- Email: [email protected]
Multiple bolus technique for lidocaine administration during the first hours of an acute myocardial infarction
Multiple Bobs Technique for Lidocaine Administration During the First Hours of an Acute Myocardial Infarction
MILFORD G. WYMAN, MD, FACC DAVID LALKA, PhD LUCILLE HAMMERSMITH, RN DAVID S. CANNOM, MD, FACC BRUCE N. GOLDREYER, MD, FACC
San Pedro, California Worcester. Massachusetts
From the Department of Cardiology, San Pedro and Peninsula Hospftal, San Pedro, California and the Research Laboratories of Astra Pharmaceutical Products, Inc., Worcester, Massachusetts. Manuscript received May 10, 1977; revised manuscript received July 28, 1977, accepted August 9, 1977. Address for reprints: Milford G. Wyman, MD, 1360 West Sixth Street, Suite 120, San Pedro, California 90732.
All patients in the San Pedro and Peninsula Hospital suspected of having a myocardial infarction are routinely given an Initial bolus injection of 75 mg of lidocaine and concomitant constant infusion. Those who continue to exhibit serious ventricular ectopy are subjected to a precise treatment protocol employing 50 mg bolus injections of lidocaine every 5 minutes, if necessary, to a total of 225 mg. The clinical success of this treatment program in 1,000 consecuthre patients with acute myocardial infarction prompted more extensive study of lldocaine kinetics in 23 patients receiving ltdocaine with the multiple bolus technique. Plasma lidocaine levels were determined 1, 3 and 5 minutes after an initial 75 mg bolus injectton and afler three subsequent 50 mg bolus injections given at 5 minute intervals. The mean peak plasma concentration was 2.3 pg/ml, and no level exceeded 4.8 pg/ml. Save for a single plasma value of 1.1 fig, 5 minutes after the initial 75 mg bolus dose, the mean plasma levels were within the accepted therapeutic range at all times. The effect of clinical left ventricular failure on plasma lidocgine levels and drug distribution was examined. Although plasma levels 1 minute after the first bolus injection were 1.0 f 0.2 and 2.0 f 0.4 pg/ml (mean f standard error of the mean) in class O-l and class 11-111 heart failure, respectively (P <0.05), mean concentrations were not significantly different (P <0.2) 5 minutes after the last bolus dose. A dosage schedule employing multiple bolus injections of lidocaine every 5 minutes, if ventricular extrasystoles are not controlled, to a total of 225 mg over 16 minutes provides adequate blood levels, results in no significant toxicity and may be safely employed with excellent results in patients with infarction irrespective of the presence of moderate congestive heart failure.
When excessive ventricular ectopic activity occurs in the setting of acute myocardial infarction, lidocaine has been universally regarded as the treatment of choice for the prevention of sudden death due to primary ventricular fibrillation. Yet no commonly accepted standards exist to guide the clinician in administering lidocaine to the patient who has received the initial bolus injection and constant infusion but continues to have ventricular extrasystoles. The problem has been compounded because the effectiveness of lidocaine during the first hours after an infarction has been questioned.1-4 A protocol for the treatment of patients with acute myocardial infarction using multiple bolus injections of lidocaine when needed has been used systematically in 1,000 consecutive cases admitted to this hospital over a period of 6 years.5 A study of the pharmacokinetics of lidocaine using the multiple bolus technique in a subset of these patients has yielded new information on the relation between the dose of lidocaine and the observed plasma levels during this early phase of treatment. This report utilizes the clinical experience from 1,000 patients with acute myocardial infarction and a subset of 23 patients with plasma lidocaine determinations to provide the data base for constructing a rational ap-
Fofwuwy 1978
The American Journal of CARDIDLDGY
Volume 41
313
LIDOCAINE DOSAGE PROTOCOL-WYMAN
ET AL
TABLE I
lidocaine (2 mg/min) was begun with the initial bolus dose of 75 mg and increased by 1 mg/min after each additional bolus injection to a maximum of 4 mg/min. If lidocaine was judged ineffective then procainamide was given intravenously in the manner previously described? Of this group, 23 patients were studied 4 to 10 days after infarction in order to determine serum lidocaine levels when the protocol was followed. The investigative nature of the study was explained and informed consent obtained in each case. An intravenous catheter was placed in one arm for the administration of lidocaine and a heparin lock inserted in the other arm for venous sampling. After the initial collection of a blank sample, a bolus injection of lidocaine was given at 5 minute intervals in the following dosages: 75,50,50 and 50 mg. Each individual dose of lidocaine was given as a constant rate infusion over 60 seconds; thus a total of 225 mg of lidocaine was administered in a 16 minute period. Electrocardiographic response, cuff brachial arterial pressure, respiratory rate and central nervous system effects were monitored every 5 minutes. Venous samples to be analyzed for lidocaine concentration were obtained 1,3 and 5 minutes after the start of each infusion. Samples were also obtained 30 and 60 minutes after the last dose. Plasma lidocaine concentration was determined using a modification of the method of Keenaghan. 6
Summary of Data on 1,000 Consecutive Patients with Acute Myocardial infarction 63.9 (range 27-29)
