Analgesics and Sedatives in Critically Ill Newborns and Infants: The Impact on Long‐Term Neurodevelopment

Abstract

Inadequate pain and/or stress management in preterm‐ and term‐born infants has been associated with increased morbidity and even mortality. However, exposure to analgosedatives during early infancy may also be one of the risk factors for subsequent neurodevelopmental impairment, at least in animal studies. Because infants admitted to neonatal or pediatric intensive care units may receive high amounts of these drugs for prolonged periods of time and the majority of these infants nowadays survive to discharge, this is of major concern. A balanced approach that incorporates the assessment and quantification of both wanted effects as well as unwanted side effects is therefore needed. In this article, the optimal dose determination of commonly used analgosedative drugs as well as their potential long‐term effects on the developing human brain and neuropsychological functioning are reviewed.

Safety Issues of Pharmacological Acute Pain Treatment in Children

“…The transport across the BBB may, therefore, vary in young infants, and drugs may gain access to the CNS with potential harm to the developing brain and resultant neurotoxicity. This has been clearly demonstrated in animals after anesthetic agent exposure but less obviously in young children . The effects of analgesics on the developing brain, especially long‐term neurodevelopmental impairments, are, therefore, a concern.…”

“…Most children treated with morphine in the early postnatal period are polymedicated and have severe pain and critical illness, which may also interfere with brain development. To date, opioids do not seem to be associated with major negative effects on neurodevelopmental outcomes, even though an impact on the brain morphology is debated …”

“…This has been clearly demonstrated in animals after anesthetic agent exposure but less obviously in young children. 18,19 The effects of analgesics on the developing brain, especially long-term neurodevelopmental impairments, are, therefore, a concern.…”

“…To date, opioids do not seem to be associated with major negative effects on neurodevelopmental outcomes, even though an impact on the brain morphology is debated. 19,[94][95][96][97]…”

Developmental Pharmacotherapy: The Interface Between Ontogeny and Drug Effect

“…An area gaining increasing focus and scrutiny involves the use of sedatives and analgesics, or so‐called analgosedatives, and their possible long‐term negative neurodevelopmental effects in neonates and young infants . Schiller and colleagues comprehensively review the important analgosedatives commonly used in children, with a focus on critically ill infants, doses used, durations employed, combinations of agents, and the emerging evidence of their possible negative effects on the brain and cognition . Schiller et al lay out a foundation for possible molecular mechanism(s) and identify at‐risk patients and the need for intense research, but above all remind pediatric practitioners of our important responsibility to always and continuously assess and monitor patients for the possible negative effects of our therapeutic intervention(s) on the multifaceted developmental changes occurring as the infant grows to adulthood.…”