eMedicine Specialties > Pediatrics: General Medicine > Rheumatology

Rhabdomyolysis

Eyal Muscal, MD, Assistant Professor, Section of Pediatric Rheumatology, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital
Marietta Morales de Guzman, MD, Assistant Professor, Department of Pediatrics, Baylor College of Medicine; Consulting Staff, Section of Pediatric Rheumatology, Department of Pediatrics, Texas Children's Hospital, Ben Taub General Hospital; Renee Wilson, MD, Clinical Assistant Instructor, Department of Emergency Medicine, SUNY-Downstate and Kings County Hospital; Binita R Shah, MD, FAAP, Professor of Clinical Pediatrics and Emergency Medicine, SUNY Health Science Center at Brooklyn, Director of Pediatric Emergency Medicine, Depts of Emergency Medicine and Pediatrics, Kings County Hospital Center

Updated: Dec 8, 2008

Introduction

Background

Rhabdomyolysis is a syndrome caused by injury to skeletal muscle and involves leakage of large quantities of intracellular contents into plasma.¹  It translates to "dissolution of skeletal muscle" and is a final pathway of diverse processes and insults.² In adults, rhabdomyolysis is characterized by the triad of muscle weakness, myalgias, and dark urine; however, all 3 symptoms are rarely seen together in many children with this condition.^3,4 Myalgias and generalized muscle weakness are the most common presenting symptoms. Life-threatening renal failure and disseminated intravascular coagulation are dreaded complications that appear to be more common in adults.⁵

Rhabdomyolysis has many etiologies and is often multifactorial in adult patients. The physician must be alert to the diagnosis of rhabdomyolysis and to its subtle presentation to prevent acute renal failure. Sensitive laboratory markers of myocyte injury include elevated plasma creatine kinase (CK) levels. The management of rhabdomyolysis primarily consists of correction of fluid and electrolyte anomalies. With adequate supportive measures, the clinical outcome of rhabdomyolysis is often favorable in children.²

Pathophysiology

Despite the multiple etiologies of rhabdomyolysis, the final common denominator appears to be disruption of the sarcolemma and release of intracellular myocyte components. Mechanisms of cell destruction in rhabdomyolysis include cellular membrane injury, muscle cell hypoxia, ATP depletion, and electrolyte disturbances that cause perturbation of sodium-potassium pumps.²

The sarcolemma, a thin membrane that encloses striated muscle fibers, contains numerous pumps that regulate cellular electrochemical gradients. The intercellular sodium concentration is normally maintained at 10 mEq/L by a sodium-potassium adenosine triphosphatase (Na/K-ATPase) pump located in the sarcolemma.⁶

The Na/K-ATPase pump actively transports sodium from the interior of the cell to the exterior. As a result, the interior of the cell is more negatively charged than the exterior because positive charges are transported across the membrane. The gradient pulls sodium to the interior of the cell in exchange for calcium through a protein carrier exchange mechanism. In addition, an active calcium exchanger promotes calcium entry into the sarcoplasmic reticulum and mitochondria.

The above processes depend on ATP as a source of energy. ATP depletion appears to be the end result of most causes of rhabdomyolysis. ATP depletion disrupts cellular transport mechanisms alters electrolyte composition.⁷ An increase in intracellular calcium levels results in hyperactivity of proteases and proteolytic enzymes and generation of free oxygen radicals. These enzymes and substances increasingly degrade myofilaments and injure membrane phospholipid with leakage of intracellular contents into plasma. These contents include potassium, phosphate, CK, urate, and myoglobin. Excess fluid may also accumulate within affected muscle tissue. Additionally, muscle damage is amplified by infiltration of activated neutrophils. An inflammatory cascade and reperfusion injury sustains muscle damage and degeneration.^8,6

Myoglobin is an important myocyte compound released into plasma. After muscle injury, massive plasma myoglobin levels exceed protein binding and can precipitate in glomerular filtrate. Excess myoglobin may thus cause renal tubular obstruction, direct nephrotoxicity, and acute renal failure.^5,9

Frequency

United States

Rhabdomyolysis is a common condition in adult populations and is understudied in pediatrics.^10,2 The National Hospital Discharge Survey reports 26,000 cases annually.¹⁰ Most adult cases of rhabdomyolysis are due to illicit drug abuse/alcohol abuse, muscular trauma and crush injuries, and myotoxic effects of prescribed drugs. Rhabdomyolysis is found in 24% of adult patients who present to emergency departments with cocaine-related conditions.

In a large adult cohort, 60% of cases had multiple factors.¹⁰ Significant pediatric etiologies include infections, trauma, metabolic conditions, and muscle diseases. In a retrospective review at a tertiary care pediatric center review spanning 10 years viral myositis accounted for most cases in patients aged 0-9 years, whereas trauma was the leading diagnosis in patients aged 9-18 years.²  

The incidence of myoglobin-induced acute renal failure in adult rhabdomyolysis ranges from 16-33%. This complication was found in 42% of pediatric patients in a small retrospective cohort study but in only 5% in the larger 10-year review mentioned above.^11,2 Approximately 28-37% of adult patients require short-term hemodialysis. Rhabdomyolysis is believed to be responsible for 5-25% of all adult cases of acute renal failure. A comparable figure in children is unavailable.

