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.1–3 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.7–12 The results of multiple studies on the systemic anti-inflammatory effects of fentanyl7–9 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
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
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.
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 , German , Spanish , and Japanese ), 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.25–27,31,34,36 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 (+),25,27,31,32,35,38–41 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.25–27,31 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.
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,1–3,50 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),62–64 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,1–5,51–54,69 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.
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.
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.
1. Cremer J, Martin M, Redl H, Bahrami S, Abraham C, Graeter T, Haverich A, Schlag G, Borst HG. Systemic inflammatory response syndrome after cardiac operations. Ann Thorac Surg 1996;61: 1714–20
2. Hill GE, Whitten CW, Landers DF. The influence of cardiopulmonary bypass on cytokines and cell-cell communication. J Cardiothorac Vasc Anesth 1997;11: 367–75
3. Hennein HA, Ebba H, Rodriguez JL, Merrick SH, Keith FM, Bronstein MH, Leung JM, Mangano DT, Greenfield LJ, Rankin JS. Relationship of the proinflammatory cytokines to myocardial ischemia and dysfunction after uncomplicated coronary revascularization. J Thorac Cardiovasc Surg 1994;108: 626–35
4. Deng MC, Dasch B, Erren M, Mollhoff T, Scheld HH. Impact of left ventricular dysfunction on cytokines, hemodynamics, and outcome in bypass grafting. Ann Thorac Surg 1996;62: 184–90
5. Meduri GU, Headley S, Kohler G, Stentz F, Tolley E, Umberger R, Leeper K. Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Plasma IL-1 beta and IL-6 levels are consistent and efficient predictors of outcome over time. Chest 1995;107: 1062–73
6. Laffey JG, Boylan JF, Cheng DC. The systemic inflammatory response to cardiac surgery: implications for the anesthesiologist. Anesthesiology 2002;97: 215–52
7. Taylor NM, Lacoumenta S, Hall GM. Fentanyl and the interleukin-6 response to surgery. Anaesthesia 1997;52: 112–5
8. Winterhalter M, Brandl K, Rahe-Meyer N, Osthaus A, Hecker H, Hagl C, Adams HA, Piepenbrock S. Endocrine stress response and inflammatory activation during CABG surgery. A randomized trial comparing remifentanil infusion to intermittent fentanyl. Eur J Anaesthesiol 2008;25: 326–35
9. Brix-Christensen V, Tonnesen E, Sorensen IJ, Bilfinger TV, Sanchez RG, Stefano GB. Effects of anaesthesia based on high versus low doses of opioids on the cytokine and acute-phase protein responses in patients undergoing cardiac surgery. Acta Anaesthesiol Scand 1998;42: 63–70
10. Murphy GS, Szokol JW, Marymont JH, Avram MJ, Vender JS. The effects of morphine and fentanyl on the inflammatory response to cardiopulmonary bypass in patients undergoing elective coronary artery bypass graft surgery. Anesth Analg 2007;104: 1334–42
11. Kawamura T, Kadosaki M, Nara N, Kaise A, Suzuki H, Endo S, Wei J, Inada K. Effects of sevoflurane on cytokine balance in patients undergoing coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth 2006;20: 503–8
12. Corcoran TB, Engel A, Sakamoto H, O'Shea A, O'Callaghan-Enright S, Shorten GD. The effects of propofol on neutrophil function, lipid peroxidation and inflammatory response during elective coronary artery bypass grafting in patients with impaired ventricular function. Br J Anaesth 2006;97: 825–31
13. Hollmann MW, Durieux ME. Local anesthetics and the inflammatory response: a new therapeutic indication? Anesthesiology 2000;93: 858–75
