DOI: https://doi.org/10.21203/rs.3.rs-1507806/v1
Study Objectives: The purpose of this study is to confirm that preoperative nasal spray esketamine administration can reduce separation anxiety in pediatric patients and can decrease the occurrence of emergence agitation in children undergoing general anesthesia with sevoflurane for strabismus surgery.
Design: Randomized, double-blind clinical controlled trial.
Patients: The trial included 90 children with American Society of Anesthesiologists physical status Ⅰand Ⅱ who underwent elective strabismus surgery.
Interventions: The children were randomly divided into 3 groups: group S1, group S2, and group C, and the intervention of each group was as follows:the children in group S1 were given 0.5mg/kg esketamine by nasal spray 10 minutes before operation, the children in group S2 were received 1mg/kg esketamine by nasal spray 10 minutes before operation, the children in group C were accepted same volume of normal saline by nasal spray 10 minutes before operation.
Measurements: The observation indicators of this test include Ramsay Sedation score, separation anxiety score, mask induction score and the incidences of postoperative emergence agitation. Patient's heart rate, blood oxygen, PACU stay time, and any adverse events were recorded.
Main Results: The Ramsay sedation score were significantly lower in the group C than those in the S1 andS2 groups (P <0.05). The separation anxiety score and mask induction scores were significantly higher in the group C than those in the S1 andS2 groups (P <0.05).The incidences of emergence agitation in the S1 and S2 groups were significantly lower than that in the group C (P <0.05). There was no difference in the PACU stay time among the 3 groups (P >0.05). All patients had no obvious clinical complications.
Conclusion: Premedication with nasal spray esketamine could reduce preoperative separation anxiety and decrease emergence agitation in preschoolers undergoing general anesthesia with sevoflurane for strabismus surgery.
Trial registration: Registered number is ChiCTR2100045441. Registered 15Apr 2021,Registration website http://www.chictr.org.cn/showproj.aspx?proj=125156
Strabismus is a common eye disease in pediatric. Strabotomy should be operated early in pediatric to ensure the normal development of visual function[1]. Pediatric cannot to cooperate strabismus surgery awake, therefore they need to undergo general anesthesia. Preschool children is highly dependent on their parents, so they often show separation anxiety even cry when separated from parents[2]. The incidence of postoperative emergence agitation in children with strabismus surgery was higher than that of other operations, which may be due disturbed vision and eye patching upon awaking[3].Emergence agitation, including restlessness,disorientation, and inconsolable crying, may bring many risks to children after strabismus surgery suture breakage and conjunctival hemorrhage.
Sevoflurane is generally the preferred anesthetic agent for induction and maintenance of general anesthesia in pediatric patients,due to its rapid induction, fast recovery characteristics and easy adjustment of anesthesia depth[4]. However,sevoflurane has some disadvantages.Although sevoflurane smell is described as “fruity”, children still can't accept its unpleasant smell and don't willing to cooperate with sevoflurane mask induction. Sevoflurane is also considered to be one of the causes of emergence agitation after general anesthesia in children[5].
Many kinds of anesthetic adjuvants, including sedatives and analgesics, have been effectively used to reduce the adverse effects of sevoflurane, such as sufentanil, midazolam, propofol, ketamine, dexmedetomidine[6]. However, due to their sedative and analgesic properties, these drugs may cause some adverse reactions, leading to delayed awakening, respiratory depression or nausea and vomiting. So we need to find a anesthetic agents that can not only produce sedative effect, reduce the separation anxiety of children before operation, decrease the occurrence of emergence agitation, but also do not to prolong the recovery time and to produce side effects such as respiratory inhibition, nausea and vomiting. Esketamine is a kind of ketamine right-lateral isomer with greater efficiency. Esketamine has both sedation and analgesia function with multiple delivery way(eg.intravenous, intramuscular, oral, nasal)[7]. Among these delivery way, nasal spray is very suitable for preoperative pediatric surgery because of its easily accepted by children and action quickly.
