Hemodynamic effects of intravenous administration of amiodarone in congestive heart failure from chronic chagas' disease

Hemodynamic Effects of IntravenousAdministrationof Amiodarone in Congestive Heart Failure from Chronic Chagas’ Disease GIOVANNI BELLOl-l-I, MD, LiLlO

A. SILVA, MD, ANTONIO ESTEVES FILHO, MD,

MIGUEL RATI, MD, ALVARO V. de MORAES, MD, JOSE ANTONIO F. RAMIRES, MD, PROTASIO da LUZ, MD, and FbLVlO PILEGGI, MD

Fourteen patients with congestive heart failure due to chronic Chagas’ disease had hemodynamic studies before and 20, 40 and 60 minutes and 24 hours after intravenous amiodarone. Amiodarone was given initially as a bolus (5 mg/kg); after 1 hour a continuous infusion was maintained for 24 hours (total dose 900 to 1,050 mg). During the first hour of observation, heart rate and cardiac index decreased and mean right atrial, left ventricular end-

diastolic pressures and pulmonary and systemic vascular resistances increased. Except for heart rate and mean right atrial pressure, all hemodynamic variables returned to control values at 24 hours. Thus, myocardial depression occurred with a dose of 5 mg/kg within the first hour of intravenous administration. Amiodarone must be cautiously administered by bolus, especially in patients with cardiac failure.(Am J Cardiol 1963;52:1046-1049)

Although intravenous infusion of amiodarone is effective in the treatment of several cardiac arrhythmias,’ m7 its hemodynamic effects on cardiac function are not well known. Because severe cardiac arrhythmias frequently occur in patients with depressed cardiac function, knowledge of the effect of amiodarone upon cardiac function is important. Few reports on the hemodynamic effects of amiodarone are available in humans and the findings are not uniform. In 6 patients with coronary artery disease, Ourback et als found decreases in heart rate, cardiac index and left ventricular (LV) work and no changes in arterial pressure and increases in peripheral resistance and diastolic pulmonary pressure and increases in peripheral resistance and diastolic pulmonary pressure. Sicart. et al,” in a study of 20 patients, found increases in cardiac index, decreases in peripheral resistance and an increase in LV end-diastolic pressure. CM et al, In in a study of 16 patients, observed significant decreases in heart rate, peripheral resistance, arterial and LV pressures and a small but significant increase in cardiac index at a dose of 5 mglkg. Coronary vascular resistance also decreased and coro-

nary blood flow increased, but the effects on lactate extraction were inconsistent. All of the observations were of short duration (1.5 minutes) and therefore may not represent the entire spectrum of amiodarone effects. The present investigation studies the short-term and 24-hour hemodynamic effects of amiodarone given intravenously in patients with the chronic form of Chagas’ cardiomyopathy and significant myocardial dysfunct ion.

From lnstituto do Cora@o, Hospital das Cknicas, Universidade de Sao Paulo, SHo Paulo, Brasil. Manuscript received April 25, 1983; revised manuscript received July 12, 1983, accepted June 14. 1983. Address for reprints: Giovanni Bellotti, MD, lnstituto do Coragao, Av. Dr. Eneas de Carvalho Aguiar 44, CEP-05403 SBo Paulo, SP, Brazil. 1046

Methods Fourteen patients were studied. Ten were men and 4 were mean age 41 years (range 28 to 57). The diagnosis of Chagas’ disease, chronic form, was established on the basis of clinical and laboratory data,” with emphasis on immunofluorescence test results. At admission, 9 patients were in women,

New York Heart Association functional class II and 5 were in class IV. All patients were taking digitalis and diuretics, and these medications were continued. Antiarrhythmic agents such as quinidine, procainamide or disopyramide were discontinued 48 to 72 hours before amiodarone was given. All patients gave informed consent to the study. Hemodynamic study was performed in the absence of sedatives. Swan-Ganz No. 7Fr catheters were used to measure pulmonary pressures and cardiac output. Left ventricular pressures were measured with a pigtail No. 8Fr Cordis catheter introduced through the femoral artery using the Judkins technique. Pressures were recorded using HP 1280 transducers and a Hewlett-Packard model 4568 with a HP 21511-A

