Concomitant Use of Intravenous Remimazolam With Inhalation Anesthesia and Subsequent Emergence Delirium in Children

Abstract

Emergence delirium (ED) is a typical postoperative complication in pediatric anesthesia, especially with inhalational agents. Remimazolam, a short-acting benzodiazepine, shows potential for reducing the occurrence of ED. Given limited evidence of its use in pediatric anesthesia, we evaluated the efficacy and safety of remimazolam by conducting a systematic review and meta-analysis.

MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and International Clinical Trials Registry Platform (ICTRP) databases were explored for studies on remimazolam in pediatric anesthesia. The studies included were randomized controlled trials (RCTs), prospective and retrospective cohort studies, case series, and case reports. Eligible patients were pediatric patients as American Society of Anesthesiologists Physical Status I or II who underwent sevoflurane-based general anesthesia. Primary outcomes included ED and emergence time. Study quality was assessed using the Risk of Bias 2 tool, and evidence certainty was evaluated by the Grading of Recommendations, Assessment, Development, and Evaluation approach. Random-effects meta-analyses estimated pooled risk ratios (RRs).

Three RCTs (n = 310) were included. A 0.2 mg/kg remimazolam bolus may result in a large reduction in ED (RR 0.26, 95% confidence intervals (CIs) 0.16 to 0.44, I² = 0%; low certainty, three studies). Continuous infusion showed similar effects (RR 0.22, 95% CIs 0.08 to 0.60, low certainty, one study). Emergence times varied by dosage and administration method, with continuous infusion associated with prolonged emergence times (mean difference 5.7 minutes, 95% CIs 3.67 to 7.73, low evidence, one study). Evidence certainty ranged from very low to low, with the 0.2 mg/kg bolus rated very low.

The concomitant use of intravenous remimazolam with inhalation anesthesia may reduce the ED in pediatric patients. However, evidence on emergence times remains inconclusive. Anesthetists could potentially use remimazolam to reduce the ED in children after inhalation anesthesia, but further investigation regarding its efficacy and safety across diverse populations is warranted.

Introduction & Background

Emergence delirium (ED) in children is characterized by a sudden onset of disorientation, perceptual problems, and hyperactive motor behavior immediately after anesthesia recovery [1,2]. It is commonly observed in pediatric anesthesia, particularly with inhalational agents, and has an incidence rate ranging between 10% and 80% [1]. This condition often leads to temporary agitation and uncooperative behavior, potentially increasing the duration of patient stay in the post-anesthesia care unit (PACU).

A variety of pharmacologic strategies has been investigated to prevent ED in children, emphasizing the ongoing need for effective interventions [3]. Propofol has traditionally been widely used for this purpose, with its efficacy supported in diverse clinical contexts [4,5]. However, the formulation of propofol includes allergens, such as soybean and egg derivatives, restricting its use in patients with specific food allergies [6]. This creates a need for alternative ED prevention options, particularly for patients at risk of allergies, prolonged sedation, or other adverse effects.

Remimazolam is a recently introduced intravenous benzodiazepine with an ultra-short duration of action. It has proved to be advantageous in clinical practice, as it offers rapid onset and subsequent recovery. Results from recent randomized controlled trials (RCTs) indicate that remimazolam could help decrease the frequency of pediatric ED [7-9]. Studies have demonstrated that both single-bolus administration and continuous infusion of remimazolam are linked to a reduced incidence of ED compared to placebo despite variations in dosing and administration methods across trials. However, the limited sample sizes of individual RCTs limit the comprehensive assessment of adverse events.

To address these limitations, we conducted a systematic review and meta-analysis (SR/MA) examining the available data regarding the efficacy and safety of remimazolam in the prevention of ED.

Review

Methods

Compliance With Reporting Guideline

We used a systematic review protocol template (Appendix G). We followed the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 [10] and the recommendations listed in the Cochrane Handbook [11].

Eligibility Criteria

This study aimed to address the research question concerning the effectiveness of the concomitant use of intravenous remimazolam with inhalation anesthesia and subsequent ED in children. Participants were defined as male or female pediatric patients aged 0 to 18 years with an American Society of Anesthesiologists Physical Status (ASA-PS) classification of I or II, who underwent general anesthesia using inhaled sevoflurane during surgery. We defined intervention as the administration of intravenous remimazolam (bolus or continuous infusion) during the perioperative period. We defined control as the administration of a placebo, no intervention, or usual care.

