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.

BACKGROUND: To inform future research and practice, we aimed to investigate the outcomes of patients who received extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS) due to different variants of SARS-CoV-2. METHODS: This retrospective study included consecutive adult patients with laboratory-confirmed SARS-CoV-2 infection who received ECMO for ARDS in 21 experienced ECMO centres in eight European countries (Austria, Belgium, England, France, Germany, Italy, Portugal, and Spain) between Jan 1, 2020, and Sept 30, 2021. We collected data on patient characteristics, clinical status, and management before and after the initiation of ECMO. Participants were grouped according to SARS-CoV-2 variant (wild type, alpha, delta, or other) and period of the pandemic (first [Jan 1-June 30] and second [July 1-Dec 31] semesters of 2020, and first [Jan 1-June 30] and second [July 1-Sept 30] semesters of 2021). Descriptive statistics and Kaplan-Meier survival curves were used to analyse evolving characteristics, management, and patient outcomes over the first 2 years of the pandemic, and independent risk factors of mortality were determined using multivariable Cox regression models. The primary outcome was mortality 90 days after the initiation of ECMO, with follow-up to Dec 30, 2021. FINDINGS: ECMO was initiated in 1345 patients. Patient characteristics and management were similar for the groups of patients infected with different variants, except that those with the delta variant had a younger median age and less hypertension and diabetes. 90-day mortality was 42% (569 of 1345 patients died) overall, and 43% (297/686) in patients infected with wild-type SARS-CoV-2, 39% (152/391) in those with the alpha variant, 40% (78/195) in those with the delta variant, and 58% (42/73) in patients infected with other variants (mainly beta and gamma). Mortality was 10% higher (50%) in the second semester of 2020, when the wild-type variant was still prevailing, than in other semesters (40%). Independent predictors of mortality were age, immunocompromised status, a longer time from intensive care unit admission to intubation, need for renal replacement therapy, and higher Sequential Organ Failure Assessment haemodynamic component score, partial pressure of arterial carbon dioxide, and lactate concentration before ECMO. After adjusting for these variables, mortality was significantly higher with the delta variant than with the other variants, the wild-type strain being the reference. INTERPRETATION: Although crude mortality did not differ between variants, adjusted risk of death was highest for patients treated with ECMO infected with the delta variant of SARS-CoV-2. The higher virulence and poorer outcomes associated with the delta strain might relate to higher viral load and increased inflammatory response syndrome in infected patients, reinforcing the need for a higher rate of vaccination in the population and updated selection criteria for ECMO, should a new and highly virulent strain of SARS-CoV-2 emerge in the future. Mortality was noticeably lower than in other large, multicentre series of patients who received ECMO for COVID-19, highlighting the need to concentrate resources at experienced centres. FUNDING: None.

Respiratory indications for ECMO: focus on COVID-19.

Extracorporeal membrane oxygenation (ECMO) is increasingly being used for patients with severe respiratory failure and has received particular attention during the coronavirus disease 2019 (COVID-19) pandemic. Evidence from two key randomized controlled trials, a subsequent post hoc Bayesian analysis, and meta-analyses support the interpretation of a benefit of ECMO in combination with ultra-lung-protective ventilation for select patients with very severe forms of acute respiratory distress syndrome (ARDS). During the pandemic, new evidence has emerged helping to better define the role of ECMO for patients with COVID-19. Results from large cohorts suggest outcomes during the first wave of the pandemic were similar to those in non-COVID-19 cohorts. As the pandemic continued, mortality of patients supported with ECMO has increased. However, the precise reasons for this observation are unclear. Known risk factors for mortality in COVID-19 and non-COVID-19 patients are higher patient age, concomitant extra-pulmonary organ failures or malignancies, prolonged mechanical ventilation before ECMO, less experienced treatment teams and lower ECMO caseloads in the treating center. ECMO is a high resource-dependent support option; therefore, it should be used judiciously, and its availability may need to be constrained when resources are scarce. More evidence from high-quality research is required to better define the role and limitations of ECMO in patients with severe COVID-19.

[Psychological aspects during and after intensive care treatment of ARDS]. / Psychologische Aspekte während und nach intensivmedizinischer Behandlung von ARDS.

Approximately 10% of all patients requiring intensive care develop acute respiratory distress syndrome (ARDS). The COVID-19 pandemic led to an accumulation of patients with severe ARDS. The experience of this severe respiratory failure is accompanied by feelings of existential anxiety in many patients.The complexity of the challenges and stresses that the disease and its treatment pose for the ARDS patient require an early multiprofessional approach to treatment already during intensive care. Psychological approaches are suitable to support the patient as well as the relatives in coping with the disease and to minimise risks for potential subsequent stress. Despite the long-term impairments of patients who have survived ARDS and the resulting need for follow-up care, suitable multimodal follow-up care concepts and the necessary care structures are still lacking. The article presents the psychological support during and after the intensive care treatment of ARDS.

