Sevoflurane is a volatile ether inhalational anaesthetic which was first developed in the 1970s. In Japan, sevoflurane has been used in more than a million patients since 1990, but it has only recently received approval in western countries. Compared with other inhalational agents, the low blood/gas-partition co-efficient of sevoflurane (0.6-0.7) provides rapid uptake and elimination of the anaesthetic. Rapid induction and fast recovery have been demonstrated for adult as well as paediatric patients. The non-pungent odour of sevoflurane, which is often described as pleasant, offers the additional advantage of low airway irritability for inhalational induction , which is especially useful for paediatric anaesthesia.
The present study, which was part of an international multicentre phase 3 trial , compares the induction, maintenance and recovery characteristics of sevoflurane and halothane anaesthesia in children. The aim of the present investigation was to assess whether sevoflurane offers clinical advantages when compared with halothane.
The study was approved by the present authors' institutional ethics committee. Forty-two consecutive patients, aged between 2 and 16 years, ASA I-III, who were scheduled for elective surgical procedures of an anticipated duration of more than 1 h (i.e. general, plastic or maxillofacial surgery) were included in the study after their parents had given written, informed consent.
All of the children were premedicated with midazolam [1 mg kg−1 rectally or 0.01 mg kg−1 intravenously (i.v.) for older children or children with an intravenous line in place] 15 min before the induction of anaesthesia. Thereafter, a sealed envelope was opened to allocate patients randomly to receive either sevoflurane or halothane for both induction and maintenance of anaesthesia, and baseline heart rate (HR) and blood pressure (BP) were obtained.
Induction of anaesthesia was initiated by inhalation of the volatile anaesthetic in nitrous oxide (4 L min−1) in oxygen (2 L min−1) via a facemask through a circuit system (Sulla 808 V or Cicero, Draegerwerk AG, Lue-beck, Germany). The inspired concentration of sevoflurane or halothane was increased every five breaths until loss of eyelash reflex, tested at each increment. Appropriately calibrated vapourizers (halothane: Vapor 19.3, Draegerwerk AG; sevoflurane: Penlon, Intermed, Abingdon, UK) were used. For halothane, the stepwise increments were 0.5% to a maximum of 1.5-2.5%. (2-3.5 MAC) Sevoflurane was increased in 1% steps to a maximum of 3-6% (1.5-3 MAC), which was considered equipotent. An i.v. cannula was inserted and an infusion of lactated Ringer's solution (10 mL kg−1 min−1) was commenced. Vecuronium was used to facilitate endotracheal intubation at the discretion of the attending anaesthesiologist. After tracheal intubation, the lungs were ventilated mechanically to maintain normocapnia and a soda lime CO2-absorber was used.
Anaesthesia was maintained with nitrous oxide in oxygen (2:1 L min−1) and inhalation of 1-1.5 MAC of halothane (0.8-1.5%) or sevoflurane (2.5-3.0%). According to Lerman et al., the MAC for sevoflurane is relatively constant (2.5-2.6%) in children between 6 months and 12 years, the age group of the majority of the children included in the present study. Therefore, age-dependency of MAC was not considered.
Analgesia was provided by i.v. increments of fentanyl (2-3 μg kg−1) or a regional anaesthetic technique. After skin closure, the volatile anaesthetic and nitrous oxide were discontinued abruptly and simultaneously.
Monitoring included continuous ECG, pulse oximetry, and inspiratory and end-tidal concentration of anaesthetics and CO2. Heart rate and automated non-invasive blood pressure (BP) using appropriately sized arm cuffs were recorded every minute for 15 min during induction, every 5 min until incision, every minute for 5 min after incision and then every 15 min until skin closure. In the recovery area, BP and HR were recorded at 10-min intervals for 2 h after the end of anaesthesia. Patients were observed by an independent, non-blinded observer throughout the study period. Time from application of the face mask to loss of eyelash reflex was recorded. Time to opening of eyes to a non-painful stimulus recorded at 1-min intervals after cessation of the anaesthetic was defined as emergence. Thereafter, time of response to age-appropriate verbal commands was recorded. A modified Aldrete score (MAS) was used to monitor physiological variables (respiration rate, BP, skin temperature, motor activity and consciousness) every 10 min during recovery; a MAS ≥8 is generally accepted as indicating adequate post-operative recovery. Children older than 6 years also rated several subjective parameters on a visual analogue scale (VAS) every 15 min in the recovery room. In a 24-h follow-up questionnaire, patients or their parents were asked if any side effects occurred, and asked to rate the quality of induction as pleasant or unpleasant and state whether they would prefer to have the same anaesthetic for a possible future operation.
