Malignant Hyperthermia

Educational Objectives

The goal of this program is to improve the diagnosis and management of malignant hyperthermia (MH). After hearing and assimilating this program, the clinician will be better able to:

1. Describe the polygenetic basis of MH.
2. Differentiate the clinical features of MH and other possible diagnoses.
3. Recognize severe masseter muscle rigidity as a strong indicator of MH susceptibility.
4. Identify central core disease as a hereditary condition definitively linked to MH.
5. Maintain vigilance in MH-susceptible patients even with safe anesthetic techniques.

Summary

Malignant hyperthermia (MH): was first described in 1900 as a febrile reaction to anesthesia; in 1929, the French named it Ombrédanne syndrome and accurately described the condition; by 1960, MH was identified as a familial disease with a mortality rate of 70% to 90%; in 1966, the full syndrome was described, with mortality still ≤60%; a major breakthrough came in 1979 with the discovery that dantrolene, previously used for muscle spasms, was effective in treating MH, reducing mortality to 10%

Genetics: MH follows an autosomal dominant inheritance pattern with variable penetrance, ie, it runs in families but lacks a predictable pattern; a defect in the ryanodine receptor on chromosome 19 was identified as a possible cause, as seen in MH-susceptible swine used for research; however, ≤70% of MH families do not have this chromosome 19 mutation, indicating a polygenetic basis; additionally, ≤50% of MH-susceptible individuals lack known pathogenic gene variants, making MH a complex, multifactorial genetic condition

Pathophysiology: MH is a skeletal muscle abnormality, potentially involving cardiac muscle; it is marked by a massive increase in intracellular calcium, though the exact cause (excess release, impaired reuptake, mitochondrial dysfunction, or membrane fragility) is unclear; this excess calcium triggers continuous muscle contraction, consuming adenosine triphosphate and generating heat, carbon dioxide (CO₂), and water; as oxygen demand rises, aerobic metabolism shifts to anaerobic, producing lactic acid and worsening acidosis; blood is shunted to muscles, reducing skin perfusion, causing core temperature to rise while skin may feel cool; increased oxygen consumption causes venous desaturation, leading to respiratory and metabolic acidosis; acidosis and increased water in the cells lead to muscle swelling and rhabdomyolysis, releasing potassium and calcium into the extracellular fluid (ECF); a rapid rise in potassium in the ECF can cause hyperkalemic cardiac arrest; the released potassium is eventually excreted by the kidneys, leading to depletion of total body potassium and calcium; elevated serum calcium and shunting of blood to the muscle can cause vasospasm, which can cause peripheral cyanosis, even with normal blood oxygen levels; blood flow to the kidneys also decreases, which, combined with myoglobinuria, can lead to renal toxicity; MH affects the heart by causing electrolyte imbalances, leading to tachycardia, ventricular fibrillation, congestive heart failure, and pulmonary edema; these may result from hypoxia, acidosis, hyperthermia, or an underlying cardiomyopathy; MH can also cause brain edema and congestion, which can lead to brain death if not treated in time

Masseter muscle rigidity (MMR): MMR after succinylcholine (SCh) administration is an early sign of MH; the chest and diaphragm relax normally, so bag ventilation is possible, but intubation is not possible because the jaw cannot be forced open; early studies found 65% to 80% of patients who experience MMR are susceptible to MH; MMR can also occur with myotonic dystrophy and Duchenne muscular dystrophy; MMR ranges from mild stiffness (common and not concerning) to severe rigidity (strongly indicates MH susceptibility); mild cases require no intervention, while moderate cases necessitate avoiding volatile agents and any additional SCh, checking creatine phosphokinase (CPK), checking urine for myoglobin, and possibly overnight observation; severe cases, where the jaw cannot be opened, require aborting elective surgery, monitoring of CPK, urine, and arterial blood gas, and likely placement of an arterial cannula; a CPK level >20,000 μg/L confirms MH without needing a muscle biopsy; if any signs of MH develop, treat with dantrolene at an initial dose of 2.5 mg/kg, and counsel the patient for muscle biopsy

Other signs of MH: tachycardia and tachypnea are always early signs; respiratory acidosis and rising end-tidal CO₂ despite adequate ventilation is very suspicious; blood pressure instability is also common, initially presenting as hypertension because of increased cardiac output and vasospasm, followed by hypotension as the heart’s reserves deplete; metabolic acidosis from anaerobic metabolism is another key indicator, often appearing before fever; cyanosis may occur despite normal partial pressure of oxygen, along with hyperkalemia, hypercalcemia, and cardiac arrhythmias; fever is a late sign, and waiting for it to diagnose MH can be dangerous; as MH progresses, coagulopathy and disseminated intravascular coagulation (DIC) may develop, followed by myoglobinuria and decreased renal blood flow, leading to potential kidney failure; if untreated, multiorgan failure involving the heart, kidneys, brain, and liver occurs, marking the final stage of the condition

