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PHARMACOKINETICS OF ALFENTANIL IN TOTAL I. V. ANAESTHESIA†
Br. J. Anaesth. (1988), 60, 755-761
PHARMACOKINETICS OF ALFENTANIL IN TOTAL I.V. ANAESTHESIA! M. P. PERSSON, A. NILSSON AND P. HARTVIG
PATIENTS, MATERIAL AND METHODS
Patients Ten female patients, undergoing elective abdominal hysterectomy, participated in the study. Their ages varied between 36 and 53 yr and their body weights between 53 and 88 kg (table I). The study was approved by the Ethics Committee of the Medical Faculty of Uppsala University ; informed consent was obtained from each patient. M. PETER PERSSON*, Department of Biopharmaceutics and Pharmacokinetics, University of Uppsala. ANDERS NILSSON
(Department of Anaesthesiology); PER HARTVIG (Hospital Pharmacy); University Hospital, Uppsala, Sweden. Accepted for Publication: November 11, 1987. *Present address, for correspondence: Sjukhusapoteket, University Hospital, S-221 85 Lund, Sweden. tPresented in part at the third World Conference on Clinical Pharmacology and Therapeutics, Stockholm, Sweden, July 27-August 1, 1986.
SUMMARY Alfentanil was administered, together with midazolam, as part of a total i.v. anaesthetic technique. The pharmacokinetics of alfentanil were determined in 10 female patients undergoing lower abdominal surgery. The dose regimen of alfentanil, based on simulation studies, consisted of a two-stage infusion following an initial bolus dose. The kinetics of alfentanil were described by a linear two-compartment open model. The total plasma clearance ranged between 93 and 431 ml min'1(mean 249 ml min~r). The apparent volume of distribution at steady-state ranged between 0.27 and 0.64 litre kg-' (mean 0.44 litre kg-1). The apparent volume of distribution (\ldp) was 0.58 litre kg~', resulting in a terminal half-life of 112 min. Alfentanil concentrations at the time of extubation and postoperative analgesic requirements were also monitored. Good correlation between respiratory depression and plasma alfentanil concentration was found. Neither lower abdominal surgery nor the simultaneous administration of midazolam seemed to affect the kinetics of alfentanil as compared with results from studies in healthy volunteers. The short ha If-life of alfentanil, resulting from a small volume of distribution, makes it suitable as part of a total i. v. technique. Consideration must be paid, however, to interindividual differences in the pharmacodynamic response and in plasma clearance.
Premedication and anaesthetic procedure
Pethidine 75 mg and atropine 0.5 mg were given i.m. as premedication 30 min before the induction of anaesthesia. Anaesthesia was induced with bolus doses of alfentanil and midazolam and maintained with infusions of these drugs. Alfentanil was administered as an initial bolus
Downloaded from http://bja.oxfordjournals.org/ at Emory University on August 23, 2015
Increasing awareness of the toxic and metabolic problems associated with the use of nitrous oxide [1-3] has led to a greater interest in the technique of total i.v. anaesthesia. The present report describes the use of midazolam and alfentanil in such a technique. Alfentanil is an analgesic which offers a rapid onset of action as well as haemodynamic stability. In addition, it has a short elimination half-life [4,5]. If alfentanil is to be included in a total i.v. technique, knowledge of its pharmacokinetics, and of its interactions with other drugs during anaesthesia, is of fundamental importance for its rational and safe use. The aims of the present investigation were: to construct a dose regimen based on simulation studies which may be used to provide analgesia during surgery; to determine the pharmacokinetics of alfentanil during major surgery; and to compare the simulated and the observed plasma concentration-time profiles.
BRITISH JOURNAL OF ANAESTHESIA
756
TABLE I. Body weight, total infusion time, total dose of alfentanil and area under the concentration-time curve (AUC) in 10 female surgical patients
No.
Weight (kg)
Duration of infusion (min)
Total dose (mg)
(mg min litre"1)
1 2 3 4 5 6 7 8 9 10
53 66 81 88 64 66 65 67 76 56
75 90 75 75 75 75 75 75 75 75
11.2 15.1 17.2 18.7 13.6 14.0 13.8 14.2 16.2 11.9
28.6 52.9 39.9 94.3 48.3 70.6 48.9 99.0 173.2 65.2
Patient
Plasma concentrations of alfentanil were determined with a specific radioimmunoassay with a claimed sensitivity of 50 pg and intra- and interindividual assay variations of 3.7 and 3.3%, respectively [6]. Postoperative observation
Before extubation of the trachea, ventilation was reduced gradually to give an end-tidal carbon dioxide concentration of at least 6%. If spontaneous ventilation did not return, naloxone 0.1 mg was given i.v. The length of time between the end of the infusion of alfentanil and the first postoperative analgesic dose of ketobemidone was recorded.
I t
1
Blood sampling and assay
~
Blood samples were collected from a peripheral vein before and at 2, 5, 10 and 15 min after the start of the infusion regimen, and then every 15 min until the infusion was terminated. After the infusion, samples were drawn at 2, 5, 10, 15, 30 and 60 min and then every 1 h for 6 h. The plasma was separated and stored at — 20 °C until assayed. TABLE II. Mean alfentanil pharmacokinelic values used for the simulation in five patients scheduled for elective surgery under general anaesthesia [5 /
Total plasma clearance (ml min"1) Apparent volume of distribution (litre kg"1) Elimination half-life (min)
235 0.44 87
600 -'.
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120 Time (min)
240
FIG. 1. Simulated concentration-time profiles for alfentanil, for the dose regimen used in the present study (—) and the dose regimen used by Fragen and colleagues [5] (-•-).
