Effect of Hyperoxia on the Arousal Response to Airway Occlusion during Sleep in Normal Subjects 1 •2
RICHARD B. BERRY and RICHARD W. LIGHT
Introduction
T he termination of obstructive apnea in the obstructive sleep apnea syndrome is believed to depend largely on arousal (1-3).Arousal can be defined as an abrupt increase in the frequency of electroencephalogram (EEG) activity and a simultaneous increase in the amplitude of the chin electromyographic (EMG) activity (4). Evidence of arousal usually precedes or coincides with the preferential increase in upper airway tone that restores airway patency and terminates the obstructive apnea (2). The precise events leading to arousal and apnea termination are still not well understood. Central nervous systemstimulation from a decrease in POl' an increase in Pco., and sensations of inspiring against an occluded airway appear to interact to produce arousal and apnea termination (5-10). Recent evidence suggests that the level of inspiratory effort may be the most important factor producing arousal from sleep (8-10). Gleeson and coworkers (8) have recently shown that the maximal negative esophageal pressure deflection preceding arousal from sleep in a given normal subject is similar whether arousal occurs after induced hypercapnia, hypoxia, or an added resistive inspiratory load. This occurs even though the ventilatory responses to these stimuli are very different. These investigators hypothesized that arousal occurs when inspiratory effort reaches a certain arousal pressure threshold. Studies in patients with the obstructive sleep apnea syndrome have also suggested that arousal occurs when the degree of inspiratory effort reaches a certain threshold (9-10) in a given subject. The factors determining the arousal threshold are still not well defined. Oxygen administration does increase apnea duration in patients with the obstructive sleep apnea syndrome (11-13). However, it is not known if falls in POl during apnea (room air breathing) decrease the arousal threshold or simply augment the rate of increase in inspiratory effort. 330
SUMMARY The effect of hyperoxla on the arousal response to airway occlusion during non-rapid eye movement (NREM) sleep was studied In six normal male subjects with a mean age (± SO) of 23.5 ± 8.7 yr by testing the response to the occlusion of a face mask covering the nose and mouth. Occlusion trials while the subjects breathed room air (room air condition) were alternated with trials in which subjects breathed a mixture of room air and oxygen adjusted to maintain a sleeping baseline arterial oxygen saturation of 98% (hyperoxlc. condition). The time to arousal (mean ± SEM) was significantly longer during oxygen administration (41.1 ± 4.5 versus 28.9 ± 4.6 s; P < 0.002). The maximal deflections In airway pressure were measured at a supraglottic location during airway occlusion to reflect the degree of Inspiratory effort. The maximal airway suction pressure preceding arousal did not differ between the room air (27.4 ± 5.4 cm H20) and hyperoxlc conditions (26.6 ± 5.9 cm H20). Conversely, the rate of Increase In Inspiratory effort (maximal pressure) during occlusion was decreased by oxygen administration. We conclude that hyperoxla prolongs the time to arousal after airway occlusion by decreasing the rate of Increase In the magnitude of Inspiratory AM REV RESPIR DIS 1992; 146:330-334 efforts, but it does not change the arousal threshold.
The effect of oxygen administration on the time to arousal or arousal threshold after mask occlusion in normal subjects is not known. During mask occlusion, such subjects exhibit increases in inspiratory effort until arousal occurs (14). We hypothesized that oxygen administration should prolong the time to arousal. Furthermore, on the basis of the work of Gleeson and coworkers (8), we reasoned that the level of inspiratory effort at arousal should not be altered by oxygen breathing. That is, oxygen breathing should increase the time to arousal by decreasing the rate 0 f increase in inspiratory effort rather than changing the level of inspiratory effort needed to induce arousal. To test these hypotheses, we compared the respiratory and arousal responses to airway occlusion during Stage 3-4 nonrapid eyemovement (NREM) sleep while normal subjects breathed room air or a mixture of air and oxygen.
tored using two pairs of EEG leads (C4-AI, 02-AI), two pairs of electrooculographic leads, and chin EM G leads using standard methods (15). An EKG lead was monitored as well.Arterial oxygen saturation (Sao.) was continuously measured using pulse oximetry (Ohmeda 3700; Ohmeda Corp., Boulder, CO). End-tidal Pco, was recorded using a capnograph (Model 223; Puritan-Bennett, Los Angeles, CA). The mask occlusion apparatus used is depicted in figure I. A face mask covering the nose and mouth was "glued" to the subjects using a medical grade silicone elastomer (Factor II, Lakeside, AZ) and held in place by head straps. A leak detector consisted of a length of plastic tubing containing multiple small holes that surrounded the mask at the mask-face interface. This tubing was connected to another CO 2 monitor (No. 7500; Marquette, Milwaukee,WI). Small mask leaks could be detected as a nonzero reading on the CO 2 monitor. The face mask contained separate inspiratory and expiratory ports. The expiratory port was fitted with a one-way valve.
