Rhabdomyolysis

Audrey K. Wagner and Deborah M. Stein

BACKGROUND

Rhabdomyolysis is a syndrome characterized by the necrosis of striated muscle and the subsequent release of intracellular contents—including myoglobin, electrolytes, creatine kinase (CK), and other sarcoplasmic proteins—into the systemic circulation.¹ Rhabdomyolysis has multiple etiologies, including physical, metabolic, toxicologic, and genetic. Presentation ranges from an asymptomatic elevation in diagnostic markers to a life-threatening emergency characterized by hypovolemic shock, renal failure, severe electrolyte abnormalities, cardiac dysrhythmias, compartment syndrome, and disseminated intravascular coagulopathy (DIC).

EPIDEMIOLOGY

While the true incidence of rhabdomyolysis is unknown, it is reported to occur in up to 85% of patients with traumatic injuries.² It affects patients of all ages and does not demonstrate a gender bias.³^–⁵ Because of their greater muscle mass, men do tend to experience a more severe clinical course and a greater alteration in diagnostic markers; however, outcomes do not differ significantly between genders.⁶ Interestingly, studies of nondisaster hospital admissions for rhabdomyolysis reveal a predominance of male patients,⁷^–¹² which likely reflects the greater incidence of traumatic injury in males.

Approximately 15% to 50% of patients with rhabdomyolysis will develop acute kidney injury (AKI), the syndrome’s most feared complication.⁷^,⁹^,¹¹^,¹³ The incidence of rhabdomyolysis-associated AKI accounts for 7% to 10% of all cases of AKI in the United States.¹⁴ Development of AKI in the setting of rhabdomyolysis portends a poor prognosis and is associated with a mortality of 40% to 59%.⁷^,⁸^,¹⁰ Fortunately, most of those who survive will recover renal function and not require long-term dialysis.¹

ETIOLOGY

Rhabdomyolysis is caused by a broad range of injuries, illnesses, toxins, and genetic influences. Table 39.1 lists the categories of common causes with representative examples of each.²^,¹³^,¹⁴ The five most commonly reported causes are (1) trauma, (2) drugs/alcohol, (3) compression/immobilization, (4) ischemia, and (5) seizures.⁷^–¹¹^,¹³^,¹⁵

TABLE 39.1 Causes of Rhabdomyolysis

HISTORY AND PHYSICAL EXAM

In patients with obvious trauma or crush injuries, the signs and symptoms concerning for the development of rhabdomyolysis are usually readily apparent. For patients with nontraumatic rhabdomyolysis, exam findings and reported symptoms may be subtler.

Classic rhabdomyolysis symptoms include muscle pain and swelling, weakness, and dark-colored urine.²^,¹³^,¹⁴ Commonly involved muscle groups include the calves, thighs, and lower back.²^,¹⁶ Muscle pain may be generalized or localized to a specific muscle group. It may be mild, severe, or—importantly—absent, as it is in up to 50% of patients eventually diagnosed with rhabdomyolysis.¹¹^,¹³ Systemic complaints can include fever, malaise, nausea, and vomiting.²^,¹⁶

In patients without history of trauma, the physical exam is frequently nonspecific. Swelling, if present, may be apparent on presentation or may develop only after the patient has received fluid resuscitation.¹³ Patients may be tachycardic due to pain, dehydration, or fluid shifts into injured muscles. Other suggestive findings include signs of limb ischemia, such as pain, pallor, paresthesias, and pulselessness, with or without associated compartmental swelling. Dermatologic findings, including skin bruising and signs of pressure necrosis, may indicate compression injury, a frequent cause of rhabdomyolysis. Given the wide variability in presentation, it is always reasonable to consider the diagnosis of rhabdomyolysis in a patient found immobile or unresponsive for an unknown or prolonged period of time.

A special note about compartment syndrome is warranted, as it can be both the cause and the result of rhabdomyolysis. In the patient being treated for rhabdomyolysis, continued monitoring of fixed compartments is necessary as exam findings consistent with compartment syndrome may be delayed in presentation until resuscitative fluids shift into the injured muscles. Any concern for compartment syndrome should trigger the measurement of pressures and a surgical consultation for possible fasciotomy.

DIAGNOSTIC EVALUATION

The diagnostic challenge of rhabdomyolysis is remembering to include it as part of one’s differential. Once considered, the diagnostic workup is relatively straightforward.

