Rhabdomyolysis

Rhabdomyolysis (literally, “dissolution of skeletal muscle”) is a syndrome caused by injury to skeletal muscle and involves leakage of large quantities of potentially toxic intracellular contents into plasma.[4] First described in the victims of crush injury during World War II,[5] it is a final pathway of diverse processes and insults.[6] The final common pathway of rhabdomyolysis may be a disturbance in myocyte calcium homeostasis.[3]

In adults, rhabdomyolysis is characterized by the triad of muscle weakness, myalgias, and dark urine.[7] In many children with this condition, however, all 3 symptoms may not be seen together.[8, 9] Myalgias and generalized muscle weakness are the most common presenting symptoms. Life-threatening renal failure and disseminated intravascular coagulation (DIC) are dreaded complications that appear to be more common in adults.[1]

Rhabdomyolysis has many etiologies and is often multifactorial in adult patients. Infection and inherited disorders appear to be the most prevalent etiologies in children.[10] The physician must be alert to the diagnosis of rhabdomyolysis and to its subtle presentation to prevent acute renal failure. Sensitive laboratory markers of myocyte injury include elevated plasma creatine kinase (CK) levels (often in excess of 4- to 5-fold the upper limit of normal).[10]

Management of rhabdomyolysis consists primarily of correction of fluid and electrolyte anomalies. With adequate supportive measures, the clinical outcome of rhabdomyolysis is often favorable in children.[6] Recurrent episodes of rhabdomyolysis, especially in children, may indicate underlying defects of muscle structure or metabolism.[3]

The multiplicity of potential causes of rhabdomyolysis notwithstanding, the final common denominator appears to be disruption of the sarcolemma and release of intracellular myocyte components. Mechanisms of cell destruction in rhabdomyolysis include cellular membrane injury, muscle cell hypoxia, adenosine triphosphate (ATP) depletion, electrolyte disturbances that cause perturbation of sodium-potassium pumps, and generation of oxidative free radicals.[6]

The sarcolemma, a thin membrane that encloses striated muscle fibers, contains numerous pumps that regulate cellular electrochemical gradients. The intercellular sodium concentration is normally maintained at 10 mEq/L by a sodium-potassium adenosine triphosphatase (Na/K-ATPase) pump located in the sarcolemma.[11]

The Na/K-ATPase pump actively transports sodium from the interior of the cell to the exterior. As a result, the interior of the cell is more negatively charged than the exterior because positive charges are transported across the membrane. The gradient pulls sodium to the interior of the cell in exchange for calcium through a protein carrier exchange mechanism. In addition, an active calcium exchanger promotes calcium entry into the sarcoplasmic reticulum and mitochondria.

These processes depend on ATP as a source of energy. ATP depletion appears to be the end result of most causes of rhabdomyolysis. This depletion disrupts cellular transport mechanisms and alters electrolyte composition.[12]

An increase in intracellular calcium levels results in hyperactivity of proteases and proteolytic enzymes and generation of free oxygen radicals. These enzymes and substances increasingly degrade myofilaments and injure membrane phospholipid with leakage of intracellular contents into plasma. These contents include potassium, phosphate, CK, urate, and myoglobin.

Excess fluid may also accumulate within affected muscle tissue. The action of phospholipases in insect and snake venom may cause hemolysis, muscle damage, endothelial necrosis, rhabdomyolysis, and acute kidney injury (AKI).[13] Additionally, muscle damage is amplified by infiltration of activated neutrophils. An inflammatory cascade and reperfusion injury sustains muscle damage and degeneration.[14, 11]

Myoglobin is an important myocyte compound released into plasma (see the image below). After muscle injury, massive plasma myoglobin levels exceed protein binding (of haptoglobin) and can precipitate in glomerular filtrate. Excess myoglobin may thus cause renal tubular obstruction, direct nephrotoxicity (ischemia and tubular injury), intrarenal vasoconstriction, and acute kidney injury (AKI; see below).[1, 2, 3]

Acute kidney injury

AKI is believed to be due to decreased extracellular volume, which results in renal vasoconstriction. It is also believed to be due to ferrihemate, which is formed from myoglobin at a pH level of 5.6 or less. Ferrihemate produces free hydroxy radicals and causes direct nephrotoxicity, often through lipid peroxidation. These heme-proteins may enhance vasoconstriction through interactions with nitric oxide (NO) and endothelin receptors. The roles of cytokines in this process have also been discussed.[14]

Renal vasoconstriction and ischemia deplete tubular ATP formation and enhance tubular cell damage. Myoglobin precipitation in renal tubules causes formation of obstructive casts. AKI rarely occurs in patients with chronic myopathies unless it is triggered by a second inciting event.[3] The risk of renal injury is low when initial CK levels are lower than 15,000-20,000 U/L. Lower CK levels may lead to renal injury in patients with sepsis, dehydration, or acidosis.[3]

Gastrointestinal (GI) ischemia is common in patients with fluid and electrolyte imbalances. This ischemia leads to endotoxin absorption, cytokine production, and perpetuation of the systemic inflammatory response.

Trauma and muscle compression

Trauma and muscle compression are believed to cause rhabdomyolysis through direct injury to muscle, resulting in disruption of the sarcolemma and direct leakage of cell contents.[1, 14] Occlusion of muscular vessels due to thromboemboli, traumatic injury, or surgical clamping may lead to rhabdomyolysis if muscle tissue ischemia is prolonged. This is the leading cause of rhabdomyolysis in children aged 9-18 years, according to one review.[6]

Orthopedic trauma, including compartment syndromes and fractures, may result in rhabdomyolysis. Such trauma commonly occurs in traffic and occupational accidents. Orthopedic injuries in natural disasters (eg, earthquakes) are compounded by immobilization, hypovolemia, and significant rates of rhabdomyolysis.

