Rhabdomyolysis Diagnosis: A Comprehensive Guide for Auto Repair Experts

Introduction

Rhabdomyolysis, often referred to as “rhabdo,” is a serious medical condition characterized by the breakdown of damaged skeletal muscle. This breakdown leads to the release of muscle cell contents, including myoglobin, electrolytes, and sarcoplasmic proteins, into the bloodstream. While traditionally associated with severe trauma, rhabdomyolysis can stem from a wide array of causes, both traumatic and non-traumatic. For auto repair experts, understanding Rhabdomyolysis Diagnosis is crucial, not only for personal health awareness given the physically demanding nature of the profession, but also for a broader understanding of conditions that can impact physical performance and well-being. The most concerning complications of rhabdomyolysis include acute kidney injury (AKI), electrolyte imbalances, and disseminated intravascular coagulation (DIC), highlighting the systemic impact of this condition. Early and accurate rhabdomyolysis diagnosis is paramount for timely intervention and preventing severe health outcomes.

Clinically, rhabdomyolysis can manifest with a spectrum of symptoms, ranging from mild muscle soreness and elevated creatine phosphokinase (CPK) levels to life-threatening emergencies like compartment syndrome and AKI. Dark, reddish-brown urine, a consequence of myoglobinuria, is a classic sign but not always present. Laboratory evaluation, particularly serum CPK levels, is the cornerstone of rhabdomyolysis diagnosis. While there isn’t a universally defined diagnostic CPK level, a significant elevation, typically several times the upper limit of normal, is indicative of muscle damage. It’s important to note that the degree of CPK elevation doesn’t always correlate directly with the severity of muscle damage or the risk of renal injury.

Rhabdomyolysis-induced AKI is a major concern. However, with prompt rhabdomyolysis diagnosis and early management, the prognosis for AKI is generally favorable. It’s essential to consider alternative causes of AKI, such as dehydration, sepsis, and medication side effects, in the differential diagnosis. Factors like seizures, alcohol and drug use, and prolonged immobilization are recognized triggers for non-traumatic rhabdomyolysis. Rarer etiologies, including genetic disorders, certain toxins, and specific infections, also warrant consideration in rhabdomyolysis diagnosis and investigation.

The historical recognition of rhabdomyolysis dates back centuries, with early accounts linking similar symptoms to quail consumption by Israelites. The understanding of myoglobin’s role in kidney damage emerged more recently, particularly from studies during wartime crush injuries. Today, rhabdomyolysis remains a relevant clinical challenge, emphasizing the ongoing need for enhanced awareness and improved strategies for rhabdomyolysis diagnosis and management.

Etiology of Rhabdomyolysis

The causes of rhabdomyolysis are broadly categorized into traumatic (physical) and non-traumatic (non-physical) etiologies. Often, the condition arises from a combination of factors, where genetic predisposition might amplify the impact of external insults. A thorough approach to rhabdomyolysis diagnosis necessitates a detailed patient history, comprehensive physical examination, and targeted laboratory investigations to pinpoint the underlying cause. Epidemiological studies have shown variations in the prevalence of different causes of rhabdomyolysis, influenced by geographic location and community-specific factors.

Traumatic or Physical Causes of Rhabdomyolysis

Traumatic rhabdomyolysis results from direct muscle injury, often due to compression or overexertion. Subclinical elevations in CPK and myoglobin are common after strenuous physical activity.

Specific traumatic causes include:

Crush Injuries: Polytrauma from motor vehicle accidents, mining incidents, and natural disasters like earthquakes, especially when individuals are trapped.
Prolonged Immobilization: Extended periods of immobility due to coma, drug or alcohol intoxication, hip fractures, or lengthy surgeries requiring specific body positioning.
Physical Abuse and Restraint: Torture, abuse, and physical restraint, particularly of children.
Vascular Injury: Fractures of the lower extremities (e.g., tibial fractures) leading to arterial occlusion from prolonged immobilization, tourniquets, or surgical clamping.
Burn Injuries: Fire accidents and explosions causing significant muscle damage.
Electrical Injuries: High-voltage electric shock and lightning strikes, which cause direct sarcoplasmic membrane damage, massive calcium influx, and severe rhabdomyolysis.
Extreme Exertion: Strenuous muscular exercise, especially in untrained individuals, heavy lifting, exercise in extreme heat, status epilepticus, tetanus, and, in rare cases, sepsis.

Non-traumatic or Non-physical Causes of Rhabdomyolysis

Non-traumatic rhabdomyolysis arises from conditions that disrupt muscle cell function without direct physical trauma. These causes often involve imbalances in oxygen supply and demand, electrolyte disturbances, and metabolic abnormalities.

Key non-traumatic causes include:

Medications: Numerous drugs can induce rhabdomyolysis, with statins being a prominent example.
Infections: Viral myositis is a common infectious cause, and SARS-CoV-2 (COVID-19) has emerged as a significant associated factor. Bacterial sepsis can also trigger rhabdomyolysis.
Electrolyte Imbalances: Hypokalemia, hypophosphatemia, hyperosmolar states, hypo- and hypercalcemia, and severe dehydration.
Endocrine Disorders: Hyperosmolar hyperglycemic state, diabetic ketoacidosis with coma, and myxedema.
Congenital Myopathies: Genetic muscle disorders, such as myotonic dystrophy, Duchenne muscular dystrophy, and Becker muscular dystrophy.
Toxins: Insect bites, snake venom, hornet stings, carbon monoxide poisoning, Haff disease, and mushroom poisoning.
Autoimmune Myositis: Conditions like polymyositis and dermatomyositis.
Thermoregulatory Dysfunction: Neuroleptic malignant syndrome, malignant hyperthermia, near drowning, hypothermia, and frostbite.
Supplements: Over-the-counter vitamins, performance-enhancing supplements, and weight-loss aids.
Capillary Leak Syndrome: Muscle edema leading to capillary leak.
Drug-related: Both drug intoxication and withdrawal can precipitate rhabdomyolysis.

