Effects of S-ketamine on emergence agitation after sevoflurane anesthesia for children: A randomized clinical trial

Abstract

Background

With the use of sevoflurane, the incidence of emergence agitation (EA) has also increased.

Objective

We aimed to investigate whether S-ketamine can prevent EA after sevoflurane anesthesia in children.

Methods

Children undergoing otolaryngology surgery were assigned to one of four groups randomly. Drugs were given five minutes before the operation was accomplished. The incidence of EA was measured by the Pediatric Anesthesia Emergence Delirium Scale (PAED) scores. Face, Legs, Activity, Cry, and Consolability scale (FLACC) scores and the rate of adverse events were evaluated.

Results

The incidence of EA was significantly lower in children given 2 mg/kg propofol, 0.25 mg/kg S-ketamine and 0.5 mg/kg S-ketamine compared with that in children given normal saline. At 3 h and 6 h after operation, the FLACC scores in children given 0.25 mg/kg S-ketamine and 0.5 mg/kg S-ketamine were significantly lower than those in children given 2 mg/kg propofol and saline (p < 0.001). No statistical differences were found in adverse reactions among children in the four groups.

Conclusion

Intravenous injection of propofol 2 mg/kg, S-ketamine 0.25 mg/kg and S-ketamine 0.5 mg/kg before end of the operation can all reduce the incidence of occurrence of emergence agitation in children undergoing tonsillectomy with or without adenoidectomy after sevoflurane anesthesia. Compared with children given propofol 2 mg/kg and S-ketamine 0.5 mg/kg, children given S-ketamine 0.25 mg/kg has the advantage of not prolonging the awakening time.

Keywords

emergence agitation S-ketamine propofol children sevoflurane anesthesia intravenous injection

1 Introduction

Sevoflurane is widely used in pediatric general anesthesia due to its rapid induction and recovery characteristics. Whereas, the occurrence of emergence agitation (EA) after Sevoflurane anesthesia is as high as 30∼80%, which has been recognized as a postoperative behavioral disturbance.^1,2 Young children, preoperative anxiety, personal characteristics, postoperative pain, fast recovery inhalation anesthesia, type of surgeries and anesthetic drugs have been reported to be risk factors for EA in children anesthesia.³ These factors are very common in children undergoing otolaryngology surgery with sevoflurane anesthesia. EA can cause many adverse events such as extraction of indwelling catheters, self-injurious behavior, disruption of surgical incision or contamination of dressing and it can also result in lower satisfaction with anesthesia among parents and medical staff.

The prevention of postoperative EA after sevoflurane anesthesia has become an important challenge for anesthesiologists. Many treatments have been reported to prevent EA from occurrence, including fentanyl, midazolam,⁴ propofol,⁵ racemic ketamine and dexmedetomidine⁶ etc. Nevertheless, each treatment has its drawbacks. Previous studies of our institution have indicated that propofol can reduce the occurrence of EA in children.⁷ Pain is the main factor contributing to postoperative EA in pediatric population, but propofol has no analgesic effect.⁸

Ketamine is a phencyclidine derivative commonly used in general anesthesia and it has properties of sedation, amnesia and analgesia. S-ketamine is the dextral of racemic ketamine, and it has neuroprotective effects with faster elimination and fewer side effects, compared to racemic ketamine.⁹ Unlike propofol, S-ketamine has definite analgesic effects. Therefore, S-ketamine may have the potential to reduce emergence agitation in children.

To address further reduction in the incidence of EA after sevoflurane anesthesia, and improve the quality of postoperative recovery, we conducted a prospective, single center, single-blind, randomized clinical trial to investigate efficacy of S-ketamine on EA during recovery in children, so as to provide reference for clinical application.

2 Materials and methods

Our study was prospective, randomized and conducted from October 2022 to May 2023 following principles of Declaration of Helsinki. The Ethics Committee of Xuzhou Children's Hospital approved our study with registration number 2021-05-13-H12. We registered this study in the China Clinical Trials Registry with registration number ChiCTR2100052520. All parents of the children have signed the informed consent form.

