Upper airway stability and apnea during nasal occlusion in newborn

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Jun 10, 1985 - BROUILLETTE,. R. T., AND B. T. THACH. A neuromuscular mecha- nism maintaining extrathoracic airway patency. J. Appl. Physiol. 46:772-779 ...
Upper airway stability and apnea during nasal occlusion in newborn infants GARY COHEN AND DAVID J. HENDERSON-SMART Department of Perinatal Medicine, Royal Prince Alfred Hospital, Sydney 2050, Australia

COHEN, GARY, AND DAVID J. HENDERSON-SMART. Upper airway stability and apnea during nasal occlusion in newborn infants. J. Appl. Physiol. 60(5): 1511-1517, 1986.-Brief endexpiratory airway occlusions were performed in 22 preterm babies, 17 with and 5 without clinical apnea, and 4 full-term babies, 1 with Pierre-Robin syndrome. Airway stability was evaluated by comparing pressures measured simultaneously in the chest and nasal passages during occluded inspiratory efforts. The airway remained patent throughout all 301 trials in 20 babies during rapid-eye-movement (REM) and quiet sleep. Airway closure occurred during 31/102 trials in 6 babies (5 preterm and 1 term with Pierre-Robin syndrome), more commonly in quiet than in REM sleep. Overall and within individuals, mean closing pressures were significantly lower than the mean maximum falls in airway pressure recorded during occlusions without closure. Mixed-obstructive and obstructive apnea was significantly more frequent in babies with airway closure than in those without (5.3 t 4.0 vs. 0.4 t 0.8 episodes/h). Pauses in breathing 33 s occurred during 28% of occlusions in preterm infants and 2% of occlusions in full-term babies. There was no significant difference between the mean frequency of pauses during occlusion and during the preceding control period or in the incidence of pauses in occlusions with vs. those without closure. It is concluded that the airway of most preterm and full-term babies is remarkably stable under load. Intermittent closure occurs in certain infants and may be related to airway muscle dysfunction.

closure during occluded breathing occurred in most babies examined, although it occurred more frequently in infants with Pierre-Robin syndrome (17). The stability of the airway of preterm infants has not yet been studied in detail. It is of particular interest in view of the frequency of spontaneous airway obstruction during apnea in these babies (7). We have studied aspects of the response to brief airway occlusion of preterm as well as full-term babies, including some babies with clinical apnea. The aim of this study was to evaluate how well airway patency was maintained throughout occluded breathing in different sleep states, to examine the relationship between airflow obstruction and ensuing central apnea, and to correlate our observations with the clinical histories of the babies. A preliminary report of this work has appeared (5). MATERIALS

AND METHODS

Subjects. Twenty-two preterm and four full-term babies were studied (15 males and 11 females). Preterm babies were born at gestations of between 25 and 34 wk (30 t 2 wk, mean t SD) and studied 3-105 days after birth, at corrected postmenstrual ages of 30-44 wk (34 t 3 wk). The four full-term babies were studied between 4 and 8 days postnatally. Seventeen of the preterm basleep state; preterm babies; airway closure; endotracheal intubies had episodes of clinical apnea on or within a day of bation study (pauses in breathing ~20 s or shorter pauses if associated with bradycardia), and four were receiving theophylline, a respiratory stimulant. Intracranial hemorSOME AIRWAY OBSTRUCTION occurs during more than rhage was diagnosed in five infants, and nine had been half of all apneas recorded polygraphically in preterm intubated for >3 days for the management of respirainfants (7). It is thought to be an important factor in tory failure. Three infants still required supplementary prolonging apneic spells and exacerbating hypoxemia in O2 (23-26s) delivered by a headbox at the time of study. these babies (23). Obstruction in infants usually occurs One of the full-term babies studied had Pierre-Robin in the upper (pharyngeal) airway (13). The pharynx is syndrome. These studies were approved by the ethics also thought to be the chief site of obstruction in adults review committee of this institution and were carried with obstructive sleep apnea (8). Airway closure can be out with the consent of the parents and the attending produced experimentally in these adults during brief physician. airway occlusions. It can be detected by mismatching of Studies. Studies were conducted between mid-morning pressure changes recorded in the chest and the nasal and midafternoon as the babies slept in Isolettes or open passagesduring occluded inspiratory efforts and suggests cribs. Babies were generally positioned so that they lay that the airway of such people is intrinsically unstable prone with the head turned to the left or right but neither during sleep (22). flexed nor extended. The Pierre-Robin infant was studThe occlusion technique has also been adapted to ied in the supine position. The electroencephalogram (EEG, parietal eminence to evaluate upper airway stability in babies. A study of normal and micrognathic (Pierre-Robin syndrome) full- mastoid process), eye movements (recorded using a pieterm babies found evidence suggesting that some airway zoelectric crystal taped over the eyelid), submental elec0161-7567/86 $1.50 Copyright