Methods Six normal male subjects were studied. The subjects were of normal body weight and did not have a history of snoring or daytime sleepiness. Written informed consent was obtained from all subjects prior to their participation in the study. The project was approved by the Institution Review Board of our hospital. The presence and stage of sleep were moni-
(Received in original form June 20, 1991 and in revised form November 15, 1991) 1 From the Pulmonary Section, Long Beach Veterans Administration Center, and the University of California, Irvine, Long Beach, California. 2 Correspondence and requests for reprints should be addressed to Richard B. Berry, M.D., Pulmonary Section 111 P, Long Beach VAMedical Center, 5901 East 7th Street, Long Beach, CA 90822.
HYPEROXIA AND AROUSAL FROM SLEEP
331
arousal was defined as an increase in the EEG frequency with the appearance of alpha waves and a simultaneous increase in the EMG amplitude (4). Such arousals were invariably associated with an abrupt change in the supraglottic pressure.
Fig. 1. The mask occlusion apparatus used.Thebiasflowwasventedfromthe systemat the time of valveocclusion by removing the stopper.
The inspiratory port did not contain a oneway valve and was connected to six feet of low compliance respiratory tubing that passed through the wall of the subject's room into the monitoring room . The tubing was connected to an occlusion apparatus allowing inspiration of room air through a one-wayvalve unless a balloon was inflated (figure I). Even though the occlusion valvewas separated from the mask by tubing, during occlusion no inspiration was possible because of the lowcompliance of the tubing. A small amount of bias flow consisting of either 4 to 5 L/min of oxygen or medical grade air was infused into the occlusion apparatus at a site proximal to the occlusion valve. Because of the one-way valve in the occlusion apparatus, this flow was directed out through the mask expiratory valve. At the time of balloon occlusion the bias flow was vented by removing a stopper. The flow rate of oxygen was chosen to maintain an arterial oxygen saturation of 98070. The bias flow prevented rebreathing of COl' The subjects' exhaled air was sampled at the nostrils using a small nasal cannula to determine the end tidal Pco., A pneumotachometer measured the flow rate of gas entering the inspiratory limb of the apparatus exclusive of the bias flow. The flow rate was integrated to obtain volume. The flow rate and volume provided qualitative estimates of the actual inspired flow and volume and were used to ensure a regular pattern of ventilation prior to occlusion trials . The level of inspiratory effort was monitored by measuring airway suction pressure in a supraglottic location. Before the mask was attached to each subjects' face, a 5 Fr catheter with a pressure transducer tip (Millar, Houston, TX) was inserted through one nos-
Data Analysis The time to arousal (ITA) after mask occlusion, the Sao, and the end-tidal Pco, preceding occlusion, and the nadir in arterial oxygen saturation after occlusion (room air condition only) were noted . Desaturation did not occur during hyperoxic trials. The time to arousal was measured from the start of the initial occluded inspiration to EEG and EMG evidence of arousal. The airway pressure (supraglottic pressure) during occlusion was analyzed in the following manner. The maximal negative pressure deflection of the initial inspiratory effort (PI) and the final complete effort preceding arousal (PF) weremeasured. A complete effort was one in which arousal did not occur before a definite maximal pressure had been obtained. The difference in the initial and final maximal pressures (APmax = PF - PI) was calculated. A mean slope of maximal pressure deflection (APmax/T) was determined by dividing APmax by the elapsed time between tril after minimal topical anesthesia with 10J0 the maximal pressure deflections on the inilidocaine was administered to one nasal pas- . tial and final efforts (T). The APmax/T was further analyzed by facsage and the upper airway. The catheter tip was placed 16 to 18 em from the nares, and toring this variable into the product of in this location it was in a supraglottic posi(APmax/#) and (#/T), where # is the numtion (16). The catheter was calibrated before ber of occluded inspiratory efforts after the insertion into the subjects by applying a nega- initial effort prior to arousal. The (APmax/#) is the mean increase in the maximal suction tive pressure to a small chamber in which the pressure per breath, and the (#/T) is the rate catheter was inserted. The chamber was connected to a water manometer. Under condiof occluded efforts (numberls). In this way tions of no flow (mask occlusion), changes it can be seen that APmax/T could vary bein the supraglottic pressure equal changes in cause of changes in the mean progressive rise in suction pressure with each succeeding inpleural (and esophageal) pressure. spiratory effort or changes in the frequency All variables wererecorded on a I2-channel of occluded efforts. Grass 78D polygraph (Grass Instruments, Quincy, MA) using a paper speed of 10mm/s . The mean values of the TTA, preocclusion A near infrared camera and video monitor end-tidal Peo l, PI, PF, APmax/T, APmax/#, system allowed continuous visual inspection and #/T for each patient were compared between the room air and hyperoxic conditions of the subjects . using the paired t test (17). A P < 0.05 was Airway Occlusion Procedure considered to show statistical significance. The inspiratory airway was closed during exThe duration of respiratory efforts during piration in stable Stage 3-4 NREM sleep from mask occlusion was analyzed as follows. The six to I3 times during both room air and oxy- inspiratory time (Tr) was defined as the time gen breathing. The mean (± SD) number of from the start of the supraglottic pressure occlusions during room air breathing was 8.8 deflection to the maximal negative deflection. ± 2.8, and during oxygen breathing it was The Tr of the initial and final pressure deflec8.3 ± 2.3. Room air and hyperoxic occlusion tions (Trl and 'llF) werecompared using analysisof variance for repeated measures (BMDP trials were alternated and the order was randomized . Subjects wererequired to have been program P2Y) with room air versus the hyperoxic conditions and time (initial versus in a stable stage of sleep without arousals for final) as within-subjects factors (18). The at least 3 min before mask occlusion was inimean rate of pressure generation on the first tiated. Oxygen was administered for at least three min before hyperoxic occlusions were and final respiratory efforts were computed performed. :Before all occlusion trials, the as (PI/'llI) and (PF/'llF) and compared in a breathing pattern was acquired to be regular, similar manner. and the end-tidal Pco, and the Sao, were required to be stable. The occlusion was quickResults ly terminated when there was evidence of The subject characteristics are listed in arousal from the EEG and EMG tracings. An
332
BERRY AND LIGHT
TABLE 1 SUBJECT CHARACTERISTICS Subject No.
Age
(yT)
Height (inches)
Weight (/bs)
-e:
U)
(%)
::> 0
a:
22 41 18 21 18 21
76 70 68 69 69 69.5
225 155 143 175 165 135
125 .7 100.0 96 .0 115.1 108.6 87.9
Mean SO
23 .5 8.7
70 .3 2.9
166.3 32 .2
105.5 13.7
table 1. Body weight is expressed both in absolute terms and as a percentage of ideal body weight (19). The time to arousal in the hyperoxic condition (mean ± SEM) was significantly greater for the group (41.1 ± 4.5 versus 28.9 ± 4.6 s; p < 0.002). The means for the individual subjects are shown in figure 2. The Sa02 preocclusion during room air breathing was 94.8 ± 0.47%. The Sa02 preocclusion in the hyperoxic condition was 98010 by study design. The nadir in the Sa02 after mask occlusion in the room air condition was 87.9 ± 3.9% . The Sa02 remained above 96% after hyperoxic occlusions. The end-tidal Pco, values preceding mask occlusion in the room air and hyperoxic conditions were 45.5 ± 1.5 and 44.9 ± 1.7mm Hg, respectively (p = NS).
TABLE 2
50
MAXIMAL PRESSURES AND RATES OF CHANGE DURING OCCLUSION"
-'
Ideal Weight
1 2 3 4 5 6
60
«
40 30
0
.... 20
w :li
....
10
•
~ ROOM AIR
•
O X YG E N
Fig . 2. The mean time to arousal during mask ocelusion for each subject in the room air and hyperoxic conditions. The closed circles are the group means. The time to arousal was significantly longer during oxygen breathing (p < 0.002).
A typical polygraph tracing for a hyperoxic occlusion trial is shown in figure 3. There was a progressive rise in the maximal supraglottic pressure swings until arousal occurred. The maximal supraglottic pressure deflections on the initial occluded breath (PI) did not differ in the hyperoxic and room air conditions (table 2). The maximal supraglottic pressure preceding arousal (PF) in the room air and hyperoxic conditions were very similar in all subjects (figure 4), and the means for the group were essentially identical (table 2). In contrast, the rate of increase in maximal suction pressure with time (~Pmax/T) was lower in the
C, - A,
°2-"" LOC-A , ROC - AI C PII" EM G End T ld, 1
PC0 2
E' G
T i dl l
i\J\J ;:~:" ':"":" '" ''' ~ ~'.'.~
~tf~1
1"'''1
' :: :~
fOCc ,u" on JI..-/1L
~
Fig . 3. A polygraph tracing showing a hyperoxic occlusion trial . The peak supraglottic pressure increased progressively with each inspiratory effort until arousal occurred . Oxygen desaturation did not occur.
