A 25-yr-old otherwise healthy male decided to have a weightlifting competition with his best friend. He was not fit and had not lifted weights since high school. The competition, which lasted over an hour, involved military and bench pressing, as well as bicep curls with slow "negatives;" it was quite vigorous. The next day, he presented to the emergency department with excruciating arm, shoulder, and chest wall pain. He reported that his urine looked like "cola" and that he could barely move his arms. His urine dipped positive for large amounts of blood, but the microscopic exam showed only two red blood cells per high-powered field. His serum creatine kinase (CK) was 25,000 units per L (U·L−1). He was subsequently diagnosed with exertional rhabdomyolysis (ER) and admitted for intravenous (IV) hydration. He was discharged after a 3-d, uneventful hospital stay. His CK peaked at 30,000 U·L−1 and was under 1000 U·L−1 upon discharge. He presents to his primary care provider's office 2 wk later and wants to start weightlifting again. His CK is currently 140 U·L−1. Can he safely return to weightlifting? Is he at risk for a recurrence of exertional rhabdomyolysis? Does he need any further medical evaluation?
A 21-yr-old African-American college football player with known sickle cell trait started summer football camp 2d ago. For the past 6 months, he has noticed that his legs felt sore, even after what he considered a moderate workout. Eight h after finishing day 3 of summer camp, he presented to the emergency room with severe bilateral leg pain. He could barely walk secondary to his quadriceps pain. He reported that he had not consumed adequate fluids during practice and had not urinated in 8 h. His urine dipped positive for a large amount of blood, but his microscopic evaluation showed no red blood cells. Serum myoglobin was sent and was pending; his serum CK level was 50,000 U·L−1. He was admitted for IV hydration with a diagnosis of ER and dehydration. He experienced mild renal failure secondary to myoglobinuria during his 8 d in the hospital; his CK peaked at 105,000 U·L−1 on day 3. Upon discharge, he was feeling better, but still sore, with a CK level of 800 U·L−1. He now presents to his primary care doctor to request clearance for returning to play college football. He is still minimally sore, but feeling much better overall. His CK level is 700 U·L−1. Can he safely return to football? Is he at risk for a recurrence of ER? Does he need any further medical evaluation?
Rhabdomyolysis is defined as the "breakdown of striated muscle fibers" due to mechanical and metabolic insults that result in the release of muscle contents (myoglobin, calcium, potassium, organic acids, proteases, etc.) into the circulation (1,2). Exertional rhabdomyolysis (ER) typically occurs in response to excessive, prolonged, or repetitive exercise, especially, but not necessarily, under hot climactic conditions (3). Other risk factors for ER include low fitness levels with early introduction to repetitive exercise, eccentric exercise, high body mass index, ongoing viral illness (influenza, human immunodeficiency, and Coxsackie virus), and high altitude (4). Serious complications of ER include acute myoglobinuric renal failure, metabolic acidosis, hyperkalemia, hypocalcemia, arrhythmia, compartment syndrome, and death. The purpose of this article is to review the definition and epidemiology of ER and assist the clinician in the identification of those individuals with clinically significant ER and guiding return to participation in sports after ER.
The exact clinical definition of ER is controversial, as there is no consensus in the literature with respect to a well defined clinical picture or associated laboratory findings. Although ER traditionally has the connotation of being an abnormal condition, it is actually a normal response to strenuous exercise and is countered by repair to facilitate adaptation for future strength gains. However, ER can represent a pathologic condition, with metabolic consequences that may include acute renal injury and death. The Uniformed Services University Consortium for Health and Military Performance (CHAMP), in conjunction with the Israeli Defense Force's Heller Institute, has been developing a joint consensus document to assist military providers in managing ER. This group has defined ER as a warfighter presenting with severe exercise-induced muscle pain and/or cola urine, but with two distinct subgroups: physiologic and clinically relevant. The presence of a serum CK level of five times the upper limit of normal and/or a urine dipstick positive for blood (indirect marker caused by myoglobin in the urine) with a microscopic urinalysis lacking red blood cells defines clinically relevant rhabdomyolysis. It is understood that this CK value is very conservative and does not take into account documented baseline differences as a function of gender, ethnicity, and previous activity (5). The provider must then evaluate and analyze the patient to discriminate pathologic from physiologic ER.
In physiologic (benign) ER, patients may develop a markedly elevated CK, but no other signs and symptoms; they usually have no muscle pain beyond that expected for the specific circumstances. The clinical picture is essentially that of delayed onset muscle soreness with elevated CK, but no other evidence of ER. It occurs commonly without clinical sequelae.
ER becomes "clinically relevant" when there is severe muscle pain, muscle swelling and/or weakness, myoglobinuria, and other manifestations typically considered part of the ER syndrome. This often occurs when excessive exertion is combined with confounding variables, such as sickle cell trait, dehydration, use of certain drugs (e.g., statins, anticholingergics, amphetamines, anabolic steroids, glycyrrhizinic acid - present in black licorice), dietary supplements (ephedra, caffeine), alcohol, metabolic or other myopathies, and excessive environmental heat stress (6,7). Clinically relevant ER requires an astute clinician to identify the individual who may be at risk for recurrence, as some cases may be either pathologic, whereas others may be physiologic. Only further testing will allow the clinician to make an informed decision.
