Rhabdomyolysis (RML)

Published Categorized as Musculoskeletal System
Rhabdomyolysis
Rhabdomyolysis is the breakdown of muscle tissue with release of intracellular contents such as myoglobin into the bloodstream. The condition usually follows major muscle trauma, especially a crush injury. It can also be caused by long-distance running, hyperthermia, infection, drugs, toxins, and electrolyte disturbances, among others. | Rhabdomyolysis: Jorge Muniz, PA-C

Rhabdomyolysis is the destruction of skeletal muscle with resultant release of intracellular enzymatic content into the bloodstream that leads to systemic complications

  • Muscle necrosis + release of intracellular muscle constituents into circulation

Clinical definitions:

In 2002, the American College of Cardiology (ACC), American Heart Association (AHA), and National Heart, Lung, and Blood Institute (NHLBI) jointly released the Clinical Advisory on the Use and Safety of Statins in an attempt to formally define myopathic events and rhabdomyolysis
Definitions of Muscle Toxicity and Rhabdomyolysis by Clinical Advisory
Definitions of Muscle Toxicity and Rhabdomyolysis by Clinical Advisory | Pasternak RC, Smith SC, Jr, Bairey-Merz CN, et al. ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins. Stroke. 2002 Sep;33(9):2337–2341.

History:

The earliest known description of this condition appears in the Old Testament’s Book of Numbers that records a plague suffered by the Jews during their exodus from Egypt after consuming large amounts of quail. The plague is widely assumed to be a reference to the signs and symptoms of myolysis, a long-observed outcome in the Mediterranean after the intake of quail. Myolysis seemingly occurs because of the poisonous hemlock that quail consume during the spring migration.

Investigations of people injured in collapsed buildings during the Blitz of London led to numerous discoveries in the mechanisms underlying kidney impairment in rhabdomyolysis
Investigations of people injured in collapsed buildings during the Blitz of London led to numerous discoveries in the mechanisms underlying kidney impairment in rhabdomyolysis. | New York Times Paris Bureau Collection; Public Domain, https://commons.wikimedia.org/w/index.php?curid=3458328

In modern times, one of the first medical descriptions of rhabdomyolysis is in German medical literature from the early 1900s, where it is termed Meyer-Betz disease. Early reports from the 1908 Messina earthquake and World War I on kidney failure after injury were followed by studies by London physicians Eric Bywaters and Desmond Beall, working at the Royal Postgraduate Medical School and the National Institute for Medical Research, on four victims of The Blitz in 1941. Myoglobin was demonstrated in the urine of victims by spectroscopy, and it was noted that the kidneys of victims resembled those of patients who had hemoglobinuria (hemoglobin rather than myoglobin being the cause of the kidney damage). In 1944, Bywaters demonstrated experimentally that the kidney failure was mainly caused by myoglobin. Already during the war, teams of doctors traveled to bombed areas to provide medical support, chiefly with intravenous fluids, as dialysis was not yet available. The prognosis of acute kidney failure improved markedly when dialysis was added to supportive treatment, which first happened during the 1950–1953 Korean War.


Etiology

Although rhabdomyolysis is most often caused by direct traumatic injury, the condition can also be the result of drugs, toxins, infections, muscle ischemia, electrolyte and metabolic disorders, genetic disorders, exertion or prolonged bed rest, and temperature-induced states such as neuroleptic malignant syndrome (NMS) and malignant hyperthermia (MH).2 Massive necrosis, manifested as limb weakness, myalgia, swelling, and commonly gross pigmenturia without hematuria, is the common denominator of both traumatic and nontraumatic rhabdomyolysis.

Physical and Nonphysical Causes of Rhabdomyolysis
Physical and Nonphysical Causes of Rhabdomyolysis | Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. N Engl J Med. 2009 Jul 2;361(1):62–72.

Drugs and other agents causing rhabdomyolysis:

A variety of drugs, toxins and venoms play a role in approximately 80% of cases with rhabdomyolysis. Ethanol, abuse drugs and statins are the drugs mostly implicated
Drugs and Other Agents That Can Cause Rhabdomyolysis
Drugs and Other Agents That Can Cause Rhabdomyolysis | Torres, P. A., Helmstetter, J. A., Kaye, A. M., & Kaye, A. D. (2015). Rhabdomyolysis: pathogenesis, diagnosis, and treatment. The Ochsner journal, 15(1), 58–69.

Statin-associated rhabdomyolysis:

Statin associated rhabdomyolysis is defined as as muscle symptoms with increased creatinine kinase, typically more than 11 times the upper limit of normal (myonecrosis) with elevated serum creatinine consistent with pigment induced nephropathy and with myoglobinuria. All statins can potentially lead to rhabdomyolysis, even as a monotherapy. Statins’ myotoxicity seems to be dose-dependent
Risk Factors for Statin-Induced Rhabdomyolysis
Risk Factors for Statin-Induced Rhabdomyolysis | Torres, P. A., Helmstetter, J. A., Kaye, A. M., & Kaye, A. D. (2015). Rhabdomyolysis: pathogenesis, diagnosis, and treatment. The Ochsner journal, 15(1), 58–69.

