduced metabolic rate in deep sleep (non-REM 3) compared to lighter sleep.10,52 Our study found a progressive and substantial reduction in metabolic rate with increasing non-REM sleep depth, by 27% from non-REM 1 to 3. This reduction was accompanied by a profound reduction in the AHI (49 to 13 events/h), increases in the proportion of stable breathing (7 to 91 % sleep time), and a virtual absence of arousals (29 to 0.5 % sleep time) consistent with previous studies.11 In agreement with other studies,54–56 we found a substantial increase in respiratory effort with deeper sleep (20 to 28 cmH2O). Of note, the observed reduction in metabolic rate with deeper sleep is greater than that expected with the observed reduction in proportion of wakefulness (%arousals, expected ~11% reduction based on wake versus sleep effects, Table 4) and the observed degree of airway occlusion (expected ~7% reduction based on the increased effort, Tables 3 and 4). It is likely, therefore, that some of this reduction in metabolic rate is truly state dependent, and if so, it is likely that the reduction in metabolic rate with deeper sleep facilitates the reduced sleep apnea severity with deeper sleep. Indeed, despite worsening airflow obstruction, alveolar gases were unchanged with deeper sleep (ie, lowered metabolic rate). Impaired blood gases would no doubt have further increased respiratory effort and made stable breathing less likely. Further investigation is required to ascertain a causal relationship between reduced metabolic rate in deeper sleep and reduced OSA severity. Phenotypic Differences in the Metabolic Rate Response to Airflow Obstruction Although airflow obstruction lowers metabolic rate during sleep (see CPAP effects), this was not seen to the same extent in all individuals. Specifically, five individuals had substantially lowered metabolic rate during sleep (defined as at least 30% below wakefulness, subgroup mean 41% below wakefulness levels), which was well beyond the normal fall in metabolic rate with sleep seen in controls (~15%).49,50,52 Consequently, there were minimal changes in PO2 and PCO2 levels accompanying obstructed breathing in these patients. Conversely, patients who did not lower their metabolic rate to the same extent from wake to sleep (mean 21% reduction from wakefulness, N = 7) exhibited lowered PO2 and increased PCO2 levels. Moreover, those who lowered metabolic rate exhibited a minimal (nonsignificant) increase in respiratory effort from wake to sleep (~30%) whereas those with more constant metabolic rate more than doubled their respiratory effort. These findings highlight two distinct metabolic responses to airflow obstruction in sleep apnea that may have distinct sleep apnea sequelae. For the patients whose VO2 is substantially reduced, the reduction in oxidative work may hamper the active house-keeping and growth/reparative processes that normally occur overnight,57–59 which may help explain metabolic consequences of OSA.60 For the patients who instead fight obstruction with increased respiratory effort, consequences might include sleepiness55 and cardiovascular effects (sympathoexcitation, hypertension, arrhythmia)29–31,61 that have been linked to intrathoracic pressures. Elucidating the reasons why subgroups of OSA patients have different OSA outcomes remains an important focus of investigation. Limitations Our study has several limitations. First, our sample size is relatively small (N = 12). However, we found that metabolic rate in stable breathing was 97.4 ± 4.1% of that during unstable breathing, such that we can rule out a greater than 11% reduction in metabolic rate with 95% confidence. Thus, any physiologically significant reduction in metabolic rate in stable breathing is highly unlikely. Second, several comparisons are observational in nature and therefore do not prove causality. The reduction in metabolic rate with deeper sleep could be a consequence of greater airflow obstruction rather than a cause of improved stability. This association in particular requires experimental verification, ie, using an intervention that promotes deeper or lighter sleep. However, our use of CPAP to improve airflow obstruction was interventional in nature and thus a causal influence of CPAP via relief of airflow obstruction on respiratory parameters may be inferred. It is possible that CPAP has influences on metabolic rate other than via the upper airway: For example, in controls during wakefulness, CPAP can activate accessory respiratory muscles and may increase work of breathing62; while we did not seek to quantify expiratory work of breathing, our finding that respiratory effort is reduced suggests that a