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Rhabdomyolysis: Diagnosis and Treatment

Preeti Jois-Bilowich, MD, Cleveland Clinic, Ohio, Hope LeBlanc, MD, and Richard Paula, MD, University of South Florida, Tampa

Published Online: July 11, 2007 - 11:11:32 AM (CDT)

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Preeti Jois-Bilowich, MD

Clinical Associate, Cleveland Clinic Department of Emergency Medicine
Cleveland, Ohio

Hope LeBlanc, MD

Resident, University of South Florida Department of Emergency Medicine
Tampa, Fla

Richard Paula, MD

Research Director, University of South Florida Department of Emergency Medicine
Tampa, Fla

The cascade of events that results in rhabdomyolysis begins with muscle injury secondary to a variety of causes. The quickest way to prevent the potentially life-threatening complications from this muscle disintegration is early and generous hydration. The precipitating event is usually evident from the patient's history. The differential diagnosis is best approached by categorizing the etiologic variables. The clinical features, however, are nonspecific. The large spectrum of presentation spans a continuum from asymptomatic myoglobinemia to renal failure. Rapid recognition and treatment of rhabdomyolysis are essential for a positive outcome.

Rhabdomyolysis is a relatively rare condition that must be recognized quickly and treated early. The name literally means striated (rhabdo) muscle (myo) disintegration (lysis). Rhabdomyolysis begins with muscle injury associated with a variety of causes. With localized necrosis of the muscle, extracellular calcium and sodium leak into the intracellular space. Finally, intracellular muscle components?potassium, phosphate, myoglobin, creatine kinase, and urate?are released into the circulation, resulting in further muscle destruction.^1-3

Etiology

The precipitating event of rhabdomyolysis is usually elicited from the patient when taking the history. When a history cannot be obtained, it is important to remember the multiple etiologies of rhabdomyolysis.² Enumerating the differential diagnosis is most easily done by categorizing the causes of rhabdomyolysis as exertional, genetic, or nonexertional.

Exertional rhabdomyolysis
Exertional rhabdomyolysis can occur in patients with normal muscle tissue, particularly if they are physically untrained, their sweating mechanism is impaired, or their physical exertion occurs in extremely hot conditions. During exercise, potassium plays an important role in the vasodilation necessary to maintain skeletal muscle blood flow, and potassium depletion can result in muscle weakness.⁴ In the absence of other risk factors, physical exertion alone usually does not cause severe rhabdomyolysis.⁵

Two factors that increase the risk for rhabdomyolysis are hypokalemia, often resulting from excessive sweating, and sickle-cell trait, especially in combination with high altitude, extreme heat and humidity, exercise-induced asthma, or preexertion fatigue.⁴ Other forms of exertion, such as excessive muscle contraction secondary to seizure activity or shivering from hypothermia, can lead to rhabdomyolysis and should not be overlooked.²

Genetic defects
Genetic defects are responsible for about 10% of all rhabdomyolysis cases.⁶ These defects include metabolic and mitochondrial myopathies, which usually result in a depletion of adenosine triphosphate during exercise, leading to muscle damage and rhabdomyolysis.⁷ Myopathies should be suspected in patients with rhabdomyolysis who have any of the following risk factors²:

Recurrent episodes of rhabdomyolysis after exertion, fasting, or viral illnesses
A history of exercise intolerance or pigmenturia that began in childhood or adolescence
A family history of rhabdomyolysis.

Nonexertional rhabdomyolysis
This extensive category encompasses the many nonexertional and nonhereditary causes of rhabdomyolysis (Table 1). These causes can operate alone or synergistically and increase the risk of rhabdomyolysis. Some of the common causes are alcohol abuse, illicit-drug use, certain prescription medications, infection, trauma, muscle compression, and seizures.^1,3 A study of 475 patients hospitalized with rhabdomyolysis identified the use of illicit drugs, alcohol, or prescription drugs as the most common cause of rhabdomyolysis, accounting for 46% of all cases.⁶ More than one cause was identified in 60% of these patients. Another study of 97 patients with rhabdomyolysis who were seen in an urban level-1 trauma emergency department showed that cocaine use, physical exercise, and prolonged immobilization were the most common causes.¹

Alcohol abuse can cause acute and chronic myopathy. Acute necrotizing myopathy is associated with an alcohol binge, causing muscle pain and weakness that may progress to renal failure. Chronic myopathy is an insidious proximal-muscle weakness that is caused by the toxic effects of alcohol on muscle or by the malnutrition that is prevalent in alcoholics.⁸

