Immune suppressant therapy is associated with improved anemia and a decrease in transfusion needs in critically ill COVID patients

Introduction: Anemia of inflammation is considered to be a main cause of anemia on the ICU. Inflammatory cytokines, most importantly IL-6, play a role in this pathogenesis. Given that both anemia and red blood cell (RBC) transfusions are associated with adverse outcomes, and iron is ineffective, novel treatments of anemia are wanted. The aim of this study is to investigate the effect of immunosuppressive agents on anemia development and RBC transfusions in critically ill COVID patients. Method(s): This retrospective cohort study included all ICU patients of two hospitals in the Netherlands between February 2020 and April 2022 with a PCR-positive COVID-19 ARDS. Actively bleeding patients were excluded. Evolving insights in the treatment protocol resulted in three treatment groups: no treatment, steroids or combination of steroids with tocilizumab. Daily lab results and number of RBC transfusion were retrieved and the decline in Hb level between ICU admission day 1 and 7 was calculated. A multiple linear regression analysis was used to compare outcomes. Result(s): In total, 719 patients were included, of which 168 in the no-treatment group, 337 in the steroid group and 212 in the steroids and tocilizumab group. Hb levels declined in all groups. The median decline in Hb level in the combination group was lowest, with -0.3 mmol/l [-0.9 to 0.2], -0.8 mmol/l [-1.3 to -0.1] in the group receiving steroids in the steroid group and [-1.6 to -0.5] in the no treatment group. The number of RBC transfusions was 1 [1-3] in the group receiving combination therapy, 3[1-6] in the group receiving steroids and 3[2-8] in the group receiving no treatment (p < 0.002). In a multivariate analysis, the receipt of combination therapy remained associated with inhibition of decline in Hb as well as with lowering the number of RBC transfusions. Conclusion(s): Treatment with either steroids or a combination of steroids and tocilizumab was associated with a slower decline in Hb levels during ICU stay and less RBC transfusions when compared to no treatment.

The efficacy and safety of intravenous imatinib in invasively ventilated patients with COVID-19 related acute respiratory distress syndrome (InventCOVID): a multicentre, randomised, double-blinded, placebocontrolled, phase II clinical study

Background: A central hallmark of ARDS is hypoxemic respiratory failure due to increased pulmonary capillary leakage. The kinase inhibitor imatinib was shown to reverse vascular leak. This study aimed to investigate the effect of intravenous imatinib on pulmonary edema in patients with COVID-19 ARDS. Method(s): This multicentre, randomised, double-blind, placebo-controlled clinical trial (ClinicalTrial.gov identifier NCT04794088) included adult patients admitted to the ICU with moderate or severe COVID-19 ARDS. Patients were randomised 1:1 to receive 200mg intravenous imatinib or placebo twice daily for seven days or until ICU discharge. The change in extravascular lung water index between day 1 and day 4, measured using a PiCCO catheter, was chosen as the primary endpoint. Secondary outcomes included the PaO2/FiO2 ratio, number of ventilator free days, length of ICU admission and 28-day mortality rate. Study drug safety was assessed by daily screening of the patient records for adverse and serious adverse event occurrence and by performing ECGs and targeted clinical laboratory tests to monitor renal, liver and cardiac function. Result(s): Between March 2021 and 2022, 67 predominantly male (58%) patients with a mean age of 63+/-10 years were randomized to receive imatinib or placebo. No adverse events were considered to be related to study drug administration. At the moment of the submission, data cleaning is still ongoing. Conclusion(s): Thus far, intravenous imatinib administration seems safe and feasible in patients with COVID-19 related ARDS.

Awake prone positioning in nonintubated spontaneous breathing ICU patients with acute hypoxemic respiratory failure (PRONELIFE)-protocol for a randomized clinical trial.

BACKGROUND: It is uncertain whether awake prone positioning can prevent intubation for invasive ventilation in spontaneous breathing critically ill patients with acute hypoxemic respiratory failure. Awake prone positioning could benefit these patients for various reasons, including a reduction in direct harm to lung tissue, and prevention of tracheal intubation-related complications. DESIGN AND METHODS: The PRONELIFE study is an investigator-initiated, international, multicenter, randomized clinical trial in patients who may need invasive ventilation because of acute hypoxemic respiratory failure. Consecutive patients admitted to participating ICUs are randomly assigned to standard care with awake prone positioning, versus standard care without awake prone positioning. The primary endpoint is a composite of tracheal intubation and all-cause mortality in the first 14 days after enrolment. Secondary endpoints include time to tracheal intubation and effects of awake prone positioning on oxygenation parameters, dyspnea sensation, and complications. Other endpoints are the number of days free from ventilation and alive at 28 days, total duration of use of noninvasive respiratory support, total duration of invasive ventilation, length of stay in ICU and hospital, and mortality in ICU and hospital, and at 28, 60, and 90 days. We will also collect data regarding the tolerance of prone positioning. DISCUSSION: The PRONELIFE study is among the first randomized clinical trials investigating the effect of awake prone positioning on intubation rate in ICU patients with acute hypoxemic failure from any cause. The PRONELIFE study is sufficiently sized to determine the effect of awake prone positioning on intubation for invasive ventilation-patients are eligible in case of acute hypoxemic respiratory failure without restrictions regarding etiology. The PRONELIFE study is a pragmatic trial in which blinding is impossible-however, as around 35 ICUs worldwide will participate in this study, its findings will be highly generalizable. The findings of the PRONELIFE study have the potential to change clinical management of patients who may need invasive ventilation because of acute hypoxemic respiratory failure. TRIAL REGISTRATION: ISRCTN ISRCTN11536318 . Registered on 17 September 2021. The PRONELIFE study is registered at clinicaltrials.gov with reference number NCT04142736 (October, 2019).

