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Anesthesia & Analgesia:
doi: 10.1213/ANE.0b013e3182662e30
Analgesia: Research Reports

Does Intraoperative Ketamine Attenuate Inflammatory Reactivity Following Surgery? A Systematic Review and Meta-Analysis

Dale, Ola MD, PhD*,†,‡; Somogyi, Andrew A. MSc, PhD*; Li, Yibai BHSc (Hon)*; Sullivan, Thomas BMa, CompSc (Hon); Shavit, Yehuda PhD*,¶

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From *Discipline of Pharmacology, Faculty of Health Sciences, University of Adelaide, Adelaide, Australia; Department of Circulation and Medical Imaging, Pain and Palliation Research Group, Norwegian University of Science and Technology, Trondheim, Norway; Department of Anaesthesia and Emergency Medicine, St. Olav's University Hospital, Trondheim, Norway; Discipline of Public Health, Faculty of Health Sciences, University of Adelaide, Adelaide, Australia; Department of Psychology, Hebrew University, Jerusalem, Israel.

Funding: Departmental funds.

The authors declare no conflict of interest.

Reprints will not be available from the authors.

Address correspondence to Ola Dale, MD, PhD, Department of Circulation and Medical Imaging, NTNU, Box 8095 MTFS, N_7491 Trondheim, Norway. Address e-mail to Ola.Dale@ntnu.no.

Accepted June 4, 2012

Published ahead of print July 23, 2012

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BACKGROUND: Reports regarding the ability of the anesthetic drug ketamine to attenuate the inflammatory response to surgery are conflicting. In this systematic review we examined the effect of perioperative ketamine administration on postoperative inflammation as assessed by concentrations of the biomarker interleukin-6 (IL-6).

METHODS: This study was based on a systematic search in PubMed, Scopus, Web of Knowledge, and the Cochrane Library. English written randomized controlled trials conducted in humans were eligible. To be included in the analysis, outcome had to relate to inflammation or immune modulation. Each study was reviewed independently by 2 assessors. Data were analyzed according to the GRADE's approach and reported in compliance with the PRISMA recommendations.

RESULTS: Fourteen studies were eligible for evaluation (684 patients). Surgery was performed under general anesthesia, and ketamine was given before or during the surgery in varied doses Eight studies involved cardiopulmonary bypass operations, 4 were for abdominal surgery, 1 thoracic surgery, and 1 cataract surgery. Three studies were deemed of low quality. Nine studies measured IL-6 concentrations within the first 6 hours postoperatively; but in 3 studies, other potent anti-inflammatory drugs were used as premedication or during the operation; thus 6 studies (n = 331) were included in the meta-analysis. Using postoperative IL-6 concentrations as an outcome, ketamine had an anti-inflammatory effect; the meta-analysis showed a mean preoperative–postoperative IL-6 concentration difference (95% confidence interval) of −71 (−101 to −41) pg/mL.

CONCLUSIONS: It can be concluded that intraoperative administration of ketamine significantly inhibits the early postoperative IL-6 inflammatory response. Future studies should further examine the anti-inflammatory effect of ketamine during major surgery, determine whether ketamine treatment alters functional outcomes, elucidate the mechanisms of its anti-inflammatory effect, and suggest an appropriate dosing regimen.

Major surgery invariably evokes the inflammatory response. It has been shown that the extent of systemic inflammatory response in cardiac surgery is associated with the outcome of the intervention.13 For instance, increased serum concentration of interleukin 6 (IL-6, a major proinflammatory cytokine) has been associated with postoperative left ventricular wall motion abnormalities and myocardial ischemic episodes,3 perioperative complications,3 and postoperative hyperdynamic instability.1 IL- 6 concentrations were correlated with postoperative morbidity and mortality in children after an open-heart surgery,4 as well as with the severity of adult respiratory distress syndrome.5 It has become increasingly appreciated that in the perioperative period, circulating concentrations of cytokines may play an important role in surgery outcome and therefore should be controlled. Indeed, several tactics have been used by clinicians to curb perioperative cytokine response.6

Strategies used in the past to reduce the systemic cytokine response include treatment with glucocorticoids or with the serine protease inhibitor aprotinin.2,6 Another strategy is to use anesthetic or subanesthetic doses of general anesthetics or opioids with potential anti-inflammatory effects.712 The results of multiple studies on the systemic anti-inflammatory effects of fentanyl79 or morphine10 are conflicting, and single studies on sevoflurane11 or propofol12 indicate anti-inflammatory effects at anesthetic doses of these drugs. Notably, local anesthetics (LA) are the most widely studied anesthetic drugs with clinically relevant endpoints. Hollmann and Durieux13 reviewed the anti-inflammatory effects of LA, and Herroeder et al.14 provided evidence that the frequently shown beneficial effects of LA on gastrointestinal recovery after surgery are most likely due to a potent modulatory effect of the proinflammatory response.

