AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Myoglobinuria is usually the result of rhabdomyolysis or muscle destruction. Any process that interferes with the storage or use of energy by muscle cells can lead to myoglobinuria. The release of myoglobin from muscle cells is often associated with an increase in levels of creatine kinase (CK), aldolase, lactate dehydrogenase (LDH), serum glutamic-pyruvic transaminase (SGPT), and other enzymes. When excreted into the urine, myoglobin, a monomer containing a heme molecule similar to hemoglobin, can precipitate, causing tubular obstruction and acute renal insufficiency.

A clinician caring for a patient with crush injuries or other causes of muscle destruction must recognize the presence and severity of myoglobinuria and initiate aggressive hydration to prevent acute renal insufficiency.

The most common causes of myoglobinuria in adults are alcohol and drug abuse, usually in relation to muscle necrosis from prolonged immobilization and pressure by the body weight. Prolonged ethanol consumption and seizure activity, similar to excessive physical activity, can produce an imbalance between muscle energy consumption and production, resulting in muscle destruction.  In children and adolescents, the most common causes of rhabdomyolysis and myoglobinuria are viral myositis, trauma, excessive exercise, drug overdose, seizures, metabolic disorders, and connective tissue disease.

Pathophysiology

Myoglobin is released from muscle tissue by cell destruction or alterations in the permeability of the cell membrane. Myoglobin is a globulin that contains an iron complex. However, it is a monomer, whereas hemoglobin is a polymer; therefore, myoglobin is more easily filtered by the glomerulus and is rapidly excreted into the urine. Plasma levels of myoglobin rapidly fall after its release.

The precipitation of myoglobin in the renal tubules with secondary obstruction, tubular toxicity, or both constitutes the primary causes for acute renal failure during myoglobinuria. The volume of urine flow and a higher urine alkalinity prevent myoglobin from precipitating as readily as it would otherwise.

Frequency

United States

The frequency of myoglobinuria varies with the incidence of natural disasters and environmental trauma. Epidemics of viral myositis may temporarily increase the incidence in local areas. In urban areas with a high incidence of drug and alcohol abuse, many patients with myoglobinuria may present to emergency departments. Hot weather increases the incidence of stress induced rhabdomyolysis, especially in young athletes.

International

Crush injuries related to earthquakes and other natural disasters are the major cause of cases reported internationally. Any person dug from the rubble of such disasters should be considered to have rhabdomyolysis, myoglobinuria, and potential acute renal failure and, therefore, should be given rapid fluid resuscitation.

Mortality/Morbidity

Myoglobinuria causes little or no morbidity or mortality unless it is associated with the secondary complications of rhabdomyolysis, including hyperkalemia, hypocalcemia, and acute renal failure.¹ However, when it is associated with severe rhabdomyolysis, myoglobinuria-induced acute renal failure is a potentially lethal complication.

In adults, rhabdomyolysis can be complicated by acute renal failure in approximately 30% of patients, with about 5% of those requiring hemodialytic support. In the pediatric age group, although previous small case series reported acute renal failure rates of 40-50%, a large retrospective review indicates that only about 5% of subjects with rhabdomyolysis develop acute renal failure.² In both adults and children, the overall mortality rate of acute severe rhabdomyolysis is reported to be 7-8% and is primarily related to acute renal failure and multiorgan failure.

Race

Race is a factor only when natural disasters and economic shortfalls increase the rates of drug and alcohol abuse and the mortality rate among certain racial groups.

Sex

Myoglobinuria tends to affect males more than females because of the former group's predisposition to trauma and participation in strenuous physical exercise. Persons who exercise and have increased muscle mass have an increased intracellular myoglobin content.

Age

In a recent large retrospective review, the median age was 11 years.² The leading cause of rhabdomyolysis in the 0-9 year age range was viral myositis, whereas the leading diagnosis in the 9-18 year age range was trauma.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The classical triad of symptoms of rhabdomyolysis includes myalgia, muscle weakness, and dark urine. The typical history may include drug use, coma, trauma, or strenuous exercise. Patients who use diuretics and develop severe potassium deficiency may be predisposed to rhabdomyolysis.

