A Case of Severe Exercise-Induced Rhabdomyolysis Associated With a Weight-Loss Dietary Supplement

Written By: Sam Savage

Published Date: June 28, 2007 Last Edited: June 28, 2007

By Burke, Jennifer Seda, Gilbert; Allen, David; Knee, Treyce S

In response to questions about the safety of ephedra-based dietary products, ephedra-free products are now available. Many contain synephrine, a sympathomimetic amine with structural similarities to ephedra. We present a 22-year-old, previously healthy, African American male with sickle cell trait who developed rhabdomyolysis after ingestion of a synephrine-containing dietary supplement. The patient developed fatigue, dehydration, and myalgias while exercising. He developed severe rhabdomyolysis, with a peak creatine phosphokinase level of 2.8 million U/L, complicated by pulmonary edema, acute renal failure, disseminated intravascular coagulation, and bilateral compartment syndromes in his lower extremities. He required prolonged hospitalization for hemodialysis, multiple wound debridements, hyperbaric oxygen therapy, and physical therapy. He has permanent sensory and motor neurological deficits in his distal lower extremities. Military physicians should routinely inquire about the use of dietary supplements, educate patients about the potential adverse reactions associated with these agents, and encourage healthy diets and exercise for weight loss. Introduction

In 2004, the Food and Drug Administration (FDA) banned ephedra- containing products because of numerous reports of adverse cardiovascular and neurological events.1 As a result, many ephedrine- containing weight-loss products were reformulated with ephedra-free compounds. Some formulations contain synephrine (Citrus aurantium), which is structurally similar to ephedrine and phenylpropanolamine. Because dietary supplements are not under state or federal regulation, the FDA relies on Medwatch and case reports to monitor their safety and efficacy. Limited studies demonstrate increased blood pressure without desired weight loss when synephrine is combined with caffeine.2 There are case reports of synephrine- associated ischemie stroke, arrhythmias, and myocardial infarction.3 We present a case of a previously healthy male subject who developed severe rhabdomyolysis, complicated by acute renal failure and bilateral compartment syndrome, while exercising and using a dietary supplement called Lipo 6 (Nutrex Research Inc., Winter Park, Illinois). Lipo 6 is a supplement containing synephrine and caffeine that is marketed to accelerate fat loss. Rhabdomyolysis is an acute, fulminating, potentially fatal disease of skeletal muscle that entails destruction of muscle, as evidenced by myoglobinemia and myoglobinuria.

Despite a lack of strong scientific evidence for their positive effects, amphetamines were heavily used for performance enhancement before the Controlled Substances Act of 1970.4 Subsequently, the market was dominated by less-potent sympathornimetic amines. The market for these sympathomimetic amines exploded after the Dietary Supplements Health Education Act was enacted in 1994, despite their decreased potency and the lack of scientific support for efficacy.4 The Dietary Supplements Health Education Act allows manufacturers to sell supplements as long as they do not make claims regarding preventing or curing disease.5 FDA regulations5″8 do not pertain to the manufacturing of these herbal remedies. The FDA relies on a system of self-reporting for adverse events, and it is estimated that

The sympathomimetic amine ephedra was banned in 2004 because of numerous reports of adverse events.1 Ephedra, an CLand a-adrenergic receptor agonist, is structurally similar to methamphetamines, phenylpropanolamine, cocaine, and pseudoephedrine.6 In 2001, ephedra products were responsible for 64% of all supplement-related adverse events, despite representing only 0.8% of all dietary supplement sales.11 In the 140 reports of adverse events Haller and Benowitz12 reviewed to determine the relationship to ephedra, cardiovascular symptoms were the most common (47%), with hypertension being the most frequent adverse cardiovascular event. Central nervous system events, including strokes and seizures, constituted 18% of the events.12 Phenylpropanolamine, a cold preparation and appetite suppressant that is also structurally related to ephedra, was shown to be an independent risk factor for hemorrhagic strokes in female subjects in the Hemorrhagic Stroke Project.13

When ephedra was removed from the market in 2004, bitter orange (C. auronttum), or synephrine, became the popular alternative.4 A systematic review of C. auraniium for weight loss by Bent et al.2 found no evidence for the efficacy of synephrine for weight loss and cautioned that consumption of this supplement could result in adverse cardiovascular events. Adverse events associated with synephrine, which is structurally related to ephedra, include case reports of myocardial infarction, arrhythmias, and ischemie stroke.H Literature review did not reveal any cases of rhabdomyolysis related to synephrine use. We present a case of severe rhabdomyolysis in a patient using a synephrinecontaining dietary supplement for weight loss.

case Report

A 22-year-old, previously healthy, obese (body mass index, 31), African American, male, active duty sailor with sickle cell trait presented to the emergency department with fatigue, lightheadedness, and myalgias, which had developed while the patient was running for the physical readiness test. The patient was diagnosed as having exercise-induced rhabdomyolysis and heat exhaustion. Rhabdomyolysis is an acute, fulminating, potentially fatal disease of skeletal muscle that entails destruction of muscle, as evidenced by myoglobinemia and myoglobinuria. The patient had a maximal creatine phosphokinase level of 14,070 U/L and elevated liver function test results but preserved renal function. An elevated creatine phosphokinase level is an indicator of skeletal or myocardial muscle injury. After a brief hospitalization, followed by outpatient observation aboard his ship, the patient’s creatine phosphokinase levels and liver function test results improved but did not return to normal. According to the patient, his health care providers did not inquire about the use of supplements and were not aware that he was using a weight-loss dietary supplement.

