BJA Advance Access published online on April 7, 2007
British Journal of Anaesthesia, doi:10.1093/bja/aem071
Oral clonidine vs midazolam in the prevention of sevoflurane-induced agitation in children. A prospective, randomized, controlled trial
1 Department of Anaesthesia, CHU-Brugmann – HUDERF, 4, Place Van Gehuchten, B-1020 Brussels, Belgium
2 Department of Anaesthesia, University Hospital Antwerp, 10, Wilrijkstraat, B-2650 Edegem, Belgium
* Corresponding author. E-mail: philippe.vanderlinden{at}chu-brugmann.be
Accepted for publication February 5, 2007.
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Abstract |
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Background: This randomized, double-blind study tested the hypothesis that, in comparison with midazolam, premedication with oral clonidine reduces the incidence of emergence agitation in preschool children anaesthetized with sevoflurane.
Methods: Sixty-eight ASA I–II children undergoing circumcision were randomized into three groups to receive different oral premedication given 30 min before anaesthesia: midazolam 0.5 mg kg–1, clonidine 2 µg kg–1, and clonidine 4 µg kg–1. Sevoflurane anaesthesia was administered via a facemask (O2/N2O: 40/60). Analgesia was with penile block (bupivacaine 0.5% 0.3 ml kg–1) and rectal paracetamol (30 mg kg–1). During the first postoperative hour, children were evaluated using a modified ‘objective pain scale’.
Results: Only the 4 µg kg–1 dose of clonidine was associated with a significant reduction in emergence agitation. Fewer children in the clonidine 4 µg kg–1 group displayed agitation (25%) than in the midazolam group (60%) (P = 0.025). Incidence of hypotension and bradycardia, time to first micturition and first drink did not differ among groups.
Conclusions: In comparison with midazolam, clonidine 4 µg kg–1 reduced sevoflurane-induced emergence agitation without increasing postoperative side-effects.
Keywords: anaesthetics volatile, sevoflurane; anaesthesia, paediatric; premedication, clonidine; recovery, postoperative
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Introduction |
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Emergence agitation is a common postoperative problem in children who have received sevoflurane anaesthesia.1 This agitation is characterized by a change in perception of the environment with signs of disorientation, hypersensitivity to stimuli, and hyperactive motor behaviour.1 Although it is usually of short duration, it may require pharmacological intervention, resulting in a prolonged post-anaesthesia care unit stay. Its aetiology remains unclear. Pain appears to be a promoting factor since administration of analgesic agents reduces its incidence.2 3 However, post-anaesthesia agitation can also appear after sevoflurane anaesthesia without surgery.4 Gender, age, type of surgery, and preoperative anxiety equally seem to be promoting factors.1 5
Clonidine provides both sedation and analgesia in children.6 7 In addition, i.v. clonidine administered after induction of anaesthesia has been shown to reduce the incidence of early post-anaesthetic agitation associated with sevoflurane.8–12 However, the effect of oral premedication with clonidine on post-anaesthetic agitation has not been fully evaluated. The hypothesis tested in the present study was that oral premedication with clonidine is effective in reducing early postoperative agitation after sevoflurane anaesthesia, provided that adequate postoperative analgesia has been achieved.
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Methods |
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After approval of the Hospital's Ethics Committee and parental written informed consent, 68 children, ASA status I or II, aged between 1 and 6 yr, and undergoing circumcision, were included in this double-blind, prospective, randomized study. Exclusion criteria included a family history of malignant hyperthermia, mental retardation, and any neurological disease potentially associated with symptoms of agitation.
Children were randomized into three groups. Each group received different premedication given orally 30 min before induction of anaesthesia: midazolam 0.5 mg kg–1 with a maximum dose of 15 mg, clonidine 2 µg kg–1, and clonidine 4 µg kg–1. This premedication was mixed with 3–5 ml of syrup. An anaesthesiologist not involved in the clinical protocol prepared the randomization envelopes. For each child included in the study, the anaesthesiologist responsible for the protocol (NT) drew the sealed envelope and administered the premedication.
Anaesthetic regimen
Premedication was administered in the recovery room in the presence of the parents. The anaesthetist who administered the premedication was excluded from the perioperative management and the postoperative assessment of the child.
