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• W2094370798 abstract "We examined the relative effects of different doses of oral clonidine on the MAC for endotracheal intubation (MACEI) and the MAC for skin incision (MAC) in children. We studied 90 children (15 in each group) (age range 2–8 yr, weight 10–27 kg, height 89–124 cm) who received one of three preanaesthetic medications: placebo (control), oral clonidine 2 μg kg–1, or oral clonidine 4 μg kg–1 100 min before anaesthesia. Anaesthesia was induced and maintained with sevoflurane in oxygen and air without i.v. anesthetics and neuromuscular relaxants. The end-tidal sevoflurane concentration was kept constant for ≥15 min before tracheal intubation or skin incision. MACs were determined using Dixon's ‘up-and-down method’. Mean (sd) MACEIs of sevoflurane were 2.9 (0.1) %, 2.5 (0.1) % and 1.9 (0.1) % (P<0.05), and MACs were 2.3 (0.1) %, 1.8 (0.1) % and 1.3 (0.1) % (P<0.05), respectively, in control, clonidine 2 μg kg–1 and clonidine 4 μg kg–1 groups. The MACEIs and MACs decreased dose-dependently. The MACEI/MAC ratio (1.4) was not affected by clonidine. We examined the relative effects of different doses of oral clonidine on the MAC for endotracheal intubation (MACEI) and the MAC for skin incision (MAC) in children. We studied 90 children (15 in each group) (age range 2–8 yr, weight 10–27 kg, height 89–124 cm) who received one of three preanaesthetic medications: placebo (control), oral clonidine 2 μg kg–1, or oral clonidine 4 μg kg–1 100 min before anaesthesia. Anaesthesia was induced and maintained with sevoflurane in oxygen and air without i.v. anesthetics and neuromuscular relaxants. The end-tidal sevoflurane concentration was kept constant for ≥15 min before tracheal intubation or skin incision. MACs were determined using Dixon's ‘up-and-down method’. Mean (sd) MACEIs of sevoflurane were 2.9 (0.1) %, 2.5 (0.1) % and 1.9 (0.1) % (P<0.05), and MACs were 2.3 (0.1) %, 1.8 (0.1) % and 1.3 (0.1) % (P<0.05), respectively, in control, clonidine 2 μg kg–1 and clonidine 4 μg kg–1 groups. The MACEIs and MACs decreased dose-dependently. The MACEI/MAC ratio (1.4) was not affected by clonidine. Clonidine, an α2-adrenergic agonist, has recently been used as a preanaesthetic medication for children,1Mikawa K Maekawa N Nishina K et al.Efficacy of oral clonidine premedication in children.Anesthesiology. 1993; 79: 926-931Crossref PubMed Scopus (106) Google Scholar and decreases the minimum alveolar concentration (MAC) in animal experiments.2Kaukinen S Pyykko K The potentiation of halothane anaesthesia by clonidine.Acta Anaesthesiol Scand. 1979; 23: 107-111Crossref PubMed Scopus (65) Google Scholar 3Bloor BC Flacke WE Reduction in halothane anesthetic requirement by clonidine, an alpha-adrenergic agonist.Anesth Analg. 1982; 61: 741-745Crossref PubMed Scopus (135) Google Scholar The MAC for endotracheal intubation (MACEI) is the end-tidal concentration of volatile anaesthetics at which a smooth tracheal intubation is possible in 50% of patients.4Yakaitis RW Blitt CD Angiulo JP End-tidal halothane concentration for endotracheal intubation.Anesthesiology. 1977; 47: 386-388Crossref PubMed Scopus (60) Google Scholar The MACEI/MAC ratio has been determined for several halogenated anaesthetics (halothane,4Yakaitis RW Blitt CD Angiulo JP End-tidal halothane concentration for endotracheal intubation.Anesthesiology. 1977; 47: 386-388Crossref PubMed Scopus (60) Google Scholar enflurane5Yakaitis RW Blitt CD Angiulo JP End-tidal enflurane concentration for endotracheal intubation.Anesthesiology. 1979; 50: 59-61Crossref PubMed Scopus (36) Google Scholar and sevoflurane6Inomata S Watanabe S Taguchi M et al.End-tidal sevoflurane concentration for tracheal intubation and minimum alveolar concentration in pediatric patients.Anesthesiology. 1994; 80: 93-96Crossref PubMed Scopus (122) Google Scholar 7Kimura T Watanabe S Asakura N et al.Determination of end-tidal sevoflurane concentration for tracheal intubation and minimum alveolar concentration in adults.Anesth Analg. 1994; 79: 378-381Crossref PubMed Scopus (93) Google Scholar). The ratio for sevoflurane is approximately 1.3 in children6Inomata S Watanabe S Taguchi M et al.End-tidal sevoflurane concentration for tracheal intubation and minimum alveolar concentration in pediatric patients.Anesthesiology. 