Ketamine and dexmedetomidine belong to different classes of pharmacological agents. They have a different therapeutic profile and are both commonly used as premedication in children.1 Ketamine can be administered by an iv, im, oral, rectal, and intranasal route2 and can produce sedation, anesthesia, immobility, analgesia, and amnesia through blocking N-methyl-D-aspartate (NMDA) receptors.3 Dexmedetomidine is a highly selective α2-adrenoceptor agonist and can inhibit sympathetic activity by activating the receptors in the central nervous system. It results in sedation and anxiolysis in a dose-dependent manner and reduction in blood pressure and heart rate with no respiratory depression.4

Although oral premedication is the most widely accepted route for premedication in children, it results in low bioavailability.5 Only about 17% of ketamine is absorbed from the oral route because of extensive first-pass metabolism as opposed to 93% from the parenteral route.6 The bioavailability of ketamine is 45–55%7 from the intranasal route compared with 30% from the sublingual route.8 Intranasal administration of dexmedetomidine is more effective than buccal administration for premedication in children9 with peak plasma concentrations at 46 min and a bioavailability of > 80%.10 When given orally, its acceptability by children is only 70% because of poor palatability.11 Moreover, compliance with nasal sedation is easier to achieve than compliance with oral sedation in young children.9 In recent years, the intranasal route of drug administration has been popular for pediatric premedication as it is safe, atraumatic, faster onset, and well tolerated. In addition, it bypasses the portal circulation with high bioavailability and does not require prior venepuncture.12,13,14 This increases patient cooperation, which is difficult to achieve in pediatric patients.15

Various randomized trials and observational studies have been conducted on the use of ketamine and dexmedetomidine in different doses through the intranasal route for premedication in pediatric patients with different control and comparator groups.16,17,18,19,20,21,22,23 Randomized controlled trials (RCTs) that compared intranasal ketamine and intranasal dexmedetomidine have shown conflicting results regarding the superiority of one over the other.24,25,26,27 The efficacy and safety of intranasal ketamine have not been compared with those of intranasal dexmedetomidine in a systematic review and meta-analysis. Therefore, we sought to conduct this systematic review and meta-analysis to compare the efficacy and safety of ketamine and dexmedetomidine as a premedication through the nasal route in pediatric patients.

Methods

The present systematic review and meta-analysis study strictly adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist.28 The study protocol was registered at PROSPERO (CRD42021262516; date of registration, 22 July 2021).

Study identification

Two investigators independently and systematically searched the databases (PubMed, PubMed Central, Scopus, LILACS, Google Scholar, the ClinicalTrials.gov registry, and the Cochrane Database of Systematic Reviews) and bibliographies of relevant review articles, systematic reviews, and meta-analysis. The search terms were as follows: (ketamine OR [NMDA] antagonist OR s-ketamine) AND (dexmedetomidine OR alpha 2 agonist) AND (premedication OR before anesthesia OR anxiolytic OR sedation) AND (pediatric patients OR children) AND (intranasal OR nebulised OR nasal drug administration OR intra nasal drug administration OR mucosal atomizer devices).

The last search was conducted on 23 September 2021. No language and time restrictions were applied to include the studies. Initially, two investigators independently assessed titles and abstracts as per the selection criteria. Subsequently, the full texts of relevant studies were assessed to decide the eligibility of retrieved articles. Any disagreements were resolved by discussion and consensus among the authors.

Selection criteria

INCLUSION CRITERIA

  • All RCTs comparing ketamine and dexmedetomidine administered through the nasal route (intranasal drug instillation/nebulization) for premedication before general anesthesia (with or without muscle relaxants and iv or inhalational anesthetic agents) for an elective procedure in pediatric patients.

EXCLUSION CRITERIA

  • Studies administering ketamine and dexmedetomidine through non-nasal routes (oral, iv, im, rectal, etc.)

  • Patients who received intranasal ketamine for purposes other than premedication (chronic pain, acute pain, postoperative pain, psychiatric conditions, etc.)

  • Studies conducted on adult patients

  • Studies conducted in an emergency setup

  • Observational studies, noninterventional studies, single-arm or non-comparative studies, case series, case reports, review articles, and animal studies

  • Duplicate publications

Types of interventions

Articles describing the use of ketamine and dexmedetomidine via the nasal route as a premedication regardless of dose, volume, and time of administration before general anesthesia were considered.