Age (mean) W) Male (%) Female (% ) Site of infarction (%) Anterior Inferior-posterior Subendocardial (9 percent of these had left bundle branch block) Complications (%)* Ventricular tachycardia Shock Congestive failure (severe) Primary ventricular fibrillation Mortality ( % ) Coronary care unit Total in-hosoital
zt 1; 26
fz 35.3 0.6 9.0 11.0
Congestive failure (severe) = presence of extensive rales or chest. X-ray evidence of advanced congestive changes; primary ventricular fibrillation = fibrillation occurring in the absence of shock or pulrrtonaly edema; shock = systolic blood pressure of 80 mm or less for 1 or more hours accompanied by evidence of decreased peripheral perfusion and oliguria. l
Left ventricular performance was classified clinically as follows: class 0, no evidence of heart failure; class I, presence
of a third heart sound; class II, presence of a third heart sound and basilar rales without X-ray evidence of congestion, and class III, presence of a third heart sound, rales and X-ray evidence of congestive failure. None of the 23 patients had shock or pulmonary edema. Eleven of the 23 patients were in class II-III congestive failure. The mean body weight of the patients with class O-l and class II-III failure was 75.5 and 77.1 kg, respectively.
preach to treatment of patients who continue to have ventricular extrasystoles after the initial bolus dose of lidocaine. Materials
and Methods
One thousand patients with a definite myocardial infarction received lidocaine as dictated by a uniform protocol. These patients include 611 from the previous report of 19745 and 389 additional patients. If significant ventricular extrasystoles occurred after the initial 75 mg bolus injection, additional 50 mg bolus injections were given every 5 minutes if necessary to a total of 225 mg. The ventricular extrasystoles were defined as significant if they occurred on the T wave or in pairs, were multifocal or exceeded 5/min. The concomitant infusion of
Results Clinical Correlations Of the 1,000 consecutive patients with an acute myocardial infarction treated over the 6 years, 315 were seen within the first hour of their symptoms and 580 within 4 hours. Thirty percent of these 1,000 patients
I
2
4 Time
February 1978
6
8
10
12
14
I
16
18
following the start of the first injection (min)
The American Journal of CARDIOLOGY
Volume 41
20
FIGURE 1. The plasma concentration-time data (mean f standard error of the mean [SEMI) observed after administration of 225 mg of lldocaine in bolus doses every 5 minutes over a 16 mtnute period as described in the text. Cp = plasma concentration; n = number of plasma determinations at 50 and 80 minutes; figures in parentheses = number of plasma determinations at the times indicated.
LIDOCAINE DOSAGE PROTOCOL-WYMAN
required between two and four bolus injections of lidocaine as dictated by protocol. Eighteen percent did not respond to lidocaine and required procainamide. The average stay in the coronary care unit was 4.5 days. The clinical profile of these patients is outlined in Table I. Primary ventricular fibrillation was a rare event, occurring in 0.6 percent of patients. Toxic and side effects: Lidocaine toxicity was confined to the central nervous system. The multiple bolus technique used during the distributions phase of the drug resulted in minor transient central nervous system side effects in less than 20 percent of the patients. These reactions included tingling and numbness of the lips and fingers. A change in hearing perception, a buzzing sound and a feeling of drowsiness were occasionally appreciated. These effects were short-lived, lasting a few minutes and in most instances were documented only by direct questioning. In one case, the infusion was discontinued after the second bolus dose because of the patient’s marked lethargy. The plasma level at that time was 2.3 pglml. No convulsions occurred either in the subset of 23 patients or in the 1,000 patients with a proved infarction who required the multiple bolus regimen of lidocaine. Convulsions were prevented by giving the bolus no faster than 50 mg/min and by using an infusion pump during the period of continuous administration of the drug. No adverse hemodynamic or electrophysiologic effects were encountered during this period. In particular, sinus nodal depression, atrioventricular (A-V) nodal or infranodal block did not result from this technique. No variation in the protocol was made if these abnormalities existed before the injections. One half of the prescribed dosage was given in the presence of shock or pulmonary edema. Pharmacokinetics
Plasma lidocaine levels: In the 23 patients studied, the mean plasma levels of lidocaine observed after each dose are presented in Figure 1. These data show that the dosage schedule utilized yielded desirable drug levels. No plasma concentration greater than 4.8 pg/ml was observed; and this value is 20 percent below the usually accepted minimal toxic concentration of lidocaine (6 pg/ml). Furthermore, if 1.2 gg/ml is accepted as a minimal effective concentration, a patient exhibiting plasma levels 1 standard error of the mean below each mean plasma level would have a subtherapeutic plasma concentration only at the fifth minute following the first bolus. However, a patient with class O-I failure is much more likely to have a subtherapeutic plasma level at these early time points than is a patient with class II-III failure (Fig. 2). Role of heart failure: It has previously been reported that patients with heart failure (cardiac index less than 2.5 liters/min per kg and pulmonary capillary wedge pressure greater than 17 mm Hg) have a smaller initial dilution volume (V, = Dose/C,O, where C,s is the extrapolated zero time plasma concentration) than normal subjects.7 In this study, we obtained all three samples after the first infusion in 15 of the 23 subjects
10
ET AL.