Trauma-related events that are particularly likely to lead to rhabdomyolysis include the following:

• Significant blunt trauma or crush injury,[15] including shaken-baby syndrome and physical abuse (blunt trauma)[16, 17]

• High-voltage electrical injury due to lightning strikes or accidental exposures[1]

• Heat stroke

• Extensive burns

• Near-drowning

• Prolonged immobilization (eg, after excess alcohol or drug consumption, after an unwitnessed incapacitating stroke, or after prolonged surgical procedures)

Infection

Researchers believe that viruses may cause rhabdomyolysis by directly attacking the muscle and generating muscle-specific toxin. While infections may lead to only 5% of adult rhabdomyolysis events, viral-induced myositis appears to be the most common etiology for rhabdomyolysis in children younger than age 9 years.[6, 18] Viral infectious disease agents that may cause rhabdomyolysis include the following[19] :

• Influenza types A and B (most common)

• Human immunodeficiency virus (HIV)[20]

• Coxsackievirus[21]

• Epstein-Barr virus

• Echovirus

• Cytomegalovirus

• Adenovirus

• Herpes simplex virus

• Parainfluenza virus

• Varicella -zoster virus[22]

• West Nile virus[23]

A case of rhabdomyolysis related to coronavirus disease 2019 (COVID-19) was reported in China.[24] Similar cases have been reported in other countries.[25, 26]

Legionella is the bacterium classically associated with rhabdomyolysis in adult patients. The pathogenesis is believed to be due to direct invasion and toxic degeneration of muscle fibers. However, any microbe that causes sepsis and toxic shock may potentiate muscle damage and necrosis. Malaria due to Plasmodium falciparum is a common cause of rhabdomyolysis outside the United States. Bacterial infectious agents that may cause rhabdomyolysis include the following[18] :

• Francisella tularensis[14, 27]

• Streptococcus pneumoniae

• Group B beta-hemolytic streptococci

• Streptococcus pyogenes

• Staphylococcus epidermidis

• Escherichia coli

• Borrelia burgdorferi

• Clostridium perfringens

• Clostridium tetani

• Viridans streptococci

• Plasmodium species

• Rickettsia species

• Salmonella species[14]

• Listeria species

• Legionella species[28]

• Mycoplasma species[29]

• Vibrio species

• Brucella species

• Bacillus species

• Leptospira species[30]

Fungal infectious agents that may cause rhabdomyolysis include the following[18] :

• Candida species

• Aspergillus species

Metabolic and genetic factors

Certain genetic muscle defects are believed to cause rhabdomyolysis because of the muscle’s inability to use ATP appropriately. Because of inadequate ATP production, the mismatch of energy supply and demand may result in the disruption of cell membranes during exercise.

Any inherited condition that impairs energy delivery to muscle may cause rhabdomyolysis.[31] Such conditions include diseases of glucose, glycogen, fatty acid, or nucleoside metabolism.[32, 33] These disorders often appear in childhood and should be suspected in recurrent cases of myoglobinuria, rhabdomyolysis, or both. Physical exertion and fasting states may exacerbate muscle damage in these disorders.[12, 34]

Electrolyte derangement such as hypophosphatemia is believed to cause rhabdomyolysis because of the resulting shortage of phosphate necessary for the production of ATP. Hypokalemia creates a negative potassium balance, which causes rhabdomyolysis.[35] Hypokalemia due to dehydration and exercise may also cause rhabdomyolysis.[36] Hyponatremia[37] and hypernatremia have also been associated with rhabdomyolysis.

Hypothyroidism, hyperthyroidism,[38] diabetic ketoacidosis and nonketotic hyperosmolar diabetic coma have been associated with rhabdomyolysis. Metabolic and genetic deficiencies that may cause rhabdomyolysis include the following:

• Glycogen phosphorylase deficiency type V (ie, McArdle disease)

• Phosphofructokinase deficiency

• Phosphoglycerate mutase deficiency

• Phosphoglycerate kinase deficiency (PGK)

• Carnitine deficiency

• Carnitine palmityl transferase deficiency (CPT I and II)

• Mitochondrial respiratory chain enzyme deficiencies (including deficiencies of the acyl-CoA dehydrogenase [ACAD] family of proteins)

• Myoadenylate deaminase deficiency

Some of these deficiencies are treatable with dietary modification.[6, 14]

Case reports of rhabdomyolysis related to anesthesia in children are believed to be due to underlying muscle disease. Conditions that lead to hyperthermia-related rhabdomyolysis include neuroleptic malignant syndrome and malignant hyperthermia.[39]

A pediatric case series described an often fatal, malignant, hyperthermia-like syndrome characterized by rhabdomyolysis during initial presentation of diabetes mellitus in adolescent males.[40] Although these cases resembled hyperglycemic hyperosmolar nonketotic syndrome (HHNS), patient courses were marked by rhabdomyolysis and cardiovascular instability. The underlying etiology of this catastrophic presentation of adolescent diabetes mellitus is unclear.

Rheumatologic disorders which rarely cause rhabdomyolysis include polymyositis, dermatomyositis, Sjögren syndrome, mixed connective tissue disease and systemic lupus erythematosus. Rhabdomyolysis also has been reported in patients with sickle cell anemia and has mistakenly been identified as a pain crisis.

