Vol. 274, Issue 4, H1113-H1120, April 1998
High-dose lidocaine does not affect defibrillation efficacy:
implications for defibrillation mechanisms
Michael R.
Ujhelyi,
J. Jason
Sims, and
Allison Winecoff
Miller
University of Georgia College of Pharmacy, Augusta Veterans Affairs
Medical Center, and Medical College of Georgia School of Medicine,
Augusta, Georgia 30912
 |
ABSTRACT |
This study assessed the effect of low (10 mg · kg
1 · h1)
and very high (18 mg · kg1 · h1)
doses of lidocaine on defibrillation energy requirements (DER) to
relate changes in indexes of sodium-channel blockade with changes in
DER values using a dose-response study design. In
group 1 (control; n = 6 pigs), DER values were
determined at baseline and during treatment with 5% dextrose in water
(D5W) and with
D5W added to D5W. In group
2 (n = 7), DER values
were determined at baseline and during treatment with low-dose
lidocaine followed by high-dose lidocaine. In group
3 (n = 3), DER values
were determined at baseline and high-dose lidocaine.
Group 3 controlled for the order of
lidocaine treatment with the addition of high-dose lidocaine after
baseline. DER values in group 1 did
not change during D5W. In
group 2, low-dose lidocaine increased
DER values by 51% (P = 0.01), whereas
high-dose lidocaine added to low-dose lidocaine reduced DER values back to within 6% of baseline values (P = 0.02, low dose vs. high dose). DER values during high-dose lidocaine in
group 3 also remained near baseline
values (16.2 ± 2.7 to 12.9 ± 2.7 J), demonstrating that treatment order had no impact on group
2. Progressive sodium-channel blockade was evident as
incremental reduction in ventricular conduction velocity as the
lidocaine dose increased. Lidocaine also significantly increased
ventricular fibrillation cycle length as the lidocaine dose increased.
However, the greatest increase in DER occurred when ventricular
fibrillation cycle length was minimally affected, demonstrating a
negative correlation (P = 0.04). In summary, lidocaine has an inverted U-shaped DER dose-response
curve. At very high lidocaine doses, DER values are similar to baseline
and tend to decrease rather than increase. Increased refractoriness
during ventricular fibrillation may be the electrophysiological
mechanism by which high-dose lidocaine limits the adverse effects that
low-dose lidocaine has on DER values. However, there is a possibility
that an unidentified action of lidocaine is responsible for these
effects.
ventricular fibrillation; ventricular defibrillation; electrical stimulation; electrophysiology; ion conductance; electropharmacology
| |
INTRODUCTION |
PATIENTS WITH IMPLANTABLE cardiac defibrillators
commonly require antiarrhythmic drugs to reduce the number of shocks
they receive (15). These agents, however, can modify
cardiac electrophysiology such that energy requirements necessary to
evoke successful defibrillation are altered (9-14, 22-26).
Regrettably, the electrophysiological mechanisms by which
antiarrhythmic drugs alter defibrillation energy requirements (DER)
remain unknown. Knowledge of how antiarrhythmic drugs affect
defibrillation efficacy could provide further insight into the
electrophysiological mechanisms that regulate successful defibrillation. Nevertheless, evidence to date suggests that specific changes in sodium or potassium conductance alter the
electrophysiological state, thereby changing defibrillation efficacy
(10, 11, 24, 26). Because it is difficult, if not
impossible, to quantitate drug-induced changes in myocardial
electrophysiology (ventricular conduction velocity and refractoriness)
during fibrillation, there are no studies indicating that changes in
these electrophysiological parameters are responsible for changing
defibrillation outcomes. Moreover, paced rhythm is a poor surrogate of
fibrillation, and thus electrophysiological changes measured during
paced rhythm often do not predict changes in DER values (11, 24, 29).
Lidocaine is a relatively pure sodium-channel blocker that raises DER
values (9). The mechanism by which lidocaine raises DER values is
unknown but likely relates to its effects on conduction velocity.
However, Ujhelyi et al. (24) have shown that the potassium-channel blocker cesium chloride, added to lidocaine, augmented the effect of
lidocaine on slowing conduction velocity but completely reversed the
negative effects that lidocaine had on defibrillation efficacy. Increases in tissue refractoriness may explain how cesium reversed the
negative effects of lidocaine. Lidocaine is also known to slow
ventricular fibrillation and thus prolong refractoriness (13). However,
it may be that the effect of lidocaine on ventricular refractoriness
during fibrillation is not sufficient to overcome the unknown mechanism
by which it raises DER values. We postulate that increasing doses of
lidocaine will eventually prolong refractoriness during ventricular
fibrillation to a point that will override its negative actions. The
result will be that high doses of lidocaine will not elevate DER
values, similar to the observed effects of cesium added to
lidocaine. Thus the purpose of this study was to investigate the effect
of low and high doses of lidocaine on DER to relate changes in
ventricular conduction velocity and fibrillation cycle length to
changes in DER values.
| |
METHODS |
Animal preparation and surgical instrumentation.
