Rhabdomyolysis is caused by the release of toxins into the bloodstream during the rapid breakdown of damaged skeletal muscle. The presentation is variable and can range from asymptomatic serum elevations of creatine kinase (CK) to life-threatening electrolyte disturbances and acute kidney injury (AKI). About 26,000 cases of rhabdomyolysis are reported annually in the United States.1,2 Because the classic triad of myalgia, muscle weakness, and dark urine often is absent, clinicians must have a high suspicion for rhabdomyolysis and recognize patients at high risk, including those with altered mental status and drug intoxication. Prompt recognition and early, aggressive intervention are necessary to prevent and/or correct volume depletion, electrolyte disturbances, cardiac dysrhythmias, and myoglobin-induced AKI associated with rhabdomyolysis. This article describes the causes and pathophysiology of rhabdomyolysis and associated AKI and discusses recommendations for diagnosis and treatment.
PATHOPHYSIOLOGY OF RHABDOMYOLYSIS
Calcium levels in myocytes are kept low by regulation of the sarcolemma's sodium-potassium-adenosine triphosphatase (ATPase) pump and voltage-gated sodium-calcium exchanger channels. The sodium-potassium-ATPase pump actively transports sodium from the cell's interior to its exterior, inducing a negative resting membrane potential. This gradient powers the sodium-calcium ion channel exchange and calcium-ATPase pump, concentrating intracellular calcium in the cell's sarcoplasmic reticulum and mitochondria. Myocytes may be damaged via trauma, infection, drugs, toxins, or conditions that alter myocyte blood supply or metabolism. In cases of strenuous patient exertion, the ATP supply-demand discordance leads to membrane instability.3 In patients with ischemic or traumatic injuries, rhabdomyolysis does not develop during the initial insult; rather, it occurs after blood flow is restored. The resulting reperfusion injury induces rhabdomyolysis as fluid, sodium, neutrophils, and inflammatory mediators migrate into the damaged tissue and produce free radicals. The final global pathologic change to the myocyte is disruption of cellular transport mechanisms that induces a rise in intracellular calcium. This activates proteolytic enzymes, degrades the myocyte, induces hypoxia, and generates oxidative free radicals, leading to apoptosis and cell lysis.1,3,4 Leakage of intracellular contents leads to elevations of plasma potassium, aldolase, phosphate, urate, CK and myoglobin, lactate dehydrogenase (LDH), and aspartate transferase (AST). When more than 100 g of muscle tissue is degraded, plasma myoglobin binding capacity is overwhelmed and free myoglobin precipitates into glomerular filtrate with the potential to cause AKI.
CAUSES OF RHABDOMYOLYSIS
Rhabdomyolysis has many causes and contributing factors. The most commonly cited causes for adults include illicit drug or alcohol abuse, muscular trauma, crush injuries, myotoxic effects of prescribed drugs, seizures, and immobility; 60% of patients have multiple contributing factors (Table 1).1,3,5 Up to 85% of victims of major trauma will experience rhabdomyolysis.2 In a retrospective study of 2,371 patients in two Boston hospitals with rhabdomyolysis and CK levels greater than 5,000 U/L, the most common causes included trauma, immobilization, sepsis, and vascular and cardiac surgeries.6 In that cohort, 47.7% developed AKI and 14.1% died during hospitalization.6 Rhabdomyolysis is found in 24% of adults presenting to EDs with cocaine-related conditions.1
The severity of muscle damage, underlying cause, and development of complications such as AKI dictate the clinical presentation of rhabdomyolysis. Patients at high risk, such as those with altered mental status, alcohol or illicit drug intoxication, and immobilization, may make it difficult to obtain an accurate medical history. Mild cases of rhabdomyolysis may be asymptomatic with only altered laboratory values. The classic triad of myalgia, muscle weakness, and dark, red or tea-colored urine rarely is present in full. The patient develops edema, stiffness, cramping, tenderness, and loses function in the affected muscles; these signs and symptoms may become more apparent after IV hydration. The thighs, calves, and lower back are most commonly affected.3,5
In large prospective studies of serologically proven rhabdomyolysis, half of patients did not report myalgia or muscle weakness and a third had no abnormality on physical examination.4 This silent condition reinforces the need for clinicians to have a high index of suspicion for rhabdomyolysis in at-risk patients. Additionally, the clinical picture may be overshadowed by consequences and/or complications of myocyte breakdown or manifestations of the condition that originally incited rhabdomyolysis.
