Trauma patients

Metabolic etiologies

Recommendation

Rhabdomyolysis presentation may vary from asymptomatic to commonly implicated clinical features, including acute muscle weakness, pain/tenderness, and swelling (dolor, tumor) of the affected extremity or body region.12 Darkened (tea-colored) urine may be an additional common finding. A low threshold of clinical suspicion in the proper laboratory and historical context is warranted to initiate appropriate therapy.

Discussion

Rhabdomyolysis is a clinical syndrome consequent to skeletal muscle cell death with release of intracellular contents (described in next section) into the circulation.12 Resultant organ dysfunction may include renal (AKI), cardiac (arrhythmia), and coagulopathy. Despite this cluster of findings, there is no formally held definition for rhabdomyolysis and clinical presentations may vary greatly. Commonly implicated muscle groups are the extremities and the lower back. Superficial pressure ulceration or blistering may suggest the diagnosis, but is not a reliable finding. At the extremes of pathology, compartment syndromes of affected muscle groups lead to increased morbidity and potential need for decompression.13

Recommendation

The most commonly implicated variables include elevated serum concentrations of CK (>5× the upper limit of normal or >1000 IU/L), myoglobin, lactate dehydrogenase (LDH), potassium, creatinine, and aspartate aminotransferase (AST). Elevated urine myoglobin provides additional evidence. A low threshold of suspicion in the proper clinical context is warranted to initiate appropriate therapy. A strategy for disease monitoring with serial CK measurement should be additionally undertaken. Interval CK values should be followed until a peak concentration is identified (typically at 24–72 hours), discontinued once the CK is reliably downtrending.

Discussion

Traumatic or non-traumatic injury to the skeletal muscle cellular membrane leads to an influx of calcium into the cytoplasm, disrupting cellular homeostasis and leading to cell death. Injury may be exacerbated by the generation of reactive oxygen species after restoration of blood flood to the affected tissue (reperfusion injury). The resulting effect is the accumulation of CK, myoglobin, LDH, and potassium in the circulation.2 In a recent systematic review, the laboratory definition of rhabdomyolysis varied to include an elevated CK level >5× the upper limit of normal or >1000 IU/L, with the CK-MM subtype being the most reflective of skeletal muscle injury.1 2 CK values may become elevated within 12 hours of injury, peak at 24 to 72 hours, and return to normal in roughly 5 days, depending on the degree of injury and appropriate therapy.

Myoglobin becomes elevated in the circulation once intrinsic binding proteins are overwhelmed. Given a shorter half-life (1–3 hours) versus CK, myoglobin may elevate and resolve prior to CK depreciating its clinical utility. Myoglobin may also be evident in the urine and, although the sensitivity has been reported up to 100%, the specificity varies widely from 15% to 88%.5 Although a causal relationship may exist between rhabdomyolysis and elevations in hepatic aminotransferases (AST, ALT: alanine transaminase), this is of unclear value as both enzymes exist within skeletal muscle and may become elevated as a result of primary muscle injury.7 8 14 15

Recommendation

Either lactated Ringer’s solution or saline (0.9% or 0.45%) is an acceptable fluid for resuscitation in rhabdomyolysis. A starting rate of 400 mL/hour can be initiated, with goal-directed therapy of urine output of 1 mL/kg/hour to 3 mL/kg/hour, and up to 300 cc/hour.

