Rhabdomyolysis is a clinical syndrome resulting from the rapid breakdown of skeletal muscle with release of intracellular contents — including creatine kinase (CK), myoglobin, potassium, phosphate, and uric acid — into the circulation. The most feared complication is acute kidney injury (AKI), which occurs in 13–50% of cases and accounts for 7–10% of all AKI in the United States. [1-3] Incidence is approximately 2 per 10,000 person-years, with a 2.5:1 male predominance. [2][4]
The following figure illustrates the pathophysiology of rhabdomyolysis-induced AKI through three concurrent mechanisms: intrarenal vasoconstriction, direct tubular cytotoxicity from myoglobin, and tubular obstruction from myoglobin-Tamm-Horsfall protein casts. [3]
1. History
- Classic triad: Myalgia, muscle weakness, and dark ("cola-colored") urine — though the full triad is present in <10–50% of cases [1][5-6]
- Characterize onset, location, and severity of muscle pain; ask about swelling, stiffness, and inability to bear weight
- Timing/triggers: Recent intense or unaccustomed exercise, prolonged immobilization, crush injury, seizures, heat exposure, recent surgery, or anesthesia exposure [1][3]
- Substance use: Alcohol binge, cocaine, amphetamines, heroin, synthetic cannabinoids [7-8]
- Medications: New statin, antipsychotic initiation or dose change, colchicine, zidovudine, SSRIs, lithium [5][7]
- Infections: Recent viral illness (influenza, COVID-19, coxsackievirus), bacterial sepsis [3-4]
- Important negatives: Chest pain (rule out MI as CK source), seizure history, trauma history, prior episodes of rhabdomyolysis (suggests inherited myopathy) [3][9]
2. Alarm Features
- Dark/tea-colored urine (myoglobinuria) — indicates significant muscle destruction (>100 g of muscle) [10]
- Oliguria or anuria — suggests AKI
- Tense, swollen extremity — concern for compartment syndrome requiring emergent fasciotomy [1][11]
- Cardiac arrhythmia symptoms (palpitations, syncope) — from hyperkalemia
- Altered mental status — may indicate uremic encephalopathy, severe electrolyte derangement, or underlying toxidrome
- DIC signs (petechiae, oozing, bleeding) [1]
- Fever + rigidity — consider neuroleptic malignant syndrome or malignant hyperthermia [12]
- CK >40,000 U/L, initial creatinine elevation, hypocalcemia, hyperphosphatemia, and metabolic acidosis all predict higher AKI risk [13-14]
3. Medications
Causative medications
- Statins (especially simvastatin; risk increases with CYP3A4 inhibitors, fibrates, renal impairment) — rhabdomyolysis incidence <0.01% but higher with drug interactions [5][15-16]
- Antipsychotics (olanzapine highest signal, quetiapine most reported) — via neuroleptic malignant syndrome or direct toxicity [17]
- SSRIs, lithium, colchicine, zidovudine, daptomycin, fibrates [7]
- Drugs of abuse: Cocaine, amphetamines, heroin, MDMA, synthetic cannabinoids, alcohol [8][10]
Treatment medications
- IV crystalloid (normal saline) — cornerstone of therapy
- Sodium bicarbonate — controversial; consider if metabolic acidosis present [3][11]
- Calcium gluconate/chloride — for symptomatic hypocalcemia or hyperkalemia with ECG changes [3]
- Insulin + dextrose, albuterol, kayexalate — for hyperkalemia management
Contraindicated/caution
- Avoid nephrotoxins (NSAIDs, aminoglycosides, contrast dye)
- Avoid calcium repletion for asymptomatic hypocalcemia (risk of rebound hypercalcemia and soft tissue calcification during recovery) [3]
- Discontinue the offending agent immediately [18]
4. Diet
- NPO or clear liquids initially if severe; transition to regular diet as tolerated
- Aggressive oral hydration in mild cases amenable to outpatient management [6]
- Avoid high-potassium foods during acute phase (bananas, oranges, potatoes)
