Introduction
Procedural sedation is a crucial aspect of pediatric clinical practice, as it helps reduce anxiety, consciousness, and pain, facilitating easier examinations or procedure completion for pediatric patients [1,2]. Various sedatives are used in pediatric anesthesia; however, due to the pain and distress caused by establishing an intravenous (IV) line, non-IV sedation is preferred, particularly in outpatient settings [3,4]. Key elements of an ideal sedation method include rapid and predictable onset, maintenance of sedation during the procedure without side effects, and quick recovery [2] that can reduce the patient’s hospital stay duration and enable healthcare providers to perform sedation and procedures more efficiently.
Chloral hydrate (CH) syrup has been used for sedation for over 150 years, providing a cost-effective option that is widely recognized and familiar to healthcare providers. However, its clinical utility is limited by its high sedation failure rate (21.8%) [3], slow onset (20–40 min), prolonged sedation, lack of analgesic effects, frequent gastrointestinal irritation, and risks of respiratory or cardiac depression, as well as potential fatality with overdose [5–7]. Although research has shown that sleep deprivation has no effect on CH sedation [8], clinical practice often incorporates it to increase sedation success rates. Similarly, strict fasting is commonly implemented due to frequent nausea and vomiting that can potentially lead to dehydration [9,10]. These requirements cause significant distress for both children and parents. Despite these issues, CH remains a primary choice for pediatric procedural sedation in South Korea, regardless of procedural pain [3,11–13]. These findings indicate the need to develop a safer and more effective non-IV sedation method for pediatric patients.
Intranasal dexmedetomidine has advantages of minimal respiratory depression and enhanced analgesic effect. However, it has a slow onset (20–30 min) at low doses (2 μg/kg) and a high incidence of bradycardia at higher doses (4 μg/kg) [14–22]. Compared with intranasal dexmedetomidine, intranasal ketamine (3–10 mg/kg) provides a sedative and analgesic effect with a relatively fast onset (3–12 min) [23]. Intranasal ketamine can preserve respiratory and airway reflexes and stimulate heart function with tachycardia, allowing it to have a complementary effect with dexmedetomidine [24,25]. Previous studies have evaluated the efficacy and safety of the intranasal combination of dexmedetomidine and ketamine (IN DEXKET) in children [21,24,26,27]. The intranasal combination of dexmedetomidine (2 μg/kg) and ketamine (1 mg/kg) has shown a sedation success rate of approximately 90%–95% in various pediatric procedures, with an onset time of 10–20 min and duration of 40–60 min [21,24,26]. However, to the best of our knowledge, no prospective studies have used intranasal dexmedetomidine and ketamine in children aged < 1 year, and no studies in South Korea have reported on pediatric sedation via intranasal administration.
Therefore, in this study, we aimed to propose a safer and more effective non-IV sedation method for pediatric patients using intranasally administered dexmedetomidine (2 μg/kg) and ketamine (3 mg/kg) and compare it with oral CH (50 mg/kg). We hypothesized that an intranasal combination of dexmedetomidine and ketamine can improve the success rate of achieving adequate sedation levels within 15 min compared with oral CH (50 mg/kg) in pediatric patients aged < 7 years.
Materials and Methods
Study design and ethics
This study was a prospective, two-center, single-blinded, parallel-arm, randomized controlled trial. Competitive enrollment was conducted at two research centers to achieve the target of 136 patients. Ethics approval was obtained from the Institutional Review boards of both centers (approval no. H-2103-124-1206, approved on April 26, 2021, and approval no. S2021-1007-0002, approved on September 3, 2021). The trial was registered prior to patient enrollment at the Clinical Research Information Service of the Republic of Korea (registration no. KCT0006358, registered on July 20, 2021), and progress was regularly updated.
The investigators assessed patient eligibility and approached their legal guardians individually to obtain written informed consent for study enrollment prior to sedation. All procedures performed in this study adhered to the principles outlined in the Declaration of Helsinki, 2013.
