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Grand Rounds: Woman, 39, With Leg Weakness After Exercise Class


A 39-year-old woman presented to the emergency department (ED) with a chief complaint of muscle aches and pain. She stated that three days earlier, she had begun exercising in a 45-minute “spinning” class (ie, riding a stationary bicycle with a weighted front wheel). The patient had not engaged in any aerobic exercise for at least six months before the spinning class. She mentioned that much older participants in the class were outperforming her, but she did not feel the need to keep up with them.

After dismounting, the woman said, she experienced weakness in her legs and had great difficulty ambulating. She went home, took 400 mg of ibuprofen, and went to bed. She awoke with pain and swelling in both thighs and continued to take ibuprofen, in addition to applying a topical mentholated preparation to her thighs. She took an Epsom salts bath two days later.

On the morning of the third day after the spinning class, she voided black urine and presented to the ED.

The patient had no significant medical history. Surgical history was limited to removal of a ganglion cyst on her wrist. She denied any history of seizure disorder, thyroid disease, hepatitis, heart disease, or hyperlipidemia.

The patient had been taking ibuprofen as needed since the spinning class. She was taking no other medications. She denied any allergies to drugs or food.

The patient admitted to smoking one pack of cigarettes per week and to occasional alcohol consumption but denied use of illicit drugs. She was employed as an executive officer for a large business association.

On physical examination, the patient’s vital signs were blood pressure, 134/73 mm/Hg; pulse, 86 beats/min; and respirations, 16 breaths/min. She was afebrile, alert, and oriented. Her sclera were nonicteric. Her neck was supple with no anterior cervical lymphadenopathy. There was no thyroid enlargement, her lungs were clear to auscultation, and her heart sounds were regular. There was no peripheral edema, and dorsalis pedis pulses were present bilaterally. Her thighs appeared swollen but were not tender to palpation.

The patient’s history, combined with an extremely high level of serum creatine phosphokinase (CPK; ie, 123,800 U/L [reference range, 45 to 260 U/L1]), confirmed a diagnosis of rhabdomyolysis. She was admitted for close observation. The patient’s urinalysis revealed 2 to 5 red blood cells and 6 to 10 white blood cells per high-power field. Moderate occult blood was detected, with no casts or protein noted. A urine myoglobin test was not performed.

The patient underwent IV hydration with dextrose 5% in water and three ampules of sodium bicarbonate after being given a 2.0-L saline bolus. Ibuprofen was discontinued. IV hydration with bicarbonate solution was continued until the patient’s CPK level declined significantly. She underwent daily laboratory testing (see Table 1). Her renal function remained stable, and she was discharged on hospital day 7.

Rhabdomyolysis is a clinical condition defined as muscle necrosis resulting from the release of intracellular skeletal muscle components (including myoglobin, CPK, potassium, phosphorus, and aldolase) into the extracellular compartment.1-3 The condition was first described during the bombing of London in World War II, with high incidence of crush injuries, shock, and associated kidney damage.4 The preponderance of such injuries during a 1988 earthquake in Armenia led the International Society of Nephrology to form its Renal Disaster Relief Task Force, which has provided support at numerous other disaster scenes since then.5

Rhabdomyolysis has been identified with a variety of pathologic events: those that cause muscle trauma, those associated with muscle use or overuse, and other etiologies involving genetic, metabolic, infectious, or pharmaceutical factors.1 Many of the reported causes of rhabdomyolysis are listed in Table 2.1,2

For patients with muscle trauma, the etiology of rhabdomyolysis is clear, but for those with other disease states, diagnosis may be more elusive. Patients who present with rhabdomyolysis after excessive exercise, for example, may have underlying metabolic disorders that predispose them to exertional rhabdomyolysis, such as chronic hypokalemia resulting from primary hyperaldosteronism.1 Others may have a muscle enzyme deficiency, as in McArdle’s syndrome or carnitine deficiency.6

Alterations in blood chemistries can also contribute to development of rhabdomyolysis, even when more obvious etiologies for muscle necrosis are evident. Hypokalemia interferes with the vasodilation that normally occurs during exercise to increase muscle blood flow.1,7,8 Continued exercise can lead to muscle necrosis, raising a concern for athletes who take diuretics.1 Hypophosphatemia leads to a state of muscle necrosis; this is of particular concern for alcoholic patients who receive hyperalimentation without repletion of phosphates.9

