ANESTHESIA AND THE IMMUNE RESPONSE: EVIDENCE FOR AN "ISOFLURANE PARADOX"?
Wagner, Florian; Radermacher, Peter; Stahl, Wolfgang
Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Klinik für Anästhesiologie, Universitätsklinikum, Ulm, Germany
It is well established that surgery and anesthesia may cause immunosuppression (1, 2), but depending on the experimental conditions (i.e., in vitro versus in vivo studies, the concentration of the molecule investigated, the inflammatory stimulus used, the method chosen to evaluate the immune response, etc.), there is some controversy about the role of anesthesia per se (3-6). For example, whereas some authors reported ether-induced leukocytosis (7, 8), others demonstrated that chloroform (9) and halothane (10) impaired lymphocyte and polymorphonuclear leukocyte motility and splenocyte antibody production (11), and thus suppressed host defense in murine peritonitis (12). Clearly, the choice of the anesthetic agent assumes major importance: "all intravenous anesthetic agents modify some aspect of the immune response" (5), however, with marked quantitative and qualitative differences between the individual substances (13-16). By contrast, despite some controversial results (15-17), most of the existing literature reported that the newer volatile anesthetics isoflurane, sevoflurane, and desflurane attenuate the release of proinflammatory cytokines after stimulation with endotoxin, TNF-α or IFN-γ, both in vitro (18-20) and in vivo (21-27). In endotoxic animals, these anti-inflammatory properties were associated with attenuated hypotension (21, 27) and lung injury (24, 27), ultimately resulting in improved survival (27). These beneficial effects were confirmed both in murine kidney ischemia/reperfusion injury (28) and cecal ligation and puncture-induced peritonitis (29).
In this issue of Shock, Soehnlein et al. (30) report on the effects of isoflurane anesthesia during ovine endotoxemia. In sharp contrast to the effects during rodent endotoxemia (21, 24, 27), isoflurane markedly enhanced the histological lung injury caused by increased tissue inflammation and activation of peripheral polymorphonuclear leukocytes. These effects coincided with hypotension and a lower cardiac output. These findings are intriguing because they originate from a long-term large-animal model, which has two major advantages: endotoxin was administered as a continuous i.v. infusion, thus avoiding the acute circulatory depression induced by bolus injection, and isoflurane was titrated to end-tidal concentrations similar to clinical practice. To explain the marked discrepancy with the existing literature, the authors raise the issue of species differences. In fact, Boyd (8) already reported that ether anesthesia produced leukocytosis or leukopenia depending on the animal studied. Nevertheless, several issues need to be addressed. First, the authors compared isoflurane-anesthetized animals with conscious awake sheep. Thus, the title of the study is somewhat misleading because the experiment does not allow concluding on anesthesia in general, but only on isoflurane anesthesia. Several other authors also emphasized that different anesthetic agents may result in a markedly different inflammatory response (13-17, 19). Furthermore, it remains open whether the necessity of mechanical ventilation also contributed to the aggravated lung injury, in particular, taking into account the possibly injurious tidal volumes of 11 mL·kg−1. Su et al. (31) demonstrated that low-tidal volume ventilation (6 mL·kg−1 vs. 12 mL·kg−1) reduced lung damage during ovine fecal peritonitis. Second, it is unclear whether the effects observed were caused by the anesthesia per se and/or to the circulatory depression affiliated with the isoflurane administration. Clearly, the isoflurane-related hypotension coincided with a lower cardiac output, which presumably caused inadequate tissue O2 supply: the isoflurane-treated animals presented with a markedly lower arterial base excess, indicating tissue ischemia, which is well established to activate various local vascular and inflammatory mediators (32). It can only be speculated, for example, whether the use of xenon, which is devoid of the isoflurane-induced circulatory depression (33), may have yielded completely different results. In this context, the fluid regimen must also be questioned: all animals received the same amount of saline (3 mL·kg−1·h−1), no matter whether they breathed spontaneously or not. This approach most likely contributed to the circulatory effect of isoflurane: central venous pressure tended to be lower despite the higher intrathoracic pressure in the anesthetized sheep, and consequently, the stroke volume derived from the cardiac output and heart rate data was approximately 25% higher in the awake animals. Third, isoflurane anesthesia was associated with a lower whole-body O2 uptake, which ultimately resulted in a lower body temperature. Clearly, core temperature did not fall less than 38°C in the isoflurane group, and thus any proinflammatory effect of hypothermia (34) most likely can be ruled out. Nevertheless, it should be noted that treatment of fever higher than 39°C resulting in core temperatures of 37.5°C to 38.5°C reduced survival time in ovine fecal peritonitis (35). Finally, heart rate was higher in the control animals, suggesting a rise in sympathetic tone with increased catecholamine levels. Endotoxemia per se not only increases blood catecholamine concentrations (36), but also stimulates catecholamine release from phagocytes, which in turn aggravates lung injury caused by α2-adrenoceptor stimulation (37). On the other hand, epinephrine administration attenuated the systemic inflammatory response during human endotoxemia because of β-adrenoceptor activation (38), and different catecholamines differentially affected proinflammatory cytokine production during porcine endotoxemia (39). Unfortunately, blood catecholamine levels were not measured, and therefore, it remains open to which extent a different endogenous catecholamine release modulated the response to the endotoxin challenge. The complex interaction of catecholamine release and inflammation, however, was reported to assume particular importance in the context of anesthesia endotoxin-induced lung injury: both the mixed adrenoceptor agonist norepinephrine (40) and the β-antagonist propranolol (41) counteracted the anti-inflammatory properties of isoflurane in rat endotoxemia.
