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
Introduction: This study was set up to investigate if and to what extent non-pharmacological analgesia is able to provide comfort to very preterm infants (VPI) during less invasive surfactant... Show moreIntroduction: This study was set up to investigate if and to what extent non-pharmacological analgesia is able to provide comfort to very preterm infants (VPI) during less invasive surfactant administration (LISA). Methods: This was a prospective non-randomized multicenter observational study performed in level IV NICUs. Inborn VPI with a gestational age between 220/7 and 316/7 weeks, signs of respiratory distress syndrome, and the need for surfactant replacement were included. Non-pharmacological analgesia was performed in all infants during LISA. In case of failure of the first LISA attempt, additional analgosedation could be administered. COMFORTneo scores during LISA were assessed. Results: 113 VPI with a mean gestational age of 27 weeks (+/− 2.3 weeks) and mean birth weight of 946 g (+/− 33 g) were included. LISA was successful at the first laryngoscopy attempt in 81%. COMFORTneo scores were highest during laryngoscopy. At this time point, non-pharmacological analgesia provided adequate comfort in 61% of the infants. 74.4% of lower gestational aged infants (i.e., 220–266 weeks) were within the comfort zone during laryngoscopy compared to 51.6% of higher gestational aged infants (i.e., 270–320 weeks) (p = 0.016). The time point of surfactant administration did not influence the COMFORTneo scores during the LISA procedure. Conclusion: Non-pharmacological analgesia provided comfort in as much as 61% of the included VPI during LISA. Further research is needed to both develop strategies to identify infants who, despite receiving non-pharmacological analgesia, are at high risk for experiencing discomfort during LISA and define patient-tailored dosage and choice of analgosedative drugs. Show less
Labrie, N.; Kunneman, M.; Veenendaal, N. van; Kempen, A. van; Vliet, L. van 2023
Objective: To develop valid and realistic manipulations for video-vignette research using expert opinion rounds, in preparation of an experimental study on clinicians' (un)reasonable argumentative... Show moreObjective: To develop valid and realistic manipulations for video-vignette research using expert opinion rounds, in preparation of an experimental study on clinicians' (un)reasonable argumentative support for treatment de-cisions in neonatal care. Methods: In three rounds, N = 37 participants (parents/clinicians/researchers) provided feedback on four video -vignette scripts and completed listing, ranking, and rating exercises to determine which (un)reasonable argu-ments clinicians may provide to support treatment decisions. Results: Round 1: participants deemed the scripts realistic. They judged that, on average, clinicians should provide two arguments for a treatment decision. They listed 13-20 reasonable arguments, depending on the script. Round 2: participants ranked the two most salient, reasonable arguments per script. Round 3: participants rated the most plausible, unreasonable arguments from a predefined list. These results guided the design of 12 experimental conditions. Conclusion: Expert opinion rounds are an effective method to develop video-vignettes that are theoretically sound and ecologically realistic and offer a powerful means to include stakeholders in experimental research design. Our study yielded some preliminary insights into what are considered prevalent (un)reasonable arguments for clinicians' treatment plans. Practice implications: We provide hands-on guidelines on involving stakeholders in the design of video-vignette experiments and the development of video-based health communication interventions - both for research and practice. 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
Aim: To determine whether the use of a respiratory function monitor (RFM) during PPV of extremely preterm infants at birth, compared with no RFM, leads to an increase in percentage of inflations... Show moreAim: To determine whether the use of a respiratory function monitor (RFM) during PPV of extremely preterm infants at birth, compared with no RFM, leads to an increase in percentage of inflations with an expiratory tidal volume (Vte) within a predefined target range.Methods: Unmasked, randomised clinical trial conducted October 2013 - May 2019 in 7 neonatal intensive care units in 6 countries. Very preterm infants (24-27 weeks of gestation) receiving PPV at birth were randomised to have a RFM screen visible or not. The primary outcome was the median proportion of inflations during manual PPV (face mask or intubated) within the target range (Vte 4-8 mL/kg). There were 42 other prespecified monitor measurements and clinical outcomes.Results: Among 288 infants randomised (median (IQR) gestational age 26(+2) (25(+3)-27(+1)) weeks), a total number of 51,352 inflations were analysed. The median (IQR) percentage of inflations within the target range in the RFM visible group was 30.0 (18.0-42.2)% vs 30.2 (14.8-43.1)% in the RFM non-visible group (p = 0.721). There were no dierences in other respiratory function measurements, oxygen saturation, heart rate or FiO(2). There were no dierences in clinical outcomes, except for the incidence of intraventricular haemorrhage (all grades) and/or cystic periventricular leukomalacia (visible RFM: 26.7% vs non-visible RFM: 39.0%; RR 0.71 (0.68-0.97); p = 0.028).Conclusion: In very preterm infants receiving PPV at birth, the use of a RFM, compared to no RFM as guidance for tidal volume delivery, did not increase the percentage of inflations in a predefined target range. Show less
Background: Extremely preterm infants require assistance recruiting the lung to establish a functional residual capacity after birth. Sustained inflation (SI) combined with positive end expiratory... Show moreBackground: Extremely preterm infants require assistance recruiting the lung to establish a functional residual capacity after birth. Sustained inflation (SI) combined with positive end expiratory pressure (PEEP) may be a superior method of aerating the lung compared with intermittent positive pressure ventilation (IPPV) with PEEP in extremely preterm infants. The Sustained Aeration of Infant Lungs (SAIL) trial was designed to study this question.Methods/Design: This multisite prospective randomized controlled unblinded trial will recruit 600 infants of 23 to 26 weeks gestational age who require respiratory support at birth. Infants in both arms will be treated with PEEP 5 to 7 cm H2O throughout the resuscitation. The study intervention consists of performing an initial SI (20 cm H2O for 15 seconds) followed by a second SI (25 cm H2O for 15 seconds), and then PEEP with or without IPPV, as needed. The control group will be treated with initial IPPV with PEEP. The primary outcome is the combined endpoint of bronchopulmonary dysplasia or death at 36 weeks post-menstrual age. Show less
Steggerda, S.J.; Bruine, F.T. de; Berg-Huysmans, A.A. van den; Rijken, M.; Leijser, L.M.; Walther, F.J.; Wezel-Meijler, G. van 2013
The content of this thesis is of two sorts: in one part, three topics about the early origins of adult disease are addressed, preceded by three related methodological studies which form the other... Show moreThe content of this thesis is of two sorts: in one part, three topics about the early origins of adult disease are addressed, preceded by three related methodological studies which form the other part. The thesis starts with a systematic review of the literature about the growth of infants born preterm. Next, three specific methodological issues related to early origins of adult disease studies are addressed. A: the most favorable regression model for analyzing and interpreting the effect of both prenatal and subsequent postnatal growth on adult health outcomes. B: the efficiency of reliability studies in the context of a multi-centre study. And C: the correct and clear assessment of reliability in case of log transformed outcomes. These methods are used ind the second part, in which three topics about the effects of prenatal and early postnatal growth on adult health outcomes are addressed, namely: A the association between birth weight and adult renal function in non-premature subjects. B: The association between birth weight and the adult metabolic syndrome, and its separate components in the same population. And finally, C: the association between early growth and adult body composition in subjects born very preterm. Show less
