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Control of Breathing in Obstructive Sleep Apnea
Control of Breathing in Obstructive Sleep Apnea* Krishnan R. Rajagopal, M.D.; Peter H. Abbrecht, M.D., Ph.D.; and Claude]. Tellis, M.D., F.C .C.P.
We studied the responses of ventilation and occlusion pressure (P..) to hypercapnia, with and without the application of im inspiratory Bow-resistive load (.12 em HsO/Usec), in eight control subjects and in eight subjects with obstructive sleep apnea who did not retain carbon dioxide while awake. The hypercapnic response was assessed by a modiGcation of the Read rebreathing technique. For a given endtidal carbon dioxide, ventilation in control subjects was the
same with or without load, and P,.. was increased with loading. In contrast, the subjects with sleep apnea decreased their ventilation during loading and did not increase theil;' P... in response to loading. Relationships between ventilation and P 100 were similar in the two groups both with and without load. We conclude that patients with occlusive sleep apnea do not exhibit the normal increase in neural drive to compensate for inspiratory Bow-resistive loading.
apnea during sleep, defined as cessation O bstructive of airHow fur at least ten seconds with continued
compensate fur this load, we postulated that abnormalities in load compensation exist in this group and that they may be present during wakefulness. TherefOre, we studied the responses of ventilation and occlusion pressure without and after the application of a flow-resistive load in a group of subjects with obstructive sleep apnea who did not retain carbon dioxide while awake. Our data suggest that abnormalities in the control of breathing exist in patients with obstructive sleep apnea.
respiratory effurt, 1 is a phenomenon that is poorly understood despite increasing investigation. Recurrent opposition of the superior lateral pharyngeal walls, 1 genioglossal hypotonia,~ and abnormalities in the chemical control of ventilation6 have all been incriminated in the pathogenesis of obstructive sieep apnea. In normal awake persons, there is an increase in the genioglossal electromyogram (EMG) in response to hypercapnia. 7•8 In contrast, it is well recognized that in subjects with sleep apnea, the genioglossal EMG, in fact, decreases during an apneic episode, despite increasing hypercapnia, until just prior to reestablishment of patency of the airway. 3 Studies on chemical control in obstructive sleep apnea including the responses of ventilation and occlusion pressure show conflicting results and include heterogeneous groups of subjects with varying degrees of hypercapnia.~11 In addition, load compensatory responses have not been assessed. The normal compensatory response to acute increases in resistance to breathing would be an increased inspiratory effurt. The occlusive apneic episode may be regarded as a situation of infinite load. Because subjects with sleep apnea demonstrate a progressive decrease in the genioglossal EMG during such episodes and do not appear to *From the Pulmonary Disease Service and Department of Clinical Investigation, Walter Reed Army Medical Center, Washington, DC, and the Departments of Physiology and Internal Medicine, Unifunned Services University of the Health Sciences, Bethesda, Md. Supported by WRAMC protocol 1701 and USPHS protocols R07648 and R07659. The opinions and assertions contained herein are the private views of the writers and are not to be construed as official or as reSecting views of the Department of the Army and the Department of Defense. Manuscript received June 24; revision accepted AugUst 16. Reprint requests: Dr. Rajagopal, Walter ReeflArmy Medical Center, Wuhington, DC 20307
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MATERIALS AND METHODS We studied eight adult male subjects with obstructive sleep apnea and eight control subjects. The control group consisted of healthy asymptomatic male volunteers matched fur age, sex, body weight, and height with the subjects with obstructive sleep apnea. Anthropometric data are shown in 'lllble 1. All subjects were nonsmokers. The mean ratio of the furced expired volume in one second to the furced vital capacity (FEV/FVC) was 77 percent in patients with obstructive sleep apnea and 80 percent in control subjects. All subjects in the study had peak inspiratory mouth pressures (taken as
Table !-Anthropometric Data for Control Subjects and Patients with Obatructive Sleep Apnea (OSA) Age, yr Case l 2 3 4 5 6 7 8 Mean :!:SE
Height, em
Control · OSA
43 59 57
44
52 57
42
46
51 21
50 21
54
55
29
34
45*
:!::5
45*
:!::4
Control 180 188 188 183 178 175 185 180 182t :!::2
Body Weight, kg
OSA
Control
OSA
178 180 180 178 178 175 178 175 l78t :!:I
78.6 130.0 97.3 119.1 84.1 72.3 98.2 122.7 100.2* :!::6.7
79.6 138.6 86.4 121.8 102.3 75.0 113.6 118.2 104.~
:!::7.0
•p = 0. 96 by t-test. tp=0.035 by t-test. *P = 0. 72 by t-test. Control of Blealhlng In Sleep Apnea (Rajagopal, Abbrecht, Tell/a)
Table 2-Data on Pulmonary Function for Control Subjecta and Patient. with Obnructive Sleep Apnea (OSA)
FVC, L
FVC, percent of predicted
100 FEV 1/ FVC
PI max, em H 20*
Case Control OSA Control OSA Control OSA Control OSA 4.80 113 1 5.56 4.05 3.47 71 2 5.55 4.61 110 3 3.36 4 4.70 93 3.81 3.72 83 5 84 4.32 3.66 6 89 4.46 2.74 7 4.01 8 4 .36 83 4.53t 3.87t 9lt Mean ±SE ±0.26 ±0.23 ±5
101 85 100 71 76 70 58 82 80:1: ±5
74 85 75 79 89 88 61 85 80§
±3
77 72 71 86 67 79 76 84 77§ ±2
122 120
llO
140 160 125 205 150 14211 ±11
160 100 130 120 120 130 170 100 12911 ±9
*PI max, maximum inspiratory pressure. tp=0.09 by t-test. :l:p=0.19 by t-test. §p=0.49 by t-test. llp=0.40 by t-test. the best of three maximal inspiratory efforts at residual volume) greater than 100 em H20. Results of tests of pulmonary function in patients with obstructive sleep apnea and in control subjects are shown in 'Illble 2. There was no history of acute respiratory infection in any subject for at least four weeks prior to the study. We excluded hypercapnic subjects so as to eliminate the influence of elevated concentrations of bicarbonate ion on the assessment of respiratory drive. 11 Patients referred to the pulmonary clinic for hypersomnolence had a detailed history and physical examination. Patients with abnormalities of the upper airway (adenoids; tonsils; obstructing lesions) were excluded from the study. All subjects included in the study had all-night polygraphic studies during sleep documenting the presence of repetitive episodes of obstructive sleep apnea. The sleep studies included simultaneous monitoring of the electroencephalogram, electro-oculogram, chin EMG, electrocardiogram, arterial oxygen saturation (SaO.) by ear oximeter (Hewlett-Packard 47201A), expired carbon dioxide fraction at the nose and mouth by carbon dioxide analyzer (Beckman LB-2), and chest wall and abdominal movement (using Hewlett-Packard Contact Sensor 21050A and a Respitrace). Sleep studies were scored in 20-second