Among the general anesthetics, ketamine is the most widely studied in the search for strategies to modulate systemic perioperative cytokine response. Ketamine is a potent anesthetic and analgesic drug. When administered IV during anesthesia in adults, ketamine decreased postoperative pain intensity for up to 48 hours, decreased cumulative 24-hour morphine consumption, and delayed the time to first request of rescue analgesic.15 On the basis of current recommendations for ketamine, there is level I evidence for an opioid- sparing effect and level II evidence for antihyperalgesic and opioid tolerance–protecting effects and for reduction in chronic postsurgical pain.16

The effect of ketamine on perioperative inflammatory responses has been studied in patients undergoing cardiac operations under cardiopulmonary bypass (CPB), off-pump cardiac surgery, hysterectomies, and abdominal surgery. Doses ranged from a small supplemental single bolus dose and up to full ketamine anesthetic doses, either with racemic drug or the pharmacologically more active S-(+)-ketamine. Ketamine has been found to act as an immune modulator. Furthermore, it has been argued that ketamine is a unique, specific anti-inflammatory drug,17 which inhibits the systemic response without affecting local healing processes.

It has been suggested that ketamine's anti-inflammatory activity might be mediated by suppression of microglia activation, as demonstrated by inhibition of extracellular signal-regulated kinase 1/2 phosphorylation in primary cultured microglia,18 or by inhibition of large-conductance Ca2+-activated K+ channels in microglia.19 Taken together with the findings that microglia respond to endogenous (e.g., heat shock protein) and exogenous (e.g., stress, infection, drugs) inflammation signals by producing proinflammatory cytokines (e.g., IL-1β, IL-6, tumor necrosis factor [TNF]α) and thus inducing hyperalgesia,20 this provoked renewed interest in the potential anti-inflammatory effects of ketamine. Although it is generally believed that ketamine has anti-inflammatory action in humans, the evidence has not been critically evaluated.

The aim of this systematic review was to evaluate the anti-inflammatory effect of ketamine in surgical patients in the early postoperative period based on randomized controlled trials (RCT) in which ketamine was used as part of the intervention. The effect of ketamine on systemic exposure of the cytokine IL-6 was of special interest because its plasma concentration serves as a useful and reliable biomarker of systemic inflammation.21

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A systematic search was performed in PubMed, Scopus, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) up to October 13, 2011. In addition the reference lists of the retrieved full articles were searched.

The following search strategy combining free text and MeSH terms (ME) was set up for PubMed:

(ketamine[tw] OR ci 581[tw] OR ci581[tw] OR ketaset[tw] OR ketanest[tw] OR kalipsol[tw] OR calypsol[tw] OR ketalar[tw]) AND (Anti-inflammatory agents[mh] OR inflammat*[tw] OR antiinflammat*[tw] OR nsaid*[tw] OR antirheumatic*[tw] OR anti rheumatic*[tw] OR cyclooxygenase inhibitor*[tw] OR cyclo oxygenase inhibitor*[tw] OR cyclooxygenase 2 inhibitor*[tw] OR cyclo oxygenase 2 inhibitor*[tw] OR cox 2 inhibitor*[tw] OR coxib*[tw] OR neutrophil*[tw] OR interleukin*[tw] OR tumor necrosis factor*[tw] OR tumor necrosis factor*[tw] OR ((“Receptors, N-Methyl-D-Aspartate”[Mesh] OR NMDA-receptor*) AND (antagonis* OR inhibitor* OR inhibiting OR blocking)) OR proinflammat* OR antiproinflammat* OR Cytokines[mesh:noexp]) AND (ex vivo[tw] OR in vivo[tw] OR double-blind method[mh] OR single-blind method[mh] OR clinical trial[pt] OR trial[tiab] OR ((singl*[tiab] OR doubl*[tiab] OR trebl*[tiab] OR tripl*[tiab]) AND (mask*[tiab] OR blind*[tiab])) OR placebos[mh] OR placebo*[tiab] OR random*[tw] OR research design [mh:noexp] OR comparative study[pt] OR evaluation studies as topic[mh] OR “Evaluation Studies” [pt] OR follow-up studies[mh] OR prospective studies[mh] OR control[tw] OR controlled[tw] OR prospectiv*[tw] OR volunteer*[tw] OR group[tiab] OR groups[tiab] OR systematic[sb]) NOT(animals[mh] NOT human[mh])

A similar search strategy was set up for CENTRAL, Scopus, and Web of Science, with search terms adapted to specific terminology and indexing characteristics. In the updating search March–October 2011 Embase was used instead of Scopus. A detailed account of the searches can be obtained from O. Dale.

