What are the causes and management of Rhabdomyolysis?

Causes of Rhabdomyolysis

Rhabdomyolysis results from skeletal muscle injury with four major etiologic categories: trauma/direct injury, excessive muscle activity, hereditary enzyme defects, and medical causes including drugs/toxins, infections, metabolic disorders, and temperature alterations. 1, 2

Traumatic and Physical Causes

• Crush injuries and severe limb trauma are primary traumatic causes, with compartment syndrome both causing and complicating rhabdomyolysis 1
• Exertional rhabdomyolysis occurs from novel overexertion or unaccustomed exercise volume/intensity, particularly during transition periods like returning after injury 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

Drug-Induced Causes

• Statins are the most common prescription medication cause, with an incidence of 1.6 per 100,000 patient-years, particularly simvastatin 80 mg which carries higher risk 1, 3
• Illicit drugs (cocaine, heroin, methamphetamine, ecstasy/MDMA) and alcohol are responsible for a significant proportion of cases, with exogenous toxins accounting for 46% of all rhabdomyolysis cases 1, 3
• Other prescription medications include antipsychotics, zidovudine, colchicine, selective serotonin reuptake inhibitors, and lithium 3
• Dietary supplements including red yeast rice containing lovastatin, creatine monohydrate, wormwood oil, licorice, and Hydroxycut are known causative agents 1

Genetic and Metabolic Causes

• Genetic mutations such as SLCO1B1 gene variants increase risk of statin-induced rhabdomyolysis 1
• Hereditary muscle enzyme defects require testing for RYR1, CACNA1S (malignant hyperthermia susceptibility), CPT2, PYGM, ACADM, AMPD1, and VLCAD genes in patients with recurrent episodes 1
• Metabolic myopathies including McArdle's disease and disorders of glycogen/lipid metabolism are predisposing factors 2, 4

Infectious and Inflammatory Causes

• Viral myositis should be considered with appropriate viral studies when clinically indicated 1
• Autoimmune myositis may require evaluation of markers such as ANA, ASMA, and ANCA 1
• Infections represent a recognized category of medical causes 2

Metabolic and Endocrine Disorders

• Electrolyte abnormalities and metabolic derangements can precipitate rhabdomyolysis 2
• Endocrine disorders are among the medical causes requiring consideration 2

Temperature-Related Causes

• Heat illness and exertional heat stroke can trigger rhabdomyolysis, particularly in those with malignant hyperthermia susceptibility 1, 2
• Temperature alterations (both hyperthermia and hypothermia) are recognized triggers 2

Muscle Hypoxia and Ischemia

• Prolonged immobilization or compression leading to muscle ischemia is a recognized cause 2
• Muscle hypoxia from any cause can precipitate the syndrome 2

Key Risk Factors

• Patient-specific factors including advanced age, diabetes, renal impairment, and cardiovascular disease increase susceptibility 1
• Polypharmacy significantly increases risk, with 60% of cases involving multiple etiologic factors 3
• History of substance abuse is a major risk factor requiring specific inquiry about recreational drug use and needle-sharing practices 1, 5

Important Clinical Considerations

• Multiple factors are present in 60% of all cases, making it essential to identify all potential contributors rather than assuming a single cause 3
• Recurrent rhabdomyolysis occurs in 11% of cases, with underlying myopathy or metabolic defects showing high recurrence rates 3
• In 7% of cases, no cause is identified despite thorough evaluation 3

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Management of Rhabdomyolysis

Immediate Fluid Resuscitation

Aggressive intravenous fluid resuscitation with isotonic saline targeting urine output of 300 mL/hour must be initiated immediately upon diagnosis to facilitate myoglobin clearance and prevent renal tubular obstruction. 6

• For severe rhabdomyolysis (CK >15,000 IU/L), administer more than 6L of fluid per day 1, 6
• For moderate cases, 3-6L per day is typically sufficient 1, 6
• Early initiation is critical, as delayed treatment significantly increases acute kidney injury risk 1, 6
• Monitor closely for fluid overload, particularly in patients with cardiac or renal compromise 6

