DOI: https://doi.org/10.21203/rs.3.rs-1588876/v1
An appropriately timed tracheostomy for adults receiving prolonged mechanical ventilation may have several benefits of tracheostomy, including decreased use of analgesics and sedatives and expedited rehabilitation. These clinical benefits may contribute to improve patient prognosis. Although randomized control trials (RCTs) and meta-analyses have researched this, each RCT has a different definition of early tracheostomy and report different outcomes. Meta-analyses that integrate results from these RCTs are also difficult to evaluate because of the conceptual heterogeneity due to the different definitions and reported parameters in each RCT. As a result, there is no established evidence for the appropriate timing of tracheostomy. Therefore, our objective was to perform a network meta-analysis (NMA) on multiple tracheostomy timings using data from existing RCTs.
MEDLINE, CENTRAL, ClinicalTrials.gov, and WHO-ICTRP were searched. We included RCTs that included mechanically ventilated patients aged 18 years or older. Multiple reviewers independently selected RCTs to compare tracheostomy timings. Considering the definitions of the timing of tracheostomy and clinical importance, we subdivided RCTs into three groups based on the time of tracheostomy as follows: within 4 days from intubation, 5–12 days, or 13 days or later. We performed the NMA with random effects and used the Confidence in NMA framework to assess the degree of treatment effect certainty. The primary and secondary outcomes were short-term mortality and adverse events, respectively.
Seven RCTs (1,021 patients) were included. There were no specific reasons for intubation, and both traumatic and non-traumatic patients were included. There was a significant difference in short-term mortality when comparing tracheostomies performed within 4 days of intubation and those performed 13 days or later (relative risk 0.65 [95% confidence interval 0.46–0.93]). There were no significant differences in adverse events between any of the examined groups.
Tracheostomy performed within 4 days of intubation may reduce short-term mortality compared with tracheostomy performed 13 days or later. However, early tracheostomy should be considered for critically ill patients based on careful consideration of whether or not intubation will be prolonged, such as patients with severe traumatic brain injury or respiratory failure.
Tracheostomy is an invasive procedure performed in patients who are expected to require prolonged mechanical ventilation or airway management. Previous studies have reported that 13–24% of patients admitted to intensive care units (ICUs) require tracheostomy [1, 2]. There are several benefits of tracheostomy, including decreased use of analgesics and sedatives due to reduced pharyngeal or oral pain and discomfort, and expedited rehabilitation due to reduced use of medication [3]. In this context, early tracheostomy might have beneficial outcomes, such as reduction in ventilator-associated pneumonia (VAP), shorter hospital stays, and reduced mortality. Tracheostomies are also associated with harmful outcomes such as surgical site infection, bleeding, and tracheal stenosis [4]. There is no definitive consensus on an appropriate timing for a tracheostomy. Guidelines for tracheostomy published in 2017 in the United States indicate that tracheostomy should be performed after 21 days of intubation; however, there is no strong evidence for this recommendation [4]. On the other hand, numerous randomised controlled trials (RCTs) have reported the results and risks of different tracheostomy timings, and several meta-analyses have integrated the results of these trials [3, 5, 6]. However, each RCT has a different definition of early tracheostomy and each trial reports different beneficial and harmful outcomes; thus, extracting a well-supported, evidence-based conclusion is challenging [3, 5, 6]. Interpreting the results of meta-analyses that integrate results from these RCTs is also difficult to evaluate because of the conceptual heterogeneity due to the different definitions and reported parameters in each RCT.
There is no established evidence in the form of RCTs or meta-analyses or evidence-based guidelines for the appropriate timing of tracheostomy. Therefore, a network meta-analysis (NMA) is essential for comparing existing RCTs and grouping them according to the timing of tracheostomy, with both beneficial and harmful outcomes accounted for. The results derived from this NMA provide clinical insight into the appropriate timing for tracheostomy, which can improve patient prognosis and decrease associated morbidity and mortality. Therefore, the objective of our study was to perform a NMA on multiple tracheostomy timings using data from the existing RCTs to assess the effect on short-term mortality and adverse events.
We conducted a systematic review and NMA. The protocol was registered in PROSPERO (CRD42021252917). Results are reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for NMA [7] (e-Table 1 in Additional file 1).
