Rhabdomyolysis …

Neuromuscular Disorders

Updated 02.11.2026
Released 09.06.1993
Expires For CME 02.11.2029

Rhabdomyolysis

Authors: Yigit Karasozen MD, Payam Soltanzadeh MD FAAN

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Editor: Nicholas E Johnson MD MSCI FAAN

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Rhabdomyolysis

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Introduction

Overview

Rhabdomyolysis refers to the rapid breakdown of striated muscle that is followed by leakage of the muscle fiber contents, including myoglobin protein and electrolytes, into the bloodstream, leading to acute renal failure and potentially death in severe cases. Myoglobinuria refers to the excretion of excess myoglobin in urine. The etiology of rhabdomyolysis is diverse and includes various hereditary (metabolic diseases, muscular dystrophies, channelopathies) and acquired disorders affecting the skeletal muscles (excessive muscular stress, ischemia, toxic damage, infections). Epidemiologic studies have shown that the etiology of a significant percentage of patients with recurrent rhabdomyolysis remains unknown. It is thought that patients with rhabdomyolysis may have undiscovered muscle metabolism disorders. In this article, the authors review the epidemiology of rhabdomyolysis in adult and pediatric populations, the metabolic causes of recurrent rhabdomyolysis, and some preventive and treatment strategies for this condition.

Key points

	• Extensive work-up for rhabdomyolysis is indicated for recurrent or familial rhabdomyolysis and myalgia or muscle cramps, especially when not provoked by exercise or trauma.
	• The most common cause of the first episode of rhabdomyolysis in an adult who does not report a history of earlier significant exertion is drugs.
	• The most common etiologies of rhabdomyolysis in the pediatric population are trauma and viral myositis.
	• Genetic testing should be the first tier of diagnostic testing in people with one or more episodes of nonprovoked rhabdomyolysis.
	• Electrodiagnostic testing and muscle biopsy should also be considered. It is always recommended to wait at least 4 to 8 weeks after an episode of rhabdomyolysis is resolved to obtain a muscle biopsy.
	• Knowing the baseline creatinine kinase (CK) in a patient who has known chronic muscle disease with recurrent rhabdomyolysis is important.

Historical note and terminology

The term “rhabdomyolysis” originates from the combination of the Greek words rhábdos (“rod”), mûs (“muscle”), and lúsis (“loosening”) and refers to the rapid breakdown of skeletal (striated) muscle. Muscle tissues contain the oxygen-binding protein myoglobin. When striated muscles break down or rhabdomyolysis occurs, muscle cell content leaks into the blood, including myoglobin, leading to an excess amount excreted into the urine. This phenomenon is called myoglobinuria (22). Rhabdomyolysis was first reported by Fleischer in Germany in 1881.

Pigmenturia, in association with symptoms of muscle injury, was recognized in the German literature in the late 19th century as a disorder that affected horses and humans (41). Over the first half of the 20th century, biochemical studies led to the identification and characterization of the muscle heme protein myoglobin and elucidation of its role in transporting oxygen from hemoglobin to mitochondria (49). Parallel clinical observations established more firmly the link between muscle injury and the urinary excretion of myoglobin and began to outline the epidemiology of this syndrome. Of special note are the studies of Bywaters, which identified rhabdomyolysis as a complication of muscle crush injuries sustained in the Battle of Britain in World War II; he described acute renal failure as a rhabdomyolysis complication and performed seminal experimental studies implicating myoglobin (rather than other constituents of injured muscle) in the pathogenesis of renal injury (16).

The term “rhabdomyolysis” has been increasingly employed since the 1960s to denote the abrupt muscle injury that causes myoglobinuria. Thus, myoglobinuria and rhabdomyolysis are not synonymous but are sometimes used interchangeably because myoglobinuria would not occur without rhabdomyolysis (67; 22). The clinical presentation is variable. The classical features are myalgia, weakness, pigmenturia, or dark, tea-colored urine. However, this triad is seen in only 10% to 18% of patients (62). The urine becomes pigmented with a brownish color when myoglobin concentration is over 100 µg/mL (11).

There was significant heterogeneity in the definition and diagnostic criteria of rhabdomyolysis in two different systematic reviews (20; 99). However, most studies defined rhabdomyolysis as an elevation of serum creatine kinase (CK) level of at least five times the upper limit of normal or greater than 1000 international units (IU) per liter (which can be considered equivalent), followed by its decrease to (near) normal values. Others use a CK level greater than 10 times the upper limit of normal or greater than 5000 IU/L; a smaller number of studies use a CK level greater than 10,000 IU/L. The chronological sequence of CK elevation should be defined as acute or within 72 hours. It should be noted that baseline CK levels can vary significantly based on different demographic and body composition characteristics and may also be affected by other factors, such as physical activity and cardiac, kidney, and chronic neuromuscular diseases (36; 99). Having a baseline CK in these settings would be highly valuable.

Clinical manifestations

Presentation and course

Muscle symptoms. The acute skeletal muscle injury that produces rhabdomyolysis typically causes myalgia and muscle swelling, the latter attributable to a shift of extracellular fluid into necrotic muscle. The severity of these symptoms is conditioned by the extent and location of muscle injury. With severe generalized muscle injury, the patient is extremely exhausted, is unable to move because of widespread muscle pain and weakness, and has tight, swollen muscles causing stiffness and exquisite pain to muscle palpation or attempted movement (58). Compared with common muscle soreness, the weakness and stiffness seem more acute and sustained in rhabdomyolysis. Also, pain tends to be present even at rest in rhabdomyolysis but abates with rest in muscle soreness (81). In some circumstances, muscle injury and symptoms may be focal. Muscle swelling in a restricted anatomic region may lead to a compartment syndrome in which the swelling blocks muscle blood flow, leading to a “second wave” of ischemic muscle necrosis and further swelling that ultimately leads to neural and vascular injury (58). Organ failure can occur, depending on the extent and severity of muscle damage, and is the cause of death in about 8% of cases (14). At the other extreme, muscle symptoms may be relatively minor or overshadowed by complications of rhabdomyolysis or by symptoms of the acute event or illness that triggered muscle injury (34).

Renal manifestations. The most important complication of rhabdomyolysis is acute kidney injury or acute renal failure, occurring in 13% to 50% of patients due to renal vasoconstriction, intraluminal cast formation, and direct myoglobin toxicity (108; 83). Pigmenturia typically occurs in close temporal relation to the acute muscle injury or when circulation is restored to necrotic muscle and is attributable to the release of myoglobin into the bloodstream with rapid clearance by the kidney. Oliguria may herald the onset of acute renal failure. The likelihood of renal failure is greatly increased by the presence of hypotension, decreased renal perfusion, dehydration, acidosis, or use of nephrotoxic drugs (22). Increased serum levels of myoglobin greater than 15,000 micrograms/L were also found to correlate significantly with developing acute kidney injury in both adult and pediatric groups (87; 83; 62).

