小剂量氯胺酮对全麻手术术后镇痛及免疫功能的影响
摘要
背景：全麻术后的患者常常伴随着免疫系统损伤，这可能与手术刺激及阿片类药物的应用相关，表现为炎症因子的过度表达和细胞介导的免疫反应受到抑制。炎症因子的过度表达不仅会引起严重的炎症和低血压、休克、多器官衰竭等复杂的术后并发症。还将加重术后疼痛程度,而术后疼痛反之进一步促进炎症因子的表达，形成恶性循环。因此给予镇痛药物减轻疼痛，可以抑制炎症因子的分泌，减少术后并发症，同时还能减少阿片类药物的使用剂量。氯胺酮（Ketamine,Ket）是N-甲基-D-天门冬氨酸（NMDA）受体非特异性拮抗剂。其可以降低术后疼痛评分，并减少吗啡用量，同时Ket与疼痛评分降低之间具有剂量正相关性。在疼痛形成的早期阶段给予小剂量Ket即能够发挥镇痛的效果。但术前应用Ket除具有良好术后镇痛作用外，是否能起到减轻由阿片类药物产生的免疫功能损伤的作用尚无定论。由此，本研究旨在通过测定手术前后血清中炎症因子的表达，探讨小剂量氯胺酮对全麻手术后镇痛及早期免疫功能的影响。
方法：全麻下行妇科腹腔镜手术患者60例，随机分为两组：对照组采用雷米芬太尼复合丙泊酚麻醉。研究组在切皮前静脉给予小剂量氯胺酮0.3mg/kg。采用VAS及SS评分评估术后疼痛及苏醒期躁动情况。同时采用双抗体夹心酶联免疫法测定两组术前以及术后4、24、48、72h血清中IL-1β、IL-2、IL-6和TNF-α水平变化，评估其免疫功能情况。
结果：研究组苏醒期躁动、镇痛、镇静效果显著优于对照组（P<0.05）。手术后4个小时，氯胺酮组IL-6水平较对照组显著降低（P<0.05）。而与术前比较，术后IL-2的分泌并没有改变。对照组中术后4小时TNF-α水平显著升高（P<0.05）。
结论：切皮前给予小剂量氯胺酮能降低炎症因子IL-6和TNF-a的分泌，并使IL-2含量保持在手术前的水平。本研究结果表明小剂量氯胺酮在防止全麻术后早期免疫功能损伤中具有重要价值。术前应用小剂量Ket患者苏醒快、术后疼痛轻、苏醒期躁动少
Background: The immune system of patients undergoing surgery isaffected by both anaesthesia and surgical trauma, with possible sequelae on thepostoperative outcome. The proinflammatory cytokines are stimulated to anexcessive degree,and cell-mediated immunity are dramatically suppressed.Theexcessive production of proinflammatory cytokines may induce severeinflammation and postoperative complications, including hypotension, shock,and multiple organ failure.Increased production of proinflammatory cytokinesmay exacerbate pain,and vice versa.An attempt to diminish the deleteriousside-effects of the opiates on the immune system could be achieved by additionof drugs with marked analgesic activity capable of attenuating pain stimuli andtherefore allowing reduction of the dosage of opiates.Ketamine,a neurotra-nsmitter acting as a N-methyl-D-asparate receptor antagonist,has been shownreduction in morphine dosage and pain score,with a direct relationship betweenKetamine dosage and pain score.Small doses of Ketamine exert analgesicaction in the early stages of formation of pain stimuli.The question of whetherKetamine,in addition to its beneficial action as a pain reliever,may attenuatethe immunosuppressive effect of opioids in patients exposed to surgery is ofinterest to the clinician.The rationale of the study was to contribute tounderstanding the role of subanaesthetic doses of Ketamine in attenuating theundesirable effect of anaesthesia and surgery on the immune system.
