It is mid-July, and a 20-year-old male presents to your ED with a chief complaint of significant muscle soreness in both thighs. His associated symptoms include malaise and urine appearing darker than usual. He is an athlete on a local college football team and is midway through 2-week training camp practices. What does your differential diagnosis include?
Exertional rhabdomyolysis (ER) is a pathologic condition caused by muscle breakdown. It is a rare condition but one that can cause significant morbidity and mortality among athletes. In the United States, there is an annual prevalence of around 12,000 cases per year.1
Exertional rhabdomyolysis is often seen in military recruits and athletes in whom exertion is continued past the point of fatigue. Athletes most at risk are those performing repetitive eccentric muscle contractions where the muscles are lengthening while simultaneously attempting to contract. This type of muscle contraction is common in exercise programs such as CrossFit and Insanity. Other at-risk activities include American football, athletics, swimming, and various outdoor sports. Individuals participating in endurance activities such as marathon running use mainly concentric muscle contractions and have a lower incidence of ER.1
Athletes are more predisposed to ER if they have a baseline of poor conditioning followed by intense training, a sudden increase in their training regimen, or if the training is complicated by high outside temperature or humidity, drug or supplement use, illness, or dehydration.2
Overall, ER has a low incidence and low risk of recurrence unless there is an underlying genetic disorder such as metabolic myopathies, disorders of calcium homeostasis, or sickle cell disease/trait.1
Pathophysiology
ER occurs when exercise leads to injury of muscle cell sarcolemma and ion pump dysfunction. This occurs via direct injury or secondary to energy depletion and subsequent dysfunction of ATPase pumps. These pumps are responsible for maintaining low intracellular calcium and sodium levels, with high intracellular potassium. When the pumps are damaged, a high intracellular calcium level develops, leading to activation of calcium dependent enzymes as well as free radical production that then causes destruction of cell membrane proteins.
The damaged cell membrane allows for leakage of cell contents including potassium, myoglobin, creatine kinase (CK), and LDH into the bloodstream. It is this release of cell products that can lead to the pain, swelling, and end organ damage of exertional rhabdo. The high intracellular calcium also leads to further muscle contraction in myocytes that
are already overactive, contributing to a vicious cycle of further muscle damage.1,2,3
Myoglobin is typically protein bound in the bloodstream, however, when such an abundant amount is present secondary to the leaking myocytes, it begins to precipitate in the renal tubules leading to obstruction and, if untreated, acute kidney injury. It is this myoglobinuria that leads to the tea-colored urine seen in ER. Other complications include abnormal electrolyte levels, specifically calcium, phosphorus, potassium, and uric acid. These electrolyte abnormalities can lead to cardiac arrhythmias. The released cell contents can also cause disseminated intravascular coagulation (DIC), while associated tissue edema can put the athlete at risk for compartment syndrome. However, despite all of this, ER is associated with a lower complication rate when compared to other causes of rhabdomyolysis. This is likely due to the fact that these athletes often do not have other significant comorbidities.1
Clinical Features
The clinical presentation of exertional rhabdomyolysis will often involve myalgia and muscle stiffness or weakness with a history that should raise suspicion. These myalgias will usually be significant, not attributable to generalized soreness from the athlete's workout, and is often noted 12-36 hours post-exercise.1 Typically, postural muscles such as the thighs, calves, and lower back are the most involved. Malaise, fatigue, nausea and vomiting can be seen, and less commonly there may be swelling, tenderness, or hemorrhagic discoloration of the skin noted as well.3 Patients may also report discoloration of their urine, often so-called "cola" colored.
Diagnosis
The generally accepted definition of exertional rhabdomyolysis is that the patient must have had muscle-related symptoms that were preceded by exercise, an elevation of CK within 12-36 hours but no more than 4 days post-exercise, along with the presence of myoglobinemia/ myoglobinuria. However, myoglobin is rapidly cleared from the blood, meaning that levels may return to normal within 6 hours. This makes serum levels unreliable, and therefore should not be required for diagnosis.1,4 Classically, urinalysis will test positive for blood without the presence of RBCs, which is suggestive of myoglobinuria. This occurs due to the fact that urine dipstick does not differentiate between hemoglobin and myoglobin.
Creatine kinase levels will rise within 2-12 hours of injury, peak in 1-3 days and decrease at a constant rate of 39% per day. If decreasing at a slower rate, there should be concern for possible ongoing muscle necrosis or an underlying neuromuscular condition.4 The severity of muscle injury correlates with the level of CK elevation, but it is not an accurate predictor of nephrotoxicity. The general consensus is that a CK level greater than 5x the upper limit of normal (ULN) is a conservative value for defining exertional rhabdomyolysis. However, Scalco et al. suggest that if the CK level is less than 50x ULN, the patient is asymptomatic, does not have myoglobinuria or ARF, then the CK elevation is likely secondary to a physiologic response to exercise and not clinically significant exertional rhabdomyolysis.1
Exertional rhabdomyolysis is considered clinically significant if the symptoms are more than simple myalgia. For example, this would include muscle weakness or swelling. Also, if the patient has an elevated body temperature suggestive of heat stroke, CK level greater than 50x ULN, renal or cardiac comorbidities, has had prior episodes of rhabdo, or myoglobinuria, there is concern for clinically significant exertional rhabdomyolysis.
