Ketamine As a Neuroprotective and Anti-Inflammatory Agent in Children
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Neurocritical Care Ketamine as a neuroprotective and anti-inflammatory agent in children undergoing surgery on cardiopulmonary bypass: A pilot randomized, double-blind, placebo-controlled trial Adnan T. Bhutta, MBBS, FAAP; Michael L. Schmitz, MD; Christopher Swearingen, PhD; Laura P. James, MD; Wendy L. Wardbegnoche, PhD; Diana M. Lindquist, PhD; Charles M. Glasier, MD; Volkan Tuzcu, MD; Parthak Prodhan, MBBS; Umesh Dyamenahalli, MD; Michiaki Imamura, MD, PhD; Robert D. B. Jaquiss, MD; Kanwaljeet J. S. Anand, MBBS, DPhil Objective: Infants are potentially more susceptible to cell postoperative temperature, respiratory rate, platelet count, death mediated via glutamate excitotoxicity attributed to cardio- and bicarbonate levels. The peak concentration of C-reactive pulmonary bypass. We hypothesized that ketamine, via N-methyl protein was lower in cases compared to controls at 24 hrs (p 5 .048) D-aspartate receptor blockade and anti-inflammatory effects, and 48 hrs (p 5 .001). No significant differences were noted in the ex- would reduce central nervous system injury during cardiopulmo- pression of various cytokines, chemokines, S100, and neuron-specific nary bypass. enolase between the cases and controls. Magnetic resonance imaging Methods: We randomized 24 infants, without chromosomal with spectroscopy studies showed that ketamine administration led to a abnormalities, to receive ketamine (2 mg/kg, n 5 13) or place- significant decrease in choline and glutamate plus glutamine/creatine bo (saline, n 5 11) before cardiopulmonary bypass for repair of in frontal white matter. No statistically significant differences oc- ventricular septal defects. Plasma markers of inflammation and curred between pre- and postoperative Bayley Scales of Infant central nervous system injury were compared at the end of sur- Development-II scores. gery, and 6, 24, and 48 hrs after surgery. Magnetic resonance Conclusions: We did not find any evidence for neuroprotection imaging and spectroscopy before cardiopulmonary bypass and at or neurotoxicity in our pilot study. A large, adequately powered the time of hospital discharge were performed in a subset of cases randomized control trial is needed to discern the central nervous and controls (n 5 5 in each group). Cerebral hemodynamics were system effect of ketamine on the developing brain. brain. (Pediatr monitored postoperatively using near-infrared spectroscopy, and Crit Care Med 2012; 13:328–337) neurodevelopmental outcomes were assessed using Bayley Scales Trial Registration: The trial is registered at www.ClinicalTrials. of Infant Development-II before and 2–3 wks after surgery. gov, NCT00556361. Results: Statistically significant differences were noted in KEY WORDS : cardiopulmonary bypass; excitotoxicity; infants; in- preoperative inspired oxygen levels, intraoperative cooling and flammation; ketamine etamine is a commonly anti-inflammatory effects. Interest in of central nervous system (CNS) injury used anesthetic agent in ketamine has increased in recent years also reduce neuronal injury (3–8). children. It provides po- since it can block neuronal death via ex- NMDA receptors, along with other tent sedation, analgesia, citotoxic mechanisms (1). This effect is glutamate receptors, are abundantly ex- Kand amnesia, and a short duration of thought to occur as a result of reduced pressed in the developing brain and play action, supporting hemodynamic and excitotoxic cell death due to reduced a key role in neuronal proliferation, mi- respiratory stability. Noncompetitive calcium entry into the neurons via gration, synaptogenesis, and synaptic antagonism of N-methyl D-aspartate NMDA receptors (2). NMDA antago- plasticity by allowing calcium entry into (NMDA) produces its primary thera- nists given prior to cardiopulmonary the cells, with subsequent activation of peutic effect and is also known to have bypass (CPB) and other animal models second messengers and alteration in gene regulation. However, in the setting of in- creased stimulation by pathologic stres- From the Departments of Pediatrics (ATB, CS, LPJ, Anand received funding from the National Institutes of sors, immature neurons appear to have WLW, VT, PP, KJSA), Anesthesiology (MLS, KJSA), Health. Dr. Imamura received honoraria/speaking fees an increased vulnerability to excitotoxic Radiology (DML, CMG), and Surgery (MI, RDBJ), University from ZymoGenetics. The remaining authors have not damage via excessive calcium entry via of Arkansas for Medical Sciences, Little Rock, AR. disclosed any potential conflicts of interest. Supported, in part, by a grant to ATB from Arkansas For information regarding this article, E-mail: these same receptors (9). Children’s Hospital