Efficacy and safety of intranasal midazolam versus intranasal ketamine as sedative premedication in pediatric patients: a meta-analysis of randomized controlled trials
BMC Anesthesiology volume 22, Article number: 399 (2022)
Intranasal midazolam and ketamine have been widely used as sedative premedication in children. It is difficult to determine which one yields better sedative effects for clinical practice. We conducted the present meta-analysis by summarizing the evidences to evaluate the efficacy and safety of intranasal midazolam versus intranasal ketamine as sedative premedication in pediatric patients.
We searched PubMed, Embase, and Cochrane Library from inception to April 2022. All randomized controlled trials (RCTs) used intranasal midazolam and ketamine as sedatives in children were enrolled. The risk of bias in RCTs was assessed by Cochrane risk of bias tool. Condition of parental separation, anesthesia induction or facemask acceptance, sedation level, different hemodynamic parameters and adverse events were considered as the outcomes in our study.
A total of 16 studies with 1066 patients were enrolled. Compared with midazolam, administration of intranasal ketamine might be associated with severer changes in hemodynamics parameters including mean blood pressure (SMD = -0.53, with 95% CI [-0.93, -0.13]) and heart rate (HR) (SMD = -1.39, with 95% CI [-2.84, 0.06]). Meanwhile, administration of intranasal midazolam was associated with more satisfactory sedation level (61.76% vs 40.74%, RR = 1.53, with 95%CI [1.28, 1.83]), more rapid onset of sedation (SMD = -0.59, with 95%CI [-0.90, -0.28]) and more rapid recovery (SMD = -1.06, with 95%CI [-1.83, -0.28]). Current evidences also indicated that the differences of various adverse effects between two groups were not significant.
Given that administration of midazolam via intranasal route provides more satisfactory sedative level with less fluctuation of hemodynamics parameters and more rapid onset and recovery, it might be considered as the preferred sedative premedication for pediatric patients compared to ketamine. However, the widespread evidences with low or moderate quality indicated that superiority of intranasal midazolam in pediatric sedation needs to be confirmed by more studies with high quality and large sample size in future.
The protocol of present study was registered with PROSPERO (CRD42022321348).
For pediatricians and anesthesiologists, relieving anxiety or stress in children before surgeries and procedures should be a recurring concern. A previous report alleged that up to 60–70% of children have experienced significant stress anxiety before surgeries . Possible reasons for such behavioral problem in children include their concerns about physical discomfort during surgeries or clinical procedures and their concerns about the condition of being separated from parents . And unfamiliar hospital environment and lack of understanding about surgeries or clinical conditions frequently frighten pediatric patients and exaggerate their unpleasant experience. It results in uncooperative physically resistance from children at the time of parental separation, mask application, or induction of anesthesia . Therefore, it’s necessary to pay particular attention to treating preoperative anxiety in pediatric patients.
Sedative premedications, which has been found to be more effective than behavioral intervention [4, 5], can allay anxiety, decrease emotional discomforts, facilitate parental separation, and lead to an atraumatic induction of anesthesia. As a short-acting anxiolytic drug, midazolam provides fast sedation and has become one of the most frequently used preanaesthetic medication in pediatric patients , and it has been revealed repeatedly to be superior to the behavioral preparation programs  (e.g., the parental presence). Ketamine, an N-methyl D-aspartate (NMDA) receptor antagonist, also produces sedative effect without respiratory depression and it has been used as sedative premedication in children .
However, anatomical factors of children, especially small veins and excess subcutaneous fat, make visualization of veins difficult. It would be challenging to obtain reliable vascular access in pediatric patients . Hence, intranasal administration, an alternative route for intravenous administration without risk of needle-stick injuries and high vascular access skill requirements, has been widely used in pediatric sedation to ensure a high level of compliance in children undergoing sedative premedication .
Recent studies indicated that both two mentioned-above pharmacological approaches have been widely used as intranasal sedatives in children [11, 12]. And a growing number of studies shifted focus to comparison between intranasal ketamine and intranasal midazolam in pediatric sedation. Gharde et al.  suggested that separation of children from their parents was more smooth in ketamine group compared to midazolam group. Meanwhile, Hosseini Jahromi et al.  and Milési et al. . indicated that intranasal midazolam was more effective than intranasal ketamine in reducing preoperative pediatric anxiety and in rapidly achieving adequate sedation. It is difficult to determine which one yields better sedative effects for clinical practice. Therefore, the inconsistent conclusions from recent published studies prompt us to perform a meta-analysis by summarizing the evidences to evaluate the efficacy and safety of intranasal midazolam versus intranasal ketamine as sedative premedication in pediatric patients.
