Rhabdomyolysis Evaluation and Emergent Management Bobby Desai, MD, FACEP Timely diagnosis and treatment of rhabdomyolysis can save lives and limbs, as well as preserve renal function. This article delineates causes and features of the syndrome and summarizes evaluation and management considerations. habdomyolysis is a clinical syndrome caused by breakdown products with electrolyte imbalances, sub- insults to myocytes and muscle membranes that sequent renal failure secondary to myoglobinuria, and Rlead to the destruction of skeletal muscle and the potential for disseminated intravascular coagu- release of muscle fiber contents into the bloodstream.1,2 lation (DIC). Approximately 10% to 50% of patients The insults that may lead to rhabdomyolysis range from with rhabdomyolysis develop acute renal failure,5 and direct muscle trauma—which is the most common some reports indicate that rhabdomyolysis causes 5% cause—to genetic causes (enzyme deficiencies), toxins to 25% of cases of acute renal failure.5-7 There is a high (including illicit drugs), infections, and endocrinologic prevalence of rhabdomyolysis in patients with acute etiologies (eg, diabetic ketoacidosis, hyperosmolar non- traumatic injuries, and mortality in those patients with ketotic states, and hypothyroidism).3 The most sensitive severe injury who develop renal failure is around 20%.8 indicator of rhabdomyolysis is an elevated serum cre- atine kinase (CK) level. In the absence of brain or car- ETIOLOGY AND PATHOPHYSIOLOGY diac issues, a CK concentration of 5,000 U/L or greater Rhabdomyolysis has many etiologies, which can be (with 50 to 250 U/L considered the normal range) is loosely separated into physical and nonphysical causes. indicative of significant muscle injury.4 Physical causes are acquired, while nonphysical causes The clinical spectrum of rhabdomyolysis ranges are typically inherited; however, nonphysical causes from mild illness with minimal elevation of serum CK also include toxins, drugs, infections, and electrolyte measurements to substantially elevated levels of muscle imbalances.4 Some physical etiologies of rhabdomyoly- sis that are seen in the emergency department include Dr. Desai is assistant professor, residency program director, exercise, prolonged immobilization, and trauma and and codirector of simulation training in the department of compression. Use of recreational drugs (eg, cocaine, emergency medicine at the University of Florida College of Medicine in Gainesville. amphetamines, opiates, and other stimulants) is a no- table nonphysical cause.9 Lipid-lowering agents, espe- www.emedmag.com JANUARY 2012 | EMERGENCY MEDICINE 11 RHABDOMYOLYSIS cially statins, also can induce rhabdomyolysis.10 occur. This syndrome is caused by activities that in- Cocaine use and abuse deserves special mention crease heat production. The late sequelae of heat stroke because it is both a physical and nonphysical cause include hypotension, hypoglycemia, lactic acidosis, and of rhabdomyolysis. Acute rhabdomyolysis is seen in DIC, which may ultimately be followed by multiorgan almost one-fourth of patients presenting to the emer- failure.14 Management of heat stroke entails removal of gency department with cocaine-associated disorders.4,11 specific inciting events to initiate cooling and reverse A mechanism by which cocaine is thought to produce the process, along with supportive care, which at times the syndrome is muscle ischemia resulting from its pro- may be intensive. Hypokalemia worsens rhabdomyoly- longed vasoconstrictive effect. Cocaine is also thought sis and increases the risk of developing heat stroke.14 to have a direct toxic effect on myofibrils. The physical Malignant hyperthermia occurs most often in the set- effects of cocaine can be caused by generalized tonic- ting of general anesthesia but can be seen with expo- clonic seizures and compression of muscle tissue sub- sure to other nonanesthetic agents, including gasoline sequent to a seizure.12 vapors and certain decongestants.15-18 This syndrome There are several purported mechanisms of renal consists of skeletal muscle rigidity, fever, hemodynamic failure in rhabdomyolysis. In addition to the direct collapse, hyperventilation, tachycardia, and cyanosis, toxic effects of myoglobin on the renal tubules, vaso- with rising end-expiratory carbon dioxide concentra- tion and lactic acidosis.15,19 Rhabdomyolysis second- ary to NMS is caused by the production of heat from Acute rhabdomyolysis is seen muscle rigidity and tremor, both of which occur due to in almost one-fourth of patients central dopaminergic blockade.20 A mimic of NMS is presenting to the emergency the serotonin syndrome. This syndrome features an al- tered mental status and neuromuscular irritability with department with