Effective doses of esketamine oral or esketamine intranasal for the prevention of preoperative anxiety in pediatric patients: A randomized double-blind dose-finding trial

Abstract

Background:

Preoperative anxiety is a prevalent concern among preschool pediatric patients. Esketamine, an S-enantiomer of ketamine, has emerged as a potential option for pediatric premedication. This study aimed to determine the 95% effective dose (ED95) of oral or intranasal esketamine for alleviating preoperative anxiety in this age group.

Methods:

Children patients aged between 1 to 6 years old who were undergoing elective surgery under general anesthesia were recruited in the study. The initial patient received a single dose of esketamine orally (2.5 mg/kg) or intranasally (1 mg/kg), which was adjusted for subsequent patients using the Dixon up-and-down method, where the dose of esketamine administered orally or intranasally to each patient depended on the sedation success of the previous patient. Doses were increased or decreased by increments of 0.5 mg/kg (oral) or 0.05 mg/kg (intranasal). An effective response was defined as having a modified Ramsay sedation score ≥3a, separation anxiety score ≤2, and mask acceptance score ≤2 during inhalational anesthesia induction.

Results:

A total of 62 children in the oral group and 66 children in the intranasal group were included in the final analysis. The ED95 for a single dose of oral or intranasal esketamine to alleviate preoperative separation anxiety in children was 8.2125 mg/kg (95% confidence interval [CI]: 7.4250–8.4597) and 2.1770 mg/kg (95% CI: 2.0952–2.1958), respectively. After surgery, the median of consciousness recovery time in esketamine oral and intranasal group was 30.00 (13.00–41.25) and 31.00 (20.00–45.00) min, respectively. Nausea, vomiting, increased secretions, and emergence delirium were the major adverse events that occurred following esketamine administration.

Conclusion:

This study demonstrates the efficacy of single-dose esketamine regimens, administered orally (ED95: 8.2125 mg/kg; 95% CI: 7.4250–8.4597 mg/kg) and intranasally (ED95: 2.1770 mg/kg; 95% CI: 2.0952–2.1958 mg/kg), in mitigating preoperative anxiety within a pediatric population. These findings highlight the safety and efficacy of esketamine for this patient group.

Key points.

• This study investigated the effectiveness of single-dose esketamine regimens, administered both orally and intranasally, for reducing preoperative anxiety in young children (aged 1–6 years) undergoing surgery.

• The findings demonstrate that esketamine administered orally or intranasally may be a valuable tool in managing anxiety within this patient population.

1. Introduction

Preoperative anxiety in young children is a pervasive concern, affecting a staggering 50% to 60% of children, particularly those preschool pediatric patients aged 1 to 6 years old.^[1,2] This anxiety, fueled by fear of the unknown, pain, and separation, can manifest in physical and emotional distress. Left unaddressed, it can lead to a prolonged hospital stay, negative psychological effects in the long-term. Furthermore, unmanaged anxiety can complicate the surgery itself. Fortunately, preoperative sedation has emerged as a powerful tool in our clinical armamentarium to combat this anxiety.^[3,4] By effectively alleviating perioperative anxiety, sedation facilitates a smoother process for both the child and their caregivers. It allows for a calmer separation from parents and a more manageable anesthesia induction, ultimately creating a more positive surgical experience for everyone involved.^[3,4]

Esketamine, the S-enantiomer of ketamine, has emerged as a potential frontrunner for preoperative sedation in the pediatric population. Unlike its parent compound, esketamine boasts a more benign side-effect profile, characterized by expedited recovery times and a swifter return to a state of awareness.^[5] This therapeutic agent exerts its action through the blockade of N-methyl-D-aspartic acid receptors within the brain, which are known to be instrumental in both pain perception and emotional regulation. By virtue of its inhibitory effect on these receptors, esketamine produces a multifaceted response, encompassing both analgesia and anxiolysis.^[6] In stark contrast to conventional sedatives like midazolam which lack analgesic properties, esketamine’s unique synergy of anxiolysis and analgesia positions it as a potentially invaluable instrument for the management of preoperative anxiety in children.

