BackgroundApnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an increased risk of death or... Show moreBackgroundApnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an increased risk of death or disability. In addition to caffeine therapy and non-invasive respiratory support, doxapram might be used to reduce hypoxemic episodes and the need for invasive mechanical ventilation in preterm infants, thereby possibly improving their long-term outcome. However, high-quality trials on doxapram are lacking. The DOXA-trial therefore aims to investigate the safety and efficacy of doxapram compared to placebo in reducing the composite outcome of death or severe disability at 18 to 24 months corrected age.MethodsThe DOXA-trial is a double blinded, multicentre, randomized, placebo-controlled trial conducted in the Netherlands, Belgium and Canada. A total of 396 preterm infants with a gestational age below 29 weeks, suffering from AOP unresponsive to non-invasive respiratory support and caffeine will be randomized to receive doxapram therapy or placebo. The primary outcome is death or severe disability, defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness, at 18-24 months corrected age. Secondary outcomes are short-term neonatal morbidity, including duration of mechanical ventilation, bronchopulmonary dysplasia and necrotising enterocolitis, hospital mortality, adverse effects, pharmacokinetics and cost-effectiveness. Analysis will be on an intention-to-treat principle.DiscussionDoxapram has the potential to improve neonatal outcomes by improving respiration, but the safety concerns need to be weighed against the potential risks of invasive mechanical ventilation. It is unknown if the use of doxapram improves the long-term outcome. This forms the clinical equipoise of the current trial. This international, multicentre trial will provide the needed high-quality evidence on the efficacy and safety of doxapram in the treatment of AOP in preterm infants.Trial registrationClinicalTrials.gov NCT04430790 and EUDRACT 2019-003666-41. Prospectively registered on respectively June and January 2020. Show less
Ceftazidime is an antibiotic commonly used to treat bacterial infections in term neonates undergoing controlled therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy after perinatal... Show moreCeftazidime is an antibiotic commonly used to treat bacterial infections in term neonates undergoing controlled therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy after perinatal asphyxia. We aimed to describe the population pharmacokinetics (PK) of ceftazidime in asphyxiated neonates during hypothermia, rewarming, and normothermia and propose a population-based rational dosing regimen with optimal PK/pharmacodynamic (PD) target attainment. Data were collected in the PharmaCool prospective observational multicenter study. A population PK model was constructed, and the probability of target attainment (PTA) was assessed during all phases of controlled TH using targets of 100% of the time that the concentration in the blood exceeds the MIC (T->MIC) (for efficacy purposes and 100% T->4xMIC and 100% T->5xMIC to prevent resistance). A total of 35 patients with 338 ceftazidime concentrations were included. An allometrically scaled one-compartment model with postnatal age and body temperature as covariates on clearance was constructed. For a typical patient receiving the current dose of 100 mg/kg of body weight/day in 2 doses and assuming a worst-case MIC of 8 mg/L for Pseudomonas aeruginosa, the PTA was 99.7% for 100% T->MIC during hypothermia (33.7 degrees C; postnatal age [PNA] of 2 days). The PTA decreased to 87.7% for 100% T->MIC during normothermia (36.7 degrees C; PNA of 5 days). Therefore, a dosing regimen of 100 mg/kg/day in 2 doses during hypothermia and rewarming and 150 mg/kg/day in 3 doses during the following normothermic phase is advised. Higher-dosing regimens (150 mg/kg/day in 3 doses during hypothermia and 200 mg/kg/day in 4 doses during normothermia) could be considered when achievements of 100% T->4xMIC and 100% T->5xMIC are desired. Show less
Background: Cyclooxygenase inhibitors are commonly used in infants with patent ductus arteriosus (PDA), but the benefit of these drugs is uncertain. Methods: In this multicenter, noninferiority... Show moreBackground: Cyclooxygenase inhibitors are commonly used in infants with patent ductus arteriosus (PDA), but the benefit of these drugs is uncertain. Methods: In this multicenter, noninferiority trial, we randomly assigned infants with echocardiographically confirmed PDA (diameter, > 1.5 mm, with left-to-right shunting) who were extremely preterm (< 28 weeks' gestational age) to receive either expectant management or early ibuprofen treatment. The composite primary outcome included necrotizing enterocolitis (Bell's stage IIa or higher), moderate to severe bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. The noninferiority of expectant management as compared with early ibuprofen treatment was defined as an absolute risk difference with an upper boundary of the one-sided 95% confidence interval of less than 10 percentage points. Results: A total of 273 infants underwent randomization. The median gestational age was 26 weeks, and the median birth weight was 845 g. A primary-outcome event occurred in 63 of 136 infants (46.3%) in the expectant-management group and in 87 of 137 (63.5%) in the early-ibuprofen group (absolute risk difference, -17.2 percentage points; upper boundary of the one-sided 95% confidence interval [CI], -7.4; P < 0.001 for noninferiority). Necrotizing enterocolitis occurred in 24 of 136 infants (17.6%) in the expectant-management group and in 21 of 137 (15.3%) in the early-ibuprofen group (absolute risk difference, 2.3 percentage points; two-sided 95% CI, -6.5 to 11.1); bronchopulmonary dysplasia occurred in 39 of 117 infants (33.3%) and in 57 of 112 (50.9%), respectively (absolute risk difference, -17.6 percentage points; two-sided 95% CI, -30.2 to -5.0). Death occurred in 19 of 136 infants (14.0%) and in 25 of 137 (18.2%), respectively (absolute risk difference, -4.3 percentage points; two-sided 95% CI, -13.0 to 4.4). Rates of other adverse outcomes were similar in the two groups. Conclusions: Expectant management for PDA in extremely premature infants was noninferior to early ibuprofen treatment with respect to necrotizing enterocolitis, bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. (Funded by the Netherlands Organization for Health Research and Development and the Belgian Health Care Knowledge Center; BeNeDuctus ClinicalTrials.gov number, ; EudraCT number, .) Show less
Knol, R.; Brouwer, E.; Akker, T. van den; DeKoninck, P.L.J.; Lopriore, E.; Onland, W.; ... ; Pas, A.B. te 2022
Background International guidelines recommend delayed umbilical cord clamping (DCC) up to 1 min in preterm infants, unless the condition of the infant requires immediate resuscitation. However,... Show moreBackground International guidelines recommend delayed umbilical cord clamping (DCC) up to 1 min in preterm infants, unless the condition of the infant requires immediate resuscitation. However, clamping the cord prior to lung aeration may severely limit circulatory adaptation resulting in a reduction in cardiac output and hypoxia. Delaying cord clamping until lung aeration and ventilation have been established (physiological-based cord clamping, PBCC) allows for an adequately established pulmonary circulation and results in a more stable circulatory transition. The decline in cardiac output following time-based delayed cord clamping (TBCC) may thus be avoided. We hypothesise that PBCC, compared to TBCC, results in a more stable transition in very preterm infants, leading to improved clinical outcomes. The primary objective is to compare the effect of PBCC on intact survival with TBCC. Methods The Aeriation, Breathing, Clamping 3 (ABC3) trial is a multicentre randomised controlled clinical trial. In the interventional PBCC group, the umbilical cord is clamped after the infant is stabilised, defined as reaching heart rate > 100 bpm and SpO(2) > 85% while using supplemental oxygen < 40%. In the control TBCC group, cord clamping is time based at 30-60 s. The primary outcome is survival without major cerebral and/or intestinal injury. Preterm infants born before 30 weeks of gestation are included after prenatal parental informed consent. The required sample size is 660 infants. Discussion The findings of this trial will provide evidence for future clinical guidelines on optimal cord clamping management in very preterm infants at birth. Show less
BackgroundInfants with a congenital diaphragmatic hernia (CDH) and expected mild pulmonary hypoplasia have an estimated survival rate of 90%. Current guidelines for delivery room management do not... Show moreBackgroundInfants with a congenital diaphragmatic hernia (CDH) and expected mild pulmonary hypoplasia have an estimated survival rate of 90%. Current guidelines for delivery room management do not consider the individual patient's disease severity, but an individualized approach with spontaneous breathing instead of routine mechanical ventilation could be beneficial for the mildest cases. We developed a resuscitation algorithm for this individualized approach serving two purposes: improving the success rate by structuring the approach and providing a guideline for other centers. MethodsAn initial algorithm was discussed with all local stakeholders. Afterwards, the resulting algorithm was refined using input from international experts. ResultsEligible CDH infants: left-sided defect, observed to expected lung-to-head ratio >= 50%, gestational age at birth >= 37.0 weeks, and no major associated structural or genetic abnormalities. To facilitate fetal-to-neonatal transition, we propose to start stabilization with non-invasive respiratory support and to adjust this individually. ConclusionsInfants with mild CDH might benefit from an individualized approach for neonatal resuscitation. Herein, we present an algorithm that could serve as guidance for centers implementing this. Show less
