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Publications and source records attributed to A G Burm.
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A method enabling quantification of R-(-)- and S-(+)-mepivacaine in human plasma in the low nanogram per milliliter range is described. The procedure involves extraction from plasma with diethyl ether, centrifugation, back-extraction into an acidified aqueous solution, washing with a mixture of pentane and isoamylalcohol, alkalinisation, followed by extraction with a mixture of n-pentane and isoamylalcohol. After evaporation of the organic phase, the residue is redissolved in the mobile phase used for the HPLC analysis, which consists of a 6.8:93.2 (v/v) isopropanol-sodium hydrogenphosphate buffer solution with the pH adjusted to 6.8 using phosphoric acid. The HPLC method has been described previously. Separation of the enantiomers is achieved with an alpha 1-AGP column and the UV detection wavelength is 210 nm. The minimal detectable concentration is ca. 3 ng/ml and the lower limit of quantification is 5 ng/ml for each enantiomer. For both enantiomers r is > 0.9995 over the plasma enantiomeric concentration range of 10.5-1053 ng/ml.
We applied a system dynamics approach to the study of the pulmonary distribution of alfentanil and sufentanil in anesthetized pigs and patients, respectively. This method allows estimation of the mean transit time through the lungs and calculation of the volume of distribution of alfentanil in the lungs. In the first part of the study the pulmonary distribution of alfentanil was studied in six anesthetized pigs during three hemodynamic states (control, partial clamping of the inferior vena cave, and complete clamping of the right pulmonary artery). In the second part of the study the pulmonary distribution of sufentanil was studied in 10 patients, scheduled for elective CABG, during and after a constant rate infusion of 10 min. Pulmonary passage of the opioids was characterized by functions of transit times, derived from the pulmonary arterial and systemic arterial concentration curves. Pulmonary distribution volumes were calculated from the mean transit time and pulmonary blood flow. Pulmonary distribution volume of alfentanil during the control measurement was significantly higher (486 +/- 88 ml) than during either partial caval clamping (346 +/- 89 ml, p < 0.05) or right pulmonary artery clamping (336 +/- 56 ml, p < 0.05). There was no change in the extravascular volume of distribution of alfentanil with each hemodynamic state. Pulmonary volume of distribution of sufentanil in the patients was 22.6 (10.9) L. Pulmonary distribution of opioids can be studied using system dynamics analysis, both after bolus injection and during and after infusion. This method can be used for periods beyond the initial passage of the drug through the lungs.
We have studied the pulmonary uptake of sufentanil in patients during and after a short infusion of the drug. We studied 10 patients undergoing elective coronary artery bypass surgery during anaesthesia with 0.4-0.8% enflurane, before surgery. Sufentanil 50 micrograms min-1 was given over 10 min by a constant rate infusion. During infusion and for 20 min thereafter, blood samples were obtained from the distal port of the pulmonary artery catheter and from a radial artery catheter. Uptake and release of sufentanil into and from the lungs were examined by mass balance and compartmental analyses. At the end of the infusion a mean of 48.9 (SD 18.6)% of the dose was retained in the lungs, and 20 min after infusion retention was 18.4 (22.4)%. Smokers had significantly higher pulmonary retention of sufentanil. The pulmonary volume of distribution of sufentanil, estimated from the two-compartment model, was 20.9 (7.7) litre. We conclude that pulmonary uptake of sufentanil is significant, if the drug is given as an infusion.
In this randomized, observer-blind study, we have examined, in elderly patients, the effect of site of injection on analgesia levels after spinal injection of 0.5% hyperbaric bupivacaine solution. Thirty male patients, aged 68-87 yr, undergoing minor urological surgery during spinal anaesthesia received 3 ml of a 0.5% hyperbaric bupivacaine solution at either the L3-4 (n = 15) or L4-5 (n = 15) interspace. The solution was injected with the patient in the sitting position. The patient remained sitting for 2 min and was then placed in the supine horizontal position. Analgesia levels were assessed bilaterally using pin-prick. The highest analgesia levels did not differ between groups (medians were approximately T7). There were no significant differences in the time to maximum cephalad spread of analgesia, maximum degree of motor block or haemodynamic changes. We conclude that injection at the L4-5 interspace has no advantage compared with injection at the L3-4 interspace.
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.
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 unpremedicated 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 microgram/ml, that was increased every 12 min by 0.5-1 microgram/ml. Every 3 min, the eyelash reflex and state of consciousness were tested an an arterial blood sample was taken for blood propofol and plasma alfentanil determination. The propofol-alfentanil 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 EC(50) of propofol decreased from 2.07 to 0.83 microgram/ml for loss of eyelash reflex and from 3.62 to 1.55 microgram/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 microgram/ml and from 2.36 to 0.04 microgram/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.
