Arie A. Vletter

The Pharmacodynamic Interaction of Propofol and Alfentanil during Lower Abdominal Surgery in Women

Background Propofol and alfentanil are frequently combined to provide general anesthesia. The purpose of this study was to characterize the pharmacodynamic interaction between propofol and alfentanil for several clinically relevant end points.

Pharmacodynamics of Propofol in Female Patients

Although the clinical properties of propofol have been studied extensively, the pharmacodynamics have not yet been described fully. We studied the propofol concentration-effect relationships for loss of eyelash reflex, loss of consciousness, and hemodynamic changes in 18 female patients, ASA physical status 1, aged 20-49 yr. Propofol was given by computer-controlled infusion. The initial target concentration of 0.5-1 microgram/ml was increased every 12 min by 0.5-1 microgram/ml until the patients lost consciousness. Every 3 min, loss of eyelash reflex and loss of consciousness were tested and an arterial blood sample was taken for analysis of the blood propofol concentration. The concentration-response relationships for loss of eyelash reflex and loss of consciousness were defined by fitting a sigmoid Emax function (where Emax = the maximum effect that can be reached; i.e., 100% of the patients showing loss of eyelash reflex or loss of consciousness) to the response/no response data versus the propofol concentration, using nonlinear regression. The effect of propofol on hemodynamic parameters was analyzed by linear regression. The propofol concentrations at which 50% and 90% of the patients showed loss of eyelash reflex were 2.07 and 2.78 micrograms/ml, respectively. The corresponding values for loss of consciousness were 3.40 and 4.34 micrograms/ml. The systolic and diastolic blood pressure decreased with increasing blood propofol concentration. The correlation coefficients for the decrease in systolic and diastolic blood pressure versus the blood propofol concentration were r2 = -0.663 and r2 = -0.243, but heart rate did not change. In conclusion, propofol concentrations inducing loss of eyelash reflex are less than those inducing loss of consciousness.

Pharmacodynamic interaction between propofol and alfentanil when given for induction of anesthesia

Background Propofol and alfentanil often are combined during induction of anesthesia. However, the interaction between these agents during induction has not been studied in detail. The influence of alfentanil on the propofol concentration-effect relationships was studied for loss of eyelash reflex, loss of consciousness, and hemodynamic function in 20 un-premedicated ASA physical status 1 patients aged 20-55 yr. Methods Patients were randomly divided into four groups to receive a computer-controlled infusion of alfentanil with target concentrations of 0, 50, 200, or 400 ng/ml (groups A, B, C, and D, respectively). While the target concentration of alfentanil was maintained constant, patients received a computer-controlled infusion of propofol, with an initial target concentration of 0.5-1 micro gram/ml, that was increased every 12 min by 0.5-1 micro gram/ml. Every 3 min, the eyelash reflex and state of consciousness were tested and an arterial blood sample was taken for blood propofol and plasma alfentanil determination. The propofol-affentanil concentration-response relationships for loss of eyelash reflex and loss of consciousness were determined by nonlinear regression, and for the percentage of change in systolic blood pressure and heart rate by logistic regression. Results The patient characteristics did not differ significantly among the four groups. The patients in groups A and B continued to breathe adequately, whereas all patients in groups C and D required assisted ventilation. End-tidal carbon dioxide partial pressure remained less than 46 mmHg in all patients. With plasma alfentanil concentrations increasing from 0 to 500 ng/ml, the EC50 of propofol decreased from 2.07 to 0.83 micro gram/ml for loss of eyelash reflex and from 3.62 to 1.55 micro gram/ml for loss of consciousness. With plasma alfentanil concentrations increasing from 0 to 500 ng/ml, the blood propofol concentrations associated with a 10% decrease in systolic blood pressure and heart rate decreased from 1.68 to 0.17 micro gram/ml and from 2.36 to 0.04 micro gram/ml, respectively. Conclusions Alfentanil significantly reduces blood propofol concentrations required for loss of eyelash reflex and loss of consciousness. In addition, alfentanil enhances the depressant effects of propofol on systolic blood pressure and heart rate. Hemodynamic stability, therefore, does not increase in patients receiving propofol in combination with alfentanil compared to those receiving propofol as the sole agent for induction of anesthesia.