cocaine- autonomic instability,21 and it can be associated with associated disorders. myoglobinuric renal failure.22 These syndromes can be FAST TRACK FAST differentiated based on the history and the context in which the syndrome has occurred, along with the ab- constriction due to a low-flow state caused by volume sence of muscular rigidity in exertional heat stroke.23 depletion produces tubular obstruction and further damage. Volume depletion may be due to a myriad of Exercise—It has long been known that elevations of factors, depending upon the clinical scenario. A cas- CK can result from moderate exercise, with associ- cade of events ensues, including the production of renal ated myoglobinemia and myoglobinuria.24 In extreme vasoconstrictors. This, along with a relative reduction circumstances, as in the case of tremendous physical of the renal vasodilator nitric oxide (due to volume de- exertion, muscle necrosis can occur, resulting in severe pletion), ultimately leads to renal ischemia, and kidney rhabdomyolysis. This effect may be potentiated by high damage is further compounded.5,13 ambient temperatures.25 The purported mechanism is a combination of direct muscle injury and thermal dam- Physical Causes age. Medical conditions that can cause muscle dam- Hyperthermic Syndromes—The hyperthermic syn- age by this mechanism include status epilepticus and dromes include exertional heat stroke, malignant hy- myoclonus.26 perthermia, neuroleptic malignant syndrome (NMS), and serotonin syndrome. (See “Case Studies in Toxi- Lightning and Electrical Injury—Rhabdomyolysis fol- cology: Toxicologic Hyperthermia” in the November lowing lightning strikes and electrical injuries is seen 2011 issue of Emergency Medicine [pp 13-16].) Exer- in approximately 10% of patients that survive the ini- tional heat stroke presents with muscle weakness, fever, tial injury.27 In this context, rhabdomyolysis presents delirium, seizures, and coma. Sweating may or may not with a natural history similar to that associated with 12 EMERGENCY MEDICINE | JANUARY 2012 www.emedmag.com RHABDOMYOLYSIS untreated crush injuries (ie, hypotension and circula- tory shock, muscle swelling, and acute myoglobinuric The classic triad should not renal failure28), and its extent is not associated with the size of the wounds or the site of entry.29,30 be relied upon to diagnose rhabdomyolysis, as these features Nonphysical Causes are seen in only 10% of patients Electrolyte Abnormalities—Electrolyte abnormalities presenting with the condition. are also associated with rhabdomyolysis. Hypokalemia, TRACK FAST hyponatremia, and hypophosphatemia are well-known examples.6 Rhabdomyolysis can result from excessive use of diuretics or cathartic drugs, as well as from any Genetic—Inherited defects of muscle metabolism can malady that produces significant electrolyte losses (eg, cause recurrent episodes of myoglobinuria, and these persistent vomiting, as in hyperemesis gravidarum) episodes can be precipitated by exercise, infection, or leading to depletion of total body potassium.31,32 malnutrition. Combined defects have also been de- scribed. These syndromes include mitochondrial cy- Infectious—Infectious etiologies, such as influenza A topathies, fatty acid oxidation disorders, and idiopathic and B, Legionella, Streptococcus, and Salmonella, have recurrent myoglobinuria.35-37 been noted as a potential cause of rhabdomyolysis. The exact mechanism is unknown, but putative mechanisms Alcoholism—Alcohol is a direct membrane toxin include damage caused by fever, invasion of muscle by that increases permeability into and out of the cell. the organism,33 and toxin generation,33 as well as the Muscle biopsy findings in patients with chronic al- effects of the treatment given for the infection. Affected coholism demonstrate elevations of sodium, calcium, patients can present with local signs of infection with chloride, and water content, along with concomitant muscle tenderness, erythema, and edema.34 decreases in potassium, magnesium, and phosphorus www.emedmag.com JANUARY 2012 | EMERGENCY MEDICINE 13 RHABDOMYOLYSIS levels.38 Rhabdomyolysis can occur after an alcohol leads to leakage of intracellular contents, including CK binge or other such prolonged periods of alcohol and potassium, into the circulatory system. The most intake. sensitive marker for significant muscle injury is a CK level five times above normal in the absence of cardiac CLINICAL FEATURES or brain injury.45 However, the rise in serum myoglobin The clinical syndrome of rhabdomyolysis classically precedes the rise in CK. Grossly visible myoglobinuria presents with a triad of features: muscle aches and does not manifest until approximately 100 g or more of pains, weakness, and tea-colored urine.39 The finding