Early Recognition Is Key

Thomas P. Brown, DO

THE PHYSICIAN AND SPORTSMEDICINE - VOL 32 - NO. 4 - APRIL 2004

In Brief: Exertional rhabdomyolysis is an uncommon diagnosis, but because its complications can be severe, clinicians need a thorough understanding of this syndrome. When skeletal muscle cell membranes are damaged, their intracellular contents enter the bloodstream and can cause potentially serious sequelae, even death. Intense exercise, some viral infections, and certain genetic disorders increase the risk. Serum creatine kinase levels are the diagnostic gold standard. The treatment of rhabdomyolysis consists of early detection, therapy for the underlying cause, measures to prevent renal failure, and correction of metabolic complications.

Exertional rhabdomyolysis, characterized by muscle necrosis and subsequent release of intracellular contents into the bloodstream, is a serious complication of exercise.¹ Although rhabdomyolysis has multiple causes, exercise is implicated in many cases. The syndrome onset may initially be insidious, but devastating complications, including cardiac dysrhythmias, renal failure, and possibly death, may occur.² The likelihood that a clinician may encounter a patient who has exertional rhabdomyolysis increases as more and more people exercise. Surprisingly, rhabdomyolysis can develop at any level of physical exertion.

The incidence of rhabdomyolysis is difficult to determine, but it is most likely underreported. In the United States, 26,000 cases from all causes are reported annually.² Most reported cases of exertional rhabdomyolysis involve military personnel (ranging from 0.3% to 3.0%)³ or law enforcement and fire department trainees (0.2%).^1,6,7 Data from these groups are deemed reliable, because both groups participate in similar strenuous activities with medical supervision.

Understanding Injury Mechanisms

Many theories about the causes of rhabdomyolysis exist, but all agree that excess intracellular calcium represents the final common pathway.^5,6 Exertional rhabdomyolysis is not well understood, but energy requirements may exceed adenosine triphosphate (ATP) production.^1,6,7 Individuals who have certain genetic defects of carbohydrate or lipid metabolism also experience a decrease in ATP production.^1,6 ATP-dependent sodium-potassium pumps subsequently fail as ATP becomes unavailable, resulting in an electrochemical derangement across the cell membrane and an increased intracellular calcium level. The increased calcium initiates activation of normally dormant proteases and catalytic enzymes that destroy the cell membrane.^1,2,6

With the destruction of the cell membrane, excessive amounts of degradation products enter the bloodstream, including myoglobin, creatine kinase, potassium, lactate dehydrogenase, uric acid, calcium, aspartate transaminase, alanine transaminase, and phosphorus. Abnormally high levels of these substances may lead to serious sequelae, such as renal failure, cardiac dysrhythmias, compartment syndrome, disseminated intravascular coagulation, lactic acidosis, and possibly death.^2,6

Complications

Multiple complications may result from rhabdomyolysis. Early complications include severe hyperkalemia that may be associated with cardiac arrhythmia and hypocalcemia.²

The kidney is the most common site of complication in rhabdomyolysis, and acute renal failure is the most serious late-stage complication.² Of the degradation products released, myoglobin is the most toxic to the renal tubules. If renal failure occurs, it is caused by more than simple mechanical obstruction formed by the heme pigment casts of myoglobin. Thus, the mere presence of myoglobinemia is not necessarily pathologic, because the exact level that results in renal failure or other pathology has not been established.⁸ As many as one third of all patients who have rhabdomyolysis may experience acute renal failure.⁶

The most common cause of acute renal failure associated with rhabdomyolysis is acute tubular necrosis.⁶ Important factors in the development of acute tubular necrosis include increased renal vascular resistance, myoglobin entering an environment of acidic urine, and hypovolemia.^3,5,6 At a pH level of 5.6 or less, myoglobin dissociates into globin and hematin. Hematin appears to be the insulting agent.⁶ Another degradation product, urate, is also nephrotoxic and precipitates in acidic urine.⁸

Exercise-Related Risk Factors

All strenuous exercise or activity results in some degree of muscle fiber breakdown, as evidenced by light microscopy.^1,5,8,9 Thus, how is it possible that someone could compete in an event as physically demanding as a marathon or other equally intense activity and not develop rhabdomyolysis?

Exertional rhabdomyolysis develops from both exercise and nonexercise risk factors (table 1). The amount of cellular damage may be affected by a subject's fitness level; the intensity, duration, and type of exercise; illness; and genetic and metabolic factors.

