PHARMACOKINETICS OF MIDAZOLAM IN TOTAL I.V. ANAESTHESIA

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1 Br. J. Anaesth. (1987), 59, PHARMACOKINETICS OF MIDAZOLAM IN TOTAL I.V. ANAESTHESIA P. PERSSON, A. NILSSON, P. HARTVIG AND A. TAMSEN Total i.v. anaesthesia, defined as anaesthesia provided solely by drugs administered i.v. has, until now, played a minor role in the provision of anaesthesia for major surgery. However, an awareness of the problems associated with nitrous oxide (Chanarin, 1980; Brodsky, 1983; Mazze, 1983; Wolf, Capuano and Hartung, 1983) has lead to an increased interest in this technique. Midazolam is a benzodiazepine with a short elimination half-life and a relatively short duration of action (Greenblatt et al., 1981; Smith, Eadie and O'Rourke Brophy, 1981). At physiological ph midazolam is un-ionized and lipophilic. As a result the onset of action after i.v. administration is rapid because of rapid uptake by the brain. An understanding of the kinetics of midazolam under the conditions pertaining during surgery, and a knowledge of the plasma concentration required to produce an hypnotic effect are essential when designing a total i.v. technique. Theoretically, the short elimination half-life of midazolam, and the negligible hypnotic effect of its metabolites (Crevoisier et al., 1983; Ziegler et al., 1983), make the administration of midazolam by i.v. infusion potentially useful. The objectives of the present study were: to construct a dose regimen, based on simulations; to determined the pharmacokinetics of midazolam in total i.v. anaesthesia during major surgery; and to compare the simulated and the observed concentration time profiles. PETER PERSSON, PHARM.D., Department of Biopharmaceutics and Pharmacokinetics, University of Uppsala, Biomedical Center, Box 580, S-1 23 Uppsala, Sweden. ANDERS NLLSSON, M.D., ANDERS TAMSEN, M.D., PHJ>. (Department of Anesthesiology); PER HARTVIG, PHARM.D., PH.D. (and P. PERSSON) (Hospital Pharmacy); University Hospital, Uppsala, Sweden. Accepted for Publication: August 1, Correspondence to P.P. SUMMARY The pharmacokinetics of midazolam during total i.v. anaesthesia were determined in 15 female patients undergoing major surgery. Midazolam was administered together with an analgesic drug and a neuromuscu/ar blocking drug. The dose regimen of midazolam. based on simulations, included two consecutive infusions following a bolus injection at the induction of anaesthesia. Multiple blood samples were drawn and a two-compartment open model was fitted to the measured plasma concentrations. Plasma clearance (483 ml min~ l ), apparent volume of distribution (1.94 litre kg~ l ) and terminal halflife (3.1 h) were in agreement with other reports. Thus, there was no obvious evidence that the surgical procedure or the concomitant use of other drugs, or both, influenced the pharmacokinetics of midazolam. The relatively rapid elimination makes midazolam suitable for use by infusion in a total i.v. technique. PATIENTS, MATERIALS AND METHODS Patients Fifteen female patients scheduled for elective hysterectomy were included in the study. Their ages varied from 36 to 53 yr and their body weights were between 45 and 88 kg (mean (± SD) 66±11 kg) (table I). The study was approved by the Ethics Committee of the Medical Faculty of Uppsala University, and informed consent was obtained from each patient. Premedication and anaesthetic procedure. Pethidine mg and atropine 0.5 mg were given i.m. as premedication. Anaesthesia was induced and maintained with midazolam (and alfentanil) as follows:

