Malignant Hyperthermia Syndrome—
nightmare or nuisance?

STEVEN C. HALL, MD

aSpring 2000

In 1960,  a young rugby player in Melbourne, Australia, was scheduled for reduction and fixation of a compound fracture of the tibia. He unexpectedly refused to allow treatment because it was to be performed under general anesthesia. He claimed that everyone in his family who had ever received a general anesthetic had died, usually in the operating room, with a high fever. The anesthesiologist confirmed this with the young man’s mother but told them not to worry because he would use a new anesthetic that was chemically different from the ether his relatives had received. Ten minutes into the halothane anesthetic, the patient’s temperature soared to 106 degrees, accompanied by ventricular tachycardia. After stopping the anesthetic and packing the young man in ice, the anesthesiologist was able to resuscitate him successfully. He was the first member of his family to survive a general anesthetic.

MORE PHYSICIANS ARE NOW AWARE OF MHS

Since this occurrence, anesthesiologists have learned a tremendous amount about the hereditary condition known as malignant hyperthermia syndrome (MHS). Of interest, MHS is one of the few medical conditions for which anesthesiologists are expected to be the local expert. Since most presentations of the syndrome occur in the perioperative period, it is the anesthesiologist who is the person most likely to diagnose and treat the acute manifestations. It is also the anesthesiologist who is expected to answer questions about prognosis, additional testing, wearing of a Med-Alert™ tag, and suitability of techniques for future surgical procedures.

Pediatricians and surgeons need to be aware of this condition in order to understand the significance of this genetic condition for the ongoing care of patients with MHS. Their practices may include families in whom the diagnosis of MHS is known and need to ensure that anesthetic care takes this fact into consideration. The pediatrician or surgeon may aid in making the diagnose when presented with a family who gives a history of unexplained mortality or morbidity during surgery in a patient or relative. Consultation with an anesthesiologist familiar with MHS is useful not only in making a diagnosis, but also in providing an additional resource for counseling of the family.

Since 1960, thousands of cases of patients with MHS attacks have been observed. In the past, unrecognized or untreated attacks of the condition had a mortality rate approaching 90%, making recognition and early treatment crucial. The attacks’ sudden and potentially life-threatening nature led to MHS being nicknamed the "anesthesiologist’s nightmare." Since 1979, when a specific therapy, intravenous dantrolene, was introduced, dramatic changes in the ability to diagnose and successfully treat this condition have emerged, and as a result, morbidity and mortality have dropped significantly. Whether this condition—as with any rare syndrome—is now a "nuisance" rather than a "nightmare" depends on the clinicians who may have contact with these patients and their ability to properly diagnose, treat, and counsel affected patients and family members.

DEMOGRAPHICS OF THE CONDITION

The earliest reports of patients with MHS came from Australia, Canada, and Wisconsin—populations primarily of Northern European ancestry. The exact incidence is difficult to estimate for several reasons, including a lack of uniformity of diagnostic criteria and the propensity of the syndrome to be recognized in a patient or family only after a clinical attack, usually during general anesthesia.

MHS has been identified in all major racial groups and in most countries, with a preponderance in Northern Europe and Northern North America. In the United States, the incidence ranges between 1:10,000 and 1:50,000 individuals undergoing general anesthesia, with a higher incidence in children than adults. The incidence may be decreasing with less use of succinylcholine, though this is speculative. Many anesthesiologists may never see a case of MHS.

It is widely accepted that MHS is a genetic disease, but there is question about the exact nature of inheritance. The traditional thinking is that the syndrome is autosomal dominant, with incomplete penetrance and variable expressivity. However, there appears to be significant variation among families. Furthermore, there are patients who definitely have MHS, but no relative who also has the syndrome can be found. It is not known whether this represents a new mutation, a recessive pattern, or other confluence of cofactors.

PATHOPHYSIOLOGY

Malignant hyperthermia is a disorder of skeletal muscle that is characterized by a hypermetabolic response to specific triggers. These triggers are typically volatile anesthetic agents or succinylcholine, though there are probably extraordinarily rare attacks that are precipitated by external stresses. The hypermetabolic response consists of increased aerobic and anaerobic metabolism. The patient develops increased oxygen consumption and carbon dioxide production, followed by increased lactate production. If allowed to continue, the attack ultimately results in muscle cell breakdown and death. The visible signs of this process include tachycardia, tachypnea, hypercarbia, dysrhythmias, sweating, flushing, dilated pupils, and dark-colored urine.

Much has been learned about MHS since it was first described as a unique syndrome by Denborough and Lovell. Research has been greatly aided by the recognition that an animal model, the porcine stress syndrome, is similar to the human syndrome. Evaluation of affected families has also yielded interesting clues to the genetics of the condition. However, there is still much that we do not understand.