- Avoid high-phosphate foods (dairy, processed meats)
- Long-term: Adequate hydration before and during exercise to prevent exertional recurrence [19]
5. Review of Systems
- Musculoskeletal: Myalgia, weakness, swelling, stiffness, inability to ambulate
- Genitourinary: Urine color change, decreased urine output
- Cardiovascular: Palpitations, chest pain, syncope (hyperkalemia-related arrhythmia)
- Neurologic: Confusion, seizures, paresthesias (hypocalcemia)
- GI: Nausea, vomiting, abdominal pain
- Constitutional: Fever, malaise, fatigue
- Skin: Signs of prolonged immobilization (pressure marks), injection sites
6. Collateral History and Family History
- Collateral: Witnesses to trauma, seizure, prolonged immobilization (found down), substance use, environmental exposure (heat stroke)
- Family history: Recurrent rhabdomyolysis episodes suggest inherited metabolic myopathy — ask about McArdle disease (glycogen storage disease type V), CPT II deficiency, mitochondrial myopathies, malignant hyperthermia susceptibility, sickle cell trait [3][9][19]
- The 'RHABDO' acronym has been proposed to guide clinicians in deciding which patients warrant genetic testing for underlying myopathy [13]
- Social context: Military training, CrossFit/extreme exercise, occupation (manual labor in heat), incarceration, homelessness (prolonged immobilization)
7. Risk Factors
- Exertional: Unaccustomed intense exercise, military training, hot/humid environments, sickle cell trait [6][19]
- Toxins/substances: Alcohol (most common single agent), cocaine, amphetamines, heroin [7][10]
- Medications: Statins (especially with interacting drugs), antipsychotics, polypharmacy [5][17]
- Trauma/compression: Crush injury, prolonged immobilization/coma, surgical positioning [3]
- Medical conditions: Seizures, DKA, hypothyroidism, hypokalemia, hypophosphatemia, infections/sepsis [3-4]
- Multiple concurrent factors are present in 60% of cases and correlate with higher AKI risk [7]
8. Differential Diagnosis
- Acute kidney injury from other causes (prerenal, ATN, glomerulonephritis)
- Myocardial infarction — elevated CK-MB; troponin differentiates
- Compartment syndrome — may coexist or be the primary presentation
- Neuroleptic malignant syndrome — fever, rigidity, autonomic instability, altered mental status [12]
- Malignant hyperthermia — post-anesthesia with volatile agents/succinylcholine
- Inflammatory myopathy (polymyositis, dermatomyositis) — subacute, proximal weakness, CK typically lower
- Hematuria — urine dipstick positive for blood but no RBCs on microscopy distinguishes myoglobinuria from true hematuria [2]
- Hemolysis — hemoglobinuria can also cause positive dipstick without RBCs; differentiate by serum haptoglobin, LDH, bilirubin
9. Past Medical History
- Prior rhabdomyolysis episodes — 11% recurrence rate; high recurrence suggests underlying metabolic myopathy [7]
- Chronic kidney disease (lower threshold for AKI)
- Hypothyroidism (increases statin myotoxicity risk) [5]
- Sickle cell trait or disease
- Known metabolic myopathy (McArdle, CPT II deficiency, mitochondrial disorders) [3][9]
- Seizure disorder
- Substance use disorder
- Surgical history (recent procedures, anesthesia exposure)
10. Physical Exam
- Vitals: Tachycardia (volume depletion), hypotension (hypovolemic shock from third-spacing), fever (NMS, infection, heat stroke)
- Musculoskeletal: Muscle tenderness, swelling, induration; assess all compartments for tenseness and pain with passive stretch (compartment syndrome) [1]
- Skin: Pressure injuries, ecchymoses, injection sites, signs of prolonged immobilization
- Neurologic: Mental status, focal deficits, rigidity (NMS), fasciculations
- Cardiovascular: Irregular rhythm (hyperkalemia)
- Abdominal: Flank tenderness (renal involvement)