Statins and Rhabdomyolysis

Statins, widely used lipid-lowering medications, are among the most common pharmaceutical causes of rhabdomyolysis. Muscle pain is reported by up to 10% of statin users. The increasing use of statins has led to a rise in rhabdomyolysis cases linked to HMG Co-A reductase inhibitors. Statin-induced muscle toxicity spans a spectrum from myopathy and myalgia to myositis and rhabdomyolysis. Proposed mechanisms involve CoQ10 depletion affecting mitochondrial function, disruption of cellular respiration, impaired calcium homeostasis, apoptosis induction, and direct effects of HMG Co-A inhibitors. Statin-related myopathy typically presents without muscle necrosis and with CPK levels below 1000 U/L, while autoimmune myopathy, a rarer form, is associated with higher CPK levels (above 1000 U/L) and muscle necrosis.

Discontinuing statin therapy often resolves statin-induced rhabdomyolysis. However, persistently elevated CPK after stopping statins should raise suspicion for necrotizing autoimmune myopathy. Concomitant use of medications like gemfibrozil, cyclosporine, cytochrome P450 inhibitors, and corticosteroids increases the risk of statin-induced rhabdomyolysis. While the overall incidence of clinically significant rhabdomyolysis requiring hospitalization due to statins is low (around 0.44 per 10,000 patients on atorvastatin, simvastatin, and pravastatin monotherapy), muscle-related side effects frequently lead to statin therapy discontinuation in clinical practice. Using the lowest effective statin dose is recommended for patients with a history of drug-induced rhabdomyolysis.

Drug Intoxication and Rhabdomyolysis

Various intoxicants can trigger rhabdomyolysis through different mechanisms. Cocaine is a known cause, with mechanisms including increased sympathetic activity, alpha-receptor stimulation in blood vessels, elevated endothelin production, and reduced nitric oxide levels. Cocaine also promotes thrombosis by activating platelets and inhibiting plasminogen.

Studies have shown a high incidence of drug-induced rhabdomyolysis in intravenous heroin users, potentially due to local injection trauma and immune-mediated mechanisms. Amphetamines are also linked to high rates of rhabdomyolysis, likely due to hyperthermia from their effects on serotonin, dopamine, and norepinephrine. Alcohol, opiates, phenobarbital, and benzodiazepines can lead to rhabdomyolysis indirectly through prolonged immobilization during intoxication, causing muscle compression. Withdrawal from opioids and baclofen (especially intrathecal baclofen) has also been associated with rhabdomyolysis. Chronic alcohol misuse is often complicated by rhabdomyolysis due to direct muscle toxicity of alcohol and associated factors like hypophosphatemia and hypokalemia.

Rhabdomyolysis in Intensive Care Settings

Admission to the intensive care unit (ICU) is a significant risk factor for rhabdomyolysis. ICU patients are often critically ill, receive multiple medications, and are susceptible to electrolyte imbalances, all of which increase rhabdomyolysis risk. In ventilated patients, propofol infusion syndrome (PRIS) should be considered. PRIS, a form of propofol toxicity, is thought to involve mitochondrial dysfunction, leading to metabolic acidosis, rhabdomyolysis, arrhythmias, AKI, and cardiovascular collapse.

Congenital Myopathies and Rhabdomyolysis

Numerous congenital myopathies can predispose to rhabdomyolysis. Some common examples include:

Glycogenolysis Disorders: Myophosphorylase deficiency (McArdle disease) and phosphorylase kinase deficiency.
Glycolysis Disorders: Phosphofructokinase, phosphoglycerate kinase, mutase, and lactate dehydrogenase deficiencies.
Purine Metabolism Disorders: Myoadenylate deaminase deficiency.
Lipid Metabolism Disorders: Carnitine and carnitine palmitoyltransferase deficiencies, short- or long-chain acyl-CoA dehydrogenase deficiency, lipin-1 deficiency, and Brody myopathy (calcium adenosine triphosphatase [CAT] deficiency).

Even without baseline CPK elevations, genetic susceptibility can increase rhabdomyolysis risk when combined with external triggers. Genes implicated in this susceptibility include ACADVL, ANO5, CPT2, DMD, DYSF, FKRP, HADHA, PGM1, LPIN1, PYGM, and RYR1. Sickle cell trait, affecting millions globally, also increases rhabdomyolysis risk, particularly during exertional dyspnea. Patients with sickle cell disease are prone to rhabdomyolysis during sickle cell crises, necessitating trigger avoidance.

Sepsis and Rhabdomyolysis

Sepsis can induce rhabdomyolysis through various mechanisms: direct muscle invasion by pathogens, muscle ischemia from hypoxia, toxin production, and cytokine-mediated muscle toxicity. Staphylococcus aureus is known to cause rhabdomyolysis via direct invasion and toxin release. Muscle biopsies from rhabdomyolysis patients have shown streptococci, salmonellae, and S. aureus. Other implicated pathogens include Staphylococcus epidermidis, Francisella tularensis, Streptococcus faecalis, Neisseria meningitidis, Hemophilus influenzae, Escherichia coli, pseudomonads, Klebsiella, Enterococcus faecalis, and Bacteroides.

Epidemiology of Rhabdomyolysis

In the United States, approximately 26,000 rhabdomyolysis cases are reported annually. The incidence of AKI in rhabdomyolysis varies widely due to inconsistent AKI definitions and the variable severity of rhabdomyolysis cases. Rhabdomyolysis can occur at any age, but it is most prevalent in adults. Men, Black individuals, those over 60, and individuals with obesity have an elevated risk. In children, infection is the most common cause of rhabdomyolysis (around 30%).

Crush syndrome incidence ranges from 30% to 50% in traumatic rhabdomyolysis. Children have a lower risk of crush syndrome and better mortality rates than adults. AKI and dialysis needs from crush injuries vary across studies. During natural disasters like earthquakes, rapid fluid resuscitation, timely extrication, and immediate multidisciplinary hospital care reduce AKI, morbidity, and mortality.

In 2002, a joint clinical advisory by the American College of Cardiology (ACC), National Heart-Lung and Blood Institute, and American Heart Association defined statin-associated rhabdomyolysis as muscle symptoms with elevated creatine kinase, typically exceeding 11 times the upper normal limit (myonecrosis), along with elevated serum creatinine consistent with pigment-induced nephropathy and myoglobinuria. Clinically significant myonecrosis may occur in about 0.5% of statin users.

The incidence of rhabdomyolysis from immobilization, alcohol intoxication, fractures, strenuous exercise, and insect bites is less precisely defined due to their sporadic nature.