BACKGROUND: This study was designed to compare the efficacy of epidural vs. intravenous administration of alfentanil for treatment of postoperative pain. METHODS: Twenty patients were randomly allocated to one of the two study groups to receive either an epidural bolus dose (0.75 mg) followed by an epidural infusion (0.36 mg/h) (EPI group) or an intravenous infusion (0.36 mg/h) of alfentanil (IV group) for 24 h. These dose regimens were chosen such that equivalent and subanalgesic plasma concentrations of alfentanil were obtained. PCA-morphine was available to both groups. Morphine consumption, pain scores measured on a Visual Analogue Scale (VAS) and the number of demands were used as variables to evaluate the efficacy of the postoperative analgesic therapy. In addition, plasma concentrations of alfentanil were measured. RESULTS: The mean plasma concentrations of alfentanil were similar and < 20 ng/ml in both groups. Total morphine consumption (EPI: 40 mg, i.v.: 43 mg), pain scores (time when the VAS-score > 3.0: EPI: median 215 min; i.v.: median 215 min) and number of valid demands (EPI: median 25; i.v.: median 34) did not differ between the groups. CONCLUSION: Compared to intravenous infusion of alfentanil epidural infusion resulting in the same plasma concentrations is not more effective in relieving postoperative pain. In view of this observation we were not able to demonstrate a spinal mechanism of alfentanil.
Using a double-indicator technique, we have studied, in 10 patients undergoing aorto-coronary bypass surgery, first-pass pulmonary retention of sufentanil. Pulmonary retention was studied at three pseudo steady-state background blood concentrations of 2.8 (0.66), 6.9 (1.2) and 15.9 (2.6) ng ml-1, respectively, produced by a computer-controlled infusion. Mean first-pass pulmonary retentions at these concentrations were 68 (95% confidence intervals 62-73), 65 (60-70) and 60 (52-67)%, respectively. First-pass pulmonary retention of sufentanil was significantly lower at the highest background concentration compared with the lowest background concentration. First-pass pulmonary retention of sufentanil was partly saturable in the range of concentrations used for clinical purposes.
This study compared the efficacy of computer-controlled infusion of alfentanil (CCiA) with patient-controlled administration of morphine (PCAM) for postoperative analgesia. Twenty patients were randomly allocated to one of the two study groups to receive either an intravenous CCiA or PCAM regimen. Pain scores measured on a visual analog scale (VAS) and the number of valid demands were used as variables to evaluate the efficacy of the postoperative analgesic therapy. In addition, the bias and inaccuracy of the pharmacokinetic data set of alfentanil used in the CCiA program were examined by determining the median performance error (MDPE), and the median absolute performance error (MDAPE). The onset of satisfactory analgesia was faster (P < 0.05) in the CCiA group (median: 20 min) than in the PCAM group (median: 50 min). The total number of demands was lower (21 vs 34, P < 0.05) and the time when the VAS score was > 3.0 was shorter (P < 0.05, 12% of the time) in the CCiA group than in the PCAM group (21% of the time). The MDPE and MDAPE were 8% and 22%, respectively. The maximum alfentanil concentrations associated with pain and the minimum effective analgesic concentrations of alfentanil varied considerably both inter- and intraindividually. In conclusion, compared to a standard intravenous PCAM regimen, a CCiA is faster in onset of analgesia and is as effective in providing postoperative analgesia.
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 computer-controlled 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%.(ABSTRACT TRUNCATED AT 250 WORDS)
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. METHODS: Twenty-one women, aged 20-55 yr, scheduled for lower abdominal surgery, were randomly assigned in a double-blind manner to one of three groups to receive a computer-controlled infusion of propofol with target concentrations of 2, 4, or 6 micrograms/ml. In addition, all patients received computer-controlled infusion of alfentanil (initial target concentration 50 ng/ml). While the target concentration of propofol was maintained constant, the target concentration of alfentanil was varied in steps of 10-50 ng/ml according to the presence or absence of patient responses to perioperative stimuli. Arterial blood samples for alfentanil and propofol determination were taken at clinically relevant stimuli. Alfentanil-propofol interactions for laryngoscopy, intubation, skin incision, the opening of the peritoneum, and awakening were determined by logistic regression over the three groups (n = 21). The alfentanil concentrations associated with a 50% probability (EC50s) of suppression of responses to intraabdominal surgical stimuli, as determined by logistic regression in the individual patients, were related to corresponding mean blood propofol concentrations by nonlinear regression analysis. RESULTS: With blood propofol concentrations increasing from 2 to 10 micrograms/ml, the EC50 of alfentanil decreased from 170 to 25 ng/ml for laryngoscopy, from 280 to 23 ng/ml for intubation, from 259 to 9 ng/ml for the opening of the peritoneum, and from 209 to 16 ng/ml for the intraabdominal surgical stimuli. With plasma alfentanil concentrations increasing from 10 to 150 ng/ml, the EC50 of propofol for the regaining of consciousness decreased from 3.8 to 0.8 microgram/ml. DISCUSSION: We defined the pharmacodynamic interaction between propofol and alfentanil for suppression of responses to perioperative stimuli during lower abdominal surgery. We conclude that propofol reduces alfentanil requirements for all studied clinical end points. In addition, alfentanil decreases propofol concentrations at which patients regain consciousness.
