Skip to main content
Download PDF

Comparison of the effects of ketamine via nebulization versus different pharmacological approaches in pediatric sedation: a systematic review and meta-analysis of randomized controlled trials

BMC Anesthesiology volume 23, Article number: 375 (2023) Cite this article

Abstract

Background

Nebulized drug delivery is commonly used in pediatric clinical practice. The growing number of literatures have reported the application of nebulized ketamine in pediatric sedation in recent years. This meta-analysis of randomized controlled trials comparing the efficacy and safety of nebulized ketamine versus different pharmacological approaches was conducted to estimate the effects of this technique in pediatric sedation.

Methods

We searched PubMed, Embase, and Cochrane Library from inception to Feb 2023. All randomized controlled trials used nebulized ketamine as presurgical and pre-procedural sedatives in children were included. Sedative effects and various adverse events were considered as the outcomes.

Results

Ten studies with 727 pediatric patients were enrolled. Compared to nebulized dexmedetomidine, using of ketamine via nebulization showed similar sedation satisfaction (54.79% vs. 60.69%, RR = 0.88, with 95%CI [0.61, 1.27]), success rate of parental separation (57.27% vs. 73.64%, RR = 0.81, with 95%CI [0.61, 1.08]), and mask acceptability (37.27% vs. 52.73%, RR = 0.71, with 95%CI [0.45, 1.10]). However, the using of combination of two medications (nebulized ketamine plus nebulized dexmedetomidine) was associated with better sedative satisfaction (33.82% vs. 68.11%, RR = 0.50, with 95%CI [0.27, 0.92]) and more satisfactory mask acceptance (45.59% vs. 71.01%, RR = 0.69, with 95%CI [0.56, 0.86]). Compared with nebulized ketamine, using of nebulized dexmedetomidine was associated with less incidence of emergence agitation (18.18% vs. 3.33%, RR = 4.98, with 95%CI [1.88, 13.16]).

Conclusions

Based on current evidences, compared to nebulized dexmedetomidine, nebulized ketamine provides inconspicuous advantages in pediatric sedation, and it has a relatively high incidence of emergence agitation. Combination of nebulized ketamine and dexmedetomidine might be considered as one preferred option in pediatric sedation as it can provide more satisfactory sedative effects. However, there is insufficient evidence regarding nebulized ketamine versus ketamine administered through other routes and nebulized ketamine versus other sedatives. The overall low or moderate quality of evidence evaluated by the GRADE system also calls for more high-quality studies with larger sample sizes in future.

Research registration

The protocol of present study was registered with PROSPERO (CRD42023403226).

Peer Review reports

Introduction

Relieving preoperative anxiety in pediatric patients remains an ongoing challenge for pediatric clinicians [1], and procedural sedation/analgesia (PSA) regimens always involve intravenous administration of sedatives. However, peripheral intravenous (IV) insertion is frequently cited as a primary cause of pain in children and is consistently linked to anxiety and distress [2]. In light of the increasing demand for PSA in children before various procedures or surgeries, exploring a pain-free alternative to IV insertion in pediatric sedation should be served as an important goal for clinicians.

Nebulization therapy is a popular approach to treating pediatric patients [3]. It carries a lower risk of adverse events compared to other routes of administration (such as intramuscular injection, intravenous injection, etc.) [4, 5]. In addition, ease of administration, superior patient compliance, and the relatively small drug volume required for effect make it a highly recommended option [6]. A series of aerosolized medications, including corticosteroids, ketamine, magnesium, lidocaine, and non-steroidal anti-inflammatory drugs (NSAIDs), have proven effective in various treatments [7,8,9].

As a traditional non-competitive N-Methyl-D-Aspartate antagonist (NMDA), ketamine has been commonly applied as presurgical and pre-procedural sedatives in children [10, 11]. It provides analgesic properties owing to its ability to antagonize NMDA receptors, reduces the levels of proinflammatory mediators during acute phase, and affects other non-NMDA pathways which are instrumental in pain and mood regulation [12].

In recent years, there have been a series of reports on use of ketamine nebulization as a preoperative sedation for pediatric patients [13, 14]. Given that, we conduct a meta-analysis from the published randomized controlled trials comparing the efficacy and safety of nebulized ketamine versus different pharmacological approaches to evaluate the effects of this technique in pediatric sedation and to provide a comprehensive understanding about its benefits and drawbacks.

Methods

Protocol and registration

The present meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [15] and Cochrane Handbook guidelines. And we registered the protocol for this review on the International Prospective Register for Systematic Reviews (PROSPERO) (https://www.crd.york.ac.uk/prospero, CRD42023403226).

Search strategy

Two authors (BL and SC) conducted a systematic search from electronic databases including PubMed, Embase, and Cochrane Library, covering the period from inception up to Feb 27, 2023. In addition, academic search engine Google Scholar was utilized as the additional information source. “Infant”, “child”, “adolescent”, “aerosoli*”, “nebuli*”, “ketamine” and “randomized controlled trial” were considered as the search terms (Appendix S1). The human studies without language limitation were considered in our present study.

Eligibility criteria

Participants

The participants of present study were children (< 18 years old) who underwent various presurgical and pre-procedural sedation.

