CASE REPORT
EXERCISE-INDUCED SYNCOPE ASSOCIATED WITH XENADRINE
Exercise-Induced Syncope Associated With QT Prolongation and Ephedra-Free Xenadrine 2ND LT JAVED M. NASIR, USAF, MC; MAJ STEVEN J. DURNING, USAF, MC; CDR MICHAEL FERGUSON, USN, MC; HELEN S. BAROLD, MD, MPH; AND MARK C. HAIGNEY, MD The Food and Drug Administration recently banned the sale of ephedra alkaloids because of their association with arrhythmic sudden death, myocardial infarction, and stroke. This has resulted in the emergence of formulations marketed for weight loss and performance enhancement that are “ephedra free” but contain other sympathomimetic substances, the safety of which has not been established. We report a case of exercise-induced syncope in a healthy 22-year-old woman that occurred 1 hour after she took the second dose of Xenadrine EFX, an ephedra-free weight-loss supplement. Electrocardiography revealed prolongation of the QT interval (corrected QT, 516 milliseconds); this resolved in 24 hours. Results of echocardiography and exercise stress testing were normal. Nine months of monitoring with an implanted loop recorder revealed no arrhythmias in the absence of Xenadrine EFX. Although this product contains a number of compounds whose pharmacologic effect is poorly characterized, notable quantities of phenylephrine are present, and the proarrhythmic potential of this compound in the setting of exercise is discussed.
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n December 30, 2003, the US Food and Drug Administration alerted consumers and manufacturers that ephedra-containing substances were no longer considered safe and would be banned in the next 60 days.1 Ephedracontaining substances have been used to promote weight loss and enhance athletic performance but have been associated with numerous reports of arrhythmic events, sudden death, myocardial infarction, and stroke.2,3 Several companies have responded to the public’s concerns regarding the safety of ephedra by offering new “ephedra-free” formulations such as Xenadrine EFX. These formulations typically contain an ephedra-like alkaloid, synephrine (phenylephrine), and large quantities of caffeine, as well as many other ingredients. Some of these compounds have pronounced sympathomimetic effects similar to ephedra.4 Although the adverse effects of ephedra ingestion have been well documented, to our knowlFrom the Uniformed Services University of the Health Sciences, Bethesda, Md (J.M.N., S.J.D., M.C.H.); and National Naval Medical Center, Bethesda, Md (S.J.D., M.F., H.S.B., M.C.H.). The views expressed in this article reflect the opinions of the authors only and not the official policy of the Uniformed Services University, the United States Navy, or the Department of Defense. Address reprint requests and correspondence to Mark C. Haigney, MD, Division of Cardiology, Uniformed Services University of the Health Sciences, Room A3060, 4301 Jones Bridge Rd, Bethesda, MD 20814 (e-mail:
[email protected]). © 2004 Mayo Foundation for Medical Education and Research
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edge, this is the first report of a possible arrhythmic complication due to an ephedra-free weight-loss supplement. REPORT OF A CASE A previously healthy 22-year-old woman presented to our emergency department after a syncopal episode that occurred while running. She had not run for 1 month before the syncopal event. She reported that she had been taking 1 ephedra-free Xenedrine EFX tablet daily for 1 year, had stopped for 3 months, and had restarted the daily regimen the evening before the episode. She drank water in the morning before she ran but did not eat, her usual routine. She said that she took 1 Xenadrine EFX tablet 45 minutes before running. Three miles into a 3.5-mile run, the patient felt lightheaded and sensed a rapid heart rhythm. She then fell to the ground and lost consciousness. The patient denied having antecedent chest For editorial pain, shortness of breath, weakness, comment, see page 979 paresthesias, cough, or a history of syncope. She had no remarkable medical or surgical history, was taking no other medications (including other supplements), and had no known drug allergies. The patient had no family history of syncope, sudden cardiac death, or drowning. Physical examination after the syncopal event revealed a well-developed, well-nourished woman in no acute distress. Vital signs on arrival at the emergency department were a temperature of 37.3°C, heart rate of 87 beats/min, respirations of 16/min, and blood pressure of 120/71 mm Hg. The patient’s pulse and blood pressure did not change substantially between supine and standing. She had no jugular venous distention. Findings on a complete physical examination were notable only for a grade II/VI systolic ejection murmur at the left upper sternal border that did not augment with Valsalva maneuver. Laboratory studies on admission included a serum potassium level of 4.1 mEq/L, calcium level of 8.8 mg/dL, anion gap acidosis level of 20 mEq/L, and glucose level of 225 mg/dL. Urinalysis revealed ketones of 40 mg/dL. The anion gap acidosis and ketosis resolved rapidly with hydration. A urine pregnancy test was negative; a toxicologic screen was not performed. Posteroanterior and lateral chest
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FIGURE 1. Twelve-lead electrocardiogram obtained approximately 2 hours after the patient’s syncopal event. The tracing is abnormal because of the presence of sinus tachycardia and QT prolongation with a corrected QT of 516 milliseconds.