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tromyogram, and chest wall movements (from a strain interval between successive breaths was measured begauge around the chest) were recorded for all subjects. tween peaks in the inspiratory mask pressure. The numRapid-eye-movement (REM) sleep was defined as the ber of pauses 23 s occurring prior to the start of the presence of eye and body movements and irregular res- occlusion was also counted. The start of the occlusion piratory efforts and quiet sleep as a trace alternant EEG, was taken to be the start of the first occluded effort, and regular respiratory pattern, and the absence of eye and the length of the preocclusion control period in which body movements except for brief startles. The electroapnea was assessedwas twice that of the subsequent cardiogram was recorded continuously and displayed as occlusion. The frequency of respiratory pauses during a rate. Esophageal pressure was recorded from a saline- occlusion (no. of pauses/no. of occlusions) and the frefilled tube (size 5-F in the preterm babies and 8-F in the quency in the preocclusion period [no. of pauses/(no. of full-term infants) lying in the lower esophagus and con- occlusions x Z)] was calculated for each infant, and nected to a Bentley pressure transducer. The tube was expressed as pauses per occlusion period. flushed periodically to ensure pressure changes were Statistical analysis of the results was undertaken using faithfully recorded. Student’s t test for unpaired observations and x2 analysis Experimental airway occlusions were performed while with Yates correction as appropriate. the baby was breathing through a low-dead-space (-1 ml) mask. The mask was moulded in fiberglass from an RESULTS impression of the infant’s nose and consisted of a flange There was some variation both in the number of occlucovering the nose and upper lip and a short piece of Plexiglas tubing (ID 6 mm) attached horizontally under sions performed during each study (mean 15 t 5, range the apex of the nose in line with the nares. Two holes 6-26) and the length of the occlusion (mean 13.0 t 4.5 s, range 3-26 s). In total, 403 occlusions were performed drilled in line with the nares allowed the baby to breathe during 27 studies of 26 babies, 206 in REM, 158 in quiet, freely through the tubing. Airflow during tidal breathing and 39 during indeterminate sleep. Occlusions during was detect.ed using a thermistor. To ensure an airtight seal the mask was attached to the nose and upper lip which the airway remained patent throughout were classified “typical”; those in which airway closure occurred using a rapidly curing adhesive polymer (Elastomere, Dow-Corning). Airway occlusion was performed man- on at least one occluded breath were classified “atypical.” 7’ypical response. In the majority of trials (372 of 403, ually by blocking both ends of this tube at end expiration, and the resulting changes in airway pressure were mea- 92%) and in the majority of babies (3 term and 17 preterm) pressure changes recorded simultaneously in sured directly from the mask using a second Bentley pressure transducer. Care was taken to ensure that an the esophagus and nasal passagesduring occluded efforts oral airway was not established during this maneuver by were similar; no evidence of airway closure was found. gently elevating the jaw when necessary. Leaks in the Maximum falls in airway pressure during individual ocmask were considered to be absent during the occlusion clusions ranged from -7 to -60 cmH20 (mean -23.5 t when esophageal and mask pressure waveforms were 9.5) (Table 1). Maximum falls in airway pressure during occlusions in REM and quiet sleep, calculated as an similar and airflow was absent. Only occlusions that commenced at end expiration, as judged by the absence overall mean for each state, were not significantly differof a positive swing in airway pressure following onset of ent (-22.5 t 9.0 vs. -24.0 t 9.0, respectively). There the occlusion, were analyzed. All variables were recorded were qualitative differences in the rate and depth of on paper using a Grass 16-channel recorder at speeds of inspiratory efforts during occlusions in different sleep states (see Figs. 1 and 2), but this difference was not 2.5-10 mm/s. Records were analyzed to determine the incidence of analyzed in detail. Atypical response. Airway closure was detected by the apnea of 10 s or more duration during the study period. failure of pressure changes in the chest to register in the Airflow, esophageal pressure, and chest wall movement traces were examined for each episode, and the apnea mask beyond a certain point, resulting in a plateau in mask pressure. Closure occurred in 5 preterm infants was classified as central (no breathing efforts), mixedcentral (predominately central but with one or more and 1 full-term infant with Pierre-Robin syndrome, during 31 (30%) of 102 occlusions. The pattern of closure obstructed breaths), mixed-obstructive (a small central component but predominately obstructed efforts), or ob- was exclusively intermittent (repeated inspiratory plateaus in mask pressure with airway reopening during the structive (no central component, entirely obstructed). Obstructed breaths were inspiratory efforts without air- expiratory phase, Fig. 3) in two infants (1 term and 1 flow. Episodes of vigorous wriggling, when the traces preterm) but predominately sustained (nasal pressure could not be accurately evaluated, were not analyzed. For plateaus maintained without airway reopening between each baby, tallies were made of the number of apneas breaths, Fig. 4) in the remaining four subjects. Closure that were predominately central (central + mixed-cenwas more common during occlusions conducted in quiet tral) and predominately obstructive (mixed-obstructive sleep than in REM sleep (19/45 vs. 8/45; P < 0.05). + obstructive), and these were expressed as rates per There was no difference between the mean number of hour by correcting for recording time. occlusion trials performed on babies with an atypical and The frequency and duration of respiratory pauses dur- those with a typical response (15 in each group). ing experimental airway occlusion was determined by Airway pressure and airway patency. Closing pressures, counting all pauses 23 s between occluded breaths. The the pressure in the nasal passages(mask) at which airway

