a b s t r a c t

Background: Rhabdomyolysis is a medical condition caused by muscle breakdown leading to potential renal dam- age. This can result in significant morbidity and mortality if not rapidly identified and treated.

Objective: This article provides an evidence-based narrative review of the diagnosis and management of rhabdo-

myolysis, with focused updates for the emergency clinician. Discussion: Rhabdomyolysis is caused by the breakdown of muscle cells leading to the release of numerous intra- cellular molecules, including potassium, calcium, phosphate, Uric acid, and creatinine kinase. There are a number of potential etiologies, including exertion, extreme temperature changes, ischemia, infections, immobility, drugs, toxins, endocrine causes, autoimmune reactions, trauma, or genetic conditions. Findings can include myalgias, muscle weakness, or dark-colored urine, but more often include non-specific symptoms. The diagnosis is often determined with an elevated creatinine kinase greater than five times the upper-limit of normal. Severe disease may result in renal failure, electrolyte derangements, liver disease, compartment syndrome, and disseminated intravascular coagulation. Treatment includes addressing the Underlying etiology, as well as aggressive intrave- nous hydration with a goal urine output of 300 mL/h. Bicarbonate, mannitol, and Loop diuretics do not possess strong evidence for improved outcomes. Renal replacement therapy should be determined on a case-by-case basis. Most patients are admitted, though some may be appropriate for discharge.

Conclusion: Rhabdomyolysis is a potentially dangerous medical condition requiring rapid diagnosis and manage- ment that may result in significant complications if not appropriately identified and treated. Emergency clinician knowledge of this condition is essential for appropriate management.

Introduction

Background

Rhabdomyolysis is a complex condition existing along a spectrum, which is defined by the breakdown of damaged muscle and release of intracellular muscle content, including myoglobin, creatine kinase (CK), lactate dehydrogenase, and electrolytes [1-6]. The disease ranges from asymptomatic with mild CK elevation to a life-threatening condi- tion with renal failure, severe electrolyte derangements, and dissemi- nated intravascular coagulation (DIC) [1,2,7-10]. Rhabdomyolysis can be classified by several means including mechanism of injury, exertional versus non-exertional, and acquired versus inherited [1,5,11].

The true frequency of rhabdomyolysis is difficult to determine, as there are no prospective studies assessing the incidence of

* Corresponding author at: 3841 Roger Brooke Dr, Fort Sam Houston, TX 78234, United States.

E-mail address: [email protected] (B. Long).

rhabdomyolysis, and many mild cases are not recognized or reported. In the United States, approximately 26,000 cases are reported annually [1,2,9-13]. One study conducted in a university hospital over a 7-year period found a 0.074% prevalence of a CK N 5000 international units/ Liter (IU/L) in their population [14], while another study in military trainees found 22.2 cases per 100,000 people annually [15]. For pediatric patients, one study reported 4 cases per 1500 patients over a one-year period [16]. Overall, rhabdomyolysis is more common among African- Americans, males, patients aged b10 and N60 years, and those with a body mass index N 40 kg/m² [11,17,18]. The overall recurrence rate of the disease is not known. However, Recurrence rates for exertional rhab- domyolysis range from 0.08% to 11%, though this may be higher in pa- tients with genetic or muscular disorders [15,19,20].

Methods

The authors searched PubMed and Google Scholar for articles using a combination of the keyword and Medical Subject Heading “rhabdomy- olysis” for production of this narrative review, including case reports

https://doi.org/10.1016/j.ajem.2018.12.061 0735-6757/

and series, retrospective and prospective studies, systematic reviews and meta-analyses, and narrative reviews. The literature search was re- stricted to studies published in English. Authors decided which studies to include for the review by consensus. Initial literature search revealed over 300 articles. A total of 82 articles were selected for inclusion in this

review, focusing on emergency department evaluation and manage-

Table 1

Etiologies of rhabdomyolysis [1-5,17-20,25-28,34-47].

Trauma or compression motor vehicle accidents, prolonged immobilization,

Crush syndrome, Electrical injury, burns

Exertion Intense exercise, seizure, Status asthmaticus, sickle cell crisis, alcohol withdrawal

ment of rhabdomyolysis. Most of the available data come from retro- spective studies and case reports, with limited prospective data. As

Extreme changes in body temperature

Serotonin syndrome, malignant hyperthermia, neuroleptic malignant syndrome, hyperthermia, hypothermia

this is a narrative review, authors did not pool individual study data. Au-

thors did not specifically evaluate crush syndrome in this review article.