Table 3-0ccummce of Apneic Periods and Period. of Disordered Breathing (DOB) during Sleep in Patient. with Obatructive Sleep Apnea
Case
No. of Apneic and DOB Episodes per Hour
2 3 4 5 6 7 8
46.84 9.02 17.96 76.31 85.46 57.43 41.38 20.05
No. of Apneic and Mean Duration of DOB Episodes by Duration, sec Individual Episodes, 10-19 20-29 >30 sec 21.68 17. 13 22.87 37.21 19.63 20.42 37.66 33.22
99 23 15 197 113 95
149 115
101 8 11 0 0 7 104
33 0 12 11 1 0 0 0
Apneic and DOB Time, Percent of Total Sleep Time 28.2 4.3 11.4 78.9 46.6 32.6 43.3 18.5
epochs using standard criteria. 13 Data on the occurrence of episodes of apnea and disordered breathing during sleep for the subjects with obstructive sleep apnea are shown in 'Illble 3. All subjects met the criteria for the diagnosis of the sleep apnea syndrome, defined as the presence of at least 30 episodes in both rapid-eye-movement (REM) sleep and non-rapid-eye-movement (NREM) sleep, some of which must appear repetitively in NREM sleep. 14 An apneic episode was defined as cessation of airflow for at least ten seconds despite continued inspiratory effort, and an episode of disordered breathing was defined as a decrease in Sa02 of at least 4 percent in the presence of continuing respiratory airflow. The hypercapnic response was assessed by a modification of the Read rebreathing technique. 15 Load compensation was assessed by repeating the rebreathing test with a flow-resistive load interposed in the inspiratory limb. Since respiratory neural drive cannot be estimated from ventilatory rates during inspiratory flow-resistive loading, neural drive was assessed by measurement of occlusion pressure. 10 The pressure generated during the first 100 msec (P1.,.) of an airway occlusion was used as an index of respiratory drive during the previous breath. 17 Subjects were instructed not to take any respiratory stimulants prior to the tests. In the pulmonary laboratory, subjects were first familiarized with the rebreathing apparatus. Ventilation and endtidal carbon dioxide pressure (Pco.) were monitored with the subjects seated and breathing through a mouthpiece and a one-way valve (Hans Rudolph 2700). Inspiratory flow rate was measured with a pneumotachygraph (Fleisch 3) coupled to a flow transducer (Hewlett-Packard) and integrated to obtain volume. End-tidal Pco2 was measured (Beckman Capnograph LB-2) from a sample in the expiratory limb. Once the subject was comfortable breathing on the apparatus, he was switched into the rebreathing circuit. The subjects then breathed 5 percent carbon dioxide in oxygen from a 13-L rubber bag. Sampled gas was returned to the rebreathing bag. End-tidal carbon dioxide, airflow, inspired volume, and airway pressure were recorded continuously on an eight-channel recorder (HewlettPackard 7758D). Airway pressure was measured by a blunt widebore needle inserted into the rubber mouthpiece and connected to a pressure transducer (Sanborn 2678). During the rebreathing period, which ordinarily lasted four to six minutes, random, periodic, temporary, inspiratory airway occlusions were made every 20 to 30 seconds for the determination of P100• A silent occlusion valve was used so that the subject was unaware of the initiation of occlusions. After completion of the rebreathing run, subjects were given a rest period of 30 minutes, following which the rebreathing study was repeated with the interposition of an inspiratory flow-resistive load. The load was produced by placing fine wire mesh screen disks in the inspiratory line. The resistance was constant at 12 em H10/Usec up to a flow rate of 1.5 Usee. The pressure transducer was calibrated using manometric methods, the pneumotachygraph using a 1-L plastic syringe (Collins), and the Capnograph using two different concentrations of carbon dioxide from preanalyzed gas cylinders. Points with a Pco2 ofless than 50 mm Hg were eliminated, since they lay on the nonlinear portion of the response curve. To describe the sensitivity of the respiratory drive to carbon dioxide, several parameters of ventilation and respiratory drive were regressed linearly against end-tidal Pco1• These parameters included minute ventilation, mean inspiratory flow rate, and P100• Minute ventilation was derived from the tidal volumes and durations of the three breaths preceding an occluded breath, and mean inspiratory flow was calculated by dividing the tidal volume of the breath preceding an occlusion by inspiratory duration. Responses without and after the addition of the load were analyzed in subjects and compared to responses obtained by the same techniques in matched controls. Statistical evaluation of the regression slope data was done by analysis of variance with repeated measures. 18 When the interaction term was significant, Duncan's multiple range test'" was used to CHEST I 85 I 2 I FEBRUARY, 1984
175
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END TIDAL PC0 2, mmHg FIGURE 1. Lines for regression of minute ventilation on end-tidal Pco1 fur control subjects and subjects with obstructive sleep apnea during nonloaded and loaded breathing. Vertical bars indicate 95 percent confidence limits. Lines whose slopes are significantly different (p < 0. 05 by Duncans multiple range test1") are indicated by asterisks.
detennine which means differed significantly from one another. RESULTS
Figure 1 compares the response of the minute ventilation of control subjects and patients to carbon dioxide measured before and during Bow-resistive loading. The slopes of the nonloaded ventilation end-tidal Pco2 regressions were not significantly different (mean ± SE, 2.17 ± 0.40 Umin/mm Hg for controls and 2.17 ± 0.23 for the patients with sleep apnea) (Table 4). Because an enhanced ventilatory response may also be manifest as a parallel shift in the response curves, ventilation at a Pco2 of 60 mm Hg was examined and found to be no different in the two groups (mean± SE, 41.44 ± 6.77 Umin/mm Hg in controls and 40.3 ± 5.16 in patients with obstructive sleep apnea). With Bow178
FIGURE 2. Lines fur regression of mean inspiratory How on P100 for control subjects and for subjects with obstructive sleep apnea. Vertical bars indicate 95 percent confidence limits. Lines whose slopes are significantly different (p <0.05 by Duncans multiple range test1") are indicated by asterisks.
