Benjamin Kautza1, Hernando Gomez2, Daniel Escobar1, Catherine Corey3, Bilal Ataya1, Jason Luciano1, Ana Maria Botero1, Lisa Gordon4, John Brumfield1, Silvia Martinez1, Andre Holder4, Olufunmilayo Ogundele4, Michael Pinsky2, Sruti Shiva5, Brian S Zuckerbraun6. 1. Department of Surgery, USA. 2. Department of Critical Care Medicine, USA; The Center for Critical Care Nephrology, USA. 3. Vascular Medicine Institute, University of Pittsburgh, USA. 4. Department of Critical Care Medicine, USA. 5. Department of Pharmacology & Chemical Biology, USA; Vascular Medicine Institute, University of Pittsburgh, USA. Electronic address: sss43@pitt.edu. 6. VA Pittsburgh Healthcare System, USA; Department of Surgery, USA; The Center for Critical Care Nephrology, USA; Vascular Medicine Institute, University of Pittsburgh, USA. Electronic address: zuckerbraunbs@upmc.edu.
Abstract
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 (NaNO2), 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 NaNO2 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 NaNO2 (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: NaNO2 limited organ injury and inflammation in murine hemorrhagic shock. A nitrate/nitrite depleted diet exacerbated organ injury, as well as mortality, and inhaled NaNO2 significantly reversed this effect. Furthermore, NaNO2 limited mitochondrial oxidant injury. In porcine HS/R, NaNO2 had no significant influence on shock induced hemodynamics. NaNO2 limited hypoxia/reoxia or HS/R-induced mitochondrial injury and promoted mitochondrial fusion. CONCLUSION: NaNO2 may be a useful adjunct to shock resuscitation based on its limitation of mitochondrial injury. Published by Elsevier Inc.
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 (NaNO2), 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 NaNO2 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 NaNO2 (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:NaNO2 limited organ injury and inflammation in murinehemorrhagic shock. A nitrate/nitrite depleted diet exacerbated organ injury, as well as mortality, and inhaled NaNO2 significantly reversed this effect. Furthermore, NaNO2 limited mitochondrial oxidant injury. In porcine HS/R, NaNO2 had no significant influence on shock induced hemodynamics. NaNO2 limited hypoxia/reoxia or HS/R-induced mitochondrial injury and promoted mitochondrial fusion. CONCLUSION:NaNO2 may be a useful adjunct to shock resuscitation based on its limitation of mitochondrial injury. Published by Elsevier Inc.
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