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American Journal of Respiratory and Critical Care Medicine Vol 166. pp. 85-91, (2002)
© 2002 American Thoracic Society

Original Article

Laryngeal Muscle Activities with Cerebral Hypoxia–Ischemia in Newborn Lambs

Alastair A. Hutchison, David J. Burchfield, John A. Wozniak and Sondra J. Mohrman

Department of Pediatrics, University of Kentucky, Lexington, Kentucky; and Department of Pediatrics, University of Florida, Gainesville, Florida

Correspondence and requests for reprints should be addressed to Alastair A. Hutchison, M.B.Ch.B., F.R.A.C.P., Division of Neonatology, Department of Pediatrics, MS-472, 800 Rose Street, Lexington, KY 40536-0298. E-mail: aahutch{at}msn.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
This study tested the hypotheses that (1) acute cerebral hypoxia–ischemia changes laryngeal adductor, laryngeal abductor, and diaphragmatic activities, resulting in central apnea with laryngeal closure; and (2) these laryngeal muscle activities act to maintain absolute lung volume. The respiratory pattern was determined in three asphyxiated, awake preterm lambs after cesarean section birth and in 12 awake, term lambs, with normal lung function, after induction of acute cerebral hypoxia–ischemia by occlusion of the brachiocephalic artery. Electrocorticogram activity, flow, volume, electromyograms of laryngeal abductor and adductor muscles and diaphragm, and, in the term lambs, trans-upper airway pressure and carotid blood flow were recorded. With either preterm birth asphyxia or induced acute cerebral hypoxia–ischemia, minute ventilation initially increased, and then hypopnea occurred. During the hypopnea, laryngeal adductor activity was prominent, accompanied by an increased upper airway pressure and a maintained/raised absolute lung volume. Thus, when acute hypoxia–ischemia limited to the upper body is induced in lambs with normal lung function, expiratory laryngeal adduction with closure of the upper airway occurs and likely functions to aid autoresuscitation.

Key Words: birth • posterior cricoarytenoid • resuscitation • thyroarytenoid


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Worldwide 4–7 million newborn babies per year require resuscitation at birth (1). If glottic closure is noted at endotracheal intubation, the resuscitator is advised that "If the cords do not open before the 20-second limit has expired, stop and ventilate with a bag and mask" (2), but this can fail (3). Glottic closure observed during resuscitation is attributed to upper airway stimulation (4). However, it occurs during gasping in the anesthetized tracheostomized adult animal exposed to progressive hypoxia alone (5), a stimulus that initially increases blood flow, offsetting hypoxia, and can reduce lung volume, producing laryngeal adductor activity (6–8). By contrast, the depressed baby at birth can present with hypoxia and severely decreased perfusion (2, 9). The ischemic component of this insult is the major determinant of central nervous system injury (10). No study has applied such a hypoxic–ischemic stimulus to the unanesthetized newborn animal and determined the laryngeal abductor and adductor muscle activity changes and their relationships to changes in flow, volume, trans-upper airway resistance, electrocorticographic activity, and cortical oxygen tension (PO2).

The establishment at birth and subsequent maintenance of a functional residual capacity in health and disease depend on the coordinated diaphragmatic and laryngeal muscle activities (7, 8, 11–13). During grunting, the timing of expiratory airflow retardation has been related to increased trans-upper airway pressure (Pua) and to reciprocal activities of the laryngeal abductors and major adductors, namely the posterior cricoarytenoid (PCA), and thyroarytenoid (TA) muscles (14). An altered central coordination of the onsets of laryngeal and diaphragmatic muscle activities has been related to increments in end-expiratory lung volume (15). No paper has supported the suggestion that laryngeal closure in asphyxial apnea could maintain lung volume and thereby aid gas exchange (5).

