Emergence agitation (EA) is a post-operative

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1 bs_bs_banner Acta Anaesthesiol Scand 2014; : Printed in Singapore. All rights reserved 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd ACTA ANAESTHESIOLOGICA SCANDINAVICA doi: /aas Review Article Dexmedetomidine for preventing sevoflurane-related emergence agitation in children: a meta-analysis of randomized controlled trials L. Sun 1, R. Guo 2 and L. Sun 1 1 Department of Anesthesiology, Cancer Institute and Hospital, National Cancer Center, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China and 2 National Center for Cardiovascular Disease Control and Research, Fuwai Hospital, National heart center, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China Emergence agitation (EA) is a common problem after sevoflurane anesthesia in children. Prophylactic dexmedetomidine has been directed at this issue; however, the efficacy remains controversial. We therefore conducted a meta-analysis of randomized controlled trials (RCTs) to evaluate the effectiveness of dexmedetomidine on the incidence of sevoflurane-related EA. A comprehensive literature search was performed to identify RCTs that compared dexmedetomidine with placebo about the reduction in the incidence of sevoflurane-related EA for children. Heterogeneity between studies was anticipated; therefore, random effects models were chosen to calculate the pooled risk ratio (RR) and 95% confidence interval (CI), and I 2 statistics were used to assess statistical heterogeneity. The funnel plot and Egger test were used to assess potential publication bias. Subgroup analysis was run to explore the possible effects of age, surgical procedure, regional block/local anesthetics, supplemental analgesic, propofol, N 2O, pre-medication and methodological quality on the incidence of EA using dexemedetomidine. Totally, 15 RCTs were included (518 patients received dexmedetomidine and 413 had placebo). Dexmedetomidine reduced the incidence of sevofurane-related EA (pooled RR = 0.351; 95% CI: ; P = 0.965; heterogeneity test, I 2 = 0.0%), and it also resulted in a lower incidence of severe EA (pooled RR = 0.119; 95% CI: ; P = 0.962; heterogeneity test, I 2 = 0.0%). All subgroup analyses for potential sources of heterogeneity showed a lower incidence of sevoflurane-related EA after dexmedetomidine administration. This meta-analysis demonstrated that dexemedetomidine was effective in reducing the incidence of sevofluraneinduced EA in children as compared with placebo. Accepted for publication 30 January The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd Emergence agitation (EA) is a post-operative behavioral disturbance, first reported in early 1960s. 1 EA is a term used to describe nonpurposeful restlessness and agitation, thrashing, crying or moaning, disorientation and incoherence during early stage of recovering from general anesthesia in children, especially those receiving sevoflurane. 2 Generally, the incidence of EA following sevoflurane anesthesia varies from 10% to 66% and is more common in pre-school children. 3 5 EA is generally short lived without obvious aftereffect. However, it still accompanies with risk of self-injury, and requires extra nursing care, which may delay the discharge and increase the cost of medical care. Liang Sun and Rui Guo contributed equally to this work and should be considered co-first authors The high incidence of EA has led many investigators to provide prophylactic treatment, such as propofol, 6,7 opioid, 7 9 midazolam, 10,11 nonsteroidal anti-inflammatory drugs (NSAIDs), 12 nitrous oxide (N 2 O), 13 ketamine, 14 5-hydroxytryptamin 3 inhibitors, 15,16 magnesium 17,18 and regional block. 19,20 Another choice is to use dexmedetomidine, an α 2 -adrenoceptor (α 2 -AR) agonist with sedative, analgesic and anxiolytic actions, which has been widely used in pediatric and adult populations. 21 Dexmedetomidine was approved by the Food and Drug Administration in 1999 for the sedation of adults receiving mechanical ventilation in an intensive care setting, and it has been an authorized drug in Europe since September ; there have been numerous studies 14,23 36 evaluating dexmedetomidine s impact on EA. However, its 1

2 L. Sun et al. efficacy remains controversial. We therefore conducted a meta-analysis of randomized controlled trials (RCTs) to evaluate the effectiveness of dexmedetomidine on the incidence of sevofuranerelated EA in children. Materials and methods Search strategy We conducted a systematic review and metaanalysis according to the Quality of Reporting of Meta-analyses recommendations for improving the quality of meta-analyses. 37 A systematic search of Pubmed, Embase, ClinicalTrials.gov and the Cochrane Central Register of Controlled Trials was performed through July 2013 for relevant studies of association between dexmedetomidine and EA caused by sevoflurane anesthesia. Search strategies for subject headings and key words as follows: (1) dexmedetomidine or α 2 -AR agonists; (2) agitation, delirium or behavior; and (3) infant or children. No restrictions were imposed. A secondary reference review was conducted. Selection criteria The titles, abstracts and full texts were reviewed respectively. The eligible studies matched the following criteria: (1) an RCT in patients with sevoflurane anesthesia; (2) EA was analyzed in recruited participants; and (3) a comparison was conducted between dexmedetomidine and placebo. Data extraction We collected the following information from each study: first author, year of publication, patient age, surgery or inspection type, pre-medication (route), supplemental analgesic, N 2 O use, propofol use, regional block/local anesthetics, intervention and EA evaluation, all presented in Table 1. Independent investigators respectively calculated and tabulated the data with a standard extraction formula. The discrepancies were discussed by our research team and compared with the related references. Quality assessment We evaluated the methodological quality of included studies using the Cochrane Collaboration s tool for assessing risk of bias in randomized trials and resolved disagreements through discussion, as shown in Table The tool consists of seven items describing random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias. As for each item, we assigned a judgment of high, low or unclear risk of material bias. 39 Statistical analyses We pooled data across studies and calculated the risk ratio (RR) and associated 95% confidence interval (CI) for each dichotomous outcome. Heterogeneity across studies was tested using the I 2 statistic, which is a quantitative measure of inconsistency across studies. P < 0.10 and I 2 > 50% indicated significant heterogeneity and prevented reliance on a combination of the study results. Considering that heterogeneity between studies was to exist, the random effects models were chosen to generate pooled effects. Sensitivity analysis was conducted to explore possible explanations for potential sources of heterogeneity. Because we were aware that age, surgery or inspection type, pre-medication, supplemental analgesic, propofol use, N 2 O, regional block/local anesthetics and methodological quality may be significant confounding factors on the incidence of EA, we classified associated sub and analyzed them separately. In the case of studies with more than one intervention group, each group was considered as a study in the meta-analysis and compared with placebo group. The possibility of publication bias was assessed by using the visual inspection of Begg funnel plots (if the number of included studies was more than 10) and Egger test. 40 All analyses were performed using STATA version 11.2 (Stata Corp. LP, College Station, TX, USA). A P-value of less than 0.05 was considered statistically significant. Results Literature search and study characteristics We initially retrieved 156 literatures from PubMed, Embase databases, ClinicalTrials.gov and the Cochrane Central Register of Controlled Trials. A majority of references were excluded according to inclusion criteria. Finally, 15 independent studies were included in our meta-analysis. 14,23 36 The detailed steps of our literature search and the study selection are described in Fig. 1. The characteristics of the 15 RCTs are presented in Table 1. As for the methodological quality, two studies 26,32 were of low risk of bias, and the other 13 studies 14,23 25,27 31,33 36 were of moderate risk of bias. The meta-analysis included 15 articles (518 2

