1 Department of Anaesthesia and Pain Management, Royal Melbourne Hospital, Parkville, Victoria, Australia. 2 Department of Anaesthesia and Pain Management, Alfred Hospital, Melbourne, Victoria, Australia. 3 North West Regional Hospital, Burnie, Tasmania, Australia. 4 Department of Anaesthesia, Department of Epidemiology and Preventive Medicine, Monash University, Clayton, Victoria, Australia
* Corresponding author. E-mail: p.myles{at}alfred.org.au
Accepted for publication April 13, 2005.
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Abstract |
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Methods. After oral pre-medication with either clonidine 3 µg kg1 or placebo, 39 subjects had lower limb vascular surgery using propofol infusion for anaesthesia. Anaesthetic depth was adjusted to a BIS of 45. Predicted plasma propofol concentrations were noted every 30 min from a target-controlled propofol infusion pump and arterial samples were taken at the same time for propofol measurements.
Results. Patients in both groups were anaesthetized to similar depths of anaesthesia as indicated by BIS readings (P=0.44). The groups had comparable mean (95% CI) arterial concentrations of propofol, 4.8 (3.56.1) µg ml1 in the patients given clonidine, and 4.6 (3.45.7) µg ml1 in the patients given placebo (P=0.81). However, the average plasma concentration predicted by the target-controlled infusion was less in the clonidine group [3.2 (2.93.5)] than in the group given placebo [3.6 (3.33.9)] µg ml1 (P<0.05).
Conclusions. Pre-medication with clonidine reduces the requirement for propofol, which is a pharmacokinetic effect and not a pharmacodynamic central sedative effect.
Keywords: anaesthetics i.v., propofol ; pharmacokinetics ; premedication, clonidine
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Introduction |
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Pre-treatment with clonidine reduces the requirement for propofol but it is not known if this is because of the sedative effect of clonidine5 7 or a change in pharmacokinetics as seen with other alpha2-agonists.8 Propofol kinetics are affected by changes in the distribution of blood volume, cardiac output, and hepatic blood flow.9 10 The extent and nature of the dose-sparing effect of clonidine, in patients having vascular surgery using propofol anaesthesia, is not known.
The bispectral index (BIS, Aspect Medical Systems Inc., Newton, MA, USA) is a measure derived from the processed electroencephalograph (EEG).11 The BIS has been shown to be superior to other processed EEG parameters in assessing depth of anaesthesia and sedation,12 13 and is approved by the US Food and Drug Administration as a measure of hypnotic depth. It is useful in adjusting propofol effects to reduce total dosage and speed recovery.14
We set out to measure the reduction in total propofol requirements after pre-medication with clonidine whilst ensuring equivalent depth of anaesthesia by continuous BIS measurement. We also wished to observe if this reduction was because of altered propofol pharmacokinetics or a direct sedative action of clonidine, by comparing actual and predicted plasma propofol concentrations.
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Methods |
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Subjects were pre-medicated 1 h before surgery with an oral dose of the study drug, prepared by our hospital pharmacy clinical trials unit using sodium chloride and flavouring to mask allocation (either clonidine 3 µg kg1 or placebo). After pre-medication, supplemental oxygen was administered. In the operating room venous and arterial cannulae were placed and standard monitoring (5-lead ECG, pulse oximetry, capnography and a peripheral nerve stimulator) applied. BIS was acquired using the BIS A1050 monitor and sensor (Aspect Medical Systems Inc., Newton, MA, USA), according to the manufacturer's instructions.