Other symptoms and complications. With catastrophic rhabdomyolysis, hypotension or shock may occur because of large fluid shifts (third spacing). In these instances, the common finding of acute hypoalbuminemia probably indicates an associated endothelial injury. Cardiac arrhythmia may occur because of hyperkalemia due to potassium release from necrotic muscle and renal compromise. Aside from hyperkalemia, other electrolyte abnormalities can also be observed: hypocalcemia, hypercalcemia, hyponatremia, hyperphosphatemia, and metabolic acidosis (83). Disseminated intravascular coagulation, possibly attributable to thromboplastin release from injured muscle, could complicate severe rhabdomyolysis, and hemorrhagic complications may also result. Acute respiratory distress syndrome (ARDS) attributable to the involvement of muscles of respiration or to pulmonary capillary hyperpermeability has been described. Ischemic or infarcted bowels have also been reported.

Skin changes of ischemic tissue injury, such as discoloration or blisters, may also be seen but are present in less than 10% of patients (42).

Laboratory findings. The rhabdomyolysis period is generally brief (hours). Creatine kinase levels tend to peak 24 to 72 hours after the acute injury (99), usually reaching levels of 1000s to 100,000s of international units (IU) per liter. CK levels then decline by about 50% approximately every 48 hours. Serum aldolase, transaminases, and lactate dehydrogenase are correspondingly elevated. Additional laboratory abnormalities may include hyperkalemia, particularly in the setting of renal failure; metabolic acidosis; hyperphosphatemia; hypocalcemia related to the deposition of calcium salts in injured muscle; and hyperuricemia. Myoglobinuric renal failure characteristically produces a disproportionately elevated creatinine relative to blood urea nitrogen. Hemoconcentration accompanies fluid shifts into injured muscle.

The major laboratory features of myoglobinuria are pigmenturia and elevation of cytoplasmic enzymes liberated from injured muscle. The myoglobin level in urine is a function of the mass of injured muscle and the rate of urine flow. Visible discoloration of the urine is apparent with myoglobin concentrations of 100 µg/mL. Radioimmunoassay quantitatively detects myoglobin to about 5 ng/mL. Normal serum levels are 30 to 80 micrograms/L, whereas urine levels are 3 to 20 micrograms/L. Myoglobinuria is diagnosed when urine concentrations exceed 20 micrograms/L (22; 83).

Although the pathologic processes responsible for rhabdomyolysis are diverse, the histologic features often are similar. Typically, a population of muscle fibers shows evidence of injury and is all at a similar stage of necrosis or regeneration, depending on the timing of the biopsy, consistent with injury affecting a susceptible population of muscle fibers within a limited time frame. A biopsy temporally remote from the episode of rhabdomyolysis (at least 4 to 8 weeks later) commonly reveals virtually normal muscle morphology, reflecting the remarkable regenerative capacity of skeletal muscle. It may also reveal the underlying cause (metabolic, mitochondrial myopathy, etc.)

Prognosis and complications

Massive muscle injury triggered by severe exertion or myotoxins may result in multiple organ failure and death. However, rhabdomyolysis generally has a good prognosis if renal failure is avoided or aggressively treated. Muscle tissue has a remarkable capacity to regenerate, and most patients recover muscle function fully. Even patients who have had multiple episodes of rhabdomyolysis may have no lasting skeletal muscle effects. However, muscle weakness and focal loss of muscle mass attributable to recurrent muscle injury can occur late in life in some metabolic muscle diseases, such as myophosphorylase deficiency and carnitine palmitoyltransferase II (CPT-2) deficiency.

Clinical vignette

After an hour of unaccustomed weightlifting to “get in shape,” a 28-year-old white male experienced pain affecting the muscles of the upper arms, chest, and back. Urine was noted to be cola colored on voiding an hour later. Twelve hours later, the patient's arms were swollen, and it hurt to move them. He felt generally unwell and nauseated and was treated symptomatically for possible flu. The following day, on presentation to an emergency room, creatine kinase was 100,000 IU, and serum creatinine and blood urea nitrogen were elevated. The patient underwent hemodialysis for acute renal failure. The admitting physician obtained a history of virtually lifelong exercise intolerance. An ischemic forearm test showed no lactate increase, and a subsequent muscle biopsy revealed absent muscle glycogen phosphorylase reactivity (McArdle disease). Genetic testing showed compound heterozygous missense and nonsense mutations in the PYGM gene.

Biological basis

Etiology and pathogenesis

The number of hereditary and acquired disease processes that may produce rhabdomyolysis, including drugs, toxins, and underlying metabolic errors, is continually expanding (Tables 1 and 2). Correspondingly, rhabdomyolysis has gone from a medical oddity to a commonly recognized event.

The main hereditary disorders predisposing to recurrent episodes of rhabdomyolysis include inborn errors of muscle metabolism affecting carbohydrate or lipid metabolism. These disorders may present with exercise intolerance, cramps, or rhabdomyolysis. In muscle glycogenolytic or glycolytic defects, the problem is forming immediate energy during exercise, and rhabdomyolysis is typically triggered by brief intense exercise. McArdle disease due to myophosphorylase deficiency (PGYM gene) is the most common glycogen storage disease involved in rhabdomyolysis. Muscle symptoms emerge rapidly with physical activity, followed by a “second wind phenomenon,” when ATP is formed via fatty acyl oxidation. Other glycogen storage causes include Tarui disease due to phosphofructokinase deficiency (PFKM gene), phosphorylase kinase deficiency (PHKA1, PHKB genes), beta-enolase (ENO3 gene), phosphoglycerate mutase (PGAM2 gene), phosphoglycerate kinase 1 (PGK1 gene), aldolase A (ALDOA gene), lactate dehydrogenase (LDHA gene), and phosphoglucomutase (PGM1 gene) deficiencies (28; 76; 23). Enzyme activities, especially myophosphorylase and phosphofructokinase, can be assessed histochemically.

Lipid disorders are another major group of metabolic disorders that can present with rhabdomyolysis. These are characterized by dysfunction of fatty acid entry into mitochondria and mitochondrial beta-oxidation. The major lipid disorder causing recurrent rhabdomyolysis is carnitine palmitoyltransferase II (CPT-2) deficiency (CPT2 gene) (28; 23). Prolonged and submaximal exercise, particularly when associated with fasting, is most often implicated; intercurrent infection may also trigger muscle injury in this disorder. Approximately two thirds of patients with fatty acid oxidation defects suffer from episodic myalgias, elevated creatine kinase, and myoglobinuria (92). Fatty acid oxidation defects disrupting the oxidation of long-chain fatty acids are more often associated with recurrent rhabdomyolysis, whereas enzyme deficiencies disrupting the oxidation of short- and medium-chain fatty acids result in rhabdomyolysis on rare occasions (104; 90; 51; 92). The most commonly described disease causing intramitochondrial fatty acid oxidation impairment is very-long-chain acylCoA dehydrogenase deficiency (VLCAD) due to mutations in the ACADVL gene. Patients typically experience exercise intolerance and recurrent pigmenturia triggered by activity, cold exposure, or fasting starting in childhood (76).

A disorder involving lipid homeostasis due to lipin-1 deficiency, which is a key enzyme in triglyceride and membrane phospholipid biosynthesis, has been described. Patients with LPIN1 mutations experience severe rhabdomyolysis episodes triggered by febrile illness, fasting, or exercise in early childhood (115; 23).