Methods:Sixty gynecology laparoscopy(GL) patients under generalanesthesia with propofol and remifentany were randomly divided into twogroups of Study and Control with30cases each.The patients in group Studywere given additional low-dose Ketamine0.3mg/kg before skinincision.Recovery from anesthesia was evaluated after surgery by SS and VAS scoring. The levels of IL-1β, IL-2,IL-6and TNF-α were examed by Doubleantibody sandwich ELISA method before and4,24,48,and72h afteroperationin60patients with acute brainstem infarction patients.
Results:Recovery of anesthesia was with less restlessness and VAS painscores,better sedation in group Study than those in group Control (P<0.05).Fourhours after operation, the cells from patients in the Ketamine group showed asignificantly suppressed production of IL-6(P<0.05)compared with controls.The production of IL-2did not change from that of the preoperationsamples.TNF-α,secretion was significantly elevated in the control group4hafter operation(P<0.05).
Conclusion:Addition of small doses of Ketamine before induction ofanaesthesia resulted in attenuation of secretion of the proinflammatorycytokines IL-6and TNF-α,and in preservation of IL-2production at itspreoperative level.It is suggested that this anaesthetic may be of value inpreventing immune function alterations in the early postoperativeperiod.Preemptive intravenous analgesia with low-dose Ketamine has theadvantage of quicker recovery from anesthesia with less incidence ofrestlessness and pain.
方法：全麻下行妇科腹腔镜手术患者60例，随机分为两组：对照组采用雷米芬太尼复合丙泊酚麻醉。研究组在切皮前静脉给予小剂量氯胺酮0.3mg/kg。采用VAS及SS评分评估术后疼痛及苏醒期躁动情况。同时采用双抗体夹心酶联免疫法测定两组术前以及术后4、24、48、72h血清中IL-1β、IL-2、IL-6和TNF-α水平变化，评估其免疫功能情况。
结果：研究组苏醒期躁动、镇痛、镇静效果显著优于对照组（P<0.05）。手术后4个小时，氯胺酮组IL-6水平较对照组显著降低（P<0.05）。而与术前比较，术后IL-2的分泌并没有改变。对照组中术后4小时TNF-α水平显著升高（P<0.05）。
结论：切皮前给予小剂量氯胺酮能降低炎症因子IL-6和TNF-a的分泌，并使IL-2含量保持在手术前的水平。本研究结果表明小剂量氯胺酮在防止全麻术后早期免疫功能损伤中具有重要价值。术前应用小剂量Ket患者苏醒快、术后疼痛轻、苏醒期躁动少
Background: The immune system of patients undergoing surgery isaffected by both anaesthesia and surgical trauma, with possible sequelae on thepostoperative outcome. The proinflammatory cytokines are stimulated to anexcessive degree,and cell-mediated immunity are dramatically suppressed.Theexcessive production of proinflammatory cytokines may induce severeinflammation and postoperative complications, including hypotension, shock,and multiple organ failure.Increased production of proinflammatory cytokinesmay exacerbate pain,and vice versa.An attempt to diminish the deleteriousside-effects of the opiates on the immune system could be achieved by additionof drugs with marked analgesic activity capable of attenuating pain stimuli andtherefore allowing reduction of the dosage of opiates.Ketamine,a neurotra-nsmitter acting as a N-methyl-D-asparate receptor antagonist,has been shownreduction in morphine dosage and pain score,with a direct relationship betweenKetamine dosage and pain score.Small doses of Ketamine exert analgesicaction in the early stages of formation of pain stimuli.The question of whetherKetamine,in addition to its beneficial action as a pain reliever,may attenuatethe immunosuppressive effect of opioids in patients exposed to surgery is ofinterest to the clinician.The rationale of the study was to contribute tounderstanding the role of subanaesthetic doses of Ketamine in attenuating theundesirable effect of anaesthesia and surgery on the immune system.
Methods:Sixty gynecology laparoscopy(GL) patients under generalanesthesia with propofol and remifentany were randomly divided into twogroups of Study and Control with30cases each.The patients in group Studywere given additional low-dose Ketamine0.3mg/kg before skinincision.Recovery from anesthesia was evaluated after surgery by SS and VAS scoring. The levels of IL-1β, IL-2,IL-6and TNF-α were examed by Doubleantibody sandwich ELISA method before and4,24,48,and72h afteroperationin60patients with acute brainstem infarction patients.