E
8” 1
6t mea”
Vc=23.3
liters
mea” Vc=52.2
liters
8 2
0.2
-
0.1
1 1
3
5
Time after first Lkfocainebolus (min) FIGURE 2. The plasma concentration-time data(meanf standard error of the mean) observed after administration of the first lidocaine bolus dose (75 mg over 1 minute) in patients judged clinically to have class O-l (0) or class 11-111 (0) heart failure. T’/s = half life of the initial phase of the decline in plasma concentration. Vc = initial dilution volume.
(7 with class O-I failure and 8 with class II-III failure). Figure 2 shows that patients with failure do exhibit a substantially decreased initial dilution level (V,)* and a decreased half-life of the initial phase of the decline of plasma concentration. + These two effects tend to compensate for one another in the multiple dose situation because in both patient populations (class O-I and class II-III) the level of lidocaine is maintained well into the therapeutic range by the end of the second injection. At that time (6 minutes into the study), C, in class O-I was 1.41 pg/ml and in class II-III was 1.90 pg/ml; at the end of the second dosing interval (10 minutes into the study), these mean levels were 1.34 and ‘Rigorous correction of the 1 minute infusion data to instantaneous outputI1 was not practical because of our inability to adequately resolve the plasma concentration-time data into a biexponential equation with acceptable confidence limits. However, the use of reported values for the pharmacokinetic constants describing the biexponential decline of lidocaine plasma concentration suggests that the error in an extrapolation of the observed plasma levels back to zero time would cause about a 5 percent underestimate of V, which is considered acceptable in a practical sense. Therefore the volume terms reported in Figure 2 are slight underestimates but are useful for the comparison of values among groups with various degrees of heart failure. tThis half-time is not that of the more rapid phase (that is, the alpha phase) of the biexponential decline of plasma concentrationi but is an index of more practical importance because the value represents the time required for the initial plasma concentration of lidocaine to decrease by 50 percent.
Fobruary 1979
The American Journal of CARDIOLOGY
Volume 41
315
LIDOCAINE
DOSAGE
PROTOCOL-WYMAN
ET AL.
1.55, respectively. After subsequent doses, enough drug is accumulated to bring plasma concentration further into the therapeutic range but still not close to the range where significant toxicity should be anticipated. For these reasons, a dosing scheme of the type reported here may be superior to those that rely upon a single bolus injection of lidocaine to achieve desired plasma levels. Discussion
Is lidocaine effective?: Although lidocaine is almost universally used for the treatment of ventricular arrhythmias in acute myocardial infarction, no clear-cut guidelines have been defined for its use in the patient who has recently sustained an infarction yet continues to have ectopic ventricular rhythms after the initial bolus dose and constant infusion of lidocaine. Various investigations1p4 have, in fact, suggested that lidocaine is ineffective against ectopic ventricular beats that occur during the first hours after infarction. A careful review of these studies reveals two unifying factors. First, the doses used were small to moderate and no blood level data were obtained from any subjects. Second, in the absence of blood level data or an indication of drugrelated toxicity it seems difficult to determine if lidoCaine is an inadequate antiarrhythmic agent or if the doses utilized were too small to achieve efficacious plasma levels in the majority of subjects in the study populations.8 Pharmacokinetics of lidocaine and clinical effects: Lidocaine is frequently used with little appreciation of the difference between the half-life during the distribution and elimination phases of the plasma concentration-time curve. When a 75 mg bolus dose of the lidocaine is injected into a peripheral vein, the drug rapidly distributes between the plasma and highly perfused tissues such as brain, lung, liver, heart and kidneys. The concentration in these organs reaches a maximum very quickly.7 The rapid decline in plasma concentration seen in Figures 1 and 2 reflects principally the distribution of drug between these highly perfused tissues and other tissues such as muscle and fat. On the basis of previously published data,7 the half-life of lidocaine plasma concentration during this initial time period can be calculated to be 7.3 minutes in patients with heart failure and about 8.3 minutes in normal volunteers.* In our study the half-life of lidocaine after the first bolus dose was approximately 8 minutes in patients with class O-I failure but only 4 minutes in those with class II-III failure. The reason for our more rapid decline of plasma levels is unclear. However, all of these data strongly suggest that the clinical effect of a single bolus dose may last no longer than a few minutes. The slower phase of lidocaine disposition kinetics l
See preceding
footnote.
