Rhabdomyolysis

Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis can result from trauma or direct muscle injuries; however, non-exertional and non-traumatic etiologies (heatstroke, immobilization, medication side effects) can also lead to muscle breakdown. The classic triad of symptoms includes myalgia, weakness, and tea-colored urine, but the presentation can be nonspecific. History and work-up generally point to diagnosis based on elevated creatine kinase levels, abnormal electrolytes with possible renal failure, and dark urine without RBCs (indicating myoglobinuria). Management of rhabdomyolysis is by using intravenous fluid resuscitation.

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Overview

Definition

Rhabdomyolysis is a syndrome marked by muscle necrosis, resulting in the release of toxic intracellular muscle constituents into the circulation (especially myoglobin).

Etiology

  • Trauma or muscle compression:
    • Crush injuries
    • Victims of restraints or torture, physically abused children
    • Surgical procedure with prolonged muscle compression
    • Acute lower-limb compartment syndrome
    • High-voltage electrical injury
  • Non-traumatic exertional rhabdomyolysis:
    • Recent exaggerated skeletal activity
    • Exertion occurring in extremely hot or humid conditions (heatstroke)
    • Seizure
  • Non-exertional and non-traumatic rhabdomyolysis:
    • Alcohol, use of illicit drugs
    • Drugs (e.g., statins, colchicine)
    • Metabolic disorders and abnormalities (e.g., inherited disorders of glycogenolysis)
    • Electrolyte abnormalities (e.g., hypokalemia)
    • Infections (e.g., viral infections)
    • Toxins (e.g., carbon monoxide)
    • Inflammatory myopathies (e.g., dermatomyositis)
    • Prolonged immobilization 

Pathophysiology

Muscle injury

  • Muscle-cell death or necrosis is triggered by different events/etiologies.
  • Disturbance in myocyte calcium homeostasis (↑ in intracellular free ionized cytoplasmic and mitochondrial calcium) is the common cause of injury.
  • ↑ Intracellular calcium leads to:
    • Activation of enzymes that produce cell injury: 
      • Phospholipasesmembrane damage
      • Proteasesmembrane- and cytoskeletal-protein degradation
      • Endonucleasesdeoxyribonucleic acid (DNA) and chromatin fragmentation
      • Adenosine triphosphatases (ATPases)adenosine triphosphate (ATP) depletion
    • ↑ Contractility of skeletal muscle cells
    • Mitochondrial damage
    • Production of reactive oxygen species (ROS)
  • Additionally, ATP depletion → dysfunction of the Na+/K+ ATPase and Ca2+ ATPase pumps → loss of myocyte integrity → cell death → release of intracellular components

Injury mechanisms of rhabdomyolysis:
1. Energy (ATP) depletion inhibits Na+/K+ ATPase function and increases intracellular sodium.
2. The 2Na+/Ca2+ exchanger increases intracellular calcium.
3. Ca2+ ATPase is not able to pump out intracellular calcium due to energy depletion.
4. Intracellular calcium activates proteases such as phospholipase 2 (PLA2), which destroy the structural components of cell membranes and allow the entry of more calcium.
5. Calcium overload disrupts mitochondrial integrity and induces apoptosis, leading to necrosis of muscle cells.

Image: “Injury mechanisms of rhabdomyolysis” by Universidad Autónoma de Baja California, Facultad de Medicina y Psicología, Tijuana, Baja California, Mexico. License: CC BY 4.0

