Rhabdomyolysis

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.[6] 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.[3][4][6] 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.[3][4]

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.[3][8] A second recognized complication is disseminated intravascular coagulation (DIC), a severe disruption in blood clotting that may lead to uncontrollable bleeding.[3][4][8]

Any form of muscle damage of sufficient severity can cause rhabdomyolysis.[4] Multiple causes can be present simultaneously in one person.[6] Some have an underlying muscle condition, usually hereditary in nature, that makes them more prone to rhabdomyolysis.[6][8]

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.[7][9] ATP depletion can itself lead to uncontrolled calcium influx.[6] The persistent contraction of the muscle cell leads to breakdown of intracellular proteins and disintegration of the cell.[6]

Neutrophil granulocytes—the most abundant type of white blood cell—enter the muscle tissue, producing an inflammatory reaction and releasing reactive oxygen species,[7] particularly after crush injury.[6] Crush syndrome may also cause reperfusion injury when blood flow to decompressed muscle is suddenly restored.[6]

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.[7] 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.[7]

Rhabdomyolysis may cause kidney failure by several mechanisms. The most important is the accumulation of myoglobin in the kidney tubules.[6][7][9] 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.[9] 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[6] and corresponds with the destruction of about 200 grams of muscle.[15] 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.[6] 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.[7][9] 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.[7]

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 suffered 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.[4][7]

The main goal of treatment is to treat shock and preserve kidney function. Initially this is done through the administration of generous amounts of intravenous fluids, usually isotonic saline (0.9% weight per volume sodium chloride solution). In victims of crush syndrome, it is recommended to administer intravenous fluids even before they are extracted from collapsed structures.[7][22] This will ensure sufficient circulating volume to deal with the muscle cell swelling (which typically commences when blood supply is restored), and to prevent the deposition of myoglobin in the kidneys.[7] Amounts of 6 to 12 liters over 24 hours are recommended.[7][23] The rate of fluid administration may be altered to achieve a high urine output (200–300 ml/h in adults),[8][23] unless there are other reasons why this might lead to complications, such as a history of heart failure.[23]

While many sources recommend additional intravenous agents to reduce damage to the kidney, most of the evidence supporting this practice comes from animal studies, and is inconsistent and conflicting.[9] Mannitol acts by osmosis to enhance urine production and is thought to prevent myoglobin deposition in the kidney, but its efficacy has not been shown in studies and there is a risk of worsening kidney function.[6] The addition of bicarbonate to the intravenous fluids may alleviate acidosis (high acid level of the blood) and make the urine more alkaline to prevent cast formation in the kidneys;[6][8] evidence suggesting that bicarbonate has benefits above saline alone is limited, and it can worsen hypocalcemia by enhancing calcium and phosphate deposition in the tissues.[4][7][9] If urine alkalinization is used, the pH of the urine is kept at 6.5 or above.[23] Furosemide, a loop diuretic, is often used to ensure sufficient urine production,[4][7] but evidence that this prevents kidney failure is lacking.[24]

Acute kidney impairment

A hemofiltration machine

Kidney dysfunction typically develops 1–2 days after the initial muscle damage.[4] If supportive treatment is inadequate to manage this, renal replacement therapy (RRT) may be required.[9] RRT removes excess potassium, acid and phosphate that accumulate when the kidneys are unable to function normally and is required until kidney function is regained.[4]

Three main modalities of RRT are available: hemodialysis, continuous hemofiltration and peritoneal dialysis. The former two require access to the bloodstream (a dialysis catheter), while peritoneal dialysis is achieved by instilling fluid into the abdominal cavity and later draining it. Hemodialysis, which is normally done several times a week in chronic kidney disease, is often required on a daily basis in rhabdomyolysis. Its advantage over continuous hemofiltration is that one machine can be used multiple times a day, and that continuous administration of anticoagulant drugs is not necessary.[7][22] Hemofiltration is more effective at removing large molecules from the bloodstream, such as myoglobin,[9] but this does not seem to confer any particular benefit.[4][7] Peritoneal dialysis may be difficult to administer in someone with severe abdominal injury,[7] and it may be less effective than the other modalities.[4]