Key characteristics impacting survival of COVID-19 extracorporeal membrane oxygenation.

BACKGROUND: Severe COVID-19 induced acute respiratory distress syndrome (ARDS) often requires extracorporeal membrane oxygenation (ECMO). Recent German health insurance data revealed low ICU survival rates. Patient characteristics and experience of the ECMO center may determine intensive care unit (ICU) survival. The current study aimed to identify factors affecting ICU survival of COVID-19 ECMO patients. METHODS: 673 COVID-19 ARDS ECMO patients treated in 26 centers between January 1st 2020 and March 22nd 2021 were included. Data on clinical characteristics, adjunct therapies, complications, and outcome were documented. Block wise logistic regression analysis was applied to identify variables associated with ICU-survival. RESULTS: Most patients were between 50 and 70 years of age. PaO2/FiO2 ratio prior to ECMO was 72 mmHg (IQR: 58-99). ICU survival was 31.4%. Survival was significantly lower during the 2nd wave of the COVID-19 pandemic. A subgroup of 284 (42%) patients fulfilling modified EOLIA criteria had a higher survival (38%) (p = 0.0014, OR 0.64 (CI 0.41-0.99)). Survival differed between low, intermediate, and high-volume centers with 20%, 30%, and 38%, respectively (p = 0.0024). Treatment in high volume centers resulted in an odds ratio of 0.55 (CI 0.28-1.02) compared to low volume centers. Additional factors associated with survival were younger age, shorter time between intubation and ECMO initiation, BMI > 35 (compared to < 25), absence of renal replacement therapy or major bleeding/thromboembolic events. CONCLUSIONS: Structural and patient-related factors, including age, comorbidities and ECMO case volume, determined the survival of COVID-19 ECMO. These factors combined with a more liberal ECMO indication during the 2nd wave may explain the reasonably overall low survival rate. Careful selection of patients and treatment in high volume ECMO centers was associated with higher odds of ICU survival. TRIAL REGISTRATION: Registered in the German Clinical Trials Register (study ID: DRKS00022964, retrospectively registered, September 7th 2020, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00022964 .

Extracorporeal Membrane Oxygenation during Respiratory Pandemics: Past, Present, and Future.

The role of extracorporeal membrane oxygenation (ECMO) in the management of severe acute respiratory failure, including acute respiratory distress syndrome, has become better defined in recent years in light of emerging high-quality evidence and technological advances. Use of ECMO has consequently increased throughout many parts of the world. The coronavirus disease (COVID-19) pandemic, however, has highlighted deficiencies in organizational capacity, research capability, knowledge sharing, and resource use. Although governments, medical societies, hospital systems, and clinicians were collectively unprepared for the scope of this pandemic, the use of ECMO, a highly resource-intensive and specialized form of life support, presented specific logistical and ethical challenges. As the pandemic has evolved, there has been greater collaboration in the use of ECMO across centers and regions, together with more robust data reporting through international registries and observational studies. Nevertheless, centralization of ECMO capacity is lacking in many regions of the world, and equitable use of ECMO resources remains uneven. There are no widely available mechanisms to conduct large-scale, rigorous clinical trials in real time. In this critical care review, we outline lessons learned during COVID-19 and prior respiratory pandemics in which ECMO was used, and we describe how we might apply these lessons going forward, both during the ongoing COVID-19 pandemic and in the future.

Key summary of German national treatment guidance for hospitalized COVID-19 patients : Key pharmacologic recommendations from a national German living guideline using an Evidence to Decision Framework (last updated 17.05.2021).