Respiratory chain and other mitochondrial disorders are increasingly recognized as causes of exercise intolerance with or without rhabdomyolysis. Such conditions include cytochrome c and b oxidase deficiencies and deficiencies of complex I, complex II, and complex III, as well as primary coenzyme Q10 deficiency (27; 76). Mutations in mtDNA, including multiple deletions or point mutations in tRNA genes, have also been associated with recurrent rhabdomyolysis (103; 66; 29). A deficiency of the dihydrolipoamide dehydrogenase enzyme (DLD) was characterized by recurrent attacks of vomiting, abdominal pain, and encephalopathy accompanied by elevated liver transaminases, prolonged prothrombin time, and occasionally associated with lactic and ketoacidemia or with rhabdomyolysis (97). Another mitochondrial disease mechanism characterized by exercise intolerance and rhabdomyolysis is impairment of mitochondrial iron-sulfur [Fe-s] cluster assembly due to nuclear DNA mutations in the ISCU and FDX2 genes, which leads to impaired muscle oxidative metabolism (74; 23). Late-onset thymidine kinase 2 deficiency, which causes mitochondrial DNA depletion syndrome, was also found to result in recurrent rhabdomyolysis and exercise intolerance in one patient (24).

Other biochemical defects associated with rhabdomyolysis include glucose 6-phosphate dehydrogenase deficiency (pentose pathway) and, rarely, myoadenylate deaminase deficiency (purine nucleotide cycle) (109).

Other causes of hereditary rhabdomyolysis include pathogenic mutations in ryanodine receptor (RYR1), which mediates calcium release from the sarcoplasmic reticulum during excitation-contraction coupling, as well as other ion channel mutations broadly termed “skeletal muscle channelopathies.” RYR1 mutations can cause a wide spectrum of muscle diseases, including various types of congenital myopathy. RYR1-related exertional rhabdomyolysis mainly occurs in individuals who also have susceptibility to malignant hyperthermia, and this trait is inherited with autosomal dominant transmission due to numerous different missense mutations. These individuals have a predisposition to develop muscle rigidity, hypermetabolism, fever, and rhabdomyolysis triggered by volatile anesthetics or depolarizing muscle relaxants, as well as exercise-induced rhabdomyolysis, but they rarely exhibit any muscle weakness. On the contrary, they may exhibit muscle hypertrophy and even superior athletic abilities (48; 94). Other ion channel genes associated with malignant hyperthermia and exertional rhabdomyolysis susceptibility are CACNA1S, which encodes an L-type Ca²⁺ channel and plays a role in calcium regulation during excitation-contraction coupling (48), and SCN4A, which encodes a voltage-gated skeletal muscle sodium channel (75). Recurrent rhabdomyolysis can be the sole finding in these channelopathies or can be seen along with congenital myopathy, periodic paralysis, or paramyotonia congenita phenotypes.

Further causes of hereditary rhabdomyolysis include muscular dystrophies. Exercise-induced rhabdomyolysis has been reported in cases with Duchenne or Becker muscular dystrophy (dystrophinopathies) and various limb-girdle muscular dystrophies (LGMDs), including dysferlinopathy (DYSF gene), calpainopathy (CAPN3 gene), anoctaminopathy (ANO5 gene), sarcoglycanopathies (SGCA, SGCB, SGCG genes), and dystroglycanopathies (FKTN and FKRP genes) (17; 76; 23). Recurrent rhabdomyolysis can rarely be the initial presentation of limb-girdle muscle dystrophies (63). A high incidence of rhabdomyolysis and muscle pain has been reported in limb-girdle muscular dystrophy 2I due to FKRP gene mutations (68). There are multiple case reports of bisphosphonate-induced and anesthesia-induced rhabdomyolysis in Duchenne muscular dystrophy (73; 77; 44), in addition to cases triggered by exercise. Ritodrine-induced rhabdomyolysis has been reported in myotonic dystrophy (91; 78).

Additional discoveries have expanded the genetic landscape of recurrent rhabdomyolysis. Obscurin, encoded by the OBSCN gene, is a muscle protein located at the M-band and Z-discs and plays an important role in the stability and maintenance of the contractile unit and microtubule network. OBSCN gene variants have been previously implicated in inherited cardiomyopathies and, more recently, biallelic loss-of-function variants have been implicated in causing exercise intolerance, rhabdomyolysis, and myoglobinuria without any evidence of concomitant cardiomyopathy in nine unrelated patients (116; 65). Mutations in TANGO2 can cause an autosomal recessive disorder characterized by developmental delay, episodic rhabdomyolysis, and cardiac arrhythmias, often diagnosed in childhood. A milder phenotype with adult-onset presentation with episodic weakness and recurrent rhabdomyolysis is also reported (98). Different homozygous variants in MYH1, encoding myosin heavy chain 1, were linked to a recurrent rhabdomyolysis phenotype in two unrelated patients (106). The list of novel genetic causes will likely continue to expand over the years.

Recurrent rhabdomyolysis precipitated by infection has been reported in yet another known hereditary condition, Marinesco-Sjögren syndrome, due to autosomal recessive mutations in SIL1, which causes a wide spectrum of central and peripheral nervous system involvement, as well as myopathy (72; 94).

Rhabdomyolysis can also be observed as the initial presenting symptom or during the course of immune-mediated muscle disease, such as dermatomyositis, overlap myositis, or immune-mediated necrotizing myopathy (76; 100). Having symptoms of acute pain and new weakness may be clues to an episode of rhabdomyolysis (76).

Single episodes of rhabdomyolysis in individuals without hereditary predisposition occur in several clinical settings. Trauma or crush injuries occur when individuals are pinned by falling debris (12) and in comatose or anesthetized individuals when muscles are compressed for prolonged periods by the weight of the patient’s body (82). In this context, it is important to highlight a report of child abuse presenting with rhabdomyolysis (26). In these clinical settings of trauma and compression, intramuscular pressure exceeds arterial pressure and renders the muscle ischemic (79). Hypotension, respiratory depression, and metabolic inhibition (when barbiturates, carbon monoxide, or related agents are involved) may contribute to muscle injury. Acute vascular occlusion with muscle infarction also produces rhabdomyolysis (02). When circulation is restored, soluble constituents of necrotic muscle are released into the bloodstream, myoglobinuria occurs, and the cascade of medical complications of acute muscle necrosis.

