Review
The Other Medical Causes of Rhabdomyolysis

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ABSTRACT

Rhabdomyolysis is the clinical and laboratory syndrome resulting from skeletal muscle injury and release of potentially toxic substances into the circulation. The severity of rhabdomyolysis varies widely from asymptomatic elevation of muscle enzymes to the life-threatening complications of acute renal failure and severe electrolyte abnormalities. The etiology of rhabdomyolysis may be considered under 4 categories: (1) trauma or direct injury, (2) excessive muscle activity, (3) hereditary muscle enzyme defects, and (4) other less obvious medical causes. The latter medical causes may be subdivided into the following: (1) drugs and toxins, (2) muscle hypoxia, (3) metabolic and endocrine disorders, (4) infections, (5) temperature alterations, and (6) miscellaneous causes. The diagnosis of rhabdomyolysis depends on recognizing the symptoms of muscle pain and weakness, detecting the presence of or history of red-to-brown urine (myoglobinuria), and finding short-term elevations of creatine kinase that are not attributable to myocardial infarction or inflammatory myopathies. The major therapeutic goal is to recognize and treat complications as soon as possible, particularly electrolyte abnormalities and acute renal failure. Knowledge of the other medical causes of rhabdomyolysis allows one to identify and treat this potentially serious condition in otherwise occult cases.

Section snippets

Muscle Anatomy, Biochemistry, and Cell Injury

Skeletal muscle accounts for about 40% of the body weight of nonobese adults.3., 6., 14. Each muscle is composed of many muscle fascicles, which in turn are composed of many muscle fibers or cells. Muscle fibers have a cell membrane called the sarcolemma. Inside the muscle fiber, myofibrils are suspended in a matrix called the sarcoplasm (muscle cytoplasm) with the usual intracellular constituents, including large quantities of potassium, magnesium, phosphorus, protein enzymes, myoglobin,

Classification of Rhabdomyolysis

In general, rhabdomyolysis may be classified according to etiology into 4 broad categories (Figure 2). The first 3 categories, trauma or direct muscle injury, excessive muscle activity, and hereditary muscle enzyme defects, may be obvious or easily suspected after the initial evaluation and are briefly summarized below. Rhabdomyolysis from other medical causes may be more obscure and even missed if the diagnosis is not considered. At times, the development of acute renal failure (ARF) without

Medical Causes of Rhabdomyolysis

In 1982, Gabow et al1 reported a series of 87 episodes of rhabdomyolysis in 77 patients from Denver, Colorado. They included patients with CK levels greater than 5 times the upper limit of normal, unless myocardial infarction or cerebrovascular accident had occurred. The most common etiological factors found were alcohol, based on a history of alcoholism or measurable blood ethanol level on admission (67%), immobilization with limb (muscle) compression (39%), and generalized seizures (24%).

Drugs and Toxins

Drugs and toxins may be the most common medical cause of rhabdomyolysis, perhaps in part because of the common abuse of ethanol and its contribution to muscle injury.1., 3., 21. The following adverse actions of ethanol on muscle have been shown experimentally and have been suggested as the mechanisms for rhabdomyolysis in patients: (1) ethanol inhibits the accumulation of calcium by the sarcoplasmic reticulum, (2) ethanol disrupts muscle cell membranes, and (3) ethanol inhibits sodium-potassium

Muscle Hypoxia

Any medical condition that leads to a prolonged loss of consciousness and immobilization may result in muscle injury when an arm or leg is compressed by the head or torso.1., 35. In situations of prolonged compression, rhabdomyolysis may appear only after the ischemic muscle is reperfused. Intravascular pressures sufficient to cause muscle ischemia and necrosis have been demonstrated by inserting wick catheters into muscles of volunteers and placing them in positions in which victims are

Metabolic and Endocrine

Hypokalemia and hypophosphatemia are recognized causes of, or contributors to, the development of rhabdomyolysis.1., 3., 8., 24. Potassium is the major intracellular cation (150 mEq/L) and is much higher than in extracellular fluid. In muscle, this gradient is maintained by the sodium-potassium ATPase pump. Such a high concentration of intracellular potassium is critical for activity of certain enzymes, electrical phenomena, muscle cell contraction, blood flow during exercise, and structural

