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Rhabdomyolysis, a syndrome of skeletal muscle breakdown with leakage of muscle contents, is frequently accompanied by myoglobinuria, and if sufficiently severe, acute renal failure with potentially life-threatening metabolic derangements may ensue.

Hyperkalemia, hyperphosphatemia, hypocalcemia, and elevations in serum uric acid and creatine kinase (MM isoenzyme) levels at presentation suggest a diagnosis of rhabdomyolysis.

Presenting Symptoms:

  • Muscle tenderness, weakness, swelling, fatigue
  • Dark urine
  • Malaise & fatigue

Intern Emerg Med. 2007 Oct;2(3):210-8. Epub 2007 Oct 1.
Bagley WH, Yang H, Shah KH.
Department of Emergency Medicine, St. Luke's-Roosevelt Hospital, University Hospital of Columbia Physicians & Surgeons, New York, NY 10025, USA.

Rhabdomyolysis is a syndrome involving the breakdown of skeletal muscle causing myoglobin and other intracellular proteins and electrolytes to leak into the circulation. The development of rhabdomyolysis is associated with a wide variety of diseases, injuries, medications and toxins. While the exact mechanisms responsible for all the causes are not fully understood, it is clear that muscle damage can occur from direct injury or by metabolic inequalities between energy consumption and energy production. Rhabdomyolysis is diagnosed by elevations in serum creatine phosphokinase (CPK), and while there is no established serum level cut-off, many clinicians use five times the upper limit of normal ( approximately 1000 U/l).

Rhabdomyolysis can be complicated by acute renal failure (occurring in 4%-33% of patients), compartment syndrome, cardiac dysrhythmias via electrolyte abnormalities, and disseminated intravascular coagulopathy.

The mainstay of treatment is hospitalisation with aggressive intravenous fluid (IVF) resuscitation with the correction/prevention of electrolyte abnormalities. There are additional adjunctive therapies to IVF, such as alkalinisation of the urine with sodium bicarbonate, diuretic therapy or combinations of both; however the lack of large randomised control studies concerning the benefits of these treatments makes it difficult to make strong recommendations for or against their use in the treatment of rhabdomyolysis.

Regardless of these controversies, the overall prognosis for rhabdomyolysis is favourable when treated with early and aggressive IVF resuscitation, and full recovery of renal function is common. Irrespective of the cause of rhabdomyolysis the mortality rate may still be as high as 8%. This is a comprehensive review of the pathophysiology, diagnosis, complications and treatment options for rhabdomyolysis.

Clinical Manifestations         REF: Goldman: Cecil Medicine, 23rd ed 2007

The classic manifestation of rhabdomyolysis
includes acute myalgia (muscle pain, tenderness, and swelling) and pigmenturia as a result of myoglobinuria in association with elevated serum muscle enzymes (CK).  

Systemic features
include tea-colored urine, chills, fever, and malaise. In extreme cases, patients complain of nausea and vomiting and demonstrate confusion, agitation, or delirium.

Clinical findings may also include the possibility of compartment syndrome, which can occur in muscle groups encased by fascia, especially the lower leg, forearm, and thigh muscle groups. Sensory abnormalities caused by nerve compression are an early manifestation of compartment syndrome; the loss of a pulse as a result of vascular compromise is a later finding. If compartment syndrome is not addressed within 6 to 8 hours, irreversible ischemic muscle and nerve damage may occur.

Laboratory findings
are related to the degree of muscle involvement. Early findings include elevated blood levels of CK, myoglobin, potassium, urea, and phosphorus. CK levels typically peak 2 to 5 days after the initial insult; levels higher than 16,000 U/L are more likely to be associated with renal failure than lower levels are. Hypocalcemia (initially), caused by the influx and deposition of Ca2+ in damaged muscle tissue, may accompany rhabdomyolysis. Moreover, an anion gap metabolic acidosis may develop because of release of organic acids from damaged muscle. With resolution of rhabdomyolysis, sequestered Ca2+ may be released back into the circulation and cause hypercalcemia (later on).

