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Randomised trials in emergency settings must quickly confirm eligibility and allocate participants to an intervention group without delaying treatment. We report rapid randomisation during two neonatal resuscitation trials using the non-commercial REDCap platform accessed via smartphone. This simple, reliable method has wide applicability for trials in emergency settings. What is Known: • Randomised trials in emergency settings need to rapidly allocate participants to an intervention group. • This process should not delay treatment. What is New: • This non-commercial, smartphone-accessible application enabled rapid, accurate randomisation at the bedside. • This has broad applicability for emergency setting trials., (© 2022. The Author(s).)

Objective: Physiological-based cord clamping (PBCC) led to a more stable cardiovascular adaptation and better oxygenation in preterm lambs, but in preterm infants, this approach has been challenging. Our aim was to assess the feasibility of PBCC, including patterns of oxygen saturation (SpO 2 ) and heart rate (HR) during stabilisation in preterm infants using a new purpose-built resuscitation table., Design: Observational study., Setting: Tertiary referral centre, Leiden University Medical Centre, The Netherlands., Patients: Infants born below 35 weeks' gestational age., Interventions: Infants were stabilised on a new purpose-built resuscitation table (Concord), provided with standard equipment needed for stabilisation. Cord clamping was performed when the infant was stable (HR >100 bpm, spontaneous breathing on continuous positive airway pressure with tidal volumes >4 mL/kg, SpO 2 ≥25th percentile and fraction of inspired oxygen (FiO 2 ) <0.4)., Results: Thirty-seven preterm infants were included; mean (SD) gestational age of 30.9 (2.4) weeks, birth weight 1580 (519) g. PBCC was successful in 33 infants (89.2%) and resulted in median (IQR) cord clamping time of 4:23 (3:00-5:11) min after birth. There were no maternal or neonatal adverse events. In 26/37 infants, measurements were adequate for analysis. HR was 113 (81-143) and 144 (129-155) bpm at 1 min and 5 min after birth. SpO 2 levels were 58%(49%-60%) and 91%(80%-96%)%), while median FiO 2 given was 0.30 (0.30-0.31) and 0.31 (0.25-0.97), respectively., Conclusion: PBCC in preterm infants using the Concord is feasible. HR remained stable, and SpO 2 quickly increased with low levels of oxygen supply., Trial Registration Number: NTR6095, results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In neonatal resuscitation, a ventilation device providing positive end-expiratory pressure (PEEP) is recommended. There is limited information about PEEP delivery in vivo, using different models of self-inflating bag (SIB) at different inflation rates and PEEP settings., Methods: We compared PEEP delivery to intubated preterm lambs using four commonly available models of paired SIBs and PEEP valves, with a T-piece, with gas flow of 8 L/min. Peak inspiratory pressure inflations of 30 cmH 2 O, combined with set PEEP of 5, 7 and 10 cmH 2 O, were delivered at rates of 20, 40 and 60/min. These combinations were repeated without gas flow. We measured mean PEEP, maximum and minimum PEEP, and its difference (PEEP reduction)., Results: A total of 3288 inflations were analysed. The mean PEEP delivered by all SIBs was lower than set PEEP (P<0.001), although some differences were <0.5 cmH 2 O. In 55% of combinations, the presence of gas flow resulted in increased PEEP delivery (range difference 0.3-2 cmH 2 O). The mean PEEP was closer to set PEEP with faster inflation rates and higher set PEEPs. The mean (SD) PEEP reduction was 3.9 (1.6), 8.2 (1.8), 2 (0.6) and 1.1 (0.6) cmH 2 O with the four SIBs, whereas it was 0.5 (0.2) cmH 2 O with the T-piece., Conclusions: PEEP delivery with SIBs depends on the set PEEP, inflation rate, device model and gas flow. At recommended inflation rates of 60/min, some devices can deliver PEEP close to the set level, although the reduction in PEEP makes some SIBs potentially less effective for lung recruitment than a T-piece., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: The use of intraosseous (IO) access during resuscitation is widely accepted and promoted in paediatric medicine but features less prominently in neonatal training. Whilst umbilical venous catheterization (UVC) is a reliable method of delivering emergency drugs and fluids, it is not always achievable in a timely manner. IO access warrants exploration as an alternative., Aim: Conduct a systematic review of existing literature to examine the evidence for efficacy and safety of IO devices in neonatal patients, from birth to discharge., Method: A search of PubMed, Ovid, Medline, and Embase was carried out. Abstracts were screened for relevance to focus on neonatal-specific literature and studies which carried out separate analyses for neonates (infants <28 days of age or resident on a neonatal unit)., Results: One case series and 12 case reports describe IO device insertion into 41 neonates, delivering a variety of drugs, including adrenaline (epinephrine) and volume resuscitation. Complications range from none to severe. Cadaveric studies show that despite a small margin for error, IO devices can be correctly sited in neonates. Simulation studies suggest that IO devices may be faster and easier to site than UVC, even in experienced hands., Conclusion: IO access should be available on neonatal units and considered for early use in neonates where other access routes have failed. Appropriate training should be available to staff in addition to existing life support and UVC training. Further studies are required to assess the optimal device, position, and whether medication can be delivered IO as effectively as by UVC. If IO devices provide a faster method of delivering adrenaline effectively than UVC, this may lead to changes in neonatal resuscitation practice., (© 2019 S. Karger AG, Basel.)