Domestic farm swine weighing between 25 and 30 kg were used in this
investigation. All procedures were approved by the Medical College of
Georgia and the Augusta Veterans Affairs Medical Center Animal Care and
Use Committees before this investigation was conducted. After an
overnight fast, the animals were premedicated with ketamine (15 mg/kg)
administered intramuscularly. Subsequently, pentobarbital sodium (25 mg/kg) was administered intravenously for initial anesthesia induction.
After the animals were intubated with a cuffed endotracheal tube, they
were mechanically ventilated with the use of a large animal Harvard
pump ventilator. A level plane of anesthesia was subsequently
maintained throughout the study period using pentobarbital sodium
(demonstrated not to affect DER) as a continuous infusion of
150-300 mg/h (3). The external jugular vein, internal
carotid artery, and femoral artery were cannulated for catheterization, drug infusion, and blood collection. With the guidance of fluoroscopy, a combination pacing and contact monophasic action potential catheter (EP Technologies, Mountain View, CA) was placed into the right ventricular apex via the external jugular vein and a second catheter was placed into the left ventricle against the left lateral wall via
the internal carotid artery. These catheters recorded local monophasic
action potential duration from the right and left ventricular endocardium and paced the ventricles. A pigtail 5-F Millar
pressure-sensing catheter was placed via the femoral artery for blood
pressure monitoring. Surface electrocardiographic leads were placed on the four limbs for monitoring of leads II and aVF. The
chest was opened by median sternotomy. A third action potential probe
(Franz Spring Cantilever Epicardial Probe, EP Technologies) was placed on the epicardium at the left ventricular apex in conjunction with a
bipolar platinum pacing wire. One
14-cm2 and one
28-cm2 titanium mesh patch
electrodes (models A and L 67, respectively; Cardiac Pacemakers, St.
Paul, MN) were sutured onto the surface of the pericardium. The large
electrode, which was placed over the anterior and lateral wall of the
right ventricle, was perpendicular to the small electrode placed over
the lateral, posterior, and apical wall of the left ventricle. The
electrodes were interfaced with an external defibrillator (Ventak ECD,
CPI Guidant, St. Paul, MN) for which the right ventricular patch served
as the anode. The defibrillator was capable of delivering a monophasic
truncated waveform at a 65% fixed tilt with a pulse duration between 5 and 8 ms. The output of this device was determined by preset voltage adjustments (1-V increments). The chest was closed, and chest tubes
were placed into the pleural space for drainage via suction. Arterial
blood gases were measured every 20-30 min (Corning 170, Ciba
Corning) and arterial pH, arterial
PO2, and arterial PCO2 were maintained between 7.37 and
7.45, 80 and 120 mmHg, and 35 and 45 mmHg, respectively.
Sodium and potassium concentrations were measured every 30 min (Nova 1, Baxter, Miami, FL), and serum sodium and potassium concentrations were
maintained between 135 and 144 meq/l and 3.4 and 4.4 meq/l,
respectively. Body temperature was monitored via a rectal probe and
maintained at 37-38°C using a surgical thermal blanket.
Adequate hydration was maintained using lactated Ringer solution at
2-5
ml · kg1 · h1.
Study design.
A total of 19 animals were studied, but data presented are for 16 animals because 3 animals died secondary to drug toxicity at the high
lidocaine dose (asystole with electrical pacing-mechanical disassociation). Each pig was randomly assigned a priori to a group
(Fig. 1). Group
1 served as a control in which DER values were
determined at baseline and during application of 5% dextrose in water
(D5W) in
treatment phase I and
D5W added to
D5W in treatment phase II (n = 6).
Lidocaine dose-response curves were evaluated in group
2, in which DER values were determined at baseline and application of low-dose lidocaine in treatment phase
I, followed by high-dose lidocaine in
treatment phase II
(n = 7). Group
3 served to control for treatment order by assessing
whether prior exposure to low-dose lidocaine affected the results of
high-dose lidocaine. In this group, DER values were determined at
baseline followed by high-dose lidocaine in treatment
phase I (n = 3). In
each study phase, DER values and electrophysiological parameters were
measured. The baseline phase was started 30 min after completion of
instrumentation. In treatment phase I,
which began immediately after completion of the baseline phase, the
treatment (D5W or lidocaine) was
administered as a 10-min loading dose (10 mg/kg lidocaine for low dose
or 18 mg/kg lidocaine for high dose) followed by a continuous infusion
(10 mg · kg1 · h1
lidocaine for low dose or 18 mg · kg1 · h1
lidocaine for high dose). Treatment phase
II began after the completion of
treatment phase I. In
group 2, high-dose lidocaine was added
as an 8-mg/kg bolus over 10 min, followed by a continuous infusion of
18 mg · kg1 · h1.
