Rev Bras Anestesiol.

2017;67(2):193---198

REVISTA
BRASILEIRA DE
ANESTESIOLOGIA Publicação Oficial da Sociedade Brasileira de Anestesiologia
www.sba.com.br

REVIEW ARTICLE

Effect of dexmedetomidine in children undergoing

general anesthesia with sevoflurane: a meta-analysis
Marco Aurélio Soares Amorim a,∗ , Catia Sousa Govêia b,c,d , Edno Magalhães c,e,f ,
Luís Cláudio Araújo Ladeira g , Larissa Govêia Moreira h , Denismar Borges de Miranda i,j

a
Centro de Ensino e Treinamento José Quinan, Goiânia, GO, Brazil
b
Universidade de Brasília (UnB), Centro de Ensino e Treinamento, Brasília, DF, Brazil
c
Sociedade Brasileira de Anestesiologia, Rio de Janeiro, RJ, Brazil
d
Universidade de Brasília (UnB), Faculdade de Ciências Médicas, Brasília, DF, Brazil
e
Universidade de Brasília (UnB), Brasília, DF, Brazil
f
Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brazil
g
Hospital Universitário de Brasília, Brasília, DF, Brazil
h
Secretaria de Saúde do Distrito Federal, Brasília, DF, Brazil
i
Pontifícia Universidade Católica de Goiás (PUC-GO), Goiânia, GO, Brazil
j
Universidade Federal de Goiás (UFG), Instituto de Medicina Tropical e Saúde Pública, Goiânia, GO, Brazil

Received 18 December 2015; accepted 15 February 2016

Available online 25 November 2016

KEYWORDS Abstract
General anesthesia; Background and objectives: Sevoflurane is often used in pediatric anesthesia and is associated
Inhalational with high incidence of psychomotor agitation. In such cases, dexmedetomidine (DEX) has been
anesthetics; used, but its benefit and implications remain uncertain. We assessed the effects of DEX on
Dexmedetomidine; agitation in children undergoing general anesthesia with sevoflurane.
Psychomotor Method: Meta-analysis of randomized clinical and double-blind studies, with children under-
agitation; going elective procedures under general anesthesia with sevoflurane, using DEX or placebo.
Meta-analysis We sought articles in English in PubMed database using the following terms: Dexmedetomidine,
sevoflurane (Methyl Ethers/sevoflurante), and agitation (Psychomotor Agitation). Duplicate arti-
cles with children who received premedication and used active control were excluded. It was
adopted random effects model with DerSimonian---Laird testing and odds ratio (OR) calculation
for dichotomous variables, and standardized mean difference for continuous variables, with
their respective 95% confidence interval (CI).
Results: Of 146 studies identified, 10 were selected totaling 558 patients (282 in DEX group
and 276 controls). The use of DEX was considered a protective factor for psychomotor agitation
(OR = 0.17; 95% CI 0.13---0.23; p < 0.0001) and nausea and vomiting in PACU (OR = 0.49; 95% CI
0.35---0.68; p < 0.0001). Wake-up time and PACU discharge time were higher in the dexmedeto-
midine group. There was no difference between groups for extubation time and duration of
anesthesia.
∗ Corresponding author.
E-mail: marcomc18@hotmail.com (M.A. Amorim).

http://dx.doi.org/10.1016/j.bjane.2016.02.007
0104-0014/© 2016 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
194 M.A. Amorim et al.

Conclusion: Dexmedetomidine reduces psychomotor agitation during wake-up time of children

undergoing general anesthesia with sevoflurane.
© 2016 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).

