Rhabdomyolysis: Review and Update


Larissa I. Velez, MD, Assistant Professor of Emergency Medicine, University of Texas Southwestern, Dallas.

Melanie J. Lippmann, MD, Department of Emergency Medicine, University of Texas Southwestern, Dallas.

Janna Welch, MD, Assistant Residency Director, University of Texas Southwestern, Dallas.

Gilberto A. Salazar, MD, Department of Emergency Medicine, University of Texas Southwestern, Dallas.

Peer Reviewer:

Frank LoVecchio, DO, Emergency Medicine Department, Maricopa Medical Center, Phoenix, AZ.

In the past few weeks, I have seen several patients with rhabdomyolysis. One of the more memorable patients was a person who had too much to drink at a party, and the guests restrained him with duct tape to keep him from driving. After a night of struggling to get free, he developed dark urine and was admitted to the hospital.

We have also seen rhabdomyolysis from self-poisoning and as a side effect of medication. Although the references suggest this disease is somewhat uncommon, it may be that we overlook some cases.

— Sandra M. Schneider, MD, Editor


Rhabdomyolysis is a syndrome with far-reaching systemic sequelae. The release of intracellular components into the vascular space following striated muscle injury produces tissue necrosis, end-organ damage, and metabolic derangements. The incidence of rhabdomyolysis is approximately two cases per 10,000 person-years in North America.1 The mortality rate is estimated to be 8%.2

Rhabdomyolysis was first described in the medical literature after the London bombings during World War II, and began to be fully recognized following studies on military recruits as early as the 1970s. Olerud published a study in 1976 detailing exertional rhabdomyolysis in Marine Corps recruits in 1976.3 The syndrome has received much more attention in the last 30 years, and now we have a much better understanding of its pathophysiology.

Striated muscle injury is at the core of mechanisms producing vast systemic insults in rhabdomyolysis. Central to the development of the syndrome is intracellular ATP depletion.4 This triggers a cascade of cellular disruptions, such as Na+ K+ ATPase pump dysfunction, impaired calcium transport, and release of free oxygen radicals.5 Intracellular calcium levels increase in unregulated fashion, leading to persistent muscle contraction.6 Eventually, there is cell death. Intracellular components such myoglobin, creatine kinase (CK), lactate dehydrogenase (LDH), uric acid, aldolase, and electrolytes (e.g., potassium) are released into the bloodstream.4

Rhabdomyolysis is a systemic event. It involves virtually every organ system. Disseminated intravascular coagulation (DIC), compartment syndrome, electrolyte abnormalities, cardiac arrhythmias, and acute renal failure form part of a large list of potentially life-threatening complications from rhabdomyolysis.7

The kidneys are exquisitely sensitive to myoglobin. Not only do the renal tubules sustain significant damage from tissue necrosis and obstruction, but there is also a direct toxic effect of ferrihemate, a byproduct of myoglobin breakdown. Hypovolemia and aciduria appear to compound the effect of myoglobin, resulting in acute renal failure. It is estimated that 30-50% of rhabdomyolysis patients develop acute renal failure.8 Seven percent to 10% of all cases of acute kidney injury in the United States are due to rhabdomyolysis.6

Similar mechanisms may be responsible for the vascular insult and tissue necrosis that affects the cardiovascular system and brain, leading to the cardiopulmonary and neurological findings associated with rhabdomyolysis.

There are many causes of rhabdomyolysis. Exercise has traditionally been considered the main culprit. Release of CK during strenuous exercise is a well-documented phenomenon.9 However, it is important to remember that there are many other causes of muscle injury. Immobilization, medications, environmental exposures, infection, and work-related hazards (e.g., electrical injury) are well known to cause muscle injury, tissue ischemia, and necrosis. It is crucial to remember that rhabdomyolysis is often multifactorial, and each cause can compound the effects of the other.8

Clinical Presentation

The assessment of the patient with rhabdomyolysis must take into consideration the systemic nature of the syndrome. The patient with rhabdomyolysis may present with classic signs and symptoms, including myalgias, weakness, and dark-colored urine. However, only approximately 50% of patients with rhabdomyolysis experience myalgias or weakness. Emergency physicians should be aware that even an obtunded patient may have rhabdomyolysis.

Knowledge of the patient's activities, behavior, and environment prior to the ED visit should trigger the addition of rhabdomyolysis to the list of differential diagnoses. A history should include a thorough medication review looking for medications associated with rhabdomyolysis.

