About this trial
Preterm infants often suffer from apnea of prematurity (AOP; a cessation of breathing) due to immaturity of the respiratory system. AOP can lead to oxygen shortage and a low heart rate which might harm the development of the newborn, especially the central nervous system. In order to prevent oxygen shortage, infants are treated with non-invasive respiratory support and caffeine. Despite these treatments, many preterm newborns still suffer from AOP and need invasive mechanical ventilation. Although this will result in complete resolution of AOP, invasive mechanical ventilation has the disadvantage of being a major risk of chronic lung disease and impaired neurodevelopmental outcome. Restrictive invasive ventilation is therefore advocated nowadays in preterm infants. Doxapram is a respiratory stimulant that has been administered off-label to treat AOP. Doxapram, as add-on treatment, seems to be effective in treating AOP and to prevent invasive mechanical ventilation. It is unclear if a preterm infant benefit from doxapram treatment on the longer term. This study compares doxapram to placebo and hypothesizes that doxapram will protect preterm infants from both invasive ventilation (and related lung disease) and AOP related oxygen shortage (and related impaired brain development).
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Admitted to the neonatal intensvie care unit (NICU) of one of the participating centres
Written informed consent of both parents or legal representatives
Gestational age at birth < 29 weeks
Caffeine therapy, adequately dosed (see also under co-medication)
Disqualifiers
Previous use of open label doxapram
Use of theophylline (to replace doxapram)
Chromosomal defects (e.g. trisomy 13, 18, or 21)
Major congenital malformations that: compromise lung function (e.g. surfactant protein deficiencies, congenital diaphragmatic hernia); result in chronic ventilation (e.g. Pierre Robin sequence); increase the risk of death or adverse neurodevelopmental outcome (congenital cerebral malformations, chromosomal abnormalities);
Trial design
Parallel
Treatments tested in this trial
Doxapram
DrugLoading dose and continuous doxapram infusion.
Placebo
DrugLoading dose and continuous placebo infusion.
Treatment groups
Trial outcomes
Primary outcomes
Death or severe disability
Disability will be defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness. Cognitive delay will be defined as a Mental Development Index score of less than 85 on the Bayley Scales of Infant and Toddler Development, Bayley Score of Infant Development (BSID) III scores. Cerebral palsy will be diagnosed if the child had a non-progressive motor impairment characterized by abnormal muscle tone and decreased range or control of movements. The level of gross motor function will be determined with the use of the Gross Motor Function Classification System. Audiometry will be performed to determine the presence or absence of hearing loss. Blindness will be defined as a corrected visual acuity less than 20/200
Secondary outcomes
Broncho pulmonary dysplasia
Diagnosed according to the National Institute of Child Health and Human Development (NICHD) criteria
Death
Death at 36 weeks post menstrual age and hospital mortality
Admission period
Length of stay at the intensive care, length of stay in hospital
Endotracheal intubations
Incidence of endotracheal intubations
Sponsors and contacts
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Erasmus Medical Center
Lead sponsor
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Collaborator
Nederlands Neonataal Netwerk (N3), the Netherlands
Collaborator
Universitaire Ziekenhuizen KU Leuven
Collaborator
Maternal, Infant, Child and Youth Research Network (MICYRN)
Collaborator