3 Dexmedetomidine on the incidence of emergence agitation Table 1 Characteristics of included studies. Study (author, country) Patient age (years) Sample size Type of surgery or inspection Pre-medication (route) Supplemental analgesia N2O Propofol Regional block Intervention Remarks Gupta et al. 23 (India) He et al. 24 (China) Chen et al. 14 (China) El-Rahmawy et al. 25 (Egypt) Xu et al. 26 (China) Meng et al. 27 (China) Özcengiz et al. 28 (Turkey) Asaad et al. 29 (Egypt) Sato et al. 30 (Japan) Erdil et al. 32 (Turkey) Saadawy et al. 31 (Egypt) Isik et al. 33 (Turkey) Guler et al. 35 (Turkey) Shukry et al. 34 (United States) Ibacache et al. 36 (Chile) Corrective surgery for SD Elective minor surface surgery 0.2 mg glycopyrrolate (intramuscular) Fentanyl 0.5 μg/kg Both No No No No Regional or local anesthetic block No No Dex at 1 μg/kg bolus over 10 min followed by 0.5 μg/kg/h as maintenance soon vs. volume-matched saline IV after the patient was positioned prone and discontinued at the beginning of skin closure Dex 0.5 μg/kg vs. Dex 1 μg/kg vs. saline IV after LMA insertion for 10 min Strabismus surgery No No No No Topical anesthesia Dex 1 μg/kg plus a 1 μg/kg/h infusion vs. normal saline 0.25 ml/kg plus a 0.25 ml/kg/h infusion IV intraoperatively and discontinued at the end of surgery Femur fracture surgery 0.5 mg/kg midazolam (oral) Fentanyl 0.5 μg/kg Vitreoretinal surgery No Remifentanil 0.5 μg/kg/min Tonsillectomy 40 μg/kg midazolam (intravenous) Esophageal dilatation procedures Elective surgical procedures (30 60 min) Same-day surgery or overnight stay surgery mg/kg paracetamol (oral) Adenoidectomy 40 mg/kg paracetamol (rectally) Unilateral inguinal hernia repair/orchidopexy Cranial MRI scanning Remifentanil μg/kg/min No Both No No Fascia iliaca compartment block Dex 2 μg/kg + 1 mg/kg 0.25% bupivacaine vs.1 mg/kg 0.25% bupivacaine by fascia iliaca injection No Yes No Dex 0.5 μg/kg given over 10 min vs. normal saline given IV over 10 min after administering atropine (before induction) No No No Dex at an initial loading dose of 0.5 μg/kg over 10 min followed by infusion of 0.2 μg/kg/h vs. an loading dose of 1 μg/kg followed by infusion of 0.4 μg/kg/h vs. lactated Ringer s over the surgery No No Dex 2.5 μg/kg vs. saline orally before induction of anesthesia No No No No Caudal block Dex 0.15 μg/kg vs. saline IV over 10 min just after intubation No Acetaminophen or diclofenac No Fentanyl 1 μg/kg Adenotonsillectomy Acetaminophen 15 mg/kg (oral) Elective outpatient surgical procedures Superficial lower abdominal and genital surgery No Both No No Local anesthetic infiltration Both No No Both No Both Dex 0.3 μg/kg vs. saline IV over 10 min after induction of anesthesia No No Dex 0.5 μg/kg vs. saline IV over 10 min after tracheal intubation Yes Caudal block Dex 1 μg/kg + 1 mg/kg 0.25% bupivacaine vs. 1 mg/kg 0.25% bupivacaine (caudal) No No Dex 1 μg/kg vs. saline IV over 2 min after induction of anesthesia No No Dex 0.5 μg/kg vs. saline IV 5 min before the end of surgery No Fentanyl None No No Dex 0.2 μg/kg/h vs. saline IV after securing the airway and discontinued 15 min following the PACU admission No No Both No Caudal block Dex 0.15 μg/kg vs. Dex 0.3 μg/kg vs. saline IV in 10 min after induction Only severe EA was compared (ACS 4 or 5) Behavior scores > 3 were considered as EA PEAD scale 10 were considered as EA PEAD scale 15 were considered as severe EA ED were considered as EA EA scale > 2 were EA scale > 2 were EA scale > 2 were Behavior scores > 3 were considered as EA EA scale > 2 were EA scale 4 were Behavior scores > 3 were considered as EA Behavior scores > 3 considered as severe EA EA scale > 3 were ED were considered as EA were EA scale > 2 were ACS, agitation Cole score; Dex, dexmedetomidine; EA, emergence agitation; ED, emergence delirium; IV, intravenously; LMA, laryngeal mask airway; MRI, magnetic resonance imaging; PACU, post-anesthesia care unit; PAED, pediatric anesthesia emergence delirium; SD, spinal dysraphism. 3

