Ethics and Registration
The study protocol was approval by the Ethics Committee of Children’s Hospital of Soochow University (No. 2021009) on June 10, 2021. This study was prospectively registered on the Chinese Clinical Trial Registry (Identifier: ChiCTR2100048477) on July 9, 2021. The study was conducted in accordance with the Declaration of Helsinki. We obtained written informed consent from the parents or guardians of all participants in this study. All patients could decline participation or request withdrawal from the study at any time, without the need to give specific reasons.
Study design
This researcher-initiated, single-center, prospective, randomized, double-blind, controlled trial was carried out at the Children’s Hospital of Soochow University from July 12, 2021 to August 30, 2021. The Children’s Hospital of Soochow University is a referral medical center, where the MRI procedures are performed in approximately 2000 pediatric patients each year. This report follows the Consolidated Standards of Reporting Trials (CONSORT) Statement [20].
Study patients
Pediatric patients aged between 6 months and 8 years with American Society of Anesthesiologists (ASA) Status Classification I or II, scheduled for 3 T MRI procedures under sedation were eligible for participation. The exclusion criteria were: (1) hemodynamic or respiratory instability (dehydration, shock, hypoadrenalism, hyperadrenalism, respiratory depression, or acute respiratory failure), (2) congenital heart disease with right-to-left shun, (3) increased intracranial or intraocular pressure, (4) cognitive impairment, or behavioral or psychological disorders, (5) history of more than three times of general anesthesia, and (6) allergies to the medications used in this study.
Randomization and blinding
An independent research assistant performed the randomization with the use of an online tool (https://www.sealedenvelope.com/randomisation/) to allocate patients into either the esketamine–propofol group or the dexmedetomidine–propofol group. The randomization was generated with an allocation ratio of 1:1 and permuted block sizes of 2 and 4. The allocation was concealed using sealed opaque envelopes. The investigators were unaware of the details of randomization. According to the randomization results, an independent research nurse who did not participate in the subsequent study prepared the study medications: esketamine diluted with normal saline to a final concentration of 0.5 mg/ml, and dexmedetomidine to 1 μg/ml. This nurse did not have contacts with the investigators. Both esketamine and dexmedetomidine were clear and colorless fluids, and they were kept in identical syringes with the labels of patient number. Thus, it was impossible to distinguish them. All patients, peri-procedure care providers, and post-procedure observers were all blinded to the group assignment.
Sedation for MRI procedures
All patients were fasted for 2 h for clear liquids, 4 h for breast milk, and 6 h for infant formula, nonhuman milk and light meal [21]. In a waiting area, the baseline heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were recorded before intravenous cannula insertion. Approximately 1 h after the use of a skin-numbing local anesthetic (Compound Lidocaine Cream), the cannulation was finished by a skilled nurse when the children were watching cartoon movies and accompanied by their parents, which minimized the fear of needles. After that, patients were transferred to the MRI room accompanied by their parents.
Supplemental oxygen at a flow of 1 L/min was delivered via nasal cannula. Throughout the study, HR, SBP, DBP, and peripheral oxygen saturation (SpO2) were monitored. After sedation induction, patients were positioned with a soft roll under the neck and shoulders. Upon the completion of MRI, the propofol infusion was stopped and the patients were transferred to a recovery room (RR). Recovery was assessed using the modified Aldrete score at 5 min intervals, and a score ≥ 9 indicated readiness for RR discharge [22,23,24]. To ensure consistency and reduce potential bias, the perioperative care for patients in this study was provided by the same multidisciplinary team.
Episodes of upper airway obstruction such as snoring, stridor, pharyngeal obstruction, and laryngospasm were managed by airway maneuvers (jaw thrust or chin lift). Oxygen desaturation was defined as SpO2 < 94% [25]. If the obstruction or desaturation was unresolved, patients received increased concentration of inspired oxygen and airway interventions (oropharyngeal airway, face mask ventilation, laryngeal mask airway, tracheal intubation, and positive-pressure ventilatory assistance). Hemodynamic data including HR, SBP, and DBP were recorded at baseline, immediately after induction, 5 min after the beginning of MRI, the end of MRI examinations, 5 min in the RR, and at the time of RR discharge. Bradycardia was defined as a decrease of HR > 20% from baseline [26, 27]. Severe bradycardia (defined as a decrease of HR > 30% from baseline) was treated with atropine 0.1 mg/kg. Hypotension (defined as a decrease of SBP > 20% from baseline) [26, 27] was treated with fluid administration and/or ephedrine based on the discretion of the anesthesiologist.
