Ineffective aeration during the first inflations at birth creates regional aeration and ventilation defects, initiating injurious pathways. This study aimed to compare a sustained first inflation at birth or dynamic end-expiratory supported recruitment during tidal inflations against ventilation without intentional recruitment on gas exchange, lung mechanics, spatiotemporal regional aeration and tidal ventilation, and regional lung injury in preterm lambs. Lambs (127 ± 2 d gestation), instrumented at birth, were ventilated for 60 minutes from birth with either lung-protective positive pressure ventilation (control) or as per control after either an initial 30 seconds of 40 cm H2O sustained inflation (SI) or an initial stepwise end-expiratory pressure recruitment maneuver during tidal inflations (duration 180 s; open lung ventilation [OLV]). At study completion, molecular markers of lung injury were analyzed. The initial use of an OLV maneuver, but not SI, at birth resulted in improved lung compliance, oxygenation, end-expiratory lung volume, and reduced ventilatory needs compared with control, persisting throughout the study. These changes were due to more uniform inter- and intrasubject gravity-dependent spatiotemporal patterns of aeration (measured using electrical impedance tomography). Spatial distribution of tidal ventilation was more stable after either recruitment maneuver. All strategies caused regional lung injury patterns that mirrored associated regional volume states. Irrespective of strategy, spatiotemporal volume loss was consistently associated with up-regulation of early growth response-1 expression. Our results show that mechanical and molecular consequences of lung aeration at birth are not simply related to rapidity of fluid clearance; they are also related to spatiotemporal pressure-volume interactions within the lung during inflation and deflation.

A sustained first inflation (SI) at birth may aid lung liquid clearance and aeration, but the impact of SI duration relative to the volume-response of the lung is poorly understood. We compared three SI strategies: 1) variable duration defined by attaining volume equilibrium using real-time electrical impedance tomography (EIT; SI plat); 2) 30 s beyond equilibrium (SI long); 3) short 30-s SI (SI30); and 4) positive pressure ventilation without SI (no-SI) on spatiotemporal aeration and ventilation (EIT), gas exchange, lung mechanics, and regional early markers of injury in preterm lambs. Fifty-nine fetal-instrumented lambs were ventilated for 60 min after applying the allocated first inflation strategy. At study completion molecular and histological markers of lung injury were analyzed. The time to SI volume equilibrium, and resultant volume, were highly variable; mean (SD) 55 (34) s, coefficient of variability 59%. SI plat and SIlong resulted in better lung mechanics, gas exchange and lower ventilator settings than both no-SI and SI30. At 60 min, alveolar-arterial difference in oxygen was a mean (95% confidence interval) 130 (13, 249) higher in SI30 vs. SIlong group (two-way ANOVA). These differences were due to better spatiotemporal aeration and tidal ventilation, although all groups showed redistribution of aeration towards the nondependent lung by 60 min. Histological lung injury scores mirrored spatiotemporal change in aeration and were greatest in SI 30 group (P Ͻ 0.01, Kruskal-Wallis test). An individualized volume-response approach to SI was effective in optimizing aeration, homogeneous tidal ventilation, and respiratory outcomes, while an inadequate SI duration had no benefit over positive pressure ventilation alone. sustained inflation; neonatal resuscitation; lung mechanics; lung volume; variability; electrical impedance tomography; lung injury THE MAJORITY OF EXTREMELY preterm infants require respiratory assistance in the delivery room (41). In part this is because many of these infants do not have the ability to generate the initial prolonged high transpulmonary pressures required to drive lung fluid from the main airways, allow alveolar aeration, establish functional residual capacity (FRC), and then maintain it during tidal ventilation, essential processes for efficient gas exchange and lung protection (19,31). Recently, applying an initial sustained inflation (SI) at birth, consisting of an elevated pressure applied for longer than needed for usual tidal inflation, followed by sufficient positive end-expiratory pressure (PEEP), has been proposed as a method of generating the initial transpulmonary pressure needed at birth (10,18,20). SI has been extensively investigated in preterm animals (15,26,29,32,33,(35)(36)(37)(38) and humans (10, 18, 34) with conflicting results. Some studies suggested SI improved aeration, FRC, and cerebral oxygen delivery (29,32,33), while others failed to demonstrate any benefit over standard respiratory support with sufficient PEEP (26,(35)(36)(37). SI was associated wi...

