Grey’s Anatomy and a Potpourri of other News

By MHAUS President Henry Rosenberg, MD

On January 5, 2012, an MH episode was portrayed on the popular TV program Grey's Anatomy.

In the episode, the young patient undergoing emergency surgery develops elevated levels of carbon dioxide, increased heart rate and elevated temperature. The anesthesiologist recognizes the signs and informs the team of the problem. One of the OR personnel is dispatched to obtain ice and the anesthesiologist whips out a vial of dantrolene, injects it and waits for the signs of MH to respond. Interestingly the patient's sibling is undergoing surgery in an adjacent OR and the team is astute enough to warn the other surgical team that the patient might develop MH also and modify the anesthetic regimen. While the writers of Grey's Anatomy got the basic elements of MH diagnosis and treatment correct, they oversimplified the critical nature of the situation and omitted many important elements.(Here is the link to the episode: http://abc.go.com/watch/greys-anatomy/SH559058.)

For starters, when treating an MH episode with dantrolene, multiple vials (any where from 9 to 20) of the drug need to be obtained and reconstituted with sterile bacteriostatic water for injection. Secondly, a variety of blood studies need to be performed to gauge the extent of the physiologic changes and to measure the response to treatment. Thirdly, the patient needs to be treated post event in a critical care unit and further doses of dantrolene need to be administered until the patient is out of danger. Usually 36 hours. However, most importantly, what was not really emphasized is that treatment of MH requires a coordinated team approach. Some members of the team need to obtain the cart containing dantrolene (the medication is not kept in the medication cart next to the anesthesia provider), and then at least one or two people need to work on reconstituting the drug and handing it to the anesthesia provider. At the same time other team members need to obtain blood specimens for analysis of acid base balance, electrolytes such as sodium and potassium, and coagulation studies. It was curious how the team just sat there waiting for the dantrolene to work; while in the actual situation, either the patient responds immediately to dantrolene, or if not additional drug needs to be administered. It would have been icing on the cake if the team had called the MH hotline. On the positive side the episode emphasized the critical role of the anesthesia provider in directing the treatment of the MH episode and the fact that MH could appear unexpectedly during surgery in an apparently healthy patient. It would have been nice to have the discussion of what happens once the syndrome is under control. The impression was from the program that once the episode is done, nothing further needs to be done.

Although, there was a gross oversimplification of MH, I applaud the team for recognizing that MH is a life threatening disorder that requires prompt diagnosis and treatment. If this episode alerts the public and health care providers to some of the essential elements of diagnosis and treatment of MH that is of benefit. I certainly could not expect a program on prime time to go into ryanodine receptor variants, DNA versus muscle biopsy testing, association with other disorders and reference to resources such as MHAUS to assist in diagnosis and management. After the program aired, I was contacted by someone who has a web site that posts questions and comments as to the authenticity of the medical condition depicted in such programs. There is a web site for everything!

Shortly after the Grey's Anatomy episode the public was made aware of a fascinating study examining the effect of a medication known to enhance athletic performance on the response to MH triggered by heat exposure in genetically susceptible mice. (reference 1) As I have mentioned previously, investigators at a variety of very well known universities, such as University of Rochester, Baylor Medical School and Harvard Medical School have developed an animal model to study MH by incorporating a known DNA change in the ryanodine receptor into mice.

These mice will develop MH on exposure to anesthetic trigger agents, as well as high environmental heat. Male mice are more at risk than female mice for reasons not well understood. In the study that was published recently, the investigators demonstrated that the drug, AICAR, acts in these animals to block release of calcium into the cell. This is also the basic defect in Malignant Hyperthermia, but curiously the drug does not block anesthesia induced MH. (AICAR works in a complex manner to reduce muscle fatigue and increase muscle endurance.) The connection between heat stroke and malignant hyperthermia has been demonstrated in some patients as I have described in several of my previous blogs. In general though the treatment of heat stroke has been limited to symptomatic treatment, namely cooling the patient with ice or infusion of cold solution. Nevertheless the mortality from heat stroke is quite significant. AICAR represents a possible means to block or prevent heat stroke in those susceptible to this syndrome. The study shows clearly that at least one ryanodine receptor genetic change that predisposes to anesthesia induced MH also predisposes, at least in the animal model of MH, to heat induced MH.

The study also shows that drugs other than dantrolene may be efficacious in anesthesia induced MH as well. For example, perhaps if the investigators used a higher dose of the drug in their model of anesthesia induced MH it would have been effective in reversing the signs of MH. Perhaps in cases of MH related to other genetic changes, it might have also been of value. Obviously, much more work is needed to determine the utility of this drug in humans.

Other intriguing studies

The ryanodine receptor a calcium channel found in skeletal muscle (RYR-1) is known to be defective in most cases of MH. For a while investigators have shown that the channel is also located in other tissues, such as certain white blood cells and even in nerves. A recent study from U Mass and U of Toronto (ref 2) again using genetically engineered MH susceptible mice demonstrated that a mutation in the RYR-1 gene affects the function of certain nerve cells (neurons) in the brain. The effect on calcium release in the neurons was measured and was found to be identical to the change in calcium movements in skeletal muscle cells in MH. Hence the ryanodine receptor in these brain neurons is important for the normal function of the neurons and therefore may affect brain cell function. The overall effect on the body depends on the role of the neuron and is hard to measure in animals. This is the first demonstration that I know of, that mutations associated with MH may have an effect on nerve cells.

Speaking of neurons yet another investigative group at the U of Texas Southwestern (ref 3) has demonstrated abnormal calcium movements in neurons in the brain of genetically engineered mice that express the signs of Huntington's disease. This fatal inherited neurodegenerative disorder comes on in early middle age in humans and is associated with uncontrolled and disabling muscle movement. The investigators demonstrated that dantrolene administration when administered to the diseased mice protects the neurons from ongoing damage and improves performance of complex tasks involving muscle coordination. Yet to be demonstrated though are specific ryanodine mutations, but all signs point to a defect in the ryanodine receptor as a key factor in some forms of Huntington's disease.

So, it seems that scientists are beginning to understand how important the ryanodine receptor is to the proper function of many organs in the body, not just skeletal and cardiac muscle. The implication is that drugs such as dantrolene and AICAR may over time prove to reverse or compensate for abnormal cell function in a variety of organ systems just as it does in skeletal muscle. Naturally there is a long road to follow between the demonstration of effect in animals and or isolated cells to studies in humans, but there are now some key insights that may underpin and explain how dantrolene may turn out to be a very effective therapeutic agent in a variety of disorders and drug reactions not involving muscle tissue directly.

Much more to follow.

References:

1. Lanner JT, Georgiou DK, Dagnino-Acosta A, Dirksen RT and Hamilton SL. AICAR prevents heat-induced sudden death in RYR-1 mutant mice independent of AMPK activation. Nature Medicine published on line 8January 2012;doi:10.1038/nm.2598
2. De Crescenzo V, Fogarty KE, Lefkowitz,JI, Walsh JV. Type 1 ryanodine receptor knock-in mutation causing central core disease of skeletal muscle also displays a neuronal phenotype. Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):610-5. Epub 2011 Dec 27.www.pnas.org/cgi/doi/10.1073/pnas.1115111108.
3. Chen X, Wu J, Lvovskaya S, Herndon E, Supnet C, Bezprozvanny I.
   Dantrolene is neuroprotective in Huntington's disease transgenic mouse model.
   Mol Neurodegener. 2011 Nov 25;6:81.
   http://www.hdsa.org/research/news/dantrolene.html