2 PHARMACOKINETICS OF MIDAZOLAM 549 TABLE I. Body weight, total duration of infusion, total dose of midazolam and area under the concentration-time curve {A UC) in 15 female surgical patients Patient No Mean ±SD Weight (kg) Duration of infusion (min) Total dose (mg) AUC (mg min" 1 litre" 1 ) Patients 1-10: a bolus injection of midazolam 0.3 mg kg" 1 was followed by an infusion regimen with an initial infusion rate of 0.68 mg kg" 1 h" 1 for 15 min followed by a maintenance infusion of mg kg" 1 h" 1 ; Patients 11-15: a bolus dose of midazolam 0.25 mg kg"" 1 followed by an initial infusion of 0.65 mg kg" 1 h" 1 for 15 min and a maintenance infusion of 0. mg kg" 1 h" 1. The mean (± SD) total duration of infusion was 82 ±14 min, corresponding to a total dose of midazolam of mg (table I). In patients 1-5 analgesia was provided by the administration of alfentanil as a bolus dose (0.05 mg kg" 1 ) followed by an infusion (0.06 mg kg" 1 h" 1 ) and additional increments of alfentanil were given when indicated. Patients 6-15 were given a bolus dose of 0.0 mg kg" 1 followed by a two-stage infusion of alfentanil 0.3 mg kg" 1 h" 1 for 15 min followed by mg kg" 1 h" 1 for as long as the midazolam infusion was maintained. Atracurium 0.5 mg kg" 1 (patients 1-5) or pancuronium 0.1 mgkg" 1 (patients 6-15) was given to provide neuromuscular blockade before intubation of the trachea. The lungs were ventilated with oxygen in air during the surgical procedure. At the end of surgery residual neuromuscular blockade was antagonized with neostigmine 2.5 mg (plus atropine 1.0 mg). Intraoperative and postoperative observations. 1*0 1 central peripheral FIG. 1. A two-compartment open model for midazolam used for the simulations. The rate constants (min" 1 ) were taken from the literature (Lauven et al., 1981). k^ represents the infusion rates. Arterial pressure, heart rate and pupil size were monitored during anaesthesia. Any evidence of lachrymation, sweating, or both was noted. End-tidal carbon dioxide concentration, EMG, EEG and train-of-four response were recorded (Datex ABM-monitor (Nilsson and colleagues, 1986; unpublished observations)). The patient's ability to give their name and date of birth and to solve simple arithmetic problems (addition and subtraction of two-figured numbers) in the postoperative period were recorded. Blood sampling and assay. Blood samples were drawn from a peripheral vein before and 2, 5, 10 and 15 min after induction. Thereafter, samples were collected every 15 min until the end of the infusion. Following the termination of the infusion, samples were drawn at 2, 5, 10, 15, 30 and 60 min and then every 1 h for 6 h. The blood was centrifuged and the plasma frozen at 20 C pending analysis. Plasma concentrations of midazolam were determined by gas chromatography using nickel-63 electron capture detection (Rutherford, 1977). Linear standard curves for the concentration range of midazolam ng ml" 1 were obtained. Design of midazolam infusion regimens The dose of midazolam received by the first 10 patients was derived from published pharmacokinetic data obtained following a single bolus dose (table II). A two-compartment open model was assumed (fig. 1) and a continuous simulation program (DARE-P) (Wait and Clarke, 1974) was used to simulate an infusion regimen. After a bolus dose of 0.3 mg kg" 1 a two-stage infusion regimen was constructed. The rapid loading infusion rate was determined after numerous simulations using the two-compartment model. The maintenance

3 550 BRITISH JOURNAL OF ANAESTHESIA TABLE II. Pharmacokinetic data of midazolam used in the simulation. Pharmacokinetic data determined in six female patients undergoing minor gynaecological surgery (Lawen el ai, 1981) Total plasma clearance (ml min" 1 ) Volume of the central compartment (litre kg" 1 ) Apparent volume of distribution (litre kg' 1 ) Distribution half-life (min) Elimination half-life (h) 900 E CD S 600 E.2 o N CO." Mean Range Time (min) FIG. 2. Simulated concentration-time profile for midazolam after two consecutive infusion rates combined with a bolus injection. The bolus injection was 0.3 mg kg" 1, while the infusion rates were 0.68 mg kg"' h" 1 for 15 min followed by mg kg" 1 h" 1 over the next 285 min. infusion was calculated from the equation (Rowland and Tozer, 1980): k o = Cl-C» (1) where k 0 was the maintenance infusion rate, Cl was the total plasma clearance and C 55 the desired steady-state concentration. In patients 1-10 this infusion regimen was theoretically expected to result in a steady-state concentration of 