Sevoflurane is a useful anesthetic for inhalational induction in children because of its low solubility in blood and relatively nonpungent odor. Clonidine has sedative and anxiolytic properties and reduces the requirement for inhalation agents. Nitrous oxide (N2O) also decreases the requirement of inhaled anesthetics, but the effect is variable. The minimum alveolar concentration for tracheal intubation (MAC(TI)) of sevoflurane was assessed with and without N2O and clonidine premedication.
Seventy-two patients, aged 3-11 yr, were assigned to one of six groups (n = 12 each). They received one of three preanesthetic medications (two groups for each premedication): placebo (control), 2 microg/kg oral clonidine or 4 microg/kg oral clonidine. In one group of each premedication, anesthesia was induced with sevoflurane in oxygen; in the other group, anesthesia was induced with sevoflurane in the presence of 60% N2O. Each concentration of sevoflurane at which tracheal intubation was attempted was predetermined according to Dixon's up-and-down method and held constant for at least 20 min before the trial
The MAC(TI) of sevoflurane in the absence of N2O (mean +/- SEM) was 3.2 +/- 0.2%, 2.5 +/- 0.1%, and 1.9 +/- 0.2% in the control, 2-microg/kg clonidine, and 4-microg/kg clonidine groups, respectively. Nitrous oxide (60%) decreased the MAC(TI) of sevoflurane by 26%, 24%, and 27% in the control, 2-microg/kg clonidine, and 4-microg/kg clonidine groups.
Oral clonidine premedication decreased the MAC(TI) of sevoflurane. Nitrous oxide also decreased the MAC(TI). The combination of clonidine and N2O lessened the MAC(TI) of sevoflurane more than did either drug alone.
Sevoflurane has been shown to be suitable for inhalational anesthesia in children because of its beneficial pharmacologic and physiochemical characteristics, [1,2] including relative nonpungency, less depressant for the cardiovascular system, rapid and smooth induction of anesthesia, and rapid emergence from anesthesia. It is reported that the minimum alveolar concentration (MAC) and the MAC for tracheal intubation (MACTI) of sevoflurane in children are 2.03% and 2.69%, respectively. 
Clonidine, a useful preanesthetic medication for children,  has been reported to decrease the MAC in animal experiments. [5,6] In humans, the concentrations of volatile anesthetics required to blunt hemodynamic responses to noxious stimuli are decreased in patients who receive clonidine as a preanesthetic medication. [7–9] After clonidine, the EEG shows increased slow-wave activity and decreased alpha activity in healthy young adults.  Clonidine has been shown to deepen isoflurane anesthesia even at lower concentrations, as assessed by electroencephalogram power spectra and somatosensory- and auditory-evoked potentials.  We also previously showed that oral clonidine decreased the induction dose of barbiturate  and the concentration of halothane required to decrease fluctuations of perioperative hemodynamics in children.  Thus we hypothesized that oral clonidine premedication may reduce the MACTIof sevoflurane in children. In addition, because nitrous oxide (N2O), which is commonly used for the inhalational induction of anesthesia, decreases the MAC of volatile anesthetics, we suspected that N2O may also decrease the MACTIof sevoflurane. We conducted the present study to test these hypotheses in children who were scheduled to undergo elective surgery.
Materials and Methods
This study was approved by the review board of the Kobe University School of Medicine. Written informed consent was obtained from a parent of each child. Eighty-six patients were enrolled in the study; 14 children were later excluded from the study before the first pair of opposite responses to intubation (described below), and the remaining 72 children were enrolled. The patients, aged 3–11 yr (classified as American Society of Anesthesiologists physical status 1), were scheduled to undergo minor surgery and were assigned to one of six groups (n = 12 each). The patients in three of these groups were premedicated with a placebo, 2 micro gram/kg clonidine or 4 micro gram/kg clonidine with a small amount of water 105 min before anesthesia. The children and their parents were blinded to the nature of the premedication. Anesthesia was induced with sevoflurane up to 5% in an incremental manner in oxygen via a face mask with 5 l/min fresh gas flow through a vaporizer (Sevotec 5; Ohmeda, Madison, WI). After loss of consciousness, venous access was obtained for the injection of drugs and infusion. Atropine sulfate (0.01 mg/kg) was administered intravenously. Then the inspired concentration of sevoflurane was changed to the predetermined concentration. End-tidal sevoflurane and carbon dioxide concentrations were continuously monitored with infrared absorption spectroscopy (RGM5250, Ohmeda) through a tube inserted into a nostril. Anesthetic concentrations were maintained constant at the target level for 20 min before tracheal intubation in each child to ensure that the end-tidal sevoflurane concentration represented the sevoflurane concentration in the brain. Tracheal intubation was attempted with an uncuffed tracheal tube without neuromuscular relaxant by an anesthetist who was blinded to the nature of the premedication. Each patient's response to tracheal intubation was evaluated as “no movement” or “movement.”“No movement” was defined as the absence of bucking or gross purposeful muscular movements during or immediately after tracheal intubation. “Movement” was recorded when mouth opening was difficult, or when bucking or gross purposeful muscular movement occurred during or after tracheal intubation. Children who moved during laryngoscopy and tracheal intubation were given 0.1 mg/kg vecuronium intravenously, and the inhaled concentration of sevoflurane was increased to 5%.