Among active or well-conditioned individuals, sporadic rhabdomyolysis may also occur in the setting of extreme and excessive exercise or with potentiating factors of dehydration and hyperthermia (54; 67). Muscle glycogen depletion may play a role. Military recruits and weekend athletes engaging in unaccustomed, intense exercise are the typical victims, and men are affected much more commonly than women. The U.S. Army regularly publishes data on cases of exertional rhabdomyolysis in active military members. Annual rates of exertional rhabdomyolysis are usually 300% to 400% higher than the estimated U.S. civilian population, and incidence rates are 6 to 10 times greater in new recruits than in all other service members (08). Exercise involving lengthening (eccentric) muscle contractions is often involved (09). In these circumstances (for example, running downhill), the muscle is both contracted and stretched, acting as a shock absorber. This type of muscle injury characteristically results in delayed onset muscle soreness with minimal symptoms immediately after exercise, but with progressive muscle pain and restricted range of motion of affected muscle groups developing 12 to 48 hours later. The onset of rhabdomyolysis may similarly be delayed to 24 to 48 hours after exercise. Poor physical conditioning and high body mass index predispose to exertional muscle injury. Physical conditioning is protective; however, even physically fit individuals who push beyond their normal limits may still develop catastrophic rhabdomyolysis (55; 67). In a systemic review of exertional rhabdomyolysis in athletes, the most common triggering activity was running in 54.3% (n = 419/772), mostly training for marathons, followed by weightlifting in 14.8% (n = 114/772) (10). Exertion-related rhabdomyolysis may also follow generalized or focal seizures as a result of muscle hyperactivity induced by drugs. Severe, rapidly progressive dystonia (“dystonic storm”) has also been associated with rhabdomyolysis (47). Acquired hyperthermic syndromes such as heat stroke can lead to muscle damage and rhabdomyolysis. Prolonged hypothermia can also cause rhabdomyolysis (109).

Toxins, drugs, and substance abuse represent a major cause of acquired rhabdomyolysis. Epidemics of paralytic rhabdomyolysis in humans and animals occurred in the 1920s and 1930s near the Frisches Haff of the Baltic Sea and in Sweden. This uncommon syndrome, characterized by intense myalgia and rhabdomyolysis, which manifests within 24 hours of consuming some type of freshwater or saltwater fish or crustaceans, was named “Haff disease” and has been reported in many different countries since then (03). The mechanism likely involves a heat-stable toxin. Quail poisoning (coturnism) is an analogous condition in which individuals ingesting quail develop rhabdomyolysis. The biblical quail episode (Numbers 11:31-33) may represent epidemic myoglobinuria. It is unclear whether what caused this was the ingested sweet parsley seeds, henbane, or hemlock. Similar accounts have been found with other birds that have ingested hemlock. Rhabdomyolysis due to venoms of insects (hornet, tarantula) and snakes (sea snake, rattlesnake) has been documented. Mushrooms, such as Russula spp and Tricholoma spp., may also induce rhabdomyolysis, especially those with genetic predispositions (05). In recent years, multiple cases of rhabdomyolysis and muscle weakness associated with jellyfish envenomation were reported in various parts of the world (89; 15).

Ethanol abuse is one of the most common causes of rhabdomyolysis. A direct toxic effect of ethanol may be the predominant mechanism of alcoholic rhabdomyolysis, but crush injury, seizures, hypokalemia, and hypophosphatemia are often present (34; 56; 76). More recently, barbiturates, heroin, cocaine, amphetamines, phencyclidine, ecstasy, phenylpropanolamine, inhalants, and related agents have all been associated with rhabdomyolysis (109). Coma with crush injury (barbiturates), direct myotoxic effects (heroin, cocaine, toluene), and muscle hyperactivity (amphetamines, phencyclidine, ecstasy, and lysergic acid diethylamide) may be involved.

Several therapeutic agents can cause muscle injury and rhabdomyolysis (Table 2), including lipid-lowering agents, such as statins and fibrates (96). The incidence of rhabdomyolysis increases when statins and other lipid-lowering agents are combined with each other (84) or with other medications, such as cyclosporin or colchicine (38; 117). Hypokalemia induced by K+ wasting agents (eg, amphotericin B, diuretics, laxative abuse) or pseudohyperaldosteronism (eg, glycyrrhizic acid in licorice) is an additional common mechanism of drug-related myolysis (109).

Rhabdomyolysis is a rare complication of antiseizure medications levetiracetam (112; 25; 60) and brivaracetam (06). Valproic acid can cause acute metabolic decompensation in patients with underlying inborn errors of metabolism. One patient with carnitine palmitoyltransferase II deficiency had acute rhabdomyolysis triggered by valproic acid (61). Gabapentinoids, which are used for many different neurologic disorders, are also associated with rhabdomyolysis. A systemic review showed that this usually occurs shortly after initiating gabapentinoids, in the setting of multiple medical comorbidities and polypharmacy, and can be due to drug-drug interactions, particularly with statins (64).

Neuroleptic malignant syndrome, a known complication of neuroleptic drugs or of abrupt discontinuation of dopaminergic agents, can cause rhabdomyolysis. In addition, neuroleptics can also be associated with rhabdomyolysis in the absence of neuroleptic malignant syndrome (71). A serotonergic syndrome due to excess serotonin activity, resulting most commonly from the combination of a selective serotonin reuptake inhibitor with monoamine oxidase inhibitors, has also been associated with rhabdomyolysis (109).

Levodopa-induced dyskinesia in advanced Parkinson disease has also been described to result in rhabdomyolysis, but this is very rare (85).

In the past few years, an increasing number of case reports have described rhabdomyolysis associated with glucagon-like peptide-1 (GLP-1) agonists semaglutide and tirzepatide. This may be a very rare complication that became apparent with increased use of these medications in recent years due to the extension of indications to weight loss. In cellular models, high concentrations of GLP-1 were shown to impair muscle differentiation and mitochondrial function, supporting a possible mechanism (13; 33; 45).

Metabolic derangements that may cause rhabdomyolysis include hypokalemia attributable to drugs, endocrine disorders (eg, primary aldosteronism), renal tubular acidosis, or GI disorders; hypophosphatemia (59); hyperosmolar states attributable to hyperglycemia, diabetic ketoacidosis, and hypernatremia; and heat stroke (54).

Numerous viral infections can cause rhabdomyolysis. Influenza is the most common viral etiology, followed by HIV infection and enteroviral infection. During the COVID-19 pandemic, there were many case reports of rhabdomyolysis in individuals with severe COVID-19 infection (53; 86; 52). The exact mechanisms remain unclear, but it is hypothesized that there may be direct muscle invasion of the virus or damage from the elicited immunologic response (35). Additionally, rhabdomyolysis has been reported as a rare adverse event following COVID-19 vaccination, particularly with mRNA vaccines, few of which led to dialysis, multiorgan failure, or death. Proposed mechanisms include immune responses triggered by the vaccine and T-cell activation against viral spike proteins (102; 52).

Table 1. Hereditary Causes of Rhabdomyolysis

Gene	Disease name	Baseline CK levels	Pattern of inheritance	Trigger for rhabdomyolysis
Disorders of glycogen metabolism
PYGM	Glycogen storage disease type V, McArdle disease	High	AR	Aerobic and anaerobic exercise, symptom onset within minutes
PFKM	Glycogen storage disease type VII, Tarui disease	High	AR	Aerobic and anaerobic exercise, symptom onset within minutes
ALDOA	Glycogen storage disease type XII	Normal Mild elevation, high	AR	Febrile illness, infection
ENO3	Glycogen storage disease type XIII	Normal High	AR	Aerobic and anaerobic exercise, symptom onset within minutes
LDHA	Glycogen storage disease type XI		AR	Aerobic and anaerobic exercise
PGAM2	Glycogen storage disease type X	High	AR	Aerobic and anaerobic exercise, symptom onset within minutes
PGK1	Phosphoglycerate kinase 1 deficiency	Normal High	X-linked	Aerobic and anaerobic exercise, symptom onset within minutes
PGM1	Glycogen storage disease type XIV	High	AR	Aerobic and anaerobic exercise, symptom onset within minutes, general anesthesia
PHKA1 PHKB	Glycogen storage disease type IX	?	X-linked AR	Aerobic and anaerobic exercise, symptom onset within minutes

