Effects of Different Non-invasive Respiratory Support in Preventing Reintubation in Patients at High Risk for Extubation Failure: A Systematic Review and Meta-Analysis

Effects of Different Non-invasive Respiratory Support in Preventing Reintubation in Patients at High Risk for Extubation Failure: A Systematic Review and Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effects of Different Non-invasive Respiratory Support in Preventing Reintubation in Patients at High Risk for Extubation Failure: A Systematic Review and Meta-Analysis Danyang Guo, Ping Jia, Shaowei Li, Li Wang, Zhenzhen Wang, Xiaorong Mao This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4705123/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Patients at high risk for extubation failure are subject to suffering reintubation or respiratory failure after extubation that adversely affects outcomes. It’s essential that rapidly identifying respiratory failure and correctly applying respiratory support for adequate treatment to avoid reintubation for patients. The high-flow nasal cannula (HFNC) is a safer and more comfortable respiratory support than noninvasive mechanical ventilation (NIV). However, whether HFNC is superior to NIV for preventing reintubation in patients at high risk of extubation failure is unclear. The present study aims to investigate the efficacy of HFNC for preventing reintubation in various high risk populations. Methods: In this systematic review and meta analysis, we searched PubMed, Embase, Web of Science, Cochrane Library, and CNKI for studies from Jan 1, 2019, to Jan 1, 2024. Two independent reviewers screened studies, extracted the data from the reports, and assessed the risk of bias. The primary outcomes were the reintubation rate within 7 days and effect size calculated as risk ratio (RR; 95% Cl), the secondary outcomes were the rate of mortality(RR; 95% Cl) and ICU length of stay (SMD; 95% Cl) and respiratory rate (SMD; 95%). Results: A total of 1,289 patients were included in 9 studies, of which 6 were randomized controlled trials and 3 were observational studies. A significant decrease in the mortality risk was found in the HFNC group(RR 0.6822 [95% Cl: 0.4795-0.9706]) compared to the NIV group. However, there was no significant difference in reintubation rate (RR 1.1729, 95% CI: 0.8679–1.5851) and ICU length of stay (SMD 0.0256, 95% CI: -0.0195–0.0708). All adverse events associated with NIV were reported in three studies. Conclusion: For patients who are at high risk of extubation failure, the HFNC can decrease the risk of mortality, to some extent, compared to NIV, but the reintubation rate and ICU length of stay were not superior to NIV. high flow nasal cannula noninvasive ventilation extubation reintubation Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Invasive mechanical ventilation has been reported to be required in approximately 40%-70% of patients in the intensive care unit (ICU) [ 1 ] , and extubation is usually considered after stabilization. [ 2 ] . It is reported [ 3 , 4 ] that about 25–30% of patients are at high risk of extubation failure, which can lead to a poorer prognosis [ 5 ] . Patients at high risk of extubation failure were regarded as those who had been on invasive mechanical ventilation for more than 24 hours and met at least one of the risk factors for extubation failure [ 6 – 8 ] , which included age ≥ 65 years, obesity, and concomitant chronic obstructive pulmonary disease (COPD) or other disease [ 8 – 10 ] . Therefore, as a preventive measure, noninvasive respiratory support is often used after extubation to avoid respiratory failure or reintubation [ 11 , 12 ] , such as NIV and HFNC. NIV delivered oxygen through a sealed mask, which was thought to be detrimental to sputum expulsion [ 13 ] . The HFNC delivers heated, humidified, and more concentrated oxygen through a small, flexible nasal cannula [ 14 , 15 ] , effectively managing the patient's respiratory secretions [ 12 ] and reducing dead space ventilation [ 16 , 17 ] . According to guideline recommendations [ 6 ] , HFNC is considered as a safer and more tolerable form of oxygen delivery compared to noninvasive ventilation. Previous systematic reviews and meta-analyses suggested that the application of HFNC can be used as an alternative treatment for NIV after extubation in critically ill patients [ 18 , 19 ] . Nevertheless, Zhao et al. [ 20 ] concluded that HFNC is superior to conventional oxygen therapy (COT), which addresses some of the limitations of COT [ 6 ] , such as unreliable FiO2 delivery and patient self-inflicted lung injury, in terms of intubation rates, it is not superior to NIV. Although there have been many meta-analyses comparing HFNC and NIV, the majority of the articles [ 20 – 22 ] included in the study are from 2015 to 2021, and only a few studies compared HFNC and NIV alone, raising concern that the real benefits may be covered. Given these uncertainty issues about the clinical benefits of HFNC and recent evidence from four trials with more than 700 additional patients, We conducted an updated systematic review and meta-analysis to evaluate the efficacy and safety of HFNC compared with NIV in patients at high risk for extubation failure. We specifically focused on articles published in the past three years to update past results. Methods Search Strategy and Selection Criteria This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines [23] and was prospectively registered with the CRD42023492756. Two independent reviewers (GDY and LSW) searched Embase, PubMed, Web of Science, the Cochrane Library, and CNKI for eligible studies from Jan 1, 2019, to Jan 1, 2024. The reference lists of included studies were reviewed for any additional eligible studies. The detailed search strategy is available in the supplementary materials. The inclusion criteria were as follows: 1. Population: A patient at high risk for extubation failure is defined as a patient who has been intubated for greater than or equal to 24 hours is ready to be extubated, and meets one of the following criteria. [7, 8, 24, 25] : (i) age ≥ 65 years; (ii) underlying cardiac or respiratory disease; (iii) Acute Physiology and Chronic Health Evaluation (APACHE II) score > 12 on extubation day; (iv) body mass index (BMI) > 30 kg/m 2 ; (v) airway patency problems, inability to deal with respiratory secretions (inadequate cough reflex or suctioning required > 2 times within 8 h before extubation); (vi) difficult or prolonged weaning (failing ≥ 1 attempt at disconnection from mechanical ventilation); (vii) comorbidities ≥ 2; (viii) mechanical ventilation ≥ 7 days, and/or hypercapnia (PaCO2 > 45 mmHg) at the end of the spontaneous breathing test (SBT). 