Results:Recovery of anesthesia was with less restlessness and VAS painscores,better sedation in group Study than those in group Control (P<0.05).Fourhours after operation, the cells from patients in the Ketamine group showed asignificantly suppressed production of IL-6(P<0.05)compared with controls.The production of IL-2did not change from that of the preoperationsamples.TNF-α,secretion was significantly elevated in the control group4hafter operation(P<0.05).
Conclusion:Addition of small doses of Ketamine before induction ofanaesthesia resulted in attenuation of secretion of the proinflammatorycytokines IL-6and TNF-α,and in preservation of IL-2production at itspreoperative level.It is suggested that this anaesthetic may be of value inpreventing immune function alterations in the early postoperativeperiod.Preemptive intravenous analgesia with low-dose Ketamine has theadvantage of quicker recovery from anesthesia with less incidence ofrestlessness and pain.
引文
[1] Costigan M, Woolf C. Pain: molecular mechanisms. J Pain2000;1:35-44.
[2] Woolf CJ. Pain: moving from symptom control toward mechanism-specificpharmacologic management. Ann Intern Med2004;140:441-51.
[3] Carr DB, Goudas L. Acute pain. Lancet1999;353:2051-8.
[4] Shipton E. Post-surgical neuropathic pain. ANZ J Surg2008;78:548-55.
[5] Schug S, Manopas A. Update on the role of non-opioids forpostoperativepain treatment. Best Pract Res Clin Anaesthesiol2007;21:15-30.
[6] Fanelli G, Berti M, Baciarello M. Updating postoperative painmanagement:from multimodal to context-sensitive treatment.Minerva Anestesiol2008;74:489-500.
[7] Dickenson A, Sullivan A. NMDA receptors and centralhyperalgesic states.Pain1991;46:344-6.
[8] De Kock MF, Lavand'homme PM. The clinical role of NMDAreceptorantagonists for the treatment of postoperative pain. BestPractice Res ClinAnaesthesiol2007;21:85-98.
[9] Cohen M, Trevor A. On the cerebral accumulation of Ketamine andtherelationship between metabolism of the drug and itspharmacological effects.J Pharmacol Exp Ther1974;189:351-8.
[10] Idvall J, Ahlgren I, Aronsen K, Stenberg P. Ketamine infusions:pharmacokinetics and clinical effects. Br J Anaesth1979;51:1167-73.
[11] Larenza M, Landoni M, Levionnois O, Knobloch M, Kronen P,TheurillatR, et al. Stereoselective pharmacokinetics of Ketamineand norKetamineafter racemic Ketamine or S-Ketamineadministration during isofluraneanaesthesia in Shetland ponies. BrJ Anaesth2007;98:204-12.
[12] Geisslinger G, Hering W, Thomann P, Knoll R, Kamp H, Brune K.Pharmacokinetics and pharmacodynamics of Ketamine enantiomersinsurgical patients using a stereoselective analytical method. Br JAnaesth1993;70:666-71.
[13] Karpinski N, Dunn J, Hansen L, Masliah E. Subpial vacuolarmyelopathyafter intrathecal Ketamine: report of a case. Pain1997;73:103-5.
[14] Vranken J, Troost D, Wegener J, Kruis M, Van Der Vegt MH.Neuropathological findings after continuous intrathecaladministration ofS(+)-Ketamine for the management ofneuropathic cancer pain. Pain2005;117:231-5.
[15] De Kock M, Lavand'homme P, Waterloos H.'Balanced analgesia'in theperioperative period: is there a place for Ketamine? Pain2001;92:373-80.
[16] Sarton E, Teppema L, Olievier C, Nieuwenhuijs D, Matthes H,Kieffer B,et al. The involvement of the mu-opioid receptor inKetamine-induced re-spiratory depression and antinociception.Anesth Analg2001;93:1495-500, table of contents.
