Background
Sevoflurane is an inhaled volatile anaesthetic that is widely used in paediatric anaesthetic practice. Since its introduction, postoperative behavioural disturbance known as emergence agitation (EA) or emergence delirium (ED) has been recognized as a problem that may occur during recovery from sevoflurane anaesthesia. For the purpose of this systematic review, EA has been used to describe this clinical entity. A child with EA may be restless, may cause self-injury or may disrupt the dressing, surgical site or indwelling devices, leading to the potential for parents to be dissatisfied with their child's anaesthetic. To prevent such outcomes, the child may require pharmacological or physical restraint. Sevoflurane may be a major contributing factor in the development of EA. Therefore, an evidence-based understanding of the risk/benefit profile regarding sevoflurane compared with other general anaesthetic agents and adjuncts would facilitate its rational and optimal use.

Objectives
To compare sevoflurane with other general anaesthetic (GA) agents, with or without pharmacological or non-pharmacological adjuncts, with regard to risk of EA in children during emergence from anaesthesia. The primary outcome was risk of EA; secondary outcome was agitation score.

Search methods
We searched the following databases from the date of inception to 19 January 2013: CENTRAL, Ovid MEDLINE, Ovid EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCOhost), Evidence-Based Medicine Reviews (EBMR) and the Web of Science, as well as the reference lists of other relevant articles and online trial registers.

Selection criteria
We included all randomized (or quasi-randomized) controlled trials investigating children < 18 years of age presenting for general anaesthesia with or without surgical intervention. We included any study in which a sevoflurane anaesthetic was compared with any other GA, and any study in which researchers investigated adjuncts (pharmacological or non-pharmacological) to sevoflurane anaesthesia compared with no adjunct or placebo.

Data collection and analysis
Two review authors independently searched the databases, decided on inclusion eligibility of publications, ascertained study quality and extracted data. They then resolved differences between their results by discussion. Data were entered into RevMan 5.2 for analyses and presentation. Comparisons of the risk of EA were presented as risk ratios (RRs) with 95% confidence intervals (CIs). Sevoflurane is treated as the control anaesthesia in this review. Sensitivity analyses were performed as appropriate, to exclude studies with a high risk of bias and to investigate heterogeneity.

Main results
We included 158 studies involving 14,045 children. Interventions to prevent EA fell into two broad groups. First, alternative GA compared with sevoflurane anaesthesia (69 studies), and second, use of an adjunct with sevoflurane anaesthesia versus sevoflurane without an adjunct (100 studies). The overall risk of bias in included studies was low. The overall Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE) assessment of the quality of the evidence was moderate to high. A wide range of EA scales were used, as were different levels of cutoff, to determine the presence or absence of EA. Some studies involved children receiving potentially inadequate or no analgesia intraoperatively during painful procedures.

Halothane (RR 0.51, 95% CI 0.41 to 0.63, 3534 participants, high quality of evidence) and propofol anaesthesia were associated with a lower risk of EA than sevoflurane anaesthesia. Propofol was effective when used throughout anaesthesia (RR 0.35, 95% CI 0.25 to 0.51, 1098 participants, high quality of evidence) and when used only during the maintenance phase of anaesthesia after sevoflurane induction (RR 0.59, 95% CI 0.46 to 0.76, 738 participants, high quality of evidence). No clear evidence was found of an effect on risk of EA of desflurane (RR 1.46, 95% CI 0.92 to 2.31, 408 participants, moderate quality of evidence) or isoflurane (RR 0.76, 95% CI 0.46 to 1.23, 379 participants, moderate quality of evidence) versus sevoflurane.

Compared with no adjunct, effective adjuncts for reducing the risk of EA during sevoflurane anaesthesia included dexmedetomidine (RR 0.37, 95% CI 0.29 to 0.47, 851 participants, high quality of evidence), clonidine (RR 0.45, 95% CI 0.31 to 0.66, 739 participants, high quality of evidence), opioids, in particular fentanyl (RR 0.37, 95% CI 0.27 to 0.50, 1247 participants, high quality of evidence) and a bolus of propofol (RR 0.58, 95% CI 0.38 to 0.89, 394 participants, moderate quality of evidence), ketamine (RR 0.30, 95% CI 0.13 to 0.69, 231 participants, moderate quality of evidence) or midazolam (RR 0.57, 95% CI 0.41 to 0.81, 116 participants, moderate quality of evidence) at the end of anaesthesia. Midazolam oral premedication (RR 0.81, 95% CI 0.59 to 1.12, 370 participants, moderate quality of evidence) and parental presence at emergence (RR 0.91, 95% CI 0.51 to 1.60, 180 participants, moderate quality of evidence) did not reduce the risk of EA.