Participants
This study was conducted at two tertiary-care hospitals in Seoul, South Korea. Pediatric patients aged < 7 years undergoing sedation for non-invasive examination or procedures were enrolled. The exclusion criteria were as follows: American Society of Anesthesiologists (ASA) classification 4–5; allergy to dexmedetomidine, ketamine, or CH; recent use of alpha-2 adrenergic receptor agonists or antagonists; swallowing difficulty (due to pediatric patients’ difficultly in taking oral CH); excessive rhinorrhea; unstable vital signs; pneumonia; upper airway infection; or when trial members considered the enrollment inappropriate.
Determination of the dose of oral chloral hydrate
The usual initial dose of CH for pediatric sedation is 40–60 mg/kg [2–4]. For magnetic resonance imaging (MRI), higher doses (60–100 mg/kg) have been reported. However, these higher doses are associated with an increased risk of gastrointestinal side effects, motor imbalance, respiratory depression, and prolonged sedation [4]. Therefore, the oral dose of CH was determined to be 50 mg/kg that is consistent with the pediatric sedation protocol used at the two tertiary hospitals recruiting the study participants.
Determination of the dose of intranasal dexmedetomidine and ketamine
The intranasal combination of dexmedetomidine and ketamine was used to 1) shorten the onset and recovery times of sedation, 2) avoid bradycardia or hypotension, and 3) provide analgesia for mild pain or discomfort during procedures. The dose of intranasal dexmedetomidine (2 μg/kg) and intranasal ketamine (3 mg/kg) was determined to achieve safe synergetic sedation with rapid onset and sustained effects.
Dexmedetomidine has been successfully used for pediatric sedation. Clinically, intranasal dexmedetomidine at doses of 1–3 μg/kg has an onset of 20–30 min, with a duration of 30–60 min [15]. Intranasal dexmedetomidine at a dose of 2–3 µg/kg achieves a success rate of approximately 74%–85% without causing significant bradycardia [28,29]. A higher dose of intranasal dexmedetomidine results in a quicker onset and greater analgesic effect; however, the duration of action is prolonged, and the risk of side effects such as bradycardia increases [16]. Intranasal dexmedetomidine 4 μg/kg successfully induced sedation for MRI in 96.2% of infants without motion artifacts, apnea, or desaturation. However, bradycardia (< 80% of baseline heart rate [HR]) occurred in 30.7%, and hypotension (< 80% of baseline mean arterial pressure) occurred in 3.8%. Based on these findings, we selected a dose of 2 μg/kg for intranasal dexmedetomidine.
Ketamine maintains cardiovascular stability due to its anticholinergic properties, such as tachycardia and bronchodilation. A recent systematic review of 25 studies comprising 161 patients found that intranasal ketamine can be administered at various doses (0.5–10 mg/kg) for sedation, painful procedures, radiology tests, and premedication for anesthesia [27]. Intranasal ketamine up to 10 mg/kg offers effective sedation and analgesia without significant side effects. The intranasal ketamine is typically administered at a dose of 5–6 mg/kg for sedation that is reported to be effective in inducing sedation in 76%–97% of cases [30–32]. In contrast, when intranasal ketamine at 2 µg/kg is combined with midazolam at 0.5 mg/kg, the sedation success rate increases to 94% [33].
An intranasal combination of dexmedetomidine and ketamine provided more satisfactory sedation and smoother induction of general anesthesia than nebulized dexmedetomidine or ketamine alone, with more rapid recovery and no significant side effects [21,24,26,27]. A retrospective analysis of the combination of intranasal dexmedetomidine (2 μg/kg) and ketamine (1 mg/kg) reported a sedation success rate of 93%, median onset time of 15 min, and median recovery time of 45 min [26]. However, the success rate for MRI sedation was only 60%, and 32.4% of patients required rescue sedation with half-doses (total intranasal dexmedetomidine 2 + 1 μg/kg and ketamine 1 + 0.5 mg/kg). Based on these studies, we selected a dose of 3 mg/kg for intranasal ketamine, to accelerate sedation onset and improve sedation success rate.
