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Malignant hyperthermia

Malignant hyperthermia (MH or MHS for "malignant hyperthermia syndrome", or "malignant hyperpyrexia due to anesthesia") is a life-threatening condition resulting from a genetic sensitivity of skeletal muscles to volatile anaesthetics and depolarizing neuromuscular blocking drugs that occurs during or after anaesthesia. It is related to, but distinct from, the neuroleptic malignant syndrome. more...

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Signs, symptoms and diagnosis

The phenomenon presents with muscular rigidity, followed by a hypermetabolic state showing increased oxygen consumption, increased carbon dioxide production and hypercarbia, and increased temperature (hyperthermia), proceeding to rhabdomyolysis with rapid rising of blood levels of myoglobin, creatine kinase (CK/CPK) and potassium.

Halothane, a once popular but now rarely used volatile anaesthetic, has been linked to a large proportion of cases, however, all volatile anesthetics are potential triggers of malignant hyperthermia. Succinylcholine, a neuromuscular blocking agent, may also trigger MH. MH does not occur with every exposure to triggering agents, and susceptible patients may undergo multiple uneventful episodes of anesthesia before developing an episode of MH. The symptoms usually develop within one hour after anesthesia.

Susceptibility testing

Testing for susceptibility to MH is by muscle biopsy done at an approved center under local anesthesia. The fresh biopsy is bathed in a solution containing caffeine and halothane (the "caffeine-halothane contracture test", CHCT) and observed for contraction; under good conditions, the sensitivity is 97% and the specificity 78% (Allen et al., 1998). Negative biopsies are not definitive, so any patient who is suspected to have MH by history is generally treated with non-triggering anesthetics even if the biopsy was negative. Some researchers advocate the use of the "calcium-induced calcium release" test in addition to the CHCT to make the test more specific.

Litman & Rosenberg (2005) give a protocol for investigating people with a family history of MH, where first-line genetic screening of RYR1 mutations is one of the options.


Disease mechanism

Malignant hyperthermia is caused in a large proportion (25-50%) of cases by a mutation of the ryanodine receptor (type 1) on sarcoplasmic reticulum (SR), the organelle within skeletal muscle cells that stores calcium (Gillard et al., 1991). In normal muscle, the receptor releases small amounts of calcium when triggered, which is then reabsorbed into the SR for the next cycle of contraction. In MH, the receptor does not close properly after having opened in response to a stimulus. The result is excessive release of calcium, which is reabsorbed into the SR in a futile cycle; this process consumes large amounts of ATP (adenosine triphosphate), the main cellular energy carrier, and generates the excessive heat (hyperthermia) that is the hallmark of the disease. The muscle cell is damaged by the depletion of ATP and possibly the high temperatures, and cellular constituents "leak" into the circulation, including potassium, myoglobin, creatine and creatine kinase.


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Malignant hyperthermia: the unknown killer - includes related articles
From Saturday Evening Post, 11/1/91 by Carolyn P. Greenberg

Susie is a ten-month-old baby, perfectly healthy except that she has a congenital abnormality of her foot, commonly known as clubfoot. Susie's parents have consulted the pediatrician, and he has recommended elective surgery to repair the clubfoot so that the child's development can progress normally--a routine surgery under routine general anesthesia. When they inquire about the safety of the operation, they learn that the odds on something going wrong with this procedure are extremely small, perhaps 1 in 10,000. They decide they want their child to have the surgery.

After Susie is brought to the operating room, the anesthesiologist places a small clear mask over her face. As she breathes normally, the anesthetic gas is taken up into her lungs, bloodstream, and brain, and she gradually drifts off to sleep. A thin plastic tube, called a catheter, is placed in a vein. A drug is then given intravenously to relax Susie's muscles to that a breathing tube may be inserted to allow the anesthesiologist to control her breathing during the operation. Sterile drapes are placed over the child, leaving only the site of surgery exposed, and this area is washed with an antiseptic solution. A check is made to be sure that all of her vital signs are stable, and an incision is made a few minutes later.

Surgery proceeds normally for about 20 minutes. Suddenly, the infant's heart rate rises dramatically--to twice the normal speed--and begins to skip beats. Her body stiffens, her skin appears flushed, and her lips are dusky. Her temperature climbs precipitously--to 105[degrees] F--and her body feels hot to the touch.

The anesthesiologist, suspecting that Susie has malignant hyperthermia (MH), responds quickly, knowing that if the infant is not treated rapidly she may die. Surgery is stopped. The entire operating-room team--doctors, nurses, technicians, aides--mobilizes to treat the life-threatening emergency.

