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Modifications in the evolution of the dominant frequency in ventricular fibrillation induced by amiodarone, diltiazem, and flecainide
Journal of Electrocardiology Vol. 29 No. 4 1996
Modifications in t h e E v o l u t i o n of the D o m i n a n t F r e q u e n c y in Ventricular Fibrillation I n d u c e d by A m i o d a r o n e , D i l t i a z e m , and Flecainide An Experimental Study
F r a n c i s c o J. C h o r r o ,
M D , * J u a n J. S ~ n c h e z - M u f i o z ,
Juan
Sanchis, MD,* Juan
Juan
Guerrero,
Cortina, MD,* Manuel
PhD,$ Jos~ Espf, PhD,$ Juan and Vicente L6pez-Merino,
MD, t
B a t a l l e r , ]PhD,$
A. R u i p 6 r e z ,
MD,§
MD*
Abstract: In 22 anesthetized mongrel dogs, spectral methods were used to analyze the surface electrocardiogram (ECG) for the time course of the dominant frequency in ventricular fibrillation and its modifications under the influence of amiodarone, diltiazem, and flecainide. The ECG was recorded over 5 minutes after triggering ventricular fibrillation. Following A/D conversion and by applying the Fourier fast transform, the frequency spectrum of the signals was obtained. In group I (5 dogs), the ECGs were obtained without prior drug administration; group 2 (5 dogs) first received amiodarone, 5 mg/kg; group 3 (7 dogs) received diltiazem, 0.2 mg/kg; and group 4 (5 dogs) received flecainide, 2 mg/kg. All drugs were administered intravenously. An initial increase in the dominant frequency of ventricular fibrillation was found in the control group and also in the groups that received amiodarone, diltiazem, or flecainide. Diltiazem significantly increased the dominant frequency and diminished the arrhythmia-slowing process. Amiodarone and flecainide tended to diminish the dominant frequency. Key words: ventricular fibrillation, spectral analysis, Fourier analysis, amiodarone, diltiazem, flecainide.
Ventricular fibrillation prevents the heart f r o m contracting in an orderly a n d effective m a n n e r , thus causing loss of cardiac m e c h a n i c a l function. The t r e a t m e n t of a r r h y t h m i a , once triggered, is based on its i m m e d i a t e detection and interruption by m e a n s of electric shock (1,2). The possibility of restoring cardiac m e c h a n i c a l function depends largely on time elapsed since the start of a r r h y t h mia (3-8). The capacity to secure effective electri-
From the *Cardiology Service, Valencia University Clinical Hospital, Valencia, -[-Cardiology Service, Morales-Meseguer University Hospital, Murcia, $Departrnent of h~formation Science and Electronics, Faculty of Physics, Valencia University, Valencia, and ~Cardiology Service, Virgin de la Arrixaca University Hospital, Murcia, Spain.
Supported by a Fondo de Investigaci6n Sanitaria Grant (Exp. No. 92/0272). Reprint requests: EJ. Chorro-Gasc6, Servicio de Cardiologfa, Hospital Clfnico Universitario, Avenida Blasco Ibafiez 17, 46010Valencia, Spain.
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Journal of Electrocardiology Vot. 29 No, 4 October 1996
cal defibrillation has been correlated with, among other factors (3-14), the characteristics of the fibrillation pattern as defined by electrocardiographic (ECG) signal analysis in the time or frequency domain (5-8,15,16). Following in the path of experimental research aimed at characterizing the developmental patterns of ventricular fibrillation and its modification by different procedures (5-7,15-17), this study focuses on the spectral analysis of the modifications over the time course of the surface ECG during ventricular fibrillation under the influence of amiodarone, diltiazem, and fiecainide. These three drugs were chosen because of their different mechanisms of action and electrophysiologic and metabolic effects. Earlier studies (6,15,17) have described and contrasted the effects of several antiarrhythmic agents and calcium channel blockers; verapamil and nifedipine have been found to delay the arrhythmia-slowing process in the course of its spontaneous evolution. This study provides further information on calcium channel blockers by analyzing the effects of diltiazem and contrasting its actions with those of two Vaughan-Williams class IC and III antiarrhythmic drugs.
Materials and Methods Study Groups and Experiment Preparation Twenty-two mongrel dogs, weighing 8-19 kg, were divided into four groups as a function of the drug used: group 1 (n = 5), control dogs; group 2 (n = 5), amiodarone; group 3 (n = 7), diltiazem; and group 4 (n = 5), flecainide. Following anesthesia with sodium thiopental (30 mg/kg, with additional doses as required) administered through the right saphenous vein, the animals were subjected to endotracheal intubation and were ventilated with atmospheric air at intermittent positive pressure. The ventilatory parameters were monitored by arterial gasometry. A right femoral v en o to my was performed, and a 6F bipolar catheter electrode was advanced under fluoroscopic control to the apex of the right ventricular cavity in order to perform endocavitary electric pacing. The ECG signals were recorded by needle electrodes positioned on the limbs of the animal and connected to Hewlett Packard 8811A bioelectric amplifiers (Hewlett Packard, Palo Alto, CA). The recordings were made simultaneously with Siemens Mingograf 34 polygraph (Siemen-Elema, Solna, Sweden) and a magnetic tape recorder (Hewlett Packard 3960). In each experiment, fibrillation was
induced by electrical pacing through the catheter electrode in the right ventricle. To this effect, a Grass $88 stimulator (Grass Instrument, Quincy, MA) was used t o deliver trains of 2-second duration and consisting of 2-ms pulses at frequencies of 20-50 Hz and a voltage five times that of the diastolic threshold, until arrhythmia was triggered. In group 1, the recordings were made without prior drug administration; in group 2, arrhythmia was induced 15 minutes after administration of intravenous amiodarone, 5 mg/kg; in group 3, arrhythmia was produced 5 minutes after intravenous diltiazem, 0.2 mg/kg; and in group 4, arrhythmia was triggered i 0 minutes after intravenous flecainide, 2 mg/kg. The animals were not defibrillated after induction of the arrhythmia. The time elapsed between administration of the drug and the onset of arrhythmia was chosen as a measure of the time required to secure significant drug effects (18-20).
Data Recorded From the ECG signals recorded on magnetic tape, an A/D conversion was made of the ECG corresponding to leads I and aVF (sampling rate, 500 Hz). Recorded intervals of 8 seconds were selected to perform the power spectrum analysis of the signals obtained immediately after triggering ventricular fibrillation, after 15 and 30 seconds, and every 30 seconds thereafter until the 5-minute recording period was completed. The spectral analysis of each of the intervals (4,096 points) was carried out by fast Fourier transform following application of the Hanning window to the digitized data and suppression of the continuous component of the signal. A graphic and a numeric representation of the signal were produced, corresponding to each of the intervals selected, and the peak positions (ie, the dominant frequency [FrD] in each m om ent studied) were characterized (Fig. 1).
Statistical Analysis The m ean _+ SD of the FrD was obtained in each study group and for each of the intervals analyzed according to the time elapsed from the onset of ventricular fibrillation. The significance of the differences observed was established by analysis of variance. Multiple comparisons were made with the Student-Newman-Keuls test. As the groups did not contain equal n u m b e r of subjects, the harmonic m ean of the sample sizes of the groups was used. Statistical significance was considered at P < .05.
