P015: NEUROTOXIC EFFECTS OF GENERAL ANESTHESIA ON THE VERY YOUNG
Aarthi Kalaichezhian, MS; Nova Southeastern University - Fort Lauderdale
Pediatric anesthesia is an intricate art which plays a crucial role in ensuring surgical success in the most susceptible and neurologically immature patient population. The field of pharmacology has witnessed thriving advances in anesthetics, sedatives, and analgesics, all of which are mandatory for surgery and investigative procedures. While these drugs are undeniably essential to regulate the body’s physiological response to noxious stimulation during surgery, the safety and long-term implications of these drugs on neurodevelopment and cognitive function, particularly in the very young, are poorly understood and should be questioned. This review aims to consolidate the resources available on animal model studies and retrospective human studies in order to assess the neurotoxic effects of general anesthesia on the very young.
Animal model studies have been widely used in assessing the toxicity of pharmacological agents as an ethical alternative to human experimental models. In humans, maximal neurodevelopment occurs between birth and two years of age and manifests via two major processes, synaptogenesis and differentiation of neurons. Synaptogenesis, the process of programmed cell death, is largely mediated by neurotropic factors which are heavily down regulated in rat models upon exposure to midazolam, nitrous oxide, and isoflurane. Migration and differentiation of neurons allow for the establishment of functional neural circuits which mediate sensory and motor processing; one key differentiation important for anesthesia is the production of neurotransmitters, glutamate and GABA and its respective receptor differentiations. In rat models, disrupting neuron differentiation through exposure to anesthetics leads to long term memory and learning deficits, particularly because GABA is a major site of pharmacological directed action. However, it is difficult to make conclusive statements regarding the detrimental effects of anesthesia on rats and apply it to humans due to stark differences in physiological processes and the lack of comparable noxious stimulation response.
Retrospective human studies assess cognitive, behavioral and academic changes as a result of anesthesia exposure through multi-nodal tests and medical record follow-ups. Currently there are four major international retrospective studies, with differing parameters, that follow patients of anesthesia exposure for an extended period of time in attempts to understand the neurocognitive changes.
Thus far, retrospective studies show minimal conclusive evidence of academic or behavioral impact from anesthesia exposure. However, recent advances have been made to develop more accurate and appropriate tests of neurocognitive function, with the primary goal to isolate anesthesia exposure as the single independent variable.
Despite the paradoxical results from animal model experiments and retrospective human assessments, overwhelming evidence across both study types support the notion that the key factors determining anesthesia-induced neurotoxicity are age of exposure, dose of anesthetics, duration and number of exposures (single vs. multiple). Therefore, with the development of highly accurate retrospective human study assessments using the new guidelines for developmental progress, augmented with higher level animal model study results, a comprehensive analysis of the neurotoxic effects of anesthesia exposure on the very young can be evaluated and understood.