Downloaded from http://bja.oxfordjournals.org/ at Emory University on August 23, 2015
dose of 75 ug kg ' in combination with a twostage infusion consisting of 5 ug kg"1 min"1 for 15 min followed by 1.0 ug kg"1 min"1 until closure of the abdomen commenced. The total duration of alfentanil infusion corresponded to doses of 11.2-18.7 mg, with a mean dose of 14.6 mg (table I). Midazolam was given as an initial bolus dose of 300 or 250 ug kg"1 (patients Nos 1-5 and 6-10, respectively) followed by a two-stage infusion consisting of 11 ug kg"1 min"1 for 15 min and 2.1 ug kg"1 min"1 for as long as the alfentanil infusion was maintained. Neuromuscular blockade was achieved with pancuronium in all patients, and artificial ventilation (end-tidal carbon dioxide = 4.0 + 0.2%) with oxygen in air (FiOz = 0.3) was provided during anaesthesia. At the end of surgery, neuromuscular blockade was antagonized with neostigmine 2.5 mg plus atropine 1.0 mg.
AUC
ALFENTANIL PHARMACOKINETICS IN I.V. ANAESTHESIA
where k0 is the maintenance infusion rate, Cl the total plasma clearance and C55 the desired steadystate plasma concentration.
obtained estimates of the micro-rate constants k10, kl2 and k21, m e following equations were used to calculate the disposition rate constants (a and P) and the apparent volume of distribution (Fd p ).
k -5L 10
(2)
~ k K2
(3) (4)
Non-compartmental pharmacokinetic analysis Based on the compartment-independent approaches, the total plasma clearance (Cl) and the apparent volume of distribution at steady-state (Fdss) were calculated from the following equations [9]:
Compartmental pharmacokinetic analysis _ Total dose • AUMC For fitting of a two-compartment open model to ~ AUC2 the observed individual plasma concentration(A • T + B- T1 -2 + B- T2) time data, the non-linear least square regression (6) program DARE-MINUIT (University of Upp2 • AUC sala, Sweden) was used. The data points were 1 1 weighted as equal or 1 /y (y = plasma concentration where 7 and T are the infusion times and A and value) to obtain the best fit. On the basis of the B are the infused doses during the infusions at the first and second rates, respectively. The area under the concentration-time curve (AUC) and the area under the curve of the product of time 1000 and drug concentration (AUMC) for the individual curves were calculated with the linear trapezoid rule up to the last data point. The extrapolated area to infinite time for AUC and AUMC beyond the last data point was estimated by integration [9]. RESULTS
3060 120
240
480
"7 (i ' Time (min) FIG. 2. The concentration-time profiles for the two patients with the lowest ( # ) and highest (A) steady-state concentrations. The solid lines show the fit and the broken line the simulated concentrations. I and II represent the durations of the first and second infusions, respectively.
The dose regimen for alfentanil resulted in a mean (±SD) plasma concentration of 291 + 132 ng ml"1 (range 146-602 ng ml"1) at the end of the infusion (table III). The concentration-time profile for the two patients with the lowest and highest steady-state concentrations are shown in figure 2. The mean plasma alfentanil concentration-time profile for all patients, and the resulting fit to these data are shown in figure 3. The mean values (±SD) of the rate constants (kw> k12 and &21) were 1.20 + 0.52, 1.83 + 0.72 and 1.29 ±0.47 h"1, respectively.
Downloaded from http://bja.oxfordjournals.org/ at Emory University on August 23, 2015
Design of alfentanil infusion regimen It was intended that the infusion of alfentanil should give a steady-state concentration of about 300 ng ml"1, which has been found to be satisfactory in patients ventilated with nitrous oxide [4]. The infusion regimen was constructed after numerous simulation studies based on published pharmacokinetic data (table II). The resulting concentration-time profile is shown in figure 1, together with the simulated profile for the dose regimen used by Fragen and colleagues [5]. Simulations were performed with the aid of the simulation program DARE-P [7]. The maintenance infusion was calculated from the equation. [8]:
757
BRITISH JOURNAL OF ANAESTHESIA
758
TABLE III. The individual plasma alfentanil concentrations and the time interval from termination of infusion to the first analgesic dose of ketobemidone given during the first 6 h after operation. * Required naloxone 0.1 mg
Plasma alfentanil concentration
1 2 3 4 5 6 7 8 9 10
146 199 195 359 228 334 219 364 602 266
at extubation (ng ml"') 85 130 75
260* 130 160 140
290* 370* 195
The total plasma clearance of alfentanil ranged between 93 and 431 ml min"1 (mean 249 ml min"1). When adjusted to body weight, the plasma clearance ranged between 1.22 and 7.42 ml min"1 kg"1. The apparent volume of distribution varied four-fold, from 0.25 to 0.96 litre kg"1, with a mean of 0.58 litre kg"1. The variation in the apparent volume of distribution at steady-state was less, with a range from 0.27 to 0.64 litre kg"1 (mean 0.44 litre kg"1). The terminal elimination half-life 1000
at the first analgesic (ng ml'1)
Time to the first analgesic (min)
28 51 — 110 21 40 — 190 — —
125 155 — 245 300 275 — 110 — —
of alfentanil ranged between 72 and 170 min (mean 112min).The individual pharmacokinetic parameters are presented in table IV. Three of the patients required naloxone because of respiratory depression at the time of extubation. In these patients the plasma concentration of alfentanil averaged 307 ng ml"1. The corresponding mean plasma concentration in those who did not require naloxone (« = 7) was 131+41 ng ml"1 (table III). This difference is statistically significant (Wilcoxon rank sum test: P < 0.02). Six patients required supplementary analgesia during the first 6 h after termination of the infusion; of these, two had been given naloxone. The mean time from the end of the infusion to the first dose of analgesic was 201 min, and at the time of this dose the mean plasma concentration of alfentanil was 73 ng ml"1 (range 21-190 ng ml"1). The concentrations in the two patients who were also given naloxone were 110 and 190 ng ml"1, which may be compared with the mean value of 35 ng ml"1 (range 21-51 ng ml"1) in the other four patients (table III). DISCUSSION
120
240 Time (min)
480
FIG. 3. Mean (+ SEM) alfentanil concentration-time profile. The solid line shows the fit and the broken line the simulated concentrations. I and II represent the durations of the first and second infusions, respectively.