300 ng ml" 1 from 45 min onwards (fig. 2), a value which has been found to provide adequate sedation during surgery (Nilsson, Tamsen and Persson, 1986). The infusion regimen for patients was based on the results obtained in patients Theoretically, the aim of this regimen was to give a steady-state concentration of midazolam 250 ng ml" 1 from 45 min onwards. Data analysis The differential equations (Appendix) were fitted to the individual plasma concentration-time data by the non-linear least square regression program DARE-MINUIT (University of Uppsala, Uppsala, Sweden). The data points were given different weights (equal, \/y) to obtain the best fit. The pharmacokinetics of midazolam were calculated using the equations given in the Appendix. Statistical analysis Mean values and standard deviations were calculated using standard equations. All data are presented as mean±sd. Comparison between groups was made with Student's t test. A P-value < 0.05 was considered significant. Linear regression was used to evaluate the relationship between the pharmacokinetics and body weight: correlation coefficients were calculated according to Pearson (Colton, 1974). RESULTS Pharmacokinetics The relationships between mean plasma midazolam concentrations and time, for the two patient groups (1-10 and 11-15) are shown in figure 3. The mean initial concentrations, 2 min after the bolus dose, were 1254 ± 626 ng ml" 1 in patients 1-10 and 919±272ngml~ 1 in patients These values were not significantly different (P > 0.05). The mean concentrations at the end of the infusion were 317 ±74 ng ml" 1 (range ng ml" 1 ) in the first group and 3±48ngml" 1 (range ng ml" 1 ) in the second group of patients (P > 0.05). The simulated concentration, 2 min after the bolus dose, was 52% lower than the mean observed concentration. At the end of the infusion this difference was 6 % in patients 1-10, compared with 47% in patients The simulated concentrations, 30 min after the end of the infusion, were 14% higher in patients 1-10 and 22% lower in patients The best individual fit to the pharmacokinetic data following i.v. infusion was obtained by a

4 PHARMACOKINETICS OF MIDAZOLAM ' r M Time (mm) Time (mini FIG. 3. Observed midazolam plasma concentrations for patients 1-10 (top) and for patients (bottom). Mean values±sem. I and II represent the duration of the first and the second infusion, respectively. two-compartment open model (fig. 1). The resulting fit to the data for one patient is shown in figure 4. The mean values of the calculated rate constants are shown in table III. The total plasma clearance (C/) of midazolam was 483 ±109 ml min" 1, range ml min" 1. After correction for body weight the variations in clearance ranged between 5.55 and ml min" 1 kg" 1. The mean clearance in patients 1-10 was 512 ml min" 1 compared with 426 ml min" 1 in patients The apparent volume of distribution (FDP) for midazolam also showed a two-fold variation ( litre kg" 1 ) with a mean of 1.94±0.55 litre kg" 1. This resulted in a mean terminal elimination half-life (TjP) of 3.1 h (range h) while the mean half-life for the distribution phase (7*j a ) was 18 min. The volume TABLE III. Mean values of the calculated rate constant! of midazolam in IS surgical patients Mean ±SD (min ') (min- 1 ) (min" 1 )

5 552 BRITISH JOURNAL OF ANAESTHESIA 1000 ^ 300 I I E Time (mm) 480 FIG. 4. Midazolam plasma concentrations for patient No. 7. The straight line represents the fit; the broken line represents the simulated concentrations. I = Initial infusion; II = maintenance infusion. of the central compartment was litre kg" 1 ±0.1. The individual pharmacokinetic parameters are presented in table IV. There was a good correlation between body weight and the total apparent volume of distribution (r = 0.72; P < 0.01) with a tendency towards a proportionate increase in volume of distribution even after correction for body weight (r = 0.428; P > 0.05) (fig. 5). Furthermore, there was a weak correlation between the elimination half-life and increasing body weight (r = 0.567; P < 0.05). On the