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Respiratory Effort During Obstructive Sleep Apnea
clinical investigations Respiratory Effort During Obstructive Sleep Apnea* Role of Age and Sleep State Jean Krieger, MD; Emilia Sforza, MD; An Boudewijns, MD; Monica Zamagni, MD; and Christophe Petiau, MD Objective: To evaluate the patients' individual characteristics predictive of the degree of respiratory effort developed during obstructive sleep apneas (OSAs). Design: Prospective consecutive sample, collection of clinical and polysomnographic data. Setting: University teaching hospital. Patients: One hundred sixteen consecutive OSA patients with clinical symptoms of OSA and more than 20 apneas per hour of sleep. Measurements: Anthropomorphic data, daytime blood gas values, and polysomnographic data. From esophageal pressure measurements during sleep, three indexes of respiratory effort during OSAs were derived: the maximal end-apneic esophageal pressure swing (PesMax), the increase in esophageal pressure swing (aPes) during the apnea, and its ratio to apnea duration (RPes). Results: The indexes of respiratory effort were significantly lower in rapid eye movement (REM) than in non-REM sleep (PesMax: 50.9±2.5 vs 39.6±1.9 em H20, p<0.001; aPes: 30.9±1.7 VS 23.4±1.4 em H 20, p<0.001; RPes: 1.05±0.05 vs 0.53±0.03 em H 20/s, p<0.001); therefore, a separate analysis was conducted in non-REM and in REM sleep. Indexes were also significantly lower in subgroups of older as compared to younger patients (PesMax: 55.6±3.5 vs 40.0±2.2 em H 20, p<0.001; aPes: 34.2±2.3 vs 24.1±1.6 em H 20, p=0.001; RPes: 1.21±0.08 vs 0.8±0.05 em H 20/s, p<0.001). The three indexes were closely correlated with each other and only PesMax correlation data are reported. In non-REM sleep, age was the most important single independent correlate of PesMax (r=-0.37, p=O.OOO). In REM sleep, the apnea-related hypoxemia, apnea duration, and age were the main contributors to the variance of PesMax. Conclusions: Respiratory effort in response to upper airway occlusion in OSA patients is lower in (CHEST 1997; 112:875-49) REM than in non-REM sleep and decreases with increasing age. Key words: age; rapid eye movement sleep; respiratory effort ; sleep apnea syndrome Abbreviations: AHI =apnea+hypopnea index (number of apneas+ hypopneas per hour of sleep); AI =apnea index (number of apneas per hour of sleep); BMI = body mass index; OSA = obstru ctive sleep apnea; Pes = esophageal pressure swing (ie, the amplitude ofthe e sophageal pressure curve from end-expiration to peak inspiration); Pes Max= highest Pes of the last three occluded respiratory efforts during an apnea; PesMin = lowest Pes of the first three occluded respiratory efforts during an apnea; PesW= average Pes of five breaths during quiet wakefuln ess; llPes =increase in Pes during an apnea (PesMax- PesMin ); REM = rapid eye movement; RIW = pulmonary resistance index during wakefuln ess (ratio of PesW to ave rag~ peak inspiratory flow of five breaths dUting quiet w akefuln ess); RPes= rati o of llPes to apnea duration; RSa0 2 = rate of decrease in Sa0 2 during apnea (ratio of 11Sa0 2 to apnea duration ); Sa0 2 = oxyhemoglobin saturation; 11Sa0 2 = decrease in Sa0 2 during apnea (difference between maximal preapneic Sa0 2 and minimal postapneic Sa0 2 )
Q bstructive sleep apnea
(OSA) is defined by the persistence of respiratory effort during the interruption of airflow. Several reports have shown that respiratory effort increases throughout the ap*From th e Sleep Disorders Unit, University Hospital, Strasbourg, France. Manuscript received O ctober 29, 1996; revision accepted April 15, 1997. Reprint requests: Jean Krieger, MD, Cli nique Neurologique, F-67091 Strasbourg Cedex, France; e-mail: jean. [email protected] f r
neas.1-3 However, these studies involved small numbers of patients and could therefore not investigate Global theme issue on Aging For editorial comment see page 868 the factors of the between-patient variability in the magnitude of respiratory effort. Given the suggested role of respiratory effmt in the consequences of sleep apneas, including arousal, 4 - 7 and hemodynamCHEST / 112 / 4 / 0CTOBER, 1997
875
ic8 •9 or endocrine 10 consequences, it seemed of interest to analyze the factors predicting the magnitude of respiratory effort. Therefore, we investigated prospectively aconsecutive group of 116 OSA patients in whom we derived from esophageal pressure measurements three indexes of respiratory effort: the maximal respiratory effort produced during apneas was measured by the maximal end-apneic esophageal pressure swing (Pes), the increase in respiratory effort during an apnea was measured by the difference between the minimum and the maximum Pes within the apnea, and the ratio of the increase in respiratory effort during a n apnea to the apnea duration provided a normalized m easure of respiratory effort taking into account the variability in apnea duration. The relationship of these indexes with variables describing the patients' individual characteristics was investigated. There was no a priori hypothesis behind this investigation, except that from our experience with routine measurements of esophageal pressure during polysomnography, we had observed that younger patients generally developed greater r espiratory efforts during apneas than older ones.
MATERIALS AND METHODS
The files and polysomnographic recordings of 116 OSA pati ents with a clinical and polysomnographi c diagnosis of OSA were evaluated. The patients were referred t o our center f or symptoms s uggestive of OSA, ie, any combination of sleepiness, snming, witnessed apneas, etc. Only patients with an apnea index (AI) > 20 apneas per hour of sleep, a total sleep time >3 h, and a percentage of obstructive +mixed apneas >80% were included. All patients underwent a standard di agnostic workup, including nocturnal polysomnography, pulmonary fun ction test, and blood gas analysis. Patients were informed that some of the data collected f or their clinical workup might be used for research pmposes, and they gave written consent. Nocturnal Polysomnography: Sleep and Breathing Variables
All-night polysomnography included EEG, electro-oculogram, electromyogram of chin muscle, and ECG. Breathing was analyzed with a pneumotachograph (Fleisch No. 2) and electronjc integrator (Godart Statham; Bilthoven, Netherl ands) attached t o a face mask; esophageal pressure was measured \vith a 10-cm latex balloon placed in the esophagus with its tip at 30 em distant from the nares and then m oved until heart beat artifacts were minimized; the balloon was connected t o apressure transducer (Validyne MP 45; Validyne; Northridge, Calif) and inflated with 1 mL of air; the pressure line was calibrated a gainst a water column; no attempt was made todefin e a zero baseline, as only Pes, ie, the difference between end-expiration and peak-inspiration v alues, was measured; oxygen satu ration was m easured continuously using ear or Hnger oximetry (Biox III; Ohmeda; Boulder, Colo). Sleep was analyzed u sing s tandard criteria. 11 Arousals from sleep (t ransient return of alpha EEG activi ty \vith or without increased electromyogram activity) were co unted separately o n the basis o ftheir duration (short awakenings lasted from 3 to 20 s, 876
long awakenings were ;::o: zo s). Central, mixed, and obstructive apneas \vi th a duration of ;::o: 10 s were defin ed by standard criteri a 12 with the detection of respi ratory effort based on the analysis o f Pes, ie, when n o Pes was de tectable, the apnea was considered central, and when n o Pes was detectable for > 5 s at the beginning o f the apnea, the apnea was considered mixed. Hypopneas were defin ed as an ateast l 50% drop in tidal volume from its value in quiet wakefulness prior to sleep onset; hypopneas must have lasted ;::o: lQ s. The AI and the apnea+hypopnea index (AH I) were established as the number of apneas and of apneas + hypopneas p er hour of sleep. The minimal oxyhemoglobin saturation (Sa0 2 ) throughout the night (Sa0 2 min) and the mean lowest Sa0 2 (mean of the minimal Sa0 2 after each apnea) were used a s indexes of noctumal oxygen saturation. Esophageal press ure readings we re pe rformed in 30 randomly selected obstru ctive apneas during nonrapid eye movement (non-REM ) sle ep and in all apneas during REM sleep. To exclude a possible interference of REM sleep, apneas occurring 15 min before the onset and after the end of a REM sleep episode were excluded from the a nalysis. Mixed and central apneas, which may have occurred in the same patient, we re not included. REM sleep apneas were a nalyzed only w henat least 10 apneas met the selection criteria; the number of paneas analyzed in REM sleep ranged from 10 to 30. The analysis of esophageal pressure has been d escribed in detail elsewhere.J3 Briefly, \vithin each apneic cycle, we measured th e Pes during th e three unoccluded breaths prececling the onset of panea and averaged these values to obtain an average preapneic Pes. Dming the apneas, Pes was measured during the first three occluded breaths and th e lowest pressure swing was computed as the minimal initial pressure (Pes Min ). In the same way, Pes during the last three occluded breaths was m easured and th e highest pressure swing was computed as the maximal fin al pressure (PesMax) . Figure 1 schematically represents this procedure. Apneas preceded b y fewer thanthree full unobstructed breaths were cliscarded; to be ble a toclearly separate the three initial and three fin al efforts, only apneas lasting ;::o:20 s were analyzed. The maximal final pressure swing (Pes Max) was taken as a measure o f th e maximal respiratory effort produced during apneas. The difference (t!.Pes) between PesMax and PesMin was taken as a meas ure of the increase in respiratory effort during an apnea. To obtain a descriptor of the change of respiratory effort during the apneas taking into account the variability in apnea duration, the ratio of t!.Pes to the duration of the apnea in seconds was computed (RPes); this ratio was established \Vithout implying any assumption on the linearity or nonlinearity of the increase in Pes during the apneas, but only to norm alize the increase in respiratory effort to apnea duration. Similarly, the mean difference between the lowest value of Sa0 2 recorded afte r each panea and its value before the apnea (t!.Sa0 2 ) and its rate of decrease (RSa0 2 ), defin ed as the ratio of t!.Sa0 2 to the apnea duration, were al so computed. Finally, we defined for each patient the mean peak inspiratory flow and the mean p eak inspiratory esophageal pressure taken from th e average of fi ve consecutive breaths during quiet wakefuln ess prior t o sleep onset; their ratio was used as an awake pulmonary resistance index (RIW). The reference for esophageal pressure measurements was atmospheri c pressure. By definiti on, inspiratmy pressure is negative (s ubatmosphe ric). T o facilitate the interpretation of the results, esophageal pressures were reported as absolute values, so that respiratory effort and esophageal pressure would vary conco rdantly; thus, an increase in respiratmy effort is represented b y a larger Pes. Clinical Investigations
Statistical Analysis
'
Max
FIGURE 1. Esophageal pressure measurements. An enlarged section of a recording shows how esophageal pressure readings were made. The upper trace is tidal volume (pneumotachograph; inspiration upwards), the lower trace is esophageal pressure. The apnea begins with the first ineffective inspiratory effort; note that there is a small expiratoty flow after the first missing inspiratory flow. The last three preapneic Pes (labeled ppp), as well as the three first and three last ineffective apneic Pes (labeled 1 2 3and a b c ,respectively) were measured. The minimal first (here 3, arrow Min) and maximal last (here b, arrow Max) were identified. The difference between Max and Min measured the increase in respiratory effort (~Pes) throughout the apnea.
