Rhabdomyolysis: Epidemiology and etiology

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.

Other aspects of rhabdomyolysis and related conditions are reviewed separately:

● Rhabdomyolysis: Clinical manifestations and diagnosis

● Crush-related acute kidney injury

● Acute compartment syndrome of the extremities

● Clinical features and diagnosis of heme pigment-induced acute kidney injury

● Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis)

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 [1]. 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. Myoglobin contains heme, which is nephrotoxic. (See "Clinical features and diagnosis of heme pigment-induced acute kidney injury", section on 'Pathogenesis'.)

CLASSIFICATION — There are multiple potential causes of rhabdomyolysis [3-7]; these can be broadly divided into three categories related to mechanism of injury (table 1):

●Traumatic or muscle compression (eg, crush syndrome or prolonged immobilization)

●Nontraumatic exertional (eg, marked exertion in untrained individuals, eccentric exercises, hyperthermia, or metabolic and other myopathies)

●Nontraumatic nonexertional (eg, drugs or toxins, infections, or electrolyte disorders)

Rhabdomyolysis can also be classified as acquired (eg, trauma, drugs, physical exertion) or inherited (eg, muscular dystrophies, metabolic and mitochondrial disorders, sickle cell trait).

The specific cause is frequently evident from the history or from the immediate circumstances preceding the disorder, such as crush injury, comatose or postictal state, postoperative surgical trauma, or extraordinary physical exertion, as in status epilepticus for example. In other cases, the precipitant may not be as immediately evident but is identified through a careful history, physical examination, and laboratory evaluation [4,5,8]. The specific causes within each of the three major categories are discussed in detail in the sections below. (See 'Trauma or direct muscle injury' below and 'Nontraumatic exertional' below and 'Nonexertional and nontraumatic' below.)

EPIDEMIOLOGY

Incidence — The true incidence of rhabdomyolysis is unknown, mainly due to its highly variable presentation and underrecognition and reporting of mild cases [9]. In the United States, there are approximately 26,000 cases of rhabdomyolysis reported each year [10].

Common causes

Adult — Trauma, infections, drugs (illicit, prescribed, and alcohol), surgery, and exercise/physical exertion are the most common causes of rhabdomyolysis reported in adults [4,11-16].

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) [11]. 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) [4]. 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 and populations studied.

Pediatric — Infections, inherited conditions, and exercise/physical exertion are the most common causes of rhabdomyolysis reported in children [12,17-19].

Recurrent rhabdomyolysis — Recurrence of rhabdomyolysis is most often associated with inherited metabolic muscle conditions. (See 'Inherited disorders' below.)

Risk factors — Risk factors for rhabdomyolysis identified in various studies include [9,12,13,20-24]:

●Male sex

●Black race

●Age <10 years and >60 years

●Body mass index >40 kg/m²

●History of prior heat injury

●Low premorbid physical fitness

●Chronic use of lipid-lowering drugs

●Dehydration

TRAUMA OR DIRECT MUSCLE INJURY — Trauma or muscle compression is a common cause of rhabdomyolysis and can be seen in the following settings:

Crush syndrome — A crush syndrome describes muscle destruction caused by direct trauma, injury, or compression [13,25]. It is observed in victims of multiple trauma, including individuals trapped in cars after crashes or in collapsed buildings from man-made and natural disasters (eg, wars, earthquakes, hurricanes, tsunamis) [25-29]. Many of these patients also experience a compartment syndrome. (See "Crush-related acute kidney injury" and "Severe crush injury in adults" and "Severe lower extremity injury in the adult patient" and "Severe upper extremity injury in the adult patient".)

Prolonged immobilization — Prolonged immobilization due to coma of any cause, sedation or incapacitation (eg, drug intoxication, stroke, hip fracture), or surgery can cause rhabdomyolysis from unrelieved pressure on body regions [30,31].

Compression of blood vessels — Application of tourniquets, surgical clamps, splints, or even pneumatic compression devices can cause muscle ischemia with development of rhabdomyolysis [32,33].

Surgery — Rhabdomyolysis can develop as a complication of surgical procedures in which there is either prolonged muscle compression due to positioning [34-36] or prolonged vascular occlusion (eg, prolonged clamping) causing muscle ischemia [34,37]. (See "Patient positioning for surgery and anesthesia in adults".)

Compartment syndrome — Rhabdomyolysis can occur in association with severe lower extremity injury (eg, tibial fracture) complicated by compartment syndrome, or arterial ischemia followed by reperfusion injury leading to compartment syndrome. Muscle injury itself can lead to muscle edema and thereby cause compartment syndrome with blood flow limitation and a vicious cycle of worsening tissue necrosis [38]. (See "Acute compartment syndrome of the extremities", section on 'Epidemiology and risk factors' and "Pathophysiology, classification, and causes of acute extremity compartment syndrome".)

