Rhabdomyolysis is a syndrome characterized by muscle necrosis and release of intracellular muscle content (creatine phosphokinase (CPK), myoglobin, calcium, potassium, organic acids, proteases, etc.) into the circulation (27). The common causes of rhabdomyolysis are listed in Table 1. Serious complications of rhabdomyolysis include acute myoglobinuric renal failure, disseminated intravascular coagulation, arrhythmias, and death (14,27). Exertional rhabdomyolysis (ER) occurs in response to excessive, prolonged, or repetitive exercise (21). Key clinical features of ER include severe muscle pain during active and passive movements, muscle swelling, and muscular weakness within the first 24 to 72 h after extreme and/or unfamiliar physical exercise. Patients’ urine during an ER episode may be described as dark, red, tea, or “cola” colored. Nonetheless parts of the symptoms that are associated with ER, especially the pain, are similar to delayed onset of muscle soreness after exercise that is not associated with ER (5), a fact that makes early diagnosis difficult.
The laboratory diagnosis of ER usually is based on elevation of CPK activity to more than five times the upper limits of normal (10,18). However this cutoff is controversial since it does not take into consideration baseline differences, and mostly since the normal CPK values are not defined clearly (3,21). Moreover serum CPK activities after physical exercise vary widely between individuals and have been suggested to correlate with gender, race, and fitness (3,21). One possible explanation for these differences may be found in muscle predominance of type II muscle fibers (8). This mechanism also has been suggested in heat stroke patients who developed significant rhabdomyolysis (9,13). Clarkson and Ebbeling (6) classified subjects as “high responders,” “low responders,” or “no responders” based on their CPK activity after exercise. The presence of myoglobin in urine (urine dipstick positive for blood) and/or serum also may be found in patients with ER (19,27).
Although there are no clear guidelines for treatment of ER or for hospitalization criteria, we recommend that ER patients with highly increased CPK activity, decreased creatinine clearance (elevated serum creatinine), myoglobinuria, metabolic abnormalities, or signs of compartment syndrome should be hospitalized. These general recommendations for hospitalization may be strengthened by a recent study by Delaney et al. (7) that found a significant correlation between known markers of rhabdomyolysis and acute kidney injury with the RIFLE (risk, injury, failure, loss, end stage) categories of renal impairment in emergency department patients. Similar recommendations have been given by George et al. (11). Treatment should include rest, rehydration, and monitoring for serious or life-threatening sequelae (acute renal failure, electrolyte, and acid-base disturbances) (14,21,24).
ER may occur as an isolated episode or as recurrent episodes, mostly (when other precipitating factors are excluded) in adults with hereditary metabolic myopathies (15). In a recent epidemiological report on the natural history of ER, Alpers and Jones (1) noted a relatively low recurrence rate of ER. In their work, however, they described 44 cases of ER among basic military trainees from the U.S. Air Force, of which only 22 were followed for recurrence over a mean time period of 31.2 months, and 1 recurrence has occurred in that group (recurrence risk of 0.08% per person per year). It should be emphasized however that although the recurrence rate demonstrated was low, the number of participants in this study was small and included a population from the U.S. Air Force only that has been reported to have a relatively low occurrence of ER compared to the other military units (20).
ER may be caused by various genetic myopathies (Table 1a), where the most common hereditary causes are carnitine palmitoyltransferase II (CPT II) deficiency and muscle phosphorylase deficiency (McArdle disease) (15). Although metabolic myopathies represent a very small percentage of ER cases, they should be suspected in patients with recurrent episodes of ER (25,26,27). Tonin et al. (26) reported a series of 77 patients with “idiopathic” myoglobinuria in whom muscle biopsies were performed and specific enzyme deficiencies were identified in 36 of the patients (47%). CPT II deficiency was the most common disorder, occurring in 17 of the 36 patients, followed by muscle phosphorylase deficiency in 10 patients. Exercise was stated as the main precipitating factor, both in patients with and without detectable myopathies. In another study (16), 23% out of 22 patients with recurrent ER had enzyme defects, from which the most common disorder was muscle phosphorylase deficiency. Other muscle diseases, muscular dystrophies, or myopathies were detected in 18% of these patients. In both studies, more than 50% of the recurrent ER cases had no known biochemical cause. Yet it should be emphasized that some less common enzyme deficiencies also were described as causing recurrent ER (Table 1a) (16,22,23,26). In another study, 475 medical records of patients with an acute neuromuscular illness/rhabdomyolysis were analyzed for a possible etiology. This study showed that the most common reasons for recurrent ER were found to be muscle diseases, illicit drug use, alcohol, medication, and idiopathic reasons (18).