2.1 Participants

The study included 160 children aged 2-7 years, ASA physical status I-II, who underwent general anesthesia with sevoflurane for tonsillectomy with or without adenoidectomy at Xuzhou Children's Hospital. They were assigned to one of the four groups according to the randomized number table method: children given 2 mg/kg propofol, children given 0.25 mg/kg S-ketamine, children given 0.5 mg/kg S-ketamine and children given normal saline. Exclusion criteria of this study included the following conditions: allergy to S-ketamine or propofol injection, abnormal preoperative biochemical test results or presence of cardiopulmonary disease, upper respiratory tract infection within one week, cognitive or developmental disorders, neurological disease, operation time less than 15 min or more than 50 min.

2.2 Anesthesia and intervention

All children included in this study received intravenous access in the ward. Also, they were made to fast for 6 h and forbid drinking for 2 h before anesthesia. All the children were intravenously injected with 0.01 mg/kg atropine before entering the operating room as a preoperative medication. A modified Yale Preoperative Anxiety Scale (mYPAS) was administered at bedside before admission.¹⁰ All the children were taken to the operation room accompanied by their parents. After admission to the operation room, all children were monitored routinely, including: regional tissue saturation oxygenation(rStO₂), saturation of pulse oximetry, ECG monitoring, non-invasive blood pressure and capnography. Anesthesia induction drugs included etomidate 0.3 mg/kg, sufentanil 0.2 μg/kg and cisatracurium 0.1 mg/kg. Mechanical ventilation was administered via a transoral tracheal tube after the drugs had taken full effect. Anesthesia maintenance included sevoflurane 2%-3% and remifentanil 0.2–0.3 μg/kg/min. Mechanical ventilation adopted pressure controlled ventilation mode to maintain end-tidal CO₂ at 35–45 mmHg by regulating respiratory rate at 14–20 times/min and tidal volume at 6–10 ml/kg. In this study, the research drugs were prepared by the anesthesiologist who was not involved in the anesthesia procedures, while the anesthesia was administered by an anesthesiologist who was unaware of the group assignments.

Five minutes before the surgery finished, children were injected with the study drug intravenously according to the assigned study group. No reversal of muscle relaxant drugs were used during the anesthesia process. At the end of operation, the sevoflurane and remifentanil were stopped and the children were immediately transferred to PACU. Extubation under deep anesthesia was performed after the children's respiratory rate was >12 times/min, tidal volume was >5 ml/kg and end-tidal CO₂ was <50 mmHg. Children with modified Aldrete score ≥9 were sent back to the ward. After returning to the ward, all children began to take ibuprofen suspension for postoperative pain relief. For children under 4 years old, 80 mg of ibuprofen was taken each time, while for children over 4 years old, 100 mg was taken each time. The medication was taken again every 8 h.

2.3 Outcome measures

The study's primary outcome was the incidence of EA assessed with Pediatric Anesthesia Emergence Delirium Scale (PAED) scores after surgery. The PAED was evaluated and measured at four times points: at the time of extubation (T₁), 10 min (T₂), 20 min (T₃) and 30 mimutes (T₄) after extubation. All the measurements were recorded by another anesthesiologist who was unaware of the group assignment. Emergence agitation was considered to have occurred at any time point with a PAED score ≥10. The PAED scale covers 22 specific behaviors in five domains and the results are derived from the cumulative scores of the five behavioral domains with a sensitivity and specificity of 64% and 86%.¹¹

Face, Legs, Activity, Cry, and Consolability scale (FLACC) scores were performed at 3, 6, 12 and 24 h postoperatively.¹² The modified Yale Preoperative Anxiety Scale (mYPAS) scores were used to measure preoperative anxiety levels. We recorded extubation time (from the cessation of anesthesia to extubation), eye-opening time (from the cessation of anesthesia until the children open their eyes) and PACU length of stay. Adverse effects such as nausea, vomiting, hypotension (blood pressure 20% lower than before surgery), increased secretions, low regional tissue saturation oxygenation(rStO₂ < 50%) and hypoxia (SpO₂ < 90%) were also recorded.