Anesthetics are discontinued, though the child still receives pure oxygen. More catheters are placed in veins and in an artery of one arm. Blood samples are drawn to determine if a dangerous imbalance of her natural body chemicals has developed. The infant is wrapped in cooling blankets and her body is then placed in ice. Dantrolene, a drug that is a specific antidote to an MH reaction, is mixed and given intravenously in several doses.

The child remains in the operating room under close observation. Her condition improves over the next 30 minutes. The excess acids that had developed in her blood have been neutralized by drugs, the stiffness has abated, her normal heart rhythm has been restored, her color is normal, and her temperature is trending downward. She is beginning to awaken from anesthesia.

She will require careful observation and treatment for the next 24 to 48 hours in the intensive-care unit. Although the acute episode of MH has been resolved, symptoms may reappear at any time in the early period after surgery. Also, the infant could develop secondary complications -- such as muscle breakdown, kidney failure, or a bleeding disorder -- during the subsequent hours.

Why would a healthy young child undergoing routine surgery suddenly -- unpredictably -- develop a potentially fatal reaction to certain anesthetic drugs? Why wouldn't there be warning signs before the anesthetic was started?

Malignant hyperthermia is caused by a genetic disorder that prompts an abnormal reaction to anethetic drugs. A vicious cycle of reactions develop in muscle cells, accelerating the body's metabolism and producing excessive heat -- and sometimes causing death.

In January 1990, the tragic death of U.S. volleyball star Judy Bellomo during thyroid surgery was attributed to malignant hyperthermia. Sudden, extreme elevation in her body temperature was reported to have caused multiple organ failure. As in most such cases, she had been unaware that she was at risk for MH.

The first case of MH -- reported in 1960 by M.A. Denborough of Australia -- occurred in a young man who nearly died following anesthesia for repair of a fractured leg. The patient's family history revealed that a number of relatives had died during or shortly after general anesthesia. Dr. Denborough concluded from this information that an inherited sensitivity to general anesthesia must exist.

There are three characteristic features of MH: accumulation of acids in the bloodstream; muscle stiffness; and a rapid and extreme rise in body temperature (to as high as 110 [degrees] F). MH most often occurs in the operating room and is triggered by certain inhaled anesthetics (halothane, enflurane, or isoflurane) or by a short-acting muscle relaxant, succinyl-choline, which is given for the insertion of the breathing tube.

The incidence of MH during general anesthesia is about 1 in 5,000 to 1 in 15,000 in children, and 1 in 20,000 to 1 in 40,000 in adults. MH can affect all races, ages, and both sexes. It is believed to be inherited as a dominant gene, but not every member of an affected family may be susceptible -- and there may be degrees of both susceptibility and manifestations even within the same family. Also, MH may not occur -- even in a susceptible patient -- during every general anesthesia.

Some individuals and their family members who are at risk for MH may have abnormal muscle development, muscle cramps, or weakness. They may also have other conditions related to muscle imbalance, such as curvature of the spine, crossed eyes, or double-jointedness. They may be subject to high fevers during periods of illness or stress, or following exercise. One adolescent boy with a family history of MH is well-known in the emergency room at Columbia Presbyterian Medical Center in New York City for his multiple appearances with high fevers and muscle cramps after vigorous games of basketball.

Some affected individuals may also be sensitive to caffeinated beverages such as coffee and soft drinks. One Saturday night at midnight, a consultant covering the MH Hotline received a call from a hysterical MH-susceptible patient who wasn't feeling well after a cheeseburger and a large cola. Fortunately, her symptoms were more compatible with indigestion than MH.

The signs and symptoms most frequently observed by the anesthesiologist are rapid heart rate, rapid or irregular breathing, abnormal heart rhythm, and body rigidity. The person's skin may become dusky, flushed, or sweaty; blood pressure may fluctuate; and, finally, a rapidly rising and sustained fever will develop -- which is the hallmark of MH.

The treatment is to immediately stop anesthesia and change all equipment that may contain MH-triggering substances. The patient is then given pure oxygen and injected with the specific antidote, dantrolene. The body is cooled to bring down fever.

Doctors then observe the patient closely over the next 24 to 72 hours, until all danger of subsequent episodes or late complications has passed. In particular, they watch for the dark, cola-colored urine that indicates breakdown of muscle tissue.

Without treatment, an episode of MH may progress to cause kidney damage, internal bleeding, massive muscle destruction, brain swelling, and death due to cardiac arrest and multiple organ failure.

Since the introduction in 1979 of dantrolene, the number of deaths from MH has been significantly reduced. Dantrolene, a product of Norwich Eaton Pharmaceuticals, blocks muscle contraction by interfering with calcium release within the muscle cells.