resistive loading the slope of the response of minute ventilation to Pco2 decreased significantly (p <0.05) in patients with obstructive sleep apnea to 1.03±0.14 Umin/mm Hg, while the ventilatory response was maintained in control subjects. In patients with obstructive sleep apnea, the slope of the response of minute ventilation to Pco2 during Bow-resistive loading was significantly lower (p<0.05) than the slope in control subjects either with or without loading. Figure 2 compares the mean inspiratory Bow for various levels of P100 in patients with obstructive sleep apnea and control subjects. Without the load, for any given level of P100, the mean inspiratory Bow was similar in patients with obstructive sleep apnea and in control subjects (Table 4). During Bow-resistive loading the mean inspiratory Bow decreased both in patients with obstructive sleep apnea (p <0.05) and control subjects (p <0.05) compared to without the load; however, for any given level of P100, the mean Control of Blealhlng In Sleep Apnea (Rajagopa/, Abbt8cht, Tellis)
Table 4-.Regreaion l.Mie Slopa for Ventilmory .Reaponau cf Control Subject. and Patient. with Olmructive Sleep Apnea (OSA) Minute Ventilation VS PC<>t, Uminlmm Hg Croup and Case Control 1 2 3 4 5 6 7 8 Mean slope SE of slopes OSA 1 2 3 4
5 6 7 8 Mean slope SE of slopes
Mean Inspiratory Flow VS p IOO• Uminlcm H10
Minute Ventilation vsPUminlcm H10
PIOO vs Pco., em H 10/mm Hg
No Load
Load
No Load
Load
No Load
Load
No Load
Load
3.57 0.65 1.95 3.56 1.98 3.19 0.99 1.49 2.17 0.40
3.08 1.45 0.96 2.19 1.04 0.91 2.74 1.61 1.75 0.30
0.127 0.127 0.203 0.177 0.187 0.212 0.112 0.159 0.163 0.013
0.052 0.059 0.097 0.031 0.022 0.029 0.025 0.108 0.053 0.012
4.93 5.95 8.49 5.92 7.11 6.04 2.99 6.13 5.95 0.56
2.23 1.72 2.60 1.81 0.56 1.31 1.15 3.57 1.87 0.33
0.613 0.237 0.227 0.461 0.224 0.514 0.989 0.338 0.4M 0.093
1.161 0.771 0.343 0.874 0.559 0.552 1.743 0.441 0.805 0.163
2.43 3.27 2.83 1.38 1.90 2.04 2.04 1.52 2.17 0.23
1.22 1.75 0.99 0.70 1.23 1.00 0.86 0.48 1.03 0.14
0.204 0.144 0.057 0.063 0.233 0.063 0.265 0.086 0.139 0.030
0.132 0.097 0.047 0.048 0.029 O.o75 0.169 0.044 0.080 0.017
6.89 4.52 7.60 2.06 9.27 2.31 5.57 2.46 5.06 0.96
4.20 1.59 1.55 1.67 1.62 3.83 4.39 1.87 2.59 0.46
0.358 0.643 1.332 0.610 0. 174 0.634 0.328 0.308 0.548 0.128
0.277 0.251 0.592 0.702 0.817 0.408 0.111 0. 160 0.415 0.090
inspiratory flow was similar in patients with obstructive sleep apnea and control subjects. These findings indicate that at any given level of respiratory drive (P100), comparable inspiratory flows were generated both in patients with obstructive sleep apnea and in control subjects, thus excluding mechanical factors as an explanation fur the differences in the ventilatory response to Pco1 in the two groups with load. Figure 3 compares the relationship between minute ventilation and P100 in patients with obstructive sleep apnea and control subjects. The minute ventilation fur any given level of P100 was lower with load than without load, both in patients with obstructive sleep apnea (p <0.05) and in control subjects (p <0.05) (Table 4); however, the slopes and intercepts of the ventilationP100 regressions fur the subjects with sleep apnea were not significantly different from those of the control subjects either with or without the load. This indicates that fur any P100 the ventilation produced was similar in patients with obstructive sleep apnea and control subjects, whether this be without or during the addition of the flow-resistive load. On the basis of Figures 2 and 3, it appears that the failure of the subjects with obstructive sleep apnea to maintain ventilation during loading (Fig 1) was probably related to changes in respiratory drive during loaded breathing, rather than to a decreased ability of the patients with sleep apnea to respond to central drive. Figure 4 shows the P100-Pco1 regression lines fur the
two groups. Without load the regression slopes were
similar in the two groups (Table 4), and the P100 at a Pco 2 140 120 c:
e ":J
100
!c
ao
z
~
I=
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= 40 1 20
0
4
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12
P100, em H20
11
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FtcURE 3. Lines lOr regression of minute ventilation on P100 lOr control subjects and lOr subjects with obstructive sleep apnea. VerlicGl ban indicate 95 percent confidence limits. Lines whose slopes are significantly dift'erent (p <0.05 by Duncan's multiple range test!V) are indicated by tJSterlslu.
CHEST I 85 I 2 I FEBRUARY, 19&4
177
20
Pco2 of60 mm Hg was significantly higher (p <0.05) during loaded breathing than without the load; however, in patients with obstructive sleep apnea, P100 at a Pco2 of 60 mm Hg during loaded breathing was no different from without the load. Thus, patients with obstructive sleep apnea do not increase their neural drive to compensate for inspiratory flow-resistive loading.
15
DISCUSSION
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N
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10
5
50
60
70
END-TIDAL Pco2, mmHg FIGURE 4. Lines for regression ofP 100 on end-tidal Pco2 for control subjects and subjects with obstructive sleep apnea. Vertical bars indicate 95 percent confidence limits. Lines whose slopes are significantly different (p <0.05 by Duncan's multiple range test'") are indicated by asterisks.
