Dataset Information

ABCB1 genotype is associated with fentanyl requirements in critically ill children.

ABSTRACT: BackgroundThe gene ABCB1 encodes p-glycoprotein, a xenobiotic efflux pump capable of transporting certain opioids, including fentanyl. ABCB1 genotype has been previously associated with patient opioid requirements and may influence fentanyl dosing requirements in critically ill children.MethodsA diagnostically diverse cohort of 61 children who received a fentanyl infusion while admitted to the pediatric intensive care unit (PICU) were included in this study. We examined associations between fentanyl requirements, pain and sedation scores, serum fentanyl levels, and ABCB1 genotype.ResultsPatients with the AA allele at ABCB1 locus rs1045642 received less fentanyl compared with patients with the AG or GG allele. A multivariable model demonstrated that patients with the AA allele received 18.6?mcg/kg/day less fentanyl than patients with either the AG or GG allele (95% confidence interval -33.4 to -3.8?mcg/kg/day; P=0.014). Incorporating race in this model demonstrated a similar association, but did not reach the threshold for multiple testing.ConclusionABCB1 genotype rs1045642 AA is associated with fentanyl administration in this cohort of children admitted to the PICU, likely because of decreased expression and activity of p-glycoprotein. Prospective evaluation of the influence of ABCB1 in sedative-analgesia administration in critically ill children is warranted.

SUBMITTER: Horvat CM

PROVIDER: S-EPMC5509475 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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ABCB1 genotype is associated with fentanyl requirements in critically ill children.

Horvat Christopher M CM Au Alicia K AK Conley Yvette P YP Kochanek Patrick M PM Li Lingjue L Poloyac Samuel M SM Empey Philip E PE Clark Robert S B RSB

Pediatric research 20170531 1

BackgroundThe gene ABCB1 encodes p-glycoprotein, a xenobiotic efflux pump capable of transporting certain opioids, including fentanyl. ABCB1 genotype has been previously associated with patient opioid requirements and may influence fentanyl dosing requirements in critically ill children.MethodsA diagnostically diverse cohort of 61 children who received a fentanyl infusion while admitted to the pediatric intensive care unit (PICU) were included in this study. We examined associations between fent ...[more]

PMID: 28388599

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Project description:ObjectiveThe objective of this study was to characterize the population pharmacokinetics of fentanyl and identify factors that contribute to exposure variability in critically ill pediatric patients.MethodsWe conducted a single-center, retrospective cohort study using electronic record data and remnant blood samples in the setting of a mixed medical/surgical intensive care unit (ICU) at a quaternary children's hospital. Children with a predicted ICU length of stay of at least 3 days and presence of an indwelling central venous or arterial line were included. Serum fentanyl measurements were performed for 278 unique remnant samples from 66 patients. Both one- and two-compartment models were evaluated to describe fentanyl disposition. Covariates were introduced into the model in a forward/backward, stepwise approach and included age, sex, race, weight, cytochrome P450 (CYP) 3A5 genotype, and the presence of CYP3A4 or CYP3A5 inducers or inhibitors. Simulations were performed using the successful model to depict the influence of inducers on fentanyl concentrations.ResultsA two-compartment base model best described the data. There was good agreement between observed and predicted concentrations in the final model. The typical fentanyl clearance for 70 kg (reference weight) and 20.1 kg (median weight) patients were 34.6 and 13.6 L/h, respectively. The magnitude of the unexplained random inter-individual variability was high for both clearance (60.7%) and apparent volume of the central compartment (V1) (107.2%). Coadministration of the known CYP3A4/5 inducers fosphenytoin and/or phenobarbital was associated with significantly increased fentanyl clearance. Simulations demonstrate that the effect of inducer administration was most pronounced following discontinuation of a fentanyl infusion.ConclusionsIn this study we show the feasibility and utility of using electronic record data and remnant blood samples to successfully construct population pharmacokinetic models for a heterogeneous cohort of critically ill children. A clinically relevant effect of concomitant CYP3A4/5 inducers was identified. Scaling this population pharmacokinetic approach is necessary to craft precision approaches to fentanyl administration for critically ill children.