This paper documents that the asphyxiated preterm lamb at birth, like the human baby, can have apnea with bradycardia and increased laryngeal adductor activity. To minimize the impacts of variables that could alter laryngeal adduction (7, 8, 11, 16, 17), upper body hypoxia–ischemia was induced by occlusion of the single brachiocephalic artery in unanesthetized term lambs (18). The hypotheses were tested that (1) acute cerebral hypoxia–ischemia changes laryngeal adductor, laryngeal abductor, and diaphragmatic activities, resulting in central apnea with laryngeal closure, and that (2) glottic closure during asphyxial apnea promotes the maintenance of absolute lung volume.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Three preterm lambs (birth weight, 3.3 ± 0.2 [mean ± SD] kg) were studied at birth (139 ± 0.6 days, 7 ± 0.6 days postoperatively). Twelve term (~ 146 days) lambs were studied at 16 ± 7 days, 2–7 days postoperatively (study weight, 5.9 ± 2.2 kg). The University of Florida (Gainesville, FL) Institutional Animal Care and Use Committee approved the studies.

Surgery
Under halothane anesthesia (~ 1%) and using sterile procedure, bipolar electrodes were implanted in the posterior cricoarytenoid (PCA), thyroarytenoid (TA), and costal diaphragm (D) muscles (14). A femoral arterial catheter was emplaced. Wire ball electrodes were placed on the parietal dura mater bilaterally to monitor the electrocorticogram (ECoG). In term lambs a pneumatic cuff was placed around the single brachiocephalic artery (2). A 3-mm ultrasound blood flow transducer was placed around the right carotid artery. In five term lambs, a tracheal pressure catheter was inserted 3 cm below the glottis. In three term lambs, a cortical surface PO2 electrode was placed via a burr hole onto the caudal sylvian gyrus and secured by a microchronic column to the skull. Fetal lambs were returned to the uterus. Surgical wounds were closed and the electrodes and catheter led subcutaneously to pouches. Ampicillin was given.

Protocols/Measurements
Preterm lambs were delivered by cesarean section under spinal anesthesia and then lay prone on a wooden table with their heads in a neutral posture (14). Rectal temperature was measured. An attempt was made to monitor airflow. Blood gases, respiratory muscle electromyograms and ECoG signals were recorded (see below).

Twelve older lambs were studied in an animal hammock (14). Rectal temperature was measured. A facemask, with an attached pneumotachograph, a pressure transducer, and an amplifier, measured flow (14). In term lambs the facemask, with a pressure port, was cemented to the lamb's nose with elastomer. Trans-upper airway pressure (Pua) was measured with mouth and tracheal catheters attached to pressure transducers (14). The precalibrated carotid artery blood flow (CBF) probe, ECoG and respiratory muscle electromyogram wires, and the cortical surface PO2 electrode were attached to amplifiers. Delays between signals and amplitude and phase shifts were minimal (14). The signals were displayed on a physiograph, recorded on magnetic tape, and digitized for computer storage and analysis (14). Baseline ventilation, arterial blood gases corrected for the lamb's temperature, ECoG activity, cortical surface PO2, CBF, Pua, and respiratory muscle electromyograms were recorded for 5 minutes. The brachiocephalic arterial cuff occluder was then inflated for 3 minutes. The lambs became limp within 15 seconds. The changes in all signals were recorded. In 10 lambs, the brachiocephalic occlusion was repeated after 30–60 minutes. The lambs were killed with an intravenous barbiturate mixture. The cortical surface PO2 electrode was removed and calibrated in room air and 100% nitrogen. Electrode positions were confirmed at necropsy.

Analysis
Qualitative and quantitative analyses were performed (14). The Student paired t test and one-way repeated measures analyses of variance with Tukey post hoc tests were used for statistical analysis. A value of p < 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
All values represent means ± SD.

Asphyxiated Preterm Lambs (n = 3) within 16 Minutes Pre- and Postdelivery
Asphyxia complicates delivery in lambs (14, 15, 19). Blood gas values were as follows: fetal: pH 7.23 ± 0.05; PaCO2, 51.2 ± 2.5 mm Hg; PaO2, 26.4 ± 8.8 mm Hg; BE, -4.3 ± 2.0; newborn: pH 6.83 ± 0.05; PaCO2, 92.1 ± 12.2 mm Hg; PaO2, 19.8 ± 1.9 mm Hg; BE, -19.9 ± 1.9. The rectal temperature of newborn lambs was 38.4 ± 1.0° C (normal 24 hours postnatally, 39–40° C), and blood glucose was greater than 80 mg/dl.

