Table 1.
Patient characteristics.
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.
Table 2.
Final model pharmacokinetic parameter estimates and SIR results.
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.