Infections

Rhabdomyolysis can occasionally be precipitated by some viral and bacterial infections, either by direct viral invasion of skeletal muscle or by toxin generation.3., 38., 39., 40. In a recent review, 59 cases of rhabdomyolysis caused by viral infections were found.40 Influenza A and B accounted for the most cases,25 with HIV and Coxsackie virus tied for the second most common cause (8 each). Although all rhabdomyolysis patients with viral infections had elevated CK levels, only 34% (20 of 59

Temperature Alterations

Altered temperature conditions, particularly malignant hyperthermia, neuroleptic malignant syndrome, and heat stroke, may result in rhabdomyolysis. In malignant hyperthermia (a syndrome of generalized muscular contraction and rigidity, hyperthermia, and metabolic acidosis after certain inhalational anesthetics in susceptible patients), rhabdomyolysis may result. Most commonly inherited in an autosomal dominant pattern, these patients have a defect in the calcium channel of the sarcoplasmic

Miscellaneous

One might expect rhabdomyolysis to be seen in inflammatory muscle diseases as well. Dermatomyositis and polymyositis typically cause proximal muscle weakness that develops over several weeks to months. Elevations of CK is nearly universal, and myoglobin is detectable in serum or urine in more than 50% of cases; however, only 8 cases of myoglobin-related ARF have been reported.42 Rhabdomyolysis has also been reported in status asthmaticus. Although the mechanism is unclear in most case reports,

Diagnostic Evaluation

The classic diagnosis of rhabdomyolysis depends on recognizing the presence of significant myalgias, muscle weakness, and red-to-brown urine and documenting elevated CK values. Of these, the diagnosis of rhabdomyolysis from medical causes may require a high index of suspicion. Whereas rhabdomyolysis may be obvious in patients with trauma or excessive muscular activity, patients with loss of consciousness, certain drug exposures, infections, or metabolic abnormalities may not present with

Treatment

The main goal in the treatment of rhabdomyolysis is to recognize and treat any complications. Although the extent of muscle injury can be so severe that it leads to long-term disability, the release of large amounts of toxic substances from dying muscle represents the immediate danger (Figure 2).10., 11. Life threatening complications include hyperkalemia, metabolic acidosis, ARF, hypovolemia, disseminated intravascular coagulation (DIC), respiratory and hepatic insufficiency, and, uncommonly,

ARF

It has been estimated that rhabdomyolysis causes approximately 10% of all cases of ARF.3., 9. Basic and clinical research has provided information that supports 3 mechanisms for the development of ARF in rhabdomyolysis.4., 17. First, renal vasoconstriction has been observed, and evidence supports a role for platelet activating factor and endothelin in this mechanism. Second, evidence also supports a direct toxicity of the heme-protein myoglobin on renal tubular cells, a toxicity that is

Electrolyte Abnormalities

Hyperkalemia is the most important complication of rhabdomyolysis because of its potential lethal effect on cardiac rhythm and function. Early identification should be followed by prompt treatment in a manner appropriate to the level of hyperkalemia. Hyperphosphatemia, which will be higher in azotemic patients, can be managed with phosphate binders when phosphorus levels greater than 7 mg/dL occur. Hypocalcemia may develop early but should be treated only if severe symptoms or severe

Compartment Syndromes

A compartment (compression) syndrome develops when tissue injury results in an elevated hydrostatic pressure within a closed osteofascial compartment sufficient to further reduce perfusion of muscles below the level necessary for cellular viability.10., 47. This threshold in skeletal muscle has been shown to be related more closely to the difference between mean arterial pressure and compartment pressure rather than tissue pressure per se. The lowest pressure difference at which a normal

DIC, Acute Pulmonary and Hepatic Dysfunction

With extensive injury, multiple system organ failure may occur. Although more common with severe trauma and crush injury, rhabdomyolysis from medical causes may also lead to DIC, acute pulmonary dysfunction (acute respiratory distress syndrome), and hepatic dysfunction.6 DIC is usually most pronounced on days 3 to 5; if severe bleeding does not occur, spontaneous improvement occurs by days 10 to 14.18 If bleeding does occur, infusion of fresh frozen plasma to replace coagulation factors and/or

Conclusion

Rhabdomyolysis is a serious and potentially lethal condition that can develop from a variety of medical causes. Optimal treatment depends on early recognition and intervention. A high clinical suspicion for the occurrence of rhabdomyolysis in the medical conditions discussed above can lead to quicker recognition and better patient care.

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