(that is, the elimination phase) depends upon other factors such as the overall volume of distribution of the drug and physiologic variables such as the rate of blood flow to the liver.g The half-life during this phase is approximately 90 minutes, and pharmacokinetic theory predicts that it would require 5 to 7 hours of constant rate infusion of lidocaine for the plasma concentration to approach a plateau (a time when drug input equals the rate of elimination). These two pharmacokinetic principles, the short half-life of the distribution phase and the 5 to 7 hours required to approach a plateau plasma concentration with use of constant rate infusion, could explain why some studies may have erroneously concluded that lidocaine is ineffective against ventricular ectopic activity during the first hours after infarction. Too little lidocaine has been used by the wrong method. Too often either a single bolus dose is given or alterations of the infusion rate are attempted. The former technique results in rapid distribution of the drug and consequently an inadequate blood level, whereas the latter has its effect hours later than clinically necessary. It should also be apparent that the constant infusion accompanying the initial bolus dose exerts little protective effect if ventricular extrasystoles recur within an hour after the initial dose because at the usual infusion rate of 2 mg/min only 120 mg of additional lidocaine would have been infused during the first hour. The data in our cases indicate that 225 mg given in 16 minutes results in plasma levels significantly below toxic concentrations. Specifically, the mean plasma level at the end of the last infusion was only 2.3 pg/ml. Therapeutic implications: In the earliest stage of acute myocardial infarction the multiple bolus technique is a safe effective method of providing minimal effective blood levels tailored to each patient’s needs.‘O This is shown by an incidence of primary ventricular fibrillation of less than 1 percent. Although large dose constant infusions may result in comparable blood levels with less variation, the technique does not allow for the patient whose ventricular extrasystoles will respond to a blood concentration of lidocaine lower than the so-called effective level. Although our data confirm the observation that the initial dilution volume of lidocaine is decreased in patients with congestive failure, toxic plasma levels were not reached even in the 11 patients with moderately severe congestive failure. For patients with shock or pulmonary edema we will continue to give one-half the dose outlined in this report until further data are available. Our study has demonstrated that 225 mg of lidocaine can be given safely in divided doses over a 16 minute period to patients with acute myocardial infarction. Despite a moderate degree of congestive failure in some patients, no toxicity occurred with this protocol.
References 1. Doubts about lignocaine. Br Med J 1:473-474, 1975 Chopra MP, Thadani U, Portal RW, et al: Lignocaine therapy for ventricular ectopic activity after acute myocardial infarction: a double-blind trial. Br Med J 3:888-870, 1971
2.
316
February 1976
The American Journal of CARDIOLOGY
3. Darby S, Cruickshank JC, Bennett MA, et al: Trial of combined intramuscular and intravenous lignocaine in prophylaxis of ventricular tachyarrhythmias. Lancet 1: 817-819, 1972 4. Pantridge JF: Emergency treatment of cardiac arrhythmias in
Volume 41
LIDOCAINE
5.
8.
7.
8.
myocardial infarction. In, Lidocaine in the Treatment of Ventricular Arrhythmias (Scott DB, Julian DG, ed). Edinburgh, Livingstone, 1971, p 77-81 Wyman ffi, Hammersmith L: Comprehensive treatment plan for the prevention of primary ventricular fibrillation in acute myocardial infarction. Am J Cardiol 33:881-667. 1974 Keenaghan JB: The determination of lidocaine and prilocaine in whole blood by gas chromatography. Anesthesiology 29: 110-l 12, 1969 Thomson PD, Melmon KL, Richardson JA, et al: Lidocaine pharmacokinetics in advanced heart failure, liver disease, and renal failure in humans. Ann Intern Med 78:499-508, 1973 Alderman EL, Kerber RE, Harrison DC: Evaluation of lidocaine
February
9.
10.
11.
12.
1978
DOSAGE PROTOCOL-WYMAN
ET AL.