• Some patients may provide a history of viral illnesses, fever, convulsions, electric shock, burns, crush injuries, or trauma of any type. Patients may have a history of sepsis, especially sepsis that affects muscle tissue, such as gas gangrene. Others may give a history of participation in organized athletics during the summer or in strenuous exercise during athletic events, such as bicycle races or mountain climbing.
• The use of some prescription drugs, such as azidothymidine (AZT) or lovastatin, or the ingestion of ethylene glycol may predispose individuals to myoglobinuria. Other drugs associated with myoglobinuria include heroin, codeine, barbiturates, amphetamines, licorice, diazepam, amphotericin-B, phencyclidine, and some dietary supplements.
• Acute tumor lysis syndrome may be associated with myoglobinuria.
• Snakebites, bites from recluse spiders, and multiple insect stings can cause muscle necrosis.
• Ingestion of quail can precipitate myoglobinuria.
• Autoimmune vesiculitis, such as dermatomyositis, may destroy muscle tissue.

Physical

• Physical examination reveals generalized muscle weakness, often with painful muscle groups, trauma, and/or areas of ischemic pressure necrosis when the patient has laid down for extended periods.
• Expect any patient with extensive trauma to have some myoglobinuria.
• The volume status of the patient should be carefully and quickly determined because volume depletion necessitates rapid correction in order to prevent acute renal failure.

Causes

• Trauma and compression: Trauma is the most common cause of myoglobinuria. Patients who experience crush injuries, such as those that occur when individuals are buried after earthquakes, have rhabdomyolysis and myoglobinuria. Volume depletion from fluid sequestration in damaged tissues and poor fluid intake accentuate the possibility of acute renal insufficiency. Electric shock can cause enough muscle damage to precipitate myoglobinuria.
• External myolysis: Exertional myoglobinuria occurs in most athletes but rarely becomes symptomatic unless combined with poor training, inadequate oral intake, dehydration, and heat exhaustion. Trauma from repeated blows to the muscle always releases myoglobin into the system. The treatment is prevention, which includes plentiful fluid, limited exercise during particularly hot periods, and avoiding muscle trauma. Athletes have more myoglobin in their muscles than other individuals and are prone to symptoms when small amounts of muscle tissue are damaged.
• Viral myositis: Viral infections from a wide variety of organisms can cause myositis and myoglobinuria. The patient usually presents with generalized weakness and myalgias, particularly in the back and proximal extremities. Children with influenza A and influenza B viral infections can present with tenderness in calves and lower extremities. Treatment is generous hydration to facilitate myoglobin excretion.
• Electrolyte disorders: Metabolic diseases, particularly those involving muscle metabolism, may be associated with myoglobinuria. Males are affected more often, and symptomatology is exacerbated by exercise and heat injuries. Potassium depletion has been particularly associated with myoglobinuria.
• Toxins, drugs, and diet
• • Snakebites and other venoms can cause muscle necrosis and myoglobinuria.
  • Some drugs predispose individuals to rhabdomyolysis, including AZT (used to treat acquired immunodeficiency syndrome [AIDS]) and lovastatin (used to treat hypercholesterolemia). However, statin-induced rhabdomyolysis is rare and occurs in less than 0.1% of all users.
  • Alcohol, cocaine, amphetamines, phencyclidine, ecstasy, and some dietary supplements can lead to myoglobinuria.³
  • Ingestion of ethylene glycol, isopropyl alcohol, and phencyclidine has been associated with myoglobinuria.
  • Overindulgence in quail can also cause myoglobinuria in some patients.
• Infection or sepsis syndromes: Syndromes involving muscle destruction include gas gangrene, tetanus, Legionnaire disease, or shigellosis. Coxsackie viral infections with myositis may be the most common cause of mild myoglobinuria.
• Endocrine disorders: Diabetic ketoacidosis, myxedema, and nonketotic hyperosmolar comas can disrupt muscle energy.
• Malignant hyperthermia and high fevers: These may be contributors.
• Hereditary myopathies
• • Hereditary myopathies, such as McArdle syndrome and muscular dystrophy, can precipitate myoglobinuria.
• • The differential diagnosis for myoglobinuria must include metabolic myopathies. This diverse and complex list of disorders is long, with new additions each year.
  • In general, patients with myopathies report exercise intolerance, muscle pain, and cramps rather than weakness. Patients with some types of muscular dystrophy or inflammatory myositis (eg, dermatomyositis, polymyositis) may present with progressive weakness.
• Metabolic Disorders
• • Patients with defects of carbohydrate metabolism (eg, myophosphorylase, phosphofructokinase, phosphohexoisomerase deficiency) have symptoms of easy fatigability or cramping induced by dynamic isometric exercise, such as heavy lifting, or prolonged exercise, such as swimming or running. Acute muscle breakdown can lead to myoglobinuria. These patients typically present after participating in high-intensity exercise, such as weight lifting.
  • Defects in lipid metabolism include carnitine deficiency, beta-oxidation enzyme deficiency, or disorders of fatty acid transport. Prolonged fasting or prolonged activity induces muscle pain and myoglobinuria. Fever, sepsis, and exposure to cold can also induce muscle fatigue in this set of disorders. These patients typically develop symptoms after prolonged low-intensity exercise, such as walking.
  • Patients with mitochondrial disorders (beta-oxidation disorders) usually present with static and progressive muscular weakness. Failure to thrive, floppy-baby syndrome, and generalized muscle weakness are present in most of these children. Patients usually present with chronic muscle cramping and weakness rather than episodic muscle cramping and weakness. Patients with some types of muscular dystrophy or inflammatory myositis may present with progressive weakness.
• Heat exhaustion and cold exposure: These conditions induce abnormal muscle metabolism by means of various mechanisms, including poor perfusion and decreased oxygenation, acidosis, rhabdomyolysis, or glucose and/or glycogen depletion. Reye syndrome may also be included in this group. Patients with recurrent exercise-induced myoglobinuria may have defective carnitine palmitoyltransferase activity.⁴