During pre-oxygenation, fentanyl 1 mg kg1 i.v. was given and then anaesthesia induced with propofol using a target-controlled infusion pump (Diprifusor®, Sydney, Australia) with the target plasma concentration set to 4 µg ml1. The target value was raised by 1 µg ml1 increments until a BIS level of 45 or less was achieved. This was taken as time zero and the predicted plasma concentration was recorded. A further dose of fentanyl 1 µg kg1 i.v. was then given. Neuromuscular block was achieved with mivacurium 0.2 µg kg1 i.v. and the lungs ventilated with oxygen until the response to peripheral nerve stimulation was suppressed. After tracheal intubation, the patients were mechanically ventilated with a mixture of air and oxygen to obtain an end-tidal carbon dioxide partial pressure of 3035 mm Hg. Spontaneous return of neuromuscular block was confirmed so that another indicator of adequate depth of anaesthesiaa lack of movement to surgical stimulicould be incorporated into the technique. Anaesthesia was maintained by target-controlled infusion of propofol titrated to a BIS of 45. A lower BIS (3540) was selected if movement occurred. Arterial blood samples were drawn at induction, 30, 60 and 90 min for plasma propofol concentration assay and to confirm normocapnia. Predicted plasma propofol concentrations were recorded from the target-controlled infusion pump, which calculates plasma and effect site concentrations using the Marsh pharmacokinetic model.15 Towards the end of the procedure the anaesthetist aimed to adjust the propofol infusion to obtain a BIS of 60 at the time of application of dressings. The time to 1 µg ml1, predicted by the target-controlled infusion pump, and the time from end of surgery to eye opening, were recorded. Residual neuromuscular block was reversed using glycopyrrolate 0.4 mg and neostigmine 2.5 mg. Morphine 0.10.15 mg kg1 was given i.v. as needed to obtain satisfactory analgesia. Patients were then transferred to the recovery room. Recovery times were measured from completion of wound dressing to obeying commands and to eligibility for discharge from the recovery room, the latter defined as a modified Aldrete score16 of 9. Adverse events and total morphine requirements were recorded.
Intra-operative adverse haemodynamic events were managed according to the study protocol. In brief, escape medication included glyceryl trinitrate infusion for hypertension, metaraminol or ephedrine for hypotension, metoprolol for tachycardia or ischaemia, glycopyrrolate for bradycardia, and fentanyl 1 µg kg1 if rapid reduction of pain response was required (see Appendix).
Patients were reviewed on the day after surgery and assessed for adverse events or complications. Quality of recovery was measured using the QoR score, a nine-item score from zero to 18.17
Arterial plasma samples were stored on ice, and later analysed for propofol with a high-performance liquid chromatography assay modified from the method of Plummer.18 This assay is linear to 20 µg ml1, has a detection limit of 0.025 µg ml1 and a coefficient of variation of 4.1% at 2 µg ml1.
Statistical analysis
The primary endpoints of time-averaged measured and predicted plasma propofol concentrations were compared using a repeated measures general linear model adjusted for baseline variables: age, gender and American Society of Anesthesiogists (ASA) physical status score. Times and morphine requirements were analysed using t-tests for parametric data. Frequencies of adverse events were compared using the 2 or Fisher's exact tests. All other comparisons used the MannWhitney U-test for non-parametric data. All analyses used SPSS for Windows v10.0 (SPSS Inc., Chicago, IL). Our hypothesis was that a propofol-sparing effect of clonidine would be demonstrated if there were a relative reduction in the predicted propofol concentration, and so a one-sided P-value of <0.05 was considered significant; all other comparisons were two-sided.
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Results |
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Arterial concentrations of propofol at 30, 60, and 90 min were similar in the two groups (Fig. 1 and Table 2), P=0.81. Comparing the predicted plasma propofol concentrations in the two groups, the predicted values in the clonidine group were 10% less than those in the placebo group (Fig. 2 and Table 2) (P<0.05). We did a correlational analysis between the actual and predicted plasma propofol concentrations at the three time periods to assess the accuracy of the target-controlled infusion pump algorithm (Table 3). In the placebo group there was a moderately strong correlation between the two variables but in the clonidine group the correlation decreased significantly over time.
