INFUSION MODEL FOR FENTANYL BASED ON PHARMACOKINETIC ANALYSIS

Br.J. Anaesth. (1980), 52, 1021

INFUSION MODEL FOR FENTANYL BASED ON PHARMACOKINETIC ANALYSIS J. H. HENGSTMANN, H. STOECKEL AND J. SCHUTTLER

SUMMARY

Inhalation anaesthesia uses the model of continuous drug delivery as a well established and practical method for adequate and efficient hypnosis and analgesia. Dosage regimens for i.v. anaesthetics are usually used according to the personal skill and experience of the anaesthetist. Nowadays, repetitive dosing is the usual regimen for balanced i.v. anaesthesia. For the inexperienced anaesthetist there are anxieties about periods when analgesia is less than desired or the total body content of drug is unnecessarily large. For practical purposes a standardization of dose intervals is not possible so that signs of reflex autonomic responses such as tachycardia, arterial pressure increase, lacrimation and sweating are commonly the criteria for the next injection. The constant infusion of i.v. anaesthetics is thought to be advantageous for a smooth and adequate depth of anaesthetic. Generally, three or four biological half-lives must pass in the case of a constant rate infusion before steady state conditions are attained. One way of reaching therapeutic concentrations rapidly is an initial bolus injection. Depending on the pharmacokinetic properties of a drug, problems may arise, however, during the early period of anaesthesia and surgery when the eflFects of the bolus injection have de-

creased and a steady state from the infusion is not established yet. For drugs with these special problems, Wagner (1974) has described a model based on two different consecutive i.v. infusion rates. Initial excessive plasma concentrations are prevented and therapeutic plasma plateaux are achieved rapidly and safely with only a minor time lag. METHODS

Fentanyl was available as the citrate salt in 10-ml vials. Doses and concentrations given refer to the free base. Concentrations of fentanyl in plasma were determined by radioimmunoassay (Michiels, Hendriks and Heykants, 1977). The coefficient of variation was ± 5 % for a concentration of l n g m P 1 (0.97± 0.05 ng ml" 1 ) and ±10.2% for a 5-ng ml" 1 sample. All the patients studied gave informed consent to the investigation. In five patients (age 32.2 ±6.1 yr, body weight 62.2 ±9.1 kg) a bolus dose of fentanyl 0.5 mg was given into a forearm vein immediately after tracheal intubation. Venous blood was sampled from another forearm vein through a plastic cannula at 2,5, 7,10,15,20, 25, 30, 45, 60, 90, 120, 180 and 240 min after injection. Six patients (age 46.3±5.9yr, body weight 63 ±9.5 kg) undergoing abdominal hysterectomy J. H. HENGSTMANN, M.D., Department of Internal Medicine; were premedicated with promethazine 50 mg and H. STOECKEL, M.D., J. SCHOTTLER, Department of Anaesthesiology; University of Bonn, D 5300 Bonn- atropine 0.5 mg, both given 1 h before operation. Venusberg, Federal Republic of Germany. Anaesthesia was induced with etomidate 20 mg.

0007-0912/80/101021-05 $01.00

© Macmillan Publishers Ltd 1980

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The calculation of pharmacokinetic parameters after a bolus injection of fentanyl allowed an i.v. infusion scheme which guarantees analgesia for the entire duration of surgery, with the advantage of steady plasma concentration and body content. In the initial phase after bolus injection, the serum concentration decreased rapidly for about 10 min, indicating extensive transfer to the peripheral compartment. This was followed by a slower elimination phase with a half-life of about 2 h. The total volume of distribution of 80 litre exceeded the body weight only slightly. The total plasma clearance was 500 ml min" 1 . In developing a model for total i.v. anaesthesia we considered two different consecutive infusion rates. The pharmacokinetic model proved to be valid for all patients. The plasma concentrations during anaesthesia coincided well with the predicted steady state plasma concentrations and provided continuous analgesia during operation.

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plied by the maintenance infusion rate, which resulted in a value of 250 ng min" 1 . Hence, after tracheal intubation, fentanyl was infused at 250 ug min~' over 5 min for induction and at 9 ug min"' for maintenance of anaesthesia in combination with 60% nitrous oxide in oxygen. Myoneural blockade was maintained with pancuronium bromide (total dose 6-8 mg). The lungs were ventilated artificially with a semi-closed system (Spiromat 650, Drager). Blood was sampled at 2,4, 6,10, 15, 20, 30, 40, 60, 80, 100, 120, 130, 150, 180, 210 and 240 min after starting the infusion.