Background: In translational animal studies both a sustained inflation (SI) and PEEP have been associated with better lung aeration at birth, but the role of each on lung injury is inconclusive. We aimed to determine the effect of different PEEP and SI strategies at birth on early development of lung injury pathways. Method: 70 antenatal-steroid exposed lambs (125d AE 1d) were instrumented during caesarean section. Lambs were randomly assigned to either 1) Positive Pressure Ventilation (PPV; n = 20) using volume targeted ventilation at PEEP 8 cmH 2 O (maximum PIP 35 cmH 2 O, V T 7 ml/kg), 2) Volumetric Sustained Inflation 1 at 35 cmH 2 O until full aeration was visualised using electrical impedance tomography (SI; n = 23), or 3) 3-min Dynamic PEEP strategy 1 guided by breath-to-breath compliance (n = 27). All lambs were treated at 10 min with surfactant 200 mg/kg, and then received PPV for 90 min, with measurement of mechanics and gas exchange throughout. Standardised samples from the gravity-dependent and non-dependent lung were analysed for early injury mRNA markers (EGR1, CYR61, CTGF, IL-6,-8,-1B) and histology. Results: All groups expressed injury in the non-dependent lung compared to unventilated fetal controls across all injury parameters (p < 0.0001 ANOVA). In the dependent lung, only SI resulted in higher EGR1, CYR61, CTGF, IL-6,-1B expression compared to PPV and dynamic PEEP (p < 0.0001 ANOVA), and both were not different from fetal controls. Dynamic PEEP had better oxygenation throughout (p < 0.0001, two-way ANOVA) Conclusions: This large preterm lamb study is the first to show significant injury differences between SI and PEEP starte-gies. Early lung injury was heterogeneous and greater in the dependent lung following a SI. This suggests that achieving aeration slowly using tidal inflations maybe more beneficial than a SI. Reference: 1. Tingay DG et al. Background: Volume targeted ventilation (VTV) is widely used and may reduce lung injury, but this assumes the clinically set V T (V Tset) is accurately delivered. The aims of this prospective observational study were to determine the relationship between V Tset , expiratory V T (V Te) and endotracheal tube leak in a modern neonatal VTV ventilator, and the resultant PaCO 2 relationship with and without VTV. Method: Continuous inflations were recorded for 24 hours in 100 infants receiving synchronised mechanical ventilation (SLE5000, SLE Ltd, UK) with VTV (n = 77 infants) or without, and either the manufacturer's V4 (n = 50) or newer V5 (n = 50) VTV algorithm. For every inflation the set V Tset , V Te and leak were determined (maximum 90000 inflations/infant). If PaCO 2 was sampled (maximum 2/infant), this was compared with the average V T data from the preceeding 15 minutes. Results: A total of 7,917,020 inflations were analysed. Using VTV the V Tset-V Te bias (95% CI) was 0.3 (−0.12, 0.19) mL/kg. Leak influenced V Tset-V Te bias with V4 algorithm (r 2 = −0.64, p < 0.0001; linear regression) but not V5 (r 2 = 0.04, p = 0.21). Overall 80% of V Te were AE...

Background:To describe the interrelationship between antenatal steroids, exogenous surfactant, and two approaches to lung recruitment at birth on oxygenation and respiratory system compliance (C dyn ) in preterm lambs. Methods: Lambs (n = 63; gestational age 127 ± 1 d) received either surfactant at 10-min life (Surfactant), antenatal corticosteroids (Steroid), or neither (Control). Within each epoch lambs were randomly assigned to a 30-s 40 cmH 2 O sustained inflation (SI) or an initial stepwise positive end-expiratory pressure (PEEP) open lung ventilation (OLV) maneuver at birth. All lambs then received the same management for 60-min with alveolar-arterial oxygen difference (AaDO 2 ) and C dyn measured at regular time points. results: Overall, the OLV strategy improved C dyn and AaDO 2 (all epochs except Surfactant) compared to SI (all P < 0.05; twoway ANOVA). Irrespective of strategy, C dyn was better in the Steroid group in the first 10 min (all P < 0.05). Thereafter, C dyn was similar to Steroid epoch in the OLV + Surfactant, but not SI + Surfactant group. OLV influenced the effect of steroid and surfactant (P = 0.005) on AaDO 2 more than SI (P = 0.235). conclusions: The antenatal state of the lung influences the type and impact of a recruitment maneuver at birth. The effectiveness of surfactant maybe enhanced using PEEPbased time-dependent recruitment strategies rather than approaches solely aimed at initial lung liquid clearance.i t is widely agreed that the optimal support of the preterm lung involves the combination of antenatal corticosteroid exposure, exogenous surfactant therapy, and early application of lung protective respiratory support strategies (1). Together, these therapies reduce the potential of assisted ventilation to injure the developmentally immature, surfactant-deficient preterm lung. The roles of early exogenous surfactant therapy (2) and antenatal corticosteroids (3) in improving lung mechanics, functional residual capacity, and reducing respiratory support are well established. The optimal respiratory support strategies are still debated (4-7).Ideally, lung protective respiratory support should commence during transition to ex utero life (1,8). During this period, the infant must rapidly clear lung liquid, aerate the lung, establish a functional residual capacity, and commence tidal ventilation, processes influenced by the intrinsic mechanical properties of the lung as well as the applied respiratory strategy (5,6,9-13). The optimal approach in preterm infants remains unclear but broadly requires an inflating pressure to drive fetal lung fluid into the alveoli and allow lung aeration, and positive end-expiratory pressure (PEEP) to maintain aeration and prevent fluid efflux back into the airways (14-17). In preterm animals, using an initial stepwise PEEP or open lung ventilation (OLV) approach during tidal ventilation from birth improves aeration and short-term respiratory outcomes in preterm animals via utilizing hysteresis and time dependency (6,11). However, clinical trials at birth...

