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 , 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 /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 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 Ke y Wo r d s : 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

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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 −70C 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 data were acquired at 1.5 T CPB-induced cellular injury in the drome or other chromosomal abnormalities on a GE LX system using General Electric’s brain is partly mediated by excitotoxicity were excluded because they might have CNS PROBE software. Brain tissue concentra- (5, 29–31) resulting from excessive stim- dysfunction or malformations associated tions of N-acetyl aspartate (NAA), creatine ulation of glutamate receptors (32–34). with their heart defect (40). (Cr), choline (Cho), and the sum of gluta- The immature neurons of neonates and mate and glutamine (Glx) were estimated (in infants are more vulnerable to excitotoxic Study Design mM/kg wet tissue) using LC Model to fit the damage because they have altered molec- spectral data (41). The concentration of wa- ter used as a reference was adjusted for each ular mechanisms of calcium signaling (2, A pilot prospective, randomized, dou- ble-blinded, placebo-controlled study was subject using the method of Toft et al (42). 35). As continued neuronal migration and Concentrations were also adjusted for the organization, myelination, and synapto- designed to compare the plasma levels of inflammatory cytokines, biomarkers of CNS amount of cerebral spinal fluid in each voxel genesis occur in the human CNS during injury, clinical, radiologic, and neurodevel- (43). No corrections for relaxation times infancy, widespread neuronal injury may opment outcomes of children who received were made. have long-term developmental conse- ketamine (cases) vs. those who received pla- Data were collected on demographic, in- quences (9, 36). cebo before CPB (controls), and to assess the traoperative, and postoperative variables, in- Nagels et al (37) performed a random- feasibility of the use of these surrogate bio- cluding anesthetic agents used, CPB length, ized controlled trial in adult subjects markers in assessing the effect of ketamine length of aortic cross-clamp, CPB flow, degree who either received S-ketamine (2.5 mg/ on the CNS. of hypothermia, vital signs, blood gas measure- kg bolus for induction of anesthesia fol- Subjects enrolled in the study were ran- ments, and routine laboratory data. Data from lowed by an infusion of 125 g/kg/min) domized to receive 2 mg/kg ketamine or equal routine near-infrared spectroscopy (NIRS) or remifentanil and propofol infusions. volumes of normal saline intravenously before monitoring were also collected up to 24 hrs af- ter surgery. NIRS data were collected using the A battery of 13 neuropsychological tests the initiation of CPB. No changes were made in the standard cardiovascular operating room INVOS 5100B cerebral oximeter (Somanetics, was used to test the cognitive perfor- clinical practices, including the use of preoper- Troy, MI). The sensors were placed on each mance between the two groups and no ative systemic steroids, moderate hypothermia side of the patient’s forehead, with the lower major differences were noted between the (~25C), and modified ultrafiltration at the end edge above the patient’s eyebrows and the S-ketamine and propofol and remifenta- of CPB in all patients. Patients received stan- medial edge of the sensor in the midline as nil gropus. The only significant difference dard postoperative care in the cardiovascular per the manufacturer’s specifications. No data reported was an improved performance by intensive care unit (ICU). obtained by this device was used for making

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PCC_13.3.indb 329 4/23/2012 9:55:49 PM clinical decisions. Data were collected every Table 1. Preoperative and operative variables in the study groups 30 secs and stored on a disk. Control Ketamine Statistical Analyses Category Demographics n = 11 n = 13 p