According to the pharmacokinetic results of the bolus injection study, dose and duration of the infusion rates for the infusion model had to be calculated as described by Wagner (1974). Given an effective fentanyl plasma concentration of 20-25 ng ml"' (Stoeckel et al., 1979) and a total plasma clearance of 450 ml min" 1 the maintenance infusion rate had to be set to 9 ug min" ! . Depending on a biological half-life of 1.5 h, and 5 min chosen for the duration of the fast initial infusion, the ratio of the infusion rates had to be read from the diagram (Wagner, 1974) and multi-

RESULTS

Following a bolus injection of fentanyl 0.5 mg plasma concentrations decreased within 10 min from 50 ng ml"' to 5 ng ml ~ ] (fig. 1). The second slope had a half-life of about 2 h. The average volume of distribution was 80 litre and total plasma clearance approximately 500 ml min" 1 . The biological half-life averaged 140 ±60 min (table I). In the six patients who received a continuous infusion the desired therapeutic concentration was exceeded 2-4 min after the start of the fast infusion

100

so 3

'" 10

B 5 £ 8

<£ ,

30

60

90

120

180

240

Time after bolus injection (mirj FIG. 1. Serum concentrations in five patients following a bolus injection of fentanyl 0.5 mg. Mean and standard deviation.

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Suxamethonium 1.5mgkg ' was given before tracheal intubation. Following bolus injection of fentanyl 0.5 mg, plasma concentrations were processed by regression analysis resulting in the hybrid constants A, B, a and /?. Calculation of the pharmacokinetic parameters was as described by Riegelman and Loo (1968). The average results of the five patients were taken for further estimation. Total plasma clearance was calculated by dividing the injected dose by the area under the plasma concentration curve from time zero to infinity. The volume of distribution (V$) was determined as the quotient of total plasma clearance and the hybrid constant

INFUSION MODEL FOR FENTANYL

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TABLE I. Pharmacokinetic parameters for the noo-compartment open model in five patients following a bolus injection offentanyl 0.5 mg

A. T. E. W. M. K. E. K. R. D. Mean

Age

Wt

Sex

(yr)

1 1 (kg) (ngmT ) (ngmT )

F F F F F

37 38 23 33 30

62 67 47 65 70

32.2

62.2

6.1

9.1

SD

A

v,

B

127.7 58.4 163.4 176.8 88.6 123.0 50.0

5.1 6.9 5.8 3.2 4.8 5.2 1.4

a

P

0.752 0.614 0.543 0.359 0.228 0.499 0.207

0.006 0.008 0.004 0.003 0.007 0.006 0.002

*n

(litre)

*»i

0.59 0.03 0.47 0.07 0.42 0.02 0.22 0.01 0.13 0.02 0.37 0.03 0.19 0.02

0.13 0.07 0.10 0.12 0.08 0.10 0.02

ClM

(litre) (ml min"1) (min)

3.8 7.4 3.0 2.7 5.3

82 64 71 102 67

490 547 311 347 447

116 87 173 231 99

4.4 2.0

77 15

428 98

141 60

110

1SO

ISO

210

240

DISCUSSION

Time during and after nfusion (jm)

There are two aims to be satisfied by an infusion model. First, therapeutic concentrations have to be reached as early as possible and, second, any

FIG. 2. Serum concentrations in six patients during and following fentanyl infusion. Mean and standard deviation.

TABLE II. Serum concentrations (ng ml ') in six patients during and after fentanyl infusion (mean ± SD) Time (min) 10

Mean SD

12.7 10.1

32.7 21.8

43.5 26.8

15

29.2 26.2 13.5 7.4

20

30

40

60

80

100

120

130

150

180

210

240

22.5 7.5

22.2 4.5

22.8 7.0

25.3 5.8

24.2 4.5

24.5 3.6

19.5 4.7

14.8 3.9

11.7 2.3

11.7 3.0

9.8 2.8

8.3 2.2

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(fig. 2). The greatest measured plasma concentrations were at 6 min. Thereafter, plasma concentrations decreased within 10 min to the desired range of 20 ng ml"' with narrow inter-individual variations (table II). The maintenance infusion could be stopped 15 min before the end of the operation (table III). The patients were awake 10 min later when nitrous oxide in the ventilating gas was replaced by oxygen.

