Dynamic of SOFA Score Predicts Functionality after ARDS Therapy (preprint)

Rationale: Health-related quality of life after surviving acute respiratory distress syndrome has come into focus in recent years, especially during the coronavirus disease 2019 pandemic. Objectives: A total of 143 patients with acute respiratory distress syndrome caused by COVID-19 or of other origin were recruited in a randomized multicenter trial. Methods: Clinical data during intensive care treatment and data up to 180 days after study inclusion were collected. Changes in the Sequential Organ Failure Assessment score were used to quantify disease severity. Disability was assessed using the Barthel index on days 1, 28, 90, and 180. Measurements: Mortality rate and morbidity after 180 days were compared between patients with and without COVID-19. Independent risk factors associated with high disability were identified using a binary logistic regression. Main Results: Mortality after 180 days and impairment measured by the Barthel index did not differ between patients with and without COVID-19. The SOFA score at day 5 was an independent risk factor for high disability in both groups, and score dynamic within the first 5 days significantly impacted disability in the non-COVID group. Conclusions: Acute respiratory distress syndrome caused by COVID-19 was not associated with increased mortality or morbidity. Resolution of organ dysfunction within the first 5 days significantly impacts long-term morbidity and emphasizes the importance of timely initiation of treatment in these critically ill patients.

Inhaled Prostacyclin Improves Oxygenation in Patients with COVID-19-induced Acute Respiratory Distress Syndrome – a randomized controlled multicenter trial (preprint)

Background. Acute Respiratory Distress Syndrome (ARDS) results in significant hypoxia, and ARDS is the central pathology of COVID-19. Inhaled prostacyclin has been proposed as a therapy for ARDS, but data regarding its role in this syndrome are unavailable. Therefore, we investigated whether inhaled prostacyclin would affect the oxygenation and survival of patients suffering from ARDS.Methods. We performed a prospective randomized controlled single-blind multicenter trial across Germany. The trial was conducted from March 2019 with final follow-up on 12th of August 2021. Patients with moderate to severe ARDS were included and randomized to receive either inhaled prostacyclin (3 times/day for 5 days) or sodium chloride. The primary outcome was the oxygenation index in the intervention and control groups on Day 5 of therapy. Secondary outcomes were mortality, secondary organ failure, disease severity and adverse events.Results. Of 707 patients approached 150 patients were randomized to receive inhaled prostacyclin (n = 73) or sodium chloride (n = 77). Data from 144 patients were analyzed. The baseline oxygenation index did not differ between groups. The primary analysis of the study was negative, and prostacyclin improved oxygenation by 20 mmHg more than NaCl (p = 0·17). Oxygenation was significantly improved in patients with ARDS who were COVID-19-positive (34 mmHg, p = 0·04). Mortality did not differ between groups. Secondary organ failure and adverse events were similar in the intervention and control groups.Conclusions. Although the primary result of our study was negative, our data suggest that inhaled prostacyclin might be a more beneficial treatment than standard care for patients with ARDS.Trial registration: The study was approved by the Institutional Review Board of the Research Ethics Committee of the University of Tübingen (899/2018AMG1) and the corresponding ethical review boards of all participating centers. The trial was also approved by the Federal Institute for Drugs and Medical Devices (BfArM, EudraCT No. 2016-003168-37) and registered at clinicaltrials.gov (NCT03111212) on April 6th 2017.

Inhaled Prostacyclin Improves Oxygenation in Patients with COVID-19-induced Acute Respiratory Distress Syndrome (preprint)

Background. Acute Respiratory Distress Syndrome (ARDS) results in significant hypoxia, and ARDS is the central pathology of COVID-19. Inhaled prostacyclin has been proposed as a therapy for ARDS, but data regarding its role in this syndrome are unavailable. Therefore, we investigated whether inhaled prostacyclin would affect the oxygenation and survival of patients suffering from ARDS. Methods. We performed a prospective randomized controlled single-blind multicenter trial across Germany. The trial was conducted from March 2019 with final follow-up on 12 th of August 2021. Patients with moderate to severe ARDS were included and randomized to receive either inhaled prostacyclin (3 times/day for 5 days) or sodium chloride. The primary outcome was the oxygenation index in the intervention and control groups on Day 5 of therapy. Secondary outcomes were mortality, secondary organ failure, disease severity and adverse events. Findings. Of 707 patients approached 150 patients were randomized to receive inhaled prostacyclin (n=73) or sodium chloride (n=77). Data from 144 patients were analyzed. The baseline oxygenation index did not differ between groups. The primary analysis of the study was negative, and prostacyclin improved oxygenation by 20 mmHg more than NaCl (p=0.17). Oxygenation was significantly improved in patients with ARDS who were COVID-19-positive (34 mmHg, p=0.04). Mortality did not differ between groups. Secondary organ failure and adverse events were similar in the intervention and control groups. Interpretation. Although the primary result of our study was negative, our data suggest that inhaled prostacyclin might be a more beneficial treatment than standard care for patients with ARDS.

Machine Learning Identifies ICU Outcome Predictors in a Multicenter COVID-19 Cohort. (preprint)

Background. Intensive Care Resources are heavily utilized during the COVID-19 pandemic. However, risk stratification and prediction of SARS-CoV-2 patient clinical outcomes upon ICU admission remain inadequate. This study aimed to develop a machine learning model, based on retrospective & prospective clinical data, to stratify patient risk and predict ICU survival and outcomes.Methods. A Germany-wide electronic registry was established to pseudonymously collect admission, therapeutic and discharge information of SARS-CoV-2 ICU patients retrospectively and prospectively. Machine learning approaches were evaluated for the accuracy and interpretability of predictions. The Explainable Boosting Machine approach was selected as the most suitable method. Individual, non-linear shape functions for predictive parameters and parameter interactions are reported. Results. 1,039 patients were included in the Explainable Boosting Machine model, 596 patients retrospectively collected, and 443 patients prospectively collected. The model for prediction of general ICU outcome was shown to be more reliable to predict “survival”. Age, inflammatory and thrombotic activity, and severity of ARDS at ICU admission were shown to be predictive of ICU survival. Patients’ age, pulmonary dysfunction and transfer from an external institution were predictors for ECMO therapy. The interaction of patient age with D-dimer levels on admission and creatinine levels with SOFA score without GCS were predictors for renal replacement therapy. Conclusions. Using Explainable Boosting Machine analysis, we confirmed and weighed previously reported and identified novel predictors for outcome in critically ill COVID-19 patients. Using this strategy, predictive modeling of COVID-19 ICU patient outcomes can be performed overcoming the limitations of linear regression models.Trial registration. “ClinicalTrials” (clinicaltrials.gov) under NCT04455451

High Dose Convalescent Plasma in COVID-19: Results from the randomized Trial CAPSID (preprint)

Rationale: COVID-19 convalescent plasma (CCP) has been considered a treatment option in COVID-19. Objectives:: To assess the efficacy of neutralizing antibody containing high-dose CCP in hospitalized adults with COVID-19 requiring respiratory support or intensive care treatment. Methods: Patients (n=105) were randomized 1:1 to either receive standard treatment and 3 units of CCP or standard treatment alone. Control group patients with progress on day 14 could cross over to the CCP group. Primary outcome was a dichotomous composite outcome of survival and no longer fulfilling criteria for severe COVID-19 on day 21. The trial is registered: clinicaltrials.gov #NCT04433910. Measurements and main results: The primary outcome occurred in 43.4% of patients in the CCP and 32.7% in the control group (p=0.32). The median time to clinical improvement was 26 days (IQR 15-not reached (n.r.)) in the CCP group and 66 days (IQR 13-n.r.) in the control group (p=0.27). Median time to discharge from hospital was 31 days (IQR 16-n.r.) in the CCP and 51 days (IQR 20-n.r.) in the control group (p=0.24). In the subgroup that received a higher cumulative amount of neutralizing antibodies the primary outcome occurred in 56.0% (versus 32.1%), with a shorter interval to clinical improvement, shorter time to hospital discharge and better survival compared to the control group. Conclusion: CCP added to standard treatment did not result in a significant difference in the primary and secondary outcomes. A pre-defined subgroup analysis showed a significant benefit for CCP among those who received a larger amount of neutralizing antibodies. Primary Funding Source: Bundesministerium fuer Gesundheit

How To Handle Disaster? – Evaluation of a Course for Disaster Medicine and Humanitarian Assistance for Undergraduate Medical Students (preprint)

Background: Disaster medicine is a component of the German medical education since 2003. However, studies have shown some inconsistencies within the implementation of the national curriculum, and limits with the number of students trained over the years. Facing the SARS-CoV-2 pandemic and other disasters, it became much more important to train medical students in disaster medicine on a coordinated basis.Methods: The University Clinic for Anaesthesiology and Intensive Care Medicine in Tübingen, Germany, expanded the existing curriculum of undergraduate disaster medicine training with fundamentals of humanitarian medicine, integrating the experience with distance learning, interactive teaching and simulation sessions. Survey tools were used to assess participants’ previous experiences and interest in the field of disaster medicine, to compare the self-reported degree of knowledge before and after training, and the programme’s quality evaluation. A mandatory pre- and post-test of knowledge was also administered to evaluate learner outcomes. The prospective and cross-sectional study evaluates the pilot course Disaster Medicine and Humanitarian Assistance carried out for third-, fourth- and fifth- year medical students over five semesters during the period between 2018 and 2020.Results: Data was collected from 107 students over five training sessions. Out of a sample of 82 students, the subjective perception of knowledge increased after the course (t [81] = 24.426, p < .001), alongside with the interest in engaging in the field of disaster medicine (t[81 ] = 7.031, p < .001). 102 students entered the mandatory knowledge assessment, with the rate of correct answers passing from 73.27% in the pre-test to 95.23% in the post-test (t [101] = 18.939, p < .001). The 93.46% of the medical students (N = 100) graded the training received with an excellent overall score (1.01 out of 6).Discussion: The study indicates a significant increase in students’ understanding of disaster medicine through the use of both subjective and objective measures, as well as an increase interest in the field of disaster and humanitarian medicine. The educational programme appears to address the deficiencies documented in previous studies, and possible adaptation with virtual reality approaches could expand access to a larger audience.Conclusion: The programme offers an effective and comprehensive tool to address the urgent need of quality education for medical students, suggesting integrated strategies to implement disaster medicine training.

cAMP prevents antibody-mediated thrombus formation in COVID-19 (preprint)

Thromboembolic events are frequently reported in patients infected with the SARS-CoV-2 virus. However, the exact mechanisms of thromboembolic events remain elusive. In this work, we show that immunoglobulin G (IgG) subclass in patients with COVID-19 trigger the formation of procoagulant PLTs in a Fc-gamma-RIIA dependent pathway leading to increased thrombus formation in vitro. Most importantly, these events were significantly inhibited via Fc-gamma-RIIA blockade as well as by the elevation of PLTs intracellular cyclic-adenosine-monophosphate (cAMP) levels by the clinical used agent Iloprost. The novel findings of Fc-gamma-RIIA mediated prothrombotic conditions in terms of procoagulant PLTs leading to higher thrombus formation as well as the successful inhibition of these events via Iloprost could be promising for the future treatment of the complex coagulopathy observed in COVID-19 disease.

Severe COVID-19 infection is associated with increased antibody-mediated platelet apoptosis (preprint)

The pathophysiology of COVID-19 associated thrombosis seems to be multifactorial, involving interplay between cellular and plasmatic elements of the hemostasis. We hypothesized that COVID-19 is accompanied by platelet apoptosis with subsequent alteration of the coagulation system. We investigated depolarization of mitochondrial inner transmembrane potential ({Delta}{Psi}m), cytosolic calcium (Ca2+) concentration, and phosphatidylserine (PS) externalization by flow cytometry. Platelets from intensive care unit (ICU) COVID-19 patients (n=21) showed higher {Delta}{Psi}m depolarization, cytosolic Ca2+ concentration and PS externalization, compared to healthy controls (n=18) and COVID-19 non-ICU patients (n=4). Moreover significant higher cytosolic Ca2+ concentration and PS was observed compared to septic ICU control group (ICU control). In ICU control group (n=5; non-COVID-19 ICU) cytosolic Ca2+ concentration and PS externalization was comparable to healthy control, with an increase in {Delta}{Psi}m depolarization. Sera from ICU COVID-19 patients induced significant increase in apoptosis markers ({Delta}{Psi}m depolarization, cytosolic Ca2+ concentration and PS externalization) compared to healthy volunteer and septic ICU control. Interestingly, immunoglobulin G (IgG) fractions from COVID-19 patients induced an Fc gamma receptor IIA dependent platelet apoptosis ({Delta}{Psi}m depolarization, cytosolic Ca2+ concentration and PS externalization). Enhanced PS externalization in platelets from ICU COVID-19 patients was associated with increased sequential organ failure assessment (SOFA) score (r=0.5635) and D-Dimer (r=0.4473). Most importantly, patients with thrombosis had significantly higher PS externalization compared to those without. The strong correlations between apoptosis markers and increased D-Dimer levels as well as the incidence of thrombosis may indicate that antibody-mediated platelet apoptosis potentially contributes to sustained increased thromboembolic risk in ICU COVID-19 patients.