Inhaled, nebulized sodium nitrite protects in murine and porcine experimental models of hemorrhagic shock and resuscitation by limiting mitochondrial injury

Objective The cellular injury that occurs in the setting of hemorrhagic shock and resuscitation (HS/R) affects all tissue types and can drive altered inflammatory responses. Resuscitative adjuncts hold the promise of decreasing such injury. Here we test the hypothesis that sodium nitrite (NaNO 2 ), delivered as a nebulized solution via an inhalational route, protects against injury and inflammation from HS/R. Methods Mice underwent HS/R to a mean arterial pressure (MAP) of 20 or 25 mmHg. Mice were resuscitated with Lactated Ringers after 90–120 min of hypotension. Mice were randomized to receive nebulized NaNO 2 via a flow through chamber (30 mg in 5 mL PBS). Pigs (30–35 kg) were anesthetized and bled to a MAP of 30–40 mmHg for 90 min, randomized to receive NaNO 2 (11 mg in 2.5 mL PBS) nebulized into the ventilator circuit starting 60 min into the hypotensive period, followed by initial resuscitation with Hextend. Pigs had ongoing resuscitation and support for up to four hours. Hemodynamic data were collected continuously. Results NaNO 2 limited organ injury and inflammation in murine hemorrhagic shock. A nitrate/nitrite depleted diet exacerbated organ injury, as well as mortality, and inhaled NaNO 2 significantly reversed this effect. Furthermore, NaNO 2 limited mitochondrial oxidant injury. In porcine HS/R, NaNO 2 had no significant influence on shock induced hemodynamics. NaNO 2 limited hypoxia/reoxia or HS/R-induced mitochondrial injury and promoted mitochondrial fusion. Conclusion NaNO 2 may be a useful adjunct to shock resuscitation based on its limitation of mitochondrial injury.