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Metabolic myopathies
Sepsis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The most important laboratory test is measurement of CK levels to assess for rhabdomyolysis.
• • Myoglobin is the first enzyme that increases, but it returns to normal levels within the first 24 hours after the onset of symptoms. This is because myoglobin is rapidly cleared from the serum into the urine. However, serum CK levels may remain elevated after serum and urine test results for myoglobin have become negative. Serum CK levels typically peak about 3 days after the onset of symptoms, and remain elevated for several days. Thus, although the detection of myoglobin in the serum is considered pathognomonic for rhabdomyolysis, the serum CK level is a more useful marker for the diagnosis and assessment of severity because of its delayed clearance from the plasma.
  • Levels of other muscle enzymes, such as aldolase, LDH, or serum glutamic-oxaloacetic transaminase (SGOT), may also be elevated.
• Electrolyte abnormalities may cause or result from rhabdomyolysis, including hyperkalemia and hyperphosphatemia from the damaged muscle cells.
• • Hypocalcemia may develop from the hyperphosphatemia or as result of calcium deposition in the damaged muscles.
  • Uric acid values may be elevated, and metabolic acidosis may develop.
• Acute renal insufficiency (elevated BUN and creatinine levels) is a consequence of severe myoglobinuria in which the globulin precipitates and blocks the urinary tubules.
• • Creatinine levels may be elevated out of proportion to BUN levels.
  • Alkalinization of the urine and increased urine flow facilitates myoglobin excretion.
• Although both myoglobinuria and hemoglobinuria may cause a tea-colored appearance of the urine, and although both cause positive results on the urine dipstick for blood, myoglobinuria may be differentiated from hemoglobinuria by performing a series of simple tests.
• • Myoglobinuria is brown, and often only a few RBCs are present in the urine.
  • Hematuria produces a reddish sediment in spun urine samples.
  • Red or brown urine with a negative dipstick result for blood indicates a dye in the urine.
  • Hemoglobin produces a reddish or brown coloration in the spun serum, whereas myoglobin does not discolor the serum.
  • CK levels are markedly elevated in myoglobinuria.
  • Results of radioimmunoassays for the specific measurement of serum or urine myoglobin can be delayed by several days and are not useful in immediate diagnosis and treatment.
• Other electrolytic abnormalities associated with rhabdomyolysis result from the extrusion of intracellular contents into the plasma and include hyperkalemia, hypercalcemia or hypocalcemia, hyperphosphatemia, and hyperuricemia.

