Chapter 89: Rhabdomyolysis

Rhabdomyolysis is the destruction of skeletal muscle, caused by any mechanism that results in injury to myocytes and their membranes. Direct muscle injury and genetic and biochemical factors can predispose to rhabdomyolysis. Acute necrosis of skeletal muscle fibers and the leakage of cellular contents into the circulation result in myoglobinuria.

Several classification systems have been developed to characterize the numerous causes of rhabdomyolysis. None of these systems is universally recognized, and each has its limitations.

Table 89-1 lists commonly recognized conditions associated with rhabdomyolysis. In general, the most common causes of rhabdomyolysis in adults appear to be alcohol and drugs of abuse, followed by medications, muscle diseases, trauma, neuroleptic malignant syndrome, seizures, immobility, infection, strenuous physical activity, and heat-related illness.^1,2 A host of drugs and toxins have been identified that are associated with or causative of rhabdomyolysis.³ Multiple causes are present in more than half of patients.¹ In children, rhabdomyolysis is less common and is thought to be more benign.³ In one study of children, the most common causes of nonrecurrent rhabdomyolysis were trauma, viral myositis, and connective tissue disease.⁴ For adults and children, inherited metabolic disorders should be suspected with recurrent episodes of rhabdomyolysis, especially if associated with exercise intolerance.

Patients in coma are at risk for rhabdomyolysis from unrelieved pressure on gravity-dependent body parts. Alcohol consumption can result in rhabdomyolysis secondary to coma-induced muscle compression and a direct toxic effect. Nutritional compromise, hypokalemia, hypomagnesemia, and hypophosphatemia, all common in alcoholics, increase the risk of rhabdomyolysis. Alcohol and drugs are thought to play a role in most cases of rhabdomyolysis in adults.¹ Drugs of abuse are commonly implicated in acute rhabdomyolysis, and many commonly prescribed medications have been associated as well.² Statin-related myopathies include myalgias with or without elevation of creatine kinase level, muscle weakness, and rhabdomyolysis. Statin-related rhabdomyolysis is rare, varies with the particular statin, and is also dose related. Drug combinations, including combinations with cyclosporine, macrolide antibiotics, warfarin, digoxin, and dual statin therapy, carry an increased risk for rhabdomyolysis.^3,5

A number of bacterial and viral infections have been associated with rhabdomyolysis.³ Strenuous physical activity, as seen in athletes, marathon runners, military recruits, and outdoor laborers, is a common cause. Physical activity that produces high-force eccentric contractions, such as strength training or heavy lifting, leads to greater breakdown in muscle and higher levels of creatine kinase than concentric contractions, such as endurance-based exercises.⁶ Factors that increase the risk in this group of patients include poor physical conditioning, inadequate fluid intake, wearing of restrictive clothing, high ambient temperatures, and high humidity levels.⁶

PATHOPHYSIOLOGY

Rhabdomyolysis is a syndrome characterized by injury to skeletal muscle with subsequent effects from the release of intracellular contents. These contents include myoglobin, creatine kinase, aldolase, lactate dehydrogenase, aspartate aminotransferase, and potassium. Although numerous causes of rhabdomyolysis have been described, the common terminal event appears to involve the disruption of the Na⁺K⁺ATPase pump and calcium transport, which results in increased intracellular calcium and subsequent muscle cell necrosis. In addition, calcium activates phospholipase A₂ and various vasoactive molecules and proteases and induces the production of free oxygen radicals.^3,7

The presenting symptoms of rhabdomyolysis are usually acute in onset and include myalgias, stiffness, weakness, malaise, low-grade fever, and dark (usually brown) urine. Muscle symptoms, however, may be present in only half of cases.⁴ Nausea, vomiting, abdominal pain, and tachycardia can occur in severe rhabdomyolysis. Mental status changes may develop from urea-induced encephalopathy. Swelling and tenderness of the involved muscle groups and hemorrhagic discoloration of overlying skin may be observed but are not common. Muscle involvement may be localized or diffuse, depending on the cause. Commonly, the postural muscles of the thighs, calves, and lower back are involved. Muscle swelling may not become apparent until after rehydration with IV fluids. An important point to remember is that acute rhabdomyolysis may be present without any of these signs or symptoms, and the patient may have normal findings on physical examination. For this reason, the diagnosis often is made only after soliciting a historical clue (e.g., recent cocaine use) or finding an elevated serum creatine kinase level or the presence of dark urine on routine laboratory testing.