2. Intervention: The intervention group received HFNC, while the control group received NIV; 3. Outcomes: All-cause reintubation within 7 days rate as the primary outcome, or secondary outcomes include mortality at longest follow-up, length of hospital stay (LOS), duration of stay ICU, and respiratory rate. The exclusion criteria were as follows: (i) the study that compared HFNC with COT or other protocol combined; (ii) data that could not be extracted by the statistical methods or non-targeted outcomes. Data Extraction Data were extracted by two independent reviewers in a blinded way to avoid bias. Extracted data were stored in a self-restraint Excel database, including study design, country, patient characteristics, intervention, and outcomes. Data Synthesis and Analysis Meta-analyses were conducted using a meta package (version 7.0-0) in R (version 4.3.1). Continuous outcomes were extracted as sample size and mean (SD) or median (IQR) provided in the studies, with the conversion of medians to estimated mean (SD). The standardized mean difference, however, has been found to have an upward bias when the sample size of a study is small [26] , especially when n≤20, Hedges’g was used to correct for small-sample bias. Dichotomous data were expressed as a risk ratio (RR). For each analysis, studies were weighted using the inverse variance method, and data were pooled using a random effects meta-analyses model accounting for the incidence. Statistical heterogeneity assessment between studies was performed by Cochran’s Q test and reported with the I² and Chi squared (χ²) statistics, in which I² indicated the degree of heterogeneity as follows: insignificant heterogeneity (0–30%), moderate heterogeneity (30–60%), substantial heterogeneity (50–90%), and considerable heterogeneity (75–100%). P-value equal to 0.05 or less was considered to be statistically significant. Then, we used the find outliers and influence cases to examine heterogeneity and verified the pooled effect estimate we found is robust based on the guideline [27] . Risk of bias assessment Two reviewers independently evaluated the methodological quality of all included studies using The Revised Cochrane risk-of-bias tool for randomized trials (RoB2) [28] . The RoB2 includes five domains: (1) Risk of bias arising from the randomization process; (2) Risk of bias due to deviations from the intended interventions (effect of assignment to intervention); (3) Missing outcome data; (4) Risk of bias in the measurement of the outcome; (5) Risk of bias in the selection of the reported result. Each domain has several signaling questions which used to assess the quality of studies. The risk of bias can be assessed as “low risk of bias”, “some concerns” and “high risk of bias” in each domain. Full details are provided in the Supplementary materials. Any disagreement regarding study selection, data extraction, or quality assessments was resolved by a consensus discussion with another investigator (JP). Results Study Selection and Characteristics A total of 4512 studies were identified based on our search strategies. We then screened 1144 titles and abstracts after the removal of duplicates, and 131 full-text articles were for eligibility. Finally, we included nine [ 9 – 11 , 29 – 34 ] studies, of which, six were RCTs [ 9 , 10 , 29 , 30 , 33 , 34 ] and three [ 11 , 31 , 32 ] were observed studies, as shown in Fig. 1 . Among 1289 patients included in this study, 1107 patients were at high risk of extubation failure, 182 patients were at very high risk of extubation failure. The study characteristics are summarised in Table 1(see the Supplementary materials). The risk of bias assessments for the primary outcome was shown in the supplementary materials. For RCTs, one was assessed as low risk of bias, four studies raised some concerns, and one was considered at high risk of bias based on The Cochrane risk-of-bias tool. Among the observation studies, two were considered at low risk of bias assessed by the NOS, and another one was considered at moderate risk of bias. Primary Outcome All the included studies reported all-cause reintubation rates within seven days for patients requiring reintubation. The pooled estimates demonstrated that there was no statistically significant difference in the rate of all-cause reintubation within seven days in patients at high risk for failure to prevent extubation in HFNC compared with NIV (RR 1.1729 [95% Cl: 0.8679–1.5851], I²=16%; Fig. 2 ). Moreover, in the subgroup analysis no significant differences in reintubation rate were found (RR 0.8268 [95% Cl 0.5985–1.1422], I²=0%; Fig. 3 ) either, which included age ≥ 65 (RR 0.9456 [95% Cl: 0.5995–1.4915], I²=10.6%) and COPD (0.7026 [95% Cl: 0.4251–1.1614], I²=0) populations (see in the Supplementary materials). Secondary outcomes All nine studies with data on mortality showed that HFNC significantly reduced the mortality rate compared to NIV(RR 0.6822 [95% Cl: 0.4795–0.9706], I²=0%; Fig. 4 ). Six studies [ 9 , 11 , 29 , 30 , 32 , 33 ] reported the ICU length of stay as an outcome, there was no significant difference between the HFNC group and the NIV group (SMD 0.0256 [95% Cl: -0.0195-0.0708], I²=0%; Fig. 5 ). Respiratory rate was reported in three studies [ 10 , 29 , 30 ] with no difference between the two groups (SMD − 0.00 [95% Cl: −0.20; 0.19], I²=0%; see in the Supplementary materials). Sensitivity analyses According to the leave-1-out sensitivity analysis, when removing 1 study at a time, the pooled results of reintubation, mortality, and ICU length of stay, no difference emerged (see in the Supplementary materials). Discussion In this systematic review and meta-analysis, our study found that HFNC was not superior to NIV in reducing the reintubation rate in patients at high risk of extubation failure, but the mortality rate was significantly lower in the HFNC group than in the NIV group. Three studies [ 9 , 30 , 33 ] reported adverse events with no complications in the HFNC group. There were, however, mild complications in the NIV group, such as skin breakdown, facial skin ulcer, and abdominal distension. Although we found HFNC lowering the reintubation rate in patients at high risk of extubation failure was not superior to the NIV, a favorable effect cannot be neglected. Furthermore, no adverse events were reported in the HFNC group across all trials. Compared to NIV, HFNC precisely regulates FiO 2 by providing moist oxygen flow, which not only helps the patient to remove excreta and promotes effective gas exchange, but also prevents the patient from open-mouth breathing, which can lead to lung damage and bloating due to respiratory effort, and makes him/her feel relatively more comfortable. [ 35 ] . In addition, there may be some correlation between the rate of reintubation and other outcomes in this study, so respiratory rate and length of hospitalization were also not statistically significant when comparing the two groups of patients. However, in contrast, NIV patients had shorter ICU stays with narrower 95% confidence intervals, although the outcome was not statistically significant. This may be due to the increased rate of reintubation in the HFNC group leading to an increase