Length of Pre-Ecmo Mechanical Ventilation Is Not Associated with Mortality in Patients with Covid-19

INTRODUCTION: Previous studies suggest that delayed initiation of extracorporeal membrane oxygenation (ECMO) is associated with higher patient mortality. Hence, we hypothesized that prolonged invasive mechanical ventilation (IMV) prior to ECMO was associated with higher mortality in patients with COVID-19. METHOD(S): The COVID-19 Critical Care Consortium, a prospective international multicenter registry, was queried for all patients with COVID-19 infection who received IMV and ECMO. Patients who were intubated prior to transfer to a study site were excluded. The primary variable was number of days on IMV prior to ECMO initiation and study endpoint was death or discharge from the study site. Cox proportional hazards model for the time between ECMO initiation and death was built using covariates including age, gender, selected comorbidities, and time intervals from ICU admission to IMV and IMV to ECMO initiation. RESULT(S): Between 1/1/2020 and 6/6/2022, A total of 593 patients from 107 study sites and 25 countries were included in the analysis. In this cohort, the median age was 50 (Interquartile range [IQR]: 40-58) years. Obesity and hypertension were prevalent among 220 (38.4%) and 223 (38.8%) of the patients, respectively. Twenty-four (4.2%) patients had chronic pulmonary disease. Prior to ECMO initiation, patients spent a median of 3.68 (IQR: 1.36-8.07) days in the ICU and a median of 2.49 (IQR: 0.88-5.65) days on IMV. Overall mortality was 47.2% with 3.9% patients' status not finalized or unknown. According to the final survival model, the number of days on IMV prior to ECMO initiation was not associated with mortality. The hazard ratios for 0, 3, 7, and 14 days of pre-ECMO IMV were 0.94 (95% confidence interval [CI]: 0.83 to 1.07), 1.02 (95% CI: 0.97 to 1.08), 1.09 (95% CI: 0.92 to 1.3) and 1.09 (95% CI: 0.83 to 1.42), respectively. Other noticeable contributory factors in the model included age and gender. CONCLUSION(S): Among patients with COVID-19 who received ECMO, the length of pre-ECMO IMV was not associated with hospital mortality. Further studies evaluating the ventilator settings before and after ECMO initiation are needed.

Hemorrhagic, coagulopathic, and thrombotic (HECTOR) complications among critically-ill patients with COVID-19: An International COVID-19 critical care consortium study

Background: Hemorrhage, coagulopathy and thrombosis (HECTOR) are reported complications of coronavirus disease 2019 (COVID-19) however, more information is needed on the prevalence of these complications and their associated outcomes in intensive care unit (ICU) settings. Aim(s): To determine the prevalence and outcomes of HECTOR complications in ICU patients with COVID-19. Method(s): Observational cohort study spanning 229 ICUs across 32 countries. Patients >=16 years admitted for severe COVID-19 from 1st January 2020, through 31st December 2021 were included. Patient characteristics and clinical data were collected. Survival analysis estimated the instantaneous impact of HECTOR complications on ICU-mortality and discharge. Result(s): HECTOR complications occurred in 1,735 (14%) of 11,972 study-eligible patients. Acute thrombosis occurred in 1,249 (10%) patients, including 712 (57%) with pulmonary embolism, 413 (33%) with myocardial infarction, 93 (7.4%) with deep vein thrombosis, and 49 (3.9%) with ischemic stroke. Hemorrhagic complications were reported in 582 (4.9%) patients, including 276 (48%) with gastrointestinal hemorrhage, 83 (14%) with hemorrhagic stroke, and 77 (13%) with pulmonary hemorrhage. Disseminated intravascular coagulation occurred in 11 (0.09%) patients. Univariate analysis identified diabetes, hypertension, cardiac and kidney disease and ECMO as statistically-significant risk factors for HECTOR complications. Patients with versus without HECTOR complications suffered higher ICU-mortality at 28 days (25%vs.13%, p < 0.001), 90 days (32%vs.15%, p < 0.0001) and overall (44%vs.36%, p < 0.001). Among ICU survivors, the ICU stay was longer (median days 19vs.12, p < 0.001). ICU mortality was similar between patients with and without HECTOR complications (HR = 1.01, 95%CI 0.92-1.12, p = 0.783) where an increased hazard of ICU mortality with hemorrhage (HR = 1.26, 1.09-1.45, p = 0.002) was balanced by a reduced hazard of thrombosis (HR = 0.88, 0.79-0.99, p = 0.03). Kaplan-Meier curves are presented in the Figure. Conclusion(s): HECTOR events are frequent complications of severe COVID-19 in ICU patients. Hemorrhagic, but not thrombotic complications are associated with increased ICU-mortality.