Introduction: Over five percent of infants born worldwide will need help breathing after birth. Delayed cord clamping (DCC) has become the standard of care for vigorous infants. DCC in non-vigorous infants is uncommon because of logistical difficulties in providing effective resuscitation during DCC. In Baby-Directed Umbilical Cord Clamping (Baby-DUCC), the umbilical cord remains patent until the infant's lungs are exchanging gases. We conducted a feasibility study of the Baby-DUCC technique., Methods: We obtained antenatal consent from pregnant women to enroll infants born at ≥32 weeks. Vigorous infants received ≥2 min of DCC. If the infant received respiratory support, the umbilical cord was clamped ≥60 s after the colorimetric carbon dioxide detector turned yellow. Maternal uterotonic medication was administered after umbilical cord clamping. A paediatrician and researcher entered the sterile field to provide respiratory support during a cesarean birth. Maternal and infant outcomes in the delivery room and prior to hospital discharge were analysed., Results: Forty-four infants were enrolled, 23 delivered via cesarean section (8 unplanned) and 15 delivered vaginally (6 via instrumentation). Twelve infants were non-vigorous. ECG was the preferred method for recording HR. Two infants had a HR < 100 BPM. All HR values were >100 BPM by 80 s after birth. Median time to umbilical cord clamping was 150 and 138 s in vigorous and non-vigorous infants, respectively. Median maternal blood loss was 300 ml., Conclusions: It is feasible to provide resuscitation to term and near-term infants during DCC, after both vaginal and cesarean births, clamping the umbilical cord only when the infant is physiologically ready., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Animal models have made and continue to make important contributions to neonatal medicine. For example, studies in fetal sheep have taught us much about the physiology of the fetal-to-neonatal transition. However, whereas animal models allow multiple factors to be investigated in a logical and systematic manner, no animal model is perfect for humans and so we need to understand the fundamental differences in physiology between the species in question and humans. Although most physiological systems are well conserved between species, some small differences exist and so wherever possible the knowledge generated from preclinical studies in animals should be tested in clinical trials. However, with the rise of evidence-based medicine the distinction between scientific knowledge generation and evidence gathering has been confused and the two have been lumped together. This misunderstands the contribution that scientific knowledge can provide. Science should be used to guide the gathering of evidence by informing the design of clinical trials, thereby increasing their likelihood of success. While scientific knowledge is not evidence, in the absence of evidence it is likely to be the best option for guiding clinical practice., (© 2018 Elsevier Ltd. All rights reserved.)

Purpose of Review: As the infant's physiology changes dramatically after birth, modern neonatal resuscitation approaches should detect and be modified in response to these changes. This review describes the changes in respiratory physiology at birth and highlights approaches that can assist these changes., Recent Findings: To better target assistance given to infants at birth, the changes in lung physiology have been classified into three phases. The first phase involves lung aeration. As little or no gas exchange can occur, assistance should focus on airway liquid clearance. During the second phase, as airway liquid resides in lung tissue, assistance should focus on minimizing the complications associated with lung edema. The third phase occurs whenever the liquid is cleared from the tissue and respiratory mechanics stabilize. Although more traditional approaches are most effective during this phase, this is not the case for the first two phases. Furthermore, the glottis actively adducts during apnea in newborns and so noninvasive respiratory support requires the infant to be breathing so that the glottis will open., Summary: The respiratory support provided to infants at birth should match the infant's changing physiology during transition, which requires a more sophisticated approach and equipment than current recommendations.

