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Blood levels of lidocaine after various infusion rates in patients with acute myocardial infarction
Blood levels of lidocaine after various rates in patients with acute myocardial
infusion infarction
Lars Ryde’n Anders Waldenstrom Ylva Winsnes* Btirje Grtengren* GBteborg, Sweden
Intravenous lidocaine is one of the most commonly used modes of treatment for ventricular tachyarrhythmias complicating acute myocardial infarction. Although very potent, lidocaine has been claimed ineffective in up to 20 per cent of patients.‘J In intravenous lidocaine treatment, a bolus injection of about 1 mg. per kilogram of body weight directly followed by a continuous infusion of 2 mg. per minute has been recommended.2 Different studies have shown that lidoCaine in this dosage regimen has an antiarrhythmic effect on ventricular tachyarrhythmias complicating acute myocardial infarction.3p4However, Ryde’n and co-workers5 found that this amount of the drug resulted in astonishingly low blood levels during the first three hours following the start of therapy. One explanation for therapeutic failure with lidocaine might be that commonly used amounts of the drug are too small to give a blood concentration within the therapeutic range. To enable further conclusions concerning a reasonable dosage regimen, blood levels of lidocaine were determined following an infusion of 4 mg. per minute in a group of patients with acute myocardial infarction. These blood levels were then compared with those obtained when infusing 2 mg. per minute. Materials
and methods
The study was performed in patients admitted to a coronary-care unit. Only patients that subseFrom the Sjukhuset, Received Reprint Clinic *Address: S6dertiilje,
470
Department Gateborg,
of Cardiology, Sweden.
for publication
May
Clinic
I, Sahlgrenska
Results
28, 1974.
requests: Dr. Lam Ryd&, I, Sahlgrenska Sjukhuset, ASTRA Research Sweden.
Medical
and
Department of Cardiology, S-413 45 Gateborg, Sweden. Development
Laboratories,
Medical S-151
quently fulfilled the World Health Organization (WHO) criteria@ for acute myocardial infarction were included. All patients had defined ventricular tachyarrhythmias which, in accordance with the routine in the coronary-care unit, indicated lidocaine treatment.7 Intravenous lidocaine (Astra, Sodertalje, Sweden) was administered as a bolus injection of 75 mg. during two minutes immediately followed by an infusion of 2 or 4 mg. per minute, respectively. The infusion rate was kept constant by means of an infusion pump (Perfusor, Braun, Melsungen, West Germany). A two per cent lidocaine solution was used. The infusion was given into an arm vein through a short polyethylene cannula. The 2 mg. per minute group has previously been described6 and was studied for three hours. The 4 mg. per minute group was closely supervised as regards possible side effects for 24 hours. Venous blood samples from the contralateral arm were taken at 15, 30, 60, 120, and 180 minutes after the start of the injection. The blood was frozen at -16” C. and sent to the Astra Laboratories, Siidertalje, Sweden, for lidocaine determinations. A gas chromatographic method was used.8zgLidoCaine levels were expressed as lidocaine base, micrograms per milliliter of whole blood. During the study, serum concentrations of glutamic oxaloacetic transaminase, bilirubin, and creatinine were determined. Statistical comparisons were made using Chisquare test and Student’s t-test.
