Days spent on non-invasive ventilation support: Can it determine when to initiate VV-ECMO? Observational study in a cohort of Covid-19 patients.

Days spent on non-invasive ventilation support: Can it determine when to initiate VV-ECMO? Observational study in a cohort of Covid-19 patients. | 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 Days spent on non-invasive ventilation support: Can it determine when to initiate VV-ECMO? Observational study in a cohort of Covid-19 patients. María P. Fuset-Cabanes, LLuisa Hernández-Platero, Joan Sabater-Riera, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2766314/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Aug, 2023 Read the published version in BMC Pulmonary Medicine → Version 1 posted 8 You are reading this latest preprint version Abstract Background: The study evaluates the impact of the time between commencing non-invasive ventilation (NIV) support and initiation of venovenous extracorporeal membrane oxygenation (VV-ECMO) in a cohort of critically ill patients with coronavirus disease 2019 (COVID-19) associated acute respiratory distress syndrome (ARDS). Methods: Prospective observational study design in an intensive Care Unit (ICU) of a tertiary hospital in Barcelona (Spain). All patients requiring VV-ECMO support due to COVID-19 associated ARDS between March 2020 and January 2022 were analysed. Survival outcome was determined at 90 days after VV-ECMO initiation. Demographic data, comorbidities at ICU admission, RESP (respiratory ECMO survival prediction) score, antiviral and immunomodulatory treatments received, inflammatory biomarkers, the need for vasopressors, the thromboprophylaxis regimen received, and respiratory parameters including the length of intubation previous to ECMO and the length of each NIV support (high-flow nasal cannula, continuous positive airway pressure and bi-level positive airway pressure), were also collated in order to assess risk factors for day-90 mortality. The effect of the time lapse between NIV support and VV-ECMO on survival was evaluated using logistic regression and adjusting the association with all factors that were significant in the univariate analysis. Results: Seventy-two patients finally received VV-ECMO support. At 90 days after commencing VV-ECMO 35 (48%) had died and 37 (52%) were alive. Multivariable analysis showed that at VV-ECMO initiation, age (p=0.02), lactate (p=0.001), and days from initiation of NIV support to starting VV-ECMO (p=0.04) were all associated with day-90 mortality. Conclusions: In our small cohort of VV-ECMO patients with COVID-19 associated ARDS, the time spent between initiation of NIV support and VV-ECMO (together with age and lactate) appear to be a better predictor of mortality than that between intubation and VV-ECMO. ARDS Extracorporeal Membrane Oxygenation Non-invasive Ventilation COVID-19 Respiratory Insufficiency. Figures Figure 1 Figure 2 Background The number of days spent on mechanical ventilation before interventions, such as venovenous extracorporeal membrane oxygenation (VV-ECMO) (1) or steroids (2), has been used to classify different clinical stages of the acute respiratory distress syndrome (ARDS) trying to differentiate between an early phase, most of the times defined within the first week from intubation when interventions could potentially change the ARDS evolution, and a late phase, normally more than seven days from intubation when interventions would theoretically be ineffective. This classification, where day 0 is defined by the day of intubation, represents a somewhat historic cohort given that most of the patients with hypoxemic acute respiratory failure (ARF) were not treated with any form of non-invasive ventilation (NIV) prior to intubation. During the coronavirus disease 2019 (COVID-19) pandemic, the use of NIV for hypoxemic ARF extraordinarily increased, initially due to logistical (3) reasons, but soon after it became a more standard practice with observational reports showing that this NIV approach could be associated with a decrease in mortality (although study designs do not allow inferring causality) especially when compared to that of an early intubation approach (4, 5, 6). NIV in whatever form it be, high-flow nasal cannula (HFNC), continuous positive airway pressure (CPAP), or bi-level positive airway pressure (BiPAP), probably heralds the initial stage of alveolar collapse of ARDS where positive pressure is required to maintain adequate oxygenation (7, 8)It seems reasonable that patients with severe stages of ARDS may require higher pressures of NIV (CPAP or BIPAP) that with HFNC can not be achieved. Some trials performed during the COVID pandemics have reported results in this direction revealing that higher pressures with NIV could be associated with lower rates of intubation or even mortality. (9, 10). However, important concerns still exist respect to the effect that these pressures may have in the lung specially regarding the patient’s self-inflicted lung injury (P-SILI) hypothesis (11) although no solid scientific data has demonstrated so far that invasive ventilation would be less harmful than non-invasive ventilation on the P-SILI mechanism, especially when high PEEP is required or recruitment manoeuvres are performed (12, 13). Of note, VV-ECMO has been extensively used during the pandemic, but some authors report that VV-ECMO outcomes appear to have worsened in parallel with an increased use of NIV (14). This has been explained, in part, through the hypothesis of a P-SILI mediated effect(11), although ARDS severity (clinical stage) might be another reason as these patients receiving previous NIV support would probably be initiated on ECMO later than those who are directly intubated. Regardless of this last hypothesis and of previous publications, no data to-date has been reported regarding the number of days VV-ECMO patients spend on NIV support that may influence their final outcome. It is interesting to observe how the scales most used and recommended by the ELSO (Extracorporeal