resistance in man using intermittent largedose infusion techniques. Am J Cardiol 34:342-349, 1974 Stenson RE, Conatantlno RT, Harrlson DC: Interrelationships of hepatic blood flow, cardiac output, and blood levels of lidocaine in man. Circulation 43:205-211, 1971 Goldreyer BN, Wyman MC%The effect of first hour hospitalization in myocardial infarction (abstr). Circulation 5O:Suppl lll:lll-120, 1974 Loo JCK, Rlegelman S: Assessment of pharmacokinetic constants from post-infusion blood curves obtained after intravenous infusion. J Pharm Sci 5953-55, 1970 Greenblatt DJ, Koch-Weser J: Clinical pharmacokinetics. N Engl J Med 293:702-705, 1975
The Amrloan
Journal of CARDtDLDGY
Volume 41
317
MILFORD G. WYMAN, MD, FACC DAVID LALKA, PhD LUCILLE HAMMERSMITH, RN DAVID S. CANNOM, MD, FACC BRUCE N. GOLDREYER, MD, FACC
San Pedro, California Worcester. Massachusetts
From the Department of Cardiology, San Pedro and Peninsula Hospftal, San Pedro, California and the Research Laboratories of Astra Pharmaceutical Products, Inc., Worcester, Massachusetts. Manuscript received May 10, 1977; revised manuscript received July 28, 1977, accepted August 9, 1977. Address for reprints: Milford G. Wyman, MD, 1360 West Sixth Street, Suite 120, San Pedro, California 90732.
All patients in the San Pedro and Peninsula Hospital suspected of having a myocardial infarction are routinely given an Initial bolus injection of 75 mg of lidocaine and concomitant constant infusion. Those who continue to exhibit serious ventricular ectopy are subjected to a precise treatment protocol employing 50 mg bolus injections of lidocaine every 5 minutes, if necessary, to a total of 225 mg. The clinical success of this treatment program in 1,000 consecuthre patients with acute myocardial infarction prompted more extensive study of lldocaine kinetics in 23 patients receiving ltdocaine with the multiple bolus technique. Plasma lidocaine levels were determined 1, 3 and 5 minutes after an initial 75 mg bolus injectton and afler three subsequent 50 mg bolus injections given at 5 minute intervals. The mean peak plasma concentration was 2.3 pg/ml, and no level exceeded 4.8 pg/ml. Save for a single plasma value of 1.1 fig, 5 minutes after the initial 75 mg bolus dose, the mean plasma levels were within the accepted therapeutic range at all times. The effect of clinical left ventricular failure on plasma lidocgine levels and drug distribution was examined. Although plasma levels 1 minute after the first bolus injection were 1.0 f 0.2 and 2.0 f 0.4 pg/ml (mean f standard error of the mean) in class O-l and class 11-111 heart failure, respectively (P <0.05), mean concentrations were not significantly different (P <0.2) 5 minutes after the last bolus dose. A dosage schedule employing multiple bolus injections of lidocaine every 5 minutes, if ventricular extrasystoles are not controlled, to a total of 225 mg over 16 minutes provides adequate blood levels, results in no significant toxicity and may be safely employed with excellent results in patients with infarction irrespective of the presence of moderate congestive heart failure.
When excessive ventricular ectopic activity occurs in the setting of acute myocardial infarction, lidocaine has been universally regarded as the treatment of choice for the prevention of sudden death due to primary ventricular fibrillation. Yet no commonly accepted standards exist to guide the clinician in administering lidocaine to the patient who has received the initial bolus injection and constant infusion but continues to have ventricular extrasystoles. The problem has been compounded because the effectiveness of lidocaine during the first hours after an infarction has been questioned.1-4 A protocol for the treatment of patients with acute myocardial infarction using multiple bolus injections of lidocaine when needed has been used systematically in 1,000 consecutive cases admitted to this hospital over a period of 6 years.5 A study of the pharmacokinetics of lidocaine using the multiple bolus technique in a subset of these patients has yielded new information on the relation between the dose of lidocaine and the observed plasma levels during this early phase of treatment. This report utilizes the clinical experience from 1,000 patients with acute myocardial infarction and a subset of 23 patients with plasma lidocaine determinations to provide the data base for constructing a rational ap-
Fofwuwy 1978
The American Journal of CARDIDLDGY
Volume 41
313
LIDOCAINE DOSAGE PROTOCOL-WYMAN
ET AL
TABLE I
lidocaine (2 mg/min) was begun with the initial bolus dose of 75 mg and increased by 1 mg/min after each additional bolus injection to a maximum of 4 mg/min. If lidocaine was judged ineffective then procainamide was given intravenously in the manner previously described? Of this group, 23 patients were studied 4 to 10 days after infarction in order to determine serum lidocaine levels when the protocol was followed. The investigative nature of the study was explained and informed consent obtained in each case. An intravenous catheter was placed in one arm for the administration of lidocaine and a heparin lock inserted in the other arm for venous sampling. After the initial collection of a blank sample, a bolus injection of lidocaine was given at 5 minute intervals in the following dosages: 75,50,50 and 50 mg. Each individual dose of lidocaine was given as a constant rate infusion over 60 seconds; thus a total of 225 mg of lidocaine was administered in a 16 minute period. Electrocardiographic response, cuff brachial arterial pressure, respiratory rate and central nervous system effects were monitored every 5 minutes. Venous samples to be analyzed for lidocaine concentration were obtained 1,3 and 5 minutes after the start of each infusion. Samples were also obtained 30 and 60 minutes after the last dose. Plasma lidocaine concentration was determined using a modification of the method of Keenaghan. 6
Summary of Data on 1,000 Consecutive Patients with Acute Myocardial infarction 63.9 (range 27-29)
Age (mean) W) Male (%) Female (% ) Site of infarction (%) Anterior Inferior-posterior Subendocardial (9 percent of these had left bundle branch block) Complications (%)* Ventricular tachycardia Shock Congestive failure (severe) Primary ventricular fibrillation Mortality ( % ) Coronary care unit Total in-hosoital
zt 1; 26
fz 35.3 0.6 9.0 11.0
Congestive failure (severe) = presence of extensive rales or chest. X-ray evidence of advanced congestive changes; primary ventricular fibrillation = fibrillation occurring in the absence of shock or pulrrtonaly edema; shock = systolic blood pressure of 80 mm or less for 1 or more hours accompanied by evidence of decreased peripheral perfusion and oliguria. l
Left ventricular performance was classified clinically as follows: class 0, no evidence of heart failure; class I, presence
of a third heart sound; class II, presence of a third heart sound and basilar rales without X-ray evidence of congestion, and class III, presence of a third heart sound, rales and X-ray evidence of congestive failure. None of the 23 patients had shock or pulmonary edema. Eleven of the 23 patients were in class II-III congestive failure. The mean body weight of the patients with class O-l and class II-III failure was 75.5 and 77.1 kg, respectively.