Daytime Investigations Conventional spirography was performed with a 10-L closed spirograph. For this study, we considered FEV1, vital capacity (VC), and the ratio FEY 1NC. Blood gas analysis was performed on an arterial blood sample taken at rest while breathing room air.
Results are given as means±SEM. To make sure that the random selection of 30 apneas did not introduce a bias, we compared the distribution of the duration of the 30 selected apneas \vith that of the remaining unselected obstructive apneas lasting 220 s, using the Kolmogorow-Smimov test. Based on the median age (54 years), the patient sample was subdivided into two subgroups of younger and older patients. A Student t test for paired values was used to compare measures performed in REM and in non-REM sleep; a Student t test for unpaired values was used to compare subgroups of older and younger patients. Bivariate correlation analysis using Pearson's correlation coefficient was peiformed \vith the indexes of respiratory effort during apneas as dependent variables and various variables describing patient characteristics as independent variables. A step\vise multiple regression analysis was performed with the indexes of respiratmy effort during apneas as dependent variables to identify the independent contributors to the variance of the dependent variables. Statistical significance was assumed for a p value <0.05. All statistical analyses were performed with a statistical software package (SPSS; SPSS Inc., Chicago) . RESULTS
Patients Clinical, laboratory, and polygraphic characteristics of the 116 patients (3 women) are listed in Table 1. The mean age of the patients was 52± 1 years (range, 22 to 77 years) and their mean body mass index (BMI) was 33:±: 1 kglm 2 (range, 22 to 53 kglm 2 ). They had moderate to severe OSA syndrome with a mean AHI of 89:±:2 events per hour and a mean AI of 76:±:2 apneas per hour. The mean
Table !-Clinical and Polygraphic Data of the 116 Patients Investigated* Total Sample (n=ll6)
Age, yr BMI, kglm 2 FEV, L VC, L Pa02 , mm Hg PaC0 2 , mm Hg AHI, no./h AI, no./h Mean apnea duration , s Mean lowest Sa02 , % Minimal Sa0 2 , % TST, min Stages 1 +2, % TST Stages 3+4, % TST Stage REM, % TST Sleep efficiency, % No. of shmt awakenings, <20 s No. of long awakenings, 2:20 s WASO, min
Mean:!:SEM
Range
Younger Group (n=58), Mean:!:SEM
Older Group (n=58), Mean:!:SEM
p Value
52.1:!::0.9 32.7:!::0.6 2.85:!::0.08 3.80:!::0.08 72.8:!::1.0 40.0:!::0.4 89.5:!::2.1 76.4:!::2.3 25.0:!::0.6 85.0:!::0.7 65.1:!:: 1.4 291.3:!::7.0 91.4:!::0.7 1.0:!::0.3 7.6::'::0.5 68.0:!::1.0 242:!::12 87::'::5 136:!::5
22- 77 22-53 0.9-5.8 1.5-6.9 41-104 30-50 37-137 21-127 13-46 47-95 39-92 179-494 67-100 0- 17 0-23 40-99 2-618 13-256 2-275
44.2:!::0.9 34.0:!::0.8 3.1:!::0.1 4.1:!::0.1 72.8:!::1.5 40.2:!::0.5 92.4:!::2.9 78.9:!::3.4 24.0:!::0.9 83.1:!::1.2 61.9:!::2.1 311.2:!::9.3 90.7::'::1.0 1.2:!::0.5 8.1:!::0.7 72.1:!:: 1.7 246.6::'::19.8 70.5::'::5.0 119.4::'::7.2
60.1:!::0.7 31.3:!::0.8 2.6:!::0.1 3.5:!::0.1 72.8:!:: 1.4 39.8:!::0.6 86.5:!::2.9 73.9:!::3.2 26.0:!::0.9 86.8 :!::0.8 68.4:!:: 1.8 271.4:!::9.9 92.1::'::1.0 0.8:!::0.4 7.1:!::0.8 63.6:!::1.8 237.4:!::16.1 102.9 ::':: 7.7 152.8:!:: 7.6
NS 0.001 0.001 NS NS NS NS NS 0.01 0.02 0.005 NS NS NS 0.001 NS 0.001 0.002
*TST=total sleep time; WASO=wake time after sleep onset; NS=not significant. CHEST I 112 I 4 I OCTOBER, 1997
877
duration of the patients' total apneas was 25 ± 1 s (range, 13 to 46 s). The patients showed a wide range of severity of nocturnal hypoxemia with a mean lowest Sa0 2 ranging from 47 to 95%, and a minimal Sa02 ranging from 39 to 92%. The older group was not different from the younger one in terms of BMI and number of apneas, but older patients had slightly less severe apnea-related hypoxemia during sleep. The older patients tended to have longer mean apnea duration, but the difference did not reach statistical significance. As a group, the patients had normal daytime Pa02 (72.8±1.0 mm Hg) and PaC02 (40.0±0.4 mm Hg). Twenty-eight patients were hypoxemic (defined as a Pa02 :::;65 mm Hg) and 15 were hypercapnic (PaC0 2 ~45 mm Hg); 7 patients had FEV 1 below 1.5 L; 14 patients had FEV 1/FVC below 0.65. The older patients had lower FEY1 and VC than the younger ones, but their daytime blood gas values were not significantly different. The difference in lung volumes was in the order of magnitude of that expected from "normal" aging (600 mL for 15 years, ie , 40 mUyr of age). Sleep structure was as expected in OSA patients, showing a reduced sleep efficiency and decreased percentages of REM and slow-wave sleep. Older patients had more light non-REM sleep (stages 1 +2) and less deep non-REM sleep (stages 3+4) and REM sleep than younger ones; the difference was significant only for stages 1 + 2. The older group had slightly fewer short awakenings (lasting <20 s) but significantly more longer awakenings (lasting >20 s), indicating that sleep was equally fragmented in both age groups, but with longer arousals in older than in younger patients, resulting in longer wake time after sleep onset in the older group. Table 2 shows the comparisons between REM and non-REM sleep of the characteristics of the selected apneas in the 88 patients with sufficient apneas in REM sleep. Although apneas in REM sleep were longer and were associated with more apnea-related desaturation, PesMax was smaller in REM sleep (despite similar preapneic Pes). This was due to a larger decrease at the beginning of the apnea and a smaller ~Pes; RPes in REM was almost half the non-REM sleep value (0.53±0.03 vs 1.05±0.05 em H 2 0/s). Because of these differences between non-REM and REM data, it was not possible to pool REM and non-REM data; therefore, further data will be presented separately for non-REM and REM sleep. Respiratory Effort in Non-REM Sleep Figure 2 shows a typical example of the changes in esophageal pressure during an obstructive apnea in 878
Table 2-Apnea Duration, Esophageal Pressure, and Sa0 2 During the Selected Apneas in Non-REM and in REM Sleep in the 88 Patients With Sufficient Apneas in REM Sleep*
Apnea duration, s Preapneie Sa0 2 , % Postapneic Sa0 2 , % ~Sa0 2 ,%
HSa0 2 , %/s Average preapneie Pes, em H 2 0 PesMin, em H 20 PesMax, em H 20 ~Pes, em H 2 0 HPes, em H 2 0/s
Non-REM sleep, Mean:tSEM
HEM Sleep, Mean:tSEM
p Value, Non-REM vs HEM Sleep
29.72:0.7 95.32:0.3 82.92:0.9 -12.32:0.8 -0.432:0.03 24.52:1.2
47.7:tl.7 94.32: 0.5 72.42:1.5 -21.82:1.2 -0.482:0.03 23.82:1.1
0.000 0.000 0.000 0.000 0.000 NS
23.22:1.7 50.92:2.5 30.92:1.7 1.052:0.05
19.32:1.0 39.62:1.9 23.42:1.4 0.532:0.03
0.000 0.000 0.000 0.000
*See text and Table l footnote for explanation of abbreviations.