Metabolic and electrolyte disturbances resulting from myocyte lysis may cause fever, fatigue, nausea, vomiting, abdominal pain, confusion, altered mental status, or seizure. Early in rhabdomyolysis, patients develop hypocalcemia as calcium precipitates in damaged muscles and is bound by large amounts of phosphate spilling from the myocyte. High-anion gap metabolic acidosis may be caused by production of lactic acid or release of uric acid from myocyte lysis.4 The likelihood of hyperkalemia-induced cardiac dysrhythmia is heightened by the resultant acidosis and hypocalcemia, if severe. Later in rhabdomyolysis, accumulated calcium is released from the myocyte and reenters circulation. This is why clinicians should refrain from correcting hypocalcemia unless the patient has dangerous hyperkalemia or severe symptoms of tetany.4 Correction may lead to hypercalcemia in 20% to 30% of patients who develop AKI.1
Oliguria or anuria is a late finding in patients with rhabdomyolysis, usually presenting 12 to 24 hours after the initial damage and possibly heralding the development of myoglobin-induced AKI.1
The most reliable laboratory marker of rhabdomyolysis is elevated plasma CK, specifically CK-MM subtype. A level of five or more times the upper limit of normal or about 1,000 U/L is generally considered diagnostic, but levels can be as high as 100,000 U/L depending on the extent of injury.1,2,4 Normal serum CK levels are 9 to 195 U/L in males and 9 to 171 U/L in females. CK levels rise 2 to 12 hours after injury, peak in 24 to 72 hours, and decline gradually in 5 to 10 days.3,4 Persistently elevated CK may indicate ongoing myocyte damage, continuing stress, or development of compartment syndrome. Myoglobin is released rapidly from damaged myocytes, overwhelms the plasma binding capacity after 100 g or more of skeletal muscle damage and spills into urine. Urine test strips may read false-positive for blood because the reagent reacts with myoglobin; no red blood cells will be identified on urine microscopy. Normal serum myoglobin levels are 30 to 80 mcg/L and urine levels are 3 to 20 mcg/L.7 In patients with rhabdomyolysis, serum myoglobin levels peak at 8 to 12 hours and are cleared from the serum within 24 hours.4 Thus, plasma CK is more useful for diagnosis and assessment of muscle injury because of its delayed clearance. The CK half-life is 1.5 days compared with 1 to 3 hours for myoglobin.4,8 Also, myoglobin's unpredictable presence in urine makes it an insensitive marker of disease. Studies reveal that only 50% of patients with rhabdomyolysis had positive urine myoglobin despite mean CK levels of 15,000 U/L; a large retrospective study cited myoglobinuria in only 19% of cases.4
Clinicians must investigate for typical electrolyte disorders expected with myocyte lysis. Of note, although blood urea nitrogen (BUN) and creatinine levels both increase in patients with rhabdomyolysis, the BUN:creatinine ratio exhibits a characteristic decrease. The normal ratio of 10:1 can be as low as 5:1 in patients with rhabdomyolysis because large amounts of creatinine are released from damaged muscle. Transaminases, abundant in both liver and myocytes, are usually elevated with larger increases in AST. Electromyography, genetic analysis, and muscle biopsy may be required to evaluate for suspected genetic myopathies in patients with recurrent rhabdomyolysis with unapparent causes. Assessment into inciting causes usually involves toxicology screening for drug or alcohol causes, and tests to rule out infectious, endocrine, or metabolic causes as indicated. Clinicians should consider combinations of risk factors that commonly affect a single patient: for example, the direct myotoxic effect of alcohol compounded by immobilization, preexisting hypokalemia and hypophosphatemia, and use of psychotropic medication.
ECG monitoring is imperative to detect cardiac dysrhythmias. Imaging studies are rarely used to diagnose rhabdomyolysis, but in cases where diagnosis is uncertain, MRI is almost 100% sensitive for myocyte changes related to rhabdomyolysis and outperforms CT and ultrasound.3,8
Myocytes are vulnerable to reperfusion injury following release from crush injury or exertional damage. An influx of a large amount of extracellular fluid (ECF) causes significant edema; expansion is limited in areas tightly bound by fascia, such as the anterior tibia muscles. Increased intercompartmental pressures can compress neurovascular structures, leading to muscle ischemia. Patients may experience severe pain out of proportion to the apparent injury, pain exacerbated by passive stretching of the involved muscles, muscle tightness and swelling, weakness, paresthesia, and pallor. Diminished two-point discrimination and vibratory sense are consistent, sensitive early findings of compartment syndrome. Loss of peripheral pulses signifies advanced compartment syndrome.
