Fiscal Year 2013-2014 Year End Review

As the calendar year comes to a close, I would like to take a few minutes of your time to highlight some of the activities and programs that MHAUS has either introduced or amplified over the past year and point out some of the scientific advances related to MH and MH related disorders.

2013 ended with a scientific conference in Toronto hosted by the director of the MH Investigation unit at the University of Toronto, and now a member of the Board of Directors of MHAUS, Dr. Sheila Riazi.  The conference focused on disorders related to the primary gene that is associated with MH, the ryanodine receptor gene, also called RYR 1.  I mention the conference because a fine summary of the conference was published in November 2014 in Canadian Journal of Anesthesia. Thanks are due to Dr. Riazi for her hard work on getting all the information collated and summarized as well as the organizing committee headed by the Chair of our Professional Advisory Council, Bob Dirksen.  The publication will serve as a reference for all those interested in MH.

2014 saw the publication, on line, of a guide related to diagnostic testing for MH.  The “Roadmap” was put together with the collaboration of MH experts, genetics experts, patients and was shepherded through completion by Dianne Daugherty, our excellent executive director. The roadmap provides concrete information concerning the various testing options and their pros and cons.

Also introduced in 2014 was a new program and concept for MHAUS called the “MH Prep Check”.  The concept is to provide expert advice for a facility in preparing for an MH crisis. The way it works is that a facility will request one of our MH hotline consultants be present during an actual MH drill at their facility. She/he visits to observe the preparation for the drill, view the drill, and comment on the areas that worked well and those that could be improved.  The “Prep Check” concept had been discussed by the Board of MHAUS, the staff and some of the consultants for a while, but final implementation occurred because of the hard work of Dianne Daugherty.  We also benefitted from a very generous grant to develop and begin implementation of the program by the family of Anita and Don Kaufman, MD, long time generous supporters of MHAUS.  I participated in one of the prep check sessions at a nearby hospital.  I was impressed by the commitment of the OR team, anesthesia and nursing staff to make sure they were well prepared for an MH emergency.

In addition to Dr. Riazi, several other people were added to the Board of MHAUS.  Kathy and Curt Keller are the parents of a young man who died from an MH-related event.  They and their family have been working hard to raise awareness and funds for MHAUS.  Dr. Riazi, as mentioned already, is in charge of the University of Toronto MH diagnostic unit and is engaged in both basic science and clinical research on MH and MH genetics.

Perhaps the biggest news of the year relative to the care of the MH patient, was the approval by the FDA in July of 2014 of a new formulation of dantrolene, called Ryanodex (web site: www.ryanodex.com).  The new preparation is a nanosuspension of dantrolene and the great advantage is that only a small volume of water is needed to reconstitute the drug to a final concentration of 50mg/ml.  So, instead of the typical 10-12 vials of the previous formulation of dantrolene (available as either Dantrium® or Revonto®) mixed with 60 ml of sterile water in each vial to treat an average adult; only 4-5 ml of Ryanodex is needed. This greatly facilitates the preparation of dantrolene and allows more rapid injection of the drug during a crisis.  The company that developed the new preparation is Eagle Pharmaceuticals.  To date the drug is only available in the US.  The cost of Ryanodex is more than the previous formulations of dantrolene, but the ease of use is greater.

During the same period of time, the Dantrium formulation was acquired from the previous manufacturer and distributor, JHP Pharmaceuticals, by Par Sterile Products, one of the largest generic drug manufacturers in the world.   Representatives of MHAUS have worked with both companies to answer questions and provide advice on how best to educate those using dantrolene.

In September 2014, a meeting of hotline and selected professional advisory council members met in Chicago to review current statements related to MH and discuss others that will provide perspective and advice on some common questions MHAUS receives on a regular basis. For example, after the conference, changes were made in our educational material concerning the use of Ryanodex.  In addition, enhanced advice concerning the use of activated charcoal filters (made by a company called Dynasthetics) during preparation of the anesthesia machine for a patient susceptible to MH and for management of an MH crisis was also updated.

