- Email: [email protected]
Effects of dobutamine on electrophysiological properties of the specialized conduction system in man
J. ELECTROCARDIOLOGY 12 (4), 1979, 361-370
Effects of Dobutamine on Electrophysiological Properties of the Specialized Conduction System in Man BY ANTONIO MASONI, M.D., PAOLO ALBONI, M.D., CARLO MALACARNE, M.D., AND LUCIANO CODECA, M.D.
SUMMARY The electrophysiological effects of Dobutamine, a new beta adrenergic drug, were investigated using intracardiac electrograms and the extrastimulus method, in 19 patients with 1:1 AV conduction and in 10 other patients, five with second and five with third degree AV block. The electrophysiological effects were studied at three concentrations of the drug: 5, 10 and 15 /~g/Kg/m'. Dobutamine induces: 1) an enhancement of SA node automaticity, showed by a decrease of the sinus cycle length ( P < 0.001 at the first concentration) and by a decrease in the corrected sinus node recovery time (P < 0.001 at the second concentration); 2) a decrease in the effective atrial refractory period ( P < 0 . 0 0 1 at the first concentration); 3) an improvement of AV conduction, showed by a decrease in AH interval (P < 0.001 at the first concentration) and by a shortening of functional and effective refractory periods (P < 0.001 at the first concentration); 4) no change in the HV interval; 5) an improvement of conduction in patients with second degree AV block proximal to the His bundle; and 6) a minimal increase in the heart rate in patients with complete AV block distal to His bundle. Dobutamine, a new sympathomimetic a m i n e w i t h b e t a a d r e n e r g i c properties, is part i c u l a r l y active in t h e t r e a t m e n t of s h o c k a n d congestive h e a r t f a i l u r e ? -6 Its electrophysiological properties h a v e not been c o m p l e t e l y i n v e s t i g a t e d in the p a s t y The purpose of this s t u d y is to e v a l u a t e t h e electrophysiological effects of D o b u t a m i n e on the s i n o a t r i a l (SA) node, t h e a t r i o - v e n t r i c u l a r (AV) node a n d the H i s - P u r k i n j e s y s t e m in man, utilizing intracardiac electrograms and the e x t r a s t i m u l u s m e t h o d .
MATERIALS AND METHODS The study was performed in 19 patients with sinus rhythm and 1:1 AV conduction, in five patients with sinus rhythm and second degree AV block and in five patients with third degree AV block which had remained unchanged for at least eight days. All cardioactive medications were discontinued at least one week prior to the time of study and none of the patients had evidence of congestive heart failure. The examination was performed in the postabsorptive, non-sedated state. A quadripolar catheter was introduced through the r i g h t a n t e c u b i t a l vein and f l u o r o s c o p i c a l l y positioned in the high right atrium. The distal two electrodes were used to stimulate the right atrium and the proximal two electrodes to § a high right atrial electrogram. Another hexapblar catheter was percutaneously introduced into the right femoral vein and positioned in the region of the tricuspid valve, in order to register the His bundle ECGs. s In addition to intracardiac leads, D1, D2, D3 and V1 leads were simultaneously recorded on a six-channel directwriting recorder (HewlettPackard 8811 A) at paper speed of 100 mm/sec. After the basic recordings, a p r o g r a m m e d
From the Division of Cardiology, St. Anna Hospital, Ferrara, Italy. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. w 1734 solely to indicate this fact. Reprint requests to: Prof. Antonio Masoni, Division of Cardiology, Arcispedale S. Anna, 44100 Ferrara, Italy. 361
362
MASONI ET AL
stimulator was utilized for atrial pacing, with the purpose of evaluating both the longest paced-atrial cycle producing second degree AV block and the corrected sinus node recovery time (CSRT)2 Sinus node suppression studies were carried out by pacing the right atrium for one minute, increasing the rate by 10 beats/m' up to a m i n i m u m of 180 beats/m'. The interval between each stimulation was one minute. Impulse duration of 1.5 msec at approximately twice the diastolic threshold was used for stimulation. Refractory period studies were performed using the extrastimulus method; ~~ the right atrium was stimulated at a predetermined basic cycle length (A~A~) and, following every eight basic driven beats, a premature atrial impulse (Aa) was introduced at progressively decreasing A~A2 intervals of 10 msec, to the point of atrial refractoriness. The $1S1 interval ranged from 460 to 600 msec. After the control studies were completed, Dobutamine was intravenously administered by the micro-drip technique and the electrophysiological studies were repeated three times at a drug concentration of 5, 10 and 15 ~tg/ Kg/nf. The studies were undertaken 10 minutes after the administration of each Dobutamine concentration and completed within 15-20 minutes. In the patients with second or third degree AV block, only the control recordings were obtained. Sinus and QRS cycle lengths were calculated as the average of 20 consecutive beats, recorded 10 minutes after the administration of each Dobutamine concentration.
The CSRT has been reported as the longest value obtained during the paced-atrial cycle lengths common to the four electrophysiological studies performed (the control study and the studies made using the three Dobutamine concentrations). Results were analyzed by means of the Student's %" test for paired data. The data obtained at the three drug concentrations were compared with the control values. Definition of terms. $1, At, H~, V~ represent the stimulus artifact, atrial electrogram, His bundle electrogram and ventricular electrogram of the basic driven beat. $2, A2, /-/2, V2 represent the stimulus artifact, atrial electrogram, His bundle electrogram and ventricular electrogram of the premature beat. A V nodal conduction time is represented by the AH interval, and is measured from the first rapid deflection of the low right atrial electrogram to the onset of the His bundle deflection. His-Purkinje conduction time is represented by the HV interval, and is measured from the onset of the His bundle deflection to the onset of ventricular activation. Corrected sinus node recovery time is calculated by the difference between the sinus escape time and the sinus cycle length. Sinus escape time is defined as the interval between the last paced atrial beat and the first sinus escape beat as verified by P-wave morphology with a high to low
TABLE I Clinical data of the patients with 1:1 AV conduction. Abbreviations: LBBB: left bundle branch block; AFB: anterior fascicular block; RBBB: right bundle branch block; LVH: left ventricular hypertrophy; PFB: posterior fascicular block; RVH: right ventricular hypertrophy.