Diagnosis typically is made clinically based on the patient's history and physical examination. Compartment pressures can be measured to assist in the diagnosis. This involves direct measurement of the fascial compartment pressure; the difference between diastolic BP and compartment pressure assesses severity. Compartment pressures greater than 30 mm Hg for 8 hours may cause muscle necrosis; higher pressures for shorter times may cause permanent neuromuscular damage resulting in contractures and gait disturbances.3 Surgical fasciotomy is the recommended treatment.
Intravascular volume depletion
Myocyte necrosis and inflammation induce extracellular fluid sequestration into the myocyte that may be profound enough to induce hypotension and shock. This shift may be greater than 15 L and exacerbates the potential for AKI; affected extremities can sequester up to 10 L per limb.4,5 Symptoms heralding hypovolemic shock include lethargy, dizziness, and change in mental status. Decreased systolic BP is a late sign that follows preemptive compensatory changes of tachycardia, delayed capillary refill, tachypnea, decreased pulse pressure, and cool clammy skin. Victims of crush syndrome should receive IV fluids before extraction to ensure sufficient extracellular fluid for myocyte third-spacing.1,4,5 Prospective studies demonstrate that AKI development is related to volume depletion, longer delay to IV fluid resuscitation, and more than 12 hours until extraction from the source of the crush injury.4
Electrolyte disturbances and cardiac dysrhythmias
Severe hyperkalemia, particularly if coupled with hypocalcemia, academia, or oliguria, can precipitate cardiac dysrhythmia or arrest. Symptoms of hyperkalemia include weakness, decreased deep tendon reflexes, fatigue, paresthesias, dyspnea, palpitations, and chest pain. ECG findings correlate with potassium level, but potentially life-threatening dysrhythmias can occur without warning at almost any level of hyperkalemia. Early ECG changes include tall, peaked T waves; a shortened QT interval; and ST-segment depression, usually corresponding to a potassium level of 5.5 to 6.5 mEq/L. At levels greater than 6.5 mEq/L, the patient's ECG shows a prolonged PR interval, a flat or absent P wave, and progressive QRS widening with conduction blocks, eventually leading to ventricular fibrillation or asystole. In patients with hypotension or ECG changes, administer IV calcium, bicarbonate, and insulin with 50% dextrose as a temporary measure to stabilize cardiac conduction and push potassium intracellularly. This is followed by cation exchange resin or dialysis. Hyperkalemia also may respond to forced diuresis with IV fluid management.
Disseminated intravascular coagulation (DIC)
Some causes of rhabdomyolysis (infection, crush injury, major surgery, snake bite) may precipitate release of tissue thromboplastin, causing disruption in hemostasis and uncontrollable bleeding.1 Patients bleed into the skin, gingiva, and gastrointestinal tract, and may have oozing from IV lines, surgical sites, drains, and catheters. Laboratory abnormalities include thrombocytopenia with schistocytes on peripheral smear, prolonged prothrombin time, and elevated fibrin degradation products and D-dimer. Clinicians must treat the underlying disorder, replace blood products as needed, and anticipate the higher likelihood of comorbid renal failure, pulmonary involvement, and liver disease.
The incidence of myoglobin-induced AKI in adults ranges from 5% to 50% with reported mortality of up to 59% in critically ill patients; 28% to 37% of adults require short-term hemodialysis.1,2,6,8 In the kidney tubule, acidified filtrate facilitates myoglobin's interaction with Tamm-Horsfall protein and high levels of uric acid to accelerate cast formation. Whether casts induce urinary obstruction or are simply evidence of poor urinary flow suggesting poor washout is debatable.4 Ferrihemate, iron particles formed from myoglobin in acidic filtrate, generate reactive oxygen species inducing direct nephrotoxicity and intrarenal vasoconstriction. Together with decreased extracellular fluid volume and angiotensin activation, ferrihemate causes tubular ischemia and necrosis result. Studies in animals indicate that the nephrotoxic effects of myoglobin are inhibited in alkaline urine, which is the main justification for treatment recommendations.