A strict anaesthetic protocol was applied. Parents were absent from the anaesthetic room at the time of induction. The child was maintained with facemask and bag ventilation throughout the surgery. Anaesthesia was induced with inspired sevoflurane 8% in a 40:60% mixture of oxygen/nitrous oxide and a fresh gas flow of 6 litre min–1. In children <15 kg, a Jackson–Rees circuit was used, whereas in children weighing 
15 kg a circle system was used. Once a sufficient depth of anaesthesia (Guedel phase 3) was achieved, inspired sevoflurane concentration was reduced to 4% and a venous catheter was inserted. Neither a Guedel airway nor a harness was used in any of the children. Ringer's lactate solution was infused according to the child's weight.13 A penile block with bupivacaine 0.5% 0.3 ml kg–1 (maximum volume: 8 ml) was performed by another anaesthetist. All the regional blocks were carried out by two experienced anaesthetists (FdG, AdV). After the block had been performed, the inspired sevoflurane concentration was reduced to 1.5% and paracetamol 30 mg kg–1 was administered rectally. Surgery was allowed to start 10 min after the injection of bupivacaine. At the beginning of skin suture, the inspired sevoflurane concentration was reduced to 0.7% and stopped at the time of the last suture while maintaining a 40:60% mixture of oxygen/nitrous oxide until the end of the wound dressing. Then the child was allowed to breathe 100% oxygen until complete recovery of his reflexes. The child was transferred to the recovery room where one of the parents was waiting.
As pain is known to promote agitation, all the children who had an inadequate penile block were excluded from the study. A penile block was considered inadequate if, under an inspiration fraction of sevoflurane 1.5%, systolic arterial pressure and heart rate increased to >15% above baseline values at surgical incision. If this was the case, the child received i.v. sufentanil (0.1 µg kg–1) and was excluded from the study.
The anaesthetist in charge of the child evaluated the quality of induction as either good or bad. Systolic and diastolic arterial pressures, heart rate, and oxygen saturation were measured every 5 min throughout the procedure.
Assessment in the recovery room
An independent observer evaluated the child in the recovery room for 2 h after surgery, in the presence of one of the parents, using the objective pain scale. The state of agitation was assessed every 15 min for the first hour by means of a modified objective pain scale.14 The full objective pain scale includes five items (Table 1); of which, the items movement, tears, and behaviour were used to assess agitation.8 15 For these three items, which constituted the modified objective pain scale, the total possible score was 6. Agitation was defined by a total score of 3 for these three items.8 15 Prolonged agitation was defined as a score of 3 lasting >15 min after arrival in the recovery room.
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Arterial pressure, heart rate, and oxygen saturation were measured every 15 min during the 2-h postoperative observation period. Occurrence of hypotension or bradycardia was recorded. Hypotension and bradycardia were defined as a value of at least 15% less than the normal mean value for the child's age.13 The time of the first urine output and of the first drink was also recorded. The child was discharged from the recovery room when all of the following criteria were met: fully awake, haemodynamic stability for 30 min, absence of pain, bleeding, nausea, and vomiting. All children stayed at least for 2 h in the recovery room.
Statistical analysis
The incidence of postoperative agitation is about 60%.4 16 A sample size of at least 20 patients in each group was calculated to be necessary to detect a 50% decrease in this incidence with a power of 0.80 and 
= 0.05.
Intra- and postoperative haemodynamic variables were compared using two-way analysis of variance for repeated measures, followed by a post-hoc testing using Tukey's test for paired comparisons. Modified objective pain scores were compared using the Friedman's analysis of variance. Incidences of agitation and prolonged agitation were compared using the Kruskall–Wallis test. Data were presented as mean (SD) or median (range) where appropriate. A P-value of <0.05 was considered statistically significant.
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Results |
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Sixty-eight children were enrolled in this study. Seven children were excluded because of ineffective penile block at the time of incision and one child because of a study protocol violation. Patient detail, duration of surgery, and time to wake up are shown in Table 2.
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The modified objective pain score (movement, tears, and behaviour) was significantly lower in the clonidine 4 µg kg–1 group with a median (interquartile range) score of 3 (0–6) as compared with the midazolam group whose score was 6.5 (2.8–17.8) (Fig. 1). It also tended to be lower in the clonidine 2 µg kg–1 group, at 5.5 (0–7), when compared with the midazolam group. Only the 4 µg kg–1 dose was associated with a significant reduction in emergence agitation. The proportion of children with agitation in the first hour after surgery was significantly lower in the clonidine 4 µg kg–1 group compared with the midazolam group, P = 0.025 (Fig. 2). The proportion of children with agitation lasting for >15 min was also significantly lower in the clonidine 4 µg kg–1 group, P = 0.047 (Fig. 2).
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The quality of induction was estimated to be good in 70% of the children in the midazolam group, compared with 50% in the clonidine 2 µg kg–1 group and 30% in the clonidine 4 µg kg–1 group (P = 0.041).
No difference in haemodynamic parameters or SpO2 could be observed between the groups before or after operation (data not shown). Similarly, the incidence of hypotension and bradycardia was low and did not differ among the groups (Table 3). Time to first micturition and ingestion of first drink was similar in the three groups (Table 3).
