title: Recombinant human activated protein C improves pulmonary function in ovine acute lung injury resulting from smoke inhalation and sepsis.
abstract: OBJECTIVE
  To investigate the effects of recombinant human activated protein C (rhAPC) on pulmonary function in acute lung injury (ALI) resulting from smoke inhalation in association with a bacterial challenge.
  
  
  METHODS
  Prospective, randomized, controlled, experimental animal study with repeated measurements.
  
  
  METHODS
  Investigational intensive care unit at a university hospital.
  
  
  METHODS
  Eighteen sheep (37.2 +/- 1.0 kg) were operatively prepared and randomly allocated to either the sham, control, or rhAPC group (n = 6 each). After a tracheotomy had been performed, ALI was produced in the control and rhAPC group by insufflation of 4 sets of 12 breaths of cotton smoke. Then, a 30 mL suspension of live Pseudomonas aeruginosa bacteria (containing 2-5 x 10(11) colony forming units) was instilled into the lungs according to an established protocol. The sham group received only the vehicle, i.e., 4 sets of 12 breaths of room air and instillation of 30 mL normal saline. The sheep were studied in the awake state for 24 hrs and were ventilated with 100% oxygen. RhAPC (24 mug/kg/hr) was intravenously administered. The infusion was initiated 1 hr post-injury and lasted until the end of the experiment. The animals were resuscitated with Ringer's lactate solution to maintain constant pulmonary artery occlusion pressure.
  
  
  RESULTS
  In comparison with nontreatment in controls, the infusion of rhAPC significantly attenuated the fall in Pao2/Fio2 ratio (control group values were 521 +/- 22 at baseline [BL], 72 +/- 5 at 12 hrs, and 74 +/- 7 at 24 hrs, vs. rhAPC group values of 541 +/- 12 at BL, 151 +/- 29 at 12 hours [p < .05 vs. control], and 118 +/- 20 at 24 hrs), and significantly reduced the increase in pulmonary microvascular shunt fraction (Qs/Qt; control group at BL, 0.14 +/- 0.02, and at 24 hrs, 0.65 +/- 0.08; rhAPC group at BL, 0.24 +/- 0.04, and at 24 hrs, 0.45 +/- 0.02 [p < .05 vs. control]) and the increase in peak airway pressure (mbar; control group at BL, 20 +/- 1, and at 24 hrs, 36 +/- 4; rhAPC group at BL, 21 +/- 1, and at 24 hrs, 28 +/- 2 [p < .05 vs. control]). In addition, rhAPC limited the increase in lung 3-nitrotyrosine (after 24 hrs [%]: sham, 7 +/- 2; control, 17 +/- 1; rhAPC, 12 +/- 1 [p < .05 vs. control]), a reliable indicator of tissue injury. However, rhAPC failed to prevent lung edema formation. RhAPC-treated sheep showed no difference in activated clotting time or platelet count but exhibited less fibrin degradation products (1/6 animals) than did controls (4/6 animals).
  
  
  CONCLUSIONS
  Recombinant human activated protein C attenuated ALI after smoke inhalation and bacterial challenge in sheep, without bleeding complications.
authors.affiliation: Department of Anesthesiology, Investigational Intensive Care Unit, The University of Texas Medical Branch, and Shriners Burn Hospital for Children, Galveston, USA.
authors.forename: Marc O
authors.initials: MO
authors.lastname: Maybauer
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Maybauer
authors.forename: John F
authors.initials: JF
authors.lastname: Fraser
authors.forename: Lillian D
authors.initials: LD
authors.lastname: Traber
authors.forename: Martin
authors.initials: M
authors.lastname: Westphal
authors.forename: Perenlei
authors.initials: P
authors.lastname: Enkhbaatar
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cox
authors.forename: Ruksana
authors.initials: R
authors.lastname: Huda
authors.forename: Hal K
authors.initials: HK
authors.lastname: Hawkins
authors.forename: Naoki
authors.initials: N
authors.lastname: Morita
authors.forename: Kazunori
authors.initials: K
authors.lastname: Murakami
authors.forename: Akio
authors.initials: A
authors.lastname: Mizutani
authors.forename: David N
authors.initials: DN
authors.lastname: Herndon
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Traber
mesh_terms: D000402:Airway Obstruction / Q000188:drug therapy; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature; D004195:Disease Models, Animal; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D007262:Infusions, Intravenous; D008168:Lung / Q000378:metabolism / Q000473:pathology; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D009929:Organ Size; D011446:Prospective Studies; D011486:Protein C / Q000032:analysis / Q000494:pharmacology*; D011654:Pulmonary Edema / Q000209:etiology; D011897:Random Allocation; D011994:Recombinant Proteins / Q000494:pharmacology*; D012129:Respiratory Function Tests; D018805:Sepsis / Q000378:metabolism*; D012756:Sheep; D015208:Smoke Inhalation Injury / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D005343:Fibrinolytic Agents; D009566:Nitrates; D009573:Nitrites; D011486:Protein C; D011994:Recombinant Proteins; C002744:3-nitrotyrosine; D014443:Tyrosine