of 60 mm Hg was no different. With the resistive load, respiratory effort in the control group increased to compensate for the increase in inspiratory resistance. This is shown by the fact that the slope of the P100-Pco2 line was significantly greater (p <0.05) during loaded breathing. In contrast, patients with obstructive sleep apnea did not increase their respiratory neural output in response to load. The slope of their P100-Pco2 regression line was no different during loaded breathing than without the load. Load compensation might also occur as a parallel shift of the P100-Pco2 line without a change in the slope. To test this possibility, we examined the P100 at a Pco 2 of60 mm Hg both with and without the load. In the control subjects, P100 at a 178
The data from the present study indicate that patients with obstructive sleep apnea do not increase respiratory neural output during inspiratory flowresistive loaded breathing while awake. The control group in this study showed the previously demonstrated16'20-24 phenomenon of load compensation, an increase in respiratory drive in response to an increase in inspiratory flow resistance. Under conditions of flow-resistive loading, because of the mechanical impairment, minute ventilation and mean inspiratory flow cannot be used as accurate indicators of neural drive; however, the airway pressure generated during the first 100 msec of an isometric contraction of inspiratory muscles may be used as a measure of respiratory drive. During loaded breathing, normal subjects increase the slope of their P100-Pco2 regression line or their P100 at a given Pco2 or both. The control group in the present study showed both an increase in the slope of their P100-PC02 line slope and an increase in their P,00 at a Pco2 of 60 mm Hg. This finding is in agreement with previously reported responses in normal subjects. In contrast, the group of patients with obstructive sleep apnea did not show an increase in the slope of their P100-Pco2 regression line with loading. Because load compensation may also be manifest as a parallel shift of the P100-Pco2 line, we examined the P100 at a Pco2 of 60 mm Hg and found no significant difference in the values obtained without and after the addition of the flow-resistive load. The lack of load compensation in patients with obstructive sleep apnea reflects an abnormality in respiratory control. Earlier studies on ventilatory control in obstructive sleep apnea have not included responses to flow-resistive loading during assessment of chemoreceptor responsiveness. While the exact region within the central nervous system that is responsible for the phenomenon ofload compensation is not known, it appears that it may well be above the brain stem. Indirect evidences to support this concept include the blunting of load compensation with light anesthesia, 25 carbon monoxide hypoxia, 26 and sleep. 27 Indeed, memory for recent events is probably involved in this response. 28 Thus, the lack ofload compensation in patients with obstructive sleep apnea reflects an abnormality in respiratory control in the central nervous system above the level of the brain stem. Because Control of Breathing in Sleep Apnea (Raiagopal, Abbrecht, Tellis)
patients included in this study were seen primarily for hypersomnolence, it is possible that the excessive daytime sleepiness was contributory to this finding. Furthermore, changes in personality and behavior to include deterioration of memory• have been noted in patients with obstructive sleep apnea. The ventilatory response to hypercapnia in patients with obstructive sleep apnea during wakefulness has been the subject of considerable interest. The findings in the current study indicate that the response of minute ventilation to hypercapnia without loading is essentially normal. Conflicting reports about this point in the literature probably reflect the heterogeneity of the groups of patients studied. Zwillich et al9 have demonstrated depressed hypoxic and hypercapnic responses in the obesity-hypoventilation syndrome which has been shown to be frequently associated with obstructive sleep apnea; however, all patients in that study were hypercapnic, making ventilatory responses difficult to interpret. Studies by Orr et al 10 in nonhypercapnic patients with obstructive sleep apnea have shown normal ventilatory responses, while Garay et al 11 have shown an inverse relationship between waking Pco2 and hypercapnic ventilatory response. Thus, the ventilatory response to hypercapnia is depressed in hypercapnic patients with obstructive sleep apnea but is essentially normal in the normocapnic patients with obstructive sleep apnea. With the addition of a flow-resistive load, the response of minute ventilation to carbon dioxide was depressed in patients with obstructive sleep apnea because of the lack ofload compensation. The demonstration of lack of compensation for an increase in respiratory load in patients with obstructive sleep apnea may have pathogenetic importance. Recent studies6 ·29.31 have shown that hypoxic and hypercapnic responses are depressed during sleep. Patients with obstructive sleep apnea who do not compensate fur loading during wakefulness may have a depression of load compensation that is greater than that seen in normal subjects32 during sleep. Indeed, the lack of an increase of genioglossus EMG or endoesophageal pressure33 during an episode of obstructive apnea would support such a hypothesis; however, an alternate explanation of the data would be that the lack of load compensation in subjects with obstructive sleep apnea could be a result of the accompanying hypersomnolence, rather than the cause of the apnea. The inability to respond to added load may be important in obstructive sleep apnea associated with hypertrophy of the tonsils and adenoids, :w-36 mandibular malfOrmation, 37 hypothyroidism, 38 and laryngeal stenosis.39 The failure to increase neural drive in response to an added inspiratory flow-resistive load during hypercapnia represents a central defect in the respiratory neuronal control of breathing in nonhyper-
capnic patients with obstructive sleep apnea. ACKNOWLEDGMENT: We thank Mr. Thomas R. McCumber and Mr. William A. Slivka for their technical assistance. REFERENCES
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22 23 24
25
26
27 28
29
hypoxic and hypercapnic ventilatory drives in man. J Appl Physiol1975; 38:1095-98 Altose MD, Kelsen SG, Stanley NN, Levinson RS, Cherniack NS, Fishman AP. Effects of hypercapnia on mouth pressure during airway occlusion in conscious man. J Appl Physiol1976; 40:338-44 Lopata M, LaFata J, Evanich J, Louren~ RV. Effects of How resistive loading on mouth occlusion pressure during CO, rebreathing. Am Rev Respir Dis 1977; 115:73-81 Schiffman PL, Westlake RE, Santiago 1V, Edelman NH. Ventilatory control in parents of victims of sudden-infant-death syndrome. NEng! J Med 1980; 302:486-91 Santiago TY, Remolina C, Scoles V, Edelman NH. Endorphins and the control of breathing-ability of naloxone to restore Howresistive load compensation in chronic obstructive pulmonary disease. N Eng! J Med 1981; 304:1190-95 Isaza GD, Posner JD, Altose MD, Kelsen SG, Cherniack NS. The effects of inspiratory How resistance and anesthesia on the isometric inspiratory muscle force during hypercapnia. Fed Proc 1975; 34:358 Chapman RW, Santiago 1V, Edelman NH. Brain hypoxia and control of breathing: neuromechanical control. J Appl Physiol Respir Environ Exercise Physiol1980; 49:497-505 Santiago TY, Sinha AK, Edelman NH. Respiratory How-resistive load compensation during sleep. Am Rev Respir Dis 1981; 123:382-87 Kelsen SG, Altose MD, Stanley NN, Levinson RS , Cherniack NS, Fishman AP. Effect of hypoxia on pressure developed by inspiratory muscles during airway occlusion. J Appl Physiol 1976; 40:372-78 Phillipson EA, Sullivan CE. Respiratory control mechanisms during non-REM and REM sleep. In: Guilleminault C, Dement WC, eds. Sleep apnea syndromes. New York: Alan R Liss,
1978:47-64 30 Douglas NJ, White DP, Wei! JV, Pickett CK, Martin RJ, Hudgel DW, et al. Hypoxic ventilatory response decreases during sleep in normal men. Am Rev Respir Dis 1982; 125:286-89 31 Douglas NJ, White DP, Wei! JV, Pickett CK, Zwillich CW. Hypercapnic ventilatory response in sleeping adults. Am Rev Respir Dis 1982; 125:758-62 32 Iber C, Berssenbrugge J, Skatrud JB, Dempsey JA. Ventilatory adaptations to resistive loading during wakefulness and nonREM sleep. J Appl Physiol Respir Environ Exercise Physiol 1982; 52:607-14 33 Martin JM, Pennock BE, Orr WC, Sanders MH, Rogers RM . Respiratory mechanics and timing during sleep in occlusive sleep apnea. J Appl Physiol Respir Environ Exercise Physiol 1980; 48:432-37 34 Levy AM, Tabakin BS, Hanson JS, Markewicz RM. Hypertrophied adenoids causing pulmonary hypertension and heart failure. N Engl J Med 1967; 277:506-11 35 Guilleminault C, Eldridge FL, Simmons FB, Dement WC. Sleep apnea in eight children. Pediatrics 1976; 58:23-30 36 Mangat D, Orr WC, Smith RO. Sleep apnea, hypersomnolence, and upper airway obstruction secondary to adenotonsillar enlargement. Arch Otolaryngol 1977; 103:383 37 Conway WA, BowerGC, Barnes ME. Hypersomnolenceand intermittent upper airway obstruction: Occurrence caused by micrognathia. JAMA 1977; 237:2740-42 38 Rajagopal KR, Derderian SS, Jabbari B, Burman KD, Hunt KK. Obstructive sleep apnea in hypothyroidism (abstract). Am Rev Respir Dis 1981; 123:188 39 Lugaresi E, Coccagna G, Mantovani M, Cirignotta F. Hypersomnia with periodic apnea. In: Guilleminault C, Dement WC, Passouant P, eds. Narcolepsy. New York: Spectrum, 1976:351
Current Concepts in Echocardiography A course in advanced echocardiographic techniques will be held at St. George's Hospital Medical School, London, England, April 3-6. For infunnation, contact The Postgraduate Secretary, St. Georges Hospital Medical School, Cranmer Terrace, London SW 17 ORE, England.
