Anton G. L. Burm

Sex differences in morphine analgesia: an experimental study in healthy volunteers.

BackgroundAnimal and human studies indicate the existence of important sex-related differences in opioid-mediated behavior. In this study the authors examined the influence of morphine on experimentally induced pain in healthy male and female volunteers. MethodsYoung healthy men and women (10 of each sex) received intravenous morphine (bolus 0.1-mg/kg dose followed by an infusion of 0.030 mg · kg−1 · h−1 for 1 h). Pain threshold and pain tolerance in response to a gradual increase in transcutaneous electrical stimulation, as well as plasma concentrations of morphine and its major metabolites (morphine-6-glucuronide and morphine-3-glucuronide) were determined at regular intervals up to 7 h after the start of morphine infusion. A population pharmacodynamic model was used to analyze the morphine-induced changes in stimulus intensity. The improvement of the model fits by inclusion of covariates (sex, age, weight, lean body mass) was tested for significance. The model is characterized by baseline current, a rate constant for equilibrium between plasma and effect-site morphine concentrations (ke0), and analgesic potency (AC50, or the morphine concentration causing a 100% increase in stimulus intensity for response). ResultsThe inclusion of the covariates age, weight, and lean body mass did not improve the model fits for any of the model parameters. For both pain threshold and tolerance, a significant dependency on sex was observed for the parameters ke0 (pain threshold: 0.0070 ± 0.0013 (± SE) min−1 in men vs. 0.0030 ± 0.0005 min−1 in women; pain tolerance: 0.0073 ± 0.0012 min−1 in men vs. 0.0024 ± 0.0005 min−1 in women) and AC50 (pain threshold: 71.2 ± 10.5 nm in men vs. 41.7 ± 8.4 nm in women; pain tolerance: 76.5 ± 7.4 nm in men vs. 32.9 ± 7.9 nm in women). Baseline currents were similar for both sexes: 21.4 ± 1.6 mA for pain threshold and 39.1 ± 2.3 mA for pain tolerance. Concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide did not differ between men and women. ConclusionsThese data show sex differences in morphine analgesia, with greater morphine potency but slower speed of onset and offset in women. The data are in agreement with observations of sex differences in morphine-induced respiratory depression and may explain higher postoperative opioid consumption in men relative to women.

Plasma Concentrations of Alfentanil Required to Supplement Nitrous Oxide Anesthesia for General Surgery

To design an efficient infusion regimen from pharmacokinetic data, it is necessary to know the alfentanil plasma concentrations required for satisfactory anesthesia. In 37 patients about to undergo lower abdominal gynecologic, upper abdominal, or breast surgery, anesthesia was induced with alfentanil 150 μg/kg iv and 66% N2O in oxygen. Thereafter, N2O anesthesia was supplemented with a continuous infusion of alfentanil that was varied between 25 and 150 μg · kg-1 · h-1, as indicated by the patients responses to surgical stimulation. Small bolus doses of alfentanil 7 or 14 μg/kg were administered and the infusion rate increased to suppress precisely defined somatic, autonomic, and hemodynamic responses. Arterial plasma concentrations of alfentanil were measured during the operation when the patient did and did not respond to noxious stimulation. Logistic regression was used to determine plasma concentration–effect curves for different stimuli. Plasma alfentanil concentrations required along with 66% N2O to obtund responses to single episodes of stimulation in 50% of the 37 patients (Cp50 ± SE) were: 475 ± 28 ng/ml for tracheal intubation, 279 ± 20 ng/ml for skin incision, and 150 ± 23 ng/ml for skin closure. Between skin incision and closure, multiple determinations of response/no response were made for each patient and an individual Cp50 was estimated. The Cp50 (mean ± SD) for the three surgical procedures were: breast, 270 ± 63 ng/ml (n = 12); lower abdominal, 309 ± 44 ng/ml (n = 14); and upper abdominal, 412 ± 135 ng/ml (n = 11). The Cp50 for satisfactory spontaneous ventilation after the discontinuation of N2O was 223 ± 13 ng/ml. These data demonstrate that different perioperative stimuli require different alfentanil concentrations to suppress undesirable responses. Thus, the alfentanil infusion rate should be varied according to the patients responsiveness to stimulation in order to maintain satisfactory anesthetic and operative conditions and to provide rapid recovery of consciousness and spontaneous ventilation.

