Activated protein C therapy in a rat heat stroke model.
OBJECTIVE
To evaluate the therapeutic effects of activated protein C in an animal model of heat stroke.


METHODS
Laboratory investigation.


METHODS
Chi-Mei Medical Center research laboratory.


METHODS
Male Sprague-Dawley rats weighing 252-304 g.


METHODS
Anesthetized animals were subjected to heat stress (40 degrees C) to induce heat stroke. A bolus injection of normal saline or recombinant human activated protein C (drotrecogin alfa, activated) was conducted via femoral catheters immediately after the onset of heat stroke. Blood sampling was done before initiation of heat stress and 0 and 40 mins after the onset of heat stroke.


RESULTS
When the vehicle-treated rats underwent heat exposure, their survival time values were found to be 56-64 mins (n = 16). Resuscitation with activated protein C significantly and dose-dependently improved survival during heat stroke (108-246 mins for doses of 0.5-20 mg of activated protein C per kilogram of body weight) (n = 32). All heat-stressed animals displayed systemic inflammation and activated coagulation, evidenced by increased tumor necrosis factor-alpha, prothrombin time, activated partial thromboplastin time, and D-dimer and decreased platelet count and protein C. Biochemical markers evidenced by cellular ischemia and injury/dysfunction included increased plasma levels of blood urea nitrogen, creatinine, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and alkaline phosphatase; increased striatal levels of glutamate, glycerol, and lactate/pyruvate ratio; and decreased striatal levels of partial pressure of oxygen and local cerebral blood flow, which were all observed during heat stroke. These heat stroke reactions were all significantly suppressed by resuscitation with activated protein C but not vehicle solution.


CONCLUSIONS
The results indicate that systemic delivery of human recombinant activated protein C at the time point of onset of heat stroke may improve survival by ameliorating systemic inflammation, hypercoagulable state, and tissue ischemia and injury in multiple organs.
Chen
Chin-Ming
CM
Department of Critical Care Medicine, Mei Medical Center, Tainan, Taiwan.
Hou
Ching-Cheng
CC
Cheng
Kuo-Chen
KC
Tian
Ru-Ling
RL
Chang
Ching-Ping
CP
Lin
Mao-Tsun
MT
D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001806:Blood Urea Nitrogen; D002560:Cerebrovascular Circulation; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D018698:Glutamic Acid / Q000097:blood; D005990:Glycerol / Q000097:blood; D018883:Heat Stroke / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D007773:Lactates / Q000097:blood; D008297:Male; D010100:Oxygen / Q000097:blood; D010313:Partial Pressure; D010314:Partial Thromboplastin Time; D010976:Platelet Count; D011486:Protein C / Q000008:administration & dosage / Q000032:analysis / Q000627:therapeutic use*; D011517:Prothrombin Time; D011773:Pyruvates / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012039:Regional Blood Flow; D000637:Transaminases / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D005338:Fibrin Fibrinogen Degradation Products; D007773:Lactates; D011486:Protein C; D011773:Pyruvates; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C036309:fibrin fragment D; D018698:Glutamic Acid; D003404:Creatinine; D000637:Transaminases; D000469:Alkaline Phosphatase; D005990:Glycerol; D010100:Oxygen