A 2020 systemic review and meta-analysis evaluated the effectiveness of intranasal dexmedetomidine (DEX) as a sole sedative during pediatric procedural sedation outside the operating room. Randomized controlled trial (RCTs) comparing intranasal DEX with another sedative or placebo during pediatric procedural sedation were included, with the primary outcome as success of the planned procedure. A total of 7 RCTs involving 730 patients were included. Patients’ ages ranged from three months to eight years in six studies, and from 4 to 14 years in one study. In the four studies comparing DEX to chloral hydrate with 570 patients, sedation was indicated for imaging: transthoracic echocardiography and computed tomography in two, auditory brainstem response testing in one, and an ophthalmic examination in one. In the three studies comparing DEX with midazolam involving 160 patients, sedation indications included dental treatment, computed tomography imaging with intravenous cannulation, and laceration repair. DEX doses ranged from 1 to 3 mcg/kg in all seven studies included. Intranasal administration utilized a mucosal atomization device in four studies, and drops from a syringe in three studies. [1]
The incidence of successfully completed procedures did not differ between intransal DEX and chloral hydrate, as indicated by a combined relative risk (RR) of 1.08 (95% confidence interval [CI] 0.98 to 1.19). However, the success rate was higher in children treated with intranasal DEX compared to midazolam (combined RR 1.52; 95% CI 1.19 to 1.94). The overall success rate for children treated with intranasal DEX was 83%. [1]
In patients receiving DEX, the onset time of sedation was 16.9 ± 2.6 minutes, and the duration was 81.5 ± 4.8 minutes. DEX demonstrated a marginally shorter onset time compared to chloral hydrate. However, the duration of sedation and time to discharge showed no significant differences between DEX and chloral hydrate recipients. The incidence of hypotension, bradycardia, or respiratory complications were not significantly different between the sedatives used. Nausea and vomiting were more prevalent in children treated with chloral hydrate compared to those treated with other sedatives. [1]
The findings suggest that intranasal DEX was a safe and effective sedative drug during pediatric procedural sedation outside the operating room. It had a similar procedural success rate to chloral hydrate but seemed to be superior to midazolam. Clinically relevant adverse events associated with intranasal DEX were rare. [1]
A 2017 meta-analysis was conducted to identify the efficacy and safety of premedication with intranasal DEX in children. The study included 1,168 participants in 13 RCTs. Four studies compared intranasal DEX to oral midazolam, while six studies compared intransal DEX to intranasal midazolam. Additionally, one study examined intranasal DEX versus intranasal clonidine, two studies compared it to intranasal normal saline, and one study each compared intranasal DEX to intranasal ketamine with intranasal normal saline. [2]
Intranasal administration of DEX as premedication resulted in more satisfactory sedation during parental separation (RR 1.45; 95% CI 1.19 to 1.76; p= 0.0002; I2= 80%) compared to alternative premedication regimens. In trials comparing intranasal DEX with oral midazolam, a subgroup analysis indicated that intransal DEX was significantly more effective than oral midazolam (RR 1.56; 95% CI 1.15 to 2.11; p= 0.005; I2= 82%). However, no significant difference was observed between intranasal DEX and intransal midazolam (RR 1.42; 95% CI 0.96 to 2.11; p= 0.08; I2= 85%). Additionally, DEX decreased the necessity for rescue analgesics (RR 0.58; 95% CI 0.40 to 0.83; p= 0.003; I2= 0%). However, no distinctions were observed in sedation during mask induction (RR 1.25; 95% CI 0.98 to 1.59; p= 0.08; I2= 71%) or in the occurrence of emergence delirium (RR 0.52; 95% CI 0.24 to 1.13; p= 0.10; I2= 67%). [2]
The use of intranasal DEX was correlated with a notably reduced incidence of nasal irritation (RR 0.05; 95% CI 0.01 to 0.36; p= 0.003; I2= 0%), and postoperative nausea and vomiting (RR 0.63; 95% CI 0.40 to 0.99; p= 0.04; I2= 0%) in comparison to other premedication treatments. Furthermore, it demonstrated a significant decrease in systolic blood pressure (weighted mean difference [WMD] -6.7 mmHg; 95% CI -10.5 to -2.9; p= 0.0006; I2= 96%) and heart rate (WMD -6.8 beats/min; 95% CI -11.3 to -2.6; p= 0.002; I2= 98%). This meta-analysis revealed that intranasal DEX provided more satisfactory sedation at parent separation and reduced the need for rescue analgesics and the incidence of nasal irritation and postoperative nausea and vomiting when compared with other premedication treatments, though caution in extrapolating these results due to high heterogeneity is encouraged. [2]
A 2022 systematic review and meta-analysis compared the efficacy and safety of intranasal ketamine with intranasal DEX as a premedication in pediatric patients undergoing general anesthesia for elective surgery or other procedures (10 RCTs). The pediatric population in all studies ranged from one to ten years old. Among the included studies, seven used intranasal ketamine and DEX instillation, while three administered premedications via nebulization. In nebulization studies, the ketamine:DEX dose ratio was consistently 100:1. In studies using intranasal instillation, dosing ratios ranged from 100:1 to 500:1. Premedication timing varied, with one study at 20 minutes, five at 30 minutes, and three at 45 minutes before anesthesia induction. Induction agents were sevoflurane in six studies and propofol in four. [3]