D5W served as the control and was
given in equal volume with the lidocaine bolus and infusion. DER and
other measurements were initiated 10 min after the end of the loading
dose (20 min after initiation of loading dose) for both treatment
phases so that testing began after adequate drug distribution.
DER.
Ventricular fibrillation was induced by delivering a stimulus drive
train with a 100-ms cycle length for 2 s at a stimulus strength of 10 V
(Grass S8800 stimulator, Quincy, MA). Defibrillation shocks were
applied using preset energy levels ~8 s after documentation of
sustained ventricular fibrillation. Energy, impedance, pulse width, and
peak current delivered to the myocardium were measured by the
defibrillator and subsequently printed. These values are accurate to
within 10% of oscilloscopic measurements made in our laboratory. The
time period between defibrillation trials was at least 4 min and was
not ended until arterial blood pressure returned to within 10% of the
preshock value. To quantitate defibrillation energy requirements, a
step-down, step-up method was used as previously described (25). This
method incorporates 12 fibrillation/defibrillation trials per study
phase, which iterates around the linear portion of the sigmoid
energy-response curve (20-80% successful response). The
defibrillation response for each energy tested was modeled to achieve
an energy-response curve. The DER values are presented as the energy
level that achieved 20 (ED20),
50 (ED50), and 80% (ED80) successful responses for
a treatment phase. This was performed using an iterative computer
program (MERFFIT, CPI Guidant) (34).
Electrophysiological parameters.
The electrophysiological variables (paced QRS duration, ventricular
conduction time, and action potential duration) were measured during
right ventricular pacing at a 300-ms cycle length and were averaged
from five consecutive beats. A fast pacing rate was chosen to simulate
ventricular tachycardia and fibrillation. This will increase the
rate-dependent sodium-channel block induced by lidocaine. Ventricular
pacing was continued for 15-20 s before measuring these parameters
to assure a near steady-state level of ion-channel conductance and
ion-channel block. Sodium-channel blockade was measured by QRS duration
(a global measure of ventricular conduction velocity) and by
interventricular conduction time. Interventricular conduction time was
the time period from the beginning of the right ventricular action
potential upstroke to the beginning of the left ventricular action
potential upstroke. Action potential upstroke was recognized as a fast
upward activation that was continuous without pauses or spikes until it
reached a plateau. Myocardial repolarization was assessed for right and
left ventricular endocardium and left ventricular epicardium by
simultaneous measurements of the monophasic action potential duration
at 90% of complete repolarization. The effective refractory period was
determined by pacing one of the three ventricular sites for eight
beats, using a stimulus intensity twice the diastolic energy
requirements at a cycle length of 300 ms, followed by one premature
stimulus. The drive train was repeated after a 3-s pause, and the
premature stimulus coupling interval was discriminated by 2 ms until
ventricular capture failed on two consecutive attempts. Ventricular
fibrillation cycle length was measured just before the defibrillation
shock (~7 s of fibrillation), at which time it has been shown that
fibrillation cycle length becomes stable (32). Fibrillation cycle
length, recorded by monophasic action potentials at the 3 ventricular
recording sites, was calculated as the average duration of 10 consecutive action potential upstrokes. Action potentials with double
potentials or those that were fractionated were counted as a single
activation (28). Spatial heterogeneity (dispersion) between recording
sites was evaluated for the electrophysiological parameters: action potential duration, ventricular refractoriness, and ventricular fibrillation cycle length. Dispersion was calculated as the difference between the maximum and minimum values of the three distant recording sites (29). All electrophysiological measurements were obtained at the
start of the DER protocol and at the end of this protocol for both
baseline and drug treatment phases. These values were then averaged for
each study phase. Electrophysiological and hemodynamic signals were
processed with Gould Universal amplifiers (Gould Instruments, Valley
View, OH) and then digitally converted and stored to disk for off-line
analysis (Datawave, Boulder, CO). Monophasic action potentials were
direct current coupled with a high-cutoff filter of 300 Hz, amplified
and stored to disk.
Data analysis.
A two-way analysis of variance (ANOVA) was used to test differences
between parameters determined at baseline and during
treatment phases I and
II within a group (measurements using
the animal as its own control). Post hoc analysis for significant
differences was determined using Tukey's test for ANOVA. Because
group 3 only consisted of three
animals, these data were not tested statistically. In
group 2, the percentage change in
ED80 DER (level with the greatest
absolute change) from baseline to treatment phase
I and from baseline to treatment phase
II were correlated with changes in measures of
myocardial electrophysiology including paced QRS, right ventricular
action potential duration, ventricular conduction time, right
ventricular effective refractory period, and right ventricular
fibrillation cycle length. Correlation analysis was performed
with linear models of best fit using the iterative computer program
Table Curve (Jandel Scientific, San Rafael, CA). All data and
statistical analyses were performed with a personal computer using
Sigma Stat 2.0 (Jandel Scientific) and Microsoft Excel 7.0 (Microsoft,
Redmond, WA). Statistical significance was set at a
P value < 0.05 using a two-tailed
test. Data are presented as means ± SE.
| |
RESULTS |
DER.
