Developmental pharmacology and age-related pharmacokinetics — formative SAQs

SAQ 1 — Neonatal toxicity on a 'standard' weight-based dose (10 marks)

A 10-day-old term neonate weighing 3.2 kg becomes apnoeic shortly after a morphine infusion is started on the ward for post-operative pain. The nurse stops the infusion. The order was written at a weight-based dose, but the team is surprised because the dose was taken from the adult drug chart. The baby is dusky with a pulse. [1] [5]

Questions

1. Outline your immediate management. (3 marks) [1]
2. Explain how each of the four ADME phases contributed to this toxicity in a term neonate. (5 marks) [2] [4]
3. State two prescribing principles that would have prevented this event. (2 marks) [5]

Model answer

Immediate management (3). Support the airway and breathing with bag-mask ventilation; give naloxone titrated to respiratory effort rather than full alertness to avoid precipitating withdrawal; call for senior paediatric and neonatal or PICU help; keep the infusion stopped and preserve the syringe and order; check whether any other child is on the same protocol; document and report; open disclosure to the family once the child is stable. [1]

ADME contribution (5). Absorption was intravenous, so gut immaturity did not apply, but the neonate's high body surface area to mass ratio means topical and transdermal exposure would have been relevant if other routes had been used. Distribution contributed strongly: total body water and extracellular fluid are far higher in the neonate, the plasma protein binding is low, and the blood-brain barrier is immature, so a larger fraction of the morphine reached the central nervous system. Metabolism contributed through slow UGT2B7 maturation — morphine is cleared by glucuronidation, which is markedly reduced in the first weeks of life. Excretion contributed through low neonatal glomerular filtration rate (about 2 to 4 mL per minute per 1.73 m² at birth), so the morphine metabolites were cleared slowly. The combined effect is a narrow therapeutic window and prolonged exposure. [2] [4]

Prevention (2). Always confirm weight in kilograms and look up the dose in a paediatric formulary (BNFc, Royal Children's Hospital Melbourne) rather than reproducing an adult dose from memory; apply maturation adjustment using postmenstrual and postnatal age for narrow-therapeutic-index drugs, and require an independent double-check of high-risk infusions such as opioids. [5]