It is desirable that drugs used in a total l.V. technique have a prompt and stable effect during surgery and that this effect ceases rapidly once the infusion is terminated. I.v. agents used in anaesthesia usually have residual postoperative side effects such as respiratory depression, excessive sedation and somnolence, resulting in prolonged recovery. The dynamics and kinetics of alfentanil,
Downloaded from http://bja.oxfordjournals.org/ at Emory University on August 23, 2015
No.
at end of infusion (ng ml"')
Patient
ALFENTANIL PHARMACOKINETICS IN I.V. ANAESTHESIA
759
TABLE IV. Individual pharmacokinetic variables of alfentanil in 10 surgical patients: total plasma clearance (Cl), volume of the central compartment (Vj) apparent volume at steady-state (Vd"), apparent volume of distribution (V
c/
Vi
No.
(ml min"1)
(ml kg"1)
Fd s s (litre kg-1)
(litre kg"1)
(min)
1 2 3 4 5 6 7 8 9 10
393 285 431 198 282 199 282 144 93 183 249 106 43
182 167 188 195 257 182 256 151 101 221 190 47 25
0.53 0.54 0.64 0.36 0.49 0.37 0.51 0.29 0.27 0.44 0.44 0.12 27
0.76 0.85 0.96 0.25 0.72 0.50 0.85 0.32 0.30 0.49 0.58 0.25 43
72 137 125 78 113 115 104 103 170 104 112 28 25
with its rapid onset of action resulting from fast distribution to the brain [10], together with its rapid plasma elimination [5], make it a promising analgesic for total i.v. anaesthesia. The lack of pharmacologically active metabolites [11] and the absence of significant interactions with other drugs are other advantages which further emphasize the suitability of alfentanil. Pharmacokinetics
partment system is the volume of distribution at steady-state (Fdss). The apparent volume of distribution (Kdp) of alfentanil is dependent on the drug elimination and overestimates Vdss, since this drug is rapidly cleared from the central compartment. Fdss is independent of drug elimination. The restricted distribution of alfentanil contrasts with that of other opioids such as fentanyl, morphine and pethidine. This difference may be explained by factors such as the high plasma protein binding and the low lipid solubility of alfentanil. The time taken for the concentration of a drug to reach steady-state is dependent upon the elimination half-life. A short half-life, as a result of a small volume of distribution rather than of high clearance, may facilitate the attainment of a steady-state value in plasma during a relatively short infusion period. The mean ratio of P/&10 for alfentanil is 0.31, as compared with 0.14 and 0.07 for fentanyl and morphine, respectively [12,15]. The ratio indicates how "two compartment" a drug is. A small value denotes a drug with a greater fraction in the peripheral compartment. Thus, the rapid distribution of alfentanil because of its small volume of distribution suggests that it is a drug for which steady-state is more rapidly attained than in the case of other opioids.
The total body clearance of a drug determines the plasma concentration at steady-state. The mean total plasma clearance of alfentanil in the present study (249 ml min"1) was of the same order as that previously observed in healthy volunteers [12]. Thus the influence of the surgical procedure, and of other concomitantly administered drugs, on the clearance of alfentanil seems to be negligible. Alfentanil is eliminated mainly by hepatic metabolism and the hepatic extraction ratio can be calculated to be about 0.3, assuming a blood:plasma ratio of 0.63 [13]. The clearance of such a drug is dependent upon protein binding in the plasma and intrinsic hepatic clearance [14]. Thus, possible changes in hepatic blood flow during the surgical procedure are probably of only minor interest, since the clearance value indicates flow-independent hepatic elimination. On the other hand, a possible increase in the plasma concentration of a!-acid glycoprotein The infusion regimen during the surgical procedure may decrease the It was the aim in the present study to reach a clearance. steady-state plasma concentration of 300 ng ml"1. The most useful volume term for describing The mean observed plasma concentration at the the apparent distribution space in a multicom- end of the infusion (291 ng ml"1) was very close
Downloaded from http://bja.oxfordjournals.org/ at Emory University on August 23, 2015
Mean + SD CV (%)
KdH
760
The postoperative period
There seems to be a correlation between respiratory depression and plasma alfentanil concentration, and the three patients with significantly higher concentrations than the others at the time of extubation were given naloxone to restore adequate ventilation (table III).