The effectiveness outcomes did not meet the comparability criteria between intranasal ketamine and intranasal DEX for sedation during parental separation (RR 0.90; 95% CI 0.79 to 1.04; I2= 89%; low quality of evidence), acceptance of the mask (RR 0.86; 95% CI 0.66 to 1.13; I2= 50%; low quality of evidence), and intravenous (IV) cannulation (RR 1.16; 95% CI 0.79 to 1.69; I2= 69%; very low quality of evidence). There were no significant differences observed between the two groups in terms of sedation onset time (standardized mean difference [SMD] 1.30; 95% CI -3.54 to 0.95; I2= 98%). Furthermore, no significant difference was observed in time to recovery from anesthesia between the two groups (SMD -0.26; 95% CI -0.87 to 0.34; I2= 90%; low quality of evidence). [3]
Patients treated with intranasal ketamine exhibited a higher incidence of nausea and vomiting (RR 2.47; 95% CI 1.24 to 4.91; I2= 0%; moderate quality evidence). There was a significantly higher occurrence of bradycardia in the intranasal DEX group (RR 0.16; 95% CI 0.04 to 0.70; I2= 40%; moderate quality of evidence) than in the ketamine group. Due to the low to very low-quality evidence in this analysis, there is neither confirmation nor refutation of comparable premedication efficacy between intranasal ketamine and DEX for parenteral separation, mask acceptance, and IV cannulation in a pediatric population. Clinical decision-making is likely to be influenced by variations in gastrointestinal and cardiovascular safety profiles. [3]
Another systematic review and meta-analysis conducted in 2022 also determined the efficacy and safety of intranasal DEX versus oral chloral hydrate for sedation in pediatric patients. A total of fourteen studies with 3,749 patients were included. In comparison to oral chloral hydrate, intranasal DEX demonstrated a significant increase in success rate of sedation (RR 1.139; 95% CI 1.051 to 1.235). Additionally, when compared to oral chloral hydrate, intranasal DEX significantly reduced the duration of sedation (WMD -2.625; 95% CI -4.481 to -0.769), latency (WMD -0.986; 95% CI -1.797 to -0.174), time to recovery from sedation (WMD -8.073; 95% CI -9.969 to -6.177), and total sedation time (WMD -6.498; 95% CI -6.722 to -6.274). Compared to oral chloral hydrate, intranasal DEX significantly reduced adverse events incidence (RR 0.282; 95% CI 0.086 to 0.928), including vomiting. However, it also led to a significant increase in bradycardia incidence (RR 4.212; 95% CI 2.173 to 8.164). No significant differences were observed in the incidence of crying or resisting (RR 0.283; 95% CI 0.077 to 1.048), hypotension (RR 1.500; 95% CI 0.939 to 2.397), and supplemental oxygen use (RR 0.396; 95% CI 0.104 to 1.515). It was suggested that intranasal DEX provided better sedation than oral chloral hydrate for pediatric patients with good safety; however, it is accompanied by an increased incidence of bradycardia, which should be kept in mind when deciding what sedative to administer. [4]
A 2019 systematic review and meta-analysis determined the safety and efficacy of intranasal DEX when used in mandibular third molar surgery. A total of 5 RCTs and 363 patients were included in the review, where half of the patients received DEX 30 minutes prior to surgery, and the other half were used as negative controls. Doses administered within the DEX group were consistent, although it should be noted that one article used 1 mcg/kg whereas the rest used 1.5 mcg/kg. During tooth extraction, the use of intranasal DEX was favored in comparison to control when looking at sedative effect; alertness and sedation via observer assessment occurred within 20 minutes of DEX administration versus control (SMD -1.20; 95% CI -1.73 to -0.67; p= 0.95; I2= 0%) and peaked at 40 minutes (SMD -3.19; 95% CI -3.95 to -2.43; p= 0.42; I2= 0%) before returning to base levels around 80 minutes. Similarly, the bispectral index, where larger values represent increased consciousness of the patient, favored the use of DEX at 40 minutes post-inhalation (SMD -11.68; 95% CI -19.49 to -3.87; p= 0.0001; I2= 89%). At 90 minutes post-inhalation, between-group differences were non-significant, indicating that the DEX group returned to basal level. Blood pressure and heart rate decreased to an extent during the operations, but did not exceed 20% of baseline, and returned to within normal limits at 90 minutes. [5]
Of the included RCTs, four evaluated pain at different temporal stages, with varying observations of pain levels (significant pain relief within 12 hours post-surgery, reduced perioperative pain, reduced postoperative pain, and no pain improvement, respectively). Adverse events reported include dry mouth, mild tremors, and mild dizziness; one study reported that the incidence of postoperative dizziness appeared significantly higher versus DEX patients. The authors concluded that intranasal DEX was significantly useful and effective in achieving optimal sedation and analgesia in third molar extraction; however, as all patients were Asian, results may not be extrapolatable to other patient populations. Additionally, reported adverse events and pain levels were scarce, thus claims about tolerability should be taken with caution. [5]