14. Herroeder S, Pecher S, Schonherr ME, Kaulitz G, Hahnenkamp K, Friess H, Bottiger BW, Bauer H, Dijkgraaf MG, Durieux ME, Hollmann MW. Systemic lidocaine shortens length of hospital stay after colorectal surgery: a double-blinded, randomized, placebo-controlled trial. Ann Surg 2007;246: 192–200
15. Elia N, Tramer MR. Ketamine and postoperative pain—a quantitative systematic review of randomised trials. Pain 2005;113: 61–70
16. Hocking G, Cousins MJ. Ketamine in chronic pain management: an evidence-based review. Anesth Analg 2003;97: 1730–9
17. Loix S, De Kock M, Henin P. The anti-inflammatory effects of ketamine: state of the art. Acta Anaesthesiol Belg 2011;62: 47–58
18. Chang Y, Lee JJ, Hsieh CY, Hsiao G, Chou DS, Sheu JR. Inhibitory effects of ketamine on lipopolysaccharide-induced microglial activation. Mediators Inflamm 2009;2009: 705379 [Epub]
19. Hayashi Y, Kawaji K, Sun L, Zhang X, Koyano K, Yokoyama T, Kohsaka S, Inoue K, Nakanishi H. Microglial Ca(2+)-activated K(+) channels are possible molecular targets for the analgesic effects of S-ketamine on neuropathic pain. J Neurosci 2011; 31: 17370–82
20. Watkins LR, Hutchinson MR, Johnston IN, Maier SF. Glia: novel counter-regulators of opioid analgesia. Trends Neurosci 2005;28: 661–9
21. Whiteley W, Jackson C, Lewis S, Lowe G, Rumley A, Sandercock P, Wardlaw J, Dennis M, Sudlow C. Inflammatory markers and poor outcome after stroke: a prospective cohort study and systematic review of interleukin-6. PLoS Med 2009;6: e1000145
22. NHS Centre for Reviews and Dissemination. Undertaking Systematic Reviews of Research on Effectiveness. CRDs' Guidance for Those Carrying Out or Commissioning Reviews. 2nd ed. York: University of York, 2001
23. Mayyas F, Fayers P, Kaasa S, Dale O. A systematic review of oxymorphone in the management of chronic pain. J Pain Symptom Manage 2010;39: 296–308
24. Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, Guyatt GH, Harbour RT, Haugh MC, Henry D, Hill S, Jaeschke R, Leng G, Liberati A, Magrini N, Mason J, Middleton P, Mrukowicz J, O'Connell D, Oxman AD, Phillips B, Schunemann HJ, Edejer TT, Varonen H, Vist GE, Williams JW Jr., Zaza S. Grading quality of evidence and strength of recommendations. BMJ 2004;328: 1490
25. Zeyneloglu P, Donmez A, Bilezikci B, Mercan S. Effects of ketamine on serum and tracheobronchial aspirate interleukin-6 levels in infants undergoing cardiac surgery. J Cardiothorac Vasc Anesth 2005;19: 329–33
26. Bartoc C, Frumento RJ, Jalbout M, Nett-Guerrero E, Du E, Nishanian E. A randomized, double-blind, placebo-controlled study assessing the anti-inflammatory effects of ketamine in cardiac surgical patients. J Cardiothorac Vasc Anesth 2006;20: 217–22
27. Cho JE, Shim JK, Choi YS, Kim DH, Hong SW, Kwak YL. Effect of low-dose ketamine on inflammatory response in off-pump coronary artery bypass graft surgery. Br J Anaesth 2009;102: 23–8
28. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7: 177–88
29. Higgins JPT, Thompson SG. Quantifying heterogeneity in meta-analysis. Stat Med 2002;21: 1539–58
30. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple graphical test. BMJ 1997;315: 629–34
31. Bonofiglio FC, Molmenti EP, de Santibanes E. Ketamine does not inhibit interleukin-6 synthesis in hepatic resections requiring a temporary porto-arterial occlusion (Pringle manoeuvre): a controlled, prospective, randomized, double-blinded study. HPB (Oxford) 2011;13: 706–11
32. Bhutta AT, Schmitz ML, Swearingen C, James LP, Wardbegnoche WL, Lindquist DM, Glasier CM, Tuzcu V, Prodhan P, Dyamenahalli U, Imamura M, Jaquiss RD, Anand KJ. Ketamine as a neuroprotective and anti-inflammatory agent in children undergoing surgery on cardiopulmonary bypass: a pilot randomized, double-blind, placebo-controlled trial. Pediatr Crit Care Med 2012;13: 328–37