Baseline mean DER values among the three groups were not significantly
different (Fig. 2). DER values for
group 1 during
treatment phase I
(D5W) and
treatment phase II
(D5W) did not differ from those at
baseline [Fig. 2, P = not
significant (NS)], showing the consistency of our data over time.
In group 2, low-dose lidocaine increased ED20,
ED50, and
ED80 DER values from baseline in
all seven animals by an average of 43 (P = 0.16), 44 (P = 0.03), and 51%
(P = 0.01), respectively (Fig. 2). The
addition of high-dose lidocaine, however, reduced
ED20,
ED50 and
ED80 DER values to within 4, 6, and 7% of baseline values, respectively (Fig. 2, P = NS). Moreover,
ED20
(P = 0.22),
ED50
(P = 0.07), and
ED80 (P = 0.03) DER values were lower at
high-dose lidocaine than at low-dose lidocaine (Fig. 2). Data from
group 3 showed that treatment order
did not alter the actions of lidocaine, because DER values during
high-dose lidocaine in treatment phase
I decreased in a manner similar to that seen in
group 2 in treatment
phase II. During high-dose lidocaine in
groups 2 and
3, the
ED80 DER values were less than
baseline values in 57 (4/7) and 100% (3/3) of animals, respectively.
This suggests that in some animals high-dose lidocaine has the ability
to lower DER values. It is clear from these data that the response for
lidocaine dose versus DER is an inverted U shape in which DER values
increase significantly above baseline values at low lidocaine doses and
then revert to baseline values at high lidocaine doses. In all cases,
defibrillation lead impedance did not change regardless of treatment or
treatment order.
View larger version (30K):
[in this window]
[in a new window]
|
Fig. 2.
Defibrillation energy requirement (DER) values are presented as energy
levels achieving 20 (ED20), 50 (ED50), and 80%
(ED80) success in
group 1 (A), group
2 (B), and
group 3 (C) for each study phase. All data
are means ± SE. * P < 0.05, baseline compared with low-dose lidocaine;
¶ P = 0.07, low-dose
lidocaine compared with high-dose lidocaine; and
§ P = 0.03, low-dose
lidocaine compared with high-dose lidocaine.
|
|
Electrophysiological parameters.
The electrophysiological values (means ± SE) for all groups are
reported in Fig. 3 and Table
1. In group
1, no changes were observed in any of the
electrophysiological parameters measured during each study phase.
Administration of low-dose lidocaine in group
2 resulted in a 36, 75, and 36% increase in paced QRS duration, ventricular conduction time, and ventricular fibrillation cycle length at each site, respectively
(P < 0.01). Low-dose lidocaine did
not significantly affect action potential duration, but it did increase
ventricular effective refractory periods. This indicates that
sodium-channel block caused postrepolarization refractoriness. High-dose lidocaine in group 2 resulted in a progressive increase in paced QRS duration, ventricular
conduction time (Fig. 3), and ventricular fibrillation cycle length.
Figures 4 and 5
show these profound effects in a representative animal. The paced
electrocardiogram shows that high-dose lidocaine grossly widened the
QRS complex, whereas the monophasic action potential recording shows
dramatic conduction delay between the right and left ventricular
recording sites (Fig. 4). Figure 5 shows that action potentials during
fibrillation were clearly fractionated in the baseline and low-dose
recordings that were characterized as abortive, disordered upstrokes
with interrupted plateau or repolarization zones of the action
potential. However, at high-dose lidocaine, action potentials at each
recording site appeared more organized. The organized action potentials were wide and had consistent diastolic potentials with few double potentials and fractionation. Ventricular effective refractory period
at the high-lidocaine dose was also significantly prolonged at all
three ventricular sites. Similar findings occurred in
group 3 when high-dose lidocaine was
added after baseline study, again demonstrating that an equal level of
sodium-channel blockade occurred regardless of treatment order. Spatial
dispersion in action potential duration, effective refractory period,
and ventricular fibrillation cycle length was not changed by low- or
high-dose lidocaine (Table 2).
View larger version (17K):
[in this window]
[in a new window]
|
Fig. 3.
Line graph of ventricular [right ventricle (RV) to left ventricle
(LV) endocardium] conduction time
(A) and paced QRS values (B) at
baseline, low-dose (10 mg/kg) lidocaine, and high-dose (18 mg/kg)
lidocaine.  , Group 1;  ,
group 2;  , group
3. * P < 0.05 vs. baseline; ** P < 0.05 vs.
baseline and low-dose lidocaine (10 mg/kg).
|
|
View larger version (13K):
[in this window]
[in a new window]
|
Fig. 4.