1994; 80: 93-96Crossref PubMed Scopus (122) Google Scholar and 3 in adults.7Kimura T Watanabe S Asakura N et al.Determination of end-tidal sevoflurane concentration for tracheal intubation and minimum alveolar concentration in adults.Anesth Analg. 1994; 79: 378-381Crossref PubMed Scopus (93) Google Scholar The effects of different doses of clonidine on the MACEI/MAC ratio have not been fully elucidated in children.8Nishina K Mikawa K Shiga M et al.Oral clonidine premedication reduces minimum alveolar concentration of sevoflurane for tracheal intubation in children.Anesthesiology. 1997; 87: 1324-1327Crossref PubMed Scopus (58) Google Scholar 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 kg−1 premedication. We studied 90 children, ASA physical status I, ranging in age from 2 to 8 yr, and scheduled for general anaesthesia for elective repair of inguinal hernia under general anaesthesia. The study was approved by our Clinical Investigation Committee, and informed consent was obtained from the parent or guardian of each patient. Patients with airway malformation, clinical evidence of a difficult airway, asthma or any sign of upper respiratory infection on preoperative examination were excluded from the study. Patients taking sedatives, antihistamines, central nervous system (CNS) depressants or anti-seizure medication, or who had CNS disorders including spinal cord dysfunction were also excluded from the study. Patients fasted for a minimum of 5 h before induction of anaesthesia. An i.v. infusion of 2% dextrose in lactated Ringer's solution at a rate of 6 ml kg−1 h−1 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 kg−1, or oral clonidine 4 μg kg−1 100 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. 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 Dixon's ‘up-and-down’ method9Dixon WJ Quantal response to valiable experimentation: the up-and-down method.in: McArthur JW Colton T Statistics in Endocrinology. MIT Press, Cambridge, MA1967: 251-264Google Scholar 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 kg−1 group, and 1.75%, 2.0% and 2.25% in the clonidine 4 μg kg−1group). 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 4–5% 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. 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 4–5% sevoflurane. Each concentration at which skin incision was attempted was predetermined according to the modification of Dixon's ‘up-and-down’ method9Dixon WJ Quantal response to valiable experimentation: the up-and-down method.in: McArthur JW Colton T Statistics in Endocrinology. MIT Press, Cambridge, MA1967: 251-264Google Scholar (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 kg−1 group, and 1.0%, 1.25% and 1.5% in the clonidine 4 μg kg−1 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 4.7–5.1 kPa during the study, while rectal temperature was maintained at 36–37°C. 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 kg−1 and clonidine 4 μg kg−1) were performed using ANOVA with Fisher's 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 Fisher's least significant difference test for post hoc analysis. In all cases, P<0.05 was considered the minimum level of statistical significance. The characteristics of each group were very similar. The mean (sd) age was 5 (2) yr in each group. The mean weight was between 18 and 20 kg, and the mean height was between 107 and 108 cm in the six groups. Figures 1 and 2 show the MACEI and MAC, respectively, for each each patient in the control (a), clonidine 2 μg kg−1 (b) and 4 μg kg−1 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.Fig 2End-tidal sevoflurane concentration and the responses of consecutive patients (15 per group) in whom skin incision was attempted. Each patient's data are represented with a circle. The mean (sd) MACs at which skin incision was possible in 50% of patients were 2.3 (0.1) %, 1.8 (0.1) % and 1.3 (0.1) % in control (a), clonidine 2 μg kg−1 (b) and clonidine 4 μg kg−1 (c) groups, respectively.View Large Image Figure ViewerDownload (PPT)Fig 3The MACEIs and MACs determined with the up-and-down method decreased dose-dependently. The MACEI/MAC ratio was 1.4 in all groups. Values are mean (SD). *P<0.05 vs control, #P<0.05 vs clonidine 2 μg kg−1 group.View Large Image Figure ViewerDownload (PPT) The MACEI/MAC ratio (1.4) was unaffected by clonidine premedication. We set out to determine the effect of oral clonidine preanaesthetic medication on the MACEI/MAC ratio in children. We compared MACEI/MAC ratios for sevoflurane in children receiving clonidine 2 or 4 μg kg−1 or a placebo. We observed a similar reduction in end-tidal sevoflurane concentrations for the two different endpoints: loss of response to tracheal intubation and loss of response to skin incision. We found in a previous study that oral clonidine 4.4 μg kg−1 decreased MAC.10Inomata S Yaguchi Y Toyooka H The effects of clonidine premedication on sevoflurane requirements and anesthetic induction time.Anesth Analg. 