Effect of clonidine pre-medication on propofol requirements during lower extremity vascular surgery: a randomized controlled trial

J. Morris1, M. Acheson2, M. Reeves3 and P. S. Myles2,4,*

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.


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
Background. Pre-medication with clonidine reduces the requirement for volatile agents during general anaesthesia. This may also be true for anaesthesia with propofol, but the amount of dose reduction has not been measured. Because clonidine also affects cardiac output and thus regional blood flow it could alter the pharmacokinetics of propofol. This randomized, double-blind placebo-controlled trial aimed to study the effect of clonidine pre-medication on dose requirement for propofol during lower extremity vascular surgery using the bispectral index (BIS) as a measure of anaesthetic depth.

Methods. After oral pre-medication with either clonidine 3 µg kg–1 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 (3.5–6.1) µg ml–1 in the patients given clonidine, and 4.6 (3.4–5.7) µg ml–1 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 (2.9–3.5)] than in the group given placebo [3.6 (3.3–3.9)] µg ml–1 (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


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
Anaesthesia for lower limb revascularization can be complicated by pre-existing medical problems. Such patients may have ischaemic heart disease and hypertension, and be predisposd to myocardial ischaemia during and after surgery. Clonidine, an alpha2-adrenergic agonist with sedative and analgesic properties,1 can reduce requirements for both volatile and i.v. anaesthetic agents.2 3 It is safe in elderly4 and high risk patients.5 6 Clonidine may reduce adverse haemodynamic events and improve outcome in high risk patients.6

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.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
After institutional ethics approval, written informed consent was obtained from 39 patients presenting for lower limb vascular surgery. Patients treated with clonidine, {alpha}-methyl dopa, sedatives or anticonvulsants, and those over 100 kg were excluded. This was a prospective, randomized, double-blind trial to compare the effect of pre-medication with clonidine or placebo. Our sample size calculation was based on our previously published variances in propofol steady state requirements5 and a predicted treatment effect of 25%, using mean (SD) values of 4.0 (1.0) and 3.0 (1.0), a type I error 0.05 and a type II error of 0.80. The sample size estimation was 34 subjects with complete data. Subjects were randomly allocated to groups using a table of random numbers, with stratification according to current beta-blocker therapy. The dose of clonidine chosen to be studied, 3 µg kg–1, was based on a previous study in vascular surgery that had demonstrated some beneficial effects at this dose.6

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 kg–1 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 kg–1 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 ml–1. The target value was raised by 1 µg ml–1 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 kg–1 i.v. was then given. Neuromuscular block was achieved with mivacurium 0.2 µg kg–1 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 30–35 mm Hg. Spontaneous return of neuromuscular block was confirmed so that another indicator of adequate depth of anaesthesia—a lack of movement to surgical stimuli—could be incorporated into the technique. Anaesthesia was maintained by target-controlled infusion of propofol titrated to a BIS of 45. A lower BIS (35–40) 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 ml–1, 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 0.1–0.15 mg kg–1 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 kg–1 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 ml–1, has a detection limit of 0.025 µg ml–1 and a coefficient of variation of 4.1% at 2 µg ml–1.

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 {chi}2 or Fisher's exact tests. All other comparisons used the Mann–Whitney 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.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
The groups were comparable for potentially confounding variables such as age, weight, gender, smoking history, co-morbidities, medications, and biochemical markers of liver and kidney function (Table 1). There was no significant difference in duration of surgery between the groups. Blood samples from four patients (one control, three clonidine) were not handled according to our protocol and assay method and were excluded from the primary endpoint analysis.


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Table 1 Patient characteristics. Values are mean (range), mean (SD) or no. (%). ACE, angiotensin converting enzyme; ALT, alanine transaminase; ASA, American Society of Anesthesiologists

 
The predicted plasma propofol concentrations from the target-controlled infusion pump following induction of anaesthesia (to BIS 45) was significantly different between groups, median (10th–90th centile): clonidine 4.0 (4.0–4.9) vs placebo 4.0 (4.0–6.5), U-test P<0.05.

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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Fig 1 Median (IQR) measured plasma propofol concentrations during surgery, indicating comparable effect site concentrations in clonidine and placebo groups (P=0.81).

