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Background: Controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants. A persistent PDA is associated with neonatal mortality and morbidity, but causality remains unproven. Although both pharmacological and/or surgical treatment are effective in PDA closure, this has not resulted in an improved neonatal outcome. In most preterm infants, a PDA will eventually close spontaneously, hence PDA treatment potentially increases the risk of iatrogenic adverse effects. Therefore, expectant management is gaining interest, even in the absence of convincing evidence to support this strategy.Methods/design: The BeNeDuctus trial is a multicentre, randomised, non-inferiority trial assessing early pharmacological treatment (24-72 h postnatal age) with ibuprofen versus expectant management of PDA in preterm infants in Europe. Preterm infants with a gestational age of less than 28 weeks and an echocardiographic-confirmed PDA with a transductal diameter of > 1.5 mm are randomly allocated to early pharmacological treatment with ibuprofen or expectant management after parental informed consent. The primary outcome measure is the composite outcome of mortality, and/or necrotizing enterocolitis Bell stage ≥ IIa, and/or bronchopulmonary dysplasia, all established at a postmenstrual age of 36 weeks. Secondary short-term outcomes are comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. This statistical analysis plan focusses on the short-term outcome and is written and submitted without knowledge of the data.Trial Registration: ClinicalTrials.gov NTR5479. Registered on October 19, 2015, with the Dutch Trial Registry, sponsored by the United States National Library of Medicine Clinicaltrials.gov NCT02884219 (registered May 2016) and the European Clinical Trials Database EudraCT 2017-001376-28. [ABSTRACT FROM AUTHOR]

Aim: Perinatal death is often preceded by an end-of-life decision (ELD). Disparate hospital policies, complex legal frameworks and ethically difficult cases make attitudes important. This study investigated attitudes of neonatologists and nurses towards perinatal ELDs.Methods: A survey was handed out to all neonatologists and neonatal nurses in all eight neonatal intensive care units in Flanders, Belgium in May 2017. Respondents indicated agreement with statements regarding perinatal ELDs on a Likert-scale and sent back questionnaires via mail.Results: The response rate was 49.5% (302/610). Most neonatologists and nurses found nontreatment decisions such as withholding or withdrawing treatment acceptable (90-100%). Termination of pregnancy when the foetus is viable in cases of severe or lethal foetal problems was considered highly acceptable in both groups (80-98%). Physicians and nurses do not find different ELDs equally acceptable, e.g. nurses more often than physicians (74% vs 60%, p = 0.017) agree that it is acceptable in certain cases to administer medication with the explicit intention of hastening death.Conclusion: There was considerable support for both prenatal and neonatal ELDs, even for decisions that currently fall outside the Belgian legal framework. Differences between neonatologists' and nurses' attitudes indicate that both opinions should be heard during ELD-making. [ABSTRACT FROM AUTHOR]

This follow-up to the STOP-BPD randomized clinical trial, which investigated the efficacy and safety of systemic hydrocortisone treatment initiated 7 to 14 days after birth in ventilator-dependent, very preterm infants in the Netherlands and Belgium at 36 weeks' postmenstrual age, examines the prespecified composite of death and neurodevelopmental impairment among these infants at 2 years' corrected age. [ABSTRACT FROM AUTHOR]

Importance: Dexamethasone initiated after the first week of life reduces the rate of death or bronchopulmonary dysplasia (BPD) but may cause long-term adverse effects in very preterm infants. Hydrocortisone is increasingly used as an alternative, but evidence supporting its efficacy and safety is lacking.Objective: To assess the effect of hydrocortisone initiated between 7 and 14 days after birth on death or BPD in very preterm infants.Design, Setting, and Participants: Double-blind, placebo-controlled randomized trial conducted in 19 neonatal intensive care units in the Netherlands and Belgium from November 15, 2011, to December 23, 2016, among preterm infants with a gestational age of less than 30 weeks and/or birth weight of less than 1250 g who were ventilator dependent between 7 and 14 days of life, with follow-up to hospital discharge ending December 12, 2017.Interventions: Infants were randomly assigned to receive a 22-day course of systemic hydrocortisone (cumulative dose, 72.5 mg/kg) (n = 182) or placebo (n = 190).Main Outcomes and Measures: The primary outcome was a composite of death or BPD assessed at 36 weeks' postmenstrual age. Twenty-nine secondary outcomes were analyzed up to hospital discharge, including death and BPD at 36 weeks' postmenstrual age.Results: Among 372 patients randomized (mean gestational age, 26 weeks; 55% male), 371 completed the trial; parents withdrew consent for 1 child treated with hydrocortisone. Death or BPD occurred in 128 of 181 infants (70.7%) randomized to hydrocortisone and in 140 of 190 infants (73.7%) randomized to placebo (adjusted risk difference, -3.6% [95% CI, -12.7% to 5.4%]; adjusted odds ratio, 0.87 [95% CI, 0.54-1.38]; P = .54). Of 29 secondary outcomes, 8 showed significant differences, including death at 36 weeks' postmenstrual age (15.5% with hydrocortisone vs 23.7% with placebo; risk difference, -8.2% [95% CI, -16.2% to -0.1%]; odds ratio, 0.59 [95% CI, 0.35-0.995]; P = .048). Twenty-one outcomes showed nonsignificant differences, including BPD (55.2% with hydrocortisone vs 50.0% with placebo; risk difference, 5.2% [95% CI, -4.9% to 15.2%]; odds ratio, 1.24 [95% CI, 0.82-1.86]; P = .31). Hyperglycemia requiring insulin therapy was the only adverse effect reported more often in the hydrocortisone group (18.2%) than in the placebo group (7.9%).Conclusions and Relevance: Among mechanically ventilated very preterm infants, administration of hydrocortisone between 7 and 14 days after birth, compared with placebo, did not improve the composite outcome of death or BPD at 36 weeks' postmenstrual age. These findings do not support the use of hydrocortisone for this indication.Trial Registration: Netherlands National Trial Register Identifier: NTR2768. [ABSTRACT FROM AUTHOR]

