Publications by authors named "John C Marshall"

347 Publications

Perspectives of patients, family members, health professionals and the public on the impact of COVID-19 on mental health.

J Ment Health 2022 Jan 4:1-10. Epub 2022 Jan 4.

Department of Respiratory Medicine, Peking University Third Hospital, Beijing, China.

Background: The coronavirus (COVID-19) pandemic has seen a global surge in anxiety, depression, post-traumatic stress disorder (PTSD), and stress.

Aims: This study aimed to describe the perspectives of patients with COVID-19, their family, health professionals, and the general public on the impact of COVID-19 on mental health.

Methods: A secondary thematic analysis was conducted using data from the COVID-19 COS project. We extracted data on the perceived causes and impact of COVID-19 on mental health from an international survey and seven online consensus workshops.

Results: We identified four themes (with subthemes in parenthesis): anxiety amidst uncertainty (always on high alert, ebb and flow of recovery); anguish of a threatened future (intense frustration of a changed normality, facing loss of livelihood, trauma of ventilation, a troubling prognosis, confronting death); bearing responsibility for transmission (fear of spreading COVID-19 in public; overwhelming guilt of infecting a loved one); and suffering in isolation (severe solitude of quarantine, sick and alone, separation exacerbating grief).

Conclusion: We found that the unpredictability of COVID-19, the fear of long-term health consequences, burden of guilt, and suffering in isolation profoundly impacted mental health. Clinical and public health interventions are needed to manage the psychological consequences arising from this pandemic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/09638237.2021.2022637DOI Listing
January 2022

A clinical case definition of post-COVID-19 condition by a Delphi consensus.

Lancet Infect Dis 2021 Dec 21. Epub 2021 Dec 21.

World Health Organization, Geneva, Switzerland.

People with COVID-19 might have sustained postinfection sequelae. Known by a variety of names, including long COVID or long-haul COVID, and listed in the ICD-10 classification as post-COVID-19 condition since September, 2020, this occurrence is variable in its expression and its impact. The absence of a globally standardised and agreed-upon definition hampers progress in characterisation of its epidemiology and the development of candidate treatments. In a WHO-led Delphi process, we engaged with an international panel of 265 patients, clinicians, researchers, and WHO staff to develop a consensus definition for this condition. 14 domains and 45 items were evaluated in two rounds of the Delphi process to create a final consensus definition for adults: post-COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include, but are not limited to, fatigue, shortness of breath, and cognitive dysfunction, and generally have an impact on everyday functioning. Symptoms might be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms might also fluctuate or relapse over time. A separate definition might be applicable for children. Although the consensus definition is likely to change as knowledge increases, this common framework provides a foundation for ongoing and future studies of epidemiology, risk factors, clinical characteristics, and therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1473-3099(21)00703-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8691845PMC
December 2021

Feasibility of conservative fluid administration and deresuscitation compared with usual care in critical illness: the Role of Active Deresuscitation After Resuscitation-2 (RADAR-2) randomised clinical trial.

Intensive Care Med 2021 Dec 16. Epub 2021 Dec 16.

Department of Critical Care, Belfast Health and Social Care Trust, Belfast, UK.

Purpose: Fluid overload is common in critical illness and is associated with mortality. This study investigated the feasibility of a randomised trial comparing conservative fluid administration and deresuscitation (active removal of accumulated fluid using diuretics or ultrafiltration) with usual care in critical illness.

Methods: Open-label, parallel-group, allocation-concealed randomised clinical feasibility trial. Mechanically ventilated adult patients expected to require critical care beyond the next calendar day were enrolled between 24 and 48 h following admission to the intensive care unit (ICU). Patients were randomised to either a 2-stage fluid strategy comprising conservative fluid administration and, if fluid overload was present, active deresuscitation, or usual care. The primary endpoint was fluid balance in the 24 h up to the start of study day 3. Secondary endpoints included cumulative fluid balance, mortality, and duration of mechanical ventilation.

Results: One hundred and eighty patients were randomised. After withdrawal of 1 patient, 89 patients assigned to the intervention were compared with 90 patients assigned to the usual care group. The mean plus standard deviation (SD) 24-h fluid balance up to study day 3 was lower in the intervention group (- 840 ± 1746 mL) than the usual care group (+ 130 ± 1401 mL; P < 0.01). Cumulative fluid balance was lower in the intervention group at days 3 and 5. Overall, clinical outcomes did not differ significantly between the two groups, although the point estimate for 30-day mortality favoured the usual care group [intervention arm: 19 of 90 (21.6%) versus usual care: 14 of 89 (15.6%), P = 0.32]. Baseline imbalances between groups and lack of statistical power limit interpretation of clinical outcomes.

Conclusions: A strategy of conservative fluid administration and active deresuscitation is feasible, reduces fluid balance compared with usual care, and may cause benefit or harm. In view of wide variations in contemporary clinical practice, large, adequately powered trials investigating the clinical effectiveness of conservative fluid strategies in critically ill patients are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00134-021-06596-8DOI Listing
December 2021

Towards a universal understanding of post COVID-19 condition.

Bull World Health Organ 2021 12 5;99(12):901-903. Epub 2021 Oct 5.

Clinical Management Team, World Health Organization, Avenue Appia 20, 1211 Geneva 27, Switzerland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2471/BLT.21.286249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8640686PMC
December 2021

Establishing Healthcare Worker Performance and Safety in Providing Critical Care for Patients in a Simulated Ebola Treatment Unit: Non-Randomized Pilot Study.

Viruses 2021 11 2;13(11). Epub 2021 Nov 2.

Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, Interdepartmental Division of Critical Care Medicine and Institute for Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON M4N 3M5, Canada.

Improving the provision of supportive care for patients with Ebola is an important quality improvement initiative. We designed a simulated Ebola Treatment Unit (ETU) to assess performance and safety of healthcare workers (HCWs) performing tasks wearing personal protective equipment (PPE) in hot (35 °C, 60% relative humidity) or thermo-neutral (20 °C, 20% relative humidity) conditions. In this pilot phase to determine the feasibility of study procedures, HCWs in PPE were non-randomly allocated to hot or thermo-neutral conditions to perform peripheral intravenous (PIV) and midline catheter (MLC) insertion and endotracheal intubation (ETI) on mannequins. Eighteen HCWs (13 physicians, 4 nurses, 1 nurse practitioner; 2 with prior ETU experience; 10 in hot conditions) spent 69 (10) (mean (SD)) minutes in the simulated ETU. Mean (SD) task completion times were 16 (6) min for PIV insertion; 33 (5) min for MLC insertion; and 16 (8) min for ETI. Satisfactory task completion was numerically higher for physicians vs. nurses. Participants' blood pressure was similar, but heart rate was higher ( = 0.0005) post-simulation vs. baseline. Participants had a median (range) of 2.0 (0.0-10.0) minor PPE breaches, 2.0 (0.0-6.0) near-miss incidents, and 2.0 (0.0-6.0) health symptoms and concerns. There were eight health-assessment triggers in five participants, of whom four were in hot conditions. We terminated the simulation of two participants in hot conditions due to thermal discomfort. In summary, study tasks were suitable for physician participants, but they require redesign to match nurses' expertise for the subsequent randomized phase of the study. One-quarter of participants had a health-assessment trigger. This research model may be useful in future training and research regarding clinical care for patients with highly infectious pathogens in austere settings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/v13112205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8622862PMC
November 2021

A Research Agenda for Precision Medicine in Sepsis and Acute Respiratory Distress Syndrome: An Official American Thoracic Society Research Statement.