The pathophysiology of MHS is most likely related to an inappropriate rise in intracellular calcium in skeletal muscle. The exact cause of this is still not clear. With the rise in intracellular calcium, there is an increase in muscle contracture and aerobic metabolism. The cells convert to anaerobic metabolism quickly because of the inability of the capillary network to provide enough oxygen to cells that continue to metabolize oxygen at a maximal rate. With the continued metabolic activity and buildup of acid and reactive intermediates, the muscle cells eventually lose cellular integrity, release potassium, creatine phosphokinase, myoglobin,and other substances into the bloodstream. Although there has been speculation about abnormalities in the sarcoplasmic reticulum, the excitation-contraction coupling mechanism, calcium release channels, and second messengers responsible for calcium release from the sarcoplasmic reticulum, questions still remain about the exact mechanism or mechanisms responsible for a clinical attack.

GENETICS

The genetics of MHS have been investigated, especially recently, as a possible means of finding a non-invasive diagnostic test. There has been great interest in identifying the gene responsible for this syndrome. Work has focused on the gene sequence responsible for the calcium channel. This area can be tagged with ryanodine, leading to the common designation as the ryanodine receptor or RYR-1 protein. Although there was great initial enthusiasm for this as a marker that could identify abnormalities in families susceptible to MHS, subsequent work has shown that it is useful in some, but not most, families with MHS. Instead, there is growing appreciation that this may be heterogenetic or polygenetic disorder. It is now believed that about 30 genetic mutations are responsible for MHS, in contrast to the swine model, where only one or two mutations are causal. It seems unlikely that there will be a highly accurate human genetic test available in the near future.

Interestingly, the majority of research on the molecular genetic basis of MHS is being done in centers outside the United States, mainly in Europe. Funding for work in the U.S. has been sparse, with few US researchers devoting much effort to the unraveling of the genetics of MHS.

CLINICAL PRESENTATION

The clinical presentation of MHS can be extraordinarily easy to diagnosis or, likewise, extraordinarily difficult. If a patient presents with rigidity, tachycardia, tachypnea, hypercarbia, dysrhythmias, sweating, flushing, dilated pupils, and dark-colored urine soon after administration of succinylcholine, it is not difficult to make the clinical diagnosis (Table 1 below).

However, not all cases present in this explicit fashion. Some cases develop slowly, with a gradual development of tachycardia and dysrhythmias, sometimes accompanied by hypercarbia. The differential diagnosis here includes sepsis, "light anesthesia," hyperthermia secondary to inadequate heat loss, hyperthyroidism, and equipment malfunctions. Some cases present as myoglobinuria, even in the postoperative period, with the differential diagnosis including blood transfusion reactions, drug-induced hemolytic reactions, and rhabdomyolysis from other sources. An arterial blood gas taken during an attack shows significant respiratory acidosis, significant metabolic acidosis, and, usually, normal oxygenation. If these changes are not present, the diagnosis of MHS should be strongly reconsidered.

One of the most troubling and contentious clinical issues related to MHS is that of masseter spasm after succinylcholine. One of the factors that has complicated the issue of masseter spasm after succinylcholine is the drug's decreased use in pediatric anesthesia practice. Because of the fear of rhabdomyolysis and sudden hyperkalemia in a child with undetected myopathy (especially Duchenne’s muscular dystrophy), anesthesiologists seldom use succinylcholine in children. Consequently, it is common for many clinicians to only use succinylcholine under stressful conditions, that of a rapid sequence induction for presumed full stomach. What is not appreciated by many clinicians is that succinyl-choline causes a significant tightening of the masseter muscles that relaxes slowly. This normal action can be interpreted as masseter spasm by clinicians who seldom work with children or who try to open the mouth shortly after fasciculations end. True masseter spasm is a prolonged, palpable tightening of the masseter muscles that does not release gradually.

What does one do if the patient has masseter spasm after succinylcholine? There are two very different approaches widely advised by experts in the U.S. and they have certain important features in common. Both approaches advise that if masseter spasm develops with the use of succinylcholine, the clinician should stop all triggering agents. The patient should be examined for other signs of MHS by clinical exam, as well as by arterial blood gas and serum CPK. If there are signs of MHS, treatment should be started. At the end of the procedure, the anesthesiologist should explain the events to the patient and/or family members and should advise the patient to have further testing to determine MHS susceptibility. Not all patients who have masseter spasm after succinylcholine have MHS; further testing is the only way to determine the patient’s real status.

