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.

Target-controlled infusion of alfentanil for postoperative analgesia: contribution of plasma protein binding to intra-patient and inter-patient variability.

We have examined the influence of plasma protein binding on inter-individual and intra-individual variability in the effective postoperative analgesic concentration (EAC) of alfentanil and on the performance of the target-controlled infusion system used. Ten patients received standardized anaesthesia and target-controlled alfentanil for postoperative analgesia. Analgesia was assessed using a visual analogue scale (VAS). Plasma protein binding of alfentanil was assessed at four different times (on arrival in the recovery room, at 21:00 on the day of surgery and at 09:00 and 21:00 on the first postoperative day). Bias and inaccuracy were examined on the day of surgery and on the first postoperative day. Unbound fractions of alfentanil varied from 5 to 15% and varied in time. In general, the unbound fractions on the day of surgery were higher than those on the first postoperative day. Thirty-nine percent of inter-individual variability in the EAC of alfentanil (range 33-140 ng ml-1) at the onset of therapy could be explained by protein binding. At the other observation times, correlations between unbound fraction and EAC were only moderate. Bias on the day of surgery was -19% and 12% on the first postoperative day (ns). Inaccuracy was 23% and 18%, respectively (ns). We conclude that inter-individual variations in plasma protein binding can explain a significant portion of inter-individual variability in the EAC of alfentanil in the early postoperative phase.

Alfentanil as an adjuvant to epidural bupivacaine in the management of postoperative pain after laparotomies: lack of evidence of spinal action.

UNLABELLED: In this double-blind study, we compared the efficacy of epidural versus i.v. administration of alfentanil in combination with small-dose bupivacaine for postoperative pain relief. Thirty-two patients were randomly allocated to one of two study groups. Patients from both groups received an epidural loading dose of 60 mg of bupivacaine (12 mL of 0.5%). Subsequently, patients in the epidural (EPI) group received an infusion (8 mL/h) of 0.125% bupivacaine (10 mg/h) plus alfentanil (0.36 mg/h) and an i.v. infusion (8 mL/h) of NaCl 0.9%. Patients in the i.v. group received an epidural infusion (8 mL/h) of 0.125% bupivacaine (10 mg/h) and an i.v. infusion (8 mL/h) of alfentanil (0.36 mg/h). Infusions were maintained for 24 h. These dose regimens were such that equivalent subanalgesic plasma concentrations of alfentanil were obtained. Patient-controlled analgesia with morphine was available to both groups. Time to onset of postoperative pain and morphine consumption were used as variables to compare the two regimens. Measured plasma concentrations of alfentanil during the postoperative observation period were similar (< 20 ng/mL) in both groups. Median times to onset of postoperative pain (EPI 600 min, i.v. 360 min) and total morphine consumption (EPI 11 mg, i.v. 10 mg) did not differ between the groups (P > 0.2). We conclude that, in combination with epidural bupivacaine 0.125%, an i.v. infusion of alfentanil is equally effective as an epidural infusion of alfentanil if the plasma concentrations are the same. The study did not demonstrate a spinal mechanism of action for alfentanil. IMPLICATIONS: This randomized, double-blind study showed that, when combined with small-dose bupivacaine (0.125%), epidurally administered alfentanil is not more effective than i.v. administered alfentanil for postoperative pain management when the regimens are such that equivalent subanalgesic plasma alfentanil concentrations are obtained. A spinal mechanism of action for alfentanil could therefore not be demonstrated.

Target-controlled infusion of alfentanil for postoperative analgesia: a feasibility study and pharmacodynamic evaluation in the early postoperative period.

We have examined the feasibility of target-controlled infusion of alfentanil (TCIA) and the pharmacodynamics of alfentanil in the early postoperative period. Patients were allocated randomly to one of the three groups to receive balanced anaesthesia with bolus injections of fentanyl (group F), sufentanil (group S) or alfentanil (group A). In the recovery room all patients received the same analgesic regimen, comprising TCIA. To evaluate the efficacy of postoperative analgesia, pain scores were measured on a visual analogue scale (VAS) and patients indicated a need for additional analgesia. EC50, the concentration at which, with a 50% probability, patients reported adequate analgesia, was estimated using logistic regression. Six patients did not complain of pain. The time from the last intraoperative bolus injection of opioid until patients complained of postoperative pain was shorter (P < 0.05) in group A (mean 68 min) than in group F (101 min) and group S (136 min). The time to onset of satisfactory analgesia was comparable in the three groups (median 18 min in group F, 15 min in group S and 14 min in group A). EC50 of alfentanil was determined in 28 patients; mean values were 26 ng ml-1 (group F), 39 ng ml-1 (group S) and 52 ng ml-1 (group A). We conclude that TCIA, under the conditions studied, resulted in a fast onset of adequate analgesia, irrespective of the opioid administered during operation. Also, there was no effect of opioids administered during operation on postoperative pharmacodynamics of alfentanil.

