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Prophylactic use of midazolam or propofol at the end of surgery may reduce the incidence of emergence agitation after sevoflurane anaesthesia.

Sevoflurane with its rapid induction and emergence, haemodynamic stability and non-irritating airway properties, has acquired widespread acceptance in children. However, sevoflurane has been reported to be associated with emergence agitation in children, with a reported incidence of up to 80% (1).

The aetiology of emergence agitation is unclear. Some studies proposed that emergence agitation was related to a variable rate of neurologic recovery in different brain areas and immaturity of neurons (2). Inhalation anaesthetics have been known to exert transient paradoxical excitatory effects in both animal and human patients, especially in children. Sevoflurane directly excites neurons in the locus caeruleus of rats, which may be associated with emergence agitation (3). The gamma([gamma])-aminobutyric acid [(GABA).sub.A] receptor is the target depressant effect site of most anaesthetic drugs including sevoflurane (4). Midazolam acts on the benzodiazepine binding site of [GABA.sub.A] receptors and results in inhibitory effects on the central nervous system. The effect of midazolam premedication, as well as midazolam administration at the end of surgery, on suppressing emergence agitation has been studied (5,6). However, the effect of midazolam on emergence agitation is still controversial (5,7). Recently, administration of propofol, another [GABA.sub.A] receptor inhibitor, at the end of surgery after discontinuation of sevoflurane, was reported to decrease the incidence of agitation without delaying discharge from the post-anaesthesia care unit (PACU) (8).

Thus we designed a randomised, double-blind study to examine the hypothesis that the prophylactic use of midazolam or propofol, which are both [GABA.sub.A] receptor inhibitors, given five minutes before the end of strabismus surgery may reduce the incidence of emergence agitation after sevoflurane anaesthesia in children.

METHODS

This study was approved by the Ethics Committee of the Korea University Hospital and informed consent was obtained from at least one of the patients' parents. The exclusion criteria included refusal by parents, neurological disease, developmental delay, history of any previous surgery, American Society of Anesthesiologists physical status score of III or IV, and airway disease. One hundred and one American Society of Anesthesiologists physical status I and II patients, aged one to 13 years, scheduled to undergo strabismus surgery under general anaesthesia were enrolled in the study. The patients were randomly assigned by means of random numbers generated by a computer to one of the propofol, midazolam or saline groups.

All patients were premedicated with intramuscular atropine 0.01 mg/kg. Continuous electrocardiogram, heart rate, blood pressure, pulse oximetry, end-tidal C[O.sub.2], and inspiratory and expiratory gas concentrations were monitored during operation. Anaesthesia was induced with intravenous thiopentone (5 mg/kg) and maintained with 50% nitrous oxide in oxygen and an end-tidal concentration of 2 to 3% sevoflurane. Intravenous rocuronium 0.6 mg/kg was used to facilitate tracheal intubation. All patients received intravenous paracetamol 10 mg/kg (Perfalgan[R]; UPSA Laboratories, Agen, France) for postoperative pain relief after induction of anaesthesia.

Approximately five minutes before the end of surgery, sevoflurane and nitrous oxide were discontinued. Children were randomly assigned to receive intravenous midazolam 0.05 mg/kg (group M, n=35), propofol 1 mg/kg (group P, n=31) or saline (group S, n=35). The trachea was extubated when the patient showed purposeful movement of all extremities and was breathing spontaneously. After extubation, all patients were transferred to the PACU. Upon arrival to the PACU, all children were received by one of their parents, who stayed with them until discharge. In the PACU, a nurse who was blinded to the patient's study group recorded the degree of emergence agitation and unexpected events (laryngospasm, nausea, vomiting, or desaturation) every 10 minutes for one hour.

Behaviour on emergence was rated on a four-point scale: 1 = calm; 2=not calm but could be easily calmed; 3=not easily calmed, moderately agitated or restless; 4=excited or disoriented (Table 1) (9). We considered that agitation had occurred when the agitation score was rated 3 or 4 over 10 minutes during the PACU stay. Severe agitation (score >4) was treated by psychological support from the parents or nurse and intravenous fentanyl 1 to 2 [micro]g/kg (10).

