Intravenous diltiazem in patients with paroxysmal re-entrant supraventricular tachycardia

In~ernatronal Journal of Cardiology.

215

23 (1989) 215-221

Elsevier

IJC 00850

Intravenous

Lorenzo

Frabetti

diltiazem in patients with paroxysmal supraventricular tachycardia

re-entrant

I, Alessandro Capucci I, Pier Silvio Gerometta 2, Claudio Susanna Leto di Priolo 3 and Bruno Magnani ’

Cavallini

I,

’ lstrtufo di Malattie dell’ilpparato Cardiocrascolare. Uniwrsitri degli Studr dl Bologna, Ita(v: ’ Centro Cardiologico Mon:ino, Milano. Ita!v; und ’ L.E.R.S., Milano. Ita!\

(Received 16 May 1988; revision accepted 74 November

Frabetti patients

1988)

L, Capucci A, Gerometta PS. Cavallini C, Leto di Priolo S, Magnani B. Intravenous diltiazem with paroxysmal re-entrant supraventricular tachycardia. Int J Cardiol 1989;23:215-221.

in

The electrophysiologic effects and efficacy of diltiazem were evaluated with programmed electrical stimulation of the heart in 12 patients with supraventricular re-entrant tachycardia (five with atrioventricular nodal tachycardia and seven with circus movement tachycardia the accessory pathway being concealed in 4). Diltiazem was infused over 1 minute at the dose of 0.25 mg/kg and the electrophysiologic parameters were evaluated at 5 and 30 minutes. Diltiazem prolonged the AH interval from.835 + 58 to 99 f 55 msec (P < O-05), effective and functional refractory periods of atrioventricular node from 244 f 40 to 268 + 56 msec (P < 0.05) and from 432 + 124 to 468 f 130 msec (P -C0.005) respectively, lowered the atrial pacing rate inducing second-degree atrioventricular block from 159 + 32 to 134 f 33 beats/min (P < 0.005) and decreased systolic and diastolic blood pressure from 143.5 f 33 to 132.5 f 22 mm Hg (P < 0.05) and from 90 f 15 to 82.5 &- 9 (P < 0.05), respectively. Diltiazem prevented the reinduction of the tachycardia tachycardia and in 4 of 7 with circus movement tachycardia. The mechanism

of action

of diltiazem

consisted

in 4 of 5 patients

of depression

with

of conduction

atrioventricular

in atrioventricular

nodal node in

anterograde fashion while there were no effects on refractoriness of the accessory pathway. The drug was well tolerated with no adverse effects. Diltiazem, therefore, appears an effective and safe drug in the acute treatment of re-entrant supraventricular tachycardia.

Key words:

Diltiazem;

Correspondence

Supraventricular

re-entrant

tachycardia:

Wolff-Parkinson-White

Introduction

to: Dr. Lorenzo Frabetti. Istituto di Malat-

tie del’Apparato Cardiovascolare. Policlinico S. Orsola. Via Massarenti 9, 40138 Bologna, Italy. 0167.5273/89/$03.50

syndrome

Diltiazem

effective

6 1989 Elsevier Science Publishers B.V. (Biomedical

hydrochloride

in the treatment

Division)

is a calcium antagonist of angina pectoris [1.2]

216

with an electrophysiological to verapamil, the first drug clinical ployed

activity comparable of this class used in

practice [3,4]. Verapamil in the management and

paroxysmal

supraventricular

arrhythmias

far. however, only few studies to the investigation of the properties

of diltiazem

fects in patients with tachycardia [6--81.