Combining cell therapy and extracorporeal membrane oxygenation for Acute Respiratory Distress Syndrome: Back to no future?

Introduction: After more than 50 years of research we are yet to develop an effective treatment for the Acute Respiratory Distress Syndrome (ARDS). This stands in contrast to the advances made in supportive care, a prime example of which is the maturation of Extracorporeal Membrane Oxygenation (ECMO). While technologies such as ECMO 'buy time' for recovery, the identification of a therapy remains crucial to improving outcomes. Recently, mesenchymal stem cells (MSCs) have shown promise as a novel treatment.1 Importantly, cell therapy may represent a means to overcome the hurdles associated with successful pharmacological intervention in ARDS. Little is known about the interaction between cell therapy and ECMO. This is a deficiency, given that those receiving ECMO for ARDS are among the most severely ill and therefore most likely to benefit. This programme of work was designed to close that gap. Objectives: Using a translational pipeline, our objective was to assess the safety and efficacy of MSCs during ECMO for ARDS. Methods: We employed several diverse methods to address our objectives, including an ex-vivo ECMO simulation, complex sheep models of ARDS and ARDS and venovenous ECMO, systematic review methodology, and unsupervised machine learning techniques. Results: In our ex-vivo model, we were the first to demonstrate potential harms associated with MSC therapy during ECMO.2 When 40 × 10∧6 clinical-grade human MSCs (Cynata Therapeutics Ltd., Australia) were added to fresh whole human blood and subjected to extracorporeal circulation using commercial components, oxygenator and pump performance was severely impaired within 4 hours. These experiments also demonstrated benefits associated with MSCs, including trends toward lower inflammatory cytokine concentrations and less neutrophil activation.3 To validate our findings, we sought to test hMSCs in a clinicallyrelevant sheep model. At the outset we undertook a systematic review of existing pre-clinical models of ARDS and ECMO.4 This has since produced an international collaborative effort to characterise pre-clinical models of ECMO across a range of indications. We subsequently described a 'double-hit' model of ARDS which combines oleic acid and intra-tracheal E. coli lipopolysaccharide. Using cluster analysis, we showed that this model shares qualitative similarities with the 'hypo-inflammatory' phenotype identified in clinical cohorts [Millar JE et al. Physiological Reports 2021. In Press]. Finally, in a 24-hour model, combining our novel injury method, VV-ECMO, and best practice ventilatory and supportive care, we performed a controlled trial of intra-tracheal hMSC therapy5 [Editorial: Del Sorbo L, Fan E. AJRCCM 2020]. This study showed that hMSCs reduce histological evidence of lung injury and ameliorate shock. However, hMSC-mediated impairment of oxygenator function was evident again. Conclusion: This work addresses a gap in our understanding of cell therapy in critical illness. The findings are of direct clinical relevance, highlighting the potential harms of cell therapy during extracorporeal circulation. With a recent explosion in the number of registered clinical trials of MSCs for severe COVID-19 in mind, the use of MSCs during ECMO cannot be recommended.