Support of the mechanically complex preterm lung needs to facilitate aeration while avoiding ventilation heterogeneities: whether to achieve this gradually or quickly remains unclear. We compared the effect of gradual vs. constant tidal inflations and a pressure-limited sustained inflation (SI) at birth on gas exchange, lung mechanics, gravity-dependent lung volume distribution, and lung injury in 131-day gestation preterm lambs. Lambs were resuscitated with either 1) a 20-s, 40-cmH2O pressure-limited SI (PressSI), 2) a gradual increase in tidal volume (Vt) over 5-min from 3 ml/kg to 7 ml/kg (IncrVt), or 3) 7 ml/kg Vt from birth. All lambs were subsequently ventilated for 15 min with 7 ml/kg Vt with the same end-expiratory pressure. Lung mechanics, gas exchange and spatial distribution of end-expiratory volume (EEV), and tidal ventilation (electrical impedance tomography) were recorded regularly. At 15 min, early mRNA tissue markers of lung injury were assessed. The IncrVt group resulted in greater tissue hysteresivity at 5 min (P = 0.017; two-way ANOVA), higher alveolar-arterial oxygen difference from 10 min (P < 0.01), and least uniform gravity-dependent distribution of EEV. There were no other differences in lung mechanics between groups, and the PressSI and 7 ml/kg Vt groups behaved similarly throughout. EEV was more uniformly distributed, but Vt least so, in the PressSI group. There were no differences in mRNA markers of lung injury. A gradual increase in Vt from birth resulted in less recruitment of the gravity-dependent lung with worse oxygenation. There was no benefit of a SI at birth over mechanical ventilation with 7 ml/kg Vt., (Copyright © 2015 the American Physiological Society.)

Background: Sustained inflations (SI) are advocated for the rapid establishment of FRC after birth in preterm and term infants requiring resuscitation. However, the most appropriate way to deliver a SI is poorly understood. We investigated whether a volume-limited SI improved the establishment of FRC and ventilation homogeneity and reduced lung inflammation/injury compared to a pressure-limited SI., Methods: 131 d gestation lambs were resuscitated with either: i) pressure-limited SI (PressSI: 0-40 cmH2O over 5 s, maintained until 20 s); or ii) volume-limited SI (VolSI: 0-15 mL/kg over 5 s, maintained until 20 s). Following the SI, all lambs were ventilated using volume-controlled ventilation (7 mL/kg tidal volume) for 15 min. Lung mechanics, regional ventilation distribution (electrical impedance tomography), cerebral tissue oxygenation index (near infrared spectroscopy), arterial pressures and blood gas values were recorded regularly. Pressure-volume curves were performed in-situ post-mortem and early markers of lung injury were assessed., Results: Compared to a pressure-limited SI, a volume-limited SI had increased pressure variability but reduced volume variability. Each SI strategy achieved similar end-inflation lung volumes and regional ventilation homogeneity. Volume-limited SI increased heart-rate and arterial pressure faster than pressure-limited SI lambs, but no differences were observed after 30 s. Volume-limited SI had increased arterial-alveolar oxygen difference due to higher FiO2 at 15 min (p = 0.01 and p = 0.02 respectively). No other inter-group differences in arterial or cerebral oxygenation, blood pressures or early markers of lung injury were evident., Conclusion: With the exception of inferior oxygenation, a sustained inflation targeting delivery to preterm lambs of 15 mL/kg volume by 5 s did not influence physiological variables or early markers of lung inflammation and injury at 15 min compared to a standard pressure-limited sustained inflation.

Objective: The 2010 ILCOR neonatal resuscitation guidelines do not specify appropriate inflation times for the initial lung inflations in apnoeic newborn infants. The authors compared three ventilation strategies immediately after delivery in asphyxiated newborn lambs., Design: Experimental animal study., Setting: Facility for animal research., Subjects: Eighteen near-term lambs (weight 3.5-3.9 kg) delivered by caesarean section., Interventions: Asphyxia was induced by occluding the umbilical cord and delaying ventilation onset (10-11 min) until mean carotid blood pressure (CBP) was ≤22 mm Hg. Animals were divided into three groups (n=6) and ventilation started with: (1) inflation times of 0.5 s at a ventilation rate 60/min, (2) five 3 s inflations or (3) a single 30 s inflation. Subsequent ventilation used inflations at 0.5 s at 60/min for all groups., Main Outcome Measures: Times to reach a heart rate (HR) of 120 bpm and a mean CBP of 40 mm Hg. Secondary outcome was change in lung compliance., Results: Median time to reach HR 120 bpm and mean CBP 40 mm Hg was significantly shorter in the single 30 s inflation group (8 s and 74 s) versus the 5×3 s inflation group (38 s and 466 s) and the conventional ventilation group (64 s and 264 s). Lung compliance was significantly better in the single 30 s inflation group., Conclusion: A single sustained inflation of 30 s immediately after birth improved speed of circulatory recovery and lung compliance in near-term asphyxiated lambs. This approach for neonatal resuscitation merits further investigation.