Pathophysiology of Rhabdomyolysis

While rhabdomyolysis has diverse causes, the ultimate pathogenic pathway involves direct myocyte injury or energy supply failure within muscle cells. The sarcoplasmic membrane’s sodium-potassium pump and sodium-calcium exchanger maintain low intracellular sodium and calcium and high intracellular potassium in resting muscle. Calcium is stored in the sarcoplasmic reticulum at rest. Muscle contraction is an energy-dependent process requiring ATP and calcium. Any insult disrupting ATP, ion channels, or the plasma membrane leads to intracellular electrolyte imbalance.

Muscle injury (trauma, exercise, thermal syndromes) or ATP depletion (medications, electrolyte imbalances, genetic and metabolic disorders, intense exercise, ischemia) causes intracellular sodium and calcium influx. Water follows sodium into the cell, causing swelling and disruption of intracellular structures and membranes. Excessive intracellular calcium activates actin-myosin cross-linking, myofibrillar contraction, and ATP depletion. It also activates calcium-dependent phospholipases and proteases, promoting cell membrane breakdown and ion channel disruption.

Reperfusion of damaged muscle triggers leukocyte migration, releasing cytokines, prostaglandins, and free radicals, which exacerbate myolysis, muscle fiber necrosis, and the release of breakdown products (potassium, myoglobin, creatine kinase, phosphate, uric acid, organic acids) into the bloodstream. This leads to hyperkalemia and hyperphosphatemia. In rhabdomyolysis, initial hypocalcemia is followed by hypercalcemia as calcium initially enters myocytes during injury and then leaks out after cell lysis.

Myoglobinuria and its Role in Rhabdomyolysis

Myoglobin, a 19 kDa heme protein, is abundant in skeletal and cardiac muscle sarcoplasm. It functions to carry and store oxygen in myocytes due to its high oxygen affinity, facilitating oxygen transfer from blood to muscle tissue.

Circulating myoglobin is primarily bound to haptoglobin and α2-immunoglobulin. However, haptoglobin saturation occurs at serum myoglobin levels above 0.5 to 1.5 mg/dL, and excess free myoglobin is filtered by the glomerulus. While kidneys normally filter and excrete small amounts of myoglobin, the massive myoglobin release in rhabdomyolysis can overwhelm this capacity, leading to AKI.

Acute Kidney Injury in Rhabdomyolysis

The kidney is particularly vulnerable to rhabdomyolysis-induced damage due to its high oxygen consumption and mitochondrial density. Muscle damage releases contents that cause inflammation and fluid sequestration. Reduced intravascular volume activates the renin-angiotensin-aldosterone system, further compromising renal blood flow. Sympathetic nervous system activation releases vasopressin, worsening renal ischemia.

Myoglobin is a key contributor to renal injury. Excess myoglobin overwhelms kidney filtration, depositing in renal tubules and causing toxicity. Myoglobin can bind oxygen, increasing free radicals and lipid peroxidation, leading to oxidative damage and renal vasoconstriction. Rhabdomyolysis also increases uric acid production, and acidosis promotes myoglobin binding to uromodulin (Tamm-Horsfall protein), forming tubular casts and worsening renal injury. Heme in myoglobin binds nitric oxide, reducing its concentration and inducing vasoconstrictors like endothelin-1, isoprostanes, and thromboxanes. Heme may also activate platelets.

AKI risk is estimated at 10% to 50% when CPK exceeds 1000 U/L. Predictors for AKI include dehydration, high initial serum creatinine, low serum bicarbonate and calcium, and high serum phosphate. Hypoalbuminemia and elevated blood urea nitrogen (BUN) are also associated with AKI development.

Compartment Syndrome as a Complication of Rhabdomyolysis

Trauma to muscle groups within confined compartments can lead to compartment syndrome. Muscle swelling increases pressure, causing further damage such as arterial occlusion and muscle necrosis. Sustained elevated compartment pressure can cause irreversible nerve palsy. Pressures above 30 mm Hg indicate significant muscle ischemia, and pressure measurement aids fasciotomy decisions. Rhabdomyolysis patients with blood loss and hypotension are at higher risk of muscle ischemia, even at lower compartment pressures. Crush injuries particularly predispose to compartment syndrome.

Disseminated Intravascular Coagulation (DIC) in Rhabdomyolysis

Heme proteins can trigger inflammatory responses and platelet activation, acting as damage-associated molecular patterns (DAMPs), inducing apoptosis, mitochondrial damage, inflammasome activation, and cytokine production. Heme is directly thrombogenic, promoting neutrophil extracellular trap (NET) formation, platelet degranulation, macrophage activation, and tissue factor expression. In a pro-inflammatory and pro-thrombotic state, DIC can also result from thromboplastin release during muscle injury. DIC is characterized by prolonged prothrombin time, activated partial thromboplastin time, elevated INR and D-dimer levels, and decreased platelet count and fibrinogen levels.

Histopathology in Rhabdomyolysis

Muscle biopsy is indicated when metabolic myopathies are suspected as underlying causes of rhabdomyolysis. Timing is critical for biopsy interpretation. Rhabdomyolysis can cause extensive muscle fiber necrosis, and biopsy during acute injury may obscure underlying myopathy. Current recommendations suggest biopsy after recovery from rhabdomyolysis to better identify underlying conditions. However, the European Federation of Neurological Societies (EFNS) Scientist Panels suggests that muscle biopsy may be considered at presentation in patients with muscle pain, weakness, CPK elevation 2-3 times normal, myoglobinuria, muscle hypertrophy or atrophy, and electromyography findings suggestive of myopathy.

Specific stains aid in identifying different myopathy types. Periodic acid Schiff and hematoxylin and eosin staining can reveal glycogen storage disorders through glycogen-containing vacuoles. Succinate dehydrogenase and cytochrome c oxidase staining, along with Gomori trichrome staining, can identify ragged red fibers in mitochondrial myopathies. Immunohistochemistry can detect enzyme deficiencies like phosphofructokinase and myophosphorylase deficiencies.

Kidney biopsies in AKI from rhabdomyolysis show varied findings. Early tubular changes can be seen by light microscopy as early as 1-12 hours post-injury, including dilated Bowman’s spaces, ruptured glomerular membranes, reduced glomerular tufts with flattened podocytes, and proximal convoluted tubule necrosis with loss of microvilli and basal infolding. Electron microscopy reveals electron-dense casts obstructing distal tubular lumens.

