Pro-apoptotic:
• Isoflurane, sevoflurane, desflurane, N2O
• Propofol, thiopental, ketamine, midazolam, diazepam, MgSO4, dexamethasone, CO2
Anti-apoptotic:
• Lithium, melatonin, clonidine
Non-apoptotic:
• Dexmedetomidine, opioids, ± xenon
Unknown:
• Muscle relaxants
Obtaining definitive clinical data on such a complex subject with so many confounding variables is an involved and extremely difficult task. Retrospective studies designed to assess the effects of anesthesia on neurodevelopmental outcomes reveal a concern for anesthetic-induced neurocognitive or behavioral effects [175–177]. These retrospective studies have major drawbacks, including but not limited to the difficulty in controlling for potential confounding variables including the lack of perioperative monitors, imprecise metrics, and measurement errors [175–179]. In contrast to these studies, a monozygotic concordant-discordant twin design failed to demonstrate a causal relationship between anesthesia and cognitive performance [180]. This study did not directly assess for learning disabilities, did not examine the effects of multiple anesthetics, nor did they disclose any details about the anesthetics that were administered. The authors of the study stated that children who are sick often have learning disabilities related to their underlying illness and require surgery and anesthesia due to that illness [180, 181]. A retrospective review of children whose mothers underwent obstetrical anesthesia did not reveal a detrimental effect of general anesthesia 5 years after exposure [182]. A retrospective Dutch cohort study in adolescent children who underwent inguinal hernia repair as infants compared a randomly selected, age-matched population and found no differences in their ninth grade academic scores [183]. At present, any suggestion of a causal relationship between early exposure to anesthetics and subsequent impaired cognition or psychomotor performance remains unproven and tenuous.
Two promising clinical studies may shed light on the clinical implications of anesthetics on neurodevelopment: first, a prospective randomized, multicenter trial and, second, a retrospective cohort study. The first study, the General Anesthesia Study (GAS), is a multisite, multinational, randomized, controlled study that was initiated to compare the long-term neurodevelopmental outcomes in infants who received general or regional anesthesia for hernia surgery [155, 184]. This trial is expected to be completed by 2016. The second study is the multisite Pediatric Anesthesia NeuroDevelopmental Assessment (PANDA) [185]. PANDA is a mixed epidemiologic design that retrospectively examines a cohort that underwent a single anesthetic before the age of 3 years compared with developmentally age-matched siblings without anesthetic exposure. Both groups will then undergo a prospective, direct assessment of global and specific neurodevelopmental endpoints as they mature.
The FDA, understanding that the investigation of anesthetic neurotoxicity is an overwhelming task requiring public and private intellectual and financial collaboration, has formed a public-private partnership with the acronym SAFEKIDS (Safety of Key Inhaled and IV Drugs in Pediatrics) [186]. SAFEKIDS evolved into SmartTots (Strategies for Mitigating Anesthesia Related neuroToxicity in Tots) in 2010 [187]. SmartTots (http://www.smarttots.org) is a “multi-year project designed to address major gaps in scientific information about the safe use of anesthetics and sedatives received by millions of children each year” [188]. The GAS and PANDA studies are now partnered with SmartTots.
If future clinical studies do reveal a risk of anesthetic-induced neuronal toxicity, how will this be balanced with the competing detrimental effects of untreated pain and stress? Unfortunately, the answers are neither forthcoming nor unambiguous, and it may be another generation before the complex interactions are completely understood. Regional anesthesia may play an important role by reducing the systemic administration of potential neurotoxic pharmacologic agents. Given the positive outcomes associated with early surgical intervention [158], surgery and thus anesthesia should not be postponed if clinically indicated. Practitioners must continue to focus on minimizing morbidity and mortality as our specialty awaits clarification of the actual risks associated with early anesthetic exposure in humans.
Conclusion
The incidence of perioperative morbidity and mortality is greatest in neonates and decreases thereafter with increasing age to adults. It is not surprising that neonates hold this position as they often present for emergency surgery with complicated multiorgan disease (respiratory and neurologic diseases), sepsis, and congenital heart disease. These coexisting disorders increase the perioperative risk. The complex environment and dynamics of an operating room combined with the vulnerabilities of a high-risk population converge to increase the likelihood of adverse events occurring. The ultimate goal in developing a successful anesthetic prescription is to prevent adverse events although a more realistic and achievable goal is to pursue strategies that decrease the number of adverse events and minimize their clinical consequences should they occur. Since perianesthetic systems require human interaction and decision-making, human errors are bound to occur. Continued improvements in perioperative and perianesthetic systems are essential to improve resiliency and decrease all types of errors. Through ongoing data collection and analysis using globally agreed-upon terms and definitions, continued education, innovative strategies, further standardization, and ever persistent diligence in the perianesthetic period, continued and significant improvement in safety and outcomes will be realized for our smallest and most vulnerable patient population, the neonate.
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