Protocol and registration
According to the recommendations in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement  and Cochrane Handbook, we performed the present meta-analysis. The protocol for this review was registered on International Prospective Register for Systematic Reviews (PROSPERO) (https://www.crd.york.ac.uk/prospero, CRD42022321348).
Electronic databases including PubMed, Embase, and Cochrane Library were searched from inception to April 20, 2022 by two authors (BL and YF). And we also considered academic search engine Google Scholar as the additional information source. “Infant”, “child”, “adolescent”, “midazolam”, “nasal”, “intranasal” and “randomized controlled trial” were considered as our search terms (Appendix S1). Only human studies published in English or Chinese were considered in our present study.
The participants of present study were children (< 18 years old) who experienced various surgical or diagnostic procedures.
Intervention and comparison
Using midazolam and ketamine via intranasal route as sedative premedication were considered as intervention and comparison.
It is generally agreed that ideal features of pediatric sedation included satisfactory separation from parents, induction of anesthesia or facemask compliance, stable hemodynamic status and limited adverse effects, thus, number of patients with satisfactory separation from parents, number of patients with satisfactory induction or mask acceptance, and number of patients with satisfactory sedation level were considered as co-primary outcomes in our present study. And the secondary outcomes were as follows: Onset of sedation, recovery time, hemodynamic status and various adverse effects between two groups.
Only randomized controlled trials (RCTs) were considered.
Reviews, conference abstracts, cases, comments, preclinical studies, protocol, ongoing trials, studies not published in English or in Chinese, and studies with inappropriate comparisons or unrelated outcome measures were excluded.
Data extraction, and assessment of the risk of bias
Literature screening and data extraction were performed by two independent authors (BL and YF), and then they crosschecked with each other. After deleting the duplicated items from different databases, the irrelevant records were excluded by scanning titles and abstracts. Then full texts of the remaining records were obtained and perused by us. The general characteristics of all enrolled studies which met the criteria were collected in Table 1. The risk of bias in RCTs was assessed by Cochrane risk of bias tool  including following aspects: random sequence generation (generation of the randomization sequence), allocation concealment, blinding of outcome assessment, incomplete outcome data, and selective reporting. All clinical researches could have classified as low, high, or unclear risk of bias across above-mentioned five domains. Any disagreement will be resolved by consulting a third investigator.
Grading the quality of evidence
We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology  to assess the quality of evidence and strength of recommendations considering risk of bias, inconsistency, indirectness, imprecision, and publication bias. The quality of evidence was classified as high, moderate, low, or very low. The analysis was performed by using the GRADE profiler software (version 3.6, provided by the Cochrane collaboration).
We used Review Manager software (Version 5.3.3, the Cochrane Collaboration 2014, the Nordic Cochrane Centre) for statistical analysis. Standardized mean difference (SMD) with 95% confidence interval (CI) was applied to estimate continuous variables, and risk ratio (RR) with 95% confidence interval (CI) and the Mantel–Haenszel method (fixed or random models) were used to analyze dichotomous data. And Heterogeneity was assessed through the I-squared (I2) test . If significant heterogeneity (present at I2 > 50%) existed, the sensitivity analysis was considered by omitting each study separately, and the random effects model was applied; otherwise, the fixed-effects model would be considered. If sufficient studies (the number exceeds 10) were included for the primary or second outcomes , a funnel plot to explore the possibility of publication bias would be performed by us.