Risk of bias assessment of included studies

Two investigators used the RoB 2 risk of bias tool to assess the methodological quality of the included randomized controlled studies.29 Each study was assessed for the randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selective outcome reporting. The studies were categorized into “low risk,” “high risk,” or having “some concerns” in the risk of bias assessment.29 The disagreements in the assessment were resolved through discussion and consensus among the authors.

Data extraction

Two investigators independently extracted the following data into an Excel 2016 (Microsoft Corporation, Redmond, WA, USA) sheet: first author, publication year, study duration, study design, demographics (age, sex), type of surgery/procedure, time of premedication, interventions (ketamine and dexmedetomidine), mode of use (type, dose, volume, intranasal instillation, or nebulization), number of participants in each intervention arm, type of general anesthesia, efficacy, and safety outcomes. The extracted data were cross-checked by a third author to ensure accuracy.

Efficacy outcomes

Primary efficacy outcomes were patients experiencing sedation at separation from parents, patients experiencing sedation at anesthesia mask induction, and patients accepting satisfactory intravenous cannulation. The secondary efficacy outcomes were onset of sedation and recovery time.

Safety outcome

The safety outcomes were emergence agitation, nausea and vomiting, excessive salivation, hemodynamic changes (systolic blood pressure and heart rate), and respiratory rate.

Data synthesis

The effect sizes were summarized as a risk ratio (RR) with 95% confidence interval (CI) in case of dichotomous data and as a standardized mean difference (SMD) with 95% CI in case of continuous data. The pooled meta-analytic summaries were estimated through the Mantle–Haenszel method using a random-effects model with the DerSimonian–Laird approach. The heterogeneity was assessed using the I2 test. We generated a forest plot to display the results of individual studies and meta-analytic summaries of each outcome.

Based on the findings of the preliminary study search, the inclusion of studies comparing different doses of ketamine and dexmedetomidine was anticipated. The analysis of efficacy and safety outcomes subgroup was planned based on the dose ratio of ketamine and dexmedetomidine. The studies that used ketamine and dexmedetomidine in the dose ratio of 100:1 (e.g., ketamine 2 mg·kg-1/dexmedetomidine 2 μg·kg-1 or ketamine 3 mg·kg-1/dexmedetomidine 3 μg·kg-1) were considered low-dose ketamine studies, while studies using these drugs in the ratio of > 100:1 to less than 500:1 (e.g., 5 mg·kg-1/2 μg·kg-1, 5 mg·kg-1/2.5 μg·kg-1) were considered intermediate-dose ketamine studies, and studies with the dose ratio of ≥ 500:1 (e.g., 5 mg·kg-1/1 μg·kg-1) were considered high-dose ketamine studies.

The sensitivity analyses of each outcome were performed based on the risk of bias assessment using the RoB 2 tool. The studies showing “some concern” or “high risk” of bias were excluded to estimate the pooled meta-analytic summary of each outcome.29 Due to a small number of included studies, the meta-analytic summary of each outcome of the DerSimonian–Laird method was converted into the Hartung–Knapp–Sidik–Jonkman method through a validated Excel sheet published by IntHout et al.30

Ketamine and dexmedetomidine were considered “comparable or equivalent” when the RR and 95% CI of the meta-analytic summary were within range of a clinically significant difference of 20% (95% CI, 0.80 to 1.20) as per DerSimonian–Laird and Hartung–Knapp–Sidik–Jonkman methods in case of dichotomous outcomes. A more than 20% difference in RR and 95% CI was considered as a superiority of interventions over each other. A similar approach was considered in case of continuous outcomes. The SMD and 95% CI of meta-analytic summary should be within the range of a clinically significant difference of 20 units (95% CI, -0.20 to 0.20) to show comparability of ketamine and dexmedetomidine. Publication bias was assessed through a visual inspection of a funnel plot for asymmetry. It was plotted using [log (OR)] of the effect size and standard error of each outcome.

We used the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach to rate the certainty of the evidence for each efficacy and safety outcome. We rated outcomes based on the risk of bias, imprecision, inconsistency, indirectness, and other factors (publication bias, magnitude of effect size, plausible confounding, and dose response gradient). Each outcome was categorized into “high,” “moderate,” “low,” or “very low” quality of evidence. The summary of findings table was created using GRADEpro software.31,32 The meta-analysis was conducted using Review Manager (RevMan software), version 5.4.1. (The Cochrane Collaboration, 2020).