2.4 Statistical analysis

Based on the results of previous studies performed in this hospital and preliminary results, approximately 50% of children in control group experienced EA. Using the PASS 15.0 software, setting α = 0.05 and 1-β = 80%, a sample size of 40 in each group was estimated to detect a reduction of 20% in EA with the consideration of a dropout rate of approximately 15%.

Data were processed by SPSS 16.0 statistical software (SPSS Inc., IBM, Chicago, IL, USA). Normally distributed variables were presented as mean ± standard deviation (mean ± SD) and were analyzed with ANOVA. Abnormally distributed variables were presented as median (interquartile range) and were analyzed with the independent samples non-parametric test. Categorical data were analyzed with Chi-square test or Fisher's exact test. Bonferroni method was used to adjust α levels for comparison of any two groups. p-value < 0.05 was considered to have statistically significant differences. (Figure 1)

Figure 1.

Flow diagram for experimental procedures.

3 Results

One hundred and sixty children were included in final statistical analysis. There were no statistical differences in general conditions among the four groups, including: age, gender distribution, ASA classification, height, weight, BMI, preoperative mYPAS scores, type of surgery, anesthesia time and operation time, as shown in Table 1.

The incidence of EA was lower in children given 2 mg/kg propofol (11 of 40, 27.5%), children given 0.25 mg/kg S-ketamine (13 of 40, 32.5%) and children given 0.5 mg/kg S-ketamine (5 of 40, 12.5%) compared with that in children given normal saline (25 of 40, 62.5%; p < 0.001 each; Table 1 and Figure 2). Compared with children given normal saline, PAED scores in children given 2 mg/kg propofol, children given 0.25 mg/kg S-ketamine and children given 0.5 mg/kg S-ketamine were significantly lower at the time of extubation (T₁), 10 min (T₂), 20 min (T₃) and 30 mimutes (T₄) after extubation [(7.9 ± 1.4) vs (5.4 ± 1.4), (5.6 ± 1.3) and (4.3 ± 1.2), p < 0.001; (8.8 ± 1.7) vs (6.4 ± 1.8), (6.5 ± 1.4) and (5.1 ± 1.1), p < 0.001; (9.7 ± 1.6) vs (7.4 ± 2.4), (7.8 ± 2.2) and (5.9 ± 2.0), p < 0.001; (8.2 ± 1.4) vs (6.5 ± 1.9), (6.6 ± 2.0) and (5.8 ± 1.3), p < 0.001; respectively; Figure 3]. PAED scores in children given 0.5 mg/kg S-ketamine were significantly lower than those in children given 0.25 mg/kg S-ketamine at all the four times points [(4.3 ± 1.2) vs (5.6 ± 1.3), p < 0.001; (5.1 ± 1.1) vs (6.5 ± 1.4), p < 0.001; (5.9 ± 2.0) vs (7.8 ± 2.2), p < 0.001; (5.8 ± 1.3) vs (6.6 ± 2.0), p = 0.028; respectively; Figure 3] and were also lower than those in children given 2 mg/kg propofol at the time of extubation (T₁), 10 min (T₂) and 20 min (T₃) after extubation [(4.3 ± 1.2) vs (5.4 ± 1.4), p < 0.001; (5.1 ± 1.1) vs (6.4 ± 1.8), p < 0.001; (5.9 ± 2.0) vs (7.4 ± 2.4), p = 0.001; respectively; Figure 3].

Figure 2.

Incidence of EA by study group. Notes: *p < 0.05 vs Normal Saline. Abbreviations: EA, emergence agitation.

Figure 3.

PAED scores at different follow-up times by study group. Notes: *p < 0.05 vs Normal saline, ^#p < 0.05 vs Propofol 2 mg/kg, ^△p < 0.05 vs S-ketamine 0.25 mg/kg. Abbreviations: PAED, Pediatric Anesthesia Emergence Delirium.

Table 1.

Demographic and perioperative characteristics of children in the four groups.

