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in category intensive care and critical care medicine

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1: Factors associated with hospitalization and critical illness among 4,103 patients with COVID-19 disease in New York City
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Posted 11 Apr 2020

Factors associated with hospitalization and critical illness among 4,103 patients with COVID-19 disease in New York City
76,112 downloads medRxiv intensive care and critical care medicine

Christopher M. Petrilli, Simon Jones, Jie Yang, Harish Rajagopalan, Luke F. O'Donnell, Yelena Chernyak, Katie Tobin, Robert J. Cerfolio, Fritz Francois, Leora Horwitz

Background: Little is known about factors associated with hospitalization and critical illness in Covid-19 positive patients. Methods: We conducted a cross-sectional analysis of all patients with laboratory-confirmed Covid-19 treated at a single academic health system in New York City between March 1, 2020 and April 2, 2020, with follow up through April 7, 2020. Primary outcomes were hospitalization and critical illness (intensive care, mechanical ventilation, hospice and/or death). We conducted multivariable logistic regression to identify risk factors for adverse outcomes, and maximum information gain decision tree classifications to identify key splitters. Results: Among 4,103 Covid-19 patients, 1,999 (48.7%) were hospitalized, of whom 981/1,999 (49.1%) have been discharged home, and 292/1,999 (14.6%) have died or were discharged to hospice. Of 445 patients requiring mechanical ventilation, 162/445 (36.4%) have died. Strongest hospitalization risks were age [&ge;]75 years (OR 66.8, 95% CI, 44.7-102.6), age 65-74 (OR 10.9, 95% CI, 8.35-14.34), BMI>40 (OR 6.2, 95% CI, 4.2-9.3), and heart failure (OR 4.3 95% CI, 1.9-11.2). Strongest critical illness risks were admission oxygen saturation <88% (OR 6.99, 95% CI 4.5-11.0), d-dimer>2500 (OR 6.9, 95% CI, 3.2-15.2), ferritin >2500 (OR 6.9, 95% CI, 3.2-15.2), and C-reactive protein (CRP) >200 (OR 5.78, 95% CI, 2.6-13.8). In the decision tree for admission, the most important features were age >65 and obesity; for critical illness, the most important was SpO2<88, followed by procalcitonin >0.5, troponin <0.1 (protective), age >64 and CRP>200. Conclusions: Age and comorbidities are powerful predictors of hospitalization; however, admission oxygen impairment and markers of inflammation are most strongly associated with critical illness.

2: Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 - Preliminary report
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Posted 07 Jan 2021

Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 - Preliminary report
44,286 downloads medRxiv intensive care and critical care medicine

The REMAP-CAP Investigators, Anthony C Gordon, Paul R. Mouncey, Farah Al-Beidh, Kathryn M. Rowan, Alistair D. Nichol, Yaseen M. Arabi, Djillali Annane, Abi Beane, Wilma van Bentum-Puijk, Lindsay R. Berry, Zahra Bhimani, Marc J.M. Bonten, Charlotte A. Bradbury, Frank M. Brunkhorst, Adrian Buzgau, Allen C Cheng, Michelle A Detry, Eamon J. Duffy, Lise J. Estcourt, Mark Fitzgerald, Herman Goossens, Rashan Haniffa, Alisa M. Higgins, Thomas E. Hills, Christopher M. Horvat, Francois Lamontagne, Patrick R. Lawler, Helen L Leavis, Kelsey M. Linstrum, Edward Litton, Elizabeth Lorenzi, John C Marshall, Florian B. Mayr, Danny McAuley, Anna McGlothlin, Shay P McGuinness, Bryan J. McVerry, Stephanie K. Montgomery, Susan C Morpeth, Srinivas Murthy, Katrina Orr, Rachael L. Parke, Jane C. Parker, Asad E. Patanwala, Ville Pettilä, Emma Rademaker, Marlene S. Santos, Christina Saunders, Christopher W. Seymour, Manu Shankar-Hari, Wendy I. Sligl, Alexis F Turgeon, Anne M. Turner, Frank L van de Veerdonk, Ryan Zarychanski, Cameron Green, Roger J. Lewis, Derek C. Angus, Colin J. McArthur, Scott Berry, Steve A. Webb, Lennie PG Derde

BackgroundThe efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. MethodsWe evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours of commencing organ support in an intensive care unit, were randomized to receive either tocilizumab (8mg/kg) or sarilumab (400mg) or standard care (control). The primary outcome was an ordinal scale combining in-hospital mortality (assigned -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with pre-defined triggers to declare superiority, efficacy, equivalence or futility. ResultsTocilizumab and sarilumab both met the pre-defined triggers for efficacy. At the time of full analysis 353 patients had been assigned to tocilizumab, 48 to sarilumab and 402 to control. Median organ support-free days were 10 (interquartile range [IQR] -1, 16), 11 (IQR 0, 16) and 0 (IQR -1, 15) for tocilizumab, sarilumab and control, respectively. Relative to control, median adjusted odds ratios were 1.64 (95% credible intervals [CrI] 1.25, 2.14) for tocilizumab and 1.76 (95%CrI 1.17, 2.91) for sarilumab, yielding >99.9% and 99.5% posterior probabilities of superiority compared with control. Hospital mortality was 28.0% (98/350) for tocilizumab, 22.2% (10/45) for sarilumab and 35.8% (142/397) for control. All secondary outcomes and analyses supported efficacy of these IL-6 receptor antagonists. ConclusionsIn critically ill patients with Covid-19 receiving organ support in intensive care, treatment with the IL-6 receptor antagonists, tocilizumab and sarilumab, improved outcome, including survival. (ClinicalTrials.gov number: NCT02735707)

3: Clinical Characteristics and Progression of 2019 Novel Coronavirus-Infected Patients Concurrent Acute Respiratory Distress Syndrome
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Posted 20 Feb 2020

Clinical Characteristics and Progression of 2019 Novel Coronavirus-Infected Patients Concurrent Acute Respiratory Distress Syndrome
22,145 downloads medRxiv intensive care and critical care medicine

