Chapter Sixteen: Other MH Studies

Chapter 16 Sub-sections

Sympathetic Nervous System

Our sympathetic nervous system investigation included: blockade of its nerves, injection of its agonists, and use of drugs that blocked its responses. Sympathetic nerves can be anesthetized within the spinal canal. A total spinal anesthetic blocks all sympathetic responses. In this situation, the patient, in our case a pig, needed to be supported by artificial respiration via an endotracheal tube, and by volume loading to maintain adequate blood pressure and overall body perfusion.

We showed that a total spinal anesthetic did not alter an MH episode triggered by halothane (Gronert, Milde et al, 1977). We followed this with several other studies showing that sympathetic drugs did not trigger a porcine MH episode (Gronert, Milde et al, 1980, Gronert, White, 1988). Further evidence was that blockers of sympathetic responses did not alter an MH episode (Gronert, 2000).

Heart, Liver, Brain Function in MH: No Primary Abnormalities

The heart has intracellular organelles, including SR, similar to skeletal muscle. Myocardial sarcolemma and SR govern fluxes of calcium. SR does not play a role in liver or brain. Since SR is the seat of MH reactions in skeletal muscle, some felt that the heart muscle could actively participate in an MH reaction. We examined this in porcine heart muscle - with pigs on cardiac bypass - so we could measure cardiac metabolic responses during an MH episode. We found that the cardiac response during MH was due to recognized sympathetic reflexes that did not involve active MH involvement (Gronert, Theye et al, 1978).

Furthermore, we observed that responses of skeletal muscle accounted for the increase in whole body oxygen consumption during MH and that the splanchnic system and liver were not actively participating (Gronert, Heffron et al, 1977). Last, as regards study of organ systems in intact pigs during MH episodes, brain metabolism was not abnormal during an MH episode (Artru et al, 1980). Thus other elements of the body do not contribute to MH episodes and have normal responses, sometimes exaggerated due to the usual reflex responses of severe stress.

We also demonstrated that depressants and non-depolarizing relaxants delayed the onset of an MH episode. Depressants included barbiturates, opiates, sedatives, or tranquilizers (Gronert, Milde, 1981). Perhaps these directly or indirectly affect calcium fluxes within muscle cells. However, there are major obstacles to study of what's going on within a cell. The very act of penetrating one to evaluate function can alter that function and may ruin the project.

Mayo Human MH Cases

In addition to the boy who developed MH during anesthesia at Mayo, described above, Mayo had a 50-year-old patient referred who had had febrile episodes for most of his life. With fatigue or stress or other problems, he would feel ill and have fevers that would not respond to aspirin or other drugs. He didn't sleep well and would take cold showers to counteract the fevers. The Mayo infectious disease specialist, Dr. Rodney Thompson, referred him because the episodes resembled what he and I had discussed regarding awake porcine episodes of MH. His biopsy was positive, and the article regarding him helped to raise awareness of rare human awake episodes (Gronert, Thompson et al, 1980).

A bit later, we cared for a 4-year-old boy with both a glycogen storage disease and acute leukemia who had developed intussusception. After surgical reduction, and beginning with recovery from the triggering anesthetic drugs enflurane and succinylcholine, he developed an MH reaction manifested by fever, tachycardia, tachypnea, mottled skin, and cyanosis. Laboratory values were typical of MH. He responded to dantrolene and improved, and then MH recurred, several times over. During the next several hours, he needed 16 mg/kg dantrolene to reverse this, a dose about seven fold greater than usual.

He unfortunately succumbed after a series of complications related to his multi-system diseases. Lymphoma patients have had a series of anesthetic responses remarkably similar to MH (Simmons et al, 1984).

Frances Foldes - a Wonderful Research Experience

The late anesthesiologist Frances Foldes was a gifted indefatigable muscle researcher. He helped introduce succinylcholine into use for clinical paralysis in the early 1950s and earned major awards in anesthesia, including the 1972 Distinguished Service Award and the 1988 Excellence in Research Award.

Early in my career, I heard him stand up to speak at our various anesthesia meetings and wondered about his work. He frequently had worked in the area being discussed and added information, although not always published. I was, frankly, skeptical. I found out in due time that he really had ‘done it all' and had universal respect.

He believed a calcium antagonist might control an MH episode, so he proposed a study to examine this theory during a visit to our laboratory. He, at 75 years old, wanted to supervise it. Most interesting was that he crosschecked every protocol, plan, and calculation (in his head) that we performed, and followed every moment of study in every animal. He delighted everyone in our laboratory. The drug he was interested in is verapamil, a calcium antagonist. Dantrolene is a calcium antagonist, and he believed that other such antagonists may aid in preventing or treating MH. But dantrolene is lipid soluble, soluble in cellular membranes, so it easily enters the interior of the cell. Other calcium antagonists are generally water soluble, do not easily penetrate a cell's outer membrane, and thus cannot interact within the cell to diminish harmful reactions.

Unfortunately, verapamil was no help in treatment of porcine MH (Gallant, Foldes, et al, 1985). Foldes was disappointed in the result, but realistic.

As he put it, "I have had two goals in life, to win a medal in the 1500 meters at the Olympics, and to win a Nobel (he pronounced it, with his accent, as ‘noble') Prize. Well, back to the 1500 meters."

As I say, we loved him. He stimulated our research program.

Ongoing MH Research

Ongoing research showed that electrical stimulation (Ahern et al, 1985), much like porcine stressful exercise or injection of either succinylcholine (Gronert, Theye, 1976) or carbachol (Gronert, Milde et al, 1980) also triggered MH. Carbachol is a drug useful only in laboratory studies. It matches the action of acetylcholine, but is long lasting - many minutes - and not practical for MH studies in intact animals. We used it in a porcine muscle preparation (Gronert, Milde et al, 1980). In evaluation of the progress of MH or its treatment, it is necessary to remember that lactate ion does not easily cross cellular membranes, as movement of substances across cell membranes is favored by lipid solubility and an unionized state. Thus the measured extracellular deficit may not reflect true intracellular lactate levels (Gronert, Ahern et al, 1986).

Finally, skeletal muscle in MH susceptible swine (and by inference, the human) is abnormal at a basic level of response, as, due to the mutation, exposure to heat by itself triggers exaggerated metabolism (Gronert, Milde et al, 1980). This has also been reported by Ording et al, 1985 and Denborough et al, 1994, 1996.

Several other factors that had been incriminated as triggers in porcine MH included carbon dioxide, calcium, digitalis preparations, and potassium. We evaluated these in separate studies (Gronert, Ahern et al, 1986). The lungs of paralyzed anesthetized pigs were ventilated with sustained concentrations of 17% carbon dioxide. This did not trigger MH. Examination of exaggerated amounts of calcium, digitalis, and potassium would result in total depression of cardiac function, so we placed anesthetized pigs on cardiac bypass, using a pump-oxygenator-heat exchanger system. Calcium and digitalis in large doses did not trigger MH responses in skeletal muscle.

Potassium, however, decidedly triggered skeletal muscle, an expected result since we knew that muscle strips in tissue baths responded to potassium with muscle contractures typical of MH. In 1996, Isaac Pessah of UC Davis, Carl Lynch of the University of Virginia, and I wrote an editorial regarding the advances in determining the role of the ryanodine receptor in MH (Pessah et al). The ryanodine receptor is the connecting link to the SR in skeletal muscle and conveys information to the SR to release calcium and begin muscle contraction. With a genetic abnormality related to MH, the ryanodine receptor begins an MH episode.