Age 26 69 58 29 77 51 55 62 44 38 63 65 56 46 47 24 68 71 68
Sex F M M M F M F M M F M M F F M M F M M
Clinical diagnosis No heart disease Arteriosclerotic heart disease Hypertensive heart disease No heart disease Arteriosclerotic heart disease 01d anterior myocardial infarction Arteriosclerotic heart disease Arteriosclerotic heart disease Rheumatic mitral regurgitation No heart disease Arteriosclerotic heart disease Arteriosclerotic heart disease Hypertensive heart disease No heart disease Arteriosclerotic heart disease No heart disease Hypertensive heart disease Arteriosclerotic heart disease Chronic cor pulmonale
ECG Normal Sinus bradycardia, f degree AV block LBBB Normal Sinus bradycardia, f degree AV block, AFB Sinus bradycardia, antero-septal infarction LBBB f degree AV block, LBBB Sinus bradycardia, f degree AV block, LVH Normal Sinus bradycardia, AFB AFB LVH, RBBB Normal f degree AV block, PFB Normal f degree AV block, RBBB, AFB f degree AV block, RBBB RVH, RBBB J. ELECTROCARDIOLOGY, VOL 12, NO. 4, 1979
EFFECTS OF DOBUTAMINE
363
TABLE II Sinus cycle length (SCL), conduction intervals, corrected sinus node recovery time (CSRT) and paced-atrial cycle length (PACL) at onset of 2 ~ degree AV block before and during Dobutamine infusion (msec). SD = standard deviation. PACL at onset of 2~ degree AV block
SCL
AH
HV
CSRT
p.g/Kg/m'
/~g/Kg/m'
/~g/Kg/m'
/~9/Kg/rn'
Control
5
10
15
Control 5
10
15
Control 5
10
15
Control 5
/~g/Kg/m' i0
15
Control 5
10
15
1
680
610
570
470
90
80
70
70
40
40
40
40
270
230
190
190
350
300
290
270
2
1120
920
650
570
190
140
130
130
40
40
40
40
680
590
380
420
550
460
430
400
3
650
540
400
370
120
120
110
110
50
50
50
50
190
180
150
140
400
330
290
270
4
800
770
740
680
80
70
70
65
45
45
45
45
270
330
320
220
400
350
350
330
6
1050
730
550
480
170
150
140
140
50
50
50
50
500
400
360
330
550
460
430
400
6
1020
780
700
680
170
150
140
140
45
45
46
45
410
310
190
180
430
350
300
250
7
670
600
510
470
80
75
70
70
70
70
70
70
130
22O
150
140
400
300
270
250
8
730
650
650
630
100
90
90
90
90
90
90
90
180
170
160
170
370
310
270
270
9
1100
920
840
780
185
160
150
150
50
50
50
50
440
490
380
350
550
400
350
330
10
750
580
500
470
70
55
55
55
45
45
45
45
150
170
120
140
350
290
260
260
11
1160
820
650
540
95
85
65
65
55
55
55
55
450
450
360
380
430
350
310
270
12
720
690
480
450
65
60
55
55
60
60
60
60
260
140
140
190
350
270
240
230
13
640
520
450
450
80
70
60
60
40
40
40
40
230
180
160
150
330
260
240
240
14
820
650
550
500
80
65
60
60
40
40
40
40
190
240
130
130
370
310
290
290
15
700
670
620
590
170
160
130
130
50
50
50
50
320
300
320
290
370
310
290
260
16
890
750
730
550
100
80
75
70
50
50
50
50
200
240
180
180
460
400
370
310
17
700
680
520
410
170
160
150
150
70
70
70
70
360
270
200
250
430
400
370
370
18
820
700
520
420
180
160
150
140
65
65
65
65
380
320
300
280
550
460
400
370
19
850
650
530
480
75
70
65
65
40
40
40
40
210
280
180
210
400
350
310
300
52.3 52.3 52.3 52.3
306.3
290
230 228.4
423.2 350.5 318.9 298.4
142.3 120.2 94.8 88.9
74.9 63.3 59.2 53.8
Mean
835.5 691.1 587.4 525.8
117.4 102.6 93.9 92.4
SD
172,2 114.9 112.4 106.6
45.0 39.5 36.2 35.2
P value
<0.001<0.001<0.001
<0.001< 0.001<0.001
atrial activation sequence, and is measured from the high right atrial electrogram recordings. Effective refractory period (ERP) of the atrium is defined as the longest $1S2 interval at which S~ fails to capture the atrium. Effective refractory "period of the A V node is defined as the longest AtA~ interval at which Aa fails to conduct to the His bundle.
Functional refractory period (FRP) of the A V node is defined as the shortest H1H2 interval that results from any AzA~ interval, provided that AV conduction is not limited by atrial refractoriness. ERP of the His-Purkinje system (HPS) is defined as the longest I-hI-Ia at which Ha fails to conduct to the ventricle. Relative refractory period (RRP) of the HPS is the longest HlI-h at which Ha conducts to the ventricle with a longer HV interval than that of the basic driven beat or with a QRS of aberrant configuration.
RESULTS Patients with 1:1 AV conduction: T h e essent i a l clinical a n d E C G d a t a a r e p r e s e n t e d in T a b l e I. F i v e p a t i e n t s h a d no e v i d e n c e of cardiac disease; t h e r e m a i n i n g h a d m a n i f e s t a J. ELECTROCARDIOLOGY. VOL 12, NO. 3, 1979
> 0.05<0.001< 0.001
<0.001<0.001<0.001
tions of c a r d i a c i n v o l v e m e n t due to v a r i o u s causes. The sinus cycle length (SCL (Table II; Fig. 1A, B) d e c r e a s e d in all p a t i e n t s w i t h t h e d r u g a t t h e first c o n c e n t r a t i o n (5 /~g/Kg/m'). T h e a v e r a g e d e c r e a s e w a s 144 m s e c ( P < 0 . 0 0 1 ) ; t h i s c o r r e s p o n d s to a m e a n i n c r e a s e of 19% in h e a r t r a t e . A t t h e second c o n c e n t r a t i o n of t h e d r u g (10 /~g/Kg/m') t h e a v e r a g e d e c r e a s e of S C L w a s 248 m s e c ( P < 0 . 0 0 1 ) ; t h i s c o r r e sponds to a m e a n i n c r e a s e of 44% in h e a r t r a t e a b o v e control v a l u e s . A t t h e m a x i m a l d r u g c o n c e n t r a t i o n ( 1 5 / ~ g / K g / m ' ) t h e a v e r a g e dec r e a s e of S C L w a s 310 m s e c ( P < 0.001); t h i s c o r r e s p o n d s to a m e a n i n c r e a s e of 62% in h e a r t r a t e a b o v e control v a l u e s . T h e s h o r t e n i n g of S C L w a s m o r e m a r k e d in t h e p a t i e n t s with bradycardia (sinus rate < 60/beats/m') t h a n in t h o s e w i t h a n o r m a l s i n u s r a t e , b u t in b o t h g r o u p s of p a t i e n t s t h e d e c r e a s e w a s s t a t i s t i c a l l y s i g n i f i c a n t ( P < 0.001). The C S R T (Table II), d u r i n g t h e i n f u s i o n of the drug at the first concentration, decreased in 11 p a t i e n t s , i n c r e a s e d in s e v e n a n d re-
364
MASONI ET AL
CONTROL
I /'
/ 720
730
II
A
V.
I
A
A~ H V
V
65 '
60
V
DOBUTAMINE
~ug/kg/m
t ,,/
2
' . . . . . __j^'\
J\
mained unchanged in one. The average decrease was 16 msec (P >0.05). During the infusion of the second concentration of the drug the CSRT decreased in 16 patients, increased in two and r e m a i n e d unc ha nge d in one. The m e a n reduction was 76 msec ( P < 0.001). During the infusion of the maximal Dobutamine concentration the CSRT decreased in 17 patients, increased in one and r e m a i n e d unchanged in one. The m e a n reduction was 78 msec ( P < 0.001). The A H ~nterval (Table II, Fig. 1A, B) during infusion of Dobutamine at the first concentration decreased in 18 patients and was u n ch an g ed in one; the m e a n decrease was 15 msec ( P < 0.001). During the infusion of the second and third concentrations this interval decreased in all patients; the m e a n decrease was 24 ( P < 0.001) and 25 msec ( P < 0.001), respectively. Th er e were no differences in the
~
Fig. 1A. Dobutamine effects on sinus rate, AV nodal and HisPurkinje conduction (Patient No. 12, Tables I, II). HRA: high right atrial electrogram. HBE: His bundle electrogram. Panel A shows sinus rhythm during the control study. The SCL measures 720 to 730 msec. The AV and HV intervals measure 65 and 60 msec, respectively. The QRS complex shows an anterior fascicular block pattern. During infusion of 5 tLg/ Kg/m' Dobutamine (Panel B) there is acceleration of the sinus rate, a decrease in the AH interval (60 msec) and an unchanged HV interval (60 msec).
r e s p o n s e to D o b u t a m i n e in p a t i e n t s w i t h normal AH i nt erval as compared with prolonged (>120 msec) AH. The H V interval (Table II, Fig. 1A, B) was unchanged in all patients during the infusion of all three Dobutamine concentrations.
The longest pace-atrial cycle producing 2 ~ degree A V block (Table II) decreased in all the patients during the infusion of the 5 t~g/Kg/m' Dobutamine concentration. The average reduction was 73 msec ( P < 0 . 0 0 1 ) . An additional decrease was observed at the second (average value: - 105 msec, P < 0.001) and at the third drug concentration (average value: - 1 2 5 msec, P < 0 . 0 0 1 ) . T here were no differences in the response to Dobutamine in patients with n o r m a l AH interval as compared w i t h prolonged AH. The atrial E R P (Table III), during the infusion of the 5 tLg/Kg/m' Dobutamine concenJ. ELECTROCARDIOLOGY. VOL 12, NO. 3, 1979)
EFFECTS
OF DOBUTAMINE
365
C
,,
A
~
At
b
At
480
480
HRA I j
'A
~~ ~
V
,
55
60
'~
55
,
,,~
l/ III
! 60 ' t
55
_.r ~ ~" *J
A
~
J. E L E C T R O C A R D I O L O G Y . V O L 12, NO. 3, 1979
q
. -- b
l/
v
Is p,glkg/m'
4,50
~"'~"~,,I ~ J
V
'
'"
J
/~
~
450
HRA
60
V / ~
~
~
DOBUTAMINE
Fig. lB. Same patient as in Fig. 1A. During the infusion of 10 ~g/ Kg/m' Dobutamine (Panel C) the SCL (480 msec) and AH interval (55 msec) decrease, while the HV interval is unchanged. During the infusion of 15 ~g/Kg/m' Dobut a m i n e (Panel D) the SCL decreases (450 msec), while the AH and HV intervals are unchanged.