A clean-up procedure to obtain a minimal detectable concentration of 5-10 ng bupivacaine enantiomer per milliliter human plasma is described. The procedure consists of precipitation of plasma proteins using acetonitrile, followed by solid-phase extraction using a cyano column. The eluate is then made alkaline, and bupivacaine is extracted using n-hexane. After evaporation of n-hexane, the residue is redissolved in the eluent used for HPLC analysis. The HPLC method has been described previously. The minimal detectable concentrations using this method are ca. 8 and 10 ng/ml for R-(+)- and S-(-)-bupivacaine, respectively. For both enantiomers, r2 is > 0.995 over the range of 9.5-760 ng/ml enantiomer.
We have studied, in 14 patients undergoing elective aorto-coronary bypass surgery, the effect of the type of ventilation on pulmonary retention of alfentanil and sufentanil using a double indicator technique. Patients were allocated to one of two groups to receive either bolus doses of sufentanil 33.2 micrograms (n = 6) or alfentanil 654 micrograms (n = 8), mixed with indocyanine green. In each patient, pulmonary first-pass retention was studied during apnoea (during the 1-min study period), normoventilation and positive end-expiratory pressure (10 mm Hg) ventilation, the order of which was randomized. After sufentanil, mean (95% confidence interval) first-pass pulmonary retention was 50.9 (41.7-60.1)% during apnoea, 50.8 (42.9-58.8)% during normoventilation and 54.4 (43.7-65.0)% during positive end-expiratory pressure ventilation. After alfentanil, first-pass pulmonary retention was 18.7 (5.4-32.0)% during apnoea, 19.9 (8.3-31.5)% during normoventilation and 16.6 (5.6-27.6)% during positive end-expiratory pressure ventilation. First-pass pulmonary retention of alfentanil and sufentanil was not significantly affected by the type of ventilation.
BACKGROUND: The effects of epidurally administered alfentanil may be due in part to its uptake into the systemic circulation. Therefore we examined the systemic absorption kinetics after epidural injection of alfentanil. METHODS: Pharmacokinetics were determined using a stable isotope method in ten patients, undergoing lower abdominal surgery under general anesthesia. After epidural injection of 0.68 mg deuterium-labeled alfentanil (alfentanil-d5), 1 mg unlabeled alfentanil was administered over 1 h by an intravenous infusion. Blood samples were collected for 12 h. Concentrations of alfentanil and alfentanil-d5 were measured by a combination of gas chromatography and mass fragmentography. The systemic absorption profiles of alfentanil-d5 were determined by deconvolution of the plasma alfentanil-d5 concentrations with the biexponential unit disposition functions, derived from the intravenous data. In addition, data were analyzed by moment analysis. RESULTS: The mean (+/- SD) steady-state volume of distribution, total plasma clearance, elimination half-life and mean residence time, derived from the unlabeled alfentanil concentration-time data, were 43.2 +/- 19.5 1,418 +/- 129 ml/min, 119 +/- 34 min, and 103 +/- 26 min, respectively. The absorption of alfentanil-d5 was monophasic in most patients. The mean systemic availability and mean absorption time derived from the deconvolution data were 100 +/- 17% and 114 +/- 24 min. The values determined by moment analysis were 107 +/- 18% and 112 +/- 36 min, respectively. CONCLUSIONS: After epidural administration alfentanil is slowly absorbed into the general circulation. Resulting plasma concentrations are very low and do not contribute appreciably to the systemic opioid effect.