Aims: Preterm infants can be inadvertently exposed to high tidal volumes (V(T)) in the delivery room, causing lung inflammation and injury, but little is known about their effects on the brain. The aim of this study was to compare an initial 15 min of high V(T) resuscitation strategy to a less injurious resuscitation strategy on cerebral haemodynamics, inflammation and injury., Methods: Preterm lambs at 126 d gestation were surgically instrumented prior to receiving resuscitation with either: 1) High V(T) targeting 10-12 mL/kg for the first 15 min (n = 6) or 2) a protective resuscitation strategy (Prot V(T)), consisting of prophylactic surfactant, a 20 s sustained inflation and a lower initial V(T) (7 mL/kg; n = 6). Both groups were subsequently ventilated with a V(T) 7 mL/kg. Blood gases, arterial pressures and carotid blood flows were recorded. Cerebral blood volume and oxygenation were assessed using near infrared spectroscopy. The brain was collected for biochemical and histologic assessment of inflammation, injury, vascular extravasation, hemorrhage and oxidative injury. Unventilated controls (UVC; n = 6) were used for comparison., Results: High V(T) lambs had worse oxygenation and required greater ventilatory support than Prot V(T) lambs. High V(T) resulted in cerebral haemodynamic instability during the initial 15 min, adverse cerebral tissue oxygenation index and cerebral vasoparalysis. While both resuscitation strategies increased lung and brain inflammation and oxidative stress, High V(T) resuscitation significantly amplified the effect (p = 0.014 and p<0.001). Vascular extravasation was evident in the brains of 60% of High V(T) lambs, but not in UVC or Prot V(T) lambs., Conclusion: High V(T) resulted in greater cerebral haemodynamic instability, increased brain inflammation, oxidative stress and vascular extravasation than a Prot V(T) strategy. The initiation of resuscitation targeting Prot V(T) may reduce the severity of brain injury in preterm neonates.

Resuscitation of very premature lambs with positive end-expiratory pressure (PEEP) improves oxygenation and reduces pulmonary blood flow (PBF). However, the effects of PEEP on blood gases and PBF have not been studied in preterm lambs receiving antenatal corticosteroids or postnatal surfactant. Lambs were delivered at 125 d of gestation (term 147 d) and ventilated with a tidal volume (VT) of 5 mL/kg using different levels of PEEP. Four treatment groups were studied: (1) antenatal betamethasone 24 and 36 h before delivery; (2) postnatal Curosurf; (3) antenatal betamethasone and postnatal Curosurf; (4) untreated controls. Blood gases, PBF, and ventilator parameters were recorded during the first 2 h. Increasing PEEP improved oxygenation even after antenatal betamethasone and postnatal Curosurf, without adverse effects on arterial PCO2. Increasing PEEP reduced PBF; this effect was not altered by betamethasone and/or Curosurf. In very preterm lambs ventilated with fixed VT, increasing levels of PEEP improved oxygenation after antenatal glucocorticoids and/or postnatal surfactant. These treatments do not alter the deleterious effects of high levels of PEEP on PBF.

Growth-restricted neonates have worse outcomes after perinatal asphyxia, with more severe metabolic acidosis than appropriately grown neonates. The cardiovascular physiology associated with fetal growth restriction (FGR) may alter their response to asphyxia. However, research on asphyxia in FGR is limited. Here we compared cardiovascular hemodynamics in preterm FGR and control lambs during mild perinatal asphyxia. We induced FGR in one twin at 89 days gestation (term 148 days), while the other served as a control. At 126 days gestation, lambs were instrumented to allow arterial blood pressure and regional blood flow recording, and then mild perinatal asphyxia was induced by umbilical cord clamping, and resuscitation followed neonatal guidelines. FGR lambs maintained carotid blood flow (CBF) for 7 min, while control lambs rapidly decreased CBF (P < 0.05). Fewer growth-restricted lambs needed chest compressions for return of spontaneous circulation (ROSC) (17 vs. 83%, P = 0.02). The extent of blood pressure overshoot after ROSC was similar, but it took longer for MAP to return to baseline in FGR lambs (18.83 ± 0.00 vs. 47.67 ± 0.00 min, P = 0.003). Growth-restricted lambs had higher CBF after ROSC (P < 0.05) and displayed CBF overshoot, unlike control lambs (P < 0.03). In conclusion, preterm growth-restricted lambs show resilience during perinatal asphyxia based on prolonged CBF maintenance and reduced need for chest compressions during resuscitation. However, CBF overshoot after ROSC may increase the risk of cerebrovascular injury in FGR. [ABSTRACT FROM AUTHOR]

