A randomized double-blind trial of intranasal dexmedetomidine versus intranasal esketamine for procedural sedation and analgesia in young children

This prospective, equally randomized (1:1), double-blind, parallel group trial was conducted in a large pediatric ED. This study was monitored by an independent regulatory unit, Karolinska Trial Alliance. Ethical approval was obtained from the Regional Ethical Review Board Stockholm. And this study was registered with European Clinical Trial Registry. The trial protocol is presented as Additional file 1.

The CONSORT guidelines [21] were used for reporting our data.

The primary outcome was pain, measured as the highest level of pain during the procedure. Procedure was defined for lacerations as suturing of the wound and for burns as wound debridement and dressing, local guidelines for the procedures were followed. Pain was assessed with Face, Legs, Activity, Cry, Consolability scale (FLACC) [23], which has been validated for procedural pain assessment by Nilsson et al. [24]. FLACC scores were classified as following: 0 = no pain, 1–3 = mild discomfort, 4–6 = moderate pain and 7–10 = severe pain [25, 26]. We considered a change of two points on the FLACC as clinically significant.

Secondary outcomes were sedation depth, parents’ satisfaction, and ED physician’s assessment of the feasibility of the procedure. Ramsay sedation scale [27] was used to evaluate sedation depth, as it is one of the most widely used tools for observationally based sedation assessment and it has been used in studies assessing sedation with intranasal dexmedetomidine [12, 14]. Ramsay score 1 = awake, 2 = awake; co-operative, orientated and tranquil, 3 = awake; responds to commands only 4 = asleep; reacts with a brisk response to a light glabellar tap or a loud auditory stimulus, 5 = asleep; reacts with a sluggish response to a light glabellar tap or a loud auditory stimulus, 6 = asleep; does not respond to pain. We considered a change of one point as clinically significant.

Parent/parents who were with the child from administration of the trial drug until recovery, received a questionnaire with four questions: (1) in your opinion; how much pain did your child have during the procedure on a scale of 0–10 (the revised Faces Pain Scale (FPS-R) [28] was shown to the parents), (2) what was your opinion about the sedation and the procedure on a scale of 1–5 (1 = not satisfied, 5 = very satisfied). (3) if your child needs procedural sedation again in the future, would you prefer the same management? (yes/no), (4) if not what would you wish to be different?

The ED physician graded the feasibility of performing the procedure on a scale of 1–5 (1 = very easy, 5 = very difficult).

All patients included in the study received oral paracetamol (40 mg/kg) no later than 1–1.5 h before the procedure.

Patients were enrolled and randomized before the administration of local anesthesia. Buffered lidocaine (10 ml 1% lidocaine + 2 ml NaHCO₃ 6 M) was used for local anesthesia. The burn area was covered with lidocaine-soaked gauze for 20–30 min before the procedure. Wounds were infiltrated with buffered lidocaine for a minimum of 5 min prior to the procedure. The maximum lidocaine dose without adrenaline was 5 mg/kg and with adrenaline 7 mg/kg.

DEX 100 mcg/ml and sKET 25 mg/ml were used without dilution. A 1 ml syringe with a nasal atomizer was used for drug administration. 2.0 mcg/kg DEX and 1.0 mg/kg sKET were used following the local and national guidelines [29]. The dose was equally divided between both nostrils when the recommended volume per nostril (0.3 ml/nostril) [30] was exceeded.

Patients were monitored from the administration of the trial drug until the patient had recovered, and Ramsay score was 1. Pain (FLACC score) and sedation (Ramsay score) were assessed at least every 5 min before and during the procedure and every 10 min after the procedure. Oxygen saturation (SpO₂) and heart rate (HR) were monitored continuously. SpO₂ and HR were recorded at the same timepoints with FLACC and Ramsay unless significant changes occurred at other times. Any aberration from normal values described in Pediatric Advanced Life Support (PALS) [31] were considered significant. Assessment and monitoring were done by two experienced pediatricians (AN, KS) who were familiar with both the FLACC and Ramsay scales. Five patients were initially evaluated together to ensure uniform assessment.

The procedure was started when Ramsay score 2 was reached. If it was not reached within 30 min and the child was not co-operative the procedure was not carried through within trial protocol and other sedation was used for the treatment. Patients were able to leave the ED when Ramsay score was 1 and the patient had returned to the habitual condition.

Patients were randomized to two groups: 1) IN DEX 2.0 mcg/kg, 2) IN sKET 1.0 mg/kg. We used block randomization (blocks of 10 subjects (5 from both arms), except one block with 12 subjects). A physician not participating in the trial created a randomization list after a random draw and filled the opaque envelopes with information (trial drug and dose table) and numbered them according to the list. Envelopes were then used in number order. Randomization was kept in a sealed envelope during trial period and the seal was intact at the time of trial closure. The blocks were used in order and the order was not known by the physician performing the assessment of the patient.