BackgroundInfants with a congenital diaphragmatic hernia (CDH) and expected mild pulmonary hypoplasia have an estimated survival rate of 90%. Current guidelines for delivery room management do not... Show moreBackgroundInfants with a congenital diaphragmatic hernia (CDH) and expected mild pulmonary hypoplasia have an estimated survival rate of 90%. Current guidelines for delivery room management do not consider the individual patient's disease severity, but an individualized approach with spontaneous breathing instead of routine mechanical ventilation could be beneficial for the mildest cases. We developed a resuscitation algorithm for this individualized approach serving two purposes: improving the success rate by structuring the approach and providing a guideline for other centers. MethodsAn initial algorithm was discussed with all local stakeholders. Afterwards, the resulting algorithm was refined using input from international experts. ResultsEligible CDH infants: left-sided defect, observed to expected lung-to-head ratio >= 50%, gestational age at birth >= 37.0 weeks, and no major associated structural or genetic abnormalities. To facilitate fetal-to-neonatal transition, we propose to start stabilization with non-invasive respiratory support and to adjust this individually. ConclusionsInfants with mild CDH might benefit from an individualized approach for neonatal resuscitation. Herein, we present an algorithm that could serve as guidance for centers implementing this. Show less
Background: Perinatal arterial ischaemic stroke (PAIS) is an important cause of neurodevelopmental disabilities. In this first-in-human study, we aimed to assess the feasibility and safety of... Show moreBackground: Perinatal arterial ischaemic stroke (PAIS) is an important cause of neurodevelopmental disabilities. In this first-in-human study, we aimed to assess the feasibility and safety of intranasally delivered bone marrow-derived allogeneic mesenchymal stromal cells (MSCs) to treat PAIS in neonates. Methods: In this open-label intervention study in collaboration with all neonatal intensive care units in the Netherlands, we included neonates born at full term (>= 36 weeks of gestation) with MRI-confirmed PAIS in the middle cerebral artery region. All eligible patients were transferred to the neonatal intensive care unit of the Wilhelmina Children's Hospital. Neonates received one dose of 45-50 x 10(6) bone-marrow derived MSCs intranasally within 7 days of presenting signs of PAIS. The primary endpoints were acute and subacute safety outcomes, including vital signs, blood markers, and the occurrence of toxicity, adverse events, and serious adverse events. The occurrence of unexpected cerebral abnormalities by a repeat MRI at 3 months of age was a secondary endpoint. As part of standard clinical follow-up at Wilhelmina Children's Hospital, we assessed corticospinal tract development on MRI and performed motor assessments at 4 months of age. This study is registered with ClinicalTrials.gov, NCT03356821. Findings: Between Feb 11, 2020, and April 29, 2021, ten neonates were enrolled in the study. Intranasal administration of MSCs was well tolerated in all ten neonates. No serious adverse events were observed. One adverse event was seen: a mild transient fever of 38 degrees C without the need for clinical intervention. Blood inflammation markers (C-reactive protein, procalcitonin, and leukocyte count) were not significantly different pre-administration versus postadministration and, although thrombocyte levels increased (p=0.011), all were within the physiological range. Followup MRI scans did not show unexpected structural cerebral abnormalities. All ten patients had initial pre-Wallerian changes in the corticospinal tracts, but only four (40%) patients showed asymmetrical corticospinal tracts at follow-up MRI. Abnormal early motor assessment was found in three (30%) infants. Interpretation: This first-in-human study demonstrates that intranasal bone marrow-derived MSC administration in neonates after PAIS is feasible and no serious adverse events were observed in patients followed up until 3 months of age. Future large-scale placebo-controlled studies are needed to determine the therapeutic effect of intranasal MSCs for PAIS. Copyright (C) 2022 Published by Elsevier Ltd. All rights reserved. Show less
Introduction Pulmonary hypertension is a major determinant of postnatal survival in infants with a congenital diaphragmatic hernia (CDH). The current care during the perinatal stabilisation period... Show moreIntroduction Pulmonary hypertension is a major determinant of postnatal survival in infants with a congenital diaphragmatic hernia (CDH). The current care during the perinatal stabilisation period in these infants might contribute to the development of pulmonary hypertension after birth-in particular umbilical cord clamping before lung aeration. An ovine model of diaphragmatic hernia demonstrated that cord clamping after lung aeration, called physiological-based cord clamping (PBCC), avoided the initial high pressures in the lung vasculature while maintaining adequate blood flow, thereby avoiding vascular remodelling and aggravation of pulmonary hypertension. We aim to investigate if the implementation of PBCC in the perinatal stabilisation period of infants born with a CDH could reduce the incidence of pulmonary hypertension in the first 24 hours after birth.Methods and analysis We will perform a multicentre, randomised controlled trial in infants with an isolated left-sided CDH, born at >= 35.0 weeks. Before birth, infants will be randomised to either PBCC or immediate cord clamping, stratified by treatment centre and severity of pulmonary hypoplasia on antenatal ultrasound. PBCC will be performed using a purpose-built resuscitation trolley. Cord clamping will be performed when the infant is considered respiratory stable, defined as a heart rate >100 bpm, preductal oxygen saturation >85%, while using a fraction of inspired oxygen of <0.5. The primary outcome is pulmonary hypertension diagnosed in the first 24 hours after birth, based on clinical and echocardiographic parameters. Secondary outcomes include neonatal as well as maternal outcomes.Ethics and dissemination Central ethical approval was obtained from the Medical Ethical Committee of the Erasmus MC, Rotterdam, The Netherlands (METC 2019-0414). Local ethical approval will be obtained by submitting the protocol to the regulatory bodies and local institutional review boards. Show less
