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Effect of lidocaine on escape rate in patients with complete atrioventricular block: B. Proximal his bundle block
Effect of Lidocaine on Escape Rate in Patients With Complete Atrioventricular Block: B. Proximal His Bundle Block CHIEN-SUU KUO, MD, FACC
C. PRATAP REDDY, MD, FACC Lexington, Kentucky
Lidocaine was administered intravenously (a loading dose of 1.5 mg/kg followed by a 3 mg/mln infusion) to 10 patlents wlth complete atrioventricular (A-V) block proximal to the His bundle and A-V junctlonal escape rhythm. A-V block was not due to an acute myocardial infarctlon in seven patients (group I) and was due to an acute Inferior wall lnfarctlon in three patlents (group II). Lidocaine had either no or only a slight depressant effect on the rate of the escape pacemaker In patients in group I but caused severe bradycardla or asystole in two of three patients In group II. Lklocaine had no consistent effect on the atrlal rate and did not change the ORS duratlon and H-V intervals In any patient. These observations are consistent wlth tbe results of anlmal studles that showed that lldocaine selectively depressed conduction in lschemlc or depolarized myocardlum. The findings also suggest that the use of lidocalne without prior insertion of a pacemaker is unsafe In patients wlth acute myocardlal infarction and complete A-V block proximal to the His bundle. body welghi
In a previous study from our laboratory,l we showed that the administration of lidocaine is unsafe in patients with complete atrioventricular (A-V) block distal to the His bundle because the drug produced severe bradycardia or asystole in some patients. Our results suggested that lidocaine-induced bradycardia was due not to decreased automaticity of the escape ventricular pacemaker but to impaired propagation of impulse from the escape focus. We postulated that the delayed conduction or block, or both, of the impulse from the escape focus resulted from selective depression by lidocaine of the abnormal and partly depolarized myocardium surrounding the escape pacemaker.l Scheinman et a1.2 reported on four patients with surgically induced A-V block in whom therapeutic concentrations of lidocaine had no effect on the automaticity or conduction of the A-V junctional escape pacemaker. However, we know of no studies dealing with the effect of lidoCaine on the A-V junctional escape pacemaker in patients with acute myocardial infarction and complete A-V block. This study was designed to assess the effect of lidocaine on the A-V junctional escape pacemaker in patients with and without acute myocardial infarction in order to increase our understanding of the mechanism of antiarrhythmic effects of lidocaine, and to test the hypothesis that lidocaine depresses selectively the ischemic myocardium. From the Deparbnent of Medicine, Cardiovascular Division, University of Kentucky Medical Center and Veteran’s Administration Medical Center, Lexington. Kentucky. Manuscript received August 25, 1980; revised manuscript received January 5, 1981. accepted January 20, 1981. Address for reprints: Chien-Suu Kuo, MD, Department of Medicine, Cardiovascular Division, University of Kentucky Medical Center, 800 Rose Street, Lexington, Kentucky 40538.
Methods Study patients: Ten patients with complete A-V block requiring permanent or temporary ventricular pacing were studied after giving informed consent. The pertinent clinical information for all patients is shown in Table I. Patients were divided into two groups: Group I consisted of seven patients (Cases 1 to ‘7) whose A-V block was not due to an acute myocardial infarction; group II consisted of three patients (Cases 8 to 10) with acute inferior wall myocardial infarction complicated by complete A-V block. No patient had congestive heart failure,
June 1991
The American Journal of CARDIOLOGY
Volume 47
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LIDOCAINE AND ATRIOVENTRICULAR JUi’)CTlONAL PACEMAKER-KU0
AND REDDY
hypotension or serum electrolyte abnormalities or was receiving antiarrhythmic agents at the time of the study. Electrophysiologic studies with lidocaine: His bundle electrograms were recorded in a standard manner3 using a trior quadripolar electrode catheter on paper moving at a speed of 100 mm/s. In all patients, a bipolar electrode catheter was placed in the right ventricular apex and connected to a Medtronic pacemaker that was controlled manually or set in demand mode at a rate of 20 beats/min. Lidocaine was administered intravenously as a loading dose of 1.5 mg/kg body weight given during a period of 2 minutes followed immediately by an infusion of 3 mg/min for 10 minutes. The electrocardiogram was recorded at 25 mm/s for 60 seconds every 2 to 5 minutes during a 30 minute period immediately preceding the administration of lidocaine and continuously during the entire study of lidocaine. The control R-R and P-P intervals were determined by averaging all R-R and P-P intervals recorded during the 60 second period preceding the administration of lidocaine. The effect of lidocaine was determined by averaging 10 consecutive R-R and P-P intervals when the duration of these intervals was maximal. In the presence of marked and abrupt changes in rate, each R-R interval was measured until the ventricular rate returned to control value or standby ventricular pacing was initiated. All patients were closely observed for potential untoward effects and their blood pressure was periodically checked throughout the study. Statistical analyses were performed using the unpaired t test and the chi-square test.
Results QRS pattern, duration of escape QRS complex and H-V interval (Table I): All patients had sinus rhythm. In each of the nine patients who had a His bundle electrogram recorded, the site of atrioventricular (A-V) block was proximal to the His bundle recording site. In one patient (Case 2) who did not have a His bundle electrogram recorded, the QRS complexes of escape rhythm were narrow and identical to the conducted QRS complexes noted before the development of complete A-V block. The rate of the escape pacemaker, the duration of the escape QRS complex and the H-V interval for each patient are shown in Table I. The QRS duration was 0.10 second or less in nine patients and 0.13 second in one patient. The QRS complexes of the escape pacemaker had a left bundle branch block pattern in one patient (Case 1) and an incomplete right bundle branch block pattern in a second patient (Case 6). A third patient (Case 9) had a transient incomplete right bundle branch block pattern before the study. H-V intervals were normal in all patients. There was no significant difference in H-V intervals between patients in group I and group II. The difference in escape rate was also not significant (mean f standard deviation 46.7 f 6.3 beats/min for group I, versus 38.3 f 10 beats/min for group II, p >O.lO).
