Remifentanil and other opioids.

Most opioids used in anaesthesia are of the anilidopiperidine family, including fentanyl, alfentanil, sufentanil and remifentanil. While all share similar pharmacological properties, remifentanil, the newest one, is probably the most original, which is the reason this review focusses especially on this drug. Remifentanil is a potent mu-agonist that retains all the pharmacodynamic characteristics of its class (regarding analgesia, respiratory depression, muscle rigidity, nausea and vomiting, pruritus, etc.) but with a unique pharmacokinetic profile that combines a short onset and the fastest offset, independent of the infusion duration. Consequently, it offers a unique titratability when its effects need to be quickly achieved or suppressed, but it requires specific drug delivery schemes such as continuous infusion, target-controlled infusion and anticipated postoperative pain treatment. Kinetic differences between opioids used in anaesthesia and some clinical uses of remifentanil are reviewed in this chapter.

Remifentanil sedation compared with propofol during regional anaesthesia.

BACKGROUND: The short onset and offset of remifentanil may allow for accurate dosing of sedative effect with few side-effects and rapid recovery. In this study remifentanil is compared with propofol for sedation during successful regional anaesthetic blocks. METHODS: After informed consent was given, 125 patients undergoing surgery under spinal or brachial plexus anaesthesia were randomized to receive, either propofol: bolus 500 microg/kg plus initial infusion 50 microgkg/min or remifentanil: bolus 0.5 microg/kg plus initial infusion 0.1 microgkg/min. Study drug infusion rate was titrated throughout the procedure according to level of sedation and side-effects. Pain, discomfort, sedation level and side-effects were recorded at regular intervals until discharge from the post operative care unit (PACU). RESULTS: Two patients in the remifentanil group versus ten in the propofol group were treated for discomfort or pain during surgery (P<0.02). Due to a significantly higher rate of respiratory depression (46% vs. 19% with propofol, P<0.01) the mean remifentanil infusion rate was decreased to 0.078 +/- 0.028 microgkg/min, whereas it was kept stable with propofol. Propofol patients had significantly higher (P<0.05) sedation levels and experienced more frequent amnesia of the procedure. Eleven propofol patients experienced pain at injection site, versus two remifentanil patients (P<0.02). Nausea and vomiting were more frequent in the remifentanil patients during infusion (27% vs. 2% in the propofol group, P<0.001) but similar postoperatively. Time to discharge from PACU was similar in the two groups. CONCLUSION: Propofol results in less respiratory depression and nausea when sedation is needed during a case with a successful regional block. Remifentanil may be considered as an alternative if pain during the procedure is a major concern or if amnesia is contraindicated.

Influence of analgesic supplementation on the target propofol concentrations for anaesthesia with 'Diprifusor' TCI.

Forty healthy patients undergoing orthopaedic surgery were randomly allocated to receive an initial blood propofol target concentration of either 4 micrograms.ml-1 or 6 micrograms.ml-1 for induction of anaesthesia with a 'Diprifusor' target controlled infusion system for propofol, and analgesic supplementation with either nitrous oxide 67% in oxygen or alfentanil 15-20 micrograms.kg-1.h-1. Anaesthesia was induced within 3 min in 80% and 95% of patients with propofol target concentrations of 4 micrograms.ml-1 and 6 micrograms.ml-1, respectively. The frequency of discomfort on infusion was similar for both target concentrations. During maintenance, supplementary doses of alfentanil were required to provide adequate surgical conditions in approximately half of the patients receiving nitrous oxide. There was no statistically significant difference between the target concentration [mean (SD)] of propofol for total intravenous anaesthesia [5.1 (2.0) micrograms.ml-1] compared with a technique using nitrous oxide [4.6 (1.2) micrograms.ml-1] supplemented as needed with small doses of alfentanil.

TCI compared with manually controlled infusion of propofol: a multicentre study.