Electrical injury and severe burn injury — High-voltage electrical injury (eg, from lightning or high-voltage power supplies) or extensive third-degree burns can cause rhabdomyolysis via direct myofibrillar injury [2,39,40]. (See "Electrical injuries and lightning strikes: Evaluation and management".)

Physical restraint — Rhabdomyolysis has been associated with individuals struggling against restraints, such as torture victims or abused children [41-44].

NONTRAUMATIC EXERTIONAL — Rhabdomyolysis occurs when the energy supply to muscle is insufficient to meet demands. Examples include extreme exertion or exertion under conditions in which muscle energy production is impaired, including inherited muscle disorders.

Physical exertion and exercise — Rhabdomyolysis may arise from physical exertion, particularly when one or more of the following risk factors is present:

●Prolonged, strenuous, or unaccustomed activity – Physical activity that is strenuous or prolonged may cause rhabdomyolysis, even in trained individuals or in the absence of other known risk factors [45-50]. The performance of unaccustomed, intense exercise also increases the risk of rhabdomyolysis (eg, a deconditioned individual joining an indoor cycling class). 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 ultramarathon race of 99 kilometers [45]. The serum CK rose 16-fold from prerace levels to a mean of 2060 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 [51].

●Severe heat and humidity – Exertion in extremely hot, humid conditions may lead to exertional heat stroke and associated organ and tissue damage, including rhabdomyolysis. (See "Exertional heat illness in adolescents and adults: Epidemiology, thermoregulation, risk factors, and diagnosis", section on 'Exertional heat stroke'.)

●Impaired heat loss – Rhabdomyolysis may occur when normal heat loss through sweating is impaired, as with the use of anticholinergic medications or heavy football equipment [52,53]. (See "Severe nonexertional hyperthermia (classic heat stroke) in adults".)

●Hypokalemia – Hypokalemia caused by potassium loss from sweating can reduce vascular perfusion of muscle [54,55]. 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 [56,57]. 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 [56]. Hypokalemia-induced impairment in muscle metabolism also may contribute to muscle dysfunction [55].

●Eccentric exercise – The performance of high-force eccentric exercises increases the risk of muscle injury [38,58].

●Sickle cell trait – Sickle cell trait is associated with a slightly higher risk of exertional rhabdomyolysis. This issue is discussed in detail separately. (See "Sickle cell trait", section on 'Rhabdomyolysis and sudden death during strenuous physical activity'.)

Seizures and other hyperkinetic states — Pathologic hyperkinetic states can lead to rhabdomyolysis in individuals with normal muscles [3,59]. Examples include:

●Grand mal seizures

●Delirium tremens

●Psychotic agitation

●Amphetamine overdose

Inherited disorders — Rhabdomyolysis may develop in patients with inherited disorders that affect muscle function, metabolism, or energy production, including [60-63]:

●Metabolic:

•Glycogen metabolism disorders (eg, McArdle disease)

•Lipid metabolism disorders (eg, fatty acid oxidation disorders)

•Mitochondrial disorders

•Pathogenic gene variants that alter gene expression (eg, MLIP), impair muscle contraction (eg, MYH1), or disrupt excitation-contraction coupling and calcium handling (eg, OBSCN)

●Muscular dystrophies and congenital myopathies

The metabolic myopathies represent a very small percentage of cases of rhabdomyolysis overall but are relatively common causes among patients, particularly children, with recurrent episodes of rhabdomyolysis after exertion or starvation [32,64,65]. 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) [65]. 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 "Metabolic myopathies caused by disorders of lipid and purine metabolism", section on 'Carnitine cycle disorders' and "Myophosphorylase deficiency (glycogen storage disease V, McArdle disease)".)

"Pseudometabolic" myopathies may present with clinical symptoms similar to metabolic myopathies but are due to an underlying genetic myopathy or muscular dystrophy such as caveolinopathy, dysferlinopathy, sarcoglycanopathy, Becker muscular dystrophy, core myopathy, or nemaline myopathy [66-70]. These disorders are discussed in detail separately. (See "Metabolic myopathies caused by disorders of lipid and purine metabolism" and "Overview of inherited disorders of glucose and glycogen metabolism" and "Mitochondrial myopathies: Clinical features and diagnosis" and "Limb-girdle muscular dystrophy" and "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis" and "Congenital myopathies".)