We included RCTs, randomised cross-over trials, and cluster RCTs comparing tracheostomy timing. The inclusion criteria were studies including patients who were 1) 18 years of age or older and 2) mechanically ventilated. Included studies were not limited by the reason for mechanical ventilation or the tracheostomy technique. To find tracheostomy timing(s) most associated with improved short-term mortality or reduced adverse events, the period of time required from intubation to tracheostomy was categorised as follows: within 4 days after mechanical ventilation, between 5 and 12 days, and 13 days or later. These periods were determined based on clinical importance, definitions from previous studies, and by including as many studies as possible so that intervention arms could be separated into different treatment groups [8–14].
The primary outcome was short-term mortality, subdivided into mortality within 28 days, 30 days, mortality within the ICU, and in-hospital mortality. The secondary outcome was adverse events associated with tracheostomy, including arrhythmia, bleeding, cardiac arrest, hypoxaemia, infection, inflammation, mispositioning of tracheostomy tube, pneumothorax, subcutaneous emphysema, tracheal or laryngeal symptoms, tracheal stenosis, and tracheoesophageal fistula. If more than one adverse event was reported in one study, the frequency and severity of the adverse event were considered comprehensively to determine which adverse events should be included in our analysis.
The following databases were searched for eligible trials: 1) The Cochrane Central Register of Controlled Trials (CENTRAL) and 2) MEDLINE via PubMed. We also searched for ongoing trials in the following trial registers: 1) The World Health Organization International Clinical Trials Platform Search Portal (ICTRP) and 2) ClinicalTrials.gov. We did not set any limitation for language or the year of publication. Details of the search strategies are described in e-Table 2 in Additional file 2. If there were unknown or unclear data, we attempted to contact the authors in each study to clarify any questions. All databases were last searched on November 25, 2021.
Two of the three physicians and co-authors of this study (HO, FF, and YK) screened the title, abstract, and full text during the first and second screenings for relevant studies; HO, FF, and YK extracted data from eligible studies into standardised data forms. We contacted the authors of abstract-only studies that could not be evaluated according to the eligibility criteria. Any disagreements between two reviewers were resolved by discussion or with a third reviewer. Data extraction during the second screening was performed by HO, FF, and YK using the Review Manager (RevMan) software V.5.4 tool [15].
The risk of bias for primary and secondary outcomes was independently assessed by two physicians (HO and FF) using the Cochrane Risk of Bias tool 2.0 [16]. Each bias from relevant studies was graded as “low risk”, “unclear risk”, or “high-risk” and discrepancies between reviewers were resolved by discussion.
We used forest plots for the meta-analysis, and effect size is expressed as relative risk (RR) with 95% confidence interval (CI). Outcome measures were pooled using a random effect model to take each study’s specific effects measures into account. Using RevMan 5.3 (RevMan 2014) [15], a two-sided p-value of < 0.05 denoted a significant difference for all analyses. Study heterogeneity for each outcome was assessed by visual inspection of the forest plots and the value of the square of I (I2). In addition, the assessment of I2 was as follows: 0–40%, might not be important; 30–60%, moderate heterogeneity; 50–90%, substantial heterogeneity; and 75–100%, considerable heterogeneity. When the value of I2 was above 50%, heterogeneity was assumed, and we investigated the reason using the chi-square test (p-value). If ≥ 10 studies were available, funnel plots, Begg’s adjusted rank correlation test, and Egger’s regression asymmetry test were used to test for the possibility of publication bias with RevMan 5.3 (RevMan 2014) [15]. If ≥ 10 studies could not be included for each outcome, funnel plot asymmetry would not be tested.
A network plot was constructed to determine the number of studies and patients included in this NMA. We performed NMA using a frequentist-based approach with multivariate random effects, and effect size is expressed as RR (95% CI). A two-sided p-value of < 0.05 denoted significant difference for all analyses using R version 4.0.3 (R Core Team. 2020 R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria.). The NMA itself was performed using the framework of Confidence in Network Meta-Analysis (CINeMA) [17]. The approach of CINeMA is based on the GRADE Framework, which consists of multiple components as outlined below.
Transitivity was evaluated by comparing the distribution of clinical and methodological variables that could act as effect modifiers across treatment comparisons.
Ranking plots expressed by P-scores were constructed to consider the probability that a given treatment had the highest event rate for each outcome. P-scores were calculated using R version 4.0.3.
The assessment of the risk of bias across studies was determined using results from the pairwise meta-analysis. Whether bias across studies was considered “suspected” or “undetected” was determined based on the presence or absence of publication bias indicated by direct comparison.