November 1, 1983

TABLE I

THE AMERICAN JOURNAL OF CARDIOLOGY

Hemodynamic Effecfs of Amiodarone

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Amiodarone

Parameters (n = 14) HR (beatsimin)

Control

20 Minutes

40 Minutes

60 Minutes

24 Hours

82i

72 f 3 p
68 f 3 p
71 & 4 P ,;“i0;

3

DAP (mm fig)

76 f 3

72N: 3

Mean AP (mm Hg)

94 f 3

90”s 4

70 f 3 p
2.4 f 0.2

2.1N2 0.3 p <0.02 29 f 3

2.1”s 0.2 p
2428N: 362 p <0.05 276 f 52 p <0.002 36 f 6 NS

2472N$ 290 NS 221 f 40 p <0.02 36 f 5 NS

Mean RAP (mm Hg)

7fl

SPAP (mm Hg)

29 f

3

DPAP (mm Hg)

14f

2

Mean PAP (mm Hg)

20 f

2

SLVP (mm Hg)

122f4

LVEDP (mm Hg)

19 f 2

SAP (mm Hg)

120f4

Cl (liters/min/m*) SI (ml/m2)

31 f3

SVR (dynes s cme5)

2107 f 283

PVR (dynes cmm5)

144 f 23

LVSWI (g-m/m*)

39 f

5

22Ns 2 p <0.02 114 f 6

p3;y;

1

NS

18f 2 p2;O&0;5

p co.05 33 f 2 NS 16f2 22N: 2

p <0.02 120f5 NS 22 f 2 D
il6&4 NS 76 f 3 NS 92 f 3 NS 1.9 f 0.2 D
lllNS 3 p co.05 19 f 3 NS 11013 7oNS 3 86Ns 3 NS 2.3 f 0.2 NS 32 f 3 NS 1843 f 195 p co.002 186 f 32 NS 41 f 5 NS

Values are mean f standard deviation. AP = arterial pressure; Cl = cardiac index; DAP = diastolic arterial pressure; DPAP = diastolic pulmonary pressure; HR = heart rate; LVEDP = left ventricular end-diastolic pressure; LVSWI = left ventricular stroke work index; NS = not significant; PAP = pulmonary pressure; PVR = pulmonary vascular resistance; RAP = right atrial pressure; SAP = systolic arterial pressure; SI = stroke index; SLVP = systolic left ventricular pressure; SPAP = systolic pulmonary pressure; SVR = systemic vascular resistance.

computer. Zero level was set at the midaxillary line. Cardiac output was measured in triplicate by thermodilution with the 9510-A computer system (Edwards Laboratories). The electrocardiogram was monitored continuously. Computer programs were used to calculate heart rate, mean right atria1 pressure, systolic, diastolic, and mean systemic arterial pressures, systolic, diastolic and mean pulmonary artery pressures, systolic LV pressure, LV end-diastolic pressure, cardiac index and stroke index. LV stroke work index was calculated as: stroke index X (mean arterial pressure - LV end-diastolic pressure) X 0.0136. Systemic vascular resistance was calculated as: (mean arterial pressure - right atria1 pressure)/cardiac output X 80. Pulmonary vascular resistance was calculated as: (mean pulmonary artery pressure - diastolic pulmonary artery pressure)/cardiac output X 80. In all patients, after hemodynamic recording in the control state, amiodarone dissolved in distilled water was injected intravenously as a dose of 5 mg/kg over 5 minutes. Hemodynamic variables were again recorded 20, 40 and 60 minutes after drug administration. Then, a continuous infusion of amiodarone, 900 to 1,050 mg, was maintained for 24 hours. At the end of this period another set of hemodynamic measurements was obtained. The paired Student t test was used for comparison of the data; the significance level was 5%.