Demographic data are presented as mean ± SD. Student's t-test was used to compare differences between groups for normally distributed data, assessed by Kolmogorov-Smirnov analysis. The Mann-Whitney U-test was used to compare differences in scores between groups. Analysis of variance (ANOVA) for repeated measures was used for HR and BP to evaluate differences over the time and between groups. A difference in induction time of ≥3 min emergence time of ≥10 min was considered clinically significant. A power analysis revealed that a sample size of 40 patients is appropriate to detect a significant difference with a power of 90%; P<0.05 was defined as statistically significant.
Patients in the halothane and sevoflurane groups were comparable with respect to sex, age, weight, type of surgery, type of analgesia (opioid vs. regional anaesthesia) and duration of anaesthesia (Table 1). Fentanyl doses administered during sevoflurane and halothane anaesthesia did not differ significantly.
Time to loss of eyelash reflex tended to be shorter with sevoflurane than with halothane, but the difference did not reach statistical significance (P=0.06). There was no difference in the incidence or severity of side effects during induction, all of which were minor (Table 2). Base-line cardiovascular variables (HR, systolic and diastolic BP) were comparable in both groups. During induction, SBP and DBP decreased by >10% of base-line in both groups (P<0.05), but HR remained unchanged (Fig. 1). During maintenance of anaesthesia, HR and BP remained stable. Arrhythmias were not observed during induction or maintenance with either sevoflurane and/or halothane.
There was a trend towards a shorter emergence time and time to response after anaesthesia with sevoflurane when compared with halothane (Table 3), but these did not reach statistical significance. No airway complications (e.g. laryngo- or bronchospasm, or breath holding) occurred during emergence, although excitement as evaluated by the independent observer was more pronounced after sevoflurane anaesthesia.
Modified Aldrete scores were slightly higher after sevoflurane (≥8 within 30 min) than after halothane (≥8 within 40 min) anaesthesia during the recovery period, which was not statistically significant (Fig. 2). Children in the halothane group rated themselves to be more sleepy as well as confused on the VAS than those in the sevoflurane group (Fig. 3), again without statistically significant differences. Pain scores on the VAS and post-operative analgesic requirements in the recovery area did not differ between sevoflurane or halothane. The incidence of post-operative nausea and vomiting was somewhat lower after sevoflurane anaesthesia (no statistical significance): one child after sevoflurane and four children after halothane rated nausea >50 on the VAS during the 120 min in the recovery area; three children, all in the halothane group, vomited during emergence or recovery. In the first 24 h after sevoflurane anaesthesia, four children complained about nausea and two children vomited; after halothane seven children who felt nausea also vomited.
In both groups, most children (14 sevoflurane/13 halothane) had amnesia of the induction, and therefore, were unable to give an opinion on the quality of induction or a preference for a future anaesthetic.
The present study demonstrates that sevoflurane provides as smooth an inhalational induction as halothane for paediatric patients, which is still the volatile agent of choice for this purpose. Thus, the present findings support the results of other authors [3-10].
Time to loss of eyelash reflex with halothane and sevoflurane varies in different studies (Table 4). The speed of induction with sevoflurane is generally faster than that of halothane. However, statistically significant differences have only been demonstrated in half the studies [4-7], and even then, the time gained with sevoflurane is less than a minute, which is of questionable clinical relevance. The blood/gas-partition coefficient of sevoflurane is markedly lower than that of halothane, 0.6 compared with 2.3 , so the rather small difference in induction time might seem unexpected. However, the rapidity of induction depends on a variety of factors besides anaesthetic solubility, including: the rate at which the maximum inspired concentration is achieved ; airway irritation; and physiological parameters, such as alveolar ventilation and cardiac output . Some authors claim that a more pronounced overpressure technique (i.e. multiples of MAC) accelerates halothane induction times compared with sevoflurane. It is argued that, with sevoflurane, this technique is limited by the vapourizer, which delivers a maximum concentration of 7% (2.8 MAC), whereas with halothane, 4.5% the maximum inspired concentration approximates 5 MAC . Furthermore, it has been suggested that there is a relation between the solubility of a given volatile anaesthetic and the MAC-attenuating effects of nitrous oxide, and that the addition of nitrous oxide potentiates halothane more than sevoflurane especially in children . Nevertheless, Sarner et al. reported that induction times with sevoflurane were prolonged in 35% of their patients because of marked excitement when nitrous oxide was omitted.
