Rhabdomyolysis

Etiology

The etiology of rhabdomyolysis can be classified into two broad categories: traumatic or physical causes and nontraumatic or nonphysical causes.[11] Many situations are multifactorial, and it is possible that genetic susceptibility, along with one or more external insults, causes rhabdomyolysis.[12] 

Careful history-taking, a comprehensive physical examination, and laboratory studies can help identify the cause of rhabdomyolysis. In addition, multiple cohort studies have shown different causes at different frequencies for rhabdomyolysis depending on the hospital location and community behaviors. 

Traumatic or Physical Causes

Traumatic or physical compression rhabdomyolysis can occur in different settings. Subclinical elevation of creatinine phosphokinase, myoglobinemia, and myoglobinuria following physical exertion is common.

Some traumatic etiologies include the following:

• Polytrauma, motor vehicle accidents, mining accidents, and earthquakes, particularly in patients who are trapped
• Prolonged immobilization due to coma, intoxication with alcohol or opioids, hip fracture, and surgeries requiring specific positions for a long duration [13]
• Abuse, torture, and the physical restraint of children
• Fractures of lower extremities (tibial fracture) causing arterial occlusion from prolonged immobilization, tourniquet, or surgical clamping [14]
• Fire accidents and explosions
• High voltage electric shock and lightning strikes, which also cause direct injury to the sarcoplasmic membrane, with massive calcium influx, along with severe rhabdomyolysis [15]
• Strenuous muscular exercise (especially in untrained individuals), lifting heavy weights, performing under exceedingly hot conditions, status epilepticus, tetanus, and rarely sepsis [16][17]

Nontraumatic or Nonphysical Causes

Nontraumatic causes of rhabdomyolysis can occur from a mismatch between oxygen supply and demand, electrolyte changes, and metabolic abnormalities.

• Medications: rhabdomyolysis is a common adverse effect of many medications, particularly statins.
• Infections: viral myositis is most common, and recently, SARS-CoV-2 is commonly associated with rhabdomyolysis.[18] See below for sepsis/bacterial infection. 
• Electrolyte abnormalities: hypokalemia, hypophosphatemia, hyperosmolar conditions, hypo- and hypercalcemia, and severe dehydration.[19]
• Endocrine: hyperosmolar hyperglycemic state, diabetic ketoacidosis with coma, myxedema.
• Congenital myopathies: most common are myotonic dystrophy, Duchenne muscular dystrophy, and Becker muscular dystrophy. See below for further details.[20]
• Toxins: insect bite, snake venom, hornet sting, carbon monoxide, Haff disease, and mushroom poisoning.[21]
• Autoimmune myositis: polymyositis, dermatomyositis. Please see StatPearls' companion references, "Dermatomyositis" and "Polymyositis."
• Dysregulated body temperature: neuroleptic malignant syndrome, malignant hyperthermia, near drowning, hypothermia, and frostbite.[22] Please see StatPearls' companion references, "Neuroleptic Malignant Syndrome" and "Malignant Hyperthermia."
• Supplements: over-the-counter vitamins, performance-enhancing supplements, and weight-loss supplements.
• Capillary leak syndrome: caused by muscle edema. [23]
• Drugs: Both drug intoxication and drug withdrawal can cause rhabdomyolysis.

Statins 

Statins are the most common pharmaceutical to cause rhabdomyolysis. Up to 10% of patients taking statins experience muscle pain.[3] With the increased use of lipid-lowering drugs, the incidence of rhabdomyolysis from HMG Co-A inhibitors is rising. Muscle toxicity from statins ranges from myopathy, myalgia, myositis, and rhabdomyolysis. Proposed mechanisms are CoQ10 depletion-causing myocyte mitochondrial dysfunction, disruption of cellular respiration, impaired calcium homeostasis, induction of apoptosis, and anti-HMG Co-A inhibitors. Statins commonly cause toxic myopathy, associated with no muscle necrosis and CPK less than 1000 U/L, and rarely autoimmune myopathy, associated with CPK greater than 1000 U/L and muscle necrosis.[24]