- Urine: Visually inspect for dark/tea/cola-colored urine
11. Lab Studies
Diagnostic
- Serum CK — the biochemical gold standard; >5× ULN (typically >1,000 U/L) confirms diagnosis; peaks at 3–5 days post-injury. A 2024 expert consensus redefined exertional rhabdomyolysis as CK >10,000 U/L [1][5-6][13]
- Urinalysis — dipstick positive for blood with few or no RBCs on microscopy (myoglobinuria) [2]
- Serum/urine myoglobin — rises and clears faster than CK; useful for early diagnosis but absence does not exclude rhabdomyolysis [5][7]
To assess complications
- BMP: Creatinine (AKI), potassium (hyperkalemia), calcium (hypocalcemia early, hypercalcemia in recovery), phosphate (hyperphosphatemia), bicarbonate (metabolic acidosis) [3][10]
- CBC: Leukocytosis, thrombocytopenia (DIC)
- LDH, AST, ALT — elevated from muscle origin (not necessarily hepatic injury) [3]
- Uric acid — hyperuricemia contributes to tubular obstruction [3]
- Coagulation studies (PT/INR, fibrinogen, D-dimer) — if DIC suspected
- Lactate — if sepsis or severe tissue ischemia suspected
Monitoring
- Serial CK every 6–12 hours until trending down
- Serial BMP every 6–12 hours (potassium, creatinine, calcium, phosphate)
- Strict I&O with urine output monitoring [1][3]
12. Imaging
- Not routinely required for diagnosis
- CT without contrast of affected extremity — if compartment syndrome suspected and clinical exam equivocal
- MRI — most sensitive for detecting muscle edema/necrosis (T2/STIR hyperintensity); useful in unclear cases or to guide biopsy
- Renal ultrasound — if AKI develops, to rule out obstructive uropathy
- CT head — if altered mental status or seizure is the suspected trigger
- Avoid IV contrast when possible due to nephrotoxicity risk
13. Special Tests
Risk stratification
The McMahon Score is the most validated tool for predicting AKI requiring renal replacement therapy (RRT) or death in rhabdomyolysis. A score ≥6 on admission is 86% sensitive and 68% specific for RRT. [20-21] It incorporates age, sex, initial creatinine, calcium, CPK, phosphate, bicarbonate, and etiology. [14][22]
Other tests
- Compartment pressures — measure if clinical suspicion; delta pressure (diastolic BP minus compartment pressure) <30 mmHg is concerning
- Genetic testing — consider in recurrent/unprovoked rhabdomyolysis using the 'RHABDO' acronym framework [9][13]
- Muscle biopsy — wait several weeks to months after the acute event; useful for metabolic myopathies [3]
- Urine drug screen — if substance use suspected
14. ECG
ECG is essential in all rhabdomyolysis patients to evaluate for electrolyte-related cardiac effects:
- Hyperkalemia (most dangerous): Peaked T waves → PR prolongation → P wave flattening → QRS widening → sine wave → VF/asystole [23-24]
- Hypocalcemia: Prolonged QTc interval, which may predispose to torsades de pointes [25]
- Combined hyperkalemia + hypocalcemia — synergistic cardiac toxicity with wide QRS and prolonged QT [25]
- Obtain serial ECGs with electrolyte monitoring; continuous telemetry for potassium >6.0 mEq/L [24]
15. Assessment
Severity stratification
- Mild: CK 1,000–5,000 U/L, normal renal function, normal electrolytes, tolerating PO
- Moderate: CK 5,000–15,000 U/L, mild electrolyte abnormalities, no AKI
- Severe: CK >15,000 U/L (especially >40,000), AKI, significant electrolyte derangements, myoglobinuria, compartment syndrome, DIC [1][13]
Typical presentation: Young male after exertion, substance use, or trauma with muscle pain and dark urine. However, presentations are frequently nonspecific — many patients lack the classic triad. [1][5]
Atypical presentations: Asymptomatic CK elevation, isolated AKI without muscle complaints, abdominal pain mimicking surgical abdomen, altered mental status without obvious muscle findings.