A patient's AKI risk is low when initial CK levels are less than 15,000 to 20,000 U/L, unless the patient has sepsis, acidosis, or is dehydrated; in those cases, CK levels up to 5,000 U/L have been reported to increase risk.1,2,8 Although CK levels directly correlate with degree of muscle injury, they are not a sensitive predictor for AKI development.4,7 Myoglobin levels are better correlated with AKI risk. Studies in ICU patients reveal that serum myoglobin best predicts AKI; an elevation in serum myoglobin to greater than 368 mcg/L significantly increases risk of AKI regardless of CK elevation.8 A study of 484 patients with rhabdomyolysis concluded a higher incidence of AKI (64.9%) with peak serum myoglobin levels greater than 15,000 mcg/L (versus a mean of 7,163 mcg/L).7 In ICU patients with CK levels greater than 5,000 IU/L, hemodialysis was necessary in 42.4% and a mortality of 27.1% was observed.8 Clinical conditions related to the highest rates of AKI or mortality included compartment syndrome, sepsis, neuroleptic malignant syndrome, prolonged surgery (more than 6 hours, as in abdominal, orthopedic, or thoracic surgeries), and having undergone cardiac resuscitation.6,8
Treatment of the underlying disease is paramount to stopping progressive myocyte destruction. For toxin-induced rhabdomyolysis, administer antidotes, gastric lavage, or hemodialysis; treat infections with antimicrobials; for heat-related rhabdomyolysis, initiate cooling measures and benzodiazepines.6 Closely monitor the patient's electrolytes, serum CK, myoglobin levels, and hemodynamics, specifically fluid intake and urinary output. In patients with preserved diuresis and no underlying medical conditions (such as severe oliguria or anuria, end-stage renal disease, or heart failure), initiate conservative measures: aggressive hydration, mannitol administration, urine alkalinization, and forced diuresis.4 Oliguria is an independent risk factor for development of secondary abdominal compartment syndrome with decreased renal perfusion and acute respiratory distress syndrome.7
Early aggressive volume expansion will treat hypotension, prevent myoglobin deposition in the renal tubules, and preserve renal function. Administer an initial infusion of a 1.5 L/hour bolus (10 to 20 mL/kg) of an isotonic solution to achieve high urine output of 200 to 300 mL/hour (3 mL/kg/hour).3,7,8 A large-volume infusion of 0.9% sodium chloride solution may induce iatrogenic hyperchloremic metabolic acidosis and will require significantly more bicarbonate to optimize urine pH levels compared with lactated Ringer solution, which has a mild alkalinizing effect.5 If 0.9% sodium chloride solution is used alone, consider discontinuing it if the patient develops metabolic acidosis. Use caution when administering lactated Ringer solution or fluids containing lactate or potassium, particularly in patients with crush injuries, because these fluids may compound rhabdomyolysis-related hyperkalemia or lactic acidosis.3 After hemodynamic stability is achieved, maintain forced diuresis with continuous IV fluids at 300 to 500 mL/hour until CK levels drop below 1,000 mcL or myoglobinuria is cleared.4,5 Be careful not to cause volume overload that could lead to tissue hypoxia.
Adding bicarbonate to IV fluids alleviates acidosis and alkalinizes urine to prevent renal cast formation and nephrotoxicity. Theoretically, forced diuresis and urine alkalinization should prevent cast precipitation and release of vasoconstricting reactive iron species; however, no clear evidence in human trials supports these beneifts.3,9 Studies recommend adding 44 mEq of bicarbonate diluted in 1 L of 0.45% sodium chloride solution, or 88 to 132 mEq of bicarbonate in 1 L of D5W to achieve an hourly fluid administration goal of 100 mL.3,5 Another supported model is 500 mL/hour of 0.9% sodium chloride solution alternating every hour with 500 mL/hour of D5W plus 50 mEq of bicarbonate for each subsequent 2 to 3 L of solution.2,10 Bicarbonate is titrated to achieve a urinary pH greater than 6.5.
Urine alkalinization in a trial involving 2,083 trauma patients did not affect the development of acute renal failure, necessity of hemodialysis, or outcome of death.9 Bicarbonate administration can worsen hypocalcemia by enhancing calcium and phosphate deposition in tissues. Discontinue bicarbonate if the patient develops severe symptomatic hypocalcemia or urinary pH does not improve after 4 to 6 hours.3,4 In patients who develop metabolic alkalosis secondary to bicarbonate administration but whose urine remains acidic, administering the carbonic anhydrase inhibitor acetazolamide may inhibit bicarbonate reabsorption and increase urinary bicarbonate excretion.3,4 However, this recommendation is not confirmed experimentally or clinically.
