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OBJECTIVE: Mechanisms of non-invasive high-frequency oscillatory ventilation (nHFOV) in preterm infants are unclear. We aimed to compare lung volume changes during apnoeas in preterm infants on nHFOV and nasal continuous positive airway pressure (nCPAP). METHODS: Analysis of electrical impedance tomography (EIT) data from a randomised crossover trial comparing nHFOV with nCPAP in preterm infants at 26-34 weeks postmenstrual age. EIT data were screened by two reviewers to identify apnoeas ≥10 s. End-expiratory lung impedance (EELI) and tidal volumes (VT) were calculated before and after apnoeas. Oxygen saturation (SpO2) and heart rate (HR) were extracted for 60 s after apnoeas. RESULTS: In 30 preterm infants, 213 apnoeas were identified. During apnoeas, oscillatory volumes were detectable during nHFOV. EELI decreased significantly during apnoeas (∆EELI nCPAP: -8.0 (-11.9 to -4.1) AU/kg, p<0.001; ∆EELI nHFOV: -3.4 (-6.5 to -0.3), p=0.03) but recovered over the first five breaths after apnoeas. Compared with before apnoeas, VT was increased for the first breath after apnoeas during nCPAP (∆VT: 7.5 (3.1 to 11.2) AU/kg, p=0.001). Falls in SpO2 and HR after apnoeas were greater during nCPAP than nHFOV (mean difference (95% CI): SpO2: 3.6% (2.7 to 4.6), p<0.001; HR: 15.9 bpm (13.4 to 18.5), p<0.001). CONCLUSION: Apnoeas were characterised by a significant decrease in EELI which was regained over the first breaths after apnoeas, partly mediated by a larger VT. Apnoeas were followed by a considerable drop in SpO2 and HR, particularly during nCPAP, leading to longer episodes of hypoxemia during nCPAP. Transmitted oscillations during nHFOV may explain these benefits. TRIAL REGISTRATION NUMBER: ACTRN12616001516471.

INTRODUCTION: Non-invasive high-frequency oscillatory ventilation (nHFOV) is an extension of nasal continuous positive airway pressure (nCPAP) support in neonates. We aimed to compare global and regional distribution of lung volumes during nHFOV versus nCPAP. METHODS: In 30 preterm infants enrolled in a randomised crossover trial comparing nHFOV with nCPAP, electrical impedance tomography data were recorded in prone position. For each mode of respiratory support, four episodes of artefact-free tidal ventilation, each comprising 30 consecutive breaths, were extracted. Tidal volumes (VT) in 36 horizontal slices, indicators of ventilation homogeneity and end-expiratory lung impedance (EELI) for the whole lung and for four horizontal regions of interest (non-gravity-dependent to gravity-dependent; EELINGD, EELImidNGD, EELImidGD, EELIGD) were compared between nHFOV and nCPAP. Aeration homogeneity ratio (AHR) was determined by dividing aeration in non-gravity-dependent parts of the lung through gravity-dependent regions. MAIN RESULTS: Overall, 228 recordings were analysed. Relative VT was greater in all but the six most gravity-dependent lung slices during nCPAP (all p<0.05). Indicators of ventilation homogeneity were similar between nHFOV and nCPAP (all p>0.05). Aeration was increased during nHFOV (mean difference (95% CI)=0.4 (0.2 to 0.6) arbitrary units per kilogram (AU/kg), p=0.013), mainly due to an increase in non-gravity-dependent regions of the lung (∆EELINGD=6.9 (0.0 to 13.8) AU/kg, p=0.028; ∆EELImidNGD=6.8 (1.2 to 12.4) AU/kg, p=0.009). Aeration was more homogeneous during nHFOV compared with nCPAP (mean difference (95% CI) in AHR=0.01 (0.00 to 0.02), p=0.0014). CONCLUSION: Although regional ventilation was similar between nHFOV and nCPAP, end-expiratory lung volume was higher and aeration homogeneity was slightly improved during nHFOV. The aeration difference was greatest in non-gravity dependent regions, possibly due to the oscillatory pressure waveform. The c