The following time intervals were recorded: duration of surgery, duration of sevoflurane administration (from the induction of anaesthesia to discontinuation of sevoflurane) and duration of anaesthesia (from the induction of anaesthesia to extubation).

Chi-squared analysis was used to compare the groups with regard to emergence agitation. For estimation of sample size, a preliminary survey was performed. A sample size of 32 in each group was calculated for the detection of a 34% effect size. The Kruskal-Wallis test and Pearson chi-squared analysis were also used to test for demographic differences between groups as well as for differences in duration of surgery and anaesthesia. The Mann-Whitney test was used to test for emergence time. All data were analysed with the Statistical Package for Social Science for Windows, version 13.0. A value of P <0.05 was considered to be significant.

RESULTS

A total of 101 children presenting for strabismus surgery under sevoflurane anaesthesia were included in the study. There were no significant differences in age, gender, weight, the type of surgical procedures (one or two eyes) and duration of surgery or anaesthesia among the three groups (Table 2).

The incidence of emergence agitation was 42.9% in group M (15/35), 48.4% in group P (15/31) and 74.3% in group S (26/35) (Table 3). The emergence agitation incidence in groups M or P was significantly less than in group S (P=0.043) (Table 3). The emergence time was prolonged in group M (14.31 [+ or -] 3.80) and P (15.65 [+ or -] 3.83) compared to group S (11.26 [+ or -] 2.94) (P <0.001) (Table 3). However, there were no significant differences in the incidence of emergence agitation and the emergence times between groups P and M.

We compared agitation scores of the children who had unilateral versus bilateral strabismus surgery. The incidence of emergence agitation was not affected by the number of operated eyes in group M. However, emergence agitation incidence was higher in bilaterally operated patients in groups P or S (Table 4). The development of severe agitation that required pharmacologic treatment was more frequent in group S (20%, 7/35) than groups M (5.7%, 2/35) or P (6.5%, 2/31) (Table 5). The incidence of postoperative adverse events (laryngospasm, nausea, vomiting, desaturation) among the three groups failed to reach statistical significance (Table 5).

DISCUSSION

We observed an incidence of 74.3% of sevoflurane-induced emergence agitation in the control group. This is comparable to a previous study which reported that the incidence is between 20% and 80% (11). However, prophylactic administration of intravenous midazolam or propofol significantly reduced the incidence of agitation to 42.9% and 48.4%, respectively, without adverse postoperative effects.

Propofol, compared with sevoflurane, has been reported to have a significantly lower incidence of emergence agitation (12,13). According to Cohen et al (14), induction of anaesthesia with propofol is not effective in decreasing the incidence of emergence agitation. This result is expected because propofol has a short duration of action so that the serum level might be too low to effectively suppress the agitation after longer procedures. Uezono et al (12) showed that the risk of emergence agitation could be eliminated when sevoflurane induction is followed by continuous infusion of propofol for anaesthesia maintenance. Furthermore, 1 mg/kg propofol administration at the end of surgery after discontinuation of sevoflurane decreased the incidence of agitation (8). Therefore, it is possible that the decreased incidence of emergence agitation may be accounted for by the residual effect of propofol. The effect of midazolam on emergence agitation is still controversial. One study showed that midazolam premedication may decrease the incidence of emergence agitation (5). In another study, midazolam premedication showed no effect on emergence agitation following sevoflurane or halothane anaesthesia (7). Arai et al (15) reported that children given the combination of midazolam and diazepam for oral premedication were less agitated than those given midazolam alone. This result is expected because midazolam has a short duration of action that may not outlast the duration of the surgery. In our study, children received midazolam 0.05 mg/kg five minutes before the end of surgery. Therefore, the effect of midazolam lasted during the recovery period.

Several studies have demonstrated that pain during impaired consciousness contributes to emergence agitation in some children (16). Therefore, some investigators have argued that the emergence agitation can be blunted or abolished by pretreatment with agents such as ketorolac (16), clonidine (17), fentanyl (18) or dexmedetomidine (19). Although pain has been described as being a contributing factor for emergence agitation (20), some recent studies reported that the incidence of emergence agitation after sevoflurane anaesthesia was still high, in pain-free children with caudal analgesia (21), or in children without a painful surgical manoeuvre (22). Despite the controversy over pain being a risk factor for agitation, we tried to reduce postoperative pain. Therefore, all patients received 10 mg/kg of intravenous paracetamol after induction of anaesthesia.