Dominant Frequency in Ventricular Fibrillation
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only one of the ECG leads (aVF). Table 1 shows the FrD values corresponding to each of the intervals analyzed, for each of the control group experiments, along with the means and standard deviations. An initial value of 8.37 + 1.22 Hz is observed (Fig. 2), followed by an initial rise to a m a x i m u m of 9.08 _+ 1.03 Hz after 30 seconds and then a progressive decrease. The m i n i m u m values were observed at the end of the recording period (3.50 _+ 2.22 Hz). The differences became statistically significant with respect to the initial value after 90 sec-
Group 1 (Control) Prior to data analysis in each group, we used a r a n d o m sample (n = 9) of the cases studied to compare the FrD values obtained for each time interval in leads I or aVE No significant differences were observed, w h i c h is in agreement with the results of other authors (6). Consequently, the results s h o w n correspond to the analyses made in
Table 1. Dominant Frequencies (Hz) of Ventricular Fibrillation Obtained Over 5 Minutes in the Control Group Ti me (seconds) Experiment No. Onset 1 2 3 4 5 Mean Mean % -+ SD P <
8.18 8.54 8.54 6.59 10.01 8.37 (100) 1.22 --
NS, n ot significant.
15
30
60
90
120
150
180
210
240
270
300
8.42 9.40 9.40 7.20 9.89 8.86 (106.2) 1.07 NS
8.42 9.40 8.68 8.18 I0.74 9.08 (109.2) 1.03 NS
7.08 8.30 7.93 7.81 9.89 8.20 (98.8) 1.04 NS
5.37 6.10 5.86 7.08 6.59 6.20 (75.8) 0.66 .01
6.35 4.52 5.49 5.49 7.32 5.83 (70.2) 1.05 .01
3.66 6.47 6.59 2.44 4.39 4.71 (55.7) 1.80 .01
3.30 5.86 5.13 3.78 7.69 5.15 (60.6) 1.75 .01
2.81 3.54 3.20 4.52 4.64 3.74 (45.7) 0.81 .001
3.30 5.49 4.03 6.10 7.08 5.20 (63.0) 1.53 .05
6.23. 4.39 3.66 3.30 3.42 4.20 (51.0) 1.21 .001
4.03 0.40 3.05 3.42 6.59 3.50 (41.5) 2.22 .01
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Journal of Electrocardiology Vol. 29 No. 4 October 1996
FrD (Hz) -I'- CONTROL
~- AMIODARONE
trol values and on considering the differences for each segment analyzed, the initial values were not significantly different. The FrD was significantly lower after 180 and 240 seconds (P < .05). The m a x i m u m average of the FrD variations expressed as percentages versus the initial value was 113.8 + 3.5% (30 seconds), with a m i n i m u m of 30.0 _+ 1 ! . 2 4 % (300 seconds).
Group 3 (Diltiazem) 0
30
60
90
120
150
180
210
240
270
300
Fig. 2. Graphic representation of the mean dominant frequencies (FrD) obtained in each study group in the course of arrhythmia.
onds (P < .01). On normalizing the FrD variations and expressing t h e m as percentages with respect to the initial value (initial FrD, 100), the m a x i m u m average was 109.2 _+ 9.0%, w h i c h corresponds to 30 seconds, while the m i n i m u m was 41.5 _+ 23.2%, obtained after 300 seconds (Table 1).
Group 2 (Amiodarone) Table 2 shows the FrD values of the experiments in group 2, w h e r e a m i o d a r o n e was given before inducing fibrillation. An initial value of 6.89 _+ 1.58 Hz was observed, followed, as in the control experiments, by an initial rise to a m a x i m u m of 7.84 + 1.84 Hz after 30 seconds and t h e n a progressive decrease to a m i n i m u m (1.96 .+ 0.50 Hz) after 300 seconds. Statistically significant differences with respect to the initial value were reached after i20 seconds (P < .05). In relation to the con-
Table 3 shows the FrD values of the experiments in group 3, w h e r e diltiazern was given before inducing ventricular fibrillation. The FrD rose from 9.87 + 1.28 Hz initially to a m a x i m u m of 10.57 _+ 2.33 Hz after 15 seconds. A progressive decrease followed, with m i n o r variations after 180 seconds, to a m i n i m u m after 300 seconds (6.12 _+ 1.85 Hz). Statistically significant differences with respect to the initial value were reached after 90 seconds (P < .01). In relation to the control values, the initial differences failed to reach statistical significance. The FrD was significantly higher at 120-300 seconds (P < .05). The m a x i m u m average of the FrD variations expressed as percentages versus the initial value was 106.1 _+ 13.9% (15 seconds), with a m i n i m u m of 63.5 _+ 22.5% (300 seconds).
Group 4 (Flecainide) Table 4 shows the FrD values of the experim e n t s in group 4, in w h i c h flecainide was a d m i n istered. A n initial value of 6.47 _+ 1.52 Hz was observed, followed, as with the o t h e r groups, by an initial rise to a m a x i m u m of 7.40 _+ 1.21 Hz after 30 seconds and t h e n a progressive decrease to a m i n i m u m after 300 seconds (2.07 _+ 1.30 Hz).
Table 2. Dominant Frequencies (Hz) of Ventricular Fibrillation Obtained Over 5 Minutes
in the Amiodarone Experiments Time (seconds) Experiment No. 1 2 3 4 5 Mean Mean % + SD P <
Onset 9.52 5.37 6.35 6.96 6.23 6.89 (100) 1.58 --
NS, n o t significant.
15 10.25 5.62 6.59 6.84 6.71 7.20 (104.4) 1.77 NS
30 10.99 6.23 7.45 7.57 6.96 7.84 (113.8) 1.84 NS
60 9.03 6.84 6.96 8.60 5.37 7.36 (108.3) 1.48 NS
90 8.91 5.37 6.35 7.57 3.30 6.30 (91.1) 2.14 NS
120 3.17 5.74 3.t7 5.86 2.32 4.05 (62.3) 1.63 .05
150 1.71 4.76 3.66 3.78 4.15 3.61 (57.0) 1.15 .01
180 0.98 2.56 3.66 3.05 2.08 2.47 (38.6) 1.02 .001
210 3.30 2.69 4.03 3.30 3.66 3.40 (50.9) 0.50 .01
240 1.71 2.69 3.05 1.95 3.91 2.66 (41.4) 0.88 .001
270 1.34 5.00 5.62 1.46 1.59 3.00 (48.4) 2.I2 .0I
300 1.83 2.20 1.40 1.71 2.69 1.96 (30.0) 0.50 .001
Dominant Frequency inVentricular Fibrillation
•
Chorro et al.
