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Background: The feasibility and benefits of continuous sustained inflations (SIs) during chest compressions (CCs) during delayed cord clamping (physiological-based cord clamping; PBCC) are not known. We aimed to determine whether continuous SIs during CCs would reduce the time to return of spontaneous circulation (ROSC) and improve post-asphyxial blood pressures and flows in asystolic newborn lambs.Methods: Fetal sheep were surgically instrumented immediately prior to delivery at ~139 days' gestation and asphyxia induced until lambs reached asystole. Lambs were randomised to either immediate cord clamping (ICC) or PBCC. Lambs then received a single SI (SIsing; 30 s at 30 cmH2O) followed by intermittent positive pressure ventilation, or continuous SIs (SIcont: 30 s duration with 1 s break). We thus examined 4 groups: ICC +SIsing, ICC +SIcont, PBCC +SIsing, and PBCC +SIcont. Chest compressions and epinephrine administration followed international guidelines. PBCC lambs underwent cord clamping 10 min after ROSC. Physiological and oxygenation variables were measured throughout.Results: The time taken to achieve ROSC was not different between groups (mean (SD) 4.3±2.9 min). Mean and diastolic blood pressure was higher during chest compressions in PBCC lambs compared with ICC lambs, but no effect of SIs was observed. SIcont significantly reduced pulmonary blood flow, diastolic blood pressure and oxygenation after ROSC compared with SIsing.Conclusion: We found no significant benefit of SIcont over SIsing during CPR on the time to ROSC or on post-ROSC haemodynamics, but did demonstrate the feasibility of continuous SIs during advanced CPR on an intact umbilical cord. Longer-term studies are recommended before this technique is used routinely in clinical practice. [ABSTRACT FROM AUTHOR]

We have examined whether changes in versican levels, or in the sulfation pattern of its chondroitin sulfate (CS) side chains, are associated with the reduction in perialveolar tissue volumes that characterize lung maturation in late-gestation fetal sheep. Lung tissue was collected from fetuses [90-142 days gestational age (GA)] and lambs (2 wk after term birth). The level and distribution of versican and CS glycosaminoglycans (GAG) were determined using immunohistochemistry, whereas fluorophore-assisted carbohydrate electrophoresis was used to determine changes in CS sulfation patterns. Versican was the predominant CS-containing proteoglycan in the lung and decreased from 19.9 [+ or -] 2.7 arbitrary units at 90 days GA to 6.0 [+ or -] 0.5 arbitrary units at 142 days GA, in close association (P < 0.05) with the reduction in tissue volumes (from 66.0 [+ or -] 4.6 to 25.3 [+ or -] 1.5% at 142 days); similar reductions occurred for both chondroitin-6-sulfate and chondroitin-4-sulfate CS side chains. Hyaluronic acid levels decreased from 3,168 [+ or -] 641 pmo1/[micro]g GAG at 90 days GA to 126 [+ or -] 9 pmol/[micro]g GAG at 142 days GA, and the predominant sulfated disaccharide changed from [DELTA]-di-6S at 90 days GA to [DELTA]-di-4S at term. These data indicate that structural development of the lung is closely associated with marked changes in versican levels and the microstructure of CS side chains in perisaccular/alveolar lung tissue. lung maturation; fetus; versican mRNA; glycosaminoglycans

Our aim was to determine whether cortisol's effect on alveolar epithelial cell (AEC) phenotypes in the fetus is mediated via a sustained alteration in lung expansion. Chronically catheterized fetal sheep were exposed to 1) saline infusion, 2) cortisol infusion (122131 days' gestation, 1.5-4.0 rag/day), 3) saline infusion plus reduced lung expansion, or 4) cortisol infusion plus reduced lung expansion. The proportions of type I and II AECs were determined by electron microscopy, and surfactant protein (SP)-A, -B, and -C mRNA levels were determined by Northern blot analysis. Cortisol infusions significantly increased type II AEC proportions (to 38.2 W. W. [+ or -] 2.2%), compared with saline-infused fetuses (23.8 [+ or -] 2.4%), and reduced type I AEC proportions (to 59.0 [+ or -] 2.2%), compared with saline-infused fetuses (70.4 [+ or -] 2.4%). Reduced lung expansion also increased type II AEC proportions (to 52.9 [+ or -] 3.5%) and decreased type I AEC proportions (to 34.2 [+ or -] 3.7%), compared with control, saline-infused fetuses. The infusion of cortisol into fetuses exposed to reduced lung expansion tended to further increase type II (to 60.3 [+ or -] 2.1%, P = 0.066) and reduce type I AEC ito 26.6 [+ or -] 2.3%, P = 0.07) proportions. SP-A, -B, and -C mRNA levels changed in parallel with the changes in type II AEC proportions. These results indicate that cortisol alters the proportion of type I and type II AECs via a mechanism unrelated to the degree of fetal lung expansion. However, reductions in fetal lung expansion appear to have a greater impact on the proportion of AECs than cortisol. lung liquid; surfactant proteins; fetus

Our objective was to determine the effects of sustained alterations in fetal lung expansion on pulmonary elastin synthesis. In fetal sheep, lung expansion was either decreased between 111 and 131 days' gestation (term ~147 days) by tracheal drainage or increased for 2, 4, 7, or 10 days by tracheal obstruction, ending at 128 days' gestation. Lung tropoelastin mRNA levels were assessed by Northern blot analysis, total elastin content was measured biochemically, and staining of lung sections was used to assess the localization and form of elastic fibers. Tracheal obstruction significantly elevated pulmonary tropoelastin mRNA levels 2.5-fold at 2 days, but values were not different from controls at 4, 7, and 10 days; elastin content tended to be increased at all time points. A sustained decrease in lung expansion by tracheal drainage reduced pulmonary tropoelastin mRNA levels 2.5-fold; elastin content was also decreased compared with controls, and tissue localization was altered. Our results indicate that the degree of lung expansion in the fetus influences elastin synthesis, content, and tissue deposition. elastin synthesis; fetus; lung development