History and Physical Examination for Rhabdomyolysis Diagnosis

While the classic triad of muscle pain, weakness, and dark urine is characteristic of rhabdomyolysis, it’s present in less than half of patients. Muscle pain is the most common symptom, reported in about 50% of adults, while dark urine occurs in 30% to 40%. Weakness typically affects proximal muscle groups. Non-specific symptoms can include muscle cramps, stiffness, swelling, malaise, abdominal pain, nausea, palpitations, and fever. In patients with known myopathies, weakness is a primary complaint, especially in adults. History taking should explore illicit drug use, insect bites, heat exposure, recent surgeries, accidents, medication changes, and supplement use. A high degree of clinical suspicion is sometimes necessary for accurate rhabdomyolysis diagnosis.

Patients with underlying myopathies may exhibit muscle atrophy or hypertrophy. Rhabdomyolysis presents with both local and systemic features, including early and late complications. Local signs include bruising, swelling, and tenderness. Systemic features may involve fever, malaise, nausea, confusion, agitation, delirium, dark urine, or anuria. In trauma patients, assess distal pulses and peripheral nerve function to rule out limb ischemia, compartment syndrome, and neuropathy. Signs of dehydration, such as dry mucous membranes and reduced skin turgor, should be noted. Early recognition is crucial for preventing complications.

Evaluation and Rhabdomyolysis Diagnosis

Initial evaluation after vital signs assessment should include basic laboratory studies: complete blood count, comprehensive metabolic panel, C-reactive protein, erythrocyte sedimentation rate, serum CPK, and urinalysis. Chest radiography and electrocardiography are also recommended. While lactate dehydrogenase, aldolase, alanine aminotransferase, and aspartate aminotransferase are also released from damaged muscles, their elevation is non-specific for rhabdomyolysis. Elevated inflammatory markers and leukocytosis are also non-specific findings.

Elevated serum CPK is the hallmark of rhabdomyolysis diagnosis. Reddish-brown urine due to myoglobinuria may be present in about half of cases. Urine dipstick tests for blood can react with myoglobin, but microscopic urinalysis distinguishes myoglobinuria from hemoglobinuria by the absence of red blood cells in myoglobinuria.

Normal serum CPK ranges from 20 to 200 U/L. A level five times the upper limit of normal is generally considered diagnostic for rhabdomyolysis. CPK exists as isoenzymes: CK-MM (skeletal muscle), CK-MB 1 and 2 (cardiac muscle), and CK-BB (brain). CK-MM is most specific for skeletal muscle injury. CPK’s half-life is 36 hours; serum levels rise within 2-12 hours post-injury, peak in 1-5 days, and decline after 3-5 days without further injury. CPK levels above 5000 IU/L generally indicate significant muscle damage and increased AKI risk.

Myoglobin has a shorter half-life of 2-4 hours and is metabolized into bilirubin. Serum myoglobin may be detectable earlier than CPK, but its transient nature means myoglobinemia may not always be detected. Proteinuria can also occur due to protein release from damaged myocytes and glomerular changes. Research continues into biomarkers for early rhabdomyolysis diagnosis and heme-pigment induced AKI.

Electrolyte imbalances, including hyperkalemia and hyperphosphatemia, are common. AKI can be complicated by resistant hyperkalemia. Hypocalcemia can occur from calcium influx into myocytes, potentially followed by hypercalcemia. Rhabdomyolysis also elevates uric acid levels and can release organic acids like lactic acid, contributing to metabolic acidosis.

Electrocardiography may show peaked T waves, prolonged PR interval, wide QRS complex, conduction blocks, ventricular tachycardia, and asystole due to hyperkalemia. Hypocalcemia can prolong the QTc interval.

Plain radiographs can reveal fractures, joint dislocations, and soft tissue swelling. Computed tomography (CT) of affected muscle groups may help diagnose compartment syndrome. Acute compartment syndrome diagnosis is primarily clinical, confirmed by invasive intra-compartmental pressure measurement or non-invasive near-infrared spectroscopy. Additional tests like MRI, muscle biopsy, or electromyography are not typically required for rhabdomyolysis diagnosis in acute settings.

Muscle biopsy is usually performed after recovery to investigate inflammatory myopathies suspected from clinical history. Inflammatory and metabolic myopathies are considered in recurrent rhabdomyolysis, exercise intolerance, muscle cramps, fatigue, and family history.

Treatment and Management of Rhabdomyolysis

The primary goal in rhabdomyolysis management is to maintain adequate fluid resuscitation and prevent AKI. The first critical step is to identify and, if possible, remove the underlying cause of muscle injury. Active management includes continuous assessment of airway, breathing, and circulation, frequent physical exams, adequate hydration for end-organ perfusion, urine output monitoring, electrolyte correction, and detection of complications like compartment syndrome and DIC.

Management of Traumatic Rhabdomyolysis

For crush injuries, IV hydration should begin as early as possible, ideally in the field and before stimulus relief. Hydration should continue during transport. Delayed fluid resuscitation can worsen hypovolemia due to third spacing. Liberal fluid administration is needed to maintain intravascular volume and diuresis, potentially 10-20 liters.

Large-volume resuscitation in crush injuries prevents AKI and reduces dialysis needs. Patients trapped longer may already have AKI upon arrival, making aggressive fluid resuscitation challenging due to volume overload risk. No studies directly compare different fluid types and rates. International Society of Nephrology Renal Disaster Relief Task Force guidelines recommend isotonic saline over alkaline fluids for field resuscitation. Dextrose in saline can provide calories and minimize hyperkalemia. Initial field resuscitation may involve 2 liters at 1 L/h for the first 2 hours, then 500 mL/h for adults, adjusted based on age, gender, body habitus, bleeding risk, and trauma nature. Potassium-containing fluids like Ringer’s lactate are generally avoided.

Hospitalized patients need close urine output monitoring. After confirming output and absence of alkalosis, urine alkalinization may prevent myoglobin precipitation in distal tubules. Alkalinization also reduces uric acid precipitation, corrects acidosis, and lowers hyperkalemia risk. Most data on alkalinization are from uncontrolled case series. Adding 50 mEq sodium bicarbonate to half-normal saline is a traditional method. Bicarbonate can precipitate hypocalcemia, causing tetany and seizures. Aim for serum pH not exceeding 7.5 and urine pH just above 6.5. Discontinue bicarbonate when serum pH reaches 7.5.

