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Common causes and pathophysiology

There are 2 general causes of rhabdomyolysis: 1) direct trauma to myocytes, and 2) metabolic insults, including toxin-mediated injuries (Box 1). The most easily recognized cause of rhabdomyolysis is muscle trauma secondary to crush injury. This direct injury to the plasma membrane of myocytes causes intracellular constituents to be expelled into circulation. This triggers postischemic reperfusion and inflammation of the involved muscles.¹ Severe physical exertion can also result in rhabdomyolysis, likely through a combination of tissue injury and adenosine triphosphate (ATP) depletion.² This has been seen most recently as a result of some popular muscle enhancement programs. Physiologic causes include anaphylaxis, hyperthermia, and electrocution.

Complications

Myoglobin, a dark-red, heme-containing protein released by damaged myocytes, is normally freely filtered by the glomerulus, endocytosed into tubule epithelial cells, and metabolized.¹ In rhabdomyolysis, serum concentrations of myoglobin rise considerably and can lead to life-threatening complications, such as ARF.^1–4,6 Although the exact mechanism of rhabdomyolysis-induced renal dysfunction is unclear, it appears that intrarenal vasoconstriction, direct and ischemic tubule injury, and obstruction in the distal tubules from concentrated myoglobin are all important contributing factors. Renal constriction occurs owing to intravascular volume depletion (hypovolemia) secondary to fluid retention in the damaged muscles, inducing activation of the renin-angiotensin system, vasopressin, and the sympathetic nervous system. Cytotoxicity might be due to uncontrolled leakage of reactive oxygen species after cellular release of myoglobin and free radicals that cause tissue injury.¹ In acidic environments, myoglobin can precipitate in the glomerular filtrate and occlude the distal tubules, causing further kidney injury. Myoglobin casts in the urine result from the interaction between myoglobin and Tamm-Horsfall protein in low-pH urine and are indicative of rhabdomyolysis-associated ARF.^1–3

Other complications of rhabdomyolysis include electrolyte abnormalities resulting from release of cellular components into circulation. Hyperkalemia is an early and fast-rising manifestation of rhabdomyolysis, regardless of the underlying cause.¹ Hyperphosphatemia, hyperuricemia, high anion gap metabolic acidosis, and hypermagnesemia (with ARF) might also occur.^1–4,6,8 Hyperuricemia is a risk factor for kidney injury, as uric acid is insoluble and can contribute to renal tubule obstruction.¹ Hypocalcemia is another early common complication of rhabdomyolysis, resulting from sequestration of calcium within the damaged muscles and calcification of necrotic muscle tissue.¹ Consequently, serial extended monitoring of electrolyte levels and renal function should begin when rhabdomyolysis is diagnosed.³

Assessment and diagnosis

Patients with acute rhabdomyolysis classically present with the triad of muscle weakness, muscle pain, and dark urine. However, more than 50% of patients report neither muscle pain nor weakness.³ Patients might also have fluid retention, malaise, fever, tachycardia, nausea, or vomiting.^1,2 The clinical picture, history, and physical examination might suggest rhabdomyolysis, but definitive diagnosis can only be confirmed through laboratory investigations.^1–4 Myoglobin is not measured directly in urine or plasma. Measurement of serum myoglobin actually has a low sensitivity for the diagnosis of rhabdomyolysis because serum myoglobin levels peak earlier than serum CK levels, and it has a short half-life and unpredictable metabolism.^1,2

Diagnosis focuses instead on CK levels and the presence of myoglobinuria. Normal CK levels are between 45 and 260 U/L.² Creatine kinase levels initially rise within the first 12 hours of muscle destruction, peak after 1 to 3 days, and decline 3 to 5 days after muscle injury ends.^2,3 In the absence of cerebral or myocardial infarction, it is generally agreed that CK levels 5 times the normal concentration (approximately 1000 U/L) are highly suggestive of rhabdomyolysis.³ Levels above 5000 U/L indicate substantial muscle injury and are closely related to the likelihood of renal involvement.¹ Myoglobinuria should be suspected when a urine dipstick test is positive for blood in the absence of red blood cells. Early in rhabdomyolysis, myoglobinuria—with its classic red-brown urine colour—might be transient or absent, making it diagnostically unreliable. It is important to note that patients with myoglobinuria might have positive test results for blood on urinary dipsticks, but no red blood cells in the urine sediment. The false-positive results occur because dipsticks cannot distinguish myoglobin from hemoglobin. This test has a sensitivity between 50% and 80% for detecting rhabdomyolysis.¹

Aspartate aminotransferase levels might also be elevated; however, in the context of rhabdomyolysis, we are unaware of any relationship between the degree of aspartate aminotransferase level elevation and that of CK level elevation.

The cause of the rhabdomyolysis must also be identified and managed (Figure 1).⁸ Although some causes of rhabdomyolysis, such as crush injuries or immobilization, might be evident from the patient history or physical examination, causes such as inherited metabolic myopathies, endocrinopathies, toxin ingestion, or infections might be less obvious and should be investigated further to avoid possible recurrence.^4,8 If no trigger can be identified, a muscle biopsy after resolution of the acute symptoms can yield structural information that might help identify a cause.⁴

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Figure 1.

Differential diagnosis for rhabdomyolysis

Management

After stabilization and resuscitation, the most important step in managing patients with rhabdomyolysis is early and aggressive repletion of fluids to maintain or improve kidney function.^1–4,7–9 Volume repletion with normal saline should be initiated promptly at a rate of 200 to 1000 mL/h, depending on the setting and severity of the condition. Urine output should be monitored, with a target of 300 mL/h.^1,3,6

If myoglobinuria is present, alkalinization of urine through intravenous sodium bicarbonate solution should be initiated, with the objective of reaching a urine pH greater than 6.50 and a serum pH between 7.40 and 7.45.^3,6 Some reports also suggest the use of osmotic diuretics, such as mannitol, to remove fluid from the damaged muscle interstitium.⁹ Diuretics might only be beneficial when there is a strong suspicion of compartment syndrome and should only be used after the patient’s hypovolemia has been corrected.⁶ Although both alkalinization and osmotic diuresis are common practices in the treatment of rhabdomyolysis, there is no strong evidence of clear benefit.^1,2,6

Evidence demonstrates benefit for patients who receive early and aggressive rehydration, with a reduction in their risk of developing ARF. For those who present with rhabdomyolysis complicated by acute renal injury and receive supportive rehydration, long-term survival is almost 80%, and most patients recover renal function.¹ Electrolyte disturbances need to be corrected quickly, with special attention to the hyperkalemia that often occurs early in the course of rhabdomyolysis.^1–4,6 Hypocalcemia will often self-correct with supportive management.⁶ If ARF occurs, along with severe hyperkalemia and acidosis, patients require close monitoring of metabolic parameters and consideration of hemodialysis.²

There are 2 reasons for us to suspect rhabdomyolysis in Earl’s case—previous chest pain and cocaine use. His workup should include toxicology screening for acetylsalicylic acid and acetaminophen; measurement of electrolyte, serum glucose, CK, and serum alcohol levels and renal function; and complete blood count. An electrocardiogram should also be part of Earl’s initial workup even in the absence of chest pain. Prompt diagnosis will permit early, rapid rehydration, the key to preventing many complications of this condition. The most important and often missed step in caring for patients like Earl is including rhabdomyolysis in your differential diagnosis.