Am J Respir Crit Care Med 2021 10;204(8):891-901

Precision medicine focuses on the identification of therapeutic strategies that are effective for a group of patients based on similar unifying characteristics. The recent success of precision medicine in non-critical care settings has resulted from the confluence of large clinical and biospecimen repositories, innovative bioinformatics, and novel trial designs. Similar advances for precision medicine in sepsis and in the acute respiratory distress syndrome (ARDS) are possible but will require further investigation and significant investment in infrastructure. This project was funded by the American Thoracic Society Board of Directors. A multidisciplinary and diverse working group reviewed the available literature, established a conceptual framework, and iteratively developed recommendations for the Precision Medicine Research Agenda for Sepsis and ARDS. The following six priority recommendations were developed by the working group: ) the creation of large richly phenotyped and harmonized knowledge networks of clinical, imaging, and multianalyte molecular data for sepsis and ARDS; ) the implementation of novel trial designs, including adaptive designs, and embedding trial procedures in the electronic health record; ) continued innovation in the data science and engineering methods required to identify heterogeneity of treatment effect; ) further development of the tools necessary for the real-time application of precision medicine approaches; ) work to ensure that precision medicine strategies are applicable and available to a broad range of patients varying across differing racial, ethnic, socioeconomic, and demographic groups; and ) the securement and maintenance of adequate and sustainable funding for precision medicine efforts. Precision medicine approaches that incorporate variability in genomic, biologic, and environmental factors may provide a path forward for better individualizing the delivery of therapies and improving care for patients with sepsis and ARDS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.202108-1908STDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534611PMC
October 2021

Essential Emergency and Critical Care: a consensus among global clinical experts.

BMJ Glob Health 2021 09;6(9)

Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden.

Background: Globally, critical illness results in millions of deaths every year. Although many of these deaths are potentially preventable, the basic, life-saving care of critically ill patients are often overlooked in health systems. Essential Emergency and Critical Care (EECC) has been devised as the care that should be provided to all critically ill patients in all hospitals in the world. EECC includes the effective care of low cost and low complexity for the identification and treatment of critically ill patients across all medical specialties. This study aimed to specify the content of EECC and additionally, given the surge of critical illness in the ongoing pandemic, the essential diagnosis-specific care for critically ill patients with COVID-19.

Methods: In a Delphi process, consensus (>90% agreement) was sought from a diverse panel of global clinical experts. The panel iteratively rated proposed treatments and actions based on previous guidelines and the WHO/ICRC's Basic Emergency Care. The output from the Delphi was adapted iteratively with specialist reviewers into a coherent and feasible package of clinical processes plus a list of hospital readiness requirements.

Results: The 269 experts in the Delphi panel had clinical experience in different acute medical specialties from 59 countries and from all resource settings. The agreed EECC package contains 40 clinical processes and 67 requirements, plus additions specific for COVID-19.

Conclusion: The study has specified the content of care that should be provided to all critically ill patients. Implementing EECC could be an effective strategy for policy makers to reduce preventable deaths worldwide.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjgh-2021-006585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458367PMC
September 2021

Upregulated PD-L1 delays human neutrophil apoptosis and promotes lung injury in an experimental mouse model of sepsis.

Blood 2021 09;138(9):806-810

Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China.

PD-L1 is a ligand for PD-1, and its expression has been shown to be upregulated in neutrophils harvested from septic patients. However, the effect of PD-L1 on neutrophil survival and sepsis-induced lung injury remains largely unknown. In this study, PD-L1 expression correlated negatively with rates of apoptosis in human neutrophils harvested from patients with sepsis. Coimmunoprecipitation assays on control neutrophils challenged with interferon-γ and LPS showed that PD-L1 complexes with the p85 subunit of phosphatidyl 3-kinase (PI3K) to activate AKT-dependent survival signaling. Conditional CRE/LoxP deletion of neutrophil PD-L1 in vivo further protected against lung injury and reduced neutrophil lung infiltration in a cecal ligation and puncture (CLP) experimental sepsis animal model. Compared with wild-type animals, PD-L1-deficient animals presented lower levels of plasma tumor necrosis factor-α and interleukin-6 (IL-6) and higher levels of IL-10 after CLP, and reduced 7-day mortality in CLP PD-L1-knockout animals. Taken together, our data suggest that increased PD-L1 expression on human neutrophils delays cellular apoptosis by triggering PI3K-dependent AKT phosphorylation to drive lung injury and increase mortality during clinical and experimental sepsis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020009417DOI Listing
September 2021

Association between sepsis survivorship and long-term cardiovascular outcomes in adults: a systematic review and meta-analysis.

Intensive Care Med 2021 09 9;47(9):931-942. Epub 2021 Aug 9.

Peter Munk Cardiac Centre, University Health Network, RFE3-410, 190 Elizabeth St, Toronto, Canada.

Purpose: We aimed to determine the association between sepsis and long-term cardiovascular events.

Methods: We conducted a systematic review of observational studies evaluating post-sepsis cardiovascular outcomes in adult sepsis survivors. MEDLINE, Embase, and the Cochrane Controlled Trials Register and Database of Systematic Reviews were searched from inception until April 21st, 2021. Two reviewers independently extracted individual study data and evaluated risk of bias. Random-effects models estimated the pooled crude cumulative incidence and adjusted hazard ratios (aHRs) of cardiovascular events compared to either non-septic hospital survivors or population controls. Primary outcomes included myocardial infarction, stroke, and congestive heart failure; outcomes were analysed at maximum reported follow-up (from 30 days to beyond 5 years post-discharge).

Results: Of 12,649 screened citations, 27 studies (25 cohort studies, 2 case-crossover studies) were included with a median of 4,289 (IQR 502-68,125) sepsis survivors and 18,399 (IQR 4,028-83,506) controls per study. The pooled cumulative incidence of myocardial infarction, stroke, and heart failure in sepsis survivors ranged from 3 to 9% at longest reported follow-up. Sepsis was associated with a higher long-term risk of myocardial infarction (aHR 1.77 [95% CI 1.26 to 2.48]; low certainty), stroke (aHR 1.67 [95% CI 1.37 to 2.05]; low certainty), and congestive heart failure (aHR 1.65 [95% CI 1.46 to 1.86]; very low certainty) compared to non-sepsis controls.

Conclusions: Surviving sepsis may be associated with a long-term, excess hazard of late cardiovascular events which may persist for at least 5 years following hospital discharge.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00134-021-06479-yDOI Listing
September 2021

Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19.

N Engl J Med 2021 Aug 4;385(9):777-789. Epub 2021 Aug 4.