Vol u me
Su tHlglo ll ic p' •• s ur. ( cmH 20)
---.!..e.-'--
51 °
_
2
eo W
a:
:>
PI) were due to a higher mean rate of inspiratory pressure generation during the final inspiratory effort. In our study, determination of the Pco, at the time of arousal was not possible because of our noninvasive methods. Subjects invariably inspired deeply the moment the mask occlusion was released, altering the end-tidal Pco. . The Pco, at arousal during hyperoxic occlusions may
TABLE 3 DURATION AND RATE OF PRESSURE GENERATION OF OCCLUDED EFFORTS' Room Air Til , s
T1F, s PIITII, cm H20/s PFITIF. cm H20/s
1.42 1.40 9.2 19.6
± ± ± ±
Oxygen
1.44 1.40 9.8 19.6
0.11 0.11 0.79 1.65t
De/inltlon a/abbreviations : Til, T'F = initial, final inspi ratory time; PI, PF tion pressure. • Values are means ± SEM. t Initial versus final occluded breath; p < 0.001.
~
± ± ± ±
0.11 0.07 0.93 1.91t
initial, final maximal suc-
Stage 3-4 rather than Stage 2 sleep. It was thought that awakening (one or more epochs of Stage wake) would be lesslikely to occur from the deeper sleep stages. We found that if airway occlusion was quickly released at the first EEG and EMG sign of arousal that the subjects usually returned quickly to deep sleep. This allowed a large number of occlusion trials in a short period of time. The results of our study differ from work by Baker and coworkers (22) in newborn lambs. They found that hyperoxia prolonged the time to arousal in active sleep (rapid eye movement sleep) but not in quiet sleep (NREM sleep). This difference is most likely due to a species difference. For example, in their study arousal after airway occlusion was prolonged in REM compared with that in NREM sleep. However, in normal humans, mask occlusion results in much more rapid arousal from REM than from NREM sleep (14). In addition, our results are consistent with studies of oxygen breathing in patients with obstructive sleep apnea (11-13). In most but not all studies, oxygen administration results in a prolongation in apnea duration. In patients with the obstructive sleep apnea syndrome, analysis of the effects of oxygen breathing on apnea duration is more complicated because oxygen breathing may affect the preapnea Pco, by reducing the ventilatory drive in the postapneic ventilation phase. This tends to increase the preapnea Pco; A low preapnea Pco, may abolish or decrease the initial occluded inspiratory efforts (23). For example, oxygenbreathing tends to convert mixed apneas to obstructive apneas (24). A higher preapnea Pco, during oxygen breathing could potentially shorten apnea duration. In our study, the oxygen breathing did not decrease the preocclusion Pco., and this did not complicate the analysis. In summary, our findings document that oxygen administration decreases the respiratory response to airway occlusion such that the time to arousal after airway occlusion is prolonged. In addition, this study provides data consistent with a model of arousal from airway occlusion in which changes in POz affect the time course of the increase in inspiratory effort but not the level of effort (threshold) needed to induce arousal. References 1. Guilleminault C, Rosekind M. The arousal
threshold : sleep deprivation, sleep fragmentation, and obstructive sleep apnea syndrome. Bull Eur Physiopathol Respir 1981; 17:341-9.
334
2. RemmersJE, Degroot WJ, Sauerland EK, Anch AM. Pathogenesis of upper airway occlusion during sleep. J Appl Physiol 1978; 44:931-8. 3. Phillipson EA, Sullivan CEoArousal: the forgotten response to respiratory stimuli. Am Rev Respir Dis 1978; 118:807-9. 4. West P, Kryger MH. Sleep and respiration: terminology and methodology. In: Kryger MH, ed. Clinics in chest medicine: sleep disorders. Philadelphia: WB Saunders, 1985; 692. 5. Phillipson EA, Sullivan CEo Ventilatory and arousal responses to hypoxia in sleeping humans. Am Rev Respir Dis 1982; 125:632-9. 6. Berthon-Jones M, Sullivan CEo Ventilation and arousal responses to hypercapnia in normal sleeping humans. J Appl Physiol 1984; 57:59-67. 7. Douglas NJ, White D, Weil JV, Pickett CK, Zwillich CWo Hypercapnic ventilatory response in sleeping adults. Am Rev Respir Dis 1982; 126: 758-62. 8. Gleeson K, Zwillich CW, White DP. Arousal from sleep in response to ventilatory stimuli occurs at a similar degreeof ventilatory effort irrespective of the stimulus. Am Rev Respir Dis 1989; 142:295-300. 9. Vincken W, Guilleminault C, Silvestri L, Cosio M, Grassino A. Inspiratory muscle activity as a trigger causing the airways to open in obstructive
BERRY AND LIGHT
sleep apnea. Am Rev Respir Dis 1987; 135:372-7. 10. Wilcox PG, Pare PD, Road JD, Fleetham J A. Respiratory muscle function during obstructive sleep apnea. Am Rev Respir Dis 1990; 142:533-9. 11. Motta J, Guilleminault C. Effects of oxygen administration in sleep induced apnea. In: Guilleminault C, Dement WC, eds. Sleep apnea syndromes. New York: Alan R. Liss, 1978; 137-44. 12. Martin RJ, Sanders MH, Gray BA, Pennock BE. Acute and long-term ventilatory effects of hyperoxia in the adult sleep apnea syndrome. Am Rev Respir Dis 1982; 125:175-80. 13. Gold AR, Schwartz AR, Bleecker ER, Smith PL. The effect of chronic nocturnal oxygenadministration upon sleep apnea. Am Rev Respir Dis 1986; 134:925-9. 14. Issa FG, Sullivan CEoArousal and breathing responses to airway occlusion in healthy sleeping adults. J Appl Physiol 1983; 55:1113-9. 15. Rechtschaffen A, Kales A. A manual of standardized terminology, techniques, and scoring system for sleep stages in human adults. Los Angeles: Brain Information Service/Brain Research Institute, University of California, Los Angeles, 1968. 16. Hudgel DW, Martin RJ, Johnson B, Hill P. Mechanics of the respiratory system and breathing pattern during sleep in normal humans. J Appl Physiol 1984; 56:133-7.