Electrocardiographic tracings (ECG) of surface lead II
(left) and monophasic action
potentials (MAP; right) from RV and
LV endocardium during baseline (A),
low-dose lidocaine (phase I;
B), and high-dose lidocaine
(phase II;
C) in a representative animal. Thick
vertical lines in MAP tracings represent beginning of MAP upstroke from
RV to onset of LV MAP upstroke.
|
|
View larger version (19K):
[in this window]
[in a new window]
|
Fig. 5.
Tracings of ventricular fibrillation recorded from MAP at LV epicardium
(EPI) and RV and LV endocardium during baseline
(A), low-dose lidocaine
(B), and high-dose lidocaine
(C) study phases in a representative
animal.
|
|
View this table:
[in this window]
[in a new window]
|
Table 2.
Spatial dispersion in electrophysiological parameters during RV pacing
and 8 s of ventricular fibrillation
|
|
The change in DER from baseline to low- and high-dose lidocaine
in group 2 was inversely correlated
with the change in ventricular fibrillation cycle length
(r = 0.55, P = 0.04) (Fig.
6). Thus lidocaine had the greatest effect
on DER values when ventricular fibrillation cycle length was minimally
affected. It can be seen from Fig. 6 that there was a good correlation
between changes in DER values with ventricular fibrillation cycle
length at low-dose lidocaine, whereas there are two outlying points at
high-dose lidocaine. No other electrophysiological values (QRS, action
potential duration, or effective refractory period) were correlated
with changes in DER values (P > 0.30).
View larger version (16K):
[in this window]
[in a new window]
|
Fig. 6.
Correlation between %change in
ED80 DER values and %change in
ventricular fibrillation cycle length (VFCL) in group
2.  , %change from baseline to low-dose lidocaine;
, %change from baseline to high-dose lidocaine. Regression
statistics combine observations from both lidocaine doses
(n = 14).
|
|
Lidocaine concentrations.
The low dose of lidocaine produced stable plasma concentrations over
the treatment phase that averaged between 6 and 7 µg/ml. The high
dose of lidocaine produced steady lidocaine concentrations between 13 and 14 µg/ml.
| |
DISCUSSION |
The findings of this study show that a low-lidocaine dose
elevated DER values by 50%, whereas high-dose lidocaine did not affect
DER values. Thus the response curve for lidocaine dose versus DER was
described as an inverted U shape. However, low- and high-dose lidocaine
increased ventricular conduction time, refractoriness, and ventricular
fibrillation cycle length in a positive and linear
fashion. The increase in conduction time and ventricular
refractoriness did not relate to changes in DER values during low- or
high-dose lidocaine. However, an increase in ventricular fibrillation
cycle length weakly correlated with less increase in DER values
(P = 0.04). These data demonstrate
that lidocaine has multiple effects on defibrillation efficacy that are
dose related.
Lidocaine is a relatively pure sodium-channel blocker that does not
affect voltage-dependent potassium currents (6, 24). This singular
ion-channel effect causes a reduction in ventricular conduction
velocity and prolongs refractoriness. In the current study, lidocaine
dramatically slowed ventricular conduction velocity, evident as a 50%
increase in paced QRS duration and conduction time at the high
lidocaine dose. Lidocaine also prolonged ventricular refractoriness,
evident as a 10% increase in effective refractory period. The result
of slowing conduction and prolonging refractoriness was a 50% increase
in ventricular fibrillation cycle length at the high lidocaine dose.
These indexes of sodium-channel block increased monotonically as the
lidocaine dose increased. However, the biphasic DER dose response
indicates a disparity between the DER and sodium-channel dose-response
curves. An explanation for this finding is that one
electrophysiological response elicited by lidocaine (perhaps conduction
velocity slowing) raises DER values, while another (perhaps increased
refractoriness) lowers DER values. For this to occur, the response that
causes DER values to increase must predominate at the lower lidocaine
dose. It is also possible that a single electrophysiological effect
(conduction velocity or refractoriness) is responsible for the biphasic
DER response, and the magnitude by which this effect is altered
dictates the direction of change in DER values. If this was the case,
then the change in DER should have been, but was not, correlated with either conduction time, refractoriness, or ventricular fibrillation cycle length in an inverted U-shaped fashion. Regardless of the responsible electrophysiological mechanism, these data support the fact
that a drug can affect defibrillation in a biphasic manner via a single
ion-channel effect.
Lidocaine and increased DER.
There are two theories of failed defibrillation that may explain how
lidocaine increases DER: 1) the
shock stimulus was not strong enough to depolarize >90% of
fibrillating myocardium and halt propagation (critical mass theory), or
2) the shock stimulus depolarizes a
critical mass of myocardium and disrupts/halts the initial fibrillation
wave fronts but induces an electrophysiological-state postshock that
allows propagation of early postshock activation fronts (4, 8, 15, 18,
30, 31). Lidocaine is likely to act through one of these mechanism by
directly altering ventricular conduction or refractoriness. The
preponderance of data indicates that sodium-channel blockade does not
affect shock-induced membrane depolarization or hyperpolarization
(critical mass), thereby ruling out the first mechanism (5, 17, 33).