Literature search results
A total of 834 studies were identified initially after databases screening and additional source searching. And then we removed 330 duplicate records, and excluded 258 records by reviewing titles and abstracts. In these 258 excluded items, 11 were studies about adult patients, 1 was the study performed in animal, 4 were comments notes, 24 were conference news or abstracts, 141 were protocols or ongoing trials, 45 were reviews, and 32 were studies focused on irrelevant topics. And consequently 230 items were excluded by full-text reviewing, 12 studies were excluded based on language (4 were written in Spanish, 3 in German, 2 in French, 1 in Italian, 1 in Turkish, and 1 in Korean), 45 were studies not focused on preoperative sedation, 32 studies were concerned with sedatives via other routes of administration, 54 studies were concerned with combined medication, 48 were studies focused on comparison of different dosages and different routes of midazolam, and 39 studies were excluded owing to the inappropriate comparisons. Eventually, 16 studies were chosen in consequent analysis [13,14,15, 18,19,20,21,22,23,24,25,26,27,28,29,30]. The details of literatures identification are described in PRISMA flowchart (Fig. 1).
Basic characteristics of enrolled studies
The enrolled studies were published from 1993 to 2022, and 1066 eligible pediatric patients (ages ranged from 24 weeks to 14 years) were involved in total. Intranasal midazolam at a dosage range of 0.2 mg/kg-0.5 mg/kg and intranasal ketamine at a dosage range of 2 mg/kg-10 mg/kg was given in children undergoing various types of surgery or procedure including cardiac surgeries, cancer surgeries, urologic surgeries, ear nose throat surgeries, corrective surgeries, dental treatment, bone marrow biopsy, endotracheal intubation, echocardiography and other elective surgeries. All studies in present analysis described the primary outcomes “number of patients with satisfactory sedation level, number of patients with satisfactory separation from parents, or number of patients with satisfactory induction or mask acceptance” [13,14,15, 18,19,20,21,22,23,24,25,26,27,28,29,30]. The outcome “Onset of sedation” was reported in 4 studies [15, 22, 23, 30], the outcome “Recovery time” was mentioned in 4 studies [18, 22, 24, 28], and 5 studies concerned the occurrence of different adverse effects [18, 23, 26, 28, 29]. The main characteristics of enrolled studies were summarized in Table 1.
Risk of bias assessment
Cochrane Collaboration’s risk of bias tool was used in evaluating validity and quality of included RCTs by us. In totally, 31.25% (5/16) studies described appropriate method of random sequence generation, only 18.75% (3/16) studies reported the allocation concealment, 37.50% (6/16) studies had low risk in blinding of participants and personnel domain, half of studies (8/16) described blinding procedure of outcome assessment. The detailed information about risk of bias assessment was showed in Fig. 2.
Number of patients with satisfactory separation from parents
Four studies involving 244 pediatric patients described the number of patients with satisfactory separation from parents, and all of them focused attention on comparison between midazolam and dexmedetomidine. The random-effects model was chosen due to the existence of statistical heterogeneity. Results indicated that no significant differences were observed between midazolam group and ketamine group (54.33% vs 61.54%, RR = 0.92, with 95%CI [0.64, 1.33], P = 0.65, I2 = 80%; Fig. 3). According to GRADE summary of findings table, the quality of evidence for this outcome was very low. It was resulted from inconsistency (I2 > 50%) and imprecision (lack of events number) (Table S1).
Number of patients with satisfactory induction or mask acceptance
A total of 340 children in five studies reported the number of patients with satisfactory induction or mask acceptance. Given that limited statistical heterogeneity was detected among the study results (I2 = 42%), the fixed-effects model was used. The results of analysis also indicated that no significant differences were observed between two groups (62.29% vs 58.79%, RR = 1.09, with 95%CI [0.94, 1.27], P = 0.23, I2 = 42%; Fig. 4). As demonstrated as GRADE summary of findings table, the quality of evidence for this outcome was moderate, and imprecision (limited number of events) was considered as the main factor (Table S1).
Number of patients with satisfactory sedation level
Although the evaluation scales or scores about pediatric sedative level vary, according to review of Cravero et al., , any sedation treatment that allows a procedure, for example, facilitating smooth anaesthetic induction, to be completed should be considered as the successful sedation. And in most of included literatures, cooperative behavior with minor fussing and struggle was served as an adequate sedation in pediatric patients. Seven studies including 472 pediatric patients were considered in analysis. Owing to absence of statistical heterogeneity (I2 = 26%), the fixed-effects model was chosen. The result indicated that the using of midazolam via intranasal route was associated with more satisfactory sedation level compared to intranasal ketamine (61.76% vs 40.74%, RR = 1.53, with 95%CI [1.28, 1.83], P < 0.0001, I2 = 26%; Fig. 5). The GRADE summary of findings table indicated that quality of evidence for present outcome was moderate. Imprecision (limited number of events) and high risk of bias were main factors (Table S1).
