The amount of propofol required at induction of anaesthesia can be influenced by a variety of individual factors and by the administration of other sedative drugs. The synergistic effect of propofol with opioids or benzodiazepines, or both, has been reported [1-5]. The short-acting opioid remifentanil has been used to supplement anaesthesia with propofol, yet the ideal loading doses and infusion rates for induction remain to be established .
Target-controlled infusion (TCI) software incorporating pharmacokinetic data has been developed for propofol and remifentanil [7-9]. These use computer-controlled devices to achieve and maintain a constant plasma drug concentration. The plasma concentration of propofol only relates to the depth of anaesthesia when there is equilibrium between the plasma and effect site. The effect site concentration (Ce) during infusion can be calculated using the equilibration rate constant (keo). Recent reports suggest that targeting the effect site concentration can be usefully applied in clinical practice [10,11].
The purpose of the present study was to assess the influence of TCI remifentanil on TCI propofol requirements at induction of anaesthesia. We also investigated whether preinduction of midazolam conferred any synergism. We observed the predicted effect site propofol concentration at induction of anaesthesia and compared it using propofol alone with that after pretreatment with either remifentanil or remifentanil and midazolam.
After approval from the local research Ethics Committee, and with informed written consent from each patient, we studied 66 consecutive adult patients presenting for elective surgery. Screening procedures before enrolment included a medical history, drug history and physical examination where height and weight were measured. Patients between the ages of 20-55 yr and ASA I-II were enrolled into the study. Patients were excluded if they had any of the following conditions: body mass index >30 kg m−2, uncontrolled hypertension, ischaemic heart disease, marked renal or hepatic dysfunction, chronic respiratory impairment or mothers who were breastfeeding. Any patient receiving medication with vasoactive drugs, night sedation, requesting a premedication or suspected of drug misuse was excluded.
Patients were randomly assigned to one of three treatment groups using preprepared sealed, opaque envelopes to which only one investigator had access. Group 1, propofol only; Group 2, 3 ng mL−1 remifentanil and propofol; Group 3, 0.03 mg kg−1 midazolam, 3 ng mL−1 remifentanil and propofol. In all groups propofol was administered with a Master TCI® pump (Fresenius Vial SA, Le Grand Chemin, France) incorporating the Diprifusor® subsystem (AstraZeneca, Macclesfield, UK), which estimated effect site concentration using a keo = 0.297 min−1. The initial target plasma concentration of propofol was set at 1 μg mL−1. At 1 min, a blinded observer assessed responsiveness to verbal instruction. If hypnosis was not achieved, the investigator increased target concentration to 2 μg mL−1. Response to call was then assessed every 15 s and the target concentration increased in 1 μg mL−1 increments at 1 min intervals until loss of response was achieved. When the patient stopped responding verbally to conversation, the predicted effect site propofol concentration and the total propofol dose on the Diprifusor® pump display were recorded. Remifentanil was administered to Groups 2 and 3 by a Graseby® 3400 pump (Graseby Ltd., Watford, Herts., UK) controlled by Stanpump® software (S. Shafer; Stanford University, CA, USA) installed on a personal computer. The system was arranged so that the maximum rate of infusion was 60 mL h−1. Simulated infusions were performed to confirm that the required effect site concentration of 3 ng mL−1 would be achieved . After the estimated plasma and effect site concentrations of remifentanil had time to equilibrate, a propofol infusion using the regimen described above was started. Group 3 patients received midazolam, 0.03 mg kg−1 intravenously (i.v.), given 4 min before the start of the remifentanil infusion. Blinding of observer and investigator to the use of premedication was achieved using preprepared syringes containing either saline (0.9% NaCl) or active drug. No other anaesthetic drugs were administered during the study. Following induction, the anaesthetist was free to use any maintenance technique and the investigators would observe and record only adverse events.
The primary outcome measure was the effect site propofol concentration (μg mL−1) at the time of loss of verbal response. We measured the dose of propofol given to each patient. The effect site remifentanil concentration and dose of remifentanil were recorded. The investigators recorded any adverse events.