Introduction: Recent reports have raised concerns of cardiorespiratory deterioration in some infants receiving respiratory support at birth. We aimed to independently determine whether respiratory support with a facemask is associated with a decrease in heart rate (HR) in some late-preterm and term infants. Methods: Secondary analysis of data from infants born at ≥32+0 weeks of gestation at 2 perinatal centres in Melbourne, Australia. Change in HR up to 120 s after facemask placement, measured using 3-lead electrocardiography, was assessed every 3 s until 60 s and every 5 s thereafter from video recordings. Results: In the 15 s after facemask placement, 10/68 (15%) infants had a decrease in mean HR by >10 beats per minute (bpm) compared with their individual baseline mean HR in the 15 s before facemask placement. In 4 (6%) infants, HR decreased to <100 bpm. Nine out of 68 (13%) infants had an increase in mean HR by >10 bpm; 7 of these infants had a baseline HR <120 bpm. In univariable comparisons, the following characteristics were found not to be risk factors for a decrease in HR by >10 bpm: prematurity; type of respiratory support; hypoxaemia; early cord clamping; mode of birth; HR <120 bpm before mask placement. Six out of 63 infants (10%) who had HR ≥120 bpm after facemask placement had a late decrease in HR to <100 bpm between 30 and 120 s after facemask placement. Conclusion: Facemask respiratory support at birth is temporally associated with a decrease in HR in a subset of late-preterm and term infants. [ABSTRACT FROM AUTHOR]

Rationale: Antenatal inflammation, usually associated with chorioamnionitis, is a major cause of premature birth. As inflammation could depress respiratory drive, we have examined the effect of clinical chorioamnionitis (CCA) on spontaneous breathing in premature infants at birth.Methods: Infants with CCA born <30 weeks' gestation were matched with control infants based on gestational age (±6 days), birth weight (±300 g), antenatal corticosteroids, sex and general anaesthesia. The primary outcome was breathing effort, assessed as minute volume (MV) of spontaneous breathing. We also measured tidal volume (Vt), respiratory rate (RR) and apnoea in the first 5 min and additional physiological parameters in the first 10 min after start of respiratory support.Results: Ninety-two infants were included (n=46 CCA infants vs n=46 controls; median (IQR) gestational age 26+4 (25+0-27+6) vs 26+6 (25+1-28+3) weeks). MV and Vt were significantly lower (MV: 43 (17-93) vs 70 (31-119) mL/kg/min, p=0.043; Vt: 2.6 (1.9-3.6) vs 2.9 (2.2-4.8) mL/kg/breath, p=0.046), whereas RR was similar in CCA infants compared with controls. Incidence of apnoea was higher (5 (2-6) vs 2 (1-4), p=0.002), and total duration of apnoea was longer (90 (21-139) vs 35 (12-98) s, p=0.025) in CCA infants. CCA infants took significantly longer to reach an oxygen saturation >80% (3:37 (2:10-4:29) vs 2:25 (1:06-3:52) min, p=0.016) and had a lower oxygen saturation at 5 min (77 (66-92) vs 91 (68-94) %, p=0.028), despite receiving more oxygen (62 (48-76) vs 54 (43-73) %, p=0.036).Conclusion: CCA is associated with reduced breathing effort and oxygenation in premature infants at birth. [ABSTRACT FROM AUTHOR]

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]

[Display omitted] • Standard-dose Endotracheal Epinephrine is ineffective in asystolic newborn lambs. • High-dose Endotracheal Epinephrine (1 mg/kg) can achieve return of circulation. • High-dose Endotracheal Epinephrine has adverse effects after resuscitation. Endotracheal (ET) epinephrine administration is an option during neonatal resuscitation, if the preferred intravenous (IV) route is unavailable. We assessed whether endotracheal epinephrine achieved return of spontaneous circulation (ROSC), and maintained physiological stability after ROSC, at standard and higher dose, in severely asphyxiated newborn lambs. Near-term fetal lambs were asphyxiated until asystole. Resuscitation was commenced with ventilation and chest compressions. Lambs were randomly allocated to: IV Saline placebo (5 ml/kg), IV Epinephrine (20 micrograms/kg), Standard-dose ET Epinephrine (100 micrograms/kg), and High-dose ET Epinephrine (1 mg/kg). After three allocated treatment doses, rescue IV Epinephrine was administered if ROSC had not occurred. Lambs achieving ROSC were monitored for 60 minutes. Brain histology was assessed for microbleeds. ROSC in response to allocated treatment (without rescue IV Epinephrine) occurred in 1/6 Saline, 9/9 IV Epinephrine, 0/9 Standard-dose ET Epinephrine, and 7/9 High-dose ET Epinephrine lambs respectively. Blood pressure during CPR increased after treatment with IV Epinephrine and High-dose ET Epinephrine, but not Saline or Standard-dose ET Epinephrine. After ROSC, both ET Epinephrine groups had lower pH, higher lactate, and higher blood pressure than the IV Epinephrine group. Cortex microbleeds were more frequent in High-dose ET Epinephrine lambs (8/8 lambs examined, versus 3/8 in IV Epinephrine lambs). The currently recommended dose of ET Epinephrine was ineffective in achieving ROSC. Without convincing clinical or preclinical evidence of efficacy, use of ET Epinephrine at this dose may not be appropriate. High-dose ET Epinephrine requires further evaluation before clinical translation. [ABSTRACT FROM AUTHOR]