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Discussion |
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The lack of difference between the groups with respect to assayed arterial plasma levels of propofol suggests that pre-medication with clonidine has no discernible pharmacodynamic effect in patients undergoing lower limb vascular surgery. Furthermore, in the placebo group there was a moderately strong correlation between the actual and predicted propofol concentrations, but the correlation decreased significantly over time in the clonidine group. This suggests that the pharmacokinetic algorithm used by the infusion pump failed to predict plasma concentrations correctly in patients treated with clonidine. The most plausible explanation is reduced hepatic clearance of propofol, because clonidine, like other alpha2-agonists,1 reduces cardiac output and is likely to reduce hepatic blood flow. This will affect the volume of distribution of propofol and, because it is a high extraction drug, its clearance.19 Propofol kinetics are affected by changes in blood volume distribution, cardiac output and hepatic blood flow.9 10 19 Pulmonary uptake contributes to propofol clearance,9 22 which may also be reduced with a decrease in cardiac output.
Although we noted predicted plasma propofol concentrations at induction we did not take arterial samples at this time, so we cannot assess the possible effect of clonidine on the initial volume of distribution of propofol. Nonetheless the mean predicted plasma concentration immediately after induction was significantly less in the study group, which suggests that the volume of distribution for propofol is reduced by pre-medication with clonidine. This supports the findings of others, for both propofol and thiopental.5 8
The overall predicted plasma levels were some 30% less than the actual levels, highlighting the limited ability of the algorithm to predict propofol concentration in these patients, despite the Marsh model being a good kinetic model for target-controlled infusion of propofol.15 The selection and titration of the target plasma concentration should be guided by the anaesthetist's assessment of anaesthetic depth, and BIS measurements should assist with this.21
The finding that clonidine reduces immediate postoperative morphine requirements was expected in view of the established analgesic efficacy of clonidine and other centrally acting alpha2-agonists.1 The sedative action of clonidine could delay discharge from the recovery room, but this was not observed in this study. Possible explanations include a limited sedative effect of the clonidine, the smaller propofol dose used, and less opioid requirements. In addition the Aldrete score may detect subtle signs of sedation caused by centrally acting alpha2-agonists.
The rate of intra-operative adverse events was similar between the groups, which support previous experience. The trend towards increased frequency of hypotension and increased use of metaraminol may indicate the action of clonidine but may also have been influenced by the greater use of preoperative ACE-inhibitors in the study group.
We did not measure cardiac output or hepatic blood flow in this study, and can only speculate on clonidine's haemodynamic and pharmacokinetic effects. Despite randomization there were some differences between the groups that might have confounded the results. Surgical stimulation may cause arousal, an increase in BIS, and/or patient movement. This is an alternative explanation for more propofol administration in the placebo group, but does not account for the difference at induction nor the discrepancy between measured and predicted levels. More patients given clonidine were being treated with ACE-inhibitors, and generally had poorer ASA physical status scores. Although these differences were not statistically significant, the study group could be considered sicker than the controls. In our statistical analysis, the general linear model adjusted for the ASA score, as well as age and gender, to reduce potential confounding. The finding of a reduced quality of recovery on the first postoperative day in this study was unexpected and is of concern. Further investigation of this issue is warranted. Although previous research has suggested a beneficial effect of clonidine on postoperative cardiovascular morbidity,23 we did not find any effect in this study because of the short nature of the study period, a lack of power to detect such differences and the general lack of immediate postoperative complications.
We found that pre-medication with clonidine, 3 µg kg1, has a propofol-sparing effect in patients having vascular surgery. Unlike with inhalation anaesthetics, this is a pharmacokinetic effect, because there was a difference between predicted and actual plasma propofol concentrations. Clonidine may reduce cardiac output and hepatic blood flow, thus reducing propofol clearance.
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Appendix |
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Hypotension (MAP <80% above baseline)
Note BIS:
Tachycardia (HR >90 beats min1)
Note BIS:
Bradycardia (HR <40 beats min1)
Administer glycopyrrolate 0.2 mg.
Myocardial ischaemia (ST-segment depression >1 mm)
Optimize patient haemodynamics and ventilation:
Patient movement
Note BIS and increase target propofol concentration 20%.
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Acknowledgments |
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References |
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