A sample size calculation was performed. A minimum of 22 patients in each group was expected to provide 90% power of detecting a difference of 1 SD, approximately 0.7 μg mL−1 in the effect site concentration between each group. Continuous data are presented as mean ± SD. Statistical tests were performed using SPSS® (SPSS Inc., Chicago, IL, USA). Demographic data such as height, weight and age were evaluated for normal distribution with the KS-2 test and a t-test for unpaired data evaluated differences between the groups. Differences in end-points between the groups were analysed using two-way ANOVA with Scheffés' test for pairs of group comparisons. Simple regression was used to produce the Ce50 and Ce95 of propofol for hypnosis in each group (Abacus Concepts; Statview II). All statistical tests were two-tailed, with statistical significance defined as P ≤ 0.05.
Hypnosis was induced in all patients in the three groups. There were no significant differences between the groups with respect to age, weight, height and male: female ratios (Table 1). The calculated effect site concentration, Ce, and the propofol induction doses were significantly different between each pair of groups (ANOVA P ≤ 0.001) (Table 2). The propofol Ce in Group 1 was 2.24 ± 0.76 μg mL−1. The propofol requirement was reduced for patients co-induced with remifentanil to 1.63 ± 0.55 μg mL−1 (ANOVA P < 0.001). Greater reduction in propofol requirement to 0.64 ± 0.39 μg mL−1 was achieved by administration of midazolam (ANOVA P < 0.001) (Fig. 1). The reduction of the Ce for propofol between Groups 1 and 2 was 29%. The reduction of the propofol Ce between groups 2 and 3 was 60%. Co-induction with midazolam and remifentanil reduced the required propofol Ce by 71% compared with using propofol alone. Measuring the propofol induction dose yielded similar percentage reductions. We calculated the effect site concentration of propofol at which 50 and 95% of our population would exhibit loss of responsiveness to verbal command. These values showed similar reductions during co-induction with remifentanil and midazolam and remifentanil (Table 2). The dose of remifentanil given at induction was less for Group 3 than for Group 2.
There were no incidents of hypotension, bradycardia or muscle rigidity requiring additional management. Two male patients were withdrawn from the trial with suspected drug misuse as they appeared heavily sedated before induction of anaesthesia.
TCI devices for anaesthetic agents are becoming increasingly available. It is useful to have some guidance about the appropriate target settings and effect site estimations during co-induction of anaesthesia. In the present study, we observed a 29% fall in TCI propofol requirements to a Ce50 = 1.55 μg mL−1 during co-induction with TCI remifentanil 3 ng mL−1. Midazolam preinduction combined with TCI remifentanil markedly reduced the induction Ce50 to 0.62 μg mL−1.
The present study also reports a Ce50 and Ce95 = 2.19 and 3.13 μg mL−1 for TCI propofol alone. Smith and colleagues  reported the propofol plasma concentrations at which 50 and 95% of patients did not respond to verbal command to be 3.3 and 5.4 μg mL−1 respectively. Vuyk and colleagues reported similar 3.4 and 4.3 μg mL−1 for EC50 and EC95, respectively, based on measured plasma concentrations. We did not measure blood propofol concentrations and it is known that predicted or calculated propofol concentrations often underestimate measured plasma concentrations, particularly at induction of anaesthesia . This may explain the apparent discrepancy between the predicted effect site Ce50 and Ce95 for propofol in the present study and the measured plasma concentration at loss of consciousness in other papers. A more likely explanation is that any change in effect site concentration will lag behind plasma concentration change. This is particularly relevant at induction of target-controlled anaesthesia where plasma level may be stable whilst effect site concentration continues to increase.
The present results agree with previous reports describing the effect of benzodiazepines and opioids on propofol requirements. Vuyk and colleagues demonstrated dose-dependent reductions in propofol concentrations during co-induction with alfentanil . The same group predicted effect site concentrations at awakening in 50% of patients varying from 1.59 μg mL−1 propofol and 2.39 ng mL−1 remifentanil to 1.88 μg mL−1 propofol and 1.84 ng mL−1 remifentanil . These can be compared with the effect site concentrations for induction of hypnosis in 50% of patients in Group 2 of 1.55 μg mL−1 propofol and 3 ng mL−1 remifentanil. Smith and colleagues showed a similar dose-dependent effect using increasing target doses of fentanyl . In their study, the propofol blood concentrations at which 50 and 95% of patients did not respond to verbal command were 3.3 and 5.4 μg mL−1 respectively.
In the present study, the addition of midazolam to a combination of opioid and propofol reduced Ce by 71%. This is consistent with recent work combining target-controlled propofol with fentanyl and midazolam where co-induction with midazolam-fentanyl reduced propofol Ce by 55% . Arndt and colleagues described co-induction of TCI propofol with alfentanil and midazolam (0.03 mg kg−1) . They predicted a propofol Ce at induction of <1.8 μg mL−1. We could find no published data describing the effect of different TCI remifentanil regimens or triple induction with TCI remifentanil and midazolam on propofol requirements.