TABLE I Clinical Characteristics of 10 Patients With Complete Atrioventrlcular Block
Case
Age (yr) & Sex
Clinical Diagnosis
ECG of Escape Complex
Site of A-V Block 8 H-V Interval
(mE$iter)
Escape Rate (beatslmin) Post %Change Pre
Atrial Rate (beatslmin) Pre Post
Plasma Lido Level @g/ml)
Group I. Patients With No Acute Myocardial Infarction 1
14F
C;;rital
LBBB; QRS
0.13 s
2
56M
LVH; QRS
0.06 s
3
53M
CHB. PVD. COPD CHB, AS,
LVH; QRS
0.10 s
4
66M
CAHlg
QRS
0.08 s
5
71M
CHB
QRS
0.09 s
6
63M
CHB, ASHD
IRBBB; QRS
7
71M
CHB. MAC
QRS
0.06 s
0.06 s
Proximal to HB; H-V 35 ms
5.1
48
47
4.2
50
50
Proximal to HB; H-V 50 ms
3.9
56
55
Proximal to HB; H-V 30 ms Proximal to HB; H-V 40 ms Proximal to HB; H-V 55 ms Proximal to HB: H-V30 ms
4.0
39
4.9
.
.
-2
86
73
5.0
120
120
2.1
-2
97
100
.
36
-9
79
a5
3.4
38
31
-19
120
115
..
4.0
46
40
-16
47
46
10.8
4.5
43
37
-17
78
a1
5.2
0
Group II. Patients With Acute Inferior Myocardial infarction a
67M
9
60M
10
61M
Acute MI, CHB Acute MI, CHB Acute MI. CHB
IMI; QRS
0.06 s
Proximal to HB; KV 45 ms IMI; transient Proximal to HB; IRBBB: QRS 0.06 s H-V 55 ms IMI; QRS 0.06 s Proximal to HB; H-V 50 ms
4.2
39
38
-5
a0
74
5.4
4.3
46
46’
-4’
120
120
6.1
4.2
28
22’
-280
91
91
5.0
These values represent the maximal change in the rate before development of severe bradycardia or asystole. Al = aortic insufficiency; AS = aortic stenosis; ASHD = atherosclerotic heart disease; AVB = atrioventricular block; CHB = complete heart block; COPD = chronic obstructive pulmonary disease: ECG = electrocardiogram; HB = His bundle; IMI = inferior myocardial infarction: lRBBB = incomplete right bundle branch block: KS = serum potassium; LBBB = left bundle branch block; Lii = lidocaine; LVH = left ventricular hypettrophy; MAC = mitral anulus calcification; Post = after lldocaine; Pre = before lidocaine; PVD = peripheral vascular disease. l
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LIDOCAINE AND ATRIOVENTRICULAR JUNCTIONAL PACEMAKER-KU0
After lidocaine, there was no change in the QRS pattern, the duration of escape QRS complex and the H-V interval in any of the 10 patients. Lidocaine produced no consistent change in atria1 rate (an increase in three, a decrease in four and no change in three patients). Effect of lidocaine on the rate of the escape pacemaker (Table I): Group I: Lidocaine produced an average decrease of 3.4 f 2.9 beatslmin (range 0 to 7 beatslmin or 9 f 8.4 percent of control rate) in the rate of the escape pacemaker. The escape rate decreased by 1 beat/min in two patients, 3 beats/min in one patient, 6 beats/min in two patients and 7 beats/min in one patient; it remained unchanged in one patient. The change in the rate of the escape pacemaker was gradual with the maximal de-
crease occurring 3 to 5 minutes after the administration of the loading dose. In all patients, the rate gradually returned to control values after the infusion of lidocaine was discontinued. Figure 1 i&r&rates a case in which lidocaine caused gradual slowing of the escape rate from 39 to 36 beats/min. Group II: In Patient 8, lidocaine caused a decrease in the rate of the escape pacemaker as in the patients in group I. In the other two patients (Cases 9 and 101, the escape rate initially decreased gradually as in patients in group I, but within 30 to 60 seconds after administration of the loading dose the rate decreased abruptly and became less than half the control rate (Fig. 2 and 3). Thus, two of the three patients in group II had marked and abrupt decrease in the escape rate whereas not one of the seven patients in Group I had such a
HR
LEAD II
CONTROL
2min
FKWRE 1. Case 4. Panel A, conb-olperiod, panels B and C, 2 and 5 minutes after the bolus injection of lidocaine. The numbers below each strip indicate R-R intervals in milliseconds. Note the progressive increase in R-R intervals without any change in P-P intervals. The plasma concentration of Mocaine at the time of maximal effect was 3.4 pg/ml. HR = heart rate (beats/min).
1
n
AND REDDY
39
HR38
HR 36
5min C
A
A
A
A
A
A
A
FIGURE 2. Case 10. His bundle electrogram during the administration of lidocaine (approximately 30 seconds after the loading dose). Panels A, Band C are continuous. In each panel from top to bottom are surface electrocardiographic leads I, II and VI and the His bundle electrogram (HRE). The arrow in panel C indicates the artificial pacemaker spike. The numbers indicate R-R intervals in milliseconds. The site of block is proximal to the His bundle recording site, and the H-V interval of the escape complexes measures 50 ms. A control recording, not shown, revealed an atrioventricular (A-V) junctional escape rhythm with an R-R interval of 2,150 ms and an H-V interval of 50 ms. The escape QRS complex was identical to the one shown in this figure. The plasma concentration of lidocaine was 5.0 pg/ml. A = atrial electrogram; H = His potential; T = time lines at 10 and 50 ms: V = ventricular electrogram. See text for details.