Results There were no significant of hemodynamic variables

differences in functional

in the response classes II and

III: therefore, the data were pooled. Table I and Figures

1 and 2 show mean values and standard deviations before and after amiodarone administration. There was a decrease in heart rate at 20,40 and 60 minutes, as well as in cardiac index, although stroke index and LV stroke work index remained unchanged. Systolic, diastolic and mean pulmonary artery pressures and left ventricular end-diastolic pressure all increased. Similarly, pulmonary and systemic vascular resistances increased. No significant changes were noted in systemic arterial pressures. A somewhat different hemodynamic pattern was observed at 24 hours. Heart rate was still lower than control values and LV systolic pressure as well as systemic vascular resistance had decreased. LV end-diastolic pressure and pulmonary pressures, cardiac index, stroke index and LV stroke work index returned to control values. Amiodarone was well tolerated in 10 patients, but in 4, important bradycardia and hypotension required atropine sulfate and cardiocirculatory stimulants. These adverse effects were observed soon after the intravenous bolus injection.

Discussion Amiodarone, initially used to treat angina,i2 has important antiarrhythmic effects in chronic recurrent supraventricular and ventricular arrhythmias711s-16 as well as in acute arrhythmias.2,17-20 In addition, ami-

AMIODARONE

FOR CONGESTIVE HEART FAILURE

25 a I e 20 t

C

20m

C

2Om

C

2Om

4Om

60m

24h

60m

24h

AFTER

A.YIOOARONE

AFTER

AFTER

AFTER

AYlODARONE

AUIOOAROWE

AFTER

AYlOOARONE

AYlODARONE

AFTER

AYlOOAROUE

9

9 D T

ta

E

20m AFTER

40m

60m

24h

AMIOOARONE

AFTER

40m

AYIOOARONE

FIGURE 1. Mean values and standard deviations of mean right atrial pressure (RAP), mean puimonary pressure (PAP), leftventricular enddiastolic pressure (LVEDP) and mean aortic pressure (AP) during control (C) and afler amiodarone.

fulfills many of the requirements of an ideal ant&rhythmic drug in that it can be given orally as well as parenterally and is relatively well tolerated even when used for long periods of time.l:i~“l Hemodynamic effects: Our results demonstrated that amiodarone dissolved in distilled water could induce important hemodynamic changes, both within 1 hour of infusion and at 24 hours. Thus, between 20 and 60 minutes of intravenous bolus administration, a significant decrease in heart rate and cardiac index was noted, and concomitant increases in systemic and pulmonary vascular resistances and mean right atrial, LV end-diastolic and pulmonary pressures (Fig. 1 and 2). These results therefore indicate that in the doses used, amiodarone can produce significant depression of cardiac function that lasts up to 60 minutes in patients with chronic Chagas’ disease. The decrease in heart rate appears to be a factor in the decrease in cardiac index, since there was no significant change in stroke index. On the other hand, the increase in left and right (as judged by mean right atria1 pressure) ventricular enddiastolic pressures could be ascribed either to a negative inotropic effect, alterations in diastolic properties of the cardiac muscle and increases in venous return or augmented resistance to ventricular ejection. Except for the increase in peripheral vascular resistance, which could, in part, explain the depression of cardiac function, our results do not permit analysis of other variables. In dogs, Singhz2 and BarroG and their co-workers noted significant depression of contractility and increments in LV end-diastolic pressure. Barros et alz3 also observed a shift to the right in the pressure-volume curve. In patients with chronic Chagas’ disease, simultaneous echocardiographic and hemodynamic studies showed odarone

FIGURE 2. Mean values and standard deviation of heart rate (HR), stroke index (SI), cardiac index (Cl), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR) and left ventricular stroke work index (LVSWI) during control (C)and after amiodarone.