Randomization and blinding
The Medical Research Collaborating Center (MRCC) of one institution provided a web-based randomization solution (https://mrcc.snuh.org/). Stratified block randomization was performed based on age (< 1 year and 1–7 years) and location, with an allocation ratio of 1:1. After patient enrollment, a nurse not involved in sedation or outcome assessment logged into the web-based randomization site. The nurse verified the patient’s date of birth and checked the inclusion and exclusion criteria before retrieving and storing the randomization results. The nurse then prepared the sedative according to the group allocation. Patients were assigned to either an IN DEXKET group (intranasal combination of dexmedetomidine 2 μg/kg and ketamine 3 mg/kg) or a CH group (oral CH 50 mg/kg) in a 1:1 ratio.
An independent outcome assessor, a pediatric sedation nurse not involved in group randomization or sedative administration, monitored HR, respiratory rate (RR), and oxygen saturation (SpO2), and assessed the level of sedation using a six-point Pediatric Sedation State Scale (PSSS) (Table 1) [34] at baseline and every 10 min until recovery from sedation.
Sedation and intervention
The sedative was administered 30 min before the scheduled examination or procedure. Patients followed the hospital fasting guidelines before sedation (clear fluids allowed [small amount]; breast milk 2 h prior, infant formula or nonhuman milk 4 h prior, and solid food 4 h prior), and the type and timing of the last meal were verified.
After measuring baseline HR, RR, and SpO2 in a calm, relaxed state, the sedative was administered according to the assigned group in a setting where only on-site trial members (Y.E.J. or E.Y.J.) and the patients’ guardians were present. In the IN DEXKET group, the guardians cleared the patient’s nose and held them in their arms to keep the head slightly elevated for facilitating intranasal absorption. After administering a combination of dexmedetomidine 2 μg/kg (100 μg/ml) and ketamine 3 mg/kg (50 mg/ml) using an intranasal mucosal atomizer device (SEDACO, Doowon Meditec) [35], the nose was gently massaged to enhance mucosal absorption. In the CH group, CH syrup 50 mg/kg (100 mg/ml) was administered orally. After administration, HR, RR, SpO2, and PSSS were measured every 10 min, at 15 min, at the onset of sedation (PSSS = 1–3), and upon recovery (PSSS = 4 or 5). Blood pressure was measured only if the HR was less than 70% of baseline due to discomfort. Failure to induce sedation was defined as a PSSS of 0, 4, or 5 after 30 min. If sedation was inadequate (PSSS = 4 or 5) for the procedure, the attending physician determined the rescue sedation method. In cases of apnea lasting ≥ 20 s or significant desaturation (SpO2 < 95% or < −10% from baseline, > 10 s), airway management and appropriate stimulation were provided. If there was significant bradycardia or hypotension (−30% from baseline), the trial staff offered interventions, such as tactile stimuli, fluid management, and IV medication. After the procedure or examination, the patient was transferred to the outpatient recovery room or a ward bed. The duration of sedation was recorded when PSSS was 4 or 5.
Outcomes
The primary outcome was success rate of sedation (six-point PSSS, scores 1–3) within 15 min of sedative administration. The secondary outcomes included onset and duration of sedation, sedation failure after 30 min of sedative administration, rescue sedation method, procedure failure, and overall complications of first-attempt sedation. The overall complications of first-attempt sedation included the lowest SpO2 (%), incidence of abnormal respiration or hemodynamic changes (such as significant apnea [> 20 s], significant desaturation [SpO2 < 95% or > 10% decrease from baseline for > 10 s], respiratory interventions, significant bradycardia [−30% from baseline], significant hypotension [−30% from baseline BP], hemodynamic interventions), and other side effects (e.g., paradoxical excitation, nausea, vomiting, or allergic reactions). Patient acceptance of drug administration was assessed using a four-point scale: (1 = excellent, can be administered without difficulty; 2 = good, brief tears or grimacing, but can be administered; 3 = fair, uncooperative but can be administered; 4 = poor, strong refusal of medication). Separation anxiety from guardians was measured on a four-point scale: (1 = easy; 2 = whimper; 3 = cry; 4 = cry and cling to parents). Physician satisfaction was assessed after the procedure using a four-point scale: (1 = excellent; 2 = good; 3 = fair; 4 = poor).