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Discussion |
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Under the conditions of the present study, oral administration of clonidine 4 µg kg–1, 30 min before induction of anaesthesia, significantly reduced postoperative agitation compared with premedication with midazolam.
Our results differ from those of Fazi and colleagues,17 who compared oral clonidine and midazolam given 60–90 min before tonsillectomy in children aged between 4 and 12 yr. In this study, pain scores were higher in the clonidine group during the early phase of recovery. Not surprisingly, children's excitement, graded with a 0 (no excitement) to 4 (severe excitement) scale, was also higher in the clonidine group. However, emergence agitation was not assessed by Fazi and colleagues.17 Different definitions of emergence agitation complicate comparisons among studies.18 In an attempt to resolve this methodological issue, we quantified the agitation by means of a scale, validated to assess pain and discomfort in children aged >1 yr, the objective pain scale.14 This multimodal scale uses five items; three of which are particularly specific for agitation: tears, movements, and behaviour. This scale has already been used previously to assess emergence agitation after sevoflurane anaesthesia.8 15 19
Our results are in agreement with those of Bergendahl and colleagues19 who compared rectal premedication with midazolam or clonidine 5 µg kg–1. In the early postoperative period, children in the clonidine group had a significantly lower objective pain scale score.
In the present study, we also evaluated the effects of two different doses of clonidine. Only the 4 µg kg–1 dose was associated with a significant reduction in emergence agitation. Side-effects were not different between the 2 and 4 µg kg–1 doses.
The effects of clonidine on post-anaesthetic agitation were compared with those of midazolam. Midazolam is frequently used as a premedication in order to reduce preoperative anxiety and to facilitate anaesthetic induction. Nevertheless, its effects on the incidence of postoperative agitation remain controversial.1 18 20 21 The results might have been different if clonidine was compared with a placebo. However, it must be noted that in our study, the incidence of emergence agitation in the midazolam group was comparable with the incidence reported by several authors in unpremedicated patients.4 16 In our institution, refraining from premedication is not considered good practice, and all children routinely receive midazolam premedication.
In the present study, the quality of induction was less satisfactory after clonidine than after midazolam premedication. There was no difference between the two clonidine groups. This may be because of the short 30 min delay between premedication and induction. Mikawa and colleagues22 observed that clonidine 4 µg kg–1 administered 105 min before anaesthetic induction induced satisfactory sedation and anxiolysis. In another double-blind, randomized study, Constant and colleagues23 showed that clonidine 4 µg kg–1 given orally 1 h before induction of anaesthesia significantly reduced agitation during sevoflurane induction when compared with rectal midazolam. In our study, the time between clonidine administration and surgical incision was about 60 min. Therefore, a significant effect of this agent could be expected at the time of recovery. Importantly, postoperative haemodynamics and time to first micturation and ingestion of fluids were not different between the midazolam and the clonidine groups.
Postoperative agitation has been more frequently described with inhalation agents with a low blood–gas partition coefficient, leading to rapid recovery. Multiple studies have demonstrated an increased incidence of agitation after sevoflurane- or desflurane-based anaesthesia compared with halothane.2 5 16 24 25 However, the reported incidence of agitation shows a great variability ranging from 18 to 80%.11 Pain and preschool age are promoting factors for post-anaesthetic agitation.2 3 5 In the present study, the effects of clonidine were evaluated in a population at high risk for agitation: preschool children undergoing sevoflurane anaesthesia. Pain can probably be excluded as a cause of agitation, because the study was performed only when penile block was judged to be efficacious. Indeed, if the penile block was suspected to be inefficient, the child was excluded from the study.
In the present study, post-anaesthetic agitation was assessed using a modified objective pain scale,14 and not the pediatric anaesthesia emergence delirium scale developed recently by Sikich and Lerman.26 Among the five items included in the objective pain scale, only movement, tears, and behaviour were used. These items are very similar to some of those used by Sikich and Lerman. In addition, these authors commented that some of their items may reflect pain and emergence agitation.26 They also recognized that although the sensitivity of their scale was fair, the false-positive rate could be quite high, as with other scales. Finally, this scale has not been used to assess the effects of clonidine on emergence agitation, while the modified objective pain scale has been used for this purpose.8 19
In conclusion, oral clonidine 4 µg kg–1 administered 30 min before sevoflurane anaesthesia in preschool children significantly reduced emergence agitation. Further studies are required to define the optimal time of administration of clonidine in order to produce adequate sedation at the time of anaesthetic induction.
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Footnotes |
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Presented in part at the 2006 European Society of Anaesthesiologists meeting, Madrid, Spain. 
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