Patients with rhabdomyolysis usually present with myalgias, darkened urine (red, brown, or black), and a clinical scenario that corroborates the diagnosis (ie, history of trauma, excessive exercise, use of an offending medication).1 Some patients may have minimal to absent symptoms or symptoms that occur only after exercise.3

A careful history is key. While traumatic causes are obvious, it is important to ask a patient with rhabdomyolysis after exertion about previous history of excessive weakness during or immediately after exercise, excessive cramping, or discoloration of urine after exercise. The family history may point to a genetic abnormality. A thorough understanding of the patient’s use of medications, including OTC agents, is also important. Rhabdomyolysis has been reported in patients who use herbal remedies, including those taken to facilitate weight loss or to improve lipid profiles.10,11

For patients suspected of having rhabdomyolysis, a serum CPK level should be obtained; results exceeding normal values by five times confirm the diagnosis.3 Measurements for potassium, phosphorus, and calcium are also important to determine, as is renal function. A high level of serum aldolase (an enzyme that breaks down glucose in muscle tissue) can also support a diagnosis of rhabdomyolysis.1,12 Urinalysis and urine myoglobin testing are also warranted, although a negative urine myoglobin test result does not rule out rhabdomyolysis in the presence of an elevated CPK level. Myoglobin is cleared rapidly by the kidneys, whereas serum CPK levels change slowly.1

Any patient who presents with acute rhabdomyolysis and low to normal values for potassium or phosphate should be evaluated further for hypokalemia and hypophosphatemia as contributing or etiologic factors. Hypocalcemia may occur in the early course of rhabdomyolysis as calcium salt is deposited in muscle tissue. Patients recovering from rhabdomyolysis may experience rebound hypercalcemia as the damaged muscle releases the deposited calcium.7,13

In most cases of rhabdomyolysis, only laboratory values are needed to make the diagnosis and follow the course of the episode.1 However, when the etiology appears to involve metabolic deficiencies or genetic etiologies, it may become necessary to order additional diagnostic tests. These may include tests for thyroid function, a carnitine level to screen for glycogen storage diseases, and toxin screening (eg, for illicit drugs, such as cocaine).2,6

Treatment and Management
Effective treatment of rhabdomyolysis relies on recognizing the underlying disorder.1 For patients with muscle trauma (eg, crush injury) or muscle overuse, the mainstay of treatment is aggressive fluid resuscitation and prevention of acute injury to the kidneys.13 As for patients with an injury induced by a pharmaceutical agent or a toxin, removal of the offending agent is required, followed by hydration and prevention of renal damage. Supportive care during an infectious illness is also essential.14

Additionally, treatment must address the complications inherent with rhabdomyolysis.1 In addition to CPK, potassium, phosphorus, and myoglobin are also released from skeletal muscle tissue. Hyperkalemia can be fatal, and potassium levels must be monitored closely to avert this condition.7,8,13 During an episode of rhabdomyolysis, normal levels of both potassium and phosphorus should raise the clinician’s suspicion for underlying hypokalemia and hypophosphatemia—conditions that may have contributed to the episode of rhabdomyolysis. Hypocalcemia may also develop.13

Released myoglobin may cause acute kidney injury, as is the case in 33% to 50% of patients with rhabdomyolysis.3 In early studies, it was determined that alkalinizing the urine with IV isotonic bicarbonate might thwart onset of acute kidney injury.1,2,15 Time is critical, and even on the battlefield or at the scene of a recent disaster, most attempts at resuscitation are begun immediately. IV access may be problematic, but administration of oral bicarbonate solutions has also proven effective.15 Close follow-up of the serum urea and creatinine levels and measurement of the urine pH during alkalinization is warranted throughout the course of the episode.

Unfortunately, some patients respond poorly to these conservative measures, and the released myoglobin can cause renal tubular blockage and necrosis, resulting in acute kidney injury.1 Renal replacement therapy may be required.16 However, most episodes of dialysis-dependent acute renal injury do subside with time.

For patients with less elusive causes of rhabdomyolysis, treatment will hinge on a workup of the possible etiologies and follow-up treatment to target the apparent cause. For example, carnitine may be administered to patients with carnitine deficiency, and hypokalemic patients may be given potassium.1,6,7 These patients will also need counseling before they consider engaging in an exercise program.

