| Rhabdomyolysis | |
|---|---|
 | |
| Urine from a person with rhabdomyolysis showing the characteristicbrown discoloration as a result ofmyoglobinuria | |
| Pronunciation | |
| Specialty | Critical care medicine,nephrology |
| Symptoms | Muscle pains, weakness,vomiting,confusion, tea-colored urine,irregular heartbeat[3][4] |
| Complications | Kidney failure,high blood potassium,low blood calcium,disseminated intravascular coagulation,compartment syndrome[3] |
| Causes | Crush injury, strenuous exercise,medications,substance use, certain infections[3] |
| Diagnostic method | Blood test (creatine kinase),urine test strip[3][5] |
| Treatment | Intravenous fluids,dialysis,hemofiltration[3] |
| Frequency | 26000 reported cases per year (U.S.)[3] |
Rhabdomyolysis (shortened asrhabdo) is a condition in which damagedskeletal muscle breaks down rapidly.[6][4][5] Symptoms may includemuscle pains, weakness,vomiting, andconfusion.[3][4] There may betea-colored urine or anirregular heartbeat.[3][5] Some of the muscle breakdown products, such as the proteinmyoglobin, are harmful to thekidneys and can causeacute kidney injury.[7][3]
The muscle damage is usually caused by acrush injury,strenuous exercise,medications, or asubstance use disorder.[3] Other causes includeinfections,electrical injury,heat stroke, prolonged immobilization,lack of blood flow to a limb, orsnake bites[3] as well as intense or prolonged exercise, particularly in hot conditions.[8]Statins (prescription drugs to lower cholesterol) are considered a small risk.[9] Some people haveinherited muscle conditions that increase the risk of rhabdomyolysis.[3] The diagnosis is supported by aurine test strip which is positive for "blood" but the urine contains nored blood cells whenexamined with a microscope.[3]Blood tests show acreatine kinase activity greater than1000 U/L, with severe disease being above5000–15000 U/L.[5]
The mainstay of treatment is large quantities ofintravenous fluids.[3] Other treatments may includedialysis orhemofiltration in more severe cases.[4][10] Once urine output is established,sodium bicarbonate andmannitol are commonly used but they are poorly supported by the evidence.[3][4] Outcomes are generally good if treated early.[3] Complications may includehigh blood potassium,low blood calcium,disseminated intravascular coagulation, andcompartment syndrome.[3]
Rhabdomyolysis is reported about 26,000 times a year in the United States.[3] It is a significant problem for those injured inearthquakes, and relief efforts for such disasters often include medical teams equipped to treat survivors with rhabdomyolysis.[11]
The wordrhabdomyolysis (/ˌræbdoʊmaɪˈɒlɪsɪs/) uses thecombining formsrhabdo- +myo- +-lysis, yielding "striated muscle breakdown".
