Assessing Long-term Neurodevelopmental Outcome Following General Anesthesia in Early Childhood: Challenges and Opportunities

Abstract

Neurodegeneration has been reported in young animals after exposure to all the commonly used general anesthetics (GA). The brain may be particularly vulnerable to anesthetic toxicity during peak synaptogenesis (in gestation and infancy). Human studies of long-term neurodevelopmental outcome following GA in early childhood report contradictory findings. This review assesses the strengths and deficiencies in human research methodologies to inform future studies. We identified 76 studies, published between 1990 and 2017, of long-term neurodevelopmental outcome following early childhood or in utero GA exposure: 49 retrospective, 9 ambi-directional, 17 prospective cohort studies and one randomized controlled trial (RCT). Forty-nine studies were explicitly concerned with anesthetic-induced neurotoxicity (AIN). Full texts were appraised for methodological challenges and possible solutions. Major challenges identified included: delineating effects of anesthesia from surgery; defining the timing and duration of exposure; selection of a surgical cohort and intervention; addressing multiple confounding life course factors; detecting modest neurotoxic effects with small sample sizes (median 131 children, IQR: 50-372); selection of sensitive neurodevelopmental outcomes at appropriate ages for different developmental domains; insufficient length of follow-up (median age: 6 years, IQR: 2-12) and sample attrition. We discuss potential solutions to these challenges. Further adequately powered, multi-center, prospective RCT of AIN in children are required. However, we believe that the inherent methodological challenges of studying AIN necessitate the parallel use of well-designed observational cohort studies.

The outcome of Bishop-Koop procedure compared to divided stoma in neonates with meconium ileus, congenital intestinal atresia and necrotizing enterocolitis

“…Surgical aspects that favor later ostomy closure include fewer postoperative abdominal adhesions, [46–48] anesthesiological aspects include potential adverse neurodevelopmental outcomes as a result of general anesthesia at a very young age. [49,50] Moreover, the unique anatomical advantage of BK anastomosis, which preserves intestinal continuity and maintains the fluid and electrolyte balance, relativizes the potential advantages of early ostomy closure. Nevertheless, there is currently no consensus for the optimal timing of ostomy reversal.…”

A systematic review of outcomes reported in pediatric perioperative research: A report from the Pediatric Perioperative Outcomes Group

“…In the vast majority of studies, outcomes were measured in the immediate perioperative period, with the duration often restricted to the postanesthesia care unit or the first 24 postoperative hours. However, more prolonged follow‐up in specific age‐based populations is required for outcomes‐related to emergent research priorities, 7 such as potential effects of general anesthesia on the developing brain, 60,61 or factors associated with an increased risk of persistent postsurgical pain 42,62 . While neonatal mortality is declining, 63 the rate of preterm birth continues to increase, 64 and neonatal comorbidities make significant contributions to years of life lost and years lived with disability 65 .…”

Effects of sevoflurane general anesthesia during early pregnancy on AIM2 expression in the hippocampus and parietal cortex of Sprague‑Dawley offspring rats

“…As an inhaled anesthetic with a rapid recovery profile, sevoflurane is prevalently used worldwide. Human neural development is similar to that of rats, and studies of model animals are helpful in research and the discovery of novel therapeutic options ( 8 , 9 ). Although previous studies have described the efficacy and safety of sevoflurane, the present study primarily focused on the effects of exposure duration on neurodevelopment ( 10 , 11 ).…”