N, Ito S. Evaluation of left atrial appendage function by measurement of changesin flow velocity patterns after electrical cardioversion in patients with isolatedAF. Am J Cardiol1997;79:615–620.14. Omran H, Jung W, Rabahieh R, Schimpf R, Wolpert C, Hagendorff A,Fehske W, Lu¨deritz B. Left atrial chamber and appendage function after interna-

latrial defibrillation: a prospective and serial transesophageal echocardiographicstudy.J Am Coll Cardiol1997;29:131–138.15. Fatkin D, Scalia G, Jacobs N, Burstow D, Leung D, Walsh W, Feneley M.Accuracy of biplane transesophageal echocardiography in detecting left atrialthrombus.Am J Cardiol1996;77:321–323.

Usefulness of Ibutilide in Facilitating SuccessfulExternal Cardioversion of Refractory Atrial Fibrillation

Huagui Li, MD, PhD, Andrea Natale, MD, Gery Tomassoni, MD, Salwa Beheiry, RN,Patricia Cooper, RN, MSc, Fabio Leonelli, MD, Arthur Easley, MD,

William Barrington, MD, and John Windle, MD

Ibutilide is an effective agent for pharmacologicconversion of new onset atrial fibrillation (AF).1,2

An experimental study in dogs showed that ibutilidealso decreased the defibrillation threshold of AF.3 Wehypothesized that ibutilide decreases the energy re-quirement for successful cardioversion of AF in hu-man patients. Such a reduction in the cardioversionenergy requirement would help to achieve successfulcardioversion in patients who have failed conventionalexternal direct-current (DC) cardioversion.

• • •Consecutive patients with AF who failed conven-

tional external DC cardioversion at the maximal en-ergy output (360 J) of the defibrillator were enrolled inthis study. Patients who were converted to sinusrhythm by conventional external DC cardioversion buthad immediate recurrence of AF were excluded. Eli-gible patients underwent repeat external DC cardio-version after ibutilde infusion. The study protocol wasapproved by the institutional review board and a writ-ten informed consent was obtained from the patientsbefore the start of the study.

To avoid the potential confounding effect of anti-arrhythmic drugs on cardioversion efficacy, antiar-rhythmic therapies remained unchanged at the time ofrepeat cardioverson with ibutilide for those patientswho had been on antiarrhythmic drug therapy at thetime of failed conventional external cardioversion.Anticoagulation was continued and a therapeutic in-ternational normalized ratio of 2 to 3 was confirmedbefore cardioversion. Blood potassium was measuredto ensure a normal level. The QT interval on thesurface electrocardiogram was measured to ensure avalue of,450 ms. Due to variations of the RR inter-vals during AF, only the maximal QT interval wasused for assessment.

Before ibutilide infusion, conventional externalDC cardioversion was repeated to eliminate any ran-dom variation of the energy requirement for success-

ful cardioversion. After the patient was sedated prop-erly, an R-wave synchronized external DC shock of360 J was attempted at least twice. For those patientswho had previously received maximal shocks of 360 Jin both the apical-interscapular (anteroposterior) andright sternal-midaxillary (anterolateral) electrode po-sitions,4 only 1 of the electrode positions (mostly theapical-interscapular position) was tested at repeat car-dioversion. For those who received the maximalshocks of 360 J in only 1 electrode position during theprevious failed conventional external cardioversion,both electrode positions were tested with shocks of360 J at least twice in each position. After cardiover-sion failure was reconfirmed, the shock electrode po-sition remained unchanged until the completion of thestudy to avoid any effect of the electrode positionalteration on cardioversion efficacy.

Due to a concern for the possible proarrhythmiceffect of ibutilide given with another oral antiarrhyth-mic drug, magnesium sulfate of 1 g was intravenouslyinjected before ibutilide administration. After thecompletion of magnesium administration, ibutilide of1 mg (University of Kentucky) or 2 mg (University ofNebraska Medical Center) was slowly injected trans-venously over 10 or 20 minutes while the patientunderwent close electrocardiographic and blood pres-sure monitoring by the physician. The end point toterminate ibutilide injection was prospectively deter-mined to be development of premature ventricularcomplexes or ventricular tachycardia.