From the University of Toronto (E.C.G., P.R.L., L.C.G., M.E.F., V.D., R.A.F., J.P.G., M.H., A.S.S.), University Health Network (E.C.G., M.H.), Peter Munk Cardiac Centre at University Health Network (P.R.L., L.C.G., M.E.F., V.D.), Ozmosis Research (L.B., V.W.), Sunnybrook Health Sciences Centre (J.P.G.), Toronto, Ottawa Hospital Research Institute (M. Carrier, L.A.C., D.A.F., G.L.G., D.M.S.), Institut du Savoir Montfort (M. Carrier, G.L.G.), and the University of Ottawa (L.A.C., D.A.F., D.M.S.), Ottawa, the University of Manitoba (A. Kumar, B.L.H., R.Z., S.A.L., D.S., G.V.-G.) and CancerCare Manitoba (B.L.H., R.Z.), Winnipeg, Université Laval and Centre Hospitalier Universitaire de Québec-Université Laval Research Center, Quebec, QC (A.F.T.), McGill University, Montreal (S.R.K., E.G.M.), St. Michael's Hospital Unity Health, Toronto (J.C.M., Z.B., M.S., A.S.S.), McMaster University and the Thrombosis and Atherosclerosis Research Institute, Hamilton, ON (P.L.G.) Université de Sherbrooke, Sherbrooke, QC (F.L.), St. Boniface Hospital, Winnipeg, MB (N.M.), the University of British Columbia, Vancouver (S. Murthy), and the University of Alberta, Edmonton (S.D.) - all in Canada; University of Bristol and University Hospitals Bristol and Weston NHS Foundation Trust, Bristol (C.A.B.), the London School of Hygiene and Tropical Medicine (B.-A.K.), Imperial College London (A.C.G., F.A.-B., M.A.L.), Imperial College Healthcare NHS Trust, St. Mary's Hospital (A.C.G.), University College London Hospital (R.H.), Kings Healthcare Partners (B.J.H.), and Intensive Care National Audit and Research Centre (ICNARC) (P.R.M., K.R.), London, Queen's University Belfast and Royal Victoria Hospital, Belfast (D.F.M.), and Oxford University (A. Beane, L.J.E., S.J.S.) and NHS Blood and Transplant (L.J.E., S. Mavromichalis, S.J.S.), Oxford - all in the United Kingdom; the University of Pittsburgh (B.J.M., D.C.A., M.M.B., M.D.N., H.F.E., J.D.F., Z.F., D.T.H., A.J.K., C.M.L., K.L., M.M., S.K.M., C.W.S., Y.Z.), University of Pittsburgh Medical Center (B.J.M., D.C.A., M.D.N., K.L.), the Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, University of Pittsburgh (T.D.G.), and University of Pittsburgh Medical Center Children's Hospital of Pittsburgh (C.M. Horvat) - all in Pittsburgh; New York University (NYU) Grossman School of Medicine (J.S.B., H.R.R., J.S.H., T.C., A.C., N.M.K., S. Mavromichalis, S.P.), NYU Langone Health, NYU Langone Hospital (T.A., T.C., A.C., J.M.H., E.Y.), and Bellevue Hospital (N.M.K.), Icahn School of Medicine at Mount Sinai (R.S.R.), and Mount Sinai Heart (R.S.R.), New York, Montefiore Medical Center (M.N.G., H.H.B., S.C., J.-T.C., A.A. Hope, R.N.) and Albert Einstein College of Medicine (M.N.G., H.H.B., B.T.G., A.A. Hope), Bronx, and NYU Langone Long Island, Mineola (A.A. Hindenburg) - all in New York; Zuckerberg San Francisco General Hospital-University of California, San Francisco (L.Z.K., C.M. Hendrickson, M.M.K., A.E.K., B.N.-G., J.J.P.), Harbor-UCLA Medical Center, Torrance (R.J.L.), Global Coalition for Adaptive Research (M. Buxton) and the University of California, Los Angeles (G.L.), Los Angeles, the University of California San Diego School of Medicine, San Diego (T.W.C.), and Stanford University School of Medicine, Palo Alto (J.G.W.) - all in California; the University of Illinois (K.S.K., J.R.J., J.G.Q.), the University of Chicago (J.D.P.), and the Chartis Group (J.S.) - all in Chicago; University Medical Center Utrecht, Utrecht University (L.P.G.D., M. Bonten, R.E.G.S., W.B.-P.), and Utrecht University (R.E.G.S.), Utrecht, and Radboud University Medical Center, Nijmegen (S. Middeldorp, F.L.V.) - all in the Netherlands; Larner College of Medicine at the University of Vermont, Burlington (M. Cushman); Inselspital, Bern University Hospital, University of Bern, Bern (T.T.), and SOCAR Research, Nyon (B.-A.K., S. Brouwer) - both in Switzerland; Instituto do Coracao, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo (L.C.G., F.G.L., J.C.N.), Avanti Pesquisa Clínica (A.S.M.), and Hospital 9 de Julho (F.O.S.), Sao Paulo, Hospital do Coração de Mato Grosso do Sul (M.P.), the Federal University of Mato Grosso do Sul (M.P.), Hospital Universitário Maria Aparecida Pedrossia (D.G.S.), and Hospital Unimed Campo Grande (D.G.S.), Campo Grande, and Instituto Goiano de Oncologia e Hematologia, Clinical Research Center, Goiânia (M.O.S.) - all in Brazil; the Australian and New Zealand Intensive Care Research Centre, Monash University (Z.M., C.J.M., S.A.W., A. Buzgau, C.G., A.M.H., S.P.M., A.D.N., J.C.P.), Monash University (A.C.C.), and Alfred Health (A.C.C., A.D.N.), Melbourne, VIC, St. John of God Subiaco Hospital, Subiaco, WA (S.A.W., E. Litton), Flinders University, Bedford Park, SA (S. Bihari), and Fiona Stanley Hospital, Perth, WA (E. Litton) - all in Australia; Berry Consultants, Austin (R.J.L., L.R.B., E. Lorenzi, S.M.B., M.A.D., M.F., A.M., C.T.S.), and Baylor Scott and White Health, Temple (R.J.W.) - both in Texas; Auckland City Hospital (C.J.M., S.P.M., R.L.P.) and the University of Auckland (R.L.P.), Auckland, and the Medical Research Institute of New Zealand, Wellington (C.J.M., A.M.T.) - all in New Zealand; Fédération Hospitalo-Universitaire Saclay and Paris Seine Nord Endeavour to Personalize Interventions for Sepsis (FHU-SEPSIS), Raymond Poincaré Hospital, Université de Versailles Saint-Quentin-en-Yvelines, Garches (D. Annane), and Aix-Marseille University, Marseille (B.C.) - both in France; King Saud bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Kingdom of Saudi Arabia (Y.M.A.); Nepal Mediciti Hospital, Lalitpur (D. Aryal), and the Nepal Intensive Care Research Foundation, Kathmandu (D. Aryal); Versiti Blood Research Institute, Milwaukee (L.B.K.); National Intensive Care Surveillance (NICS)-Mahidol Oxford Tropical Medicine Research Unit (MORU), Colombo, Sri Lanka (A. Beane); Jena University Hospital, Jena, Germany (F.B.); Cleveland Clinic, Cleveland (A.D.), and the University of Cincinnati, Cincinnati (K.H.) - both in Ohio; Ochsner Medical Center, University of Queensland-Ochsner Clinical School, New Orleans (M.B.E.); Instituto Mexicano del Seguro Social, Mexico City (J.E., E.M.G.); Brigham and Women's Hospital (B.M.E., Y.K., S.M.H.), Massachusetts General Hospital (N.S.R., A.B.S.), and Harvard Medical School (B.M.E., Y.K., N.S.R., A.B.S.) - all in Boston; University of Alabama, Birmingham (S.G.); TriStar Centennial Medical Center, Nashville (A.L.G.); University of Antwerp, Wilrijk, Belgium (H.G.); Rutgers New Jersey Medical School, Newark, New Jersey (Y.Y.G.); University of Oxford, Bangkok, Thailand (R.H.); the University of Michigan, Ann Arbor (R.C.H., P.K.P.), Beaumont Health, Royal Oak (G.B.N.), and Oakland University William Beaumont School of Medicine, Auburn Hills (G.B.N.) - all in Michigan; Apollo Speciality Hospital OMR, Chennai, India (D.J.); Oregon Health and Science University, Portland (A. Khan); National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (A. Kindzelski, E.S.L.); University of Mississippi Medical Center, Jackson (M.E.K.); IdiPaz Research Institute, Universidad Autonoma, Madrid (J.L.-S.); University College Dublin, Dublin (A.D.N.); the University of Kansas School of Medicine, Kansas City (L.S.); and Duke University Hospital, Durham, North Carolina (L.W.).

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 <1.2], 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. (REMAP-CAP, ACTIV-4a, and ATTACC ClinicalTrials.gov numbers, NCT02735707, NCT04505774, NCT04359277, and NCT04372589.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa2103417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362592PMC
August 2021

Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19.

N Engl J Med 2021 Aug 4;385(9):790-802. Epub 2021 Aug 4.

