Neuromuscular Disorders Pose Special Risks, But Preparation Minimizes Dangers

by Margaret Wahl
Coping With Anesthesia

Wendy Hinton says she "still gets goosebumps" when she thinks about the morning of Oct. 25, 1989.

She and her husband, Doug, had brought their 2-year-old son, Shayne, to St. Anthony's Central Hospital in Denver to have a routine procedure that doctors thought might help the child's frequent ear infections and difficulty breathing through his nose.

But, less than 15 minutes later, something went terribly wrong.

"We saw red lights flashing, alarms going off, people with machines running down the hall," Wendy says. "My husband and I stepped out of the room to see what was going on, and nurses came and pushed us back in."

Over the next 45 minutes, which Wendy describes as "the worst of our lives," the hospital staff supplied the Hintons with a priest, two crisis counselors and a telephone. Shayne, they were almost certain, wasn't going to make it.

Once-Deadly Syndrome Now Under Better Control

Thanks to persistent resuscitation efforts, Shayne Hinton is alive today. After recovering from his near-death in the operating room, the child was found to have experienced a rare but extremely dangerous reaction to anesthesia drugs known as malignant hyperthermia (MH). (It means "seriously high temperature.")

He was also found to have Duchenne muscular dystrophy, one of many conditions that doctors now say may increase the risk of malignant hyperthermia reactions.

In the 1960s, surgical teams first began to recognize and name this condition in which, shortly after receiving general anesthetic agents, surgical patients began to go downhill. Patients became stiff instead of relaxed, their body temperatures soared, sometimes to as high as 110 degrees, and their metabolic processes became so abnormal that they usually didn't survive.

Later research found the source of the problem: In MH-susceptible people, muscle cells react in an unusual way to some of the most commonly used drugs in the operating room. Inside these cells, a molecular gate opens and stays open, allowing an excessive and uncontrolled release of calcium, when MH-susceptible people are given commonly used inhalational agents (such as halothane, enflurane and isoflurane), especially if they're combined with a muscle-relaxing drug called succinylcholine.

This excessive calcium release causes muscles to contract continuously and generates a massive amount of heat, enough to disrupt almost every body process.

"The mortality rate from MH in the 1960s was 70 percent," says Gerald Gronert, who recently retired as professor of anesthesiology at the University of California at Davis. "It's probably less than 5 percent now."

The marked decrease in MH mortality is the result of better preoperative testing, better monitoring during surgery, the use of "nontriggering" anesthetic agents for at-risk patients and, perhaps most importantly, the development of a drug called dantrolene. This drug, a specific antidote for MH, stops the flow of calcium from inside muscle cells and "turns off" the reaction.

Recent research has found that, while nearly everyone with a neuromuscular disease may have a slightly increased risk of developing MH during surgery, the highest risk occurs in people with central core disease, a disorder that specifically involves an abnormality in calcium regulation inside muscle cells.

Estimates of the incidence of MH reactions in the United States during anesthesia range from 1 in 65,000 people to 1 in 5,000, when special risk factors aren't taken into account. The risk for people with muscular dystrophy and related disorders remains uncertain.

If you're planning surgery for yourself or a child and have a neuromuscular disorder in the family, talk to your doctor. Information about testing for MH susceptibility can be obtained from the Malignant Hyperthermia Association at or (800) 986-4287.

Beyond MH

The good news, for the Hintons and thousands of other families, is that MH is far better understood and controlled today than ever before.

The bad news is that many more anesthesia-related troubles have been discovered for people with neuromuscular disorders.


Normal Neuromucular Junction
At a normal neuromuscular junction, a nerve cell transmits chemical signals that float across a microscopic space and dock on acetylcholine receptors on a muscle cell.


Myasthenia Gravis
At a neuromuscular junction in myasthenia gravis, there are fewer than the usual number of acetylcholine receptors on the muscle cell. Therefore, a large percentage of them can be blocked by a muscle-relaxing drug, leading to temporary paralysis.

Malignant Hyperthermia
At a neuromuscular junction in malignant hyperthermia, a molecular gate deep inside the muscle cell stays open, releasing a dangerously large amount of calcium into the cell.

At a neuromuscular junction in spinal muscular atrophy or amyotrophic lateral sclerosis, an abnormal nerve cell can fail to transmit signals to a muscle cell. In response, the muscle cell sprouts many new acetylcholine receptors. When these are activated by a muscle-relaxing drug, a dangerously large amount of potassium can be released from inside the muscle cell.

"I think it would be a mistake for either the patient or the anesthesiologist to fixate on malignant hyperthermia as the most important issue with neuromuscular disease," says Harvey Rosenbaum, anesthesiologist and co-director of the Malignant Hyperthermia Program at the University of California at Los Angeles.