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 abnormalblood tests in the context of other problems. More severe rhabdomyolysis is characterized bymuscle pain, tenderness,weakness, andswelling of the affected muscles.[10] If the swelling is very rapid, as may happen with acrush injury after someone is released from under heavy collapsed debris, the movement of fluid from the bloodstream into damaged muscle may causelow blood pressure andshock. Other symptoms arenonspecific and result either from the consequences of muscle tissue breakdown or from the condition that originally led to the muscle breakdown.[3][4][10] Release of the components of muscle tissue into the bloodstream causeselectrolyte disturbances, which can lead tonausea,vomiting,confusion,coma orabnormal heart rate and rhythm. The urine may be dark, often described as "tea-colored", due to the presence ofmyoglobin. Damage to the kidneys may give rise todecreased orabsent urine production, usually 12 to 24 hours after the initial muscle damage.[3][4]
Swelling of damaged muscle occasionally leads tocompartment syndrome—compression of surrounding tissues, such as nerves andblood vessels, in the samefascial 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][12] A second recognized complication isdisseminated intravascular coagulation (DIC), a severe disruption inblood clotting that may lead to uncontrollable bleeding.[3][4][12]
Any form of muscle damage of sufficient severity can cause rhabdomyolysis.[4] Multiple causes can be present simultaneously in one person.[10] Some have an underlying muscle condition, usually hereditary, that makes them more prone to rhabdomyolysis.[10][12]
| Type | Causes |
|---|---|
| Exercise-related | Extremephysical exercise (particularly when poorly hydrated),delirium tremens (alcohol withdrawal),tetanus, prolongedseizures orstatus epilepticus[4][10] |
| Crush | Crush syndrome,blast injury, car crash,physical torture orabuse, or confinement in a fixed position such as after astroke, due toalcohol intoxication or in prolongedsurgery[4][10] |
| Blood supply | Arterial thrombosis (blood clots forming locally) orembolism (clots or other debris from elsewhere in the body),clamping of an artery during surgery[4][10] |
| Metabolism | Hyperglycemic hyperosmolar state,hyper- andhyponatremia (elevated or reduced blood sodium levels),hypokalemia (low potassium levels),hypocalcemia (low calcium levels),hypophosphatemia (low phosphate levels),ketoacidosis (e.g., indiabetic ketoacidosis) orhypothyroidism (abnormally low thyroid function)[4][10][12] |
| Body temperature | Hyperthermia (high body temperature) andheat illness,hypothermia (very low body temperature)[4][10] |
| Drugs and toxins | Many medications increase the risk of rhabdomyolysis.[13] The most important ones are:[4][10][12]
Poisons linked to rhabdomyolysis areheavy metals andvenom from insects or snakes.[4]Hemlock may cause rhabdomyolysis, either directly orafter eating quail that have fed on it.[4][12] Fungi such asRussula subnigricans andTricholoma equestre are known to cause rhabdomyolysis.[15]Haff disease is rhabdomyolysis after consuming fish; a toxic cause is suspected but has not been proven.[16] Drugs of recreational use, includingalcohol,amphetamine,cocaine,heroin,ketamine andMDMA (ecstasy)[4][12] |
| Infection | Coxsackie virus,influenza A virus andinfluenza B virus,Epstein-Barr virus,primary HIV infection,Plasmodium falciparum (malaria),herpes viruses,Legionella pneumophila andsalmonella[4][10][12] |
| Inflammation | Autoimmune muscle damage:polymyositis,dermatomyositis[4][12] |
Recurrent or episodic rhabdomyolysis is commonly due to intrinsic muscle enzyme deficiencies, which are usually inherited and often appear during childhood.[10][13] 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.[10] Inherited muscle disorders and infections together cause the majority of rhabdomyolysis in children.[13]
The following hereditary disorders of the muscle energy supply may cause recurrent and usually exertional rhabdomyolysis:[10][13][17]
Damage to skeletal muscle may take various forms. Crush and other physical injuries cause damage tomuscle cells directly or interfere with blood supply, while non-physical causes interfere with muscle cellmetabolism. When damaged, muscle tissue rapidly fills with fluid from the bloodstream, includingsodium 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 thesarcoplasmic reticulum leads to continuousmuscle contraction and depletion ofATP, the main carrier of energy in the cell.[11][13] ATP depletion can itself lead to uncontrolled calcium influx.[10] The persistent contraction of the muscle cell leads to the breakdown of intracellular proteins and the disintegration of the cell.[10]
Neutrophil granulocytes—the most abundant type ofwhite blood cell—enter the muscle tissue, producing aninflammatory reaction and releasingreactive oxygen species,[11] particularly after crush injury.[10] Crush syndrome may also causereperfusion injury when blood flow to decompressed muscle is suddenly restored.[10]
