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Departments of *Anesthesiology,
Neuropsychology, and
Laboratory Medicine, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Belgium
Address correspondence and reprint requests to Nagels Werner, MD, Department of Anesthesiology, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Belgium. Address e-mail to werner.nagels{at}skynet.be
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Abstract |
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IMPLICATIONS: N-methyl-D-aspartic acid receptors play an important role during ischemic brain injury. We could not demonstrate that S(+)-ketamine resulted in greater neuroprotective effects compared with remifentanil during cardiopulmonary bypass procedures when both were combined with propofol.
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Introduction |
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S(+)-ketamine reduces postischemic neuronal cell loss in the cortex (8) and improves neurological outcome after cerebral ischemia in rats (9). Himmelseher et al. (10) demonstrated that S(+)-ketamine protects neurons after glutamate damage. Arrowsmith et al. (11) demonstrated a small beneficial effect on cognitive performance with remacemide, also a N-methyl-D-aspartic acid (NMDA)-receptor antagonist, after cardiac surgery, although there was no difference in the frequency of cognitive decline.
Racemic ketamine in combination with propofol during cardiac surgery is associated with a stable hemodynamic profile (12). The sympatho-adrenergic and hemodynamic effects of S(+)-ketamine and racemic ketamine are generally identical (13). The aim of the present study was to evaluate whether S(+)-ketamine has neuroprotective effects during open-heart surgery through the use of neurocognitive tests.
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Methods |
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The patients had to Dutch speaking, aged between 18 and 75 yr old, and undergoing elective, primary open-heart procedures. Patients who were only scheduled for primary coronary bypass operations were not included. Patients with previous valve or coronary bypass surgery, epilepsy, psychiatric, and other cerebral disorders, hepatic impairment (aspartate aminotransferase or alanine aminotransferase more than twice the upper limit of normal value), renal failure (creatinine >2 mg/dL), drug abuse, alcohol dependence, and endocrine disease except diabetes and controlled thyroid dysfunction were excluded.
The volunteers for the study were randomized by using closed envelopes containing a note that allocated the patient to the control or S(+)-ketamine group. One closed envelope was drawn and opened by the anesthesiologist an hour before surgery.
The patients and those investigators performing the pre- and postoperative neuropsychometric assessments were blinded to the group assignment. Only the physicians involved in the intraoperative care of these patients were aware of the treatment group.
All patients were premedicated with lorazepam 0.05 mg/kg sublingually 1 h before surgery. An arterial and two large bore venous catheters were inserted under local anesthesia. After the induction of anesthesia, a central venous and pulmonary artery thermodilution catheters were inserted.
The control group received a plasma concentration target controlled infusion (TCI) of remifentanil and a TCI of propofol targeted at 6–14 ng/mL and 1–4 µg/mL, respectively. A portable computer with the pharmacological software program RUGLOOP©, version 3.05 (written by T. De Smet and M. Struys, Ghent University Hospital, Ghent, Belgium) was used to control the remifentanil infusion pump (Graseby® 3500 syringe pump, SIMS Graseby Ltd., Herts, England). The pharmacokinetic variables were obtained from Minto’s model (14). Propofol (Diprivan® 1%, Zeneca, Billingham Cleveland, United Kingdom) was administered with an IVAC-TCI pump® (Alaris® Medical Systems, Hampshire, United Kingdom). Induction was started with a calculated plasma concentration of remifentanil 6 ng/mL. This was increased to at least 8 ng/mL before tracheal intubation and 10 ng/mL before sternotomy. At the start of cardiopulmonary bypass (CPB), remifentanil was decreased to 8 ng/mL.
In the S(+)-ketamine group, a bolus of S(+)-ketamine (Pfizer, Karlsruhe, Germany) 2.5 mg/kg was administered, followed by an infusion of 125 µg · kg–1 · min–1. This infusion rate was maintained throughout the whole procedure. These patients also received a TCI propofol infusion at a variable rate between 1 and 4 µg/mL, depending on the patient’s mean arterial blood pressure (MAP).