Electrolyte alterations Hypokalemia, hypophosphatemia, hypocalcemia,

hyponatremia, hypernatremia, hyperglycemic states

Muscle ischemia/hypoxia

Artery occlusion due to embolus, thrombus, or during vascular surgery

Discussion

Anatomy and pathophysiology

Rhabdomyolysis results from a direct injury to muscle cells, known as myocytes, leading to reduced energy supply to the cell [1,2,21-25]. Normal myocyte physiology is regulated by Na⁺/K⁺ and Na⁺/Ca²⁺ pumps on the plasma membrane of myocytes that maintain low intra- cellular concentrations of Na⁺ and Ca²⁺ and high concentrations of K⁺ [2,22-27]. In a normal myocyte, cell depolarization causes Ca²⁺ to flood into the cytoplasm, resulting in actin-myosin cross-linking and contraction [1,2,22-24]. This process relies on sufficient energy from adenosine triphosphate (ATP), and any disruption of the ion channels or reduced ATP will result in an electrolyte imbalance and increased cel- lular permeability [2-4,22]. Muscle injury or decreased ATP resulting in cell wall destruction causes an influx of Na⁺ and Ca²⁺, increasing water content and destroying cellular attachments [2-4,22]. The high Ca²⁺ levels can result in prolonged muscle contraction, resulting in further ATP decreases, while the elevated Ca²⁺ levels also directly promote cell lysis [6,12,28-30]. These mechanisms result in an inflammatory myolytic cascade with myocyte necrosis, which releases muscle con- tents (including potassium, calcium, sodium, phosphate, myoglobin, CK) into the bloodstream and interstitial spaces [1-3,31]. Myoglobin normally functions as a carrier of oxygen in muscle. It is typically bound to plasma globulins in the blood and concentrates in the renal tu- bules [2-4,23,29,30]. In rhabdomyolysis, myoglobin levels exceed the blood’s protein-binding capacity and, within the acidic environment, can precipitate and damage the kidneys through obstruction of the renal tubules, oxidative mechanisms, and direct vasoconstrictive effects [12,32,33]. Tamm-Horsfall protein is a glycoprotein produced in the thick ascending limb of the loop of Henle and is excreted in the urine. In rhabdomyolysis, this protein can precipitate, interact with myoglo- bin, and form granular casts, resulting in obstruction of renal tubules and renal injury [6,12,28-30,33]. This precipitation worsens in acidic urine. In the setting of reperfusion injury (e.g., acute ischemic limb com- partment syndrome), ischemia-induced rhabdomyolysis may occur in a delayed fashion [1-5].

Key Point. Rhabdomyolysis is due to muscle breakdown releasing po- tassium, calcium, sodium, phosphate, myoglobin, and CK. This has a va- riety of potential consequences, including renal injury.

Etiologies

While traumatic injury or overexertion is a common cause of rhab- domyolysis, a variety of other etiologies have also been described, which include both inherited and acquired causes (Table 1) [1-5,17- 20,25-28,33-35]. Approximately 75% of first-time episodes of rhabdo- myolysis are due to an acquired cause [31,36,37], with 60% of patients possessing >=2 risk factors [2]. In the United States, exercise/overexer- tion, drug intoxication, and immobility are responsible for a significant number of cases [3]. Multiple episodes of rhabdomyolysis, recurrent muscle cramps with exercise, and a positive family history of rhabdo- myolysis and muscular or Genetic disorders should raise the suspicion

Infections Influenza, coxsackie, Epstein-Barr virus, herpes virus, HIV, Salmonella, Streptococcus pyogenes, Staphylococcus aureus, Clostridium species, Legionella, sepsis

Drugs and toxins Statins, anti-lipid agents (ezetimibe, clofibrate,

gemfibrozil), proton pump inhibitors, psychiatric medication (SSRIs, SNRIs, TCAs, benzodiazepines, barbiturates, phenothiazines, lithium), alcohol, cocaine, opiates, amphetamines, LSD, phencyclidine, Synthetic cannabinoids, bath salts, antihistamines, propofol, arsenic, carbon monoxide, azathioprine, quinidine, salicylates, succinylcholine, thiazides, vasopressin, pentamidine, terbutaline, theophylline

