Haslund-Krog Sissel Sundell, Hertel Steen, Dalhoff Kim, Poulsen Susanne, Christensen Ulla, Wilkins Diana, van den Anker John, Brink Henriksen Tine, Holst Helle
Department of Clinical Pharmacology, Bispebjerg Hospital, Copenhagen, Denmark.
Neonatal Intensive Care Unit, Rigshospitalet, Copenhagen, Denmark.
BMJ Paediatr Open. 2019 Mar 30;3(1):e000427. doi: 10.1136/bmjpo-2018-000427. eCollection 2019.
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.
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.
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.
Ethics Comittee: H-17027244, EudraCT no: 2017-002724-25, BFH-2017-106, 05952.
在许多新生儿重症监护病房，新生儿预期或实际的疼痛会导致使用对乙酰氨基酚来延长疼痛缓解时间。检测新生儿接触对乙酰氨基酚安全性的临床试验持续时间较短（1 - 3天），并且在同一研究中很少报告肝脏生物标志物和对乙酰氨基酚代谢情况。我们旨在通过测量肝脏生物标志物、对乙酰氨基酚及其代谢物的血浆浓度和疼痛评分，研究新生儿长期接触对乙酰氨基酚的安全性（肝脏耐受性）和有效性。此外，我们研究乙醇与对乙酰氨基酚之间可能的相互作用。
一项多中心干预队列研究。纳入任何孕周且出生后至44周龄，接受口服或静脉注射对乙酰氨基酚治疗的新生儿。在基线或治疗开始后24小时内测量丙氨酸转氨酶（ALT）和胆红素。在稳态时以及每2天（机会性地）与ALT和胆红素一起测量对乙酰氨基酚及其代谢物，最后在治疗停止后测量。纵向收集COMFORT neo疼痛评分。将使用非线性混合效应模型同时分析COMFORT neo疼痛评分和对乙酰氨基酚样本的群体药代动力学分析。将测试具有一级消除的一室和二室模型的处置情况。此外，如果患者接受含有乙醇作为辅料的静脉或口服苯巴比妥的联合治疗，则测量血浆乙醇。
在首次给予对乙酰氨基酚剂量后24小时可以推迟纳入患者。这旨在使纳入过程对父母的压力更小。本研究使用标准给药策略。潜在风险是额外的血样，这些血样是机会性收集的，以减少额外的足跟采血。
伦理委员会：H - 17027244，欧盟临床试验注册号：2017 - 002724 - 25，BFH - 2017 - 106，05952 。
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