Canadian Journal of Anesthesia

, Volume 48, Issue 8, pp 819–823 | Cite as

Ketamine isomers suppress superantigen-induced proinflammatory cytokine production in human whole blood

  • Chika Kawasaki
  • Takashi Kawasaki
  • Masanori OgataEmail author
  • Koichiroh Nandate
  • Akio Shigematsu
Neuroanesthesia and Intensive Care



To investigate the efficacy of S(+)-ketamine and R(−)-ketamine on staphylococcal enterotoxin B (SEB)-induced tumour necrosis factor (TNF)-, interleukin (IL)-6, and IL-8 production in human whole bloodin vitro.


After Ethics Committee approval and informed consent, blood samples were obtained from ten healthy volunteers and diluted with five volumes of RPMI 1640. After adding different doses of ketamine isomers (0–1000 μM), the blood was stimulated with SEB (10 ng·mL−1). After a six-hour incubation period, the plasma TNF-activity was determined by the L929 cell cytotoxic assay and IL-6 and IL-8 concentrations were measured using an enzyme-linked immunoassay.


Ketamine isomers significantly suppressed SEB-induced TNF-production at concentrations exceeding 50 μM. Ketamine isomers at concentrations exceeding 100 μM also significantly suppressed SEB-induced IL-6 production. Furthermore, ketamine isomers at concentrations exceeding 500 μM significantly suppressed SEB-induced IL-8 production. There were no significant differences between the suppressive effects of S(+)-ketamine and R(−)-ketamine on SEB-induced proinflammatory cytokine production.


This study demonstrated that ketamine isomers suppressed SEB-induced TNF-, IL-6, and IL-8 production in human whole blood.


Ketamine Keta Staphylococcal Enterotoxin Proinflammatory Cytokine Production Tumour Necrosis Factor Production 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Les isomères de la kétamine suppriment la production de cytokine pro-inflammatoire induite par des superantigènes dans le sang complet humain



Vérifier l’efficacité de la S(+)-kétamine et de la R(−)-kétamine sur la production du facteur nécrosant des tumeurs (FNT)-a, de l’interleukine (IL)-6 et de l’IL-8, induits par l’entérotoxine B d’origine staphylococcique (EBS), dans le sang complet humain in vitro.


Après avoir obtenu l’approbation du Comité d’éthique et le consentement éclairé des participants, nous avons recueilli des échantillons sanguins chez dix volontaires en santé et les avons dilué dans cinq volumes de RPMI 1640. Après l’addition de différentes doses d’isomères de kétamine (0–1000 μM), le sang a été stimulé avec l’EBS (10 ng·mL−1). À la suite d’une incubation de six heures, l’activité plasmatique de TNF-a a été déterminée par le dosage de la cytotoxicité cellulaire L929, et les concentrations d’IL-6 et d’IL-8 ont été mesurées au moyen d’un dosage immuno-enzymatique.


Les isomères de kétamine ont supprimé de façon significative la production du TNF-a induit par l’EBS à des concentrations dépassant 50 μM, la production d’IL-6 induite par l’EBS à des concentrations au delà de 100 μM et la production d’IL-8 induite par l’EBS à des concentrations de plus de 500 μM. Il n’y a pas eu de différence significative entre les effets suppresseurs de la S(+)-kétamine et de la R(−)-kétamine sur la production de cytokine pro-inflammatoire induite pas l’EBS.


Cette étude démontre que les isomères de kétamine suppriment la production du FNT-a, d’IL-6 et d’IL-8, induits par l’EBS, dans le sang complet humain.