PALAVRAS-CHAVE Efeito da dexmedetomidina em crianças submetidas à anestesia geral

Anestesia geral; com sevoflurano: uma metanálise
Anestésicos
Resumo
inalatórios;
Justificativa e objetivos: Sevoflurano é frequentemente usado em anestesia pediátrica e está
Dexmedetomidina;
associado à alta incidência de agitação psicomotora ao despertar. Nesses casos a dexmedeto-
Agitação
midina (dex) tem sido usada, porém permanecem incertos seus benefícios e suas implicações.
psicomotora;
Foram avaliados os efeitos da dex sobre a agitação no despertar de crianças submetidas à
Metanálise
anestesia geral com sevoflurano.
Método: Metanálise de ensaios clínicos randomizados e duplamente encobertos, com crianças
submetidas a procedimentos eletivos sob anestesia geral com sevoflurano, que usaram dex
ou placebo. Buscaram-se artigos em língua inglesa na base de dados Pubmed com termos
como Dexmedetomidine, sevoflurane (Methyl Ethers/sevoflurane) e agitation (Psychomotor
Agitation). Artigos duplicados, com crianças que receberam medicação pré-anestésica e que
usaram controle ativo foram excluídos. Adotou-se modelo de efeitos aleatórios com testes de
DerSimonian-Laird e cálculo de odds ratio (OR) para variáveis dicotômicas e diferença de média
padronizada para variáveis contínuas, com seus respectivos intervalos de confiança de 95% (IC).
Resultados: Dos 146 estudos identificados, 10 foram selecionados, com 558 pacientes (282 no
grupo dex e 276 controles). O uso da dex foi considerado fator de proteção para agitação psi-
comotora (OR = 0,17; 95% IC 0,13-0,23; p < 0,0001) e para náuseas e vômitos na SRPA (OR = 0,49;
95% IC 0,35-0,68; p < 0,0001). Tempo para despertar e para alta da SRPA foram maiores no grupo
dexmedetomidina. Não houve diferença entre os grupos para tempo de extubação e duração
da anestesia.
Conclusão: A dexmedetomidina reduz a agitação psicomotora no despertar de crianças sub-
metidas à anestesia geral com sevoflurano.
© 2016 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. Este é um
artigo Open Access sob uma licença CC BY-NC-ND (http://creativecommons.org/licenses/by-
nc-nd/4.0/).

Introduction of studies to improve perioperative care delivered to

children.
Sevoflurane is widely used in pediatric anesthesia for its Dexmedetomidine (Dex), dextrorotatory enantiomer of
pharmacological profile, which allows rapid inhalational medetomidine, is a highly selective ␣2 -adrenergic, with an
induction and awakening from anesthesia, low hepatotox- ␣2 :␣1 receptor ratio of 1,600:1, and important sedative and
icity and hemodynamic stability.1 However, the occurrence analgesic effects.5 Its sedative effect occurs through inter-
of agitation is a common phenomenon in children undergoing action with postsynaptic ␣2 -receptors in the locus coeruleus,
general anesthesia with sevoflurane.1 reduces noradrenalin release, and facilitates the action of
Emergence agitation in children was first described in inhibitory neurons, particularly gamma-aminobutyric acid
the early 1960s and is characterized by a dissociated system. The analgesic effect is promoted by the action of ␣2 -
state of consciousness in which the child becomes incon- receptors on dorsal horn and supraspinal cord and decreased
solable, irritable, uncooperative, and sometimes aggressive. release of substance P.6
Although temporary, it is an extremely distressing event for Dexmedetomidine has been used to reduce psychomotor
children, parents, and health professionals.2 agitation, although the actual benefits and implications in
Prevalence of agitation varies from 25% to 80% in anesthetic practice are still uncertain. Thus, the aim of this
the literature, depending on the definition and criteria meta-analysis was to evaluate the effects of dexmedetomi-
used by the authors.1,3 It is influenced by the technique dine on emergence agitation in children undergoing general
and anesthetic agents.4 Different drugs such as opioids, anesthesia with sevoflurane, including the incidence of post-
ketamine, benzodiazepines, and ␣2 -agonists,2 have been operative nausea and vomiting (PONV), emergence time,
used in the prevention and treatment of agitation, but extubation time, duration of anesthesia, and time of dis-
with varying success, which contributes to the development charge from the post-anesthesia recovery room (PACU).
Effect of dexmedetomidine in children undergoing general anesthesia with sevoflurane 195

