INTRODUCTION
Rhabdomyolysis is a syndrome characterized by the necrosis of myocytes and the release of their intracellular contents into the circulation. Literally, it means “dissolution of striated muscle”. Approximately 26,000 cases of rhabdomyolysis occur every year in the United States.1 The syndrome can be lethal. It can range from asymptomatic elevations of muscle enzymes in the serum to fatal cases associated with extreme enzyme elevations, electrolyte imbalances, and acute renal failure. Management and treatment of rhabdomyolysis varies from observation to intravenous fluids and hemodialysis. There are many causes of rhabdomyolysis, but the common connection between them is the breakdown of muscle and biochemical reactions at the cellular level.
HISTORICAL PERSPECTIVE
The first cases of rhabdomyolysis were described by Bywaters and Beall, who in 1941 reported four cases of crush victims during the bombing of London in the Battle of Britain.2 All of the patients developed acute renal failure and died within one week. On autopsy, they found pigmented casts in the renal tubules. However, at that time the relationship between muscle injury and renal failure was not known. In 1959, rhabdomyolysis was divided into exertional and non-exertional types and a genetic component was identified. The first review of rhabdomyolysis and its clinical manifestations was published in 1972.2
CLINICAL MANIFESTATIONS
There are a variety of signs and symptoms of rhabdomyolysis and they often depend on the initial cause. Any history of trauma, “crush injury” or genetic tendency should be obtained from the patient. Local signs and symptoms include myalgias, muscle swelling, weakness and malaise. The most important systemic sign is tea-colored urine due to myoglobinuria. The degree of myoglobinuria depends upon the amount of myoglobin filtered by the kidneys. The extent of pigmenturia does not correlate with the severity of disease. Other systemic signs include fever, oliguria and even stupor. It is important to have a high clinical suspicion of rhabdomyolysis in the light of the patient’s history and presentation.
DIAGNOSIS
In addition to the clinical presentation, laboratory tests including muscle enzymes, electrolytes, and renal function tests, help define rhabdomyolysis.
Muscle Enzymes
The most important sign of rhabdomyolysis is an elevation of the creatinine kinase (CK). It is typically greater than 10,000 IU/L and may rise to 100,000 IU/L3. The CK is mostly composed of the MM fraction (skeletal muscle) but a small amount of MB fraction (myocardial) may be present. Elevation of the serum aminotransferases are often seen and sometimes make the diagnosis difficult to delineate from liver disease. Other enzymes that tend to rise in rhabdomyolysis include lactate dehydrogenase (LDH) and aldolase. Because myoglobin is cleared from the serum more rapidly than CK, it is not unusual for serum CK levels to remain elevated in the absence of myoglobinuria.
Electrolytes
Abnormalities in serum concentrations of potassium, phosphorous, calcium, bicarbonate and uric acid are common with rhabdomyolysis. Hyperkalemia and hyperphosphatemia result from the release of potassium and phosphorous from damaged myocytes. Hypocalcemia may also occur in the first few days for two main reasons: depositition of calcium salts in damaged muscle and a decrease in the bone’s response to parathyroid hormone. Severe hyperuricemia may develop due to the release of purines from damaged muscle cells, even in the setting of normal renal function. Metabolic acidosis is also frequently observed. The severity of the metabolic and electrolyte abnormalities correlates with the extent of muscle damage.
Renal Function
Acute oliguric renal failure is a common and sometimes fatal finding in rhabdomyolysis. Acute renal failure in the setting of rhabdomyolysis usually occurs due to acute tubular necrosis, caused by volume depletion leading to renal ischemia, destruction of renal tubules and pigmented casts in the urine. Free iron released from myocyte breakdown can also damage renal tubules. Hence, urinalysis can be helpful in detecting the myoglobinuria associated with rhabdomyolysis. About 50% of rhabdomyolysis cases show heme positive urine without red blood cells.1 However, because myoglobin is such a small protein in weight and is cleared in one to six hours by the kidney, serum levels typically must exceed 1,500 to 3,000 ng/ml before myoglobin is detected in the urine.1 Therefore, myoglobinuria is transient and it is not necessary to confirm diagnosis.
ETIOLOGY
The causes of rhabdomyolysis vary and can be multi-factorial. In a review of rhabdomyolysis in a civilian, urban population of 77 adult patients (age range 21–85 years), the most common causes included alcohol and drug abuse, muscle compression, and seizures, followed by a variety of metabolic derangements and infectious etiologies.3 Attempts to categorize the many diverse causes have generally broken down causes into traumatic and non-traumatic etiologies. The non-traumatic groups can be further divided into exertional and non-exertional etiologies.
Traumatic
Trauma and compression are common causes of rhabdomyolysis. In crush injuries, rhabdomyolysis typically occurs as the necrotic muscle cell contents are released into the systemic circulation, especially after the patient has been rescued, removed from entrapment and muscle compression is relieved. Individuals who have been struggling against restraints or who have been immobilized for long periods may develop rhabdomyolysis, as can patients who undergo surgical procedures that require prolonged muscle compression or vascular occlusion. Other less-likely traumatic causes include burns and lightening strikes.
Non-traumatic
Rhabdomyolyis also occurs when there is no identifiable trauma. As mentioned earlier, nontraumatic rhabdomyolysis is typically classified as exertional or non-exertional. Exertional causes of rhabdomyolysis are those which involve extremes of muscle activity or contractions (ie. prolonged seizures or strenuous activity).4 Temperature-related causes of rhabdomyolysis include heat stroke, malignant hyperthermia and neuroleptic malignant syndrome. Other non-traumatic exertional causes include inherited diseases, such as mitochondrial and metabolic myopathies, which are typically seen in the young and tend to reoccur frequently.
