Malignant Hyperthermia Part I

Hazardous material (HAZMAT) teams are community resources that maintain constant vigilance against toxic contamination of the environment. Each HAZMAT team maintains training and readiness for the rarest and worst of all toxic contamination accidents ,a nuclear reactor meltdown, even though it is extremely rare. Likewise, perfusionists should also maintain their readiness to deal with a catastrophic medical meltdown known as malignant hyperthermia (MH) and its variants.

MH was first described in 1960 as a life-threatening, hypermetabolic condition, usually triggered by the use of volatile anesthetics (excepting nitrous oxide) or the use of depolarizing muscle relaxants. Physiologically, MH interferes with ionized calcium re-entry into the sarcoplasmic reticulum after a muscle contraction.

Other things that have been implicated in MH precipitation include cresol (a preservative for insulin) and persistently elevated serum creatine kinase (CK) levels (often indicative of an occult myotonia). Patients susceptible to MH carry heterogeneous, autosomal dominant genes for sensitivity to MH. Therefore, a family history of MH is a vital screening tool. Patients with various myotonias caused by things such as Duchenne’s muscular dystrophy, osteogenesis imperfecta and central core disease are at greater risk for MH. MH is more common in the Midwestern United States and its incidence is higher in children (1:12,000 general anesthetics) than adults (1 :40,000). The most common age range for MH is 3-30 years old. However, it has been reported in children 3 months old and the elderly. In children, it is most commonly associated with Ear, Nose and Throat surgical procedures. Untreated MH carries a mortality as high as 70%, but if diagnosed swiftly and correct treatment is applied, the mortality is less than 10%. MH has also been reported after cardiopulmonary bypass on several occasions.

The standard test for the determination of susceptibility to MH is the caffeine-halothane-contracture test. This test is invasive, costly and is performed at only a limited number of medical centers throughout the United States. As a result, this test is not practical for routine screening of large numbers of at-risk patients. CK is released during MH; however this is not a good screening tool in the perioperative period because the trauma of the surgery itself may also increase the CK.

Symptoms include skeletal muscle rigidity (particularly masseter muscle rigidity), hypermetabolism, hypercapnia, increased end-tidal C02, hypertension, tachypnea, tachycardia, rhabdomyolysis, elevated body temperature (as high as 43.3 C / 110 F), cardiac arrest and death. Upon analysis blood gases will demonstrate an acidosis and a large base deficit. Venous blood gases are preferable to arterial blood gases since the elevated blood pC02 may be normalized upon passage through hyperventilated lungs. In children, there is a 50% concordance between masseter muscle rigidity and MH, especially if a depolarizing muscle relaxant is used. Elevated body temperature is often a late sign of the condition and may not develop at all.

The most dangerous aspect of MH is rhabdomyolysis which is the breakdown of skeletal muscle cells. In extreme cases, this can result in the release of massive amounts of potassium and myoglobin into the general circulation. The elevated potassium (sometimes over 10 mEq/L) causes cardiac fibrillation and finally asystole that is unresponsive to inotropic drugs, defibrillation and external cardiac pacing. The myoglobin can cause acute renal failure that further aggravates the blood potassium levels. Hyperglycemia or hypoglycemia may be present. The presence of hyperglycemia can aggravate the hypermetabolic state in the brain causing central nervous system damage. If the patient is hypoglycemic, insulin and dextrose may be given in an attempt to reduce the blood potassium levels. The use of ionized calcium, such as calcium chloride or calcium gluconate to stimulate cardiac contraction is controversial. This is because the physiology of MH involves the inappropriate transfer of ionized calcium within muscle cells and it is thought that additional ionized calcium may aggravate the situation. However, the North American Malignant Hyperthermia Group protocol now allows for the limited use of ionized calcium supplement if needed for cardiac stimulation.