The Impact of Morbid Obesity on Patients with COVID-19 who Develop Respiratory Failure requiring Extracorporeal Membrane Oxygenation

Background: In patients with COVID-19 and respiratory failure, class 3 obesity (body mass index > 40 kg/m2) has been associated with worse survival. Obese patients on mechanical ventilation with progressively more severe acute respiratory syndrome (ARDS) may be offered venovenous (VV) extracorporeal membrane oxygenation (ECMO) therapy. The impact of morbid obesity on the outcome of COVID-19 patients supported with VV ECMO has been underexplored. Methods: This is a multicenter, retrospective observational cohort analysis of critically ill adults with COVID-19 ARDS requiring advanced mechanical ventilation with or without VV ECMO. Data was collected from 236 international institutions forming the COVID-19 Critical Care Consortium international registry. Patients were admitted between January 2020 to December 2021. Included patients were stratified by ECMO status and a BMI threshold at 40 kg/m2. Median values with interquartile range (IQR) were used to summarize continuous variables and multi-state analysis was used to explore the effect of Class 3 obesity on the study endpoints of patient survival to discharge or death. Results: Complete data was available on 8851 of 9059 patients on mechanical ventilation, of which 767 patients required VV ECMO. For the entire study group, older age and male gender were associated with an increased risk of death. The demographics and comorbidities of the higher BMI (H >40 kg/m2) and lower BMI (L ≤40 kg/m2) cohorts were similar with the exception of age and weight. Patients with a higher BMI were younger. The median age of the H, non-ECMO cohort was 56 years (46-64), and the H, ECMO cohort was 41 years (35-51) versus the L, non-ECMO cohort of 64 years(55-71), and the L, ECMO cohort of 53years (45-60). Patients requiring VV ECMO had higher SOFA scores, experienced longer ICU and hospital lengths of stay, and a longer duration of total mechanical ventilation. Table The median time to intubation was longer in the mechanical ventilation only group (2 versus 0 days). Predictors for requiring ECMO included younger age, higher BMI and male gender. Risk factors for death included advancing age (every 10 years), male gender and increasing BMI (every 5kg/m2). The association between BMI and a higher rate of death was reduced in the mechanical ventilation only group (HR 0.92, 95% confidence interval 0.85 to 0.99). Conclusion: In patients with severe ARDS due to COVID-19 requiring mechanical ventilation, the likelihood of progressing to VV ECMO therapy or experiencing death is impacted by age, gender and higher BMI. The cohort of COVID-19 patients that ultimately required ECMO appear to be sicker at time hospital admission owing to the shorter time until mechanical ventilation. It appears the association between increasing BMI and death differs among the ECMO and mechanical ventilation alone cohorts. We would advocate for a prospective study to determine the benefit of VVECMO for the obese patient requiring VV-ECMO for COVID-19 ARDS. (Figure Presented).

Mid and Long-term Neurological and Neuropsychiatric Manifestations of PostCOVID-19 Syndrome: A Meta-analysis

Objective: To determine the prevalence of neurological and neuropsychiatric symptoms reported 12 weeks (3 months) or more after acute COVID-19 onset in adults. Background: Neurological and neuropsychiatric symptoms that persist or develop three months after the onset of COVID-19 pose a significant threat to the global healthcare system. These symptoms are yet to be synthesized and quantified via meta-analysis. Design/Methods: A systematic search of PubMed, EMBASE, Web of Science, Google Scholar and Scopus was conducted for studies published between January 1 , 2020 and August 1 , 2021. Studies were included if the length of follow-up satisfied the National Institute for Healthcare Excellence definition of post-COVID-19 syndrome. Additional criteria included reporting of neurological or neuropsychiatric symptoms in individuals with COVID-19. The primary outcome was the prevalence of neurological and neuropsychiatric symptoms reported ≥3 months post onset of COVID-19. Results: Of 1,458 articles, 19 studies, encompassing a total of 11,324 patients, were analysed. Overall prevalence for neurological post-COVID-19 symptoms were: fatigue (37%, 95% CI: 24%- 50%), brain fog (32%, 9%-55%), memory issues (27%, 18%-36%), attention disorder (22%, 10%- 34%), myalgia (18%, 4%-32%), anosmia (12%, 7%-17%), dysgeusia (11%, 4%-17%) and headache (10%, 1%-21%). Neuropsychiatric conditions included sleep disturbances (31%, 18%-43%), anxiety (23%, 13%-33%) and depression (12%, 7%-21%). Neuropsychiatric symptoms substantially increased in prevalence between mid- and long-term follow-up. Compared to non-hospitalised patients, patients hospitalised for acute COVID-19 had reduced risk of anosmia, anxiety, depression, dysgeusia, fatigue, headache, myalgia, and sleep disturbance at three (or more) months post-infection. Conversely, hospital admission was associated with higher frequency of memory issues (OR: 1.9, 95% CI: 1.4-2.3). Conclusions: Fatigue, brain fog and sleep disturbances appear to be key features of post-COVID19 syndrome. Psychiatric manifestations (sleep disturbances, anxiety, and depression) increase significantly in prevalence over time. Randomised controlled trials are necessary to develop intervention strategy to reduce disease burden.

