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Genetic risk signatures of opioid-induced respiratory depression following pediatric tonsillectomy.

ABSTRACT: Background: Respiratory depression is a clinically and economically important but preventable complication of opioids. Genetic factors can help identify patients with high risk for respiratory depression. Methods: In this prospective genotype blinded clinical study, we evaluated the effect of a panel of variants in candidate genes on opioid-related respiratory depression in 347 children following tonsillectomy. Results: Using unsupervised hierarchical clustering and a combination of candidate genotypes and clinical variables, we identified several distinct clusters of patients at high risk (36-38%) and low risk (10-17%) of respiratory depression; the relative risk of respiratory depression for high versus low risk clusters was 2.1-3.8 (p = 0.003). Conclusion: Genetic risk predictions (genetic signatures) along with clinical risk factors effectively identify children at higher and lower risks of opioid-induced respiratory depression. Genetic signatures of respiratory depression offer strategies for improved clinical decision support to guide clinicians to balance the risks of opioid adverse effects with analgesia. Original submitted 9 July 2014; Revision submitted 19 September 2014.

SUBMITTER: Biesiada J

PROVIDER: S-EPMC4287371 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Genetic risk signatures of opioid-induced respiratory depression following pediatric tonsillectomy.

Biesiada Jacek J Chidambaran Vidya V Wagner Michael M Zhang Xue X Martin Lisa J LJ Meller Jaroslaw J Sadhasivam Senthilkumar S

Pharmacogenomics 20141101 14

Background: Respiratory depression is a clinically and economically important but preventable complication of opioids. Genetic factors can help identify patients with high risk for respiratory depression. Methods: In this prospective genotype blinded clinical study, we evaluated the effect of a panel of variants in candidate genes on opioid-related respiratory depression in 347 children following tonsillectomy. Results: Using unsupervised hierarchical clustering and a combination of candidate ge ...[more]

PMID: 25493568

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Project description:BackgroundSafe postoperative pain relief with opioids is an unmet critical medical need in children. There is a lack of objective, noninvasive bedside tool to assess central nervous system (CNS) effects of intraoperative opioids. Proactive identification of children at risk for postoperative respiratory depression (RD) will help tailor analgesic therapy and significantly improve the safety of opioids in children. Quantitative pupillometry (QP) is a noninvasive, objective, and real-time tool for monitoring CNS effect-time relationship of opioids. This exploratory study aimed to determine the association of QP measures with postoperative RD, as well as to identify the best intraoperative QP measures predictive of postoperative RD in children.MethodsAfter approval from the institutional review board and informed parental consent, in this prospective, observational study of 220 children undergoing tonsillectomy, QP measures were collected at 5 time points: awake preoperative baseline before anesthesia induction (at the time of enrollment [T1]), immediately after anesthesia induction before morphine administration (T2), 3 minutes after intraoperative morphine administration (T3), at the end of surgery (T4), and postoperatively when awake in postanesthesia recovery unit (PACU) (T5). Intraoperative use of opioid and incidence of postoperative RD were collected. Analyses were aimed at exploring correlations of QP measures with the incidence of RD and, if found significant, to develop a predictive model for postoperative RD.ResultsPerioperative QP measures of percentage pupil constriction (CONQ, P = .027), minimum pupillary diameter (MIN, P = .027), and maximum pupillary diameter (MAX, P = .034) differed significantly among children with and without postoperative RD. A predictive model including the minimum pupillary diameter 3 minutes after morphine administration (MIN3), minimum pupillary diameter normalized to baseline (MIN31), and percentage pupillary constriction after surgery (T4) standardized to baseline (T1) (CONQ41), along with the weight-based morphine dose performed the best to predict postoperative RD in children (area under the curve [AUC], 0.76).ConclusionsA model based on pre- and intraoperative pupillometry measures including CONQ, MIN, along with weight-based morphine dose-predicted postoperative RD in our cohort of children undergoing tonsillectomy. More studies with a larger sample size are required to validate this finding.

Project description:OBJECTIVE:This systematic review and meta-analysis aim to evaluate the risk factors associated with postoperative opioid-induced respiratory depression (OIRD). DESIGN:Systematic review and meta-analysis. DATA SOURCES:PubMed-MEDLINE, MEDLINE in-process, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, PubMed and Clinicaltrials.gov (January 1946 to November 2017). ELIGIBILITY CRITERIA:The inclusion criteria were: (1) adult patients 18 years or older who were administered opioids after surgery and developed postoperative OIRD (OIRD group); (2) all studies which reported both OIRD events and associated risk factors; (3) all studies with reported data for each risk factor on patients with no OIRD (control group) and (4) published articles in English language. DATA ANALYSIS:We used a random effects inverse variance analysis to evaluate the existing evidence of risk factors associated with OIRD. Newcastle-Ottawa scale scoring system was used to assess quality of study. RESULTS:Twelve observational studies were included from 8690 citations. The incidence of postoperative OIRD was 5.0 cases per 1000 anaesthetics administered (95%?CI: 4.8 to 5.1; total patients: 841 424; OIRD: 4194). Eighty-five per cent of OIRD occurred within the first 24?hours postoperatively. Increased risk for OIRD was associated with pre-existing cardiac disease (OIRD vs control: 42.8% vs 29.6%; OR: 1.7; 95%?CI: 1.2 to 2.5; I2: 0%; p<0.002), pulmonary disease (OIRD vs control: 17.8% vs 10.3%; OR: 2.2; 95%?CI: 1.3 to 3.6; I2: 0%; p<0.001) and obstructive sleep apnoea (OIRD vs control: 17.9% vs 16.5%; OR: 1.4; 95%?CI: 1.2 to 1.7; I2: 31%; p=0.0003). The morphine equivalent daily dose of the postoperative opioids was higher in the OIRD group than in the control; (24.7±14?mg vs 18.9±13.0?mg; mean difference: 2.8; 95%?CI: 0.4 to 5.3; I2: 98%; p=0.02). There was no significant association between OIRD and age, gender, body mass index or American Society of Anesthesiologists physical status. CONCLUSION:Patients with cardiac, respiratory disease and/or obstructive sleep apnoea were at increased risk for OIRD. Patients with postoperative OIRD received higher doses of morphine equivalent daily dose.

Dataset Information

Genetic risk signatures of opioid-induced respiratory depression following pediatric tonsillectomy.

Publications

Genetic risk signatures of opioid-induced respiratory depression following pediatric tonsillectomy.

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