TABLE 1. Factors in the Development of Exertional Rhabdomyolysis Exercise Factors Patient experience and fitness level Intensity Duration Type (concentric vs eccentric) Nonexercise Factors Metabolic myopathies Malignant hyperthermia Illness Sickle cell trait High ambient temperature

Fitness level. Paul et al¹⁰ showed that muscle tissue adapts to exercise, allowing the tissue to perform more work, resist damage, and repair at a faster rate. Thus, it would seem logical that an experienced athlete would be less likely to develop exercise-induced rhabdomyolysis.

A study⁴ of candidates for the New York City Fire Department showed that those with prior physical conditioning had an inverse risk of developing rhabdomyolysis. For the candidates engaged in physical activity (both work and leisure activity >50 hr/week), the relative risk was 0.2 (95% confidence interval = 0.1 to 0.9). Military reports^11-13 note a positive correlation in the development of rhabdomyolysis in sedentary recruits versus conditioned recruits.

A study conducted at The Ohio State University¹⁰ compared the differences between exercise sessions of experienced and inexperienced weight lifters. Using serum levels of myoglobin, creatine kinase, and urinary 3-methylhistidine as markers, researchers revealed that the experienced group had statistically less tissue damage.

Intensity and duration. In contrast to the rigors of running a marathon or a triathlon, a case report¹⁴ noted the development of rhabdomyolysis in a 29-year-old man who performed just 30 to 40 sit-ups per day for 5 days. He reported only lower back pain. The diagnosis was made using bone scan imaging when intense uptake of technetium-99m methylene diphosphonate was noted in the rectus abdominis muscle. Recent literature discusses the use of bone scans as a diagnostic indicator for rhabdomyolysis.^1,14 The higher the serum creatine kinase level is, the greater the radiotracer uptake in injured muscle. In the reported case, the creatine kinase level had increased to 12,586 U/L (normal range: 55 to 170 U/L). The deposition of radiotracer in damaged muscle is reversible, and the disappearance of the radiotracer can be related to healing.¹⁴

Studies^15,16 show that increasing the intensity of an activity (eg, lifting heavier weight, pedaling faster) resulted in higher creatine kinase levels when compared with increasing the duration (eg, more repetitions with less weight, longer bicycling with slower pedaling).

Type of exercise. Different amounts of cellular destruction occur between concentric exercise (shortening the muscle; eg, curling a barbell to your chest) and eccentric exercise (lengthening the muscle; eg, lowering a barbell down to the starting position). Eccentric activities cause more destruction, resulting in higher levels of intracellular contents in the bloodstream. Higher levels noted with eccentric exercise peak at day 5 or 6; higher levels occurring with concentric exercise peak at day 1.^3,5

Nonexercise Risk Factors

Other intrinsic factors may contribute to the risk of exercise-induced rhabdomyolysis.

Metabolic myopathies. Many individuals who develop rhabdomyolysis possess an inherited disorder of muscle energy metabolism (table 2). As many as 50% of patients who have recurrent rhabdomyolysis may possess a muscle enzyme defect in the metabolism of glycogen and lipids.^2,9 Inherited muscle enzyme defects decrease the synthesis of ATP, which diminishes muscle cell integrity.¹⁷ Of these, type 2 carnitine palmityltransferase deficiency is the most common cause of aerobic exercise–induced rhabdomyolysis; myophosphorylase deficiency is the most common cause of anaerobic exercise–induced rhabdomyolysis.¹⁷ (See "Metabolic Myopathies and Physical Activity: When Fatigue Is More Than Simple Exertion," June 2002)

TABLE 2. Metabolic Myopathies Associated With Exertional Rhabdomyolysis Carnitine palmityltransferase Lactate dehydrogenase Myoadenylate deaminase Myophosphorylase Phosphofructokinase Phosphoglycerate kinase Phosphoglycerate mutase Phosphorylase kinase

The diagnosis is made by performing a muscle biopsy and demonstrating abnormally increased glycogen or lipid deposits and the absence of specific enzymes noted during histochemical staining.^1,17 Other tests may include ischemic forearm testing and ³¹P magnetic resonance spectroscopy with exercise.