The physical examination may vary widely, and may even be normal. However, fever, tachycardia, hypertension, hypotension, tachypnea, evidence of immobilization, agitation, central nervous system (CNS) depression, seizure activity, edema, and increased muscle tone may be found. Patients with altered mental status and rhabdomyolysis may be particularly difficult to diagnose. The emergency physician should consider the diagnosis when the history is suggestive.

The laboratory workup is essential in determining optimal management of the patient suspected of having rhabdomyolysis. A CK level of 5000 IU/L, or five times the normal level, is considered by most to be rhabdomyolysis, although a definitive number varies in the published literature.10 The CK should be monitored serially, as its rise may be evidence of ongoing muscle injury. An electrolyte panel, including renal function, magnesium, phosphorus, and calcium should be obtained. A bedside capillary blood glucose is extremely useful in ruling out hypoglycemia. An arterial blood gas is helpful in determining serum pH. Serum and urine myoglobin may be obtained as part of the workup. The patient's coagulation may be useful, as DIC is a severe complication of rhabdomyolysis. Obtain a complete blood cell count with differential, blood culture, and urine culture when infection is highly suspected as the cause of rhabdomyolysis. Chest radiography may help delineate the cause when a pulmonary source is suspected in patients with rhabdomyolysis. A lumbar puncture should be considered in the patient with rhabdomyolysis who have a clinical suspicion of bacterial meningitis.

Cardiac ischemia is a potential complication of rhabdomyolysis, particularly in patients with comorbidities or those known to abuse sympathomimetic drugs. An electrocardiogram and cardiac markers suffice as an initial cardiac workup. A toxicologic workup aids in delineating possible triggers for muscle injury, but a positive test should not stop the search for other possible causes. Panels testing for drugs of abuse are widely available, but other offending agents, such as salicylates, alcohol, and opiate narcotics, must be considered. When altered mental status is present, a CT of the brain should be considered as an adjunct when intracranial pathology enters the differential diagnosis.

Table 1: Major Causes of Rhabdomyolysis

     • Genetic predisposition
     • Heat or cold
Electrolyte abnormalities

Causes of Rhabdomyolysis

Exertional. The most common causes of non-traumatic rhabdomyolysis are hypermetabolic exertional stress injury. Strenuous exercise will increase serum CK in normal humans. Exertional rhabdomyolysis, or "hyper-CK-emia" occurs in individuals who have a sudden increase in overall levels of physical activity and can demonstrate CK levels more than five times normal. There is an increased incidence in males, African-Americans, and individuals with high muscle mass.9 The majority of these individuals do not have muscle soreness, weakness, and myoglobinuria, and have CK levels that rapidly return to normal. When hyperCKemia and myoglobinuria occur in a patient with muscle soreness and weakness, the patient has exertional rhabdomyolysis. A common factor in exertional rhabdomyolysis cases is repetitive exercise or exertion beyond when fatigue would compel an individual to normally stop (for example, new military recruits and participants in long-distance running events). It is exacerbated by high ambient temperatures.

Exertional rhabdomyolysis occurs when exertional energy requirements exceed ATP production. Depletion of ATP within the myocyte during exertion causes a release of calcium into the cell and, therefore, cellular necrosis. The myocytes then become permeable, swollen with fluid, and leak their components into the intracellular matrix. This results in intravascular volume depletion from third spacing and lactic acidosis. There is a resultant rapid increase in serum creatinine. The prognosis for exertional rhabdomyolysis is better than for other forms of rhabdomyolysis and less often results in acute kidney injury. However, exertional rhabdomyolysis exacerbated by severe heat injury will increase risk of renal injury.

Anyone may develop exertional rhabdomyolysis when under enough mechanical and environmental stress. However, exertional rhabdomyolysis can also be triggered by genetic influences that predispose the individual to the development of exercise and heat-related illness. These genetic abnormalities cause abnormal intracellular skeletal muscle calcium regulation via disorders of carbohydrate metabolism, lipid metabolism, or mitochondrial disorders. Recognized genetic causes include McArdle's disease, CPT2 deficiency, and AMPD deficiency.9 In McArdle's disease, the individual lacks the enzyme to break down muscle glycogen to continue to fuel cells after circulating ATP are spent. Carnitine palmitoyl transferase (CPT2) deficiency causes an increase in open-state probability of RYRI calcium channels, so there is a much lower threshold for high calcium levels within cells to cause cell breakdown. In adenosine monophosphate deaminase deficiency (AMPD), a critical enzyme for muscle energy metabolism is present in abnormally low levels, therefore decreasing exercise capacity and shortening the time to tissue ischemia. Polymorphic variations in angiotensin-converting enzyme, CK muscle isoform, and myosin light-chain kinase have also been associated with exertional rhabdomyolysis.9 Hereditary causes are listed in Table 2.