International

Large numbers of patients may develop rhabdomyolysis and renal failure during disasters such as earthquakes. Severe crush injuries and delayed extrication of survivors characterize such events. Organizations such as the International Society of Nephrology have implemented measures to support local agencies in providing life-saving dialysis treatments for patients with rhabdomyolysis.⁵

Mortality/Morbidity

• Electrolyte abnormalities are prominent features of rhabdomyolysis. Hyperphosphatemia, hyperkalemia, hypocalcemia, hyperuricemia, and hypoalbuminemia have been described.^1,8
  • Hyperkalemia may be a result of both muscle injury and renal insufficiency or failure. This abnormality may cause life-threatening arrhythmias and should be immediately addressed.
  • Hypocalcemia is another common metabolic abnormality, resulting from deposition of calcium phosphate. It may also be due to a decreased level of 1,25-dihydroxycholecalciferol in patients with renal failure. Severe hypocalcemia may lead to cardiac arrhythmias, muscular contractions, and seizures. These events may further damage affected muscles.
  • Hypoalbuminemia results from proteinuria and direct leakage of protein, whereas hyperuricemia is caused by direct damage to muscle and may contribute to renal tubular damage.
• Compartment syndrome may be a complication of or an inciting cause of rhabdomyolysis. Muscle injury results from decreased tissue perfusion, which is caused by increased pressure within the affected space. High intracompartmental pressures mediate further ischemia, damage, and necrosis. Compartment pressures should be measured when significant muscle injury has occurred; a fasciotomy is advocated when the pressure is more than 30 mm Hg. Prolonged elevated intracompartmental pressure may lead to irreversible peripheral nerve injury.⁵
• Acute renal failure is the most severe complication of rhabdomyolysis and accounts for approximately 5-25% of adult cases of renal failure.¹⁰
  • Approximately one third of adult patients with rhabdomyolysis develop renal failure if not adequately treated. This figure may be as low as 5% in children.^10,2
  • Mechanisms of renal failure include renal vasoconstriction, intraluminal myoglobin cast formation, and heme-protein cellular toxicity.
  • Myoglobin and hemoglobin have no direct toxic effect on the glomerulus in the absence of aciduria and hypovolemia.
  • Acute renal failure is believed to be due to decreased extracellular volume, which results in renal vasoconstriction. It is also believed to be due to ferrihemate, which is formed from myoglobin at a pH level of 5.6 or less. Ferrihemate produces free hydroxy radicals and causes direct nephrotoxicity, often through lipid peroxidation. These heme-proteins may enhance vasoconstriction through interactions with nitric oxide (NO) and endothelin receptors. The roles of cytokines in this process have also been discussed.⁸
  • Renal vasoconstriction and ischemia deplete tubular ATP formation and enhance tubular cell damage.
  • Myoglobin precipitation in renal tubules causes formation of obstructive casts.
  • Gastrointestinal ischemia is common in patients with fluid and electrolyte imbalances. This ischemia leads to endotoxin absorption, cytokine production, and perpetuation of the systemic inflammatory response.

Clinical

History

The classic triad of rhabdomyolysis consists of myalgias, generalized weakness, and darkened urine. However, rhabdomyolysis presentation significantly varies, and only about 50% of adult patients actually present with this triad. This figure may be even lower in children.⁶  Additional nonspecific symptoms include fevers, nausea, and vomiting.

In most cases, the history reflects the inciting cause of rhabdomyolysis, such as alcohol use and resultant unresponsiveness, agitation and illicit drug use, the use of prescribed medications, or heat stroke.^10,12,13,14 In children, history of recent infection and trauma is most common.² Caregivers in contact with the patient prior to hospitalization may be able to provide useful information about how the patient was found or his or her most recent activities. Obtain information about prolonged immobilization from the patient, if possible, or from an informant.
 
In some patients, the history tends to be nonspecific and is unreliable in assisting with diagnosis.
Clinicians may need to investigate metabolic causes, such as diabetic ketoacidosis and diabetes mellitus, and other nontraumatic causes, such as congenital defects, viral infection, anesthesia use, physical exertion, and seizure disorder. Inflammatory myopathies of recent and acute onset may manifest as rhabdomyolysis.⁶

Physical

The initial physical examination findings may be nonspecific (especially in pediatric populations).^2,6

Patients may have muscular pain and tenderness, decreased muscle strength, soft tissue swelling, and skin changes consistent with pressure necrosis. The most commonly involved muscle groups in adults include the calves and the lower back. Back, chest, and calf pain often mimics other common conditions such as deep vein thrombosis or angina.

Hyperthermia, hypothermia, and electrical injuries are known to cause rhabdomyolysis and can often be detected upon physical examination. Examine for any crush injuries or deformities in long bones if orthopedic injures after trauma are suspected.

Do not discount the presence of rhabdomyolysis if the patient lacks classic history, physical examination findings, or both. If evolving rhabdomyolysis is suspected based on the clinical scenario, perform an appropriate laboratory evaluation.⁵