17. Ott L. An introduction to statistical methods and data analysis. Boston: Duxbury, 1984; 166-7. 18. Keppel G. Design and analysis. Englewood Cliffs: Prentice Hall, 1982. 19. Russell RM, McGandy RB, Jelliffe D. Reference Weights. Am J Med 1984; 76:767-9. 20. McNicholas WT, Coffey M, McDonnell T, O'Reagan R, Fitzgerald MX. Upper airway obstruction during sleep in normal subjects after selective topical oropharyngeal anesthesia. Am Res Respir Dis 1987; 135:1316-9. 21. Basner R, Ringler J, Garpestad E, Schwartzstein R, Weinberger S, Weiss JW. Upper airway anesthesia prolongs the time to arousal from airway occlusion induced during NREM sleep (abstract). Am Rev Respir Dis 1990; 141:AI27. 22. Baker SB, FewellJE. Effects of hyperoxia on the arousal response to upper airway obstruction in lambs. Pediatr Res 1987; 21:116-20. 23. Iber C, Davies SF, Chapman RC, Mahowald MM. A possible mechanism for mixed apnea in obstructive sleep apnea. Chest 1986; 89:800-5. ·24. Gold AR, BleeckerER, Smith PL. A shift from central and mixed sleep apnea to obstructive sleep apnea resulting from low-flow oxygen. Am Rev Respir Dis 1985; 132:220-3.
RICHARD B. BERRY and RICHARD W. LIGHT
Introduction
T he termination of obstructive apnea in the obstructive sleep apnea syndrome is believed to depend largely on arousal (1-3).Arousal can be defined as an abrupt increase in the frequency of electroencephalogram (EEG) activity and a simultaneous increase in the amplitude of the chin electromyographic (EMG) activity (4). Evidence of arousal usually precedes or coincides with the preferential increase in upper airway tone that restores airway patency and terminates the obstructive apnea (2). The precise events leading to arousal and apnea termination are still not well understood. Central nervous systemstimulation from a decrease in POl' an increase in Pco., and sensations of inspiring against an occluded airway appear to interact to produce arousal and apnea termination (5-10). Recent evidence suggests that the level of inspiratory effort may be the most important factor producing arousal from sleep (8-10). Gleeson and coworkers (8) have recently shown that the maximal negative esophageal pressure deflection preceding arousal from sleep in a given normal subject is similar whether arousal occurs after induced hypercapnia, hypoxia, or an added resistive inspiratory load. This occurs even though the ventilatory responses to these stimuli are very different. These investigators hypothesized that arousal occurs when inspiratory effort reaches a certain arousal pressure threshold. Studies in patients with the obstructive sleep apnea syndrome have also suggested that arousal occurs when the degree of inspiratory effort reaches a certain threshold (9-10) in a given subject. The factors determining the arousal threshold are still not well defined. Oxygen administration does increase apnea duration in patients with the obstructive sleep apnea syndrome (11-13). However, it is not known if falls in POl during apnea (room air breathing) decrease the arousal threshold or simply augment the rate of increase in inspiratory effort. 330
SUMMARY The effect of hyperoxla on the arousal response to airway occlusion during non-rapid eye movement (NREM) sleep was studied In six normal male subjects with a mean age (± SO) of 23.5 ± 8.7 yr by testing the response to the occlusion of a face mask covering the nose and mouth. Occlusion trials while the subjects breathed room air (room air condition) were alternated with trials in which subjects breathed a mixture of room air and oxygen adjusted to maintain a sleeping baseline arterial oxygen saturation of 98% (hyperoxlc. condition). The time to arousal (mean ± SEM) was significantly longer during oxygen administration (41.1 ± 4.5 versus 28.9 ± 4.6 s; P < 0.002). The maximal deflections In airway pressure were measured at a supraglottic location during airway occlusion to reflect the degree of Inspiratory effort. The maximal airway suction pressure preceding arousal did not differ between the room air (27.4 ± 5.4 cm H20) and hyperoxlc conditions (26.6 ± 5.9 cm H20). Conversely, the rate of Increase In Inspiratory effort (maximal pressure) during occlusion was decreased by oxygen administration. We conclude that hyperoxla prolongs the time to arousal after airway occlusion by decreasing the rate of Increase In the magnitude of Inspiratory AM REV RESPIR DIS 1992; 146:330-334 efforts, but it does not change the arousal threshold.
