Malignant hyperthermia

JOSEPH L. MOORE, M.D., and E. LEE RICE, D.O. San Diego Sports Medicine Center, San Diego, California

Malignant hyperthermia is a rare syndrome that occurs in genetically susceptible individuals who are exposed to frequently used inhalation anesthetics. The disorder is most common in children and young adults. It is triggered through a defect in the ability of skeletal muscles to concentrate and release calcium. Signs of malignant hyperthermia include hypercarbia, muscle rigidity and tachycardia. Temperature elevation is often a late sign of the syndrome. Treatment begins with stopping all inhaled anesthetics at the earliest sign of the syndrome. The use of dantrolene has significantly reduced mortality from malignant hyperthermia. No simple screening test exists. Family members or those with a suspicious history need to be counseled and should consider muscle biopsy and testing prior to surgery.

Malignant hyperthermia is a rare but potentially fatal hypermetabolic disorder that occurs in the genetically susceptible child or young adult who is undergoing general anesthesia. Aggressive efforts must be undertaken to cool the body in malignant hyperthermic crisis, and dantrolene (Dantrium) is the mainstay of medical therapy.

Family physicians and team physicians providing care for young athletes need to be aware of the risk factors for malignant hyperthermia, and they should routinely ask their patients whether they have a personal or family history of anesthetic complications before these patients undergo surgery. To date, only muscle biopsy and in vitro contracture testing can accurately identify patients at risk for the disorder.

Illustrative Case

A 23-year-old female elite athlete presented with a cystic swelling in the left anterior cervical region. Ultrasound examination and magnetic resonance imaging (MRI) demonstrated a cystic mass near the left upper pole of the thyroid gland. The patient had no personal or family history of anesthetic complications.

Excisional biopsy of the mass was completed without difficulty under general anesthesia. On the first postoperative day, the patient reported that her quadriceps muscles felt fatigued and sore, as if she had completed a difficult physical workout. These symptoms resolved spontaneously over two days.

Pathologic examination revealed that the lining of the cyst contained papillary carcinoma of the thyroid. Subsequently, the patient underwent thyroidectomy and left radical neck exploration.

Induction of general anesthesia was uneventful and consisted of precurarization followed by the administration of thiopental and an intubating dose of succinylcholine, 2 mg per kg. No masseter muscle rigidity was noted. Anesthesia was maintained with isoflurane and nitrous oxide.

Approximately four and one-half hours into the operation, frequent cardiac arrhythmias developed. At this time, the patient's temperature rose from 37.2*C (99*F) to 39*C (102.2*F).

A treatment protocol for malignant hyperthermia was immediately started. The procedure and all anesthetics were stopped. The patient was removed from the breathing circuit, 100 percent oxygen was given and dantrolene was administered intravenously. Cooling maneuvers consisted of ice lavage to the bladder, cooled intravenous fluids and packing in ice.

The patient progressed to a fulminant malignant hyperthermic crisis with hypotension, hemorrhage secondary to disseminated intravascular coagulation, and renal failure. Resuscitative efforts included circulatory assist with cardiac bypass and the administration of vasopressors, high volumes of packed red blood cells and blood products. Despite these efforts, the patient's condition deteriorated, and she died approximately 12 hours later. Her highest documented temperature was 42 [degrees]C (107.6*F).

The patient's past medical and family history was again reviewed with family members. They recalled that as a child she had had one or two episodes of unexplained fever for which she was "packed in ice." These episodes were not associated with the administration of any anesthetics. To date, no family member has undergone muscle biopsy for in vitro contracture testing.

Epidemiology

In North America, the incidence of malignant hyperthermia is 1 case per 15,000 children receiving anesthesia and 1 case per 150,000 to 1.5 million young adults receiving anesthesia. After age 30, the incidence of the disorder declines dramatically.

Malignant hyperthermia occurs more frequently in males than in females. Genetic studies have described both autosomal dominant and recessive inheritance patterns.