other hand, total clearance (Cl) did not change significantly with increasing body weight (r = ; P > 0.05). The mean blood loss during the investigation was around ml (includes surgery and blood sampling). Correlation between performance and plasma concentration The mean plasma concentration of midazolam at the time of extubation was 166 ±38 ng ml" 1. TABLE IV. Individual pharmacokinetic parameters of midazolam in 15 surgical patients: total plasma clearance (Cl), volume of the central compartment (V,), apparent volume of distribution (Vr/), distribution half-life (T ") and the elimination half-life ^ Pauent No. Cl (ml min" 1 ) (litre kg (litre kg~ J f (min) 'IT (h) Mean ±SD :

6 PHARMACOKINETICS OF MIDAZOLAM o E ~ 160 a o N CD S 120 'S Body weight (kg) r FIG. 5. Correlation of total body weight to midazolam volume of distribution (Kr>P) (expressed both with and without correction for total body weight). Solid lines were determined by linear regression analysis. Mean time from extubation until the patient was able to give her name and date of birth was 76 ±62 min; mean plasma concentration of midazolam at this time was 104 ±38 ngml" 1. The ability to solve simple arithmetic problems was established at 89 ±63 min after extubation; the corresponding plasma concentration of midazolam was 96 ±42 ngml" 1. DISCUSSION Drugs administered i.v. in anaesthetic practice are usually characterized by a rapid onset, and a short duration, of action. For most agents, the short duration of action results from a rapid decrease in plasma concentration as a result of extensive redistribution from brain to poorly-perfused tissues. However, when an infusion is administered i.v. at a constant rate, the total body 90 clearance of the drug determines the steady-state plasma concentration, and the terminal elimination half-life has an important influence on the duration of action after the discontinuation of the infusion. When considering the pharmacodynamic and pharmacokinetic properties of drugs in total i.v. anaesthesia, account has to be taken of the various factors which can influence the action of the drugs, such as the hepatic blood flow, protein binding and the drug metabolizing capacity of the patient as well as the concomitant use of other drugs. Knowledge of the plasma concentration required for hypnotic or analgesic effects as well as reliable pharmacokinetic data are also essential. Pharmacokinetics of midazolam A three-compartment model for midazolam has been proposed (Smith, Eadie and O'Rourke Brophy, 1981; Avram, Fragen and Caldwell, 1983). However, a biexponential elimination gave the best fit to the individual data in this study, and the midazolam kinetics obtained were similar to those reported by others. The mean total plasma clearance of 483 ml min" 1 was similar to those found in healthy volunteers (Greenblatt et al., 1984; Smith, Eadie and O'Rourke Brophy, 1981) and in surgical patients (Lauven et al., 1981; Avram, Fragen and Caldwell, 1983; Harper et al., 1985). Changes in hepatic blood flow during surgery may influence total body clearance. However, the clearance values found in the present study did not differ from those reported from studies in healthy volunteers indicating a negligible influence of surgery. The apparent volume of distribution (FDP) of midazolam obtained in the present study (1.94 litre kg" 1 ) was comparable to those in previous studies (Lauven et al., 1981; Smith Eadie and O'Rourke Brophy, 1981; Harper et al., 1985). The tendency towards an increasing volume of distribution with increasing body weight (fig. 5) indicates that the bolus injection and loading infusion should be relatively higher in obese patients. On the other hand, there was no indication for a different maintenance infusion in these patients, since the plasma clearance did not depend on body weight. The influence of body weight on midazolam disposition is consistent with the findings of others for midazolam (Greenblatt et al., 1984), and for other lipophilic benzodiazepines such as diazepam (Abernethy and Greenblatt, 1982).

