Explain rhabdomyolysis.

Rhabdomyolysis: Clinical Overview

Definition and Pathophysiology

Rhabdomyolysis is the rapid breakdown of skeletal muscle with release of intracellular contents—including myoglobin, creatine kinase (CK), and electrolytes—into the bloodstream, potentially causing life-threatening complications including acute kidney injury, severe electrolyte disturbances, and cardiac arrhythmias. 1, 2

The pathophysiological hallmark involves increased intracellular free ionized calcium due to cellular energy depletion or direct plasma membrane rupture, which activates proteases, intensifies muscle contractility, induces mitochondrial dysfunction, and increases reactive oxygen species production, ultimately resulting in skeletal muscle cell death. 3

Clinical Presentation

The classic triad consists of:

• Muscle pain and tenderness 1, 2
• Muscle weakness 1, 4
• Dark (tea-colored or brown) urine from myoglobinuria 2, 4

However, this complete triad is present in less than 10% of cases. 2 Additional symptoms may include muscle stiffness, cramping, and severe fatigue. 1

Early signs of compartment syndrome (which can both cause and complicate rhabdomyolysis) include pain, tension, paresthesia, and paresis, while late signs like pulselessness and pallor indicate irreversible damage. 1

Diagnostic Approach

Laboratory Diagnosis

Total creatine kinase (CK) is the biochemical gold standard for diagnosis, with levels ≥10 times the upper limit of normal (typically >1,000 U/L) considered diagnostic. 1, 5 CK levels peak 24-120 hours after the inciting event, not immediately. 1

Do not use CK-MB for rhabdomyolysis diagnosis—it lacks sensitivity and specificity; always order total CK instead. 1

Myoglobin is the gold standard for prognostication, particularly in non-traumatic cases. 2 Urinalysis showing brown color, cloudiness, and positive for blood without RBCs indicates myoglobinuria. 1

Essential Initial Laboratory Panel

• Complete metabolic panel with particular attention to potassium (hyperkalemia can cause fatal arrhythmias), calcium, phosphorus, and creatinine 1, 5
• Total CK (not CK-MB) 1
• Urinalysis for myoglobinuria 1
• Complete blood count 1
• Liver function tests (AST, ALT)—commonly elevated due to muscle enzyme release 1
• Arterial blood gas if severe (to assess metabolic acidosis) 1
• ECG to evaluate for hyperkalemia-induced cardiac changes 1
• Coagulation studies if severe (to evaluate for disseminated intravascular coagulation) 1

Repeated Monitoring

Serial measurements of CK, creatinine, and electrolytes (particularly potassium) should be performed daily until CK is declining and renal function is stable. 1

Common Etiologies

Traumatic Causes

• Crush injuries and severe limb trauma 1
• Prolonged immobilization 6
• Compartment syndrome 1

Important caveat: Impact trauma from a fall can drastically increase CK levels without reflecting true muscle breakdown, and CK elevation from simple contusion may not carry the same risk of acute kidney injury as true rhabdomyolysis. 1 However, if CK is rising on serial measurements, assume true muscle breakdown until proven otherwise. 1

Exertional Causes

• Novel overexertion or unaccustomed exercise volume/intensity 1
• Exercise-induced rhabdomyolysis can produce CK levels >3,000 U/L, with levels peaking 24-120 hours post-exercise 1

Medication and Drug-Induced

• Statins (most common drug cause, incidence 1.6 per 100,000 patient-years) 7, 1
• Fibrates, particularly gemfibrozil (10-fold higher risk than fenofibrate when combined with statins) 7, 1
• Drug interactions via CYP450 3A4 system (cyclosporine, macrolide antibiotics, certain antifungals, niacin) 7
• Recreational drugs: cocaine, methamphetamine, ecstasy (MDMA), ketamine, heroin 1
• Dietary supplements: red yeast rice containing lovastatin, creatine monohydrate, wormwood oil, licorice, Hydroxycut 1

Metabolic and Endocrine

• Hypothyroidism (predisposes to statin-induced muscle toxicity) 1
• Electrolyte abnormalities 4

Infectious and Other

• Viral myositis 1
• Temperature alterations (hyperthermia, hypothermia) 4
• Muscle hypoxia 4

Genetic Risk Factors

• SLCO1B1 gene mutations (increase risk of statin-induced rhabdomyolysis) 1
• RYR1 and CACNA1S gene mutations (malignant hyperthermia susceptibility) 1
• Metabolic myopathies: CPT2, PYGM, ACADM, AMPD1, VLCAD gene defects 1