Discontinuation of statins is an effective treatment method for statin-induced rhabdomyolysis. However, persistent elevation of CPK after discontinuation of statins should raise concern for necrotizing autoimmune myopathy. Concomitant use of other medications like gemfibrozil, cyclosporine, cytochrome P450 inhibitors, and corticosteroids poses an increased risk for statin-induced rhabdomyolysis. Clinically significant rhabdomyolysis requiring hospital admission was noted in about 0.44 per 10000 patients treated with atorvastatin, simvastatin, and pravastatin as monotherapy. Even though the incidence of rhabdomyolysis is very low with statin use, in clinical practice, muscle-related side effects are a frequent cause for discontinuation of statin therapy. Use of the lowest tolerable statin dose is recommended in patients with a history of drug-induced rhabdomyolysis.[24][25]

Drug Intoxication

Intoxicants can cause rhabdomyolysis via various mechanisms. Cocaine is a well-known instigator of rhabdomyolysis. The mechanisms involve increased sympathetic stimulation of alpha receptors in the vasculature, increased endothelin production, and decreased nitrous oxide concentrations. Cocaine is also thrombogenic, as it activates platelets and inhibits plasminogen.[26]

One study found the highest incidence of drug-induced rhabdomyolysis in those who used heroin intravenously, thought to be from local mechanical trauma from injection, with possible immune mechanisms contributing. Amphetamines also have a high rate of rhabdomyolysis, thought to be due to hyperthermia caused by amphetamine's effects on serotonin, dopamine, and norepinephrine. Alcohol, opiates, phenobarbital, and benzodiazepines may cause mechanical trauma from lying in one position for an extended period while intoxicated.[17]  Withdrawal from opioids and baclofen (particularly intrathecal baclofen) has also been associated with rhabdomyolysis.[27][28] Patients with alcohol misuse disorder often have rhabdomyolysis related to direct muscle toxicity of alcohol as well as other insults, such as hypophosphatemia and hypokalemia.[29]

Intensive Care Admission

Admission to the intensive care unit (ICU) is also highly correlated with rhabdomyolysis.[2][18] ICU patients are severely ill, on multiple medications, and prone to electrolyte abnormalities; all of these factors predispose to rhabdomyolysis.[30] In addition, patients who are ventilated often receive propofol, and propofol infusion syndrome (PRIS) must be considered. PRIS is a manifestation of propofol toxicity, which is thought to result in uncoupled oxidative phosphorylation in the mitochondrial electron transport chain. This results in metabolic acidosis, rhabdomyolysis, arrhythmias, acute kidney injury, and cardiovascular collapse.[2] Please see StatPearls' companion reference, "Propofol Toxicity," for further information

Congenital Myopathies 

The number of congenital myopathies that can cause rhabdomyolysis is too numerous to list. Some common congenital myopathies that are known to cause rhabdomyolysis include:

Disorders of glycogenolysis: myophosphorylase deficiency (McArdle disease) and phosphorylase kinase deficiency

Disorders of glycolysis: phosphofructokinase, phosphoglycerate kinase, mutase, and lactate dehydrogenase deficiencies

Disorders of purine metabolism: myoadenylate deaminase deficiency

Disorders of lipid metabolism: carnitine and carnitine palmitoyltransferase deficiencies, short- or long-chain acyl-CoA dehydrogenase deficiency, lipin-1 deficiency, and Brody myopathy (calcium adenosine triphosphatase [CAT] deficiency) [31]

In addition, patients may not have any baseline CPK elevations but may have genetic susceptibility if exposed to external triggers. Mutations in the following genes are proposed to be associated with this risk: ACADVL, ANO5, CPT2, DMD, DYSF, FKRP, HADHA, PGM1, LPIN1, PYGM, and RYR1.[12] Sickle cell trait affects 300 million people worldwide and also confers an increased risk. Rhabdomyolysis in people with sickle cell trait is especially common with exertional dyspnea. Patients with sickle cell disease are known to have rhabdomyolysis during sickle cell crises, and triggers should be avoided.[32][33][34]