that intravenous amiodarone depressed the end-systolic stress/end-systolic volume relation, indicating a negative inotropic action.“4 In addition, amiodarone increased ventricular volume, diastolic stiffness and the diastolic stress-strain ratio, with a subsequent increment in elasticity modulus of left ventricle, and no changes in peak systolic stress.s4 Therefore, increments in diastolic pressures may be due both to a negative inotropic effect and to modifications in diastolic properties of both ventricles. Nevertheless, additional studies are necessary to clarify this phenomenon and to assess the contributions of venous return. Our study revealed 2 phases in the action of amiodarone. First, in the initial 60 minutes there was a marked depression of cardiac index and increase in vascular resistance and filling pressures, coincident with the rapid intravenous administration. At 24 hours, resistance decreased and cardiac index returned to normal, suggesting that a peripheral vasodilatatory effect was present. Thus, not only the total dose, but also its rate of administration, may determine the effect. A comparison between our results and those of others is necessary. Sicart,s CBti\,1O and their co-workers, using the same dose of amiodarone in normal subjects and patients with coronary insufficiency, observed increases in heart rate and cardiac index and decreases in sys-

November 1, 1983

temic vascular resistance in the initial 15 minutes. Sicart et akg however, noted that several of those effects could have been due to the action of the diluent Tween 80 rather than to amiodarone itself. Our short-term findings using amiodarone not dissolved in Tween 80, however, are in agreement with those of Ourback et al,8 who noted (also in the initial 15 minutes) decreases in heart rate and cardiac index with increases in systemic and pulmonary vascular resistances and pulmonary diastolic pressure, especially in patients with coronary insufficiency. Our investigation was done only in subjects with a particular cardiomyopathy-Chagas’ disease. Furthermore, the patients clearly had abnormal resting ventricular function as indicated by elevated end-diastolic pressure and reduced cardiac output. The interpretation of our results, therefore, may not be valid in other clinical conditions. Clinical implications: Due to its documented efficacy as an antiarrhythmic agent,25 intravenous amiodarone is likely to be used intravenously for the treatment of life-threatening arrhythmias. Our study documents a significant depression of cardiac function when amiodarone was given by rapid intravenous infusion in patients with impaired resting ventricular function. Therefore, the drug should be used cautiously in this situation. References 1. O’Byrm P, Ladauarin B, Lofsance D, Rosenval 0. Chlorydrate d’amiodarone et anesthesie en chirurgie cardiaque. Utilisation de la forme injectable dans la correction des troubles du rythme per-operatoires. Ann Anesthesiol Fr 1976;17:567-575. 2. Brochler M, Fauchier JP, Charbonnier B, Latour F, Perrottn D. Effects benefiques de I’amiodarone injectable sur I’etat de mal syncopal de I’angor de Prinzmetal. Nouv Presse Med 1976;6:1480. 3. Benaim R, Denlzeau JP, Melon J, Domengie B, Kolsky H, Chapelle M, Chlche P. Les effects antiarythmiques de I’amiodarone a propos de 100 cas. Arch Mal Coeur 1976;69:513-522. 4. Waleffe A, Brunlnx P, Kulbertus HE. Effects of amiodarone studied by programmed electrical stimulation of the heart in patients with paroxysmal re-entrant supraventricular tachycardia. J Electrocardiol 1978; 11:253260. 5. Chapman JR, Boyd MJ. Intravenous amiodarone in ventricular fibrillation. Br Med J 1981;282:951-952.