Methods Results

This is a meta-analysis of clinical trials evaluating the Initially, 146 studies were identified (116 studies in Pubmed
use of dexmedetomidine to prevent emergence agi- and 30 manually searched), of which 10 were selected to
tation in children undergoing general anesthesia with compose this meta-analysis, as shown in Fig. 1.
sevoflurane. PRISMA guidelines7 were followed to per- The 10 studies included 558 patients, 282 in the inter-
form a systematic review and meta-analysis of random- vention group, and 276 in the control group (Table 1).
ized controlled trials. Articles in English (2000---2014) Three studies were conducted in Turkey,17---19 three studies
were selected in the Pubmed database with key- in China,21---23 and others studies in Chile,1 United States,16
words such as Dexmedetomidine, sevoflurane (Methyl Japan,20 and South Korea.24
Ethers/sevoflurante) and agitation (Psychomotor Agitation), Emergence agitation was assessed in 10 studies, and the
or its synonyms separated by AND/OR interlocutors with use of dexmedetomidine was considered a protection fac-
the following search strategy: (dexmedetomidine[MeSH tor (OR = 0.17; 95% CI 0.13---0.23; p < 0.0001), as shown in
Terms]) OR adrenergic alpha agonists[MeSH Terms]) Fig. 2. Surgery subgroup analysis showed no effect change
OR dexmedetomidine[Title/Abstract]) OR dexmedetomi- (urogenital1,24 with OR = 0.14; 95% 0.04---0.44; p = 0.0008;
dine) OR adrenergic alpha agonists) AND anesthet- ophthalmic21,23 with OR = 0.06; 95% CI 0.01---0.45; p = 0.0067,
ics, intravenous[MeSH Terms]) OR anesthetics, intra- ENT,17,19 with OR = 0.20; 95% CI 0.14---0.30; p < 0.0001).
venous[Title/Abstract]) AND (hypnotics and sedatives[MeSH The use of dexmedetomidine reduces the incidence
Terms])) OR (hypnotics and sedatives[Title/Abstract])) of PONV (Fig. 3), with OR = 0.49 (95% CI 0.35---0.68 and
AND sevoflurane) OR sevoflurane[Title/Abstract]) OR p < 0.0001).
sevoflurane[Supplementary Concept])) AND children[MeSH Emergence time was assessed in seven studies,17---19,21---23
Terms])) AND agitation, psychomotor[MeSH Terms]. In addi- (SMD = 1.78; 95% CI 1.12---2.44; p = 0.0001) and PACU dis-
tion to the search, we reviewed manually the references of charge in four studies1,16,18,23 (SMD = 8.54; 95% CI 6.62---10.44;
studies meeting the inclusion criteria, in order to identify p < 0.0001), higher in dexmedetomidine group.
original studies that were not previously found. There was no difference between groups regarding extu-
Randomized, double-blind, controlled studies, with bation time (SMD = 0.70; 95% CI 0.33---1.06; p = 0.0002),
children (under 10 years old) undergoing elective proce- assessed in eight studies,1,16---19,21---23 and duration of anes-
dures under general anesthesia with sevoflurane, using thesia (SMD = 3.19; 95% CI −0.79---7.14; p = 0.11), assessed in
dexmedetomidine or placebo were included. Duplicate arti- seven studies.1,16,18---20,23,24
cles or with children using premedication, involving only Based on the funnel plot analysis (Fig. 4), there is an
sedation and using active control were excluded. asymmetry with no small sample studies to the right of
Two independent researchers (MA and CG) conducted the summary effect, which supports a potential for publica-
a preliminary assessment of the titles/abstracts and data tion bias confirmed by Begg’s (p = 0.02) and Egger’s (p = 0.03)
extraction. Selected studies were read in full considering tests.
the inclusion and exclusion criteria. In case of disagree-
ment, a third researcher (LC) made the final evaluation. Discussion
Data regarding patient’s age, anesthesia (Dex dose), type
of procedure, and outcomes were recorded on a standard- This meta-analysis consists of 10 randomized controlled tri-
ized form developed by the authors. For this study, the als published between 2004 and 2014, which assessed the
following outcomes were considered: emergence agitation effect of dexmedetomidine on emergence agitation in chil-
(defined by each paper according to the scale used: Pae- dren undergoing general anesthesia with sevoflurane.
diatric Anaesthesia Emergence Delirium --- PAED,8 Watcha,9
and five-point scale)10 ; PONV (present or absent); and times
for extubation, emergence, PACU discharge, and duration of Search result
anesthesia (time interval described by articles in minutes). (n=146)
Sensitivity analysis was planned to explore sources of Excluded duplicates
heterogeneity between studies, when present. Statistical (n=20)
heterogeneity was calculated using the chi-square method
(2 ) and Higgins’ test (I2 ).11 Presence of heterogeneity Title and abstract
was considered at p < 0.05 and I2 ≥ 50%. Odds ratio (OR) reading (n=126)
with 95% confidence interval (CI) was used to quantify Excluded: not relevant
(n=104), adults (n=6) and
the statistical difference between groups for dichotomous active control (n=1)
variables and standardized mean difference (SMD) for con-
tinuous variables (time in minutes). After assessing the Eligible for full-text
reading (n=15)
quality and statistical heterogeneity of studies, we adopted
the random effects model using the DerSimonian---Laird12 Excluded for using
® premedication (n=5)
method and statistical analysis using the BioEstat 5.0
software.13 The assessment of potential for publication bias
Studies included in the
was made by visual analysis of funnel plots and Begg’s14 meta-analysis (n=10)
and Egger’s15 tests, with statistical significance level set
at 5%.
Figure 1 Diagram of study selection.
196 M.A. Amorim et al.