This prospective, randomised multicentre study was designed to determine the clinical profile of 'Diprifusor' target controlled infusion compared with manually controlled infusion of propofol in 562 patients, aged 18-85 years, in a range of surgical procedures in 29 centres. The dose of propofol required for loss of consciousness was statistically significantly lower in the target controlled infusion group [1.69 (0.50) vs. 2.31 (0.75) mg.kg-1, p < 0.001] but the overall rate of propofol administration was slightly, but significantly, higher [12.1 (5.1) vs. 11.0 (6.0) mg.kg-1.h-1, p < 0.05]. The target concentration (CT) required for induction decreased with increasing age and ASA class, with premedication and with the administration of an opioid before induction. However, the amount of opioid given did not influence the CT required for induction, but enhanced the haemodynamic effects of propofol induction in both groups. Most investigators expressed an overall preference for target controlled infusion (93%) and found it easier to use (76%). Despite the lack of experience of most investigators in using target controlled infusion, the clinical profiles of both propofol administrations were similar. Data suggest that the clinical profile of target controlled infusion may be improved with experience, for example by more active titration of CT to effect. Target controlled infusion may well become the preferred choice for anaesthetists.

A comparison of 2% and 1% formulations of propofol for the induction and maintenance of anaesthesia in surgery of moderate duration.

This study, conducted in 110 patients undergoing surgery of moderate duration, compared the pharmacodynamic equivalence, efficacy and safety of 1% and 2% formulations of propofol. Anaesthesia was induced with propofol 2 mg.kg-1 given over 40 s and supplementary bolus injections of propofol were given if needed. There were no significant differences between the groups in mean induction times, total induction doses of propofol, frequency and mean duration of apnoea, fentanyl requirements or mean recovery times (times to eyes opening and to orientation). Isolated statistically significant group differences in systolic and diastolic blood pressures and heart rates during induction were not considered clinically significant. Discomfort on injection occurred in 40% and 52% of those given 1% (n = 55) and 2% (n = 55) propofol, respectively; there was no statistically significant group difference in severity. No major adverse effects were reported. This study showed that the 2% formulation has a similar safety and pharmacodynamic profile to the 1% formulation.

Repeated doses of rocuronium bromide administered to cirrhotic and control patients receiving isoflurane. A clinical and pharmacokinetic study.

BACKGROUND: Steroid muscle relaxants often display pharmacodynamic changes in patients with cirrhosis because of alterations in elimination processes. Rocuronium is a new steroid muscle relaxant possibly eliminated through the liver. This study was designed to compare rocuronium pharmacodynamics and pharmacokinetics in cirrhotic and healthy patients. METHODS: Rocuronium was administered to 26 cirrhotic patients and 24 control subjects anesthetized with isoflurane for an elective procedure. Patients were randomly allocated to received an initial dose of rocuronium: 120, 180, 250, or 300 micrograms.kg-1. Dose-response curves were established, and ED50 was calculated. Preselected maintenance doses (75, 150, or 225 micrograms.kg-1) were administered at 25% recovery of twitch height to compare clinical duration of action. At the end of the procedure, relaxation was reversed in half of the patients, and the time course of recovery was compared in the two groups. Blood samples drawn during the procedure and after the last maintenance dose allowed pharmacokinetic analysis in six cirrhotic patients and six control subjects. RESULTS: ED50 of the initial dose was 144 micrograms.kg-1 in cirrhotic patients and 60 micrograms.kg-1 in control subjects, related to a higher initial volume of distribution (cirrhotic 78.5 +/- 31.7 ml.kg-1, control 29.8 +/- 17.3 ml.kg-1). Time from complementary dose to 25% recovery was longer in cirrhotic patients (41.0 +/- 20.7 min vs 30.2 +/- 9.7 min), but time course of action during maintenance was not statistically different in the two groups. In cirrhotic patients receiving five maintenance doses or more, prolongation of the duration of action with successive maintenance doses could be statistically demonstrated. Spontaneous recovery was delayed in cirrhotic patients, because of impaired elimination processes: greater volume of distribution at steady-state (264 +/- 92 vs. 151 +/- 59 ml.kg-1); trend toward a lower clearance (189 +/- 60 vs. 296 +/- 169 ml.min-1). CONCLUSIONS: Rocuronium pharmacodynamics are moderately altered by cirrhosis, possible because of pharmacokinetic alterations. Individual variability in response to rocuronium is great, and dosage should be carefully titrated to that required.