TREATMENT

Discontinuation of the trigger may be adequate treatment for acute MH if the onset is slow or if exposure was brief. Dantrolene, the therapeutic mainstay, is packaged in 20-mg bottles with sodium hydroxide for a pH of 9 to 10 (otherwise it will not dissolve) and mannitol (converts the hypotonic solution to isotonic). Dantrolene must be dissolved in sterile water rather than solutions because the extra molecules lead to a salting-out effect and greater difficulty in dissolving it. It may be heated to hasten solution.^[120] In a large adult, as many as 10 bottles may be required. Dantrolene's cardiac effects are complex and include interactions with calcium antagonists (see "Calcium"). Dantrolene has a half-life of at least 10 hours in children and adults.^{[121] [122]} It does not paralyze; peak effects include moderate muscle weakness with adequate strength for deep breathing and coughing. Weakness is accentuated in myopathic patients. Aside from cholestasis during long-term (>3 weeks) therapy, dantrolene has no serious side effects.

Acute therapy for MH can be summarized as follows:

1. Discontinue all anesthetic agents and hyperventilate with 100% oxygen. Normal ventilation is that required to remove metabolic carbon dioxide. With increased aerobic metabolism, normal ventilation must increase. However, carbon dioxide production is also increased because of neutralization of fixed acid by bicarbonate; hyperventilation removes this additional carbon dioxide.
2. Repeat administration of dantrolene (2 mg/kg, every 5 minutes to a total dose of 10 mg/kg, if needed, although doses to 29 mg/kg have been used).^[123]
3. Administer bicarbonate (2 to 4 mEq/kg). Continued efflux of lactate from skeletal muscle may result in recurrent acidosis^[124] because lactate, being ionized, slowly crosses the muscle cell membrane to extracellular fluid.
4. Control fever by iced fluids, surface cooling, cooling of body cavities with sterile iced fluids, and a heat exchanger with a pump oxygenator.^[93] The clinician must not become so preoccupied with cooling and other busy work that he or she neglects the prime factor in therapy: intravenous administration of dantrolene. Cooling should be halted at 38°C to 39°C to prevent inadvertent hypothermia.
5. Monitor urinary output to prevent shock to kidneys or acute tubular necrosis and to examine for myoglobinuria.
6. Further therapy is guided by blood gases, electrolytes, temperature, arrhythmia, muscle tone, and urinary output.
7. Analyze electrolytes; CK concentrations; liver profile; levels of blood urea nitrogen, lactate, and glucose; coagulation studies (e.g., INR, platelet count, prothrombin time, fibrinogen, fibrin-split or degradation products); and serum hemoglobin and myoglobin and urine hemoglobin and myoglobin.

The clinical course determines further therapy and studies. Dantrolene should probably be repeated at least every 10 to 15 hours (its half-life) for several doses.^{[121] [122]} Recrudescence of MH can approach 50%, usually within 6.5 hours.^[123] Treatment of hyperkalemia should be slow. The plasma K⁺ level must be serially monitored because it may be an important factor in treatment (e.g., persistently elevated K⁺ level may prevent defibrillation).^[93] The most effective way to lower serum potassium is reversal of MH by effective doses of dantrolene. Calcium administration is indicated only for related arrhythmias or for poor cardiac function. However, when indicated, calcium and cardiac glycosides may be safely used because their administration to the susceptible pig does not trigger MH.^[52] They can be lifesaving during persistent hyperkalemia.^{[90] [91] [92]}

Permanent neurologic sequelae, such as coma or paralysis, may occur in advanced cases, probably from inadequate cerebral oxygenation and perfusion for the increased metabolism and because of the fever, acidosis, hypo-osmolality with fluid shifts, and potassium release. Even satisfactory care during anesthesia may not prevent neurologic complications. Measurements of intracranial pressure may help in the evaluation of cerebral edema. Disseminated intravascular coagulation or consumptive coagulopathy may be caused by hemolysis, release of tissue thromboplastins, overt tissue damage, or shock. The best treatment is adequate therapy for MH to prevent stagnation of peripheral blood flow and to lower temperature.

Among the ineffective therapeutic adjuncts are calcium antagonists and sympathetic antagonists. Calcium antagonists do not increase porcine survival. ^{[50] [51]} They may interact with dantrolene to produce hyperkalemia, which can result in retriggering MH^[52] or in myocardial depression.^[49] Magnesium reduces the increase in intracellular calcium during porcine MH but does not prevent the increase in metabolism. Although it may play a role in MH mechanisms (see "Pathophysiology and Molecular Biology"),^[38] its therapeutic value appears to be minimal.

Early diagnosis and treatment of MH are essential. Complications are difficult to treat and may lead to serious and permanent sequelae. Retriggering may occur as dantrolene is redistributed or metabolized. The physician should contact the MH Hotline to verify treatment and report the case using an AMRA form.