However, in the present study, the authors found that sevoflurane and halothane in nitrous oxide/oxygen offered equally favourable conditions for inhalational induction, with minimal signs of airway reflex stimulation.
Heart rate remained unchanged and blood pressure decreased significantly during induction with either sevoflurane or halothane. Most studies report a decrease in SBP after sevoflurane. In some studies [6,7], this decrease is smaller during induction with sevoflurane than with halothane. Lerman  found that the decrease in SBP with sevoflurane was age dependent and less pronounced with increasing age. The decrease in BP is mainly caused by decreased peripheral resistance, although myocardial depression has been described at higher concentrations .
Heart rate is maintained [4,7,8] or increased [5,12] during induction with sevoflurane when compared with control values. With halothane, heart rate changes have not been regularly observed. It has been speculated  that the baroreceptor reflex, attenuated by halothane, is better preserved during sevoflurane anaesthesia. Sevoflurane is less arrhythmogenic than halothane, and like other ethers, does not sensitize the myocardium to catecholamines .
In the studies mentioned in Table 4, children anaesthetized with sevoflurane recovered faster than after halothane anaesthesia, although these differences were not statistically significant in the present study. Also, in contradistinction with other studies [4,5,9,10], MAS scores and subjective parameters as rated by the children on the VAS, did not differ significantly after sevoflurane or halothane in the present study.
Although children were more excited after sevoflurane than after halothane, post-operative restlessness was not a major problem in the present study. Several authors [3,4,7] describe marked agitation in children after sevoflurane anaesthesia, which can be effectively treated with analgesics. When a regional anaesthetic technique was used to provide intra- and post-operative analgesia , no remarkable excitement was observed during recovery. These results indicate that faster recovery after sevoflurane leads to an earlier perception of post-operative pain, expressing itself as increased excitement in children. Therefore, the need for adequate post-operative analgesia seems to be enhanced when sevoflurane is used as an inhalational anaesthetic.
It has been reported that unpremedicated children prefer induction with sevoflurane compared with halothane [4,10]. However, the premedication used in the present study appeared to eliminate unpleasant experiences during induction of anaesthesia.
Inspired concentrations of volatile anaesthetic agents as well as different opioid and premedication regimens may all account for the fact that the advantage achieved with sevoflurane is only slight. Equipotent concentrations of about 1-1.5 MAC of sevoflurane and halothane were used in both the present and in the other studies. In comparison with other studies, where either unpremedicated children [3,4,8,9] were studied or low doses of midazolam were used [5,7], the children in the present study received a rather large dose of midazolam for premedication. However, the duration of anaesthesia in the present study was longer than in most of the other studies. Therefore, and because of the comparatively short half-life of midazolam, any effects of premedication on recovery time are highly unlikely.
Most of the children in the present study received fentanyl for intra-operative analgesia. The effect of fentanyl on the awakening concentration of sevoflurane is rather small compared with the overall scatter of the MACawake (the end-tidal concentration of sevoflurane associated with eye-opening on command in 50% of patients) . For halothane, only morphine has been studied , which does not alter the MACawake of either halothane or sevoflurane .
It could be argued that a combination of a relatively high dose of premedication, opioid analgesia and a longer duration of anaesthesia in the present study masked the expected faster recovery after sevoflurane anaesthesia. Interestingly, recovery times after sevoflurane in the present study were comparable with other studies [4,5], whereas recovery after halothane was faster (Table 4). However, the present results closely resemble those of the multicentre trial . In the multi-centre trial, differences of less than a minute during induction and less than 4 min during recovery (Table 4) reached statistical significance because of the large number of patients included. Furthermore, obtaining 95% confidence intervals from the multicentre trial data revealed a maximum difference of only 6.8 min during emergence. Interestingly, they failed to demonstrate any differences for post-operative orientation or discharge times from the recovery area. Therefore, there is no evident clinical benefit obtained with sevoflurane.
Sevoflurane and halothane are excellent anaesthetic agents for paediatric patients. The findings from the present study do not support evidence for a real clinical benefit of sevoflurane. Whether other characteristics of sevoflurane, such as the reported lower arrhythmogenic potential, renders it preferable over halothane remains to be evaluated in further clinical practice.
We thank Professor R. N. Sladen for his constructive criticism of this manuscript.
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