Results

Study characteristics

From the literature search, we retrieved 2,445 references and assessed 29 full-text articles. A total of ten RCTs fulfilling the selection criteria were included in the analysis (Fig. 1).24,25,26,27,33,34,35,36,37,38 All included studies used a double-blind randomized controlled design. The general characteristics of all included studies are presented in Table 1. All the studies included a pediatric population ranging from one year to ten years of age and an American Society of Anesthesiologists Physical Status Classification (ASA PS) of I and II, except two studies that did not specify the ASA PS grading.33,34 Among the included studies, seven studies used intranasal instillation of ketamine and dexmedetomidine.24,27,33,34,35,36,37 The remaining three studies administered premedications via nebulization.25,26,38 The dose ratio of ketamine:dexmedetomidine was 100:1 in all three studies using nebulization (2 mg·kg-1/2 μg·kg-1 and 3 mg·kg-1/3 μg·kg-1), while a dosing ratio of 100:1 to 500:1 (5 mg·kg-1/1 μg·kg-1, 5 mg·kg–1 /2 μg·kg-1, 5 mg·kg-1/2.5 μg·kg-1, 7 mg·kg-1/3 μg·kg-1) was used in studies using intranasal instillation. Premedication was given 20 min before induction of anesthesia in one study,27 30 min before in five studies,25,26,36,37,38 and 45 min before in three studies.24,34,35 In one study conducted by Gyanesh et al., dexmedetomidine was given 60 min and ketamine 30 min before the induction of anesthesia.33 Therefore, we included this study only for assessing safety outcomes. Sevoflurane was used for induction of anesthesia in six studies and propofol was used in four studies.

Fig. 1
figure 1

Revised PRISMA flow diagram

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Table 1 General characteristics of the included studies
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Among the included studies, eight studies reported ease of parenteral separation, four studies reported satisfactory mask acceptance, three studies reported ease of iv cannulation, three studies reported sedation onset time, seven studies reported recovery time, five studies reported emergence agitation, nine studies reported incidence of postoperative nausea and vomiting, three studies reported incidence of increased salivation, and four studies reported bradycardia.

Risk of bias in included studies

The risk of bias assessment in individual RCTs is presented in Fig. 2. In overall risk of bias assessment, three studies were considered to have “some concern” as per the RoB 2 tool.29 The other seven RCTs were considered to have a “low” risk of bias.

Fig. 2
figure 2

Risk of bias assessment

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Efficacy outcomes

SATISFACTORY SEDATION AT PARENT SEPARATION

A total of eight studies (n = 856 patients) reported satisfactory sedation at parent separation. This outcome was evaluated by a four-point sedation scale in seven studies and a parent separation anxiety scale in one study. There was no significant difference in satisfactory sedation at parent separation between intranasal ketamine and dexmedetomidine (RR, 0.90; 95% CI, 0.79 to 1.04; I2 = 89%) (Fig. 3). The GRADE approach suggested a low quality of evidence (Table 2). A subgroup analysis revealed no difference between intranasal ketamine and dexmedetomidine at any of the dose ratios. The funnel plot was asymmetrical on visual inspection (Electronic Supplementary Material [ESM], eFig. 1a). A sensitivity analysis based on risk of bias assessment did not affect the findings (ESM eTable 1). Sensitivity analysis based on the Hartung–Knapp–Sidik–Jonkman method showed a similar trend (RR, 0.90; 95% CI, 0.76 to 1.07) (ESM eTable 2).

Fig. 3
figure 3

Sedation at parent separation

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Table 2 GRADE quality of evidence for the primary efficacy outcomes
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SATISFACTORY MASK ACCEPTANCE

A total of four studies with 240 patients reported satisfactory mask acceptance. This outcome was evaluated on a four-point scale (from “poor acceptance” to “excellent acceptance”) in all included studies. As shown in Fig. 4, there was no significant difference in satisfactory mask acceptance between intranasal ketamine and dexmedetomidine (RR, 0.86; 95% CI, 0.66 to 1.13; I2 = 50%; GRADE approach evidence, low). A subgroup analysis revealed no difference between intranasal ketamine and dexmedetomidine for any dose regimen (low, intermediate, and high ketamine). The funnel plot was asymmetrical on visual inspection (ESM eFig. 1b). Sensitivity analysis based on the risk of bias assessment did not affect the findings. Sensitivity analysis based on the Hartung–Knapp–Sidik–Jonkman method showed a similar trend (RR, 0.86; 95% CI, 0.55 to 1.35) (ESM eTable 2).