323
Table 3. Dominant Frequencies (Hz) of Ventricular Fibrillation Obtained Over 5 Minutes in the Diltiazem Experiments
Time (seconds) Experiment No. Onset 1 2 3 4 5 6 7 Mean Mean % _+ SD P <
10.62 9.03 10.01 7.32 10.62 10.62 10.86 9.87 (100) 1.28 --
15
30
60
90
120
150
180
210
240
270
300
9.64 9.89 10.99 6.10 12.33 12.94 12.08 10.57 (106.1) 2.33 NS
9.89 9.16 10.74 7.20 9.77 12.08 10.50 9.91 (100.4) 1.51 NS
11.23 9.28 7.93 7.20 8.30 10.74 8.06 8.96 (91.4) 1.52 NS
9.03 7.93 6.47 7.08 6.47 8.54 8.67 7.74 (79.3) 1.07 .01
9.89 6.71 5.37 7.20 6.47 10.01 8.91 7.89 (79.5) 1.96 .05
7.81 6.59 5.25 4.52 6.71 10.62 8.06 7.08 (71.1) 2.01 .01
9.40 8.06 5.25 5.13 5.37 10.50 8.30 6.92 (75.2) 1.88 .01
7.93 6.59 5.37 7.20 6.I0 9.16 8.18 7.22 (74.1) 1.31 .01
9.03 5.74 -7.20 5.86 9.03 8.18 7.51 (77.1) 1.49 .01
7.45 7.08 -7.69 5.13 8.54 7.08 7.18 (74.6) 1.26 .01
8.67 5.25 4.64 7.20 4.27 8.18 4.64 6.12 (63.5) 1.85 .001
NS, n ot significant.
Statistically significant differences with respect to the initial value w e r e r e a c h e d after 90 seconds (P < .05). In relation to the control values, the initial differences did n o t r e a c h statistical significance. The FrD was significantly l o w e r after 60, 180, a n d 240 seconds (P < .05). The m a x i m u m a v e r a g e of the FrD variations e x p r e s s e d as percentages versus the initial value was 117.2 _ 2 0 . 4 % (30 seconds), w i t h a m i n i m u m of 33.1 _+ 2 0 . 0 % (300 seconds). The FrD values in the diltiazem g r o u p w e r e significantly higher t h a n in the flecainide g r o u p for all the intervals a n a l y z e d in the course of the d e v e l o p m e n t of a r r h y t h m i a (P < .05). In turn, the diltiazem g r o u p exhibited significantly greater FrD values t h a n the a m i o d a r o n e g r o u p initially, as well as after 15 seconds, 120 seconds, a n d the following intervals up to 300 seconds (P < .05). In c o m p a r i s o n , the FrD averages in groups 2 a n d 4 o n l y s h o w e d significant differences after 60 seconds (P < .05).
Discussion Ventricular fibrillation is a complex arrhythmia, the analysis of which has received different methodologic approaches. Some of the earliest studies w e r e based on the analysis of the surface ECG (21-23). The subsequent introduction of spectral techniques has yielded c o m p l e m e n t a r y inform a t i o n in the frequency domain, with an i m p r o v e d characterization of the d e v e l o p m e n t a l stages of arrhythmia, pharmacologic modifications of the frequency domain, and its relation to the efficacy of electrical defibrillation (4--8,15-17,24,25). The initial grouping of the m a i n signal c o m p o n e n t s in the frequency d o m a i n a r o u n d defined values has b e e n described; these values are in the 8 - 1 2 - H z range in dogs (4-6,15,17) and s o m e w h a t lower in h u m a n s (16,24). The changes in the f r e q u e n c y d o m a i n as the p o w e r s p e c t r u m evolves h a v e b e e n characterized, initial i n c r e m e n t s being observed in the first seconds of the a r r h y t h m i a , followed by progressive
Table 4. Dominant Frequencies (Hz) of Ventricular Fibrillation Obtained Over 5 Minutes
in the Flecainide Experiments Ti me (seconds) Experiment No.
Onset
15
30
1 2 3 4 5 Mean Mean % -+ SD
6.96 6.84 8.54 4.64 5.37 6.47 (100) 1.52
8.18 6.96 8.30 5.62 6.47 7.11 (111.6) 1.14
8.30 6.23 8.79 6.10 7.57 7.40 (117.2) 1.21
--
NS
P<
NS, not significant.
NS
60 6.71 5.13 5.13 5.86 4.88 5.54 (89.7) 0.75
NS
90 5.86 4.27 3.30 4.39 4.69 4.50 (73.4) 0.92
.05
120 5.00 3.30 3.42 3.17 3.54 3.69 (58.8) 0.79
.01
I50 4.64 3.05 2.56 2.56 1.22 2.81 (43.8) 1.23
.01
I80
210
240
270
300
4.27 1.22 3.05 2.56 1.58 2.54 (39.9) 1.22
3.91 1.95 2.08 1.71 3.17 2.56 (41.0) 0.94
3.66 1.83 2.44 2.08 3.30 2.66 (42.9) 0.79
3.54 1.95 2.20 1.83 3.30 2.56 (41.2) 0.80
3.78 0.24 2.20 1.59 2.56 2.07 (33.1) 1.30
.01
.001
.001
.001
001
324
Journal of Electrocardiology Vol. 29 No. 4 October 1996
decreases that coincide with the disorganization of the spectrum (5,6,15,17). Analyses have also been made of the effects of different drugs on the pattern of evolution of ventricular fibrillation; the results suggest possible positive effects on the course of the arrhythmia, associated with greater success of electrical defibrillation (6,15,I7). The information provided by the spectral analysis of the ECG signal during ventricular fibrillation could yield a n u mb er of indicators for estimating defibrillation success or evaluating the effects of drugs and of maneuvers used during the intervention in order to achieve an effective cardiac rhythm. In this study, we observed a time course pattern analogous to that reported elsewhere (4--6,15,I7), with initial frequencies in the control group of 8.37 _+ 1.22 Hz, early increases in the first 15-30 seconds, and a final progressive decrease in the frequency domain over time. Statistically significant changes appeared after 90 seconds. The initial rise of the FrD has been attributed to both intrinsic and extrinsic factors. One possible explanation may be found in the action of the sympathetic system, which becomes activated in the early moments of arrhythmia in response to the sudden decrease in cardiac output. Carlisle et al. (17) observed no such increase in animals previously treated with propranolol. In contrast, Martin et al. (6) recorded an increase following pharmacologic block of the autonomous nervous system. It is thus likely that factors related to the organization of the arrhythmia in its initial period may also influence the changes recorded immediately after the triggering of arrhythmia, as suggested by Clayton et al. (24). The progressive slowing, expressed by the displacement of the dominant components of the frequency spec'trum (and particularly apparent after 90 seconds), is associated with a progressive loss of the capacity to achieve effective defibrillation (3-6,15,17). This decrease in the FrD is related to the metabolic deterioration of the myocardium, for if coronary perfusion is maintained, both the peak frequency of the spectrum and the ability to achieve defibrillation are preserved, without electromechanical dissociation (6,16). This observation has led a num be r of authors to postulate that maintenance of the peak frequencies in the spectrum by administering different drugs may help to secure effective defibrillation (5,6,17). In this connection, it has been demonstrated that the calcium antagonists nifedipine and verapamil retard the slowing process (6,15,17), with effective defibrillation in the case of nifedipine (6). In our study, diltiazem, like nifedipine and verapamil, produced an increase in the FrD of the spectrum, followed by a slower reduction over the
time course of the arrhythmia. The mechanisms responsible for these changes are not clear. The maintenance of the FrD could imply both the persistence of the rapid and relatively well organized activity in the ventricular myocardium considered globally and the abolition of the slow and more disorganized activity in zones more affected by the metabolic and electrolytic changes; activity would persist in the endocardial zones, where it has been shown (I7) that the fast components of the spectrum are maintained for prolonged periods over the time course of the arrhythmia. Nevertheless, the calcium channel blockers have been postulated (6,I7) to counter the calcium overload and potassium accumulation favored by the ischemia, as both elements are present in the evolution of the arrhythmia (26). In this study, although we do not know w het her the diltiazem-induced changes in the time course of fibrillation are associated with an effective defibrillation-favoring effect after prolonged periods, the above results suggest that the pattern of evolution of the arrhythmia is favored. Both amiodarone and flecainide were found to exert an arrhythmia-slowing effect. These results appear to be more directly linked to the electrophysiologic actions of the drugs (12,18,20,27). The correlation of the changes in the FrD of the spectrum with the changes in electrophysiologic parameters induced by the drugs is complex. Carlisle et al. found that lidocaine reduces the FrD of ventricular fibrillation in the initial moments of arrhythmia (17). They suggested that the prolonged refractoriness and retarded conduction produced by the drug are responsible for this phenomenon, although they failed to observe such marked effects when using bretylium, despite the effects of the latter on the duration of the action potentials and effective refractory periods. Among the factors that may be implicated in the decrease in the FrD of the spectrum are the degree of organization of ventricular activity during fibrillation and the greater or lesser activation frequency of the myocardial cells during arrhythmia. The wavelength of the changing circuits inherent to fibrillation (28,29) and its inverse (frequency) are dependent on the duration of the refractory periods and on conduction velocity. In this sense, a decrease in conduction velocity as a result of flecainide action would imply a decreased wavelength, which appears to contradict the observed facts; a concomitant effect involving a prolongation of refractoriness would therefore have to be considered. This effect has been demonstrated at rapid activation frequencies in atrial myocardium (30), and it may possibly also be found at the ventricular level.
