Early Tracheal Extubation for Postoperative Recovery in Cardiac Surgery: Systematic Review and Meta-Analysis

Background: How to promote the rapid recovery of patients undergoing cardiac surgery and quality of life has been the focus of doctors’ attention. To compare the safety and ecacy of early cardiac extubation with conventional extubation (late extubation) in patients undergoing cardiac surgery. Methods: Ovid MEDLINE, Ovid Embase, EBSCOhost, Cochrane Library and ISIWeb of Science (1946–November 25, 2019) were searched to obtain randomized controlled trials of early tracheal extubation in patients undergoing cardiac surgery. Results: Compared with the conventional care group, in terms of effectiveness, the intensive care unit (ICU) stay and hospital length of stay in the early tracheal extubation was signicantly shorter. In terms of security, most outcomes, including mortality, bleeding, stroke, acute renal failure and arrhythmia, were not statistically signicant, except for myocardial infarction. However, the risk of re-intubation in the early tracheal extubation was higher than that of conventional extubation. Conclusions: This meta-analysis conrmed that early tracheal extubation may effectively reduce ICU hospitalization time, hospital length of stay and the risk of myocardial infarction. Although early tracheal extubation does not increase the risk of safety events, the clinicians need to pay more attention to be aware of possible risk of re-intubation. Meanwhile, as a key time point for extubation within 4 hours, it may help a little to reduce the risk of re-intubation and myocardial infarction. acute renal failure, major bleeding and re-intubation; (5) Study design: Randomized controlled trial (RCT).


Introduction
Until now, how to promote the rapid recovery of patients undergoing cardiac surgery has been the focus of doctors' attention [1,2]. Traditionally, cardiac surgical patients were ventilated overnight following surgery and given a regimen of high-dose opioid-based anesthesia and postoperative analgesia. Until recently, overnight ventilation has been proved to be safe [3]. But overnight ventilation tends to cost more. In the 1990s, fast-track cardiac anaesthesia (FTCA) was introduced to address the increasing demand for cardiac surgery that with limited medical functions and available resources [4].
Early tracheal extubation as a common post-cardiac care strategy was considered to be effective in improving the prognosis of cardiac surgery [3]. Studies have shown that early tracheal extubation effectively reduces ICU hospital stay and saves a lot of costs [5,6]. After cardiac surgery, the traditional tracheal extubation time is usually within 8 hours [7,8]. Early tracheal extubation is an important part of the rapid recovery of cardiac surgery, and many clinical studies and meta-analysis had con rmed its safety [5,7,[9][10][11][12][13]. Recently, guidelines concluded the early tracheal extubation time was 6 hours [14]. Moreover, extubation for more than 6 hours may lead to an increase in the incidence of pneumonia [15]. Further, study had presented that tracheal extubation time could be further shortened within 6 hours [16]. The previous meta-analysis was unable to achieve meta-analysis with a subgroup of 4 hours due to lack of evidence [12]. Mean tracheal extubation time was within 4 hours revealed by some studies [17,18] and even tracheal extubation [18,19] immediately after surgery [20], which bring possibility to further shorten the time of tracheal extubation using this meta-analysis to evaluate this possibility.

Study eligibility criteria
The key words, such as "cardiac surgery", "early tracheal extubation", "coronary artery bypass", "hospital stay" and "intensive care" has been used as MESH terms search trials in the following databases: Ovid MEDLINE, Ovid Embase, EBSCOhost, Cochrane Central Register of Controlled Trials, and ISIWeb of Science, the period is from 1946 to November 25, 2019. No language restrictions were applied.

Identi cation And Selection Of Studies
Studies were included in this systemic review and meta-analysis if they meet the following criteria: (1) Participants: patients over 18 years of age undergoing cardiac surgery; (2) Intervention: early extubation based on early extubation criteria from all original researches; (3) Comparison: normal extubation (according to the original research setting); (4) Outcomes: The primary outcomes were de ned as ICU stay time and hospital stay, the secondary outcome were de ned as postoperative complications, including myocardial infarction, stroke, acute renal failure, major bleeding and re-intubation; (5) Study design: Randomized controlled trial (RCT).

