Recombinant human activated protein C improves pulmonary function in ovine acute lung injury resulting from smoke inhalation and sepsis

Marc O. Maybauer, Dirk M. Maybauer, John F. Fraser, Lillian D. Traber, Martin Westphal, Perenlei Enkhbaatar, Robert A. Cox, Ruksana Huda, Hal K. Hawkins, Naoki Morita, Kazunori Murakami, Akio Mizutani, David Herndon, Daniel L. Traber

Research output: Contribution to journalArticle

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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. 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.

Original languageEnglish (US)
Pages (from-to)2432-2438
Number of pages7
JournalCritical Care Medicine
Volume34
Issue number9
DOIs
StatePublished - Sep 2006

Fingerprint

Acute Lung Injury
Protein C
Smoke
Inhalation
Sheep
Sepsis
Lung
Control Groups
Fibrin Fibrinogen Degradation Products
Pressure
Tracheotomy
Insufflation
Wounds and Injuries
Platelet Count
Pseudomonas aeruginosa
Pulmonary Artery
Intensive Care Units
Edema
Suspensions
Stem Cells

Keywords

  • 3-nitrotyrosine
  • Acute lung injury
  • Acute respiratory distress syndrome
  • Airway
  • Nitric oxide
  • Septic shock
  • Sheep

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Recombinant human activated protein C improves pulmonary function in ovine acute lung injury resulting from smoke inhalation and sepsis. / Maybauer, Marc O.; Maybauer, Dirk M.; Fraser, John F.; Traber, Lillian D.; Westphal, Martin; Enkhbaatar, Perenlei; Cox, Robert A.; Huda, Ruksana; Hawkins, Hal K.; Morita, Naoki; Murakami, Kazunori; Mizutani, Akio; Herndon, David; Traber, Daniel L.

In: Critical Care Medicine, Vol. 34, No. 9, 09.2006, p. 2432-2438.

Research output: Contribution to journalArticle

Maybauer, MO, Maybauer, DM, Fraser, JF, Traber, LD, Westphal, M, Enkhbaatar, P, Cox, RA, Huda, R, Hawkins, HK, Morita, N, Murakami, K, Mizutani, A, Herndon, D & Traber, DL 2006, 'Recombinant human activated protein C improves pulmonary function in ovine acute lung injury resulting from smoke inhalation and sepsis', Critical Care Medicine, vol. 34, no. 9, pp. 2432-2438. https://doi.org/10.1097/01.CCM.0000230384.61350.FA
Maybauer, Marc O. ; Maybauer, Dirk M. ; Fraser, John F. ; Traber, Lillian D. ; Westphal, Martin ; Enkhbaatar, Perenlei ; Cox, Robert A. ; Huda, Ruksana ; Hawkins, Hal K. ; Morita, Naoki ; Murakami, Kazunori ; Mizutani, Akio ; Herndon, David ; Traber, Daniel L. / Recombinant human activated protein C improves pulmonary function in ovine acute lung injury resulting from smoke inhalation and sepsis. In: Critical Care Medicine. 2006 ; Vol. 34, No. 9. pp. 2432-2438.
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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. 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.",
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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 A.

AU - Huda, Ruksana

AU - Hawkins, Hal K.

AU - Morita, Naoki

AU - Murakami, Kazunori

AU - Mizutani, Akio

AU - Herndon, David

AU - Traber, Daniel L.

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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