Dominant Frequency in Ventricular Fibrillation A n o t h e r f a c t o r to b e t a k e n i n t o a c c o u n t is r e d u c t i o n of t h e s t i m u l a t i n g efficacy b y t h e drug, w h i c h l o w e r s t h e s a f e t y f a c t o r for c o n d u c t i o n across t h e m y o c a r d i u m a n d c o n s e q u e n t l y c o n t r i b u t e s to a d e c r e a s e in t h e m y o c a r d i a l cell a c t i v a t i o n freq u e n c y . I n t h e case of a m i o d a r o n e , t h e effects of t h e d r u g i n v o l v e s e v e r a l m e c h a n i s m s , w h i c h differ in p a r t d e p e n d i n g o n w h e t h e r it is g i v e n a c u t e l y or c h r o n i c a l l y (18). A m i o d a r o n e e x e r t s a n o n c o m p e t itive a n t a g o n i s t i c a c t i o n o n a l p h a - a n d b e t a a d r e n o r e c e p t o r s a n d also a c a l c i u m a n t a g o n i s t i c effect; w h e n g i v e n acutely, it also gives rise to a u s e - d e p e n d e n t l e n g t h e n i n g of a c t i o n p o t e n t i a l d u r a t i o n a n d r e f r a c t o r i n e s s , a l t h o u g h to a lesser d e g r e e t h a n w h e n a d m i n i s t e r e d c h r o n i c a l l y . T h e s e effects c o u l d b e i m p l i c a t e d in a n i n c r e a s e in w a v e l e n g t h (or d e c r e a s e in f r e q u e n c y of t h e w a v e l e t s ) , w h i c h w o u l d i n d u c e s i g n i f i c a n t c h a n g e s in t h e FrD b y a d d i n g to t h e effects of h y p o x i a a n d t h e m e t a b o l i c and electrolytic alterations, which gradually accum u l a t e o v e r t i m e in t h e c o u r s e of t h e a r r h y t h m i a .
Conclusion O u r r e s u l t s m a y b e s u m m a r i z e d as follows: 1. T h e initial i n c r e a s e in t h e FrD of v e n t r i c u l a r fibr i l l a t i o n w a s also o b s e r v e d u n d e r t h e i n f l u e n c e of a m i o d a r o n e , d i l t i a z e m , or f l e c a i n i d e . 2. D i l t i a z e m i n c r e a s e d t h e FrD of v e n t r i c u l a r fibrillation and diminished the arrhythmia-slowing process. 3. A m i o d a r o n e a n d f l e c a i n i d e t e n d e d to r e d u c e t h e FrD of v e n t r i c u l a r fibrillation.
References 1. Kerber RE: External direct current defibrillation and cardioversion, p. 954. In Zipes DP, Jalife J (eds): Cardiac electrophysiology. WB Saunders, Philadelphia, 1990 2. Akhtar M, Avitall B, Jazayeri M e t ah Role of implantable cardioverter defibrillator therapy in the m a n a g e m e n t of high-risk patients. Circulation 85 (suppl 1):I31, 1992 3. Geuze RH, Devente J: Effects of duration of ventricular fibrillation and heart massage on haemodynamic responses after defibrillation in dogs. Cardiovasc Res 17:282, 1983 4. Carlisle EJF, Allen JD, Bailey A et ah Fourier analysis of ventricular fibrillation and synchronization of DC countershocks in defibrillation. J Electrocardiol 21:337, 1988 5. Carlisle EJF, Allen JD, Kernohan WG et al: Fourier analysis of ventricular fibrillation of varied aetiology. Eur Heart J 11:173, 1990
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6. Martin G, Cosin J, Such M e t al: Relation between power spectrum time course during ventricular fibrillation and electromechanical dissociation. Effects of coronary perfusion and nifedipine. Eur Heart J 7: 560, 1986 7. Brown CG, Griffith RE Van Ligten P e t ah Median frequency. A new parameter for predicting defibrillation success rate. Ann Emerg Med 20:787, 1991 8. Weaver DW, Cobb LA, Dennis D et al: Amplitude of ventricular fibrillation waveform and outcome of cardiac arrest. Ann Intern Med 102:53, 1985 9. Moore EN, Spear JF: Ventricular fibrillation threshold: its physiological and pharmacological importance. Arch Intern Med 135:446, 1975 10. Babbs CE Yim GKW, Whistler SJ et al: Elevation of ventricular defibrillation thresholds by antiarrhythmic drugs. Am Heart J 98:345, 1979 l l. Hernandez R, M a n n DE, Breckinridge SJ et al: Effects of flecainide on defibrillation thresholds in the anesthetized dog. J Am Coil Cardiol 14:777, 1989 i2. Quesada A, Sanchis J, Chorro FJ et al: Changes in canine ventricular fibrillation threshold induced by verapamil, flecainide and bretylium. Eur Heart J 14:712, 1993 13. Fain ES, Lee JT, Winkle RA: Effects of acute intravenous and chronic oral amiodarone on defibrillation energy requirements. Am Heart J 114:8, 1987 14. Manz M, Jung W, Lfideritz B: Interactions between drugs and devices: experimental and clinical studies. Am Heart J 127:978, 1994 15. Martin G, Gimeno JV, Guillem MI, Cosin J: Effects of calcium antagonists on time course of ECG power spectrum during ventricular fibrillation. Comput Cardiol 83:213, 1983 16. Strohmenger HU, Lindner KH, Lurie KG et al: Frequency of ventricular fibrillation as a predictor of defibrillation success during cardiac surgery. Anesth Analg 79:434, 1994 17. Carlisle EJF, Allen JD, Kernohan G e t ah Pharmacological analysis of established ventricular fibrillation. Br J Pharmacol 100:530, 1990 i8. Singh BN: Amiodarone: electropharmacologic properties, p. 335. In Vaughan Williams EM (ed): Antiarrhythmic drugs. Springer-Verlag, Berlin, 1989 19. Chorro FJ, Ferrero JA, Navarro J e t al: Efectos electrofisioldgicos del diltiazem intravenoso. Estudio experimental en perros. Rev Esp Cardiol 39:373, I986 20. Roden DM, Woosley RL: Drug therapy: fiecainide. N Engl J Med 315:36, 1986 21. Wiggers CJ: Studies on ventricular fibrillation produced by electric shock. Part II. Cinematographic and electrocardiographic observations on the natural process in the dog heart. Am Heart J 5:351, 1930 22. Moe GK, Harris S, Wiggers CJ: Analysis of the initiation of fibrillation by electrocardiographic studies. Am J Physiol 134:473, 1941 23. Jones DL, Klein GJ: Ventricular fibrillation: the importance of being coarse? J Electrocardiol 17:393, 1984
