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.

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 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.

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.

• Authors: 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 N Herndon, Daniel L Traber
• Journal: Critical care medicine (Crit Care Med) Vol. 34 Issue 9 Pg. 2432-8 (Sep 2006) ISSN: 0090-3493 [Print] United States
• PMID: 16810106 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Fibrinolytic Agents
• Nitrates
• Nitrites
• Protein C
• Recombinant Proteins
• 3-nitrotyrosine
• Tyrosine

Topics

• Airway Obstruction (drug therapy)
• Animals
• Blood Pressure (drug effects)
• Body Temperature
• Disease Models, Animal
• Female
• Fibrinolytic Agents (pharmacology)
• Infusions, Intravenous
• Lung (metabolism, pathology)
• Nitrates (blood)
• Nitrites (blood)
• Organ Size
• Prospective Studies
• Protein C (analysis, pharmacology)
• Pulmonary Edema (etiology)
• Random Allocation
• Recombinant Proteins (pharmacology)
• Respiratory Function Tests
• Sepsis (metabolism)
• Sheep
• Smoke Inhalation Injury (metabolism)
• Tyrosine (analogs & derivatives, metabolism)