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LIDOCAINE AND ATRIOVENTRICULAR JUNCTIONAL PACEMAKER-KU0
1270
1250
1290
1310
1270
1290
1320
AND REDDY
1300
1310 FIGURE 3. Case 9. Panel A, control study; panels 6, C and D, continuous strips recorded 20 to 30 seconds after lhe loading dose of Iklocaine was given. The last complex in panel C marked with an asterisk is repeated in the beginning of panel D. The plasma concentration of lidocaine was 6.1 pglml. Note that the P-P interval did not change after lidocaine. Abbreviations as in Figure 1. See text for details.
change in the escape rate. This difference is statistically significant (chi-square = 5.83, p X0.02). Figure 2 (Case 10) shows complete A-V block proximal to the His bundle with a junctional escape rhythm. The H-V interval measures 50 ms. During the control period, the escape rate was 28 beats/min (R-R interval 2,150 ms). Within 30 seconds after the end of the loading dose, the R-R interval increased first gradually to 2,750 ms (first R-R interval in panel A), and then abruptly to 5,310, 2,810 and 6,750 ms in three consecutive cycles (panels A and B). The last of these cycles was followed by a prolonged asystole that was terminated by the activation of the ventricular pacemaker (panel C). Infusion of lidocaine was discontinued, and the patient was
bpmr
8.‘. Imml
. 2
.
3 1
. 5 TIME (MINUTE1
FIGURE 4. Plasma lidocaine concentration @g/ml) and pacemaker escape rate (vertkal axle) are plotted against time (minutes) (horlzonlal axls) in six patients (Cases 1,2,4 and 6 to 8). Squares and circles indicate mean escape rates and mean plasma lidocaine concentrations, respectively. Verlkal bars indicate f 1 standard deviation. bpm = beats per minute; Imm = immediately after the loading dose.
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monitored until the rate of the escape pacemaker returned to the control value. Lidocaine did not change the QRS complex and the H-V interval. In Figure 3 (Case 9), the rate of the escape pacemaker before lidocaine was 48 beats/min (R-R interval 1,250 ms) (panel A). During the administration of lidocaine, the R-R interval gradually increased (panels B and C), and within 30 seconds after termination of the loading dose, the escape pacemaker suddenly failed and the demand ventricular pacemaker was activated (panel D). The interval between the last escape complex and the first paced complex measured 2,850 ms, which is more than two times the preceding R-R interval. Infusion of lidocaine was discontinued and the patient was monitored until the rate of the escape pacemaker returned to the control value.
Plasma lidocaine concentrations: Plasma concentrations of lidocaine were measured in eight patients and ranged from 2.1 to 10.8 pg/ml (mean f standard deviation 5.4 f 2.5 pg/ml). Plasma lidocaine concentrations were not determined in two patients (Cases 3 and 5). Serial plasma lidocaine concentrations were determined at the following intervals: immediately and 1, 2, 3 and 5 minutes after the loading dose. Figure 4 shows the relation between the escape rate and plasma lidocaine concentrations in six patients (Cases 1,2,4 and 6 to 8) during the first 5 minutes after administration of lidocaine. Whereas maximal lidocaine concentration was achieved at 2 minutes, the maximal decrease in the escape rate occurred 3 to 5 minutes after the loading dose. For Patients 8 and 9, such plasma concentration-escape rate relation curves could not be constructed because of artificial pacemaker activation within 2 minutes after the administration of lidocaine. Adverse effects: One patient complained of transient dizziness immediately after the bolus injection. Lidocaine produced no hypotension or other untoward effects.
Discussion Electrophysiologic effect of lidocaine on Purkinje and ventricular fibers: Studies in isolated
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LIDOCAINE AND ATRlOVENTRlClKAR
Purkinje and ventricular fibers and in intact animal hearts have shown that lidocaine in therapeutic concentrations depresses or abolishes the spontaneous phase 4 depolarization in Purkinje fibers, decreases diastolic excitability without changing the threshold potential, but does not change the maximal first derivative (dV/dt),,, of the upstroke of the action potential and conduction velocity in nondepolarized Purkinje and ventricular fibers.4-11 However, in the presence of high extracellular potassium concentration4J*12 or myocardial ischemia,6s7 lidocaine reduces (dV/dt),,, and depresses conduction in Purkinje fibers and ventricular myocardium. Therapeutic concentrations of lidocaine do not affect the pacemaker activity or upstroke velocity of pacemaker fibers dependent on slow channel activity,‘” such as that postulated to be responsible for the pacemaker activity of the sinoatrial node.14 However, toxic concentrations of the drug may depress slow channel-dependent automaticity.lZ3 Effects of lidocaine on A-V heart block: The results of our study show that therapeutic doses of lidoCaine may cause severe bradycardia or asystole in patients with complete A-V block due to acute myocardial infarction, but not in patients whose A-V block is not due to acute myocardial infarction. We do not know which electrophysiologic properties of lidocaine were responsible for the observed differences between patients in groups I and II. Although plasma lidocaine levels in two patients in group II who had marked slowing of the escape pacemaker were slightly higher than the generally accepted therapeutic levels, they were not significantly different from lidocaine levels in patients in group I or in the third patient (Case 8) in group II. Furthermore, these concentrations did not prolong the QRS duration or H-V interval of escape complexes. Serum potassium concentration was normal in all patients and not significantly different in the two groups. Effect of lidocaine on the A-V junctional escape pacemaker: The exact site and the characteristics of the A-V junctional escape pacemaker in our patients are not known. An escape pacemaker situated in. the proximal portion of the His bundle may be suppressed by lidocaine because the electrophysiologic characteristics of pacemaker fibers in this region are similar to those of a Purkinje fiber. However, if an escape pacemaker is situated within the A-V node and is dependent on slow channel activity, l5 it may be insensitive to the therapeutic concentrations of lidocaine. The possibility that different effects of lidocaine were due to different types of escape pacemakers in patients in groups I and II is unlikely because lidocaine had no effect on the rate of the sinoatrial node, a slow channel-dependent pacemaker, and because the manner in which the escape rate decreased suggested an exit block rather than a gradual suppression of spontaneous phase 4 depolarization. In Case 10, the control escape rate was markedly slower than in the remaining patients. This finding raises the possibility that in this patient the escape pacemaker may be located more distally within the His bundle and