180
Control of Breathing In Sleep Apnea (Rajagopal, Abbrflcht, Tallis)
We studied the responses of ventilation and occlusion pressure (P..) to hypercapnia, with and without the application of im inspiratory Bow-resistive load (.12 em HsO/Usec), in eight control subjects and in eight subjects with obstructive sleep apnea who did not retain carbon dioxide while awake. The hypercapnic response was assessed by a modiGcation of the Read rebreathing technique. For a given endtidal carbon dioxide, ventilation in control subjects was the
same with or without load, and P,.. was increased with loading. In contrast, the subjects with sleep apnea decreased their ventilation during loading and did not increase theil;' P... in response to loading. Relationships between ventilation and P 100 were similar in the two groups both with and without load. We conclude that patients with occlusive sleep apnea do not exhibit the normal increase in neural drive to compensate for inspiratory Bow-resistive loading.
apnea during sleep, defined as cessation O bstructive of airHow fur at least ten seconds with continued
compensate fur this load, we postulated that abnormalities in load compensation exist in this group and that they may be present during wakefulness. TherefOre, we studied the responses of ventilation and occlusion pressure without and after the application of a flow-resistive load in a group of subjects with obstructive sleep apnea who did not retain carbon dioxide while awake. Our data suggest that abnormalities in the control of breathing exist in patients with obstructive sleep apnea.
respiratory effurt, 1 is a phenomenon that is poorly understood despite increasing investigation. Recurrent opposition of the superior lateral pharyngeal walls, 1 genioglossal hypotonia,~ and abnormalities in the chemical control of ventilation6 have all been incriminated in the pathogenesis of obstructive sieep apnea. In normal awake persons, there is an increase in the genioglossal electromyogram (EMG) in response to hypercapnia. 7•8 In contrast, it is well recognized that in subjects with sleep apnea, the genioglossal EMG, in fact, decreases during an apneic episode, despite increasing hypercapnia, until just prior to reestablishment of patency of the airway. 3 Studies on chemical control in obstructive sleep apnea including the responses of ventilation and occlusion pressure show conflicting results and include heterogeneous groups of subjects with varying degrees of hypercapnia.~11 In addition, load compensatory responses have not been assessed. The normal compensatory response to acute increases in resistance to breathing would be an increased inspiratory effurt. The occlusive apneic episode may be regarded as a situation of infinite load. Because subjects with sleep apnea demonstrate a progressive decrease in the genioglossal EMG during such episodes and do not appear to *From the Pulmonary Disease Service and Department of Clinical Investigation, Walter Reed Army Medical Center, Washington, DC, and the Departments of Physiology and Internal Medicine, Unifunned Services University of the Health Sciences, Bethesda, Md. Supported by WRAMC protocol 1701 and USPHS protocols R07648 and R07659. The opinions and assertions contained herein are the private views of the writers and are not to be construed as official or as reSecting views of the Department of the Army and the Department of Defense. Manuscript received June 24; revision accepted AugUst 16. Reprint requests: Dr. Rajagopal, Walter ReeflArmy Medical Center, Wuhington, DC 20307
174
MATERIALS AND METHODS We studied eight adult male subjects with obstructive sleep apnea and eight control subjects. The control group consisted of healthy asymptomatic male volunteers matched fur age, sex, body weight, and height with the subjects with obstructive sleep apnea. Anthropometric data are shown in 'lllble 1. All subjects were nonsmokers. The mean ratio of the furced expired volume in one second to the furced vital capacity (FEV/FVC) was 77 percent in patients with obstructive sleep apnea and 80 percent in control subjects. All subjects in the study had peak inspiratory mouth pressures (taken as
Table !-Anthropometric Data for Control Subjects and Patients with Obatructive Sleep Apnea (OSA) Age, yr Case l 2 3 4 5 6 7 8 Mean :!:SE
Height, em
Control · OSA
43 59 57
44
52 57
42
46
51 21
50 21
54
55
29
34
45*
:!::5
45*
:!::4
Control 180 188 188 183 178 175 185 180 182t :!::2
Body Weight, kg
OSA
Control
OSA
178 180 180 178 178 175 178 175 l78t :!:I
78.6 130.0 97.3 119.1 84.1 72.3 98.2 122.7 100.2* :!::6.7
79.6 138.6 86.4 121.8 102.3 75.0 113.6 118.2 104.~
:!::7.0
•p = 0. 96 by t-test. tp=0.035 by t-test. *P = 0. 72 by t-test. Control of Blealhlng In Sleep Apnea (Rajagopal, Abbrecht, Tell/a)
Table 2-Data on Pulmonary Function for Control Subjecta and Patient. with Obnructive Sleep Apnea (OSA)
FVC, L
FVC, percent of predicted
100 FEV 1/ FVC
PI max, em H 20*
Case Control OSA Control OSA Control OSA Control OSA 4.80 113 1 5.56 4.05 3.47 71 2 5.55 4.61 110 3 3.36 4 4.70 93 3.81 3.72 83 5 84 4.32 3.66 6 89 4.46 2.74 7 4.01 8 4 .36 83 4.53t 3.87t 9lt Mean ±SE ±0.26 ±0.23 ±5
101 85 100 71 76 70 58 82 80:1: ±5
74 85 75 79 89 88 61 85 80§
±3
77 72 71 86 67 79 76 84 77§ ±2
122 120
llO
140 160 125 205 150 14211 ±11
160 100 130 120 120 130 170 100 12911 ±9