The assessment of indirectness of each study was determined based on each study’s relevance to the research question, and consisted of the study population, interventions, outcomes, and study setting. Indirectness was classified as low, moderate, or high.
The assessment of imprecision was determined based on the width of the 95% CI of each analysis. We considered 95% CI of RR estimates below 0.75 and above 1.33 as clinically important.
The assessment of heterogeneity was determined by comparing the posterior distribution of the estimated heterogeneity variance and predictive distribution [18]. Consistency across assessments, based on CI and prediction intervals, was used to assess the importance of heterogeneity. We considered prediction intervals of RR below 0.75 and above 1.33 as clinically important.
Inconsistency was assessed based on inconsistency factors and their uncertainty; the design-by-treatment interaction test was used [19]. The assessment of incoherence was as follows: comparisons informed only by direct evidence, with no disagreement between evidence sources, no concern; only indirect evidence was included, some concern; and if the p-value of the design-by-treatment interaction test was < 0.05, major concern.
We identified 2,617 citations. After duplicates were removed, 2,163 studies remained. Of these, we assessed 88 full-text articles after excluding 2,005 reports based on the titles and abstracts. We included seven trials, with 1,021 participants total (e-Fig. 1. in Additional file 3) [8–14]. None of the studies were a three-group study. Four studies compared tracheostomy within 4 days after intubation vs. 13 days or later [8, 9, 12, 13], two studies compared tracheostomy within 4 days vs. 5–12 days [11, 13], and one study compared tracheostomy 5–12 days vs. 13 days or later after intubation [10] (Fig. 1a, 1b, and e-Table 3). The characteristics of each study included in this meta-analysis are summarised in e-Table 4 in Additional file 3. The main reason for ICU admission was critical illness with mixed trauma and non-trauma, followed by surgery. Overall, there was no evidence of concern about the transitivity across the comparisons.
The risk of bias within included studies is shown in e-Table 5–8 in Additional file 3. The participants and clinicians of all studies were not blinded, but the evaluation of outcome may have been minimally affected; therefore, performance bias was thought to be low. On the other hand, the selection bias of almost all studies was high, since certain numbers of patients were assigned to the late tracheostomy group but did not undergo tracheostomy. However, almost all other domains of the risk of bias were low (e-Table 6–8 in Additional file 3). Almost all studies were judged as having a high risk of bias for outcomes because of those judgements (risk of bias across studies) (Fig. 1a, 1b).
The results of pairwise comparisons of short-term mortality and adverse events between studies are shown in e-Table 9a, 10a, and 11a in Additional file 3. The funnel plot of each outcome was not described because the number of studies included for each comparison was less than 10.
Seven studies were included in the analysis of short-term mortality. Compared with tracheostomy performed within 4 days after intubation, 5–12 days displayed RR 0.68 ([95% CI 0.41–1.13]: very low certainty); and 13 days or later displayed RR 0.65 ([95% CI 0.46–0.93]: very low certainty). Comparing 5–12 days with 13 days or later yielded the following results: RR 0.96 ([95% CI 0.59–1.56]: very low certainty) (Table 1, Fig. 2a, and e-Table 12a, 13a, and 14a in Additional file 3). There was significant difference only when comparing between 4 days and 13 days or later; no significant difference was detected between within 4 days and 5–12 days, or between 5–12 days and 13 days or later.