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 ATP and creatine phosphate. The maintenance of muscle cell integrity is thereby compromised [71]. (See "Approach to the metabolic myopathies", section on 'Myoglobinuria and rhabdomyolysis' and "Energy metabolism in muscle" and 'Pathophysiology' above.)

Thermal extremes and dysregulation — Rhabdomyolysis may occur with hyperthermia associated with exertional heat stroke (see 'Physical exertion and exercise' above). Other causes of rhabdomyolysis in the setting of temperature dysregulation or thermal extremes include:

●Malignant hyperthermia – Rhabdomyolysis is considered a later manifestation of malignant hyperthermia (MH). Susceptibility to MH is usually due to an inherited abnormality, most commonly identified in the ryanodine receptor, that causes the unregulated passage of calcium from the sarcoplasmic reticulum into the intracellular space. The persistent elevation of calcium causes sustained muscle contraction and results in ATP depletion, which causes hyperkalemia and rhabdomyolysis. The most common MH triggers are the use of inhalation anesthetics or succinylcholine. However, there have been a number of reports of an MH-like event (some fatal) after strenuous exercise, exposure to hot environments, or both, unrelated to exposure to anesthetics, in patients who were MH susceptible. (See "Susceptibility to malignant hyperthermia: Evaluation and management" and "Malignant hyperthermia: 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 and anti-Parkinson medications. Rhabdomyolysis has been reported [72]. (See "Neuroleptic malignant syndrome".)

●Near drowning/hypothermia – Rhabdomyolysis with myoglobinuric acute kidney failure can occur after prolonged water immersion [73,74]. 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 — Nonexertional and nontraumatic causes of rhabdomyolysis include drugs and toxins, infections, electrolyte abnormalities, endocrinopathies, inflammatory myopathies, muscular dystrophies [69,75], and others [2,4-6].

Drugs — Both prescribed medications and drugs of abuse have been implicated in rhabdomyolysis [4,76].

Prescription medications — The most commonly reported prescription medications associated with rhabdomyolysis are [32]:

●Lipid-lowering drugs (statins and fibrates)

●Psychiatric medications (antipsychotics, lithium, serotonin-specific reuptake inhibitors, valproate)

●Antibiotics (protease inhibitors, trimethoprim-sulfamethoxazole, quinolones, amphotericin B)

●Antihistamines

●Others (aminocaproic acid, erlotinib, colchicine, glucocorticoids, narcotics, sunitinib, vasopressin)

An analysis of cases of drug-associated rhabdomyolysis reported to the US Food and Drug Administration (FDA) between 2004 and 2009 described 16,435 suspected drugs in 8610 reported cases of rhabdomyolysis, among which statin drugs were the most commonly reported [76]. (See "Statin muscle-related adverse events".)

Drugs of abuse — In addition to alcohol, drugs of abuse that have been implicated as causes of rhabdomyolysis include [32]:

●Cocaine

●Amphetamines and methamphetamines

●Heroin

●Lysergic acid diethylamide (LSD)

●Methadone

Mechanisms — The prescribed and illicit drugs cause rhabdomyolysis through various mechanisms [77,78]:

●Immobilization – Coma induced by alcohol, opioid overdose, or other central nervous system (CNS) depressants leads to prolonged immobilization and ischemic compression or crush injury of muscle. (See 'Trauma or direct muscle injury' above.)

●Myotoxicity – Some medications, including statins and colchicine, are direct myotoxins (see "Drug-induced myopathies", section on 'Drugs causing direct myotoxicity'). In addition, statins can increase the risk of rhabdomyolysis in patients with other predisposing conditions, such as hypothyroidism or an inflammatory myopathy. Muscle toxicity of statin medications is reviewed in detail elsewhere. (See "Statin muscle-related adverse events".)

●Malignant hyperthermia (MH) – Patients exposed to volatile anesthetic agents (eg, halothane, isoflurane, sevoflurane, desflurane) with or without administration of succinylcholine may develop MH. (See "Malignant hyperthermia: Diagnosis and management of acute crisis".)

●Drug-induced energy demands – 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 – These 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 human immunodeficiency virus (HIV) infection. (See "Drug-induced myopathies" and "Statin muscle-related adverse events".)

●Multiple mechanisms – In some individuals exposed to drugs, multiple mechanisms may contribute to muscle damage; as an example, rhabdomyolysis with alcohol binges may result from a combination of hypokalemia, hypophosphatemia, coma, agitation, and direct muscle toxicity.

●Dietary supplements – Dietary supplements used for weight loss or enhanced physical performance, which typically contain multiple ingredients, are associated with rhabdomyolysis, possibly as a result of metabolic stress [79,80]. In one report, use of nutritional supplements for strength training was associated with rhabdomyolysis in otherwise healthy individuals [79].