Intervention

Using ketamine via nebulization (e.g., administered with a nasal mucosal atomizer device, nebulizer, or spray) as premedication were considered as intervention.

Comparisons

Using ketamine via other route or using different pharmacological approaches as premedication were considered as comparisons.

Outcome measures

Consensus exists regarding the optimal characteristics of pediatric sedation, including successful separation from parents, achievement of anesthesia induction or facemask compliance, rapid onset and recovery, and minimal adverse effects. Therefore, we identified (1) number of patients who achieved a satisfactory level of sedation sufficient for procedures (venipuncture, diagnostics, surgical procedures, etc.)., (2) the number of children with satisfactory separation from parents and (3) the number of children with satisfactory mask acceptance as the co-primary outcomes. Onset of sedation, recovery time, and the incidence of adverse events (e.g., vomiting, nystagmus, abnormal movement, hypersalivation, hypotension, bradycardia, sneezing, coughing and emergence agitation) were considered as the secondary outcomes.

Study design

Only randomized controlled trials (RCTs) were considered in our present study.

Exclusion criteria

Reviews, conference abstracts, letters, cases, comments, preclinical studies, protocol, ongoing trials, studies performed in adults and studies with inappropriate comparisons or unrelated outcomes were excluded by us.

Data extraction, and assessment of the risk of bias

Two authors (BL and SC) conducted literature screening and data extraction independently, followed by crosschecking with each other. Duplicated items from different databases were removed, and irrelevant records were excluded after scrutinizing their titles and abstracts. Then we perused the original texts of remaining records when information could not be ascertained. We collected the general characteristics of all studies that met the criteria (Table 1). The Cochrane risk of bias tool [16] was used to evaluate the risk of bias in RCTs based on the following aspects: random sequence generation (generation of the randomization sequence), allocation concealment, blinding of outcome assessment, incomplete outcome data, and selective reporting. Clinical research was categorized as having low, high, or unclear risk of bias based on these domains mentioned above. In the case of any disagreement, a third investigator was consulted to resolve the issue.

Grading the quality of evidence

The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology [17] was employed to appraise the quality of evidence and potency of recommendations, taking into account the risk of bias, inconsistency, indirectness, imprecision, and publication bias. The quality of evidence was classified as high, moderate, low, or very low, and the analysis was conducted by using the GRADE profiler software (version 3.6, provided by the Cochrane collaboration) [18].

Statistical analysis

The statistical analysis was conducted by using Review Manager software (Version 5.3.3, the Cochrane Collaboration 2014, the Nordic Cochrane Centre). Continuous variables were estimated by using the mean difference (MD) with a 95% confidence interval (CI). The risk ratio (RR) with a 95% confidence interval (CI) and the Mantel-Haenszel method were used to analyze dichotomous data. Heterogeneity was assessed by I-squared (I2) test [19]. In cases where significant heterogeneity was detected (present at I2 > 50%), the random effects model was applied, and a sensitivity analysis was conducted by omitting each study separately; otherwise, the fixed-effects model would be considered. Begg’s test and Egger’s test were used to evaluate publication bias if the number of included studies over ten [20]. The tests were conducted using version 1.2.4 of the metabias program and Stata/MP 12.0 for Windows (StataCorp LP, 4905 Lakeway Drive, College Station, TX 77,845, USA). A less-than 0.05 P value was considered statistically significant.

Results

Literature search results

A total of 290 studies were identified initially after screening various databases and searching additional sources. Subsequently, 199 duplicate records were removed, and 125 records were excluded by a thorough review of titles and abstracts. In these 125 excluded items, 10 were focused on adult patients, 1 was conducted on animals, 12 were conference abstracts, comments notes or letters, 50 were protocols or ongoing trials, 6 were reviews, and 46 were studies with irrelevant topics. Consequently, 64 items were further excluded following full-text review, and 3 of them were not relevant to the outcomes of the study, 4 of them did not focus on ketamine, 56 of them focused on ketamine administered not via nebulization, and 1 of them was not a randomized controlled trial. Eventually, 10 studies were selected for subsequent analysis [14, 21,22,23,24,25,26,27,28,29]. The PRISMA flowchart (Fig. 1) provides details on the identification of the literature.

Fig. 1
figure 1

PRISMA flow diagram showing literature search results

Full size image

Basic characteristics of enrolled studies

The involved studies were published from 2015 to 2022, with a total of 727 eligible pediatric patients ranging in age from 1 to 12 years. Among the included studies, six examined the effects of nebulized ketamine versus nebulized dexmedetomidine, while three focused on the effects of nebulized ketamine versus nebulized midazolam. Furthermore, three studies examined the effects of nebulized ketamine versus combination of nebulized ketamine and dexmedetomidine. In addition, one study reported findings on effects of nebulized ketamine versus oral ketamine, and one study examined the effects of nebulized ketamine versus intravenous ketamine. An overview of the main characteristics of the enrolled studies was presented in Table 1 including the following information: first author, publication year, range of age, American Society of Anesthesiologists status, type of surgery/procedure, drug dosage, sample size, scale used for sedation measurement and outcomes.