Before CPB, the MAP was maintained between 50 and 100 mm Hg by changing remifentanil and propofol target concentrations in the allowed range or by administering phenylephrine, ephedrine, or isosorbide dinitrate as required.
In both groups, the target plasma concentration of propofol was decreased to 1 µg/mL at the start of CPB.
In both groups, cisatracurium 0.2 mg/kg was used to induce neuromuscular blockade. All patients were tracheally intubated 5 min after the beginning of the induction. After tracheal intubation, the lungs were ventilated with a mixture of air and oxygen.
The CPB apparatus consisted of a membrane oxygenator (Medos®, Medizintechik AG, Stolberg, Germany), a roller pump (Stockert Instrumente, Munich, Germany), and a 37-µm arterial filter (Affinity®, Medtronic, Minneapolis, MN). Extracorporal circulation was initiated after heparin 300 U/kg was administered. The patients were cooled to 28°C–32°C, and a nonpulsatile blood flow was maintained at 2–2.4 L · min–1 · m–2. Alfa-stat blood-gas management was used. During CPB, phenylephrine, noradrenaline, or isosorbide dinitrate was used to maintain the MAP between 50 and 90 mm Hg if changing the propofol or remifentanil target concentration during CPB was not sufficient to achieve these values. A NIH-2 myocardial protection solution was used for retrograde blood cardioplegia or antegrade crystalloid cardioplegia. If the blood sugar level increased to more than 200 mg/dL, an insulin infusion was started.
The patients were rewarmed to at least 36°C rectal temperature for weaning of CPB. The blood temperature of the arterial inflow was limited to 37.5°C. Increases of the core temperature more than 37°C were avoided. Inotropes were used when required.
At the end of surgery, the patients were transferred to the intensive care unit (ICU). Sedation was maintained with a propofol infusion. At the end of the procedure, patients from the control group received a bolus dose of piritramide (0.1–0.2 mg/kg) followed by an infusion (4 mg/h). In the S(+)-ketamine group, piritramide was only administered in the ICU when required. Tracheal extubation was performed as soon as the local criteria were met. All patients had routine ICU care.
The plasma S(+)-ketamine concentration was measured in blood samples of 11 patients chosen randomly. The blood samples were taken just before aortic cannulation, 20 min after the beginning of CPB, at the end of CPB, at the end of surgery, and 24 h after CPB. The blood samples were immediately sent to the laboratory and centrifuged. The plasma was stored at –20°C.
The S(+)-ketamine concentrations were determined using a gas chromatography and mass spectrometry method developed and validated in the laboratory of our hospital. Twenty microliters of internal standard solution (naphazoline nitrate, Hoechst Marrion Roussel, Romainville, France) was added to 200 µL of plasma sample, giving a final concentration of 20 µg/mL of naphazoline. Samples were alkalinized by addition of 20 µL of 25% ammonia and 20 µL of ammoniacal buffer with a pH value of 9.5. Extraction was performed by the addition of 400 µL of butylchloride and vigorous mixing, followed by centrifugation. Two hundred microliters of the organic phase supernatant was removed, evaporated under nitrogen flow, and redissolved in 200 µL of methanol. One microliter of the sample was injected (split mode, 1:40) onto a Finnigan GCQ gas chromatograph equipped with a J&W DB-5 ms column (Finnigan Matt, San Jose, CA). A mass spectrum scan was used for identification and quantification. Finnigan GCQ Data Processing software was used for the calculation of the concentrations.
Neuropsychological assessments were performed before surgery (the day before surgery), 1 wk, and 10 wk after surgery. These were done by two highly trained nurses who were blinded to the patient’s group assignment. The neuropsychological test battery assesses a broad array of cognitive domains (Table 1). The tests have been recommended by a previous consensus statement (15). Immediate memory and long-term memory scores were calculated for the Rey Auditory Verbal Learning Test. The former test score is the average number of words remembered during the first five exercises, and the latter one was calculated by subtracting the number of words remembered 20 min after the last exercise had ended from the number of words remembered during the fifth exercise.
