eMedicine Specialties > Pediatrics: General Medicine > Rheumatology

Rhabdomyolysis

Author: Eyal Muscal, MD, Assistant Professor, Section of Pediatric Rheumatology, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital
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; 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
Contributor Information and Disclosures

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

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