We included RCTs, prospective and retrospective cohort studies, case series, and case reports on the relationship between ED and intravenous remimazolam in children undergoing general anesthesia with inhaled sevoflurane. We did not apply language, country, or publication year restrictions. We excluded pediatric participants who were ASA-PS ≥ 3 and were scheduled for elective surgery under total intravenous anesthesia. We also excluded adult (over 18 years of age) participants. We considered both published and unpublished studies, including conference abstracts and correspondence.

Outcomes of Interest

The primary outcomes of interest focused on the incidence of ED (within 30 minutes in the PACU) and emergence time (during the follow-up period). We used the Pediatric Anesthesia Emergence Delirium (PAED) scale to assess ED [12]. ED was defined as a global PAED score ≥ 10. A score of 10 or greater indicates a sensitivity of 0.64 and a specificity of 0.14 [12]. The PAED scale includes five parameters: eye contact, purposeful behavior, awareness of surroundings, restlessness, and inconsolability. Items 1, 2, and 3 are scored on a scale ranging from 4, representing “not at all,” to 0, representing “extremely so,” with intermediate values of 3 for “a little,” 2 for “a lot,” and 1 for “very much.” In contrast, items 4 and 5 are scored inversely. We defined emergence time as the interval between the termination of inhaled anesthetics and the opening of the eye upon verbal commands.

Secondary outcomes encompassed the duration of PACU stay (during follow-up), the severity of delirium (during follow-up), and all adverse events (during hospitalization). We defined the duration of PACU stay as the time elapsed from the patient’s arrival in the PACU to their discharge readiness. The peak PAED score was used as an indicator of delirium severity. Adverse events were classified according to the definitions provided by the original study authors.

Information Sources and Search Strategy

Our search was conducted across multiple databases, including MEDLINE (via PubMed), EMBASE (via Ovid), and the Cochrane Central Register of Controlled Trials (Cochrane Library). Additionally, we reviewed the World Health Organization International Clinical Trials Platform Search Portal (ICTRP) and ClinicalTrials.gov to capture both ongoing research and unpublished trials. The complete search strategy is provided in Appendix F. We checked the reference lists of international guidelines and eligible studies (including those awaiting classification) as well as articles citing the eligible studies (including those awaiting classification).

Selection Process

Two independent reviewers (YN and KK) assessed the titles and abstracts to identify potentially relevant studies and examined the full texts to confirm their eligibility. If relevant data were missing, we contacted the original authors. Any disagreements between the two reviewers were resolved through discussion, and when consensus could not be reached, a third reviewer arbitrated (YK).

Data Collection Process

Two reviewers (YN and KK) independently extracted data from the included studies using a standardized data collection form, Rayyan [13]. Disagreements were discussed, and if they could not be resolved, a third reviewer arbitrated (YK).

Data Items

The collected information encompassed the study context, including the primary author, year of publication, and location; study design; study population (number of participants, age, and procedure type); interventions (remimazolam dose); and outcomes (incidence of ED, emergence time, length of PACU stay, severity of delirium, and all adverse events). Disagreements were discussed, and if they could not be resolved, a third reviewer arbitrated (YK).

Risk of Bias Assessment

Two reviewers (YN and KK) independently reviewed and analyzed the risk of bias using the Risk of Bias 2 tool [14]. Disagreements were discussed, and if they could not be resolved, a third reviewer arbitrated (YK).

Effect Measures

We pooled the relative risk ratios (RRs), risk difference (RD), and 95% confidence intervals (CIs) for the binary variable, incidence of ED. We pooled the mean differences and 95% CIs for the continuous variables: emergence time, severity of delirium, and length of PACU stay. We summarized adverse events based on the definition in the original article, but we did not perform a meta-analysis. When both the intention-to-treat and per-protocol effects were reported, we selected the per-protocol effect.