Pre-admission anticoagulant therapy and mortality in hospitalized COVID-19 patients: A covid predict retrospectivecohort study

Background : A high incidence of venous thromboembolism (VTE) is observed in patients with COVID-19. Furthermore, several studies show that hypercoagulability is associated with mortality. Aims : To investigate whether pre-admission anticoagulant therapy is associated with a lower risk of all-cause mortality in hospitalized COVID-19 patients. Methods : Retrospective data from 1,851 consecutive patients with PCR-confirmed SARS-CoV-2 infection hospitalized in eight Dutch centres between February 27 th and August 1 st 2020 were used. During this period, Dutch guidelines recommended routine thromboprophylaxis for all hospitalized COVID-19 patients. After 1:1 propensity score nearest-neighbour matching based on age, sex, and 17 comorbidities, the association between pre-admission anticoagulant therapy for VTE, atrial fibrillation, or other indications (i.e. direct oral anticoagulants or vitamin K antagonists) and all-cause mortality and intensive care unit (ICU) admission was evaluated. A secondary analysis was performed with a broader definition of antithrombotic therapy including anticoagulants and antiplatelet drugs. Results : Mean age was 66.4 years (SD, 14.8) and 39% were women. Pre-admission, 678 patients (37%) were using anticoagulant and/or antiplatelet therapy of whom 287 (16%) used anticoagulant therapy only, 408 (22%) antiplatelet therapy only, and 17 both anticoagulant and antiplatelet therapy. 253 anticoagulant users and 253 patients not using therapeutic anticoagulation were matched. During a median follow-up of 21 days [IQR: 9.8-21.0], anticoagulant therapy was neither associated with all-cause mortality (hazard ratio [HR], 0.95;95%-CI, 0.70-1.27;Figure 1) nor with ICU admission (HR, 1.0;95%-CI, 0.59-1.70). Results did not materially change in the secondary analysis of anticoagulant and/or antiplatelet therapy (HR for mortality, 1.18 [95%-CI, 0.87-1.59] and HR for ICU admission, 2.98 [95%-CI, 0.60-1.39]). Conclusions : In this retrospective cohort study, pre-admission anticoagulant use was not associated with a lower risk of mortality or ICU admission in hospitalized COVID-19 patients. Further data from randomized controlled trials are needed to determine the riskbenefit ratio of initiating anticoagulant therapy during admission for COVID-19.

Incidence of thrombotic complications and overall survival in hospitalized patients with COVID-19 in the second and first wave.

INTRODUCTION: In the first wave, thrombotic complications were common in COVID-19 patients. It is unknown whether state-of-the-art treatment has resulted in less thrombotic complications in the second wave. METHODS: We assessed the incidence of thrombotic complications and overall mortality in COVID-19 patients admitted to eight Dutch hospitals between September 1st and November 30th 2020. Follow-up ended at discharge, transfer to another hospital, when they died, or on November 30th 2020, whichever came first. Cumulative incidences were estimated, adjusted for competing risk of death. These were compared to those observed in 579 patients admitted in the first wave, between February 24th and April 26th 2020, by means of Cox regression techniques adjusted for age, sex and weight. RESULTS: In total 947 patients with COVID-19 were included in this analysis, of whom 358 patients were admitted to the ICU; 144 patients died (15%). The adjusted cumulative incidence of all thrombotic complications after 10, 20 and 30 days was 12% (95% confidence interval (CI) 9.8-15%), 16% (13-19%) and 21% (17-25%), respectively. Patient characteristics between the first and second wave were comparable. The adjusted hazard ratio (HR) for overall mortality in the second wave versus the first wave was 0.53 (95%CI 0.41-0.70). The adjusted HR for any thrombotic complication in the second versus the first wave was 0.89 (95%CI 0.65-1.2). CONCLUSIONS: Mortality was reduced by 47% in the second wave, but the thrombotic complication rate remained high, and comparable to the first wave. Careful attention to provision of adequate thromboprophylaxis is invariably warranted.