Performance of Computer-Controlled Infusion of Propofol: An Evaluation of Five Pharmacokinetic Parameter Sets

Computer-controlled infusion of propofol is used with increasing frequency for the induction and maintenance of anesthesia. The performance of computer-controlled infusion devices is highly dependent on how well the implemented pharmacokinetic parameter set matches the pharmacokinetics of the patient. This study examined the performance of a computer-controlled infusion device when provided with five different pharmacokinetic parameter sets of propofol in female patients. The infusion rate-time data that had been stored on a disk from 19 female patients who had been given propofol by computercontrolled infusion, using the pharmacokinetic parameter set from Gepts et al. (Anesth Analg 1987;66:1256-63), were entered into a computer simulation program to recalculate predicted propofol concentrations that would have been obtained with four other pharmacokinetic parameter (Shafer et al., Anesthesiology 1988;69:348-56; Kirkpatrick et al., Br J Anesth 1988;60:146-50; Cockshott et al., Br J Anesth 1987;59:941P; Tackley et al., Br J Anesth, 1989;62:46-53) sets of propofol, had these been implemented. The performance error (PE) was determined for each measured blood propofol concentration, on the basis of each of the five pharmacokinetic parameter sets. Then, for each of the five pharmacokinetic parameter sets, the performance in the population was determined by the median absolute performance error (MDAPE), the median performance error (MDPE), the wobble (the median absolute deviation of each PE from the MDPE), and the divergence (the percentage change of the absolute PE with time). The MDPE and MDAPE were compared between the parameter sets by the multisample median test. The initially used pharmacokinetic parameter set from Gepts et al. resulted in a MDPE of 24% and MDAPE of 26%. In comparison with this parameter set (Gepts et al.), the computer simulations revealed that the pharmacokinetic parameter set of Kirkpatrick et al. resulted in a significantly worse performance (MDPE, and MDAPE: 106%, P < 0.001), whereas with the three other pharmacokinetic parameter sets the performance did not differ. For all five pharmacokinetic parameters sets the divergence (median and range) in the patients in Group A, who had received a stepwise increasing target propofol concentration, was significantly greater (median 42%; range, 31%-59%) compared to the corresponding divergence in the patients in Group B (median 1%; range -18%-4%; P < 0.05), who had received a single constant target propofol concentration. The PE thus did not increase with time but with increasing target propofol concentration. In conclusion, the pharmacokinetic parameter sets of propofol described by Gepts et al., Shafer et al., Cockshott et al., and Tackley et al. result in an equally clinical acceptable, but not optimal, performance of the computer-controlled infusion of propofol in the type of patients studied above. With all five pharmacokinetic parameter sets, the underprediction of the measured concentration increases with the increasing target concentration. (Anesth Analg 1995;81:1275-82)

Quantification of the EEG effect of midazolam by aperiodic analysis in volunteers. Pharmacokinetic/pharmacodynamic modelling.

SummaryThe effects of midazolam on the EEG were related to plasma midazolam concentrations in 8 healthy male volunteers in order to develop a pharmacokinetic-pharmacodynamic model. The EEG parameters were derived by aperiodic analysis.The EEG was recorded between Fp1-M1 and FP2-M2. Following a 15-minute baseline EEG registration, midazolam 15mg was given intravenously over 5 minutes. Venous blood samples were taken until 8 hours after the start of the infusion. Within 2 to 4 minutes of starting the infusion all subjects became asleep, with loss of eyelid reflex. The most obvious EEG changes, in the β frequency range (12 to 30Hz), were observed within 2 minutes of the start of drug administration. Seven subjects awoke 60 to 70 minutes after the start of the infusion and 1 awoke after 45 minutes.The EEG parameter that best characterised the effect of midazolam was the total number of waves per second in the frequency range 12 to 30Hz (TNW12–30). This was used as the effect parameter in the pharmacokinetic-pharmacodynamic modelling. The plasma concentration-time data were characterised by a triexponential function for all subjects. To allow for a possible delay between plasma midazolam concentration and EEG effect, a hypothetical effect compartment was included in the pharmacokinetic-pharmacodynamic model. A sigmoid maximum effect (Emax) model was used to characterise the effect compartment midazolam concentration-TNW2–30 data. The plasma drug concentration corresponding to half the maximum increase in TNW12–30 (EC50) was 290 ± 98 μg/L. The half-life reflecting equilibration between plasma concentration and effect (t 00BDkeo) was estimated by a nonparametnc method and was 1.7 ± 0.7 minutes (mean ± SD).The concentration at which the volunteers awoke was 131 ± 14 Mg/L. The EEG had returned to the baseline value 3 hours after the start of the infusion; at this time the plasma midazolam concentration was 60 ± 9 μg/L.The conclusion is reached that, in volunteers, the effect of midazolam on the EEG can be quantified and adequately described with a sigmoid Emax model. TNW12–30, a parameter derived from aperiodic analysis of the EEG, is a suitable, and possibly superior, alternative to psychomotor tests for the assessment of the central nervous system effects of this drug.