Discussion

Although early-volume resuscitation in rhabdomyolysis is well accepted as a mainstay of promoting renal tubule flow, diluting nephrotoxins such as myoglobin, and supplying adequate renal perfusion to prevent AKI, the best type of crystalloid for this purpose remains controversial.1 16–18 The two most commonly cited fluids used for this resuscitation are lactated Ringer’s solution and saline (0.9% or 0.45%). Saline is promoted due to its lack of potassium; in rhabdomyolysis, crush injury can lead to hyperkalemia and there is a theoretic concern for worsening this issue by using a potassium-containing fluid for resuscitation. Conversely, receiving large amounts of resuscitation with normal saline can lead to metabolic acidosis, which can be counterproductive if urine alkalinization is desired.16 The only randomized controlled trial comparing these crystalloid fluid types evaluated patients with doxylamine-induced rhabdomyolysis.19 Of note, in this study, urine pH was a targeted end goal, with a goal pH >6.5. In patients who received lactated Ringer’s solution, urine and serum pH were significantly higher after 12 hours of aggressive resuscitation with significantly less need for bicarbonate administration to achieve goal urine pH, and there was no difference between groups in serum potassium level. However, there was also no difference in median time to serum CK less than 200 IU/L, which arguably is the most clinically relevant outcome in the study. There have been no other randomized controlled trials comparing lactated Ringer’s solution and normal saline or 0.45% saline and therefore no clear recommendation as to which fluid type is better. It does appear that use of either type of fluid is safe in the treatment of rhabdomyolysis, so although this area certainly requires further study, at this time the type of fluid used for management of rhabdomyolysis may be at the discretion of the treating physician.

The rate of administration of intravenous fluids in rhabdomyolysis should be targeted to the patient as there is significant risk of volume overload should an excessive amount of fluid be given without goal-directed therapy. A starting rate of 400 cc/hour with a range of 200 cc/hour to 1000 cc/hour is considered reasonable but should be titrated to urine output, ensuring the patient is receiving adequate resuscitation without suffering from fluid creep.1 19

Urine output is the traditional method by which one can determine the adequacy of resuscitation in rhabdomyolysis. The most commonly cited urine output goals for intravenous fluid rehydration are 1 mL/kg/hour to 3 mL/kg/hour, and up to 300 mL/hour.1–4 18 20–22 However, should the patient remain anuric despite escalating rates of intravenous fluid administration, the need for RRT may be necessary as ongoing aggressive fluid resuscitation without renal clearance could lead to significant and life-threatening volume overload.

Recommendation

Clinical studies evaluating the efficacy of sodium bicarbonate and/or diuretic use (mannitol, loop diuretics) for prevention of rhabdomyolysis-induced AKI are limited by a lack of appropriate control groups, standardized definitions, retrospective design, and low statistical power. Given these significant limitations, the use of sodium bicarbonate or diuretics for prevention of AKI in rhabdomyolysis is not recommended.

Discussion

The precise mechanism of AKI in rhabdomyolysis is controversial and likely multifactorial. The two important factors in the development of myoglobin-induced renal toxicity are hypovolemia and aciduria.23 Ferrihemate, which is a breakdown product of myoglobin, in the presence of a low pH can generate free radicals which can lead to direct renal cell injury. Furthermore, heme proteins can potentiate renal vasoconstriction, which may have been initiated by hypovolemia and can activate the cytokine cascade.23–25 Pigmented casts, which are the hallmark of rhabdomyolysis-associated AKI, have been suggested to arise as a result of an interaction between the Tamm-Horsfall protein and myoglobin in an acidic environment. Other mechanisms that have been suggested propose that the precipitation of heme protein and its ability to generate free radicals at a low pH with resultant toxicity to the tubules is what may give way to cast formation.23 24 Ultimately, AKI is the result of the combination of vasoconstriction, oxidant injury, and tubular obstruction, which leads to decreased glomerular filtration.