Live Support Organization) to predict mortality before the start of ECMO is the RESP score (respiratory ECMO survival prediction) and includes the number of days that patients have been on mechanical ventilation, but this period of time only includes since the start of ECMO. The patient was intubated and does not consider the time on previous NIV to intubation (15, 16, 17). Our hypothesis is that the time lapse between NIV initiation and VV-ECMO is as important as the time lapse between intubation and VV-ECMO when considering initiating a patient on VV-ECMO due to hypoxemic ARF. To demonstrate this hypothesis, we studied all patients requiring VV-ECMO during the COVID-19 pandemics and we evaluated all mortality risk factors with special consideration to all those factors related to the use of NIV previous to VV-ECMO. The aim in this single centre study was to examine the relationship between the use of NIV and mortality in VV-ECMO patients during the COVID-19 pandemic and whether this could be correlated with the time spent on NIV rather than to the use of NIV, per se. Methods We collected data prospectively from our intensive care unit (ICU) of our university hospital (Hospital Universitari de Bellvitge, Barcelona) in Spain. We included all adults with ARDS who required VV-ECMO (according to Berlin definition) (18) and SARS-Cov-2 infection as tested by real-time reverse transcriptase-polymerase chain reaction in respiratory fluids, between March 2020 to January 2022. All demographic data, relevant comorbidities, and Sequential Organ Failure Assessment (SOFA) score at ICU admission were collected. SOFA and RESP scores were noted on initiation of VV-ECMO. Antiviral and immunomodulatory treatments received, the need for vasopressors (yes/no), the thromboprophylaxis regimen received, and respiratory parameters including the length of each ventilation support were also collected. Criteria for endotracheal intubation (ETI) and VV-ECMO initiation followed the recommendations from the Spanish critical care society (SEMICYUC) (19) and ELSO respectively (20) although application of these criteria did depend on our hospital crisis capacity, especially during the first two months of pandemic (March-June, 2020). Survival at 90 days after VV-ECMO was monitored and initiation of NIV was considered when patients started on any available modality (HFNC, CPAP, or BiPAP). In order to evaluate the global effect of the time lapse between NIV and VV-ECMO, we had to make the presumption that in those patients who did not receive NIV, their day 0 was the day of intubation. Bivariable analyses were conducted to explore the association between death at 90 days after VV-ECMO initiation and each of the predefined risk factors. Continuous variables were compared using sample t-test and Mann Whitney test. Categorical data were compared using the Chi-square test or Fisher exact test. The effect of the time lapse between NIV and VV-ECMO on survival was evaluated using logistic regression and adjusting the association with all factors that were significant in the univariate analysis. The association measures were calculated (adjusted odds ratio [OR]) with a confidence interval (CI) of 95%. The study was approved by the medical ethics committee at Bellvitge Hospital (PR40/21). Results From March 2020 to January 2022, 519 subjects fulfilling the study criteria were admitted to the ICU. 429 patients (83%) had received some modality of NIV before ICU admission with a median (IQR) time of 1 (0-3) days. Within the first day from ICU admission 318 patients (61%) had been intubated but the other 201 (39%) subjects continued on NIV support from which 118 (59%) were finally intubated. Among these ARDS patients, for the purpose of our study we only evaluated the 72 subjects (14%) that were finally initiated on VV-ECMO (Figure 1) . The median (IQR) time from intubation to VV-ECMO was 4 (2-9) days whereas the complete median time spent from NIV support to ECMO (which also includes the time spent with intubation) was 9 (5-15) days. Supplementary Table 1 , shows the demographic data, clinical characteristics and outcomes of these 72 patients according to their survival status 90 days after VV-ECMO initiation. As demonstrated 35 (48%) had died and 37 (52%) were alive. Patients who were alive at 90 days after VV-ECMO initiation were more likely to be younger and have a shorter length of days from NIV to VV-ECMO. Figure 2 , shows the mortality across the different groups according to NIV or IMV. Interestingly, RESP score and D-dimer at ECMO initiation were higher among survivors whereas lactate was lower. Times from hospital to VV-ECMO, ICU to VV-ECMO, or intubation to VV-ECMO were all shorter in those patients who survived to day 90 although none of them were statistically significant. Multivariable analysis ( Table 1 ) showed that at VV-ECMO initiation, age, lactate and days from NIV support to VV-ECMO were strongly associated with day-90 mortality. Table 1. Multivariable Logistic Regression of Factors Associated with 90-Day Mortality. OR 95% P Value Age, yr 1.06 1.01-1.12 0.02 PEEP, cm H 2 O 0.93 0.81-1.07 0.3 Days NIV -ECMO 1.03 1.01-1.05 0. 