Direct Muscle Injury

Traumatic rhabdomyolysis is primarily the result of motor vehicle crashes, occupational injuries, or environmental tragedy (i.e., mine collapse, earthquakes, war). Muscle compression may also occur during torture and abuse, long-term confinement in the same position (as with orthopedic injuries or during restraint of psychiatric patients), prolonged surgical interventions with improper positioning (high lithotomy or lateral decubitus position), and coma. Compression causes muscle ischemia as tissue pressure exceeds capillary perfusion pressure. Additionally, direct mechanical injury to the sarcolemma causes an incipient rise in intracellular calcium. Calcium activates destructive enzymes within the cell that facilitate necrosis and death of the myocyte.

Infection

Bacterial, viral, parasitic, and rickettsial infections have been associated with rhabdomyolysis. The most common viral cause is influenza. Viruses cause rhabdomyolysis both by direct muscle invasion and by endotoxins and exotoxins that are responsible for skeletal muscle injury and subsequent release of myoglobin. Legionella is the most common bacterial cause, with its myotoxic effects mediated through an endotoxin. Salmonella and Streptococcus also induce rhabdomyolysis through direct myocyte invasion and inhibition of glycolytic enzymes.

Excessive Muscle Contraction

Strenuous exercise by both trained and untrained athletes can cause rhabdomyolysis. The degree of muscle injury is related to the duration and intensity of the exercise, and damage is frequently confined to the lower extremities. Muscle injury is exacerbated by hot, humid conditions; lack of heat acclimatization; prolonged, profuse sweating; and insufficient intake of salt. Patients at increased risk include athletes, marathon runners, new military recruits (“march myoglobinuria”), outdoor workers, and persons unaccustomed to strenuous exercise (“white collar rhabdomyolysis”).

Pathologic causes of excessive muscle activity such as status epilepticus, myoclonus, dystonia, tetanus, chorea, and mania also lead to rhabdomyolysis. Additionally, patients suffering from a multitude of intoxications, including isoniazid, strychnine, amoxapine, loxapine, theophylline, water hemlock, and lithium, may experience excessive motor activity and seizures producing rhabdomyolysis.

Excessive muscle activity causes rhabdomyolysis through dehydration, increased activity of heat-sensitive degradative enzymes, and depletion of cellular energy (ATP) with prolonged exercise. These insults lead to failure of the sarcolemmal sodium-potassium adenosine triphosphatase (Na⁺,K⁺-ATPase) and Ca²⁺ pumps, which results in increased intracellular calcium and cell necrosis.

Medications

Drugs in almost every category have been implicated as a cause of rhabdomyolysis. The medications of most concern are the lipid-lowering agents, including 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors (lovastatin, simvastatin) and fibric acid derivates that decrease triglyceride synthesis (gemfibrozil and clofibrate). HMG-CoA reductase inhibitors block the production of coenzyme Q, which plays an important role in the production of ATP in mitochondria. The resultant decrease in ATP production leads to cell death and subsequent rhabdomyolysis. Patients with preexisting renal dysfunction are at increased risk.

Immediate withdrawal of these drugs is mandatory if patients complain of muscle dysfunction or if their CK level rises to more than three times normal. The risk for drug-induced muscle disease is aggravated by the simultaneous administration of danazol, nicotinic acid, cyclosporine, itraconazole, or erythromycin. The combination of HMG-CoA reductase inhibitors with gemfibrozil also carries a high rate of myotoxicity.

Drugs of Abuse

Substance abuse is one of the most common causes of rhabdomyolysis, largely because of the high incidence of ethanol abuse and its direct toxicity to the myocyte membrane. Other drugs of abuse implicated in cases of rhabdomyolysis include cocaine, heroin, methamphetamine, phencyclidine hydrochloride (PCP), lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA; “ecstasy”), benzodiazepines, and barbiturates. Most abused drugs cause muscle damage through direct toxic effects or immunologic reactions to the contaminants found mixed with the drug. Cocaine is also toxic to the sarcolemma and induces vasospasm resulting in ischemia. Cocaine increases energy demands of the cell that outstrip energy production.

