TY - JOUR
T1 - Recombinant human activated protein C improves pulmonary function in ovine acute lung injury resulting from smoke inhalation and sepsis
AU - Maybauer, Marc O.
AU - Maybauer, Dirk M.
AU - Fraser, John F.
AU - Traber, Lillian D.
AU - Westphal, Martin
AU - Enkhbaatar, Perenlei
AU - Cox, Robert
AU - Huda, Ruksana
AU - Hawkins, Hal
AU - Morita, Naoki
AU - Murakami, Kazunori
AU - Mizutani, Akio
AU - Herndon, David
AU - Traber, Daniel L.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2006/9
Y1 - 2006/9
N2 - 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. DESIGN: Prospective, randomized, controlled, experimental animal study with repeated measurements. SETTING: Investigational intensive care unit at a university hospital. SUBJECTS: 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 × 10 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 μg/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. MEASUREMENTS AND MAIN 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.
AB - 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. DESIGN: Prospective, randomized, controlled, experimental animal study with repeated measurements. SETTING: Investigational intensive care unit at a university hospital. SUBJECTS: 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 × 10 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 μg/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. MEASUREMENTS AND MAIN 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.
KW - 3-nitrotyrosine
KW - Acute lung injury
KW - Acute respiratory distress syndrome
KW - Airway
KW - Nitric oxide
KW - Septic shock
KW - Sheep
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U2 - 10.1097/01.CCM.0000230384.61350.FA
DO - 10.1097/01.CCM.0000230384.61350.FA
M3 - Article
C2 - 16810106
AN - SCOPUS:33747604392
SN - 0090-3493
VL - 34
SP - 2432
EP - 2438
JO - Critical care medicine
JF - Critical care medicine
IS - 9
ER -