High vs. Low Initial Oxygen to Improve the Breathing Effort of Preterm Infants at Birth: Study Protocol for a Randomized Controlled Trial

Background: Although most preterm infants breathe at birth, their respiratory drive is weak and supplemental oxygen is often needed to overcome hypoxia. This could in turn lead to hyperoxia. To reduce the risk of hyperoxia, currently an initial low oxygen concentration (21–30%) is recommended during stabilization at birth, accepting the risk of a hypoxic period. However, hypoxia inhibits respiratory drive in preterm infants. Starting with a higher level of oxygen could lead to a shorter duration of hypoxia by stimulating breathing effort of preterm infants, and combined with subsequent titration based on oxygen saturation, prolonged hyperoxia might be prevented.Study design: This multi-center randomized controlled trial will include 50 infants with a gestational age between 24 and 30 weeks. Eligible infants will be randomized to stabilization with an initial FiO2 of either 1.0 or 0.3 at birth. Hereafter, FiO2 will be titrated based on the oxygen saturation target range. In both groups, all other interventions during stabilization and thereafter will be similar. The primary outcome is respiratory effort in the first 5 min after birth expressed as average minute volume/kg. Secondary outcomes include inspired tidal volumes/kg, rate of rise to maximum tidal volume/kg, percentage of recruitment breaths with tidal volumes above 8 mL/kg, duration of hypoxia and hyperoxia and plasma levels of markers of oxidative stress (8-iso-prostaglandin F2α).Discussion: Current resuscitation guidelines recommend oxygen titration if infants fail to achieve the 25th percentile of the SpO2 reference ranges. It has become clear that, using this approach, most preterm infants are at risk for hypoxia in the first 5 min after birth, which could suppress the breathing effort. In addition, for compromised preterm infants who need respiratory support at birth, higher SpO2 reference ranges in the first minutes after birth might be needed to prevent prolonged hypoxia. Enhancing breathing effort by achieving an adequate level of oxygenation could potentially lead to a lower incidence of intubation and mechanical ventilation in the delivery room, contributing to a lower risk on lung injury in high-risk preterm infants. Measuring 8-iso-prostaglandin F2α could lead to a reflection of the true amount of oxygen exposure in both study groups

Bicaudal D2, Dynein, and Kinesin-1 Associate with Nuclear Pore Complexes and Regulate Centrosome and Nuclear Positioning during Mitotic Entry

Mammalian Bicaudal D2 is the missing molecular link between cytoplasmic motor proteins and the nucleus during nuclear positioning prior to the onset of mitosis

Preterm Brain Injury, Antenatal Triggers, and Therapeutics:Timing Is Key

With a worldwide incidence of 15 million cases, preterm birth is a major contributor to neonatal mortality and morbidity, and concomitant social and economic burden Preterm infants are predisposed to life-long neurological disorders due to the immaturity of the brain. The risks are inversely proportional to maturity at birth. In the majority of extremely preterm infants

Multicentre paired non-inferiority study of the cardiorespiratory monitoring performance of the wireless and non-adhesive Bambi® belt measuring diaphragm activity in neonates: Study protocol