At about the same time, a study performed by Drs. Marilyn Larach, Barbara Brandom, Greg Allen and others based on data in the North American MH Registry of MHAUS was published, demonstrating how monitoring “core” body temperature during anesthesia reduces death from MH.  They showed that those patients who did not have their core temperature monitored during anesthesia were at 14 times increased risk of dying from MH during a crisis!  An accompanying editorial in the journal Anesthesia and Analgesia underlined that all patients undergoing general anesthesia for more than a few minutes should have their body temperature monitored continuously. The MHAUS statement concerning temperature monitoring was placed on the MHAUS web site for comment and will be posted as a final recommendation very soon.

As usual, MHAUS exhibited at a variety of medical and nursing meetings.  Exhibits at the American Association of Nurse Anesthetists, the Association of OR Nurses and the American Society of Anesthesiologists (ASA) allow us to disseminate the latest information and answer questions concerning MH for thousands of clinicians. Many of our experts give presentations at these meetings.  For example, Dr. Ron Litman, Medical Director of the Hotline, gave a lecture at the ASA reviewing the essential elements of MH.    During the ASA, I was surprised to learn that I will be awarded the Distinguished Service Award by the ASA at the Annual Meeting in October 2015.  There were many who advocated for me to receive this award, without my knowledge, and I thank them and the ASA for the recognition.

In December, MHAUS exhibited at the New York Post Graduate Assembly, the second largest meeting of anesthesia clinicians in the US.  We held a reception in conjunction with the meeting and had the opportunity to meet many anesthesiologists, nurse anesthetists, OR nurses and patients at that time.  Dr. Charlie Watson, one of our most devoted hotline consultants and chair of the hotline quality improvement committee, was given an award for his dedicated service to the organization.  Dr. Watson is the Chairman of Anesthesia at Bridgeport Hospital in Connecticut.

Another first for MHAUS was the support of the first MH symposium in India in collaboration with the Indian College of Anesthesiologists and the Department of Anesthesiology, University of Minnesota in November 2014 at Bengaluru, India.  Special thanks go to Dr. Kumar Belani for helping to organize a very successful meeting.  People in many parts of the world are hungry for information about MH.  MHAUS is happy to fulfill that need and provide guidance in helping form local organizations for patients and clinicians. This has been one of my long term goals.  Our restriction for more aggressively meeting this need is limited resources.

Another innovative program that began in 2014 is the MHAUS Partnership membership.  This effort was suggested and advanced by Board Member, Bonnie Denholm.  Now members of the Association of OR Nurses may obtain full membership in MHAUS at a greatly reduced rate.  The American Association of Nurse Anesthetists (AANA) and the Society of Ambulatory Anesthesia (SAMBA) have also taken advantage of this opportunity.   The concept has been and will be extended to other organizations as well. This is yet another way that we extend the reach of MHAUS.

Although great advances are being made concerning the role of molecular genetics in diagnosing disorders and guiding clinicians in the use of pharmaceuticals, progress in applying molecular genetic diagnostic techniques to MH is progressing at a rate that is slower than I would like.  In a large part this is due to the low incidence of MH and the complexity of interpreting DNA changes in the very large gene responsible for most cases of MH; and because there are probably other genes or gene changes that lead to susceptibility to MH.  The good news is that more specialties, particularly pediatric neurologists, have recognized the connection between the ryanodine receptor gene and a variety of muscle disorders. They, in turn, have begun to focus their laboratory studies on the RYR 1 gene and the relationship between MH and other disorders.  A few centers, such at the one in Leeds, England, have begun to employ “next generation” sequencing techniques to the study of MH in the hope of identifying other genetic changes that predispose to the disorder.

The European MH group made up of clinicians and scientists interested in MH continues to refine the muscle biopsy contracture test and also to add to the list of DNA changes (mutations) that predispose an individual to the disorder.  The hope is that a panel of genetic changes will be used to screen, or more easily confirm, susceptibility to MH than current tests, but it is unlikely to happen very soon.

