Chapter Fourteen: Malignant Hyperthermia, Eerie Erratic Metabolic Mayhem

Chapter 14 Sub-sections

Now we began research into MH. This is an inherited disorder of skeletal muscle that occurs in swine and humans. Susceptible patients who appear perfectly normal, given a typical anesthetic, abruptly and disastrously change. They develop muscle rigidity, tachycardia, increased expired carbon dioxide, profound acidosis, and a rapid increase in temperature. These changes quickly result in heart failure, a shock-like blood pressure, and demise, with temperatures greater than 106º F, or 41º C. This is due to anesthetic-invoked increases in metabolism of skeletal muscle, which acts as though the patient is performing exhaustive full-scale exercise, such as finishing a marathon.

There is production of heat and acid, release of toxic intracellular substances, and fatal increases in acidosis and temperature if untreated. For the anesthesia provider, the typical safe anesthetic abruptly triggers this explosive alteration in vital signs and a devastating destruction of the normal state. The resulting alterations push the patient's tolerance to stress to an extreme. Dantrolene (reported in a swine study in 1975 (Harrison) and approved by the FDA in 1979) reverses these changes, but anesthetic agents must be quickly discontinued and dantrolene given before MH becomes uncontrolled. Because it can kill quickly, MH, although rare, even now continues to be a major consideration in the field of anesthesia. Effectiveness in porcine MH, almost identical to human MH, provided confidence that dantrolene would be effective in humans. It was a challenge to confirm dantrolene's effectiveness in human MH, since episodes occur in only about one in 50,000 general anesthetics. Efficacy was confirmed in a cooperative study involving 65 hospitals in the US and Canada in which dantrolene was stocked and ready to go, and given to those patients who unexpectedly developed an MH episode (Kolb et al, 1982).

I say ‘confirmed,' although a statistical expert who analyzed the data said that the results merely ‘whispered' efficacy (Forrest, 1982). Whisper or not, dantrolene is now, after years of use in treatment, fully recognized as the unique miracle drug in treating MH. The present mortality rate is estimated as less than 5%.

During my first year at Mayo in 1966-67, Kai Rehder, in a discussion in our then joint office, introduced me to MH. He had seen a few cases in Germany and was overwhelmed with their disastrous course. It was documented in humans in a 1960 case report from Australia (Denborough, Lovell). The anaesthetist was Jim Villiers, who displayed admirable judgment in preventing a catastrophe (Ball, 2007). Prior to that, there had been subtle evidence about what, in time, was identified as MH, because there had been unusual familial fatal anesthetic responses.

As a teen, John Kampine, chair of anesthesia for many years at the Medical College of Wisconsin in Milwaukee, made rounds with his family doctor father in Wausau, Wisconsin. He'd see someone on the street, and tell John that that's a family whose members die during anesthesia. George Locher (Rockford, 1977) later practiced anesthesia in Wausau and was bothered by these unusual deaths. When he contacted the Department of Anesthesiology at the University of Wisconsin, Professor Karl Siebecker told him to return for updating his practice. That really irritated George, for he knew that these deaths were not the fault of his care, and were decidedly unusual.

As to the Denborough-Lovell case report, Villiers (Ball, 2007) was to anesthetize a 20-year-old man with a broken leg. The young man didn't fear surgery, but was terrified about anesthesia because ten of his relatives had died while anesthetized. The patient had had an appendectomy at age 12, and his anesthetic was infiltration of local anesthetic into his abdominal wall to avoid a general anesthetic. Villiers calmed him by saying that they'd use the new volatile anesthetic halothane. The young man had told Villiers that some of his relatives had died with high temperatures during anesthesia, so they measured it as they began anesthesia. A few minutes after starting anesthesia, the young man's limbs became stiff and rigid and his temperature increased, so the surgeon quickly finished and Villiers discontinued the anesthetic. This halted the MH episode before it could advance. It was later learned that halothane was a prime and potent trigger of MH.

The article by Denborough and Lovell opened a new field of research into abnormal metabolism, genetic analysis, and effects of anesthetics on skeletal muscle. In the 1960s and 70s, the mortality rate was greater than 70%. These patients could not be diagnosed as MH susceptible in the absence of anesthesia, as they appeared normal, and only certain stresses would trigger an episode. In addition, their muscle did not show abnormalities on histological examination under a microscope, as the abnormality is not structural, but functional. Biochemical processes became markedly abnormal once an MH episode began. This mandated development of a valid test for its detection. As with progress in emotional areas of medicine, MH testing has had an uneven course, with tests sometimes supported by enthusiastic investigators' faith rather than discipline and objectivity.

Muscle contraction occurs with a greater than 1000 fold increase in intracellular calcium concentration, and relaxation occurs when the extra free unbound ionized calcium is re-bound within the cell, mainly by the sarcoplasmic reticulum (SR). This control of calcium concentration is normally tight. SR function is lost during an MH episode, and calcium concentration increases out of control.

