To investigate the effects of bilateral intrathoracic vagotomy on the establishment of continuous breathing and effective gas exchange at birth, we studied 8 chronically instrumented, unanesthetized, sham-operated and 14 vagotomized newborn lambs after a spontaneous, unassisted vaginal delivery. Fetal lambs were instrumented in utero to record sleep states, diaphragmatic electromyogram, blood pressure, arterial pH, and blood-gas tensions. Six of eight sham-operated lambs established effective gas exchange within 10 min of birth, whereas 12 of 14 vagotomized animals developed respiratory acidosis and hypoxemia (P = 0.008). Breathing frequency in vagotomized newborns was significantly lower during the entire postnatal period compared with sham-operated newborns. Vagotomized subjects also remained hypothermic during the entire postnatal period (P < 0.05). Bronchoalveolar lavage indicated an increased minimum surface tension, whereas lung histology showed perivascular edema and partial atelectasis in the vagotomized group. We conclude that stimulation of breathing and effective gas exchange are critically dependent on intact vagal nerves during the transition from fetal to neonatal life.

ABSTRACT. Lung distension with 100% 0 2 at a continuous positive airway pressure of 30 cm H 2 0 may induce continuous fetal breathing movements (FBM) in sheep. The objectives of this study were 1 ) to investigate the relative roles of lung distension and oxygenation and 2) to test the hypothesis that FBM can be induced during labor, when normally they are greatly reduced or absent. We studied 13 chronically instrumented, unanesthetized fetal sheep between 128 and 144 d of gestation (term = 147 f 2 d). Each fetus was instrumented to record sleep states, diaphragm electromyogram, blood pressure, arterial pH, and blood gas tensions. The fetal lungs were distended via an in situ endotracheal tube with four different concentrations of O2 (0, , it has been known that fetal sheep make irregular, rapid, and episodic breathing movements (2). One of the many unique and vital changes occumng at birth is the establishment of continuous breathing. Mechanisms for the control of FBM or the initiation of continuous breathing at birth remain unknown. In sheep, during late gestation (1 15-120 d; term = 147 k 2 d), FBM occupy 40% of the total time and occur normally only during LV-ECoG and are absent during HV-ECoG. Although the precise control mechanism for FBM has yet to be explained, FBM are susceptible to modulation. Isocapnic hypoxemia suppresses and normoxic hypercapnia stimulates FBM (3, 4); morphine, meclofenamate, indomethacin, pilocarpine, doxapram, aminophylline, caffeine, and 5-hydroxytryptophan stimulate, whereas general anesthetics, barbiturates, diazepam, and prostaglandin E2 depress FBM (2, 5-8).We have recently shown that distending fetal lungs with 100% O2 at a CPAP of approximately 30 cm H 2 0 may induce continuous FBM (9). However, the relative roles of distending pressure and oxygenation remain unknown. Nor is it known if these FBM can be induced during spontaneous onset of labor when normally these are absent or greatly reduced. Therefore, we designed a study I ) to investigate the relative roles of oxygenation and distending pressure by using various concentrations of O2 and different levels of distending pressures and 2) to test the hypothesis that FBM can be induced during spontaneous onset of labor. MATERIALS AND METHODSAnimal preparation. We studied 13 fetal sheep between 128 and 144 d of gestation. Surgery was performed on time-dated, pregnant ewes of mixed breed between 124 and 132 (127 + 2) d of gestation using 4% halothane in O2 for induction of anesthesia and 1.5 to 2% for maintenance. After the skin was cleansed with iodine and 70% alcohol, the abdominal wall was opened by a midline incision using sterile technique. Avoiding major vessels, the uterine cavity was opened and the fetal head and neck were exteriorized. The uterine wall and fetal skin were brought together with several Babcock forceps to minimize loss of amniotic fluid. An incision was made at the upper dorsal part of the neck to tunnel four color-coded electrode wires to record ECoG, EOG, EMGNK, and diaphragm electromyogram. The elect...

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To investigate the effects of bilateral cervical vagotomy on arousal and breathing responses, we studied eight sham-operated and eight chronically instrumented unanesthetized vagotomized sheep fetuses between 136 and 144 days of gestation (term approximately 147 days). Each fetus was instrumented to record sleep states, diaphragmatic electromyogram, blood pressure, pH, and blood gas tensions. In a randomized order, fetal lungs were distended with four different O2 concentrations: 0 (100% N2), 21, 50, and 100% at a continuous positive airway pressure of 30 cmH2O via an in situ Y-endotracheal tube. Under control conditions, inspiratory time and the duration of the single longest breathing episode decreased from 598 +/- 99 (SD) ms and 24 +/- 10 min in sham group to 393 +/- 162 ms and 11.0 +/- 3.0 min in vagotomized group (P = 0.04 and 0.033), respectively. In response to lung distension with 100% N2, breathing time decreased from 44 +/- 17 to 20 +/- 18% (P = 0.045) in sham-operated fetuses, whereas it remained unchanged in the vagotomized group. In response to 100% O2, fetal arterial PO2 increased in five of eight fetuses sham-operated from 18.2 +/- 5.1 to 227 +/- 45 Torr (P = 0.0001) and in six of eight vagotomized fetuses from 18.5 +/- 4.4 to 172 +/- 39 Torr (P < 0.001). Although arousal was observed in all oxygenated fetuses at the onset of breathing, the duration of arousal was markedly attenuated in vagotomized fetuses (14 +/- 10 vs. 46 +/- 29 min in sham group; P = 0.024). Frequency and amplitude of breathing and respiratory output (frequency x amplitude) increased only in sham group (P = 0.02, 0.004, and 0.0002, respectively). We conclude that in response to lung distension and oxygenation, arousal and stimulation of breathing during active and quite sleep are critically dependent on intact vagal nerves.

Afferent volume feedback plays a vital role in neonatal respiratory control. Mechanisms for the profound respiratory depression and life-threatening apnoeas observed in vagally denervated neonatal animals remain unclear. We investigated the roles of sleep states, hypoxic-hypercapnia and afferent volume feedback on respiratory depression using reversible perineural vagal block during the early postnatal period. Seven lambs were instrumented during the first 48 h of life to record/analyse sleep states, diaphragmatic electromyograph, arterial blood gas tensions, systemic arterial blood pressure and rectal temperature. Perineural cuffs were placed around the vagi to attain reversible blockade. Postoperatively, during the awake state, both vagi were blocked using 2% xylocaine for up to 30 min. Compared to baseline values, pH , and decreased and increased during perineural blockade (P< 0.05). Four of seven animals exhibited apnoeas of ≥20 s requiring the immediate termination of perineural blockade. Breathing rates decreased from the baseline value of 53 ± 12 to 24 ± 20 breaths min during blockade despite an increased (P< 0.001). Following blockade, breathing patterns returned to baseline values despite marked hypocapnia ( 33 ± 3 torr; P = 0.03). Respiratory depression and apnoeas were independent of sleep states. The present study provides the much needed physiological evidence indicating that profound apnoeas and life-threatening respiratory failure in vagally denervated animals do not result from a lack of arousal or hypoxaemia. Rather, a change in sleep state and concomitant respiratory depression result from a lack of afferent volume feedback, which appears to be critical for the maintenance of normal breathing patterns and adequate gas exchange during the early postnatal period.