Creatine Kinase

Serum CK—and specifically the muscle isoenzyme CK-MM—is the most sensitive marker of muscle injury and the universally accepted test for rhabdomyolysis.¹⁷ Serum CK begins to rise within 2 to 12 hours of the onset of muscle injury, peaks in 1 to 3 days, and declines 3 to 5 days after muscle injury has stopped.¹⁴ Rhabdomyolysis does not have a diagnostic CK cutoff value; however, a level five times the upper limit of normal is strongly suggestive.¹⁷ CK levels that do not decline as expected raise the likelihood of continued injury and compartment syndrome.

Urinalysis

Myoglobinuria is found almost exclusively as a result of rhabdomyolysis and begins to occur when plasma levels of myoglobin reach 0.5 to 1.5 mg/dL.¹^,¹³ When rhabdomyolysis is suspected in the emergency department (ED), the initial test of choice is a urine dipstick and microscopic analysis. A urine dipstick positive for blood, combined with an absence of red blood cells on microscopy, is suggestive of rhabdomyolysis. However, the utility of this diagnostic method is limited, as the reported sensitivities of dipsticks for blood range from 14% to 82%¹³^,¹⁸ and because the presence of red blood cells on microscopy does not exclude concomitant myoglobinuria, especially in the setting of trauma.

CK and Serum Myoglobin

Although CK is generally accepted as the most sensitive test for diagnosis and monitoring of rhabdomyolysis, some investigators argue that serum myoglobin, as the pathogenic entity, is the preferred marker to follow over time. Studies correlating CK and myoglobin levels with the incidence of renal failure have had widely disparate results.⁸^,⁹^,¹⁹^,²⁰ Debate about their efficacy hinges on elimination kinetics; myoglobin has a half-life of 12 hours, versus 42 hours for CK.²¹ Some authors argue that the rapid clearance of myoglobin makes it a less sensitive marker for muscle injury²² and that longer and more consistent elevations of CK make it more reliable.¹² Others argue that myoglobin is more accurate precisely because of its faster elimination kinetics.¹⁹ Test cost and availability are additional considerations; while assays exist for testing serum myoglobin directly, they are expensive and not readily available or expedient in most hospitals. For these reasons, CK remains the more commonly used diagnostic marker.

Additional Studies

Additional studies that assess for complications of rhabdomyolysis include an electrocardiogram (ECG), complete blood count, basic metabolic profile, calcium, phosphate, uric acid, albumin, coagulation studies, troponin, and an arterial blood gas.

Potassium

Hyperkalemia is a life-threatening complication of rhabdomyolysis. It is caused by the release of high levels of potassium from the intracellular space of the necrotic muscle cells.¹⁴ AKI and metabolic acidosis sustained as part of rhabdomyolysis may exacerbate this complication.

Phosphate and Calcium

In the early phase of rhabdomyolysis, phosphorus released from the cells results in hyperphosphatemia, which, in turn, causes calcium deposition in damaged tissues and subsequent hypocalcemia.¹⁶ Later in the course of the disease, calcium is released from the cells; this, together with secondary hyperparathyroidism from the initial hypocalcemia, may result in hypercalcemia. Consequently, calcium should not be given to treat the initial hypocalcemia—except in cases of tetany or hyperkalemia-induced ECG changes—as doing so may result in metastatic calcification.¹⁴^,¹⁶^,²³

BUN/Creatinine

Renal function should be monitored in all patients with either suspected or established rhabdomyolysis, as AKI is a serious and common complication of the disease. As a rule, any rise in creatinine should be interpreted as a sign of worsening renal clearance and should raise concern for AKI. It has been suggested that elevated creatinine may relate to both renal injury and to the release of preformed creatinine from damaged muscles, although several studies have failed to support this hypothesis.¹³^,¹⁴

Anion Gap/Coagulation

Other lab abnormalities may include an elevated anion gap and hypoalbuminemia. Anion gap elevations result from the release of lactate, uric acid, and other organic acids from muscle cells. A falling serum albumin, which portends a poor prognosis, occurs because of leakage of albumin from damaged capillaries into interstitial tissues.¹⁶ Finally, DIC is a common complication of severe rhabdomyolysis; high-risk patients should be screened for DIC with a complete blood count and coagulation studies.¹⁴

MANAGEMENT GUIDELINES

The management of rhabdomyolysis consists of (1) identifying and treating the underlying cause and (2) minimizing subsequent complications. As a complete discussion of etiologies of rhabdomyolysis lies outside the scope of this chapter, the discussion here will focus on minimizing complications.

