Rhabdomyolysis

Rhabdomyolysis is a syndrome caused by the rapid breakdown of striated skeletal muscle, which releases large amounts of potentially toxic muscle cell contents into the blood and often leads to kidney damage or failure and heart arrhythmias. Although rhabdomyolysis can have many different causes, exertional rhabdomyolysis (ER, rhabdo) is caused by excessive muscle exertion.

Rhabdomyolysis is common in certain adult populations, with approximately 26,000 cases reported annually in the United States. Most adult cases are caused by muscular trauma and crush injuries, drug or alcohol abuse, or toxic effects on the muscles from prescription drugs; however, the incidence of ER is increasing. Rhabdomyolysis is more common in males than in females, especially cases caused by trauma or an inherited enzyme deficiency. Rhabdomyolysis and resultant kidney failure are particularly common after disasters such as earthquakes, in which there can be many severe crush injuries and delayed extraction of survivors. Among adults treated in emergency departments for cocaine-related conditions, 24% have rhabdomyolysis. In children, rhabdomyolysis is most often due to inherited muscular pathologies, such as Duchenne muscular dystrophy, or inherited enzyme deficiencies that affect carbohydrate or lipid metabolism.

Rhabdomyolysis is caused by damaged muscle cells leaking their contents into the blood. In particular, the red-pigmented protein myoglobin that carries oxygen to muscle tissue is released and filtered out of the blood by the kidneys. The iron-heme oxygen-carrying portion of myoglobin is toxic to kidney cells and turns the urine reddish-brown or tea-colored, a condition known as myoglobinuria. Potassium also leaks out of the damaged muscle cells, and calcium rushes in, affecting the electrolyte and acid-base balance of muscle tissue and blood. Other cell contents leak into the bloodstream including uric acid and various enzymes.

Rhabdomyolysis was first described during World War II as a syndrome that developed following crush injuries and severe trauma. It is now known that a wide range of traumas, hereditary defects, and toxic exposures can lead to rhabdomyolysis. Like other forms of rhabdomyolysis, ER is caused by acute muscle fiber death (necrosis) that causes the cells to break open and release myoglobin, electrolytes, enzymes, and other proteins into the blood. Exercise intolerance is the primary symptom of both ER and rhabdomyolysis caused by metabolic problems. Exercise intolerance is characterized by fatigue and muscle cramping and pain during or after exertion. Repeated bouts of rhabdomyolysis can lead to chronic or permanent muscle weakness.

The severity of rhabdomyolysis varies from increased muscle enzymes in the blood that cause no symptoms to extremely high blood-enzyme levels, acute kidney injury (AKI), acute renal failure (ARF), or life-threatening electrolyte imbalances. ARF occurs in 10%–40% of rhabdomyolysis patients, and 5%–15% of ARF cases and 5%–20% of adult AKI cases are due to rhabdomyolysis. Other life-threatening complications include heart arrhythmias; compartment syndrome (dangerous buildup of pressure in a muscle compartment); hypovolemic shock from severe, rapid fluid loss; and a condition known as disseminated intravascular coagulation, in which uncontrolled clotting throughout the circulatory system leads to hemorrhaging from the depletion of clotting factors.

Risk factors for rhabdomyolysis include overexertion and/or a myriad of conditions, injuries, and drugs. Risk factors for ER include extreme or unusual conditioning programs, such as performing hundreds of push-ups or squats beyond the point of fatigue. In particular, the CrossFit program has been linked to an increase in ER.

Any condition or injury that damages skeletal muscle has the potential to cause rhabdomyolysis. Multiple factors often contribute to rhabdomyolysis in adults: in one large study, multiple factors were involved in 60% of cases. Although ER from extreme physical exertion, such as calisthenics or marathon running, is relatively rare, it is common enough to have earned the nickname “Uncle Rhabdo” among some cross-training enthusiasts. In children, rhabdomyolysis is most often caused by an inherited metabolic or muscle disorder, infection, or trauma.

