rhabdomyolysis rhabdomyolysis rhabdomyolysis (also called rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. symptoms may include muscle pains, weakness, vomiting, and confusion. there may be tea-colored urine or an irregular heartbeat. some of the muscle breakdown products, such as the protein myoglobin, are harmful to the kidneys and can cause acute kidney injury. rhabdomyolysisurine from a person with rhabdomyolysis showing the characteristic brown discoloration as a result of myoglobinuriapronunciation/ˌræbdoʊmaɪˈɒlɪsɪs/ specialtycritical care medicine, nephrologysymptomsmuscle pains, weakness, vomiting, confusion, tea-colored urine, irregular heartbeatcomplicationskidney failure, high blood potassium, low blood calcium, disseminated intravascular coagulation, compartment syndromecausescrush injury, strenuous exercise, medications, substance use, certain infectionsdiagnostic methodblood test (creatine kinase), urine test striptreatmentintravenous fluids, dialysis, hemofiltrationfrequency26,000 reported cases per year (u.s.) the muscle damage is mostly caused by a crush injury, strenuous exercise, medications, or a substance use disorder. other causes include infections, electrical injury, heat stroke, prolonged immobilization, lack of blood flow to a limb, or snake bites. statins (prescription drugs to lower cholesterol) are considered a small risk. some people have inherited muscle conditions that increase the risk of rhabdomyolysis. the diagnosis is supported by a urine test strip which is positive for "blood" but the urine contains no red blood cells when examined with a microscope. blood tests show a creatine kinase activity greater than 1,000 u/l, with severe disease being above 5,000-15,000 u/l. the mainstay of treatment is large quantities of intravenous fluids. other treatments may include dialysis or hemofiltration in more severe cases. once urine output is established, sodium bicarbonate and mannitol are commonly used but they are poorly supported by the evidence. outcomes are generally good if treated early. complications may include high blood potassium, low blood calcium, disseminated intravascular coagulation, and compartment syndrome. rhabdomyolysis is reported about 26,000 times a year in the united states. while the condition has been commented on throughout history, the first modern description was following an earthquake in 1908. important discoveries as to its mechanism were made during the blitz of london in 1941. it is a significant problem for those injured in earthquakes, and relief efforts for such disasters often include medical teams equipped to treat survivors with rhabdomyolysis. signs and symptoms the symptoms of rhabdomyolysis depend on its severity and whether kidney failure develops. milder forms may not cause any muscle symptoms, and the diagnosis is based on abnormal blood tests in the context of other problems. more severe rhabdomyolysis is characterized by muscle pain, tenderness, weakness and swelling of the affected muscles. if the swelling is very rapid, as may happen with a crush injury after someone is released from under heavy collapsed debris, the movement of fluid from the bloodstream into damaged muscle may cause low blood pressure and shock. other symptoms are nonspecific and result either from the consequences of muscle tissue breakdown or from the condition that originally led to the muscle breakdown. release of the components of muscle tissue into the bloodstream causes electrolyte disturbances, which can lead to nausea, vomiting, confusion, coma or abnormal heart rate and rhythm. the urine may be dark, often described as "tea-colored", due to the presence of myoglobin. damage to the kidneys may give rise to decreased or absent urine production, usually 12 to 24 hours after the initial muscle damage. swelling of damaged muscle occasionally leads to compartment syndrome—compression of surrounding tissues, such as nerves and blood vessels, in the same fascial compartment—leading to the loss of blood supply and damage or loss of function in the part(s) of the body supplied by these structures. symptoms of this complication include pain or reduced sensation in the affected limb. a second recognized complication is disseminated intravascular coagulation (dic), a severe disruption in blood clotting that may lead to uncontrollable bleeding. causes any form of muscle damage of sufficient severity can cause rhabdomyolysis. multiple causes can be present simultaneously in one person. some have an underlying muscle condition, usually hereditary in nature, that makes them more prone to rhabdomyolysis. common and important causes type causes exercise related extreme physical exercise (particularly when poorly hydrated), delirium tremens (alcohol withdrawal), tetanus, prolonged