04 Lactate, mmol/L 1.27 1.11-1.44 0.001 D-Dimer, µg/L 1 0.99-1.01 0.5 paO 2 /FIO 2 , ratio 0.99 0.97-1.01 0.2 Definition of abbreviations: PEEP Positive end Expiratory Pressure, NIV Non Invasive Ventilation, ECMO Extracorporeal Membrane Oxygenation Discussion A recent large multicenter study showed an increased mortality in ECMO patients with COVID-19 associated ARDS who had received NIV previous to intubation (21) Many of the patients who received NIV during the pandemic are ARDS patients who in other circumstances or in other centers would have been intubated. (22, 23). Furthermore, the majority of scores that predict mortality in VV-ECMO only include the time spent on invasive mechanical ventilation before ECMO (but not on NIV support) (24). In our cohort of VV-ECMO patients with COVID-19 associated ARDS, the time lapse between NIV support and commencing VV-ECMO (together with age and lactate) seems a better predictor when evaluating survival than the time between intubation and VV-ECMO. Our results suggest the significance that NIV support plays on ARDS patients and in our opinion, this is not only related to a hypothetical P-SILI effect (11), but also reflects a more advanced clinical stage of ARDS when VV-ECMO is finally initiated. Age and lactate are clearly related to mortality when VV-ECMO is initiated as in the majority of critically ill patients who present any kind of organ dysfunction (21, 24). In fact, both age and lactate are included in the majority of the risk-assessment severity scores used for any kind of ECMO support (25, 26). Nevertheless, due to the improvement of organ transplant programs (including lung transplant), the better quality of life of older people, and due to other more complex social demands, age keeps being a time changing criteria and nowadays treatment indications are being extended to groups of age that not long ago would have been excluded. This includes also VV-ECMO indications that in the past were clearly age-limited but nowadays have to be patient-personalised because some of these “older” patients might even be candidates for lung transplant or might have excellent qualities of life with no other comorbidities (27). Although in our small cohort of patients the time lapse from ETI to VV-ECMO was not significant in terms of mortality it is one of the most employed criteria when evaluating the mortality risk of the technique as those patients initiated more than 7 days after ETI have proved to have worse outcomes than those initiated within the first week. This is probably related to a more advanced stage of ARDS in those patients with a delayed initiation of VV-ECMO when compared to those with an early initiation of VV-ECMO. However, this phenomenon is common to other forms of mechanical organ support in critically ill patients such as renal replacement therapy or invasive mechanical ventilation, where a delayed initiation strategy is associated with a worse outcome when organ support is finally required, but also with a much better outcome when patients finally do not require organ support (28). An early identification of all those patients who will finally require organ support in a delayed and deleterious period is probably one of the most compelling brain exercises that still exist in critical care medicine together with the appropriate quantity of fluids to be used in patients with shock. An important confounding variable in the assessment of time from NIV initiation to VV-ECMO is the duration of invasive ventilation that somehow makes our hypothesis seem overly simplistic. This is an important limitation of our study design. In our study, no association was found between the use of NIV previous to VV-ECMO and mortality, although the small size of the population is another important limitation. On the other hand, the lack of information on the pressures applied to these patients and the absence of cross-sectional protocols does not allow the identification of patients who have been treated with high parameters perhaps comparable to those of intubated patients. A confounding variable in most studies could be the failure to differentiate patients who received high flow from those who received BiPAP or CPAP, understanding that these last patients who require higher pressures are those who present severe ARDS (SAFE-LUNG study) (9,10) Conclusions We suggest, based on our findings, that the time spent between NIV support and initiation of VV-ECMO should be included in the mortality prediction scores for VV-ECMO (29) although further and larger studies are needed to confirm our findings. Abbreviations VV-ECMO: veno venous extracorporeal membrane oxygenator. COVID-19: coronavirus disease 2019. NIV: Non-invasive ventilation HFNC: High Flow nasal cannula BiPAP: Bi-level positive airway pressure CPAP: Continuous positive airway pressure NIPPV: Non-invasive positive pressure ventilation ARDS: Acute respiratory distress syndrome ARF: Acute respiratory failure ICU: intensive care unit P-SILI: patient self-inflicted lung injury SOFA: Sequential Organ Failure Assessment RESP: respiratory ECMO survival prediction IQR: Interquartile range CI: Confidence interval OR: odds ratio PEEP: Positive end expiratory pressure ETI: endotracheal intubation SEMICYUC: Spanish critical care society ELSO: Extracorporeal Life Support Organization Declarations Ethics approval and consent to participate: The study was finally approved by the local ethics committee at Bellvitge University Hospital in January 2021 (PR40/21), who waived the need for informed consent and confirmed that all procedures were followed in accordance with the institutional ethical standards and with the Helsinki Declaration of 1975. Consent for publication: Not applicable. Availability of data and materials: All data generated or analysed during this study are included in this published article [and its supplementary information files]. Competing interests: None. Funding: None. Authors' contributions: M.P.F., L.H., and X.P contributed equally to this work. M.G., F.P., P.C., M.P., P.S., J.Y., A.G., and K.M. collected data. M.P.F. and X.P. performed the analysis. M.P.F., L.H., and X.P. wrote the manuscript. J.S. critically reviewed the manuscript. All authors approved the final version of the manuscript. Acknowledgement: Not applicable. References Combes A, Hajage D, Capellier G, et al: EOLIA Trial Group, REVA, and ECMONet. Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome. N Engl J Med. 2018 May 24; 378(21):1965-1975. Steinberg KP, Hudson LD, Goodman RB, et al: National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. 