Disorders of fatty acid metabolism
ACADVL	Deficiency of very-long-chain acyl-CoA dehydrogenase	Normal High	AR	Fasting, prolonged exercise, cold, infections, fever
CPT2	Carnitine palmitoyl-transferase deficiency	Normal	AR	Prolonged exercise, fasting, fever, infection, high fat intake, cold exposure, heat, emotional stress, drugs
ETFA ETFB	Glutaric aciduria type II Multiple acyl-coenzyme A dehydrogenase deficiency (MADD)	Normal to moderately elevated	AR	Physical exercise, fasting, irregular diet, or infection
HADHA HADHB	Mitochondrial trifunctional protein (MTP) deficiency	Normal	AR	Strenuous exercise
Mitochondrial disorders
COI (MTCO1)		Normal	Maternal inheritance	Prolonged or repetitive exercise
COII (MTCO2)		Normal	Maternal inheritance	Exercise
COIII (MTCO3)		Normal	Maternal inheritance	Prolonged exercise, viral illness
DGUOK	Mitochondrial DNA depletion syndrome	?	AR	Viral illness
FDX2	Episodic mitochondrial myopathy without optic atrophy or reversible leukoencephalopathy (MEOAL)	Normal High	AR	After exercise
ISCU	Hereditary myopathy and lactic acidosis	Normal	AR	Strenuous activity
MTCYB
ISCU	Iron-sulphur cluster deficiency myopathy	?	AR	Exercise
MTCYB	Cytochrome b deficiency	Normal	? Sporadic mutations	Exercise
POLG	Mitochondrial DNA depletion syndrome, Progressive external ophthalmoplegia	High	AD, AR	Seizures
Muscular dystrophies
ANO5	LGMD-R12	High	AR	Unprovoked
CAPN3	LGMD-R1, LGMD-D4		AR, AD	Exercise
DMD	Duchenne muscular dystrophy, Becker muscular dystrophy	High	X-linked	Exercise, anesthesia
DYSF	LGMD-R2, Miyoshi myopathy	High	AR	Exercise
FKTN	Fukuyama congenital muscular dystrophy, LGMD-R13	High	AR	Halothane and succinylcholine
FKRP	LGMD-R9	High	AR	Exercise
SGCA SGCB	LGMD-R3, LGMD-R4, LGMD-R5 (Sarcoglycanopathies)	High	AR	Exercise
Channelopathies
RYR1	Malignant hyperthermia susceptibility, Congenital myopathy	Normal or mildly to moderately elevated	AD, AR	Exercise, heat, illness, alcohol, anesthesia
CACNA1S	Malignant hyperthermia susceptibility, Periodic paralysis, Congenital myopathy	Normal, high	AD, AR	Exercise, heat, anesthesia
SCN4A	Periodic paralysis, Congenital myopathy, Congenital myasthenic syndrome, Paramyotonia congenita	Normal, high	AD	Emotional stress, illness, exercise, infection
Miscellaneous
LPIN1	Phosphatidic acid phosphatase deficiency	Normal, high	AR	Febrile infection, anesthesia, and fasting
OBSCN	Cardiomyopathy	Normal	AR	Exercise, heal
SIL1	Marinesco-Sjogren syndrome	Normal, high	AR	Febrile infection
TSEN54	Pontocerebellar hypoplasia type 2	Normal, high	AR	Hyperthermia
TANGO2	Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration	Normal	AR
MLIP	Myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis	High	AR	Exercise
MYH1	Recurrent episodes of rhabdomyolysis and muscle weakness	High	AR
(76; 94; 24)

Table 2. Major Categories of Acquired (Sporadic) Rhabdomyolysis

Nontraumatic
Nonexertional causes	- Alcohol/drug abuse: ethanol, methanol, ethylene glycol, heroin, methadone, barbiturates, cocaine, caffeine, amphetamine, lysergic acid diethylamide, 3,4- methylenedioxymethamphetamine (MDMA, ecstasy), phencyclidine, benzodiazepines, toluene (from glue sniffing), gasoline/paint sniffing. - Medication: salicylates, statins, fibrates, corticosteroids, neuroleptics, antipsychotics, benzodiazepines, quinine, antiepileptics (levetiracetam, brivaracetam, gabapentin, pregabalin, valproic acid), theophylline, selective serotonin reuptake inhibitors, lithium, antibiotics (fluoroquinolones, pyrazinamide, trimethoprim/sulfonamide, amphotericin B, itraconazole, micafungin), zidovudine, antihistamines, GLP-1 agonists (semaglutide, tirzepatide) aminocaproic acid, phenylpropanolamine, kinase inhibitors (MEK- and BRAF- inhibitors). - Toxic agents: carbon monoxide, cyanide, hemlock herbs from quail (coturnism), snake bites, spider venom, massive honeybee envenomation, Tricholoma equestre (mushroom), buffalo fish, or other freshwater fish in Frishes Haff of Baltic Sea (Haff disease). - Anesthetics and neuromuscular blocking agents: barbiturates, benzodiazepines, propofol, succinylcholine, sevoflurane. - Infections: viral: influenza A and B, HIV, enterovirus, adenovirus, coronavirus, Dengue, cytomegalovirus, herpes simplex virus, varicella-zoster virus, West Nile virus, COVID-19. Bacterial: Legionella species, Salmonella species, Francisella species, Streptococcus pneumoniae, Staphylococcus aureus, Enterococcus, Pseudomonas aeruginosa, Neisseria meningitidis, Haemophilus influenza, Coxiella burnetii, Leptospira species, Mycoplasma species, Escherichia coli, Tetanus. Fungal and malaria infections. - Electrolyte disturbances: hyponatremia, hypernatremia, hypokalemia, hypophosphatemia (especially in conjunction with alcohol), hypocalcemia, hyperosmotic conditions. - Endocrine disorders: hypothyroidism, hyperthyroidism, diabetic ketoacidosis, nonketotic hyperosmolar diabetic coma, hyperaldosteronism. - Idiopathic inflammatory myopathies: polymyositis, dermatomyositis, immune-mediated necrotizing myopathy. - Temperature extremes: heatstroke, malignant hyperthermia, exposure to cold. - Muscle ischemia, thrombosis/embolism, compartment syndrome.
Exertional causes:	- Extreme physical exertion, physical overexertion in Sickle cell disease. - Status epilepticus.
Traumatic causes:	- Multiple injury, crush injury, bombings, earthquakes, building collapse, mine accidents, train or motor vehicle accidents, high-voltage electrical injury, extensive third-degree burns.
	- Vascular/orthopedic surgery: intraoperative use of tourniquets, tight dressings or casts, prolonged application of air splints or pneumatic antishock garments and clamping of vessels during surgery. - Prolonged immobility: immobilization after trauma, anesthesia, coma, drug or alcohol-induced unconsciousness.
(118; 76; 32; 99; 05).