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FIG. 1. Nasal mask occlusion in a baby of 33 wk postmenstrual age during quiet sleep (note trace alternant EEG). Onset of occlusion is indicated by cessation of airflow and fall in mask pressure. Note progressive increase in inspiratory pressures and similarity of pressure waves recorded in esophagus and mask, indicative of airway patency. There is a brief apnea between 1st and 2nd occluded breaths.

closure occurred, were tabulated for each of 196 such breaths, and expressed as a mean closing pressure (&SD) for each of the 6 babies in this group (Table l), and as an overall mean. Closing pressure was consistently and significantly lower than the maximum fall in airway pressure during each of the 372 typical occlusions, both when mean pressures overall were considered (-9.5 t 5.0 vs. -23.5 t 9.5 cmH,O; P < 0.001) and when comparisons were made in the 5 of the 6 babies individually (there were no occlusions without closure in the baby with Pierre-Robin syndrome) (Table 1). Airway stability and spontaneous apnea. The incidence of different types of apnea during the study periods, corrected for recording time, are listed for each baby in Table 1. There was no significant difference between the mean rate of predominately central apnea in babies with airway closure and those without observed closure (5.8 t 6.0 vs. 2.4 t 3.0 episodes/h; P < 0.5). The mean rate of apnea with a predominant obstructive component was significantly greater in babies with airway closure during occlusion than in those without (5.3 zk 4.0 vs. 0.4 t 0.8 episodes/h; P < 0.02). Respiratory pauses during airway occlusion. Pauses 23 s occurred during 100 occlusions, 99 in the preterm infants (28% of 354 trials) and 1 in the full-term babies (2% of 49 trials). The rate of such pauses during airway occlusion, calculated as a mean of the rates for individual babies, was the same as the rate of pauses in the preoc-

elusion control period (0.3 vs. 0.3 apneas/occlusion period). Brief pauses occurred in a similar proportion of occlusions with and without airway closure (23 and 25%, respectively). Occlusions with an intervening pause in breathing efforts were twice as frequent in preterms with than in those without clinical apnea (31% of 287 trials vs. 15% of 67 trials; P < 0.02) and were relatively more frequent in REM than in quiet sleep (33% of REM trials vs. 22% of quiet sleep trials; P C 0.05). Pauses were slightly longer in the clinically apneic than the clinically nonapneic babies (4.7 t 1.9 vs. 3.8 zlt:0.8 s, range 3-9 s; P c 0.01). DISCUSSION

The principal finding of this study has been that the airway of most preterm and full-term babies examined remained patent during occluded inspiratory efforts, even though airway pressure fell substantially. This contrasts with postmortem observations in babies showing that even slight negative pressure can cause airway closure (25). Animal studies demonstrate that airway stability is due largely to the action of upper airway muscles (2). These muscles splint the airway and resist the constricting effects of negative airway pressure. We have shown that the airway of neonates breathing spontaneously is considerably more stable than postmortem studies suggest, implying that neuromuscular mechanisms also contribute substantially to airway stability in

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sleep occlusion in same baby as in Fig. 1 (note eye movements). Breathing efforts and mask pressures are identical; airway is therefore patent throughout occlusion.