Table 1 The general characteristics of the enrolled studies
Full size table

Risk of bias assessment

Cochrane Collaboration’s risk of bias tool was employed to appraise the validity and quality of the RCTs by us. In all 10 enrolled studies, 8 studies (80.00%) delineated an appropriate method of random sequence generation, 7 studies (70.00%) reported adequate allocation concealment, 8 studies (80.00%) showed a low risk in blinding of participants and personnel domain, and all studies described the blinding procedure of outcome assessment. The detailed information about risk of bias assessment is presented in Fig. 2.

Fig. 2
figure 2

Risk of bias summary of included the trails: evaluation of bias risk items for each included study. Green circle, low risk of bias; red circle, high risk of bias; yellow circle, unclear risk of bias

Full size image

Primary outcomes

Number of patients with satisfactory sedation levels

Five studies compared nebulized ketamine to nebulized dexmedetomidine described the number of patients with satisfactory sedation levels [14, 23, 26,27,28]. Owing to existence of statistical heterogeneity, the random-effects model was chosen in present analysis. And the results indicated that no significant differences were observed between nebulized ketamine group and nebulized dexmedetomidine group (54.79% vs. 60.69%, RR = 0.88, with 95%CI [0.61, 1.27], P = 0.49, I2 = 71%; Fig. 3; Table 2). The sensitivity analysis indicated that the heterogeneity (I2 = 71%) derived from the Geetha K et al. study [27]. And heterogeneity was resolved (I2 = 0%) by omitting this study, the more reliable results indicated that the summary estimate was changed (46.36% vs. 63.64%, RR = 0.77, 95% CI [0.63, 0.94], P = 0.009).

Fig. 3
figure 3

Forest plot: Number of children with satisfactory sedation. No significant differences were observed between nebulized ketamine group and nebulized dexmedetomidine group (RR = 0.88, with 95%CI [0.61, 1.27], P = 0.49); Nebulization of dexmedetomidine plus ketamine can provide better sedative effect than nebulized ketamine alone (RR = 0.50, with 95%CI [0.27, 0.92], P = 0.03)

Full size image
Table 2 Outcomes
Full size table

Three studies compared nebulized ketamine to nebulized ketamine plus dexmedetomidine reported the number of patients with satisfactory sedation levels [14, 26, 29]. Existence of statistical heterogeneity prompted us to applied random-effects model. The results indicated that nebulization of dexmedetomidine plus ketamine can provide better sedative effect than nebulized ketamine alone (33.82% vs. 68.11%, RR = 0.50, with 95%CI [0.27, 0.92], P = 0.03, I2 = 58%; Fig. 3; Table 2). The sensitivity analysis showed that the heterogeneity (I2 = 58%) was attributed to the Dharamkhele SA et al. [29] study. Following excluding this study, the heterogeneity was resolved (I2 = 0%), and the summary estimate was unchanged essentially (46.67% vs. 75.56%, RR = 0.63, 95% CI [0.44, 0.89], P = 0.009).

According to the GRADE summary of findings table, the quality of evidence pertaining to these outcomes was low. It was attributed to both inconsistency (I2 > 50%) and imprecision (lack of events number) (Table S1).

The results of Abdel-Ghaffar HS et al. [23] study indicated that no significant differences were observed between group midazolam and group ketamine (22/30 (73.33%) vs. 25/30 (83.33%); Table 2). According to Abdel-Ghaffar HS et al. [21] study, children in nebulized ketamine group showed more satisfactory sedation levels compared with children in the intravenous ketamine group (5/25 (20.00%) vs. 0/25 (0.00%); Table 2) and the control group (5/25 (20.00%) vs. 0/25 (0.00%); Table 2). However, the results of Kamel AAF et al. [22] study described that number of patients with satisfactory sedation levels was highly statistically significant difference in oral ketamine group than in nebulized ketamine group (9/31 (29.03%) vs. 31/31 (100.00%); Table 2).

Number of children with satisfactory separation from parents

Four studies compared nebulized ketamine to nebulized dexmedetomidine reported number of children with satisfactory separation from parents [14, 23, 26, 28]. The value of I2 (I2 = 59%) indicated that the statistical heterogeneity was existed, then we chose the random-effects model for analysis. Compared to nebulized dexmedetomidine, nebulized ketamine provided no obvious advantage in satisfactory separation from parents (57.27% vs. 73.64%, RR = 0.81, with 95%CI [0.61, 1.08], P = 0.15, I2 = 59%; Fig. 4; Table 2). After excluding the source of heterogeneity (Mohammad Hazem I et al. [26]), the heterogeneity was resolved (I2 = 39%) and the summary estimate was unchanged (68.24% vs. 80.00%, RR = 0.87, 95% CI [0.70, 1.08], P = 0.21).