Introduction Cardiorespiratory monitoring is used in the neonatal intensive care unit (NICU) to assess the clinical status of newborn infants and detect critical deteriorations in cardiorespiratory function. Currently, heart rate (HR) is monitored by electrocardiography (ECG) and respiration by chest impedance (CI). Disadvantages of current monitoring techniques are usage of wired adhesive electrodes which may damage the skin and hinder care. The Bambi® belt is a wireless and non-adhesive alternative that enables cardiorespiratory monitoring by measuring electrical activity of the diaphragm via transcutaneous electromyography. A previous study showed feasibility of the Bambi® belt and this study compares the belt performance to ECG and CI. Methods and analysis This multicentre non-inferiority paired study will be performed in the NICU of the Máxima Medical Center (MMC) in Veldhoven and the Emma Children's Hospital, Amsterdam University Medical Centre (AmsterdamUMC) in Amsterdam, The Netherlands. 39 infants in different postmenstrual age groups (minimally 10 infants32 weeks) will be recruited. These infants will be monitored with the Bambi® belt in addition to standard ECG and CI for 24 hours. The primary outcome is the HR, studied with three criteria: (1) the limits of agreement of the HR measurements in terms of the second-to-second difference in the HR between the belt and standard ECG, (2) the detection of cardiac events consisting of bradycardia and tachycardia and (3) the quality of HR-monitoring. The secondary outcome is the respiratory rate (RR), studied with the criteria (1) agreement in RR-trend monitoring, (2) apnoea and tachypnoea detection and (3) reliable registrations. Ethics and dissemination This protocol was approved by the Medical Ethical Committee of the MMC and the Central Committee for Human Research. The MMC started patient recruitment in July and the AmsterdamUMC in August 2021. The results will be presented at conferences and published in peer-reviewed journals

Physiological-based cord clamping in very preterm infants:the Aeration, Breathing, Clamping 3 (ABC3) trial—statistical analysis plan for a multicenter randomized controlled trial

Background: Mortality, cerebral injury, and necrotizing enterocolitis (NEC) are common complications of very preterm birth. An important risk factor for these complications is hemodynamic instability. Pre-clinical studies suggest that the timing of umbilical cord clamping affects hemodynamic stability during transition. Standard care is time-based cord clamping (TBCC), with clamping irrespective of lung aeration. It is unknown whether delaying cord clamping until lung aeration and ventilation have been established (physiological-based cord clamping, PBCC) is more beneficial. This document describes the statistical analyses for the ABC3 trial, which aims to assess the efficacy and safety of PBCC, compared to TBCC. Methods: The ABC3 trial is a multicenter, randomized trial investigating PBCC (intervention) versus TBCC (control) in very preterm infants. The trial is ethically approved. Preterm infants born before 30 weeks of gestation are randomized after parental informed consent. The primary outcome is intact survival, defined as the composite of survival without major cerebral injury and/or NEC. Secondary short-term outcomes are co-morbidities and adverse events assessed during NICU admission, parental reported outcomes, and long-term neurodevelopmental outcomes assessed at a corrected age of 2 years. To test the hypothesis that PBCC increases intact survival, a logistic regression model will be estimated using generalized estimating equations (accounting for correlation between siblings and observations in the same center) with treatment and gestational age as predictors. This plan is written and submitted without knowledge of the data. Discussion: The findings of this trial will provide evidence for future clinical guidelines on optimal cord clamping management at birth. Trial registration: ClinicalTrials.gov NCT03808051. Registered on 17 January 2019.</p

Doxapram versus placebo in preterm newborns : a study protocol for an international double blinded multicentre randomized controlled trial (DOXA-trial)

Abstract: 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 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

Physiological-based cord clamping in very preterm infants: the Aeration, Breathing, Clamping 3 (ABC3) trial—study protocol for a multicentre randomised controlled trial

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, 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 SpO2 > 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. Trial registration: ClinicalTrials.gov NCT03808051. First registered on January 17, 2019

Physiological-based cord clamping in very preterm infants:the Aeration, Breathing, Clamping 3 (ABC3) trial-study protocol for a multicentre randomised controlled trial

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, 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. Trial registration: ClinicalTrials.gov NCT03808051. First registered on January 17, 2019

Physiological-based cord clamping in very preterm infants: the Aeration, Breathing, Clamping 3 (ABC3) trial—study protocol for a multicentre randomised controlled trial

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, 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 SpO2 > 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. Trial registration: ClinicalTrials.gov NCT03808051. First registered on January 17, 2019

Additional file 1 of Doxapram versus placebo in preterm newborns: a study protocol for an international double blinded multicentre randomized controlled trial (DOXA-trial)

Additional file 1