Pediatric Rhabdomyolysis 

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;^[3] however, all 3 symptoms are rarely seen together in many children with this condition.^{[4, 5]} 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.^[6]

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] Recurrent episodes of rhabdomyolysis may indicate underlying defects of muscle structure or metabolism.^[7]

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.^[8]

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.^[9] 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. The action of phospholipases in insect and snake venom may cause hemolysis, muscle damage, endothelial necrosis, rhabdomyolysis, and acute renal injury.^[10] Additionally, muscle damage is amplified by infiltration of activated neutrophils. An inflammatory cascade and reperfusion injury sustains muscle damage and degeneration.^{[11, 8]}

Myoglobin is an important myocyte compound released into plasma (see image below). 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 (ischemia and tubular injury), intrarenal vasoconstriction, and acute renal failure.^{[6, 12, 7]}

Frequency

United States

Rhabdomyolysis is a common condition in adult populations and is understudied in pediatrics.^{[13, 2]} The National Hospital Discharge Survey reports 26,000 cases annually.^[13] 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.^[13] 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.^{[14, 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.^[6]

Mortality/Morbidity

Electrolyte abnormalities are prominent features of rhabdomyolysis. Hyperphosphatemia, hyperkalemia, hypocalcemia, hyperuricemia, and hypoalbuminemia have been described.^{[1, 11]}

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.^[6]

Acute renal failure is the most severe complication of rhabdomyolysis and may account for as many as 25% of adult cases of renal failure and 7-10% of acute kidney injuries in the United States.^{[13, 7]}

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.^{[13, 2]} Mechanisms of renal failure are multifactorial and may include renal vasoconstriction, intraluminal myoglobin cast formation, and heme-protein cellular toxicity. Myoglobin and hemoglobin toxic effect on the glomerulus are enhanced by 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.^[11]

Renal vasoconstriction and ischemia deplete tubular ATP formation and enhance tubular cell damage. Myoglobin precipitation in renal tubules causes formation of obstructive casts. Acute kidney injury rarely occurs in patients with chronic myopathies unless triggered by a second inciting event.^[7] Risk of renal injury is low when initial CK levels are less than 15,000-20,000 U/L. Lower CK levels may lead to renal injury in patients with sepsis, dehydration, and/or acidosis.^[7] GI 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.