Rhabdomyolysis is a condition caused by skeletal muscle injury and release of muscle cell contents into the circulation. It may result in myoglobinuria, the filtration of myoglobin into the urine, and is often associated with acute renal failure ( ARF ). Rhabdomyolysis may complicate many different disease states. In some, such as crush injury, muscle injury is obvious; in others, such as drug overdose, it may never be apparent. It may occur in the setting of an altered mental status, and even in the conscious patient may occur with minimal symptoms or physical findings. Therefore diagnosis requires a high level of suspicion and appropriate sensitivity to abnormal laboratory values. Many insults can precipitate rhabdomyolysis and myoglobinuria. Disruption of the muscle cell membrane may result from a direct mechanical or toxic insult to the membrane or an inability to maintain ionic gradients across the membrane ( as in ischemia or extreme exertion ).
In addition to complicating many critical illnesses, rhabdomyolysis may require intensive care because of its lifethreatening complications. Hypovolemia may be profound and hyperkalemia may require electrocardiographic monitoring and emergent dialysis. Thus, rhabdomyolysis and myoglobinuria pose a challenge to physicians in many specialties and to the intensivist in particular. Table 1 lists some of the precipitants of rhabdomyolysis, categorized by the mechanism of muscle injury. It is apparent that several of these conditions, such as ischemia, severe metabolic derangements and seizures are common to many disease states seen in the intensive care unit.
The clinical presentation is variable. In the awake, cooperative patient symptoms may include cramping pain in the involved muscle group(s), frequently the calves and lower back; progressive weakness; and discoloration of the urine. However, these complaints may be absent 50 % of the time, even in the alert patient. Physical examination may be notable for fever or volume depletion. The muscles involved may demonstrate swelling, tenderness, and a firm consistency. Hemorrhagic discoloration of overlying skin is sometimes noted. Once again, these findings are not universal, with only about 5 % of patients having objective findings of muscle injury on presentation.
Gross examination of the urine may suggest the diagnosis, as circulating myoglobin is not highly protein bound and is readily filtered at the glomerulus. Thus, release of myoglobin in large amounts results in its filtration into the urine, being visible at concentrations exceding 100mg / L. Since serum concentrations rarely exceed 25mg / L, its discoloration is very unusual in rhabdomyolysis and should suggest hemolysis.
Laboratory values reflect acute muscle cell lysis, as well as the primary insult or its complications. Disruption of cell membranes allows the release of potassium, phosphate, proteins and purines : hyperkalemia, hyperphosphatemia and hyperuricemia may be prominent abnormalities. The hallmark of muscle damage is elevation of creatine kinase ( CK ) concentration, which is present in all patients with rhabdomyolysis. CK is elevated to such a degree that myocardial infarction and cerebrovascular accident is excluded. Serum analysis for myoglobin is diagnostic but requires special techniques. Aldolase, LDH and SGOT are also frequently elevated, but only aldolase is specific for muscle injury. Calcium deposition in the damaged muscle may cause hypocalcemia. Release of creatine from muscle and its spontaneous hydration to creatinine results in its elevation, which may be disproportional to BUN elevations in the absence of prerenal azotemia. Disseminated intravascular coagulation is frequently seen.
The presence of myoglobin in the urine establishes the diagnosis of rhabdomyolysis and myoglobinuria. However, myoglobinuria is not always detected. It may be detected by urine dipstick tests ( orthotoluidine ), which also reacts with the globin fragment of hemoglobin. Therefore, in the presence of red blood cells or hemolysis, its specificity is limited. However, in the absence of significant hematuria its presence should suggest rhabdomyolysis or hemolysis. In one series of patients with rhabdomyolysis without hematuria, 74 % were noted to have orthotoluidine - positive urine. Radioimmunoassay is more sensitive and specific than dipstick.
