CHEST

Rhabdomyolysis

Postgraduate Education Corner

CONTEMPORARY REVIEWS IN CRITICAL CARE MEDICINE

Janice L. Zimmerman, MD, FCCP; and Michael C. Shen, MD

Rhabdomyolysis is a well-known clinical syndrome of muscle injury associated with myoglobinuria, electrolyte abnormalities, and often acute kidney injury (AKI). The pathophysiology involves injury to the myocyte membrane and/or altered energy production that results in increased intracellular calcium concentrations and initiation of destructive processes. Myoglobin has been identied as the primary muscle constituent contributing to renal damage in rhabdomyolysis. Although rhabdomyolysis was rst described with crush injuries and trauma, more common causes in hospitalized patients at present include prescription and over-the-counter medications, alcohol, and illicit drugs. The diagnosis is conrmed by elevated creatine kinase levels, but additional testing is needed to evaluate for potential causes, electrolyte abnormalities, and AKI. Treatment is aimed at discontinuation of further skeletal muscle damage, prevention of acute renal failure, and rapid identication of potentially life-threatening complications. Review of existing published data reveals a lack of high-quality evidence to support many interventions that are often recommended for treating rhabdomyolysis. Early and aggressive uid resuscitation to restore renal perfusion and increase urine ow is agreed on as the main intervention for preventing and treating AKI. There is little evidence other than from animal studies, retrospective observational studies, and case series to support the routine use of bicarbonate-containing uids, mannitol, and loop diuretics. Hyperkalemia and compartment syndrome are additional complications of rhabdomyolysis that must be treated effectively. A denite need exists for well-designed prospective studies to determine the optimal management of rhabdomyolysis. CHEST 2013; 144 (3):10581065
Abbreviations: AKI 5 acute kidney injury; CK 5 creatine kinase; CRRT 5 continuous renal replacement therapy; IVF 5 IV uid

is dened as injury of the skeletal Rhabdomyolysis muscle, which results in the release of intracel-

lular contents into the circulation. Skeletal muscle comprises 40% of body mass, and a large insult can result in the accumulation of cellular contents in the extracellular space such that elimination mechanisms are overwhelmed. The resulting effects are recognized as a clinical syndrome of muscle injury that is associated with the development of myoglobinuria, electrolyte abnormalities, and often acute kidney injury (AKI). Rhabdomyolysis has long been recognized as a primary condition or comorbidity in hospitalized and critically ill patients. The initial understanding of the syndrome originated from experiences of warfare during and following World War II, as well as from natural disasters. Rhabdomyolysis was caused primarily by crush injury or other physical trauma in these circumstances. Any form of therapy that prevented renal failure or avoided death was deemed successful because experience suggested that the out-