33. Tu KL, Kaye SB, Sidaras G, Taylor W, Shenkin A. Effect of intraocular surgery and ketamine on aqueous and serum cytokines. Mol Vis 2007;13: 1130–7
34. Welters ID, Feurer MK, Preiss V, Muller M, Scholz S, Kwapisz M, Mogk M, Neuhauser C. Continuous S-(+)-ketamine administration during elective coronary artery bypass graft surgery attenuates pro-inflammatory cytokine response during and after cardiopulmonary bypass. Br J Anaesth 2011;106: 172–9
35. Beilin B, Rusabrov Y, Shapira Y, Roytblat L, Greemberg L, Yardeni IZ, Bessler H. Low-dose ketamine affects immune responses in humans during the early postoperative period. Br J Anaesth 2007;99: 522–7
36. D'Alonzo RC, Bennett-Guerrero E, Podgoreanu M, D'Amico TA, Harpole DH, Shaw AD. A randomized, double blind, placebo controlled clinical trial of the preoperative use of ketamine for reducing inflammation and pain after thoracic surgery. J Anesth 2011;25: 672–8
37. Mostafa H, Ela AMA, El-Tweel N. S (+) ketamine suppresses TNF-α, IL-6 and IL-8 production in blood in major abdominal surgery under combined epidural-general anesthesia. J Med Sci 2010;8: 137–42
38. Roytblat L, Roy-Shapira A, Greemberg L, Korotkoruchenko A, Schwartz A, Peizer J, Douvdevani A. Preoperative low dose ketamine reduces serum interleukin-6 response after abdominal hysterectomy. Pain Clinic 1996;9: 327–34
39. Zilberstein G, Levy R, Rachinsky M, Fisher A, Greemberg L, Shapira Y, Appelbaum A, Roytblat L. Ketamine attenuates neutrophil activation after cardiopulmonary bypass. Anesth Analg 2002;95: 531–6
40. Akhlagh AH, Zeighami D, Koshravi MB, Maghsoodi B, Azemati S, Alipour A. The effect of low dose of ketamine infusion on stress responses in coronary bypass graft surgery. Iranian Cardiovasc Res J 2008;4: 28–32
41. Roytblat L, Talmor D, Rachinsky M, Greemberg L, Pekar A, Appelbaum A, Gurman GM, Shapira Y, Duvdenani A. Ketamine attenuates the interleukin-6 response after cardiopulmonary bypass. Anesth Analg 1998;87: 266–71
42. Cao DQ, Chen YP, Zou DG. Effects of ketamine on cardiopulmonary bypass induces interleukin-6 and interleukin-8 response and its significance. Bull Hunan Med Univ 2001;26: 350–2
43. Huang C, Liu A. Effect of preemptive analgesia by intravenous small-dose ketamine on cytokine response to upper abdominal surgery. Med J Wuhan Univ 2006;27: 682–4
44. Yang Z, Chen ZQ, Jiang XQ. Effects of subanesthetic dose of ketamine on perioperative serum cytokines in orthoptic liver transplantation. J South Med Univ 2006;26: 802–4
45. Xin MG, Ye H, Zhang YZ, Be FH. Effects of ketamine and propofol on levels of perioperative plasma cytokines in gastric cancer patients underwent radical gastrectomy. J Jilin Univ Med Ed 2007;33: 1070–2
46. Xia JG, Peng J, Xiao H, Sun JB. Effect of intravenous patient-controlled intravenous analgesia with a small dose of ketamine during shock stage on cytokine balance in patients with severe burn. Chin Crit Care Med 2006;18: 32–5
47. Kanda T, Takahashi T. Interleukin-6 and cardiovascular diseases. Jpn Heart J 2004;45: 183–93
48. Cruickshank AM, Fraser WD, Burns HJ, Van DJ, Shenkin A. Response of serum interleukin-6 in patients undergoing elective surgery of varying severity. Clin Sci (London) 1990; 79: 161–5
49. Amar D, Zhang H, Park B, Heerdt PM, Fleisher M, Thaler HT. Inflammation and outcome after general thoracic surgery. Eur J Cardiothorac Surg 2007;32: 431–4
50. Rallidis LS, Zolindaki MG, Manioudaki HS, Laoutaris NP, Velissaridou AH, Papasteriadis EG. Prognostic value of C-reactive protein, fibrinogen, interleukin-6, and macrophage colony stimulating factor in severe unstable angina. Clin Cardiol 2002;25: 505–10
51. Oka Y, Murata A, Nishijima J, Yasuda T, Hiraoka N, Ohmachi Y, Kitagawa K, Yasuda T, Toda H, Tanaka N. Circulating interleukin 6 as a useful marker for predicting postoperative complications. Cytokine 1992;4: 298–304