[17] Smith D, Bouchal R, Desanctis C, Monroe P, Amedro J, Perrotti J,et al.Properties of the interaction between Ketamine and opiatebinding sites invivo and in vitro. Neuropharmacology1987;26:1253-60.
[18] Hustveit O, Maurset A, Oye I. Interaction of the chiral forms ofKetaminewith opioid, phencyclidine, sigma and muscarinicreceptors. PharmacolToxicol1995;77:355-9.
[19] Mikkelsen S, Ilkjaer S, Brennum J, Borgbjerg F, Dahl J. The effectofnaloxone on Ketamine-induced effects on hyperalgesia andKetamine-induced side effects in humans. Anesthesiology1999;90:1539-45.
[20] Sun J, Wang X, Liu H, Xu J. Ketamine suppresses endotoxin-inducedNF-kappaB activation and cytokines production in theintestine. ActaAnaesthesiol Scand2004;48:317-21.
[21] Hill G, Anderson J, Lyden E. Ketamine inhibits theproinflammatorycytokine-induced reduction of cardiacintracellular cAMP accumulation.Anesth Analg1998;87:1015-9.
[22] Bartoc C, Frumento R, Jalbout M, Bennett-Guerrero E, Du E,Nishanian E.A randomized, double-blind, placebo-controlled studyassessing theanti-inflammatory effects of Ketamine in cardiacsurgical patients. JCardiothorac Vasc Anesth2006;20:217-22.
[23] Shibakawa Y, Sasaki Y, Goshima Y, Echigo N, Kamiya Y,Kurahashi K, etal. Effects of Ketamine and propofol oninflammatory responses of primaryglial cell cultures stimulatedwith lipopolysaccharide. Br J Anaesth2005;95:803-10.
[24] Visser E, Schug S. The role of Ketamine in pain management.BiomedPharmacother2006;60:341-8.
[25] Himmelseher, S. and Durieux, M. E.(2005) Anesthesiology,102(1),211-220.
[26] Elia, N. and Tramèr, M. R.(2005) Pain,113,61-70.
[27] Subramaniam, K.; Subramaniam, B. and Steinbrook, R. A.(2004)Anesth.Analg.,94,482-495.
[28] De Kock, M.; Lavand’Homme, P. and Waterloos, H.(2001) Pain,92,373-380.
[29] Angelini, G.; Ketzler, J. T. and Coursin, D. B (2001) Crit. CareClin.,17(4),863-880.
[30] Guillou, N.; Tanguy, M.; Seguin, P.; Branger, B.; Campion, J. P.andMalledant, Y.(2003) Anesth. Analg.,97(3),843-847.
[31] Dinarello CA. Proinflammatory and anti-inflammatory cytokines asmediators in the pathogenesis of septic shock. Chest,1997;112:321S–7S
[32] Beilin B, Shavit Y, Trabekin E, et al. The effects of postoperative painmanagement on immune response to surgery. Anesth Analg,2003;97:822–7
[33] Katz J, McCartney CJ. Current status of preemptive analgesia. Curr OpinAnaesthesiol,2002;15:435-441
[34] Cherry DA, Plummer JL, Gourlay GK, et al. Ketamine as an adjunct tomorphine in treatment of pain. Pain,1995;62:119–21
[35] Tverskoy M, Oz Y, Isakson A, et al. Preemptive effect of fentanyl andKetamine on postoperative pain and wound analgesia. Anesth Analg,1994;78:205–9
[36] Roytblat L, Korotkoruchko A, Katz J, et al. Postoperative pain: the effectof low-dose Ketamine in addition to general anesthesia. AnesthAnalg,1993;77:1161–3
[37] Hahnenkamp K, Nollet J, Van Aken HK, et al. Remifentail directlyactivates human N-methy1-D-aspartate receptors expressed in Xenopuscaveis oocytes. Anesthesiology,2004,100:1531-1537.
[38] Vanderah TW, Ossipov MH, Lai J, et al. Mechanisms of opioid inducedpain and antinociceptive tolerance: Descending facilitation and spinaldynorphin.Pain,2001;92:5-9.