The trial physician, ED physician and nurses caring for the patient, as well as the patient and parents were blinded to the trial drug, as were all other staff working in the ED. Trial drug was prepared and administered by a nurse who was not involved in the care of the patient otherwise. Trial physician, ED physician and nurses caring for the patient were not present at the time of drug administration. Patients and their parents did not have knowledge about the trial drugs (e.g., smell or taste, nasal irritation) or the difference between the volume of the two drugs.

An a priori power analysis was conducted to test the null hypothesis of this superiority trial. We aimed for a mean difference of 2 on FLACC which would be the smallest clinically relevant difference. Assuming a within-group standard deviation of 2.5 we would need n = 26 patient per group to obtain 0.80 power for the test.

Continuous variables are presented using medians and interquartile ranges (IQRs) and tested with Mann–Whitney U test and tested correlations using the Spearman method. Categorical variables are presented using counts and percentages and tested using Fisher’s test. We considered p-values below 0.05 significant. All analyses were done using R version 4.2.2. [32].

One parent in group IN sKET did not wish to answer the questionnaire. The parents of the two patients not receiving sufficient sedation and analgesia with the trial drug only stated they did not wish for the same treatment in the future. 12 (85.7%) of the parents in the group IN DEX were”very satisfied” with the procedure and sedation and 6 (46.2%) in group IN sKET, p-value 0.10. 13/14 of the parents of patients receiving IN DEX and 10 out of 13 parents of patients receiving IN sKET would be satisfied with the same procedural sedation and analgesia if needed in the future. Parents’ assessment of their child’s pain score (FPS-R) median (IQR) was 2.5 (0–5) in group IN DEX and 5 (0–8) in group IN sKET, p-value 0.44.

The ED physician graded the feasibility of the procedure as 1 = very easy in 8 (57.1%) cases in group IN DEX, whereas 3 (21.4%) cases in group IN sKET were graded 1, p-value 0.21.

No severe adverse events were reported. Two patients in group IN sKET and one in group IN DEX had SpO2 94% very briefly, no drop in HR was noted and no intervening from hospital staff was required. No patients had HR under the 1st age normative percentile.

The main limitation of this study is not reaching the power needed to show statistical significance. We did not reach the estimated sample size during the study period of two years even though this study was conducted in a large pediatric ED. There are several explanations for this. During the study period there was a change in the streaming protocol for children with minor injuries in the region due to the opening of a number of low-acuity emergency care centers in Stockholm treating children with minor injuries which resulted in fewer patients attending the ALB ED, reducing the number of eligible patients for our study. Furthermore, the topical lidocaine, adrenaline, tetracaine gel and tissue glue changed the treatment practice for laceration repair and therefore procedural sedation was needed less frequently. Moreover, the study team could not be expanded as the Karolinska Trial alliance strongly recommended physicians to perform the patient assessment during the trial. Hence the study was required to be done by physicians, which in turn was a limiting factor as there are few experienced pediatric emergency physicians available both at ALB and other centers. Continued enrollment during 2020 was initially planned but could not be executed due to the Covid-19 pandemic. In addition, we could potentially have reached sample size if study drugs were administered in two doses, this would have allowed children weighing more than 15 kg to be enrolled.

There were two trial physicians doing all the assessments, which can be seen as both a strength and a limitation. A strength, as this reduces the variability in the FLACC and Ramsay scores. On the other hand, this obviously can have affected the number of patients enrolled as the trial physicians could not be present at all times.

The dosage of sedative drugs used in this study can be discussed. For IN sKET we followed the national guidelines from the Swedish Medical Product Agency regarding procedural sedation and analgesia for children [29]. The recommended dose for IN sKET is 1.0 mg/kg in children and with a maximum weight of 15 kg as otherwise the intranasal volume would become too large for good absorption from the nasal mucosa. 23 children were excluded from this study as they weighed more than 15 kg. This could have been avoided by administering the drugs twice with a specific time interval. However, we chose to follow the Swedish guidelines. Before 2017 most of the studies on IN DEX were done with the maximum dose of 2.0 mcg/kg [13, 33]. In addition, the local guidelines and the experience from IN DEX for imaging in ALB impacted our choice of the dose. In 2023 Poonai et al. suggested that 3 or 4 mcg/kg could be considered as an optimal dose of IN DEX in laceration repair [36].

This trial was limited to the age group 1–3 years. Lacerations and burns are common minor injury types in this age group and were therefore selected for this trial. Unfortunately, all patients with burns received IN DEX for trial drug as a follow to the random allocation. These limitations need to be taken into consideration when treating children in other age groups and different procedures requiring analgesia and sedation are in question.