Malignant Hyperthermia

MALIGNANT HYPERTHERMIA

Malignant hyperthermia (MH) is a rare (1:15,000 in pediatric patients and 1:40,000 adult patients) genetic hypermetabolic muscle disease, the charac-teristic phenotypical signs and symptoms of which most commonly appear with exposure to inhaled general anesthetics or succinylcholine (triggering agents). MH may occasionally present more than an hour after emergence from an anesthetic, and rarely may occur without exposure to known trig-gering agents. Most cases have been reported in young males; almost none have been reported in infants, and few have been reported in the elderly. Nevertheless, all ages and both sexes may be affected. The incidence of MH varies greatly from country to country and even among different geographic locali-ties within the same country, reflecting varying gene pools. The upper Midwest appears to have the great-est incidence of MH in the United States.

Pathophysiology

A halogenated anesthetic agent alone may trigger an episode of MH (Table 52–2). In many of the early reported cases, both succinylcholine and a haloge-nated anesthetic agent were used. However, succi-nylcholine is less frequently used in modern practice, and about half of the cases in the past decade were associated with volatile anesthetics as the only triggering agents. Nearly 50% of patients who experience an episode of MH have had at leastone previous uneventful exposure to anesthesia dur-ing which they received a recognized triggering agent. Why MH fails to occur after every exposure totriggering agent is unclear. Investigations into the biochemical causes of MH reveal an uncontrolled increase in intracellular calcium in skeletal muscle. The sudden release of calcium from sarcoplasmic reticulum removes the inhibition of troponin, resulting in sustained muscle contraction. Markedly increased adenosine triphosphatase activity results in an uncontrolled increase in aerobic and anaerobic metabolism. The hypermetabolic state markedly increases oxygen consumption and CO ₂ production, producing severe lactic acidosis and hyperthermia.

One early focus of investigations into the mech-anisms of MH has been the gene for the ryanodine (Ryr ₁) receptor, located on chromosome 19. Ryr₁ is

an ion channel responsible for calcium release from the sarcoplasmic reticulum and it plays an impor-tant role in muscle depolarization. Subsequent reports linked MH with mutations involving the sodium channel on chromosome 17. An autosomal recessive form of MH has been associated with the King–Denborough syndrome. Most patients with an episode of MH have a history of relatives with similar episode or with an abnormal halothane– caffeine contracture test . The complex-ity of genetic inheritance patterns in families reflects the fact that MH can be caused by mutations of one or more genes on more than one chromosome. To date genetic studies in humans have revealed at least five different chromosomes and more than 180 indi-vidual mutations associated with MH. Genetic test-ing, although available, currently screens for less than 20% of recognized mutations. A patient with a bona fide clinical history of MH has about a 30–50% chance of testing positive.

Clinical Manifestations

The earliest signs of MH during anesthesia are succinylcholine-induced masseter musclerigidity (MMR) or other muscle rigidity, tachycar-dia, and hypercarbia (due to increased CO₂ pro-duction) (Table 52–3). Two or more of these signs greatly increase the likelihood of MH. Tachypnea is prominent when muscle relaxants are not used. Overactivity of the sympathetic nervous system produces tachycardia, arrhythmias, hypertension, and mottled cyanosis. Hyperthermia may be a late sign, but when it occurs, core temperature can rise as much as 1°C every 5 min. Generalized muscle rigidity is not consistently present. Hypertension may be rapidly followed by hypotension if cardiac depression occurs. Dark-colored urine reflects myo-globinemia and myoglobinuria.

Laboratory testing typically reveals mixed metabolic and respiratory acidosis with a marked base deficit, hyperkalemia, hypermagnesemia, and reduced mixed-venous oxygen saturation. Some case reports describe isolated respiratory acido-sis early in the course of an episode of MH. Serum ionized calcium concentration is variable: it may initially increase before a later decrease. Patients typically have increased serum myoglobin, creatine

kinase (CK), lactic dehydrogenase, and aldolase lev-els. When peak serum CK levels (usually 12–18 h after anesthesia) exceed 20,000 IU/L the diagnosis is strongly suspected. It should be noted that succi-nylcholine administration to some normal patients without MH may cause serum myoglobin and CK levels to increase markedly.