Causes

• Trauma and muscle compression^5,8
• Trauma and muscle compression are believed to cause rhabdomyolysis through direct injury to muscle, resulting in disruption of the sarcolemma and direct leakage of cell contents. Occlusion of muscular vessels due to thromboemboli, traumatic injury, or surgical clamping may lead to rhabdomyolysis if muscle tissue ischemia is prolonged. This is the leading cause of rhabdomyolysis in children aged 9-18 years, according to one review.²
• Orthopedic trauma, including compartment syndromes and fractures, may result in rhabdomyolysis. Such trauma commonly occurs in traffic and occupational accidents. Orthopedic injuries in natural disasters (eg, earthquakes) are compounded by immobilization, hypovolemia, and significant rates of rhabdomyolysis.
• Infection
• The most common viruses known to cause rhabdomyolysis are influenza A and influenza B. Researchers believe that the viruses may directly attack the muscle and that muscle-specific toxin may be generated. Viral causes may also include Epstein-Barr virus, parainfluenza, cytomegalovirus, herpes family viruses (including varicella), and human immunodeficiency virus (HIV). Viral myositis appears to be the most common etiology for rhabdomyolysis in children younger than age 9 years.^2,15
• Legionella is the bacterium classically associated with rhabdomyolysis in adult patients. The pathogenesis is believed to be due to direct invasion and toxic degeneration of muscle fibers. Group A beta hemolytic streptococcal infection is another known bacterial cause. Any microbe that causes sepsis and toxic shock may potentiate muscle damage and necrosis. Additional causes of rhabdomyolysis include Salmonella species infection and tularemia (due to Francisella tularensis).⁸
• Rhabdomyolysis-causing infections commonly seen outside the United States include malaria (due to Plasmodium falciparum).
• Metabolic and genetic factors
• Certain genetic muscle defects are believed to cause rhabdomyolysis because of the muscle's inability to appropriately use ATP. Because of inadequate ATP production, the mismatch of energy supply and demand may result in the disruption of cell membranes during exercise. Any inherited condition that impairs energy delivery to muscle may cause rhabdomyolysis. These include glucose, glycogen, fatty acid, or nucleoside metabolism diseases. These disorders often appear in childhood and should be suspected in recurrent cases of myoglobinuria, rhabdomyolysis, or both. Physical exertion and fasting states may exacerbate muscle damage in these disorders.^7,16
• Electrolyte derangement such as hypophosphatemia is believed to cause rhabdomyolysis because of the resulting shortage of phosphate necessary for the production of ATP. Hypokalemia creates a negative potassium balance, which causes rhabdomyolysis. Hypokalemia due to dehydration and exercise may also cause rhabdomyolysis.¹⁷
• Examples of metabolic and genetic deficiencies include glycogen phosphorylase deficiency type V (ie, McArdle disease), phosphofructokinase deficiency, phosphoglycerate mutase deficiency, phosphoglycerate kinase deficiency (PGK), carnitine deficiency, carnitine palmityl transferase deficiency, mitochondrial respiratory chain enzyme deficiencies, and myoadenylate deaminase deficiency. Some of these deficiencies are treatable using dietary modification.^2,8
• Case reports of rhabdomyolysis related to anesthesia in children are believed to be due to underlying muscle disease. Conditions that lead to hyperthermia-related rhabdomyolysis include neuroleptic malignant syndrome and malignant hyperthermia.¹⁸ A pediatric case series described an often fatal, malignant, hyperthermialike syndrome characterized by rhabdomyolysis during initial presentation of diabetes mellitus in adolescent males.¹⁹ Although these cases resembled hyperglycemic hyperosmolar nonketotic syndrome (HHNS), patient courses were marked by rhabdomyolysis and cardiovascular instability. The underlying etiology of this catastrophic presentation of adolescent diabetes mellitus is unclear.
• Drugs and myotoxins⁸
• Ethanol is the prototype of this group and causes metabolic derangement by direct toxic effect and disruption of the muscle blood supply due to immobilization. Ethanol abuse may cause hypophosphatemia and hypokalemia, which are additive causes of rhabdomyolysis. However, any drug that impairs skeletal muscle ATP production or increases energy requirements may cause rhabdomyolysis. Direct drug-induced sarcolemmal injury is often mediated by activation of phospholipase A.
• Patients who overdose on narcotics and sedative hypnotics often have an altered sensorium and remain immobilized for extended periods. They may have pressure necrosis that results in rhabdomyolysis. Cocaine can directly damage muscle tissue by causing vasoconstriction and tissue ischemia. 
• Additional abused drugs implicated in adolescent causes of rhabdomyolysis include ketamine hydrochloride, amphetamines, and 3,4 methylenedioxymethamphetamine (MDMA, also known as ecstasy).^14,13
• Many prescribed medications, including antipsychotics, sedative hypnotics, antilipemic agents, and, rarely, antihistamines in children, have been implicated as rhabdomyolysis triggers. Although tolerated by most patients, statins can cause myositis and, rarely, rhabdomyolysis. Cerivastatin was withdrawn from the market because of its association with rhabdomyolysis-related deaths.^20,21 Statins appear to affect ATP production by impairing the electron transport chain. Statins may also alter the balance between protein repair and degradation by affecting ubiquitin proteosome pathway gene expression.²²
• Other causes 
• Exertional activity may cause rhabdomyolysis in the pediatric population, especially in untrained individuals. Such events often occur under extremely hot or humid conditions and are related to exertional heat stress and heatstroke. Factors that increase the risk of exertional rhabdomyolysis and renal failure in adolescents include dehydration, use of nutritional supplements, drug use, sickle cell trait, and malignant hyperthermia.^12,23,24
• Rhabdomyolysis as a complication of respiratory failure and status asthmaticus has been reported. Whether mechanical ventilation, corticosteroids, or neuromuscular blockade are risk factors in this condition is unclear.²⁵
• Shaken-baby syndrome is reported to have caused rhabdomyolysis.²⁶
• Cold exposure in addition to heatstroke is an environmental cause of rhabdomyolysis. Electrical injury (high-voltage) due to lightning strikes or accidental exposures can cause rhabdomyolysis due to thermal injury and disruption of sarcolemmal membranes.⁵
• Snake or insect envenomation (spider and hornet) are additional causes of rhabdomyolysis. Injection of iron-dextran has been reported as a potential cause.⁸