is widely prophylaxis

and

emof

[5]. So

its antiarrhythmic

ef-

supraventricular

The aim of this study was to assess the electrophysiologic mechanism of action of a single intravenous dose of diltiazem in patients with paroxysmal cardia lation

reentrant

supraventricular

by means of programmed of the heart. Materials

tachy-

electrical

The and

study

stimu-

alld Methods

The

characteristics study

(9 males,

population

consisted aged

recurrent

ular tachycardia. Two hypertension and one

of 12 patients

19 to 74 years

symptomatic

(mean

supraventric-

patients had mild arterial a dilated cardiomyopathy

without symptoms of heart failure. In nine, the arrhythmia represented the only cardiac problem. The electrocardiogram showed features of ventricular pre-excitation with a delta wave in three. first degree atrioventricular block in one and was normal in eight. Electrophysiological Patients

gave

study informed

consent

withdrawn at least 48 hours (two months for amiodarone). catheters

atria1 and

rected

recovery

time;

effective

refractory

were

introduced

and

all drugs

before

the study

percutaneously

from the femoral veins. A tripolar catheter was placed across the tricuspid valve for recording from the His bundle. a quadripolar catheter in the high right atrium both to stimulate and to record; two bipolar catheters were positioned at the apex of the right ventricle and in the coronary sinus or in the pulmonary trunk. Tracings were recorded on a 4 channel OTE model 1237 recorder. Stimuli were delivered by a

periods

of right atrium and ventricle: anterograde retrograde effective and functional refractory ods of atrioventricular node and accessory

and peripath-

way (when lar pacing

present); the lowest atrial and ventricurate inducing second-degree atrio-

ventricular initiation

and ventriculoatrial and termination of zone:

pattern

Electrophysiological described

block; mode of the tachycardia;

of atria1

activation

[9.10]

definitions

procedures

as well

are reported

as criteria

for

the

related

setachyto

the

in the literature diagnosis

of an

accessory pathway with retrograde conduction during tachycardia [lo,1 11. The indirect brachial arterial blood pressure was measured by a sphygmomanometer. Diltiazem hydrochloride 0.25 mg/kg diluted with 10 ml isotonic saline was administered intravenously over 60 seconds. All the described procedures were repeated 5 and 30 minutes after completion of drug infusion. Plasma

were

Four

of incremental

up to atrioventricular

quence during induced supraventricular cardia and during ventricular pacing.

3 females)

49 t 20) with

first

pacing

lengths. The following parameters were evaluated: atrioventricular conduction times; sinus node cor-

tachycardia Patients

consisted

ventricular

ventriculoatrial block and secondly of atrial and ventricular single extrastimulus testing at 3 cycle

have been dedicated electrophysiological

paroxysmal

Device model 4372 programmable stimulator. Impulses of 2 msec duration at twice the diastolic threshold were used.

levels

Blood samples drawn 5, 15 and The drug

assay

for diltiazem 30 minutes

plasma levels were after drug infusion.

was performed

by Dr. V. Ascalone

(Pharmacokinetic Unit. L.E.R.S.. Milano, Italy) by high pressure liquid chromatography according to a method set up by L.E.R.S. Synthelabo technicians. Statistical

evaluation

Data are presented as the deviation. Statistical evaluation Student’s

f-test

for paired data.

mean + standard was performed by

217

Easel

Diltiarrm

I

I

I

=

I

Fig. 1. Patient 6. Basal conditions: initiation of tachycardia by a single premature ventricular beat (Vz) at 290 msec (A) and 280 msec (B) during ventricular pacing at a basic cycle length (V,-V, ) of 530 msec. C. After diltiazem. during ventricular pacmg at the same basic cycle length of 530 msec (V,-Vz). a single premature ventricular beat (Vz) at 290 msec is conducted back to the atria and is followed by an atrial echo beat (A,). Re-entry is blocked m spite of an A,-H interval of 180 msec which before the drug elicited the tachycardia, the weak link being in the atrioventricular node in the anterograde way. D. A single premature ventricular beat (V, ) at 280 msec is conducted back to the atria. but shortly after it is blocked in the atrioventricular node in the anterograde way and no echo beat follows. TABLE 1 Electrophysiologic

parameters

in basal conditions

Parameter Sinus cycle length (msec) PA interval (msec) Right atrium ERP (msec) CSNRT (msec) AH interval (msec) Lowest atrial pacing rate inducing 2nd degree AV block (beats/min) AV node ERP (msec) AV node FRP (msec) HV interval (msec) a Right ventricle ERP (msec) VACS ERP (msec) Lowest ventricular pacing rate inducing 2nd degree VA block (beats/min) ’ AP anterograde ERP (msec) AP retrograde ERP (msec)

and 5 minutes

after diltiazem

infusion.

