title: Ketamine as a neuroprotective and anti-inflammatory agent in children undergoing surgery on cardiopulmonary bypass: a pilot randomized, double-blind, placebo-controlled trial.
abstract: OBJECTIVE
  Infants are potentially more susceptible to cell death mediated via glutamate excitotoxicity attributed to cardiopulmonary bypass. We hypothesized that ketamine, via N-methyl D-aspartate receptor blockade and anti-inflammatory effects, would reduce central nervous system injury during cardiopulmonary bypass.
  
  
  METHODS
  We randomized 24 infants, without chromosomal abnormalities, to receive ketamine (2 mg/kg, n = 13) or placebo (saline, n = 11) before cardiopulmonary bypass for repair of ventricular septal defects. Plasma markers of inflammation and central nervous system injury were compared at the end of surgery, and 6, 24, and 48 hrs after surgery. Magnetic resonance imaging and spectroscopy before cardiopulmonary bypass and at the time of hospital discharge were performed in a subset of cases and controls (n = 5 in each group). Cerebral hemodynamics were monitored postoperatively using near-infrared spectroscopy, and neurodevelopmental outcomes were assessed using Bayley Scales of Infant Development-II before and 2-3 wks after surgery.
  
  
  RESULTS
  Statistically significant differences were noted in preoperative inspired oxygen levels, intraoperative cooling and postoperative temperature, respiratory rate, platelet count, and bicarbonate levels. The peak concentration of C-reactive protein was lower in cases compared to controls at 24 hrs (p = .048) and 48 hrs (p = .001). No significant differences were noted in the expression of various cytokines, chemokines, S100, and neuron-specific enolase between the cases and controls. Magnetic resonance imaging with spectroscopy studies showed that ketamine administration led to a significant decrease in choline and glutamate plus glutamine/creatine in frontal white matter. No statistically significant differences occurred between pre- and postoperative Bayley Scales of Infant Development-II scores.
  
  
  CONCLUSIONS
  We did not find any evidence for neuroprotection or neurotoxicity in our pilot study. A large, adequately powered randomized control trial is needed to discern the central nervous system effect of ketamine on the developing brain. brain.
  
  
  BACKGROUND
  The trial is registered at www.ClinicalTrials.gov, NCT00556361.
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA. bhuttaadnant@uams.edu
authors.forename: Adnan T
authors.initials: AT
authors.lastname: Bhutta
authors.forename: Michael L
authors.initials: ML
authors.lastname: Schmitz
authors.forename: Christopher
authors.initials: C
authors.lastname: Swearingen
authors.forename: Laura P
authors.initials: LP
authors.lastname: James
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Wardbegnoche
authors.forename: Diana M
authors.initials: DM
authors.lastname: Lindquist
authors.forename: Charles M
authors.initials: CM
authors.lastname: Glasier
authors.forename: Volkan
authors.initials: V
authors.lastname: Tuzcu
authors.forename: Parthak
authors.initials: P
authors.lastname: Prodhan
authors.forename: Umesh
authors.initials: U
authors.lastname: Dyamenahalli
authors.forename: Michiaki
authors.initials: M
authors.lastname: Imamura
authors.forename: Robert D B
authors.initials: RD
authors.lastname: Jaquiss
authors.forename: Kanwaljeet J S
authors.initials: KJ
authors.lastname: Anand
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000187:drug effects; D001930:Brain Injuries / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D002097:C-Reactive Protein / Q000378:metabolism; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D002490:Central Nervous System / Q000187:drug effects / Q000293:injuries; D002657:Child Development; D016207:Cytokines / Q000097:blood; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006345:Heart Septal Defects, Ventricular / Q000601:surgery*; D006801:Humans; D007223:Infant; D007249:Inflammation / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D007275:Injections, Intravenous; D057194:Intention to Treat Analysis; D007649:Ketamine / Q000494:pharmacology / Q000627:therapeutic use*; D016014:Linear Models; D008279:Magnetic Resonance Imaging; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010865:Pilot Projects; D019265:Spectroscopy, Near-Infrared; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D016207:Cytokines; D018696:Neuroprotective Agents; D007649:Ketamine; D002097:C-Reactive Protein