High dose oral amiodarone loading: Electrophysiologic effects and clinical tolerance

1dCC . Vol 19. No. I lnnoory 1993 169-71

169

High Dose Oral Amiodarone Loading : Flectrophysiologic Effects and Clinical Tolerance STEVEN JAMES LORING EVANS, MD, MARK MYERS, MD . CAROL ZAHER, MD, FACC, • JAY SIMONSON, MD, PETER NALOS . MD, FACC, CAROL VAUGHN, RN, DANIEL OSERAN, MD, FACC . ELI GANG . MD, FACC, THOMAS PETER, MD . FACC, WILLIAM MANDEL, M?), FACC Los A„g.lvs -J Pan,- C.-.

C.Irf-d.

Although amlodarone Is an effective d mg for re treatment of IifeAhrentenlng ventrinemr arrhytsiov, rrte'town C oral oadtng dose protocd has been defined, and ptknlo often undergo prolonged brtgdtatiratlen fn- amindaeonr lw:ng . High dose (>i,66 mg/day) oral loading has usually bear rescrsed roe uesmtge patients with lntessaat ventricular tl lyarrh!jhmiao . The current study was designed to 1) exambr! the clin ;ral and eleeteopt 1vlot gin huts of a high dose prat andndaroae Wading region in mere stable ptewts ; and 2) ascertain Its safety and t11.+'r-, ; wbly idl"ir.g shortened amiodarooe kwdece pert. ads and potentially decreased length or hospital stay. The study group Included 16 patients with a history of recurrent ventricular aebythmln red decreased left ventriniyr rune60a, who were refractory to prior antiarkythmic drug therapy . The oral lnadingp-otocot was 50 mg/kg per day ofamiodarone for 3 dews, then 30 niglkg per day for 2 days . followed by maintenance therapy of 300 to 400 mg twice daily . Eleetrophysiologic testing was performed at baseline, on days I and 5 and during week 6 .

Anliodarone and desethylamfodnrene levels were Measured and symptoms monkcred . Clinically . the high dose loading protocol was well tolerated in 13 of the 16 patimtr . Arrkylhmias were reordered nohiedsdble by day 1 in three pulkuts and remained ---'- - "- throughout the study period in two of the three . The reinstating pad" motioned to have inducible ventricular taehyedrdia . VentriCular 1sdlycArdin cyets length and right ventricular efedive refractory pvi-A both progressively Inerprr(d ugciiiirne'y over brolhle, starting a day 1 . The 15 patients who remained in the study had no o eL'irard side effects during the loading period. Eleven pti uio have bzen Mowed up for >2 yeas witdeot ay cliiral recurrence of their presenting arrhythmia. High dose oral amiodarone loading In ckudodly well tolerated it patients with fffe•threulzdog ventrkalar artbythmlas who have depressed ventricularfnectlw .This reghnet,gayc"_ A-oyy1 loading periods, thereby permitting ,Sorter hospital gays in this patient population, (J Am Cull Cardiol 1992 ;79:169-73)

Amiodarone is an effective drug for the therapy of life . threatening ventricular arrhythmias 11), but treatment protocols are not standardized in terms of loading dosage, length of loading period or maintenance dosage . Loading doses of 400 Iv 1 .800 mg/day of amiodarune for I to 6 weeks, followed by variable maintenance doses of 200 to 800 rg rd~sy . have been reported to be effective in suppressing ventricular arrhyrhmias and improving survival (2_6) . High loading doses (>800 mg/day) have in general been avoided, predominantly because of concern for precipitation of acute side etecis, such as severe exacerbation of congestive heart

failure and proarrhythmia . However . two groups using oral amiodaront. loading doses of up to 4 .4 g/day have reported rapid suppression of spontaneous severe complex ventri v.utar arrhythmia, (7,8). In addition, these dosages were clinically well tolerated, The selection ref the appropriate loading dose regimen still

F.. the Dcpdaw,i aF C rdirbgy, Cedar-Sinai stoical Cener . Los Auxek;, Pad *Kaiser-Permamaw. Parlomma City. Catifnrnia This research s,rpp.rm m part by a payee F- Tire Clectrxardiotuaohic Heartbeat Oraairedou, 611edy Silts, 6111011ta . Manuscript evccived November 27, x391) : revised maoicdpt received July l, 1991 . acepnd July 18. 1991 . Adieesc for maule wimm L Mondet, MD, 1c+pa.r . l of C:erdiobgy. CedaevSinei M-dkd Center. 07m Beverly goulev .d, Ls _cooler, CalilorNa 90a.

