Pharmacokinetics of morphine in encephalopathic neonates treated with therapeutic hypothermia

Abstract

Objective: Morphine is a commonly used drug in encephalopathic neonates treated with therapeutic hypothermia after perinatal asphyxia. Pharmacokinetics and optimal dosing of morphine in this population are largely unknown. The objective of this study was to describe pharmacokinetics of morphine and its metabolites morphine-3-glucuronide and morphine-6-glucuronide in encephalopathic neonates treated with therapeutic hypothermia and to develop pharmacokinetics based dosing guidelines for this population.

Study design: Term and near-term encephalopathic neonates treated with therapeutic hypothermia and receiving morphine were included in two multicenter cohort studies between 2008-2010 (SHIVER) and 2010-2014 (PharmaCool). Data were collected during hypothermia and rewarming, including blood samples for quantification of morphine and its metabolites. Parental informed consent was obtained for all participants.

Results: 244 patients (GA mean (sd) 39.8 (1.6) weeks, BW mean (sd) 3,428 (613) g, male 61.5%) were included. Morphine clearance was reduced under hypothermia (33.5°C) by 6.89%/°C (95% CI 5.37%/°C- 8.41%/°C, p<0.001) and metabolite clearance by 4.91%/°C (95% CI 3.53%/°C- 6.22%/°C, p<0.001) compared to normothermia (36.5°C). Simulations showed that a loading dose of 50 μg/kg followed by continuous infusion of 5 μg/kg/h resulted in morphine plasma concentrations in the desired range (between 10 and 40 μg/L) during hypothermia.

Conclusions: Clearance of morphine and its metabolites in neonates is affected by therapeutic hypothermia. The regimen suggested by the simulations will be sufficient in the majority of patients. However, due to the large interpatient variability a higher dose might be necessary in individual patients to achieve the desired effect.

Trial registration: www.trialregister.nl NTR2529.

Fig 1. Observed morphine plasma concentrations (μg/L).

Dotted lines indicate the proposed therapeutic window of 10–40 μg/L; solid line indicates the potentially toxic limit of 300 μg/L.

Fig 2

Average predicted morphine clearance over time before, during and after TH for neonates with BW 3.5 and GA 36, 38, 40 and 42 weeks, respectively (left) and for neonates with GA 40 weeks and BW 2.5, 3.0, 3.5 and 4.0 kg, respectively (right). Solid vertical lines represent the start and end of TH (33.5°C) simulated between 5h and 77h after birth; dashed vertical line indicates the return to normothermia (36.5°C) with rewarming simulated at. 0.4°C/h; TH = therapeutic hypothermia, BW = birth weight GA = gestational age.

Fig 3. Simulated morphine plasma concentrations of the proposed dosing regimen of 5 μg/kg/h after loading dose of 50 μg/kg.

Solid line indicates the mean morphine plasma concentration; gray area represents the 95% prediction interval. Dotted horizontal lines indicate the proposed therapeutic window of 10–40 μg/L. Solid vertical lines indicate the start and end of TH (33.5°C) simulated between 5h and 77h after birth; dashed vertical line indicates the return to normothermia (36.5°C) with rewarming simulated at 0.4°C/h; TH = therapeutic hypothermia.