Frank H. M. Engbers

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.

Propofol reduces perioperative remifentanil requirements in a synergistic manner: response surface modeling of perioperative remifentanil-propofol interactions.

Background Remifentanil is often combined with propofol for induction and maintenance of total intravenous anesthesia. The authors studied the effect of propofol on remifentanil requirements for suppression of responses to clinically relevant stimuli and evaluated this in relation to previously published data on propofol and alfentanil. Methods With ethics committee approval and informed consent, 30 unpremedicated female patients with American Society of Anesthesiologists physical status class I or II, aged 18–65 yr, scheduled to undergo lower abdominal surgery, were randomly assigned to receive a target-controlled infusion of propofol with constant target concentrations of 2, 4, or 6 &mgr;g/ml. The target concentration of remifentanil was changed in response to signs of inadequate anesthesia. Arterial blood samples for the determination of remifentanil and propofol concentrations were collected after blood–effect site equilibration. The presence or absence of responses to various perioperative stimuli were related to the propofol and remifentanil concentrations by response surface modeling or logistic regression, followed by regression analysis. Both additive and nonadditive interaction models were explored. Results With blood propofol concentrations increasing from 2 to 7.3 &mgr;g/ml, the C50 of remifentanil decreased from 3.8 ng/ml to 0 ng/ml for laryngoscopy, from 4.4 ng/ml to 1.2 ng/ml for intubation, and from 6.3 ng/ml to 0.4 ng/ml for intraabdominal surgery. With blood remifentanil concentrations increasing from 0 to 7 ng/ml, the C50 of propofol for the return to consciousness decreased from 3.5 &mgr;g/ml to 0.6 &mgr;g/ml. Conclusions Propofol reduces remifentanil requirements for suppression of responses to laryngoscopy, intubation, and intraabdominal surgical stimulation in a synergistic manner. In addition, remifentanil decreases propofol concentrations associated with the return of consciousness in a synergistic manner.

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.

Response surface modeling of remifentanil-propofol interaction on cardiorespiratory control and bispectral index.

Background Since propofol and remifentanil are frequently combined for monitored anesthesia care, we examined the influence of the separate and combined administration of these agents on cardiorespiratory control and bispectral index in humans. Methods The effect of steady-state concentrations of remifentanil and propofol was assessed in 22 healthy male volunteer subjects. For each subject, measurements were obtained from experiments using remifentanil alone, propofol alone, and remifentanil plus propofol (measured arterial blood concentration range: propofol studies, 0–2.6 &mgr;g/ml; remifentanil studies, 0–2.0 ng/ml). Respiratory experiments consisted of ventilatory responses to three to eight increases in end-tidal Pco2 (Petco2). Invasive blood pressure, heart rate, and bispectral index were monitored concurrently. The nature of interaction was assessed by response surface modeling using a population approach with NONMEM. Values are population estimate plus or minus standard error. Results A total of 94 responses were obtained at various drug combinations. When given separately, remifentanil and propofol depressed cardiorespiratory variables in a dose-dependent fashion (resting &OV0312;i: 12.6 ± 3.3% and 27.7 ± 3.5% depression at 1 &mgr;g/ml propofol and 1 ng/ml remifentanil, respectively; &OV0312;i at fixed Petco2 of 55 mmHg: 44.3 ± 3.9% and 57.7 ± 3.5% depression at 1 &mgr;g/ml propofol and 1 ng/ml remifentanil, respectively; blood pressure: 9.9 ± 1.8% and 3.7 ± 1.1% depression at 1 &mgr;g/ml propofol and 1 ng/ml remifentanil, respectively). When given in combination, their effect on respiration was synergistic (greatest synergy observed for resting &OV0312;i). The effects of both drugs on heart rate and blood pressure were modest, with additive interactions when combined. Over the dose range studied, remifentanil had no effect on bispectral index even when combined with propofol (inert interaction). Conclusions These data show dose-dependent effects on respiration at relatively low concentrations of propofol and remifentanil. When combined, their effect on respiration is strikingly synergistic, resulting in severe respiratory depression.

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)

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.

Alfentanil and placebo analgesia : No sex differences detected in models of experimental pain

Background:To assess whether patient sex contributes to the interindividual variability in alfentanil analgesic sensitivity, the authors compared male and female subjects for pain sensitivity after alfentanil using a pharmacokinetic–pharmacodynamic modeling approach. Methods:Healthy volunteers received a 30-min alfentanil or placebo infusion on two occasions. Analgesia was measured during the subsequent 6 h by assaying tolerance to transcutaneous electrical stimulation (eight men and eight women) of increasing intensity or using visual analog scale scores during treatment with noxious thermal heat (five men and five women). Sedation was concomitantly measured. Population pharmacokinetic–pharmacodynamic models were applied to the analgesia and sedation data using NONMEM. For electrical pain, the placebo and alfentanil models were combined post hoc. Results:Alfentanil and placebo analgesic responses did not differ between sexes. The placebo effect was successfully incorporated into the alfentanil pharmacokinetic–pharmacodynamic model and was responsible for 20% of the potency of alfentanil. However, the placebo effect did not contribute to the analgesic response variability. The pharmacokinetic–pharmacodynamic analysis of the electrical and heat pain data yielded similar values for the potency parameter, but the blood–effect site equilibration half-life was significantly longer for electrical pain (7–9 min) than for heat pain (0.2 min) or sedation (2 min). Conclusions:In contrast to the ample literature demonstrating sex differences in morphine analgesia, neither sex nor subject expectation (i.e., placebo) contributes to the large between-subject response variability with alfentanil analgesia. The difference in alfentanil analgesia onset and offset between pain tests is discussed.

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.

Target-controlled infusion systems: role in anaesthesia and analgesia.

Drug delivery by target-controlled infusion (TCI) allows automatic adjustments of the infusion rate of a drug to maintain a desired target concentration. Since drug effect is more closely related to blood concentration than to infusion rate, drug delivery via TCI is capable of creating stable blood concentrations of intravenous anaesthetics and analgesics.In this article the concept and history of TCI are described. The rational administration of TCI requires an appropriate pharmacokinetic data set and knowledge of the concentration-effect relationship; therefore, general pharmacokinetic and pharmacodynamic aspects of intravenous anaesthetics and analgesics are also addressed. Intraoperative investigations have demonstrated that TCI drug delivery allows rapid titration to a desired effect. The use of TCI for postoperative analgesia is still experimental, but TCI can, in part, overcome the disadvantages associated with continuous infusions and patient-controlled analgesia regimens in the postoperative period.Although TCI is capable of creating stable blood concentrations, when the target concentration is changed the resulting effect correlates better with a theoretical effect site concentration. The efficacy of TCI systems that can perform effect-site steering are still to be explored.