non-REM sleep. Pes increased progressively throughout the apnea, and the PesMax was recorded during the second or third last occluded effort. Table 3 describes the apneas selected for analysis. Their mean duration was 29.4±0.6 s. Their duration distribution was not different from tl1at of the remaining unselected apneas lasting ~20 s in any of the patients (Kolmogorov-Smirnov test p>O.OS in all patients). There was a slight drop in respiratory effort from the mean preapneic Pes to PesMin (from 23.0 to 18.7 em H 2 0), then Pes increased to reach an end-apneic maximum (PesMax) close to 50 em H 2 0, with a wide range from 13 to 124 em H 2 0 . The overall increase in Pes (APes) was about 30 em H 2 0, again with a wide range, from 5 to 86 em H 2 0. Sa0 2 decreased by a mean of -12.0±0.7% during the analyzed apneas. Table 3 shows that all indexes of respiratory effort were lower in older patients than in younger ones, including preapneic Pes and apneic Pes (Pes Min and PesMax). In addition, APes was smaller in older than in younger patients, despite a trend toward longer apnea duration in older patients. As a result, RPes was smaller in older subjects. PesW, as well RIW, were not different between both age groups. Table 4 shows the results of the bivariate correlation analysis. The three indexes of respiratory effort were strongly correlated with each oilier (Pes Max with ~Pes, r=0.94; PesMax with RPes, r=0.90; ~Pes witll RPes, r=0.93; p<0.001 for tile tllree correlations). Therefore, for tile sake of simplicity, only the correlation analysis of one of tile variables (PesMax) is reported. PesMax was correlated witll tile average preapneic and PesMin, as well as with age, BMI, apnea index, apnea duration, Clinical Investigations
L
0.5
-
0
----4
0.5
-
%
v
~
~
1
~
~
100
-
80
10 s
-80FIGURE 2. Typical example of the slow-speed recording that was used to make esophageal press ure measurements, including tidal volume (V, L), arterial oxygen saturation (Sa0 2 , %) and esophageal pressure (Pes, em H 2 0 ) in an OSA patient during non-REM sleep (Flow, which was also obtained , is not shown on this figure).
Table 3- Polygraphic Characteristics of the Apneas Selected f or Esophageal Pressure Analysis in Non-REM Sleep* Total Sample (n=ll6)
PesW, em H 20 RI'I'V, em H 2 0 /Us Apnea duration, s Preapneic Sa0 2 , % Postapneie Sa0 2 , % .6.Sa0 2 ,% RSa0 2 ,% Average preapneic Pes, em H 2 0 Pes Min, em H 2 0 PesMax, em H 2 0 .6-Pes, em H2 0 RPes, em H 2 0 /s
Mean:!:SEM
Range
Younger Group (n=58), Mean:!:SEM
Older Group (n =58), Mean:!:SEM
p Value
8.9:!:0.5 0.8 :!:0.0 29.4:!:0.6 95.4:!:0.3 83.4:!:0.8 -12.0:!:0.7 -0.42:!:0.03 23.0:!:1.0 18.7:!: 1.0 47.9:!:2.2 29.1:!: 1.5 1.01 :!: 0.05
2-26 0.1- 2.4 21- 53 82-99 41- 94 -431--3 -1.99-- 0.ll 7-65 5-49 13-124 5--86 0.2-2.8
9.2:!: 0.7 0.9:!:0.1 28.3:!:0.7 94.9:!: 0.4 81.5:!: 1.3 -13.5:!:1.1 -0.49:!: 0.04 26.7:!:1.6 21.5:!: 1.5 55.6:!:3.5 34.2:!:2.3 1.21:!:0.08
8.6:!:0.6 0.8:!: 0.1 30.4:!:0.9 95.9:!:0.2 85.3:!:0.8 -10.6:!:0.7 -0.35:!:0.02 19.2:!:0.9 16.0:!: 1.0 40.0:!: 2.2 24.1:!:1.6 0.80:!:0.05
NS NS NS NS 0.02 0.03 0.006 0.000 0.003 0.000 0.001 0.000
*See text and Table 1 footnote for explanation of abbreviations.
mean lowest and minimal Sa02 during sleep, and the fall in Sa02 during the apnea. It was also correlated with PesW and RIW. The multiple stepwise regression analysis, including the above variables as independent variables and PesMax as the dependent variable, revealed that the ave rage preapneic Pes and PesMin accounted for most of the variance of PesMax. When these variables were left out of the multiple regression analysis, age was the most important single independent contributor to the
variance of PesMax, with a far lower contribution of RIW and the AI (Table 5).
Respiratory Effort in REM Sleep
In REM sleep, the changes in Pes during the apneas were less regular and more erratic than in non-REM sleep. Only 88 patients had sufficient well-defined REM sleep to meet the criteria of at least 10 apneas longer CHEST I 112 I 4 1 OCTOBER, 1997
879
Table 4-Bivariate Correlation Analysis: Variables Significantly Correlated With PesMax in Non-REM Sleep
Pes Max Age BMI PesW RIW Apnea index Apnea duration Minimal Sa0 2 Mean lowest Sa0 2 Average preapneic Pes PesMin 6.Sa0 2
Correlation Coefficient (r)
p Value
-0 .37 -0.37 0.26 0.29 0.25 0.20 -0.34 -0.24 0.86 0.84 -0.21
0.000 0.000 0.005 0.002 0.006 0.027 0.000 0.008 0.000 0.000 0.025
than 20 s when the periods of 15 min before and after non-REM/REM sleep transitions were excluded. As in non-REM sleep, the three indexes of respiratory effort were strongly correlated with each other (PesMax with .!lPes, r=0.90; PesMax with RPes, r=0.72; .!lPes with RPes, r=0.82; p<0.001 for the three correlations) and again, only correlation data for PesMax are reported. Despite the differences in respiratory effort between non-REM and REM sleep, the bivariate correlation analysis showed similar correlations with PesMax in REM as compared to non-REM sleep, with fewer correlations reaching statistical significance, presumably owing to smaller sample size (Table 6). Again, when all variables were entered in a stepwise multiple regression analysis, the preapneic Pes and Pes Min accounted for most of the variance of PesMax. When these variables were left out of the multiple regression analysis, the results were somewhat different from non-REM sleep: decrease in Sa0 2 , apnea duration, and age independently contributed to the variance of PesMax (r 2 =0.13; r 2 =0.05; ~ =0.05, respectively; p=O.OO, p=0.01 , p=O.Ol, respectively).
DISCUSSION
The novelty in our data is the demonstration of a lower respiratory effort during apneas with increasing age in a group of unselected OSA patients . Although these data were obtained in a cross-sectional study and should be confirmed in a longitudinal study, they suggest that aging causes respiratory effort during apneas to decrease. 880
Methodologic Points
Before discussing the implications of the findings of this study, some methodologic points should be made. Concerning the analysis of respiratory effort, only 30 obstructive apneas were analyzed in each patient in non-REM sleep and at least 10 apneas in REM sleep, yielding a total number of at least 4,360 apneas from which 3 preapneic Pes and the first 3 and last 3 apneic Pes were visually read, ie, the study was based on at least 39,240 esophageal pressure readings, suggesting that although not all apneas could be analyzed, a sufficient number were taken into account. The absence of a difference between the duration distributions of the selected apneas and the remaining apneas lasting ~20 s ensures that the random sampling technique did not introduce a selection bias. Only apneas lasting ~20 s were included, in order to make a reading of six respiratory efforts during each apnea possible, and to make sure that a reasonable amount of respiratory effort could develop before apnea termination . Therefore, our results may not apply to patients whose majority of apneas last <20 s. The order of magnitude of changes in Pes found in our study is in the range of that reported in previous studies. Martin et aF reported an increase in Pes during the apneas of 25 em H 2 0; the maximal end-apneic pressure swing in the study of Kimoff et aF was 56 em H 2 0 , somewhat higher than the 47.5 em H 2 0 found in our study; however, since Kimoff et al 7 actually measured transdiaphragmatic pressure, after withdrawal of the small contribution of gastric pressure, the values are very similar. The three indexes of respiratory effort that we used in this study represent the amount of respiratory effort developed by the patient in response to upper airvvay occlusion, and therefore, it is not surprising that they were strongly correlated with each other. However, they represent a somewhat different measure of respiratory effort, which can be expressed in the following way: the maximal inspiratory Pes at the end of an apnea (PesMax, our first index) is determined by two components: (1) the esophageal pressure before apnea, and (2) the overall increase in esophageal pressure during an apnea (.!lPes, our second index) which itself depends on the apnea duration and the rate of increase in esophageal pressure after airway occlusion. If one assumes that Pes increases steadily throughout an apnea, without intervening decreases in respiratmy effort, which seems to be generally the case in non-REM sleep but was not systematically investigated in this study, then the ratio of the overall increase in Pes to the apnea duration (RPes, our third index) can be considered Clinical Investigations
Table 5-Stepwise Regression Analysis of Variables Contributing to PesMax in Non-REM Sleep Dependent Variable
Independent Variable
Regression Coefficient
SSE of Regression Coefficient
R2 Change
p Value
Age RIW Apnea index
-0.87 12.0 0.18
0.20 4.16 0.07
0.13 0.05 0.03
0.00 0.01 0.02 0.000
Pes Max
F (3,ll2 )=1l.2
Table 6-Bivariate Correlation Analysis: Variables Significantly Correlated With PesMax in REM Sleep
PesMax Age Minimal Sa0 2 Apnea index Mean apnea duration Apnea duration Average preapneic Pes Pes Min Postapneic Sa0 2 ~Sa0 2
Correlation Coefficient (r)
p Value
-0.24 -0.31 0.24 0.33 0.41 0.77 0.76 -0.28 -0.38
0.027 0.004 0.025 0.002 0.000 0.000 0.000 0.009 0.000
as an acceptable evaluation of the average rate of increase of Pes throughout the apnea, even if the increase is not linear.
