Analysis of the Inflammatory and Hemostatic Changes and Their Relation to Outcomes in an Experimental Model of Heatstroke in Baboons.
Authors: Roberts George , Olliver Veronique , Chollet-Martin Sylvie , Al-Mohanna Fallah , El-Sayed Rafat , Nakeeb Shaheen , Eldali Abdelmoneim , de Prost Dominique , Davis Heidi , Lach Boleslaw , Bouchama Abderrezak 
Published: April 2020

The mortality and neurologic morbidity in heatstroke have been attributed to the host inflammatory and hemostatic responses to heat stress, with the corollary that immunomodulating them may improve outcome. We aimed to examine whether an experimental baboon model of heatstroke will reproduce these responses and clinical outcomes similar to that in humans, thereby providing a model for testing new therapeutic strategies. Eight anesthetized juvenile baboons (Papio hamadryas) were subjected to heat stress in an incubator where the environmental temperature was maintained at 44.2±1.5°C until rectal temperature attained 42.5°C (moderate heatstroke; n=4) or systolic arterial pressure fell to &lt; 90 mmHg, (severe heatstroke; n=4). Animals were then allowed to recover at room temperature. Four sham-heated baboons served as a control group. Plasma IL-6, global coagulation tests and molecular markers of coagulation and fibrinolysis as well as endothelial cell activation/injury were determined at baseline, end of heat exposure or onset of heatstroke (T+0), then at T+1, +2, +3, +12, and +36 hours. The rectal temperature at the end of heat stress was 42.5±0.0 and 43.3±0.2°C for moderate and severe heatstroke respectively. All heat stressed animals had systemic inflammation, and activation of coagulation at onset of heatstroke, indicated by increased plasma IL-6 (345±67 vs 280±130 vs 24±15pg/ml, mean ± SD for severe, moderate and control group respectively, ANOVA-repeated measurements; p&lt;0.001) and thrombin-antithrombin complexes (TAT) levels, 48 ±21 vs 13± 5 vs 6.6±0.9 ng/ml; p&lt;0.01). Tissue factor pathway inhibitor (TFPI) levels were significantly elevated and protein C was decreased but this was not statistically significant. Early activation of fibrinolysis was evidenced by significantly increased D-dimer and tissue plasminogen activator (tPA) levels. Plasminogen activator inhibitor (PAI) was undetectable at onset of heatstroke and at anytime thereafter. No evidence of early endothelial cell injury/activation, as assessed by soluble thrombomodulin (TM), was noted. No baboons with severe heatstroke survived. Neurological morbidity, but no mortality was observed in animals with moderate heatstroke. During passive cooling at room temperature (T+0 to T+3hr), non-surviving animals displayed a different pattern, with significantly greater coagulopathy (peak or nadir levels of TAT, TFPI, and Protein C were 493±66 vs 18±8.6 ng/ml, 64±44 vs 7.2±3.2 ng/ml and 23±11 vs 62±8%), inflammatory activity (IL6, 1770±466 vs 320±76 pg/ml) and endothelial injury (TM, 46±16 vs 9.2±3.2ng/ml) than survivors. Sham heated animals had an uneventful course. These data show that heat stress elicits different patterns of inflammatory and hemostatic responses that were associated with outcome. Additionally, the data suggests that experimental baboon model of heatstroke is suitable for testing whether immunomodulation of the host responses can improve outcome.