The swollen, inflamed muscle may directly compress structures in the samefascial compartment, causingcompartment syndrome. The swelling may also further compromise the blood supply to the area. Finally, destroyed muscle cells release potassium ions,phosphate ions, theheme-containing proteinmyoglobin, theenzymecreatine kinase anduric acid (a breakdown product ofpurines fromDNA) into the blood. Activation of the coagulation system may precipitatedisseminated intravascular coagulation.[11]High potassium levels may lead to potentially fataldisruptions in heart rhythm. Phosphate binds to calcium from the circulation, leading tolow calcium levels in the blood.[11]
Rhabdomyolysis may cause kidney failure by several mechanisms. The most important is the accumulation of myoglobin in thekidney tubules.[10][11][13] Normally, the blood proteinhaptoglobin binds circulating myoglobin and other heme-containing substances, but in rhabdomyolysis the quantity of myoglobin exceeds the binding capacity of haptoglobin.[13]Myoglobinuria, the presence of myoglobin in the urine, occurs when the level inplasma exceeds0.5–1.5 mg/dL; once plasma levels reach100 mg/dL, the concentration in the urine becomes sufficient for it to be visibly discolored[10] and corresponds with the destruction of about 200 grams of muscle.[18] As the kidneys reabsorb more water from thefiltrate, myoglobin interacts withTamm–Horsfall protein in thenephron to formcasts (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.[10] 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 toconstriction 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 toacute tubular necrosis, the destruction of the cells of the tubules.[11][13]Glomerular filtration rate falls, and the kidney is unable to perform its normal excretory functions. This disrupts electrolyte regulation, leading to a further rise in potassium levels, and interferes withvitamin D processing, further worsening the low calcium levels.[11]
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 increasingcreatinine andurea levels, falling urine output) or reddish-brown discoloration of the urine.[4][11]
The most reliable test in the diagnosis of rhabdomyolysis is the level ofcreatine kinase (CK) in the blood.[5] This enzyme is released by damaged muscle, and levels above1000 U/L (5 times the upper limit of normal (ULN)) indicate rhabdomyolysis.[5] More than5000 U/L indicates severe disease, but depending on the extent of the rhabdomyolysis, concentrations up to100000 U/l are not unusual.[5][11] CK concentrations rise steadily for 12 hours after the original muscle injury, remain elevated for1–3 days and then fall gradually.[4] 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.[19] There is no specific concentration of CK above which kidney impairment definitely occurs; concentrations below20000 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".[10][18] Myoglobin has a short half-life, and is therefore less useful as a diagnostic test in the later stages.[4] Its detection in blood or urine is associated with a higher risk of kidney impairment.[19] Despite this, the use of urine myoglobin measurement is not supported by evidence as it lacksspecificity and the research studying its utility is of poor quality.[20]
Elevated concentrations of the enzymelactate dehydrogenase (LDH) may be detected.[13][19] Other markers of muscle damage, such asaldolase,troponin,carbonic anhydrase type 3 andfatty acid-binding protein (FABP), are mainly used in chronic muscle diseases.[19] Thetransaminases, enzymes abundant in both liver and muscle tissue, are also usually increased; this can lead to the condition being confused with acute liver injury, at least in the early stages. The incidence of actual acute liver injury is 25% in people with non-traumatic rhabdomyolysis; the mechanism for this is uncertain.[4]
High potassium levels tend to be a feature of severe rhabdomyolysis.[4]Electrocardiography (ECG) may show whether the elevated potassium levels are affecting the conduction system of the heart, as suggested by the presence ofT wave changes or broadening of theQRS complex.[21] Lowcalcium levels may be present in the initial stage due to binding of free calcium to damaged muscle cells.[4]
As detectable levels ofmyoglobinemia andmyoglobinuria occur,blood tests andurine tests may show elevated levels of myoglobin. For example, aurine test strip may reveal a positive result for "blood", even though nored blood cells can be identified onmicroscopy of the urine; this occurs because the reagent on the test strip reacts with myoglobin.[11] The same phenomenon may happen in conditions that lead tohemolysis, the destruction of red blood cells; in hemolysis, theblood serum is also visibly discolored, while in rhabdomyolysis it is normal.[13][18] If kidney damage has occurred, microscopy of the urine also revealsurinary casts that appear pigmented and granular.[10]
