How is rhabdomyolysis classified by etiology, severity, and presence of complications?

Rhabdomyolysis Classification

Rhabdomyolysis is classified by etiology into four major categories (trauma/direct injury, excessive muscle activity, hereditary enzyme defects, and medical causes), by severity based on creatine kinase levels and complications (mild: CK <15,000 IU/L; moderate: CK 15,000-50,000 IU/L; severe: CK >50,000 IU/L with acute kidney injury), and by the presence of life-threatening complications including acute kidney injury, severe electrolyte abnormalities, metabolic acidosis, compartment syndrome, and disseminated intravascular coagulation. 1, 2, 3

Classification by Etiology

Rhabdomyolysis etiologies are organized into four primary categories that guide diagnostic workup and management 3:

1. Trauma or Direct Injury

• Crush injuries and severe limb trauma represent the classic traumatic causes, with early signs including pain, tension, paresthesia, and paresis indicating potential compartment syndrome 1
• Impact trauma from falls can drastically increase CK levels, though simple contusion may not carry the same acute kidney injury risk as true rhabdomyolysis 1
• Late signs of compartment syndrome (pulselessness and pallor) often indicate irreversible damage 1

2. Excessive Muscle Activity

• Exertional rhabdomyolysis occurs particularly with novel overexertion or unaccustomed exercise volume/intensity 1
• Exercise-induced cases can produce CK levels greater than 3,000 U/L after maximal resistance training 1
• CK levels peak 24-120 hours after the exercise event, not immediately post-exercise 1

3. Hereditary Muscle Enzyme Defects

• Genetic testing should include RYR1 and CACNA1S gene sequencing for malignant hyperthermia susceptibility in patients with exertional rhabdomyolysis or heat illness 1, 2
• Metabolic myopathy testing includes CPT2, PYGM, ACADM, AMPD1, and VLCAD genes for recurrent rhabdomyolysis 1
• Patients with recurrent episodes, exercise intolerance, or family history of neuromuscular disorders require genetic and metabolic workup 1

4. Medical Causes (Subdivided)

Drugs and Toxins

• Statins are the most common drug cause, with an incidence of 1.6 per 100,000 patient-years 1
• Risk factors include SLCO1B1 gene mutations, age, diabetes, renal impairment, cardiovascular disease, and drug interactions 1
• Gemfibrozil with any statin carries a 10-fold higher rhabdomyolysis risk compared to fenofibrate 1
• Dietary supplements to discontinue include red yeast rice containing lovastatin, creatine monohydrate, wormwood oil, licorice, and Hydroxycut 1
• Recreational drugs including cocaine, methamphetamine, ecstasy (MDMA), ketamine, and heroin are important triggers 1

Muscle Hypoxia

• Prolonged immobilization and sepsis are frequent causes 4

Metabolic and Endocrine Disorders

• Hypothyroidism predisposes patients to statin-induced rhabdomyolysis and muscle toxicity 1
• Electrolyte abnormalities and endocrine disorders contribute to muscle breakdown 3, 5

Infections

• Viral myositis should be considered with appropriate viral studies if clinically indicated 6, 2

Temperature Alterations

• Heat illness and temperature extremes are recognized triggers 5

Autoimmune Causes

• Autoimmune myositis requires testing for ANA, ASMA, ANCA, anti-CCP, rheumatoid factor, and myositis-specific antibodies 6, 2

Classification by Severity

The severity stratification is based on CK levels, renal function, and complications 1, 2:

Mild Rhabdomyolysis

• CK elevation <15,000 IU/L 1, 2
• Normal renal function 2
• No significant electrolyte abnormalities 2
• Generally managed with standard fluid resuscitation 1

Moderate Rhabdomyolysis

• CK 15,000-50,000 IU/L 1, 2
• Mild renal dysfunction 2
• Requires 3-6L fluid resuscitation per day 1, 2

Severe Rhabdomyolysis

• CK >50,000 IU/L 1, 2
• Acute kidney injury present 2
• Requires >6L fluid resuscitation per day 1, 2
• High risk for life-threatening complications 2
• CK levels above 75,000 IU/L are associated with >80% risk of acute kidney injury in crush syndrome patients 6

Classification by Complications

Rhabdomyolysis complications determine prognosis and guide intensive management 3, 5:

Life-Threatening Complications

Acute Kidney Injury

• Myoglobin-induced renal tubular obstruction and toxicity represents the most serious systemic complication and can lead to dialysis-requiring acute kidney injury 1
• Myoglobinuria is indicated by brown or dark urine that is positive for blood without red blood cells present 2
• Early fluid resuscitation is critical, as delayed treatment is associated with higher acute kidney injury risk 1

Severe Electrolyte Abnormalities

• Hyperkalemia can precipitate life-threatening cardiac arrhythmias and cardiac arrest 1, 2
• Hypocalcemia and hyperphosphatemia are common complications requiring close monitoring 2
• Electrolytes, particularly potassium, should be checked every 6-12 hours in severe cases 2

Metabolic Acidosis

• Commonly occurs in severe rhabdomyolysis and requires arterial blood gas assessment 6, 2

Compartment Syndrome

• Can both cause and complicate rhabdomyolysis 1
• Early fasciotomy is indicated when compartment pressure exceeds 30 mmHg or when differential pressure (diastolic blood pressure minus compartment pressure) is <30 mmHg 1

Disseminated Intravascular Coagulation

• Coagulation studies should be evaluated to assess for this complication 6, 5

Cardiac Complications

• ECG and cardiac troponin should be performed in severe cases to rule out cardiac involvement 6, 2
• Cardiac arrhythmias are particularly concerning in the setting of electrolyte abnormalities 6

Diagnostic Criteria

The diagnosis relies on three key elements 3, 4:

1. Clinical symptoms: Muscle pain, weakness, or soreness 1
2. Myoglobinuria: Red-to-brown urine (history or presence) 3
3. CK elevation: CK ≥5-10 times the upper limit of normal is diagnostic 2

CK levels peak 24-120 hours after the inciting event, so initial levels may not represent the peak 1. Serial CK measurements are important to monitor the course of rhabdomyolysis 6.

Common Pitfalls

• Do not use the 1.5 mg/dL creatinine threshold as a trigger for intervention in rhabdomyolysis, as this threshold is specific to cirrhotic patients with acute kidney injury and not applicable to trauma-related rhabdomyolysis 1
• Impact trauma can elevate CK without true rhabdomyolysis, but given a doubling trend, assume true muscle breakdown until proven otherwise 1
• At 9 hours post-exercise, CK levels are typically still rising and have not reached their maximum, so repeat measurement at 24 hours is essential if clinical suspicion remains high 1
• Avoid succinylcholine in patients at risk for rhabdomyolysis, as it can exacerbate the condition 1