Management
If deemed physiologic rhabdomyolysis, it is recommended to have the patient rest for 72 hours, eliminate risk factors, and orally rehydrate. After this rest period, the patient should follow up for repeat CK levels. If the CK level has returned to below 5x ULN, no further studies are needed. If the CK level remains elevated above 5x ULN for more than 2 weeks, expert consultation is recommended.
For patients found to have clinically significant exertional rhabdomyolysis, IV hydration should be initiated as soon as possible. The aim is to produce a urine output of 200-400 cc/hr for the first 24 hours, which may necessitate amounts as high as 1-2L/hr initially.
The goal of treatment is to prevent kidney injury. If CK levels continue to rise, if urine output remains low, or if the patient has profound acidosis or hyperkalemia, admission to the ICU for dialysis should be considered. An EKG should be obtained to evaluate for cardiac involvement due to electrolyte abnormalities. If this is a recurrent episode, if there is family history, or if
the story does not sufficiently explain the severity (ie, accustomed exercise), one should further investigate genetic causes.
While trending CK levels, if a secondary rise is noted, this should raise concern for occult compartment syndrome.4 If deemed clinically significant and further inpatient management is warranted, the risk for acute renal failure (ARF) should be assessed. Risk factors for ARF include a CK level > 40,000 IU/L, age over 50, female sex, and initial creatinine > 1.4.
Other treatment modalities are not typically recommended, as their use has not been shown to have a proven benefit. However, in refractory cases, the use of bicarbonate for significant acidosis or mannitol for inadequate urine output may be considered.1,5
Return to Play
There are no evidence-based guidelines regarding return to play decisions. However, the decision-making process can be simplified by dividing the population into high and low risk.
If a patient is considered low risk, once their CK level has normalized, there is no myoglobinuria present, no muscle pain, and the patient is otherwise symptom free, light activity may be resumed. After 1 week, if the patient remains asymptomatic, normal athletic activity can be resumed gradually.
However, if the patient is thought to be high risk, return to play should be delayed. High risk patients are considered to be those who had a course complicated by ARF, a recovery period longer than 1 week despite appropriate rest, or an elevated CK level beyond 2 weeks post- injury.
Athletes with sickle cell trait, a family history of exertional rhabdo, or malignant hyperthermia are also considered to be high risk. These athletes should be closely monitored by the team physician, along with further follow up to assess for an underlying genetic disorder.1,2,4
Conclusion
Exertional rhabdomyolysis is a rare but potentially fatal condition that should be considered in any athlete with significant post-exercise myalgias. Uncomplicated cases can be managed with rest, oral rehydration, and outpatient follow-up. However, in more severe cases, admission for IV hydration and monitoring is necessary. Return to play should be based on the individual athlete, but once symptoms and labs have returned to baseline, gradual return to normal activity is acceptable. If the patient is considered high risk or if return to play results in return of symptoms, further work-up is warranted.
Case Resolution
The patient was found to have an elevated serum CK level, myoglobinuria on urinalysis, and a slightly elevated creatinine. He was admitted for IV hydration, after which the serum CK and creatinine trended down appropriately. As he was deemed low risk, he began a graduated return to play under the supervision of his team physician and athletic trainer. No symptoms recurred and he was therefore cleared to return to full activity. He was cautioned to avoid such intense, unaccustomed exercise in the future.
References
1. Scalco RS, Snoeck M, Quinlivan R, et al. Exertional rhabdomyolysis: physiological response or manifestation of an underlying myopathy? BMJ Open Sport & Exercise Medicine. 2016;2:e000151.
2. Tietze DC, Borchers J. Exertional Rhabdomyolysis in the Athlete. Sports Health. 2014;6(4):336-339.
3. Stapczynski JS, Tintinalli JE. Tintinalli’s Emergency Medicine: a Comprehensive Study Guide, 8th Edition. New York: McGraw-Hill Education; 2016.
4. Asplund CA, O’Connor FG. Challenging Return to Play Decisions: Heat Stroke, Exertional Rhabdomyolysis, and Exertional Collapse Associated with Sickle Cell Trait. Sports Health. 2015;8(2):117-125.
5. Manspeaker S, Henderson K, Riddle D. Treatment of exertional rhabdomyolysis among athletes: a systematic review protocol. JBI Database System Rev Implement Rep. 2014;12(3):112-120.