Inclusion criteria included the following: English written RCT conducted in humans were eligible. Ketamine had to be part of the intervention, and study outcomes had to relate to inflammation/immune modulation. If the primary outcome was not a clinical measure, any surrogate outcomes had to be measured directly in a biological sample (in vivo), or resulting from manipulation of such a sample (ex vivo). If eligibility could not be determined from the title of the study or its abstract, the full paper was retrieved. During the search process, several relevant publications in Chinese were identified. These were preliminarily reviewed by one of the authors (Y.L.) with native knowledge of Chinese.

The following were summarized in a data extraction form: publication details, study design and limitations, patient population details, settings, interventions, validity of methods for assessing outcomes, results, internal and external validity, and narrative summary of the main findings. Each study was reviewed and rated independently by 2 assessors (O.D. and Y.S.). The internal validity of each RCT was assessed using a checklist adapted from the criteria recommended in the National Health Service Centre for Reviews and Dissemination guidance document,22 as described earlier.23 Data were analyzed in accordance with the GRADE's approach,24 which includes reporting of an evidence profile for the outcome. This profile consists of the number and type of eligible studies, number of participants, study limitations, consistency, directness, precision, publication bias, and factors that might increase quality of evidence. On this basis a recommendation was given. Finally, the process was reported in accordance with the PRISMA requirements (www.prisma-statement.org/), although the review protocol was not registered as recommended.

On the basis of the evaluation process, we conducted a meta-analysis on the most consistently reported outcome, plasma concentrations of IL-6 within the first 6 postoperative hours. Pre- to postoperative changes in plasma or serum IL-6 concentrations were extracted for each randomized group within each study. The precise data for postoperative IL-6 concentration were not reported by Zeyneloglu et al.,25 Bartoc et al.,26 and Cho et al.27 but were collected by consulting the authors by e-mail. Differences between groups (ketamine vs control treated) were then pooled using a random effects meta-analysis model according to the DerSimonian–Laird method.28 Heterogeneity in mean differences was assessed using the I-squared statistic29 and a χ2 test of goodness of fit. Publication bias in the meta-analysis was assessed visually using a funnel plot.30

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Ketamine had an anti-inflammatory effect based on the 6 studies included in the meta-analysis (Table 1, Figs. 1 and 2) when using postoperative plasma/serum IL-6 as an outcome. The overall mean (95% confidence interval [CI]) difference was −71 (−101 to −41) pg/mL (P < 0.001). No dose response was observed. The degree of heterogeneity was high when all studies were pooled (I-squared = 91.1%), but low for the CPB studies (I-squared = 0.0%). Using Egger's funnel plot,30 we observed no sign of publication bias. Including the studies in which a potent anti-inflammatory drug was given25,31,32 in the meta-analysis (results not shown) did not abolish the major finding, although the mean effect estimate (95% CI) was reduced to −50 (−75 to −25) pg/mL.

Table 1
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In total, the search for relevant studies yielded 1187 + 136 (original + additional search, respectively) records as follows: PubMed (148 + 28), Scopus/Embase (925 + 82), CENTRAL (0), and Web of Science (114 + 26) (Fig. 1). No additional records were identified through other sources, and 1033 + 113 records remained after removing duplicates. Removing 10 records (articles written in non-English languages—Chinese [6], German [2], Spanish [1], and Japanese [1]), left 1136 records for screening. A total of 1083 + 13 records were removed on the basis of their titles or after reading the abstract when deemed necessary. Forty full-text articles were retrieved, and 26 were not rated eligible for further analysis.

Since one of the authors (Y.L.) is native Chinese, and since 5 of the Chinese publications were relevant to the aim of this review, these publications underwent a separate evaluation (was not included in the primary evaluation, but as a supplement), as described under Methods.

