It was found in our study that oral Midazolam in combination with the use of 3 ug/kg or 2 ug/kg intranasal DEX had a similar sedation effect and showed no significant difference in safety between the two combination regimens. The one-time sedation success rate and sedation onset time were rational and effective in both combinations.

MRI examination usually lasts a relatively long period and produces large noises, which may affect the quality of examination in young children due to crying, anxiety, and fear. To improve the accuracy of imaging diagnosis, it is necessary to use sedatives in preschool children and young children with chronic diseases who need to undergo MRI examination [6].

Midazolam is a type of short-acting benzodiazepine with anti-anxiety, anti-convulsion, sedative, and hypnotic activities [7]. Also, it has a certain respiratory inhibitory effect, depending on the severity of the disease and the dose of the drug. But as it has a minimal effect on the cardiovascular system, it is a commonly used sedative in clinical practice [8], especially in young children. Research finds that Midazolam or a like drug alone is often ineffective [9, 10], and therefore it is often used in combination with other drugs. Oral Midazolam in combination with intranasal DEX can largely increase the success rate of sedation and offers a good sedative outcome. However, many medical institutions prepared the oral Midazolam solution by mixing its intravenous injection form with syrup, but it still tastes bitter and irritable, which often induces nausea and vomiting and therefore is unacceptable by young children. The locally available commercial product of oral Midazolam tastes sweet and is easy to be accepted by young children and complies with the ethical rule.

DEX is an α2 adrenoceptor agonist and can induce a state similar to natural sleep [11].

Compared with other sedatives, it has minimal impact on respiration, with a low

occurrence of respiratory depression [12] and a potent sedative effect. Compared with

chloral hydrate, DEX can provide a more effective sedation action [13, 14]. A meta-analysis

showed Intranasal administration of DEX is superior to oral chloral hydrate for sedation

during pediatric CT/MRI examinations and has a better safety profile [15]. Intranasal

administration of DEX has good tolerance and the sedative effect that it produces is

similar to the intravenous injection form [16]. It has therefore been gradually and more

commonly used in clinical practice.

Procedural sedation using the combination of intranasal Dexmedetomidine and ketamine

is associated with acceptable effectiveness, low rates of adverse events, and may shorten

the sedation induction time [17, 18]. However, the instructions of ketamine show that

mental symptoms such as hallucinations, restlessness, and nightmares may occur during

the recovery period of anesthesia. Therefore, further research is required on the mental side effects. Combined use of oral Midazolam and intranasal DEX can offer a high one-time sedation success rate with a good sedative effect, therefore avoiding a second examination, and saving the manpower, financial resources, and time of the family. In addition, the sedated child is easy to recover and the basic parameters remain stable during the process of sedation.

The main result of the present study revealed that the sedation onset time, sedation maintenance time, and moderate-deep sedative effect of combined used of oral Midazolam and intranasal DEX were similar to what was reported in previous studies. Li et al reported their combined use of buccomucosal Midazolam with intranasal DEX during CT examination in children with autism and achieved a 95% examination success rate without the occurrence of respiratory depression or hemodynamic disturbance that needed clinical intervention [19, 20]. Cozzi et al [21] reported an 84% sedation success rate in their 108 children undergoing MRI examination by using 0.5 mg/kg Midazolam plus 3 ug/kg intranasal DEX, Li BL et al. explored the efficacy and safety of using 3 ug/kg intranasal DEX plus 0.2 mg/Kg oral Midazolam [22], believing that Midazolam in combination with intranasal DEX is a safe and effective regimen for sedation. Although they did not observe significant adverse reactions, the dose of the two drugs that they used is significantly larger than that we used in this study, indicating that their regimen is not safe as ours, and therefore should be selected with caution in clinical practice. This discrepancy may be due to the following reasons. First, the age of the children in our study was narrow, while Cozzi ‘s study included children ranging in age from 4 to 209 months. The study participants mentioned by Cozzi were older than ours. Therefore, the required drug dose for DEX is smaller in our research. The second reason should be attributed to the DOR’s formulation. The medication we used this time is an oral formulation rather than the intravenous formulation used in many previous studies, so the absorption effect would be better, and result in a lower dose of medication required. In addition, the present study mainly observed the sedation effect in young children during MRI examination. Although they had various types of diseases, the examiners and technical parameters were relatively fixed, which provided good tacit cooperation between the technicians and therefore indirectly improved the efficiency and success rate of examination. Therefore, our study applied a lower dose of Dexmedetomidine to achieve the same clinical effect. Although the use of two different drugs and drug administrations is more time-consuming and complex as compared with propofol and other narcotics alone, it reduces the risk of respiratory depression and avoids vascular injection. Although the use of a relatively high dose of DEX does not seem to induce significant respiratory depression, it affects hemodynamics [23] and therefore it is necessary to determine an appropriate dose to achieve a satisfactory outcome of sedation. Some studies reported that the dose of intranasal DEX was 1-4 ug/kg. Li et al reported that the ED95 of intranasal DEX used for pulmonary function tests in children aged 1-3 years was 2.64 ug/kg [24]. According to the report by Miller et al [25], 2.5-3 ug/kg intranasal DEX could obtain an even higher success rate of sedation as compared with intranasal inhalation of a low dose (1-2 ug/kg) of atomized DEX for sedation of transthoracic echocardiography (TTE) in pediatric patients with CHD. Given the above findings, we used two regimens (3 ug/kg DEX+0.2 mg/kg Midazolam in group A, and 2 ug/kg DEX+0.2 mg/kg Midazolam in group B) in our study. The results showed no significant difference in sedation onset time and recovery time between the two groups (P>0.05). Although the sedation success rate in group A was slightly higher than that in group B, the difference was not statistically significant (P>0.05), probably because the synergistic effect of Midazolam reduced the required dose of DEX.

The effect of the sympathetic nerve block of DEX may reduce HR and BP [26]， but no hemodynamic change that needed clinical intervention occurred in the cohort of patients in our study. In addition, there was no significant difference in the occurrence of abnormal HR between the two groups (P>0.05). Weconclude that either 2 ug/kg or 3 ug/kg DEX can be safely used for sedation in young children. No hypoxia, nausea, or vomiting occurred during the sedation period in both groups, indicating that Midazolam and DEX are well tolerated by sick children.

Our study had some limitations. First, there was a lack of specific thresholds for prospective airway and hemodynamic interventions. Second, as we were unable to perform the study in a double-blind manner and did not employ a third party to make the evaluation, subjective deviation could not be avoided completely. Third, this is a single-center study and therefore the findings and conclusions obtained in this study may not be universally significant. Fourth, some retrospective memory of some parents or guardians may produce selective deviation and informative errors which may affect the results of the experiment. Finally, we failed to build up a complete set of drug dose combinations and therefore the result obtained in this study only indicates that the dose combination of the sedative reported herein is safe and effective and does not represent the optimal dose.

In summary, 2 ug/kg or 3 ug/kg DEX +0.2 mg/kg Midazolam can provide a high one-time sedation success rate in young children for brain MRI examination without inducing significant changes in vital signs. A small dose (2 ug/kg) of intranasal DEX and 0.2 mg/kg oral Midazolam should be an even safer compatible dose and worthy of clinical promotion.