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Experimentally modified breathing pattern in human subjects, by varying the inspired gas mixture or administering different neuromodulators, has been studied extensively in the past, yet unmodified breathing has not. Moreover, most data refer to infants during sleep and adults during wakefulness. We studied the baseline breathing pattern of preterm infants [n = 10; GA 30 (27-34) wk (median, range)]; term infants [n = 10; GA 40 (39-41) wk)], and adult subjects [n = 10; age 31 (17-48) y)] during quiet sleep. A flow-through system was used to measure ventilation. We found: (i) instantaneous ventilation was 0.273 ± 0.006, 0.200 ± 0.003, and 0.135 ± 0.002 L · min[sup -1] · kg[sup -1] in preterm, term infants, and adult subjects; the coefficients of variation were 39%, 25%, and 14% (p < 0.01). The greater coefficient of variation in neonates compared to adults related to increased variability in Vt (39% and 25% in preterm and term infants vs 14% in adults; p < 0.01) and f (39% and 22% vs 9%; p < 0.01). The major determinant of frequency in preterm infants was Te (81% variability), Ti varying less (25% variability); (ii) V[sub T]/Ti decreased and Ti/Ttot increased with age; (iii) the higher breath-to-breath variability in preterm infants was associated with larger changes in alveolar PCO[sub 2] and a larger variability in O[sub 2] saturation than later in life. We conclude: (i) the high breath-to-breath variability in frequency in preterm infants closely relates to variation in Te; (ii) decreased effective inspiratory timing (Ti/Ttot) in preterm infants compared with adults likely reflects their high pulmonary impedance; and (iii) greater breath-to-breath variability in ventilation in neonates with large variations in alveolar PCO[sub 2] and O[sub 2] saturation remains when compared with values in the sleeping adult. We speculate that high variability in Te early in life represents an effort to maintain lung volume through increased post-inspiratory diaphragmatic activity and increased upper airway resistance in an attempt to avoid collapse due to poor chest wall recoil. [ABSTRACT FROM AUTHOR]

Airway closure during mixed apneas in preterm infants may be due to lack of tone in the upper airway followed by collapse and obstruction or diaphragmatic action inducing obstruction. We examine whether respiratory efforts are necessary for airway closure using a new method of detecting airway obstruction, based on the disappearance of an amplified cardiac pulse observed on the respiratory flow tracing. We analyzed 198 episodes of mixed apnea of various lengths (> or = 3 seconds) observed in 33 preterm infants (birth weight, 1.4 +/- 0.1 kg [mean +/- SEM]; study weight, 1.7 +/- 0.1 kg; gestational age, 29 +/- 1 weeks; post-natal age, 33 +/- 4 days). The great majority of these episodes (88%) had a central, followed by an obstructive, component. Infants were studied by using a nosepiece and a flow-through system. Respiratory efforts (abdominal and chest movements) were recorded. Of the apneas, 20 were < 5 seconds; 78, 5 to < 10 seconds; 45, 10 to < 15 seconds; 27, 15 to < 20 seconds; and 28, > or = 20 seconds. Of the 198 mixed apneas, 151 (76%) occurred in the absence of any respiratory effort; 43 (22%) showed a simultaneous cessation of the cardiac oscillation and respiratory effort; and 4 (2%) showed diaphragmatic activity appearing after cessation of the cardiac oscillation (airway occlusion). Respiratory efforts never preceded the cessation of the cardiac oscillation. The findings suggest that diaphragmatic action is not needed to occlude the airway in mixed apneas. The simultaneous cessation of cardiac oscillations (airway occlusion) and onset of respiratory efforts may indicate that such effort contributes to closure or is induced by the same stimulus that closes the airway. We speculate that the mechanism for airway closure in mixed apneas is most likely a lack of upper airway tone, which normally occurs with the cessation of a central drive to breathe.

The timing and magnitude of airway narrowing in central apneas is unknown. We have developed a method of apnea classification that relies on the transmission of cardiac airflow oscillation to indicate airway patency. Using a theoretical model, we showed that the amplitude of the cardiac airflow oscillation is proportional to airway diameter for small lumens. While in the majority of central apneas the amplitude of the cardiac airflow oscillation remains nearly constant, in a subset of events the waveform decreases with time, suggesting airway narrowing. We hypothesized that this is not a random occurrence but reflects a critical period of airway instability during central apnea. To test this hypothesis we studied 41 preterm infants. Of 4,456 central apneas, 585 had a decrease in the amplitude of the cardiac oscillation. The amplitude of the cardiac airflow oscillation during an apnea was recorded to provide a dynamic measure of changes in airway diameter with time. To allow for comparisons between patients the amplitude of each cardiac airflow oscillation was expressed as a proportion of the maximum amplitude observed in each infant. We then compared the amplitude at multiple successive 0.5 s intervals with the amplitude of the cardiac airflow oscillation observed at the apnea outset using ANOVA. We found a significant decrease in cardiac airflow oscillation after only 1 s irrespective of the apnea duration (3 to 16 s). We conclude that airway narrowing during central apnea is not a random occurrence but appears shortly after the onset of the apnea. We speculate that the phenomenon is secondary to passive airway relaxation.

