Exertional Rhabdomyolysis

Abstract

Introduction Rhabdomyolysis is defined as the breakdown of muscle fibers that results in the release of muscle proteins and other cellular constituents into the circulation. Exercise, particularly when strenuous and unaccustomed, causes damage and subsequent muscle fiber breakdown, known as exertional rhabdomyolysis [1]. Evidence of muscle damage is derived from microscopic analysis of muscle biopsy samples taken from subjects who have undergone strenuous exercise [1]. Muscle fibers from these subjects show focal disruption in the banding patterns; particularly evident is Z-line streaming [2]. Determination of muscle damage is often made from analysis of blood samples; the most common measure of muscle damage is creatine kinase (CK), although many other muscle constituents have been assessed in blood samples, such as myoglobin, lactate dehydrogenase, troponin I, and myosin heavy chain [3]. Symptoms of exertional muscle damage are muscle soreness, pain, swelling, and stiffness. Pain generally develops in the hours after exercise and peaks between 24 and 48 hours postexercise [1]. The muscle has a tremendous capacity to repair itself, and it is suggested that the damage/repair process may be the stimulus for muscle growth and adaptation to exercise [4]. Pain is generally tolerable and temporary, and therefore of little clinical concern. However, rhabdomyolysis becomes clinically relevant when pain becomes debilitating, a compartment syndrome ensues, or elevated levels of circulating myoglobin precipitate in the kidney tubules. These precipitates can obstruct the renal tubules, lead to tubular necrosis, and effectively shut down the kidneys [5–7]. The increase in blood concentration of myoglobin after strenuous exercise is significantly correlated with the increase in CK activity [8]. Because of the relationship of CK and myoglobin, and the fact that measuring CK is less expensive and produces test results faster than myoglobin, elevated CK levels have been used as a surrogate for myoglobin and taken to indicate a risk of acute renal failure. In fact, recent attention has been drawn to monitoring CK in patients taking cholesterol-lowering drugs (statins) to assess the risk of myopathy and renal failure [9]. However, there appears to be little consensus concerning the amount of CK in the blood that would indicate a risk [9]. In cases of exertional rhabdomyolysis, there is no commonly accepted CK threshold for determining when to hospitalize and treat individuals who present with elevated CK [8]. Terpilowski and Criddle [10] published an algorithm in which a CK greater than 20,000 U/L was the threshold to begin treatment to prevent renal failure with rhabdomyolysis. In the acute clinical setting, this arbitrary CK threshold of 20,000 U/L seems reasonable and prudent. Granted, CK values of up to 20,000 U/L are common and can seem benign in exertional rhabdomyolysis. For example, a study of serial CK values in 12 football players participating in two-a-day practices showed that, by day 4 their mean CK level was just over 5000 U/L, with one player at nearly 19,000 U/L, yet no player had any problems [11]. Also, as cited below and often discussed anecdotally among sports medicine physicians, cases of exertional rhabdomyolysis exist in patients with initial CK values well over 20,000 U/L, yet who recover simply with oral hydration. This may be why most experts who advise on management of exertional rhabdomyolysis do not cite a CK threshold for hospital admission [12–14]. What is key is not the CK level per se, but the setting, degree, stage, and tempo of the exertional rhabdomyolysis. Comorbidities such as heat stress, dehydration, shock, acidosis, and pre-existing illness can accelerate and compound the clinical problems. Life-threatening hyperkalemia can develop quickly, compartment syndromes can ensue, and initially it is difficult to predict whether, or how fast, renal failure may develop. Oral hydration and outpatient observation may suffice for a stable patient with CK of 20,000 to 50,000 U/L (and possibly higher), normal creatinine, and good urine flow. But in light of the clinical uncertainties cited above, it seems reasonable to argue that most patients who present to the emergency room with evidence of acute exertional rhabdomyolysis and a CK threshold of 20,000 U/L should be treated with vigorous intravenous hydration and close monitoring in the hospital for at least a day or two. CK Increase After Exercise Most strenuous exercise results in an increase in blood CK activity because of the stress placed on the contracting muscle fibers. Peaks of up to 80,000 U/L have been reported after exercise with no clinical consequence [8]. However, endurance exercises, even as prolonged and strenuous as marathon running, result in only relatively small increases in CK for the amount of muscle mass involved in the exercise. For example, Smith et al. [15] reported that CK activity in 34 runners immediately after the London Marathon was 707.8 U/L. Similar values were reported in a group of 16 runners immediately after a marathon with a peak increase of 2477 U/L at 24 hours