Epidural vs. intravenous infusion of alfentanil in the management of postoperative pain following laparotomies.

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.

Computer-controlled infusion of alfentanil versus patient-controlled administration of morphine for postoperative analgesia: a double-blind randomized trial.

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.

The effect of epidural administration of alfentanil on intra-operative intravenous alfentanil requirements during nitrous oxide-oxygen-alfentanil anaesthesia for lower abdominal surgery.

The effects of epidural administration of alfentanil on the intravenous alfentanil dose requirements and the plasma concentrations required to suppress responses to surgical stimulation during nitrous oxide-oxygen-alfentanil anaesthesia in 20 patients undergoing lower abdominal surgery were studied. Before induction of anaesthesia, patients in one group (E) received an epidural injection of 1 mg alfentanil, followed by an epidural infusion of alfentanil 0.2 mg.h-1 until skin closure, whilst patients in the other group (C, control) received a continuous infusion of sodium chloride via a sham catheter in order to blind the main investigator to the treatment. Anaesthesia was induced and maintained with nitrous oxide (66%) in oxygen and a 'target'-controlled intravenous infusion of alfentanil. During surgery, the 'target' alfentanil concentration was increased or decreased according to patients' responses. The number of responses to surgical stimulation was smaller in patients from group E (median 1, range 0-3) than in patients from group C (median 4, range 1-15; p < 0.005), even though the alfentanil intravenous infusion rates were smaller in group E [mean (SD): 1.6(0.5) micrograms.kg-1 min-1] than in group C [2.9(1.2) micrograms.kg-1 min-1, p < 0.02]. Both the lowest concentrations associated with no response [133(40) ng.ml-1] and the highest concentrations associated with a response [155(65) ng.ml-1] in group E were lower than those in group C [238(100) ng.ml-1, p < 0.01 and 334(163) ng.ml-1, p < 0.05, respectively]. We concluded that epidural administration of alfentanil reduces intravenous alfentanil requirements during nitrous oxide-oxygen-alfentanil anaesthesia for lower abdominal surgery. The results indicate a spinal mechanism of action of epidural alfentanil.

[Postoperative pain control in The Netherlands]. / Postoperatieve pijnbestrijding in Nederland.

OBJECTIVE: To determine how postoperative analgesia care is managed in the Netherlands. DESIGN: Descriptive study (questionnaire). SETTING: Departments of anaesthesiology in all 168 Dutch hospitals. METHOD: Questionnaires were sent inquiring about postoperative pain therapies and their complications, the organisation and management of postoperative analgesic care, the importance of effective pain control, factors of influence on patient's assessment of pain and the management of the quality of postoperative analgesia. RESULTS: The questionnaires of 73% (n = 122) of the hospitals were suitable for analysis. Locoregional analgesic techniques are used, but intermittent intramuscular administration of an opioid is still the analgesic therapy of choice in the postoperative period. 89% of the interviewed anaesthesiologists assess the average intensity of postoperative pain as moderate or severe, and more than half of the interviewed anaesthesiologists answered that effective postoperative pain management is of substantial influence on the postoperative recovery of the patient. CONCLUSION: It is essential to improve postoperative pain control in the Netherlands. Frequent assessments and precise documentation of the intensity of pain and pain relief, on which further therapy can be based, might be a first step in improving postoperative pain control. Optimal postoperative pain management requires the input of equipment and staff.

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 intraoperative 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.

Rectal methohexital: concentration and length of the rectal catheters.

In the study, the authors evaluated the concentration of rectal methohexital (1% vs 10%) and the length of the rectal catheter (3.8 vs 12.7 cm), on sleep-success rate, administration-sleep time, methohexital plasma concentrations, and recovery time in 85 healthy children scheduled for elective ophthalmic or ear, nose, or throat operations lasting approximately 1 h. At a dose of 25 mg/kg, the 1% solution of rectal methohexital was associated with a significant (P less than 0.05) higher sleep-success rate (95% vs 70%), shorter administration-sleep time (5.7 +/- 1.9 vs 7.0 +/- 2.0 min), higher methohexital plasma concentrations at 20 min (6.5 vs 4.7 ng/mL) and at 30 min (5.3 vs 3.7 ng/mL), and prolonged recovery time (53.2 +/- 31.1 vs 32.4 +/- 18.5 min). The length of the rectal catheters did not significantly affect sleep-success rate, administration-sleep time, methohexital plasma concentrations, or recovery time. The use of 25 mg/kg of 1% rectal methohexital solution to induce anesthesia in children is superior to the use of 25 mg/kg of 10% methohexital solution for induction of anesthesia in children, particularly in operations 1 h or longer in duration.