Pharmacodynamics of Alfentanil as a Supplement to Propofol or Nitrous Oxide for Lower Abdominal Surgery in Female Patients

Background:Although propofol and alfentanil are given in combination in clinical practice, the pharmacodynamic interaction between these drugs has not been described. Methods:The pharmacodynamics of alfentanil when given as a supplement to propofol were studied in 10 ASA physical status 1 female patients (group P) undergoing lower abdominal surgery and compared to the pharmacodynamics of alfentanil when given as a supplement to nitrous oxide (group N, n=10). Anesthesia was induced by either computer-controlled infusion of propofol and alfentanll at target concentrations of 3 µg/ml and 100 ng/ml (group P) or computer-controlled infusion of 400 ng/ml alfentanll as a supplement to nitrous oxide and oxygen (ratio 2:1; group N). The target concentration of alfentanil was varied to patient responses, and the nitrous oxide and propofol concentrations were maintained constant. A sigmoid Emax model was fitted to response/no response data versus plasma alfentanil concentrations at intubation, skin incision, and the opening of the peritoneum in both groups and for the intraabdominal part of surgery in the individual patients. In addition, the speed of recovery in both groups was determined by a deletlon-of-ps test. Results:The EC50 (the concentration at which, with a 50% probability, the patients did not respond to the surgical stimuli) of alfentanil during propofol anesthesia was 92 ng/ml for intubation, 55 ng/ml for skin incision, 84 ng/ml for the opening of the peritoneum, and 66 ± 38 ng/ml (mean ± SD) for the intraabdominal part of surgery. The corresponding values during nitrous oxide anesthesia were significantly higher: 429 ng/ml for intubation, 101 ng/ml for skin incision, and 206 ± 65 ng/ml for the intraabdomlnal part of surgery (P<0.001). The speed of recovery was similar in both groups. Conclusions:The alfentanil requirements in ASA physical status 1 female patients undergoing lower abdominal surgery are less when given as a supplement to propofol (4 µg/ml) compared to 66% N2O.

Computer-controlled infusion of alfentanil for postoperative analgesia. A pharmacokinetic and pharmacodynamic evaluation.

Background:Although computer-controlled infusion (CCI) of alfentanil has been shown to be effective intraoperatively, this technique has not been validated for postoperative use. Therefore, the authors examined the efficacy of this technique in providing postoperative pain relief. The study comprised both a validation of published pharmacokinetic data sets and the definition of the minimum effective analgesic concentrations after major orthopedic surgery. Methods:The bias and inaccuracy of the implemented pharmacokinetic data set were examined, in 20 patients who had undergone major orthopedic surgery, by determination of the median performance error (MDPE) and median absolute performance error (MDAPE). The performance of two other published pharmacokinetic data sets was also examined by simulating the plasma concentrations that would have been predicted, had these data sets been implemented. The minimum effective analgesic concentrations (MEAC) were determined at the following time points: at the onset of pain, at 9:00 PM on the day of surgery, and at 9:00 AM and 9:00 PM on the first postoperative day. Results:Measured plasma concentration-time profiles generally were parallel to the target concentration-time profiles. The MDPE and MDAPE obtained were 12% and 28%, respectively. The MEACs ranged from < 1 to 175 ng/ml and showed substantial interindividual variability. The median MEACs at the four study times were 59, 52, 65, and 43 ng/ml. The MEAC at 9:00 PM on the first postoperative day was significantly lower than those at the other study times (P < 0.05). Conclusion:Computer-controlled infusion of alfentanil provides adequate postoperative analgesia. The study demonstrated that pharmacokinetic data sets that are useful for intraoperatlve CCI of alfentanil are equally valid in the postoperative phase. Although required plasma concentrations of alfentanil are reasonably stable in time, interindividual variations are large, necessitating individual titration.

The effect of age on the systemic absorption, disposition and pharmacodynamics of bupivacaine after epidural administration.