Malignant hyperthermia and exertion. Rhabdomyolysis has been reported in individuals who are susceptible to malignant hyperthermia while exercising in hot ambient temperatures.¹⁸ Malignant hyperthermia is an inherited muscle membrane disorder in which the individual experiences a hypermetabolic state after anesthesia with suxamethonium chloride or volatile halogenated anesthetic agents. During malignant hyperthermia, the core temperature rises, muscle rigidity and pain increase, and creatine kinase and myoglobin levels increase dramatically. The underlying cause is an increased calcium level in the myoplasm secondary to a defect in calcium binding by the sarcoplasmic reticulum.

Tests commonly used to assess malignant hyperthermia susceptibility include an in vitro muscle contracture test and genetic testing for mutations in the ryanodine receptor gene.¹⁸

Viral illness. Exercising while ill increases the risk of rhabdomyolysis^3,19,20 Viruses commonly associated with rhabdomyolysis include influenza A and B, coxsackievirus, Epstein-Barr, herpes simplex, parainfluenza, adenovirus, echovirus, human immunodeficiency, and cytomegalovirus. The mechanism of muscle damage caused by viral infections has not been clearly established. Acute and convalescent viral titers are helpful in making the diagnosis.²⁰

Sickle cell trait. An association between sickle cell trait and the development of rhabdomyolysis is evident.^3,4 A report from the US Army²¹ noted a 200-fold increase in occurrence in military recruits who had the trait when compared with recruits who lacked the trait. Participants who have sickle cell trait do not have to be excluded from exercise, but heat, humidity, and hydration status need to be monitored very closely.

Sex. Studies, such as a report by Shumate et al,²² compare the occurrence of rhabdomyolysis in male and female athletes. The "sex-linked phenomenon" of the 1970s, in which women seemed less likely to develop rhabdomyolysis, has been refuted. In a case report⁴ by the New York City Department of Health, 16,506 candidates participated in the firefighting physical fitness test; 32 male participants (0.2%) developed rhabdomyolysis. Of the 84 female candidates, none developed the condition.

Making the Diagnosis

Exertional rhabdomyolysis should be considered in the differential diagnosis of any patient who reports recent exercise with myalgias, dark urine, and tenderness or swelling of muscles, but only 50% of patients who have rhabdomyolysis will present with these classic symptoms.⁶ Patients who have an underlying metabolic myopathy may also recall long-standing difficulties with exercise intolerance. More than one episode of rhabdomyolysis or the development of rhabdomyolysis in childhood should raise suspicion and trigger an appropriate workup for metabolic myopathies.

Laboratory testing is the most reliable method of diagnosing rhabdomyolysis. For many years, serum and urine myoglobin levels were the cornerstone for the diagnosis. Unfortunately, these markers have intrinsic flaws. Myoglobin, because it is not bound to a carrier protein, may be cleared from the bloodstream within 1 to 6 hours after injury,⁶ even before the patient arrives at a physician's office or emergency department. Additionally, myoglobin is not detected until serum levels reach 1.5 mg/dL, which is equivalent to the dissolution of approximately 100 g of skeletal muscle.²³ Also, to achieve pigmenturia, which is often the reason that prompts the patient to seek medical care, the concentration of myoglobin must exceed 100 mg/dL, which is equivalent to the dissolution of 7 kg of muscle.^6,23

Urine dipstick tests also have their limitations. The reaction between the heme portion of the myoglobin molecule and the orthotoluidine in the dipstick mimics the reaction between free hemoglobin of red blood cells and orthotoluidine. This reaction is not uncommon in distance runners who may not have rhabdomyolysis.

Creatine kinase is the most reliable diagnostic indicator for rhabdomyolysis.^6,12 Creatine kinase levels peak within 24 to 36 hours postinjury, about the time the patient usually arrives at a medical office or emergency department. Levels in the range of 10,000 to 300,000 U/L are not uncommon in patients who have rhabdomyolysis.⁵ Unfortunately, no standard creatine kinase level is diagnostic for rhabdomyolysis, although most authors consider creatine kinase levels five times normal or greater to be diagnostic.^5,6

Studies, such as one by Randall et al,⁷ have also shown a poor correlation between creatine kinase levels and the degree of muscle damage.⁹ Because skeletal muscle has a small amount of intrinsic creatine kinase myocardial band (CK-MB), it would not be unusual during times of considerable muscle injury to see an elevation of CK-MB. This elevation, however, rarely exceeds 3% to 5% of the total creatine kinase level.⁶

Emergency Treatment

The severity of symptoms and lab results will guide treatment decisions. The goal of initial management is to minimize injury to the renal tubules with fluids and buffering.