JUNCTIONAL PACEMAKER--KU0
AND REDDY
the marked slowing of the escape pacemaker by lidoCaine may be due to the distal location of the escape pacemaker. However, this explanation is unlikely because (1) a similar effect was also observed in Case 9 in whom the escape rate was comparable with or faster than that in many group I patients, and (2) our previous study’ has shown that lidocaine had minimal depressant effect on the automaticity of an escape pacemaker located distal to the His bundle. Effect of lidocaine on ischemic versus normal myocardium: The most likely explanation for the different effects of lidocaine on the escape pacemaker in patients in groups I and II is the selective drug effect on depolarized ischemic myocardium. Therapeutic concentrations of lidocaine do not affect conduction in normal myocardium but they slow conduction in the ischemic myocardium and decrease diastolic excitability more in the ischemic than in the normal myocardium.“*7 Because both the atrioventricular node and the proximal His-Purkinje system have a common source of blood .~upply,~~ it is reasonable to assume that the escape pacemaker or t,he surrounding myocardium, or both, had variable degrees of ischemic injury. This finding suggests that a critical depression of conduction or excitability, or both, by lidocaine in this area my result in sudden and marked decrease in the escape rate without change in the QRS duration or H-V interval as observed in our patients. The absence of significant slowing of rate of the escape pacemaker in one patient with acute myocardial infarction must be attributed to the probable absence of ischemic damage to the ectopic pacemaker and the adjacent myocardium in this patient. We believe that our observation provides the first clinical evidence in support of the concept that lidocaine has a greater depressant, effect on ischemic than on nonischemic myocardium as shown previously in animal studies.fi,7 Clinical implications: Our results may be relevant to the understanding of the mechanism of ant.iarrhythmic effects of lidocaim in human beings. LidoCaine in plasma concentrations considered therapeutic in suppressing ventricular arrhythmia apparently has no significant depressant effect on the escape pacemaker in the absence of acute myocardial infarction but inhibits escape activity in the presence of acute myocardial infarction. The differences between the effect of the drug on the acutely ischemic and the apparently nonischemic myocardium suggest that the antiarrhythmic effect of lidocaine may be due to its ability to depress conduction in ischemic myocardium rather than to improve conduction or to suppress the normal or abnormal automaticity. Further progress in the understanding of the antiarrhythmic action of lidocaine must await a better understanding of the mechanism of the arrhythmias affected by the drug. Acknowledgment We thank Borys Surawicz, MI) for his thoughtful critique of the manuscript, Linda Hrandenburg for her technical assistance and Joann Buckley for her secretarial help.
June 1981
The American
Journal
of CARDIDLDGY
Volume 47
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AND REDDY
References 1. Aravindakshan V, Kuo CS, Gettes LS. Effect of lidocaine on escape rate in patients with complete at&ventricular block. A. Distal His bundle block. Am J Cardiol 1977;40: 177-83. 2. ScMrnnan Y, Desai J, Gonzalez i?, Peters I?, Thomas A, Dhdzio 8. The effect of lfdocaine on His bundle automaticity and rhythm in man (abstr). Circulation 1978;58:11- 11. 3. Sciwiag BJ, Lau 94, Hettant RH, Berkowitz WD, Stein E, Damato AN. Catheter technique for recording His bundle activity in man. Circulation 1969;39: 13-8. 4. Ghan CM, Gettes LS, Katzung BG. Effect of lidocaine and quinidine on steady state characteristics and recovery kinetics of (dV/dt) max. in guinea-pig ventricular myocardium. Circ Res 1975;37: 20-9. 5. Salto S, Chen CM, Buchanan J, Gattes LS, Lynch MR. Steady state and timedependent slowing of conduction in canine hearts. Effect of potassium and lidocaine. Circ Res 1978;42:246-54. 6. Lazzara I?, Hope RR, El-Sherit N, Schehq BJ. Effects of ltdocaina on hypoxic and ischemic cardiac cells. Am J Cardiol 1978;41: 872-9. 7. Kupersmith J. Electrophysiological and antiarrhythmic effects of lidocaine in canine acute myocardial ischemia. Am Heart J 1979;97:360-6. 8. David LD, Temle JV. Electrophysiological acttons of lidocaine on canine ventricular muscle and Purkinje fibers. Circ Res 1969;
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24:639-55. 9. B@jer JT, Man&M WJ. Effect of lidocaine on the electrophysiological properties of ventricufar muscle and Ptiinje fibers. J Clin Invest 1970;49:63-77. 10. Ryden L, Konqren M. The effect of lignocaine on the stimulation threshold and conduction disturbances in patients treated with pacemaker. Cardiovasc Ftes 1969;3:415-8. 11. Amadorf MF, Bi99er Jl. The effect of Mocaine on components of excitability in long mammalian cardiac Purkinje fibers. J Pharmacol Exp Ther 1975;195:206-15. 12. Obayaehl K, Hayakawa H, Mandei WJ. interrelationships between external potassium concentration and lidocaine effects of canine Purkinje fiber. Am Heart J 1975:89:221-6. 13. imanhihl S, McAtMster RG Jr, Suawicz B. The effects of verapamil and lidocaine on the automatic depolarizations in guinea-pig ventricular myocardium. J Pharmacol Exp Ther 1978;207:294-303. 14. Cranefield PF. Sustained rhythmic activity. In: The Conduction of the Cardiac Impulse. Chapter VI. Mount Kisco, NY: Futura, 1975:199-265. 15. Watanabe Y, Dreifus LS. Sites of impulse formation within the atrioventricular junction of the rabbit. Circ Res 1968;22:71727. 16. Frink RJ, James TN. Normal blood supply to the human His bundle and proximal bundle branches. Circulation 1973;47:8-18.