REF:  Ferri: Ferri's Clinical Advisor 2010  
  • • Exertion (exercise-induced)
  • • Electrical injury
  • Drug-induced (statins, combination of statins with fibrates, or erythromycin, simvastatin and amiodarone, amphetamines, haloperidol)
  • • Compartment syndrome
  • Multiple trauma
  • Prolonged static positioning (after trauma or syncope)
  • • Malignant hyperthermia
  • • Limb ischemia
  • • Reperfusion after revascularization procedures for ischemia
  • • Extensive surgical (spinal) dissection, bariatric surgery
  • • Tourniquet ischemia
  • • Prolonged static positioning during surgery
  • • Infectious and inflammatory myositis
  • • Metabolic myopathies
  • • Hypovolemia and urinary acidification are important precipitating causes in the development of acute renal failure
  • • Sickle cell trait is a predisposing condition

  • • Screening for myoglobinuria with a simple urine dipstick test using orthotoluidine or benzidine  
  • Increased serum CK (Creatine Kinase)
  • • Blood urea nitrogen, creatinine
  • • Hyperkalemia
  • • Hypocalcemia
  • • Hyperphosphatemia
  • • Increased urinary myoglobin
  • • Pigmented granular casts
  • • Hyperuricemia

REF: Goldman: Cecil Medicine, 23rd ed 2007


Creatine Kinase Levels  
A diagnosis of rhabdomyolysis is made when there is clinical evidence of myonecrosis with release into the systemic circulation of muscle cell contents, including myoglobin, creatinine, CK, organic acids, potassium, aldolase, lactate dehydrogenase, and hydroxybutyrate dehydrogenase. The skeletal muscle subtype CK-MM of the CK enzyme is abundantly present in skeletal muscle and released as a result of muscle destruction. Serum levels exceeding 100,000 U/L are not uncommon with rhabdomyolysis. Because CK remains in the circulation longer than myoglobin does and is both easy and efficient to detect clinically, it is the most frequently used marker to diagnose rhabdomyolysis. Levels in excess of five times normal are accepted as evidence of significant muscle breakdown and are generally considered to be consistent with a diagnosis of rhabdomyolysis.

Myoglobin Testing

Myoglobin should be the best marker and the diagnostic cornerstone because myoglobinuria does not occur in the absence of rhabdomyolysis. However, testing for serum or urine myoglobin is problematic and not always consistent. Myoglobin is normally bound to plasma globulins, and therefore only a small fraction reaches the glomeruli. In the face of severe muscle damage, blood levels of myoglobin overwhelm the binding capacity of the circulating proteins, so free myoglobin reaches the glomeruli and eventually the renal tubules. Elevations in serum myoglobin occur before a rise in serum CK, but the elimination kinetics of serum myoglobin is more rapid than that of CK, which makes the often evanescent rises in serum myoglobin a less reliable marker of muscle injury. Furthermore, the liver can quickly metabolize myoglobin. Diagnostic tests for urine myoglobin are often not readily available, and it may take more than 24 hours to obtain results. However, urine screening for rhabdomyolysis may be performed by dipstick if the urine sediment is also examined. The orthotoluidine portion of the dipstick turns blue in the presence of hemoglobin or myoglobin, so if the urine sediment does not contain erythrocytes, one can assume, in the appropriate clinical setting, that the positive dipstick reading reflects the presence of myoglobin.

Other associated laboratory findings in acute rhabdomyolysis can include hypocalcemia or hypercalcemia, hyperphosphatemia, metabolic (lactic) acidosis, thrombocytopenia, and disseminated intravascular coagulation.


• Early, aggressive, high-volume IV fluid replacement with mannitol to induce diuresis to prevent acute renal failure

• Treatment of electrolyte imbalances

• Alkalinization of urine is controversial but appears helpful in research models


Treatment of rhabdomyolysis begins with a careful history and physical examination to identify and manage any underlying illness and then focuses on preserving renal function. All patients require aggressive, early management because it is difficult to stratify risk initially. Careful observation plus treatment of potential early and late complications is critical. Accordingly, vital signs, urine output, serial electrolyte levels, and CK levels should be obtained as soon as possible. Intensive care monitoring may be required, depending on the clinical situation.


Hydration is the cornerstone of preserving renal function in patients with rhabdomyolysis.
Providing fluids addresses the early threats to survival: hypovolemic shock and hyperkalemia. Currently, no clinical prediction rule exists for risk-stratifying patients with rhabdomyolysis or for determining in whom acute renal failure will develop, but CK levels greater than 15,000 U/L are thought to portend an increased risk.

Patients with mild symptoms and serum CK levels less than 3000 U/L are considered to be at low risk and may be treated as outpatients with hydration, limited physical activity, and careful follow-up.

Victims of collapse, trauma, or exertional heat injury or patients who demonstrate moderate early symptoms with more than mild elevations in CK or an abnormal metabolic panel should be treated with intravenous hydration in an inpatient setting. Hydration is accomplished by aggressive intravenous fluid therapy with isotonic fluids at a rate that will result in a urine output of 200 mL/hr until CK levels begin to decrease. When fluid resuscitation fails to correct intractable hyperkalemia and acidosis, dialysis should be considered.