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24. Clayton RH, Murray A, Campbell RWF: Changes in the surface electrocardiogram during the onset of spontaneous ventricular fibrillation in man. Eur Heart J 15:184, 1994 25. Clayton RH, Campbell RWF: Frequency analysis of ventricular fibrillation in three surface ECG leads. Comput Cardiol 92:155, 1992 26. Koretsune Y, Harban E: Cell calcium in the pathophysiology of ventricu!ar fibrillation and in the pathogenesis of postarrhythmic contractile dysfunction. Circulation 80:369, 1989 27. Guehler J, Gornick CC, Tobler HG et al: Electrophysiologic effects of flecainide acetate and its major metabolites in the canine heart. Am J Cardiol 55: 807, 1985 28. Altessie M, Lammers WJEP, Bonke FI, Hollen J: Experimental evaluation of Moe's multiple wavelet hypothesis of atrial fibrillation, p. 265. In Zipes DP, Jalife J (eds): Cardiac electrophysiology and arrhythmias. Grune & Stratton, Orlando, 1985 29. Allessie MA, Bonke FIM, Schopman FJG: Circus movement in rabbit atrial muscle as a mechanism of
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tachycardia. Part III. The "leading circle" concept: a new model of circus movement in cardiac tissue without the involvement of an anatomic obstacle. Circ Res 41:9, 1977 Wang Z, Nattel S: Mechanism of flecainide's antiarrhythmic action in experimental atrial fibrillation. Circ Res 71:271, 1992 Sanna G, Arcidiacono R: Chemical ventricular defibrillation of the h u m a n heart with bretylium tosylate. Am J Cardiol 32:982, 1973 Wesley RC Jr, Farkhani F, Morgan D, Zimmerman D: Ibutilide: enhanced defibrillation via plateau sodium current activation. Am J Physiol 244:H1269, 1993 Nygards ME, Hylting J: Recognition of ventricular fibrillation utilizing the power spectrum of the ECG. Comput Cardiol 77:393, 1977 Herbschleb JN, Heethaar RM, Van der TweeI I e t ah Signal analysis of ventricular fibrillation. Comp Cardiol 79:49, 1979 Herbschleb JN, Heethaar RM, Van der Twee] I, Mei]ler FL: Frequency analysis of the ECG before and during ventricular fibrillation. Comput Cardiol 81:365, 1981
Modifications in t h e E v o l u t i o n of the D o m i n a n t F r e q u e n c y in Ventricular Fibrillation I n d u c e d by A m i o d a r o n e , D i l t i a z e m , and Flecainide An Experimental Study
F r a n c i s c o J. C h o r r o ,
M D , * J u a n J. S ~ n c h e z - M u f i o z ,
Juan
Sanchis, MD,* Juan
Juan
Guerrero,
Cortina, MD,* Manuel
PhD,$ Jos~ Espf, PhD,$ Juan and Vicente L6pez-Merino,
MD, t
B a t a l l e r , ]PhD,$
A. R u i p 6 r e z ,
MD,§
MD*
Abstract: In 22 anesthetized mongrel dogs, spectral methods were used to analyze the surface electrocardiogram (ECG) for the time course of the dominant frequency in ventricular fibrillation and its modifications under the influence of amiodarone, diltiazem, and flecainide. The ECG was recorded over 5 minutes after triggering ventricular fibrillation. Following A/D conversion and by applying the Fourier fast transform, the frequency spectrum of the signals was obtained. In group I (5 dogs), the ECGs were obtained without prior drug administration; group 2 (5 dogs) first received amiodarone, 5 mg/kg; group 3 (7 dogs) received diltiazem, 0.2 mg/kg; and group 4 (5 dogs) received flecainide, 2 mg/kg. All drugs were administered intravenously. An initial increase in the dominant frequency of ventricular fibrillation was found in the control group and also in the groups that received amiodarone, diltiazem, or flecainide. Diltiazem significantly increased the dominant frequency and diminished the arrhythmia-slowing process. Amiodarone and flecainide tended to diminish the dominant frequency. Key words: ventricular fibrillation, spectral analysis, Fourier analysis, amiodarone, diltiazem, flecainide.
Ventricular fibrillation prevents the heart f r o m contracting in an orderly a n d effective m a n n e r , thus causing loss of cardiac m e c h a n i c a l function. The t r e a t m e n t of a r r h y t h m i a , once triggered, is based on its i m m e d i a t e detection and interruption by m e a n s of electric shock (1,2). The possibility of restoring cardiac m e c h a n i c a l function depends largely on time elapsed since the start of a r r h y t h mia (3-8). The capacity to secure effective electri-
From the *Cardiology Service, Valencia University Clinical Hospital, Valencia, -[-Cardiology Service, Morales-Meseguer University Hospital, Murcia, $Departrnent of h~formation Science and Electronics, Faculty of Physics, Valencia University, Valencia, and ~Cardiology Service, Virgin de la Arrixaca University Hospital, Murcia, Spain.
Supported by a Fondo de Investigaci6n Sanitaria Grant (Exp. No. 92/0272). Reprint requests: EJ. Chorro-Gasc6, Servicio de Cardiologfa, Hospital Clfnico Universitario, Avenida Blasco Ibafiez 17, 46010Valencia, Spain.
319
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cal defibrillation has been correlated with, among other factors (3-14), the characteristics of the fibrillation pattern as defined by electrocardiographic (ECG) signal analysis in the time or frequency domain (5-8,15,16). Following in the path of experimental research aimed at characterizing the developmental patterns of ventricular fibrillation and its modification by different procedures (5-7,15-17), this study focuses on the spectral analysis of the modifications over the time course of the surface ECG during ventricular fibrillation under the influence of amiodarone, diltiazem, and fiecainide. These three drugs were chosen because of their different mechanisms of action and electrophysiologic and metabolic effects. Earlier studies (6,15,17) have described and contrasted the effects of several antiarrhythmic agents and calcium channel blockers; verapamil and nifedipine have been found to delay the arrhythmia-slowing process in the course of its spontaneous evolution. This study provides further information on calcium channel blockers by analyzing the effects of diltiazem and contrasting its actions with those of two Vaughan-Williams class IC and III antiarrhythmic drugs.