Fig. 4
figure 4

Mask acceptance

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EASE OF INTRAVENOUS CANNULATION

Three studies including 157 patients, with a low-dose and intermediate-dose ketamine reported ease of iv cannulation. All studies used a four-point scale from poor to excellent for the assessment of ease of iv cannulation. As shown in Fig. 5, there was no significant difference in ease of iv cannulation between intranasal ketamine and dexmedetomidine (RR, 1.16; 95% CI, 0.79 to 1.69; I2 = 69%; GRADE approach evidence, very low). Subgroup analysis revealed no difference between intranasal ketamine and dexmedetomidine. As shown in ESM eTable 1, sensitivity analysis based on a risk of bias assessment showed a significantly better outcome in the ketamine group than in the dexmedetomidine group (RR, 1.40; 95% CI, 1.01 to 1.94; I2 = 0%). An I2 of 0% suggested a low degree of between-trial heterogeneity. Sensitivity analysis based on the Hartung–Knapp–Sidik–Jonkman method showed a similar trend (RR, 1.16; 95% CI, 0.64 to 2.11) (ESM eTable 2). The funnel plot was asymmetrical on visual inspection (ESM eFig. 1c).

Fig. 5
figure 5

Intravenous cannulation

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SECONDARY EFFICACY OUTCOMES

Among all the included studies, three studies with 282 patients reported sedation onset time (intermediate-dose ketamine). As shown in ESM eFig. 2, no significant difference was observed between the two groups (SMD, 1.30; 95% CI, -3.54 to 0.95; I2 = 98%). The GRADE approach suggested a very low quality of evidence (ESM eTable 3). A sensitivity analysis also did not affect the findings.

Recovery time was reported in six studies involving 472 patients. No significant difference in time to recovery from anesthesia was observed between the two groups (SMD, -0.26; 95% CI, -0.87 to 0.34; I2 = 90%; GRADE evidence, low) (ESM eFig. 3 and eTable 3). Subgroup analysis also did not find any significant differences between the groups. Sensitivity analysis also did not affect the findings.

Safety outcomes

EMERGENCE AGITATION

The incidence of emergence agitation was extracted from five trials with 414 patients. Emergence agitation was evaluated by a three-point scale, a four-point sedation scale, the Pediatric Anesthesia Emergence Delirium scale, and Aono’s four-point scale. Overall, there was no significant difference between the two groups (RR, 2.26; 95% CI, 0.90 to 5.6; I2 = 18%; GRADE evidence, moderate) (ESM eFig. 4 and eTable 3). Sensitivity analysis did not affect the overall findings.

INCIDENCE OF NAUSEA AND VOMITING

The incidence of nausea and vomiting was evaluated in eight studies with 612 patients. A significantly higher incidence was observed with intranasal ketamine than with dexmedetomidine (RR, 2.47; 95% CI, 1.24 to 4.91; I2 = 0%). Subgroup analysis also showed a significantly higher incidence of nausea and vomiting in intermediate-dose ketamine groups (RR, 2.98; 95% CI, 1.16 to 7.6; I2 = 0%; GRADE evidence, moderate). Nevertheless, no difference was observed between the two drugs in low-dose and high-dose ketamine regimens in subgroup analysis (ESM eFig. 5 and eTable 3). Sensitivity analysis based on the Hartung–Knapp–Sidik–Jonkman method showed a similar trend (RR, 2.47; 95% CI, 1.50 to 4.06) (ESM eTable 2). Sensitivity analysis based on the risk of bias assessment showed no significant difference in the incidence of nausea and vomiting in the two groups (ESM eTable 1).

INCREASED SALIVATION

Three studies reported the incidence of increased salivation in 209 patients. We found no significant difference in increased salivation between the two drugs (RR, 3.54; 95% CI, 0.38 to 32.6; I2 = 40%; GRADE evidence, very low). Subgroup analysis did not show any difference between the two drugs with respect to dose regimens (ESM eFig. 6). Sensitivity analysis did not affect the findings.

IMPACT ON HEMODYNAMIC PARAMETERS (HEART RATE AND BLOOD PRESSURE)

The incidence of bradycardia was reported in four trials including 261 patients. No studies reported bradycardia with the use of ketamine. A significantly lower incidence of bradycardia was observed in ketamine-treated patients than in dexmedetomidine-treated patients (RR, 0.1; 95% CI, 0.04 to 0.70; I2 = 40%; GRADE evidence, moderate) (ESM eFig. 7 and eTable 3). A sensitivity analysis suggested a similar trend in the incidence of bradycardia (eTable 1 and eTable 2).