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5 set 3. Example of intermittent airway closure during occluded breathing in a baby of 44 wk postmenstrual age who had a history of obstructive apnea. Mask and esophageal pressures are equal on 1st occluded breath, but subsequently mask pressure plateaus despite falling esophageal pressure, indicating airway closure has occurred. Note that airway reopens during expiration. FIG.

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FIG. 4. Example of sustained airway closure during occlusion. Baby of 34 wk postmenstrual age also with a history of obstructive apnea. Airway closure occurs on 1st occluded breath and remains closed for a number of consecutive breaths. Airway reopens briefly during a short apnea but closes again when breathing efforts resume. Small decrements in mask pressure are associated with each inspiratory effort, presumably reflecting effect of intrathoracic pressure changes on compliant upper airway.

TABLE 1. Summary of airway pressure measurements and frequency of apnea in individual babies

Subj Preterm

co* GY*

KE ST MC*

Rate of Central and Mixed-Central Apnea, episodes/h

Rate of Obstructive and Mixed-Obstructive Apnea, episodes/h

infants

EA RI PR* JS* Ls* FA* sP* GO* MI GU* DU HO* cu* ML PE* HI* JA* ON* WR” RI* Study 1 Study 2

Full-term WY

Mean Airway Closing Pressure, cmHzO

Mean Maximum Airway Pressure, cmHzO

-18.2t3.9 -3O.Ot5.8 -15.9t2.5 -13.2t3.6 -17.3t3.3 -17.8t5.0 -17.0t5.6 -34.8t6.4 -22.6t3.3 -21.526.7 -20.8t5.3 -22.2t4.8 -34.729.6 -33.9k8.9 -20.9t5.3 -23.1t7.0 -18.6t5.2 -21.8k3.7 -2O.Ot5.0 -33.3tll.O -3o.ot9.9 -13.3t4.7 -21.5 (n = 1)

infants

-6.8+1.6”f -8.8+2.2-f-8.3+5.4? -15.4+5.8$ -3.8+0.4-t -12.5t5.4

-

-29.6t5.6

-7.ot2.9

-37.228.0 -24.2t4.7 -

Pressure measurements are means t SD. Mean occlusions without closure. Mean airway closing t P < 0.001. $ P < 0.01.

-

maximum pressure

airway pressure calculated from

4.0 0.7 3.1 3.0 3.7 14.5 1.8 0.3 0.0 0.6 1.3 5.3 0.8 1.0 0.2 2.8 0.9 1.6 1.8 14.0 14.0 6.9 2.0

0.0 0.0 1.3 0.4 0.0 0.5 0.2 0.0 0.0 0.0 1.0 0.3 0.0 0.0 2.7 0.0 0.2 1.6 6.4 9.6 11.3 4.9 1.0

2.6 1.0 1.5 0.0

0.0

0.8 0.0 2.3

calculated from the most negative mask pressure during individual all occluded breaths with closure. * Babies with clinical apnea.