Data Extraction And Quality Assessment
The two commentators (YFZ and ZDH) rst scanned the title and abstract of the relevant article independently. Based on the results, a complete article is obtained for nal screening. Relevant information was independently extracted by two reviewers (YFZ and ZDH), including patients, type of surgery, extubation time, relevant outcomes, and study bias. Two reviewers independently assessed the quality of the included studies based on the criteria reported in the Cochrane's handbook [22]. All the differences in this process were solved through discussion by (CZ). When analyzing the difference of continuous data, the mean difference (MD) with 95% con dence interval (CI) is used as the effect size [23]; when analyzing the difference of the binary data, the relative risk (RR) with 95% CI is used as the effect size. Heterogeneity was examined using the I 2 statistic that indicates the proportion of total variability in estimates that can be attributed to heterogeneity [24]. In order to further investigation of heterogeneity from early tracheal extubation strategy, the meta-regression with early tracheal extubation group's mean extubation time as the covariable were employed. Meanwhile, the confounding factor, including the early tracheal extubation time and type of surgery, were identi ed as important sources of heterogeneity, and were involved in the subgroup analysis. We used the funnel plot and Egger test [25] for detecting publication bias. All statistical analyses were performed using R software.

Search results
The Ovid MEDLINE, Ovid Embase, EBSCOhost, Cochrane Central Register of Controlled Trials, and ISIWeb of Science were systematically searched until April 25, 2018. The search resulted in 3,834 articles. After initial evaluation, 781 studies were removed for being duplicates, 2,267 for being irrelevant (as determined by reading the title and abstracts). Ultimately, 14 studies for reasons determined by reading the full text ( Figure 1).

Research characteristics and assessment of quality
Summarizes patient characteristics (i,e, author, population, age, gender, type of surgery, and outcomes). This analysis included 14 published double-blind, parallel RCTs, 1,554 patients need heart surgery and underwent extubation. All patients met risk criteria for mild or moderate cardiac surgery by the EuroSCORE [21] used as a basis for diagnosing. All characteristics of included study are presented in Table 1. All patients were adults, primarily with regard to CABG or valve or aortic valve replacement (AVR) surgery. In all of the included studies, 9 studies [7, 9, 10, 17-20, 26, 27] in the experimental group were ventilated within 4 hours, and 4 studies [5,8,28,29] were performed within 8 hours. The overall risks of bias in the study are shown in Table 2.
Primary outcomes ICU length of stay A total of 8 studies [5, 7-9, 18, 27, 28, 30] , involving 912 patients with a summary of data reported the length of ICU hospitalization of early tracheal extubation and conventional extubation. Compared with the conventional extubation group, the early tracheal extubation was signi cantly shortened for the ICU stay time In a subgroup analysis of extubation time (  (Table 5).

Myocardial infarction
A total of 1127 patients in 9 studies [5, 7-9, 19, 20, 27, 29, 30] recorded the number of patients with postoperative myocardial infarction, and 3 of them reported no patients with myocardial infarction. The risk of myocardial infarction was 1.6% in the early tracheal extubation group and 4.3% in the conventional extubation group. The risk of early extubation was lower than that of conventional extubation (RR = 0.43, 95% CI [0.23, 0.79], I 2 = 0%), and the difference was statistically signi cant.
In a subgroup analysis of extubation time (  (Table 5).

Bleeding
A total of 684 patients in 8 studies [5,7,9,17,19,20,28] recorded major bleeding after surgery. The risk of major bleeding in the early tracheal extubation group was 11.2%, and the conventional care group is 9.8%. The risk of major bleeding in the early group was slightly higher than that in the conventional group. The difference between the two groups (RR=0.94, 95%CI [0.67, 1.32], I 2 = 0%) have no obvious difference.
In a subgroup analysis of extubation time (  13.93], I 2 =NA) and no signi cant difference was represented (Table 5).