In utero, the lambs were in the high-voltage ECoG state: diaphragmatic and PCA activities absent and tonic TA activity present (17). The ECoG activity changed to low voltage before (two lambs) or during cesarean section delivery (Figure 1) . At birth, the lambs were awake with eyes open and purposeful movements. During the first 20 seconds, experimental manipulations and movements occurred. Episodes of expiratory apnea were defined as lasting 15 seconds or more with no diaphragmatic activity, and the presence of TA activity and variable PCA activity (Figure 1). Sixteen episodes (9, 5, and 2 in Lambs 1, 2, and 3) lasting 22 ± 6 seconds were studied, with increased TA activity being uniform in two of three lambs. Closure of the larynx was confirmed at endotracheal intubation for resuscitation.



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  		Figure 1. A time trace of the ECoG, flow, volume, and activities of the PCA, TA, and D muscles is shown at cesarean section delivery of a preterm lamb: time of the delivery (0M), 1-minute mark (1M), and 2-minute mark (2M) are indicated. Before delivery, high-voltage ECoG activity (see 1) is noted. At delivery there is an instantaneous onset of PCA, TA, and D activity preceding a change to the low-voltage ECoG state. Behaviorally, the lamb aroused. An attempt was made to suppress initial respiration by placing a glove containing sterile water over the lamb's nose. The volume integrator reset is marked as r. Thereafter, the respiratory pattern is characterized by PCA and D activities with minimal TA activity (see 2)—the tidal volumes were small, perhaps related to facemask leak. At 1M, increasing expiratory TA activity was noted between short bursts of PCA and D activities (see 3). The onset of expiratory apnea followed (see 4). During the apnea (see 4 and 5), PCA and D burst activities were absent for 15 seconds or more: at A, D activity was induced—see rub down; B, PCA burst activity was minimal; C, increased TA activity was prominent; A–D, heart rate was slow; see ECG artifact on D signal; E, ECoG frequency slowed and amplitude increased; F, at 2M, the ECoG became isoelectric but increased expiratory TA activity and tonic PCA activity persisted. DEMG = electromyogram at delivery; ECoG = electrocorticogram; PCA = posterior cricoarytenoid; TA = thyroarytenoid; V· = flow; VOL = lung volume.

 
Upper Body Ischemia in 12 Older Lambs
The awake lambs had normal blood gases: pH 7.38 ± 0.04; PaCO2, 40.8 ± 5.3 mm Hg; PaO2, 94.1 ± 7.0 mm Hg. They did not change during the occlusions: pH 7.37 ± 0.07; PaCO2, 38.6 ± 8.9 mm Hg; PaO2, 92.3 ± 9.9 mm Hg in 21 of 22 occlusions. The rectal temperature was 39.7 ± 0.3° C.

Twenty-two occlusions of the brachiocephalic artery were performed (2 occlusions in 10 lambs and 1 occlusion in 2 lambs). The lambs became inactive and limp within seconds and appeared to be asleep. The changes in ECoG, CBF, airflow, respiratory rate, tidal volume, and the activities of the laryngeal muscles and diaphragm are shown (Figures 2–4) . After the occlusion, CBF fell from 74 ± 14 to 7 ± 6 ml/minute (data from 20 occlusions [11 lambs]).



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  		Figure 2. A time trace of ECoG, carotid blood flow (CBF), airflow, trans-upper airway pressure (Pua), and PCA, TA, and D muscle activities is shown. Inspiration (i) and expiration (e) are indicated. Acute cerebral hypoxia–ischemia is induced by brachiocephalic artery occlusion. As the CBF drops toward zero, the ECoG slows and its amplitude increases. Tachypnea occurs with increased PCA and D activities and the onset of minor TA activity that increases until expiratory flow retardation is noted with increases in Pua (see end of the tachypneic period). Hypopnea ensues with prominent expiratory TA activity, minor tonic PCA, increased expiratory Pua, and minimal ECoG activity.