Background Despite the theoretical benefits of high-frequency oscillatory ventilation (HFOV) in preterm infants, systematic reviews of randomized clinical trials do not confirm improved outcomes. We hypothesized that oscillating a premature lung with multiple frequencies simultaneously would improve gas exchange compared to traditional single-frequency oscillatory ventilation (SFOV). The goal of this study was to develop a novel method for HFOV, termed ‘multi-frequency oscillatory ventilation’ (MFOV), which relies on a broadband flow waveform more suitable for the heterogeneous mechanics of the immature lung. Methods Thirteen intubated preterm lambs were randomized to either SFOV or MFOV for 1 hour, followed by crossover to the alternative regimen for 1 hour. The SFOV waveform consisted of a pure sinusoidal flow at 5 Hz, while the customized MFOV waveform consisted of a 5 Hz fundamental with additional energy at 10 and 15 Hz. Per standardized protocol, mean pressure at airway opening (P̅ao) and inspired O2 fraction were adjusted as needed, and root mean square of the delivered oscillatory volume waveform (Vrms) was adjusted 15-minute intervals. A ventilatory cost function for SFOV and MFOV was defined as VC=false(Vrms2PanormalCO2false)normalWt−1, where Wt denotes body weight. Results Averaged over all time points, MFOV resulted in significantly lower VC (246.9±6.0 vs. 363.5±15.9 mL2 mmHg kg−1) and P̅ao (12.8±0.3 vs. 14.1±0.5 cmH2O) compared to SFOV, suggesting more efficient gas exchange and enhanced lung recruitment at lower mean airway pressures. Conclusions Oscillation with simultaneous multiple frequencies may be a more efficient ventilator modality in premature lungs compared to traditional single-frequency HFOV.

Background: Aerosolization of exogenous surfactant remains a challenge. This study is aimed to evaluate the efficacy of atomized poractant alfa (Curosurf ) administered with a novel atomizer in preterm lambs with respiratory distress syndrome. Methods: Twenty anaesthetized lambs, 127 ± 1 d gestational age, (mean ± SD) were instrumented before birth and randomized to receive either (i) positive pressure ventilation without surfactant (Control group), (ii) 200 mg/kg of bolus instilled surfactant (Bolus group) at 10 min of life or (iii) 200 mg/kg of atomized surfactant (Atomizer group) over 60 min from 10 min of life. All lambs were ventilated for 180 min with a standardized protocol. Lung mechanics, regional lung compliance (electrical impedance tomography), and carotid blood flow (CBF) were measured with arterial blood gas analysis. results: Dynamic compliance and oxygenation responses were similar in the Bolus and Atomizer groups, and both better than Control by 180 min (all P < 0.05; two-way ANOVA). Both surfactant groups demonstrated more homogeneous regional lung compliance throughout the study period. There were no differences in CBF conclusion: In a preterm lamb model, atomized surfactant resulted in similar gas exchange and mechanics as bolus administration. This study suggests evaluation of supraglottic atomization with this system when noninvasive support is warranted. s urfactant replacement therapy is a well-established standard of care for the treatment and prevention of neonatal respiratory distress syndrome (RDS), significantly reducing mortality and morbidity (1). Currently, endotracheal instillation is the only approved method of administration. However, over the last decade, the management of mild to moderate RDS has dramatically changed, endotracheal tube (ETT) intubation is often avoided and infants were managed with noninvasive modalities, such as continuous positive airway pressure whilst spontaneously breathing. In this population, surfactant administration is generally only provided when oxygen requirement increases and intubation is necessary (2,3).The increase in noninvasive ventilation use has led to less invasive methods of surfactant delivery during continuous positive airway pressure being developed (4,5). All reported methods require technical skills, some degree of invasive intervention, and still involve instillation of liquid surfactant directly into the trachea via a process that is not dissimilar to intubation (6-8). Nebulization of surfactant offers an attractive alternative. Unfortunately, studies of nebulized surfactant have shown inconsistent clinical response and surfactant distribution (9-16). Moreover, most of the studies, even those in which a lung function improvement was observed, reported very low (<10%) fractions of surfactant deposition into the lung (9,12,(17)(18)(19)(20). Notwithstanding differences in nebulizer design, and thus particle size production, such modest deposition is likely due to the fact that most studies used aerosols generated extracorporeally by ...