The demographic, preoperative, and Sex 75% Female 66.6% Female intraoperative data were analyzed using Race 66.6% Caucasian 75% Caucasian an intention-to-treat analysis. Continuous Age (months) 5.44  2.3 5.44  2.4 .99 Weight (kg) 5.76  1.48 5.62  1.27 .79 variables meeting the assumption of nor- Height (cm) 59.88  1.48 62.48  4.32 .36 mality (i.e., having an underlying Gaussian Pre-CPB: clinical distribution), were analyzed using t test or Pre-CPB heart rate 129.67  19.08 134.08  10.74 .49 analysis of variance. Otherwise, the non- Pre-CPB blood pressure parametric analogs Mann-Whitney U or Systolic 88.25  9.82 87.58  12.30 .88 Kruskal-Wallis test were utilized. Repeated- Diastolic 46.42  5.81 47.33  8.95 .77 measures analysis of variance was performed Pre-CPB temperature 35.73  0.57 35.93  0.59 .39 on MRS data. For plasma inflammation Pre-CPB respiratory rate 29.58  16 27.33  11.09 .69 markers where baseline and four postopera- Pre-CPB central venous pressure 7.45  2.21 6  1.60 .08 Pre-CPB Fi o % 35.12  8.74 28.25  4.71 .03 tive measurements were obtained on each 2 Pre-CPB: laboratory subject, differences between groups over Pre-CPB pH 7.41  0.06 7.38  0.06 .41 time were estimated using a general lin- c o Pre-CPB P 2 41.55  5.48 40.83  7.02 .78 ear mixed model framework to account for o Pre-CPB Pa 2 184.83  107.71 110.25  52.64 .04 – the repeated measurements. Inflammation Pre-CPB HCO3 25.88  5.09 24.33  3.4 .39 markers were also evaluated for normality Pre-CPB base excess 1.33  5.61 –1.42  3.32 .16 and normalizing transformations were em- Pre-CPB lactate 0.81  0.37 0.74  0.22 .60 ployed if any marker was found to violate Pre-CPB hematocrit 26.75  6.57 28.42  2.31 .42 the normality assumption. Demographic, Intraoperative variables CPB time (mins) 70.33  15.36 74.5  24.34 .62 intraoperative, and postoperative data Cross-clamp time (mins) 43.67  13.13 48.5  20.30 .50 were analyzed using MedCalc version 9.6 CPB flow (L/min) 1.08  0.29 1.11  0.26 .73 (MedCalc Software, Mariakerke, Belgium) CPB cooling 26.75  2.34 28.75  1.42 .02 and GraphPad InStat 3.0 (GraphPad Pre-CPB NIRS (head) 60.18  13.5 64.85  12.33 .39 Software, San Diego, CA). Linear analy- CPB end NIRS 55.18  10.35 53.77  9.91 .74 sis of NIRS data and plasma markers were Chest closure NIRS 62.09  66.51 66.54  10.53 .32 analyzed using Stata 11.1 (College Station, Length of anesthesia (min) 275  36.97 273.08  63.31 .93 TX). Linear analysis of NIRS was performed Anesthetic use by excluding missing values and compar- % hr 1.36  1.27 2.22  2.20 .26 % hr 1.64  0.81 1.55  1.44 .86 ing hourly averaged values between the two % hr 19  27.07 18.67  19.09 .97 groups. Nonlinear analysis of the NIRS data (g/kg) 62.92  91.55 72.33  89.97 .80 was performed and sample entropy and de- Cisatracurium (mg) 0.58  2.02 0.33  1.15 .71 trended fractal analysis were calculated us- Fentanyl (g/kg) 51.04  20.25 49.1  28.47 .85 ing Matlab software. Versed (mg/kg) 0.37  0.24 0.31  0.17 .52 Pancuronium (mg/kg) 2.33  0.2 2  0.31 .76 RESULTS Nimbex (mg/kg) 0.077  0.27 0.0533  0.18 .80 CPB, cardiopulmonary bypass; NIRS, near-infrared spectroscopy. Baseline Characteristics, Data are presented as mean  s d unless otherwise noted. Intraoperative Data, and Postoperative Data 39.16 K/L, p  .008), and bicarbonate groups or following surgery. In the fron- levels on postoperative day 1 (26.26  tal cortex white matter, there were no Data on preoperative and intraop- 2.24 mmol/L vs. 24.67  1.42 mmol/L, significant differences in Cr concentra- erative variables by treatment group p  .046). tions. A significant decrease was noted in assignment are presented in Table 1. Glx concentration in the ketamine group Data collected at admission and at Markers of CNS Injury compared to the control group postop- 24 hrs after surgery are shown in eratively, and to its preoperative values Table 2. Statistically significant differ- 1) Expression of Plasma Biomarkers. (p  .006 and p  .048, respectively, in ences were noted in preoperative in- Peak plasma levels of NSE occurred at 6 spired oxygen levels (35.12%  8.74% hrs post-CPB. There was no statistically the 35-msec TE sequence by repeated- in controls vs. 28.25%  4.71% in significant difference between the cases measures analysis of variance). Cho con- ketamine, p  .025), intraoperative cool- and controls (Fig. 1). No differences oc- centrations were significantly reduced for ing (26.75  2.34C in controls vs. 28.75 curred in the expression of S100β protein all patients postoperatively (p  .006 for  1.42C in ketamine, p  .02), postop- between the two groups. cases and p   .001 for controls in the erative temperature (35.6  1.04C vs. 2) Changes in MRI/MRS. No structural 144-msec TE sequence respectively). The 36.85  0.99C, p  .008), respiratory abnormalities were noted in the preoper- NAA concentration in the control group rate at admission to ICU (23.36  3.08 ative or postoperative MRI images in any was statistically significantly higher pre- breaths/min vs. 34  11.52 breaths/min, of the ten patients who underwent the operatively (p  .026 in 35-msec TE se- p  .006), platelet count on postoperative study. There were no differences in the quence), and this led to a lower NAA/Cr day 1 (114.82  26.91 K/L vs. 155.92  apparent diffusion coefficients between ratio in the control group postoperatively