Endocrine Hyperthyroidism, hypothyroidism, hyperaldosteronism

Autoimmune Dermatomyositis, polymyositis

Genetic Lipid metabolism disorders, Krebs cycle disorders, mitochondrial chain disorders, G6PD deficiency, muscular dystrophies

Foodborne Ingestion of burbot, eel, pike, crayfish, buffalo fish, and

several other fish/crustacean species

HIV, human immunodeficiency virus; SSRI, Selective serotonin reuptake inhibitors; SNRI, serotonin norepinephrine reuptake inhibitors; TCA, triCyclic antidepressants; LSD, lysergic acid diethylamide; G6PD, glucose-6-phosphate dehydrogenase.

for an inherited underlying etiology of rhabdomyolysis [12,38-41]. Statin use may be associated with muscle soreness and rhabdomyolysis [9,1040,41]. Approximately 10% of patients on a statin medication will experience Muscle pain or swelling, but the overall the risk of rhabdo- myolysis is low in patients on a statin (1-2 patients for every 100,000 patients taking a statin) [9,10,40,41]. Statin-associated rhabdomyolysis occurs with greater frequency in older patients, who may be taking mul- tiple higher-risk medications concurrently (see Table 1), and have a greater proportion of comorbidities (e.g., renal disease, cardiovascular disease, diabetes, hepatic disease) [9,10,40,41]. Exertional rhabdomyol- ysis possesses an incidence of 29.9 cases per 100,000 patient-years and is associated with a variety of exercises and sports including running, spinning, football, bodybuilding, and swimming, among others [42,43]. Hyperthermia, recent changes to the exercise routine, eccentric or extreme exercise, dehydration, Sickle cell anemia, medications (e.g., non-steroidal anti-inflammatory medications), and preexisting disease (autoimmune or Metabolic disorders) predispose athletes to ex- ertional rhabdomyolysis [1-5,17-20,25-28,34-47].

History and physical examination

Disease presentation varies widely, ranging from asymptomatic to severe cases with end-organ damage, acute renal failure, DIC, and car- diac dysrhythmias [1-5,12,47-55]. The presentation reflects both the primary disease and associated symptoms from the complications (e.g., muscle injury, renal failure) [1-3]. When evaluating a patient with suspected rhabdomyolysis, clinicians should first obtain a focused history concerning symptoms of rhabdomyolysis, risk factors, family history of rhabdomyolysis, urine output and changes in color, and prior episodes of rhabdomyolysis. The conventional triad includes acute or subacute myalgias, transient muscle weakness, and darker- colored urine [1-4,7,27,31,49]. However, the presence of all three symp- toms is found in b10% of patients with rhabdomyolysis [1-5,12]. Patients

often experience non-specific symptoms, which may include swelling, fever, weakness, palpitations, tachycardia, nausea, emesis, confusion, agitation, and oliguria or anuria [1,4,25]. The most common symptoms include muscle pain (N80%), weakness (N70%), and muscle swelling (8%) [56,57]. Muscle weakness typically includes the affected body part, with the proximal legs most frequently affected [1-5,7]. Pediatric patients more commonly complain of myalgias, fever, and a viral pro- drome [35]. Urine findings are dependent on the patient’s muscle mass, urine concentration, severity of the muscular injury, and renal function [12,21-24,50-52]. Dark-colored urine is described in b5% of cases and should not be relied upon to exclude the diagnosis [2,35].

Key Point. Though the classic triad includes acute or subacute myal- gias, transient muscle weakness, and darker-colored urine, this occurs in only 10% of patients. The most common symptoms include muscle pain (N80%), weakness (N70%), and muscle swelling (8%), and non- specific symptoms are common.