The purpose of present study was to determine the effects of premedication with nasal spray esketamine on preoperative separation anxiety and postoperative emergence agitation in preschoolers undergoing general anesthesia with sevoflurane for strabismus surgery.
The research was approved by ethics committee of Tianjin eye hospital. The test was registered in Chinese clinical trial registry with the number (ChiCTR2100045441,first registration date 15/4/2021). The trial included 90 children with American Society of Anesthesiologists physical status Ⅰand Ⅱ who underwent elective strabismus surgery. The approval of the parents was then obtained, and informed consent was signed. The exclusion criteria are as follows: moderate upper tract infection, neurologic illness, parental refusal, other contraindications to the use of esketamine.
Randomization grouping of 96 children screened, six of them withdrew the trial. Finally 90 children were randomized divided into 3 groups, groups C and S1, and S2 by computer-generated randomization program. The flow chart of subjects was shown in Fig. 1.The patients, guardians and the anesthesiologist who conducted the nasal spray were blinded to reduce bias.
The specification of esketamine used in this test is 50mg/2ml, and the initial concentration is 25mg/ml. Children in group S2 were treated with undiluted esketamine stock solution, whereas children in group S1 were received with 12.5/ml of esketamine diluted twice with normal saline. Finally, the volume of nasal spray received by each group was 0.4ml/kg. Patients in group accepted the same volume of sterile normal saline. Esketamine or saline were sprayed into the nostrils of the children accompanied by their parents 10 minutes before anesthesia induction.
The intravenous indwelling needle was placed with the parents the night before operation to reduce the adverse stimulation of preoperative venipuncture to children. Solid food was forbidden for 8h, formula milk was forbidden for 6h and sugar water was forbidden for 2h before operation. All children were given 0.01mg/kg penehyclidine hydrochloride intramuscularly 30 minutes before operation to reduce oral and respiratory secretions. Patients separation anxiety score and sedation scores were recorded when children enter the operation alone and separated from their parents. Anesthesia induction was performed using a mask with 6% sevoflurane and oxygen flow at 5 L/min.The degree of mask acceptance was recorded by anesthesiologists who did not know the preoperative drug grouping according to a modified 3-point scale (1 = calm, cooperative or asleep; 2 = moderate fear of the mask, cooperative with reassurance; and 3 = combative, crying)[8–9]. Child struggled and cried seriously during mask induction was recorded score of 3 and regarded as dissatisfied with the preoperative medication, and intravenous propofol of 1mg / kg was given immediately as a remedy. The mask acceptance score of 1–2 is considered to be effective for this nasal spray. Insert the reinforced flexible laryngeal mask (LMA) after the patient's jaw relaxed and the throat reflex disappeared. Sufentanil 0.1-0.2ug/kg was given intravenously for intraoperative analgesia, and 2–4 drops of local anesthetic were used in the conjunctiva for intraoperative analgesia before the operation. Intraoperative anesthesia maintenance combined intravenous and inhalation anesthesia with intravenous infusion of propofol 2-4mg/kg/hand inhaling 3–4% sevoflurane. No muscle relaxants were used during the whole anesthesia process, and the patient kept spontaneous breathing throughout the whole process. Routine intraoperative monitoring included electrocardiogram, blood pressure, heart rate, blood pressure, pulse oxygen saturation respiratory rate, tidal volume, end-tidal carbon dioxide, end respiratory sevoflurane concentration, MAC value. In case of respiratory depression during operation, auxiliary ventilation should be given in time to maintain end-tidal CO2 pressure levels between 35 and 50 mm Hg. Close sevoflurane volatilization tank after operation and increase oxygen flow to 6 L/min to eliminate sevoflurane from breathing. Patients were transferred with LMA to the PACU with adequate spontaneous ventilation.