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babies. In babies, as in adults, motoneuron excitability is reduced during REM sleep. This is generally evident as a loss of skeletal muscle tone. In REM sleep in adults the respiratory activity of some upper airway muscles during quiet breathing disappears (18), implying that these muscles are also less active and that there may be some loss of airway stability. In fact we measured a similar range of transmural pressures in REM and quiet sleep but found no differences in airway stability in the majority of subjects. This suggests that the stabilizing action of upper airway muscles is preserved during REM sleep in the preterm and full-term newborn, even though the reflex excitation of other muscles is often depressed (19) Airway closure of the sort we have occasionally detected during occlusions in six infants has also been reported in adult sleep apnea patients (22) and in normal and micrognathic (Pierre-Robin syndrome) full-term babies (17). We observed closure in a small number of babies (5 preterm and 1 term with Pierre-Robin syndrome) and found that these babies had significantly more spontaneous episodes of predominately obstructive apnea than those in whom closure was not detected. These findings differ somewhat from those of Roberts et al. (l7), who reported airway closure on a small number (6%) of occluded breaths in normal full-term infants who had no prior clinical history of obstructive apnea. The reason for the variation in findings is not clear. It may be related to differences in the maturity of the study groups or it may be explained by differences in occlusion technique. Roberts et al. (17) used a relatively more invasive method to measure airway pressures, and this may have influenced their observations. Although the level at which airway closure occurred was not determined in our study, the patterns we observed have generally been ascribed to events in the upper (naso- or oro-) pharynx (2, 17, 22). Closure is thought to occur when pharyngeal structures are sucked together as airway pressure falls during inspiration (8, 25). The tendency for this to occur may be accentuated by a variety of factors, some of which might contribute to the intrinsic instability we detected in certain individuals. Airway abnormalities alter the dynamics of airflow, increase the load on airway muscles, and produce airway instability in some (e.g., Pierre-Robin syndrome) babies (6, 24). Posture is important, since neck flexion during sleep accentuates airway obstruction in babies (20). We attempted to limit postural effects by studying infants in a head-neutral position (neck neither flexed nor extended). Neurological abnormalities (3,9) prolonged intubation for mechanical ventilation (3) and respiratory distress syndrome (I) are significantly correlated with a predominant pattern of mixed and obstructive apnea in preterm infants. Airway instability in these infants may reflect damage to centers within the brain influencing the activity of upper airway muscles, or it may reflect structural damage to the airway itself. Airway receptors are important in regulating the phasic activity of upper airway muscles (II), as well as other events such as the rate and

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depth of breathing (10, 12). Damage to these receptors may contribute to upper airway dysfunction by modifying certain reflexes. Changes in the quality or quantity of airway mucus may also affect airway stability either directly or by pooling at the sites of closure and making airway reopening more difficult (16). This could explain why during occlusions in some babies the airway, once closed, tended to remain so. Finally, behavioral state may have important effects on airway stability, since we observed that airway instability in infants with an atypical response to occlusion was accentuated in quiet sleep. This may be related to the dependence of the respiratory control system on autonomic drive in this state (21). Spontaneous airway obstruction in babies in whom the upper airway was judged to be stable was infrequent and generally brief; apnea was predominately central or mixed-central in these infants. Episodic airway obstruction of this sort is common during apneic spells in preterm infants (7), particularly during longer events (3). Unlike obstructive apnea it does not appear to be significantly associated with risk factors such as those discussed above. It may occur for reasons associated with the rapid increase in chemoreceptor drive occurring during the initial central component of mixed apneas. There is some evidence that in the newborn the activity of the diaphragm increases before that of the upper airway muscles in response to chemical stimulation. This might explain why the airway is often briefly obstructed as breathing efforts resume (3) a Apnea in response to occlusion. During lung function studies, Milner et al. (15) noticed that preterm babies tended to become apneic in response to airway occlusion and suggested that this might help explain the high incidence of sudden and unexpected death in preterm infants. We have shown that brief respiratory pauses do occur during nasal occlusion but that the frequency of these brief events is similar to the frequency of similar events occurring spontaneously prior to occlusion. Such pauses occurred more frequently in individuals and at times in which spontaneous respiratory irregularities are common; in preterm babies, especially those with clinical apnea, and during REM sleep. This suggests that apnea occurring during airway occlusion is not a specific response to airflow obstruction. Differences in methodology might explain the differences between our observations and those of Milner et al. The method of performing the occlusions may influence the observed response, since in babies facial (trigemminal) stimuli affect ventilation (4). In contrast to the method used in the present study, Milner et al. used a mask pressed over the nose and mouth, transmitting airway pressure during occlusion to the face. Also the preterm babies studied by Milner et al. were slightly younger than those we studied, so the response they documented may have been that of a more immature infant. The data presented in this previous study are somewhat incomplete, however, and the phenomena reported may actually have been the same as that reported here. Airway closure itself might inhibit respiratory efforts (14). During most of the occlusions in which we detected

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airway closure, breathing efforts continued without interruption, and the proportion in which brief respiratory pauses did occur (23%) was similar to that in occlusions without closure ( 25%). There would not therefore appear to be a simple relationship between the mechanical stimulus presumably arising from airway closure and en suing central apnea. This project was supported by grants from the National Health and Medical Research Council of Australia, Ramaciotti Foundation, Optical Prescription Spectacle Makers Foundation, and the Postgraduate Medical Foundation of the University of Sydney. Received

10 June 1985; accepted

in final

form

20 November

1985.

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