Renin-angiotensin-aldosterone system inhibition is associated with reduced in-hospital mortality in critically ill covid-19 patients with pre-existing hypertension

Background: The virus responsible for COVID-19 enters human cells by binding angiotensinconverting enzyme 2. The influence of renin-angiotensin-aldosterone system (RAAS) inhibitors, including angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs), remains uncertain. Aim: To examine the role of ACEi / ARB exposure on outcomes in COVID-19 patients with preexisting hypertension (HTN) admitted to intensive care units (ICU). Methods: The COVID-19 Critical Care Consortium is a prospective, observational cohort study of patients requiring ICU admission for active COVID-19 spanning 354 participating sites in 54 countries. Patients >18 years old with pre-existing HTN requiring antihypertensive therapy were analysed. Length of stay and in-hospital mortality to 90 days post ICU admission were analysed as time-to-eventoutcomes by multistate survival analysis, and the influence of ACEi / ARB use on the hazards of death and discharge by multi-state Cox proportional hazard modelling and sensitivity analysis. Results: From December 1, 2019 through December 30, 2020, 663 eligible patients were registered. Of these, 480 patients had received ACEi and / or ARB therapy (median age 65 years, 67% male) in the 2 weeks before ICU admission, while 183 had not (66 years, 61% male). Average lengths of ICU and general ward stays were longer in the ACEi / ARB than non-ACEi / ARB group (20.8 days and 6.5 days vs. 15.5 and 6.0 days, respectively). ACEi / ARB use was associated with a decreased hazard of death (HR, 0.69, 95% CI, 0.54 -0.88) that persisted after adjusting for propensity scores (0.67, 0.53 -0.86). Cumulative probabilities (unadjusted for baseline characteristics) for death and discharge post ICU admission are depicted in the figure for ACEi/ARB (red) and non-ACEi / ARB (blue) patients. Conclusions: In 663 critically ill COVID-19 patients with pre-existing HTN, RAAS inhibition pre-ICU admission was linked to reduced in-hospital mortality.

Long covid syndrome: Why efforts like aftercor are needed

Introduction: The AFTERCOR study was developed by the COVID-19 Critical Care Consortium (>7000 intensive care unit [ICU] and >400 extracorporeal membrane oxygenation [ECMO] patients currently) to enhance understanding of occurrence and progression of long-term dysfunction post-COVID-19. Design: Prospective longitudinal (24 months) study of ICU survivors of COVID-19 to describe recovery of the following aspects: a) health-related quality of life b) dynamics of organ dysfunction and recovery and c) pulmonary function. Countries involved Italy, Spain, Ireland, Austria, South Africa, Australia, USA, Argentina, Brazil, Colombia. Protocol specifics available at https://www.aftercorstudy.com. Inclusion Criteria: 1) COVID-19 infection requiring ICU admission;2) informed consent;3) age ≥18 years. Exclusion Criteria: 1) pregnancy;2) pre-COVID paralysis;3) history of pulmonary resection;4) prior lung transplant;5) inability to perform 6-min walk test or participate in interview. Methods: Goal enrollment is 1000 patients. Follow-up visits are at 3, 6, 12, 18 and 24-month post-ICU discharge. Assessments include: 1) Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36);2) Montreal Cognitive Assessment;3) any subsequent admission 4) St. George's Respiratory Questionnaire;5) Pulmonary function testing;6) chest radiography;7) 6-minute-walk test;8) Patient Health Questionnaire 9 (PHQ-9) and 9) full blood count and biochemistry. CT chest at 6 months and repeat ECHO at 3, 12 and 24 months if performed during COVID-19 hospitalization. If results are normal, subsequent testing will not be performed. Summary: The AFTERCOR study represents a comprehensive evaluation for long-term effects from COVID-19. Interested centers are sought and invited to participate.