Sepsis

Sepsis can cause rhabdomyolysis via multiple mechanisms, including direct muscle invasion by the infecting pathogen, muscle ischemia from hypoxia, toxin generation, and cytokine-mediated muscle toxicity. Staphylococcus aureus is known to cause rhabdomyolysis by direct muscle invasion and toxin production. Streptococci, salmonellae, and S aureus have been demonstrated in muscle biopsies of patients with rhabdomyolysis. Other pathogens associated with rhabdomyolysis include Staphylococcus epidermidis, Francisella tularensis, Streptococcus faecalis, meningococci, Hemophilus influenzae, Escherichia coli, pseudomonads, Klebsiella, Enterococcus faecalis, and Bacteroides.[35] 

Epidemiology

Approximately 26,000 cases of rhabdomyolysis are reported each year in the United States. There is a large variation in the incidence of acute kidney injury (AKI) in patients with rhabdomyolysis; AKI is inconsistently defined, and the degree of rhabdomyolysis is highly variable.[36] Rhabdomyolysis can occur at any age, but most cases are seen in adults. Men, Black individuals, patients older than 60 years, and individuals with obesity are at increased risk. The most common cause of rhabdomyolysis in children is infection (30%). 

The incidence of crush syndrome is between 30% to 50% with traumatic rhabdomyolysis. Children are at low risk for crush syndrome and have lower mortality rates compared to adults. Crush injury-related AKI and dialysis requirements varied across multiple studies. During natural disasters like earthquakes, early fluid resuscitation, extrication, and immediate hospitalization with a multidisciplinary team approach reduce AKI, morbidity, and mortality.

In 2002, the American College of Cardiology (ACC), the National Heart-Lung and Blood Institute, and the American Heart Association jointly released a clinical advisory. It defined statin-associated rhabdomyolysis as muscle symptoms with increased creatine kinase, typically more than 11 times the upper limit of normal (myonecrosis) with elevated serum creatinine consistent with pigment-induced nephropathy and myoglobinuria.[37] About 0.5% of patients taking statins might develop clinically significant myonecrosis.[38] 

The incidence of rhabdomyolysis secondary to immobilization, alcohol intoxication, fractures, strenuous muscle exercises, and insect bites is imprecise, as these are more sporadic incidents. 

Pathophysiology

There are multiple causes for rhabdomyolysis, but the final common pathogenic pathway is direct myocyte injury or energy supply failure in the muscle cell.[39] The sodium-potassium pump and sodium-calcium exchanger on the sarcoplasmic membrane maintain low intracellular/sarcoplasmic sodium and calcium and high potassium concentrations in the resting muscle. At rest, calcium is stored in the sarcoplasmic reticulum. Muscle contraction is an active process using adenosine triphosphate (ATP) and calcium. Any insult that disrupts the ATP, ion channels, and plasma membrane results in a loss of intracellular electrolyte equilibrium.

Muscle injury (trauma, exercise, thermal dependent syndromes) or lack of myocyte intracellular ATP (medicines, electrolytes, hereditary and metabolic disorders, intense exercise, ischemia) results in intracellular sodium and calcium influx. Water is drawn into the cell along with sodium, causing cellular swelling and disruption of intracellular and membraneous structures. Excessive intracellular calcium leads to activation of actin-myosin crosslinkage, myofibrillar contraction, and depletion of ATP. Excessive intracellular calcium also activates calcium-dependent phospholipases and proteases, promoting cell membrane dissolution and disruption of ion channels.

With reperfusion, leukocytes migrate into the damaged muscle and cause an increased number of cytokines, prostaglandins, and free radicals, causing further myolysis, necrosis of muscle fibers, and release of muscle breakdown products like potassium, myoglobin, creatine kinase, phosphate, uric acid, and various organic acids into the bloodstream.[22] This leads to the complications of hyperkalemia and hyperphosphatemia. In rhabdomyolysis, hypocalcemia is observed initially, followed by hypercalcemia. This is because calcium first moves into the myocyte during injury, and then it leaks out into extracellular spaces after cell lysis. 