Complications to anticipate
- AKI (13–50%) [2]
- Life-threatening hyperkalemia
- Hypocalcemia (early) → hypercalcemia (recovery phase) [3]
- Compartment syndrome
- DIC
- Hepatic dysfunction (from muscle enzyme release)
- Cardiac arrhythmias
16. Treatment Plan
Initial stabilization
- ABCs — address airway if altered mental status; IV access ×2 large-bore
- Treat hyperkalemia emergently if K >6.0 or ECG changes: calcium gluconate 10% 10 mL IV (membrane stabilization), insulin 10 units + D50 IV, albuterol nebulization [23]
Fluid resuscitation (cornerstone of therapy)
- Aggressive IV normal saline — initial bolus 1–2 L, then titrate to maintain urine output 200–300 mL/hr [1][3][26]
- Patients may require up to 10 L/day depending on severity [3]
- Monitor for fluid overload, especially in patients with cardiac or renal comorbidities
Adjunctive therapies (controversial/limited evidence)
- Sodium bicarbonate — consider if metabolic acidosis present; alkalinizes urine to reduce myoglobin precipitation. Discontinue if urine pH does not rise after 4–6 hours or symptomatic hypocalcemia develops [3]
- Mannitol — no strong evidence; avoid if >200 g/day or inadequate diuresis; monitor osmolal gap [3]
- Loop diuretics — no demonstrated benefit; avoid unless volume overloaded [1][11]
Renal replacement therapy
- Indicated for uremic encephalopathy, refractory hyperkalemia, severe metabolic acidosis, or volume overload unresponsive to medical management [2]
- CRRT may offer advantages in removing myoglobin [2]
Treat the underlying cause
- Discontinue offending medications [18]
- Treat infection/sepsis
- Correct hypothyroidism, DKA, or other metabolic triggers
- Fasciotomy for compartment syndrome [1]
17. Disposition
Admit (most patients)
- CK >5,000 U/L with any electrolyte abnormality or AKI
- CK >20,000 U/L regardless [6]
- Myoglobinuria
- Inability to tolerate adequate oral hydration
- McMahon score ≥6 (high risk for RRT/death) [20-21]
- Hyperkalemia, metabolic acidosis, or hypocalcemia
- Compartment syndrome concern
- Sickle cell trait carrier with exertional rhabdomyolysis [6]
ICU admission
- Severe hyperkalemia with ECG changes
- Hemodynamic instability
- Need for RRT
- DIC
- Compartment syndrome requiring fasciotomy
Discharge considerations (select mild cases)
- Mild CK elevation (<5,000 U/L) with normal renal function, normal electrolytes, adequate oral intake, and clear etiology (e.g., mild exertional) [1][6]
- Must ensure reliable follow-up within 24–48 hours with repeat labs
Specialist consultation triggers
- Nephrology — AKI, need for RRT, refractory electrolyte abnormalities
- Surgery — compartment syndrome
- Toxicology — drug/toxin-related rhabdomyolysis
- Neurology — recurrent/unprovoked episodes, suspected inherited myopathy [9]
18. Follow Up / Return Precautions
Follow-up timing
- Discharged patients: Repeat CK and BMP in 24–48 hours to confirm downtrend [6]
- CK should peak within 1–4 days and normalize within 1–2 weeks of rest [5][13]
- For exertional rhabdomyolysis, a gradual phased return to activity over 3–4 weeks with clinical and laboratory monitoring is recommended [6]
Return precautions — instruct patients to return immediately for:
- Dark or cola-colored urine
- Decreased urine output
- Worsening muscle pain, swelling, or weakness
- Palpitations, chest pain, or lightheadedness
- Nausea/vomiting preventing oral hydration
- Fever or confusion
Patient counseling
- Maintain aggressive oral hydration (target clear/pale urine)
- Avoid strenuous activity until cleared
- Avoid nephrotoxins (NSAIDs, supplements like creatine)
- If recurrent episodes, referral for genetic evaluation is warranted [9][13]
- Psychological sequelae (anxiety, fear of exercise) should be assessed at follow-up [13]
Expected recovery
- mortality is low (~3.4%)[7][27]
References
1. An Evidence-Based Narrative Review of the Emergency Department Evaluation and Management of Rhabdomyolysis. — Long B, Koyfman A, Gottlieb M. The American Journal of Emergency Medicine. 2019.
2. Continuous Renal Replacement Therapy (CRRT) for Rhabdomyolysis. — Zeng X, Zhang L, Wu T, Fu P. The Cochrane Database of Systematic Reviews. 2014.
3. Rhabdomyolysis and Acute Kidney Injury. — Bosch X, Poch E, Grau JM. The New England Journal of Medicine. 2009.
4. Clinical and Epidemiological Characteristics of Rhabdomyolysis: A Retrospective Study. — Sun K, Shi Z, Abudureheman Y, et al. International Journal of Clinical Practice. 2023.