7 554 The infusion regimen This study was based on the assumption that the hypnotic effect of midazolam is correlated with its plasma concentration (Allonen, Ziegler and Klotz, 1981; Aaltonen et al., 1985). Compared with midazolam, the main metabolite a-hydroxy midazolam has less hypnotic activity and a shorter elimination half-life (Crevoisier et al., 1983; Ziegler et al., 1983), indicating that a continuously maintained plasma concentration of midazolam should give a stable therapeutic effect without cumulation. In a previous study, a plasma concentration of midazolam of around ng ml" 1 was found to produce satisfactory anaesthesia during major surgery when used in combination with fentanyl (Nilsson, Tamsen and Persson, 1986). The time taken to attain a steady-state plasma concentration is dependent upon the half-life of the drug. Approximately 90 % of the steady-state concentration will be attained after three halflives, that is about 9 h for midazolam. However, in a two-compartment system (as for midazolam) the time to reach the steady-state plasma concentration depends on the fraction of the total area (AUC) associated with the terminal phase. If this fraction is small, then the time to reach a plasma steady-state will be governed mainly by the distribution half-life (7^ ). However, for midazolam the terminal half-life will primarily determine the time to reach a steady-state plasma concentration, since the terminal phase represents the major part of the total area. To achieve a steady-state concentration more rapidly, a bolus dose was combined with a two-stage infusion regimen. There are several possible approaches to designing an infusion regimen (Wagner, 1974; Schwilden et al., 1983). The advantage of the present method is that the high initial concentration produced a relatively rapid onset of action. It is an advantage to have a relatively high concentration of the anaesthetic drug at the moment of intubation and at the beginning of surgery, and the high therapeutic index (Pieri et al., 1981) of midazolam did not contraindicate this method. Prolonged infusion will not, with the present infusion strategy, result in an increasing plasma concentration of midazolam. This is important, since a high concentration at the end of surgery could lead to marked postoperative sedation. BRITISH JOURNAL OF ANAESTHESIA The dose regimen calculated from simulations in a two-compartment model indicated a constant concentration of midazolam from 45 min onwards (fig. 2). In some patients, however, a steady-state concentration was not achieved during the infusion. The main reason for the discrepancy between simulated and observed data in these patients is probably the assumption of instantaneous equilibrium within each compartment in the simulation model. In reality, the distribution process within each compartment might have been slower. This is probably the explanation of the fact that the observed concentration, 2 min after the bolus dose, was significantly higher than the simulated concentration. Moreover, the relatively short period of infusion was probably insufficient to establish steady-state conditions. However, there is a tendency to a plateau phase (fig. 3) with reasonably good correlations with predicted values, although there were rather large interindividual differences. Midazolam is almost completely metabolized in the liver indicating an intermediate value of hepatic extraction ratio of midazolam. Thus, the clearance of midazolam depends on the metabolic capacity of the liver, the fraction of unbound midazolam and the hepatic blood flow (Rowland, Benet and Graham, 1973; Wilkinson and Shand, 19). Interindividual differences in these indices may influence the concentration at, and the time to achieve, steady-state. In fact, the interindividual variability in the pharmacokinetics was greater in the present study than in the study by Lauven and colleagues (1981) (table II; table IV). Patients 1-10 showed a slightly higher plasma clearance than had initially been assumed. Patients had their infusion regimen modified based on the results from these first 10 patients. The aim of the modified regimen was to decrease the steady-state value and, thereby, decrease postoperative sedation. However, the steady-state value achieved in patients did not differ from that in the first 10 patients, most probably as a result of the fact that patients had a lower mean plasma clearance than patients On the other hand, the peak values were reduced. Concentration and effect of midazolam after infusion The initial decrease in the plasma concentration of midazolam after the termination of the infusion was rapid, from about 350 ng ml" 1 to 150 ng ml" 1 in 1 h. Clinically, these values correspond to an