Results of secondary outcomes including hemodynamic parameters, onset of sedation, recovery time and various adverse effects were summarized in Table 2. Hemodynamic parameters including heart rate (HR), systolic blood pressure (SBP), mean blood pressure (MBP), and oxygen saturation were reported separately in 4 studies [21, 24,25,26], 1 study , 2 studies [24, 25], and 2 studies [21, 24]. The results indicated that intranasal ketamine was associated with significant higher value of MBP (SMD = -0.53, with 95% CI [-0.93, -0.13], P = 0.009; I2 = 0%) and oxygen saturation (SMD = -0.57, with 95% CI [-1.13, -0.02], P = 0.04; I2 = 57%). Additionally, the result indicated that intranasal ketamine might be associated with higher value of HR (SMD = -1.39, with 95% CI [-2.84, 0.06], P = 0.06; I2 = 96%). Meanwhile the results also indicated that intranasal midazolam was associated with more rapid onset of action (SMD = -0.59, with 95% CI [-0.90, -0.28], P = 0.0002; I2 = 0%) and more rapid recovery (SMD = -1.06, with 95% CI -1.06 [-1.83, -0.28], P = 0.008; I2 = 82%) compared to ketamine. The current evidences also indicated that the differences of adverse effects (e.g. agitation, oxygen saturation below 90%, nauseas and vomiting) between two groups were not significant.
Sensitivity analysis and assessment of publication bias
According to the results, substantial heterogeneity only existed in analysis for one primary outcome “ Number of patients with satisfactory separation from parents” (I2 = 80%), however, the source could not be attributed to one particular study by sensitivity analysis; therefore, we applied random effects model in analysis. Given that each outcome included fewer than 10 studies, there were insufficient data for any publication bias analysis [33, 35].
Both midazolam and ketamine have been widely used in pediatric sedation. As an ultra-short acting sedative and anxiolytic, application of midazolam is frequently associated with rapid onset and with better recovery profile . And ketamine is also one sedative option for its hypnotic and analgesic effect . Compared with intravenous administration, intranasal administration is noninvasive and is highly preferred for pediatric sedation. It provides rapid drug absorption and leads to high drug bioavailability. According to studies published in recent years, two sedatives have been regarded as the most commonly used preoperative sedatives via intranasal route. However, the inconsistent conclusions from recent published studies [13,14,15] indicated that it is difficult to determine the preferred one for clinical sedation. To our knowledge, no relevant study has been established to examine the effects between two medications via intranasal route in pediatric sedation. Therefore, we performed present meta-analysis to evaluate efficacy and safety of two interventions as sedative premedication in pediatric patients.
The main objectives of preoperative sedation and optimal sedative level in children may vary with the specific procedure, but generally encompass alleviating anxiety, controlling excessive movement and facilitating parental separation. Therefore, parental separation, anesthesia induction or facemask acceptance, sedation level were considered as the major concerns in present study. In our study, a total of 16 RCTs including over 1000 pediatric patients were included. The current results of primary outcome indicated that intranasal premedication of midazolam might provide more satisfactory sedation level compared to ketamine (61.76% vs 40.74%, RR = 1.53, with 95%CI [1.28, 1.83], P < 0.0001, I2 = 26%; Fig. 5). However, the results also indicated that no significant differences were observed between two groups in number of patients with satisfactory separation from parents and in number of patients with satisfactory induction or mask acceptance. The inconsistent results from these co-primary outcomes might be resulted from small numbers of studies included in analysis, especially for the first two outcomes (Fig. 3 and Fig. 4), and the limited number of events was also the contributing factor to imprecision and unreliability.