The pathogenesis of AKI in rhabdomyolysis is a prerenal state caused by (1) the sequestration of fluid in injured muscles and an associated intravascular volume depletion and (2) intrinsic disease, caused both by myoglobin’s cytotoxic effects on the tubular epithelial cells and by the formation of obstructing casts in the distal nephrons. Patients with AKI require fluid administration not only to achieve and maintain hemodynamic stability but also to limit the myoglobinuric injury to the kidney by increasing renal perfusion, urine flow, and toxin clearance.

There is no strong evidence to guide the treatment of rhabdomyolysis as it relates to the prevention of AKI. Much of the available data come from retrospective analyses and case series. The strength of these studies is limited and the results difficult to compare because of population heterogeneity and the lack of control groups. Additionally, investigators employ differing definitions of rhabdomyolysis and renal failure (ranging from creatinine >1.5 mg/dL to the need for hemodialysis) and recommend significantly variable treatment approaches.

Timing and Volume of Fluids

Based on available data, it is recommended that fluid resuscitation be initiated as early as possible, ideally within 6 hours of evidence of injury and, when appropriate, in the prehospital setting.¹^,²^,¹⁷^,²⁴ Several case series support early and aggressive hydration to lower renal failure risk.²⁵^–²⁷ In a report of the sixteen crush victims from the 2003 earthquake in Turkey, those patients requiring hemodialysis had a significantly longer wait time between rescue and initiation of fluid resuscitation (average 9.2 hours) compared to those who did not require hemodialysis (average 3.7 hours). Victims who required hemodialysis also received significantly less fluid volume (11 ± 2.5 L vs. 21.8 ± 2.7 on day 1).²⁸ Case studies of other earthquake victims have reported similar outcomes.⁵^,²⁹

The optimal fluid volume for resuscitation is unknown. No controlled studies compare specific volumes or targeted urine goals, and there are no established formulas (such as the Parkland formula for burn victims) to help direct resuscitation. Guidelines for fluid administered generally advise an initial 2 to 3 L at 1 to 1.5 L per hour, followed by an ongoing infusion of 200 to 700 mL per hour until diuresis is established, at which point fluid administration should be titrated for a urine output of about 300 mL per hour.¹⁷^,²⁴^,³⁰^,³¹

It is important to remember that elderly patients and those suffering from congestive heart failure may not tolerate aggressive volume resuscitation and should be closely monitored for signs of volume overload. Either invasive or noninvasive hemodynamic monitoring may be useful to help guide fluid administration. All critically ill patients should have a urinary catheter placed to facilitate careful monitoring of urine output.

Choice of Fluid

The only prospective randomized single-blind study addressing the question of crystalloid choice compared the use of normal saline (NS) to lactated Ringer’s (LR) in 28 patients with rhabdomyolysis caused by doxylamine overdose (a first generation antihistamine).³² Although the NS group used more bicarbonate and diuretics, there was no significant difference in median time to CK normalization between the groups (96 h in LR group, 120 h in NS group). The study’s small size may, however, have left it underpowered to detect a difference. Of note, no problems with hyperkalemia were noted in the LR group, and lactate seemed to be protective against—and not causal of—metabolic acidosis.

Sodium Bicarbonate and Mannitol

The most controversial aspect of rhabdomyolysis management is the role, if any, for sodium bicarbonate and mannitol. Few studies address this question directly, in part because the majority of rhabdomyolysis studies report using both therapies and provide limited data on patients administered only crystalloid. Additionally, there are no controlled studies evaluating the efficacy of bicarbonate and mannitol individually, making it difficult to determine the relative importance of either in the prevention of AKI.²⁸^,³³

Both sodium bicarbonate and mannitol have theoretical benefits in the treatment of rhabdomyolysis. Sodium bicarbonate alkalinizes the urine, which is thought to minimize tubular damage and cast formation by increasing myoglobin’s solubility and limiting its precipitation with the Tamm-Horsfall protein, a principal urinary glycoprotein.¹^,³⁴ A nonreabsorbed solute, sodium bicarbonate, also promotes diuresis and may be beneficial in managing the hyperkalemia often seen in rhabdomyolysis.³⁴ In addition to these proposed benefits, sodium bicarbonate can ameliorate metabolic acidosis, which may be present in patients with severe rhabdomyolysis and which may be compounded by administration of large volumes of NS.¹^,³¹

