Email updates

Keep up to date with the latest news and content from Critical Care and BioMed Central.

Commentary

Dantrolene and heatstroke: a good molecule applied in an unsuitable situation

Pierre Hausfater

Author Affiliations

MD, Service d'accueil des urgences, Centre Hospitalier Universitaire Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France

Critical Care 2005, 9:23-24  doi:10.1186/cc2939


See related review article http://ccforum.com/content/9/1/86


The electronic version of this article is the complete one and can be found online at:


Published:3 September 2004

© 2004 BioMed Central Ltd

Abstract

Because they share one pathognomonic sign (major hyperthermia), classic or environmental heatstroke and malignant hyperthermia have often been confronted from the therapeutic point of view. As expected and according to major physiopathological discrepancies between both syndromes, analysis of published data does not support effectiveness of dantrolene in heatstroke despite its significant reduction in mortality in malignant hyperthermia. If cooling methods still represent the cornerstone of the heatstroke therapeutic approach, the magnitude of heat-related deaths and the morbidity associated with the August 2003 French heatwave have highlighted the need for more ambitious methods of treatment.

Keywords:
dantrolene; health care; heatstroke; heatwave; malignant hyperthermia

Commentary

The magnitude of heat-related deaths during the August 2003 heatwave in France and conflicting discussions about Earth's global warming consequences have forced physicians to revisit an up to now rare disease: classic or environmental heatstroke (CHS) [1,2]. Indeed, most reported cases of CHS are sporadic except for a few previously published epidemics linked to unusual heatwaves [3,4]. The CHS therapeutic approach to date has therefore been limited to human case reports or experimental data on animal models.

CHS is often compared with other extreme hyperthermia syndromes such as malignant hyperthermia and neuroleptic malignant syndrome, two situations where dantrolene administration has proved to reduce mortality. It therefore seemed superficially attractive to study the usefulness of dantrolene in CHS. The review by Hadad and colleagues aims to summarize previously published data on dantrolene use in CHS [5]. Overall, although there are conflicting results, analysis does not support the use of dantrolene in this situation. Notably, the few case reports that exhibited a beneficial effect were not confirmed in controlled studies. Moreover, heterogeneous study designs make data interpretation difficult, as dantrolene was used either as a preventive or curative therapeutic, either on humans or animals, and either in CHS or exertional heatstroke.

The temptation to use dantrolene in CHS is the result of a misjudgement about pathophysiology. Dantrolene effectiveness in malignant hyperthermia does not result from direct action on the hypothalamic setpoint, but from reducing muscular heat production. Indeed, as discussed by Hadad and colleagues, malignant hyperthermia/neuroleptic malignant syndrome and CHS represent two clinical hyperthermia entities with quite different heat-generating pathophysiology: although muscular rigidity is the cornerstone of heat production in the former, massive thermoregulatory failure related to prolonged environmental heat exposure seems to be predominant in CHS [5,6]. So, although they share a pathognomonic sign (major hyperthermia), CHS and malignant hyperthermia/neuroleptic malignant syndrome are two distinct entities with only a few overlaps concerning heat production mechanisms.

Moreover, there are some arguments against dantrolene use in CHS. First, dantrolene is known to cause potential hepatic injury. This is of major concern in the context of CHS, a disease frequently associated with hepatic failure and/or disseminated intravascular coagulation [6]. Second, there are some experimental animal studies reporting negative inotropic effects of dantrolene on myocardium and diaphragm muscle [7,8]. As CHS predominantly affects elderly patients, a population with frequent cardiac impairment, dantrolene could theoretically be detrimental in this situation.

After the August 2003 French experience, we were able to draw several lessons from CHS care. In the first place, the health care structure appeared to be the cornerstone of epidemic management and effectiveness. As a delay to benefit from efficient cooling therapeutics dramatically influences the immediate prognosis, the most useful action is undoubtedly to put the patient into the hands of an expert 'cooling team' as quickly as possible. In order to initiate patient cooling earlier, prehospital emergency care (Service d'Aide Médicale d'Urgence; SAMU) and rescue teams began to apply ice to the skin of CHS-suffering patients immediately at the site of care (nursing homes, apartments, public thoroughfares) until they reached the Emergency Department. Interestingly, in the study of Bouchama and colleagues, no difference in the cooling rate could be demonstrated between the group of patients receiving dantrolene and the group of patients who did not [9]. However, both treatment groups achieved satisfactory cooling in less than 1 hour using a body-cooling unit, which was obviously the key therapeutic procedure in this study [9].