A I H
V
~
A
"
^i ' t
V
_
.
_
A
~
V
',.~_~--
366
MASONI ET AL
TABLE III Refractory period data before and during Dobutamine infusion (msec). N~
S1S1 cycle Control
ERP of atrium
ERP of AV node
FRP of AV node
~g/Kg/m'
/~g/Kg/m'
/~g/Kg/m'
5
10
15 *
Control
5
10
15"
Control
5
10
15*
1
500
220
220
210
x
260
240
240
x
420
360
340
X
2
600
420
380
390
x
520
460
450
x
630
510
490
X
3
460
210
210
x
x
290
250
x
x
500
340
x
X
4
500
200
180
180
180
400
340
310
300
520
400
390
270
5
600
320
310
x
x
530
500
x
6
460
260
230
240
210
390
300
240
7
500
230
230
x
x
260
<230
x
x
380
+
x
x
8
460
220
210
210
210
290
270
260
260
350
330
320
310
x <210
600
580
x
X
480
400
340
+
9
600
270
230
220
210
530
450
380
370
640
520
450
430
10
500
170
160
x
x
270
250
x
x
310
280
x
11
500
290
280
260
240
380
350
500
430
+
x +
12
460
210
190
x
x
<210
<190
x
x
+
+
x
x
13
460
230
180
x
x
<230
<180
x
x
+
+
x
x
14
500
240
210
190
, x
280
250
230
x
330
320
320
15
460
240
320
210
200
<240
<230
<210
+
+
+
x +
16
550
280
220
200
x
360
300
260
x
630
500
540
x
17
460
210
200
190
x
330
310
280
x
430
390
350
x
18
600
260
210
x
x
480
410
x
x
570
520
x
x
19
460
290
300
290
x
300
<300
x
390
+
+
X
261.7
240.8
232.5
373.3
294.4
492.2
414.4
58.8
97.4
74.5
120.6
Mean SD P value
58.7
9 54.7 <0.001
<0.001
324.4 80.2 <0.001
<260
<290
<0.001
<240
<200
393.3
77.2
80.9
<0.001
<0.001
+ Studies limited by atrial refractoriness x Studies limited by increase in the sinus rate * At this drug concentration no statistical significance tests have been performed due to scarcity of the data
tration, decreased in 15 patients, increased in one and was unchanged in three. The average d e c r e a s e ( p a i r e d d a t a ) w a s 21 m s e c (P<0.001). At the second Dobutamine concentration, the atrial E R P was unchanged in one patient and decreased in the 11 other patients in whom the comparison was possible (mean decrease: 29 msec, P<0.001). In the remaining patients the comparison was limited by the increase in the sinus rate. The A V nodal E R P (Table III, Fig. 2), during the infusion of the 5 and 10 /~g/Kg/m' Dobutamine concentration, decreased in the nine patients in whom it could be compared. The increase in the sinus rate and atrial refractory period prevented the comparison in the other patients. At the first and second drug concentrations the average decreases w e r e 49 m s e c ( P < 0 . 0 0 1 ) a n d 79 m s e c ( P < 0.001) respectively. There were no differences in the response to Dobutamine in patients with normal AH iriterval as compared with prolonged AH.
The A V nodal FRP (Table III, Fig. 2) during t h e i n f u s i o n of t h e 5 a n d 10 /~g/Kg/m' Dobutamine concentration, decreased in the nine patients in whom it could be compared. Increase in the heart rate and atrial refractory period prevented the comparison in the other patients. At the first and second drug concentrations the average decreases were 78 msec (P<0.001) and 99 msec (P<0.001) respectively. There were no differences in the r e s p o n s e to D o b u t a m i n e in p a t i e n t s with normal AH interval as compared with prolonged AH. The E R P of the His-Purkinje system could not be determined in a n y patients in this s t u d y b e c a u s e c o m p l e t e block w i t h i n the His-Purkinje system did not occur either during the control or during the Dobutamine infusion. The R R P of the His-Purkinje system was reached in four patients during the control study and only in one patient during drug infusion. In this l a t t e r patient the R R P deJ. ELECTROCARDIOLOGY. VOL 12, NO. 3, 1979
EFFECTS OF DOBUTAMINE
367
CONTROL
!
HRA~!
A1
~J
95
Fig. 2. Effect of Dobutamine on effective and functional refractory periods of the AV node (Patient No. 10, Tables [, III). In all panels the basic atrial cycle length is constant at 500 msec. In Panel A (control) an atrial premature depolarization (A2), coupled to a basic driven beat (A~) at an interval of 280 msec, is conducted with an A2I-h interval of 130 msec. The H~H2 interval measures 310 msec and is the shortest interval t h a t results from a n y A~A2, thus defining the functional refractory period (FRP) of the AV node. In Panel B the AIA2 coupling interval is reduced to 270 msec and the premature atrial depolarization (A2) is blocked in the AV node. This is the longest A~A2 interval at which A2 fails to propagate to the His-Purkinje system, thus defining the effective r e f r a c t o r y period (ERP) of the AV node du~ing the control period. In Panel C (during 5 t~g/Kg/m' Dobutamine infusion) an atrial premature depolarization (A2), coupled to the basic driven (A~) at an A~A~ interval of 260 msec is conducted with an A2H2 interval of 65 msec. H~I-I2 interval m e a s u r e s 280 msec and is the shortest interval that results from any A~A~, thus defining the FRP of the AV node during 5 ~g/Kg/m' Dobutamine infusion. In Panel D the A~A2 coupling is reduced to 250 msec and the premature depolarization (A2) is blocked in the AV node, thus defining the ERP of this tissue, d u r i n g 5 t~g/Kg/m' Dobutamine infusion.
;
500
4s
1
Sl q
500
~
A1
I
~
2
|
A1
i
:
45 t
500
;!
95
:,
~|:
.I
;
2 0
DOBUTAMINE 5,g/ky/m C
;
A1
",
A1
49'
,I 45 A
f
I
~
A1
A,~
45" i
45Hh
A
D
A,
i,
A1
I
.~
I
!
46:
$
J. ELECTROCARDIOLOGY. VOL 12. NO. 4. 1979
25oms~
A2
t !, "
368
MASONI ET AL
CONTROL
M~ I
A
A
& ,,
B
--
DOBUTAMINE 5#g/kg/m'
v~
HBE
A
A
,
H
V
A
H
V
A
A 6O
C
vI
DOBUTAMINE lopg/kg/m'
_
:
A
-r
A
vl
~l
A
A
DOBU TAMINE 15~g/kg/m'
D
HBE
A
H
%.,o
V
A
H
V
.,o
A
H
V
A
H
V
A
.r
,_ t
250 msec
Fig. 3. Recording demonstrating disappearance of Wenckebach AV block proximal to the His bundle, during Dobutamine infusion. (Table IV) A, control strip showing a 3:2 Wenckebach period. B, during 5 /~g/Kg/m' Dobutamine infusion, the second degree AV block remains. C, recordings obtained during 10/~g/Kg/m' Dobutamine infusion, showing 1:1 AV conduction. The SCL measures 570 msec and the AH and HV intervals 130 and 45 msec, respectively. D, during 15 /~g/Kg/m' Dobutamine infusion, the SCL measures 470 msec and the AH and HV intervals are 160 and 45 msec, respectively.
J. ELECTROCARDIOLOGY. VOL 12, NO. 3, 1979
EFFECTS OF DOBUTAMINE
creased from 440 to 410 msec during 10 ~g/ Kg/m' Dobutamine infusion. P a t i e n t s w i t h s e c o n d d e g r e e AV block* (Fig.