Dealing With Missing Data

When needed, we requested the study authors to provide data that were not included in their study [11]. A meta-analysis was conducted using the data available from the included studies. For results presented as medians with interquartile ranges, we transformed the data to mean ± standard deviation, as proposed by Wan et al. [15].

Assessment of Heterogeneity

We assessed the statistical heterogeneity by visually examining the forest plots and calculating the I² statistic. The interpretation of I² values was as follows: 0% to 40% was considered “might not be important,” 30% to 60% was interpreted as “may represent moderate heterogeneity,” 50% to 90% was regarded as “may represent substantial heterogeneity,” and 75% to 100% was categorized as “considerable heterogeneity.” In cases where substantial heterogeneity (I² > 50%) was identified, we explored potential sources of variability.

Meta-Analysis

Meta-analysis was conducted using Review Manager software (RevMan 5.4, Cochrane Collaboration, London, United Kingdom), and random-effects models were applied.

Subgroup Analysis

To examine the impact of effect modifiers on the outcomes, we conducted subgroup analyses on the primary outcomes, based on different administration patterns of remimazolam (bolus dosage or continuous dosage) [7-9].

Reporting Bias Assessment

We did an extensive literature search for unpublished trials by searching clinical trial registration systems (ClinicalTrials.gov and ICTRP). We assessed the potential publication bias by searching for the trial registrations through ICTRP and ClinicalTrials.gov and the discrepancies between the reported studies and trial registrations.

Certainty Assessment

Two reviewers (YN and KK) assessed the certainty of the evidence using the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach [16]. Disagreements between the reviewers were resolved through discussion, and if consensus could not be reached, a third reviewer arbitrated (YK). In accordance with the Cochrane Handbook [11], a summary of findings (SoF) table was prepared to summarize the results for the incidence of ED, emergence time, severity of delirium, and length of PACU stay.

Results

Search Results and Characteristics of the Included Trials

After removing duplicates, 276 records were retrieved from database searches conducted on June 30, 2024 (Figure 1). In total, 38 reports were identified, and 36 underwent full-text screening for eligibility. Ultimately, 32 reports were excluded, leaving three studies (n = 310) that met all eligibility criteria, including those identified through citation tracking and manual searches (Appendix C) [7-9].

Figure 1: PRISMA 2020 flow diagram for this study

CENTRAL: Cochrane Central Register of Controlled Trials; ICTRP: International Clinical Trials Registry Platform; RCTs: randomized controlled trials; PRISMA: Preferred Reporting Items for Systematic Review and Meta-Analysis

As summarized in Table 1, all included studies [7-9] were carried out in China, with sample sizes of 90-119 per study. This systematic review included three separate studies, each involving procedures performed under general anesthesia with sevoflurane. These studies included bilateral tonsillectomies and adenoidectomies, laparoscopic inguinal hernia repairs, and dental procedures. All studies involved pediatric patients no older than seven years with an ASA-PS classification of I or II. In all studies, saline was used as a placebo control, and remimazolam was used as an intervention in one or two different ways. One study [7] compared it to a single dose of 0.2 mg/kg administered at the conclusion of the surgery, coinciding with the cessation of sevoflurane and nitrous oxide. Another study [9] compared it to either a single dose of 0.2 mg/kg given approximately five minutes before the end of the surgery or a continuous infusion until approximately five minutes before the end of the surgery. The third study [8] compared it to a single dose of either 0.2 mg/kg or 0.1 mg/kg given about five minutes before the end of the surgery.

Figure 2: Risk of bias for each outcome in included studies

References: [7-9]

PACU: post-anesthesia care unit

Primary Outcomes

The SoFs used in this study are listed in Table 2. For more details, see Appendix D.

Figure 3: Forest plot for emergence delirium (risk ratio)

The square for each study (first author and publication year) represents the risk ratio (RR). The corresponding horizontal line indicates a 95% confidence interval (CI). The upper diamond represents the pooled RR of the subgroup (remimazolam 0.2 mg/kg bolus) with a 95% CI. The lower diamond indicates the pooled RR with the 95% CI.

