Effects of sleep deprivation on respiratory events during sleep in healthy infants

This study was designed to determine the effects of sleep deprivation on respiratory events during sleep in healthy infants. Ten unsedated full-term infants (1-6 mo) were monitored polygraphically during "afternoon naps" on a control day and on the day after sleep deprivation. Respiratory events, i.e., central apnea, obstructive apnea and hypopnea, and periodic breathing were tabulated. Results for respiratory events were expressed as 1) indexes of the total number of respiratory events and of specific respiratory events per hour of total sleep (TST), "quiet" sleep (QS) and "active" sleep (AS) times; 2) total duration of total and specific respiratory events, expressed as a percentage of TST, QS, and AS times. After sleep deprivation, significant increases were observed for 1) respiratory event (P less than 0.001), central apnea (P less than 0.05), and obstructive respiratory event (P less than 0.01) indexes; 2) respiratory event time as a percentage of TST (P less than 0.002) and as a percentage of AS time (P less than 0.001); 3) obstructive respiratory event time as a percentage of TST (P less than 0.01), QS (P less than 0.05), and AS times (P less than 0.002). The present study shows that short-term sleep deprivation in healthy infants increases the number and timing of respiratory events, especially obstructive events in AS.     

Regulation of end-expiratory lung volume during sleep in premature infants

To investigate the regulation of end-expiratory lung volume (EEV) in premature infants, we recorded airflow, tidal volume, diaphragm electromyogram (EMG), and chest wall displacement during sleep. In quiet sleep, EEV during breathing was 10.8 +/- 3.6 (SD) ml greater than the minimum volume reached during unobstructed apneas. In active sleep, no decrease in EEV was observed during 28 of 35 unobstructed apneas. Breaths during quiet sleep had a variable extent of expiratory airflow retardation (braking), and inspiratory interruption occurred at substantial expiratory flow rates. During active sleep, the expiratory flow-volume curve was nearly linear, proceeding nearly to the volume axis at zero flow, and diaphragm EMG activity terminated near the peak of mechanical inspiration. Expiratory duration (TE) and inspiratory duration (TI) were significantly shortened in quiet sleep vs. active sleep although tidal volume was not significantly different. In quiet sleep, diaphragmatic braking activity and shortened TE combined to maintain EEV during breathing substantially above relaxation volume. In active sleep, reduced expiratory braking and prolongation of TE resulted in an EEV that was close to relaxation volume. We conclude that breathing strategy to regulate EEV in premature infants appears to be strongly influenced by sleep state.     

Effect of caffeine on peripheral chemoreceptor activity in premature neonates: interaction with sleep stages.

Caffeine is widely used for the treatment of apnea in premature neonates. However, the localization of caffeine's target site (central nervous system and/or peripheral chemoreceptors) is not well defined, especially for sleeping neonates whose sleep stages interact with respiratory control. The aim of this study was to assess the activity of the peripheral chemoreceptors in relation to sleep stages in premature neonates treated (or not) with caffeine for idiopathic apnea. Peripheral chemoreceptor activity was assessed in 22 neonates (postconceptional age of 36 +/- 1 wk with birth weights ranging from 790 to 1,910 g) by performing a 30-s hyperoxic test during active and quiet sleep. Eleven neonates received caffeine treatment (4.0 +/- 0.5 mg.kg(-1).day(-1)) and 11 served as controls. For all neonates, the decrease in minute ventilation observed during hyperoxia was greater during active than during quiet sleep. Neonates receiving caffeine showed a significantly greater decrease in ventilation during hyperoxia in both sleep stages, compared with controls (caffeine; -29.7 +/- 12.8% vs. control; -22.0 +/- 7.4%; F(1,15) = 4.6, P = 0.04). We conclude that caffeine administration increases the effectiveness of chemoreceptor activity. Because sleep stage durations were not affected by the treatment, it is likely that the decrease in apneic episodes typically observed with caffeine therapy is only related to respiratory processes and is independent of the sleep stage organization.     