In a 2020 meta-analysis, the efficacy and safety of intranasal DEX in infants and toddlers was compared with those of oral chloral hydrate, which has been a commonly used method for diagnostic procedures sedation. Five studies involving a total of 720 patients were considered. Out of these RCTs, 402 patients (55.8%) underwent sedation with intranasal DEX as opposed to oral chloral hydrate. Intranasal DEX demonstrated a significantly higher success rate of sedation (RR 1.12; 95% CI 1.02 to 1.24; p = 0 .02; I2 = 74%) compared to oral chloral hydrate. Additionally, it demonstrated a significantly shorter onset time (WMD -1.79; 95% CI -3.23 to -0.34; p = 0 .02; I2 = 69%). However, there were no statistically significant differences in recovery time (WMD -10.53; 95% CI -24.17 to 3.11; p = 0 .13; I2 = 92%), and the proportion of patients returning to normal activities (RR 1.11; 95% CI 0.77 to 1.60; p = 0.57; I2 = 0%). Notably, intranasal DEX was associated with a significantly lower incidence of nausea and vomiting (RR 0.05; 95% CI 0.01 to 0.22; p <0 .0001; I2 = 0%) versus oral chloral hydrate. Although adverse events like bradycardia, hypotension, and hypoxia were not synthesized due to a lack of data, no clinical interventions, except oxygen supplementation, were required in any patients. Overall, it is believed that intranasal DEX could be more effective and acceptable sedation method for infants and toddlers undergoing diagnostic procedures than oral chloral hydrate, despite a transient trend of lower blood pressure and heart rate observed. [6]
In a 2017 meta-analysis, the sedative and clinical effects of intranasal DEX were compared with other sedative drugs and saline administered through various routes, including oral, buccal, and intranasal routes. The meta-analysis incorporated 11 RCTs. Involving 262 participants across four RCTs, this study assessed the efficacy and side effects of intranasal DEX pretreatments compared to intranasal saline. Additionally, the effect size of buccal DEX was compared with intranasal DEX, and comparisons were made between intranasal DEX and intranasal benzodiazepine, fentanyl, and ketamine. Seven trials employed 1 mcg/kg DEX doses, while three studies utilized a 2 mcg/kg DEX dose. Additionally, one study employed a 0.5 mcg/kg DEX dose. [7]
In trials specifically examining intranasal DEX versus intranasal saline, the sedation score associated with intranasal DEX showed an SMD of -2.45 (95% CI -3.33 to -1.58). In a subgroup analysis examining intranasal DEX compared with intranasal saline and oral benzodiazepines, the RR for unsatisfactory patient outcomes was 0.42 (95% CI 0.26 to 0.68; I2= 45%) and 0.43 (95% CI 0.32 to 0.58; I2 = 0%), respectively. Among trials comparing intranasal DEX with oral benzodiazepines, the sedation score associated with intranasal DEX showed an SMD of -0.41 (95% CI -1.09 to 0.27; I2= 69%). Importantly, there were no reported side effects, including nausea, vomiting, hyperglycemia, or delirium. These findings suggest that intranasal DEX is associated with better sedative effects than oral benzodiazepines without producing respiratory depression, but has a significantly delayed onset of effects. [7]
Finally, a recent meta-analysis aimed to evaluate the efficacy and safety of α2-adrenoceptor agonists and midazolam in children. A total of 21 studies involving 1,495 patients were included in the analysis. The majority of studies focused on evaluating midazolam versus DEX, with only one study addressing the comparison between midazolam and clonidine. The findings indicated that patients in the clonidine group exhibited significantly better facemask acceptance compared to those in the midazolam group. In contrast to midazolam, the use of DEX was associated with a higher rate of satisfactory parental separation (75.18% vs. 52.88%; RR 0.70; 95% CI 0.55 to 0.90; p= 0.005, I2= 76%, moderate quality of evidence). The use of DEX was linked to a slightly higher rate of satisfactory induction or mask acceptance compared to midazolam; however, no significant difference was observed between the two groups (59.68% vs. 69.23%; RR = 0.85; 95% CI 0.64 to 1.12; p = 0.24; I2 = 76%). Patients in the midazolam group had a higher incidence of nasal irritation/discomfort (32.39% vs. 0.00%; RR 24.00; 95% CI 3.33 to 172.78; p <0.002; I2 = 0%) compared to those in the DEX group. Based on these findings, the authors suggest that DEX should be regarded as the preferred intranasal sedative option for pediatric patients, emphasizing that it offers a more satisfactory sedative level with a lower incidence of several side effects. However, the lack of sufficient evidence regarding the effects of intranasal clonidine, along with overall low and moderate-quality evidence, suggests that the superiority of intranasal α2-adrenoceptor agonists in pediatric sedation needs validation through future studies with high-quality and large sample sizes. [8]