Study interventions
An attending anesthesiologist performed the sedation procedure consisting of an induction phase and a titration phase, which was standardized for all patients in this study. For induction of sedation, a loading dose of propofol 1.5 mg/kg was administered to all patients. After that, the esketamine–propofol group received esketamine 0.15 mg/kg intravenously over 3 min, and the dexmedetomidine–propofol group received dexmedetomidine 0.3 μg/kg intravenously over 3 min [7, 28, 29]. We administered propofol prior to study drugs to induce a prompt sedation status in children, as propofol has a fast onset profile.
At the commencement of MRI, the target level of sedation was a Ramsey sedation score (RSS) of 6 (no response to a light glabellar tap or loud auditory stimulus) [30]. During the scanning, the anesthesiologist continuously monitored the level of sedation with the RSS target of 5–6 (a sluggish or no response to loud auditory stimulus). The target level of sedation was achieved using propofol titration. Propofol was infused at a rate of 50–300 μg/kg/min using an infusion system suitable for MRI, and boluses of 0.3–0.5 mg/kg could be administered at the discretion of the anesthesiologist. If the anesthesiologist noticed a deep sedation with signs of airway obstruction, hypotension, or bradycardia, the infusion of propofol was stopped. Inadequate sedation was defined as that the MRI procedures could not be completed due to body movement during the scanning. If inadequate sedation occurred, patients would receive general anesthesia with laryngeal mask using remifentanil, sevoflurane, and rocuronium to complete the MRI examination.
Primary and secondary outcomes
The primary outcome of this study was the total dose of propofol (expressed as μg/kg/min), defined as the loading dose (during the induction phase) plus the continuous infusion dose and the boluses (during the titration phase).
The secondary outcomes included the dose of propofol for titration (continuous infusion dose and boluses), the incidences of adverse events (upper airway obstruction, oxygen desaturation, bradycardia, and bradycardia with intervention), time to emergence from sedation (defined as the time interval between discontinuing propofol infusion and reaching an RSS of 2), and time to RR discharge (defined as the time interval between discontinuing propofol infusion and discharge from RR).
Peri-procedure and follow-up data
The peri-procedure data included hemodynamic changes, RSS scores, excessive salivation, hypotension, laryngospasm, scanning time, radiologist satisfaction scores, nausea and vomiting, the incidence of emergence delirium, and the pediatric anesthesia emergence delirium (PAED) scores. Emergence delirium was assessed using the PAED scores at emergence, 15 min after emergence, and RR discharge. The PAED consists of 5 dimensions: eye contact, purposeful actions, awareness of surroundings, restlessness, and inconsolability (a score of 0–4 for each item). A score of PAED ≥ 10 indicates the occurrence of emergence delirium [31,32,33]. The 24 h follow-up data were collected via telephone, including poor appetite, nausea and vomiting, and parent satisfaction scores. Radiologist and parent satisfactions were assessed using a numerical rating scale (NRS) of 0–10 (0 = not satisfied; 10 = very satisfied).
Sample size calculation
In our pilot observation using dexmedetomidine–propofol sedation for 30 children undergoing 3 T MRI (unpublished data), the mean total dose of propofol was 232.3 μg/kg/min with the standard deviation (SD) of 91.3 μg/kg/min. A recent study showed that a low-dose esketamine reduced the total dose of propofol by 21% for sedation in endoscopic procedures [29]. Based on these, we hypothesized that the use of esketamine would reduce the total dose of propofol by 20% in our patients. With an α = 0.05, a power = 80%, and a possible dropout rate of 10%, a total of 114 patients were planned in this study (n = 57 in each arm). The number of patients required in this study was calculated using the PASS software (version 11.0.7; NCSS, LCC, Kaysville, UT).
Statistical analysis
Continuous variables were checked for normal distribution using the Kolmogorov–Smirnov test. Normally distributed data are presented as mean ± SD and analyzed using the independent Student’s t test or repeated measures analysis of variance followed by Dunnett or Sidak test, as appropriate. Skewed data are presented as median (interquartile range, IQR) and analyzed using the Mann–Whitney U test. Categorical data are presented as number (%) and analyzed using chi-square test or Fisher’s exact test.
For the primary outcome, a two-sided P value < 0.05 denotes a statistically significant difference. For the 7 secondary outcomes, multiple testing corrections were applied using the Bonferroni method, with a P value < 0.007 (i.e., 0.05/7) indicating a statistically significant difference. To assess the between-group differences, the effect size was analyzed using difference in means for normally distributed data, difference in medians for skewed data, or attributable risk for categorical data, with their 95% confidence intervals (CIs). Difference in medians and the 95% CIs were estimated using Hodges–Lehman estimation of location shift.
All analyses were done on the intention-to-treat basis. No interim analysis was planned. As we expected that missing data would be rare in our data set, we did not have plan for missing data imputation. Statistical analyses were performed using the GraphPad Prism software (version 9.00; GraphPad, San Diego, CA).