Results of a Phase 1 Multicentre Investigation of Dexmedetomidine Bolus and Infusion in Corrective Infant Cardiac Surgery

Authors

Athena F Zuppa
Susan C Nicolson
Nicole S Wilder
Juan C Ibla
Erin A Gottlieb
Kristin M Burns
Mario Stylianou
Felicia Trachtenberg
Hua Ni
Tera H Skeen
Dean B Andropoulos

Publication Date

12-1-2019

Journal

British Journal of Anaesthesia

DOI

10.1016/j.bja.2019.06.026

PMID

31623840

PMCID

PMC6993105

PubMedCentral® Posted Date

10-14-2019

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Cardiac Surgical Procedures, Dexmedetomidine, Dose-Response Relationship, Drug, Female, Heart Defects, Congenital, Humans, Hypnotics and Sedatives, Infant, Infant, Newborn, Infusions, Intravenous, Male, anaesthesia, congenital heart surgery, dexmedetomidine, pharmacokinetics, tetralogy of Fallot, transposition of the great arteries, ventricular septal defect

Abstract

BACKGROUND: Dexmedetomidine (DEX) is increasingly used intraoperatively in infants undergoing cardiac surgery. This phase 1 multicentre study sought to: (i) determine the safety of DEX for cardiac surgery with cardiopulmonary bypass; (ii) determine the pharmacokinetics (PK) of DEX; (iii) create a PK model and dosing for steady-state DEX plasma levels; and (iv) validate the PK model and dosing.

METHODS: We included 122 neonates and infants (0-180 days) with D-transposition of the great arteries, ventricular septal defect, or tetralogy of Fallot. Dose escalation was used to generate NONMEM® PK modelling, and then validation was performed to achieve low (200-300 pg ml

RESULTS: Five of 122 subjects had adverse safety outcomes (4.1%; 95% confidence interval [CI], 1.8-9.2%). Two had junctional rhythm, two had second-/third-degree atrioventricular block, and one had hypotension. Clearance (CL) immediately postoperative and CL on CPB were reduced by approximately 50% and 95%, respectively, compared with pre-CPB CL. DEX clearance after CPB was 1240 ml min

CONCLUSIONS: When used with a careful dosing strategy, DEX results in low incidence and severity of adverse safety events in infants undergoing cardiac surgery with cardiopulmonary bypass. This validated PK model should assist clinicians in selecting appropriate dosing. The results of this phase 1 trial provide preliminary data for a phase 3 trial of DEX neuroprotection.

Comments

Clinical Trials Registration: NCT01915277.

Associated Data