ASA October 2003 Newsletter

Since first described many years ago, the threat of major morbidity and mortality related to malignant hyperthermia (MH) has decreased substantially. The reasons for this success relate to education, better patient monitoring, widespread availability of dantrolene and support services such as those offered by the Malignant Hyperthermia Association of the United States (MHAUS).

Diagnosing MH Susceptibility
One lesson that has been learned over the years is that there are many clinical presentations of MH. These range, for example, from masseter muscle rigidity after succinylcholine to rhabdomyolysis following surgery to possible “awake” episodes of MH. At present the definitive diagnosis of MH and MH susceptibility relies on the halothane-caffeine contracture test on biopsied muscle. The test is available in the United States at only a few centers and is invasive and costly. Therefore an accurate, minimally invasive diagnostic test is crucial for unraveling the many different threads that make up the MH syndrome.

The good news is that a variety of new approaches to MH diagnosis are under development. This is the result of rapid advances in molecular genetics, biochemistry and cellular physiology. Some of these approaches involve harvesting a small amount of muscle cells and growing them in cell culture. Using specific dyes, it is then possible to view the changes in cellular calcium ion concentration upon exposure to halothane, caffeine or other drugs that lead to cellular calcium release in real time. Cells from MH-susceptible patients will show an enhanced release of cellular calcium compared to normals as well as a dramatic drop in pH. B lymphocytes have been found to contain ryanodine receptor sites (the calcium-release channel), much as muscle cells. The B lymphocytes from MH patients also display exaggerated changes in cellular calcium levels upon exposure to caffeine and other calcium-release agents compared to normals. Another approach has been the use of nuclear magnetic resonance spectroscopy to noninvasively measure adenosine triphosphate, pH, creatine phosphate and other high-energy phosphates. With exercise MH susceptibles demonstrate a greater depletion of high-energy phosphates and fall in pH compared to normals.

Yet other investigators have shown that in vivo microinjection of caffeine in muscle elicits an accentuated rise in CO₂ output and hydrogen ion in MH susceptibles.

As promising as these studies are, in my opinion and in the opinion of members of the MHAUS Professional Advisory Council, molecular genetic diagnostics holds the greatest promise for a minimally invasive, specific diagnostic test. Molecular genetic testing has the advantage of being highly reproducible and very specific, requiring only small amounts of biologic material and may with time become relatively inexpensive. DNA may be harvested and stored for many years without sophisticated storage techniques.

Beginning in the early 1990s, investigations have demonstrated that mutations in the gene that encodes the calcium-release channel in skeletal muscle, the ryanodine receptor, are most often responsible for MH susceptibility. More than 40 mutations in this gene have been described as being causal for MH. (A few other genes also have been linked to MH susceptibility, but in only a few patients.) This has led to the development of guidelines for clinical molecular genetic testing by the European MH group.

In order to consider introducing molecular genetic diagnostic testing in North America, MHAUS sponsored a meeting of molecular geneticists and members of the MHAUS PAC in September 2002. There was consensus that 17 mutations in the ryanodine receptor gene should form the initial screening panel while further studies continue to clarify what other molecular genetic factors are causal for MH. A full report on that meeting will be published in Anesthesiology within the next few months. At this time, MHAUS is seeking a Clinical Laboratories Improvement Act-certified laboratory to make such testing available to patients. It is anticipated that initial funding for the laboratory will be supplied by a grant from MHAUS derived from donations. Issues such as genetic counseling for patients, guidelines for testing and the cost of testing are just some of the hurdles to overcome.

Given the initial successes in the use of molecular genetic analysis in European centers — in terms of reducing the need for invasive biopsy, especially in families with a known history of MH — we feel that molecular genetic testing will help us to better understand the many different clinical presentations of MH, both inside and outside of the operating room (O.R.).

The North American MH Registry will serve as a very important part of this effort. The registry contains the phenotypic description and biopsy results of close to 3,000 patients with MH susceptibility or a suspicion of MH. Not only will the database be important in alerting patients to the availability of the molecular genetic test, it will enable the correlation of phenotype with genotype, one of the main aims of all genetic tests.

At present the registry is completing a restructuring of the database in order to make access to the data easier and also enable less complex data entry. Registry Director Barbara W. Brandom, M.D., of Children’s Hospital of Pittsburgh, Pennsylvania, also has spent considerable time and effort to ensure that the registry conforms to Health Insurance Portability and Accountability Act regulations as well as regulations involving clinical research protocols.

