Key PointsQuestion
Is the timing of tracheostomy placement in critically ill patients associated with the rate of ventilator-associated pneumonia and duration of mechanical ventilation?
Findings
This meta-analysis assessed findings from 17 randomized clinical trials with 3145 participants and found that early tracheotomy in adults undergoing ventilator support for critical illness was associated with improved clinical outcomes.
Meaning
These findings suggest that tracheostomy placement no more than 7 days after ventilator support may lower the rates of ventilator-associated pneumonia and ventilator duration.
Importance
The timing of tracheostomy placement in adult patients undergoing critical care remains unestablished. Previous meta-analyses have reported mixed findings regarding early vs late tracheostomy placement for ventilator-associated pneumonia (VAP), ventilator days, mortality, and length of intensive care unit (ICU) hospitalization.
Objective
To compare the association of early (≤7 days) vs late tracheotomy with VAP and ventilator days in critically ill adults.
Data Sources
A search of MEDLINE, CINAHL, Cochrane Central Register of Controlled Trials, references of relevant articles, previous meta-analyses, and gray literature from inception to March 31, 2020, was performed.
Study Selection
Randomized clinical trials comparing early and late tracheotomy with any of our primary outcomes, VAP or ventilator days, were included.
Data Extraction and Synthesis
Two independent reviewers conducted all stages of the review. The Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was followed. Pooled odds ratios (ORs) or the mean difference (MD) with 95% CIs were calculated using a random-effects model.
Main Outcomes and Measures
Primary outcomes included VAP and duration of mechanical ventilation. Intensive care unit days and mortality (within the first 30 days of hospitalization) constituted secondary outcomes.
Results
Seventeen unique trials with a cumulative 3145 patients (mean [SD] age range, 32.9 [12.7] to 67.9 [17.6] years) were included in this review. Individuals undergoing early tracheotomy had a decrease in the occurrence of VAP (OR, 0.59 [95% CI, 0.35-0.99]; 1894 patients) and experienced more ventilator-free days (MD, 1.74 [95% CI, 0.48-3.00] days; 1243 patients). Early tracheotomy also resulted in fewer ICU days (MD, −6.25 [95% CI, −11.22 to −1.28] days; 2042 patients). Mortality was reported for 2445 patients and was comparable between groups (OR, 0.66 [95% CI, 0.38-1.15]).
Conclusions and Relevance
Compared with late tracheotomy, early intervention was associated with lower VAP rates and shorter durations of mechanical ventilation and ICU stay, but not with reduced short-term, all-cause mortality. These findings have substantial clinical implications and may result in practice changes regarding the timing of tracheotomy in severely ill adults requiring mechanical ventilation.
Tracheotomy is a commonly performed procedure for patients requiring prolonged mechanical ventilation.1 Benefits from a tracheotomy include patient comfort and less exposure to sedatives.2,3 Evidence also suggests that tracheotomies improve pulmonary recruitment and decrease the length of hospitalization in severely ill patients.4,5 Accordingly, earlier tracheostomy placement may provide benefit in adults requiring prolonged assisted ventilation.
Despite multiple trials, the optimal timing of tracheostomy placement is still an area of contention. Previous meta-analyses assessing early vs late tracheotomy6-10 have demonstrated differing results on clinical outcomes. For instance, no difference was found for the duration of mechanical ventilation, incidence of ventilator-associated pneumonia (VAP), or short-term mortality between early vs late tracheotomy in studies by Szakmany et al11 and Hosokowa et al.12 However, a study by Siempos and colleagues6 showed that early tracheotomy lowered the incidence of VAP, but no difference was noted for short-term mortality. Similar to previous findings, a Cochrane review13 concluded that mortality at 28 days was similar between early and late tracheotomy, yet survival was improved in the early intervention group when observed at long-term follow-up.
Starting in 2014, several large-scale trials2,14,15 have attempted to untangle these questions. These trials have not been incorporated in most meta-analyses, and incorporating these studies may address the inconsistencies reported on the topic. Thus, our objective was to collate, critically appraise, and analyze all randomized clinical trials examining the effects of timing of tracheotomy on the primary outcomes of incidence of VAP and duration of mechanical ventilation and secondary outcomes of short-term, all-cause mortality and intensive care unit (ICU) days.
We conducted a systematic review and meta-analysis according to recommendations from the Cochrane Handbook for Systematic Reviews of Interventions and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. The protocol was submitted to PROSPERO international prospective register of systematic reviews.