CPAP-induced increase in work of breathing during sleep in patients with sleep apnea is extremely unlikely. The finding of increased VO2 on CPAP relies on the observed increase in ventilation with CPAP in conjunction with the relative constancy of PO2 levels. In this regard, CPAP could potentially affect the calculation of metabolic rate through the introduction of leaks, which might lead to (1) underestimation of the observed tidal volume or (2) overestimation of expired PO2 mixing with air; however, both of these effects would bias toward a lower VO2, whereas we observed a greater value on CPAP. Of note, a major emphasis was placed on ensuring the absence of mask leak on CPAP in our study. We also considered the possibility that CPAP may upset the gas sampling calibration, eg, by potentially forcing gas through the sampling tube at a higher rate; however, we found no impact of CPAP on the PO2/PCO2 levels measured in bench tests. Moreover, the increase in ventilation with CPAP is well established3 and is consistent with the independently observed halving of respiratory effort. The relative constancy of PO2 levels is consistent with negligible changes in mean oxygen saturation we observed with CPAP (<1% difference in SpO2 between CPAP, stable and unstable breathing periods in non-REM stage 2; 97.6 ± 0.9, 97.1 ± 0.4, 97.6 ± 0.3, respectively). Thus, we are confident that our findings cannot be discounted by methodological limitations. CONCLUSIONS Unexpectedly, patients with OSA switch “spontaneously” from unstable to stable breathing during sleep without a change in metabolic rate. However, state-related resolution of OSA (deeper versus lighter non-REM) is associated with a decline in metabolic rate. Through CPAP administration, we found that metabolic rate falls consequent to obstructive sleep disordered breathing, illustrating that obstructed breathing per se is expected to contribute to weight gain, and that CPAP-related weight gain cannot be readily explained by direct effects of CPAP on metabolic rate. Finally, some patients exhibit a profound sleep-related metabolic decline (>30% of wake levels); while this decline may adversely impact nocturnal cellular processes, these same patients are protected against PCO2 and PO2 disturbances and increased respiratory effort which may ultimately circumvent key OSA sequelae. SUPPLEMENTARY MATERIAL Supplementary data are available at SLEEPJ online. FUNDING This work was supported by the National Institutes of Health (NIH): 5 R01 HL102321-02 and P01 HL095491 as well as the Harvard Catalyst Clinical Research Center: UL1 RR 025758-01. This work also received generous philanthropic funding from Fan Hongbing, President of OMPA Corporation, Kaifeng, China. CMM is supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Ministry of Education of Brazil. LT-M was supported by the American Heart Association (15POST25480003). MM is supported by FAPESP, Sao Paulo. SAS was supported by the American Heart Association (15SDG25890059 and 17POST33410436), the National Health and Medical Research Council of Australia (NHMRC, Early Career Fellowship 1053201), the Menzies Foundation, the American Thoracic Society Foundation and was Co-Investigator on grants from the NHMRC (1064163) and NIH (R01 HL128658, 2 R01 HL102321, P01 HL10050580). DISCLOSURE STATEMENT This was not an industry sponsored study. CMM, JPB, and MM declare no conflicts of interest. LT-M served as consultant for Novion Pharmaceuticals Inc. and Cambridge Sound Management. DPW receives salary from Apnicure Inc. and served as a consultant for Philips Respironics and Night Balance. AW receives research support from Philips Respironics and served as consultant for Cambridge Sound Management. SAS also served as consultant for Cambridge Sound Management. All other authors have no conflicts to disclose and do not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. ACKNOWLEDGMENTS The authors would like to thank Lauren Hess for her invaluable technical assistance. Conception and design: CMM, SAS; Acquisition and analysis: CMM, LTM, SAS; Interpretation of results, drafting the manuscript for important intellectual content: All authors. REFERENCES 1. Younes M . Contributions of upper airway mechanics and control mechanisms to severity of obstructive apnea . 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TI - Stable Breathing in Patients With Obstructive Sleep Apnea Is Associated With Increased Effort but Not Lowered Metabolic Rate
JF - SLEEP
DO - 10.1093/sleep/zsx128
DA - 2017-10-01
UR - https://www.deepdyve.com/lp/oxford-university-press/stable-breathing-in-patients-with-obstructive-sleep-apnea-is-0C5JX8AdTP
VL - 40
IS - 10
DP - DeepDyve
ER -