Differential Diagnoses

Other Problems to Be Considered

Traumatic injuries
Viral infections
Myalgias from other etiologies
Bacterial infections
Pyomyositis
Heatstroke
Cold exposure
Snakebite
Malignant hyperthermia
Muscle phosphorylase deficiency
Phosphofructokinase deficiency
Carnitine palmityl transferase deficiency
Phosphoglycerate mutase deficiency
Other inborn errors of metabolism
Hyperosmotic conditions
Guillain-Barré syndrome
Inflammatory myositis

Workup

Laboratory Studies

• Creatinine kinase (CK) tests
  • The diagnosis of rhabdomyolysis can be confirmed using certain laboratory studies. The most reliable and sensitive indicator of muscle injury is CK. Assessing CK levels is most useful because of its ease of detection in serum and its presence in serum immediately after muscle injury.
  • The CK levels rise within 12 hours of muscle injury, peak in 24-36 hours, and decrease at a rate of 36-40% per day. The serum half-life of CK is approximately 36 hours. CK levels decline 3-5 days after resolution of muscle injury.⁸
  • Failure of CK levels to decrease suggests ongoing muscle injury. The peak CK level, especially when more than 5000 U/L, may be predictive of renal failure.
  • CK levels 5 times the reference range suggest rhabdomyolysis. CK levels in rhabdomyolysis are frequently as much as or more than 100 times the reference range.
• Myoglobin tests⁸
  • Plasma myoglobin measurements are not reliable because the half-life of myoglobin is 1-3 hours and it is cleared from plasma within 6 hours. Myoglobin levels not measured at the right time may produce a false-negative result. A positive test result may help to confirm the diagnosis.
  • Urine myoglobin is presumed if the urine is positive for blood but negative for RBCs. A urine myoglobin assay is helpful in patients with coexisting hematuria (confirmed with microscopic examination) when myoglobin presence is suspected.
• Other tests: CBC count including hemoglobin, hematocrit, and platelets; serum chemistries including BUN, creatinine, glucose, calcium, phosphate, uric acid, and liver function tests; prothrombin time (PT); activated partial thromboplastin time (aPTT); serum aldolase; and lactate dehydrogenase are other useful laboratory tests that should be included. Renal failure and disseminated intravascular coagulation often develop 12-72 hours after initial muscle damage.

Imaging Studies

• Obtain radiographs when fractures are suspected.
• Head CT scanning may be necessary on a case-by-case basis when a patient with an altered sensorium is evaluated.²⁷
  
  
  • Patients with significant head trauma may require head CT scanning.
  • A head CT scan may also be obtained in patients with first-time seizure activity or prolonged seizures or in patients with neurologic deficits of unknown etiology.

Other Tests

• Obtain an ECG initially to evaluate for cardiac dysrhythmias related to hyperkalemia or hypocalcemia.
• Specific disease testing may be indicated to determine definitive etiologies during or after short-term management of rhabdomyolysis.

Procedures

• Measure compartment pressures in patients with suspected compartment syndromes.
• A fasciotomy may be needed if compartment pressures are high.⁵

Histologic Findings

• Histology demonstrates necrotic muscle fibers in patients with rhabdomyolysis.
• A muscle biopsy may be required to demonstrate immunohistochemical features of necrosis only if underlying muscle disease is a concern. Immunoblotting, immunofluorescence, and genetic studies may be necessary to find evidence of inflammatory conditions or dystrophinopathies.⁸

Treatment

Medical Care

• The inciting cause of rhabdomyolysis must be identified and corrected. Expansion of extracellular volume is the cornerstone of treatment. Other supportive measures include correction of electrolyte imbalances.^5,28 Few studies on these treatments in children are available.⁶
  • Aggressive and early hydration with isotonic sodium chloride solution is important for the prevention of pigment-associated renal failure. Initial fluid use in young children has been recommended at 20 mL/kg and 1-2 L/h in adolescents. Subsequent hydration 2-3 times maintenance may be sufficient.^6,29
  • Insert a Foley catheter for careful monitoring of urine output.
  • Alkalinization of urine is believed to be helpful and is based on the observation that acidic urine is necessary to cause acute tubular necrosis (ATN). Some authorities believe that aggressive hydration sufficiently causes a solute diuresis that alkalinizes the urine. Mannitol is often used to induce diuresis in adult patients. Its efficacy has not been compared with that of aggressive hydration regimens.^8,30
  • Sodium bicarbonate is used with care to prevent metabolic acidosis because it may potentiate hypocalcemia. Intravenous bicarbonate concentration is often adjusted to achieve a urine pH level of more than 6.5. This level of alkalinization inhibits precipitation of myoglobin and hemoglobin in the tubules.
• Ferrihemate and globin are the breakdown products of myoglobin when pH levels fall to less than 5.6. Ferrihemate is one of the agents responsible for ATN. It contains iron, a transition element, which is free to accept and donate electrons. This results in the generation of free radicals, which cause direct renal cell injury. Heme-proteins may also affect nitrous oxide (NO), endothelin receptors, and cytokines.⁸
• Frequently monitor serum electrolyte levels, urine pH levels, and acid-base status (eg, every 2 h). Metabolic abnormalities should also be addressed. 
  • Treat hyperkalemia by administering insulin and glucose, a nebulized beta agonist, and a potassium exchange resin such as Kayexalate. These measures transiently shift potassium from extracellular to intracellular compartments.^6,27
  • Correct hypocalcemia only if the patient has cardiac dysrhythmias or seizures. Calcium may combine with phosphate, forming a metastatic calcification, often intramuscularly. Control hyperphosphatemia using alkaline diuresis. Hypercalcemia may develop during the recovery phase.
• If urine output is adequate, consider the use of diuretics such as mannitol (in adults) and furosemide. Mannitol, acting as an osmotic diuretic, is thought to increase urinary flow and reduce myoglobin cast obstruction in renal tubules.⁵
• Dialysis may be required in patients with oliguric renal failure, persistent hyperkalemia, other electrolyte abnormalities, pulmonary edema, congestive heart failure, and persistent metabolic acidosis.
• The role of free-radical scavengers and antioxidants in rhabdomyolysis has been studied in animal models of ischemia-reperfusion injuries. Their clinical uses remain unclear.⁸