Treatment of MH with a favorable outcome includes astute vigilance on the part of the anesthesia personnel, accurate diagnosis, and the rapid and appropriate implementation of treatment. Treatment includes the immediate cessation of volatile anesthetics and changeout of the breathing circuit, hyperventilation with 100% oxygen and the administration of dantrolene. Dantrolene is a relatively benign drug whose side effects include visual symptoms, dizziness, fatigue and weakness of the extremities. If temperature elevation is present cooling should be attempted with topical ice packs, lavage of body orifices with cold saline solutions and starting IV’s with cold solutions. About 90% of the time these interventions will resolve the MH. However, should action be delayed or the patient remain unresponsive to the normal interventions, then the necessary supportive measures should be taken, including resuscitation and CPR. If the episode occurs during surgery a decision needs to be made whether or not to terminate the procedure.

Successful resuscitation can be lengthy in MH cases, exceeding 90 minutes and resulting in favorable outcome with minimal morbidity. This makes sense because the cause of the cardiac failure is exogenic to the cardiopulmonary system. Therefore, once the underlying metabolic disruption is controlled, cardiopulmonary function should return to normal. In one case, an adolescent with an MH variant developed ventricular fibrillation followed by asystole that was unresponsive to inotropic drugs, defibrillation and external pacing. CPR lasted for over 2 hours during which time the patient was transferred to another hospital for placement on cardiopulmonary bypass for an additional two hours before weaning was successful. The blood potassium from the accompanying rhabdomyolysis exceeded 10 mEq/L. Treatment with glucose, insulin and bicarbonate only dropped the potassium to about 8 mEq/L. Acute kidney damage from myoglobin release resulted in the need for hemodialysis for 6 weeks following the MH episode. However, the patient fully recovered, thereafter. In other patients, extensive brain damage from hypoxia and hypermetabolism can result. Hyperthermia of 41 C has been reported for up to two hours in postmortem MH patients.

One variant of MH is neuroleptic malignant syndrome (NMS). This is a rare condition characterized by many of the same symptoms as MH; hyperthermia, autonomic dysfunction, skeletal muscle rigidity, elevated CK and rhabdomyolysis. However, NMS is associated with the use of neuroleptic drugs rather than volatile anesthetics or depolarizing muscle relaxants. NMS can be related to starting a neuroleptic drug, a change in the type of neuroleptic drug, a change in the dosage of the drug, physical stress or the absence of any precipitating event. In particular, the use of haloperidol is associated with NMS. NMS is thought to occur from hypothalamus and basal ganglia dopamine depletion. Other neurotransmitters such as serotonin, noradrenaline and GABA may also mediate NMS. NMS is even rarer than MH and has a mortality of 20% associated with it. This is most probably because the episode occurs in a clinical setting rather than the operating room, recovery room or some other intensive care area. Death is often in relation to respiratory failure due to delayed admission to the intensive care unit rather than the cardiac failure usually seen in MH. Treatment is similar to MH, including the use of dantrolene. However, two other drugs are also effective; bromcriptine mesylate and levodopa. All other neuroleptic treatment should be stopped immediately.

Another variant of MH is rhabdomyolysis without hyperthermia. Once more frequently seen in military recruits undergoing extreme physical stress, mild rhabdomyolysis is now seen more often in amateur athletes. The hallmark of mild rhabdomyolysis is severe muscle soreness and dark urine. In more extreme cases, acute renal failure can occur. In the hospital setting, rhabdomyolysis can be associated with hyperthermia like as seen in MH and NMS, or it can occur as a normothermic variant. If the rhabdomyolysis is associated with MH or NMS, the typical treatment regimen is begun. A dangerous complication is acute renal failure from high levels of blood myoglobin. If rhabdomyolysis becomes extreme and causes severe potassium and myoglobin increases then the treatment options should also include the IV infusion of normal saline to dilute the potassium and myoglobin. Bicarbonate should also be given to prevent the development of a larger base deficit from hemodilution. Mannitol should be given to reduce edema and promote renal function unless the patient is in a hyperosmolar state.

Anesthesia associated rhabdomyolysis has been seen in the pediatric population. It is associated with the use of depolarizing muscle relaxants and carries a mortality of over 20%, despite the absence of hyperthermia. Rhabdomyolysis can also be seen in trauma patients and patients undergoing treatment with mannitol to reverse brain swelling from head trauma. It has also been associated with other severe metabolic disturbances.