Other exciting and potentially significant developments that are in process are:

• The study of the relationship between heat stroke, exercise-induced muscle breakdown and susceptibility to MH. If this connection is clarified, dantrolene (i.e., the Ryanodex preparation) may turn out to be the first drug to be effective in treating heat stroke.
• The effectiveness of dantrolene in the management of life-threatening hyperthermia resulting from other drugs (such as Ecstasy) or medical conditions (such as sepsis).  Small studies suggest that dantrolene can reverse refractory hyperthermia.
• The use of lymphocytes (a form of white blood cells) for diagnosis of MH.  About 12 years ago, scientists found that the same ryanodine receptor that exists in muscle, is also found in lymphocytes.  Preliminary studies are showing that such white blood cells, when exposed to drugs that cause accentuated responses in muscle from MH patients, also enhance the metabolism of the lymphocytes.  The result of this increased metabolism can be measured by release of products of the increased breakdown of energy sources (e.g., ATP) such as adenosine or the intracellular concentration of calcium.
• The relationship between MH susceptibility and a variety of unusual muscle disorders and muscle breakdown associated with statin (lipid-lowering) drugs.
• The North American MH Registry is now contributing data to the Global Rare Disease Registry of NIH/NCATS ( https://grdr.ncats.nih.gov/ ). The goal of the GRDR is  to facilitate research in rare diseases.  A  photo donated by a MHAUS family and the title, North American Malignant Hyperthermia Registry may be viewed on the home page of the GRDR.. The open access web site of GRDR is expected to be functioning in May 2015.

Two new foundations related to muscle disorders associated with the ryanodine receptor were formed recently. Concerned that research into diagnosis and treatment of muscle disorders associated with the ryanodine receptor was not getting the attention it deserved, the Goldberg family of Baltimore and Pittsburgh established the RYR1 Foundation (www.ryr1.org).  The newly formed foundation will enhance awareness of such muscle disorders as Central Core Disease, Multiminicore Disease, and Nemaline myopathy, which may be associated with muscle weakness and stimulate research into treatment of the disorders.   Another foundation “Cure CMD” ( www.curecmd.org) was introduced a few years ago emphasizing the need for more research into congenital muscle disorders of all kinds.  This group is facilitating connections between patients and researchers interested in such muscle disorders.

Finally, I must express gratitude to all those who support the mission of MHAUS. Special thanks go to Par Sterile Products, Eagle Pharmaceuticals, the Kaufman family, the Napolitano family and to all those who took me up on the end of the year President’s Challenge, as well as the many members and supporters of MHAUS, especially those who responded to our Year End Appeal.  The work of MHAUS cannot go forward without the dedicated efforts of our hotline consultants, professional advisory council members, the Board of Directors and the dedicated staff of MHAUS: Dianne Daugherty, Gloria Artist, Fay Kovak, Michael Wesolowski, Elaina Morgan and Sara Prosser.

I would like to wish you a very Happy and Healthy New Year.

What follows is a selection of peer-reviewed publications on MH and related topics during 2014 (and a few from 2013): Underlined are members of the Professional Advisory Council and Hotline consultants.