Table 1. Each estimated value and details of assessments of certainty of estimates from NMA of the timing of tracheostomy of short-term mortality
|
|
Direct risk ratio (95% CI) |
Certainty |
Indirect risk ratio (95% CI) |
Certainty |
Network meta-analysis risk ratio (95% CI) |
Certainty |
|
|
Within 4 days vs. 5–12 days |
0.55 (0.26–1.15) |
⨁⨁◯◯ Low |
0.82 (0.41–1.66) |
⨁◯◯◯ Very low |
0.68 (0.41–1.13) |
⨁◯◯◯ Very low |
|
|
Within 4 days vs. 13 days or later |
0.69 (0.47–1.01) |
⨁⨁◯◯ Low |
0.46 (0.18–1.18) |
⨁⨁◯◯ Low |
0.65 (0.46–0.93) |
⨁◯◯◯ Very low |
|
|
5–12 days vs. 13 days or later |
0.84 (0.46–1.52) |
⨁◯◯◯ Very low |
1.25 (0.55–2.88) |
⨁◯◯◯ Very low |
0.96 (0.59–1.56) |
⨁◯◯◯ Very low |
|
Abbreviations: CI, confidence interval
Confidence in the RR of each comparison and short-term mortality assessed by the GRADE system is shown in Figure 3a. Reporting bias, indirectness, and incoherence of RRs were not observed for any of the three comparisons. The judgement of incoherence was based on the p-values of inconsistency (e-Table 15a and 16a in Additional file 3). Imprecision of RRs between each comparison was as follows: within 4 days vs. 5–12 days, some concerns; within 4 days vs. 13 days or later, no concerns; and 5–12 days vs. 13 days or later, major concerns. The 95% CI of RR between within 4 days and 13 days or later extended into clinically important effects. The 95% CI of RR between 5–12 days and 13 days or later extended into clinically important effects in both directions (Table 1). Heterogeneity of RRs between each comparison was as follows: within 4 days vs. 5–12 days, some concerns; within 4 days vs. 13 days or later, major concerns; and 5–12 days vs. 13 days or later, no concerns. Prediction interval of RR within 4 days and 13 days or later extended into clinically important effects in both directions, and 5–12 days and 13 days or later extended into clinically important or unimportant effects. (e-Table 17a in Additional file 3). The ranking analysis results are shown in Table 2. The hierarchy for efficacy in reducing short-term mortality was within 4 days (P-score 0.96) > 5–12 days (P-score 0.32) > 13 days or later (P-score 0.22).
Table 2. P-scores for treatment of short-term mortality and adverse events.
|
|
Short-term mortality |
Adverse event |
|
Within 4 days |
0.96 |
0.95 |
|
5–12 days |
0.32 |
0.15 |
|
13 days or later |
0.22 |
0.40 |
Adverse events
Six studies were included in the analysis of adverse events. Compared with tracheostomy performed within 4 days after intubation, 5–12 days showed an RR of 0.45 ([95% CI 0.16–1.25]: very low certainty) and 13 days or later had an RR of 0.63 ([95% CI 0.38–1.04]: very low certainty). Comparing 5–12 days with 13 days or later, the finding was as follows: RR 1.41 ([95% CI 0.56–3.54]: very low certainty) (Table 3, Fig. 2b, and e-Table 12b, 13b, and 14b in Additional file 3). There was no significant difference within each comparison. Confidence in the RR of each comparison and adverse events assessed by the GRADE system is shown in Figure 3b. Reporting bias, indirectness, and incoherence of RRs were not observed for any of the three comparisons. The judgement of incoherence was based on the p-values of inconsistency (e-Table 15b and 16b in Additional file 3). Imprecision of RRs between each comparison was as follows: within 4 days vs. 5–12 days, some concerns; within 4 days vs. 13 days or later, major concerns; and 5–12 days vs. 13 days or later, some concerns. The 95% CI of RR between within 4 days and 13 days or later, and 5–12 days and 13 days or later, both extended into clinically important effects. Moreover, the 95% CI of RR between within 4 days and 13 days or later extended into clinically important effects in both directions (Table 1). Heterogeneity of RRs between each comparison was as follows: within 4 days vs. 5–12 days, some concerns; within 4 days vs. 13 days or later, no concerns; and 5–12 days vs. 13 days or later, some concerns. Prediction interval of RR within 4 days and 13 days or later, and 5–12 days and 13 days or later, extended into clinically important effects in both directions (e-Table 17b in Additional file 3). The ranking analysis results are shown in Table 3. The hierarchy for efficacy in reducing short-term mortality was within 4 days (P-score 0.95) > 13 days or later (P-score 0.40) > 5–12 days (P-score 0.15).