comes from rhabdomyolysis were generally poor.1,2 However, in the mostly civilian setting of current health care, the characteristics of rhabdomyolysis are different. Pharmaceutical agents, alcohol, and illicit drugs are now signicant causes of rhabdomyolysis, in addition to trauma.3-6 This article focuses on the causes of rhabdomyolysis likely to be encountered in hospitalized patients, current diagnosis and evaluation of the syndrome and its associated complications, and treatment of rhabdomyolysis, with an emphasis on prevention of AKI. Pathophysiology The common pathway leading to muscle injury and death in rhabdomyolysis is an increase in cytoplasmic ionized calcium.7 The major mechanisms that result in increased intracellular calcium are injury to the myocyte membrane and altered energy production. Direct disruption of the muscle cell membrane results in an inux of calcium, with further release of calcium
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from the damaged sarcoplasmic reticulum and mitochondria. Impaired metabolism (production, use, or consumption) of adenosine triphosphate disrupts the function of sodium-potassium and sodium-calcium ion pumps, leading to intracellular calcium accumulation. The increase in calcium activates multiple destructive processes, resulting in the eventual lysis of the cell and release of contents. High concentrations of muscle cell contents are absorbed into the bloodstream; these include electrolytes (potassium, calcium, and phosphates), enzymes (creatine kinase [CK], lactate dehydrogenase, aspartate transaminase, and aldolase), proteins (myoglobin), and purine metabolites (uric acid). Myoglobin, an iron-containing protein in skeletal muscle that stores oxygen for aerobic mitochondrial metabolism, is an important factor in rhabdomyolysis. Myoglobin is excreted by the kidneys, and a urine concentration . 100 mg/dL is responsible for the red or brown staining of urine that can occur in rhabdomyolysis.8 The term myoglobinuria is essentially synonymous with rhabdomyolysis; the latter term is preferred because it describes the pathophysiologic process more accurately. Myoglobin has been implicated consistently as the primary nephrotoxin in rhabdomyolysis, with proposed mechanisms of toxicity that include tubular obstruction, oxidant injury, and vasoconstriction.9-11 Animal studies suggest that myoglobin alone may not be nephrotoxic in the absence of hypovolemia and acidosis,12 but acute renal failure has been described in patients without signicant hypovolemia.13,14 Myoglobin is readily ltered by glomeruli in the kidneys and concentrated in the renal tubules. Myoglobin can then be precipitated out of solution in the acidic environment of the renal tubules through interaction with Tamm-Horsfall protein. Myoglobin precipitation can be exacerbated by intravascular volume depletion and systemic acidosis, but hypovolemia leading to renal hypoperfusion may be a more important factor in AKI than tubular obstruction. Oxidant injury can result from dissociation of the iron in myoglobin, resulting in the release of free radical species and oxidative damage to the renal parenchyma.15 Studies also suggest that myoglobin can induce lipid peroxidation, resulting in the generation of isoprostanes. These molecules are potent
Manuscript received August 12, 2012; revision accepted January 31, 2013. Afliations: From The Methodist Hospital (Drs Zimmerman and Shen), Houston, TX; and Weill Cornell Medical College (Dr Zimmerman) New York, NY. Correspondence to: Janice L. Zimmerman, MD, FCCP, 6550 Fannin, Ste 1001, Houston, TX 77030; e-mail: janicez@tmhs.org 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.12-2016
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vasoconstrictors and can contribute to renal arteriolar dysregulation and hypoperfusion.11,15-17 Homeostatic activation of the sympathetic nervous system and the renin-angiotensin system due to intravascular hypovolemia can also contribute to vasoconstriction. Despite the signicant contribution of myoglobin to AKI, coexisting factors found in patients with rhabdomyolysis, such as hypovolemia, other injuries, metabolic abnormalities, and drug effects, also impact renal function. Cause Rhabdomyolysis has numerous and diverse causes, and Table 1 contains a listing of some of the most relevant. A useful approach is to consider the mechanisms of skeletal muscle damage. The insult can usually be categorized into one of four mechanisms: hypoxic, physical, chemical, or biologic. Many patients have multiple factors that contribute to the development of rhabdomyolysis, and a signicant number of patients may have no cause identied.3,4 Skeletal muscle is more prone to hypoxic injury and vascular compromise because of its peripheral location. Limbs are at increased risk of prolonged pressure during an unconscious state, leading to vascular occlusion and ischemia. Pressure-related muscle injury causing rhabdomyolysis is now recognized in obese patients as a complication of bariatric surgery, as well as in nonobese patients undergoing prolonged surgeries.18-21 A higher BMI and longer operating times may increase the risk of rhabdomyolysis. Arterial and venous thrombosis, as well as diffuse occlusion of the microvasculature (eg, sickle cell trait, vasculitis), can result in ischemic muscle injury and rhabdomyolysis.22,23 The physical causes of rhabdomyolysis can be due to external factors such as trauma or internal factors such as exertion. Trauma results in overt muscle injury, but rhabdomyolysis can also be precipitated by less obvious injury. Internal factors can result from voluntary and involuntary injury. Common voluntary injuries causing rhabdomyolysis follow overstrenuous or prolonged exertion during military, recreational, and sports events.24 Exertional rhabdomyolysis has also occurred as a result of prolonged electronic gaming.25 Genetic polymorphic variations may play a role in the variable susceptibility to exertion-related muscle injury.26 Involuntary muscle overuse usually stems from some predisposing medical condition such as seizures or status asthmaticus.27 Chemical causes now account for most cases of rhabdomyolysis.3,4 This category includes prescription and over-the-counter medications, illicit drugs, inorganic toxins, and electrolyte abnormalities. Table 2 lists selected drugs implicated as a cause of rhabdomyolysis. Psychiatric medications (eg, quetiapine,
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Table 1Causes of Rhabdomyolysis