The MACTIwas determined using a modification of Dixon's up-and-down method (starting with 2.8%, with 0.2% as a step size). Each child contributed one datum point toward the measurement of the MAC sub TI for the study group. The determination of the MACTIof each group began only after the first pair of opposite responses to tracheal intubation of the subjects within the group. Twelve children were used to determine the MACTIin each group. The MACTIwas the mean of the concentrations of the 12 patients in each group. The standard error of the mean (SEM) was calculated using a method of Taylor and Lerman.  The SEM of MACTIwas the standard deviation of the mean concentrations of the three subgroups within each group. A subgroup was defined as four sequential children.
The remaining three groups of children (with three different premedications) were studied to evaluate the effect of N2O on the MACTI. They were premedicated, anesthetized, and monitored as stated above except that anesthesia was induced with sevoflurane in 60% N2O and oxygen instead of in 100% oxygen.
Parametric data were analyzed using analysis of variance. The significance of nonparametric data was determined the using the chi-square test. For all comparisons, P < 0.05 was considered significant.
The children in the six groups were comparable with respect to age, weight, height, and premedication time (Table 1). As shown in Figure 1(A), clonidine reduced the MACTIof sevoflurane in the absence of N2O. Figure 1(B) indicates that the inhalation of N2O decreased the MACTIfrom 3.2% to 2.4% in the children who received the placebo. In the presence of N2O, oral clonidine also decreased the sevoflurane MACTI. The reductive effects of 4 micro gram/kg clonidine and 60% N2O on the MACTIwas larger than that of either drug alone (40%, 26%, and 56% reduction by 4 micro gram/kg clonidine, 60% N2O, and the combination of them, respectively).
We have shown that the MACTIof sevoflurane was 3.2% in unpremedicated children aged 3–11 yr. Oral clonidine at 4 micro gram/kg successfully decreased the MACTIby 40% in the absence of N2O, whereas the inhalation of 60% N2O reduced the MACTIby 26% in the children who received a placebo. We have shown that the reduction of the MACTIby the combination of oral clonidine and 60% N2O inhalation was greater (maximum 56%) than that by either drug (clonidine or N2O) alone.
The MACTIof sevoflurane has been reported as 2.69  and 2.83% in children. The calculation using a value of sevoflurane MAC (2%) reported in one of the previous studies  revealed that the MACTI/MAC ratio of the anesthetic is 1.33. The MAC sub TI /MAC ratio of other volatile anesthetics, halothane  and enflurane,  has been shown to be approximately 1.3. Sevoflurane seems to meet this formula. The MACTIin the present study (3.2%) was higher compared with the previously reported values. Several studies have determined that the MAC of sevoflurane is approximately 2.5% in children (2.49% and 2.5%). In our investigation, the MACTI/MAC of sevoflurane was estimated to be 1.28 using a MAC of 2.5% and 1.6 using a MAC of 2%. The MACTI/MAC ratio remains to be determined in our clinical setting.
The degree to which N2O reduces the MAC of inhalation anesthetics has been shown to vary among agents and with the age of the patients. The use of 64% N2O decreases the sevoflurane MAC by 61% in adults,  whereas 60% N2O decreases it by only 20% in children. [20,21] In the present study using children, the inhalation of 60% N2O reduced the MACTI of sevoflurane to a similar degree regardless of the clonidine dose (26%, 24%, and 27% reductions in the placebo, 2-micro gram/kg clonidine, and 4-micro gram/kg clonidine groups, respectively). This finding indicates that oral clonidine does not change the sevoflurane-sparing effect of N2O.
Clonidine has been reported to decrease the requirement of volatile anesthetics in animal experiments and human clinical studies. In the present study, 4 micro gram/kg clonidine reduced the MACTIof sevoflurane by approximately 40% in the presence and absence of N2O. In rabbits that received 50 micro gram/kg clonidine daily for 3 days, the MAC for halothane decreased from 1.29% to 1.09%(16% reduction).  Intraperitoneal clonidine (10–1000 micro gram/kg) reduced the MAC for halothane by 32–42% in rats.  We recently showed that 4 micro gram/kg clonidine decreased the halothane requirement to attenuate fluctuation of blood pressure and heart rate from 1.1% to 0.6% in children (45% reduction).  Ghignone et al.  reported that the isoflurane requirement was reduced by 40% in hypertensive patients receiving 5 micro gram/kg oral clonidine. Further, the analyses of electroencephalograph power spectra and somatosensory- and auditory-evoked potentials revealed that the depth of anesthesia was sufficient despite a reduction in end-expiratory isoflurane concentrations after two consecutive injections of clonidine at 5 micro gram/kg.  These findings suggest that clonidine reduces the MAC of volatile anesthetics or their requirements to depress hemodynamic changes to surgical stimuli by not more than 45%.
In conclusion, oral clonidine premedication reduced the MACTIof sevoflurane in children. The inhalation of 60% N2O decreased the MACTIin children who were not premedicated. The reduction of the MACTIby the combination of oral clonidine and inhaled N2O was greater than that by either drug alone.