Can you explain rhabdomyolysis, including its causes, clinical presentation, diagnostic findings, and management?

Rhabdomyolysis: Comprehensive Overview

Definition and Pathophysiology

Rhabdomyolysis is a clinical syndrome characterized by skeletal muscle destruction with release of intracellular contents—including creatine kinase (CK), myoglobin, and electrolytes—into the bloodstream, potentially leading to life-threatening complications including acute kidney injury, severe electrolyte abnormalities, and cardiac arrhythmias. 1, 2

The condition results from muscle necrosis, which triggers the release of myoglobin that causes renal tubular obstruction and direct nephrotoxicity, representing the most serious systemic complication. 1 Myocyte death occurs through calcium overload mechanisms, leading to both immediate and delayed complications. 1

Clinical Presentation

Classic Triad (Present in <10% of Cases)

• Muscle pain (myalgia) 1, 3
• Muscle weakness 1, 3
• Dark/brown urine (myoglobinuria) 1, 3

Additional Clinical Features

• Muscle stiffness and cramping 1
• Severe fatigue 1
• Muscle tenderness and swelling 1

Critical point: The classic triad is seen in less than 10% of patients, so absence of these symptoms does not exclude rhabdomyolysis. 4 Many cases are clinically asymptomatic and only detected through routine laboratory testing. 5

Diagnostic Approach

Primary Diagnostic Marker

Creatine kinase (CK) elevation is the diagnostic standard for rhabdomyolysis. 1 A reasonable diagnostic threshold is CK elevation of at least 10 times the upper limit of normal, followed by a rapid decrease toward normal values. 4

Severity Stratification by CK Level

• Moderate rhabdomyolysis: CK 5,000-15,000 IU/L 1
• Severe rhabdomyolysis: CK >15,000 IU/L 1
• Very high risk for acute kidney injury: CK >75,000 IU/L (>80% risk) 6

Important timing consideration: CK levels peak 24-120 hours after the inciting event, not immediately. 1 At 9 hours post-event, CK may still be rising significantly and has not reached maximum levels. 1 Optimal blood sampling for peak CK is 24-120 hours after the event. 1

Essential Laboratory Tests

Initial workup should include: 1, 6

• Total CK (not CK-MB, which lacks sensitivity/specificity for rhabdomyolysis) 1
• Serum myoglobin (detects earlier than CK but shorter half-life) 6
• Complete electrolyte panel: potassium, calcium, phosphorus, magnesium 1, 6
• Renal function tests: BUN, creatinine 6
• Urinalysis: brown/cloudy urine, positive for blood without RBCs indicates myoglobinuria 1
• Complete blood count with differential 1
• Liver function tests: AST, ALT, alkaline phosphatase (commonly elevated due to muscle enzyme release) 1, 6

Additional muscle enzymes to measure: 1

• LDH, aldolase (commonly elevated in rhabdomyolysis)

Assess for complications: 1, 6

• Arterial blood gas (metabolic acidosis is common in severe cases)
• Coagulation studies (evaluate for disseminated intravascular coagulation)
• ECG and cardiac troponin (rule out cardiac involvement, especially in severe cases)

Monitoring Frequency

• Severe rhabdomyolysis (CK >5,000 IU/L): Monitor CK, electrolytes, and renal function every 6-12 hours initially 6
• Once CK begins decreasing: Reduce to daily monitoring 6
• Continue until: CK is declining and renal function is stable 1

Etiology-Specific Testing

If viral myositis suspected: Viral studies 1, 6

If autoimmune myositis suspected: ANA, ASMA, ANCA 1, 6

If metabolic/hereditary disorder suspected: 1

• Serum calcium, phosphorus, alkaline phosphatase, PTH, 25-hydroxy-vitamin D
• Genetic testing for SLCO1B1 gene mutations (statin-induced cases)

For recurrent rhabdomyolysis, exercise intolerance, or family history of neuromuscular disorders: 1, 4

• RYR1 and CACNA1S gene sequencing (malignant hyperthermia susceptibility)
• CPT2, PYGM, ACADM, AMPD1, VLCAD gene testing (metabolic myopathies)
• Consider referral for malignant hyperthermia susceptibility investigation 6

Common Causes and Risk Factors

Traumatic Causes

• Crush injuries and severe limb trauma 1
• Prolonged immobilization 3, 4
• Compartment syndrome (both cause and complication) 1

Important caveat: Impact trauma from falls can drastically increase CK levels without reflecting true muscle breakdown. 1 Simple contusion may not carry the same acute kidney injury risk as true rhabdomyolysis. 1 However, if CK is trending upward, assume true muscle breakdown until proven otherwise. 1

Non-Traumatic Causes

Medications (most common drug cause): 1

• Statins (incidence 1.6 per 100,000 patient-years) 1
  • Higher risk with simvastatin 80 mg 1
  • SLCO1B1 gene mutations increase risk 1
  • Risk factors: age, diabetes, renal impairment, cardiovascular disease, hypothyroidism 1
  • Gemfibrozil + statin carries 10-fold higher risk than fenofibrate + statin 1

Dietary supplements to discontinue: 1

• Red yeast rice (contains lovastatin)
• Creatine monohydrate
• Wormwood oil
• Licorice
• Hydroxycut

Recreational drugs: 1

• Cocaine, methamphetamine, ecstasy (MDMA), ketamine, heroin

Other causes: 3, 4

• Sepsis
• Alcohol abuse
• Epileptic seizures
• Exertional (novel overexertion or unaccustomed exercise volume/intensity) 1

Patient-Specific Risk Factors for Drug-Induced Rhabdomyolysis

• Hypothyroidism (predisposes to muscle toxicity, especially with statins) 1
• Advanced age 1
• Diabetes 1
• Renal impairment 1
• Cardiovascular disease 1