Exertional rhabdomyolysis, to include both physiologic and clinically relevant, has been reported primarily in military and paramilitary personnel, with few civilian case reports (8,9). The incidence of ER has been shown to vary between 0.3% in one group of Marine recruits to 3.0% in a group of Army officer candidates. In one report, 35 of 225,000 emergency department visits in a tertiary care hospital were for evaluation and treatment of ER (10). In another series, 57% of ultra-marathoners demonstrated myoglobinemia/ER without serious sequelae (11). During military basic training, acute ER occurs in 2%-40% of individuals, usually within the first 6 d of training (12).
The exact incidence of ER is unknown, but has occurred during physical fitness testing in high school gym classes. In Taiwan, 43% of students developed ER after a fitness test that involved eccentric exercise (13). Finally, among New York City firefighters, 32 of 16,506 candidates (0.2%) were hospitalized for ER-related renal failure after a physical fitness test (14).
Athletes with ER typically present with severe muscle pain during active and passive muscle action, muscle swelling, and muscular weakness within the first 24-72 h after extreme, prolonged, repetitive, or non-familiar exercise. The pain is typically out of proportion to what would be expected from the athlete's described level of previous exertion. The athlete's urine may be described as dark, red, tea, or cola colored. The diagnosis for clinically relevant or pathologic ER, albeit controversial and not clearly defined for athletes, is a serum CK level of five times the upper limit of normal and/or a urine dipstick positive for blood (indirect marker due to myoglobin in the urine), but lacking red blood cells under microscopic urinalysis (4). If available in the evaluation setting, the presence of urine and/or serum myoglobin after exertion will confirm ER (15). The treatment of ER typically involves rest, aggressive and complete re-hydration to augment urine production, monitoring for serious or life-threatening sequelae, and treatment of co-morbidities, such as compartment syndrome and acute renal failure (4,16). The treatment of ER is beyond the scope of this article. A CHAMP algorithm that outlines a strategy for managing ER may be accessed at http://champ.usuhs.mil.
RETURN TO PHYSICAL ACTIVITY AFTER ER
Three major issues must be addressed after an athlete recovers from ER. First, who is at risk for recurrence and requires further evaluation? Second, for those athletes not requiring further evaluation, when can they safely return to sport? Finally, should any restrictions be placed upon the athlete, and if so, for how long? To our knowledge, no standard guidelines exist to determine return to play after an episode of ER. Although several authors have recommended resuming play once symptoms resolve, no consensus exists regarding what is an acceptable CK level or what the rate of progression should be (17-19). The authors, from a military perspective, endorse the following return to play process (Table). We recognize that this approach may be viewed as overly conservative in a sports environment; however, in caring for a large and heterogeneous population, this approach minimizes the opportunity for missing the individual(s) at risk for recurrent ER.
An athlete who experiences clinically relevant ER should first be risk-stratified as either low or high risk for a recurrence. To be considered "suspicious for high risk,' at least one of the following conditions must exist or be present:
a. Delayed recovery (more than 1 wk) when activities have been restricted
b. Persistent elevation of CK (greater than five times the upper limit of the normal lab range) despite rest for at least 2 wk
c. ER complicated by acute renal injury of any degree
d. Personal or family history of ER
e. Personal or family history of recurrent muscle cramps or severe muscle pain that interferes with activities of daily living or sports performance
f. Personal or family history of malignant hyperthermia, or family history of unexplained complications or death following general anesthesia
g. Personal or family history of sickle cell disease or trait
h. Muscle injury after low to moderate work or activity
i. Personal history of significant heat injury (heat stroke)
j. Serum CK peak ≥ 100,000 U·L−1.
The athlete in Case #2 would be categorized as high risk for recurrence because he has sickle cell trait, had a prolonged recovery with a serum CK level peaking over 100,000 U·L−1, and experienced renal failure. This athlete should be carefully evaluated by an appropriate specialist.
To be considered a "low risk" athlete, none of the high-risk conditions should exist, and at least one of the following conditions must exist or be present:
a. Rapid clinical recovery and CK normalization after exercise restrictions
b. Sufficiently fit or well trained athlete with a history of very intense training/exercise bout
c. No personal or family history of rhabdomyolysis or previous reporting of debilitating exercise-induced muscle pain, cramps, or heat injury
d. Existence of other group or team-related cases of ER during the same exercise sessions
e. Suspected or documented concomitant viral illness or infectious disease
f. Taking a drug or dietary supplement that could contribute to the development of ER
Using these criteria, the athlete in Case #1 would be considered low risk for recurrence because he met none of the conditions mentioned in the high-risk category, had no prior history of muscle pain with exertion, and had an extremely strenuous exercise bout for which he was not accustomed.
