Doxapram for Apnoea of Prematurity (DoxAPrem) Dosage Study

INTERVENTION: Oral doxapram as a single loading dose of 48 mg/kg followed by a maintenance dose of 24 mg/kg 6‐hourly for 5 days (Treatment B). Compliance with dosing will be assessed from hospital drug charts. CONDITION: Apnoea of prematurity; ; Apnoea of prematurity Reproductive Health and Childbirth ‐ Complications of newborn Respiratory ‐ Other respiratory disorders / diseases PRIMARY OUTCOME: Proportion of infants with steady state doxapram plasma concentration in the therapeutic range of 1.5 to 4.0 mg/L, assessed at 2 to 4 hours after 4th or 5th maintenance dose[A single plasma sample taken 2 to 4 hours after 4th or 5th maintenance dose. ] SECONDARY OUTCOME: Confirmed or probable seizure: case 1 or 2 definition by standardised criteria INCLUSION CRITERIA: Infants are eligible for this study if they are born at <32 weeks’ gestation, are admitted to neonatal intensive care and meet all of the following criteria: a) Greater than or equal to 72 h old b) Maximum non‐invasive respiratory support (bubble nasal CPAP greater than or equal to 8 cmH20) c) Optimised dose of caffeine citrate (greater than or equal to 15 mg/kg/day) d) Evidence of significant apnoea/bradycardia/desaturation events in the past 48 hours, defined as one or more of the following: hypercapnia (PC02 greater than or equal to 8 kPa); hypoxaemia (peripheral oxygen saturation <90% for greater than or equal to 30% of time over greater than or equal to 6 hours; greater than or equal to 1 ABD event requiring positive pressure inflation; greater than or equal to 6 significant desaturations in 6 hours (peripheral oxygen saturation <80% associated with bradycardia <100/min and requiring nursing intervention). ; Determined from review of medical records and video‐EEG, if available[First 14 days after randomisation] Death[First 14 days after randomisation] Discontinuation of study intervention due any other adverse event that is considered serious as reported to the PI or determined from the medical record[First 14 days after randomisation] Duration of use of doxapram as determined from the medical record[From randomisation to primary hospital discharge] Intermittent hypoxaemia rate/h by pulse oximetry[Day 2 post randomisation] Intermittent hypoxaemia rate/h by pulse oximetry[Day 5 post randomisation] Intestinal perforation as determined from the medical record[First 14 days after randomisation] Mean Fi02 as determined from medical records[Day 2 post randomisation] Mean Fi02 as determined from medical records[Day 5 post randomisation] Mean heart rate by pulse oximetry[Day 2 post randomisation] Mean heart rate by pulse oximetry[Day 5 post randomisation] Mean Sp02 by pulse oximetry[Day 2 post randomisation] Mean Sp02 by pulse oximetry[Day 5 post randomisation] Mean systolic blood pressure (mmHg) by oscillometric machine[Day 2 post randomisation] Mean systolic blood pressure (mmHg) by oscillometric machine[Day 5 post randomisation] Mechanical ventilation received (yes/no), determined from bedside chart.[First 5 days after randomisation] Moderate‐severe undisturbed tremors by Finnegan score[Day 2 post randomisation] Moderate‐severe undisturbed tremors by Finnegan score[Day 5 post randomisation] Necrotising enterocolitis stage 2 or 3 as determined from the medical record[First 14 days after randomisation] PCO2 (kPa) by blood gas[Day 5 post randomisation] PCO2 (kPa) by blood gas[Day2 post randomisation] Percentage change of maximal antral cross‐sectional area (ACSA) by pulse oximetry[Day 2 post randomisation] Percentage change of maximal antral cross‐sectional area by ultrasound[Day 5 post randomisation] Proportion of time Sp02 <80% by pulse oximetry[Day 2 post randomisation] Proportion of time Sp02 <80% by pulse oximetry[Day 5 post randomisation] Proportion of time Sp02 <90% by pulse oximetry[Day 2 post randomisation] Proportion of time Sp02 <90% by pulse oximetry[Day 5 post randomisation] Superior mesenteric artery peak systolic velocity by pulse oximetry[Day 2 post randomisation] Superior mesenteric artery peak systolic velocity by ultrasound[Day 5 post randomisation] Superior mesenteric artery pulsatility index by pulse oximetry[Day 2 post randomisation] Superior mesenteric artery pulsatility index by ultrasound[Day 5 post randomisation] Systolic hypertension by oscillometric machine greater than or equal to the 95th centile for post‐menstrual age[Day 2 post randomisation] Systolic hypertension by oscillometric machine greater than or equal to the 95th centile for post‐menstrual age[Day 5 post randomisation]