  1. 1.
    Leibovici L, Samra Z, Konigsberger H, Drucker M, Ashkenazi S, Pitlik SD. Long-term survival following bacteremia or fungemia. JAMA 1995; 274: 807–12.PubMedCrossRefGoogle Scholar
  2. 2.
    Bates DW, Pruess KE, Lee TH. How bad are bacteremia and sepsis? Outcomes in a cohort with suspected bacteremia. Arch Intern Med 1995; 155: 593–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Geerdes HF, Ziegler D, Lode H, et al. Septicemia in 980 patients at a university hospital in Berlin: prospective studies during 4 selected years between 1979 and 1989. Clin Infect Dis 1992; 15: 991–1002.PubMedGoogle Scholar
  4. 4.
    Marrack P, Kappler J. The staphylococcal enterotoxins and their relatives. Science 1990; 248: 705–11.PubMedCrossRefGoogle Scholar
  5. 5.
    Kappler J, Kotzin B, Herron L, et al. Vß-specific stimulation of human T cells by staphylococcal toxins. Science 1989; 244: 811–3.PubMedCrossRefGoogle Scholar
  6. 6.
    Kotb M. Bacterial pyrogenic exotoxins as superantigens. Clin Microbiol Rev 1995; 8: 411–26.PubMedGoogle Scholar
  7. 7.
    Lippmann M, Appel PL, Mok MS, Shoemaker WC. Sequential cardiorespiratory patterns of anesthetic induction with ketamine in critically ill patients. Crit Care Med 1983; 11: 730–4.PubMedCrossRefGoogle Scholar
  8. 8.
    Yli-Hankala A, Kirvelä M, Randell T, Lindgren L. Ketamine anaesthesia in a patient with septic shock. Acta Anaesthesiol Scand 1992; 36: 483–5.PubMedGoogle Scholar
  9. 9.
    White PF, Way WL, Trevor AJ. Ketamine — its pharmacology and therapeutic uses. Anesthesiology 1982; 56: 119–36.PubMedCrossRefGoogle Scholar
  10. 10.
    Takenaka I, Ogata M, Koga K, Matsumoto T, Shigematsu A. Ketamine suppresses endotoxin-induced tumor necrosis factor alpha production in mice. Anesthesiology 1994; 80: 402–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Koga K, Ogata M, Takenaka I, Matsumoto T, Shigematsu A. Ketamine suppresses tumor necrosis factor-activity and mortality in carrageenan-sensitized endotoxin shock model. Circ Shock 1995; 44: 160–8.Google Scholar
  12. 12.
    Kawasaki T, Ogata M, Kawasaki C, Ogata J, Inoue Y, Shigematsu A. Ketamine suppresses proinflammatory cytokine production in human whole blood in vitro. Anesth Analg 1999; 89: 665–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Ogata M, Fletcher MF, Kloczewiak M, et al. Effect of anticoagulants on binding and neutralization of lipopolysaccharide by the peptide immunoglobulin conjugate CAP18106–138 -immunoglobulin G in whole blood. Infect Immun 1997; 65: 2160–7.PubMedGoogle Scholar
  14. 14.
    Ruff MR, Gifford GE. Purification and physio-chemical characterization of rabbit tumor necrosis factor. J Immunol 1980; 125: 1671–7.PubMedGoogle Scholar
  15. 15.
    Akatsuka H, Imanishi K, Inada K, Yamashita H, Hoshida M, Uchiyama T. Production of tumor necrosis factors by human T cells stimulated by a superantigen, toxic shock syndrome toxin-1. Clin Exp Immunol 1994; 96: 422–6.PubMedGoogle Scholar
  16. 16.
    Bergdoll MS. Enterotoxins.In: Ajl SJ, Monte TC, Kadis S (Eds.) Microbial Toxins. New York: Academic Press, 1970: 265–326.Google Scholar
  17. 17.
    Matsuyama S, Koide Y, Yoshida TO. HLA class II molecule-mediated signal transduction mechanism responsible for the expression of interleukin-1ß and tumor necrosis factorgenes induced by a staphylococcal superantigen. Eur J Immunol 1993; 23: 3194–202.PubMedCrossRefGoogle Scholar
  18. 18.
    Cauwels A, Wan E, Leismann M, Tuomanen E. Coexistence of CD-14-dependent and independent pathways for stimulation of human monocytes by gram-positive bacteria. Infect Immun 1997; 65: 3255–60.PubMedGoogle Scholar
  19. 19.
    Yan Z, Yang DCH, Neill R, Jett M. Production of tumor necrosis factor alpha in human T lymphocytes by staphylococcal enterotoxin B correlates with toxininduced proliferation and is regulated through protein kinase C. Infect Immun 1999; 67: 6611–8.PubMedGoogle Scholar
  20. 20.
    Domino EF, Zsigmond EK, Domino LE, Domino KE, Kothary SP, Domino SE. Plasma levels of ketamine and two of its metabolites in surgical patients using a gas Chromatographic mass fragmentographic assay. Anesth Analg 1982; 61: 87–92.PubMedCrossRefGoogle Scholar
  21. 21.
    Klepstad P, Maurset A, Moberg ER, Øye I. Evidence of a role for NMDA receptors in pain perception. Eur J Pharmacol 1990; 187: 513–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Hustveit O, Maurset A, Øye I. Interaction of the chiral forms of ketamine with opioid, phencyclidine, and muscarinic receptors. Pharmacol Toxicol 1995; 77: 355–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Szekely A, Heindl B, Zahler S, Conzen PF, Becker BF. S(+)-ketamine, but not R(−)-ketamine, reduces postischemic adherence of neutrophils in the coronary system of isolated guinea pig hearts. Anesth Analg 1999; 88: 1017–24.PubMedCrossRefGoogle Scholar
  24. 24.
    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.PubMedCrossRefGoogle Scholar

Copyright information

© Canadian Anesthesiologists 2001

Authors and Affiliations

  • Chika Kawasaki
    • 1
  • Takashi Kawasaki
    • 1
  • Masanori Ogata
    • 1
    Email author
  • Koichiroh Nandate
    • 1
  • Akio Shigematsu
    • 1
  1. 1.Department of AnesthesiologyUniversity of Occupational and Environmental HealthKitakyushuJapan

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