title: Newly postulated neurodevelopmental risks of pediatric anesthesia: theories that could rock our world.
abstract: OBJECTIVE
  General anesthetics can induce apoptotic neurodegeneration and subsequent maladaptive behaviors in animals. Retrospective human studies suggest associations between early anesthetic exposure and subsequent adverse neurodevelopmental outcomes. The relevance of animal data to clinical practice is unclear and to our knowledge the causality underlying observed associations in humans is unknown. We reviewed newly postulated neurodevelopmental risks of pediatric anesthesia and discuss implications for the surgical care of children.
  
  
  METHODS
  We queried the MEDLINE®/PubMed® and EMBASE® databases for citations in English on pediatric anesthetic neurotoxicity with the focus on references from the last decade.
  
  
  RESULTS
  Animal studies in rodents and primates demonstrate apoptotic neuropathology and subsequent maladaptive behaviors after exposure to all currently available general anesthetics with the possible exception of α2-adrenergic agonists. Similar adverse pathological and clinical effects occur after untreated pain. Anesthetic neurotoxicity in animals develops only after exposure above threshold doses and durations during a critical neurodevelopmental window of maximal synaptogenesis in the absence of concomitant painful stimuli. Anesthetic exposure outside this window or below threshold doses and durations shows no apparent neurotoxicity, while exposure in the context of concomitant painful stimuli is neuroprotective. Retrospective human studies suggest associations between early anesthetic exposure and subsequent adverse neurodevelopmental outcomes, particularly after multiple exposures. The causality underlying the associations is unknown. Ongoing investigations may clarify the risks associated with current practice.
  
  
  CONCLUSIONS
  Surgical care of all patients mandates appropriate anesthesia. Neurotoxic doses and the duration of anesthetic exposure in animals may have little relevance to clinical practice, particularly surgical anesthesia for perioperative pain. The causality underlying the observed associations between early anesthetic exposure and subsequent adverse neurodevelopmental outcomes is unknown. Anesthetic exposure may be a marker of increased risk. Especially in young children, procedures requiring general anesthesia should be performed only as necessary and general anesthesia duration should be minimized. Alternatives to general anesthesia and the deferral of elective procedures beyond the first few years of life should be considered, as appropriate. Participation in ongoing efforts should be encouraged to generate further data.
authors.affiliation: Division of Pediatric Anesthesiology, Vanderbilt University School of Medicine and Pediatric Pain Services, Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee 37232-9070, USA. stephen.hays@vanderbilt.edu
authors.forename: Stephen Robert
authors.initials: SR
authors.lastname: Hays
authors.forename: Jayant K
authors.initials: JK
authors.lastname: Deshpande
mesh_terms: D000758:Anesthesia / Q000009:adverse effects*; D000777:Anesthetics / Q000009:adverse effects*; D000818:Animals; D002648:Child; D004195:Disease Models, Animal; D006801:Humans; D009420:Nervous System / Q000187:drug effects* / Q000254:growth & development*; D020258:Neurotoxicity Syndromes / Q000209:etiology*
chemical_list: D000777:Anesthetics