preach to treatment of patients who continue to have ventricular extrasystoles after the initial bolus dose of lidocaine. Materials
and Methods
One thousand patients with a definite myocardial infarction received lidocaine as dictated by a uniform protocol. These patients include 611 from the previous report of 19745 and 389 additional patients. If significant ventricular extrasystoles occurred after the initial 75 mg bolus injection, additional 50 mg bolus injections were given every 5 minutes if necessary to a total of 225 mg. The ventricular extrasystoles were defined as significant if they occurred on the T wave or in pairs, were multifocal or exceeded 5/min. The concomitant infusion of
Results Clinical Correlations Of the 1,000 consecutive patients with an acute myocardial infarction treated over the 6 years, 315 were seen within the first hour of their symptoms and 580 within 4 hours. Thirty percent of these 1,000 patients
I
2
4 Time
February 1978
6
8
10
12
14
I
16
18
following the start of the first injection (min)
The American Journal of CARDIOLOGY
Volume 41
20
FIGURE 1. The plasma concentration-time data (mean f standard error of the mean [SEMI) observed after administration of 225 mg of lldocaine in bolus doses every 5 minutes over a 16 mtnute period as described in the text. Cp = plasma concentration; n = number of plasma determinations at 50 and 80 minutes; figures in parentheses = number of plasma determinations at the times indicated.
LIDOCAINE DOSAGE PROTOCOL-WYMAN
required between two and four bolus injections of lidocaine as dictated by protocol. Eighteen percent did not respond to lidocaine and required procainamide. The average stay in the coronary care unit was 4.5 days. The clinical profile of these patients is outlined in Table I. Primary ventricular fibrillation was a rare event, occurring in 0.6 percent of patients. Toxic and side effects: Lidocaine toxicity was confined to the central nervous system. The multiple bolus technique used during the distributions phase of the drug resulted in minor transient central nervous system side effects in less than 20 percent of the patients. These reactions included tingling and numbness of the lips and fingers. A change in hearing perception, a buzzing sound and a feeling of drowsiness were occasionally appreciated. These effects were short-lived, lasting a few minutes and in most instances were documented only by direct questioning. In one case, the infusion was discontinued after the second bolus dose because of the patient’s marked lethargy. The plasma level at that time was 2.3 pglml. No convulsions occurred either in the subset of 23 patients or in the 1,000 patients with a proved infarction who required the multiple bolus regimen of lidocaine. Convulsions were prevented by giving the bolus no faster than 50 mg/min and by using an infusion pump during the period of continuous administration of the drug. No adverse hemodynamic or electrophysiologic effects were encountered during this period. In particular, sinus nodal depression, atrioventricular (A-V) nodal or infranodal block did not result from this technique. No variation in the protocol was made if these abnormalities existed before the injections. One half of the prescribed dosage was given in the presence of shock or pulmonary edema. Pharmacokinetics
Plasma lidocaine levels: In the 23 patients studied, the mean plasma levels of lidocaine observed after each dose are presented in Figure 1. These data show that the dosage schedule utilized yielded desirable drug levels. No plasma concentration greater than 4.8 pg/ml was observed; and this value is 20 percent below the usually accepted minimal toxic concentration of lidocaine (6 pg/ml). Furthermore, if 1.2 gg/ml is accepted as a minimal effective concentration, a patient exhibiting plasma levels 1 standard error of the mean below each mean plasma level would have a subtherapeutic plasma concentration only at the fifth minute following the first bolus. However, a patient with class O-I failure is much more likely to have a subtherapeutic plasma level at these early time points than is a patient with class II-III failure (Fig. 2). Role of heart failure: It has previously been reported that patients with heart failure (cardiac index less than 2.5 liters/min per kg and pulmonary capillary wedge pressure greater than 17 mm Hg) have a smaller initial dilution volume (V, = Dose/C,O, where C,s is the extrapolated zero time plasma concentration) than normal subjects.7 In this study, we obtained all three samples after the first infusion in 15 of the 23 subjects
10
ET AL.