A study by Vivante et al used whole exome sequencing in a cohort of 21 unrelated families with rhabdomyolysis and detected causative mutations in candidate genes in 43% of the families. The study also reported disease-causing mutations in eight of 58 genes (fatty acid metabolism disorders, glycogen metabolism disorders, abnormal skeletal muscle relaxation disorders, and purine metabolism disorders).[41]  

A study by Nelson et al found that sickle cell trait was associated with a higher risk of exertional rhabdomyolysis (similar to the risk associated with tobacco use) among 47,944 soldiers who had undergone testing for hemoglobin AS.[42]

Drugs and myotoxins

Any drug that impairs skeletal muscle ATP production or increases energy requirements may cause rhabdomyolysis.[14] Direct drug-induced sarcolemmal injury is often mediated by activation of phospholipase A.

Toxin-mediated rhabdomyolysis may result from substance abuse, in both adults and adolescents, including abuse of the following:

• Ethanol

• Methanol

• Ethylene glycol

• Isopropanol

• Heroin

• Methadone

• Barbiturates

• Cocaine

• Amphetamines[43, 44]

• Ketamine hydrochloride[43, 44]

• Phencyclidine

• 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy)[43, 44]

• Lysergic acid diethylamide (LSD)

Ethanol causes metabolic derangement through direct toxicity and disruption of the muscle blood supply by immobilization. Ethanol abuse may cause hypophosphatemia and hypokalemia, which are additive causes of rhabdomyolysis. Alcohol withdrawal, along with delirium tremens and seizures, may be additional factors. Patients who overdose on narcotics and sedative-hypnotics often remain immobilized for extended periods and may have pressure necrosis that results in rhabdomyolysis. Cocaine can directly damage muscle tissue by causing vasoconstriction and tissue ischemia.

Rhabdomyolysis may also result from the use of prescription and nonprescription medications, including the following[43] :

• Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors)[45, 46, 47]

• Antihistamines (particularly in children)

• Salicylates

• Caffeine[48]

• Fibric acid derivatives (eg, bezafibrate, clofibrate, fenofibrate, and gemfibrozil)[49]

• Neuroleptics/antipsychotics[50]

• Anesthetic and paralytic agents (the malignant hyperthermia syndrome)

• Amphotericin B

• Quinine

• Corticosteroids

• Colchicine

• Theophylline

• Cyclic antidepressants

• Selective serotonin reuptake inhibitors (the serotonin syndrome)

• Aminocaproic acid

• Phenylpropanolamine (recalled from the US market)

• Propofol (continuous infusion)[51]

• Protease inhibitors

According to a retrospective analysis of FDA records (2004-2009),[46] the most commonly suspected drug exposure in children younger than 10 years was propofol.

Statins, though tolerated by most adult patients, can cause myopathy and, rarely, rhabdomyolysis.[52, 53] They appear to affect ATP production by impairing mitochondrial function. Specific impairments may involve the electron transport chain. Statins may also alter the balance between protein repair and degradation by affecting ubiquitin proteosome pathway gene expression.[54] Other mechanisms of statin myopathy include depletion of isoprenoids and coenzyme Q10.

Statin-related myopathy risk appears higher in adults with complex medical problems and medication use.[55] Statins appear safe when used in children with hypercholesterolemia.[56]

Environmental toxins that may cause rhabdomyolysis include the following:

• Carbon monoxide[57]

• Toluene

• Hemlock herbs from quail – Rhabdomyolysis after the consumption of quail is well known in the Mediterranean region; it occurs as the result of intoxication by hemlock herbs that the quails consume

• Snake venom, spider (eg, black widow spider) venom, hornet venom, and massive envenomations of Africanized honey bees

• Iron-dextran[14, 13]

Other causes

Exertional activity (eg, marathons, squats, pushups, sit-ups, high-intensity interval training, and other intense repetitive physical exercises)[31]  may cause rhabdomyolysis, especially in untrained individuals. Such events often occur under extremely hot or humid conditions and are related to exertional heat stress and heatstroke.[58, 59] Most of these events occur in military recruits and competitive athletes. Cold exposure in addition to heatstroke is an environmental cause of rhabdomyolysis.[60] Factors that increase the risk of exertional rhabdomyolysis and renal failure include the following[61, 62, 63] :

• Dehydration

• Use of nutritional supplements

• Drug use

• Sickle cell trait

• Malignant hyperthermia

Rhabdomyolysis as a complication of respiratory failure and status epilepticus or status asthmaticus has been reported.[64] Whether mechanical ventilation, corticosteroids, or neuromuscular blockade are risk factors in this condition is unclear.[65] Rhabdomyolysis may occur after other conditions associated with excessive muscular activity, including severe dystonia, acute psychosis, and excessive computer keyboard use or gaming.[66]

United States statistics

Rhabdomyolysis is a common condition in adult populations and is understudied in pediatrics.[67, 6] The National Hospital Discharge Survey reports 26,000 cases annually.[67] Most adult cases of rhabdomyolysis are due to abuse of illicit drugs or alcohol, muscular trauma, crush injuries, and myotoxic effects of prescribed drugs. Rhabdomyolysis is found in 24% of adult patients who present to emergency departments (EDs) with cocaine-related conditions.

In a large adult cohort, 60% of cases of rhabdomyolysis had multiple factors.[67] Significant pediatric etiologies include infections, trauma, metabolic conditions, and muscle diseases. In a retrospective review at a tertiary care pediatric center review spanning 10 years, viral myositis accounted for most cases of rhabdomyolysis in patients aged 0-9 years, whereas trauma was the leading diagnosis in patients aged 9-18 years.[6]

The incidence of myoglobin-induced acute kidney injury in adult rhabdomyolysis ranges from 17-35%. This complication was found in 42% of pediatric patients in a small, retrospective cohort study, in 8.7% in a review of nontraumatic causes in children younger than 7 years,[68] and in only 5% in the larger 10-year review mentioned above.[6, 69] Approximately 28-37% of adult patients require short-term hemodialysis. Rhabdomyolysis is believed to be responsible for 5-20% of all adult cases of acute kidney injury. A comparable figure in children is unavailable.