	Propofol 2 mg/kg (n = 40)	S-ketamine 0.25 mg/kg (n = 40)	S-ketamine 0.5 mg/kg (n = 40)	Normal Saline (n = 40)	p-value
Age (years)	4.5 ± 1.1	4.4 ± 1.1	4.4 ± 1.2	4.4 ± 1.4	0.949
Gender (n, %)					0.674
male	27 (67.5)	26 (65.0)	30 (75.0)	30 (75.0)
famale	13 (32.5)	14 (35.0)	10 (25.0)	10 (25.0)
ASA classification					0.669
I	33 (97.5%)	31 (95.0%)	34 (92.5%)	35 (95.0%)
II	7 (2.5%)	9 (5.0%)	6 (7.5%)	5 (5.0%)
Height (cm)	109.5 ± 8.4	108.8 ± 8.0	109.0 ± 10.5	107.9 ± 10.9	0.893
Weight (kg)	18.5 ± 3.4	18.0 ± 2.7	18.4 ± 4.3	18.1 ± 4.6	0.904
BMI (kg/m2)	15.3 ± 1.3	15.1 ± 1.5	15.4 ± 2.2	15.4 ± 1.8	0.889
mYPAS scores	54.3 ± 4.5	55.9 ± 7.6	55.4 ± 4.9	53.6 ± 5.3	0.255
Type of surgery(n, %)					0.998
Tonsillectomy	3(7.5)	2(5.0)	2(5.0)	2(5.0)
Adenoidectomy	5(12.5)	5(12.5)	5(12.5)	4(10.0)
Tonsillectomy and Adenoidectomy	32(80.0)	33(82.5)	33(82.5)	34(85.0)
Anesthesia time (h)	46.0 ± 4.9	47.2 ± 5.3	45.9 ± 4.3	48.1 ± 4.8	0.163
Operation time (h)	29.1 ± 4.7	31.1 ± 5.2	30.7 ± 4.3	30.5 ± 5.2	0.289

Notes: Data are presented as mean ± SD for age, height, weight, BMI, mYPAS scores, anesthesia time and operation time; and number of children (%) for gender, ASA classification. There were no significant differences among the four groups (p > 0.05).

At 3 h and 6 h after operation, the FLACC scores in children given 0.25 mg/kg S-ketamine [(3.9 ± 1.0) and (3.2 ± 0.6)] were significantly lower than those in children given 2 mg/kg propofol [(4.5 ± 1.1) and (3.9 ± 0.7); (p = 0.017 and p < 0.001); Figure 4] and children given normal saline [(4.6 ± 1.3) and (4.1 ± 0.9); p < 0.001; respectively; Figure 4]. Also, the FLACC scores in children given 0.5 mg/kg S-ketamine [(3.1 ± 0.9) and (2.7 ± 0.6)] were significantly lower than those in children given 2 mg/kg propofol [(4.5 ± 1.1) and (3.9 ± 0.7); p < 0.001; respectively; Figure 4], children given 0.25 mg/kg S-ketamine [(3.9 ± 1.0) and (3.2 ± 0.6); (p = 0.001 and p = 0.005) ;Figure 4] and children given normal saline [(4.6 ± 1.3) and (4.1 ± 0.9); p < 0.001; respectively; Figure 4]. At 12 h after surgery, the FLACC scores in children given 0.5 mg/kg S-ketamine were significantly lower than those in children given saline [ (2.7 ± 0.6) vs (3.1 ± 0.7); p = 0.009; Figure 4].

Figure 4.

FLACC scores at different follow-up times by study group. Notes: *p < 0.05 vs Normal saline, ^#p < 0.05 vs Propofol 2 mg/kg, ^△p < 0.05 vs S-ketamine 0.25 mg/kg. Abbreviations: FLACC, Face, Legs, Activity, Cry, and Consolability.

Postoperative outcomes and adverse events of children are presented in Table 2. The extubation and eye-opening time were significantly longer in children given 2 mg/kg propofol and children given 0.5 mg/kg S-ketamine when compared with those in children given 0.25 mg/kg S-ketamine and children given normal saline (p < 0.001; Table 2). No statistical differences were detected in PACU length of stay among children given 2 mg/kg propofol, children given 0.25 mg/kg S-ketamine and children given normal saline but were all shorter than those in children given 0.5 mg/kg S-ketamine (p < 0.001; Table 1). Children of the four groups didn’t differ in the occurrence of associated side effects, as shown in Table 2.