in their length of hospitalization. This could be the reason why the guidelines recommend the use of NIV more to reduce the rate of reintubation [ 6 ] . A notable disparity in mortality was observed in this system review and meta analysis, which was in line with the findings in the recently published studies [ 9 – 11 , 29 , 31 ] . Nevertheless, in previous meta-analyses [ 20 , 22 , 36 ] , it was insignificant between two groups. The difference may be that fewer studies were included in previous meta-analyses to compare the effect of receiving NIV or HFNC alone and high heterogeneity was also observed. Furthermore, previous research studies have also demonstrated that compared to receiving NIV, the implementation of HFNC + NIV contributes to a decrease in reintubation rate among patients at high risk of extubation failure [ 32 ] , but the mortality rate increased [ 22 ] . NIV + HFNC used interchangeably may be an effective strategy to reduce reintubation rate after extubation [ 37 ] . However, in comparison to the solitary utilization of NIV, the question of whether the combination of NIV + HFNC provides greater benefits for the high-risk extubation failure population, or if it may potentially lead to an increase in adverse outcomes, remains to be determined through further multicenter studies. At the same time, consideration also needs to be given to the economic burden on patients post-hospital admission with a combination of NIV and HFNC. Several reasons may explain the higher mortality of NIV. First, among the included studies, most trials used NIV prophylactically, while three studies [ 11 , 30 , 34 ] started NIV at the time of respiratory failure or the emergence of a window for pulmonary infection control. Using NIV to treat respiratory insufficiency after extubation (post-extubation failure) was not recommended in an international consensus conference [ 38 ] . Moreover, two RCTs [ 39 , 40 ] showed that no benefit could get from the use of NIV after respiratory failure to avoid reintubation. Reintubation of patients with respiratory failure after using NIV leads to delayed intubation, and the time between extubation and reintubation is an independent risk factor for increased mortality in reintubated patients [ 41 ] . In the study by Ferrer et al [ 7 ] , respiratory failure was the most common cause of death in these patients, and the early application of NIV is effective in avoiding respiratory failure and reducing extubation failure in high-risk patients.. Therefore, prophylactic use of NIV is important for the prognosis of people at high risk of extubation [ 7 , 42 ] . Second, most of the people at high risk for extubation failure in the studies included in this paper had respiratory diseases such as COPD, and severe pneumonia. These respiratory conditions may result in inadequate secretion clearance or narrowing of the airway [ 43 ] . The use of NIV in patients with respiratory disease may lead to airway obstruction or infection, as the sealed environment of oxygenation using a mask may cause sputum to accumulate and not be easily expelled, and respiratory failure may be induced by obstruction of the upper airway, which may lead to failure of the NIV treatment. The study of Liu et al [ 31 ] similarly reached a consistent conclusion, demonstrating a higher mortality rate in the NIV group (14.3%) compared to the HFNC group (9.1%) among patients with sputum volume ≥ 20 mL within 24 hours. Moreover, the inability to spontaneously remove secretions is considered a relative contraindication for NIV [ 44 ] , especially in patients with impaired consciousness and weak cough reflex [ 45 ] , careful consideration and individualized assessment are crucial before initiating NIV [ 46 ] . Therefore, patients at high risk of extubation failure with respiratory disease need to carefully consider to use of NIV. Concerning the risk of bias assessment, the main issue concerned the blinding. Patients are aware of the implementation of interventions post-enrollment, which could not impact outcome assessment. As the time of reintubation is beyond the control of patients, with the majority of trials [ 9 , 10 , 29 , 30 , 32 , 34 ] indicating that the decision for reintubation is based on pre-established criteria. In most included studies, apart from the different of intervention of ventilation [ 29 , 30 , 32 , 34 ] , both intervention and control groups received consistent medical management. Although one study [ 33 ] that did not employ randomization in grouping was considered low quality, the rest were considered high quality. Furthermore, among the articles included, only one is a multicenter conducted study [ 30 ] , and some studies [ 10 , 29 , 33 ] were small sample sizes, potentially introducing bias into the results. Strengths and limitations We used two approaches [ 38 ] (find outlier and influence cases ) to avoid one or more studies with extreme effect sizes from distorting our pooled effect estimate and certifying if the pooled effect estimate we found is robust. Eventually, we did not find outliers, but the studies of Hernández et al [ 9 ] and Liu et al [ 31 ] may be regarded as potentially relevant cases since they contribute heavily to the overall heterogeneity in our meta-analysis. Therefore, we conducted and reported the results and pooled estimates in which both studies were excluded. The results were robust, and further sensitivity analysis was approved (see in the Supplementary materials), indicating that no individual study had impacted the overall results. There are several limitations in this study. First, only a few studies reported the results separately based on the diagnosis of the population, such as COPD, acute heart failure, and the change of patient’s arterial blood gas. Therefore, we were not able to assess the impact of HFNC on patient outcomes with concrete disease. Second, only interventions with HFNC and NIV were included in this meta-analysis, thus the results might not be generalizable to other intervention protocols. Further studies could try a program that combines HFNC and NIV, merging the strengths of each measure to maximize its effect. Conclusion High Flow Nasal Cannula may be a promising treatment for patients at high risk of extubation failure, although the benefit of decreasing the risk of reintubation was not significantly superior to noninvasive ventilation, the impact on mortality was notable. Moreover, patients in the NIV group reported small number of adverse events, such as facial skin breakdown and bloating, while no adverse events were found in the HFNC group. Thus, larger sample sizes and more rigorous studies need to be conducted exploring the impact on HFNC and NIV for patients at high risk of extubation failure . Abbreviations HFNC High Flow Nasal Cannula NIV Noninvasive Ventilation COT Conventional oxygen therapy IPAP inspired positive airway pressure EPAP Expiratory Positive Airway Pressure COPD chronic obstructive pulmonary disease BMI Body Mass Index ICU Intensive care unit Declarations Ethics approval and consent to participate: Not applicable Consent for publication: Not applicable Availability of data and materials: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Competing interest: The authors declare that they have no competing interests. Funding: Project from Sichuan Provincial Science and Technology Department (2023YFS007). Author’s contribution: GDY, MXR designed the study. GDY, MXR, LSW, and JP acquired the data. GDY, MXR, and LSW drafted the manuscript. GDY, MXR, JP, LSW, WL, and WZZ performed the statistical analyses. GDY, MXR, and LSW are guarantors of the data and manuscript. 