 


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  		Figure 4. This time trace of ECoG, airflow, volume, Pua, and PCA, TA, and D muscle activities shows the relationships between the laryngeal muscle activities, end-expiratory volume, and Pua. Inspiration (i) and expiration (e) are indicated. The end-expiratory volume or functional residual capacity (FRC) is also shown. With brachiocephalic artery occlusion, the ECoG slows and the amplitude increases. Tachypnea occurs (A on the flow trace). The PCA and D activities increase, as does the TA activity, producing expiratory flow retardation, and Pua increases. Hypopnea is characterized by variable PCA and prominent TA activity. When PCA activity increases relative to TA activity, a decrease in expiratory volume and Pua occur (see B). In contrast, at C, PCA activity decreases relative to TA activity and Pua remains high after a small initial decline. In association with the PCA and TA activities during hypopnea FRC is maintained (B) or even incremented (C), whereas ECoG activity has decreased to baseline (D).

 


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  		Figure 3. A time trace of ECoG, cortical surface PO2, CBF, airflow, volume, and PCA, TA, and D muscle activities is shown. Inspiration (i) and expiration (e) are indicated. With brachiocephalic artery occlusion, the CBF and cortical surface PO2 drop toward zero, the ECoG slows, and the amplitude increases. Tachypnea occurs with increased PCA and D activities and the onset of minor TA activity that increases, producing expiratory flow/volume retardations. During the expiratory pauses of hypopnea, prominent and persistent TA activity and minor PCA activity occur. The gasping breaths and expiratory laryngeal muscle activities act to maintain or increment the end-expiratory volume—see dotted line on the volume signal. The ECoG activity shows minimal activity during hypopnea.

 
In all lambs after the occlusion, the ECoG frequency slowed and its amplitude increased at 9.6 ± 1.5 seconds (Figures 2– 4). The onset of the ECoG changes was the time when the amplitude increased by two or more times baseline and the frequency slowed to <= 5 Hz. Isoelectric activity was identified as the absence of ECoG waves and background amplitude. In 15 of 22 occlusions (9 of 12 lambs), the ECoG became isoelectric or nearly so with the onset of hypopnea with gasping (Figures 2– HREF="#FIG4">4). The slow frequency persisted in the remainder, accompanied in two of three lambs by a decrease in amplitude. Subsequently the ECoG frequency increased, probably related to the establishment of anastomotic channels, and the respiratory pattern altered from hypopnea to a more regular pattern, with present but less marked laryngeal braking of expiratory airflow.

In four of six studies (three lambs) the cortical surface PO2 recording was acceptable because (1) the baseline signal was stable; (2) it decreased during the occlusion; and (3) it returned to baseline after release of the occlusion. After occlusion, the cortical surface PO2 fell from a baseline of 30.1 ± 8.8 to 6.5 ± 3.3 mm Hg during hypopnea when the ECoG activity was minimal (Figure 3).

Baseline data consisted of 95 ± 31 breaths of regular breathing periods sampled in the 4 minutes before occlusion, including in all lambs the 30 seconds immediately before the occlusion. The lambs had normal baseline ventilation: respiratory rate, 53 ± 16 breaths/minute; tidal volume, 9.6 ± 3.1 ml/kg; minute ventilation, 487 ± 144 ml/kg per minute. Each parameter increased after brachiocephalic artery occlusion (p < 0.001; Figure 4). Minute ventilation peaked between 10 and 30 seconds, respiratory rate after 19 ± 11 seconds, and tidal volume after 22 ± 11 seconds. The respiratory rate slowed after 32 ± 11 (range, 20–64) seconds at the onset of hypopnea, which was defined by the onset of a breath with an expiratory time (TE) >= 2 seconds followed by breaths with TE >= 2 seconds or apnea (>= 15 seconds). The cessation of hypopnea was the onset of the first of two breaths with TE < 2 seconds and tidal volumes >= baseline. The changes in the ventilatory parameters were averaged over 5-second epochs during the first 30 seconds postocclusion and during the entire hypopneic period and were expressed as percentage changes from baseline (Figure 5) . The respiratory pattern during hypopnea was irregular with gasping, which was identified by short bursts of augmented diaphragmatic activity with rapid onsets and declines in activity. The hypopnea characteristics were as follows: mean duration, 49 seconds (range, 4–103 seconds); mean breath number, 5 (range, 1–12); mean breath duration, 9.4 seconds; mean TE, 8.5 seconds. The mechanical inspiratory time-to-expiratory time ratio decreased: hypopnea, 0.110 ± 0.06 versus baseline, 0.71 ± 0.08 (p < 0.001). The tidal volume increased: hypopnea, 16.4 ± 7.1 ml/kg versus baseline, 9.6 ± 3.1 ml/kg (data from 18 occlusions; p < 0.001; Figure 5). The rate and minute ventilation fell below baseline values (p < 0.001) in all lambs (Figure 5). During the prolonged expirations, the end-expiratory lung volume was maintained (7 of 12 lambs, 9 of 22 occlusions) (Figures 3 and 4).