r

12199[ by Me

A.nrign College

of Cardlooy

poses a major challenge to clinicians because of amiodarone's unusual pharmacokinetic protxrthts. It is a very lipophilic drug with a half-life of up to 40 days, whose major metabolite, desethylamiodarone, has an even longer half-life than its parent compound (9) . The antiarrhyttmic proletties of amiodarone may be manifested before total body tissue equilibration has occurred, and desethylumiddarone nay cad,ibute to the overall long-term antiarrhythmic effects (10)The uncertainties with regard to the short-term administration of amiodarone are clinically signibcant . High dose oral amiodarone loading bee been previously studied in patients with incessant ventricular arrhythmia, (8), a group that comprises a relatively small proportion of the total 0715-I09T9253 .30

170

EVAN'S ET AL . HIGH DOSE 05A1 . AMIODARONE LOADING

population of patients with life-threate tins velanculat orrhythmias . The present study was undertaken in patients with a history of e-th•m ate.^.irb ventricular arrhythmias and depressed ventricular function who do not have incessant ventricular arehythuuas. The aims were I) to determine the clinical tolerance of a high dose oral amiodorone loading regimen in such patients : 21 to examine the electraphysiologic effects of such a high dose regimen both immediately and at 6 weeks ; 3) to ascertain whether such n rcg4 tee, could potentially be used to decrease the length of lime of amiodarenc loading in this patient group ; and 4) to observe the outcome Sunny !ong-term file; s-tip . Methods Patients. Sixteen patients were initially entered into the study . One patient, with a diagnosis of left vcnhicular aneurysm secondary to myocardial infarction . congestive heart failure and an ejection fraction of 12%, had an exacerbation of congestive heart failure after the first loading dose. Although successfully treated with increased doses of diuretics, he was withdrawn from the study at the request of his physician and started on a regimen of lower doses of amiodarone . No follow-up electrophysiologic testing was performed in this patient . Thos, the study group included 15 patients (Table I) with a history of recurrent ventricular tachycardia who had undergone a mean of 2 .7 prior unsuccessful trials of antiarrtt imic drugs . The average age was 64 years, and the average ejection fraction was 29b . The unde:lyiug eiiutngy wa. I,ahcmic heart disease in all patients . No patient had bad a myocardial infarction within the month preceding the study . All patients Pad inducrhie sustained ventricular tachycardia, but no patient had incessant ventricular arrhtlhmias. Electrophysbltlgk testing protocol . After informed cansent was obtained, electrophysiologic testing was performed with the patient in the postabsorptive state . All antiarrhythmic therapy was discontinued for at least 5 half-lives before the baseline electrophysiologic study was performed . The details of our stimulation protocol have been reported previously (I1). A new catheter was placed for each study, and the same protocol followed. Ventricular tachycardia cycle length, right ventricular effective refractory period at a paring cycle length of 550 ms and two times diastolic threshold, number ofexuastimuli required to induce ventricular tachycardia, ventricular tachycardia configuration, method of lachycmdia termination . and symptoms during ventricular tachycardia were carefully recorded . Amiodartne Wing. The dosing protocol was based au prior high dose loading regimens J7,9) : 50 mf kg body weight per day of oral amiodarone was given on days I through 3, and 30 mglkg per day on days 4 and 5, after baseline electrophysielogic testing . This protocol resulted in the administration of 3 to 5 .2 Flday of amiodarone for the 1st 3 days, and of 1 .7 to 3 .1 g/day on days 4 and 5 . Maintenance dosing was then instituted at 300 to 400 mg twice daily .