Diagnostic testing

Initial diagnostic testing should include an electrocardiogram (ECG), complete blood count , electrolytes (including calcium and phosphate), renal and liver function testing, CK, uric acid, and urinalysis [58,59]. Common metabolic derangements accompanying rhabdomyolysis can include hyperkalemia, hyponatremia, metabolic acidosis, hypo- or hypercalcemia, hyperphosphatemia, and hyper- uricemia [3,4,22,51]. Due to the potential risk of hematologic abnor- malities, a coagulation panel should be obtained in toxic-appearing patients [1-4]. Renal injury occurs in up to 50% of cases [52]. An ele- vated CK is diagnostic, with many experts using a threshold level of five times the upper-limit of normal or approximately 1000 IU/L. [3,4,6,11,58,59] CK levels typically increase 2-12 h after the injury, peak over 24-72 h, and decline gradually over 5-10 days [6,11,56]. It is important to note that baseline CK levels may be greater than five times the upper-limit of normal in patients with chronic muscle diseases (e.g., muscular dystrophy, inflammatory myopathies) [56]. In these patients, it can be valuable to compare their current CK level with their baseline values and correlate with clinical symptoms [39,56]. A meta-analysis suggests mean CK level and risk of Acute kidney injury may be correlated in the setting of Crush injuries, but CK levels in the setting of rhabdomyolysis due to other causes are not predictive of AKI [11,51,60]. Serum myoglobin is not required routinely for patients with suspected rhabdomyolysis. It has a shorter half-life than CK (3 h versus 36 h) and can normalize within 6-8 h, resulting in a poor sensitivity that cannot reliably exclude rhabdomyolysis [4,59,61]. Myoglobin may be more valuable for assessing trends in the disease but can miss cases of rhabdomyolysis that present in a delayed fashion [59,62]. Data regarding myoglobin ability to predict AKI are inconclusive, and myoglobin should not be currently used to predict risk of AKI [4,11,51,61].

Due to the underlying pathophysiology, rhabdomyolysis can involve several other organ systems. Patients with severe disease may experi- ence organ failure, which can lead to death in upwards of 8% of cases [1,4,12]. Renal failure may develop in 14% to 46% of patients with rhab- domyolysis, typically occurring due to acute tubular necrosis from myo- globin deposition and obstruction [1,2,7,12,36,47-55]. Urine pH demonstrates an inverse relationship with urine myoglobin precipita- tion: as urine pH decreases, myoglobin precipitation increases [4]. Hyperkalemia and hypocalcemia may result in cardiac dysrhythmia and death [12,24-26,47-50]. Liver dysfunction occurs in one quarter of cases and is likely multifactorial [1,7,8,49,54]. DIC occurs due to the sys- temic activation of the coagulation pathway from myocyte components [1,2,4].

Urinalysis may demonstrate the presence of moderate or large blood with few red blood cells on microscopy [3,11]. This is caused by

myoglobin release, which is subsequently filtered through the urine resulting in a false positive urine blood reading. However, when assessed via a Urine dipstick, this finding is only 41% sensitive for rhab- domyolysis and should not be used to exclude the diagnosis [62]. Alter- natively, urinary myoglobin levels can be detected in small amounts (i.e., <=5 ug/L) in many patients, but levels N 20 ug/L are suggestive of rhabdomyolysis [63,64]. Importantly, while an elevated urinary myo- globin is highly sensitive, it has poor specificity, ranging from 15% to 91% [61]. Data concerning urine myoglobin as a predictor of AKI in rhab- domyolysis are of low quality, though low myoglobin clearance may be suggestive of increased risk of AKI [4,61,65]. This requires further study before routine use.

Key Point. Diagnostic testing should include ECG, CBC, electrolytes, renal and liver function testing, CK, uric acid, and urinalysis. Serum myoglobin is not required for diagnosis and has poor sensitivity. Serum CK is a reliable means of diagnosis.

Treatment

Treatment should be targeted at both the underlying etiology and the consequent rhabdomyolysis [59]. If the etiology is temperature- related, active cooling or warming should be initiated. Compartment syndrome requires emergent fasciotomy, while Arterial occlusions should receive thrombectomy or vascular intervention as indicated [1,2]. Infections should receive appropriate antibiotics, and all drug- or medication-related causes should have the medication discontinued and receive an appropriate antidote (antivenom for en- venomation, fomepizole for toxic alcohol ingestion, etc.) if applicable [59].