Myoglobinuria

Myoglobin is a 19 kD, iron-containing heme protein found predominantly in the sarcoplasm of skeletal and cardiac muscles. Due to the heme moiety, myoglobin carries and stores oxygen in myocytes. Myoglobin has a greater affinity for oxygen than hemoglobin and can acquire oxygen from hemoglobin, transferring oxygen from the blood to the muscle tissues.

Circulating myoglobin is mainly bound to haptoglobin and α2- immunoglobulin. However, circulating haptoglobin is saturated at serum myoglobin levels higher than 0.5 to 1.5 mg/dL, and the glomerulus filters the excess free myoglobin.[40] Although small amounts of myoglobin are normally filtered and quickly excreted by the kidneys, the large amount of myoglobin released in rhabdomyolysis can lead to AKI.[41]

Acute Kidney Injury

The kidney is especially vulnerable to damage from rhabdomyolysis due to its high oxygen consumption and mitochondrial density. Once muscles are damaged, their contents are released, causing inflammation and fluid sequestration. The reduction in intravascular volume activates the renin-angiotensin-aldosterone axis, further compromising renal blood flow. The sympathetic nervous system is also activated, releasing vasopressin, which worsens renal ischemia.

The myoglobin released by damaged myocytes is a main contributor to renal injury. The kidney's filtering capacity becomes overwhelmed by excess myoglobin, which then deposits in renal tubules, causing renal toxicity. The myoglobin can also bind oxygen, increasing free radicals and lipid peroxidation, which causes further oxidative damage and renal vasoconstriction. Rhabdomyolysis also leads to increased uric acid production, and the acidosis facilitates myoglobin binding with uromodulin (ie, Tamm-Horsfall protein) to form tubular casts and potentiate further renal injury. Heme also binds nitrous oxide, depleting its concentration and inducing expression of the vasoconstrictors endothelin-1, isoprostanes, and thromboxanes.[3][42] In addition, heme is thought to activate platelets.[43]

The risk of AKI is estimated between 10% and 50% when CPK is greater than 1000 U/L.[3] The best predictors for developing AKI appear to be a state of hydration, high initial serum creatine, low serum bicarbonate, low serum calcium, and increased serum phosphate. Hypoalbuminemia and increased blood urea nitrogen (BUN) have also been associated with the development of AKI.   

Compartment Syndrome

Trauma of muscle groups in specific compartments can lead to compartment syndrome due to muscle swelling, which further causes additional pressure-related damage like arterial occlusion and muscle necrosis. Persistently raised compartment pressure may lead to irreversible peripheral nerve palsy. Compartment pressure of more than 30 mm Hg produces significant muscle ischemia, and measurement of compartmental pressure is helpful in decision-making for fasciotomy. Patients with rhabdomyolysis, severe blood loss, and hypotension are at increased risk for muscle ischemia, even with lesser compartment pressures.[44] Patients with crush injuries are particularly susceptible to compartment syndrome.

Disseminated Intravascular Coagulation

The heme protein has the potential to cause many inflammatory actions; it activates platelets, functions as a damage-associated molecular pattern (DAMP), induces apoptosis, damages mitochondria, activates inflammasomes, and produces cytokines. Heme is also directly thrombogenic by promoting the formation of neutrophil extracellular traps (NETs) and inducing platelet degranulation, macrophage activation, and tissue factor expression.[42] In an underlying inflammatory and thrombogenic state, disseminated intravascular coagulation (DIC) may also be due to thromboplastin released during muscle injury.[45][46] Laboratory values will show increased prothrombin time, activated thromboplastin time, INR, and serum D-dimer levels and decreased platelet count and fibrinogen levels. 