Heart rate at 30 min after premedication was reported in four studies for 259 patients. Intranasal ketamine premedication significantly increased heart rate compared with intranasal dexmedetomidine (SMD, 1.42; 95% CI, 0.25 to 2.59; I2 = 94%; GRADE evidence, very low) (ESM eFig. 8 and eTable 3). The subgroup analysis found no significant difference among the two groups at lower doses of ketamine (SMD, 0.12; 95% CI, -0.39 to 0.62). Sensitivity analysis did not find any significant difference between the two groups (ESM eTable 1 and eTable 2).

Two studies provided data on systolic blood pressure. One study used a low dose of ketamine and one study used a high dose of ketamine. A significantly higher systolic blood pressure was observed in ketamine-treated patients compared with dexmedetomidine-treated patients (SMD, 1.10; 95% CI, 0.17 to 2.03; I2 = 83%; GRADE evidence, low) (ESM eFig. 9 and eTable 3). Sensitivity analysis did not find any significant difference between the two groups (ESM eTable 2).

RESPIRATORY RATE

Respiratory rate was reported in two studies for 136 patients and no significant difference was found between groups (MD, 0.17; 95% CI, -0.42 to 0.77; I2 = 67%; GRADE evidence, very low) (ESM eFig. 10 and eTable 3). A similar result was observed in the sensitivity analysis.

Discussion

This systematic review and meta-analysis pooled results from ten RCTs that compared the efficacy and safety of intranasal ketamine and dexmedetomidine as premedication in pediatric patients before general anesthesia. The primary outcome of the study was the efficacy of the two drugs as premedication with regard to satisfactory sedation at parent separation, mask acceptance, and iv cannulation. There is insufficient evidence to infer that there is superiority, inferiority, or equivalence between ketamine and dexmedetomidine as premedication. The quality of evidence for the efficacy outcomes ranged from “low” to “very low.” Clinical decision-making is likely to be influenced by differences in safety profiles. Both drugs had a comparable incidence of emergence agitation and increased salivation. Intranasal ketamine-treated patients experienced a higher incidence of nausea and vomiting, whereas intranasal dexmedetomidine-treated patients had a higher incidence of bradycardia. It was difficult to interpret the findings of other safety outcomes because of wide CIs. The quality of evidence for the safety outcomes ranged from “moderate” to “low.”

Our meta-analysis found that neither intranasal premedication with ketamine nor dexmedetomidine was superior to the other in the overall analysis. This is in contrast with the meta-analysis by Jun et al., which included 13 studies comparing intranasal dexmedetomidine with other premedication drugs (midazolam, ketamine, clonidine).39 Their findings suggested that intranasal dexmedetomidine is superior other premedication drugs with regard to satisfactory sedation at parent separation and need for rescue analgesics. Nevertheless, ketamine was the comparator in only one included RCT for satisfactory sedation at parent separation. No study comparing ketamine was included for rescue analgesia.39 In a recent meta-analysis, Qiu et al. compared the sedation efficacy of ketamine and dexmedetomidine (intranasal or oral) in pediatric patients undergoing dental surgery and observed comparable sedation levels, intraoperative analgesia, and postoperative analgesia.40 They included only four randomized studies with small sample sizes and did not compare safety outcomes. Moreover, there was no restriction on the route of study medications (intranasal or oral) and type of anesthesia (local or general anesthesia). In an earlier meta-analysis, Peng et al. compared dexmedetomidine with other premedication in pediatric patients but could not pool any data with ketamine because of nonsimilar outcomes in the included studies.41 In an earlier systematic review, Poonai et al. compared intranasal ketamine (with or without a coadministered agent) to any comparator premedication to determine the adequacy of sedation in pediatric patients undergoing anesthetic premedication procedures.42 The authors did not statistically pool the results. They concluded that intranasal ketamine provides adequate sedation for nonpainful procedures. This systematic review included 23 trials using intranasal ketamine as premedication, four of which compared dexmedetomidine with ketamine. Most children were adequately sedated in all trials and observed inconsistent results for the superiority of intranasal ketamine over other comparators.42 This could be because of different dose regimens of comparators and interventions. Similarly, we also found different doses of ketamine and dexmedetomidine in our included studies. Ketamine was used from 1 mg·kg-1 to 7 mg·kg-1 while dexmedetomidine was used from 1 μg·kg-1 to 3 μg·kg-1. We explored the outcomes based on the dose ratio through subgroup analysis but could not show dose-dependent differences in outcomes. This could be because the number of studies in each subgroup was small or because the methods of drug administration were different. The studies with low-dose ratios used nebulization techniques, while studies with intermediate-dose and high-dose ratios used intranasal instillation methods to administer study drugs. The onset of sedation was reported in three studies using an intermediate-dose ketamine regimen and onset of sedation ranged from 8.7 to 22.19 min. This is consistent with intranasal ketamine's time to peak plasma concentration of 18 min43 to 21 min.44 The onset of sedation of dexmedetomidine in a dose of 1 μg·kg-1 was reported to be 25 to 45 min and we observed a similar range (16.35–23.80 min) in our study.15