We tested the hypothesis that the surge of norepinephrine at birth is associated with the establishment of continuous breathing. Therefore, we studied whether the administration of norepinephrine could enhance fetal breathing during administration of oxygen, or 100% O2 plus cord occlusion, and if phenoxybenzamine would reverse these changes. Fetal sheep were instrumented in late gestation to measure electrocortical activity and diaphragmatic electromyography. These parameters and blood gases were measured before and during in utero administration of nitrogen, 100% O2, 100% O2 plus umbilical cord occlusion, and subsequently during umbilical reperfusion and recovery. Nine fetuses (14 experiments) received continuous norepinephrine (0.13 microgram/kg/min) throughout the experiment while 9 other fetuses (18 experiments) underwent the same treatment without the hormonal infusion. We found that norepinephrine inhibited the breathing induced by 100% O2 plus cord occlusion, despite a significant increase in the duration of low-voltage electrocortical activity; phenoxybenzamine reverted these changes. The findings suggest that the surge of norepinephrine at birth is probably not the primary mechanism for establishment of continuous breathing.

Previous studies have revealed a placental extract that inhibits breathing in fetal sheep. In the present study of 29 chronically instrumented sheep at 132+/-1 days of gestation, infusion of the 1-10 kDa extract inhibited breathing in 76% of the experiments whereas Krebs' solution inhibited it in 24%. It retained this activity after 6 months of freezing, after lyophilization, and upon lowering the pH during purification from 8.0 to 4.0, but it inhibited breathing in only 35% when the pH was lowered to 2.0. A significant dose-dependent effect was observed from a 16-fold dilution to a 4-fold concentration. Treatment of the extract with proteinase K or boiling reduced the activity to 30% or 26% inhibition, respectively. The activity was not adsorbed to an ion-exchange column at pH 7.0 or 8.0, but it was at pH 9.0 and it eluted with increasing NaCl concentrations. On a polyacrylamide gel the activity was eluted at a K(av) of 0.66 (82% inhibition), corresponding to between 2.5 and 4.5 kDa. These findings suggest that a peptide produced by the placenta, with a molecular mass between 2.5 and 4.5 kDa, inhibits fetal breathing.

The mechanism underlying the biphasic ventilatory response to hypoxia in neonates is poorly understood. Because alveolar PCO2 (PaCO2) decreases and remains low during hypoxia, it has been argued that a decrease in metabolism may occur. We hypothesized that if the late decrease in ventilation during hypoxia is due to a decrease in CO2 production, an increase in PACO2 should abolish it. We studied 27 preterm infants [birth weight, 1,700 +/- 41 g (mean +/- SEM); study weight, 1,760 +/- 36 g; gestational age 32 +/- 0.2 weeks; postnatal age, 17 +/- 1 days]. A flow-through system and Beckman analyzers were used to measure ventilation and alveolar gases. Metabolism was expressed as changes in oxygen consumption. Infants were studied randomly during hypoxia alone (15% O2 + N2, n = 55) and during hypoxia plus CO2 (0.5% CO2, n = 30; 2% CO2, n = 10). Each experiment consisted of 2 minutes of control measurements (21% O2), 5 minutes of measurements during hypoxia alone or hypoxia plus CO2, followed by 2 minutes of recovery (21% O2). We found a biphasic response to hypoxia with or without CO2 supplementation, the percent change in ventilation from initial peak hyperventilation to late hypoventilation at 5 minutes being -16 +/- 2 on 15% O2; -9 +/- 3 on 15% O2 + 0.5% CO2; and -15 +/- 9 on 15% O2 + 2% CO2 (P < 0.05). The decrease in ventilation was primarily due to a significant decrease in frequency; tidal volume increased. Oxygen consumption decreased similarly with the various inspired gas mixtures during hypoxia. These findings indicate that the decrease in ventilation during hypoxia is unlikely to be solely due to a decrease in metabolism since the late decrease in ventilation following initial hyperventilation still occurred despite the elimination of a fall in PACO2. We speculate that the mechanism underlying the late decrease in ventilation is likely of central origin, probably mediated through the release of inhibitory neurotransmitters.

