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.
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