One or more factors designated as high risk of bias were noted in less than 10% of the included studies. Sensitivity analyses of these studies showed no clinically relevant changes in the risk of EA. Heterogeneity was significant with respect to these comparisons: halothane; clonidine; fentanyl; midazolam premedication; propofol 1 mg/kg bolus at end; and ketamine 0.25 mg/kg bolus at end of anaesthesia. With investigation of heterogeneity, the only clinically relevant changes to findings were seen in the context of potential pain, namely, the setting of adenoidectomy/adenotonsillectomy (propofol bolus; midazolam premedication) and the absence of a regional block (clonidine).

Authors' conclusions
Propofol, halothane, alpha-2 agonists (dexmedetomidine, clonidine), opioids (e.g. fentanyl) and ketamine reduce the risk of EA compared with sevoflurane anaesthesia, whereas no clear evidence shows an effect for desflurane, isoflurane, midazolam premedication and parental presence at emergence. Therefore anaesthetists can consider several effective strategies to reduce the risk of EA in their clinical practice. Future studies should ensure adequate analgesia in the control group, for which pain may be a contributing or confounding factor in the diagnosis of EA. Regardless of the EA scale used, it would be helpful for study authors to report the risk of EA, so that this might be included in future meta-analyses. Researchers should also consider combining effective interventions as a multi-modal approach to further reduce the risk of EA.

Effects of sevoflurane versus other general anaesthesia on emergence agitation in children

Emergence delirium (ED) is a complex of perceptual disturbances and psychomotor agitation that occurs most commonly in preschool-aged children in the early postanesthetic period The incidence of ED varies between 10 and 80% in children and is perceived as a troublesome clinical situation by 42% of pediatric anesthesiologists Although these events are often short lived, they increase the risk of self-injury and delayed discharge, require additional nursing staff and can increase medical care costs, all of which are causes for concern The prevalence of ED has increased with the introduction and growing use of sevoflurane and desflurane, two low-solubility inhalational anesthetics These agents promote early arousal post anesthetic, which contributes to ED Physiological factors, pharmacological factors, the type of procedure, the anesthetic agent administered, painful stimuli, and various patient factors can all contribute to ED and thus need to be considered Recent literature debates the cause-effect relationship between ED and pain, suggesting that they often occur concurrently but are sometimes independent findings The consistent relation between ED and sevoflurane-based anesthesia has guided many studies to investigate its incidence compared with using other anesthetic techniques or various adjuncts The risk of ED is lowest when propofol is used as a single-agent anesthetic compared with sevoflurane-based anesthetics Adjunctive agents can be rated in the following order of most effective to least effective interventions: dexmedetomidine, fentanyl, ketamine, clonidine, and propofol bolus at the end of sevoflurane-based anesthesia This review summarizes the factors that may predict ED and provides an intervention algorithm to guide effective prevention and treatment

Emergence Delirium in Pediatric Anesthesia.

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, N2O, 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: 0.275-0.449; 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: 0.033-0.422; 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 sevoflurane-induced EA in children as compared with placebo.

Dexmedetomidine for preventing sevoflurane-related emergence agitation in children: a meta-analysis of randomized controlled trials.

Background The aim of our study was to compare the efficacy of dexmedetomidine, ketamine, and midazolam for sedative premedication administered by nebuliser 30 min before general anaesthesia in preschool children undergoing bone marrow biopsy and aspiration. Methods Ninety children aged 3–7 yr were randomly allocated into three equal groups to be premedicated with either nebulised ketamine 2 mg kg−1 (Group K), dexmedetomidine 2 μg kg−1 (Group D), or midazolam 0.2 mg kg−1 (Group M). The primary endpoint was a five-point sedation score on arrival in the operating room 30 min after end of study drug administration. Secondary outcomes included: parental separation anxiety scale; medication and mask acceptance scales; haemodynamic variables; recovery time; postoperative face, legs, activity, cry, and consolability scale; emergence agitation scale; and adverse effects. Results The median (range) sedation score on arrival in the operating room was 3.5 (1–4), 2.0 (2–3) and 2.0 (1–3) in Groups M, D, and K, respectively (P=0.000). Subjects in Group D showed higher medication (P Conclusions Preschool children premedicated with nebulised dexmedetomidine had more satisfactory sedation, shorter recovery time, and less postoperative agitation than those who received nebulised ketamine or midazolam. Clinical trial registration NCT02935959 .