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6. Hayes PC, Love GH, Tulloch JA. Intravenous amicxdarone in atrial fibrillation complicating myocardial infarction. Br Med J 1982;284:506-507. 7. Marcus FI, Fontalne GH, Frank R, Grosgogeat Y. Clinical pharmacology and therapeutic applicatrons of the antiarrhythmic agent, amiodarone. Am Heart J 1981;101:480-493. 6. Durback P, Rocher R, Azlza JP, Manin JP, Vagner D, Leclerc M, Maurice P. Effects hemodynamiques de I’injection intra-veineuse de I’chlorhydrate d’amiodarone ches le suiet normal et le coronarien. Arch Mal Coeur 1976;69:293-298. . 9. Slcarf M, Besse P, Choussat A, Bricaud H. Action hemodynamique de I’amiodarone intra-veineuse chez I’homme. Arch Mal Coeur 1977:70: 219-227. 10. C&B P, Bourassa MG, Delaye J, Janin A, Froment R, David P. Effects of amiodarone on cardiac and coronary hemodynamics and on myocardial metabolism in oatients with coronarv. artery_ disease. Circulation 1979; 59:1165-1172: 11. Fuchs AP, Fferattl VL, Mello VA, Boalnam E. Serologic diagnosis of Chagas’ disease. Comparative study of various technics. Rev lnst Med Trop Sao Paula 1980;22:242-245. 12. Vastesaager M, Glllot P, Rasson G. Etude clinique dune nouvelle medication antiangoreuse. Acta Cardiol 1967;22:483-500. 13. Rosenbaum MB. Chiale PA. Haloern MS. Nau GJ. Przvbvlskl J. Leve RJ. Lazzarl Jo, Ellzarl MV. Clinical eificacy of amiodarone as an anti&rhythmic agent. Am J Cardiol 1976;38:934-944. 14. Rosenbaum MB, Chfale PA, Ryba D, Ellzarl MV. Control of tachyarrhythmias associated with Wolff-Parkinson-White syndrome by amiodarone hydrochloride. Am J Cardiol 1974;34:215-223. 15. Leak D. Evdl JN. Control of refractcKv cardiac arrhvthmias with amiodarone. Arch )ntein Med 1979;139:425-428. 16. Swan JH, Chlsholm AW. Control of recurrent supraventricular tachycardia with amiodarone hydrochloride. Can Med Assoc J 1976; 114:43-44. 17. Ward DE, Camm AJ, Spurrell RA. Clinical antiarrhythmic effects of amiodarone in patients with resistant paroxysmal tachycardias. Br Heart J 1980;44:91-95. 16. Podrld PJ, Lown B. Amiodarone therapy in symptomatic, sustained refractory atrial and ventricular tachyarrhythmias. Am Heart J 1981;lOl: 374-379. 19. Kaskl JC, Glrottl LA, Messutl H, Rutltzky B, Rosanbaum MB. Long-term management of sustained recurrent, symptomatic ventricular tachycardia with amiodarone. Circulation 1981;64:273-279. 20. Hager JJ, Prystowsky EN, Jackman WM, Naccarelll GV, Warfel KA, Rlnkenberger RL, Zipes DP. Amiodarone: clinical efficacy and electrophysiology during long-term therapy for recurrent ventricular tachycardia or ventricular fibrillation. N Engl J Med 1981;305:539-545. 21. Waxman, HL, Groh WC, Marchllnskl FE, Buxton AE, Sadowski LY, Horowltz LN, Josephson ME, Kastor JA. Amiodarone for control of sustained ventricular tachyarrhythmias: clinical and electrophysiologic effects in 51 patients. Am J Cardiol 1982;50:1066-1074. 22. Slngh BN, Jewltt DE, Downey JM, Klrk ES, Sonnenbllck EH. Effects of amiodarone and L 8040, novel antianginal and antiarrhythmic drugs, on cardiac and coronary hemodynamics and on cardiac intracellular potentials. Clin Exp Pharmacol Physiol 1978;3:427-442. 23. Montelro De Barros LF, Chagas ACP, Murad Neto A, Holjnd B, Quelroz RM, Plleggl F, Da Luz PL. Efeito hemodinamico da amiodarona durante F;;,emia miocardica experimental. Arq Bras Cardrol 1981;37(suppl 1): 24. Eelloltl G, Moraes AV, Lello AS, Gallano N, Rat1 M, Esteves Fllho A, Ramlrez JhF, Plleggl F. Efeitos da amiodarona nas propriedades elasticas do ventriculo esauerdo da cardiomiooatia chaaasica crbnica. Ara Bras Cardiol 1983;41:71-75. and 26. Rofmensch HH, Belhassen B, Ferguson RK. Amiodarone-benefits risk in perspective. AmHeartJ 1982;104:1117-1119.