For those athletes where a high risk of recurrence is suspected, it is recommended that the clinician conduct a complete history and physical exam, and consult a regional or national expert/expert to consider further myopathic disorders before allowing return to play in any moderate- to high-intensity sport. Further diagnostic evaluation may include, but not be limited to, muscle biopsy, electromyographic studies (EMG), caffeine-halothane muscle contracture test, and/or an exercise challenge test (20). While describing each of these diagnostic tests and their potential results is beyond the scope of this article, high-risk athletes often require an extensive evaluation before returning to sports. During the evaluation, an athlete's activity level can be individualized to allow physical exertion within a "reasonably safe range.' If a thorough evaluation is completed satisfactorily and expert consultants are in agreement, an athlete may attempt participation in sports once again using the "low risk" athlete return to sport guideline (Table).
We recommend the three-phase guideline outlined in the Table for those athletes deemed low risk for recurrence. Adherence to the guidelines outlined in the Table also is recommended for those with physiologic ER (evidence of muscle breakdown on laboratory testing but never meeting the criteria for "clinically relevant" rhabdomyolysis).
ER can have serious and fatal consequences, so risk stratification for recurrence, expert consultation for high risk athletes, gradual return to activities, and close medical monitoring are crucial for safe return to sport. When an athlete complains of severe pain, swelling, and/or cola-colored urine after prolonged exertion/exercise, the clinician must use a systematic approach to evaluate and manage these post-exertional symptoms. Measuring serum CK and performing a urinalysis can assist the clinician in distinguishing physiologic from clinically relevant ER. If the diagnosis of clinically relevant ER is confirmed, then the athlete must be further risk-stratified for recurrence. Low risk athletes may gradually return to sport, while those athletes deemed high risk for recurrent ER should be discussed with a regional expert in myopathic disorders to determine whether further evaluative testing is warranted. If a diagnostic workup reveals an underlying myopathy or other metabolic condition, then return to play should be guided in consultation with appropriate regional experts. Athletes without an underlying chronic muscle or other disorder may begin a gradual return to activity protocol with close medical supervision.
1. Allison, R.C., and D.L. Beldole. The other medical causes of rhabdomyolysis. Am. J. Med. Sci.
2. Huerta-Alardin, A.L., J. Varon, andP.E. Marik. Bench-to-bedside review: rhabdomyolysis - an overview for clinicians. Crit. Care.
3. Carter III, R., S.N. Cheuvront, J.O. Williams, et al. Epidemiology of hospitalizations and deaths from heat illness in soldiers. Med. Sci. Sports Exerc.
4. O'Connor, F.G., and P.A. Deuster. Rhabdomyolysis. In: Cecil Medicine
Edition, L. Goldman and D. Ausiello (Eds.). Philadelphia: Saunders Elseveir, 2008, pp. 798-802.
5. Brewster, L.M., G. Mairuhu, A. Sturk, and G.A. van Montfrans. Distribution of creatine kinase in the general population: implications for statin therapy. Am. Heart J.
6. Coco, T.J., and A.E. Klasner. Drug-induced rhabdomyolysis. Curr. Opin. Pediatr.
7. Black, C., and H. Jick. Etiology and frequency of rhabdomyolysis. Pharmacotherapy.
8. Demos, M.A., E.L. Gitin, and L.J. Kagen. Exercise myoglobinemia and acute exertional rhabdomyolysis. Arch. Intern. Med.
9. Greenberg, J., and L. Arneson. Exertional rhabdomyolysis with myoglobinuria in a large group of military trainees. Neurology
10. Sinert, R., L. Kohl, T. Rainone, and T. Scalea. Exercise-induced rhabdomyolysis. Ann. Emerg. Med.
11. Schiff, H.B., and E.T. MacSearraigh, et al. Myoglobinuria, rhabdomyolysis and marathon running. Q. J. Med.
12. Olerud, J.E., L.D. Homer, and H.W. Carroll. Incidence of acute exertional rhabdomyolysis. Serum myoglobin and enzyme levels as indicators of muscle injury. Arch. Intern. Med.
13. Hsingwen, L., W. Chie, and H. Lien. Epidemiological analysis of factors influencing an episode of exertional rhabdomyolysis in high school students. Am. J. Sports Med.
14. Sayers, S.P., and P.M. Clarkson. Exercise-induced rhabdomyolysis. Curr. Sports Med. Rep.
15. Sauret, J.M., and G.K. Wang. Rhabdomyolysis. Am. Fam. Physician.
16. Clinical Practice Guideline for the Management of Exertional Rhabdomyolysis in Warfighters, http://champ.usuhs.mil
, O'Connor, Francis G, et al. Date of access: to be determined.
17. Clarkson, P.M. Exertional rhabdomyolysis and acute renal failure in marathon runners. Sports Med.
18. Galvez, R., J. Stacy, and A. Howley. Exertional rhabdomyolysis in seven division 1 swimming athletes. Clin. J. Sports Med.
19. Eichner, E.R. Exertional rhabdomyolysis. Curr. Sports Med. Rep.
20. Heled, Y., M.S. Bloom, and T.J. Wu, et al. CK-MM and ACE genotypes and physiological prediction of the creatine kinase response to exercise. J. Appl. Physiol.