Yanli Liu, Wenwu Sun, Jia Li, Liangkai Chen, Yujun Wang, Lijuan Zhang, Li Yu

BackgroundIn December 2019, the outbreak of novel coronavirus (2019-nCoV) infection lead to a cluster of pneumonia cases. We report the clinical characteristics of 2019-nCoV infected patients with acute respiratory distress syndrome (ARDS) and further investigate the treatment and the progression of the disease. MethodsThe longitudinal study included 109 patients with novel coronavirus-infected pneumonia (COVID-19) admitted to the Central Hospital of Wuhan between January 2 and February 1, 2020. Patients were followed up to February 12, 2020. Epidemiological, clinical, and laboratory characteristics, treatment, and outcomes data were collected from electronic medical records. The difference in treatment and progression between patients with ARDS and without ARDS was compared. ResultsAmong 109 patients with COVID-19, the median age was 55 years (IQR, 43-66 years; range, 22-94 years), and 59 (54.1%) patients were men. The median hospital days were 15 days (interquartile range, 11-24 days), and 31 (28.4%) patients had died and 78 (71.6%) survived. Among them, 53 (48.6%) patients developed ARDS. Compared with non-ARDS patients, patients with ARDS were more likely to have coexisting conditions, including diabetes (20.8% vs. 1.8%), cerebrovascular (11.3% vs. 0%) and chronic kidney disease (15.1% vs. 3.6%). Compared with patients with mild ARDS (n = 1/19 [5.3%]), those with moderate and severe ARDS had a higher mortality rate (n = 15/24 [62.5%] for moderate ARDS and n = 10/10 [100.0%] for severe ARDS). The mortality rate increased concomitantly with the severity of ARDS. We have not observed a significant effect of antivirus, glucocorticoid, or immunoglobulin treatment on survival in patients with ARDS. ConclusionsOur findings indicated that 2019-nCoV infected patients with moderate-to-severe ARDS had higher mortality rates and the beneficial effects of current treatments were not satisfactory, which are warranted attention from clinicians.

4: Therapeutic Anticoagulation in Non-Critically Ill Patients with Covid-19
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Posted 17 May 2021

Therapeutic Anticoagulation in Non-Critically Ill Patients with Covid-19
14,940 downloads medRxiv intensive care and critical care medicine

Patrick R. Lawler, Ewan C Goligher, Jeffrey S Berger, Matthew D Neal, Bryan J. McVerry, Jose C. Nicolau, Michelle N Gong, Marc Carrier, Robert S. Rosenson, Harmony R Reynolds, Alexis F Turgeon, Jorge Escobedo, David T Huang, Charlotte Ann Bradbury, Brett L Houston, Lucy Z Kornblith, Anand Kumar, Susan R Kahn, Mary Cushman, Zoe McQuilten, Arthur S Slutsky, Keri S Kim, Anthony C Gordon, Bridget-Anne Kirwan, Maria M Brooks, Alisa M. Higgins, Roger J. Lewis, Elizabeth Lorenzi, Scott M Berry, Lindsay R. Berry, Derek C. Angus, Colin J. McArthur, Steven A Webb, Michael E Farkouh, Judith S Hochman, Ryan Zarychanski

Background Thrombo-inflammation may contribute to morbidity and mortality in Covid-19. We hypothesized that therapeutic-dose anticoagulation may improve outcomes in non-critically ill patients hospitalized for Covid-19. Methods In an open-label adaptive multiplatform randomized controlled trial, non-critically ill patients hospitalized for Covid-19, defined by the absence of critical care-level organ support at enrollment, were randomized to a pragmatic strategy of therapeutic-dose anticoagulation with heparin or usual care pharmacological thromboprophylaxis. The primary outcome combined survival to hospital discharge and days free of organ support through 21 days, which was evaluated with Bayesian statistical models according to baseline D-dimer. Results The trial was stopped when prespecified criteria for superiority were met for therapeutic-dose anticoagulation in groups defined by high ([&ge;]2-fold elevated) and low (<2-fold elevated) D-dimer. Among 2219 participants in the final analysis, the probability that therapeutic anticoagulation increased organ support-free days compared to thromboprophylaxis was 99.0% (adjusted odds ratio 1.29, 95% credible interval 1.04 to 1.61). The adjusted absolute increase in survival to hospital discharge without organ support with therapeutic-dose anticoagulation was 4.6% (95% credible interval 0.7 to 8.1). In the primary adaptive stopping groups, the final probabilities of superiority for therapeutic anticoagulation were 97.3% in the high D-dimer group and 92.9% in the low D-dimer group. Major bleeding occurred in 1.9% and 0.9% of participants randomized to therapeutic anticoagulation and thromboprophylaxis, respectively. Conclusions In non-critically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increases the probability of survival to hospital discharge with reduced use of organ support.

5: The definition and risks of Cytokine Release Syndrome-Like in 11 COVID-19-Infected Pneumonia critically ill patients: Disease Characteristics and Retrospective Analysis
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Posted 27 Feb 2020

The definition and risks of Cytokine Release Syndrome-Like in 11 COVID-19-Infected Pneumonia critically ill patients: Disease Characteristics and Retrospective Analysis
14,655 downloads medRxiv intensive care and critical care medicine

Wang Wenjun, Liu Xiaoqing, Wu Sipei, Lie Puyi, Huang Liyan, Li Yimin, Cheng Linling, Chen Sibei, Nong Lingbo, Lin Yongping, He Jianxing