Two investigators (K.C. and A.M.) systematically searched MEDLINE, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and the Cochrane Central Register of Controlled Trials from inception of the database to March 31, 2020. Search terms included (tracheostomy OR tracheotomy) AND (early OR late OR timing) (eMethods in the Supplement). Searches within MEDLINE and Cochrane Registry were filtered for clinical trials. Furthermore, we manually searched references from the retrieved articles and reviewed conference proceedings.
There was no limit for language, location, or sample size for included studies. Last, we reviewed previously published meta-analyses on early vs late tracheotomy and supplemented additional articles that were not found in our original search. Two investigators (K.C. and A.M.) independently reviewed the titles and abstracts of all citations to determine suitability based on our primary outcomes. This was followed by independent review of the full-text articles to confirm eligibility. Disagreements were reviewed by a third author (A.H.).
Studies were included if they were randomized clinical trials that compared early vs late tracheotomy and reported the incidence of VAP or ventilator days. Studies that randomized patients to no tracheotomy (eg, prolonged intubation) were assigned to the late tracheotomy group. We included all approaches (eg, percutaneous vs surgical tracheotomy) and accepted studies that enrolled critically ill adult patients (≥18 years) admitted to any ICU setting (eg, medical, surgical, or burn). We excluded studies in children and neonates because the threshold for tracheostomy placement in this population differs from that for adults. Retrospective studies, case reports, clinical overviews, editorials, commentaries, and practice guidelines were also excluded.
Two authors (K.C. and A.M.) independently extracted study data specific for patient characteristics, interventions, and clinical outcomes using a standardized collection form in Excel, version 2007 (Microsoft Corporation). Disagreements were resolved after thorough discussion with the panel of investigators. We collected the following data: first author, country of origin, study period, clinical setting, sample size, age of patients, sex, and day of tracheostomy placement.
To assess the risk of bias in randomized clinical trials (RCTs), the investigators used the Cochrane Collaboration tool. This guide is structured into 5 domains that evaluate different aspects of trial design, conduct, and reporting. The domains are characterized by a series of questions examining selection, performance, detection, attrition, and reporting bias. The risk of bias in each domain can be judged as high, low, or unclear. Studies were deemed as having moderate risk of bias if they had 2 high-risk components and high risk of bias with 4 or more high-risk components. Studies with low risk of bias and those with no more than 3 risk of bias domains judged as unclear were included in the meta-analysis.
Early tracheotomy was defined as intervention no more than 7 days after initiation of mechanical ventilation. We defined late as tracheostomy placement after 7 days or no tracheotomy. If a study defined early tracheotomy after 7 days, we did not include the study in this review. We had 2 distinct primary outcomes: VAP and mechanical ventilator days. Studies that provided data on at least 1 of our primary outcomes were included in the review. If the primary outcome was assessed multiple times during the hospitalization (eg, 30-day VAP vs VAP during the entire hospitalization), we chose the earliest point. Secondary outcomes included (1) short-term, all-cause mortality, defined as death in the first 30 days of hospitalization, and (2) ICU days.
Data from each study were tabulated and checked by investigators (K.C. and A.M.). Continuous data were recorded as mean with SD. If outcome data were presented as median with interquartile range, we calculated the mean (SD) per Wan et al.16
For categorical data, we aggregated the number of patients who had each outcome per total number of patients in that group. Continuous variables were presented as mean differences (MDs) with 95% CI, whereas dichotomous variables were presented as pooled odds ratios (ORs) with 95% CI. All analyses used random effects (DerSimonian and Laird approach) with significance defined as 2-sided P < .05.17
Given the range of participants, inclusion criteria, timing of procedure, and outcome measures, we expected our review to have variability (eg, heterogeneity). As such, we calculated the statistical heterogeneity using the I2 statistic, which provides a percentage of the variability in effect estimates. If I2 was ≥50%, we performed a sensitivity analysis (eg, recalculated the meta-analysis) by removing 1 article at a time (guided by highest I2) until the sensitivity was below our threshold of 50%.18 To evaluate publication bias, we created funnel plots. Funnel plots scatter the studies according to their size, effect estimate, and SE of the effect estimate. Because precision improves with larger studies, their representation in funnel plots is typically scattered toward the peak. Ideally, the plot should have a symmetrical distribution (eg, low publication bias). All statistical analyses were performed in R, version 3.6.2 (R Program for Statistical Computing).
Identification of Eligible Studies
Our electronic search yielded 474 publications, of which 47 were reviewed in full. A total of 17 trials3,4,14,19-32 met inclusion criteria and were described in the systematic review. Meta-analyses were performed in the 14 studies3,4,14,22-32 that were deemed low risk of bias. The flow diagram of selected articles is shown in Figure 1.