IACCVOL I!,NO I mosey taut 67-73

kepeal eiechophysiologic studies were performed on days I and 5 and at week 6 . Symptoms were closely monitored during the loading phase, and plasma levels of amiudarone and desethyiamiodarone wine measured at tae ti of the repeal clectrophysiologic studies (whether or not this lime represented the imerdosage trough point) . Results Elertrephysiobgk varhtbhs, Aii 15 patients who tolerated cn . fall h:¢ dose loading protocol underwent dedrophvsinhtgic, testing or baseline and on days I and 5 ; 13 patients had follow-up eleclmpbysiologic testing at week 611 moved away. I refused further follow-upl . The mean total dose of amiedarone by day 5 was 11.9 g (Table I1. Clinical and electrophysiol-)gic changes werrobseeved to start at day I (Table 2) . At baseline, all 15 patients had inducible, sustained ventricular tachycardia . By day l, ventricular tachycardia was not inducible in two patients and only nonsustained ventricular tachycardia was inducible in one patient, At day 5, ventricular tachycardia remained noninducible in the two patients who had noninducible arrhythmia on day I (one had ventricular fibrillation that was considered to be a nanciinicat, rather than a proarrhylhmic response); however, the patient with nonsustainest ventricular racbyear':a again had stained yrvtricular rnwi ycardia. At the 6 week follow-up, one o: the patients with previously index ible arrhythmia crossed over into the group with noninducible arrhythmia (nonsustained ventricular tachyeardial, and arrhythmia continued o be rmninducihle in the two patients with previously noninducihle arrhythmia (with the same patient having nanctinical ventricular fibriltat!o .^.p . The ventricular tachycardia cycle length at baseline was 259 ± 64 ms (Table 2) ; by day 1, it had increased significantly to 315 ± 101 ms (p < 0 .05 from day t) . At day 5, there was no significant increase over baseline or day I in )lu : ventricular tachycardia cycle length, but by week ti the cycle length had increased significantly to 37 1. . 66 ms from day I and day 5 (p < 0 .05 vs . baseline, day I and day 5). The right ventricular effective refractory period followed a similar pattern initially. The baseline right ventricular effective refractory period was 252 ± 22 ms (Table 2), which increased significantly to 279 ± 17 ms on day I (p < 0 .05) . On day 5 there was no significant increase over baseline or day I in the right ventricular effective refractory period, but by week 6 it had significantly increased from day I to 307 `72 ms (p < (I .05 vs- besetine and day I) . Them was no consistent change in number of extrastimuli necessary to induce ventricular tachycardia associated with the increases in ventriculu- tachycardia cycle length and right ventricular effective refractory pertain . Seven patients had the same and six patients had a different ventricular tachycardia configuration after receiving amiodaronc, but there was no significant difference in she increase in ventricular tachycardia cycle length between the two groups. There was also no consistent change in the symptoms reported during the

2ACC vd, 19, No . I lewvy 1992:169-71

171

EVANS ET AL . HIGH 0056 UR, L sMIODARONL LOADING

Table 1. Clinical Chumoeristies and Cumulative Antiodarene lose on Day 5 in 15 Patients

Duueovs

Symiaoms Ilunng VTNF

13

611' 67 M

CAF d1.CABG MI MLCABU MI Ml MLCABG MLLVA 1.11 Mi,LVA MLLVA M1 MI .CABG.LVA

Hypolnns SCD Chest pain Dimness Syacape Syncope Syncope Syncope SCD SCD Syncope SCD Syncope

14

7( V

MI

S'.__

15 Mean SD

6 /M 6

&I i

. Dime

Pr. No

Age (yrll Gender 7EIM'

2

£SIM

I

61733 57/f

4

7216

$9/N 6 vM 7//N 66M 74/11 37114 .

12

Indr Drug Tnaa

C'mulaiw Dose on Day' 481

Ami b rave E ISr' T

I1-6

3 3 3

12 .6

11 .6 11 .3 12.0 Hb

133 11 .5 13 .8

3 7

11 .2

2 3

28

13 .5

3"

108

3

16

9.9

3

31

10.7

35 29% 10%

10 1t .9

2 .75 03

1.4

All values are mean velpes t SO. CABG = coronary artery bypn, ae, ;,.i-CHF= eoll1suve heart failure ; EF = electron fm-ion : F = feelae : Hyposens = sympranaic hypaensivr. LVA = left veovieular anelrysln ; M-male:MI=nyo;ardiolinfarcoon :SCD=suddeecardiacdea'h :VF=-IocularEk ;illaioe VT=rentrkdar tachycardia.

ventricular tachycardia or in the method

of

tachycardia

termination .