Mannitol can improve urine output in crush injuries but should only be used after urine output is at least 20 mL/h. No specific guidelines exist for mannitol. A 60 mL 20% mannitol IV infusion over 5 minutes can assess for increased urine output. If output increases 30-50 mL/h, mannitol can be continued. Avoid mannitol in AKI, oliguria, or anuria due to volume overload and hyperosmolality risks. Current evidence does not support combined mannitol and bicarbonate use for AKI prevention.

Preventing or worsening hyperkalemia is critical. Avoid potassium-containing IV fluids. Oral sodium polystyrene sulfonate and sorbitol are commonly used for hyperkalemia in crush injuries. New potassium binders’ role is unclear due to limited studies. Point-of-care testing and ECG monitoring are important in suspected hyperkalemia.

Patients with crush syndrome need a Foley catheter and IV fluids to maintain urine output at 200-300 mL/h until myoglobinuria resolves and CPK levels decrease. Minimize Foley catheter duration to reduce infection risk. Loop diuretics can be used for volume overload. Hemodialysis is indicated for anuric AKI, hyperkalemia, and volume overload unresponsive to conservative measures. Peritoneal dialysis is less preferred in trauma settings.

Management of Non-traumatic Rhabdomyolysis

Non-traumatic rhabdomyolysis management is similar to traumatic cases. Isotonic saline resuscitation is needed, adjusted to the cause. Management includes removing the offending agent, titrating IV fluids to maintain 200-300 mL/h urine output, and daily CPK monitoring. In CPK levels below 5000 U/L, aggressive fluid resuscitation is discouraged due to lower AKI risk. Alkaline diuresis can be considered for severe cases with CPK over 30,000 U/L without oliguria, anuria, or AKI. Mannitol is less common in non-traumatic rhabdomyolysis. Loop diuretics can manage volume overload from aggressive fluids. Hemodialysis is considered for persistent oliguria/anuria and AKI. Dialysis’s effectiveness in myoglobin removal is not established.

Management of Electrolyte Abnormalities in Rhabdomyolysis

Rhabdomyolysis is associated with hyperkalemia, hypocalcemia, hyperuricemia, and hyperphosphatemia. Hyperkalemia (potassium <6 mEq/L, no ECG changes) is managed with potassium binders and bicarbonate in fluids. Hyperkalemia (potassium ≥6 mEq/L, with or without ECG changes) requires D50 and regular insulin, and IV sodium bicarbonate. Calcium gluconate or chloride is often used in emergency settings for hyperkalemia but should be used cautiously in rhabdomyolysis due to the risk of late-phase hypercalcemia.

Symptomatic hypocalcemia (tetany, seizures, arrhythmias) is treated with IV calcium gluconate. Excessive calcium replacement can cause hypercalcemia during recovery. Hyperuricemia (uric acid >8 mg/dL) should be managed with allopurinol. Hemodialysis is needed for volume overload, severe acidosis, uremia, and refractory hyperkalemia. Peritoneal dialysis may be insufficient for severe electrolyte imbalances in rhabdomyolysis.

Other Supportive Care for Rhabdomyolysis

Antibiotics and vasopressors are needed for concurrent sepsis. Malignant hyperthermia is treated with dantrolene sodium. Steroids are used in inflammatory myopathies. Emergent orthopedic consultation is needed for compartment syndrome. DIC is managed with fresh frozen plasma, cryoprecipitate, and platelet transfusions.

Dietary Considerations in Metabolic Myopathies

Dietary changes can improve symptoms in hereditary myopathies. Glucose and fructose supplementation can reduce pain and fatigue in phosphorylase deficiency. High-carbohydrate, low-fat diets with frequent meals can improve muscle pain and myoglobinuria in carnitine palmityl transferase deficiency. Other metabolic abnormalities may benefit from tailored dietary interventions, requiring consultation with a specialist dietician.

Differential Diagnosis of Rhabdomyolysis

The differential diagnosis for rhabdomyolysis includes:

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

Pertinent Studies and Ongoing Trials in Rhabdomyolysis

Preclinical studies have explored interventions like vasodilators, antioxidants, curcumin, haptoglobin, hemopexin, hepcidin, and α1-microglobulin, but their effectiveness in rhabdomyolysis has not been proven clinically.

Gene therapy is being investigated for inherited muscular dystrophies like Duchenne and Becker, including read-through of stop codons and exon skipping. Edasalonexent (CAT-1004), an NF-κB inhibitor, has shown some success in a phase 3 trial (NCT03703882). Vamorolone, a glucocorticoid stabilizing membranes and inhibiting NF-kB inflammation, has also shown symptom improvement. Many novel treatments are under study.

Prognosis of Rhabdomyolysis

Mortality rates for hospitalized patients developing AKI from rhabdomyolysis range from 30% to 50%. Renal injury severity and duration are key prognostic indicators. Crush injury severity and duration also correlate with hemodialysis need.

Complications of Rhabdomyolysis

Major 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 prolonged hospitalization

Consultations for Rhabdomyolysis Management

Acute rhabdomyolysis patients with AKI, hyperkalemia, compartment syndrome, hypotension, or arrhythmias may require ICU admission and ventilatory support. Consultations with critical care, nephrology, trauma surgery, vascular surgery, or orthopedic surgery may be necessary depending on severity and cause.

Deterrence and Patient Education for Rhabdomyolysis

Patients should be educated about rhabdomyolysis risk factors and prevention. Suspected inflammatory and metabolic myopathies require further evaluation, including biopsy. Traumatic rhabdomyolysis survivors may need counseling and medication. For genetic metabolic disorders, family screening for heritable causes is recommended.

Pearls and Key Issues in Rhabdomyolysis Diagnosis and Management

Rhabdomyolysis is classified into traumatic and non-traumatic causes.
Elevated CPK levels are the most sensitive diagnostic test.
CPK levels above 5000 U/L often indicate risk of systemic damage, but other factors are also important.
Crush injury and massive trauma patients are at risk for compartment syndrome, requiring distal pulse checks and compartment pressure monitoring. Pressures over 30 mm Hg indicate high ischemia risk.
DIC can complicate rhabdomyolysis due to platelet activation and inflammation.
Maintaining high urine output and urine alkalinization are key to minimizing kidney injury.
Recurrent rhabdomyolysis or cases with minimal trauma/exertion should prompt screening for genetic abnormalities.
Individuals with sickle cell trait are at increased risk of rhabdomyolysis, requiring precautions during exercise.
Dietary changes may manage symptoms of genetic myopathies.