In illicit-drug users, rhabdomyolysis can develop secondary to pressure and ischemic necrosis from the limb compression that is associated with a prolonged loss of consciousness, ischemia caused by vasoconstriction, or damage from direct toxicity of the drugs.⁸ Similarly, drug-induced seizures and cocaine-induced hyperthermia cause excess muscle energy demands and may lead to rhabdomyolysis.²

Prescription medications are well-known precipitants of rhabdomyolysis (Table 2), resulting from drug?drug interactions or from medication side effects. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are associated with a much higher incidence of rhabdomyolysis when they are combined with drugs metabolized by the cytochrome P450-3A4 enzyme pathway. Review of data from more than 250,000 patients treated with statins for lipid reduction identified 24 patients with rhabdomyolysis who required hospitalization.⁹ The average incidence of rhabdomyolysis per 10,000 person-years treated with atorvastatin (Lipitor), pravastatin (Pravachol), or simvastatin (Zocor) was 0.44; this incidence increased to 5.98 when any of these agents was combined with a fibrate.

Medication side effects that can lead to rhabdomyolysis include²:

Malignant hyperthermia from inhaled anesthetics
Neuroleptic malignant syndrome from phenothiazines, such as haloperidol (Haldol)
Dystonic reactions from antipsychotics.

Bacterial infection can also result in rhabdomyolysis, because of direct muscle infection (seen with Staphylococcus or Streptococcus soft-tissue infections) or from septicemia, in which the muscle is damaged by a toxin. Rigors and dehydration associated with the febrile response to infection can lead to muscle breakdown. And although the exact mechanism is not well understood, viral and rickettsial diseases are also known to cause rhabdomyolysis.²

Diagnosis

Prompt recognition of rhabdomyolysis is essential to prevent serious complications, but diagnosis is complicated by the variable and nonspecific nature of the clinical features. Rhabdomyolysis can present on a continuum ranging from asymptomatic myoglobinemia to life-threatening renal failure.^2,5

Signs and symptoms
The signs and symptoms can be divided into local and systemic features. Some patients present with localized muscle pain, tenderness, swelling, bruising, or weakness. Others present with nonspecific systemic signs, such as nausea, emesis, malaise, or fever. Patients may appear confused, agitated, or delirious, or be anuric.³

The most common presentation of rhabdomyolysis is tea-colored (golden-brown) urine, accompanied by muscle weakness, pain, cramps, and swelling.⁵ Rhabdomyolysis associated with electrolyte abnormalities is typically characterized by muscle weakness, with hypokalemia-induced pain and weakness. Pigmenturia may not be observed if the amount of filtered myoglobin is small or if the patient has delayed seeking medical attention.²

Serum markers
The hallmark of rhabdomyolysis is an elevation of serum muscle enzymes.² Experts, however, debate which parameter would be best for diagnosis?creatine kinase or myoglobin. Serum creatine kinase is mostly of the MM fraction for skeletal muscle. A small percentage of MB fraction is found in skeletal muscle.² Myoglobin is normally bound by serum haptoglobin. When myoglobin levels increase, they can overwhelm the haptoglobin and become filtered by the kidneys.^2,3

Myoglobin levels increase first, within approximately 6 hours, and are cleared rapidly. Creatine kinase levels rise more slowly but remain consistently elevated for several days to weeks.⁵ A urine dipstick screening can be used to test for myoglobin, with a follow-up microscopic urinalysis. A positive urine dipstick with the absence of red blood cells in the urine sediment suggests myoglobinuria.

Urine or serum can be tested for myoglobin, but results may not be quickly available in the emergency department setting.³ No consensus exists about which is the most reliable marker for assessing the presence and severity of muscle damage.⁶ Furthermore, no standard creatine kinase values that conclusively diagnose rhabdomyolysis have been established, although various values have been postulated. Some experts speculate that a level of ≥10,000 U/L is indicative of "clinically significant rhabdomyolysis."⁵ Others suggest a creatine kinase level of 5000 U/L as the critical value at which serious muscle injury occurs,¹⁰ and yet others cite 5000 U/L as the level at which the risk for renal failure increases significantly.¹¹ In contrast, some studies have shown a poor correlation between the level of creatine kinase elevation and the degree of muscle damage.¹²

In addition to elevations in muscle enzymes, serum tests may show mildly increased aminotransferase and lactate dehydrogenase levels.¹³ Hepatic dysfunction secondary to proteases released from injured muscle is a common risk factor and is seen in 25% of patients with rhabdomyolysis.¹⁴ Other factors that should alert the physician to the possibility of rhabdomyolysis are²:

Pressure necrosis of the skin
Multiple trauma or crush injury
Increased muscle tone
Hyperkalemia, hyperphosphatemia, or hypocalcemia.

