OBJECTIVES\nDESIGN\nSETTING\nPATIENTS\nINTERVENTIONS\nMEASUREMENTS AND MAIN RESULTS\nCONCLUSIONS\nTo compare the pharmacokinetics and pharmacodynamics of IV midazolam after cardiac surgery between... Show moreOBJECTIVES\nDESIGN\nSETTING\nPATIENTS\nINTERVENTIONS\nMEASUREMENTS AND MAIN RESULTS\nCONCLUSIONS\nTo compare the pharmacokinetics and pharmacodynamics of IV midazolam after cardiac surgery between children with and without Down syndrome.\nProspective, single-center observational trial.\nPICU in a university-affiliated pediatric teaching hospital.\nTwenty-one children with Down syndrome and 17 without, 3-36 months, scheduled for cardiac surgery with cardiopulmonary bypass.\nPostoperatively, nurses regularly assessed the children's pain and discomfort with the validated COMFORT-Behavioral scale and Numeric Rating Scale for pain. A loading dose of morphine (100 µg/kg) was administered after coming off bypass; thereafter, morphine infusion was commenced at 40 µg/kg/hr. Midazolam was started if COMFORT-Behavioral scale score of greater than 16 and Numeric Rating Scale score of less than 4 (suggestive of undersedation). Plasma midazolam and metabolite concentrations were measured for population pharmacokinetic- and pharmacodynamic analysis using nonlinear mixed effects modeling (NONMEM) (Version VI; GloboMax LLC, Hanover, MD) software.\nTwenty-six children (72%) required midazolam postoperatively (15 with Down syndrome and 11 without; p = 1.00). Neither the cumulative midazolam dose (p = 0.61) nor the time elapsed before additional sedation was initiated (p = 0.71), statistically significantly differed between children with and without Down syndrome. Population pharmacokinetic and pharmacodynamics analysis revealed no statistically significant differences between the children with and without Down syndrome. Bodyweight was a significant covariate for the clearance of 1-OH-midazolam to 1-OH-glucuronide (p = 0.003). Pharmacodynamic analysis revealed a marginal effect of the midazolam concentration on the COMFORT-Behavioral score.\nThe majority of children with and without Down syndrome required additional sedation after cardiac surgery. This pharmacokinetic and pharmacodynamic analysis does not provide evidence for different dosing of midazolam in children with Down syndrome after cardiac surgery. Show less
Titrating analgesic and sedative drugs in pediatric intensive care remains a challenge for caregivers due to the lack of pharmacodynamic knowledge in this population. The aim of the current study... Show moreTitrating analgesic and sedative drugs in pediatric intensive care remains a challenge for caregivers due to the lack of pharmacodynamic knowledge in this population. The aim of the current study is to explore the concentration-effect relationship for morphine-associated oversedation after cardiac surgery in children aged 3 months to 3 years. Data on morphine dosing, as well as morphine plasma concentrations, were available from a previous study on the pharmacokinetics of morphine after cardiac surgery in children. Oversedation was defined as scores below 11 on the validated COMFORT-behavioral scale. Population pharmacokinetic-pharmacodynamic modeling was performed in NONMEM 7.3. The probability of oversedation as a function of morphine concentration was best described using a step function in which the EC50 was 46.3 ng/mL. At morphine concentrations below the EC50, the probability of oversedation was 2.9% (0.4& to 18%), whereas above the EC50 percentages were 13% (1.9% to 52%) (median value [95% prediction interval from interindividual variability]). Additionally, the risk of oversedation was found to be increased during the first hours after surgery (P < .001) and was significantly lower during mechanical ventilation (P < .005). We conclude that morphine concentrations above approximately 45 ng/mL may increase the probability of oversedation in children after cardiac surgery. The clinician must evaluate, on a case-by-case basis, whether the analgesic benefits arising from dosing regimen associated with such concentrations outweigh the risks. Show less