Does that mean that we should only focus on improving our cooling methods instead of studying adjunctive therapies in CHS? The answer rests in the mortality rate (20–50%) attributed to CHS despite active cooling procedures [6].

CHS therapeutic care may benefit from advances in sepsis management, in that both syndromes share some pathophysiological similarities: cytokine and acute-phase protein production, coagulation disorders and, finally, multiorgan dysfunction [6]. Notably, treatment with corticosteroids improves prognosis in animal models of heatstroke, as was reported in patients with septic shock using low doses of hydrocortisone [10,11]. Similarly, improvement in knowledge of coagulation disorders observed in CHS may lead to the indication of replacement therapy with recombinant activated protein C, as reported in severe sepsis [12].

Overall, the traumatic experience shared by French emergency physicians during the August 2003 heatwave, along with the severe outcome still associated with CHS, justifies ambitious therapeutic trials. Undoubtedly, Earth's global warming will especially expose urban populations to future heatwaves and thereby to the risk of CHS. If preventive procedures and identification of vulnerable populations are crucial, emergency and critical care physicians must take up the challenge for reducing CHS morbidity and mortality.

Competing interests

None declared.

Abbreviations

CHS = classic or environmental heatstroke.

References

  1. Grynszpan D: Lessons from the French heatwave.

    Lancet 2003, 362:1169-1170. PubMed Abstract | Publisher Full Text OpenURL

  2. Dhainaut JF, Claessens YE, Ginsburg C, Riou B: Unprecedented heat-related deaths during the 2003 heatwave in Paris: consequences on emergency departments.

    Crit Care 2004, 8:1-2. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  3. Jones TS, Liang AP, Kilbourne EM, Griffin MR, Patriarca PA, Was-silak SG, Mullan RJ, Herrick RF, Donnell HD Jr, Choi K, et al.: Morbidity and mortality associated with the July 1980 heat wave in St-Louis and Kansas City, MO.

    JAMA 1982, 247:3327-3331. PubMed Abstract | Publisher Full Text OpenURL

  4. Semenza JC, Rubin CH, Falter KH, Selanikio JD, Flanders WD, Howe HL, Wilhelm JL: Heat-related deaths during the July 1995 heat wave in Chicago.

    N Engl J Med 1996, 335:84-90. PubMed Abstract | Publisher Full Text OpenURL

  5. Hadad E, Cohen-Sivan Y, Heled Y, Epstein Y: Clinical review: Treatment of heat stroke: should dantrolene be considered?

    Crit Care 2004, in press. OpenURL

  6. Bouchama A, Knochel JP: Heat stroke.

    N Engl J Med 2002, 346:1978-1988. PubMed Abstract | Publisher Full Text OpenURL

  7. Fratea S, Langeron O, Lecarpentier Y, Coriat P, Riou B: In vitro effects of dantrolene on rat myocardium.

    Anesthesiology 1997, 86:205-215. PubMed Abstract | Publisher Full Text OpenURL

  8. Orliaguet G, Langeron O, Coirault C, Fratea S, Coriat P, Riou B: Effects of Dantrolene on rat diaphragm muscle during postnatal maturation.

    Anesthesiology 2001, 94:468-474. PubMed Abstract | Publisher Full Text OpenURL

  9. Bouchama A, Cafege A, Devol EB, Labdi O, El-Assil K, Seraj M: Ineffectiveness of dantrolene sodium in the treatment of heatstroke.

    Crit Care Med 1991, 19:176-180. PubMed Abstract OpenURL

  10. Liu CC, Chien CH, Lin MT: Glucocorticoids reduce interleukin-1 concentration and result in neuroprotective effects in rat heatstroke.

    J Physiol 2000, 27:333-343. Publisher Full Text OpenURL

  11. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, et al.: Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock.

    JAMA 2002, 288:862-871. PubMed Abstract | Publisher Full Text OpenURL

  12. Dhainaut JF, Yan SB, Claessens YE: Protein C/activated protein C pathway: overview of clinical trial results in severe sepsis [review].

    Crit Care Med 2004, 32:S194-S201. PubMed Abstract | Publisher Full Text OpenURL