The mean plasma concentration at the time when supplementary analgesia was required (73 ng ml"1) (« = 6) is an indication of the minimum analgesic plasma concentration of alfentanil reached in the postoperative period. This minimum plasma concentration, however, showed a large interindividual variation, which could be explained by the concomitant administration of midazolam or by variations in the endogenous pain inhibitory system—that is, the endorphine system, a determinant of postoperative analgesic requirement [18]. Furthermore, the administration of naloxone at the time of extubation in two of these patients may have influenced the value. The mean plasma concentration of 35 ng ml"1 found for the four patients who did not require naloxone, may be a better indication of the minimum effective analgesic concentration of alfentanil. CONCLUSION
Alfentanil has a rapid distribution and a short half-life which are not influenced by anaesthesia or concomitantly administered midazolam. Furthermore, the pharmacokinetic properties of alfentanil in combination with its high analgesic potency make it suitable for infusion in a total i.v. technique. Consideration must be paid, however, to interindividual variations in the pharmacokinetic data, and to variations in analgesic requirements during the various stages of surgery. REFERENCES 1. Chanarin I. Cobalamines and nitrous oxide: a review. Journal of Clinical Pathology 1980; 33: 909-916. 2. Brodsky JB. The toxicity of nitrous oxide. In: Clinics in Anaesthesiology. Eastbourne: Saunders, 1983; 455-467. 3. Mazze RI. Waste anaesthetic gases: A health hazard? In: Clinics in Anaesthesiology. Eastbourne: Saunders, 1983; 431-454. 4. Bovill JG, Sebel PS, Blackburn CL, Heykants J. The pharmacokinetics of alfentanil: A new opioid analgesic. Anesthesiology 1982; 57: 439-443. 5. Fragen RJ, Booij LHDJ, Braak GJJ, Vree TB, Heykants J, Crul JF. Pharmacokinetics of the infusion of alfentanil in man. British Journal of Anaesthesia 1983; 55: 10771081. 6. Michiels M, Hendricks R, Heykants J. Radioimmunoassay of the new opiate analgesics alfentanil and sufentanil. Preliminary pharmacokinetic profile in man. Journal of Pharmacy and Pharmacology 1983; 35: 86-93. 7. Wait JV, Clarke F. DARE-P, a Portable Digital Simulation System. Tuscon, USA: University of Arizona, 1974. 8. Kruger-Theimer E. Continuous intravenous infusion and
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to the predicted concentration. The plasma clearance, however, varied more than four-fold, resulting in large interindividual differences in concentration at the end of the infusion (fig. 2, table III). These differences in plasma clearance were probably caused by variation in the hepatic metabolic capacity [16]. Furthermore, interindividual differences in protein binding may also influence clearance. Even so, the attempt to achieve steady-state can be considered successful, since the concentration was stable in most patients during the maintenance infusion. The accuracy of using average pharmacokinetic data to design infusion regimens could be evaluated by comparing the predicted with the observed concentrations. The correlation between the predicted and mean observed plasma concentrations was excellent during the maintenance infusion (fig. 3). However, the large variation in observed concentrations at steady-state (fig. 2) demonstrate the difficulty in predicting doses for individual patients. There was a difference between predicted and mean observed concentrations after the infusion, since the terminal half-life found in the present study was somewhat longer than the value used for the simulation (tables II, IV). Fragen and colleagues [5] used the combination of a bolus (80 ug kg"1) with a single constant i.v. infusion (3 ug kg"1 min"1) to achieve rapidly and maintain plasma concentrations necessary to provide adequate analgesia. The advantage of the present infusion regimen over that used by Fragen and colleagues is that prolonged infusion will not result in increasing concentrations of alfentanil (fig. 1). A high concentration at the end of an infusion will lead to postoperative respiratory depression. The disadvantage of a fixed infusion rate is that no consideration is paid to the interindividual variation in the pharmacokinetics or to the varying degree of surgical stimulation. Our maintenance infusion rate of 1.0 ug min"1 kg"1 is in accord with published data on the dose requirements of alfentanil in combination with nitrous oxide [17].
BRITISH JOURNAL OF ANAESTHESIA
ALFENTANIL PHARMACOKINETICS IN I.V. ANAESTHESIA
9. 10. 11. 12. 13.
Rowland M, Benet LZ, Graham GC. Clearance concepts in pharmacokinetics. Journal of Pharmacokinetics and Biopharmaceutics 1973; 1: 123-136. Sawe J, Dahlstrom B, Paalzow L, Rane A. Morphine kinetics in cancer patients. Clinical Pharmacology and Therapeutics 1981; 30: 629-634. Henthorn TK, Spina E, Birgersson C, Ericsson O, von Bahr C. In vitro competitive inhibition of desipramine hydroxylation by alfentanil and fentanyl. Anesthesiology 1985; 63: A305. Ausems ME, Hug CC, de Lange, S. Variable rate infusion of alfentanil as a supplement to nitrous oxide anesthesia for general surgery. Anesthesia and Analgesia 1983; 62: 982-986. Tamsen A, Sakurada T, Wahlstrom A, Terenius L, Hartvig P. Postoperative demand for analgesics in relation to individual levels of endorphines and substance P in cerobrospinal fluid. Pain 1982; 13: 171-183.
Downloaded from http://bja.oxfordjournals.org/ at Emory University on August 23, 2015
multicompartment accumulation. European Journal of 14. Pharmacology 1968: 4: 317-324. Benet LZ, Galeazzi RL. Noncompartmental determination of the steady-state volume of distribution. Journal of 15. Pharmaceutical Sciences 1979; 8: 1071-1074. Spierdijk J, van Kleef J, Nauta J, Stanley TH, de Lange S. Alfentanil: a new narcotic anesthetic induction agent. 16. Anesihesiology 1980; S3: S32. Niemegeers CJE, Janssen PAJ. Alfentanil (R 39 209)—A particularly short-acting intravenous narcotic analgesic in rats. Drug Development Research 1981; 1: 83-88. 17. Bower, S, Hull CJ. Comparative pharmacokinetics of fentanyl and alfentanil. British Journal of Anaesthesia 1982; 54: 871-877. Meuldermans WEG, Hurkmans RMA, Heykants JJP. 18. Plasma protein binding and distribution of fentanyl, sufentanil, alfentanil and lofentanil in blood. Archives Internationales de Pharmacodynamie et de Therapie 1982; 25: 4-19.
