Rhabdomyolysis

The term rhabdomyolysis refers to disintegration of striated muscle, which results in the release of muscular cell constituents into the extracellular fluid and the circulation. One of the key compounds released is myoglobin, an 18,800-Dalton oxygen carrier. It resembles hemoglobin, but contains only one heme moiety. Normally, myoglobin is loosely bound to plasma globulins and only small amounts reach the urine. When massive amounts of myoglobin are released, the binding capacity of the plasma protein is exceeded. Myoglobin is then filtered by the glomeruli and reaches the tubules, where it may cause obstruction and renal dysfunction (1). The degree of rhabdomyolysis that can manifest ranges from a subclinical rise of creatine kinase (CK) to a medical emergency comprising interstitial and muscle cell edema, contraction of intravascular volume, and pigment-induced acute renal failure (ARF). Today, rhabdomyolysis is one of the leading causes of ARF (1,2). The prognosis of rhabdomyolysis-associated ARF is relatively benign (3). One major cause of rhabdomyolysis is the crush syndrome, i.e., myolysis is linked to traumatic compression of muscle followed by reperfusion, as is frequently seen in accidents or disasters. Muscular trauma, however, does not always lead to rhabdomyolysis, not all rhabdomyolysis leads to ARF, and not all ARF related to crush is attributable to rhabdomyolysis. Alternative causes of ARF in rhabdomyolysis may include dehydration, sepsis, and drug nephrotoxicity. Most cases of rhabdomyolysis in peacetime are nontraumatic; they are most frequently the consequence of seizures, alcohol abuse, or compression as a result of coma (see below) (4). Historical Notes Rhabdomyolysis was observed in ancient times (5). The Old Testament refers to a plague suffered by the Israelites during their exodus from Egypt after abundant consumption of quail (Book of Numbers 11:31-35). Myolysis after the consumption of quail is well known in the Mediterranean region. It is the result of intoxication by hemlock herbs, which are consumed by quails during their spring migration (6). Remarkably, indirect evidence substantiates that this biblical episode occurred in springtime (5). In modern times, the first cases of crush syndrome and ARF were reported during the Sicilian earthquake in Messina in 1908 and in the German military medical literature during World War I (7). The latter concerned cases of rhabdomyolysis observed after soldiers had been buried in trenches. In modern English medical literature, the authors of the first detailed report of ARF related to the crush syndrome were Bywaters and Beall. They observed the condition in four victims of the bombing of London during the Battle of Britain in 1940 (7). The authors pointed to the link between rhabdomyolysis and renal failure. The role of myoglobin was later classified in greater detail in an experimental publication (8). It was only decades later, in the early 1970s, that nontraumatic causes of rhabdomyolysis were recognized and identified as a potential cause of ARF (9, 10). Etiology It is beyond the scope of this review to discuss the many conditions in which rhabdomyolysis may occur, but we shall summarize the most frequent ones (Table 1).Table 1: Etiology of rhabdomyolysisTrauma and Compression Traumatic rhabdomyolysis is mainly the result of traffic or occupational accidents. Compression of the muscles may also be induced by torture, abuse, or long-term confinement in the same position (orthopedic problems; surgical interventions necessitating specific positions for a long time; psychiatric conditions; coma). Occlusion of the Muscular Vessels Thrombosis, embolism, or clamping of vessels during surgery may all result in muscle cell necrosis if oxygen deprivation is maintained for prolonged periods (11). ARF occurs only if a critical mass of muscle has become necrotic, e.g., after total vascular occlusion involving at least one limb, after multiple diffuse emboli, or during generalized shock. Strainful Exercise of Muscles Strenuous muscular exercise may cause myolysis, especially in untrained subjects or in individuals exercising under extremely hot or humid conditions (12, 13). Muscle necrosis more frequently occurs after downhill walking than after uphill climbing. The combination of muscular exertion, hypoxemia, and corticosteroid-induced myopathy may cause myolysis in patients with status asthmaticus (14). Because K+ is essential for vasodilation of the microvasculature of the muscles, exercise will cause more rapid muscle ischemia in hypokalemic subjects (15). Electrical Current High-voltage electrical injury and lightning strikes cause rhabdomyolysis in at least 10% of the subjects surviving the primary accident, even if the wounds of the site of entry are small (16). Myolysis is attributable to thermal injury, or to electrical disruption of sarcolemmal membranes. The latter results in pore formation, loss of barrier function, and massive calcium influx (17). Hyperthermia An excessive body temperature may result in muscle damage. One cause of hyperthermia-associated rhabdomyolysis is the neuroleptic malignant syndrome, which is characterized by high fever in patients treated with phenothiazides or haloperidol (18). Another potential cause is malignant hyperthermia, an inheritable condition that is characterized by a rapid rise of body temperature (1°C/5 min), typically after anesthesia with halogenated hydrocarbons or succinylcholine (19). As a result of excessive sweating, these patients often also have hypokalemia, which may aggravate damage to the muscles. Metabolic Myopathies Exceptional causes of rhabdomyolysis are inherited diseases that have in common failure of energy delivery to the muscles because of defects in glucose, glycogen, lipid, or nucleoside metabolism. These disorders usually start during childhood and should be suspected if muscular weakness or myoglobinuria recur frequently, or appear in association with events that are unlikely to precipitate rhabdomyolysis in healthy subjects (20). In most cases, the final common pathway leading to muscle cell disintegration is deficient delivery of adenosine triphosphate (ATP), so that cell integrity cannot be maintained (21). Viral infection, exertion, or fasting are aggravating factors. In separate reports, Poels and Gabreëls and Brumback et al. have provided a detailed description of the relevant metabolic defects (22,23). Drugs and Toxins Regular and illegal drugs that cause rhabdomyolysis, together with their mechanisms of action, are listed in Table 2. Perhaps the most frequent cause of drug-induced rhabdomyolysis today is the administration of HMG-CoA reductase inhibitors. Immediate withdrawal of these drugs is mandatory if patients complain of muscle problems or if CK rises to more than three times above normal levels. The risk of drug-induced muscle disease is aggravated by simultaneous administration of danazol, nicotinic acid, cyclosporine, itraconazole, or erythromycin. The combination of HMG-CoA reductase inhibitors with gemfibrozil also carries a high risk of myotoxicity (24). Finally, fibrates alone may cause myotoxicity, particularly in patients with renal failure, because most fibrates accumulate when GFR is decreased.Table 2: Main drugs responsible for rhabdomyolysis, together with the mechanism causing ARFaIn patients with acute or chronic alcohol intoxication, muscle dysfunction is attributable to a combination of immobilization, hypokalemia, hypophosphatemia, agitation, and/or direct myotoxicity. Such a combination of etiologic factors is also seen in patients treated with psychotropic drugs, or in whom aggression, restraint, intramuscular injections, and/or extrapyramidal effects may act in concert to cause muscle dysfunction (25). Rhabdomyolysis as a result of exposure to toxins is seen not only after ingestion of quails, but also after eating of certain fish species (Haff disease) (26) or after contact with several snake and insect venoms (e.g., hornet and spider). Infections Locally invasive infection of muscle (pyomyositis), diffuse metastatic infection of muscles during septicemia, and infection with microbes causing toxic shock syndrome may result in extensive muscle necrosis. Electrolyte Abnormalities Hypokalemia, hypocalcemia, hypophosphatemia, hyponatremia, and, particularly, hypernatremia and hyperosmotic conditions all have been associated with rhabdomyolysis. The myotoxicity of alcohol is related in part to electrolyte abnormalities, i.e., hypophosphatemia or hypokalemia (27), but malnutrition and severe illness also may cause electrolyte disturbances that induce rhabdomyolysis. Hypokalemia and hypophosphatemia disappear after overt myonecrosis and renal failure have developed; hence, their causative role is often overlooked. Pathophysiology of Myolysis Changes in Cellular Metabolism Stretching or exhaustive work of muscle cells increases sarcoplasmic influx of sodium, chloride, and water, which results in cell swelling and autodestruction (22). Calcium enters the cell, in exchange for intracellular sodium. Large quantities of free calcium ions trigger persistent contraction, resulting in energy depletion and cell death (23). In addition, calcium activates phospholipase A2, as well as various vasoactive molecules and proteases. Furthermore, it leads to the production of free oxygen radicals (1). Damaged muscle is invaded by activated neutrophils that amplify the damage by releasing proteases and free radicals (16). The result is an inflammatory, self-sustaining myolytic reaction, rather than pure necrosis. Reperfusion Injury In ischemic tissue injury (e.g., myocardial infarction, acute renal failure), most of the damage is not inflicted during the period of ischemia, but after the blood flow into the damaged tissue is restored (reperfusion injury). Leukocytes migrate into the damaged tissue only after reperfusion has started, and production of free radicals starts only when oxygen is amply available. A similar mechanism is at work in both traumatic and nontraumatic muscular damage (28). In the case of traumatic rhabdomyolysis, the muscles are initially compressed and ischemic, and muscle dysfunction starts to develop only when the patient is evacuated, i.e., when perfusion of the damaged muscles is restored. This is the main reason that Better and Stein proposed starting infusion of large amounts of fluid before victims of trauma are extricated (29). Compartment Syndrome Most striated muscles are contained within rigid compartments formed by fasciae, bones, and other structures. If the energy-dependent transcellular pump systems fail in the traumatized tissue, the muscle cells swell. As a result, intracompartmental pressure rises and may occasionally reach excessive values. High intracompartmental pressure provokes additional damage and necrosis. Because such compartments are non-communicating, closed systems, the only way to decrease