Compartment syndrome is a clinical diagnosis, i.e., nodiagnostic test conclusively proves its presence or absence, but direct measurement of the pressure in a fascial compartment,[11] and the difference between this pressure and the blood pressure,[22] may be used to assess its severity. High pressures in the compartment and a small difference between compartment pressure and blood pressure indicate that the blood supply is likely to be insufficient, and that surgical intervention may be needed.[22][23]
Disseminated intravascular coagulation, another complication of rhabdomyolysis and other forms of critical illness, may be suspected based on unexpected bleeding or abnormalities in hematological tests, such as a decreasingplatelet count or prolongation of theprothrombin time. The diagnosis can be confirmed with standard blood tests for DIC, such asD-dimer.[24]
If an underlying muscle disease is suspected, for instance, if there is no obvious explanation or there have been multiple episodes, it may be necessary to perform further investigations.[13] During an attack, low levels ofcarnitine in the blood and high levels of acylcarnitine in blood and urine may indicate a lipid metabolism defect, but these abnormalities revert to normal during convalescence. Other tests may be used at that stage to demonstrate these disorders.[12] Disorders ofglycolysis can be detected by various means, including the measurement oflactate after exercise; a failure of the lactate to rise may be indicative of a disorder in glycolysis,[12] while an exaggerated response is typical ofmitochondrial diseases.[17]Electromyography (EMG) may show particular patterns in specific muscle diseases; for instance,McArdle's disease andphosphofructokinase deficiency show a phenomenon calledcramp-like contracture.[18] There are genetic tests available for many of the hereditary muscle conditions that predispose to myoglobinuria and rhabdomyolysis.[12][13]
Muscle biopsy can be useful if an episode of rhabdomyolysis is thought to be the result of an underlying muscle disorder. A biopsy sample taken during an episode is often uninformative, as it will show only evidence ofcell death or may appear normal. Taking the sample is therefore delayed for several weeks or months.[10] Thehistopathological appearance on the biopsy indicates the nature of the underlying disorder. For instance, mitochondrial diseases are characterized byragged red fibers.[12] Biopsy sites may be identified bymedical imaging, such asmagnetic resonance imaging, as the muscles may not be uniformly affected.[17]
The main goal of treatment is to treat shock and preserve kidney function. Initially, this is done through the administration of generous amounts ofintravenous fluids, usuallyisotonic saline (0.9%weight per volumesodium chloride solution). In victims of crush syndrome, it is recommended to administer intravenous fluids even before they are extracted from collapsed structures.[11][25] 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.[11] Amounts of 6 to 12 liters over 24 hours are recommended.[11][26] The rate of fluid administration may be altered to achieve a high urine output (200–300 mL/h in adults),[12][26] unless there are other reasons why this might lead to complications, such as a history ofheart failure.[26]
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.[13]Mannitol acts byosmosis 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.[10] The addition ofbicarbonate to the intravenous fluids may alleviateacidosis (high acid level of the blood) and make the urine morealkaline to prevent cast formation in the kidneys;[10][12] 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][11][13] If urine alkalinization is used, the pH of the urine is kept at 6.5 or above.[26]Furosemide, aloop diuretic, is often used to ensure sufficient urine production,[4][11] but evidence that this prevents kidney failure is lacking.[27]
In the initial stages, electrolyte levels are often abnormal and require correction. High potassium levels can be life-threatening, and respond to increased urine production andrenal replacement therapy (see below).[12]Temporary measures include the administration of calcium to protect against cardiac complications,insulin orsalbutamol to redistribute potassium into cells, and infusions of bicarbonate solution.[21]
Calcium levels initially tend to be low, but as the situation improves, calcium is released from where it has precipitated with phosphate, and vitamin D production resumes, leading tohypercalcemia (abnormally high calcium levels). This "overshoot" occurs in 20–30% of those people who have developed kidney failure.[4][13]