Treatment: Rapid Intervention Is Crucial

It cannot be overstated that rapid recognition and treatment are essential for a favorable outcome. The quickest way to prevent the complications from rhabdomyolysis is to hydrate the patient early and generously. In fact, crush injury victims have the best outcome when intravenous (IV) fluids are started before the trapped limb is freed and decompressed.¹⁵

Patients diagnosed with rhabdomyolysis need massive amounts of crystalloid fluid (6-12 L) to maintain urine output; they can sequester up to 12 L of fluid in the injured areas.³ Advanced age and comorbid conditions, such as cardiovascular disease or renal insufficiency, limit the amount and rate that IV hydration can be used. During the acute phase of treatment, normal saline should be started at 1.5 L/hour and continued at a level that will maintain urine output at 300 mL/hour, until testing shows no myoglobinuria or the serum creatine kinase level falls to <1000 U/L.³

Standard practice has been to change IV fluids to 0.45% saline (1/2 normal saline), with bicarbonate and mannitol, to maintain adequate urine output. Mannitol enhances the elimination of myoglobin casts from the renal tubules via osmotic diuresis. Sodium bicarbonate decreases the toxicity of myoglobin in the tubules by alkalinizing the urine to a pH value of ≥6.5.³ The proposed theory behind the use of bicarbonate and mannitol is the need to increase the solubility of myoglobin in the alkalotic urine and ultimately enhance myoglobin excretion.¹¹ However, the majority of evidence in support of using bicarbonate and mannitol for rhabdomyolysis therapy comes from animal studies, case reports, and retrospective clinical trials with small sample sizes and/or no control groups.^11,16

A study of more than 2000 trauma patients with rhabdomyolysis showed that among those with a creatine kinase level >5000 U/L, no difference was seen in the incidence of renal failure or mortality between those who did and those who did not receive bicarbonate and mannitol.¹¹ This led the authors to recommend a reevaluation of the practice of administering bicarbonate/mannitol therapy to patients with posttraumatic rhabdomyolysis.

Serial measurements of serum potassium, phosphate, calcium, and creatinine are recommended and are useful for estimating the degree of damage.² Laboratory abnormalities are common in the setting of myoglobinuric renal failure. Potassium levels need to be closely monitored to avoid life-threatening dysrhythmias from hyperkalemia.^2,5

The management of metabolic abnormalities is similar to that used in other settings, with one exception. Hypocalcemia is common in the acute phase of rhabdomyolysis because of the deposition of calcium phosphate in damaged muscle and soft tissue. IV or oral calcium supplementation should be avoided, because it can worsen ectopic calcification. For the same reason, hyperkalemia should be corrected by using other standard techniques, such as IV insulin and 50% dextrose, sodium bicarbonate, and sodium polystyrene sulfonate (Kayexalate, Kionex), with calcium replacement reserved for hyperkalemia-induced dysrhythmias.

The presence of tetany is the only other situation that warrants calcium replacement.^2,5 In the diuretic phase of recovery, serum calcium will begin to rise as the calcium deposits dissolve.^3,5 This delayed hypercalcemia can beaged with continued, aggressive fluid replacement and a loop diuretic. Hyperphosphatemia can be managed with oral binders and dialysis if necessary.⁵

Complications

The complications of rhabdomyolysis can occur early or late in the disease. Early complications occur within the first 12 hours and include:

Hyperkalemia
Hypocalcemia
Hepatic inflammation
Cardiac dysrhythmia
Cardiac arrest.

Late complications usually develop after the initial 12 to 24 hours and include disseminated intravascular coagulation (DIC) and acute renal failure. DIC usually worsens between the 3rd and 5th day after initial presentation, and it usually resolves spontaneously if the rhabdomyolysis is treated appropriately.³

Acute renal failure develops in up to two thirds of patients.¹⁷ Renal failure has been attributed to ischemia secondary to decreased fluid volume, tubular injury from free chelatable iron, and myoglobin-induced obstructionor oxidation injury to the kidney.¹⁸

Disposition

Individuals presenting with exercise-induced rhabdomyolysis, even with a significantly elevated creatine kinase level, may be treated as outpatients in the absence of signs of nephrotoxicity, urinary sediment, or metabolic abnormalities. However, such patients must be able to take ample fluids by mouth and ensure that they will follow-up within 48 hours. Any patient with rhabdomyolysis presenting with elevated potassium, phosphate, or uric acid levels should have aggressive treatment initiated even while hospitalization is being arranged.⁵ Admission to the intensive care unit is necessary only for elderly patients and for those with comorbid cardiovascular disorders or with preexisting renal dysfunction. Such patients need close monitoring to avoid fluid overload and may even require invasive hemodynamic monitoring.^3,15