The mortality rate for malignant hyperthermia is approximately 7 percent overall. [1,2] Fewer than 10 percent of all cases progress to fulminant malignant hyperthermia, which has a mortality rate of 10 to 15 percent. [2]

Association with Other Myopathies

Malignant hyperthermia may develop in children with certain muscle disorders. For example, the most common myopathy in childhood, Duchenne type muscular dystrophy, is associated with an increased risk of malignant hyperthermia. Other muscle diseases associated with malignant hyperthermia are listed in Table 1. [3] The strongest association is with a rare hereditary disorder called central core disease of muscle. [3]

Pathophysiology

The pathophysiology of malignant hyperthermia is not fully known, but most research places the triggering defect for the disease within the sarcoplasmic reticulum of skeletal muscle. The sarcoplasmic reticulum extends throughout the intracellular substance of the muscle fiber and surrounds each myofibril in a closemeshed canalicular network.

In the resting state, most calcium in muscle is concentrated within the sarcoplasmic reticulum. In the case of malignant hyperthermia, evidence points to a defect in the ability of the sarcoplasmic reticulum to store and release ionized calcium, which results in sustained skeletal muscle contraction. [4]

Clinical Presentation

Malignant hyperthermia is usually triggered by certain inhalation anesthetics or by succinylcholine (Anectine, Quelicin, Sucrostin), a neuromuscular blocking agent (Table 2). [5] Several environmental factors, such as emotional stress and heat stroke, are possible triggering events, but conclusive evidence linking malignant hyperthermia to these events is lacking. [1] Medications and anesthetics considered safe for patients susceptible to malignant hyperthermia, including amide and ester local anesthetics, nitrous oxide, barbiturates, narcotics and tranquilizers, are listed in Table 3. [5]

Malignant hyperthermia may not occur during the first or even the second exposure to a known anesthetic triggering agent, but it may develop during a subsequent procedure. Presentations range from mild symptoms to fulminant hypermetabolic crisis. [2]

The findings in classic malignant hyperthermia include skeletal muscle rigidity, tachycardia, fever, metabolic and respiratory acidosis, cardiac arrhythmias, an elevated serum creatine kinase level and electrolyte abnormalities. Muscle damage leads to myoglobinemia, myoglobinuria and acute tubular necrosis due to tubular myoglobin deposition. The most sensitive and often the earliest sign of the syndrome in the monitored patient under general anesthesia is an increase in the endexpired carbon dioxide concentration. [2]

Tachycardia is seen in more than 95 percent of patients manifesting early signs of malignant hyperthermia. It may occur within 30 minutes of the induction of anesthesia and is independent of temperature rise. Tachycardia probably represents an increase in catecholamine release and can be blunted experimentally with propranolol (Inderal). [4] A primary myocardial defect similar to that seen in skeletal muscle has not been demonstrated. [4]

Skeletal muscle rigidity in malignant hyperthermia is often characterized as a rigor mortis-like state and is caused by an increase in resting muscle tone. Rigidity may be marked or clinically inapparent, with the degree of rigidity depending primarily on the intracellular concentration of unbound calcium. [6] The most common muscles exhibiting rigidity are those of the jaw, the chest and the extremities. Fasciculation may occur in the facial area.

Rigidity most commonly begins in the masseter muscles, especially in patients receiving succinylcholine as an adjunct to the induction of anesthesia. Masseter muscle rigidity occurs in approximately 1 percent of children undergoing induction of anesthesia with halothane (Fluothane) and/or succinylcholine. Approximately 50 percent of these children, when tested by in vitro methods, appear susceptible to malignant hyperthermia. [7,8] As a result, many anesthesiologists discontinue anesthesia and cancel surgery following masseter spasm.

Fever, the hallmark of malignant hyperthermia, is a late manifestation of the disease. Body temperatures above 41[degrees]C (105.8*F) are typical, and temperatures of 44*C (111.2*F) have been described. [4] Various conditions, including sepsis, pheochromocytoma and thyrotoxicosis, can mimic malignant hyperthermia.

Laboratory Findings

Laboratory findings in malignant hyperthermia include metabolic and respiratory acidosis, hyperkalemia, hypercalcemia, hyperglycemia, increased plasma and urine myoglobin levels, and an elevated serum magnesium level. As the disease progresses, serum calcium and potassium levels may fall precipitously, and malignant dysrhythmias may occur.