Stroke
A total of 750 patients in 7 studies [5,8,9,20,21,28,30] recorded postoperative stroke, and there are no stroke patients in the three studies. The risk of stroke in the early tracheal extubation group was 0.02%, and that in the routine care group was 1.5%. After comparison between the two groups (RR = 0.52, 95% CI [0.17, 1.56], I 2 = 0%), there was no signi cant difference.
In a subgroup analysis of extubation time (  (Table 5).
Acute renal failure A total of 597 patients in 5 studies [8,20,21,27,28] recorded acute renal failure after surgery, and no patients with renal failure are shown in either study. The risk of severe acute renal failure in the early group was 1.1%, which was similar to the conventional care group (0.9%). Statistical differences between the two groups (RR=1.06, 95%CI [0.33, 3.41], I 2 =0%) have no striking difference.
In a subgroup analysis of extubation time (  (Table 5).

Arrhythmia
A total of 6 studies [5,8,19,20,29,30] , and a total of 750 patients got postoperative arrhythmias, and no arrhythmia patients was reported in one of the studies. The risk of arrhythmia was 16.6% in the early tracheal extubation group and 18.3% in the conventional extubation group. The statistical difference between the early tracheal extubation group and the conventional extubation group (RR=1.25, 95%CI [0.93, 1.68], I 2 =5%) have no conspicuous difference.
In a subgroup analysis of extubation time (  (Table 5).

Meta-regression
The meta-regression results are presented below, the incidence of bleeding

Discussion
In this meta-analysis, in terms of effectiveness, early tracheal extubation can signi cantly reduce the length of stay in ICU and slightly reduced the average hospital stays. As for security, compared with previous meta-analysis [11,13], the risk of re-intubation in the early extubation group is signi cantly higher than in the conventional extubation group. Seven of the ten studies reporting re-intubation risk reported a higher risk of extubation than the conventional extubation group. However, the risk of myocardial infarction in the early extubation group was lower than that in the conventional extubation group. The researchers of this paper also compared deaths from tracheal extubation at different period, and it found that there were no signi cant differences between hospital deaths in both tracheal extubation and deaths within 30 days after discharge. Moreover, in all deaths, no signi cant difference was shown in the risk of both tracheal extubation, including deaths in the hospital and death within 30 days after discharge.
In the subgroup based on the different types of cardiac surgery, the results have shown that the risk of re-intubation and arrhythmia in the CABG/valve group was higher than that in the other groups. Nevertheless, the ICU hospital stays in this group was signi cantly shorter than other types of surgery, and the heterogeneity was higher. Even though early tracheal extubation might be more effective in reducing the cost of medical care for patients requiring valve surgery, there might be a greater risk of medical safety for the patients.
The researchers of this paper investigated the feasibility of extubation 4 hours after cardiac surgery. The average time of early tracheal extubation within 4 hours was better than that of more than 4 hours in the three outcomes of the ICU length of stay, re-intubation and myocardial infarction. The ICU length of stay shortened the incidence of MD = 10.69, myocardial infarction and decreased the incidence of RR = 0.21. Although the reduction in the risk of reintubation is not statistically signi cant, the signi cant increase in the risk of reintubation in the group over 4 h is of signi cant statistical importance, which indicates that further shortening the extubation time may lead to a reduction in risk, perhaps the use of auxiliary schemes to assist related extubation decisions in the future can shorten the time and maintain safety [31]. Whereas, the increase in complications within mean 4-hour tracheal extubation were mainly manifested in bleeding and acute renal failure. However, neither of the two results was statistically signi cant.
Currently, of the fourteen studies included, nine of them had an average extubation time within 4 hours of surgery. Four studies [9,18,19,27] have demonstrated the feasibility of average extubation time within 2 hours, and two studies [18,19] had few reports of complication outcomes. Salah et al. [27] reported a signi cantly increase in the risk of bleeding. In the studies of immediate extubation, early tracheal extubation was undoubtedly reduced hospital stay, but there were few reports on safety. Study have shown that ultra-rapid (1-2 h) extubation can also reduce the hospitalization time and cost of ICU, and will not increase related complications [32]. There were no descriptions ways to prevent major bleeding in 14 studies, but studies have shown [33] that interventions such as thromboembolic diagnosis and treatment in blunt patients can effectively reduce the risk of major bleeding in patients with early tracheal extubation.
Many studies have set the time standard for early extubation. If the ventilation time of patients exceeds this standard, it will be excluded from the early extubation group. The researchers of this paper hope to determine the most effective time standard by comparing different standards. Of the 14 included articles, ve studies did not set the standard time for early extubation [19,20,[27][28][29]. Four studies set the maximum time limit for early extubation to 8 hours [7][8][9][10], and three studies set the maximum time limit for early extubation to 6 hours [5,18,30], the standards of the remaining two studies are all within 4 hours [17,26]. Except for studies based on the 8-hour criterion that have proven the bene ts in reducing hospital stays, almost all results are not statistically signi cant. Therefore, the researchers of this paper are not sure when the extubation time standard is bene cial to the effect of early extubation.
Our meta-regression analysis illuminated that the risk of bleeding, acute renal failure and routine hospital stay were negatively correlated with early tracheal extubation time, and the remaining six results were positively correlated with early tracheal extubation time. It indicates that shortening of extubation time is more bene cial.
Finally, the effects on quality of overall cost effectiveness need to be clari ed in future studies. If the length of stay in ICU and hospitals is signi cantly reduced, rapid treatment for cardiac surgery patients is likely to be cost-effective. Studies [34,35] believe that early extubation can effectively reduce total hospital cost. Lu et al.
[36] believe the early extubation intervention was associated with a reduction in departmental cost savings in uncomplicated CABG surgery. This meta-analysis of early tracheal extubation in cardiac surgery only appropriately applied in the e cacy and safety of early tracheal extubation rather than FTCA, and is more accurate than the previous article, which pointed out risk of complications that not indicated by previous meta-analysis. Provided an newest idea to further shorten the time of extubation and a comprehensive reference for the safety of early tracheal extubation strategies in patients with different cardiac operations.