TABLE III. Age, body measurements and clinical data in six patients undergoing fentanyl infusion and nitrous oxide anaesthesia. Individual values (mean ± SD)

Patient K. S. M. M. T. M. I. M. I. W. S. L. Mean SD

Duration of infusion (min)

Duration of surgery (min)

Awake after (min)

Age

Wt

Ht

(yr)

(kg)

(cm)

47 42 57 46 46 40

70 57 61 79 56 55

155 172 165 164 160 164

105 125 100 95 120 120

120 150 120 100 135 130

140 155 125 110 145 135

46.3

63.0

163.3

5.9

9.5

5.7

110.8 12.4

125.8 16.9

135.0 15.8

Total dose (mg) 2.15 2.33 2.11 2.06 2.29 2.29 2.21 0.11

1024

thereby enabling nitrous oxide to be replaced by i.v. hypnotics or benzodiazepines. If nitrous oxide as used in the present model is replaced by other drugs, it is necessary to change the infusion rate of fentanyl by a factor which can be found out by comparison of the modified steady state plasma concentrations with pharmacodynamic parameters indicating the depth of anaesthesia. In a modified model, the principle of the described infusion scheme will be left unchanged; only the amounts of fentanyl in the initial and maintenance infusion periods have to be adjusted. ACKNOWLEDGEMENTS

We are grateful to Drs Michiels and Heykants, Janssen Pharmaceutica, Research Laboratoria, Beerse/Bclgium for the gift of 3H-fentanyl and fentanyl antibodies. This work was supported by a grant from Ministerium fur Wissenschaft und Forschung, NRW, Germany (06/0604/68511). J. H. H. was supported by Deutsche Forschungsgcmeinschaft (He 791). REFERENCES

Michiels, M., Hendriks, R., and Heykants, J. (1977). A sensitive radioimmunoassay for fentanyl plasma level in man. Ear. J. Clin. Pharmacol., 12, 153. Riegelman, S., and Loo, J. (1968). Shortcomings in pharmacokinetic analysis by conceiving the body to exhibit properties of a single compartment. J. Pharm. Set., 57, 117. Stoeckel, H., Hengstmann, J. H., and Schuttler, J. (1979). Pharmacokinetics of fentanyl as a possible explanation for recurrence of respiratory depression. Br. J. Anaesth., 51, 741. Lange, H., Burr, W., Hengstmann, J. H., and Schuttler, J. (1979). EEG-Spektralanalyse zur Dokumentation der Narkosctiefe. Korrelation mit phannakokinetischen Daten von Fentanyl. Prakt. Andsth., 14, 227. Wagner, J. G. (1974). A safe method for rapidly achieving plasma concentration plateaus. Clin. Pharmacol. Ther., 16, 691. MODELE DE PERFUSION POUR LE FENTANYL BASE SUR UNE ANALYSE PHARMACOCINETIQUE RESUME

Le calcul des parametres pharmacocinctiques apres l'injection d'un bol de fentanyl a permis dc faire un projet de perfusion intraveincuse qui garantit l'onalgesie pendant toute la duree de rintervention chirurgicale, tout en presentant les avantages d'une concentration reguliere dans le plasma et dans la teneur en corpuscules. Dans la phase initiale qui suit Tinjection du bol, la concentration dans le serum a diminue rapidement pendant environ 10 mn, ce qui a indique qu'il se produisait un transfert tres important au compartment pcripherique. Ceci a ete suivi d'une phase d'elimination plus lente avec une demi-vie d'environ 2 h. Le volume total de repartition de 80 litre n'a depasse que tres legerement le poids du corps. Le coefficient

