Round Table on Malignant Hyperthermia in Physically Active Populations: Meeting Proceedings

Definition of Malignant Hyperthermia

Malignant hyperthermia (MH) is an anesthetic-induced, autosomal-dominant, pharmacogenetic disorder of skeletal muscle, triggered by inhalation anesthetic agents or succinylcholine and resulting in hypermetabolism, skeletal muscle damage, hyperthermia, and if left untreated, death.

The MH-like syndrome is a nonanesthetic-induced, often exertion-related episode, presenting with 2 or more of the following signs and symptoms: markedly elevated body temperature, muscle pain with muscle breakdown, and muscle rigidity. This syndrome is often identified in the absence of another readily identifiable diagnosis; these patients require further evaluation to assess the cause of their signs and symptoms.

History, Cause, and Pathophysiology of MH

Michael Denborough, MD, and his colleagues first described MH in the early 1960s.⁸ Later that decade, Beverly Britt, MD, conducted pioneering research on the occurrence and manifestations of MH.⁹ This seminal work demonstrated that MH was precipitated by exposure to potent inhalational anesthetics and the paralyzing agent succinylcholine but not to other anesthetics. The MH syndrome was determined to be inherited in an autosomal-dominant manner and was independent of ethnicity.^10,11

Skeletal muscle from MH-susceptible individuals displayed an accentuated muscle-contraction response when exposed to the anesthetic halothane and to calcium-releasing agents such as caffeine.¹² It became clear that MH was a muscle disorder caused by uncontrolled calcium release from the sarcoplasmic reticulum. In the 1990s, MH susceptibility was genetically linked to the skeletal muscle-specific calcium channel RYR1. Mutations of RYR1 are found in approximately 70% of MH-susceptible patients.¹³ Hundreds of DNA variants exist for the RYR1 gene, but fewer than 40 have been definitively identified as causing MH.¹⁴ Additionally, although many proteins regulate calcium flux, another gene, calcium channel, voltage-dependent, L type, alpha 1S subunit (CACNA1S), has been associated with MH in fewer than 1% of cases.¹⁵ It should be noted that genetic changes in the RYR1 are also found in a variety of muscle disorders (eg, central core disease) that demonstrate abnormal histopathology and result in muscle weakness. The muscle weakness in these myopathies is caused by reductions in calcium release and muscle activation.¹⁶

The pathophysiology of MH is linked to the impairment of myoplasmic calcium homeostasis, which leads to increased muscle tension and metabolism. Malignant hyperthermia manifests as increased production of carbon dioxide and heart rate and is often accompanied by accentuated muscle rigidity, hyperkalemia, increased acid content in the blood, release of myoglobin into the urine, and release of the muscle enzyme creatine kinase.¹ Downstream metabolic effects include adenosine triphosphate breakdown and increased cell membrane leakage and acidosis. Hypermetabolism also results in hyperthermia that may reach fatal levels of greater than 40.5°C (105°F), which may lead to symptoms such as failure of the blood coagulation system.¹⁷

Through the 1970s, MH mortality was close to 80%.⁹ When anesthesiologists were made aware of the signs of MH and the steps required to treat it, mortality rates declined.¹⁸ However, a specific antidote, dantrolene sodium, was not approved by the Federal Drug Administration until 1979. The efficacy of dantrolene was demonstrated first in naturally occurring breeds of heavily muscled swine and then tested in humans.¹⁹ With the widespread use of dantrolene sodium, mortality rates decreased to 15% or lower. Most developed countries now require dantrolene to be available in all operating rooms, yet in many parts of the world, this is not standard practice, despite the very high likelihood that a patient who develops MH will die without the administration of dantrolene.

Although early MH researchers discovered the syndrome in association with exposure to anesthetics, MH was also observed to develop in specific breeds of pigs exposed to nonpharmacologic stress, environmental heat stress, or exercise. Four decades ago, Wingard and Gatz²⁰ hypothesized that EHS and MH could be 2 phenotypes of a latent skeletal muscle disorder. This hypothesis was substantiated by later case reports suggesting that human patients may also present with an MH-like syndrome on exposure to exertion and environmental heat stress in the absence of anesthesia. Not all cases of EHS are due to the calcium-dependent pathophysiology of MH, but the relationship between MH-like syndromes and MH is under intensive study.⁴

Epidemiology of MH

Current Knowledge

1. Episodes of MH occur predominantly in young, muscular males.^21,22 All ethnicities are affected. The estimated incidence of MH is 1 in 250 000 surgeries involving all types of anesthesia and 1 in 62 000 uses of potent inhalational anesthetics or succinylcholine.²³ In a study²¹ of New York hospitals, the prevalence rate of MH was 0.96 per 100 000 surgical discharges.