Pathophysiology

Rhabdomyolysis is a complex medical condition involving the rapid dissolution of damaged or injured skeletal muscle. This disruption of skeletal muscle integrity leads to the direct release of intracellular muscle components, including myoglobin, creatine kinase (CK), aldolase, and lactate dehydrogenase, as well as electrolytes, into the bloodstream and extracellular space.

Injury mechanisms of rhabdomyolysis
Injury mechanisms of rhabdomyolysis: (1) Energy (ATP) depletion inhibits Na+/K+ ATPase function, thus increasing 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 structural components of the cell membrane, allowing the entrance of more calcium. (5) Calcium overload disrupts mitochondrial integrity and induces apoptosis leading to muscle cell necrosis | 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

Myoglobin:

Myoglobin is a 17 kDa small chromoprotein like hemoglobin. They are both filtered through the glomeruli and reabsorbed in the proximal tubules by endocytosis. In acidic environment (pH<5.6) the globin chain dissociates from the iron-containing ferrihemate portion of the molecule. This normally happens in lysosomes, where free iron is rapidly converted to ferritin. However, in rhabdomyolysis the amount of myoglobin delivered to the proximal tubule cells overwhelms their ability to convert iron to ferritin, resulting in intracellular ferrihemate accumulation. Iron as a metal has the ability to donate and accept electron as well as the capability to generate oxygen free radicals. This leads to oxidative stress and injury of the renal cell. The decreased acidic pH of the urine because of the metabolic acidosis (damaged muscle cells release acids) has an important role in iron release.
(A) the iron-containing porphyrin ring, (B) myoglobin, (C) hemoglobin | Slater MS, Mullins RJ. Rhabdomyolysis and myoglobinuric renal failure in trauma and surgical patients: A review. J Am Coll Surg. 1998;186:693–716.

Myoglobin can not be reabsorbed when in excessive amounts in the tubules. Systemic vasoconstriction and hypovolemia result in water reabsorption in renal tubules which in turn increases further myoglobin concentration in urine. The later causes formation of casts that obstruct renal tubules. Apoptosis of epithelial cells contributes in casts formation. Besides iron toxic effect, the heme center of myoglobin initiates lipid peroxidation and renal injury.

Acute kidney injury:

ARF/AKI is the most significant and acutely life-threatening complication of rhabdomyolysis. An estimated 10%-40% of patients with rhabdomyolysis develop ARF, and up to 15% of all cases of ARF can be attributed to rhabdomyolysis.

The obstruction of renal tubules by the myoglobin casts, the formation of free radicals from iron, the vasoconstriction and hypoxia due to hypovolemia are the main causes of acute renal failure in rhabdomyolysis.

Acute kidney injury in rhabdomyolysis
Acute kidney injury in rhabdomyolysis: Enzymes*: creatine kinase, aldolase, lactate dehydrogenase. After muscle destruction, myoglobin and enzymes released into the circulation damage capillaries, leading to leakage and edema. Hypovolemia and the decrease in renal bood flow is associated with acute kidney injury. Myoglobin cytotoxicity affects the kidney by lipid peroxidation and production of reactive oxygen species. Tubular obstruction by myoglobin is also associated with AKI | Chavez, L.O., Leon, M., Einav, S. et al. Beyond muscle destruction: a systematic review of rhabdomyolysis for clinical practice. Crit Care 20, 135 (2016). https://doi.org/10.1186/s13054-016-1314-5

Kidney biopsy:

Renal biopsy is not required to make the diagnosis of RML. The characteristic biopsy feature is acute tubular injury with globular red-brown casts which are positive for myoglobin by immunohistochemistry.
Kidney biopsy rhabdomyolysis
Kidney biopsy showing positive immunoperoxidase staining for myoglobin pigmented casts in a young female with heavy cocaine use and acute kidney injury. | Mansoor et al : Systematic review of nephrotoxicity of drugs of abuse, 2005-2016. BMC Nephrol [Internet]. 2017 Dec 29 [cited 2020 Apr 30];18. Open access article distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/

Presentation

Rhabdomyolysis ranges from an asymptomatic illness with elevation in the CK level to a life-threatening condition associated with extreme elevations in CK, electrolyte imbalances, acute renal failure (ARF), and disseminated intravascular coagulation.