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PCC_13.3.indb 330 4/23/2012 9:55:50 PM Table 2. Postoperative variables in the study groups significant differences were noted in the myoinositol concentrations. Control Ketamine 3) Changes in NIRS. There were no Category n = 11 n = 13 p statistically significant differences in Admission: clinical data the mean NIRS values between the two Heart rate 135.73  10.95 141.38  18.31 .380 groups, either in the cardiovascular op- Blood pressure erating room or in the cardiovascular Systolic 100.64  12.3 111.92  17.12 .082 ICU. Nonlinear analysis of the postopera- Diastolic 58.45  8.129 65.08  13.24 .163 tive data to assess variability trended to- Temperature 35.6  1.04 36.85  0.99 .008 Cardiovascular intensive 22.64  4.34 27.15  10.61 .201 ward lower mean sample entropy in the care unit respiratory rate ketamine group compared to the control Central venous pressure 7.91  3.51 7.62  2.79 .821 group, although this difference was not Oxygen saturation 99.18  1.47 99  1.35 .756 statistically significant (0.69  0.33 vs. Fi o % 42.5  6.35 40.83  11.84 .694 2 1.09  0.48; p  .07). Cerebral near-infrared spectroscopy 64.18  12.56 64.31  9.81 .978 Inotrope score 4.46  2.15 4.79  1.39 .660 4) Developmental Assessments. No Admission: laboratory statistically significant difference oc- pH 7.42  0.069 7.4  0.047 .489 curred on the pre- and postoperative Pc o 41.75  5.62 40.85  4.23 .660 2 BSID-II assessments, although slight im- o Pa 2 143.78  60.79 132.07  43.41 .600 – provements in the mental developmental HCO3 26.26  2.24 24.67  1.42 .046 Base excess 1.54  2.62 0.338  1.68 .190 index and psychomotor developmental Lactate 1.382  0.275 1.31  0.39 .600 index occurred in the cases but not con- Glucose 181.45  47.662 160.46  36.96 .237 trols (Fig. 2). K 4.2  0.42 4.48  0.51 .162 White blood cell count 10.66  2.98 11.68  3.34 .443 Polymorphs% 55.74  23.46 58.21  12.3 .744 Effects on Inflammatory Lymphocytes% 19.28  7.01 18.85  6.61 .879 Markers Hematocrit 39.01  9.08 41.73  6.17 .393 Platelet 114.82  26.91 155.92  39.16 .008 Of the 30 inflammatory markers (29- 24 hrs post-ICU admission: clinical data plex panel and CRP) examined in this Heart rate 137.91  17.78 139.15  12.22 .860 study, 13 had 70% of observations re- Blood pressure Systolic 96.91  13.49 98.15  14.73 .832 corded and were unable to be analyzed. Diastolic 51.18  5.69 55.38  6.53 .110 Several of these observations were beyond Temperature 37.2  0.58 36.94  0.81 .381 the limit of detection of the particular as- Respiratory rate 23.36  3.08 34  11.52 .006 say. Due to the small sample size of this Central venous pressure 9  3.92 11.45  3.88 .166 pilot study, sophisticated statistical meth- Oxygen saturation 92.36  23.68 99  1.58 .693 Near-infrared spectroscopy 62.09  21.31 70.15  8.77 .225 ods that can jointly model limit of detec- 24 hrs post-ICU admission: laboratory data tion with actual measurements could not pH 7.4  0.029 7.41  0.041 .510 be used. Of the remaining 17 markers, Pc o 43.86  3.13 37.15  12.66 .120 2 only CRP was found to be statistically sig- o Pa 2 156.79  47.94 143.4  95.11 .693 – nificant in the repeated-measures analy- HCO3 26.54  2.11 23.32  7.86 .225 Base excess 1.81  2.15 1.79  1.83 .980 sis (Table 4), with significantly lower CRP Lactate 0.94  0.21 0.886  0.36 .681 detected in the ketamine group at 24 hrs Glucose 103  10.41 96.62  31.75 .551 (45.28 [17.59] vs. 67.37 [31.67] mg/dL, K 3.76  0.3 3.8  0.49 .815 p  .048) and 48 hrs (62.22 [28.47] vs. Blood urea nitrogen 14.82  4.854 14.62  4.35 .915 Creatinine 0.3  0.078 0.323  0.073 .459 105.73 [48.62], p  .001) postoperatively Outcome (Figs. 3). Log-transformed results of the ICU stay (days) 3.28  1.33 3.01  1.01 .570 other 16 markers are shown in Table Ventilation time (hrs) 25.08  36.79 14  14.99 .340 4 and show no statistically significant Mortality (%) 0 0 differences. ICU, intensive care unit. Data are presented as mean  s d . DISCUSSION also. NAA/Cho increased after surgery in the NAA/Cr ratio in the controls (p  .009 Our pilot, prospective, randomized, both cases and controls, which reflected the in the-35 msec TE sequence) and altered double-blinded, placebo-controlled study reduction in Cho concentration (Table 3). the Glx/Cr ratio in the control group also sought to compare the plasma levels of In the BG, the Cr concentration in- (p  .03). NAA/Cr ratios were lower in biomarkers of CNS injury, inflammatory creased significantly in the postoperative both groups postoperatively in the 144- cytokines, clinical, radiologic, and neu- period in the control group (p  .017 in msec TE sequence (p  .036 in cases and rodevelopment outcomes of infants who 35-msec TE sequence), but there were no p  .003 in controls), while the Cr/Cho received ketamine vs. those who received significant differences noted in Cr con- ratios increased in the controls only (p  placebo before CPB. We found that ket- centration in the ketamine group follow- .016) (Table 3). amine use led to specific changes noted on ing surgery. This increase in Cr resulted We found no evidence of lactate in MRS and it decreased CRP levels but had no in a statistically significant decrease in any spectrum from either region, and no discernible effect on other plasma proteins.

