Know rhabdomyolysis: pathophysiology, etiology, prevention, clinical manifestations, diagnostics, treatments, and complications.
INTRODUCTION — Rhabdomyolysis is a syndrome characterized by muscle necrosis and the release of intracellular muscle constituents into the circulation. Creatine kinase 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 clinical manifestations and diagnosis of rhabdomyolysis will be reviewed here. The causes of rhabdomyolysis; the clinical features and diagnosis of acute kidney injury due to rhabdomyolysis; the management of patients with rhabdomyolysis, including methods to prevent acute kidney injury and related metabolic complications; and the prevention and management of acute compartment syndrome are discussed in detail separately. (See "Clinical features and diagnosis of heme pigment-induced acute kidney injury (acute renal failure)" and "Prevention and treatment of heme pigment-induced acute kidney injury (acute renal failure)" and "Crush-related acute kidney injury (acute renal failure)" and "Acute compartment syndrome of the extremities" .)
CLINICAL MANIFESTATIONS — Rhabdomyolysis is characterized clinically by myalgias, red to brown urine due to myoglobinuria, and elevated serum muscle enzymes (including creatine kinase) [ 1 ]. The degree of muscle pain and other symptoms varies widely. Rhabdomyolysis associated with viral infection is discussed in further detail separately. (See "Viral myositis", section on 'Viral myositis with rhabdomyolysis' .)
Symptoms — The characteristic triad of complaints in rhabdomyolysis is muscle pain, weakness, and dark urine [ 2-5 ]. However, more than half of patients may not report muscular symptoms [ 3 ]; in contrast, occasional others may experience very severe pain. Muscle pain, when present, is typically most prominent in proximal muscle groups, such as the thighs and shoulders, and in the lower back and calves [ 2,5 ]. Other muscle symptoms include stiffness and cramping.
Additional symptoms that are more common in severely affected patients include malaise, fever, tachycardia, nausea and vomiting, and abdominal pain [ 2 ]. Altered mental status may occur from the underlying etiology (eg, toxins, drugs, trauma, or electrolyte abnormalities).
Physical findings — Muscle tenderness and swelling may be seen, but detectable muscle swelling in the extremities generally develops, when it occurs, with fluid repletion. Such swelling is much less common on hospital admission [ 3 ]. Muscle weakness may be present, depending upon the severity of muscle injury. Limb induration is occasionally present. Skin changes of ischemic tissue injury, such as discoloration or blisters, may also be seen but are present in less than 10 percent of patients [ 5,6 ].
Laboratory findings — The hallmark of rhabdomyolysis is an elevation in creatine kinase and other serum muscle enzymes. The other characteristic finding is the reddish-brown urine of myoglobinuria, but because this may be observed in only half of cases, its absence does not exclude the diagnosis.
Creatine kinase — Serum creatine kinase (CK) levels at presentation are usually at least five times the upper limit of normal, but range from approximately 1500 to over 100,000 international units/L. The mean peak CK reported for each of a variety of different causes and for patients with both single and multiple causes ranged from approximately 10,000 to 25,000 in the largest series [ 7 ]; exceptions were the three patients with malignant hyperthermia, whose values averaged almost 60,000.
The CK is generally entirely or almost entirely of the MM or skeletal muscle fraction; a small proportion of the total CK may be from the MB or myocardial fraction. The presence of MB reflects the small amount found in skeletal muscle rather than the presence of myocardial disease. Elevations in serum aminotransferases are common and can cause confusion if attributed to liver disease. (See "Muscle enzymes in the evaluation of neuromuscular diseases" .)
The serum CK begins to rise within 2 to 12 hours following the onset of muscle injury and reaches its maximum within 24 to 72 hours. A decline is usually seen within three to five days of cessation of muscle injury. CK has a serum half-life of about 1.5 days and declines at a relatively constant rate of about 40 to 50 percent of the previous day’s value [ 5,6,8 ]. In patients whose CK does not decline as expected, continued muscle injury or the development of a compartment syndrome may be present.