Surgical Care

• Surgical care may be necessary, depending on the cause of rhabdomyolysis.⁵
• Measure compartment pressures and perform a fasciotomy if pressures are high (>30 mm Hg).
• Limb fractures may require surgical and orthopedic treatment.³¹

Consultations

• Consult a nephrologist for patients who have significant rhabdomyolysis, show evidence of renal failure, or require dialysis.
• Consult a neurologist for patients with status epilepticus or newly onset seizures.
• Consult an orthopedic surgeon for patients with a limb fracture or compartment syndrome.
• Notify the poison control center in cases of overdose or snake envenomation.
• Consult a rheumatologist for patients with suspected inflammatory myopathies, systemic lupus erythematosus, or sarcoidosis.
• Consult a geneticist and metabolism specialist for patients with genetic or metabolic abnormalities. Diagnosis of inborn errors of metabolism and prompt metabolic interventions may be life saving.

Diet

• Dietary modification may help to reduce the symptoms associated with some of the metabolic disorders and inborn errors of metabolism.⁷
• Dietary supplementation with glucose or fructose may decrease the pain and fatigue associated with phosphorylase deficiency.
• The muscle pain and myoglobinuria due to carnitine palmityl transferase deficiency may be reduced with frequent meals and a low-fat, high-carbohydrate diet. Substitution of medium-chained triglycerides may also be helpful.
• Dietary modification does not seem to change the muscle symptoms of phosphofructokinase deficiency or phosphoglycerate mutase deficiency.

Activity

• Strenuous activities (eg, competitive sports) should be avoided if they cause recurrent myalgias, myopathy, or rhabdomyolysis.⁷
• Alcohol abuse should be stopped.
• Use of narcotics and sedative hypnotics should be avoided, and inciting prescribed medications must be stopped.
• High-school coaches and trainers must ensure proper hydration and maintain fluid balance during practice sessions and games. Signs and symptoms of heat exhaustion must be evaluated in a timely fashion during hot and humid conditions.¹²

Medication

Hydration with isotonic sodium chloride solution (0.9% NaCl) is the cornerstone of therapy. Many clinicians recommend the use of sodium bicarbonate. Use furosemide or other diuretics (such as mannitol in adults) with sufficient hydration if urine output is inadequate. Hyperkalemia should also be addressed.

Diuretic agents

Diuretics promote the excretion of water and electrolytes by the kidneys.

Furosemide (Lasix)

Increases water excretion by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule.

Dosing

Adult

20-80 mg/d PO in divided doses q6-12h

Pediatric

1-2 mg/kg/d PO in divided doses q6-12h; not to exceed 10 mg/kg/d

Interactions

Metformin decreases concentrations; furosemide interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; coadministration with aminoglycosides may increase auditory toxicity; varying degrees of hearing loss may occur; may enhance anticoagulant activity of warfarin; may increase plasma lithium levels and toxicity

Contraindications

Documented hypersensitivity; hepatic coma; anuria; severe electrolyte depletion

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Excessive diuresis may cause dehydration and blood volume reduction with circulatory collapse; increased blood glucose levels may be observed, and precipitation of diabetes mellitus has been reported (rarely); asymptomatic hyperuricemia can occur, and gout may be precipitated (rarely); patients with sulfonamide allergy may exhibit cross-allergenicity; exacerbation of systemic lupus erythematosus is possible

Intracellular potassium transporters

These are used to decrease serum potassium levels. Insulin and glucose cause a transcellular shift of potassium into muscle cells, thereby temporarily lowering serum levels of potassium.

Insulin (Humulin) and dextrose, intravenous

Stimulates cellular potassium uptake within 20-30 min. Administer with dextrose to prevent hypoglycemia. Monitor blood sugar levels frequently.

Dosing

Adult

10 U IV with 50 mL dextrose 50% IV bolus or 500 mL dextrose 10% infused IV over 1 h

Pediatric

0.1 U/kg IV with 0.5 g/kg (2 mL/kg) dextrose 25% IV infused over 30 min

Interactions

Medications that may decrease hypoglycemic effects include acetazolamide, AIDS antivirals, asparaginase, phenytoin, nicotine isoniazid, diltiazem, diuretics, corticosteroids, thiazide diuretics, thyroid estrogens, ethacrynic acid, calcitonin, oral contraceptives, diazoxide, dobutamine, phenothiazines, cyclophosphamide, dextrothyroxine, lithium carbonate, epinephrine, morphine sulfate, and niacin
Medications that may increase hypoglycemic effects include calcium, ACE inhibitors, alcohol, tetracyclines, beta blockers, lithium carbonate, anabolic steroids, pyridoxine, salicylates, MAOIs, mebendazole, sulfonamides, phenylbutazone, chloroquine, clofibrate, fenfluramine, guanethidine, octreotide, pentamidine, and sulfinpyrazone

Contraindications

Documented hypersensitivity; hypoglycemia

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Hyperthyroidism may increase renal clearance of insulin and may require increased dose to treat hyperkalemia; hypothyroidism may delay turnover and may require decreased dose to treat hyperkalemia; monitor glucose carefully; dose adjustments of insulin may be necessary in renal and hepatic dysfunction

Beta2- adrenergic agonists

These agents are used adjunctively to temporarily decrease serum potassium levels. Albuterol and other beta-adrenergic agents induce the intracellular movement of potassium via stimulation of the Na/K-ATPase pump. Some studies in adults and children using nebulized albuterol indicate that this method of therapy is effective in lowering serum potassium levels, but peak response is unclear. Therefore, nebulized albuterol has not been established as a first-line therapy in severe hyperkalemia.