Basal conditions

Diltiazem

10 7 10 10

792 + 29& 210& 314* 83+

751 + 27+ 221 & 358 f 99*

6 7 6 9 10 3

159+ 32 244 i 40 432 + 124 53* 3 220 * 22 245 + 9

134* 33 268 +_ 56 468 2 130 53* 3 215+ 26 285 f 51

P < 0.005 P < 0.05 P < 0.005 NS NS NS

5

180? 38 295i 21 26-I_+ 31

152& 285 i 265 i

P i 0.05 NS NS

Number patients 10

2

4

of

157 12 22 110 58

158 13 22 206 55

51 7 17

Statistical evaluation NS NS NS

NS P < 0.005

ERP = effective refractory period; CSNRT = corrected sinus node recovery time: AV = atrloventncular: FRP = functional period; VACS = ventriculoatrial conduction system; VA = ventriculoatrial: AP = accessory pathway; NS = not significant. with Wolff-Parkinson-White syndrome are excluded. h Patients with accessory pathway re-entry are excluded.

refractory ’ Patients

218 TABLE 2 Tachycardia Patient

electrophysiologic

basis and diltiazem

electrophysiologic

effects.

Arrhythmia

Electrophysiologic basis

Efficacy

Echo beats persistence

Diltiazem

1

AVNT

Dual AV pathways

+

+

2

AVNT

Dual AV pathways

+

3

AVNT

Dual AV pathways

+

+

4

AVNT

Dual AV pathways

5

AVNT

Dual AV pathways

+

+

6 7 8 9

CMT CMT CMT CMT

+ + _

+

10 11 12

CMT CMT CMT

Concealed AP AP (WPW) AP (WPW) Concealed AP Dual AV pathways Concealed AP AP (WPW) (1) Concealed AP (I)

+ +

+ +

AVCV slowing; increased anterograde slow pathway refractoriness? AVCV slowing; increased anterograde slow pathway refractoriness; D ERP unchanged AVCV slowing; increased anterograde slow pathway refractoriness: D ERP unchanged. Insufficient AVCV slowing and insufficient increase of anterograde slow pathway refractoriness: D ERP unchanged. AVCV slowing: increased anterograde slow pathway refractoriness; D ERP unchanged. AVCV slowing; increased AV node refractoriness. Increased AV node refractoriness; D ERP reduction. None. Tachycardia zone widening owing to increased anterograde fast pathway refractoriness. Indeterminable. Indeterminable. Indeterminable.

electrophysiologic

effects

CMT = circus movement AVNT = atrioventricular nodal tachycardia: tachycardia: AP = accessory pathway: WPW = WolffParkinson-White syndrome: I = isoproterenol infusion: AVCV = atrioventricular node conduction velocity: D ERP = difference between the effective refractory periods of the two pathways of the re-entry circuit.

Results Electrophysiologic effects

All patients had inducible and sustained supraventricular tachycardia. In two of them, the tachycardia could be induced only during isoproterenoi infusion, which was repeated after diltiazem. In consequence, they were excluded from statistical evaluation. Five patients had an atrioventricular nodal tachycardia with a pattern of dual atrioventricular pathways with re-entry by the fast pathway as the retrograde limb. Seven patients had a circus movement tachycardia with re-entry by an accessory pathway as the retrograde limb, with was concealed in four. Diltiazem infusion was well tolerated and there were no adverse effects. The results of basal evaluation and of the effects of diltiazem (evaluation 5 minutes after drug infusion, time at which we observed its maximum effect) are shown in Table 1.