[39] Borgland SL.A cute opioid receptor desensitization and tolerance: is therea link? Clin Exp Pharmacol Physiol,2001;28:147-154.
[40] Roytblat L, Talmor D, Rachinsky M, et al. Ketamine attenuates theinterleukin-6response after cardiopulmary bypass. Anesth Analg,1998;87:266–71
[41] Taniguchi T, Takemoto Y, Kanakura H, et al. The dose-related effects ofKetamine on mortality and cytokine responses to endotoxin-induced shockin rats. Anesth Analg,2003;97:1769–72
[42] Roytblat L, Roy-Shapira A, Geemberg L, et al. Preoperative low doseKetamine reduces serum interleukin-6response after abdominal hys-terectomy. Pain Clin,1996;9:327–34
[43] Xia JG, Peng J, Xiao H, et al. Effect of intravenous patient-controlledintravenous analgesia with small dose of Keta-mine during shock stage oncytokine balance in patients with severe burn. Zhongguo Wei Zhong BingJi Jiu Yi Xue,2006;18:32–5
[44] Kawasaki C, Kawasaki T, Ogata M, et al. Ketamine isomers suppresssuperantigen-induced proinflammatory cytokine production in humanwhole blood. Can J Anaesth,2001;48:819–23
[45] Kawasaki T, Ogata M, Kawasaki C, et al. Ketamine suppressesproinflammatory cytokine production in human whole blood in vitro.Anesth Analg,1999;89:665–9
[46] Marano MA, Fong Y, Moldawer LL, et al. Serum cachectin/tumor necrosisfactor in critically ill patients with burns correlates with infections andmortality. Surg Gynecol Obstet,1990;170:32–8
[47] Casey LC, Balk RA, Bone RC. Plasma cytokine and endotoxin levelscorrelate with survival in patients with the sepsis syndrome. Ann InternMed,1993;119:771–8
[48] Hill GA, Anderson JL, Lyden ER. Ketamine inhibits the proinflam-matory cytokine-induced reduction of cardiac intracellular cAMP accum-ulation. Anesth Analg,1998;87:1015–9
[49] Ying S, Robinson DS, Varney V, et al. TNFa mRNA expression in allergicinflammation. Clin Exp Allergy,1991;21:745–50
[50] Matsumori A, Yamada T, Suzuki H, et al. Increased circulating cytokinesin patients with myocarditis and cardiomyopathy. Br Heart J,1994;72:561–6
[51] Feghali CA, Wright TM. Cytokines in acute and chronic inflammation.Front Biosci,1997;2: d12–26
[2] Woolf CJ. Pain: moving from symptom control toward mechanism-specificpharmacologic management. Ann Intern Med2004;140:441-51.
[3] Carr DB, Goudas L. Acute pain. Lancet1999;353:2051-8.
[4] Shipton E. Post-surgical neuropathic pain. ANZ J Surg2008;78:548-55.
[5] Schug S, Manopas A. Update on the role of non-opioids forpostoperativepain treatment. Best Pract Res Clin Anaesthesiol2007;21:15-30.
[6] Fanelli G, Berti M, Baciarello M. Updating postoperative painmanagement:from multimodal to context-sensitive treatment.Minerva Anestesiol2008;74:489-500.
[7] Dickenson A, Sullivan A. NMDA receptors and centralhyperalgesic states.Pain1991;46:344-6.
[8] De Kock MF, Lavand'homme PM. The clinical role of NMDAreceptorantagonists for the treatment of postoperative pain. BestPractice Res ClinAnaesthesiol2007;21:85-98.
[9] Cohen M, Trevor A. On the cerebral accumulation of Ketamine andtherelationship between metabolism of the drug and itspharmacological effects.J Pharmacol Exp Ther1974;189:351-8.
[10] Idvall J, Ahlgren I, Aronsen K, Stenberg P. Ketamine infusions:pharmacokinetics and clinical effects. Br J Anaesth1979;51:1167-73.