None of the included trials reported any serious adverse drug events due to ketamine and dexmedetomidine. Emergence agitation can be a challenging situation in the postoperative period in children recovering from general anesthesia.45 Its occurrence depends on various factors such as pain, preoperative anxiety, type of surgical procedure performed, type of anesthetic used, and duration of anesthesia.46 No significant difference was observed in the incidence of emergence agitation between ketamine and dexmedetomidine in our study. Sevoflurane was used in three out of five studies reporting emergence agitation and propofol in two studies. Wang et al. performed a network meta-analysis and showed that dexmedetomidine and ketamine significantly reduced pediatric anesthesia emergence delirium in sevoflurane anesthesia compared with placebo.47 Another network meta-analysis by Fang et al. also found a significantly lower incidence of emergence agitation in children with ketamine and dexmedetomidine than with placebo; however, they observed weak evidence that dexmedetomidine is more effective than ketamine in preventing sevoflurane-related emergence agitation.48 Nausea and vomiting, a known side effects of ketamine,49,50 were reported in eight trials and a significantly higher incidence was noted in the intranasal ketamine group. We also noted that higher doses of ketamine (5–7 mg·kg-1) were associated with a higher incidence of nausea and vomiting. Nausea caused by intranasal ketamine is most likely due to NMDA receptor blockade in the vestibular system.51

In this meta-analysis, hemodynamic parameters were found to be better maintained in patients who received intranasal ketamine than dexmedetomidine. This is in line with the previous meta-analysis by Qiu et al.40 Bradycardia is an important hemodynamic event associated with dexmedetomidine.52,53 Four included studies in this meta-analysis reported bradycardia in 11 patients out of 130 patients treated with dexmedetomidine. Although blood pressure is reduced by iv dexmedetomidine, a biphasic response is observed with rapid iv bolus administration because of a direct α2-adrenergic receptor-induced vasoconstrictive response in the peripheral vasculature followed by a lower arterial pressure from a decreased sympathetic outflow.54,55 Nevertheless, these adverse events are seldom observed following non-intravenous administration.

The present systematic review and meta-analysis has several limitations. Although ten RCTs were included, all studies were conducted in Asian countries. Our findings do not confirm that there is no difference in efficacy between intranasal ketamine and intranasal dexmedetomidine. The results should be interpreted cautiously as most outcomes have wide confidence intervals and an insufficient sample size. The sample sizes of all the included trials were relatively small and the methodological quality was variable. Furthermore, various sedation scales and measurements affected the data synthesis. A large range of dosing regimens also limits outcome data interpretation. The subgroup analysis based on dosing regimen could not influence the interpretation of the results because of the small sample size. Therefore, more randomized trials are needed to evaluate the efficacy and safety of intranasal ketamine premedication. The preparation, volume, and administration of the intranasal drug were also variable among the included studies; therefore, the data should be interpreted with caution because of heterogeneity across the included trials. For example, heterogeneity was observed for sample composition (e.g., socio-demographics), surgical procedures, dose regimens, method of drug administration, duration of surgical procedure and anesthesia, type of anesthetic used, variations of outcome measurement scales, and nonvalidated rating instruments. Considering this heterogeneity, we used a random-effects model for our meta-analysis. Publication bias was observed in all outcomes, which may have affected the precision of the outcomes because positive results are more likely to be published than negative results. Lastly, we did not analyze the level of sedation between the two groups because of variation in the sedation scales and different expression methods (mean with standard deviation, median with interquartile range, and % of patients with adequate sedation) although it was an important measure of premedication efficacy.

Conclusion

Due to the low to very low quality of evidence, the present systematic review and meta-analysis neither confirm nor refute comparable premedication efficacy of intranasal ketamine and dexmedetomidine in terms of parental separation, mask acceptance, and iv cannulation in pediatric patients. Regarding the safety profile, the incidence of bradycardia with dexmedetomidine is a concern in pediatric patients. Large-scale randomized studies of intranasal ketamine and dexmedetomidine are needed to provide better quality evidence and recommendations.