Fig. 4
figure 4

Forest plot: Number of children with satisfactory separation from parents. No significant differences were observed between nebulized ketamine group vs. nebulized dexmedetomidine group (RR = 0.81, with 95%CI [0.61, 1.08], P = 0.15), and nebulized ketamine group vs. nebulized ketamine plus dexmedetomidine group (RR = 0.92, with 95%CI [0.74, 1.14], P = 0.42)

Full size image

Three studies compared nebulized ketamine to nebulized ketamine plus dexmedetomidine described the number of children with satisfactory separation from parents [14, 26, 29]. On account of existed statistical heterogeneity, the random-effects model was applied in present analysis. Analysis from the three studies found that nebulized ketamine plus dexmedetomidine has no statistical difference in number of children with satisfactory separation from parents compared to nebulized ketamine alone (64.71% vs. 73.91%, RR = 0.92, with 95%CI [0.74, 1.14], P = 0.42, I2 = 57%; Fig. 4; Table 2). Sensitivity analysis indicated that the heterogeneity (I2 = 57%) was attributable to the Dharamkhele SA et al. [29] study. Heterogeneity was resolved (I2 = 0%) by removing the study, and the summary estimate was unchanged (48.89% vs. 62.22%, RR = 0.84, with 95%CI [0.69, 1.03], P = 0.09, I2 = 0%).

The GRADE summary of findings table indicated that quality of evidence for present outcomes low. Inconsistency (I2 > 50%) and imprecision (limited number of events) were main factors (Table S1).

Abdel-Ghaffar HS et al. [23] found that no significant differences were observed between midazolam group and ketamine group(21/30 (70.00%) vs. 28/30 (93.33%); Table 2) in number of children with satisfactory separation from parents. Kamel AAF et al. [22] found that number of patients with satisfactory sedation levels was highly statistically significant difference in oral ketamine group than in nebulized ketamine group (8/31 (25.81) vs. 31/31 (100.00%); Table 2). Abdel-Ghaffar HS et al. [21] study indicated that patients in nebulized ketamine groups showed higher sedation scores compared with patients in the intravenous ketamine group (0.5 mg/kg) and the control group (P = 0.041), and there was no significant difference between nebulized ketamine group 1 (1 mg/kg) and nebulized ketamine group 2 (2 mg/kg) (P = 0.763).

Number of children with satisfactory mask acceptance

Four studies compared nebulized ketamine to nebulized dexmedetomidine described number of children with satisfactory mask acceptance [14, 23, 26, 28]. We applied random-effects model in analysis as the existed statistical heterogeneity (I2 = 50%). Analysis from the four studies found that no significant differences were observed between Nebulized Ketamine Group and Nebulized Dexmedetomidine Group (37.27% vs. 52.73%, RR = 0.71, with 95%CI [0.45, 1.10], P = 0.13, I2 = 50%; Fig. 5; Table 2). Sensitivity analysis showed that the heterogeneity (I2 = 50%) was attributable to the Mohammad Hazem I et al. [26] study. After omitting this study, the heterogeneity was resolved (I2 = 20%) and the summary estimate was unchanged (42.35% vs. 52.94%, RR = 0.84, with 95%CI [0.59, 1.19], P = 0.32, I2 = 20%).

Fig. 5
figure 5

Forest plot: Number of children with satisfactory mask acceptance. No significant differences were observed between nebulized ketamine group and nebulized dexmedetomidine group (RR = 0.71, with 95%CI [0.45, 1.10], P = 0.13); Nebulized ketamine plus dexmedetomidine was associated with more satisfactory mask acceptance in pediatric patients compared to nebulized ketamine alone (RR = 0.69, with 95%CI [0.56, 0.86], P = 0.001)

Full size image

The GRADE summary of findings table showed that quality of evidence for this outcome was low. Inconsistency (I2 > 50%) and imprecision (lack of events number) were considered as main reasons (Table S1).

Three studies compared nebulized ketamine to nebulized ketamine plus dexmedetomidine described the number of children with satisfactory mask acceptance [14, 26, 29]. Given that no statistical heterogeneity (I2 = 0%) was detected, the fixed-effects model was used for analysis. The results indicated that using of ketamine plus dexmedetomidine via nebulization was associated with more satisfactory mask acceptance in pediatric patients compared to nebulized ketamine alone (45.59% vs. 71.01%, RR = 0.69, with 95%CI [0.56, 0.86], P = 0.001, I2 = 0%; Fig. 5; Table 2).

According to GRADE summary of findings table, quality of evidence for present outcome was moderate. The imprecision (lack of events number) was considered as the main reason (Table S1).

In addition, the results of Abdel-Ghaffar HS et al. study [23] indicated that no significant differences were observed between midazolam group and ketamine group (20/30 (66.67%) vs. 17/30 (56.67%); Table 2) in number of children with satisfactory mask acceptance.

Secondary outcomes

Results of secondary outcomes including onset of sedation, recovery time, various adverse effects and hemodynamic status were summarized in Table 2.

Onset of sedation and recovery time

Geetha K et al. [27] found that the time to onset of sedation was significantly less in nebulized dexmedetomidine group compared to nebulized ketamine group (19.73 ± 8.43 min vs. 26.00 ± 7.33 min, P = 0.002). However, analysis of two studies found that no significant differences were observed between nebulized ketamine group and nebulized dexmedetomidine group in recovery time (MD = -2.96, with 95% CI [-8.69, 2.77], P = 0.31, I2 = 98%; Table 2).