Renal injury

  • Most common systemic complication of rhabdomyolysis
  • Factors contributing to renal failure:
    • Hypovolemia:
      • Released enzymes (including creatine kinase (CK)) can damage capillaries
      • Subsequently, there is fluid leakage and sequestration in the extracellular spaces.
      • ↓ Intravascular volume → stimulation of renin-angiotensin-aldosterone (RAA) system
      • RAA effect: reduced renal blood flow
    • Release of myoglobin from necrotic muscles:
      • Myoglobin is cytotoxic to nephrons.
      • Myoglobin scavenges nitric oxide: ↑ renal injury
      • Myoglobin also results in lipid peroxidation of renal cell membranes.
      • Other components, including free iron, can generate ROS and damage renal tubules.
    • Metabolic acidosis: ↑ lactic acid from damaged/ischemic muscles
    • Hyperphosphatemia in necrotic muscles:
      • Leads to hypocalcemia
      • Leads to deposition of calcium phosphate → renal damage
    • Uric acid release: 
      • Nucleosides from cell nuclei → uric acid 
      • Deposition of uric acid crystals increases in an acidic environment, leading to tubular obstruction.

Acute kidney injury (AKI) in rhabdomyolysis (enzymes*: creatine kinase, aldolase, lactate dehydrogenase):
After muscle destruction, myoglobin and enzymes are released into the circulation, damaging capillaries and leading to leakage and edema. Hypovolemia and reduced renal blood flow are associated with AKI. Myoglobin cytotoxicity affects the kidney due to lipid peroxidation and production of reactive oxygen species. Tubular obstruction by myoglobin is also associated with AKI.

Image: “Kidney injury in rhabdomyolysis” by Chavez et al. License: Public Domain

Clinical Presentation

Signs and symptoms

  • Classic triad:
    1. Weakness
    2. Myalgia
    3. Tea-colored urine
  • < 10% of patients present with the classic triad. 
  • Children: Muscle pain/tenderness, fever, and viral prodromes are common symptoms. 
  • Other patients present with nonspecific symptoms (nausea, fever, vomiting).

Additional clues

  • History: 
    • Exertion (increased activity) or trauma
    • Immobility
    • Underlying conditions and medications
    • Infections
  • Findings that raise suspicion:
    • Dark urine without presenting genitourinary symptoms
    • Abnormal laboratory tests on presentation (electrolyte imbalance)
    • Arrhythmias (from resultant electrolyte imbalance)

Tea-colored urine of a patient being treated for rhabdomyolysis

Image: “Urine appearance” by the Department of General Medicine, Sri Ramachandra University Chennai, Tamil Nadu, India. License: CC BY 3.0

Diagnosis

  • Laboratory abnormalities:
    • CK (5 times the normal upper limit)
    • ↑ Myoglobin:
      • Red-to-brown urine
      • Detected by urinalysis as myoglobinuria: positive test for blood on the urine dipstick, but no RBCs on microscopic examination
    • Electrolyte abnormalities: 
      • Hyperkalemia
      • Hyperphosphatemia
      • Hyperuricemia: release of purines from the damaged muscle
      • Hypocalcemia: due to soft-tissue and muscle-cell damage → calcium enters myocytes and calcium salts are deposited in the damaged muscle
    • Lactic acidosis
    • Elevation of serum aminotransferases
  • Acute renal failure (from hypovolemia, myoglobin toxicity, and/or uric acid and calcium phosphate deposition in the renal tubules), resulting in oliguria or anuria

Management

  • Initial approach:
    • Airway, breathing, circulation (ABC) assessment for all patients with trauma history
    • Exclude and treat other potential injuries (compartment syndrome, vascular compromise, fractures, dislocations, and wounds).
  • Aggressive intravenous fluid resuscitation to correct:
    • Hypoperfusion
    • Lactic acidosis
    • Acute renal impairment
  • Bicarbonate therapy (no supporting evidence for pediatric population) may be considered for severe rhabdomyolysis (rising CK or > 5,000 units/L) with:
    • pH < 7.5 (acidosis)
    • No hypocalcemia 
    • Bicarbonate level < 30 mEq/L
  • Manage electrolyte abnormalities: Hypocalcemia and hyperkalemia are associated with cardiac arrhythmias.
  • Monitoring:
    • Electrolytes, renal function
    • Urine output
    • Electrocardiogram and cardiac monitoring
  • Removal of offending agents (if medication is suspected)
  • Analgesia

Patient with rhabdomyolysis and hyperkalemia:
Electrocardiogram of a patient treated for rhabdomyolysis, showing peaked T waves and wide QRS. The patient had a serum potassium level of 8 mEq/L.

