What is the diagnostic workup and differential diagnosis (Ddx) for a patient suspected of having rhabdomyolysis?

Diagnostic Workup and Differential Diagnosis for Rhabdomyolysis

Diagnostic Criteria

Rhabdomyolysis is diagnosed by creatine kinase (CK) elevation of at least 10 times the upper limit of normal (typically >1,000 IU/L, with severe cases >15,000 IU/L), followed by a rapid decrease toward normal values. 1

The classic triad of myalgia, weakness, and pigmenturia (dark/brown urine) occurs in less than 10% of patients, so maintain high clinical suspicion even with non-specific symptoms. 1, 2

Essential Initial Laboratory Tests

Order these tests immediately upon suspicion:

• Creatine kinase (CK) - the primary diagnostic marker; levels >5,000 IU/L indicate moderate risk, >15,000 IU/L indicates high risk requiring aggressive fluid resuscitation (>6L/day). 3, 4

• Serum creatinine and BUN - to assess for acute kidney injury, the most common serious complication occurring particularly when CK >16,000 IU/L. 3, 1

• Complete electrolyte panel including potassium, calcium, phosphorus, and magnesium - hyperkalemia can cause life-threatening cardiac arrhythmias and requires emergent correction. 3, 4

• Urinalysis - look for brown/cloudy urine that is positive for blood without RBCs (myoglobinuria), which is pathognomonic for rhabdomyolysis. 3

• Plasma myoglobin - should be measured serially along with CK and potassium for repeated bioassessment. 3

Additional Laboratory Tests

• Liver function tests (AST, ALT, alkaline phosphatase) - commonly elevated due to muscle enzyme release; AST and ALT are muscle enzymes that help confirm diagnosis. 3

• Additional muscle enzymes (LDH, aldolase) - commonly elevated and support the diagnosis. 3

• Arterial blood gas - essential to assess for metabolic acidosis, which commonly occurs in severe rhabdomyolysis. 3

• Coagulation studies - to evaluate for disseminated intravascular coagulation, a potential complication of severe disease. 3

• Complete blood count with differential - to evaluate for infection or other systemic processes. 3

• ECG and cardiac troponin - to rule out cardiac involvement in severe cases. 3

Etiology-Specific Testing

Perform targeted testing based on clinical context:

• Medication review - document all prescription medications (especially statins), over-the-counter drugs, herbal supplements, and performance-enhancing products. Immediately discontinue causative agents. 3

• Toxicology screen - ask about recreational drug use including cocaine, methamphetamine, ecstasy (MDMA), ketamine, and heroin. 3

• Viral studies - if viral myositis is suspected clinically. 3

• Autoimmune markers (ANA, ASMA, ANCA) - if autoimmune myositis is suspected. 3

• Thyroid function tests - hypothyroidism is a risk factor for statin-induced rhabdomyolysis. 5

Genetic and Metabolic Testing for Recurrent Cases

Consider genetic testing if the patient has:

• Recurrent episodes of rhabdomyolysis
• History of exercise intolerance
• Family history of neuromuscular disorders
• Exertional rhabdomyolysis or heat illness 3, 1

Specific genetic tests to order:

• RYR1 and CACNA1S gene sequencing - for malignant hyperthermia susceptibility, particularly in exertional rhabdomyolysis or heat illness. 3

• CPT2, PYGM, ACADM, AMPD1, and VLCAD gene testing - for metabolic myopathies causing recurrent rhabdomyolysis. 3

• SLCO1B1 gene mutations - increase risk of statin-induced rhabdomyolysis. 3

• Serum calcium, phosphorus, alkaline phosphatase, parathyroid hormone, and 25-hydroxy-vitamin D - if metabolic or hereditary disorder is suspected. 3

Differential Diagnosis by Etiology Category

Trauma and Physical Causes

• Crush injuries and severe limb trauma - assess for compartment syndrome with pain, tension, paresthesia, and paresis as early signs; pulselessness and pallor are late signs indicating irreversible damage. 3

• Exertional causes - novel overexertion or unaccustomed exercise volume/intensity, particularly during transition periods (e.g., returning after injury). 3

• Prolonged immobilization - common in intoxicated or altered mental status patients. 6

Medications and Toxins

• Statins - most common drug cause with incidence of 1.6 per 100,000 patient-years; risk factors include age, diabetes, renal impairment, cardiovascular disease, drug interactions (especially gemfibrozil, which carries 10-fold higher risk than fenofibrate). 5, 3

• Red yeast rice containing lovastatin - a known cause of drug-induced rhabdomyolysis. 3

• Other supplements to discontinue - creatine monohydrate, wormwood oil, licorice, and Hydroxycut. 3

• Alcohol and recreational drugs - cocaine, methamphetamine, ecstasy (MDMA). 3

Metabolic and Endocrine Disorders

• Hypothyroidism - predisposes to muscle toxicity, especially with statins. 5

• Electrolyte abnormalities - hypokalemia, hypophosphatemia, hypocalcemia. 7

• Hereditary muscle enzyme defects - consider in recurrent cases with exercise intolerance. 1, 7

Infections

• Viral myositis - consider viral studies if clinically indicated. 3

• Bacterial infections - particularly those causing sepsis or direct muscle invasion. 7

Temperature Alterations

• Hyperthermia - heat stroke, malignant hyperthermia, neuroleptic malignant syndrome. 7

• Hypothermia - prolonged cold exposure. 7

Muscle Hypoxia

• Ischemia - arterial occlusion, compartment syndrome, prolonged positioning during surgery. 7

Critical Timing Considerations

CK levels peak 24-120 hours after the inciting event, not immediately. 3 If clinical suspicion remains high but initial CK is only mildly elevated, repeat measurement at 24 hours post-event. The lymphatic clearance mechanism explains this delay, as the large CK molecule (82 kDa) cannot directly enter the bloodstream. 3

Common pitfall: Impact trauma from a fall can drastically increase CK levels without reflecting true muscle breakdown. However, if CK is doubling on serial measurements, assume true rhabdomyolysis until proven otherwise. 3

Monitoring During Treatment

Serial monitoring requirements:

• Daily CK, creatinine, and electrolytes - continue until CK is declining and renal function is stable. 3

• Potassium levels - monitor closely for life-threatening hyperkalemia. 3, 4

• Urine output - goal is >300 mL/hour with aggressive IV hydration; adequate output is >0.5 mL/kg/hr. 4, 2

• Compartment pressure measurements - if compartment syndrome is suspected; fasciotomy is indicated when pressure exceeds 30 mmHg or when differential pressure (diastolic BP - compartment pressure) is <30 mmHg. 3