For one thing, many people with neuromuscular conditions have associated respiratory or cardiac impairment, something that makes surgery and anesthesia more complicated and which has to be carefully evaluated and prepared for before any surgical procedure.

For another, people with muscle disorders may simply have more fragile muscles, subject to breaking down under stress. The stress of surgery itself, of lying in an awkward position with one part of the body pressing on another (necessary in some procedures), of having a tourniquet applied during an operation, of experiencing postoperative shivering, may all contribute to complications in some patients, experts say.

Then, too, many drugs used for anesthesia act on cell membranes, thin coverings that surround each cell. Since many neuromuscular disorders involve abnormalities in these membranes, it's not too surprising that drug-membrane interactions in neuromuscular disorders could go wrong.

Orthopedic surgeon Irwin Siegel, who co-directs the MDA clinic at Rush-Presbyterian-St. Luke's Medical Center in Chicago, recommends that the surgical team be well versed in the patient's neuromuscular disorder and preferably well practiced in doing surgery on such patients.

His advice: "not to avoid surgery, but to make sure you're in a situation where your risks are as well covered as humanly possible." That may include asking your surgeon some tough questions, Siegel says, and sometimes postponing surgery until you can get to a major medical center.

Siegel tells his patients, "If you ever have a fracture, go to the emergency room and have them call me. If you have an operation, it shouldn't be done at a local hospital by someone who doesn't have experience treating your particular illness."

Trouble Where Nerve Meets Muscle

Modern anesthesia actually uses a combination of drugs. Most of these drugs have multiple actions, but each has a principal action: to induce unconsciousness, relieve pain or relax muscles (this last being required in varying degrees depending on the nature of the operation).

The muscle-relaxing drugs act at the neuromuscular junction, the place where nerve and muscle meet and where nerve cells transmit chemical signals that float across microscopic spaces and "dock" on muscle cell membranes at specific sites known as acetylcholine receptors (see illustration).

After this docking, submicroscopic gates known as ion channels open in the thin membrane covering each muscle cell. Sodium and calcium ions flow into the cell, potassium flows out, and then gates deeper inside the cell release calcium into the interior - the final step that lets tiny filaments slide over each other, which is the molecular foundation of muscle contraction.

What happens when an abnormal neuromuscular junction meets a chemical muscle relaxant can sometimes be unexpected - and unfortunate.

In myasthenia gravis, for instance, there are too few acetylcholine receptors on the muscle side of the junction, because these docking sites are destroyed by the body's immune system in this autoimmune disorder. When people with MG are given the usual dose of any of several drugs designed to block a certain percentage of acetylcholine receptors and cause muscle relaxation, they may have so few receptors left that virtually all of them are blocked. Such a blockade can lead to total (though temporary) paralysis, including cessation of the muscle activity required for breathing. These muscle relaxants are known as non-depolarizing. This group includes almost all relaxants except succinylcholine.

Among the most serious reactions to a muscle relaxant, however, are those found in people with spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), diseases in which the nerve cells that normally control muscles (motor neurons) are lost and signals from nerve to muscle are diminished or absent.

SMA and ALS are denervation (loss of nerve) syndromes. When a muscle cell loses the signal it expects to get from a nerve cell, it begins to sprout new acetylcholine receptors, Gronert explains. It's as if the muscle is making a last-ditch effort to reach out to a nerve cell that's no longer transmitting signals.

Without signals from nerves, muscles eventually die, too, becoming scarred and weakened. When that happens, Gronert says, there usually isn't much problem with anesthesia drugs. (In fact, not much medication, if any, is needed to relax muscles that are already this weakened.) It's in the early stages of a denervation disorder, when the muscle cells are still reaching out to the nerve, that trouble occurs.

Normally, Gronert says, when people are given the drug succinylcholine to relax muscles, a little bit of potassium from inside the muscle cells leaks out into the bloodstream. This is because succinylcholine, like its cousin acetylcholine, docks on the receptors and opens some gates in the cell, letting certain molecules flow in and out.

Normally, this poses no problem. But when there has been a massive increase in the number of receptors on muscle cells, succinylcholine "interacts with all those receptors, and they all release potassium," Gronert says. If the potassium level in the blood gets high enough, heart rhythm is disturbed. Extremely high potassium levels can stop the heart, something Gronert says can happen in SMA or ALS patients unwittingly given succinylcholine.

"The amount of potassium coming out [of the cells] can be large and life-threatening," he says. The solution: not to use succinylcholine in motor neuron disorders.

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