85
A total of 41 patients were included in the investigation of whom 16 belonged to the 2 mg. per minute and 25 to the 4 mg. per minute group. Pertinent data concerning the patients are preApril,
1975, Vol. 89, No. 4, pp. 470-473
Blood
sented in Table I and, as may be seen, there are no significant differences between the two groups concerning their clinical comparability. Blood levels of lidocaine are presented in Fig. 1. The 4 mg. per minute group had significantly higher blood levels after only 15 minutes. In the 2 mg. per minute group, lidocaine in the blood reached or exceeded 1.2 wg per milliliter at 120 minutes after the injection in three patients only and at 180 minutes in as few as seven patients. In the 4 mg. per minute group, the mean blood level of lidocaine exceeded 1.2 kg per milliliter at 30 minutes and after 180 minutes all patients had blood levels exceeding 1.2 pg per milliliter. The highest individual blood level during the first three hours after injection was 4.7 pg per milliliter which was observed in one of the 4 mg. per minute patients at 180 minutes. Side effects. Some of the patients in both groups experienced slight dizziness immediately following the bolus injection. Apart from this, no patient in either group experienced any discomfort that could be ascribed to lidocaine during the first three hours. Concerning the 2 mg. per minute group, it was impossible to make any statements concerning side effects after that period since close observation ended at that time. During the time of study (24 hours) the 4 mg. per minute infusion was stopped in 10 cases for the following reasons: in one case the cause was therapeutic failure and in two cases, technical problems with the infusion pump. In two cases, lidocaine side effects were suspected (hypotension and impaired consciousness, respectively). In these cases, the subsequent events, however, did not confirm these suspicions. In five cases, lidoCaine side effects were probable. These patients were withdrawn at 260 minutes because of impaired consciousness (lidocaine in blood 2.1 Fg per milliliter), at 780 minutes because of nausea (5.2 pg per milliliter), at 920 minutes because of blurred vision (3.2 pg per milliliter), at 280 minutes because of hypotension, and at 650 minutes because of nausea. The blood concentrations of lidocaine were not available for the last two cases. Discussion
In intravenous lidocaine treatment, a plasma level of 1.2 Fg per milliliter has been considered the lowest effective therapeutic level.‘O A widely recommended dosage regimen is a bolus injection of about 1 mg. per kilogram of body weight American
Heart Journal
Table
lru~~ls
of lidocaine
I. Selected data from the two groups of pa-
tients --
-----
__-
2 mg.lmin. in = 181 NO.
4 mg.lmin. in = 2.5) No.
16 2
20 5
1 2 6 7 2
1 1 14 8 1
11 4 3
10 11 4
12 3
20 3 2
Sex: Male Female Age: 30-39 years 40-49 years 50-59 years 60-69 years 70-79 years Site of infarction: Anterior Posterior Uncertain Previous infarction: 0 1 22
:i
Previous heart failure: Yes 6 No 12 Left heart failure day of study: Yes 6 No 12 Blood pressure (Mean + S. E. M.): Systolic 144 * 4.7 Diastolic 89 + 3.4 SGOT maximum (normal ~20): 520 1 21-100 11 101-200 3 >200 3 Creatinine, mg./lOO ml. (normal s 1.2): 51.2 16 > 1.2 2 Bilirubin, mg.1100 ml. (normal s 1.21: s1.2 38 j1.2 0
5 20 2 23 138 + 4.9 88 + 2.8 0 11 11 2 21 3 21 3
directly followed by a continuous infusion of 2 mg. per minute. With this intravenous dosage schedule, it has been claimed that lidocaine blood levels above 1.2 pg per milliliter should be reached at about 20 minutes. This statement is based upon results of normal volunteer subjects with the assumption that the distribution volume for lidocaine in patients with acute myocardial infarction is about half that of normal subjects.2J1 The astonishingly low lidocaine blood levels reached in the present 2 mg. per minute group with acute myocardial infarction do not confirm this. One explanation might be lack of agreement 471
Ryd6n et al.
Time
(minutes)
Fig. 1. Blood levels of lidocaine base after intravenous administration of a 75 mg. bolus injection followed by an infusion of 2 mg. per minute and 4 mg. per minute. Mean level of the group + S.E.M.