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  		Figure 5. After the onset of acute cerebral hypoxia–ischemia in 12 term lambs, the mean percent changes (± SE) from baseline (time 0) are shown for respiratory rate (solid circles), tidal volume (open squares), minute ventilation (solid triangles) (left), for peak PCA (solid inverted triangles) and D (open diamonds) amplitudes and for D slope (solid circles) (middle), and for the respiratory outputs of PCA (solid circles) and D (open squares) (right). Increases in respiratory rate and tidal volume occur initially. The latter remains increased during hypopnea (mean breaths, 5; mean duration, 9.4 seconds) but minute ventilation decreases. Increases in peak PCA amplitude, peak D amplitude, and D slope occur during tachypnea and hypopnea. Both PCA and D respiratory outputs increase in the initial tachypneic period and fall during hypopnea.

 
Baseline laryngeal muscle activities (n = 95 ± 31 breaths) were characterized by (1) inspiratory PCA activity accompanying that of the diaphragm and (2) expiratory PCA activity with minimal TA activity (Figures 2–4). During the increased minute ventilation following brachiocephalic artery occlusion, inspiratory PCA, expiratory PCA, and diaphragmatic activities increased (Figures 2–4). The changes in the electromyogram moving time average values of these parameters (for signal processing see [14]) were averaged over 5-second epochs during the first 30 seconds postocclusion and during the entire hypopneic period and were expressed as percentage changes from baseline (Figure 5). The percentage change in peak inspiratory PCA amplitude increased above baseline values by 15–19 seconds postocclusion, whereas that of the diaphragm electromyogram was greater but not noted until 25–29 seconds (p < 0.001; Figure 5). The percentage increases in peak inspiratory PCA and diaphragm activities and the increase in the diaphragm slope, measured by computer-assisted analysis as the angle subtended by a line drawn from the onset to the peak of the diaphragm moving time average signal (14), were maintained during hypopnea (Figure 5). However, the respiratory drive output, defined by the percentage change in peak amplitude x the respiratory rate, decreased markedly for both PCA and diaphragm during the period of hypopnea (Figure 5). The greater increase in peak diaphragmatic amplitude relative to that of the PCA did not alter the inspiratory trans-upper airway resistance, measured at the point of maximum trans-upper airway pressure (hypopnea, 0.0018 ± 0.008 cm H2O/L per second; baseline, 0.0020 ± 0.002 cm H2O/L per second). Expiratory PCA activity increased in the postocclusion tachypneic period but during hypopnea was usually minor (Figures 2 and 3) or variably present (Figure 4). Expiratory TA burst activity increased during the postocclusion tachypnea but was prominent during hypopnea when TE was prolonged and little or no expiratory airflow occurred (Figures 2–4). The increases in expiratory Pua during hypopnea (hypopnea, 12.3 ± 4.3 cm H2O; baseline Pua, 1.98 ± 1.13 cm H2O [p < 0.001]) were temporally associated with increased TA burst activity and severe retardation/absence of expiratory airflow (Figures 3 and 4), indicating that TA activity led to glottic closure (15). Only during hypopnea was the expiratory upper airway resistance increased (hypopnea, 0.011 ± 0.008 cm H2O/L per second; baseline, 0.002 ± 0.001 cm H2O/L per second [p < 0.001]). The expiratory airflow retardation maintained the end-expiratory lung volume during hypopnea and end-expiratory increments in lung volume could occur (Figures 3 and 4).