Enhancing Healthcare Team Outcomes in Rhabdomyolysis

Rhabdomyolysis management research often lacks high-quality randomized controlled trials. Education on prevention is crucial. Nurses and pharmacists play vital roles in patient education upon discharge, covering muscle breakdown causes and prevention strategies. Students should be educated on heat-related injuries and hydration. Rehabilitation or physical therapy may be needed for muscle mass and joint function recovery. Recovery can take months, with some patients experiencing residual pain for years. Pharmacists should warn the public about rhabdomyolysis risks from recreational drugs, alcohol, and prescription medications.

Care coordination is essential for efficient patient care. Physicians, advanced practitioners, nurses, pharmacists, and other professionals must collaborate from diagnosis through follow-up. This coordination minimizes errors, delays, and enhances safety, improving outcomes and patient-centered care for rhabdomyolysis. An interprofessional team approach, including primary clinicians, specialists, nurses, and pharmacists, optimizes outcomes and minimizes long-term sequelae.

Review Questions

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References

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1.Aleckovic-Halilovic M, Pjanic M, Mesic E, Storrar J, Woywodt A. From quail to earthquakes and human conflict: a historical perspective of rhabdomyolysis. Clin Kidney J. 2021 Apr;14(4):1088-1096. [PMC free article: PMC8023192] [PubMed: 33841854]

2.Mokhtari AK, Maurer LR, Christensen MA, Moheb ME, Naar L, Alser O, Gaitanidis A, Langeveld K, Kapoen C, Breen K, Velmahos GC, Kaafarani HMA. Rhabdomyolysis in Severe COVID-19: Male Sex, High Body Mass Index, and Prone Positioning Confer High Risk. J Surg Res. 2021 Oct;266:35-43. [PMC free article: PMC8023200] [PubMed: 33975028]

3.Młynarska E, Krzemińska J, Wronka M, Franczyk B, Rysz J. Rhabdomyolysis-Induced AKI (RIAKI) Including the Role of COVID-19. Int J Mol Sci. 2022 Jul 26;23(15) [PMC free article: PMC9329740] [PubMed: 35897810]

4.Lámeire N, Matthys E, Vanholder R, De Keyser K, Pauwels W, Nachtergaele H, Lambrecht L, Ringoir S. Causes and prognosis of acute renal failure in elderly patients. Nephrol Dial Transplant. 1987;2(5):316-22. [PubMed: 3122108]

5.Woodrow G, Brownjohn AM, Turney JH. The clinical and biochemical features of acute renal failure due to rhabdomyolysis. Ren Fail. 1995 Jul;17(4):467-74. [PubMed: 7569117]

6.Vanholder R, Sever MS, Erek E, Lameire N. Rhabdomyolysis. J Am Soc Nephrol. 2000 Aug;11(8):1553-1561. [PubMed: 10906171]

7.Bandeira AC, Campos GS, Ribeiro GS, Cardoso CW, Bastos CJ, Pessoa TL, Araujo KA, Grassi MFR, Castro AP, Carvalho RH, Prates APPB, Gois LL, Rocha VF, Sardi SI. Clinical and laboratory evidence of Haff disease – case series from an outbreak in Salvador, Brazil, December 2016 to April 2017. Euro Surveill. 2017 Jun 15;22(24) [PMC free article: PMC5479974] [PubMed: 28661391]

8.Ogundare O, Jumma O, Turnbull DM, Woywodt A. Searching for the needle in the Haystacks. Lancet. 2009 Sep 05;374(9692):850. [PubMed: 19733782]

9.Bywaters EG, Beall D. Crush Injuries with Impairment of Renal Function. Br Med J. 1941 Mar 22;1(4185):427-32. [PMC free article: PMC2161734] [PubMed: 20783577]

10.Peiris D. A historical perspective on crush syndrome: the clinical application of its pathogenesis, established by the study of wartime crush injuries. J Clin Pathol. 2017 Apr;70(4):277-281. [PubMed: 27920043]

11.Gabow PA, Kaehny WD, Kelleher SP. The spectrum of rhabdomyolysis. Medicine (Baltimore). 1982 May;61(3):141-52. [PubMed: 7078398]

12.Kruijt N, van den Bersselaar LR, Kamsteeg EJ, Verbeeck W, Snoeck MMJ, Everaerd DS, Abdo WF, Jansen DRM, Erasmus CE, Jungbluth H, Voermans NC. The etiology of rhabdomyolysis: an interaction between genetic susceptibility and external triggers. Eur J Neurol. 2021 Feb;28(2):647-659. [PMC free article: PMC7821272] [PubMed: 32978841]

13.Malik GH, Sirwal IA, Reshi AR, Najar MS, Tanvir M, Altaf M. Acute renal failure following physical torture. Nephron. 1993;63(4):434-7. [PubMed: 8459879]

14.Szewczyk D, Ovadia P, Abdullah F, Rabinovici R. Pressure-induced rhabdomyolysis and acute renal failure. J Trauma. 1998 Feb;44(2):384-8. [PubMed: 9498517]

15.Brumback RA, Feeback DL, Leech RW. Rhabdomyolysis following electrical injury. Semin Neurol. 1995 Dec;15(4):329-34. [PubMed: 8848649]

16.Schiff HB, MacSearraigh ET, Kallmeyer JC. Myoglobinuria, rhabdomyolysis and marathon running. Q J Med. 1978 Oct;47(188):463-72. [PubMed: 751088]

17.Amanollahi A, Babeveynezhad T, Sedighi M, Shadnia S, Akbari S, Taheri M, Besharatpour M, Jorjani G, Salehian E, Etemad K, Mehrabi Y. Incidence of rhabdomyolysis occurrence in psychoactive substances intoxication: a systematic review and meta-analysis. Sci Rep. 2023 Oct 17;13(1):17693. [PMC free article: PMC10582156] [PubMed: 37848606]

18.Folkestad T, Brurberg KG, Nordhuus KM, Tveiten CK, Guttormsen AB, Os I, Beitland S. Acute kidney injury in burn patients admitted to the intensive care unit: a systematic review and meta-analysis. Crit Care. 2020 Jan 02;24(1):2. [PMC free article: PMC6941386] [PubMed: 31898523]

19.Singhal PC, Kumar A, Desroches L, Gibbons N, Mattana J. Prevalence and predictors of rhabdomyolysis in patients with hypophosphatemia. Am J Med. 1992 May;92(5):458-64. [PubMed: 1580292]