Table 2: Hereditary Conditions Associated with Rhabdomyolysis

Carnitine Metabolism Disorders
     • Carnitine palmitoyl transferase (CPT2) deficiency
     • VLCAD (very long chain acyl CoA deficiency)
Adenosine monophosphate deaminase deficiency (AMPD)
McArdle's disease (glycogen storage disease type 5)
Malignant hyperthermia
Phosphorylase kinase deficiency
Duchenne muscular dystrophy
11-hydroxylase deficiency
Phosphofructokinase deficiency

Trauma. Traumatic injury is the most common cause of rhabdomyolysis.11 Table 3 lists the common trauma causes of rhabdomyolysis. The two types of trauma that result in rhabdomyolysis include crush and electrical injuries. Physical beating has also been associated with rhabdomyolysis.12 Electrical injuries may be caused by lightning or high-voltage electrical current. Due to the short duration of exposure, lightning injuries do not cause significant burns or muscle breakdown. In contrast, high-voltage electrical injuries commonly cause rhabdomyolysis in patients who survive the initial insult. In such cases, rhabdomyolysis cannot be predicted by the size of external wound or site of electrical current entry.8,13 Up to 10% of patients with severe electrical injuries will develop rhabdomyolysis.14

Table 3: Trauma Conditions Associated with Rhabdomyolysis

  • Crush injury
  • Compartment syndrome
  • Physical torture and abuse
  • Exercise
  • Heat stroke
  • High voltage electrical injury
  • Lightning
  • Elevated ambient temperature (heat exposure)
  • Low ambient temperature (cold exposure)

Crush injury is the most common traumatic cause of rhabdomyolysis, as it is seen in natural disasters such as earthquakes and landslides, or in war zones, in which individuals are trapped under fallen buildings.14 Epidemics of traumatic and crush injuries have been described following massive earthquakes.15,16 Crush injuries occur when a patient is trapped or compressed under the weight of external forces. Due to external pressure compressing the affected limb, there is inadequate blood pressure to deliver blood and oxygen to the tissue. Intramuscular compartment pressure may rapidly exceed arterial blood pressure, resulting in muscle tamponade, compartment syndrome, and muscular necrosis within the first 30 minutes of injury.14 Severe crush injury may result in transient flaccid paralysis without spinal cord injury secondary to an increase in compartment pressures and ischemia to peripheral nerves.

Decreased blood flow and lactic acidosis from tissue ischemia causes the release of vasodilatory nitric oxide in crushed muscle. As a result, there is rapid swelling within muscle compartments once the injured limb is released from entrapment. This massive third spacing often causes sudden hypotension, hypocalcemia, and hyperkalemia.14 Pre-renal azotemia from hypotension, along with lactic acidosis and hyperCKemia, result in oliguria and acute kidney injury. Renal failure causes further sudden increases in potassium levels. The cardiotoxic effects of hyperkalemia are aggravated by hypocalcemia from muscle breakdown. Hypovolemic shock and arrhythmias are the most common early causes of death.17

Drug-related. The list of drugs associate with rhabdomyolysis is extensive, including more than 200 medications.18 It is estimated that drugs and medications cause about one-third of the cases of adult rhabdomyolysis.18

There are some common mechanisms for drug-induced rhabdomyolysis:19

• Inadequate delivery of oxygen and nutrients to the tissue.19 This can be due to pressure ischemia from prolonged immobilization that can occur with any central nervous system (CNS) depressant. Examples include the narcotics, general anesthetics, benzodiazepines (BDZ), tricyclic antidepressants (TCAD), antihistamines, ethanol, barbiturates, and carbon monoxide (CO). The syndrome can also be due to increased pressure within specific compartments, as when the person passes out in an awkward position.

Some drugs cause significant vasospasm or vasoconstriction that can restrict blood flow. One example is vasopressin. Other drugs result in a "functional anemia" due to the production of abnormal hemoglobins that cannot transport and/or deliver oxygen to the tissues. Carboxyhemoglobin and methemoglobin are examples of such drugs. Finally, drugs that cause hemodynamic shock have the potential to cause rhabdomyolysis.

