Lisa B. Selzer, M.S., Arnold B. Weinrib, B.S., Richard J. Marina, M.D., and. John J. Lima, Pharm.D. Columbus, Ohio. Divisions of Pharmacy Practice and ...
A comparison of methods of lidocaine administration in
patients three-step method for administering lidocaine intravenously was developed and tested in 19 patients. Of all plasma concentrations measured, 70% were within the desired range of 2 to 4 pcglml after the new method of lidocaine administration. Compared with other methods it is superior with respect to percent of time in the therapeutic range. No ventricular arrhythmias were evident, and no toxicities were associated with the new method. Infusions of lidocaine for more than 6 hr were associated with progressive increases in plasma concentrations that were higher (p < 0.01) at 24 hr than at 6 hr. A
Lisa B. Selzer, M.S., Arnold B. Weinrib, B.S., Richard J. Marina, M.D., and John J. Lima, Pharm.D. Columbus, Ohio Divisions of Pharmacy Practice and Cardiology, Colleges of Pharmacy and Medicine, The Ohio State University
The effectiveness of lidocaine as an antiarrhythmic drug5 depends in part on the rapid achievement and maintenance of therapeutic plasma levels of 1.5 to 5.5 jig/m1.3' 10 Concentrations above this range have been associated with toxic effects including convulsions, coma, and respiratory arrest.7' 10 Because subjective toxic effects such as drowsiness and dizziness may occur at concentrations above 4 Ag/m1,10' 17 plasma concentrations of 2 to 4 jig/m1 are considered optimal." The usual method of administering lidocaine, consisting of a 50- to 100-mg bolus* followed by a 1- to 2-mg/min continuous infusion, often results in subtherapeutic serum concentrations for a long latency after beginning treatment.
Received for publication Dec. 27, 1980. Accepted for publication Jan. 13, 1981. Reprint requests to: John J. Lima, Pharm.D., College of Pharmacy, Ohio State University, 500 West 12th Ave., Columbus, OH 43210. *We refer to a dose given over 2 mm.
0009-9236181/050617+08800.8010
C
This period, referred to as the "therapeutic gap," may exceed 1 to 2 hr." The gap occurs when time is critical for the patient, because the incidence of life-threatening arrhythmias is highest in the first few hours after an acute myocardial infarction." 18' 20 It is therefore important that a method of lidocaine administration be developed to eliminate the gap. Several techniques have been suggested to overcome the gap. A larger bolus may eliminate the gap but may also result in toxicity." Multiple-bolus techniques consisting of an initial bolus and maintenance infusion with a second bolus 15 to 20 min after the first or several bolus doses at 5-min intervals have been suggested." 28 A therapeutic gap may still be present, and large fluctuations in plasma concentration of the drug occur."' 28 Greenblatt et using computer simulations, compared plasma concentrations of lidocaine following various methods of administration. It was concluded that a two-step method consisting of a loading infusion followed by a maintenance infusion is
1981 The C. V. Mosby Co.
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Clin. Pharmacol. Ther. May 1981
618 Salzer et al.
DOSE,
IV ki2
Vc
Vt
k21
ki0
Fig. 1. Kinetic model describing lidocaine disposition. Vc., volume of central compartment; Vt, volume of tissue compartment; k10, elimination rate constant; k,2 and k21, intercompartmental rate constants.
a means of eliminating the therapeutic gap. Levy et al.16 used this method to administer lidocaine to patients. While the two-infusion method of administering lidocaine rapidly achieved and maintained therapeutic plasma concentrations, the immediate antiarrhythmic effects of a bolus were lost. A three-step method for lidocaine administration was designed to achieve and maintain plasma concentrations of 2 to 4 ,u,g/m1 instantaneously. Our study was undertaken to test the metnod in patients and to compare it with other methods.