IMPORTANCECOVID-19-infected pneumonia patients with severe immune abnormalities and risk of cytokine release syndrome. The definition, prevention, and treatment of COVID-19-infected pneumonia in critically ill patients with cytokine release syndrome symptoms is an important problem. OBJECTIVETo define the cytokine release syndrome-like (CRSL) in COVID-19-infected pneumonia in critically ill patients and study the risk factors and therapeutic strategies. DESIGN, SETTING, AND PARTICIPANTSThis is a retrospective, single center case study of 11 COVID-19-infected pneumonia patients with acute respiratory distress syndrome (ARDS) from The First Affiliated Hospital of Guangzhou Medical University in China from January 26, 2020 to February 18, 2020. The follow-up termination date was February 19, 2020. EXPOSERESEleven COVID-19-infected pneumonia patients with ARDS in the ICU. Some of these patients also had cytokine release syndrome-like (CRSL). Immunologic detection, clinical characteristics, and clinical treatment analysis were carried out to define the CRSL in these COVID-19-infected pneumonia patients. MAIN OUTCOMES AND MEASURESClinical, radiological, immunology (including immune cell subsets and cytokines analysis), laboratory, and clinical treatment data were collected and analyzed. The critically ill patients with CRSL were defined. Prevention and control strategies were studied. RESULTSOf 11 critically ill patients in the ICU, the median age was 58 (Inter-Quartile Range{IQR}, 49-72; range, 26-72 years), and 10 (83.3%) were males. Ten (83.3%) patients had extensive pulmonary inflammation and ARDS (the median time from the first symptom to ARDS was 10.0 d), fever, and hypoxia; four (28.6%) patients experienced shock. The lymphocyte subpopulations including CD3 (CD3 + CD45+), CD4 (CD3 + CD4+), CD8 (CD3 + CD8+), NK (CD3-CD16 + CD56 +), Tregs (CD4 + CD25 + CD127 low), B lymphocyte (CD3-CD19 +) cells; and cytokines including IL-2, IL-4, IL-6, IL-10, TNF-, IFN-{gamma} were detected at different time points. All of the patients had a decrease of CD3 (IQR,169-335; range, 50-635 cells/L), CD4 (IQR,101-303; range, 27-350 cells/L), CD8 (IQR, 33-141; range, 21-277 cells/L); ten (90.9%) patients have a decrease in NK immune cells (IQR,8-72; range, 5-170 cells/L); both of Tregs (IQR,3.3-7.8;rang,2.3-9.4%) and B immune cells (IQR,61-146; rang,44-222 cells/L)were decreased in two (18.2%) patients. And nine patients were increase in CD4 / CD8 (IQR,3.3-7.8%; range, 2.3-9.7%). All patients had a significant increase of IL-6 (IQR,14.26-92.2; range, 4.58-1182.91ng/L). Eight (72.7%) patients were determined to have CRSL characteristics, including pulmonary inflammation, fever, a decrease of CD4, CD8, and NK cells; an increase of CD4/CD8, a significant increase of IL-6, and the dysfunction of non-pulmonary organs. The numbers of CD4, CD8, and NK cells and the level of IL-6 in peripheral blood were correlated with the area of pulmonary inflammation in CT images (P<0.05). Mechanical-ventilation used to increase blood oxygen concentration could increased the numbers of CD4 (after Vs before ventilation=259{+/-}53 VS 507{+/-}101; P=0.013, and CD8 (after Vs before ventilation=193{+/-}38 VS 279{+/-}63; P=0.048), while decreasing the level of IL-6 (after Vs before ventilation=223.2{+/-} 89.9 VS 26.8{+/-}10; P=0.041). The increased of IL-6 was occurred earlier than the decrease of CD4{middle dot}, CD8 in the patients with rapidly worsened after ICU. CONCLUSIONS AND RELEVANCEIn this retrospective analysis of 11 critically ill pneumonia patients infected with COVID-19, we defined and identified eight patients (72.7%) with cytokine release syndrome-like (CRSL). We found that a large area of lung injury ([&ge;]50%) with an decrease of CD4, CD8 (Lower than 50% minimum normal range) and increase of IL-6 in peripheral blood was the highest risk factor of CRSL. IL-6 was a early indicators of CRSL in COVID-19-infected pneumonia. We also found that reduce injury to the lung is a useful method to prevent and improve COVID-19-infected pneumonia-related CRSL in critically ill pneumonia patients.

6: Lactate dehydrogenase, a Risk Factor of Severe COVID-19 Patients
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Posted 27 Mar 2020

Lactate dehydrogenase, a Risk Factor of Severe COVID-19 Patients
13,395 downloads medRxiv intensive care and critical care medicine

Yi Han, Haidong Zhang, Sucheng Mu, Wei Wei, Chaoyuan Jin, Yuan Xue, Chaoyang Tong, Yunfei Zha, Zhenju Song, Guorong Gu

BACKGROUNDThe World Health Organization (WHO) has recently declared coronavirus disease 2019 (COVID-19) a public health emergency of global concern. Updated analysis of cases might help identify the characteristic and risk factors of the illness severity. METHODSWe extracted data regarding 47 patients with confirmed COVID-19 from Renmin Hospital of Wuhan University between February 1 and February 18, 2020. The degree of severity of COVID-19 patients (severe vs. non-severe) was defined at the time of admission according to American Thoracic Society (ATS) guidelines for community-acquired pneumonia (CAP). RESULTSThe median age was 64.91 years, 26 cases (55.31%) were male of which, and 70.83% were severe cases. Severe patients had higher APACHE II (9.92 vs 4.74) and SOFA (3.0 vs 1.0) scores on admission, as well as the higher PSI (86.13 vs 61.39), Curb-65 (1.14 vs 0.48) and CT semiquantitative scores (5.0 vs 2.0) when compared with non-severe patients. Among all univariable parameters, APACHE II, SOFA, lymphocytes, CRP, LDH, AST, cTnI, BNP, et al were significantly independent risk factors of COVID-19 severity. Among which, LDH was most positively related both with APACHE II (R = 0.682) and SOFA (R = 0.790) scores, as well as PSI (R = 0.465) and CT (R = 0.837) scores. To assess the diagnostic value of these selected parameters, LDH (0.9727) had maximum sensitivity (100.00%) and specificity (86.67%), with the cutoff value of 283. As a protective factor, lymphocyte counts less than 1.045 [x] 109 /L showed a good accuracy for identification of severe patients with AUC = 0.9845 (95%CI 0.959-1.01), the maximum specificity (91.30%) and sensitivity (95.24%). In addition, LDH was positively correlated with CRP, AST, BNP and cTnI, while negatively correlated with lymphocyte cells and its subsets, including CD3+, CD4+ and CD8+ T cells (P < 0.01). CONCLUSIONSThis study showed that LDH could be identified as a powerful predictive factor for early recognition of lung injury and severe COVID-19 cases. And importantly, lymphocyte counts, especially CD3+, CD4+, and CD8+ T cells in the peripheral blood of COVID-19 patients, which was relevant with serum LDH, were also dynamically correlated with the severity of the disease. FUNDINGKey Project of Shanghai Municipal Health Bureau (2016ZB0202)