PURPOSE: This executive summary of a national living guideline aims to provide rapid evidence based recommendations on the role of drug interventions in the treatment of hospitalized patients with COVID-19. METHODS: The guideline makes use of a systematic assessment and decision process using an evidence to decision framework (GRADE) as recommended standard WHO (2021). Recommendations are consented by an interdisciplinary panel. Evidence analysis and interpretation is supported by the CEOsys project providing extensive literature searches and living (meta-) analyses. For this executive summary, selected key recommendations on drug therapy are presented including the quality of the evidence and rationale for the level of recommendation. RESULTS: The guideline contains 11 key recommendations for COVID-19 drug therapy, eight of which are based on systematic review and/or meta-analysis, while three recommendations represent consensus expert opinion. Based on current evidence, the panel makes strong recommendations for corticosteroids (WHO scale 5-9) and prophylactic anticoagulation (all hospitalized patients with COVID-19) as standard of care. Intensified anticoagulation may be considered for patients with additional risk factors for venous thromboembolisms (VTE) and a low bleeding risk. The IL-6 antagonist tocilizumab may be added in case of high supplemental oxygen requirement and progressive disease (WHO scale 5-6). Treatment with nMABs may be considered for selected inpatients with an early SARS-CoV-2 infection that are not hospitalized for COVID-19. Convalescent plasma, azithromycin, ivermectin or vitamin D3 should not be used in COVID-19 routine care. CONCLUSION: For COVID-19 drug therapy, there are several options that are sufficiently supported by evidence. The living guidance will be updated as new evidence emerges.

Observational study of changes in utilization and outcomes in mechanical ventilation in COVID-19.

BACKGROUND: The role of non-invasive ventilation (NIV) in severe COVID-19 remains a matter of debate. Therefore, the utilization and outcome of NIV in COVID-19 in an unbiased cohort was determined. AIM: The aim was to provide a detailed account of hospitalized COVID-19 patients requiring non-invasive ventilation during their hospital stay. Furthermore, differences of patients treated with NIV between the first and second wave are explored. METHODS: Confirmed COVID-19 cases of claims data of the Local Health Care Funds with non-invasive and/or invasive mechanical ventilation (MV) in the spring and autumn pandemic period in 2020 were comparable analysed. RESULTS: Nationwide cohort of 17.023 cases (median/IQR age 71/61-80 years, 64% male) 7235 (42.5%) patients primarily received IMV without NIV, 4469 (26.3%) patients received NIV without subsequent intubation, and 3472 (20.4%) patients had NIV failure (NIV-F), defined by subsequent endotracheal intubation. The proportion of patients who received invasive MV decreased from 75% to 37% during the second period. Accordingly, the proportion of patients with NIV exclusively increased from 9% to 30%, and those failing NIV increased from 9% to 23%. Median length of hospital stay decreased from 26 to 21 days, and duration of MV decreased from 11.9 to 7.3 days. The NIV failure rate decreased from 49% to 43%. Overall mortality increased from 51% versus 54%. Mortality was 44% with NIV-only, 54% with IMV and 66% with NIV-F with mortality rates steadily increasing from 62% in early NIV-F (day 1) to 72% in late NIV-F (>4 days). CONCLUSIONS: Utilization of NIV rapidly increased during the autumn period, which was associated with a reduced duration of MV, but not with overall mortality. High NIV-F rates are associated with increased mortality, particularly in late NIV-F.

Clinical Practice Guideline: Recommendations on the In-hospital Treatment of Patients with COVID-19.

BACKGROUND: The mortality of COVID-19 patients who are admitted to a hospital because of the disease remains high. The implementation of evidence-based treatments can improve the quality of care. METHODS: The new clinical practice guideline is based on publications retrieved by a systematic search in the Medline databases via PubMed and in the Cochrane COVID-19 trial registry, followed by a structured consensus process leading to the adoption of graded recommendations. RESULTS: Therapeutic anticoagulation can be considered in patients who do not require intensive care and have an elevated risk of thromboembolism (for example, those with D-dimer levels ≥ 2 mg/L). For patients in intensive care, therapeutic anticoagulation has no benefit. For patients with hypoxemic respiratory insufficiency, prone positioning and an early therapy attempt with CPAP/noninvasive ventilation (CPAP, continuous positive airway pressure) or high-flow oxygen therapy is recommended. Patients with IgG-seronegativity and, at most, low-flow oxygen should be treated with SARS-CoV-2-specific monoclonal antibodies (at present, casirivimab and imdevimab). Patients needing no more than low-flow oxygen should additionally be treated with janus kinase (JAK) inhibitors. All patients who need oxygen (low-flow, high-flow, noninvasive ventilation/CPAP, invasive ventilation) should be given systemic corticosteroids. Tocilizumab should be given to patients with a high oxygen requirement and progressively severe COVID-19 disease, but not in combination with JAK inhibitors. CONCLUSION: Noninvasive ventilation, high-flow oxygen therapy, prone positioning, and invasive ventilation are important elements of the treatment of hypoxemic patients with COVID-19. A reduction of mortality has been demonstrated for the administration of monoclonal antibodies, JAK inhibitors, corticosteroids, tocilizumab, and therapeutic anticoagulation to specific groups of patients.

Effectiveness of extended shutdown measures during the ´Bundesnotbremse´ introduced in the third SARS-CoV-2 wave in Germany.