Comparison of nebulised dexmedetomidine, ketamine, or midazolam for premedication in preschool children undergoing bone marrow biopsy.

Background Midazolam has been widely studied for preventing emergence agitation. The authors previously reported that in children with sevoflurane anesthesia, intravenous administration of midazolam (0.05 mg/kg) before the end of surgery reduced the incidence of emergence agitation but prolonged the emergence time. This study was designed to test the hypothesis that a lower midazolam dose could suppress emergence agitation with minimal disturbance of the emergence time in children with sevoflurane anesthesia. Methods In this randomized, double-blind, placebo-controlled trial, 90 children (1 to 13 yr of age) having strabismus surgery were randomized to 1:1:1 to receive 0.03 mg/kg of midazolam, 0.05 mg/kg of midazolam, or saline just before the end of surgery. The primary outcome, the incidence of emergence agitation, was evaluated by using the pediatric anesthesia emergence delirium scale and the four-point agitation scale. The secondary outcome was time to emergence, defined as the time from sevoflurane discontinuation to the time to extubation. Results The incidence of emergence agitation was lower in patients given 0.03 mg/kg of midazolam (5 of 30, 16.7%) and patients given 0.05 mg/kg of midazolam (5 of 30, 16.7%) compared with that in patients given saline (13/of 30, 43.3%; P = 0.036 each). The emergence time was longer in patients given 0.05 mg/kg of midazolam (17.1 ± 3.4 min, mean ± SD) compared with that in patients given 0.03 mg/kg of midazolam (14.1 ± 3.6 min; P = 0.0009) or saline (12.8 ± 4.1 min; P = 0.0003). Conclusion Intravenous administration of 0.03 mg/kg of midazolam just before the end of surgery reduces emergence agitation without delaying the emergence time in children having strabismus surgery with sevoflurane anesthesia.

/pdf/comparison-of-the-effects-of-0-03-and-0-05-mg-kg-midazolam-1qokilvvkz.pdf

Comparison of the effects of 0.03 and 0.05 mg/kg midazolam with placebo on prevention of emergence agitation in children having strabismus surgery

Background Emergence agitation is a common problem in pediatric anesthesia, especially after sevoflurane induction and maintenance anesthesia. The purpose of this study was to investigate the effect of sufentanil to reduce emergence agitation after sevoflurane anesthesia in children undergoing adenotonsillectomy compared with fentanyl. Methods One hundred and five children, aged 3 - 11 years, were randomly allocated to receive normal saline (control group), sufentanil 0.2 µg/kg (S2) or fentanyl 2 µg/kg (F2) 1 minute after loss of the eyelash reflex. Anesthesia was induced and maintained with sevoflurane. Time to tracheal extubation, recovery time, Paediatric Anesthesia Emergence Delirium (PAED) scale, and emergence behavior were assessed. Results The incidence of severe agitation was significantly lower in S2 and F2 groups vs. the control group, 4/32 and 15/34 vs. 24/34 respectively, (P = 0.002, 0.009, respectively). PAED scales were significantly different among three groups (P = 0.007), and lower in the S2 and F2 groups than in the control group (P = 0.007 and P = 0.025, respectively). And the incidence of severe agitation and the PAED scale score was significantly different between the S2 and F2 groups (P = 0.007, P = 0.019, respectively). Time to tracheal extubation and recovery time were similar in all three groups. Conclusions Administration of sufentanil at 0.2 µg/kg after induction of anesthesia reduced emergence agitation in children receiving sevoflurane anesthesia for adenotonsillectomy compared with fentanyl. This was without delaying the recovery time or causing significant hypotension.

Sufentanil reduces emergence agitation in children receiving sevoflurane anesthesia for adenotonsillectomy compared with fentanyl.

