Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19

Importance: Therapies that improve survival in critically ill patients with coronavirus disease 2019 (COVID-19) are needed. Tocilizumab, a monoclonal antibody against the interleukin 6 receptor, may counteract the inflammatory cytokine release syndrome in patients with severe COVID-19 illness. Objective: To test whether tocilizumab decreases mortality in this population. Design, Setting, and Participants: The data for this study were derived from a multicenter cohort study of 4485 adults with COVID-19 admitted to participating intensive care units (ICUs) at 68 hospitals across the US from March 4 to May 10, 2020. Critically ill adults with COVID-19 were categorized according to whether they received or did not receive tocilizumab in the first 2 days of admission to the ICU. Data were collected retrospectively until June 12, 2020. A Cox regression model with inverse probability weighting was used to adjust for confounding. Exposures: Treatment with tocilizumab in the first 2 days of ICU admission. Main Outcomes and Measures: Time to death, compared via hazard ratios (HRs), and 30-day mortality, compared via risk differences. Results: Among the 3924 patients included in the analysis (2464 male [62.8%]; median age, 62 [interquartile range {IQR}, 52-71] years), 433 (11.0%) received tocilizumab in the first 2 days of ICU admission. Patients treated with tocilizumab were younger (median age, 58 [IQR, 48-65] vs 63 [IQR, 52-72] years) and had a higher prevalence of hypoxemia on ICU admission (205 of 433 [47.3%] vs 1322 of 3491 [37.9%] with mechanical ventilation and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of <200 mm Hg) than patients not treated with tocilizumab. After applying inverse probability weighting, baseline and severity-of-illness characteristics were well balanced between groups. A total of 1544 patients (39.3%) died, including 125 (28.9%) treated with tocilizumab and 1419 (40.6%) not treated with tocilizumab. In the primary analysis, during a median follow-up of 27 (IQR, 14-37) days, patients treated with tocilizumab had a lower risk of death compared with those not treated with tocilizumab (HR, 0.71; 95% CI, 0.56-0.92). The estimated 30-day mortality was 27.5% (95% CI, 21.2%-33.8%) in the tocilizumab-treated patients and 37.1% (95% CI, 35.5%-38.7%) in the non-tocilizumab–treated patients (risk difference, 9.6%; 95% CI, 3.1%-16.0%). Conclusions and Relevance: Among critically ill patients with COVID-19 in this cohort study, the risk of in-hospital mortality in this study was lower in patients treated with tocilizumab in the first 2 days of ICU admission compared with patients whose treatment did not include early use of tocilizumab. However, the findings may be susceptible to unmeasured confounding, and further research from randomized clinical trials is needed.The writing committee was supported by grants F32HL149337 (Dr. Admon), K23DK120811 (Dr. Srivastava), R01HL085757 (Dr. Parikh), R01HL144566 and R01DK125786 (Dr. Leaf), K12HL138039 (Dr. Donnelly), K23HL130648 (Dr. Mathews), R37AI102634 (Dr. Hernán), F32DC017342 (Dr. Gupta), K08GM134220 and R03AG060179 (Dr. Shaefi), K23HL143053 (Dr. Semler), and R01HL153384 (Dr. Hayek) from the NIH and grant U-M G024231 from the Frankel Cardiovascular Center COVID-19: Impact Research Ignitor (Dr. Hayek)

Thrombosis, Bleeding, and the Observational Effect of Early Therapeutic Anticoagulation on Survival in Critically Ill Patients With COVID-19

This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.Background: Hypercoagulability may be a key mechanism of death in patients with coronavirus disease 2019 (COVID-19). Objective: To evaluate the incidence of venous thromboembolism (VTE) and major bleeding in critically ill patients with COVID-19 and examine the observational effect of early therapeutic anticoagulation on survival. Design: In a multicenter cohort study of 3239 critically ill adults with COVID-19, the incidence of VTE and major bleeding within 14 days after intensive care unit (ICU) admission was evaluated. A target trial emulation in which patients were categorized according to receipt or no receipt of therapeutic anticoagulation in the first 2 days of ICU admission was done to examine the observational effect of early therapeutic anticoagulation on survival. A Cox model with inverse probability weighting to adjust for confounding was used. Setting: 67 hospitals in the United States. Participants: Adults with COVID-19 admitted to a participating ICU. Measurements: Time to death, censored at hospital discharge, or date of last follow-up. Results: Among the 3239 patients included, the median age was 61 years (interquartile range, 53 to 71 years), and 2088 (64.5%) were men. A total of 204 patients (6.3%) developed VTE, and 90 patients (2.8%) developed a major bleeding event. Independent predictors of VTE were male sex and higher D-dimer level on ICU admission. Among the 2809 patients included in the target trial emulation, 384 (11.9%) received early therapeutic anticoagulation. In the primary analysis, during a median follow-up of 27 days, patients who received early therapeutic anticoagulation had a similar risk for death as those who did not (hazard ratio, 1.12 [95% CI, 0.92 to 1.35]). Limitation: Observational design. Conclusion: Among critically ill adults with COVID-19, early therapeutic anticoagulation did not affect survival in the target trial emulation