Albuterol nebulized (Proventil, Ventolin)

Adrenergic agonist that increases plasma insulin concentrations. Increase in insulin may shift potassium into intracellular space. Onset of decreased potassium is 30 min. Duration is dose dependent and typically lasts 2-5 h.

Dosing

Adult

2.5 mg in 3 mL 0.9% NaCl inhaled via nebulizer; higher adult doses have also been used (ie, 10-20 mg) in various clinical trials

Pediatric

Note: Albuterol for nebulization is diluted in 0.9% NaCl before inhalation
Infants: 0.05-0.15 mg/kg/d
1-5 years: 1.25-2.5 mg/d
5-12 years: 2.5 mg/d
>12 years: 2.5-5 mg/d

Interactions

Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilatation; cardiovascular effects may increase with MAOIs, inhaled anesthetics, tricyclic antidepressants, and sympathomimetic agents

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in cardiovascular disease, convulsive disorders, and unusual unresponsiveness to sympathomimetic amine
High doses may inhibit uterine contraction (unlikely with the nebulized dosage); resistance to lower potassium in ESRD is common

Potassium exchange resin

Potassium exchange resins decrease serum potassium levels. Sodium polystyrene sulfonate is an exchange resin that can be used to treat mild-to-moderate hyperkalemia. Each mEq of potassium is exchanged for 1 mEq of sodium.

Sodium polystyrene sulfonate (Kayexalate)

Exchanges sodium for potassium and binds it in the gut, primarily large intestine. Decreases total-body potassium levels. Onset of action after PO administration ranges from 2-12 h and is longer when administered rectally.
Do not use as first-line therapy for severe life-threatening hyperkalemia. May use in the second stage of therapy to reduce total-body potassium levels. Resin typically mixed in 25% sorbitol before administration.

Dosing

Adult

1 g/kg/dose, up to 15 g PO or 30-50 g as a retention enema

Pediatric

Exchange ratio is 1 mEq K per 1 g resin
Calculate dosage according to desired exchange
Usual dose: 1 g/kg/dose PO/PR

Interactions

Coadministration with nonabsorbable cation-donating antacids and laxatives may reduce resin potassium exchange capability and increases serum carbon dioxide levels, leading to metabolic alkalosis; intestinal obstruction reported when coadministered with aluminium hydroxide; toxic effects of digitalis exaggerated with hypokalemia

Contraindications

Documented hypersensitivity; hyperkalemia and hypernatremia; PO administration in bowel obstruction; rectal manipulation in patients with bleeding tendency (eg, neutropenia, thrombocytopenia)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in patients who cannot tolerate even a small increase in sodium load; administer with sorbitol to prevent constipation

Follow-up

Further Inpatient Care

• In general, patients with rhabdomyolysis should be admitted for observation and correction of fluid and electrolyte imbalances.
• Provide patients with adequate hydration and record urine output. Assess for development of acute renal failure and need for dialysis.
• Monitor cardiac function and check and correct electrolyte levels, as indicated.
• Monitor creatine kinase (CK) levels to show resolution of rhabdomyolysis.

Further Outpatient Care

• Once well-hydrated, patients with normal renal function, normal electrolyte levels, alkaline urine, and an isolated cause of muscle injury may be discharged and monitored as outpatients.

Inpatient & Outpatient Medications

• Adequate hydration is required, and no specific outpatient medications are needed. Inciting myotoxic agents should be stopped.

Transfer

• The patient should be initially stabilized, and life-threatening electrolyte abnormalities should be corrected. Once stabilized, the patient may be transferred if the hospital is not equipped to provide the critical care monitoring and specialized orthopedic procedures.
• In natural disasters, patients often have to be evacuated out of affected areas and transported to locations that can provide dialysis services.⁵

Deterrence/Prevention

• Once identified, the patient must avoid any preventable inciting cause of rhabdomyolysis. 
• Exercise should be reduced or avoided if this is the cause or exacerbating factor of rhabdomyolysis.
• Alcohol should be avoided.
• Overdose of drugs such as narcotics, sedative hypnotics, or any other drug known to cause immobilization and, hence, pressure necrosis should be avoided. Proper mental health and drug rehabilitation services should be offered to individuals with substance use disorders.
• Use of stimulants (eg, cocaine, amphetamines, ecstasy) should be discouraged.
• Compliance with seizure and asthma medications may reduce status epilepticus, status asthmaticus, or both.
• Risky behavior that results in trauma should be avoided.

Complications

• Electrolyte abnormalities are prominent features of rhabdomyolysis. Hyperphosphatemia, hyperkalemia, hypocalcemia, hyperuricemia, and hypoalbuminemia have been reported.
• Compartment syndrome may be a complication of or the inciting cause of rhabdomyolysis. Measure compartment pressures if muscle injury has occurred and perform a fasciotomy if the pressure is more than 30 mm Hg.⁵
• Acute renal failure and disseminated intravascular coagulation are the most severe complications of rhabdomyolysis.
  