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Supplementary Files SupplementaryTable1.docx Cite Share Download PDF Status: Published Journal Publication published 26 Aug, 2023 Read the published version in BMC Pulmonary Medicine → Version 1 posted Editorial decision: Major revision 03 May, 2023 Reviews received at journal 18 Apr, 2023 Reviewers agreed at journal 17 Apr, 2023 Reviewers invited by journal 17 Apr, 2023 Editor assigned by journal 13 Apr, 2023 Editor invited by journal 13 Apr, 2023 Submission checks completed at journal 13 Apr, 2023 First submitted to journal 01 Apr, 2023 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. 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Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alejandro","middleName":"","lastName":"García-Zaloña","suffix":""},{"id":191496315,"identity":"42f674bf-ec68-4226-9e06-aa4ed3cc4d45","order_by":11,"name":"Javiera Puentes-Yañez","email":"","orcid":"","institution":"Bellvitge University Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Javiera","middleName":"","lastName":"Puentes-Yañez","suffix":""}],"badges":[],"createdAt":"2023-04-01 23:59:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2766314/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2766314/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12890-023-02605-2","type":"published","date":"2023-08-26T15:01:17+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":35893972,"identity":"04e23c2f-75a6-4d16-bd40-0ccdd468c10a","added_by":"auto","created_at":"2023-04-17 20:43:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":28212,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-2766314/v1/f6855412c9e818a736c5ca71.png"},{"id":35893970,"identity":"bfb9f32c-b2cb-4d4e-9293-3bd1a13ed808","added_by":"auto","created_at":"2023-04-17 20:43:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":33330,"visible":true,"origin":"","legend":"\u003cp\u003eMortality\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-2766314/v1/041f876d3619fec3d96c25b3.png"},{"id":42781261,"identity":"95c317e4-bf2b-43de-af6e-4d1eec36d01f","added_by":"auto","created_at":"2023-09-07 15:09:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":310486,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2766314/v1/330a96c5-4e22-43b2-aea5-ca82505d59aa.pdf"},{"id":35893971,"identity":"37503c3b-2ca8-4e90-8908-330294505e1e","added_by":"auto","created_at":"2023-04-17 20:43:43","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":13419,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-2766314/v1/b8c5abe91878a52bb4716210.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Days spent on non-invasive ventilation support: Can it determine when to initiate VV-ECMO? Observational study in a cohort of Covid-19 patients.","fulltext":[{"header":"Background","content":"\u003cp\u003eThe number of days spent on mechanical ventilation before interventions, such as venovenous extracorporeal membrane oxygenation (VV-ECMO)\u0026nbsp;(1)\u0026nbsp;or steroids\u0026nbsp;(2), has been used to classify different clinical stages of the acute respiratory distress syndrome (ARDS) trying to differentiate between an early phase, most of the times defined within the first week from intubation when interventions could potentially change the ARDS evolution, and a late phase, normally more than seven days from intubation when interventions would theoretically be ineffective. This classification, where \u003cem\u003eday 0\u003c/em\u003e is defined by the day of intubation, represents a somewhat historic cohort given that most of the patients with hypoxemic acute respiratory failure (ARF) were not treated with any form of non-invasive ventilation (NIV) prior to intubation. During the coronavirus disease 2019 (COVID-19) pandemic, the use of NIV for hypoxemic ARF extraordinarily increased, initially due to logistical (3) reasons, but soon after it became a more standard practice with observational reports showing that this NIV approach could be associated with a decrease in mortality (although study designs do not allow inferring causality) especially when compared to that of an early intubation approach (4, 5, 6). NIV in whatever form it be, high-flow nasal cannula (HFNC), continuous positive airway pressure (CPAP), or bi-level positive airway pressure (BiPAP), probably heralds the initial stage of alveolar collapse of ARDS where positive pressure is required to maintain adequate oxygenation (7, 8)It seems reasonable that patients with severe stages of ARDS may require higher pressures of NIV (CPAP or BIPAP) that with HFNC can not be achieved. Some trials performed during the COVID pandemics have reported results in this direction revealing that higher pressures with NIV could be associated with lower rates of intubation or even mortality. (9, 10). However, important concerns still exist respect to the effect that these pressures may have in the lung specially regarding the patient’s self-inflicted lung injury (P-SILI) hypothesis (11) although no solid scientific data has demonstrated so far that invasive ventilation would be less harmful than non-invasive ventilation on the P-SILI mechanism, especially when high PEEP is required or recruitment manoeuvres are performed (12, 13). Of note, VV-ECMO has been extensively used during the pandemic, but some authors report that VV-ECMO outcomes appear to have worsened in parallel with an increased use of NIV (14). This has been explained, in part, through the hypothesis of a P-SILI mediated effect(11), although ARDS severity (clinical stage) might be another reason as these patients receiving previous NIV support would probably be initiated on ECMO later than those who are directly intubated. Regardless of this last hypothesis and of previous publications, no data to-date has been reported regarding the number of days VV-ECMO patients spend on NIV support that may influence their final outcome. It is interesting to observe how the scales most used and recommended by the ELSO (Extracorporeal Live Support Organization) to predict mortality before the start of ECMO is the RESP score (respiratory ECMO survival prediction) and includes the number of days that patients have been on mechanical ventilation, but this period of time only includes since the start of ECMO. The patient was intubated and does not consider the time on previous NIV to intubation (15, 16, 17).