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      ABCB1 Genotype is Associated with Fentanyl Requirements in Critically Ill Children

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          Abstract

          Background

          The 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.

          Methods

          A 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.

          Results

          Patients with the AA allele at ABCB1 locus rs1045642 received less fentanyl compared to 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.

          Conclusion

          ABCB1 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.

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          Most cited references 26

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          Beyond Bonferroni: Less conservative analyses for conservation genetics

           Shawn Narum (2006)
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            The FLACC: a behavioral scale for scoring postoperative pain in young children.

            To evaluate the reliability and validity of the FLACC Pain Assessment Tool which incorporates five categories of pain behaviors: facial expression; leg movement; activity; cry; and consolability. Eighty-nine children aged 2 months to 7 years, (3.0 +/- 2.0 yrs.) who had undergone a variety of surgical procedures, were observed in the Post Anesthesia Care Unit (PACU). The study consisted of: 1) measuring interrater reliability; 2) testing validity by measuring changes in FLACC scores in response to administration of analgesics; and 3) comparing FLACC scores to other pain ratings. The FLACC tool was found to have high interrater reliability. Preliminary evidence of validity was provided by the significant decrease in FLACC scores related to administration of analgesics. Validity was also supported by the correlation with scores assigned by the Objective Pain Scale (OPS) and nurses' global ratings of pain. The FLACC provides a simple framework for quantifying pain behaviors in children who may not be able to verbalize the presence or severity of pain. Our preliminary data indicates the FLACC pain assessment tool is valid and reliable.
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              Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.

              To evaluate whether alterations in the multidrug-resistance (MDR)-1 gene correlate with intestinal MDR-1 expression and uptake of orally administered P-glycoprotein (PGP) substrates, we analyzed the MDR-1 sequence in 21 volunteers whose PGP expression and function in the duodenum had been determined by Western blots and quantitative immunohistology (n = 21) or by plasma concentrations after orally administered digoxin (n = 8 + 14). We observed a significant correlation of a polymorphism in exon 26 (C3435T) of MDR-1 with expression levels and function of MDR-1. Individuals homozygous for this polymorphism had significantly lower duodenal MDR-1 expression and the highest digoxin plasma levels. Homozygosity for this variant was observed in 24% of our sample population (n = 188). This polymorphism is expected to affect the absorption and tissue concentrations of numerous other substrates of MDR-1.
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                Author and article information

                Journal
                0100714
                6400
                Pediatr Res
                Pediatr. Res.
                Pediatric research
                0031-3998
                1530-0447
                21 April 2017
                31 May 2017
                July 2017
                30 November 2017
                : 82
                : 1
                : 29-35
                Affiliations
                [1 ]Departments of Critical Care Medicine and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA
                [2 ]Brain Care Institute at the Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA
                [3 ]Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA
                [4 ]Department of Human Genetics and School of Nursing, University of Pittsburgh, Pittsburgh, PA
                [5 ]Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA
                [6 ]Department of Pharmacy and Therapeutics, Center for Clinical Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA
                Author notes
                [* ]Corresponding Author: Robert S. B. Clark, MD, Children’s Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA 15224, Tel: (412)692-5164, Fax: (412)692-6076, clarkrs@ 123456ccm.upmc.edu
                Article
                NIHMS865696
                10.1038/pr.2017.103
                5509475
                28388599

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                Pediatrics

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