[11] Larenza M, Landoni M, Levionnois O, Knobloch M, Kronen P,TheurillatR, et al. Stereoselective pharmacokinetics of Ketamineand norKetamineafter racemic Ketamine or S-Ketamineadministration during isofluraneanaesthesia in Shetland ponies. BrJ Anaesth2007;98:204-12.
[12] Geisslinger G, Hering W, Thomann P, Knoll R, Kamp H, Brune K.Pharmacokinetics and pharmacodynamics of Ketamine enantiomersinsurgical patients using a stereoselective analytical method. Br JAnaesth1993;70:666-71.
[13] Karpinski N, Dunn J, Hansen L, Masliah E. Subpial vacuolarmyelopathyafter intrathecal Ketamine: report of a case. Pain1997;73:103-5.
[14] Vranken J, Troost D, Wegener J, Kruis M, Van Der Vegt MH.Neuropathological findings after continuous intrathecaladministration ofS(+)-Ketamine for the management ofneuropathic cancer pain. Pain2005;117:231-5.
[15] De Kock M, Lavand'homme P, Waterloos H.'Balanced analgesia'in theperioperative period: is there a place for Ketamine? Pain2001;92:373-80.
[16] Sarton E, Teppema L, Olievier C, Nieuwenhuijs D, Matthes H,Kieffer B,et al. The involvement of the mu-opioid receptor inKetamine-induced re-spiratory depression and antinociception.Anesth Analg2001;93:1495-500, table of contents.
[17] Smith D, Bouchal R, Desanctis C, Monroe P, Amedro J, Perrotti J,et al.Properties of the interaction between Ketamine and opiatebinding sites invivo and in vitro. Neuropharmacology1987;26:1253-60.
[18] Hustveit O, Maurset A, Oye I. Interaction of the chiral forms ofKetaminewith opioid, phencyclidine, sigma and muscarinicreceptors. PharmacolToxicol1995;77:355-9.
[19] Mikkelsen S, Ilkjaer S, Brennum J, Borgbjerg F, Dahl J. The effectofnaloxone on Ketamine-induced effects on hyperalgesia andKetamine-induced side effects in humans. Anesthesiology1999;90:1539-45.
[20] Sun J, Wang X, Liu H, Xu J. Ketamine suppresses endotoxin-inducedNF-kappaB activation and cytokines production in theintestine. ActaAnaesthesiol Scand2004;48:317-21.
[21] Hill G, Anderson J, Lyden E. Ketamine inhibits theproinflammatorycytokine-induced reduction of cardiacintracellular cAMP accumulation.Anesth Analg1998;87:1015-9.
[22] Bartoc C, Frumento R, Jalbout M, Bennett-Guerrero E, Du E,Nishanian E.A randomized, double-blind, placebo-controlled studyassessing theanti-inflammatory effects of Ketamine in cardiacsurgical patients. JCardiothorac Vasc Anesth2006;20:217-22.
[23] Shibakawa Y, Sasaki Y, Goshima Y, Echigo N, Kamiya Y,Kurahashi K, etal. Effects of Ketamine and propofol oninflammatory responses of primaryglial cell cultures stimulatedwith lipopolysaccharide. Br J Anaesth2005;95:803-10.
[24] Visser E, Schug S. The role of Ketamine in pain management.BiomedPharmacother2006;60:341-8.
[25] Himmelseher, S. and Durieux, M. E.(2005) Anesthesiology,102(1),211-220.
[26] Elia, N. and Tramèr, M. R.(2005) Pain,113,61-70.
[27] Subramaniam, K.; Subramaniam, B. and Steinbrook, R. A.(2004)Anesth.Analg.,94,482-495.
[28] De Kock, M.; Lavand’Homme, P. and Waterloos, H.(2001) Pain,92,373-380.
[29] Angelini, G.; Ketzler, J. T. and Coursin, D. B (2001) Crit. CareClin.,17(4),863-880.
[30] Guillou, N.; Tanguy, M.; Seguin, P.; Branger, B.; Campion, J. P.andMalledant, Y.(2003) Anesth. Analg.,97(3),843-847.