References: [7-9]

Figure 4: Forest plot for emergence delirium (risk difference)

The square for each study (first author and publication year) represents the risk difference (RD) for individual trials. The corresponding horizontal line indicates the 95% CI. The upper diamond represents the pooled RR of the subgroup (remimazolam 0.2 mg/kg bolus) with a 95% CI. The lower diamond indicates the pooled RR with the 95% CI.

References: [7-9]

Emergence time: A bolus of 0.1 mg/kg remimazolam may result in little to no difference in emergence time (one study, 60 participants, mean difference (MD) 0.5 min, 95% CI -0.31 to 1.13, heterogeneity could not be assessed; low certainty evidence). The evidence regarding the effect of a 0.2 mg/kg bolus of remimazolam on emergence time is very uncertain (three studies, 240 participants, MD 2.81 min, 95% CI -1.5 to 7.12, I² = 99%; very low certainty evidence). Continuous infusion of remimazolam may result in a slight increase in emergence time (one study, 80 participants, MD 5.7 min, 95% CI 3.67 to 7.73, heterogeneity cannot be assessed; low certainty evidence) (Figure 5).

Figure 5: Forest plot for emergence time

The square for each study (first author and publication year) represents the mean difference (MD) of individual trials. The corresponding horizontal line indicates the 95% CI. The upper diamond represents the pooled MD of the 0.2 mg/kg remimazolam bolus group with a 95% CI. The lower diamond represents the pooled MD with a 95% CI.

SD: standard deviation; CI: confidence interval

References: [7-9]

Secondary Outcomes

Length of PACU: A bolus of 0.1 mg/kg remimazolam may result in a slight increase in PACU stay (one study, 60 participants, MD 2.10 min, 95% CI 0.55 to 3.65, heterogeneity cannot be assessed; low certainty evidence). The evidence is very uncertain about the effect of a 0.2 mg/kg bolus of remimazolam on PACU stay duration (two studies, 161 participants, MD 2.01 min, 95% CI -4.94 to 8.97, I², 99%; very low certainty evidence) (Appendix A).

Severity of delirium: A bolus of 0.2 mg/kg remimazolam may result in a slight reduction in the severity of delirium (one study, 101 participants, MD -2.30, 95% CI -2.52 to -2.08, heterogeneity cannot be assessed; low certainty evidence) (Appendix B).

The PRISMA 2020 checklist for this study is available in Appendix E.

Discussion

In this study, we investigated the concomitant use of intravenous remimazolam with inhalation anesthesia and its effects on ED in children through an SR/MA. We included three RCTs involving 310 pediatric patients. Although evidence regarding the effect of remimazolam on emergence time is very uncertain, both bolus and continuous infusion of remimazolam may result in a reduction in the incidence of ED. The concomitant use of intravenous remimazolam with inhalation anesthesia may be a feasible option, particularly when physicians are concerned about subsequent ED.

Concomitant use of remimazolam and inhaled anesthetics may reduce ED incidence during general anesthesia in children. In pediatric anesthesia, the concomitant use of propofol is considered among the most effective agents for reducing the risk of ED [4,5]. According to a previous SR/MA, a propofol prophylactic dose of 1 mg/kg significantly reduced the incidence of ED when compared to placebo (RR 0.57, 95% CI, 0.43-0.76) [4]. Another SR/MA showed that propofol, administered at doses between 0.5 mg/kg and 3.0 mg/kg, was effective in reducing the incidence of ED (RR 0.51, 95% CI 0.39-0.67) [5]. These results were similar to those obtained in our analysis. Remimazolam may serve as an alternative when propofol is not suitable due to allergies or other concerns. In addition to propofol, other agents have also been reported to decrease the incidence of ED. An SR/MA using ketamine at doses between 0.25 mg/kg and 1 mg/kg demonstrated that ketamine effectively decreased the incidence of ED in pediatric patients (OR 0.23, 95% CI: 0.11-0.46) [17]. Another SR/MA that included various administration routes of dexmedetomidine showed that dexmedetomidine, regardless of the administration route, was highly effective in reducing ED in pediatric patients. (OR 0.22, 95% CI: 0.16-0.32) [18]. In contrast, a previous network meta-analysis indicated that midazolam was less effective than other agents, such as dexmedetomidine and ketamine, and its preventive effect alone was limited [19]. Although direct comparisons between remimazolam and these agents are limited by background differences in dosage, study design, and surgical procedures, remimazolam may offer similar benefits in preventing ED. Further studies are required to directly compare remimazolam to other agents.