With this uncontrollable increase in free ionized unbound intracellular skeletal muscle calcium concentration, there is an exaggeration of what happens during normal contraction. With this increase in calcium, metabolism of mitochondria is dramatically stimulated, to provide additional ATP for energy. During an MH episode, energy demands explode and oxygen consumption increases, with a related increase in carbon dioxide production, and a resulting respiratory acidosis. It's fascinating that oxygen consumption does not increase during MH near as much as with severe exercise, likely related to some sort of malfunction in the overall response to increased oxygen demand. There is also increased production of lactate, again to produce added ATP. This results in a metabolic acidosis, which is buffered in the body by bicarbonate, and excreted by the kidneys. Some of the bicarbonate is converted to carbon dioxide, again cleared by the lungs.

The intracellular SR stores huge amounts of calcium and rapidly releases and re-binds it during muscle contraction and relaxation. Furthermore, the mitochondria of muscle, by producing ATP, provide the energy needed for these muscle actions; mitochondria secondarily, during extreme stress, can store calcium. Finally, sarcolemma, the surface membrane of the muscle cell, is important, as there is a constant flux towards entrance of calcium from outside the muscle cell into its interior. Thus there is a constant metabolic energy use by all three components: sarcoplasmic reticulum, mitochondria, and sarcolemma, to maintain the calcium gradient even in the normal state, whether resting or during exercise.

Muscle Types

Some muscle has a greater blood supply (crudely, red muscle), with continuing renewal of oxygen, and does not rapidly lose energy stores during increased production of carbon dioxide. This is muscle typical of the distance runner, or distance cyclist, who relies on oxygen metabolism to maintain a prolonged effort. Other muscle has less vascularity (crudely, white muscle), with a lesser blood supply. It relies on glycogen stores within muscle. This muscle, during an MH episode, produces greater amounts of lactate, and a metabolic acidosis. This muscle is typical of the sprinter, or short distance cycling racer (or lizard or alligator), who can maintain immense energy expenditure for brief periods, until glycogen stores within muscle have been consumed. At that point, they ‘hit the wall' and are unable to be competitive. Thus, the degree and type of acidosis during MH depends in part upon the type of affected muscle. However most muscular people do not have muscle diseases.

Example of a Normal Muscular Person

In the mid 1980s, at Mayo, I provided anesthesia to a retired former star of the Chicago Bears professional football team. He was about 6 feet tall, some 250 pounds, seemingly none of it fat. He was an example of a highly muscular person who had no abnormalities related to being muscular and had been a superbly coordinated athlete. He needed carpal tunnel releases on both wrists, as he had compression of the median nerve. He was uncomplaining, gentle, nice, and easy to care for. His hands and wrists were huge and highly muscular, and it wasn't surprising that he had finally developed a compression-type carpal tunnel syndrome.

His head, neck, and face were likewise large and muscular, and managing his airway under anesthesia appeared challenging. I did the anesthetic myself, and chose to use a mask without tracheal intubation. It was tricky to hold the mask but things went smoothly. As I was trained, and as I preferred, I didn't use a head strap to hold the mask in place, only my left hand. The head strap, as Dr. Virtue always hounded us, pushes the jaw back and helps obstruct the airway. This was a satisfying experience, to care for a retired professional athlete, who appreciated whatever we did. Would I do that by mask now? An LMA was not then available, and probably would have worked well. I was an expert at holding a mask for prolonged periods, and, even now, I might use it. I have more confidence than many providers in mask anesthesia; most change to an LMA early in the anesthetic if the case isn't too long.

Not very long afterwards, this athlete and one of our Mayo nurse anesthetists had abdominal surgery and awakened in the recovery room still mostly paralyzed from the non-depolarizing muscle relaxant. Contrary to almost everyone's usual practice, the senior staff anesthesiologist, per his habit, avoided reversal of curare-type muscle relaxants at the end of a procedure. This led to a sedated but in time aware patient who realized that effective movement was not possible and that tracheal extubation was not yet feasible. They each had to wait an hour or so until the effect wore off. Both were vocally unhappy, and rightly so. Further, our nurse anesthetist knew that this unpleasant episode was unnecessary.

Cycling the Douglas Trail

While at Mayo, I began to commute by bicycle, using an abandoned railroad that had been re-worked to a gravel surface (now paved), the Douglas Trail, connecting Pine Island to Rochester via Douglas. The trail is picturesque, avoids roads, and winds its way among the fields and woods and a few modest hills, a 17-mile-ride each way. The trail was safe, whether dark or light, as traffic was never a challenge. In tolerable temperatures it was rejuvenating. Minnesota thunderstorms were a hazard, as the lightning could be vicious. You had to temporarily abandon your metallic bike and crouch under bushes until these passed. The other hazard was skunks. I'd come upon one walking along the trail ahead of me; when I'd attempt to pass, s/he would aim her/his tail at me and I'd retreat. I'd finally take a detour through the woods.