title: Effects of inhalation of low-dose nitrite or carbon monoxide on post-reperfusion mitochondrial function and tissue injury in hemorrhagic shock swine.
abstract: BACKGROUND
  Tissue reperfusion following hemorrhagic shock may paradoxically cause tissue injury and organ dysfunction by mitochondrial free radical expression. Both nitrite and carbon monoxide (CO) may protect from this reperfusion injury by limiting mitochondrial free radial production. We explored the effects of very small doses of inhaled nitrite and CO on tissue injury in a porcine model of hemorrhagic shock.
  
  
  METHODS
  Twenty pigs (mean wt. 30.6 kg, range 27.2 to 36.4 kg) had microdialysis catheters inserted in muscle, peritoneum, and liver to measure lactate, pyruvate, glucose, glycerol, and nitrite. Nineteen of the pigs were bled at a rate of 20 ml/min to a mean arterial pressure of 30 mmHg and kept between 30 and 40 mmHg for 90 minutes and then resuscitated. One pig was instrumented but not bled (sham). Hemorrhaged animals were randomized to inhale nothing (control, n = 7), 11 mg nitrite (nitrite, n = 7) or 250 ppm CO (CO, n = 5) over 30 minutes before fluid resuscitation. Mitochondrial respiratory control ratio was measured in muscle biopsies. Repeated measures from microdialysis catheters were analyzed in a random effects mixed model.
  
  
  RESULTS
  Neither nitrite nor CO had any effects on the measured hemodynamic variables. Following inhalation of nitrite, plasma, but not tissue, nitrite increased. Following reperfusion, plasma nitrite only increased in the control and CO groups. Thereafter, nitrite decreased only in the nitrite group. Inhalation of nitrite was associated with decreases in blood lactate, whereas both nitrite and CO were associated with decreases in glycerol release into peritoneal fluid. Following resuscitation, the muscular mitochondrial respiratory control ratio was reduced in the control group but preserved in the nitrite and CO groups.
  
  
  CONCLUSIONS
  We conclude that small doses of nebulized sodium nitrite or inhaled CO may be associated with intestinal protection during resuscitation from severe hemorrhagic shock.
authors.affiliation: Department of Critical Care Medicine, Cardiopulmonary Research Laboratory, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA, 15260, USA. hakon.haugaa@medisin.uio.no.|Department of Emergencies and Critical Care, Oslo University Hospital, Sognsvannsveien 27 0424, Oslo, Norway. hakon.haugaa@medisin.uio.no.|Institute of Clinical Medicine, University of Oslo, Sognsvannsveien 20 0424, Oslo, Norway. hakon.haugaa@medisin.uio.no.
authors.forename: Håkon
authors.initials: H
authors.lastname: Haugaa
authors.affiliation: Department of Critical Care Medicine, Cardiopulmonary Research Laboratory, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA, 15260, USA. gomezh@upmc.edu.|Center for Critical Care Nephrology, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA, 15261, USA. gomezh@upmc.edu.
authors.forename: Hernando
authors.initials: H
authors.lastname: Gómez
authors.affiliation: Department of Critical Care Medicine, Cardiopulmonary Research Laboratory, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA, 15260, USA. maberry50@gmail.com.
authors.forename: Donald R
authors.initials: DR
authors.lastname: Maberry
authors.affiliation: Department of Critical Care Medicine, Cardiopulmonary Research Laboratory, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA, 15260, USA. holderal@upmc.edu.
authors.forename: Andre
authors.initials: A
authors.lastname: Holder
authors.affiliation: Department of Critical Care Medicine, Cardiopulmonary Research Laboratory, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA, 15260, USA. ogundele99@gmail.com.
authors.forename: Olufunmilayo
authors.initials: O
authors.lastname: Ogundele
authors.affiliation: Institute of Clinical Medicine, University of Oslo, Sognsvannsveien 20 0424, Oslo, Norway. aboteroqui@nshs.edu.
authors.forename: Ana Maria B
authors.initials: AM
authors.lastname: Quintero
authors.affiliation: Institute of Clinical Medicine, University of Oslo, Sognsvannsveien 20 0424, Oslo, Norway. escobarda@uthscscsa.edu.
authors.forename: Daniel
authors.initials: D
authors.lastname: Escobar
authors.affiliation: Department of Emergencies and Critical Care, Oslo University Hospital, Sognsvannsveien 27 0424, Oslo, Norway. t.i.tonnessen@medisin.uio.no.|Institute of Clinical Medicine, University of Oslo, Sognsvannsveien 20 0424, Oslo, Norway. t.i.tonnessen@medisin.uio.no.
authors.forename: Tor Inge
authors.initials: TI
authors.lastname: Tønnessen
authors.affiliation: Department of Critical Care Medicine, Safar Center for Resuscitation Research University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA, 15261, USA. airgood@susqu.edu.
authors.forename: Hannah
authors.initials: H
authors.lastname: Airgood
authors.affiliation: Department of Critical Care Medicine, Safar Center for Resuscitation Research University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA, 15261, USA. dezfulianc@upmc.edu.
authors.forename: Cameron
authors.initials: C
authors.lastname: Dezfulian
authors.affiliation: Department of Critical Care Medicine, Safar Center for Resuscitation Research University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA, 15261, USA. kenny.elizabeth@medstudent.pitt.edu.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kenny
authors.affiliation: Department of Pharmacology and Chemical Biology, Vascular Medicine Institute, Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA, 15261, USA. sss43@pitt.edu.
authors.forename: Sruti
authors.initials: S
authors.lastname: Shiva
authors.affiliation: Department of Surgery, University of Pittsburgh, 3380 Boulevard of the Allies 390, Pittsburgh, PA, 15213, USA. zuckerbraunbs@upmc.edu.
authors.forename: Brian
authors.initials: B
authors.lastname: Zuckerbraun
authors.affiliation: Department of Critical Care Medicine, Cardiopulmonary Research Laboratory, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA, 15260, USA. pinskymr@ccm.upmc.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Pinsky
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D002248:Carbon Monoxide / Q000008:administration & dosage*; D017551:Microdialysis / Q000379:methods; D008928:Mitochondria / Q000502:physiology*; D009573:Nitrites / Q000008:administration & dosage*; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013552:Swine; D016896:Treatment Outcome
chemical_list: D009573:Nitrites; D002248:Carbon Monoxide