4 L. Sun et al. Table 2 Individual randomized controlled trial (RCT) methodological quality. Free of other bias Free of selective reporting Incomplete outcome data addressed Blinding of outcome assessment Blinding of participants and personnel Allocation concealment Study (author, country) Random sequence generation Gupta et al. 23 (India) Yes? Yes Yes Yes Yes Yes He et al. 24 (China) Yes? Yes Yes Yes Yes Yes Chen et al. 14 (China) Yes? Yes Yes? Yes Yes El-Rahmawy et al. 25 (Egypt) Yes? Yes Yes Yes Yes Yes Xu et al. 26 (China) Yes Yes Yes Yes Yes Yes Yes Meng et al. 27 (China) Yes? Yes Yes Yes Yes? Özcengiz et al. 28 (Turkey) Yes? Yes Yes Yes Yes? Asaad et al. 29 (Egypt)??? Yes Yes Yes Yes Sato et al. 30 (Japan) Yes? Yes Yes Yes Yes? Erdil et al. 32 (Turkey) Yes Yes Yes Yes Yes Yes Yes Saadawy et al. 31 (Egypt) Yes? Yes Yes Yes Yes Yes Isik et al. 33 (Turkey) Yes? Yes Yes Yes Yes Yes Guler et al. 35 (Turkey) Yes? Yes Yes Yes Yes? Shukry et al. 34 (United States) Yes? Yes Yes? Yes? Ibacache et al. 36 (Chile) Yes? Yes Yes Yes Yes Yes Yes indicates low risk of bias ; No indicates high risk of bias ;? indicates unclear risk of bias. Fig. 1. Flowchart of meta-analysis. RCT, randomized controlled trial. patients in the dexmedetomidine group and 413 in the placebo group). Among these studies, three studies 14,23,33 reported the incidence of severe sevoflurane-related EA (EA-severe), and 13 studies 14,24 32,34 36 focused on EA-not classified (the severity of EA was not classified). Dexmedetomidine and the incidence of sevoflurane-related EA Dexmedetomidine was associated with a decreased incidence of sevoflurane-related EA both at the EA-not classified group and EA-severe group: pooled RR = (95% CI: ) and (95% CI: ), respectively, with no heterogeneity in both (P = 0.965, I 2 = 0.0%; P = 0.962, I 2 = 0.0%), as shown in Fig. 2. Subgroup analyses To explore the effects of known confounding factors on the effect of dexmedetomidine for preventing sevoflurane-related EA, we also performed subgroup analyses (EA-not classified group). The pooled analyses were restricted to following aspects: pre-school children (patient age 7 years old), adenotonsillectomy, pre-medication, supplemental analgesic, N 2 O use, propofol use, regional block/local anesthetics and methodological quality. 4

5 Dexmedetomidine on the incidence of emergence agitation Fig. 2. Forest plot of meta-analysis of dexmedetomidine prevention in emergence agitation (EA)-severe or EA-not classified (severity of EA was not differentiated). The square shown for each study (first author and year of publication) is the risk ratio (RR) for individual trials, and the corresponding horizontal line is the 95% confidence interval (CI). The diamond is the pooled RR with the 95% CI. Studies with more than one intervention group were numbered [author (1), year of publication and author (2), year of publication]. Dex, dexmedetomidine. These results strengthened the evidence for a lower incidence of sevoflueane-related EA by administering dexmedetomidine, as shown in Table 3. Publication bias Visual inspection of the funnel plot did not indicate any evidence of obvious substantial asymmetry. The Egger linear regression test also did not support the presence of publication bias, presented in Fig. 3 (Egger s test, P = 0.303). Discussion Our meta-analysis of 15 RCTs confirmed that dexmedetomidine had a prophylactic effect in preventing sevoflurane-induced EA as compared with placebo, and it also reduced the incidence of severe EA caused by sevoflurane anesthesia (Fig. 2). This meta-analysis allowed the inclusion of 931 patients, with 518 patients allocated to dexmedetomidine therapy and 413 patients to