Mechanism of injury. The mechanisms of muscle injury in rhabdomyolysis are likely diverse, but two general themes are common. Sudden, widespread muscle injury due to trauma, toxins, venoms, or drugs suggests that these agents cause direct muscle membrane injury. Muscle necrosis may follow due to increased cellular levels of sodium and calcium.

Another common theme is a low level of cellular energy availability relative to demand, as in muscle ischemia, carbon monoxide poisoning, exhaustive exercise, or muscle energy defects. Illustrative are metabolic myopathies in which a superimposed stress (usually exercise) exposes a weak link in energy production and results in an acute energy crisis. Data suggest that ATP produced via substrate-level phosphorylation in glycolysis preferentially supports or regulates sarcolemmal function (46; 83). This could account for the propensity of muscle glycolytic defects to produce recurrent exertional rhabdomyolysis. Alternatively, muscle injury could be mediated by hydrolysis products of ATP. A small decline in ATP is associated with a much greater relative increase in the concentration of ADP, inorganic phosphate, and related metabolites (eg, [H+]). Physiologic studies suggest that high levels of these metabolites may impair muscle function by inhibiting enzymes (ATPases) that couple ion transport to ATP hydrolysis, leading to premature muscle fatigue and cramping.

A decrease of Na⁺, K⁺ - ATPase activity reduces the transmembrane electric voltage and promotes cellular accumulation of sodium ions. The resulting diminution of the sodium gradient reduces 2Na⁺:Ca²⁺ exchange, promoting accumulation of Ca²⁺ in the cytosol that, in turn, can activate Ca²⁺-dependent hydroxylases, nucleases, phospholipases, and proteases. Activation of these enzymes has been related to degradation of myofibrillar, cytoskeletal, and sarcolemmal proteins; injury to sarcolemma and other organelles, including the mitochondria, leading to further ATP depletion and production of free radicals (57; 83).

Renal failure is more likely to occur in the presence of volume depletion, fever, metabolic acidosis, and the excretion of concentrated, acid urine (16). There appears to be a direct relationship between myoglobin concentration in the urine and the propensity to develop acute renal failure (30).

There are three mechanisms believed to cause renal failure:

(1) Renal vasoconstriction that results from reduced renal blood flow due to decreased extracellular fluid, causing activation of the renin-angiotensin-aldosterone system. In addition, myoglobin appears to form complexes with nitric oxide, which exaggerates vasoconstriction of the renal vasculature.

(2) Formation of intratubular casts as myoglobin interacts with Tamm-Horsfall protein, which can be potentiated further by decreased renal blood flow and acidic environment.

(3) Direct toxicity of myoglobin to kidney tubular cells, as heme oxygenase-1 in proximal tubular cells degrades myoglobin and releases free iron. Reactive oxygen species are then made from redox cycling between ferric (Fe³⁺) and ferryl (Fe⁴⁺) myoglobin, which has negative effects on the tubular cells and surrounding organelles. This myoglobin-induced lipid peroxidation is prevented in alkaline conditions because Fe⁴⁺ is stabilized in this pH, decreasing the reactivity of myoglobin to lipids and lipid hydroperoxides.

Epidemiology

The global incidence of rhabdomyolysis is still unknown as there have been no large-scale prospective studies on the incidence of rhabdomyolysis, and many mild cases probably go unrecognized. Approximately 26,000 cases are reported annually in the United States (118). In the pediatric population, an incidence of 0.26% (four cases of rhabdomyolysis per 1500 patient consultations) has been reported in a 3-year single-center retrospective study (19). Certain conditions, such as morbid obesity, chronic use of lipid-lowering medications, and postoperative status, may increase the risk of rhabdomyolysis (18). The fact that only a few subjects exposed to exhaustive exercise, drugs, or toxins develop this complication is consistent with the possibility that unrecognized genetic factors may influence individual susceptibility. For example, the sickle cell trait apparently increases the risk of exertional rhabdomyolysis, particularly at high altitudes, possibly by impairing blood flow to working muscles (88). Genetic investigations are rarely conducted after the initial episode.

Other epidemiological studies assessing the etiology of sporadic rhabdomyolysis disclose variable results. In a cohort of 177 cases of rhabdomyolysis, Alpers and Jones showed that exertion-induced rhabdomyolysis occurred in 35%, trauma in 20%, toxins in 13%, infections in 7%, heat illness in 7%, seizures in 4%, metabolic myopathy in 3%, and endocrine disturbances in 2% (07). In a study by Melli and colleagues, illicit drugs, alcohol, and prescribed drugs were responsible for 46% of the cases of rhabdomyolysis in a cohort of 475 hospitalized patients (70). Among the prescription drugs, antipsychotics, statins, zidovudine, colchicine, selective serotonin reuptake inhibitors, and lithium were the most frequently involved. Multiple factors may be detected in 9% to 60% of cases (34; 70; 07; 01).

A study by Paternostro and colleagues examined the incidence and clinical spectrum of rhabdomyolysis in general neurology (80). Of 248 patients diagnosed with rhabdomyolysis, seizures (31.9%), illicit drug use or alcohol (9.7%), and exercise (8.5%) were the most common triggers. Common diagnoses associated with high cases of rhabdomyolysis were myopathies (49.8/1,000 person-years, 95% CI 32.3–67.4), followed by epilepsy (16.4/1,000 person-years, 95% CI 12.8–20.0) and stroke (11.9/1,000 person-years, 95% CI 8.4–15.4). In this cohort, 60.5% were males and had a median age of 49.6 (30.5-66.8) and a BMI of 25.4 (22.8-29.0).

An underlying muscle metabolic error is likely in patients with recurrent rhabdomyolysis and a positive family history, or in whom common acquired causes of rhabdomyolysis can be excluded. Analysis of 77 patients with adult-onset rhabdomyolysis, where alcohol and drug abuse had been excluded, showed that 46% of the patients had an underlying enzyme deficiency. The most frequent enzyme defect was carnitine palmitoyltransferase II deficiency (22%), followed by myophosphorylase deficiency (13%) and phosphorylase kinase deficiency (5%) (105). Analysis of 22 adult patients from Finland with recurrent rhabdomyolysis showed that 23% had an identifiable enzyme deficiency, and 18% had muscle dystrophy or myopathy. The most frequent enzyme deficiency among this population was myophosphorylase deficiency (18%), followed by phosphofructokinase deficiency (5%) and phosphorylase kinase deficiency (5%). The authors concluded that the prevalence of enzyme defects causing rhabdomyolysis might vary in different populations (66).

The exact incidence of rhabdomyolysis in the pediatric population is unclear, but several large cohort studies from different countries highlight the underlying etiologies and outcomes. In a systemic review and meta-analysis of pediatric rhabdomyolysis, collecting 15 cohort studies and 10,514 patients, the most common etiology was infectious (40.6%), with the majority of them viral infections and the most common pathogen being the influenza virus. This was followed by trauma (19%) and exercise (14.7%). Other etiologies accounted for less than 10% of rhabdomyolysis cases ie, seizures (7.2%), drugs (5.8%), metabolic abnormalities (4.4%), burns (2.9%), connective tissue disorder (2.7%), and muscular dystrophies (2.6%). This was consistent with most individual cohort studies, which reported viral myositis in up to 75% of pediatric cases. Interestingly, 21.3% of the pediatric patients developed acute kidney injury, but the incidence of chronic kidney disease was low (1.1%), suggesting that long-term kidney complications are rare (62; 40; 114).

