Departments of 1Anaesthesiology, Institute of Clinical Medicine and 2Clinical Pharmacy, University of Tsukuba, Tsukuba City, Ibaraki 305-8575, Japan. 3Magill Department of Anaesthesia, Imperial College School of Medicine, 369 Fulham Road, London SW10 9NH, UK,*
Accepted for publication: June 26, 2000
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Abstract |
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Br J Anaesth 2000; 85: 7004
Keywords: anaesthetics volatile, sevoflurane; interactions (drug); monitoring, end-tidal concentration; potency, minimum alveolar concentration
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Introduction |
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To study this interaction, we conducted a randomized, single-blind comparison of MACEI/MAC ratios for sevoflurane in children receiving a placebo, or clonidine 2 or 4 µg kg1 premedication.
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Methods |
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General procedure
Patients fasted for a minimum of 5 h before induction of anaesthesia. An i.v. infusion of 2% dextrose in lactated Ringers solution at a rate of 6 ml kg1 h1 was started. A precordial stethoscope was used to monitor heart and breath sounds. The patients were monitored with an electrocardiogram, a pulse oximeter and by measuring indirect arterial pressure. Throughout the study the inspired and end-tidal concentrations of agents were measured with a gas monitor (AS/3; Datex, Helsinki, Finland) which was calibrated before each use. Before tracheal intubation with a non-cuffed, appropriately sized tube, the end-tidal concentrations of agents were measured at the nose via a cannula; after intubation, they were measured from the distal end of the tracheal tube using a cannula that had been inserted through the elbow of the circuit so that its tip was within 1 cm the tip of the tracheal tube. Accuracy of end-tidal measurements was maximized by confirming the return of the end-tidal carbon dioxide trace to zero and a plateau of the exhaled concentration values.
The patients were randomly allocated to one of six groups (15 patients per group) using computer-generated numbers. The patients received one of three premedications (two groups for each premedication): placebo (control), oral clonidine 2 µg kg1, or oral clonidine 4 µg kg1 100 min before anaesthesia. Anaesthesia was induced with 5% sevoflurane in oxygen without intravenous anaesthetics and neuromuscular relaxants. The end-tidal sevoflurane concentrations and intervals used in MAC and MACEI determination were chosen from a pilot study.
Experimental protocol
Measurement of MACEI
Initially spontaneous respiration was assisted, and then respiration was controlled manually. When the end-tidal sevoflurane concentration reached a predetermined value, then end-tidal concentration was kept constant for 15 min before tracheal intubation. Laryngoscopy and tracheal intubation were attempted quickly using a curved laryngoscope and an uncuffed tracheal tube without neuromuscular relaxants or adjuvants. Each concentration at which laryngoscopy and tracheal intubation were attempted was chosen according to the modification of Dixons up-and-down method9 with 0.25% as a step size (2.5%, 2.75%, 3.0% and 3.25% in the control group; 2.25%, 2.5% and 2.75% in the clonidine 2 µg kg1 group, and 1.75%, 2.0% and 2.25% in the clonidine 4 µg kg1group). A single measurement was obtained per patient. When tracheal intubation was accomplished without gross purposeful muscular movements, it was considered smooth. Coughing and bucking were considered purposeful. Patients who moved during laryngoscopy or after tracheal intubation were immediately given 45% sevoflurane. They were regarded as not having been intubated smoothly. A single anaesthesiologist performed all tracheal intubations.
Time for tracheal intubation was defined as the time between discontinuation of face-mask ventilation and connection of the endotracheal tube to the anaesthesia circuit.
Measurement of MAC
Tracheal intubation was facilitated with 5% sevoflurane in oxygen without i.v. anaesthetics and neuromuscular relaxants, then anaesthesia was maintained with sevoflurane in oxygen and air. The lungs were mechanically ventilated using a volume-cycled ventilator. After the end-tidal sevoflurane concentration had reached a predetermined value, the concentration was maintained for at least 15 min before skin incision. Before skin incision, we recorded end-tidal sevoflurane for calculation. After skin incision, the patients were observed for 1 min for gross purposeful muscular movements. Coughing, bucking and straining were not considered purposeful. Patients who showed purposeful muscular movements during and/or after skin incision were immediately given 45% sevoflurane. Each concentration at which skin incision was attempted was predetermined according to the modification of Dixons up-and-down method9 (2.0%, 2.25%, 2.5% and 2.75% in the control group; 1.5%, 1.75% and 2.0% in the clonidine 2 µg kg1 group, and 1.0%, 1.25% and 1.5% in the clonidine 4 µg kg1 group).