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PCC_13.3.indb 331 4/23/2012 9:55:51 PM analgesia and surrogate biomarkers for generating hypotheses that can be tested formally in larger randomized, controlled trials. Randomized clinical trials can be designed only if perioperative variables have been identified and salient outcomes have been correlated with surrogate markers in lieu of reliable, reproducible, neurobehavioral assessments. Plasma bio- markers indicative of cellular injury, such as NSE and S100β proteins, changes in cerebral oxygenation measured noninva- sively by NIRS, and structural/biochemi- cal abnormalities detected by MRI/MRS, were the surrogate markers used in this pilot study (45). Differences were detected in some of the physiologic, laboratory, or clinical outcomes between the cases and con- trols (Tables 1 and 2). There was a sta- Figure 1. There was no statistically significant difference in the maximum expression of neuron- tistically significant difference noted in specific enolase in the cases (K) compared to controls (C) (p  .70). the mean preoperative oxygen require- ment between control and ketamine The results were not overtly suggestive of Neurobehavioral assessments of postop- (35% vs. 28%). The degree of cool- either a neuroprotective or neurotoxic ef- erative critically ill infants are difficult to ing achieved intraoperatively differed fect of the drug in this pilot study. perform and notoriously unreliable due between the two groups, and the The long-term effects of CPB-assisted to various comorbidities, young age, use temperature of patients in the post- surgery on neurodevelopmental out- of sedatives, analgesics, and occasionally, operative period on arrival in the ICU comes are increasingly a source of con- muscle relaxants. Based on preclinical was also different. Intraoperative hypo- cern, but the prediction or early detection data (1, 44), we designed this pilot trial to thermia is a well-known neuroprotective of these outcomes remains problematic. seek any associations between ketamine strategy to decrease CNS injury on CPB,

