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570 SECTION 10: Renal and Genitourinary Disorders prior serum creatinine and serum B-type natriuretic peptide to the cur rent value can help determine if the acute presentation is more likely due to a primary heart disorder where the B-type natriuretic peptide will be elevated from baseline in a higher proportion than creatinine or due to a primary renal disorder where serum creatinine will be elevated from baseline in a higher proportion than B-type natriuretic peptide. Treatment includes management of acute decompensated heart fail ure (see Chapter 53, “ Acute Heart Failure”), with special consideration for the use of ultrafiltration to manage fluid overload. Ultrafiltration is a form of renal replacement therapy primarily used to remove excess fluid. A meta-analysis and systematic review of randomized trials including 608 patients comparing diuretics with ultrafiltration found similar outcomes between groups assessing mortality and risk for renal deterioration. 60 Most patients in the trials met criteria for AKIN stage ≤2 AKI, with creatinine ranging from 1.4 to 2.2 milligrams/dL. According to the Heart Failure Society of America, the European Society of Cardi ology, and the Canadian Cardiovascular Society, ultrafiltration should be reserved for patients refractory to diuretics. 61-63 See “Furosemide Stress Test” above. Immediate ultrafiltration or other renal replacement therapy should be considered for life-threatening hyperkalemia or pul monary edema unresponsive to less invasive treatment; otherwise, early renal replacement therapy has not been shown to improve survival or renal recovery.  IV CONTRAST IN PATIENTS TAKING METFORMIN Metformin is one of the most frequently prescribed treatments for patients with type 2 diabetes mellitus. The most significant adverse effect of metformin therapy is a metformin-associated lactic acidosis, which is most likely to occur in patients who have been prescribed metformin despite an existing contraindication to the drug. Taking a more con servative approach, the U.S. Food and Drug Administration states that metformin should be withheld temporarily in patients receiving iodin ated contrast media if their GFR is between 30 and 60 mL/min/1.73 m and restarted after creatinine has been checked 48 hours after contrast administration, and patients with lower GFRs should have metformin held and not restarted. 65 In contrast, the American College of Radiol ogy has reviewed the data on metformin-associated acidosis following the administration of contrast media and found the complication to be uncommon in patients with normal or near-normal renal function. The American College of Radiology has made the following recommenda tions. For patients with estimated GFR ≥30 mL/min/1.73 m 2, there is no need to discontinue metformin prior to the procedure or following the procedure. For patients with eGFR ≤30 mL/min/1.73 m 2, metformin should be withheld at the time of the contrast infusion and for 48 hours after the procedure. 32 The renal function should be reassessed at 48 hours to determine the safe administration of subsequent metformin therapy. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Rhabdomyolysis Francis L. Counselman INTRODUCTION AND EPIDEMIOLOGY Rhabdomyolysis is the destruction of skeletal muscle caused by any mechanism that results in injury to myocytes and their membranes.

ion of subsequent metformin therapy. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Rhabdomyolysis Francis L. Counselman INTRODUCTION AND EPIDEMIOLOGY Rhabdomyolysis is the destruction of skeletal muscle caused by any mechanism that results in injury to myocytes and their membranes. Acute necrosis of skeletal muscle fibers and the leakage of cellular con tents into the circulation result in myoglobinuria. CHAPTER Table 89-1 lists commonly recognized conditions associated with rhabdomyolysis. In general, the most common causes of rhabdomy olysis in adults are drugs of abuse and alcohol, followed by medica tions, muscle diseases, trauma, neuroleptic malignant syndrome, seizures, immobility, infection, strenuous physical activity, and heat-related illness. 1,2 Multiple causes are present in more than half of patients.1 In children, rhabdomyolysis is less common and is more benign.3,4 In a large study of children, the most common causes of non recurrent rhabdomyolysis were viral myositis, trauma, and connective tissue disease. 