761
PHARMACOKINETICS OF ALFENTANIL IN TOTAL I.V. ANAESTHESIA! M. P. PERSSON, A. NILSSON AND P. HARTVIG
PATIENTS, MATERIAL AND METHODS
Patients Ten female patients, undergoing elective abdominal hysterectomy, participated in the study. Their ages varied between 36 and 53 yr and their body weights between 53 and 88 kg (table I). The study was approved by the Ethics Committee of the Medical Faculty of Uppsala University ; informed consent was obtained from each patient. M. PETER PERSSON*, Department of Biopharmaceutics and Pharmacokinetics, University of Uppsala. ANDERS NILSSON
(Department of Anaesthesiology); PER HARTVIG (Hospital Pharmacy); University Hospital, Uppsala, Sweden. Accepted for Publication: November 11, 1987. *Present address, for correspondence: Sjukhusapoteket, University Hospital, S-221 85 Lund, Sweden. tPresented in part at the third World Conference on Clinical Pharmacology and Therapeutics, Stockholm, Sweden, July 27-August 1, 1986.
SUMMARY Alfentanil was administered, together with midazolam, as part of a total i.v. anaesthetic technique. The pharmacokinetics of alfentanil were determined in 10 female patients undergoing lower abdominal surgery. The dose regimen of alfentanil, based on simulation studies, consisted of a two-stage infusion following an initial bolus dose. The kinetics of alfentanil were described by a linear two-compartment open model. The total plasma clearance ranged between 93 and 431 ml min'1(mean 249 ml min~r). The apparent volume of distribution at steady-state ranged between 0.27 and 0.64 litre kg-' (mean 0.44 litre kg-1). The apparent volume of distribution (\ldp) was 0.58 litre kg~', resulting in a terminal half-life of 112 min. Alfentanil concentrations at the time of extubation and postoperative analgesic requirements were also monitored. Good correlation between respiratory depression and plasma alfentanil concentration was found. Neither lower abdominal surgery nor the simultaneous administration of midazolam seemed to affect the kinetics of alfentanil as compared with results from studies in healthy volunteers. The short ha If-life of alfentanil, resulting from a small volume of distribution, makes it suitable as part of a total i. v. technique. Consideration must be paid, however, to interindividual differences in the pharmacodynamic response and in plasma clearance.
Premedication and anaesthetic procedure
Pethidine 75 mg and atropine 0.5 mg were given i.m. as premedication 30 min before the induction of anaesthesia. Anaesthesia was induced with bolus doses of alfentanil and midazolam and maintained with infusions of these drugs. Alfentanil was administered as an initial bolus
Downloaded from http://bja.oxfordjournals.org/ at Emory University on August 23, 2015
Increasing awareness of the toxic and metabolic problems associated with the use of nitrous oxide [1-3] has led to a greater interest in the technique of total i.v. anaesthesia. The present report describes the use of midazolam and alfentanil in such a technique. Alfentanil is an analgesic which offers a rapid onset of action as well as haemodynamic stability. In addition, it has a short elimination half-life [4,5]. If alfentanil is to be included in a total i.v. technique, knowledge of its pharmacokinetics, and of its interactions with other drugs during anaesthesia, is of fundamental importance for its rational and safe use. The aims of the present investigation were: to construct a dose regimen based on simulation studies which may be used to provide analgesia during surgery; to determine the pharmacokinetics of alfentanil during major surgery; and to compare the simulated and the observed plasma concentration-time profiles.
BRITISH JOURNAL OF ANAESTHESIA
756
TABLE I. Body weight, total infusion time, total dose of alfentanil and area under the concentration-time curve (AUC) in 10 female surgical patients
No.
Weight (kg)
Duration of infusion (min)
Total dose (mg)
(mg min litre"1)
1 2 3 4 5 6 7 8 9 10
53 66 81 88 64 66 65 67 76 56
75 90 75 75 75 75 75 75 75 75
11.2 15.1 17.2 18.7 13.6 14.0 13.8 14.2 16.2 11.9
28.6 52.9 39.9 94.3 48.3 70.6 48.9 99.0 173.2 65.2
Patient
Plasma concentrations of alfentanil were determined with a specific radioimmunoassay with a claimed sensitivity of 50 pg and intra- and interindividual assay variations of 3.7 and 3.3%, respectively [6]. Postoperative observation
Before extubation of the trachea, ventilation was reduced gradually to give an end-tidal carbon dioxide concentration of at least 6%. If spontaneous ventilation did not return, naloxone 0.1 mg was given i.v. The length of time between the end of the infusion of alfentanil and the first postoperative analgesic dose of ketobemidone was recorded.
I t
1
Blood sampling and assay
~
Blood samples were collected from a peripheral vein before and at 2, 5, 10 and 15 min after the start of the infusion regimen, and then every 15 min until the infusion was terminated. After the infusion, samples were drawn at 2, 5, 10, 15, 30 and 60 min and then every 1 h for 6 h. The plasma was separated and stored at — 20 °C until assayed. TABLE II. Mean alfentanil pharmacokinelic values used for the simulation in five patients scheduled for elective surgery under general anaesthesia [5 /
Total plasma clearance (ml min"1) Apparent volume of distribution (litre kg"1) Elimination half-life (min)
235 0.44 87
600 -'.