Besides its direct toxicity, ethanol has multiple additional mechanisms by which it causes muscle damage. Its sedative and hypnotic properties may cause prolonged immobilization of a body part, with external compression of its blood supply leading to ischemia. Rhabdomyolysis can be induced by excessive motor activity when associated with alcohol-related seizures and delirium tremens. Poor nutrition inhibits the rate of ethanol metabolism, and the resultant higher blood ethanol concentration at the cell membrane for prolonged periods leads to increased sarcolemmal damage.

Toxins

Toxins that cause direct myocyte damage include venom from the European adder, the Australian tiger snake, the Australian king brown snake, the death adder, and North and South American rattlesnakes. These snakes deploy a single venom with multiple myocyte toxins that cause direct muscle injury and rhabdomyolysis. Stings from Africanized bees (killer bees) and honeybees mediate rhabdomyolysis through myotoxins. Quail fed hellebores or hemlock have also been associated with outbreaks of rhabdomyolysis (coturnism). Outbreaks of Haff disease occur intermittently in the United States as a result of contaminated fish.

Toxins that act at the molecular level by interfering with the production of ATP are capable of producing damage to skeletal muscle. Carbon monoxide, cyanide, hydrogen sulfide, and phosphine inhibit electron transport in mitochondria; salicylates and chlorphenoxy herbicides uncouple oxidative phosphorylation; and iodoacetate and sodium fluoroacetate inhibit glycolysis in the Krebs cycle.

Genetic Disorders

Rhabdomyolysis can result from genetic defects in glycolysis, glycogenolysis, fatty acid oxidation, and mitochondrial function. These disorders cause inappropriate use of carbohydrate and lipids, which leads to an imbalance between energy supply and demand in myocytes.

Genetic defects should be suspected in patients in whom the cause of rhabdomyolysis is obscure. Symptoms often begin before the age of 20 years, and attacks occur intermittently. Examples include recurrent rhabdomyolysis after minimum to moderate exercise, after viral infections starting in childhood, or in patients with a family history of rhabdomyolysis. In glycogenolytic disorders, the mode of inheritance is usually autosomal dominant; phosphoglycerate kinase deficiency is X-linked.

Diagnosis of an inherited muscle enzyme defect is based on muscle biopsy findings demonstrating abnormally increased glycogen or lipid deposits, as well as histochemical staining demonstrating a decrease or absence of specific enzymes.

Creatine Kinase

CK is the enzyme responsible for reversible transfer of the terminal phosphate group of ATP to creatine to form phosphocreatine. Serum CK begins to rise 2 to 12 hours after the destruction of more than 200 g of muscle, with the peak level occurring between 1 and 3 days. Levels decline within 3 to 5 days after the muscle injury ceases. Serum CK levels remain elevated longer than those of myoglobin because of relatively slow plasma clearance (serum t_1/2 = 1.5 days). CK decreases at a steady rate of 39% per day. Rhabdomyolysis is suspected at minimum thresholds for CK of between 1000 and 10,000 U/L.

A rise in serum CK follows the rise in serum myoglobin. Three isoenzymes of CK exist in human tissues: MM, MB, and BB. The predominant source of the CK-MM isoenzyme is skeletal and cardiac muscle; CK-BB is found in brain tissue and CK-MB mainly in cardiac muscle. In rhabdomyolysis, the primary CK isoenzyme elevated is CK-MM. Creatine phosphokinase is a serum marker of CK-MM reported by many clinical laboratories.

Myoglobin

Myoglobin is a small protein with a free circulating concentration that is very low under normal physiologic conditions. Myoglobin functions as an oxygen reservoir in muscles; serum myoglobin levels rise within 1 hour of skeletal muscle damage. Myoglobin levels become normal within 1 to 6 hours after the cessation of muscle injury because of rapid clearing both by renal excretion and by metabolism to bilirubin.

When myoglobin levels reach 15 mg/L, it can be detected by urine dipstick, and at 1 g/L it may cause the color of urine to appear dark, like cola. Myoglobinuria does not always result in dark urine, however; discoloration depends on (1) the amount of myoglobin released from muscle into plasma, (2) the glomerular filtration rate, and (3) the urine concentration.