ER is a dangerous, life-threatening syndrome. In many cases, the cause to recurrent ER can be explained, but in some cases, the existence of possible inherent, unfamiliar causes should be considered. Moreover recurrent events due to acquired myopathies have not been looked at scientifically as far as we know. This manuscript emphasizes the need to further investigate this assumption.
Reasons for recurrent episodes of ER often remain unknown, but we can point to a few possible causes and mechanisms for a recurrent injury.
The first possible explanation is the existence of an undiagnosed metabolic disorder; since less common enzymatic deficiencies are usually not tested for (Table 1a), we cannot completely rule out this possibility (16,26). Nevertheless the presence of a hereditary disorder might be argued against when patients had no prior episodes of ER despite being highly physically active. On the other hand, some metabolic disorders may be expressed only under certain conditions such as prolonged exercise, cold, fasting, a low-carbohydrate and high-fat diet, and infections (15). Krivickas (15) reported on a collegiate athlete with recurrent ER, without any prior history of ER, who was diagnosed finally with a mutation in the CPT II gene. In that case, the trigger for the initial episode seemed to be a combination of prolonged exercise and fasting.
Another potential explanation for recurrent ER may be premature return to physical activity. Returning to physical activity before complete recovery may lead to recurrent episodes of ER due to incomplete regeneration of the injured muscle tissue despite clinical recovery. Indeed a lag between clinical recovery and morphological recovery from ER, diagnosed by MRI, has been recently reported (2).
Another theoretical explanation may be a post-ER acquired myopathy. Such a disorder may be caused, for example, by dysregulation of the muscle repair mechanism. There is evidence that exercise increases plasma concentration of transforming growth factor-beta (TGF-b-1), probably due to mechanical load on the muscle tissues (12). In dysregulated muscle regeneration, there is a persistent inflammatory response and overexpression of proteins, such as TGF-b-1 and myostatin, which promote the formation of fibrotic tissue to replace damaged myofibers (4). Such dysregulated muscle regeneration may occur following ER and may lead to the formation of a weakened muscle tissue (possibly through the TGF-b-1 pathway), which may be more vulnerable to recurrent muscle breakdown and ER. This hypothetical mechanism, as well as other mechanisms, needs further investigation.
Return to physical activity after an episode of ER should include a thorough medical investigation (21). When no known etiology for the acute episode is found, evaluation for metabolic myopathies should be considered. Recurrent episodes of ER increase the level of suspicion for existing metabolic disorders (15), but in many cases, the recurrent injury is not associated with any known pathology. From a practical point of view, we suggest that even if no positive findings are found during the medical investigation of post-ER patients, they should be educated about the causes, signs, and symptoms of ER prior to return to physical activity.
Currently proper guidelines for return to physical activity after ER still are needed. It is recommended however that patients who have experienced ER should be evaluated and risk stratified as high or low risk prior to returning to activity (Table 2) (21). The evaluation may include severity of the injury, time for recovery, type of activity that caused the injury, personal and familial history, suspicion of metabolic myopathies, malignant hyperthermia, and sickle cell trait. High-risk patients will require further medical evaluation prior to return to physical activity, such as genetic testing for metabolic myopathies (Table 1a).
Several possible mechanisms for recurrence of ER in the absence of a known cause have been discussed in this report including less common hereditary metabolic myopathies, premature return to activity due to incomplete recovery of the muscle tissue despite clinical recovery, and an acquired post-ER muscular disorder. Further investigation is required in order to determine the exact mechanism of recurrent ER in patients without known metabolic myopathies. This investigation should include proper consideration of the possibility for temporary or permanent higher susceptibility to recurrent events after severe ER due to an acquired myopathy in the damaged muscles. Furthermore the level of medical investigation required for patients experiencing single or recurrent episodes of ER is not well established in the literature and varies from meticulous investigation of the medical history to an extensive genetic and metabolic investigation and muscle biopsy. Accordingly proper guidelines for treatment and return to physical activity after ER are needed. It should include a thorough medical investigation along with risk stratification, and when no known etiology for the acute episode is found, evaluation for metabolic myopathies should be considered. Moreover the guidelines should include the length of time required before return to physical activity.
This study was not funded by any source. None of the authors has any professional relationships with companies or manufacturers who will benefit from the results of the present study. In addition, the results of the present study do not constitute endorsement by Current Sports Medicine Reports or the American College of Sports Medicine.
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