Introduction: During delayed umbilical cord clamping, the factors underpinning placental transfusion remain unknown. We hypothesised that reductions in thoracic pressure during inspiration would enhance placental transfusion in spontaneously breathing preterm lambs.Objective: Investigate the effect of spontaneous breathing on umbilical venous flow and body weight in preterm lambs.Methods: Pregnant sheep were instrumented at 132-133 days gestational age to measure fetal common umbilical venous, pulmonary and cerebral blood flows as well as arterial and intrapleural (IP) pressures. At delivery, doxapram and caffeine were administered to promote breathing. Lamb body weights were measured continuously and breathing was assessed by IP pressure changes.Results: In 6 lambs, 491 out of 1117 breaths were analysed for change in body weight. Weight increased in 46.6% and decreased in 47.5% of breaths. An overall mean increase of 0.02±2.5 g per breath was calculated, and no net placental transfusion was observed prior to cord clamping (median difference in body weight 52.3 [-54.9-166.1] g, p=0.418). Umbilical venous (UV) flow transiently decreased with each inspiration, and in some cases ceased, before UV flow normalised during expiration. The reduction in UV flow was positively correlated with the standardised reduction in (IP) pressure, increasing by 109 mL/min for every SD reduction in IP pressure. Thus, the reduction in UV flow was closely related to inspiratory depth.Conclusions: Spontaneous breathing had no net effect on body weight in preterm lambs at birth. UV blood flow decreased as inspiratory effort increased, possibly due to constriction of the inferior vena cava caused by diaphragmatic contraction, as previously observed in human fetuses. [ABSTRACT FROM AUTHOR]

Erythropoietin (EPO) is being trialled in preterm infants to reduce brain injury, but high doses increase lung injury in ventilated preterm lambs. We aimed to determine whether early administration of lower doses of EPO could reduce ventilation-induced lung injury and systemic inflammation in preterm lambs. Ventilation was initiated in anaesthetized preterm lambs [125 ± 1 (SD) days gestation] using an injurious strategy for the first 15 min. Lambs were subsequently ventilated with a protective strategy for a total of 2 h. Lambs were randomized to receive either intravenous saline (Vent; n = 7) or intravenous 300 ( n = 5), 1,000 (EPO1000; n = 5), or 3,000 (EPO3000; n = 5) IU/kg of human recombinant EPO via an umbilical vein. Lung tissue was collected for molecular and histological assessment of inflammation and injury and compared with unventilated control lambs (UVC; n = 8). All ventilated groups had similar blood gas and ventilation parameters, but EPO1000 lambs had a lower fraction of inspired oxygen requirement and lower alveolar-arterial difference in oxygen. Vent and EPO lambs had increased lung interleukin (IL)-1β, IL-6, and IL-8 mRNA, early lung injury genes connective tissue growth factor, early growth response protein 1, and cysteine-rich 61, and liver serum amyloid A3 mRNA compared with UVCs; no difference was observed between Vent and EPO groups. Histological lung injury was increased in Vent and EPO groups compared with UVCs, but EPO3000 lambs had increased lung injury scores compared with VENT only. Early low-doses of EPO do not exacerbate ventilation-induced lung inflammation and injury and do not provide any short-term respiratory benefit. High doses (≥3,000 IU/kg) likely exacerbate lung inflammation and injury in ventilated preterm lambs. NEW & NOTEWORTHY Trials are ongoing to assess the efficacy of erythropoietin (EPO) to provide neuroprotection for preterm infants. However, high doses of EPO increase ventilation-induced lung injury (VILI) in preterm lambs. We investigated whether early lower doses of EPO may reduce VILI. We found that lower doses did not reduce, but did not increase, VILI, while high doses (≥3,000 IU/kg) increase VILI. Therefore, lower doses of EPO should be used in preterm infants, particularly those receiving respiratory support. [ABSTRACT FROM AUTHOR]