Effects of Age Our data show that all three indexes were lower in older patients, suggesting that respiratory effort during OSA decreases with aging. One possible explanation for decreased respiratory effort during obstructive apneas in older subjects might be suggested by the physiologic changes in sleep with aging; it is known that older subjects have less stable sleep than younger ones, with more light non-REM sleep and less deep non-REM sleep, and more arousals. 14 Our data do show the expected differences in sleep structure between older and younger patients. It could therefore be proposed that due to higher arousability, older patients develop less respirat01y effort than younger ones simply because they arouse earlier. This hypothesis would not explain why older patients also have lower Pes during the interapneic period. In addition, if this hypothesis were correct, older patients would have shorter apneas than younger ones , which was not the case; on the contrary, the apneas in older patients were longer than in younger ones. Finally, the rate of increase in Pes was lower; for all these reasons, lesser respiratory effort developed by older patients cannot be caused by shorter apnea duration. Conversely, it could be suggested that the longer apnea duration observed in older patients is due to
Multiple R2 =0.21
the lesser increase in respiratory effort, given the role of respiratory effort in the arousal which terminates sleep apneas; 4 - 7 lesser respiratory effort might allow the apnea to last longer before the "arousal threshold" of respiratory effort is reached. Another possible explanation to the decrease in respiratory effort during apneas in older patients may be decreased respiratory drive or decreased respiratory performance, involving either the diaphragm or the chest wall. Data from the literature suggest that both may be involved. A longitudinal study in 32 healthy men demonstrated that with aging from a mean of 33 to a mean of 42 years, there was a significant attenuation of the awake ventilatory response to hypoxia, but no demonstrable change in hypercapnic response, 15 and several cross-sectional studies demonstrated reduced responsiveness to hypoxia and hypercapnia in elderly subjects (68 to 80 years of age) when compared with young adults (20 to 40 years of age).l 6 · 17 Since the occlusion pressure responses to hypoxia and hypercapnia were also reduced, and the differences in pulmonary mechanics were small, it was suggested that reduction in neuromuscular output was likely to be the major factor. 17 Dming sleep, several studies showed that the reduction in ventilation from wakefulness to nonREM sleep was not more important in a group of elderly (>65 years) than in a group of young adults (19 to 29 years). 18-20 Naifeh et al21 failed to demonstrate a greater sleep-induced reduction of an estimate of hypercapnic ventilatory response in older subjects (>60 years) as compared with younger subjects (30 to 48 years). Similarly, in dogs, Phillipson and Kozar22 showed a decrease in minute ventilation during slow-wave sleep with aging, but no change in the ventilatory and arousal responses to hyperoxic hypercapnia. In contrast, there was a decrement in the ventilatory response to isocapnic hypoxia over a span from 3 to 7 years (corresponding biologically to 12 to 24 human years) indicating an effect of aging on the metabolic respirat01y control system, rather than an attenuation of the waking neural drive to breathing. They suggested that these changes reflected a specific effect of aging on the carotid-body chemoreceptors. These data suggest CHEST I 112 I 4 I OCTOBER, 1997
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that aging may be associated with a lesser ventilatory response to hypoxia, whereas baseline ventilatory drive during wakefulness as well as during sleep and the response to hypercapnia are less affected by aging. The decreased response to hypoxia could explain a lesser increase in respiratory effort during an OSA. Data from the literature also suggest a role for changes in pulmonary mechanics. In animals, Zhang and Kelsen 23 studied the effects of aging from 4 to 19 months on the isolated diaphragms of Golden hamsters and found decreased maximal isometric tension with a slowing of contractile kinetics and reduced endurance with aging, whereas Van Lunteren et al 24 found no significant changes in diaphragm properties with aging from 3 to 20 months in rats. Changes in lung and chest wall mechanics and respiratory muscle activity with aging have also been reported in cross-sectional studies in humans, including decreased chest wall compliance 25 ·26 and loss of elastic recoil.2 7 The observed decrease in respiratory effort with aging may explain the somewhat unexpected spontaneous improvement over time in sleep apnea "severity," ie, less numerous respiratory disturbances during sleep, recently reported by Sforza et al28 in untreated OSA patients. A decrease in respiratory effort during sleep results in a lower suction pressure, and thereby in a lesser likelihood of the upper airway collapsing during sleep.
Other Correlates of Respiratory Effort Indexes of respiratory effort were also correlated with the AI. This correlation is likely to reflect the increased likelihood of upper airway collapse with increased Pes. Finally, the maximal end-apneic Pes was also correlated with the awake Pes and the awake index of pulmonary resistance. These correlations could be interpreted as a consequence of the fact that patients with increased pulmonary resistance develop more respiratory effort to maintain an adequate level of ventilation and that those patients who develop more respiratory effort during wakefulness will also develop more respiratory effort during sleep during the preapneic and during the apneic phases. This mechanism could also account for the correlations between preapneic and initial apneic Pes and the maximal end-apneic Pes.
Effects of Sleep State Another interesting finding of our study was that all three indexes of respiratory effort were lower in REM than in non-REM sleep. Although the preapneic Pes values were of similar magnitude, the 882
end-apneic Pes values were smaller, indicating a lesser increase in Pes (LlPes ) during the apnea, despite a longer apnea duration, meaning that the average rate of increase in Pes was also less in REM than in non-REM sleep. It should also be noted that the lesser increase in Pes may contribute to the prolongation of apnea duration, because of the delayed stimulation of mechanoreceptors. Several reports have mentioned a smaller minute ventilation in REM than in non-REM sleep,l9.29-32 suggesting a lower ventilatory drive in REM , although others have described increased minute ventilation in REM sleep.33 ·34 However, the ventilatory response to hypoxia35-37 and to hypercapnia38-40 was found to be decreased in REM as compared to non-REM sleep. Although several studies have reported a blunting of the respiratory timing response to added resistance in non-REM sleep,41 -44 the specific point of the response of the respiratory system to increased respiratory resistive load in REM sleep as compared to non-REM sleep has been little investigated. Issa and Sullivan4 observed in response to experimental upper airway occlusion in normal young subjects a breath-by-breath progressive increase in suction pressure in non-REM sleep, whereas in REM sleep, the occlusion induced a shallow pattern of breathing, which is in accordance with our observations in OSA patients. However, in normal subjects, arousal invariably occurred after a shorter duration in REM sleep than in non-REM sleep, which contrasts with the observation oflonger apneas in REM sleep in OSA patients; since the experimental upper airway occlusion was applied via a nasal mask, this difference led the authors to suggest that in normal subjects, nasal ancl!or nasopharyngeal mechanoreceptors play a major role in REM sleep arousal, and that in OSA, these receptors cannot be stimulated because of the site of the upper airway occlusion. Thus, our data in OSA patients, as well as data from the literature in normal subjects, suggest a definitely lesser response to an upper airway occlusion (ie, infinite resistive load) in REM sleep. However, impaired lung and chest wall mechanics, specific to REM sleep, may also conhibute to the lower Pes we observed in REM sleep. Despite the differences in the level of respiratory effort in REM as compared to non-REM sleep, the variables correlated with the magnitude of respiratory effort in REM sleep were similar to those correlated in non-REM sleep. However, the multiple regression analysis showed fewer independent contributors, and resulted in weaker models, in accordance with the impression of less systematic changes in Pes during REM sleep. This observation may also be related to the shallow breathing pattern observed after upper airway occlusion in normal subjects. 4 Clinical Investigations
In conclusion, our data suppmt the view that respiratory effort in response to upper ailway occlusion in OSA patients is lower in REM sleep than in non-REM sleep, and that it decreases with increasing age. ACKNOWLEDGMENTS: The authors thank M.P. Bilger, M. Favier, E. Georges, B. Kowalski, C. Mansouri, A. Peter, C. Reppel, and C. Sella! for technical assistance.
