title: Hydrogen sulfide improves resuscitation via non-hibernatory mechanisms in a porcine shock model.
abstract: BACKGROUND
  Hydrogen sulfide (H2S) has been demonstrated to induce a "suspended animation-like" state in rodent models by reversible inhibition of cellular respiration and marked metabolic suppression and has been proposed as a potential pharmacologic adjunct to resuscitation from shock states. There are few data currently available about the mechanisms and efficacy of H2S in larger animals or humans. We examined H2S as a pharmacologic adjunct to resuscitation in a porcine model of severe traumatic shock.
  
  
  METHODS
  Twenty-one adult swine were assigned to three study arms: sham, H2S, and saline vehicle controls (SC). All pigs underwent laparotomy and instrumentation, and the two study arms then underwent a 35% controlled hemorrhage followed by 50 min of truncal ischemia via aortic cross-clamp. H2S (5 mg/kg) or saline was administered immediately before reperfusion, followed by 6 h of resuscitation. Resuscitation requirements, laboratory parameters, end-organ histology, and inflammatory product gene expression (by reverse transcription-polymerase chain reaction) were measured and compared between groups.
  
  
  RESULTS
  All animals survived to the 6-h postresuscitation time point. Both treatment arms demonstrated severe shock characterized by fluid and vasopressor requirements, metabolic acidosis, and hypotension compared with sham animals. Animals treated with H2S demonstrated significantly lower resuscitative requirements (total epinephrine 727 versus 3052 μg; P < 0.05), decreased fluid requirements, and lower serum lactate levels (7 versus 10 mmol/L) versus SC. Cardiac output was slightly decreased with H2S treatment but all other hemodynamic and metabolic parameters were equivalent between H2S and C groups. Serum liver and kidney biomarkers were unchanged, but administration of H2S was associated with a significant improvement in histopathologic liver and kidney injury scores compared with SC (both P < 0.05). Both study groups demonstrated significantly increased gene expression of hypoxia-inducible factor 1α and nitric oxide synthase (endogenous nitric oxide synthase, inducible nitric oxide synthase [iNOS]2, iNOS3) relative to sham animals. However, H2S was associated with increased expression of hypoxia-inducible factor 1α and decreased iNOS2 levels compared with SC.
  
  
  CONCLUSIONS
  Administration of H2S in a large-animal model of severe traumatic shock resulted in a significant decrease in resuscitative requirements, decreased metabolic acidosis, and less end-organ histologic injury compared with standard resuscitation. H2S did not induce profound metabolic suppression as seen in rodents, and appears to have alternative mechanisms of action in large animals.
authors.affiliation: Department of Surgery, Madigan Army Medical Center, Tacoma, Washington.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Satterly
authors.affiliation: Department of Clinical Investigation, Madigan Army Medical Center, Tacoma, Washington.
authors.forename: Shashikumar
authors.initials: S
authors.lastname: Salgar
authors.affiliation: Department of Pathology, Madigan Army Medical Center, Tacoma, Washington.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Hoffer
authors.affiliation: Department of Pathology, Madigan Army Medical Center, Tacoma, Washington.
authors.forename: James
authors.initials: J
authors.lastname: Hempel
authors.affiliation: Department of Clinical Investigation, Madigan Army Medical Center, Tacoma, Washington.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: DeHart
authors.affiliation: Department of Clinical Investigation, Madigan Army Medical Center, Tacoma, Washington.
authors.forename: Mark
authors.initials: M
authors.lastname: Wingerd
authors.affiliation: Department of Clinical Investigation, Madigan Army Medical Center, Tacoma, Washington.
authors.forename: Huang
authors.initials: H
authors.lastname: Raywin
authors.affiliation: Department of Clinical Investigation, Madigan Army Medical Center, Tacoma, Washington.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Stallings
authors.affiliation: Department of Surgery, Madigan Army Medical Center, Tacoma, Washington; Trauma and Acute Care Surgery Service, Legacy Emanuel Medical Center, Portland, Oregon. Electronic address: matthew.j.martin16.mil@mail.mil.
authors.forename: Matthew
authors.initials: M
authors.lastname: Martin
mesh_terms: D000138:Acidosis / Q000209:etiology / Q000517:prevention & control; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002302:Cardiac Output / Q000187:drug effects; D003131:Combined Modality Therapy; D006706:Homeostasis / Q000187:drug effects; D006862:Hydrogen Sulfide / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009102:Multiple Organ Failure / Q000209:etiology / Q000517:prevention & control; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D012151:Resuscitation / Q000379:methods*; D012771:Shock, Hemorrhagic / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D013552:Swine
chemical_list: D015415:Biomarkers; D020011:Protective Agents; D006862:Hydrogen Sulfide
keywords: Acidosis; Hydrogen sulfide; Multiorgan system failure; Resuscitation; Trauma