Absence of any purposeful movements was determined by a single anaesthesiologist who was blinded to the tested sevoflurane concentration and whether clonidine was given or not. End-tidal concentration of carbon dioxide was maintained at 4.75.1 kPa during the study, while rectal temperature was maintained at 3637°C.
Data analysis
We determined MACEI and MAC by calculating the midpoint concentration of all independent pairs of patients involving a crossover (i.e. movement or no movement). MACEI or MAC was defined as the average of the crossover midpoints in each crossover subgroup. In addition, the standard deviation of MACEI or MAC was the standard deviation of the crossover midpoint in each group. Patient characteristics and pre-anaesthetic oral clonidine doses are expressed as mean (SD). Statistical comparisons among the three premedication groups (control, clonidine 2 µg kg1 and clonidine 4 µg kg1) were performed using ANOVA with Fishers least significant difference test for post hoc analysis (Stat View software, SAS Institute Inc., NC, USA and a Macintosh computer). Statistical comparisons between the same premedication groups were performed using two-factor factorial ANOVA with Fishers least significant difference test for post hoc analysis. In all cases, P<0.05 was considered the minimum level of statistical significance.
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Results |
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Figures 1 and 2 show the MACEI and MAC, respectively, for each each patient in the control (A), clonidine 2 µg kg1 (B) and 4 µg kg1 clonidine (C) groups, each measurement being represented with a circle. The MACEIs and MACs determined with the up-and-down method decreased dose-dependently (P<0.05) (Fig. 3). The MACEI was greater than the MAC for each clonidine dose (P<0.05). Time for tracheal intubation did not exceed 10 s. No patients had dysrhythmia, bradycardia or hypotension that necessitated treatment during the study.
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Discussion |
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We previously reported that the MACEI and MACEI/MAC ratio for sevoflurane were 2.69% and 1.3, respectively, in children.6 The MACEI/MAC ratio for other volatile anaesthetics, halothane4 and enflurane, 5 has been shown to be 1.3. In the present study, we found that the MACEI/MAC ratio was approximately 1.4 at each clonidine dose (0, 2 or 4 µg kg1). This relationship seems to be maintained in patients receiving oral clonidine premedication.
In a study of rabbits given clonidine 50 µg kg1 daily for 3 days, the MAC for halothane decreased by 16%.2 In rats given intraperitoneal clonidine (101000 µg kg1), the MAC for halothane was reduced by 3242%.14 We found that oral clonidine 4 µg kg1 reduced the MAC or MACEI for sevoflurane by 43% or 34%, respectively, in this study. These findings suggest that clonidine, in doses clinically used, reduces the MACs of volatile anesthetics by no more than 45%.
It has been reported that the MAC for sevoflurane in children is approximately 2.5%.15 16 In the present study, we found a similar MAC (2.33% in the placebo group), which was slightly higher than a value previously reported by us (2%).6 The difference in MACs between studies may be explained in part by the step size used in MAC determination (0.25% in the present study and 0.5% in our previous one). The fact that the MACEI value in the present study (2.92% in the placebo group) was slightly greater than our previous reported value (2.7%)6 may also partly depend on the step size used in MACEI determination (0.25% in the present study and 0.5% in our previous one). Further investigation is required to explain these differences fully. We determined the end-tidal sevoflurane concentrations and intervals from a pilot study, and used 0.25% as a step size in order to obtain precise values in this study.
Because the elimination half-life of clonidine ranges from 6 to 24 h, with a mean of about 12 h,17 clonidine is likely to remain effective over the time of the study, and changes in the effect of clonidine are unlikely to alter determination of MACEI and MAC.
In conclusion, clonidine reduced MACEI and MAC in a dose-dependent way. The MACEI/MAC ratio was unaffected by clonidine premedication, being 1.4 in each group.
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Footnotes |
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References |
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