Suppression of natural killer cell activity and promotion of tumor metastasis by ketamine, thiopental, and halothane, but not by propofol: mediating mechanisms and prophylactic measures.
Postoperative immunosuppression is partly ascribed to anesthesia and has been suggested to compromise patients' resistance to infection and tumor metastasis. We compared the effects of various anesthetics on natural killer (NK) cell activity and on resistance to experimental metastasis, and studied mediating mechanisms and prophylactic measures. Fischer 344 rats served as controls or were anesthetized for 1 h with ketamine, thiopental, halothane, or propofol. Anesthetized rats were either maintained in normothermia or left to spontaneously reach 33 degrees C-35 degrees C. Rats were then injected IV with MADB106 tumor cells, and 24 h later lung tumor retention was assessed, or 3 wk later, lung metastases were counted. Additionally, the number and activity of circulating NK cells were assessed after anesthesia. All anesthetics, except propofol, significantly reduced NK activity and increased MADB106 lung tumor retention or lung metastases. Hypothermia had no significant effects. Ketamine increased metastasis most potently, and this effect was markedly reduced in rats pretreated with a beta-adrenergic antagonist (nadolol) or with chronic small doses of an immunostimulator (polyriboinosinic:polyribocytidylic acid). Overall, the marked variation in the NK-suppressive effects of anesthetics seems to underlie their differential promotion of MADB106 metastasis. Prophylactic measures may include perioperative immunostimulation and the use of beta-blockers.


CONCLUSIONS
This study in a rat model of pulmonary metastasis demonstrates that some anesthetics, but not others, increase susceptibility to tumor metastasis, apparently by suppressing natural killer cell activity. Ketamine was most deleterious, and its effects were prevented by peripheral blockade of beta-adrenoceptors combined with low levels of immunostimulation.
*Neuroimmunology Research Unit, Department of Psychology, Tel Aviv University, Tel Aviv, Israel; and †Department of Anesthesiology, Rabin Medical Center-Beilinson Campus, Petach Tikva, affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Rivka
R
Melamed
Shahar
S
Bar-Yosef
Guy
G
Shakhar
Keren
K
Shakhar
Shamgar
S
Ben-Eliyahu
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000777:Anesthetics / Q000494:pharmacology*; D000778:Anesthetics, Dissociative / Q000494:pharmacology; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D018686:Anesthetics, Intravenous / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D006221:Halothane / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects*; D008175:Lung Neoplasms / Q000473:pathology; D008297:Male; D009248:Nadolol / Q000494:pharmacology; D009362:Neoplasm Metastasis / Q000473:pathology* / Q000517:prevention & control; D011070:Poly I-C / Q000494:pharmacology; D015742:Propofol / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013874:Thiopental / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D000319:Adrenergic beta-Antagonists; D000777:Anesthetics; D000778:Anesthetics, Dissociative; D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D000998:Antiviral Agents; D009248:Nadolol; D007649:Ketamine; D013874:Thiopental; D011070:Poly I-C; D006221:Halothane; D015742:Propofol