slight incoordinalion and milu nausea in a patient receiving 800 mg/day and paresthesias and headache in a patient

I'hsr msiodamue and desethylandodaronp leveb . Plasma

amiodarone levels were 2 .6 . I mg/iter on day I liable 2) . There was no ftmher significant change by day 5 or week 6 . Desethy tvnindarone levels were 0.4 ± 0.2 mgititer on day I (Table 21 However, by day 5 . the rev lr had risen signific-anuy over day I values to 0 .6 6 0.2 mglitcr (p < 0.05) and by week

receiving 800 mglday) . One pa dent was admitted to the huspital I month after the week 6 fallow-up eleeimphysioioglc study with a non Q wave myocardial infarction and ventricular tachyerrdia of two different configurations from

that seen during the testing period ; he underwent successful cardioversion .

had increased furfner l .1 l .1 { 03 mg/liter (p < 0 .09 vs . day I and day 5). SW effects . One pawith a left vacate star ejection fraction of 12%, was withdrawn from the leading protocol because of an exacerbation of congestive Sean failute . The remaining 15 patients included in the study had no cardiovascular, neurologic or gastrointestinal symptoms during the loading period. At 6 week follow-up, three patients had

High dose oral amiodarone loading was clinically well tolerated in l5 of 16 patients with repressed ventricular

developed new symptom. (tremor, insomnia and new con-

through

gestive heart tailure in one patient receiving 600 mg/day ;

vival .

6

fL:es~Glcis

function and life-threatening ventricular arrhylhmias . Elec-

trnphysiologic changes were mated by day 1, and continued changes in the electraphysiologic variables were observed

week

6 . Follow-up

revealed

good long-term sur-

Table 2. Eectrophysiolopic Findings and Amiadarone and Desethylamiodarone Levels in tllc i5 Study Patents Variable

Baseline

Day I

Day 5

W.1,6

54 of patients with inducible VTNF VTCL (ms3 RVERP (ms), Pouma aminda .mre level (mylirer) PI .- desahllan:odsrone'svel (mppiren

100% II51 259 t 64 (151 252 : 22 (141

405E 1151 315 ± 101 . 1121 219 '- 17. [151 7 .6 7 11151 0.4 - 021151

93%(151 340 t 134• 1131 303 *_ 36. 1141 2 .0 s oh 114] 0.6 m 02-1131

M (13I 373 1 56't ;1101 307 2 22-f 1131 2.1 *- 0.41131 1.1 a Itt It31

-, e, t = p < a.m versus baseline 1'1, day 1(1) or da15131 . p V . were o6ucivA 6y I>.i,.d Ilea usil she Bonferronconec0cs foe meaple rompansws . : Unless oo.-i. indicated, al values are mean vaues t SD. The numbers in Makers indicate the sapper of pa tent, (fray tin total whoa of 151 with the measured variable . RVERP = right ventricular eFecdve refractory period ; VF = , eanwlar hbrillcfan ; VT = ventricuhr each wudia ; VICL = wiring. laahycarna cycle kagih.