In the prevention of ED, careful consideration must be given to both the effectiveness of the intervention and its potential impact on emergence time. Our study found that the effect of remimazolam on emergence time varied with dose and route of administration. While the administration of remimazolam could cause a minor delay in emergence time compared with its absence, this delay might not have a clinical impact. This aligns with findings from prior SR/MA studies of propofol [4,5], which also showed a small delay in emergence time without a clinically meaningful effect. In children, the context-sensitive half-life of remimazolam is approximately 17 minutes following an infusion lasting an hour [20], whereas that of propofol ranges from 10.4 minutes after a one-hour infusion to 19.6 minutes after a four-hour infusion [21], suggesting that the two agents might be considered pharmacologically equivalent. However, the evidence regarding remimazolam’s effect on emergence time was highly uncertain in our review, making it difficult to assess its clinical implications with confidence.

The primary strength of our study is that it is the first SR/MA to evaluate the efficacy of remimazolam in reducing ED after general anesthesia in children with inhaled anesthetics. Furthermore, we conducted an extensive investigation to identify relevant evidence following the PRISMA guidelines [10] and applied the GRADE approach [16] to assess the certainty of the evidence.

This study has several limitations. First, it included only three studies [7-9], leading to a limited dataset. Second, all the studies were conducted within China and focused on pediatric patients without the inclusion of neonates or infants, which may restrict the generalization of results to other countries or different age groups. Healthcare systems and genetic factors may also influence the effects of remimazolam. Hu et al. demonstrated that genetic factors affect the metabolism of midazolam and similar effects could be seen with remimazolam as well [22]. Therefore, further studies in different populations and genetic backgrounds are necessary to confirm these findings. Previous studies have identified multiple risk factors for ED. In pediatric patients, age, anesthesia methods, preoperative anxiety, and pain have been reported as significant contributors [23]. In adults, particularly older adults, preoperative anxiety, inadequate pain management, opioid use, and type of surgery have been associated with an increased risk of ED [24,25]. Additionally, several risk factors for postoperative delirium have been identified, including advanced age, multiple comorbidities, severity of illness, low functional reserve or frailty, and preexisting cognitive impairment [25,26]. While some of these factors were evaluated in the included studies, their assessment was inconsistent and often incomplete, raising concerns about the generalizability of our findings. Future studies should incorporate more comprehensive documentation of these variables to better evaluate their interactions and overall impact on ED outcomes. Finally, the overall risk of bias varied among the included studies, with some showing “some concerns” or “high risk of bias” in the selection of the reported results. Additional high-quality studies with larger sample sizes are necessary to establish definitive conclusions.

Conclusions

In conclusion, this SR/MA suggests that the concomitant use of remimazolam might decrease the incidence of ED after pediatric anesthesia without a clinically meaningful prolongation of emergence time. Therefore, anesthetists could potentially use remimazolam to reduce ED in children after inhalation anesthesia. While the evidence remains limited, our findings indicate a potential association between remimazolam administration and a reduction in ED incidence. However, variations in study design and sample sizes warrant cautious interpretation. Further, high-quality RCTs are needed to establish definitive conclusions regarding efficacy and safety across diverse populations and to guide their optimal use in clinical practice.

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Appendices

Appendix A

Figure 6: Forest plot for the length of PACU. The square for each study (first author and year of publication) represents the MD of individual trials. The corresponding horizontal line indicates the 95% CI. The upper diamond represents the pooled MD of the 0.2 mg/kg Remimazolam bolus group with a 95% CI. The lower diamond represents the pooled MD with a 95% CI

MD: mean difference; PACU: post-anesthesia care unit

Appendix B

Figure 7: Forest plot for severity of delirium. The square for a study (first author and publication year) represents the MD of individual trials. The corresponding horizontal line indicates the 95% CI. The diamond represents the MD of the 0.2 mg/kg Remimazolam bolus group with a 95% CI

MD: mean difference

Appendix C

Appendix D

Appendix E

Appe