Upon completion of the ibutilide injection, thepatient was sedated again. With the shock electrode,the position remained exactly the same as that of thefailed conventional external DC cardioversion; R-wave synchronized DC shock at 360 J was repeated.Based on the known high-energy requirement for car-dioversion, the shock energy was started at 360 J atthe repeat cardioversion to reduce the number of car-dioversion shocks. Thus, we did not attempt to di-rectly measure the atrial defibrillation threshold. Ac-cording to the protocol design, repeat shock was al-lowed twice.

After successful cardioversion, the patients werenot allowedd to receive any antiarryhthmic drugs for 4hours. Patients were discharged 24 hours after cardio-version. Patients were then followed in the clinic 1

From the University of Nebraska Medical Center, Omaha, Nebraska;and University of Kentucky, Lexington, Kentucky. Dr. Li’s address is:Cardiology Section, Department of Internal Medicine, University ofNebraska Medical Center, 982265 Nebraska Medical Center,Omaha, Nebraska 68198-2265. E-mail: huaguili@unmc.edu. Manu-script received April 15, 1999; revised manuscript received andaccepted June 9, 1999.

1096 ©1999 by Excerpta Medica, Inc. All rights reserved. 0002-9149/99/$–see front matterThe American Journal of Cardiology Vol. 84 November 1, 1999 PII S0002-9149(99)00509-3

month after the cardioversion and every 3 monthsthereafter.

Continuous data were presented as mean6 SD.Comparison of multiple group means was performedusing variance of analysis. A p value of,0.05 wasconsidered statistically significant.

Since October 1998, 14 patients were identified aseligible for the study. These patients were referred forinternal DC cardioversion of AF after they failedconventional external DC cardioversion. One patientdeclined participation in the study. Another patientwas successfully cardioverted to sinus rhythm on therepeat conventional external DC cardioversion beforeibutilide injection on the day of the study. The other12 patients remained in AF after the repeat conven-tional external DC cardioversion of 360 J and formedthe basis for this study. The patient characteristics arepresented in Table I. Most patients were men with amean age of 616 7 years. Over half of the patientswere overweight with a body weight of.100 kg.Most patients (9 of 12) had systemic hypertension.The left ventricular ejection fraction was normal($50%) in 8 patients and mildly reduced (,50%) in 4patients. Most (9 of 12) patients had mild to moderateenlargement of the left atrium (left atrial diameter.40 mm) as seen by echocardiography.

The duration of AF ranged from 2 to 24 months(10 6 9). All patients had symptoms during AF,including fatigue in 11 patients, palpitations in 8,dyspnea in 7, and chest pain in 1 patient.

Before failed conventional external cardioversion,9 patients underwent trials of 1 to 2 antiarrhythmicdrugs but failed to maintain sinus rhythm. The failedantiarrhythmic drugs included propafenone in 5 pa-tients, procainamide in 2, sotalol in 3, and quinidine in1 patient. At the time of the repeat cardioversion withibutilide, 9 patients were on oral antiarrhytmic drugs.These included amiodarone in 6 patients, propafenonein 2, and sotalol in 1 patient. The time interval be-

tween the previously failed conventional external car-dioversion and the repeat cardioversion with ibutilidewas 1 to 20 days (median 15 days). All patientsreceived $2 shocks (2 to 5) at 360 J during thepreviously failed conventional external cardioversion.

On the day of the repeat cardioversion, 2 to 4shocks (2.36 0.7) at 360 J were delivered by theconventional approach before ibutilide injection. Asdescribed previously, only 1 patient was converted tosinus rhythm and the other 12 patients remained inAF. All patients completed ibutilide injection withoutcomplications. No patient had spontaneous conversionof AF after ibutilide injection. At the repeat cardio-version after ibutilide injection, 11 patients (92%)were successfully converted to sinus rhythm by the360 J shock. Six patients received 1 mg of ibutilideand 6 patients received 2 mg of ibutilide. One patientfailed the repeat cardioversion after 1 mg of ibutilidebut had successful cardioversion after 2 mg of ibutil-ide. The shock electrode positions at the successfulcardioversion were apical-interscapular in 8 and rightsternal-midaxillary in 3 patients. One patient, whoreceived 2 mg of ibutilide, remained in AF after 2shocks of 360 J. This patient subsequently had suc-cessful internal cardioversion.