2
1
60
120
240 TIME, minutes 180
Computer simulation studies. Simulated plasma concentrations of lidocaine were obtained with the aid of a digital computer program that uses the fourth-order Runga Kutta approximations for integrating differential equations.8 The kinetic disposition of lidocaine was assumed to follow a two-compartment open model consisting of a central compartment V, and a tissue compartment Vt (Fig. 1).4 Elimination was assumed to occur exclusively from the V, and to be governed by the first-order eliminaand tion rate constant The rate constants 1(21 describe the intercompartmental transfer of
k.
k
360
Fig. 2. Simulated plasma lidocaine levels after four dosing techniques. Kinetic parameters were obtained from the literature. Capital letters refer to the methods of lidocaine administration explained in the text.
drug. Values of the rate constants and volumes for computer simulation studies were obtained from the literature" 26 as follows: V, = 0.53 = 0.02 min', 1/kg, V, = 0.79 1/kg, `, 12 = 0.06 min-1, and k, = 0.03 min-1. V, and V, for patients with congestive heart failure were assumed to be 0.30 and 0.58 1/kg.26 Plasma concentrations of lidocaine at various times after four suggested dosing techniques were simulated for a patient weighing 70 kg. The techniques were (1) conventional-100-mg bolus and 2-mg/min maintenance infusion21; (2) multiple bolus-100-mg bolus and 2-mg/min maintenance infusion with an additional 50-mg bolus at 20 min"; (3) two-infusion-8-mg/min infusion for 25 min followed by a 2-mg/min maintenance infusion"; and (4) recommended
k
Methods
300
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619
Table I. Lidocaine doses and plasma concentration-time data after lidocaine by the three-step method Lidocaine HC1
Plasma lidocaine level (gglml)
Patient
Bolus (mg)
Li(mg)
Mi (mg/mm)
Cpa
Cpb
Cpc
Cpd
G. B. R. W.1 L. W. R. C. J. E.
100
200 200 250 200 250 (20 min) 200
2.0 2.0
3.3 2.8
2.3 1.4
2.5
4.4
4.2 2.0 3.4
2.0 2.0
3.4 3.8
2.0 2.0 3.2 2.9
2.0
100 150 100 125
1.0 1.5 1.0 1.0
300
3.0
2.8
150
1.5
1.1
200 265 240 (30 min) 240 (30 min)
2.0 3.0 2.0
5.9 2.5
4.8
3.0 4.2 2.5 4.3
2.0
2.6
180
1.5
2.4
90 120 100
90
L.
100
K. M.
H. R. R. W. S. D. P. J. L. M. V. G. H.
50 75 50 60 150 75 100 80 100
J. W.
100
D. R. L. B.
75
1.6
3.6 3.5 2.0
2.8 3.8 2.6 1.7
2.4 2.0
2.0 2.4
2.0 3.0
1.1
1.6
2.3
2.0
2.0
3.0
1.5
1.3 1.7
1.3
3.0 5.2 3.0
3.7 2.9
3.7 2.1
3.3
4.4
1.9
1.8
1.6
2.3
2.7
3.6
(30 min) Li, Loading infusion, total dose given over 25 mm unless otherwise indicated; Mi, maintenance infusion; Cpa, plasma concentration at end of loading infusion; Cps, plasma concentration at 60 or 90 min, whichever was lower; Cpe, plasma concentration at 6 hr; Cpa, plasma concentration at 24 hr.
three-step-100-mg bolus and 8-mg/min infusion for 25 min followed by a 2-mg/min maintenance infusion. Our recommended technique was also simulated using kinetic parameters reported by Thomson et al.26 for patients with congestive heart failure. Simulated plasma concentrations of lidocaine after each dosing technique are shown in Fig. 2. The times that simulated concentrations of lidocaine were in the range of 2 to 4 ,u,g/m1 during the first 3 hr of treatment for each technique were compared. The first 3 hr were used because the therapeutic gap occurred during this period and all techniques resulted in simulated concentrations above 2 Lg/m1 after 3 hr. Techniques 2, 3, and 4 were all superior to technique 1. Techniques 1, 2, and 3 resulted in concentrations in the therapeutic range 20%, 56.1%, and 52.2% of the time. Plasma lidocaine levels after our recommended technique 4 were in the therapeutic range all the time.
