Background: Spontaneous breathing is essential for successful non-invasive respiratory support delivered by a facemask at birth. As hypoxia is a potent inhibitor of spontaneous breathing, initiating respiratory support with a high fraction of inspired O2 may reduce the risk of hypoxia and increase respiratory effort at birth.Methods: Preterm rabbit kittens (29 days gestation, term ~32 days) were delivered and randomized to receive continuous positive airway pressure with either 21% (n = 12) or 100% O2 (n = 8) via a facemask. If apnea occurred, intermittent positive pressure ventilation (iPPV) was applied with either 21% or 100% O2 in kittens who started in 21% O2, and remained at 100% O2 for kittens who started the experiment in 100% O2. Respiratory rate (breaths per minute, bpm) and variability in inter-breath interval (%) were measured from esophageal pressure recordings and functional residual capacity (FRC) was measured from synchrotron phase-contrast X-ray images.Results: Initially, kittens receiving 21% O2 had a significantly lower respiratory rate and higher variability in inter-breath interval, indicating a less stable breathing pattern than kittens starting in 100% O2 [median (IQR) respiratory rate: 16 (4–28) vs. 38 (29–46) bpm, p = 0.001; variability in inter-breath interval: 33.3% (17.2–50.1%) vs. 27.5% (18.6–36.3%), p = 0.009]. Apnea that required iPPV, was more frequently observed in kittens in whom resuscitation was started with 21% compared to 100% O2 (11/12 vs. 1/8, p = 0.001). After recovering from apnea, respiratory rate was significantly lower and variability in inter-breath interval was significantly higher in kittens who received iPPV with 21% compared to 100% O2. FRC was not different between study groups at both timepoints.Conclusion: Initiating resuscitation with 100% O2 resulted in increased respiratory activity and stability, thereby reducing the risk of apnea and need for iPPV after birth. Further studies in human preterm infants are mandatory to confirm the benefit of this approach in terms of oxygenation. In addition, the ability to avoid hyperoxia after initiation of resuscitation with 100% oxygen, using a titration protocol based on oxygen saturation, needs to be clarified.

Approximately 53% of near-term newborns admitted into intensive care, experience respiratory distress. These newborns are commonly delivered by caesarean section and have elevated airway liquid volumes at birth, which can cause respiratory morbidity. We investigated the effect of providing respiratory support with a positive end expiratory pressure (PEEP) of 8cmH2O on lung function in newborn rabbit kittens with elevated airway liquid volumes at birth.Near-term rabbits (30d; term=32d) with airway liquid volumes that corresponded to vaginal delivery (~7mL/kg, Control, n=11) or caesarean section (~37mL/kg; Elevated Liquid (EL), n=11) were mechanically ventilated (tidal volume=8mL/kg). The PEEP was changed after lung aeration from 0 to 8 to 0 cmH2O (Control, n=6; EL, n=6) and in a separate group of kittens, PEEP was changed after lung aeration from 8 to 0 to 8 cmH2O (Control, n=5; EL, n=5). Lung function (ventilator parameters, compliance, lung gas volumes and distribution of gas within the lung) was evaluated using plethysmography and synchrotron-based phase contrast X-ray imaging. EL kittens initially receiving 0 cmH2O PEEP had reduced functional residual capacities and lung compliance, requiring higher inflation pressures to aerate the lung compared to Control kittens. Commencing ventilation with 8 cmH2O PEEP mitigated the adverse effects of EL, increasing lung compliance, functional residual capacity and the uniformity and distribution of lung aeration, but did not normalize aeration of the distal airways. Respiratory support with PEEP supports lung function in near-term newborn rabbits with elevated airway liquid volumes at birth who are at greater risk of suffering respiratory distress.

Congenital diaphragmatic hernia (CDH) is a major cause of severe lung hypoplasia and pulmonary hypertension in the newborn. While the pulmonary hypertension is thought to result from abnormal vascular development and arterial vasoreactivity, the anatomical changes in vascular development are unclear. We have examined the 3D structure of the pulmonary arterial tree in rabbits with a surgically induced diaphragmatic hernia (DH). Fetal rabbits (n = 6) had a left‐sided DH created at gestational day 23 (GD23), delivered at GD30, and briefly ventilated; sham‐operated litter mates (n = 5) acted as controls. At postmortem the pulmonary arteries were filled with a radio‐opaque resin before the lungs were scanned using computed tomography (CT). The 3D reconstructed images were analyzed based on vascular branching hierarchy using the software Avizo 2020.2. DH significantly reduced median number of arteries (2,579 (8440) versus 576 (442), p = .017), artery numbers per arterial generation, mean total arterial volume (43.5 ± 8.4 vs. 19.9 ± 3.1 μl, p = .020) and mean total arterial cross‐sectional area (82.5 ± 2.3 vs. 28.2 ± 6.2 mm2, p =.036). Mean arterial radius was increased in DH kittens between the eighth and sixth branching generation and mean arterial length between the sixth and 28th branching generation. A DH in kittens resulted in threefold reduction in pulmonary arterial cross‐sectional area, primarily due to reduced arterial branching. Thus, the reduction in arterial cross‐sectional area could be a major contributor to pulmonary hypertension infants with CDH.

IMPACT STATEMENT• Although preterm infants are commonly supported with 4-8 cmH 2 O CPAP at birth, preclinical studies have shown that higher PEEP levels improve lung aeration.• In this study, CPAP levels of 15 cmH 2 O improved lung aeration and reduced apnea in preterm rabbit kittens immediately after birth. 15 cmH 2 O CPAP did not increase the risk of lung over-expansion (indicated by bulging between the ribs), pneumothorax, or CPAP belly.• These results can be used when designing future studies on CPAP strategies for preterm infants in the delivery room.

Preterm newborns commonly receive intermittent positive pressure ventilation (iPPV) at birth, but the optimal approach that facilitates uniform lung aeration is unknown, particularly in a partially aerated lung. As both inflation time and exogenous surfactant facilitate uniform lung aeration, we investigated whether they can improve lung aeration and lung mechanics in a partially aerated lung immediately after birth. Preterm rabbit kittens (29 days gestation, term ~32 days) were delivered by caesarean section and partial lung aeration was created by intubating and mechanically ventilating the right lung. The tube was then withdrawn to ventilate both lungs using inflation times of 0.2 s or 1.0 s, with or without exogenous surfactant (Curosurf 200 mg/kg), and a tidal volume (Vt) of 8 mL/kg. Simultaneous phase contrast X-ray imaging and plethysmography were used to measure lung aeration and mechanics. Kittens ventilated with longer inflation times (1.0 s) reached their target Vt with fewer inflations, required lower inflation pressures (28.5 ± 1.1 vs. 33.5 ± 1.3 cmH2O, p=0.01) and had higher dynamic lung compliances (0.54 ± 0.3 vs. 0.40 ± 0.3 cmH2O/mL/kg, p=0.003). Surfactant increased functional residual capacity (FRC; 31.9 ± 3.2 vs. 18.0 ± 3.9 mL/kg, p=0.02) and the proportion of the Vt entering the previously unaerated lung but had no effect on dynamic lung compliance. Combining early surfactant treatment with longer inflation times increases FRC levels, improves dynamic lung compliance, reduces inflation pressures and markedly increases the proportion of the lungs being ventilated during iPPV in preterm kittens with a partially aerated lung.