REFERENCES 1 Guilleminault C, Tilkian A, Dement WC. The sleep apnea syndromes. Annu Rev Med 1976; 27:465-84 2 Martin RJ, Pennock BE, Orr WC, eta!. Respiratmy mechanics and timing during sleep in occlusive apnea. JAppl Physiol 1980; 48:432-37 3 Wilcox PC, Pare PD, Road JD, et a!. Respiratory muscle function during obstructive apnea. Am Rev Respir Dis 1990; 142:533-39 4 Issa FG, Sullivan CE. Arousal and breathing responses to airway occlusion in healthy sleeping adults. J Appl Physiol 1983; 55:1113-19 5 Gleeson K, Zwillich CW, White DP. The influence of increasing ventilatory effort on arousal from sleep. Am Rev Respir Dis 1990; 142:295-300 6 Vincken W, Guilleminault C, Silvestri L, et al. Inspiratory muscle activity as a t1igger causing the airways to open in obstructive sleep apnea. Am Rev Respir Dis 1987; 135:372-77 7 KimoffRJ, Cheong TH, Olha AE, eta!. Mechanisms of apnea termination in obstructive sleep apnea: role of chemoreceptor and mechanoreceptor stimuli. Am J Respir Crit Care Med 1994; 149:707-14 8 Lea S, Ali NJ, Goldman M, et a!. Systolic blood pressure swings reflect inspiratory effort during simulated obstructive sleep apnea. Sleep '90. Bochum: Pontenagel Press, 1990; 178-81 9 Shiomi T, Guilleminault C, Stoohs R, et al. Leftward shift of the interventricular septum and pulsus paradoxus in obstructive sleep apnea syndrome. Chest 1991; 100:894-902 10 Krieger J , Follenius M, Sforza E, et al. Effects of treatment with nasal continuous positive airway pressure on atrial natriuretic peptide and arginine vasopressin release dming sleep in obstructive sleep apnea. Clin Sci 1991; 80:443-49 11 Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Los Angeles: Brain Information Service, Brain Research Institute, 1968 12 Gastaut H , Tassinari CA, Duron B. Etude polygraphique des manifestations episodiques (hypniques et respiratoires) du syndrome de Pickwick. Rev "'eurol 1965; 112:568-79 13 Sforza E, Krieger J, Bacon W, et al. Determinants of effective continuous positive airway pressure in obstructive sleep apnea: role of respiratory effort. Am J Respir Crit Care Med; 1995; 151:1852-56 14 Bliwise DL. Normal aging. In: K1yger MI-l, Roth T, Dement WC, eds. Principles and practice in sleep medicine. 2nd ed. Philadelphia: Saunders, 1994; 26-39 15 Nishimura M, Yamamoto M, Yoshioka A, eta!. Longitudinal analysis of respiratory chemosensitivity in normal subjects. Am Rev Respir Dis 1991; 143:1278-81 16 Kronenberg RS, Drage CW. Attenuation of the ventilatory and heart rate responses to hypoxia and hypercapnia with aging in normal men. J Clin Invest 1973; 52:1812-19 17 Peterson DD, Pack AI, Silage DA, et a!. Effects of aging on ventilatory and occlusion pressure responses to hypoxia and hypercapnia. Am Rev Respir Dis 1981; 124:387-91
18 Krieger J, Turlot JC, Mangin P, eta!. Breathing during sleep in normal young and elderly subjects: hypopneas, apneas, and correlated factors. Sleep 1983; 6:108-20 19 Shore ET, Millman RP, Silage DA, et a!. Ventilatory and arousal patterns during sleep in normal young and elderly subjects. J Appl Physiol 1985; 59:1607-15 20 Naifeh K, Severinghaus JW, Kamiya J. Effect of aging on sleep-related changes in respiratory variables. Sleep 1987; 10:160-71 21 Naifeh K, Seve1inghaus JW, Kamiya J, et a!. Effect of aging on estimates of hypercapnic ventilatory response during sleep. J Appl Physiol 1989; 66:1956-64 22 Phillipson EA, Kozar LF. Effect of aging on metabolic respiratory control in sleeping dogs. Am Rev Respir Dis 1993; 147:1521-25 23 Zhang Y, Kelsen SG. Effects of aging on diaphragm contractile function in golden hamsters. Am Rev Respir Dis 1990; 142:1396-1401 24 Van Lunteren E, Vafaie H, Salomone RJ. Comparative effects of aging on phmyngeal and diaphragm muscles. Respir Physiol 1995; 99:113-25 25 Frank NR, Mead J , Ferris BG. The mechanical behavior of the lungs in healthy elderly persons. J Clin Invest 1957; 36:1680-89 26 Mittman C, Edelman NI-l, Norris AI-l, et a!. Relationship between chest wall and pulmonary compliance and age. J Appl Physiol 1965; 20:1211-16 27 Gibson GJ, Pride NB, O'Cain C, eta!. Sex and age differences in pulmonary mechanics in normal nonsmoking subjects. J Appl Physiol 1976; 41:20-25 28 Sforza E, Addati G, Cirignotta F, et a!. Natural evolution of sleep apnoea syndrome: a 5-year longitudinal study. Eur Respir J 1994; 7:1765-70 29 Douglas NJ, White DP, Pickett CK, eta!. Respiration during sleep in normal man. Thorax 1982; 37:840-44 30 Hudgel DW, Martin RJ, Johnson B, e t al. Mechanics of respiratory system and breathing pattern during sleep in normal humans. J Appl Physiol 1984; 56:133-37 31 Krieger J, Mangin P, Kurtz D. Incidence of sleep disordered breathing in normal younger and older subjects: correspondence analysis of related factors: sleep 1982; Sixth European Congress on Sleep Research. Basel: Karger, 1983; 308-11 32 Stradling JR, Chadwick GA, Frew AJ. Changes in ventilation and its components in normal subjects during sleep. Thorax 1985; 40:364-70 33 Tabachnik E, Muller NL, Bryan AC, et a!. Changes in ventilation and chest wall mechanics dming sleep in normal adolescents. J Appl Physiol 1981; 51:557-64 34 White DP, Wei! JV, Zvvillich CW. Metabolic rate and breathing during sleep. J Appl Physiol1985; 59:384-91 35 Berthon-Jones M, Sullivan CE. Time course of change in ventilatory response to C0 2 with long-term CPAP therapy for obstructive sleep apnea. Am Rev Respir Dis 1987; 135:144-47 36 Douglas NJ , White DP, \Veil JV, e t a!. Hypoxic ventilatory response decreases during sleep in normal men. Am Rev Respir Dis 1982; 125:286-89 37 White DP, Douglas NJ, Pickett CK, et al. Hypoxic ventilatory response during sleep in normal premenopausal women. Am Rev Respir Dis 1982; 126:530-33 38 Berthon-Jones M, Sullivan CE. Ventilation and arousal responses to hypercapnia in normal sleeping humans. J Appl Physiol 1984; .57:59-67 39 Douglas NJ, White DP, Wei] JV, et a!. Hypercapnic ventilatOiy response in sleeping adults. Am Rev Respir Dis 1982; 126:758-62 40 White DP. Occlusion pressure and ventilation during sleep in normal humans. J Appl Physioll986; 61:1279-87 CHEST /112 I 41 OCTOBER, 1997
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41 Gugger M, Molloy J, Gould GA, eta!. Ventilatory and arousal responses to added inspiratory resistance during sleep. Am Rev Respir Dis 1989; 140:1301-07 42 Rudge! DW, Mulholland M, Hendricks C. Neuromuscular and mechanical responses to inspiratory resistive loading during sleep. JAppl Physiol 1987; 63:603-08
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43 Iber C, Berssenbrugge A, Skatrud JB, et a!. Ventilatory adaptations to resistive loading during wakefulness and nonREM sleep. JAppl Physiol1982; 52:607-14 44 Wiegand L, Zwillich CW, White DP. Sleep and the ventilatory response to resistive loading in normal man. J Appl Physiol 1988; 64:1186-95
Clinical Investigations
Q bstructive sleep apnea
(OSA) is defined by the persistence of respiratory effort during the interruption of airflow. Several reports have shown that respiratory effort increases throughout the ap*From th e Sleep Disorders Unit, University Hospital, Strasbourg, France. Manuscript received O ctober 29, 1996; revision accepted April 15, 1997. Reprint requests: Jean Krieger, MD, Cli nique Neurologique, F-67091 Strasbourg Cedex, France; e-mail: jean. [email protected] f r
neas.1-3 However, these studies involved small numbers of patients and could therefore not investigate Global theme issue on Aging For editorial comment see page 868 the factors of the between-patient variability in the magnitude of respiratory effort. Given the suggested role of respiratory effmt in the consequences of sleep apneas, including arousal, 4 - 7 and hemodynamCHEST / 112 / 4 / 0CTOBER, 1997
875
ic8 •9 or endocrine 10 consequences, it seemed of interest to analyze the factors predicting the magnitude of respiratory effort. Therefore, we investigated prospectively aconsecutive group of 116 OSA patients in whom we derived from esophageal pressure measurements three indexes of respiratory effort: the maximal respiratory effort produced during apneas was measured by the maximal end-apneic esophageal pressure swing (Pes), the increase in respiratory effort during an apnea was measured by the difference between the minimum and the maximum Pes within the apnea, and the ratio of the increase in respiratory effort during a n apnea to the apnea duration provided a normalized m easure of respiratory effort taking into account the variability in apnea duration. The relationship of these indexes with variables describing the patients' individual characteristics was investigated. There was no a priori hypothesis behind this investigation, except that from our experience with routine measurements of esophageal pressure during polysomnography, we had observed that younger patients generally developed greater r espiratory efforts during apneas than older ones.