*PI max, maximum inspiratory pressure. tp=0.09 by t-test. :l:p=0.19 by t-test. §p=0.49 by t-test. llp=0.40 by t-test. the best of three maximal inspiratory efforts at residual volume) greater than 100 em H20. Results of tests of pulmonary function in patients with obstructive sleep apnea and in control subjects are shown in 'Illble 2. There was no history of acute respiratory infection in any subject for at least four weeks prior to the study. We excluded hypercapnic subjects so as to eliminate the influence of elevated concentrations of bicarbonate ion on the assessment of respiratory drive. 11 Patients referred to the pulmonary clinic for hypersomnolence had a detailed history and physical examination. Patients with abnormalities of the upper airway (adenoids; tonsils; obstructing lesions) were excluded from the study. All subjects included in the study had all-night polygraphic studies during sleep documenting the presence of repetitive episodes of obstructive sleep apnea. The sleep studies included simultaneous monitoring of the electroencephalogram, electro-oculogram, chin EMG, electrocardiogram, arterial oxygen saturation (SaO.) by ear oximeter (Hewlett-Packard 47201A), expired carbon dioxide fraction at the nose and mouth by carbon dioxide analyzer (Beckman LB-2), and chest wall and abdominal movement (using Hewlett-Packard Contact Sensor 21050A and a Respitrace). Sleep studies were scored in 20-second
Table 3-0ccummce of Apneic Periods and Period. of Disordered Breathing (DOB) during Sleep in Patient. with Obatructive Sleep Apnea
Case
No. of Apneic and DOB Episodes per Hour
2 3 4 5 6 7 8
46.84 9.02 17.96 76.31 85.46 57.43 41.38 20.05
No. of Apneic and Mean Duration of DOB Episodes by Duration, sec Individual Episodes, 10-19 20-29 >30 sec 21.68 17. 13 22.87 37.21 19.63 20.42 37.66 33.22
99 23 15 197 113 95
149 115
101 8 11 0 0 7 104
33 0 12 11 1 0 0 0
Apneic and DOB Time, Percent of Total Sleep Time 28.2 4.3 11.4 78.9 46.6 32.6 43.3 18.5
epochs using standard criteria. 13 Data on the occurrence of episodes of apnea and disordered breathing during sleep for the subjects with obstructive sleep apnea are shown in 'Illble 3. All subjects met the criteria for the diagnosis of the sleep apnea syndrome, defined as the presence of at least 30 episodes in both rapid-eye-movement (REM) sleep and non-rapid-eye-movement (NREM) sleep, some of which must appear repetitively in NREM sleep. 14 An apneic episode was defined as cessation of airflow for at least ten seconds despite continued inspiratory effort, and an episode of disordered breathing was defined as a decrease in Sa02 of at least 4 percent in the presence of continuing respiratory airflow. The hypercapnic response was assessed by a modification of the Read rebreathing technique. 15 Load compensation was assessed by repeating the rebreathing test with a flow-resistive load interposed in the inspiratory limb. Since respiratory neural drive cannot be estimated from ventilatory rates during inspiratory flow-resistive loading, neural drive was assessed by measurement of occlusion pressure. 10 The pressure generated during the first 100 msec (P1.,.) of an airway occlusion was used as an index of respiratory drive during the previous breath. 17 Subjects were instructed not to take any respiratory stimulants prior to the tests. In the pulmonary laboratory, subjects were first familiarized with the rebreathing apparatus. Ventilation and endtidal carbon dioxide pressure (Pco.) were monitored with the subjects seated and breathing through a mouthpiece and a one-way valve (Hans Rudolph 2700). Inspiratory flow rate was measured with a pneumotachygraph (Fleisch 3) coupled to a flow transducer (Hewlett-Packard) and integrated to obtain volume. End-tidal Pco2 was measured (Beckman Capnograph LB-2) from a sample in the expiratory limb. Once the subject was comfortable breathing on the apparatus, he was switched into the rebreathing circuit. The subjects then breathed 5 percent carbon dioxide in oxygen from a 13-L rubber bag. Sampled gas was returned to the rebreathing bag. End-tidal carbon dioxide, airflow, inspired volume, and airway pressure were recorded continuously on an eight-channel recorder (HewlettPackard 7758D). Airway pressure was measured by a blunt widebore needle inserted into the rubber mouthpiece and connected to a pressure transducer (Sanborn 2678). During the rebreathing period, which ordinarily lasted four to six minutes, random, periodic, temporary, inspiratory airway occlusions were made every 20 to 30 seconds for the determination of P100• A silent occlusion valve was used so that the subject was unaware of the initiation of occlusions. After completion of the rebreathing run, subjects were given a rest period of 30 minutes, following which the rebreathing study was repeated with the interposition of an inspiratory flow-resistive load. The load was produced by placing fine wire mesh screen disks in the inspiratory line. The resistance was constant at 12 em H10/Usec up to a flow rate of 1.5 Usee. The pressure transducer was calibrated using manometric methods, the pneumotachygraph using a 1-L plastic syringe (Collins), and the Capnograph using two different concentrations of carbon dioxide from preanalyzed gas cylinders. Points with a Pco2 ofless than 50 mm Hg were eliminated, since they lay on the nonlinear portion of the response curve. To describe the sensitivity of the respiratory drive to carbon dioxide, several parameters of ventilation and respiratory drive were regressed linearly against end-tidal Pco1• These parameters included minute ventilation, mean inspiratory flow rate, and P100• Minute ventilation was derived from the tidal volumes and durations of the three breaths preceding an occluded breath, and mean inspiratory flow was calculated by dividing the tidal volume of the breath preceding an occlusion by inspiratory duration. Responses without and after the addition of the load were analyzed in subjects and compared to responses obtained by the same techniques in matched controls. Statistical evaluation of the regression slope data was done by analysis of variance with repeated measures. 18 When the interaction term was significant, Duncan's multiple range test'" was used to CHEST I 85 I 2 I FEBRUARY, 1984
175
60
I
I
I
I
4
I
1/,1
CONTROL-NO LOAD~,:
PATlENT-NO
LOAD£/._~ ~~~ ~ ll ~
c
"::J z a
a
I
I
I
I
I
I
I
/ 8
***
~I
u u
.,
':J . C) ~
~I
>-
...