Urine findings and myoglobinuria — Myoglobin, a heme-containing respiratory protein, is released from damaged muscle in parallel with CK. Myoglobin is a monomer that is not significantly protein bound and is, therefore, rapidly excreted in the urine, often resulting in the production of red to brown urine. It appears in the urine when the plasma concentration exceeds 1.5 mg/dL [ 5 ]. Visible changes in the urine only occur once urine levels exceed from about 100 to 300 mg/dL, although it can be detected by the urine (orthotolidine) dipstick at concentrations of only 0.5 to 1 mg/dL [ 3,6 ]. Myoglobin has a half-life of only two to three hours, much shorter than that of CK. Because of its rapid excretion and metabolism to bilirubin, serum levels may return to normal within six to eight hours.
Thus, it is not unusual for CK levels to remain elevated in the absence of myoglobinuria [ 3 ]. Routine urine testing for myoglobin by urine dipstick evaluation may be negative in up to half of patients with rhabdomyolysis [ 2 ]. Pigmenturia will be missed in rhabdomyolysis if the filtered load of myoglobin is insufficient or has largely resolved before the patient seeks medical attention due to its rapid clearance.
Both hemoglobin and myoglobin can be detected on the urine dipstick as “blood”; microscopic evaluation of the urine generally shows few red blood cells (less than five per high-powered field) in patients with rhabdomyolysis whose positive test results from myoglobinuria [ 2 ]. Such testing is not a reliable method for rapid detection of myoglobin if red blood cells are present or in patients with hemolysis due to its lack of specificity for myoglobin. Hemoglobin, the other heme pigment capable of producing pigmented urine, is much larger (a tetramer) than myoglobin and is protein bound. As a result, much higher plasma concentrations are required before red to brown urine is seen, resulting in a change in plasma color. (See "Etiology and evaluation of hematuria in adults", section on 'Red to brown urine' .)
Proteinuria may also be seen, due to the release of myoglobin and other proteins by the damaged myocytes [ 2 ]. In one study, it was detected by dipstick in 45 percent of patients [ 3 ].
Other manifestations — Other manifestations of rhabdomyolysis include fluid and electrolyte abnormalities, many of which precede or occur in the absence of kidney failure, and hepatic injury [ 9 ]; additionally, cardiac dysrhythmias and risk of cardiac arrest may result from the severe hyperkalemia that occurs with significant myonecrosis [ 5 ]. Later complications include acute kidney injury, compartment syndrome, and, rarely, disseminated intravascular coagulation.
Fluid and electrolyte abnormalities — Hypovolemia and abnormalities in serum electrolytes and uric acid are common in patients with rhabdomyolysis [ 3,10,11 ]:
Hypovolemia results from “third-spacing” due to the influx of extracellular fluid into injured muscles and increases the risk of acute kidney injury [ 12 ].
Hyperkalemia and hyperphosphatemia result from the release of potassium and phosphorus from damaged muscle cells. Levels of potassium may increase rapidly, but the levels of potassium and phosphate decrease as they are excreted in the urine. Hyperkalemia is more common in patients with oliguric acute kidney injury [ 3 ].
Hypocalcemia, which can be extreme, occurs in the first few days because of entry into damaged myocytes and both deposition of calcium salts in damaged muscle and decreased bone responsiveness to parathyroid hormone [ 13,14 ]. During the recovery phase, serum calcium levels return to normal and may rebound to significantly elevated levels due to the release of calcium from injured muscle, mild secondary hyperparathyroidism from the acute renal failure, and an increase in calcitriol (1,25-dihydroxyvitamin D) [ 13,14 ]. (See "Etiology of hypocalcemia in adults", section on 'Extravascular deposition' and "Etiology of hypercalcemia", section on 'Rhabdomyolysis and acute renal failure' .)
Severe hyperuricemia may develop because of the release of purines from damaged muscle cells and, if acute kidney injury occurs, reduced urinary excretion.
Metabolic acidosis is common, and an increased anion gap may be present.