Table 2.

Postoperative outcomes and complications of children.

	Propofol 2 mg/kg (n = 40)	S-ketamine 0.25 mg/kg (n = 40)	S-ketamine 0.5 mg/kg (n = 40)	Normal Saline (n = 40)	p-value
Incidence of EA (n, %)	11(27.5) *	13(32.5)*	5(12.5)*	25(62.5)	<0.001
Extubation time (min)	15.7 ± 2.2*	12.9 ± 1.8^#	14.9 ± 2.5^*△	12.4 ± 2.1	<0.001
Eye-opening time (min)	19.5 ± 2.7*	16.3 ± 2.1^#	18.9 ± 3.0^*△	15.7 ± 2.8	<0.001
PACU length of stay (min)	31.5 ± 3.8	31.6 ± 2.5	36.6 ± 4.7^*#△	30.1 ± 3.6	<0.001
Postoperetive adverse events(n, %)	2(5.0)	3(7.5)	4(10.0)	3(7.5)	0.975
Nausea	1(2.5)	2(5.0)	2(5.0)	2(5.0)	1.000
Vomiting	1(2.5)	0(0.0)	0(0.0)	0(0.0)	1.000
Hypotension	0(0.0)	2(5.0)	2(5.0)	1(2.5)	0.757
Increased secretion	3(7.5)	0(0.0)	0(0.0)	0(0.0)	0.059
Hypoxemia	7(17.5)	7(17.5)	8(20.0)	6(15.0)	0.866

Notes: Data are presented as mean ± SD for extubation time, eye-opening time, PACU lenth of stay; and number of children (%) for Incidence of EA, Postoperetive adverse events.

*p < 0.05 vs Normal saline, ^#p < 0.05 vs Propofol 2 mg/kg, ^△p < 0.05 vs S-ketamine 0.25 mg/kg.

4 Discussion

Tonsillectomy with or without adenoidectomy should be considered in children with obstructive sleep apnea that affects growth, academic performance or behavior or leads to recurrent throat infections.¹³ It has become one of the most common procedures in children.

Emergence agitation is a common complication after tonsillectomy with or without adenoidectomy under sevoflurane anesthesia in children, which can lead to destruction of venous access, pulling out drainage tube, affecting wound healing, increasing difficulty of nursing and prolonged hospital stay.¹⁴ Risk factors for EA include younger patients, otorhinolaryngologic surgery, inhalation anesthesia, rapid recovery from anesthesia and preoperative anxiety.¹⁵ Therefore, children aged 2–7 years who underwent sevoflurane anesthesia for tonsillectomy with or without adenoidectomy were selected for this study.

In this study, we used propofol and two different doses of S-ketamine to prevent EA. Both the PAED scores at four time points and the incidence of EA in children given 2 mg/kg propofol, 0.25 mg/kg S-ketamine and 0.5 mg/kg S-ketamine were significantly lower than those in children given normal saline. It suggested that both propofol and S-ketamine can prevent EA from occurrence after sevoflurane anesthesia. Previous studies of our institution shows that 2 mg/kg propofol was effective in reducing the occurrence of EA in children during the awakening period, so we chose 2 mg/kg propofol for comparison.⁷ The mechanism by which propofol prevents EA is still unclear. Different metabolic rates of volatile anesthetics in different areas of central nervous systems can lead to differences in the recovery rate of brain function.^16,17 Cognitive function recovers more slowly than the others (such as movement and hearing), which leads to a state of confusion.¹⁸ The rising prevalence of emergence delirium caused by fast-acting volatile agents has provided evidence in favor of this hypothesis.¹⁹ The sedative effect of propofol may eliminate this difference in metabolic rates. Ketamine is also effective in preventing the occurrence of EA during the awakening period in children, but its side effects are still common.^20,21 Compared with propofol, ketamine has obvious effects on analgesic and is useful in preventing pain-induced agitation during the awakening period. However, Chen et al. revealed that propofol was more effective than ketamine in preventing emergence agitation with fewer side effects.²² The side effects of racemic ketamine are dose-dependent including excessive salivation, nausea, vomiting and psychiatric side effects such as excessive dreaming, blurred vision and delirium. The dextral form of ketamine, known as S-ketamine, is two times more potent than racemic ketamine, providing greater analgesia with fewer side effects and shorter sedation times. Therefore, compared with propofol, S-ketamine can provided better analgesic effects to reduce EA, and may cause fewer side effects. This is the main reason why we chose to study S-ketamine for prevention of EA in Children. Although there are no significant differences among children given 2 mg/kg propofol, 0.25 mg/kg S-ketamine and 0.5 mg/kg S-ketamine, the PAED scores in children given 0.5 mg/kg S-ketamine are lower than those in children given 2 mg/kg propofol, 0.25 mg/kg S-ketamine at the first three time points. This suggested that S-ketamine can prevent EA dose-dependently after sevoflurane anesthesia.