Imaging Studies

• Imaging studies are rarely of use in this metabolic disorder.
• Intravenous (IV) pyelograms may reveal a dense renogram, but most are normal.

Other Tests

• Tests for sickle cell disease (eg, sickle preparations, hemoglobin electrophoresis) may reveal patients who are prone to rhabdomyolysis.
• A drug and metabolic screen of the urine, blood, or both may indicate illicit drug use.
• Complements and antinuclear antibodies may help in differentiating autoimmune polymyositis from other conditions.
• In patients with acute renal insufficiency due to myoglobinuria, fractional excretion of sodium (FENa) is less than 1%, probably because tubular obstruction and damage is the cause of oliguria rather than glomerular damage.

Procedures

• Muscle biopsy may be of use when a metabolic myopathy is suspected.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

All patients with suspected myoglobinuria or rhabdomyolysis should be admitted for IV hydration and management of complications. Initial treatment focuses on preventing myoglobin precipitation in the urine by inducing and maintaining a brisk diuresis. Immediately administer saline to patients with suspected myoglobinuria or rhabdomyolysis because early hydration is the key to ameliorate acute renal failure. Achievement of a minimum urine output goal of 2 mL/kg/h is recommended.

Follow-up with mannitol to induce diuresis, supported by adequate IV fluids, has been advocated. Mannitol causes diuresis, which minimizes intratubular myoglobin deposition, acts as a free radical scavenger and reduces tubule cell damage, and may act as a direct renal vasodilator. However, the clinical benefit of this therapy remains unproven. In retrospective studies, volume expansion with saline alone prevented acute renal failure, and mannitol had no additional benefit.⁵ 

Raising the pH of the urine to 6.5 or more can be facilitated by adding sodium bicarbonate to the fluids. Alkalinization of the urine has been postulated to minimize the breakdown of myoglobin into its nephrotoxic metabolites and to reduce crystallization of uric acid, thereby decreasing damage to tubule cells. However, this modality of therapy remains somewhat controversial because large volumes of crystalloid alone may be sufficient to alkalinize the urine and because bicarbonate therapy can aggravate the hypocalcemia. No large randomized trials have demonstrated that alkalinization of urine is superior to early aggressive hydration with crystalloid in the management of rhabdomyolysis.

• Hyperkalemia and hypocalcemia may require emergent treatment.
• Patients with crush injuries and trauma require treatment for the soft tissue and bony injuries.
• Patients with compartment compression due to muscle edema may require fasciotomy.
• CK levels generally peak on day 3 and then rapidly decrease by half every 24-48 hours.

Surgical Care

Surgical debridement may be needed if muscle damage or necrosis is extensive. Fasciotomy may be required to manage compartment compression syndrome.

Consultations

Nephrologists may facilitate the safe initiation of diuresis to avoid dialysis. If dialysis is needed, consultation with a nephrologist is necessary.

Activity

Activity is restricted by the extent of muscle damage. Persons who have had exertional myoglobinuria must limit their future activity and maintain adequate hydration.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Administer a sodium chloride solution for volume depletion as 0.9% NaCl solution, lactated Ringers solution, or a solution of 0.45% NaCl and sodium bicarbonate 50 mEq/L. Mannitol may be administered to facilitate osmotic diuresis. Diuretics such as furosemide are less desirable because they may accentuate intravascular volume depletion.

Drug Category: Osmotic diuretics

These agents raise the osmolality of plasma and renal tubular fluid, which creates an osmotic inhibition of water transport in the proximal tubule. This effect subsequently decreases the gradient for passive sodium absorption in the ascending limb of the loop of Henle. The increased urinary flow is achieved by means of nonelectrolyte solute diuresis. Increased glomerular filtration rate may also be observed.

