Inflammatory, hemostatic, and clinical changes in a baboon experimental model for heatstroke

Abstract

The mortality and neurological morbidity in heatstroke have been attributed to the host's inflammatory and hemostatic responses to heat stress, suggesting that immunomodulation may improve outcome. We postulated that an experimental baboon model of heatstroke will reproduce human responses and clinical outcome to allow testing of new therapeutic strategies. Eight anesthetized juvenile baboons (Papio hamadryas) were subjected to heat stress in an incubator maintained at 44-47 degrees C until rectal temperature attained 42.5 degrees C (moderate heatstroke; n = 4) or systolic arterial pressure fell to <90 mmHg (severe heatstroke; n = 4) and were allowed to recover at room temperature. Four sham-heated animals served as a control group. Rectal temperature at the end of heat stress was 42.5 +/- 0.0 and 43.3 +/- 0.1 degrees C, respectively. All heat-stressed animals had systemic inflammation and activated coagulation, indicated by increased plasma IL-6, prothrombin time, activated partial thromboplastin time, and D-dimer levels, and decreased platelet count. Biochemical markers and/or histology evidenced cellular injury/dysfunction: plasma levels of thrombomodulin, creatinine, creatine kinase, lactic dehydrogenase, and alanine aminotransferase were increased, and varying degrees of tissue damage were present in liver, brain, and gut. No baboon with severe heatstroke survived. Neurological morbidity but no mortality was observed in baboons with moderate heatstroke. Nonsurvivors displayed significantly greater coagulopathy, inflammatory activity, and tissue injury than survivors. Sham-heated animals had an uneventful course. Heat stress elicited distinct patterns of inflammatory and hemostatic responses associated with outcome. The baboon model of heatstroke appears suitable for testing whether immunomodulation of the host's responses can improve outcome.

Hsp-72, a candidate prognostic indicator of heatstroke

“…On the day of the experiment, juvenile baboons (Papio hamadryas) weighing 4-6 kg were anesthetized, then intubated, and arterial and venous catheters were inserted, as described previously (Bouchama et al 2005). The anesthesia protocol consisted of a continuous intravenous infusion of ketamine (20-25 mg/kg/h) and diazepam (0.4-0.8 mg/kg) intravenously every 2 h).…”

“…The mechanisms of MODS are not fully understood but include direct tissue injury and cell death from hyperthermia, sustained organ dysfunction and damage secondary to activation of the host inflammatory and coagulation responses (Bouchama and Knochel 2002;Bouchama et al 2005;Roberts et al 2008). Consequently, in spite of optimal cooling and supportive treatment in intensive care, the overall mortality can exceed 60%, because as yet, there is no specific treatment available (Misset et al 2006;Argaud et al 2007).…”

“…We have recently established that baboons subjected to environmental heat stress mimic the clinical spectrum from moderate to severe heatstroke seen in human heatstroke (Bouchama et al 2005;Roberts et al 2008). Baboons with moderate heatstroke display hyperthermia, neurologic alteration, and MODS, which subside after 72 h with full recovery, whereas baboons with severe heatstroke develop hypotension and rapidly progressing MODS that can culminate in death (Bouchama et al 2005;Roberts et al 2008).…”

“…Baboons with moderate heatstroke display hyperthermia, neurologic alteration, and MODS, which subside after 72 h with full recovery, whereas baboons with severe heatstroke develop hypotension and rapidly progressing MODS that can culminate in death (Bouchama et al 2005;Roberts et al 2008). The objectives of the present study were to use these two experimental baboon models of heatstroke to: (1) examine the expression of Hsp-60 and Hsc-70, together with inducible Hsp72; (2) determine whether Hsp-60 and Hsp-72 are released into the circulation, and if so, (3) analyze their time course and relation with biomarkers of cell injury, organ dysfunction, as well as death in heatstroke.…”

An adaptability limit to climate change due to heat stress

“…Human skin temperature is strongly regulated at 35°C or below under normal conditions, because the skin must be cooler than body core in order for metabolic heat to be conducted to the skin (17). Sustained skin temperatures above 35°C imply elevated core body temperatures (hyperthermia), which reach lethal values (42-43°C) for skin temperatures of 37-38°C even for acclimated and fit individuals (18,19,20,21). We would thus expect sufficiently long periods of T W > 35°C to be intolerable.…”