Evidence-Based Morphine Dosing for Postoperative Neonates and Infants

Krekels, Elke H. J.; Tibboel, Dick; Wildt, Saskia N. de; Ceelie, Ilse; Dahan, Albert; Dijk, Monique van; Danhof, Meindert; Knibbe, Catherijne A. J.

doi:10.1007/s40262-014-0135-4

Cited by 75 publications

(75 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Figure 4 shows the relation between postoperative morphine dosages in our research population (except for in those who died within 72 h after surgery) and the morphine dosages calculated according to the PK/PD model of Krekels et al [17]. This validated model is based on term newborns that undergo major noncardiac surgery and receive a loading dose of 100 μg/kg in the operating room.…”

Section: Resultsmentioning

confidence: 99%

“…The advised morphine dosages according to the PK/PD model of Krekels et al [17], based on the birth weight and postnatal age, were also calculated.…”

Section: Methodsmentioning

confidence: 99%

“…Postoperative morphine dosages were compared with the recently advised morphine dosage for postoperative neonates after major noncardiac surgery by Krekels et al [17]. Median COMFORTneo scores, NRS pain and NRS distress before and after surgery were compared with the Wilcoxon signed-rank test.…”

Section: Methodsmentioning

confidence: 99%

“…For premature infants weighing <1,000 g, 10 μg/kg/h of morphine or 0.5-2 μg/kg/h continuous fentanyl is considered a reasonable dosage to relieve NEC-related pain [16], although there is no evidence for this assumption. Based on the latest population pharmacokinetic/pharmacodynamic (PK/PD) model for morphine, lower postoperative dosages might be more appropriate in neonates undergoing major noncardiac surgery, particularly when they are <10 days of age [17,18], but the question remains whether this holds for NEC patients as well.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Infants Operated on for Necrotizing Enterocolitis: Towards Evidence-Based Pain Guidelines

et al. 2016

Self Cite

View full text Add to dashboard Cite

Background: Necrotizing enterocolitis (NEC) is known as an extremely painful childhood condition. Objectives: The objective of this study was to explore pain management around NEC-related surgery in our neonatal intensive care unit (NICU) from a chart review of prospectively collected data on 60 operated NEC patients admitted between 2008 and 2013 with a median (IQR) gestational age of 28.3 (25.5-31.6) weeks. Methods: Pain medication data and pain scores (i.e. COMFORTneo and Numerical Rating Scale pain and distress scores) from 72 h before until 72 h after surgery were collected. Results: Preoperatively, 95% of the patients received morphine versus 100% postoperatively, with a median dosage of 10.0 (IQR 9.7-14.5) and 16.9 (IQR 10.1-20.0) μg/kg/h, respectively. Postoperatively, 28 patients (46.7%) received additional fentanyl intermittently and 14 (23.3%) received midazolam, which was part of palliative treatment for 6 patients (42.9%). In patients receiving pain medication, median COMFORTneo scores were 10 (IQR 10-11) preoperatively and 11 (10-12) postoperatively. The pain scores were comparable with those of other patients admitted to the NICU in the same time period. Conclusions: Continuous morphine of 10 μg/kg/h preoperatively, with an increase to 15 μg/kg/h postoperatively, seems to constitute a good starting dose for further individualized pain management guided by pain scores.

show abstract

Section: Resultsmentioning

confidence: 99%

“…The advised morphine dosages according to the PK/PD model of Krekels et al [17], based on the birth weight and postnatal age, were also calculated.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Infants Operated on for Necrotizing Enterocolitis: Towards Evidence-Based Pain Guidelines

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…While pediatric dosing regimens are mostly empirically derived using extrapolations based on body weight (2,3), it has been shown before that dosing in children should be guided by the understanding of developmental changes in the pharmacokinetic and/or pharmacodynamic relation of drugs (2,4,5). More specifically, translation of results from pharmacokinetic modeling studies has been shown to result in individualized dosing guidelines for many different drugs in pediatric clinical practice (5)(6)(7)(8)(9).…”

mentioning

confidence: 99%

Towards Rational Dosing Algorithms for Vancomycin in Neonates and Infants Based on Population Pharmacokinetic Modeling