concerning the method of expressing lidocaine levels and differences caused by determination of lidocaine in plasma or whole blood. Such divergences are, however, insufficient to explain the entire differences.5 Another and more probable explanation for the relatively low blood levels of lidocaine in the 2 mg. per minute group is that the volume of distribution and the rate of metabolic degradation of lidocaine in patients with acute myocardial infarction are more equal to that of normal persons than has been suggested. The results in the 4 mg. per minute group confirm this hypothesis as the blood levels are in agreement with previous results from normal subjects. It is known that cardiac insufficiency as well as impaired hepatic function may be followed by higher lidocaine blood levels.12J3 The patients in both groups were in a relatively good circulatory condition despite their acute myocardial infarction and defined arrhythmias. There is no reason to believe that the present patient material in this respect differs from what is usual in coronary-care units. Although limited, the data in the present study suggest that side effects of lidocaine are not necessarily associated only with high blood levels. Strong and Atkinson14 reported an investigation
472
in which patients with suspected side effects from lidocaine had normal or low plasma levels of the drug, but high levels of metabolites. That this might be an important factor for side effects has earlier also been suggested by Boyes and coworkers.” It must be remembered how difficult it is to differentiate between true side effects and symptoms derived from the acute myocardial infarction per se, as these symptoms are very often of the same type as the side effects. The symptoms of side effects during the 4 mg. per minute infusion disappeared rapidly after stopping the infusion. In the present, closely supervised patient material, lidocaine infusion was stopped immediately after the onset of symptoms. The concentration of lidocaine and/or metabolites at that time might be very near the toxic level for that patient and stopping the infusion then could cause a fairly rapid decrease below the toxic level. This need not be contradictory to the known half-life of lidocaine in blood at steadystate kinetics.15 Even considering a probably somewhat higher risk of side effects, it seems justified to increase the routinely recommended infusion rate of lidoCaine to patients with acute myocardial infarction but without obvious signs of cardiac or April, 1975, Vol. 89, No. 4
Blood
hepatic failure. Our suggestion is to use 1 mg. per kilogram of body weight as a bolus injection directly followed by 4 mg. per minute for at least three hours. An initially high infusion rate has also been suggested by Bassan and co-workers,16 who in a recent study showed that there is a slow increase in levels of lidocaine following a continous infusion with a steady-state level after only 10 hours. In patients with obvious cardiac or hepatic failure the dose in the future, as at present, must be balanced according to the clinical condition of the patient.
REFERENCES 1.
2. 3. 4. 5.
Summary
Blood levels of lidocaine were estimated following two different infusion rates in patients with acute myocardial infarction. Forty-one patients received lidocaine as a bolus injection of 75 mg. directly followed by an infusion. The infusion rate was, in 16 patients, 2 mg. per minute and in 25 patients, 4 mg. per minute. Blood levels of lidoCaine were determined at different times up to 180 minutes after the start of drug administration. The levels in the 2 mg. per minute group were lower than had been expected and the mean level It S.E. was, after three hours, only 1.1 pg per milliliter. Many of the 2 mg. per minute patients did not, during the time period observed, reach 1.2 pg per milliliter, which has been considered as the lowest effective therapeutic level. In the 4 mg. per minute group, mean level of lidoCaine already at 15 minutes was significantly higher than in the 2 mg. per minute group Cl,1 f 0.14 and 0.6 + 0.05, respectively; p ( 0.05). After three hours, the mean blood level in the 4 mg. per minute group was 2.6 pg per milliliter. Although the blood levels were not followed after three hours, a careful observation did not reveal any severe toxic effects in the 4 mg. per minute group during next 21 hours. In five cases, however, lidoCaine side effects were probable. These symptoms disappeared rapidly after cessation of the infusion. In order to reach therapeutic blood levels of lidocaine within a reasonable time, the infusion rate of 4 mg. per minute is recommended at least for the first three hours.
American
Heart Journal
levrls of lidocaine
6.
Bigger, J. T., and Heissenbuttel, R. H.. The use of procaine amide and lidocaine in the treatment of cardiac arrhythmias, Progr. Cardiovasc. Dis. 11:515, 1969. Harrison. D. C.. and Alderman, E. L.: The oharmacoloav and clinical use of lidocaine as an antiarrhythmic drug, Mod. Treat. 9139, 1972. Mogensen, L.: Ventricular tachyarrhythmias and lignoCaine prophylaxis in acute myocardial infarction Acta Med. !&and. 188:513, Pitt, A., Lipp, H., and Anderson, S. T.: Lignocaine given prophylactically to patients with acute myocardial infarction, Lancet 1:612, 19’71. Ryden, L., Waldenstr6m, A., Ehn, L., Holmberg, S., and Husaini, M.: Comparison between effectiveness of intramuscular and intravenous lignocaine on ventricular arrhythmia complicating acute myocardial infarction, Br. Heart J. 35:1124, 1973. World Health Organization. Report: lschaemic Heart Disease Register (EURO 5010 (4) Copenhagen, 1970, pp.
32-33. 7. Henning, 8.
9.
10.
11.
12.
13.
14.
15.
16.
