Introduction
Sevoflurane is the most widely used inhalation anaesthetics in paediatric anaesthetic practice. However, after sevoflurane anaesthesia emergence delirium is a common complication in children with a reported incidence up to 70%.1,2 3
The pathogenesis of postoperative emergence delirium remains unclear and various pharmacological agents have been tried for reducing the incidence of emergence delirium.4 5,6 7 8 9 10,11 12
The primary aim of this prospective, double-blind, randomised study was to compare the effectiveness of pre-operative intranasal dexmedetomidine administration with oral midazolam for the prevention of emergence delirium after sevoflurane anaesthesia in children. In the current study, we hypothesised that the prevalence of emergence delirium would be lower with intranasal dexmedetomidine premedication in children following strabismus surgery.
Methods
Design and participants
The current prospective, placebo-controlled, randomised, double-blind trial was conducted at Fujian Provincial Hospital, China, from September 2013 to August 2014. This trial followed the CONSORT statement and the Code of Ethics of the World Medical Association (Declaration of Helsinki).13 www.clinicaltrials.gov
Patients with American Society of Anaesthesiologists (ASA) physical status I or II, aged 2 to 6 years old, and undergoing general anaesthesia for elective unilateral strabismus surgery were eligible for trial inclusion. Exclusion criteria included hypersensitivity to study medications, pre-existing mental or physical health disorders, use of analgesic drugs or sedatives and any sign of upper respiratory infection.
After obtaining written informed consent from the parent or legal guardian, patients were randomised to one of the three groups: premedication with intranasal dexmedetomidine (Group D), oral midazolam (Group M) or 0.9% saline (Group P). The randomisation was performed on a 1 : 1 : 1 ratio according to a computer-generated table. Group assignments were enclosed in sealed, opaque, sequentially numbered envelopes by a research nurse not involved in the study. All the attending anaesthesiologists, the parents and the data collectors were blinded to group assignment throughout the entire study period.
Intervention
All patients received premedication or placebo in the pre-operative holding area in the presence of one parent. Patients in Group D were received intranasal dexmedetomidine (2 μg kg−1 ) 45 min and oral 0.9% saline 30 min before induction of anaesthesia. Patients in Group M received intranasal 0.9% saline 45 min and oral midazolam (0.5 mg kg−1 ) 30 min before induction of anaesthesia. Patients in Group P received intranasal 0.9% saline 45 min and oral 0.9% saline 30 min before the installation of anaesthesia. Dexmedetomidine (100 μg ml−1 ) (Hengrui Pharmaceutical Co., Ltd, Lianyungang, China) was drawn up undiluted in a 1-ml syringe by an anaesthesia nurse not involved in the study. The total volume of intranasal solution was 0.02 ml kg−1 and half of this volume was administered into each nostril. The volume of oral administrated solution was not more than 5 ml.
Anaesthetic procedure
Upon arrival in the operation room, all patients were monitored with ECG, noninvasive blood pressure, peripheral pulse oximetry, capnography and temperature measurement. General anaesthesia was induced with 5% sevoflurane and 50% nitrous oxide in oxygen via a paediatric circle system, and the fresh gas flow was set at 6 l min−1 . After achieving an adequate depth of anaesthesia, an intravenous line was placed. Then, sufentanil (0.5 μg kg−1 ) and propofol (2.0 mg kg−1 ) were administered intravenously to facilitate laryngeal mask airway (LMA) insertion. Using pressure controlled mechanical ventilation an end-tidal carbon dioxide partial pressure (PaCO2 ) of 35 to 45 mmHg was maintained. Anaesthesia was maintained with a sevoflurane and 50% nitrous oxide in oxygen mixture. All patients received topical anaesthesia with two drops of 0.5% proparacaine hydrochloride before and after the surgical procedure, and intravenous paracetamol (15 mg kg−1 ) for postoperative analgesia. Upon completion of the surgery, the operated eye was covered with a dressing, and then sevoflurane and nitrous oxide were discontinued. The LMA was removed when adequate spontaneous breathing resumed. The patients were then transferred to the PACU, where one of the parents was waiting.
Outcomes assessment
The primary outcome was the incidence of emergence delirium assessed with the Paediatric Anaesthesia Emergence Delirium (PAED) scale.14 −1 ) was injected to deal with emergence delirium.