The Table provides study details of the combined population of 3145 patients (1619 in the early tracheotomy group vs 1526 in the late tracheotomy group). Fourteen trials were conducted in the medical and/or surgical ICU, and 9 studies14,22-26,28,30,31 (52.9%) were performed in Europe. Patients included had a variety of indications for being intubated, and trials varied with respect to definitions of early vs late tracheotomy. The patient population was predominantly male (1975 of 3070 [64.3%], with 2 trials not reporting sex) with a mean (SD) age ranging from 32.9 (12.7) to 67.9 (17.6) years.
Overall, 14 clinical trials3,4,14,22-32 were deemed to have low risk of bias, and 3 trials19-21 had moderate to high risk of bias. Most of the RCTs (14 trials3,4,14,19-21,23-27,29,30,32 [83.4%]) were classified as unclear risk for the domain pertaining to detection bias. Three trials (17.6%)19-21 had a high risk for random sequence generation, whereas selective reporting was the domain with the lowest risk of bias. A more detailed description of the risk of bias table can be found in the eTable in the Supplement.
The incidence of VAP was lower in patients with mechanical ventilation who underwent early tracheotomy compared with late tracheotomy (OR, 0.59 [95% CI, 0.35-0.99]; I2 = 64%; 1894 patients) (Figure 2). Our other primary outcome was duration of mechanical ventilation, and this was expressed as ventilator days (10 trials3,4,23-29,32 [58.8%]) and ventilator-free days (4 trials14,22,30,32 [23.5%]). Early tracheotomy was not associated with any change in ventilator days (MD, −2.40 [95% CI, −5.09 to 0.29] days; I2 = 92%; 1610 patients) (Figure 3A). In contrast, early tracheotomy was associated with more ventilator-free days with an MD of 1.74 (95% CI, 0.48-3.00 days; I2 = 0%; 1243 patients) (Figure 3B).
Early tracheotomy was not associated with reduced short-term, all-cause mortality. The pooled OR for 2445 patients was 0.66 (95% CI, 0.38-1.15; I2 = 59%) (Figure 4). Duration of ICU stay was decreased in the early tracheotomy cohort, with a pooled MD of −6.25 (95% CI, −11.22 to −1.28) days (I2 = 96%; 2042 patients) (eFigure 1 in the Supplement). Two RCTs22,32 (11.8%), with a total of 538 individuals, showed improvement in ICU-free days in the early group (MD, 2.09 [95% CI, 0.58-3.60]; I2 = 15%) (eFigure 2 in the Supplement).
Sensitivity Analysis and Publication Bias
We conducted sensitivity analyses on primary outcomes with high heterogeneity (I2 ≥50%). After removal of 2 RCTs14,27 with high heterogeneity, the incidence of VAP remained lower in the early tracheotomy group compared with the late tracheotomy group (OR, 0.60 [95% CI, 0.38-0.96]; I2 = 49%) (eFigure 3 in the Supplement). For duration of mechanical ventilation, 4 trials4,26,27,29 had high heterogeneity and were removed for sensitivity analysis. Early tracheotomy was associated with decreased mechanical ventilation time (MD, −2.80 [95% CI, −4.65 to −0.95]; I2 = 30%) (eFigure 4 in the Supplement). Sensitivity analysis showed no benefit in short-term, all-cause mortality in the early tracheotomy group (OR, 0.75 [95% CI, 0.43-1.31]; I2 = 37%) (eFigure 5 in the Supplement). For ICU days, 3 trials26,28,30 remained after removing those with high heterogeneity. Early tracheotomy reduced ICU days by an MD of −4.48 (95% CI, −7.94 to −1.02) days (I2 = 37%) (eFigure 6 in the Supplement).
Publication bias was low for all primary and secondary outcomes. Plots can be viewed in eFigures 7 to 11 in the Supplement.
Our systematic review and meta-analysis of 17 RCTs showed that early tracheotomy was associated with improvement in 3 major clinical outcomes: VAP, ventilator-free days, and ICU stay. No difference was noted in mortality between early vs late tracheotomy. Herein, we supply an updated comprehensive systematic review and robust meta-analysis comparing clinical outcomes for early and late tracheotomy in critically ill adult patients.