Thus it is more likely that lidocaine raises DER values by increasing
the propensity that postshock activations will propagate, thereby
reinitiating fibrillation or allowing it to continue (18, 31).
Lidocaine has been shown (2) to decrease conduction velocity and
enhance anisotropic conduction. If this occurs immediately postshock, then lidocaine could increase the potential for conduction block and
nonuniform propagation of postshock activations. Computational studies
(1), in which slow conduction was shown to initiate and sustain
fibrillation, support this possibility. Moreover, this may occur
regardless of the fact that lidocaine does not appear to affect
dispersion in refractoriness (Table 2) (16, 21, 22).
Lidocaine and decreased DER.
The electrophysiological mechanism by which sodium-channel blockade can
facilitate defibrillation may relate to an increase in ventricular
refractoriness and/or a reduction in the number of fibrillating
circuits. Lidocaine can slow ventricular conduction and increase
ventricular refractoriness at pacing rates similar to those during
fibrillation (20). The net effect is a dramatic increase in ventricular
fibrillation cycle length (7), as seen in the current study. At very
high heart rates (>200 beats/min) the increase in refractoriness
predominates, thereby increasing the wavelength of the impulse (20).
Increasing wavelength via sodium-channel blockade produces fewer
fibrillation circuits (19, 27), whereas increasing refractoriness
causes the myocardium to be less vulnerable to colliding wave fronts. A
reduction in the number of fibrillation circuits in the setting of
increased refractoriness will decrease the number of fractionated or
double potentials, making the action potentials appear more organized (7, 12). Hence, it is not surprising that high-dose lidocaine in the
current study qualitatively reduced the number of double and
fractionated potentials (Fig. 5). Moreover, high-dose lidocaine altered
action potential morphology such that diastolic intervals were
consistently observed. These findings, depicted at the bottom of Fig.
5, and the dramatic slowing of ventricular fibrillation indicate that
the tissue is more refractory and that the number of fibrillation
circuits is likely reduced (7).
The profound changes that high-dose lidocaine had on action potential
morphology were similar to those observed with agents known to reduce
DER values (blockers of the outward potassium channel, or ibutilide)
(9-12, 24, 28). These agents also prolong refractoriness, slow
ventricular fibrillation, and decrease the number of fibrillation
circuits without altering conduction velocity (9, 11, 19). These data,
as well as the data from the current study, suggest that increased
refractoriness during fibrillation may be the common
electrophysiological mechanism by which a drug can improve
defibrillation efficacy. The importance of tissue refractoriness and
defibrillation efficacy has been recently established. Optical
recordings demonstrated (18) that failed defibrillation occurs when
postshock activations propagate from the border of shock depolarized
and nondepolarized tissue. When the tissue at this border zone was
depolarized early in the cardiac cycle (within 50% of the fibrillation
cycle length), postshock propagation was not observed and
defibrillation succeeded. Depolarizing the tissue later in
repolarization (80% of fibrillation cycle length) resulted in failed
defibrillation. These data indicated that tissue
refractoriness plays a critical role in preventing postshock
propagation. This suggests that increasing refractoriness of
fibrillating myocardium will increase the probability that a shock will
depolarize the myocardium during its refractory period and produce
successful defibrillation. Hence, these studies would predict that
low-and high-dose lidocaine should decrease DER values, but only if
lidocaine did not produce another effect that opposed this action. The
current study supports this supposition. These data suggest that
increasing refractoriness and perhaps decreasing the number of
fibrillation circuits can facilitate defibrillation, and this action
can oppose the mechanism by which lidocaine raises DER values.
This scenario may also explain the results of a previous report (24)
that the potassium-channel blocker cesium chloride (known to increase fibrillation cycle length) was shown to reverse the effect of lidocaine
on DER.
In summary, lidocaine has an inverted U-shaped DER dose-response curve.
At very high lidocaine doses, DER values are similar to baseline and
tend to decrease rather than increase. It is likely that lidocaine, via
sodium-channel blockade, exerts two electrophysiological actions: one
that raises DER values, and one that lowers DER values. It appears that
high-dose lidocaine may not affect or improve defibrillation efficacy
by increasing tissue refractoriness, and this effect may overcome the
mechanism by which lidocaine increases DER values as the lidocaine dose
increases. However, there is a possibility that an unidentified action
of lidocaine is responsible for these effects.
| |
ACKNOWLEDGEMENTS |
This work was supported by a Grant-in-Aid from the
American Heart Association, Georgia Affiliate. The authors are grateful for the laboratory support provided by the Augusta Veterans Affairs Medical Center. Support of this study in the form of defibrillation equipment was provided by CPI Guidant (St. Paul, MN).
| |
FOOTNOTES |
Address for reprint requests: M. R. Ujhelyi, Medical College of
Georgia, Clinical Pharmacy Program CJ-1020, Augusta, GA 30912.
