46: Malignant Hyperthermia and Other Motor Diseases

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CHAPTER 46 Malignant Hyperthermia and Other Motor Diseases

James Duke, MD, MBA

1 What is malignant hyperthermia and its underlying defect?

Malignant hyperthermia (MH) is a myopathy characterized by an uncontrolled increase in skeletal muscle metabolism after exposure to a triggering agent. Patients with MH have an uncontrolled release of calcium from the sarcoplasmic reticulum caused by an abnormal ryanodine receptor (RyR1) isoform, a protein crucial for the release of calcium during normal excitation-contraction coupling. RyR1 mutations on chromosome 19 are found in 25% of known MH-susceptible individuals in North America. There are also associations between MH and another protein associated with the calcium channel, the dihydropyridine receptor. The gene for this protein is located on chromosome 7. Other RyR1 mutations are noted in other countries.

2 What are the inheritance pattern and triggering agents for malignant hyperthermia?

MH is inherited as an autosomal-dominant disorder with reduced penetrance and variable expressivity. Succinylcholine and the halogenated inhalational agents may precipitate an episode in a susceptible patient. MH is rare in infants and decreases after 50 years of age.

3 Describe the cellular events, presentation, and metabolic abnormalities associated with malignant hyperthermia

Hypermetabolism of skeletal muscle leads to hydrolysis of adenosine triphosphate, glycolysis, glycogenolysis, uncoupled oxidative phosphorylation, increase in oxygen consumption, and heat production. The earliest symptom is often unexplained tachycardia. The sine qua non of MH is an unexplained rise in end-tidal CO2. Patients may demonstrate peculiar rigidity, even after nondepolarizing relaxants have been administered. If untreated, the patient develops numerous metabolic abnormalities, including metabolic acidosis, respiratory acidosis, hypoxemia, hyperthermia, rhabdomyolysis, hyperkalemia, hypercalcemia, hyperphosphatemia, elevations in creatine kinase, myoglobinuria, acute renal failure, cardiac dysrhythmias, and disseminated intravascular coagulation. Death is common if the problem is unrecognized and untreated. Data from the North American Malignant Hyperthermia Registry (NAMHR) have determined a rate of cardiac arrest of 2.7% and of death 1.4%. Interestingy, although the malady is called MH, temperature increase is a relatively late manifestation.

4 How is malignant hyperthermia treated?

image Call for assistance because aggressive therapy requires more than one person.
image Turn off all triggering agents and hyperventilate the patient with 100% oxygen.
image Change to a non-triggering anesthetic such as propofol infusion.
image Notify the surgeon and operating-room personnel of the situation at hand and expedite conclusion of the procedure, even if it may require that surgery go unfinished.
image Administer dantrolene, 2 mg/kg; repeat every 5 minutes to a total dosage of 10 mg/kg if needed. Dantrolene sodium inhibits calcium release via RyR1 antagonism.
image Monitor blood gases. Administer bicarbonate, 2 to 4 mEq/kg for a pH < 7.1.
image Cool the patient, using interventions such as iced fluids and cooling blankets, but become less aggressive in reducing body temperature at about 38° C.
image Promote urine output (2 ml/kg/hr), principally with aggressive fluid therapy, although mannitol and furosemide may also be required.
image Treat hyperkalemia with calcium chloride, bicarbonate, and insulin.
image Check for hypoglycemia and administer dextrose, particularly if insulin has been administered.
image Treat dysrhythmias with procainamide and calcium chloride, 2 to 5 mg/kg intravenously (calcium chloride is used to treat the hyperkalemia-associated dysrhythmias).

5 How does dantrolene work? How is dantrolene prepared?

Dantrolene impairs calcium-dependent muscle contraction. This rapidly halts the increases in metabolism and secondarily results in a return to normal levels of catecholamines and potassium. The solution is prepared by mixing 20 mg of dantrolene with 3 g of mannitol in 60 ml of sterile water. Since dantrolene is relatively insoluble, preparation is tedious and time consuming, and its preparation should not be the responsibility of the primary anesthesiologist involved in the patient’s management.

6 How is malignant hyperthermia susceptibility assessed in an individual with a positive family history or prior suggestive event?

The diagnosis of MH is immensely difficult. There are clinical grading scales that have been used to help determine how likely a suspected episode is a true MH episode. The gold standard for diagnosis is the caffeine-halothane contracture test (CHCT). The patient’s muscle is exposed to incremental doses of halothane and caffeine, and the muscle is evaluated for the degree of contracture. The test is offered at only five centers in the United States and two in Canada. The test is 85% to 90% specific and 99% to 100% sensitive. It is important that patients who have experienced MH episodes undergo further evaluation because some of these patients will be found to be MH negative.

Genetic testing for the abnormal RyR1 isoform is now available in the United States and other selected countries. The role for genetic testing is expanding. It is much cheaper than muscle biopsy and CHCT and can be performed on children too young to have CHCT (less than 10 years of age or less than 40 kg). Genetic testing is especially valuable in homogeneous populations in whom the genetic defect is constant. However, if genetic testing is negative in a susceptible individual, a CHCT must be performed.

7 What are the indications for muscle biopsy and halothane-caffeine contracture testing?

image Definite indications: Suspicious clinical history for MH, family history of MH, prior episode of masseter muscle rigidity
image Possible indications: Unexplained rhabdomyolysis during or after surgery, sudden cardiac arrest caused by hyperkalemia, exercise-induced hyperkalemia, moderate-to-mild masseter muscle rigidity with evidence of rhabdomyolysis
image Probably not indications: Diagnosis of neuroleptic malignant syndrome or sudden unexplained cardiac arrest during anesthesia or early postoperative period not associated with rhabdomyolysis

8 What is masseter muscle rigidity and what is its relation to malignant hypothermia?

Masseter muscle rigidity (MMR) is defined as jaw muscle tightness with limb muscle flaccidity following a dose of succinylcholine. There is a spectrum of masseter response, from a tight jaw to a rigid jaw to severe spasticity, or trismus, otherwise described as jaws of steel

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