Hypoxic External Carbon monoxide exposure Cyanide exposure Internal Compartment syndrome Vascular compression Immobilization Bariatric surgery Prolonged surgery Sickle cell trait Vascular thrombosis Vasculitis Physical External Crush injury Trauma Burns Electrocution Hypothermia Hyperthermia (heat stroke) Internal Prolonged and/or extreme exertion Seizures Status asthmaticus Severe agitation (delirium tremens, psychosis) Neuroleptic malignant syndrome Malignant hyperthermia Chemical External Alcohol Prescription medications Over-the-counter medications Illicit drugs Internal Hypokalemia Hypophosphatemia Hypocalcemia Hypo-/hypernatremia Biologic External Bacterial, viral, and parasitic myositis Organic toxins Snake venom Spider bites Insect stings (ants, bees, wasps) Internal Dermatomyositis, polymyositis Endocrinopathies Adrenal insufciency Hypothyroidism Hyperaldosteronism Diabetic ketoacidosis Hyperosmolar state

aripiprazole) rank as one of the most frequent precipitants, with a portion related to neuroleptic malignant syndrome.4 Statins are also implicated frequently. Fewer than 1% of those taking statins alone will develop rhabdomyolysis resulting in hospitalization or kidney injury, but the risk increases to 6% when used concomitantly with a brate.28 The risk of rhabdomyolysis is also higher when statins are combined with drugs that inhibit statin metabolism by cytochrome P450 isoenzymes (cyclosporine, warfarin, amiodarone, azole antifungals, and calcium channel blockers). Genetic polymorphisms of transporter proteins that facilitate hepatic uptake of statins, the cytochrome P isoenzyme system, and enzymes of the coenzyme Q10 synthetic pathway have been associated with a higher risk of statin-associated myopathy.29 Although less common, rhabdomyolysis can also result from medications administered to hospitalized patients. Rhabdomyolysis can accompany the development of propofol-related infusion syndrome, a potentially fatal complication of prolonged or highdose propofol use.30 Daptomycin, often used to treat serious hospital-acquired infections, has also been associated with clinically signicant rhabdomyolysis.13,14 Illicit drugs are well-described precipitants of rhabdomyolysis.6,31 Few of these drugs have direct cytotoxic effects on myocytes; instead, multiple factors coincide to inict muscle damage. Stimulants such as cocaine, methamphetamines, amphetamines, and bath salts (mephedrone, methylenedioxypyrovalerone) can increase physical activity to deleterious levels, precipitate seizures or hyperthermia, and produce ischemia from arterial vasoconstriction.31-33 Alcohol may act as a direct toxin to muscles and cause rhabdomyolysis via other effects.34 Intoxication can lead to immobilization associated with compression and ischemic injury. In addition, the diuretic
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effect of alcohol can lead to dehydration and increase the risk of AKI. Chronic alcoholism also predisposes to rhabdomyolysis because of malnutrition, limited energy stores, electrolyte abnormalities, and enzyme deciencies. Biologic causes make up the last category of causes of rhabdomyolysis. Although almost any bacteria can cause myositis, gram-positive organisms predominate, and the most common viruses associated with myositis are inuenza A and B, enteroviruses, and HIV.35 Organic toxins that affect skeletal muscles via stings and bites have been reported for bees, wasps, hornets, ants, centipedes, scorpions, and brown recluse spiders.36-38 Genetic inborn errors of metabolism and muscular dystrophies can present with rhabdomyolysis later in life, and additional evaluation should be considered in patients with recurrent episodes of rhabdomyolysis.39 Clinical Evaluation and Diagnosis Rapid recognition of rhabdomyolysis is important to implement timely, appropriate treatment. Evaluation requires an assessment of risk factors for rhabdomyolysis, a thorough history and physical examination, and laboratory testing. The history should elicit information on prior exertional activities; environmental exposures; prolonged immobilization; trauma; prescription and over-the-counter medication use; illicit drug or alcohol use; symptoms of infection, rash, or arthralgias; and change in urine color or quantity. The physician should be aware that intoxicated, psychotic, agitated, and unconscious patients are at high risk of rhabdomyolysis. Psychiatric patients are also considered higher risk because of use of antipsychotic and antidepressant medications. The variable clinical manifestations in rhabdomyolysis may result from the precipitating cause (ie, inuenza,
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Table 2Selected Drugs Associated With Rhabdomyolysis