Histopathology

Muscle biopsy is a necessary test when metabolic myopathies are suspected. The timing of muscle biopsy is crucial in the identification of appropriate diseases. Rhabdomyolysis can be associated with excessive muscle fiber necrosis, and obtaining a biopsy during acute injury may miss an underlying myopathy. The current literature recommends muscle biopsy only after complete recovery from rhabdomyolysis. The European Federation of Neurological Societies (EFNS) Scientist Panels suggests patients with muscle pain, weakness, CPK elevation 2 to 3 times normal, myoglobinuria, hypertrophic or atrophic muscles, and electromyography suggestive of myopathy can undergo muscle biopsy at the time of presentation.[47] 

Specific stains can help identify different types of myopathies. Glycogen storage disorders can be identified by periodic acid Schiff and hematoxylin and eosin staining showing glycogen-containing vacuoles. Succinyl dehydrogenase and cytochrome oxidase staining, along with Gomori trichrome staining, identify ragged red fibers in patients with mitochondrial myopathies. Immunohistochemistry can identify enzyme deficiencies like phosphokinase and myophosphorylase deficiencies.[33]

Kidney biopsy in patients with AKI from rhabdomyolysis may reveal varied findings. The earliest findings of tubular changes can be visualized via light microscopy as early as 1 to 12 hours after injury. Findings typical of this stage include dilated Bowman spaces with a ruptured glomerular membrane and reduced glomerular tufts with flattened podocytes. Significant necrosis with loss of microvilli and reduction in basal infolding is seen in the proximal convoluted tubule. Electron microscopy clearly shows electron-dense casts occupying the entire distal tubular lumen.[48]

History and Physical

Even though muscle pain, weakness, and tea-colored urine are the characteristic triad of rhabdomyolysis, these findings are seen in less than one-half of patients. Muscle pain is the most common presenting symptom and is reported in about 50% of adults with rhabdomyolysis, and dark-colored urine is seen in about 30% to 40%.[11] Weakness typically involves proximal muscle groups. Nonspecific symptoms like muscle cramps, stiffness, muscle swelling, weakness, malaise, abdominal pain, nausea, palpitations, and fever may be present. In patients with known myopathies, weakness is the most common complaint in adults but less so in children. Depending on the cause of rhabdomyolysis, patients may report a history of illicit drug use, insect bites, heat exertion, recent surgical procedures, accidents, recent increasing dosages of regularly used medications, new medications, or over-the-counter supplements. A high index of suspicion is sometimes necessary when diagnosing rhabdomyolysis. 

Patients with underlying myopathy may have atrophic or hypertrophic muscles. The clinical features of rhabdomyolysis can be nonspecific. Rhabdomyolysis has both local and systemic features, with early and late complications. Local features include bruising, swelling, and tenderness. Systemic features include fever, malaise, nausea, confusion, agitation, delirium, tea-colored urine, or anuria.[49] In trauma patients with rhabdomyolysis, a detailed examination of distal pulses and the peripheral nerve should be evaluated for limb ischemia, compartment syndrome, and peripheral neuropathy. Signs of dehydration, such as dry oral mucosa and decreased skin turgor, should be noted. Early recognition of rhabdomyolysis is critical to preventing complications. 

Evaluation

After documenting vital signs, basic laboratory studies should be obtained. The studies should include a complete blood count, comprehensive metabolic panel, C-reactive protein, erythrocyte sedimentation rate, serum CPK, and urinalysis. Additionally, chest radiography and electrocardiography should be performed. In addition to CPK, lactate dehydrogenase, aldolase, alanine aminotransferase, and aspartate aminotransferase are enzymes released from muscles during rhabdomyolysis, but serum elevations of these enzymes are nonspecific. Elevated inflammatory markers and a leukocytosis are also nonspecific for rhabdomyolysis.

