Introduction Paracetamol is a mainstay analgesic for neonatal pain and is increasingly used for management of patent ductus arteriosus (PDA) in very premature infants. The BNF for Children (BNFC) gives no dose recommendations for babies <28 weeks gestational age (GA) for analgesia and no recommendations for management of PDA. A recent review¹ of current literature only covered babies of ≥32 weeks gestation. We report on the paracetamol levels and safety profiles obtained in thirteen babies of <28 weeks GA, using an extended dosage regimen² over five days with maximum daily dose of 60 mg/kg/day; twice that recommended by the BNFC for analgesia in infants <32 weeks gestation.

Method Babies <28 weeks GA, received regular paracetamol for five days intravenously for PDA³ based on the following regimen initially introduced to the unit as part of a clinical trial (PDA TOLERATE)⁴ babies did not have to participate in the trial to receive paracetamol for PDA.

Regimen: 20 mg/kg loading dose followed by 10 or 12.5 mg/kg QID depending on corrected gestational age (CGA) lower dose for those 23+0 to 25+6 and =7 days at time of treatment, incrementing to a maximum of 15 mg/kg QID. Target paracetamol levels were 1520 mg/l with dose reduction if >25 mg/l and discontinuation if >40 mg/l. Since the major concern about paracetamol is liver toxicity plasma transaminases and bilirubin were obtained before and after (within 96 hours) treatment.

Results Thirteen babies were treated with paracetamol for PDA. Median gestation at birth was 24+3 weeks (range 23+2–26+2) with a median CGA at treatment of 26+4 weeks (range 25+3–28+0). Median weight was 735 g (range 520 g – 990 g). All babies had paracetamol levels <25 mg/L with a median level of 12.7 mg/L (range 7–24). No dose reductions were required. Serum transaminases and bilirubin were normal before and after treatment. There were no clinical gastrointestinal side effects.

Conclusion These data suggests these higher doses of paracetamol may be safe for babies of <28 weeks gestation requiring regular dosing, for up to five days, regardless of indication. Paracetamol levels obtained were lower than the target levels set for PDA TOLERATE but consistent with weight based pharmacokinetic models in moderate preterm and term infants in previous studies.⁴ Given the variation in levels obtained it may be beneficial to monitor paracetamol levels in babies receiving regular dosing.

References

1. Mian P, Knibbe CA, Tibboel D, et al. What is the dose of intravenous paracetamol for pain relief in neonates?Arch Dis Child2017;102:653–654.

2. El-Khuffash A, Jain A, Corcoran D, et al. Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies. Pediatr Res2014;76(3):238–244.

3. Early Treatment Versus Delayed Conservative Treatment of the Patent Ductus Arteriosus (PDA:TOLERATE). ClinicalTrials.gov Identifier USA NCT0195832, NHS HRA UK Clinicaltrials.gov identifier NCT01958320.

4. Allegaert K, Palmer GM, Anderson BJ. The pharmacokinetics of intravenous paracetamol in neonates: Size matters most. Arch Dis Child2011;96:575–5802.