Drug Category: Alkalinizing agents

Sodium bicarbonate is used as a gastric, systemic, and urinary alkalinizer. Sodium bicarbonate is administered IV to alkalinize the urine in patients with rhabdomyolysis because it may prevent the toxicity that can result from the presence of myoglobin in acidic urine and prevent the crystallization of uric acid.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Hemodialysis or continuous veno-veno hemodialysis (CVVHD) may be needed to treat acute renal insufficiency. Recovery often occurs in 10-14 days.
• Electrolyte complications of rhabdomyolysis, including hyperkalemia and hypocalcemia, may need immediate treatment.
• In the recovery phase, patients may develop hypercalcemia as calcium precipitated in damaged tissue returns to the circulation.
• Long-term diuresis may cause hypokalemia.

Further Outpatient Care

• Patients may need extensive rehabilitation for muscle damage.

Deterrence/Prevention

• Patients with metabolic muscle diseases must avoid trauma, overexertion, dehydration, and heat injuries.

Complications

• The most serious complication of myoglobinuria is acute renal failure.
• Other complications can result from renal shutdown or from the intracellular products released into the system by rhabdomyolysis.

Prognosis

• Patients with uncomplicated cases of myoglobinuria recover without sequelae.

Patient Education

• Patients who develop exercise-induced rhabdomyolysis need education in maintaining adequate fluid intake, in oral rehydration, and in pacing their exercise in hot weather or extreme conditions.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Monitor the patient with a crush injury or extensive muscle damage for rhabdomyolysis and acute renal failure.
• Administer fluids to a dehydrated patient or any patient with possible muscle injury until the degree of severity is determined.
• Warn patients against stressful exercise.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Fernandez WG, Hung O, Bruno GR, Galea S, Chiang WK. Factors predictive of acute renal failure and need for hemodialysis among ED patients with rhabdomyolysis. Am J Emerg Med. Jan 2005;23(1):1-7. [Medline].
2. Mannix R, Tan ML, Wright R, Baskin M. Acute pediatric rhabdomyolysis: causes and rates of renal failure. Pediatrics. Nov 2006;118(5):2119-25. [Medline].
3. Coco TJ, Klasner AE. Drug-induced rhabdomyolysis. Curr Opin Pediatr. Apr 2004;16(2):206-10. [Medline].
4. Huerta-Alardin AL, Varon J, Marik PE. Bench-to-bedside review: Rhabdomyolysis -- an overview for clinicians. Crit Care. Apr 2005;9(2):158-69. [Medline].
5. Brown CV, Rhee P, Chan L, et al. Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference?. J Trauma. Jun 2004;56(6):1191-6. [Medline].
6. David WS. Myoglobinuria. Neurol Clin. Feb 2000;18(1):215-43. [Medline].
7. Giannoglou GD, Chatzizisis YS, Misirli G. The syndrome of rhabdomyolysis: Pathophysiology and diagnosis. Eur J Intern Med. Mar 2007;18(2):90-100. [Medline].
8. Kilfoyle D, Hutchinson D, Potter H, George P. Recurrent myoglobinuria due to carnitine palmitoyltransferase II deficiency: clinical, biochemical, and genetic features of adult-onset cases. N Z Med J. Feb 25 2005;118(1210):U1320. [Medline].
9. Lin AC, Lin CM, Wang TL, Leu JG. Rhabdomyolysis in 119 students after repetitive exercise. Br J Sports Med. Jan 2005;39(1):e3. [Medline].
10. Malinoski DJ, Slater MS, Mullins RJ. Crush injury and rhabdomyolysis. Crit Care Clin. Jan 2004;20(1):171-92. [Medline].
11. Melli G, Chaudhry V, Cornblath DR. Rhabdomyolysis: an evaluation of 475 hospitalized patients. Medicine (Baltimore). Nov 2005;84(6):377-85. [Medline].
12. Ocana J, Echarri R, Liano F. Rhabdomyolysis. Am J Kidney Dis. Jan 2006;47(1):A32, e1-2. [Medline].
13. Sharp LS, Rozycki GS, Feliciano DV. Rhabdomyolysis and secondary renal failure in critically ill surgical patients. Am J Surg. Dec 2004;188(6):801-6. [Medline].

Article Last Updated: Dec 19, 2007