Acute kidney injury — Acute kidney injury (AKI, acute renal failure) is a common complication of rhabdomyolysis. The reported frequency of AKI ranges from 15 to over 50 percent [ 3,7,15 ]. The risk of AKI is lower in patients with CK levels at admission less than 15 to 20,000 units/L; risk factors for AKI in patients with lower values include dehydration, sepsis, and acidosis [ 12 ]. Volume depletion resulting in renal ischemia, tubular obstruction due to heme pigment casts, and tubular injury from free chelatable iron all contribute to the development of renal dysfunction. Reddish-gold pigmented casts are often observed in the urine sediment. AKI in patients with rhabdomyolysis is discussed separately. (See "Clinical features and diagnosis of heme pigment-induced acute kidney injury (acute renal failure)" .)
Compartment syndrome — A compartment syndrome exists when increased pressure in a closed anatomic space threatens the viability of the muscles and nerves within the compartment [ 16 ]. Compartment syndrome is a potential complication of severe rhabdomyolysis that may develop after fluid resuscitation, with worsening edema of the limb and muscle [ 17 ]. Lower extremity compartment syndrome can also be a cause of rhabdomyolysis, as may occur after tibial fractures. Compartment syndrome is discussed separately. (See "Acute compartment syndrome of the extremities" .)
Disseminated intravascular coagulation — Infrequently, severe rhabdomyolysis may be associated with the development of disseminated intravascular coagulation due to the release of thromboplastin and other prothrombotic substances from the damaged muscle [ 5,18,19 ]. (See "Pathogenesis and etiology of disseminated intravascular coagulation" and "Clinical features, diagnosis, and treatment of disseminated intravascular coagulation in adults" .)
EVALUATION AND DIAGNOSIS
Indications for diagnostic testing — Diagnostic testing should be performed in individuals with:
Both myalgias and pigmenturia
Either myalgias or pigmenturia, with a history suggesting the presence or recent exposure to a potential cause or event (see "Causes of rhabdomyolysis", section on 'Causes' )
The absence of myalgias or pigmenturia in a clinical setting associated with increased risk for rhabdomyolysis, as symptoms may be vague or absent in up to 50 percent of patients. The diagnosis should be suspected following prolonged immobilization, in any stuporous or comatose patient or in a patient who is otherwise unable to provide a medical history and has one or more of the following:
Evidence of pressure necrosis of the skin
Signs of multiple trauma or a crush injury
Blood chemistry abnormalities suggesting the possibility of increased cell breakdown, such as hyperkalemia, hyperphosphatemia, and /or hypocalcemia
Evidence of acute kidney injury
Diagnostic evaluation — We obtain the following key diagnostic laboratory studies:
Creatine kinase — Fractionation of the CK is generally not required but may be helpful, in addition to the clinical history and examination, in excluding other potential causes of CK elevation such as acute myocardial infarction, stroke, and other diseases of the heart and brain. (See 'Creatine kinase' above.)
Urinalysis, including dipstick and microscopic evaluation — Evidence of myoglobinuria should be sought by routine urine dipstick evaluation combined with microscopic examination. Testing of the unspun urine or the supernatant of the centrifuged urine will be positive for “heme” on dipstick if myoglobinuria is present, even if red to reddish brown urine is not evident macroscopically. The visual and microscopic examination of the sediment from a fresh urine specimen is required to exclude the presence of red blood cells (RBC) as the cause of positive testing; RBC in an older specimen may hemolyze over time, confounding the results. (See 'Urine findings and myoglobinuria' above.)
In patients with persistent red to reddish-brown urine, myoglobinuria is suggested when the urine tests positive for heme by dipstick after centrifugation, while the plasma has a normal color and tests negative for heme ( algorithm 1 ). (See "Etiology and evaluation of hematuria in adults", section on 'Red to brown urine' .)
Myoglobinuria lacks sensitivity as a test for rhabdomyolysis; it may be absent in 25 to 50 percent of patients with rhabdomyolysis due to the more rapid clearance of myoglobin, compared with CK, following muscle injury. Myoglobin also decreases rapidly in a similar fashion in patients with renal failure, suggesting a role for extrarenal metabolism and clearance in such patients [ 20,21 ].