International statistics

Large numbers of patients may develop rhabdomyolysis and renal failure during disasters such as earthquakes. Severe crush injuries and delayed extrication of survivors characterize such events. Organizations such as the International Society of Nephrology have implemented measures to support local agencies in providing life-saving dialysis treatments for patients with rhabdomyolysis.[1]

Age- and sex-related demographics

Rhabdomyolysis is more common in adults, though it may occur in infants, toddlers, and adolescents who have inherited enzyme deficiencies of carbohydrate or lipid metabolism or who have inherited myopathies, such as Duchenne muscular dystrophy and malignant hyperthermia.

The incidence of rhabdomyolysis is higher in males than in females, especially in the subgroups of patients with trauma and inherited enzyme deficiencies.

The overall mortality for patients with rhabdomyolysis is approximately 5%; however, the risk of death for any single patient is dependent on the underlying etiology and any existing comorbid conditions that may be present and may be significantly higher in patients with AKI and extremely elevated CPK levels.

Implementation of the treatment modalities currently used (see Treatment) has reduced morbidity and mortality. In a 10-year retrospective pediatric review, only 13 of 191 (6%) of patients died. Of these 13 patients, 9 presented in cardiopulmonary arrest and could not be resuscitated.[6]

Rapid intervention and appropriate supportive treatment of rhabdomyolysis-related kidney injury and renal failure improve outcomes in traumatic crush injuries. The ability of medical response teams to provide aggressive hydration and dialysis services enhances survival in large-scale natural disasters such as earthquakes. If treatment modalities are implemented early, many patients recover completely.

Educate patients about the causes of rhabdomyolysis and its prevention. Provide genetic counseling for families with inherited muscle enzyme and energy substrate deficiencies. Educate high-school and college athletes about signs of dehydration and heat-related injuries. Advise patients with rhabdomyolysis caused by hyperthermia or inordinate exertion to exercise in moderation, with careful attention to hydration and external methods of cooling.

Caution patients that intense exertional activity, such as marathons, squats, pushups, sit-ups, and high-intensity interval training, can cause rhabdomyolysis, particularly in untrained individuals. Such episodes often occur under extremely hot or humid conditions and are related to exertional heat stress and heatstroke.

Advise patients with rhabdomyolysis related to ethanol, recreational drugs, or prescription medications to discontinue use of the offending agent. Refer these patients to a rehabilitation program if necessary.

The classic triad of rhabdomyolysis comprises the following:

• Myalgias

• Generalized weakness

• Darkened urine

In practice, however, the presentation of rhabdomyolysis varies considerably. The classic triad is actually seen in only about 50% of adult patients, and it may be even less common in children.[11] Additional nonspecific symptoms include fevers, unusual or severe fatigue,  nausea, and vomiting.

In most cases, the history reflects the inciting cause (eg, alcohol use and resultant unresponsiveness, agitation and illicit drug use, use of prescribed medications, or heatstroke).[67, 61, 44, 43] In children, infection and trauma are the most common causes.[6] Caregivers in contact with the patient before hospitalization may provide useful information about how the patient was found or what he or she had been doing most recently. Obtain information about prolonged immobilization from the patient (if possible) or an informant.

In some patients, the history is nonspecific and therefore is unreliable for diagnostic purposes.

Clinicians may need to investigate metabolic causes (eg, diabetic ketoacidosis and diabetes mellitus) and other nontraumatic causes (eg, congenital defects, viral infection, anesthesia use, physical exertion, and seizure disorder). Inflammatory myopathies of recent and acute onset may manifest as rhabdomyolysis.[11]

The initial physical examination findings may be nonspecific (especially in pediatric populations).[6, 11]

Patients may have muscle pain and tenderness, decreased muscle strength, soft tissue swelling, and skin changes consistent with pressure necrosis. The most commonly involved muscle groups in adults include the calves and the lower back. Back, chest, and calf pain often mimics other common conditions such as deep vein thrombosis or angina.

On the whole, focal or diffuse skeletal muscle swelling is rare. In one series, only 5% of the patients presented with muscle edema. Tense and tender muscle compartments suggest compartment syndrome; peripheral pulses that are within reference range do not rule out compartment syndrome, because loss of distal pulses is a very late sign.

Hyperthermia, hypothermia, and electrical injuries are known to cause rhabdomyolysis and can often be detected upon physical examination. Examine for any crush injuries or skeletal deformities in long bones if orthopedic injures after trauma are suspected.

The presence of rhabdomyolysis should not be discounted if the patient lacks classic history, physical examination findings, or both. If evolving rhabdomyolysis is suspected based on the clinical scenario, an appropriate laboratory evaluation should be performed to diagnose muscle damage and organ dysfunction.[1]

Electrolyte abnormalities are prominent features of rhabdomyolysis. Hyperphosphatemia, hyperkalemia, hypocalcemia (early), hypercalcemia (late) hyperuricemia, and hypoalbuminemia have been described.[4, 14]

Hyperkalemia may be a result of both muscle injury and renal insufficiency or failure. This abnormality may cause life-threatening arrhythmias and should be immediately addressed.

Hypocalcemia is another common metabolic abnormality, resulting from deposition of calcium phosphate. It may also be due to a decreased level of 1,25-dihydroxycholecalciferol in patients with renal failure. Severe hypocalcemia may lead to cardiac arrhythmias, muscular contractions, and seizures. These events may further damage affected muscles. Late findings of hypercalcemia may be related of Ca leakage from damaged muscles and poor clearance if the case is complicated by kidney injury.

Hypoalbuminemia results from proteinuria and direct leakage of protein, whereas hyperuricemia is caused by direct damage to muscle and may contribute to renal tubular damage.