E
8” 1
6t mea”
Vc=23.3
liters
mea” Vc=52.2
liters
8 2
0.2
-
0.1
1 1
3
5
Time after first Lkfocainebolus (min) FIGURE 2. The plasma concentration-time data(meanf standard error of the mean) observed after administration of the first lidocaine bolus dose (75 mg over 1 minute) in patients judged clinically to have class O-l (0) or class 11-111 (0) heart failure. T’/s = half life of the initial phase of the decline in plasma concentration. Vc = initial dilution volume.
(7 with class O-I failure and 8 with class II-III failure). Figure 2 shows that patients with failure do exhibit a substantially decreased initial dilution level (V,)* and a decreased half-life of the initial phase of the decline of plasma concentration. + These two effects tend to compensate for one another in the multiple dose situation because in both patient populations (class O-I and class II-III) the level of lidocaine is maintained well into the therapeutic range by the end of the second injection. At that time (6 minutes into the study), C, in class O-I was 1.41 pg/ml and in class II-III was 1.90 pg/ml; at the end of the second dosing interval (10 minutes into the study), these mean levels were 1.34 and ‘Rigorous correction of the 1 minute infusion data to instantaneous outputI1 was not practical because of our inability to adequately resolve the plasma concentration-time data into a biexponential equation with acceptable confidence limits. However, the use of reported values for the pharmacokinetic constants describing the biexponential decline of lidocaine plasma concentration suggests that the error in an extrapolation of the observed plasma levels back to zero time would cause about a 5 percent underestimate of V, which is considered acceptable in a practical sense. Therefore the volume terms reported in Figure 2 are slight underestimates but are useful for the comparison of values among groups with various degrees of heart failure. tThis half-time is not that of the more rapid phase (that is, the alpha phase) of the biexponential decline of plasma concentrationi but is an index of more practical importance because the value represents the time required for the initial plasma concentration of lidocaine to decrease by 50 percent.
Fobruary 1979
The American Journal of CARDIOLOGY
Volume 41
315
LIDOCAINE
DOSAGE
PROTOCOL-WYMAN
ET AL.
1.55, respectively. After subsequent doses, enough drug is accumulated to bring plasma concentration further into the therapeutic range but still not close to the range where significant toxicity should be anticipated. For these reasons, a dosing scheme of the type reported here may be superior to those that rely upon a single bolus injection of lidocaine to achieve desired plasma levels. Discussion
Is lidocaine effective?: Although lidocaine is almost universally used for the treatment of ventricular arrhythmias in acute myocardial infarction, no clear-cut guidelines have been defined for its use in the patient who has recently sustained an infarction yet continues to have ectopic ventricular rhythms after the initial bolus dose and constant infusion of lidocaine. Various investigations1p4 have, in fact, suggested that lidocaine is ineffective against ectopic ventricular beats that occur during the first hours after infarction. A careful review of these studies reveals two unifying factors. First, the doses used were small to moderate and no blood level data were obtained from any subjects. Second, in the absence of blood level data or an indication of drugrelated toxicity it seems difficult to determine if lidoCaine is an inadequate antiarrhythmic agent or if the doses utilized were too small to achieve efficacious plasma levels in the majority of subjects in the study populations.8 Pharmacokinetics of lidocaine and clinical effects: Lidocaine is frequently used with little appreciation of the difference between the half-life during the distribution and elimination phases of the plasma concentration-time curve. When a 75 mg bolus dose of the lidocaine is injected into a peripheral vein, the drug rapidly distributes between the plasma and highly perfused tissues such as brain, lung, liver, heart and kidneys. The concentration in these organs reaches a maximum very quickly.7 The rapid decline in plasma concentration seen in Figures 1 and 2 reflects principally the distribution of drug between these highly perfused tissues and other tissues such as muscle and fat. On the basis of previously published data,7 the half-life of lidocaine plasma concentration during this initial time period can be calculated to be 7.3 minutes in patients with heart failure and about 8.3 minutes in normal volunteers.* In our study the half-life of lidocaine after the first bolus dose was approximately 8 minutes in patients with class O-I failure but only 4 minutes in those with class II-III failure. The reason for our more rapid decline of plasma levels is unclear. However, all of these data strongly suggest that the clinical effect of a single bolus dose may last no longer than a few minutes. The slower phase of lidocaine disposition kinetics l
See preceding
footnote.