1. Larach MG, Brandom BW, Allen GC, Gronert GA, Lehman EB. Malignant hyperthermia deaths related to inadequate temperature monitoring, 2007-2012: a report from the north american malignant hyperthermia registry of the malignant hyperthermia association of the United States. Anesth Analg. 2014 Dec;119(6):1359-66
2. Pinyavat T, Rosenberg H, Lang BH, Wong CA, Riazi S,Brady JE, Sun LS, Li G.  Accuracy of Malignant Hyperthermia Diagnoses in Hospital Discharge Records.  Anesthesiology. 2014 Sep 30. [Epub ahead of print] PubMed PMID: 25272246.
3. Hedenmalm K, Granberg AG, Dahl ML. Statin-induced muscle toxicity and susceptibility to malignant hyperthermia and other muscle diseases: a population-based case-control study including 1st and 2nd degree relatives. Eur J Clin Pharmacol. 2014 Nov 1.
4. Bina S, Capacchione J, Munkhuu B, Muldoon S, Bünger R. Is Lymphocyte Adenosine a Diagnostic Marker of Clinical Malignant Hyperthermia? A Pilot Study. Crit Care Med. 2014 Dec 4.
5. Broman M, Kleinschnitz I, Bach JE, Rost S, Islander G, Müller CR.  Next-generation DNA sequencing of a Swedish malignant hyperthermia cohort. Clin Genet. 2014 Sep 25. doi: 10.1111/cge.12508.
6. Perry SM. Chapter 7 Investigations on the Relationship Between the Autonomic Nervous System and the Triggering of Malignant Hyperthermia: A State-of-the-Science Review. Annu Rev Nurs Res. 2014;32(1):135-54.
7. Riazi S, Kraeva N, Muldoon SM, Dowling J, Ho C, Petre MA, Parness J, Dirksen RT, Rosenberg H. Malignant hyperthermia and the clinical significance of type-1 ryanodine receptor gene (RYR1) variants: proceedings of the 2013 MHAUS Scientific Conference. Can J Anaesth. 2014 Nov;61(11):1040-9.
8. Seifert PC, Wahr JA, Pace M, Cochrane AB, Bagnola AJ. Crisis management of malignant hyperthermia in the OR. AORN J. 2014 Aug;100(2):189-202.
9. Roesl C, Sato K, Schiemann A, Pollock N, Stowell KM. Functional characterisation of the R2452W ryanodine receptor variant associated with malignant hyperthermia susceptibility. Cell Calcium. 2014 Sep;56(3):195-201.
10. Zhao X, Song Q, Gao Y. Hypothesis: exertional heat stroke-induced myopathy and genetically inherited malignant hyperthermia represent the same disorder, the human stress syndrome. Cell Biochem Biophys. 2014 Nov;70(2):1325-9.
11. Stewart MW. Anesthetic drugs and malignant hyperthermia. J Perianesth Nurs. 2014 Jun;29(3):253-5.
12. Ranganathan P, Phillips JH, Attaallah AF, Vallejo MC. The use of cognitive aid checklist leading to successful treatment of malignant hyperthermia in an infant undergoing cranioplasty. Anesth Analg. 2014 Jun;118(6):1387.
13. Aderibigbe T, Lang BH, Rosenberg H, Chen Q, Li G. Cost-effectiveness analysis of stocking dantrolene in ambulatory surgery centers for the treatment of malignant hyperthermia. Anesthesiology. 2014 Jun;120(6):1333-8.
14. Litman RS, Joshi GP. Malignant hyperthermia in the ambulatory surgery center: how should we prepare? Anesthesiology. 2014 Jun;120(6):1306-8.
15. DNA testing for malignant hyperthermia: the reality and the dream. Stowell KM.Anesth Analg. 2014 Feb;118(2):397-406.
16. Schuster F, Moegele S, Johannsen S, Roewer N. Malignant hyperthermia in the intensive care setting. Crit Care. 2014 Feb 26;18(1):411.

From 2013

1. RYR1 mutations as a cause of ophthalmoplegia, facial weakness, and malignant hyperthermia. Shaaban S, Ramos-Platt L, Gilles FH, Chan WM, Andrews C, De Girolami U, Demer J, Engle EC.JAMA Ophthalmol. 2013 Dec;131(12):1532-40.
2. Exome sequencing reveals novel rare variants in the ryanodine receptor and calcium channel genes in malignant hyperthermia families. Kim JH, Jarvik GP, Browning BL, Rajagopalan R, Gordon AS, Rieder MJ, Robertson PD, Nickerson DA, Fisher NA, Hopkins PM.  Anesthesiology. 2013 Nov;119(5):1054-65.
3. Using exome data to identify malignant hyperthermia susceptibility mutations. Gonsalves SG, Ng D, Johnston JJ, Teer JK, Stenson PD, Cooper DN, Mullikin JC, Biesecker LG; NISC Comparative Sequencing Program.  Anesthesiology. 2013 Nov;119(5):1043-53
4. Exome sequencing: one small step for malignant hyperthermia, one giant step for our specialty – why exome sequencing matters to all of us, not just the experts. Nagele P. Anesthesiology. 2013 Nov;119(5):1006-8.