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Disclosures: Marc L Miller, MD Nothing to disclose. Ira N Targoff, MD Consultant/Advisory Boards: Oklahoma Medical Research Foundation Clinical Immunology Laboratory (myositis antibody testing). Jeremy M Shefner, MD, PhD Grant/Research/Clinical Trial Support: GlaxoSmithKline (ALS); Biogen Idec (ALS); Cytokinetics (ALS). Consultant: Trophos (SMA); ISIS Pharmaceuticals (SMA); Synaerion (ALS). Research Support: Sanofi Aventis (ALS); Synapse Biomedical (ALS). Monica P Ramirez, MD, MPH Employee of UpToDate, Inc.
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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 adenosine triphosphate (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 (CK) and other muscle enzymes, myoglobin, and various electrolytes.
●Traumatic or muscle compression (eg, crush syndrome or prolonged immobilization)
●Nontraumatic exertional (eg, marked exertion in untrained individuals, hyperthermia, or metabolic myopathies)
●Nontraumatic nonexertional (eg, drugs or toxins, infections, or electrolyte disorders)
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 has been reported in several large series of hospitalized patients [3,4,8]. In a study that included 2371 patients with rhabdomyolysis, the most frequently associated clinical conditions included trauma (26 percent), immobilization (18 percent), sepsis (10 percent), vascular surgery (8 percent) and cardiac surgery (6 percent) . In another series of 475 patients, the most common causes were exogenous toxins (46 percent), including alcohol and illicit drugs (34 percent) and medical drugs (11 percent) . Up to 60 percent of patients had more than one etiologic factor. Underlying myopathy or muscle metabolic defects were seen in 10 percent of the cases, in which there was a higher rate of recurrence and only one etiologic factor. No cause was identified in 7 percent of patients. Differences in the reported frequencies and the causes of rhabdomyolysis between these studies are likely related to differences in case ascertainment. (See 'Drugs' below.)
Another series with more than 50 patients focused on patients with infectious causes .
Trauma or muscle compression — Trauma or muscle compression is a common cause of rhabdomyolysis and can be seen in the following settings:
●A crush syndrome in victims of multiple traumata, particularly individuals trapped in cars after crashes or in collapsed buildings from earthquakes [10-13]. Many of these patients also experience a compartment syndrome. (See "Crush-related acute kidney injury (acute renal failure)".)
●Individuals struggling against restraints, torture victims, or abused children [14,15].
●Immobilization due to coma of any cause or in conscious individuals forced to lie in one position for hours, such as elderly hip fracture victims [16,17].
●Surgical procedures in which there is either prolonged muscle compression due to positioning during a long procedure [13,18,19], or vascular occlusion because of tourniquet use in orthopedic or vascular reconstruction procedures [13,20].
●Acute lower extremity compartment syndrome, with tibial fractures being the most common cause. (See "Acute compartment syndrome of the extremities", section on 'Epidemiology and risk factors'.)
●High-voltage electrical injury (eg, from lightning or high-voltage power supplies) or extensive third-degree burns, causing direct myofibrillar injury [2,21]. (See "Environmental electrical injuries".)
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 creatine kinase (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:
●The individual is physically untrained.
●Exertion occurs in extremely hot, humid conditions, which may lead to exertional heat stroke [24,25]. (See "Severe nonexertional hyperthermia (classic heat stroke) in adults".)
●Normal heat loss through sweating is impaired, as with the use of anticholinergic medications or heavy football equipment [25,26]. (See "Severe nonexertional hyperthermia (classic heat stroke) in adults".)
●Sickle cell trait occurs in an individual who exercises at high altitude, a setting in which the decreased partial pressure of oxygen causes erythrocyte sickling with subsequent vascular occlusion and muscle ischemia [27,28]. (See "Sickle cell trait", section on 'Risk for sudden death and athletic participation'.)
