Adverse respiratory patterns in near-term spontaneously breathing newborn lambs with elevated airway liquid volumes at birth.

Introduction: Recent evidence indicates that respiratory distress (RD) in near-term infants is caused by elevated airway liquid (EL) volume at the beginning of air-breathing after birth. While the adverse effects EL volumes on newborn lung function are known, the effects on respiratory control and breathing patterns shortly after birth (<4 h) are unknown. We investigated the effects of EL volumes on cardiorespiratory function and breathing patterns in spontaneously breathing near-term newborn lambs in the first hours after birth. Methods: At 137-8 days gestation (2-3 days prior to delivery; term ∼147 days), sterile surgery was performed on fetal sheep (n = 17) to implant catheters and blood flow probes. At 140 days, lambs were delivered via caesarean section under spinal anaesthesia. Airway liquid volumes were adjusted to mimic the level expected following vaginal delivery (∼10 ml/kg; Controls; n = 7), or elective caesarean section (∼30 ml/kg; elevated airway liquid group; EL; n = 10). Spontaneous breathing and cardiorespiratory parameters were recorded over four hours after birth. Non-invasive respiratory support with supplemental oxygen was provided if required. Results: EL lambs required higher inspired oxygen levels (p = 0.0002), were less active (p = 0.026), fed less (p = 0.008) and had higher respiratory morbidity scores than Controls (p < 0.0001). EL lambs also displayed higher rates of breathing patterns associated with RD, such as expiratory braking and tachypnoea. These patterns were particularly evident in male EL lambs who displayed higher levels of severe respiratory morbidity (e.g., expiratory braking) than female EL lambs. Conclusion: The study demonstrates that EL volumes at birth trigger respiratory behaviour and breathing patterns that resemble clinically recognised features of RD in term infants.

Respiratory patterns in spontaneously breathing near-term lambs delivered by caesarean section under spinal anaesthesia.

Introduction: The transition to newborn life has typically been studied in intubated and mechanically ventilated newborn lambs delivered via caesarean section (CS) under general anaesthesia. As a result, little is known of the spontaneous breathing patterns in lambs at birth, particularly those at risk of developing respiratory distress (RD). We have developed a method for delivering spontaneously breathing near-term lambs to characterise their breathing patterns in the immediate newborn period. Methods: At 137-8 days gestation (2-3 days prior to delivery; term ∼147 days), fetal lambs (n = 7) were partially exteriorised for instrumentation (insertion of catheters and flow probes) before they were returned to the uterus. At 140 days, lambs were delivered via CS under light maternal sedation and spinal anaesthesia. Lambs were physically stimulated and when continuous breathing was established, the umbilical cord was clamped. Breathing patterns were assessed by measuring intrapleural and upper-tracheal pressures during the first four hours after birth. Results: Newborn lambs display significant heterogeneity in respiratory patterns in the immediate newborn period that change with time after birth. Seven distinct breathing patterns were identified including: (i) quiet (tidal) breathing, (ii) breathing during active periods, (iii) breathing during oral feeding, (iv) tachypnoea, (v) expiratory braking manoeuvres, (vi) expiratory pauses or holding, and (vii) step changes in ventilation. Conclusions: We have described normal respiratory behaviour in newborn lambs, in order to identify respiratory behaviours that are indicative of RD in term newborn infants.

VDUP1: a potential mediator of expansion-induced lung growth and epithelial cell differentiation in the ovine fetus.

The degree of fetal lung expansion is a critical determinant of fetal lung growth and alveolar epithelial cell (AEC) differentiation, although the mechanisms involved are unknown. As VDUP1 (vitamin D3-upregulated protein 1) can modulate cell proliferation, can induce cell differentiation, and is highly expressed in the lung, we have investigated the effects of fetal lung expansion on VDUP1 expression and its relationship to expansion-induced fetal lung growth and AEC differentiation in fetal sheep. Alterations in fetal lung expansion caused profound changes in VDUP1 mRNA levels in lung tissue. Increased fetal lung expansion significantly reduced VDUP1 mRNA levels from 100+/-8% in control fetuses to 37+/-4, 46+/-4, and 45+/-9% of control values at 2, 4, and 10 days of increased fetal lung expansion, respectively. Reduced fetal lung expansion increased VDUP1 mRNA levels from 100+/-16% in control fetuses to 162+/-16% of control values after 7 days. VDUP1 was localized to airway epithelium in small bronchioles, AECs, and some mesenchymal cells. Its expression was inversely correlated with cell proliferation during normal lung development (R2=0.972, P<0.002) as well as in response to alterations in fetal lung expansion (R2=0.956, P<0.001) and was positively correlated with SP-B expression during normal lung development (R2=0.803, P<0.0001) and following altered lung expansion (R2=0.817, P<0.001). We suggest that VDUP1 may be an important mediator of expansion-induced lung cell proliferation and AEC differentiation in the developing lung.