Several weeks later, the patient resumed participation in the physical readiness test, without medical clearance, and experienced a second episode of exercise-induced rhabdomyolysis and heat exhaustion while running. After this episode, the patient admitted using a dietary supplement twice daily for the past 3 months. He presented to the emergency department with hypotension, tachycardia, tachypnea, and myalgias. Initial laboratory studies revealed combined lactic acidosis and respiratory acidosis with concomitant metabolic alkalosis stemming from muscle hypoxia and ischemia in the setting of pending respiratory failure. Other significant laboratory studies were an elevated white blood cell count of 24,000 cells per mm3, an elevated D-dimer level (an indicator of disseminated intravascular coagulation or venous thrombosis), and an elevated creatinine level of 4.4 mg/dL (an indicator of acute renal failure). Urinalysis revealed proteinuria and mild hematuria. Chest radiographs revealed no acute cardiopulmonary process, an echocardiogram revealed no evidence of impaired ventricular function, and a ventilation perfusion scan revealed no evidence of venous pulmonary thromboembolism. The initial creatine phosphokinase level was elevated at 704 U/L; within 24 hours, levels peaked at an incredible 2.8 million U/L, evidence of severe muscle injury. Another indicator of severe muscle injury was a urinary myoglobin level of 3.6 million [mu]g/mL. Urine drug screen results were negative. The serum aldolase level (a test for diagnosing myopathies) was normal.

Over the next 96 hours, the patient’s hospital course was complicated by hypovolemic shock requiring resuscitation with fluids and vasopressors, respiratory failure requiring intubation, acute renal failure requiring emergency dialysis, and disseminated intravascular coagulation. The patient had no evidence of cardiogenic or septic shock. Within 48 hours, he developed severe tightness, pallor, and pain in his lower extremities. He required emergency fasciotomies for left thigh and bilateral lower-extremity compartment syndromes. In this condition, increased pressure in a confined anatomical space adversely affects the circulation and threatens the function and viability of skeletal muscle, requiring incision of the fascia to relieve the pressure. Despite rapid surgical intervention, the patient sustained severe skeletal muscle ischemia and necrosis.

Over the next 6 weeks, the patient received hemodialysis because of his renal failure. Two weeks into treatment, the patient developed hypercalcemia, presumed to be a late phase of recovery from his rhabdomyolysis, in which calcium is released from calcium salts from injured muscle. His compartment syndrome required multiple debridements for removal of ischemic muscle, wound vacuum- assisted closure devices on both extremities to facilitate wound healing, and repeated transfusions because of blood loss from open wounds. The patient required hyperbaric oxygen therapy to promote increased perfusion of his lower extremities. After 6 weeks, his renal function improved and he no longer required hemodialysis. Despite intensive management by the surgical and medical staffs, the patient sustained permanent bilateral sensory and motor neurological deficits in both distal lower extremities, requiring prolonged physical therapy and braces on both lower extremities to walk. The patient was medically discharged from military service and required vocational and physical rehabilitation through the Veteran’s Administration. Discussion

In rhabdomyolysis, muscle injury is induced by trauma, infection, inflammatory myopathies, metabolic disorders, endocrine disorders, medications, or supplements. We found no other case reports in the literature of severe rhabdomyolysis in patients using synephrine- containing dietary supplements. Although this patient had several predisposing factors for rhabdomyolysis, including a recent episode of rhabdomyolysis, sickle cell trait, and exercising in a warm climate, we suspect the severity of the rhabdomyolysis was aggravated by the use of a dietary supplement. The patient had no history of exerciseassociated rhabdomyolysis when performing the physical readiness test without dietary supplements.

The dietary supplement this patient was taking contained synephrine, caffeine, and yohimbine. Several of these compounds are associated with adverse reactions. Synephrine has reported associations with ischemie stroke, arrhythmias, myocardial infarction, hypertension, and syncope.14 Caffeine has a synergistic effect with synephrine.14 case reports implicate caffeine in rhabdomyolysis at toxic doses; when combined with synephrine, it is also associated with hypertension, seizures, and arrhythmias.15,16 Yohimbine is associated with hypertensive crisis when combined with sympathomimetic agents such synephrine, and there is one report of renal failure attributable to the combination.17,18 We hypothesize that the synephrine and caffeine in this patient’s dietary supplement increased this patient’s risk of rhabdomyolysis via ischemic injury to muscle through vasoconstriction or vasospasm, myocyte thermoregulatory dysfunction, toxin-associated myocyte injury, or impaired calcium homeostasis causing myonecrosis. We cannot eliminate the fact that the sickle cell trait increased the patient’s propensity for rhabdomyolysis.19-21 Further research is warranted to investigate the effects of dietary supplements on skeletal muscle during exercise, especially in patients with risk factors such as sickle cell trait.