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major deviation from the therapeutic concentration during the course of surgery should be prevented. This is most important for longer surgical procedures. Without pharmacokinetic analysis unwanted accumulation of drug may occur. On the other hand, empirically established dosage regimens have the disadvantage of decreasing efficacy because the amount of drug in the body may become too small. All these disadvantages may be overcome by continuous infusion with constant plasma concentrations. Theoretically therapeutic plasma concentration plateaux can be attained by one or several bolus injections, by a loading dose followed by a continuous infusion, and by two different consecutive infusion rates (Wagner, 1974). For the "Wagner scheme" some pharmacokinetic parameters have to be established from plasma data following a bolus injection. However, secondary increases in plasma concentrations were observed in some patients (Stoeckel, Hengstmann and Schuttler, 1979). Therefore, we omitted the concentration values during this phase and calculated our parameters according to an open two-compartment model. The problem of the optimum effective steady state plasma concentration was solved by comparison with spectral analysis of the e.e.g. (Stoeckel et al., 1979). For our anaesthetic model using a combination of fentanyl with 60% nitrous oxide in oxygen, myoneural block and artificial ventilation without any additional drugs, concentrations of 20-25 ng ml" 1 of fentanyl in plasma were found to be optimal concentrations for operations with a pain level comparable to gynaecological laparotomy in patients with normal circulatory function, body-weight of about 65 ±15 kg and non-geriatric age. This target concentration is, however, only necessary for the anaesthetic model described. If other drugs such as those commonly used in neuroleptanaesthesia are added, smaller target concentrations are required. Because adequate analgesia in our model depended on significantly greater plasma fentanyl concentrations compared with those used in neuroleptanaesthesia, the plasma concentrations at the end of surgery were such that the needs of postoperative care must be demanding, and adequate antagonism by naloxone is necessary and continuing artificial ventilation may be required. The fentanyl infusion scheme can also be used in combination with other anaesthetic drugs,

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INFUSION MODEL FOR FENTANYL

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total d'cpuration du plasma a etc de 500 ml mo '. En mettant au point un modele pour une anesthcsie totale par voie intraveineuse nous avons tenu compte des deux taux consecutifs de perfusion differents. II a cte prouve que le molele pharmacocinetique est valable pour tous les patients. Les concentrations qui se produisent dans le plasma pendant l'anesthcsie coincident bien avec l'equilibrc tinetique prcvu pour les concentrations dans le plasma et ont assure une anesthesic continue pendant l'intervention chirurgicalc.

Infusionsschema mit zwei unterschiedlichen aufeinanderfolgenden Infusionstraten. Das pharmakokinetisch begrundet: Modcll zeigte bei alien Patienten annahernd die vorausberechneten Plasmaspiegel und gewahrleistete eine adaequate Narkosetiefe uber die gesamte Operationsdauer.

AUF PHARMAKOKINETISCHER ANALYSE BASIERENDES INFUSIONSMODELL FUR FENTANYL

El calculo de los parametros farmacocineticos, despues de la inyeccion de un bolo de fentanil, permitio llevar a cabo un programa dc infusion intravenosa que garantizo analgesia durante la duration total de la operacion, con la ventaja de presentar una concentracion constantc de plasma y un contcnido constantc de cucrpos. En la fase inicial despues de la inyeccion del bolo, la concentracion de suero disminuyo rapidamente por espacio de 10 minutos, indicando la transfcrencia extensiva al compartimiento pcriferico. A esto le siguio una fase dc eliminacion mas lenta con una vida media de 2 horas aproximadamente. El volumen total de la distribution de 80 litros, excedi6 el peso del cuerpo tan solo de forma ligera. La separation total del plasma fue de 500 ml min ~ '. Al desarrollar un modclo para la anestesia total intravenosa se consideraron dos regimenes de infusion diferentes y consccutivos. El modelo farmacotinctico demostro ser valido para todos los patientes. Las concentrationes de plasma durante la anestesia coincidieron de forma adecuada con las concentrationes predichas de plasma de cstado constante y proveyeron una analgesia conrinua durante la operacion.

MODELO DE INFUSION PARA FENTANIL, BASADO EN EL ANALISIS FARMACOCINETICO SUMARIO

ZUSAMMENFASSUNG

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Die Errechnung von pharmakokinetischen Parametern nach einer Fcntanyl-Bolusinjektion erlaubte die Ausarbeitung cines intravenosen Infusionsschemas, welches einerseits einc adaequate Analgesietiefe fur die gesamte Operationsdaucr garantierte und andercrseits sowohl konstante Plasmaspiegel als auch einen gleichbleibleibenden Korperbestand von Fentanyl gewahrleistete. Nach Bolusinjektion von Fentanyl 0,5 mg zeigt sich ein schnelles initiales Absinken der Plasmaspiegel uber einen Zeitraum von 10 Minuten. Dieser wird von einer zweitcn langsamen Eliminationsphase gefolgt, die eine Halbwertzeit von ca. 2 Stunden aufweist. Das Gesamtverteilungsvolumen iibersteigt mit 80 Litern nur gering das Korpergewicht. Die totale Plasmaclearancc erreicht einen Wert von fast 500 ml min~'. Bei der Entwicklung eincs Modells fur die totale intravendse Anasthesie entschieden wir uns fur cin