Calibration of respiratory inductive plethysmography during quiet and active sleep in lambs

Respiratory inductive plethysmography provides a noninvasive method of measuring breathing patterns. Calibration of respiratory inductive plethysmography requires calculation of gain factors for ribcage and abdomen transducers utilizing 2 breathing patterns with different ribcage and abdomen contributions and tidal volume measured by either spirometry or integrated pneumotachography. The purpose of this study was to determine if respiratory inductive plethysmography can be calibrated to provide accurate measurements during quiet and active sleep in lambs. We used a least squares linear regression calibration technique with breaths selected from quiet sleep and active sleep to calculate gain factors in 6 tracheostomized lambs. Validation of gain factors was performed by comparing tidal volumes obtained simultaneously by respiratory inductive plethysmography and pneumotachography during quiet sleep and active sleep. Tidal volume differences between respiratory inductive plethysmography and pneumotachography on validation runs of 15 consecutive breaths each revealed 90% of validation breaths within +/- 20% during quiet sleep and 82% of validation breaths within +/- 20% during active sleep. These data provide evidence that respiratory inductive plethysmography can be calibrated to allow breathing pattern measurement during sleep.     

Impact of age on breathing and resistive pressure in people with and without sleep apnea.

We investigated the effect of age on breathing and total pulmonary resistance (RL) during sleep by studying elderly (>65 yr) and young (25-38 yr) people without sleep apnea (EN and YN, respectively) matched for body mass index (BMI). To determine the impact of sleep apnea on age-related changes in breathing, we studied elderly and young apneic patients (EA and YA, respectively) matched for apnea and BMI. In all groups (n = 11), breathing during periods of stable sleep was analyzed to evaluate the intrinsic variability of respiratory control mechanisms. In the absence of sleep apnea, the variability of the breathing was similar in the elderly and young [mean (+/- SD) coefficient of variation (CV) of tidal volume (VT); wake: EN 21.0 +/- 14.9%, YN 14.7 +/- 5.5%; sleep: EN 14.0 +/- 6.0%; YN 11.5 +/- 6.4%]. In patients with sleep apnea, breathing during stable sleep was more irregular, but there were no age-related differences (CV of VT; wake: EA 22.0 +/- 11.6%, YA 16.7 +/- 11.3%; sleep: EA 32.8 +/- 24.9%, YA 25.2 +/- 16.3%). In addition, EN tended to have a higher RL (n = 6, RL midinspiration, wake: EN 7.1 +/- 3.0; YN 9.1 +/- 6.4 cmH(2)O. l(-1). s, sleep: EN 17.5 +/- 11.7; YN 9.8 +/- 2.0 cmH(2)O. l(-1). s). We conclude that aging per se does not contribute to the intrinsic variability of respiratory control mechanisms, although there may be a lower probability of finding elderly people without respiratory instability.     

Measurement of the CO2 apneic threshold in newborn infants: possible relevance for periodic breathing and apnea.

We measured the PCO2 apneic threshold in preterm and term infants. We hypothesized that, compared with adult subjects, the PCO2 apneic threshold in neonates is very close to the eupneic PCO2, likely facilitating the appearance of periodic breathing and apnea. In contrast with adults, who need to be artificially hyperventilated to switch from regular to periodic breathing, neonates do this spontaneously. We therefore measured the apneic threshold as the average alveolar PCO2 (PaCO2) of the last three breaths of regular breathing preceding the first apnea of an epoch of periodic breathing. We also measured the PaCO2 of the first three breaths of regular breathing after the last apnea of the same periodic breathing epoch. In preterm infants, eupneic PaCO2 was 38.6 +/- 1.4 Torr, the preperiodic PaCO2 apneic threshold was 37.3 +/- 1.4 Torr, and the postperiodic PaCO2 was 37.2 +/- 1.4 Torr. In term infants, the eupneic PaCO2 was 39.7 +/- 1.1 Torr, the preperiodic PaCO2 apneic threshold was 38.7 +/- 1.0 Torr, and the postperiodic value was 37.9 +/- 1.2 Torr. This means that the PaCO2 apneic thresholds were 1.3 +/- 0.1 and 1.0 +/- 0.2 Torr below eupneic PaCO2 in preterm and term infants, respectively. The transition from eupneic PaCO2 to PaCO2 apneic threshold preceding periodic breathing was accompanied by a minor and nonsignificant increase in ventilation, primarily related to a slight increase in frequency. The findings suggest that neonates breathe very close to their PCO2 apneic threshold, the overall average eupneic PCO2 being only 1.15 +/- 0.2 Torr (0.95-1.79, 95% confidence interval) above the apneic threshold. This value is much lower than that reported for adult subjects (3.5 +/- 0.4 Torr). We speculate that this closeness of eupneic and apneic PCO2 thresholds confers great vulnerability to the respiratory control system in neonates, because minor oscillations in breathing may bring eupneic PCO2 below threshold, causing apnea.     

