title: Translational research in acute central nervous system injury: lessons learned and the future.
abstract: OBJECTIVE
  Research to improve outcomes from acute central nervous system (CNS) injury has progressed little, although limited examples (eg, induced hypothermia for out-of-hospital ventricular fibrillation cardiac arrest and birth asphyxia and tissue plasminogen activator for ischemic stroke) have proved that it is possible to favorably alter outcome.
  
  
  OBJECTIVE
  To chronicle the evolution of preclinical research designed to provide therapeutic interventions for acute CNS injury.
  
  
  METHODS
  Preclinical literature cited by major clinical intervention trials was systematically assessed with respect to fulfillment of fundamental elements of experimental design in current guidelines.
  
  
  RESULTS
  Preclinical studies of acute CNS injury to date have a poor record of adhering to basic tenets of experimental design, including randomization, concealment of treatment allocation, definition of sustained robustness of therapeutic benefit, and emulation of clinical disease. Major clinical trials continue to be justified and conducted on the basis of weak preclinical evidence. Publication of preclinical research guidelines and endorsement by scientific journals have been insufficient to alter practice. Novel approaches to preclinical therapeutic development, including multicenter phase 3 trials and preclinical trial registries that document a priori experimental design and primary dependent variables, may overcome this intransigence and enhance possibility for therapeutic breakthroughs.
  
  
  CONCLUSIONS
  Current knowledge of acute CNS injury dictates that therapeutic discovery and translation apply known tenets of sound experimental design and emulation of the clinical disorder targeted for therapeutic intervention. Peer-review systems must demand these qualities in proposed and published research to assess validity and potential for clinical translation.
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina2Department of Neurobiology, Duke University Medical Center, Durham, North Carolina3Department of Surgery, Duke University Medical Center, Durham, North Carolina.
authors.forename: David S
authors.initials: DS
authors.lastname: Warner
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina4Department of Neurology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Michael L
authors.initials: ML
authors.lastname: James
authors.affiliation: Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina2Department of Neurobiology, Duke University Medical Center, Durham, North Carolina4Department of Neurology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Laskowitz
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Eelco F
authors.initials: EF
authors.lastname: Wijdicks
mesh_terms: D000208:Acute Disease; D001930:Brain Injuries / Q000628:therapy*; D002545:Brain Ischemia / Q000628:therapy*; D002493:Central Nervous System Diseases / Q000628:therapy; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D006801:Humans; D007036:Hypothermia, Induced / Q000379:methods; D020521:Stroke / Q000628:therapy*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use; D057170:Translational Research, Biomedical
chemical_list: D018691:Excitatory Amino Acid Antagonists; D010959:Tissue Plasminogen Activator