3). Three out of the five patients presented with a Wenckebach AV block with variable conduction ratio and the remaining two presented with a 2:1 AV block. In the first three p a t i e n t s the i n t r a c a r d i a c e l e c t r o g r a m s showed the block to be proximal to the His bundle; during Dobutamine infusion at 5 ~g/Kg/m' the conduction ratio was almost unchanged, while during the infusion of the second concentration the conduction ratio improved up to 1:1 (Fig. 4). In the two patients with 2:1 AV block the intracardiac electrograms showed a distal His bundle block, which did not change at any drug concentration. P a t i e n t s w i t h c o m p l e t e A V b l o c k . * I n the five p a t i e n t s with complete AV block the intracardiac electrograms showed a block distal to the His bundle, which did not change at any drug concentration. The QRS complexes were narrow (P < 0.10 sec) in two cases and wide in all three. In all patients the QRS cycle length decreased progressively at the three drug concentrations without a change in the morphology and the duration of the QRS complexes. D u r i n g the i n f u s i o n of t h e 5 ~tg/Kg/m' Dobutamine concentration the average decrease in the QRS cycle length was 68 msec (P<0.001) and the average heart rate increased from 41 to 42/m'. At the second drug concentration the average decrease in the QRS cycle length was 108 msec (P<0.001); the mean heart rate increased up to 44/m'. At the third drug concentration the mean decrease in the QRS cycle length was 134 msec (P< 0.001) and the heart rate increased up to 45/m'.
DISCUSSION Our data show the following effects of Dobutamine: - - enhancement of SA automaticity; decrease in the atrial effective refractory period; - - decrease of both conduction time and effective and functional refractory periods of the AV node; - - no change in His-Purkinje conduction time and a decrease in the RRP of the His-Purkinje system in the only patient in whom it could be measured; - - minimal increase in heart rate during complete AV block. The enhanced SA node automaticity is manifest by acceleration of the sinus rate and J. ELECTROCARDIOLOGY, VOk 12, NO. 4, 1979
369
by a decrease in the CSRT. This change in sinus rate is moderate (19%) during the infusion of the first Dobutamine concentration and becomes more evident at the second (44%) and the third (64%) drug concentration. Tachycardia induced by Dobutamine is well tolerated, with the exception of some patients at the highest drug concentration. The increase in heart rate during betaadrenergic drugs infusion is already well known, 1H3 while, to our knowledge, the CSRT has not been previously investigated during the infusion of such drugs. The atrial E R P decreased significantly (P<0.001) during the infusion of the drug at the first concentration. This decrease in refractory period, not previously evaluated during Dobutamine infusion, is more marked than during isoproterenol infusion. ~3 However, due to the lack of a homogeneous patient population, it is impossible to make a valid c o m p a r i s o n of D o b u t a m i n e w i t h isoproterenol, the most commonly used betaadrenergic agent. The AV conduction time, as noted by Bianchi et al. 7 decreases during Dobutamine infusion. The effective and functional refractory periods of the AV node also decrease during infusion of the first d r u g c o n c e n t r a t i o n (P<0.001). This effect, not previously reported, is quantitatively similar to that obtained during isoproterenol infusion. ~3 The conduction time in the His-Purkinje system is not changed by Dobutamine, as previously observed in a n i m a l s ~4-16 and in man 7,~,~3 during beta-receptor stimulation. In the three patients with Wenckebach AV block, DobQtamine caused the disappearance of second degree AV block, even though the sinus cycle length showed a decrease indicating a marked improvement of AV nodal conduction. On the contrary, the conduction is not improved in the second degree AV block localized within the His-Purkinje system. In the patients with complete infra-His AV block, the Dobutamine decreases the QRS cycle length, as previously observed during isoproterenol infusion. ~2 Such a reduction is statistically significant at the first concentration of the drug, but not significant from the clinical point of view. Dhingra et al., ~2 in some patients with intra- and infra-His complete AV block, observed 2:1 or 3:1 AV conduction during isoproterenol infusion. These results are questionable since no author before observed an i m p r o v e m e n t of c o n d u c t i o n in t h e HisPurkinje system during beta-receptor stimulation. Such conduction variations might be *The Tables on t h e r e s p o n s e to Dobutamine in p a t i e n t s with second and t h i r d degree AV block are a v a i l a b l e upon request from the authors.
370
MASONI ET AL
s p o n t a n e o u s , t h a t is, i n d e p e n d e n t , of a n isop r o t e r e n o l effect. Clinical implications. The results of our s t u d y s h o w t h a t D o b u t a m i n e is efficacious in t h e t r e a t m e n t of s i n u s b r a d y c a r d i a , a n d imp r o v e s c o n d u c t i o n in the first d e g r e e a n d in W e n c k e b a c h A V b l o c k , w h i c h is m a i n l y l o c a l i z e d p r o x i m a l to t h e H i s b u n d l e . T h e e l e c t r o p h y s i o l o g i c a l effects o b s e r v e d in t h e AV node i n d i c a t e t h a t D o b u t a m i n e c a n increase the heart rate during atrial fibrillation w i t h slow v e n t r i c u l a r response. T h e s e effects a r e p a r t i c u l a r l y useful since t h e c o n d u c t i o n disturbances are often associated with h a e m o d y n a m i c d e r a n g e m e n t s , w h i c h represent the principal indication for use of Dobutamine. A c k n o w l e d g m e n t : T h e A u t h o r s w i s h to t h a n k Dr. G. C a n d i n i of t h e H e a l t h P h y s i c s D e p a r t m e n t of t h e A r c i s p e d a l e S. A n n a , for his h e l p in e l a b o r a t i n g s t a t i s t i c a l d a t a . REFERENCES 1. AKHTAR, N, MIKULIC, E, COHN, J N AND CHAUDHRY, M N: Haemodynamic effects of Dobutamine in patients with severe heart failure. Am J Cardiol 36:202, 1975 2. BEREGOVICH, J, BIANCHI, C, D'ANGELO, R, DIAZ, R, AND RUBLER, R: Haemodynamic effects of a new inotropic agent (dobutamine) in chronic cardiac failure. Br H e a r t J 37:629, 1975 3. ROBIE, N W, AND GOLDBERG,L I: Comparative systemic and regional haemodynamic effects of d o p a m i n e a n d d o b u t a m i n e . Am H e a r t J 90:340, 1975 4. TUTTLE, R R, AND MILLS, J: Dobutamine: Development of a new catecholamine to selectively increase cardiac contractility. Circ Res 36:185, 1975 5. LOEB, H S, BREDAKIS, J, AND GUNNAR, R M: Superiority of Dobutamine over Dopamine for
6. 7.
8.
9. 10.
11.
12,
13.
14. 15.
16.
augmentation of cardiac output in patients with chronic low output cardiac failure. Circulation 55:375, 1977 SAKAMOTO,T, AND YAMADA, T: Hemodynamic effects of Dobutamine in patients following open heart surgery. Circulation 55:525, 1977 BIANCHI, C, DIAZ, R, GONZALES, C, AND BEREGOVICH,J: Effects of Dobutamine on atrioventricular conduction. Am Heart J 90:474, 1975 SCHERLAG,B G, LAU, S H, HELFANT,R H, BERKOWITZ, V D, STEIN, E AND DAMATO, A H: Catheter technique for recording His bundle activity in man. Circulation 39:13, 1969 NARULA, O S, SAMET, P, AND JAVmR, P: Significance of the sinus node recovery time. Circulation 45:140, 1972 WIT, A L, DAMATO, A N, WEISS, M B AND STEINER, C: Phenomenon of the gap in atrioventricular conduction in the human heart. Circ Res 27:679, 1970 DAMATOA N, LAU,S H, HELFANT,R H, STEIN, E, BERKOWITZ,W AND Cohen, S I: Study of atrioventricular conduction in man using electrode catheter recordings of His bundle activity. Circulation 39:287, 1969 DHINGRA,R C, WILSON, E, PUGET, J, RAHIMTOOLA, S AND ROSEN, K M: The effect of isoproterenol on a t r i o v e n t r i c u l a r and intraventricular conduction. Am J Cardiol 32:629, 1973 VARGAS, G, AKHTAR, M AND DAMATO, A N: Electrophysiologic effects of isoproterenol on cardiac conduction in man. Am Heart J 90:25, 1975 WALLACE,A G AND SARNOFF, S J: Effects of cardiac sympathetic nerve stimulation on conduction of the heart. Circ Res 14:86, 1964 KASSEBAUM,D G AND VAN DYKE, A R: Electrophysiological effects of isoproterenol on Purkinje fibers of the heart. Circ Res 19:940, 1966 PRIOLA,D V: Effects of beta receptor stimulation and blockade on AV nodal and bundle branch conduction in the canine heart. Am J Cardiol 31:35, 1973
J. ELECTROCARDIOLOGY. VOL 12, NO. 3, 1979
Effects of Dobutamine on Electrophysiological Properties of the Specialized Conduction System in Man BY ANTONIO MASONI, M.D., PAOLO ALBONI, M.D., CARLO MALACARNE, M.D., AND LUCIANO CODECA, M.D.