7: Interleukin-6 in COVID-19: A Systematic Review and Meta-Analysis
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Posted 03 Apr 2020

Interleukin-6 in COVID-19: A Systematic Review and Meta-Analysis
10,984 downloads medRxiv intensive care and critical care medicine

Eric A. Coomes, Hourmazd Haghbayan

PurposeCoronaviruses may activate dysregulated host immune responses. As exploratory studies have suggested that interleukin-6 (IL-6) levels are elevated in cases of complicated COVID-19 and that the anti-IL-6 biologic tocilizumab may be beneficial, we undertook a systematic review and meta-analysis to assess the evidence in this field. MethodsWe systematically searched MEDLINE and EMBASE for studies investigating the immunological response in COVID-19 or its treatment with tocilizumab; additional grey literature searches were undertaken. Meta-analysis was undertaken using random effects models. ResultsEight published studies, three pre-prints, and five registered trials were eligible. Meta-analysis of mean IL-6 concentrations demonstrated 2.9-fold higher levels in patients with complicated COVID-19 compared with patients with non-complicated disease (six studies; n=1302; 95%CI, 1.17-7.19; I2=100%). A single non-randomized, single-arm study assessed tocilizumab in patients with severe COVID-19, demonstrating decreased oxygen requirements, resolution of radiographic abnormalities, and clinical improvement. No adverse events or deaths were observed. ConclusionsIn patients with COVID-19, IL-6 levels are significantly elevated and associated with adverse clinical outcomes. While inhibition of IL-6 with tocilizumab appears to be efficacious and safe in preliminary investigation, the results of several ongoing clinical trials should be awaited to better define the role of tocilizumab in COVID-19 prior to routine clinical application. PROSPERO RegistrationCRD42020175879

8: Genetic mechanisms of critical illness in Covid-19
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Posted 25 Sep 2020

Genetic mechanisms of critical illness in Covid-19
10,618 downloads medRxiv intensive care and critical care medicine

Erola Pairo-Castineira, Sara Clohisey, Lucija Klaric, Andrew D. Bretherick, Konrad Rawlik, Nick Parkinson, Dorota Pasko, Susan Walker, Anne Richmond, Max Head Fourman, Andy Law, James Furniss, Elvina Gountouna, Nicola Wrobel, Clark D Russell, Loukas Moutsianas, Bo Wang, Alison Meynert, Zhijian Yang, Ranran Zhai, Chenqing Zheng, Fiona Griffith, Wilna Oosthuyzen, Barbara Shih, Seán Keating, Marie Zechner, Chris S Haley, David Porteous, Caroline Hayward, Julian Knight, Charlotte Summers, Manu Shankar-Hari, Lance Turtle, Antonia Ho, Charles Hinds, Peter Horby, Alistair D Nichol, David Maslove, Lowell Ling, Paul Klenerman, Danny McAuley, Hugh Montgomery, Timothy Walsh, The GenOMICC Investigators, The ISARIC4C Investigators, The Covid-19 Human Genetics Initiative, Xia Shen, Kathy Rowan, Angie Fawkes, Lee Murphy, Chris P Ponting, Albert Tenesa, Mark J Caulfield, Richard Scott, Peter JM Openshaw, Malcolm Gracie Semple, Veronique Vitart, James F Wilson, J Kenneth Baillie

The subset of patients who develop critical illness in Covid-19 have extensive inflammation affecting the lungs[PMID: 32526193] and are strikingly different from other patients: immunosuppressive therapy benefits critically-ill patients, but may harm some non-critical cases.[PMID: 32678530] Since susceptibility to life-threatening infections and immune-mediated diseases are both strongly heritable traits, we reasoned that host genetic variation may identify mechanistic targets for therapeutic development in Covid-19.[PMID: 24855243] GenOMICC (Genetics Of Mortality In Critical Care, <a href="https://genomicc.org">genomicc.org</a>) is a global collaborative study to understand the genetic basis of critical illness. Here we report the results of a genome-wide association study (GWAS) in 2244 critically-ill Covid-19 patients from 208 UK intensive care units (ICUs), representing >95% of all ICU beds. Ancestry-matched controls were drawn from the UK Biobank population study and results were confirmed in GWAS comparisons with two other population control groups: the 100,000 genomes project and Generation Scotland. We identify and replicate three novel genome-wide significant associations, at chr19p13.3 (rs2109069, p = 3.98 x 10-12), within the gene encoding dipeptidyl peptidase 9 (DPP9), at chr12q24.13 (rs10735079, p = 1.65 x 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), and at chr21q22.1 (rs2236757, p = 4.99 x 10-8) in the interferon receptor gene IFNAR2. Consistent with our focus on extreme disease in younger patients with less comorbidity, we detect a stronger signal at the known 3p21.31 locus than previous studies (rs73064425, p = 4.77 x 10-30).

9: Therapeutic Anticoagulation in Critically Ill Patients with Covid-19-Preliminary Report
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Posted 12 Mar 2021

Therapeutic Anticoagulation in Critically Ill Patients with Covid-19-Preliminary Report
9,561 downloads medRxiv intensive care and critical care medicine

Ewan C Goligher, Charlotte Ann Bradbury, Bryan J. McVerry, Patrick R. Lawler, Jeffrey S Berger, Michelle N Gong, Marc Carrier, Harmony R Reynolds, Anand Kumar, Alexis F Turgeon, Lucy Z Kornblith, Susan R Kahn, John C Marshall, Keri S Kim, Brett L Houston, Lennie P. G. Derde, Mary Cushman, Tobias Tritschler, Derek C. Angus, Lucas C Godoy, Zoe McQuilten, Bridget-Anne Kirwan, Michael E Farkouh, Maria M Brooks, Roger J. Lewis, Anthony Gordon, Scott Berry, Colin J. McArthur, Matthew D Neal, Judith S Hochman, Steven A Webb, Ryan Zarychanski