In conclusion, what do we learn from the intriguing findings by Soehnlein et al. (30)? Anesthetic agents may have profound immunomodulatory properties in vivo, but appropriate experimental conditions and control groups are mandatory to differentiate between direct effects of anesthesia per se and indirect effects related to systemic hemodynamics and/or release of other mediators that influence the immune system.
1. Humphrey LJ, Wingard DW, Lang R: The effect of surgery and anesthesia on the immunologic responsiveness of the rat. Surgery
2. Walton B: Effects of anaesthesia and surgery on immune status. Br J Anaest
3. Bruce DL, Wingard DW: Anesthesia and the immune response. Anesthesiology
4. Edwards AE, Gemmel LW, Mankin PP, Smith CJ, Allen JC, Hunter A: The effects of three different anaesthestics on the immune response. Anaesthesia
5. Galley HF, DiMatteo MA, Webster NR: Immunomodulation by anaesthetic, sedative and analgesic agents: does it matter? Intensive Care Med
6. Kotani N, Hashimoto H, Sessler DI, Moraoka M, Hashiba E, Kubota T, Matsuki A: Supplemental intraoperative oxygen augments antimicrobial and proinflammatory responses of alveolar macrophages. Anesthesiology
7. Chadbourne TL: Ether leukocytosis. Philadelphia Med J
8. Boyd EM: Post-anaesthetic leucocytosis. CMAJ
9. Lowenburg H: Studies on the effect of narcosis on the rate of locomotion of polymorphonuclear leukocytes in vitro
. Am J Med Sci
10. Nunn JF, Sharp JA, Kimball KL: Reversible effect of an inhalational anaesthetic on lymphocyte motility. Nature
11. Humphrey LJ, Wingard DW, Lang R: Effect of halothane on spleen cells: in vitro
studies on reversibility of immunosuppression. Surgery
12. Bruce DL: Effect of halothane anesthesia on experimental Salmonella
peritonitis in mice. J Surg Res
13. Takenaka I, Ogata M, Koga K, Matsumoto T, Shigematsu A: Ketamine suppresses endotoxin-induced tumor necrosis factor alpha production in mice. Anesthesiology
14. Larsen B, Hoff G, Wilhelm W, Buchinger H, Wanner GA, Bauer M: Effect of intravenous anaesthetics on spontaneous and endotoxin-stimulated cytokine response in cultured human blood. Anesthesiology
15. Nader-Djalal N, Knight PR, Bacon MF, Taiut AR, Kennedy TI, Johnson KJ: Alterations in the course of acid-induced lung injury in rats after general anesthesia: volatile anesthetics versus ketamine. Anesth Analg
16. Takala RSK, Soukka HR, Salo MS, Kirvelä OA, Kääpä PO, Rajamäki AA, Riutta A, Aantaa RE: Pulmonary inflammatory mediators after sevoflurane and thiopentone anaesthesia in pigs. Acta Anaesthesiol Scand
17. Itoh T, Hirota K, Hisano T, Namba T, Fukuda K: The volatile anesthetics halothane and isoflurane differentially modulate proinflammatory cytokine-induced p38 mitogen-activated protein kinase activation. J Anesth
18. Sato W, Enzan K, Masaki Y, Kayaba M, Suzuki M: The effect of isoflurane on the secretion of TNF-α and IL-1β from LPS-stimulated human peripheral monocytes. Masui
19. de Rossi L, Brueckmann M, Rex S, Barderschneider M, Buhre W, Rossaint R: Xenon and isoflurane differentially modulate lipopolysaccharide-induced activation of the nuclear transcription factor κB and production of tumor necrosis factor-α and interleukin-6 in monocytes. Anesth Analg
20. Kim JA, Li L, Zuo Z: Delayed treatment with isoflurane attenuates lipopolysaccharide and interferon γ-induced activation and injury of mouse microglial cells. Anesthesiology
21. Plachinta RV, Hayes JK, Cerilli LA, Rich GF: Isoflurane pre-treatment inhibits lipopolysaccharide-induced inflammation in rats. Anesthesiology
22. Hofstetter C, Flondor M, Boost KA, Koehler P, Bosman M, Pfeilschifter J, Zwissler B, Mühl H: A brief exposure to isoflurane (50 s) significantly impacts on plasma cytokine levels in endotoxemic rats. Int Immunopharmacol