An elevated serum creatine kinase is the most sensitive and reliable indicator of muscle injury. The degree of elevation correlates with the amount of muscle injury and the severity of illness, but not the development of renal failure or other morbidity. Most investigators consider a fivefold or greater increase above the upper threshold of normal in serum creatine kinase level, in the absence of cardiac or brain injury, as the requirement for the diagnosis of rhabdomyolysis. In general, the level begins to rise approximately 2 to 12 hours after the onset of muscle injury, peaks within 24 to 72 hours, and then declines at the relatively constant rate of 39% of the previous day's value. Ongoing muscle necrosis should be suspected in patients with elevated values that fail to decrease in this manner. The isoenzyme CK-MM (found in skeletal and cardiac muscle) is responsible in large part for the elevation in serum creatine kinase. The MB fraction of creatine kinase (found primarily in cardiac but also in skeletal muscle) also may be elevated but should not exceed 5% of the total creatine kinase.

Myoglobin is an oxygen-binding protein found in skeletal and cardiac muscle and is involved in oxidative metabolism. Myoglobinuria develops once skeletal muscle injury is >100 grams.² Myoglobin elevation occurs before creatine kinase elevation, and then is rapidly cleared from the plasma through renal excretion and metabolism to bilirubin. Myoglobin enters the urine when the plasma concentration is >1.5 milligrams/dL and causes the typical reddish brown discoloration when the urine myoglobin level is >100 milligrams/dL.^3,8 Because myoglobin contains heme, qualitative tests such as the dipstick test (which uses the orthotoluidine reaction) do not differentiate among hemoglobin, myoglobin, and red blood cells. Therefore, suspect myoglobinuria when the urine dipstick test is positive for blood but no red blood cells are present on microscopic examination. Radioimmunoassay is slightly more sensitive than the dipstick technique in identifying myoglobinuria, but usually is not necessary. Because myoglobin levels may return to normal within 1 to 6 hours after the onset of muscle necrosis, the absence of an elevated serum myoglobin level or of myoglobinuria does not exclude the diagnosis. In one study, only 19% of patients with rhabdomyolysis demonstrated myoglobinuria.¹

Other laboratory studies may be useful to identify the common complications of rhabdomyolysis and the underlying cause. Serum electrolyte, calcium, phosphorus, and uric acid levels should be determined to identify hyperkalemia, abnormal calcium and phosphorus levels, and hyperuricemia. Urinalysis should be obtained for all patients. Serum creatinine and BUN levels are needed to identify acute renal failure. Because disseminated intravascular coagulation is a potential complication, a baseline CBC should be obtained and a coagulopathic screen considered [e.g., prothrombin time, partial thromboplastin time, fibrin split products, and fibrinogen level (see chapter 233, Acquired Bleeding Disorders)]. Other common laboratory findings in rhabdomyolysis include elevated levels of aldolase, lactate dehydrogenase, urea, creatine, and aminotransferases. Further laboratory testing to identify the underlying cause(s) of rhabdomyolysis should be based on the medical history and clinical presentation.

DIFFERENTIAL DIAGNOSIS

Other causes of muscle pain and weakness besides rhabdomyolysis should be considered in the appropriate clinical setting. Such causes include acute myopathies, periodic paralysis, polymyositis or dermatomyositis, or Guillain-Barré syndrome. Rhabdomyolysis associated with strenuous exercise or fasting or repeat episodes of rhabdomyolysis suggest an inherited metabolic myopathy.³

PREHOSPITAL CARE

For victims of crush injury, patients strongly suspected of having rhabdomyolysis, or accident victims with prolonged extrication and transport times, early and vigorous IV fluid resuscitation is the most important treatment to prevent acute renal failure.^9,10 Once a limb is extricated, IV normal saline should be initiated at 1 L/h. After extrication, IV normal saline should be continued at 500 mL, alternating with 5% dextrose in normal saline at 1 L/h. Avoid potassium- or lactate-containing solutions. There is no evidence that the administration of sodium bicarbonate is beneficial.

ED CARE

Once the patient is in the ED, continue aggressive IV rehydration for the next 24 to 72 hours. One method is rapid correction of the fluid deficit with IV crystalloids followed by infusion of 2.5 mL/kg/h, with the goal of maintaining a minimum urine output of 2 mL/kg/h.¹¹ Another method is a goal of 200 to 300 mL of urine output each hour.¹²

No prospective controlled studies have demonstrated benefit from alkalinization of the urine with sodium bicarbonate or forced diuresis with mannitol or loop diuretics.^12,13,14 Bicarbonate is widely recommended but without an evidence base. If bicarbonate is given, maintain an isotonic solution and avoid metabolic alkalosis or hypokalemia.¹² Mannitol may be harmful because it may cause osmotic diuresis in hypovolemic patients.

Place a urinary catheter in patients in critical condition and those with acute renal failure to monitor urine output. Institute cardiac monitoring because electrolyte and metabolic complications can cause dysrhythmias. For patients with heart disease, comorbid conditions, or preexisting renal disease or for elderly patients, hemodynamic monitoring may be necessary to avoid fluid overload. Serial measurements of urine pH, electrolytes, creatine kinase, calcium, phosphorus, BUN, and creatinine are needed.