Arousal pattern following central and obstructive breathing abnormalities in infants and children

McNamara, Frances, Faiq G. Issa, and Colin E. Sullivan.Arousal pattern following central and obstructive breathing abnormalities in infants and children. J. Appl.Physiol. 81(6): 2651-2657, 1996.We analyzed thepolysomnographic records of 15 children and 20 infants with obstructivesleep apnea (OSA) to examine the interaction between central andobstructive breathing abnormalities and arousal from sleep. Eachpatient was matched for age with an infant or child who had no OSA. Wefound that the majority of respiratory events in infants and childrenwas not terminated with arousal. In children, arousals terminated 39.3 ± 7.2% of respiratory events during quiet sleep and 37.8 ± 7.2% of events during active (rapid-eye-movement) sleep. In infants,arousals terminated 7.9 ± 1.0% of events during quiet sleep and7.9 ± 1.2% of events during active sleep. In both infants andchildren, however, respiratory-related arousals occurred more frequently after obstructive apneas and hypopneas than after central events. Spontaneous arousals occurred in all patients with OSA duringquiet and active sleep. The frequency of spontaneous arousals was notdifferent between children with OSA and their matched controls. Duringactive sleep, however, infants with OSA had significantly fewerspontaneous arousals than did control infants. We conclude that arousalis not an important mechanism in the termination of respiratory eventsin infants and children and that electroencephalographic criteria arenot essential to determine the clinical severity of OSA in thepediatric population.

     

Role of bronchopulmonary C-fiber afferents in the apneic response to cigarette smoke

The role of vagal bronchopulmonary C-fiber afferents in eliciting the immediate changes in breathing pattern after acute inhalation of cigarette smoke was assessed with a selective blockade of myelinated vagal afferents (innervating both stretch and irritant receptors) utilizing the method of differential cooling. In 15 of 17 chloralose-anesthetized dogs tested, spontaneous inhalation of cigarette smoke (19.7% avg conc, 500-700 ml vol) reproducibly caused the following immediate responses: apnea, bradycardia, and hypotension. These responses occurred within 1 to 2 breaths of smoke inhalation and were followed by a delayed hyperpnea. The apneic duration reached 326 +/- 33% (SE) (n = 15) of the mean base-line expiratory duration. Differential cold block of both vagi (coolant temperature 8.4 +/- 0.3 degrees C) abolished the reflex apnea induced by a positive-pressure (7-10 cmH2O) lung inflation but did not affect the apneic response to smoke inhalation (345 +/- 35%). The smoke-induced apnea was completely abolished by lowering the coolant temperature to -1.3 +/- 0.2 degrees C (n = 10) or by bilateral vagotomy (n = 5) and returned to the control level after both vagi were rewarmed. Based on these results, we suggest that the immediate apneic response to inhaled cigarette smoke is elicited by a stimulation of vagal C-fiber afferents in the lungs and airways.     

Influence of sleep state on frequency of swallowing, apnea, and arousal in human infants.

Apnea and arousal are modulated with sleep stage, and swallowing may interfere with respiratory rhythm in infants. We hypothesized that swallowing itself would display interaction with sleep state. Concurrent polysomnography and measurement of swallowing allowed time-matched analysis of 3,092 swallows, 482 apneas, and 771 arousals in 17 infants aged 1-34 wk. The mean rates of swallowing, apnea, and arousal were significantly different, being 23.3 +/- 8.5, 9.4 +/- 8.8, and 15.5 +/- 10.6 h(-1), respectively (P < 0.001 ANOVA). Swallows occurred before 25.2 +/- 7.9% and during 74.8 +/- 6.3% of apneas and before 39.8 +/- 6.0% and during 60.2 +/- 6.0% of arousals. The frequencies of apneas and arousals were both strongly influenced by sleep state (active sleep > indeterminate > quiet sleep, P < 0.001), whether or not the events coincided with swallowing, but swallowing rate showed minimal independent interaction with sleep state. Interactions between swallowing and sleep state were predominantly influenced by the coincidence of swallowing with apnea or arousal.     