Compartment syndrome may be either a complication of or the inciting cause of rhabdomyolysis. If muscle injury has occurred, measure compartment pressures; if the pressure is higher than 30 mm Hg, fasciotomy is indicated.[1]

Acute kidney injury (AKI) occurs in 17-35% of adult patients[70] and in 5-42% in 2 pediatric case series.[6] Etiologies of AKI may be related to hypovolemia, vasoconstriction, and myoglobin toxicity.

AKI and disseminated intravascular coagulation (DIC, a late complication) are the most severe complications of rhabdomyolysis, often developing 12-72 hours after initial muscle damage. AKI may account for as many as 35% of adult cases. This figure may be as low as 5% in children.[6, 67] Rhabdomyolysis may account for 7-10% of acute kidney injuries in the United States.[3, 67]

Renal failure may also develop in patients treated with optimal measures. Mechanisms of renal injury are multifactorial and may include renal vasoconstriction, intraluminal myoglobin cast formation, and heme-protein cellular toxicity. Myoglobin and hemoglobin toxic effect on the glomerulus are enhanced by aciduria and hypovolemia.

Because patients may present without any obvious history or physical sign of rhabdomyolysis, clinicians must be aware of the potentially subtle presentation and keep the possibility of rhabdomyolysis in mind. In the evaluation of blunt trauma in children, it is vital to remain vigilant for signs of child abuse (nonaccidental injury). Consider rhabdomyolysis in cases of child abuse, drug-overdoses, heat-related events and pediatric orthopedic injuries.

Failure to consider this diagnosis could result in the most severe complication of rhabdomyolysis: pigment-associated renal injury. Rhabdomyolysis accounts for 5-25% of cases of acute kidney injury (AKI) in adult patients; rates in pediatric patients are unknown.

Useful laboratory tests that should be ordered include the following:

• Complete blood count (CBC), including hemoglobin, hematocrit, and platelets

• Serum chemistries, including blood urea nitrogen (BUN), creatinine, glucose, calcium, potassium, phosphate, uric acid, and liver function tests (LFTs)

• Prothrombin time (PT)

• Activated partial thromboplastin time (aPTT) – Thromboplastin released from injured myocytes can cause disseminated intravascular coagulation (DIC)

• Serum aldolase

• Lactate dehydrogenase (LDH)

Hyperkalemia, an immediate threat to life in the hours immediately after injury, occurs in 10-40% of cases. Liberated potassium can cause life-threatening dysrhythmias and death. Hyperphosphatemia does not require specific therapy. Hypocalcemia occurs early in the course of rhabdomyolysis. Supplemental calcium is not recommended. Increased purine metabolism causes hyperuricemia. Specific therapy with uricosuric agents or allopurinol is not indicated.

The BUN-creatinine ratio may be decreased because of the conversion of liberated muscle creatine to creatinine. In an emergency department (ED)-based study of 97 adults with rhabdomyolysis, no patient presenting in an ED setting with an initial creatinine level of less than 1.7 mg/dL developed ARF.[71]

One series of 109 ED patients with rhabdomyolysis found that 50% had an elevated cardiac troponin I level. Of these, 58% were ultimately found (on the basis of electrocardiography [ECG] and echocardiography) to be true positives, 33% were false positives, and 9% were indeterminate.[72]

A study analyzed the specific features and mortality of patients with rhabdomyolysis and the relation between creatinine, creatine kinase and mortality. The study concluded that despite being a diagnostic marker for rhabdomyolysis, initials creatine kinase levels do not predict mortality. However, the authors added that creatinine initial levels are related to progression to acute renal injury and mortality at 30 days.[73]

Creatine kinase

The diagnosis of rhabdomyolysis can be confirmed using certain laboratory studies.[14] The most reliable and sensitive indicator of muscle injury is creatine kinase (CK). Assessing CK levels is most useful because of its ease of detection in serum and its presence in serum immediately after muscle injury.

CK levels rise within 12 hours of muscle injury, peak in 24-36 hours, and decrease at a rate of 30-40% per day.[74] The serum half-life of CK is approximately 36 hours. CK levels decline 3-5 days after resolution of muscle injury[14] ; failure of CK levels to decrease suggests ongoing muscle injury or development of a compartment syndrome. The peak CK level, especially when it is higher than 15,000 U/L, may be predictive of renal failure.[75]

Total CK elevation is a sensitive but nonspecific marker for rhabdomyolysis. CK levels 5 times the reference range suggest rhabdomyolysis, though CK levels in rhabdomyolysis are frequently as high as 100 times the reference range or even higher. Suspect early rhabdomyolysis in patients with serum CK levels in excess of 2-3 times the reference range and risk factors for rhabdomyolysis; initiate a full laboratory workup. Because the total CK may increase from the initial values, draw repeat total CK levels every 6-12 hours until a peak level is established.

Myoglobin

Plasma myoglobin measurements are not reliable, because myoglobin has a half-life of 1-3 hours and is cleared from plasma within 6 hours. Myoglobin levels not measured at the right time may produce a false-negative result, though a positive result may help confirm the diagnosis. Urine myoglobin measurements are therefore preferable.

A urine myoglobin assay is helpful in patients with coexisting hematuria (confirmed with microscopic examination) when the presence of myoglobin is suspected. A urine dipstick test for blood that has positive findings in the absence of red blood cells (RBCS) suggests myoglobinuria. Myoglobinuria may be sporadic or resolve early in the course of rhabdomyolysis. Urine dipstick findings are positive in fewer than 50% of patients with rhabdomyolysis; thus, a normal test result does not rule out this condition.[76]

Imaging studies generally play little role in the initial diagnosis of rhabdomyolysis. However, radiographs should be obtained when fractures are suspected. Computed tomography (CT) of the head may be necessary on a case-by-case basis when a patient with an altered sensorium is evaluated.[77] Patients with significant head trauma may require head CT. A head CT scan may also be obtained in patients with first-time seizure activity or prolonged seizures or in patients with neurologic deficits of unknown etiology.