52. Holmes JH, Connolly NC, Paull DL, Hill ME, Guyton SW, Ziegler SF, Hall RA. Magnitude of the inflammatory response to cardiopulmonary bypass and its relation to adverse clinical outcomes. Inflamm Res 2002;51: 579–86
53. Hudetz JA, Gandhi SD, Iqbal Z, Patterson KM, Pagel PS. Elevated postoperative inflammatory biomarkers are associated with short- and medium-term cognitive dysfunction after coronary artery surgery. J Anesth 2011;25: 1–9
54. Danesh J, Kaptoge S, Mann AG, Sarwar N, Wood A, Angleman SB, Wensley F, Higgins JP, Lennon L, Eiriksdottir G, Rumley A, Whincup PH, Lowe GD, Gudnason V. Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review. PLoS Med 2008;5: e78
55. Sun T, Wang X, Liu Z, Chen X, Zhang J. Plasma concentrations of pro- and anti-inflammatory cytokines and outcome prediction in elderly hip fracture patients. Injury 2011;42: 707–13
56. Inaba H, Kochi A, Yorozu S. Suppression by methylprednisolone of augmented plasma endotoxin-like activity and interleukin-6 during cardiopulmonary bypass. Br J Anaesth 1994;72: 348–50
57. Kawamura T, Inada K, Okada H, Okada K, Wakusawa R. Methylprednisolone inhibits increase of interleukin 8 and 6 during open heart surgery. Can J Anaesth 1995;42: 399–403
58. Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006;63: 856–64
59. Mitchell AC, Fallon MT. A single infusion of intravenous ketamine improves pain relief in patients with critical limb ischaemia: results of a double blind randomised controlled trial. Pain 2002;97: 275–81
60. Hollmann MW, Herroeder S, Kurz KS, Hoenemann CW, Struemper D, Hahnenkamp K, Durieux ME. Time-dependent inhibition of G protein-coupled receptor signaling by local anesthetics. Anesthesiology 2004;100: 852–60
61. Welters ID, Hafer G, Menzebach A, Muhling J, Neuhauser C, Browning P, Goumon Y. Ketamine inhibits transcription factors activator protein 1 and nuclear factor-kappaB, interleukin-8 production, as well as CD11b and CD16 expression: studies in human leukocytes and leukocytic cell lines. Anesth Analg 2010;110: 934–41
62. Shaked G, Czeiger D, Dukhno O, Levy I, Artru AA, Shapira Y, Douvdevani A. Ketamine improves survival and suppresses IL-6 and TNFalpha production in a model of gram-negative bacterial sepsis in rats. Resuscitation 2004;62: 237–42
63. Lankveld DP, Bull S, Van DP, Fink-Gremmels J, Hellebrekers LJ. Ketamine inhibits LPS-induced tumour necrosis factor-alpha and interleukin-6 in an equine macrophage cell line. Vet Res 2005;36: 257–62
64. Wu GJ, Chen TL, Ueng YF, Chen RM. Ketamine inhibits tumor necrosis factor-alpha and interleukin-6 gene expressions in lipopolysaccharide-stimulated macrophages through suppression of toll-like receptor 4-mediated c-Jun N-terminal kinase phosphorylation and activator protein-1 activation. Toxicol Appl Pharmacol 2008;228: 105–13
65. Weigand MA, Schmidt H, Zhao Q, Plaschke K, Martin E, Bardenheuer HJ. Ketamine modulates the stimulated adhesion molecule expression on human neutrophils in vitro. Anesth Analg 2000;90: 206–12
66. Mazar J, Rogachev B, Shaked G, Ziv NY, Czeiger D, Chaimovitz C, Zlotnik M, Mukmenev I, Byk G, Douvdevani A. Involvement of adenosine in the antiinflammatory action of ketamine. Anesthesiology 2005;102: 1174–81
67. Li CY, Chou TC, Wong CS, Ho ST, Wu CC, Yen MH, Ding YA. Ketamine inhibits nitric oxide synthase in lipopolysaccharide-treated rat alveolar macrophages. Can J Anaesth 1997;44: 989–95
68. Ward JL, Adams SD, Delano BA, Clarke C, Radhakrishnan RS, Weisbrodt NW, Mercer DW. Ketamine suppresses LPS-induced bile reflux and gastric bleeding in the rat. J Trauma 2010;68: 69–75
69. Hauser GJ, Ben-Ari J, Colvin MP, Dalton HJ, Hertzog JH, Bearb M, Hopkins RA, Walker SM. Interleukin-6 levels in serum and lung lavage fluid of children undergoing open heart surgery correlate with postoperative morbidity. Intensive Care Med 1998;24: 481–6