Patient’s Outcome
The case patient presented with exertional rhabdomyolysis; improper hydration, severe deconditioning, and a relatively low serum potassium level may all have contributed to the muscle necrosis she experienced. She was given IV alkaline solutions and did not develop acute kidney injury. She was discharged from the hospital and at the time of this writing was awaiting outpatient follow-up.

It should be interesting to see whether the case patient experiences any further episodes of severe weakness after engaging in exercise. Her low-normal potassium level (reference range, 3.5 to 5.3 mmol/L17) warrants further follow-up, as does her mildly elevated thyroid-stimulating hormone level (reference range, 0.5 to 4.7 mcIU/mL17).

Patients with rhabdomyolysis may present with muscle aches, darkened urine, and/or weakness; an elevated CPK level confirms the diagnosis. Management is mainly conservative, with IV hydration accompanied by alkalinizing the urine and correcting any metabolic abnormalities, such as potassium deficiencies. For the few patients who experience severe acute kidney injury, renal replacement therapy may be necessary.

While most causes of rhabdomyolysis have obvious clinical scenarios, such as a crush injury, a search for muscle enzyme deficiencies, disorders of potassium homeostasis, and thyroid abnormalities is also warranted in patients who present with exertional rhabdomyolysis.

1. Huerta-Alardín AL, Varon J, Marik PE. Bench-to-bedside review: rhabdomyolysis—an overview for clinicians. Crit Care. 2005;9(2):158-169.

2. Warren JD, Blumbergs PC, Thompson PD. Rhabdomyolysis: a review. Muscle Nerve. 2002;25(3):332-347.

3. Lima RSA, da Silva GB Jr, Liborio AB, Daher ED. Acute kidney injury due to rhabdomyolysis. Saudi J Kidney Dis Transpl. 2008;19(5):721-729.

4. Bywaters EG, Beall D. Crush injuries with impairment of renal function [reprinted from BMJ, 1941]. J Am Soc Nephrol. 1998;9(2):322-332.

5. Vanholder R, Van Biesen W, Lameire N, Sever MS; International Society of Nephrology/Renal Disaster Relief Task Force. The role of the International Society of Nephrology/Renal Disaster Relief Task Force in the rescue of renal disaster victims. Contrib Nephrol. 2007;156:325-332.

6. Toledo R, López V, Martín G, et al. Rhabdomyolysis due to enzyme deficiency in muscles. Nefrología. 2009;29(1):77-80.

7. Agrawal S, Agrawal V, Taneja A. Hypokalemia causing rhabdomyolysis resulting in life-threatening hyperkalemia. Pediatr Nephrol. 2006;221(2): 289-291.

8. Knochel JP, Schlein EM. On the mechanism of rhabdomyolysis in potassium depletion. J Clin Invest. 1972:51(7):1750-1758.

9. Knochel JP. Hypophosphatemia and rhabdomyolysis. Am J Med. 1992;92(5):455-457.

10. Mansi IA, Huang J. Rhabdomyolysis in response to weight-loss herbal medicine. Am J Med Sci. 2004; 327(6): 356-357.

11. Heber D, Yip I, Ashley JM, et al. Cholesterol-lowering effects of a proprietary Chinese red-yeast-rice dietary supplement. Am J Clin Nutr. 1999;69(2): 231-236.

12. Hooda AK, Narula AS. Exertional rhabdomyolysis causing acute renal failure. Med J Armed Forces India. 2005;61(4):395-396.

13. Chatzizisis YS, Misirli G, Hatzitolios AI, Giannoglou GD. The syndrome of rhabdomyolysis: complications and treatment. Eur J Intern Med. 2008;19(8): 568-574.

14. Blanco JR, Zabalza M, Salcedo J, et al. Rhabdomyolysis of infectious and noninfectious causes. South Med J. 2002;95(5):542-544.

15. Ron D, Taitelman U, Michaelson M, et al. Prevention of acute renal failure in traumatic rhabdomyolysis. Arch Intern Med. 1984;144(2):277-280.

16. Soni SS, Nagarik AP, Adikey GK, Raman A. Using continuous renal replacement therapy to manage patients of shock and acute renal failure. J Emerg Trauma Shock. 2009;2(1):19-22.

17. Normal laboratory values. In: Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:2526-2546.

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