Initial treatment for patients with confirmed rhabdomyolysis in- cludes intravenous (IV) fluid rehydration, with a goal urine output of 300 mL/h, which may require an infusion up to 1.5 L/h of IV fluids [3,63,66,67]. However, in patients who are anuric, fluids can lead to in- terstitial or pulmonary edema and should be used cautiously [22]. Fluid selection may include either a balanced crystalloid (e.g., lactated Ringer‘s solution) or 0.9% normal saline. One study found no significant difference in serum potassium level or CK clearance between 0.9% nor- mal saline versus lactated Ringer’s solution [67]. While 0.9% normal sa- line may be given initially, multiple liters can lead to iatrogenic Hyperchloremic metabolic acidosis, which can decrease urinary clear- ance of myoglobin [12].

Key Point. Management includes treatment of the underlying etiology and fluid rehydration, with a goal urine output of 300 mL/h.

As discussed, rhabdomyolysis is also associated with decreased urine pH [4,6]. Therefore, some experts have suggested adding bicar- bonate (one ampule in 1 L of half normal saline or 2-3 ampules in 1 L of 5% dextrose) to IV fluids to facilitate renal excretion of myoglobin and reduce urine acidosis [6,12]. It is important to note that Large doses of bicarbonate may worsen the degree of hypocalcemia, and cau- tion is recommended if patients are already significantly hypocalcemic [3,4,11]. However, in the setting of hypocalcemia, administration of cal- cium chloride or gluconate should be avoided unless the patient de- velops hyperkalemic ECG changes, as calcium supplementation can worsen muscular injury and may lead to delayed-onset hypercalcemia [3,11]. Mannitol is an osmotic diuretic which was originally thought to promote increased renal blood flow, reduce renal cast formation, and act as a free-radical scavenger, administered as a 0.5 g/kg IV bolus of 20% mannitol, followed by a 0.1 g/kg/h infusion after restoration of in- travascular volume [3,6,22,66,68,69].

There is no randomized controlled trial evidence to suggest addi-

tional benefit with sodium bicarbonate or mannitol over aggressive fluid resuscitation alone in reducing acute renal injury, need for dialysis, or death [3,4,13,51]. Mannitol may worsen renal perfusion and injury if

administered before restoration of intravascular volume. One study of patients with mild rhabdomyolysis (CK b 5000 IU/L) compared patients treated with bicarbonate and mannitol with those treated with saline alone and found no significant difference in renal outcomes [70]. An- other study of trauma patients with rhabdomyolysis demonstrated no significant difference in outcomes with bicarbonate or mannitol up to a CK of 30,000 IU/L. [13] It is unclear whether this would be beneficial among patients with more Severe rhabdomyolysis and CK levels above 30,000 IU/L. [13] Furosemide 40-120 mg per day has been previously advocated for forced diuresis [4]. However, similar to mannitol and bi- carbonate, it does not demonstrate additional benefits in rhabdomyoly- sis beyond fluid resuscitation [12,51,66]. Loop diuretics may worsen urine acidosis, and there is no benefit in mortality, need for dialysis, or length of stay for furosemide in patients with rhabdomyolysis and renal injury [1-4,71]. Mannitol, sodium bicarbonate, and furosemide should not be routinely used for rhabdomyolysis based on the present literature.

While Conservative therapy using the above strategies is pre-

ferred, Renal replacement therapy , specifically continuous RRT (CRRT), should be considered in patients who are anuric with el- evated creatinine or who experience life-threatening hyperkalemia, hypercalcemia, or hyperazotemia [22,58]. However, only 4% to 20% of patients with AKI caused by rhabdomyolysis typically require RRT [31,72,73]. CRRT is associated with more stable patient hemody- namics compared to intermittent RRT while removing myoglobin and other inflammatory molecules [74,75]. A Cochrane review states there is low quality evidence that CRRT may improve myoglobin clearance, as well as improve serum creatinine, blood urea nitrogen, and Potassium levels [75]. However, it does not improve mortality [75]. Discussion of RRT should be made in conjunction with a nephrologist.

Key Point. Sodium bicarbonate, mannitol, and loop diuretics are not as- sociated with improved outcomes. CRRT should be considered in anuric patients with elevated creatinine or those with life-threatening hyperkalemia, hypercalcemia, or hyperazotemia.