Statistical methods
The primary outcome, i.e., success rate of sedation (PSSS = 1 to 3) within 15 min of sedative administration, was assumed based on previously reported literature [26,29,36,37]. After oral CH (50 mg/kg) administration in children, the mean (standard deviation) onset of sedation was 22.4 (7.8) min, and the success rate of sedation was 76% [29]. Another study showed that the mean (standard deviation) onset of sedation was 23 (10.8) min, and the success rate of sedation within 20 min was 50% after CH (50–100 mg/kg) in children [36]. Following intranasal combination of dexmedetomidine 2 μg/kg and ketamine 1–2 mg/kg, the median onset time was 15 (15–20) min, and the success rate of sedation within 30 min was 93%–100% in children [26,37]. Based on these findings, we hypothesized that the success rate of sedation within 15 min in the CH group would be 55%, compared to the 80% in the IN DEXKET group. With a 5% alpha error and 85% power, 122 patients were needed with a 1:1 allocation between the intervention and control groups. Assuming a 10% dropout rate, we planned to enroll 136 patients.
All data are expressed as mean ± standard deviation or median (Q1, Q3), unless otherwise specified. Distribution was assessed using the Shapiro–Wilk normality test. Baseline characteristics of the study population were evaluated using independent t-tests and Mann–Whitney U tests. Outcomes were analyzed on an intention-to-treat basis. The primary outcome, the success rate of sedation within 15 min of sedative administration, was analyzed using the chi-squared (χ2) test. The secondary outcomes were assessed using the χ2 test, Fisher’s exact test, independent t-tests, and Mann–Whitney U tests. Statistical analyses were performed using IBM® SPSS® Statistics 23 (IBM Corp.). Statistical significance was set at a two-tailed P value of < 0.05. The post-hoc power was calculated using G*Power Version 3.1.9.7 (Franz Faul, University of Kiel, 2020) for the primary outcome, i.e., success rate of sedation within 15 min. To evaluate safety, HR, RR, and SpO2 were monitored and collected throughout the study. For repeated measures data, a mixed model analysis was performed to compare the two groups over time.
Stratified block randomization was performed based on age (< 1 year and 1–7 years). A subgroup analysis by age group (< 1 year and 1–7 years) was conducted for the primary outcome and several secondary outcomes. In the subgroup analysis, Fisher’s exact test and the Mann–Whitney U test were used to compare the primary and secondary outcomes due to the reduced sample size.
Results
A total of 136 pediatric patients were assessed for eligibility and randomly allocated to the IN DEXKET group (n = 68) and CH group (n = 68). Among these, six patients in the IN DEXKET group and two in the CH group were excluded due to cancellation of procedural sedation (Fig. 1). Therefore, 128 children (IN DEXKET: n = 62; CH: n = 66) received sedation according to their designated group (Fig. 2) and were finally included in the analysis. The baseline characteristics of the patients and the type of procedures and examinations were comparable between the two groups (Table 2). The most common examination in both the groups was echocardiography, followed by computed tomography and procedures involving both echocardiography and computed tomography. Other examinations included electroencephalography, hearing tests, and other non-painful procedures.
The IN DEXKET group showed no significant difference in the success rate of sedation within 15 min, defined as PSSS scores of 1–3, compared with the CH group (75.8% [47/62] vs. 66.7% [44/66], P = 0.330, odds ratio [OR]: 1.567, 95% CI [0.722–3.399]) (Table 3). The post-hoc power for the primary outcome for two-tailed testing with alpha = 0.05 was calculated to be 0.17.
No significant difference was observed in sedation failure after 30 min in the IN DEXKET group compared with that in the CH group (9.7% [6/62] vs. 21.2% [14/66], P = 0.090, OR: 0.398, 95% CI [0.142–1.113]). In the IN DEXKET group (n = 6), rescue sedation was induced with intranasal dexmedetomidine 2 µg/kg (n = 5) or formula milk (n = 1). In the CH group (n = 14), three patients were sedated after waiting for more than 30 min (31, 37, and 37 min), and four patients completed the procedure with positional restraint by parents. Five patients were sedated after receiving an additional dose of CH (50 mg/kg), and the procedure failed in one of those patients even after rescue sedation. Two patients underwent rescue sedation with intranasal dexmedetomidine 2 µg/kg and ketamine 3 mg/kg.