Differential diagnosis

Confusing conditions

The most important aspect of differential diagnosis is the differentiation of rhabdomyolysis from muscle disorders with severe muscle breakdown. Some muscular dystrophies and immune-mediated necrotizing myopathies may have CK levels that exceed 10,000 IU/L. Acute presentations of immune-mediated necrotizing myopathy with 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) or single recognition particle antibodies can be difficult to distinguish due to overlap in symptoms and CK levels. It is important to recognize these conditions and quickly start appropriate immunomodulatory treatments.

The diagnosis of rhabdomyolysis should not be based solely on CK testing; clinical symptoms of severe myalgia, muscle swelling, muscle weakness, and myoglobinuria should also be present. It should also be noted that “normal” CK levels vary significantly in healthy individuals, and ranges above the reference values do not always indicate a pathology. In a population study of approximately 10,000 individuals, CK levels varied substantially with race, gender, body composition, and age, and modestly by chronic kidney disease and unusual recent exercise in the 3 days prior to testing. It is estimated that 29.8% of black men have a baseline CK level above the reference range (36). Exercise also causes CK and myoglobin elevation, and there is no established cutoff for CK levels to make a diagnosis of exertional rhabdomyolysis. Although some authors suggest an increase in CK to more than 5000 IU/L or evidence of end-organ signs of kidney or liver function impairment (31), others report that even CK levels of 10,000 IU/L could be normal after exercise, and a CK cutoff equal to 15,000 IU/L or more is predictive of renal impairment (21).

Associated or underlying disorders

Rhabdomyolysis is associated with many different genetic risk factors (Table 1). These should be investigated in all patients with recurrent episodes; baseline muscle weakness or other muscle symptoms, such as easy cramping or stiffness; or a positive family history of rhabdomyolysis.

Diagnostic workup

Serum CK, myoglobin, electrolytes, and kidney function labs (eg, creatinine, urea nitrogen) should be checked in patients who report symptoms of acute weakness, muscle swelling, soreness and cramps, severe pain, dark colorization of the urine, nausea, fever, or anuria. Furthermore, a urine test should be considered to determine myoglobinuria. Other causes of pigmenturia, such as hematuria, hemoglobinuria, or porphyria, should be considered. Next, the cause of rhabdomyolysis should be established. The initial evaluation should include a careful history and a toxicology screen to identify drugs or toxins known to produce rhabdomyolysis and screen for metabolic derangements known to cause rhabdomyolysis (Table 2). Basic blood counts, chemistry, electrolyte levels, kidney function tests, and thyroid function tests should be performed in all patients. Antibody tests may also be warranted in patients with suspected autoimmune myopathies (118; 76).

Extensive work-up for rhabdomyolysis is indicated for patients with a high likelihood of having a genetic cause. The acronym “RHABDO” (Table 3) was suggested to highlight these risk factors (107). Patients fitting these criteria should be evaluated for the genetic causes summarized in Table 1. The recommendation is to start with genetic testing panels as the initial investigation (107). Various commercial genetic testing companies offer next-generation sequencing panels, including 125 to 160 genes associated with metabolic myopathy and rhabdomyolysis. If the genetic testing panel is negative or inconclusive, as in the case of variants of uncertain significance, ancillary investigations, such as muscle imaging with MRI or ultrasound; electromyography; biochemical testing for metabolic errors, such as plasma acylcarnitine profile and urine organic acids, or direct testing of enzyme activity; forearm exercise test; and muscle biopsy (at least 4 to 8 weeks after episode) should be considered.

Table 3. Factors To Identify Genetic Susceptibility To Develop Rhabdomyolysis

R	Recurrent episodes of exertional rhabdomyolysis
H	HyperCKemia persisting 8 weeks after the event
A	Accustomed physical exercise: the intensity of the exercise cannot explain the rhabdomyolysis event
B	Blood CK > 50x upper limit of normal (> 10,000 IU/L)
D	Drugs/medication/supplements and other exogenous and endogenous triggers cannot sufficiently explain the rhabdomyolysis severity
O	Other family members affected/Other exertional symptoms (cramps, myalgia)

Glycogen metabolism disorders should be suspected in early rhabdomyolysis triggered by activity, with elevated baseline CK. In myophosphorylase deficiency, the second-wind phenomenon during exercise occurs, wherein fatigue and pain abate after resting, and activity can then be resumed. Phosphofructokinase deficiency may have the same symptoms as McArdle disease but without the second wind phenomenon and with an additional finding of compensated hemolysis, evidenced by hyperuricemia and reticulocytosis. In contrast, fatty acid oxidation disorders are suspected with rhabdomyolysis triggered by prolonged submaximal exertion, fasting, stress, or illness.

These symptoms are suggestive of an inborn error of muscle metabolism, and further investigation with a forearm exercise test, muscle biopsy, and biochemical testing may be pursued if not confirmed with genetic testing. The forearm exercise test protocol was initially developed by McArdle in 1951 but has since been revised multiple times. This test relies on the measurement of levels of lactate, pyruvate, and ammonia periodically over 10 minutes following isometric exercise. If there is an increase in ammonia levels but not a matching increase in lactate, this means that there is a disruption of glycogen utilization and its conversion to pyruvate (76). Acylcarnitine profile is a noninvasive method to investigate fatty acid oxidation disorders. When a muscle biopsy is indicated, obtaining the muscle sample at least 4 to 8 weeks after the patient has recovered from rhabdomyolysis is recommended. If performed sooner, the biopsy can be misleading due to prominent muscle fiber necrosis. Better diagnostic outcomes with biopsies are observed in patients with myopathic findings on electromyography, second wind phenomenon, or muscle hypertrophy/atrophy (76). Voermans and colleagues suggested the illustrated scheme for the workup of patients with rhabdomyolysis (107).

Rhabdomyolysis diagnostic workup

(Contributed by Dr. Yigit Karasozen.)

A study by Xu and colleagues retrospectively looked at 50 patients diagnosed with rhabdomyolysis after having an ultrasound (110). Among these, 26 were diagnosed with exertional rhabdomyolysis, and 12 underwent serology tests only after changes suspicious for rhabdomyolysis were detected by ultrasound. Imaging found blurred muscle fiber structure, ground glass changes, or muscle thickening. Patients diagnosed earlier were found to have shorter hospital stays. The authors then included ultrasound as a possible tool in early diagnosis of exertional rhabdomyolysis.

Management

The major complications of rhabdomyolysis are outlined in Table 4. Because volume depletion greatly increases the risk of acute renal failure, early and adequate fluid replacement (normal saline or one-half normal saline in dextrose) is essential to maintain renal perfusion. Ideally, this should be started within 6 hours of symptom onset (20; 37). Most studies recommend maintaining urine output of 200 to 300 ml/hour until rhabdomyolysis resolves. In a systematic review of the treatment of exertional rhabdomyolysis, the range of intravenous fluid resuscitation rate ranged from 120 to 300 ml/hour. The average hospital stay length was 4.5 days (67).