To date, no studies have investigated the 95% effective dose (ED95) of esketamine for managing preoperative anxiety in children, whether administered orally or intranasally. Therefore, this study aims to address this critical gap in knowledge by investigating the ED95 of esketamine administered orally or intranasally for the management of preoperative anxiety in children.

2. Materials and methods

2.1. Study design and ethics

We conducted 2 separate, prospective, double-blinded, dose-finding trials between April and June 2024. The study received approval from the Xi’an International Medical Center Hospital’s Institutional Review Board under protocol number 202412 (date: March 6, 2024, V1). Written informed consent was obtained from each participant’s legal guardian. The study was registered at www.chictr.org.cn (registration number: ChiCTR2400082312; registration date: March 26, 2024) and conducted at the Anesthesia and Comfort Medical Center within Xi’an International Medical Center Hospital, Shaanxi Province, China. The study adhered to Good Clinical Practice guidelines and the principles outlined in the Declaration of Helsinki.

2.2. Patients

Children aged 1 to 6 years with a body mass index between the 5th and 95th percentiles (approximately corresponding to 13–20 kg/m²), classified as American Society of Anesthesiologists physical status I or II, who were otherwise healthy with normal age-appropriate growth and development, scheduled for elective surgery requiring general anesthesia were eligible for inclusion. Exclusion criteria comprised preexisting endocrine, severe respiratory (e.g., obstructive sleep apnea, acute infections, uncontrolled asthma, active bleeding, or pulmonary hypertension), cardiac, mental health (including autism, attention-deficit/hyperactivity disorder, or schizophrenia), neurological (including abnormal development or cognitive dysfunction, coma, brain injury, or prior neurosurgery), hepatic (defined as aspartate aminotransferase or alanine aminotransferase ≥ 2.5 × ULN, where ULN = upper limit of normal, or total bilirubin ≥ 1.5 × ULN), or renal dysfunction (blood urea nitrogen ≥ 1.5 × ULN, serum creatinine > ULN), known allergies to benzodiazepines, opiates, etomidate, propofol, ketamine, or other study medications, use of sedative medications within 48 hours of surgery, prematurity, or any other condition potentially affecting study results.

2.3. Study protocols

Prior to anesthesia induction, participants fasted from clear liquids for 2 hours and solid food for 6 hours. Upon arrival at the preoperative holding area with their parents, standard vital sign monitoring, including pulse oximetry (SpO₂), was performed on the participants. In the oral esketamine group, parents administered a 1:4 mixture of esketamine injection (Hengrui Pharma, China) with 50% glucose solution. The intranasal group received a predetermined esketamine dose administered by a qualified anesthesiologist. The maximum single nostril dose was 0.3 mL.^[6] For larger doses, the medication was administered in divided aliquots, with a total volume per nostril not exceeding 1 mL.^[7] This minimized nasal mucosal saturation and potential leakage or drainage into the pharynx.

Following oral or intranasal esketamine administration, an independent observer conducted serial assessments. Specifically, sedation levels were evaluated every 5 minutes using the modified Ramsay Sedation Scale (mRSS) (Table 1).^[8] Once the mRSS reached 3a, an attempt was made to separate the participant from their parent(s), and the Parental Separation Anxiety Scale (PSAS) was recorded.^[8] This was assessed using a 4-point scale (Table 2), where a score ≤ 2 indicated successful separation. If the PSAS score exceeded 2, the participant continued to wait for up to 30 minutes for the esketamine to take effect. If the waiting period exceeded 30 minutes, separation was considered unsuccessful, and intramuscular S-ketamine was administered as rescue medication (2 mg/kg).

Table 1.

Modified Ramsay Sedation Scale (mRSS).

Score	Characteristics
1	Awake and alert, minimal or no cognitive impairment.
2*	Awake but tranquil, purposeful responses to verbal commands at conversation level.
3*	Appears asleep, purposeful responses to verbal commands at conversation level.
4†	Appears asleep, purposeful responses to verbal commands but at louder than usual conversation level or requiring light glabellar tap.
5†	Asleep, sluggish purposeful responses only to loud verbal commands or strong glabellar tap.
6‡	Asleep, sluggish purposeful responses only to painful stimuli.
7§	Asleep, reflex withdrawal to painful stimuli only (no purposeful responses).
8§	Unresponsive to external stimuli, including pain.

^*Minimal.

^†Moderate.

^‡Deep.

^§General anesthesia.

Table 2.

Parental Separation Anxiety Score (PSAS).

Behaviour of the child during separation from parents	Criteria	Score
Excellent	Patient unafraid, cooperative, or asleep	1
Good	Slightly afraid/crying, quiet with reassurance	2
Fair	Moderately afraid and crying, not quiet with reassurance	3
Poor	Crying, need for restraint	4

If the PSAS score was ≤2, the participant was transferred to the operating room, where standard monitoring (electrocardiogram, SpO₂, heart rate, noninvasive blood pressure, and Bispectral Index) was initiated. Inhalational induction was performed using 8% sevoflurane (Maruishi Pharmaceutical, Japan), and mask acceptance was assessed by an independent observer using a 1 to 4 point mask acceptance score.^[8] A score of 1 indicated no fear of the mask and easy acceptance, 2 indicated mild fear with ease of comfort, 3 indicated moderate fear requiring additional reassurance, and 4 indicated significant fear with crying or struggling.

Anesthesia was induced once the end-tidal sevoflurane concentration reached 2 minimum alveolar concentration. The induction regimen included propofol (3 mg/kg, AstraZeneca, UK), cisatracurium (0.2 mg/kg, Xianju Pharma, China), and sufentanil (0.4 µg/kg, Humanwell Healthcare, China). Maintenance of anesthesia involved a continuous infusion of propofol (6–10 mg/kg/h) and remifentanil (0.1–0.3 µg/kg/min, Humanwell Healthcare, China) titrated to maintain a Bispectral Index value between 45 and 60, as well as stable hemodynamic parameters (blood pressure and heart rate within 20% of baseline values). A continuous infusion of cisatracurium (2 µg/kg/min) was administered throughout the surgical procedure. Cisatracurium infusion was discontinued 30 minutes before the end of surgery. Postoperative analgesia included intravenous administration of ketorolac tromethamine (0.5 mg/kg, Hualu Pharma, China), dexamethasone (0.1 mg/kg, Xinhua Pharma, China), and tropisetron (0.1 mg/kg, Qilu Pharma, China). Upon completion of surgery, all patients were transferred to the post-anesthesia care unit (PACU). Extubation was performed once patients had regained spontaneous ventilation and their SpO₂ was maintained between 99% and 100%.

2.4. Outcomes

The primary objective of this study was to determine the ED95 of oral and intranasal esketamine for the alleviation of preoperative anxiety in pediatric patients. A Dixon up-and-down (Dixon-UDM) design was employed to estimate the ED95. This adaptive design sequentially adjusts the dose for each participant based on the binary response (effective or ineffective sedation) of the immediately preceding participant: a successful response leads to a dose decrease by the fixed step size for the next patient, while an ineffective response leads to a dose increase. This process creates a sequence of doses that clusters around the target effective dose, efficiently estimating quantiles with modest sample sizes. In this study, the dose of esketamine administered to each participant was adjusted based on the response of the previous participant. A successful response (positive reaction) was defined as a mRSS score ≥ 3a upon separation from parents, a PSAS score ≤ 2, and a mask acceptance score ≤ 2 during sevoflurane inhalational induction. A failed response (negative reaction) was defined as the absence of these criteria. Starting with an initial dose of 2.5 mg/kg orally or 1.0 mg/kg intranasally, the dose was increased or decreased by 1 concentration unit (0.5 mg/kg orally or 0.05 mg/kg intranasally) based on the previous participant’s response. To ensure adequate statistical power and precision for ED95 estimation, at least 6 “effective-ineffective” pairs were required for each treatment group.^[9] In addition, simulation studies suggest that including at least 20 to 40 patients will provide stable estimates of the target dose for most realistic scenarios.^[10] In this study, the oral group included 21 pairs (62 patients) and the intranasal group included 16 pairs (66 patients), meeting and exceeding these requirements.

The secondary outcomes included the patient’s behavioral score during esketamine administration,^[11] the need for rescue sedation, the time to successful separation (defined as achieving a mRSS score of ≥3a), parental satisfaction with the separation process, and the occurrence of adverse events such as hypoxemia (SpO₂ < 95%), respiratory depression (SpO₂ ≤ 90% for ≥ 10 seconds), nausea, vomiting, and agitation^[12] during sedation and recovery. The patient behavioral score was rated on a 4-point Likert scale: 1 = calm and cooperative; 2 = anxious but reassurable; 3 = anxious and not reassurable; 4 = crying or resisting. Parental satisfaction was assessed using a 5-point Likert scale: 1 = very poor; 2 = poor; 3 = moderate; 4 = good; 5 = excellent.

2.5. Blinding

To ensure blinding, a designated individual not involved in patient care or data analysis prepared the predetermined dose of oral or intranasal esketamine. Anesthesiologists, patients, parents, and research personnel were blinded to the specific drug dose. The dose was determined by an independent statistician who was not involved in patient care or data analysis, based on the response of the previous participant. All data were collected by independent research personnel.

2.6. Statistics

The ED95 of oral and intranasal esketamine, the dose required to achieve a successful outcome in 95% of participants, was estimated using an isotonic regression model (pooled adjacent violators algorithm) with bias-corrected percentile bootstrap confidence intervals (CIs) (2000 replications). A Bayesian approach was employed with a non-informative prior distribution for the model parameters. The 95% CI for the ED95 was calculated using a bias-corrected percentile bootstrap method with 2000 replications.

In accordance with the characteristics of sequential Dixon-UDM designs, sample size was not determined by a conventional power calculation. Instead, recruitment continued until a sufficient number of effective–ineffective crossover pairs was obtained, allowing reliable estimation of the ED95 using isotonic regression. A minimum of 6 pairs and at least 20 to 40 patients are typically required for ED95 estimation. In this study, we prospectively aimed for a larger number of pairs and ultimately achieved 21 pairs (62 patients) in the oral group and 16 pairs (66 patients) in the intranasal group, exceeding conventional minimum requirements and aligning with sample sizes reported in similar pediatric anesthesia dose-finding trials.

Data were analyzed using R version 3.4.4 (R Core Team, 2014). Continuous variables were presented as median (interquartile range), and categorical variables were reported as frequencies and percentages. The Shapiro–Wilk test was used to assess normality, and the Mann–Whitney U test or chi-square test (or Fisher exact test) was used for comparisons between groups, as appropriate. A P-value of <.05 was considered statistically significant.

3. Results

A total of 70 patients were screened for the oral esketamine group, of whom 6 were excluded (2 due to parental refusal and 4 due to ineligibility). Of the remaining 64 patients, 2 dropped out due to medication refusal or incomplete dosing. Data from 62 patients were included in the final analysis (Fig. 1A).

Figure 1.

Subject flow diagram of esketamine oral and intranasal group were shown in (A) and (B), respectively.

In the intranasal esketamine group, 84 patients were screened, with 9 exclusions (4 due to parental refusal, 5 due to ineligibility). Of the remaining 75 patients, 9 dropped out due to medication refusal, incomplete dosing, or missing data. Data from 66 patients were included in the final analysis (Fig. 1B).

Table 3 presents the demographic characteristics of the study participants. In the oral esketamine group, 28 of 62 patients (45.2%) had an effective response to treatment, while 34 (54.8%) had an ineffective response (Fig. 1A). In the intranasal group, 22 of 66 patients (33.3%) had an effective response, and 44 (66.7%) had an ineffective response (Fig. 1B). The Dixon-UDM sequences for oral and intranasal esketamine are depicted in Figures 2A and B, respectively. Statistical analysis revealed that the ED95 for oral and intranasal esketamine to alleviate preoperative separation anxiety was 8.2125 mg/kg (95% CI: 7.4250–8.4597) and 2.1770 mg/kg (95% CI: 2.0952–2.1958), respectively. Table 4 presents the number and rate of effective responses, adjusted using pooled adjacent violators algorithm.

Table 3.

The demographic data of the patients.

Groups	Esketamine oral	Esketamine intranasal
Gender (male/female)	43/19	35/31
Age (yr)	3 (2–4)	2 (1–4)
BMI (kg/m2)	15.04 (14.63–16.77)	16.19 (15.24–17.58)
ASA (I/II)	54/8	58/8
Surgical time (min)	43 (24.75–121.00)	53 (30–145.00)

ASA = American Society of Anesthesiologists.

Figure 2.

The complete sequential data of Dixon-UDM. Patients’ reactions in the esketamine oral and intranasal group were shown in (A) and (B), respectively. The negative reaction was shown with yellow square (), and the positive reactions was shown with blue cycle (●).

Table 4.

Comparison of positive reaction rates for different doses of esketamine.

Groups	Doses	Positive number	Patient number	Positive rate (%)	Positive rates adjusted by PAVA
Esketamine oral group	2.50	0	3	0	0
	3.00	2	5	0.40	0.37
	3.50	2	6	0.33	0.37
	4.00	3	8	0.38	0.38
	4.50	4	6	0.67	0.40
	5.00	1	4	0.25	0.40
	5.50	2	3	0.67	0.40
	6.00	0	4	0	0.40
	6.50	3	7	0.43	0.43
	7.00	4	8	0.50	0.50
	7.50	4	5	0.80	0.65
	8.00	1	2	0.50	0.65
	8.50	1	1	1.00	1.00
Esketamine intranasal group	1.00	0	1	0	0
	1.05	0	2	0	0
	1.10	1	2	0.50	0.05
	1.15	0	1	0	0.05
	1.20	0	1	0	0.05
	1.25	0	1	0	0.05
	1.30	0	1	0	0.05
	1.35	0	1	0	0.05
	1.40	0	1	0	0.05
	1.45	0	1	0	0.05
	1.50	0	1	0	0.05
	1.55	0	4	0	0.05
	1.60	3	6	0.50	0.30
	1.65	2	4	0.50	0.30
	1.70	1	2	0.50	0.30
	1.75	0	1	0	0.30
	1.80	0	5	0	0.30
	1.85	4	6	0.67	0.37
	1.90	1	4	0.25	0.37
	1.95	2	3	0.67	0.37
	2.00	0	3	0	0.37
	2.05	2	7	0.29	0.37
	2.10	4	5	0.80	0.65
	2.15	1	2	0.50	0.65
	2.20	1	1	1.00	1.00

PAVA = pooled adjacent violators algorithm.

The time to satisfactory sedation, defined as achieving a Ramsay Sedation Scale score of ≥3a, was assessed. In the oral group, 29 patients achieved satisfactory sedation with a mean time of 18.89 ± 5.06 min. In the intranasal group, 22 patients achieved satisfactory sedation with a mean time of 15 ± 6.17 min.

Patient behavior during esketamine administration was evaluated using a 4-point Likert scale. In the oral group, 84.38% of patients (54/64) exhibited behavior scores of <3 (Table 5). In the intranasal group, 64% of patients (48/75) exhibited behavior scores of <3 (Table 5).

Table 5.

Patient behavioral scores and parental behavioral scores during the sedation.

Scores	Patient behavior scale, n (%)		Parental satisfaction score, n (%)
	Esketamine oral	Esketamine intranasal	Esketamine oral	Esketamine intranasal
1	42 (65.63)	15 (20.00)	0	0
2	12 (18.75)	33 (44.00)	0	2 (3.03)
3	3 (4.69)	7 (9.33)	3 (4.84)	35 (53.03)
4	7 (10.93)	20 (26.67)	34 (54.84)	11 (16.67)
5	n/a	n/a	25 (40.32)	18 (27.27)
Total	64 (100)	75 (100)	62 (100)	66 (100)

Parental satisfaction with the sedation protocol was assessed using a 5-point Likert scale. In the oral group, no parents rated satisfaction as very poor or poor. In the intranasal group, 2 parents (3.03%) rated satisfaction as poor (Table 5).

After surgery, the median of consciousness recovery time in esketamine oral and intranasal group was 30.00 (13.00–41.25) and 31.00 (20.00–45.00) min, respectively (Table 6).

Table 6.

The adverse events after sedation administration.

Adverse events, n (%)	Esketamine oral group	Esketamine intranasal group
Overall concurring rate	17 (27.42%)	29 (43.94%)
Hypoxemia	0	0
Respiratory depression	0	0
Nausea	4 (6.45)	4 (6.06)
Vomiting	4 (6.45)	4 (6.06)
Increased secretion	4 (6.45)	3 (4.55)
Emergency delirium	12 (19.35)	24 (36.36)

In the 62 patients of esketamine oral group, 4 of them experienced nausea, vomiting and increased secretion after drug administration. None of the patients experienced hypoxemia, respiratory depression. During anesthesia recovery period, 12 patients experienced emergence delirium in PACU (Table 6) .

In the 66 patients of esketamine intranasal group, none of the patients experienced hypoxemia, respiratory depression. However, 4 of them experienced nausea, vomiting, 3 of them experienced increased secretion, 24 children experienced emergence delirium in PACU (Table 6).

4. Discussion

This study establishes the ED95 of oral and intranasal esketamine for alleviating preoperative anxiety in pediatric patients at 8.2125 mg/kg (95% CI: 7.4250–8.4597 mg/kg) and 2.1770 mg/kg (95% CI: 2.0952–2.1958 mg/kg), respectively. To our knowledge, this is the first investigation to quantify the efficacious oral and intranasal esketamine dose for this specific application in children.

Prior research has documented a dose-dependent increase in successful pediatric sedation (45–80%) with oral ketamine (3–10 mg/kg).^[13–15] Notably, this range translates to a theoretical esketamine dose of 1.5 to 5 mg/kg, which falls below the ED95 identified in our study. Additionally, Oyedepo et al^[13] reported a 64% mask acceptance rate with 10 mg/kg oral ketamine (equivalent to 5 mg/kg esketamine),^[16] again lower than our ED95. This discrepancy may be attributable to potentially stricter sedation success definitions employed in our investigation. Our criteria mandated a mRSS score ≥ 3, a PSAS ≤ 2, and a mask induction score ≤ 2, potentially signifying deeper sedation compared to prior studies that relied on simpler sedation scores or behavioral measures during parental separation.

Previous investigations have demonstrated the efficacy and safety of intranasal ketamine (0.5–4 mg/kg), alone or combined with other sedatives like midazolam, for achieving adequate sedation during diagnostic procedures.^[17] Notably, Cristoforo et al reported that intranasal ketamine at 5 mg/kg achieved an anxiolysis rate of 80% in pediatric patients.^[18] The ED95 of 2.1770 mg/kg in our study translates to a theoretical ketamine dose of 4.354 mg/kg, which aligns with the aforementioned studies. More recently, Wang et al^[19] evaluated the sedative effects of intranasal esketamine following oral midazolam (0.5 mg/kg) premedication in children. They reported an ED95 of 1.99 mg/kg for intranasal esketamine in outpatient pediatric dental procedures, which appears lower than our findings. However, considering this dose was determined following oral midazolam administration, our results remain comparable to Wang study.

To address the paucity of research on oral esketamine, we extrapolated the initial dosage from established oral ketamine (5 mg/kg). Considering esketamine’s 2-fold potency, we commenced with 2.5 mg/kg. Prior studies suggest a 2 to 10 mg/kg range for intranasal ketamine in pediatric preoperative sedation, aligning with our initial 1 mg/kg dose selection based on current literature.^[20] To optimize effective dose determination while minimizing patient exposure, we employed the efficient Dixon-UDM method with isotonic regression. This methodology is particularly well-suited for pediatric studies as it facilitates reliable effective dose estimates with smaller sample sizes.^[21] While the standard Dixon method typically requires a minimum of 6 “effective-ineffective” pairs for analysis, our study yielded a higher number in both the oral (21 pairs) and intranasal (16 pairs) groups. This is partly because this study is the 1st to investigate the ED95 of oral and intranasal esketamine for alleviating preoperative anxiety in children, and we aimed to obtain more accurate results by increasing the sample size. Additionally, we chose a lower starting dose, and to achieve a value closer to the effective dose, more “effective-ineffective” pairs were thereby needed.

Oral premedication for reducing preoperative anxiety proved well-established and noninvasive in this study. A high level of patient cooperation was observed, with 84.38% of children in the oral group exhibiting minimal behavioral resistance during medication administration. This finding aligns with previous research by Oyedepo et al^[13] and Gomes et al,^[22] supporting the good tolerability of oral medication in this pediatric population. In contrast, the intranasal route displayed lower patient acceptance. Only 64% of children in the intranasal group showed minimal resistance during medication administration. This suggests that the oral route might be better tolerated by preschool-aged children undergoing premedication.

The intranasal group exhibited a higher incidence of adverse events (43.94%) compared to the oral group (27.42%), though these were mostly mild and transient. This difference likely stems from the unique absorption rates of each administration route. Intranasal delivery allows for rapid drug absorption into the bloodstream, leading to a quicker onset of action, which may contribute to the increased occurrence of temporary adverse events, especially the emergence delirium which may be associated with concurring of psychiatric symptoms such as hallucination caused by esketamine.

Importantly, no severe adverse events, such as respiratory depression, were observed, underscoring the safety of both methods. The overall rate of adverse events was slightly higher than previously reported studies,^[23,24] likely due to the relatively higher doses used in our research. Given the established link between higher doses and increased adverse reactions, our findings are significant in determining precise and effective dosage guidelines for future combined regimens. These results are particularly relevant as they align with the growing trend toward combination therapy for pediatric preoperative sedation.^[19,25] By refining dosage parameters, we can improve the efficacy and safety of these combined treatments, ultimately enhancing patient outcomes.

Achieving optimal anxiolysis and facilitating procedural cooperation are essential in pediatric premedication. In the oral group, 28 patients reached the desired sedation state with an average time of 18.89 ± 5.06 minutes. This finding is consistent with the known pharmacokinetics of oral ketamine, which typically induces adequate sedation within 30 minutes.^[15,26]

In the intranasal group, 22 patients successfully achieved sedation, with an average time of 15 ± 6.17 minutes, similar to the findings of Weber et al^[27] However, Lu et al reported a significantly longer time (28.00 [21.00–40.00] min) for satisfactory sedation using 1 mg/kg intranasal esketamine.^[25] Lu et al study used a Modified University of Michigan Sedation Scale of 2 as the benchmark for successful sedation. Patients not meeting this criterion would naturally extend the overall sedation time. In contrast, our study focused on separation time for successfully sedated children, providing a more precise and clinically relevant assessment.