Clinical studies. Subjects. Our subjects were patients in the
cardiac, intensive care, and medical units of the Ohio State University Hospitals. Subjects received lidocaine according to the study method when the physician determined that antiarrhythmic or prophylactic lidocaine therapy was needed. The subjects' cardiac function was roughly classified before treatment according to a classification proposed by Killip and KimbalP3: class 1, no clinical signs of congestive heart failure; class 2, pulmonary rales; class 3, pulmonary edema; class 4, cardiogenic shock. Liver function of each patient was assessed by physical examination, liver function tests, serum albumin concentration, and coagulation times. Patients received lidocaine HC1 according to the following three-step regimen, which is identical to technique 4 in the computer simulation studies: (1) 1.5 mg/kg bolus, (2) 120 ,u,g/ kg/min rapid infusion for 25 min, and (3) 30 ,u,g/kg/min maintenance infusion. Patients with congestive heart failure received one half to three fourths of the dose,
din. Pharmacol.
620 Salzer et al.
Ther. May 1981
Table II. Lidocaine kinetics Derived parameters
Least-squares estimates k12
Mean SD
0.046 0.057
V,
(min')
(min')
Vd
(1/kg)
(1/kg)
0.074 0.125
0.017 0.011
0.62 0.24
1.38
1.62
0.40
0.52
k21
depending on the severity of heart failure. All infusions were administered by IMED (IMED Corp.) infusion pumps. Kinetics. Initially, blood (5 ml) for analysis of lidocaine was drawn into a heparinized syringe from the arm opposite the infusion site at 0, 25, 60, and 90 min and at 6 and 24 hr. Computer simulation studies had shown that a minimum of five data points at these intervals were required to fit data to a two-compartment open model. The plasma concentrationtime data were fitted by the computer program NONLIN." Computer fitting of the data was necessary to obtain the least-squares estimates of the kinetic parameters of lidocaine in each patient. The time that plasma concentrations were in the range of 2 to 4 ,ug/m1 could thus be more accurately estimated and compared with plasma levels after other dosing techniques. These include the volume of distribution at steady state (Vds,), postdistributive volume of distribution (Vdp), total body clearance (C1T), and elimination half-life (t1/20). Doses were converted to lidocaine base for computer fitting and simulations (10 mg lidocaine HC1 = 8.65 lidocaine base). In seven of the initial 14 patients studied, plasma lidocaine levels at the end of 24 hr were higher than at 6 hr when steadystate concentrations were expected based on known lidocaine kinetics. In three patients plasma levels were much the same at 6 and 24 hr; in the remaining subjects blood samples were not collected at either 6 or 24 hr. Unexpectedly high lidocaine levels associated with prolonged infusion have been noted by others." Consequently, in the last three patients studied more blood samples were drawn during the first 6 hr and were used to determine kinetic parameters in these patients. Plasma lidocaine was assayed in duplicate by the EMIT homogeneous enzyme immunoassay
Vdp (1/kg)
Clr
t1/2g
(1/hrlkg)
(hr)
0.52 0.13
2.40 1.23
(supplied by Syva Laboratories), which measures lidocaine between 1 and 12 ,u,g/m1 with a coefficient of variation less than 10%. 23 Clinical studies have shown no significant cross-reactivity in patients receiving other medications such as procainamide, quinidine, and propranoloI.23 Studies in our laboratory showed no crossreactivity between lidocaine and its two major metabolites, monoethylglycinexylidide and glycinexylidide. Results
Patients. Our subjects were 19 patients (12 men and seven women). Mean ( ± SD) age and weight of the patients were 66 (±12) yr and 77 (± 17) kg. All had normal liver size, liver function tests, coagulation times, and serum albumin concentrations. Four patients were classified as cardiac functional class 1; nine, class 2; five, class 3; and one, class 4. Ten had ventricular arrhythmias. The ventricular arrhythmias were associated with myocardial infarction in eight patients, digitalis toxicity in one, and pulmonary embolism in another. Nine patients had no ectopy and were treated with lidocaine prophylactically because of suspected myocardial infarction. Ventricular dysrhythmic activity in the 10 patients disappeared during the loading infusion and did not recur while lidocaine was being administered. In patients who received lidocaine prophylactically, no arrhythmias developed. Because of the loading infusion, more drug was used than by conventional treatments, yet plasma lidocaine levels were in a safe range and no toxicity was noted. Lidocaine doses and plasma concentrations. Lidocaine doses and plasma concentrationtime data for 17 patients are presented in Table I. Two patients were excluded, because lidocaine levels were not measurable in