●Hypokalemia caused by potassium loss from sweating occurs [29,30]. The role of potassium in the regulation of skeletal muscle blood flow appears to be important in the pathogenesis in this setting . During exercise, there is normally an appropriate increase in muscle perfusion to meet enhanced energy demands. This hyperemic response is mediated in part by the release of potassium from skeletal muscle cells. The ensuing local elevation in the potassium concentration causes vasodilation, which enhances regional blood flow [31,32]. However, the cellular release of potassium is impaired by potassium depletion. As a result, there is a lesser increase in blood flow, possibly resulting in cramps, ischemic necrosis, and rhabdomyolysis . Hypokalemia-induced impairment in muscle metabolism also may contribute to muscle dysfunction .
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:
●Grand mal seizures
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:
●Malignant hyperthermia – Rhabdomyolysis is considered a later perioperative manifestation of malignant hyperthermia. Susceptibility is usually due to an inherited abnormality in the ryanodine receptor that causes the unregulated passage of calcium from the sarcoplasmic reticulum into the intracellular space. The most common trigger is the use of inhalation anesthetics. The persistent elevation of calcium causes sustained muscle contraction and results in ATP depletion, which causes hyperkalemia and rhabdomyolysis. (See "Susceptibility to malignant hyperthermia: Evaluation and management" and "Malignant hyperthermia: Clinical diagnosis and management of acute crisis".)
●Neuroleptic malignant syndrome – The neuroleptic malignant syndrome is a disorder in which high fever (with or without generalized muscle contraction or tremor) develops after exposure to neuroleptic drugs and anti-Parkinsonian drugs. Rhabdomyolysis has been reported . (See "Neuroleptic malignant syndrome".)
●Near drowning/hypothermia – Rhabdomyolysis with myoglobinuric acute renal failure can occur after prolonged immersion . The mechanism of rhabdomyolysis in this setting may involve hypothermia with muscle injury from marked vasoconstriction or from excessive shivering and/or generalized hypoxia. (See "Drowning (submersion injuries)".)
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]:
●Coma induced by alcohol, opioid overdose, or other central nervous system (CNS) depressants leads to immobilization and ischemic compression of muscle.
●Some drugs, including statins and colchicine, are direct myotoxins. In addition, statins can increase the risk of rhabdomyolysis in patients with other predisposing conditions, such as hypothyroidism or an inflammatory myopathy [43-45]. (See "Statin myopathy".)
●Drug-induced agitation states, drug-induced seizures, dystonic reactions, and cocaine-induced hyperthermia are associated with excess muscle energy demands. (See "Drug-induced myopathies", section on 'Cocaine'.)
●Drug-drug interactions may be responsible for rhabdomyolysis in some individuals. The nature of the interactions varies. As an example, some drugs interfere with the clearance of statins and lead to elevated plasma levels; offending agents include macrolide antibiotics (eg, erythromycin and clarithromycin), cyclosporine, gemfibrozil, and some protease inhibitors used in the treatment of HIV infection. (See "Drug-induced myopathies" and "Statin myopathy".)
●In some individuals exposed to drugs, multiple mechanisms may contribute to muscle damage; as an example, rhabdomyolysis with alcoholic binges may result from a combination of hypokalemia, hypophosphatemia, coma, agitation, and direct muscle toxicity.
●Dietary supplements used for weight loss or enhanced physical performance, which typically contain multiple ingredients, may lead to rhabdomyolysis, possibly as a result of metabolic stress [46,47]. In one report, nutritional supplements used in strength training caused rhabdomyolysis in otherwise healthy individuals . Nutritional supplements containing ephedra, creatine, and large doses of caffeine have been implicated, but these findings have also been reported in patients using supplements lacking these compounds .
●Patients undergoing isolated limb perfusion for locally recurrent melanoma may develop rhabdomyolysis as a complication of therapy [48,49]. The degree of injury is influenced by the specific drug administered and other factors, possibly including ischemia and hyperthermia. (See "Cutaneous melanoma: Management of local recurrence", section on 'Isolated limb perfusion'.)
