The (Re) Discovery of Malignant Hyperthermia

April 2008

The (Re) Discovery of Malignant Hyperthermia

     MH was first formally described in 1960 by physicians in Australia, including an anesthesiologist and a geneticist (Michael Denborough).

   By the mid 1970s the disorder was widely, although not frequently, recognized by anesthesia providers throughout the world and many cases of the syndrome were described from all parts of the world.  However, deaths from MH were occurring fairly regularly.  A great deal changed with the  introduction of dantrolene to treat the syndrome in MH  as well as widespread education about the disorder by organizations such as MHAUS.

   There followed an explosive growth of knowledge concerning MH during the 1980s and 1990s.  Many reports and studies were published  in the medical and nursing literature related to the specialty of anesthesiology, but not often in the literature read by other specialists.

   However, in recent years there has been greater and greater interest in MH by the medical community in general as well as basic scientists. The reasons for this are many, including the recognition that certain disorders of muscle predispose patients to MH, the concern that some MH patients may have muscle related problems without anesthesia, but one of the most important reasons is the growing interest in the subject of pharmacogenetics.

  Pharmacogenetics means the study of how DNA changes may alter the response to medications and drugs. For example, the sensitivity to the anticoagulant warfarin is linked to the presence or absence of certain enzymes whose presence is a function of a person’s genetic makeup (their DNA).  Some have advised that all those who are taking the medication should have their DNA checked to see which enzymes they manufacture.

  MH is a prototypic pharmacogenetic disorder. The inheritance of susceptibility to MH  in humans and animals has been defined, many (but NOT ALL) of the DNA changes that are causal for the syndrome have been determined; the drugs that precipitate MH have been identified and the site of the protein that malfunctions (the ryanodine receptor - a calcium channel in skeletal muscle), along with the nature of the change, has been elegantly described in sophisticated biochemical studies of cellular metabolism. In addition, the antidote drug, dantrolene, has been shown to act at a specific site and in a certain manner on this protein.   (For further details, please refer to my slide show on the MHAUS web site.)

   The depth of understanding of this pharmacogenetic disorder is far greater than that for most other pharmacogenetic disorders. Hence, basic and clinical scientists are looking to MH as a model for understanding other pharmacogenetic disorders.

  The development of a way to incorporate one or more MH-related DNA changes into an animal, thereby producing an MH susceptible investigational animal by a group headed by Drs. Paul Allen, Isaac Passah, Bob Dirksen and Susan Hamilton,  has opened up yet new vistas. For example, the mice that are  genetically engineered to be MH susceptible regularly develop MH signs on exposure to not only the known anesthetic triggers, but also to high environmental temperature.  This suggests that some MH susceptible humans might also be at risk to heat stroke and heat prostration, i.e., that some cases of heat stroke are really a form of MH . I caution the reader that such an extrapolation from one species to another is fraught with danger, particularly as the genetic environment of different animals may modify the expression of the DNA.

   For those of us who have had an intense interest in MH for many years, it is gratifying to see such renewed interest. Yet it is also disappointing that aside from a few academic anesthesia department in the US, there seems to be limited interest in clarifying the full clinical implications of the syndrome. For example, there are now only about six MH biopsy testing centers for MH  in the US and Canada, where previously there were close to twenty. There are only two molecular genetic testing sites in the US and only one research laboratory focused on the molecular genetics of MH in humans.  In contrast, there are about 20 biopsy testing centers in Europe and multiple research laboratories working on the problems of MH.

  Some practitioners consider MH as a non problem since there are “only” two to three reported MH related deaths per year in the US. Yet how many deaths or problems from heat stroke or vigorous exercise are related to the MH defect is just about unknown.  In addition, one death from MH is still too many; and for each death there are several “near misses” and probably some adverse events that we are unaware of.

     (In my next piece, I will discuss the recent problems related to MH that are arising with greater frequency  in the ambulatory surgery center and office setting, in some cases leading to death.)

    In my opinion, the information derived from the study of MH can provide lessons and guidance for the study of other pharmacogenetic disorders.

   By the lessons learned from collecting cases of MH through our hotline and Registry, we can show others how to collect and characterize a pharmacogenetic disorder. We can show how to use the clinical characterization of a patient or an episode to explore the genetics of the disorders.  We also can show how to educate the medical and patient community to recognize a disorder, to link investigators with clinicians and promote interchange among patients, clinicians and basic scientists. We can demonstrate how it is possible to do all of this without governmental grants (to MHAUS), by developing alternative funding streams.   We can show how to enlist and work with physicians, nurses, pharmaceutical firms, professional societies and interested patients in order to achieve scientific breakthroughs and translate them into better care and better outcomes.

   MHAUS has indeed been exceedingly fortunate to have a cadre of dedicated physicians, nurses and lay people who donate their time and expertise in pursuit of a goal of zero mortality from MH and MH-related syndromes.

   As always thanks for your support. I welcome your comments.