Specific Therapeutic Measures

Several retrospective clinical studies and case reports, as well as animal models, promote the addition of bicarbonate and mannitol, but no prospective clinical trials have been conducted to support or refute their benefits in managing rhabdomyolysis. Alkalinization of urine is advocated for the purpose of decreasing cast formation, minimizing the toxic effects of myoglobin on the renal tubules, inhibiting lipid peroxidation, and decreasing the risk for hyperkalemia. However, this approach can cause Ca2+ to precipitate and be deposited in the soft tissues, as well as contribute to a hyperosmolar state. Mannitol serves as an osmotic diuretic, volume expander, and free radical scavenger; it should be used very carefully in patients with marginal cardiac function and only after adequate renal function is established.

For rhabdomyolysis caused by crush syndrome, both mannitol and a forced alkaline diuresis are recommended when CK levels are greater than 20,000 U/L. The treatment goals of this algorithm are to (1) achieve a urine output of 200 mL/hr, (2) maintain urine pH between 6 and 7, (3) keep serum pH below 7.50, and (4) achieve hemodynamic stability and prevent volume overload. The fluid resuscitation recommendation begins with a bolus of 1 L of 5% dextrose plus 0.22% NaCl and 100 mEq NaHCO3 over a 30-minute period, followed by an infusion at 2 to 5 mL/kg/hr. A 20% mannitol infusion at a dose of 0.5 g/kg is given over a 15-minute period and subsequently followed by an infusion at 0.1 g/kg/hr. Adjustments are made to maintain urine output at greater than 200 mL/hr. Urinary and serum pH levels are monitored, with acetazolamide added if the serum pH exceeds 7.45 or urinary pH remains below 6.0. However, the use of mannitol and forced alkaline diuresis in patients with crush syndrome, as well as other clinical manifestations of rhabdomyolysis, has not been tested in randomized trials.

Managing Metabolic Abnormalities

Deposition of Ca2+, which occurs early in rhabdomyolysis, is directly related to the degree of muscle destruction and administration of Ca2+. Reversal of hypocalcemia may in fact worsen ectopic calcification and exacerbate hypercalcemia during the resolution phase. Accordingly, hypocalcemia should be treated only when clinical symptoms, signs of tetany, or severe hyperkalemia develops.

Management of Compartment Syndrome

Compartment syndrome ( Chapter 113 ) is a well-described late complication as well as a potential cause of rhabdomyolysis. Compartment syndrome can occur as a direct consequence of muscle injury with increased vascular permeability, aggressive fluid resuscitation, or restoration of reperfusion. In patients in whom a compartment syndrome is suspected, such as when the muscles are tense and swollen or there is evidence of neurovascular compromise, compartment pressures should be promptly measured; in the proper clinical setting, pressures in excess of 30 mm Hg should prompt consideration of fasciotomy. However, late fasciotomy (>12 hours after the onset of symptoms) may be counterproductive by converting a closed injury to an open wound with an increased risk for uncontrollable infection. Accordingly, late fasciotomy is relatively contraindicated.

Management of Crush Injury

Management of crush injury victims ( Chapter 113 ) is unique in that many individuals have the opportunity for treatment before extrication and reperfusion. Current recommendations for on-site management of trauma victims before extrication include aggressive hydration with intravenous normal saline. In the event of massive damage, amputation of the extremity may be required to protect the patient's overall health. A Mangled Extremity Severity Score (MESS) may be used to identify nonsalvageable extremities prospectively. The MESS is a grading system based on four groups of clinical criteria, including the degree of skeletal/soft tissue injury, rating of blood pressure (shock) and pulse (ischemia), and age. Scores from each group are added to obtain a total score that ranges from 0 to 14; higher scores indicate more severe involvement, and a score of 7 or greater has a positive predictive value of nearly 100% for amputation. Ongoing clinical trials in this population will, it is hoped, elucidate the role of antioxidant therapy (glutathione and vitamin E) in scavenging free radicals, dantrolene sodium in inhibiting Ca2+ release, and deferoxamine in reducing the direct toxic effects of myoglobin on the kidneys.

Malignant Hyperthermia

One cause of rhabdomyolysis that requires rapid and aggressive management is malignant hyperthermia ( Chapter 458 ). Episodes of malignant hyperthermia occur most commonly in the operating room and are recognized by the anesthesiologist. The typical clinical features represent an uncontrolled, exaggerated, hypermetabolic state; an increase in end-tidal CO2 during ventilation is the most sensitive sign. On clinical recognition of impending malignant hyperthermia, anesthetics should be discontinued, and the patient should be treated with dantrolene sodium; the usual initial dose is 2.5 to 4.0 mg/kg, followed by about 1 mg/kg every 4 hours for up to 48 hours to avoid recrudescence.