the placebo group. This relatively large sample size made it possible to reveal the significant difference between dexmedetomidine intervention and placebo. Furthermore, because of our comprehensive search strategy, it is unlikely that any important trials have been omitted. We did not detect any explicit publication bias (Fig. 3). The results of subgroup analyses (Table 3), no heterogeneity (Fig. 2) and publication bias (Fig. 3) of pooled data strengthened our inference. EA attributes to numerous factors, including patient temperament, pre-existed anxiety, pain, age, type of surgical procedures, rapid awakening and anesthetic technique. 41 Not a single reason can 5

6 L. Sun et al. Table 3 Subgroup analsis for the potential sources of significant heterogeneity. Age Subgroup Number of patients 7 years (pre-school children) References Pooled RR (95% CI) (fixed/random effects model) P-value (fixed/random effects model) Heterogeneity: I 2 ; P-value (fixed/random effects model) ,24 26,31,32, ( )/0.278 ( ) < 0.001/< %; 0.943/0.0%; Type of procedure Adenotonsillectomy ,32, ( )/0.366 ( ) < 0.001/< %; 0.726/0.0%; Nonadenotonsillectomy ,24,26,28 31, ( )/0.347 ( ) < 0.001/< %; 0.909/0.0%; Pre-medication Yes ,27,28,32, ( )/0.327 ( ) < 0.001/< %; 0.830/0.0%; No ,24,26,29 31,34, ( )/0.372 ( ) < 0.001/< %; 0.874/0.0%; Regional block/local Yes ,24,25,29 31, ( )/0.351 ( ) < 0.001/< %; 0.820/0.0%; anesthetics No ,32,34, ( )/0.352 ( ) < 0.001/< %; 0.892/0.0%; Supplemental analgesic Yes ,30,31, ( )/0.379 ( ) < 0.001/< %; 0.715/0.0%; No ,24,28,29,32,35, ( )/0.328 ( ) < 0.001/< %; 0.946/0.0%; N2O Yes ,31,32,35, ( )/0.321 ( ) < 0.001/< %; 0.956/0.0%; No ,24 27,29,30, ( )/0.367 ( ) < 0.001/< %; 0.787/0.0%; Propofol Yes , ( )/0.227 ( ) < 0.001/< %; 0.968/0.0%; No ,24,25,27 30,32, ( )/0.350 ( ) < 0.001/< %; 0.949/0.0%; Methodological quality Low risk of bias , ( )/0.303 ( ) < 0.001/< %; 0.553/0.0%; Moderate risk of bias ,24,25,27 31, ( )/0.358 ( ) < 0.001/< %; 0.939/0.0%; CI, confidence interval; RR, risk ratio. 6

7 Dexmedetomidine on the incidence of emergence agitation Fig. 3. Funnel plot of the studies included in the meta-analysis of dexmedetomidine prevention in emergence agitation (EA)-not classified (Egger s test, P = 0.303). RR, risk ratio. explain the etiology of EA. It has been reported that surgeries of head and neck (tonsils, thyroid, middle ear and eye) and short duration surgeries like circumcision have a higher incidence of EA. 1 It is widely believed that relieving pain decreases the incidence of EA associated with anesthetic agents such as sevoflurane. Several studies demonstrated that regional block, 19,20 opioids 7 9 and NSAIDs 12 decrease the incidence of EA. However, EA often occurs even after adequate pain treatment or after procedures that are not associated with pain. 3 The reasons for the higher incidence of EA after sevoflurane anesthesia remain largely unknown. In particular situations, sevoflurane may cause an irritating side effect on the central nervous system, as epileptiform seizure activity in nonepileptic patients has been observed during sevoflurane anesthesia. 42,43 However, desflurane, which also has a high incidence of EA, 44 has not been shown to be epileptogenic in humans. Furthermore, until now, there were only some case reports or reviews discussing on this phenomenon, 45,46 and there was no evidence indicating that epileptiform electroencephalogram changes have been seen in same patients who experience EA. Therefore, the epileptogenicity of sevoflurane is unlikely to be a major reason for the higher incidence of EA in children. Because volatile anesthetics with low blood/ gas partition coefficient generally cause a higher incidence of EA, rapid awakening has been posited as a cause for this phenomenon. 41 However, rapid awakening after propofol has not been associated with EA. 47 We need to further study on the mechanisms of EA in the future. Dexmedetomidine, a potent and highly selective α 2 -AR agonist, is widely used as an anesthetic adjuvant because of its sedative property. 