| Popis: |
Background: Pain control in neonates is an important clinical concern with potential long-term adverse neurodevelopmental effects. Intravenous morphine is routinely administered for pain management post-operatively, but the neonatal morphine dosing-concentration-response relationship is not well characterized. Neonatal pain is difficult to measure challenging the ability to titrate the drug effectively. The current literature provides dosing guidelines but also describes and fails to account for the large unexplained variability in morphine clearance and response. In addition, it is still unknown if these recommended neonatal dosing regimens lead to the analgesic morphine exposure suggested by the literature.Objective: The purpose of this study was to evaluate morphine pharmacokinetics and exposure in post-operative critically ill neonates. We hypothesized that the inter-patient variability in morphine clearance would frequently result in morphine concentrations outside the tentative target analgesic range.Design/Methods: This was an open label, prospective, opportunistic study using discarded blood samples in infants receiving morphine as part of their standard care from Sept 2014 to March 2015. Concentration data were analyzed using a pediatric population PK model with Bayesian estimation (MW/Pharm). PK model-based concentration-time profiles were predicted based on the measured morphine concentrations.Results: Data on 20 patients who underwent 27 interventions with a total of 60 samples were available for analysis. Morphine concentrations ranged from 2.6-529.7 µg/L. Morphine clearance showed large inter-patient variability (4.28-205.3 L/h/(Wt/70 kg)0.75) with a 48-fold range. Of the morphine samples, 13 (21.7%) were in the target exposure range while 19 (31.7%) were below and 28 (46.7%) were above the target range. From the study population in only two (7.4%) cases was a steady-state morphine concentration in the target range within the first 24 hours post-operative period achieved. Both cases occurred in the same patient.Conclusion: In critically ill neonates a large variability was noted in morphine concentrations which were frequently well outside of the goal target range. This large interpatient variability in morphine concentration suggests that dosing guidelines should be individualized in this population to optimize the response of morphine in neonates. Further pharmacometric analysis with PK-PD modeling and research to identify important predictive pharmacokinetic and pharmacogenetic factors to individualize morphine treatment is warranted. |