Urinalysis

The urine dipstick is a commonly used screening test for rhabdomyolysis. The orthotoluidine test on the urine dipstick will react in the presence of either myoglobin or hemoglobin. A report of “large blood” on the urine dipstick and absence of red blood cells on microscopy classically suggests the presence of free myoglobin in urine. Figure 169.1 shows the typical urine appearance in the setting of myoglobinuria. Unfortunately, clinical data do not fully support this screening practice, with microscopic hematuria occurring in about 30% of patients with rhabdomyolysis. In addition, myoglobinuria may be transient and not identified at the time of urinalysis despite the presence of significant clinical rhabdomyolysis. Dipstick testing will detect a urine myoglobin level higher than 1.0 mg/dL, which correlates with a serum value of approximately 100 mg/dL.

Fig. 169.1 Myoglobinuria.

The dipstick is strongly positive for blood, with no red blood cells seen on microscopy.

(From Roberts JR, Hedges JR. Clinical procedures in emergency medicine. 5th ed. Copyright 2009 Saunders, an imprint of Elsevier.)

Other common findings on urinalysis include the presence of tubular casts, proteinuria, and evidence of acute tubular necrosis.

Renal Function Tests

Though not consistently observed in all analyses, creatinine has at times been shown to rise faster with rhabdomyolysis than with other causes of acute renal failure. Markedly high creatinine levels or a relatively low ratio of blood urea nitrogen to creatinine should raise suspicion for rhabdomyolysis (Box 169.3).

Acute Kidney Injury

Acute kidney injury is the most important cause of morbidity in patients with rhabdomyolysis. Rhabdomyolysis induces acute kidney injury by three main pathophysiologic mechanisms. First, the heme protein in myoglobin exerts direct toxicity on renal tubular cells by initiating lipid peroxidation. This toxicity is potentiated by an acidic urine. Second, myoglobin precipitates in the renal tubules and causes intraluminal cast formation and tubular obstruction. Degradation of intratubular myoglobin results in the release of unbound iron, which catalyzes free radical production and further enhances the ischemic damage. Third, renal vasoconstriction is promoted by platelet-activating factor and endothelin.

Acute kidney injury caused by rhabdomyolysis may be oliguric (most common), nonoliguric, or occasionally anuric. It typically results in a higher anion gap acidosis and higher uric acid levels and often leads to a more rapid increase in serum creatinine than do other forms of acute kidney injury. Fractional excretion of sodium is often less than 1%, in contrast to other forms of acute tubular necrosis. It is difficult to predict the patients in whom acute kidney injury will develop based on laboratory values at initial evaluation.³

Metabolic and Electrolyte Derangements

Hyperkalemia occurs in 10% to 40% of patients with rhabdomyolysis. It is the most serious electrolyte derangement observed with rhabdomyolysis because of its potential lethal effect on cardiac rhythm and function. More than 15 mmol of potassium is released with necrosis of only 150 g of muscle and results in an acute 1.0-mmol/L increase in extracellular potassium. The degree of increase is further dependent on renal function, which is often concurrently impaired.

Hypocalcemia is the most common metabolic complication of rhabdomyolysis; low calcium levels are present early and are usually asymptomatic. Hypocalcemia results from deposition of calcium salts in necrotic muscle secondary to hypophosphatemia and decreased 1,25-dihydroxycholecalciferol. Soft tissue calcifications can be seen on radiographs of the involved limbs. Hypocalcemia should be treated only if severe symptoms or hyperkalemia develops and leads to cardiac arrhythmias, muscular contraction, and seizures. Later, as calcium is mobilized from tissues, serum calcium levels rise and symptomatic hypercalcemia may develop. Hypercalcemia usually occurs in patients with acute renal failure during the diuretic phase, typically when urinary output is greater than 1500 mL/24 hr. Hypercalcemia also occurs more frequently if Ca²⁺ is supplemented in the hypocalcemic stage. Volume expansion alone is usually adequate treatment, but diuretics may be needed.