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.[13] 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 andperitoneal dialysis. The former two require access to the bloodstream (adialysis catheter), and peritoneal dialysis is achieved by instilling fluid into the abdominal cavity and later draining it. Hemodialysis, which is normally done several times a week inchronic kidney disease, is often required daily in rhabdomyolysis. Its advantage over continuous hemofiltration is that one machine can be used multiple times a day, and that continuous administration ofanticoagulant drugs is not necessary.[11][25] Hemofiltration is more effective at removing large molecules from the bloodstream, such as myoglobin,[13] but this does not seem to confer any particular benefit.[4][11] Peritoneal dialysis may be difficult to administer in someone with severe abdominal injury,[11] and it may be less effective than the other modalities.[4]
Compartment syndrome is treated with surgery to relieve the pressure inside the muscle compartment and reduce the risk of compression on blood vessels and nerves in that area.Fasciotomy is the incision of the affected compartment. Often, multiple incisions are made and left open until the swelling has reduced. At that point, the incisions are closed, often requiringdebridement (removal of non-viable tissue) andskin grafting in the process.[23] The need for fasciotomy may be decreased if mannitol is used, as it can relieve muscle swelling directly.[25][26]
Disseminated intravascular coagulation generally resolves when the underlying causes are treated, butsupportive measures are often required. For instance, if theplatelet count drops significantly and there is resultant bleeding, platelets may be administered.[28]
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 amortality 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.[10] Most people who have sustained kidney impairment due to rhabdomyolysis fully recover their kidney function.[10]
The exact number of cases of rhabdomyolysis is difficult to establish because different definitions have been used.[3][10] 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][10] 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.[10] Rhabdomyolysis accounts for 7–10% of all cases of acute kidney injury in the U.S.[10][13]
Crush injuries are common in major disasters, especially in earthquakes. The aftermath of the1988 Spitak earthquake prompted the establishment, in 1995, of the Renal Disaster Relief Task Force, a working group of theInternational Society of Nephrology (a worldwide body of kidney experts). Its volunteer doctors and nurses assisted for the first time in the1999 İzmit earthquake inTurkey, 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, asaftershocks could potentially injure or kill staff and make equipment unusable.[4][25]
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.[29] Another group at increased risk is firefighters.[30][31]
The Bible may contain an early account of rhabdomyolysis. TheBook of Numbers says that while traveling in the desert, people ate large quantities of quail meat, after which an illness killed numerous people. Rhabdomyolysis after consuming quail was described in more recent times and calledcoturnism (afterCoturnix, the main quail genus).[12][32] Migrating quail consume large amounts ofhemlock, a known cause of rhabdomyolysis.[4]
In modern times, early reports from the1908 Messina earthquake and World War I on kidney failure after injury were followed by studies by London physiciansEric Bywaters andDesmond Beall, working at theRoyal Postgraduate Medical School and theNational Institute for Medical Research, on four victims ofthe Blitz in 1941.[12][33][34] Myoglobin was demonstrated in the urine of victims byspectroscopy, and it was noted that the kidneys of victims resembled those of patients who hadhemoglobinuria (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.[11][34] 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.[34] The prognosis of acute kidney failure improved markedly when dialysis was added to supportive treatment, which first happened during the 1950–1953Korean War.[35]
Rhabdomyolysis is recognized in horses.[36] Horses can develop several muscle disorders, many of which may progress to rhabdomyolysis. Of these, some cause isolated attacks of rhabdomyolysis (e.g., dietary deficiency invitamin E andselenium, poisoning associated with pasture or agricultural poisons such asorganophosphates), while others predispose to exertional rhabdomyolysis (e.g., the hereditary conditionequine polysaccharide storage myopathy).[37] 5–10% ofthoroughbred horses and somestandardbred horses have the conditionequine exertional rhabdomyolysis; no specific cause has been identified, but an underlying muscle calcium regulation disorder is suspected.[37]
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,[38] and a seasonal pattern has been observed.[37] Very high creatine kinase levels are detected, and mortality from this condition is 89%.[37]
Media related toRhabdomyolysis at Wikimedia Commons