OBJECTIVE: We sought to determine the effect of stimulation during positive pressure ventilation (PPV) on the number of spontaneous breaths, exhaled tidal volume (VTe), mask leak and obstruction. DESIGN: Secondary analysis of a prospective, randomised trial comparing two face masks. SETTING: Single-centre delivery room study. PATIENTS: Newborn infants ≥34 weeks' gestation at birth. METHODS: Resuscitations were video recorded. Tactile stimulations during PPV were noted and the timing, duration and surface area of applied stimulus were recorded. Respiratory flow waveforms were evaluated to determine the number of spontaneous breaths, VTe, leak and obstruction. Variables were recorded throughout each tactile stimulation episode and compared with those recorded in the same time period immediately before stimulation. RESULTS: Twenty of 40 infants received tactile stimulation during PPV and we recorded 57 stimulations during PPV. During stimulation, the number of spontaneous breaths increased (median difference (IQR): 1 breath (0-3); padj<0.001) and VTe increased (0.5 mL/kg (-0.5 to 1.7), padj=0.028), whereas mask leak (0% (-20 to 1), padj=0.12) and percentage of obstructed inflations (0% (0-0), padj=0.14) did not change, compared with the period immediately prior to stimulation. Increased duration of stimulation (padj<0.001) and surface area of applied stimulus (padj=0.026) were associated with a larger increase in spontaneous breaths in response to tactile stimulation. CONCLUSIONS: Tactile stimulation during PPV was associated with an increase in the number of spontaneous breaths compared with immediately before stimulation without a change in mask leak and obstruction. These data inform the discussion on continuing stimulation during PPV in term infants. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trial Registry (ACTRN12616000768493).

Rationale: There is increasing evidence for a clinical benefit of noninvasive high-frequency oscillatory ventilation (nHFOV) in preterm infants. However, it is still unknown whether the generated oscillations are effectively transmitted to the alveoli.Objectives: To assess magnitude and regional distribution of oscillatory volumes (VOsc) at the lung level.Methods: In 30 prone preterm infants enrolled in a randomized crossover trial comparing nHFOV with nasal continuous positive airway pressure, electrical impedance tomography recordings were performed. During nHFOV, the smallest amplitude to achieve visible chest wall vibration was used, and the frequency was set at 8 hertz.Measurements and Main Results: Thirty consecutive breaths during artifact-free tidal ventilation were extracted for each of the 228 electrical impedance tomography recordings. After application of corresponding frequency filters, Vt and VOsc were calculated. There was a signal at 8 and 16 Hz during nHFOV, which was not detectable during nasal continuous positive airway pressure, corresponding to the set oscillatory frequency and its second harmonic. During nHFOV, the mean (SD) VOsc/Vt ratio was 0.20 (0.13). Oscillations were more likely to be transmitted to the non-gravity-dependent (mean difference [95% confidence interval], 0.041 [0.025-0.058]; P < 0.001) and right-sided lung (mean difference [95% confidence interval], 0.040 [0.019-0.061]; P < 0.001) when compared with spontaneous Vt.Conclusions: In preterm infants, VOsc during nHFOV are transmitted to the lung. Compared with the regional distribution of tidal breaths, oscillations preferentially reach the right and non-gravity-dependent lung. These data increase our understanding of the physiological processes underpinning nHFOV and may lead to further refinement of this novel technique.