SUMMARY The electrophysiological effects of Dobutamine, a new beta adrenergic drug, were investigated using intracardiac electrograms and the extrastimulus method, in 19 patients with 1:1 AV conduction and in 10 other patients, five with second and five with third degree AV block. The electrophysiological effects were studied at three concentrations of the drug: 5, 10 and 15 /~g/Kg/m'. Dobutamine induces: 1) an enhancement of SA node automaticity, showed by a decrease of the sinus cycle length ( P < 0.001 at the first concentration) and by a decrease in the corrected sinus node recovery time (P < 0.001 at the second concentration); 2) a decrease in the effective atrial refractory period ( P < 0 . 0 0 1 at the first concentration); 3) an improvement of AV conduction, showed by a decrease in AH interval (P < 0.001 at the first concentration) and by a shortening of functional and effective refractory periods (P < 0.001 at the first concentration); 4) no change in the HV interval; 5) an improvement of conduction in patients with second degree AV block proximal to the His bundle; and 6) a minimal increase in the heart rate in patients with complete AV block distal to His bundle. Dobutamine, a new sympathomimetic a m i n e w i t h b e t a a d r e n e r g i c properties, is part i c u l a r l y active in t h e t r e a t m e n t of s h o c k a n d congestive h e a r t f a i l u r e ? -6 Its electrophysiological properties h a v e not been c o m p l e t e l y i n v e s t i g a t e d in the p a s t y The purpose of this s t u d y is to e v a l u a t e t h e electrophysiological effects of D o b u t a m i n e on the s i n o a t r i a l (SA) node, t h e a t r i o - v e n t r i c u l a r (AV) node a n d the H i s - P u r k i n j e s y s t e m in man, utilizing intracardiac electrograms and the e x t r a s t i m u l u s m e t h o d .
MATERIALS AND METHODS The study was performed in 19 patients with sinus rhythm and 1:1 AV conduction, in five patients with sinus rhythm and second degree AV block and in five patients with third degree AV block which had remained unchanged for at least eight days. All cardioactive medications were discontinued at least one week prior to the time of study and none of the patients had evidence of congestive heart failure. The examination was performed in the postabsorptive, non-sedated state. A quadripolar catheter was introduced through the r i g h t a n t e c u b i t a l vein and f l u o r o s c o p i c a l l y positioned in the high right atrium. The distal two electrodes were used to stimulate the right atrium and the proximal two electrodes to § a high right atrial electrogram. Another hexapblar catheter was percutaneously introduced into the right femoral vein and positioned in the region of the tricuspid valve, in order to register the His bundle ECGs. s In addition to intracardiac leads, D1, D2, D3 and V1 leads were simultaneously recorded on a six-channel directwriting recorder (HewlettPackard 8811 A) at paper speed of 100 mm/sec. After the basic recordings, a p r o g r a m m e d
From the Division of Cardiology, St. Anna Hospital, Ferrara, Italy. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. w 1734 solely to indicate this fact. Reprint requests to: Prof. Antonio Masoni, Division of Cardiology, Arcispedale S. Anna, 44100 Ferrara, Italy. 361
362
MASONI ET AL
stimulator was utilized for atrial pacing, with the purpose of evaluating both the longest paced-atrial cycle producing second degree AV block and the corrected sinus node recovery time (CSRT)2 Sinus node suppression studies were carried out by pacing the right atrium for one minute, increasing the rate by 10 beats/m' up to a m i n i m u m of 180 beats/m'. The interval between each stimulation was one minute. Impulse duration of 1.5 msec at approximately twice the diastolic threshold was used for stimulation. Refractory period studies were performed using the extrastimulus method; ~~ the right atrium was stimulated at a predetermined basic cycle length (A~A~) and, following every eight basic driven beats, a premature atrial impulse (Aa) was introduced at progressively decreasing A~A2 intervals of 10 msec, to the point of atrial refractoriness. The $1S1 interval ranged from 460 to 600 msec. After the control studies were completed, Dobutamine was intravenously administered by the micro-drip technique and the electrophysiological studies were repeated three times at a drug concentration of 5, 10 and 15 ~tg/ Kg/nf. The studies were undertaken 10 minutes after the administration of each Dobutamine concentration and completed within 15-20 minutes. In the patients with second or third degree AV block, only the control recordings were obtained. Sinus and QRS cycle lengths were calculated as the average of 20 consecutive beats, recorded 10 minutes after the administration of each Dobutamine concentration.
The CSRT has been reported as the longest value obtained during the paced-atrial cycle lengths common to the four electrophysiological studies performed (the control study and the studies made using the three Dobutamine concentrations). Results were analyzed by means of the Student's %" test for paired data. The data obtained at the three drug concentrations were compared with the control values. Definition of terms. $1, At, H~, V~ represent the stimulus artifact, atrial electrogram, His bundle electrogram and ventricular electrogram of the basic driven beat. $2, A2, /-/2, V2 represent the stimulus artifact, atrial electrogram, His bundle electrogram and ventricular electrogram of the premature beat. A V nodal conduction time is represented by the AH interval, and is measured from the first rapid deflection of the low right atrial electrogram to the onset of the His bundle deflection. His-Purkinje conduction time is represented by the HV interval, and is measured from the onset of the His bundle deflection to the onset of ventricular activation. Corrected sinus node recovery time is calculated by the difference between the sinus escape time and the sinus cycle length. Sinus escape time is defined as the interval between the last paced atrial beat and the first sinus escape beat as verified by P-wave morphology with a high to low
TABLE I Clinical data of the patients with 1:1 AV conduction. Abbreviations: LBBB: left bundle branch block; AFB: anterior fascicular block; RBBB: right bundle branch block; LVH: left ventricular hypertrophy; PFB: posterior fascicular block; RVH: right ventricular hypertrophy.
Age 26 69 58 29 77 51 55 62 44 38 63 65 56 46 47 24 68 71 68
Sex F M M M F M F M M F M M F F M M F M M
Clinical diagnosis No heart disease Arteriosclerotic heart disease Hypertensive heart disease No heart disease Arteriosclerotic heart disease 01d anterior myocardial infarction Arteriosclerotic heart disease Arteriosclerotic heart disease Rheumatic mitral regurgitation No heart disease Arteriosclerotic heart disease Arteriosclerotic heart disease Hypertensive heart disease No heart disease Arteriosclerotic heart disease No heart disease Hypertensive heart disease Arteriosclerotic heart disease Chronic cor pulmonale
ECG Normal Sinus bradycardia, f degree AV block LBBB Normal Sinus bradycardia, f degree AV block, AFB Sinus bradycardia, antero-septal infarction LBBB f degree AV block, LBBB Sinus bradycardia, f degree AV block, LVH Normal Sinus bradycardia, AFB AFB LVH, RBBB Normal f degree AV block, PFB Normal f degree AV block, RBBB, AFB f degree AV block, RBBB RVH, RBBB J. ELECTROCARDIOLOGY, VOL 12, NO. 4, 1979
EFFECTS OF DOBUTAMINE
363
TABLE II Sinus cycle length (SCL), conduction intervals, corrected sinus node recovery time (CSRT) and paced-atrial cycle length (PACL) at onset of 2 ~ degree AV block before and during Dobutamine infusion (msec). SD = standard deviation. PACL at onset of 2~ degree AV block
SCL
AH
HV
CSRT
p.g/Kg/m'
/~g/Kg/m'
/~g/Kg/m'
/~9/Kg/rn'
Control
5
10
15
Control 5
10
15
Control 5
10
15
Control 5
/~g/Kg/m' i0
15
Control 5
10
15
1
680
610
570
470
90
80
70
70
40
40
40
40
270
230
190
190
350
300
290
270
2
1120
920
650
570
190
140
130
130
40
40
40
40
680
590
380
420
550
460
430
400
3
650
540
400
370
120
120
110
110
50
50
50
50
190
180
150
140
400
330
290
270
4
800
770
740
680
80
70
70
65
45
45
45
45
270
330
320
220
400
350
350
330
6
1050
730
550
480
170
150
140
140
50
50
50
50
500
400
360
330
550
460
430
400
6
1020
780
700
680
170
150
140
140
45
45
46
45
410
310
190
180
430
350
300
250
7
670
600
510
470
80
75
70
70
70
70
70
70
130
22O
150
140
400
300
270
250
8
730
650
650
630
100
90
90
90
90
90
90
90
180
170
160
170
370
310
270
270
9
1100
920
840
780
185
160
150
150
50
50
50
50
440
490
380
350
550
400
350
330
10
750
580
500
470
70
55
55
55
45
45
45
45
150
170
120
140
350
290
260
260
11
1160
820
650
540
95
85
65
65
55
55
55
55
450
450
360
380
430
350
310
270
12
720
690
480
450
65
60
55
55
60
60
60
60
260
140
140
190
350
270
240
230
13
640
520
450
450
80
70
60
60
40
40
40
40
230
180
160
150
330
260
240
240
14
820
650
550
500
80
65
60
60
40
40
40
40
190
240
130
130
370
310
290
290
15
700
670
620
590
170
160
130
130
50
50
50
50
320
300
320
290
370
310
290
260
16
890
750
730
550
100
80
75
70
50
50
50
50
200
240
180
180
460
400
370
310
17
700
680
520
410
170
160
150
150
70
70
70
70
360
270
200
250
430
400
370
370
18
820
700
520
420
180
160
150
140
65
65
65
65
380
320
300
280
550
460
400
370
19
850
650
530
480
75
70
65
65
40
40
40
40
210
280
180
210
400
350
310
300
52.3 52.3 52.3 52.3
306.3
290
230 228.4
423.2 350.5 318.9 298.4
142.3 120.2 94.8 88.9
74.9 63.3 59.2 53.8
Mean
835.5 691.1 587.4 525.8
117.4 102.6 93.9 92.4
SD
172,2 114.9 112.4 106.6
45.0 39.5 36.2 35.2
P value
<0.001<0.001<0.001
<0.001< 0.001<0.001
atrial activation sequence, and is measured from the high right atrial electrogram recordings. Effective refractory period (ERP) of the atrium is defined as the longest $1S2 interval at which S~ fails to capture the atrium. Effective refractory "period of the A V node is defined as the longest AtA~ interval at which Aa fails to conduct to the His bundle.
