Glucocorticoids Do Not Protect Against the Lethal Effects of Experimental Heatstroke in Baboons

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 degrees C to 47 degrees 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 > 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.

Successful treatment with hydrocortisone for heat stroke with critical illness-related corticosteroid insufficiency: transitional changes in serum cytokine and cortisol concentrations

“…In contrast, an experiment in a baboon heat stroke model suggested that glucocorticoid did not reduce mortality [14]. Although there are no available data in humans, we think that hydrocortisone was effective to improve an infl ammatory imbalance in our patient.…”

Toll-Like Receptor 4 and High-Mobility Group Box 1 Are Critical Mediators of Tissue Injury and Survival in a Mouse Model for Heatstroke

“…Neutralizing studies in animal models of heatstroke have established that this systemic inflammation has a significant role but it remains unclear whether it is beneficial or deleterious. As shown previously, inhibition of the inflammatory response with administration of IL-1 receptor antagonist [8], anti-inflammatory steroids [12] or recombinant activated protein C [7], [10] prevented organ damage and improved survival while other studies using IL-6 and tumor necrosis factor (TNF) receptors knockout mice [9] or primate models [11] reported enhanced mortality. One of the reasons that might explain these conflicting findings is that the molecular mechanisms that initiate and propagate the inflammatory response to heat stress are not known, although earlier studies have suggested that lipopolysaccharide (LPS) leaking into the systemic circulation from heat damaged gut is the primary stimulus [3], [9].…”

“…Clinical and experimental studies consistently demonstrated the presence of a systemic inflammatory response to heat stress that correlated with severity and outcome [5], [6], [7], [8], [9], [10], [11], [12]. Neutralizing studies in animal models of heatstroke have established that this systemic inflammation has a significant role but it remains unclear whether it is beneficial or deleterious.…”

Heat Stroke

“…No pharmacological treatment has been found to be beneficial. Antipyretics have no role in heat stroke and may be toxic to the liver, whereas experimental findings in a primate classic heat stroke model do not support the clinical use of corticosteroids or activated protein C in the prevention or treatment of classic heat stroke (48,49).…”