The major difference to the two approaches occurs in the patient who has masseter spasm but no other signs of an MHS attack. One school of thought is that an elective case should be canceled and the patient sent for definitive testing before surgery proceeds. The other school of thought is that the clinician may elect to proceed with the case using non-triggering agents after advising the surgeon that there is a risk that the case may have to be aborted if signs of MHS do develop. Which is the better approach? This is a decision that should be made by the individual clinicians, based on their resources, risk tolerance, and general philosophy. It is my personal opinion is that it is useful for each anesthesiology department to discuss this issue and try to reach consensus about a general approach. This makes the decision easier in an emergent situation; it also provides some consistency in explaining decisions to patient/families and surgeons. Obviously, each case must be decided on its individual characteristics, but it is useful to consider a general approach as a guide.

Evidence shows that the signs of MHS appear during anesthesia or in the early postoperative period. There is no recorded case of a confirmed attack of MHS occurring later than four hours after an anesthetic. Fever initially appearing more than four hours after the anesthetic, fever that responds to antipyretics, fever that is not associate with severe respiratory and metabolic acidosis, or fever that is not associated with cardiopulmonary instability (extreme tachycardia and tachypnea) is unlikely to represent MHS. Although it has sometimes been challenging to differentiate MHS from sepsis, allergic drug reactions, pheochromocytoma, or the neuroleptic malignant syndrome (related to antipsychotic medications), the clinical profile usually becomes clear with analysis of arterial blood gas results.

TREATMENT OF AN ATTACK

The treatment of an attack of MHS is straightforward. All triggering agents should be stopped. Hyperventilation with 100% oxygen should be started. The definitive therapy is administration of dantrolene sodium, which quickly stops release of calcium from the sarcoplasmic reticulum. The usual recommended dosage is 2.5 mg/kg. Dantrolene administration is continued if signs recur. There is no maximum dose of dantrolene, although an arbitrary figure of 10 mg/kg is given in the package insert. After the patient has been stabilized, dantrolene is usually continued intravenously or by mouth for another 36 hours at 1 mg/kg every 6 hours. This is done empirically, since there is no evidence that this prevents a further attack or halts unidentified hypermetabolism.

Supportive therapy of cooling, hyperventilation, treatment of dysrhythmias, and treatment of hyperkalemia are given, as needed. Although it is frequently recommended that diuretics should be given, this is often not needed. Administration of 2.5 mg/kg of dantrolene results in administration of 0.33 gm/kg of mannitol in the solution, usually producing a brisk diuresis.

Monitoring should include blood pressure, ECG, capnography, pulse oximetry, and urine output, at a minimum. Central venous pressure and intra-arterial monitoring should be added if the patient is unstable. Laboratory studies should include arterial blood gases, CPK, electrolytes (especially potassium), and urine myoglobin.

It is appropriate to monitor these patients in an intensive care setting after a clinical attack. Discharge should be dependent on clinical stability without residua, as well as lack of evidence of an ongoing metabolic abnormality. Although there are no strict criteria for safe discharge from an intensive care unit, one commonly used measure is to keep the patient until CPK levels start to decline. This often occurs in the first 18 to 24 hours.

SAFE ANESTHETIC AGENTS AND TECHNIQUES

Can an MHS-susceptible patient be treated safely in a community hospital, or do all these patients need to be referred to a tertiary center? As long as appropriate monitoring and drugs are used, MHS-susceptible patients should be able to have any surgical procedure needed in a community setting.

Monitoring is crucial in these patients. Capnography is extremely valuable for early detection of the hypermetabolic state and must be used. Also, there should be rapid access to blood gas analysis. Normal equipment can be used, but the soda lime and rubber goods in the circuit should not have been exposed to volatile agents. Flushing of the machine with 100% oxygen can be done for a much shorter period of time than previously thought; 10 to 15 minutes is reasonable.

In the past, amide-type local anesthetics were suspected as triggering agents, leaving only ester-type agents for local or regional anesthesia. That thinking has changed. The potential calcium-releasing effects of these agents are seen only at concentrations above the clinical range, so regional and local anesthetic techniques with amide-type agents are now acceptable in MHS-susceptible patients and in fact have been used extensively. In addition, some of the newer agents such as propofol, remifentanil, and rocuronium are administered for a wide variety of surgical procedures.

Although it has been suggested that phenothiazines and ketamine are not drugs of choice in these patients because they may affect temperature regulation and sympathetic tone, there is no evidence that they trigger MHS. Recent work has shown that ketamine and droperidol can safely be used in MHS-susceptible patients but that the anti-psychotic drug haloperidol should be avoided.

Of the commonly used general anesthetics, sedatives, and muscle relaxants, only succinylcholine, all the volatile agents, and haloperidol are contraindicated currently.

Intravenous dantrolene should be available if an MHS-susceptible patient is going to receive a general anesthetic. More importantly, intravenous dantrolene in sufficient doses should be available in every institution where general anesthesia is given. This includes hospitals, ambulatory surgical centers, and offices. It would be considered negligence to practice without this safeguard for a rare, but life-threatening, condition.