This case study raises several important points for Armed Forces medicine. Often our patients are overweight and under enormous pressures to maintain normal weight for active duty status. Carlton et al.22 found that active duty men used diet pills at a year-round rate of 3.5% but the rate increased to 14.9% around the times for weigh-ins and measurements. The weight standards, although important for military bearing and readiness, place our service members at higher risk for eating disorders, unhealthy diets, and use of supplements for weight loss. The sale of supplements at military faculties, combined with the assumption of safety if they are sold over the counter, increases the vulnerability of our active duty consumers.

Service members can benefit from education regarding the effects and risks associated with dietary supplement use, as well as healthy ways to promote weight loss and fitness. Physicians should be aware of the potential side effects of supplements and should routinely question and caution patients on their use. We propose that the use of dietary supplements might have increased the propensity for rhabdomyolysis and subsequent complications in our patient’s case. Our case illustrates the importance of physicians routinely asking their patients about supplement use and encouraging the reporting of adverse events, to monitor for trends.

References

1. Food and Drug Administration: Final rule declaring dietary supplements containing ephedrine alkaloids adulterated because they present an unreasonable risk, December 2004. Available at http:// www.fda.gov/oc/initiatives/ephedra/ febraary2004/finalsummary.html; accessed February 6, 2006.

2. Bent S, Padula A, Neuhaus J: Safety and efficacy of Citrus ourontium for weight loss. Am J Cardiol 2004; 94: 1359-61.

3. Haller CA, Benowitz NL, Jacob P III: Hemodynamic effects of ephedra-free weight-loss supplementation in humans. Am J Med 2005; 118: 998-1003.

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5. Dietary Supplement Health and Education Act of 1994, Pub. L. 103-417, [section]l(a), 109 Stat. 4325, October 25, 1994.

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10. Blowey DL: Nephrotoxicity of over-the-counter analgesics, natural medicine, and illicit drugs. Adolesc Med 2005; 16: 31-43.

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12. Haller CA, Benowitz NL: Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med 2000; 343: 1833-8.

13. Keman WN, Viscoli CM, Brass LM, et al: Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med 2000; 343: 1826- 32.

14. Bouchard NC, Howland MA, Greller HA, Hoffman RS, Nelso LS: Ischemic stroke associated with use of an ephedra-free dietary supplement containing synephrine. Mayo Clin Proc 2005; 80: 541-5.

15. Wrenn KD, Oschner I: Rhabdomyolysis induced by a caffeine overdose. Ann Emerg Med 1989; 18: 94-7.

16. Michaelis HC, Sharift S, Schoel G: Rhabdomyolysis after suicidal ingestion of an overdose of caffeine, acetaminophen, and phenazone as a fixed-dose combination (Spalt N). J Toxicol Clin Toxicol 1991; 29: 521-6.

17. Sandier B, Aronson P: Yohimbine-induced cutaneous drug eruption, progressive renal failure, and lupus-like syndrome. Urology 1993; 41: 343-5.

18. Ruck B, Shih RD, Marcus SM: Hypertensive crisis from herbal treatment of impotence. Am J Emerg Med 1999; 17: 317-8.

19. Dincer HE, Raza T: Compartment syndrome and fatal rhabdomyolysis in sickle cell trait. WMJ 2005; 104: 67-71.

20. Eisenbach CH, Pohl J, Dikow R, Stremmel W, Encke J: Severe rhabdomyolysis and renal failure triggered by a sauna visit in sickle cell trait: a case report. Clin Nephrol 2005; 63: 229-31.

21. Gardner JW, Kark JA: Fatal rhabdomyolysis presenting as mild heat illness in military training. Milit Med 1994; 159: 160-3.

22. Carlton JR, Manos GH, Van Slyke JA: Anxiety and abnormal eating behaviors associated with cyclical readiness testing in naval hospital active duty populations. Milit Med 2005; 170: 663-7.

Guarantor: CDRTreyce S. Knee, MC USN

Contributors: LT Jennifer Burke, MC USNR*; LCDR Gilbert Seda, MC USN[dagger]; LCDR David Alien, MC USNR[dagger]; CDRTreyce S. Knee, MC USN[dagger]

* Regional Support Organization Norfolk, Norfolk, VA 23511.

[dagger] Naval Medical Center Portsmouth, Portsmouth, VA 23708.

Presented at the American College of Physicians, U.S. Navy Chapter Scientific Meeting, October 6-8, 2005, San Diego, CA.

The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, the Department of Defense, or the U.S. government.

This manuscript was received for review in March 2006. The revised manuscript was accepted for publication in November 2006.

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