• Excessive energy use by the muscle.19 Any drug that results in excessive exertion, delirium, agitation, and seizures can cause rhabdomyolysis. This group of drugs is extensive and includes the sympathomimetics, LSD, and PCP. Isoniazid (INH), strychnine, theophylline, and lithium are some of the drugs known to result in seizures and status epilepticus. The withdrawal from ethanol, BDZ, and gamma hydroxybutyrate (GHB) can also cause both agitation and seizures.

Drugs that cause movement disorders like dystonias and choreoathetosis are also in this category, such as the phenothiazines and butyrophenones.

Depolarizing neuromuscular blockers like succinylcholine have been associated with rhabdomyolysis in children.

• Metabolic poisons, which are drugs that interfere with the production or use of ATP.19 Drugs in this category include the inhibitors of the electron transport chain (cyanide [CN], hydrogen sulfide (HS), CO, and phosphine); the uncouplers of oxidative phosphorylation (salicylates and chlorophenoxy herbicides; and the inhibitors of glycolysis [sodium fluoroacetate]). Rarer agents in this group include the heavy metals like mercury, selenium, copper, and tetra ethyl lead.

• Potassium depletion.19 Patients in this category include those taking diuretics or mineralocorticoids (like licorice), and toluene users. The mechanism for rhabdomyolysis in hypokalemia is thought to be due to inadequate cell release of potassium, which helps with vasodilation during exercise.

• Other miscellaneous mechanisms.19 Ethanol. Ethanol is thought to account for about 20% of cases of myoglobinuria.19 The mechanism for this is not clear, but could in part be behavioral and also due to a local toxic effect.

HMG-CoA reductase inhibitors (statins). Statins are the drug class most commonly associated with drug-induced rhabdomyolysis.4 This is probably because they are one of the most widely prescribed drug classes.20 The myopathies from statins are a spectrum of disease, ranging from isolated CK elevation with no symptoms, to pain or weakness with little CK elevation, to profound rhabdomyolysis.

Rhabdomyolysis due to statins is thought to be due to inhibition of HMG-CoA reductase, which leads to decreased levels of ubiquinone (Coenzyme Q).20 Ubiquinone is a key player in electron transport chain, and is also an intracellular antioxidant.21 However, the exact mechanism has not been elucidated.

Higher serum statin concentrations have been associated with a higher likelihood of rhabdomyolysis.22 Statins undergo glucuronidation in the liver. Drugs like gemfibrozil, which have a similar metabolism, can increase serum statin levels.20 Subsequently, most statins are metabolized by cytochrome oxidase 3A4 (CYP 3A4), so co-administration of drugs such as macrolide antibiotics, non-dihydropyridine calcium channel blockers, and protease inhibitors may also increase blood concentrations of statins and precipitate rhabdomyolysis.20

There is no consensus on screening for rhabdomyolysis in patients taking statins, but patients taking other drugs that can result in elevated statin levels, or patients on high-dose simvastatin, should be recognized as at high risk for developing the syndrome.20,22

Propofol. Propofol is a widely used sedative and short-acting anesthetic due to its very favorable neurologic profile and its quick "on and off" properties.23 Propofol is toxic to the mitochondria and elevates malonyl-carnitine levels, which results in inhibited fatty acid transport. It also uncouples oxidative phosphorylation and inhibits the respiratory chain.4 The toxicity of propofol is also thought to be mediated to beta antagonism and catecholamine inhibition.24

The Propofol Infusion Syndrome (PRIS) was first termed by Bray in 1998. In this series, he described 18 children who developed bradycardia leading to asystole with at least one of the following: metabolic acidosis, rhabdomyolysis or myoglobinuria, lipemic plasma, and enlarged or fatty liver. Most patients had a respiratory illness. The mortality in this report was 83%.25 In more recent reports, the mortality from PRIS has been 18%.26 Between 1996-2000, the first adult cases were reported. In 2001, a report first showed a dose relationship in the development of PRIS in adult head-injured patients.27 In this series, patients taking doses of less than 5 mg/kg/hr did not develop PRIS; those taking doses between 5-6 mg/kg/hr had a 17% incidence; and those taking doses greater than 6 mg/kg/hr had a 31% incidence.

