Residency · Residency · Anesthesiology
Malignant Hyperthermia: Recognition and Dantrolene Protocol
Introduction
Malignant hyperthermia (MH) is a rare, life-threatening pharmacogenetic disorder of skeletal muscle triggered by volatile anesthetic agents and succinylcholine. Untreated, mortality exceeds 70%. With early recognition and dantrolene administration, mortality has decreased to less than 5%. Every anesthesiology resident must be able to recognize MH and execute the treatment protocol without hesitation.
Pathophysiology
The Molecular Defect
MH results from uncontrolled release of calcium from the sarcoplasmic reticulum via the ryanodine receptor (RyR1). RyR1 gene mutations on chromosome 19q13.1 account for approximately 70% of MH-susceptible families. Additional mutations in the CACNA1S gene (dihydropyridine receptor, DHPR) and the STAC3 gene account for some remaining cases. Inheritance follows an autosomal dominant pattern with variable penetrance and expressivity. Prevalence is estimated at 1 in 5,000 to 100,000 anesthetics, though genetic susceptibility may be as high as 1 in 2,000.
Cascade of Events
The triggering agent activates the abnormal RyR1 channel, causing massive, sustained calcium release into the myoplasm. Sustained muscle contraction and hypermetabolism follow, with increased oxygen consumption, increased carbon dioxide production, and heat generation. ATP depletion leads to loss of cellular membrane integrity, rhabdomyolysis, and hyperkalemia. Metabolic and respiratory acidosis, hyperthermia, and multiorgan failure develop if the condition is left untreated.
Triggering Agents
Known Triggers
All volatile anesthetic agents are triggers, including sevoflurane, desflurane, isoflurane, halothane, and enflurane. Succinylcholine can trigger MH alone or potentiate a volatile agent-triggered crisis. The combination of succinylcholine with a volatile agent represents the highest-risk scenario.
Safe Agents
Nitrous oxide is safe. All intravenous anesthetics are safe, including propofol, ketamine, etomidate, and barbiturates. All opioids (fentanyl, morphine, remifentanil, and others), all benzodiazepines (midazolam, diazepam), and all non-depolarizing neuromuscular blocking agents (rocuronium, vecuronium, cisatracurium, and others) are safe. All local anesthetics are safe, having been previously controversial but now confirmed. Dexmedetomidine is also safe.
| Category | Triggering Agents | Safe Agents |
|---|---|---|
| Volatile anesthetics | Sevoflurane, desflurane, isoflurane, halothane, enflurane | N2O (safe) |
| NMBAs | Succinylcholine | All non-depolarizing agents (rocuronium, vecuronium, cisatracurium) |
| IV induction agents | None | Propofol, ketamine, etomidate, barbiturates |
| Opioids | None | All (fentanyl, morphine, remifentanil, etc.) |
| Sedatives | None | All benzodiazepines, dexmedetomidine |
| Local anesthetics | None | All (previously controversial; now confirmed safe) |
| Dantrolene Formulation | Dantrium / Revonto | Ryanodex |
|---|---|---|
| Dose per vial | 20 mg | 250 mg |
| Reconstitution volume | 60 mL sterile water per vial | 5 mL sterile water per vial |
| Vials for 2.5 mg/kg (70 kg) | ~9 vials | 1 vial |
| Preparation time | Time-consuming (multiple vials) | Rapid |
| Stock requirement | 36 vials minimum | 3 vials minimum |
Clinical Presentation
Early Signs
A rapidly rising EtCO2 that is disproportionate to ventilation and unresponsive to increased minute ventilation is often the earliest and most sensitive sign. Masseter muscle rigidity (MMR) after succinylcholine presents as jaw tightness that makes intubation difficult and may be an early warning of MH susceptibility. Unexplained tachycardia, often sinus tachycardia or ventricular arrhythmias, is common. Mixed respiratory and metabolic acidosis develops. Tachypnea may be observed in spontaneously breathing patients.
Late Signs
Hyperthermia with temperature rising 1 to 2 degrees Celsius every 5 minutes, potentially exceeding 43 degrees Celsius, is a characteristic but often late sign; treatment should not be delayed while waiting for fever to develop. Generalized skeletal muscle rigidity occurs. Hyperkalemia from rhabdomyolysis can cause lethal cardiac arrhythmias. Rhabdomyolysis produces elevated CK that may exceed 100,000 IU/L and myoglobinuria with dark "cola-colored" urine. Disseminated intravascular coagulation (DIC) and acute renal failure from myoglobin deposition may follow. Cardiac arrest can result from hyperkalemia, acidosis, or hyperthermia.
MH Clinical Grading Scale
The Clinical Grading Scale (CGS) assigns points based on signs and laboratory findings to estimate the likelihood that an event is MH. A score of 50 or higher indicates "almost certain" MH. The scale is useful for retrospective classification and research.