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Impact of endotracheal intubation on septic shock outcome: A post hoc analysis of the SEPSISPAM trial [J]. J Crit Care, 2015, 30(6): 1174-8.DOI: 10.1016/j.jcrc.2015.08.018. Jaber S, Monnin M, Girard M, et al. Apnoeic oxygenation via high-flow nasal cannula oxygen combined with non-invasive ventilation preoxygenation for intubation in hypoxaemic patients in the intensive care unit: the single-centre, blinded, randomised controlled OPTINIV trial [J]. Intensive Care Med, 2016, 42(12): 1877-87.DOI: 10.1007/s00134-016-4588-9. Ozyilmaz E, Ugurlu A O, Nava S. Timing of noninvasive ventilation failure: causes, risk factors, and potential remedies [J]. BMC Pulm Med, 2014, 14: 19.DOI: 10.1186/1471-2466-14-19. Carlucci A, Richard J C, Wysocki M, et al. Noninvasive versus conventional mechanical ventilation. An epidemiologic survey [J]. Am J Respir Crit Care Med, 2001, 163(4): 874-80.DOI: 10.1164/ajrccm.163.4.2006027. Ambrosino N, Vagheggini G. Noninvasive positive pressure ventilation in the acute care setting: where are we? [J]. Eur Respir J, 2008, 31(4): 874-86.DOI: 10.1183/09031936.00143507. Additional Declarations No competing interests reported. Supplementary Files Supplementarymaterials.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4705123","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":335668784,"identity":"17f641e8-5321-43fa-b79b-3243bdcc62ee","order_by":0,"name":"Danyang Guo","email":"","orcid":"","institution":"University of Electronic Science and Technology of China","correspondingAuthor":false,"prefix":"","firstName":"Danyang","middleName":"","lastName":"Guo","suffix":""},{"id":335668785,"identity":"badef2f9-32f8-458a-bbdd-2faa75f0bb63","order_by":1,"name":"Ping Jia","email":"","orcid":"","institution":"Sichuan Academy of Medical Sciences \u0026 Sichuan Provincial People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ping","middleName":"","lastName":"Jia","suffix":""},{"id":335668786,"identity":"f63e360d-238a-44ae-95ab-77c59fb6d974","order_by":2,"name":"Shaowei Li","email":"","orcid":"","institution":"Zhejiang Normal University","correspondingAuthor":false,"prefix":"","firstName":"Shaowei","middleName":"","lastName":"Li","suffix":""},{"id":335668787,"identity":"750de922-abde-49e2-8536-5d3c81558c03","order_by":3,"name":"Li Wang","email":"","orcid":"","institution":"Sichuan Academy of Medical Sciences \u0026 Sichuan Provincial People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Wang","suffix":""},{"id":335668788,"identity":"dfe955af-520d-44d5-b324-e2a8936e8ee4","order_by":4,"name":"Zhenzhen Wang","email":"","orcid":"","institution":"Sichuan Academy of Medical Sciences \u0026 Sichuan Provincial People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhenzhen","middleName":"","lastName":"Wang","suffix":""},{"id":335668789,"identity":"5ce38875-1b65-4450-a761-b942067d8296","order_by":5,"name":"Xiaorong Mao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyUlEQVRIiWNgGAWjYDACZmTOB5K1MM4g3UYeYlQZHGd++Lii4o5dg9jhh49tyqwZ+Nu7E/BqkWxmMzY8c+ZZcoN0mrFxzrl0BokzZzfg1cLPzGAm2dh2OJlBOsFMOrftMIOBRC5+LWzM7N+gWtK/SVsSo4WfmQdsix2DdI6ZNCMxWiSbeYoNG84cTgBqKTbsOZfOQ9AvBuePb3zYUHHYHuiwjQ9+lFnL8bf34tcCA4n7D0C8RlTUgIE9hGJjxq9sFIyCUTAKRiQAAIX8P8mqosETAAAAAElFTkSuQmCC","orcid":"","institution":"Sichuan Academy of Medical Sciences \u0026 Sichuan Provincial People's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Xiaorong","middleName":"","lastName":"Mao","suffix":""}],"badges":[],"createdAt":"2024-07-08 11:18:47","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4705123/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4705123/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":62189949,"identity":"b1142a19-7776-4114-8a90-3b83e43d380d","added_by":"auto","created_at":"2024-08-10 12:24:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":536923,"visible":true,"origin":"","legend":"\u003cp\u003eThe PRISMA flow diagram of selected studies.\u003c/p\u003e","description":"","filename":"Figure1.pic.png","url":"https://assets-eu.researchsquare.com/files/rs-4705123/v1/911d274a8c0b374d1fa1f6f2.png"},{"id":62189948,"identity":"6a20aa72-9429-42a6-8f05-36178f167dd2","added_by":"auto","created_at":"2024-08-10 12:24:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":164380,"visible":true,"origin":"","legend":"\u003cp\u003eThe all-cause of reintubation rate within 7 days.\u003c/p\u003e","description":"","filename":"Figure2.pic.png","url":"https://assets-eu.researchsquare.com/files/rs-4705123/v1/f4478f9295c608519b643e3a.png"},{"id":62190809,"identity":"c9c315b0-cb4d-4fa0-85a2-714bed80a240","added_by":"auto","created_at":"2024-08-10 12:32:35","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":232103,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup of the all-cause of reintubation rate within 7 days according to age and diagnosis.\u003c/p\u003e","description":"","filename":"Figure3.pic.png","url":"https://assets-eu.researchsquare.com/files/rs-4705123/v1/1f1e408cbec42b11461dfaae.png"},{"id":62189952,"identity":"08918122-1b1c-468d-a361-5e867f76aef4","added_by":"auto","created_at":"2024-08-10 12:24:35","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":138559,"visible":true,"origin":"","legend":"\u003cp\u003eMortality rate\u003c/p\u003e","description":"","filename":"Figure4.pic.png","url":"https://assets-eu.researchsquare.com/files/rs-4705123/v1/c49a4af9f60f3072ab194f22.png"},{"id":62189951,"identity":"9157698d-3e73-49a0-b8d0-3c0aa8d9dc32","added_by":"auto","created_at":"2024-08-10 12:24:35","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":137988,"visible":true,"origin":"","legend":"\u003cp\u003eICU length of stay\u003c/p\u003e","description":"","filename":"Figure5.pic.png","url":"https://assets-eu.researchsquare.com/files/rs-4705123/v1/dcad72e036019fc828b56e73.png"},{"id":62191024,"identity":"806bf56c-bac8-4244-b4a1-ac2a6ff7c879","added_by":"auto","created_at":"2024-08-10 12:40:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":436956,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4705123/v1/3b3df8a1-6da8-485f-b13a-22f25b68f620.pdf"},{"id":62190810,"identity":"ff5303ea-ec24-4e5e-928d-63611af351d2","added_by":"auto","created_at":"2024-08-10 12:32:35","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":863367,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-4705123/v1/70d25b88a5e1b3b5e62fd383.