4 For adults and children, inherited metabolic disorders should be suspected with recurrent episodes of rhabdomyolysis, espe cially if associated with exercise intolerance. Patients in coma are at risk for rhabdomyolysis from unrelieved pressure on gravity-dependent body parts. Alcohol consumption can result in rhabdomyolysis secondary to coma-induced muscle com pression and a direct toxic effect. Drugs of abuse and alcohol should be suspected as a primary or contributing cause of rhabdomyolysis in adults. Statin-related myopathies include myalgias with or without elevation of creatine kinase level, muscle weakness, and rhabdomyolysis. Statin-related rhabdomyolysis varies with the particular statin and is dose related. Polypharmacy, including combinations with cyclosporine, macrolide antibiotics, warfarin, digoxin, and dual statin therapy, carries an increased risk for rhabdomyolysis. 3,5 A number of bacterial and viral infections including human immunodeficiency virus have been associated with rhabdomyolysis.3,6 Strenuous physical activity, as seen in athletes, marathon runners, military recruits, and outdoor laborers, is a common cause of rhabdomyolysis but is less likely than other etiologies to provoke acute kidney injury. 7 Physical activity that produces high-force eccentric contractions (resistance), such as strength training or heavy lifting, leads to greater breakdown in muscle and higher levels of creatine kinase than concentric contractions, such as endurance-based (aerobic) exercises. 7 Factors that increase the risk in this group of patients include poor physical conditioning, male sex, inadequate fluid intake, wearing of restrictive clothing, high ambi ent temperatures, and high humidity levels. PATHOPHYSIOLOGY Rhabdomyolysis is a syndrome characterized by injury to skeletal muscle with subsequent effects from the release of intracellular contents. These contents include myoglobin, creatine kinase, aspartate amino transferase, and potassium. Although numerous causes of rhabdomyolysis have been described, the common terminal event appears to involve the disruption of the Na +K+ATPase pump and calcium transport, which results in increased intracellular calcium and subsequent muscle cell necrosis. In addition, calcium activates phospholipase A 2 and various vasoactive molecules and proteases and induces the production of free oxygen radicals. 3,8 CLINICAL FEATURES The presenting symptoms of rhabdomyolysis are usually acute in onset and include myalgias, weakness, malaise, low-grade fever, and dark (usually brown) urine. Muscle symptoms, however, may be present in only half of cases. 3,4 Nausea, vomiting, abdominal pain, and tachycardia can occur in severe rhabdomyolysis.

EATURES The presenting symptoms of rhabdomyolysis are usually acute in onset and include myalgias, weakness, malaise, low-grade fever, and dark (usually brown) urine. Muscle symptoms, however, may be present in only half of cases. 3,4 Nausea, vomiting, abdominal pain, and tachycardia can occur in severe rhabdomyolysis. Mental status changes may develop from urea-induced encephalopathy. Swelling and tenderness of the involved muscle groups and hemorrhagic discoloration of overlying skin may be observed but are not common. Muscle involvement may be localized or diffuse, depending on the cause. Commonly, the postural muscles of the thighs, calves, and lower back are involved. Muscle swelling may not become apparent until after rehydration with IV fluids. Acute rhabdomyolysis may be present without any signs or symptoms, with a normal physical examination. DIAGNOSIS An elevated serum creatine kinase is the most sensitive and reliable indicator of muscle injury. The degree of elevation correlates with the Tintinalli_Sec10_p0563-0606.indd 570 8/2/19 6:54 PM

ith IV fluids. Acute rhabdomyolysis may be present without any signs or symptoms, with a normal physical examination. DIAGNOSIS An elevated serum creatine kinase is the most sensitive and reliable indicator of muscle injury. The degree of elevation correlates with the Tintinalli_Sec10_p0563-0606.indd 570 8/2/19 6:54 PM CHAPTER 89: Rhabdomyolysis 571 TABLE 89-1 Common Conditions Associated With Rhabdomyolysis in Adults Trauma Immunologic diseases involving muscle Medications Crush injury Dermatomyositis Antipsychotics Electrical or lightning injury Polymyositis Barbiturates Drugs of abuse Bacterial infection   Benzodiazepines Amphetamines [including ecstasy (3,4-methylenedioxymethamphetamine)] Clostridium Chemotherapeutic agents Group A β-hemolytic