Reduction in standard MAC and MAC for intubation after clonidine premedication in children

S. Inomata1,3, S. Kihara1, Y. Yaguchi1, Y. Baba2, Y. Kohda2 and H. Toyooka1

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


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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 kg1, or oral clonidine 4 µg kg1 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 kg1 and clonidine 4 µg kg1 groups. The MACEIs and MACs decreased dose-dependently. The MACEI/MAC ratio (1.4) was not affected by clonidine.

Br J Anaesth 2000; 85: 700–4

Keywords: anaesthetics volatile, sevoflurane; interactions (drug); monitoring, end-tidal concentration; potency, minimum alveolar concentration


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Clonidine, an {alpha}2-adrenergic agonist, has recently been used as a preanaesthetic medication for children,1 and decreases the minimum alveolar concentration (MAC) in animal experiments.2 3 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.4 The MACEI/MAC ratio has been determined for several halogenated anaesthetics (halothane,4 enflurane5 and sevoflurane6 7). The ratio for sevoflurane is approximately 1.3 in children6 and 3 in adults.7 The effects of different doses of clonidine on the MACEI/MAC ratio have not been fully elucidated in children.8

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.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patient selection
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.

General procedure
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.

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 Dixon’s ‘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 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.

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 4–5% sevoflurane. Each concentration at which skin incision was attempted was predetermined according to the modification of Dixon’s ‘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 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.

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 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.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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.



View larger version (16K):
[in this window]
[in a new window]
 
Fig 1 End-tidal sevoflurane concentration and the responses of consecutive patients (15 in each group) in whom endotracheal intubation was attempted. Each patient’s data are represented with a circle, mean (SD) MACEIs at which smooth endotracheal intubation was possible in 50% of patients were 2.9 (0.1) %, 2.5 (0.1) % and 1.9 (0.1) %, in control (A), clonidine 2 µg kg–1 (B) and clonidine 4 µg kg–1 (C) groups, respectively.

 


View larger version (31K):
[in this window]
[in a new window]
 
Fig 3 The 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.

 
The MACEI/MAC ratio (1.4) was unaffected by clonidine premedication.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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.10 Our current findings that oral clonidine 4 µg kg–1 decreased MAC and MACEI by 43% and 35%, respectively, support our previous studies. {alpha}2-Adrenergic agonists have an analgesic effect, involving both supra-spinal and spinal sites.11 12 A selective {alpha}2-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.13

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 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%.2 In rats given intraperitoneal clonidine (10–1000 µg kg–1), the MAC for halothane was reduced by 32–42%.14 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%.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.



View larger version (16K):
[in this window]
[in a new window]
 
Fig 2 End-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.

 

    Footnotes
 
* Corresponding author (at University of Tsukuba) Back


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Mikawa K, Maekawa N, Nishina K et al. Efficacy of oral clonidine premedication in children. Anesthesiology 1993; 79: 926–31[ISI][Medline]

2 Kaukinen S, Pyykko K. The potentiation of halothane anaesthesia by clonidine. Acta Anaesthesiol Scand 1979; 23: 107–11[ISI][Medline]

3 Bloor BC, Flacke WE. Reduction in halothane anesthetic requirement by clonidine, an alpha-adrenergic agonist. Anesth Analg 1982; 61: 741–5[Abstract]

4 Yakaitis RW, Blitt CD, Angiulo JP. End-tidal halothane concentration for endotracheal intubation. Anesthesiology 1977; 47: 386–8[ISI][Medline]

5 Yakaitis RW, Blitt CD, Angiulo JP. End-tidal enflurane concentration for endotracheal intubation. Anesthesiology 1979; 50: 59–61[ISI][Medline]

6 Inomata S, Watanabe S, Taguchi M et al. End-tidal sevoflurane concentration for tracheal intubation and minimum alveolar concentration in pediatric patients. Anesthesiology 1994; 80: 93–6[ISI][Medline]

7 Kimura 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: 378–81[Abstract]

8 Nishina K, Mikawa K, Shiga M et al. Oral clonidine premedication reduces minimum alveolar concentration of sevoflurane for tracheal intubation in children. Anesthesiology 1997; 87: 1324–7[ISI][Medline]

9 Dixon WJ. Quantal response to valiable experimentation: the up-and-down method. In: McArthur JW, Colton T, eds. Statistics in Endocrinology. Cambridge, MA: MIT Press, 1967; 251–64

10 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]

11 Pertovaara A, Kauppila T, Jyvasjarvi E, Kalso E. Involvement of supraspinal and spinal segmental {alpha}2-adrenergic mechanisms in the medetomidine-induced antinociception. Neuroscience 1991; 44: 705–14.

12 Correa-Sales C, Rabin BC, Maze M. A hypnotic response to dexmedetomidine, an {alpha}2 agonist, is mediated in the locus coeruleus in rats. Anesthesiology 1992; 76: 948–52[ISI][Medline]

13 Vickery RG, Sheridan BC, Segal IS et al. Anesthetic and hemodynamic effects of the stereoisomers of medetomidine, an {alpha}2-agonist, in halothane-anesthetized dogs. Anesth Analg 1988; 67: 611–5[Abstract]

14 Maze M, Birch B, Vickery RG. Clonidine reduces halothane MAC in rats. Anesthesiology 1987; 67: 868–9[ISI][Medline]

15 Lerman L, Sikich N, Kleinman S et al. The pharmacology of sevoflurane in infants and children. Anesthesiology 1994; 80: 814–24[ISI][Medline]

16 Katoh T, Ikeda K. Minimum alveolar concentration of sevoflurane in children. Br J Anaesth 1992; 68: 139–41[Abstract]

17 Lowenthal DT, Matzek KM, MacGregor TR. Clinical pharmacokinetics of clonidine. Clin Pharmacokinet 1988; 14: 287–310[ISI][Medline]