During hypopnea PCA activity was variable (Figures 1–4) but the mechanical effect of TA activity was dominant as shown by diminished or absent expiratory airflow (Figures 2–4). However, concurrent PCA and TA activities could alter trans-upper airway pressure and the degree of expiratory volume loss (Figure 4). In the first breath of the hypopneic period (A) in Figure 4, the mechanical impact of expiratory TA activity dominates concurrent PCA activity with little trans-upper airway pressure change or volume loss. In the second breath (Figure 4, B), PCA activity increases over time relative to TA activity with decreased trans-upper airway pressure and increased expiratory volume loss. In the third breath (Figure 4, C), PCA activity diminishes relative to TA activity with maintenance of trans-upper airway pressure and absence of expiratory volume loss. The latter pattern is similar to mixed expiratory apnea.

Reversal of PCA and diaphragm onsets can augment lung volume (15), but in general during hypopnea the onsets of PCA and diaphragm activities were not reversed, nor was there a shorter interval between PCA and diaphragm onsets (hypopnea, 94 ± 109 milliseconds versus baseline, 89 ± 45 milliseconds). Retention of lung volume at end-expiration was therefore a function of persistence of TA activity into neural inspiration (15).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This is the first demonstration that during the central apnea of acute cerebral hypoxia–ischemia there are increases in trans-upper airway resistance and Pua that are temporally related to increased TA and variably decreased PCA activities that maintain absolute lung volume. Thus during a severe hypoxic–ischemic event, similar to that which occurs spontaneously in the human baby or preterm lamb at birth, glottic closure occurs independent of upper airway stimulation or respiratory system abnormalities.

Insights into the motor mechanisms of autoresuscitation are provided. Ideally, in the face of life-threatening asphyxial apnea, the neonate's pattern of respiration will offset the respiratory consequences of asphyxia (20) through motor activities that improve absolute lung volume and oxygenation and enhance spontaneous, continuous respiration, that is, accomplish autoresuscitation. During the hypopnea of acute cerebral hypoxia–ischemia, glottic closure increased Pua and resulted in absolute lung volume being maintained between gasps (Figures 3 and 4). The increased TA and decreased PCA expiratory activities were similar to those noted at the onset of respiration (8, 15), or during grunting in respiratory distress (13, 14). The advantages attributed to expiratory glottic closure include improved pulmonary expansion and inspiratory distribution of air to underventilated areas (21). The generation of expiratory positive airway pressure favors an increase in transpulmonary pressure during the ensuing inspiration (22, 23) and this increases tidal volume. In addition, the presence of end-expiratory positive airway pressure at the onset of the gasps and the short durations of the PCA and diaphragmatic inspiratory activities are factors that can decrease upper airway collapse during inspiration. Thus, during the gasps in this study, there was no upper airway obstruction—tidal volume was elevated and trans-upper airway resistance was unaltered (Figures 3–5). Adoption of a maintained inflation pattern, similar to that seen during hypopnea of cerebral hypoxia–ischemia (Figures 3 and 4), improves artificial resuscitation of the depressed human neonate at birth (24).

Autoresuscitation likely involves incrementing lung volume, a process typified by expiratory lung volume maintenance, and then inspiratory flow onset without significant end-expiratory flow (Figures 3 and 4) (15). This end-expiratory flow/volume pattern occurs with prolongation of TA activity into neural inspiration and reversal of the timings of PCA and diaphragm onsets (15). The latter can occur in experimentally induced chronic gasping (25). In this study the volume increments in gasping were principally dependent on persistence of TA activity after diaphragmatic activity onset, similar to that reported in the early gasps of asphyxiated anesthetized adult rabbits in which inversion of the PCA–diaphragm onsets appears in later gasps (5). This study focused on acute cerebral hypoxia–ischemia but TA activity will likely diminish with prolongation of the insult (26–29), leading to passive glottic opening.