streptococci Clofibrate Caffeine Klebsiella Colchicine Cocaine Legionella Corticosteroids Ethanol Mycoplasma Diphenhydramine Heroin Salmonella   Hypnotics and sedatives Lysergic acid diethylamide Shigella   Isoniazid Methadone Staphylococcus aureus Lithium Methamphetamines Streptococcus pneumoniae   Monoamine oxidase inhibitors Opiates Viral infection Narcotics Phencyclidine Coxsackievirus Neuroleptic agents Environment and excessive muscular activity Cytomegalovirus   Phenothiazines Contact sports Epstein-Barr virus Propofol Delirium tremens Enterovirus Salicylates Dystonia   Hepatitis virus Selective serotonin reuptake inhibitors Excessive exercise (e.g., CrossFit, spinning)   Herpes simplex virus Statins Immobilization   Human immunodeficiency virus Theophylline Psychosis   Influenza virus (A and B) Tricyclic antidepressants Seizures Rotavirus Zidovudine Marathons, military basic training Ischemic injury Heatstroke Compartment syndrome Genetic disorders Compression Glycolysis and glycogenolysis disorders Fatty acid oxidation disorders Mitochondrial and respiratory chain metabolism disorders amount of muscle injury and the severity of symptoms, but not the development of acute kidney injury or other morbidity. Most authors consider a fivefold or greater increase above the upper threshold of normal in serum creatine kinase level, in the absence of cardiac or brain injury, as the requirement for the diagnosis of rhabdomyolysis (approximately 800 to 1000 IU/L). 3 In general, the level begins to rise approximately 2 to 12 hours after the onset of muscle injury, peaks within 24 to 72 hours, and then declines at the relatively constant rate of 39% of the previous day’s value. 1 Ongoing muscle necrosis should be suspected in patients with elevated values that fail to decrease in this manner. The MB fraction of creatine kinase (found primarily in cardiac but also in skeletal muscle) also may be elevated but should not exceed 5% of the total creatine kinase. Myoglobinuria develops once skeletal muscle injury is >100 grams. Myoglobin elevation occurs before creatine kinase elevation, and then is rapidly cleared from the plasma through renal excretion and metabolism to bilirubin. Myoglobin causes the typical reddish brown discoloration when the urine myoglobin level is >100 milligrams/dL. 3,9 Because myoglobin contains heme, qualitative tests such as the dipstick test do not differentiate among hemoglobin, myoglobin, and red blood cells. Therefore, suspect myoglobinuria when the urine dipstick test is posi tive for blood but zero or rare red blood cells are present on microscopic examination. Because myoglobin levels may return to baseline quickly, the absence of an elevated serum myoglobin level or of myoglobinuria does not exclude the diagnosis. In a study of 475 patients with rhabdo myolysis, only 19% were found to have myoglobinuria. Urinalysis is essential. Other laboratory studies may be useful to identify the common complications of rhabdomyolysis and the under lying cause.

elevated serum myoglobin level or of myoglobinuria does not exclude the diagnosis. In a study of 475 patients with rhabdo myolysis, only 19% were found to have myoglobinuria. Urinalysis is essential. Other laboratory studies may be useful to identify the common complications of rhabdomyolysis and the under lying cause. Obtain serum electrolyte, calcium, phosphorus, and uric acid levels to identify hyperkalemia, abnormal calcium and phosphorus levels, and hyperuricemia. Obtain an ECG if hyperkalemia is suspected clinically or confirmed with testing. Serum creatinine and BUN levels are needed to identify acute kidney injury. Because disseminated intravas cular coagulation is a potential complication, obtain a baseline CBC and consider a coagulopathic screen (e.g., prothrombin time, partial thromboplastin time, fibrin split products, and fibrinogen level [see Chapter 233, “ Acquired Bleeding Disorders”]). Other common laboratory findings in rhabdomyolysis include elevated levels of lactate dehydrogenase, urea, creatine, and aminotransferases. In addition, a falsely elevated cardiac troponin I (TnI) is common, especially in elderly patients. 10 Further laboratory testing to identify the underlying cause(s) of rhabdomyolysis should be based on the medical history and clinical presentation. Imaging plays a secondary role in the diagnosis, after clinical and laboratory studies. 