Research Institute’s Children’s [email protected] Conversely, concerns have been raised University Medical Group award, and American Heart Copyright © 2012 by the Society of Critical Care about ketamine use, since it has been Association Heartland Affiliate’s Beginning Grant-in-Aid. Medicine and the World Federation of Pediatric Intensive associated with neurotoxicity via apoptot- Dr. Bhutta received funding from the American and Critical Care Societies ic mechanisms in neonatal animal mod- Heart Association, CUMG, and the Dean’s award from DOI: 10.1097/PCC.0b013e31822f18f9 Arkansas Children’s Hospital Research Institute. Dr. els. These models showed that large doses 328 Pediatr Crit Care Med 2012 Vol. 13, No. 3 PCC_13.3.indb 328 4/23/2012 9:55:49 PM (20 mg/kg administered subcutaneously), the S-ketamine group on the trail mak- Measurements given repeatedly or as a continuous infu- ing B test (a test of visual attention and sion for prolonged periods, can induce associated with brain impairment) at the Blood samples were collected on ice just widespread apoptotic cell death (10–15). 10-wk postoperative assessment (37, 38). before surgery, at the end of CPB, and 6, 24, and 48 hrs postoperatively. Blood plasma More recent animal studies show that However, since the neonatal and infancy was removed after centrifugation, stored in ketamine’s neuroapoptosis is dose-related period of life are marked by very active a −70C freezer, and later analyzed for bio- and exposure-time dependent, i.e., doses periods for various CNS developmental markers of CNS injury and inflammatory of 5 or 10 mg/kg (subcutaneous or intra- processes, such as neuronal myelination, mediators. Neuron-specific enolase (NSE) muscular) given singly or repeatedly do synapse formation, glial cell proliferation, and S100b were measured using enzyme- not induce cell death in neonatal rodent and axonal sprouting (39), damage to the linked immunosorbent assay-based assays model and no cell death or injury is ob- CNS in this period can have long-term (Nanogen, San Diego, CA). Inflammatory served at 3 hrs of continuous infusion of potential consequences. We therefore hy- mediators were measured by the human 29- 20-50 mg/kg/hr of ketamine in a neonatal pothesized that a single dose of ketamine plex panel (Millipore, Billerica, MA) using the primate model, but can be observed at 9 (2 mg/kg), administered intravenously Luminex xMAP technology (Luminex, Austin, hrs or greater (16). before initiation of CPB in infants, would TX), whereas C-reactive protein (CRP) was measured using the IMMAGE automated CPB allows for perfusion of vital or- block the excitotoxic and inflammatory gans during cardiac surgery, but its use is analyzer (Beckman Coulter, Fullerton, CA). changes induced by CPB via NMDA re- Subjects were assessed using Bayley Scales of associated with multiorgan dysfunction, ceptor blockade and anti-inflammatory Infant Development, second edition (BSID-II, including injury to the CNS (17). During effects, thus offering potential neuropro- Psychological Assessment Resources, Lutz, CPB, ischemia, hypoxemia, and microem- tective effects. FL) on the day before surgery and 2–3 wks boli may contribute to CNS injury (18). after surgery. Activation of the systemic inflammatory METHODS Five subjects from each group also un- response syndrome also contributes sig- derwent magnetic resonance imaging with nificantly to postoperative organ dysfunc- spectroscopy (MRI/MRS) just before surgery tion (19–21). Study Population and just before hospital discharge. The MRI scan included axial proton density, sagittal Refinement in surgical and CPB tech- Following institutional review board ap- T1, axial T2, axial inversion recovery (for niques has improved mortality rates proval from the University of Arkansas for estimation of cerebral spinal fluid), and following CPB, but has exposed the neu- Medical Sciences and written parental con- diffusion-weighted images. Four single voxel rologic injury and impaired functional sent, infants ,1 yr of age undergoing CPB water-suppressed proton spectra from two outcomes of these patients (22). Children surgery for repair of ventricular septal defects voxels were acquired using a repetition time were enrolled from July 2004 to November with congenital heart disease have lower of 2 secs and echo times (TE) of 35 and 144 2007. We chose infants with ventricular cognitive abilities, impaired speech and msecs using a double-spin echo sequence. septal defects to decrease the likelihood of motor skills, and problems with behavior The voxels were located in the frontal cor- and executive function compared to con- preexisting CNS injury due to hypoxemia or ischemia resulting from their congenital tex white matter and basal ganglia gray mat- trols (23–28). heart disease. Children with Down’s syn- ter (BG). The