After the children transferred to PACU,the blood pressure, heart rate and blood oxygen were continuously monitored. The children were given safe and comfortable care by the anesthesia nurse during the whole recovery process. Children were evaluated every 5 minutes for emergence time after arriving at the PACU.The scores of children were continuously evaluated according to the Pediatric Anesthesia Emergence Delirium (PAED) scale [10] and the Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) scores [11] and the maximal scores were recorded. The evaluation standard of postoperative agitation was PAED scores > 10; moreover, intravenous propofol 1mg/kg should be given immediately for sedation as a remedial measure once the score exceeds 15. All adverse incidents including but not limited to respiratory depression, postoperative nausea or vomiting and laryngospasm were recorded.
In this study, we took the separation anxiety score as the main observation end point. Through the pilot study (unpublished), we obtained that the mean separation anxiety score of the three groups (n = 8) were 1.8, 1.3 and 2.8 respectively, and the standard deviation was 0.6, 0.5 and 0.6 respectively according to α = 0.05, β = 0.1, the sample size calculated by the sample size calculation formula of multi group mean comparison is 18 cases, and the sample size of each group is 27 according to the 50% shedding rate of each group.
Continuous data were expressed as the means ± SD or means of the patients, and these variables were analyzed by 1-way analysis of variance. The statistical software used was SPSS for Windows version 21.0. A P value less than 0.05 was considered to be statistical difference.
The trial initially recruited 96 participants, and finally 90 subjects were included in the trial due to some reasons in the exclusion criteria (Fig. 1). Finally 90 children were randomized divided into 3 groups, groups C and S1, and S2 by computer-generated randomization program received different dosages of nasal spray normal saline or esketamine. We counted the general conditions of the patients, including weights, the ages, American Society of Anesthesiologists physician status, ratios of sex, duration of anesthesia and surgery. There was no statistical difference in the above descriptions among 3 groups (P > 0.05, Table 1).
|
S1 group Esketamine 0.5mg/kg |
S2 group esketamine 1mg/kg |
C group normal saline |
Age(y) |
4.12±0.51 |
4.58±0.13 |
4.87±0.42 |
Weight(kg) |
15.77±2.33 |
16.47±1.67 |
16.04±1.56 |
ASA 1/2 |
30 |
30 |
30 |
Duration of anesthesia (min) |
33.38±4.86 |
34.18±3.28 |
32.42±2.16 |
Duration of surgery (min) |
21.20±3.56 |
20.19±2.35 |
21.54±1.57 |
Eyes operated, 1/2 |
20/10 |
19/11 |
17/13 |
Data are presented as mean ± SD or number of patients. None of these parameters differed significantly among the 3 groups. ASA = American Society of Anesthesiologists |
All of the patients were sedated and easy to be separated from parents without cry after nasal sketamine treatment in groups S1 andS2, whereas There was no sedative effect in children with normal saline spray in group C. The Ramsay sedation score were significantly lower in the group C than those in the S1 andS2 groups (P < 0.05). The separation anxiety score were significantly lower in the group S1 and groups S2 than those in the group C (P < 0.05). Patients who received nasal spray esketamine showed more cooperation for mask induction.The acceptance scores of masks in S1 and S2 groups were significantly lower than those in C group (P < 0.05; Table 2);
S1 group esketamine 0.5mg/kg |
S2 group esketamine 1mg/kg |
C group normal saline |
|
---|---|---|---|
Ramsay Sedation score |
3.2a ± 0.23 |
3.5a ± 0.36 |
1.3 ± 0.28 |
separation anxiety score |
1.8a ± 0.6 |
1.3a ± 0.4 |
2.8 ± 0.5 |
mask induction score |
1.5 ± 0.2 |
1.2a ± 0.17 |
2.8 ± 0.16 |
Data are presented as mean ± SD | |||
Compared with group C, aP<0.05 |
The evaluation criteria of postoperative emergence agitation was PAED score greater than 10 in this study, and we found that pretreatment with different dosages of nasal spray esketamine significantly decreased the incidence of emergence agitation as compared with the group C, the number of postoperative emergence agitation in each group were (7 in group S1 and 4 in group S2 vs 18 in group C, P < 0.05; Table 3). Furthermore, PAED scores scores were consistent with the above results, groups S1 and S2 were statistically lower than those in group C (P < 0.05; Table 3).
