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Anesth Analg 2000;91:305-308
© 2000 International Anesthesia Research Society

PEDIATRIC ANESTHESIA

The Awakening Concentration of Sevoflurane in Children

Shinichi Kihara, MD*, Shinichi Inomata, MD*, Yuichi Yaguchi, MD*, Hidenori Toyooka, MD*, Yasuyuki Baba, BSPharm{dagger}, and Yukinao Kohda, PhD{dagger}

Departments of *Anesthesiology and {dagger}Clinical Pharmacology, University of Tsukuba, Tsukuba City, Ibaraki, Japan

Address correspondence and reprint requests to Dr. Shinichi Kihara, Department of Anesthesia, Mito Saiseikai General Hospital, Futabadai 3-3-10, Mito, Ibaraki 311-4198, Japan. Address e-mail to sin-ki{at}fa2.so-net.ne.jp


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Sevoflurane is frequently used as a rapidly acting drug for the induction of anesthesia. We investigated the awakening concentration (MAC-awake) of sevoflurane in ASA physical status I children (age range 2–10 yr). We also investigated the effects of two different doses of clonidine (2 and 4 µg/kg) on the MAC-awake of sevoflurane. Subjects were randomly divided into three groups and received placebo (n = 24), clonidine 2 µg/kg (n = 17), or clonidine 4 µg/kg (n = 22) orally, 100 min before the induction of anesthesia. Sedation scores were estimated, by using a five-point scale, after entry into the operating room, and anesthesia was induced and maintained with sevoflurane in oxygen and balanced nitrogen, without an additional anesthetic. After surgery, end-tidal sevoflurane was decreased stepwise by 0.2% at 15-min intervals, a standardized verbal command was played to the patients, and the MAC-awake was determined. The MAC-awake of sevoflurane alone was 0.78% ± 0.24% (mean ± SD), which decreased to 0.36% ± 0.09% and 0.36% ± 0.16% (both P <0.0001, compared with the control group) after premedication with the small and large doses of clonidine, respectively. The lack of any dose-response relationship might be explained by a plateau effect.

Implications: The awakening concentration of sevoflurane in unpremedicated children was 0.78%. Oral clonidine premedication at a dose of 2 µg/kg reduced the awakening concentration to 0.36%. However, an additional decrease in this value was not observed after the administration of the larger dose of clonidine premedication (4 µg/kg).


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Sevoflurane is an effective anesthetic for the inhaled induction of anesthesia. The relative lack of airway irritation and myocardial suppression effects, compared with other available anesthetics, and the rapid induction of and emergence from anesthesia make sevoflurane a suitable anesthetic for children. To prevent emergence delays and/or intraoperative awareness, it is important for anesthesiologists to know the awakening concentrations of anesthetics. However, although the minimum alveolar anesthetic concentration (MAC) for skin incision for sevoflurane is well known (1–4), data on the MAC for the awakening response (MAC-awake) for sevoflurane in children have never been examined. Clonidine, an {alpha}2-adrenoreceptor agonist, has been shown to reduce the requirements for IV anesthetics, such as opioids, as well as volatile anesthetics. Clonidine preadministration decreases the MAC-awake of volatile anesthetics in adults (5,6), but these effects have not been investigated in children. In this study, we test the hypotheses that the MAC-awake of sevoflurane in children is greater than that in adults and that the MAC-awake is decreased by clonidine premedication in children as well as in adults.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Institutional review board approval and parental informed consent were obtained for this study. Sixty-three children (age range 2–10 yr), ASA physical status I, who were undergoing inguinal hernia or cryptorchidism repair were enrolled in the study. The subjects were randomly divided into three groups, by using an envelope technique. In the control group, patients received placebo as the premedication. In the Clonidine-2 and Clonidine-4 groups, the patients received 2 and 4 µg/kg oral clonidine, respectively. All premedication was administered 100 min before the induction of anesthesia.