Voiumo 47
C. PRATAP REDDY, MD, FACC Lexington, Kentucky
Lidocaine was administered intravenously (a loading dose of 1.5 mg/kg followed by a 3 mg/mln infusion) to 10 patlents wlth complete atrioventricular (A-V) block proximal to the His bundle and A-V junctlonal escape rhythm. A-V block was not due to an acute myocardial infarctlon in seven patients (group I) and was due to an acute Inferior wall lnfarctlon in three patlents (group II). Lidocaine had either no or only a slight depressant effect on the rate of the escape pacemaker In patients in group I but caused severe bradycardla or asystole in two of three patients In group II. Lklocaine had no consistent effect on the atrlal rate and did not change the ORS duratlon and H-V intervals In any patient. These observations are consistent wlth tbe results of anlmal studles that showed that lldocaine selectively depressed conduction in lschemlc or depolarized myocardlum. The findings also suggest that the use of lidocalne without prior insertion of a pacemaker is unsafe In patients wlth acute myocardlal infarction and complete A-V block proximal to the His bundle. body welghi
In a previous study from our laboratory,l we showed that the administration of lidocaine is unsafe in patients with complete atrioventricular (A-V) block distal to the His bundle because the drug produced severe bradycardia or asystole in some patients. Our results suggested that lidocaine-induced bradycardia was due not to decreased automaticity of the escape ventricular pacemaker but to impaired propagation of impulse from the escape focus. We postulated that the delayed conduction or block, or both, of the impulse from the escape focus resulted from selective depression by lidocaine of the abnormal and partly depolarized myocardium surrounding the escape pacemaker.l Scheinman et a1.2 reported on four patients with surgically induced A-V block in whom therapeutic concentrations of lidocaine had no effect on the automaticity or conduction of the A-V junctional escape pacemaker. However, we know of no studies dealing with the effect of lidoCaine on the A-V junctional escape pacemaker in patients with acute myocardial infarction and complete A-V block. This study was designed to assess the effect of lidocaine on the A-V junctional escape pacemaker in patients with and without acute myocardial infarction in order to increase our understanding of the mechanism of antiarrhythmic effects of lidocaine, and to test the hypothesis that lidocaine depresses selectively the ischemic myocardium. From the Deparbnent of Medicine, Cardiovascular Division, University of Kentucky Medical Center and Veteran’s Administration Medical Center, Lexington. Kentucky. Manuscript received August 25, 1980; revised manuscript received January 5, 1981. accepted January 20, 1981. Address for reprints: Chien-Suu Kuo, MD, Department of Medicine, Cardiovascular Division, University of Kentucky Medical Center, 800 Rose Street, Lexington, Kentucky 40538.
Methods Study patients: Ten patients with complete A-V block requiring permanent or temporary ventricular pacing were studied after giving informed consent. The pertinent clinical information for all patients is shown in Table I. Patients were divided into two groups: Group I consisted of seven patients (Cases 1 to ‘7) whose A-V block was not due to an acute myocardial infarction; group II consisted of three patients (Cases 8 to 10) with acute inferior wall myocardial infarction complicated by complete A-V block. No patient had congestive heart failure,
June 1991
The American Journal of CARDIOLOGY
Volume 47
1315
LIDOCAINE AND ATRIOVENTRICULAR JUi’)CTlONAL PACEMAKER-KU0
AND REDDY
hypotension or serum electrolyte abnormalities or was receiving antiarrhythmic agents at the time of the study. Electrophysiologic studies with lidocaine: His bundle electrograms were recorded in a standard manner3 using a trior quadripolar electrode catheter on paper moving at a speed of 100 mm/s. In all patients, a bipolar electrode catheter was placed in the right ventricular apex and connected to a Medtronic pacemaker that was controlled manually or set in demand mode at a rate of 20 beats/min. Lidocaine was administered intravenously as a loading dose of 1.5 mg/kg body weight given during a period of 2 minutes followed immediately by an infusion of 3 mg/min for 10 minutes. The electrocardiogram was recorded at 25 mm/s for 60 seconds every 2 to 5 minutes during a 30 minute period immediately preceding the administration of lidocaine and continuously during the entire study of lidocaine. The control R-R and P-P intervals were determined by averaging all R-R and P-P intervals recorded during the 60 second period preceding the administration of lidocaine. The effect of lidocaine was determined by averaging 10 consecutive R-R and P-P intervals when the duration of these intervals was maximal. In the presence of marked and abrupt changes in rate, each R-R interval was measured until the ventricular rate returned to control value or standby ventricular pacing was initiated. All patients were closely observed for potential untoward effects and their blood pressure was periodically checked throughout the study. Statistical analyses were performed using the unpaired t test and the chi-square test.
Results QRS pattern, duration of escape QRS complex and H-V interval (Table I): All patients had sinus rhythm. In each of the nine patients who had a His bundle electrogram recorded, the site of atrioventricular (A-V) block was proximal to the His bundle recording site. In one patient (Case 2) who did not have a His bundle electrogram recorded, the QRS complexes of escape rhythm were narrow and identical to the conducted QRS complexes noted before the development of complete A-V block. The rate of the escape pacemaker, the duration of the escape QRS complex and the H-V interval for each patient are shown in Table I. The QRS duration was 0.10 second or less in nine patients and 0.13 second in one patient. The QRS complexes of the escape pacemaker had a left bundle branch block pattern in one patient (Case 1) and an incomplete right bundle branch block pattern in a second patient (Case 6). A third patient (Case 9) had a transient incomplete right bundle branch block pattern before the study. H-V intervals were normal in all patients. There was no significant difference in H-V intervals between patients in group I and group II. The difference in escape rate was also not significant (mean f standard deviation 46.7 f 6.3 beats/min for group I, versus 38.3 f 10 beats/min for group II, p >O.lO).