23. Boost KA, Hofstetter C, Flondor M, Betz C, Homann M, Pfeilschifter J, Muehl H, Zwissler B: Desflurane differentially affects the release of proinflammatory cytokines in plasma and bronchoalveolar fluid of endotoxemic rats. Int J Mol Med
24. Reutersham J, Chang D, Hayes JK, Ley K: Protective effects of isoflurane pretreatment in endotoxin-induced lung injury. Anesthesiology
25. Hofstetter C, Boost KA, Flondor M, Basagan-Mogol E, Betz C, Homann M, Muhl H, Pfeilschifter J, Zwissler B: Anti-inflammatory effects of sevoflurane and mild hypothermia in endotoxemic rats. Acta Anaesthesiol Scand
26. Flondor M, Hofstetter C, Boost KA, Betz C, Homann M, Zwsiller B: Isoflurane inhalation after induction of endotoxemia in rats attenuates the systemic cytokine response. Eur Surg Res
27. Li QF, Zhu YS, Jiang H, Xu H, Sun Y: Isoflurane preconditioning ameliorates endotoxin-induced acute lung injury and mortality in rats. Anesth Analg
28. Lee HT, Kim M, Kim M, Kim NL, Billings FT, D'Agati VD, Emala CW: Isoflurane protects against renal ischemia and reperfusion injury and modulates leukocyte infiltration in mice. Am J Physiol Renal Physiol
29. Lee HT, Emala CW, Joo JD, Kim M: Isoflurane improves survival and protects against renal and hepatic injury in murine septic peritonitis. Shock
30. Soehnlein O, Eriksson S, Hjelmqvsit H, Andersson A, Mörgelin M, Lindbom L, Rundsgren M, Frithiof R: Anesthesia aggravates lung damage and precipitates hypotension in endotoxemic sheep. Shock
31. Su F, Nguyen ND, Creteur J, Cai Y, Nagy N, Anh-Dung H, Amaral A, Bruzzi de Carvalho F, Chochrad D, Vincent JL: Use of low tidal volume in septic shock may decrease severity of subsequent acute lung injury. Shock
32. Nathan C: Oxygen and the inflammatory cell. Nature
33. Wappler F, Rossaint R, Baumert J, Scholz J, Tonner PH, van Aken H, Berendes E, Klein J, Gommers D, Hammerle A, et al.: Xenon Multicenter Study Research Group: multicenter randomized comparison of xenon and isoflurane on left ventricular function in patients undergoing elective surgery. Anesthesiology
34. Stewart CR, Landseadel JP, Gurka MJ, Fairchild KD: Hypothermia increases interleukin-6 and interleukin-10 in juvenile endotoxemic mice. Pediatr Crit Care Med
35. Su F, Nguyen ND, Wang Z, Cai Y, Rogiers P, Vincent JL: Fever control in septic shock: beneficial or harmful? Shock
36. Fong YM, Marano MA, Moldawer LL, Wei H, Calvano SE, Kenney JS, Allison AC, Cerami A, Shires GT, Lowry SF: The acute splanchnic and peripheral tissue metabolic response to endotoxin in humans. J Clin Invest
37. Flierl MA, Rittirsch D, Nadeau BA, Chen AJ, Sarma JV, Zetoune FS, McGuire SR, List RP, Day DE, Hoesel LM, et al.: Phagocyte-derived catecholamines enhance acute inflammatory injury. Nature
38. van der Poll T, Coyle SM, Barbosa K, Braxton CC, Lowry SF: Epinephrine inhibits tumor necrosis factor-alpha and potentiates interleukin 10 production during human endotoxemia. J Clin Invest
39. Bergmann M, Gornikiewicz A, Tamandl D, Exner R, Roth E, Függer R, Götzinger P, Sautner T: Continuous therapeutic epinephrine but not norepinephrine prolongs splanchnic IL-6 production in porcine endotoxic shock. Shock
40. Hofstetter C, Boost KA, Hoegl S, Flondor M, Scheller B, Muhl H, Pfeilschifter J, Zwissler B: Norepinephrine and vasopressin counteract anti-inflammatory effects of isoflurane in endotoxemic rats. Int J Mol Med
41. Boost KA, Flondor M, Hofstetter C, Platacis I, Stegewerth K, Hoegl S, Nguyen T, Muhl H, Zwissler B: The beta-adrenoceptor antagonist propranolol counteracts anti-inflammatory effects of isoflurane in rat endotoxemia. Acta Anaesthesiol Scand
©2010The Shock Society
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read