Classical triad:

Clinically, rhabdomyolysis is exhibited by a triad of symptoms: myalgia, weakness, and myoglobinuria, manifested as the classically described tea-colored urine. However, this rigid depiction of symptoms can be misleading as the triad is only observed in <10% of patients, and >50% of patients do not complain of muscle pain or weakness, with the initial presenting symptom being discolored urine.
  • Myalgia (muscle pain)
  • Muscle weakness
  • Myoglobinuria (Cola/tea coloured urine)

Non specific systemic manifestations:

These appear along with classical (local) symptoms. The clinical manifestations of ARF, disseminated intravascular coagulation, and multiorgan failure may subsequently appear.
  • Tachycardia
  • General malaise, fever
  • Nausea and vomiting

Complications:

Potential complications of rhabdomyolysis include compartment syndrome and acute kidney injury
Complications of rhabdomyolysis.
Complications of rhabdomyolysis | Elsayed EF, Reilly RF. Rhabdomyolysis: a review, with emphasis on the pediatric population. Pediatr Nephrol. 2010 Jan;25(1):7–18

Diagnosis

Serum creatine kinase (CK):

Serum CK concentration, mainly the CK-MM subtype, is the most sensitive indicator of damage to muscles. A CK cut-off value of >1000 IU/L or CK > 5 times upper limit of normal (ULN) in correct clinical context could diagnose mild RML. The concentration of CK is directly proportional to the extent of muscle injury. A persistently elevated CK level suggests continuing muscle injury or development of a compartment syndrome.
  • Normal plasma CK: 45-260 U/L
  • Rhabdomyolysis:
    • Begins to rise 2-12 hours after onset of muscle injury
    • Peaks within 24-72 hours
    • Declines at the relatively constant rate of 39% of previous day’s value

Serum and urine myoglobin:

Myoglobin is normally bound to plasma globulins, and has a rapid renal clearance with a half-life of 2-3 hours. A small quantity of filtered myoglobin (0.01-5%) is normally excreted with urine. Before the urine becomes discoloured (dirty-brown) by myoglobin, the level of myoglobin in the urine must exceed 57000 nmol/L (100 mg/ dl)
  • Normal concentrations:
    • Serum myoglobin: < 5.7nmol/L (100 μg/L)
    • Urine myoglobin: < 0.57nmol/L (10 μg/L)
  • Rhabdomyolysis: Detection of myoglobin in the blood or urine is pathognomonic for the diagnosis of RML, provided that it is made in the initial phases of the syndrome (i.e., within the first 24 h).
    • Increases within 1–3 h after the onset of the injury
    • Peaks at 8–12 h
    • Returns to normal within 24 h
Rise and fall of myoglobin and creatine kinase (CK) during the course of rhabdomyolysis
Rise and fall of myoglobin and creatine kinase (CK) during the course of rhabdomyolysis. Myoglobin is the first enzyme that increases, but returns to normal levels within the first 24 hours after onset of symptoms. CK increases a few hours later, reaches its peak value within the first 24 hours, and remains at these levels for 3 days. Even though the presence of myoglobin in serum is the key feature of rhabdomyolysis, CK is considered to be a more useful marker for the diagnosis and assessment of the severity of muscular injury due to its delayed clearance from the plasma and the wide availability for diagnostic testing. (Giannoglou et al, Copyright 2007 Elsevier)

Management

Treatment for rhabdomyolysis, at least initially, is mainly supportive, centering on the management of the ABCs (airway, breathing, circulation) and measures to preserve renal function, including vigorous rehydration.

Correct fluid & electrolyte abnormalities:

When rhabdomyolysis is suspected, regardless of the underlying etiology, one of the most important treatment goals is to avoid acute kidney injury. Because of the possible accumulation of fluids in muscular compartments and the associated hypovolemia, fluid management is imperative to prevent prerenal azotemia.
  • Aggressive hydration at a rate of 1.5 L/h, or
  • Normal saline: 500 mL/h alternated every hour with 500 mL/h of 5% glucose with 50 mmol of sodium bicarbonate for each subsequent 2-3 L of solution
  • A urinary output goal of 200 mL/h, urine pH >6.5, and plasma pH <7.5 should be achieved.
Aims of Early Vigorous Fluid Resuscitation in Rhabdomyolysis
Aims of Early Vigorous Fluid Resuscitation in Rhabdomyolysis | Better OS, Abassi ZA. Early fluid resuscitation in patients with rhabdomyolysis. Nat Rev Nephrol. 2011 May 17;7(7):416–422.

Treat compartment syndrome (if present):

Fasciotomy may be required in compartment syndrome to limit damage to muscles and kidneys.
Compartment syndrome and fasciotomy incisions
Compartment syndrome and fasciotomy incisions: 1. Normal anatomy of the right calf 2. Compartment syndrome 3. Fasciotomy incisions | Efstratiadis, G., Voulgaridou, A., Nikiforou, D., Kyventidis, A., Kourkouni, E., & Vergoulas, G. (2007). Rhabdomyolysis updated. Hippokratia, 11(3), 129–137.

Summary

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