Sufentanil and Midazolam Dosing and Pharmacogenetic Factors in Pediatric Analgosedation and Withdrawal Syndrome

Abstract

Our aim was to describe the effect of dosing and genetic factors on sufentanil- and midazolam-induced analgosedation and withdrawal syndrome (WS) in pediatric population. Analgosedation and withdrawal syndrome development were monitored using COMFORT-neo/-B scores and SOS score. Length of therapy, dosing of sufentanil and midazolam were recorded. Genotypes of selected candidate polymorphisms in CYP3A5, COMT, ABCB1, OPRM1 and PXR were analysed. In the group of 30 neonates and 18 children, longer treatment duration with midazolam of 141 h (2 – 625) vs. 88 h (7 – 232) and sufentanil of 326.5 h (136 – 885) vs. 92 h (22 – 211) (median; range) was found in the patients suffering from WS vs. non-WS group, respectively. Median midazolam cumulative doses were in the respective values of 18.22 mg/kg (6.93 – 51.25) vs. 9.94 mg/kg (2.12 – 49.83); P=0.03, and the respective values for sufentanil were 88.60 µg/kg (20.21 – 918.52) vs. 21.71 µg/kg (4.5 – 162.29); P<0.01. Cut off value of 177 hours for sufentanil treatment duration represented predictive factor for WS development with 81 % sensitivity and 94 % specificity. SNPs in the candidate genes COMT, PXR and ABCB1 affected the dosing of analgosedative drugs, but were not associated with depth of analgosedation or WS. Cumulative dose and length of analgosedative therapy with sufentanil significantly increases the risk of WS in critically ill neonates and children.