The most remarkable effects of diltiazem were on the atrioventricular node. It prolonged the AH interval from 83.5 t- 58 to 99 k 55 msec (P < 0.05). the effective and functional refractory periods of the node from 244 &-40 to 268 + 56 msec (P < 0.05) and from 432 k 124 to 468 * 130 msec (P < 0.005) respectively, lowered the pacing rate inducing second degree atrioventricular or ventriculoatrial block from 159 f 32 to 134 f 33 beats/mm (P < 0.005) and from 180 k 38 to 152 k 51 beats/min (P < 0.05) respectively. The length of the sinus cycle decreased in seven patients. but the overall reduction was not statistically significant. There were no effects on either the right atrium or ventricle or on the refractoriness of the accessory pathway. Diltiazem prevented the reinduction of the tachycardia in 8 out of 12 patients, 4 out of 5 with atrioventricular nodal tachycardia and 4 out of 7 with circus movement tachycardia. It was not possible to compare the refractory periods before and after diltiazem in all the patients because of miscellaneous events. This fact

219

Eamal

-;1---m

-‘p-f---+--.-/,L----

Fig. 2. Patient 9. Atria1 pacing at a basic cycle length of 630 msec: a single atrial premature beat with an A,-AZ interval of 370 and 350 msec (A and B) gives AZ-H, intervals of 150 and 180 msec. respectively. Instead a prematurity of 320 msec (C) gtves a longer A,-H, interval of 240 msec with an atria1 echo beat (Ar.) which elicits the tachycardia. After diltiazem. during atrial pacing at the same cycle length of 630 msec, single atria1 premature beats with A,-A2 intervals of 390 and 370 msec both give AZ-Hz intervals of 240 msec with initiation of the tachycardia (D and E). In this case the effective refractory period of the fast pathway IS very much prolonged and also beats with a low prematurity are conducted along the slow pathway with re-entry along the accessory pathway, while the depressant effect on the slow pathway is not sufficient to prevent the perpetuation of the tachycardia.

did not preclude the identification of the type of arrhythmia, but in a few cases the mechanism of action of diltiazem could not be fully understood. Essentially, it consisted of a critical depression of anterograde atrioventricular conduction (Table 2).

tachycardia zone due to the increased ness of the fast pathway (Fig. 2).

Single atria1 echo beats persisted in six of eight patients in which diltiazem was effective, three

from 143.5 + 33 to 132.5 f 22 mm Hg (P < 0.05) and from 90 + 15 to 82.5 + 9 mm Hg (P < 0.05). respectively.

with dual atrioventricular pathways and three with accessory pathway re-entry (Table 2 and Fig. 1). One patient (no. 9) had both a concealed accessory pathway and dual atrioventricular pathways; after diltiazem he showed a widening of the

Effects

refractori-

on blood pressure

Systolic

Diltiazem

and diastolic

plasma

blood pressure

decreased

levels

Peak plasma levels of diltiazem five minutes after infusion were 603 k 340 ng/ml. In three

patients, the levels obtained seemed exceedingly high. probably because of technical problems, and were excluded from the computation. In these patients, moreover, the electrophysiologic effects of diltiazem were not more marked than in the other patients. Furthermore, the patients in which diltiazem was not effective did not have lower plasma levels.

Discussion Effects on electrophysiologic pressure

parameters and blood

Our study has shown that diltiazem lengthens atrioventricular nodal conduction times both in anterograde and retrograde directions and prolongs atrioventricular functional and effective refractory periods without significant effects on atria1 and ventricular tissues, His-Purkinje system and accessory pathways, in agreement with other reports [4,6,7,12]. The effects of diltiazem on heart rate after acute intravenous infusion are controversial. Some authors report a decrease or no effect on heart rate [3,4.13], while in our and others’ experience [12], a tendency of the sinus rate to increase was observed as a consequence of the peripheral vasodilator effects, which produce both a reflex sympathetic stimulation and a reduction of parasympathetic tone [8.14]. These discrepancies regarding the effects of diltiazem on heart rate deserve further investigation. Experimental studies in the denervated heart showed a negative inotropic and chronotropic action of diltiazem, which is not evident in the clinical use in man thanks to reflex autonomic stimulation. Nevertheless, an unmasking of sinus node dysfunction is reported for patients with apparent normal sinus node automaticity [8.15]. One of our patients (no.]) showed an abnormal corrected sinus node recovery time (850 msec) which did not increase after diltiazem infusion. Although no adverse effects occurred in this patient, we believe that diltiazem should be either avoided or used with great caution in patients with known or suspected sinus node dysfunction.