Limitations
Firstly, the early tracheal extubation strategy is di cult to implement the blinding, this may affect the quality of our research. At the same time, the lack of data in some studies may lead to some controversy over the effectiveness of the results. Secondly, different studies used different anesthesia criteria, high doses of anesthesia require longer ventilation support, remifentanil has faster recovery and less respiratory depression, and there are also ways to speed up recovery after discharge. This is a confounding factor that we have di culty assessing. Thirdly, due to the insu cient number of studies, the validity and veracity of subgroup analysis, meta-regression and publication bias may be affected.

Conclusion
Early tracheal extubation may effectively reduce ICU hospitalization time, hospital length of stay and the risk of myocardial infarction. Although early tracheal extubation does not increase the risk of safety events, the clinicians need to pay more attention to be aware of possible risk of re-intubation, and it is not recommended for coronary artery bypass graft or valve. Meanwhile, as a key time point for extubation within 4 hours, it may help a little to reduce the risk of re-intubation and myocardial infarction. Based on sample size limitations, the conclusions of this study need to be veri ed by large sample clinical studies.

Declarations
Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable.
Availability of data and materials: Not applicable.
Competing interests: All authors declare that they have no competing interests.
Funding: Not applicable.
Authors' contributions: CZ and GLG had full access to all of the data in the study, and took responsibility for the integrity of the data and the accuracy of the data analysis. YFZ, ZDH and HYG designed the study. ZDH and YFZ developed and tested the data collection forms. YFZ and ZDH acquired the data. YFZ and ZDH conducted the analysis and interpreted the data. YFZ and ZDH drafted the manuscript. All authors critically revised the manuscript. CZ and GLG had guarantor.         Forest of mortality