In neonatal intensive care units (NICUs), 87.5% of alarms by the monitoring system are false alarms, often caused by the movements of the neonates. Such false alarms are not only stressful for the neonates as well as for their parents and caregivers, but may also lead to longer response times in real critical situations. The aim of this project was to reduce the rates of false alarms by employing machine learning algorithms (MLA), which intelligently analyze data stemming from standard physiological monitoring in combination with cerebral oximetry data (in-house built, OxyPrem). MATERIALS & METHODS Four popular MLAs were selected to categorize the alarms as false or real: (i) decision tree (DT), (ii) 5-nearest neighbors (5-NN), (iii) naïve Bayes (NB) and (iv) support vector machine (SVM). We acquired and processed monitoring data (median duration (SD): 54.6 (± 6.9) min) of 14 preterm infants (gestational age: 26 6/7 (± 2 5/7) weeks). A hybrid method of filter and wrapper feature selection generated the candidate subset for training these four MLAs. RESULTS A high specificity of >99% was achieved by all four approaches. DT showed the highest sensitivity (87%). The cerebral oximetry data improved the classification accuracy. DISCUSSION & CONCLUSION Despite a (as yet) low amount of data for training, the four MLAs achieved an excellent specificity and a promising sensitivity. Presently, the current sensitivity is insufficient since, in the NICU, it is crucial that no real alarms are missed. This will most likely be improved by including more subjects and data in the training of the MLAs, which makes pursuing this approach worthwhile.

BACKGROUND Randomised trial protocols may incorporate interim analyses, with the potential to stop the study for futility if early data show insufficient promise of a treatment benefit. Previously, we have shown that this approach will theoretically lead to mis-estimation of the treatment effect. We now wished to ascertain the importance of this phenomenon in practice. METHODS We reviewed the methods and results in a set of trials that had stopped for futility, identified through an extensive literature search. We recorded clinical areas, interventions, study design, outcomes, trial setting, sponsorship, planned and actual treatment effects, sample sizes; power; and if there was a data safety monitoring board, or a published protocol. We identified: if interim analyses were pre-specified, and how many analyses actually occurred; what pre-specified criteria might define futility; if a futility analysis formed the basis for stopping; who made the decision to stop; and the conditional power of each study, i.e. the probability of statistically significant results if the study were to continue to its complete sample size. RESULTS We identified 52 eligible trials, covering many clinical areas. Most trials had multiple centres, tested drugs, and 40% were industry sponsored. There were 75% where at least one interim analysis was planned a priori; a majority had only one interim analysis, typically with about half the target total sample size. A majority of trials did not pre-define a stopping rule, and a variety of reasons were given for stopping. Few studies calculated and reported low conditional power to justify the early stop. When conditional power could be calculated, it was typically low, especially under the current trend hypothesis. However, under the original design hypothesis, a few studies had relatively high conditional power. Data collection often continued after the interim analysis. CONCLUSIONS Although other factors will typically be involved, we conclude t

Objective To evaluate outcome trends of neonates born very preterm in 11 high-income countries participating in the International Network for Evaluating Outcomes of neonates. Study design In a retrospective cohort study, we included 154 233 neonates admitted to 529 neonatal units between January 1, 2007, and December 31, 2015, at 240/7 to 316/7 weeks of gestational age and birth weight <1500 g. Composite outcomes were in-hospital mortality or any of severe neurologic injury, treated retinopathy of prematurity, and bronchopulmonary dysplasia (BPD); and same composite outcome excluding BPD. Secondary outcomes were mortality and individual morbidities. For each country, annual outcome trends and adjusted relative risks comparing epoch 2 (2012-2015) to epoch 1 (2007-2011) were analyzed. Results For composite outcome including BPD, the trend decreased in Canada and Israel but increased in Australia and New Zealand, Japan, Spain, Sweden, and the United Kingdom. For composite outcome excluding BPD, the trend decreased in all countries except Spain, Sweden, Tuscany, and the United Kingdom. The risk of composite outcome was lower in epoch 2 than epoch 1 in Canada (adjusted relative risks 0.78; 95% CI 0.74-0.82) only. The risk of composite outcome excluding BPD was significantly lower in epoch 2 compared with epoch 1 in Australia and New Zealand, Canada, Finland, Japan, and Switzerland. Mortality rates reduced in most countries in epoch 2. BPD rates increased significantly in all countries except Canada, Israel, Finland, and Tuscany. Conclusions In most countries, mortality decreased whereas BPD increased for neonates born very preterm.