Currently the classification of neonatal apnea relies upon an inference of airway closure based upon the presence of breathing efforts against such an obstruction. In this study we evaluate a new method of classification which utilizes the presence or absence of cardiac airflow oscillation to detect airway closure. Specifically, this evaluation consisted of an examination of the transmission characteristics of an artificially produced airflow oscillation through discrete airway narrowing in a model system; a confirmation that voluntary upper airway occlusion in adult volunteers uniformly induces complete loss of the oscillation; and a comparison of the cardiac oscillation method with the traditional method of apnea classification in a cohort of 4,309 apneas in 32 infants. We determined that the amplitude of the oscillation is negatively correlated with resistance (r = 0.97) and positively with the radius (r = 0.98) of narrowing in a model system, and that voluntary airway obstruction in adult subjects uniformly results in loss of transmitted cardiac oscillations. Moreover, although there was similarity in the frequency distribution of central, obstructive, and mixed apneas in our infants, there were statistically significantly greater obstructive events detected by the cardiac oscillation method. In addition, the cardiac oscillation method had the additional advantage of providing information regarding the timing of airway obstruction during apnea.

To examine the influence of sleep state, respiratory pattern, and ventilation on cyclical fluctuations (CF) in cerebral blood flow (CBF) velocity (CBFV), we studied 21 'healthy' preterm infants: birth weight 1,790 +/- 162 g (SEM), study weight 1,960 +/- 165 g, gestational age 32 +/- 1 weeks, postnatal age 20 +/- 4 (range 8-57) days. The CBFV was measured using on-line pulsed Doppler ultrasound by insonating the middle cerebral artery. Breathing was measured using a flow through system. The sleep state was monitored according to conventional criteria. Three hundred and seventy-five epochs of 1 min each were analyzed; 207 during quiet sleep (QS) and 168 during rapid eye movement (REM) sleep. CFs in CBFV were detected in all babies. The frequency of CF ranged from 0.5 to 6 cycles/min. The proportion of epochs showing CF was similar during both sleep states (56% QS vs. 59% REM; p = NS). Although the mean CBFV (cm/s) was similar in these two sleep states, the mean coefficient of variation, a measure of CF amplitude, was significantly higher during REM as compared with QS (6 +/- 0.5 vs. 4.3 +/- 0.2%; p < 0.05). Similarly, the mean CBFVs were similar with various respiratory patterns, but the coefficient of variation was significantly higher in periodic and apneic patterns as compared with regular and irregular respiratory patterns (5.6 +/- 0.6% periodic, 5.6 +/- 0.3% apneic, 3.6 +/- 0.3% regular, and 4.1 +/- 0.5% irregular, p < 0.05). The amplitude of CF was associated with the variability of the heart rate (p < 0.05), but not with the variability of the respiratory measurements. These findings suggest: (1) REM sleep is associated with a greater CBF variability than QS, and (2) periodic and apneic breathing are associated with a greater CBF variability than regular or irregular breathing. We speculate that sleep state and respiratory pattern do not determine but modulate the CBF. Our data suggest that in studies involving interpretation of CBFV data using the Doppler technique, breathing patterns should be taken into account in addition to sleep state.

To determine the changes in alveolar PCO2 (PACO2) and PO2 (PAO2) during periodic and regular breathing epochs in the same infants, we studied 11 preterm infants during quiet sleep (birth weight 1,630 +/- 94 g; gestational age 31 +/- 1 weeks; postnatal age 32 +/- 3 days). A total of 94 breathing/apneic cycles were analyzed and compared with regular periods. During periodic and regular breathing epochs, there were negative correlations of PAO2 on PACO2. Short (< or = 5 s) and long (> 5 s) apneas for individual infants occurred along the regression line for that infant. There was not a single overall critical PACO2 below which apnea occurred, but for individual infants the PACO2 and the PAO2 of the breath preceding apnea varied within a limited range. Apneas occurred in clusters of PACO2 and PAO2 along the average regression line of PAO2 on PACO2. Analysis of the data showed that apnea occurred at the lowest PACO2 and highest PAO2 levels if allowance was made for circulation time. During apnea, 'the best fit' for the increase in PACO2 and the decrease in PAO2 was linear, rather than logarithmic. The findings suggest the following. (1) There is not a single overall critical level of PACO2 for apnea to occur, but in a given infant this level varies within a limited range. This indicates that these infants are likely breathing near the apnea threshold. (2) Short and long apneas appear to occur randomly along the regression of PAO2 on PACO2 for a particular infant. (3) The changes in alveolar gases are linear during apnea.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine the effects of sleep on diaphragmatic activity and ventilation we studied 10 preterm infants (birth weight 1,840 +/- 50 g, gestational age 33 +/- 0.6 weeks, and postnatal age 9.4 +/- 1.4 days). We measured surface and esophageal diaphragmatic electromyograms (EMGdi). Ventilation was measured using a nasal flowmeter and a flow-through system. Diaphragmatic activity was analyzed for total phasic activity, expiratory phasic activity, the expiratory to total phasic activity ratio, and the presence of 'tonic' activity. The latter was defined by the presence of electrical activity and the end of expiration. There was a decrease in the average total phasic activity (1.25 vs. 0.71 s, p = 0.001), expiratory phasic activity (0.67 vs. 0.21 s, p = 0.002), the expiratory to total phasic activity ratio (0.51:0.27 s, p = 0.001) and tonic activity (51 to 5%, p = 0.01) from quiet to REM sleep in the surface EMGdi. Similar changes were found in the esophageal EMGdi, except that tonic activity was rarely observed. In parallel with these changes in electrical activity of the diaphragm, minute ventilation and alveolar ventilation increased from quiet to REM sleep. This increase was primarily related to an increase in frequency with a negligible change in tidal volume. The increase in frequency was primarily due to shortening of inspiratory time. The findings that tonic activity recorded via surface electrodes decreased substantially from quiet to REM sleep and was not observed in the esophageal EMGdi suggests that this tonic activity may represent electrical activity of the postural muscles of the chest wall rather than the diaphragm.