From the Peter Munk Cardiac Centre at University Health Network (P.R.L., M.E.F., V.D., J.P.G., L.C.G., G.H.), the University of Toronto (P.R.L., E.C.G., A.S.S., M.E.F., V.D., R.A.F., L.C.G., G.H., M.H.), University Health Network (E.C.G., M.H.), St. Michael's Hospital Unity Health (A.S.S., Z.B., J.C.M., M.S.), Ozmosis Research (L.B., L.P.G.D., V.W.), and Sunnybrook Health Sciences Centre (J.P.G.), Toronto, Ottawa Hospital Research Institute (M. Carrier, L.A.C., D.A.F., G.L.G., D.M.S.), Institut du Savoir Montfort (Marc Carrier, G.L.G.), and the University of Ottawa (L.A.C., D.A.F., D.M.S.), Ottawa, Université Laval (A.F.T.) and CHU de Québec-Université Laval Research Center (A.F.T.), Quebec, QC, the University of Manitoba (B.L.H., A. Kumar, R.Z., S.A.L., D.S., G.V.-G.), CancerCare Manitoba (B.L.H., R.Z.), and St. Boniface Hospital (N.M.), Winnipeg, MB, McGill University, Montreal (S.R.K., E.G.M.), McMaster University (P.L.G.) and the Thrombosis and Atherosclerosis Research Institute (P.L.G.), Hamilton, ON, Université de Sherbrooke, Sherbrooke, QC (F.L.), the University of British Columbia, Vancouver (S. Murthy, K.R.), and the University of Alberta, Edmonton (S.D.) - all in Canada; NYU Grossman School of Medicine (J.S.B., H.R.R., J.S.H., T.C., N.M.K., S.P.), the Icahn School of Medicine at Mount Sinai and Mount Sinai Heart (R.S.R.), NYU Langone Health, NYU Langone Hospital (T.C., J.M.H., E.Y.), and Bellevue Hospital (N.M.K.), New York, Montefiore Medical Center (M.N.G., H.H.B., S.C., J.T.C., R.N.) and Albert Einstein College of Medicine (M.N.G., H.H.B., B.T.G., A. Hope), Bronx, and NYU Langone Long Island, Mineola (R.D.H., A. Hindenburg) - all in New York; the University of Pittsburgh (M.D.N., B.J.M., D.T.H., M.M.B., D.C.A., A.J.K., C.M.L., K.L., S.K.M., C.W.S.), UPMC (M.D.N., B.J.M., D.C.A., K.L., S.K.M.), the Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, University of Pittsburgh (T.D.G.), and UPMC Children's Hospital of Pittsburgh (C. Horvat), Pittsburgh, and Emergency Medicine, Penn State Hershey Medical Center, Hershey (S.C.M.) - all in Pennsylvania; Instituto do Coracao, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo (J.C.N., L.C.G., F.G.L.), Avanti Pesquisa Clínica (A.S.M.), Hospital de Julho (F.O.S.), and Hospital do Coracao (F.G.Z.), Sao Paulo, Hospital do Coração de Mato Grosso do Sul and the Federal University of Mato Grosso do Sul (M.P.), Hospital Universitário Maria Aparecida Pedrossia (D.G.S.J.), and Hospital Unimed Campo Grande (D.G.S.J.), Campo Grande, and INGOH, Clinical Research Center, Goiânia (M.O.S.) - all in Brazil; Instituto Mexicano del Seguro Social, Mexico City (J.E., Y.S.P.G.); the University of Bristol and University Hospitals Bristol and Weston NHS Foundation Trust (C.A.B.), Bristol, Imperial College London (A.C.G., F.A.-B., M.A.L.), Imperial College Healthcare NHS Trust, St. Mary's Hospital (A.C.G.), the London School of Hygiene and Tropical Medicine (B.-A.K.), University College London Hospital (R.H.), Kings Healthcare Partners (B.J.H.), the Intensive Care National Audit and Research Centre (P.R.M.), Guy's and St. Thomas' NHS Foundation Trust (M.S.-H.), and King's College London (M.S.-H.), London, Oxford University (A. Beane, S.J.S.) and NHS Blood and Transplant (L.J.E., S.J.S.), Oxford, and Queen's University Belfast and Royal Victoria Hospital, Belfast (D.F.M.) - all in the United Kingdom; Zuckerberg San Francisco General Hospital, University of California, San Francisco (L.Z.K., C. Hendrickson, M.M.K., A.E.K., M.A.M., B.N.-G.), Harbor-UCLA Medical Center, Torrance (R.J.L., S. Brouwer), Global Coalition for Adaptive Research (M. Buxton) and the University of California Los Angeles (G.L.), Los Angeles, the University of California San Diego School of Medicine, San Diego (T.W.C.), and Stanford University School of Medicine, Palo Alto (J.G.W.) - all in California; Larner College of Medicine at the University of Vermont, Burlington (M. Cushman); Australian and New Zealand Intensive Care Research Centre, Monash University (Z.M., A.M.H., C.J.M., S.A.W., A. Buzgau, C.G., S.P.M., A.D.N., J.C.P., A.C.C.), and Alfred Health (A.C.C., A.D.N.), Melbourne, VIC, St. John of God Subiaco Hospital (S.A.W., E. Litton) and Fiona Stanley Hospital (E. Litton), Perth, WA, and Flinders University, Bedford Park, SA (S. Bihari) - all in Australia; the University of Illinois (K.S.K., J.R.J., J.G.Q.), Cook County Health and Rush Medical College (S. Malhotra), and the University of Chicago (J.D.P.) - all in Chicago; SOCAR Research SA, Nyon (B.-A.K.), and Inselspital, Bern University Hospital, University of Bern (T.T.), Bern - all in Switzerland; Berry Consultants, Austin (R.J.L., E. Lorenzi, S.M.B., L.R.B., M.A.D., M.F., A.M., C.T.S.), University of Texas Southwestern Medical Center, Dallas (A.P.), and Baylor Scott and White Health, Temple (R.J.W.) - all in Texas; Auckland City Hospital (C.J.M., S.P.M., R.L.P.) and the University of Auckland (R.L.P.), Auckland, and the Medical Research Institute of New Zealand, Wellington (C.J.M., A.M.T.) - all in New Zealand; Vanderbilt University Medical Center (A.W.A.) and TriStar Centennial Medical Center (A.L.G.) - both in Nashville; Fédération Hospitalo Universitaire, Raymond Poincaré Hospital, Université de Versailles Saint-Quentin-en-Yvelines, Garches (D. Annane), and Aix-Marseille University, Marseille (B.C.) - both in France; King Saud bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Saudi Arabia (Y.M.A.); Nepal Mediciti Hospital, Lalitpur, and Nepal Intensive Care Research Foundation, Kathmandu (D. Aryal) - both in Nepal; Versiti Blood Research Institute, Milwaukee (L.B.K., L.J.E.), and the University of Wisconsin School of Medicine and Public Health, Madison (J.P.S.); National Intensive Care Surveillance-Mahidol Oxford Tropical Medicine Research Unit, Colombo, Sri Lanka (A. Beane); the University Medical Center Utrecht, Utrecht University, Utrecht (M. Bonten, R.E.G.S., W.B.-P.), and Radboud University Medical Center, Nijmegen (S. Middeldorp, F.L.V.) - both in the Netherlands; Jena University Hospital, Jena, Germany (F.B.); Cleveland Clinic (A.D.) and Case Western Reserve University, the Metro Health Medical Centre (V.K.) - both in Cleveland; Ochsner Medical Center, University of Queensland-Ochsner Clinical School, New Orleans (M.B.E.); Harvard Medical School (B.M.E., Y.K., N.S.R., A.B.S), Brigham and Women's Hospital (B.M.E., Y.K., S.M.H.), Boston University School of Medicine and Boston Medical Center (N.M.H.), and Massachusetts General Hospital (A.B.S., N.S.R.) - all in Boston; University of Alabama, Birmingham (S.G.); Hospital Ramón y Cajal (S.G.-M., J.L.L.-S.M., R.M.G.) and IdiPaz Research Institute, Universidad Autonoma (J.L.-S.), Madrid, and University Hospital of Salamanca-University of Salamanca-IBSAL, Salamanca (M.M.) - all in Spain; University of Antwerp, Wilrijk, Belgium (H.G.); Rutgers New Jersey Medical School, Newark (Y.Y.G.); University of Oxford, Bangkok, Thailand (R.H.); Ascension St. John Heart and Vascular Center, Tulsa (N.H.), and the University of Oklahoma College of Medicine, Oklahoma City (N.H.); the University of Cincinnati, Cincinnati (K.H.); University of Michigan, Ann Arbor (R.C.H., P.K.P.), Beaumont Health, Royal Oak, and the OUWB School of Medicine, Auburn Hills (G.B.N.) - all in Michigan; Mayo Clinic, Rochester (V.N.I.), and the Hennepin County Medical Center, Minneapolis (M.E.P.) - both in Minnesota; Apollo Speciality Hospital-OMR, Chennai, India (D.J.); Oregon Health and Science University, Portland (A. Khan, E.S.L.); the National Heart, Lung, and Blood Institute, Bethesda, MD (A.L.K.); University of Mississippi Medical Center, Jackson (M.E.K.); University College Dublin, Dublin (A.D.N.); University of Kansas School of Medicine, Kansas City (L.S.); Duke University Hospital, Durham, NC (L.W.); and Emory University, Atlanta (B.J.W.).