Background: Perinatal asphyxia and resulting hypoxic-ischemic encephalopathy is a major cause of death and long-term disability in term born neonates. Up to 20,000 infants each year are affected by HIE in Europe and even more in regions with lower level of perinatal care. The only established therapy to improve outcome in these infants is therapeutic hypothermia. Allopurinol is a xanthine oxidase inhibitor that reduces the production of oxygen radicals as superoxide, which contributes to secondary energy failure and apoptosis in neurons and glial cells after reperfusion of hypoxic brain tissue and may further improve outcome if administered in addition to therapeutic hypothermia. Methods: This study on the effects of ALlopurinol in addition to hypothermia treatment for hypoxic-ischemic Brain Injury on Neurocognitive Outcome (ALBINO), is a European double-blinded randomized placebo-controlled parallel group multicenter trial (Phase III) to evaluate the effect of postnatal allopurinol administered in addition to standard of care (including therapeutic hypothermia if indicated) on the incidence of death and severe neurodevelopmental impairment at 24 months of age in newborns with perinatal hypoxic-ischemic insult and signs of potentially evolving encephalopathy. Allopurinol or placebo will be given in addition to therapeutic hypothermia (where indicated) to infants with a gestational age ≥ 36 weeks and a birth weight ≥ 2500 g, with severe perinatal asphyxia and potentially evolving encephalopathy. The primary endpoint of this study will be death or severe neurodevelopmental impairment versus survival without severe neurodevelopmental impairment at the age of two years. Effects on brain injury by magnetic resonance imaging and cerebral ultrasound, electric brain activity, concentrations of peroxidation products and S100B, will also be studied along with effects on heart function and pharmacokinetics of allopurinol after iv-infusion. Discussion: This trial will provide d

OBJECTIVE: To explore population characteristics, organization of health services and comparability of available information for very low birth weight or very preterm neonates born before 32 weeks' gestation in 11 high-income countries contributing data to the International Network for Evaluating Outcomes of Neonates (iNeo). STUDY DESIGN: We obtained population characteristics from public domain sources, conducted a survey of organization of maternal and neonatal health services and evaluated the comparability of data contributed to the iNeo collaboration from Australia, Canada, Finland, Israel, Italy, Japan, New Zealand, Spain, Sweden, Switzerland and UK. RESULTS: All countries have nationally funded maternal/neonatal health care with >90% of women receiving prenatal care. Preterm birth rate, maternal age, and neonatal and infant mortality rates were relatively similar across countries. Most (50 to >95%) between-hospital transports of neonates born at non-tertiary units were conducted by designated transport teams; 72% (8/11 countries) had designated transfer and 63% (7/11 countries) mandate the presence of a physician. The capacity of 'step-down' units varied between countries, with capacity for respiratory care available in <10% to >75% of units. Heterogeneity in data collection processes for benchmarking and quality improvement activities were identified. CONCLUSIONS: Comparability of healthcare outcomes for very preterm low birth weight neonates between countries requires an evaluation of differences in population coverage, healthcare services and meta-data.

