Anti-inflammatory therapies are associated with delayed onset of anemia and reduction in transfusion requirements in critically ill patients:results from two studies

BACKGROUND: Anemia is a hallmark of critical illness, which is largely inflammatory driven. We hypothesized that the use of anti-inflammatory agents limits the development of anemia and reduces the need for red blood cell (RBC) transfusions in patients with a hyper-inflammatory condition due to COVID-19. METHODS: An observational cohort (n = 772) and a validation cohort (a subset of REMAP-CAP, n = 119) of critically ill patients with hypoxemic respiratory failure due to COVID-19 were analyzed, who either received no treatment, received steroids or received steroids plus IL-6 blocking agents. The trajectory of hemoglobin (Hb) decline and the need for RBC transfusions were compared using descriptive statistics as well as multivariate modeling. RESULTS: In both cohorts, Hb level was higher in the treated groups compared to the untreated group at all time points. In the observational cohort, incidence and number of transfused patients were lower in the group receiving the combination treatment compared to the untreated groups. In a multivariate analysis controlling for baseline Hb imbalance and mechanical ventilation, receipt of steroids remained associated with a slower decline in Hb level and the combination treatment remained associated with a slower decline of Hb and with less transfusions. Results remained the same in the validation cohort. CONCLUSION:Immunomodulatory treatment was associated with a slower decline in Hb level in critically ill patients with COVID-19 and with less transfusion. Findings point toward inflammation as an important cause for the occurrence of anemia in the critically ill.</p

Interrater agreement in classifying infections during extracorporeal membrane oxygenation

Infectious complications are common during extracorporeal membrane oxygenation (ECMO) and may negatively impact outcomes. However, there is considerable variation in the reported rates of incidence, which hampers the use of infections as a quality benchmark for ECMO centers. To assess the contributing role of poor interrater agreement, three independent raters reviewed medical records from all intensive care unit (ICU) patients who received ECMO for &gt;24 h in our tertiary center between October 2019 and October 2021 for suspected episodes of infection, which were rated based on their date of onset and presumed site/diagnosis. To establish a gold standard, any discrepancies were resolved using an expert panel consisting of two intensivists/infectious disease specialists. During 83 ECMO-runs in 77 patients, we observed a total of 62 adjudicated infectious episodes (incidence rate 62, 95% CI: 48–80, per 1000 days at risk). Among 81 episodes suspected by at least one observer, 66 (81%) were identified by two, and only 44 (54%) by all three raters, resulting in Fleiss’ kappa of 0.10 (95% CI: 0.00–0.19; slight agreement). However, if raters concurred regarding infection onset, subsequent agreement on infection site was good (concordance 89%; kappa 0.85, 95% CI: 0.72–0.98; near perfect agreement). In conclusion, adjudication of infectious episodes during ECMO is associated with poor interrater agreement regarding occurrence—but not site—of infection. This finding might partially explain the significant disparities observed in reported infection rates during ECMO, emphasizing the need for caution when interpreting infection data in this particular population due to the potential for inherent measurement error.</p

Anti-inflammatory therapies are associated with delayed onset of anemia and reduction in transfusion requirements in critically ill patients:results from two studies

BACKGROUND: Anemia is a hallmark of critical illness, which is largely inflammatory driven. We hypothesized that the use of anti-inflammatory agents limits the development of anemia and reduces the need for red blood cell (RBC) transfusions in patients with a hyper-inflammatory condition due to COVID-19. METHODS: An observational cohort (n = 772) and a validation cohort (a subset of REMAP-CAP, n = 119) of critically ill patients with hypoxemic respiratory failure due to COVID-19 were analyzed, who either received no treatment, received steroids or received steroids plus IL-6 blocking agents. The trajectory of hemoglobin (Hb) decline and the need for RBC transfusions were compared using descriptive statistics as well as multivariate modeling. RESULTS: In both cohorts, Hb level was higher in the treated groups compared to the untreated group at all time points. In the observational cohort, incidence and number of transfused patients were lower in the group receiving the combination treatment compared to the untreated groups. In a multivariate analysis controlling for baseline Hb imbalance and mechanical ventilation, receipt of steroids remained associated with a slower decline in Hb level and the combination treatment remained associated with a slower decline of Hb and with less transfusions. Results remained the same in the validation cohort. CONCLUSION:Immunomodulatory treatment was associated with a slower decline in Hb level in critically ill patients with COVID-19 and with less transfusion. Findings point toward inflammation as an important cause for the occurrence of anemia in the critically ill.</p

Reframing sepsis immunobiology for translation: towards informative subtyping and targeted immunomodulatory therapies

Sepsis is a common and deadly condition. Within the current model of sepsis immunobiology, the framing of dysregulated host immune responses into proinflammatory and immunosuppressive responses for the testing of novel treatments has not resulted in successful immunomodulatory therapies. Thus, the recent focus has been to parse observable heterogeneity into subtypes of sepsis to enable personalised immunomodulation. In this Personal View, we highlight that many fundamental immunological concepts such as resistance, disease tolerance, resilience, resolution, and repair are not incorporated into the current sepsis immunobiology model. The focus for addressing heterogeneity in sepsis should be broadened beyond subtyping to encompass the identification of deterministic molecular networks or dominant mechanisms. We explicitly reframe the dysregulated host immune responses in sepsis as altered homoeostasis with pathological disruption of immune-driven resistance, disease tolerance, resilience, and resolution mechanisms. Our proposal highlights opportunities to identify novel treatment targets and could enable successful immunomodulation in the future

Therapeutic anticoagulation with heparin in critically ill patients with covid-19

Copyright © 2021 Massachusetts Medical Society. BACKGROUND Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19. METHODS In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. RESULTS The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, −1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, −1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio \u3c1.2], 99.9%). The percentage of patients who survived to hospital discharge was similar in the two groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84; 95% credible interval, 0.64 to 1.11). Major bleeding occurred in 3.8% of the patients assigned to therapeutic-dose anticoagulation and in 2.3% of those assigned to usual-care pharmacologic thromboprophylaxis. CONCLUSIONS In critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin did not result in a greater probability of survival to hospital discharge or a greater number of days free of cardiovascular or respiratory organ support than did usual-care pharmacologic thromboprophylaxis