TABLE I Clinical Characteristics of 10 Patients With Complete Atrioventrlcular Block
Case
Age (yr) & Sex
Clinical Diagnosis
ECG of Escape Complex
Site of A-V Block 8 H-V Interval
(mE$iter)
Escape Rate (beatslmin) Post %Change Pre
Atrial Rate (beatslmin) Pre Post
Plasma Lido Level @g/ml)
Group I. Patients With No Acute Myocardial Infarction 1
14F
C;;rital
LBBB; QRS
0.13 s
2
56M
LVH; QRS
0.06 s
3
53M
CHB. PVD. COPD CHB, AS,
LVH; QRS
0.10 s
4
66M
CAHlg
QRS
0.08 s
5
71M
CHB
QRS
0.09 s
6
63M
CHB, ASHD
IRBBB; QRS
7
71M
CHB. MAC
QRS
0.06 s
0.06 s
Proximal to HB; H-V 35 ms
5.1
48
47
4.2
50
50
Proximal to HB; H-V 50 ms
3.9
56
55
Proximal to HB; H-V 30 ms Proximal to HB; H-V 40 ms Proximal to HB; H-V 55 ms Proximal to HB: H-V30 ms
4.0
39
4.9
.
.
-2
86
73
5.0
120
120
2.1
-2
97
100
.
36
-9
79
a5
3.4
38
31
-19
120
115
..
4.0
46
40
-16
47
46
10.8
4.5
43
37
-17
78
a1
5.2
0
Group II. Patients With Acute Inferior Myocardial infarction a
67M
9
60M
10
61M
Acute MI, CHB Acute MI, CHB Acute MI. CHB
IMI; QRS
0.06 s
Proximal to HB; KV 45 ms IMI; transient Proximal to HB; IRBBB: QRS 0.06 s H-V 55 ms IMI; QRS 0.06 s Proximal to HB; H-V 50 ms
4.2
39
38
-5
a0
74
5.4
4.3
46
46’
-4’
120
120
6.1
4.2
28
22’
-280
91
91
5.0
These values represent the maximal change in the rate before development of severe bradycardia or asystole. Al = aortic insufficiency; AS = aortic stenosis; ASHD = atherosclerotic heart disease; AVB = atrioventricular block; CHB = complete heart block; COPD = chronic obstructive pulmonary disease: ECG = electrocardiogram; HB = His bundle; IMI = inferior myocardial infarction: lRBBB = incomplete right bundle branch block: KS = serum potassium; LBBB = left bundle branch block; Lii = lidocaine; LVH = left ventricular hypettrophy; MAC = mitral anulus calcification; Post = after lldocaine; Pre = before lidocaine; PVD = peripheral vascular disease. l
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LIDOCAINE AND ATRIOVENTRICULAR JUNCTIONAL PACEMAKER-KU0
After lidocaine, there was no change in the QRS pattern, the duration of escape QRS complex and the H-V interval in any of the 10 patients. Lidocaine produced no consistent change in atria1 rate (an increase in three, a decrease in four and no change in three patients). Effect of lidocaine on the rate of the escape pacemaker (Table I): Group I: Lidocaine produced an average decrease of 3.4 f 2.9 beatslmin (range 0 to 7 beatslmin or 9 f 8.4 percent of control rate) in the rate of the escape pacemaker. The escape rate decreased by 1 beat/min in two patients, 3 beats/min in one patient, 6 beats/min in two patients and 7 beats/min in one patient; it remained unchanged in one patient. The change in the rate of the escape pacemaker was gradual with the maximal de-
crease occurring 3 to 5 minutes after the administration of the loading dose. In all patients, the rate gradually returned to control values after the infusion of lidocaine was discontinued. Figure 1 i&r&rates a case in which lidocaine caused gradual slowing of the escape rate from 39 to 36 beats/min. Group II: In Patient 8, lidocaine caused a decrease in the rate of the escape pacemaker as in the patients in group I. In the other two patients (Cases 9 and 101, the escape rate initially decreased gradually as in patients in group I, but within 30 to 60 seconds after administration of the loading dose the rate decreased abruptly and became less than half the control rate (Fig. 2 and 3). Thus, two of the three patients in group II had marked and abrupt decrease in the escape rate whereas not one of the seven patients in Group I had such a
HR
LEAD II
CONTROL
2min
FKWRE 1. Case 4. Panel A, conb-olperiod, panels B and C, 2 and 5 minutes after the bolus injection of lidocaine. The numbers below each strip indicate R-R intervals in milliseconds. Note the progressive increase in R-R intervals without any change in P-P intervals. The plasma concentration of Mocaine at the time of maximal effect was 3.4 pg/ml. HR = heart rate (beats/min).
1
n
AND REDDY
39
HR38
HR 36
5min C
A
A
A
A
A
A
A
FIGURE 2. Case 10. His bundle electrogram during the administration of lidocaine (approximately 30 seconds after the loading dose). Panels A, Band C are continuous. In each panel from top to bottom are surface electrocardiographic leads I, II and VI and the His bundle electrogram (HRE). The arrow in panel C indicates the artificial pacemaker spike. The numbers indicate R-R intervals in milliseconds. The site of block is proximal to the His bundle recording site, and the H-V interval of the escape complexes measures 50 ms. A control recording, not shown, revealed an atrioventricular (A-V) junctional escape rhythm with an R-R interval of 2,150 ms and an H-V interval of 50 ms. The escape QRS complex was identical to the one shown in this figure. The plasma concentration of lidocaine was 5.0 pg/ml. A = atrial electrogram; H = His potential; T = time lines at 10 and 50 ms: V = ventricular electrogram. See text for details.