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.

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)

Mechanism of action of an epidural top-up in combined spinal epidural anesthesia.

The purpose of this study was to elucidate the mechanism of action by which an epidural top-up reinforces anesthesia in combined spinal epidural anesthesia. Thirty patients scheduled to undergo lower limb orthopedic surgery were randomly allocated to three groups of 10 patients each. In all patients, a 16-gauge Tuohy needle was introduced into the epidural space. Using the needle through needle technique, each patient received a subarachnoid injection of 10 mg plain bupivacaine 0.5% through a long 27-gauge Whitacre spinal needle introduced into the subarachnoid space through the Tuohy needle. After withdrawal of the spinal needle, an epidural catheter was introduced into the epidural space. After the maximum level of sensory block after the subarachnoid injection had been established, an epidural top-up with 10 mL bupivacaine 0.5% (Group 1) or 10 mL saline (Group 2) was administered; patients in Group 3 received no epidural top-up. The maximum level of sensory block was then assessed for an additional 30 min. After the epidural top-up the maximum level of sensory block increased significantly by 4.8 +/- 1.6 segments in Group 1 and 2.0 +/- 2.0 segments in Group 2. In Group 3 there was a nonsignificant increase of 0.3 +/- 0.5 segments. Intergroup comparisons showed that this increase in Group 1 was significant compared with those in Groups 2 and 3, and that the increase in Group 2 was significant compared with that in Group 3. We conclude that the mechanism of action by which an epidural top-up reinforces anesthesia in combined spinal epidural anesthesia can be explained partly by an epidural volume effect and partly by an effect of the local anesthetic itself. (Anesth Analg 1996;83:382-6)

The Effects of Age on Neural Blockade and Hemodynamic Changes After Epidural Anesthesia with Ropivacaine

We studied the influence of age on the neural blockade and hemodynamic changes after the epidural administration of ropivacaine 1.0% in patients undergoing orthopedic, urological, gynecological, or lower abdominal surgery. Fifty-four patients were enrolled in one of three age groups (Group 1: 18–40 yr; Group 2: 41–60 yr; Group 3: ≥61 yr). After a test dose of 3 mL of prilocaine 1.0% with epinephrine 5 &mgr;g/mL, 15 mL of ropivacaine 1.0% was administered epidurally. The level of analgesia and degree of motor blockade were assessed, and hemodynamic variables were recorded at standardized intervals. The upper level of analgesia differed among all groups (medians: Group 1: T8; Group 2: T6; Group 3: T4). Motor blockade was more intense in the oldest compared with the youngest age group. The incidence of bradycardia and hypotension and the maximal decrease in mean arterial blood pressure during the first hour after the epidural injection (median of Group 1: 11 mm Hg; Group 2: 16 mm Hg; Group 3: 29 mm Hg) were more frequent in the oldest age group. We conclude that age influences the clinical profile of ropivacaine 1.0%. The hemodynamic effects in older patients may be caused by the high thoracic spread of analgesia, although a diminished hemodynamic homeostasis may contribute.

Influence of age on the pharmacokinetics of alfentanil gender dependence

SummaryStudies on the effects of age on the pharmacokinetics of alfentanil are inconclusive. A possible factor in explaining the differences between various studies could be the effect of gender. The authors studied the effects of age on the pharmacokinetics of alfentanil in female (n = 21) and male (n = 15) patients undergoing lower abdominal surgery under nitrous oxide alfentanil anaesthesia. There was a significant negative correlation (r = −0.79, p < 0.001) between plasma alfentanil clearance (CL) and age in women (<50y, median CL 24.84 L/h; >50y, median CL 14.52 L/h), but not in men (<50y, median CL 19.44 L/h; >50y, median CL 16.2 L/h). The conclusion is drawn that the effects of age on the pharmacokinetics of alfentanil are gender-dependent.