Table 1 Description of selected studies.

Study Year of publication Study details n Age Procedure type
1 2004 −1 1---10
Ibacache Dex 0.3 mcg kg 30 Inguinal hernia repair, orchidopexy
Saline solution 30 and circumcision
Shukry16 2005 Dex 0.2 mcg kg−1 23 1---10 Elective surgeries
Saline solution 23
Guler17 2005 Dex 0.5 mcg kg−1 30 3---7 Adenotonsillectomy
Saline solution 30
Isik18 2006 Dex 1 mcg kg−1 21 1---10 Magnetic resonance imaging
Saline solution 21
Erdil19 2009 Dex 0.5 mcg kg−1 30 2---7 Adenoidectomy with or without
Saline solution 30 myringotomy
Sato20 2010 Dex 0.3 mcg kg−1 39 1---9 Outpatient surgery
Saline solution 42
Lili21 2012 Dex 0.5 mcg kg−1 30 3---7 Vitrectomy
Saline solution 30
He22 2013 Dex 1 mcg kg−1 32 3---7 Small superficial surgeries
Saline solution 26
Chen23 2013 Dex 1 mcg kg−1 27 2---7 Strabismus
Saline solution 24
Kim24 2014 Dex 1 mcg kg−1 20 1---5 Hernioplasty or orchidopexy
Saline solution 20

Study Dex Control Weight (%) OR (95% CI)

(n/N) (n/N)
Ibacache 2004 3/30 11/30 9.39 0.22 (0.06-0.82)

Shukry 2005 6/23 14/23 11.21 0.24 (0.07-0.82)

Guler 2005 5/30 17/30 12.27 0.17 (0.05-0.53)

Isik 2006 1/21 10/21 4.82 0.08 (0.01-0.51)

Erdil 2009 5/30 14/30 12.32 0.24 (0.08-0.78)

Sato 2010 7/39 27/42 19.39 0.23 (0.09-0.57)

Lili 2012 3/30 13/30 9.54 0.16 (0.04-0.62)

He 2013 2/32 11/26 7.40 0.11 (0.02-0.49)

Chen 2013 3/27 11/24 8.87 0.17 (0.04-0.66)

Kim 2014 1/20 11/20 4.75 0.06 (0.01-0.41)

Total 38/282 139/276 100 0.17 (0.13-0.23)

0.01 0.1 0.2 0.5 1.0 2.0 5.0 10.0

Heterogeneity test; Favors Favors Overall effect test:
2
χ2 = 3.19; df=9 (p=0.96); I = 0% dexmedetomidine control Z=11.92 (p<0.0001)

Figure 2 Meta-analysis of dexmedetomidine effect on emergence agitation in children undergoing general anesthesia with
sevoflurane.