(that is, the elimination phase) depends upon other factors such as the overall volume of distribution of the drug and physiologic variables such as the rate of blood flow to the liver.g The half-life during this phase is approximately 90 minutes, and pharmacokinetic theory predicts that it would require 5 to 7 hours of constant rate infusion of lidocaine for the plasma concentration to approach a plateau (a time when drug input equals the rate of elimination). These two pharmacokinetic principles, the short half-life of the distribution phase and the 5 to 7 hours required to approach a plateau plasma concentration with use of constant rate infusion, could explain why some studies may have erroneously concluded that lidocaine is ineffective against ventricular ectopic activity during the first hours after infarction. Too little lidocaine has been used by the wrong method. Too often either a single bolus dose is given or alterations of the infusion rate are attempted. The former technique results in rapid distribution of the drug and consequently an inadequate blood level, whereas the latter has its effect hours later than clinically necessary. It should also be apparent that the constant infusion accompanying the initial bolus dose exerts little protective effect if ventricular extrasystoles recur within an hour after the initial dose because at the usual infusion rate of 2 mg/min only 120 mg of additional lidocaine would have been infused during the first hour. The data in our cases indicate that 225 mg given in 16 minutes results in plasma levels significantly below toxic concentrations. Specifically, the mean plasma level at the end of the last infusion was only 2.3 pg/ml. Therapeutic implications: In the earliest stage of acute myocardial infarction the multiple bolus technique is a safe effective method of providing minimal effective blood levels tailored to each patient’s needs.‘O This is shown by an incidence of primary ventricular fibrillation of less than 1 percent. Although large dose constant infusions may result in comparable blood levels with less variation, the technique does not allow for the patient whose ventricular extrasystoles will respond to a blood concentration of lidocaine lower than the so-called effective level. Although our data confirm the observation that the initial dilution volume of lidocaine is decreased in patients with congestive failure, toxic plasma levels were not reached even in the 11 patients with moderately severe congestive failure. For patients with shock or pulmonary edema we will continue to give one-half the dose outlined in this report until further data are available. Our study has demonstrated that 225 mg of lidocaine can be given safely in divided doses over a 16 minute period to patients with acute myocardial infarction. Despite a moderate degree of congestive failure in some patients, no toxicity occurred with this protocol.
References 1. Doubts about lignocaine. Br Med J 1:473-474, 1975 Chopra MP, Thadani U, Portal RW, et al: Lignocaine therapy for ventricular ectopic activity after acute myocardial infarction: a double-blind trial. Br Med J 3:888-870, 1971
2.
316
February 1976
The American Journal of CARDIOLOGY
3. Darby S, Cruickshank JC, Bennett MA, et al: Trial of combined intramuscular and intravenous lignocaine in prophylaxis of ventricular tachyarrhythmias. Lancet 1: 817-819, 1972 4. Pantridge JF: Emergency treatment of cardiac arrhythmias in
Volume 41
LIDOCAINE
5.
8.
7.
8.
myocardial infarction. In, Lidocaine in the Treatment of Ventricular Arrhythmias (Scott DB, Julian DG, ed). Edinburgh, Livingstone, 1971, p 77-81 Wyman ffi, Hammersmith L: Comprehensive treatment plan for the prevention of primary ventricular fibrillation in acute myocardial infarction. Am J Cardiol 33:881-667. 1974 Keenaghan JB: The determination of lidocaine and prilocaine in whole blood by gas chromatography. Anesthesiology 29: 110-l 12, 1969 Thomson PD, Melmon KL, Richardson JA, et al: Lidocaine pharmacokinetics in advanced heart failure, liver disease, and renal failure in humans. Ann Intern Med 78:499-508, 1973 Alderman EL, Kerber RE, Harrison DC: Evaluation of lidocaine
February
9.
10.
11.
12.
1978
DOSAGE PROTOCOL-WYMAN
ET AL.
resistance in man using intermittent largedose infusion techniques. Am J Cardiol 34:342-349, 1974 Stenson RE, Conatantlno RT, Harrlson DC: Interrelationships of hepatic blood flow, cardiac output, and blood levels of lidocaine in man. Circulation 43:205-211, 1971 Goldreyer BN, Wyman MC%The effect of first hour hospitalization in myocardial infarction (abstr). Circulation 5O:Suppl lll:lll-120, 1974 Loo JCK, Rlegelman S: Assessment of pharmacokinetic constants from post-infusion blood curves obtained after intravenous infusion. J Pharm Sci 5953-55, 1970 Greenblatt DJ, Koch-Weser J: Clinical pharmacokinetics. N Engl J Med 293:702-705, 1975
The Amrloan
Journal of CARDtDLDGY
Volume 41
317