the pressure is to decompress the fascial system surgically by fasciotomy. Not all investigators are enthusiastic about early fasciotomy, because the procedure may create a potential source of infection (29). On the other hand, prolonged pressure may provoke irreversible paralytic damage to the peripheral nerves. It is generally accepted that compartment pressures >30 mmHg produce clinically significant muscle ischemia. In hypotensive patients, even lower compartment pressures will cause perfusion problems. The measurement of intramuscular pressure provides an objective parameter for the decision to perform fasciotomy. In nonhypotensive patients, this should be done when the intramuscular pressure exceeds 50 mmHg or if pressure values between 30 and 50 mmHg show no tendency to decrease after a maximum of 6 h. Metabolic Derangements during the Course of Rhabdomyolysis Release of constituents of necrotic muscle results in altered plasma concentrations of several anorganic and organic compounds, which are responsible for toxic and sometimes life-threatening complications (30). The accumulation of these compounds is aggravated by the simultaneous development of renal failure. Necrosis of the muscles, together with inflammation, results in the accumulation of substantial amounts of fluid in the affected limbs (up to 10 L per limb). Unless large amounts of volume are administered, shock, hypernatremia, and deterioration of renal function will supervene. If muscles recover faster than the kidneys, fluid is released into the circulation at a later stage. Delayed renal elimination may then result in expansion of the extracellular and plasma volume. At an early stage, dehydration causes hyperalbuminemia, whereas later malnutrition, inflammation, capillary leak, and fluid overload cause hypoalbuminemia. Changes in serum albumin may result in the misinterpretation of total plasma calcium concentrations. Release of organic acids from dying muscle cells provokes high anion gap acidosis (4). In particular, hypoxic muscles release lactic acid into the circulation; its removal by the liver is inadequate if the patient is hypovolemic. Acidosis will have a deleterious effect on numerous metabolic functions and will enhance the hyperkalemia. The lower urinary pH and intratubular acidosis will facilitate intratubular precipitation of myoglobin and uric acid. During the early stages of rhabdomyolysis, calcium accumulates in the muscles. Sometimes massive calcification of necrotic muscles or even heterotopic ossification is seen (31,32). In the presence of hyperkalemia, severe hypocalcemia may lead to cardiac arrhythmia, muscular contraction, or seizures. The latter damage the muscles even further. Remarkably, some of the patients with rhabdomyolysis do not show hypocalcemia (4). During later stages of the disease, the accumulated calcium is released from the storage sites. This is often associated with hyperparathyroidism and hypervitaminosis D (33), and overt hypercalcemia. However, the hyperparathyroidism and hypervitaminosis D are not seen in all cases (34). Hypercalcemia occurs more frequently if calcium has been supplemented in the hypocalcemic phase. Phosphorus is released from damaged muscle and accumulates in patients with renal insufficiency. Hyperphosphatemia causes tissular deposition of calcium-phosphate complexes in tissues and suppression of 1 α-hydroxylase, the enzyme responsible for the production of the active vitamin D analogue calcitriol. All of these factors together further contribute to the early hypocalcemia. In patients with massive breakdown of muscles, substantial amounts of potassium are released into the blood. Elimination via the kidneys fails if patients have ARF. Frequently, hyperkalemia in patients with rhabdomyolysis is life-threatening, requiring immediate treatment. In nontraumatic rhabdomyolysis, hyperkalemia is not consistently present at the time of admission (4). Nucleosides are released from disintegrating cell nuclei into the blood and metabolized in the liver to purines such as xanthine, hypoxanthine, and uric acid, among which the latter may contribute to tubular obstruction. The precursor of creatinine, creatine, is one of the main constituents of muscle, where it plays a role in energy delivery. It is massively released from nonviable muscle cells and transformed into creatinine. It has been postulated that in rhabdomyolysis, serum creatinine levels should be exceedingly high (9), but such a disproportionate rise is not seen, which may be explained by kinetic and mechanistic considerations (35). Serum creatinines are indeed higher in some patients with rhabdomyolysis, but this may be explained by the fact that those patients are younger than those with other causes of ARF (3). Pathophysiology of ARF The pathophysiology of myoglobinuric ARF has been studied extensively in the animal model of glycerol-induced ARF. The main pathophysiologic mechanisms are renal vasoconstriction, intraluminal cast formation, and direct heme-protein-induced cytotoxicity (1). Myoglobin is easily filtered through the glomerular basement membrane. Water is progressively reabsorbed in the tubules, and the concentration of myoglobin rises proportionally, until it precipitates and causes obstructive cast formation. Dehydration and renal vasoconstriction, which decrease tubular flow and enhance water reabsorption, favor this process (1) (Figure 1). The high rates of generation and urinary excretion of uric