Background: Although beneficial in clinical practice, the INtubate-SURfactant-Extubate (IN-SUR-E) method is not successful in all preterm neonates with respiratory distress syndrome, with a reported failure rate ranging from 19 to 69 %. One of the possible mechanisms responsible for the unsuccessful IN-SUR-E method, requiring subsequent re-intubation and mechanical ventilation, is the inability of the preterm lung to achieve and maintain an "optimal" functional residual capacity. The importance of lung recruitment before surfactant administration has been demonstrated in animal studies showing that recruitment leads to a more homogeneous surfactant distribution within the lungs. Therefore, the aim of this study is to compare the application of a recruitment maneuver using the high-frequency oscillatory ventilation (HFOV) modality just before the surfactant administration followed by rapid extubation (INtubate-RECruit-SURfactant-Extubate: IN-REC-SUR-E) with IN-SUR-E alone in spontaneously breathing preterm infants requiring nasal continuous positive airway pressure (nCPAP) as initial respiratory support and reaching pre-defined CPAP failure criteria.Methods/design: In this study, 206 spontaneously breathing infants born at 24(+0)-27(+6) weeks' gestation and failing nCPAP during the first 24 h of life, will be randomized to receive an HFOV recruitment maneuver (IN-REC-SUR-E) or no recruitment maneuver (IN-SUR-E) just prior to surfactant administration followed by prompt extubation. The primary outcome is the need for mechanical ventilation within the first 3 days of life. Infants in both groups will be considered to have reached the primary outcome when they are not extubated within 30 min after surfactant administration or when they meet the nCPAP failure criteria after extubation.Discussion: From all available data no definitive evidence exists about a positive effect of recruitment before surfactant instillation, but a rationale exists for testing the following hypothesis: a lung recruitment maneuver performed with a step-by-step Continuous Distending Pressure increase during High-Frequency Oscillatory Ventilation (and not with a sustained inflation) could have a positive effects in terms of improved surfactant distribution and consequent its major efficacy in preterm newborns with respiratory distress syndrome. This represents our challenge.Trial Registration: ClinicalTrials.gov identifier: NCT02482766 . Registered on 1 June 2015. [ABSTRACT FROM AUTHOR]

The objective of this study was to assess how frequently end-of-life decisions (ELDs) with a possible or certain life-shortening effect in neonates and infants were discussed with parents, and to determine if consultation of parents was associated with the type of ELD, (clinical) characteristics of the patient, and socio-demographic characteristics of the physician. A retrospective study of all deaths of live born infants under the age of one year was conducted in Flanders, Belgium. For 292 of all 298 deaths in a 1-year period (between 1 August 1999 and 31 July 2000) the attending physician could be identified and was sent an anonymous questionnaire. All cases with an ELD and containing information regarding the consultation of parents were included. The response rate was 87% (253/292). In 136 out of 143 cases, an ELD was made and information on the consultation of parents was obtained. According to the physician, the ELD was discussed with parents in 84% (114/136) of cases. The smaller the gestational age of the infant, the more the parental request for an ELD was explicit (p=0.025). When parents were not consulted, the ELD was based more frequently on the fact that the infant had no chance to survive and less on quality-of-life considerations (p=0.001); the estimated shortening of life due to the ELD was small in all cases, but significantly smaller (p<0.001) if parents were not consulted. It is concluded that the majority of parents of children dying under the age of one year are consulted in ELD-making, especially for decisions based on quality-of-life considerations (95.1%). Parents of infants with a small gestational age more often explicitly requested an ELD. [ABSTRACT FROM AUTHOR]