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 [80]. Creatine is a commonly used supplement, and evidence does not support its link to increased risk of rhabdomyolysis [38,81,82].

●Isolated limb perfusion – Patients undergoing isolated limb perfusion for locally recurrent melanoma may develop rhabdomyolysis as a complication of therapy [83,84]. 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 [5,61]. 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 [85,86].

●Insect venoms, including wasp and bee stings [5,87,88].

●Mushroom poisoning [89-92]. (See "Clinical manifestations and evaluation of mushroom poisoning", section on 'Delayed rhabdomyolysis'.)

●An unidentified toxin found in certain types of fish [93-97]. The development of rhabdomyolysis within 24 hours of ingesting fish is referred to as Haff disease.

●Quail poisoning from eating quails that consumed Galeopsis ladanum seeds, which are toxic for humans [98].

Infections — Rhabdomyolysis has been associated with numerous infections, including viral, bacterial, fungal, and protozoal [7,32,99-101].

●Viral – Acute viral infections associated with rhabdomyolysis include influenza A and B, coxsackievirus, Epstein-Barr, herpes simplex, parainfluenza, adenovirus, echovirus, HIV, and cytomegalovirus (see "Overview of viral myositis", section on 'Pathogenesis') [100,102,103]. The most common viral etiologies of rhabdomyolysis are influenza and HIV [101]. Rhabdomyolysis can occur with the initial or end stages of HIV infection or be associated with antiretroviral therapy or opportunistic infections [104,105]. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), may also be associated with rhabdomyolysis [106-110]. (See "COVID-19: Clinical features", section on 'Laboratory findings'.).

●Bacterial – Bacterial infections associated with rhabdomyolysis include Clostridium, Coxiella burnetii (Q fever), ehrlichiosis, Escherichia coli, Legionella, leptospirosis, Mycoplasma pneumoniae, Salmonella, staphylococcal infection, Streptococcus, tularemia, and bacterial pyomyositis [5,99,111-113]. The most common bacterial etiologies of rhabdomyolysis are Legionella, Streptococcus, and Salmonella species [101].

●Others – Malaria caused by Plasmodium falciparum infection has been associated with rhabdomyolysis [114,115].

●Sepsis – In patients with septicemia without direct muscle infection, muscle damage may be caused by a bacterial toxin or from associated fever, rigors, and dehydration [116,117]. Toxic shock syndrome, most commonly caused by circulating streptococcal or staphylococcal exotoxins, may also result in rhabdomyolysis [118,119]. (See "Invasive group A streptococcal infection and toxic shock syndrome: Epidemiology, clinical manifestations, and diagnosis" and "Staphylococcal toxic shock syndrome".)

Electrolyte disorders — Rhabdomyolysis has been associated with a variety of electrolyte disorders, particularly hypokalemia [120,121] and hypophosphatemia [122,123]. The latter association is most often seen in patients with an alcohol use disorder and those receiving hyperalimentation without phosphate supplementation [122]. 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 [124-126]. (See "Clinical manifestations and treatment of hypokalemia in adults", section on 'Severe muscle weakness or rhabdomyolysis' and "Hypophosphatemia: Clinical manifestations of phosphate depletion", section on 'Skeletal and smooth muscle' and "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment", 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. (See 'Physical exertion and exercise' above.)

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 [122].

Other electrolyte disorders have been occasionally associated with rhabdomyolysis. These include hypocalcemia [127]; hyponatremia, mostly due to primary polydipsia [128,129]; and hypernatremia [130,131].

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 [124-126]. (See 'Electrolyte disorders' above.)

Hypothyroidism is frequently accompanied by myalgias and mild to moderate serum creatine kinase (CK) elevations. Hypothyroid myopathy manifests additionally with mild proximal muscle weakness, muscle hypertrophy, and myoedema. In addition, overt rhabdomyolysis has been described, and concurrent statin therapy may be a risk factor. (See "Hypothyroid myopathy", section on 'Rhabdomyolysis'.)

Rhabdomyolysis has also been infrequently described in several other endocrine disorders. These include hyperthyroidism [132] and pheochromocytoma [133].

Inflammatory myopathies — Rhabdomyolysis has only rarely been described in patients with the inflammatory myopathies, dermatomyositis and polymyositis [134-136]. (See "Clinical manifestations of dermatomyositis and polymyositis in adults".)

Note that statin-associated immune-mediated necrotizing myopathy (IMNM) can have a subacute to acute onset with very elevated CK levels. The evaluation is reviewed in the algorithm (algorithm 1). IMNM and statin myopathy are discussed in detail separately. (See "Clinical manifestations and diagnosis of immune-mediated necrotizing myopathy" and "Statin muscle-related adverse events".)