Primary triggers of MH: include SCh and all volatile anesthetic agents, including desflurane, sevoflurane, and isoflurane; local anesthetics, including esters and amides, are not triggers; non-drug-related triggers include intense exercise, stress, heat exposure, hypoxia, systemic infections, trauma, carbon tetrachloride, caffeine, ethanol, calcium salts, and quinidine; MH onset can have a latency period, making diagnosis challenging; among volatile agents, halothane (historically used) had the fastest onset, while desflurane has the slowest; SCh after volatile exposure accelerates onset and increases severity; MH can still occur even after prolonged anesthetic exposure, with cases reported ≤8 hr into isoflurane anesthesia; always maintain a high index of suspicion for MH

Differential diagnosis (DD): includes several conditions with similar presentations; neuroleptic malignant syndrome, triggered by major tranquilizers, eg, haloperidol and chlorpromazine, involves central nervous system dysfunction rather than muscle pathology but responds to dantrolene; serotonin syndrome, triggered by monoamine oxidase inhibitors, meperidine (Demerol), amphetamines, and cocaine, presents similarly but is distinct; other DDs include central hyperthermia from hypothalamic dysfunction, heat stroke, endocrine disorders (eg, thyrotoxicosis, pheochromocytoma), and systemic infections or sepsis; some rare hereditary conditions, eg, central core disease and King-Denborough syndrome, are definitively linked to MH, while others (eg, Duchenne and Becker muscular dystrophy, myotonia congenita, osteogenesis imperfecta) have possible associations; conditions once thought to be linked, including frequent muscle cramps, strabismus, elevated serum CPKs, and postoperative myoglobinuria, are now considered unrelated

Management: requires immediate action; the first step is stopping the trigger agents, eg, inhalation anesthetics and SCh, and calling for help; minute ventilation should be increased to control rising end-tidal CO₂, and, if possible, the anesthesia machine should be changed to remove volatile agents; the primary treatment is intravenous (IV) dantrolene 2 to 3 mg/kg, repeated every 5 to 10 min up to 10 mg/kg, or more if symptoms persist; dantrolene works by inhibiting calcium release from the sarcoplasmic reticulum, halting the MH crisis at its source; it also lowers serum potassium and typically takes effect within 5 to 20 min; an arterial line is recommended for frequent blood gas monitoring; dantrolene is available in different forms; the original formulation (Dantrium) contains 3 g of mannitol in every bottle; some newer dantrolene formulations contain mannitol and some do not; read the label; if the available dantrolene formulation does not contain mannitol, consider administering mannitol in addition because of its effect on the kidneys; Dantrium and generic dantrolene come in 20-mg vials that must be mixed with 60 mL of sterile water, which is time-consuming, making assistance necessary; a newer formulation, Revonto, also comes in 20-mg vials but is more soluble in water and easier to mix; another newer formulation, Ryanodex, is much more concentrated, so only 1 vial is needed for an average-size patient instead of 10, and only 5 mL of saline is required for mixing; however, Ryanodex is significantly more expensive and has a shorter shelf life

Adverse effects: dantrolene’s key adverse effect is muscle weakness (can delay extubation), along with nausea, vomiting, lethargy, phlebitis, cardiac collapse (especially with calcium blockers), uterine atony, and potentiation of nondepolarizing muscle relaxants; it also crosses the placenta

Cooling measures: in addition to administering dantrolene, initiate cooling measures, including external methods (eg, ice baths, convective cooling) and internal options (eg, body cavity, rectal, or bladder lavage); cold IV fluids should be given, but without potassium initially because of muscle breakdown-related hyperkalemia; cardiopulmonary bypass may be necessary in severe cases; overcooling to below 38°C to 39°C should be avoided; acidosis should be corrected by monitoring blood gases and administering sodium bicarbonate (2-4 mg/kg IV) within 20 min if no immediate blood gas is available; try to maintain pH in the normal range; hyperkalemia should be managed with insulin and glucose, anticipating later hypokalemia; kidney function must be preserved through adequate urine output, supported by fluids, furosemide (eg, Furoscix, Diaqua-2, Lasix), or mannitol; tachydysrhythmias can be treated with short-acting β-blockers (eg, esmolol) or procainamide, but calcium channel blockers should be avoided; if cerebral or muscle edema is suspected, steroids (eg, 2-4 g hydrocortisone) may be administered; dantrolene therapy should continue at 1 to 2 mg/kg IV every 4 hr, transitioning to an oral dose of 1 mg/kg every 4 to 8 hr for 2 days to ensure the MH process is fully reversed

Recurrence: MH can recur ≤36 hr after the initial episode, often preceded by a “smoldering” phase; this phase is marked by persistent hyperkalemia, residual muscle rigidity, high fluid requirements, oliguria or anuria, and DIC; smoldering MH also involves altered membrane permeability, leading to significant fluid shifts, total body edema, and weight gain because of extracellular fluid accumulation