The patients in this study had high risk factors for EA, such as young age, preoperative separation anxiety, and severe postoperative pain etc. There are no significantly differences in general condition of the children. In this study, sufentanil and remifentanil were used as a combination of anesthesia and analgesia, and the postoperative FLACC score showed that the analgesia effect was basically satisfactory. At 3 h and 6 h postoperatively, the FLACC scores in children given 0.25 mg/kg S-ketamine were significantly lower than those in children given 2 mg/kg propofol and children given saline. Also, the FLACC scores in children given 0.5 mg/kg S-ketamine were statistically lower than those in children given 2 mg/kg propofol, children given 0.25 mg/kg S-ketamine and children given normal saline . This indicated that the pain scores within six hours after surgery were relatively high, and S-ketamine plays a certain analgesic effect. It was also suggested that the preventive effect of S-ketamine on EA may be largely due to its analgesic effect.

Most sedative and analgesic drugs are dose-dependent (such as S-ketamine). Higher dose may lead to prolonged recovery time and increased side effects. In this study, the extubation and eye-opening time were significantly longer in children given 2 mg/kg propofol and children given 0.5 mg/kg S-ketamine when compared with those in children given 0.25 mg/kg S-ketamine and children given normal saline. No statistical differences were found in PACU length of stay among children given 2 mg/kg propofol, children given 0.25 mg/kg S-ketamine and children given normal saline but were all shorter than those in children given 0.5 mg/kg S-ketamine. This indicated that the introduction of 0.5 mg/kg S-ketamine may increase children's duration of stay in the operation room. There were no differences among the four groups in complications including nausea, vomiting, hypotension, increased secretion and hypoxemia. This suggests that the three medications used in this study are safe. This might because the sample size was calculated based on the primary outcome, while for the secondary outcomes, the sample size might be insufficient. In addition, we can speculate that 0.25 mg/kg S-ketamine may both enhance the satisfaction of caregivers for pediatric patients and increase the turnover efficiency of operating rooms.

Our study still has its limitations. Firstly, the postoperative follow-up period was only up to 24 h postoperatively and the effect of S-ketamine on long-term postoperative behavioral changes in children still needs further investigation. Secondly, single-center study has its geographical limitations to the applicability of the findings. In the future, multi-center long-term follow-up studies can be conducted on this basis.

5 Conclusion

Footnotes

Acknowledgments

The authors thank colleagues in the department for their support for this study.

Ethics approval and consent to participate

The study was approved by the ethics committee of Xuzhou Children's Hospital, China and written informed consents were signed by the patients and/or guardians.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was supported by Science Foundation of Xuzhou Health Commission, Jiangsu, China [grant numbers XWKYHT20220072].

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

Han

Cai

Zhang

, et al. Effects of prophylactic nalbuphine on emergence agitation and postoperative pain in pediatric patients undergoing ENT surgery with sevoflurane anesthesia. Front Pediatr 2024; 12: 1353027.

Bhat

Santhosh

Annigeri

, et al. Comparison of intranasal dexmedetomidine and dexmedetomidine-ketamine for premedication in pediatrics patients: a randomized double-blind study. Anesth Essays Res 2016; 10: 349–355.

