Introduction A chart-review of 200 neonates randomly selected from the Neonatal Intensive Care Unit (NICU) of the university hospital in Copenhagen revealed that ap-proximately 10% received intravenous (i.v.) paracetamol≥4 days (unpublished data). Paracetamol (acetaminophen) is commonly used to control mild-to-moderate pain or to reduce opioid exposure either by oral, rectal or intrave-nous route. The newborn population includes a hetero-geneous group with substantial differences in their drug disposition characteristics. Hence, reflecting their degree of immaturity, organ dysfunction, as well as genetic vari-ation in drug metabolising enzymes and potential drug interactions. Different types of pain and pain assessment tools are used in neonatology. The pharmacokinetics and metabolism of i.v. paracetamol have been extensively published but there is very limited data on the pharma-codynamics (PD) and safety of this drug. The PARASHUTE trial will explore intravenous paracetamol in neonates in relation to: Primary objective: Safety of prolonged use (>72 hours); Secondary key objectives: Analgesic effect (PD) in neonates with chest tubes. Drug-excipient interaction with ethanol containing drugs (CYP2E1)
Endpoints Primary endpoints: To described the concentration-time data of plasma paracetamol (APAP), APAP-sulphate, APAP-glucuronide, oxidative metabolites and liver bio-markers (ALAT, PP, bilirubin) in neonates treated with i.v. paracetamol every sixth hour.
Secondary endpoints: Pain scores (COMFORTneo pain scale) combined with paracetamol concentrations and cumulative rescue dosages of morphine.Levels of oxida-tive metabolites of paracetamol and levels of p-ethanol in patients receiving one or more ethanol containing drugs.
Design A multicenter phase IV safety trial on prolonged i.v paracetamol administration in neonates combined with a randomised placebo controlled trial assessing ef-fect on pain.
Participants Neonates at any gestational age at birth for the safety and excipient study. However, for the for the PD study patients with chest tube due to pneumothorax or pleural effusion without prior operation are eligible for inclusion. For the PD and drug-excipient study the patient must weigh >1 kg.
Sample size Safety and excipient trial: 60; PD trial: 48:29 (unequal allocation)
Intervention The safety trial will follow clinical practice and i.v. paracetamol (10 mg/kg) will be administered. Plasma samples will be collected through an arterial line if present for clinical reasons. In neonates without arteri-al access, two heel pricks are necessary (start and end of trial) to collect blood. Additional plasma samples will only be collected when venipuncture is performed for clinical indications i.e. opportunistically.
Patients with chest tubes are, after bolus morphine and insertion of tube, unequally allocated to i.v. paracetamol + rescue morphine or i.v. saline + res-cue morphine. In addition to COMFORTneo pain scores and p-paracetamol, safety parameters will be gathered.