Diagnosis of MH susceptibility: begins with family history and a resting CPK test, as elevated levels (≤10 times normal) are found in 70% of MH-positive individuals; if a first-degree relative of a confirmed MH patient has significantly elevated CPK, they are considered positive without needing further testing; if CPK is normal (<400 μg/L) on 3 separate tests in a person suspected of MH susceptibility, a muscle biopsy using the caffeine-halothane contracture test is required; this test, performed at a limited number of centers, is the gold standard with 99% sensitivity and 78% specificity; indications for testing include suggestive MH episodes, persistent unexplained elevated CPK, muscle cramps, or a first-degree relative with confirmed MH; the test involves triggering a muscle sample with caffeine and halothane to measure contractile response

Anesthesia for patients susceptible to MH: dantrolene prophylaxis is debated, with some recommending a single preoperative dose of 2.5 mg/kg IV 30 to 60 min before induction, while others rely on avoiding triggering agents; the speaker’s preference is to administer a single dose of dantrolene prophylaxis for a long or stressful surgery but not for minor surgery; safe anesthetic management involves avoiding triggering agents, moderate to heavy premedication to reduce stress, and using regional anesthesia with sedation when appropriate; if general anesthesia is required, use a clean anesthesia machine that has been flushed for ≥2 hr; use a balanced anesthetic; nitrous oxide, narcotics, propofol, barbiturates, and nondepolarizing muscle relaxants are all safe to use; closely monitor end-tidal CO₂, heart rate, and core temperature; consider an arterial cannula; avoid stress and maintain deep anesthesia; postoperatively, patients should be observed for ≥4 hr, with further monitoring of arterial blood gases, serial CPK levels, and urine myoglobin if any suspicious signs appear; overnight observation is recommended if abnormalities are detected

For reliable information and emergency support: the Malignant Hyperthermia Association of the United States (MHAUS) is a valuable resource; their website (www.mhaus.org) offers in-service videos, free brochures, and checklists for operating and recovery rooms, including a wallet-sized version; they also provide a 24-hr emergency hotline (800-644-9737), connecting callers to MH experts in real time; additionally, MHAUS publishes “The Communicator”, an online journal available for >30 yr

MH kit: maintaining an MH kit or “tackle box” is essential, stocked with ≥36 vials of dantrolene (or its alternatives), sterile water, sodium bicarbonate, mannitol, procainamide, and other necessary medications in large quantities to manage an MH crisis effectively

Recent updates in MH: triggering agents are now limited to SCh, volatile anesthetics, and stress; the incidence remains rare, occurring in ≈1 in 100,000 adult surgeries and 1 in 30,000 pediatric cases, with a higher likelihood in undiagnosed children; in MH-susceptible patients, even with safe anesthetics, the risk is 1 in 2000, emphasizing the need for vigilance; the caffeine-halothane muscle biopsy remains the gold standard for diagnosis, though its availability is limited to a small number of centers; dantrolene prophylaxis is optional but should be considered alongside a safe anesthetic technique and ≥4 hr postoperative observation; early and aggressive treatment is key, with dantrolene dosing up to 20 mg/kg

Readings

Gong X. Malignant hyperthermia when dantrolene is not readily available. BMC Anesthesiol. 2021;21(1):119. Published 2021 Apr 16. doi:10.1186/s12871-021-01328-3; Gregory H, Weant KA. Pathophysiology and treatment of malignant hyperthermia. Adv Emerg Nurs J. 2021;43(2):102-110. doi:10.1097/TME.0000000000000344; Hopkins PM, Girard T, Dalay S, et al. Malignant hyperthermia 2020: guideline from the Association of Anaesthetists. Anaesthesia. 2021;76(5):655-664. doi:10.1111/anae.15317; Hudig K, Pollock N, Bulger T, et al. Masseter muscle rigidity and the role of DNA analysis to confirm malignant hyperthermia susceptibility. Anaesth Intensive Care. 2019;47(1):60-68. doi:10.1177/0310057X18811816; Kaur H, Katyal N, Yelam A, et al. Malignant hyperthermia. Mo Med. 2019;116(2):154-159; Miller DM, Daly C, Aboelsaod EM, et al. Genetic epidemiology of malignant hyperthermia in the UK. Br J Anaesth. 2018;121(4):944-952. doi:10.1016/j.bja.2018.06.028; Neshati M, Azadeh M, Neshati P, et al. Malignant hyperthermia: report of two cases with a neglected complication in cardiac surgery. J Tehran Heart Cent. 2017;12(4):175-183.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. Barker has been a consultant at Masimo Corporation. Members of the planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Barker was recorded exclusively for Audio Digest. Audio Digest thanks Dr. Barker for his cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.75 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.75 CE contact hours.

Lecture ID:

AN671701

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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