BACKGROUND: In humans the ventilatory response to isocapnic hypoxia is biphasic: an initial increase in minute ventilation (VE) from baseline, the acute hypoxic response, is followed after 3-5 min by a slow ventilatory decay, the hypoxic ventilatory decline, and a new steady state, 25-40% greater than baseline VE, is reached in about 15-20 min. The transition from 20 min of isocapnic hypoxia into normoxia results in a rapid decrease in VE, the off-response. In humans, halothane, at subanesthetic concentrations, is known to decrease the acute hypoxic response. In order to investigate the effects of halothane on sustained hypoxia we quantified the effects of 0.15 minimum alveolar concentration halothane on the ventilatory response at the onset of 20 min of hypoxia and at the termination of 20 min of hypoxia by normoxia in healthy volunteers. METHODS: Step changes in end-tidal oxygen tension were performed against a background of constant mild hypercapnia (end-tidal carbon dioxide tension about 1 mmHg above individual resting values) in fourteen male subjects. The end-tidal oxygen tension was forced as follows: 5-10 min at 110 mmHg, 20 min at 44 mmHg, and 10 min at 110 mmHg. In each subject we performed one trial before and one during 0.15 minimum alveolar concentration halothane administration. RESULTS: Ten responses into hypoxia and nine out of hypoxia were considered for analysis. All control trials were performed during wakefulness. Using behavioral characteristics, the central nervous system arousal state of the subjects during halothane inhalation was defined as "anesthesia-induced hypnosis." The acute hypoxic response averaged 10.4 +/- 4.7 l/min for control versus 3.7 +/- 2.4 l/min for halothane trials (P < 0.01). The hypoxic ventilatory decline was 4.8 +/- 2.5 l/min versus 3.9 +/- 2.9 l/min (NS), the off-response was 6.7 +/- 3.2 l/min versus 3.7 +/- 3.0 l/min (P < 0.05) for control versus halothane, respectively. All values are mean +/- SD. CONCLUSIONS: Our results indicate that halothane caused VE to be less than control levels during acute and sustained hypoxia as well as when sustained hypoxia is replaced by normoxia. It is argued that the depression of VE during acute hypoxia is attributed to an effect of halothane on the peripheral chemoreceptors. During sustained hypoxia halothane had no effect on the magnitude of the hypoxic ventilatory decrease, which is probably related to an increase by halothane of inhibitory neuromodulators within the central nervous system. With halothane, the ventilatory decrease when sustained hypoxia is replaced by normoxia is related to the removal of the hypoxic drive at the site of the peripheral chemoreceptors.
The efficacy of thoracic epidural sufentanil 50 micrograms was compared with bupivacaine 0.5% with adrenaline 5 micrograms.ml-1 (dose 40 mg) or saline, in 30 patients (n = 10 in each group) undergoing lateral thoracotomy. Sufentanil, bupivacaine or saline was administered epidurally after induction of anaesthesia with sufentanil 1 microgram.kg-1 and thiopentone 2-5 mg.kg-1. Anaesthesia was maintained with nitrous oxide 66% and halothane 0.3%. Supplementary sufentanil 25 micrograms was given whenever the systolic arterial blood pressure increased more than 15 mmHg above the pre-operative value, whenever heart rate exceeded 90 beat.min-1 in the absence of hypovolaemia, or when other autonomic or somatic signs occurred. Fewer patients in the epidural sufentanil (n = 4, p < 0.005) and bupivacaine (n = 1, p < 0.001) groups required supplementary sufentanil compared to the placebo group, in which all patients needed supplementary sufentanil, but there was no statistical difference between the sufentanil and bupivacaine groups. One or more hypotensive episodes occurred in five patients in the sufentanil group, in all patients in the bupivacaine group and in no patient in the placebo group, and the differences were significant (p < 0.02).
The efficacy of thoracic epidural sufentanil 50 micrograms was compared with lumbar epidural sufentanil 50 micrograms in 30 patients (n = 15 in each group) undergoing lateral thoracotomy. Sufentanil was administered epidurally after induction of anaesthesia with sufentanil 1 microgram.kg-1 and thiopentone 2-5 mg.kg-1 intravenously. Anaesthesia, nitrous oxide 66%, halothane 0.3% and sufentanil 25 micrograms intravenously were given whenever the systolic arterial blood pressure increased more than 15 mmHg above the preoperative value and heart rate exceeded 90 beat.min-1 in the absence of hypovolaemia, or when other autonomic or somatic signs were seen. Four patients in the thoracic epidural group and five in the lumbar epidural group needed supplementary sufentanil. Six patients in the thoracic epidural group and three in the lumbar epidural group each had a single hypotensive episode. Lumbar and thoracic epidural sufentanil are equally effective in contributing to intra-operative analgesia for lateral thoracotomy.