Differential response of respiratory muscles to airway occlusion in infants

The effect of end-expiratory occlusion on respiratory muscle activity was studied in 10 unsedated preterm infants during sleep. Electromyograms (EMG) of the upper airway were recorded from surface electrodes placed over the submental (SM) area; diaphragm (DIA) EMGs were obtained with identical electrodes over the right subcostal margin. Phasic SM EMG accompanied 56 +/- 36% of breaths during spontaneous breathing and increased to 80 +/- 26% (P less than 0.05) on the first inspiratory effort after occlusion. Occlusion increased peak amplitude (P less than 0.001) and total duration (P less than 0.005) of the SM EMG without significant changes in its initial rate of rise. In contrast, only the total duration of the DIA EMG increased (P less than 0.005) during occlusion. Inspiratory time increased from 470 +/- 120 to 720 +/- 210 ms (P less than 0.001) during the first occluded effort, but expiratory time did not change. With sustained occlusion, peak amplitude of the SM EMG progressively increased, but DIA EMG only significantly increased by the third occluded effort. Pharyngeal patency was invariably maintained throughout the induced airway occlusions. Sharp bursts of SM EMG activity coincided with resolution of spontaneous obstructive apneic episodes in four infants. The immediate increase in SM EMG associated with airway occlusion may be a mechanism that prevents the development of obstructive apnea.     

Behavioral arousal in newborn infants and its association with termination of apnea

Arousal is an important protective mechanism that aids in the resolution of obstructive sleep apnea in adults and children, but its role in neonatal apnea has not been investigated. The primary aim of the present study was to determine the role of arousal in the termination of apnea in preterm infants. Videorecording was used to identify spontaneous behavioral arousal in a group of healthy full-term (n = 7) and preterm (n = 10) infants before and during polygraphic monitoring of cardiorespiratory variables and in a group of preterm infants with apnea (n = 10) during similar polygraphic monitoring. Spontaneous arousal rates (mean +/- SE) in full-term infants before and during polygraphic monitoring were 0.18 +/- 0.03 and 0.23 +/- 0.07 episodes/min, respectively. Corresponding values in nonapneic preterm infants were 0.24 +/- 0.03 and 0.24 +/- 0.02 episodes/min. In apneic preterm infants, mean spontaneous arousal rate during polygraphic recording was 0.26 +/- 0.02, but it was considerably higher during apneic sleep periods (0.59 +/- 0.17) than during nonapneic sleep periods (0.25 +/- 0.01). The frequency of occurrence of arousal was significantly higher (P less than 0.005) in long vs. short apnea, mixed vs. central apnea, and severe vs. mild apnea. Although a clear association between arousal and apneic resolution was observed in preterm infants, lack of arousal responses in a large number of apneic episodes suggests that behavioral arousal is not essential for the termination of apnea in these infants.     

Effects of inhaled oxygen (up to 40%) on periodic breathing and apnea in preterm infants.

To discover whether increases in inhaled O2 fraction (FIO2; up to 40%) decrease apnea via an increase in minute ventilation (VE) or a change in respiratory pattern, 15 preterm infants (birth weight 1,300 +/- 354 g, gestational age 29 +/- 2 wk, postnatal age 20 +/- 9 days) breathed 21, 25, 30, 35, and 40% O2 for 10 min in quiet sleep. A nosepiece and a flow-through system were used to measure ventilation. Alveolar PCO2, transcutaneous PO2, and sleep states were also assessed. All infants had periodic breathing with apneas greater than or equal to 3 s. With an increase in FIO2 breathing became more regular and apneas decreased (P less than 0.001). This regularization in breathing was not associated with significant changes in VE. However, the variability of VE, tidal volume, and expiratory and inspiratory times decreased significantly. The results indicate that the more regular breathing observed with small increases in FIO2 was not associated with significant changes in ventilation. The findings suggest that the increased oxygenation decreases apnea and periodicity in preterm infants, not via an increase in ventilation, but through a decrease in breath-to-breath variability of VE.     

Ventilatory long-term facilitation in mice can be observed during both sleep and wake periods and depends on orexin.

Respiratory long-term facilitation (LTF) is a long-lasting (>1 h) augmentation of respiratory motor output that occurs even after cessation of hypoxic stimuli, is serotonin-dependent, and is thought to prevent sleep-disordered breathing such as sleep apnea. Raphe nuclei, which modulate several physiological functions through serotonin, receive dense projections from orexin-containing neurons in the hypothalamus. We examined possible contributions of orexin to ventilatory LTF by measuring respiration in freely moving prepro-orexin knockout mice (ORX-KO) and wild-type (WT) littermates before, during, and after exposure to intermittent hypoxia (IH; 5 x 5 min at 10% O2), sustained hypoxia (SH; 25 min at 10% O2), or sham stimulation. Respiratory data during quiet wakefulness (QW), slow wave sleep (SWS), and rapid-eye-movement sleep were separately calculated. Baseline ventilation before hypoxic stimulation and acute responses during stimulation did not differ between the ORX-KO and WT mice, although ventilation depended on vigilance state. Whereas the WT showed augmented minute ventilation (by 20.0 +/- 4.5% during QW and 26.5 +/- 5.3% during SWS; n = 8) for 2 h following IH, ORX-KO showed no significant increase (by -3.1 +/- 4.6% during QW and 0.3 +/- 5.2% during SWS; n = 8). Both genotypes showed no LTF after SH or sham stimulation. Sleep apnea indexes did not change following IH, even when LTF appeared in the WT mice. We conclude that LTF occurs during both sleep and wake periods, that orexin is necessary for eliciting LTF, and that LTF cannot prevent sleep apnea, at least in mice.     