Toxins — Rhabdomyolysis may result from exposures to toxins other than medications . These include:
●Metabolic poisons, such as carbon monoxide, which lead to insufficient muscle energy production. (See "Carbon monoxide poisoning".)
●Snake venoms, which occur from certain snake bites and are most often reported from Asia, Africa, and South America [50,51].
●Insect venoms, including wasp and bee stings [5,52,53].
●Mushroom poisoning [54-57]. (See "Clinical manifestations and evaluation of mushroom poisoning", section on 'Delayed rhabdomyolysis'.)
●An unidentified toxin found in certain types of fish [58-61]. The development of rhabdomyolysis within 24 hours of ingesting fish is referred to as Haff disease.
Infections — Rhabdomyolysis has been associated with a variety of infections, both viral and bacterial [9,62-64].
Acute viral infections associated with rhabdomyolysis include influenza A and B, Coxsackievirus, Epstein-Barr, herpes simplex, parainfluenza, adenovirus, echovirus, human immunodeficiency virus, and cytomegalovirus [62-64]. (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:
●Mycoplasma pneumoniae infection [65-67]. (See "Mycoplasma pneumoniae infection in adults", section on 'Other'.)
●Bacterial infections with a variety of microbial organisms, including Legionella, tularemia, Streptococcus and Salmonella, E. coli, leptospirosis, Coxiella burnetii (Q fever), and staphylococcal infection [5,9].
In patients with septicemia without direct muscle infection, muscle damage may be caused by a toxin, or from associated fever, rigors, and dehydration [69,70]. Toxic shock syndrome, most commonly caused by circulating streptococcal or staphylococcal exotoxins, may also result in rhabdomyolysis [71,72]. (See "Epidemiology, clinical manifestations, and diagnosis of streptococcal toxic shock syndrome" and "Staphylococcal toxic shock syndrome".)
●Human granulocytic anaplasmosis (ehrlichiosis) .
●Falciparum malaria .
Electrolyte disorders — Rhabdomyolysis has been associated with a variety of electrolyte disorders, particularly hypokalemia [75,76] and hypophosphatemia [77,78]. 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 [79-81]. (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 [79-81].
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 [89-91]. (See "Clinical manifestations of dermatomyositis and polymyositis in adults".)
Miscellaneous — Rhabdomyolysis is associated with a number of other conditions in occasional patients:
●Status asthmaticus, in which muscle injury may be due to respiratory muscle overexertion and/or generalized muscle hypoxia .
●The administration of non-depolarizing muscle blocking agents to critically ill intensive care unit patients who require mechanical ventilation. A hypothesis is that muscle was "primed" for such injury by the underlying disease state, the administration of high-dose glucocorticoids, or the presence of an additional factor related to the critical illness . (See "Use of neuromuscular blocking medications in critically ill patients".)
●The "capillary leak syndrome," a rare condition in which there are sudden, recurrent episodes of markedly increased capillary permeability, causing shifts of fluid from the intravascular to interstitial compartments. This shift leads to marked edema, limb swelling and possible compartment syndrome, hypovolemia, hypotension, and, in some cases, rhabdomyolysis [94,95]. (See "Idiopathic systemic capillary leak syndrome".)
SUMMARY AND RECOMMENDATIONS
●The clinical manifestations and complications of rhabdomyolysis result from muscle cell death, with the release of intracellular muscle constituents into the circulation. (See 'Introduction' above and 'Pathophysiology' above.)
•Traumatic or muscle compression (see 'Trauma or muscle compression' above)
●The most common clinical conditions associated with rhabdomyolysis include trauma, immobilization, sepsis, and vascular and cardiac surgeries. Other common causes of rhabdomyolysis include overexertion, and drugs and toxins such as lipid-lowering agents, alcohol, and cocaine. The majority of patients have more than one etiologic factor, and less than 10 percent have no identifiable cause. Rhabdomyolysis rarely occurs in association with an inflammatory myopathy. (See 'Causes' above and 'Inflammatory myopathies' above.)
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