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INTRODUCTION — Rhabdomyolysis is a syndrome characterized by muscle necrosis and the release of intracellular muscle constituents into the circulation. Creatine kinase (CK) levels are typically markedly elevated, and muscle pain and myoglobinuria may be present. The severity of illness ranges from asymptomatic elevations in serum muscle enzymes to life-threatening disease associated with extreme enzyme elevations, electrolyte imbalances, and acute kidney injury.
The causes of rhabdomyolysis will be reviewed here. The clinical manifestations and diagnosis of rhabdomyolysis; the clinical features and diagnosis of acute kidney injury due to rhabdomyolysis; the management of patients with rhabdomyolysis, including methods to prevent acute kidney injury and related metabolic complications; and the prevention and management of acute compartment syndrome are discussed in detail separately. (See "Clinical manifestations and diagnosis of rhabdomyolysis" and "Clinical features and diagnosis of heme pigment-induced acute kidney injury (acute renal failure)" and "Prevention and treatment of heme pigment-induced acute kidney injury (acute renal failure)" and "Crush-related acute kidney injury (acute renal failure)" and "Acute compartment syndrome of the extremities".)
PATHOPHYSIOLOGY — The clinical manifestations and complications of rhabdomyolysis result from muscle cell death, which may be triggered by any of a variety of initiating events. The final common pathway for injury is an increase in intracellular free ionized cytoplasmic and mitochondrial calcium. This may be caused by depletion of ATP, the cellular source of energy, and/or by direct injury and rupture of the plasma membrane [1,2]. The latter pathway of injury also results in ATP depletion.
The increased intracellular calcium leads to activation of proteases, increased skeletal muscle cell contractility, mitochondrial dysfunction, and the production of reactive oxygen species, resulting in skeletal muscle cell death . ATP depletion causes dysfunction of the Na/K-ATPase and Ca2+ATPase pumps that are essential to maintaining integrity of the myocyte. ATP depletion leads to myocyte injury and the release of intracellular muscle constituents, including creatine kinase and other muscle enzymes, myoglobin, and various electrolytes.
The specific cause is frequently evident from the history or from the immediate circumstances preceding the disorder, such as crush injury, a comatose or postictal state, postoperative surgical trauma, or extraordinary physical exertion. In other cases, however, the precipitant may not be as immediately evident but is identified through a careful history and physical and laboratory evaluation [4,5,7]. The specific causes within each of the three major categories are discussed in detail in the sections below.
The relative frequency of the different etiologies among patients with rhabdomyolysis is illustrated by two large series of hospitalized patients [3,4]. The most common causes in the larger and more recent series of 475 patients were exogenous toxins (46 percent), including alcohol and illicit drugs (34 percent) and medical drugs (11 percent) . Underlying myopathy or muscle metabolic defects were seen in 10 percent of the cases in this study, usually as the sole etiologic factor. There was a higher rate of recurrence in those with an underlying myopathy or metabolic muscle defect (26 percent) than in patients with other etiologies, except for neuroleptic malignant syndrome, which had a similar rate of recurrence. (See 'Drugs' below.)
Up to 60 percent of patients had more than one etiologic factor in the two large studies; however, no cause was identified in 3 to 7 percent of patients [3,4]. Other series with more than 50 patients have included one focused on patients with infectious causes  and another limited to patients with marked creatine kinase (CK) elevations .
Trauma or muscle compression — Trauma or muscle compression is a common cause of rhabdomyolysis and can be seen in the following settings:
Nontraumatic exertional rhabdomyolysis — Rhabdomyolysis occurs in individuals with normal muscles when the energy supply to muscle is insufficient to meet demands. Examples include extreme exertion or exertion under conditions in which muscle oxygenation is impaired, including metabolic myopathies.
Subclinical myoglobinemia, myoglobinuria, and elevation in serum CK are common following physical exertion. As an example, myoglobinemia was found in 25 of 44 participants (57 percent) in an ultra-marathon race of 99 kilometers . The serum CK rose 16-fold from pre-race levels to a mean of 2060 international units/L. Myoglobin was detected in the urine of five individuals, but acute kidney injury did not occur. In a second study, 39 percent of 337 military recruits developed myoglobinemia during the first six days of basic training, but none had pigmenturia or reported muscle symptoms .
Massive rhabdomyolysis may arise with marked physical exertion, particularly when one of more of the following risk factors is present:
Rhabdomyolysis can also occur in trained individuals following physical exertion in the absence of these risk factors [22,33].
In addition, pathologic hyperkinetic states can lead to rhabdomyolysis in individuals with normal muscles [3,34]. Examples include:
Metabolic myopathies — Rhabdomyolysis may develop in patients with abnormal muscle, such as individuals with inherited disorders of glycogenolysis, glycolysis, or lipid metabolism (table 2). These disorders are discussed in detail separately. (See "Causes of metabolic myopathies" and "Overview of inherited disorders of glucose and glycogen metabolism".)