= c = E "' ~ C)
..,z ..,>t~
I
r'//
2
=
z
I
I
q_'t-
I
I
I
~
.T
/!('
z
cw
~
!i
~
~i>:r
..... .....
40
I
I
~~/I / ~/ $~ ~/ ~
3
I
·e
~
I
/'/~ I ~
50
c: .....
I
I
I
1
/
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0
I
('
/'/
4
/.
~
8
12
16
20
P1oo• em H20 50
60
70
END TIDAL PC0 2, mmHg FIGURE 1. Lines for regression of minute ventilation on end-tidal Pco1 fur control subjects and subjects with obstructive sleep apnea during nonloaded and loaded breathing. Vertical bars indicate 95 percent confidence limits. Lines whose slopes are significantly different (p < 0. 05 by Duncans multiple range test1") are indicated by asterisks.
detennine which means differed significantly from one another. RESULTS
Figure 1 compares the response of the minute ventilation of control subjects and patients to carbon dioxide measured before and during Bow-resistive loading. The slopes of the nonloaded ventilation end-tidal Pco2 regressions were not significantly different (mean ± SE, 2.17 ± 0.40 Umin/mm Hg for controls and 2.17 ± 0.23 for the patients with sleep apnea) (Table 4). Because an enhanced ventilatory response may also be manifest as a parallel shift in the response curves, ventilation at a Pco2 of 60 mm Hg was examined and found to be no different in the two groups (mean± SE, 41.44 ± 6.77 Umin/mm Hg in controls and 40.3 ± 5.16 in patients with obstructive sleep apnea). With Bow178
FIGURE 2. Lines fur regression of mean inspiratory How on P100 for control subjects and for subjects with obstructive sleep apnea. Vertical bars indicate 95 percent confidence limits. Lines whose slopes are significantly different (p <0.05 by Duncans multiple range test1") are indicated by asterisks.
resistive loading the slope of the response of minute ventilation to Pco2 decreased significantly (p <0.05) in patients with obstructive sleep apnea to 1.03±0.14 Umin/mm Hg, while the ventilatory response was maintained in control subjects. In patients with obstructive sleep apnea, the slope of the response of minute ventilation to Pco2 during Bow-resistive loading was significantly lower (p<0.05) than the slope in control subjects either with or without loading. Figure 2 compares the mean inspiratory Bow for various levels of P100 in patients with obstructive sleep apnea and control subjects. Without the load, for any given level of P100, the mean inspiratory Bow was similar in patients with obstructive sleep apnea and in control subjects (Table 4). During Bow-resistive loading the mean inspiratory Bow decreased both in patients with obstructive sleep apnea (p <0.05) and control subjects (p <0.05) compared to without the load; however, for any given level of P100, the mean Control of Blealhlng In Sleep Apnea (Rajagopa/, Abbt8cht, Tellis)
Table 4-.Regreaion l.Mie Slopa for Ventilmory .Reaponau cf Control Subject. and Patient. with Olmructive Sleep Apnea (OSA) Minute Ventilation VS PC<>t, Uminlmm Hg Croup and Case Control 1 2 3 4 5 6 7 8 Mean slope SE of slopes OSA 1 2 3 4
5 6 7 8 Mean slope SE of slopes
Mean Inspiratory Flow VS p IOO• Uminlcm H10
Minute Ventilation vsPUminlcm H10
PIOO vs Pco., em H 10/mm Hg
No Load
Load
No Load
Load
No Load
Load
No Load
Load
3.57 0.65 1.95 3.56 1.98 3.19 0.99 1.49 2.17 0.40
3.08 1.45 0.96 2.19 1.04 0.91 2.74 1.61 1.75 0.30
0.127 0.127 0.203 0.177 0.187 0.212 0.112 0.159 0.163 0.013
0.052 0.059 0.097 0.031 0.022 0.029 0.025 0.108 0.053 0.012
4.93 5.95 8.49 5.92 7.11 6.04 2.99 6.13 5.95 0.56
2.23 1.72 2.60 1.81 0.56 1.31 1.15 3.57 1.87 0.33
0.613 0.237 0.227 0.461 0.224 0.514 0.989 0.338 0.4M 0.093
1.161 0.771 0.343 0.874 0.559 0.552 1.743 0.441 0.805 0.163
2.43 3.27 2.83 1.38 1.90 2.04 2.04 1.52 2.17 0.23
1.22 1.75 0.99 0.70 1.23 1.00 0.86 0.48 1.03 0.14
0.204 0.144 0.057 0.063 0.233 0.063 0.265 0.086 0.139 0.030
0.132 0.097 0.047 0.048 0.029 O.o75 0.169 0.044 0.080 0.017
6.89 4.52 7.60 2.06 9.27 2.31 5.57 2.46 5.06 0.96
4.20 1.59 1.55 1.67 1.62 3.83 4.39 1.87 2.59 0.46
0.358 0.643 1.332 0.610 0. 174 0.634 0.328 0.308 0.548 0.128
0.277 0.251 0.592 0.702 0.817 0.408 0.111 0. 160 0.415 0.090
inspiratory flow was similar in patients with obstructive sleep apnea and control subjects. These findings indicate that at any given level of respiratory drive (P100), comparable inspiratory flows were generated both in patients with obstructive sleep apnea and in control subjects, thus excluding mechanical factors as an explanation fur the differences in the ventilatory response to Pco1 in the two groups with load. Figure 3 compares the relationship between minute ventilation and P100 in patients with obstructive sleep apnea and control subjects. The minute ventilation fur any given level of P100 was lower with load than without load, both in patients with obstructive sleep apnea (p <0.05) and in control subjects (p <0.05) (Table 4); however, the slopes and intercepts of the ventilationP100 regressions fur the subjects with sleep apnea were not significantly different from those of the control subjects either with or without the load. This indicates that fur any P100 the ventilation produced was similar in patients with obstructive sleep apnea and control subjects, whether this be without or during the addition of the flow-resistive load. On the basis of Figures 2 and 3, it appears that the failure of the subjects with obstructive sleep apnea to maintain ventilation during loading (Fig 1) was probably related to changes in respiratory drive during loaded breathing, rather than to a decreased ability of the patients with sleep apnea to respond to central drive. Figure 4 shows the P100-Pco1 regression lines fur the
two groups. Without load the regression slopes were
similar in the two groups (Table 4), and the P100 at a Pco 2 140 120 c:
e ":J
100
!c
ao
z
~
I=
z ...., > ~
60
= 40 1 20
0
4
a
12
P100, em H20
11
20
FtcURE 3. Lines lOr regression of minute ventilation on P100 lOr control subjects and lOr subjects with obstructive sleep apnea. VerlicGl ban indicate 95 percent confidence limits. Lines whose slopes are significantly dift'erent (p <0.05 by Duncan's multiple range test!V) are indicated by tJSterlslu.