radiographs showed a normal-sized heart. A slight convexity was noted in the region of the pulmonary trunk. An electrocardiogram in the emergency department revealed sinus tachycardia at a rate of 100 beats/min and a QT interval of 400 milliseconds (corrected QT [QTc], 516 milliseconds), consistent with QT prolongation (Figure 1). Electrocardiography repeated 4 hours later revealed normal sinus rhythm, a heart rate of 82 beats/min, a QT interval of 400 milliseconds, and a borderline prolonged QTc of 466 milliseconds. The patient was admitted to the hospital telemetry unit for further evaluation. Transthoracic echocardiography, performed to investigate the murmur identified on admission, showed no evidence of valvular heart disease. The right and left ventricles were of normal size, with normal
systolic function, normal wall thickness, and no wall motion abnormalities. An exercise stress test was performed the next day. The patient exercised for 10.5 minutes; no ischemic ST changes or ventricular ectopy was seen. The QT interval and QTc at rest were normal (QT interval, 400 milliseconds with a heart rate of 50 beats/min; QTc, 364 milliseconds) (Figure 2). An implantable loop recorder was placed subcutaneously 3 days after the syncopal episode. The patient was discharged home. Atenolol, 25 mg/d, was prescribed, but she discontinued use of this drug after 2 months. No spontaneous arrhythmias were recorded during 9 months of monitoring, and the patient has had no subsequent episodes of syncope or presyncope. Electrocardiography has remained normal.
FIGURE 2. Twelve-lead electrocardiogram obtained approximately 24 hours after the patient’s syncopal event. The tracing is abnormal because of the presence of sinus bradycardia, but the QT prolongation has resolved. The corrected QT is 364 milliseconds.