seizures or status epilepticus crush crush syndrome, blast injury, car accident, physical torture or abuse, or confinement in a fixed position such as after a stroke, due to alcohol intoxication or in prolonged surgery blood supply arterial thrombosis (blood clots forming locally) or embolism (clots or other debris from elsewhere in the body), clamping of an artery during surgery metabolism hyperglycemic hyperosmolar state, hyper- and hyponatremia (elevated or reduced blood sodium levels), hypokalemia (low potassium levels), hypocalcemia (low calcium levels), hypophosphatemia (low phosphate levels), ketoacidosis (e.g., in diabetic ketoacidosis) or hypothyroidism (abnormally low thyroid function) body temperature hyperthermia (high body temperature) and heat illness, hypothermia (very low body temperature) drugs and toxins many medications increase the risk of rhabdomyolysis. the most important ones are: statins and fibrates, both used for elevated cholesterol, especially in combination; cerivastatin (baycol) was withdrawn in 2001 after numerous reports of rhabdomyolysis. other statins have a small risk of 0.44 cases per 10,000 person-years. previous chronic kidney disease and hypothyroidism increase the risk of myopathy due to statins. it is also more common in the elderly, those who are severely disabled, and when statins are used in combination with particular other medicines, such as ciclosporin. antipsychotic medications may cause neuroleptic malignant syndrome, which can cause severe muscle rigidity with rhabdomyolysis and hyperpyrexia neuromuscular blocking agents used in anesthesia may result in malignant hyperthermia, also associated with rhabdomyolysis medications that cause serotonin syndrome, such as ssris medications that interfere with potassium levels, such as diuretics poisons linked to rhabdomyolysis are heavy metals and venom from insects or snakes. hemlock may cause rhabdomyolysis, either directly or after eating quail that have fed on it. fungi such as russula subnigricans and tricholoma equestre are known to cause rhabdomyolysis. haff disease is rhabdomyolysis after consuming fish; a toxic cause is suspected but has not been proven. drugs of recreational use, including: alcohol, amphetamine, cocaine, heroin, ketamine and mdma (ecstasy) infection coxsackie virus, influenza a virus and influenza b virus, epstein-barr virus, primary hiv infection, plasmodium falciparum (malaria), herpes viruses, legionella pneumophila and salmonella inflammation autoimmune muscle damage: polymyositis, dermatomyositis genetic predisposition recurrent rhabdomyolysis may result from intrinsic muscle enzyme deficiencies, which are usually inherited and often appear during childhood. many structural muscle diseases feature episodes of rhabdomyolysis that are triggered by exercise, general anesthesia or any of the other causes of rhabdomyolysis listed above. inherited muscle disorders and infections together cause the majority of rhabdomyolysis in children. the following hereditary disorders of the muscle energy supply may cause recurrent and usually exertional rhabdomyolysis: glycolysis and glycogenolysis defects: mcardle's disease, phosphofructokinase deficiency, glycogen storage diseases viii, ix, x and xi lipid metabolism defects: carnitine palmitoyltransferase i and ii deficiency, deficiency of subtypes of acyl coa dehydrogenase (lcad, scad, mcad, vlcad, 3-hydroxyacyl-coenzyme a dehydrogenase deficiency), thiolase deficiency mitochondrial myopathies: deficiency of succinate dehydrogenase, cytochrome c oxidase and coenzyme q10 others: glucose-6-phosphate dehydrogenase deficiency, myoadenylate deaminase deficiency and muscular dystrophies mechanism schematic diagram of myoglobin, a heme-containing protein that participates in oxygen storage in normal muscle but is responsible for kidney damage in rhabdomyolysis damage to skeletal muscle may take various forms. crush and other physical injuries cause damage to muscle cells directly or interfere with blood supply, while non-physical causes interfere with muscle cell metabolism. when damaged, muscle tissue rapidly fills with fluid from the bloodstream, including sodium ions. the swelling itself may lead to destruction of muscle cells, but those cells that survive are subject to various disruptions that lead to rise in intracellular calcium ions; the accumulation of calcium outside the sarcoplasmic reticulum leads to continuous muscle contraction and depletion of atp, the main carrier of energy in the cell. atp depletion can itself lead to uncontrolled calcium influx. the persistent contraction of the muscle cell leads to breakdown of intracellular proteins and disintegration of the cell. neutrophil granulocytes—the most abundant type of white blood