Elevated serum CPK levels are the hallmark of rhabdomyolysis. In addition, reddish-brown urine from myoglobinuria may be present in about 50% of cases. However, the peroxidase agent used on a urine dipstick to detect blood with also react with myoglobin. Microscopic urinalysis differentiates myoglobinuria from hemoglobinuria, as myoglobinuria is associated with an absence of red blood cells.[50]

The normal range of serum CPK is 20 to 200 U/L. Usually, an elevation of 5 times the upper limit of normal is considered necessary to diagnose rhabdomyolysis.[36] CPK exists in 4 significant isoenzymes: CK-MM, CK-MB 1 and 2, and CK-BB. CK-MM is most specific for skeletal muscle, CK-MB 1 and 2 are specific for cardiac muscle, and CK-BB is specific for the brain. The half-life of CPK is 36 hours; serum CPK levels begin to rise within 2 to 12 hours after the injury and peak within 1 to 5 days. Levels start to decline after 3 to 5 days without further muscle injury.[3][51] In general, CPK levels of more than 5000 IU/L will have some amount of significant muscle injury and place patients at higher risk of AKI.[3]

The half-life of myoglobin is 2 to 4 hours, and it is metabolized into bilirubin. Serum myoglobin can be detected before the CPK elevation, but because of the shorter half-life and rapid metabolism, myoglobinemia may not always be detectable. Sometimes, proteinuria may also be seen secondary to proteins released by damaged myocytes and changes in the glomerulus. Various other biomarkers are being investigated for early diagnosis of heme-containing pigment-induced AKI.[52]

Excessive tissue breakdown from rhabdomyolysis causes electrolyte changes, including hyperkalemia and hyperphosphatemia. AKI can be complicated by resistant hyperkalemia. Excessive calcium influx into the myocytes can cause hypocalcemia, which may be severe depending on the nature of the injury. Excessive cell breakdown causes increased uric acid levels. Rhabdomyolysis can also cause the release of organic acids like lactic acid and contribute to metabolic acidosis with or without an anion gap.[11]

Electrocardiography may demonstrate peaked T waves, a prolonged PR interval, a wide QRS interval with or without conduction blocks, ventricular tachycardia, and asystole secondary to hyperkalemia. Hypocalcemia can manifest as QTC prolongation. 

Plain radiographs can explain underlying bone fractures, dislocation of the joints, and sometimes soft tissue swelling. Computed tomography (CT) of the involved muscle groups may identify compartment syndrome.[53] Diagnosis of acute compartment syndrome is primarily clinical; this diagnosis can be confirmed by measuring intra-compartmental pressure (invasive) or near-infrared spectroscopy (noninvasive). Additional testing like magnetic resonance imaging, muscle biopsy, or electromyography is not required to diagnose rhabdomyolysis.

Muscle biopsy is generally performed after complete recovery from rhabdomyolysis and helps identify inflammatory myopathies when suspected from the clinical history. Inflammatory and metabolic myopathies are considered in the differential diagnosis in patients with recurrent rhabdomyolysis, poor exercise tolerance, muscle cramps, easy fatigue, and a positive family history.

Treatment / Management

The goal of rhabdomyolysis management is to maintain adequate fluid resuscitation and prevent AKI. The first step in effective management is identifying the underlying cause of the muscle injury and removing that stimulus, if possible. The active management of rhabdomyolysis should include continuous assessment of the airway, breathing, and circulation, frequent physical examinations, appropriate hydration to improve end-organ perfusion, close monitoring of urine output, correction of electrolyte abnormalities, and identification of complications like compartment syndrome and disseminated intravascular coagulation. 

Management of Traumatic Rhabdomyolysis

In patients with a crush injury or injuries, initiating intravenous (IV) hydration and fluid resuscitation should begin as early as possible, ideally in the field and, when possible, before relieving the injurious stimulus. Hydration should be continued during transport. Delaying fluid resuscitation may cause worsening hypovolemia secondary to third spacing. Fluids should be liberally administered to maintain adequate intravascular volume and diuresis; volumes of 10 L to 20 L may be required.[54]