48 It is used widely off label in adult and pediatric patients because of its potential benefits such as anestheticsparing, sympatholytic, hemodynamic-stabilizing and analgesic properties, and lack of adverse respiratory effects. 21,25,49 A meta-analysis has shown that analgesics alone are unlikely to be associated with a low incidence of EA, and sedation during emergence may also decrease the incidence of EA. 5 Therefore, potentiation of both analgesia and sedation during emergence may be important in reducing the incidence of EA following sevoflurane anesthesia. 14 This meta-analysis demonstrates that dexmedetomidine has the effect of preventing sevoflurane-induced EA, and we hypothesize that it mainly relies on the sedative, anxiolytic and analgesic characteristics of dexmedetomidine. Interestingly, dexmedetomidine may have neuroprotective effects, and thus it can attenuate neurocognitive impairment (mainly delirium and agitation) following anesthesia, and this could be another mechanism explaining dexmedetomidine s effect on preventing EA following sevoflurane anesthesia. 50 A previous meta-analysis showed that using α 2 -AR agonists (dexmedetomidine or clonidine) was an effective method of sevoflurane- and desfluranerelated EA prevention. 5 However, considering the following concerns, it is of great importance to conduct this meta-analysis focusing only on dexmedetomidine for preventing EA caused by sevoflurane: (1) the inconsistent incidence of EA between sevoflurane and desflurane 44 ; (2) pharmacological difference of dexmedetomidine and clonidine; and (3) the obvious publication bias. It is well known that many confounding factors may affect the initiation of sevoflurane-related EA (patient age, surgery type, pre-medication, supplemental analgesic, N 2 O use, propofol use, regional block/local anesthetics and methodological quality), 41,51,52 subgroup analyses were conducted accordingly and the pooled data strengthened the evidence that dexmedetomidine had its beneficial effect on preventing sevoflurane-induced EA (Table 3). There are some limitations in our meta-analysis. Firstly, the number of patients in some included studies was limited. Secondly, whereas only 2 of 15 included trials were designed with low risk of bias, other 13 studies were of moderate risk of bias. Thirdly, we did not evaluate the safety of administrating dexmedetomidine because it may cause deleterious cardiovascular effects. Finally, we did not 7

8 L. Sun et al. investigate possible effect of dexmedetomidine on the incidence of sevoflurane-related EA because of its dosing and regimens. In summary, meta-analysis of the currently available RCTs illustrated the effectiveness of dexmedetomidine for the prevention of the incidence of sevoflurane-related EA, as well as severe EA. Acknowledgements We acknowledge Guang Hao, National Center for Cardiovascular Disease Control and Research, Fuwai Hospital, National Heart Center, Chinese Academy of Medical Sciences and Peking Union Medical College for assistance with the statistical analysis. Authors contribution: Liang Sun: study design, data collection and manuscript write up. Rui Guo: study design and data analysis. Li Sun: review of draft, assistance and editing of draft. Conflict of interest: None. Funding: Supported by the Post-graduate Research Institute of Peking Union Medical College (grant no ). References 1. Eckenhoff JE, Kneale DH, Dripps RD. 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9 Dexmedetomidine on the incidence of emergence agitation 29. Asaad OM, Hafez M, Mohamed MY, El-mahgoup SS. Comparative study between prophylactic single dose of fentanyl and dexmedetomidine in the management of agitation after sevoflurane anesthesia in children. Egypt J Anaesth 2011; 27: Sato M, Shirakami G, Tazuke-Nishimura M, Matsuura S, Tanimoto K, Fukuda K. Effect of single-dose dexmedetomidine on emergence agitation and recovery profiles after sevoflurane anesthesia in pediatric ambulatory surgery. J Anesth 2010; 24: Saadawy I, Boker A, Elshahawy MA, Almazrooa A, Melibary