Secondary outcomes included the quality of the inhalational induction, emergence time, postoperative pain intensity, length of stay in the PACU, the incidence of postoperative nausea or vomiting (PONV) and parents’ satisfaction. The quality of inhalation induction was assessed using a numeric rank score, where 1 = crying and needs restraint; 2 = moderate fear and reassured with difficulty; 3 = slight concern but can be encouraged quickly; 4 = asleep or awake but co-operative.15 16 −1 ) was administered as rescue analgesia. The children were discharged from the PACU when their modified Aldrete score reached 10.17
Statistical analysis
Our sample size calculation was based on the incidence of emergence delirium in the literature: the prevalence of emergence delirium undergoing strabismus surgery is reported at approximately 47%.18
The normality of quantitative variables was assessed with the Shapiro–Wilk test. Continuous variables are expressed as mean ± SD or median [IQR]. Categorical variables are described as number (%). Quantitative variables were compared using a one-way ANOVA test or Kruskal–Wallis test, where appropriate. Categorical variables were compared using Fisher's exact test or χ2 test. In addition, the relative risk (RR) with 95% confidence intervals (CIs) was used to compare the incidence of emergence delirium between groups. A P value of less than 0.05 was considered statistically significant. SPSS 25.0 software (SPSS, Chicago, Illinois, USA) was used for all statistical analyses.
Results
We assessed 172 patients for eligibility (Fig. 1 ). Of these, nine patients did not meet the inclusion criteria, and seven patients declined to participate. Of the remaining 156 patients, three patients were subsequently excluded after randomisation (two patients from the midazolam group and one patient from the placebo group) because of protocol breaches (refused the premedication). No patient complained of discomfort with intranasal drug administration. Thus, 153 patients completed the study, and their data were included in the final analysis. Patients among the three groups were comparable in age, sex, height, body weight, ASA physical status and duration of surgery (Table 1 ).
Fig. 1: Participant recruitment and loss.
Table 1 -
Patient characteristics
Group dexmedetomidine, n =52
Group midazolam, n =50
Group saline, n =51
P value
Age (years)
4.9 ± 0.9
4.6 ± 0.9
4.5 ± 1.0
0.1
Height (cm)
109.5 ± 8.2
108.1 ± 9.0
106.6 ± 8.6
0.222
Weight (kg)
19.3 ± 3.1
19.0 ± 2.9
19.3 ± 4.2
0.888
ASA physical status (I/II)
52/0
50/0
51/0
NS
Sex (male/female)
30/22
33/17
37/14
0.283
Duration of anaesthesia (min)
84.3 ± 4.4
83.9 ± 4.3
85.6 ± 4.5
0.153
Duration of surgery (min)
44.0 ± 2.7
43.1 ± 3.0
44.1 ± 3.3
0.202
Propofol dose (mg kg−1 )
2 [2 to 2]
2 [2 to 3]∗
2 [2 to 3]
<0.001
Sufentanil dose (μg kg−1 )
0.5
0.5
0.5
NS
Data are presented as mean ± SD, or median [IQR], n /n . ASA, American Society of Anaesthesiologists.
∗ P < 0.001, dexmedetomidine group versus the midazolam group.
The median [IQR] peak PAED scores were 6 [5 to 7] in Group D, 8.5 [8 to 12] in Group M and 9 [8 to 12] in Group P (Fig. 2 ). Using a threshold of at least 10, the incidences of emergence delirium in Groups D, M and P were 11.5% (6 of 52), 44% (22 of 50) and 49% (25 of 51), respectively. The incidence of emergence delirium in Group D was significantly lower than that in Group M (P < 0.001, RR = 0.262, 95% CI 0.116 to 0.592) and in Group P (P < 0.001, RR = 0.235, 95% CI 0.105 to 0.525). There were no significant differences between Groups M and P (P
= 0.256, RR = 0.898, 95% CI 0.59 to 1.366).
Fig. 2: Violin plots of the peak Paediatric Anaesthesia Emergence Delirium scores while in the postanaesthesia care unit. The peak Paediatric Anaesthesia Emergence Delirium scores in the dexmedetomidine group were significantly lower than that in the midazolam and saline groups (both P < 0.001). The violin plots represent the distributional shape of the data using kernel density estimation. The white dot represents the median, the thick bar represents the interquartile range and the thin line represents the rest of the distribution.
As shown in Table 2 , there were no significant between-group differences in the postoperative pain scores (modified CHEOPS) in the PACU (P
= 0.269). The quality of induction in Group D was significantly higher than that of Groups M and P during sevoflurane induction (both P < 0.001). The emergence time of Group D was longer than that of Groups M and P (both P < 0.001). However, length of stay in PACU was similar among the three groups (P = 0.537). The incidence of PONV within the first 24 h after surgery was significantly lower in Group D (3.8%, 2 of 52) than in the Group M (22%, 11 of 50; P = 0.006) or Group P (29.4% 15 of 51; P < 0.001). Furthermore, the parent's satisfaction scores were significantly higher in Group D than in Groups M and P (both P < 0.001).