Materials and Methods Study Groups and Experiment Preparation Twenty-two mongrel dogs, weighing 8-19 kg, were divided into four groups as a function of the drug used: group 1 (n = 5), control dogs; group 2 (n = 5), amiodarone; group 3 (n = 7), diltiazem; and group 4 (n = 5), flecainide. Following anesthesia with sodium thiopental (30 mg/kg, with additional doses as required) administered through the right saphenous vein, the animals were subjected to endotracheal intubation and were ventilated with atmospheric air at intermittent positive pressure. The ventilatory parameters were monitored by arterial gasometry. A right femoral v en o to my was performed, and a 6F bipolar catheter electrode was advanced under fluoroscopic control to the apex of the right ventricular cavity in order to perform endocavitary electric pacing. The ECG signals were recorded by needle electrodes positioned on the limbs of the animal and connected to Hewlett Packard 8811A bioelectric amplifiers (Hewlett Packard, Palo Alto, CA). The recordings were made simultaneously with Siemens Mingograf 34 polygraph (Siemen-Elema, Solna, Sweden) and a magnetic tape recorder (Hewlett Packard 3960). In each experiment, fibrillation was
induced by electrical pacing through the catheter electrode in the right ventricle. To this effect, a Grass $88 stimulator (Grass Instrument, Quincy, MA) was used t o deliver trains of 2-second duration and consisting of 2-ms pulses at frequencies of 20-50 Hz and a voltage five times that of the diastolic threshold, until arrhythmia was triggered. In group 1, the recordings were made without prior drug administration; in group 2, arrhythmia was induced 15 minutes after administration of intravenous amiodarone, 5 mg/kg; in group 3, arrhythmia was produced 5 minutes after intravenous diltiazem, 0.2 mg/kg; and in group 4, arrhythmia was triggered i 0 minutes after intravenous flecainide, 2 mg/kg. The animals were not defibrillated after induction of the arrhythmia. The time elapsed between administration of the drug and the onset of arrhythmia was chosen as a measure of the time required to secure significant drug effects (18-20).
Data Recorded From the ECG signals recorded on magnetic tape, an A/D conversion was made of the ECG corresponding to leads I and aVF (sampling rate, 500 Hz). Recorded intervals of 8 seconds were selected to perform the power spectrum analysis of the signals obtained immediately after triggering ventricular fibrillation, after 15 and 30 seconds, and every 30 seconds thereafter until the 5-minute recording period was completed. The spectral analysis of each of the intervals (4,096 points) was carried out by fast Fourier transform following application of the Hanning window to the digitized data and suppression of the continuous component of the signal. A graphic and a numeric representation of the signal were produced, corresponding to each of the intervals selected, and the peak positions (ie, the dominant frequency [FrD] in each m om ent studied) were characterized (Fig. 1).
Statistical Analysis The m ean _+ SD of the FrD was obtained in each study group and for each of the intervals analyzed according to the time elapsed from the onset of ventricular fibrillation. The significance of the differences observed was established by analysis of variance. Multiple comparisons were made with the Student-Newman-Keuls test. As the groups did not contain equal n u m b e r of subjects, the harmonic m ean of the sample sizes of the groups was used. Statistical significance was considered at P < .05.
Dominant Frequency in Ventricular Fibrillation
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only one of the ECG leads (aVF). Table 1 shows the FrD values corresponding to each of the intervals analyzed, for each of the control group experiments, along with the means and standard deviations. An initial value of 8.37 + 1.22 Hz is observed (Fig. 2), followed by an initial rise to a m a x i m u m of 9.08 _+ 1.03 Hz after 30 seconds and then a progressive decrease. The m i n i m u m values were observed at the end of the recording period (3.50 _+ 2.22 Hz). The differences became statistically significant with respect to the initial value after 90 sec-
Group 1 (Control) Prior to data analysis in each group, we used a r a n d o m sample (n = 9) of the cases studied to compare the FrD values obtained for each time interval in leads I or aVE No significant differences were observed, w h i c h is in agreement with the results of other authors (6). Consequently, the results s h o w n correspond to the analyses made in
Table 1. Dominant Frequencies (Hz) of Ventricular Fibrillation Obtained Over 5 Minutes in the Control Group Ti me (seconds) Experiment No. Onset 1 2 3 4 5 Mean Mean % -+ SD P <
8.18 8.54 8.54 6.59 10.01 8.37 (100) 1.22 --
NS, n ot significant.
15
30
60
90
120
150
180
210
240
270
300
8.42 9.40 9.40 7.20 9.89 8.86 (106.2) 1.07 NS
8.42 9.40 8.68 8.18 I0.74 9.08 (109.2) 1.03 NS
7.08 8.30 7.93 7.81 9.89 8.20 (98.8) 1.04 NS
5.37 6.10 5.86 7.08 6.59 6.20 (75.8) 0.66 .01
6.35 4.52 5.49 5.49 7.32 5.83 (70.2) 1.05 .01
3.66 6.47 6.59 2.44 4.39 4.71 (55.7) 1.80 .01
3.30 5.86 5.13 3.78 7.69 5.15 (60.6) 1.75 .01
2.81 3.54 3.20 4.52 4.64 3.74 (45.7) 0.81 .001
3.30 5.49 4.03 6.10 7.08 5.20 (63.0) 1.53 .05
6.23. 4.39 3.66 3.30 3.42 4.20 (51.0) 1.21 .001
4.03 0.40 3.05 3.42 6.59 3.50 (41.5) 2.22 .01
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Journal of Electrocardiology Vol. 29 No. 4 October 1996
FrD (Hz) -I'- CONTROL
~- AMIODARONE
trol values and on considering the differences for each segment analyzed, the initial values were not significantly different. The FrD was significantly lower after 180 and 240 seconds (P < .05). The m a x i m u m average of the FrD variations expressed as percentages versus the initial value was 113.8 + 3.5% (30 seconds), with a m i n i m u m of 30.0 _+ 1 ! . 2 4 % (300 seconds).
Group 3 (Diltiazem) 0
30
60
90
120
150
180
210
240
270
300
Fig. 2. Graphic representation of the mean dominant frequencies (FrD) obtained in each study group in the course of arrhythmia.
onds (P < .01). On normalizing the FrD variations and expressing t h e m as percentages with respect to the initial value (initial FrD, 100), the m a x i m u m average was 109.2 _+ 9.0%, w h i c h corresponds to 30 seconds, while the m i n i m u m was 41.5 _+ 23.2%, obtained after 300 seconds (Table 1).
Group 2 (Amiodarone) Table 2 shows the FrD values of the experiments in group 2, w h e r e a m i o d a r o n e was given before inducing fibrillation. An initial value of 6.89 _+ 1.58 Hz was observed, followed, as in the control experiments, by an initial rise to a m a x i m u m of 7.84 + 1.84 Hz after 30 seconds and t h e n a progressive decrease to a m i n i m u m (1.96 .+ 0.50 Hz) after 300 seconds. Statistically significant differences with respect to the initial value were reached after i20 seconds (P < .05). In relation to the con-
Table 3 shows the FrD values of the experiments in group 3, w h e r e diltiazern was given before inducing ventricular fibrillation. The FrD rose from 9.87 + 1.28 Hz initially to a m a x i m u m of 10.57 _+ 2.33 Hz after 15 seconds. A progressive decrease followed, with m i n o r variations after 180 seconds, to a m i n i m u m after 300 seconds (6.12 _+ 1.85 Hz). Statistically significant differences with respect to the initial value were reached after 90 seconds (P < .01). In relation to the control values, the initial differences failed to reach statistical significance. The FrD was significantly higher at 120-300 seconds (P < .05). The m a x i m u m average of the FrD variations expressed as percentages versus the initial value was 106.1 _+ 13.9% (15 seconds), with a m i n i m u m of 63.5 _+ 22.5% (300 seconds).