Project description:BackgroundDown syndrome (DS), or Trisomy 21, is defined by the existence of an additional chromosome 21. Various physiological considerations in DS patients might lead to challenges in adequate pain management and sedation after surgery. The aim of this systematic review and meta-analysis is to evaluate the variations of the requirement needed for pain management and sedation in patients with DS who have undergone surgery compared to patients without DS.MethodsA systematic review and meta-analysis of studies were conducted, focusing on critically ill patients with DS who were admitted to Intensive care units (ICUs) post-surgery and received opioids and/or benzodiazepines. Searches were conducted in four databases from their inception to November 18, 2023 (Pubmed, Scopus, Cochrane Library, and Web of Science). The primary outcome measured was the dosage of Oral Morphine Equivalent (OME) administered in the days following surgery. Fixed-effect models were used, an approach advisable when only a limited number of studies are available.ResultsOut of the 992 studies initially screened, the systematic review included ten studies, encompassing 730 patients, while the meta-analysis consisted of seven studies, encompassing 533 patients. Of the seven studies included in the analysis, 298 patients were identified to have DS, and 235 patients served as controls. Patients with DS showed a slight increase in OME needs on the first day, but this increase was not statistically significant (mean difference [MD] = 0.09; 95% Confidence Interval [CI]: [-0.02, 0.20]; P = 0.11). There was also no significant difference in the requirement for Midazolam on the first day among DS patients (MD = 0.01; CI [-0.16, 0.19]; P = 0.88). In addition, the duration of mechanical ventilation was not statistically significant in patients with DS compared with the control group (MD = -1.46 hours; 95% CI [-9.74, 6.82]; P = 0.73).ConclusionPatients with Down syndrome did not require more sedation or analgesia in the first three days after surgery than patients without Down syndrome. Additionally, the two groups showed no significant difference in the duration of mechanical ventilation.

Project description:Objective: Bleeding can be a severe complication of critical illness, but its true epidemiologic impact on children has seldom been studied. Our objective is to describe the epidemiology of bleeding in critically ill children, using a validated clinical tool, as well as the hemostatic interventions and clinical outcomes associated with bleeding. Design: Prospective observational cohort study. Setting: Tertiary pediatric critical care unit Patients: All consecutive patients (1 month to 18 years of age) admitted to a tertiary pediatric critical care unit Measurements and Main Results: Bleeding events were categorized as minimal, moderate, severe, or fatal, according to the Bleeding Assessment Scale in Critically Ill Children. We collected demographics and severity at admission, as evaluated by the Pediatric Index of Mortality. We used regression models to compare the severity of bleeding with outcomes adjusting for age, surgery, and severity. Over 12 months, 902 critically ill patients were enrolled. The median age was 64 months (IQR 17; 159), the median admission predicted risk of mortality was 0.5% (IQR 0.2; 1.4), and 24% were post-surgical. Eighteen percent of patients experienced at least one bleeding event. The highest severity of bleeding was minimal for 7.9% of patients, moderate for 5.8%, severe for 3.8%, and fatal for 0.1%. Adjusting for age, severity at admission, medical diagnosis, type of surgery, and duration of surgery, bleeding severity was independently associated with fewer ventilator-free days (p < 0.001) and fewer PICU-free days (p < 0.001). Adjusting for the same variables, bleeding severity was independently associated with an increased risk of mortality (adjusted odds ratio for each bleeding category 2.4, 95% CI 1.5; 3.7, p < 0.001). Conclusion: Our data indicate bleeding occurs in nearly one-fifth of all critically ill children, and that higher severity of bleeding was independently associated with worse clinical outcome. Further multicenter studies are required to better understand the impact of bleeding in critically ill children.

Dataset Information

ABCB1 genotype is associated with fentanyl requirements in critically ill children.

Publications

ABCB1 genotype is associated with fentanyl requirements in critically ill children.

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