Drugs Medications Lipid-lowering agents Statins Fibrates Psychiatric medications Neuroleptics/antipsychotics (including haloperidol, atypical antipsychotics) Selective serotonin reuptake inhibitors Lithium Valproic acid Antimicrobial agents Antiretroviral medications (protease inhibitors) Trimethoprim-sulfamethoxazole Daptomycin Macrolide antibiotics Quinolones Amphotericin B Anesthetics/paralytics Succinylcholine Propofol Antihistamines Doxylamine Diphenhydramine Appetite suppressants Phentermine Ephedra Others Sunitinib, erlotinib Narcotics Colchicine Vasopressin Amiodarone Aminocaproic acid Illicit drugs Cocaine Amphetamines/methamphetamines Hallucinogens Heroin Methylenedioxypyrovalerone, mephedrone (bath salts) Phencyclidine

trauma), the muscle injury (direct or indirect), and the complications associated with rhabdomyolysis. Muscle injury may manifest as pain, swelling, tenderness, or weakness, but such ndings may be absent or may be overshadowed by other conditions. Signicant limb pain in the setting of trauma should raise the suspicion for compartment syndrome. Nonspecic symptoms may include fatigue, nausea, vomiting, and fever. Red or brown urine suggests signicant myoglobin excretion but its absence does not preclude the presence of rhabdomyolysis. Detection of rhabdomyolysis that develops during hospitalization may be more difcult, because it may not be suspected and patients may not be able to communicate complaints. Patients who do complain of myalgias or develop a change in urine color should
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have medications reviewed and diagnostic testing initiated. Laboratory monitoring may be indicated in patients with risk factors such as obesity, prolonged surgery, statin use, alcohol abuse, prolonged seizure activity, severe agitation, propofol use, unexplained hyperkalemia, and deterioration of renal function. Less commonly, patients may present with manifestations due to complications of rhabdomyolysis. The edema and inammation resulting from muscle damage in the limbs can secondarily increase local pressure and compromise circulatory ow, resulting in compartment syndrome. Circulation should be evaluated periodically in any severely affected limb, especially after volume resuscitation. Some patients, especially those with extensive crush injuries, may present with arrhythmias or sudden death resulting from hyperkalemia. Urine output may be decreased on presentation if AKI has already developed. Diagnostic laboratory testing for rhabdomyolysis is straightforward (Table 3); serum should be sent for measurement of CK, which is more specic for the diagnosis of rhabdomyolysis than are other markers that may also be elevated. Normal CK levels are usually , 100 IU/L. The CK level for clinical concern is uncertain; an arbitrary value of 500 to 1,000 IU/L, or ve to 10 times the upper limit of normal is frequently used to dene rhabdomyolysis. Higher CK levels correlate with a greater degree of muscle injury, but levels correlate marginally with the development of AKI or mortality.3,4,6,40-43 A reasonable consensus recommendation suggests close monitoring of renal function in patients with CK levels . 5,000 IU/L and creatinine . 1.5 mg/dL.44 Some studies suggest that patients with CK levels , 5,000 IU/L are not at risk of developing AKI42,44; otherwise, it is difcult to use the magnitude of the CK value to estimate the risk of kidney injury. Serial CK measurements should be monitored; increasing levels, or failure of levels to decline despite therapy, suggest ongoing muscle injury or the development of renal failure. Serum myoglobin levels are not needed for the diagnosis or management of rhabdomyolysis. Myoglobin is cleared more rapidly than CK, and therefore is less sensitive for detecting rhabdomyolysis, especially when presentation is delayed.3 When initially evaluating a patient with dark-colored urine, a positive urine dipstick test for blood without evidence of RBCs on microscopy is a clue to the presence of rhabdomyolysis, because myoglobin will also react with the orthotolidine test reagent. Urine myoglobin is not a sensitive test for rhabdomyolysis, nor is it specic for the development of AKI; therefore, it is not necessary for routine testing. Additional laboratory testing is needed to determine the potential precipitating factors and complications resulting from rhabdomyolysis. A metabolic
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Table 3Selected Laboratory Testing for Initial Evaluation