Several studies suggested that intranasal midazolam should be considered as one safe medication for its minor influence on respiratory and cardiovascular parameters, [23, 38]. In our study, several side effects including nauseas/vomiting, agitation, and several common hemodynamics parameters were evaluated. The results of secondary outcomes indicated that children received ketamine via intranasal route was associated with higher value of hemodynamics parameters compared to midazolam. In fact, acute changes, especially the increased blood pressure and heart rate, in the cardiovascular status of patients are always considered as the side effects of ketamine, which were predominantly attributed to its sympathomimetic actions by direct stimulation of central nervous system structures . And actually, most cardiovascular effects were reported as occurring during or immediately after intravenous ketamine administration . According to traditional view, nauseas/vomiting and agitation may be resulted mainly from the perioperative use of inhalational anaesthesia and opioids [41, 42]. Although views differ widely on whether these premedications are effective in alleviating the side effects [43,44,45], current evidences from present study demonstrated that no difference was found in incidences of agitation, nauseas and vomiting between two groups. And our study also indicated that children received intranasal midazolam as premedication might be associated with rapid onset of action and recovery profile, which strengthened the findings from several previous studies [46, 47].
There are some limitations in our present study should be noted. One would be widespread low or moderate quality in outcomes evaluated by GRADE system. Inconsistency (high heterogeneity) and imprecision (lack of events number) might be considered as main factors. Another limitation was the lack of studies with large sample size in most outcomes of our meta-analysis. In present study, some unpublished materials (e.g., data from some registered ongoing trials) and articles published in languages other than English or Chinese were not included as they did not provide sufficient accessible information to allow our analysis. To compensate for the lack of information resource, we performed a thorough search for grey literature from websites “http://www.greylit.org/” and “http://greyguide.isti.cnr.it/” by using terms “midazolam” and “ketamine” (Accessed 19, Oct, 2022), but no results were found. Moreover, a search strategy as comprehensive as possible and a search considered additional source from Google scholar were also applied by us. However, the number of enrolled pediatric patients was still insufficient, studies with large sample size in future were required to draw more reliable conclusions. In addition, owing to each outcome in present study included fewer than 10 studies, data for publication bias analysis were insufficient and the analysis did not conducted by us [33, 35].
Moreover, considering that sedating children for diagnostic or surgical procedures has evolved into an important clinical issue involving diverse specialties outside of anesthesia. The emphasis in future should be placed on evaluation the optimal sedative premedication option with optimal dose range in different procedures.
Both intranasal midazolam and intranasal ketamine have been widely used in pediatric sedation for many years. Based on all current evidences gathered from our analysis, no significant differences are found in adverse effects (e.g. agitation, oxygen saturation below 90%, nauseas and vomiting) between two groups., but intranasal midazolam provides more adequate sedative level, more rapid onset and recovery with less fluctuation of hemodynamics parameters, therefore, it might be considered as the preferred intranasal sedative option for pediatric patients compared to ketamine. However, overall low and moderate quality evidences in primary outcomes evaluated by GRADE system suggest that superiority of intranasal midazolam in pediatric sedation needs to be validated, and more studies with high quality and large sample size in future will be needed to draw a more reliable conclusion.
Availability of data and materials
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
Randomized controlled trials
Standardized mean difference
Systolic blood pressure
Mean blood pressure
Grading of recommendations assessment, development, and evaluation
Preferred reporting items for systematic reviews and meta-analyses statement
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.
Kain ZN, Mayes LC. Anxiety in children during the perioperative period. In: Borestein M, Genevro J, Mahwah NJ, editors. Child Development and Behavioral Pediatrics. Mahwah: Lawrence Erlbaum Associates; 1996. p. 85–103.
Watson AT, Visram A. Children’s preoperative anxiety and postoperative behaviour. Pediatr Anesth. 2003;13:188–204.
Kain ZN, Mayes LC, Wang SM, Caramico LA, Hofstadter MB. Parental presence during induction of anesthesia versus sedative premedication: which intervention is more effective? Anesthesiology. 1998;89(5):1147–56.
McCann ME, Kain ZN. The management of preoperative anxiety in children: an update. Anesth Analg. 2001;93:98–105.
Kain ZN, Hofstadter MB, Mayes LC, Krivutza DM, Alexander G, Wang SM, Reznick JS. Midazolam effects on amnesia and anxiety in children. Anesthesiology. 2000;93:676–84.
Rosenbaum A, Kain ZN, Larsson P, LÖNNQVIST PA, Wolf AR. The place of premedication in pediatric practice. Paediatr Anaesth. 2009;19(9):817–28.
