title: Advantages and pitfalls of combining intravenous antithrombin with nebulized heparin and tissue plasminogen activator in acute respiratory distress syndrome.
abstract: BACKGROUND
  Pulmonary coagulopathy has become an important therapeutic target in adult respiratory distress syndrome (ARDS). We hypothesized that combining intravenous recombinant human antithrombin (rhAT), nebulized heparin, and nebulized tissue plasminogen activator (TPA) more effectively improves pulmonary gas exchange compared with a single rhAT infusion, while maintaining the anti-inflammatory properties of rhAT in ARDS. Therefore, the present prospective, randomized experiment was conducted using an established ovine model.
  
  
  METHODS
  Following burn and smoke inhalation injury (40% of total body surface area, third-degree flame burn, and 4 × 12 breaths of cold cotton smoke), 18 chronically instrumented sheep were randomly assigned to receive intravenous saline plus saline nebulization (control), intravenous rhAT (6 IU/kg/h) started 1 hour after injury plus saline nebulization (AT i.v.) or intravenous rhAT combined with nebulized heparin (10,000 IU every 4 hours, started 2 hours after injury), and nebulized TPA (2 mg every 4 hours, started 4 hours after injury) (triple therapy, n = 6 each). All animals were mechanically ventilated and fluid resuscitated according to standard protocols during the 48-hour study period.
  
  
  RESULTS
  Both treatment approaches attenuated ARDS compared with control animals. Notably, triple therapy was associated with an improved PaO2/FiO2 ratio (p = 0.007), attenuated pulmonary obstruction (p = 0.02) and shunting (p = 0.025), as well as reduced ventilatory pressures (p < 0.05 each) versus AT i.v. at 48 hours. However, the anti-inflammatory effects of sole AT i.v., namely, the inhibition of neutrophil activation (neutrophil count in the lymph and pulmonary polymorphonuclear cells, p < 0.05 vs. control each), pulmonary transvascular fluid flux (lymph flow, p = 0.004 vs. control), and systemic vascular leakage (cumulative net fluid balance, p < 0.001 vs. control), were abolished in the triple therapy group.
  
  
  CONCLUSIONS
  Combining intravenous rhAT with nebulized heparin and nebulized TPA more effectively restores pulmonary gas exchange, but the anti-inflammatory effects of sole rhAT are abolished with the triple therapy. Interferences between the different anticoagulants may represent a potential explanation for these findings.
authors.affiliation: From the Investigational Intensive Care Unit (S.R., Y.Y., L.E.S., C.J., D.S.P., P.E.), Department of Anesthesiology, and Department of Pathology (R.A.C.), The University of Texas Medical Branch; and Shriners Hospital for Children (R.A.C., P.E.), Galveston, Texas; and Department of Anesthesiology, Intensive Care and Pain Medicine (S.R.), University of Muenster, Muenster, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Rehberg
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Linda E
authors.initials: LE
authors.lastname: Sousse
authors.forename: Collette
authors.initials: C
authors.lastname: Jonkam
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cox
authors.forename: Donald S
authors.initials: DS
authors.lastname: Prough
authors.forename: Perenlei
authors.initials: P
authors.lastname: Enkhbaatar
mesh_terms: D000280:Administration, Inhalation; D061605:Administration, Intravenous; D000818:Animals; D000991:Antithrombins / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D006493:Heparin / Q000008:administration & dosage / Q000627:therapeutic use*; D009330:Nebulizers and Vaporizers; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012121:Respiration, Artificial; D012128:Respiratory Distress Syndrome / Q000188:drug therapy*; D012756:Sheep; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D000991:Antithrombins; D011994:Recombinant Proteins; D006493:Heparin; D010959:Tissue Plasminogen Activator