MATERIALS AND METHODS
The files and polysomnographic recordings of 116 OSA pati ents with a clinical and polysomnographi c diagnosis of OSA were evaluated. The patients were referred t o our center f or symptoms s uggestive of OSA, ie, any combination of sleepiness, snming, witnessed apneas, etc. Only patients with an apnea index (AI) > 20 apneas per hour of sleep, a total sleep time >3 h, and a percentage of obstructive +mixed apneas >80% were included. All patients underwent a standard di agnostic workup, including nocturnal polysomnography, pulmonary fun ction test, and blood gas analysis. Patients were informed that some of the data collected f or their clinical workup might be used for research pmposes, and they gave written consent. Nocturnal Polysomnography: Sleep and Breathing Variables
All-night polysomnography included EEG, electro-oculogram, electromyogram of chin muscle, and ECG. Breathing was analyzed with a pneumotachograph (Fleisch No. 2) and electronjc integrator (Godart Statham; Bilthoven, Netherl ands) attached t o a face mask; esophageal pressure was measured \vith a 10-cm latex balloon placed in the esophagus with its tip at 30 em distant from the nares and then m oved until heart beat artifacts were minimized; the balloon was connected t o apressure transducer (Validyne MP 45; Validyne; Northridge, Calif) and inflated with 1 mL of air; the pressure line was calibrated a gainst a water column; no attempt was made todefin e a zero baseline, as only Pes, ie, the difference between end-expiration and peak-inspiration v alues, was measured; oxygen satu ration was m easured continuously using ear or Hnger oximetry (Biox III; Ohmeda; Boulder, Colo). Sleep was analyzed u sing s tandard criteria. 11 Arousals from sleep (t ransient return of alpha EEG activi ty \vith or without increased electromyogram activity) were co unted separately o n the basis o ftheir duration (short awakenings lasted from 3 to 20 s, 876
long awakenings were ;::o: zo s). Central, mixed, and obstructive apneas \vi th a duration of ;::o: 10 s were defin ed by standard criteri a 12 with the detection of respi ratory effort based on the analysis o f Pes, ie, when n o Pes was de tectable, the apnea was considered central, and when n o Pes was detectable for > 5 s at the beginning o f the apnea, the apnea was considered mixed. Hypopneas were defin ed as an ateast l 50% drop in tidal volume from its value in quiet wakefulness prior to sleep onset; hypopneas must have lasted ;::o: lQ s. The AI and the apnea+hypopnea index (AH I) were established as the number of apneas and of apneas + hypopneas p er hour of sleep. The minimal oxyhemoglobin saturation (Sa0 2 ) throughout the night (Sa0 2 min) and the mean lowest Sa0 2 (mean of the minimal Sa0 2 after each apnea) were used a s indexes of noctumal oxygen saturation. Esophageal press ure readings we re pe rformed in 30 randomly selected obstru ctive apneas during nonrapid eye movement (non-REM ) sle ep and in all apneas during REM sleep. To exclude a possible interference of REM sleep, apneas occurring 15 min before the onset and after the end of a REM sleep episode were excluded from the a nalysis. Mixed and central apneas, which may have occurred in the same patient, we re not included. REM sleep apneas were a nalyzed only w henat least 10 apneas met the selection criteria; the number of paneas analyzed in REM sleep ranged from 10 to 30. The analysis of esophageal pressure has been d escribed in detail elsewhere.J3 Briefly, \vithin each apneic cycle, we measured th e Pes during th e three unoccluded breaths prececling the onset of panea and averaged these values to obtain an average preapneic Pes. Dming the apneas, Pes was measured during the first three occluded breaths and th e lowest pressure swing was computed as the minimal initial pressure (Pes Min ). In the same way, Pes during the last three occluded breaths was m easured and th e highest pressure swing was computed as the maximal fin al pressure (PesMax) . Figure 1 schematically represents this procedure. Apneas preceded b y fewer thanthree full unobstructed breaths were cliscarded; to be ble a toclearly separate the three initial and three fin al efforts, only apneas lasting ;::o:20 s were analyzed. The maximal final pressure swing (Pes Max) was taken as a measure o f th e maximal respiratory effort produced during apneas. The difference (t!.Pes) between PesMax and PesMin was taken as a meas ure of the increase in respiratory effort during an apnea. To obtain a descriptor of the change of respiratory effort during the apneas taking into account the variability in apnea duration, the ratio of t!.Pes to the duration of the apnea in seconds was computed (RPes); this ratio was established \Vithout implying any assumption on the linearity or nonlinearity of the increase in Pes during the apneas, but only to norm alize the increase in respiratory effort to apnea duration. Similarly, the mean difference between the lowest value of Sa0 2 recorded afte r each panea and its value before the apnea (t!.Sa0 2 ) and its rate of decrease (RSa0 2 ), defin ed as the ratio of t!.Sa0 2 to the apnea duration, were al so computed. Finally, we defined for each patient the mean peak inspiratory flow and the mean p eak inspiratory esophageal pressure taken from th e average of fi ve consecutive breaths during quiet wakefuln ess prior t o sleep onset; their ratio was used as an awake pulmonary resistance index (RIW). The reference for esophageal pressure measurements was atmospheri c pressure. By definiti on, inspiratmy pressure is negative (s ubatmosphe ric). T o facilitate the interpretation of the results, esophageal pressures were reported as absolute values, so that respiratory effort and esophageal pressure would vary conco rdantly; thus, an increase in respiratmy effort is represented b y a larger Pes. Clinical Investigations
Statistical Analysis
'
Max
FIGURE 1. Esophageal pressure measurements. An enlarged section of a recording shows how esophageal pressure readings were made. The upper trace is tidal volume (pneumotachograph; inspiration upwards), the lower trace is esophageal pressure. The apnea begins with the first ineffective inspiratory effort; note that there is a small expiratoty flow after the first missing inspiratory flow. The last three preapneic Pes (labeled ppp), as well as the three first and three last ineffective apneic Pes (labeled 1 2 3and a b c ,respectively) were measured. The minimal first (here 3, arrow Min) and maximal last (here b, arrow Max) were identified. The difference between Max and Min measured the increase in respiratory effort (~Pes) throughout the apnea.
Daytime Investigations Conventional spirography was performed with a 10-L closed spirograph. For this study, we considered FEV1, vital capacity (VC), and the ratio FEY 1NC. Blood gas analysis was performed on an arterial blood sample taken at rest while breathing room air.
Results are given as means±SEM. To make sure that the random selection of 30 apneas did not introduce a bias, we compared the distribution of the duration of the 30 selected apneas \vith that of the remaining unselected obstructive apneas lasting 220 s, using the Kolmogorow-Smimov test. Based on the median age (54 years), the patient sample was subdivided into two subgroups of younger and older patients. A Student t test for paired values was used to compare measures performed in REM and in non-REM sleep; a Student t test for unpaired values was used to compare subgroups of older and younger patients. Bivariate correlation analysis using Pearson's correlation coefficient was peiformed \vith the indexes of respiratory effort during apneas as dependent variables and various variables describing patient characteristics as independent variables. A step\vise multiple regression analysis was performed with the indexes of respiratmy effort during apneas as dependent variables to identify the independent contributors to the variance of the dependent variables. Statistical significance was assumed for a p value <0.05. All statistical analyses were performed with a statistical software package (SPSS; SPSS Inc., Chicago) . RESULTS
Patients Clinical, laboratory, and polygraphic characteristics of the 116 patients (3 women) are listed in Table 1. The mean age of the patients was 52± 1 years (range, 22 to 77 years) and their mean body mass index (BMI) was 33:±: 1 kglm 2 (range, 22 to 53 kglm 2 ). They had moderate to severe OSA syndrome with a mean AHI of 89:±:2 events per hour and a mean AI of 76:±:2 apneas per hour. The mean
Table !-Clinical and Polygraphic Data of the 116 Patients Investigated* Total Sample (n=ll6)
Age, yr BMI, kglm 2 FEV, L VC, L Pa02 , mm Hg PaC0 2 , mm Hg AHI, no./h AI, no./h Mean apnea duration , s Mean lowest Sa02 , % Minimal Sa0 2 , % TST, min Stages 1 +2, % TST Stages 3+4, % TST Stage REM, % TST Sleep efficiency, % No. of shmt awakenings, <20 s No. of long awakenings, 2:20 s WASO, min
Mean:!:SEM
Range
Younger Group (n=58), Mean:!:SEM
Older Group (n=58), Mean:!:SEM
p Value
52.1:!::0.9 32.7:!::0.6 2.85:!::0.08 3.80:!::0.08 72.8:!::1.0 40.0:!::0.4 89.5:!::2.1 76.4:!::2.3 25.0:!::0.6 85.0:!::0.7 65.1:!:: 1.4 291.3:!::7.0 91.4:!::0.7 1.0:!::0.3 7.6::'::0.5 68.0:!::1.0 242:!::12 87::'::5 136:!::5
22- 77 22-53 0.9-5.8 1.5-6.9 41-104 30-50 37-137 21-127 13-46 47-95 39-92 179-494 67-100 0- 17 0-23 40-99 2-618 13-256 2-275
44.2:!::0.9 34.0:!::0.8 3.1:!::0.1 4.1:!::0.1 72.8:!::1.5 40.2:!::0.5 92.4:!::2.9 78.9:!::3.4 24.0:!::0.9 83.1:!::1.2 61.9:!::2.1 311.2:!::9.3 90.7::'::1.0 1.2:!::0.5 8.1:!::0.7 72.1:!:: 1.7 246.6::'::19.8 70.5::'::5.0 119.4::'::7.2
60.1:!::0.7 31.3:!::0.8 2.6:!::0.1 3.5:!::0.1 72.8:!:: 1.4 39.8:!::0.6 86.5:!::2.9 73.9:!::3.2 26.0:!::0.9 86.8 :!::0.8 68.4:!:: 1.8 271.4:!::9.9 92.1::'::1.0 0.8:!::0.4 7.1:!::0.8 63.6:!::1.8 237.4:!::16.1 102.9 ::':: 7.7 152.8:!:: 7.6
NS 0.001 0.001 NS NS NS NS NS 0.01 0.02 0.005 NS NS NS 0.001 NS 0.001 0.002
*TST=total sleep time; WASO=wake time after sleep onset; NS=not significant. CHEST I 112 I 4 I OCTOBER, 1997
877
duration of the patients' total apneas was 25 ± 1 s (range, 13 to 46 s). The patients showed a wide range of severity of nocturnal hypoxemia with a mean lowest Sa0 2 ranging from 47 to 95%, and a minimal Sa02 ranging from 39 to 92%. The older group was not different from the younger one in terms of BMI and number of apneas, but older patients had slightly less severe apnea-related hypoxemia during sleep. The older patients tended to have longer mean apnea duration, but the difference did not reach statistical significance. As a group, the patients had normal daytime Pa02 (72.8±1.0 mm Hg) and PaC02 (40.0±0.4 mm Hg). Twenty-eight patients were hypoxemic (defined as a Pa02 :::;65 mm Hg) and 15 were hypercapnic (PaC0 2 ~45 mm Hg); 7 patients had FEV 1 below 1.5 L; 14 patients had FEV 1/FVC below 0.65. The older patients had lower FEY1 and VC than the younger ones, but their daytime blood gas values were not significantly different. The difference in lung volumes was in the order of magnitude of that expected from "normal" aging (600 mL for 15 years, ie , 40 mUyr of age). Sleep structure was as expected in OSA patients, showing a reduced sleep efficiency and decreased percentages of REM and slow-wave sleep. Older patients had more light non-REM sleep (stages 1 +2) and less deep non-REM sleep (stages 3+4) and REM sleep than younger ones; the difference was significant only for stages 1 + 2. The older group had slightly fewer short awakenings (lasting <20 s) but significantly more longer awakenings (lasting >20 s), indicating that sleep was equally fragmented in both age groups, but with longer arousals in older than in younger patients, resulting in longer wake time after sleep onset in the older group. Table 2 shows the comparisons between REM and non-REM sleep of the characteristics of the selected apneas in the 88 patients with sufficient apneas in REM sleep. Although apneas in REM sleep were longer and were associated with more apnea-related desaturation, PesMax was smaller in REM sleep (despite similar preapneic Pes). This was due to a larger decrease at the beginning of the apnea and a smaller ~Pes; RPes in REM was almost half the non-REM sleep value (0.53±0.03 vs 1.05±0.05 em H 2 0/s). Because of these differences between non-REM and REM data, it was not possible to pool REM and non-REM data; therefore, further data will be presented separately for non-REM and REM sleep. Respiratory Effort in Non-REM Sleep Figure 2 shows a typical example of the changes in esophageal pressure during an obstructive apnea in 878
Table 2-Apnea Duration, Esophageal Pressure, and Sa0 2 During the Selected Apneas in Non-REM and in REM Sleep in the 88 Patients With Sufficient Apneas in REM Sleep*
Apnea duration, s Preapneie Sa0 2 , % Postapneic Sa0 2 , % ~Sa0 2 ,%
HSa0 2 , %/s Average preapneie Pes, em H 2 0 PesMin, em H 20 PesMax, em H 20 ~Pes, em H 2 0 HPes, em H 2 0/s
Non-REM sleep, Mean:tSEM
HEM Sleep, Mean:tSEM
p Value, Non-REM vs HEM Sleep
29.72:0.7 95.32:0.3 82.92:0.9 -12.32:0.8 -0.432:0.03 24.52:1.2
47.7:tl.7 94.32: 0.5 72.42:1.5 -21.82:1.2 -0.482:0.03 23.82:1.1
0.000 0.000 0.000 0.000 0.000 NS
23.22:1.7 50.92:2.5 30.92:1.7 1.052:0.05
19.32:1.0 39.62:1.9 23.42:1.4 0.532:0.03
0.000 0.000 0.000 0.000
*See text and Table l footnote for explanation of abbreviations.