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The prebypass cardiovascular stability with S(+)-ketamine was investigated in 14 consecutive patients. The heart rate, MAP, and systolic and diastolic arterial blood pressures were measured before tracheal intubation, before laryngoscopy, 2 min after tracheal intubation, 2 min after incision, and 2 min after sternotomy. Phenylephrine and ephedrine consumption were noted.
It was estimated that 35% of the patients would suffer from 2 or more deficits 10 wk after surgery. A sample size of 100 patients was calculated to detect a reduction to 12% (three times fewer patients affected).
The StatView® 4.5 software package (Abacus Concepts, Berkeley, CA) for Apple® was used for statistical analysis. Unpaired Student’s t-test or Mann-Whitney U-test was used for the comparison of continuous variables between the two groups. Proportions were analyzed by using the 
2 or Fisher’s exact tests. P < 0.05 was considered significant.
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Results |
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Discussion |
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We used Z-scores and deficits to evaluate the neuropsychological status of the patients. The negative Z-scores in both groups after 1 week reflect a cognitive decline, probably because of a combination of neurological injury, use of analgesics, sleep deprivation, recovery from major surgery, and the hospital environment. After 10 weeks, the Z-scores were slightly positive in the S(+)-ketamine and control group because of neurological recovery and practice effects. The better results on the Trailmaking B test in the S(+)-ketamine group are probably caused by chance. The number of patients with two or more deficits were not statistically different between groups. The disadvantage of using deficits is that it involves a somewhat arbitrary convention (17). The more tests that are used, the more deficits to be expected. This kind of analysis also compares an individual’s change with the group norm (18). Actually, there is no universally accepted method of analyzing neurocognitive test results (3).
Ketamine binds to the phencyclidine binding site of the NMDA receptor (19). This receptor also has binding sites for glutamate and glycine and incorporates an ion channel that is permeable to calcium and sodium (20). S(+)-ketamine is a noncompetitive NMDA receptor antagonist and the dextrorotatory enantiomer of racemic ketamine. S(+)-ketamine is 1.9–3.6 times as potent as the R(-)-enantiomer (21) and has a greater clearance rate (22). S(+)-ketamine may decrease the severity of cerebral ischemic injuries by several mechanisms. First, S(+)-ketamine may prevent necrotic cell death by preventing excitotoxic injury (10). Ischemic neurons release glutamate into the extracellular space, which leads to overactivation of NMDA receptors. Increased intracellular calcium levels are produced that cause cell death (23). The glutamate-calcium overload hypothesis is recognized as a prominent mechanism in neuronal injury in the ischemic brain, although it is not the only cause of neuronal cell loss (24). Second, S(+)-ketamine may influence apoptosis. Apoptosis may be the consequence of less severe cerebral ischemia and leads to a slow cell death. Engelhard et al. (25) have shown that S(+)-ketamine mediates changes in apoptosis-regulating proteins. Third, S(+)-ketamine may interfere with the inflammatory response to cardiac surgery. The inflammatory response is believed to play a role in the development of neurologic injury after CPB (26). Ketamine attenuates the interleukin-6 (IL-6) response after CPB (27). Ketamine also suppresses lipopolysaccharide-induced tumor necrosis factor 
, IL-6, and IL-8 production (28). Szekely et al. (29) showed that S(+)-ketamine reduces postischemic adherence of neutrophils in the coronary system of isolated guinea pig hearts. Inhibition of polymorphonuclear neutrophils adherence protects the reperfused heart by limiting the coronary vascular leak after ischemia. A similar mechanism in the brain might be of importance during transient cerebral ischemia.
The results of several human clinical trials with NMDA antagonists administered for ischemic brain injury have been disappointing. It has only been shown that remacemide for CPB procedures had a positive secondary outcome, although its primary outcome was negative (11). NMDA receptor overactivation is important during focal brain ischemia, but it is not a predominant mechanism.1 Alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptors also play a major role during glutamate-induced excitotoxicity (30). Synaptically released zinc, which might be analogous to glutamate, may contribute to ischemic brain injury (31).