172

EVANtETAL . HIGH DOSE ORAL AMIODARONE LOADING

Clinical tolerance. Few studies air available documenting the short-term effects of high dose oral amiodarone loading (7,g) . Apart from the our patient who was withdrawn from the study because of symptomatic congestive hca •t failure after the first lvatang dose, no patient experienced symptoms of drug toxicity during the loading pc .iod . This observation reveals that, even in patients with markedly depressed left ventricular funduu, high dose loading is unlikely to ause significant hemodytmmic compromise . Hence, when urgent amiodarone loading is not required, this regimen may be safer than rapid intravenous amiodarone loading, which may result in hemodynamic compromise (12) . Although not universally accepted, significant positive correlations between plasma amiodarone levels and toxicity stave seen previously reported (7, t3). T e paucity of symptoms in our patient group during the acute loading phase may therefore relate to a nontoxic range of their scram amid darone concentrations during the loading period . Not unexpectedly, several patients did experience minor symptoms reported at the 6-week follow-up period, and the mainte . nance dose of amiodarone was readjusted at that point . Eledroph}sioiogk tfleets. The increases in ventricular tachycardia cycle length and right ventricular effective refractory period seen in our patients are similar to those reported previously (2,3 .10,14-17) with lower dose loading protocols and eleclrophysiologic testing performed I to 20 weeks after the it itiatior of amiodarone therapy . With the loading protocol used in our study, significant prolongations of the ventricular tachycardia cycle length and right ventricular effective refractory period were already noted by day t . Although still controversial, evidence suggests that dcc trophysiologic testing may ne adsantarenus to predict ;ht long-term outcome of amiodarone therapy (17-21) . Report _d positive prognostic indicators obtained during electrophy Biologic testing after amiodarone loading have included eo ..r,epltsu ionfarhytminducbly(19,20) a change from inducible sustained ventricular tachycardia to nonsustained ventrcular tachycardia (17), improved hemodynamic tolerance of th, induced arrhythmia (14) and an increase in the cycle length of the induced ventriculra tachycardia 121). Although early significant changes were seen in the ventricular tachycardia cycle length and right ventricular effective refractory period in our study . tachycardia remained inducible in most patients . and there were no significant changes in hamodynnmic tolerance of the ventricular laehycardia . The reasons for the disparity between the electrophysio logic effects of amiodarone and its clinical efficacy are unknown, but several groups, including ours, have reported similar findings (2.3.14.15) . Hence, although nodinducibihty of arrhythmia after amiodarone therapy may be a he:pfui prognostic invicatur(19,22), treatment with a .miudarone may confer significant protection from arrhythmia recurrence and sudden cardiac death despite persistent inducibility (14,15)Amiodarone levels, The amiodarone levels achieved within the I it 24 b Gfthe study were similar to those reported

IM'C v.a 19 . No. I January 1992'.169-73

by Moslew el al, (8), whose patients received up to 4 4 g of amiodarone daily- The e!eclrophysiologic effects of amiodarone were also noted to he signifie''u :E a:; :tdn i ri s pert d . it has been shown that there are measurable tissue amiodarone levels after a single oral i7) or intmvc,toos (23) dose, a time when deselhy lamiodarone levels area'- 'cent or low. Hence . it is likely that amiodarone itself has etc trophysiologic effects independent of those of desethylami darone . and contrite. utestotheoverall antiarrhythmicprnr ttiesofthedrug(24) . Although the amiodarone levels remained arable c'_r t„e follow-up period, the desethylamindarone levels continued in rise, in conjunction with a continued increase in the ventricular tachycardia cycle length and night venrcular effective refractory period . Similar results were reported by Mitchell et al . (10). It has been postulated that desethylamiodarone contributes to the antiarrhythmic effects of amio . darone (10 24,25), Therefore, the further increases in the electraphysiologic variables may have been in part related to the higher desechytamiesarone levels, as well as to the equilibration of amiodarone and desethylamiodarone throughout all body tissues (23). Several groups have examined the relation between amiodarone levels amt inducibility of ventricular tachycardia at electrophysiologic study. No correlation has been observed between plasma concentration of amiodarone or desethylamiodarone and inducibility of ventricular mchyeardia at electrophysiologic study (3,22). number of estrastimuli required for induction (26) of ventricular tachycardia or clinicl recurrence of ventricular arrhythmia, .3,221- This sugg :sts That although the etectrapt:ysidloeic efiecif ,f amiodarone are related to the plasma levels of amiodarone and desethylarnfodarnne . monitoring of plasma levels in addition to electlophysiolagic study is not helpful in predicting the arrhythmia recurrence . Laog•rerm follow-up. The patient initially excluded from the study was no, followed up . In addition, two patients were lost to follow-up lone moved away, one refused further follow-ep) . Two patients died of nonarrhythmic causes 3cithin 6 months of their 6-week follow-up electrophysiologic study lone of intractable congestive heart failure and one of metastatic carcinoma) . The remaining Il patients have all been followed up for >2 years without clinical recurrence of their presenting arrhythmia . One patient received an implantable defibrillator . Amiodarone was discontinued in one patient because of visual side effects thought to be secondary to amioda: one, and mexilitene was substituted . Ten of the 15 patients continue to receive art» odarone . The clinical toler . ance of amiodarone in the present study compares favorably with results reported recently in two long-term follow-up studies of much larger numbers of patients both at this institutior. (271 and elsewhere (28) . Conclusions. The present study has shown that the use of a high dose loading regimen of amiodarone is clinically well tolerated in patients with life-threatening ventricular orrhythmnias and depressed ventricalr function . Furthermore, the electrophysiologic effects of amiodarone are manifested