To determine the effects of inhaled CO2 and abdominal loading on diaphragmatic electromyography (EMGdi) and ventilation during sleep, we studied 10 preterm infants (birth weight 1,840 +/- 50 g; gestational age 32 +/- 0.6 weeks and postnatal age 10.4 +/- 1.4 days). We measured surface and esophageal diaphragmatic activity. Ventilation was measured using a nasal flowmeter and a flow-through system. Diaphragmatic activity was analyzed for the duration of total phasic and expiratory activities, the expiratory to total phasic activity ratio and the presence of tonic activity (defined by the presence of electrical activity of the diaphragm at the end of expiration). With 3% CO2 in quiet and REM sleep, the intensity of EMGdi increased, but the duration of total phasic activity, the expiratory to total phasic activity ratio and tonic activity did not change. During quiet sleep with 3% CO2, ventilation increased (0.392 +/- 0.028 to 0.616 +/- 0.058 l/min; p = 0.001) due to an increase in tidal volume and frequency. Similar changes occurred in REM sleep. Abdominal loading with sandbags increased the duration of total phasic activity (0.68-0.78 s; p = 0.03), expiratory phasic activity (0.21-0.32 s; p = 0.01), the expiratory to total phasic activity ratio (0.28-0.39; p = 0.03) and diaphragmatic tonic activity (20-60%; p = 0.04) as measured with surface electrodes in REM sleep. It also increased the expiratory to total phasic activity ratio and tonic activity, as measured with surface electrodes in quiet sleep. Abdominal loading did not alter ventilation or the structure of the average breath in either sleep state.(ABSTRACT TRUNCATED AT 250 WORDS)

To test the hypothesis that sighs are mechanistically important in triggering apnea, we studied 10 preterm infants, group 1: body weight 1.8 +/- 0.1 kg, gestational age 33 +/- 1 weeks, postnatal age 21 +/- 4 days, and 10 term infants, group 2: body weight 3.9 +/- 0.15 kg, gestational age 40 +/- 0.4 weeks, postnatal age 1.4 +/- 0.2 days. Instantaneous ventilatory changes associated with a sigh were studied in another 10 preterm infants, group 3: body weight 1.6 +/- 0.11 kg, gestational age 32 +/- 0.4 weeks, postnatal age 25 +/- 4 days. Ventilation was measured using a nosepiece and a flow-through system. Sleep states were recorded. Sighs were more frequent in preterm than in term infants (0.4 +/- 0.04 vs. 0.18 +/- 0.03 sighs/min; p = 0.03) and in rapid eye movement than in quiet sleep (0.5 +/- 0.05 vs. 0.3 +/- 0.05 sighs/min; p = 0.05). Of 722 apneas, 235 (33%) were associated with a sigh; of these, 113 (48%) preceded and 122 (52%) followed a sigh. Sighs induced with airway occlusion (groups 1 and 2) were more frequent after occlusion on 21 than on 35% O2, particularly when O2 saturation was low and negative airway pressure high. Instantaneous ventilation measured over 10 breaths preceding a sigh did not show any trend indicating the possible appearance of a sigh. Tidal volume increased from 7.5 +/- 0.7 before the sigh to 18.9 +/- 0.7 ml/kg (p < 0.01) during a sigh, with a significant increase in inspiratory drive. Ventilation increased from 0.327 +/- 0.041 to 0.660 +/- 0.073 l/min/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Traditionally, the increase in ventilation occurring after approximately 4 s of CO2 inhalation in preterm infants has been attributed to an action at the peripheral chemoreceptors. However, on a few occasions, we have observed a short apnea (2-3 s) in response to 3-5% CO2 in these infants. To test the hypothesis that this apnea reflects a respiratory sensory reflex to CO2, we gave nine preterm infants [birth wt 1.5 +/- 0.1 (SE) kg, gestational age 31 +/- 1 wk] 7-8% CO2 while they breathed 21% O2. To study the dose-response relationship, we also gave 2, 4, 6, and 8% CO2 to another group of seven preterm infants (birth wt 1.5 +/- 0.1 kg, gestational age 31 +/- 1 wk). In the first group of infants, minute ventilation during 21% O2 breathing (0.232 +/- 0.022 l.min-1.kg-1) decreased after CO2 administration (0.140 +/- 0.022, P < 0.01) and increased with CO2 removal (0.380 +/- 0.054, P < 0.05). This decrease in ventilation was related to an apnea (12 +/- 2.6 s) occurring 7.7 +/- 0.8 s after the beginning of CO2 inhalation. There was no significant change in tidal volume. In the second group of infants, minute ventilation increased during administration of 2, 4, and 6% CO2 but decreased during 8% CO2 because of the presence of an apnea. These findings suggest that inhalation of a high concentration of CO2 (> 6%) inhibits breathing through a respiratory sensory reflex, as described in adult cats (H. A. Boushey and P. S. Richardson. J. Physiol. Lond. 228: 181-191, 1973).(ABSTRACT TRUNCATED AT 250 WORDS)