We also obtain the following tests, which may help in prompt recognition of other potentially dangerous manifestations, in differential diagnosis, and in identifying the cause (see 'Management' below):
Complete blood count, including differential and platelet count
Blood urea nitrogen, creatinine, and routine electrolytes including potassium
Calcium, phosphate, albumin, and uric acid
Additional testing, such as evaluation of suspected metabolic myopathy or toxicology screening for drugs of abuse, depends upon the clinical context. (See 'When to suspect metabolic myopathy' below and "Substance use disorders: Principles for recognition and assessment in general medical care" and "Screening for unhealthy use of alcohol and other drugs" .)
Diagnosis — We make the diagnosis of rhabdomyolysis in a patient with either an acute neuromuscular illness or dark urine without other symptoms, plus a marked acute elevation in serum creatine kinase (CK). The CK is typically at least five times the upper limit of normal, and is usually greater than 5000 international units/L. No absolute cut-off value for CK elevation can be defined, and the CK should be considered in the clinical context of the history and examination findings. (See 'Creatine kinase' above.)
The following additional points should be considered in making the diagnosis:
Other muscle enzymes in addition to CK are typically elevated (eg, aldolase, aminotransferases, lactate dehydrogenase), but such testing is not usually necessary to make the diagnosis. However, elevations in aminotransferases or lactate dehydrogenase may suggest the need for CK testing if it has not been performed in a patient in whom such abnormalities may potentially be due to muscle injury rather than hepatic injury or another cause.
In patients with dark urine, but without elevation in the CK, additional diagnostic considerations should be explored. (See "Etiology and evaluation of hematuria in adults", section on 'Red to brown urine' .)
A muscle biopsy is generally not required. Findings on biopsy include loss of normal cross-striations and cell nuclei and the absence of inflammatory cells [ 22 ].
Electromyography (EMG) is generally not required. Findings are most often normal and are only mild when present. In one study of 15 patients with acute rhabdomyolysis, EMG testing was normal in three-quarters of the tested muscles [ 23 ]. One-third of patients had myopathic changes in one to several muscles (eg, proximal myopathic motor unit action potentials), and none exhibited persistent fibrillation potentials. Nerve conduction studies were normal, except for one patient with a preexisting polyneuropathy.
Magnetic resonance imaging (MRI) is generally not required. Findings in affected muscle include increased signal intensity on T2-weighted images and good contrast between normal and abnormal muscles on STIR images [ 24 ]. MRI appears to be more sensitive than either ultrasound or computerized tomography in detecting abnormal muscle.
Rhabdomyolysis associated with viral infection is discussed in further detail separately. (See "Viral myositis", section on 'Diagnosis' .)
When to suspect metabolic myopathy — There are subtle differences in the clinical manifestations of the various metabolic myopathies, but one of these conditions should be suspected when the following clinical circumstances are present:
There are recurrent episodes of rhabdomyolysis after exertion or in association with fasting or a viral illness. The last two associations occur most commonly with carnitine palmitoyltransferase deficiency and the other disorders of lipid metabolism.
There is a history of exercise intolerance, recurrent cramps, and fatigue beginning in childhood, and episodes of pigmenturia occurring in adolescence.
There is a family history of rhabdomyolysis or exercise intolerance, particularly in siblings, thereby suggestive of an autosomal recessive inheritance pattern.
The individual has normal strength and muscle enzymes during interictal periods. One exception is muscle phosphorylase deficiency, a disorder in which chronic muscle weakness may develop after repeated episodes and CK levels do not return to normal between attacks. (See "Muscle phosphorylase deficiency (glycogen storage disease V, McArdle disease)" .)
The diagnostic approach to a suspected metabolic myopathy is discussed separately. Histochemical analysis of a muscle biopsy specimen will demonstrate the deficient enzyme. (See "Approach to the metabolic myopathies", section on 'Diagnosis' and "Approach to the patient with muscle weakness" .)