Effective lidocaine administration
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one and blood samples were not obtained at appropriate times in another. Of all plasma levels measured, 70% were within the range of 2 to 4 p,g/ml, 8% were higher than 4 cg/m1, and 22% were less than 2 pg/ml. For most patients the highest plasma lidocaine level during the first 6 hr was at the end of the loading infusion and averaged 3.07 -± 1.22 ug/m1 SD). The concentration was lowest between 60 and 90 min for most patients and averaged 2.38 ± 0.82 pg/ml. Mean concentration at the end of 6 hr was 2.57 ± 1.01 pg/ml. According to single-dose lidocaine kinetics,24 the t1/20 is short enough that steady-state conditions should be achieved at the end of 6 hr when lidocaine is given by our three-step method. Maintenance infusion averaged 1.63 mg/min (1.88 mg/min lidocaine HC1) and the total clearance, calculated from the ratio of the maintenance infusion and the apparent steady-state plasma concentration at 6 hr, averaged 37.8 1/hr, in good agreement with the literature 24, 26 Plasma lidocaine levels at the end of 24 hr averaged 3.06 -± 0.88 pg/m1 (± SD) and were higher than the concentration at the end of 6 hr, which averaged 2.43 ± 0.73 pg/m1 in the 13 patients in whom blood samples were drawn at both times (p < 0.01 by paired Student t test). In only four of the 13 patients was there close agreement ( 0.10 by Student t test), these clearances were grouped together and compared with the average clearance in classes 3 and 4, 31.7 ± 6.101/hr. Although the average clearance in classes 3 and 4 was about 33% lower than the combined clearance of classes 1 and 2, which averaged 45.8 ± 14.6 1/hr, the difference was not statistically significant (p = 0.10 by Student t test). Kinetics. The least-squares estimates of lidocaine kinetics could be obtained in only six patients (Table II) and are in good agreement with values cited from single-dose studies.24 When plasma levels in our six patients were computer fitted, the ratio of the observed minus the calculated levels and the calculated level was less than 0.15 for 95% of the data points. In three of
621
3 PATIENT RW,
ctbzon---`1 2
4
8
12
16
20
24
TIME, hours
Fig. 3. Plasma lidocaine levels (o) after lidocaine according to technique 4 in patients LW (few data points, constant plasma levels), JW (many data points, constant plasma levels), and RW2 (many data points, increasing plasma levels). The lines are computer fitted; the points are measured values.
the first 14 patients studied, plasma lidocaine levels at 6 hr were within 10% of those at 24 hr. Realistic parameter estimates were obtained from good computer fits. (Computer fits were considered good if the ratio of the observed less the calculated concentrations and the calculated concentration averaged less than 0.10 for each patient.) In the remaining 11 patients good fits were not obtained, or increasing plasma levels associated with prolonged infusion resulted in good fits but kinetic parameters differed substantially from those reported (i.e., t1/20 of 9 to 92 hr as against cited values of 1 to 4 hr). Additional blood samples were therefore collected from the last three patients studied during the first 6 hr of therapy so that 6-hr data could be fitted. In two of the three, fitting 24-hr data resulted in unrealistic estimates from increasing plasma levels, but realistic estimates were obtained from good fits of 6-hr data. In the third subject the plasma concentration at 24 hr was within 10% of that at 6 hr, and realistic estimates
Clin. Pharmacol. Ther. May 1981
622 Salzer et al.
Table III. Percent of time within 2 to 4 jug Iml during the first 3 hr after lidocaine by four dosing techniques Dosing techniques
Patient L. W.
3
2
1
66.7
120*
97.9
120* 60*
2.5t
4
91.7
2501
100.0
2.5t
2.5t R. C.