Test CK Potassium Phosphorous Calcium Creatinine BUN:creatinine Anion gap Blood alcohol level Urine blood dipstick Urine drug screen Abnormal Value for Rhabdomyolysis . 500 IU/L . 6.0 mmol/L , 2.0 mmol/L . 6.0 mg/dL , 2.0 mg/dL Decreased (, 8.0 mg/dL) Increased , 10:1, often , 6:1 Increased Elevated Positive Positive Comments Diagnostic for rhabdomyolysis; increased risk of kidney injury if . 5,000 IU/L Marker of severity of muscle injury and renal dysfunction Potential cause of rhabdomyolysis Marker of severity of muscle injury and renal dysfunction Potential cause of rhabdomyolysis Deposition in damaged muscle Marker of decreased renal function Increased conversion of muscle creatine to creatinine Increased organic acids due to muscle injury or renal dysfunction Potential cause of rhabdomyolysis Detects myoglobinuria in absence of RBCs in urine Potential drug-related cause of rhabdomyolysis

BUN 5 blood urea nitrogen; CK 5 creatine kinase.

panel that includes electrolytes (potassium, calcium, phosphorous) and renal function should be obtained routinely. The results screen for hypokalemia and hypophosphatemia as potential causes and identify potentially life-threatening hyperkalemia. Calcium levels are often low initially, secondary to precipitation of calcium with phosphates in damaged muscles.3,45 Calcium mobilization from damaged muscles in the recovery phase of rhabdomyolysis and AKI may subsequently result in hypercalcemia.45 An elevated creatinine level with a blood urea nitrogen-to-creatinine ratio , 10:1 is often noted on presentation.3 The disproportionate increase in creatinine early in rhabdomyolysis is possibly due to metabolism of released muscle creatine. The anion gap in rhabdomyolysis is often increased more than expected for the degree of AKI and may be due to phosphates and organic acids released from muscle.3 Hyperuricemia resulting from the release of muscle purines is common. A coagulation panel should be assessed for evidence of the disseminated intravascular coagulation that can occur with rhabdomyolysis. An ECG can be obtained quickly to screen for conduction abnormalities and evidence of hyperkalemia (P-R interval prolongation, peaked T waves, and widened QRS complex). A urine drug screen may be indicated to conrm exposure to specic drugs. Therapy There are no randomized, controlled trials in rhabdomyolysis that offer denitive guidance for treatment. Only a few interventional clinical trials in rhabdomyolysis have been reported in the past 10 years. The lack of high-quality evidence must be acknowledged and considered when reviewing recommendations for interventions. Most recommendations are based on retrospective observational studies with small numbers of patients, animal models, case reports or series, and opinion. The treatment of rhabdomyolysis usu1062