The QT interval was 3836 33 ms (360 to 410)before ibutilide injection, 4646 47 ms (410 to 560)upon completion of ibutilide injection, and 5076 71ms (420 to 680) after successful cardioversion, respec-tively (p ,0.05). The QTc interval was 4686 56 ms(417 to 573) before ibutilide injection, 5576 91 ms(483 to 601) upon completion of ibutilide injection,and 5346 17 ms (504 to 559) after the successfulcardioversion, respectively (p,0.05). The heart ratewas 906 30 beats/min (64 to 152) before ibutilideinjection, 886 29 beats/min (62 to 150) upon com-pletion of ibutilide injection, and 676 3 beats/min (62to 71) after the succesful cardioversion (p,0.01). Nopatient developed torsade de pointes. All patients weredischarged from the hospital in sinus rhythm.

During the follow-up of 476 29 days (30 to 120),all patients were alive and none had symptoms sug-gesting ventricular tachyarrhythmia. All patients ex-cept 1 remained in sinus rhythm. The single patientwith AF recurrence received amiodarone 400 mg/daywith a previous loading dose of 1,200 mg/day for 2weeks at the time of recurrence. AF recurred 3 daysafter successful cardioversion in this patient. It wasdecided to discontinue the rhythm control strategy andcontrol the ventricular rate with anticoagulation only.

• • •In the present study, we have demonstrated that

many patients who failed conventional external car-dioversion can be successfully cardioverted followingibutilide injection. Thus, these patients did not have togo through internal cardioversion. Our study demon-strates that repeat cardioversion following ibutilideinjection provides a useful alternative to internal car-dioversion of AF.

The effect of antiarrhythmic drugs on the atrialdefibrillation threshold has been inconsistent as foundin different studies. The result of a nonrandomized

TABLE I Patient Characteristics

Patient

Age(yr)/Sex

BodyWeight

(kg)Cardiovascular

Diagnosis

EjectionFraction

(%)

LeftAtrialSize(mm)

AFDuration

(mo)

1 41M 71 Hypertension 58 41 62 62M 95 Moderate

mitralregurgitation

55 44 12

3 67M 139 Hypertension 62 54 124 60M 140 Hypertension 40 54 25 59M 127 Hypertension 60 49 246 70M 109 Hypertension 45 40 67 68M 82 Hypertension,

coronarydisease

45 50 3

8 61M 104 Coronarydisease

40 39 3

9 57M 100 Hypertension,diabetes

60 36 3

10 64F 80 Diabetes 55 48 2411 59M 95 Hypertension 78 41 212 62F 77 Hypertension 50 44 24

BRIEF REPORTS 1097

study by Guarnieri et al5 suggested that the use ofclass Ic antiarrhythmic drugs might have caused anincreased energy requirement for cardioversion of AF.Another small randomized study of 27 patients by vanGelder et al6 also suggested that flecainide might haveincreased the defibrillation threshold of AF. However,in a randomized study of 100 patients, Bianconi et al7

showed that propafenone did not affect the meandefibrillation threshold of AF. In contrast, Borinani etal8 showed that flecainide caused a reduction of theAF defibrillation threshold. In a study by Lau andLok,9 intravenous sotalol was found to reduce theatrial defibrillation threshold only in acute AF but notin chronic AF patients. A study by Sagrista-Sauleda etal10 suggested a reduced energy requirement for suc-cessful cardioversion of AF by amiodarone. In thepresent study, we kept the antiarrhythmic drugs un-changed between the failed conventional external car-dioversion and the repeat cardioversion with ibutilide.Thus, the possible confounding effect of the oral an-tiarrhythmic drugs on the cardioversion efficacy wasmaximally reduced. It remains unknown if the cardio-version failure by conventional external shock wasrelated to the use of antiarrhythmic drugs, particularlyamiodarone, in those patients taking oral antiarrhyth-mic drugs. Because the shock electrode positions re-mained unchanged, the successful cardioversion afteributilide injection was apparently due to the effect ofibutilide. To our knowledge, magnesium had noknown effect on the atrial defibrillation threshold.Only 1 patient had successful cardioversion by con-ventional external cardioversion at the repeat attempton the day of the study, suggesting that random vari-ation of the cardioversion energy requirement is infre-quent. Such a variation was further reduced by the useof conventional external cardioversion before ibutilideinjection in our study.