Table 3. Metabolite concentrations by treatment group and time point

Echo Control Ketamine Repeated-Measures Analysisa Times, Structure msec Metabolite Pre Post Pre Post Post Pre Ketamine Control

Frontal Cortex White 35 NAA 6.4 (0.6) 5.5 (0.9) 5.7 (0.8) 5.5 (0.7) .957 .176 .614 .026 Matter Cr 4.6 (0.4) 4.6 (0.5) 4.5 (0.5 4.5 (0.4) .723 .549 .904 .891 Glx 12.0 (1.6) 11.6 (1.4) 11.0 (0.9) 9.6 (0.4) .006 .203 .048 .663 NAA/Cr 1.4 (0.2) 1.2 (0.1) 1.3 (0.2) 1.2 (0.1) .741 .292 .403 .013 Glx/Cr 2.6 (0.4) 2.6 (0.5) 2.5 (0.2) 2.2 (0.2) .046 .592 .125 .940 144 NAA 11.1 (2.0) 10.1 (1.5) 10.6 (1.7) 10.2 (2.0) .902 .696 .525 .106 Cr 5.7 (0.6) 5.3 (0.8) 5.5 (0.8) 5.0 (0.9) .584 .697 .207 .286 Cho 3.1 (0.2) 2.6 (0.5) 3.3 (0.2) 2.9 (0.2) .106 .297 .006 <.001 NAA/Cr 2.0 (0.4) 1.9 (0.2) 1.9 (0.3) 2.0 (0.1) .503 .910 .588 .810 Cho/Cr 0.5 (0.0) 0.5 (0.1) 0.6 (0.1) 0.6 (0.1) .118 .300 .911 .441 NAA/Cho 3.7 (0.8) 4.0 (0.7) 3.3 (0.6) 3.5 (0.6) .331 .409 .012 .001 Cr/Cho 1.9 (0.1) 2.1 (0.5) 1.7 (0.2) 1.7 (0.3) .084 .420 .872 .243 Basal Ganglia Gray 35 NAA 7.2 (0.5) 7.2 (0.6) 7.3 (0.5) 6.9 (1.0) .508 .852 .334 .906 Matter Cr 5.4 (0.4) 6.2 (0.5) 6.1 (0.8) 5.8 (0.6) .308 .061 .453 .017 Glx 12.9 (1.2) 12.9 (1.9) 12.2 (1.9) 11.7 (2.0) .279 .548 .459 .977 NAA/Cr 1.4 (0.2) 1.2 (0.1) 1.2 (0.1) 1.2 (0.1) .740 .064 .693 .009 Glx/Cr 2.4 (0.3) 2.1 (0.3) 2.0 (0.3) 2.0 (0.2) .665 .031 .844 .030 144 NAA 17.0 (1.7) 15.4 (2.9) 16.6 (2.5) 15.1 (3.5) .889 .828 .090 .064 Cr 9.0 (0.7) 9.5 (1.3) 9.1 (0.6) 9.8 (1.6) .712 .851 .221 .341 Cho 4.2 (0.6) 3.9 (0.6) 4.6 (0.1) 4.3 (0.2) .114 .204 .148 .062 NAA/Cr 2.0 (0.2) 1.6 (0.2) 1.8 (0.2) 1.5 (0.2) .603 .166 .036 .003 Cho/Cr 0.5 (0.2) 0.4 (0.1) 0.5 (0.0) 0.4 (0.1) .550 .836 .176 .012 NAA/Cho 4.1 (0.7) 4.1 (0.9) 3.6 (0.5) 3.5 (0.9) .315 .368 .740 .912 Cr/Cho 2.0 (0.5) 2.5 (0.4) 2.0 (0.2) 2.3 (0.5) .436 .787 .086 .016

Pre, preoperative; Post, postoperative; NAA, N-acetyl aspartate; Cr, creatine; Glx, sum of glutamate and glutamine; Cho, choline. ap values reported are postestimation tests of change in the metabolite concentrations by: Post, ketamine vs. control postsurgery; Pre, ketamine vs. control presurgery; Ketamine, ketamine pre vs. post; Control, control pre vs. post.