For the aforementioned reasons, it has been suggested that alkalinization of the urine may minimize renal injury in rhabdomyolysis and may ameliorate or prevent AKI. Furthermore, mannitol, an osmotic diuretic, is a potentially attractive therapeutic option in this setting, given its capacity for renal vasodilation, free radical scavenging, and potential for reduction of muscle compartment pressures.1 26 There is no strong clinical evidence supporting the use of sodium bicarbonate administration and/or mannitol to prevent AKI in rhabdomyolysis.26–28 Randomized controlled studies are lacking and the literature is composed mainly of retrospective studies or small case series. Many of these studies also lack a therapeutic endpoint such as measurement of urinary pH, and furthermore most of the studies couple mannitol use along with sodium bicarbonate.18 One of the larger studies from Brown et al 4 reviewed 382 patients with rhabdomyolysis, composed of a subset of 1771 patients with CK >5000 U/L; 154 (40%) received bicarbonate and mannitol and 228 (60%) did not receive either bicarbonate or mannitol. There was no difference between groups in the rate of AKI or the need for RRT.4 Similarly, Homsi et al,29 in a study of 24 patients, retrospectively compared saline versus a combination of saline/mannitol/bicarbonate resuscitation for rhabdomyolysis (CK >500 IU/L) and found no difference in the incidence of renal failure between groups.29 Nielsen et al 30 retrospectively evaluated normal saline with mannitol and bicarbonate versus normal saline alone in patients with traumatic rhabdomyolysis. They used a predefined protocol at their institution for patients with rhabdomyolysis with CK >10 000 U/L. Only 46 of 56 patients who would have qualified for the protocol had received it. When comparing these 46 with the 10 patients who did not receive the protocol, they recognized a significant decrease in the development of AKI in those patients receiving the protocol (26%) versus those who did not (70%).30 The question as to which particular component of the protocol was beneficial and the impact of a standardized approach was not answered in this study. Furthermore this study also highlights the fact that the majority of the studies are fairly small and underpowered to demonstrate a clear benefit. A recent comprehensive review of the role of bicarbonate and mannitol in rhabdomyolysis demonstrates that aggressive early-volume therapy with normal saline should be the primary management and that bicarbonate and mannitol utilization should be discouraged.26

The clinical evidence supporting the use of loop diuretics in this setting is sparse and composed primarily of case reports.31–34 As such, it cannot be interpreted with any confidence. Although loop diuretics have been shown to reduce metabolic demand and oxygen consumption by the proximal tubular cells, they have also been shown to worsen renal afferent arteriole vasoconstriction, acidify urine, and promote aggregation of the Tamm-Horsfall protein within the tubular lumen. Taken together, the pathophysiologic consequences of loop diuretics may potentiate precipitation of myoglobin and worsen the distal tubular obstruction.35 36 Additionally, hypokalemia due to loop diuretic use has been reported to result in hypokalemic myopathy and rhabdomyolysis.37

Recommendation

Hyperkalemia, hyperphosphatemia, and hypocalcemia are electrolyte abnormalities most commonly encountered when treating rhabdomyolysis. Correcting biochemical equilibrium and electrolytes during rhabdomyolysis should proceed meticulously to avoid complications from treatment. Hyperkalemia is the electrolyte abnormality that requires timely correction to reduce risk of cardiac arrhythmia.

Discussion

In rhabdomyolysis, electrolyte abnormalities occur as a result of cellular component release associated with induced AKI. Electrolyte abnormalities that occur due to rhabdomyolysis are hyperkalemia, hyperphosphatemia, hypocalcemia, and hypomagnesemia.

AKI in rhabdomyolysis is often associated with excessive potassium levels and correlates with the volume of muscle destruction. Baseline levels of potassium and all pertinent electrolytes should be evaluated when the possibility of rhabdomyolysis development is present. Hyperkalemia that occurs in rhabdomyolysis-induced AKI occurs early in the course of the disease process and should be monitored closely. Potassium levels should be serially evaluated. Patients with high potassium levels (>6 mmol/L) should have cardiac monitoring. ECG should be obtained and assessed for manifestations of severe hyperkalemia (QRS widening, small p waves, and severe arrhythmias). Hypocalcemia aggravates the electrical effects of hyperkalemia and should be aggressively treated with calcium chloride or calcium gluconate in this scenario. Elevated potassium levels should be treated with insulin and glucose infusions. Consider administration of a β-2 adrenergic agent such as albuterol via aerosol inhalation. Lastly, consider potassium removal via cation exchange resin or dialysis as indicated.1 2 38 39

Similar to hyperkalemia, hyperphosphatemia occurs as a result of phosphate release from damaged muscle cells. High levels of phosphate may be problematic because phosphate binds to calcium and this complex deposits in the soft tissues. Additionally, by inhibiting 1α-hydroxylase, hyperphosphatemia inhibits calcitriol formation and thus limits formation of the active form of vitamin D. Treatment of hyperphosphatemia should be done with caution since treatment involves administration of a calcium chelator which can increase precipitation of calcium phosphate in injured muscle. Early hyperphosphatemia typically decreases as phosphate is excreted in the urine.1 2