Multiple studies have demonstrated the benefit of large-volume resuscitation in patients with crush injuries to prevent rhabdomyolysis-related AKI and reduce the need for hemodialysis. Patients trapped for longer periods may have already developed AKI by the time they present at the hospital; aggressive fluid resuscitation in these patients is particularly challenging, as they are prone to volume overload.[55] Unfortunately, no studies have directly compared the outcomes of different types and rates of fluid resuscitation. Current International Society of Nephrology Renal Disaster Relief Task Force guidelines recommend field resuscitation with isotonic saline rather than alkaline fluids.[56] The addition of dextrose to normal saline can be beneficial in supplying some calories and minimizing hyperkalemia. Two liters should be administered at 1 L/h for the first 2 hours, followed by 500 mL/h in a well-built adult. The rate of fluid administration is also dependent on age, gender, body habitus, the possibility of bleeding, and the nature of trauma. Potassium-containing IV fluids like Ringer's lactate are generally avoided in managing rhabdomyolysis.(B2)

Once hospitalized, close monitoring of urine output is essential. After confirming urine output and obtaining labs documenting the absence of alkalosis, consideration should be given to the alkalinization of urine to prevent the precipitation of myoglobin in the distal convoluted tubule. Urine alkalinization also decreases the precipitation of uric acid, corrects underlying metabolic acidosis, and reduces the risk of hyperkalemia. Most data regarding the alkalinization of the urine are from uncontrolled case series. Adding 50 mEq of sodium bicarbonate to half-normal saline is the traditional method to alkalinize urine. Alkalinization with a bicarbonate infusion is associated with the precipitation of hypocalcemia, which can trigger tetany and seizures. The goal of alkaline fluid infusion is to maintain a serum pH not to exceed 7.5 and a urine pH just above 6.5. Bicarbonate in IV fluids should be promptly discontinued when serum pH is at 7.5.[57]

Mannitol is commonly used to improve urine output in patients with a crush injury but should only be initiated after the patient maintains adequate urine output of at least 20 mL/h. There are no specific conscientious guidelines regarding mannitol administration. A trial of intravenous infusion of 60 mL of 20% mannitol given over 5 minutes can be used to assess for increased urine output. If there is an increase in urine output of 30 to 50 mL/h compared to the baseline, mannitol can be continued.[58] Mannitol should be avoided in patients with AKI, oliguria, or anuria. Adverse events associated with mannitol use are volume overload and hyperosmolality. The current literature does not support concomitantly using mannitol and bicarbonate to prevent pigment-induced acute kidney injury.[59][60] (B2)

Every attempt should be made to prevent the development or worsening of hyperkalemia. Potassium-containing IV fluids like Ringer's lactate should be avoided. A combination of oral sodium polystyrene sulfate and sorbitol is commonly given to patients with crush injuries and hyperkalemia. The role of new potassium-binding agents is unclear because of a lack of studies. Appropriate use of point-of-care devices and electrocardiography should be utilized in patients with suspected hyperkalemia.[61]

Patients with crush syndrome should have a Foley catheter placed; IV fluids should be given to maintain urine output at 200 to 300 mL/h. Adequate IV fluid resuscitation should be continued until myoglobinuria is wholly resolved and CPK levels are down-trending. Foley catheters should be used for the shortest time possible to minimize complications like infection. Consideration should be given to loop diuretics in patients with volume overload states. Appropriate use of hemodialysis can be used with anuric AKI, hyperkalemia, and volume overload after conservative measures fail. Peritoneal dialysis is not preferred in the setting of trauma.

Management of Nontraumatic Rhabdomyolysis

Rhabdomyolysis from nontraumatic causes is managed similarly to that secondary to trauma. Adequate and appropriate fluid resuscitation with normal isotonic saline should be provided depending on the underlying cause of rhabdomyolysis. Management includes removing the offending agent at diagnosis, titration of IV fluids to maintain a urine output of 200 to 300 mL/h, and serial daily monitoring of serum CPK levels to document trends. In patients with serum CPK levels less than 5000 U/L, aggressive fluid resuscitation is discouraged as these patients are less likely to develop AKI.[62] Forceful alkaline diuresis can be considered in severe cases where the CPK is more than 30,000 U/L without oliguria, anuria, or AKI. Mannitol is not commonly used in nontraumatic rhabdomyolysis. Loop diuretics can be considered in the setting of volume overload from aggressive fluid resuscitation. Patients who remain oliguric or anuric, even with aggressive fluid resuscitation, and develop AKI should be considered for hemodialysis. The role of dialysis in the removal of myoglobin has not been demonstrated.[41](B3)