Risk factors for the development of PRIS include: severe head injury; respiratory illness; young age; large total cumulative dose; high catecholamine and glucocorticoid levels; low carbohydrate/high fat intake; critical illness; and inborn errors of fatty oxidation.27

The proposed adult criteria for PRIS are:

  • Age between 18-55 years;
  • Progressive heart failure with arrhythmias;
  • Two of the following: metabolic acidosis, hyperkalemia, or evidence of muscle cell destruction;
  • Exclusion of other causes for symptoms.23

Cardiac dysfunction or a Brugada-like ECG may be the first clue of PRIS. This is thought to be due to NA channel blockade or unmasking of a genetic channel defect.23

A recently published report, the largest one to date, gives an incidence of 1.1% for PRIS. Most patients developed symptoms by the first 24 hours. In this study, most patients (91%) were receiving vasopressors. Interestingly, only 18% of patients were receiving propofol at a rate greater than 5 mg/kg/hr doses, demonstrating that PRIS can occur at low doses.26

To prevent the development of PRIS, when possible propofol infusions should be less than 4 mg/kg/hr and they should not be continued longer than 48 hours.23 However, cases of PRIS have been reported even after propofol has been used for procedural sedation.23 The propofol infusion should be stopped and the patient appropriately resuscitated. Case reports have shown some success with hemodialysis, hemoperfusion, and extracorporeal membrane oxygenation (ECMO).4,23

Drugs of Abuse. Virtually all the sympathomimetics have been associated with rhabdomyolysis. Most notably, cocaine has been reported to cause rhabdomyolysis in about 5% of all cocaine-related visits in one ED study.28 As expected, the degree of agitation was the best predictor for the development of rhabdomyolysis. Patients with cocaine-induced rhabdomyolysis have been reported to have high mortality.29 The mechanism for cocaine-induced rhabdomyloysis is thought to be multifactorial, including agitation, seizures, vasoconstriction, and other causes of skeletal muscle dysfunction like neuroleptic malignant syndrome (NMS), serotonin syndrome (SS), and malignant hyperthermia (MH).

The newer synthetic amphetamines like MDMA and N-benzylpiperazine have also been reported to result in rhabdomyolysis. Finally, the synthetic cathinone derivatives, such as "bath salts" (MDPV and mephedrone), have also been associated with rhabdomyolysis.30,31

Table 4 lists the drugs that have been associated with rhabdomyolysis.

Table 4: Medication/Drug Causes of Rhabdomyolysis19

  • Ethanol
  • Cocaine and other sympathomimetics
  • Anticholinergic agents
  • Sedatives and hypnotics
  • Metabolic poisons (cyanide, carbon monoxide)
  • Colchicine
  • Steroids
  • Zidovudine
  • Statins
  • Propofol (infusion)
  • Daptomycin
  • Sunitinib and Imatinib
  • Leflunomide
  • Serotonin syndrome
  • Neuroleptic malignant syndrome

Toxins/Venoms. Rare cases of rhabdomyolysis have been documented after red fire ant bites, massive stings from Africanized bees, wasp stings, and following snake bites.32-35 The spread of Africanized honey bees across the southern United States has increased the incidence of massive stings. When the bee colony feels threatened by human activity, the bees swarm in defense. In contrast to anaphylaxis secondary to a bee or wasp sting with laryngeal constriction, bronchospasm, and hypotension, rhabdomyolysis occurs secondary to massive envenomation from hundreds of stings. Melittin, the pain-inducing compound in bee venom, in conjunction with phospholipase A2, compromise red blood cell membrane integrity. The mast-cell degranulating protein, hyaluronidase, and neurotoxic apamin allow bee venom to infiltrate tissues and propagate cell apoptosis, resulting in rhabdomyolysis and renal failure.35

Fire ant venom contains formic acid, which in large quantities acts as an inhibitor of the mitochondrial cytochrome oxidase complex.33 Rhabdomyolysis may occur secondary to tissue ischemia from the formic acid. Severe scorpion stings from certain species (most notably the Centruroides species, known also as the "bark scorpion") are reported to result in elevated CK, but in patients who also suffered severe neurotoxic and cardiotoxic effects.36 Bites from pit vipers with hemotoxic or myotoxic venom may also cause rhabdomyolysis, which in conjunction with disseminated intravascular coagulation (DIC), hypotension, and hemorrhage may result in renal failure.32 Table 5 lists common envenomations associated with rhabdomyolysis.