JACC Vet . 19. No, I Jamtary 1952 .1!4-73

EVANS ET AL. 11151 1 ttJSL 0003 . AMIDIYARUNE LOADINfi

early during high dose loading and may be due to the parent drug. The further changes observed with time in electrophy:tialogic variables. despite stable amiodarone plasma lelrels . suggest an additional effect of desethylamiodarane Despite persistent arrhythmia indueib!!ity_ long-term follow-up of these patients shows a survivsl rate similar to that of patients who have received lower dose loading regimens . Although there is a small potential to exacerbate preexisting depressed left ventricular function, the use of a high dose oral amiodarone loading regimen appears to be clinically safe . Because of its clinical safety snd good Ioleracce, high dose oral amiodarone loading stay permit shorter loading periods, thereby allowing a shorter nospital stay for patients who reyts ;ro amiodarone therapy for life-threatening ventricular arrhythmia. . Further studies with lzrger numbers of patients are warranted to determine the best high dose oral loading regimen .

References 1 . 7pes DZ. Pryslowsky EN. Heger JJ, Amlodarmte : ekdroph1n :otngic actions . phanvacokki,1, s . and d :ni:- edeas . I .Am Colt Cardiol 1%4. 3:J059-71 . 2 . Kennedy EE . Roseneld LE M;Fhrnon CA, Easrerd WI, Evaluuion by serial dedraphyaob~c s udieso~ an abtre .iated orl loading neirncn ofamiodarune. Am I Cordial 1953:`..:861-7I . 3 . Gmcobcrg ML, Lnrrun BB, 5hipeJR, Kaiser DL, DM .,. 3P. Rrlaaun Ire'— amiwan,ne and ernehy3aariadarrne planar. cnreemmmes rd elnctrophysielogic eRecn . dtlcasy. and [.skits. I Am Coll Cardkl 196!9'.1741-55 . 4. Me T . Homer A . Weins D. Mandel Wl . Pr marts after sudden cardiac death without associmest myocardial infartiua : or scar fialtos-ap d empine therapy wilt amiedarnne. Am Heart 119714:10'.209- S. 5. Hsffaiee CL I.ave JC . Alpen 1S . ,tsdoudan GK, icons KC, F lousy and sz'ely of kmg.te.m -mod.- in Imar,n .nl - a carduc anhylhminc dosage eapelience . Am Hem 1 1981 :106:9143. 6 . Heger Jl. Pry .-As EN . Zipas DP. Clinical sMsmy of atnioRuane in trezlmrnt Of rrcurrnl vemricubr lachy:ardu and ventncular fibnllauo1 .Am Heart 11983:1%sw-'-94. 7 . E : eouber K. Caumel P, Ponm JM, et d. Suppression of arrhylhmfie wAhin hours after a stride alai dace of amindaroncand relation to plasma cod myoaaudid coucemrations. Am 1 Cardiol 195535 :6sf-tN7 . 8. Mosrw ND. Vtohel TR. Neon D. R AU L . Rapid wwrnsion of mnpiec ventricular erhyt:)mias with high dnsc ant amirdanme. Ciru. Wan 1986 ;73 :123'-f 9. Hall DW . Tucker GT . Jackson Pit . Storey GCA . Amiadarom sib-cokindics. Am Heart I IWl:IO&840-7. [0. Mitchell LB, Wyse G, Gillis AM . Duff Hl . Eleampharnwcokgy of odarone Ihrnpy :niruran :lirreeoarses of onset ofelwrophysblagiv and antiarhythmic effects . Circulalan 80:1989:34-42 . 11 . Gsern DS. Gang ES. Hamrr AW. et al. Mode of viia.iaries server msponse: validation of a protocol farindudion of ventrialrrchycardia . Am Han 1 191ta]0:6W-`7 .