Group 4 (Flecainide) Table 4 shows the FrD values of the experim e n t s in group 4, in w h i c h flecainide was a d m i n istered. A n initial value of 6.47 _+ 1.52 Hz was observed, followed, as with the o t h e r groups, by an initial rise to a m a x i m u m of 7.40 _+ 1.21 Hz after 30 seconds and t h e n a progressive decrease to a m i n i m u m after 300 seconds (2.07 _+ 1.30 Hz).
Table 2. Dominant Frequencies (Hz) of Ventricular Fibrillation Obtained Over 5 Minutes
in the Amiodarone Experiments Time (seconds) Experiment No. 1 2 3 4 5 Mean Mean % + SD P <
Onset 9.52 5.37 6.35 6.96 6.23 6.89 (100) 1.58 --
NS, n o t significant.
15 10.25 5.62 6.59 6.84 6.71 7.20 (104.4) 1.77 NS
30 10.99 6.23 7.45 7.57 6.96 7.84 (113.8) 1.84 NS
60 9.03 6.84 6.96 8.60 5.37 7.36 (108.3) 1.48 NS
90 8.91 5.37 6.35 7.57 3.30 6.30 (91.1) 2.14 NS
120 3.17 5.74 3.t7 5.86 2.32 4.05 (62.3) 1.63 .05
150 1.71 4.76 3.66 3.78 4.15 3.61 (57.0) 1.15 .01
180 0.98 2.56 3.66 3.05 2.08 2.47 (38.6) 1.02 .001
210 3.30 2.69 4.03 3.30 3.66 3.40 (50.9) 0.50 .01
240 1.71 2.69 3.05 1.95 3.91 2.66 (41.4) 0.88 .001
270 1.34 5.00 5.62 1.46 1.59 3.00 (48.4) 2.I2 .0I
300 1.83 2.20 1.40 1.71 2.69 1.96 (30.0) 0.50 .001
Dominant Frequency inVentricular Fibrillation
•
Chorro et al.
323
Table 3. Dominant Frequencies (Hz) of Ventricular Fibrillation Obtained Over 5 Minutes in the Diltiazem Experiments
Time (seconds) Experiment No. Onset 1 2 3 4 5 6 7 Mean Mean % _+ SD P <
10.62 9.03 10.01 7.32 10.62 10.62 10.86 9.87 (100) 1.28 --
15
30
60
90
120
150
180
210
240
270
300
9.64 9.89 10.99 6.10 12.33 12.94 12.08 10.57 (106.1) 2.33 NS
9.89 9.16 10.74 7.20 9.77 12.08 10.50 9.91 (100.4) 1.51 NS
11.23 9.28 7.93 7.20 8.30 10.74 8.06 8.96 (91.4) 1.52 NS
9.03 7.93 6.47 7.08 6.47 8.54 8.67 7.74 (79.3) 1.07 .01
9.89 6.71 5.37 7.20 6.47 10.01 8.91 7.89 (79.5) 1.96 .05
7.81 6.59 5.25 4.52 6.71 10.62 8.06 7.08 (71.1) 2.01 .01
9.40 8.06 5.25 5.13 5.37 10.50 8.30 6.92 (75.2) 1.88 .01
7.93 6.59 5.37 7.20 6.I0 9.16 8.18 7.22 (74.1) 1.31 .01
9.03 5.74 -7.20 5.86 9.03 8.18 7.51 (77.1) 1.49 .01
7.45 7.08 -7.69 5.13 8.54 7.08 7.18 (74.6) 1.26 .01
8.67 5.25 4.64 7.20 4.27 8.18 4.64 6.12 (63.5) 1.85 .001
NS, n ot significant.
Statistically significant differences with respect to the initial value w e r e r e a c h e d after 90 seconds (P < .05). In relation to the control values, the initial differences did n o t r e a c h statistical significance. The FrD was significantly l o w e r after 60, 180, a n d 240 seconds (P < .05). The m a x i m u m a v e r a g e of the FrD variations e x p r e s s e d as percentages versus the initial value was 117.2 _ 2 0 . 4 % (30 seconds), w i t h a m i n i m u m of 33.1 _+ 2 0 . 0 % (300 seconds). The FrD values in the diltiazem g r o u p w e r e significantly higher t h a n in the flecainide g r o u p for all the intervals a n a l y z e d in the course of the d e v e l o p m e n t of a r r h y t h m i a (P < .05). In turn, the diltiazem g r o u p exhibited significantly greater FrD values t h a n the a m i o d a r o n e g r o u p initially, as well as after 15 seconds, 120 seconds, a n d the following intervals up to 300 seconds (P < .05). In c o m p a r i s o n , the FrD averages in groups 2 a n d 4 o n l y s h o w e d significant differences after 60 seconds (P < .05).
Discussion Ventricular fibrillation is a complex arrhythmia, the analysis of which has received different methodologic approaches. Some of the earliest studies w e r e based on the analysis of the surface ECG (21-23). The subsequent introduction of spectral techniques has yielded c o m p l e m e n t a r y inform a t i o n in the frequency domain, with an i m p r o v e d characterization of the d e v e l o p m e n t a l stages of arrhythmia, pharmacologic modifications of the frequency domain, and its relation to the efficacy of electrical defibrillation (4--8,15-17,24,25). The initial grouping of the m a i n signal c o m p o n e n t s in the frequency d o m a i n a r o u n d defined values has b e e n described; these values are in the 8 - 1 2 - H z range in dogs (4-6,15,17) and s o m e w h a t lower in h u m a n s (16,24). The changes in the f r e q u e n c y d o m a i n as the p o w e r s p e c t r u m evolves h a v e b e e n characterized, initial i n c r e m e n t s being observed in the first seconds of the a r r h y t h m i a , followed by progressive
Table 4. Dominant Frequencies (Hz) of Ventricular Fibrillation Obtained Over 5 Minutes
in the Flecainide Experiments Ti me (seconds) Experiment No.
Onset
15
30
1 2 3 4 5 Mean Mean % -+ SD
6.96 6.84 8.54 4.64 5.37 6.47 (100) 1.52
8.18 6.96 8.30 5.62 6.47 7.11 (111.6) 1.14
8.30 6.23 8.79 6.10 7.57 7.40 (117.2) 1.21
--
NS
P<
NS, not significant.