The 14 studies eligible for evaluation included 684 patients. In all (except for 2 studies including 3 groups26,33), 2 groups were compared. Ten studies were double-blind, 2 single-blinde34,35 (one did not report this originally,35 but confirmed single-blinding upon request), and 2 of the studies were open.25,33 Three studies31,34,36 reported patient flow according to CONSORT agreement. All but 2 studies25,32 were conducted in adults. In 7 studies, CPB was used; in another, cardiac surgery was conducted off-pump27; 4 studies included major abdominal operations35,37,38; 1 thoracic surgery36; and in 1,33 cataract surgery was performed. All patients underwent surgery under general anesthesia, except one group in Tu et al.'s study,33 and a varying number of patients who received epidural anesthesia in the control and interventions groups in D'Alonzo et al.'s study.36 Total subject numbers varied from 24 to 142 patients, with the sample size justified in 6 studies.2527,31,34,36 One of the studies had a clinical primary outcome (neurodevelopment),32 12 measured surrogate outcomes such as markers of inflammations directly in blood samples, and 2 measured similar outcome in “stimulated” blood samples (ex vivo).35,39 All studies (except for Akhlag et al.40 and Zilberstein et al.39) measured IL-6. Samples were drawn at a myriad of different time points, from 4 hours to 8 days. All studies (but 234,40) used racemic ketamine. The intervention varied from an anesthesia based entirely on (S)-ketamine (single dose of 2 to 4 mg/kg followed by 2 to 4 mg/kg/h34), racemic ketamine single dose (1 to 2 mg/kg) followed by infusion (1.5 to 3.5 mg/kg/h),25 low dose (S+)-ketamine infusion (0.075 mg/kg/h),40 or low (0.15 to 0.5/mg/kg) single doses. In Tu et al.'s study33 one group received ketamine 1 mg/kg infused over the duration of surgery. In all studies, ketamine was given at induction of anesthesia, except Bhutta et al.,32 in which ketamine was administered just before CPB.

Of the 14 eligible studies, 2 were deemed high quality (++),26,34 9 were of medium quality (+),25,27,31,32,35,3841 and 3 were of low (−) quality and therefore excluded from the qualitative analysis: Mostafa et al.37 because of lack of preoperative sampling, Tu et al.33 because of large losses to follow–up, and D'Alonzo et al.36 primarily because of heterogeneity of study groups, and also lack of control of preoperative use of nonsteroidal anti-inflammatory drugs. One study reported regular use of nonsteroidal anti-inflammatory drugs before the operation that was similar in the study groups.26 Thus, 11 studies were included in the qualitative analysis. Of these, drugs with significant anti-inflammatory effects (methyl prednisolone, dexamethasone, and ibuprofen) were administered as premedication or during the operations in 3 studies,25,31,32 respectively; this fact may cancel the effects of ketamine on inflammatory biomarkers. Three of the studies used questionable statistics, such as failing to consider the fact that repeated measures were conducted, or not compensating for multiple comparisons.38,40,41 Primary endpoints were stated clearly in 2 studies,34,36 but could be anticipated in 4 studies.2527,31 The primary endpoints chosen in the included studies were all different, and only Welters et al.34 and D'Alonzo et al.36 reported their primary endpoint in a precise manner.

Five of the studies (Table 1) reported that racemic or (S)-ketamine significantly reduced the inflammatory response after surgery,26,34,35,38,41 as measured by plasma/ serum IL-6 concentrations (Table 1). Effect size was larger and lasted for a longer time period in early studies38,41 in comparison with the later studies by Bartoc et al. and Welters et al.,26,34 all conducted in patients undergoing CPB. The study of off-pump cardiac surgery patients did not show ketamine's effect.27 Moreover, effect size was smaller and duration was shorter in patients undergoing major abdominal surgery.35,38

Overall, plasma/serum C-reactive protein, IL-8, or TNF-α concentrations either did not show differences or decreased in a fashion similar to IL-6 in ketamine-treated patients,26,34,35,40 while IL-10 concentrations increased in the 2 high-quality studies.26,34 Zilberstein et al. have reported that the addition of low-dose ketamine to general anesthesia attenuated postoperative neutrophil activation up to 6 days after CPB.39

Among the 5 papers in Chinese, 1 was excluded because it could not be asserted whether it was an RCT,42 and another because the reported baseline IL-6 concentrations deviated significantly from all other studies.43 Two of the remaining studies included abdominal operations44,45 and 1, acute burn patients given analgesia.46 Neither of the abdominal studies showed an effect of ketamine on plasma IL-6, while the latter supported the findings of the meta-analysis (−120 [−156 to –84]) pg/mL (95% CI for the difference). It should be noted that the ketamine intervention started after the trauma (burn); thus this study had starting IL-6 concentrations of about 120 pg/mL, which increased over 48 hours in the control group but decreased in the ketamine-exposed groups.