postexercise, returning to near baseline by 96 hours postexercise [16]. Cycling for 2 hours resulted in an increase in CK of 542 U/L at 24 hours after the exercise [17]. Downhill running is often used as a laboratory model to produce muscle soreness and damage because the eccentric (muscle lengthening) contractions are exaggerated in this form of activity as the muscles produce a braking action to counterbalance the downhill forces. Although eccentric actions are known to produce muscle damage, the increase in CK activity after downhill running is relatively small because the contractions are not forceful. For example, Peake et al. [18] reported a CK increase of 1000 U/L 24 hours after a 45-minute bout of downhill running at 60% VO2max, and Pizza et al. [19] reported peak CK values of about 850 U/L 12 hours after 60 minutes of downhill running at 70% VO2max. From these studies and others [3,20,21], CK peaks about 24 hours after endurance-type exercise with peaks generally less than 5000 U/L. High-force eccentric contractions produce a large strain on muscle fibers resulting in considerably greater damage compared with endurance-type activities [1]. Over the past 20 years, our laboratory has used strenuous one-arm exercise to examine elevated CK levels produced by muscle injury [7,22–27]. Most of these studies used small sample sizes, but we and others have occasionally observed that some subjects are “high-responders” to this standard exercise, with postexercise blood CK values as high as 80,000 U/L [8,26]. We recently examined blood CK activity in 208 subjects who performed 50 maximal eccentric contractions of the elbow flexor muscles. The average CK increase was about 7500 U/L, peaking at 4 days postexercise and returning to near baseline by 10 days postexercise. In a study from another laboratory [28], nine subjects performed 100 maximal eccentric contractions of the knee extensors; the peak CK activity at 4 days postexercise was 18,129 U/L, and at 11 days postexercise CK remained elevated at 1009 U/L, then returned to baseline by 14 days. High-force eccentric contractions of isolated muscle groups show a larger (often > 5000 U/L) and more delayed peak (4–5 days postexercise) in circulating CK activity compared with endurance type exercises. Relationship of CK and Renal Function Although we and others have reported cases in which CK is profoundly elevated after controlled exercise in laboratory experiments, we have never provoked renal failure, nor has renal failure been reported in the numerous laboratory studies of exercise-induced muscle damage. However, these studies have typically not monitored renal function to determine possible renal compromise. Clinical definitions of acute renal failure are commonly based on changes in creatinine, blood urea nitrogen (BUN), and urine output. In a recent report [8], we presented data on measures of renal function (potassium, osmolality, BUN, creatinine, phosphorus, and uric acid) in the 208 subjects who performed strenuous one-arm eccentric exercise. Despite CK levels for 11 subjects between 15,000 and 20,000 U/L, 16 subjects between 21,000 and 30,000 U/L, and eight subjects between 31,000 and 80,000 U/L, there was no impairment in renal function. Hurley [29] described a case of a 16-year-old boy who presented at an office visit with a 2-day history of dark urine and painful, swollen arms produced from a 2-hour weight lifting regimen performed 3 days prior. His CK was 181,690 U/L, myoglobinuria was positive, and creatinine was normal. He was not hospitalized and recovered with supportive therapy of rest, fluids, and analgesics. We [30] described the case of a 37-year-old emergency room physician who performed excessive exercise in a health club under direction of a personal trainer. The day after the exercise session, he noted severe arm pain, and on the following day, dark urine. His blood CK levels over a 3-day period were 19,746, 70,158, and 45,461 U/L. He was not hospitalized and recovered with self-treatment of oral hydration and bicarbonate. There have been many reports of rhabdomyolysis induced by recreational exercise [30–45], but fewer incidents of concomitant acute renal failure when there is no other underlying problem (eg, drug or alcohol abuse, or underlying genetic predisposition such as sickle cell trait or carnitine palmitoyltransferase deficiency) [45–48]. Demos et al. [38] reported data on 11 Marine Corps recruits who were hospitalized with muscle pain and swelling of the shoulders and arms on the third day of basic training that included push-ups, pull-ups, rope climbs and other upper body exercises. Eight of the 11 men noted dark urine and dipstick analysis indicated the presence of heme pigment for all patients. Serum BUN, creatinine, electrolytes, calcium, phosphate, and total and direct bilirubin levels were normal. The men were hospitalized, treated with fluid infusion, and had an uneventful recovery. The CKs on the day after admission ranged from 26,708 U/L to 109,609 U/L. Sinert et al. [49] reported 35 cases of exertional rhabdomyolysis in young healthy male prisoners who had performed exercise, specifically repetitive squat