Malignant Hyperthermia, Dantrolene, and the Pharmacist

Volatile anesthetic agents and succinylcholine can trigger malignant hyperthermia (MH), which affects skeletal muscle calcium channel homeostasis and can create a hypermetabolic response. It is a pharmacogenetic disorder that can result in a rare anesthetic emergency. MH is estimated to occur between 1 in 10,000 cases and 1 in 150,000 cases during general anesthetics, but clinicians have noted that this rate may be an underestimate. On average, individuals may undergo anesthesia up to 3 times before developing a fulminant MH reaction, with the prevalence of genetic abnormalities being 1 in every 400 people.^1-3

Early recognition is crucial, as MH can be fatal. Manifestations can occur within 10 minutes of exposure, with variable timing of reactions. Reactions are not typically reported after 1 hour of discontinuing volatile agents. The highest number of reported incidents occur in males and pediatric populations. Yet, all populations require monitoring during anesthesia and the early postoperative period.

Upon clinical presentation, a 3-pronged approach should be taken to reverse the MH reaction. For the first step, the clinician should eliminate the triggering agent. Next, the clinician should give intravenous dantrolene. Lastly, active body cooling should occur.^1,2

Upon clinical presentation, a 3-pronged approach should be taken to reverse the MH reaction. Image Credit: © LIGHTFIELD STUDIOS - stock.adobe.com

The activation of muscle contraction occurs with exposure to anesthetic agents at the ryanodine receptor isoform 1 (RYR1). At this juncture, an excitation-contraction coupling triggers an abrupt membrane depolarization. As an efflux of calcium ions flow from the sarcoplasmic reticulum into the myoplasm, ATP demand is exacerbated, and muscle rigidity follows as the energy used for muscle contractibility is inefficient at 30% to 60%.^2,3

Core temperature increases by 1 to 2 degrees every 5 minutes, producing hyperthermia using rapid consumption of ATP stores. The hypermetabolic reaction proceeds into respiratory and metabolic acidosis as oxygen consumption and carbon dioxide production increase. If untreated, the stressors on the membrane result in acute sequelae, leading to widespread organ dysfunction from skeletal muscle breakdown and ensuing myocyte death.^2-4

Dantrolene is the only available medication that is effective in treating MH syndrome. The drug works as a direct-acting skeletal muscle relaxant decoupling excitation-contraction at the RYR1 site, resulting in diminished muscle contraction without an effect on the action potential. Dantrolene is an efficient and potent MH antidote in the acute phase of treatment whenever general anesthesia is administered.⁴

Dantrolene is highly lipophilic and dissolves poorly in water. Each vial is dissolved in 60 ml of sterile water containing 20 mg of lyophilized dantrolene and 3 g of mannitol (improving solubility). Reconstitution may require 5 minutes of vigorous shaking, with all preparations used within 6 hours. From a practical viewpoint, each syringe should be administered as the solution appears clear and without particles into a large vein or fast-running infusion. The solution is highly alkaline and irritable to peripheral veins with a pH of 9.5; continuous infusion is not recommended as it contributes to phlebitis, which occurs in 10% of the population.^1,2,4

During the acute response, there should be immediate withdrawal of all trigger agents, hyperventilation, and rapid administration of dantrolene. Dantrolene therapy is initiated at 2.5 mg/kg boluses and repeated in 5-minute intervals until normalization of the hypermetabolic state. If resolution does not occur following a cumulative dose of 10 mg/kg, it may indicate a differential diagnosis. Greater emphasis should be placed on cooling as dantrolene may not be effective in severe muscle necrosis.³

The 2.5 mg/kg bolus was determined based on pharmacokinetic studies. Dantrolene’s disposition was comparable in children and adults, with dosing based on actual body weight. Most lipophilic drugs require a loading dose. However, actual body weight is recommended, as there have been no studies in the obese population. An average dose of 2.4 mg/kg was established in healthy populations to achieve the plasma concentrations needed to obtund skeletal muscle in preparation for in vitro twitch responses; plasma concentrations of 4.2 ug/ml remained therapeutic 5 hours after administration, blocking up to 75% of muscle contractions.^2,4

In over 80% of MH reactions, there is a subsequent occurrence of sinus tachycardia, arrhythmias, and unstable blood pressure. Relevant anti-arrhythmic agents in acute crisis treatment include amiodarone, a short-acting beta-blocker, or magnesium.

Administration of calcium channel blockers with dantrolene should be avoided as they can interact to produce profound hypotension and hyperkalemia. Because hyperkalemia can arise due to the hypermetabolic response, sodium bicarbonate, glucose, and insulin can be used. However, evidence suggests caution should be used with calcium chloride, as an extracellular calcium influx contributes to myoplasm's calcium overload.^2,3

Reoccurrence of this hypermetabolic state appears in up to 25% of patients in the first 48 to 72 hours in the post-reaction phase. Notably, prophylactic dosing is not recommended due to muscle weakness and nausea. If required, a further bolus of dantrolene is determined by the reaction time: 2.5 mg/kg if greater than 6 hours, or 1 mg/kg every 6 hours (if within 6 hours) for at least 24 hours or clinically indicated.^1-3

Mortality in MH has been reduced from 80% in the 1960s to less than 10% today, thanks to the progress in understanding the clinical manifestation of the syndrome. The Malignant Hyperthermia Association of the United States should be available whenever general anesthesia is administered.

REFERENCES

1. Rosenberg H, Pollock N, Schiemann A, Bulger T, Stowell K. Malignant hyperthermia: a review. Orphanet J Rare Dis. 2015;10:93. doi:10.1186/s13023-015-0310-1
2. Hopkins PM, Girard T, Dalay S, et al. Malignant hyperthermia 2020: Guideline from the Association of Anaesthetists. Anesthesia. 2021;76(5):655-664. doi:10.1111/anae.15317
3. Riazi S, Kraeva N, Hopkins PM. Updated guide for the management of malignant hyperthermia. Can J Anaesth. 2018;65(6):709-721. doi:10.1007/s12630-018-1108-0
4. Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F. Dantrolene--a review of its pharmacology, therapeutic use and new developments. Anaesthesia. 2004;59(4):364-373. doi:10.1111/j.1365-2044.2004.03658.x