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300 \
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100
30
60
120 Time (min)
240
FIG. 1. Simulated concentration-time profiles for alfentanil, for the dose regimen used in the present study (—) and the dose regimen used by Fragen and colleagues [5] (-•-).
Downloaded from http://bja.oxfordjournals.org/ at Emory University on August 23, 2015
dose of 75 ug kg ' in combination with a twostage infusion consisting of 5 ug kg"1 min"1 for 15 min followed by 1.0 ug kg"1 min"1 until closure of the abdomen commenced. The total duration of alfentanil infusion corresponded to doses of 11.2-18.7 mg, with a mean dose of 14.6 mg (table I). Midazolam was given as an initial bolus dose of 300 or 250 ug kg"1 (patients Nos 1-5 and 6-10, respectively) followed by a two-stage infusion consisting of 11 ug kg"1 min"1 for 15 min and 2.1 ug kg"1 min"1 for as long as the alfentanil infusion was maintained. Neuromuscular blockade was achieved with pancuronium in all patients, and artificial ventilation (end-tidal carbon dioxide = 4.0 + 0.2%) with oxygen in air (FiOz = 0.3) was provided during anaesthesia. At the end of surgery, neuromuscular blockade was antagonized with neostigmine 2.5 mg plus atropine 1.0 mg.
AUC
ALFENTANIL PHARMACOKINETICS IN I.V. ANAESTHESIA
where k0 is the maintenance infusion rate, Cl the total plasma clearance and C55 the desired steadystate plasma concentration.
obtained estimates of the micro-rate constants k10, kl2 and k21, m e following equations were used to calculate the disposition rate constants (a and P) and the apparent volume of distribution (Fd p ).
k -5L 10
(2)
~ k K2
(3) (4)
Non-compartmental pharmacokinetic analysis Based on the compartment-independent approaches, the total plasma clearance (Cl) and the apparent volume of distribution at steady-state (Fdss) were calculated from the following equations [9]:
Compartmental pharmacokinetic analysis _ Total dose • AUMC For fitting of a two-compartment open model to ~ AUC2 the observed individual plasma concentration(A • T + B- T1 -2 + B- T2) time data, the non-linear least square regression (6) program DARE-MINUIT (University of Upp2 • AUC sala, Sweden) was used. The data points were 1 1 weighted as equal or 1 /y (y = plasma concentration where 7 and T are the infusion times and A and value) to obtain the best fit. On the basis of the B are the infused doses during the infusions at the first and second rates, respectively. The area under the concentration-time curve (AUC) and the area under the curve of the product of time 1000 and drug concentration (AUMC) for the individual curves were calculated with the linear trapezoid rule up to the last data point. The extrapolated area to infinite time for AUC and AUMC beyond the last data point was estimated by integration [9]. RESULTS
3060 120
240
480
"7 (i ' Time (min) FIG. 2. The concentration-time profiles for the two patients with the lowest ( # ) and highest (A) steady-state concentrations. The solid lines show the fit and the broken line the simulated concentrations. I and II represent the durations of the first and second infusions, respectively.
The dose regimen for alfentanil resulted in a mean (±SD) plasma concentration of 291 + 132 ng ml"1 (range 146-602 ng ml"1) at the end of the infusion (table III). The concentration-time profile for the two patients with the lowest and highest steady-state concentrations are shown in figure 2. The mean plasma alfentanil concentration-time profile for all patients, and the resulting fit to these data are shown in figure 3. The mean values (±SD) of the rate constants (kw> k12 and &21) were 1.20 + 0.52, 1.83 + 0.72 and 1.29 ±0.47 h"1, respectively.
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Design of alfentanil infusion regimen It was intended that the infusion of alfentanil should give a steady-state concentration of about 300 ng ml"1, which has been found to be satisfactory in patients ventilated with nitrous oxide [4]. The infusion regimen was constructed after numerous simulation studies based on published pharmacokinetic data (table II). The resulting concentration-time profile is shown in figure 1, together with the simulated profile for the dose regimen used by Fragen and colleagues [5]. Simulations were performed with the aid of the simulation program DARE-P [7]. The maintenance infusion was calculated from the equation. [8]:
757
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TABLE III. The individual plasma alfentanil concentrations and the time interval from termination of infusion to the first analgesic dose of ketobemidone given during the first 6 h after operation. * Required naloxone 0.1 mg
Plasma alfentanil concentration
1 2 3 4 5 6 7 8 9 10
146 199 195 359 228 334 219 364 602 266
at extubation (ng ml"') 85 130 75
260* 130 160 140
290* 370* 195
The total plasma clearance of alfentanil ranged between 93 and 431 ml min"1 (mean 249 ml min"1). When adjusted to body weight, the plasma clearance ranged between 1.22 and 7.42 ml min"1 kg"1. The apparent volume of distribution varied four-fold, from 0.25 to 0.96 litre kg"1, with a mean of 0.58 litre kg"1. The variation in the apparent volume of distribution at steady-state was less, with a range from 0.27 to 0.64 litre kg"1 (mean 0.44 litre kg"1). The terminal elimination half-life 1000
at the first analgesic (ng ml'1)
Time to the first analgesic (min)
28 51 — 110 21 40 — 190 — —
125 155 — 245 300 275 — 110 — —
of alfentanil ranged between 72 and 170 min (mean 112min).The individual pharmacokinetic parameters are presented in table IV. Three of the patients required naloxone because of respiratory depression at the time of extubation. In these patients the plasma concentration of alfentanil averaged 307 ng ml"1. The corresponding mean plasma concentration in those who did not require naloxone (« = 7) was 131+41 ng ml"1 (table III). This difference is statistically significant (Wilcoxon rank sum test: P < 0.02). Six patients required supplementary analgesia during the first 6 h after termination of the infusion; of these, two had been given naloxone. The mean time from the end of the infusion to the first dose of analgesic was 201 min, and at the time of this dose the mean plasma concentration of alfentanil was 73 ng ml"1 (range 21-190 ng ml"1). The concentrations in the two patients who were also given naloxone were 110 and 190 ng ml"1, which may be compared with the mean value of 35 ng ml"1 (range 21-51 ng ml"1) in the other four patients (table III). DISCUSSION
120
240 Time (min)
480
FIG. 3. Mean (+ SEM) alfentanil concentration-time profile. The solid line shows the fit and the broken line the simulated concentrations. I and II represent the durations of the first and second infusions, respectively.