R., and Holmberg, S.: Erfarenheter fran Sahlgrenska sjukhusets hjiirtinfarktavdelning, Lakartidningen 6S:36!3, 1971. Svinhufvud, G., Ortengren, B., and Jacobsson, S. E.: The estimation of lidocaine and prilocaine in biological material by gas chromatography, Stand. J. Clin. Lab. Invest 17:162, 1965. Ryde’n, L., Wasir, H., Conradsson, T. B., and Olsson, B.: Blood levels of lignocaine after intramuscular administration to patients with proven or suspected acute myocardial infarction, Br. Heart J. 341012, 1972. Gianelly, R., von der Groeben, J. O., Spivack, A. P., and Harrison, D. C.: Effect of lidocaine on ventricular arrhythmias in patients with coronary heart disease, N. Engl. J. Med. 277:1215, 1967. Boyes, R. N., Scott, D. B., Jebson, P. J., Godman, M. J., and Julian, D. G.: Pharmacokinetics of lidocaine in man, Clin. Pharmacol. Ther. 12:105, 1971. Stenson, R. E., Constantino, R. T., and Harrison, D. C.: Interrelationships of hepatic blood flow, cardiac output, and blood levels of lidocaine in man, Circulation 43:205, 1971. Thomson, P. D., Melmon, K. L., Richardson, J. A., Cohn, K., Steinbrunn, W., Cudihee, R., and Rowland, M.: LidoCaine pharmacokinetics in advanced heart failure, liver disease, and renal failure in humans, Ann. Intern. Med. 78:499, 1973. Strong, J. M., and Atkinson, A. J.: Simultaneous measurement of plasma concentrations of lidocaine and its desethylated metabolite by mass fragmentography, Anal. Chem. -2287, 1972. Prescott, L. F., and Nimmo, J.: Plasma lidocaine concentrations during and after prolonged infusions in patients with myocardial infarction. In: Lidocaine in the Treatment of Ventricular Arrhythmias, Scott, D. B., and Julian, D. G., editors. Edinburgh, 1971, E. & S. Livingstone, pp. 168-177. Bassan, M. M., Weinstein, S. R., and Mandel, W. J.: Use of lidocaine by continuous infusion, AM. HEART J. 87:302. 1974.
473
infusion infarction
Lars Ryde’n Anders Waldenstrom Ylva Winsnes* Btirje Grtengren* GBteborg, Sweden
Intravenous lidocaine is one of the most commonly used modes of treatment for ventricular tachyarrhythmias complicating acute myocardial infarction. Although very potent, lidocaine has been claimed ineffective in up to 20 per cent of patients.‘J In intravenous lidocaine treatment, a bolus injection of about 1 mg. per kilogram of body weight directly followed by a continuous infusion of 2 mg. per minute has been recommended.2 Different studies have shown that lidoCaine in this dosage regimen has an antiarrhythmic effect on ventricular tachyarrhythmias complicating acute myocardial infarction.3p4However, Ryde’n and co-workers5 found that this amount of the drug resulted in astonishingly low blood levels during the first three hours following the start of therapy. One explanation for therapeutic failure with lidocaine might be that commonly used amounts of the drug are too small to give a blood concentration within the therapeutic range. To enable further conclusions concerning a reasonable dosage regimen, blood levels of lidocaine were determined following an infusion of 4 mg. per minute in a group of patients with acute myocardial infarction. These blood levels were then compared with those obtained when infusing 2 mg. per minute. Materials
and methods
The study was performed in patients admitted to a coronary-care unit. Only patients that subseFrom the Sjukhuset, Received Reprint Clinic *Address: S6dertiilje,
470
Department Gateborg,
of Cardiology, Sweden.
for publication
May
Clinic
I, Sahlgrenska
Results
28, 1974.
requests: Dr. Lam Ryd&, I, Sahlgrenska Sjukhuset, ASTRA Research Sweden.
