Far Reaching New Information Concerning the Diagnosis and Management of MH and Exertional Heat Stroke

The views expressed in this posting are mine alone and do not necessarily represent the views of other professionals or Board Members of MHAUS.

A “new “ dantrolene?

 In 1979 dantrolene was approved by the FDA for the treatment of Malignant Hyperthermia. Dantrium (dantrolene)  was developed by a small company  located in upstate New York called Norwich Eaton Pharmaceuticals.  Procter & Gamble Company (yes, the soap, detergent and household product company) acquired Norwich Eaton prior to the approval of the drug by the FDA. A major effort led by Mary Elizabeth Kolb, spearheaded the effort resulting in approval of the drug in record time.   Dantrolene  was instantly embraced by the anesthesia community as it was the only drug that was effective in treating and reversing MH. Many hundreds, if not thousands, of lives have been saved thanks to dantrolene.

In addition to introducing Dantrium (dantrolene) into clinical use, P&G provided generous support to MHAUS, at that time a fledgling organization, for our  educational programs.  They continued that support  until 2007 when Dantrium was sold to a relatively new company called JHP Pharmaceuticals located in Parsippany, NJ with rights of distribution in Canada (Methapharm), the US and several other countries. The European rights were acquired by SPE Pharma located in Holland, which was recently acquired by another company, Norgine Pharmceuticals.  JHP, realizing that dantrolene was a life-saving drug not only continued to sell the drug, but also made some modifications in the preparation in order  to make the drug easier to get into solution. As many of you know, dantrolene is available in vials containing 20mg of dantrolene, along with 3g of mannitol in a powdered form. 60ml of sterile water for injection without a bacteriostatic agent must be added to each vial, and then mixed thoroughly in order prepare the medication for injection.  The reformulation shortened the mixing time from about one minute to less than 30 seconds. Nevertheless, because at least nine vials are needed for the treatment of MH in the average adult, and additional medication needed to prevent recrudescence, time and personnel are needed to prepare the medication for administration.  As has been demonstrated repeatedly in studies from the North American MH Registry of MHAUS, delays in administering dantrolene increase the risk of complications from MH, including coagulation problems, muscle breakdown, and cardiac problems.  We are grateful to JHP for its continued support of the educational programs offered by MHAUS. 

 In February 2014, we learned that JHP is being acquired by a larger company, PAR Pharmaceuticals, in Woodcliff Lakes NJ (www.parpharm.com). We anticipate continued support of dantrolene as well as the programs of MHAUS in the future, based on communications with the current management of JHP Pharma. 

I should also mention another company, US WorldMeds also sells generic formulation of dantrolene in the US.

Realizing that a major issue with the current formulations of dantrolene is the drug’s relative insolubility, various modifications of the product (not the molecule itself but the chemicals that are used to assure stability of the molecule) have been tried in order to make dantrolene easier to prepare and use.  Recently, this effort has resulted in a formulation of dantrolene that meets this  goal.  This new formulation, called Ryanodex, when properly mixed, produces a final concentration of 50mg/ml obviating the need for reconstituting multiple vials.

[The product will contain 250mg in a 20ml vial and is reconstituted with  only 5ml of sterile water, (therefore containing 50mg/ml)].  The company that has accomplished this feat is Eagle Pharmaceuticals, also located in Woodcliff Lakes, NJ.  You can learn more about Eagle and Ryanodex, by viewing the company’s web site: www.eagleus.com.  Ryanodex is not approved for clinical use by the FDA at this time,  but is under consideration by the agency.  (In the spirit of full disclosure I have consulted with Eagle regarding the clinical utility of Ryanodex).  Ryanodex has been used successfully in the treatment of MH in the pigs that are susceptible to MH.  This information can be found in the peer reviewed medical literature (Schutte JK, Becker S, Burmester S, et al. Comparison of the therapeutic effectiveness of a dantrolene sodium solution and a novel nanocrystalline suspension of dantrolene sodium in malignant hyperthermia normal and susceptible pigs. European J of Anaesthesiology 2011;28:256-264).

I do not know when the FDA will make a final determination on the drug, but since the information is in the public domain, I thought it appropriate that the MH community should be aware of these developments.

If and when Ryanodex is approved, our experts at MHAUS will have to consider the implications of this new preparation in the management of MH.

Exertional Heat Stroke and MH

I and others have often written about the possible relationship between exertional heat stroke (EHS) and MH.  There are isolated reports in the literature and presentations at meetings, (which often do not get published) demonstrating that some patients who develop exertional heat stroke harbor genetic changes that are found in MH susceptibles.  However, it has been difficult to identify  a significant number of patients who developed EHS and then were tested for MH susceptibility either by genetic tests or by the standard caffeine halothane contracture test.  A very recent publication in the journal Military Medicine by a group of French investigators associated with the French army who have been studying the problem of MH and heat stroke for several years, demonstrate that 138 of 295 patients (47%) who suffered heat stroke were determined to be MH susceptible, based on the European version of the caffeine halothane contracture test which has been shown to be both highly sensitive and specific in diagnosing MH susceptibility (Sagui et al. Military Medicine 179;342, 2014). Unfortunately, they did not report on the molecular genetics of these patients.  In addition, the muscle that was harvested for testing was not from the thigh, which is the agreed-upon standard site. However, several MH testing centers in Europe and the US have demonstrated, with a lesser number of patients, that  many who experienced  heat stroke also harbor MH related mutations in the ryanodine receptor gene.

I believe that it is now safe to conclude  that a significant percent of  patients who experience heat stroke are  MH susceptible according to the testing procedures currently available.  One of the implications of this finding bears on the new formulation of dantrolene. If indeed dantrolene is more easily prepared (one or two syringes will contain enough dantrolene to treat an adult patient without extensive mixing with large volumes of fluid), then perhaps dantrolene could be used in the emergent treatment of heat stroke along with the standard cooling measures.  This is further amplified on the Eagle US website.  Again, the FDA has not approved Ryanodex for treatment of exertional heat stroke. If approved it will be the first drug available to treat heat stroke.

Another implication of these findings is  a  recommendation that all patients who develop heat stroke undergo genetic testing for  malignant hyperthermia susceptibility.  A further speculation might be that those who participate in competitive sports undergo genetic testing for MH susceptibility.  Please remember this is speculation at this point in time.

Yet another  implication is that emergency room physicians and first responders will need to become familiar with the use of dantrolene for the acute treatment of exertional heat stroke.

I believe that there are more  significant advances in the understanding of MH and its implications taking place now  than I can recall since the introduction of dantrolene in 1979, the introduction of routine real time analysis  of carbon dioxide excretion during general anesthesia, which facilitates early diagnosis of MH,  and the identification of the genetic changes associated with MH in 1990.

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