OBJECTIVES: To compare survival rates and age at death among very preterm infants in 10 national and regional neonatal networks. METHOD(S): A cohort study of very preterm infants, born between 24 and 29 weeks' gestation and weighing <1500 g, admitted to participating neonatal units between 2007 and 2013 in the International Network for Evaluating Outcomes of Neonates. Survival was compared by using standardized ratios (SRs) comparing survival in each network to the survival estimate of the whole population. RESULT(S): Network populations differed with respect to rates of cesarean birth, exposure to antenatal steroids and birth in nontertiary hospitals. Network SRs for survival were highest in Japan (SR: 1.10; 99% confidence interval: 1.08-1.13) and lowest in Spain (SR: 0.88; 99% confidence interval: 0.85-0.90). The overall survival differed from 78% to 93% among networks, the difference being highest at 24 weeks' gestation (range 35%-84%). Survival rates increased and differences between networks diminished with increasing gestational age (GA) (range 92%-98% at 29 weeks' gestation); yet, relative differences in survival followed a similar pattern at all GAs. The median age at death varied from 4 days to 13 days across networks. CONCLUSION(S): The network ranking of survival rates for very preterm infants remained largely unchanged as GA increased; however, survival rates showed marked variations at lower GAs. The median age at death also varied among networks. These findings warrant further assessment of the representativeness of the study populations, organization of perinatal services, national guidelines, philosophy of care at extreme GAs, and resources used for decision-making.© Copyright 2017 by the American Academy of Pediatrics.

OBJECTIVES: To compare survival rates and age at death among very preterm infants in 10 national and regional neonatal networks. METHOD(S): A cohort study of very preterm infants, born between 24 and 29 weeks' gestation and weighing <1500 g, admitted to participating neonatal units between 2007 and 2013 in the International Network for Evaluating Outcomes of Neonates. Survival was compared by using standardized ratios (SRs) comparing survival in each network to the survival estimate of the whole population. RESULT(S): Network populations differed with respect to rates of cesarean birth, exposure to antenatal steroids and birth in nontertiary hospitals. Network SRs for survival were highest in Japan (SR: 1.10; 99% confidence interval: 1.08-1.13) and lowest in Spain (SR: 0.88; 99% confidence interval: 0.85-0.90). The overall survival differed from 78% to 93% among networks, the difference being highest at 24 weeks' gestation (range 35%-84%). Survival rates increased and differences between networks diminished with increasing gestational age (GA) (range 92%-98% at 29 weeks' gestation); yet, relative differences in survival followed a similar pattern at all GAs. The median age at death varied from 4 days to 13 days across networks. CONCLUSION(S): The network ranking of survival rates for very preterm infants remained largely unchanged as GA increased; however, survival rates showed marked variations at lower GAs. The median age at death also varied among networks. These findings warrant further assessment of the representativeness of the study populations, organization of perinatal services, national guidelines, philosophy of care at extreme GAs, and resources used for decision-making.© Copyright 2017 by the American Academy of Pediatrics.

OBJECTIVES: To compare survival rates and age at death among very preterm infants in 10 national and regional neonatal networks. METHODS: A cohort study of very preterm infants, born between 24 and 29 weeks' gestation and weighing <1500 g, admitted to participating neonatal units between 2007 and 2013 in the International Network for Evaluating Outcomes of Neonates. Survival was compared by using standardized ratios (SRs) comparing survival in each network to the survival estimate of the whole population. RESULTS: Network populations differed with respect to rates of cesarean birth, exposure to antenatal steroids and birth in nontertiary hospitals. Network SRs for survival were highest in Japan (SR: 1.10; 99% confidence interval: 1.08-1.13) and lowest in Spain (SR: 0.88; 99% confidence interval: 0.85-0.90). The overall survival differed from 78% to 93% among networks, the difference being highest at 24 weeks' gestation (range 35%-84%). Survival rates increased and differences between networks diminished with increasing gestational age (GA) (range 92%-98% at 29 weeks' gestation); yet, relative differences in survival followed a similar pattern at all GAs. The median age at death varied from 4 days to 13 days across networks. CONCLUSIONS: The network ranking of survival rates for very preterm infants remained largely unchanged as GA increased; however, survival rates showed marked variations at lower GAs. The median age at death also varied among networks. These findings warrant further assessment of the representativeness of the study populations, organization of perinatal services, national guidelines, philosophy of care at extreme GAs, and resources used for decision-making.