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effects of Different Non-invasive Respiratory Support in Preventing Reintubation in Patients at High Risk for Extubation Failure: A Systematic Review and Meta-Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eInvasive mechanical ventilation has been reported to be required in approximately 40%-70% of patients in the intensive care unit (ICU) \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e, and extubation is usually considered after stabilization.\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIt is reported\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e that about 25\u0026ndash;30% of patients are at high risk of extubation failure, which can lead to a poorer prognosis\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Patients at high risk of extubation failure were regarded as those who had been on invasive mechanical ventilation for more than 24 hours and met at least one of the risk factors for extubation failure\u003csup\u003e[\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e, which included age\u0026thinsp;\u0026ge;\u0026thinsp;65 years, obesity, and concomitant chronic obstructive pulmonary disease (COPD) or other disease\u003csup\u003e[\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. Therefore, as a preventive measure, noninvasive respiratory support is often used after extubation to avoid respiratory failure or reintubation\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e, such as NIV and HFNC. NIV delivered oxygen through a sealed mask, which was thought to be detrimental to sputum expulsion\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. The HFNC delivers heated, humidified, and more concentrated oxygen through a small, flexible nasal cannula\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e, effectively managing the patient's respiratory secretions\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e and reducing dead space ventilation\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. According to guideline recommendations\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e, HFNC is considered as a safer and more tolerable form of oxygen delivery compared to noninvasive ventilation. Previous systematic reviews and meta-analyses suggested that the application of HFNC can be used as an alternative treatment for NIV after extubation in critically ill patients\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. Nevertheless, Zhao et al.\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e concluded that HFNC is superior to conventional oxygen therapy (COT), which addresses some of the limitations of COT\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e, such as unreliable FiO2 delivery and patient self-inflicted lung injury, in terms of intubation rates, it is not superior to NIV.\u003c/p\u003e \u003cp\u003eAlthough there have been many meta-analyses comparing HFNC and NIV, the majority of the articles\u003csup\u003e[\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e included in the study are from 2015 to 2021, and only a few studies compared HFNC and NIV alone, raising concern that the real benefits may be covered. Given these uncertainty issues about the clinical benefits of HFNC and recent evidence from four trials with more than 700 additional patients, We conducted an updated systematic review and meta-analysis to evaluate the efficacy and safety of HFNC compared with NIV in patients at high risk for extubation failure. We specifically focused on articles published in the past three years to update past results.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eSearch Strategy and Selection Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines\u003csup\u003e[23]\u003c/sup\u003e and was prospectively registered with the CRD42023492756.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTwo independent reviewers (GDY and LSW) searched Embase, PubMed, Web of Science, the Cochrane Library, and CNKI for eligible studies from Jan 1, 2019, to Jan 1, 2024. The reference lists of included studies were reviewed for any additional eligible studies. The detailed search strategy is available in the supplementary materials.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe inclusion criteria were as follows:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e1. Population: A patient at high risk for extubation failure is defined as a patient who has been intubated for greater than or equal to 24 hours is ready to be extubated, and meets one of the following criteria.\u003csup\u003e[7, 8, 24, 25]\u003c/sup\u003e: (i) age ≥ 65 years; (ii) underlying cardiac or respiratory disease; (iii) Acute Physiology and Chronic Health Evaluation (APACHE II) score \u0026gt; 12 on extubation day; (iv) body mass index (BMI) \u0026gt; 30 kg/m\u003csup\u003e2\u003c/sup\u003e; (v) airway patency problems, inability to deal with respiratory secretions (inadequate cough reflex or suctioning required \u0026gt; 2 times within 8 h before extubation); (vi) difficult or prolonged weaning (failing ≥ 1 attempt at disconnection from mechanical ventilation); (vii) comorbidities ≥ 2; (viii) mechanical ventilation ≥ 7 days, and/or hypercapnia (PaCO2 \u0026gt; 45 mmHg) at the end of the spontaneous breathing test (SBT).\u003c/p\u003e\n\u003cp\u003e2. Intervention: The intervention group received HFNC, while the control group received NIV;\u003c/p\u003e\n\u003cp\u003e3. Outcomes: All-cause reintubation within 7 days rate as the primary outcome, or secondary outcomes include mortality at longest follow-up, length of hospital stay (LOS), duration of stay ICU, and respiratory rate.\u003c/p\u003e\n\u003cp\u003eThe exclusion criteria were as follows: (i) the study that compared HFNC with COT or other protocol combined; (ii) data that could not be extracted by the statistical methods or non-targeted outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Extraction\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData were extracted by two independent reviewers in a blinded way to avoid bias. Extracted data\u0026nbsp;were stored in a self-restraint Excel database, including study design, country, patient characteristics, intervention, and outcomes.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Synthesis and Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMeta-analyses were conducted using a meta package (version 7.0-0) in R (version 4.3.1). Continuous outcomes were extracted as sample size and mean (SD) or median (IQR) provided in the studies,\u0026nbsp;with the conversion of medians to estimated mean (SD).\u0026nbsp;The standardized mean difference, however, has been found to have an upward bias when the sample size of a study is small\u003csup\u003e[26]\u003c/sup\u003e, especially when n≤20, Hedges’g was used to correct for small-sample bias.