\u003c/p\u003e\n\u003cp\u003eOur hypothesis is that the time lapse between NIV initiation and VV-ECMO is as important as the time lapse between intubation and VV-ECMO when considering initiating a patient on VV-ECMO due to hypoxemic ARF. To demonstrate this hypothesis, we studied all patients requiring VV-ECMO during the COVID-19 pandemics and we evaluated all mortality risk factors with special consideration to all those factors related to the use of NIV previous to VV-ECMO. The aim in this single centre study was to examine the relationship between the use of NIV and mortality in VV-ECMO patients during the COVID-19 pandemic and whether this could be correlated with the time spent on NIV rather than to the use of NIV, per se.\u0026nbsp;\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eWe collected data prospectively from our intensive care unit (ICU) of our university hospital (Hospital Universitari de Bellvitge, Barcelona) in Spain. We included all adults with ARDS who required VV-ECMO (according to Berlin definition) (18) and SARS-Cov-2 infection as tested by real-time reverse transcriptase-polymerase chain reaction in respiratory fluids, between March 2020 to January 2022.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll demographic data, relevant comorbidities, and Sequential Organ Failure Assessment (SOFA) score at ICU admission were collected. SOFA and RESP scores were noted on initiation of VV-ECMO. Antiviral and immunomodulatory treatments received, the need for vasopressors (yes/no), the thromboprophylaxis regimen received, and respiratory parameters including the length of each ventilation support were also collected. Criteria for endotracheal intubation (ETI) and VV-ECMO initiation followed the recommendations from the Spanish critical care society (SEMICYUC) (19) and ELSO respectively (20) although application of these criteria did depend on our hospital crisis capacity, especially during the first two months of pandemic (March-June, 2020). Survival at 90 days after VV-ECMO was monitored and initiation of NIV was considered when patients started on any available modality (HFNC, CPAP, or BiPAP). In order to evaluate the global effect of the time lapse between NIV and VV-ECMO, we had to make the presumption that in those patients who did not receive NIV, their day 0 was the day of intubation. Bivariable analyses were conducted to explore the association between death at 90 days after VV-ECMO initiation and each of the predefined risk factors. Continuous variables were compared using sample t-test and Mann Whitney test. Categorical data were compared using the Chi-square test or Fisher exact test. The effect of the time lapse between NIV and VV-ECMO on survival was evaluated using logistic regression and adjusting the association with all factors that were significant in the univariate analysis. The association measures were calculated (adjusted odds ratio [OR]) with a confidence interval (CI) of 95%. The study was approved by the medical ethics committee at Bellvitge Hospital (PR40/21).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFrom March 2020 to January 2022, 519 subjects fulfilling the study criteria were admitted to the ICU. 429 patients (83%) had received some modality of NIV before ICU admission with a median (IQR) time of 1 (0-3) days. Within the first day from ICU admission 318 patients (61%) had been intubated but the other 201 (39%) subjects continued on NIV support from which 118 (59%) were finally intubated. Among these ARDS patients, for the purpose of our study we only evaluated the 72 subjects (14%) that were finally initiated on VV-ECMO \u003cstrong\u003e(Figure 1)\u003c/strong\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe median (IQR) time from intubation to VV-ECMO was 4 (2-9) days whereas the complete median time spent from NIV support to ECMO (which also includes the time spent with intubation) was 9 (5-15) days. \u003cstrong\u003eSupplementary Table 1\u003c/strong\u003e, shows the demographic data, clinical characteristics and outcomes of these 72 patients according to their survival status 90 days after VV-ECMO initiation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs demonstrated 35 (48%) had died and 37 (52%) were alive. Patients who were alive at 90 days after VV-ECMO initiation were more likely to be younger and have a shorter length of days from NIV to VV-ECMO. \u003cstrong\u003eFigure 2\u003c/strong\u003e, shows the mortality across the different groups according to NIV or IMV.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInterestingly, RESP score and D-dimer at ECMO initiation were higher among survivors whereas lactate was lower. Times from hospital to VV-ECMO, ICU to VV-ECMO, or intubation to VV-ECMO were all shorter in those patients who survived to day 90 although none of them were statistically significant. Multivariable analysis (\u003cstrong\u003eTable 1\u003c/strong\u003e) showed that at VV-ECMO initiation, age, lactate and days from NIV support to VV-ECMO were strongly associated with day-90 mortality.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eMultivariable Logistic Regression of Factors Associated with 90-Day Mortality.\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"566\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e95%\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003eP Value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003eAge, yr\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e1.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e1.01-1.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.02\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003ePEEP, cm H\u003csub\u003e2\u003c/sub\u003eO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e0.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e0.81-1.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003eDays NIV -ECMO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e1.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e1.01-1.