Erythropoietin (EPO) is being trialed in preterm neonates for neuroprotection. We have recently demonstrated that a single high bolus dose (5,000 IU/kg) of recombinant human EPO amplified preterm lung and brain ventilation-induced injury. We aimed to determine the optimal dose of EPO to reduce ventilation-induced cerebral white matter inflammation and injury in preterm lambs. Lambs (0.85 gestation) were ventilated with an injurious strategy for 15 min followed by conventional ventilation for 105 min. Lambs were randomized to no treatment (VENT; n = 8) or received a bolus dose of EPO (EPREX ® ): 300 IU/kg (EPO 300; n = 5), 1,000 IU/kg (EPO 1,000; n = 5), or 3,000 IU/kg (EPO 3,000; n = 5). Physiological parameters were measured throughout the study. After 2 h, brains were collected for analysis; real-time quantitative polymerase chain reaction and immunohistochemistry were used to assess inflammation, cell death, and vascular leakage in the periventricular and subcortical white matter (PVWM; SCWM). Molecular and histological inflammatory indices in the PVWM were not different between groups. EPO 300 lambs had higher IL-6 (p = 0.006) and caspase- 3 (p = 0.025) mRNA expression in the SCWM than VENT lambs. Blood-brain barrier (BBB) occludin mRNA levels were higher in EPO 3,000 lambs in the PVWM and SCWM than VENT lambs. The number of blood vessels with protein extravasation in the SCWM was lower in EPO 1,000 (p = 0.010) and EPO 3,000 (p = 0.025) lambs compared to VENT controls but not different between groups in the PVWM. Early administration of EPO at lower doses neither reduced nor exacerbated cerebral white matter inflammation or injury. 3,000 IU/kg EPO may provide neuroprotection by improving BBB integrity. [ABSTRACT FROM AUTHOR]

Mechanical ventilation is a risk factor for cerebral inflammation and brain injury in preterm neonates. The risk increases proportionally with the intensity of treatment. Recent studies have shown that cerebral inflammation and injury can be initiated in the delivery room. At present, initiation of intermittent positive pressure ventilation (IPPV) in the delivery room is one of the least controlled interventions a preterm infant will likely face. Varying pressures and volumes administered shortly after birth are sufficient to trigger pathways of ventilation-induced lung and brain injury. The pathways involved in ventilation-induced brain injury include a complex inflammatory cascade and haemodynamic instability, both of which have an impact on the brain. However, regardless of the strategy employed to deliver IPPV, any ventilation has the potential to have an impact on the immature brain. This is particularly important given that preterm infants are already at a high risk for brain injury simply due to immaturity. This highlights the importance of improving the initial respiratory support in the delivery room. We review the mechanisms of ventilation-induced brain injury and discuss the need for, and the most likely, current therapeutic agents to protect the preterm brain. These include therapies already employed clinically, such as maternal glucocorticoid therapy and allopurinol, as well as other agents, such as erythropoietin, human amnion epithelial cells and melatonin, already showing promise in preclinical studies. Their mechanisms of action are discussed, highlighting their potential for use immediately after birth. [ABSTRACT FROM AUTHOR]