Normally, muscle filaments contract by the interaction of two proteins, called actin and myosin -- all under the influence of calcium, which is released during the contraction process. The calcium is then returned to a storage depot within the cell, and the muscle relaxes.

With MH, the calcium inside the cell instead of returning to the storage depot. This excessive amount of calcium fuels a "fire" within the cell that results in complete breakdown of the energy factory and energy stores -- and the abnormal production of acids, carbon dioxide, heat, and persistent binding of the muscle filaments creates a sustained contraction, or "contracture."

Dantrolene is effective in treating an MH crisis because it inhibits the release of calcium within the cell. Unfortunately, dantrolene is expensive (up to $1,200 per treatment for a 150-pound adult), complicated to use, and has a limited shelf life. A person who is at risk for MH and who faces surgery should make sure that an adequate supply of the drug, unexpired, will be available in the operating room and that the anesthesiologist knows how to administer it. The anesthesiologist's preoperative evaluation should include a detailed medical and anesthetic history, a family history of anesthetic exposure, any unexpected deaths or muscle disorders in the family, and any occurrence of dark urine or high fever after anesthesia.

How can a person find out if he or she is MH-susceptible? The only test currently considered valid is a muscle biopsy with testing of the contracture -- or stretch response -- of the skeletal muscle. This procedure is recommended for individuals who have had suspicious reactions to anesthesia or for members of families with an MH history.

Contracture testing requires a nerve block or general anesthetic of a nontriggering type for the minor surgery to obtain the muscle. The cost (which may be covered by medical insurance) is more than $2,000, and there is the incovenience of having to undergo the procedure. The patient must be at an MH center to have this testing done because fresh muscle tissue is required; there are only 12 centers in North America performing the analysis. For these reasons it is difficult, if not impossible, to test all potentially susceptible individuals. In the absence of testing, the status of possibly susceptible individuals is unknown. To be on the safe side, they must be treated as if they are MH-positive during subsequent surgery and anesthesia.

Since MH is a genetic disorder and may affect other family members, immediate blood relatives should be notified of the possibility of their susceptibility to MH, where information may be obtained, and how they may be tested. Until they've had a muscle biopsy, all close family members are considered at risk, even if they have received successful anesthesia in the past. With improved monitoring, versatile "nontriggering" techniques, and availability of dantrolene, there is little inconvenience in assuming susceptibility in the operating room.

A simple, accurate, inexpensive, noninvasive diagnostic test is definitely needed. This is likely to come within a few years as current fruitful research on the genetic determinants for MH proceeds. Presently, the gene for MH has been localized to chromosome 19 at a site that controls calcium activity within the cell. Once the genetic basis for MH is determined, a means of definitive testing will most likely follow. This will be a major breakthrough.

For the benefit of MH-positive individuals traveling to underdeveloped countries who are councerned about being prepared in case of a surgical emergency. Norwich Eaton has prepared a "travel pack" of dantrolene that can be prescribed by a physician and returned if unused. A young woman who had experienced a nearly fatal episode of MH at a New York hospital even took this travel pack on her honeymoon in the Carribean. Luckily, she didn't need to use it.

Surgery may be managed safely for MH-positive individuals with local, regional, or general anesthesia techniques. Local anesthesia such as Novocaine or Xylocaine may be injected into the operative site. Xylocaine and other similar local anesthetics have recently been shown to be safe. Regional anesthethics include spinal, epidural, and nerve-block techniques. In addition, sedation may be safely provided with narcotics, barbiturates, and tranquilizers. General anesthetics considered safe for patients at risk for MH include nitrous oxide (laughing gas); narcotics such as morphine, Demerol, and fentanyl; sedative-hypnotics such as sodium pentothal or propofol; tranquilizers such as Valium, midazolam, and droperidol; and what we term "nondepolarizing" muscle relaxants: pancuronium, metocurine, atracurium, and vecuronium.

Increasing awareness among the medical community, particularly anesthesiologist, has improved recognition of, and prognosis for, MH. Still, there are many unsolved issues related to MH, particularly in the realm of inheritance and diagnosis. One of the few certainties is that successful outcome depends on early recognition and prompt treatment.

The chance of dying during an episode of MH was once 70 percent. With the use of dantrolene, modern anesthetic techniques, and increased awareness by anesthesiologists, mortality from MH has been reduced to about 10 percent. nevertheless, there are still 8 to 12 reported deaths from MH in the United States each year. Vigilance, early diagnosis, and adequate treatment will, hopefully, reduce deaths even more.

COPYRIGHT 1991 Saturday Evening Post Society
COPYRIGHT 2004 Gale Group

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