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.\u003c/strong\u003e\u003cstrong\u003e04\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003eLactate, mmol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e1.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e1.11-1.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003eD-Dimer, \u0026micro;g/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e0.99-1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e0.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003epaO\u003csub\u003e2\u003c/sub\u003e/FIO\u003csub\u003e2\u003c/sub\u003e, ratio\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e0.97-1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eDefinition of abbreviations:\u003c/em\u003e PEEP Positive end Expiratory Pressure, NIV Non Invasive Ventilation, ECMO Extracorporeal Membrane Oxygenation \u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eA recent large multicenter study showed an increased mortality in ECMO patients with COVID-19 associated ARDS who had received NIV previous to intubation (21) Many of the patients who received NIV during the pandemic are ARDS patients who in other circumstances or in other centers would have been intubated. (22, 23). Furthermore, the majority of scores that predict mortality in VV-ECMO only include the time spent on invasive mechanical ventilation before ECMO (but not on NIV support) (24). In our cohort of VV-ECMO patients with COVID-19 associated ARDS, the time lapse between NIV support and commencing VV-ECMO (together with age and lactate) seems a better predictor when evaluating survival than the time between intubation and VV-ECMO. Our results suggest the significance that NIV support plays on ARDS patients and in our opinion, this is not only related to a hypothetical P-SILI effect (11), but also reflects a more advanced clinical stage of ARDS when VV-ECMO is finally initiated.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAge and lactate are clearly related to mortality when VV-ECMO is initiated as in the majority of critically ill patients who present any kind of organ dysfunction (21, 24). In fact, both age and lactate are included in the majority of the risk-assessment severity scores used for any kind of ECMO support (25, 26). Nevertheless, due to the improvement of organ transplant programs (including lung transplant), the better quality of life of older people, and due to other more complex social demands, age keeps being a time changing criteria and nowadays treatment indications are being extended to groups of age that not long ago would have been excluded. This includes also VV-ECMO indications that in the past were clearly age-limited but nowadays have to be patient-personalised because some of these \u0026ldquo;older\u0026rdquo; patients might even be candidates for lung transplant or might have excellent qualities of life with no other comorbidities (27). \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAlthough in our small cohort of patients the time lapse from ETI to VV-ECMO was not significant in terms of mortality it is one of the most employed criteria when evaluating the mortality risk of the technique as those patients initiated more than 7 days after ETI have proved to have worse outcomes than those initiated within the first week. This is probably related to a more advanced stage of ARDS in those patients with a delayed initiation of VV-ECMO when compared to those with an early initiation of VV-ECMO. However, this phenomenon is common to other forms of mechanical organ support in critically ill patients such as renal replacement therapy or invasive mechanical ventilation, where a delayed initiation strategy is associated with a worse outcome when organ support is finally required, but also with a much better outcome when patients finally do not require organ support (28). An early identification of all those patients who will finally require organ support in a delayed and deleterious period is probably one of the most compelling brain exercises that still exist in critical care medicine together with the appropriate quantity of fluids to be used in patients with shock.\u003c/p\u003e\n\u003cp\u003eAn important confounding variable in the assessment of time from NIV initiation to VV-ECMO is the duration of invasive ventilation that somehow makes our hypothesis seem overly simplistic. This is an important limitation of our study design. In our study, no association was found between the use of NIV previous to VV-ECMO and mortality, although the small size of the population is another important limitation. On the other hand, the lack of information on the pressures applied to these patients and the absence of cross-sectional protocols does not allow the identification of patients who have been treated with high parameters perhaps comparable to those of intubated patients. \u0026nbsp;A confounding variable in most studies could be the failure to differentiate patients who received high flow from those who received BiPAP or CPAP, understanding that these last patients who require higher pressures are those who present severe ARDS (SAFE-LUNG study) (9,10)\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eWe suggest, based on our findings, that the time spent between NIV support and initiation of VV-ECMO should be included in the mortality prediction scores for VV-ECMO (29) although further and larger studies are needed to confirm our findings.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eVV-ECMO: veno venous extracorporeal membrane oxygenator.\u003c/p\u003e\n\u003cp\u003eCOVID-19: coronavirus disease 2019.