Foundational Principles of Rhabdomyolysis: Epidemiology, Pathophysiology, and Risk Factors
Lesson Objective
Describe foundational principles of rhabdomyolysis, including its pathophysiology, clinical presentation, and risk factors.
1. Overview and Definitions
Rhabdomyolysis is defined by skeletal muscle breakdown with release of intracellular constituents—creatine kinase (CK), myoglobin, and electrolytes—into the circulation. Early recognition relies on biochemical criteria and clinical signs.
Diagnostic Criteria:
- Serum CK >5× upper limit of normal (ULN) or >1,000 IU/L
- Myoglobinuria: urine dipstick positive for blood without red blood cells
- Dark (“tea-colored”) urine and oliguria in the appropriate clinical context
Key Pearl
CK magnitude does not always correlate with AKI risk; trends and clinical context guide management.
2. Epidemiology and Incidence
In ICU populations, rhabdomyolysis incidence varies by patient cohort—highest in trauma, burn, and severe sepsis. Elevated biomarkers correlate with AKI rates and mortality.
ICU Incidence Data:
- Trauma with crush injuries or prolonged immobilization: 20–40%
- Burn patients (≥20% total body surface area): 10–30%
- Severe sepsis/septic shock: 5–15%
Outcome Metrics:
- AKI develops in 13–50% of rhabdomyolysis cases
- Mortality ranges 3%–20%, driven by AKI severity and need for renal replacement therapy
High-Risk Cohorts:
- Statin users, especially with CYP450 inhibitors
- Illicit drug or heavy alcohol users
- Underlying metabolic myopathies or genetic enzyme defects
Clinical Scenario: A 35-year-old man with a crush injury presents with CK 12,000 IU/L and oliguria. Early aggressive fluids target urine output >200 mL/hr to prevent AKI.
Key Pearl
Serum myoglobin >15,000 μg/L strongly predicts need for dialysis.
3. Pathophysiology
Mechanical, ischemic, or toxic insults disrupt the sarcolemma, triggering calcium overload, protease activation, and release of myocyte contents.
1. Initial Insults
Various triggers cause muscle injury:
- Mechanical (Crush, Trauma)
- Ischemic (Pressure, Vascular)
- Toxic (Drugs, Infections)
2. Sarcolemma Disruption
The muscle cell membrane (sarcolemma) is damaged.
3. Intracellular Events
Disruption leads to:
- Calcium (Ca²⁺) Overload
- Protease Activation
4. Release of Myocyte Contents
Damaged cells release:
- Myoglobin
- Creatine Kinase (CK)
- Electrolytes (K⁺, PO₄³⁻, Uric Acid)
5. Myoglobin-Mediated Renal Injury (AKI)
Myoglobin causes kidney damage through:
- Tubular Obstruction
- Oxidative Stress
- Renal Vasoconstriction
Ultimately leading to Acute Kidney Injury (AKI).
A. Mechanisms of Muscle Injury
- Mechanical: crush, blunt trauma, compartment syndrome
- Ischemic: vascular compromise, prolonged pressure
- Toxic: statins, illicit drugs, infections, electrolyte disturbances
B. Intracellular Content Release
- Myoglobin (17.5 kDa): filtered at glomerulus, nephrotoxic at high concentrations
- Creatine kinase: sensitive marker of muscle injury
- Electrolytes: K⁺, PO₄³⁻, uric acid → risk of hyperkalemia, hyperphosphatemia
C. Myoglobin-Mediated Renal Injury
- Tubular obstruction: myoglobin–Tamm–Horsfall protein casts in acidic urine
- Oxidative stress: free radicals damage tubular epithelium
- Vasoconstriction: nitric oxide scavenging and vasoactive mediators reduce renal blood flow
Key Pearl
Acidic urine potentiates tubular myoglobin precipitation; urine alkalinization to pH >6.5 is theoretical but not routinely proven to improve outcomes and may carry risks.
4. Influence of Chronic Comorbidities
Pre-existing CKD, diabetes, and metabolic syndrome compromise renal reserve and magnify muscle and renal injury in rhabdomyolysis.
Chronic Kidney Disease
- Reduced nephron mass impairs myoglobin clearance
- Baseline CK elevations may confound new injury detection
Diabetes and Metabolic Syndrome
- Microvascular disease and hyperglycemia enhance oxidative injury
- Impaired muscle perfusion increases ischemic vulnerability
Medication-Related Factors
- Statins (HMG-CoA reductase inhibitors): dose-dependent myopathy risk
- Interacting agents (e.g., macrolides, azoles) and renal impairment raise rhabdomyolysis risk
Key Pearl
Patients with CKD on high-dose statins plus interacting drugs represent a ‘‘triple threat’’ for rhabdomyolysis.
5. Social Determinants of Health
Socioeconomic status, health literacy, and system barriers influence recognition, presentation timing, and outcomes in rhabdomyolysis.
Medication Access & Adherence
- Cost or formulary restrictions → nonadherence, abrupt discontinuation
Health Literacy
- Low literacy delays recognition of muscle pain and dark urine
Systemic Barriers
- Insurance status and rural location delay ICU presentation
Mitigation Strategies
- Pharmacist-led education on symptom recognition and medication safety
- Community outreach to high-risk groups; telehealth follow-up
Real-World Example: A rural patient on limited income delays reporting muscle pain post-statin start, presenting late with anuric AKI.
Key Pearl
Early pharmacist intervention in medication review and patient teaching can prevent drug-induced rhabdomyolysis.
References
- Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. N Engl J Med. 2009;361(1):62–72.
- Kodadek L, Carmichael H, Sagraves SG, et al. Rhabdomyolysis: AAST Clinical Consensus Document. Trauma Surg Acute Care Open. 2022;7:e000836.
- Petejova N, Martinek A. Acute kidney injury due to rhabdomyolysis and renal replacement therapy: a critical review. Crit Care. 2014;18:224.
- Melli G, Chaudhry V, Cornblath DR. Rhabdomyolysis: an evaluation of 475 hospitalized patients. Medicine (Baltimore). 2005;84(6):377–85.
- Huerta-Alardin AL, Varon J, Marik PE. Bench-to-bedside review: rhabdomyolysis – an overview for clinicians. Crit Care. 2005;9(2):158–69.