 

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Table 2 Arterial assay and predicted plasma propofol concentrations (µg ml–1) at different times. Values are mean (SD); combined averages over time are mean (95% confidence intervals).

 


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Fig 2 Median (IQR) predicted plasma propofol concentrations, based on a pharmocokinetic model, in patients treated with clonidine compared with those given placebo (P=0.042).

 

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Table 3 Pearson correlation coefficients between measured arterial and predicted plasma propofol concentrations

 
Patients in both groups had equivalent depths of anaesthesia, judged by the time-averaged BIS readings during surgery (Table 4). There was no significant difference between the groups either for predicted time to awakening or actual time to obeying commands (Table 4). In the recovery room there was no difference between the groups, comparing time to fitness for discharge and QoR score. Patients receiving clonidine required significantly less morphine in the recovery room than patients in the placebo group (Table 4). The QoR score on the day after surgery for patients given clonidine was significantly less than that of the placebo group (Table 4). Adverse event rates were similar between the groups (Table 5), as were interventions with escape medications: metaraminol (P=0.10), glycopyrrolate (P=0.38), fentanyl (P=0.19), esmolol (P>0.99), and metoprolol (P=0.88).


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Table 4 Secondary endpoints. Values are mean (SD) unless otherwise stated. QoR=Quality of recovery.

 

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Table 5 Number (as %) of adverse events in each group

 
There was no morbidity in either group during the study period, up to 24 h after surgery.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
We found that clonidine reduces propofol dose requirements. Clonidine reduced the dose of propofol required to achieve induction of anaesthesia. Unlike the effect of clonidine seen with inhalation anaesthetics,1 2 this can be attributed to a pharmacokinetic effect. There was a difference between clonidine and placebo groups in their predicted and actual plasma propofol concentrations. The predicted concentration of propofol is calculated from a pharmacokinetic algorithm incorporated into the target-controlled infusion pump and so is affected by pharmacokinetic variables,15 20 but in this study the actual measured plasma concentration of propofol reflected the dose required to obtain the desired anaesthetic effect, assessed by the BIS value. Thus, less rapid propofol administration will achieve the same BIS value in patients treated with clonidine.

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 kg–1, 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.


    Appendix
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
Guidelines for management of intra-operative adverse events
Hypertension (MAP >20% above baseline)
Note BIS:

if BIS >45, optimize BIS: increase target propofol concentration 20%;
if BIS <45, optimize analgesia: administer fentanyl 1 µg kg–1, and consider metoprolol 1–2 mg or GTN infusion 10–100 µg min–1.

Hypotension (MAP <80% above baseline)
Note BIS:

if BIS >45, use metaraminol 0.25 mg or ephedrine 3 mg;
if BIS <45, decrease propofol target concentration 20% and use vasopressor (as above, if required).

Tachycardia (HR >90 beats min–1)
Note BIS:

if BIS >45, optimize BIS: increase target propofol concentration 20% and, if indicated, fentanyl 1 µg kg–1;
if BIS <45, administer metoprolol 1–2 mg.

Bradycardia (HR <40 beats min–1)
Administer glycopyrrolate 0.2 mg.

Myocardial ischaemia (ST-segment depression >1 mm)
Optimize patient haemodynamics and ventilation:

if HR >60, administer metoprolol 1–2 mg;
if HR <60, administer GTN infusion 10–100 µg min–1.

Patient movement
Note BIS and increase target propofol concentration 20%.


    Acknowledgments
 
We would like to thank the Alfred Hospital Pharmacy Clinical Trials Unit for preparation of the study drug, and Andrew Bjorksten for the propofol assays. Funding: Supported by an Australian Society of Anaesthetists/Abbott Research Grant.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix
 References
 
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2 Entholzner EK, Mielke LL, Hargasser SR, et al. Intravenous clonidine decreases minimum end tidal isoflurane for induction of EEG burst suppression. Anesth Analg 1997; 85: 193–8[Abstract]

3 Imai Y, Mammoto T, Murakami K, et al. The effects of preanesthetic oral clonidine on total requirement of propofol for general anesthesia. J Clin Anaesth 1998; 10: 660–5[CrossRef][ISI][Medline]