  
  • If rhabdomyolysis is not adequately treated, approximately one-third of adult patients develop renal failure. This figure may be significantly lower in children.²
  • Renal failure may also develop in patients treated with optimal measures.
  • If renal failure and electrolyte abnormalities are not addressed, death can occur from causes such as cardiac arrhythmias (and hyperkalemic cardiac arrest) and seizures.

Prognosis

• Implementation of the treatment modalities above (see Treatment) has reduced morbidity and mortality. In a 10-year retrospective pediatric review, only 13 of 191 (6%) of patients died. Nine of these patients presented in cardiopulmonary arrest and could not be resuscitated.²
• Rapid intervention and appropriate supportive therapies of rhabdomyolysis-related renal failure improve outcomes in traumatic crush injuries. The ability of medical response teams to provide aggressive hydration and dialysis services enhances survival in large-scale natural disasters such as earthquakes. If treatment modalities are implemented early, many patients completely recover.

Patient Education

• Educate patients about the causes of rhabdomyolysis and its prevention.
• Provide genetic counseling for families with inherited muscle enzyme and energy substrate deficiencies.
• Educate high-school and college athletes about proper hydration and signs of dehydration and heat-related injuries.

Miscellaneous

Medicolegal Pitfalls

• Patients may present without any obvious history or physical sign of rhabdomyolysis. The physician must be aware of the subtle presentation and keep the diagnosis in mind. Failure to consider this diagnosis could result in the most severe complication of rhabdomyolysis, pigment-associated renal failure.
• Rhabdomyolysis accounts for 5-25% of cases of renal failure in adult patients. Rates in pediatric patients are unknown.

Special Concerns

• Consider rhabdomyolysis in cases of child abuse, drug-overdoses, heat-related events and pediatric orthopedic injuries.

References

1. Beetham R. Biochemical investigation of suspected rhabdomyolysis. Ann Clin Biochem. 2000;37:581-587. [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. Gabow PA, Kaehny WD, Kelleher SP. The spectrum of rhabdomyolysis. Medicine (Baltimore). May 1982;61(3):141-52. [Medline].

4. Watemberg N, Leshner RL, Armstrong BA, Lerman-Sagie T. Acute pediatric rhabdomyolysis. J Child Neurol. Apr 2000;15(4):222-7. [Medline].

5. Vanholder R, Sever MS, Erek E, Lameire N. Rhabdomyolysis. J Am Soc Nephrol. Aug 2000;11(8):1553-61. [Medline]. [Full Text].

6. Luck RP, Verbin S. Rhabdomyolysis review of clinical presentation, etiology, diagnosis and management. Pediatr Emerg Care. 2008;24:262-8. [Medline].

7. Brumback RA, Feeback DL, Leech RW. Rhabdomyolysis in childhood. A primer on normal muscle function and selected metabolic myopathies characterized by disordered energy production. Pediatr Clin North Am. Aug 1992;39(4):821-58. [Medline].

8. Huerta-Alardín AL, Varon J, Marik PE. Bench-to-bedside review: Rhabdomyolysis -- an overview for clinicians. Crit Care. Apr 2005;9(2):158-69. [Medline]. [Full Text].

9. Paller MS. Hemoglobin- and myoglobin-induced acute renal failure in rats: role of iron in nephrotoxicity. Am J Physiol. Sep 1988;255(3 Pt 2):F539-44. [Medline].

10. Melli G, Chaudhry V, Cornblath DR. Rhabdomyolysis: An Evaluation of 475 Hospitalized Patients. Medicine. 2005;84 (6):377-385. [Medline].

11. Chamberlain MC. Rhabdomyolysis in children: a 3-year retrospective study. Pediatr Neurol. May-Jun 1991;7(3):226-8. [Medline].

12. Bergeron MF, McKeag DB, Casa DJ, et al. Youth Football: Heat Stress and Injury Risk. Med Sci Sports Exerc. 2005;37 (8):1421-1430. [Medline].

13. Hall AP, Henry JA. Acute toxic effects of 'Ecstasy' (MDMA) and related compounds: overview of pathophysiology and clinical management. Br J Anaesth. Jun 2006;96(6):678-85. [Medline].

14. Coco TJ, Klasner AE. Drug-induced rhabdomyolysis. Curr Opin Pediatr. Apr 2004;16(2):206-10. [Medline].

15. Singh U, Scheld WM. Infectious etiologies of rhabdomyolysis: three case reports and review. Clin Infect Dis. Apr 1996;22(4):642-9. [Medline].

16. Lofberg M, Jankala H, Paetau A, et al. Metabolic causes of recurrent rhabdomyolysis. Acta Neurol Scand. Oct 1998;98(4):268-75. [Medline].

17. Knochel JP. Hypophosphatemia and rhabdomyolysis. Am J Med. May 1992;92(5):455-7. [Medline].

18. Pedrozzi NE, Ramelli GP, Tomasetti R, et al. Rhabdomyolysis and anesthesia: a report of two cases and review of the literature. Pediatr Neurol. Oct 1996;15(3):254-7. [Medline].

19. Hollander AS, Olney RC, Blackett PR, Marshall BA. Fatal malignant hyperthermia-like syndrome with rhabdomyolysis complicating the presentation of diabetes mellitus in adolescent males. Pediatrics. 2003;111:1447-1452. [Medline]. [Full Text].