We have recently shown that hyperoxemia alone or combined with umbilical cord occlusion causes continuous breathing and arousal in the fetal sheep (Baier, Hasan, Cates, Hooper, Nowaczyk & Rigatto, 1990). We have not however analyzed the changes in the pattern of breathing associated with these events. To do this, we measured the changes in breathing pattern, electrocortical activity and behaviour on 29 occasions in 15 fetal sheep in late gestation. Fetuses were studied during rest, and during lung distention (about 30 cm H2O) with 100% nitrogen (control), 17% oxygen, 100% oxygen and umbilical cord occlusion. Lung distention was obtained using a high frequency oscillator (Senko Co) and in some fetuses a stroke volume of 0 to 20 cm H2O was used to keep PaCO2 near-constant. We found that lung distention with nitrogen or 17% oxygen did not alter the pattern of breathing or behaviour. In 12 out of 34 (35%) experiments 100% oxygen induced continuous breathing, PaO2 increasing to about 250 torr. In the remaining 22 experiments, PaO2 increased to about 100 torr only and breathing was not continuous but it became continuous upon cord occlusion; with occlusion there was a further increase in PaO2 to 190 torr. The increased breathing with oxygen and occlusion was associated with an increase in breathing output (integral of EMGdi x f), an increase in inspiratory drive (integral of EMGdi/Ti), and a decrease in inspiratory (Ti) and expiratory (Te) times. In ten experiments PaCO2 was kept near-constant and the magnitude of the changes remained.(ABSTRACT TRUNCATED AT 250 WORDS)

We tested the hypothesis that the continuous breathing response to oxygen or oxygen plus umbilical cord occlusion, in the fetal sheep, could be modified by gestational age or labour. We studied 35 chronically instrumented fetal sheep on 84 occasions during late gestation (124 to 141 days), using our window model (Rigatto, 1984). After a resting cycle (1 low-voltage followed by 1 high-voltage electrocortical activity epoch), the fetal lung was distended via an endotracheal tube using mean airway pressure of about 30 cm H2O. Inspired nitrogen, and 100% O2 were given to the fetus during one cycle each. While on 100% O2 the umbilical cord was occluded using a balloon cuff. We found that: (1) the continuous breathing response to 100% O2 occurring in 8% of the experiments at a gestational age less than 130 days, in 25% from 130 to 134 days and in 45% at gestational ages greater than 134 days (P < 0.01); (2) at similar gestational age intervals the breathing responses to umbilical cord occlusion were 67%, 84%, and 100% (P < 0.01); and (3) in the presence of labour, 45% of the experiments responded to O2 with continuous breathing as compared to 23% in the absence of labour (P < 0.01). Cord occlusion did not affect these values. Because the highest PaO2 achieved increased significantly to 128 days but not thereafter it is unlikely that these results can be explained on the basis of an increase in PaO2 alone. We speculate that there is an age related maturation of the inhibition of breathing normally present in the fetus.(ABSTRACT TRUNCATED AT 250 WORDS)

