The conclusions expressed in this essay and the projections for the future are mine and have not yet gone through the rigorous review process of MHAUS.
I have focused a large component of my professional life in the study of MH and have been thinking of how my experience with this deadly disorder might be related to the issues with COVID-19.
I started my interest in MH in the late 60s as I was finishing my anesthesia training at one of the foremost training institutions, the Hospital of the University of Pennsylvania, Philadelphia. The Chairman at the time was one of the giants of the specialty, Dr. Robert D. Dripps, who was passionate about research in general and research in anesthesiology in particular. Virtually all the rather small group of faculty members had an ongoing research project. Shortly after starting my training, I was informed that a healthy student nurse who was undergoing general anesthesia, developed a high fever and died. It took a while to figure out that she succumbed to Malignant Hyperthermia, which had been described in the early 1960s.
One of the faculty, Dr. George Strobel, with the help of several well-known pharmacologists at Penn, developed a lab to investigate the effect of general anesthetics on muscle physiology since by the mid-1960s it was pretty clear that the basic defects leading to MH arose in the skeletal muscle. His lab partner and technologist was Susan Reed. After George left to pursue other career options, I inherited the lab and quickly started to perform muscle biopsy testing for MH using protocols suggested by investigators such as Mike Denborough, F. Richard Ellis, and others. I also began to study the effect of anesthetics on muscle physiology with Dr. Neils Haugaard and his wife, Dr. Ella Haugaard, of the Pharmacology Department. I also attended many MH meetings in the US and Europe.
One of the great advances in treatment of MH came from the work of an investigator from South Africa, Dr. Gaisford Harrison. He was studying MH in susceptible pigs, a naturally occurring animal model for MH. Dr. Keith Ellis who was a scientist at Norwich Eaton Pharmaceuticals noted in his work that one of the molecules he was studying, related to Macrodantin, caused muscle relaxation and weakness, but not complete paralysis. You can hear more about that on the video interview that I had with him that is displayed on our web site. He felt it may have had some relevance in the management of the muscle rigidity found in MH cases.
That compound was dantrolene. Dr. Ellis read about MH as a note in one of the journals that he received. He therefore suspected that it may help in managing MH syndromes in animals. He then wrote to several investigators studying MH and found out about Dr. Harrison’s work. He eventually sent Dr. Harrison samples of the new drug, who then demonstrated its remarkable effectiveness. The report was presented verbally, not as an official presentation but as a news report, at the second International Workshop on MH in Denver in 1975 which I attended.
Dantrolene was a product of Norwich Eaton Pharmaceuticals in Norwich, NY which was later acquired by Procter and Gamble. Dr. Mary Elizabeth Kolb moved the compound along with clinical studies and, in 1979, it was approved by the FDA
Prior to dantrolene, there were studies showing that certain local anesthetics might help in treating acute MH, but the efficacy was limited. Paul Bianchi, a senior pharmacologist at Penn was studying the action of local anesthetics in general. Fortunately for all of us there was an animal model ( certain pig breeds) that resembled MH in many (not all) ways, so there was a way to investigate the pathophysiology of MH and its possible treatment. Dr. Tom Nelson, at that time an agricultural scientist, had been studying Porcine Stress Syndrome, as MH in pigs was called, and was one of the scientists who bridged the world of animal and human medicine. He even spent a year in Australia with Dr. Denborough and others. On his return to the USA he developed an MH testing center with his associate, Dr. Trey Flewellyn, in Houston. About the same time, other scientists, particularly Drs. Beverly Britt, Werner Kalow, and David MacLennan, who were interested in MH, were using the animal model to learn more about MH and educate the community.
So, there were three key factors in clarifying the pathophysiology and clinical manifestations of MH: Curious, accomplished scientists who were in communication with clinicians and other scientists; previous work and information on the inheritance and manifestations of MH, and an animal model for the disorder that permitted careful analysis of the pathophysiology and treatment of the disorder. The story gets more complex and will be described in a history of MH; a work in process by Dr. Nelson.
Getting back to MH and COVID-19, they seem to be unrelated to one another; one is an infectious disorder, the other an inherited pharmacologic metabolic disorder. There is much fantastic scientific research ongoing into COVID-19, primarily in human tissue. There are also several studies exploring medications that might help deal with the syndrome, but I have heard very little concerning an animal model for the disorder which, in my opinion, is essential for understanding an unknown disorder and testing treatments.
Why not? Perhaps some of the standard animal models are not suitable for COVID-19 study or perhaps animal research has become a challenge for other reasons. Perhaps there is ongoing research and I have missed the references as I am not following the field closely. Matter of fact, Dr. Stanley Caroff tells me that he attended a symposium on COVID-19 at the University of Pennsylvania where scientists were exploring an animal model for the disorder.
When I first heard of the COVID-19 syndrome, I thought that based on our vast knowledge of viruses and how they cause tissue destruction as well as the vast number of agents that affect viral physiology, we would be further along in the cure of this dreaded disorder. I was wrong! Perhaps I was forgetting that MH was described in 1961/2 and dantrolene introduced in 1979. Hopefully, with the entire worldwide scientific community focused on COVID-19 the key findings will be soon forthcoming to control the syndrome. I have my fingers crossed.