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EXERCISE-INDUCED SYNCOPE ASSOCIATED WITH XENADRINE
TABLE 1. Contents of Xenadrine EFX*
DISCUSSION Highly publicized reports of arrhythmic events, sudden death, myocardial infarction, and stroke associated with ephedra use2,3 have resulted in manufacturers of dietary supplements offering ephedra-free formulations such as Xenedrine EFX. The US Food and Drug Administration does not regulate these compounds pursuant to the Dietary Supplements Health and Education Act of 1994, and there are concerns about the quality and quantity of active ingredients in these formulations.5 Most importantly, the safety of these ephedra-free products has not been studied formally. We conducted a thorough literature review to identify other cases of syncope due to ephedra-free weight-loss supplements. Search engines used for this review were PubMed, which includes the new MEDLINE (from 1966 to the present), and the National Library of Medicine’s Gateway Search (from 1951 to the present). We were unable to identify any prior reports of syncope associated with ephedra-free products such as Xenedrine EFX. Although the precise cause of our patient’s syncope cannot be established in the absence of an electrocardiogram at the time of the event, several lines of evidence point to the possibility of Xenadrine EFX–induced arrhythmia. The event occurred approximately 1 hour after the patient ingested the compound and was associated with QT prolongation immediately thereafter. Her sensation of palpitations before losing consciousness is more consistent with onset of a tachyarrhythmia than a vasovagal event.6 The lack of prior syncopal events, absence of spontaneous arrhythmias despite continuous monitoring, and normalization of the QT interval after cessation of Xenadrine EFX also are consistent with drug-induced proarrhythmia. The contents of herbally derived food supplements such as Xenadrine EFX are not subject to rigorous analysis or control, and it is unclear which constituent is responsible for our patient’s syncopal episode; label contents of Xenadrine EFX are listed in Tables 1 and 2. The most hemodynamically active component of Xenadrine EFX is bitter orange (Citrus aurantium).7 This compound was recently associated with an acute myocardial infarction in a 55-year-old woman, but the mechanism is unknown.8 C aurantium contains several biologically active components including synephrine (phenylephrine), tyramine, and octopamine. Of these 3 biologically active compounds, phenylephrine has been studied the most rigorously. Phenylephrine’s effects on the cardiovascular system are due to its agonism of α1- and α2-adrenergic receptors. Although its vasoconstrictive properties during intravenous administration can be profound, this vasoactive ability has also been shown with oral doses comparable to Mayo Clin Proc.
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Ingredient Vitamin C Vitamin B6 Pantothenic acid Magnesium Proprietary Thermodyne Complex
Amount (mg) 100 10 12 10 1415
*Also known as ephedra-free Xenadrine.
amounts found in many herbal weight-loss formulations. Significant increases in total peripheral resistance were noted in human volunteers given 10 mg of synephrine orally; this effect peaked approximately 3 hours after ingestion.9 Additionally, phenylephrine has been associated with proarrhythmia in rats, and oral administration of C aurantium caused the appearance of ventricular arrhythmias.10 Moreover, phenylephrine has been shown to prolong the action potential duration11 and induce early afterdepolarizations in isolated Purkinje cells12; such events are thought to act as the trigger for torsades de pointes. Finally, phenylephrine has been shown to increase the dispersion of repolarization in patients with congenital long QT syndrome.13 Patients with congenital QT prolongation frequently experience syncope during exercise because of stimulation of the sympathetic nervous system.14 In such patients, the combination of phenylephrine and a β-adrenergic stimulant has been used to simulate exercise-associated sympathetic nervous system stimulation and provoke repolarization abnormalities.15 Although it remains unclear whether our patient has an ion channel abnormality, the combination of exercise and Xenadrine EFX clearly appears to be undesirable in patients thought to be at risk for QT prolongation.
TABLE 2. Contents of the Proprietary Compound Thermodyne Complex, an Ingredient of Xenadrine EFX* Tyroplex (proprietary blend of L-tyrosine and acetyl-L-tyrosine) Green tea extract (standardized for epigallocatechin gallate, caffeine, and polyphenols) Seropro (proprietary cocoa extract standardized for phenylethylamine, tyramine, and theobromine) Yerba mate (standardized for caffeine and methylxanthines) Dl-methionine Ginger root (standardized for gingerols) Isotherm (proprietary blend of 3,3′,4′,5-7-pentahydroxyflavone and 3,3′,4′,7-tetrahydroxyflavone) Bitter orange (standardized for synephrine, N-methyltyramine, hordenine, octopamine, and tyramine) 2-Dimethylaminoethanol Grape seed extract (standardized for catechins) *Also known as ephedra-free Xenadrine.