2. Malignant hyperthermia has a variable presentation, ranging from a full metabolic crisis after induction of anesthesia to a slowly appearing reaction up to 1 hour after termination of anesthesia. The penetrance is also variable, meaning that MH-susceptible patients do not develop the syndrome with every exposure to triggering agents.^1,22

3. The condition is a genetically heterogeneous disorder, with variants in the RYR1 and CACNA1S genes responsible for 50% to 75% and 1% of MH cases, respectively.²⁴ The prevalence of genetic variants associated with MH susceptibility was estimated at 1 in 3000.^1,25 To date, 34 RYR1 variants and 2 CACNA1S variants have been confirmed as causing MH and recommended for diagnostic genetic testing by the European Malignant Hyperthermia Group.¹⁴

4. Nonanesthesia-related MH-like syndromes may share a common pathogenic mechanism with MH. This possibility is based on similarities of the clinical signs (Table 1), the presence of an RYR1 variant in 30% of patients, and a positive in vitro contracture test or caffeine halothane contracture rest test (CHCT) in 45% of this population.^2,4,26

Table 1.  Suggested Similarities Between Malignant Hyperthermia-Like Syndrome and Other Medical Diagnoses Based on Current Supporting Evidence Extended on Next Page

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Table 1.  Extended From Previous Page

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Association of MH with EHS and ER

Current Knowledge

1. Multiple MH-like syndrome case reports and case series suggest similarities and associations among MH-susceptible, EHS, and ER patients (Table 2).^6,9–35

2. Common signs and symptoms among the 3 conditions include hyperthermia, hypermetabolism, and muscle breakdown, resulting in death if untreated.

3. The MH-like syndrome, EHS, and ER are mechanistically similar in that they share triggers such as exercise, hot or humid environmental conditions, and recent illness.³¹

4. In unexplained or recurrent cases of EHS and ER, MH susceptibility has been reported, which suggests involvement of MH-related genetic mutations as some of the underlying risk factors for EHS and ER.^30,31

5. Assessing an MH-like syndrome includes neuromuscular evaluation and, in the absence of a clinical diagnosis, muscle biopsy and CHCT or genetic screening. Ongoing research will define the relationship among MH-like syndromes, EHS, and ER.

Table 2.  Summary of Case Reports

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Identification of MH-Like Syndrome

Recommendations for Acute Management of MH-Like Syndrome

The Malignant Hyperthermia Association of the United States (MHAUS) is a valuable resource for information about MH and its treatment.³⁸ The MHAUS provides a hotline with direct access to providers for real-time management of patients with MH and MH-like syndrome.¹ Recommendations for acute care based on our knowledge to date using the Strength of Recommendation Taxonomy³⁹ are as follows:

1. Initial attention should focus on basic life support with rapid interventions for those who may require airway management or early chest compressions and defibrillation. Evidence Category: C

2. Clinicians must obtain a rectal temperature to confirm initial body temperature and any changes. Any patient with a rectal temperature greater than 40.5°C (105°F) with coexisting signs or symptoms of central nervous system dysfunction should be aggressively cooled before being transported to a hospital. Whole-body immersion in cold water is recommended until rectal temperature is reduced to 38.3°C to 38.9°C (101°F−102°F).^1,40,41 Other methods, such as wrapping in ice-chilled or filled towels or sheets or providing chilled intravenous fluids and ice packs are acceptable only during transport or when whole-body water immersion is not available.^42,43 Evidence Category: C

3. If an MH-like syndrome is suspected or known to be present, succinylcholine is contraindicated because it will exacerbate an MH crisis. Similarly, volatile anesthetics are contraindicated in anyone suspected of having experienced an MH-like crisis. Evidence Category: C

4. If the clinician suspects an MH-like syndrome, the receiving hospital should be notified (ie, “code blue”) to have an anesthesiologist or another provider with experience in MH available to prepare dantrolene. Evidence Category: C

