Pulmonary embolism risk in critically ill patients with COVID-19: an instrumental variable analysis using differential application of thromboprophylaxis guidelines (preprint)

Thrombotic complications are common in Coronavirus disease 2019 (COVID-19) patients, with pulmonary embolism (PE) being the most frequent. Randomised trials have provided inconclusive results on the optimal dosage of thromboprophylaxis in critically ill COVID-19 patients. We utilized data from the multicentre CAPACITY-COVID patient registry to assess the effect of differential application of Low Molecular Weight Heparin (LMWH) dose protocols on PE and in-hospital mortality risk in critically ill COVID-19 patients. An instrumental variable analysis was performed to estimate the intention-to-treat effect, utilizing differences in thromboprophylaxis prescribing behaviour between hospitals. We included 939 patients with PCR confirmed SARS-CoV-2 infection from 34 hospitals. Two-hundred-and-one patients (21%) developed a PE. The adjusted cause-specific HR of PE was 0.92 (95% CI: 0.73–1.16) per doubling of LMWH dose. The adjusted cause-specific HR for in-hospital mortality was 0.82 (95% CI: 0.65–1.02) per doubling of LMWH dose. This dose-response relationship was shown to be non-linear. To conclude, this study did not find evidence for an effect of LMWH dose on the risk of PE, but suggested a non-linear decreased risk of in-hospital mortality for higher doses of LMWH. However, uncertainty remains, and the dose-response relationship between LMWH dose and in-hospital mortality needs further investigation in well-designed studies.

Longitudinal Trends in Bleeding Complications on Extracorporeal Life Support (ECLS) Over the Past Two Decades – ELSO Registry Analysis (preprint)

Background: The use of extracorporeal life support (ECLS) has increased worldwide over the last decade including for new emerging indications like extracorporeal cardiopulmonary resuscitation, trauma, and COVID-19. Bleeding complications remain feared and frequent, with high morbidity and increased mortality. Yet, data about trends, and in-hospital outcomes, have been poorly investigated.Methods: The Extracorporeal Life Support Organization (ELSO) Registry database was explored for patients who received veno-venous (V-V) and veno-arterial (V-A) ECLS between the years 2000 and 2020. Trends in bleeding complications and mortality were analyzed. Bleeding complications were classified according to site (gastro-intestinal, cannulation site, surgical site, pulmonary, tamponade and central nervous system) and analyzed separately. Multivariable analysis was performed to identify risk factors for bleeding complications.Results: ELSO database analysis included 53.644 patients with single ECLS runs, mean age 51.4± 15.9 years, 33.859 (64.5%) male. Study cohort included 19.748 patients cannulated for V-V ECLS and 30.696 patients for V-A ECLS. Bleeding complications were reported in 14.786 patients (27.6%) and occurred more often in V-A-modalities compared to V-V modalities (30.0% versus 21.9%, p<0.001). Patients with a bleeding complication had a lower hospital survival in the V-V ECLS (49.6% versus 66.6%, p<0.001) and V-A ECLS subgroup (33.9 versus 44.9%, p<0.001). Bleeding complications in V-V ECLS and V-A ECLS have been decreasing over the past two decades with coefficient of -1.124; P<0.001 and -1.661; P<0.001, respectively. Cannulation site bleeding and surgical site bleeding rates showed the highest negative trend in both V-V and V-A ECLS patients. No change in mortality rates over time in V-V or V-A ECLS patients (coef.: -0.147; P=0.442 and coef.: -0.195; P=0.139) was observed. For V-V ECLS supported patients, multivariate regression revealed the following independent association with bleeding: advanced age, ECLS duration, surgical cannulation, pre-ECLS support with cardiopulmonary bypass, renal replacement therapy, prone positioning, vasodilatory and anti-hypotensive agents. For V-A ECLS supported patients, predictors for bleeding included: female gender, ECLS duration, pre-ECLS arrest or bridge to transplant, therapeutic hypothermia, surgical cannulation and pre-ECLS support with cardiopulmonary bypass, ventricular assist devices, cardiac pacemakers, vasodilatory and anti-hypotensive agents.Conclusions: The steady decrease in particular cannulation and surgical site related bleeding complications over the past 20 years suggests advances in equipment development (membrane and tubes surfaces) as well as better understanding of anticoagulation management. However, the high incidence of bleeding and association with hospital mortality reinforces the need for studies to understand bleeding complications more thoroughly during ECLS.Funding Information: No funding.Declaration of Interests: Prof. Dr. Lorusso is a consultant for Medtronic, Getinge and LivaNova and medical advisory board member for EUROSETS, all unrelated to this work; all honoraria to the university for research funding. Dr. Tonna is supported by a Career Development Award from the National Institutes of Health/National Heart, Lung, And Blood Institute (K23 HL141596). Dr. Tonna received speaker fees and travel compensation from LivaNova and Philips Healthcare, unrelated to this work. Prof. Ten Cate received research support from Bayer and Pfizer, is a consultant for Alveron and stockholder with Coagulation Profile; all unrelated to this work. Prof Zoe McQuilten is supported by an Australian National Health and Medical Council (NHMRC) Investigator Grant.Other authors have no conflict of interest to declare.Ethics Approval Statement: Each institution participating in ELSO Registry approves data reported to the registry through their local institutional review board. This study involved only analysis of pre-existing de-identified data from an international registry, and as such no ethics approval was required. Similarly, no patient consent was required.