Saline infusion. The mainstay of treatment to prevent acute renal complications is early and aggressive saline infusion. Large quantities may be required to achieve a urinary output of 200 to 300 mL/hr.⁶ Fluids are given in an attempt to prevent injury to the renal tubules, increase renal perfusion pressure, dilute toxic substances, and facilitate excretion. In the elderly or those with compromised cardiovascular or renal disease, central hemodynamic monitoring should be used to prevent fluid overload. If the desired urinary output cannot be achieved with fluid administration alone, intravenous furosemide (40 mg) or 20% solution of mannitol (15 mL/min) should be considered to aid in diuresis.

Buffering. Alkalization of the urine is often used in the treatment of rhabdomyolysis, because myoglobin and urate are toxic to the tubules in an acidic environment.^5,6 Alkalization of the urine may be achieved by adding 2 ampules of bicarbonate per liter of saline. The goal is to keep the urine pH level at 7.5 or higher.⁵ Close nephrology support is wise if there is any question of impending renal compromise, because dialysis is occasionally warranted.

Blood workup. Lab tests should be obtained early in the course of treatment, including levels of electrolytes, blood urea nitrogen, calcium, magnesium, phosphorus, creatinine, and transaminases, in addition to complete blood count, prothrombin time, and partial thromboplastin time. Of the electrolyte abnormalities, hyperkalemia is the most lethal, and early recognition and treatment are warranted to avoid cardiac dysrhythmias.^1,2

Drugs. Dantrolene sodium used for 4 days postrhabdomyolysis has been reported as an adjunctive treatment. As noted earlier, patients who have rhabdomyolysis have an increased intracellular calcium level caused by calcium release from the sarcoplasmic reticulum of the damaged cells.^5,6,24 In one study,²⁴ dantrolene reduced the intracellular calcium level by 83% and was associated with clinical improvement of muscle pain, stiffness, and rigidity. Dantrolene was administered intravenously at 2.5 mg/kg of body weight on day 1 and orally at 2.0 mg/kg on days 2 through 4.

Dantrolene is the medication of choice for patients who have a history of malignant hyperthermia and a clinical picture of rhabdomyolysis. The drug is administered by continuous intravenous push, starting at 1 mg/kg and continuing until the symptoms subside or the maximum cumulative dose of 10 mg/kg of body weight has been reached.

Subacute Treatment

Patients who have milder symptoms with little more than muscle soreness and a mildly elevated creatine kinase level may be treated less aggressively in an outpatient setting. It is important to ensure that the patient has no difficulty passing urine, the urinary sediment is reasonably clear, and the metabolic profile is normal. Patients should be instructed to drink adequate amounts of fluids and must be seen in follow-up within 48 hours.⁹

An often overlooked aspect of treatment is aggressive physical therapy. This includes range-of-motion exercises, both active and passive, aerobic training, and gradual resistance training. This may be started once the patient has been cleared of ongoing pathologic processes. Most patients may return to training within 4 weeks of the onset of rhabdomyolysis.⁷

Minimizing Risk

The best treatment for rhabdomyolysis is prevention. Participants need to increase the intensity of their exercise programs at a pace that will allow muscle tissue time to adapt. Avoiding exercise during high temperature and humidity conditions and limiting exercise during times of illness are also advised.⁵ Patients who have predisposing risk factors, such as metabolic myopathies, sickle cell trait, or certain viral infections, should be instructed to observe precautions when exercising.

The author wishes to acknowledge CAPT Ann Yoshihashi, MD, MC, USN for her review of the article.

The opinions or assertions presented here are the private views of the author and are not to be construed as official or as reflecting the views of the US Department of the Navy or Department of Defense.

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Dr Brown is the senior flight surgeon at Training Wing 6, Naval Air Station Pensacola, in Pensacola, Florida. Address correspondence to CDR Thomas P. Brown, 3178 Coquina Way, Gulf Breeze, FL 32563; e-mail to cdr-thomas.p.brown@cnet.navy.mil.

Disclosure information: Dr Brown discloses no significant relationship with any manufacturer of any commercial product mentioned in this article. No drug is mentioned in this article for an unlabeled use.