Treatment

Successful treatment of malignant hyperthermia involves early recognition of the syndrome followed by quick removal of the offending anesthetic agent, aggressive cooling maneuvers and the administration of intravenous dantrolene. Surgery should be aborted as soon as possible, the anesthetic discontinued and the anesthetic tubing changed. Hyperventilation with high oxygen flow rates dissipates rapidly accumulating carbon dioxide and accelerates respiratory heat loss.

Aggressive efforts to decrease body temperature need to begin as soon as malignant hyperthermia is recognized. Cooling blankets, ice-water baths, and ice packs placed about the axillae, head and groin have all been employed. One effective method of dissipating heat is convective evaporation, which involves the steady application of tepid water to the patient's body and the use of fans to increase air movement over the skin surface in order to maximize evaporation. Cool saline lavage of the bladder, stomach, operative wound and peritoneal cavity aids body cooling and may help prevent rebound hyperthermia.

Dantrolene is an essential part of the medical treatment of malignant hyperthermia. The drug, a member of the hydantoin class, is a direct skeletal muscle relaxant. It inhibits the release of calcium at the level of the sarcoplasmic reticulum, reestablishing calcium equilibrium within the muscle fiber. [9] Dantrolene has no effect on cardiac or smooth muscle.

The average dosage of dantrolene is 1 to 2.5 mg per kg to a maximum of 10 mg per kg administered intravenously over 15 minutes. Muscle rigidity decreases within minutes. Maintenance doses of 1 to 2 mg per kg every three to four hours are often necessary during the metabolic crisis. [1]

Dantrolene is packaged in powdered form as a 20-mg preparation with 3 g of mannitol per vial. The drug is relatively insoluble and requires up to 20 minutes for intravenous preparation. Obviously, body cooling maneuvers should be initiated before and during drug mixing.

Fluid hydration with a buffered solution should be adequate to maintain a urine output of 1 to 2 mL per kg per hour. An early consideration is the placement of central venous pressure lines for monitoring and for the administration of mannitol to achieve diuresis.

A suggested protocol for laboratory studies and emergency treatment of malignant hyperthermia is given in Table 4. Ideally, effective management requires an intensive effort by a multidisciplinary team working in a critical care facility.

In Vitro Contracture Testing

Individuals susceptible to malignant hyperthermia can only be identified through the in vitro muscle contracture test. The test is based on the observation that muscle fibers from individuals susceptible to malignant hyperthermia will show a greater force of contraction and greater peak tension when exposed to specific concentrations of halothane and caffeine, either alone or in combination. [10,11]

Although the in vitro contracture test is specific and reproducible, several factors complicate its routine use. The test is invasive and requires a section of muscle fiber about 3.5 x 1.5 x 1.5 cm in size, which is taken from the rectus abdominis muscle or the vastus lateralis muscle. [11] In addition, many centers use slightly different protocols or criteria for a positive test. Efforts to standardize the test are still ongoing. [11]

A current listing of the 19 muscle biopsy centers that perform in vitro contracture testing may be obtained from the Malignant Hyperthermia Association of the United States (P.O. Box 191, Westport, CT 06881-0191; telephone: 203-655-3007).

The use of simpler tests to screen for susceptibility to malignant hyperthermia has been attempted. Markedly elevated serum creatine kinase levels have been reported in individuals with malignant hyperthermia. [7] However, no correlation has been established between the susceptibility to malignant hyperthermia (as documented by a positive in vitro contracture test) and baseline creatine kinase levels. [12]

Alternative Anesthestic Regimens

Alternative anesthetic regimens should be used in patients who are susceptible to malignant hyperthermia, such as children with masseter muscle spasm or muscular dystrophy, and in patients with a positive in vitro contracture test. In some cases, regional anesthesia may be used. In general anesthesia, succinylcholine and volatile anesthetics should not be used. Induction of anesthesia should begin with a nondepolarizing paralytic, and nitrous oxide and opioids should be used for general anesthesia.