20.Rawls A, Diviak BK, Smith CI, Severson GW, Acosta SA, Wilson-Rawls J. Pharmacotherapeutic Approaches to Treatment of Muscular Dystrophies. Biomolecules. 2023 Oct 17;13(10) [PMC free article: PMC10605463] [PubMed: 37892218]

21.Sitprija V, Gopalakrishnakone P. Snake bite, rhabdomyolysis, and renal failure. Am J Kidney Dis. 1998 Jun;31(6):l-lii. [PubMed: 9631832]

22.Huerta-Alardín AL, Varon J, Marik PE. Bench-to-bedside review: Rhabdomyolysis — an overview for clinicians. Crit Care. 2005 Apr;9(2):158-69. [PMC free article: PMC1175909] [PubMed: 15774072]

23.Siddall E, Khatri M, Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology, and management. Kidney Int. 2017 Jul;92(1):37-46. [PubMed: 28318633]

24.Sharma U. Statin-induced delayed rhabdomyolysis. BMJ Case Rep. 2019 Sep 06;12(9) [PMC free article: PMC6731870] [PubMed: 31494591]

25.Attardo S, Musumeci O, Velardo D, Toscano A. Statins Neuromuscular Adverse Effects. Int J Mol Sci. 2022 Jul 28;23(15) [PMC free article: PMC9369175] [PubMed: 35955495]

26.Iftikhar MH, Dar AY, Haw A. Cocaine-induced rhabdomyolysis and compartment syndrome. BMJ Case Rep. 2022 May 19;15(5) [PMC free article: PMC9121409] [PubMed: 35589265]

27.Gangahar D. A case of rhabdomyolysis associated with severe opioid withdrawal. Am J Addict. 2015 Aug;24(5):400-2. [PubMed: 26095066]

28.Hanna J, Swetter S. A Case of Delirium and Rhabdomyolysis in Severe Iatrogenic Opioid Withdrawal. Psychosomatics. 2018 Jul-Aug;59(4):405-407. [PubMed: 29325983]

29.Segal M, Avital A, Rusakov A, Sandbank S, Weizman A. Serum creatine kinase activity differentiates alcohol syndromes of dependence, withdrawal and delirium tremens. Eur Neuropsychopharmacol. 2009 Feb;19(2):92-6. [PubMed: 19062261]

30.Saxena P, Dhooria S, Agarwal R, Prasad KT, Sehgal IS. Rhabdomyolysis in Intensive Care Unit: More than One Cause. Indian J Crit Care Med. 2019 Sep;23(9):427-429. [PMC free article: PMC6775710] [PubMed: 31645829]

31.Tonin P, Lewis P, Servidei S, DiMauro S. Metabolic causes of myoglobinuria. Ann Neurol. 1990 Feb;27(2):181-5. [PubMed: 2156480]

32.Pinto VM, De Franceschi L, Gianesin B, Gigante A, Graziadei G, Lombardini L, Palazzi G, Quota A, Russo R, Sainati L, Venturelli D, Forni GL, Origa R. Management of the Sickle Cell Trait: An Opinion by Expert Panel Members. J Clin Med. 2023 May 12;12(10) [PMC free article: PMC10219090] [PubMed: 37240547]

33.Nance JR, Mammen AL. Diagnostic evaluation of rhabdomyolysis. Muscle Nerve. 2015 Jun;51(6):793-810. [PMC free article: PMC4437836] [PubMed: 25678154]

34.Ashorobi D, Ramsey A, Killeen RB, Bhatt R. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Feb 25, 2024. Sickle Cell Trait. [PubMed: 30725815]

35.Kumar AA, Bhaskar E, Palamaner Subash Shantha G, Swaminathan P, Abraham G. Rhabdomyolysis in community acquired bacterial sepsis–a retrospective cohort study. PLoS One. 2009 Sep 29;4(9):e7182. [PMC free article: PMC2747002] [PubMed: 19787056]

36.Gupta A, Thorson P, Penmatsa KR, Gupta P. Rhabdomyolysis: Revisited. Ulster Med J. 2021 May;90(2):61-69. [PMC free article: PMC8278949] [PubMed: 34276082]

37.Pasternak RC, Smith SC, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C., American College of Cardiology. American Heart Association. National Heart, Lung and Blood Institute. ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins. Stroke. 2002 Sep;33(9):2337-41. [PubMed: 12215610]

38.Boccuzzi SJ, Bocanegra TS, Walker JF, Shapiro DR, Keegan ME. Long-term safety and efficacy profile of simvastatin. Am J Cardiol. 1991 Nov 01;68(11):1127-31. [PubMed: 1951069]

39.Al-Ismaili Z, Piccioni M, Zappitelli M. Rhabdomyolysis: pathogenesis of renal injury and management. Pediatr Nephrol. 2011 Oct;26(10):1781-8. [PubMed: 21249398]

40.Slater MS, Mullins RJ. Rhabdomyolysis and myoglobinuric renal failure in trauma and surgical patients: a review. J Am Coll Surg. 1998 Jun;186(6):693-716. [PubMed: 9632160]

41.Holt S, Moore K. Pathogenesis of renal failure in rhabdomyolysis: the role of myoglobin. Exp Nephrol. 2000 Mar-Apr;8(2):72-6. [PubMed: 10729745]

42.Nath KA, Singh RD, Croatt AJ, Adams CM. Heme Proteins and Kidney Injury: Beyond Rhabdomyolysis. Kidney360. 2022 Nov 24;3(11):1969-1979. [PMC free article: PMC9717624] [PubMed: 36514409]

43.Zeng Q, Zhong L, Zhang N, He L, Lin Q, Song J. Nomogram for predicting disseminated intravascular coagulation in heatstroke patients: A 10 years retrospective study. Front Med (Lausanne). 2023;10:1150623. [PMC free article: PMC10050446] [PubMed: 37007768]

44.Better OS, Stein JH. Early management of shock and prophylaxis of acute renal failure in traumatic rhabdomyolysis. N Engl J Med. 1990 Mar 22;322(12):825-9. [PubMed: 2407958]

45.Rastogi V, Singh D, Kaur B, Arora P, Gadikota JP. Rhabdomyolysis: A Rare Adverse Effect of Levetiracetam. Cureus. 2018 May 29;10(5):e2705. [PMC free article: PMC6063379] [PubMed: 30062079]