Magnetic resonance imaging (MRI) may be useful in distinguishing various etiologies of myopathy. One study suggests that bacterial myositis, focal myositis, and idiopathic rhabdomyolysis show a characteristic gadolinium enhancement on MRI. Abscesses were found only in bacterial myositis. Polymyositis and dermatomyositis have a characteristic uniform distribution pattern with emphasis on the quadriceps muscles.

MRI is the imaging modality of choice for evaluating the distribution and extent of injury of affected muscles, especially when fasciotomy or involvement of deep compartments is considered.[78]

ECG should be performed early in the course of evaluation to evaluate for cardiac dysrhythmias related to hyperkalemia or hypocalcemia. ECG may reveal changes reflective of acute hyperkalemia, including peaked T waves, prolongation of the PR and QRS intervals, and loss of the P wave or the sine wave. Specific disease testing may be indicated to determine definitive causes during or after short-term management of rhabdomyolysis.

The compartment pressures should be measured in any patient with severe focal muscle tenderness and a firm muscle compartment. A fasciotomy may be needed if compartment pressures in excess of 25-30 mm Hg are sustained.[1]

Histology demonstrates necrotic muscle fibers in patients with rhabdomyolysis. A muscle biopsy may be required to demonstrate immunohistochemical features of necrosis only if underlying and often inherited muscle disease is a concern. Immunoblotting, immunofluorescence, and genetic studies may be necessary to find evidence of inflammatory conditions or dystrophinopathies.[14]

Assess the ABCs (A irway, B reathing, C irculation), and provide supportive care as needed. Ensure adequate hydration, and record urine output. Insert a Foley catheter for careful monitoring of urine output. Identify and correct the inciting cause of rhabdomyolysis (eg, trauma, infection, or toxins).[79]

General recommendations for the treatment of rhabdomyolysis include fluid resuscitation and prevention of end-organ complications (eg, acute renal failure [ARF]). Other supportive measures include correction of electrolyte imbalances.[1, 80] Obtain an ECG to monitor effects of hyperkalemia and other electrolyte disturbances.

Serial physical examinations and laboratory studies are indicated to monitor for compartment syndrome, hyperkalemia, acute oliguric or nonoliguric renal failure, and disseminated intravascular coagulation (DIC). Compartment syndrome necessitates immediate orthopedic consultation for fasciotomy. DIC should be treated with fresh frozen plasma, cryoprecipitate, and platelet transfusions. Monitor cardiac function. Monitor creatine kinase (CK) levels to show resolution of rhabdomyolysis.

Once the patient’s condition has been stabilized and life- and limb-threatening conditions have been addressed, he or she may be transferred to another facility if necessary. Follow the guidelines of the Consolidated Omnibus Budget Reconciliation Act (COBRA) and the Emergency Medical Treatment and Labor Act (EMTALA). In natural disasters, patients often have to be evacuated out of affected areas and transported to locations that can provide dialysis services.[1]

Once they are well hydrated, patients with normal renal function, normal electrolyte levels, alkaline urine, and an isolated cause of muscle injury may be discharged and monitored as outpatients. Any diagnostic or genetic tests during inpatient stay should be communicated to primary care or outpatient specialty physicians.

Expansion of extracellular volume is the cornerstone of treatment and must be initiated as soon as possible. No randomized trials of fluid repletion regimens in any age group have been done.[3] Retrospective studies of patients with severe crush injuries resulting in rhabdomyolysis suggest that the prognosis is better when prehospital personnel provide fluid resuscitation.[80] Support of intravascular volume increases the glomerular filtration rate (GFR) and oxygen delivery and dilutes myoglobin and other renal tubular toxins.

Patients with a CK elevation in excess of 2-3 times the reference range, appropriate clinical history, and risk factors should be suspected of having rhabdomyolysis. Obtain intravenous (IV) access with a large-bore catheter. For adults, administer isotonic fluids at a rate of approximately 400 mL/h (may be up to 1000 mL/h based on type of condition and severity) and then titrate to maintain a urine output of at least 200 mL/h.[3]

Because injured myocytes can sequester large volumes of extracellular fluid, crystalloid requirements may be surprisingly large. In patients with CK levels of 15,000 IU/L or greater, higher volumes of fluid, on the order of at least 6 L in adults, are required.[81] (Consider central venous pressure measurement or Swan-Ganz catheterization in patients with cardiac or renal disease. These invasive studies can assist in the assessment of the intravascular volume.) Repeat the CK assay every 6-12 hours to determine the peak CK level.

Aggressive and early hydration with isotonic sodium chloride solution is important for the prevention of pigment-associated renal failure. The composition of repletion fluid is controversial and may also include sodium bicarbonate. Initial fluid use in young children has been recommended to be 20 mL/kg; in adolescents, 1-2 L/h has been recommended. Subsequent hydration at a level 2-3 times maintenance may be sufficient.[11, 82] Few studies of fluid repletion regimens in children are available.[11]

ARF develops in 30-40% of patients with rhabdomyolysis. Suggested mechanisms include the following:

• Precipitation of myoglobin and uric acid crystals within renal tubules

• Decreased glomerular perfusion

• Nephrotoxic effect of ferrihemate

Ferrihemate and globin are the breakdown products of myoglobin when pH levels fall to less than 5.6. Ferrihemate is one of the agents responsible for acute tubular necrosis (ATN). It contains iron, a transition element, which is free to accept and donate electrons. This results in the generation of free radicals, which cause direct renal cell injury. Heme-proteins may also affect nitrous oxide (NO), endothelin receptors, and cytokines.[14]

Suggested predictors of the development of AKI and potentially renal failure include the following[70] :

• Peak CK level higher than 6000 IU/L

• Dehydration (hematocrit >50, serum sodium level >150 mEq/L, orthostasis, pulmonary wedge pressure < 5 mm Hg, urinary fractional excretion of sodium < 1%)

• Sepsis

• Hyperkalemia or hyperphosphatemia on admission

• Hypoalbuminemia

AKI has occasionally developed in severely dehydrated patients with peak CK levels as low as 2000 IU/L. To prevent renal failure, many authorities advocate urinary alkalization, mannitol, and loop diuretics.