After entry into the operating room, the level of sedation was assessed by using a five-point sedation scale (1 = afraid, combative, and crying; 2 = awake but not crying; 3 = eyes closed but responds to name call; 4 = eyes closed but responds to minor stimulation; 5 = does not respond to minor stimulation), by three blinded observers. Blood pressure (measured noninvasively) and heart rate were recorded before the induction of anesthesia. Anesthesia was induced with 5% sevoflurane in 6 L/min oxygen by using the incremental increase technique and was maintained with 2%–3% sevoflurane in oxygen and balanced nitrogen (fraction of inspired oxygen = 0.4), via a face mask. No other volatile or IV anesthetics were administered during surgery. At the end of the operation, a 0.2-mL/kg dose of 1% lidocaine was injected around the surgical wound. After the completion of surgery, the end-tidal concentration of sevoflurane was adjusted to 1.2% in the control group and 0.8% in the clonidine-treated groups. These starting points were established in a preliminary trial. The end-tidal sevoflurane concentration was maintained for at least 15 min to ensure equilibration with the cerebral anesthetic partial pressure. All patients then received a standardized verbal command to open their eyes, via a tape-recorded message through occlusive headphones. No other stimuli were used during the study period. If the patient failed to open his or her eyes, the end-tidal concentration was decreased by 0.2% and again kept constant for 15 min. This process was repeated until an end-tidal concentration was reached at which the patient fully opened his or her eyes. Three observers who were blinded to both the nature of the premedication and the concentration of sevoflurane judged the patient eye opening. Brief fluttering of the eyelids was not considered eye opening. The concentration midway between the value permitting the response and that just preventing the response was defined as the MAC-awake. Gas samples were collected via a Teflon® (DuPont, Wilmington, DE) catheter placed at the nasal cavity, at the rate of 200 mL/min. The Teflon® catheter was positioned to obtain square wave forms with plateaus by using an end-tidal carbon dioxide monitor. The concentrations of sevoflurane and carbon dioxide were measured continuously by using an infrared multigas analyzer (AS/3®; Datex, Helsinki, Finland) that had been previously calibrated with a standard gas mixture (Quick Cal®; Datex). Values are presented as mean ± SD. Results were analyzed by using one-way analysis of variance with Bonferroni’s correction for parametric data, the {chi}2 test for categorical data, and the Kruskal-Wallis test for nonparametric data. P < 0.05 was considered statistically significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
There were no significant differences in the duration of surgery or anesthesia or the demographic data among the three groups (Table 1 ). Rectal temperatures were similar among the groups. There were no episodes of hypotension (systolic blood pressure < 80 mm Hg) or bradycardia (heart rate < 50 bpm) during the induction of anesthesia. In the control group, 67% (16 of 24) of the children cried during the separation period. Sixty-five percent (11 of 17) of the children in the Clonidine-2 group were awake but did not cry, and 73% (16 of 22) of children in the Clonidine-4 group had closed their eyes but responded to their names. The medians of the sedation scores were significantly different among the groups (P < 0.0001).


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  		Table 1. Demographic Characteristics
 
The mean MAC-awake value for the sevoflurane-alone group (0.78% ± 0.24%) was significantly greater than those observed for the Clonidine-2 group (0.36% ± 0.09%, P < 0.0001) and the Clonidine-4 group (0.36 ± 0.16%, P < 0.0001). There were no significant differences in MAC-awake values between the clonidine-premedicated groups (P = 0.91) (Figure 1 ).



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  		Figure 1. Awakening concentration (MAC-awake) of sevoflurane. {bigcirc} = MAC-awake (the concentration midway between the value permitting the response and that just preventing the response) for each patient. = mean of the MAC-awake for each group. *P < 0.0001, compared with the control group.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In this study, the MAC-awake value for sevoflurane in unpremedicated children was 0.78%. This value is greater than the range previously reported for adults (0.60%–0.67%) (6–9). This is consistent with a previous report that the MAC-awake values for volatile anesthetics increase as patient age decreases (7). The sevoflurane MAC has been reported to be 1.71%–2.05% (9–12), and the MAC-awake/MAC ratio can be calculated to be 0.29–0.39 in adults. The sevoflurane MAC range is greater (2.03%–2.5%) in children (age range 1–12 yr) (1–4). When the MAC-awake/MAC ratio is calculated by using the MAC-awake values we obtained, the ratio range is 0.31–0.38, which is very similar to the values observed for adult patients.

The factors that influence the MAC-awake values for volatile anesthetics after premedication are not fully understood. In this study, oral clonidine premedication, in both the 2 and 4 µg/kg dose groups, reduced the MAC-awake by approximately 50%. In adults, oral clonidine premedication using a 5-µg/kg dose has been shown to reduce MAC-awake by 15% to 47% (5,6,9). Other anesthetics, such as epidural lidocaine, decrease MAC-awake values in adults (13), but caudal bupivacaine has not been shown to have any effects on MAC-awake in children (14). IV morphine does not affect the MAC-awake values in either adults (15,16) or children (14). IV fentanyl produces a dose-dependent decrease in both the MAC and MAC-awake of sevoflurane in adult patients (8).

{alpha}2-Adrenoceptors are located on primary afferent terminals (at both peripheral and spinal endings), on neurons in the superficial laminae of the spinal cord, and within brainstem nuclei. Evidence supports a spinal action of clonidine in producing analgesia in human patients. Locus nuclei that are located in the brainstem and regulate the sleep/wakefulness cycle have many {alpha}2-adrenoceptors. It is possible to achieve preoperative sedative effects and reduction of the MAC-awake of volatile anesthetics through the effects of clonidine on this site. Clonidine has been shown to be most effective as an oral preanesthetic medication at doses of 3–4 µg/kg. The reduced MAC-awake values for both clonidine-treated groups suggested that the effects on MAC-awake may already be maximal at the smaller dose of clonidine that we investigated. Whether there is a dose-dependent effect of clonidine premedication on MAC-awake at smaller doses is unclear.