NS
60 6.71 5.13 5.13 5.86 4.88 5.54 (89.7) 0.75
NS
90 5.86 4.27 3.30 4.39 4.69 4.50 (73.4) 0.92
.05
120 5.00 3.30 3.42 3.17 3.54 3.69 (58.8) 0.79
.01
I50 4.64 3.05 2.56 2.56 1.22 2.81 (43.8) 1.23
.01
I80
210
240
270
300
4.27 1.22 3.05 2.56 1.58 2.54 (39.9) 1.22
3.91 1.95 2.08 1.71 3.17 2.56 (41.0) 0.94
3.66 1.83 2.44 2.08 3.30 2.66 (42.9) 0.79
3.54 1.95 2.20 1.83 3.30 2.56 (41.2) 0.80
3.78 0.24 2.20 1.59 2.56 2.07 (33.1) 1.30
.01
.001
.001
.001
001
324
Journal of Electrocardiology Vol. 29 No. 4 October 1996
decreases that coincide with the disorganization of the spectrum (5,6,15,17). Analyses have also been made of the effects of different drugs on the pattern of evolution of ventricular fibrillation; the results suggest possible positive effects on the course of the arrhythmia, associated with greater success of electrical defibrillation (6,15,I7). The information provided by the spectral analysis of the ECG signal during ventricular fibrillation could yield a n u mb er of indicators for estimating defibrillation success or evaluating the effects of drugs and of maneuvers used during the intervention in order to achieve an effective cardiac rhythm. In this study, we observed a time course pattern analogous to that reported elsewhere (4--6,15,I7), with initial frequencies in the control group of 8.37 _+ 1.22 Hz, early increases in the first 15-30 seconds, and a final progressive decrease in the frequency domain over time. Statistically significant changes appeared after 90 seconds. The initial rise of the FrD has been attributed to both intrinsic and extrinsic factors. One possible explanation may be found in the action of the sympathetic system, which becomes activated in the early moments of arrhythmia in response to the sudden decrease in cardiac output. Carlisle et al. (17) observed no such increase in animals previously treated with propranolol. In contrast, Martin et al. (6) recorded an increase following pharmacologic block of the autonomous nervous system. It is thus likely that factors related to the organization of the arrhythmia in its initial period may also influence the changes recorded immediately after the triggering of arrhythmia, as suggested by Clayton et al. (24). The progressive slowing, expressed by the displacement of the dominant components of the frequency spec'trum (and particularly apparent after 90 seconds), is associated with a progressive loss of the capacity to achieve effective defibrillation (3-6,15,17). This decrease in the FrD is related to the metabolic deterioration of the myocardium, for if coronary perfusion is maintained, both the peak frequency of the spectrum and the ability to achieve defibrillation are preserved, without electromechanical dissociation (6,16). This observation has led a num be r of authors to postulate that maintenance of the peak frequencies in the spectrum by administering different drugs may help to secure effective defibrillation (5,6,17). In this connection, it has been demonstrated that the calcium antagonists nifedipine and verapamil retard the slowing process (6,15,17), with effective defibrillation in the case of nifedipine (6). In our study, diltiazem, like nifedipine and verapamil, produced an increase in the FrD of the spectrum, followed by a slower reduction over the
time course of the arrhythmia. The mechanisms responsible for these changes are not clear. The maintenance of the FrD could imply both the persistence of the rapid and relatively well organized activity in the ventricular myocardium considered globally and the abolition of the slow and more disorganized activity in zones more affected by the metabolic and electrolytic changes; activity would persist in the endocardial zones, where it has been shown (I7) that the fast components of the spectrum are maintained for prolonged periods over the time course of the arrhythmia. Nevertheless, the calcium channel blockers have been postulated (6,I7) to counter the calcium overload and potassium accumulation favored by the ischemia, as both elements are present in the evolution of the arrhythmia (26). In this study, although we do not know w het her the diltiazem-induced changes in the time course of fibrillation are associated with an effective defibrillation-favoring effect after prolonged periods, the above results suggest that the pattern of evolution of the arrhythmia is favored. Both amiodarone and flecainide were found to exert an arrhythmia-slowing effect. These results appear to be more directly linked to the electrophysiologic actions of the drugs (12,18,20,27). The correlation of the changes in the FrD of the spectrum with the changes in electrophysiologic parameters induced by the drugs is complex. Carlisle et al. found that lidocaine reduces the FrD of ventricular fibrillation in the initial moments of arrhythmia (17). They suggested that the prolonged refractoriness and retarded conduction produced by the drug are responsible for this phenomenon, although they failed to observe such marked effects when using bretylium, despite the effects of the latter on the duration of the action potentials and effective refractory periods. Among the factors that may be implicated in the decrease in the FrD of the spectrum are the degree of organization of ventricular activity during fibrillation and the greater or lesser activation frequency of the myocardial cells during arrhythmia. The wavelength of the changing circuits inherent to fibrillation (28,29) and its inverse (frequency) are dependent on the duration of the refractory periods and on conduction velocity. In this sense, a decrease in conduction velocity as a result of flecainide action would imply a decreased wavelength, which appears to contradict the observed facts; a concomitant effect involving a prolongation of refractoriness would therefore have to be considered. This effect has been demonstrated at rapid activation frequencies in atrial myocardium (30), and it may possibly also be found at the ventricular level.
Dominant Frequency in Ventricular Fibrillation A n o t h e r f a c t o r to b e t a k e n i n t o a c c o u n t is r e d u c t i o n of t h e s t i m u l a t i n g efficacy b y t h e drug, w h i c h l o w e r s t h e s a f e t y f a c t o r for c o n d u c t i o n across t h e m y o c a r d i u m a n d c o n s e q u e n t l y c o n t r i b u t e s to a d e c r e a s e in t h e m y o c a r d i a l cell a c t i v a t i o n freq u e n c y . I n t h e case of a m i o d a r o n e , t h e effects of t h e d r u g i n v o l v e s e v e r a l m e c h a n i s m s , w h i c h differ in p a r t d e p e n d i n g o n w h e t h e r it is g i v e n a c u t e l y or c h r o n i c a l l y (18). A m i o d a r o n e e x e r t s a n o n c o m p e t itive a n t a g o n i s t i c a c t i o n o n a l p h a - a n d b e t a a d r e n o r e c e p t o r s a n d also a c a l c i u m a n t a g o n i s t i c effect; w h e n g i v e n acutely, it also gives rise to a u s e - d e p e n d e n t l e n g t h e n i n g of a c t i o n p o t e n t i a l d u r a t i o n a n d r e f r a c t o r i n e s s , a l t h o u g h to a lesser d e g r e e t h a n w h e n a d m i n i s t e r e d c h r o n i c a l l y . T h e s e effects c o u l d b e i m p l i c a t e d in a n i n c r e a s e in w a v e l e n g t h (or d e c r e a s e in f r e q u e n c y of t h e w a v e l e t s ) , w h i c h w o u l d i n d u c e s i g n i f i c a n t c h a n g e s in t h e FrD b y a d d i n g to t h e effects of h y p o x i a a n d t h e m e t a b o l i c and electrolytic alterations, which gradually accum u l a t e o v e r t i m e in t h e c o u r s e of t h e a r r h y t h m i a .
Conclusion O u r r e s u l t s m a y b e s u m m a r i z e d as follows: 1. T h e initial i n c r e a s e in t h e FrD of v e n t r i c u l a r fibr i l l a t i o n w a s also o b s e r v e d u n d e r t h e i n f l u e n c e of a m i o d a r o n e , d i l t i a z e m , or f l e c a i n i d e . 2. D i l t i a z e m i n c r e a s e d t h e FrD of v e n t r i c u l a r fibrillation and diminished the arrhythmia-slowing process. 3. A m i o d a r o n e a n d f l e c a i n i d e t e n d e d to r e d u c e t h e FrD of v e n t r i c u l a r fibrillation.
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