\u003c/p\u003e\n\u003cp\u003eNIV: Non-invasive ventilation\u003c/p\u003e\n\u003cp\u003eHFNC: High Flow nasal cannula\u003c/p\u003e\n\u003cp\u003eBiPAP: Bi-level positive airway pressure\u003c/p\u003e\n\u003cp\u003eCPAP: Continuous positive airway pressure\u003c/p\u003e\n\u003cp\u003eNIPPV: Non-invasive positive pressure ventilation\u003c/p\u003e\n\u003cp\u003eARDS: Acute respiratory distress syndrome\u003c/p\u003e\n\u003cp\u003eARF: Acute respiratory failure\u003c/p\u003e\n\u003cp\u003eICU: intensive care unit\u003c/p\u003e\n\u003cp\u003eP-SILI: patient self-inflicted lung injury\u003c/p\u003e\n\u003cp\u003eSOFA: Sequential Organ Failure Assessment\u003c/p\u003e\n\u003cp\u003eRESP: respiratory ECMO survival prediction\u003c/p\u003e\n\u003cp\u003eIQR: Interquartile range\u003c/p\u003e\n\u003cp\u003eCI: Confidence interval\u003c/p\u003e\n\u003cp\u003eOR: odds ratio\u003c/p\u003e\n\u003cp\u003ePEEP: Positive end expiratory pressure\u003c/p\u003e\n\u003cp\u003eETI: endotracheal intubation\u003c/p\u003e\n\u003cp\u003eSEMICYUC: Spanish critical care society\u003c/p\u003e\n\u003cp\u003eELSO: Extracorporeal Life Support Organization\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate: The study was finally approved by the local ethics committee at Bellvitge University Hospital in January 2021 (PR40/21), who waived the need for informed consent and confirmed that all procedures were followed in accordance with the institutional ethical standards and with the Helsinki Declaration of 1975.\u003c/p\u003e\n\u003cp\u003eConsent for publication: Not applicable.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials: All data generated or analysed during this study are included in this published article [and its supplementary information files].\u003c/p\u003e\n\u003cp\u003eCompeting interests: None.\u003c/p\u003e\n\u003cp\u003eFunding: None.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions: M.P.F., L.H., and X.P contributed equally to this work. M.G., F.P., P.C., M.P., P.S., J.Y., A.G., and K.M. collected data. M.P.F. and X.P. performed the analysis. M.P.F., L.H., and X.P. wrote the manuscript. J.S. critically reviewed the manuscript. All authors approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003eAcknowledgement: Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eCombes A, Hajage D, Capellier G, et al: EOLIA Trial Group, REVA, and ECMONet. Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome. N Engl J Med. 2018 May 24; 378(21):1965-1975.\u003c/li\u003e\n \u003cli\u003eSteinberg KP, Hudson LD, Goodman RB, et al: National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006 Apr 20; 354(16):1671-84.\u003c/li\u003e\n \u003cli\u003eDocherty AB, Mulholland RH, Lone NI, et al: Changes in in-hospital mortality in the first wave of COVID-19: a multicentre prospective observational cohort study using the WHO Clinical Characterisation Protocol UK. Lancet Respir Med. 2021 Jul; 9(7):773-785.\u003c/li\u003e\n \u003cli\u003ePapoutsi E, Giannakoulis VG, Xourgia E, Routsi C, Kotanidou A, Siempos II. Effect of timing of intubation on clinical outcomes of critically ill patients with COVID-19: a systematic review and meta-analysis of non-randomized cohort studies. \u003cem\u003eCrit Care\u003c/em\u003e. 2021; 25(1):121.\u003c/li\u003e\n \u003cli\u003eSun Q, Qiu H, Huang M, Yang Y. Lower mortality of COVID-19 by early recognition and intervention: experience from Jiangsu Province. Ann Intensive Care. 2020 Mar 18; 10(1):33.\u003c/li\u003e\n \u003cli\u003eMenzella F, Barbieri C, Fontana M, et al. Effectiveness of noninvasive ventilation in COVID-19 related-acute respiratory distress syndrome. \u003cem\u003eClin Respir J\u003c/em\u003e. 2021; 15(7):779-787.\u003c/li\u003e\n \u003cli\u003eNavalesi P., Maggiore SM. Positive end-expiratory pressure. In: Tobin M.J. (Ed). Principles and Practice of Mechanical Ventilation. 3rd ed. McGraw Hill Medical; New York, NY, USA: 2013. pp. 253\u0026ndash;302.\u003c/li\u003e\n \u003cli\u003eFrat JP, Quenot JP, Badie J, et al. Effect of High-Flow Nasal Cannula Oxygen vs Standard Oxygen Therapy on Mortality in Patients With Respiratory Failure Due to COVID-19: The SOHO-COVID Randomized Clinical:10.1001/jama.2022.15613\u003c/li\u003e\n \u003cli\u003eGrieco DL, et al. Effect of Helmet Noninvasive Ventilation vs High-Flow Nasal Oxygen on Days Free of Respiratory Support in Patients With COVID-19 and Moderate to Severe Hypoxemic Respiratory Failure: The HENIVOT Randomized Clinical Trial. JAMA. 202\u003c/li\u003e\n \u003cli\u003ePerkins GD, Ji C, Connolly BA, et al. Effect of Noninvasive Respiratory Strategies on Intubation or Mortality Among Patients With Acute Hypoxemic Respiratory Failure and COVID-19: The RECOVERY-RS Randomized Clinical Trial. \u003cem\u003eJAMA\u003c/em\u003e. 2022; 327(6):546-558. doi:10.1001/jama.2022.0028\u003c/li\u003e\n \u003cli\u003eGrieco DL, Menga LS, Eleuteri D, et al: Patient self-inflicted lung injury: implications for acute hypoxemic respiratory failure and ARDS patients on non-invasive support. Minerva Anestesiol. 2019; 85(9):1014-1023.\u003c/li\u003e\n \u003cli\u003eRocco PR, Pelosi P, de Abreu MG. Pros and cons of recruitment maneuvers in acute lung injury and acute respiratory distress syndrome. Expert Rev Respir Med. 2010 Aug; 4(4):479-89.\u003c/li\u003e\n \u003cli\u003eWriting Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators et al. \u0026ldquo;Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial.\u0026rdquo; JAMA vol. 318, 14 (2017): 1335-1345.\u003c/li\u003e\n \u003cli\u003eBarbaro RP, MacLaren G, Boonstra PS, et al: Extracorporeal membrane oxygenation for COVID-19: evolving outcomes from the international Extracorporeal Life Support Organization Registry. Lancet. 2021 2-8 October; 398(10307): 1230\u0026ndash;1238.\u003c/li\u003e\n \u003cli\u003eSchmidt M, Bailey M, Sheldrake J et al. Predicting survival after extracorporeal membrane oxygenation for severe acute respiratory failure. The Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) score. Am J Respir Crit Care Med. 2014 Jun 1; 189(11):1374-82\u003c/li\u003e\n \u003cli\u003eMajithia-Beet G, Naemi R, Issitt R. Efficacy of outcome prediction of the respiratory ECMO survival prediction score and the predicting death for severe ARDS on VV-ECMO score for patients with acute respiratory distress syndrome on extracorporeal membrane oxygenation. Perfusion. 2022 Jul 13:26.