Medical
and
Department of Cardiology, S-413 45 Gateborg, Sweden. Development
Laboratories,
Medical S-151
quently fulfilled the World Health Organization (WHO) criteria@ for acute myocardial infarction were included. All patients had defined ventricular tachyarrhythmias which, in accordance with the routine in the coronary-care unit, indicated lidocaine treatment.7 Intravenous lidocaine (Astra, Sodertalje, Sweden) was administered as a bolus injection of 75 mg. during two minutes immediately followed by an infusion of 2 or 4 mg. per minute, respectively. The infusion rate was kept constant by means of an infusion pump (Perfusor, Braun, Melsungen, West Germany). A two per cent lidocaine solution was used. The infusion was given into an arm vein through a short polyethylene cannula. The 2 mg. per minute group has previously been described6 and was studied for three hours. The 4 mg. per minute group was closely supervised as regards possible side effects for 24 hours. Venous blood samples from the contralateral arm were taken at 15, 30, 60, 120, and 180 minutes after the start of the injection. The blood was frozen at -16” C. and sent to the Astra Laboratories, Siidertalje, Sweden, for lidocaine determinations. A gas chromatographic method was used.8zgLidoCaine levels were expressed as lidocaine base, micrograms per milliliter of whole blood. During the study, serum concentrations of glutamic oxaloacetic transaminase, bilirubin, and creatinine were determined. Statistical comparisons were made using Chisquare test and Student’s t-test.
85
A total of 41 patients were included in the investigation of whom 16 belonged to the 2 mg. per minute and 25 to the 4 mg. per minute group. Pertinent data concerning the patients are preApril,
1975, Vol. 89, No. 4, pp. 470-473
Blood
sented in Table I and, as may be seen, there are no significant differences between the two groups concerning their clinical comparability. Blood levels of lidocaine are presented in Fig. 1. The 4 mg. per minute group had significantly higher blood levels after only 15 minutes. In the 2 mg. per minute group, lidocaine in the blood reached or exceeded 1.2 wg per milliliter at 120 minutes after the injection in three patients only and at 180 minutes in as few as seven patients. In the 4 mg. per minute group, the mean blood level of lidocaine exceeded 1.2 kg per milliliter at 30 minutes and after 180 minutes all patients had blood levels exceeding 1.2 pg per milliliter. The highest individual blood level during the first three hours after injection was 4.7 pg per milliliter which was observed in one of the 4 mg. per minute patients at 180 minutes. Side effects. Some of the patients in both groups experienced slight dizziness immediately following the bolus injection. Apart from this, no patient in either group experienced any discomfort that could be ascribed to lidocaine during the first three hours. Concerning the 2 mg. per minute group, it was impossible to make any statements concerning side effects after that period since close observation ended at that time. During the time of study (24 hours) the 4 mg. per minute infusion was stopped in 10 cases for the following reasons: in one case the cause was therapeutic failure and in two cases, technical problems with the infusion pump. In two cases, lidocaine side effects were suspected (hypotension and impaired consciousness, respectively). In these cases, the subsequent events, however, did not confirm these suspicions. In five cases, lidoCaine side effects were probable. These patients were withdrawn at 260 minutes because of impaired consciousness (lidocaine in blood 2.1 Fg per milliliter), at 780 minutes because of nausea (5.2 pg per milliliter), at 920 minutes because of blurred vision (3.2 pg per milliliter), at 280 minutes because of hypotension, and at 650 minutes because of nausea. The blood concentrations of lidocaine were not available for the last two cases. Discussion
In intravenous lidocaine treatment, a plasma level of 1.2 Fg per milliliter has been considered the lowest effective therapeutic level.‘O A widely recommended dosage regimen is a bolus injection of about 1 mg. per kilogram of body weight American
Heart Journal
Table
lru~~ls
of lidocaine
I. Selected data from the two groups of pa-
tients --
-----
__-
2 mg.lmin. in = 181 NO.
4 mg.lmin. in = 2.5) No.