Another factor believed to contribute to emergence agitation is a rapid emergence in a foreign environment (23). According to our results, the emergence time in group M and P was prolonged and emergence agitation incidence was lower. The emergence time difference between the treatment groups and control group was four (group M) to five (group P) minutes. However, it is difficult to conclude that the delayed emergence may affect the occurrence of agitation, because rapid awakening after propofol anaesthesia has not been associated with emergence agitation (12,13).

Eckenhoff et al (20) speculated that the incidence of emergence agitation may be increased in patients undergoing head and neck procedures. Also, ophthalmology procedures in children may increase the incidence of emergence agitation (9). When vision is disturbed following surgery and eye patching, the reactivity of the children to a hostile environment upon awakening from anaesthesia may be distorted (2). Our study showed that the children undergoing bilateral eye surgery, in comparison with unilateral eye surgery, had a higher incidence of emergence agitation in group S or P (Table 4). In contrast to the results of Aouad et al (8), who reported that the administration of propofol may have neutralised the negative effect of bilateral eye surgery on emergence agitation, we showed that propofol had no suppressive effect on emergence agitation in bilateral eye surgery. However, we identified that midazolam reduced the emergence agitation following bilateral eye surgery.

Our study had several limitations. First, similar to other studies of emergence agitation, our study suffered from the lack of a validated tool for measuring emergence agitation. The Pediatric Anesthesia Emergence Delirium Scale is validated and reliable. However, its usefulness in the assessment of emergence agitation after strabismus surgery is limited. After strabismus surgery, the presence of an eye patch and eye ointment may interfere with the ability of the child to make eye contact with the caregiver. Therefore, we used a simple graded measurement that is very similar to those used by other investigators (9,12,13). Second, the doses of midazolam and propofol used in this study are arbitrary. This is, in part, due to the fact that there are not equipotent doses of midazolam and propofol. Therefore, we chose the propofol dose of 1 mg/kg, in accordance with the previous study of Aouad et al8. It has previously been shown, in paediatric patients, that sedation with intravenous midazolam (0.05 to 0.1 mg/kg; maximum single dose of 2 mg, maximum total dose of 4 mg) is safe and effective for invasive or lengthy procedures (24). Therefore, we chose the minimum sedation midazolam dose of 0.05 mg/kg in the present study. Further study is needed to determine whether a smaller dose of midazolam may be effective to suppress emergence agitation as we could not eliminate the possibility that the patients could become re-anaesthetised, given that the elimination half-life of midazolam in this patient population is usually one to two hours.

We conclude that propofol or midazolam administration before the end of surgery may be effective in reducing the incidence of emergence agitation in children undergoing strabismus surgery after sevoflurane anaesthesia.

ACKNOWLEDGEMENT

This study was supported by a Korea University Research Grant.

REFERENCES

(1.) Kulka PJ, Bressem M, Tryba M. Clonidine prevents sevoflurane-induced agitation in children. Anesth Analg 2001; 93: 335-338.

(2.) Aouad MT, Nasr VG. Emergence agitation in children. Curr Opin Anaesthesiol 2005; 18:614-619.

(3.) Yasui Y, Masaki E, Kato F. Sevoflurane directly excites locus coeruleus neurons of rats. Anesthesiology 2007; 107:992-1002.

(4.) Campagna JA, Miller KW, Forman SA. Mechanisms of actions of inhaled anesthetics. N Engl J Med 2003; 348:2110-2124.

(5.) Lapin SL, Auden SM, Goldsmith LJ, Reynolds AM. Effects of sevoflurane anaesthesia on recovery in children: a comparison with halothane. Paediatr Anaesth 1999; 9:299-304.

(6.) Kulka PJ, Bressem M, Wiebalck A, Tryba M. [Prevention of "post-sevoflurane delirium" with midazolam]. Anaesthesist 2001; 50:401-405.