Background Thrombosis may contribute to morbidity and mortality in Covid-19. We hypothesized that therapeutic anticoagulation would improve outcomes in critically ill patients with Covid-19. Methods We conducted an open-label, adaptive, multiplatform, randomized, clinical trial. Patients with severe Covid-19, defined as the requirement for organ support with high flow nasal cannula, non-invasive ventilation, invasive ventilation, vasopressors, or inotropes, were randomized to receive therapeutic anticoagulation with heparin or pharmacological thromboprophylaxis as per local usual care. The primary outcome was an ordinal scale combining in-hospital mortality (assigned -1) and days free of organ support to day 21. Results Therapeutic anticoagulation met the pre-defined criteria for futility in patients with severe Covid-19. The primary outcome was available for 1,074 participants (529 randomized to therapeutic anticoagulation and 545 randomized to usual care pharmacological thromboprophylaxis). Median organ support-free days were 3 days (interquartile range -1, 16) in patients assigned to therapeutic anticoagulation and 5 days (interquartile range -1, 16) in patients assigned to usual care pharmacological thromboprophylaxis (adjusted odds ratio 0.87, 95% credible interval (CrI) 0.70-1.08, posterior probability of futility [odds ratio<1.2] 99.8%). Hospital survival was comparable between groups (64.3% vs. 65.3%, adjusted odds ratio 0.88, 95% CrI 0.67-1.16). Major bleeding occurred in 3.1% of patients assigned to therapeutic anticoagulation and 2.4% of patients assigned to usual care pharmacological thromboprophylaxis. Conclusions In patients with severe Covid-19, therapeutic anticoagulation did not improve hospital survival or days free of organ support compared to usual care pharmacological thromboprophylaxis.

10: ICU and ventilator mortality among critically ill adults with COVID-19
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Posted 26 Apr 2020

ICU and ventilator mortality among critically ill adults with COVID-19
6,775 downloads medRxiv intensive care and critical care medicine

Sara Auld, Mark Caridi-Scheible, James M. Blum, Chad J. Robichaux, Colleen S Kraft, Jesse Thomas Jacob, Craig S Jabaley, David Carpenter, Roberta Kaplow, Alfonso C. Hernandez, Max W. Adelman, Gregory S. Martin, Craig M. Coopersmith, David J. Murphy, Emory COVID-19 Quality and Clinical Research Collaborative

We report preliminary data from a cohort of adults admitted to COVID-designated intensive care units from March 6 through April 17, 2020 across an academic healthcare system. Among 217 critically ill patients, mortality for those who required mechanical ventilation was 29.7% (49/165), with 8.5% (14/165) of patients still on the ventilator at the time of this report. Overall mortality to date in this critically ill cohort is 25.8% (56/217), and 40.1% (87/217) patients have survived to hospital discharge. Despite multiple reports of mortality rates exceeding 50% among critically ill adults with COVID-19, particularly among those requiring mechanical ventilation, our early experience indicates that many patients survive their critical illness.

11: Variation in Aerosol Production Across Oxygen Delivery Devices in Spontaneously Breathing Human Subjects
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Posted 20 Apr 2020

Variation in Aerosol Production Across Oxygen Delivery Devices in Spontaneously Breathing Human Subjects
6,265 downloads medRxiv intensive care and critical care medicine

Theodore John Iwashyna, Andre Boehman, Jesse Capelcelatro, Amy M Cohn, James M Cooke, Deena Kelly Costa, Richard M Eakin, Hallie C Prescott, Margaret S Woolridge

We sought to assess whether HHFNC results in greater production of aerosolized particles than 6 liters per minute nasal cannula, using state-of-the-art techniques of aerosol measurement, in spontaneously breathing human volunteers in a simulated hospital room. For each volunteer, we first measured background aerosol levels in the room immediately prior to testing. We then measured aerosol levels while the healthy volunteer laid in bed - - with the head of bed at 30 degrees - - wearing the following oxygen delivery devices: (a) 6L/min nasal canula (NC) with humidification; (b) non-re-breather mask (NRB) with 15L/min gas flow, non-humidified; (c) HHFNC with 30L/min gas flow; (d) HHFNC with 60L/min gas flow. Two scanning mobility particle sizing (SMPS) systems (TSI 3080/3030, TSI 3080/3750) were used to measure aerosols 10 to 500 nanometer (nm) in size for each of the oxygen delivery devices. There was no variation in aerosol level within patients between room air, 6 L/min NC, 15 L/min NRB, 30 L/min HHFNC, and 60 L/min HHFNC, regardless of coughing.

12: Characterization and Clinical Course of 1000 Patients with COVID-19 in New York: retrospective case series
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Posted 22 Apr 2020

Characterization and Clinical Course of 1000 Patients with COVID-19 in New York: retrospective case series
5,954 downloads medRxiv intensive care and critical care medicine

Michael Argenziano, Samuel L Bruce, Cody L Slater, Jonathan R Tiao, Matthew R Baldwin, R. Graham Barr, Bernard P Chang, Katherine H Chau, Justin J Choi, Nicholas Gavin, Parag Goyal, Angela M Mills, Ashmi A Patel, Marie-Laure S Romney, Monika M Safford, Neil W Schluger, Soumitra Sengupta, Magdalena E Sobieszczyk, Jason Zucker, Paul A Asadourian, Fletcher M Bell, Rebekah Boyd, Matthew F Cohen, MacAlistair I Colquhoun, Lucy A Colville, Joseph H de Jonge, Lyle B Dershowitz, Shirin A Dey, Katherine A Eiseman, Zachary P Girvin, Daniella T Goni, Amro A Harb, Nicholas Herzik, Sarah Householder, Lara E Karaaslan, Heather Lee, Evan Lieberman, Andrew Ling, Ree Lu, Arthur Y Shou, Alexander C Sisti, Zachary E Snow, Colin P Sperring, Yuqing Xiong, Henry W Zhou, Karthik Natarajan, George Hripcsak, Ruijun Chen