DIFFERENTIAL DIAGNOSIS — The differential diagnoses of myalgia, elevated CK and other muscle enzymes, and dark urine are fairly extensive. However, when present together, and if the CK elevation is acute and myoglobinuria is present, the diagnosis of rhabdomyolysis can generally be made with confidence. The following conditions may be considered, depending upon the combination of findings that are present, but distinctions can usually be made with readily available information from the medical history as well as the physical and laboratory examinations:
Myocardial infarction —Although serum CK also rises acutely with myocardial infarction, patients with rhabdomyolysis alone do not have ischemic chest pain or ECG signs of myocardial infarction. Additionally, the CK-MM fraction is elevated, while little or no CK-MB is present. Assays for cardiac troponin I appear to have high specificity for cardiac muscle injury, while assays for cardiac troponin T may exhibit cross-reactions with skeletal muscle troponin. Further study in patients with rhabdomyolysis is needed [ 25,26 ]. (See "Troponins and creatine kinase as biomarkers of cardiac injury" and "Troponins and creatine kinase as biomarkers of cardiac injury", section on 'Troponins' and 'Creatine kinase' above and "Criteria for the diagnosis of acute myocardial infarction" .)
Hematuria and hemoglobinuria — Both hematuria and hemoglobinuria (due to hemolysis) may result in red to reddish-brown urine and may be confused with myoglobinuria. Careful examination of the urine for red blood cells (present in hematuria, by definition), of serum for evidence of hemolysis, and of the CK (which is not elevated in hemolysis, or most patients with hematuria) will help distinguish these conditions. Other causes of red to brown urine include various foods and drugs, but such patients lack evidence of skeletal muscle injury, including CK elevation. (See 'Urine findings and myoglobinuria' above and 'Evaluation and diagnosis' above and "Etiology and evaluation of hematuria in adults", section on 'Red to brown urine' .)
Inflammatory myopathy — Patients with inflammatory myopathy can also exhibit myalgias and elevated CK and may exhibit myoglobinuria [ 27 ]. These patients can be differentiated from patients with rhabdomyolysis by the chronicity of disease, usually symmetric proximal muscle weakness developing over weeks to months, relative stability of the laboratory abnormalities compared with patients with rhabdomyolysis, and the systemic features associated with the inflammatory myopathies, such as dermatomyositis.
Patients with rhabdomyolysis generally do not exhibit electromyographic or histologic changes suggestive of myositis except in rare patients in whom both are present [ 28-30 ]; concurrent statin therapy may be a risk factor [ 31 ]. (See 'Evaluation and diagnosis' above and "Clinical manifestations and diagnosis of adult dermatomyositis and polymyositis" .)
Immune-mediated necrotizing myopathy — Patients on statin medications may develop an immune-mediated necrotizing myopathy with markedly elevated levels of CK and weakness that does not improve with discontinuation of statins but that does respond to aggressive immunosuppressive therapy [ 32-35 ]. These patients can be distinguished from patients with rhabdomyolysis by the persistence of symptoms and findings, including the elevation in CK, in the absence of treatment with immunosuppressives and by their histopathologic changes.
Deep vein thrombosis — In patients who present with severe calf pain, a deep vein thrombosis (DVT) may be an initial consideration. DVT can be diagnosed in most patients by appropriate noninvasive studies and is not associated with marked CK elevations or myoglobinuria. (See "Diagnosis of suspected deep vein thrombosis of the lower extremity" .)
Renal colic — In patients presenting with back pain, rhabdomyolysis may be confused with renal colic. Additionally, urine dipstick testing may be positive for blood. However, urolithiasis is not associated with marked elevations of the CK, and myoglobinuria is not present. (See "Diagnosis and acute management of suspected nephrolithiasis in adults" .)
MANAGEMENT — The major issues in the treatment of patients with rhabdomyolysis, which are discussed in detail separately, include:
Recognition and management of fluid and electrolyte abnormalities, which should be initiated regardless of renal function and which may prevent severe metabolic disturbances and acute kidney injury (see "Clinical features and diagnosis of heme pigment-induced acute kidney injury (acute renal failure)" and "Prevention and treatment of heme pigment-induced acute kidney injury (acute renal failure)" )
Identification of the specific causes and the use of appropriate countermeasures directed at the triggering events, including discontinuation of drugs or other toxins that may be etiologic factors (see "Causes of rhabdomyolysis", section on 'Causes' )
Prompt recognition, evaluation, and treatment of compartment syndrome in patients in whom it is present (see "Crush-related acute kidney injury (acute renal failure)" and "Acute compartment syndrome of the extremities" )