Several studies of clonidine premedication have been conducted in children (17–19). Oral clonidine premedication at 4 µg/kg has been shown to yield better separation from parents and better acceptance of the mask, compared with 0.4 mg/kg diazepam premedication (17). Clonidine also decreases the dose of thiamylal required to induce anesthesia (18) and decreases the MAC of sevoflurane for tracheal intubation (19).

Although we did not measure the plasma concentrations of clonidine, these levels increase rapidly after a single oral dose, peak approximately 1.5 hours after oral administration, and remain detectable in plasma for >10 hours (20,21). These findings suggest that the plasma concentrations of clonidine would be maintained at reasonably high levels throughout surgical procedures lasting 1–1.5 hours. The present protocol did not allow us to determine the awakening time from anesthesia, so the effects of clonidine premedication on the depth of anesthesia may delay recovery from anesthesia.

MAC-awake values defined by using tracheal intubation may not reflect the pure hypnotic potency of volatile anesthetics (8). We investigated MAC-awake using mask ventilation. Local anesthetic was infiltrated around the surgical field, to avoid the effects of wound pain on MAC-awake. However, this effect could not be completely eliminated. It was difficult to estimate the degree of pain immediately after emergence for children, and this may confound our results.

In conclusion, the MAC-awake of sevoflurane was observed to be 0.78% in children who had not been premedicated with clonidine. Oral clonidine premedication at 2 µg/kg reduced the MAC-awake to 0.36%. However, an additional decrease in this value was not observed after administration of a larger dose of clonidine premedication (4 µg/kg).


   Acknowledgments
 
We are very grateful to F. H. Noormohamed (Academic Therapeutics, Chelsea and Westminster Hospital, Imperial College School of Medicine, London, UK) for numerous suggestions and encouragement.


   Footnotes
 
This work was presented in part at the 73rd Annual Meeting of the International Anesthesia Research Society, Los Angeles, CA, March 16, 1999.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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  3. Lerman J, Sikich N, Kleinman S, Yentis S. The pharmacology of sevoflurane in infants and children. Anesthesiology 1994;80:814–24.[ISI][Medline]
  4. Katoh T, Ikeda K. Minimum alveolar concentration of sevoflurane in children. Br J Anaesth 1992;68:139–41.[Abstract/Free Full Text]
  5. Goyagi T, Tanaka M, Nishikawa T. Oral clonidine premedication reduces the awakening concentration of isoflurane. Anesth Analg 1998;86:410–3.[Abstract]
  6. Katoh H, Ikeda K. The effect of clonidine on sevoflurane requirements for anaesthesia and hypnosis. Anaesthesia 1997;52:377–81.[ISI][Medline]
  7. Katoh T, Suguro Y, Ikeda T, et al. Influence of age on awakening concentrations of sevoflurane and isoflurane. Anesth Analg 1993;76:348–52.[ISI][Medline]
  8. Katoh T, Ikeda K. The effects of fentanyl on sevoflurane requirements for loss of consciousness and skin incision. Anesthesiology 1998;88:18–24.[ISI][Medline]
  9. Inomata S, Yaguchi Y, Toyooka H. The effects of clonidine premedication on sevoflurane requirements and anesthetic induction time. Anesth Analg 1999;89:204–8.[Abstract/Free Full Text]
  10. Katoh H, Ikeda K. The effect of clonidine on sevoflurane requirements for anaesthesia and hypnosis. Anaesthesia 1997;52:377–81.
  11. Katoh T, Ikeda K. The minimum alveolar concentration (MAC) of sevoflurane in humans. Anesthesiology 1987;66:301–3.[ISI][Medline]
  12. Scheller MS, Partrigi BL, Saidman LJ. MAC of sevoflurane in humans and New Zealand white rabbit. Can Anesth Soc J 1988;35:153–6.
  13. Inagaki Y, Mashimo T, Kuzukawa A, et al. Epidural lidocaine delays arousal from isoflurane anesthesia. Anesth Analg 1994;79:368–72.[Abstract/Free Full Text]
  14. Watcha MF, Lagueruela RG, White PF. Effect of intraoperative analgesic therapy on end-expired concentrations of halothane associated with spontaneous eye opening in children. Anesth Analg 1991;72:190–3.[ISI][Medline]
  15. Gross JB, Alexander CM. Awakening concentrations of isoflurane are not affected by analgesic doses of morphine. Anesth Analg 1988;67:27–30.[Abstract/Free Full Text]
  16. Katoh T, Suguro Y, Kimura T, Ikeda K. Morphine does not affect the awakening concentration of sevoflurane. Can J Anaesth 1993;40:825–8.[Abstract/Free Full Text]
  17. Mikawa K, Maekawa N, Nishina K, et al. Efficacy of oral clonidine premedication in children. Anesthesiology 1993;79:926–31.[ISI][Medline]
  18. Nishina K, Mikawa K, Maekawa N, et al. Clonidine decreases the dose of thiamylal required to induce anesthesia in children. Anesth Analg 1994;79:766–8.[Abstract/Free Full Text]
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Accepted for publication May 1, 2000.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press