Background: Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.

Methods: In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. 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. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.

Results: The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis.

Conclusions: In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa2105911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362594PMC
August 2021

Advancing precision medicine for acute respiratory distress syndrome.

Lancet Respir Med 2022 01 23;10(1):107-120. Epub 2021 Jul 23.

Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, and Department of Anesthesia, University of California San Francisco, San Francisco, CA, USA.

Acute respiratory distress syndrome (ARDS) is a heterogeneous clinical syndrome. Understanding of the complex pathways involved in lung injury pathogenesis, resolution, and repair has grown considerably in recent decades. Nevertheless, to date, only therapies targeting ventilation-induced lung injury have consistently proven beneficial, and despite these gains, ARDS morbidity and mortality remain high. Many candidate therapies with promise in preclinical studies have been ineffective in human trials, probably at least in part due to clinical and biological heterogeneity that modifies treatment responsiveness in human ARDS. A precision medicine approach to ARDS seeks to better account for this heterogeneity by matching therapies to subgroups of patients that are anticipated to be most likely to benefit, which initially might be identified in part by assessing for heterogeneity of treatment effect in clinical trials. In October 2019, the US National Heart, Lung, and Blood Institute convened a workshop of multidisciplinary experts to explore research opportunities and challenges for accelerating precision medicine in ARDS. Topics of discussion included the rationale and challenges for a precision medicine approach in ARDS, the roles of preclinical ARDS models in precision medicine, essential features of cohort studies to advance precision medicine, and novel approaches to clinical trials to support development and validation of a precision medicine strategy. In this Position Paper, we summarise workshop discussions, recommendations, and unresolved questions for advancing precision medicine in ARDS. Although the workshop took place before the COVID-19 pandemic began, the pandemic has highlighted the urgent need for precision therapies for ARDS as the global scientific community grapples with many of the key concepts, innovations, and challenges discussed at this workshop.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2213-2600(21)00157-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302189PMC
January 2022

The Multiple Organ Dysfunction Syndrome: Syndrome, Metaphor, and Unsolved Clinical Challenge.

Crit Care Med 2021 09;49(9):1402-1413

Keenan Research Centre for Biomedical Science and the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CCM.0000000000005139DOI Listing
September 2021

Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial.

Intensive Care Med 2021 Aug 12;47(8):867-886. Epub 2021 Jul 12.

Medical Research Institute of New Zealand, Wellington, New Zealand.

Purpose: To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19).

Methods: Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable.

Results: We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (- 1 to 15), 0 (- 1 to 9) and-1 (- 1 to 7), respectively, compared to 6 (- 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively).

Conclusion: Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00134-021-06448-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274471PMC
August 2021

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis.

JAMA 2021 08;326(6):499-518

Medanta-The Medicity, Institute of Liver Transplantation and Regenerative Medicine, Gurugram, India.

Importance: Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm.

Objective: To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes.

Data Sources: Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts.

Study Selection: Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria.

Data Extraction And Synthesis: In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality.

Main Outcomes And Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days.

Results: A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16).

Conclusions And Relevance: In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.

Trial Registration: PROSPERO Identifier: CRD42021230155.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2021.11330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261689PMC
August 2021

Cytoprotective Mechanisms of DJ-1: Implications in Cardiac Pathophysiology.

Molecules 2021 Jun 22;26(13). Epub 2021 Jun 22.

Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON M5B 1W8, Canada.

DJ-1 was originally identified as an oncogene product while mutations of the gene encoding DJ-1/PARK7 were later associated with a recessive form of Parkinson's disease. Its ubiquitous expression and diversity of function suggest that DJ-1 is also involved in mechanisms outside the central nervous system. In the last decade, the contribution of DJ-1 to the protection from ischemia-reperfusion injury has been recognized and its involvement in the pathophysiology of cardiovascular disease is attracting increasing attention. This review describes the current and gaps in our knowledge of DJ-1, focusing on its role in regulating cardiovascular function. In parallel, we present original data showing an association between increased DJ-1 expression and antiapoptotic and anti-inflammatory markers following cardiac and vascular surgical procedures. Future studies should address DJ-1's role as a plausible novel therapeutic target for cardiovascular disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules26133795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270312PMC
June 2021

A core outcome set for studies evaluating interventions to prevent and/or treat delirium for adults requiring an acute care hospital admission: an international key stakeholder informed consensus study.

BMC Med 2021 06 18;19(1):143. Epub 2021 Jun 18.

Watford General Hospital, Watford, UK.

Background: Trials of interventions to prevent or treat delirium in adults in an acute hospital setting report heterogeneous outcomes. Our objective was to develop international consensus among key stakeholders for a core outcome set (COS) for future trials of interventions to prevent and/or treat delirium in adults with an acute care hospital admission and not admitted to an intensive care unit.

Methods: A rigorous COS development process was used including a systematic review, qualitative interviews, modified Delphi consensus process, and in-person consensus using nominal group technique (registration http://www.comet - initiative.org/studies/details/796 ). Participants in qualitative interviews were delirium survivors or family members. Participants in consensus methods comprised international representatives from three stakeholder groups: researchers, clinicians, and delirium survivors and family members.

Results: Item generation identified 8 delirium-specific outcomes and 71 other outcomes from 183 studies, and 30 outcomes from 18 qualitative interviews, including 2 that were not extracted from the systematic review. De-duplication of outcomes and formal consensus processes involving 110 experts including researchers (N = 32), clinicians (N = 63), and delirium survivors and family members (N = 15) resulted in a COS comprising 6 outcomes: delirium occurrence and reoccurrence, delirium severity, delirium duration, cognition, emotional distress, and health-related quality of life. Study limitations included exclusion of non-English studies and stakeholders and small representation of delirium survivors/family at the in-person consensus meeting.

Conclusions: This COS, endorsed by the American and Australian Delirium Societies and European Delirium Association, is recommended for future clinical trials evaluating delirium prevention or treatment interventions in adults presenting to an acute care hospital and not admitted to an intensive care unit.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12916-021-02015-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211534PMC
June 2021

Epidemiological and Clinical Characterization of Superinfections in Critically Ill Coronavirus Disease 2019 Patients.

Crit Care Explor 2021 Jun 11;3(6):e0430. Epub 2021 Jun 11.

Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy.

To describe the epidemiology of superinfections (occurring > 48 hr after hospital admission) and their impact on the ICU and 28-day mortality in patients with coronavirus disease 2019 with acute respiratory distress syndrome, requiring mechanical ventilation.

Design: Retrospective analysis of prospectively collected observational data.

Setting: University-affiliated adult ICU.

Patients: Ninety-two coronavirus disease 2019 patients admitted to the ICU from February 21, 2020, to May 6, 2020.

Interventions: None.

Measurements And Main Results: The prevalence of superinfection at ICU admission was 21.7%, and 53 patients (57.6%) had at least one superinfection during ICU stay, with a total of 75 (82%) ventilator-associated pneumonia and 57 (62%) systemic infections. The most common pathogens responsible for ventilator-associated pneumonia were ( = 26, 34.7%) and ( = 14, 18.7%). Bloodstream infection occurred in 16 cases, including methicillin-resistant ( = 8, 14.0%), species ( = 6, 10.5%), and species ( = 2, 3.5%). Fungal infections occurred in 41 cases, including 36 probable (30 by , six by ) and five proven invasive candidiasis (three , two ). Presence of bacterial infections (odds ratio, 10.53; 95% CI, 2.31-63.42; = 0.005), age (odds ratio, 1.17; 95% CI, 1.07-1.31; = 0.001), and the highest Sequential Organ Failure Assessment score (odds ratio, 1.27; 95% CI, 1.06-1.63; = 0.032) were independently associated with ICU or 28-day mortality.

Conclusions: Prevalence of superinfections in coronavirus disease 2019 patients requiring mechanical ventilation was high in this series, and bacterial superinfections were independently associated with ICU or 28-day mortality (whichever comes first).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CCE.0000000000000430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202543PMC
June 2021

Mesenchymal stromal (stem) cell therapy modulates miR-193b-5p expression to attenuate sepsis-induced acute lung injury.

Eur Respir J 2022 Jan 6;59(1). Epub 2022 Jan 6.

Dept of Medicine, University of Washington, Seattle, WA, USA.

Although mesenchymal stromal (stem) cell (MSC) administration attenuates sepsis-induced lung injury in pre-clinical models, the mechanism(s) of action and host immune system contributions to its therapeutic effects remain elusive. We show that treatment with MSCs decreased expression of host-derived microRNA (miR)-193b-5p and increased expression of its target gene, the tight junctional protein occludin (Ocln), in lungs from septic mice. Mutating the Ocln 3' untranslated region miR-193b-5p binding sequence impaired binding to Ocln mRNA. Inhibition of miR-193b-5p in human primary pulmonary microvascular endothelial cells prevents tumour necrosis factor (TNF)-induced decrease in Ocln gene and protein expression and loss of barrier function. MSC-conditioned media mitigated TNF-induced miR-193b-5p upregulation and Ocln downregulation When administered , MSC-conditioned media recapitulated the effects of MSC administration on pulmonary miR-193b-5p and Ocln expression. MiR-193b-deficient mice were resistant to pulmonary inflammation and injury induced by lipopolysaccharide (LPS) instillation. Silencing of Ocln in miR-193b-deficient mice partially recovered the susceptibility to LPS-induced lung injury. inhibition of miR-193b-5p protected mice from endotoxin-induced lung injury. Finally, the clinical significance of these results was supported by the finding of increased miR-193b-5p expression levels in lung autopsy samples from acute respiratory distress syndrome patients who died with diffuse alveolar damage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.04216-2020DOI Listing
January 2022

Intracellular and Extracellular Lipopolysaccharide Signaling in Sepsis: Avenues for Novel Therapeutic Strategies.

J Innate Immun 2021 18;13(6):323-332. Epub 2021 May 18.

Keenan Research Center for Biomedical Science of Unity Health Toronto, Toronto, Ontario, Canada.

Sepsis is defined as organ dysfunction due to a dysregulated systemic host response to infection. During gram-negative bacterial infection and other acute illness such as absorption from the gut infection, lipopolysaccharide (LPS) is a major mediator in sepsis. LPS is able to trigger inflammation through both intracellular and extracellular pathways. Classical interactions between LPS and host cells first involve LPS binding to LPS binding protein (LBP), a carrier. The LPS-LBP complex then binds to a receptor complex including the CD14, MD2, and toll-like receptor 4 (TLR4) proteins, initiating a signal cascade which triggers the secretion of pro-inflammatory cytokines. However, it has been established that LPS is also internalized by macrophages and endothelial cells through TLR4-independent pathways. Once internalized, LPS is able to bind to the cytosolic receptors caspases-4/5 in humans and the homologous caspase-11 in mice. Bound caspases-4/5 oligomerize and trigger the assembly of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome followed by the activation of inflammatory caspase-1 resulting in subsequent release of interleukin-1β. Caspases-4/5 also activate the perforin gasdermin D and purinergic receptor P2X7, inducing cell lysis and pyroptosis. Pyroptosis is a notable source of inflammation and damage to the lung endothelial barrier during sepsis. Thus, inhibition of caspases-4/5/1 or downstream effectors to block intracellular LPS signaling may be a promising therapeutic approach in adjunction with neutralizing extracellular LPS for treatment of sepsis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000515740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8613564PMC
January 2022

A Core Outcome Set for Research Evaluating Interventions to Prevent and/or Treat Delirium in Critically Ill Adults: An International Consensus Study (Del-COrS).

Crit Care Med 2021 09;49(9):1535-1546

Watford General Hospital, Watford, United Kingdom.

Objectives: Delirium in critically ill adults is highly prevalent and has multiple negative consequences. To-date, trials of interventions to prevent or treat delirium report heterogenous outcomes. To develop international consensus among key stakeholders for a core outcome set for future trials of interventions to prevent and/or treat delirium in critically ill adults.

Design: Core outcome set development, as recommended by the Core Outcome Measures in Effectiveness Trials Handbook. Methods of generating items for the core outcome set included a systematic review and qualitative interviews with ICU survivors and family members. Consensus methods include a two-round web-based Delphi process and a face-to-face meeting using nominal group technique methods.

Subjects: International representatives from three stakeholder groups: 1) clinical researchers, 2) ICU interprofessional clinicians, and 3) ICU survivors and family members.

Setting: Telephone interviews, web-based surveys, and a face-to-face consensus meeting held at the 2019 European Delirium Association's annual meeting in Edinburgh, Scotland.

Intervention: None.

Measurements And Main Results: Qualitative interviews with 24 ICU survivors and family members identified 36 potential outcomes; six were additional to the 97 identified from the systematic review. After item reduction, 32 outcomes were presented in Delphi Round 1; 179 experts participated, 38 ICU survivors/family members (21%), 100 clinicians (56%), 41 researchers (23%). Three additional outcomes were added to Round 2; 134 Round 1 participants (75%) completed it. Upon conclusion of the consensus building processes, the final core outcome set comprised seven outcomes: delirium occurrence (including prevalence or incidence); delirium severity; time to delirium resolution; health-related quality of life; emotional distress (i.e., anxiety, depression, acute and posttraumatic stress); cognition (including memory); and mortality.

Conclusions: This core outcome set, endorsed by the American and Australian Delirium Societies and European Delirium Association, is recommended for future clinical trials evaluating delirium prevention or treatment interventions in critically ill adults.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CCM.0000000000005028DOI Listing
September 2021

National Preclinical Sepsis Platform: developing a framework for accelerating innovation in Canadian sepsis research.

Intensive Care Med Exp 2021 Mar 19;9(1):14. Epub 2021 Mar 19.

Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada.