The prognosis depends on the underlying cause and whether any complications occur. Rhabdomyolysis complicated by acute kidney impairment in patients with traumatic injury may have a mortality rate of 20%.[4] Admission to the intensive care unit is associated with a mortality of 22% in the absence of acute kidney injury, and 59% if kidney impairment occurs.[6] Most people who have sustained kidney impairment due to rhabdomyolysis fully recover their kidney function.[6]

The exact number of cases of rhabdomyolysis is difficult to establish because different definitions have been used.[3][6] In 1995, hospitals in the U.S. reported 26,000 cases of rhabdomyolysis.[3] Up to 85% of people with major traumatic injuries will experience some degree of rhabdomyolysis.[4] Of those with rhabdomyolysis, 10–50% develop acute kidney injury.[4][6] The risk is higher in people with a history of illicit drug use, alcohol misuse or trauma when compared to muscle diseases, and it is particularly high if multiple contributing factors occur together.[6] Rhabdomyolysis accounts for 7–10% of all cases of acute kidney injury in the U.S.[6][9]

Crush injuries are common in major disasters, especially in earthquakes. The aftermath of the 1988 Spitak earthquake prompted the establishment, in 1995, of the Renal Disaster Relief Task Force, a working group of the International Society of Nephrology (a worldwide body of kidney experts). Its volunteer doctors and nurses assisted for the first time in the 1999 İzmit earthquake in Turkey, where 17,480 people died, 5392 were hospitalized and 477 received dialysis, with positive results. Treatment units are generally established outside the immediate disaster area, as aftershocks could potentially injure or kill staff and make equipment unusable.[4][22]

Acute exertional rhabdomyolysis happens in 2% to 40% of people going through basic training for the United States military. In 2012, the United States military reported 402 cases.[26] Another group at increased risk is firefighters.[27][28]

Investigations of people injured in collapsed buildings during the Blitz of London led to numerous discoveries in the mechanisms underlying kidney impairment in rhabdomyolysis.

The Bible may contain an early account of rhabdomyolysis. In Numbers 11:4–6,31–33, the Pentateuch says that the Jews demanded meat while traveling in the desert; God sent quail in response to the complaints, and people ate large quantities of quail meat. A plague then broke out, killing numerous people. Rhabdomyolysis after consuming quail was described in more recent times and called coturnism (after Coturnix, the main quail genus).[8][29] Migrating quail consume large amounts of hemlock, a known cause of rhabdomyolysis.[4]

In modern times, 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.[8][30][31] 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.[7][31] 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.[31] The prognosis of acute kidney failure improved markedly when dialysis was added to supportive treatment, which first happened during the 1950–1953 Korean War.[32]

The word rhabdomyolysis ( /ˌræbdoʊmaɪˈɒlɪsɪs/) uses the combining forms rhabdo- + myo- + -lysis, yielding "striated muscle breakdown".

Rhabdomyolysis is recognized in horses.[33] Horses can develop a number of muscle disorders, many of which may progress to rhabdomyolysis. Of these, some cause isolated attacks of rhabdomyolysis (e.g., dietary deficiency in vitamin E and selenium, poisoning associated with pasture or agricultural poisons such as organophosphates), while others predispose to exertional rhabdomyolysis (e.g., the hereditary condition equine polysaccharide storage myopathy).[34] 5–10% of thoroughbred horses and some standardbred horses suffer from the condition equine exertional rhabdomyolysis; no specific cause has been identified, but an underlying muscle calcium regulation disorder is suspected.[34]

Rhabdomyolysis affecting horses may also occur in outbreaks; these have been reported in many European countries, and later in Canada, Australia, and the United States. It has been referred to as "atypical myopathy" or "myoglobinuria of unknown etiology". No single cause has yet been found, but various mechanisms have been proposed,[35] and a seasonal pattern has been observed.[34] Very high creatine kinase levels are detected, and mortality from this condition is 89%.[34]