TESTING FOR MHS SUSCEPTIBILITY

If a patient has an obvious fulminant attack, further testing is not necessary. However, if the patient’s status is not clear, testing is indicated. The only test that consistently predicts MHS susceptibility in patients with clear clinical histories is halothane-caffeine contracture testing. In MHS, fresh skeletal muscle exhibits an exaggerated contracture response to caffeine and halothane, as well as to ryanodine. The methodology for this testing has been standardized between laboratories in both the United States and Europe. Because of the costs involved, only nine centers in the United States perform the test; Northwestern University’s Diagnostic and Testing Center is the only one in Chicago.

Two major issues are important when discussing susceptibility testing. The first is the search for a non-invasive reliable test. Recent tests such as genetic analysis, MRI imaging of skeletal muscle, lymphocyte assays, and platelet assays were initially promising but have not been shown to be sensitive and specific. Although a correlation exists between elevated CPK levels in first-degree relatives of known MHS-susceptible patients and susceptibility, there is no correlation between elevated CPK levels and susceptibility in the general population. The second important aspect of testing is often overlooked in the excitement over determining MHS susceptibility. Some patients who present with abnormal responses to anesthetics actually have other significant myopathies, such as Duchenne’s muscular dystrophy. Testing should address this issue, especially in children, because Duchenne’s muscular dystrophy, for instance, is a much more serious diagnosis than MHS susceptibility.

COUNSELING

It is unusual for anesthesiologists to find themselves acting as primary physicians. However, anesthesiologists are often the physicians in the hospital with the most knowledge and insight into MHS and its ramifications. It is incumbent on them to not only be well versed in the subject of MHS but also be willing to help susceptible patients understand their condition; they are also valuable sources of information for relatives, pediatricians, surgeons and family practitioners (see Table 2).

Counseling of the patient and family should include careful discussion with the patient/family and an understandable letter for the family’s files. It should also include recommending a Med-Alert™ tag, a referral to someone they can contact for further help, and referral to a support group like the Malignant Hyperthermia Association of the United States (see Table 3). This group offers a 24-hour hotline without charge to provide advice on MHS. The phone number for the hotline is 1-800-98-MHAUS.

SUMMARY

General anesthesia for children was, at one time, something feared by many parents, and viewed with alarm by many pediatricians because of the perceived risk to the child. However, with modern monitoring, drugs, techniques, and understanding of physiology and pharmacology, the risk of general anesthesia has become extraordinarily small. There is one condition, malignant hyperthermia syndrome, that continues to rarely produce a life-threatening condition for the child. Even so, the proper diagnosis, treatment, and counseling of the family can take what was once the "anesthesiologist’s nightmare," and change it to a rare condition that can not only be successfully treated, but managed such that patients with the syndrome can have any surgical procedure they may need with safety and convenience.

FOR FURTHER READING

1. Allen GC, Larach MG, Kunselman AR, and the North American Malignant Hyperthermia Registry of MHAUS: The sensitivity and specificity of the caffeine-halthane contracture test. Anesthesiology 1998;88:579–588.

2. Birmingham PK, Stevenson GW, Uejima T, Hall SC: Isolated postoperative myoglobinuria in a pediatric outpatient. A case report of malignant hyperthermia. Anesth Analg 1989;69:846–849.

3. Carr AS, Lerman J, Cunliffe M, et al: Incidence of malignant hyperthermia reactions in 2,214 patients undergoing muscle biopsy. Can J Anaesth 1995;42:281–286.

4. Fierobe L, Nivoche Y, Mantz J, et al: Perioperative severe rhabdomyolysis revealing susceptibility to malignant hyperthermia. Anesthesiology 1998;88:263–265.

5. Hopkins PM, Ellis FR, Halsall PJ, Stewart AD: An analysis of the predictive probability of the in vitro contracture test for determining susceptibility to malignant hyperthermia. Anesth Analg 1997;84:648–656.

6. Lynch PJ, Krivosic-Horber R, Reyford H, et al: Identification of heterozygous and homozygous individuals with the novel RYR1 mutation Cys35Arg in a large kindred. Anesthesiology 1997;86:620–626.

7. Hogan K. (editorial) Molecular medicine and malignant hyperthermia. Anesthesiology 1997;86:511–513.

8. Mezin P, Payen JF, Bosson JL, Brambilla E, Stieglitz P: Histological support for the difference between malignant hyperthermia susceptible (MHS), equivocal (MHE) and negative (MHN) muscle biopsies. Br J Anaesth 1997;79:327–331.

9. Weglinski MR, Wedel DJ, Engel AG: Malignant hyperthermia testing in patients with persistent increased serum creatine kinase levels. Anesth Analg 1997;84:1038–1041.

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