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Ketamine as a neuroprotective and anti-inflammatory agent in children undergoing surgery on cardiopulmonary bypass: A pilot randomized, double-blind, placebo-controlled trial

Bhutta, Adnan T. MBBS, FAAP; Schmitz, Michael L. MD; Swearingen, Christopher PhD; James, Laura P. MD; Wardbegnoche, Wendy L. PhD; Lindquist, Diana M. PhD; Glasier, Charles M. MD; Tuzcu, Volkan MD; Prodhan, Parthak MBBS; Dyamenahalli, Umesh MD; Imamura, Michiaki MD, PhD; Jaquiss, Robert D. B. MD; Anand, Kanwaljeet J. S. MBBS, DPhil

Pediatric Critical Care Medicine: May 2012 - Volume 13 - Issue 3 - p 328–337
doi: 10.1097/PCC.0b013e31822f18f9
Neurocritical Care

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.

Trial Registration: The trial is registered at www.ClinicalTrials.gov, NCT00556361.

From the Departments of Pediatrics (ATB, CS, LPJ, WLW, VT, PP, KJSA), Anesthesiology (MLS, KJSA), Radiology (DML, CMG), and Surgery (MI, RDBJ), University of Arkansas for Medical Sciences, Little Rock, AR.

Supported, in part, by a grant to ATB from Arkansas Children’s Hospital Research Institute’s Children’s University Medical Group award, and American Heart Association Heartland Affiliate’s Beginning Grant-in-Aid.

Dr. Bhutta received funding from the American Heart Association, CUMG, and the Dean’s award from Arkansas Children’s Hospital Research Institute. Dr. Anand received funding from the National Institutes of Health. Dr. Imamura received honoraria/speaking fees from ZymoGenetics. The remaining authors have not disclosed any potential conflicts of interest.

For information regarding this article, E-mail: bhuttaadnant@uams.edu

©2012The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies