Effect of oral esketamine on preoperative sedation and venipuncture analgesia in pediatric patients: a prospective randomized double-blind controlled clinical trial

doi:10.21203/rs.3.rs-2323639/v1

Background

Anxiety and uncooperation are common among pediatric patients during the preoperative preparation, which requires adequate and appropriate analgesia and sedation.

Methods

We performed a prospective, randomized, double-blind, controlled clinical trial involving 1–6-year-old pediatric patients scheduled for elective tonsillectomy or adenoidectomy between December 2020 and May 2021. Patients were randomly assigned to control (group C), esketamine 1 mg.kg^− 1 (group EK1), or esketamine 2 mg.kg^− 1 (group EK2) group. Venipuncture analgesia, cooperation, and sedation, as well as satisfaction upon parent–child separation, cooperation, sedation, and adverse events, were compared among the three groups. Dynamic changes in the sedation score and vital signs were monitored.

Results

A total of 88 pediatric patients were analyzed, with 29, 29, and 30 patients in groups C, EK1, and EK2, respectively. Compared with group C, groups EK1 and EK2 both had better analgesia during venipuncture (P < 0.001). In addition, better cooperation and sedation was noticed in groups EK1 and EK2 during parent–child separation and venipuncture than in group C. Compared with the baseline, the mean respiratory rate had a significant decrease from 25.6 ± 0.3 to 24.6 ± 0.4 breaths/min at 30 min after the esketamine administration in group EK2, although it was still within normal limits (P = 0.030). There were no significant differences in adverse events among three groups.

Conclusions

Preoperative oral administration of 1 or 2 mg.kg^− 1 esketamine in pediatric patients could achieve effective analgesia and sedation. Oral medication of 2 mg.kg^− 1 esketamine had more pronounced effects.

Trial registration

: This clinical trial was registered at the Chinese Clinical Trial Registry (ChiCTR2000040739) on 08/12/2020.

esketamine

analgesia

sedation

parent–child separation

pediatrics

Preoperative anxiety among pediatric patients can affect clinical management and have a great impact on the clinical procedures, prognoses, and mental health of children[1]. Preoperative parent–child separation and venipuncture—the first steps before pediatric anesthesia—are difficult to complete with an uncooperative child, so adequate sedation and analgesia should be provided. At present, sevoflurane, dexmedetomidine, midazolam, and ketamine are commonly used in the preoperative or procedural sedation and analgesia of pediatric patients[2, 3], although they have the disadvantages of being environmental pollutants, with poor acceptance and inadequate analgesic effects.

Esketamine, the dextrorotatory isomer of ketamine, retains the conventional characteristics of ketamine without cardiovascular and respiratory depression[4, 5]. Moreover, esketamine has stronger sedative and analgesic effects than ketamine, and it has been used successfully in pediatric procedural sedation and analgesia[6, 7]. The safety and feasibility of oral administration of esketamine has been previously studied to treat patients with depression[8]. No other studies have investigated whether esketamine could be used for preoperative parent—child separation and venipuncture analgesia.

Here, we report a prospective, randomized, double-blind, controlled clinical trial that evaluates the efficacy and safety of the oral administration of esketamine in children during the preoperative period. Its findings will allow clinicians to better prepare children for any necessary procedures.

Study design and registration

Our study was a prospective, randomized, double-blind, controlled clinical trial conducted in the Liaocheng People’s Hospital, Shandong, China, between December 2020 and May 2021. The study was approved by the Ethics Committee of Liaocheng People’s Hospital. Written informed consent was obtained from the guardians of each recruited pediatric patient. This study was registered in the Chinese Clinical Trial Registry on 08/12/2020 (ChiCTR, https://www.chictr.org.cn/index.aspx; Registration Number ChiCTR2000040739).

Participant selection and group assignment

Male or female pediatric patients aged 1–6 years, weighing 10–30 kg, in ASA (American Society of Anesthesiology) class I or II, and scheduled for elective tonsillectomy or adenoidectomy were recruited. Children with a history of allergic reactions to esketamine or ketamine; abnormal cardiac, lung, liver, and kidney function; or with systemic or congenital diseases, abnormal intellectual development, history of neuronal or mental diseases, prior establishment of intravenous access, or other types of surgery were excluded from the study.

Eligible pediatric patients were assigned to either a placebo control group (group C), esketamine 1 mg.kg^-1 group (group EK1), or esketamine 2 mg.kg^-1 group (group EK2) based on a random number generated in MS Excel software (Microsoft Corporation, Redmond, WA, USA). The group assignment was blinded to the investigators, clinical physicians, pediatric patients, and their families.

Study protocol and interventions

Patients fasted from midnight prior to the surgery date. Heart rate (HR), respiratory rate (RR), electrocardiogram (ECG), and oxygen saturation (SpO₂) were monitored after the pediatric patient entered the preoperative room. A dedicated nurse prepared the esketamine solution (Hengrui Pharma, Jiangsu, China) and orally administered it to the patients based on their group assignment. Pediatric patients in groups EK1 and EK2 received 10% glucose solution (0.2 ml.kg^-1) containing 1 mg.kg^-1 or 2 mg.kg^-1 esketamine, respectively. Group C patients received a 10% glucose solution (0.2 ml.kg^-1). The parent–child separation was performed approximately 15 min after oral medication administration, which was followed by venipuncture. After a successful venipuncture, the pediatric patients were transferred to the operating room. Then, every child received general anesthesia induction and tracheal intubation from the same anesthesia team. A nursing staff member who was blinded to the group assignment was responsible for recording vital signs and outcome scores during the perioperative period.

Outcome measurements

The primary outcome was the analgesic score during venipuncture (supplementary Table S1). The secondary outcomes were parent–child separation cooperation, venipuncture cooperation, and sedation (supplementary Table S1). The onset time of medication was based on the mental changes (i.e., being quiet, blurred eyes, or sleepy blinking) of pediatric patients after medication was administered. The Ramsay Sedation Scale was used to assess the level of sedation. The details of these evaluations are described in the literature[9–11].

In addition, we also measured the Ramsay sedation scores, HR, RR, and SpO₂before and 5, 10, 15, 20, 25, and 30 min after medication administration. Incidences of adverse events (including nausea or vomiting), increased secretion, nystagmus, dizziness, and molar accompanied involuntary head swing were recorded from esketamine administration until the end of the recovery period.

Statistical analyses

The sample size was calculated based on the analgesic scores. According to the preliminary experimental results, the analgesic scores of group C, group EK1, and group EK2 were 3.0±1.1, 2.5±1.1, and 2.0 ±1.1, respectively. At α=0.05 and 1-β=90%, a two-sided ANOVA (analysis of variance) would require 22 participants in each of the groups C, EK1, and EK2. Taking into account a 20% lost-to-follow-up ratio, at least 28 cases were therefore recruited into each group (PASS [version 11.0] software; NCSS LLC, Kaysville, UT, USA).

Statistical analyses were conducted using SPSS (version 23.0) software (IBM, New York, NY, USA). Categorical data are expressed as numbers (percentage) and compared using the Chi-squared test. Continuous data are expressed as mean ± standard deviation (±s) and compared by one-way ANOVA. Intergroup comparisons were performed using one-way ANOVA with repeated measures. P<0.05 was considered statistically significant.

Characteristics of study participants

A total of 192 pediatric patients scheduled for elective tonsillectomy or adenoidectomy were assessed. After excluding 102 patients, 90 patients entered the randomization stage. One child from group C and group EK1, respectively, spat out the esketamine solution due to its bitter taste. Finally, 88 patients completed the clinical trials and were analyzed, with 29 pediatric patients in group C, 29 in group EK1, and 30 in group EK2, respectively (Fig. 1). There were no significant differences among the three groups in age, gender, height, body mass index, ASA class, surgery type, and the time of venipuncture initiation after esketamine administration. However, body weight was significantly different (P=0.019) between the groups (Table 1).

Primary outcome comparisons

As shown in Table 2, the EK1 and EK2 groups had better analgesia during the venipunctures compared with group C.

Secondary outcome comparisons

As shown in Table 2, compared with Group C, Group EK1 and EK2 patients exhibited better venipuncture cooperation, venipuncture sedation, and parent–child separation cooperation. Compared with group C, group EK2 participants had better parent–child separation sedation. Moreover, compared with group EK1, group EK2 participants had better venipuncture sedation. There were no statistically significant differences in the other secondary outcomes.

The dynamic changes in the sedation scores are shown in Figure 2 (Fig. 2). Significantly lower sedation scores were determined after 25 min in the C group than at baseline (P=0.001), suggesting a poor sedation status during the time point of venipuncture. Sedation scores were higher at each time point after esketamine administration in the EK1 group and EK2 group compared to baseline.

To evaluate the safety of esketamine administration, we monitored the HR, RR, and SpO₂ in these pediatric patients. In group C, HR was significantly higher at 25 min (P<0.001) and 30 min (P<0.001) than the baseline, which was the time point for venipuncture, suggesting that HR increased following venipuncture (Fig. 3). A similar significant increase in HR was observed 25 min after the administration of medication (P=0.021) in group EK1. However, we did not observe a significant difference in HR at each time point among the EK2 group patients (Fig. 3). No significant difference in RR at each time point was detected in either group C or group EK1 patients (Fig. 4). In group EK2, a significantly decreased RR (from 25.6 ± 0.3 to 24.6 ± 0.4 breaths/min) was observed 30 min after esketamine administration (P=0.030) (Fig. 4). After successful intravenous catheterization, an oxygen mask was routinely placed on the patients to prepare for anesthesia induction. As a result, SpO₂ was gradually elevated in all three groups (Fig. 5).

Adverse event comparisons

No statistically significant differences in adverse events were identified among the three groups (Table 3).

In the present study, we showed that pediatric patients had better analgesia, sedation, and cooperation after receiving oral esketamine during the preoperative period. The parent–child separation performance, venipuncture cooperation, and venipuncture analgesia were also rated higher in pediatric patients who received oral esketamine compared to the control patients. There were no significant differences in adverse events between pediatric patients with or without oral esketamine.

Anxiety was reported in approximately 60–80% of pediatric patients during the preoperative period[12, 13]. Indeed, preoperative anxiety can negatively impact surgical outcomes and cause short- or long-term psychiatric issues. Various factors, such as pain, parent–child separation, types of surgery, and the degree of cooperation, could affect preoperative anxiety in children[14]. Studies have investigated different pharmacological or non-pharmacological methods to decrease pain and improve cooperation to minimize preoperative anxiety in pediatric patients.

Esketamine is a phencyclidine derivative. Studies have reported that esketamine is one of the medications commonly used for procedure sedations[2, 3]. Several previous studies have investigated the effects of esketamine during the perioperative period. Lu et al. compared intranasal dexmedetomidine, esketamine, and the combination of dexmedetomidine and esketamine during the induction of anesthesia[15]. The results showed that the combination group had better sedation and cooperation and fewer incidences of agitation and delirium than either the dexmedetomidine or esketamine groups. In 2021, Xin et al. performed a prospective study and found that intranasal esketamine at 0.5 mg/kg was similar to a high dose of dexmedetomidine at 2.0 µg/kg in terms of sedation onset time and analgesia in children for dental surgery[16]. Another retrospective study analyzed the sedation procedure with intravenous esketamine in 151 pediatric patients with forearm fractures and showed that esketamine was a safe and effective medication during fracture reduction[17]. During the procedure sedation for intussusception reduction in children, 0.5–1 mg.kg^− 1 intravenous esketamine was also shown to have better efficacy and similar safety to morphine[18].

In the present study, we tested an oral esketamine solution during pediatric preoperative sedation. Unlike the strong sour and bitter flavor of midazolam[11], the esketamine solution was only slightly bitter[19]. However, to mask its unpleasant taste, we prepared esketamine in 10% glucose solution. As a result, only one child from Group C and Group EK1, respectively, spat out the medication, suggesting that most pediatric patients were able to tolerate the esketamine–glucose solution taste. Hence, our use of esketamine with glucose solution provides another option for pediatricians administering this medication to children.

In the present study, we tested the efficacy of esketamine as a pediatric preoperative sedative. Our study showed the sedative and analgesic effects of esketamine in this patient population, which are consistent with the aforementioned studies. In addition, we compared different doses of esketamine during preoperative sedation. Our results showed that high-dose esketamine (2 mg.kg^− 1) had better sedative, analgesic, and cooperative effects than low-dose esketamine (1 mg.kg^− 1); however, there was no significant difference in the incidence of adverse events between these two different esketamine doses. The higher (2 mg.kg^− 1) dose of esketamine was also rated better in parent-child separation, venipuncture cooperation, and analgesia compared with the lower esketamine dose. Although a significant decrease in respiratory rate was observed 30 min after the administration of a high-dose esketamine (2 mg.kg^− 1), it was still within normal limits.

A recent study by Zheng et al. compared different intravenous doses of esketamine in combination with propofol in children undergoing endoscopic examination. They suggested that an intravenous dose of esketamine should not exceed 1 mg.kg^− 1 in order to avoid esketamine-related adverse events. Weber et al. tested intranasal esketamine at concentrations of 1 mg.kg^− 1 and 2 mg.kg^− 1 in combination with midazolam and demonstrated a satisfactory anesthesia induction and safety profile[20]. Marhofer et al. reported that the preoperative rectal administration of 1.5 mg.kg^− 1 esketamine had a low incidence of side effects but insufficient sedation efficacy[21]. Thus, esketamine administrations using different routes (e.g., oral, rectal) can result in different bioavailability and maximum concentrations of the medication[22]. Based on our observations, we believe that oral esketamine is safe in the dose range of 1–2 mg.kg^− 1 with no increase in the incidence of perioperative adverse events. However, oral doses of esketamine greater than 2 mg.kg^− 1 require further studies to determine the benefits and risks.

Esketamine is the dextrorotatory isomer of ketamine. Currently, midazolam, dexmedetomidine, and ketamine are the most frequently studied preoperative sedative and analgesic medications for pediatric patients. Most evidence supports the superior preoperative sedative efficacy of dexmedetomidine compared to midazolam, although dexmedetomidine has the disadvantages of slow onset time and decreased HR or blood pressure in pediatric patients[23]. A randomized controlled trial presented similar sedation and analgesia scores for nasal administration of 1 µg.kg^− 1 dexmedetomidine and 5 mg.kg^− 1 ketamine, but the onset time of dexmedetomidine (about 45 min) lagged remarkably behind that of ketamine (about 5–10 min)[24]. In a study reported by Xin et al., the onset time for intranasal esketamine was 12 min. In our study, the oral administration of esketamine was 13.6 ± 3.5 and 12.5 ± 3.0 min for groups EK1 and EK2, respectively, which was similar to the intranasal administration of esketamine but slightly longer than the intranasal administration of ketamine. However, the adverse events reported here with esketamine (in less than 25% of the patients) were fewer than that with ketamine administration (33%)[25]. Compared with etomidate, midazolam, propofol, and nitrous oxide, ketamine had the highest incidence of vomiting during the sedation procedure[26]. These pieces of evidence suggest that esketamine could provide sedative effects similar to ketamine, but with a better safety profile and fewer adverse events.

The strength of our present research was that it was the first study to investigate and compare different doses of oral esketamine during preoperative sedation in pediatric patients. However, our study has several limitations. First, we did not monitor blood pressure after the administration of esketamine. Second, our study was performed in a single research center, which might limit the generalizability of the results. Hence, multi-center prospective studies with large sample sizes are required to validate our study results.

Oral administration of esketamine could effectively relieve preoperative anxiety, provide a high-quality parent-child separation experience, and achieve satisfactory sedation and analgesia effects during venipuncture on pediatric patients. Preoperative oral administration of either 1 mg.kg^− 1 or 2 mg.kg^− 1 esketamine in pediatric patients could achieve effective analgesia and sedation. Oral medication of 2 mg.kg^− 1 esketamine had more pronounced effects.

A

adenoidectomy

ANOVA

analysis of variance

ASA

American Society of Anesthesiology

AT

adenoidectomy and tonsillectomy

ECG

electrocardiogram

HR

Heart Rate

RR

respiratory rate

SpO₂

oxygen saturation

SPSS

Statistical Package for Social Science

T

tonsillectomy.

Ethics approval and consent to participate

This research was approved by the ethical committee of Liaocheng People’s Hospital (approval number 2020069; approval date, December 14, 2020). The study was done as per the declaration of Helsinki. Each participant was informed and signed an informed consent form to participate in the trial voluntarily, with the right to withdraw from the study at any time.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

Competing of interests

The authors declare that they have no competing interests.

Funding

No external funding.

Authors’ contributions

LZ conceptualized the study. WX, WG, and XH collected data. XH analyzed the data. LZ, LL, LG, and ZH drafted the manuscript and revised the manuscript. All the authors read and approved the final version of the manuscript.

Acknowledgments

The authors thank the nursing team in the Eye, Ear, Nose, and Throat Operating Room of Liaocheng People's Hospital. We also thank Medjaden Inc. for the scientific editing of this manuscript.

Author details

Department of Anesthesiology, Liaocheng People’s Hospital, Liaocheng, China 252000

Das S, Kumar A. Preoperative Anxiety in Pediatric Age Group—A Brief Communication. J Anesth Crit Care Open Access. 2017;8:1-2.
Sauer H, Lobenhofer M, Abdul-Khaliq H. Analgosedation for diagnostic and interventional procedures: a countrywide survey of pediatric centers in Germany. Ital J Pediatr. 2020;46:14.
Kuypers MI, Smits GJP, Baerends EP, Oskam E, Reijners EPJ, Mignot-Evers LAA, Thijssen WAMH, Plötz FB, Korsten EHM. Paediatric procedural sedation and analgesia by emergency physicians in a country with a recent establishment of emergency medicine. Eur J Emerg Med. 2019;26:168-73.
Saponjic J, Radulovacki M, Carley DW. Modulation of respiratory pattern and upper airway muscle activity by the pedunculopontine tegmentum: role of NMDA receptors.Sleep & breathing = Schlaf & Atmung. 2006;10:195.
Shulman D, Bar-Yishay E, Godfrey S. Drive and timing components of respiration in young children following induction of anaesthesia with halothane or ketamine. Canadian journal of Anaesthesia. 1988;35:368-374.
Patel D, Talbot C, Luo W, Mulvaney S, Byrne E. The use of esketamine sedation in the Emergency Department for manipulation of paediatric forearm fractures: A 5 year study. Injury. 2021;52:1321-30.
Bunt J, Veldhoen ES, Nievelstein R, Hulsker C, Schouten A, Herwaarden M. Effects of esketamine sedation compared to morphine analgesia on hydrostatic reduction of intussusception: A case-cohort comparison study. Pediatric Anesthesia. 2017;27:1091-7.
Smith-Apeldoorn S Y, Veraart J, Kamphuis J, Asselt A, Touw DJ, Aan Het Rot M, Schoevers RA. Oral esketamine for treatment-resistant depression: rationale and design of a randomized controlled trial. BMC Psychiatry. 2019;19:375.
Wang L, Huang L, Zhang T, Peng W. Comparison of Intranasal Dexmedetomidine and Oral Midazolam for Premedication in Pediatric Dental Patients under General Anesthesia: A Randomised Clinical Trial. Biomed Res Int.2020;2020:5142913.
Ekerci S, Dnmez A, Ate Y, Okten F. Oral ketamine premedication in children (placebo controlled double-blind study). European Journal of Anaesthesiology. 1996;13:606-11.
Singh R, Kumar N, Vajifdar H. Midazolam as a sole sedative for computed tomography imaging in pediatric patients. Paediatric Anaesthesia. 2010;19:899-904.
Liang Y, Huang W, Hu X, Jiang M, Liu T, Yue H, Li X. Preoperative anxiety in children aged 2-7 years old: a cross-sectional analysis of the associated risk factors. Translational Pediatrics. 2021;10(8):2024-34.
Getahun AB, Endalew NS, Mersha AT, Admass BA. Magnitude and Factors Associated with Preoperative Anxiety Among Pediatric Patients: Cross-Sectional Study. Pediatric Health, Medicine and Therapeutic. 2020;11:485-94.
Liu W, Xu R, Jia J, Shen Y, Li W, Bo L. Research Progress on Risk Factors of Preoperative Anxiety in Children: A Scoping Review. International Journal of Environmental Research and Public Health. 2022;19(16):9828.
Lu X, Tang L, Lan H, Li C, Lin H. A Comparison of Intranasal Dexmedetomidine, Esketamine or a Dexmedetomidine-Esketamine Combination for Induction of Anaesthesia in Children: A Randomized Controlled Double-Blind Trial. Frontiers in Pharmacology. 2021;12:808930.
Xin N, Xu H, Yue C. Comparison between dexmedetomidine and esketamine in pediatric dentistry surgery. Translational Pediatrics. 2021;10(12):3159-65.
Patel D, Talbot C, Luo W, Mulvaney S, Byrne E. The use of esketamine sedation in the emergency department for manipulation of paediatric forearm fractures: A 5 year study. Injury. 2021;52(6):1321-30.
Bunt J, Veldhoen E S, Nievelstein R, Hulsker C, Schouten A, van Herwaarden M. Effects of esketamine sedation compared to morphine analgesia on hydrostatic reduction of intussusception: A case‐cohort comparison study. Pediatric Anesthesia. 2017;27(11):1091-7.
Bossaller NA, Shelton RC. Real-world approach to managing dysgeusia following the use of esketamine nasal spray: a case report. Annals of General Psychiatry. 2020;19:13.
Weber F, Wulf H, Saeidi G E. Premedication with nasal s-ketamine and midazolam provides good conditions for induction of anesthesia in preschool children. Canadian Journal of Anesthesia. 2003;50:470-5.
Marhofer P, Freitag H, Hchtl A, Greher M, Erlacher W, Semsroth M. S(+)-Ketamine for Rectal Premedication in Children. Anesthesia & Analgesia. 2001;92:62-5.
Peltoniemi MA, Hagelberg NM, Olkkola KT, Saariet TI. Ketamine: areview of clinical pharmacokinetics and pharmacodynamics in anesthesia and pain therapy. Clin Pharmacokinet. 2016;55:1059–77.
Sun Y, Lu Y, Huang Y, Jiang H. Is dexmedetomidine superior to midazolam as a premedication in children? A meta-analysis of randomized controlled trials. Paediatr Anaesth. 2014;24:863-74.
Gyanesh P, Haldar R, Srivastava D, Agrawal PM, Tiwari AK, Singh PK. Comparison between intranasal dexmedetomidine and intranasal ketamine as premedication for procedural sedation in children undergoing MRI: a double-blind, randomized, placebo-controlled trial. Journal of Anesthesia. 2014;28:12-18.
Weisz K, Bajaj L, Deakyne S J, Brou L, Brent A,Wathen J. Roosevelt GE: Adverse Events During a Randomized Trial of Ketamine Versus Co-Administration of Ketamine and Propofol for Procedural Sedation in a Pediatric Emergency Department. Journal of Emergency Medicine. 2017;53(1):1-9.
Bellolio MF, Puls HA, Anderson JL, Gilani WI, Murad MH. Incidence of adverse events in paediatric procedural sedation in the emergency department: a systematic review and meta-analysis. BMJ Open. 2016;6(6):e011384.

Table 1 Baseline characteristic comparisons among the three groups

Characteristics	Group C (N=29)	Group EK1 (N=29)	Group EK2 (N=30)	P
Sex (male/female)	19/10	19/10	20/10	0.994
Age, (year, ±s)	4.2±1.18	4.0±1.1	3.8±0.8	0.257
Body weight (kg, ±s)	19.3±3.9	19.4±4.8	16.7±3.5	0.019
Height (m, ±s)	110.7±9.6	110.3±9.9	106.6±8.1	0.166
Body mass index (kg/m², ±s)	15.7±2.4	15.7±2.1	14.7±2.2	0.106
ASA class I/II	23/6	26/3	26/4	0.520
Type of surgery (A/AT/T)*	5/22/2	5/24/0	1/28/1	0.229
Time of venipuncture initiation after esketamine administration (min, ±s)	24.5±2.6	24.3±3.2	24.5±3.4	0.948

* A, adenoidectomy; AT, adenoidectomy and tonsillectomy; T, tonsillectomy.

Table 2 Outcome comparisons among the three groups

Outcomes	Group C (N=29)	Group EK1 (N=29)	Group EK2 (N=30)	P
Venipuncture analgesia (grades, ±s)	3.0±0.9	2.0±0.9^a	1.8±0.9^a	<0.001
Parent-child separation cooperation (grades, ±s)	1.9±0.9	1.4±0.7^a	1.4±0.6^a	0.011
Parent-child separation sedation (grades, ±s)	1.8±0.4	2.1±0.6	2.3±1.1^a	0.031
Venipuncture cooperation (grades, ±s)	2.8±0.9	1.9±0.9^a	1.5±0.7^a	<0.001
Venipuncture sedation (grades, ±s)	1.3±0.5	1.8±0.6^a	2.3±0.7^ab	<0.001
Onset time of medication (min, ±s)		13.6±3.5	12.5±3.0	0.218
Duration of parent-child separation (min, ±s)	20.0±2.5	20.0±2.7	21.2±3.7	0.192
Medication cooperation (grades, ±s)	1.8±0.7	1.6±0.6	1.5±0.8	0.342

^aP<0.05, vs. C group; ^bP<0.05 vs. EK1 group

Table 3 Adverse event comparisons

N (%)	Group C (N=29)	Group EK1 (N=29)	Group EK2 (N=30)	P
Nausea or vomiting	3 (10.3)	3 (10.3)	4 (13.3)	0.916
Increased secretion
Period after medication to intubation	2 (6.9)	2 (6.9)	3 (10.0)	0.878
During recovery from general anesthesia	6 (20.7)	7 (24.1)	7 (23.3)	0.948
Nystagmus	0 (0.0)	0 (0.0)	1 (3.3)	0.376
Dizziness	0 (0.0)	1 (3.5)	2 (6.7)	0.370
Tooth grinding with involuntary head swing	0 (0.0)	0 (0.0)	1 (3.3)	0.376

No competing interests reported.

SupplementaryinformationDec13.docx

Effect of oral esketamine on preoperative sedation and venipuncture analgesia in pediatric patients: a prospective randomized double-blind controlled clinical trial

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Trial registration

Figures

Background

Methods

Results

Discussion

Conclusions

Abbreviations

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1