Table 5: Envenomations Associated with Rhabdomyolysis19

  • Ants (fire ants in particular)
  • Bees
  • Centipedes
  • Wasps
  • Scorpions
  • Snakes (hemotoxic and myotoxic snakes)

Infection. Many infections have been related to the development of rhabdomyolysis. In adults, infections may represent only about 5% of total cases of rhabdomyolysis, but in the pediatric population, infection is the most common cause of rhabdomyolysis.18 In at least one adult cohort study of patients with sepsis, the presence of rhabdomyolysis carried a mortality of 59%.37 Table 6 summarizes infectious causes of rhabdomyolysis.

Table 6: Infections Associated with Rhabdomyolysis


  • Influenza (H1N1; A; B)
  • Coronavirus
  • Herpesvirus
  • HIV
  • Dengue
  • Parainfluenza
  • Varicella
  • West Nile encephalitis
  • Mononucleosis (Epstein-Barr)
  • Cytomegalovirus (CMV)
  • Coxsackie


  • Staphylococcus aureus
  • Salmonella typhi
  • Pseudomonas aeruginosa
  • Mycoplasma pneumoniae
  • Bacillus cereus
  • Clostridium tetani
  • E. coli
  • Listeria monocytogenes
  • Legionella pneumophila
  • Tularemia
  • Tetanus


  • P. vivax (malaria)

Other. There are many additional causes of rhabdomyolysis, including tumors, endocrine, electrolyte derangements, hereditary, and dietary. All are listed in Table 7.

Table 7: Miscellaneous Causes of Rhabdomyolysis


  • Hypokalemia
  • Hypernatremia
  • Hypocalcemia
  • Hypophosphatemia


  • Quail ingestion (coturnism)38
  • Mushrooms
  • Licorice
  • Red yeast rice (Monascus purpureus)39


  • Thyrotoxicosis
  • Hyperaldosteronism
  • DKA


  • Status asthmaticus
  • Massage
  • Polymyositis
  • Dermatomyositis
  • Neurosarcoidosis
  • Sjögren's syndrome

Complications of Rhabdomyolysis

As rhabdomyolysis is a multi-organ disease, its complications are many. The most common and obvious complication is acute renal failure (ARF).19,40 The association was first reported by Bywaters in 1941.41 It is thought that rhabdomyolysis causes 5-8% of all cases of ARF in hospitals. Renal failure occurs when released myoglobin, which is partly bound to alpha-2 globulin, dissociates into ferrihemate and globin. This occurs predominantly at low serum pH. Ferrihemate results in direct toxicity to the kidney. Additionally, there is alteration of renal blood flow (RBF), and tubular obstruction due to precipitation of heme pigment casts and uric acid crystals.18,19 Other aspects of rhabdomyolysis that contribute to ARF include: intravascular volume depletion with renal hypoperfusion and ischemia; oxidative stress to the kidney from iron-mediated free radical formation; myoglobin-induced nitric oxide scavenging; circulation of inflammatory mediators; and activation of innate immune system.42 The ARF can be oliguric or non-oliguric.

Nearly half of patients with rhabdomyolysis develop hyperkalemia.43 Potassium is released from damaged muscle, and its clearance is impaired from fall in glomerular filtration rate (GFR) and decreased renal function.19,40 Profound hyperuricemia, as high as 36 mg/dL, has also been reported.19,40 Purines released from injured muscle are converted to uric acid by the liver. Due to the falling renal function, uric acid levels may rise.19 Other electrolytes are also deranged in rhabdomyolysis, including hypocalcemia, found in 63% of patients.40 Both calcium and phosphorus are sequestered and deposited in injured muscle. Later, once ARF ensues, these low levels resolve, and hypercalcemia can develop.19

Disseminated intravascular coagulation (DIC) has been reported to be associated with rhabdomyolysis. It could result from temperature elevation or from systemic release of substances such as plasminogen activator or thromboplastin.19,40 Metabolic (lactic) acidosis is also common and has many contributors, including hypocalcemia, renal failure, and strenuous exertion leading to anaerobic metabolism.19,40

Rarer complications include hepatic damage, cardiomyopathy, ECG changes, arrhythmias, and cardiogenic shock.40 Respiratory failure, delayed compartment syndromes, and peripheral neuropathies have also been reported.19

Laboratory Evaluation

Creatine kinase (CK) is the most sensitive indicator of rhabdomyolysis. Most authors will use a CK greater than five times the upper limit of normal as a definition for rhabdomyolysis, but there is no absolute number that defines the syndrome.10 The CK starts increasing within 12 hours from injury, peaks at 1-3 days, and declines 3-5 days after the insult ceases (declines by about 39% from the previous day's value).10,11 It should be noted that these criteria and elevations are variable and poorly studied, especially in heat-related illness and drug-induced rhabdomyolysis. Once 100 grams of muscle are damaged, myoglobin is released into the circulation.