Functional refractory period (FRP) of the A V node is defined as the shortest H1H2 interval that results from any AzA~ interval, provided that AV conduction is not limited by atrial refractoriness. ERP of the His-Purkinje system (HPS) is defined as the longest I-hI-Ia at which Ha fails to conduct to the ventricle. Relative refractory period (RRP) of the HPS is the longest HlI-h at which Ha conducts to the ventricle with a longer HV interval than that of the basic driven beat or with a QRS of aberrant configuration.
RESULTS Patients with 1:1 AV conduction: T h e essent i a l clinical a n d E C G d a t a a r e p r e s e n t e d in T a b l e I. F i v e p a t i e n t s h a d no e v i d e n c e of cardiac disease; t h e r e m a i n i n g h a d m a n i f e s t a J. ELECTROCARDIOLOGY. VOL 12, NO. 3, 1979
> 0.05<0.001< 0.001
<0.001<0.001<0.001
tions of c a r d i a c i n v o l v e m e n t due to v a r i o u s causes. The sinus cycle length (SCL (Table II; Fig. 1A, B) d e c r e a s e d in all p a t i e n t s w i t h t h e d r u g a t t h e first c o n c e n t r a t i o n (5 /~g/Kg/m'). T h e a v e r a g e d e c r e a s e w a s 144 m s e c ( P < 0 . 0 0 1 ) ; t h i s c o r r e s p o n d s to a m e a n i n c r e a s e of 19% in h e a r t r a t e . A t t h e second c o n c e n t r a t i o n of t h e d r u g (10 /~g/Kg/m') t h e a v e r a g e d e c r e a s e of S C L w a s 248 m s e c ( P < 0 . 0 0 1 ) ; t h i s c o r r e sponds to a m e a n i n c r e a s e of 44% in h e a r t r a t e a b o v e control v a l u e s . A t t h e m a x i m a l d r u g c o n c e n t r a t i o n ( 1 5 / ~ g / K g / m ' ) t h e a v e r a g e dec r e a s e of S C L w a s 310 m s e c ( P < 0.001); t h i s c o r r e s p o n d s to a m e a n i n c r e a s e of 62% in h e a r t r a t e a b o v e control v a l u e s . T h e s h o r t e n i n g of S C L w a s m o r e m a r k e d in t h e p a t i e n t s with bradycardia (sinus rate < 60/beats/m') t h a n in t h o s e w i t h a n o r m a l s i n u s r a t e , b u t in b o t h g r o u p s of p a t i e n t s t h e d e c r e a s e w a s s t a t i s t i c a l l y s i g n i f i c a n t ( P < 0.001). The C S R T (Table II), d u r i n g t h e i n f u s i o n of the drug at the first concentration, decreased in 11 p a t i e n t s , i n c r e a s e d in s e v e n a n d re-
364
MASONI ET AL
CONTROL
I /'
/ 720
730
II
A
V.
I
A
A~ H V
V
65 '
60
V
DOBUTAMINE
~ug/kg/m
t ,,/
2
' . . . . . __j^'\
J\
mained unchanged in one. The average decrease was 16 msec (P >0.05). During the infusion of the second concentration of the drug the CSRT decreased in 16 patients, increased in two and r e m a i n e d unc ha nge d in one. The m e a n reduction was 76 msec ( P < 0.001). During the infusion of the maximal Dobutamine concentration the CSRT decreased in 17 patients, increased in one and r e m a i n e d unchanged in one. The m e a n reduction was 78 msec ( P < 0.001). The A H ~nterval (Table II, Fig. 1A, B) during infusion of Dobutamine at the first concentration decreased in 18 patients and was u n ch an g ed in one; the m e a n decrease was 15 msec ( P < 0.001). During the infusion of the second and third concentrations this interval decreased in all patients; the m e a n decrease was 24 ( P < 0.001) and 25 msec ( P < 0.001), respectively. Th er e were no differences in the
~
Fig. 1A. Dobutamine effects on sinus rate, AV nodal and HisPurkinje conduction (Patient No. 12, Tables I, II). HRA: high right atrial electrogram. HBE: His bundle electrogram. Panel A shows sinus rhythm during the control study. The SCL measures 720 to 730 msec. The AV and HV intervals measure 65 and 60 msec, respectively. The QRS complex shows an anterior fascicular block pattern. During infusion of 5 tLg/ Kg/m' Dobutamine (Panel B) there is acceleration of the sinus rate, a decrease in the AH interval (60 msec) and an unchanged HV interval (60 msec).
r e s p o n s e to D o b u t a m i n e in p a t i e n t s w i t h normal AH i nt erval as compared with prolonged (>120 msec) AH. The H V interval (Table II, Fig. 1A, B) was unchanged in all patients during the infusion of all three Dobutamine concentrations.
The longest pace-atrial cycle producing 2 ~ degree A V block (Table II) decreased in all the patients during the infusion of the 5 t~g/Kg/m' Dobutamine concentration. The average reduction was 73 msec ( P < 0 . 0 0 1 ) . An additional decrease was observed at the second (average value: - 105 msec, P < 0.001) and at the third drug concentration (average value: - 1 2 5 msec, P < 0 . 0 0 1 ) . T here were no differences in the response to Dobutamine in patients with n o r m a l AH interval as compared w i t h prolonged AH. The atrial E R P (Table III), during the infusion of the 5 tLg/Kg/m' Dobutamine concenJ. ELECTROCARDIOLOGY. VOL 12, NO. 3, 1979)
EFFECTS
OF DOBUTAMINE
365
C
,,
A
~
At
b
At
480
480
HRA I j
'A
~~ ~
V
,
55
60
'~
55
,
,,~
l/ III
! 60 ' t
55
_.r ~ ~" *J
A
~
J. E L E C T R O C A R D I O L O G Y . V O L 12, NO. 3, 1979
q
. -- b
l/
v
Is p,glkg/m'
4,50
~"'~"~,,I ~ J
V
'
'"
J
/~
~
450
HRA
60
V / ~
~
~
DOBUTAMINE
Fig. lB. Same patient as in Fig. 1A. During the infusion of 10 ~g/ Kg/m' Dobutamine (Panel C) the SCL (480 msec) and AH interval (55 msec) decrease, while the HV interval is unchanged. During the infusion of 15 ~g/Kg/m' Dobut a m i n e (Panel D) the SCL decreases (450 msec), while the AH and HV intervals are unchanged.