Despite decades of preclinical research, no experimentally derived therapies for sepsis have been successfully adopted into routine clinical practice. Factors that contribute to this crisis of translation include poor representation by preclinical models of the complex human condition of sepsis, bias in preclinical studies, as well as limitations of single-laboratory methodology. To overcome some of these shortcomings, multicentre preclinical studies-defined as a research experiment conducted in two or more research laboratories with a common protocol and analysis-are expected to maximize transparency, improve reproducibility, and enhance generalizability. The ultimate objective is to increase the efficiency and efficacy of bench-to-bedside translation for preclinical sepsis research and improve outcomes for patients with life-threatening infection. To this end, we organized the first meeting of the National Preclinical Sepsis Platform (NPSP). This multicentre preclinical  research collaboration of Canadian sepsis researchers and stakeholders was established to study the pathophysiology of sepsis and accelerate movement of promising therapeutics into early phase clinical trials. Integrated knowledge translation and shared decision-making were emphasized to ensure the goals of the platform align with clinical researchers and patient partners. 29 participants from 10 independent labs attended and discussed four main topics: (1) objectives of the platform; (2) animal models of sepsis; (3) multicentre methodology and (4) outcomes for evaluation. A PIRO model (predisposition, insult, response, organ dysfunction) for experimental design was proposed to strengthen linkages with interdisciplinary researchers and key stakeholders. This platform represents an important resource for maximizing translational impact of preclinical sepsis research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40635-020-00366-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973346PMC
March 2021

Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19.

N Engl J Med 2021 04 25;384(16):1491-1502. Epub 2021 Feb 25.

From Imperial College London (A.C.G., F.A.-B.), Imperial College Healthcare NHS Trust, St. Mary's Hospital (A.C.G.), Intensive Care National Audit and Research Centre (P.R.M., K.M.R.), University College London Hospital (R.H.), King's College London (M.S.-H.), and Guy's and St. Thomas' NHS Foundation Trust (M.S.-H.), London, University of Oxford (A. Beane) and NHS Blood and Transplant (L.J.E.), Oxford, and University of Bristol, Bristol (C.A.B.) - all in the United Kingdom; Monash University (A.D.N., A. Buzgau, A.C.C., A.M.H., S.P.M., J.C.P., C.G., S.A.W.) and Alfred Health (A.D.N., A.C.C.), Melbourne, VIC, Fiona Stanley Hospital (E. Litton, K.O.) and University of Western Australia (E. Litton), Perth, WA, University of Sydney and Royal Prince Alfred Hospital, Sydney (A.E.P.), and St. John of God Hospital, Subiaco, WA (S.A.W.) - all in Australia; University College Dublin, Dublin (A.D.N.); King Saud bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Saudi Arabia (Y.M.A.); Hospital Raymond Poincaré (Assistance Publique-Hôpitaux de Paris) and Université Paris Saclay-Université de Versailles Saint-Quentin-en-Yvelines-INSERM, Garches, and Université de Versailles Saint-Quentin-en-Yvelines-Université Paris Saclay, Montigny-le-Bretonneux - all in France (D.A.); University Medical Center Utrecht, Utrecht (W.B.-P., M.J.M.B., H.L.L., E.R., L.P.G.D.), and Radboudumc, Nijmegen (F.L.V.) - both in the Netherlands; Berry Consultants, Austin, TX (L.R.B., M.A.D., M.F., E. Lorenzi, A.M., C.T.S., R.J.L., S.B.); St. Michael's Hospital Unity Health (Z.B., J.C.M., M.S.S.) and University Health Network and University of Toronto (P.R.L.), Toronto, Université de Sherbrooke, Sherbrooke, QC (F.L.), University of British Columbia, Vancouver (S.M.), University of Alberta, Edmonton (W.I.S.), Université Laval, Québec City (A.F.T.), and University of Manitoba, Winnipeg, MB (R.Z.) - all in Canada; Jena University Hospital, Jena, Germany (F.M.B.); Auckland City Hospital (E.J.D., T.E.H., S.P.M., R.L.P., C.J.M.), Middlemore Hospital (S.C.M.), and University of Auckland (R.L.P.), Auckland, and Medical Research Institute of New Zealand, Wellington (T.E.H., S.P.M., A.M.T.) - all in New Zealand; University of Antwerp, Wilrijk, Belgium (H.G.); University of Oxford, Bangkok, Thailand (R.H.); National Intensive Care Surveillance, Colombo, Sri Lanka (R.H.); UPMC Children's Hospital of Pittsburgh (C.M.H.) and University of Pittsburgh (K.M.L., F.B.M., B.J.M., S.K.M., C.W.S., D.C.A.), Pittsburgh; Queen's University Belfast and Royal Victoria Hospital, Belfast, Northern Ireland (D.F.M.); University of Helsinki and Helsinki University Hospital, Helsinki (V.P.); and Harbor-UCLA Medical Center, Torrance, CA (R.J.L.).

Background: The efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear.

Methods: We evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours after starting organ support in the intensive care unit (ICU), were randomly assigned to receive tocilizumab (8 mg per kilogram of body weight), sarilumab (400 mg), or standard care (control). The primary outcome was respiratory and cardiovascular organ support-free days, on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with predefined criteria for superiority, efficacy, equivalence, or futility. An odds ratio greater than 1 represented improved survival, more organ support-free days, or both.

Results: Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support-free days was 10 (interquartile range, -1 to 16) in the tocilizumab group, 11 (interquartile range, 0 to 16) in the sarilumab group, and 0 (interquartile range, -1 to 15) in the control group. The median adjusted cumulative odds ratios were 1.64 (95% credible interval, 1.25 to 2.14) for tocilizumab and 1.76 (95% credible interval, 1.17 to 2.91) for sarilumab as compared with control, yielding posterior probabilities of superiority to control of more than 99.9% and of 99.5%, respectively. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08) and a posterior probability of superiority of more than 99.9%. All secondary analyses supported efficacy of these interleukin-6 receptor antagonists.

Conclusions: In critically ill patients with Covid-19 receiving organ support in ICUs, treatment with the interleukin-6 receptor antagonists tocilizumab and sarilumab improved outcomes, including survival. (REMAP-CAP ClinicalTrials.gov number, NCT02735707.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa2100433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953461PMC
April 2021

Operationalisation of the Randomized Embedded Multifactorial Adaptive Platform for COVID-19 trials in a low and lower-middle income critical care learning health system.

Wellcome Open Res 2021 28;6:14. Epub 2021 Jan 28.

Office of Research, Innovation & Commercialization (ORIC), Zuiddin University, Karachi, Pakistan.

The Randomized Embedded Multifactorial Adaptive Platform (REMAP-CAP) adapted for COVID-19) trial is a global adaptive platform trial of hospitalised patients with COVID-19. We describe implementation in three countries under the umbrella of the Wellcome supported Low and Middle Income Country (LMIC) critical  care network: Collaboration for Research, Implementation and Training in Asia (CCA). The collaboration sought to overcome known barriers to multi centre-clinical trials in resource-limited settings. Methods described focused on six aspects of implementation: i, Strengthening an existing community of practice; ii, Remote study site recruitment, training and support; iii, Harmonising the REMAP CAP- COVID trial with existing care processes; iv, Embedding REMAP CAP- COVID case report form into the existing CCA registry platform, v, Context specific adaptation and data management; vi, Alignment with existing pandemic and critical care research in the CCA. Methods described here may enable other LMIC sites to participate as equal partners in international critical care trials of urgent public health importance, both during this pandemic and beyond.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.12688/wellcomeopenres.16486.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883321PMC
January 2021

Intravenous immune globulin in septic shock: a Canadian national survey of critical care medicine and infectious disease specialist physicians.

Can J Anaesth 2021 06 18;68(6):782-790. Epub 2021 Feb 18.

Department of Medicine, Section of Critical Care Medicine, University of Manitoba, Winnipeg, MB, Canada.

Purpose: This national survey evaluated the perceived efficacy and safety of intravenous immune globulin (IVIG) in septic shock, self-reported utilization patterns, barriers to use, the population of interest for further trials and willingness to participate in future research of IVIG in septic shock.

Methods: We conducted a cross-sectional survey of critical care and infectious diseases physicians across Canada. We summarized categorical item responses as counts and proportions. We developed a multivariable logistic regression model to identify physician-level predictors of IVIG use in septic shock.