jumps, chin-ups, or lifting weights, as a consequence of losing a game of dominoes. The prisoners presented to the hospital an average of 2.7 days after the exercise exertion with symptoms of thigh or arm pain and a change in urine color. The range in CK was 700 U/L to 165,000 U/L. None presented with hyperkalemia, acidosis, or elevated creatinine or BUN, and other blood tests were normal. All patients tested positive for blood in the urine without microscopic hematuria. Although some of these men presented with alarmingly high CK levels, by the time they presented to the hospital, they were likely already on the way to healing. However, patients were hospitalized and all but one treated with intravenous forced bicarbonate diuresis. No patient developed renal failure. In most of the cases, treatment did not occur until at least 48 hours after the exercise, which is common in cases of exertional rhabdomyolysis, in which patients do not present to the emergency room until 48 hours after the event when the urine is either noticeably dark and/or the pain is severe. Generally heat stress, dehydration, exercise-induced aciduria (which decreases myoglobin's solubility), or trauma are factors when exertional rhabdomyolysis (high CK) results in acute renal failure in otherwise healthy people [49]. Seedat et al. [46] examined hospital records over an 18-year time frame (1969–1986) and noted that 19 runners who participated in the Comrades Marathon in South Africa were admitted to the renal unit for treatment of acute renal failure, where dehydration and hypotension were present. Another case report [48] described a 25-year-old woman who hiked down the Grand Canyon in an ambient temperature of 100°F for 4 hours and suddenly collapsed. Four hours later she was transported to the hospital, where her laboratory test results indicated a serum creatinine of 3.2 mg/dL, BUN of 21 mg/dL, and an impressive CK of 1.6 million U/L. She was treated for heat stroke and acute renal failure. Even those with moderate increases in CK may develop acute renal failure. Hurley [29] described the case of a 17-year-old young man who presented with nausea and back pain 48 hours after participating in a high school football game and a session of bongo drum playing. Because of the back pain and possibility of trauma, an intravenous pyelogram was performed that showed poorly functioning kidneys with faint nephrogram. His CK on hospital admittance was 1723 U/L and increased the next day to 2423 U/L. Creatinine levels were 3.0 on admittance and 5.9, 9.0, and 2.5 mg/dL over the next several days. It was concluded that the myoglobinemia (from exercise) and radiographic contrast material led to acute renal failure. Baysal et al. [45] described a case of a 21-year-old man who participated in 1.5 hours of weight lifting exercise. He appeared to have no evidence of dehydration, heat stress, or other intervening factors, and presented 4 days later with painful, swollen arms and dark urine. CK was 101,080 U/L, BUN was 73 mg/dL, and creatinine was 8.4 mg/dL. A kidney biopsy showed acute tubular necrosis with eosinophilic material in the tubules. The authors suggested that the swelling produced a type of compartment syndrome leading to continued muscle breakdown. Conclusions Recreational activity frequently produces large increases in circulating CK activity without consequence. Thus, high CK levels alone do not portend renal failure. Most cases of exertional rhabdomyolysis can, and probably do, resolve on their own without treatment. When taking a blood sample during a routine check, for example in monitoring patients on statin therapy, a high blood CK activity may indicate that strenuous exercise was performed in the previous 10 days. Patients should be queried as to their exercise history during this time. Snow shoveling, dirt shoveling, lifting and lowering heavy boxes, strenuous resistance training, and excessive calisthenics (such as push-ups and pull-ups) are exercises that may dramatically increase circulating CK activity for several days due to forceful eccentric contractions. In addition to elevated CK, factors such as underlying disease, dehydration, environmental heat stress, or genetic predisposition (eg, sickle cell trait) are likely required for exertional rhabdomyolysis to result in acute renal failure [8]. Persons who present to the emergency room with painful, swollen muscles about 2 days after a bout of strenuous exercise should be monitored for kidney function (BUN and creatinine), evidence of myoglobinuria and dehydration, and be queried regarding hydration, heat stress during the exercise, and possible trauma. In cases of exertional rhabdomyolysis, especially in laboratory situations, CK levels up to 100,000 U/L in the absence of nephrotoxic factors have been found to resolve without consequence when no treatment is provided. However, because few data confirm this in a clinical situation in which there may be comorbidities, it remains conservative and prudent in the emergency room to hydrate intravenously and monitor closely to help avoid hyperkalemia and/or acute renal failure in the face of fulminant exertional rhabdomyolysis.