Much of the problem in diagnosing MH arises from its variable presentation. Fever is an inconsis-tent and often late-presenting sign. An unantici-pated doubling or tripling of end-tidal CO₂ (in the absence of a ventilatory change) is one of the earliest and most sensitive indicators of MH. If the patient survives the first few minutes, acute kidney failure and disseminated intravascular coagulation (DIC) can rapidly ensue. Other complications of MH include cerebral edema with seizures and hepatic failure. Most MH deaths are due to DIC and organ failure due to delayed or no treatment with dantrolene.

Susceptibility to MH is increased in sev-eral musculoskeletal diseases. These includecentral-core disease, multi-minicore myopathy, and King–Denborough syndrome. The latter syndrome is seen primarily in young boys who exhibit short stature, mental retardation, cryptorchidism, kypho-scoliosis, pectus deformity, slanted eyes, low-set ears, webbed neck, and winged scapulae. Duchenne’s and other muscular dystrophies, nonspecific myopathies, heat stroke, and osteogenesis imperfecta have been associated with MH-like symptoms in some reports; however, their association with MH is controversial. Other possible clues to susceptibility include a fam-ily history of anesthetic complications, or a history of unexplained fevers or muscular cramps. There are several reports of MH episodes occurring in patients with a history of exercise-induced rhabdomyolysis. Prior uneventful anesthesia procedures and absence of a positive family history are notoriously unreli-able predictors of lack of susceptibility to MH. Any patient who develops MMR during induction of anesthesia should be considered potentially suscep-tible to MH.

Intraoperative Considerations

Treatment of an MH episode is directed at terminating the episode and treating complications such as hyperthermia and acidosis. The mortality rate for MH, even with prompt treat-ment, ranges from 5% to 30%. Table 52-4 illustrates

a standard protocol for management of MH. First and most importantly, the triggering agent must be stopped and dantrolene must be given immediately.

A. Acute Treatment Measures

Volatile agents and succinylcholine must be dis-continued immediately. Even trace amounts of anesthetics absorbed by soda lime, breathing tubes, and breathing bags may be detrimental. The patient should be hyperventilated with 100% oxygen to minimize the effects of uncontrolled CO ₂ produc-tion and increased oxygen consumption.

B. Dantrolene Therapy

The mainstay of therapy for MH is immediate administration of intravenous dantrolene. Dan-trolene, a hydantoin derivative, directly interferes with muscle contraction by binding the Ryr₁ receptor channel and inhibiting calcium ion release from the sarcoplasmic reticulum. The dose is 2.5 mg/kg intravenously every 5 min until the episode is terminated (upper limit, 10 mg/kg). Dantrolene is packaged as 20 mg of lyophilized powder to be dis-solved in 60 mL of sterile water. Depending on the dose required and drug formulation used, reconsti-tution can be time consuming. An assistant may beneeded. A new formulation isavailable that recon-stitutes in about one third the time (20 versus 86 s) required for the older formulation. The effective half-life of dantrolene is about 6 h.

After initial control of symptoms, 1 mg/kg of dantrolene intravenously is recommended every 6 h for 24–48 h to prevent relapse (MH can recur within 24 h of an initial episode). Dantrolene is a relatively safe drug that is also used to decrease temperature in patients with thyroid “storm” and neuroleptic malignant syndrome. Although its use in chronic therapy for spastic disorders has been associated with hepatic dysfunction, the most serious com-plication following acute administration is general-ized muscle weakness that may result in respiratory insufficiency or aspiration pneumonia. Dantrolene can cause phlebitis in small peripheral veins and should be given through a central venous line if one is available. The safety and efficacy of dantrolene therapy mandate its immediate use in this poten-tially life-threatening situation. Following adminis-tration of dantrolene, most patients revert to normalacid–base status promptly and no further pharma-cological treatment is necessary.

C. Correction of Acid–Base/ Electrolyte Imbalances

Persisting metabolic acidosis should be treated with intravenous sodium bicarbonate, recogniz-ing that this treatment will worsen the hypercarbia. Hyperkalemia should be treated with glucose, insu-lin, and diuresis. There is no useful role for intrave-nous calcium in this setting. Antiarrhythmic agents, vasopressors, and inotropes should be administered, if indicated. Calcium channel blockers should not be given to patients receiving dantrolene because this combination appears to promote hyperkalemia. Furosemide may be used to establish diuresis and prevent acute kidney failure, which may develop as a consequence of myoglobinuria. Dantrolene contains a considerable amount of mannitol (3 g per 20-mg bottle); thus furosemide or bumetanide should be used in preference to mannitol for diuresis.