The overall evidence profile as rated according to the GRADE recommendation24 for intraoperative ketamine on the postoperative Il-6 response was considered high.

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This systematic review substantiates the notion that intraoperative ketamine has an anti-inflammatory effect, as indicated by the meta-analysis showing a considerable reduction in circulating concentrations of the proinflammatory cytokine IL-6 during the first 6 hours after surgery.

IL-6 concentration in the first 6 postoperative hours was chosen as a representative outcome for the inflammatory response for several reasons. First, IL-6 was the most consistently reported inflammation biomarker in the studies included in this review, and most studies provided data in the early postoperative phase. Second, it has a proinflammatory action, and ketamine has been suggested to act as an anti-inflammatory drug.17 Third, any action of ketamine given intraoperatively should last into the early postoperative phase to have any potential clinical relevance, and possibly even be more prominent at this stage than later. Numerous studies have indicated the importance of IL-6 as a reliable and particularly sensitive biomarker of inflammatory activation and a predictor of subsequent organ dysfunction and death.47,48 For example, higher plasma/ serum concentrations of IL-6 have been associated with increased risk for major cardiopulmonary complications after general thoracic surgery,49 postoperative morbidity after cardiac surgery,13,50 postoperative complications,51,52 cognitive dysfunction after coronary artery surgery,53 increased risk of coronary heart disease,54 adverse postoperative outcome (mortality and complications) in elderly patients undergoing hip fracture surgery,55 and poor outcome and death after stroke.21

The overall effect size of ketamine on IL-6 was large even when including, in a separate meta-analysis, the 3 studies using potent anti-inflammatory drugs in the perioperative period.25,31,32 This was especially true for surgeries with CPB in which ketamine reduced IL-6 concentrations to about one third of those of the control group.26,34,41 This effect size was of the same magnitude (or larger) as reported for pretreatment with methylprednisolone (30 mg/kg) in which IL-6 was measured at declamping of the aorta during CPB surgery,56 or 60 minutes later.57 The effect of methylprednisolone in the former study, however, was short-lived and did not last beyond 1 hour after termination of the extracorporal circulation.

According to the GRADE approach the evidence level is rated high because it is based upon RCTs.24 Studies with questionable quality did not enter the qualitative analysis, while studies that included potent anti-inflammatory drugs did not enter the quantitative analysis. The meta-analysis showed consistent data for the chosen endpoint. The data, however, were inconsistent with regard to the duration of action of intraoperative ketamine. There are no signs of publication bias. Perhaps the weakest of the GRADE evidence elements is related to directness, because IL-6 may be a “narrow” or rather indirect measure of inflammation and its clinical consequences.

According to GRADE, a dose–response association would strengthen the evidence.24 In the present review neither a more pronounced effect nor a longer duration of action was seen, although the doses ranged from a single subanesthetic dose up to doses required for full ketamine-based anesthesia. This lack of dose response is difficult to understand, but the studies all have in common the fact that a bolus dose of at least 0.15 mg/kg ketamine was given before the surgical intervention. If this bolus dose is at the top of the dose-response curve for ketamine's anti-inflammatory effect, higher bolus doses or infusion may be futile. However, the study of Welters34 comparing ketamine anesthesia with sufentanil-based anesthesia presents important evidence that ketamine itself has an anti-inflammatory effect.

Although not derived from the meta-analysis, it is noteworthy that the duration of action of intraoperative ketamine differed substantially among studies. Duration of up to 6 hours postoperatively was documented in the present review. Furthermore, some of the studies reported duration of action of up to 24 hours,26 or even up to 8 days.38,39,41 Although there are statistical concerns with the last 3 studies, the findings are corroborated by other reports (not included in this review), showing long-term effects (5 to 7 days) after short-duration infusions (4 hours or less) of ketamine in both depression58 and pain relief in patients with critical limb ischemia.58,59

Most of the studies included other measures of inflammation in addition to IL-6. Among these were C-reactive protein, IL-8, IL-10, and TNFα. Only the data for IL-10 were consistent, showing that ketamine increased the concentrations of this anti-inflammatory cytokine, providing further evidence to the main observation of this review, i.e., that ketamine plays an anti-inflammatory role. Moreover, since the most consistent finding was related to IL-6, this review lends credibility to the suggestion that ketamine primarily acts as an antiinflammatory drug.17

