Afferent neural feedback overrides the modulating effects of arousal, hypercapnia and hypoxaemia on neonatal cardiorespiratory control.

KEY POINTS: Evidence obtained at whole animal, organ-system, and cellular and molecular levels suggests that afferent volume feedback is critical for the establishment of adequate ventilation at birth. As a result of the irreversible nature of the vagal ablation studies performed to date, it was difficult to quantify the roles of afferent volume input, arousal and changes in blood gas tensions on neonatal respiratory control. During reversible perineural vagal block, profound apnoeas and hypoxaemia and hypercarbia were observed, necessitating the termination of perineural blockade. Respiratory depression and apnoeas were independent of sleep state. We demonstrate that profound apnoeas and life-threatening respiratory failure in vagally denervated animals do not result from a lack of arousal or hypoxaemia. 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. ABSTRACT: 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, pHa , Pao2 and Sao2 decreased and Paco2 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-1 during blockade despite an increased Paco2 (P < 0.001). Following blockade, breathing patterns returned to baseline values despite marked hypocapnia ( Paco2 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.

Prenatal cigarette smoke exposure and postnatal respiratory responses to hypoxia and hypercapnia.

Prenatal cigarette smoke (CS) exposure, in combination with hypoxia and/or hyperthermia can lead to gasping and attenuated recovery from hypoxia in 7 days old rat pups. We studied 95 unanesthetized spontaneously breathing 14 days old rat pups to investigate if the destabilizing effects of increased ambient temperature and prenatal CS exposure on respiratory control observed in 7 days old rats were still evident at day 14. This postnatal age was selected as it is beyond the analogous risk period for SIDS in human. Furthermore, we investigated if the breathing responses to hypercapnia are affected by prenatal CS exposure. Since high ambient (HA) temperature can lead to gasping and aberrant respiratory control, we recorded respiratory patterns at low (24-25°C) and high (29-30°C) ambient temperatures, and under hypoxic or hypercapnic states. No gasping was observed in 14 days old rat pups. During hypoxia, breathing frequency increased in the CS-exposed group under low and HA temperatures. Rectal temperature decreased only in the sham group in response to low ambient temperature hypoxia. At HA temperature, breathing frequency increased in both sham and CS-exposed groups during hypercapnia, however, it remained elevated during washout period only in the sham group. We demonstrate that prenatal CS exposure continues to have profound effects on respiratory and thermoregulatory responses to hypoxia and hypercapnia at day 14. The attenuated respiratory and thermoregulatory responses to acute hypoxia and hypercapnia on day 14 demonstrate a strong interaction between CS exposure, respiratory control, and thermoregulation during postnatal maturation.

Respiratory control in neonatal rats exposed to prenatal cigarette smoke.

RATIONALE: Prenatal cigarette smoke (CS) exposure, increased environmental temperature, and hypoxic episodes have been postulated as major risk factors for sudden infant death syndrome. OBJECTIVES: To test the hypothesis that maternal CS exposure disrupts eupneic breathing and depresses breathing responses of neonatal rats to thermal and hypoxic challenges. METHODS: Experiments were performed on 1-week-old rat pups exposed prenatally to CS (n = 39) or room air (sham; n = 30). Breathing patterns were recorded by whole-body plethysmography during thermoneutral or hyperthermic states under normoxic and hypoxic conditions. MEASUREMENTS AND MAIN RESULTS: Mean pup weight, breaths per minute, and gasping respiratory patterns were measured for both smoke- and sham-exposed groups during thermoneutral and hyperthermic states under normoxic and hypoxic conditions. Under thermoneutral conditions, hypoxia caused gasping in CS-exposed animals but not in sham-exposed animals. Furthermore, under hyperthermic conditions, whereas hypoxia induced gasping in both groups, only CS-exposed animals exhibited a pronounced and longer lasting respiratory depression after the termination of hypoxia. CONCLUSIONS: We show that prenatal CS exposure increases the likelihood of gasplike respiration and provide the first experimental evidence that the combined effects of prenatal CS exposure and hyperthermia dramatically prolong the time required for neonates to return to eupneic breathing after hypoxia. These observations provide important evidence of how prenatal CS exposure, hypoxic episodes, and hyperthermia might place infants at higher risk for sudden infant death syndrome.