1999; 89: 204-208PubMed Google Scholar Our current findings that oral clonidine 4 μg kg−1 decreased MAC and MACEI by 43% and 35%, respectively, support our previous studies. α2-Adrenergic agonists have an analgesic effect, involving both supra-spinal and spinal sites.11Pertovaara A Kauppila T Jyvasjarvi E Kalso E Involvement of supraspinal and spinal segmental α2-adrenergic mechanisms in the medetomidine-induced antinociception.Neuroscience. 1991; 44: 705-714Crossref PubMed Scopus (86) Google Scholar 12Correa-Sales C Rabin BC Maze M A hypnotic response to dexmedetomidine, an α2 agonist, is mediated in the locus coeruleus in rats.Anesthesiology. 1992; 76: 948-952Crossref PubMed Scopus (338) Google Scholar A selective α2-adrenergic agonist, dexmedetomidine, has been shown in animal studies to decrease the MAC for halothane so much that it may act as an anaesthetic by itself at high doses.13Vickery RG Sheridan BC Segal IS et al.Anesthetic and hemodynamic effects of the stereoisomers of medetomidine, an α2-agonist, in halothane-anesthetized dogs.Anesth Analg. 1988; 67: 611-615PubMed Google Scholar We previously reported that the MACEI and MACEI/MAC ratio for sevoflurane were 2.69% and 1.3, respectively, in children.6Inomata S Watanabe S Taguchi M et al.End-tidal sevoflurane concentration for tracheal intubation and minimum alveolar concentration in pediatric patients.Anesthesiology. 1994; 80: 93-96Crossref PubMed Scopus (122) Google Scholar The MACEI/MAC ratio for other volatile anaesthetics, halothane4Yakaitis RW Blitt CD Angiulo JP End-tidal halothane concentration for endotracheal intubation.Anesthesiology. 1977; 47: 386-388Crossref PubMed Scopus (60) Google Scholar and enflurane, 5Yakaitis RW Blitt CD Angiulo JP End-tidal enflurane concentration for endotracheal intubation.Anesthesiology. 1979; 50: 59-61Crossref PubMed Scopus (36) Google Scholar 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 kg−1). This relationship seems to be maintained in patients receiving oral clonidine premedication. In a study of rabbits given clonidine 50 μg kg−1 daily for 3 days, the MAC for halothane decreased by 16%.2Kaukinen S Pyykko K The potentiation of halothane anaesthesia by clonidine.Acta Anaesthesiol Scand. 1979; 23: 107-111Crossref PubMed Scopus (65) Google Scholar In rats given intraperitoneal clonidine (10–1000 μg kg−1), the MAC for halothane was reduced by 32–42%.14Maze M Birch B Vickery RG Clonidine reduces halothane MAC in rats.Anesthesiology. 1987; 67: 868-869Crossref PubMed Scopus (40) Google Scholar We found that oral clonidine 4 μg kg−1 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%.15Lerman L Sikich N Kleinman S et al.The pharmacology of sevoflurane in infants and children.Anesthesiology. 1994; 80: 814-824Crossref PubMed Scopus (439) Google Scholar 16Katoh T Ikeda K Minimum alveolar concentration of sevoflurane in children.Br J Anaesth. 1992; 68: 139-141Crossref PubMed Scopus (96) Google Scholar 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%).6Inomata S Watanabe S Taguchi M et al.End-tidal sevoflurane concentration for tracheal intubation and minimum alveolar concentration in pediatric patients.Anesthesiology. 1994; 80: 93-96Crossref PubMed Scopus (122) Google Scholar 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%)6Inomata S Watanabe S Taguchi M et al.End-tidal sevoflurane concentration for tracheal intubation and minimum alveolar concentration in pediatric patients.Anesthesiology. 1994; 80: 93-96Crossref PubMed Scopus (122) Google Scholar 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,17Lowenthal DT Matzek KM MacGregor TR Clinical pharmacokinetics of clonidine.Clin Pharmacokinet. 1988; 14: 287-310Crossref PubMed Scopus (135) Google Scholar 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." @default.
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• W2094370798 title "Reduction in standard MAC and MAC for intubation after clonidine premedication in children" @default.
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