Disposition

Most patients with rhabdomyolysis will require admission for rehy- dration and evaluation for complications. However, exertional rhabdo- myolysis is often a benign disease, with the majority of patients recovering without long-term renal injury or the need for RRT [42,43,76-80]. Patients with mild symptoms, clear etiology, normal vital signs, normal renal function and electrolytes, and ability to

Table 2

risk prediction score for renal failure or mortality among patients with rhabdomyolysis [73].

Variable Score

Age (years)

N50 to <=70 1.5

N70 to <=80 2.5

N80 3

Female sex 1

Initial creatinine (mg/dL)

1.4 to 2.2 1.5

N2.2 3

Initial calcium b 7.5 mg/dL	2
Initial CK N 40,000 IU/L	2
Origin not seizures, syncope, exercise, statins, or myositis	3
Initial phosphate (mg/L) 4.0 to 5.4	1.5
N5.4	3
Initial bicarbonate b 19 mEq/L	2
CK, creatinine kinase.

take oral fluids may be appropriate for discharge with follow up [42,43,76-80]. However, patients with uncertain etiology, laboratory ab- normalities (including renal injury), those with prior episodes of rhab- domyolysis, and Abnormal vital signs should be admitted for further treatment and evaluation [1-5,77]. While CK values in isolation are poorly predictive of the need for RRT [51,60,76-80], McMahon and col- leagues derived and validated a risk stratification tool comprised of age, gender, underlying etiology, and initial laboratory values (i.e., calcium, CK, phosphate, and bicarbonate) (Table 2) [73]. Based on the study, pa- tients at the lowest risk score (b5) had a 2.3% risk of death or need for RRT, while patients at the highest risk score (N10) had a 61.2% risk of death or need for RRT [73]. Knowledge of these risks may assist with de- termining whether patients should be admitted to the general medical floor or intensive care unit.

Several other rules have been produced to determine the risk of AKI

with rhabdomyolysis [81,82]. However, these scores utilize lactate de- hydrogenase, serum creatinine, and Uric acid levels on multiple days, limiting their use in the ED. [81,82] Overall, there are limited to no high-quality data evaluating discharge for rhabdomyolysis, or the use of Observation Units. Further study is needed.

Key Point. Patients with uncertain etiology for rhabdomyolysis, labora- tory abnormalities (including renal injury), those with prior episodes of rhabdomyolysis, and abnormal vital signs should be admitted. How- ever, patients with a first episode of exertional rhabdomyolysis may be appropriate for discharge in the setting of mild symptoms, normal vital signs, normal renal function and electrolytes, and ability to take oral fluids.

Conclusions

Rhabdomyolysis is a medical condition caused by muscle break- down leading to the release of a number of intracellular elements and protein molecules, including potassium, calcium, phosphate, uric acid, and creatinine kinase. Potential etiologies include trauma, exertion, ex- treme temperature changes, ischemia, infections, immobility, drugs, toxins, Endocrine disorders, autoimmune reactions, and genetic condi- tions. history and examination findings can include myalgias, muscle weakness, or dark-colored urine, but often are non-specific. The diagno- sis is determined by an elevated creatinine kinase, typically defined as greater than five times the upper-limit of normal. Treatment includes addressing the underlying etiology, as well as aggressive rehydration with a goal urine output of 300 mL/h. Bicarbonate, mannitol, and loop diuretics are not associated with improved outcomes. Renal re- placement therapy should be determined on a case-by-case basis in consultation with a nephrologist. Emergency physicians should be knowledgeable regarding appropriate diagnosis and treatment op- tions, as they are likely to care for such patients on a regular basis in the ED.

Conflicts of interest

None.

Acknowledgements

MG, BL, and AK conceived the idea for this manuscript, obtained per- mission for submission from Dr. White, and contributed substantially to the writing and editing of the review. This manuscript did not utilize any grants or funding, and it has not been presented in abstract form. This clinical review has not been published, it is not under consideration for publication elsewhere, its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted, it will not be published elsewhere in the same form, in English or in any other language, including

electronically without the written consent of the copyright-holder. This review does not reflect the views or opinions of the U.S. govern- ment, Department of Defense, U.S. Army, U.S. Air Force, or SAUSHEC EM Residency Program.

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