Objective: To characterize patients with coronavirus disease 2019 (COVID-19) in a large New York City (NYC) medical center and describe their clinical course across the emergency department (ED), inpatient wards, and intensive care units (ICUs). Design: Retrospective manual medical record review. Setting: NewYork-Presbyterian/Columbia University Irving Medical Center (NYP/CUIMC), a quaternary care academic medical center in NYC. Participants: The first 1000 consecutive patients with laboratory-confirmed COVID-19. Methods: We identified the first 1000 consecutive patients with a positive RT-SARS-CoV-2 PCR test who first presented to the ED or were hospitalized at NYP/CUIMC between March 1 and April 5, 2020. Patient data was manually abstracted from the electronic medical record. Main outcome measures: We describe patient characteristics including demographics, presenting symptoms, comorbidities on presentation, hospital course, time to intubation, complications, mortality, and disposition. Results: Among the first 1000 patients, 150 were ED patients, 614 were admitted without requiring ICU-level care, and 236 were admitted or transferred to the ICU. The most common presenting symptoms were cough (73.2%), fever (72.8%), and dyspnea (63.1%). Hospitalized patients, and ICU patients in particular, most commonly had baseline comorbidities including of hypertension, diabetes, and obesity. ICU patients were older, predominantly male (66.9%), and long lengths of stay (median 23 days; IQR 12 to 32 days); 78.0% developed AKI and 35.2% required dialysis. Notably, for patients who required mechanical ventilation, only 4.4% were first intubated more than 14 days after symptom onset. Time to intubation from symptom onset had a bimodal distribution, with modes at 3-4 and 9 days. As of April 30, 90 patients remained hospitalized and 211 had died in the hospital. Conclusions: Hospitalized patients with COVID-19 illness at this medical center faced significant morbidity and mortality, with high rates of AKI, dialysis, and a bimodal distribution in time to intubation from symptom onset.

13: Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study
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Posted 20 Apr 2020

Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study
5,787 downloads medRxiv intensive care and critical care medicine

Matthew J Cummings, Matthew R Baldwin, Darryl Abrams, Samuel D Jacobson, Benjamin J Meyer, Elizabeth M Balough, Justin G Aaron, Jan Claassen, LeRoy E Rabbani, Jonathan Hastie, Beth R Hochman, John Salazar-Schicchi, Natalie H Yip, Daniel Brodie, Max R O'Donnell

Background: Nearly 30,000 patients with coronavirus disease-2019 (COVID-19) have been hospitalized in New York City as of April 14th, 2020. Data on the epidemiology, clinical course, and outcomes of critically ill patients with COVID-19 in this setting are needed. Methods: We prospectively collected clinical, biomarker, and treatment data on critically ill adults with laboratory-confirmed-COVID-19 admitted to two hospitals in northern Manhattan between March 2nd and April 1st, 2020. The primary outcome was in-hospital mortality. Secondary outcomes included frequency and duration of invasive mechanical ventilation, frequency of vasopressor use and renal-replacement-therapy, and time to clinical deterioration following hospital admission. The relationship between clinical risk factors, biomarkers, and in-hospital mortality was modeled using Cox-proportional-hazards regression. Each patient had at least 14 days of observation. Results: Of 1,150 adults hospitalized with COVID-19 during the study period, 257 (22%) were critically ill. The median age was 62 years (interquartile range [IQR] 51-72); 170 (66%) were male. Two-hundred twelve (82%) had at least one chronic illness, the most common of which were hypertension (63%; 162/257) and diabetes mellitus (36%; 92/257). One-hundred-thirty-eight patients (54%) were obese, and 13 (5%) were healthcare workers. As of April 14th, 2020, in-hospital mortality was 33% (86/257); 47% (122/257) of patients remained hospitalized. Two-hundred-one (79%) patients received invasive mechanical ventilation (median 13 days [IQR 9-17]), and 54% (138/257) and 29% (75/257) required vasopressors and renal-replacement-therapy, respectively. The median time to clinical deterioration following hospital admission was 3 days (IQR 1-6). Older age, hypertension, chronic lung disease, and higher concentrations of interleukin-6 and d-dimer at admission were independently associated with in-hospital mortality. Conclusions: Critical illness among patients hospitalized with COVID-19 in New York City is common and associated with a high frequency of invasive mechanical ventilation, extra-pulmonary organ dysfunction, and substantial in-hospital mortality.

14: Delirium Incidence, Duration and Severity in Critically Ill Patients with COVID-19
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Posted 01 Jun 2020

Delirium Incidence, Duration and Severity in Critically Ill Patients with COVID-19
5,742 downloads medRxiv intensive care and critical care medicine

Sikandar H Khan, Heidi Lindroth, Anthony J Perkins, Yasser Jamil, Sophia Wang, Scott Roberts, Mark O Farber, Omar Rahman, Sujuan Gao, Edward R Marcantonio, Malaz Boustani, Roberto Machado, Babar A Khan

Background Delirium incidence, duration and severity in patients admitted to the intensive care unit (ICU) due to COVID-19 is not known. Methods We conducted an observational study at two large urban academic Level 1 trauma centers. Consecutive patients admitted to the ICU with a positive SARS-CoV-2 nasopharyngeal swab polymerase chain reaction test from March 1st, 2020 to April 27, 2020 were included. Individuals younger than 18 years of age, without any documented delirium assessments (CAM-ICU), or without a discharge disposition were excluded. The primary outcomes were delirium rates and delirium duration and the secondary outcome was delirium severity. Outcomes were assessed for up to the first 14 days of ICU stay. Results Of 243 consecutive patients with confirmed COVID-19 admitted to the ICU, 144 met eligibility criteria and were included in the analysis. Delirium occurred in 73.6% (106/144) and delirium or coma occurred in 76.4% (110/144). Sixty-three percent of patients were positive for delirium on the first CAM-ICU assessment. The median duration of delirium and coma was 7 days (IQR: 3-10), and the median delirium duration was 5 days (IQR: 2-7). The median CAM-ICU-7 score was 6 (IQR: 4-7) representing severe delirium. Mechanical ventilation was associated with greater odds of developing delirium (OR: 42.1, 95%CI: 13.0-137.1). Mortality was 26.4% in patients with delirium compared to 15.8% in patients without delirium. Conclusions 73.6% of patients admitted to the ICU with COVID-19 experience delirium that persists for approximately 1 week. Invasive mechanical ventilation is significantly associated with odds of delirium. Clinical attention to prevent and manage delirium and reduce delirium duration and severity is urgently needed for patients with COVID-19.