(7.) Breschan C, Platzer M, Jost R, Stettner H, Likar R. Midazolam does not reduce emergence delirium after sevoflurane anesthesia in children. Paediatr Anaesth 2007; 17:347-352.

(8.) Aouad MT, Yazbeck-Karam VG, Nasr VG, El-Khatib MF, Kanazi GE, Bleik JH. A single dose of propofol at the end of surgery for the prevention of emergence agitation in children undergoing strabismus surgery during sevoflurane anesthesia. Anesthesiology 2007; 107:733-738.

(9.) Aono J, Ueda W, Mamiya K, Takimoto E, Manabe M. Greater incidence of delirium during recovery from sevoflurane anesthesia in preschool boys. Anesthesiology 1997; 87:1298-1300.

(10.) Cravero JP, Beach M, Thyr B, Whalen K. The effect of small dose fentanyl on the emergence characteristics of pediatric patients after sevoflurane anesthesia without surgery. Anesth Analg 2003; 97:364-367.

(11.) Cole JW, Murray DJ, McAllister JD, Hirshberg GE. Emergence behaviour in children: defining the incidence of excitement and agitation following anaesthesia. Paediatr Anaesth 2002; 12:442-447.

(12.) Uezono S, Goto T, Terui K, Ichinose F, Ishguro Y, Nakata Y et al. Emergence agitation after sevoflurane versus propofol in pediatric patients. Anesth Analg 2000; 91:563-566.

(13.) Picard V, Dumont L, Pellegrini M. Quality of recovery in children: sevoflurane versus propofol. Acta Anaesthesiol Scand 2000; 44:307-310.

(14.) Cohen IT, Drewsen S, Hannallah RS. Propofol or midazolam do not reduce the incidence of emergence agitation associated with desflurane anaesthesia in children undergoing adenoton sillectomy. Paediatr Anaesth 2002; 12:604-609.

(15.) Arai YC, Fukunaga K, Hirota S. Comparison of a combination of midazolam and diazepam and midazolam alone as oral premedication on preanesthetic and emergence condition in children. Acta Anaesthesiol Scand 2005; 49:698-701.

(16.) Davis PJ, Greenberg JA, Gendelman M, Fertal K. Recovery characteristics of sevoflurane and halothane in preschoolaged children undergoing bilateral myringotomy and pressure equalization tube insertion. Anesth Analg 1999; 88:34-38.

(17.) Tesoro S, Mezzetti D, Marchesini L, Peduto VA. Clonidine treatment for agitation in children after sevoflurane anesthesia. Anesth Analg 2005; 101:1619-1622.

(18.) Cohen IT, Hannallah RS, Hummer KA. The incidence of emergence agitation associated with desflurane anesthesia in children is reduced by fentanyl. Anesth Analg 2001; 93:88-91.

(19.) Ibacache ME, Munoz HR, Brandes V, Morales AL. Single-dose dexmedetomidine reduces agitation after sevoflurane anesthesia in children. Anesth Analg 2004; 98:60-63.

(20.) Eckenhoff JE, Kneale DH, Dripps RD. The incidence and etiology of postanesthetic excitment. A clinical survey. Anesthesiology 1961; 22:667-673.

(21.) Weldon BC, Bell M, Craddock T. The effect of caudal analgesia on emergence agitation in children after sevoflurane versus halothane anesthesia. Anesth Analg 2004; 98:321-326.

(22.) Dalens BJ, Pinard AM, Letourneau DR, Albert NT, Truchon RJ. Prevention of emergence agitation after sevoflurane anesthesia for pediatric cerebral magnetic resonance imaging by small doses of ketamine or nalbuphine administered just before discontinuing anesthesia. Anesth Analg 2006; 102:1056-1061.

(23.) Wells LT, Rasch DK. Emergence "delirium" after sevoflurane anesthesia: a paranoid delusion? Anesth Analg 1999; 88:1308-1310.

(24.) Parker RI, Mahan RA, Giugliano D, Parker MM. Efficacy and safety of intravenous midazolam and ketamine as sedation for therapeutic and diagnostic procedures in children. Pediatrics 1997; 99:427-431.