There are many pitfalls in the evaluation of neuroprotective therapies (32). The most important issues concerning CPB trials are that preclinical studies concentrate on the protection of gray matter and rely on infarct sizes and early outcomes to judge therapeutic efficacy. Clinical trials rely on behavioral outcomes and late assessment. The optimal duration of the administration of a neuroprotective drug is also unknown. Another problem is that experimental stroke models are homogenous, whereas human stroke or ischemia events are heterogenous. The choice of outcome measures is also not clear, although a recommended core neuropsychologic test battery has been suggested (15).
Patients undergoing cardiac surgery are probably not the best patient population for the study of neuroprotective effects of S(+)-ketamine. It is believed that the insult during cardiac surgery is caused by embolic showers to the brain superimposed by an inflammatory response (33). A well conducted CPB is not associated with brain ischemia per se. Cerebral vasoconstriction with reduction of embolic burden is thought to be the reason for the neuroprotective effect of alpha-stat as opposed to pH-stat blood gas management during CPB (3). S(+)-ketamine is a cerebral vasodilator and therefore may impose a greater embolic burden on the brain at the time of aortic cross-clamp release, when the brain has just been rewarmed and is probably most vulnerable to injury. This could have negated any neuroprotective effects of its NMDA-antagonism or its antiinflammatory action. It is possible that the combination of propofol and ketamine did not cause cerebral vasodilation, but without transcranial Doppler or some measurement of the magnitude of the embolic burden, there is no way to prove that.
In this study, we compared the effects of the combination S(+)-ketamine-propofol versus remifentanil-propofol on the neurocognitive status after CPB. We did not investigate the neurocognitive protective effects of S(+)-ketamine per se. Propofol may reduce the delivery of microemboli to the cerebral circulation by decreasing the cerebral blood flow (34). It has also been suggested that propofol has a direct neuroprotective effect in vitro (35), although Roach et al. (36) could not demonstrate a protective effect of propofol during open-heart surgery. Propofol enhances the antiinflammatory response to surgery by several mechanisms (26). This might have masked a neuroprotective effect of S(+)-ketamine because propofol was administered in both groups.
The infusion regimen we used provided large S(+)-ketamine plasma concentrations. McLean (37) obtained serum concentrations of the less potent racemic ketamine mixture that were smaller but already considered as neuroprotective. The brain tissue concentrations are likely to be larger than the plasma concentrations because of the high lipid solubility of S(+)-ketamine. During a five-hour procedure (induction until transfer to ICU), a total dose of 40 mg/kg of S(+)-ketamine was administered. This is a very large dose in a clinical setting. Reeker et al. (9) infused 90 mg/kg of S(+)-ketamine in their laboratory investigation with a positive neurological outcome after brain ischemia in rats. Such a massive dose cannot be used in a normal clinical practice. Although the postoperative data (ICU stay, duration of intubation, and hospital stay) for S(+)-ketamine were not statistically different from the control group, larger doses of S(+)-ketamine for clinical use are probably not recommended because psychic emergence reactions and increased sedation may occur (38).
Piritramide is a 4-amino piperidine derivative and has full µ-receptor agonist activity (39). It is probably slightly less potent than morphine and may have a less frequent incidence of nausea and vomiting. The patients in the S(+)-ketamine group did not receive a bolus of piritramide after surgery because this would not add any analgesic benefit because of the high plasma levels of S(+)-ketamine and would only delay the time of tracheal extubation. Although the initial postoperative analgesia treatment was different between the two groups, we do not think that this influenced our results. It has never been shown that piritramide has any neuroprotective effects, and postoperative pain was not a problem in the S(+)-ketamine group; however, we did not collect these data systematically.