S, Abdellatif AA, Afifi W. Effect of dexmedetomidine on the characteristics of bupivacaine in a caudal block in pediatrics. Acta Anaesthesiol Scand 2009; 53: Erdil F, Demirbilek S, Begec Z, Ozturk E, Ulger MH, Ersoy MO. The effects of dexmedetomidine and fentanyl on emergence characteristics after adenoidectomy in children. Anaesth Intensive Care 2009; 37: Isik B, Arslan M, Tunga AD, Kurtipek O. Dexmedetomidine decreases emergence agitation in pediatric patients after sevoflurane anesthesia without surgery. Paediatr Anaesth 2006; 16: Shukry M, Clyde MC, Kalarickal PL, Ramadhyani U. Does dexmedetomidine prevent emergence delirium in children after sevoflurane-based general anesthesia? Paediatr Anaesth 2005; 15: Guler G, Akin A, Tosun Z, Ors S, Esmaoglu A, Boyaci A. Single-dose dexmedetomidine reduces agitation and provides smooth extubation after pediatric adenotonsillectomy. Paediatr Anaesth 2005; 15: Ibacache ME, Munoz HR, Brandes V, Morales AL. Singledose dexmedetomidine reduces agitation after sevoflurane anesthesia in children. Anesth Analg 2004; 98: Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet 1999; 354: Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA. The Cochrane Collaboration s tool for assessing risk of bias in randomised trials. BMJ 2011; 343: d Higgins JPT, Altman DG. Assessing risk of bias in included studies. In: Higgins JPT, Green S eds. Cochrane handbook for systematic reviews of interventions. Oxford: Wiley, 2008: Egger M, Davey SG, Schneider M, Minder C. Bias in metaanalysis detected by a simple, graphical test. BMJ 1997; 315: Kuratani N, Oi Y. Greater incidence of emergence agitation in children after sevoflurane anesthesia as compared with halothane: a meta-analysis of randomized controlled trials. Anesthesiology 2008; 109: Komatsu H, Taie S, Endo S, Fukuda K, Ueki M, Nogaya J, Ogli K. Electrical seizures during sevoflurane anesthesia in two pediatric patients with epilepsy. Anesthesiology 1994; 81: Woodforth IJ, Hicks RG, Crawford MR, Stephen JP, Burke DJ. Electroencephalographic evidence of seizure activity under deep sevoflurane anesthesia in a nonepileptic patient. Anesthesiology 1997; 87: Welborn LG, Hannallah RS, Norden JM, Ruttimann UE, Callan CM. Comparison of emergence and recovery characteristics of sevoflurane, desflurane, and halothane in pediatric ambulatory patients. Anesth Analg 1996; 83: Pilge S, Jordan D, Kochs EF, Schneider G. Sevofluraneinduced epileptiform electroencephalographic activity and generalized tonic-clonic seizures in a volunteer study. Anesthesiology 2013; 119: Constant I, Seeman R, Murat I. Sevoflurane and epileptiform EEG changes. Paediatr Anaesth 2005; 15: Cohen IT, Finkel JC, Hannallah RS, Hummer KA, Patel KM. Rapid emergence does not explain agitation following sevoflurane anaesthesia in infants and children: a comparison with propofol. Paediatr Anaesth 2003; 13: Farag E, Argalious M, Abd-Elsayed A, Ebrahim Z, Doyle DJ. The use of dexmedetomidine in anesthesia and intensive care: a review. Curr Pharm Des 2012; 18: Abdallah FW, Abrishami A, Brull R. The facilitatory effects of intravenous dexmedetomidine on the duration of spinal anesthesia: a systematic review and meta-analysis. Anesth Analg 2013; 117: Sanders RD, Xu J, Shu Y, Januszewski A, Halder S, Fidalgo A, Sun P, Hossain M, Ma D, Maze M. Dexmedetomidine attenuates isoflurane-induced neurocognitive impairment in neonatal rats. Anesthesiology 2009; 110: Na HS, Song IA, Hwang JW, Do SH, Oh AY. Emergence agitation in children undergoing adenotonsillectomy: a comparison of sevoflurane versus sevoflurane-remifentanil administration. Acta Anaesthesiol Scand 2013; 57: Mizuno J, Nakata Y, Morita S, Arita H, Hanaoka K. Predisposing factors and prevention of emergence agitation. Masui 2011; 60: Address: Li Sun Department of Anesthesiology, Cancer Institute and Hospital National Cancer Center, Chinese Academy of Medical Sciences Peking Union Medical College No. 22 Panjiayuannanli Road, Chaoyang District Beijing China heimingway1984@163.com 9

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