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1270
1250
1290
1310
1270
1290
1320
AND REDDY
1300
1310 FIGURE 3. Case 9. Panel A, control study; panels 6, C and D, continuous strips recorded 20 to 30 seconds after lhe loading dose of Iklocaine was given. The last complex in panel C marked with an asterisk is repeated in the beginning of panel D. The plasma concentration of lidocaine was 6.1 pglml. Note that the P-P interval did not change after lidocaine. Abbreviations as in Figure 1. See text for details.
change in the escape rate. This difference is statistically significant (chi-square = 5.83, p X0.02). Figure 2 (Case 10) shows complete A-V block proximal to the His bundle with a junctional escape rhythm. The H-V interval measures 50 ms. During the control period, the escape rate was 28 beats/min (R-R interval 2,150 ms). Within 30 seconds after the end of the loading dose, the R-R interval increased first gradually to 2,750 ms (first R-R interval in panel A), and then abruptly to 5,310, 2,810 and 6,750 ms in three consecutive cycles (panels A and B). The last of these cycles was followed by a prolonged asystole that was terminated by the activation of the ventricular pacemaker (panel C). Infusion of lidocaine was discontinued, and the patient was
bpmr
8.‘. Imml
. 2
.
3 1
. 5 TIME (MINUTE1
FIGURE 4. Plasma lidocaine concentration @g/ml) and pacemaker escape rate (vertkal axle) are plotted against time (minutes) (horlzonlal axls) in six patients (Cases 1,2,4 and 6 to 8). Squares and circles indicate mean escape rates and mean plasma lidocaine concentrations, respectively. Verlkal bars indicate f 1 standard deviation. bpm = beats per minute; Imm = immediately after the loading dose.
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monitored until the rate of the escape pacemaker returned to the control value. Lidocaine did not change the QRS complex and the H-V interval. In Figure 3 (Case 9), the rate of the escape pacemaker before lidocaine was 48 beats/min (R-R interval 1,250 ms) (panel A). During the administration of lidocaine, the R-R interval gradually increased (panels B and C), and within 30 seconds after termination of the loading dose, the escape pacemaker suddenly failed and the demand ventricular pacemaker was activated (panel D). The interval between the last escape complex and the first paced complex measured 2,850 ms, which is more than two times the preceding R-R interval. Infusion of lidocaine was discontinued and the patient was monitored until the rate of the escape pacemaker returned to the control value.
Plasma lidocaine concentrations: Plasma concentrations of lidocaine were measured in eight patients and ranged from 2.1 to 10.8 pg/ml (mean f standard deviation 5.4 f 2.5 pg/ml). Plasma lidocaine concentrations were not determined in two patients (Cases 3 and 5). Serial plasma lidocaine concentrations were determined at the following intervals: immediately and 1, 2, 3 and 5 minutes after the loading dose. Figure 4 shows the relation between the escape rate and plasma lidocaine concentrations in six patients (Cases 1,2,4 and 6 to 8) during the first 5 minutes after administration of lidocaine. Whereas maximal lidocaine concentration was achieved at 2 minutes, the maximal decrease in the escape rate occurred 3 to 5 minutes after the loading dose. For Patients 8 and 9, such plasma concentration-escape rate relation curves could not be constructed because of artificial pacemaker activation within 2 minutes after the administration of lidocaine. Adverse effects: One patient complained of transient dizziness immediately after the bolus injection. Lidocaine produced no hypotension or other untoward effects.
Discussion Electrophysiologic effect of lidocaine on Purkinje and ventricular fibers: Studies in isolated
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LIDOCAINE AND ATRlOVENTRlClKAR
Purkinje and ventricular fibers and in intact animal hearts have shown that lidocaine in therapeutic concentrations depresses or abolishes the spontaneous phase 4 depolarization in Purkinje fibers, decreases diastolic excitability without changing the threshold potential, but does not change the maximal first derivative (dV/dt),,, of the upstroke of the action potential and conduction velocity in nondepolarized Purkinje and ventricular fibers.4-11 However, in the presence of high extracellular potassium concentration4J*12 or myocardial ischemia,6s7 lidocaine reduces (dV/dt),,, and depresses conduction in Purkinje fibers and ventricular myocardium. Therapeutic concentrations of lidocaine do not affect the pacemaker activity or upstroke velocity of pacemaker fibers dependent on slow channel activity,‘” such as that postulated to be responsible for the pacemaker activity of the sinoatrial node.14 However, toxic concentrations of the drug may depress slow channel-dependent automaticity.lZ3 Effects of lidocaine on A-V heart block: The results of our study show that therapeutic doses of lidoCaine may cause severe bradycardia or asystole in patients with complete A-V block due to acute myocardial infarction, but not in patients whose A-V block is not due to acute myocardial infarction. We do not know which electrophysiologic properties of lidocaine were responsible for the observed differences between patients in groups I and II. Although plasma lidocaine levels in two patients in group II who had marked slowing of the escape pacemaker were slightly higher than the generally accepted therapeutic levels, they were not significantly different from lidocaine levels in patients in group I or in the third patient (Case 8) in group II. Furthermore, these concentrations did not prolong the QRS duration or H-V interval of escape complexes. Serum potassium concentration was normal in all patients and not significantly different in the two groups. Effect of lidocaine on the A-V junctional escape pacemaker: The exact site and the characteristics of the A-V junctional escape pacemaker in our patients are not known. An escape pacemaker situated in. the proximal portion of the His bundle may be suppressed by lidocaine because the electrophysiologic characteristics of pacemaker fibers in this region are similar to those of a Purkinje fiber. However, if an escape pacemaker is situated within the A-V node and is dependent on slow channel activity, l5 it may be insensitive to the therapeutic concentrations of lidocaine. The possibility that different effects of lidocaine were due to different types of escape pacemakers in patients in groups I and II is unlikely because lidocaine had no effect on the rate of the sinoatrial node, a slow channel-dependent pacemaker, and because the manner in which the escape rate decreased suggested an exit block rather than a gradual suppression of spontaneous phase 4 depolarization. In Case 10, the control escape rate was markedly slower than in the remaining patients. This finding raises the possibility that in this patient the escape pacemaker may be located more distally within the His bundle and