Hypocalcemia observed early in rhabdomyolysis usually requires no treatment. Calcium should be given only to treat hyperkalemia-induced cardiotoxicity or profound signs and symptoms of hypocalcemia. If hypercalcemia is symptomatic, continue saline diuresis. Treat hyperphosphatemia with oral phosphate binders when serum levels are >7 milligrams/dL. Treat hypophosphatemia when the serum level is <1 milligram/dL. Hyperkalemia, which is usually most severe in the first 12 to 36 hours after muscle injury, can be significant and prolonged. Traditional insulin and glucose therapy, although recommended, may not be as effective in rhabdomyolysis-induced hyperkalemia. The use of ion-exchange resins (e.g., sodium polystyrene sulfonate) is effective. Dialysis may be needed (see chapter 17, Fluids and Electrolytes).

Avoid prostaglandin inhibitors such as nonsteroidal anti–inflammatory drugs because of their vasoconstrictive effects on the kidney. Finally, treat the underlying cause.

The complications of rhabdomyolysis include acute renal failure, metabolic derangements, disseminated intravascular coagulation, and mechanical complications (e.g., compartment syndrome or peripheral neuropathy)¹⁵ (Table 89-2). Factors that contribute to rhabdomyolysis-induced acute renal failure include hypovolemia, acidosis or aciduria, tubular obstruction, and the nephrotoxic effects of myoglobin.^3,12 In exertional rhabdomyolysis, acute renal failure is rare without the presence of factors like dehydration, heat stress, trauma, or underlying disease such as sickle cell anemia.⁶ Renal tubular obstruction occurs secondary to precipitation of uric acid and myoglobin. Ferrihemate, the breakdown product of myoglobin, is responsible for the direct toxic effect on the kidneys. This effect, however, appears to occur only in the presence of hypovolemia and aciduria (pH <5.6). Renal failure may be oliguric (most common) or nonoliguric. Patients with initially elevated creatinine and BUN and a large base deficit^16,17 have an increased risk for rhabdomyolysis-induced acute renal failure. However, neither the presence of myoglobinuria nor the degree of creatine kinase elevation is predictive of acute renal failure.

Anticipate a rise in the serum potassium level due to release of potassium from injured skeletal muscle. Renal function, however, appears to be the most important determinant of the degree of elevation. Hyperkalemia can be a significant complication of rhabdomyolysis if acute renal failure occurs.

Elevated uric acid levels can occur, especially in crush injures, due to release of muscle adenosine nucleotides and the subsequent conversion to uric acid by the liver. Uric acid levels usually correlate with serum creatine kinase levels.

Serum phosphorus levels initially may be elevated, due to the leakage of phosphorus from injured muscle. Later in the disease course, mild hypophosphatemia may be seen but rarely requires treatment. Hypocalcemia occurs early and is usually asymptomatic. It results from the deposition of calcium salts in necrotic muscle, due to the hyperphosphatemia and decreased levels of 1,25-dihydroxycholecalciferol. Soft tissue calcifications sometimes can be observed on radiographs of the involved limb muscles. Hypocalcemia can occur, however, without elevated levels of phosphorus. Later, as calcium is mobilized from damaged muscle, hypercalcemia may be observed.

Disseminated intravascular coagulation occurs in severe rhabdomyolysis and can result in hemorrhagic complications.

The mechanical complications of rhabdomyolysis consist of compartment syndrome and peripheral nerve injury. The associated muscle swelling may exert pressure on peripheral nerves, resulting in neuronal ischemia and causing paresthesias or paralysis. Nerve injury is often proximal, and multiple nerves may be involved in the same extremity.¹⁵ Compartment syndrome occurs secondary to marked swelling and edema of the involved muscle groups and is discussed in chapter 278, Compartment Syndrome.

The majority of healthy patients with exertional rhabdomyolysis and without comorbidities (i.e., heat stress, dehydration, trauma) can usually be treated with oral or IV rehydration, observed in the ED, and then released.⁶ Otherwise, patients should be admitted for IV hydration, diuresis, management of complications, and treatment of the underlying cause. For at least the initial 24 to 48 hours, admission should be to a monitored bed to identify dysrhythmias. The nephrology service should be consulted to evaluate the need for dialysis, especially for patients with hyperkalemia unresponsive to therapy.

PRACTICE GUIDELINES

No internationally recognized organization has published validated guidelines for the management of rhabdomyolysis, but the Finnish Medical Society has issued nonvalidated literature-based guidelines that are available on the Internet (see Useful Web Resource).