In addition to physical exertion, causes of rhabdomyolysis include:

People with metabolic disorders that affect the muscles are often prone to episodes of rhabdomyolysis characterized by severe muscle pain during or up to several hours after exercise. In people with carbohydrate-processing disorders, the condition can be triggered by either aerobic exercise, such as running or jumping, or by isometric exercises such as weight training or squats. In people with CPT deficiency, rhabdomyolysis is usually triggered by moderate, prolonged exercise, especially on an empty stomach.

The classic triad of rhabdomyolysis signs and symptoms in adults are:

Other symptoms include:

Typical ER symptoms are muscle cramps and/or pain during or after exercise. Furthermore, exercise intolerance is the primary symptom of most metabolic myopathies, although the degree of exercise intolerance varies greatly depending on the individual and the specific disorder. Some people have symptoms when walking only a short distance, whereas others only experience symptoms when jogging. People with a metabolic defect in a carbohydrate-processing pathway often experience extreme fatigue during the first 10–15 minutes of exercise and then either recover within 10–15 minutes or experience severe muscle cramping.

Early diagnosis of rhabdomyolysis is critical so that treatment can be initiated to prevent AKI. The physical exam will reveal tender or damaged muscles, but since muscle pain and weakness are common and usually temporary, it is important to determine if the patient has risk factors for rhabdomyolysis.

The standard test for rhabdomyolysis is the CK level in the blood. Muscle-cell injury often causes CK levels to be fourfold or fivefold higher than normal; however, athletes generally have significantly higher CK levels than nonathletes. Myoglobin levels in blood serum begin rising two hours after the initial injury, and myoglobin must reach a threshold level in the kidneys before it is detectable in the urine. Other tests for rhabdomyolysis include:

Procedures that may be performed under some circumstances include:

Emergency management of rhabdomyolysis includes:

Prognosis depends on the degree of kidney damage. Overall mortality from rhabdomyolysis is about 5%. AKI and ARF are common; myoglobin-induced AKI occurs in 17%–35% of adult patients. However, prompt treatment of AKI and ARF reduces the risk of permanent kidney damage. Patients with milder rhabdomyolysis may return to normal activities within a few weeks, although fatigue and muscle pain may linger. With adequate support, the prognosis in children is often good, although recurrent episodes may indicate underlying metabolic or muscle structural defects. In large-scale natural disasters, such as earthquakes, the ability of emergency medical teams to provide hydration and dialysis improves survival, and many patients recover completely.

It was previously thought that CK levels were proportional to the degree of muscle damage and a prognostic predictor. However, a recent study found that various factors in addition to CK levels were independent predictors of outcome, including:

Athletes with ER may be allowed to return to light activity after 72 hours of rest with sufficient fluid intake and eight hours of nightly sleep, provided that renal function and CK levels have returned to normal. Once muscle weakness, swelling, pain, and/or soreness are gone, they may gradually return to training.

People at high risk for recurrence of ER include those with:

Prevention involves recognizing the causes and precipitating events of rhabdomyolysis. It is very important to drink plenty of fluids during and after strenuous exercise and in any circumstances in which skeletal muscle may have been damaged. Drinking fluids dilutes the urine and helps flush any myoglobin out of the kidneys. It is also essential to pay immediate attention to signs of heat exhaustion in hot, humid conditions. High-school and college athletes should be educated about the signs of dehydration and heat-related injuries. Patients at risk for exercise-induced or hyperthermia-induced rhabdomyolysis should avoid overly strenuous exercise and ensure adequate hydration and body cooling when exercising.

Patients should contact their physician if they experience moderate-to-severe muscle aches when first taking a statin. They should stop the drug immediately if signs and symptoms of rhabdomyolysis develop. Patients should also discontinue the use of recreational or prescription drugs or alcohol that contributed to the development of their rhabdomyolysis.

Patients with metabolic disorders may be able to prevent rhabdomyolysis with dietary modifications. Families with inherited deficiencies in muscle enzymes and metabolism should seek genetic counseling.

Margaret Alic, PhD