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Whether this combination is safe in any person is unproved at this time. CONCLUSION Although an ephedra-containing product, Metabolife 356, was recently found to cause significant QT prolongation in healthy persons,16 no well-designed clinical trials have examined the safety of newer “ephedra-free” proprietary compounds. Our case of syncope associated with QT prolongation was provoked by the ephedra-free weight-loss supplement Xenadrine EFX. This formulation contains bitter orange, which has complex electrophysiological and pharmacological effects. Physicians need to be aware of the dangers of this herbal remedy and should specifically inquire about the use of this product in patients with unexplained syncope. Our findings are consistent with prior reports that state that ephedra free does not mean danger free.17 REFERENCES 1. U.S. Food and Drug Administration. Consumer Alert: FDA Plans Regulation Prohibiting Sale of Ephedra-Containing Dietary Supplements and Advises Consumers to Stop Using These Products. December 30, 2003. Available at: www.fda.gov/oc/initiatives/ephedra/december2003/advisory.html. Accessibility verified June 24, 2004. 2. Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med. 2000;343:1833-1838. 3. Samenuk D, Link MS, Homoud MK, et al. Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine [published correction appears in Mayo Clin Proc. 2003;78:1055]. Mayo Clin Proc. 2002;77:12-16.
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4. Pellati F, Benvenuti S, Melegari M, Firenzuoli F. Determination of adrenergic agonists from extracts and herbal products of Citrus aurantium L. var. amara by LC. J Pharm Biomed Anal. 2002;29:1113-1119. 5. Niemann RA, Gay ML. Determination of ephedrine alkaloids and synephrine in dietary supplements by column-switching cation exchange highperformance liquid chromatography with scanning-wavelength ultraviolet and fluorescence detection. J Agric Food Chem. 2003;51:5630-5638. 6. Calkins H, Seifert M, Morady F. Clinical presentation and long-term follow-up of athletes with exercise-induced vasodepressor syncope. Am Heart J. 1995;129:1159-1164. 7. Cytodyne LLC. Product Information: Xenadrine EFX. Available at: www.cytodyne.com/products.html?32GEFR. Accessibility verified June 24, 2004. 8. Nykamp DL, Fackih MN, Compton AL. Possible association of acute lateral-wall myocardial infarction and bitter orange supplement. Ann Pharmacother. 2004;38:812-816. 9. Thomas SH, Clark KL, Allen R, Smith SE. A comparison of the cardiovascular effects of phenylpropanolamine and phenylephrine containing proprietary cold remedies. Br J Clin Pharmacol. 1991;32:705-711. 10. Calapai G, Firenzuoli F, Saitta A, et al. Antiobesity and cardiovascular toxic effects of Citrus aurantium extracts in the rat: a preliminary report. Fitoterapia. 1999;70:586-592. 11. Robinson RB, Liu QY, Rosen MR. Ionic basis for action potential prolongation by phenylephrine in canine epicardial myocytes. J Cardiovasc Electrophysiol. 2000;11:70-76. 12. Drouin E, Charpentier F, Gauthier C. Alpha1-adrenergic stimulation induces early afterdepolarizations in ferret Purkinje fibers. J Cardiovasc Pharmacol. 1996;27:320-326. 13. Khositseth A, Nemec J, Hejlik J, Shen WK, Ackerman MJ. Effect of phenylephrine provocation on dispersion of repolarization in congenital long QT syndrome. Ann Noninvasive Electrocardiol. 2003;8:208-214. 14. Moss AJ. Long QT syndrome. JAMA. 2003;289:2041-2044. 15. Nemec J, Ackerman MJ, Tester DJ, Hejlik J, Shen WK. Catecholamineprovoked microvoltage T wave alternans in genotyped long QT syndrome. Pacing Clin Electrophysiol. 2003;26:1660-1667. 16. McBride BF, Karapanos AK, Krudysz A, Kluger J, Coleman CI, White CM. Electrocardiographic and hemodynamic effects of a multicomponent dietary supplement containing ephedra and caffeine: a randomized controlled trial. JAMA. 2004;291:216-221. 17. Marcus DM, Grollman AP. Ephedra-free is not danger-free [letter]. Science. 2003;301:1669-1671.
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