A I H
V
~
A
"
^i ' t
V
_
.
_
A
~
V
',.~_~--
366
MASONI ET AL
TABLE III Refractory period data before and during Dobutamine infusion (msec). N~
S1S1 cycle Control
ERP of atrium
ERP of AV node
FRP of AV node
~g/Kg/m'
/~g/Kg/m'
/~g/Kg/m'
5
10
15 *
Control
5
10
15"
Control
5
10
15*
1
500
220
220
210
x
260
240
240
x
420
360
340
X
2
600
420
380
390
x
520
460
450
x
630
510
490
X
3
460
210
210
x
x
290
250
x
x
500
340
x
X
4
500
200
180
180
180
400
340
310
300
520
400
390
270
5
600
320
310
x
x
530
500
x
6
460
260
230
240
210
390
300
240
7
500
230
230
x
x
260
<230
x
x
380
+
x
x
8
460
220
210
210
210
290
270
260
260
350
330
320
310
x <210
600
580
x
X
480
400
340
+
9
600
270
230
220
210
530
450
380
370
640
520
450
430
10
500
170
160
x
x
270
250
x
x
310
280
x
11
500
290
280
260
240
380
350
500
430
+
x +
12
460
210
190
x
x
<210
<190
x
x
+
+
x
x
13
460
230
180
x
x
<230
<180
x
x
+
+
x
x
14
500
240
210
190
, x
280
250
230
x
330
320
320
15
460
240
320
210
200
<240
<230
<210
+
+
+
x +
16
550
280
220
200
x
360
300
260
x
630
500
540
x
17
460
210
200
190
x
330
310
280
x
430
390
350
x
18
600
260
210
x
x
480
410
x
x
570
520
x
x
19
460
290
300
290
x
300
<300
x
390
+
+
X
261.7
240.8
232.5
373.3
294.4
492.2
414.4
58.8
97.4
74.5
120.6
Mean SD P value
58.7
9 54.7 <0.001
<0.001
324.4 80.2 <0.001
<260
<290
<0.001
<240
<200
393.3
77.2
80.9
<0.001
<0.001
+ Studies limited by atrial refractoriness x Studies limited by increase in the sinus rate * At this drug concentration no statistical significance tests have been performed due to scarcity of the data
tration, decreased in 15 patients, increased in one and was unchanged in three. The average d e c r e a s e ( p a i r e d d a t a ) w a s 21 m s e c (P<0.001). At the second Dobutamine concentration, the atrial E R P was unchanged in one patient and decreased in the 11 other patients in whom the comparison was possible (mean decrease: 29 msec, P<0.001). In the remaining patients the comparison was limited by the increase in the sinus rate. The A V nodal E R P (Table III, Fig. 2), during the infusion of the 5 and 10 /~g/Kg/m' Dobutamine concentration, decreased in the nine patients in whom it could be compared. The increase in the sinus rate and atrial refractory period prevented the comparison in the other patients. At the first and second drug concentrations the average decreases w e r e 49 m s e c ( P < 0 . 0 0 1 ) a n d 79 m s e c ( P < 0.001) respectively. There were no differences in the response to Dobutamine in patients with normal AH iriterval as compared with prolonged AH.
The A V nodal FRP (Table III, Fig. 2) during t h e i n f u s i o n of t h e 5 a n d 10 /~g/Kg/m' Dobutamine concentration, decreased in the nine patients in whom it could be compared. Increase in the heart rate and atrial refractory period prevented the comparison in the other patients. At the first and second drug concentrations the average decreases were 78 msec (P<0.001) and 99 msec (P<0.001) respectively. There were no differences in the r e s p o n s e to D o b u t a m i n e in p a t i e n t s with normal AH interval as compared with prolonged AH. The E R P of the His-Purkinje system could not be determined in a n y patients in this s t u d y b e c a u s e c o m p l e t e block w i t h i n the His-Purkinje system did not occur either during the control or during the Dobutamine infusion. The R R P of the His-Purkinje system was reached in four patients during the control study and only in one patient during drug infusion. In this l a t t e r patient the R R P deJ. ELECTROCARDIOLOGY. VOL 12, NO. 3, 1979
EFFECTS OF DOBUTAMINE
367
CONTROL
!
HRA~!
A1
~J
95
Fig. 2. Effect of Dobutamine on effective and functional refractory periods of the AV node (Patient No. 10, Tables [, III). In all panels the basic atrial cycle length is constant at 500 msec. In Panel A (control) an atrial premature depolarization (A2), coupled to a basic driven beat (A~) at an interval of 280 msec, is conducted with an A2I-h interval of 130 msec. The H~H2 interval measures 310 msec and is the shortest interval t h a t results from a n y A~A2, thus defining the functional refractory period (FRP) of the AV node. In Panel B the AIA2 coupling interval is reduced to 270 msec and the premature atrial depolarization (A2) is blocked in the AV node. This is the longest A~A2 interval at which A2 fails to propagate to the His-Purkinje system, thus defining the effective r e f r a c t o r y period (ERP) of the AV node du~ing the control period. In Panel C (during 5 t~g/Kg/m' Dobutamine infusion) an atrial premature depolarization (A2), coupled to the basic driven (A~) at an A~A~ interval of 260 msec is conducted with an A2H2 interval of 65 msec. H~I-I2 interval m e a s u r e s 280 msec and is the shortest interval that results from any A~A~, thus defining the FRP of the AV node during 5 ~g/Kg/m' Dobutamine infusion. In Panel D the A~A2 coupling is reduced to 250 msec and the premature depolarization (A2) is blocked in the AV node, thus defining the ERP of this tissue, d u r i n g 5 t~g/Kg/m' Dobutamine infusion.
;
500
4s
1
Sl q
500
~
A1
I
~
2
|
A1
i
:
45 t
500
;!
95
:,
~|:
.I
;
2 0
DOBUTAMINE 5,g/ky/m C
;
A1
",
A1
49'
,I 45 A
f
I
~
A1
A,~
45" i
45Hh
A
D
A,
i,
A1
I
.~
I
!
46:
$
J. ELECTROCARDIOLOGY. VOL 12. NO. 4. 1979
25oms~
A2
t !, "
368
MASONI ET AL
CONTROL
M~ I
A
A
& ,,
B
--
DOBUTAMINE 5#g/kg/m'
v~
HBE
A
A
,
H
V
A
H
V
A
A 6O
C
vI
DOBUTAMINE lopg/kg/m'
_
:
A
-r
A
vl
~l
A
A
DOBU TAMINE 15~g/kg/m'
D
HBE
A
H
%.,o
V
A
H
V
.,o
A
H
V
A
H
V
A
.r
,_ t
250 msec
Fig. 3. Recording demonstrating disappearance of Wenckebach AV block proximal to the His bundle, during Dobutamine infusion. (Table IV) A, control strip showing a 3:2 Wenckebach period. B, during 5 /~g/Kg/m' Dobutamine infusion, the second degree AV block remains. C, recordings obtained during 10/~g/Kg/m' Dobutamine infusion, showing 1:1 AV conduction. The SCL measures 570 msec and the AH and HV intervals 130 and 45 msec, respectively. D, during 15 /~g/Kg/m' Dobutamine infusion, the SCL measures 470 msec and the AH and HV intervals are 160 and 45 msec, respectively.
J. ELECTROCARDIOLOGY. VOL 12, NO. 3, 1979
EFFECTS OF DOBUTAMINE
creased from 440 to 410 msec during 10 ~g/ Kg/m' Dobutamine infusion. P a t i e n t s w i t h s e c o n d d e g r e e AV block* (Fig.