Mannitol has been used in rhabdomyolysis management as an osmotic agent to extract fluid from injured muscles and expand plasma volume and increase urinary flow, theoretically increasing the excretion of myoglobin and limiting its blockage of renal tubules. Through its osmotic effects on muscles, mannitol may aid in the prevention and treatment of compartment syndrome.²⁶ Studies suggest that mannitol may also protect the kidney from oxidant injury by scavenging free radicals,³⁵ although in at least one animal model, this did not prove true.³⁶

There are two English-language controlled studies that have evaluated the efficacy of bicarbonate/mannitol (BIC/MAN) versus crystalloid alone. The first was a retrospective review of all adult trauma ICU admissions over 5 years at a level 1 trauma center; of these, 382 patients had a peak CK > 5,000. At the surgeon’s discretion, 154 (40%) of these patients were treated with bicarbonate and mannitol and 228 (60%) were not. There was no statistical difference in the incidence of acute renal failure (defined as creatinine >2.0 mg/dL), dialysis, or mortality between the two groups. It is notable, however, that there was a significant difference in the peak CK between the two groups, with the BIC/MAN group having an average peak CK of about 23.5 K and the no BIC/MAN group having an average peak CK of 9.8 K. A subsequent subgroup analysis of patients by peak CK level revealed no statistically significant difference in the incidence of AKI, need for dialysis, or mortality, but among patients with CK > 30 K, there was a strong trend toward improved outcomes for those treated with BIC/MAN. This finding suggests that patients with severe rhabdomyolysis may benefit from BIC/MAN; however, the authors concluded that overall, BIC/MAN does not prevent AKI, need for dialysis, or mortality in patients with CK > 5 K and recommend that its use in posttraumatic rhabdomyolysis patients be reevaluated.¹²

The strengths of this study include its size and the presence of a control group. It was not, however, a randomized trial, and data regarding the type, quantity, and timing of volume resuscitation were not made available, making it difficult to draw conclusions about the relative importance of BIC/MAN versus quality of fluid resuscitation.

A second smaller study evaluated the efficacy of saline versus saline/bicarbonate/mannitol (SBM) in preventing rhabdomyolysis. This retrospective review of ICU patients at risk for developing renal failure (not defined) from rhabdomyolysis (defined as CK > 500) included only 24 patients; 15 were treated with SBM, and 9 received saline only. Both groups had similar demographics and similar average initial creatinine values, but significantly different initial CK levels (SBM’s average CK 3,351 IU/L, saline group 1,747 IU/L). Outcomes between the groups were not significantly different: No patients developed worsening AKI, and all had resolution of their mild azotemia.³⁷ The authors concluded that the progression to renal failure can be completely avoided with prophylactic treatment and that once appropriate saline expansion is provided, the addition of mannitol and bicarbonate is unnecessary.³⁷ However, this study reported on patients with a mild degree of rhabdomyolysis, which limits its applicability to more severe cases.

Summary of Fluid Administration Recommendations

The absence of a randomized controlled study addressing ideal fluid composition in the treatment of rhabdomyolysis makes it difficult to advocate for or against a specific resuscitative regimen. A 2013 systematic review of 27 studies evaluating therapies used to prevent AKI in rhabdomyolysis concluded that no high-level evidence exists to suggest fluid therapy combined with sodium bicarbonate and/or mannitol is superior to fluid therapy alone.²⁴ The review offers the following recommendations regarding the timing, volume, and type of fluid used in the prevention of AKI in rhabdomyolysis²⁴:

1.Fluid administration should be initiated as soon as possible, preferably within the first 6 hours after muscle injury.

2.Fluids should be administered at a rate that maintains a urine output of 300 mL per hour or more for at least the first 24 hours, unless a medical condition precludes giving enough fluids to meet this goal.

3.Intravenous sodium bicarbonate should only be administered if necessary to correct systemic acidosis.

4.Mannitol should only be administered when fluid administration fails to maintain a urine output of 300 mL per hour and should be discontinued in patients in whom it does not augment urine output.

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