Background: Globally, the majority of newborns requiring resuscitation at birth are full term or late-preterm infants. These infants typically have their umbilical cord clamped early (ECC) before moving to a resuscitation platform, losing the potential support of the placental circulation. Physiologically based cord clamping (PBCC) is clamping the umbilical cord after establishing lung aeration and holds promise as a readily available means of improving early newborn outcomes. In mechanically ventilated lambs, PBCC improved cardiovascular stability and reduced hypoxia. We hypothesised that PBCC compared to ECC would result in higher heart rate (HR) in infants needing resuscitation, without compromising safety.Methods and Findings: Between 4 July 2018 and 18 May 2021, infants born at ≥32+0 weeks' gestation with a paediatrician called to attend were enrolled in a parallel-arm randomised trial at 2 Australian perinatal centres. Following initial stimulation, infants requiring further resuscitation were randomised within 60 seconds of birth using a smartphone-accessible web link. The intervention (PBCC) was to establish lung aeration, either via positive pressure ventilation (PPV) or effective spontaneous breathing, prior to cord clamping. The comparator was early cord clamping (ECC) prior to resuscitation. The primary outcome was mean HR between 60 to 120 seconds after birth, measured using 3-lead electrocardiogram, extracted from video recordings blinded to group allocation. Nonrandomised infants had deferred cord clamping (DCC) ≥120 seconds in the observational study arm. Among 508 at-risk infants enrolled, 123 were randomised (n = 63 to PBCC, n = 60 to ECC). Median (interquartile range, IQR) for gestational age was 39.9 (38.3 to 40.7) weeks in PBCC infants and 39.6 (38.4 to 40.4) weeks in ECC infants. Approximately 49% and 50% of the PBCC and ECC infants were female, respectively. Five infants (PBCC = 2, ECC = 3, 4% total) had missing primary outcome data. Cord clamping occurred at a median (IQR) of 136 (126 to 150) seconds in the PBCC arm and 37 (27 to 51) seconds in the ECC arm. Mean HR between 60 to 120 seconds after birth was 154 bpm (beats per minute) for PBCC versus 158 bpm for ECC (adjusted mean difference -6 bpm, 95% confidence interval (CI) -17 to 5 bpm, P = 0.39). Among 31 secondary outcomes, postpartum haemorrhage ≥500 ml occurred in 34% and 32% of mothers in the PBCC and ECC arms, respectively. Two hundred ninety-five nonrandomised infants (55% female) with median (IQR) gestational age of 39.6 (38.6 to 40.6) weeks received DCC. Data from these infants was used to create percentile charts of expected HR and oxygen saturation in vigorous infants receiving DCC. The trial was limited by the small number of infants requiring prolonged or advanced resuscitation. PBCC may provide other important benefits we did not measure, including improved maternal-infant bonding and higher iron stores.Conclusions: In this study, we observed that PBCC resulted in similar mean HR compared to infants receiving ECC. The findings suggest that for infants ≥32+0 weeks' gestation who receive brief, effective resuscitation at closely monitored births, PBCC does not provide additional benefit over ECC (performed after initial drying and stimulation) in terms of key physiological markers of transition. PBCC was feasible using a simple, low-cost strategy at both cesarean and vaginal births. The percentile charts of HR and oxygen saturation may guide clinicians monitoring the transition of at-risk infants who receive DCC.Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12618000621213. [ABSTRACT FROM AUTHOR]

Respiratory distress is relatively common in infants born at or near-term, particularly in infants delivered following elective cesarean section. The pathophysiology underlying respiratory distress at term has largely been explained by a failure to clear airway liquid, but recent physiological evidence has indicated that it results from elevated airway liquid at the onset of air-breathing. We have investigated the effect of elevated airway liquid volumes at birth on cardiorespiratory function in preterm and near-term lambs. Preterm (130 ± 0 days gestation, term °147 days gestation; n = 12) and near-term (139 ± 1 days gestation; n = 13) lambs were instrumented (to measure blood pressure, blood flow, and blood gas status) and, at delivery, airway liquid volumes were adjusted to mimic levels expected following vaginal delivery (Controls; °7 mL/kg) or elective cesarean section with no labor (elevated liquid (EL); 37 mL/kg). Lambs were delivered, mechanically ventilated, and monitored for blood gas status, oxygenation, ventilator requirements, blood flows (carotid artery and pulmonary artery), and blood pressure during the first few hours of life. Preterm and near-term EL lambs had poorer gas exchange and required greater ventilatory support to maintain adequate oxygenation. Pulmonary blood flow was reduced and carotid artery blood flow, mean arterial blood pressure, and heart rate were reduced in EL near-term but not preterm lambs. These data provide further evidence that greater airway liquid volumes at birth adversely affect newborn cardiorespiratory function, with the effects being greater in near-term newborns. NEW & NOTEWORTHY We provide evidence for adverse effects of elevated airway liquid volumes at birth on pulmonary blood flow and gas exchange in both preterm and near-term lambs, although the effects were greatest in near-term newborns. Our study is an important step toward understanding the fundamental physiology underlying the cardiorespiratory morbidity associated with near-term newborns with elevated airway liquid volumes leading to respiratory distress soon after birth. [ABSTRACT FROM AUTHOR]