The complications of rhabdomyolysis arise from the local effects of muscle cell lysis and the systemic effects of the substances released, as shown in Table 2. when sarcolemmal integrity is compromised there are several ionic exchanges between the extracellular and intracellular compartments. These electrolyte and solute shifts may cause significant acute biochemical and hemodynamic abnormalities in the hours to days following muscle injury.
The influx of fluid into the damages muscles may cause hypovolemia to the point of shock. Volume requirements soon after muscle injury may exceed 10 L / day. Indices of volume status such as urine output, urine sodium concentration and BUN : creatinine ratio may all be misleading, with better assessment being made with invasive hemodynamic monitoring (Swan - Ganz catheter ). The release of larg amounts of potassium can cause lifethreatening hyperkalemia, which theoretically is less responsive than to traditional therapy that relies on shifting potassium intracellularly, such as the infusion of insulin and glucose, as its transport mechanisms are likely impaired in injured muscle and transported potassium may leak from the intracellular compartment. Hyperphosphatemia, caused by release of intracellular phosphate, may worsen hypocalcemia by decreasing the production of 1-25 dihydroxycholecalciferol. In the presence of normal calcium levels the calcium-phosphate product may increase and cause metastatic clacification. The release of purines and subsequent hepatic conversion to uric acid can cause hyperuricemia, which, particularly in the setting of hypovolemia with low urine flow and pH, may cause sludging of urate crystals in the renal tubules, contributing to the pathogenesis of acute renal failure in rhabdomyolysis. Sulfur-containig proteins released in large amounts can lead to hydrogen and sulfate loads that overwhelm renal excretory mechanisms, resulting in an anion gap acidosis, which may be severe. Other causes of acidosis in the setting of rhabdomyolysis include lactic acidosis from ischemia and the acidosis of uremia. It is also interesting to note that, although hypocalcemia predominates acutely in rhabdomyolysis and during oliguric myoglobinuric renal failure, hypercalcemia may complicate the diuretic phase of resolution of renal failure, as calcium is mobilized from those deposited in injured muscles and increased quntities of 1-25 dihydroxycholecalciferol produced by the recovering kidneys.
Perhaps the most significant complication of rhabdomyolysis is acute renal failure ( ARF ), seen in about 30 % of patients. It may be caused by direct nephrotoxic effexts of myoglobin, by its precipitation in renal tubules, or by its conversion to ferrihemate at a pH < 5.6, which is toxic to renal tubules and also precipitates. Recently several authors have demontrated a potential role for oxygen-free radicals in renal injury in myoglobinuria, as well as hemoglobinuria. The laboratory values, as described above, are typical of ARF of any etilogy, except that hyperkalemia and hyperphosphatemia tend to occur early, and serum creatinine concentration tends to be higher than expected for a given level of azotemia, because of the release of previously formed creatine from damaged muscle. Dialysis may be required in 50-70 % of patients.
Disseminated intravascular coagulation ( DIC ) may complicate rhabdomyolysis. It probably results from the activation of the clotting cascade by components released from the damaged muscles. Overt clinical bleeding or thrombosis rarely complicates DIC in the setting of rhabdomyolysis, laboratory abnormalities making the diagnosis ( see other article in this section ). It should be noted that cocaine ingestion and hyperthermia may be complicated by fulminant hepatic failure, and careful evaluation to distinguish DIC and liver failure should be undertaken, where appropriate.
In addition to these systemic complications, local complications may occur as well. Injured muscles often become edematous. In muscles confined by fascial planes, swelling may cause a rise in pressure whithin the compartment, leading to reduced blood flow with ischemia and further muscle and nerve damage. This further muscle damage is manifest as the " second wave phenomenon ", the persistent elevation or rebound elevation in CK levels at 48 to 72 hours after the initial insult. Failure of the CK to decrease by approximately 50 % every 48 h should raise the suspicion of further ischemic muscle damage.