Y. H. KIM *, S. Z. YOON ([dagger]), H. J. LIM ([double dagger]), S. M. YOON ([double dagger])

Department of Anaesthesiology and Pain Medicine, College of Medicine, Korea University, Seoul, Korea

* M.D., Resident.

([dagger]) M.D., Ph.D., Assistant Professor.

([double dagger]) M.D., Ph.D., Professor.

Address for correspondence: Professor S. Z. Yoon, Department of Anaesthesiology and Pain Medicine, College of Medicine, Korea University, 5 Anam-dong Sungbuk-gu, Seoul 136-705, Korea.

Accepted for publication on May 12, 2011.
TABLE 1
Four-point emergence scale

 Emergence
Score Behaviour agitation

1 Calm No

2 Not calm but could be easily No
 calmed

3 Not easily calmed, moderately Yes
 agitated or restless

4 Excited or disoriented Yes

TABLE 2
Demographics, surgery and anaesthetic data

 Group M, n=35 Group P, n=31

Age, months 72 (15- 124) 76 (16-155)

Gender, M/F 15/20 13/18

Weight, kg 22.60 [+ or -] 7.90 25.65 [+ or -] 10.89

Eyes operated, one 22/13 16/15
eye/two eyes

Duration of 52.0 [+ or -] 31.17 51.26 [+ or -] 24.63
surgery, min

Duration of 68.49 [+ or -] 31.63 70.52 [+ or -] 27.57
anaesthesia, min

 Group S, n=35

Age, months 81 (9-120)

Gender, M/F 21/14

Weight, kg 24.93 [+ or -] 9.20

Eyes operated, one 21/14
eye/two eyes

Duration of 47.69 [+ or -] 28.31
surgery, min

Duration of 67.89 [+ or -] 27.82
anaesthesia, min

Data presented as median (range) or mean [+ or -] SD. There were
no statistically significant differences between the three groups.
Group M=midazolam 0.05 mg/kg, Group P=propofol 1 mg/kg,
Group S=saline, M=male, F=female.

TABLE 3
Incidence of emergence agitation and emergence time

 Group M, n=35 Group P, n=31

Emergence 14.31 [+ or -] 3.80 15.65 [+ or -] 3.83
time *, min

Emergence 15 (42.9%) 15 (48.4%)
agitation **

 Group S, n=35 P

Emergence 11.26 [+ or -] 2.94 <0.05
time *, min

Emergence 26 (74.3%) <0.05
agitation **

Data presented as mean [+ or /] SD or numbers of patients
(percentage). Group M=midazolam 0.05 mg/kg, Group P=propofol 1 mg/kg,
Group S=saline. * Midazolam vs saline, propofol vs saline, P <0.001.
Midazolam vs propofol, P=0.206. ** Midazolam vs saline, propofol vs
saline, P <0.043. Midazolam vs propofol, P=0.805.

TABLE 4
The incidence of emergence agitation according to type of surgery

 Group M, Group P, Group S,
 n=35 n=31 n=35

Unilateral eye 40.9% (9/22) 31.3% (5/16) 57.1% (12/21)
surgery

Bilateral eyes 46.2% (6/13) 66.7% (10/15) 100% (14/14)
surgery

P NS <0.05 <0.05

Data presented as number of agitated children/total number of
children. Group M=midazolam 0.05 mg/kg, Group P=propofol
1 mg/kg, Group S=saline, NS=no significance.

TABLE 5
The incidence of postoperative unexpected events and the need
for fentanyl

 Group M, Group P, Group S, P
 n=35 n=31 n=35

Nausea, vomiting 0 1 0 NS
Laryngospasm 0 1 1 NS
Desaturation 0 0 0 NS
Need for fentanyl 2 2 7 <0.05

Data presented as number of postoperative unexpected events
or the need for fentanyl to treat severe agitation. Group
M=midazolam 0.05 mg/kg, Group P=propofol 1 mg/kg, Group
S=saline, NS=no significance.
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Article Details
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Author:Kim, Y.H.; Yoon, S.Z.; Lim, H.J.; Yoon, S.M.
Publication:Anaesthesia and Intensive Care
Article Type:Report
Geographic Code:9SOUT
Date:Sep 1, 2011
Words:3245
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