\u0026nbsp;Dichotomous data were expressed as a risk ratio (RR).\u0026nbsp;For each analysis, studies were weighted using the inverse variance method, and data were pooled using a random effects meta-analyses model accounting for the incidence.\u003c/p\u003e\n\u003cp\u003eStatistical heterogeneity assessment between studies was performed by Cochran’s Q test and reported with the I² and Chi squared (χ²) statistics, in which I² indicated the degree of heterogeneity as follows: insignificant heterogeneity (0–30%), moderate heterogeneity (30–60%), substantial heterogeneity (50–90%), and considerable heterogeneity (75–100%). P-value equal to 0.05 or less was considered to be statistically significant. Then, we used the find outliers and influence cases to examine heterogeneity and verified the pooled effect estimate we found is robust based on the guideline\u003csup\u003e[27]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRisk of bias assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo reviewers independently evaluated the methodological quality of all included studies using The Revised Cochrane risk-of-bias tool for randomized trials (RoB2)\u003csup\u003e[28]\u003c/sup\u003e. The RoB2 includes five domains: (1) Risk of bias arising from the randomization process; (2) Risk of bias due to deviations from the intended interventions (effect of assignment to intervention); (3) Missing outcome data; (4) Risk of bias in the measurement of the outcome; (5) Risk of bias in the selection of the reported result. Each domain has several signaling questions which used to assess the quality of studies. The risk of bias can be assessed as “low risk of bias”, “some concerns” and “high risk of bias” in each domain. Full details are provided in the Supplementary materials. Any disagreement regarding study selection, data extraction, or quality assessments was resolved by a consensus discussion with another investigator (JP).\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStudy Selection and Characteristics\u003c/h2\u003e \u003cp\u003eA total of 4512 studies were identified based on our search strategies. We then screened 1144 titles and abstracts after the removal of duplicates, and 131 full-text articles were for eligibility. Finally, we included nine \u003csup\u003e[\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan additionalcitationids=\"CR30 CR31 CR32 CR33\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003estudies, of which, six were RCTs\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e and three \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e were observed studies, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Among 1289 patients included in this study, 1107 patients were at high risk of extubation failure, 182 patients were at very high risk of extubation failure. The study characteristics are summarised in Table\u0026nbsp;1(see the Supplementary materials).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe risk of bias assessments for the primary outcome was shown in the supplementary materials. For RCTs, one was assessed as low risk of bias, four studies raised some concerns, and one was considered at high risk of bias based on The Cochrane risk-of-bias tool. Among the observation studies, two were considered at low risk of bias assessed by the NOS, and another one was considered at moderate risk of bias.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePrimary Outcome\u003c/h2\u003e \u003cp\u003eAll the included studies reported all-cause reintubation rates within seven days for patients requiring reintubation. The pooled estimates demonstrated that there was no statistically significant difference in the rate of all-cause reintubation within seven days in patients at high risk for failure to prevent extubation in HFNC compared with NIV (RR 1.1729 [95% Cl: 0.8679\u0026ndash;1.5851], I\u0026sup2;=16%; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eMoreover, in the subgroup analysis no significant differences in reintubation rate were found (RR 0.8268 [95% Cl 0.5985\u0026ndash;1.1422], I\u0026sup2;=0%; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) either, which included age\u0026thinsp;\u0026ge;\u0026thinsp;65 (RR 0.9456 [95% Cl: 0.5995\u0026ndash;1.4915], I\u0026sup2;=10.6%) and COPD (0.7026 [95% Cl: 0.4251\u0026ndash;1.1614], I\u0026sup2;=0) populations (see in the Supplementary materials).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eSecondary outcomes\u003c/h2\u003e \u003cp\u003eAll nine studies with data on mortality showed that HFNC significantly reduced the mortality rate compared to NIV(RR 0.6822 [95% Cl: 0.4795\u0026ndash;0.9706], I\u0026sup2;=0%; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSix studies\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e reported the ICU length of stay as an outcome, there was no significant difference between the HFNC group and the NIV group (SMD 0.0256 [95% Cl: -0.0195-0.0708], I\u0026sup2;=0%; Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Respiratory rate was reported in three studies\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e with no difference between the two groups (SMD \u0026minus;\u0026thinsp;0.00 [95% Cl: \u0026minus;0.20; 0.19], I\u0026sup2;=0%; see in the Supplementary materials).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analyses\u003c/h2\u003e \u003cp\u003eAccording to the leave-1-out sensitivity analysis, when removing 1 study at a time, the pooled results of reintubation, mortality, and ICU length of stay, no difference emerged (see in the Supplementary materials).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this systematic review and meta-analysis, our study found that HFNC was not superior to NIV in reducing the reintubation rate in patients at high risk of extubation failure, but the mortality rate was significantly lower in the HFNC group than in the NIV group. Three studies\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e reported adverse events with no complications in the HFNC group. There were, however, mild complications in the NIV group, such as skin breakdown, facial skin ulcer, and abdominal distension.\u003c/p\u003e \u003cp\u003eAlthough we found HFNC lowering the reintubation rate in patients at high risk of extubation failure was not superior to the NIV, a favorable effect cannot be neglected. Furthermore, no adverse events were reported in the HFNC group across all trials. Compared to NIV, HFNC precisely regulates FiO\u003csub\u003e2\u003c/sub\u003e by providing moist oxygen flow, which not only helps the patient to remove excreta and promotes effective gas exchange, but also prevents the patient from open-mouth breathing, which can lead to lung damage and bloating due to respiratory effort, and makes him/her feel relatively more comfortable.