This osmotic diuretic draws fluid from the interstitial space into the vasculature and may reduce muscle swelling to relieve compartment pressures, increase renal blood flow, promote renal vasodilation, and decrease myoglobin trapping and cast formation.7 Mannitol should only be administered once the patient is hemodynamically stable and intravascular volume has been restored; avoid using it in patients with oliguria. Mannitol is given as a 20% IV infusion (loading dose, 0.5 g/kg over 15 minutes), followed by a 0.1 g/kg/hour infusion.3,5 A study of mannitol use in postoperative cardiac patients showed increased urine flow of greater than 61% without adverse reactions to filtration fraction or renal oxygenation.7 Mannitol also scavenges free radical oxygen species that cause renal tubular damage. Despite this, clinical trials have not shown mannitol to be more beneficial than IV fluids alone in rhabdomyolysis studies. Additionally, excess administration (more than 200 g/day or an accumulated 800 g) can induce AKI via compensatory renal vasoconstriction and osmotic nephrosis.9
Monitor the patient's osmolality gap (the difference between measured and calculated serum osmolality) when administering mannitol; discontinue therapy if the gap is greater than 55 mOsm/kg.9 Of note, loop diuretics are not recommended as no evidence supports they prevent AKI in patients with rhabdomyolysis, and these drugs acidify the urine and may worsen hypocalemia.4
Glutathione, aqueous-soluble vitamin analogues, and acetaminophen show potential in animal trials to minimize the risk of myoglobin-related AKI.4 These antioxidants inhibit free radical formation and interfere with oxidation processes.4 Acetaminophen proved effective both before the initiation of oxygen-radical creation as well as after the induction of oxygen radicals in the body.11 In studies, acetaminophen was the only available, safely administered medication that inhibited AKI by reducing or preventing myoglobin- and oxidative-induced injury in patients with rhabdomyolysis.11 More research is under way on this subject.
Patients with rhabdomyolysis who develop kidney failure may need renal replacement therapy via hemodialysis, continuous hemofiltration, or peritoneal dialysis. Indications for emergent dialysis include uncorrectable metabolic acidosis, life-threatening hyperkalemia, or other electrolyte disturbances despite medical management, manifestations of uremia, and anuria or oliguria despite aggressive volume expansion with complications of fluid overload unresponsive to diuretics. Renal replacement therapy is managed based on renal impairment, not on CK or myoglobin levels, and should be monitored clinically and based on patient response to therapy.
Conventional hemodialysis is a viable option, but is unable to filter myoglobin effectively due to myoglobin's large molecular size. Hemodialysis also has a tendency to cause metabolic alkalosis in patients after dialysis. Various studies used techniques to improve therapy, including daily hemodialysis with concurrent plasmapheresis for 5 days, and although myoglobin clearance improved significantly, other large proteins and substances were removed (hypoalbuminemia was a common result).7,12
PROGNOSIS AND COMPLICATIONS
Outcomes of rhabdomyolysis depend on the underlying cause. Poor outcomes are strongly related to development of complications, particularly AKI. Over a span of 11 years, McMahon's rhabdomyolysis studies showed an overall mortality of 14.1% in patients with a CK greater than 5,000 U/L2. Of these patients, ICU admission increased mortality to 27.1%.8 A separate study of ICU patients reported mortality up to 22% in those without AKI and up to 59% in those with AKI.9 Most patients with AKI due to rhabdomyolysis recover renal function without complications if hydration is initiated early and comorbidities and underlying factors are addressed early and effectively.9 McMahon and colleagues developed a validated prediction rule for kidney failure and death in patients with rhabdomyolysis using significant predictors:
- increasing age (50 years and older)
- female sex
- hypocalcemia (initial value less than 7.5 mg/dL)
- high creatinine levels (initial value greater than 1.4 mg/dL)
- hyperphosphatemia (initial value greater than 4 mg/dL)
- an initial serum CK greater than 40,000 U/L
- initial bicarbonate of less than 19 mEq/L
- lack of seizure, syncope, exercise, myositis, or medication.6
The prediction rule is point-based with a total possible risk score of 17.5. A score less than 5 was not associated with a high risk of death or renal replacement therapy. A score greater than 10 correlates with a very high mortality and need for renal replacement therapy. Other conditions associated with increased mortality include ischemic limb (32% mortality overall), AKI due to traumatic rhabdomyolysis (20% mortality), poor prognostic factors including hypoalbuminemia, prolonged immobilization over 12 hours, fluid loss, and inefficient dialysis.1,4,8,9
Clinicians in all practices should be armed with knowledge of the causes and pathophysiology of rhabdomyolysis and myoglobin-induced AKI, and familiar with clinical and physiologic consequences of this syndrome. Improved rapid, evidence-based approaches in the diagnosis and treatment of rhabdomyolysis will help to prevent AKI and renal failure and optimize patient outcomes.