15: Retrospective Analysis of Clinical Features in 101 Death Cases with COVID-19
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Posted 12 Mar 2020

Retrospective Analysis of Clinical Features in 101 Death Cases with COVID-19
5,506 downloads medRxiv intensive care and critical care medicine

Hua Fan, Lin Zhang, Bin Huang, Muxin Zhu, Yong Zhou, Huan Zhang, Xiaogen Tao, Shaohui Cheng, Wenhu Yu, Liping Zhu, Jian Chen

BackgroundThe illness progress of partial patient of COVID-19 is rapid and the mortality rate is high.we aim to describe the clinical features in death cases with COVID-19. MethodsIn this single center, observational study, We recruited all Death Cases with COVID-19 from Dec 30, 2019 to Feb 16, 2020 in Intensive care unit of Wuhan Jinyintan Hospital.Demographics, basic diseases, X-ray/CT results, possible therapy strategies and test results when their entrance into admission, ICU and 48 h before death were collected and analyzed. ResultsThis study involved 101 COVID-19 dead cases in Intensive care unit of Wuhan Jinyintan Hospital.47 patients went directly to the ICU because of critical condition, and 54 patients were transferred to ICU with aggravated condition.57 (56.44%) were laboratory confirmed by RT-PCR, and 44 (43.6%) were consistent with clinical diagnostic criteria.The cases included 64 males and 37 females with average age of 65.46 years (SD 9.74). The blood type distribution was significantly different, with type A 44.44%, type B 29.29%, type AB 8.08% and type O 18.19%.The clinical manifestations of new coronavirus pneumonia are non-specific,the common symptom was fever (91 [90.10%] of 101 patients),Cough (69[68.32%]) and dyspnea (75[74.26%]). Neutrophils, PCT, CRP,IL-6,D-dimer gradually increased as time went on.Myocardial enzymes were abnormal in most patients at admission,with the progress of the disease, myocardial damage indicators were significantly increased.61(60.40%) used antiviral drugs,59(58.42%) used glucocorticoids, 63.37% used intravenous immunoglobulins, and 44.55% used thymosin preparations. All patients received antibiotic treatment, 63(62.38%) used restricted antibiotics, 23(22.78%) used antifungal drugs.84(83.17%) used non-invasive ventilator or high-flow oxygen therapy equipment, and 76.24% used invasive mechanical ventilation. 7 patients were treated with ECMO and 8 patients were treated with CRRT.The median time from ARDS to invasive mechanical ventilation was 3.00 days(IQR 0.00-6.00). The duration of invasive mechanical ventilation was 5 days (IQR2.00-8.00). ConclusionsCritical COVID-19 can cause fatal respiratory distress syndrome and multiple organ failure with high mortality rate. Heart may be the earliest damaged organ except the lungs. Secondary infection in the later period is worthy of attention.

16: IL6 inhibition in critically ill COVID-19 patients is associated with increased secondary infections
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Posted 20 May 2020

IL6 inhibition in critically ill COVID-19 patients is associated with increased secondary infections
5,183 downloads medRxiv intensive care and critical care medicine

Lucas M Kimmig, David Wu, Matthew Gold, Natasha N Pettit, David Pitrak, Jeffrey Mueller, Aliya N Husain, Ece A Mutlu, Gokhan M Mutlu

Background: Anti-inflammatory therapies such as IL-6 inhibition have been proposed for COVID-19 in a vacuum of evidence-based treatment. However, abrogating the inflammatory response in infectious diseases may impair a desired host response and predispose to secondary infections. Methods: We retrospectively reviewed the medical record of critically ill COVID-19 patients during an 8-week span and compared the prevalence of secondary infection and outcomes in patients who did and did not receive tocilizumab. Additionally, we included representative histopathologic post-mortem findings from several COVID-19 cases that underwent autopsy at our institution. Results: 111 patients were identified, of which 54 had received tocilizumab while 57 had not. Receiving tocilizumab was associated with a higher risk of secondary bacterial (48.1% vs. 28.1%, p=0.029 and fungal (5.6% vs. 0%, p=0.112) infections. Consistent with higher number of infections, patients who received tocilizumab had higher mortality (35.2% vs. 19.3%, p=0.020). Seven cases underwent autopsy. In 3 cases who received tocilizumab, there was evidence of pneumonia on pathology. Of the 4 cases that had not been given tocilizumab, 2 showed evidence of aspiration pneumonia and 2 exhibited diffuse alveolar damage. Conclusions: Experimental therapies are currently being applied to COVID-19 outside of clinical trials. Anti-inflammatory therapies such as anti-IL-6 therapy have the potential to impair viral clearance, predispose to secondary infection, and cause harm. We seek to raise physician awareness of these issues and highlight the need to better understand the immune response in COVID-19.

17: Early Awake Prone and Lateral Position in Non-intubated Severe and Critical Patients with COVID-19 in Wuhan: A Respective Cohort Study
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Posted 13 May 2020

Early Awake Prone and Lateral Position in Non-intubated Severe and Critical Patients with COVID-19 in Wuhan: A Respective Cohort Study
5,138 downloads medRxiv intensive care and critical care medicine

Wei Dong, Yiping Gong, Juan Feng, Lang Bai, Haomiao Qing, Peng Zhou, Yu Du, Junchen Zhu, Shanling Xu

Background Previous studies suggest applying prone position (PP) and lateral position (LP) in patients with severe acute respiratory distress syndrome (ARDS) for their efficacy in improving oxygenation and lung recruitment.This paper aims to share clinical experiences and outcome of using PP and LP in combination with oxygen therapy (OT) and Non-invasive ventilation (NIV) in severe and critical patients with COVID-19. Methods Clinical data of 48 severe and critical patients have been retrieved from medical records and reviewed. The primary outcome is the survival rate. Secondary outcome is the rate of patients requiring intubation. Results In total, 25 patients were finally included in the study.The mean respiratory rate of all 25 patients decreased from 28.4 breaths/min to 21.3 breaths/min. CT results showed increase in lung recruitment. All patients tolerated PP and LP well. No deterioration or severe adverse events associated with PP and LP occurred. All patients recovered and survived without intubation. Follow-up to date showed that all patients have been discharged except one with mild symptoms and positive RNA test. Conclusion: Clinical outcomes of early application of PP and LP in combination with OT and NIV in severe and critical patients with COVID-19 indicated well tolerance of the therapy and resulted in improving patients' oxygenation in a safe and effective manner. Therefore, this strategy can be explored as an early intervention in managing patients in early stage of disease development under the context of pandemic and limited medical resources.