Several potentially interesting studies written in Chinese were identified. Since one of the authors (Y.L.) is a native Chinese, it was decided to do a preliminary evaluation of these studies in addition to the primary papers written in English. These studies for reasons stated above added little. However, the study comparing the effect of ketamine on IL-6, as a part of the acute pain control regimen in burn patients,46 attracted attention, since evidence suggests a role for inflammation as an inducer of microglial-mediated hyperalgesia.20 Interestingly, the effect size reported by Xia et al.46 for IL-6 was of the same magnitude as that after CPB.26,34,41 The study also indicated that ketamine may potentially reduce the inflammatory response even when given after a trauma, at a time when biomarkers such as IL-6 are already increased.

Various studies, including clinical and preclinical research, in vivo and in vitro, have shown that in addition to its anesthetic activity, ketamine has an anti-inflammatory effect (for a recent review, see Loix et al.17). The mechanisms by which ketamine produces its anti-inflammatory actions needs to be elucidated. The acute analgesic effects of ketamine are generally believed to be mediated through the blockade of phencyclidine binding site of N-methyl-D-aspartate (NMDA) receptors of the nociceptive neurons; this mechanism could also partly account for the anti-inflammatory effects of ketamine. However, ketamine has also been reported to interact with opioid, monoamine, cholinergic, purinergic, and adenosine receptor systems. The functional anti-inflammatory effects of ketamine without affecting local healing processes (blunting neutrophil activation but sparing endothelial production of cytokines) shares similarities to those of LAs,13 which is considered to be due to their effect on G-protein-coupled-receptor signaling, specifically Gq downregulation.60 Because ketamine also has local anesthetic effects,60 it remains speculative as to whether they share a common anti-inflammatory mechanism.

Moreover, numerous mechanisms in addition to those discussed above have been shown to mediate the anti-inflammatory effects of ketamine. A nonexhaustive list of proposed mechanisms include inhibition of transcription factors nuclear factor-κB and activator protein 1,61 inhibition of proinflammatory cytokine production (IL-6 and TNFα),6264 inhibition of neutrophil functions,65 the release of adenosine,66 the blockade of large-conductance KCa channels on microglia (BK channels),19 or the inhibition of nitric oxide production in macrophages.67 Ketamine has been shown to downregulate the proinflammatory enzymes cyclooxygenase 2 and inducible nitric oxide synthase, while preserving expression of the anti-inflammatory enzyme heme-oxygenase-1.68 This review does not shed light on the mechanisms of the anti-inflammatory action of ketamine in the perioperative period. Whether it is mediated by NMDA or non-NMDA mechanisms remains to be elucidated, but the finding of this review should certainly stimulate basic researchers to clarify these aspects.

In this systematic search, no studies examining any clinical outcome were found. Although there are some indications that IL-6 is associated with a clinical outcome,15,5154,69 the bulk of evidence seems weak. Therefore, clinical outcome studies are warranted, and the evidence presented in this review suggests that subanesthetic single doses should be examined first. It is also intriguing to examine whether the anti-inflammatory effect of ketamine may have an impact on postoperative pain management.

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Name: Ola Dale, MD, PhD.

Contribution: This author helped design the study, collect data, evaluate the candidate papers independently, analyze the overall data, and write the manuscript.

Name: Andrew A. Somogyi, MSc, PhD.

Contribution: This author helped design the study, analyze the overall data, and write the manuscript.

Name: Yibai Li, BHSc (Hon).

Contribution: This author helped analyze the overall data and write the manuscript.

Name: Thomas Sullivan, BMa, CompSc (Hon).

Contribution: This author helped conduct the meta analysis, analyze the overall data, and write the manuscript.

Name: Yehuda Shavit, PhD.

Contribution: This author helped evaluate the candidate papers independently, analyze the overall data, and write the manuscript.

This manuscript was handled by: Spencer S. Liu, MD.

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The authors greatly appreciate the support for the searches provided by Mr. Michael Draper, Research Librarian, University of Adelaide, Adelaide, Australia, and Ingrid Riphagen MSc, AKF, Norwegian University of Science and Technology, Trondheim, Norway. This work was facilitated by the Leon and Clara Sznajderman Chair of Psychology (to Y.S.). We are also grateful to Drs. P. Zeyneloglu, C. Bartoc, and Y.L. Kwak, who gave us access to their original data on IL-6, and to Dr. B. Beilin for confirming his blinding procedure.

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