1Institute of Anaesthesiology, University Hospital Zurich, Switzerland. 2Department of Biostatistics, University of Zurich, Switzerland. 3Institute for Clinical Chemistry, University Hospital Zurich, Switzerland.*Corresponding author: Institute of Anaesthesiology, University Hospital, Rämistrasse 100, CH-8091 Zurich, Switzerland
Accepted for publication: December 12, 2000
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Abstract |
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Br J Anaesth 2001; 86: 62732
Keywords: anaesthesia i.v., propofol; pharmacology, clonidine; monitoring, bispectral index
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Introduction |
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Materials and methods |
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After obtaining institutional review board approval and written informed consent, we studied 50 German-speaking patients, aged 1870 yr, American Society of Anesthesiologists physical status I or II, scheduled for superficial surgical procedures expected to last at least 45 min. Patients with cardiopulmonary, neuropsychiatric or hearing disorders and patients taking any medication affecting cardiovascular or neurological function were excluded. Patients received no premedication.
After admission of the patients to the operating room, an i.v. cannula was placed and standard monitoring was established. In addition, the level of consciousness was surveyed by bispectral EEG analysis (Aspect A-1000 EEG monitor, software module 3.12; Aspect Medical Systems, Natick, MA, USA) and expressed as the BIS. After preparation of the skin, four disposable, self-prepping, low-impedance electrodes (Zipprep; Aspect Medical Systems) were positioned over the left and right prefrontal cortex (Fp1, Fp2) and referenced to a central vertex electrode (Cz) according to a standard montage. Impedances were kept at less than 5000 .
Anaesthesia was induced by propofol infusion using a target-controlled infusion (TCI) pump (Graseby 3500; Graseby Medical, Watford, UK). The target plasma concentration of propofol (µg ml1) was raised in incremental steps until the patient became unconscious, as defined by the loss of the eyelash reflex. The corresponding BIS was recorded. To intubate the trachea, anaesthesia was deepened by increasing the target plasma concentration of propofol and muscle paralysis was achieved with rocuronium 0.6 mg kg1. During the whole procedure, the patients lungs were ventilated with 40% oxygen in air. The target plasma concentration of propofol was adjusted to achieve a constant level of anaesthesia, indicated by a BIS corresponding to the BIS at loss of eyelash reflex (pre-BIS). The target concentration of propofol was adjusted in steps of 0.10.5 µg ml1. A steady state was assumed only when the calculated effect site concentration equalled the target plasma concentration.
Keeping the propofol target concentration constant, we allocated the patients randomly to receive either an infusion of clonidine 4 µg kg1 or placebo in 0.9% NaCl 100 ml during the following 10 min. If the BIS was altered 15 min after the end of infusion, the target plasma concentration of propofol was reduced until the pre-BIS value was reached (Fig. 1). Heart rate, arterial blood pressure, the BIS and target plasma concentration of propofol were recorded every 2 min. Blood samples for measuring the blood concentration of propofol were taken via an additionally established 14 G cannula in a large vein on the contralateral arm before (pre phase) and 15 min after clonidine or placebo infusion (hold phase) and after adjusting the propofol target concentration (post phase), to achieve a steady state, defined as a constant BIS (= pre-BIS ±3) over a period of at least 5 min. The blood samples (4 ml heparinized tubes) were stored immediately at 20°C and analysed by high-performance liquid chromatography with fluorescence detection.9
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Statistical analysis
The duration of the different phases of the intra-operative course and memory test items were analysed using the MannWhitney U-test and Fishers exact test. Repeated measures analysis of variance with two within-group factors [phase (pre, hold, post) and repetition (steady state values in each phase)] and one between-group factor (clonidine/placebo) and post hoc t-test with Bonferroni correction were performed to evaluate differences in the progression of the preoperative phases pre, hold and post. To analyse differences between phases (pre, hold post) within groups (clonidine, placebo), paired t-tests with Bonferroni correction were used. Continuous data are presented as mean (SD). P values less than 0.05 were considered significant.
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Results |
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Discussion |
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Clonidine affects the EEG in a variety of ways: it increases slow-wave activity (delta) and attenuates the physiological alpha fluctuations.7 11 Although no data exist regarding the specific effect of clonidine on the BIS, clonidine causes sedation12 and therefore may also affect the BIS,13 which indeed was demonstrated in the present study.
The propofol saving in the current study of nearly 20% is comparable with earlier studies in which an isoflurane saving of approximately 40% was reported.14 15 The somewhat greater isoflurane saving in that study may be explained by a different EEG analysis, a larger dose of clonidine (5 vs 4 µg kg1) and perhaps especially because isoflurane dosing was guided mainly by haemodynamic responses. Another trial investigated the effect of clonidine on i.v. anaesthesia with propofol and fentanyl and found a reduction of approximately 40% in the propofol requirement with similar doses of fentanyl after clonidine.5 Despite similar anaesthetics and a relatively small dose of oral clonidine (150 µg), this study revealed a greater reduction of propofol in comparison with our study. This may be explained by dosing propofol according to arterial blood pressure and heart rate but without any monitoring of brain function, such as the BIS.
Larger doses of clonidine may allow greater reductions in anaesthetic drug use, but may lengthen the time required for recovery from anaesthesia.6 This was not observed in the present study and the time to extubation was similarly short in the two groups. The restrictive propofol dosing in our control group may be another reason for the relatively small propofol saving compared with previous studies. This might be linked to continuous monitoring of the BIS, which has been reported to facilitate immediate recovery and to decrease the consumption of anaesthetics.16
Clonidine administration resulted in a lower propofol requirement for a certain level of anaesthesia to be achieved, as defined by similar BIS values. The fact that no explicit intra-operative awareness occurred and no signs of implicit memory were observed indicates that the anaesthetic state induced by clonidine and low-dose propofol may be similar to the anaesthetic state induced by a larger dose of propofol alone. It is evident that larger trials will be necessary to show conclusively that a lower dose of propofol combined with clonidine is as safe as a larger dose propofol in preventing intra-operative awareness.
We analysed the propofol concentration of venous blood to avoid the insertion of an arterial catheter or repeated arterial puncture. In addition, we ensured that the time to steady state was always more than 10 min, and thus arterial and venous propofol concentrations should have been stable and in a fixed ratio to each other.17 Therefore, venous propofol concentrations may be considered representative of the blood concentration of propofol when comparing different phases and the two groups.
Clonidine did not have any additional effect in reducing the intra-operative requirement for remifentanil. This is in agreement with a study by Engelman and colleagues, describing similar intra-operative opioid requirements with and without clonidine.18 However, clonidine has been reported to reduce post-operative opioid requirements.19 Because the primary site of analgesic action of clonidine has been proposed to be the spinal dorsal horn, it is conceivable that systemically administered clonidine has a relatively limited analgesic efficacy, enabling modulation of post-operative pain but being less effective against the more intense intra-operative pain.20
In summary, the pharmacodynamic effect of i.v. clonidine can be monitored with the BIS. Intravenous clonidine causes a significant decrease in the BIS and allows a lower propofol dose to be used at a similar level of anaesthesia without intra-operative awareness or prolonged recovery times.
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Acknowledgements |
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References |
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