\u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e. In addition, there may be some correlation between the rate of reintubation and other outcomes in this study, so respiratory rate and length of hospitalization were also not statistically significant when comparing the two groups of patients. However, in contrast, NIV patients had shorter ICU stays with narrower 95% confidence intervals, although the outcome was not statistically significant. This may be due to the increased rate of reintubation in the HFNC group leading to an increase in their length of hospitalization. This could be the reason why the guidelines recommend the use of NIV more to reduce the rate of reintubation\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eA notable disparity in mortality was observed in this system review and meta analysis, which was in line with the findings in the recently published studies\u003csup\u003e[\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. Nevertheless, in previous meta-analyses\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e, it was insignificant between two groups. The difference may be that fewer studies were included in previous meta-analyses to compare the effect of receiving NIV or HFNC alone and high heterogeneity was also observed. Furthermore, previous research studies have also demonstrated that compared to receiving NIV, the implementation of HFNC\u0026thinsp;+\u0026thinsp;NIV contributes to a decrease in reintubation rate among patients at high risk of extubation failure\u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e, but the mortality rate increased\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eNIV\u0026thinsp;+\u0026thinsp;HFNC used interchangeably may be an effective strategy to reduce reintubation rate after extubation\u003csup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e. However, in comparison to the solitary utilization of NIV, the question of whether the combination of NIV\u0026thinsp;+\u0026thinsp;HFNC provides greater benefits for the high-risk extubation failure population, or if it may potentially lead to an increase in adverse outcomes, remains to be determined through further multicenter studies. At the same time, consideration also needs to be given to the economic burden on patients post-hospital admission with a combination of NIV and HFNC.\u003c/p\u003e \u003cp\u003eSeveral reasons may explain the higher mortality of NIV. First, among the included studies, most trials used NIV prophylactically, while three studies\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e started NIV at the time of respiratory failure or the emergence of a window for pulmonary infection control. Using NIV to treat respiratory insufficiency after extubation (post-extubation failure) was not recommended in an international consensus conference\u003csup\u003e[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/sup\u003e. Moreover, two RCTs\u003csup\u003e[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/sup\u003e showed that no benefit could get from the use of NIV after respiratory failure to avoid reintubation. Reintubation of patients with respiratory failure after using NIV leads to delayed intubation, and the time between extubation and reintubation is an independent risk factor for increased mortality in reintubated patients\u003csup\u003e[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/sup\u003e. In the study by Ferrer et al\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e, respiratory failure was the most common cause of death in these patients, and the early application of NIV is effective in avoiding respiratory failure and reducing extubation failure in high-risk patients.. Therefore, prophylactic use of NIV is important for the prognosis of people at high risk of extubation\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]\u003c/sup\u003e. Second, most of the people at high risk for extubation failure in the studies included in this paper had respiratory diseases such as COPD, and severe pneumonia. These respiratory conditions may result in inadequate secretion clearance or narrowing of the airway\u003csup\u003e[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]\u003c/sup\u003e. The use of NIV in patients with respiratory disease may lead to airway obstruction or infection, as the sealed environment of oxygenation using a mask may cause sputum to accumulate and not be easily expelled, and respiratory failure may be induced by obstruction of the upper airway, which may lead to failure of the NIV treatment. The study of Liu et al\u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003esimilarly reached a consistent conclusion, demonstrating a higher mortality rate in the NIV group (14.3%) compared to the HFNC group (9.1%) among patients with sputum volume\u0026thinsp;\u0026ge;\u0026thinsp;20 mL within 24 hours. Moreover, the inability to spontaneously remove secretions is considered a relative contraindication for NIV\u003csup\u003e[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]\u003c/sup\u003e, especially in patients with impaired consciousness and weak cough reflex\u003csup\u003e[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]\u003c/sup\u003e, careful consideration and individualized assessment are crucial before initiating NIV\u003csup\u003e[\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]\u003c/sup\u003e. Therefore, patients at high risk of extubation failure with respiratory disease need to carefully consider to use of NIV.\u003c/p\u003e \u003cp\u003eConcerning the risk of bias assessment, the main issue concerned the blinding. Patients are aware of the implementation of interventions post-enrollment, which could not impact outcome assessment. As the time of reintubation is beyond the control of patients, with the majority of trials\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003eindicating that the decision for reintubation is based on pre-established criteria. In most included studies, apart from the different of intervention of ventilation\u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e, both intervention and control groups received consistent medical management. Although one study\u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e that did not employ randomization in grouping was considered low quality, the rest were considered high quality. Furthermore, among the articles included, only one is a multicenter conducted study\u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e, and some studies\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e were small sample sizes, potentially introducing bias into the results.