Received 10 March 1997; accepted in final form 10 December 1997.
| |
REFERENCES |
1.
Abildskov, J. A.
Induced termination of fibrillation.
J. Cardiovasc. Electrophysiol.
7:
71-81,
1996[Medline].
2.
Anderson, K. P.,
R. Walker,
R. L. Lux,
P. R. Ershler,
R. Menlove,
M. R. Williams,
R. Krall,
and
D. Moddrelle.
Conduction velocity depression and drug-induced ventricular tachyarrhythmias: effects of lidocaine in the intact canine heart.
Circulation
81:
1024-1038,
1990[Abstract/Free Full Text].
3.
Babbs, C. F.
Effect of pentobarbital anesthesia on ventricular defibrillation threshold in dogs.
Am. Heart J.
95:
331-337,
1978[Medline].
4.
Bonometti, C.,
C. Hwang,
D. Hough,
J. J. Lee,
M. C. Fishbein,
H. Karagueuzian,
and
P.-S. Chen.
Interaction between strong electrical stimulation and reentrant wavefronts in canine ventricular fibrillation.
Circ. Res.
77:
407-416,
1995[Abstract/Free Full Text].
5.
Cha, Y.-M.,
B. B. Peters,
and
P.-S. Chen.
The effects of lidocaine on the vulnerable period during ventricular fibrillation.
J. Cardiovasc. Electrophysiol.
5:
571-580,
1994[Medline].
6.
Colatsky, T. J.
Mechanisms of action of lidocaine and quinidine on action potential duration in rabbit cardiac Purkinje fibers: an effect on steady state sodium currents?
Circ. Res.
50:
17-27,
1982[Free Full Text].
7.
Damle, R. S.,
N. S. Robinson,
D. Z. Ye,
S. I. Roth,
R. Greene,
J. J. Goldberger,
and
A. H. Kadish.
Electrical activation during ventricular fibrillation in the subacute and chronic phases of healing canine myocardial infarction.
Circulation
92:
535-545,
1995[Abstract/Free Full Text].
8.
Dillon, S. M.
Synchronized repolarization after defibrillation: a possible component of the defibrillation process demonstrated by optical recordings in rabbit heart.
Circulation
85:
1865-1878,
1992[Abstract/Free Full Text].
9.
Dorian, P.,
E. S. Fain,
J.-M. Davy,
and
R. A. Winkle.
Lidocaine causes a reversible, concentration-dependent increase in defibrillation energy requirements.
J. Am. Coll. Cardiol.
8:
327-332,
1986[Abstract].
10.
Dorian, P.,
and
D. Newman.
Tedisamil increases coherence during ventricular fibrillation and decreases defibrillation energy requirements.
Cardiovasc. Res.
33:
485-494,
1997[Abstract/Free Full Text].
11.
Dorian, P.,
D. Newman,
R. Sheahan,
A. Tang,
M. Green,
and
J. Mitchell.
d-Sotalol decreases defibrillation energy requirements in humans: a novel indication for drug therapy.
J. Cardiovasc. Electrophysiol.
7:
952-961,
1996[Medline].
12.
Dorian, P.,
P. A. Penkoske,
and
F. X. Witkowski.
Order in disorder: effect of barium on ventricular fibrillation.
Can. J. Cardiol.
12:
399-406,
1996[Medline].
13.
Echt, D. S.,
J. N. Black,
J. T. Barbey,
D. R. Coxe,
and
E. Cato.
Evaluation of antiarrhythmic drugs on defibrillation energy requirements in dogs. Sodium channel block and action potential prolongation.
Circulation
79:
1106-1117,
1989[Abstract/Free Full Text].
14.
Fain, E. S.,
P. Dorian,
J.-M. Davy,
R. E. Kates,
and
R. A. Winkle.
Effects of encainide and its metabolites on energy requirements for defibrillation.
Circulation
73:
397-405,
1986.
15.
Hillsley, R. E.,
J. M. Wharton,
A. W. Case,
P. D. Wolf,
and
R. E. Ideker.
Why do some patients have high defibrillation thresholds at defibrillator implantation? Answers from basic research.
Pacing Clin. Electrophysiol.
17:
222-239,
1994[Medline].
16.
Jalife, J.,
J. M. Davidenko,
and
D. C. Michaels.
A new perspective on the mechanisms of arrhythmias and sudden cardiac death: spiral waves of excitation in heart muscle.
J. Cardiovasc. Electrophysiol.
2:
S133-S152,
1991.
17.
Kodama, I.,
N. Shibata,
I. Sakuma,
K. Mitsui,
M. Iida,
R. Suzuki,
Y. Fukui,
S. Hosoda,
and
J. Toyama.
Aftereffects of high-intensity DC stimulation on the electromechanical performance of ventricular muscle.
Am. J. Physiol.
267 (Heart Circ. Physiol. 36):
H248-H258,
1994[Abstract/Free Full Text].