JUNCTIONAL PACEMAKER--KU0
AND REDDY
the marked slowing of the escape pacemaker by lidoCaine may be due to the distal location of the escape pacemaker. However, this explanation is unlikely because (1) a similar effect was also observed in Case 9 in whom the escape rate was comparable with or faster than that in many group I patients, and (2) our previous study’ has shown that lidocaine had minimal depressant effect on the automaticity of an escape pacemaker located distal to the His bundle. Effect of lidocaine on ischemic versus normal myocardium: The most likely explanation for the different effects of lidocaine on the escape pacemaker in patients in groups I and II is the selective drug effect on depolarized ischemic myocardium. Therapeutic concentrations of lidocaine do not affect conduction in normal myocardium but they slow conduction in the ischemic myocardium and decrease diastolic excitability more in the ischemic than in the normal myocardium.“*7 Because both the atrioventricular node and the proximal His-Purkinje system have a common source of blood .~upply,~~ it is reasonable to assume that the escape pacemaker or t,he surrounding myocardium, or both, had variable degrees of ischemic injury. This finding suggests that a critical depression of conduction or excitability, or both, by lidocaine in this area my result in sudden and marked decrease in the escape rate without change in the QRS duration or H-V interval as observed in our patients. The absence of significant slowing of rate of the escape pacemaker in one patient with acute myocardial infarction must be attributed to the probable absence of ischemic damage to the ectopic pacemaker and the adjacent myocardium in this patient. We believe that our observation provides the first clinical evidence in support of the concept that lidocaine has a greater depressant, effect on ischemic than on nonischemic myocardium as shown previously in animal studies.fi,7 Clinical implications: Our results may be relevant to the understanding of the mechanism of ant.iarrhythmic effects of lidocaim in human beings. LidoCaine in plasma concentrations considered therapeutic in suppressing ventricular arrhythmia apparently has no significant depressant effect on the escape pacemaker in the absence of acute myocardial infarction but inhibits escape activity in the presence of acute myocardial infarction. The differences between the effect of the drug on the acutely ischemic and the apparently nonischemic myocardium suggest that the antiarrhythmic effect of lidocaine may be due to its ability to depress conduction in ischemic myocardium rather than to improve conduction or to suppress the normal or abnormal automaticity. Further progress in the understanding of the antiarrhythmic action of lidocaine must await a better understanding of the mechanism of the arrhythmias affected by the drug. Acknowledgment We thank Borys Surawicz, MI) for his thoughtful critique of the manuscript, Linda Hrandenburg for her technical assistance and Joann Buckley for her secretarial help.
June 1981
The American
Journal
of CARDIDLDGY
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References 1. Aravindakshan V, Kuo CS, Gettes LS. Effect of lidocaine on escape rate in patients with complete at&ventricular block. A. Distal His bundle block. Am J Cardiol 1977;40: 177-83. 2. ScMrnnan Y, Desai J, Gonzalez i?, Peters I?, Thomas A, Dhdzio 8. The effect of lfdocaine on His bundle automaticity and rhythm in man (abstr). Circulation 1978;58:11- 11. 3. Sciwiag BJ, Lau 94, Hettant RH, Berkowitz WD, Stein E, Damato AN. Catheter technique for recording His bundle activity in man. Circulation 1969;39: 13-8. 4. Ghan CM, Gettes LS, Katzung BG. Effect of lidocaine and quinidine on steady state characteristics and recovery kinetics of (dV/dt) max. in guinea-pig ventricular myocardium. Circ Res 1975;37: 20-9. 5. Salto S, Chen CM, Buchanan J, Gattes LS, Lynch MR. Steady state and timedependent slowing of conduction in canine hearts. Effect of potassium and lidocaine. Circ Res 1978;42:246-54. 6. Lazzara I?, Hope RR, El-Sherit N, Schehq BJ. Effects of ltdocaina on hypoxic and ischemic cardiac cells. Am J Cardiol 1978;41: 872-9. 7. Kupersmith J. Electrophysiological and antiarrhythmic effects of lidocaine in canine acute myocardial ischemia. Am Heart J 1979;97:360-6. 8. David LD, Temle JV. Electrophysiological acttons of lidocaine on canine ventricular muscle and Purkinje fibers. Circ Res 1969;
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24:639-55. 9. B@jer JT, Man&M WJ. Effect of lidocaine on the electrophysiological properties of ventricufar muscle and Ptiinje fibers. J Clin Invest 1970;49:63-77. 10. Ryden L, Konqren M. The effect of lignocaine on the stimulation threshold and conduction disturbances in patients treated with pacemaker. Cardiovasc Ftes 1969;3:415-8. 11. Amadorf MF, Bi99er Jl. The effect of Mocaine on components of excitability in long mammalian cardiac Purkinje fibers. J Pharmacol Exp Ther 1975;195:206-15. 12. Obayaehl K, Hayakawa H, Mandei WJ. interrelationships between external potassium concentration and lidocaine effects of canine Purkinje fiber. Am Heart J 1975:89:221-6. 13. imanhihl S, McAtMster RG Jr, Suawicz B. The effects of verapamil and lidocaine on the automatic depolarizations in guinea-pig ventricular myocardium. J Pharmacol Exp Ther 1978;207:294-303. 14. Cranefield PF. Sustained rhythmic activity. In: The Conduction of the Cardiac Impulse. Chapter VI. Mount Kisco, NY: Futura, 1975:199-265. 15. Watanabe Y, Dreifus LS. Sites of impulse formation within the atrioventricular junction of the rabbit. Circ Res 1968;22:71727. 16. Frink RJ, James TN. Normal blood supply to the human His bundle and proximal bundle branches. Circulation 1973;47:8-18.
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