16 2
20 5
1 2 6 7 2
1 1 14 8 1
11 4 3
10 11 4
12 3
20 3 2
Sex: Male Female Age: 30-39 years 40-49 years 50-59 years 60-69 years 70-79 years Site of infarction: Anterior Posterior Uncertain Previous infarction: 0 1 22
:i
Previous heart failure: Yes 6 No 12 Left heart failure day of study: Yes 6 No 12 Blood pressure (Mean + S. E. M.): Systolic 144 * 4.7 Diastolic 89 + 3.4 SGOT maximum (normal ~20): 520 1 21-100 11 101-200 3 >200 3 Creatinine, mg./lOO ml. (normal s 1.2): 51.2 16 > 1.2 2 Bilirubin, mg.1100 ml. (normal s 1.21: s1.2 38 j1.2 0
5 20 2 23 138 + 4.9 88 + 2.8 0 11 11 2 21 3 21 3
directly followed by a continuous infusion of 2 mg. per minute. With this intravenous dosage schedule, it has been claimed that lidocaine blood levels above 1.2 pg per milliliter should be reached at about 20 minutes. This statement is based upon results of normal volunteer subjects with the assumption that the distribution volume for lidocaine in patients with acute myocardial infarction is about half that of normal subjects.2J1 The astonishingly low lidocaine blood levels reached in the present 2 mg. per minute group with acute myocardial infarction do not confirm this. One explanation might be lack of agreement 471
Ryd6n et al.
Time
(minutes)
Fig. 1. Blood levels of lidocaine base after intravenous administration of a 75 mg. bolus injection followed by an infusion of 2 mg. per minute and 4 mg. per minute. Mean level of the group + S.E.M.
concerning the method of expressing lidocaine levels and differences caused by determination of lidocaine in plasma or whole blood. Such divergences are, however, insufficient to explain the entire differences.5 Another and more probable explanation for the relatively low blood levels of lidocaine in the 2 mg. per minute group is that the volume of distribution and the rate of metabolic degradation of lidocaine in patients with acute myocardial infarction are more equal to that of normal persons than has been suggested. The results in the 4 mg. per minute group confirm this hypothesis as the blood levels are in agreement with previous results from normal subjects. It is known that cardiac insufficiency as well as impaired hepatic function may be followed by higher lidocaine blood levels.12J3 The patients in both groups were in a relatively good circulatory condition despite their acute myocardial infarction and defined arrhythmias. There is no reason to believe that the present patient material in this respect differs from what is usual in coronary-care units. Although limited, the data in the present study suggest that side effects of lidocaine are not necessarily associated only with high blood levels. Strong and Atkinson14 reported an investigation
472
in which patients with suspected side effects from lidocaine had normal or low plasma levels of the drug, but high levels of metabolites. That this might be an important factor for side effects has earlier also been suggested by Boyes and coworkers.” It must be remembered how difficult it is to differentiate between true side effects and symptoms derived from the acute myocardial infarction per se, as these symptoms are very often of the same type as the side effects. The symptoms of side effects during the 4 mg. per minute infusion disappeared rapidly after stopping the infusion. In the present, closely supervised patient material, lidocaine infusion was stopped immediately after the onset of symptoms. The concentration of lidocaine and/or metabolites at that time might be very near the toxic level for that patient and stopping the infusion then could cause a fairly rapid decrease below the toxic level. This need not be contradictory to the known half-life of lidocaine in blood at steadystate kinetics.15 Even considering a probably somewhat higher risk of side effects, it seems justified to increase the routinely recommended infusion rate of lidoCaine to patients with acute myocardial infarction but without obvious signs of cardiac or April, 1975, Vol. 89, No. 4
Blood
hepatic failure. Our suggestion is to use 1 mg. per kilogram of body weight as a bolus injection directly followed by 4 mg. per minute for at least three hours. An initially high infusion rate has also been suggested by Bassan and co-workers,16 who in a recent study showed that there is a slow increase in levels of lidocaine following a continous infusion with a steady-state level after only 10 hours. In patients with obvious cardiac or hepatic failure the dose in the future, as at present, must be balanced according to the clinical condition of the patient.
REFERENCES 1.
2. 3. 4. 5.