\u003c/p\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and limitations\u003c/h2\u003e \u003cp\u003eWe used two approaches\u003csup\u003e[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/sup\u003e (find outlier and influence cases ) to avoid one or more studies with extreme effect sizes from distorting our pooled effect estimate and certifying if the pooled effect estimate we found is robust. Eventually, we did not find outliers, but the studies of Hern\u0026aacute;ndez et al\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e and Liu et al\u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e may be regarded as potentially relevant cases since they contribute heavily to the overall heterogeneity in our meta-analysis. Therefore, we conducted and reported the results and pooled estimates in which both studies were excluded. The results were robust, and further sensitivity analysis was approved (see in the Supplementary materials), indicating that no individual study had impacted the overall results.\u003c/p\u003e \u003cp\u003eThere are several limitations in this study. First, only a few studies reported the results separately based on the diagnosis of the population, such as COPD, acute heart failure, and the change of patient\u0026rsquo;s arterial blood gas. Therefore, we were not able to assess the impact of HFNC on patient outcomes with concrete disease. Second, only interventions with HFNC and NIV were included in this meta-analysis, thus the results might not be generalizable to other intervention protocols. Further studies could try a program that combines HFNC and NIV, merging the strengths of each measure to maximize its effect.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eHigh Flow Nasal Cannula may be a promising treatment for patients at high risk of extubation failure, although the benefit of decreasing the risk of reintubation was not significantly superior to noninvasive ventilation, the impact on mortality was notable. Moreover, patients in the NIV group reported small number of adverse events, such as facial skin breakdown and bloating, while no adverse events were found in the HFNC group. Thus, larger sample sizes and more rigorous studies need to be conducted exploring the impact on HFNC and NIV for patients at high risk of extubation failure .\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eHFNC\u003c/p\u003e\n\u003cp\u003eHigh Flow Nasal Cannula\u003c/p\u003e\n\u003cp\u003eNIV\u003c/p\u003e\n\u003cp\u003eNoninvasive Ventilation\u003c/p\u003e\n\u003cp\u003eCOT\u003c/p\u003e\n\u003cp\u003eConventional oxygen therapy\u003c/p\u003e\n\u003cp\u003eIPAP\u003c/p\u003e\n\u003cp\u003einspired positive airway pressure\u003c/p\u003e\n\u003cp\u003eEPAP\u003c/p\u003e\n\u003cp\u003eExpiratory Positive Airway Pressure\u003c/p\u003e\n\u003cp\u003eCOPD\u003c/p\u003e\n\u003cp\u003echronic obstructive pulmonary disease\u003c/p\u003e\n\u003cp\u003eBMI\u003c/p\u003e\n\u003cp\u003eBody Mass Index\u003c/p\u003e\n\u003cp\u003eICU\u003c/p\u003e\n\u003cp\u003eIntensive care unit\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u0026nbsp;\u003c/strong\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest:\u003c/strong\u003e The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eProject from Sichuan Provincial Science and Technology Department (2023YFS007).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor’s contribution:\u0026nbsp;\u003c/strong\u003eGDY, MXR designed the study. GDY, MXR, LSW, and JP acquired the data. GDY, MXR, and LSW drafted the manuscript. GDY, MXR, JP, LSW, WL, and WZZ performed the statistical analyses. GDY, MXR, and LSW are guarantors of the data and manuscript. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTobin M, Manthous C. Mechanical Ventilation [J]. Am J Respir Crit Care Med, 2017, 196(2): P3-p4.DOI: 10.1164/rccm.1962P3.\u003c/li\u003e\n\u003cli\u003eWalter K. Mechanical Ventilation [J]. Jama, 2021, 326(14): 1452.DOI: 10.1001/jama.2021.13084.\u003c/li\u003e\n\u003cli\u003eEsteban A, Anzueto A, Al\u0026iacute;a I, et al. How is mechanical ventilation employed in the intensive care unit? An international utilization review [J]. 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Eur Respir J, 2008, 31(4): 874-86.DOI: 10.1183/09031936.00143507.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"high flow nasal cannula, noninvasive ventilation, extubation, reintubation","lastPublishedDoi":"10.21203/rs.3.rs-4705123/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4705123/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003ePatients at high risk for extubation failure are subject to suffering reintubation or respiratory failure after extubation that adversely affects outcomes. It’s essential that rapidly identifying respiratory failure and correctly applying respiratory support for adequate treatment to avoid reintubation for patients. The high-flow nasal cannula (HFNC) is a safer and more comfortable respiratory support than noninvasive mechanical ventilation (NIV). However, whether HFNC is superior to NIV for preventing reintubation in patients at high risk of extubation failure is unclear. The present study aims to investigate the efficacy of HFNC for preventing reintubation in various high risk populations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e In this systematic review and meta analysis, we searched PubMed, Embase, Web of Science, Cochrane Library, and CNKI for studies from Jan 1, 2019, to Jan 1, 2024. Two independent reviewers screened studies, extracted the data from the reports, and assessed the risk of bias. The primary outcomes were the reintubation rate within 7 days and effect size calculated as risk ratio (RR; 95% Cl), the secondary outcomes were the rate of mortality(RR; 95% Cl) and ICU length of stay (SMD; 95% Cl) and respiratory rate (SMD; 95%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e A total of 1,289 patients were included in 9 studies, of which 6 were randomized controlled trials and 3 were observational studies. A significant decrease in the mortality risk was found in the HFNC group(RR 0.6822 [95% Cl: 0.4795-0.9706]) compared to the NIV group. However, there was no significant difference in reintubation rate (RR 1.1729, 95% CI: 0.8679–1.5851) and ICU length of stay (SMD 0.0256, 95% CI: -0.0195–0.0708). All adverse events associated with NIV were reported in three studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e For patients who are at high risk of extubation failure, the HFNC can decrease the risk of mortality, to some extent, compared to NIV, but the reintubation rate and ICU length of stay were not superior to NIV.\u003c/p\u003e","manuscriptTitle":"Effects of Different Non-invasive Respiratory Support in Preventing Reintubation in Patients at High Risk for Extubation Failure: A Systematic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-10 12:24:30","doi":"10.21203/rs.3.rs-4705123/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0ab07067-4bcb-446c-807a-3aa4109ec4d1","owner":[],"postedDate":"August 10th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-10-09T11:53:40+00:00","versionOfRecord":[],"versionCreatedAt":"2024-08-10 12:24:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4705123","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4705123","identity":"rs-4705123","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}