Image: “ Electrocardiogram” by Department of Medicine, Union Memorial Hospital, Baltimore, MD, USA. License: CC BY 2.0

Clinical Relevance

  • ABC assessment: a mainstay management approach in managing critically ill patients, which constitutes the 1st essential step in many situations, including unresponsive patients, cardiac arrest, patients with a history of trauma, or critically ill patients. In patients with trauma, ABC is included in the primary survey, initial evaluation, and management of injuries. 
  • Acute renal failure: a sudden drop in the glomerular filtration rate resulting from kidney damage, which occurs within a few hours to few days. Acute renal failure is classified as prerenal, intrinsic, or postrenal, depending on the etiology. Management is based on causation and often revolves around aggressive fluid hydration. Rhabdomyolysis results in acute tubular necrosis from excessive filtered myoglobin, leading to acute renal failure.
  • Hyperkalemia: serum potassium (K+) level > 5.0 mEq/L. Hyperkalemia results from several causes. Acute elevation in serum K+ (usually ≥ 7 mEq/L) can lead to cardiac arrhythmias and muscle weakness. Management involves myocardium stabilization, decreasing extracellular K+ levels, and enhancing K+ removal from the body.
  • Hypocalcemia: occurs when calcium levels are < 2.2 mmol/L or < 8.5 mg/dL. Calcium levels are regulated by the parathyroid hormone (PTH). If the body fails to maintain normal calcium levels (especially ≤ 7.5 mg/dL), patients present with arrhythmias, seizures, and tetany. Management is by calcium replacement.
  • Hyperuricemia: elevated uric acid levels resulting from accelerated purine degradation (observed in high cell-turnover states, including rhabdomyolysis). Large uric acid deposits in renal tubules cause acute renal injury. Management involves aggressive intravenous hydration.
  • Compartment syndrome: a surgical emergency occurring secondary to trauma. Compartment syndrome is marked by increased pressure within a compartment, compromising circulation and tissue function. Long-bone fractures are the most common cause. Patients present with pain, pallor, pulselessness, paresthesia, poikilothermia, and paralysis (the “6 Ps”). Diagnosis is clinical but compartment-pressure measurement can be used. Management is by emergency fasciotomy. 
  • Crush syndrome: systemic manifestations (renal failure, shock) resulting from compressive traumatic injury. Compartment syndrome and/or rhabdomyolysis can occur in Crush syndrome. Field management with intravenous fluids and extrication is crucial in reducing the risk of complications and death. 
  • Heatstroke: a condition associated with hyperthermia (elevation of core body temperature above the normal diurnal range of 36ºC–37.5ºC (96.8ºF–99.5ºF) owing to failure in thermoregulation). Heatstroke is either exertional or non-exertional and can be complicated by rhabdomyolysis. Cooling measures with fluid and electrolyte replacement are recommended.

References

  1. Beck M.A., & Haller P. (2020). Compartment syndrome. In: Tintinalli J.E., & Ma O., & Yealy D.M., & Meckler G.D., & Stapczynski J, & Cline D.M., & Thomas S.H. (Eds.), Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 9e. McGraw-Hill.
  2. Chavez L.O., Leon M., Einav S., & Varon J. (2016). Beyond muscle destruction: A systematic review of rhabdomyolysis for clinical practice. Critical care (London, England), 20(1), 135. https://doi.org/10.1186/s13054-016-1314-5
  3. Miller M. (2020). Causes of rhabdomyolysis. Retrieved 14 January 2021, from https://www.uptodate.com/contents/causes-of-rhabdomyolysis
  4. Stanley M, Adigun R. (2020) Rhabdomyolysis. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Retrieved 19 January 2021, from https://www.ncbi.nlm.nih.gov/books/NBK448168/

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