The use of target-controlled infusions of propofol for the induction and maintenance of anaesthesia has been extensively reported, particularly with reference to the Diprifusor® device . Application of target-control techniques to remifentanil infusions has been described during conscious sedation and general anaesthesia [16,17]. The present study used a remifentanil target concentration of 3 ng mL−1. Other studies have reported targets of up to 16 ng mL−1. The mean dose of remifentanil (TCI = 3 ng mL−1) at loss of consciousness was 3.09 and 2.48 μg kg−1 for Groups 2 and 3 respectively. These doses correlate with previous dosing studies where a remifentanil dose of 4 μg kg−1 in combination with 2 mg kg−1 propofol provided adequate anaesthesia for tracheal intubation . The reason why the remifentanil dose was less in Group 3 (midazolam-remifentanil-propofol) is probably related to the reduction in time to loss of consciousness compared with Group 2 who received no midazolam.
The reduction by opioids of the propofol requirement for hypnosis is much less than their reduction for lack of response to skin incision. Smith and colleagues found that 3 ng mL−1 fentanyl reduced this for propofol by 89%. Using opioid infusions in combination with propofol for induction may therefore enable a smoother changeover to the therapeutic levels required for surgery.
We have used predicted effect site concentration (Ce) as an end-point in the present study. It is important to remember that the effect site is a virtual compartment and so it is impossible to measure Ce correctly. Ce is calculated using a time-constant keo. The Diprifusor® used here has keo = 0.297 min−1 and the effect site concentrations reported herein are valid only for systems using this keo. Wakeling and colleagues report a median propofol Ce = 4.55 μg mL−1 for loss of responsiveness using a keo = 0.63 min−1. Computer simulations in the same study demonstrated that altering keo can markedly influence effect site targeting. It is likely that there is considerable interindividual variability in keo that could introduce bias into the present results. However, actual doses (mg kg−1) of propofol also showed significant differences between the three groups. The time to 95% equilibration between the plasma and effect site concentrations could be >10 min as reported in 20-55-yr-olds when measured using the bispectral index of the electroencephalogram . We did not allow sufficient time for equilibration between plasma and effect site concentration. This was to reflect observations that can be made during routine use of the Diprifusor® device. This has allowed us to assess the usefulness of the predicted Ce in determining the conscious level.
The use of a single indicator, verbal responsiveness, to measure the loss of consciousness may have introduced bias. In addition, more than one observer was used to make this assessment. Ordinal scales such as the observer's assessment of alertness/sedation scale have been described and used in similar studies . Use of these scales may reduce observer bias.
Synergism between midazolam and propofol has been postulated for some time . Changes in GABA (A) receptor function may underlie the interaction between midazolam and propofol . A small bolus dose of midazolam was used for the present study. A midazolam dose of 0.05 mg kg−1 has been shown to delay recovery . A dose of 0.03 mg kg−1 was chosen after pilot studies showed it to have an effect without delaying recovery.
Total i.v. anaesthesia using the target-controlled technique described in the present study may offer a number of benefits to patients. Doyle and colleagues have described the cardiovascular stability and rapid emergence associated with remifentanil infusions . Induction with remifentanil will allow a smoother transition to therapeutic levels required for intraoperative anaesthesia and analgesia. The triple technique used in the present study may have further benefits. The reduction in propofol requirements with a midazolam bolus should reduce costs and potentially improve cardiovascular stability. Induction with three agents is a recognized tool in total i.v. anaesthesia and we believe the present findings help to quantify the doses and concentrations required with target-controlled infusions.
In conclusion, we have demonstrated that a target-controlled remifentanil infusion can be used to reduce target-controlled propofol requirements at the induction of anaesthesia. This effect can be further enhanced by a small preinduction dose of midazolam. We have used the predicted effect site concentration to determine propofol requirement at loss of consciousness and believe that this measure may have useful clinical applications.
The authors thank Dr Steven L Shafer, MD, for the use of the Stanpump® software; the Anesthesiology Service (112A), PAVAMC, 3801 Miranda Avenue, Palo Alto, CA 94304, USA; and Dr Valerie Hillier, Department of Biostatistics, University of Manchester, UK.
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