Influence of breathing pattern on functional residual capacity in sleeping newborn infants

The present study was designed to assess the influence of breathing pattern on the variations of functional residual capacity during sleep in newborn infants. Functional residual capacity was measured by the He-dilution method. Neurophysiologic criteria were used to identify sleep states. Movements of chest and abdomen were monitored. Twenty-six healthy newborn infants were studied. Sixteen were premature and 10 were at term. Functional residual capacity did not change in relation to changes in sleep states. In active sleep it was 1.48 +/- 0.07 ml/cm compared with 1.50 +/- 0.06 ml/cm in quiet sleep. Functional residual capacity decreased when rib cage and abdomen moved out-of-phase with a value of 1.38 +/- 0.09 ml/cm as compared to 1.56 +/- 0.09 ml/cm when in phase (P less than 0.01), in the 7 infants who displayed these two opposite patterns.     

A model of ventilatory instability induced in the unrestrained rat.

A classic conditioning paradigm was used to examine the hypothesis that perturbations during sleep in the neonate rat can have a lasting impact on breathing. During the first 4 wk of life, stimuli were presented to rats during behaviorally defined sleep. In a conditioned hypoxic (CH) group, brief periods of hypoxic gas were used as the unconditioned stimulus. Tactile and auditory stimuli were used as the conditioned stimuli. In a conditioned control (CC) group, air was used as the unconditioned stimulus. A third group of unconditioned control (UC) rats was not exposed to the conditioning paradigm. Animals were provided routine care for 3.5 mo; ventilation was then assessed using plethysmography. Conditioning during neonatal life produced increased ventilatory irregularities and apnea during behaviorally defined sleep in adult rats. Both CH and CC rats showed a significantly greater number of apneic events compared with UC rats. Over a 2-h sleep period, CH rats exhibited a total of 105.1 +/- 9.4 (SE) apneic events, CC rats 69.4 +/- 4.2 events, and UC rats 42.1 +/- 3.1 events [F(2,18) = 25.568; P < 0.0001]. These findings suggest that experiences in the first few weeks of life will alter ventilatory patterning in the adult animal.     

Plasma levels of DSIP in infants in the first year of life and SIDS risk.

In searching for abnormalities related to the sudden infant death syndrome (SIDS), delta sleep-inducing peptide (DSIP), a regulatory peptide with sleep promoting actions, was investigated in the first year of life in four groups of children: (1) preterm infants (n = 28), (2) infants with a high mean apnea duration evaluated polysomnographically (n = 26), (3) healthy full-term infants (n = 37) and (4) siblings of SIDS-victims (n = 26). DSIP was radioimmunoassayed in plasma. Half of the infants were also investigated polygraphically during sleep. The ratio between quiet sleep and active sleep was determined. There was no age dependence of the plasma level of DSIP in the first year of life but there was an increase in the ratio of quiet/active sleep depending of maturity. The level of DSIP in healthy full-term infants was significantly higher (P less than 0.05) (median: 1885 pmol/l, interquartile range: 757 pmol/l) than in preterms (1595; 385) and in infants with a high mean apnea duration (1542; 373). There was no significant difference in DSIP concentrations between healthy full-term infants and SIDS-siblings (1605; 271).     

Periodicities in respiration and heart rate in newborns

Periodic breathing is common in normal infants, but may be associated with prolonged apnea leading to crib death. The mechanisms of periodic breathing and its relation to normal breathing patterns are unclear. We recorded respiratory and heart rate (HR) patterns of 11 healthy newborn infants during quiet sleep, in both normal and periodic breathing. Spectral analysis of the respiratory pattern revealed a low-frequency (LF) periodicity in normal breathing approximately equal to the frequency of periodic breathing when this occurs. Periodic breathing thus appears to be an exaggeration of an underlying slow amplitude variation which is present in regular breathing. LF periodicity also appeared in the HR pattern in both normal and periodic breathing, suggesting an LF modulation of cardiovascular control as well. The lack of a definite phase relation between HR and ventilation at LF may indicate dominant peripheral, rather than central, interactions between HR and respiration at these frequencies.     