Schofield S, Schutz J, Babl FE. Procedural sedation and analgesia for reduction of distal forearm fractures in the paediatric emergency department: a clinical survey. EMA. 2013;25(3):241–7.
Kuensting LL, DeBoer S, Holleran R, Shultz BL, Steinmann RA, Venella J. Difficult venous access in children: taking control. J Emerg Nurs. 2009;35(5):419–24.
Türker S, Onur E, Ózer Y. Nasal route and drug delivery systems. Pharm World Sci. 2004;26(3):137–42. https://doi.org/10.1023/B:PHAR.0000026823.82950.ff.
Malia L, Laurich VM, Sturm JJ. Adverse events and satisfaction with use of intranasal midazolam for emergency department procedures in children. Am J Emerg Med. 2019;37(1):85–8.
Tsze DS, Steele DW, Machan JT, Akhlaghi F, Linakis JG. Intranasal ketamine for procedural sedation in pediatric laceration repair: a preliminary report. Pediatric Emergency Care. 2012;28(8):767–70 (PMID:22858745).
Gharde P, Chauhan S, Kiran U. Evaluation of efficacy of intranasal midazolam, ketamine and their mixture as premedication and its relation with bispectral index in children with tetralogy of fallot undergoing intracardiac repair. Ann Card Anaesth. 2006;9(1):25–30.
Hosseini Jahromi SA, Hosseini Valami SM, Adeli N, Yazdi Z. Comparison of the effects of intranasal midazolam versus different doses of intranasal ketamine on reducing preoperative pediatric anxiety: a prospective randomized clinical trial. J Anesth. 2012;26(6):878–82.
Milési C, Baleine J, Mura T, Benito-Castro F, Ferragu F, Thiriez G, et al. Nasal midazolam vs ketamine for neonatal intubation in the delivery room: a randomised trial. Arch Dis Child Fetal Neonatal Ed. 2018;103(3):F221–6.
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;29(372):n71.
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.
Abrams R, Morrison JE, Villasenor A, Hencmann D, Da Fonseca M, Mueller W. Safety and effectiveness of intranasal administration of sedative medications (ketamine, midazolam, or sufentanil) for urgent brief pediatric dental procedures. Anesth Prog. 1993;40(3):63–6.
Kazemi AP, Kamalaipour H, Seddighi M. Comparison of intranasal midazolam versus ketamine as premedication in 2–5 years old pediatric surgery patients. Pak J Med Sci. 2005;21(4):460–4.
Gautam SN, Bhatta S, Sangraula D, Shrestha BC, Rawal SB. Intranasal midazolam Vs ketamine as premedication in paediatric surgical procedure for child separation and induction. Nepal Med Coll J. 2007;9(3):179–81.
Mostafa MG, Morsy KM. Premedication with intranasal dexmedetomidine, midazolam and ketamine for children undergoing bone marrow biopsy and aspirate. Egyt J Anesth. 2013;29:131–5.
Natarajan Surendar M, Kumar Pandey R, Kumar Saksena A, Kumar R, Chandra G. A comparative evaluation of intranasal dexmedetomidine, midazolam and ketamine for their sedative and analgesic properties: a triple blind randomized study. J Clin Pediatr Dent. 2014;38(3):255–61.
Narendra PL, Naphade RW, Samson N, Shanawaz M. A comparison of intranasal ketamine and intranasal midazolam for pediatric premedication. Anesth Essays Res. 2015;9(2):213–8.
Fei J, Tang X, Liang H, Li Y, Tang J, Deng Y, et al. The preoperative sedation comparison of dexmedetomindine, midazolam, and ketamine on children with the pediatric tumor after surgery by nasal medicine delivery. Anti-tumor Pharmacy. 2017;7(6):702–7. https://doi.org/10.3969/j.issn.2095-1264.2017.06.13.
Akcay ME, Kılıç ET, Akdemir MS. The Comparison of the Efficacy and Safety of Midazolam, Ketamine, and Midazolam Combined with Ketamine Administered Nasally for Premedication in Children. Anesth Essays Res. 2018;12(2):489–94.
Alp H, Elmacı AM, Alp EK, Say B. Comparison of intranasal midazolam, intranasal ketamine, and oral chloral hydrate for conscious sedation during paediatric echocardiography: results of a prospective randomised study. Cardiol Young. 2019;29(9):1189–95.