\u003c/li\u003e\n \u003cli\u003eHuespe IA, Lockhart C, Kashyap R, Palizas F Jr, Colombo M, Romero MDP, Prado E, Casabella Garc\u0026iacute;a CA, Las Heras M, Carboni Bisso I. Evaluation of the discrimination and calibration of predictive scores of mortality in ECMO for patients with COVID-19. Artif Organs. 2022 Dec 29:10.\u003c/li\u003e\n \u003cli\u003eARDS Definition Task Force, Ranieri VM, Rubenfeld GD, et al: acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012; 307(23):2526-2533.\u003c/li\u003e\n \u003cli\u003eVidal-Cort\u0026eacute;s P, D\u0026iacute;az-Santos E, Aguilar-Alonso E, et al. Recommendations for the management of critically ill patients with COVID-19 in Intensive Care Units. Med Intensiva (Engl Ed). 2022 Feb; 46(2):81-89\u003c/li\u003e\n \u003cli\u003eBadulak J, Antonini MV, Stead CM, et al. Extracorporeal Membrane Oxygenation for COVID-19: Updated 2021 Guidelines from the Extracorporeal Life Support Organization, ASAIO Journal: May 2021 - Volume 67 - Issue 5 - p 485-495\u003c/li\u003e\n \u003cli\u003eSchmidt, Matthieu et al. \u0026ldquo;Comparative outcomes of extracorporeal membrane oxygenation for COVID-19 delivered in experienced European centres during successive SARS-CoV-2 variant outbreaks (ECMO-SURGES): an international, multicentre, retrospective cohort study.\u0026rdquo; \u003cem\u003eThe Lancet. Respiratory medicine\u003c/em\u003e vol. 11,2 (2023): 163-175.\u003c/li\u003e\n \u003cli\u003eForrest IS, Jaladanki SK, Paranjpe I, Glicksberg BS, Nadkarni GN, Do R. Non-invasive ventilation versus mechanical ventilation in hypoxemic patients with COVID-19. Infection. 2021 Oct; 49(5):989-997.\u003c/li\u003e\n \u003cli\u003eBrioni M, Meli A, Grasselli G. Mechanical Ventilation for COVID-19 Patients. \u003cem\u003eSemin Respir Crit Care Med\u003c/em\u003e. 2022; 43(3):405-416.\u003c/li\u003e\n \u003cli\u003eGallaher J, Raff L, Schneider A, Reid T, Miller MB, Boddie O, Charles A. The role of ECMO in COVID-19 acute respiratory failure: Defining risk factors for mortality. Am J Surg. 2022 Dec 24:S0002-9610(22)00799-1.\u003c/li\u003e\n \u003cli\u003ePladet LCA, Barten JMM, Vernooij LM, Kraemer CVE, Bunge JJH, Scholten E, Montenij LJ, Kuijpers M, Donker DW, Cremer OL, Meuwese CL. Prognostic models for mortality risk in patients requiring ECMO. Intensive Care Med. 2023 Feb; 49(2):131-141\u003c/li\u003e\n \u003cli\u003eFisser, C.; Rincon-Gutierrez, L.A.; Enger, T.B.; Taccone, F.S.; Broman, L.M.; Belliato, M.; Nobile, L.; Pappalardo, F.; Malfertheiner, M.V. Validation of Prognostic Scores in Extracorporeal Life Support: A Multi-Centric Retrospective Study. Membranes 2021, 11, 84.\u003c/li\u003e\n \u003cli\u003eFriedrichson B, Mutlak H, Zacharowski K, Piekarski F. Insight into ECMO, mortality and ARDS: a nationwide analysis of 45,647 ECMO runs. Crit Care. 2021 Jan 28; 25(1):38.\u003c/li\u003e\n \u003cli\u003eCombes A, Hajage D, Capellier G, Demoule A, Lavou\u0026eacute; S, Guervilly C, Da Silva D, Zafrani L, Tirot P, Veber B, Maury E, Levy B, Cohen Y, Richard C, Kalfon P, Bouadma L, Mehdaoui H, Beduneau G, Lebreton G, Brochard L, Ferguson ND, Fan E, Slutsky AS, Brodie D, Mercat A; EOLIA Trial Group, REVA, and ECMONet. Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome. N Engl J Med. 2018 May 24; 378(21):1965-1975.\u003c/li\u003e\n \u003cli\u003eMan MY, Shum HP, Lam SM, et al: An External Validation of Scoring Systems in Mortality Prediction in Veno-Venous Extracorporeal Membrane Oxygenation. ASAIO J. 2022 Feb 1; 68(2):255-261.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"ARDS, Extracorporeal Membrane Oxygenation, Non-invasive Ventilation, COVID-19, Respiratory Insufficiency. ","lastPublishedDoi":"10.21203/rs.3.rs-2766314/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2766314/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eThe study evaluates the impact of the time between commencing non-invasive ventilation (NIV) support and initiation of venovenous extracorporeal membrane oxygenation (VV-ECMO) in a cohort of critically ill patients with coronavirus disease 2019 (COVID-19) associated acute respiratory distress syndrome (ARDS).\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Prospective observational study design in an intensive Care Unit (ICU) of a tertiary hospital in Barcelona (Spain). All patients requiring VV-ECMO support due to COVID-19 associated ARDS between March 2020 and January 2022 were analysed. Survival outcome was determined at 90 days after VV-ECMO initiation. Demographic data, comorbidities at ICU admission, RESP (respiratory ECMO survival prediction) score, antiviral and immunomodulatory treatments received, inflammatory biomarkers, the need for vasopressors, the thromboprophylaxis regimen received, and respiratory parameters including the length of intubation previous to ECMO and the length of each NIV support (high-flow nasal cannula, continuous positive airway pressure and bi-level positive airway pressure), were also collated in order to assess risk factors for day-90 mortality. The effect of the time lapse between NIV support and VV-ECMO on survival was evaluated using logistic regression and adjusting the association with all factors that were significant in the univariate analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Seventy-two patients finally received VV-ECMO support. At 90 days after commencing VV-ECMO 35 (48%) had died and 37 (52%) were alive. Multivariable analysis showed that at VV-ECMO initiation, age (p=0.02), lactate (p=0.001), and days from initiation of NIV support to starting VV-ECMO (p=0.04) were all associated with day-90 mortality. \u003cstrong\u003eConclusions: \u003c/strong\u003eIn our small cohort of VV-ECMO patients with COVID-19 associated ARDS, the time spent between initiation of NIV support and VV-ECMO (together with age and lactate) appear to be a better predictor of mortality than that between intubation and VV-ECMO.\u003c/p\u003e","manuscriptTitle":"Days spent on non-invasive ventilation support: Can it determine when to initiate VV-ECMO? 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