Background: Preterm infants can be inadvertently exposed to high tidal volumes (VT) during resuscitation in the delivery room due to limitations of available equipment. High VT ventilation of preterm lambs produces cerebral white matter (WM) pathology similar to that observed in preterm infants who develop cerebral palsy. We hypothesized that human amnion epithelial cells (hAECs), which have anti-inflammatory and regenerative properties, would reduce ventilation-induced WM pathology in neonatal late preterm lamb brains. Methods: Two groups of lambs (0.85 gestation) were used, as follows: (1) ventilated lambs (Vent; n = 8) were ventilated using a protocol that induces injury (VT targeting 15 ml/kg for 15 min, with no positive end-expiratory pressure) and were then maintained for another 105 min, and (2) ventilated + hAECs lambs (Vent+hAECs; n = 7) were similarly ventilated but received intravenous and intratracheal administration of 9 × 107 hAECs (18 × 107 hAECs total) at birth. Oxygenation and ventilation parameters were monitored in real time; cerebral oxygenation was measured using near-infrared spectroscopy. qPCR (quantitative real-time PCR) and immunohistochemistry were used to assess inflammation, vascular leakage and astrogliosis in both the periventricular and subcortical WM of the frontal and parietal lobes. An unventilated control group (UVC; n = 5) was also used for qPCR analysis of gene expression. Two-way repeated measures ANOVA was used to compare physiological data. Student's t test and one-way ANOVA were used for immunohistological and qPCR data comparisons, respectively. Results: Respiratory parameters were not different between groups. Interleukin (IL)-6 mRNA levels in subcortical WM were lower in the Vent+hAECs group than the Vent group (p = 0.028). IL-1β and IL-6 mRNA levels in periventricular WM were higher in the Vent+hAECs group than the Vent group (p = 0.007 and p = 0.001, respectively). The density of Iba-1-positive microglia was lower in the subcortical WM of the parietal lobes (p = 0.010) in the Vent+hAECs group but not in the periventricular WM. The number of vessels in the WM of the parietal lobe exhibiting protein extravasation was lower (p = 0.046) in the Vent+hAECs group. Claudin-1 mRNA levels were higher in the periventricular WM (p = 0.005). The density of GFAP-positive astrocytes was not different between groups. Conclusions: Administration of hAECs at the time of birth alters the effects of injurious ventilation on the preterm neonatal brain. Further studies are required to understand the regional differences in the effects of hAECs on ventilation-induced WM pathology and their net effect on the developing brain. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: A cornerstone of neonatal resuscitation teaching suggests that a rapid vagal-mediated bradycardia is one of the first signs of perinatal compromise. As this understanding is based primarily on fetal studies, we investigated whether the heart rate and blood pressure response to total asphyxia is influenced by whether the animal is in utero or ex utero. Methods: Fetal sheep were instrumented at ∼139 days of gestation and then asphyxiated by umbilical cord occlusion until mean arterial blood pressure decreased to ∼20 mmHg. Lambs were either completely submerged in amniotic fluid (in utero; n = 8) throughout the asphyxia or were delivered and then remained ex utero (ex utero; n = 8) throughout the asphyxia. Heart rate and arterial blood pressure were continuously recorded. Results: Heart rate was higher in ex utero lambs than in utero lambs. Heart rates in in utero lambs rapidly decreased, while heart rates in ex utero lambs initially increased following cord occlusion (for ∼1.5 min) before they started to decrease. Mean arterial pressure initially increased then decreased in both groups. Conclusions: Heart rate response to asphyxia was markedly different depending upon whether the lamb was in utero or ex utero. This indicates that the cardiovascular responses to perinatal asphyxia are significantly influenced by the newborn's local environment. As such, based solely on heart rate, the stage and severity of a perinatal asphyxic event may not be as accurate as previously assumed. [ABSTRACT FROM AUTHOR]

Background and Aim: High tidal volume (VT) ventilation during resuscitation of preterm lambs results in brain injury evident histologically within hours after birth. We aimed to investigate whether magnetic resonance spectroscopy (MRS) and/or diffusion tensor imaging (DTI) can be used for early in vivo detection of ventilation-induced brain injury in preterm lambs. Methods: Newborn lambs (0.85 gestation) were stabilized with a “protective ventilation” strategy (PROT, n = 7: prophylactic Curosurf, sustained inflation, VT 7 mL/kg, positive end expiratory pressure (PEEP) 5 cmH2O) or an initial 15 minutes of “injurious ventilation” (INJ, n = 10: VT 12 mL/kg, no PEEP, late Curosurf) followed by PROT ventilation for the remainder of the experiment. At 1 hour, lambs underwent structural magnetic resonance imaging (Siemens, 3 Tesla). For measures of mean/axial/radial diffusivity (MD, AD, RD) and fractional anisotropy (FA), 30 direction DTI was performed. Regions of interests encompassed the thalamus, internal capsule, periventricular white matter and the cerebellar vermis. MRS was performed using a localized single-voxel (15×15×20 mm3, echo time 270 ms) encompassing suptratentorial deep nuclear grey matter and central white matter. Peak-area ratios for lactate (Lac) relative to N-acetylaspartate (NAA), choline (Cho) and creatine (Cr) were calculated. Groups were compared using 2-way RM-ANOVA, Mann-Whitney U-test and Spearman's correlations. Results: No cerebral injury was seen on structural MR images. Lambs in the INJ group had higher mean FA and lower mean RD in the thalamus compared to PROT lambs, but not in the other regions of interest. Peak-area lactate ratios >1.0 was only seen in INJ lambs. A trend of higher mean peak-area ratios for Lac/Cr and Lac/Cho was seen, which correlated with lower pH in both groups. Conclusion: Acute changes in brain diffusion measures and metabolite peak-area ratios were observed after injurious ventilation. Early MRS/DTI is able to detect the initiation of ventilation-induced brain injury. [ABSTRACT FROM AUTHOR]