It was not a study objective to determine how acute hypoxia–ischemia alters the motor control of laryngeal muscles. However, the use of lambs with normal lung function eliminated any pre-existing pulmonary or rib cage factors that would favor laryngeal closure (7, 13, 17, 30, 31). The peripheral effects of hypoxia on laryngeal muscle activities are complex (7, 14, 31). Acute and chronic animal studies indicate that hyperpnea resulting from breathing hypoxic or hypercapnic gases increases pulmonary stretch receptor input that maintains laryngeal abduction (7, 14, 31). In awake pulmonary vagotomized lambs breathing a hypoxic gas mixture, laryngeal abduction is found if normocapnia is maintained (31). By contrast, during hypoxia and hypocapnia, a Dejours test produces apnea and increased TA activity (31). This and other studies (31–35) demonstrate that TA activity during central apnea can occur without increased carotid body input. Thus, it is unlikely that carotid body or vagal afferent input produces the laryngeal closure during the hypopnea of hypoxic ischemia.

Brainstem hypoxia can stimulate some neurons while depressing others (36) and could result in apnea/hypopnea and increased TA activity with glottic closure. This is supported by the similarity of respiratory pattern changes seen after brachiocephalic arterial occlusion and that of animals asphyxiated by exclusion of air (26). Both the respiratory patterns and ECoG changes (Figures 2– 4) mimic those seen with airway occlusion in rabbits (6), with breathing 100% nitrogen in adult humans (37), and with severe hypoxia in human babies (38). Finally, the nature of the respiratory pattern during asphyxia is related to the degree of hypoxemia (6). Because the main difference between the hypoxic–ischemic stimulus and that of exposure to progressive hypoxia/anoxia is the rapidity of the decrease in cortical PO2 and onset of hypopnea/apnea (Figure 3), the respiratory changes may reflect the severity of the initial hypoxia. However, increased TA activity occurs during nonhypoxemic central apnea (29, 31–35), and the mechanism of glottic closure in cerebral hypoxia–ischemia may be indirect.

The origins of the respiration pattern of glottic closure during hypopnea/apnea may be in fetal life, when the PaO2 is low and when glottic closure during the apnea of quiet sleep is thought to maintain absolute lung volume and be critical for lung growth (21). In normal neonates the dominant respiratory strategy continues to focus on absolute lung volume maintenance (39, 40). It has been speculated that the respiratory pattern of fetal quiet sleep may reappear at any age (41) and there is increasing awareness that upper airway closure can occur during prolonged apnea in the preterm neonate (42, 43). This may be relevant in the sudden infant death syndrome (44) and emphasizes the need for investigation of central inputs that control laryngeal motoneurons (45).

The potential benefit of adopting a breathing pattern with prominent expiratory laryngeal adductor activity may relate to minimizing the energy requirements for respiratory system stability, for example, by reptiles, amphibians, and newborn animals including humans (8, 22), and to conserving oxygen, for example, in hyaline membrane disease and neonatal apnea (13, 14, 41, 43). This pattern occurs in the human at birth (11, 12). The first breath, recorded in one lamb (Figure 1), occurred before any respiratory or cord manipulation, was instantaneous and involved expiratory TA activity with upper airway closure (11, 12, 46), a pattern also typical of arousal in lambs (47). The teleological benefit of such a pattern at arousal/birth would be to stabilize absolute lung volume and protect the upper airway during a change in behavioral state. Indeed, it has been suggested that this pattern appears throughout life as part of the "wake-up stretch" accompanying arousal from sleep (41).

In summary, acute cerebral hypoxia–ischemia in the awake lamb is associated with hypopnea, gasps, and expiratory laryngeal closure. It is argued that the central coordination of laryngeal and diaphragmatic muscle activities produces mechanical effects that promote autoresuscitation. Phylogenetically and ontogenetically, these patterns of respiratory muscle activities may be potent survival mechanisms that occur in other forms of apnea, respiratory distress, and arousal, and sometimes in eupnea.


   Acknowledgments
 
The authors thank Drs. R. M. Abrams, P. W. Davenport, and D. F. Speck for technical advice and manuscript review, and Nancy L. Hargrove for technical assistance.

Supported in part by grants from the American Lung Association of Florida; the National Heart, Lung, and Blood Institute (NHLBI grant HL-39858); and the University of Florida Children's Miracle Network Telethon.

Received in original form January 8, 2001; accepted in final form January 11, 2002


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
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