SummaryThe influence of age on the systemic absorption and disposition of bupivacaine following epidural administration in 20 male patients (22 to 81 years) was examined using a stable isotope method to determine whether pharmacokinetics play a role in age-related pharmacodynamic changes seen with the drug. After epidural bupivacaine administration a deuterium-labelled analogue was administered intravenously. Bi- and triexponential functions were fitted to plasma concentration-time data of deuterium-labelled bupivacaine. The systemic absorption was described by 2 parallel first-order absorption processes. The upper level of analgesia and the duration of analgesia at dermatome T-12 increased with age (r = 0.68, p < 0.001; r = 0.56, p < 0.01, respectively). The time to maximal caudad spread of analgesia and the time to onset of motor block decreased with age (r = −0.76, p < 0.0001; r = −0.72, p < 0.001, respectively). Age did not influence systemic absorption or disposition of bupivacaine. We conclude that the changes in the clinical profile of bupivacaine with age are not due to altered pharmacokinetics, but may be related to changes in the pharmacodynamics of the drug.

THE EFFECT OF AGE ON SYSTEMIC ABSORPTION AND SYSTEMIC DISPOSITION OF BUPIVACAINE AFTER SUBARACHNOID ADMINISTRATION

In order to evaluate the role of the pharmacokinetics of the age-related changes in the clinical profile of spinal anesthesia with bupivacaine, we studied the influence of age on the systemic absorption and systemic disposition of bupivacaine after subarachnoid administration in 20 male patients (22-81 yr), ASA Physical Status 1 or 2, by a stable isotope method. After subarachnoid administration of 3 ml 0.5% bupivacaine in 8% glucose, a deuterium-labeled analog (13.4 mg) was administered intravenously. Blood samples were collected for 24 h. Plasma concentrations of unlabeled and deuterium-labeled bupivacaine were determined with a combination of gas chromatography and mass fragmentography. Biexponential functions were fitted to the plasma concentration-time data of the deuterium-labeled bupivacaine. The systemic absorption was evaluated by means of deconvolution. Mono- and biexponential functions were fitted to the data of fraction absorbed versus time. The maximal height of analgesia and the duration of analgesia at T12 increased with age (r = 0.715, P less than 0.001; r = 0.640, P less than 0.01, respectively). In 18 patients the systemic absorption of bupivacaine was best described by a biexponential equation. The half-life of the slow systemic absorption process (r = -0.478; P less than 0.05) and the mean absorption time (r = -0.551; P less than 0.02) decreased with age. The total plasma clearance decreased with age (r = -0.650, P less than 0.002), whereas the mean residence time and terminal half-life increased with age (r = 0.597, P less than 0.01; r = 0.503, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic-pharmacodynamic modelling of the interaction between flumazenil and midazolam in volunteers by aperiodic EEG analysis.

SummaryThe CNS effects resulting from the combined administration of midazolam and flumazenil were studied in 8 healthy volunteers to develop a model of the pharmacokinetic-pharmacodynamic interaction. Electroencephalograms (EEG) were recorded between Fp1-M1 and FP2-M2. The EEG parameter total number of waves between 12 and 30Hz (TNW12–30) derived by aperiodic analysis was used to quantify the effect. Following a 15 min baseline EEG recording, infusion of placebo or flumazenil was started. Infusion regimens for flumazenil were designed so that ‘steady-state’ concentrations of 10 and 20 µg/L were obtained. Doses of midazolam 15, 30 and 60mg over 5 min were given 30 min after the start of placebo infusion (session A) or flumazenil infusion to 10 µg/L (session B) or 20 µg/L (session C), respectively. Venous blood samples were taken until 8h after the start of the flumazenil or placebo infusion. A sigmoid maximum effect (Emax) model was used to characterise the relationship between the plasma concentration of midazolam which is in equilibrium with the effect compartment concentration (Cem) [Cem/Kp] and TNW 12–30.Within 2 to 5 min of starting the midazolam infusion all subjects fell asleep, with loss of eyelid reflex. They awoke between 25 and 82 min later in all 3 sessions. The mean (± SD) plasma drug concentrations of midazolam corresponding to half the maximum increase in TNW 12–30 (EC50) were 276 ± 64, 624 ± 187 and 1086 ± 379 µg/L in sessions A, B and C, respectively. The half-lives reflecting equilibration between plasma concentration and effect (t½ke0), estimated by a nonparametric method, were 2.2 ± 1.2, 3.3 ± 3.3 and 2.9 ± 1.2 min for the 3 different sessions. Emax and N were not affected by flumazenil. In each subject the plot of the average measured steady-state plasma flumazenil concentration versus the EC50 of midazolam showed a linear relationship. The plasma concentration of flumazenil that doubled the EC50 of midazolam (Cf,2) was 6.5 ± 1.0 µg/L. The observed interaction is consistent with the competitive nature of the antagonism of midazolam by flumazenil.