Most cases of rhabdomyolysis can be attributed to non-exertional causes, including alcohol and drug abuse, toxins, inflammatory myopathies and infections. Drugs and medications, especially cocaine, amphetamines, ecstacy or LSD, may either cause indirect muscle damage or simply predispose one to rhabdomyolysis. Other pharmaceuticals are direct myotoxins, the most common being statins, colchicine, itraconazole, zidovudine and cyclosporine1,4. Non-pharmaceutical causes of non-exertional rhabdomyolysis include dermatomyositis and polymyositis, in which myoglobinuria may be seen in 50% of cases but rarely leads to acute renal failure.1 Infectious etiologies such as Influenza A and B, Legionella, Streptococci and Salmonella have been implicated in rhabdomyolysis, presumably due to direct viral or bacterial invasion of skeletal muscle and toxin generation.3 The human immunodeficiency virus (HIV) has been associated with episodes of myoglobinuria, but it is still disputed whether or not the virus itself can cause rhabdomyolysis. Finally, certain endocrine and metabolic disorders, particularly hypothyroidism, can predispose a patient to rhabdomyolysis.
PATHOPHYSIOLOGY
The pathophysiology of rhabdomyolysis is best explained by the cascade of events that occur at the cellular level. No matter the cause, muscle injury results in the leakage of extracellular calcium into the intracellular space. This excess calcium causes a pathologic interaction of actin and myosin that then ends in muscle destruction and fiber necrosis. With the death of the muscle cell, large quantities of potassium, phosphate, myoglobin, CK and urate leak into the circulation.
Under physiologic circumstances, the plasma concentration of myoglobin is very low (0 to 0.003 mg per dL).3 If more than 100 gm of skeletal muscle is damaged, serum haptoglobin binding capacity becomes saturated.3 The circulating myoglobin then is free to enter systemic systemic circulation. When the kidneys try to clear myoglobin into the glomerular filtrate, the large molecule may precipitate, leading to tubular damage, acute tubular necrosis and renal failure. This process may be worsened by fluid sequestration by the necrotic muscle tissue, which leads to a pre-renal hypovolemia and may worsen the renal failure.
MANAGEMENT
The general management of patients with rhabdomyolysis involves treating the underlying illness, while simultaneously trying to avoid acute renal failure due to hypovolemia and myoglobinuria. Hence, the most important key to managing these patients is aggressive volume resuscitation. Infusion of fluids is important even in patients who are not hypovolemic, presumably due to the increased urine flow which helps to protect the kidney tubules from myoglobinuric damage. The longer it takes for rehydration to be initiated, the more likely it is that oliguric renal failure or anuric renal failure will occur.5 Investigators in one study found that forced diuresis within the first six hours of admission prevented all episodes of acute renal failure.3
Initially, normal saline should be given at a rate of 1.5 liters per hour, with the goal urine output to be 300 mL per hour, until any myoglobinuria has resolved and until serum CK level falls to or below 1,000 IU/ L.5 If these measures are unsuccessful and the patient develops oliguria, a forced diuresis can be tried using 0.45 percent saline with 40 mEq sodium bicarbonate and 10 grams per liter of mannitol; however, there is no clear evidence that alkalinization of diuresis is more effective than a saline diuresis.3,4 Additionally the alkalinization can cause a hyperosmolar state, precipitate calcium phosphate and worsen the already present hypocalcemia.
Despite treatment, many patients still develop oliguric renal failure. In this situation, hemodialysis should be initiated and implemented aggressively. With time, many patients partially or completely recover renal function and need not be dialysis-dependent. Emergent hemodialysis also may be needed to treat severe cases of metabolic acidosis and severe electrolyte imbalances sometimes seen in rhabdomyolysis.
COMPLICATIONS
The complications of rhabdomyolysis can be classified as early or late. Earlier complications generally include metabolic derangements, while later complications typically include renal failure, multi-organ failure and compartment syndrome.
Of all metabolic abnormalities associated with rhabdomyolysis, hyperkalemia is the most concerning (and most lethal) because of its potential effects on cardiac rhythm and function. Close observation and management of potassium levels should be implemented, and hemodialysis may be needed if hyperkalemia is persistent. Hyperphosphatemia, when greater than 7 mg/dl, can be managed with phosphate binders. Hypocalcemia may develop early but should be treated only if severe symptoms or severe hyperkalemia develop. Additionally, in severe cases, myonecrosis is so extensive that metabolic acidosis and hyperuricemia develop.
It has been estimated that rhabdomyolysis causes approximately 10% of all cases
of acute renal failure.5 There is a loose predictive correlation between CK levels and the development of acute renal failure, with levels higher than 16,000 u/L more likely to be associated with renal failure.3 In patients with extensive injuries, multiple system organ failure may occur. Disseminated intravascular coagulation (DIC), acute pulmonary dysfunction (acute respiratory distress syndrome) and hepatic dysfunction are seen more commonly in traumatic rhabdomyolysis and crush injuries. If DIC appears, it typically occurs on days 3 to 5 after the initial injury, and may require plasma and platelets for temporary management before it resolves.1 Hepatic dysfunction, due to release of proteases from damaged myocytes, is seen in approximately 25 percent of cases.1 Compartment syndrome is a rare complication, typically only seen with severe crush injuries or trauma.
REFERENCES