3). Three out of the five patients presented with a Wenckebach AV block with variable conduction ratio and the remaining two presented with a 2:1 AV block. In the first three p a t i e n t s the i n t r a c a r d i a c e l e c t r o g r a m s showed the block to be proximal to the His bundle; during Dobutamine infusion at 5 ~g/Kg/m' the conduction ratio was almost unchanged, while during the infusion of the second concentration the conduction ratio improved up to 1:1 (Fig. 4). In the two patients with 2:1 AV block the intracardiac electrograms showed a distal His bundle block, which did not change at any drug concentration. P a t i e n t s w i t h c o m p l e t e A V b l o c k . * I n the five p a t i e n t s with complete AV block the intracardiac electrograms showed a block distal to the His bundle, which did not change at any drug concentration. The QRS complexes were narrow (P < 0.10 sec) in two cases and wide in all three. In all patients the QRS cycle length decreased progressively at the three drug concentrations without a change in the morphology and the duration of the QRS complexes. D u r i n g the i n f u s i o n of t h e 5 ~tg/Kg/m' Dobutamine concentration the average decrease in the QRS cycle length was 68 msec (P<0.001) and the average heart rate increased from 41 to 42/m'. At the second drug concentration the average decrease in the QRS cycle length was 108 msec (P<0.001); the mean heart rate increased up to 44/m'. At the third drug concentration the mean decrease in the QRS cycle length was 134 msec (P< 0.001) and the heart rate increased up to 45/m'.
DISCUSSION Our data show the following effects of Dobutamine: - - enhancement of SA automaticity; decrease in the atrial effective refractory period; - - decrease of both conduction time and effective and functional refractory periods of the AV node; - - no change in His-Purkinje conduction time and a decrease in the RRP of the His-Purkinje system in the only patient in whom it could be measured; - - minimal increase in heart rate during complete AV block. The enhanced SA node automaticity is manifest by acceleration of the sinus rate and J. ELECTROCARDIOLOGY, VOk 12, NO. 4, 1979
369
by a decrease in the CSRT. This change in sinus rate is moderate (19%) during the infusion of the first Dobutamine concentration and becomes more evident at the second (44%) and the third (64%) drug concentration. Tachycardia induced by Dobutamine is well tolerated, with the exception of some patients at the highest drug concentration. The increase in heart rate during betaadrenergic drugs infusion is already well known, 1H3 while, to our knowledge, the CSRT has not been previously investigated during the infusion of such drugs. The atrial E R P decreased significantly (P<0.001) during the infusion of the drug at the first concentration. This decrease in refractory period, not previously evaluated during Dobutamine infusion, is more marked than during isoproterenol infusion. ~3 However, due to the lack of a homogeneous patient population, it is impossible to make a valid c o m p a r i s o n of D o b u t a m i n e w i t h isoproterenol, the most commonly used betaadrenergic agent. The AV conduction time, as noted by Bianchi et al. 7 decreases during Dobutamine infusion. The effective and functional refractory periods of the AV node also decrease during infusion of the first d r u g c o n c e n t r a t i o n (P<0.001). This effect, not previously reported, is quantitatively similar to that obtained during isoproterenol infusion. ~3 The conduction time in the His-Purkinje system is not changed by Dobutamine, as previously observed in a n i m a l s ~4-16 and in man 7,~,~3 during beta-receptor stimulation. In the three patients with Wenckebach AV block, DobQtamine caused the disappearance of second degree AV block, even though the sinus cycle length showed a decrease indicating a marked improvement of AV nodal conduction. On the contrary, the conduction is not improved in the second degree AV block localized within the His-Purkinje system. In the patients with complete infra-His AV block, the Dobutamine decreases the QRS cycle length, as previously observed during isoproterenol infusion. ~2 Such a reduction is statistically significant at the first concentration of the drug, but not significant from the clinical point of view. Dhingra et al., ~2 in some patients with intra- and infra-His complete AV block, observed 2:1 or 3:1 AV conduction during isoproterenol infusion. These results are questionable since no author before observed an i m p r o v e m e n t of c o n d u c t i o n in t h e HisPurkinje system during beta-receptor stimulation. Such conduction variations might be *The Tables on t h e r e s p o n s e to Dobutamine in p a t i e n t s with second and t h i r d degree AV block are a v a i l a b l e upon request from the authors.
370
MASONI ET AL
s p o n t a n e o u s , t h a t is, i n d e p e n d e n t , of a n isop r o t e r e n o l effect. Clinical implications. The results of our s t u d y s h o w t h a t D o b u t a m i n e is efficacious in t h e t r e a t m e n t of s i n u s b r a d y c a r d i a , a n d imp r o v e s c o n d u c t i o n in the first d e g r e e a n d in W e n c k e b a c h A V b l o c k , w h i c h is m a i n l y l o c a l i z e d p r o x i m a l to t h e H i s b u n d l e . T h e e l e c t r o p h y s i o l o g i c a l effects o b s e r v e d in t h e AV node i n d i c a t e t h a t D o b u t a m i n e c a n increase the heart rate during atrial fibrillation w i t h slow v e n t r i c u l a r response. T h e s e effects a r e p a r t i c u l a r l y useful since t h e c o n d u c t i o n disturbances are often associated with h a e m o d y n a m i c d e r a n g e m e n t s , w h i c h represent the principal indication for use of Dobutamine. A c k n o w l e d g m e n t : T h e A u t h o r s w i s h to t h a n k Dr. G. C a n d i n i of t h e H e a l t h P h y s i c s D e p a r t m e n t of t h e A r c i s p e d a l e S. A n n a , for his h e l p in e l a b o r a t i n g s t a t i s t i c a l d a t a . REFERENCES 1. AKHTAR, N, MIKULIC, E, COHN, J N AND CHAUDHRY, M N: Haemodynamic effects of Dobutamine in patients with severe heart failure. Am J Cardiol 36:202, 1975 2. BEREGOVICH, J, BIANCHI, C, D'ANGELO, R, DIAZ, R, AND RUBLER, R: Haemodynamic effects of a new inotropic agent (dobutamine) in chronic cardiac failure. Br H e a r t J 37:629, 1975 3. ROBIE, N W, AND GOLDBERG,L I: Comparative systemic and regional haemodynamic effects of d o p a m i n e a n d d o b u t a m i n e . Am H e a r t J 90:340, 1975 4. TUTTLE, R R, AND MILLS, J: Dobutamine: Development of a new catecholamine to selectively increase cardiac contractility. Circ Res 36:185, 1975 5. LOEB, H S, BREDAKIS, J, AND GUNNAR, R M: Superiority of Dobutamine over Dopamine for
6. 7.
8.
9. 10.
11.
12,
13.
14. 15.
16.
augmentation of cardiac output in patients with chronic low output cardiac failure. Circulation 55:375, 1977 SAKAMOTO,T, AND YAMADA, T: Hemodynamic effects of Dobutamine in patients following open heart surgery. Circulation 55:525, 1977 BIANCHI, C, DIAZ, R, GONZALES, C, AND BEREGOVICH,J: Effects of Dobutamine on atrioventricular conduction. Am Heart J 90:474, 1975 SCHERLAG,B G, LAU, S H, HELFANT,R H, BERKOWITZ, V D, STEIN, E AND DAMATO, A H: Catheter technique for recording His bundle activity in man. Circulation 39:13, 1969 NARULA, O S, SAMET, P, AND JAVmR, P: Significance of the sinus node recovery time. Circulation 45:140, 1972 WIT, A L, DAMATO, A N, WEISS, M B AND STEINER, C: Phenomenon of the gap in atrioventricular conduction in the human heart. Circ Res 27:679, 1970 DAMATOA N, LAU,S H, HELFANT,R H, STEIN, E, BERKOWITZ,W AND Cohen, S I: Study of atrioventricular conduction in man using electrode catheter recordings of His bundle activity. Circulation 39:287, 1969 DHINGRA,R C, WILSON, E, PUGET, J, RAHIMTOOLA, S AND ROSEN, K M: The effect of isoproterenol on a t r i o v e n t r i c u l a r and intraventricular conduction. Am J Cardiol 32:629, 1973 VARGAS, G, AKHTAR, M AND DAMATO, A N: Electrophysiologic effects of isoproterenol on cardiac conduction in man. Am Heart J 90:25, 1975 WALLACE,A G AND SARNOFF, S J: Effects of cardiac sympathetic nerve stimulation on conduction of the heart. Circ Res 14:86, 1964 KASSEBAUM,D G AND VAN DYKE, A R: Electrophysiological effects of isoproterenol on Purkinje fibers of the heart. Circ Res 19:940, 1966 PRIOLA,D V: Effects of beta receptor stimulation and blockade on AV nodal and bundle branch conduction in the canine heart. Am J Cardiol 31:35, 1973
J. ELECTROCARDIOLOGY. VOL 12, NO. 3, 1979