20. Graham DJ, Staffa JA, Shatin D et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid lowering-drugs. JAMA. 2004;292:2585-2590. [Medline].

21. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA. Apr 2 2003;289(13):1681-90. [Medline].

22. Urso ML, Clarkson PM, Hittel D, Hoffman EP, Thompson PD. Changes in ubiquitin proteasome pathway gene expression in skeletal muscle with exercise and statins. Arterioscler Thromb Vasc Biol. Dec 2005;25(12):2560-6. [Medline]. [Full Text].

23. Hurley JK. Severe rhabdomyolysis in well conditioned athletes. Mil Med. May 1989;154(5):244-5. [Medline].

24. Sinert R, Kohl L, Rainone T, Scalea T. Exercise-induced rhabdomyolysis. Ann Emerg Med. Jun 1994;23(6):1301-6. [Medline].

25. Mehta R, Fisher LE Jr, Segeleon JE, Pearson-Shaver AL, and Wheeler DS. Acute rhabdomyolysis complicating status asthmaticus in children: case series and review. Pediatr Emerg Care. 2006;22:587-91. [Medline].

26. Schwengel D, Ludwig S. Rhabdomyolysis and myoglobinuria as manifestations of child abuse. Pediatr Emerg Care. Dec 1985;1(4):194-7. [Medline].

27. Salluzzo R, Schwartz M, ed. Rhabdomyolysis. In: Emergency Clinical Practice. 4^th ed. 1998:2478-86.

28. Better OS, Stein JH. Early management of shock and prophylaxis of acute renal failure in traumatic rhabdomyolysis. N Engl J Med. Mar 22 1990;322(12):825-9. [Medline].

29. Gunn VL, Nechyba C, eds. The Harriet Lane Handbook. 16^th ed. St Louis, MO: Mosby Elsevier, Inc.; 2002:45.

30. Brown C, Rhee P, Chan L et al. Preventing renal failure in patients with rhabdomyolysis: do bicarbonate and mannitol make a difference?. J Trauma. 2004;56:1191-1196. [Medline].

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Keywords

rhabdomyolysis, muscle weakness, myalgia, dark urine, myoglobinuria, sarcolemma, acute renal failure, myoglobin-induced acute renal failure, nephrotoxicity, malignant hyperthermia, crush injury, disseminated intravascular coagulation, cellular membrane injury, muscle cell hypoxia, ATP depletion, myoglobin-induced acute renal failure, hyperphosphatemia, hyperkalemia, hypocalcemia, hyperuricemia, hypoalbuminemia, viral myositis, renal insufficiency, diabetic ketoacidosis, compartment syndromes, Epstein-Barr virus, parainfluenza, cytomegalovirus, herpes family viruses varicella, human immunodeficiency virus, HIV, tularemia, Legionella infection, Salmonella species, neuroleptic malignant syndrome, hyperglycemic hyperosmolar nonketotic syndrome, cocaine, respiratory failure, status asthmaticus

Contributor Information and Disclosures

Author

Eyal Muscal, MD, Assistant Professor, Section of Pediatric Rheumatology, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital
Eyal Muscal, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Rheumatology, and Clinical Immunology Society
Disclosure: Nothing to disclose.

Coauthor(s)

Marietta Morales de Guzman, MD, Assistant Professor, Department of Pediatrics, Baylor College of Medicine; Consulting Staff, Section of Pediatric Rheumatology, Department of Pediatrics, Texas Children's Hospital, Ben Taub General Hospital
Marietta Morales de Guzman, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Rheumatology, and Texas Pediatric Society
Disclosure: Nothing to disclose.

Renee Wilson, MD, Clinical Assistant Instructor, Department of Emergency Medicine, SUNY-Downstate and Kings County Hospital
Renee Wilson, MD is a member of the following medical societies: Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Binita R Shah, MD, FAAP, Professor of Clinical Pediatrics and Emergency Medicine, SUNY Health Science Center at Brooklyn, Director of Pediatric Emergency Medicine, Depts of Emergency Medicine and Pediatrics, Kings County Hospital Center
Binita R Shah, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics
Disclosure: Nothing to disclose.

Medical Editor

Barry L Myones, MD, Associate Professor, Departments of Pediatrics and Immunology, Pediatric Rheumatology Section, Baylor College of Medicine; Director of Research, Pediatric Rheumatology Center, Texas Children's Hospital
Barry L Myones, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American College of Rheumatology, American Heart Association, American Society for Microbiology, Clinical Immunology Society, and Texas Medical Association
Disclosure: Nothing to disclose.

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Managing Editor

David D Sherry, MD, Director, Clinical Rheumatology, Attending Physician, Pain Management, The Children's Hospital of Philadelphia; Professor of Pediatrics, University of Pennsylvania
David D Sherry, MD is a member of the following medical societies: American College of Rheumatology and American Pain Society
Disclosure: Nothing to disclose.

CME Editor

Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine
Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine
Disclosure: Baxter Honoraria Consulting; Pfizer Honoraria Consulting

Chief Editor

Herbert S Diamond, MD, Professor of Medicine, Temple University School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital
Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, and Phi Beta Kappa
Disclosure: medifocus Honoraria Review panel membership; health dialogs Honoraria Consulting; Merck, Amgen, Biogen, Zimmer, Wyeth, Johnson&Johnson, Stryker, Medtronic, Zimmer.Abbott,  Ownership interest Other; West Penn Allegheny Health System Consulting fee Consulting; Alpharma Honoraria Consulting; Proctor&Gamble Grant/research funds Independent contractor

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