Golmohammadi

Sane

Ghavipanjeh Rezaei

, et al. Investigating the effect of dexmedetomidine in controlling postoperative emergence agitation in children under sevoflurane anesthesia. Anesthesiol Res Pract 2024; 2024: 6418429.

Kawai

Kurata

Sanuki

, et al. The effect of midazolam administration for the prevention of emergence agitation in pediatric patients with extreme fear and non-cooperation undergoing dental treatment under sevoflurane anesthesia, a double-blind, randomized study. Drug Des Devel Ther 2019; 13: 1729–1737.

Xiao

Jin

Zhang

, et al. Efficacy of propofol for the prevention of emergence agitation after sevoflurane anaesthesia in children: a meta-analysis. Front Surg 2022; 9: 1031010.

Kim

Kwak

, et al. Premedication with dexmedetomidine to reduce emergence agitation: a randomized controlled trial. BMC Anesthesiol 2019; 19: 44.

Cao

Shan

, et al. Efficacy and safety of propofol in preventing emergence agitation after sevoflurane anesthesia for children. Exp Ther Med 2019; 17: 3136–3140.

Lee

Sung

. Emergence agitation: current knowledge and unresolved questions. Korean J Anesthesiol 2020; 73: 471–485.

Wang

Zhao

, et al. Sedative effect and safety of different doses of S-ketamine in combination with propofol during gastro-duodenoscopy in school-aged children: a prospective, randomized study. BMC Anesthesiol 2022; 22: 46.

10.

Silveira

KNM

Alves

Nascimento Júnior

, et al. Children's preoperative stress according to the parental presence evaluated by salivary cortisol and mYPAS: quasi-randomized trial. Rev Esc Enferm USP 2024; 58: e20230232.

11.

Kain

Mayes

Caldwell-Andrews

, et al. Preoperative anxiety, post-operative pain, and behavioral recovery in young children undergoing surgery. Pediatrics 2006; 118: 651–658.

12.

Turco

Cerulo

Del Conte

, et al. Correlation between FLACC scale score and analgesic requirement in children undergoing minimally invasive surgery. Pediatr Med Chir 2023; 45. doi: 10.4081/pmc.2023.288

13.

Schneuer

Bell

Dalton

, et al. Adenotonsillectomy and adenoidectomy in children: The impact of timing of surgery and post-operative outcomes. J Paediatr Child Health 2022; 58: 1608–1615.

14.

Lee

Sohn

Hwang

, et al. Effect of a repeated verbal reminder of orientation on emergence agitation after general anaesthesia for minimally invasive abdominal surgery: a randomised controlled trial. Br J Anaesth 2023; 130: 439–445.

15.

Menser

Smith

. Emergence agitation and delirium: considerations for epidemiology and routine monitoring in pediatric patients. Local Reg Anesth 2020; 27: 73–83.

16.

Voepel-Lewis

Malviya

Tait

. A prospective cohort study of emergence agitation in the pediatric postanesthesia care unit. Anesth Analg 2003; 96: 1625–1630.

17.

Dahmani

Stany

Brasher

, et al. Pharmacological prevention of sevoflurane- and desflurane-related emergence agitation in children: a meta-analysis of published studies. Br J Anaesth 2010; 104: 216–223.

18.

Dahmani

Delivet

Hilly

. Emergence delirium in children: an update. Curr Opin Anaesthesiol 2014; 27: 309–315.

19.

Kuratani

. Greater incidence of emergence agitation in children after sevoflurane anesthesia as compared with halothane: a meta-analysis of randomized controlled trials. Anesthesiology 2008; 109: 225–232.

20.

Hassan

Saleh

. Comparison of dexmedetomidine, ketamine, and magnesium sulfate for the prevention of emergence agitation following sevoflurane-based anesthesia in pediatric cardiac catheterization. Minerva Anestesiol 2025; 91: 139–146.

21.

Abitağaoğlu

Köksal

Alagöz

, et al. Effect of ketamine on emergence agitation following septoplasty: a randomized clinical trial. Braz J Anesthesiol 2021; 71: 381–386.

22.

Chen

, et al. Emergence agitation after cataract surgery in children: a comparison of midazolam, propofol and ketamine. Pediatr Anaesth 2010; 20: 873–879.