Liquid-based perinatal life support (PLS) technology will probably be applied in a first-in-human study within the next decade. Research and development of PLS technology should not only address... Show moreLiquid-based perinatal life support (PLS) technology will probably be applied in a first-in-human study within the next decade. Research and development of PLS technology should not only address technical issues, but also consider socio-ethical and legal aspects, its application area, and the corresponding design implications. This paper represents the consensus opinion of a group of healthcare professionals, designers, ethicists, researchers and patient representatives, who have expertise in tertiary obstetric and neonatal care, bio-ethics, experimental perinatal animal models for physiologic research, biomedical modeling, monitoring, and design. The aim of this paper is to provide a framework for research and development of PLS technology. These requirements are considering the possible respective user perspectives, with the aim to co-create a PLS system that facilitates physiological growth and development for extremely preterm born infants. Show less
The Platelets for Neonatal Thrombocytopenia (PlaNeT-2) trial reported an unexpected overall benefit of a prophylactic platelet transfusion threshold of 25 x 10(9)/L compared with 50 x 10(9)/L for... Show moreThe Platelets for Neonatal Thrombocytopenia (PlaNeT-2) trial reported an unexpected overall benefit of a prophylactic platelet transfusion threshold of 25 x 10(9)/L compared with 50 x 10(9)/L for major bleeding and/or mortality in preterm neonates (7% absolute-risk reduction). However, some neonates in the trial may have experienced little benefit or even harm from the 25 x 10(9)/L threshold. We wanted to assess this heterogeneity of treatment effect in the PlaNet-2 trial, to investigate whether all preterm neonates benefit from the low threshold. We developed a multivariate logistic regression model in the PlaNet-2 data to predict baseline risk of major bleeding and/or mortality for all 653 neonates. We then ranked the neonates based on their predicted baseline risk and categorized them into 4 risk quartiles. Within these quartiles, we assessed absolute-risk difference between the 50 x 10(9)/L- and 25 x 10(9)/L-threshold groups. A total of 146 neonates died or developed major bleeding. The internally validated C-statistic of the model was 0.63 (95% confidence interval, 0.58-0.68). The 25 x 10(9)/L threshold was associated with absolute-risk reduction in all risk groups, varying from 4.9% in the lowest risk group to 12.3% in the highest risk group. These results suggest that a 25 x 10(9)/L prophylactic platelet count threshold can be adopted in all preterm neonates, irrespective of predicted baseline outcome risk. Future studies are needed to improve the predictive accuracy of the baseline risk model. Show less
The Platelets for Neonatal Thrombocytopenia (PlaNeT-2) trial reported an unexpected overall benefit of a prophylactic platelet transfusion threshold of 25 x 10(9)/L compared with 50 x 10(9)/L for... Show moreThe Platelets for Neonatal Thrombocytopenia (PlaNeT-2) trial reported an unexpected overall benefit of a prophylactic platelet transfusion threshold of 25 x 10(9)/L compared with 50 x 10(9)/L for major bleeding and/or mortality in preterm neonates (7% absolute-risk reduction). However, some neonates in the trial may have experienced little benefit or even harm from the 25 x 10(9)/L threshold. We wanted to assess this heterogeneity of treatment effect in the PlaNet-2 trial, to investigate whether all preterm neonates benefit from the low threshold. We developed a multivariate logistic regression model in the PlaNet-2 data to predict baseline risk of major bleeding and/or mortality for all 653 neonates. We then ranked the neonates based on their predicted baseline risk and categorized them into 4 risk quartiles. Within these quartiles, we assessed absolute-risk difference between the 50 x 10(9)/L- and 25 x 10(9)/L-threshold groups. A total of 146 neonates died or developed major bleeding. The internally validated C-statistic of the model was 0.63 (95% confidence interval, 0.58-0.68). The 25 x 10(9)/L threshold was associated with absolute-risk reduction in all risk groups, varying from 4.9% in the lowest risk group to 12.3% in the highest risk group. These results suggest that a 25 x 10(9)/L prophylactic platelet count threshold can be adopted in all preterm neonates, irrespective of predicted baseline outcome risk. Future studies are needed to improve the predictive accuracy of the baseline risk model. Show less
Hundscheid, T.; Onland, W.; Overmeire, B. van; Dijk, P.; Kaam, A.H.L.C. van; Dijkman, K.P.; ... ; Boode, W.P. de 2018