Children who develop masseter muscle spasm de novo need to be treated as if they are susceptible to malignant hyperthermia. If possible, surgery should be discontinued and a work-up for malignant hyperthermia should be performed.

Parents, siblings and children of patients identified as being susceptible to malignant hyperthermia need to be warned about their risk of the disease and should consider in vitro muscle testing.

Final Comment

The family physician providing care for a young patient who is scheduled for general anesthesia should ask about risk factors for malignant hyperthermia (Table 5). All anesthesiology departments should have a treatment protocol for malignant hyperthermia and should keep an adequate number of dantrolene vials on hand. Dantrolene is expensive; at least 35 20-mg vials are required to supply a dose of 10 mg per kg for a patient weighing 70 kg (154 lb).

All medical personnel should be familiar with the Malignant Hyperthermia Association of the United States and with the Medic Alert Hotline (209-634-4917), which provides referral to on-call anesthesiologists for consultation on malignant hyperthermia emergencies 24 hours a day.

Patients susceptible to malignant hyperthermia should wear a medic alert bracelet. In addition, first-degree relatives of these patients need to be alerted to the implications of the diagnosis. All family physicians, dentists and school nurses should be notified of the condition in writing. Wallet cards outlining safe and unsafe medications, as well as the anesthetic management plan, are available through the Malignant Hyperthermia Association of the United States.

The authors thank Jay R. Albrandt, a certified athletic trainer, for helping preparethis. manuscript.

REFERENCES

1. Tomarken JL, Britt BA. Malignant hyperthermia. Ann Emerg Med 1987; 16: 1253-65.

2. Rosenberg H. Clinical presentation of malignant hyperthermia. Br J Anaesth 1988;60: 268-73.

3. Brownell AK. Malignant hyperthermia: relationship to other diseases. Br J Anaesth 1988; 60:303-8.

4. Heffron JJ. Malignant hyperthermia: biochemical aspects of the acute episode. Br J Anaesth 1988;60:2 74-8.

5. Malignant Hyperthermia Association of the United States (MHAUS). 1990 Clinical update. Westport, Conn.: Malignant Hyperthermia Association of the United States, 1990.

6. Gronert GA, Mott J, Lee J. Aetiology of malignant hyperthermia. Br J Anaesth 1988;60: 253-67.

7. Rosenberg H, Fletcher JE. Masseter muscle rigidity and malignant hyperthermia susceptibility. Anesth Analg 1986; 65:161-4.

8. Larach MG, Rosenberg H, Larach DR, Broennle AM. Prediction of malignant hyperthermia susceptibility by clinical signs. Anesthesiology 1987; 66:547-50.

9. Harrison GG. Malignant hyperthermia. Dantrolene--dynamics and kinetics. Br J Anaesth 1988;60:279-86.

10. Larach MG. Standardization of the caffeinehalothane muscle contracture test. North American Malignant Hyperthermia Group. Anesth Analg 1989;69:511-5.

11. Melton AT, Martucci RW, Kien ND, Gronert GA. Malignant hyperthermia in humans-- standardization of contracture testing protocol. Anesth Analg 1989;69:437-43.

12. Paasuke RT, Brownell AK. Serum creatine kinase level as a screening test for susceptibility to malignant hyperthermia. JAMA 1986;255:769-71.

The Authors

JOSEPH L. MOORE, M.D. is a staff family physician and head of the sports medicine program at the Naval Hospital, Camp Pendleton, Calif. A graduate of the University of Virginia School of Medicine, Charlottesville, Dr. Moore completed a family practice residency at the Naval Hospital, Camp Pendleton, and a fellowship in sports medicine at the San Diego Sports Medicine Center.

E. LEE RICE, D.O. is medical director of the San Diego Sports Medicine Center. He also serves as team physician for the San Diego Gulls and Soccers, as well as medical director for San Diego State University's intercollegiate sports and the U.S. national volleyball teams. In addition, Dr. Rice is an assistant clinical professor at the University of California, San Diego, School of Medicine, and a clinical professor of family medicine/sports medicine at the College of Osteopathic Medicine of the Pacific, Los Angeles.

COPYRIGHT 1992 American Academy of Family Physicians
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