332 Pediatr Crit Care Med 2012 Vol. 13, No. 3

PCC_13.3.indb 332 4/23/2012 9:55:52 PM and for every 1C decrease in brain tem- perature, cerebral metabolic rate decreases by 7% (46). Thus, the 2C mean difference between the controls and cases may have provided an additional protective effect to the control group and affected our post- operative results. The postoperative tem- perature on arrival in the ICU was higher in the ketamine group but did not consti- tute hyperthermia, and probably is reflec- tive of their higher mean intraoperative temperature. There were differences also noted in the postoperative values of the platelet count. Ketamine is known to inhibit platelet ag- gregation (47, 48) and thus may elevate the platelet count in the postoperative period. We compared the expression of plas- ma markers of CNS injury between cases and controls. S100β is an acidic calcium- binding protein found in high concen- tration in Schwann and glial cells, while NSE is a glycolytic enzyme localized in neurons and cells of neuroectodermal or- igin. Elevations of these proteins in blood and cerebrospinal fluid occur reliably in clinical scenarios associated with CNS injury, including CPB (49–61). Elevation of S100β and NSE are independent pre- Figure 2. The mean scores of the cases and controls showed no statistically significant differences on dictors of poor neuropsychological out- both components of the Bayley Scale of Infant Development (the mental developmental index ]MDI[ comes after surgery (62). We did not detect and psychomotor developmental index [PDI]). any statistically significant differences in

Table 4. Differences in 16 inflammatory markers by treatment group over timea

Baseline 0 Hours 6 Hours 24 Hours 48 Hours

Inflammatory Marker Control Ketamine p Control Ketamine p Control Ketamine p Control Ketamine p Control Ketamine p

log10 Eotaxin 1.72 (0.39) 1.79 (0.51) .640 1.96 (0.26) 2.03 (0.26) .666 1.43 (0.35) 1.47 (0.32) .860 1.70 (0.23) 1.59 (0.45) .463 1.69 (0.25) 1.69 (0.45) .963

log10 Granulocyte colony- 1.99 (0.23) 2.10 (0.19) .352 1.81 (0.23) 1.52 (0.53) .152 2.43 (0.22) 2.55 (0.31) .446 2.65 (0.66) 2.44 (0.43) .229 2.18 (0.42) 1.97 (0.41) .467 stimulating factor

log10 Granulocyte 1.01 (0.39) 0.81 (0.27) .203 0.79 (0.49) 0.67 (0.33) .479 0.87 (0.29) 0.80 (0.24) .491 0.85 (0.33) 0.71 (0.60) .251 0.90 (0.37) 0.73 (0.43) .255 macrophage colony- stimulating factor

log10 Monocyte chemotactic 1.67 (0.38) 1.64 (0.37) .834 1.76 (0.26) 1.77 (0.21) .960 1.80 (0.18) 1.90 (0.19) .286 2.00 (0.24) 1.96 (0.17) .66 1.92 (0.23) 1.81 (0.20) .269 protein-1

log10 Vascular endothelial 1.57 (0.20) 1.48 (0.22) .266 1.40 (0.27) 1.36 (0.18) .385 1.43 (0.26) 1.38 (0.21) .367 1.42 (0.24) 1.34 (0.27) .476 1.42 (0.35) 1.42 (0.27) .764 growth factor

log10 IL-1 2.27 (0.46) 2.22 (0.56) .779 2.36 (0.41) 2.15 (0.62) .288 2.44 (0.39) 2.16 (0.61) .179 2.37 (0.38) 2.08 (0.64) .183 2.42 (0.35) 2.07 (0.66) .136

log10 IL-1 receptor 2.10 (0.42) 2.09 (0.42) .959 2.13 (0.41) 2.21 (0.22) .785 3.20 (0.84) 3.22 (0.59) .922 2.82 (1.10) 2.71 (0.72) .645 2.37 (0.24) 2.44 (0.39) .754 antagonist

