Prospectively assessed neurodevelopmental outcomes in studies of anaesthetic neurotoxicity in children: a systematic review and meta-analysis

Ing, Caleb; Jackson, William M.; Zaccariello, Michael J.; Goldberg, Terry E.; McCann, Mary Ellen; Grobler, Anneke; Davidson, Andrew; Sun, Lena S.; Li, Guohua; Warner, David O.

doi:10.1016/j.bja.2020.10.022

Cited by 81 publications

(74 citation statements)

References 33 publications

(36 reference statements)

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“…Brief (<1 h) exposure to general anesthesia has not been shown to alter neurodevelopmental outcome at age five years as compared to awake/regional anesthesia and general anesthesia exposure before age three years and is not associated with deficits in general intelligence [ 216 , 217 ]. Systematic review of studies evaluating neurodevelopmental outcomes and prospectively enrolling children exposed to a single GA procedure compared with unexposed children demonstrated that a single GA exposure is associated with statistically significant increases in parent reports of behavioral problems with, again, no difference in general intelligence [ 218 ]. Given key differences between general anesthesia and ICU sedation, such as the duration of exposure and the use of multimodal analgosedative regimen in the ICU, it is difficult to draw conclusions about PICU sedation from these general anesthesia studies.…”

Section: Neurodevelopmental Outcomesmentioning

confidence: 99%

Current State of Analgesia and Sedation in the Pediatric Intensive Care Unit

Egbuta

Mason

2021

JCM

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Critically ill pediatric patients often require complex medical procedures as well as invasive testing and monitoring which tend to be painful and anxiety-provoking, necessitating the provision of analgesia and sedation to reduce stress response. Achieving the optimal combination of adequate analgesia and appropriate sedation can be quite challenging in a patient population with a wide spectrum of ages, sizes, and developmental stages. The added complexities of critical illness in the pediatric population such as evolving pathophysiology, impaired organ function, as well as altered pharmacodynamics and pharmacokinetics must be considered. Undersedation leaves patients at risk of physical and psychological stress which may have significant long term consequences. Oversedation, on the other hand, leaves the patient at risk of needing prolonged respiratory, specifically mechanical ventilator, support, prolonged ICU stay and hospital admission, and higher risk of untoward effects of analgosedative agents. Both undersedation and oversedation put critically ill pediatric patients at high risk of developing PICU-acquired complications (PACs) like delirium, withdrawal syndrome, neuromuscular atrophy and weakness, post-traumatic stress disorder, and poor rehabilitation. Optimal analgesia and sedation is dependent on continuous patient assessment with appropriately validated tools that help guide the titration of analgosedative agents to effect. Bundled interventions that emphasize minimizing benzodiazepines, screening for delirium frequently, avoiding physical and chemical restraints thereby allowing for greater mobility, and promoting adequate and proper sleep will disrupt the PICU culture of immobility and reduce the incidence of PACs.

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Section: Neurodevelopmental Outcomesmentioning

confidence: 99%

Current State of Analgesia and Sedation in the Pediatric Intensive Care Unit

Egbuta

Mason

2021

JCM

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“…Observational reports do not directly or objectively measure cognition, but measure observable adaptive skills or behavior, and, as such, studies show proxy reports often differ substantially from formal neuropsychological evaluation of cognitive function, with outside factors confounding results (Kurowski et al, 2013;Toplak et al, 2013). Highlighting this point, a meta-analysis by Ing et al (2021) included over 800 children who were prospectively enrolled in trials that collected neurodevelopmental data after a singular anesthetic exposure showed a 68% increased risk of reported "significant impairment" on the Behavior Rated Inventory of Executive Function by parent or caregiver (BRIEF, n.d.;Toplak et al, 2013) and a 47% increased risk of significant emotional/behavioral disturbances on the Child Behavior Checklist (CBCL; Achenbach, 2011;Achenbach and Rescorla, 2013). However, in this same meta-analysis there was no effect of anesthesia on formal evaluation of the Full-scale Intelligence Quotient (FSIQ).…”

Section: Limitations With Current Approach On Measuring Cognitive Outcomes In Picu Survivorsmentioning

confidence: 99%

Cognitive Dysfunction After Analgesia and Sedation: Out of the Operating Room and Into the Pediatric Intensive Care Unit

Turner

Sullivan

Drury

et al. 2021

Front. Behav. Neurosci.

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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.

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“…28 By 2019, there were 90 studies published evaluating neurodevelopmental outcomes after surgery and anesthesia. 29…”

Section: Current State Of the Clinical Evidencementioning

confidence: 99%

Anesthesia and Developing Brains: Unanswered Questions and Proposed Paths Forward

Ing

Warner²,

Sun

et al. 2022

Anesthesiology

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Anesthetic agents disrupt neurodevelopment in animal models, but evidence in humans is mixed. The morphologic and behavioral changes observed across many species predicted that deficits should be seen in humans, but identifying a phenotype of injury in children has been challenging. It is increasingly clear that in children, a brief or single early anesthetic exposure is not associated with deficits in a range of neurodevelopmental outcomes including broad measures of intelligence. Deficits in other domains including behavior, however, are more consistently reported in humans and also reflect findings from nonhuman primates. The possibility that behavioral deficits are a phenotype, as well as the entire concept of anesthetic neurotoxicity in children, remains a source of intense debate. The purpose of this report is to describe consensus and disagreement among experts, summarize preclinical and clinical evidence, suggest pathways for future clinical research, and compare studies of anesthetic agents to other suspected neurotoxins.

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Prospectively assessed neurodevelopmental outcomes in studies of anaesthetic neurotoxicity in children: a systematic review and meta-analysis

Cited by 81 publications

References 33 publications

Current State of Analgesia and Sedation in the Pediatric Intensive Care Unit

Current State of Analgesia and Sedation in the Pediatric Intensive Care Unit

Cognitive Dysfunction After Analgesia and Sedation: Out of the Operating Room and Into the Pediatric Intensive Care Unit

Anesthesia and Developing Brains: Unanswered Questions and Proposed Paths Forward

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