There was variation in dexmedetomidine dosage but with uncertain results.2 This meta-analysis presents
(0.2---1.0 mcg kg−1 ), as well as in administration technique. dexmedetomidine as a protective factor for emergence
One used continuous infusion of dexmedetomidine16 and agitation in children undergoing general anesthesia with
the others used it for a short period, ranging from 5 to sevoflurane, similar result already described by other
10 min. Regarding the time of administration, only one authors.2 Although the actual mechanism for this effect
study administered the drug at the end of the procedure17 remains unknown, it is believed that the analgesic and
and all others after induction of anesthesia, with similar sedative effects of dexmedetomidine contribute to this
results regarding emergence agitation, which confirms that phenomenon, as postoperative analgesic consumption was
there is no ideal time for dexmedetomidine administration. lower.2
The causes of emergence agitation following general Sevoflurane has been associated with high incidence
anesthesia are multifactorial; it may involve pain, anxiety, of emergence agitation in children undergoing general
and disorientation on rapid awakening.25 In an attempt to anesthesia,1,17 even without surgery.18 This fact is not yet
minimize this event, numerous drugs have been used, such fully understood. It has been hypothesized that sevoflu-
as opioids, ketamine, benzodiazepines, and ␣2 -agonists, rane can exert an irritating effect on the central nervous
Effect of dexmedetomidine in children undergoing general anesthesia with sevoflurane 197

Study Dex Control Weight (%) OR (95% CI)

(n/N) (n/N)

Guler 2005 11/30 16/30 40.34 0.52 (0.19-1.43)

Isik 2006 1/21 2/21 9.26 0.57 (0.07-4.74)

Erdil 2009 1/30 1/30 7.72 1.00 (0.10-10.18)

Sato 2010 3/42 3/39 17.31 0.92 (0.20-4.35)

Chen 2013 4/27 11/24 25.37 0.22 (0.06-0.81)

Total 20/150 33/144 100 0.49 (0.35-0.68)

0.01 0.1 0.2 0.5 1.0 2.0 5.0 10.0

Heterogeneity test; Favors Favors Overall effect test:
χ2=2.46; df=4 (p=0.65); I2=0% dexmedetomidine control Z=4.21 (p<0.0001)

Figure 3 Meta-analysis of dexmedetomidine effect on nausea and vomiting incidence in children undergoing general anesthesia
with sevoflurane.

The meta-analysis quality depends on the selection of rel-

0.280
Standard error

evant studies, heterogeneity, and detection bias.2 Despite

the different strategies used in this study to minimize possi-
ble biases, it may not be discarded. A search was conducted
1.120