The metabolic myopathies represent a very small percentage of cases of rhabdomyolysis overall but are relatively common causes among patients with recurrent episodes of rhabdomyolysis after exertion [35,36]. In a series of 77 patients evaluated for "idiopathic" myoglobinuria in whom muscle biopsies were performed, specific enzyme deficiencies were identified in 36 (47 percent) . Carnitine palmitoyltransferase deficiency was the most common disorder, occurring in 17 of the 36 patients, followed by muscle phosphorylase deficiency (McArdle disease) in 10. (See "Causes of metabolic myopathies", section on 'Fatty acid transport defects' and "Muscle phosphorylase deficiency (glycogen storage disease V, McArdle disease)".)
The precise mechanism of muscle necrosis in the metabolic myopathies has not yet been established, but it is likely that insufficient energy production in exercising muscle leads to depletion of adenosine triphosphate (ATP) and creatine phosphate. The maintenance of muscle cell integrity is thereby compromised . (See "Approach to the metabolic myopathies", section on 'Myoglobinuria and rhabdomyolysis' and "Energy metabolism in muscle" and 'Pathophysiology' above.)
Postexertional rhabdomyolysis has also been described in individuals with mitochondrial myopathies due to defects in respiratory chain enzymes .
Thermal extremes and dysregulation — Rhabdomyolysis may occur with hyperthermia associated with heat stroke (see 'Nontraumatic exertional rhabdomyolysis' above). Other causes of rhabdomyolysis in the setting of temperature dysregulation or thermal extremes include:
Nonexertional and nontraumatic rhabdomyolysis — Nonexertional and nontraumatic causes of rhabdomyolysis include drugs and toxins, infections, electrolyte abnormalities, endocrinopathies, inflammatory myopathies, and others [2,4-6].
Drugs — A large number of prescription drugs and drugs of abuse can cause rhabdomyolysis . In addition to alcohol, other drugs of abuse that have been implicated as causes include heroin, cocaine, amphetamines, methadone, and D-lysergic acid diethylamide (LSD). In one large series, the prescription drugs most commonly responsible were antipsychotics, followed by statins, selective serotonin reuptake inhibitors, zidovudine, colchicine, lithium, antihistamines, and several others .
The illicit and prescribed agents cause rhabdomyolysis through several different mechanisms [41,42]:
Toxins — Rhabdomyolysis may result from exposures to toxins other than medications . These include:
Infections — Rhabdomyolysis has been associated with a variety of infections, both viral and bacterial [8,58-60].
Acute viral infections associated with rhabdomyolysis include influenza A and B, Coxsackievirus, Epstein-Barr, herpes simplex, parainfluenza, adenovirus, echovirus, human immunodeficiency virus, and cytomegalovirus [58-60]. (See "Viral myositis", section on 'Viral myositis with rhabdomyolysis' and "Muscle disease in HIV-infected patients".)
The mechanism of muscle damage due to viral infections has not been established, as the presence of virus in affected muscle has been difficult to demonstrate consistently.
Other infections associated with rhabdomyolysis include:
Electrolyte disorders — Rhabdomyolysis has been associated with a variety of electrolyte disorders, particularly hypokalemia [68,69] and hypophosphatemia [70,71]. The latter association is most often seen in alcoholic patients and those receiving hyperalimentation without phosphate supplementation . Cases associated with hyperosmolality due to diabetic ketoacidosis or nonketotic hyperglycemia have also been described, and hypophosphatemia may contribute to the risk of rhabdomyolysis in some of these patients [72-74]. (See "Clinical manifestations and treatment of hypokalemia", section on 'Severe muscle weakness or rhabdomyolysis' and "Signs and symptoms of hypophosphatemia", section on 'Skeletal and smooth muscle' and "Treatment of diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults", section on 'Phosphate depletion'.)
Potassium release from muscle cells during exercise normally mediates vasodilation and the appropriately increased blood flow to muscles. Decreased potassium release due to profound hypokalemia (serum potassium less than 2.5 mEq/L) may promote the development of rhabdomyolysis by decreasing blood flow to muscles in response to exertion.
In both hypokalemic and hypophosphatemic rhabdomyolysis, the serum potassium and phosphate levels may underestimate or mask the underlying total body depletion because of the release of these electrolytes from intracellular stores due to the myonecrosis .
Endocrine disorders — Several endocrine disorders, including diabetes and thyroid diseases, have been associated with rhabdomyolysis, sometimes in combination with other causes. As noted in the previous section, both diabetic ketoacidosis and nonketotic hyperglycemia have been associated with rhabdomyolysis due at least in part to phosphate depletion and other electrolyte imbalances associated with this condition [72-74].
Hypothyroidism is frequently accompanied by myalgias and mild to moderate serum CK elevations. In addition, overt rhabdomyolysis has been described, and concurrent statin therapy may be a risk factor. (See "Hypothyroid myopathy", section on 'Rhabdomyolysis'.)
Inflammatory myopathies — Rhabdomyolysis has only rarely been described in patients with the inflammatory myopathies, dermatomyositis and polymyositis [82-84]. (See "Clinical manifestations of dermatomyositis and polymyositis in adults".)
Miscellaneous — Rhabdomyolysis is associated with a number of other conditions in occasional patients:
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