18.
Kwaku, K. F.,
and
S. M. Dillon.
Shock-induced depolarization of refractory myocardium prevents wave-front propagation in defibrillation.
Circ. Res.
79:
957-973,
1996[Abstract/Free Full Text].
19.
Nattel, S.,
G. Bourne,
and
M. Talajic.
Insights into mechanisms of antiarrhythmic drug action from experimental models of atrial fibrillation.
J. Cardiovasc. Electrophysiol.
8:
469-480,
1997[Medline].
20.
Rensma, P. L.,
M. A. Allessie,
W. J. Lammers,
F. I. M. Bonke,
and
M. J. Schalij.
Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs.
Circ. Res.
62:
395-410,
1988[Abstract/Free Full Text].
21.
Shah, S. S.,
P. W. E. Hsia,
G. Harrington,
and
R. J. Daminao.
Quantifying myocardial organization using coherence analysis during ventricular fibrillation and for defibrillation research: a single reference electrode approach.
In: Computers in Cardiology. Los Alamitos, CA: IEEE Computer Soc., 1995, p. 801-804.
22.
Ujhelyi, M. R.,
S. Oskouei,
A. P. Winecoff,
S. Carter,
S. Li,
and
M. L. Markel.
Dispersion in post-shock activations predicts defibrillation success during lidocaine (Abstract).
Circulation
94:
I132,
1996.
23.
Ujhelyi, M. R.,
M. Schur,
T. Frede,
M. B. Bottorff,
M. Gabel,
and
M. L. Markel.
Hypertonic saline does not reverse the sodium channel blocking actions of lidocaine: evidence from electrophysiologic and defibrillation studies.
J. Cardiovasc. Pharmacol.
29:
61-68,
1997[Medline].
24.
Ujhelyi, M. R.,
M. Schur,
T. Frede,
M. B. Bottorff,
M. Gabel,
and
M. L. Markel.
Mechanisms of antiarrhythmic drug-induced changes in defibrillation threshold: role of potassium and sodium channel conductance.
J. Am. Coll. Cardiol.
27:
1534-1542,
1996[Abstract].
25.
Ujhelyi, M. R.,
M. Schur,
T. Frede,
M. Gabel,
and
M. L. Markel.
Differential effects of lidocaine on defibrillation threshold with monophasic versus biphasic shock waveforms.
Circulation
92:
1644-1650,
1995[Abstract/Free Full Text].
26.
Ujhelyi, M. R.,
A. P. Winecoff,
M. Schur,
T. Frede,
M. B. Bottorff,
M. Gabel,
and
M. L. Markel.
Influence of hypertonic saline infusion on defibrillation efficacy.
Chest
110:
784-790,
1996[Abstract/Free Full Text].
27.
Wang, Z.,
P. Page,
and
S. Nattel.
Mechanisms of flecainide's antiarrhythmic action in experimental atrial fibrillation.
Circ. Res.
71:
271-287,
1992[Abstract/Free Full Text].
28.
Wesley, R. C.,
F. Farkhani,
D. Morgan,
and
D. Zimmerman.
Ibutilide: enhanced defibrillation via plateau sodium current activation.
Am. J. Physiol.
264 (Heart Circ. Physiol. 33):
H1269-H1274,
1993[Abstract/Free Full Text].
29.
Winecoff, A. P.,
J. J. Sims,
M. L. Markel,
and
M. R. Ujhelyi.
Pinacidil's effects on defibrillation outcomes: role of increased potassium conductance via the KATP channel.
J. Cardiovasc. Pharmacol. Ther.
2:
171-79,
1997.
30.
Witkowski, F. X.,
P. A. Penkoske,
and
R. Plonsey.
Mechanism of cardiac defibrillation in open-chest dogs with unipolar DC-coupled simultaneous activation and shock potential recordings.
Circulation
82:
244-260,
1990[Abstract/Free Full Text].
31.
Zhou, X.,
J. P. Daubert,
P. D. Wolf,
W. M. Smith,
and
R. E. Ideker.
Epicardial mapping of ventricular defibrillation with monophasic and biphasic shocks in dogs.
Circ. Res.
72:
145-160,
1993[Abstract/Free Full Text].
32.
Zhou, X.,
P. Guse,
P. D. Wolf,
D. L. Rollins,
W. M. Smith,
and
R. E. Ideker.
Existence of both fast and slow channel activity during the early stages of ventricular fibrillation.
Circ. Res.
71:
773-786,
1992.
33.
Zhou, Z.,
W. M. Smith,
D. L. Rollins,
and
R. E. Ideker.
Transmembrane potential changes caused by shocks in guinea pig papillary muscle.
Am. J. Physiol.
271 (Heart Circ. Physiol. 40):
H2536-H2546,
1996[Abstract/Free Full Text].
AJP Heart Circ Physiol 274(4):H1113-H1120
Top
Abstract
Introduction