Bronchopulmonary dysplasia (BPD), the main consequence of prematurity, has a significant heritability, but little is known about predisposing genes. The aim of this study was to identify gene loci predisposing infants to BPD. The initial genome-wide association study (GWAS) included 174 Finnish preterm infants of gestational age 24–30 weeks. Thereafter, the most promising single-nucleotide polymorphisms (SNPs) associated with BPD were genotyped in both Finnish (n = 555) and non-Finnish (n = 388) replication cohorts. Finally, plasma CRP levels from the first week of life and the risk of BPD were assessed. SNP rs11265269, flanking the CRP gene, showed the strongest signal in GWAS (odds ratio [OR] 3.2, p = 3.4 × 10⁻⁶). This association was nominally replicated in Finnish and French African populations. A number of other SNPs in the CRP region, including rs3093059, had nominal associations with BPD. During the first week of life the elevated plasma levels of CRP predicted the risk of BPD (OR 3.4, p = 2.9 × 10⁻⁴) and the SNP rs3093059 associated nominally with plasma CRP levels. Finally, SNP rs11265269 was identified as a risk factor of BPD (OR 1.8, p = 5.3 × 10⁻⁵), independently of the robust antenatal risk factors. As such, in BPD, a potential role for variants near CRP gene is proposed.

OBJECTIVES: The aim of this research is to assess causes and circumstances of deaths in extremely low gestational age neonates (ELGANs) born in Switzerland over a 3-year period. DESIGN: Population-based, retrospective cohort study. SETTING: All nine level III perinatal centres (neonatal intensive care units (NICUs) and affiliated obstetrical services) in Switzerland. PATIENTS: ELGANs with a gestational age (GA) <28 weeks who died between 1 July 2012 and 30 June 2015. RESULTS: A total of 594 deaths were recorded with 280 (47%) stillbirths and 314 (53%) deaths after live birth. Of the latter, 185 (59%) occurred in the delivery room and 129 (41%) following admission to an NICU. Most liveborn infants dying in the delivery room had a GA ≤24 weeks and died following primary non-intervention. In contrast, NICU deaths occurred following unrestricted life support regardless of GA. End-of-life decision-making and redirection of care were based on medical futility and anticipated poor quality of life in 69% and 28% of patients, respectively. Most infants were extubated before death (87%). CONCLUSIONS: In Switzerland, most deaths among infants born at less than 24 weeks of gestation occurred in the delivery room. In contrast, most deaths of ELGANs with a GA ≥24 weeks were observed following unrestricted provisional intensive care, end-of-life decision-making and redirection of care in the NICU regardless of the degree of immaturity.

Caffeine, a methylxanthine and nonspecific inhibitor of adenosine receptors, is an example of a drug that has been in use for more than 40 years. It is one of the most commonly prescribed drugs in neonatal medicine. However, until 2006, it had only a few relatively small and short-term studies supporting its use. It is thanks to the efforts of Barbara Schmidt and the Caffeine for Apnea of Prematurity (CAP) Trial Group that we now have high-quality and reliable data not only on short-term but also long-term outcomes of caffeine use for apnea of prematurity. CAP was an international, multicenter, placebo-controlled randomized trial designed to determine whether survival without neurodevelopmental disability at a corrected age of 18 months is improved if apnea of prematurity is managed without methylxanthines in infants at a high risk of apneic attacks. CAP was kept simple and pragmatic in order to allow for maximum generalizability and applicability. Infants with birth weights of 500-1,250 g were enrolled during the first 10 days of life if their clinicians considered them to be candidates for methylxanthine therapy. The most frequent indication for therapy reported in CAP was treatment of documented apnea, followed by the facilitation of the removal of an endotracheal tube. Only about 20% of the neonatologists in the trial started caffeine for the prevention of apnea and the findings of CAP cannot automatically be extrapolated to an exclusive prophylactic indication. However, recent data suggest that the administration of prophylactic methylxanthine by neonatologists is now common practice.