What is the approach to assessing rhabdomyolysis, including definition, classification, differential diagnosis, history, physical examination, investigations, empiric treatment, and indications for referral?

Approach to Assessment of Rhabdomyolysis

Definition

Rhabdomyolysis is skeletal muscle injury with release of intracellular contents (myoglobin, CK, electrolytes) into circulation, defined by CK elevation ≥10 times the upper limit of normal with rapid subsequent decrease. 1

• Severity ranges from asymptomatic enzyme elevation to life-threatening acute kidney injury and electrolyte abnormalities 2, 3
• The pathophysiological hallmark is increased intracellular free ionized calcium causing proteolytic activation, mitochondrial dysfunction, and muscle cell death 4

Classification by Severity

Severe rhabdomyolysis: CK >15,000 IU/L (requires >6L fluid resuscitation) 5

Moderate rhabdomyolysis: CK 5,000-15,000 IU/L (requires 3-6L fluid daily) 5

Mild rhabdomyolysis: CK <5,000 IU/L 6

• CK >75,000 IU/L carries >80% risk of acute kidney injury 6
• CK >16,000 IU/L significantly increases acute renal failure risk 1

Differential Diagnosis by Etiology Category

Trauma/Direct Injury

• Crush injuries and severe limb trauma 5
• Compartment syndrome (both cause and complication) 5
• Impact trauma from falls (may elevate CK without true rhabdomyolysis) 5

Excessive Muscle Activity

• Novel overexertion or unaccustomed exercise volume/intensity 5
• Exertional rhabdomyolysis in poorly calibrated training 5
• Seizures 1

Drugs and Toxins

• Statins (incidence 1.6 per 100,000 patient-years) 5
• Red yeast rice containing lovastatin 5
• Creatine monohydrate, wormwood oil, licorice, Hydroxycut 5
• Antipsychotics with CYP3A4-metabolized statins 5
• Succinylcholine (avoid in susceptible patients) 5

Metabolic/Hereditary Disorders

• RYR1 and CACNA1S mutations (malignant hyperthermia susceptibility) 5
• CPT2, PYGM, ACADM, AMPD1, VLCAD defects (metabolic myopathies) 5
• SLCO1B1 gene mutations (statin-induced) 5

Infections

• Viral myositis 6

Temperature Alterations

• Heat illness 5

Autoimmune

• Autoimmune myositis 6

History

Character of Symptoms

The classic triad of myalgia, weakness, and pigmenturia occurs in <10% of patients. 1

• Severe muscle pain and stiffness 5
• Muscle cramping 5
• Severe fatigue 5
• Red-to-brown urine (myoglobinuria) 2
• Weakness 2, 1

Red Flags

• Pain, tension, paresthesia, paresis (early compartment syndrome signs) 5
• Pulselessness and pallor (late compartment syndrome—indicates irreversible damage) 5
• Mental confusion 5
• Oliguria or anuria 2

Risk Factors to Elicit

• Recent trauma or crush injury 5
• Novel or unaccustomed exercise 5
• Current medications: statins, antipsychotics, supplements 5
• Age, diabetes, renal impairment, cardiovascular disease 5
• Family history of neuromuscular disorders 5
• History of exercise intolerance 5
• Recurrent episodes of rhabdomyolysis 5
• Recent viral illness 6
• Heat exposure 5
• Perioperative status 5

Physical Examination (Focused)

Musculoskeletal

• Muscle tenderness, swelling, firmness 5
• Muscle weakness on strength testing 1
• Compartment assessment: pain with passive stretch, tense compartments 5, 6

Cardiovascular

• Cardiac monitoring for arrhythmias (hyperkalemia risk) 5
• Pulse assessment in affected limbs 5

Skin

• Pallor of affected limbs 5
• Rash (consider immune checkpoint inhibitor myositis) 6

Neurological

• Paresthesia in affected areas 5
• Mental status changes 5

Investigations and Expected Findings

Core Laboratory Tests (Initial)

CK elevation ≥10 times upper limit of normal is diagnostic. 1

• Serum CK: Markedly elevated (may reach 100,000 IU/L); monitor serially 5, 1
• Serum myoglobin: Elevated earlier than CK but shorter half-life 6
• Urinalysis: Brown/cloudy, positive for blood without RBCs (myoglobinuria) 5, 2
• Complete electrolyte panel: Hyperkalemia, hypocalcemia, hyperphosphatemia 5, 6
• Renal function: BUN and creatinine (assess for acute kidney injury) 6
• Complete blood count with differential: Evaluate for infection 5

Additional Tests

• Liver function tests: AST, ALT elevated (transaminitis from muscle enzyme release) 5, 6
• Arterial blood gas: Metabolic acidosis 5, 6
• Coagulation studies: Assess for disseminated intravascular coagulation 5, 6
• ECG and cardiac troponin: Rule out cardiac involvement 5, 6
• Plasma potassium: Critical for cardiac arrhythmia risk 5

Etiology-Specific Testing

• Viral studies: If viral myositis suspected 5, 6
• Autoimmune markers: ANA, ASMA, ANCA if autoimmune myositis suspected 5, 6
• Medication review: Identify causative agents 5
• Genetic testing: RYR1, CACNA1S (malignant hyperthermia); CPT2, PYGM, ACADM, AMPD1, VLCAD (metabolic myopathies); SLCO1B1 (statin sensitivity) 5
• Metabolic workup: Calcium, phosphorus, alkaline phosphatase, PTH, 25-OH vitamin D if hereditary disorder suspected 5
• Compartment pressure measurement: If >30 mmHg or differential pressure <30 mmHg 5