in an important database and selected works were submitted

–4.00 –2.00 0.00 to two independent evaluators. Double-blind randomized
Log odds ratio clinical trials were included. The use of random effects
model is justified by the observation of clinical hetero-
Figure 4 Funnel plot of dexmedetomidine effect on emer- geneity identified in studies: different doses and times of
gence agitation in children undergoing general anesthesia with dexmedetomidine administration, procedures, and emer-
sevoflurane. gence assessment scales. Another limitation of this study
refers to the use of only one database for search, which
system.26 The decrease in emergence agitation provided by confirms the occurrence of publication bias, as identified in
dexmedetomidine may also be justified by the lower con- this meta-analysis.
sumption of sevoflurane.27 Due to its good hemodynamic stability, dexmedetomidine
PONV are common complications in children undergo- has been used as an adjuvant anesthetic and may be used
ing general anesthesia with sevoflurane.18 Studies have as pre-anesthetic medication, during anesthesia, or even
shown conflicting results on the effect of dexmedetomi- postoperatively, and provides sedation and analgesia5 with-
dine for this complication.20,23 In the present study, the out respiratory depression.17,18,20,30 Its use entails benefits,
use of dexmedetomidine appeared as a protective fac- such as lower consumption of inhalational anesthetics,21 less
tor for the incidence of nausea and vomiting. The use of need for postoperative analgesic and opioid drugs,2,28 and
dexmedetomidine has been associated with reduced need lower oxygen consumption.31
for postoperative opioid analgesics, which implies a lower In conclusion, this meta-analysis highlights the use of
incidence of nausea and vomiting induced by opioid.28 More- dexmedetomidine in reducing emergence agitation in chil-
over, dexmedetomidine has been used successfully in the dren undergoing general anesthesia with sevoflurane.
treatment of cyclical vomiting syndrome in children, by yet-
unknown mechanisms.29
In this study, the times of emergence and PACU discharge Conflicts of interest
were considered statistically higher in dexmedetomidine
group, justified by its sedative effect,5 but without clinical The authors declare no conflicts of interest.
repercussions.17---19,22
Regarding the time of extubation and duration of anes-
thesia, this meta-analysis found no statistically significant References
difference between dexmedetomidine and control groups.
This result disagrees with some individual studies, by find- 1. Ibacache ME, Muñoz HR, Brandes V, et al. Single-dose
dexmedetomidine reduces agitation after sevoflurane anesthe-
ing a longer extubation time and duration of anesthesia in
sia in children. Anesth Analg. 2004;98:60---3.
dexmedetomidine group.17,18 2. Pickard A, Davies P, Birnie K, et al. Systematic review
It is noteworthy that the studies used different scales and meta-analysis of the intraoperative ␣2 -adrenergic ago-
to assess agitation. One study23 used the PAED scale8 , nists on postoperative behaviour in children. Br J Anaesth.
four studies1,16,21,24 used the Watcha scale,9 and five 2014;112:982---90.
studies17---20,22 used the five-point scale.10 Although only the 3. Cravero J, Surgenor S, Whalen K. Emergence agitation in pae-
PAED scale has been validated,8 the others are widely used diatric patients after sevoflurano anaesthesia and no surgery: a
in clinical researches. comparison with halothane. Paediatr Anaesth. 2000;10:419---24.
198 M.A. Amorim et al.

