Treatment of exertional rhabdomyolysis among athletes: a systematic review protocol

Review question/objective The objective of this review is to identify effective treatment methods associated with exertional rhabdomyolysis in athletes. The review questions are: Among athletes, is fluid resuscitation/replacement or nutritional intervention more effective in treating exertional rhabdomyolysis? Does one specific method of fluid resuscitation/replacement lead to decreased time to return to physical activity when compared to another? Does length of hospital stay influence time to return to activity? Background Exertional rhabdomyolysis (ER) is a breakdown of skeletal muscle tissue induced by exercise. It is defined as "a clinical and biochemical syndrome, resulting from skeletal muscle injury that alters the integrity of the muscle cell membrane sufficiently to allow the release of muscle cell contents into the plasma".1 The release of muscle proteins into circulation, particularly creatine kinase (CK) and myoglobin may result in acute renal failure and possibly death.2 The incidence of rhabdomyolysis has been reported to be approximately 26,000 cases per year in the United States; though the exact number of those classified specifically as exertional in nature is unknown.3 While ER is typically caused by a crush injury or drug toxicity, these mechanisms for the development of the condition are not frequently seen in the athletic population. Reports of ER in the military are numerous; however the incidence in trained and untrained adults and older teens is increasing.2 In the athletic population, this condition is of great concern given the high incidence of death if not treated quickly and effectively. Furthermore, athletes carrying the sickle cell trait are at increased risk for the development of this condition, particularly during the first few days of intense exercise.4 There does not seem to be a conclusive set of criteria for the diagnosis of ER. Several features should be considered in each suspected case: an event of muscle destruction, an increase in serum levels of skeletal muscle enzymes, an increase in serum myoglobin levels and the presence of myoglobin in the urine, or myoglobinuria, which presents as a reddish brown urine.5 Non-specific complaints include muscle pain (myalgia) and weakness, muscle stiffness, and swelling.5 In order to establish the presence of ER, it is helpful to determine the timeframe of symptom onset and identify other signs such as the aforementioned severity of muscle soreness and changes in urine color.6 It is common in group-based exercise, such as athletics, for energy exertion to persist beyond the point of fatigue, which may contribute to the development of ER.7 These vigorous bouts of exercise may coincide with factors that cause renal dehydration, heat-related illness, and sickle cell trait. Individuals carrying the sickle cell trait may have a decreased ability to conserve water during strenuous activity, particularly in a high heat environment, nor can they properly concentrate urine, thus leading to limited renal blood flow.4,8 Typically, a history of strenuous exercise can be identified by the presence of factors that contribute to muscle breakdown, such as eccentric (lengthening) muscle contractions or repetitive, strenuous exercise.9,10 Significant muscle soreness that cannot be attributed to general soreness from a workout, occurs 24-48 hours post-exercise, and is typically identified as Delayed Onset Muscle Soreness (DOMS), is also an indication of ER.10 When diagnosing ER, blood tests often demonstrate elevated muscle enzymes, specifically creatine kinase (CK). There are three types of CK isoenzymes in human tissue, each located within a specific type of tissue, either the brain, lungs, heart or skeletal muscle.1 The muscle enzyme CK-BB (or CPK-1) is predominantly found in brain and lung tissue, CK-MB (or CPK-2) is primarily found in cardiac tissue but also exists in skeletal muscle, while CK-MM (CPK-3) is located within skeletal muscle tissue.1 A CK level of 20,000 U/L or greater has been shown as the threshold value to begin treatment. If CK-MB exceeds 5% of the total CK activity, there could potentially be involvement of the myocardium thus warranting additional cardiac diagnostic tests.1,7 Although myocardial involvement is not a typical sequelae of ER, progression to include this condition could impact morbidity. Other literature suggests that a CK level greater than 10-times the upper limit of the normal range should be used to determine the necessity of hospitalization.10 Baseline serum CK levels can vary depending on race, gender, and physical activity levels.7 Unlike cardiovascular conditions, CK levels are not typically evaluated during the pre-participation examination; therefore, it is difficult to use this value as an absolute indicator of ER. Instead, it is used to assist in differentially diagnosing the condition from sickle cell crisis, DOMS, and muscle strains.11 An additional diagnostic indicator of ER is