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Interventional cohort study of prolonged use (>72 hours) of paracetamol in neonates: protocol of the PARASHUTE study
Sissel Sundell Haslund-Krog1, Steen Hertel2, Kim Dalhoff1
1Department of Clinical Pharmacology, Bispebjerg Hospital, Copenhagen, Denmark.
Insights
This study assessed prolonged paracetamol use in neonates, measuring liver function and drug levels to ensure safety and effectiveness. Results will inform optimal pain management strategies for vulnerable infants.
Area of Science:
- Neonatal intensive care
- Pharmacology
- Pediatric pain management
Background:
- Paracetamol is used for prolonged pain relief in neonates, but safety data from short-term trials are limited.
- Hepatic biomarkers and paracetamol metabolism are rarely studied together in neonate safety trials.
Purpose of the Study:
- To investigate the safety and effectiveness of prolonged paracetamol exposure in neonates.
- To measure hepatic biomarkers, paracetamol and metabolite plasma concentrations, and pain scores.
- To explore potential interactions between ethanol and paracetamol.
Main Methods:
- Multicenter interventional cohort study including neonates up to 44 weeks postmenstrual age.
- Measurement of alanine aminotransferase (ALT), bilirubin, plasma paracetamol, and metabolites at various time points.
- Longitudinal collection of COMFORT neo pain scores and population pharmacokinetic analysis using non-linear mixed effects models.
Main Results:
- Data on hepatic biomarkers, paracetamol metabolism, and pain scores were collected during and after treatment.
- Pharmacokinetic analysis was performed to understand paracetamol disposition.
- Concomitant ethanol levels were measured in neonates receiving phenobarbital-containing medications.
Conclusions:
- The study provides crucial data on the safety and effectiveness of prolonged paracetamol use in neonates.
- Findings will help optimize pain management protocols in neonatal intensive care units.
- Understanding paracetamol metabolism and potential drug interactions is vital for infant safety.
Introduction:
Anticipated or actual pain in neonates results in use of paracetamol for prolonged pain relief in many neonatal intensive care units. Clinical trials examining safety of paracetamol exposure in neonates have been of short duration (1-3 days) and hepatic biomarkers and paracetamol metabolism are rarely reported in the same studies.We aim to investigate the safety (hepatic tolerance) and effectiveness of prolonged paracetamol exposure in neonates by measuring hepatic biomarkers, plasma concentrations of paracetamol and its metabolites and pain scores. In addition, we study a possible interaction between ethanol and paracetamol.
Methods And Analysis:
A multicentre interventional cohort study.Neonates of any gestational age and up to 44 weeks postmenstrual age, treated with oral or intravenous paracetamol can be included.Alanine aminotransferase (ALT) and bilirubin are measured at baseline or within 24 hours after treatment initiation. P-paracetamol and metabolites are measured at steady state and every 2 days (opportunistically) together with ALT and bilirubin and lastly after discontinuation of treatment. COMFORT neo pain scores are collected longitudinally. COMFORT neo pain scores and population pharmacokinetic analysis of paracetamol samples will be analysed simultaneously using non-linear mixed effects models. One and two compartment models with first-order elimination will be tested for disposition. In addition, plasma ethanol is measured if the patient receives concomitant treatment with intravenous or oral phenobarbital containing ethanol as an excipient.
Ethics And Dissemination:
Inclusion of patients can be postponed 24 hours after the first paracetamol dose. This is intended to make the inclusion process less stressful for parents. This study uses standard dosing strategies. The potential risks are additional blood samples, which are collected opportunistically to reduce additional heel pricks.
Trial Registrationnumber:
Ethics Comittee: H-17027244, EudraCT no: 2017-002724-25, BFH-2017-106, 05952.
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