Alkalization of urine is believed to be helpful and is based on the observation that acidic urine is necessary to cause ATN. Alkalinization may also reduce the occurrence of cast formation (ferrihemate and myoglobin). Some authorities believe that aggressive hydration sufficiently causes a solute diuresis that alkalizes the urine. Evidence for the use of these agents is mostly from animal studies and retrospective adult studies. There is no supporting evidence in the pediatric literature regarding alkalinization of urine.[10] It is recommended for patients with rhabdomyolysis and CK levels higher than 6000 IU/L.

Urinary alkalization should be considered earlier in patients with acidemia, dehydration, or underlying renal disease. A suggested regimen for adult patients is isotonic sodium chloride solution (0.9% NaCl) with 1 ampule of sodium bicarbonate administered at 100 mL/h. Sodium bicarbonate is used with care because it may potentiate hypocalcemia. The IV bicarbonate concentration is often adjusted to achieve a urine pH higher than 6.5-7.0. This level of alkalization inhibits precipitation of myoglobin and hemoglobin in the tubules. If the pH of urine less than 6.5, alternate each liter of normal saline with 1 L of 5% dextrose plus 100 mmol of bicarbonate.

If urine output is inadequate, consider the use of diuretics such as mannitol (in adults) and furosemide. Mannitol, acting as an osmotic diuretic, is thought to increase urinary flow and reduce myoglobin cast obstruction in renal tubules.[1] Its efficacy has not been adequately compared with that of aggressive hydration regimens.[3, 14, 83] Loop diuretics such as furosemide may be used to enhance urinary output in patients who are oliguric despite adequate intravascular volume. It is recommended that aggressive volume expansion is to be maintained until myoglobinuria is cleared. Prospective multicenter studies may be necessary to understand the efficacy of bicarbonate and mannitol in patients with rhabdomyolysis.

Frequently monitor serum electrolyte levels, urine pH levels, and acid-base status.[1, 80] Metabolic abnormalities should also be addressed.

Treatment of hyperkalemia consists of IV sodium bicarbonate, glucose, and insulin; oral or rectal sodium polystyrene sulfonate; and hemodialysis. These measures transiently shift potassium from extracellular to intracellular compartments.[11, 77] Administer IV calcium chloride for patients who are hemodynamically compromised and hyperkalemic.

Hypocalcemia is noted early in the course of rhabdomyolysis and generally is not of clinical significance. Correct hypocalcemia only if the patient has cardiac dysrhythmias or seizures. Calcium may combine with phosphate, forming a metastatic calcification, often intramuscularly. Calcium supplementation is not recommended, as hypercalcemia may be seen in the recovery phase (late).

Hyperuricemia and hyperphosphatemia rarely are of clinical significance and rarely require treatment. Control of hyperphosphatemia, if required, is achieved by using alkaline diuresis. Hypercalcemia may develop during the recovery phase, especially if there is acute kidney injury.

Dialysis may be required in patients with oliguric renal failure, persistent hyperkalemia, other electrolyte abnormalities, pulmonary edema, congestive heart failure, and persistent metabolic acidosis.

The role of free-radical scavengers and antioxidants in rhabdomyolysis (eg, pentoxifylline, vitamin E, and vitamin C) has been studied in animal models of ischemia-reperfusion injuries. Controlled studies evaluating the efficacy of these agents have not been performed, and their clinical use remains unclear.[14, 3]

With adequate hydration ensured, no specific outpatient medications are needed. Inciting myotoxic agents should be stopped.

Surgical care may be necessary, depending on the cause of rhabdomyolysis.[1]

Compartment pressures should be measured when significant muscle injury has occurred (see Workup). Muscle injury results from decreased tissue perfusion, which is caused by increased pressure within the affected space. High intracompartmental pressures mediate further ischemia, damage, and necrosis. When the intracompartmental pressure exceeds 30 mm Hg, a fasciotomy is advocated. Prolonged elevated intracompartmental pressure may lead to irreversible peripheral nerve injury.[1]

Limb fractures may require surgical and orthopedic treatment.[84]

Dietary modification may help to reduce the symptoms associated with some of the metabolic disorders and inborn errors of metabolism.[12]

Dietary supplementation with glucose or fructose may decrease the pain and fatigue associated with phosphorylase deficiency. The muscle pain and myoglobinuria due to carnitine palmityl transferase deficiency may be reduced with frequent meals and a low-fat, high-carbohydrate diet. Substitution of medium-chained triglycerides may also be helpful.

Dietary modification does not seem to change the muscle symptoms of phosphofructokinase deficiency or phosphoglycerate mutase deficiency.

Strenuous activities (eg, competitive sports) should be avoided if they cause recurrent myalgias, myopathy, or rhabdomyolysis.[12] Children and adolescents with recurrent rhabdomyolysis related to exertion require further medical evaluation.