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12 . Manors Ft. Fontaine CH. Frank R. « al . Clinical nharmacalogy and I orapeutic apptiralions of the anlrarrhythmic agera. nmiodarnne. Am Heart 11981 :101 :4$3-93. 13 . Haffaje< CL. love JC, Canada AT . Lesko W . Asdoudan G. Alpert IS . Chn ,cal pharmawkianus and Fleecy d an"Warnne fnn ref-awry mchyarrhylhmias.10000500 198347:1347-55 . 14 Kadish All . Buxton AL, %=a,. AL . Fl- B, ksephson ME, Marchlinsti FE. Usefulness ofsleclrophysialepe study tc d .moist. the . of anhythmia recurtences during amiodarone!herpy. diuical "trim I Am CA] lardiul 1987:10 :90-6 . 15. Homer AW. Finermm WB . Petrel, Mandel WI . Unparity between the din ie01 and alecrrophy,lol gle 00005 at amiadrone is the vealment of eras rent vie,:ideulartoatgarthydlmias . Am Heart 11981 ;102:992-1000. 16, Nademanre K. Hendrickson J. Kannm R, Seals RN. Aniaerhythmic efficacy end slavophysiolo®c a fiin of amiadarone in patients with Ide-threatening ventricular arnryllnnras : Ismenl suppression orsponlaue . ously occumlg tachyanhylbntias ve.susimcmsistenl zboliion of induced ventricular uchyeardia. Am Hean 11992:10"504. t7 . Menu'; : AS, Lricchin F . Esc, NAM III: prognostic value of early elecnophysioktgic studies ire vemncu!ar luhycardia recutreme in pIlents v:i,h coronary anerydisease rreated with zasiddarone . :m J Cordial 199 ;'s I:to52 7. la . Iturowitz LN, Spidnun SR . Greenspxl AM, Webb CR. Kay HR. Vat-la, arhydettm : use of eleclruphysiabgic studies . Am Heat 1 1983 .145 8864 . 19 . Lavery D. Saksena 5. Maoagensenl of refractory sustained ventricular t uhy cardu win, amiodnone : a reappraisal. Am Heart 11987 :113 :49-5e. 20. McGovernE,GaraoH .MarconRF,nat L ag-lermdineatoutcaoeof venrriralet rachyeard'm ar hbriiWian !reeled with amiodaraue. Am J Cudiol 1984,53:1551-63. 21, Yaeaki Y . Haf4Jee CL, Gold R1 .. FAShop RL. AIM IS. Ekctrophysiolo0c pmdictons of tongdenn caned o!nrome with arstiodamne fine ttfrutery venln vlartxhywdia secondary Ie coronary artery disease . Am I Cardlal 1981:80293.7 . 22. Hnmwfrr LM . Spielman SR . Greenspan AM . in aL Usefulness of akc . Irn+hv9 -dingo lemirg in evoluatien f -kW- therapy for sustained ieaternachyarrhoohmsaswciatedwahwrmarylmartdineasaA . J Candir' 1915 :55 :$7-71 . 23. Tahjw M . DeRaade MR, Nauel 5 . Comparative ekctrophysiobgie edecn of intravenous amlpdararr x94 desr.'rdamfodume In dogs: cvidnuce for elin'ruBy rekamr aria ill d the retabWile . Cirata on 1987 ;75105-71 . 24. Heger 11. Prystowsky EN . dupes W . RtlHimsrdpstxtwren alniodarane dosage, dust eoneemrasisna and adverse side effects . Am Heart I 1983 :.0031-5. 25. Latin R, Can ndly Sl, Kate, RE . Myasardtal dispocidon of amiodaranr in th . 405.1 Pharntaeni Fop Tiler t983 :224403-n, no . DCarioLA,MnradyF,denaitrierM,BoramtJM,^xhurigL,Anoesky T . Effecn of dnotfe amiadarone therapy on vee riadu lachyeardu -1- 11, prnpamnad voodrimlar alonalatiaa. Aa Head J 1987;113 : 57-64. 27 . Myen M, Peter CT . Weiss D. el M . Beheft( and risks of long-term amtodarone thrrapy far sostainma ."finder rchyiardiarhbri lufon : um of 11rcee-year fell -up in 145 patirms. Am Hart 1 1990 :119 : 8-14, 28 . Hour 3M . Save MJ . Mande P. er al . Lang-term mwlts of arnkdamne therpy in pains, with rrnrrem sonalned sentriwtar rchycardk or ventricular fib,illatnm . J Am Call Cordial 1939 ;13:442-9.