22.9
58.3
100
60.4
100
2.0
50
200 2.0
100.0
0
2.1
100
200
41.7
2.0 2.1
100
2.0
2.0
50
93.8
91.7
100
2.0 91.7
100
2.0
50
240 2.0
100.0
4.2
6.3
100
100 50
2.0
6.3
240
31.3
2.0
75 1.5
75
16.7
2.0 27.1
37.5
180 1.5
100.0
1.5
Mean -±.SD
45.5
31.3 39.8
*Bolus (mg). I'Maintenance infusion (mg/min). Additional bolus at 20 mm (mg). §Loading infusion dose given over 25
43.1
mm
100
240
2.0 0
100
240 2.0
2.0 J. W.
100
200
2.0 G. H.
2.51. 100
200
2.0 D. L.
120*
250§
43.2 43.3
75 180 1.5
78.8 33.0
(mg).
were obtained by fitting 24-hr data. Fig. 3 shows examples of patient data that were well fitted and resulted in realistic parameter estimates. Table III compares the fitted plasma concentration-time data after the three-step method with simulated plasma levels following other techniques. Simulations were based on doses of lidocaine equivalent to those administered by the three-step method and the least-squares estimates of kinetic parameters for the six patients referred to above. Proportions of time in the therapeutic range for the first 3 hr after methods 1, 2, and 3 averaged 31.3%, 45.5%, and 43.2% and differed from method 4, which averaged 78.8% (p < 0.05 by paired Student t test). The three-step method resulted in the highest proportion of time in the desired range of 2 to 4 ggiml for each of the six patients. The multiple-bolus and two-infusion methods resulted in lower proportions, and the single-bolus method usually resulted in the shortest time in the desired range.
Discussion When lidocaine was given by the three-step method, 70% of the plasma lidocaine levels were between 2 and 4 mg/mi. Measured lidocaine levels were in the range of 2 to 4 pcg/m1 80% of the time during the first 3 hr in six patients, significantly longer than the time in the desired range after simulations of other methods of lidocaine use. Similar comparisons were not made in the remaining patients, because reasonable estimates of kinetic parameters could not be obtained. The data from six patients suggest that our method is superior to the other methods with respect to time within the therapeutic range. Methods of lidocaine administration not examined in our study may overcome the therapeutic gap but require more complicated techniques .2' 5' 12 Our three-step method was easily administered and well accepted by nursing and medical staff. The rising plasma lidocaine levels in our
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studies have been reported by others. LeLorier et al." reported that plasma levels averaged 1.85 and 4.32 ,ug/m1 at 6 and 39 hr after the infusion started in patients with uncomplicated myocardial infarction. The ratio of the mean 24-to 6-hr plasma levels in our studies was 1.3, and Fredrick and Boersma9 reported an identical ratio between 60 and 26 hr. These data suggest that plasma lidocaine levels begin to rise between 6 and 24 hr and continue 26 hr after the beginning of the infusion. Plasma lidocaine levels should be monitored during infusion. Rising plasma levels may require that infusion rates be decreased to prevent toxicity. The rising plasma levels and prolonged lidocaine t1/2g associated with prolonged infusions in other studies and the progressive rise in levels in our study probably result from decreased lidocaine clearance. Lidocaine is one of a few drugs with nonrestrictive clearance27 limited by liver blood flow.25 It is unlikely that a change in liver blood flow would affect lidocaine clearance sufficiently to account for the observed increases in plasma levels (almost double in one patient). Intrinsic clearance, however, may decrease to such an extent that lidocaine clearance becomes less dependent on liver blood flow. Plasma lidocaine levels would then become more dependent on intrinsic clearance and rise with time. Such a decrease in the intrinsic lidocaine clearance after prolonged infusions has been demonstrated in dogs.15 It has been postulated that one or more of the metabolites of lidocaine may be responsible,22 possibly by competing with the parent drug for metabolic sites in the liver.