log10 IL-4 2.41 (0.48) 2.30 (0.57) .622 2.33 (0.52) 2.17 (0.76) .448 2.48 (0.52) 2.35 (0.56) .565 2.55 (0.47) 2.27 (0.60) .245 2.58 (0.49) 2.23 (0.65) .181

log10 IL-6 1.54 (0.29) 1.49 (0.54) .796 1.70 (0.41) 1.61 (0.41) .591 2.08 (0.29) 2.26 (0.24) .195 2.33 (0.39) 2.29 (0.14) .787 2.04 (0.34) 1.98 (0.17) .661

log10 IL-8 1.36 (0.19) 1.23 (0.44) .283 1.44 (0.31) 1.44 (0.28) .987 1.73 (0.24) 1.76 (0.15) .785 1.79 (0.42) 1.72 (0.22) .570 1.62 (0.23) 1.56 (0.28) .563

log10 IL-10 1.82 (0.27) 1.98 (0.41) .270 2.88 (0.47) 2.90 (0.48) .862 2.06 (0.27) 2.02 (0.31) .803 1.81 (0.36) 1.74 (0.28) .620 1.57 (0.30) 1.73 (0.41) .265

log10 IL-12p70 1.00 (0.45) 0.98 (0.28) .868 0.76 (0.22) 0.87 (0.26) .315 0.90 (0.29) 0.96 (0.27) .606 0.93 (0.39) 0.85 (0.21) .603 0.91 (0.39) 0.86 (0.24) .695

log10 IL-13 2.13 (0.24) 2.00 (0.47) .459 2.11 (0.37) 1.95 (0.58) .396 2.16 (0.40) 2.03 (0.49) .520 2.12 (0.38) 1.88 (0.69) .285 2.16 (0.37) 2.05 (0.46) .260

log10 Interferon gamma- 2.10 (0.55) 2.16 (0.41) .740 2.60 (0.26) 2.68 (0.38) .631 2.49 (0.55) 2.36 (0.44) .502 2.30 (0.75) 2.26 (0.47) .853 2.09 (0.55) 2.16 (0.43) .739 induced protein 10

log10 Macrophage 1.31 (0.26) 1.20 (0.24) .446 1.25 (0.50) 1.18 (0.27) .598 1.26 (0.21) 1.35 (0.51) .583 1.28 (0.30) 1.36 (0.54) .743 1.28 (0.20) 1.14 (0.40) .336 inflammatory protein-1

log10 Soluble CD40 ligand 3.50 (0.87) 3.20 (0.82) .245 3.49 (0.30) 3.45 (0.30) .895 3.36 (1.07) 3.41 (0.94) .862 3.15 (0.67) 3.21 (0.87) .869 3.38 (1.15) 3.25 (0.86) .736

IL, interleukin. aResults of linear contrasts estimated from a general linear mixed model are given as mean (s d ).