Jafarnejad S, Mehrabi I, Rezai M, Ebrahimi HK. Comparison of intranasal ketamine and midazolam in peripheral iv access in children presenting to the emergency department, a randomized clinical trial. Pak J Med Sci. 2020;14(3):1412–7.
Khoshrang H, Alavi CE, Rimaz S, Mirmansouri A, Farzi F, Biazar G, et al. Efficacy of intranasal ketamine and midazolam for pediatric sedation: A double-blind, randomized clinical trial. Caspian J Intern Med. 2021;12(4):539–43.
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;15:61–9.
Abusinna RG, Algharabawy WS, Mowafi MM. Comparative evaluation of intranasal midazolam, dexmedetomidine, ketamine for their sedative effect and to facilitate venous cannulation in pediatric patients: A prospective randomized study. Egyt J Anesth. 2022;38(1):124–30.
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.
Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–58.
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.
Cravero JP, Blike GT. Review of pediatric sedation. Anesth Analg. 2004;99(5):1355–64.
Sterne JAC, Egger M, Moher D, Boutron I (editors). Chapter 10: Addressing reporting biases. In: Higgins JPT, Churchill R, Chandler J, Cumpston MS (editors), Cochrane Handbook for Systematic Reviews of Interventions version 5.2.0 (updated June 2017), Cochrane, 2017. Available from http://www.training.cochrane.org/handbook.
Fazi L, Jantzen EC, Rose JB, Kurth CD, Watcha MF. A comparison of oral clonidine and oral midazolam as preanesthetic medications in the pediatric tonsillectomy patient. Anesth Analg. 2001;92(1):56–61.
Pandey RK, Bahetwar SK, Saksena AK, Chandra G. A comparative evaluation of drops versus atomized administration of intranasal ketamine for the procedural sedation of young uncooperative pediatric dental patients: a prospective crossover trial. J Clin Pediatr Dent. 2011;36(1):79–84.
Wilton NC, Leigh J, Rosen DR, Pandit UA. Preanesthetic sedation of preschool children using intranasal midazolam. Anesthesiology. 1988;69:972–5.
Chodoff P. Evidence for central adrenergic action of ketamine: Report of a case. Anesth Analg. 1972;51:247–50.
Short B, Fong J, Galvez V, Shelker W, Loo CK. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry. 2018;5(1):65.
Kanaya A. Emergence agitation in children: risk factors, prevention, and treatment. J Anesth. 2016;30(2):261–7.
Smith HS, Laufer A. Opioid induced nausea and vomiting. Eur J Pharmacol. 2014;5(722):67–78.
Kim YH, Yoon SZ, Lim HJ, Yoon SM. Prophylactic Use of Midazolam or Propofol at the End of Surgery May Reduce the Incidence of Emergence Agitation after Sevoflurane Anaesthesia. Anaesth Intensive Care. 2011;39(5):904–8.
Kim KM, Lee KH, Kim YH, Ko MJ, Jung JW, Kang E. Comparison of effects of intravenous midazolam and ketamine on emergence agitation in children: Randomized controlled trial. J Int Med Res. 2016;44(2):258–66.
Cohen IT, Drewsen S, Hannallah RS. Propofol or midazolam do not reduce the incidence of emergence agitation associated with desflurane anaesthesia in children undergoing adenotonsillectomy. Paediatr Anaesth. 2002;12(7):604–9.
Malionovsky JM, Lejus C, Populaire C, Lepage JY, Cozain A, Pinaud M. Premedication with midazolam in children Effect of intranasal, rectal and oral routes on plasma concentration. Anaethesia. 1995;50:351–4.
Lejus C, Renaudin M, Testa S, Malinovsky JM, Vigier T, Souron R. Midazolm for premedication in children nasal vs. rectal administration. Eur J Anaethesia. 1977;14:244–9.
The present study was supported by the Science and Technology Plan Project of Sichuan Province (2020YFS0035).
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Lang, B., Wang, H., Fu, Y. et al. Efficacy and safety of intranasal midazolam versus intranasal ketamine as sedative premedication in pediatric patients: a meta-analysis of randomized controlled trials. BMC Anesthesiol 22, 399 (2022). https://doi.org/10.1186/s12871-022-01892-2