Hypocalcemia occurs early in rhabdomyolysis due to calcium entry into damaged cells and calcium phosphate deposition in necrotic muscle. Early hypocalcemia treatment in rhabdomyolysis should be avoided unless patients are symptomatic or severe hyperkalemia is present. Correction of hypocalcemia with calcium chloride or gluconate should be avoided since calcium deposition may occur in injured muscle. During the recovery phase, serum calcium levels return to normal and may rebound, causing hypercalcemia due to release of calcium from injured muscle and mild secondary hyperparathyroidism secondary to AKI.1 2 40 41

Hypermagnesemia seen with rhabdomyolysis is infrequent but when it occurs is typically in association with AKI and should be treated accordingly with hemodialysis.1

Recommendation

There is no role for RRT (either continuous (CRRT) or intermittent) in rhabdomyolysis to prevent AKI. The utilization of RRT in patients with rhabdomyolysis should be based on traditional indications for AKI and the degree of renal impairment.

In patients with rhabdomyolysis who develop AKI and need RRT, either CRRT or intermittent RRT should be used based on the degree of renal impairment and the clinical status of the patient. There are no recommendations regarding RRT modalities (filtration vs. diffusion), filter type (low vs. high cut-off membranes), or high-flow versus low-flow dialysis.

Discussion

Since AKI in rhabdomyolysis is associated with myoglobinuria, it has been proposed that extracorporeal removal of myoglobin may be an effective preventative strategy.1 42 Despite case reports using plasmapheresis,43 it has not been shown to have an effect on outcome or myoglobin clearance.44 Furthermore, there is insufficient evidence to recommend RRT in the prevention of AKI in rhabdomyolysis.38 45 Indeed, a Cochrane review evaluated CRRT for rhabdomyolysis. It sought to assess the efficacy of CRRT in myoglobin reversal, the influence of CRRT on mortality and kidney-related outcomes, and to evaluate the safety of CRRT for treatment in patients with rhabdomyolysis.39 46–48 There was no significant difference in mortality compared with conventional therapy. The review concluded that overall the studies had poor quality and there was insufficient evidence to determine any benefits of CRRT over conventional therapy for rhabdomyolysis and prevention of AKI in rhabdomyolysis.

There have been several studies investigating myoglobin clearance using different dialysis modalities, filters, and flow types. The RRT techniques in these studies were initiated based on traditional indications for AKI and sought to determine if any of these different modalities, filter, and flow types facilitate myoglobin clearance and hence affect kidney-related outcomes. Since myoglobin has a molecular weight of 17 KDa and is thought to be poorly cleared by diffusion (dialysis), investigators have studied whether the technique of RRT (continuous vs. intermittent), hemodiafiltration versus hemofiltration, use of special high cut-off membrane filters (which enhance clearance of larger molecules), as well as high-flow versus low-flow dialysis improve overall or kidney-related outcomes.49–53 The overall studies are small in number and seem to lack sufficient evidence to make any recommendations.

The utilization of RRT in patients with rhabdomyolysis should be based on traditional indications for AKI and the degree of renal impairment, such as severe acid/base disturbances, electrolyte abnormalities, and hypervolemia, all of which are refractory to medical management.

Recommendation

Clinicians should monitor for a variety of complications, ranging from an asymptomatic elevation of muscle protein to an accumulation of electrolyte imbalances, edema, and toxic cellular components. Morbidity can present early or late, including hyperkalemia, hepatic dysfunction, cardiac dysfunction, AKI, acute renal failure (ARF), disseminated intravascular coagulation (DIC), and compartment syndrome. AKI is the most common systemic complication of rhabdomyolysis and is responsible for most of the morbidity and mortality associated with rhabdomyolysis.

