Enhanced oxidative and nitrosative stress resulting from increased formation of reactive oxygen (ROS) and reactive nitrogen (RNS) species is a common phenomenon during sepsis and referred to assume major importance during the development of shock-related hypotension, impairment of microcirculatory perfusion, mitochondrial dysfunction, and tissue injury (1). Because there is evidence in the literature that increasing the FIO2 leads to enhanced ROS production (2), current guidelines recommend that the least inspiratory O2 fraction (FIO2) be used that is associated with an arterial O2 tension (PaO2) of 55 to 80 mmHg or an arterial hemoglobin O2 saturation of 88% to 95%. In fact, the toxic effects of hyperoxia are well established for more than a century (2), the lung being particularly vulnerable to O2 toxicity, which presents as alveolitis, hyaline membranes and hemorrhagic pulmonary edema (2, 3). However, nothing is simple and easy: hyperoxia-related lung injury requires either prolonged exposure or the combination with “injurious ventilation” (3). Moreover, in various shock models of hemorrhagic shock (4) and ischemia/reperfusion injury (5, 6), pure O2 breathing reversed arterial hypotension (4, 5) and exerted anti-inflammatory (5) and antiapoptotic (6) properties, and these beneficial effects were confirmed during murine (7) and porcine fecal (3) peritonitis. It must be emphasized that both timing and dosing of hyperoxia seem to be crucial in this context: During murine zymosan-induced shock, pure O2 breathing improved survival, reduced hyperinflammation as documented by attenuated cytokine release, and increased the activity of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase. However, the therapeutic effects of pure O2 breathing were present only when hyperoxia was initiated within the first 12 h, and the treatment was most efficacious when applied within the first 4 h (8). Moreover, even early administration of hyperoxia failed to exert major beneficial effects when the duration of the individual exposure was longer than 3 h (8). Unfortunately, this study (8) investigated an unresuscitated murine model of zymosan-induced shock, i.e., a condition of sterile systemic hyperinflammation, which certainly does not represent the clinical reality of septic shock. In this issue of Shock, Waisman et al. (9) now report on the effect of various dosing and timing-regimens of O2 breathing in rats with polymicrobial sepsis resulting from cecal ligation and puncture. The authors compared continuous 100% O2 breathing for 20 h, continuous 70% O2 breathing for 48 h, and intermittent 100% O2 breathing, the latter being applied for 6 h daily over 48 h. Videomicroscopy was used to assess pulmonary microvascular perfusion and capillary leakage, bronchoalveolar lavage fluid was obtained for measurement of cytokines and parameters of ROS and RNS release, and tissue morphometry allowed investigating lung inflammation and parenchymal condensation. Intermittent hyperoxia markedly attenuated lung injury and inflammation and did not aggravate oxidative or nitrosative stress. Of note, albeit hyperoxia was previously reported to cause macrocirculatory and microcirculatory vasoconstriction as a result of decreased local NO availability (10), it did not exert deleterious effects of capillary blood flow. In this context, the hyperoxia-induced respiratory acidosis may have assumed importance: Waisman et al. confirmed the well-known pure O2 breathing-induced fall in respiratory drive already described in conscious volunteers some decades ago, and this increase in arterial CO2 partial pressure (from 32 ± 3 mmHg in the air-breathing animals to 54 ± 6 mmHg in rats that had intermittent 100% O2) may have counterbalanced any hyperoxia-related microvascular constriction. Why can hyperoxia exert anti-inflammatory properties during systemic hyperinflammation after trauma and hemorrhage, sepsis, or ischemia/reperfusion injury? Clearly, at least during the acute phase, all these conditions are associated with tissue hypoxia resulting from circulatory depression and impaired microcirculatory perfusion. Furthermore, if present, additional blunt chest trauma causes (regional) alveolar hypoxia and, consecutively, hypoxemia. All these factors are known as most potent triggers of systemic inflammation (11), which could be counteracted by appropriately timed and dosed hyperoxia. The findings by Waisman et al. are fascinating, because they originate from a polymicrobial model of sepsis rather than a condition of sterile systemic hyperinflammation. Clearly, it can be argued that it has only limited clinical relevance because of the lacking resuscitative measures and the fact that the hyperoxic exposure was always initiated simultaneously with the induction of cecal ligation and puncture, i.e., nearly using a pretreatment design. Nevertheless, the authors have the merit of highlighting the potential benefit of pure O2 breathing during sepsis, provided the window of opportunity and the appropriate dosing are respected. Therefore, as far as (early and transitory) hyperoxia in sepsis is concerned: more than just enhanced O2 transport, it is time to recognize! ACKNOWLEDGMENTS Supported by the Deutsche Forschungsgemeinschaft (Klinische Forschergruppe 200 “Die Entzündungsantwort nach Muskulo-Skeletalem Trauma”).
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Dec 30, 2013
Donald M Null + 9