46.Wen Z, Liang Y, Hao Y, Delavan B, Huang R, Mikailov M, Tong W, Li M, Liu Z. Drug-Induced Rhabdomyolysis Atlas (DIRA) for idiosyncratic adverse drug reaction management. Drug Discov Today. 2019 Jan;24(1):9-15. [PMC free article: PMC7050640] [PubMed: 29902520]

47.Kyriakides T, Angelini C, Schaefer J, Mongini T, Siciliano G, Sacconi S, Joseph J, Burgunder JM, Bindoff LA, Vissing J, de Visser M, Hilton-Jones D. EFNS review on the role of muscle biopsy in the investigation of myalgia. Eur J Neurol. 2013 Jul;20(7):997-1005. [PubMed: 23627674]

48.Ponraj D, Gopalakrishnakone P. Renal lesions in rhabdomyolysis caused by Pseudechis australis snake myotoxin. Kidney Int. 1997 Jun;51(6):1956-69. [PubMed: 9186889]

49.Sauret JM, Marinides G, Wang GK. Rhabdomyolysis. Am Fam Physician. 2002 Mar 01;65(5):907-12. [PubMed: 11898964]

50.Schifman RB, Luevano DR. Value and Use of Urinalysis for Myoglobinuria. Arch Pathol Lab Med. 2019 Nov;143(11):1378-1381. [PubMed: 31116043]

51.Khan FY. Rhabdomyolysis: a review of the literature. Neth J Med. 2009 Oct;67(9):272-83. [PubMed: 19841484]

52.Trof RJ, Di Maggio F, Leemreis J, Groeneveld AB. Biomarkers of acute renal injury and renal failure. Shock. 2006 Sep;26(3):245-53. [PubMed: 16912649]

53.Olson SA, Glasgow RR. Acute compartment syndrome in lower extremity musculoskeletal trauma. J Am Acad Orthop Surg. 2005 Nov;13(7):436-44. [PubMed: 16272268]

54.Gunal AI, Celiker H, Dogukan A, Ozalp G, Kirciman E, Simsekli H, Gunay I, Demircin M, Belhan O, Yildirim MA, Sever MS. Early and vigorous fluid resuscitation prevents acute renal failure in the crush victims of catastrophic earthquakes. J Am Soc Nephrol. 2004 Jul;15(7):1862-7. [PubMed: 15213274]

55.Kazancioğlu R, Korular D, Sever MS, Türkmen A, Aysuna N, Kayacan SM, Tahin S, Yildiz A, Bozfakioğlu S, Ark E. The outcome of patients presenting with crush syndrome after the Marmara earthquake. Int J Artif Organs. 2001 Jan;24(1):17-21. [PubMed: 11266037]

56.Sever MS, Lameire N, Van Biesen W, Vanholder R. Disaster nephrology: a new concept for an old problem. Clin Kidney J. 2015 Jun;8(3):300-9. [PMC free article: PMC4440471] [PubMed: 26034592]

57.Reis ND, Michaelson M. Crush injury to the lower limbs. Treatment of the local injury. J Bone Joint Surg Am. 1986 Mar;68(3):414-8. [PubMed: 3949835]

58.Sever MS, Vanholder R., RDRTF of ISN Work Group on Recommendations for the Management of Crush Victims in Mass Disasters. Recommendation for the management of crush victims in mass disasters. Nephrol Dial Transplant. 2012 Apr;27 Suppl 1:i1-67. [PubMed: 22467763]

59.Ron D, Taitelman U, Michaelson M, Bar-Joseph G, Bursztein S, Better OS. Prevention of acute renal failure in traumatic rhabdomyolysis. Arch Intern Med. 1984 Feb;144(2):277-80. [PubMed: 6696564]

60.Homsi E, Barreiro MF, Orlando JM, Higa EM. Prophylaxis of acute renal failure in patients with rhabdomyolysis. Ren Fail. 1997 Mar;19(2):283-8. [PubMed: 9101605]

61.Vanholder R, Borniche D, Claus S, Correa-Rotter R, Crestani R, Ferir MC, Gibney N, Hurtado A, Luyckx VA, Portilla D, Rodriguez S, Sever MS, Vanmassenhove J, Wainstein R. When the earth trembles in the Americas: the experience of Haiti and Chile 2010. Nephron Clin Pract. 2011;117(3):c184-97. [PubMed: 20805691]

62.de Meijer AR, Fikkers BG, de Keijzer MH, van Engelen BG, Drenth JP. Serum creatine kinase as predictor of clinical course in rhabdomyolysis: a 5-year intensive care survey. Intensive Care Med. 2003 Jul;29(7):1121-5. [PubMed: 12768237]

63.Bladen CL, Salgado D, Monges S, Foncuberta ME, Kekou K, Kosma K, Dawkins H, Lamont L, Roy AJ, Chamova T, Guergueltcheva V, Chan S, Korngut L, Campbell C, Dai Y, Wang J, Barišić N, Brabec P, Lahdetie J, Walter MC, Schreiber-Katz O, Karcagi V, Garami M, Viswanathan V, Bayat F, Buccella F, Kimura E, Koeks Z, van den Bergen JC, Rodrigues M, Roxburgh R, Lusakowska A, Kostera-Pruszczyk A, Zimowski J, Santos R, Neagu E, Artemieva S, Rasic VM, Vojinovic D, Posada M, Bloetzer C, Jeannet PY, Joncourt F, Díaz-Manera J, Gallardo E, Karaduman AA, Topaloğlu H, El Sherif R, Stringer A, Shatillo AV, Martin AS, Peay HL, Bellgard MI, Kirschner J, Flanigan KM, Straub V, Bushby K, Verschuuren J, Aartsma-Rus A, Béroud C, Lochmüller H. The TREAT-NMD DMD Global Database: analysis of more than 7,000 Duchenne muscular dystrophy mutations. Hum Mutat. 2015 Apr;36(4):395-402. [PMC free article: PMC4405042] [PubMed: 25604253]

64.Hatamizadeh P, Najafi I, Vanholder R, Rashid-Farokhi F, Sanadgol H, Seyrafian S, Mooraki A, Atabak S, Samimagham H, Pourfarziani V, Broumand B, Van Biesen W, Lameire N. Epidemiologic aspects of the Bam earthquake in Iran: the nephrologic perspective. Am J Kidney Dis. 2006 Mar;47(3):428-38. [PubMed: 16490621]

Disclosure: Michael Stanley declares no relevant financial relationships with ineligible companies.

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