The renal threshold for myoglobin is 15 mg/dL. Once this threshold is reached, myoglobinuria ensues. Myoglobinuria can be detected using the orthotolidine reaction, in which myoglobin is detected as blood in urine. This test is very sensitive.19 Visible urine discoloration occurs at myoglobin levels of more than 1,000 mg/L. At alkaline pHs, myoglobin is red or pink; at acidic pHs, it is dark red-brown (from ferrihemate). But, it is important to note that the discoloration also depends on urine flow and GFR and is therefore very variable.19

As discussed before, the electrolytes, particularly hyperkalemia, hypocalcemia, and hyperuricemia are also clues to the presence of rhabdomyolysis. Both the creatinine and the BUN are elevated in rhabdomyolysis, but the normal ratio of 10:1 decreases to about 6:1.11


Intravenous Crystalloid Fluid Resuscitation. The cornerstone for the successful treatment of rhabdomyolysis and the prevention of ARF is prompt and aggressive intravenous isotonic crystalloid resuscitation.16,44 Fluid sequestration in injured skeletal muscles of rhabdomyolysis patients leads to intravascular volume depletion, and repletion of up to 10-12 liters per day is often needed to maintain adequate urine output.6,45

Numerous studies have confirmed an increased incidence of acute kidney injury (AKI) when fluid initiation is delayed or not aggressive.14,45,46 Thus, prompt administration of large-volume crystalloid repletion is important. Aggressive fluid resuscitation can improve long-term patient outcomes and prevent progression to ARF. Similarly, pre-hospital EMS providers can assist by beginning the process while en route to the ED. Maintaining a high index of suspicion for the development of rhabdomyolysis in the appropriate setting of presumed skeletal muscle injury is key to early and effective treatment.

Following an initial fluid bolus of 20 cc/kg, intravenous fluids should be continued at a rate of approximately 400-500 cc/hr.6,47 Placement of a urinary catheter is necessary to closely monitor urine output, which should be maintained at a target of 2-3 cc/kg/hr (or approximately 200-300 cc/hr).6,45,47 Volume overload and pulmonary edema is infrequent, even after infusion of these large volumes. In older and more frail patients, however, volume overload can occur. It is important that these patients be monitored for signs of pulmonary edema.45

No large, randomized, controlled trials exist to demonstrate the superiority of 0.9% normal saline (NS) versus lactated Ringer's (LR) as the solution of choice for volume resuscitation in rhabdomyolysis patients. However, because large volumes of NS lead to the development of a metabolic acidosis, some authors advocate LR.6,47 In a small study that randomized 28 patients to NS versus LR resuscitation for the treatment of rhabdomyolysis induced by doxylamine intoxication, Cho and colleagues found that in order to maintain an alkaline urine (pH > 6.5), the addition of sodium bicarbonate was required more frequently in the NS group as compared to the LR group. They thus concluded that LR is a superior crystalloid in this setting.47 However, no patients in either group developed renal failure necessitating dialysis, and time to CK normalization (recovery) did not differ significantly between the two groups. Most case series of patients with crush injuries use normal saline as the fluid of choice.45 Particularly in the early ED phase of volume resuscitation, the choice of NS versus LR is likely less important.

During the initiation of treatment for significant rhabdomyolysis, patients should be placed on a cardiac monitor, and electrolytes checked frequently due to the risk of dysrhythmias relating to metabolic derangements, particularly hyperkalemia. Hemodynamic monitoring may also be required to avoid fluid overload in susceptible patients. Patients with significant rhabdomyolysis should be admitted to a monitored bed setting for these reasons. The rigorous treatment of hyperkalemia, which typically first begins early in the disease process, is paramount and may require dialysis if severe.

With the goal of preventing ARF, it is also important to minimize patient exposure to additional potential renal insults, including intravenous contrast material, nephrotoxic antibiotics, and other nephrotoxic medications such as ACE inhibitors and NSAIDs.6 It is also imperative to search for and treat the underlying cause of rhabdomyolysis, and to exclude or treat compartment syndrome in affected injured muscle groups.