The effect of oxygen administration on the time to arousal or arousal threshold after mask occlusion in normal subjects is not known. During mask occlusion, such subjects exhibit increases in inspiratory effort until arousal occurs (14). We hypothesized that oxygen administration should prolong the time to arousal. Furthermore, on the basis of the work of Gleeson and coworkers (8), we reasoned that the level of inspiratory effort at arousal should not be altered by oxygen breathing. That is, oxygen breathing should increase the time to arousal by decreasing the rate 0 f increase in inspiratory effort rather than changing the level of inspiratory effort needed to induce arousal. To test these hypotheses, we compared the respiratory and arousal responses to airway occlusion during Stage 3-4 nonrapid eyemovement (NREM) sleep while normal subjects breathed room air or a mixture of air and oxygen.
tored using two pairs of EEG leads (C4-AI, 02-AI), two pairs of electrooculographic leads, and chin EM G leads using standard methods (15). An EKG lead was monitored as well.Arterial oxygen saturation (Sao.) was continuously measured using pulse oximetry (Ohmeda 3700; Ohmeda Corp., Boulder, CO). End-tidal Pco, was recorded using a capnograph (Model 223; Puritan-Bennett, Los Angeles, CA). The mask occlusion apparatus used is depicted in figure I. A face mask covering the nose and mouth was "glued" to the subjects using a medical grade silicone elastomer (Factor II, Lakeside, AZ) and held in place by head straps. A leak detector consisted of a length of plastic tubing containing multiple small holes that surrounded the mask at the mask-face interface. This tubing was connected to another CO 2 monitor (No. 7500; Marquette, Milwaukee,WI). Small mask leaks could be detected as a nonzero reading on the CO 2 monitor. The face mask contained separate inspiratory and expiratory ports. The expiratory port was fitted with a one-way valve.
Methods Six normal male subjects were studied. The subjects were of normal body weight and did not have a history of snoring or daytime sleepiness. Written informed consent was obtained from all subjects prior to their participation in the study. The project was approved by the Institution Review Board of our hospital. The presence and stage of sleep were moni-
(Received in original form June 20, 1991 and in revised form November 15, 1991) 1 From the Pulmonary Section, Long Beach Veterans Administration Center, and the University of California, Irvine, Long Beach, California. 2 Correspondence and requests for reprints should be addressed to Richard B. Berry, M.D., Pulmonary Section 111 P, Long Beach VAMedical Center, 5901 East 7th Street, Long Beach, CA 90822.
HYPEROXIA AND AROUSAL FROM SLEEP
331
arousal was defined as an increase in the EEG frequency with the appearance of alpha waves and a simultaneous increase in the EMG amplitude (4). Such arousals were invariably associated with an abrupt change in the supraglottic pressure.
Fig. 1. The mask occlusion apparatus used.Thebiasflowwasventedfromthe systemat the time of valveocclusion by removing the stopper.
The inspiratory port did not contain a oneway valve and was connected to six feet of low compliance respiratory tubing that passed through the wall of the subject's room into the monitoring room . The tubing was connected to an occlusion apparatus allowing inspiration of room air through a one-wayvalve unless a balloon was inflated (figure I). Even though the occlusion valvewas separated from the mask by tubing, during occlusion no inspiration was possible because of the lowcompliance of the tubing. A small amount of bias flow consisting of either 4 to 5 L/min of oxygen or medical grade air was infused into the occlusion apparatus at a site proximal to the occlusion valve. Because of the one-way valve in the occlusion apparatus, this flow was directed out through the mask expiratory valve. At the time of balloon occlusion the bias flow was vented by removing a stopper. The flow rate of oxygen was chosen to maintain an arterial oxygen saturation of 98070. The bias flow prevented rebreathing of COl' The subjects' exhaled air was sampled at the nostrils using a small nasal cannula to determine the end tidal Pco., A pneumotachometer measured the flow rate of gas entering the inspiratory limb of the apparatus exclusive of the bias flow. The flow rate was integrated to obtain volume. The flow rate and volume provided qualitative estimates of the actual inspired flow and volume and were used to ensure a regular pattern of ventilation prior to occlusion trials . The level of inspiratory effort was monitored by measuring airway suction pressure in a supraglottic location. Before the mask was attached to each subjects' face, a 5 Fr catheter with a pressure transducer tip (Millar, Houston, TX) was inserted through one nos-