An appraisal of respiratory system compliance in mechanically ventilated COVID-19 patients

Rationale Heterogeneous respiratory system static compliance (CRS) values and levels of hypoxemia in patients with novel coronavirus disease (COVID-19) requiring mechanical ventilation have been reported in previous smallcase series or studies conducted at a national level.Methods We designed a retrospective observational cohort study with rapid data gathering from the international COVID-19 Critical Care Consortium study to comprehensively describe the impact of CRS on the ventilatory management and outcomes of COVID-19 patients on mechanical ventilation (MV), admitted to intensive care units (ICU) worldwide.Results We enrolled 318 COVID-19 patients enrolled into the study from January 14th through September 31th, 2020 in 19 countries and stratified into two CRS groups. CRS was calculated as: tidal volume/[airway plateau pressure-positive endexpiratory pressure (PEEP)] and available within 48h from commencement of MV in 318 patients. Patients were mean±SD of 58.0±12.2, predominantly from Europe (54%) and males (68%). Median CRS (IQR) was 34.1 mL/cmH2O (26.5-45.5) and PaO2/FiO2 was 119 mmHg (87.1-164) and was not correlated with CRS. Female sex presented lower CRS than in males (95% CI:-13.8 to-8.5 P<0.001) and higher body mass index (34.7±10.9 vs 29.1±6.0, p<0.001). Median (IQR) PEEP was 12 cmH2O (10-15), throughout the range of CRS, while median (IQR) driving pressure was 12.3 (10-15) cmH2O and significantly decreased as CRS improved (p<0.001). No differences were found in comorbidities and clinical management between CRS strata. In addition, 28-day ICU mortality and hospital mortality did not differ between CRSgroups.Conclusions This multicentre report provides a comprehensive account of CRS in COVID-19 patients on MV-predominantly males or overweight females, in their late 50s-admitted to ICU during the first international outbreaks. Phenotypes associated with different CRS upon commencement of MV could not be identified.

Neuromuscular blocking agents in critically-ill COVID-19 patients requiring mechanical ventilation

RATIONALE. Neuromuscular blocking agents (NMBA) are used in patients with moderate to severe acute respiratory distress syndrome. NMBA have also been used in COVID-19 patients who required mechanical ventilation (MV), but their benefit-to-risk ratio remains uncertain.METHODS. We investigated the effects associated with the use of NMBA in COVID-19 patients who required MV from January 1, 2020 to October 31, 2020 in 153 hospitals across 6 continents, comprising the COVID-19 Critical Care Consortium. Cox proportional hazards analysis was conducted to study the impact of NMBA on 28-day intensive care unit (ICU) mortality. Hospital/ICU lengths of stay were appraised. We performed a propensity score (PS) matching analysis to control confounding factors.RESULTS. 1227 patients were eligible for analysis, among those 598 (48.7%) received NMBA for 2 days or longer, with a median time from ICU admission to commencement of NMBA therapy of 0 day (IQR 0-1 days). The median duration of NMBA therapy was 2 days (N=789, IQR 1-5). In comparison with standard of care, treatment with NMBA was more frequent in obese (31% vs. 39%, P = 0.03) and diabetic patients (2% vs. 8%, P <0.01) and less frequent in patients with hypertension (52% vs. 46%, P =0.04) or cardiac diseases (21% vs. 14%, P =0.003). Upon commencement of MV, patients who underwent NMBA therapy vs those who did not presented a PaO2/FiO2 of 136.1±69.2 vs. 162.7 ±125.8 (p<0.01), required more often ECMO (10% vs 5.2%, p <0.01) and prone position (25.1% vs 6.2%, p <0.01). Unadjusted 28-day all-cause mortality was similar (58.2% vs. 62.4%, P =0.134) between patients without or with NMBA therapy, respectively, but length of MV (3 days [2-5] vs. 6 [3-12] P <0.01) and ICU stay (8 days [4-14] vs. 13 [7-19] P <0.01) were prolonged. After PS matching, NMBA therapy was strongly associated with 28-day ICU mortality (adjusted HR 3.18, 95% CI 2.65-3.81, P <0.01). CONCLUSION. Use of NMBA in COVID-19 patients requiring MV is associated with increased 28-day mortality, delayed discontinuation of MV and prolonged ICU stay.