cell—enter the muscle tissue, producing an inflammatory reaction and releasing reactive oxygen species, particularly after crush injury. crush syndrome may also cause reperfusion injury when blood flow to decompressed muscle is suddenly restored. the swollen, inflamed muscle may directly compress structures in the same fascial compartment, causing compartment syndrome. the swelling may also further compromise blood supply into the area. finally, destroyed muscle cells release potassium ions, phosphate ions, the heme-containing protein myoglobin, the enzyme creatine kinase and uric acid (a breakdown product of purines from dna) into the blood. activation of the coagulation system may precipitate disseminated intravascular coagulation. high potassium levels may lead to potentially fatal disruptions in heart rhythm. phosphate binds to calcium from the circulation, leading to low calcium levels in the blood. rhabdomyolysis may cause kidney failure by several mechanisms. the most important is the accumulation of myoglobin in the kidney tubules. normally, the blood protein haptoglobin binds circulating myoglobin and other heme-containing substances, but in rhabdomyolysis the quantity of myoglobin exceeds the binding capacity of haptoglobin. myoglobinuria, the presence of myoglobin in the urine, occurs when the level in plasma exceeds 0.5–1.5 mg/dl; once plasma levels reach 100 mg/dl, the concentration in the urine becomes sufficient for it to be visibly discolored and corresponds with the destruction of about 200 grams of muscle. as the kidneys reabsorb more water from the filtrate, myoglobin interacts with tamm–horsfall protein in the nephron to form casts (solid aggregates) that obstruct the normal flow of fluid; the condition is worsened further by high levels of uric acid and acidification of the filtrate, which increase cast formation. iron released from the heme generates reactive oxygen species, damaging the kidney cells. in addition to the myoglobinuria, two other mechanisms contribute to kidney impairment: low blood pressure leads to constriction of the blood vessels and therefore a relative lack of blood flow to the kidney, and finally uric acid may form crystals in the tubules of the kidneys, causing obstruction. together, these processes lead to acute tubular necrosis, the destruction of the cells of tubules. glomerular filtration rate falls and the kidney is unable to perform its normal excretory functions. this causes disruption of electrolyte regulation, leading to a further rise in potassium levels, and interferes with vitamin d processing, further worsening the low calcium levels. diagnosis the m-subunit of creatine kinase. in skeletal muscle, creatine kinase exists predominantly in dimers containing two m-subunits, also referred to as "ck-mm". a diagnosis of rhabdomyolysis may be suspected in anyone who has sustained trauma, crush injury or prolonged immobilization, but it may also be identified at a later stage due to deteriorating kidney function (abnormally raised or increasing creatinine and urea levels, falling urine output) or reddish-brown discoloration of the urine. general investigations the most reliable test in the diagnosis of rhabdomyolysis is the level of creatine kinase (ck) in the blood. this enzyme is released by damaged muscle, and levels above 1000 u/l (5 times the upper limit of normal (uln)) indicate rhabdomyolysis. more than 5,000 u/l indicates severe disease but depending on the extent of the rhabdomyolysis, concentrations up to 100,000 u/l are not unusual. ck concentrations rise steadily for 12 hours after the original muscle injury, remain elevated for 1–3 days and then fall gradually. initial and peak ck levels have a linear relationship with the risk of acute kidney failure: the higher the ck, the more likely it is that kidney damage will occur. there is no specific concentration of ck above which kidney impairment definitely occurs; concentrations below 20,000 u/l are unlikely to be associated with a risk of kidney impairment, unless there are other contributing risk factors. mild rises without kidney impairment are referred to as "hyperckemia". myoglobin has a short half-life, and is therefore less useful as a diagnostic test in the later stages. its detection in blood or urine is associated with a higher risk of kidney impairment. despite this, use of urine myoglobin measurement is not supported by evidence as it lacks specificity and the research studying its utility is of poor quality. elevated concentrations of the enzyme lactate dehydrogenase (ldh) may be detected. other markers of muscle damage, such as aldolase, troponin, carbonic anhydrase type 3 and fatty acid-binding protein (fabp), are mainly used in chronic muscle diseases. the transaminases, enzymes abundant in