5. Diagnostic evaluation of rhabdomyolysis. — Nance JR, Mammen AL. Muscle & Nerve. 2015.
6. Heat-Related Illnesses. — Gauer RL, McNutt R, Bryan K. American Family Physician. 2026.
7. Rhabdomyolysis: An Evaluation of 475 Hospitalized Patients. — Melli G, Chaudhry V, Cornblath DR. Medicine. 2005.
8. Incidence of Rhabdomyolysis Occurrence in Psychoactive Substances Intoxication: A Systematic Review and Meta-Analysis. — Amanollahi A, Babeveynezhad T, Sedighi M, et al. Scientific Reports. 2023.
9. The utility of electrodiagnostic testing in unprovoked rhabdomyolysis in the era of next‐generation sequencing. — Skolka MP, Milone M, Litchy WJ, et al. Muscle & Nerve. 2024.
10. Rhabdomyolysis: A review. — Warren JD, Blumbergs PC, Thompson PD. Muscle & Nerve. 2002.
11. Rhabdomyolysis. — Zimmerman JL, Shen MC. Chest. 2013.
12. Neuroleptic Malignant Syndrome. — Wijdicks EFM, Ropper AH. The New England Journal of Medicine. 2024.
13. 276th ENMC International Workshop: Recommendations on Optimal Diagnostic Pathway and Management Strategy for Patients With Acute Rhabdomyolysis Worldwide. 15th-17th March 2024, Hoofddorp, the Netherlands. — Kruijt N, Laforet P, Vissing J, et al. Neuromuscular Disorders : NMD. 2025.
14. Creatine Kinase and McMahon Score as Predictors for Acute Kidney Injury, Renal Replacement Therapy, and Mortality Associated With Poisoning-Induced Rhabdomyolysis. — Kamel NA, Masry ME, Mohammed SS. Biomarkers : Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals. 2025.
15. Lipid Management in Patients With Endocrine Disorders: An Endocrine Society Clinical Practice Guideline. — Newman CB, Blaha MJ, Boord JB, et al. The Journal of Clinical Endocrinology and Metabolism. 2020.
16. FDA Drug Label. — Updated date: 2025-11-14. Food and Drug Administration.
17. Evaluation of Atypical Antipsychotics Associated Rhabdomyolysis Using the FDA Adverse Event Reporting System Database. — Yin Y, Jiang J, Jin Y. Scientific Reports. 2025.
18. Rhabdomyolysis. — Grover KM, Sripathi N. Muscle & Nerve. 2026.
19. Risk Factors and Future Directions for Preventing and Diagnosing Exertional Rhabdomyolysis. — Carneiro A, Viana-Gomes D, Macedo-da-Silva J, et al. Neuromuscular Disorders : NMD. 2021.
20. Rhabdomyolysis. — Cabral BMI, Edding SN, Portocarrero JP, Lerma EV. Disease-a-Month : DM. 2020.
21. Rhabdomyolysis and Acute Kidney Injury: Creatine Kinase as a Prognostic Marker and Validation of the McMahon Score in a 10-Year Cohort: A Retrospective Observational Evaluation. — Simpson JP, Taylor A, Sudhan N, Menon DK, Lavinio A. European Journal of Anaesthesiology. 2016.
22. Updates on Rhabdomyolysis: A Clinically Oriented Narrative Review. — Richert Q, Miller N, Cameron S, et al. Chest. 2026.
23. Part 10: Adult and Pediatric Special Circumstances of Resuscitation: 2025 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. — Cao D, Arens AM, Chow SL, et al. Circulation. 2025.
24. Update to Practice Standards for Electrocardiographic Monitoring in Hospital Settings: A Scientific Statement From the American Heart Association. — Sandau KE, Funk M, Auerbach A, et al. Circulation. 2017.
25. Dynamic Changes in Electrocardiograms of a Premature Infant With Hyperkalemia and Hypocalcemia. — Du X, Zhang Y. Journal of Electrocardiology. 2020.
26. Early Fluid Resuscitation in Patients With Rhabdomyolysis. — Better OS, Abassi ZA. Nature Reviews. Nephrology. 2011.
27. Clinical Outcomes of Rhabdomyolysis & Validation of McMahon Score for Risk Prediction. — Mathew M, Pillai SCB. The Indian Journal of Medical Research. 2024.