11 US and CT provide only nonspecific findings, unless being used to rule out vascular (or boney) injury that could have provoked rhabdomyolysis. MRI is the imaging modality of choice for evaluating focal muscle damage but is rarely needed for managment. 11 See discus sion below and Chapter 278, “Compartment Syndromes, ” for diagnostic criteria of associated compartment syndrome.  DIFFERENTIAL DIAGNOSIS Other causes of muscle pain and weakness besides rhabdomyolysis should be considered in the appropriate clinical setting. Such causes include acute myopathies, periodic paralysis, polymyositis or dermato myositis, or Guillain-Barré syndrome. Rhabdomyolysis associated with strenuous exercise or fasting or repeat episodes of rhabdomyolysis suggest an inherited metabolic myopathy. Tintinalli_Sec10_p0563-0606.indd 571 8/2/19 6:54 PM

setting. Such causes include acute myopathies, periodic paralysis, polymyositis or dermato myositis, or Guillain-Barré syndrome. Rhabdomyolysis associated with strenuous exercise or fasting or repeat episodes of rhabdomyolysis suggest an inherited metabolic myopathy. Tintinalli_Sec10_p0563-0606.indd 571 8/2/19 6:54 PM 572 SECTION 10: Renal and Genitourinary Disorders TREATMENT  PREHOSPITAL CARE For victims of crush injury, patients strongly suspected of having rhabdomyolysis, or accident victims with prolonged extrication and transport times, early and vigorous IV fluid resuscitation is the most important treatment to prevent acute kidney injury. 12,13 Once a limb is extricated, IV normal saline should be initiated at 1 L/h. After extrica tion, IV normal saline should be continued at 500 mL, alternating with 5% dextrose in normal saline at 1 L/h. Because rhabdomyolysis may be associated with hyperkalemia and lactic acidosis, avoid potassium- or lactate-containing solutions until electrolyte and acid-base status is known.  EMERGENCY DEPARTMENT CARE Once the patient is in the ED, continue aggressive IV rehydration for the next 24 to 72 hours. One method is rapid correction of the fluid deficit with IV crystalloids followed by infusion of 4 mL/kg/h, with the goal of maintaining a minimum urine output of 3 to 4 mL/ kg/h. 3,14 Another method is a goal of 200 to 300 mL of urine output each hour.15 No prospective controlled studies have identified ideal fluid choice or demonstrated benefit from alkalinization of the urine with sodium bicarbonate or forced diuresis with mannitol or loop diuretics. 13-17 However, one recent 10-year retrospective study found that the use of mannitol and bicarbonate in patients with a creatine kinase greater than 10,000 IU/L decreased the development of acute renal dysfunc tion (creatinine >2 milligrams/dL [152.50 µmol/L]). 18 If bicarbonate is given, maintain an isotonic solution and avoid metabolic alkalosis or hypokalemia. 15 Mannitol may be harmful because it may cause osmotic diuresis in hypovolemic patients. In nontraumatic rhabdomyolysis, lactated Ringer’s solution was compared to normal saline in a cohort of 28 patients. 19 The rate of reduction of creatine kinase and the prevalence of acute kidney injury was not different between groups; none of the 13 patients receiving lactated Ringer’s developed metabolic acidosis (mean serum pH 7.44), whereas many of the patients receiving normal saline developed acidosis (mean serum pH 7.25). Place a urinary catheter in patients in critical condition and those with acute kidney injury to monitor urine output. Institute cardiac monitoring because electrolyte and metabolic complications can cause dysrhythmias. For patients with heart disease, comorbid conditions, or preexisting renal disease or for elderly patients, hemodynamic monitoring may be necessary to avoid fluid overload. Hypocalcemia observed early in rhabdomyolysis usually requires no treatment. Calcium should be given only to treat hyperkalemia-induced cardiotoxicity or profound signs and symptoms of hypocalcemia. If hypercalcemia is symptomatic, continue saline diuresis. Hyperka lemia, which is usually most severe in the first 12 to 36 hours after muscle injury, can be significant and prolonged. Traditional insulin and glucose therapy, although recommended, may not be as effective in rhabdomyolysis-induced hyperkalemia. The use of ion-exchange resins (e.g., sodium polystyrene sulfonate) may be effective. Treat hyperphos phatemia with oral phosphate binders when serum levels are >7 mil ligrams/dL (2.25 µmol/L). See Chapter 17, “Fluids and Electrolytes, ” for further discussion. Ultimately, dialysis may be needed; see Chapter 88, “ Acute Kidney Injury, ” for indications.