A third SARS-CoV-2 infection wave has affected Germany from March 2021 until April 24th, until the ´Bundesnotbremse´ introduced nationwide shutdown measures. The ´Bundesnotbremse´ is the technical term which was used by the German government to describe nationwide shutdown measures to control the rising infection numbers. These measures included mainly contact restrictions on several level. This study investigates which effects locally dispersed pre- and post-´Bundesnotbremse´ measures had on the infection dynamics. We analyzed the variability and strength of the rates of the changes of weekly case numbers considering different regions, age groups, and contact restrictions. Regionally diverse measures slowed the rate of weekly increase by about 50% and about 75% in regions with stronger contact restrictions. The 'Bundesnotbremse' induced a coherent reduction of infection numbers across all German federal states and age groups throughout May 2021. The coherence of the infection dynamics after the 'Bundesnotbremse' indicates that these stronger measures induced the decrease of infection numbers. The regionally diverse non-pharmaceutical interventions before could only decelerate further spreading, but not prevent it alone.

[Intensive care bed requirements for COVID-19 in the fall/winter of 2021 : Simulation of different scenarios under consideration of incidences and vaccination rates]. / Intensivbettenbedarf für COVID­19 im Herbst/Winter 2021 : Simulation unterschiedlicher Szenarien unter Berücksichtigung von Inzidenzen und Impfquoten.

BACKGROUND: Despite the increasing vaccination rates against SARS-CoV­2, there is a risk of a renewed wave of infections in autumn 2021 due to the high seasonality of the pathogen, with the associated renewed possible heavy burden on intensive care. In the following manuscript we simulated different scenarios using defined mathematical models to estimate the burden of intensive care treatment by COVID-19 patients within certain limits during the coming autumn. METHODS: The simulation of the scenarios uses a stationary model supplemented by the effect of vaccinations. The age group-specific risk profile for intensive care unit (ICU)-associated disease progression is calculated using third wave ICU admission data from sentinel hospitals, local DIVI registry occupancy data and the corresponding local incidence rates by linear regression with time lag. We simulated vaccination rates of 15% for the over 18-year-old cohort, 70% for the 15-34 year cohort, 75%/80%/85% for the 35-59 year cohort and 85%/90%/95% for the over 60-year-old cohort. The simulations take into account that vaccination provides 100% protection against disease progression requiring intensive care. Regarding protection against infection in vaccinated persons the simulations are depicted for the scenario of 70% protection against infection in vaccinated persons and for the scenario of 85% protection against infection in vaccinated persons. RESULTS: The incidence is proportional to ICU bed occupancy. The proportionality factor is higher than in the second and third waves, so that comparable ICU bed occupancy is only achieved at a higher incidence. A 10% increase in vaccination rates of the over 35-year-olds to 85% and of the over 60-year-olds to 95% leads to a significant reduction in ICU bed occupancy. DISCUSSION: There will continue to be a close and linear relationship between SARS-CoV­2 incidence and ICU bed occupancy in the coming months. Even above incidences of 200/100,000 a considerable burden of ICUs with more than 3000 COVID-19 patients can be expected again, unless the vaccination rate is significantly increased. A few percentage points in the vaccination rate have a significant impact on potential ICU occupancy in the autumn, so efforts to increase vaccination acceptance should be a priority in the coming weeks. For intensive care medicine, the vaccination rate of those over 35 years of age is crucial.

6-month mortality and readmissions of hospitalized COVID-19 patients: A nationwide cohort study of 8,679 patients in Germany.

BACKGROUND: COVID-19 frequently necessitates in-patient treatment and in-patient mortality is high. Less is known about the long-term outcomes in terms of mortality and readmissions following in-patient treatment. AIM: The aim of this paper is to provide a detailed account of hospitalized COVID-19 patients up to 180 days after their initial hospital admission. METHODS: An observational study with claims data from the German Local Health Care Funds of adult patients hospitalized in Germany between February 1 and April 30, 2020, with PCR-confirmed COVID-19 and a related principal diagnosis, for whom 6-month all-cause mortality and readmission rates for 180 days after admission or until death were available. A multivariable logistic regression model identified independent risk factors for 180-day all-cause mortality in this cohort. RESULTS: Of the 8,679 patients with a median age of 72 years, 2,161 (24.9%) died during the index hospitalization. The 30-day all-cause mortality rate was 23.9% (2,073/8,679), the 90-day rate was 27.9% (2,425/8,679), and the 180-day rate, 29.6% (2,566/8,679). The latter was 52.3% (1,472/2,817) for patients aged ≥80 years 23.6% (1,621/6,865) if not ventilated during index hospitalization, but 53.0% in case of those ventilated invasively (853/1,608). Risk factors for the 180-day all-cause mortality included coagulopathy, BMI ≥ 40, and age, while the female sex was a protective factor beyond a fewer prevalence of comorbidities. Of the 6,235 patients discharged alive, 1,668 were readmitted a total of 2,551 times within 180 days, resulting in an overall readmission rate of 26.8%. CONCLUSIONS: The 180-day follow-up data of hospitalized COVID-19 patients in a nationwide cohort representing almost one-third of the German population show significant long-term, all-cause mortality and readmission rates, especially among patients with coagulopathy, whereas women have a profoundly better and long-lasting clinical outcome compared to men.

COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is presenting as a systemic disease associated with vascular inflammation and endothelial injury. Severe forms of SARS-CoV-2 infection induce acute respiratory distress syndrome (ARDS) and there is still an ongoing debate on whether COVID-19 ARDS and its perfusion defect differs from ARDS induced by other causes. Beside pro-inflammatory cytokines (such as interleukin-1 ß [IL-1ß] or IL-6), several main pathological phenomena have been seen because of endothelial cell (EC) dysfunction: hypercoagulation reflected by fibrin degradation products called D-dimers, micro- and macrothrombosis and pathological angiogenesis. Direct endothelial infection by SARS-CoV-2 is not likely to occur and ACE-2 expression by EC is a matter of debate. Indeed, endothelial damage reported in severely ill patients with COVID-19 could be more likely secondary to infection of neighboring cells and/or a consequence of inflammation. Endotheliopathy could give rise to hypercoagulation by alteration in the levels of different factors such as von Willebrand factor. Other than thrombotic events, pathological angiogenesis is among the recent findings. Overexpression of different proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) or placental growth factors (PlGF) have been found in plasma or lung biopsies of COVID-19 patients. Finally, SARS-CoV-2 infection induces an emergency myelopoiesis associated to deregulated immunity and mobilization of endothelial progenitor cells, leading to features of acquired hematological malignancies or cardiovascular disease, which are discussed in this review. Altogether, this review will try to elucidate the pathophysiology of thrombotic complications, pathological angiogenesis and EC dysfunction, allowing better insight in new targets and antithrombotic protocols to better address vascular system dysfunction. Since treating SARS-CoV-2 infection and its potential long-term effects involves targeting the vascular compartment and/or mobilization of immature immune cells, we propose to define COVID-19 and its complications as a systemic vascular acquired hemopathy.

Different spreading dynamics throughout Germany during the second wave of the COVID-19 pandemic: a time series study based on national surveillance data.

BACKGROUND: The second wave of the COVID-19 pandemic led to substantial differences in incidence rates across Germany. METHODS: Assumption-free k-nearest neighbour clustering from the principal component analysis of weekly incidence rates of German counties groups similar spreading behaviour. Different spreading dynamics was analysed by the derivative plots of the temporal evolution of tuples [x(t),x'(t)] of weekly incidence rates and their derivatives. The effectiveness of the different shutdown measures in Germany during the second wave is assessed by the difference of weekly incidences before and after the respective time periods. FINDINGS: The implementation of non-pharmaceutical interventions of different extents resulted in four distinct time periods of complex, spatially diverse, and age-related spreading patterns during the second wave of the COVID-19 pandemic in Germany. Clustering gave three regions of coincident spreading characteristics. October 2020 showed a nationwide exponential growth of weekly incidence rates with a doubling time of 10 days. A partial shutdown during November 2020 decreased the overall infection rates by 20-40% with a plateau-like behaviour in northern and southwestern Germany. The eastern parts exhibited a further near-linear growth by 30-80%. Allover the incidence rates among people above 60 years still increased by 15-35% during partial shutdown measures. Only an extended shutdown led to a substantial decrease in incidence rates. These measures decreased the numbers among all age groups and in all regions by 15-45%. This decline until January 2021 was about -1•25 times the October 2020 growth rates with a strong correlation of -0•96. INTERPRETATION: Three regional groups with different dynamics and different degrees of effectiveness of the applied measures were identified. The partial shutdown was moderately effective and at most stopped the exponential growth, but the spread remained partly plateau-like and regionally continued to grow in a nearly linear fashion. Only the extended shutdown reversed the linear growth. FUNDING: Institutional support and physical resources were provided by the University Witten/ Herdecke and Kliniken der Stadt Köln, German ministry of education and research 'Netzwerk Universitätsmedizin' (NUM), egePan Unimed (01KX2021).