Discussion

In rhabdomyolysis, hyperkalemia is the most significant electrolyte abnormality.54 Hepatic dysfunction occurs in approximately 25% of patients with rhabdomyolysis. Proteases released from injured muscle may be implicated in hepatic inflammation. Cardiac symptoms may be secondary to electrolyte abnormalities, such as severe hyperkalemia, and range from dysrhythmia to cardiac arrest.2

The overall mortality among inpatients with CK >5000 IU/L is approximately 14%.22 ARF develops in up to 15% of patients. Among those requiring RRT, mortality may be as high as 59%.54 Additionally, the release of intracellular products may activate the clotting cascade, leading to DIC in patients with rhabdomyolysis.22 54 This presentation is often subclinical with prolonged coagulation studies, thrombocytopenia, and elevated fibrin degradation studies without significant bleeding or thrombosis.54 Compartment syndrome may be an early or late complication, resulting from direct muscle injury or vigorous muscle activity. This complication occurs primarily due to limited muscle expansion from enveloping tight fascia. A delay of more than 6 hours in diagnosing this complication can lead to irreversible muscle damage or death.53

Recommendation

The risk of AKI, RRT, and/or in-hospital mortality in patients with rhabdomyolysis can be estimated using admission demographic, clinical, and laboratory variables. Risk prediction scores may not directly influence treatment; however, they may be useful in estimating prognosis and setting expectations.

As no single laboratory value is sufficient to predict the course of rhabdomyolysis, a combined index of metrics, the McMahon Score (table 1), may be calculated at admission for prognostication.3 A score greater than or equal to 6 is predictive of a need for high-volume fluid resuscitation, RRT, and death.

Discussion

Rhabdomyolysis is a syndrome characterized by deposition of muscle protein that can be life-threatening, and identification of severity biomarkers is key. CK is usually taken as a reference to estimate prognosis; however, this is not the most effective parameter.22 McMahon et al 55 performed a retrospective cohort study to develop a risk prediction tool to identify patients at greatest risk of RRT or in-hospital mortality. In total, these outcomes occurred in 19.0% of patients with rhabdomyolysis.55 The independent predictors identified were age, female sex, cause of rhabdomyolysis, and values of initial creatinine, creatine phosphokinase, phosphate, calcium, and bicarbonate. In the validation cohort, among patients with the lowest risk score (<5), 2.3% died or needed RRT. Among patients with the highest risk score (>10), 61.2% died or needed RRT.54 Rodríguez et al 56 conducted a retrospective observational cohort study to assess the risk factors for AKI and to develop a risk score for early prediction. The variables of peak CK, hypoalbuminemia, metabolic acidosis, and decreased prothrombin time were independently associated with AKI. A risk score for AKI was calculated for each patient, with an OR of 1.72 (95% CI 1.45 to 2.04).56

Several other retrospective studies brought forth other prediction variables for AKI, ARF, and need for RRT. Baeza-Trinidad et al 57 found initial creatinine levels associated with progression to AKI and mortality at 30 days. The cut-off point of creatinine of 1.15 mg/dL had the best ratio of sensitivity (74.6%) and specificity (67.4%) to predict mortality.57 Chen et al 58 looked at predictive factors for ARF including dark urine, initial and peak serum myoglobin level, rhabdomyolysis caused by body temperature change, and elevated serum potassium. Risk factors for RRT initiation were peak BUN (Blood Urea Nitrogen)/creatinine levels and CK level on the third day as rhabdomyolysis developed. The initial serum myoglobin threshold associated with development of ARF is 600 ng/mL.58 In ambiguous cases, clinical suspicion of rhabdomyolysis is confirmed by a positive urine or serum test for myoglobin. There is a loose correlation between CK levels and the development of ARF, with levels higher than 16 000 IU/L more likely to be associated with renal failure.22

The McMahon Score is a prospectively validated risk prediction tool to identify patients at high risk of RRT or in-hospital mortality (table 1). When calculated at admission from demographic and blood chemistry data, a score ≥6 is 86% sensitive and 68% specific for patients who will require RRT. In this setting, the authors recommend the initiation of renal protective therapy with a target urine output of 1 mL/kg/hour to 3 mL/kg/hour, and up to 300 cc/hour.1–4 18 20–22