Our findings indicate that early tracheotomy (≤7 days) may reduce the incidence of VAP. This is in congruence to the meta-analysis by Siempos and colleagues.6 Our results are also in accordance with the findings by Wang et al,10 in which their OR of 0.65 favored early tracheotomy. This outcome is clinically important because VAP is the most common nosocomial infection in the ICU setting.33 Evidence supports that patients diagnosed with VAP have longer ICU and hospital stays, incur higher hospital costs, and have an increased risk for mortality.22,34
Other notable findings in this review included the benefit of early tracheotomy on ventilator-free days and ICU stay. These findings align with the meta-analysis conducted by Hosokawa and colleagues.12 Their MD in ventilator days was slightly higher than ours (2.12 vs 1.74 days), but most likely owing to differences on how medians and/or means were handled prior to analysis. Unlike a meta-analysis published in 2015,11 we observed a decrease in ICU stay when patients underwent early tracheostomy placement. This is most likely attributable to the addition of several trials after 2014.14,21,23,24 A more recent review also concluded that early tracheotomy reduced ICU days.35 Our initial analysis of early tracheotomy on ventilator days did not show benefit; however, the heterogeneity was significantly high at an I2 of 92%. After removing outliers, sensitivity analysis suggests that early tracheotomy may also reduce ventilator days.
Timing of tracheostomy placement on overall mortality is a controversial topic in the field. Our study demonstrated that early tracheostomy placement was not associated with improved short-term, all-cause mortality (eg, first 30 days in the ICU). We are fully cognizant that this outcome is speculative given that mortality was a secondary outcome and our study inclusion focused on VAP and/or ventilator days. Regardless of this shortcoming, many previous meta-analyses have failed to show that early tracheotomy improves the rate of short-term mortality. On the contrary, early tracheotomy may provide benefit in the long-term assessment of survival. For instance, a Cochrane review by Andriolo et al13 and the meta-analysis by Hosokowa et al12 concluded that early tracheotomy reduced mortality at the longest follow-up time and when evaluated as a composite of 6-month, 1-year, and hospital mortality, respectively.
In view of the current coronavirus disease 2019 (COVID-19) pandemic, important messages from the present study can be translated. For example, a substantial number of patients positive for COVID-19 require long periods of mechanical ventilation and care in the ICU, posing tremendous challenges to health care systems.36 It is possible that early tracheostomy placement may facilitate weaning from the ventilator and potentially increase the availability of ICU beds, mechanical ventilators, and clinicians.
This study has several limitations. First, we included patients with diverse diseases and admitted in multiple ICU settings. Although this led to a more global approach to our primary question, the differences between the ages and disease processes may have influenced our outcomes. For instance, the inclusion of patients in the neuro-ICU may have led to some of the positive findings observed. Many of the studies that we include are single-center trials, which inherently affects the generalizability of our findings. Because some RCTs took more than 5 years to complete, the role new protocols, guidelines, or clinical decisions have with the overall effect is also brought into question. The implementation of multidisciplinary teams that consist of clinicians, respiratory therapists, otolaryngologists, speech language pathologists, nurses, and family members have improved overall tracheotomy outcomes.37,38
Another limitation involved the range in severity of illness for participants. In some trials, the mean Acute Physiology and Chronic Health Evaluation II score was as low as 10 whereas in others it was as high as 27.4. In addition, we limited the study population to adults and therefore excluded 2 studies involving children.39,40
Using a systematic review and meta-analysis approach, we examined whether clinical differences were evident in early vs late tracheotomy in critically ill adults. In a combined analysis of 17 trials (3145 individuals), early tracheotomy improved VAP, ventilator, and ICU days, but not short-term all-cause mortality. These findings may influence current clinician attitudes and ICU/surgical guidelines entailing the timing of tracheostomy placement.
Accepted for Publication: January 11, 2021.
Published Online: March 11, 2021. doi:10.1001/jamaoto.2021.0025
Corresponding Author: Alvaro Moreira, MD, MSc, Division of Neonatology, Department of Pediatrics, University of Texas Health–San Antonio, San Antonio, TX 78229 ([email protected]).
Author Contributions: Dr Chorath and Mr Hoang contributed equally as co–first authors. Drs Chorath and Moreira had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Chorath, Moreira.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Chorath, Hoang, Moreira.
Critical revision of the manuscript for important intellectual content: Chorath, Rajasekaran, Moreira.
Statistical analysis: Chorath, Moreira.
Supervision: Rajasekaran, Moreira.
Conflict of Interest Disclosures: Dr Moreira reported receiving grants from the Parker B. Francis Foundation and the National Heart, Lung, and Blood Institute outside the submitted work. No other disclosures were reported.
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