4. Dahmani S, Stany I, Brasher C, et al. Pharmacological prevention 19. Erdil F, Demirbilek S, Begec Z, et al. The effects of
of sevoflurano and desflurane related emergence agitation in dexmedetomidine and fentanyl on emergence characteris-
children: a meta-analysis of published studies. Br J Anaesth. tics after adenoidectomy in children. Anaesth Intensive Care.
2010;104:216---23. 2009;37:571---6.
5. Villela NR, Nascimento Junior P. Uso de dexmedetomidina em 20. Sato M, Shirakami G, Tazuke-Nishimura M, et al. Effect of single-
anestesiologia. Rev Bras Anestesiol. 2003;53:97---113. dose dexmedetomidine on emergence agitation and recovery
6. Gertler R, Brown HC, Mitchell DH, et al. Dexmedetomidine: profiles after sevoflurane anesthesia in pediatric ambulatory
a novel sedative analgesic agent. Proc (Bayl Univ Med Cent). surgery. J Anesth. 2010;24:675---82.
2001;14:13---21. 21. Lili X, Jianjun S, Haiyan Z. The application of dexmedeto-
7. Moher D, Liberati A, Tetziaff J, et al. Preferred reporting items midine in children undergoing vitreoretinal surgery. J Anesth.
for systematic reviews and meta-analyses: the PRISMA state- 2012;26:556---61.
ment. Ann Intern Med. 2009;151:264---9. 22. He L, Wang X, Zheng S, et al. Effects of dexmedetomidine
8. Sikich N, Lerman J. Development and psychometric evaluation infusion on laryngeal mask airway removal and postoperative
of the pediatric anesthesia emergence delirium scale. Anesthe- recovery in children anaesthetised with sevoflurane. Anaesth
siology. 2004;100:1138---45. Intensive Care. 2013;41:328---33.
9. Watcha MF, Ramirez-Ruiz M, White PF, et al. Periopera- 23. Chen JY, Jia JE, Liu TJ, et al. Comparison of the effects
tive effects of oral ketorolac and acetaminophen in children of dexmedetomidine, ketamine, and placebo on emergence
undergoing bilateral myringotomy. Can J Anaesth. 1992;39: agitation after strabismus surgery in children. Can J Anesth.
649---54. 2013;60:385---92.
10. Cole JW, Murray DJ, McAlister JD, et al. Emergence behaviour 24. Kim NY, Kim SY, Yoon HJ, et al. Effect od dexmedetomidine on
in children: defining the incidence of excitement and agitation sevoflurane requirements and emergence agitation in children
following anaesthesia. Paediatr Anaesth. 2002;12:442---7. undergoing ambulatory surgery. Yonsei Med J. 2014;55:209---15.
11. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta- 25. Vlajkovic GP, Sindjelic RP. Emergence delirium in children: many
analysis. Stat Med. 2002;15:1539---58. questions, few answers. Anesth Analg. 2007;104:84---91.
12. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control 26. Woodforth IJ, Hicks RG, Crawford MR, et al. Electroen-
Clin Trials. 1986;7:177---88. cephalographic evidence of seizure activity under deep
13. Ayres M, Ayres Junior M, Ayres DL, et al. BioEstat: aplicação sevoflurane anesthesia in a nonepileptic patient. Anesthesiol-
estatística nas áreas das ciências biomédicas. 4rd ed. Belém; ogy. 1997;87:1579---82.
2007. 27. Na HS, Song IA, Hwang JW, et al. Emergence agitation in children
14. Begg CB, Mazumdar M. Operating characteristics of a rank corre- undergoing adenotonsillectomy: a comparison of sevoflurane
lation test for publication bias. Biometrics. 1994;50:1088---101. vs. sevoflurane-remifentanil administration. Acta Anaesthesiol
15. Egger M, Davey Smith G, Schneider M, et al. Bias in Scand. 2013;57:100---5.
meta-analysis detected by a simple, graphical test. BMJ. 28. Lin TF, Yeh YC, Lin FS, et al. Effect of combining dexmedetomi-
1997;315:629---34. dine and morphine for intravenous patient-controlled analgesia.
16. Shukry M, Clyde MC, Kalarickal PL, et al. Does dexmedetomidine Br J Anaesth. 2009;102:117---22.
prevent emergence delirium in children after sevoflurane-based 29. Tobias JD. Dexmedetomidine in the treatment of cyclic vomiting
general anesthesia? Paediatr Anaesth. 2005;15:1098---104. syndrome. Paediatr Anaesth. 2005;15:709---10.
17. Guler G, Akin A, Tosun Z, et al. Single-dose dexmedeto- 30. Mason KP, Lerman J. Dexmedetomidine in children: cur-
midine reduces agitation and provides smooth extubation rent knowledge and future applications. Anesth Analg.
after pediatric adenotonsillectomy. Paediatr Anaesth. 2005;15: 2011;113:1129---42.
762---6. 31. Taittonen MT, Kirvela OA, Aantaa R, et al. Effect of cloni-
18. Isik B, Arslan M, Dogan A, et al. Dexmedetomidine decreases dine and dexmedetomidine premedication on perioperative
emergence agitation in pediatric patients after sevoflurane oxygen consumption and haemodynamic state. Br J Anaesth.
anesthesia without surgery. Paediatr Anaesth. 2006;16:748---53. 1997;78:400---6.