Conclusion

Rhabdomyolysis must be promptly recognized by the treating physician. Despite its many etiologies, the management and treatment principles remain the same, regardless of the cause. The most common presenting symptoms are myopathy, weakness, cramps, and goldenbrown or dark-colored urine. Elevated creatine kinase levels are a prominent feature and are associated with other metabolic abnormalities. The approach to the correction of metabolic abnormalities is similar to that used in other conditions.

It is important to be aware of the potential complications of rhabdomyolysis that can occur in either the early or late phase. Early complications include metabolic abnormalities, which can lead to cardiac dysrhythmias and ultimately cardiac arrest. Late complications include DIC and acute renal failure. Any patient presenting with rhabdomyolysis needs to be treated promptly and aggressively. Appropriate disposition is also important for positive outcomes.

PRACTICE POINTS

Rhabdomyolysis can be lifethreatening and requires quick recognition and treatment.
The many clinical features are nonspecific; the most common presentation includes golden-brown urine, accompanied by muscle weakness, pain, cramps, and swelling.
Illicit-drug use or excessive alcohol intake, as well as a large number of prescription drugs, can cause this condition.
Elevation of serum muscle enzymes is the hallmark of rhabdomyolysis.
Treatment includes early and aggressive hydration. Monitor serum electrolyte levels to avoid complications, such as hyperkalemia or hypocalcemia.

SELF-ASSESSMENT TEST

1. Which of these factors is not a typical cause of rhabdomyolysis?

Shivering from hypothermia
Hyperkalemia
Alcohol abuse
Prolonged immobilization

2. All the following causes suggest a predispositional genetic defect, except:

Tea-colored urine
History of child-onset exercise intolerance
Mother with rhabdomyolysis
Recurrent rhabdomyolysis after viral illness

3. The following features are generally associated with rhabdomyolysis, except:

Vomiting
Twitching
Fever
Confusion

4. Which of the following statements about laboratory values in rhabdomyolysis is not true?

A creatine kinase level of 5000 U/L is pathognomonic
Myoglobin levels increase within 6 hours
Elevated creatine kinase levels can persist for weeks
Lactate dehydrogenase levels may be mildly elevated

5. What IV treatment is best in the acute phase of rhabdomyolysis?

Calcium
Bicarbonate
Mannitol
Normal saline

(Answers at end of references list)

References

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Sauret JM, Marinides G, Wang GK. Rhabdomyolysis. Am Fam Physician. 2002;65:907-912.
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Voermans NC, van Engelen BG, Kluijtmans LA, et al. Rhabdomyolysis caused by an inherited metabolic disease: very long-chain acyl-CoA dehydrogenase deficiency. Am J Med. 2006;119:176-183.
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Brown CV, Rhee P, Chan L, et al. Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference? J Trauma. 2004;56:1191-1196.
Manfredi TG, Fielding RA, O'Reilly KP, et al. Plasma creatine kinase activity and exercise-induced muscle damage in older men. Med Sci Sports Exerc. 1991;23:1028-1034.
Tsironi M, Andriopoulos P, Xamodraka E, et al. The patient with rhabdomyolysis: have you considered quail poisoning? CMAJ. 2004; 171:325-326.
Akmal M, Massry SG. Reversible hepatic dysfunction associated with rhabdomyolysis. Am J Nephrol. 1990;10:49-52.
Gunal AI, Celiker H, Dogukan A, et al. Early and vigorous fluid resuscitation prevents acute renal failure in the crush victims of catastrophic earthquakes. J Am Soc Nephrol. 2004;15:1862-1867.
Malinoski DJ, Slater MS, Mullins RJ. Crush injury and rhabdomyolysis. Crit Care Clin. 2004;20:171-192.
de Meijer AR, Fikkers BG, de Keijzer MH, et al. Serum creatine kinase as predictor of clinical course in rhabdomyolysis: a 5-year intensive care survey. Intensive Care Med. 2003;29:1121-1125.
Moore KP, Holt SG, Patel RP, et al. A causative role for redox cycling of myoglobin and its inhibition by alkalinization in the pathogenesis and treatment of rhabdomyolysis-induced renal failure. J Biol Chem. 1998;273:31731-31737.

Answers: 1. B; 2. A; 3. B; 4. A; 5. D.