Pediatr Crit Care Med 2012 Vol. 13, No. 3 333

PCC_13.3.indb 333 4/23/2012 9:55:53 PM in Glx concentration in the frontal cortex was noted by investigators who adminis- tered , a NMDA receptor an- tagonist, to healthy volunteers (69). Since both ketamine and memantine block glutamate receptors, it is possible that this finding is a result of drug-receptor interaction leading to altered glutamate- glutamine metabolism. We also noted a statistically significant decrease in Cho levels in both groups postoperatively. A decrease in Cho lev- els is suggestive of decreased membrane turnover. This finding needs further cor- roboration. An elevated NAA level preop- eratively in the controls was also noted (42, 65). We saw no lactate in our spectra Figure 3. The geometric mean of the maximum expression of C-reactive protein was significantly lower and the NAA/Cr and NAA/Cho ratios were in cases (K) compared to controls (C) (58.41 mg/L [95% confidence interval 45.01-75.79] vs. 89.02 not suggestive of any hypoxic-ischemic mg/L [95% confidence interval 67.03-118.22]; p  .02). The mean C-reactive protein values were not injury occurring either before or after statistically significantly different at baseline among the cases and controls (3.46 vs. 3.71 mg/L, p  surgery. .96), post-cardiopulmonary bypass (CPB) (3.16 vs. 3.35 mg/L, p  .98) or at 6 hrs (5.28 vs. 7.88 mg/L, Although NIRS signals between the p  .669). However, there were significant differences noted at 24 hrs post-CPB (45.28 vs. 67.37 mg/L, two groups were not different, the post- p  .048) and at 48 hrs post-CPB (62.22 vs. 105.73, p  .001). operative sample entropy trended to be lower in the cases vs. controls. Entropy is the plasma levels of S100β or NSE. The brain and an important neurotrans- a measure of the disorder or chaos with- elevations in NSE and S100 levels were mitter while glutamine is its primary in a system. More ordered systems have low and similar to those seen in mild derivative and found primarily in astro- lower entropy. Anesthetic use has been traumatic brain injury (63, 64). These cytes. Increases in Glx levels are seen associated with lower entropy in electro- mild elevations may not provide enough with processes involving neuronal de- encephalogram measurements (70), but discriminatory power to serve as a use- struction (65). no previous data exist on entropy mea- ful outcome measure in a large random- A previously published study by Ashwal sures using NIRS values. This novel find- ized controlled trial. Hence no definitive et al (68) has shown that CPB reduces ing might represent a longer subclinical statement can be made about the drug’s MRS measures of NAA/Cr in gray matter anesthetic effect of ketamine. Ketamine neuroprotective effect based on these as- in children. However, in their study of 11 is extremely lipophilic (71) and it is pos- says, and other plasma biomarkers may patients, the decreased NAA/Cr ratio was sible that low levels of the drug remain in need to be included in future studies to a result of an absolute decrease in NAA the brain tissue for 24 hrs after surgery. detect CNS damage . only, while the Cr levels did not change However, we cannot speculate on the sig- MRS noninvasively provides biochem- significantly. The change in NAA/Cr ratio nificance of lower entropy on the CNS in ical information from small regions of seen in the BG in our patients appears to regards to protection or toxicity without the brain, and in our study we chose fron- be a combination of decreased NAA and an further data. tal cortex white matter and BG as areas increase in Cr concentrations postopera- We used the BSID-II to assess the ef- of interest based on our animal studies. tively. The increase in Cr concentration fects of ketamine on cognitive, language, Commonly measured metabolites in- was statistically significant in the control and motor development by performing clude NAA, Cr, Cho, and Glx (65). NAA is group postoperatively in the BG, but this preoperative and postoperative assess- almost exclusively localized in neurons increase did not occur in the cases, which ments in the two randomized groups. and its decrease is seen in processes in- suggests that there were differences in en- The BSID-II has only a moderate corre- volving neuronal or impaired neuronal ergy metabolism between the two groups. lation with tests of general cognition in function. Cr is a marker of brain energy The clinical significance of these findings preschool children (72). We saw no sta- metabolism and is considered an inter- is not clear and warrant further investiga- tistically significant differences between nal standard due to its stable levels, but tion. No other major difference was noted the two groups, although slight improve- its levels can either increase (bipolar in the concentration of metabolites in ments occurred in BSID-II subscales in disorder, trauma, hyperosmolar, age) or the BG. There were differences noted in the ketamine group. Our postoperative decrease (stroke, hypoxia, progressive some of the metabolite ratios, such as a testing occurred only 2–4 wks after sur- multifocal leukoencephalopathy, neo- significantly increased Cr/Cho ratio in the gery and therefore may reflect a very plasia, etc) under certain conditions (66, controls postoperatively, and an increase brief period of CNS development. Future 67). Cho levels are inherently linked to in the Glx/Cr ratio in the preoperative studies must examine the intermedi- changes in cell membrane biochemistry controls. ate and long-term effects of ketamine and its elevation is considered a marker In the frontal white matter, we found a anesthesia on cognitive outcomes, par- of myelin breakdown. Glx is a composite significant decrease in the Glx level in the ticularly on the frontal lobe-dependent of glutamate and glutamine. Glutamate ketamine group postoperatively on the executive functions, among infants sub- is the most abundant amino acid in the 35-msec TE sequences. A similar decrease jected to surgery requiring CPB using a

334 Pediatr Crit Care Med 2012 Vol. 13, No. 3

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