To measure the response time of the peripheral chemoreceptors, we studied 13 preterm infants [birth weight 1602 +/- 230 g (mean +/- SEM); gestational age 31 +/- 1 wk; postnatal age 15 +/- 1 d] during inhalation of 21% O2 (15 +/- 5 s) followed by 100% O2 (1 min). We used a flow-through system to measure ventilation and gas analyzers to measure alveolar gases. Hypoventilation was observed at 3.6 +/- 0.6 s and was maximal at 6.8 +/- 1 s after O2 began. This maximal response was always associated with an apnea (greater than 3 s). Alveolar PO2 increased from 13.5 +/- 0.1 kPa (101 +/- 0.8 torr) (control) to 28.0 +/- 1.2 kPa (210 +/- 9 torr) (1st O2 breath), to 42.0 +/- 2.4 kPa (315 +/- 18 torr) (1st hypoventilation), to 45.9 +/- 4.1 kPa (344 +/- 31 torr) (breath preceding maximal response), and to 53.6 +/- 4.1 kPa (402 +/- 31 torr) (at maximal response). Minute ventilation was 0.192 +/- 0.011 (control), 0.188 +/- 0.011 (1st O2 breath), 0.088 +/- 0.016 (1st hypoventilation; p less than 0.0001), 0.122 +/- 0.016 (breath preceding maximal response; p less than 0.0002), and 0.044 +/- 0.011 L/min/kg at maximal response (p less than 0.0001). This decrease in ventilation was due to a decrease in frequency with no appreciable change in tidal volume. The initial period of hypoventilation (19 +/- 4 s) was followed by a breathing interval (10 +/- 2 s) and a second period of hypoventilation (14 +/- 3 s) before continuous breathing resumed.(ABSTRACT TRUNCATED AT 250 WORDS)

Although the administration of 100% O2 alone or combined with umbilical cord occlusion induces continuous breathing and arousal in the fetal sheep (Baier, Hasan, Cates, Hooper, Nowaczyk & Rigatto, 1990a), the individual contribution of O2 and cord occlusion to the response have not been determined. We hypothesized that if O2 is an important factor in the induction of continuous breathing, administration of O2 low enough (10%) to bring fetal arterial PO2 to about 20 torr while the fetus is breathing continuously should reverse these changes. Thus we subjected 12 chronically instrumented fetal sheep to 10% O2 for 10 minutes after the establishment of continuous breathing by O2 (4 fetuses; 137 +/- 1 days) or by O2 plus umbilical cord occlusion (8 fetuses; 134 +/- 1 days). Arterial PO2 decreased from about 250 torr to 20 torr during 10% O2. This induced a significant decrease in breathing output (EMGdi x f) related primarily to a decrease in frequency (f). In 3/5 experiments in 4 fetuses, with O2 alone, apnoea developed within 4 +/- 0.6 min; in 12/13 experiments in 8 fetuses, with added cord occlusion it developed at 5 +/- 0.6 min. With the decrease in PaO2, electrocortical activity (ECoG) switched from low to high-voltage within 6 minutes in 5/5 experiments (O2 alone) and in 11/13 (O2 plus cord occlusion). The findings suggest that umbilical cord occlusion alone is not sufficient to maintain breathing continuously and an increased PaO2 is needed. We speculate that in the fetus there is a vital link between PaO2, breathing and ECoG with low PaO2 inhibiting and high PaO2 favouring breathing and arousal.

The measurement of the ventilatory response to inhaled CO2 is unphysiologic because the CO2 that normally stimulates breathing is endogenous (tissue or venous CO2). We took advantage of the spontaneous changes in alveolar PCO2 and ventilation occurring in preterm infants during periodic breathing to calculate the ventilatory response to endogenous CO2. This response was obtained in 20 infants and compared with those obtained using the more conventional methods of steady-state inhalation of CO2 (12 infants) and rebreathing of CO2 (11 infants); it was also compared with a transient change in alveolar CO2 obtained by inhalation of 7% CO2 in air for 10 s (CO2 "bolus"; 11 infants). All groups of infants had similar birth weight and gestational ages. To calculate the response to endogenous CO2, delta PACO2 was measured as the difference between lowest and highest PaCO2 and delta VE was the difference between the corresponding instantaneous ventilation. To adjust for circulation time, values for PACO2 were made lowest for the last breath before apnea and highest for the first breath after apnea. The coefficient of variation of the method was 8%. The slope of the ventilatory response to endogenous CO2 was 0.067 +/- 0.009 (mean +/- SE) L.min-1.kg-1.mm Hg PACO2(-1), a value greater than that using steady-state and rebreathing methods (0.038 +/- 0.004 and 0.040 +/- 0.006 L.min-1.kg-1.mm Hg PACO2(-1), respectively), but similar to that of infants inhaling a CO2 "bolus" (0.051 +/- 0.009 L.min-1.kg-1.mm Hg PACO2(-1)).(ABSTRACT TRUNCATED AT 250 WORDS)

We hypothesized that enteral doxapram would effectively treat apnea of prematurity without the appearance of major side effects. Of 16 infants, 10 (BW 1,520 +/- 102 g) received doxapram alone and 6 (BW 1,020 +/- 35 g) received doxapram plus theophylline. Apneas decreased from 16.7 +/- 1.9 to 2.1 +/- 0.6 in infants receiving doxapram alone, and from 38.2 +/- 4.4 to 7.9 +/- 2.2 apneas/24 h in those receiving doxapram plus theophylline. This was associated with an increase in alveolar ventilation, a shift of the ventilatory response to CO2 to the left, and no change in the immediate ventilatory response to 100% oxygen. Side effects included premature teeth buds corresponding to the lower central incisors, prevalence of occult blood in stool and necrotizing enterocolitis. The findings suggest that doxapram effectively controls apnea when given enterally, but should be used cautiously because of potentially harmful side effects.