non-REM sleep. Pes increased progressively throughout the apnea, and the PesMax was recorded during the second or third last occluded effort. Table 3 describes the apneas selected for analysis. Their mean duration was 29.4±0.6 s. Their duration distribution was not different from tl1at of the remaining unselected apneas lasting ~20 s in any of the patients (Kolmogorov-Smirnov test p>O.OS in all patients). There was a slight drop in respiratory effort from the mean preapneic Pes to PesMin (from 23.0 to 18.7 em H 2 0), then Pes increased to reach an end-apneic maximum (PesMax) close to 50 em H 2 0, with a wide range from 13 to 124 em H 2 0 . The overall increase in Pes (APes) was about 30 em H 2 0, again with a wide range, from 5 to 86 em H 2 0. Sa0 2 decreased by a mean of -12.0±0.7% during the analyzed apneas. Table 3 shows that all indexes of respiratory effort were lower in older patients than in younger ones, including preapneic Pes and apneic Pes (Pes Min and PesMax). In addition, APes was smaller in older than in younger patients, despite a trend toward longer apnea duration in older patients. As a result, RPes was smaller in older subjects. PesW, as well RIW, were not different between both age groups. Table 4 shows the results of the bivariate correlation analysis. The three indexes of respiratory effort were strongly correlated with each oilier (Pes Max with ~Pes, r=0.94; PesMax with RPes, r=0.90; ~Pes witll RPes, r=0.93; p<0.001 for tile tllree correlations). Therefore, for tile sake of simplicity, only the correlation analysis of one of tile variables (PesMax) is reported. PesMax was correlated witll tile average preapneic and PesMin, as well as with age, BMI, apnea index, apnea duration, Clinical Investigations
L
0.5
-
0
----4
0.5
-
%
v
~
~
1
~
~
100
-
80
10 s
-80FIGURE 2. Typical example of the slow-speed recording that was used to make esophageal press ure measurements, including tidal volume (V, L), arterial oxygen saturation (Sa0 2 , %) and esophageal pressure (Pes, em H 2 0 ) in an OSA patient during non-REM sleep (Flow, which was also obtained , is not shown on this figure).
Table 3- Polygraphic Characteristics of the Apneas Selected f or Esophageal Pressure Analysis in Non-REM Sleep* Total Sample (n=ll6)
PesW, em H 20 RI'I'V, em H 2 0 /Us Apnea duration, s Preapneic Sa0 2 , % Postapneie Sa0 2 , % .6.Sa0 2 ,% RSa0 2 ,% Average preapneic Pes, em H 2 0 Pes Min, em H 2 0 PesMax, em H 2 0 .6-Pes, em H2 0 RPes, em H 2 0 /s
Mean:!:SEM
Range
Younger Group (n=58), Mean:!:SEM
Older Group (n =58), Mean:!:SEM
p Value
8.9:!:0.5 0.8 :!:0.0 29.4:!:0.6 95.4:!:0.3 83.4:!:0.8 -12.0:!:0.7 -0.42:!:0.03 23.0:!:1.0 18.7:!: 1.0 47.9:!:2.2 29.1:!: 1.5 1.01 :!: 0.05
2-26 0.1- 2.4 21- 53 82-99 41- 94 -431--3 -1.99-- 0.ll 7-65 5-49 13-124 5--86 0.2-2.8
9.2:!: 0.7 0.9:!:0.1 28.3:!:0.7 94.9:!: 0.4 81.5:!: 1.3 -13.5:!:1.1 -0.49:!: 0.04 26.7:!:1.6 21.5:!: 1.5 55.6:!:3.5 34.2:!:2.3 1.21:!:0.08
8.6:!:0.6 0.8:!: 0.1 30.4:!:0.9 95.9:!:0.2 85.3:!:0.8 -10.6:!:0.7 -0.35:!:0.02 19.2:!:0.9 16.0:!: 1.0 40.0:!: 2.2 24.1:!:1.6 0.80:!:0.05
NS NS NS NS 0.02 0.03 0.006 0.000 0.003 0.000 0.001 0.000
*See text and Table 1 footnote for explanation of abbreviations.
mean lowest and minimal Sa02 during sleep, and the fall in Sa02 during the apnea. It was also correlated with PesW and RIW. The multiple stepwise regression analysis, including the above variables as independent variables and PesMax as the dependent variable, revealed that the ave rage preapneic Pes and PesMin accounted for most of the variance of PesMax. When these variables were left out of the multiple regression analysis, age was the most important single independent contributor to the
variance of PesMax, with a far lower contribution of RIW and the AI (Table 5).
Respiratory Effort in REM Sleep
In REM sleep, the changes in Pes during the apneas were less regular and more erratic than in non-REM sleep. Only 88 patients had sufficient well-defined REM sleep to meet the criteria of at least 10 apneas longer CHEST I 112 I 4 1 OCTOBER, 1997
879
Table 4-Bivariate Correlation Analysis: Variables Significantly Correlated With PesMax in Non-REM Sleep
Pes Max Age BMI PesW RIW Apnea index Apnea duration Minimal Sa0 2 Mean lowest Sa0 2 Average preapneic Pes PesMin 6.Sa0 2
Correlation Coefficient (r)
p Value
-0 .37 -0.37 0.26 0.29 0.25 0.20 -0.34 -0.24 0.86 0.84 -0.21
0.000 0.000 0.005 0.002 0.006 0.027 0.000 0.008 0.000 0.000 0.025
than 20 s when the periods of 15 min before and after non-REM/REM sleep transitions were excluded. As in non-REM sleep, the three indexes of respiratory effort were strongly correlated with each other (PesMax with .!lPes, r=0.90; PesMax with RPes, r=0.72; .!lPes with RPes, r=0.82; p<0.001 for the three correlations) and again, only correlation data for PesMax are reported. Despite the differences in respiratory effort between non-REM and REM sleep, the bivariate correlation analysis showed similar correlations with PesMax in REM as compared to non-REM sleep, with fewer correlations reaching statistical significance, presumably owing to smaller sample size (Table 6). Again, when all variables were entered in a stepwise multiple regression analysis, the preapneic Pes and Pes Min accounted for most of the variance of PesMax. When these variables were left out of the multiple regression analysis, the results were somewhat different from non-REM sleep: decrease in Sa0 2 , apnea duration, and age independently contributed to the variance of PesMax (r 2 =0.13; r 2 =0.05; ~ =0.05, respectively; p=O.OO, p=0.01 , p=O.Ol, respectively).
DISCUSSION
The novelty in our data is the demonstration of a lower respiratory effort during apneas with increasing age in a group of unselected OSA patients . Although these data were obtained in a cross-sectional study and should be confirmed in a longitudinal study, they suggest that aging causes respiratory effort during apneas to decrease. 880
Methodologic Points
Before discussing the implications of the findings of this study, some methodologic points should be made. Concerning the analysis of respiratory effort, only 30 obstructive apneas were analyzed in each patient in non-REM sleep and at least 10 apneas in REM sleep, yielding a total number of at least 4,360 apneas from which 3 preapneic Pes and the first 3 and last 3 apneic Pes were visually read, ie, the study was based on at least 39,240 esophageal pressure readings, suggesting that although not all apneas could be analyzed, a sufficient number were taken into account. The absence of a difference between the duration distributions of the selected apneas and the remaining apneas lasting ~20 s ensures that the random sampling technique did not introduce a selection bias. Only apneas lasting ~20 s were included, in order to make a reading of six respiratory efforts during each apnea possible, and to make sure that a reasonable amount of respiratory effort could develop before apnea termination . Therefore, our results may not apply to patients whose majority of apneas last <20 s. The order of magnitude of changes in Pes found in our study is in the range of that reported in previous studies. Martin et aF reported an increase in Pes during the apneas of 25 em H 2 0; the maximal end-apneic pressure swing in the study of Kimoff et aF was 56 em H 2 0 , somewhat higher than the 47.5 em H 2 0 found in our study; however, since Kimoff et al 7 actually measured transdiaphragmatic pressure, after withdrawal of the small contribution of gastric pressure, the values are very similar. The three indexes of respiratory effort that we used in this study represent the amount of respiratory effort developed by the patient in response to upper airvvay occlusion, and therefore, it is not surprising that they were strongly correlated with each other. However, they represent a somewhat different measure of respiratory effort, which can be expressed in the following way: the maximal inspiratory Pes at the end of an apnea (PesMax, our first index) is determined by two components: (1) the esophageal pressure before apnea, and (2) the overall increase in esophageal pressure during an apnea (.!lPes, our second index) which itself depends on the apnea duration and the rate of increase in esophageal pressure after airway occlusion. If one assumes that Pes increases steadily throughout an apnea, without intervening decreases in respiratmy effort, which seems to be generally the case in non-REM sleep but was not systematically investigated in this study, then the ratio of the overall increase in Pes to the apnea duration (RPes, our third index) can be considered Clinical Investigations
Table 5-Stepwise Regression Analysis of Variables Contributing to PesMax in Non-REM Sleep Dependent Variable
Independent Variable
Regression Coefficient
SSE of Regression Coefficient
R2 Change
p Value
Age RIW Apnea index
-0.87 12.0 0.18
0.20 4.16 0.07
0.13 0.05 0.03
0.00 0.01 0.02 0.000
Pes Max
F (3,ll2 )=1l.2
Table 6-Bivariate Correlation Analysis: Variables Significantly Correlated With PesMax in REM Sleep
PesMax Age Minimal Sa0 2 Apnea index Mean apnea duration Apnea duration Average preapneic Pes Pes Min Postapneic Sa0 2 ~Sa0 2
Correlation Coefficient (r)
p Value
-0.24 -0.31 0.24 0.33 0.41 0.77 0.76 -0.28 -0.38
0.027 0.004 0.025 0.002 0.000 0.000 0.000 0.009 0.000
as an acceptable evaluation of the average rate of increase of Pes throughout the apnea, even if the increase is not linear.