ally involves three components: discontinuation of further skeletal muscle damage, prevention of acute renal failure, and rapid identication of potentially life-threatening complications. Specic measures to stop ongoing muscle injury will vary with the cause of the rhabdomyolysis. Interventions may include control of agitation, discontinuation of medications, treatment of infection, correction of metabolic abnormalities, cooling or warming, surgery, and others. The major effort in the treatment of rhabdomyolysis is directed toward prevention of renal failure. AKI has been observed in 10% to 60% of patients presenting with rhabdomyolysis,3,4,6,40,42,43,46 and 10% of AKI has been attributed to rhabdomyolysis.10 The cause of muscle injury, intravascular volume status, patient comorbidities, and initial laboratory results may be helpful in determining the risk of progression to AKI. Although CK, myoglobin, potassium, bicarbonate, albumin, lactate dehydrogenase, and creatinine levels at presentation have been evaluated, no single marker or predictive model has been able to reliably assess the risk of AKI. The reason for this difculty is at least twofold: the multifactorial nature of kidney injury, with rhabdomyolysis being only one of the contributing factors, and the heterogeneity in the causes of rhabdomyolysis. Suggested markers and models of AKI are derived from the results of singlecenter retrospective studies and are difcult to generalize. Serial trends of laboratory markers may be more appropriate than single results to assess the risk of AKI. Patients with elevated CK levels secondary to chronic myositis due to statins, HIV infection, or inammatory myopathies may be at a lower risk of developing AKI.4 Patients with exertional rhabdomyolysis also appear to be at a much lower risk of AKI.47 Trauma patients and those with comorbidities such as chronic alcoholism or drug use may be at a higher risk. There is complete agreement that early and aggressive volume resuscitation to restore adequate renal
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perfusion and increase urine ow is the mainstay for preventing and treating AKI in rhabdomyolysis.9,10,44,48,49 The administration of IV uid (IVF) dilutes nephrotoxins and promotes renal tubule ow, which may prevent the accumulation of myoglobin and toxic products in the renal parenchyma. More controversy exists regarding the type and volume of uid and the use of diuretics. When a patient is suspected or recognized to have rhabdomyolysis, IVF should be administered rapidly as an initial bolus. Isotonic saline is preferred because it is readily available and does not contain potassium. In disaster situations, prompt IVF administration prior to or during extrication of crush victims may help prevent later renal complications.48 IVF is continued by infusion until resolution of rhabdomyolysis or until the development of oliguric AKI limits further uid administration. A prospective, randomized trial compared the effects of lactated Ringers vs 0.9% saline administered at 400 mL/h in patients with mild rhabdomyolysis secondary to doxylamine.50 At the end of 12 h of infusion, the serum and urine pH were higher in the lactated Ringers group; however, the clinical signicance of this outcome is unclear. Large amounts of IVF within the rst 24 h are associated with improved outcomes.1 No specic rate of infusion or target urine output has been demonstrated to be superior to another. For the rst 24 h after presentation, as little as 3 L to as much as 24 L have been administered effectively. A target of 6 to 12 L within 24 h is a reasonable goal, as long as complications from volume overload can be avoided. Traditionally, urine output goals of 200 to 300 mL/h have been recommended. There has been minimal investigation of uid administration in high-risk patients to prevent the development of rhabdomyolysis prior to injury. A prospective, randomized trial of intraoperative isotonic uids in bariatric surgery patients at 15 mL/kg vs 40 mL/kg total body weight did not nd any difference in the incidence of rhabdomyolysis.51 Alkalinization of the urine is also a common intervention in rhabdomyolysis, but evidence of a clinical benet is lacking. The concept of urine alkalinization derives from the precipitation of myoglobin in an acidic environment, and therefore, urinary alkalinization (pH . 6.5) theoretically can decrease the deposition of myoglobin in renal tubules. Alkalinization therapy was shown to be more effective than IVF alone in animal models, and two small retrospective observational case series (27 patients in total) are often cited to suggest the benet of bicarbonate and mannitol administration in rhabdomyolysis.1,2 However, several other retrospective studies were not able to show that bicarbonate coadministered with mannitol was more effective than volume infusion with isotonic saline.42,52 The largest retrospective study of bicarjournal.publications.chestnet.org