In the foetal sheep, administration of morphine induces apnoea followed by hyperpnoea; during hyperpnoea the foetus arouses. We tested the hypothesis that naloxone, an opiate antagonist, would block these responses. In 14 foetal sheep between 123 and 140 days of gestation, we measured electrocortical activity (ECoG), eye movements (EOG), diaphragmatic activity (EMGdi), blood pressure and amniotic pressure. Morphine (1 mg/kg) was injected in the foetal jugular vein during low-voltage ECoG. Saline or naloxone (0.1, 0.5 and 2.0 mg) were given, in randomized order, before the morphine injection, shortly after morphine injection during apnoea, and during maximum hyperpnoea. Saline alone had no effect on breathing or behaviour. When saline and naloxone preceded the morphine injection the length of apnoea was 26.6 +/- 7.7 and 19.5 +/- 7.0 min (SEM, P = 0.25) while the length of sustained hyperpnoea was 104.8 +/- 11.4 and 29.6 +/- 8.4 min respectively (P = 0.001). When administered during the maximum breathing response, naloxone decreased the length of breathing from 92.2 +/- 8.4 (saline) to 8.8 +/- 2.9 min (P = 0.001). Respiratory output (fEMGdi x f) also decreased from 6545 +/- 912 arbitrary units post saline to 3841 +/- 629 arbitrary units after naloxone (P = 0.05). Arousal disappeared with the decrease in breathing response. The negligible effect of naloxone on apnoea and its strong inhibition of hyperpnoea suggest that morphine may act on two distinct central regions or on two subtypes of opioid receptors to produce apnoea, hyperpnoea and arousal.

To test the hypothesis that continuous fetal breathing could be induced by hyperoxemia alone or by hyperoxemia and umbilical cord occlusion, even in the absence of a rise in arterial PCO2 (PaCO2), we studied 18 chronically instrumented fetal sheep on 34 occasions using our window model (18). After a resting cycle (1 low-voltage followed by 1 high-voltage electrocortical activity epoch), the fetal lung was distended via an endotracheal tube using mean airway pressure of approximately cmH2O. Inspired N2, 17% O2, and 100% O2 were given to the fetus during one cycle each. While 100% O2 was given, the umbilical cord was occluded (balloon cuff).(ABSTRACT TRUNCATED AT 250 WORDS)

In the unanesthetized fetal sheep the administration of morphine causes initial apnoea followed by hyperpnoea. We thought that a section of the brain at midcollicular level might separate these two effects. Therefore we sectioned the brain stem of five fetuses at 132 +/- 1 (SEM) days of gestation and compared their responses to morphine (17 experiments) with that observed in seven intact fetuses at similar gestational ages (15 experiments). Brain stem sections were confirmed morphologically and histologically. Morphine, 1 mg/kg was injected in the fetal jugular vein during low-voltage electrocortical activity (ECoG). We measured ECoG, eye movements, diaphragmatic activity, blood pressure and amniotic pressure. Sectioned fetuses before the administration of morphine had a complete dissociation between ECoG and breathing activity. With the administration of morphine we found: (i) the length of the apnoea was 139.8 +/- 15.5 min in sectioned fetuses and 17.0 +/- 5.8 min in intact fetuses (P less than 0.01); and (ii) there was no hyperpneic response in the sectioned fetus whereas the length of hyperpnoea in the intact group was 99.1 +/- 11.8 min (P less than 0.001). The results support the idea of two central distinct areas of action of morphine in the fetal brain. The absence of hyperpnoea in the sectioned fetuses suggests that neurons inhibiting the 'respiratory neurons' are located rostrally to the mid-collicular line.