Summary
Blood levels of lidocaine were estimated following two different infusion rates in patients with acute myocardial infarction. Forty-one patients received lidocaine as a bolus injection of 75 mg. directly followed by an infusion. The infusion rate was, in 16 patients, 2 mg. per minute and in 25 patients, 4 mg. per minute. Blood levels of lidoCaine were determined at different times up to 180 minutes after the start of drug administration. The levels in the 2 mg. per minute group were lower than had been expected and the mean level It S.E. was, after three hours, only 1.1 pg per milliliter. Many of the 2 mg. per minute patients did not, during the time period observed, reach 1.2 pg per milliliter, which has been considered as the lowest effective therapeutic level. In the 4 mg. per minute group, mean level of lidoCaine already at 15 minutes was significantly higher than in the 2 mg. per minute group Cl,1 f 0.14 and 0.6 + 0.05, respectively; p ( 0.05). After three hours, the mean blood level in the 4 mg. per minute group was 2.6 pg per milliliter. Although the blood levels were not followed after three hours, a careful observation did not reveal any severe toxic effects in the 4 mg. per minute group during next 21 hours. In five cases, however, lidoCaine side effects were probable. These symptoms disappeared rapidly after cessation of the infusion. In order to reach therapeutic blood levels of lidocaine within a reasonable time, the infusion rate of 4 mg. per minute is recommended at least for the first three hours.
American
Heart Journal
levrls of lidocaine
6.
Bigger, J. T., and Heissenbuttel, R. H.. The use of procaine amide and lidocaine in the treatment of cardiac arrhythmias, Progr. Cardiovasc. Dis. 11:515, 1969. Harrison. D. C.. and Alderman, E. L.: The oharmacoloav and clinical use of lidocaine as an antiarrhythmic drug, Mod. Treat. 9139, 1972. Mogensen, L.: Ventricular tachyarrhythmias and lignoCaine prophylaxis in acute myocardial infarction Acta Med. !&and. 188:513, Pitt, A., Lipp, H., and Anderson, S. T.: Lignocaine given prophylactically to patients with acute myocardial infarction, Lancet 1:612, 19’71. Ryden, L., Waldenstr6m, A., Ehn, L., Holmberg, S., and Husaini, M.: Comparison between effectiveness of intramuscular and intravenous lignocaine on ventricular arrhythmia complicating acute myocardial infarction, Br. Heart J. 35:1124, 1973. World Health Organization. Report: lschaemic Heart Disease Register (EURO 5010 (4) Copenhagen, 1970, pp.
32-33. 7. Henning, 8.
9.
10.
11.
12.
13.
14.
15.
16.
R., and Holmberg, S.: Erfarenheter fran Sahlgrenska sjukhusets hjiirtinfarktavdelning, Lakartidningen 6S:36!3, 1971. Svinhufvud, G., Ortengren, B., and Jacobsson, S. E.: The estimation of lidocaine and prilocaine in biological material by gas chromatography, Stand. J. Clin. Lab. Invest 17:162, 1965. Ryde’n, L., Wasir, H., Conradsson, T. B., and Olsson, B.: Blood levels of lignocaine after intramuscular administration to patients with proven or suspected acute myocardial infarction, Br. Heart J. 341012, 1972. Gianelly, R., von der Groeben, J. O., Spivack, A. P., and Harrison, D. C.: Effect of lidocaine on ventricular arrhythmias in patients with coronary heart disease, N. Engl. J. Med. 277:1215, 1967. Boyes, R. N., Scott, D. B., Jebson, P. J., Godman, M. J., and Julian, D. G.: Pharmacokinetics of lidocaine in man, Clin. Pharmacol. Ther. 12:105, 1971. Stenson, R. E., Constantino, R. T., and Harrison, D. C.: Interrelationships of hepatic blood flow, cardiac output, and blood levels of lidocaine in man, Circulation 43:205, 1971. Thomson, P. D., Melmon, K. L., Richardson, J. A., Cohn, K., Steinbrunn, W., Cudihee, R., and Rowland, M.: LidoCaine pharmacokinetics in advanced heart failure, liver disease, and renal failure in humans, Ann. Intern. Med. 78:499, 1973. Strong, J. M., and Atkinson, A. J.: Simultaneous measurement of plasma concentrations of lidocaine and its desethylated metabolite by mass fragmentography, Anal. Chem. -2287, 1972. Prescott, L. F., and Nimmo, J.: Plasma lidocaine concentrations during and after prolonged infusions in patients with myocardial infarction. In: Lidocaine in the Treatment of Ventricular Arrhythmias, Scott, D. B., and Julian, D. G., editors. Edinburgh, 1971, E. & S. Livingstone, pp. 168-177. Bassan, M. M., Weinstein, S. R., and Mandel, W. J.: Use of lidocaine by continuous infusion, AM. HEART J. 87:302. 1974.
473