Abstract
Exposure to general anesthesia has been reported to induce neurotoxicity, impair learning, memory, attention, motor functions, as well as affect behavior in adult rodents and nonhuman primates. Though many have speculated similar effects in humans, previous literature has shown conflicting findings. To investigate the differences in risk of developmental delay among young children exposed to general anesthesia compared to matched unexposed individuals, a population-based cohort study was conducted with a longitudinal dataset spanning 2000 to 2013 from the Taiwan National Health Insurance Research Database (NHIRD). Procedure codes were used to identify children who received anesthesia. For each exposed child, two unexposed children matched by gender and age were enrolled into the comparison cohort. Neurocognitive outcome was measured by the presence of ICD-9-CM codes related to developmental delay (DD). Cox regression models were used to obtain hazard ratios of developing DD after varying levels of anesthesia exposure. After excluding 4,802 individuals who met the exclusion criteria, a total of 11,457 children who received general anesthesia before two years of age was compared to 22,914 children (matched by gender and age) unexposed to anesthesia. Increased risk of DD was observed in the exposure group with a hazard ratio (HR) of 1.320 (95% CI 1.143–1.522, P < 0.001). Subgroup analysis demonstrated further elevated risks of DD with multiple anesthesia exposures (1 anesthesia event: HR 1.145, 95% CI 1.010–1.246, P = 0.04; 2 anesthesia events: HR 1.476, 95% CI 1.155–1.887, P = 0.005; ≥3 anesthesia events: HR 2.222, 95% CI 1.810–2.621, P < 0.001) and longer total anesthesia durations (Total anesthesia <2 hours: HR 1.124, 95% CI 1.003–1.499, P = 0.047; Total anesthesia 2–4 hours: HR 1.450, 95% CI 1.157–1.800, P = 0.004; Total anesthesia > 4 hours: HR 1.598, 95% CI 1.343–1.982, P < 0.001) compared with children unexposed to anesthesia. These results suggest that children exposed to general anesthesia before two years of age have an increased risk of DD. This risk is further elevated with increased frequency of anesthesia, and longer total anesthesia duration. The findings of this study should prompt clinical practitioners to proceed with caution when assessing young patients and planning managements involving procedures requiring general anesthesia.
Highlights
Recent preclinical evidence demonstrates that drugs for GA may cause structural injury at the cerebral cortex and thalamus as well as long-term neurodevelopment impairment in young animals, including apoptotic cell death and changes in dendritic morphology [1, 2]
4,802 patients were excluded, including those already diagnosed with developmental delay, those who received neurosurgeries, mortality cases and incomplete data entries, with a remaining total of 11,457 patients assigned to the GA cohort as the study group
The demographic characteristics of patients included in this study are listed in Table 1, grouped by gender, household income, catastrophic illness certificate status, mean age at time of enrollment, comorbidities, level of facility where medical care was received, and length of hospitalization
Summary
Recent preclinical evidence demonstrates that drugs for GA may cause structural injury at the cerebral cortex and thalamus as well as long-term neurodevelopment impairment in young animals, including apoptotic cell death and changes in dendritic morphology [1, 2]. These changes have been observed with several different GA agents in studies with rodents and nonhuman primates. At the same time delaying necessary procedures may have unintended harmful consequences [6] In this retrospective observational study, a cohort of medical insurance enrollees of the Taiwan National Health Insurance (NHI) was used to compare children exposed to GA with matched children with no anesthesia exposure. The purpose of this study is to better understand the association between exposure of different degrees of general anesthesia in pediatric patients and the risks of subsequent developmental disorders
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