High-school coaches and trainers must ensure proper hydration and maintain fluid balance during practice sessions and games. Signs and symptoms of heat exhaustion must be evaluated in a timely fashion during hot and humid conditions.[61]

Once a preventable inciting cause of rhabdomyolysis is identified, the patient must make an effort to avoid it. Exercise should be reduced or avoided if it is causing or exacerbating rhabdomyolysis.[85]

Alcohol should be avoided. Overdose of narcotics, sedative-hypnotics, or any other drugs known to cause immobilization and, hence, pressure necrosis should be avoided. Proper mental health and drug rehabilitation services should be offered to individuals with substance use disorders. Use of stimulants (eg, cocaine, amphetamines, or Ecstasy) should be discouraged.

Compliance with seizure and asthma medications may reduce status epilepticus, status asthmaticus, or both.

Any risky behavior that results in trauma should be avoided.

Consult a nephrologist for patients who have significant rhabdomyolysis, show evidence of renal failure, or require dialysis. Indications for hemodialysis include hyperkalemia that is persistent despite therapy, severe acid-base disturbances, refractory pulmonary edema, and progressive renal failure.

Consult a neurologist for patients with status epilepticus or new-onset seizures.

Consult an orthopedic surgeon for patients with a limb fracture or suspected compartment syndrome.

Notify the poison control center in cases of overdose or snake/insect envenomation.

Consult a geneticist or metabolism specialist for patients with genetic or metabolic abnormalities. Diagnosis of inborn errors of metabolism and prompt metabolic interventions may be life-saving.

Consult a rheumatologist for patients with suspected inflammatory myopathies, systemic lupus erythematosus, or sarcoidosis.

Medical therapy for rhabdomyolysis focuses on restoring adequate intravascular volume. Hydration with isotonic sodium chloride solution (0.9% NaCl) is the cornerstone of rhabdomyolysis therapy. Many clinicians recommend the use of sodium bicarbonate. Use furosemide or other diuretics (such as mannitol in adults) with sufficient hydration if urine output is inadequate. Hyperkalemia should also be addressed.

Class Summary

The use of crystalloid solutions is the cornerstone of rhabdomyolysis therapy.

Sodium chloride 0.9%

Aggressive and early hydration with isotonic sodium chloride solution is important for the prevention of pigment-associated renal failure.

Class Summary

Loop diuretics promote the excretion of water and electrolytes by the kidneys.

Furosemide (Lasix)

Furosemide increases water excretion by interfering with the chloride-binding cotransport system; this, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and the distal renal tubule. Dosing must be individualized. Depending on the response, administer at increments of 20-40 mg every 6-8 hours until the desired diuresis occurs. When treating infants, titrate in increments of 1 mg/kg until a satisfactory effect is achieved.

Class Summary

Osmotic diuretics increase osmolarity of glomerular filtrate and induce diuresis. They hinder tubular reabsorption of water, causing sodium and chloride excretion to increase.

Mannitol (Osmitrol)

Mannitol is an alternative diuretic used when urine output is inadequate despite aggressive fluid therapy. Initially, assess for adequate renal function in adults by administering a test dose of 200 mg/kg intravenously (IV) over 3-5 minutes; this should produce a urine flow of at least 30-50 mL/h over 2-3 hours. In children, assess for adequate renal function by administering a test dose of 200 mg/kg IV over 3-5 minutes; this should produce a urine flow of at least 1 mL/h over 1-3 hours.

Class Summary

Intracellular potassium transporters are used to decrease serum potassium levels. Insulin causes a transcellular shift of potassium into muscle cells, thereby temporarily lowering serum levels of potassium.

Potassium exchange resins decrease serum potassium levels. Sodium polystyrene sulfonate is an exchange resin that can be used to treat mild-to-moderate hyperkalemia. Each 1 mEq of potassium is exchanged for 1 mEq of sodium.

Insulin regular human (Humulin, Novolin)

Regular human insulin stimulates cellular potassium uptake within 20-30 minutes. Administer with dextrose to prevent hypoglycemia. Monitor blood sugar levels frequently.

Sodium polystyrene sulfonate (Kayexalate)

Sodium polystyrene sulfonate exchanges sodium for potassium and binds it in the gut, primarily the large intestine. It decreases total-body potassium levels. Onset of action after oral administration ranges from 2-12 hours and takes longer after rectal administration.

Sodium polystyrene sulfonate should not be used as first-line therapy for severe life-threatening hyperkalemia. It may be used in the second stage of therapy to reduce total-body potassium levels. The resin is typically mixed in 25% sorbitol before administration.

Class Summary

Beta2 -adrenergic agents are used adjunctively to decrease serum potassium levels temporarily. Albuterol and other beta-adrenergic agents induce the intracellular movement of potassium via stimulation of the sodium-potassium adenosine triphosphatase (Na/K-ATPase) pump. Some studies using nebulized albuterol in adults and children indicate that this method of therapy is effective in lowering serum potassium levels, but peak response is unclear. Therefore, nebulized albuterol has not been established as a first-line therapy in severe hyperkalemia.

Albuterol (AccuNeb, Proair HFA, ProAir RespiClick)

Nebulized albuterol is an adrenergic agonist that increases plasma insulin concentrations. This increase in insulin may shift potassium into the intracellular space. The onset of the decrease in potassium occurs at about 30 minutes. The duration of action is dose-dependent and is typically between 2 and 5 hours.

Class Summary

Sodium bicarbonate is administered IV to alkalize urine in patients with rhabdomyolysis. This may prevent toxicity caused by the presence of myoglobin in acidic urine and crystallization of uric acid.

Sodium bicarbonate (Neut)

Sodium bicarbonate is useful in alkalization of urine to prevent acute myoglobinuric renal failure. Titrate the dose to raise the pH above 6.5-7.0.