D. Cooling the Patient

If fever is present, cooling measures should be insti-tuted immediately. Surface cooling with ice packs over major arteries, cold air convection, and cooling blankets are used. Iced saline lavage of the stomach and any open body cavities (eg, in patients under-going abdominal surgery) should also be instituted. Use of hypothermic cardiopulmonary bypass may be appropriate if other measures fail.

E. Management of the Patient with Isolated Masseter Muscle Spasm

MMR, or trismus, is a forceful contraction of the jaw musculature that prevents full mouth open-ing. This contrasts with incomplete jaw relaxation, which is a fairly common finding. Both myotonia and MH can cause masseter spasm. The two disor-ders can be differentiated by the medical history, neurological examination, and electromyography. The historical incidence of MMR following admin-istration of succinylcholine with halothane in pedi-atric patients at some medical centers was higher than 1%. Isolated MMR occurs in only 15–30% of true MH episodes. Moreover, less than 50% of patients in whom MMR develops prove to be sus-ceptible to MH by muscle testing. In the past, theconsensus of clinicians was to assume that any occurrence of MMR was diagnostic of MH and to postpone elective surgery. However, if there is no other sign of MH, and if monitoring and treatment capabilities are readily available, many anesthesi-ologists now advocate allowing surgery to continue using safe (nontriggering) anesthetic agents. Serum CK levels should be followed for 24 h after an epi-sode of MMR, because an elevation of this enzyme may indicate an underlying myopathy.

Postoperative Considerations

A. Confirmation of the Diagnosis

Patients who have survived an unequivocal episode of MH are considered susceptible; in these patients a muscle biopsy need not be performed for diagnosis. If the diagnosis remains in doubt postoperatively,fresh biopsy specimen of living skeletal muscle is obtained and exposed to a caffeine, halothane, or combination caffeine–halothane bath. The halo-thane–caffeine contracture test may have a 10–20% false-positive rate, but the false-negative rate is close to zero. Because of the relative complexity of this test, only a few centers worldwide perform it. If the halothane–caffeine contracture test is posi-tive, genetic counseling and testing of family mem-bers are appropriate. Baseline CK may be elevated chronically in 50–70% of people at risk for MH, but the only reliable way to diagnose MH susceptibility is by muscle testing.

Both European and North American MH regis-tries have been established to help physicians iden-tify and treat patients with suspected MH, as well as provide standardization between testing centers. The Malignant Hyperthermia Association of the United States (MHAUS, telephone 1-800-986-4287) operates a 24-hour hotline (1-800-644-9737) and a web site (http://www.mhaus.org).

1. Differential diagnosis—Severaldisorders maysuperficially resemble MH (Table 52–5). However, MH is associated with greater degrees of metabolic acidosis and venous desaturation than any of these other conditions. In current practice, the most common condition confused with MH is hypercar-bia from CO₂ insufflation for laparoscopy, with or without subcutaneous emphysema. This condition can result in an unexpected increase in end-tidal

CO₂ with accompanying tachycardia. Surgery and anesthesia can precipitate thyroid storm in undiag-nosed or poorly controlled hyperthyroid patients. The signs of thyroid storm include tachycardia, tachyarrhythmias (particularly atrial f briillation), hyperthermia (often ≥40°C), hypotension, and in some cases congestive heart failure. In contrast to MH, hypokalemia is very common. Also unlike the typical intraoperative presentation of MH, thy-roid storm generally develops postoperatively . Pheochromocytoma is associated with dramatic increases in heart rate and blood pressure but not with an increase in CO₂ production, endtidal CO ₂, or temperature . Car-diac arrhythmias or ischemia may also be prominent. Rarely such patients may have hyperthermia (>38°C), which is generally thought to be due to increased heat production from catecholamine-mediated increases in metabolic rate together with decreased heat elimination from intense vasocon-striction. Sepsis shares several characteristics with MH, including fever, tachypnea, tachycardia, and metabolic acidosis . Sepsis can be difficult to diagnose if there is no obvious primary site of infection.