5. When an MH-like syndrome is suspected, administration of intravenous dantrolene should be considered on the patient's arrival at the hospital.¹ The initial dose of dantrolene is 2.5 mg/kg intravenously, repeated as needed every 10 to 15 minutes to control signs of the crisis. Dantrolene is a relatively benign medication in the normal population but may induce some muscle weakness. Aggressive cooling is also warranted if the patient is hyperthermic. After initial treatment, the patient should be admitted to the intensive care unit for 24 to 36 hours to be monitored for recurrence of an MH-like syndrome.³⁶ Evidence Category: C

Special Considerations for Physically Active Populations

Given the potential associations among MH, EHS, and ER, clinicians who work with physically active populations may implement the following practices to prevent and mitigate the risk of potential MH events.

1. Team physicians should add questions regarding MH to the athlete's preparticipation examination (Table 3). If the evaluation identifies a risk (yes to a previous history of MH, complications with anesthesia, or recurrent EHS or ER), referral to a neuromuscular specialist is encouraged for electromyography and muscle histology testing is encouraged to investigate a differential diagnosis of myopathy. Genetic testing and counseling may also be required. Currently, 5 CHCT testing sites are available in North America (Uniformed Services University of the Health Sciences, University of California-Davis, University of Minnesota, University of Toronto, and Wake Forest University). A complete genetic workup may cost $3000 to $5000, and RYR1 screening is approximately $1000. A commercial laboratory, PreventionGenetics (Marshfield, WI), offers genetic testing for MH and multiple other genetic disorders. The Robert Guthrie Biochemical & Molecular Genetics Laboratory at Buffalo General Hospital (Buffalo, NY) also offers genetic testing for MH and related disorders. Evidence Category: C

2. Create an MH-like syndrome-specific emergency action plan for acute referral of a patient from the field to the hospital. If an MH-like syndrome is suspected, the first responder (eg, athletic trainer, team physician) should notify emergency medical services and the receiving hospital about any previous history of adverse reactions to anesthesia and instruct them to avoid the use of succinylcholine and volatile anesthetics. Additionally, the first responder should prompt the hospital to prepare dantrolene in case of fulminant MH. It should be noted that the lack of a previous history of complications from anesthesia does not eliminate the risk or concern for MH or MH-like episodes. Evidence Category: C

3. Implement measures to address risk factors for EHS and ER. Probable risks for MH-like syndromes can be mitigated by optimizing hydration throughout exercise, providing athletes with heat-acclimatization periods before exercising in the heat for the first time, selecting exercise intensities that are appropriate for each individual, and avoiding physical activities when ill.⁴⁰ Evidence Category: C

4. Return-to-play considerations after an MH-like syndrome. Currently, no evidence-based guidelines exist to direct return-to-play after an MH-like event. The athlete's condition should be discussed with an appropriate consultant to guide a prudent reintroduction to activity, with careful attention to both exercise and environmental acclimatization. The athlete should obtain a medical alert bracelet, and the athletic training staff should be well prepared to implement the emergency action plan. Evidence Category: C

5. Be aware of the potential risk during elective surgeries for injuries. If the family history suggests a risk of MH susceptibility, physicians should be notified to avoid the use of succinylcholine and volatile anesthetics. Severe cases of MH-like syndrome do not always occur at the patient's first exposure to these anesthetic triggers. A genetically susceptible patient may manifest clinical signs at any point in his or her life.²⁹ Evidence Category: C

6. Education for staff and athletes. If an athlete with known MH susceptibility is participating, the clinicians should develop an MH-specific emergency action plan and prepare an on-site cooling plan. Athletes with MH susceptibility should not exercise alone and should notify their medical providers (eg, athletic trainer, team physician) about the condition. Furthermore, clinicians should call the MHAUS 24-hour hotline at 800-644-9737 if they suspect a fulminant MH or MH-like syndrome. Evidence Category: C

Table 3.  Preparticipation Examination Questions Regarding Malignant Hyperthermia

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Future Directions for Research

The clinical implications of MH in physically active populations constitute a critical gap in knowledge for researchers and medical professionals. We identify 3 main future areas of research to fill this gap: (1) evaluation of MH susceptibility in individuals with recurrent EHS or ER episodes of unknown cause, (2) tests to identify individuals with an MH-like syndrome, and (3) standard treatments of MH-like syndromes induced in an exercise-related setting.