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5 Myles PS, Hunt JO, Holdgaard HO, et al. Clonidine and cardiac surgery: haemodynamic and metabolic effects, myocardial ischaemia and recovery. Anaesth Intensive Care 1999; 27: 137–47[ISI][Medline]

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7 Kulka PJ, Tryba M, Sczepanski U, Zenz M. Does clonidine modify the hypnotic effect of propofol? [German] Anaesthetist 1993; 42: 630–7[ISI][Medline]

8 Buhrer M, Mappes A, Lauber R, Stanski DR, Maitre PO. Dexmedetomidine decreases thiopental dose and alters distribution pharmacokinetics. clearance. Anesthesiology 1994; 80: 1216–27[ISI][Medline]

9 Upton RN, Ludbrook GL, Grant C, Martinez AM. Cardiac output is a determinant of the initial concentrations of propofol after short-infusion administration. Anesth Analg 1999; 89: 545–52[Abstract/Free Full Text]

10 Kazama T, Ikeda K, Morita K, et al. Relation between initial blood distribution volume and propofol induction dose requirement. Anesthesiology 2001; 94: 205–10[CrossRef][ISI][Medline]

11 Sigl JC, Chamoun NG. An introduction to bispectral analyses for the electroencephalogram. J Clin Mon 1994; 10: 392–404[CrossRef][ISI]

12 Struys M, Versichelen, Mortier E, et al. Comparison of spontaneous frontal EMG, EEG power spectrum and bispectral index to monitor propofol drug effect and emergence. Acta Anaesthesiol Scand 1998; 42: 628–36[ISI][Medline]

13 Doi M, Gajraj RJ, Mantzaridis H, Kenny GN. Relationship between calculated blood concentration of propofol and electrophysiological variables during emergence from anaesthesia: comparison of bispectral index, spectral edge frequency, median frequency and auditory evoked potential index. Br J Anaesth 1997; 78: 180–4[Abstract/Free Full Text]

14 Struys M, Versichelen L, Byttebier G, et al. Clinical usefulness of the bispectral index for titrating propofol target effect-site concentration. Anaesthesia 1998; 53: 4–12[CrossRef][ISI][Medline]

15 Marsh B, White M, Morton N, Kenny GN. Pharmacokinetic model driven infusion of propofol in children. Br J Anaesth 1991; 67: 41–8[Abstract]

16 Aldrete JA. The post-anaesthetic recovery score revisited. J Clin Anesth 1995; 7: 89–91[CrossRef][ISI][Medline]

17 Myles PS, Hunt J, Nightingale CE, et al. Development and psychometric testing of a quality of recovery score after general anesthesia and surgery. Anesth Analg 1999; 88: 83–90[Abstract/Free Full Text]

18 Plummer G. Improved method for the determination of propofol in blood by high performance liquid chromatography with fluorescence detection. J Chromatogr 1987; 421: 171–6[Medline]

19 Krejcie TC, Avram MJ. What determines anesthetic induction dose? It's the front-end kinetics, doctor! Anesth Analg 1999; 83: 541–4[CrossRef]

20 Coetzee JF, Glen JB, Wium CA, Boshoff L. Pharmacokinetic model selection for target controlled infusions of propofol. Assessment of three parameter sets. Anesthesiology 1995; 82: 1328–45[CrossRef][ISI][Medline]

21 Gan TJ, Glass PS, Windsor A, et al. Bispectral Index monitoring allows faster emergence and improved recovery from propofol, alfentanil, and nitrous oxide anesthesia. Anesthesiology 1997; 87: 808–15[CrossRef][ISI][Medline]

22 Kuipers JA, Boer FMD, Olieman W, Burm AGL, Bovill JG. First-pass lung uptake and pulmonary clearance of propofol: assessment with a recirculatory indocyanine green pharmacokinetic model. Anesthesiology 1999; 91: 1780–7[CrossRef][ISI][Medline]

23 Nishina K, Mikawa K, Uesugi T, et al. Efficacy of clonidine for prevention of perioperative myocardial ischemia: a critical appraisal and meta-analysis of the literature. Anesthesiology 2002; 96: 323–9[CrossRef][ISI][Medline]





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