It is desirable that drugs used in a total l.V. technique have a prompt and stable effect during surgery and that this effect ceases rapidly once the infusion is terminated. I.v. agents used in anaesthesia usually have residual postoperative side effects such as respiratory depression, excessive sedation and somnolence, resulting in prolonged recovery. The dynamics and kinetics of alfentanil,
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No.
at end of infusion (ng ml"')
Patient
ALFENTANIL PHARMACOKINETICS IN I.V. ANAESTHESIA
759
TABLE IV. Individual pharmacokinetic variables of alfentanil in 10 surgical patients: total plasma clearance (Cl), volume of the central compartment (Vj) apparent volume at steady-state (Vd"), apparent volume of distribution (V
c/
Vi
No.
(ml min"1)
(ml kg"1)
Fd s s (litre kg-1)
(litre kg"1)
(min)
1 2 3 4 5 6 7 8 9 10
393 285 431 198 282 199 282 144 93 183 249 106 43
182 167 188 195 257 182 256 151 101 221 190 47 25
0.53 0.54 0.64 0.36 0.49 0.37 0.51 0.29 0.27 0.44 0.44 0.12 27
0.76 0.85 0.96 0.25 0.72 0.50 0.85 0.32 0.30 0.49 0.58 0.25 43
72 137 125 78 113 115 104 103 170 104 112 28 25
with its rapid onset of action resulting from fast distribution to the brain [10], together with its rapid plasma elimination [5], make it a promising analgesic for total i.v. anaesthesia. The lack of pharmacologically active metabolites [11] and the absence of significant interactions with other drugs are other advantages which further emphasize the suitability of alfentanil. Pharmacokinetics
partment system is the volume of distribution at steady-state (Fdss). The apparent volume of distribution (Kdp) of alfentanil is dependent on the drug elimination and overestimates Vdss, since this drug is rapidly cleared from the central compartment. Fdss is independent of drug elimination. The restricted distribution of alfentanil contrasts with that of other opioids such as fentanyl, morphine and pethidine. This difference may be explained by factors such as the high plasma protein binding and the low lipid solubility of alfentanil. The time taken for the concentration of a drug to reach steady-state is dependent upon the elimination half-life. A short half-life, as a result of a small volume of distribution rather than of high clearance, may facilitate the attainment of a steady-state value in plasma during a relatively short infusion period. The mean ratio of P/&10 for alfentanil is 0.31, as compared with 0.14 and 0.07 for fentanyl and morphine, respectively [12,15]. The ratio indicates how "two compartment" a drug is. A small value denotes a drug with a greater fraction in the peripheral compartment. Thus, the rapid distribution of alfentanil because of its small volume of distribution suggests that it is a drug for which steady-state is more rapidly attained than in the case of other opioids.
The total body clearance of a drug determines the plasma concentration at steady-state. The mean total plasma clearance of alfentanil in the present study (249 ml min"1) was of the same order as that previously observed in healthy volunteers [12]. Thus the influence of the surgical procedure, and of other concomitantly administered drugs, on the clearance of alfentanil seems to be negligible. Alfentanil is eliminated mainly by hepatic metabolism and the hepatic extraction ratio can be calculated to be about 0.3, assuming a blood:plasma ratio of 0.63 [13]. The clearance of such a drug is dependent upon protein binding in the plasma and intrinsic hepatic clearance [14]. Thus, possible changes in hepatic blood flow during the surgical procedure are probably of only minor interest, since the clearance value indicates flow-independent hepatic elimination. On the other hand, a possible increase in the plasma concentration of a!-acid glycoprotein The infusion regimen during the surgical procedure may decrease the It was the aim in the present study to reach a clearance. steady-state plasma concentration of 300 ng ml"1. The most useful volume term for describing The mean observed plasma concentration at the the apparent distribution space in a multicom- end of the infusion (291 ng ml"1) was very close
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Mean + SD CV (%)
KdH
760
The postoperative period
There seems to be a correlation between respiratory depression and plasma alfentanil concentration, and the three patients with significantly higher concentrations than the others at the time of extubation were given naloxone to restore adequate ventilation (table III).