Life-Threatening Complications

Severe rhabdomyolysis progresses to: 1

• Acute kidney injury (most serious complication; occurs in ~10% of all acute renal failure cases) 1, 5
  • Particularly likely if CK >16,000 IU/L (may reach 100,000 IU/L) 4
  • Caused by myoglobin-induced renal tubular obstruction and direct toxicity 1
• Hyperkalemia (can precipitate life-threatening cardiac arrhythmias) 1, 6
• Hypocalcemia 6, 5
• Hyperphosphatemia 6
• Metabolic acidosis 1, 6
• Compartment syndrome 1, 6
• Disseminated intravascular coagulation 1, 6

Mortality rate is approximately 10%, significantly higher in patients with acute renal failure. 4

Management Strategy

Immediate Actions

1. Discontinue all causative agents immediately: 1

• Stop statins (especially if drug-induced) 1
• Discontinue all dietary supplements associated with rhabdomyolysis risk 1
• Stop any other potentially offending medications 1

2. Initiate aggressive fluid resuscitation early: 1

• Early initiation is critical—delayed treatment increases acute kidney injury risk 1
• Use isotonic saline (0.9% NaCl) as initial fluid of choice 1
• Avoid hypotonic solutions like Ringer's lactate if head trauma concern 1

Fluid volume requirements: 1

• Severe rhabdomyolysis (CK >15,000 IU/L): May require >6L per day
• Moderate rhabdomyolysis: 3-6L per day typically sufficient

Goal: Maintain adequate urine output and prevent myoglobin precipitation in renal tubules. 5 Forced diuresis with sodium bicarbonate may protect kidney function from acidosis and myoglobin precipitation. 5

Electrolyte Management

Monitor and correct emergently: 1, 6

• Hyperkalemia (highest priority—can cause fatal arrhythmias) 1
• Hypocalcemia 6
• Hyperphosphatemia 6
• Metabolic acidosis 1, 6

Trend CK, creatinine, and electrolytes daily until CK is declining and renal function is stable. 1

Compartment Syndrome Assessment and Management

Early signs (reversible): 1

• Pain
• Tension
• Paresthesia
• Paresis

Late signs (often irreversible damage): 1

• Pulselessness
• Pallor

Surgical intervention: 1

• Early fasciotomy indicated for established compartment syndrome
• Consider fasciotomy when:
  • Compartment pressure >30 mmHg, OR
  • Differential pressure (diastolic BP – compartment pressure) <30 mmHg

Pain Management

First-line: 1

• Acetaminophen 500-1000 mg (onset 15-30 minutes)
• Maximum daily dose: 4-6 grams
• Preferred because it avoids nephrotoxic effects

Agents to avoid: 1

• All NSAIDs (ibuprofen, ketoprofen, diclofenac, naproxen, mefenamic acid) due to gastrointestinal and renal toxicity

For severe pain unresponsive to acetaminophen: 1

• Oral morphine 20-40 mg for opioid-naive patients (first choice for moderate-severe pain)
• Oral to parenteral morphine ratio: 1:2 to 1:3
• If acute kidney injury with eGFR <30 ml/min: Use fentanyl or buprenorphine (safest choices)
• Provide round-the-clock dosing with rescue doses (10-15% of total daily dose) for breakthrough pain 1

Renal Replacement Therapy

Hemodialysis is necessary in patients with acute renal failure. 5 Plasmapheresis may enhance elimination of myoglobin from plasma. 5

Special Medication Considerations

For patients requiring lipid management after statin-induced rhabdomyolysis: 1

• Consider non-statin alternatives: ezetimibe, PCSK9 inhibitors, bempedoic acid
• If statin needed: Use hydrophilic statins (pravastatin, fluvastatin) with minimal CYP450 metabolism and lower drug interaction potential 1
• Never combine gemfibrozil with any statin (10-fold higher rhabdomyolysis risk vs. fenofibrate) 1

Medications to avoid in at-risk patients: 1

• Succinylcholine (especially in susceptible individuals)
• Statins metabolized by CYP3A4 when combined with interacting drugs

Altered Mental Status Evaluation

When patient presents with altered mental status and elevated CK, determine if AMS is: 1

• A precipitating cause (seizures, prolonged immobilization, drug intoxication)
• A consequence (electrolyte disturbances, uremia from acute kidney injury)
• An unrelated complicating condition (neuroleptic malignant syndrome, serotonin syndrome)

Admission Criteria

Hospitalize patients with rhabdomyolysis who have: 1

• Immunocompromised state
• Pain management needs
• Mental confusion
• Pulmonary infiltrates
• Abnormal spinal fluid findings
• Specific organ failure

Prognosis

The repair mechanisms of striated musculature function extremely well. 5 The prognosis for muscular recovery after the acute stage is excellent, as is the prognosis for acute renal failure recovery. 5 However, survival and extent of complications strongly depend on early diagnosis and adequate therapy initiation. 5

Most patients experience only one episode of rhabdomyolysis. 4 In cases of recurrent rhabdomyolysis, exercise intolerance history, or positive family history for neuromuscular disorders, further investigations are needed to identify underlying genetic disorders. 4

Prevention Strategies

For exertional rhabdomyolysis prevention: 1

• Properly calibrate training and conditioning sessions
• Avoid novel overexertion or unaccustomed exercise volume/intensity
• Pay special attention during transition periods (e.g., returning after injury)
• Maintain adequate hydration throughout perioperative period 1

For medication-related prevention: 1

• Document all over-the-counter medications, herbal supplements, and performance-enhancing products
• Screen for hypothyroidism before initiating statins in at-risk patients 1
• Monitor CK if myalgia develops during statin treatment 1