Management of Electrolytes Abnormalities in Rhabdomyolysis

Rhabdomyolysis is associated with hyperkalemia, hypocalcemia, hyperuricemia, and hyperphosphatemia. Hyperkalemia with potassium levels less than 6 mEq/L without ECG changes should be managed with potassium binders and the use of bicarbonate in the fluids. Hyperkalemia with potassium levels 6 mEq/L or above with or without ECG changes should be treated with an ampule of D50 followed by 10 units of regular insulin and IV sodium bicarbonate. In general, calcium gluconate or calcium chloride is commonly used in the emergency room with hyperkalemia. However, rhabdomyolysis, especially from trauma, is associated with late occurrences of hypercalcemia, so calcium should be used with caution in the management of hyperkalemia due to rhabdomyolysis. 

Symptomatic hypocalcemia, such as tetany, seizures, and arrhythmias, should be treated with IV calcium gluconate. Excessive calcium replacement can precipitate hypercalcemia during the recovery phase. Hyperuricemia from rhabdomyolysis should be managed with allopurinol and only if the serum uric acid is more than 8 mg/dL. Patients with volume overload, severe acidosis, uremia, and refractory hyperkalemia need hemodialysis. Peritoneal dialysis may not be sufficient to correct the excess amount of electrolyte changes and rhabdomyolysis.

Other Supportive Care

Appropriate use of antibiotics and vasopressors is needed when concomitant sepsis is present. Malignant hyperthermia should be treated with dantrolene sodium. Steroids are used in inflammatory myopathies. Emergent orthopedic consultation is required in the management of compartment syndrome. DIC is managed with fresh frozen plasma, cryoprecipitate, and platelet transfusion.

Diet in Metabolic Myopathies

Dietary changes may improve symptoms associated with hereditary myopathies. Pain and fatigue associated with phosphorylase deficiency can be decreased with glucose and fructose supplementation. Frequent meals with a high carbohydrate, low-fat diet improve muscle pain and myoglobinuria from carnitine palmityl transferase deficiency. Other metabolic abnormalities may improve with different dietary interventions, and this should be examined closely with a dietician who specializes in such disorders.

Differential Diagnosis

The differential diagnosis of rhabdomyolysis includes:

• Hypothermia
• Malignant hyperthermia
• Neuroleptic malignant syndrome
• Sepsis
• Inflammatory myositis
• Inherited myopathies
• Guillain-Barré syndrome
• Hyperosmolar conditions

Pertinent Studies and Ongoing Trials

Preclinical studies have been conducted on the following interventions in rhabdomyolysis but have not proven effective:

• Vasodilators
• Antioxidants
• Curcumin
• Haptoglobin
• Hemopexin
• Hepcidin
• α1-microglobulin.

Gene therapy is being explored for treating inherited muscular dystrophies such as Duchenne and Becker. This includes various technologies such as read-through of early stop codons and exon skipping. Edasalonexent (CAT-1004, an NF-κB inhibitor) combines structural elements of salicylic acid and docosahexenoic acid and has also been tested in a phase 3 placebo-controlled clinical trial with some success (NCT03703882). Vamorolone is a glucocorticoid that stabilizes membranes by reducing lipid peroxidation and inhibiting NF-kB-mediated inflammation; it has also demonstrated functional improvement of symptoms. Many other novel treatments are being studied.[20][63]

Prognosis

For hospitalized patients who develop AKI in the setting of rhabdomyolysis, the mortality rate is 30% to 50%. Severity and duration of the renal injury are the most significant prognostic indicators.[3] There is also a correlation between the severity and duration of crush injury and the need for hemodialysis.[64]

Complications

The most significant complications of rhabdomyolysis include:

• Acute kidney injury
• Electrolyte abnormalities
• Arrhythmias
• Compartment syndrome
• Disseminated intravascular coagulation 
• End-stage renal disease requiring renal replacement therapy
• Infections from a prolonged hospital stay.