Various adverse effects

The results involving various adverse effects indicated that no significant differences were found between nebulized ketamine group and nebulized dexmedetomidine group in incidence of vomiting (7.06% vs. 3.53%, RR = 1.86, with 95%CI [0.53, 6.55], P = 0.34,I2 = 0%; Fig. 6; Table 2), and nebulized ketamine was associated with higher incidence of emergence agitation (18.18% vs. 3.33%, RR = 4.98, with 95%CI [1.88, 13.16], P = 0.001, I2 = 0%; Table 2) compared to nebulized dexmedetomidine. And no significant differences were observed between nebulized ketamine group vs. nebulized midazolam group (13.33% vs. 1.67%, RR = 5.67, with 95%CI [1.03, 31.20], P = 0.05, I2 = 8%; Fig. 6) and nebulized ketamine group vs. nebulized ketamine plus dexmedetomidine group (4.44% vs. 6.67%, RR = 0.71, with 95%CI [0.15, 3.48], P = 0.68, I2 = 31%; Fig. 6) in the incidence of vomiting. In addition, for the occurrence of other adverse effects (e.g., hypotension, bradycardia, abnormal movement, nystagmus), the existing evidence was still lacking, and it was difficult to judge whether nebulized ketamine brings benefits compared with other sedative approaches.

Fig. 6
figure 6

Forest plot: Incidence of Vomiting. No significant differences were observed between nebulized ketamine group vs. nebulized midazolam group (RR = 5.67, with 95%CI [1.03, 31.20], P = 0.05), nebulized ketamine group vs. nebulized dexmedetomidine group (RR = 1.86, with 95%CI [0.53, 6.55], P = 0.34), and nebulized ketamine group vs. nebulized ketamine plus dexmedetomidine group (RR = 0.71, with 95%CI [0.15, 3.48], P = 0.68)

Full size image

Hemodynamic parameters

The results of general hemodynamic parameters indicated that nebulized ketamine provided more steady value of MAP (MD = 3.35, with 95% CI [0.61, 6.09], P = 0.02, I2 = 3%; Table 2) after administration compared to nebulized midazolam. And according to Shereef KM et al. study [25], the hemodynamic parameters (HR and MAP) showed statistically significant decrease throughout the perioperative period in nebulized dexmedetomidine group when compared with nebulized ketamine group.

Discussion

As a recent technique, nebulized medication delivery provides improved usability issues and better bioavailability data [30] compared with common intranasal administration. In addition, Primosch et al. [31] suggested that administration by atomization is associated with significantly less adverse behaviors compared with administration by conventional drops in children undergoing dental procedures. Therefore, in order to estimate the effects of nebulized ketamine in pediatric sedation, the present study comparing the efficacy and safety of nebulized ketamine versus different pharmacological approaches was conducted by us.

Abdel-Ghaffar et al. [21] demonstrated that children who received nebulized ketamine achieved better sedation scores than those who received either placebo or intravenous ketamine. However, Kamel AAF et al. [22] found that oral ketamine as premedication is more effective than nebulized ketamine in producing more satisfactory sedation. The contradictory findings reported from the two aforementioned literatures were confusing. Investigation from Jonkman et al. [32] study on the bioavailability of inhaled ketamine may shed light on this issue. They found that the substantial reduction in bioavailability of nebulized ketamine could be attributed to residual liquid ketamine that remained in the nebulizer container, or aerosolized ketamine that adhered to the mouthpiece, or the large inhaled aerosol particles that trapped in the oropharynx. The available literatures regarding nebulized ketamine in comparison to other routes of administration remain limited. Its superiority over other routes such as oral and intravenous injection requires further investigation.

In addition, existing evidences indicated that nebulized ketamine provides inconspicuous advantages in sedative effects in children compared to nebulized dexmedetomidine. The results of co-primary outcomes in our study (including number of children with satisfactory sedation, number of children with satisfactory separation from parents, and number of children with satisfactory mask acceptance) showed that the differences among such two treatments were not significant. Our findings regarding adverse reactions indicated that nebulized dexmedetomidine may be a more appropriate option for pediatric sedation than nebulized ketamine due to its lower incidence of emergence agitation. Ketamine injection contains the preservative benzothonium chloride (BCl), which is often considered to be neurotoxic and is associated with a series of adverse reactions [33]. Meanwhile, Vranken JH et al. believed that preservative free ketamine might also be neurotoxic [34]. According to recent literatures, preservative-free s-ketamine has been applied in pediatric sedation or analgesia via intravenous, nasal drop, and rectal administration [35,36,37]. However, for included clinical trials in our present study, no researchers used preservative-free s-ketamine for nebulization in pediatric sedation. Therefore, whether preservative-free s-ketamine administrated via nebulization can reduce adverse reactions remains question for further study. Our study also found that administration of dexmedetomidine was associated with intense decrease in hemodynamic parameters (HR and MAP), which may be derived from the biphasic effects of α2-adrenoceptor [38]. And it was still accepted as a viable sedative option for pediatric patients in some studies, as such great hemodynamic changes could be mitigated by decelerating the rate of drug infusion [39, 40]. Moreover, the present study has demonstrated that the co-administration of dexmedetomidine and ketamine via nebulization can produce a more pronounced sedative effect compared to nebulization of ketamine alone. This finding indicates the potential significance of investigating the combined use of these two agents in future research endeavors.

One limitation in present study would be widespread low quality in the majority of outcomes assessed by the GRADE system, which might be mainly attributed to inconsistency (high heterogeneity) and imprecision (lack of events number). A systematic review of studies brings together material with an element of diversity. They differ in design and conduct as well as in participants, interventions, exposures, etc., and such diversity is commonly referred to as methodological or clinical heterogeneity [19]. Considering that high heterogeneity might add uncertainty to the results and influence the conclusions of the meta-analysis, subgroup or sensitivity analyses should be performed to determine the source of variation [41]. For substantial heterogeneity (present at I2 > 50%) existing in our present study, the sensitivity analysis was considered by us through omitting each study separately and we finally determined these origins of heterogeneity. In addition, although the thorough search strategy and an additional source from Google scholar were considered by us to ensure comprehensive coverage of the relevant literature, the number of enrolled pediatric patients was still insufficient in present study.

Therefore, it is imperative to conduct studies with large sample sizes in future to generate more dependable conclusions. Moreover, due to the fact that each outcome in the present study encompassed fewer than 10 studies, data for publication bias analysis were insufficient and we did not conduct it [20].

Conclusions

Nebulized ketamine has been found to provide inconspicuous advantages in sedative effects to nebulized dexmedetomidine, and it is associated with a relatively high incidence of emergence agitation. Combination of nebulized ketamine and dexmedetomidine might be considered as one preferred option in pediatric sedation as it can provide more satisfactory sedative effects. However, the evidence available to date is insufficient to compare nebulized ketamine with ketamine administered through other routes or with other sedatives. The GRADE system indicated that overall quality of evidences was low or moderate, therefore, future studies with larger sample sizes and high quality are required to obtain more reliable conclusions.

Data availability

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Abbreviations

RCTs:

Randomized controlled trials

MD:

Mean difference

CI:

Confidence interval

RR:

Risk ratio

NMDA:

N-Methyl-D-Aspartate antagonist

MAP:

Mean arterial pressure

HR:

Heart rate

GRADE:

Grading of recommendations assessment, development, and evaluation

PRISMA:

Preferred reporting items for systematic reviews and meta-analyses statement

References

  1. Kain ZN, Mayes LC, O’Connor TZ, Cicchetti DV. Preoperative anxiety in children: predictors and outcomes. Arch Pediatr Adolesc Med. 1996;150(12):1238–45.

    Article  CAS  PubMed  Google Scholar 

  2. Humphrey GB, Boon CM, van den Heuvell GFE, van de Wiel C. The occurrence of high levels of acute behavioral distress in children and adolescents undergoing routine venipunctures. Pediatrics. 1992;90:87–91.

    Article  CAS  PubMed  Google Scholar 

  3. Rubin BK. Pediatric aerosol therapy: new devices and new drugs. Respir Care. 2011;56(9):1411–23.

    Article  PubMed  Google Scholar 

  4. Jia J, Chen J, Hu X, Li W. A randomised study of intranasal dexmedetomidine and oral ketamine for premedication in children. Anaesthesia. 2013;68(9):944–9.

    Article  CAS  PubMed  Google Scholar 

  5. Stapleton SJ, Valdez AM, Killian M, Bradford JY, Cooper M, Horigan A, et al. Clinical practice Guideline: Intranasal Medication Administration. J Emerg Nurs. 2018;44(1):5e1–43. https://doi.org/10.1016/j.jen.2017.11.003.

    Article  Google Scholar 

  6. Yu J, Ren L, Min S, Yang Y, Lv F. Nebulized pharmacological agents for preventing postoperative sore throat: a systematic review and network meta-analysis. PLoS ONE. 2020;10(8):e0237174.

    Article  Google Scholar 

  7. Parraga CB, Peng Y, Cen E, Dove D, Fassassi C, Davis A, et al. Paraphimosis pain treatment with nebulized ketamine in the emergency department. J Emerg Med. 2022;62(3):e57–9.

    Article  Google Scholar 

  8. Soltani HA, Aghadavoudi O. The effect of different lidocaine application methods on postoperative cough and sore throat. J Clin Anesth. 2002;14(1):15–8.

    Article  CAS  PubMed  Google Scholar 

  9. Schuh S, Sweeney J, Rumantir M, Coates AL, Willan AR, Stephens D, et al. Effect of nebulized magnesium vs placebo added to albuterol on hospitalization among children with refractory acute asthma treated in the emergency department: a randomized clinical trial. JAMA. 2020;24(20):2038–47.

    Article  Google Scholar 

  10. Simonini A, Brogi E, Cascella M, Vittori A. Advantages of ketamine in pediatric anesthesia. Open Med (Wars). 2022;17(1):1134–47.

    Article  CAS  PubMed  Google Scholar 

  11. Bergman SA. Ketamine: review of its pharmacology and its use in pediatric anesthesia. Anesth Prog. 1999;46(1):10–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Cohen SP, Bhatia A, Buvanendran A, Schwenk ES, Wasan AD, Hurley RW, et al. Consensus guidelines on the use of intravenous ketamine infusion for chronic pain from the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018;43:521–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Chen C, Cheng X, Lin L, Fu F. Preanesthetic nebulized ketamine vs preanesthetic oral ketamine for sedation and postoperative pain management in children for elective surgery: a retrospective analysis for effectiveness and safety. Med (Baltim). 2021;12(6):e24605.

    Article  Google Scholar 

  14. Zanaty OM, El Metainy SA. A comparative evaluation of nebulized dexmedetomidine, nebulized ketamine, and their combination as premedication for outpatient pediatric dental surgery. Anesth Analg. 2015;121(1):167–71.

    Article  CAS  PubMed  Google Scholar 

  15. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hofmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;29(372):n71.

    Article  Google Scholar 

  16. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA, editors. Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Cochrane. 2022. Available from http://www.training.cochrane.org/handbook.

  17. Guyatt GH, Oxman AD, Schünemann HJ, Tugwell P, Knottnerus A. GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology. J Clin Epidemiol. 2011;64:380–2.

    Article  PubMed  Google Scholar 

  18. GRADE profiler [computer program]. Version 3.6 2011. Available at: www.gradeworkinggroup.org.

  19. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–58.

    Article  PubMed  Google Scholar 

  20. Song F, Hooper L, Loke Y. Publication bias: what is it? How do we measure it? How do we avoid it? Open Access J Clin Trials. 2013;5:71–81.

    Article  Google Scholar 

  21. Abdel-Ghaffar HS, Abdel-Wahab AH, Roushdy MM, Osman AMM. Preemptive nebulized ketamine for pain control after tonsillectomy in children: randomized controlled trial. Braz J Anesthesiol. 2019;69(4):350–7.

    PubMed  PubMed Central  Google Scholar 

  22. Kamel AAF, Amin OAI. Analgo-Sedative Effects of oral or nebulized ketamine in Preschoolers undergoing elective surgery: a comparative, randomized, double-blind study. Pain Physician. 2020;23(2):E195–E202.

    Article  PubMed  Google Scholar 

  23. Abdel-Ghaffar HS, Kamal SM, El Sherif FA, Mohamed SA. Comparison of nebulised dexmedetomidine, ketamine, or midazolam for premedication in preschool children undergoing bone marrow biopsy. Br J Anaesth. 2018;121(2):445–52.

    Article  CAS  PubMed  Google Scholar 

  24. Verma I, Sharma RN, Trivedi V, Dhaked SS. Comparison of intranasal ketamine and intranasal midazolam for pediatric premedication in patients undergoing congenital heart disease surgery. Egypt J Cardiothorac Anesth. 2021;15(3):61.

    Article  Google Scholar 

  25. Shereef KM, Chaitali B, Swapnadeep S, Gauri M. Role of nebulised dexmedetomidine, midazolam or ketamine as premedication in preschool children undergoing general anaesthesia-A prospective, double-blind, randomised study. Indian J Anaesth. 2022;66(Suppl 4):200–S206.

    Google Scholar 

  26. Sabry MHIA, El Gamal NA, Elhelw N, Ammar RA. Comparison of the use of nebulized dexmedetomidine, ketamine, and a mixture thereof as premedication in pediatric patients undergoing tonsillectomy: a double-blind randomized study. Res Opin Anesth Intensive Care. 2020;7:70–4.

    Article  Google Scholar 

  27. Geetha K, Padhy S, Karishma K. Comparison of single-shot nebuliser protocol between dexmedetomidine and ketamine in children undergoing magnetic resonance imaging. J Perioper Pract. 2022;32(12):346–53.

    CAS  PubMed  Google Scholar 

  28. Singariya G, Malhotra N, Kamal M, Jaju R, Aggarwal S, Bihani P. (2022). Comparison of nebulized dexmedetomidine and ketamine for premedication in pediatric patients undergoing hernia repair surgery: a randomized comparative trial. Anesth Pain Med 2022; 17:173–181.

  29. Dharamkhele SA, Singh S, Honwad MS, Gollapalli VK, Gupta N. Comparative evaluation of nebulized ketamine and its combination with dexmedetomidine as premedication for paediatric patients undergoing surgeries under general anaesthesia. Med J Armed Forces India. 2022;78(Suppl 1):213–S218.

    Article  Google Scholar 

  30. Bryant ML, Brown P, Gurevich N, McDougall IR. Comparison of the clearance of radiolabelled nose drops and nasal spray as mucosally delivered vaccine. Nuclear Med Commun. 1999;20(2):171–4.

    Article  CAS  Google Scholar 

  31. Primosch RE, Guelmann M. Comparison of drops versus spray administration of intranasal midazolam in two- and three-year-old children for dental sedation. Pediatr Dent. 2005;27:401–8.

    PubMed  Google Scholar 

  32. Jonkman K, Duma A, Olofsen E, Henthorn T, van Velzen M, Mooren R. Pharmacokinetics and bioavailability of inhaled esketamine in healthy volunteers. Anesthesiology. 2017;127:675–83.

    Article  CAS  PubMed  Google Scholar 

  33. Malinovsky JM, Lepage JY, Cozian A, Mussini JM, Pinaudt M, Souron R. Is ketamine or its preservative responsible for neurotoxicity in the rabbit? Anesthesiology. 1993;78(1):109–15.

    Article  CAS  PubMed  Google Scholar 

  34. Vranken JH, Troost D, De Haan P, Pennings FA, van der Vegt MH, Dijkgraaf MG, Hollmann MW. Severe toxic damage to the rabbit spinal cord after intrathecal administration of preservative-free S (+)-ketamine. Anesthesiology. 2006;105(4):813–8.

    Article  CAS  PubMed  Google Scholar 

  35. Liu F, Kong F, Zhong L, Wang Y, Xia Z, Wu J. Preoperative esketamine alleviates postoperative pain after endoscopic plasma adenotonsillectomy in children. Clin Med Res. 2023;21(2):79–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Qian Q, Liu HX, Li YQ. Effect of esketamine nasal drops on pain in children after tonsillectomy using low temperature plasma ablation. Front Pediatr. 2023;11:1110632.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Marhofer P, Freitag H, Höchtl A, Greher M, Erlacher W, Semsroth M. S (+)-ketamine for rectal premedication in children. Anesth Analg. 2001;92(1):62–5.

    Article  CAS  PubMed  Google Scholar 

  38. Talke P, Chen R, Thomas B, Aggarwall A, Gottlieb A, Thorborg P, et al. The hemodynamic and adrenergic effects of perioperative dexmedetomidine infusion after vascular surgery. Anesth Analg. 2000;90(4):834–9.

    Article  CAS  PubMed  Google Scholar 

  39. Chrysostomou C, Schmitt CG. Dexmedetomidine: sedation, analgesia and beyond. Expert Opin Drug Metab Toxicol. 2008;4:619–27.

    Article  CAS  PubMed  Google Scholar 

  40. Mason KP, Zgleszewski SE, Prescilla R, Fontaine PJ, Zurakowski D. Hemodynamic effects of dexmedetomidine sedation for CT imaging studies. Paediatr Anaesth. 2008;18:393–402.

    Article  PubMed  Google Scholar 

  41. Esteves SC, Majzoub A, Agarwal A. The problem of mixing ‘apples and oranges’ in meta-analytic studies. Transl Androl Urol. 2017;6(Suppl 4):412–S413.

    Article  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

The present study was supported by Science and Technology Plan Project of Sichuan Province (2020YFS0035).

Author information

Author notes

  1. Xiao Liu and Bingchen Lang contributed equally to this work, and both of them were first authors.

Authors and Affiliations

  1. Department of Pharmacy, The Third People’s Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, Chengdu, China

    Xiao Liu

  2. Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, China

    Bingchen Lang, Linan Zeng, Liang Huang, Zhi-Jun Jia & Lingli Zhang

  3. Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, 610041, China

    Bingchen Lang, Linan Zeng, Liang Huang, Zhi-Jun Jia & Lingli Zhang

  4. National Medical Products Administration (NMPA) Key Laboratory for Technical Research on Drug Products In Vitro and In Vivo Correlation, Chengdu, China

    Bingchen Lang, Linan Zeng, Liang Huang, Zhi-Jun Jia & Lingli Zhang

  5. Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Chengdu, China

    Bingchen Lang, Linan Zeng, Liang Huang, Shouming Chen, Zhi-Jun Jia, Guo Cheng, Qin Yu & Lingli Zhang

  6. Department of Anesthesiology, West China Second University Hospital, Sichuan University, Chengdu, China

    Shouming Chen

  7. West China School of Pharmacy, Sichuan University, Chengdu, China

    Zhi-Jun Jia

  8. Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China

    Guo Cheng

  9. Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Sichuan University, Chengdu, China

    Guo Cheng

  10. National Drug Clinical Trial Institute, West China Second University Hospital, Sichuan University, Chengdu, China

    Qin Yu

  11. Chinese Evidence-based Medicine Center, West China Hospital, Sichuan University, Chengdu, China

    Lingli Zhang

Authors
  1. Xiao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bingchen Lang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Linan Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liang Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shouming Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhi-Jun Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guo Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Qin Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lingli Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

X Liu, B Lang, L Zeng, S Chen and L Zhang helped contributed to the conception and design of the study, and write the manuscript; L Zhang, G Cheng, Q Yu and Z Jia provided the administrative support; B Lang and S Chen contributed to collection and analysis of data; L Zeng, L Huang, L Zhang and participated in the critical review of the manuscript; All authors read and approved the final manuscript.

Corresponding author

Correspondence to Lingli Zhang.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Supplementary Material 2

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, X., Lang, B., Zeng, L. et al. Comparison of the effects of ketamine via nebulization versus different pharmacological approaches in pediatric sedation: a systematic review and meta-analysis of randomized controlled trials. BMC Anesthesiol 23, 375 (2023). https://doi.org/10.1186/s12871-023-02298-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12871-023-02298-4

Keywords

BMC Anesthesiology

ISSN: 1471-2253

Contact us