Therapy of rhabdomyolysis should be directed at two objectives. the first is the treatment of any reversible cause of muscle damage, as infections and carbon monoxide poisoning. The second is the managment and prevention of complications. Because hypovolemia is often present, agressive volume ressucitation should be instituted. Two to three liters of saline per hour are often required during the initial managment, and 300 to 500 ml / h once hemodynamic stability has been achieved. Failure to provide adequate volume replacement is probably the most frequent error made in the management of rhabdomyolysis. Assessment of volume status often needs central venous or pulmonary artery pressure monitoring.
Electrolyte abnormalities in the acute stages of rhabdomyolysis often will require therapy. Hyperkalemia should be corrected if potassium levels exceeds 6 mEq / L or cause conduction disturbances. Conventional therapy with insulin and glucose infusions, beta agonists and sodium bicarbonate may be ineffective because of loss of sarcolemmal integrity, and, therefore, early use of exchange resins and dialysis may be necessary. If hyperuricemia is severe ( uric acid > 20 mg/ dl ), allopurinol can be used. Hyperphosphatemia should be treated with phosphate binders. Calcium infusion can worsen the deposition in injured muscles and lead to higher levels of hypercalcemia in the diuretic phase of recovery of ARF. So, calcium administration should only be used for the therapy of severe hyperkalemia or if ventricular dysfunction causes hypoperfusion.
Therapy aimed at preventing the onset of ARF is controversial. It is clear from animal studies that low urine volumes and aciduria potentiate the initial renal insult, with vigorous fluid administration to maximize urine flow and alkalinization with bicarbonate protecting against myoglobinuric renal injury. Clinical studies suggest that alkaline diuresis is effective in preventing ARF in myoglobinuria. It is clear that increased urine volume is beneficial, and its alkalinization with bicarbonate probably adds to the beneficial of high urine flow, but weather its effect is clinically relevant and worth the potential risk remains to be studied. Bicarbonate administration may be detrimental, as metabolic alkalosis could worsen the hypocalcemia . Furthermore, high urine flows may increase urinary pH without bicarbonate administration. Similarly, the role of mannitol is controversial. It may reduce renal tubular oxygen consumption by reducing sodium resorption, which can reduce renal ischemic damage. Caution should should be used in administering mannitol bacause an osmotic diuresis without adequate volume replacement might worsen hypovolemia.
In summary, treatment to prevent the development of ARF in rhabdomyolysis is controversial. A rational approach follows : if myoglobin is found in the urine or if serum CK exceeds 5.000 IU, then normal saline infusion is instituted with a goal to achieve a urine flow in excess of 200 ml / h, which may require administration of as much as 500 ml / h of fluids intravenously. If the urine pH is < 6, then sodium bicarbonate is administered as well, the serum pH being followed closely and if it exceeds 7.45 the bicarbonate infusion is discontinued or acetazolamide administered. If a successful diuresis is not achieved with vigorous volume administration then central venous pressure monitoring is used to ensure adequate volume ressucitation. If the patient is no longer hypovolemic, mannitol is added at a dose of 25 g every 6h. These measures are continued until myoglobinuria has resolved, unless volume overload limits intravenous fluid or serum osmolality limits mannitol administration. If there is no response in urine output to these measures, then furosemide is administered at a dose of 40 mg intravenously and increased to 200 mg or until a diuresis occurs.
Local therapy is extremely important in rhabdomyolysis of either traumatic or nontraumatic origin. Close attention should be paid to the decline of serum CK levels. If does not fall by 50 % over 48 h, a careful search should be made for evidence of increased tissue pressures in the involved muscle groups. If it is found, close attention should be focused on neurovascular function in affected limbs. If circulatory compromise is evident, fasciotomy should be performed. In the absence of compartment syndrome, debridement of necrotic muscle with intact overlying skin is contraindicated given the risk of infection in the open wound. This contrasts with situations where the skin has been broken, such as a compound crush injury where wide debridement of the necrotic muscle is indicated.
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