References Adgey AAJ, Allen JD, Geddes JS, et al: Acute phase of myocardial infarction. Lancet 2:501504, 1971. Aps C, Bell JA, Jenkins BS, et al: Logical approach to lignocaine therapy. Br Med J 1:13-15, 1976. Benowitz NL, Meister W: Clinical pharmacokinetics of lignocaine. Clin Pharmacokinet 3: 177-201, 1978. Boyes RN, Scott DB, Jebson PJ, et al: Pharmacokinetics of lidocaine in man. CLIN PHARMACOL THER 12:105-116, 1971. Collinsworth KA, Kalman SM, Harrison DC:
Effective lidocaine administration
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The clinical pharmacology of lidocaine as an antiarrhythmic drug. Circulation 50:1217-1230, 1974.
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. Foldes FF, Mollay R, McNall PG, et al: Comparison of toxicity of intravenously given local anesthetic agents in man. JAMA 172:14931498, 1960. Ford LR: Differential equations, ed. 2. New York, 1955, McGraw-Hill Publishing Co., pp. 208-224. Fredrick DS, Boersma RB: Lidocaine infusions: Effect of duration and method of discontinuation on recurrence of arrhythmias and pharmacokinetic variables. Am J Hosp Pharm 36:779-781, 1979. Gianelly R, Von der Groeben JO, Spivach AP, et al: Effect of lidocaine on ventricular arrhythmias in patients with coronary heart disease. N Engl J Med 227:1215-1219, 1967. Greenblatt DJ, Bolognini F, Koch-Weser J, Hormatz JS: Pharmacokinetic approach to the clinical use of lidocaine intravenously. JAMA 236:273-277, 1976. Jeliffe R, Goicoechea F, Tuey D, et al: An improved computer program for lidocaine infusion regimens. Clin Res 23:125 A, 1975. Killip T, Kimball JT: Treatment of myocardial infarction in a coronary care unit: A two year experience with 250 patients. Am J Cardiol 20:457-464, 1967. LeLorier J, et al: Pharmacokinetics of lidocaine after prolonged intravenous infusions in uncomplicated myocardial infarction. Ann Intern Med 87:700-702, 1977. LeLorier J, Moisan R, Caine G: Lidocaine kinetics after prolonged intravenous infusions in dogs. Pharmacologist 18:149, 1976. (Abst.) Levy RA, Charuzi Y, Mandel WJ: Lignocaine: A new technique for intravenous administration. Br Heart J 39:1026-1028, 1977. Lie KI, Wellens Hi, van Capelle FJ, Durrer D: Lidocaine in the prevention of primary ventricular fibrillation. N Engl J Med 291:1324-1326, 1974. Lie KI, Wellens HJ, Durrer D: Characteristics and predictability of primary ventricular fibrillation. Eur J Cardiol 1:379-384, 1974. Metzler CM: NONLIN: A computer program for parameter estimation in nonlinear situations. Report No. 7292/69/7292/005, Kalamazoo, Mich., Nov. 25, 1969, Upjohn Co. Pantridge JF, Geddes JS: A mobile intensive care unit in the management of myocardial infarction. Lancet 2:271-273, 1967. Physician 's Desk Reference, ed. 34. Oradell,
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N.J., 1980, Medical Economics Co., pp. 584585. Prescott LF, Adjepon-Yamoah KK, Talbot RJ: Impaired lidocaine metabolism in patients with myocardial infarction and cardiac failure. Br Med J 1:939-941, 1976. Product information, Emit-CAD lidocaine assay. Syva Laboratories, Palo Alto, Calif. Rowland M, Thomson PD, Guichard A, et al: Disposition kinetics of lidocaine in normal subjects. Ann NY Acad Sci 179:383-398, 1971. Stenson RE, Constantino RT, Harrison DC: Interrelationships of hepatic blood flow, cardiac output, and blood levels of lidocaine in man. Circulation 43:205-211, 1971.
Thomson PD, Melmon KL, Richardson JA, et al: Lidocaine pharmacokinetics in advanced heart failure, liver disease and renal failure in adults. Ann Intern Med 78:499-508, 1973. Wilkinson GR, Shand DG: A physiological approach to hepatic drug clearance. CLIN PHARMACOL THER 18:377-390, 1975. Wyman MG, Lalka D, Hammersmith L, et al: Multiple bolus technique for lidocaine administration during the first hours of an acute myocardial infarction. Am J Cardiol 41:313-317, 1978.
