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Acta Anaesthesiol &and 1992: 36: 846-847

Alfentanil infusion in total intravenous anaesthesia (TIVA). Population pharmacokinetics fails to predict plasma concentration of alfentanil M. JENSTRUP, K. FRUERGARD, J. NIELSEN, A-M. MBLLER and F. WIBERG-JQRGENSEN Department of Anaesthesiology, Central Hospital, Hillerad, Denmark

In order to evaluate the ability to predict plasma concentrations from population-corrected pharmacokinetics, a prospective study comprising 14 women admitted for elective hysterectomy was done. Alfentanil was given in combination with propofol in a total intravenous anaesthesia technique. The predicted median alfentanil concentration (289(256-363) ng ml-I) was significantly lower than the measured median plasma concentration of 368( 168-666) ng ml-I). In conclusion, population-based pharmacokinetics were found not to be accurate as they underestimate plasma concentrations of alfentanil. Received 2 October 1991, acceptedfor publication 19 January 1992

Kcy words: Analgesics: alfentanil; hypnotics: propofol; pharmacokinetics: alfentanil; total intravenous anaesthesia.

Intravenous anaesthetics with pharmacokinetic profiles suitable for continuous infusion are of increasing interest. Alfentanil is such a drug. It has a short bloodbrain equilibration time, resulting in a rapid onset of analgesia, and a short duration of action because of fast elimination (terminal half-life (T1/2p)of 70 min) (1, 2). To identify factors that may influence the pharmacokinetics of alfentanil, Maitre and colleagues (3) described the variability in population pharmacokinetics based on single-dose data pooled from previously reported studies. They found a significant influence of total body weight (TBW) on the volume ofdistribution (vd), and a decrease with age of total body clearance (Cl). A small but significant effect of sex on the Vd was also observed. The aim of our study was a prospective evaluation of the ability to predict plasma concentrations from the population-corrected pharmacokinetics of Maitre et al. (3) in a group of patients having a total intravenous anaesthesia (TIVA).

MATERIAL AND METHODS Fourteen women, ASA physical status 1-2, admitted for elective hysterectomy, were included in the study. The patients were premedicated with diazepam 0.2 mg kg-' orally. Anaesthesia was induced with a bolus of propofol 1.5 mg kg-I, followed by an infusion of 9 mg kg-' h-I. After 10 min the rate was reduced to a sustained 6 mg kg-' h - ' until the last skin suture. Likewise, the patients had a bolus of alfentanil 60 pg kg-' followed by an infusion of 240 pg kg-l h-'.

After 10 min the rate was reduced to 180 pg kg-' h-', and then successively reduced after 30 min to 120 pg kg-' h-l and after I h to 100 pg min-' until closure of the abdominal fascia, when the infusion was stopped. Pancuronium (Pavulon) was given to facilitate tracheal intubation and for further relaxation. Data are expressed as median and quartiles. Plasma concentration of alfentanil was measured 10, 30 and 60 min after induction, at the end of infusion, and when the patients opened their eyes. For each measured value a predicted value was calculated using a computer programme that allowed prediction of the alfentanil plasma concentration, including the 68% confidence limits of the prediction. The difference between the predicted and the measured concentration of alfentanil (prediction error, PE) was calculated for each sample in accordance with the method ofAusems et al. (4). The median prediction error (MPE) was evaluated by examining the corresponding 95% confidence intervals. A value o f P < 0.05 was regarded as statistically significant.

RESULTS The anaesthesia was smooth for all patients, with only minor fluctuations in blood pressure. The median predicted alfentanil concentration during maintenance was 289(256-363) ng ml-' versus a measured median plasma concentration of 368(168-666) ng ml-'. Fig. 1 shows the individual measured plasma concentration as a function of time and the 68% confidence interval of the predicted values. Six of the 14 patients (43%) had plasma concentrations above the predicted area; the rest were within it. The MPE was - 70.5 ng ml-' with quartiles - 143.3 - + 23.3. The MPE was significant, as the 95% confidence limits ( - 108 and -9) did not include zero.

ALFENTANIL, PREDICTION O F PLASMA CONCENTRATION ngml

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technique (arterial versus venous) (5) or a different study design (bolus versus infusion technique and blood sampling exclusively in the peroperative period) (5). We conclude that the population-based pharmacokinetics of Maitre et al. (3) are not accurate and that they underestimate plasma concentrations of alfentanil. REFERENCES

10 30 60 El EO min Fig. I. Measured plasma concentration for each patient. Shaded area indicates the predicted 68% confidence interval of alfentanil. EI, end of infusion. EO, eyes open.

DISCUSSION Raemer et al. (5) also found, in a prospective study, a substantial underestimate when using the data from Maitre et al. (3). Raemer et al.’s (5) and our results indicate that the population-based pharmacokinetic parameters of Maitre et al. (3) were not appropriate. The reason for the underestimation could be that the influence of age, sex and TBW on pharmacokinetics was different in our population, or it could be a result of a drug interaction between alfentanil and propofol ( 6 ) . It might also be a result of a different sample

1. Hull C J. The pharmacokinetics of alfentanil in man. Br J Anacsth 1983: 5: Suppl 2: 157-167. 2. Bovill J G, Sebel P S, Blackburn C L, Heykants J. The pharmacokinetics of alfentanil (R 39 209): a new opioid analgesic. Anesthesiology 1982: 57: 43W43. 3. Maitre P 0,Vozeh S, Heykants J, Thomson D A, Stanski D R. Population pharmacokinetics of alfentanil: the average doseplasma concentration relationship and interindividual variability in patients. Anesthesiology 1987: 66: 3-12. 4. Ausems M E, Stanski D R, Hug C C. An evaluation of the accuracy of pharmacokinetic data for the computer-assisted infusion of alfentanil. Br 3 Anaesth 1985: 57: 1217-1225. 5. Raemer D B, Buschman A, Varvel J R et al. The prospective use of population pharmacokinetics in a computer-driven infusion system for alfentanil. Anesthesiology 1990: 73: 66-72. 6. Gepts E, Jonckheer K, Maes V, Sonck W, Camu F. Disposition kinetics of propofol during alfentanil anaesthesia. Anucsthcsia 1988: 43 (suppl.): 8-13.

Address: Dr. Morten Jenstrup Pilegardsparken 26 3460 Birkered Denmark

Alfentanil infusion in total intravenous anaesthesia (TIVA). Population pharmacokinetics fails to predict plasma concentration of alfentanil.

In order to evaluate the ability to predict plasma concentrations from population-corrected pharmacokinetics, a prospective study comprising 14 women ...
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