Background: The death of a child before or shortly after birth is frequently preceded by an end-of-life decision (ELD). Population-based studies of incidence and characteristics of ELDs in neonates and infants are rare, and those in the foetal-infantile period (> 22 weeks of gestation - 1 year) including both neonates and stillborns, are non-existent. However, important information is missed when decisions made before birth are overlooked. Our study protocol addresses this knowledge gap.Methods: First, a new and encompassing framework was constructed to conceptualise ELDs in the foetal-infantile period. Next, a population mortality follow-back survey in Flanders (Belgium) was set up with physicians who certified all death certificates of stillbirths from 22 weeks of gestation onwards, and infants under the age of a year. Two largely similar questionnaires (stillbirths and neonates) were developed, pilot tested and validated, both including questions on ELDs and their preceding decision-making processes. Each death requires a postal questionnaire to be sent to the certifying physician. Anonymity of the child, parents and physician is ensured by a rigorous mailing procedure involving a lawyer as intermediary between death certificate authorities, physicians and researchers. Approval by medical societies, ethics and privacy commissions has been obtained.Discussion: This research protocol is the first to study ELDs over the entire foetal-infantile period on a population level. Based on representative samples of deaths and stillbirths and applying a trustworthy anonymity procedure, the research protocol can be used in other countries, irrespective of legal frameworks around perinatal end-of-life decision-making. [ABSTRACT FROM AUTHOR]

Background: The Thompson encephalopathy score is a clinical score to assess newborns suffering from perinatal asphyxia. Previous studies revealed a high sensitivity and specificity of the Thompson encephalopathy score for adverse outcomes (death or severe disability). Because the Thompson encephalopathy score was developed before the use of therapeutic hypothermia, its value was reassessed.Objective: The purpose of this study was to assess the association of the Thompson encephalopathy score with adverse short-term outcomes, defined as death before discharge, development of severe epilepsy, or the presence of multiple organ failure in asphyxiated newborns undergoing therapeutic hypothermia.Methods: The study period ranged from November 2010 to October 2014. A total of 12 tertiary neonatal intensive care units participated. Demographic and clinical data were collected from the "PharmaCool" multicenter study, an observational cohort study analyzing pharmacokinetics of medication during therapeutic hypothermia. With multiple logistic regression analyses the association of the Thompson encephalopathy scores with outcomes was studied.Results: Data of 142 newborns were analyzed (male: 86; female: 56). Median Thompson score was 9 (interquartile range: 8 to 12). Median gestational age was 40 weeks (interquartile range 38 to 41), mean birth weight was 3362 grams (standard deviation: 605). All newborns manifested perinatal asphyxia and underwent therapeutic hypothermia. Death before discharge occurred in 23.9% and severe epilepsy in 21.1% of the cases. In total, 59.2% of the patients had multiple organ failure. The Thompson encephalopathy score was not associated with multiple organ failure, but a Thompson encephalopathy score ≥12 was associated with death before discharge (odds ratio: 3.9; confidence interval: 1.3 to 11.2) and with development of severe epilepsy (odds ratio: 8.4; confidence interval: 2.5 to 27.8).Conclusion: The Thompson encephalopathy score is a useful clinical tool, even in cooled asphyxiated newborns. A score ≥12 is associated with adverse outcomes (death before discharge and development of severe epilepsy). The Thompson encephalopathy score is not associated with the development of multiple organ failure. [ABSTRACT FROM AUTHOR]

Context: Making end-of-life decisions (ELDs) in neonates involves ethically difficult and distressing dilemmas for health care providers. Insight into which factors complicate or facilitate this decision-making process could be a necessary first step in formulating recommendations to aid future practice.Objectives: This study aimed to identify barriers to and facilitators of the ELD-making process as perceived by neonatologists and nurses.Methods: We conducted semistructured face-to-face interviews with 15 neonatologists and 15 neonatal nurses, recruited through four neonatal intensive care units in Flanders, Belgium. They were asked what factors had facilitated and complicated previous ELD-making processes. Two researchers independently analyzed the data, using thematic content analysis to extract and summarize barriers and facilitators.Results: Barriers and facilitators were found at three distinct levels: the case-specific context (e.g., uncertainty of the diagnosis and specific characteristics of the child, parents, and health care providers, which make decision making more difficult), decision-making process (e.g., multidisciplinary consultations and advance care planning, which make decision making easier), and overarching structure (e.g., lack of privacy and complex legislation making decision making more challenging).Conclusion: Barriers and facilitators found in this study can lead to recommendations, some simpler to implement than others, to aid the complex ELD-making process. Recommendations include establishing regular multidisciplinary meetings to include all health care providers and reduce unnecessary uncertainty, routinely implementing advance care planning in severely ill neonates to make important decisions beforehand, creating privacy for bad-news conversations with parents, and reviewing the complex legal framework of perinatal ELD making. [ABSTRACT FROM AUTHOR]