Monitoring Frequency

For severe rhabdomyolysis (CK >5,000 IU/L), monitor CK, electrolytes, and renal function every 6-12 hours initially. 6

• Reduce to daily monitoring once CK begins decreasing 6
• Repeat CK at 24 hours post-trauma if initial normal but clinical suspicion high (CK peaks 24-120 hours post-injury) 5

Empiric Treatment

Immediate Management

Early initiation of aggressive fluid resuscitation is critical—delayed treatment increases acute kidney injury risk. 5

• Severe rhabdomyolysis (CK >15,000 IU/L): >6L fluid resuscitation 5
• Moderate rhabdomyolysis: 3-6L per day 5
• Maintain adequate hydration throughout treatment 5

Discontinue Causative Agents

Immediately discontinue the offending agent if drug-induced rhabdomyolysis suspected. 5

• Stop statins, red yeast rice, creatine monohydrate, wormwood oil, licorice, Hydroxycut 5
• Avoid succinylcholine in susceptible patients 5
• Discontinue dietary supplements before elective surgery 5

Electrolyte Management

Monitor and correct significant electrolyte abnormalities, particularly life-threatening hyperkalemia. 5

• Repeated potassium measurements essential 5
• Correct hypocalcemia, hyperphosphatemia 6

Pain Management

Acetaminophen 500-1000 mg is the preferred initial analgesic (onset 15-30 minutes, max 4-6g/day) to avoid nephrotoxic NSAIDs. 5

• Avoid all NSAIDs (ibuprofen, ketoprofen, diclofenac, naproxen, mefenamic acid) due to renal toxicity 5
• For severe pain unresponsive to acetaminophen: Oral morphine 20-40 mg for opioid-naive patients 5
• If eGFR <30 ml/min: Use fentanyl or buprenorphine 5
• Provide round-the-clock dosing with rescue doses (10-15% of total daily dose) for breakthrough pain 5

Surgical Intervention

Early fasciotomy is indicated for established compartment syndrome. 5

• Consider when compartment pressure >30 mmHg 5
• Consider when differential pressure (diastolic BP – compartment pressure) <30 mmHg 5

Alternative Lipid Management (Post-Statin Rhabdomyolysis)

• Consider ezetimibe, PCSK9 inhibitors, or bempedoic acid 5
• If statin needed, use hydrophilic statins (fluvastatin, pravastatin) with fewer metabolic interactions 5

Indications to Refer/Hospitalize

Immediate Hospitalization Required

Hospitalize patients with rhabdomyolysis who have immunocompromised state, severe pain requiring management, mental confusion, pulmonary infiltrates, abnormal spinal fluid findings, or organ failure. 5

• CK >5,000 IU/L (requires intensive monitoring) 6
• Acute kidney injury or renal failure 2, 1
• Significant electrolyte abnormalities (especially hyperkalemia) 5
• Compartment syndrome 5, 6
• Cardiac arrhythmias 5
• Metabolic acidosis 5

Specialty Referral Indications

Refer for malignant hyperthermia susceptibility investigation if exertional rhabdomyolysis, recurrent episodes, persistently elevated CK after neurological workup, or family history of neuromuscular disorders. 5, 6

• Recurrent rhabdomyolysis requiring genetic/metabolic testing 5
• History of exercise intolerance 5
• Idiopathic hyperCKemia after full neurological evaluation 5
• Suspected autoimmune myositis 6
• Need for EMG and MRI in inflammatory myositis cases 6

Critical Pitfalls

Diagnostic Pitfalls

• Missing the diagnosis: Classic triad (myalgia, weakness, pigmenturia) present in <10% of cases 1
• Single CK measurement: CK peaks 24-120 hours post-trauma; repeat at 24 hours if initial normal but suspicion high 5
• Confusing contusion with rhabdomyolysis: Impact trauma can elevate CK without true muscle breakdown or acute kidney injury risk 5
• Late recognition of compartment syndrome: Pulselessness and pallor indicate irreversible damage 5

Treatment Pitfalls

• Delayed fluid resuscitation: Associated with higher acute kidney injury risk 5
• Inadequate fluid volume: Severe cases require >6L, not standard maintenance fluids 5
• Using NSAIDs for pain: Nephrotoxic in patients already at high acute kidney injury risk 5
• Continuing causative medications: Failure to immediately discontinue statins or other offending agents 5
• Inadequate electrolyte monitoring: Hyperkalemia can cause fatal cardiac arrhythmias 5

Monitoring Pitfalls

• Insufficient monitoring frequency: Severe cases require electrolytes and renal function every 6-12 hours initially 6
• Missing compartment syndrome: Requires serial clinical assessment for pain, tension, paresthesia, paresis 5, 6
• Ignoring cardiac monitoring: ECG essential to detect arrhythmias from electrolyte abnormalities 6

Etiology Investigation Pitfalls

• Failing to identify genetic causes: Recurrent episodes, exercise intolerance, or family history warrant genetic testing 5
• Missing medication/supplement causes: Thorough review including over-the-counter supplements essential 5
• Overlooking malignant hyperthermia susceptibility: Requires referral for specialized testing in appropriate cases 5, 6