S1 group esketamine 0.5mg/kg |
S2 group esketamine 1mg/kg |
C group normal saline |
|
---|---|---|---|
Incidence of emergence agitation |
7(23%)a |
4(13%)a |
18(60%) |
PAED scale score |
7.26a ± 0.76 |
5.23a ± 0.61 |
15.3 ± 0.85 |
CHEOPS score |
2.13±0.24 |
2.09±0.36 |
2.25 ± 0.46 |
Anesthesia duration(min) |
25.58 ± 2.35 |
24.78 ± 3.04 |
26.70 ± 2.02 |
PACU stay time(min) |
28.34 ± 5.62 |
29.33 ± 4.20 |
28.52 ± 5.11 |
PAED = Pediatric Anesthesia Emergence Deliium; CHEOPS = Children's Hospital of Eastern Ontario Pain Scale. | |||
Data are presented as mean ± SD | |||
Compared with group C, aP<0.05 |
The nasal spray of esketamine did not prolong the time of PACU. From Table 3, we can see that there is no statistical difference in PACU stay time among the three groups(P > 0 .05; Table 3). Although the heart rate of children in S1 and S2 group was faster than that of children in C group (P < 0.05; Table 4), the times of acceleration had no clinical significance and did not need special drug treatment. There was no respiratory depression during preoperative sedation in S1 and S2 groups, and there was no significant difference in blood oxygen compared with group C(P > 0 .05; Table 4). No nausea, vomiting and laryngospasm occurred in all the children in the operating room
Group |
T1(baseline) |
T2(5min) |
T3(10min) |
|
---|---|---|---|---|
C group |
SpO2 |
98 ± 0.9 |
99 ± 0.5 |
99 ± 0.6 |
HR |
114 ± 5.3 |
113 ± 6.8 |
115 ± 6.2 |
|
S1 group |
SpO2 |
99 ± 1.1 |
98 ± 0.8 |
99 ± 0.4 |
HR |
118 ± 3.8 |
120a ± 4.1 |
123a ± 4.8 |
|
S2 group |
SpO2 |
98 ± 0.7 |
99 ± 1.6 |
98 ± 1.3 |
HR |
116 ± 3.9 |
124a ± 4.2 |
126a ± 3.1 |
|
Compared with group C, aP<0.05 |
The study testified that nasal spray esketamine could not only reduce preoperative separation anxiety but also decreased the high incidence of postoperative emergence agitation in preschoolers underwent general anesthesia with sevoflurane for strabismus surgery. Moreover, the advantage of esketamine are that the nasal spray is easy to be been accepted by the children and action quickly. There are no side effects such as respiratory depression and prolonged PACU staying time.
Preschool children were emotionally vulnerable and highly depended on their parents, so when separated from parents they often show anxiety, fear and even crying refused to separate [2, 12].Children with preoperative adverse separation memory will affect the implementation of the anesthesia induction and the quality of anesthesia leading to emergence agitation [13, 14], more serious may cause mental trauma, fear, urinary incontinence, depression, anxiety and other sequelae. So it is very important meaningful to reduce the separation anxiety before anesthesia in children undergo strabismus surgery. Preoperative psychological intervention and non-drug measures can ease some children with the separation anxiety rate, but preoperative medication is still is the most effective way to relieve patients preoperative separation anxiety.