Consider genetic testing in patients with recurrent rhabdomyolysis, exercise intolerance, family history of neuromuscular disorders, or persistently elevated CK after full neurological evaluation. 1

Acute Management

Immediate Actions

Discontinue all causative agents immediately, particularly statins, fibrates, and any supplements associated with rhabdomyolysis risk. 1

Fluid Resuscitation (Most Critical Intervention)

Initiate aggressive intravenous crystalloid resuscitation immediately with isotonic saline (0.9% NaCl) to maintain urine output ≥300 mL/hour. 1, 5

Early initiation of fluid resuscitation is critical—delayed treatment is associated with higher risk of acute kidney injury. 1

Volume requirements based on severity:

• Severe rhabdomyolysis (CK >15,000 IU/L): >6L per day may be required 1
• Moderate cases: 3-6L per day typically sufficient 1

Avoid Ringer's lactate if there is any concern for head trauma. 1

Continue intravenous fluids until CK levels are <1,000 U/L. 5

Electrolyte Management

Monitor potassium levels closely and correct hyperkalemia emergently, as it can precipitate life-threatening cardiac arrhythmias. 1, 5 Obtain ECG to evaluate for hyperkalemia-induced changes. 1

Monitor and correct significant abnormalities in calcium, phosphorus, and magnesium. 1

Compartment Syndrome Management

Early fasciotomy is indicated for established compartment syndrome. 1

Consider fasciotomy when compartment pressure exceeds 30 mmHg or when differential pressure (diastolic blood pressure minus compartment pressure) is <30 mmHg. 1

Adjunctive Therapies

Sodium bicarbonate can be used for patients who are acidotic, though evidence from animal models is still debated. 6 Mannitol can be used for those whose urine output is not at goal. 5

Medications to Avoid

Avoid succinylcholine in the perioperative setting. 1

Avoid all NSAIDs (ibuprofen, ketoprofen, diclofenac, naproxen, mefenamic acid) due to nephrotoxic effects in patients already at high risk for acute kidney injury. 1

Pain Management

Acetaminophen 500-1000 mg (maximum 4-6 grams daily) is the preferred initial analgesic, as it avoids nephrotoxic effects. 1

Reserve opioids for severe muscle pain unresponsive to acetaminophen. 1 For opioid-naive patients, start oral morphine 20-40 mg. 1 In patients with established acute kidney injury (eGFR <30 mL/min), fentanyl or buprenorphine are the safest opioid choices. 1

Major Complications

Acute Kidney Injury (Most Serious Complication)

AKI occurs in 13-50% of rhabdomyolysis cases, caused by myoglobin-induced renal tubular obstruction and direct toxicity. 1, 2 This can progress to myoglobinuric renal failure requiring dialysis. 1

Life-Threatening Complications

• Severe electrolyte abnormalities (particularly hyperkalemia causing cardiac arrhythmias) 1, 5
• Metabolic acidosis 1, 5
• Compartment syndrome 1, 5
• Disseminated intravascular coagulation 1, 5
• Cardiac arrhythmias and arrest 5

Special Considerations for Statin-Associated Rhabdomyolysis

The incidence of severe myopathy with statin monotherapy is approximately 0.08-0.09%. 7 Fatal rhabdomyolysis is extremely rare (<1 death per million prescriptions). 7

Risk is dramatically increased with drug interactions, particularly gemfibrozil (10-fold higher risk than fenofibrate). 7, 1

Patient-specific risk factors include: age, diabetes, renal impairment, cardiovascular disease, hypothyroidism, and genetic factors (SLCO1B1 mutations). 1

Post-Rhabdomyolysis Lipid Management

After statin discontinuation for rhabdomyolysis, consider alternative lipid-lowering strategies: 1

• Hydrophilic statins with minimal CYP450 metabolism (pravastatin or fluvastatin) have lower drug interaction potential 1
• Non-statin alternatives: ezetimibe, PCSK9 inhibitors, or bempedoic acid 1

Never use gemfibrozil with any statin—it carries a 10-fold higher rhabdomyolysis risk compared to fenofibrate. 1

Altered Mental Status Considerations

In patients with altered mental status and elevated CK, determine whether the AMS is: 1

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

Admission Criteria

Hospitalize patients with rhabdomyolysis who have immunocompromised state, pain management needs, mental confusion, pulmonary infiltrates, abnormal spinal fluid findings, or specific organ failure. 1