evident when a patient presents with myoglobinuria. This condition occurs when myoglobin is released into the bloodstream following muscle damage, enters the urine and reaches a plasma concentration exceeding 15 mg/l. It has been found that myoglobin has a nephrotoxic effect and may cause renal constriction and ischemia, myoglobin cast formation, and has a direct cytotoxic action on epithelial cells of the proximal convoluted tubules.5 These complications, along with increased CK levels and dehydration, may lead to acute renal failure.10 While ER may present with myoglobinuria, this sign may not exist in all cases. Furthermore, it should be noted that myoglobinuria does not exist without rhabdomyolysis and is therefore an important factor in the diagnosis of this condition. Increased serum myoglobin levels will often precede increased serum CK levels, but myoglobin levels can return to normal within 1 to 6 hours after termination of the activity that led to muscle injury. Myoglobin serum and urine levels have been used as early diagnostic factors, and thus the absence of these elevated levels has been shown to be effective in excluding a diagnosis of ER.1 Early recognition of the signs and symptoms of ER should occur to best initiate appropriate fluid replacement, ensuring permanent damage to the vital organs is minimized and to secure the best possibility of a prompt return to regular activity. In the athletic population, particular attention should be paid to recognizing ER signs and symptoms in persons known to be carrying the sickle cell trait and participating in strenuous exercise in heated environments,12,13 as they are at an increased risk of developing ER. There are several factors that are uncertain in the recognition and treatment of ER. Baseline CK levels are of concern during the process of differential diagnosis however, they are not currently measured in athletes prior to participation in exhaustive exercise. This lack of baseline measure therefore makes it difficult to establish when a 5% increase in these values has occurred. Additionally, CK levels cannot be measured on the field; they must be determined in a hospital setting and thus, a delay in diagnosis and treatment may occur. Following diagnosis of ER, fluid replacement/resuscitation is typically achieved through introduction of intravenous (IV) fluids. The primary goal of early fluid replacement is to preserve renal function and this is typically accomplished through the administration of normal saline (NS) given at a rate of 1.5 mL/hr.14,15 While the administration of saline is accepted for treatment of ER, the literature is inconsistent in determining if isolated saline administration is best practice, or if combined saline and other pharmacological and/or nutritional interventions improve patient recovery and return to physical activity. Several options have been identified in the literature as factors to consider during the treatment of ER. For example, it has been suggested that when CK levels have decreased to a level at or below 1,000 units per liter, 1-2 ampules of Sodium Bicarbonate may be added to the saline.15 The addition of the Sodium Bicarbonate is used for alkalization of the urine which has been shown to decrease the toxicity of the myoglobin to the tubules.14-16 Alternately, the use of Mannitol to increase renal flow has been discussed by several authors, but overall results are inconclusive.14-16 It is believed that urinary output should be maintained between 200-300 mL/hr until myogloburia has ceased; though at this time it is unclear how this output is influenced by the practice of combining fluid replacement methods.14,15 Once treatment is initiated, it is not known what volumes of fluid replacement and nutritional interventions are best practice, in order to ensure return to normal CK and myoglobin levels within the body, as current literature has yet to demonstrate a conclusive algorithm for the treatment of rhabdomyolysis or the more specific form, ER.10 As a result, the average time to return to normal body function, and ultimately return to regular physical activity, is also yet to be determined. It is important to identify which method is best in minimizing organ damage, length of time a patient is hospitalized, and also in maximizing the opportunity for return to play. No randomized controlled trials have been conducted comparing fluid replacement/resuscitation methods in patients experiencing ER, and triangulation of literature to this point has not consistently demonstrated that one method is superior to others. The purpose of this review is to evaluate the treatment of ER among athletes. Specifically, the effectiveness of fluid rescusitation/replacement versus nutritional interventions will be examined as well as the potential influence of treatment on time to return to activity. An initial review of the Cochrane Library, JBI Database of Systematic Reviews and Implementation Reports, CINAHL and other relevant databases did not reveal any current or planned reviews on this topic.