[31] Dinarello CA. Proinflammatory and anti-inflammatory cytokines asmediators in the pathogenesis of septic shock. Chest,1997;112:321S–7S
[32] Beilin B, Shavit Y, Trabekin E, et al. The effects of postoperative painmanagement on immune response to surgery. Anesth Analg,2003;97:822–7
[33] Katz J, McCartney CJ. Current status of preemptive analgesia. Curr OpinAnaesthesiol,2002;15:435-441
[34] Cherry DA, Plummer JL, Gourlay GK, et al. Ketamine as an adjunct tomorphine in treatment of pain. Pain,1995;62:119–21
[35] Tverskoy M, Oz Y, Isakson A, et al. Preemptive effect of fentanyl andKetamine on postoperative pain and wound analgesia. Anesth Analg,1994;78:205–9
[36] Roytblat L, Korotkoruchko A, Katz J, et al. Postoperative pain: the effectof low-dose Ketamine in addition to general anesthesia. AnesthAnalg,1993;77:1161–3
[37] Hahnenkamp K, Nollet J, Van Aken HK, et al. Remifentail directlyactivates human N-methy1-D-aspartate receptors expressed in Xenopuscaveis oocytes. Anesthesiology,2004,100:1531-1537.
[38] Vanderah TW, Ossipov MH, Lai J, et al. Mechanisms of opioid inducedpain and antinociceptive tolerance: Descending facilitation and spinaldynorphin.Pain,2001;92:5-9.
[39] Borgland SL.A cute opioid receptor desensitization and tolerance: is therea link? Clin Exp Pharmacol Physiol,2001;28:147-154.
[40] Roytblat L, Talmor D, Rachinsky M, et al. Ketamine attenuates theinterleukin-6response after cardiopulmary bypass. Anesth Analg,1998;87:266–71
[41] Taniguchi T, Takemoto Y, Kanakura H, et al. The dose-related effects ofKetamine on mortality and cytokine responses to endotoxin-induced shockin rats. Anesth Analg,2003;97:1769–72
[42] Roytblat L, Roy-Shapira A, Geemberg L, et al. Preoperative low doseKetamine reduces serum interleukin-6response after abdominal hys-terectomy. Pain Clin,1996;9:327–34
[43] Xia JG, Peng J, Xiao H, et al. Effect of intravenous patient-controlledintravenous analgesia with small dose of Keta-mine during shock stage oncytokine balance in patients with severe burn. Zhongguo Wei Zhong BingJi Jiu Yi Xue,2006;18:32–5
[44] Kawasaki C, Kawasaki T, Ogata M, et al. Ketamine isomers suppresssuperantigen-induced proinflammatory cytokine production in humanwhole blood. Can J Anaesth,2001;48:819–23
[45] Kawasaki T, Ogata M, Kawasaki C, et al. Ketamine suppressesproinflammatory cytokine production in human whole blood in vitro.Anesth Analg,1999;89:665–9
[46] Marano MA, Fong Y, Moldawer LL, et al. Serum cachectin/tumor necrosisfactor in critically ill patients with burns correlates with infections andmortality. Surg Gynecol Obstet,1990;170:32–8
[47] Casey LC, Balk RA, Bone RC. Plasma cytokine and endotoxin levelscorrelate with survival in patients with the sepsis syndrome. Ann InternMed,1993;119:771–8
[48] Hill GA, Anderson JL, Lyden ER. Ketamine inhibits the proinflam-matory cytokine-induced reduction of cardiac intracellular cAMP accum-ulation. Anesth Analg,1998;87:1015–9
[49] Ying S, Robinson DS, Varney V, et al. TNFa mRNA expression in allergicinflammation. Clin Exp Allergy,1991;21:745–50
[50] Matsumori A, Yamada T, Suzuki H, et al. Increased circulating cytokinesin patients with myocarditis and cardiomyopathy. Br Heart J,1994;72:561–6
[51] Feghali CA, Wright TM. Cytokines in acute and chronic inflammation.Front Biosci,1997;2: d12–26