., sodium polystyrene sulfonate) may be effective. Treat hyperphos phatemia with oral phosphate binders when serum levels are >7 mil ligrams/dL (2.25 µmol/L). See Chapter 17, “Fluids and Electrolytes, ” for further discussion. Ultimately, dialysis may be needed; see Chapter 88, “ Acute Kidney Injury, ” for indications. Avoid prostaglandin inhibitors such as NSAIDs because of their vasoconstrictive effects on the kidney. Finally, treat the underlying cause of the rhabdomyolysis, which may require consultation. DISEASE COMPLICATIONS The complications of rhabdomyolysis include acute kidney injury, acidbase derangements (both acidosis and alkalosis) electrolyte disturbances (potassium, calcium, phosphorus), disseminated intravascular coagulation, and mechanical complications (e.g., compartment syndrome or TABLE 89-2 McMahon Score to Predict Death or Dialysis Laboratory Parameters at Time of Admission International Units (IU) Traditional Units Points Creatinine 124–194 µmol/L 1.4–2.2 milligrams/dL 1.5 >194 µmol/L >2.2 milligrams/dL 2.5 Calcium <1.875 mmol/L <7.5 milligrams/dL 2 Creatine kinase >40,000 IU/L >40,000 IU/L 2 Phosphate 1.3–1.174 mmol/L 4.0–5.4 milligrams/dL 1.5 >1.74 mmol/L >5.4 milligrams/dL 3 Bicarbonate <19 mmol/L <19 mEq/L 2 Historical Variables Value Points Etiology of rhabdomyolysis NOT seizures, syncope, exercise, statins, or myositis Sex Female 1 Age 50–70 y 1.5 71–80 y 2.5 >80 y 3 Note. A score of 5 or less indicates a 3% risk of either renal replacement therapy or death. A score of at least 10 indicates a 52% risk of renal replacement therapy or death. peripheral neuropathy). 20 Factors that contribute to rhabdomyolysisinduced acute kidney injury include hypovolemia, acidosis or aciduria, tubular obstruction, and the nephrotoxic effects of myoglobin. 3,15 Renal tubular obstruction occurs secondary to precipitation of uric acid and myoglobin. Over all, neither the presence of myoglobinuria nor the degree of creatine kinase elevation is predictive of acute kidney injury; however, the correlation of creatine kinase elevation and acute kidney injury is stronger in traumatic rhabdomyolysis. 21 A risk prediction score for mortality or need for dialysis in patients with rhabdomyolysis was initially derived and validated in 2013 22 and was recently externally validated in 201623 (Table 89-2). The authors suggest that the score can be used to determine the need for aggressive resuscitation when faced with a patient who is at risk for the complications of resuscitation (e.g., a patient with heart failure). The mechanical complications of rhabdomyolysis consist of com partment syndrome and peripheral nerve injury. The associated muscle swelling may exert pressure on peripheral nerves, resulting in neuronal ischemia and causing paresthesias or paralysis. Nerve injury is often proximal, and multiple nerves may be involved in the same extremity. 18 Compartment syndrome occurs secondary to marked swelling and edema of the involved muscle groups and is discussed in Chapter 278. DISPOSITION AND FOLLOW-UP The majority of healthy patients with exertional rhabdomyolysis and without comorbidities (e.g., heat stress, dehydration, trauma) can usu ally be treated with PO or IV rehydration, observed in the ED, and then released. 6 Otherwise, patients should be admitted for IV hydration, management of complications of rhabdomyolysis, and treatment of the underlying cause. For at least the initial 24 to 48 hours, admission should be to a monitored bed to identify dysrhythmias as well as worsening renal function. The nephrology service should be consulted to evaluate the need for dialysis for patients with hyperkalemia unresponsive to therapy or for patients with a high McMahon risk score.

or at least the initial 24 to 48 hours, admission should be to a monitored bed to identify dysrhythmias as well as worsening renal function. The nephrology service should be consulted to evaluate the need for dialysis for patients with hyperkalemia unresponsive to therapy or for patients with a high McMahon risk score. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Tintinalli_Sec10_p0563-0606.indd 572 8/2/19 6:54 PM