The mean plasma concentration at the time when supplementary analgesia was required (73 ng ml"1) (« = 6) is an indication of the minimum analgesic plasma concentration of alfentanil reached in the postoperative period. This minimum plasma concentration, however, showed a large interindividual variation, which could be explained by the concomitant administration of midazolam or by variations in the endogenous pain inhibitory system—that is, the endorphine system, a determinant of postoperative analgesic requirement [18]. Furthermore, the administration of naloxone at the time of extubation in two of these patients may have influenced the value. The mean plasma concentration of 35 ng ml"1 found for the four patients who did not require naloxone, may be a better indication of the minimum effective analgesic concentration of alfentanil. CONCLUSION
Alfentanil has a rapid distribution and a short half-life which are not influenced by anaesthesia or concomitantly administered midazolam. Furthermore, the pharmacokinetic properties of alfentanil in combination with its high analgesic potency make it suitable for infusion in a total i.v. technique. Consideration must be paid, however, to interindividual variations in the pharmacokinetic data, and to variations in analgesic requirements during the various stages of surgery. REFERENCES 1. Chanarin I. Cobalamines and nitrous oxide: a review. Journal of Clinical Pathology 1980; 33: 909-916. 2. Brodsky JB. The toxicity of nitrous oxide. In: Clinics in Anaesthesiology. Eastbourne: Saunders, 1983; 455-467. 3. Mazze RI. Waste anaesthetic gases: A health hazard? In: Clinics in Anaesthesiology. Eastbourne: Saunders, 1983; 431-454. 4. Bovill JG, Sebel PS, Blackburn CL, Heykants J. The pharmacokinetics of alfentanil: A new opioid analgesic. Anesthesiology 1982; 57: 439-443. 5. Fragen RJ, Booij LHDJ, Braak GJJ, Vree TB, Heykants J, Crul JF. Pharmacokinetics of the infusion of alfentanil in man. British Journal of Anaesthesia 1983; 55: 10771081. 6. Michiels M, Hendricks R, Heykants J. Radioimmunoassay of the new opiate analgesics alfentanil and sufentanil. Preliminary pharmacokinetic profile in man. Journal of Pharmacy and Pharmacology 1983; 35: 86-93. 7. Wait JV, Clarke F. DARE-P, a Portable Digital Simulation System. Tuscon, USA: University of Arizona, 1974. 8. Kruger-Theimer E. Continuous intravenous infusion and
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to the predicted concentration. The plasma clearance, however, varied more than four-fold, resulting in large interindividual differences in concentration at the end of the infusion (fig. 2, table III). These differences in plasma clearance were probably caused by variation in the hepatic metabolic capacity [16]. Furthermore, interindividual differences in protein binding may also influence clearance. Even so, the attempt to achieve steady-state can be considered successful, since the concentration was stable in most patients during the maintenance infusion. The accuracy of using average pharmacokinetic data to design infusion regimens could be evaluated by comparing the predicted with the observed concentrations. The correlation between the predicted and mean observed plasma concentrations was excellent during the maintenance infusion (fig. 3). However, the large variation in observed concentrations at steady-state (fig. 2) demonstrate the difficulty in predicting doses for individual patients. There was a difference between predicted and mean observed concentrations after the infusion, since the terminal half-life found in the present study was somewhat longer than the value used for the simulation (tables II, IV). Fragen and colleagues [5] used the combination of a bolus (80 ug kg"1) with a single constant i.v. infusion (3 ug kg"1 min"1) to achieve rapidly and maintain plasma concentrations necessary to provide adequate analgesia. The advantage of the present infusion regimen over that used by Fragen and colleagues is that prolonged infusion will not result in increasing concentrations of alfentanil (fig. 1). A high concentration at the end of an infusion will lead to postoperative respiratory depression. The disadvantage of a fixed infusion rate is that no consideration is paid to the interindividual variation in the pharmacokinetics or to the varying degree of surgical stimulation. Our maintenance infusion rate of 1.0 ug min"1 kg"1 is in accord with published data on the dose requirements of alfentanil in combination with nitrous oxide [17].
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ALFENTANIL PHARMACOKINETICS IN I.V. ANAESTHESIA
9. 10. 11. 12. 13.
Rowland M, Benet LZ, Graham GC. Clearance concepts in pharmacokinetics. Journal of Pharmacokinetics and Biopharmaceutics 1973; 1: 123-136. Sawe J, Dahlstrom B, Paalzow L, Rane A. Morphine kinetics in cancer patients. Clinical Pharmacology and Therapeutics 1981; 30: 629-634. Henthorn TK, Spina E, Birgersson C, Ericsson O, von Bahr C. In vitro competitive inhibition of desipramine hydroxylation by alfentanil and fentanyl. Anesthesiology 1985; 63: A305. Ausems ME, Hug CC, de Lange, S. Variable rate infusion of alfentanil as a supplement to nitrous oxide anesthesia for general surgery. Anesthesia and Analgesia 1983; 62: 982-986. Tamsen A, Sakurada T, Wahlstrom A, Terenius L, Hartvig P. Postoperative demand for analgesics in relation to individual levels of endorphines and substance P in cerobrospinal fluid. Pain 1982; 13: 171-183.
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multicompartment accumulation. European Journal of 14. Pharmacology 1968: 4: 317-324. Benet LZ, Galeazzi RL. Noncompartmental determination of the steady-state volume of distribution. Journal of 15. Pharmaceutical Sciences 1979; 8: 1071-1074. Spierdijk J, van Kleef J, Nauta J, Stanley TH, de Lange S. Alfentanil: a new narcotic anesthetic induction agent. 16. Anesihesiology 1980; S3: S32. Niemegeers CJE, Janssen PAJ. Alfentanil (R 39 209)—A particularly short-acting intravenous narcotic analgesic in rats. Drug Development Research 1981; 1: 83-88. 17. Bower, S, Hull CJ. Comparative pharmacokinetics of fentanyl and alfentanil. British Journal of Anaesthesia 1982; 54: 871-877. Meuldermans WEG, Hurkmans RMA, Heykants JJP. 18. Plasma protein binding and distribution of fentanyl, sufentanil, alfentanil and lofentanil in blood. Archives Internationales de Pharmacodynamie et de Therapie 1982; 25: 4-19.
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