Contents
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
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.
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.
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
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
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.
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.
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.
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.
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
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
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.
Treat compartment syndrome (if present):
Fasciotomy may be required in compartment syndrome to limit damage to muscles and kidneys.
Summary