Discontinue Causative Agents

• Immediately stop all offending medications, particularly statins, antipsychotics, and any prescription drugs that may contribute 1, 6
• Discontinue dietary supplements including red yeast rice, creatine monohydrate, wormwood oil, licorice, and Hydroxycut 1, 6
• Avoid succinylcholine and inhaled anesthetics in anesthesia settings for patients with muscular dystrophy or at-risk populations 6

Electrolyte Monitoring and Correction

• Check electrolyte panels every 6-12 hours in severe cases, with repeated bioassessment including plasma myoglobin, CK, and potassium 1, 6
• Correct hyperkalemia emergently, as it can precipitate cardiac arrhythmias and arrest 1, 6
• Monitor and correct hypocalcemia and hyperphosphatemia 6
• Assess for metabolic acidosis via arterial blood gas, which commonly occurs in severe cases 1, 6
• Trend CK, creatinine, and electrolytes daily until CK is declining and renal function is stable 1

Laboratory Monitoring

• Essential initial tests include complete blood count, comprehensive metabolic panel, CK, creatinine, BUN, liver function tests, and urinalysis 1
• Urinalysis showing brown color, cloudiness, and positive for blood without RBCs indicates myoglobinuria 1
• Cardiac assessment including ECG and cardiac troponin should be performed in severe cases to rule out cardiac involvement 1
• Coagulation studies should be performed to evaluate for disseminated intravascular coagulation 1

Compartment Syndrome Surveillance

• Maintain high suspicion for compartment syndrome, monitoring for early signs including pain, tension, paresthesia, and paresis 1, 6
• Perform early fasciotomy when compartment pressure exceeds 30 mmHg or when differential pressure (diastolic BP - compartment pressure) is <30 mmHg 1, 6
• Late signs including pulselessness and pallor indicate irreversible damage 1, 6

Pain Management

• Acetaminophen (500-1000 mg) is the preferred initial analgesic, with onset in 15-30 minutes and maximum daily dose of 4-6 grams 1, 6
• Avoid all NSAIDs (ibuprofen, ketoprofen, diclofenac, naproxen, mefenamic acid) due to gastrointestinal and renal toxicity 1, 6
• Reserve opioids for severe muscle pain unresponsive to acetaminophen, using oral morphine 20-40 mg for opioid-naive patients 1, 6
• In patients with acute kidney injury (eGFR <30 mL/min), use fentanyl or buprenorphine as safest opioid choices 1, 6

Renal Replacement Therapy

• Consider RRT for refractory hyperkalemia, severe metabolic acidosis, or progressive acute kidney injury 6
• Initiate RRT if CK remains persistently elevated despite 4 days of adequate hydration 6
• Consider discontinuation when urine output recovers adequately (>100 mL/day) 6

Genetic and Metabolic Testing

• For recurrent episodes or family history, test for RYR1 and CACNA1S genes (malignant hyperthermia susceptibility) 1
• For metabolic myopathies, consider CPT2, PYGM, ACADM, AMPD1, and VLCAD gene testing 1
• If metabolic disorder suspected, test serum calcium, phosphorus, alkaline phosphatase, parathyroid hormone, and 25-hydroxy-vitamin D 1

Discharge Planning and Follow-Up

• Schedule laboratory evaluation within 3-7 days after discharge to assess kidney recovery, including creatinine, BUN, and electrolyte panels 7
• Continue weekly monitoring of creatinine if kidney function has not fully normalized 7
• Arrange nephrology follow-up for patients with severe kidney injury, pre-existing chronic kidney disease, diabetes, or proteinuria 7
• Maintain adequate oral hydration to support continued myoglobin clearance 7
• Cease the specific physical activity that triggered the episode and return to normal activities in a graded fashion 7

Critical Pitfalls to Avoid

• Do not delay fluid resuscitation, as this is associated with higher risk of acute kidney injury and worse outcomes 6
• Do not use inadequate fluid volume, which may fail to prevent renal complications 6
• Do not miss compartment syndrome, particularly in traumatic or severe exertional cases 6
• Do not delay follow-up laboratory assessment beyond 7 days, as this can miss early signs of kidney function deterioration 7
• Do not resume causative medications or supplements too early, as this increases risk of recurrent episodes 7