Factors associated with mortality in patients with COVID-19 requiring mechanical ventilation: An international cohort study from 139 intensive care unit across 6 continents

Rationale: Patients with COVID-19 commonly develop severe hypoxemic respiratory failure and require invasive mechanical ventilation (MV). The disease burden and predictors of mortality in this population remain uncertain. Methods: Prospective observational cohort study from 139 intensive care units of the international COVID-19 Critical Care Consortium. Patients enrolled from January 14th through November 31st 2020 were included in the analysis. Patient's characteristics and clinical data were assessed. Multivariable Cox proportional hazards analysis was conducted to identify indipendent predictors of mortality within 28 days from commencement of MV. Results: 1578 patients on MV were included into the analysis. Mean±SD age was 59 years±13 and patients were predominantly males (66%). 542 Patients (34.4%) died within 28 days from commencement of MV. Nonsurvivors were slightly older (mean age±SD 62±13 vs. 59±13) and presented more frequently hypertension, chronic cardiac disease and diabetes. Median (IQR) PaO2/FiO2 upon commencement of MV was 96 (68-135) and 111 (81-173) in patients who did not survive vs. survivors, respectively (p=0.04). ECMO (13% vs 25%, p<0.01), inhaled nitric oxide (11% vs 15%, p=0.02) and recruitment manoeauvres (26% vs 31%, p<0.01) were used less frequently in patients who did not survive. Independent risk factors associated with 28-day mortality included age older than 70 years (hazard ratio [HR], 2.83;95% CI, 1.32-6.07), higher creatinine levels upon ICU admission (HR, 1.20;95% CI, 1.03-1.40), and lower pH within 24h from commencement of MV (HR, 0.12;95% CI, 0.02-0.62), while a shorter period (day) from early symptoms to hospitalisation reduced mortality risks (HR, 0.96;95% CI, 0.93-0.99). Conclusions: Our findings from a large international cohort of critically-ill COVID-19 patients on mechanical ventilation emphasises that elderly patients, not promptly admitted to the hospital, and who present higher creatinine levels and acidosis are at higher risk of mortality.

Prone position during veno-venous extracorporeal membrane oxygenation for COVID-19

Objective: Prone positioning for severe acute respiratory distress syndrome (ARDS) is associated with improved outcome. It is unclear whether prone positioning during Venovenous extracorporeal membrane oxygenation (VV ECMO) has survival benefit. The study investigated the impact of prone positioning on survival during VV ECMO support for COVID-19 acute respiratory failure. Methods: An observational analysis of VV ECMO patients using the COVID-19 Critical Care Consortium (COVID Critical) international registry. We used a multi-state survival model to compare the outcomes of patients treated with or without prone positioning during ECMO. Results: There were 213 COVID-19 patients at 67 participating institutions who were supported with VV ECMO from February 19, 2020, to October 31, 2020. Proning was used in 160 patients (75%) before initiation of ECMO and in 67 patients (31%) during ECMO. Prone positioning during ECMO support was associated with reduced mortality (hazard ratio 0.33, 95% CI, 0.15 to 0.73). Conclusions: Our study highlights that prone-positioning during VV ECMO support for refractory COVID- 19-related ARDS is associated with reduced mortality. Given our observational study design, a randomized controlled trial of prone positioning on VV ECMO is needed to confirm these findings.