The McMahon score, first described in 2013, is a scoring system calculated at the time of the initial presentation of patients with rhabdomyolysis to predict the risk of mortality and acute kidney injury requiring renal replacement therapy (69). Age, gender, creatinine, CK, calcium, phosphate, and bicarbonate levels and triggering etiology are used to calculate the score. This scoring system has now been validated in multiple different cohorts and can be a useful clinical tool, especially in the setting of natural disasters, such as earthquakes, when healthcare facilities are overrun with crush injuries (111).

Alkalization of the urine with intravenous sodium bicarbonate reduces cast formation and, thereby, promotes excretion of myoglobin. Increasing urine pH to around 6.5 may help reduce heme toxicity to the tubules (04). A systematic review and meta-analysis on rhabdomyolysis treatment looked at 12 studies, the majority of them retrospective, to aid in creating management guidelines. Consequently, the practice management guidelines from the Eastern Association for the Surgery of Trauma recommended against treatment with bicarbonate or mannitol in patients with rhabdomyolysis due to conflicting and low-quality evidence and failure to show improvement in the incidence of acute renal failure. However, they did recommend aggressive intravenous fluid resuscitation to improve outcomes of acute renal failure and lessen the need for dialysis (93).

Oliguria is an independent risk factor for compartment syndrome or acute respiratory distress syndrome. Persistent oliguria (urine flow less than 20 cc/hour) despite correction of hypotension and using mannitol, furosemide, and sodium bicarbonate suggests acute tubular necrosis. Further volume replacement in this setting risks interstitial and pulmonary edema. Such patients often require early and aggressive hemodialysis or high-flux dialysis to reduce myoglobin (83; 95).

Hyperkalemia due to intracellular potassium release from necrotic muscle may cause life-threatening cardiac arrhythmias or even cardiac arrest, particularly in the setting of renal failure and, thus, should be rapidly corrected (20). The effect of hyperkalemia is potentiated by hypocalcemia, attributable to hyperphosphatemia and deposition of calcium salts in injured muscle. The electrocardiographic findings of hyperkalemic cardiotoxicity are more sensitive than serum potassium levels per se. Emergent treatment of hyperkalemia includes intravenous glucose and insulin, calcium salts, and hyperventilation to promote cellular uptake of potassium. Oral disodium polystyrene sulfonate is useful but acts slowly. Hemodialysis may be required. Frequent monitoring of CK and electrolytes is warranted in this clinical setting (62).

There has been anecdotal evidence of dexamethasone use in rhabdomyolysis. Dexamethasone was effective in alleviating symptoms and decreasing CK levels in two pediatric cases, one with an LPIN1 gene variant of unknown significance and the other with exertion and respiratory tract infection as potential triggers for rhabdomyolysis (101).

Muscle compartment syndrome may require fasciotomy to avert limb-threatening ischemia and peripheral nerve injury.

Table 4. Mechanisms and Management of Complications of Rhabdomyolysis

Complication (mechanism)	Management
Acute renal failure (toxic effect of myoglobin, potentiated by hypovolemia, acidosis)	• Maintain urine output with aggressive intravenous fluid resuscitation • Hemodialysis
Hyperkalemia (release of intracellular K+, impaired K+ clearance by kidney due to renal insufficiency)	• Glucose and insulin • Calcium administration • K+ binding resins • Hemodialysis
Hypocalcemia (deposition of calcium salts in injured muscle)—potentiates cellular effects of hyperkalemia	• No specific treatment • Monitor ECG for effects of hyperkalemia; treat hyperkalemia as above
Hyperphosphatemia (release of phosphate from injured muscle)	• No specific treatment
Hemorrhage (related to disseminated intravascular coagulation, thrombocytopenia, fibrinolysis, capillary injury)	• Fresh frozen plasma
Adult respiratory distress syndrome	• Artificial ventilation
Ischemic bowel syndrome	• Correct hypovolemia
Compartment syndrome (ischemia due to muscle injury and swelling)	• Fasciotomy may be required

Outcomes

Among the exertional rhabdomyolysis cohort, after the resolution of kidney injury and return of CK to baseline, slow progression or graded return to baseline activity is expected.

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Yigit Karasozen MD

Dr. Karasozen of UCLA Health has no relevant financial relationships to disclose.
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Payam Soltanzadeh MD FAAN

Dr. Soltanzadeh of UCLA Health received clinical trial funding from Avidity Biosciences as principal investigator.
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Editor

Nicholas E Johnson MD MSCI FAAN

Dr. Johnson of Virginia Commonwealth University received consulting fees and/or research grants from AMO Pharma, Avidity, Dyne, Novartis, Pepgen, Sanofi Genzyme, Sarepta Therapeutics, Takeda, and Vertex, consulting fees and stock options from Juvena, and honorariums from Biogen Idec and Fulcrum Therapeutics as a drug safety monitoring board member.
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Former Authors

Ronald G Haller MD
James P Knochel MD
Roser Pons MD
Jun Ho Kim MD
Carmela San Luis MD
Mohamed Kazamel MD BCh
Emma Ciafaloni MD FAAN

Patient Profile

Age range of presentation: 6 to 65+ years
Sex preponderance: male>female, >1:1
Heredity: heredity may be a factor
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Myoglobinuria: R82.1
ICD-11: Myoglobinuria: MF95
OMIM: Myoglobinuria, familial paroxysmal paralytic: #268200

Ryanodine receptor 1; RYR1: *180901

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Rhabdomyolysis

Associated Disorders

Aconitase deficiency
Acute renal failure
Acute respiratory distress syndrome
Carnitine palmityl transferase deficiency
Disseminated intravascular coagulation
- Dystrophin deficiency
- Endocrine disorders
- Gastrointestinal disorders
- Glycogen storage diseases
- Influenza
- Lactate dehydrogenase deficiency
- Legionnaire disease
- Lipid myopathies
- Long-chain acyl CoA dehydrogenase deficiency
- Muscle glycolytic defect
- Phosphofructokinase deficiency
- Phosphoglycerate kinase deficiency
- Phosphoglycerate mutase deficiency
- Phosphorylase deficiency
- Renal tubular acidosis
- Short-chain L-3 hydroxyacyl CoA dehydrogenase deficiency
- Succinate dehydrogenase deficiency
- Toxic shock syndrome
- Trifunctional protein deficiency
- Very long-chain acyl-CoA dehydrogenase deficiency

Differential Diagnosis

other causes of pigmenturia
inborn error of metabolism
autoimmune myositis

Also Relevant

Alcoholic myopathy
Becker muscular dystrophy
Carnitine palmitoyltransferase II deficiency
Long-chain fatty acid oxidation defects
Malignant hyperthermia
- Nonlysosomal muscle glycogenoses

Clinical Categories

Neuromuscular Disorders

Web References

Testing

Mitochondrial DNA Deletion Syndromes

Rhabdomyolysis

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Table 1. Hereditary Causes of Rhabdomyolysis

Table 2. Major Categories of Acquired (Sporadic) Rhabdomyolysis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Table 3. Factors To Identify Genetic Susceptibility To Develop Rhabdomyolysis

Management

Table 4. Mechanisms and Management of Complications of Rhabdomyolysis

Outcomes

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

Also in This Category

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Nusinersen

Risdiplam

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