Objective Previous neuroimaging studies have shown abnormal brain-bladder control network in children with primary nocturnal enuresis (PNE). The hippocampus, which has long been considered to be an important nerve center for memory and emotion, has also been confirmed to be activating during micturition in several human imaging studies. However, few studies have explored hippocampus-related functional networks of PNE in children. In this study, the whole resting-state functional connectivity (RSFC) of hippocampus was investigated in children with PNE. Methods Functional magnetic resonance imaging data of 30 children with PNE and 29 matched healthy controls (HCs) were analyzed in our study. We used the seed-based RSFC method to evaluate the functional connectivity of hippocampal subregions defined according to the Human Brainnetome Atlas. Correlation analyses were also processed to investigate their relationship with disease duration time, bed-wetting frequency, and bladder volume. Results Compared with HCs, children with PNE showed abnormal RSFC of the left rostral hippocampus (rHipp) with right fusiform gyrus, right Rolandic operculum, left inferior parietal lobule, and right precentral gyrus, respectively. Moreover, decreased RSFC of the left caudal hippocampus (cHipp) with right fusiform gyrus and right supplementary motor area was discovered in the PNE group. There were no significant results in the right rHipp and cHipp seeds after multiple comparison corrections. In addition, disease duration time was negatively correlated with RSFC of the left rHipp with right Rolandic operculum (r = −0.386, p = 0.035, uncorrected) and the left cHipp with right fusiform gyrus (r = −0.483, p = 0.007, uncorrected) in the PNE group, respectively. In the Receiver Operating Characteristic (ROC) analysis, all the above results of RSFC achieved significant performance. Conclusions To our knowledge, this is the first attempt to examine the RSFC patterns of hippocampal subregions in children with PNE. These findings indicated that children with PNE have potential dysfunctions in the limbic network, sensorimotor network, default mode network, and frontoparietal network. These networks may become less efficient with disease duration time, inducing impairments in brain-bladder control, cognition, memory, and emotion. Further prospective research with dynamic observation of brain imaging, bladder function, cognition, memory, and emotion is warranted.

Abnormal resting-state functional connectivity of hippocampal subregions in children with primary nocturnal enuresis

Objective Primary nocturnal enuresis (PNE) is a common developmental condition in school-aged children. The objective is to better understand the pathophysiology of PNE by using insula-centered resting-state functional connectivity (rsFC). Methods We recruited 66 right-handed participants in our analysis, 33 with PNE and 33 healthy control (HC) children without enuresis matched for gender and age. Functional and structural MRI data were obtained from all the children. Seed-based rsFC was used to examine differences in insular functional connectivity between the PNE and HC groups. Correlation analyses were carried out to explore the relationship between abnormal insula-centered functional connectivity and clinical characteristics in the PNE group. Results Compared with HC children, the children with PNE demonstrated decreased left and right insular rsFC with the right medial superior frontal gyrus (SFG). In addition, the bilateral dorsal anterior insula (dAI) seeds also indicated the reduced rsFC with right medial SFG. Furthermore, the right posterior insula (PI) seed showed the weaker rsFC with the right medial SFG, while the left PI seed displayed the weaker rsFC with the right SFG. No statistically significant correlations were detected between aberrant insular rsFC and clinical variables (e.g., micturition desire awakening, bed-wetting frequency, and bladder volume) in results without global signal regression (GSR) in the PNE group. However, before and after setting age as a covariate, significant and positive correlations between bladder volume and the rsFC of the left dAI with right medial SFG and the rsFC of the right PI with right medial SFG were found in results with GSR in the PNE group. Conclusion To the best of our knowledge, this study explored the rsFC patterns of the insula in children with PNE for the first time. These results uncovered the abnormal rsFC of the insula with the medial prefrontal cortex without and with GSR in the PNE group, suggesting that dysconnectivity of the salience network (SN)-default mode network (DMN) may involve in the underlying pathophysiology of children with PNE. However, the inconsistent associations between bladder volume and dysconnectivity of the SN-DMN in results without and with GSR need further studies.

/pdf/altered-resting-state-functional-connectivity-of-insula-in-11cjyxoq.pdf

Altered resting-state functional connectivity of insula in children with primary nocturnal enuresis

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Sufentanil reduces emergence agitation in children receiving sevoflurane anesthesia for adenotonsillectomy compared with fentanyl.

Abnormal resting-state functional connectivity of hippocampal subregions in children with primary nocturnal enuresis

Altered resting-state functional connectivity of insula in children with primary nocturnal enuresis