title: Antithrombin attenuates myocardial dysfunction and reverses systemic fluid accumulation following burn and smoke inhalation injury: a randomized, controlled, experimental study.
abstract: BACKGROUND
  We hypothesized that maintaining physiological plasma levels of antithrombin attenuates myocardial dysfunction and inflammation as well as vascular leakage associated with burn and smoke inhalation injury. Therefore, the present prospective, randomized experiment was conducted using an established ovine model.
  
  
  METHODS
  Following 40% of total body surface area, third degree flame burn and 4 × 12 breaths of cold cotton smoke, chronically instrumented sheep were randomly assigned to receive an intravenous infusion of 6 IU/kg/h recombinant human antithrombin (rhAT) or normal saline (control group; n = 6 each). In addition, six sheep were designated as sham animals (not injured, continuous infusion of vehicle). During the 48 h study period the animals were awake, mechanically ventilated and fluid resuscitated according to standard formulas.
  
  
  RESULTS
  Compared to the sham group, myocardial contractility was severely impaired in control animals, as suggested by lower stroke volume and left ventricular stroke work indexes. As a compensatory mechanism, heart rate increased, thereby increasing myocardial oxygen consumption. In parallel, myocardial inflammation was induced via nitric oxide production, neutrophil accumulation (myeloperoxidase activity) and activation of the p38-mitogen-activated protein kinase pathway resulting in cytokine release (tumor necrosis factor-alpha, interleukin-6) in control vs. sham animals. rhAT-treatment significantly attenuated these inflammatory changes leading to a myocardial contractility and myocardial oxygen consumption comparable to sham animals. In control animals, systemic fluid accumulation progressively increased over time resulting in a cumulative positive fluid balance of about 4,000 ml at the end of the study period. Contrarily, in rhAT-treated animals there was only an initial fluid accumulation until 24 h that was reversed back to the level of sham animals during the second day.
  
  
  CONCLUSIONS
  Based on these findings, the supplementation of rhAT may represent a valuable therapeutic approach for cardiovascular dysfunction and inflammation after burn and smoke inhalation injury.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Rehberg
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Eva
authors.initials: E
authors.lastname: Bartha
authors.forename: Linda E
authors.initials: LE
authors.lastname: Sousse
authors.forename: Collette
authors.initials: C
authors.lastname: Jonkam
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhu
authors.forename: Lillian D
authors.initials: LD
authors.lastname: Traber
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cox
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Traber
authors.forename: Perenlei
authors.initials: P
authors.lastname: Enkhbaatar
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000097:blood / Q000627:therapeutic use*; D002056:Burns / Q000188:drug therapy* / Q000503:physiopathology*; D002196:Capillaries / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006321:Heart / Q000503:physiopathology*; D006439:Hemodynamics; D007249:Inflammation / Q000503:physiopathology*; D009504:Neutrophils / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010101:Oxygen Consumption; D011446:Prospective Studies; D011659:Pulmonary Gas Exchange; D011994:Recombinant Proteins / Q000097:blood / Q000627:therapeutic use; D012756:Sheep; D015208:Smoke Inhalation Injury / Q000188:drug therapy* / Q000503:physiopathology*; D014882:Water-Electrolyte Balance / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000991:Antithrombins; D016207:Cytokines; D011994:Recombinant Proteins; D009569:Nitric Oxide; D048051:p38 Mitogen-Activated Protein Kinases