Effects of Age Our data show that all three indexes were lower in older patients, suggesting that respiratory effort during OSA decreases with aging. One possible explanation for decreased respiratory effort during obstructive apneas in older subjects might be suggested by the physiologic changes in sleep with aging; it is known that older subjects have less stable sleep than younger ones, with more light non-REM sleep and less deep non-REM sleep, and more arousals. 14 Our data do show the expected differences in sleep structure between older and younger patients. It could therefore be proposed that due to higher arousability, older patients develop less respirat01y effort than younger ones simply because they arouse earlier. This hypothesis would not explain why older patients also have lower Pes during the interapneic period. In addition, if this hypothesis were correct, older patients would have shorter apneas than younger ones , which was not the case; on the contrary, the apneas in older patients were longer than in younger ones. Finally, the rate of increase in Pes was lower; for all these reasons, lesser respiratory effort developed by older patients cannot be caused by shorter apnea duration. Conversely, it could be suggested that the longer apnea duration observed in older patients is due to
Multiple R2 =0.21
the lesser increase in respiratory effort, given the role of respiratory effort in the arousal which terminates sleep apneas; 4 - 7 lesser respiratory effort might allow the apnea to last longer before the "arousal threshold" of respiratory effort is reached. Another possible explanation to the decrease in respiratory effort during apneas in older patients may be decreased respiratory drive or decreased respiratory performance, involving either the diaphragm or the chest wall. Data from the literature suggest that both may be involved. A longitudinal study in 32 healthy men demonstrated that with aging from a mean of 33 to a mean of 42 years, there was a significant attenuation of the awake ventilatory response to hypoxia, but no demonstrable change in hypercapnic response, 15 and several cross-sectional studies demonstrated reduced responsiveness to hypoxia and hypercapnia in elderly subjects (68 to 80 years of age) when compared with young adults (20 to 40 years of age).l 6 · 17 Since the occlusion pressure responses to hypoxia and hypercapnia were also reduced, and the differences in pulmonary mechanics were small, it was suggested that reduction in neuromuscular output was likely to be the major factor. 17 Dming sleep, several studies showed that the reduction in ventilation from wakefulness to nonREM sleep was not more important in a group of elderly (>65 years) than in a group of young adults (19 to 29 years). 18-20 Naifeh et al21 failed to demonstrate a greater sleep-induced reduction of an estimate of hypercapnic ventilatory response in older subjects (>60 years) as compared with younger subjects (30 to 48 years). Similarly, in dogs, Phillipson and Kozar22 showed a decrease in minute ventilation during slow-wave sleep with aging, but no change in the ventilatory and arousal responses to hyperoxic hypercapnia. In contrast, there was a decrement in the ventilatory response to isocapnic hypoxia over a span from 3 to 7 years (corresponding biologically to 12 to 24 human years) indicating an effect of aging on the metabolic respirat01y control system, rather than an attenuation of the waking neural drive to breathing. They suggested that these changes reflected a specific effect of aging on the carotid-body chemoreceptors. These data suggest CHEST I 112 I 4 I OCTOBER, 1997
881
that aging may be associated with a lesser ventilatory response to hypoxia, whereas baseline ventilatory drive during wakefulness as well as during sleep and the response to hypercapnia are less affected by aging. The decreased response to hypoxia could explain a lesser increase in respiratory effort during an OSA. Data from the literature also suggest a role for changes in pulmonary mechanics. In animals, Zhang and Kelsen 23 studied the effects of aging from 4 to 19 months on the isolated diaphragms of Golden hamsters and found decreased maximal isometric tension with a slowing of contractile kinetics and reduced endurance with aging, whereas Van Lunteren et al 24 found no significant changes in diaphragm properties with aging from 3 to 20 months in rats. Changes in lung and chest wall mechanics and respiratory muscle activity with aging have also been reported in cross-sectional studies in humans, including decreased chest wall compliance 25 ·26 and loss of elastic recoil.2 7 The observed decrease in respiratory effort with aging may explain the somewhat unexpected spontaneous improvement over time in sleep apnea "severity," ie, less numerous respiratory disturbances during sleep, recently reported by Sforza et al28 in untreated OSA patients. A decrease in respiratory effort during sleep results in a lower suction pressure, and thereby in a lesser likelihood of the upper airway collapsing during sleep.
Other Correlates of Respiratory Effort Indexes of respiratory effort were also correlated with the AI. This correlation is likely to reflect the increased likelihood of upper airway collapse with increased Pes. Finally, the maximal end-apneic Pes was also correlated with the awake Pes and the awake index of pulmonary resistance. These correlations could be interpreted as a consequence of the fact that patients with increased pulmonary resistance develop more respiratory effort to maintain an adequate level of ventilation and that those patients who develop more respiratory effort during wakefulness will also develop more respiratory effort during sleep during the preapneic and during the apneic phases. This mechanism could also account for the correlations between preapneic and initial apneic Pes and the maximal end-apneic Pes.
Effects of Sleep State Another interesting finding of our study was that all three indexes of respiratory effort were lower in REM than in non-REM sleep. Although the preapneic Pes values were of similar magnitude, the 882
end-apneic Pes values were smaller, indicating a lesser increase in Pes (LlPes ) during the apnea, despite a longer apnea duration, meaning that the average rate of increase in Pes was also less in REM than in non-REM sleep. It should also be noted that the lesser increase in Pes may contribute to the prolongation of apnea duration, because of the delayed stimulation of mechanoreceptors. Several reports have mentioned a smaller minute ventilation in REM than in non-REM sleep,l9.29-32 suggesting a lower ventilatory drive in REM , although others have described increased minute ventilation in REM sleep.33 ·34 However, the ventilatory response to hypoxia35-37 and to hypercapnia38-40 was found to be decreased in REM as compared to non-REM sleep. Although several studies have reported a blunting of the respiratory timing response to added resistance in non-REM sleep,41 -44 the specific point of the response of the respiratory system to increased respiratory resistive load in REM sleep as compared to non-REM sleep has been little investigated. Issa and Sullivan4 observed in response to experimental upper airway occlusion in normal young subjects a breath-by-breath progressive increase in suction pressure in non-REM sleep, whereas in REM sleep, the occlusion induced a shallow pattern of breathing, which is in accordance with our observations in OSA patients. However, in normal subjects, arousal invariably occurred after a shorter duration in REM sleep than in non-REM sleep, which contrasts with the observation oflonger apneas in REM sleep in OSA patients; since the experimental upper airway occlusion was applied via a nasal mask, this difference led the authors to suggest that in normal subjects, nasal ancl!or nasopharyngeal mechanoreceptors play a major role in REM sleep arousal, and that in OSA, these receptors cannot be stimulated because of the site of the upper airway occlusion. Thus, our data in OSA patients, as well as data from the literature in normal subjects, suggest a definitely lesser response to an upper airway occlusion (ie, infinite resistive load) in REM sleep. However, impaired lung and chest wall mechanics, specific to REM sleep, may also conhibute to the lower Pes we observed in REM sleep. Despite the differences in the level of respiratory effort in REM as compared to non-REM sleep, the variables correlated with the magnitude of respiratory effort in REM sleep were similar to those correlated in non-REM sleep. However, the multiple regression analysis showed fewer independent contributors, and resulted in weaker models, in accordance with the impression of less systematic changes in Pes during REM sleep. This observation may also be related to the shallow breathing pattern observed after upper airway occlusion in normal subjects. 4 Clinical Investigations
In conclusion, our data suppmt the view that respiratory effort in response to upper ailway occlusion in OSA patients is lower in REM sleep than in non-REM sleep, and that it decreases with increasing age. ACKNOWLEDGMENTS: The authors thank M.P. Bilger, M. Favier, E. Georges, B. Kowalski, C. Mansouri, A. Peter, C. Reppel, and C. Sella! for technical assistance.
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41 Gugger M, Molloy J, Gould GA, eta!. Ventilatory and arousal responses to added inspiratory resistance during sleep. Am Rev Respir Dis 1989; 140:1301-07 42 Rudge! DW, Mulholland M, Hendricks C. Neuromuscular and mechanical responses to inspiratory resistive loading during sleep. JAppl Physiol 1987; 63:603-08
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Clinical Investigations