Muscular dystrophies — Rhabdomyolysis has also been reported as a presenting manifestation of muscular dystrophies, with a variety of causative genes. The onset of rhabdomyolysis is commonly associated with a trigger (exercise or fever) but may be unprovoked in 23 percent [69]. (See "Limb-girdle muscular dystrophy" and "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis".)

RYR1 pathogenic variants — The RYR1 gene encodes for the skeletal muscle ryanodine receptor, a calcium release channel. Pathogenic variants in the RYR1 gene are frequently identified in patients with exercise intolerance and elevated CK levels, which is part of a continuum between exertional rhabdomyolysis, malignant hyperthermia, and RYR1-related congenital myopathies [137-140]. RYR1 pathogenic variants leading to rhabdomyolysis are inherited in an autosomal dominant pattern [141].

OTHER UNCOMMON CONDITIONS — Rhabdomyolysis is associated with a number of other conditions in occasional patients:

●Reports from hospital centers in Italy have described migrants arriving from West Africa presenting with severe rhabdomyolysis and fever. Evidence of viral infections (mostly Epstein-Barr virus [EBV] and coxsackievirus) was present in one-third of cases. Other factors such as trauma, nutritional factors, toxins, and sickle cell trait may have also contributed to the development of rhabdomyolysis [142,143].

●Status asthmaticus, in which muscle injury may be due to respiratory muscle overexertion and/or generalized muscle hypoxia [144].

●The administration of nondepolarizing 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 [145]. (See "Neuromuscular blocking agents in critically ill patients: Use, agent selection, administration, and adverse effects".)

●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 [146,147]. (See "Idiopathic systemic capillary leak syndrome".)

●Abrupt withdrawal of the gamma-aminobutyric acid (GABA) agonist baclofen, particularly if given intrathecally, which can lead to severe muscle spasticity and muscle necrosis [148,149].

●TASER-associated rhabdomyolysis [150-152]. Reported cases are rare, and the risk appears to be low. The mechanism may be sustained muscle contraction with depletion of ATP, the cellular source of energy. Most reported cases had coexisting risk factors or predisposing conditions for rhabdomyolysis. (See "Evaluation and management of injuries from conductive energy devices (eg, TASERs)", section on 'Impact of muscle contraction'.)

SUMMARY AND RECOMMENDATIONS

●Pathophysiology – Rhabdomyolysis results from muscle cell death due to direct injury of the plasma membrane or to energy depletion. The release of intracellular muscle constituents into the circulation leads to the clinical manifestations and complications of rhabdomyolysis. (See 'Introduction' above and 'Pathophysiology' above.)

●Classification – The multiple potential causes of rhabdomyolysis can be broadly divided into three categories, which are (table 1):

•Trauma or direct muscle injury – This category of rhabdomyolysis is seen in clinical settings that include crush syndrome (ie, direct muscle trauma, injury, or compression), prolonged immobilization, compression of blood vessels, surgery, compartment syndrome, electrical injury, severe burn injury, and physical restraint. (See 'Trauma or direct muscle injury' above.)

•Nontraumatic exertional – This category includes physical exertion and exercise (particularly when prolonged, strenuous, and/or performed in hot, humid conditions), seizures and other hyperkinetic states, inherited disorders (eg, metabolic myopathies), and thermal extremes/dysregulation (eg, exertional heat stroke, malignant hyperthermia). (See 'Nontraumatic exertional' above.)

•Nontraumatic nonexertional – This category includes prescribed and illicit drugs (eg, statins, cocaine), toxins (eg, carbon monoxide), infections (eg, influenza virus, Legionella species), electrolyte disorders (eg, hypokalemia), endocrine disorders (eg, diabetic ketoacidosis), and, rarely, inflammatory myopathies or muscular dystrophies. (See 'Nonexertional and nontraumatic' above.)

The etiology of rhabdomyolysis can also be related to acquired factors (eg, trauma, drugs, physical exertion) or genetic predisposition (eg, muscular dystrophies, metabolic and mitochondrial disorders, sickle cell trait). (See 'Classification' above.)

●Most common causes – The most common clinical conditions associated with rhabdomyolysis in adults are trauma, infections, drugs (illicit and prescribed), and surgery. The most common conditions associated with rhabdomyolysis in children are infections, inherited conditions, and exercise/physical exertion. Most patients have more than one etiologic factor, and less than 10 percent have no identifiable cause. (See 'Common causes' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marc L Miller, MD, who contributed to an earlier version of this topic review.