Table 2 -
Quality of inhalational induction and postoperative data
Group dexmedetomidine, n =52
Group midazolam, n =50
Group saline, n =51
P value
Inhalational induction quality
3 [3 to 4]
2.5 [2 to 3]∗
2 [2 to 3]∗∗
<0.001
Emergence time (min)
21 [19.3 to 23.8]
17 [16 to 18]∗
14 [13 to 15]∗∗
<0.001
Peak PAED score ≥10
6 (11.5)
22 (44)∗
25 (49)
<0.001
Postoperative modified CHEOPS score
1 [0.25 to 1]
1 [1 to 1]
1 [0 to 1]
0.269
Number of patients who received propofol in PACU
6
22∗
25
<0.001
Number of patients who received morphine in PACU
0
0
0
NS
Length of stay in PACU (min)
21 [19 to 24]
22 [20 to 24]
22 [20 to 24]
0.537
Parents’ satisfaction
10 [9 to 10]
8 [7 to 9]∗
7 [6 to 8]∗∗
<0.001
Occurrence of PONV
2 (3.8)
11 (22)∗
15 (29.4)∗∗
<0.001
Data are presented as median [IQR], or number (percentage). CHEOPS, Children's Hospital of Eastern Ontario Pain Scale; PACU, postanaesthesia care unit; PAED, Paediatric Anaesthesia Emergence Delirium; PONV, postoperative nausea or vomiting.
∗ P < 0.05, dexmedetomidine group versus midazolam group.
∗∗ P < 0.05, the midazolam group versus the saline group.
The heart rates (HRs) were significantly lower than baseline at 15, 30 and 45 min in Group D compared with Groups M and P (all P < 0.001, Fig. 3 ). During the observation period, no adverse effects such as bradycardia, hypotension, laryngospasm or hypoxemia were identified.
Fig. 3: Changes in heart rate after patients received intranasal dexmedetomidine (2 μg kg−1 ) (●), oral midazolam (0.5 mg kg−1 ) (▪) or 0.9% saline (▴) as a premedication. Heart rate was reduced significantly from baseline at 15, 30 and 45 min in the dexmedetomidine group compared with the midazolam and saline groups (all P < 0.001). Data are represented as mean and SD.
Discussion
The current study demonstrated that intranasal dexmedetomidine premedication is superior to oral midazolam in terms of reducing the incidence of emergence delirium after sevoflurane anaesthesia, without extending the time until discharge from the PACU or increasing clinically relevant adverse events. Furthermore, intranasal dexmedetomidine premedication is useful in facilitating a smooth inhalational induction, reducing the incidence of PONV and improving the parent's satisfaction.
Emergence delirium is characterised as a dissociated state of consciousness, which occurs typically in preschool children after sevoflurane anaesthesia. Although emergence delirium remains a poorly understood phenomenon, there are many risk factors including pre-operative anxiety, pain and rapid awakening in an unknown environment which should be considered. To alleviate pre-operative anxiety and achieve a smooth induction of inhalation anaesthesia, both midazolam and dexmedetomidine have been proposed as pre-operative anxiolytics to minimise the distress of children in the operating room. A recent systematic review has identified gaps in the literature for comparing the effectiveness of pre-operative intranasal dexmedetomidine against oral midazolam for emergence delirium in the paediatric population.12
Oral midazolam is a widely used premedication in the paediatric population. However, its efficacy in preventing emergence delirium is debateable. Some studies have suggested that midazolam premedication can reduce the incidence of emergence delirium, whereas others have shown that it does not. The current study found that midazolam was ineffective in preventing emergence delirium after sevoflurane anaesthesia for strabismus correction, as noted previously.6
Intranasal administration is an effective and noninvasive route for delivering dexmedetomidine to paediatric patients.19 −1 ) prolonged emergence by some 4 to 8 min, and this may be one possible explanation for the reduction in emergence delirium. However, the delayed emergence from anaesthesia did not prolong the time to discharge from the PACU. In addition, a report has pointed out that most parents prefer a calm and sedated child during the first 24 h postoperatively,20 21
Pain is widely regarded as a significant contributing or confounding factor to emergence delirium22 23
There are some limitations to the current study that require consideration when interpreting the results. First, we did not assess the dose–response relationship of dexmedetomidine premedication. The dose of dexmedetomidine (2 μg kg−1 ) was standardised based on our routine clinical practice and previous studies.24,25
In summary, when compared with oral midazolam (0.5 mg kg−1 ) for premedication, intranasal dexmedetomidine (2 μg kg−1 ) was shown to be superior in reducing both the incidence of emergence delirium and postoperative nausea and vomiting.
Acknowledgements relating to this article
Assistance with the study: we gratefully acknowledge Prof Zhiwei Li (Department of Ophthalmology, Fujian Provincial Hospital, Fuzhou, China) and Guiqin Wu (Department of Surgical Nursing, Fujian Provincial Hospital, Fuzhou, China), for their support and co-operation.
Financial support and sponsorship: this study was supported by Fujian Joint Funds for the Innovation of Science and Technology (grant number 2017Y9066), Natural Science Foundation of Fujian Province (grant number 2018J01246), Fujian Medical University Startup Fund for scientific research (grant number 2018QH1110), Fujian Medical Innovation Project (grant number 2019-CXB-6) and High-level hospital foster grants from Fujian Provincial Hospital (grant number 2020HSJJ01).
Conflicts of interest: none.
Presentation: none.
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