Effects of progesterone on apneic events during behaviorally defined sleep in male rats

Drug therapy with progesterone has been applied to the patients with sleep apnea syndrome, but its clinical efficacy is equivocal. In the present study, we examined the effects of progesterone (1 and 30 mg/kg, i.p.) on the apneic events during behaviorally defined sleep in male rats at 4, 14 and 26 weeks of age by using a whole body plethysmographic measurement. The number of events of spontaneous apnea (SA) and post-sigh apnea (PSA) increased with aging. The duration of SA or PSA was also prolonged in old rats. A low dose (1 mg/kg) of progesterone significantly decreased the number of both SA and PSA, and this effect increased in an age-dependent manner. However, progesterone had no effect on the duration of SA and PSA. Neither the basal respiratory rate nor the total sleep time was changed. On the other hand, a higher dose (30 mg/kg) of progesterone had no effect on the number of SA and PSA, while it prolonged the duration of PSA. It also prolonged the total sleep time without affecting the basal respiratory rate. Pretreatment with mifepristone (5 mg /kg, i.p.), an antagonist of progesterone receptors, inhibited the effects of the low dose of progesterone, but did not show any antagonistic effect on the high dose-induced changes. These results suggest that the progesterone-mediated mechanisms are involved, at least partly, in respiratory function during sleep and the progesterone therapy is possibly effective within an appropriate dose range for the sleep apnea syndrome.     

Compensatory responses to upper airway obstruction in obese apneic men and women

Defective structural and neural upper airway properties both play a pivotal role in the pathogenesis of obstructive sleep apnea. A more favorable structural upper airway property [pharyngeal critical pressure under hypotonic conditions (passive Pcrit)] has been documented for women. However, the role of sex-related modulation in compensatory responses to upper airway obstruction (UAO), independent of the passive Pcrit, remains unclear. Obese apneic men and women underwent a standard polysomnography and physiological sleep studies to determine sleep apnea severity, passive Pcrit, and compensatory airflow and respiratory timing responses to prolonged periods of UAO. Sixty-two apneic men and women, pairwise matched by passive Pcrit, exhibited similar sleep apnea disease severity during rapid eye movement (REM) sleep, but women had markedly less severe disease during non-REM (NREM) sleep. By further matching men and women by body mass index and age (n = 24), we found that the lower NREM disease susceptibility in women was associated with an approximately twofold increase in peak inspiratory airflow (P = 0.003) and inspiratory duty cycle (P = 0.017) in response to prolonged periods of UAO and an ～20% lower minute ventilation during baseline unobstructed breathing (ventilatory demand) (P = 0.027). Thus, during UAO, women compared with men had greater upper airway and respiratory timing responses and a lower ventilatory demand that may account for sex differences in sleep-disordered breathing severity during NREM sleep, independent of upper airway structural properties and sleep apnea severity during REM sleep.     

Control of breathing in the echidna (Tachyglossus aculeatus) during hibernation

Resting non-hibernating echidnas are characterised by low metabolic rates, but also have a very low respiratory frequency and a variable respiratory minute volume, often resulting in low levels of arterial O(2) and high CO(2). As the echidna lies at one physiological extreme among the hibernators, in terms of its large size and low metabolism and ventilatory requirement when not hibernating, a study of control of breathing during hibernation in echidnas should provide a useful test of the generality of various models. We used non-invasive techniques to study breathing patterns and the control of ventilation in 6 echidnas. Hibernating echidnas (T(b) range 7-10 degrees C) showed episodic breathing with bursts of breaths (average 36+/-16 breaths in 24+/-5 min) followed by a period of apnea (76+/-17 min) then a series (8+/-4) of slow breaths at 14+/-1 min intervals leading up to the next burst. Increasing CO(2) levels in the inspired air increased the number of breaths in a burst, eventually leading to continuous breathing. Inter burst breaths were controlled by O(2): hypoxia increased inter burst breaths, and decreased burst length, while hyperoxia abolished inter burst breaths and increased the apneic period. Overall, while CO(2) was a strong respiratory stimulus in hibernating echidnas, O(2) had little effect on total ventilation, but did have a strong effect on the breathing pattern.