Abstract
In the midst of concerns for potential neurodevelopmental effects after surgical anesthesia, there is a growing awareness that children who require sedation during critical illness are susceptible to neurologic dysfunctions collectively termed pediatric post-intensive care syndrome, or PICS-p. In contrast to healthy children undergoing elective surgery, critically ill children are subject to inordinate neurologic stress or injury and need to be considered separately. Despite recognition of PICS-p, inconsistency in techniques and timing of post-discharge assessments continues to be a significant barrier to understanding the specific role of sedation in later cognitive dysfunction. Nonetheless, available pediatric studies that account for analgesia and sedation consistently identify sedative and opioid analgesic exposures as risk factors for both in-hospital delirium and post-discharge neurologic sequelae. Clinical observations are supported by animal models showing neuroinflammation, increased neuronal death, dysmyelination, and altered synaptic plasticity and neurotransmission. Additionally, intensive care sedation also contributes to sleep disruption, an important and overlooked variable during acute illness and post-discharge recovery. Because analgesia and sedation are potentially modifiable, understanding the underlying mechanisms could transform sedation strategies to improve outcomes. To move the needle on this, prospective clinical studies would benefit from cohesion with regard to datasets and core outcome assessments, including sleep quality. Analyses should also account for the wide range of diagnoses, heterogeneity of this population, and the dynamic nature of neurodevelopment in age cohorts. Much of the related preclinical evidence has been studied in comparatively brief anesthetic exposures in healthy animals during infancy and is not generalizable to critically ill children. Thus, complementary animal models that more accurately “reverse translate” critical illness paradigms and the effect of analgesia and sedation on neuropathology and functional outcomes are needed. This review explores the interactive role of sedatives and the neurologic vulnerability of critically ill children as it pertains to survivorship and functional outcomes, which is the next frontier in pediatric intensive care.
Highlights
Concerns for adverse neurologic effects after surgical anesthesia in young children prompted a Safety Communication from the United States Food and Drug Administration in 2016 warning against the prolonged or repeated use of general anesthesia in children under the age of 3 years and pregnant women (United States Food and Drug Administration Safety Communication (FDA), 2019)
In pediatric intensive care units (PICUs) across the world, hundreds of thousands of children are necessarily treated with analgesics and sedatives pharmacologically similar to surgical anesthesia for prolonged periods during the neurologic stress of critical illness
While clinical evidence of anesthetic neurotoxicity is less definitive than animal models would suggest, clinical studies of neurologic dysfunction in critically ill children are far more convincing but with a paucity of translational basic science
Summary
Concerns for adverse neurologic effects after surgical anesthesia in young children prompted a Safety Communication from the United States Food and Drug Administration in 2016 warning against the prolonged or repeated use of general anesthesia in children under the age of 3 years and pregnant women (United States Food and Drug Administration Safety Communication (FDA), 2019). In pediatric intensive care units (PICUs) across the world, hundreds of thousands of children are necessarily treated with analgesics and sedatives pharmacologically similar to surgical anesthesia for prolonged periods during the neurologic stress of critical illness. It is important to separate testable cognition (e.g., neuropsychological direct assessment) from functional or social cognition (e.g., parent or teacher proxy, academic performance) as the field moves forward in unifying the structure and approach for assessing cognitive outcomes within the PICS-p framework With this distinction in mind, clinicians and researchers should be mindful of what available outcomes tools measure in the realm of pediatric cognition, functional or adaptive skills, and development
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