acid further contribute to tubular obstruction by uric acid casts. Another factor favoring precipitation of myoglobin and uric acid is a low pH of tubular urine, which is common because of underlying acidosis. The degradation of intratubular myoglobin results in the release of free iron, which catalyzes free radical production and further enhances ischemic damage (1). Even without invoking release of free iron, the heme center of myoglobin will initiate lipid peroxidation and renal injury (36). Alkaline conditions prevent this effect by stabilizing the reactive ferryl myoglobin complex.Figure 1.: Pathophysiology of acute renal failure in rhabdomyolysis.Gastrointestinal ischemia is responsible for absorption of endotoxin and release of cytokines, which amplify the inflammatory reaction and cause hemodynamic instability. Diagnosis and Differential Diagnosis Myoglobinemia and Myoglobinuria Myoglobinuria does not occur without rhabdomyolysis, but rhabdomyolysis not necessarily results in visible myoglobinuria. Myoglobin causes discoloration of the urine but not of the plasma. Urinary myoglobin provokes a typical reddish-brown (port-wine-like) color, even in the absence of hematuria (Table 3). The kidneys and urinary tract may have been damaged by trauma, however, so the presence of hematuria in posttraumatic cases does not absolutely exclude the presence of myoglobinuria. Myoglobin is rapidly and unpredictably eliminated by hepatic metabolism. Therefore, tests for myoglobin in plasma or urine are not a sensitive diagnostic procedure.Table 3: Causes of reddish-brown discoloration of the urineRed discoloration of the urine when erythrocytes cannot be detected by microscopy must be due to hemoglobinuria or myoglobinuria (Table 4), unless the color of the urine is due to drugs or metabolites (Table 3).Table 4: Characteristics of urine and plasma in the different conditions that may cause red discoloration of the urineaHemoglobin is structurally and functionally related to myoglobin. Although the molecular weight of is higher than that of myoglobin is to the glomerular barrier and induce ARF. In patients with but not in patients with the plasma will be as It is to that the urinary does not between myoglobin, hemoglobin, and red blood The enzyme CK is present in striated When muscle cells CK is released into the of CK some of are in striated muscle in cardiac muscle During rhabdomyolysis, quantities of are released and concentrations of or more are not Because degradation and removal are the concentration of CK and in a more than that of myoglobin. CK is more than myoglobin in the presence and of damage to the muscles. and The primary is to prevent the factors that cause ARF, volume tubular and free radical The fluid for patients with rhabdomyolysis of or to which is This combination may be by 10 of if urinary flow is present (Table overt renal failure has the only is blood administration in patients with or traumatic may result from of water by muscles and must be by the administration of (29). volume the of fluid is as high as 10 L or more per In cases in which muscles are compressed as a result of trauma, it is to start administration of fluid before the is extricated from under the (30). or should be of the can be as This to the acidosis induced by the release of from damaged muscles, to prevent precipitation of myoglobin in the tubules, and to the risk of hyperkalemia. It should be that was during World War as in the of Bywaters and (7). The only of administration is the decrease of serum The of to the fluid several (1) increases renal blood flow and is an that fluid from the interstitial and muscular swelling and is an that increases urinary flow and obstructive myoglobin and free and tubular flow and decrease the risk of precipitation of myoglobin, urine and calcium may be because it the production of uric acid and also as a free radical Another has been in the of rhabdomyolysis because of its capacity to enhance capillary flow and decrease and An is of hyperkalemia. that cause a of potassium from the extracellular to the intracellular compartment glucose, have only a If renal function does not those should be followed by more such as administration of potassium or Calcium and calcium should be with because they enhance the risk of intramuscular calcium If is not only in patients with overt hyperkalemia, but also in patients in whom serum potassium rises Although hypocalcemia is a common in the of rhabdomyolysis, it usually does not particularly because this the risk of intramuscular calcium for the of hypocalcemia are seizures, acute renal failure has been or severe hyperkalemia and acidosis are the patient overload is a to start because patients to be due to massive fluid accumulation in the damaged has several in these (1) it provides removal of and it the of without in traumatized and it provides the to several patients per on the same or for the removal of and of fluid The for is a especially in traumatized with by administration of quantities of calcium is on the of with this is to in patients with trauma and often will be for the removal of potassium and other It however, especially if during are not available. of myoglobin by plasma exchange has no and also is because the metabolic of myoglobin is Rhabdomyolysis in Large of patients all rhabdomyolysis at the same time are observed after particularly in several earthquake of patients with ARF. 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