8 PHARMACOKINETICS OF MIDAZOLAM 555 anaesthetized patient and to a patient responding to verbal stimuli in the postoperative period, respectively. This rapid decline is partly the result of metabolism and partly the result of the continuous re-distribution of midazolam from the central to the peripheral compartment. Following this rapid phase, however, the decline in plasma concentration is slower, the patients often drifting back into sleep when undisturbed. This phase lasts for several hours, indicating that midazolam is being released slowly from the peripheral compartment. The data demonstrated a relatively good correlation between the plasma concentrations of midazolam and postoperative sedation, despite the variations in the alfentanil plasma concentrations (Persson and colleagues, 1986; unpublished observations). Concentrations of midazolam in excess of 50- ng ml" 1 signify postoperative drowsiness. When simulated and observed plasma concentrations are compared, a tendency is seen for the simulated concentration to be lower during the infusion and higher after the termination of the infusion. This could partly be explained, as mentioned above, by the fact that a steady-state condition was not achieved during the investigation. After the termination of the infusion this would result in a greater distribution from the central to the peripheral compartment than that predicted by the simulation. After the infusion, distribution will have less influence than elimination on the plasma concentration decay with time. Theoretically, this implies that the duration of the hypnotic effect and hence, postoperative sedation, might be more pronounced after the infusion, than following a single i.v. bolus. CONCLUSION This investigation showed that, during surgery and in combination with the opioid drug alfentanil, midazolam showed a pharmacokinetic behaviour not unlike that previously reported from studies in healthy volunteers. We believe that the predictable, and relatively rapid, elimination of midazolam (and the low hypnotic activity of its metabolites) make midazolam a suitable hypnotic for use in a total i.v. technique. APPENDIX Midazolam kinetics after the infusion regimen are described by differential equations according to a two-compartment model (fig. 1): Change of the amount of drug (/I,) with time in the central compartment: da,/dt = J? ln,-*,o At-k,, A, +* A, where R tal = rate of infusion (mg min" 1 )- Change of the amount of drug (A,) with time in the peripheral compartment: The resulting concentration-time profile in the central compartment (C,) was obtained by the following relationship: where V l = volume of central compartment (1). The disposition rate constants (or and ft) were estimated from the fractional rate constants: The total plasma clearance (CO and the apparent volume of distribution (VD$) were calculated from: Total dose AUC The area under the concentration-time curve (AUC) was calculated by the trapezoidal rule. The residual area beyond the last sampling point to infinity was determined from the calculated concentration at the final sampling time divided by the terminal slope (/J). ACKNOWLEDGEMENT The authors thank Ms Veiny Eriksson for technical assistance. The study was financially supported by a grant from Roche-Produkter AB, Sweden. REFERENCES Aaltonen, L., Himberg, J.-J., Kanto, J., and Vouri, A. (1985). The usefulness of radiorecoptor assay and gas liquid chromatography in pharmacokinetic studies on midazolam. Int. J. Clin. Pharm. Ther. Toxicol., 23, 247. Abemethy, D. R., and Greenblatt, D. J. (1982). Pharmacokinetics of drugs in obesity. Clin. Pharmacokinet., 7, 108. Allonen, H., Ziegler, G., and Klotz, U. (1981). Midazolam kinetics. Clin. Pharmacol. Ther., 30, 653. Avram, M. J., Fragen, R. J., and Caldwell, N. J. (1983). Midazolam kinetics in women of two age groups. Clin. Pharmacol. Ther., 34, 505. Brodsky, J. B. (1983). The toxicity of nitrous oxide; in Clinics in Anaesthesiology, 1, p Eastbourne: Saunders. Chanarin, I. (1980). Cobalamine and nitrous oxide: a review. J. Clin. Pathol., 33, 909. Colton, T. (1974). Statistics in Medicine, p Boston: Little, Brown and Company. Crevoisier, C, Ziegler, W. H., Eckert, M., and Heizmann, P. (1983). Relationship between plasma concentration and effect of midazolam after oral and intravenous administration. Br.J. Clin. Pharmacol., 16, 5IS.

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