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What More Is there to Learn about Malignant Hyperthermia?

On September 20, 2010 I had the privilege of being a visiting professor at the University of Colorado, Denver Medical School and delivering the annual Hermann B. Stein MD, endowed lecture. Dr. Stein practiced anesthesiology in Denver for many years in the 1920s, 30s and 40s. His son then became an anesthesiologist and practiced the specialty for close to 40 years. One of his daughters is now a practicing anesthesiologist in New England.  Three generations of anesthesiologists. Pretty striking.

I was very impressed with the excellence of the Department of Anesthesiology led by Dr. Thomas Henthorn. I was privileged to have interesting conversations with some of the researchers and clinicians in the Department. Fortuitously, about nine days prior to my visit a patient undergoing an endoscopic examination developed a somewhat atypical case of MH. The astute anesthesiologist and nurse anesthetist recognized what was happening and began appropriate treatment immediately with good results.

I had visited the medical center years ago, once in the mid 1970s when the second International Workshop on Malignant Hyperthermia took place there.  At that time the Medical Center was located not far from the downtown section of Denver. It was at that meeting that we received the galley proofs of the article by Harrison and colleagues showing that dantrolene had been used to treat MH in swine. No other drug had worked like dantrolene.  I remember the announcement vividly.

The Medical Center moved to Aurora, Colorado just outside Denver proper a few years ago when the Fitzsimmons Army Hospital closed and was sold to the Medical Center for $1. The multiacre site is now a large, modern medical complex housing a University Hospital, Children’s Hospital, several research buildings, and a variety of other buildings that I did not have time to visit.  It is quite impressive. The Medical Center and the University have attracted patients, first class researchers and clinicians from all over the world.  It is very nice; I am sure, to work in new facilities with state of the art equipment.

Back to my visit.  The topic of my talk was “Fifty Years of MH: What Have We Learned, What Do We Have to Learn?”

As many of you know, the first case of what would turn out to be MH was reported from Australia in 1960 by Drs. Denborough and Lovell.  Since that time thousands of MH cases have been reported from many countries and thanks to education, early intervention and dantrolene, the mortality rate from MH has declined from the initial 70-80% to below 20%.   As part of my talk, I discussed the history of MH and the clinical and laboratory findings from hundreds of investigators over decades that have improved the care of MH patients and their families.  I also, of course, described the origins of MHAUS as well as the European MH Group.  It is truly an international story and one that represents a significant advance in medical/anesthesia care. I traced the history of the development of first the muscle biopsy contracture test and more recently the molecular genetic test. (I have been privileged to have seen many of these advances and changes first hand and to have had the honor to meet many of those whose work made anesthesia care safer.) Unfortunately, in one hour, I did not have the time to amplify on topics such as the pathophysiology of MH, the relation of MH to other disorders, the epidemiology of MH and many aspects of the molecular genetics of MH.

Rather than concentrate on what I did not speak about, I thought it might be of interest to relate some of the issues that remain to be solved and the challenges that remain ahead.

In our pursuit of a minimally invasive highly accurate test for MH susceptibility most research labs have focused on the molecular genetics of MH.  However, we don’t know all the mutations that are “causal” for MH. We know that the ryanodine receptor gene is associated with MH susceptibility in probably close to 70% of cases but, with the exception of about 30 mutations we have not proven which of the over 200 DNA changes lead to protein changes that result in the clinical syndrome.

Furthermore we are not sure if the clinical severity of the syndrome is related solely to molecular genetic changes. Why, for example, do some patients with a specific mutation develop signs of MH which include a dramatic evolution, while others don’t?  Is it related to drug use, to other genetic or environmental factors?

Still on the genetic issue, we know now that some patients with ryanodine receptor mutations will display signs of MH, albeit rarely, without anesthesia. In most cases, the signs seem to be precipitated by heat and exercise, but even that is not the whole story.

How often does “awake” MH happen? What are the predisposing factors?

We know that certain muscle disorders are associated with MH susceptibility, particularly Central Core Disease, an uncommon myopathy, while others are not associated with MH susceptibility. We are not sure if a large number of other muscle disorders predispose to MH.  In particular why, do patients with muscular dystrophy have muscle breakdown which can lead to sudden death on exposure to the MH trigger agents when the defect in those disorders is not directly related to either of the two genes associated with MH, the ryanodine receptor gene and the dihidropyridine receptor gene?

We are very well aware that dantrolene is a very specific and very effective drug for the treatment of MH. However, the mode of action is not clearly understood. Recent studies also have shown that dantrolene can protect other cells from destruction due to dysfunctional or structural changes in the ryanodine receptor that are specific for those cells. For example, there is a specific ryanodine receptor that mediates calcium movement in cardiac tissue. If there are mutations in that calcium channel gene, those patients are at risk to arrhythmias that may be fatal. In fact there is some evidence that cardiac ryanodine receptor changes may lead to heart failure. Preliminary studies have shown that dantrolene will prevent the biochemical changes in both of those syndromes.

Of course, we are still struggling with the necessity of mixing multiple vials of dantrolene when treating an MH crisis. Although the preparations of dantrolene that are now on the market allow more rapid mixing, it still is a chore to do that, requiring an extra pair of hands to effect rapid mixing.

As mentioned before, some patients who display genetic changes found in MH patients also experience heat stroke with exercise and heat.  We don’t really know how many of the patients who experience heat stroke in athletic competition do so because the ryanodine mutations place them at risk.  There have been no epidemiologic studies of this phenomenon, largely because until the past decade the only reliable test for MH susceptibility was the muscle biopsy contracture test.  Furthermore, what do we advise these patients as well as MH susceptibles in general regarding exercise in hot environments and in general, is it necessary to change life-style?

 At our recent MHAUS sponsored symposium we heard that some patients who develop muscle breakdown when taking lipid lowering drugs harbor MH causal mutations. Do these changes predispose to the muscle breakdown?  If so, how often and what can be done about it?

We should not forget of course that most cases of MH occur upon exposure to anesthetic gases and the paralyzing agent succinylcholine.  Are all facilities prepared with stock of Dantrium IV?  Do they perform team training for treating MH?  How well prepared are outpatient centers and, in particular, office surgery centers, to manage the MH crisis?  Are the transfer plans well described? Do they conduct drills for patient transfer during an MH crisis?  Do they know if the receiving facility has adequate stock of Dantrium and are the personnel prepared to treat the syndrome?

Another major concern for MHAUS and MH community is the diminishing number of muscle biopsy contracture testing centers.  We are now down to six testing centers in the US and Canada.  Although the molecular genetic test is available, many individuals do not meet the criteria for testing, many insurance companies will not pay for testing, and the test does not detect all those who are MH susceptibles. The muscle biopsy contracture test is still the “gold standard” diagnostic test for MH.

Finally, MHAUS has been incredibly fortunate in receiving financial support from companies such as Procter and Gamble Pharmaceuticals in the past and now JHP Pharma. We are grateful to the American Society of Anesthesiologists and the American Association of Nurse Anesthetists as well as thousands of individual anesthesia providers, nurses and patients for their financial aid. A small organization such as MHAUS is always struggling to obtain the financial resources for introduction of new educational material, direct patient and provider support as well as assistance for those interested in expanding the depth of knowledge concerning MH and MH-like syndromes. 

I can only wonder what the next 50 years will bring. 

Thanks for your support. As usual, I welcome your comments and suggestions.



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  • General
The mission of MHAUS is to promote optimum care and
scientific understanding of MH and related disorders.