Skip to main content


We’d like to understand how you use our websites in order to improve them. Register your interest.

Pathogenetic mechanisms of heatstroke and novel therapies

Heatstroke, a life-threatening condition defined by a rapidly increasing core temperature greater than 40°C and multiple organ system dysfunction, is a leading cause of morbidity and mortality during heat waves [1]. The heat wave that affected Europe during August 2003 led to an unprecedented 70,000 excess deaths of which up to 40% were confirmed to be due to heatstroke [2]. Sophisticated climate models predict increasing frequency and severity of heat waves and so the incidence of heat-related death could rise if proactive measures and novel therapy to address this threat are not adopted [3].

The mechanisms of multiple organ system dysfunction in heatstroke are not fully understood and include direct tissue injury and cell death resulting from heat cytotoxicity together with delayed organ dysfunction and damage secondary to activation of inflammatory and coagulation pathways. Histopathological changes include endothelial injury, disseminated intravascular thrombosis, neutrophils infiltration and apoptosis [4, 5]. Despite cooling and optimal treatment in intensive care the overall mortality from heatstroke exceeds 60%, due in large part to the fact that no specific treatment is available [6, 7].

Experimental evidence from rodent models of heatstroke suggest that immunomodulation of the host response may alter the clinical course of heatstroke and thereby improve outcome [810]. Heatstroke in induces systemic and local (central nervous system) production of TNFα and IL-1, and severe coagulopathy. This is associated with multiple organ system dysfunction including severe neuronal injury, and high mortality. Administration of an IL-1 receptor antagonist [8], corticosteroids [9] or activated protein C [10] before the onset of heatstroke attenuates the multiple organ system dysfunction and improves survival. However, extrapolation of these data from these small animal models to humans is problematic because of inter-species differences.

Baboons represent the most appropriate model for the study of the host inflammatory and hemostatic responses to heat stress and their relation to cellular injury and death as well as for testing novel therapy, which targets these pathways. Moreover, the findings may have direct applicability to human heatstroke, and could represent the basis for clinical trial. In this review, we show that baboons subjected to heat stress reproduce both the clinical and immunological changes similar to those seen in humans [11]. Using this experimental model, we report that immunomodulating the host systemic inflammatory and coagulation responses failed to translate into improved survival, suggesting that further basic research on the pathogenesis of heatstroke is required [1214].


  1. 1.

    Bouchama A, Knochel JP: Heat stroke. N Engl J Med. 2002, 346: 1978-1988. 10.1056/NEJMra011089.

  2. 2.

    Robine JM, Cheung SL, Le Roy S, Van Oyen H, Griffiths C, Michel JP, Herrmann FR: Death toll exceeded 70,000 in Europe during the summer of 2003. C R Biol. 2008, 331: 171-178. 10.1016/j.crvi.2007.12.001.

  3. 3.

    Easterling DR, Meehl GA, Parmesan C, Changnon SA, Karl TR, Mearns LO: Climate extremes: observations, modeling, and impacts. Science. 2000, 289: 2068-2074. 10.1126/science.289.5487.2068.

  4. 4.

    Malamud N, Haymaker W, Custer R: Heatstroke: a clinico-pathologic study of 125 fatal cases. Milit Surg. 1946, 99: 397-449.

  5. 5.

    Chao TC, Sinniah R, Pakiam JE: Acute heat stroke deaths. Pathology. 1981, 13: 145-156. 10.3109/00313028109086837.

  6. 6.

    Misset B, De Jonghe B, Bastuji-Garin S, Gattolliat O, Boughrara E, Annane D, Hausfater P, Garrouste-Orgeas M, Carlet J: Mortality of patients with heatstroke admitted to intensive care units during the 2003 heat wave in France: a national multiple-center risk-factor study. Crit Care Med. 2006, 34: 1087-1092. 10.1097/01.CCM.0000206469.33615.02.

  7. 7.

    Argaud L, Ferry T, Le QH, Marfisi A, Ciorba D, Achache P, Ducluzeau R, Robert D: Short- and long-term outcomes of heatstroke following the 2003 heat wave in Lyon, France. Arch Intern Med. 2007, 167: 2177-2183. 10.1001/archinte.167.20.ioi70147.

  8. 8.

    Lin MT, Liu HH, Yang YL: Involvement of interleukin-1 receptor mechanisms in development of arterial hypotension in rat heatstroke. Am J Physiol. 1997, 273 (4 Pt 2): H2072-H2077.

  9. 9.

    Liu CC, Chien CH, Lin MT: Glucocorticoids reduce interleukin-1 concentration and result in neuroprotective effects in rat heatstroke. J Physiol. 2000, 527 (Pt 2): 333-343.

  10. 10.

    Chen CM, Hou CC, Cheng KC, Tian RL, Chang CP, Lin MT: Activated protein C therapy in a rat heat stroke model. Crit Care Med. 2006, 34: 1960-1966. 10.1097/01.CCM.0000224231.01533.B1.

  11. 11.

    Bouchama A, Roberts G, Al Mohanna F, El-Sayed R, Lach B, Chollet-Martin S, Ollivier V, Al Baradei R, Loualich A, Nakeeb S, et al: Inflammatory, hemostatic, and clinical changes in a baboon experimental model for heatstroke. J Appl Physiol. 2005, 98: 697-705.

  12. 12.

    Bouchama A, Kwaasi A, Dehbi M, Al Mohanna F, Eldali A, El-Sayed R, Tbakhi A, Alzahrani AS, Roberts AG: Glucocorticoids do not protect against the lethal effects of experimental heatstroke in baboons. Shock. 2007, 27: 578-583. 10.1097/01.shk.0000246903.40142.aa.

  13. 13.

    Bouchama A, Kunzelmann C, Dehbi M, Kwaasi A, Eldali A, Zobairi F, Freyssinet JM, de Prost D: Recombinant activated protein C attenuates endothelial injury and inhibits procoagulant microparticles release in baboon heatstroke. Arterioscler Thromb Vasc Biol. 2008, 28: 1318-1325. 10.1161/ATVBAHA.107.161737.

  14. 14.

    Bouchama A, Al-Mohanna F, Assad L, Baturcam E, Eldali A, Owaidah T, et al: Tissue factor/factor VIIa pathway mediates coagulation activation in induced-heat stroke in the baboon. Crit Care Med. 2011, 40: 1229-1236.

Download references

Author information



Corresponding author

Correspondence to Abderrezak Bouchama.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bouchama, A. Pathogenetic mechanisms of heatstroke and novel therapies. Crit Care 16, A7 (2012).

Download citation


  • Heat Stress
  • Heat Wave
  • Neutrophil Infiltration
  • Excess Death
  • Small Animal Model