The combination of S(+)-ketamine with propofol can be a suitable technique during heart valve surgery, but the intubation response is not always completely blunted. A retrospective analysis of the cardiovascular data could not demonstrate a difference in adverse events (arrhythmias, conduction abnormalities, and ischemia) between the 2 groups. S(+)-ketamine must be used with caution in severely compromised patients, but we do not think that the cardiovascular effects of S(+)-ketamine were of major importance in the neurocognitive outcome of the patients.
There are several other limitations to this study. We have not included the level of education in our evaluation, and the mean age of the patients is rather young. Older patients have an increased risk of developing neurocognitive problems after cardiac surgery (7). It was not possible to blind the anesthesiologist for the treatment that was given during surgery, and this may have introduced the potential for bias. The limited test battery we used a week after surgery is another potential limitation, although it may be very demanding for the patient to accomplish a large number of tests in the early postoperative period. This may influence the results and make the tests more difficult to interpret. The same S(+)-ketamine infusion regimen was used in all patients, but the S(+)-ketamine concentrations were only measured in a small portion of patients. Therefore, we cannot assure that a proper treatment was given to all patients. The final end-point, a neurocognitive evaluation 10 weeks after surgery, may also be a shortcoming of the study. It may be that the potential neuroprotective effects of S(+)-ketamine may only appear many months or even years after surgery.
Another limitation could be the number of patients used in this study. The actual proportion of patients with 2 or more deficits was less than estimated for the calculation of the sample size. It is difficult to determine the sample sizes in studies evaluating the neuropsychological outcome after CPB procedures. There are no standard outcome measures to be used for calculating the required number of patients, and it is not known which differences are clinically relevant. Data obtained in one center may not be relevant in another one. Some investigators may argue that thousands of patients are required to evaluate the neuroprotective properties of drugs. To detect a reduction of 25%–20% in the incidence of people with 2 or more deficits, more than 2000 patients would be required to achieve a power of 80% ( = 0.05, two-sided). However, a statistical difference does not always represent a clinically important difference. A study with 88 patients demonstrated that lidocaine decreases the occurrence of cognitive dysfunction in the early postoperative period after CABG surgery (40). In our study, we were not able to show any obvious neuroprotective effects of S(+)-ketamine. Although our study results do not suggest the presence of a major protective effect on neurocognitive function during CPB procedures, a large, well-powered trial could be considered to assure that S(+)-ketamine truly lacks any neuroprotective properties in this clinical setting.
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Acknowledgments |
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Footnotes |
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References |
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2-agonist dexmedetomidine and the NMDA antagonist S(+)-ketamine on the expression of apoptosis-regulating proteins after incomplete cerebral ischemia and reperfusion in rats. Anesth Analg 2003; 96: 524–31.This article has been cited by other articles:
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  C. Neuhauser, V. Preiss, M.-K. Feurer, M. Muller, S. Scholz, M. Kwapisz, M. Mogk, and I. D. Welters Comparison of S-(+)-ketamine- with sufentanil-based anaesthesia for elective coronary artery bypass graft surgery: effect on troponin T levels Br. J. Anaesth., June 1, 2008; 100(6): 765 - 771. [Abstract] [Full Text] [PDF]
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 I. Szalma, A. Kiss, L. Kardos, G. Horvath, E. Nyitrai, Z. Tordai, and L. Csiba Piracetam prevents cognitive decline in coronary artery bypass: a randomized trial versus placebo. Ann. Thorac. Surg., October 1, 2006; 82(4): 1430 - 1435. [Abstract] [Full Text] [PDF]
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S. Shibuta, S. Varathan, and T. Mashimo Ketamine and thiopental sodium: individual and combined neuroprotective effects on cortical cultures exposed to NMDA or nitric oxide Br. J. Anaesth., October 1, 2006; 97(4): 517 - 524. [Abstract] [Full Text] [PDF]
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 S. Himmelseher and M. E. Durieux Revising a Dogma: Ketamine for Patients with Neurological Injury? Anesth. Analg., August 1, 2005; 101(2): 524 - 534. [Abstract] [Full Text] [PDF]
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