Titrating analgesic and sedative drugs in pediatric intensive care remains a challenge for caregivers due to the lack of pharmacodynamic knowledge in this population. The aim of the current study... Show moreTitrating analgesic and sedative drugs in pediatric intensive care remains a challenge for caregivers due to the lack of pharmacodynamic knowledge in this population. The aim of the current study is to explore the concentration-effect relationship for morphine-associated oversedation after cardiac surgery in children aged 3 months to 3 years. Data on morphine dosing, as well as morphine plasma concentrations, were available from a previous study on the pharmacokinetics of morphine after cardiac surgery in children. Oversedation was defined as scores below 11 on the validated COMFORT-behavioral scale. Population pharmacokinetic-pharmacodynamic modeling was performed in NONMEM 7.3. The probability of oversedation as a function of morphine concentration was best described using a step function in which the EC50 was 46.3 ng/mL. At morphine concentrations below the EC50, the probability of oversedation was 2.9% (0.4& to 18%), whereas above the EC50 percentages were 13% (1.9% to 52%) (median value [95% prediction interval from interindividual variability]). Additionally, the risk of oversedation was found to be increased during the first hours after surgery (P Show less
Children undergoing cardiac surgery often receive acetaminophen (paracetamol) as part of their postoperative pain treatment. To date, there is no information on the pharmacokinetics (PK) of... Show moreChildren undergoing cardiac surgery often receive acetaminophen (paracetamol) as part of their postoperative pain treatment. To date, there is no information on the pharmacokinetics (PK) of acetaminophen in this special population, even though differences, as a result of altered hemodynamics and/or use of cardiopulmonary bypass, may be anticipated. Therefore, the aim of this study was to investigate the PK of intravenous acetaminophen in children after cardiac surgery with cardiopulmonary bypass. In the study, both children with and without Down syndrome were included. A population PK analysis, using NONMEM 7.2, was performed based on 161 concentrations of acetaminophen, acetaminophen sulfate, acetaminophen glucuronide, and oxidative metabolites from 17 children with Down syndrome and 13 children without Down syndrome of a previously published study (median age, 177 days [range, 92–944], body weight, 6.1 kg [4.0–12.9]). All children received 3 intravenous acetaminophen doses of 7.5 mg/kg (<10 kg) or 15 mg/kg (≥10 kg) at 8–hour intervals after cardiac surgery. For acetaminophen and its metabolites, 1‐compartment models were identified. Clearance of acetaminophen and metabolites increased linearly with body weight. Acetaminophen clearance in a typical child of 6.1 kg is 0.96 L/h and volume of distribution 7.96 L. Down syndrome did not statistically significantly impact any of the PK parameters for acetaminophen, nor did any other remaining covariate. When comparing the PK parameters of acetaminophen in children after cardiac surgery with cardiopulmonary bypass with those from children of the same age following noncardiac surgery reported in the literature, clearance of acetaminophen was lower and volume of distribution higher. Show less
OBJECTIVE:To compare the pharmacodynamics and pharmacokinetics of IV morphine after cardiac surgery in two groups of children-those with and without Down syndrome.DESIGN:Prospective, single-center... Show moreOBJECTIVE:To compare the pharmacodynamics and pharmacokinetics of IV morphine after cardiac surgery in two groups of children-those with and without Down syndrome.DESIGN:Prospective, single-center observational trial.SETTING:PICU in a university-affiliated pediatric teaching hospital.PATIENTS:Twenty-one children with Down syndrome and 17 without, 3-36 months old, scheduled for cardiac surgery with cardiopulmonary bypass.INTERVENTIONS:A loading dose of morphine (100 μg/kg) was administered after coming off bypass; thereafter, morphine infusion was commenced at 40 μg/kg/hr. During intensive care, nurses regularly assessed pain and discomfort with validated observational instruments (COMFORT-Behavior scale and Numeric Rating Scale-for pain). These scores guided analgesic and sedative treatment. Plasma samples were obtained for pharmacokinetic analysis.MEASUREMENTS AND MAIN RESULTS:Median COMFORT-Behavior and Numeric Rating Scale scores were not statistically significantly different between the two groups. The median morphine infusion rate during the first 24 hours after surgery was 31.3 μg/kg/hr (interquartile range, 23.4-36.4) in the Down syndrome group versus 31.7 μg/kg/hr (interquartile range, 25.1-36.1) in the control group (p = 1.00). Population pharmacokinetic analysis revealed no statistically significant differences in any of the pharmacokinetic variables of morphine between the children with and without Down syndrome.CONCLUSIONS:This prospective trial showed that there are no differences in pharmacokinetics or pharmacodynamics between children with and without Down syndrome if pain and distress management is titrated to effect based on outcomes of validated assessment instruments. We have no evidence to adjust morphine dosing after cardiac surgery in children with Down syndrome. Show less