Data Analysis The time to arousal (ITA) after mask occlusion, the Sao, and the end-tidal Pco, preceding occlusion, and the nadir in arterial oxygen saturation after occlusion (room air condition only) were noted . Desaturation did not occur during hyperoxic trials. The time to arousal was measured from the start of the initial occluded inspiration to EEG and EMG evidence of arousal. The airway pressure (supraglottic pressure) during occlusion was analyzed in the following manner. The maximal negative pressure deflection of the initial inspiratory effort (PI) and the final complete effort preceding arousal (PF) weremeasured. A complete effort was one in which arousal did not occur before a definite maximal pressure had been obtained. The difference in the initial and final maximal pressures (APmax = PF - PI) was calculated. A mean slope of maximal pressure deflection (APmax/T) was determined by dividing APmax by the elapsed time between tril after minimal topical anesthesia with 10J0 the maximal pressure deflections on the inilidocaine was administered to one nasal pas- . tial and final efforts (T). The APmax/T was further analyzed by facsage and the upper airway. The catheter tip was placed 16 to 18 em from the nares, and toring this variable into the product of in this location it was in a supraglottic posi(APmax/#) and (#/T), where # is the numtion (16). The catheter was calibrated before ber of occluded inspiratory efforts after the insertion into the subjects by applying a nega- initial effort prior to arousal. The (APmax/#) is the mean increase in the maximal suction tive pressure to a small chamber in which the pressure per breath, and the (#/T) is the rate catheter was inserted. The chamber was connected to a water manometer. Under condiof occluded efforts (numberls). In this way tions of no flow (mask occlusion), changes it can be seen that APmax/T could vary bein the supraglottic pressure equal changes in cause of changes in the mean progressive rise in suction pressure with each succeeding inpleural (and esophageal) pressure. spiratory effort or changes in the frequency All variables wererecorded on a I2-channel of occluded efforts. Grass 78D polygraph (Grass Instruments, Quincy, MA) using a paper speed of 10mm/s . The mean values of the TTA, preocclusion A near infrared camera and video monitor end-tidal Peo l, PI, PF, APmax/T, APmax/#, system allowed continuous visual inspection and #/T for each patient were compared between the room air and hyperoxic conditions of the subjects . using the paired t test (17). A P < 0.05 was Airway Occlusion Procedure considered to show statistical significance. The inspiratory airway was closed during exThe duration of respiratory efforts during piration in stable Stage 3-4 NREM sleep from mask occlusion was analyzed as follows. The six to I3 times during both room air and oxy- inspiratory time (Tr) was defined as the time gen breathing. The mean (± SD) number of from the start of the supraglottic pressure occlusions during room air breathing was 8.8 deflection to the maximal negative deflection. ± 2.8, and during oxygen breathing it was The Tr of the initial and final pressure deflec8.3 ± 2.3. Room air and hyperoxic occlusion tions (Trl and 'llF) werecompared using analysisof variance for repeated measures (BMDP trials were alternated and the order was randomized . Subjects wererequired to have been program P2Y) with room air versus the hyperoxic conditions and time (initial versus in a stable stage of sleep without arousals for final) as within-subjects factors (18). The at least 3 min before mask occlusion was inimean rate of pressure generation on the first tiated. Oxygen was administered for at least three min before hyperoxic occlusions were and final respiratory efforts were computed performed. :Before all occlusion trials, the as (PI/'llI) and (PF/'llF) and compared in a breathing pattern was acquired to be regular, similar manner. and the end-tidal Pco, and the Sao, were required to be stable. The occlusion was quickResults ly terminated when there was evidence of The subject characteristics are listed in arousal from the EEG and EMG tracings. An
332
BERRY AND LIGHT
TABLE 1 SUBJECT CHARACTERISTICS Subject No.
Age
(yT)
Height (inches)
Weight (/bs)
-e:
U)
(%)
::> 0
a:
22 41 18 21 18 21
76 70 68 69 69 69.5
225 155 143 175 165 135
125 .7 100.0 96 .0 115.1 108.6 87.9
Mean SO
23 .5 8.7
70 .3 2.9
166.3 32 .2
105.5 13.7
table 1. Body weight is expressed both in absolute terms and as a percentage of ideal body weight (19). The time to arousal in the hyperoxic condition (mean ± SEM) was significantly greater for the group (41.1 ± 4.5 versus 28.9 ± 4.6 s; p < 0.002). The means for the individual subjects are shown in figure 2. The Sa02 preocclusion during room air breathing was 94.8 ± 0.47%. The Sa02 preocclusion in the hyperoxic condition was 98010 by study design. The nadir in the Sa02 after mask occlusion in the room air condition was 87.9 ± 3.9% . The Sa02 remained above 96% after hyperoxic occlusions. The end-tidal Pco, values preceding mask occlusion in the room air and hyperoxic conditions were 45.5 ± 1.5 and 44.9 ± 1.7mm Hg, respectively (p = NS).