Table 3. Each estimated value and details of assessments of certainty of estimates from NMA of the timing of tracheostomy of adverse events
|
|
Direct risk ratio (95% CI) |
Certainty |
Indirect risk ratio (95% CI) |
Certainty |
Network meta-analysis risk ratio (95% CI) |
Certainty |
|
Within 4 days vs. 5–12 days |
0.20 (0.01–4.00) |
⨁⨁◯◯ Low |
0.50 (0.17–1.49) |
⨁◯◯◯ Very low |
0.45 (0.16–1.25) |
⨁◯◯◯ Very low |
|
Within 4 days vs. 13 days or later |
0.65 (0.39–1.07) |
⨁◯◯◯ Very low |
0.26 (0.01–6.02) |
⨁◯◯◯ Very low |
0.63 (0.38–1.04) |
⨁◯◯◯ Very low |
|
5–12 days vs. 13 days or later |
1.29 (0.49–3.40) |
⨁◯◯◯ Very low |
3.23 (0.15–66.7) |
⨁◯◯◯ Very low |
1.41 (0.56–3.54) |
⨁◯◯◯ Very low |
Abbreviations: CI, confidence interval
In our NMA for short-term mortality, there was significant difference in the comparison results of tracheostomy performed within 4 days after intubation and 13 days or later (RR 0.65 [95% CI 0.46–0.93]). In NMA for adverse events, there were no significant differences in all comparisons. In addition, ranking analysis of short-term mortality and adverse events were as follows: within 4 days (P-score 0.96) > 5–12 days (P-score 0.32) > 13 days or later (P-score 0.22) and within 4 days (P-score 0.95) > 13 days or later (P-score 0.40) > 5–12 days (P-score 0.15). In summary, compared with tracheostomy performed 13 days or later after intubation, tracheostomy within 4 days might lower short-term mortality. However, the upper limit of the 95% CI was close to 1, and it is difficult to conclude that there is a benefit.
In our NMA, in the comparison between tracheostomy within 4 days after intubation vs. 13 days or later, the significant decrease in mortality in the group of within 4 days might have been influenced by the rehabilitation and decreased dosage of sedative drug due to the decreased physical restraint and improved activity. The RCTs included in our NMA did not report results on the implementation of rehabilitation, but two RCTs did report on the use of sedative drugs [8, 13]. Rumbak et al. compared tracheostomy within 2 days after intubation with 14-16 days after in 120 patients admitted to the ICU. The duration of sedation (mean ± standard deviation [SD]) was significantly shorter in the early tracheostomy group (3.2 ± 0.4 vs. 14.1 ± 2.9 days; p < 0.001) [8]. Similarly, Bösel et al. compared tracheostomy within 3 days after intubation and 7–14 days after for 60 patients with severe stroke, and the rate of sedative drug use and ICU stay was significantly shorter in the early tracheostomy group (62% vs. 42%; p = 0.02) [13]. However, previous studies suggest that muscle strength showed improvement and ventilator-free days are shortened by enhanced rehabilitation [20], and that prognoses improved through the decreased use of sedative drugs [21, 22]. As the pathophysiological benefits of enhanced rehabilitation and decreased use of sedative drugs are apparent, the benefit attributed to early tracheostomy is arguable. It should also be noted that the results of our NMA suggest that early tracheostomy might improve the prognosis in patients who require tracheostomy. All RCTs included patients who were predicted to require tracheostomy; therefore, the results of our NMA are not applicable to patients who are not predicted to require tracheostomy. If patients who are predicted to require tracheostomy are identified earlier and more accurately, the possibility of performing an early tracheostomy in the optimal population may result in improved patient prognoses. Therefore, for future studies, a model for accurately predicting patients who need tracheostomy might be beneficial.
Two RCTs included in our NMA reported different results regarding short-term mortality when comparing tracheostomy within 4 days after intubation vs. 13 days or later [9, 12]. The reason for the difference in results might be that the patients included in these RCTs were less severely ill, and the timing of tracheostomy might have had a lesser effect on mortality. Zheng et al. compared tracheostomy on 3 days after intubation vs. 15 days for 119 patients admitted to the ICU, and 28-day mortality was similar in both groups (13.8% vs. 9.8%; p = 0.55) [12]. The mean value of Acute Physiology and Chronic Health Evaluation II scores in both groups was 19.5 with a predicted mortality rate of 10%–20%, which is not severe. Therefore, due to the low severity of the disease, it is possible that there was no difference in 28-day mortality [23]. Alternatively, Blot et al. compared tracheostomy within 4 days vs. 14 days after intubation for 123 patients admitted to the ICU [9]. The median value of Simplified Acute Physiology Score II for both groups was 50, and the predicted mortality rate was 40%–50%, but there was no difference in 28-day mortality (20% vs. 24%; p = 0.62) [9, 24]. However, in this study, 60 patients (98%) in the early tracheostomy group underwent a tracheostomy compared with only 16 patients (26%) in the late tracheostomy group. Although the study does not provide any justification for this, we presume that patients in the late tracheostomy group who did not undergo tracheostomy may have been extubated. The severity of patient conditions included in this study was high at the time of inclusion; however, over time, the severity of respiratory failure and their prognosis may have improved. Therefore, the 28-day mortality in the late tracheostomy group might have been underestimated, and there would have been no difference in 28-day mortality in this study without bias.