bonate and mannitol therapy vs no use of this therapy in trauma patients did not nd any difference between groups in the incidence of renal failure, need for dialysis, or mortality.42 A current consensus statement suggests that sodium bicarbonate administration is not necessary and not superior to normal saline diuresis in increasing urine pH.44 Urine alkalinization is generally accomplished by the administration of bicarbonate, either by direct infusion or by adding it to IVF. Alkalinization of the urine may be difcult to achieve without causing a systemic metabolic alkalosis. Conversely, some bicarbonate-containing uids may be helpful if 0.9% saline administration causes a dilutional metabolic acidosis. If the decision is made to alkalinize urine, care must be taken to ensure that other electrolytes remain balanced. Forced diuresis with mannitol and loop diuretics has also been used to promote urine output and prevent AKI. Theoretically, diuresis may prevent the accumulation of debris in the renal tubules, thereby decreasing the risk of obstruction contributing to AKI. Mannitol also acts as an intravascular volume expander and vasodilator, which may ameliorate renal injury, along with other proposed protective mechanisms.9,53 A variety of dosing regimens using intermittent bolus and continuous infusion of mannitol have been reported. Mannitol has not been evaluated as a sole intervention in a controlled trial of rhabdomyolysis. The same small retrospective studies of bicarbonate administered with mannitol in rhabdomyolysis are cited to suggest treatment success with mannitol.1,2 Routine use of mannitol is not recommended for rhabdomyolysis, and it should not be administered to hypovolemic or anuric patients. Use of loop diuretics has been advocated to convert oliguria or anuria to nonoliguria, but with very limited published experience. Care must be taken not to exacerbate hypokalemia or hypocalcemia if loop diuretics are used; conversely, use may be benecial to treat hyperkalemia before renal recovery or hemodialysis. Anecdotal use of corticosteroids, acetazolamide, and various antioxidants has been reported, but these agents cannot be recommended.54,55 Laboratory studies have suggested that acetaminophen and l-carnitine may be able to ameliorate nephrotoxicity from myoglobin, but more clinical research is needed.17,56,57 If AKI develops, or fails to reverse despite aggressive uid administration, renal replacement therapy may be required to manage the complications of rhabdomyolysis. Indications for hemodialysis include hyperkalemia, metabolic acidosis, volume overload, and azotemia.9,44 Hyperkalemia tends to be the major indication for early renal replacement therapy because of the potassium load released from muscle. Currently, there are no data to support the use of continuous
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renal replacement therapy (CRRT) over intermittent hemodialysis in rhabdomyolysis, but CRRT may be better tolerated in patients with hypotension or in those at risk of hypotension. CRRT using conventional high-ux lters has been found to remove myoglobin despite its large molecular weight, and experimental super-high-ux lters may be even more effective.58 However, it is not clear that removal of myoglobin prevents or alters the clinical course of AKI, and CRRT is not advocated for myoglobin removal.9,44 At the same time that IVF is initiated, the physician should assess the likelihood of electrolyte complications with laboratory testing and an ECG. Signicant hyperkalemia should be treated according to standard management principles.59 Treatment of hypocalcemia is not recommended because of the high intracellular concentrations in injured muscle and the potential for precipitation. Exceptions are concomitant hyperkalemia with signicant ECG changes and symptomatic hypocalcemia (tetany). Calcium levels should be monitored throughout the hospital course to detect later development of hypercalcemia. Oral phosphate binders can be considered for significant hyperphosphatemia. If compartment syndrome is suspected, surgical consultation should be obtained for measurement of intracompartment pressures and/or fasciotomy.60 Outcome Outcomes from rhabdomyolysis vary considerably with the type of patient population, cause, and comorbidities. A consistent nding is that the mortality of patients with rhabdomyolysis and acute renal failure is higher than in patients with no renal failure.1,42 It is not surprising that hospital length of stay is noted to be longer in patients with signicant renal compromise.6 Most patients with acute renal failure from rhabdomyolysis recover function within a few months. Mortality in rhabdomyolysis also ranges from 1.7% to 46%, and the variability is likely due to differing causes, coexisting conditions, and improved treatment over time (especially for trauma patients).1,2,6,42,43,47 Conclusions Rhabdomyolysis continues to be a signicant syndrome leading to hospitalization or developing in hospitalized patients. The prominent role of medications, alcohol, and illicit drugs as causes of rhabdomyolysis requires careful consideration when evaluating patients. Aggressive uid resuscitation with isotonic uids is probably sufcient to prevent AKI in the majority of patients with rhabdomyolysis. There is little evidence to support the routine use other interventions with bicarbonate, mannitol, and loop diuretics. Prospective well-designed trials in rhabdomyolysis
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are sorely needed to provide more denitive guidance on treatment interventions. Acknowledgments
Financial/nonnancial disclosures: The authors have reported to CHEST that no potential conicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

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