Immediate Management: The Dantrolene Protocol
Step-by-Step Treatment
The first step is to discontinue all triggering agents immediately by turning off vaporizers and removing them from the machine if possible. The patient is then hyperventilated with 100% oxygen at high fresh gas flows of 10 L/min or greater to wash out the volatile agent and manage hypercarbia. It is not necessary to change the anesthesia machine or circuit if high flows are used. Help is called because MH requires a team response, and roles should be designated.
Dantrolene is then administered. Dantrolene sodium (Dantrium/Revonto) comes in 20 mg vials, each requiring 60 mL of sterile water for reconstitution, which is time-consuming. Ryanodex is a lyophilized formulation with 250 mg per vial reconstituted in only 5 mL of sterile water, making it significantly faster to prepare. The initial dose is 2.5 mg/kg IV bolus, repeated every 5 minutes until signs resolve (tachycardia, hypercarbia, rigidity). There is no maximum dose; some patients require 10 mg/kg or more, though the average effective dose is 2.5 to 5 mg/kg. The surgeon should be notified and the surgery concluded as soon as possible.
Concurrent Treatments
Hyperkalemia is treated with calcium chloride 10 mg/kg IV or calcium gluconate 30 mg/kg IV, sodium bicarbonate 1 to 2 mEq/kg IV, regular insulin 0.1 units/kg IV with dextrose 0.5 g/kg IV, and hyperventilation. Calcium channel blockers must never be used because a lethal interaction with dantrolene causes hyperkalemia and cardiovascular collapse.
Active cooling involves cold IV saline (not run through a blood warmer), ice packs to the axillae, groin, and neck, and lavage of body cavities with cold saline if open. The target temperature is 38 degrees Celsius, and cooling should be stopped to avoid hypothermia overshoot. Arrhythmias are treated with amiodarone for ventricular arrhythmias after correcting hyperkalemia first. Urine output should be maintained above 2 mL/kg/hr with aggressive IV fluids and mannitol (already present in the dantrolene preparation), with furosemide considered as needed. Monitoring includes an arterial line, central venous catheter, Foley catheter, and core temperature. Serial labs including ABG, potassium, calcium, CK, myoglobin, coagulation studies, and lactate are checked frequently.
Post-Crisis Management
Transfer to the ICU for a minimum of 24 hours of monitoring is required. Recrudescence occurs in approximately 25% of cases, with recurrence of signs hours after initial control. Dantrolene is continued at 1 mg/kg IV every 4 to 6 hours for at least 24 to 48 hours. CK levels are monitored serially (peak at 12 to 24 hours), and levels exceeding 10,000 IU/L indicate significant rhabdomyolysis. Aggressive hydration and urine alkalinization are maintained to prevent myoglobin-induced renal failure. DIC is monitored with PT, PTT, fibrinogen, D-dimer, and platelet count.
Susceptibility Testing and Future Anesthetics
Caffeine-Halothane Contracture Test (CHCT)
The CHCT is the gold standard diagnostic test for MH susceptibility. It requires an open muscle biopsy, typically from the vastus lateralis. Muscle strips are exposed to incremental concentrations of caffeine and halothane, and contracture at specific thresholds indicates susceptibility. This test is available only at designated MH testing centers.
Genetic Testing
RyR1 gene sequencing can identify known pathogenic variants. A positive genetic test confirms susceptibility, but a negative test does not exclude it because many variants are of uncertain significance and not all causative mutations are known. Genetic testing is recommended for family members of confirmed MH-susceptible individuals.
Safe Anesthesia for MH-Susceptible Patients
A trigger-free technique is used with TIVA employing propofol, opioids, and non-depolarizing NMBAs. The anesthesia machine does not need to be specially prepared if volatile agents are not used, as modern guidelines have simplified this. However, if an abundance of caution is desired, the machine can be flushed with oxygen at 10 L/min for 20 to 90 minutes (depending on the machine) with new circuits. Dantrolene must be immediately available (36 vials of Dantrium or 1 to 2 vials of Ryanodex). EtCO2 and core temperature are monitored throughout.
Key Clinical Pearls
Rapidly rising EtCO2 refractory to increased minute ventilation is the earliest and most reliable sign of MH; treatment should not be delayed until hyperthermia develops. There is no maximum dose of dantrolene, and dosing should continue until the crisis resolves; under-dosing is a far greater risk than over-dosing. Calcium channel blockers must never be administered to a patient receiving dantrolene because this combination causes fatal hyperkalemia and cardiovascular collapse. The MHAUS Hotline (1-800-644-9737) should be contacted for real-time expert guidance during any suspected MH crisis.
References
- Rosenberg H, Pollock N, Schiemann A, Bulger T, Stowell K. Malignant hyperthermia: a review. Orphanet J Rare Dis. 2015;10:93.
- Malignant Hyperthermia Association of the United States (MHAUS). Emergency therapy for malignant hyperthermia. https://www.mhaus.org. Updated 2023.
- Hopkins PM, Ruffert H, Snoeck MM, et al. European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility. Br J Anaesth. 2015;115(4):531-539.
- Larach MG, Gronert GA, Allen GC, Brandom BW, Lehman EB. Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006. Anesth Analg. 2010;110(2):498-507.