Results: Our survey was disseminated to 674 eligible respondents with a final response rate of 60%. Most (91%) respondents reported having prescribed IVIG to patients with septic shock at least once, 86% for septic shock due to necrotizing fasciitis, 52% for other bacterial toxin-mediated causes of septic shock, and 5% for undifferentiated septic shock. The majority of respondents expressed uncertainty regarding the impact of IVIG on mortality (97%) and safety (95%) in septic shock. Respondents were willing to participate in further IVIG research with 98% stating they would consider enrolling their patients into a trial of IVIG in septic shock. Familiarity with published evidence was the single greatest predictor of IVIG use in septic shock (odds ratio, 10.2; 95% confidence interval, 3.4 to 30.5; P < 0.001).

Conclusions: Most Canadian critical care and infectious diseases specialist physicians reported previous experience using IVIG in septic shock. Respondents identified inadequacy of existing research as the greatest barrier to routine use of IVIG in septic shock. Most respondents support the need for further studies on IVIG in septic shock, and would consider enrolling their own patients into a trial of IVIG in septic shock.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12630-021-01941-3DOI Listing
June 2021

Sepsis Subclasses: A Framework for Development and Interpretation.

Crit Care Med 2021 05;49(5):748-759

Department of Critical Care Medicine, The Clinical Research, Investigation, and Systems Modeling of Acute illness (CRISMA) Center, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Sepsis is defined as a dysregulated host response to infection that leads to life-threatening acute organ dysfunction. It afflicts approximately 50 million people worldwide annually and is often deadly, even when evidence-based guidelines are applied promptly. Many randomized trials tested therapies for sepsis over the past 2 decades, but most have not proven beneficial. This may be because sepsis is a heterogeneous syndrome, characterized by a vast set of clinical and biologic features. Combinations of these features, however, may identify previously unrecognized groups, or "subclasses" with different risks of outcome and response to a given treatment. As efforts to identify sepsis subclasses become more common, many unanswered questions and challenges arise. These include: 1) the semantic underpinning of sepsis subclasses, 2) the conceptual goal of subclasses, 3) considerations about study design, data sources, and statistical methods, 4) the role of emerging data types, and 5) how to determine whether subclasses represent "truth." We discuss these challenges and present a framework for the broader study of sepsis subclasses. This framework is intended to aid in the understanding and interpretation of sepsis subclasses, provide a mechanism for explaining subclasses generated by different methodologic approaches, and guide clinicians in how to consider subclasses in bedside care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CCM.0000000000004842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8627188PMC
May 2021

Surfactant therapy for COVID-19 related ARDS: a retrospective case-control pilot study.

Respir Res 2021 Jan 18;22(1):20. Epub 2021 Jan 18.

Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.

Background: COVID-19 causes acute respiratory distress syndrome (ARDS) and depletes the lungs of surfactant, leading to prolonged mechanical ventilation and death. The feasibility and safety of surfactant delivery in COVID-19 ARDS patients have not been established.

Methods: We performed retrospective analyses of data from patients receiving off-label use of exogenous natural surfactant during the COVID-19 pandemic. Seven COVID-19 PCR positive ARDS patients received liquid Curosurf (720 mg) in 150 ml normal saline, divided into five 30 ml aliquots) and delivered via a bronchoscope into second-generation bronchi. Patients were matched with 14 comparable subjects receiving supportive care for ARDS during the same time period. Feasibility and safety were examined as well as the duration of mechanical ventilation and mortality.

Results: Patients showed no evidence of acute decompensation following surfactant installation into minor bronchi. Cox regression showed a reduction of 28-days mortality within the surfactant group, though not significant. The surfactant did not increase the duration of ventilation, and health care providers did not convert to COVID-19 positive.

Conclusions: Surfactant delivery through bronchoscopy at a dose of 720 mg in 150 ml normal saline is feasible and safe for COVID-19 ARDS patients and health care providers during the pandemic. Surfactant administration did not cause acute decompensation, may reduce mortality and mechanical ventilation duration in COVID-19 ARDS patients. This study supports the future performance of randomized clinical trials evaluating the efficacy of meticulous sub-bronchial lavage with surfactant as treatment for patients with COVID-19 ARDS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12931-020-01603-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812332PMC
January 2021

Core Outcome Measures for Trials in People With Coronavirus Disease 2019: Respiratory Failure, Multiorgan Failure, Shortness of Breath, and Recovery.

Crit Care Med 2021 03;49(3):503-516

Nova Medical School, CHRC, New University of Lisbon, Polyvalent Intensive Care Unit, Sao Francisco Xavier Hospital, CHLO, Lisbon, Portugal.

Objectives: Respiratory failure, multiple organ failure, shortness of breath, recovery, and mortality have been identified as critically important core outcomes by more than 9300 patients, health professionals, and the public from 111 countries in the global coronavirus disease 2019 core outcome set initiative. The aim of this project was to establish the core outcome measures for these domains for trials in coronavirus disease 2019.

Design: Three online consensus workshops were convened to establish outcome measures for the four core domains of respiratory failure, multiple organ failure, shortness of breath, and recovery.

Setting: International.

Patients: About 130 participants (patients, public, and health professionals) from 17 countries attended the three workshops.

Interventions: None.

Measurements And Main Results: Respiratory failure, assessed by the need for respiratory support based on the World Health Organization Clinical Progression Scale, was considered pragmatic, objective, and with broad applicability to various clinical scenarios. The Sequential Organ Failure Assessment was recommended for multiple organ failure, because it was routinely used in trials and clinical care, well validated, and feasible. The Modified Medical Research Council measure for shortness of breath, with minor adaptations (recall period of 24 hr to capture daily fluctuations and inclusion of activities to ensure relevance and to capture the extreme severity of shortness of breath in people with coronavirus disease 2019), was regarded as fit for purpose for this indication. The recovery measure was developed de novo and defined as the absence of symptoms, resumption of usual daily activities, and return to the previous state of health prior to the illness, using a 5-point Likert scale, and was endorsed.

Conclusions: The coronavirus disease 2019 core outcome set recommended core outcome measures have content validity and are considered the most feasible and acceptable among existing measures. Implementation of the core outcome measures in trials in coronavirus disease 2019 will ensure consistency and relevance of the evidence to inform decision-making and care of patients with coronavirus disease 2019.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CCM.0000000000004817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892260PMC
March 2021

Mesenchymal Stem/Stromal Cells Increase Cardiac miR-187-3p Expression in a Polymicrobial Animal Model of Sepsis.

Shock 2021 07;56(1):133-141

Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

Abstract: Sepsis-induced myocardial dysfunction (MD) is an important pathophysiological feature of multiorgan failure caused by a dysregulated host response to infection. Patients with MD continue to be managed in intensive care units with limited understanding of the molecular mechanisms controlling disease pathogenesis. Emerging evidences support the use of mesenchymal stem/stromal cell (MSC) therapy for treating critically ill septic patients. Combining this with the known role that microRNAs (miRNAs) play in reversing sepsis-induced myocardial-dysfunction, this study sought to investigate how MSC administration alters miRNA expression in the heart. Mice were randomized to experimental polymicrobial sepsis induced by cecal ligation and puncture (CLP) or sham surgery, treated with either MSCs (2.5 × 105) or placebo (saline). Twenty-eight hours post-intervention, RNA was collected from whole hearts for transcriptomic and microRNA profiling. The top microRNAs differentially regulated in hearts by CLP and MSC administration were used to generate a putative mRNA-miRNA interaction network. Key genes, termed hub genes, within the network were then identified and further validated in vivo. Network analysis and RT-qPCR revealed that septic hearts treated with MSCs resulted in upregulation of five miRNAs, including miR-187, and decrease in three top hit putative hub genes (Itpkc, Lrrc59, and Tbl1xr1). Functionally, MSC administration decreased inflammatory and apoptotic pathways, while increasing cardiac-specific structural and functional, gene expression. Taken together, our data suggest that MSC administration regulates host-derived miRNAs production to protect cardiomyocytes from sepsis-induced MD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/SHK.0000000000001701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240645PMC
July 2021
-->