Hyperphosphatemia is caused by leakage of phosphate from injured myocytes and is higher in azotemic patients. Phosphate binders should be used when phosphate levels exceed 7 mg/dL. Hypophosphatemia may be seen later in the disease course but rarely requires treatment. Hypermagnesemia may occur in patients with renal insufficiency. Standard management is appropriate. Hyperuricemia is especially common in crush injury as a result of the release of muscle adenosine nucleotides, which are subsequently converted to uric acid in the liver. Uric acid levels typically correlate with serum CK levels.

Organic acids, especially lactic acid, are released from hypoxic, necrotic muscle cells and produce a pronounced anion gap acidosis.

Compartment Syndrome

Most striated muscles are contained within rigid compartments formed by fascia and bones. When the muscle is traumatized, marked swelling and edema occur within a closed osteofascial compartment, and muscle perfusion is reduced to a level below that required for cellular viability. As intracompartmental pressure rises above 30 to 35 mm Hg, compartment syndrome develops and significant muscle ischemia ensues and requires decompressive fasciotomy. Figure 169.2 shows an example of compartment syndrome.

Fig. 169.2 Compartment syndrome.

This man was in coma from a heroin overdose and had been lying on his arm for a number of hours. He was hypotensive, in renal failure, comatose, and on a ventilator. The entire arm was swollen and rhabdomyolysis was suspected correctly. Because of the coma, he was unable to voice any complaint of pain. When he awakened 20 hours later, the pain was severe, and measurement of compartment pressure demonstrated the need for fasciotomy. Heroin can cause rhabdomyolysis and hypotension on reperfusion, and certainly prolonged pressure on the muscles may have exacerbated the condition.

(From Roberts JR, Hedges JR. Clinical procedures in emergency medicine. 5th ed. Copyright 2009 Saunders, an imprint of Elsevier.)

Classic signs and symptoms of compartment syndrome include pain, pallor, paresthesias, poikilothermia, paralysis, and pulselessness. Paresthesias are the most reliable sign—muscle edema exerts pressure on peripheral nerves, which results in neuronal ischemia, paresthesias, and paralysis. Decompressive fasciotomy reverses the peripheral neuropathies within a few days to weeks, although symptoms may be permanent in a minority of patients.

Disseminated Intravascular Coagulation

DIC occurs in patients with severe rhabdomyolysis when extensive injury results in multisystem organ failure. Although this disorder is more common with severe trauma and crush injury, rhabdomyolysis from medical causes may lead to DIC. Severe bleeding is most pronounced on days 3 to 5 of illness. If severe bleeding does not occur, spontaneous improvement can be expected by days 10 to 14. When severe bleeding does occur, infusion of fresh frozen plasma (to replace coagulation factors) and transfusion of platelets may be indicated.

Hepatic Dysfunction

Hepatic dysfunction occurs in approximately 25% of patients with rhabdomyolysis. The proteases released from injured muscle may be implicated in hepatic inflammation.

General Measures

Rhabdomyolysis is physiologically and clinically similar to cell degradation states such as tumor lysis syndrome and sepsis. An organized, aggressive treatment strategy should focus on clinical end points similar to those for other cell lysis conditions. The emergency treatment of rhabdomyolysis, in an early goal-directed fashion, is summarized in Figure 169.3.

Fig. 169.3 Early goal-directed therapy for rhabdomyolysis.

CK, Creatine kinase; CVP, central venous pressure; D₅NL bicarb, 5% dextrose in normal sodium bicarbonate solution; EGDT, early goal-directed therapy; IV, intravenous; IVF, intravenous fluid; NS, normal saline; RRT, renal replacement therapy; UOP, urinary output.

The main goal of therapy is prevention of acute renal failure through high-volume resuscitation.⁴ The two most common reasons for the development of acute kidney injury are slow fluid resuscitation and inadequate fluid resuscitation. Normal saline is superior to lactated Ringer solution for the treatment of rhabdomyolysis because normal saline is not associated with risk for phosphate toxicity. More than 10 L of normal saline is typically administered in the first 24 hours of therapy to maintain high-volume dilute urine output.

