What are the causes, diagnosis, and management of rhabdomyolysis?

Rhabdomyolysis: Causes, Diagnosis, and Management

Causes of Rhabdomyolysis

Rhabdomyolysis results from skeletal muscle injury with release of intracellular contents into the circulation, most commonly caused by exogenous toxins (particularly illicit drugs, alcohol, and prescribed medications accounting for 46% of cases), trauma, and excessive muscle activity. 1

Major Etiologic Categories

Drugs and Toxins:

• Statins are among the most common prescribed medications causing rhabdomyolysis, with an incidence of 1.6 per 100,000 patient-years 2
• Other high-risk medications include antipsychotics, zidovudine, colchicine, selective serotonin reuptake inhibitors, and lithium 1
• Red yeast rice containing lovastatin is a known cause of drug-induced rhabdomyolysis 3
• Dietary supplements including creatine monohydrate, wormwood oil, licorice, and Hydroxycut should be discontinued due to rhabdomyolysis risk 2
• Genetic factors such as SLCO1B1 gene mutations increase the risk of statin-induced rhabdomyolysis 2

Trauma and Physical Causes:

• Crush injuries and severe limb trauma are significant risk factors 2
• Exertional causes, particularly novel overexertion or unaccustomed exercise volume/intensity 2
• Prolonged immobilization and muscle compression 4
• Compartment syndrome can both cause and complicate rhabdomyolysis 2

Other Medical Causes:

• Muscle hypoxia and ischemia 5
• Infections (including viral myositis) 5, 6
• Temperature extremes (hyperthermia and hypothermia) 6
• Metabolic and endocrine disorders 5
• Hereditary muscle enzyme defects (responsible for 10% of cases) 1
• Seizures and severe infections 4

Important Clinical Context:

• In 60% of cases, multiple etiologic factors are present simultaneously 1
• In 11% of cases, rhabdomyolysis is recurrent 1
• Patient-specific risk factors include advanced age, diabetes, renal impairment, and cardiovascular disease 2

Diagnosis of Rhabdomyolysis

The diagnosis is established by creatine kinase (CK) elevation greater than 5 times the upper limit of normal (>975 IU/L), combined with clinical symptoms and detection of myoglobinuria. 7, 1

Clinical Presentation

Classic Triad (often incomplete):

• Muscle pain (myalgias) and tenderness 7
• Muscle weakness 7
• Dark-colored (red-to-brown) urine indicating myoglobinuria 5

Additional Symptoms:

• Muscle stiffness and cramping 2
• Severe fatigue 2
• Non-specific symptoms are common, requiring high index of suspicion 6

Early Signs of Compartment Syndrome:

• Pain, tension, paresthesia, and paresis 2
• Late signs include pulselessness and pallor, indicating irreversible damage 2

Laboratory Workup

Essential Initial Tests:

• Creatine kinase (CK): Diagnostic threshold >5 times upper limit of normal; repeated measurements needed 2, 7
• Serum myoglobin: Part of repeated bioassessment 2
• Complete electrolyte panel: Including potassium (critical for cardiac arrhythmia risk), calcium, phosphorus, and magnesium 2
• Serum creatinine: To assess for acute kidney injury 2
• Urinalysis: Brown color, cloudiness, positive for blood without RBCs indicates myoglobinuria 2

Important Diagnostic Caveat:

• Urine myoglobin detected by dipstick/ultrafiltration is positive in only 19% of cases, so absence does not exclude rhabdomyolysis 1

Additional Tests Based on Clinical Context:

• Liver function tests to assess hepatic involvement 2
• Coagulation studies to evaluate for disseminated intravascular coagulation 2
• Arterial blood gas for metabolic acidosis assessment 2
• ECG and cardiac troponin in severe cases to rule out cardiac involvement 2

Etiology-Specific Testing:

• Viral studies if viral myositis suspected 2
• Autoimmune markers (ANA, ASMA, ANCA) if autoimmune myositis suspected 2
• Comprehensive medication review to identify causative agents 2

Monitoring Parameters:

• Repeated electrolyte measurements, particularly potassium, to monitor for life-threatening hyperkalemia 2
• Compartment pressure measurement when indicated (>30 mmHg or differential pressure <30 mmHg suggests need for fasciotomy) 2

Management of Rhabdomyolysis

Aggressive intravenous fluid resuscitation is the cornerstone of treatment, with a goal urine output of 300 mL/hour, while immediately discontinuing any offending agents. 7, 2

Immediate Management

Fluid Resuscitation:

• For severe rhabdomyolysis (CK >15,000 IU/L): Volumes greater than 6L may be required 2
• For moderate cases: 3-6L per day is typically sufficient 2
• Early initiation is critical, as delayed treatment increases risk of acute kidney injury 2
• Maintain adequate hydration throughout treatment 2

Discontinue Offending Agents:

• Immediately stop statins or other suspected causative medications 2
• Discontinue dietary supplements associated with myositis risk (red yeast rice, creatine monohydrate, wormwood oil, licorice, Hydroxycut) 2
• Avoid medications that can exacerbate rhabdomyolysis, particularly succinylcholine 2

Electrolyte Management

Hyperkalemia Management:

• Monitor potassium closely, as hyperkalemia can lead to cardiac arrhythmias, ventricular tachycardia, fibrillation, or cardiac arrest 2, 8
• Approximately 98% of body potassium is intracellular; muscle breakdown releases large amounts into circulation 8
• Risk is further increased when rhabdomyolysis leads to acute kidney injury, impairing potassium excretion 8
• Correct significant electrolyte abnormalities promptly 2

Urinary Alkalinization:

• Maintain urine pH at 6.5 to help prevent complications 8
• Bicarbonate administration to induce urinary alkalosis can be considered, though not definitively proven effective 4

Surgical Intervention

Fasciotomy Indications:

• Early fasciotomy for established compartment syndrome 2
• Consider when compartment pressure exceeds 30 mmHg 2
• Consider when differential pressure (diastolic blood pressure minus compartment pressure) is <30 mmHg 2

Renal Replacement Therapy

• Determine need on a case-by-case basis 7
• Some evidence suggests early initiation can improve outcomes 4
• Acute renal failure occurs in 46% of hospitalized rhabdomyolysis patients 1

Therapies Without Strong Evidence

Limited or No Proven Benefit:

• Mannitol does not possess strong evidence for improved outcomes 7
• Loop diuretics do not possess strong evidence for improved outcomes (though may be considered once euvolemia/hypervolemia achieved) 7, 4

Disposition and Follow-up

Admission Criteria:

• Most patients require hospitalization 7
• Clinical indications include immunocompromised state, pain management needs, mental confusion, pulmonary infiltrates, abnormal spinal fluid findings, or specific organ failure 3

Post-Treatment Considerations:

• For patients requiring continued lipid management after statin discontinuation, consider nonstatin therapies such as ezetimibe, PCSK9 inhibitors, or bempedoic acid 2
• Patients with underlying myopathy or muscle metabolic defects have high recurrence rates but lower incidence of acute renal failure 1

Prognosis

• With appropriate care, death is rare (3.4% mortality in large case series) 1
• Prognosis depends on underlying etiologies and complications 6
• Linear correlation exists between CK levels and creatinine, and between multiple etiologic factors and acute renal failure 1