However, the IN DEXKET group demonstrated a significant reduction in the overall complication rate (3.2% [2/62] vs. 16.7% [11/66]; P = 0.017; OR 0.167; 95% CI, 0.035–0.786). Moreover, the IN DEXKET group showed more favorable patient acceptance of drug administration than the CH group (P < 0.001). No significant differences were observed between the groups in separation anxiety from guardians or physician satisfaction.
In the subgroup analysis of patients aged < 1 year (Table 4), the IN DEXKET group showed no significant difference in the success rate of sedation within 15 min compared with the CH group (73.7% [28/38] vs. 80.0% [28/35], P = 0.588, OR: 0.700, 95% CI [0.233–2.100]) or in the sedation failure rate after 30 min (15.8% [6/38] vs. 14.3% [5/35], P = 1.000, OR: 1.125, 95% CI [0.311–4.075]). However, the IN DEXKET group had a significantly lower overall complication rate (2.6% [1/38] vs. 22.9% [8/35], P = 0.012, OR: 0.091, 95% CI [0.011–0.773]), mainly due to a decrease in respiration or hemodynamic complications (2.6% [1/38] vs. 20.0% [7/35], P = 0.024, OR: 0.108, 95% CI [0.013–0.930]). Patient acceptance of drug administration was also more favorable in the IN DEXKET group (P < 0.001).
In the subgroup analysis of patients aged 1–7 years (Table 5), the IN DEXKET group showed a significantly higher sedation success rate within 15 min than the CH group (79.2% [19/24] vs. 51.6% [16/31], P = 0.049, OR: 3.563, 95% CI [1.061–11.959]) and a significant reduction in sedation failure after 30 min (0% vs. 29.0% [9/31], P = 0.003). No significant differences were observed between the groups in terms of overall complications (P = 0.624) or patient acceptance of drug administration (P = 0.051).
Discussion
In this study, we evaluated the efficacy of combined intranasal dexmedetomidine (2 μg/kg) and ketamine (3 mg/kg) as a non-IV sedation method for pediatric patients, compared to CH (50 mg/kg). We found that intranasal combination of dexmedetomidine (2 μg/kg) and ketamine (3 mg/kg) showed a similar success rate of sedation within 15 min compared to CH (50 mg/kg), while significantly reducing side effects in pediatric patients < 7 years. Additionally, this combination offered a more convenient administration for pediatric patients compared to CH. These properties make IN DEXKET highly beneficial in pediatric sedation clinical practice.
The intranasal combination of dexmedetomidine and ketamine offers several advantages in pediatric sedation. It can be administered non-invasively, and intranasal administration is significantly easier and more convenient than oral administration [27]. Additionally, the combination of dexmedetomidine and ketamine allows for dose reduction of each drug while obtaining a high sedation success rate, rapid onset, sufficient duration for procedures, and stable respiratory and hemodynamic effects through their complementary actions [21,24,26,27].
Our results showed significantly favorable patient acceptance of drug administration in the IN DEXKET group, whereas many patients did not cooperate with oral CH administration. The use of a mucosal atomizer device might further enhance the quick and broad dispersion of the sedative across the nasal mucosa, facilitating efficient absorption [35]. Since CH has a bitter taste, children may cry or attempt to spit it out during oral administration that can lead to desaturation or vomiting [2–4]. Therefore, many hospitals still adhere to strict fasting guidelines for CH use, despite recent evidence supporting more liberal fasting practices in pediatric anesthesia and sedation [38,39]. Given that no vomiting occurred in the IN DEXKET group, this method appears more suitable for liberal fasting or for administering rescue sedation without prior fasting. Additionally, the ease of administration can alleviate discomfort and distress for patients and caregivers while enhancing the work efficiency of healthcare providers involved in procedural sedation.