Janssen

Välitalo

Allegaert

et al. 2016

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

iBecause of the recent awareness that vancomycin doses should aim to meet a target area under the concentration-time curve (AUC) instead of trough concentrations, more aggressive dosing regimens are warranted also in the pediatric population. In this study, both neonatal and pediatric pharmacokinetic models for vancomycin were externally evaluated and subsequently used to derive model-based dosing algorithms for neonates, infants, and children. For the external validation, predictions from previously published pharmacokinetic models were compared to new data. Simulations were performed in order to evaluate current dosing regimens and to propose a model-based dosing algorithm. The AUC/MIC over 24 h (AUC 24 /MIC) was evaluated for all investigated dosing schedules (target of >400), without any concentration exceeding 40 mg/liter. Both the neonatal and pediatric models of vancomycin performed well in the external data sets, resulting in concentrations that were predicted correctly and without bias. For neonates, a dosing algorithm based on body weight at birth and postnatal age is proposed, with daily doses divided over three to four doses. For infants aged <1 year, doses between 32 and 60 mg/kg/day over four doses are proposed, while above 1 year of age, 60 mg/kg/day seems appropriate. As the time to reach steady-state concentrations varies from 155 h in preterm infants to 36 h in children aged >1 year, an initial loading dose is proposed. Based on the externally validated neonatal and pediatric vancomycin models, novel dosing algorithms are proposed for neonates and children aged <1 year. For children aged 1 year and older, the currently advised maintenance dose of 60 mg/kg/day seems appropriate. In the pediatric population, drugs are often administered in an off-label or unlicensed manner (1). While pediatric dosing regimens are mostly empirically derived using extrapolations based on body weight (2, 3), it has been shown before that dosing in children should be guided by the understanding of developmental changes in the pharmacokinetic and/or pharmacodynamic relation of drugs (2, 4, 5). More specifically, translation of results from pharmacokinetic modeling studies has been shown to result in individualized dosing guidelines for many different drugs in pediatric clinical practice (5-9).The antibacterial agent vancomycin is commonly used to treat infections caused by Gram-positive organisms, like methicillinresistant Staphylococcus aureus (MRSA) and amoxicillin-resistant Enterococcus species, in both adults and pediatric patients (10). In neonates, MRSA infection is relatively rare, and coagulase-negative staphylococci are the most commonly identified infectious organisms necessitating vancomycin treatment (11,12). For vancomycin, it has been shown that bacterial killing of S. aureus is best predicted by the area under the concentration-time curve over 24 h (AUC 24 ) divided by the MIC for the infecting pathogen (AUC 24 / MIC) (13-15). In adult patients, an AUC 24 /MIC of Ն400 resulted in a superior clinical and...

show abstract

Influence of OCT1 Ontogeny and Genetic Variation on Morphine Disposition in Critically Ill Neonates: Lessons From PBPK Modeling and Clinical Study

Hahn

Emoto

Euteneuer

et al. 2018

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

Morphine is commonly used for analgesia in the neonatal intensive care unit (NICU) despite having highly variable pharmacokinetics (PKs) between individual patients. The pharmacogenetic (PG) effect of variants at the loci of organic cation transporter 1 (OCT1) and UDP-glucuronosyltransferase 2B7 (UGT 2B7) on age-dependent morphine clearance were evaluated in a cohort of critically ill neonatal patients using an opportunistic sampling design. Our primary results demonstrate the significant influence of OCT1 genotype (P < 0.05) and gestational age (P ≤ 0.005) on morphine PKs. A physiologically based pharmacokinetic (PBPK) model for morphine that accounted for OCT1 ontogeny and PG effect in post-term neonates adequately described the clinically observed variability in morphine PKs. This study serves as a proof of concept for genotype-dependent drug transporter ontogeny in neonates.Morphine is widely used for management of perioperative pain and/or neonatal abstinence syndrome in the neonatal intensive care unit (NICU) of many hospitals. Wide interpatient variability in morphine exposure and response among neonates and small infants is a major limitation to morphine pharmacotherapy within these younger populations, making it difficult for clinicians to determine appropriate individualized dosage. Suboptimal dose titration is associated with both inadequate pain control in the case of underexposure, and often life-threatening side effects (primarily excessive sedation and respiratory depression) in the case of overexposure. 1,2 The variability in exposure and response to morphine observed in patients has been presumed to correlate with differences in morphine pharmacokinetics (PKs). 3,4 In young patients, the factors underlying morphine PKs are complex due to increase in body size (growth), pharmacogenetic (PG) effects, age-related physiological differences, and/or disease condition/progress. Especially in neonatal and small infant patients, the ontogeny of metabolic enzyme and drug transporter expression should

show abstract

Evidence-Based Morphine Dosing for Postoperative Neonates and Infants

Cited by 75 publications

References 17 publications

Infants Operated on for Necrotizing Enterocolitis: Towards Evidence-Based Pain Guidelines

Infants Operated on for Necrotizing Enterocolitis: Towards Evidence-Based Pain Guidelines

Towards Rational Dosing Algorithms for Vancomycin in Neonates and Infants Based on Population Pharmacokinetic Modeling

Influence of OCT1 Ontogeny and Genetic Variation on Morphine Disposition in Critically Ill Neonates: Lessons From PBPK Modeling and Clinical Study

Contact Info

Product

Resources

About