Esketamine, a dextral ketamine isomers is now available in China.It has twice the anesthetic potency of racemic ketamine[15]and produces less psychomimetic side effects than racemic ketamine [16].Because awake children are more likely to receive nasal spray, so we used nasal spray esketamine in the present study. Moreover, the benzene ring structure of esketamine enhances its fat solubility. After nasal spray administration, it is easy to penetrate the cell membrane of nasal mucosa, and the onset time is fast. In this experiment, it is observed that the onset time is 5–10 minutes after nasal spray, which is faster than that before dexmedetomidine surgery reported by Cimen ZS [17].
Strabismus surgery is a short surgery with little stimulation but needs meticulous operation [1],therefore, the anesthesia for pediatric strabismus surgery requires absolute braking and appropriate analgesia. Sevoflurane inhalation anesthesia induction and laryngeal mask to maintain spontaneous breathing is a very suitable anesthesia scheme for pediatric strabismus surgery[18]. Sevoflurane inhalation anesthesia induction and maintenance is widely used in pediatric anesthesia, because sevoflurane can retain the patient's spontaneous breathing, the induction of recovery is fast and controllable[19–20]. Although sevoflurane does not stimulate the respiratory tract, many children still often resist sevoflurane mask induction due to the unpleasant smell. Moreover,the unpleasant experience induced by anesthesia induction has been demonstrated to impact on postoperative emergence agitation when waking up.Therefore, it is necessary to give appropriate sedation before anesthesia induction [5]. In the our study, we found that esketamine nasal spray provided adequate sedation effect for pediatric patients undergoing inhalational mask induction, and nasal spray esketamine (0.5 or 1 mg/kg) significantly reduced the mask scores as compared with group C. The quality of anesthesia induction was improved.
Postoperative emergence agitation is very common in children under sevoflurane general anesthesia, and the incidence of ophthalmic surgery is higher [21]. Postoperative pain is often considered to be one of the main causes of postoperative agitation [22]; however, due to less surgical stimulation and the application of local anesthetics, the severity of postoperative pain after strabismus surgery is relative low, and the VAS score is 1 to 2 [23]. There was no difference in CHEOPS scores among 3 groups in our study. We speculate that the main causes of postoperative emergence agitation are the use of sevoflurane and postoperative visual field occlusion. Previous studies have reported, a single dose or continuous infusion of ketamine has been shown to reduce emergence agitation after sevoflurane in children[24]. Interestingly, we found that a single dose of esketamine spay prior to induction can also suppress postoperative emergence agitation without prolonging emergence time.
Furthermore, we found that 0.5 or 1mg/kg nasal spray of esketamine has no respiratory depression and can be safely used for preoperative sedation in children. We observed that the whole course of blood oxygen in the three groups was more than 97%. There are some limitations in our study. No midazolam or dexmedetomidine group was established to compare the effects with esketamine in preschoolers.
In conclusion, nasal spray esketamine 0.5 or 1mg/kg significantly reduced separation anxiety and also decreased the incidence of postoperative emergence agitation in children undergoing general anesthesia with sevoflurane for strabismus surgery.
Ethics approval and consent to participate
This study was approved by Tianjin eye Hospital ethical committee and registered at the Chinese Clinical Trial Registry with registration number ChiCTR2100045441.All the experiment protocol for involving humans was in accordance to the guiding principles of the Helsinki declaration. All parents of the included pediatric patients provided written, informed consent.Informed consent was obtained and the consent form was signed by the parents of each participant.
Funding
This study was funded by anesthesiology departmental of Tianjin eye hospital.
Authors’ contributions
Liu Wei and Ruiqiang Sun contributed to the conception and design of the study and manuscript drafting. Xuesong Gao and Shuzhen Wang were involved in the acquisition, analysis, and interpretation of the data. Wei Liu an Ruiqiang Sun contributed equally to this work and shared the co-first authorship. All authors have given final approval of the version to be published.
Competing interests
The authors declare that they have no competing interests.
Acknowledgements
Not applicable
Publication and availability of data material
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Consent for publication
Not applicable