The results of our NMA might be useful for selecting an appropriate timing of tracheostomy for critically ill patients because tracheostomy performed within 4 days from intubation might reduce short-term mortality in a greater proportion of patients (27–209 patients per 1000) than tracheostomies 13 days or later after intubation. This means that, in patients who are predicted to be on prolonged intubation for more than 13 days and who are tracheostomy candidates, tracheostomy performed within 4 days might reduce short-term mortality. Empirically, patients with severe traumatic brain injury (TBI) or severe respiratory failure are predicted to be on prolonged intubation for more than 13 days. Therefore, it might be important and beneficial to consider an early tracheostomy for these patients, as they are critically ill and predicted to be on prolonged intubation.
There are some limitations in our NMA. First, different grouping for tracheostomy timing might yield different results. In our NMA, we divided the patients into three groups to ensure clinical validity and inclusion of as many studies as possible. This means that, for example, RCTs comparing tracheostomy within 5 days after intubation vs. 5 days after were excluded because they did not fit into our grouping. If the groups were subdivided for smaller time spans or different study methods and if different RCTs were included, our NMA may have yielded different results. Second, the results of our NMA might not be wholly accurate because the number of patients who underwent tracheostomies in the late tracheostomy group in each of the RCTs differed significantly. For example, in a study by Blot et al., only 26% of patients in the late tracheostomy group underwent tracheostomy [9]. In contrast, in the studies by Koch et al. and Bösel et al., 100% of patients in the late tracheostomy group underwent tracheostomy [11, 13]. If extubation was a common reason for not performing tracheostomy, patients with good prognoses were analysed as the late tracheostomy group and the mortality rate may have been underestimated. Therefore, in our NMA, the short-term mortality of the tracheostomy 5–12 days after intubation group and 13 days or later group might have been underestimated, resulting in skewed or inaccurate results. Third, due to the conceptual heterogeneity of the integrated studies, the results of our NMA might not be as reliable as they seem. In other words, if the NMA was limited to a specific clinical cause for ICU admission (i.e.,, disease), different results might have been obtained. For example, in patients with severe TBI who are expected to be on prolonged intubation, early tracheostomy will allow for more enhanced rehabilitation earlier than usual. Thus, early tracheostomy might lead to a decrease in VAP and an improvement in ADLs, thereby leading to better prognoses. Fourth, the number of patients included in our NMA were insufficient for detecting statistically significant differences. An example would be 160 patients included for the comparison of tracheostomy within 4 days after intubation vs. 5–12 days and short-term mortality in our NMA; thus, 160 patients may not have been enough to yield generalisable results. If more knowledge about this subject is accumulated in the future and more studies or patients are included in future NMAs, different results might be obtained. Finally, the results of our NMA were influenced by the effect modifier; patients included in the RCTs in our NMA differed in the causes of respiratory failure and the severity of illness in each study, which might have been effect modifiers. In addition, there are other factors that might have been effect modifiers, such as the use or no use of sedative drugs, organ failure, and the dose of sedative administered. Therefore, the analysis of our NMA might have been influenced by these effect modifiers.
Tracheostomy performed within 4 days after intubation might reduce short-term mortality compared with tracheostomy 13 days or later after intubation (RR 0.65 [95% CI 0.46–0.93]). However, early tracheostomy should be considered for critically ill patients based on careful consideration of whether or not intubation will be prolonged, such as patients with severe TBI or respiratory failure.
CI, confidence interval; ICU, intensive care unit; NMA, network meta-analysis; RCT, randomised controlled trials; RR, risk ratio; VAP, ventilator-associated pneumonia
Ethics approval and consent to participate
The protocol was registered in PROSPERO (CRD42021252917) and consent to participate was not needed.
Consent for publication
Not applicable.
Availability of data and materials
Dataset is available on request, accompanied by an appropriate scientific rationale and research plan.
Competing Interests
The authors declare no conflict of interest.
Funding
Not applicable.
Author contributions
YK, HY and MK conceived and designed the analysis. YK, HO and FF screened the records and extracted the data. YK performed the analysis under the supervision of HY. YK interpreted the results and drafted the manuscript. HY, MK and TM provided revisions to the manuscript. All authors read and approved the final manuscript.
Acknowledgments
The authors acknowledge the support of Editage (www.editage.jp) for English language editing.
Authors' information (optional)
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