Copyright @ 2007 by the Shock Society. Unauthorized reproduction of this article is prohibited. GLUCOCORTICOIDS DO NOT PROTECT AGAINST THE LETHAL EFFECTS OF EXPERIMENTAL HEATSTROKE IN BABOONS Abderrezak Bouchama,* Aaron Kwaasi,* Mohammed Dehbi,* Falah Al Mohanna,* Abdelmoneim Eldali, † Raafat El-Sayed,* Abdelghani Tbakhi, ‡ Ali S. Alzahrani, § and George Roberts ‡ Departments of *Comparative Medicine, and † Biostatistics Epidemiology & Scientific Computing, ‡ Pathology and Laboratory Medicine; and § Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia Received 7 Aug 2006; first review completed 29 Aug 2006; accepted in final form 18 Sep 2006 ABSTRACT—The mortality and neurological morbidity in heatstroke have been attributed to the host’s inflammatory responses to heat stress, suggesting that anti-inflammatory therapy may improve outcome. We tested the hypothesis that a high dose of dexamethasone protects baboons against the lethal effects of heatstroke. Ten anesthetized baboons (Papio hamadryas) were assigned randomly to dexamethasone (n = 5) or control group (n = 5). Dexamethasone (2 mg/kg i.v.) was administered in four divided doses every 6 h starting immediately before heat stress and continuing during cooling. All animals were heat-stressed in a prewarmed neonatal incubator at 44-C to 47-C until systolic blood pressure fell less than 90 mmHg and then cooled passively at the ambient temperature. Mortality and neurological morbidity were noted, and biochemical markers of tissue injury/organ dysfunction were determined. Circulating interleukin (IL) 6 and complement components (C3 and C4) were measured sequentially. All heat-stressed animals had systemic inflammation indicated by increased plasma IL-6 and decreased C3 and C4 levels. Dexamethasone attenuated the complement system activation and maintained a higher plasma concentration of IL-6, with a significant augmentation of arterial blood pressure. Dexamethasone did not prevent the occurrence of severe heatstroke but unexpectedly aggravated significantly the tissue injury and multiorgan system dysfunction. Two animals (40%) in the control group and one in the steroid group survived (P 9 0.05). Dexamethasone failed to protect the baboons from the lethal effects of heatstroke. These results do not support clinical testing of corticosteroids as beneficial in preventive or therapeutic strategies for the treatment of heatstroke in humans. KEYWORDS—Heat stress, hyperthermia, IL-6, primates, complement INTRODUCTION Classic heatstroke is a leading cause of mortality and neurological morbidity during a heat wave (1Y3). The heat wave that affected Europe in 2003 led to 15,000 excess deaths in France over a period of 9 days (1, 2). One third of these deaths was attributed to heatstroke, a clinical syndrome characterized by a rapid rise in core temperature more than 40-C and widespread tissue injury in which encephalopathy predominates (1, 2). Although early recognition of heatstroke, prompt cooling and supportive therapy reduce mortality, more than one third of those who survive the initial deleterious effects of hyperthermia progress to multiorgan dysfunction syndrome, culminating in death or permanent neurological damage (4, 5). The mortality rate among patients requiring intensive care ranges from 21% to 67% (4Y6). Experimental and clinical studies suggest that endotoxemia and the host inflammatory response to heat stress may cause and exacerbate cell and organ dysfunction and thereby contribute to the mortality (7Y15). In experimental models of heatstroke and in heatstroke patients, high-circulating levels of endotoxin and proinflammatory and anti-inflammatory cytokines have been documented, and their magnitude correlates with the severity of injury and outcome (7Y15). Early reports showed that pretreatment with high-dose methylprednisolone suppresses endotoxemia and improves survival in experimental heatstroke in monkeys (14, 15). More recent reports show that blocking the signal transduction of IL-1 by the administration of IL-1 receptor antagonist or glucocorticoids prevents the lethal effects of heatstroke in laboratory rats and rabbits, thus establishing a causal relation- ship between inflammation and tissue injury (10Y13). These findings suggest that pharmacological anti-inflammatory intervention can alter the clinical course in patients with heatstroke and improve survival. To translate this protective strategy to humans, we developed a baboon model that replicates the inflammatory response, cell injury, organ dysfunction, and death seen in human heatstroke (16, 17). Using this model, we tested the hypothesis that a high dose of dexamethasone given before and during heat stress and cooling attenuates the host inflammatory response and thereby protects against the lethal effects of heatstroke. Glucocorticoids exert complex actions during stress involv- ing maintenance of vascular tone and integrity, augmentation of the vasoconstrictor action of catecholamines, and modu- lation of complement system and cytokine network activation (18). Thus, in this study, the circulating levels of complement components C3 and C4 and interleukin (IL) 6, were measured to assess the host inflammatory response to heat stress. 578 SHOCK, Vol. 27, No. 5, pp. 578Y583, 2007 Address reprint requests to Abderrezak Bouchama, MD, Department of Comparative Medicine (MBC03), King Faisal Specialist Hospital & Research Centre, PO Box 3354, Riyadh 11211, Saudi Arabia. E-mail: abouchama@ kfshrc.edu.sa. This study was supported by the King Faisal Specialist Research Centre (grant no. 2020 017), the Office of Research Affairs, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia. DOI: 10.1097/01.shk.0000246903.40142.aa Copyright Ó 2007 by the Shock Society