18: Mechanical Ventilator Milano (MVM):A Novel Mechanical Ventilator Designed for Mass Scale Production in response to the COVID-19 Pandemics
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Posted 27 Mar 2020

Mechanical Ventilator Milano (MVM):A Novel Mechanical Ventilator Designed for Mass Scale Production in response to the COVID-19 Pandemics
4,965 downloads medRxiv intensive care and critical care medicine

C. Galbiati, W. Bonivento, M. Caravati, S. De Cecco, T. Dinon, G. Fiorillo, D. Franco, F. Gabriele, C. L. Kendziora, I. Kochanek, An. Ianni, A. McDonald, L. Molinari Tosatti, M. Malosio, D. Minuzzo, S. H. Pordes, A. Prini, A. Razeto, M. Razeti, M. Rescigno, D. Sablone, E. Scapparone, G. Testera, R. Tartaglia, H. Wang, A. Zardoni

We present here the design of the Mechanical Ventilator Milano (MVM), a novel mechanical ventilator designed for mass scale production in response to the COVID-19 pandemics, to compensate for the dramatic shortage of such ventilators in many countries. This ventilator is an electro-mechanical equivalent of the old, reliable Manley Ventilator. Our design is optimized to permit large sale production in short time and at a limited cost, relying on off-the-shelf components, readily available worldwide from hardware suppliers. Operation of the MVM requires only a source of compressed oxygen (or compressed medical air) and electrical power. The MVM control and monitoring unit can be connected and networked via WiFi so that no additional electrical connections are necessary other than the connection to the electrical power. At this stage the MVM is not a certified medical device. Construction of the first prototypes is starting with a team of engineers, scientists and computing experts. The purpose of this paper is to disseminate the conceptual design of the MVM broadly and to solicit feed-back from the scientific and medical community to speed the process of review, improvement and possible implementation.

19: Can Nebulised Heparin Reduce Time to Extubation in SARS CoV 2 The CHARTER Study Protocol
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Posted 01 May 2020

Can Nebulised Heparin Reduce Time to Extubation in SARS CoV 2 The CHARTER Study Protocol
4,743 downloads medRxiv intensive care and critical care medicine

Barry Dixon, Roger Smith, Antonio Artigas, John Laffey, Bairbre McNicholas, Eric Schmidt, Quentin Nunes, Mark Andrew Skidmore, Marcelo Andrade de Lome, John Moran, Frank Van Haren, Gordon Doig, Sachin Gupta, Angajendra Ghosh, Simone Said, John Santamaria

Introduction: COVID 19 is associated with the development of ARDS displaying the typical features of diffuse alveolar damage with extensive pulmonary coagulation activation resulting in fibrin deposition in the microvasculature and formation of hyaline membranes in the air sacs. The anticoagulant actions of nebulised heparin limit fibrin deposition and progression of lung injury. Serendipitously, unfractionated heparin also inactivates the SARS CoV 2 virus and prevents its entry into mammalian cells. Nebulisation of heparin may therefore limit both fibrin mediated lung injury and inhibit pulmonary infection by SARS CoV 2. For these reasons we have initiated a multicentre international trial of nebulised heparin in patients with COVID 19. Methods and intervention: Mechanically ventilated patients with confirmed or strongly suspected SARS CoV 2 infection, hypoxaemia and an acute pulmonary opacity in at least one lung quadrant on chest Xray, will be randomised to nebulised heparin 25,000 Units every 6 hours or standard care for up to 10 days while mechanically ventilated. The primary outcome is the time to separation from invasive ventilation to day 28, where non survivors to day 28 are treated as though not separated from invasive ventilation. Ethics and dissemination: The study protocol has been submitted to the human research and ethics committee of St Vincents Hospital, Melbourne, Australia. Submission is pending in other jurisdictions. Results of this study will be published in scientific journals and presented at scientific meetings.

20: Observational Study of Metformin and Risk of Mortality in Patients Hospitalized with Covid-19
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Posted 20 Jun 2020

Observational Study of Metformin and Risk of Mortality in Patients Hospitalized with Covid-19
4,632 downloads medRxiv intensive care and critical care medicine

Carolyn T Bramante, Nicholas Ingraham, Thomas Murray, Schelomo Marmor, Shane Hoversten, Jessica Gronski, Chace McNeil, Ruoying Feng, Gabriel Guzman, Nermine Abdelwahab, Samantha King, Thomas Meehan, Bradley Benson, Kathryn Pendleton, Deneen Vojta, Christopher J. Tignanelli

Background Type 2 diabetes (T2DM) and obesity are significant risks for mortality in Covid19. Metformin has been hypothesized as a treatment for COVID19. Metformin has sex specific immunomodulatory effects which may elucidate treatment mechanisms in COVID-19. In this study we sought to identify whether metformin reduced mortality from Covid19 and if sex specific interactions exist. Methods De-identified claims data from UnitedHealth were used to identify persons with at least 6 months continuous coverage who were hospitalized with Covid-19. Persons in the metformin group had at least 90 days of metformin claims in the 12 months before hospitalization. Unadjusted and multivariate models were conducted to assess risk of mortality based on metformin as a home medication in individuals with T2DM and obesity, controlling for pre-morbid conditions, medications, demographics, and state. Heterogeneity of effect was assessed by sex. Results 6,256 persons were included; 52.8% female; mean age 75 years. Metformin was associated with decreased mortality in women by logistic regression, OR 0.792 (0.640, 0.979); mixed effects OR 0.780 (0.631, 0.965); Cox proportional-hazards: HR 0.785 (0.650, 0.951); and propensity matching, OR of 0.759 (0.601, 0.960). TNF-alpha inhibitors were associated with decreased mortality in the 38 persons taking them, by propensity matching, OR 0.19 (0.0378, 0.983). Conclusions Metformin was significantly associated with reduced mortality in women with obesity or T2DM in observational analyses of claims data from individuals hospitalized with Covid-19. This sex-specific finding is consistent with metformin reducing TNF-alpha in females over males, and suggests that metformin conveys protection in Covid-19 through TNF-alpha effects. Prospective studies are needed to understand mechanism and causality.

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