Supplementary Material for: Parameters Used to Discontinue Dialysis in Acute Kidney Injury Recovery: A Survey of United States Nephrologists

<b><i>Background:</i></b> Despite advances in the approach to cure acute kidney injury (AKI), including definition, classification and treatment methods, there are no standard criteria to withdraw dialysis in the setting of improving AKI. We conducted this survey to elucidate parameters that United States (US) nephrologists used to determine when to stop dialysis with improving renal function in AKI. We hypothesized that there would be a difference in approach to weaning a patient off dialysis based on years in practice or the number of cases of AKI treated per year. <b><i>Methods:</i></b> This was an anonymous electronic survey of practicing nephrologists who treated AKI. Data was de-identified and analyzed using descriptive statistics. <b><i>Results:</i></b> The commonest criteria used to stop dialysis when renal function improved was, in decreasing order of importance, resolution in oliguria (51%), resolution of volume overload (29%), improvement in serum creatinine (26.7%) and resolution of hyperkalemia (21%). The most common reasons for re-starting dialysis within 28 days did not show a specific trend but respondents (20%) reported re-starting if estimated glomerular filtration rates (eGFR) declined. There was no significant pattern in approach to withdrawing dialysis or resuming dialysis based on the number of years in nephrology practice. However, responses of nephrologists who saw more than 20 AKI patients/year were significantly different in stopping dialysis with clinical stabilization of blood pressure (p < 0.001), improvement in respiratory parameters (p = 0.005), improvement in pre-dialysis blood urea nitrogen (BUN) levels despite the same dose of dialysis (p = 0.05) and resolution of oliguria (p = 0.025) compared to those who saw fewer cases. <b><i>Conclusion:</i></b> Resolution of oliguria was the commonest factor used to help deciding to stop dialysis in improving AKI. However, considerable variation was noted among US nephrologists who participated in this survey, regarding what criteria they used to withdraw dialysis in the setting of improving AKI. These results call for more studies in withdrawing dialysis in the setting of AKI that could lead to guideline formulation

AKI Treated with Renal Replacement Therapy in Critically Ill Patients with COVID-19

AKI is a common sequela of coronavirus disease 2019 (COVID-19). However, few studies have focused on AKI treated with RRT (AKI-RRT). We conducted a multicenter cohort study of 3099 critically ill adults with COVID-19 admitted to intensive care units (ICUs) at 67 hospitals across the United States. We used multivariable logistic regression to identify patient-and hospital-level risk factors for AKI-RRT and to examine risk factors for 28-day mortality among such patients. A total of 637 of 3099 patients (20.6%) developed AKI-RRT within 14 days of ICU admission, 350 of whom (54.9%) died within 28 days of ICU admission. Patient-level risk factors for AKI-RRT included CKD, men, non-White race, hypertension, diabetes mellitus, higher body mass index, higher d-dimer, and greater severity of hypoxemia on ICU admission. Predictors of 28-day mortality in patients with AKI-RRT were older age, severe oliguria, and admission to a hospital with fewer ICU beds or one with greater regional density of COVID-19. At the end of a median follow-up of 17 days (range, 1-123 days), 403 of the 637 patients (63.3%) with AKI-RRT had died, 216 (33.9%) were discharged, and 18 (2.8%) remained hospitalized. Of the 216 patients discharged, 73 (33.8%) remained RRT dependent at discharge, and 39 (18.1%) remained RRT dependent 60 days after ICU admission. AKI-RRT is common among critically ill patients with COVID-19 and is associated with a hospital mortality rate of >60%. Among those who survive to discharge, one in three still depends on RRT at discharge, and one in six remains RRT dependent 60 days after ICU admission