Optimizing Sedative Dose in Preterm Infants Undergoing Treatment for Respiratory Distress Syndrome

Abstract

The Intubation-Surfactant-Extubation (INSURE) procedure is used worldwide to treat pre-term newborn infants suffering from respiratory distress syndrome, which is caused by an insufficient amount of the chemical surfactant in the lungs. With INSURE, the infant is intubated, surfactant is administered via the tube to the trachea, and at completion the infant is extubated. This improves the infant’s ability to breathe and thus decreases the risk of long term neurological or motor disabilities. To perform the intubation safely, the newborn infant first must be sedated. Despite extensive experience with INSURE, there is no consensus on what sedative dose is best. This paper describes a Bayesian sequentially adaptive design for a multi-institution clinical trial to optimize the sedative dose given to pre-term infants undergoing the INSURE procedure. The design is based on three clinical outcomes, two efficacy and one adverse, using elicited numerical utilities of the eight possible elementary outcomes. A flexible Bayesian parametric trivariate dose-outcome model is assumed, with the prior derived from elicited mean outcome probabilities. Doses are chosen adaptively for successive cohorts of infants using posterior mean utilities, subject to safety and efficacy constraints. A computer simulation study of the design is presented.

Neonatal medicines research: challenges and opportunities

“…A smaller study is not only cheaper, but also sooner finalized, and data to base clinical decisions on will become available sooner. Adaptive designs or effective dose (ED 50 or ED 90 ) studies have been reported, for example, patent ductus arteriosus and ibuprofen (continual reassessment method) [95] or endotracheal intubation and propofol (ED 50 for endotracheal intubation) [96].…”

A Dose Finding Design for Seizure Reduction in Neonates

“…Moreover, Thall et al . () and Zhong et al . () did not consider adding a second agent during the course of treatment.…”

“…Thall et al . () proposed a dose finding method for neonates with respiratory distress syndrome based on three clinical outcomes.…”

Evaluation of an Intubation Readiness Score to Assess Neonatal Sedation before Intubation

“…One of these scores is the sedation score described by Naulaers et al [20] that we used to develop our IRS. Another score to assess the level of sedation prior to intubation in neonates is the “good sedation state” from Thall et al [23]. This score is based on the Neonatal Pain, Agitation and Sedation Scale developed by Hummel et al [24] and consists of 5 variables: crying/irritability, behavior state, facial expression, extremity tone, and vital parameters.…”

“…Each item is scored on a 5-point scale from –2, corresponding to highest sedation, to +2, corresponding to highest infant discomfort. According to Thall et al [23], good sedation for endotracheal intubation is defined as a total score between –7 and –3. To the best of our knowledge, further evaluation of this score has not been performed.…”