title: Inhaled, nebulized sodium nitrite protects in murine and porcine experimental models of hemorrhagic shock and resuscitation by limiting mitochondrial injury.
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.
  
  
  CONCLUSIONS
  NaNO2 may be a useful adjunct to shock resuscitation based on its limitation of mitochondrial injury.
authors.affiliation: Department of Surgery, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kautza
authors.affiliation: Department of Critical Care Medicine, USA; The Center for Critical Care Nephrology, USA.
authors.forename: Hernando
authors.initials: H
authors.lastname: Gomez
authors.affiliation: Department of Surgery, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Escobar
authors.affiliation: Vascular Medicine Institute, University of Pittsburgh, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Corey
authors.affiliation: Department of Surgery, USA.
authors.forename: Bilal
authors.initials: B
authors.lastname: Ataya
authors.affiliation: Department of Surgery, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Luciano
authors.affiliation: Department of Surgery, USA.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Botero
authors.affiliation: Department of Critical Care Medicine, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Gordon
authors.affiliation: Department of Surgery, USA.
authors.forename: John
authors.initials: J
authors.lastname: Brumfield
authors.affiliation: Department of Surgery, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Martinez
authors.affiliation: Department of Critical Care Medicine, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: Holder
authors.affiliation: Department of Critical Care Medicine, USA.
authors.forename: Olufunmilayo
authors.initials: O
authors.lastname: Ogundele
authors.affiliation: Department of Critical Care Medicine, USA; The Center for Critical Care Nephrology, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Pinsky
authors.affiliation: Department of Pharmacology & Chemical Biology, USA; Vascular Medicine Institute, University of Pittsburgh, USA. Electronic address: sss43@pitt.edu.
authors.forename: Sruti
authors.initials: S
authors.lastname: Shiva
authors.affiliation: 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.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Zuckerbraun
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D009330:Nebulizers and Vaporizers; D009573:Nitrites / Q000097:blood; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000517:prevention & control*; D012977:Sodium Nitrite / Q000494:pharmacology*; D013552:Swine
chemical_list: D009573:Nitrites; D012977:Sodium Nitrite
keywords: Hemorrhage; Mitochondria; Nitrite; Respiration; Shock