Urine Alkalization Using Sodium Bicarbonate and Mannitol Osmotic Diuresis. Despite the common practice of urine alkalinization to a pH greater than 6.5 using sodium bicarbonate and forced diuresis with mannitol, no randomized, controlled trials support their superiority to adequate fluid resuscitation alone for the treatment of rhabdomyolysis and prevention of ARF.6,11 Most of the data to support their use come from the cardiothoracic and the renal transplant literature.45

Homsi and colleagues performed a retrospective review of rhabdomyolysis patients admitted to an ICU setting and found no difference in the rate of ARF in patients receiving saline, sodium bicarbonate, and mannitol versus those receiving saline alone.46 Similarly, in a retrospective analysis of trauma ICU patients with rhabdomyolysis, Brown et al noted no difference in the rates of ARF as defined by a creatinine greater than 2.0 mg/dL (22% vs. 18%), need for dialysis (7% vs. 6%), or mortality (15% vs. 18%) among patients receiving fluid resuscitation with the addition of sodium bicarbonate and mannitol compared to those who received only volume replacement.48 These authors concluded the standard practice of bicarbonate and mannitol therapy should be reconsidered for the treatment of rhabdomyolysis.

While the only clear disadvantage of urine alkalinization with sodium bicarbonate is exacerbation of the hypocalcemia associated with the initial phase of rhabdomyolysis, mannitol has been found to actually worsen renal failure if it is used without adequate fluid resuscitation or if used late in the course of rhabdomyolysis.6,45 One possible additional benefit of sodium bicarbonate is the concomitant treatment of hyperkalemia and of metabolic acidosis.


Despite appropriate fluid therapy, approximately 10-50% of rhabdomyolysis patients progress to develop ARF.11,14,44,48 In a retrospective review of 2,083 trauma ICU patients, CK levels of 5000 U/L and higher were found to be associated with an increased risk of developing of ARF.48 In such cases of rhabdomyolysis-induced ARF complicated by oliguria, severe hyperkalemia, acidosis, or volume overload, hemodialysis (HD) is often required. Either daily HD or continuous hemofiltration can be used successfully to correct fluid and electrolyte abnormalities resulting from such processes as the release of excess potassium and urea from necrotic skeletal muscle. HD has also been shown to remove large amounts of myoglobin when used before ARF is established.49 Continuous venovenous hemofiltration may be more advantageous in critically ill patients with hemodynamic instability, as it is not associated the hypotension and dysrhythmias caused by the rapid fluid shifts of HD.14,44 The use of plasmapheresis for removal of myoglobin has been shown to be beneficial in a few case reports, but its routine use is not indicated.50

Experimental Therapies

Isolated case reports have documented the success of high-dose corticosteroids for rhabdomyolysis unresponsive to fluid resuscitation2 and the possible benefit of rasburicase, a urate oxidase enzyme, for the treatment of hyperuricemia in patients with rhabdomyolysis and renal failure.51 Small case series, case reports, and experimental models support the use of antioxidants and free-radical scavengers such as pentoxifylline and vitamins C and E, in addition to deferoxamine for the prevention of myoglobinuric renal failure.6,11,14 Another animal model showed decreased CK release from muscle after exposure to ethanol, cocaine, and electricity with the use of dantrolene sodium.52 However, none of these therapies is proven by controlled studies, and, thus, sufficient evidence of their efficacy is lacking.

In summary, early and aggressive crystalloid fluid resuscitation remains the mainstay of treatment of rhabdomyolysis and the prevention of rhabdomyolysis-associated renal failure. The addition of sodium bicarbonate should be considered in patients with crush injury and in those with severe metabolic acidosis, but its routine use is not supported by published evidence.


Rhabdomyolysis is a complex syndrome that has a multitude of causes. The classic description of muscle pain, muscle weakness, and dark urine is seldom completely present, so a high index of suspicion must be maintained for those at high risk of the syndrome: a history of heavy exertion, trauma (especially crush injuries), agitation, motor excitation, and seizures. However, other causes should also be considered, such as infections and drugs. In the ED, the insult should be identified if possible and promptly removed.

Aggressive, early isotonic crystalloid resuscitation is central to the prevention of ARF, the most common complication from rhabdomyolysis. In patients with metabolic acidosis and/or hyperkalemia, sodium bicarbonate can be used, although there is no definitive evidence showing its benefit.


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