Activated protein C therapy in a rat heat stroke model*

Abstract

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.

Heat stroke: Role of the systemic inflammatory response

“…Recombinant human activated protein C (rhAPC) has been approved in the United States for the treatment of severe sepsis and has anti-inflammatory and anticoagulant properties that warrant consideration for the treatment of heat stroke. In heat stroke patients and experimental models, rhAPC attenuated inflammation, resolved multi-organ system dysfunction, and improved survival (5,10,23). However, the efficacy of rhAPC was dependent on the timing of administration and specific characteristics of the patient population and did not protect against mortality in all heat stroke models, indicating that additional studies are needed to warrant its use as a heat stroke treatment (10,23,87).…”

Recombinant Activated Protein C Attenuates Endothelial Injury and Inhibits Procoagulant Microparticles Release in Baboon Heatstroke

“…14 In a rat heatstroke model, administration of rhAPC attenuated the inflammatory response, normalized the coagulopathy, and thereby improved survival. 15 However, this evidence remains insufficient to justify its use in human victims of heatstroke particularly as, because of interspecies differences, extrapolation of data from small laboratory animals cannot predict reliably the human responses.…”

“…11 Recent observations suggest that therapeutic intervention with rhAPC can also alter the clinical course of heatstroke and improve survival. 14,15 In humans, rhAPC given to sporadic cases of severe heatstroke resulted in resolution of MOSD and improved survival without bleeding complications. 14 In a rat heatstroke model, administration of rhAPC attenuated the inflammatory response, normalized the coagulopathy, and thereby improved survival.…”

Microvascular Injury, Thrombosis, Inflammation, and Apoptosis in the Pathogenesis of Heatstroke

“…1,8 -10 Increased circulating proinflammatory cytokines was documented in human and experimental heatstroke and their levels correlated with outcome. 7,8,11,12 In laboratory rats, administration of interleukin (IL)-1 receptor antagonist or activated protein C (APC) at onset of heatstroke prevented severe arterial hypotension, organ injury, and improved survival. 11,12 Disseminated intravascular coagulation (DIC), a syndrome characterized by widespread intravascular thrombosis that can compromise adequate blood supply to various organs, has been implicated in the MOSD and high mortality of heatstroke.…”

“…7,8,11,12 In laboratory rats, administration of interleukin (IL)-1 receptor antagonist or activated protein C (APC) at onset of heatstroke prevented severe arterial hypotension, organ injury, and improved survival. 11,12 Disseminated intravascular coagulation (DIC), a syndrome characterized by widespread intravascular thrombosis that can compromise adequate blood supply to various organs, has been implicated in the MOSD and high mortality of heatstroke. 9,10,13 In a large series of 132 patients with heatstroke, the DIC with clinically mild to severe bleeding that was observed in 30% of the patients contributed directly to death in half of them.…”