Success of the MH Hotline
Each year at the ASA Annual Meeting, MHAUS recognizes significant service from our hotline consultants at a special recognition reception. The Hotline Partnership Award for 2002 was given to Jordan D. Miller, M.D., Professor of Anesthesiology, University of California-Los Angeles, and Abdel Ali El-Dawlatly, M.D., in their handling of a case in Saudi Arabia. The case involved a young woman in her 20s who experienced an episode of MH during a discectomy. The team in the O.R. recognized her symptoms and contacted the MH hotline when Dr. Miller was on call. The two doctors communicated by beepers, via the Internet, with Dr. Miller assisting Dr. El-Dawlatly until the patient was stabilized.

Further Dr. Miller reminded the team in Saudi Arabia of the genetic nature of MH, which allowed them to prevent the woman’s grandmother, who was scheduled for elective surgery the following morning, from exposure to what undoubtedly would have been a triggering anesthetic.

This case was unusual because of the role the Internet played in linking two doctors half a world apart in order to save two lives. But the MH hotline continues to save lives every day, thanks to the team of volunteer hotline consultants who handled almost 300 emergencies this past year.

As Dr. Miller states, “The nature of the hotline is such that we (the consultant) are only contacted if there is a problem already identified and the anesthesiologist has already decided that the patient is possibly having an MH episode. What we do is help them to decide the probability and make sure they do not forget things that they might otherwise forget in their rush to take care of the patient. We are able to add another perspective not only because we are experts, but because we are available as a sounding board when no one else is around. Many times the anesthesiologist may feel the patient probably doesn’t have MH but just needs that reassurance.”
At this year’s recognition reception, the Daniel Massik MHAUS Anesthesia Resident Awards will be presented to two promising anesthesiology residents who submit an article or paper on the subject of MH. Last year, the first Massik Award went to Gary W. Haber, M.D., for his work on “Early Recognition of Malignant Hyperthermia and its Impact on Outcome.”

New Programs
MHAUS added a new office-based version to its stable of procedural manuals this summer. (There are also hospital and ambulatory care center versions as well.)

The manuals serve the needs of surgeons and anesthesiologists who provide anesthesia care in an office setting. These manuals prepare medical personnel to handle all aspects of an MH crisis by utilizing mock drills and in-service workshops. They contain a video, responsibility flowchart, staff worksheets, the recommended MH cart/kit supplies checklist, an event drill form, an MH treatment poster, various brochures and an “Adverse Metabolic Reaction to Anesthesia” report to be filed with the North American MH Registry in the event of an MH crisis.

Also new in 2003 is a risk-management presentation in slideshow or CD-ROM format. This presentation, “Managing Malignant Hyperthermia Risk in Today’s Surgical Environment,” reviews the risk of MH and assesses current trends in the management of MH in both inpatient and outpatient settings. This program is arranged so that it can also be used as a self-study program to enhance individual knowledge of MH and the risks involved.

A new “Interview” section is coming soon to the MHAUS Web site <www.mhaus.org> that will answer such questions as: How often does MH happen? How many people does it affect? What is MH? What are the signs of MH? How do you know whether family members have it? Is MH more common in certain areas of the country? What medication is available in case of an MH episode? What questions should patients ask their surgeons? What questions should patients ask their anesthesiologists? Is there a test available to determine MH susceptibility? What are the advantages and disadvantages of having a muscle biopsy for MH? What steps is MHAUS taking to inform people about MH? What is the MH Hotline? Are there any lawsuits involving MH?

The MHAUS Patient Liaison Committee has many projects under way to help MHAUS improve its patient services. One such project, the “MH Message Board,” is now online and allows patients to share ideas, experiences and concerns with other patients while fostering interaction and communication among people with a common interest in understanding MH.

Many different individuals contribute to the success of MHAUS, including the many hotline consultants and the members of the board and staff of the MHAUS office.

Finally special thanks and good wishes go to two individuals who have contributed substantially to our understanding of MH, Gerald A. Gronert, M.D., and Thomas E. Nelson, Ph.D., who have recently retired from their respective positions at the University of California-Davis and Bowman Gray School of Medicine.

For more information about MHAUS’ programs or membership, please call the general information line at (607) 674-7901; write MHAUS, P.O. Box 1069, 11 E. State St., Sherburne, NY 13460-1069; or go online at <www.mhaus.org>.

Henry Rosenberg, M.D., is Director, Department of Medical Education, Saint Barnabas Medical Center, Livingston, New Jersey.

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