TABLE 2
50
MAXIMAL PRESSURES AND RATES OF CHANGE DURING OCCLUSION"
-'
Ideal Weight
1 2 3 4 5 6
60
«
40 30
0
.... 20
w :li
....
10
•
~ ROOM AIR
•
O X YG E N
Fig . 2. The mean time to arousal during mask ocelusion for each subject in the room air and hyperoxic conditions. The closed circles are the group means. The time to arousal was significantly longer during oxygen breathing (p < 0.002).
A typical polygraph tracing for a hyperoxic occlusion trial is shown in figure 3. There was a progressive rise in the maximal supraglottic pressure swings until arousal occurred. The maximal supraglottic pressure deflections on the initial occluded breath (PI) did not differ in the hyperoxic and room air conditions (table 2). The maximal supraglottic pressure preceding arousal (PF) in the room air and hyperoxic conditions were very similar in all subjects (figure 4), and the means for the group were essentially identical (table 2). In contrast, the rate of increase in maximal suction pressure with time (~Pmax/T) was lower in the
C, - A,
°2-"" LOC-A , ROC - AI C PII" EM G End T ld, 1
PC0 2
E' G
T i dl l
i\J\J ;:~:" ':"":" '" ''' ~ ~'.'.~
~tf~1
1"'''1
' :: :~
fOCc ,u" on JI..-/1L
~
Fig . 3. A polygraph tracing showing a hyperoxic occlusion trial . The peak supraglottic pressure increased progressively with each inspiratory effort until arousal occurred . Oxygen desaturation did not occur.
Vol u me
Su tHlglo ll ic p' •• s ur. ( cmH 20)
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PI) were due to a higher mean rate of inspiratory pressure generation during the final inspiratory effort. In our study, determination of the Pco, at the time of arousal was not possible because of our noninvasive methods. Subjects invariably inspired deeply the moment the mask occlusion was released, altering the end-tidal Pco. . The Pco, at arousal during hyperoxic occlusions may
TABLE 3 DURATION AND RATE OF PRESSURE GENERATION OF OCCLUDED EFFORTS' Room Air Til , s
T1F, s PIITII, cm H20/s PFITIF. cm H20/s
1.42 1.40 9.2 19.6
± ± ± ±
Oxygen
1.44 1.40 9.8 19.6
0.11 0.11 0.79 1.65t
De/inltlon a/abbreviations : Til, T'F = initial, final inspi ratory time; PI, PF tion pressure. • Values are means ± SEM. t Initial versus final occluded breath; p < 0.001.
~
± ± ± ±
0.11 0.07 0.93 1.91t
initial, final maximal suc-
Stage 3-4 rather than Stage 2 sleep. It was thought that awakening (one or more epochs of Stage wake) would be lesslikely to occur from the deeper sleep stages. We found that if airway occlusion was quickly released at the first EEG and EMG sign of arousal that the subjects usually returned quickly to deep sleep. This allowed a large number of occlusion trials in a short period of time. The results of our study differ from work by Baker and coworkers (22) in newborn lambs. They found that hyperoxia prolonged the time to arousal in active sleep (rapid eye movement sleep) but not in quiet sleep (NREM sleep). This difference is most likely due to a species difference. For example, in their study arousal after airway occlusion was prolonged in REM compared with that in NREM sleep. However, in normal humans, mask occlusion results in much more rapid arousal from REM than from NREM sleep (14). In addition, our results are consistent with studies of oxygen breathing in patients with obstructive sleep apnea (11-13). In most but not all studies, oxygen administration results in a prolongation in apnea duration. In patients with the obstructive sleep apnea syndrome, analysis of the effects of oxygen breathing on apnea duration is more complicated because oxygen breathing may affect the preapnea Pco, by reducing the ventilatory drive in the postapneic ventilation phase. This tends to increase the preapnea Pco; A low preapnea Pco, may abolish or decrease the initial occluded inspiratory efforts (23). For example, oxygenbreathing tends to convert mixed apneas to obstructive apneas (24). A higher preapnea Pco, during oxygen breathing could potentially shorten apnea duration. In our study, the oxygen breathing did not decrease the preocclusion Pco., and this did not complicate the analysis. In summary, our findings document that oxygen administration decreases the respiratory response to airway occlusion such that the time to arousal after airway occlusion is prolonged. In addition, this study provides data consistent with a model of arousal from airway occlusion in which changes in POz affect the time course of the increase in inspiratory effort but not the level of effort (threshold) needed to induce arousal. References 1. Guilleminault C, Rosekind M. The arousal
threshold : sleep deprivation, sleep fragmentation, and obstructive sleep apnea syndrome. Bull Eur Physiopathol Respir 1981; 17:341-9.
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