To define the dose response of apnea and breathing to morphine we studied 12 fetuses at 116-141 days of gestation using our window technique. We instrumented the fetus to record electrocortical activity (ECoG), eye movements (EOG), diaphragmatic activity (integral of EMGdi), heart rate, carotid blood pressure, and amniotic pressure. Saline and morphine in doses of 0.03, 0.1, 0.5, 1, and 3 mg/kg were injected in random order in the jugular vein of the fetus during low-voltage ECoG. Fetuses were videotaped for evaluation of fetal behavior. We found 1) that saline did not elicit a response; 2) apnea, associated with a change from low- to high-voltage ECoG, increased from 2.2 +/- 1.5 (SE) min in two fetuses at a dose of 0.03 mg to 20 +/- 6.3 min in seven fetuses at 3 mg/kg (P less than 0.005); 3) the length of the breathing responses, associated with a change from high- to low-voltage ECoG, were 15 +/- 1.8 and 135.9 +/- 18.1 min (P less than 0.0005); 4) integral of EMGdi X frequency, an index equivalent to minute ventilation, increased from 1,763 +/- 317 arbitrary units to 10,658 +/- 1,843 at 1.0 mg/kg and then decreased to 7,997 +/- 1,335 at 3.0 mg/kg. These changes were related to a steady increase in integral of EMGdi, whereas frequency decreased at 3 mg/kg. There was an increase in breathing response to morphine plasma concentrations or morphine doses.(ABSTRACT TRUNCATED AT 250 WORDS)

We hypothesized that infants recovering from severe bronchopulmonary dysplasia have airway constriction that is, at least in part, related to borderline hypoxia. If this hypothesis were correct, pulmonary resistance should decrease with the administration of oxygen. To test this hypothesis, we studied 10 infants recovering from severe bronchopulmonary dysplasia (study weight 2490 +/- 275 gm; birth weight 1010 +/- 89 gm; postnatal age 73 +/- 7 days; postconceptional age 38.5 +/- 1.6 weeks) and 10 matched control infants (study weight 2430 +/- 179 gm; birth weight 2320 +/- 195 gm; postnatal age 25 +/- 4 days; postconceptional age 37.5 +/- 0.8 weeks). Resistance and compliance were measured by means of a mask with a flowmeter and an esophageal balloon (with the PEDS computer program). Measurements in both groups were made in quiet sleep, without sedation, during the inhalation of room air and during the fifth minute of oxygen inhalation. We found that (1) total pulmonary resistance, significantly higher in infants with bronchopulmonary dysplasia than in control infants, decreased from 206.1 +/- 47 cm H2O.L-1.sec-1 during inhalation of room air to 106.5 +/- 20.9 during inhalation of 100% oxygen (p less than 0.05) and (2) pulmonary dynamic compliance, lower in infants with bronchopulmonary dysplasia than in control infants, increased significantly with the administration of 100% oxygen. The results suggest that infants with bronchopulmonary dysplasia have airway constriction and that this is alleviated by inhalation of oxygen.

We wanted to know whether the ventilatory response to low concentrations of CO2 is measurable in the absence of change in alveolar PCO2, is sleep state dependent, and is dictated by the resting respiratory pattern. Therefore, we gave 11 preterm infants (birth weight, 1,565 +/- 122 g; gestational age, 32 +/- 1 wk; postnatal age, 28 +/- 5 days) 0.5 to 1.5% CO2 after a control period of breathing 21% O2. They were studied on 2 or 3 occasions, the aim being to have 5 infants in each of 2 categories, periodic to regular breathing, and regular to regular breathing, after administration of CO2 in both sleep states (n = 20). In both sleep states, when low CO2 increased ventilation, alveolar PCO2 also increased. The increase in ventilation was primarily due to an increase in breathing frequency if breathing was periodic, and to an increase in tidal volume if breathing was regular. This response was not affected by sleep state. We conclude that changes in respiratory pattern with low inhaled CO2 are fundamentally dependent on whether the baseline respiration is periodic or regular.

To examine the influence of feeding on the chemical control of breathing in neonates, we studied the ventilatory response to 3% CO2 in air in nine bottle fed (BOT) and eight breast fed (BR) term infants during feeding while the infants were alert. Control responses were obtained either before or after feeding, VE, respiratory frequency, tidal volume, inspiratory time, expiratory time, and sum of inspiratory and expiratory time, VT/Ti/Ttot, PACO2 and slope (S) of CO2 response (liter/min/kg/mmHg) were determined. During 3% CO2 while resting BR had a lower VE, VT, VT/Ti than BOT and S in BR was 40% of BOT (P less than 0.05). During feeding and CO2 when compared to resting and CO2 there was no difference in either BR or BOT in VT/Ti but Ti/Ttot decreased in both groups. During feeding, S in BOT was reduced from 0.049 +/- 0.012 (mean +/- S.E.) to 0.013 +/- 0.002 (74% reduction) and in BR from 0.020 +/- 0.002 to 0.009 +/- 0.002 (55%). Thus, behavioral activity (either BR or BOT) markedly depresses the ventilatory response to chemical stimuli (CO2). This modification is primarily related to changes in "effective" respiratory timing (Ti/Ttot) rather than mean inspiratory flow (VT/Vi).