Supraventricular

tachycardia inducibility

Our results are in agreement with those of other reports which have shown that diltiazem is effective in the treatment and prophylaxis of re-entrant supraventricular tachycardia in virtue of its depressant effects on atrioventricular node [6-8. 121. Diltiazem. as well as other antiarrhythmic drugs. may prevent the initiation of a re-entrant tachycardia with different mechanisms [16]. In patients with atrioventricular nodal tachycardia. diltiazem prolongs the refractory periods of both pathways and re-entry is still often possible. as shown by the persistence of atria1 echo beats during premature stimulation. One can suppose that the prolongation of the refractory period of the anterograde atrioventricular nodal part of the re-entry circuit prevents the atria1 echo from returning to the ventricle and initiating the tachycardia [5.6]. In the patients in which no echo beats persist, the increased anterograde effective refractory period may prevent an appropriate atrioventricular delay so as to find the retrograde pathway excitable [6,7]. When, in spite of an appropriate atrioventricular delay, atria1 echo beats are not elicited by premature stimulation. one can suppose that the weak link is in the retrograde fast pathway [6-81. In our series, however. a depression of anterograde atrioventricular conduction was the only observed mechanism of action of diltiazem. The same considerations can be made for patients with accessory pathways except for the effects on the retrograde part of the re-entry circuit, as calcium blockers have no effect on the accessory pathway [5,8]. In those with WolffParkinson-White syndrome, an antiarrhythmic drug may also be effective by suppressing any difference in refractory period length between the two pathways, like in our patient no. 7 (Table 2). The efficacy of diltiazem in our patients may appear relatively poor if compared to the other series with both diltiazem and verapamil [5,8] where the drug was infused during the tachycardia, but it is not rare that a re-entrant supraventricular tachycardia can still be induced during

221

programmed stimulation following drug administration. in spite of the fact that the same drug had been able to stop the induced tachycardia. In fact, the delicate equilibrium between conduction velocity and duration of the functional refractory periods in the re-entry circuit required to perpetuate the re-entry may also be affected by autonomous nervous system reflex stimulation during acute infusion of the drug [16]. 1n conclusion, diltiazem stands besides verapamil in the acute treatment and in the prophylaxis of supraventricular tachycardia, even if it deserves further investigation when prescribed in the oral form. Diltiazem does not have any significant clinical negative inotropic effect [1,4.14] so that it can be used in patients with latent or manifest heart failure. References Yabe Y, Abe H. Yashimura S. Effect of diltiazem on coronary hemodynamics and its clinical significance. Jpn Heart J 1979;20:83-93. Rosenthal SJ. Ginsburg R. Lamb I. Bairn DS. Schroeder JS. Efficacy of diltiazem for control of symptoms of coronary arterial spasm. Am J Cardiol 1980;46:1027-1032. Kawai C, Komsht T. Matsuyama A, Okazaki H. Comparative effects of three calcium antagonists, diltiazem. verapamil and nifedipine, on the sinoatrial and atrioventricular nodes: experimental and clinical studies. Circulation 1981:63:1035-1042. Oyama Y. Hemodynamics and electrophysiological evaluation of diltiazem hydrochloride: a clinical study. In: Bing RJ. ed. New drug therapy with a calcium antagonist. Diltiazem Hakone Symposium. Amsterdam. Princeton. Excerpta Medica, 1978;169-189. Wellens HJJ. Tan SL. Bar FWH, Duren DR. Lie KI, Dohmen HM. Effect of verapamil studied by programmed

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