Less commonly, drug-induced hyperthermia may be encountered in the perioperative period. In these cases, the drugs appear to markedly increase serotonin activity in the brain, causing hyperther-mia, confusion, shivering, diaphoresis, hyperreflexia, and myoclonus. Drug combinations associated with this “serotonin syndrome” include monoamine oxidase inhibitors (MAOIs) and meperidine, and MAOIs and selective serotonin reuptake inhibitors (SSRIs). Hyperthermia can also be caused by some illicit drugs, including 3,4-methylenedioxymetham-phetamine (MDMA or “ecstasy’), “crack” cocaine, amphetamines, phencyclidine (PCP), and lysergic acid diethylamine (LSD).

Iatrogenic hyperthermia is not uncommon, particularly in pediatric patients. Common sources of excessive heat in the operating room include humidifiers on ventilators, warming blankets, heat lamps, and increased ambient temperature. Injuries to the brainstem, hypothalamus, or nearby regions can be associated with marked hyperthermia.

2. Neuroleptic malignant syndrome (NMS)—This syndrome is characterized by hyperthermia, muscle rigidity with extrapyramidal signs (dyskine-sia), altered consciousness, and autonomic lability in patients receiving antidopaminergic agents. The syndrome is caused by an imbalance of neurotrans-mitters in the central nervous system. It can occur either during drug therapy with antidopaminergic agents (eg, phenothiazines, butyrophenones, thio-xanthenes, or metoclopramide) or less commonly following the withdrawal of dopaminergic agonists (levodopa or amantadine) in patients with Parkin-son’s disease. Thus, it appears to involve abnormal central dopaminergic activity, as opposed to the al-tered peripheral calcium release seen in MH. These differing mechanisms probably explain why nonde-polarizing relaxants reverse the rigidity of NMS, but not the rigidity associated with MH.

NMS does not appear to be inherited and typi-cally takes hours to weeks to develop; the majority of episodes develop within 2 weeks of a dose adjust-ment. Hyperthermia generally tends to be mild, and appears to be proportional to the amount of rigidity. Autonomic dysfunction results in tachycardia, labile blood pressure, diaphoresis, increased secretions, and urinary incontinence. Muscle rigidity can pro-duce dyspnea and respiratory distress and, together with the increased secretions, can promote aspiration pneumonia. CK levels are typically elevated; some patients may develop rhabdomyolysis resulting in myoglobinemia, myoglobinuria, and kidney failure.

Mild forms of NMS promptly resolve after withdrawal of the causative drug (or reinstitution of antiparkinsonian therapy). Initial treatment of more severe forms of NMS should include oxygen therapy and endotracheal intubation for respiratory distress or altered consciousness. Marked muscle rigidity can be controlled with muscle paralysis, dantrolene, or a dopaminergic agonist (amantadine, bromocriptine, or levodopa), depending on the severity and acuity of the syndrome. Resolution of the muscle rigidity usually decreases body temperature.

This syndrome is considered a separate entity from MH; nevertheless some clinicians believe that NMS may predispose patients to MH and recom-mend that patients with NMS should not receive succinylcholine or a volatile anesthetic. In contrast to patients with NMS, patients susceptible to MH can safely receive phenothiazines.

B. Prophylaxis, Postanesthesia Care, and Discharge

Propofol, etomidate, benzodiazepines, ket-amine, thiopental, methohexital, opiates,droperidol, nitrous oxide, nondepolarizing muscle relaxants, and all local anesthetics are nontrigger-ing agents that are safe for use in MH-susceptible patients. An adequate supply of dantrolene should always be available wherever general anesthesia is provided. Prophylactic administration of intrave-nous dantrolene to susceptible patients is not nec-essary if a nontriggering anesthetic is administered.

For MH-susceptible patients, the consensus is that the vaporizers should be removed from the anesthesia workstation (or fixed in an “off ” position) and the machine should be flushed with 10 L/min of fresh gas (air or oxygen) for at least 5 min. This step should reduce concentrations of volatile anesthetics to less than 1 part per million. Additionally, the CO₂ absorbent and circle system (or other anesthetic cir-cuit), hoses should be changed.

MH-susceptible patients who have under-gone an uneventful procedure with a nontrigger-ing anesthetic can be discharged from the PACU or ambulatory surgery unit when they meet standard criteria. There are no reported cases of MH-susceptible patients experiencing MH after receiving a nontriggering anesthetic during unevent-ful surgery.