Initial fluid administration with normal saline is titrated to achieve a goal urine output of 200 to 300 mL/hr. It is important that intravenous (IV) fluid resuscitation be started as soon as possible; fluid resuscitation before the extrication of crushed and trapped patients is preferred. After diuresis is established and urine pH is less than 6.5, fluids are changed to a more alkaline solution (i.e., 75 mmol of sodium bicarbonate added to 1 L of one-half isotonic saline), with the rate titrated to achieve the goal of 200 to 300 mL/hr of urine output. Alternating normal saline with sodium bicarbonate is also an option. If urine pH is higher than 6.5, normal saline is continued. Mannitol, an osmotic diuretic, can be considered in this situation, but only after adequate fluid repletion has been attained.

With moderate to severe alkalemia (serum pH higher than 7.5), acetazolamide can be considered. The goal urine output remains 200 to 300 mL/hr. Fluid repletion is continued until the CK level falls below 5000 to 10,000 U/L and the myoglobinuria clears.

If initial diuresis is not achieved with fluid replacement alone or the patient has contraindications to further fluid replacement, additional diuretics should be considered and a nephrologist consulted for possible renal replacement therapy.

Vital signs, cardiac rhythm, and urine output should be monitored continuously. Medication dosages should be adjusted according to renal function, and drugs that are potentially nephrotoxic should be avoided.

Pharmacologic Therapy

Renal Replacement Therapy and Hemodialysis

Early hemodialysis is not necessary unless crush injuries or certain complications have occurred (e.g., severe hyperkalemia, refractory metabolic acidosis, oliguria or anuria, volume overload). Early consultation with a nephrologist is warranted. Myoglobin molecules can be removed by hemofiltration, but not by hemodialysis or peritoneal dialysis.

Reductions in morbidity and mortality have been observed in victims of mass casualty incidents who underwent dialysis within 4 to 6 hours of injury.

Experimental Therapy

Several promising experimental therapies for rhabdomyolysis have been studied in animal models but have not been well tested in humans. Nitric oxide may prevent acute renal failure by promoting renal vasodilation, and lazaroids (21-aminosteroids) inhibit oxidant-induced lipid peroxidation in animals. Other experimental treatment modalities include deferoxamine (an iron chelator), glutathione, vitamin E, carvedilol, and dantrolene.

Avoid Calcium Supplementation and Loop Diuretics

Patients with rhabdomyolysis often have acute hypocalcemia. The hypocalcemia results from deposition of calcium salts in necrotic muscle. Supplemental calcium administration should be avoided if possible because it can exacerbate the cytoplasmic injury. During the rebound and recovery phases of rhabdomyolysis, calcium is remobilized and hypercalcemia becomes a true risk. Only if the patient is symptomatic or if severe hyperkalemia is present should calcium be considered, and even then other measures to ameliorate the hyperkalemia should be undertaken first.

Loop diuretics (e.g., furosemide) should generally be avoided because they contribute to urine acidification and tubular cast formation. Forced diuresis is best facilitated with mannitol. Under alkalemic conditions, acetazolamide can be considered.

Surgical Therapy

Surgical therapy is a consideration for patients with rhabdomyolysis caused by crush syndrome. Amputation removes damaged muscle that serves as the source of cellular toxins.

Physiologic amputation can act as temporizing measure when immediate surgical care is not available, particularly in the setting of disasters or military combat. To perform physiologic amputation, one or two tourniquets are applied firmly to the extremity above the level of injury or entrapment, and dry ice is applied distal to the tourniquet. Combat surgery hospitals beginning in World War II through current conflicts have performed this procedure with success. Physiologic amputation rapidly reduces myoglobin and other intracellular toxins associated with crushed, ischemic, or septic extremities. This can dramatically reduce myoglobinuria and reperfusion injury. Physiologic tourniquets have allowed definitive surgery to be delayed for up to 32 days. Emergency physicians must be aware, however, that physiologic amputation will inevitably result in loss of the affected limb.

Early prophylactic fasciotomy increases the need for transfusions and the risk for both sepsis and death. Fasciotomy is not indicated unless signs of compartment syndrome are observed.⁵