Although the number of studies is limited, all stud-ies have consistently shown that ibutilide reduces thedefibrillation energy requirement, both in the ventricleand the atrium. Experimental studies have shown thatibutilide decreases the ventricular defibrillation thres-hold.11,12 In a canine model of AF induced by vagalstimulation, Khoury et al3 showed that ibutilide de-creased the defibrillation threshold of AF from 0.8360.5 to 0.536 0.29 J (p5 0.02). In a recent study, Oralet al13 demonstrated a significant reduction of the AFdefibrillation threshold by external shocks. In thepresent study, we did not directly measure the defi-

brillation threshold of AF because of the ethical con-cern about the increased number of shocks. However,our results clearly showed that ibutilide apparentlyreduced the defibrillation energy requirement of AF inour patients. Such a reduction of the energy require-ment brought the defibrillation threshold of AF intothe range of the maximal defibrillator output andhelped to achieve successful cardioverison. Becauseof such an enhancing effect on cardioversion efficacy,most of our patients regained sinus rhythm without theneed for internal cardioversion.

Our study demonstrates that ibutilide facilitatessuccessful cardioversion of AF in patients whofailed conventional external cardioversion. Wesuggest that repeat cardioversion after ibutilideadministration may serve as an alternative to in-ternal cardioversion in most patients with refrac-tory AF.

1. Ellenbogen KA, Stambler BS, Wood MA, Sager PT, Wesley RC, MeissnerMD, Zoble RG, Wakefield LK, Perry KT, VanderLugt JT, for the IbutilideInvestigators.J Am Coll Cardiol 1996;28:130–136.2. Stambler BS, Wood MA, Ellenbogen KA, Perry KT, Wakefield LK,VanderLugt JT, and the Ibutilide Repeat Dose Study Investigators. Efficacy andsafety of repeated intravenous doses of ibutilide for rapid conversion of atrialflutter or fibrillation.Circulation 1996;94:1613–1621.3. Khoury DS, Assar MD, Sun H. Pharmacologic enhancement of atrial electricaldefibrillation efficacy: role of ibutilide.J Interv Electrophysiol1997;1:291–298.4. Kerber R. Transthoracic cardioversion of atrial fibrillation and flutter: standardtechniques and new advances.J Am Cardiol1996;78:A22–26.5. Guarnieri T, Tomaselli G, Griffith LSC, Brinker J. The interaction of antiar-rhythmic drugs and the energy for cardioversion of chronic atrial fibrillation.PACE1991;14:1007–1012.6. Van Gelder I, Crijins HJGM, van Gilst WH, de Langen CDJ, van Wijik LM,Lie KI. Effects of flecainide on the atrial defibrillation threshold.Am J Cardiol1989;63:112–116.7. Bianconi L, Mennuni M, Lukic V, Castro A, Chieffi M, Santini M. Effects oforal propafenone administration before electrical cardioversion of chronic atrialfibrillation. A placebo-controlled study.J Am Coll Cardiol1996;28:700–706.8. Borinani G, Biffi M, Capucci A, Bronzetti G, Ayers GM, Zannoli R, Branzi A,Magani B. Favorable effects of flecainide in transvenous internal cardioversion ofatrial fibrillation. J Am Coll Cardiol1999;33:333–341.9. Lau C-P, Lok N-S. A comparison of transvenous atrial defibrillation of acuteand chronic atrial fibrillation and the effect of intravenous sotalol on human atrialdefibrillation threshold.PACE1997;20:2442–2452.10. Sagrista-Sauleda J, Permanyer-Miralda G, Soler-Soler J. Electrical cardio-version after amiodarone administration.Am Heart J1992;123:1536–1542.11. Wesley RC, Farkhani F, Morgan D, Zimmerman D. Ibutilide: Enhanceddefibrillation via plateau sodium current activation.Am J Physiol1993;264:H1269–1274.12. Labhasetwar V, Underwood T, Heil RW, Gallagher M, Langberg J, Levy RJ.Epicardial administration of ibutilide from polyurethane matrices: effects ondefibrillation threshold and electrophysiologic parameters.J Cardiovasc Phar-macol1994;24:826–840.13. Oral H, Souza JJ, Flemming M, Kim MH, Pelosi F, Tse H-F, Michaud GF,Knight BP, Goyal R, Strickberger SA, Morady F. Effect of ibutilide on atrialdefibrillation energy requirement (abstr).J Am Coll Cardiol1999;33:132A.

1098 THE AMERICAN JOURNAL OF CARDIOLOGYT VOL. 84 NOVEMBER 1, 1999