The IN DEXKET group demonstrated a similar sedation success rate within 15 min compared to the CH group. The IN DEXKET group also showed a trend toward a faster onset and a lower sedation failure rate at 30 min than the CH group, although these differences were not statistically significant due to limited power. Procedural sedation aims not only to achieve adequate sedation but also to facilitate examinations or procedures; therefore, delays in achieving sedation can lead to inefficient use of limited medical resources. In this context, IN DEXKET offers the advantage of rapidly achieving sedation, thereby minimizing the need for additional rescue sedation and ensuring optimal timing for procedures.
Sedation-related complications were significantly reduced in the IN DEXKET group in pediatric patients < 7 years. Pediatric patients who require diagnostic procedures at a young age are more likely to have underlying diseases. A recent study identified risk factors for CH-related complications, including congenital syndromes, congenital heart disease, preterm birth, and oxygen dependency [3]. In our study, approximately 80% of the participants were ASA II or III patients who required evaluation for congenital heart diseases. While the CH group experienced a high incidence (13.6%) of respiratory complications, the IN DEXKET group did not experience bradycardia, a common side effect associated with dexmedetomidine [28,29]. In this context, IN DEXKET may be a safer sedation option for pediatric patients with underlying diseases and a better choice for healthy pediatric patients.
Notably, the proportion of participants aged under one year was relatively high at 57%, due to stratified block randomization (age groups of less than 1 year and 1–7 years). The previous literature regarding the intranasal combination of dexmedetomidine and ketamine did not include participants aged under one year [37] or did not clearly specify the proportion of participants [26]. The results of the subgroup analysis by age group provided informative insights into the advantages of IN DEXKET over CH at different ages. In neonates and infants, the CH group exhibited a higher incidence of respiratory complications (20%). The IN DEXKET group demonstrated a significant reduction in the sedation-related complication rate while maintaining a similar success rate within 15 min and a comparable sedation failure rate at 30 min compared to the CH group. Therefore, IN DEXKET appears to offer a safety advantage over CH in neonates and infants, a population characterized by limited cardiorespiratory reserves. Among pediatric patients aged 1 to 7 years, the IN DEXKET group exhibited a higher sedation success rate within 15 min and a lower sedation failure rate at 30 min after sedative administration compared to the CH group. These findings suggest that IN DEXKET is a more efficient sedation method than CH for children aged 1 to 7 years.
The study has several limitations. First, using a combination of two sedatives introduces complexity compared with using a single sedative. However, it is notable that no adverse effects, such as ketamine-associated hypersalivation or dexmedetomidine-associated bradycardia, were observed. Second, the study did not include pediatric patients undergoing MRI, that commonly requires sedation. Moderate sedation for MRI was already provided by pediatric anesthesiologists or specialized sedation teams at both centers. Future studies may clarify the effects of IN DEXKET in pediatric MRI sedation. Third, the calculated power for the primary endpoint was low, indicating that the sample size of the current study was insufficient to detect a statistically significant difference in the primary outcome, although a trend of difference was observed. In addition, the subgroup analysis was performed with a relatively small sample size. Therefore, a large-scale follow-up study is needed to evaluate the difference in sedation success rates within 15 min between IN DEXKET and oral CH. Fourth, some secondary outcomes, including patients’ acceptance of drug administration, separation anxiety from guardians, and physicians’ satisfaction, were measured using non-validated, researcher-developed scales. Fifth, to ensure that the scheduled procedure or examination could proceed, rescue sedation was performed if adequate sedation was not achieved within 30 min after the initial administration of sedative. This may have influenced the assessment of separation anxiety from guardians and physicians’ satisfaction.
In conclusion, the study findings suggest that intranasal combination of dexmedetomidine (2 μg/kg) and ketamine (3 mg/kg) is as effective as CH (50 mg/kg), while being a much safer method for pediatric sedation. Further large-scale studies are needed to demonstrate the superiority of the intranasal combination of dexmedetomidine and ketamine.
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