P. Mian*, C.A.J. Knibbe, E.A.M. Calvier, D. Tibboel and K. Allegaert Pages 5839 - 5849 ( 11 )
Background: Intravenous paracetamol (acetaminophen) has not been licensed for analgesia in preterm neonates or infants < 2 years, respectively, in Europe and the United States. A variety of dosing regimens is therefore used off-label. Because evidence supports the use of the same target mean steady state paracetamol concentration (Cssmean, 9-11 mg/L) for pain relief in neonates compared to older children and adults, dosing regimens based on this Cssmean were evaluated in a two-step approach.
Methods: First, a systematic search was performed to provide pharmacokinetic (PK)-based dosing guidelines for pain in neonates (with subsequent searches on safety in these papers). Second, concentration-time profiles based on these dosing guidelines were generated to provide a dosing advice for paracetamol to treat neonatal pain. Results: Of 2334 potentially relevant articles, 9 studies were included. For typical term neonates, dosages specified in packaging (labels) resulted in Cssmean below target (7.65 mg/L), while dosages from investigator-initiated studies resulted in either a Cssmean above (15.31), or around the target (11.78 and 10.21) for (pre)term neonates >32 weeks. Only one study suggested a dosing resulting in a tailored concentration (8.7) in preterm neonates <32 weeks. Conclusion: A loading dose 20 mg/kg, followed by 10 mg/kg/6h is recommended for 32-44 weeks' neonates, which is supported by short-term safety. For neonates < 32 weeks, a loading dose of 12 mg/kg and a maintenance dose of 6mg/kg/6h seems to lead to the target Cssmean, though additional clinical studies are needed to support its safety.Paracetamol, propacetamol, pharmacokinetics, neonates, intravenous, pain, paediatric study decision tree.
Erasmus MC Sophia Children's Hospital, Intensive Care and Department of Paediatric Surgery, Rotterdam, Erasmus MC Sophia Children's Hospital, Intensive Care and Department of Paediatric Surgery, Rotterdam, Division of Pharmacology, LACDR, Leiden University, Leiden, Erasmus MC Sophia Children's Hospital, Intensive Care and Department of Paediatric Surgery, Rotterdam, Erasmus MC Sophia Children's Hospital, Intensive Care and Department of Paediatric Surgery, Rotterdam