Our ED95 estimates for esketamine also differ from those reported for nebulized racemic ketamine in pediatric premedication studies, such as Ahmad Sabry et al,^[28] who used 3 mg/kg nebulized ketamine for tonsillectomy in children aged 3 to 6 years. In that trial, nebulized ketamine provided acceptable sedation but was inferior to dexmedetomidine (3 μg/kg) in Ramsay scores, parental separation, and mask acceptance, with no intergroup differences in recovery/discharge times or analgesia needs. Complication rates were low, though ketamine-related respiratory issues (productive cough and secretions in 20% of the mixture group, vomiting in 8%) were noted (consistent with our mild, transient adverse events (increased secretions in 11.3–18.2%, vomiting in 8.1–13.6%)).

Dose differences can be attributed to multiple factors. Esketamine’s higher potency (2-fold vs racemic ketamine) means our intranasal ED95 (2.1770 mg/kg) equates to 4.35 mg/kg racemic, exceeding Ahmad Sabry et al 3 mg/kg (potentially due to route variations (intranasal mucosal absorption vs nebulized pulmonary/buccal)), our more stringent composite endpoint requiring simultaneous success in sedation, separation, and mask acceptance (vs primarily Ramsay score), and procedural context (broad elective surgeries vs tonsillectomy-specific anxiety patterns). Similarly, our oral ED95 (8.2125 mg/kg; 16.4 mg/kg racemic equivalent) reflects reduced bioavailability from first-pass metabolism, necessitating higher doses than nebulized routes. Ahmad Sabry et al contrasted their tonsillectomy results with prior dental surgery studies, attributing outcome variations to patient populations, underscoring how surgery type influences premedication efficacy and safety. These insights emphasize the need for route- and procedure-tailored regimens in pediatric anxiolysis, with esketamine offering a favorable profile in our cohort despite higher relative doses.

5. Limitations

This study is subject to several inherent limitations. First, the absence of stratification by age and gender precludes definitive conclusions regarding the influence of these demographic characteristics on outcomes. Future studies incorporating such stratification would provide a more nuanced understanding of the effects observed. Second, the study design did not permit the delineation of peak plasma concentration for esketamine administered via either oral or intranasal routes within the context of pediatric preoperative anxiety. Given the established importance of peak plasma concentration in informing clinical decision-making, further research is warranted to address this knowledge gap. Finally, the potential impact of preoperative sleep patterns on the efficacy of sedation regimens remains unexplored. Elucidating this potential association could offer valuable clinical insights for optimizing pediatric premedication protocols.

6. Conclusion

This study demonstrates the efficacy of single-dose esketamine regimens, administered orally (ED95: 8.2125 mg/kg; 95% CI: 7.4250–8.4597 mg/kg) and intranasally (ED95: 2.1770 mg/kg; 95% CI: 2.0952–2.1958 mg/kg), in mitigating preoperative anxiety within a pediatric population. These findings highlight the safety and efficacy of esketamine for this patient group.

Author contributions

Conceptualization: Hongfei Xiong, Siyuan Li, Rongliang Xue.

Data curation: Yingxue Xu, Jing Liu.

Funding acquisition: Hongfei Xiong, Siyuan Li.

Formal analysis: Yingxue Xu, Jing Liu, Gang Xiao.

Investigation: Guangbo Liu, Yunyun Zhang, Ziwen Wei, Wenwen Liang, Xuemei Zhao.

Methodology: Guangbo Liu, Yunyun Zhang, Ziwen Wei, Wenwen Liang, Xuemei Zhao.

Project administration: Hongfei Xiong, Siyuan Li, Rongliang Xue.

Software: Yingxue Xu, Jing Liu, Gang Xiao.

Writing – original draft: Hongfei Xiong.

Writing – review & editing: Siyuan Li, Rongliang Xue.