CHEST I 85 I 2 I FEBRUARY, 19&4
177
20
Pco2 of60 mm Hg was significantly higher (p <0.05) during loaded breathing than without the load; however, in patients with obstructive sleep apnea, P100 at a Pco2 of 60 mm Hg during loaded breathing was no different from without the load. Thus, patients with obstructive sleep apnea do not increase their neural drive to compensate for inspiratory flow-resistive loading.
15
DISCUSSION
= 2:
N
~
10
5
50
60
70
END-TIDAL Pco2, mmHg FIGURE 4. Lines for regression ofP 100 on end-tidal Pco2 for control subjects and subjects with obstructive sleep apnea. Vertical bars indicate 95 percent confidence limits. Lines whose slopes are significantly different (p <0.05 by Duncan's multiple range test'") are indicated by asterisks.
of 60 mm Hg was no different. With the resistive load, respiratory effort in the control group increased to compensate for the increase in inspiratory resistance. This is shown by the fact that the slope of the P100-Pco2 line was significantly greater (p <0.05) during loaded breathing. In contrast, patients with obstructive sleep apnea did not increase their respiratory neural output in response to load. The slope of their P100-Pco2 regression line was no different during loaded breathing than without the load. Load compensation might also occur as a parallel shift of the P100-Pco2 line without a change in the slope. To test this possibility, we examined the P100 at a Pco 2 of60 mm Hg both with and without the load. In the control subjects, P100 at a 178
The data from the present study indicate that patients with obstructive sleep apnea do not increase respiratory neural output during inspiratory flowresistive loaded breathing while awake. The control group in this study showed the previously demonstrated16'20-24 phenomenon of load compensation, an increase in respiratory drive in response to an increase in inspiratory flow resistance. Under conditions of flow-resistive loading, because of the mechanical impairment, minute ventilation and mean inspiratory flow cannot be used as accurate indicators of neural drive; however, the airway pressure generated during the first 100 msec of an isometric contraction of inspiratory muscles may be used as a measure of respiratory drive. During loaded breathing, normal subjects increase the slope of their P100-Pco2 regression line or their P100 at a given Pco2 or both. The control group in the present study showed both an increase in the slope of their P100-PC02 line slope and an increase in their P,00 at a Pco2 of 60 mm Hg. This finding is in agreement with previously reported responses in normal subjects. In contrast, the group of patients with obstructive sleep apnea did not show an increase in the slope of their P100-Pco2 regression line with loading. Because load compensation may also be manifest as a parallel shift of the P100-Pco2 line, we examined the P100 at a Pco2 of 60 mm Hg and found no significant difference in the values obtained without and after the addition of the flow-resistive load. The lack of load compensation in patients with obstructive sleep apnea reflects an abnormality in respiratory control. Earlier studies on ventilatory control in obstructive sleep apnea have not included responses to flow-resistive loading during assessment of chemoreceptor responsiveness. While the exact region within the central nervous system that is responsible for the phenomenon ofload compensation is not known, it appears that it may well be above the brain stem. Indirect evidences to support this concept include the blunting of load compensation with light anesthesia, 25 carbon monoxide hypoxia, 26 and sleep. 27 Indeed, memory for recent events is probably involved in this response. 28 Thus, the lack ofload compensation in patients with obstructive sleep apnea reflects an abnormality in respiratory control in the central nervous system above the level of the brain stem. Because Control of Breathing in Sleep Apnea (Raiagopal, Abbrecht, Tellis)
patients included in this study were seen primarily for hypersomnolence, it is possible that the excessive daytime sleepiness was contributory to this finding. Furthermore, changes in personality and behavior to include deterioration of memory• have been noted in patients with obstructive sleep apnea. The ventilatory response to hypercapnia in patients with obstructive sleep apnea during wakefulness has been the subject of considerable interest. The findings in the current study indicate that the response of minute ventilation to hypercapnia without loading is essentially normal. Conflicting reports about this point in the literature probably reflect the heterogeneity of the groups of patients studied. Zwillich et al9 have demonstrated depressed hypoxic and hypercapnic responses in the obesity-hypoventilation syndrome which has been shown to be frequently associated with obstructive sleep apnea; however, all patients in that study were hypercapnic, making ventilatory responses difficult to interpret. Studies by Orr et al 10 in nonhypercapnic patients with obstructive sleep apnea have shown normal ventilatory responses, while Garay et al 11 have shown an inverse relationship between waking Pco2 and hypercapnic ventilatory response. Thus, the ventilatory response to hypercapnia is depressed in hypercapnic patients with obstructive sleep apnea but is essentially normal in the normocapnic patients with obstructive sleep apnea. With the addition of a flow-resistive load, the response of minute ventilation to carbon dioxide was depressed in patients with obstructive sleep apnea because of the lack ofload compensation. The demonstration of lack of compensation for an increase in respiratory load in patients with obstructive sleep apnea may have pathogenetic importance. Recent studies6 ·29.31 have shown that hypoxic and hypercapnic responses are depressed during sleep. Patients with obstructive sleep apnea who do not compensate fur loading during wakefulness may have a depression of load compensation that is greater than that seen in normal subjects32 during sleep. Indeed, the lack of an increase of genioglossus EMG or endoesophageal pressure33 during an episode of obstructive apnea would support such a hypothesis; however, an alternate explanation of the data would be that the lack of load compensation in subjects with obstructive sleep apnea could be a result of the accompanying hypersomnolence, rather than the cause of the apnea. The inability to respond to added load may be important in obstructive sleep apnea associated with hypertrophy of the tonsils and adenoids, :w-36 mandibular malfOrmation, 37 hypothyroidism, 38 and laryngeal stenosis.39 The failure to increase neural drive in response to an added inspiratory flow-resistive load during hypercapnia represents a central defect in the respiratory neuronal control of breathing in nonhyper-
capnic patients with obstructive sleep apnea. ACKNOWLEDGMENT: We thank Mr. Thomas R. McCumber and Mr. William A. Slivka for their technical assistance. REFERENCES
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Current Concepts in Echocardiography A course in advanced echocardiographic techniques will be held at St. George's Hospital Medical School, London, England, April 3-6. For infunnation, contact The Postgraduate Secretary, St. Georges Hospital Medical School, Cranmer Terrace, London SW 17 ORE, England.
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Control of Breathing In Sleep Apnea (Rajagopal, Abbrflcht, Tallis)