title: A systematic review of methodology applied during preclinical anesthetic neurotoxicity studies: important issues and lessons relevant to the design of future clinical research.
abstract: Preclinical evidence suggests that anesthetic agents harm the developing brain thereby causing long-term neurocognitive impairments. It is not clear if these findings apply to humans, and retrospective epidemiological studies thus far have failed to show definitive evidence that anesthetic agents are harmful to the developing human brain.
  
  
  OBJECTIVE
  The aim of this systematic review was to summarize the preclinical studies published over the past decade, with a focus on methodological issues, to facilitate the comparison between different preclinical studies and inform better design of future trials.
  
  
  METHODS
  The literature search identified 941 articles related to the topic of neurotoxicity. As the primary aim of this systematic review was to compare methodologies applied in animal studies to inform future trials, we excluded a priori all articles focused on putative mechanism of neurotoxicity and the neuroprotective agents. Forty-seven preclinical studies were finally included in this review.
  
  
  RESULTS
  Methods used in these studies were highly heterogeneous-animals were exposed to anesthetic agents at different developmental stages, in various doses and in various combinations with other drugs, and overall showed diverse toxicity profiles. Physiological monitoring and maintenance of physiological homeostasis was variable and the use of cognitive tests was generally limited to assessment of specific brain areas, with restricted translational relevance to humans.
  
  
  CONCLUSIONS
  Comparison between studies is thus complicated by this heterogeneous methodology and the relevance of the combined body of literature to humans remains uncertain. Future preclinical studies should use better standardized methodologies to facilitate transferability of findings from preclinical into clinical science.
authors.affiliation: Department of Anesthesia, Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Disma
authors.affiliation: Department of Pediatric Anesthesia and Intensive Care Unit, University Hospital Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Mondardini
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Niccolò
authors.initials: N
authors.lastname: Terrando
authors.affiliation: Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Absalom
authors.affiliation: Section of Neuroanesthesia and Neurocritical Care, Department of Anesthesiology, Critical Care and Pain Medicine, "Sapienza" University of Rome, Rome, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Bilotta
mesh_terms: D000777:Anesthetics / Q000009:adverse effects*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D000882:Haplorhini; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020258:Neurotoxicity Syndromes / Q000517:prevention & control*; D051381:Rats
chemical_list: D000777:Anesthetics; D018696:Neuroprotective Agents
keywords: anesthetic-related neurotoxicity in the developing age; cognitive-behavioral impairment; general anesthetic neurotoxicity