Publications by authors named "Fernando G Zampieri"

71 Publications

Effect of Slower vs Faster Intravenous Fluid Bolus Rates on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial.

JAMA 2021 Sep;326(9):830-838

HCor Research Institute, São Paulo, Brazil.

Importance: Slower intravenous fluid infusion rates could reduce the formation of tissue edema and organ dysfunction in critically ill patients; however, there are no data to support different infusion rates during fluid challenges for important outcomes such as mortality.

Objective: To determine the effect of a slower infusion rate vs control infusion rate on 90-day survival in patients in the intensive care unit (ICU).

Design, Setting, And Participants: Unblinded randomized factorial clinical trial in 75 ICUs in Brazil, involving 11 052 patients requiring at least 1 fluid challenge and with 1 risk factor for worse outcomes were randomized from May 29, 2017, to March 2, 2020. Follow-up was concluded on October 29, 2020. Patients were randomized to 2 different infusion rates (reported in this article) and 2 different fluid types (balanced fluids or saline, reported separately).

Interventions: Patients were randomized to receive fluid challenges at 2 different infusion rates; 5538 to the slower rate (333 mL/h) and 5514 to the control group (999 mL/h). Patients were also randomized to receive balanced solution or 0.9% saline using a factorial design.

Main Outcomes And Measures: The primary end point was 90-day survival.

Results: Of all randomized patients, 10 520 (95.2%) were analyzed (mean age, 61.1 years [SD, 17.0 years]; 44.2% were women) after excluding duplicates and consent withdrawals. Patients assigned to the slower rate received a mean of 1162 mL on the first day vs 1252 mL for the control group. By day 90, 1406 of 5276 patients (26.6%) in the slower rate group had died vs 1414 of 5244 (27.0%) in the control group (adjusted hazard ratio, 1.03; 95% CI, 0.96-1.11; P = .46). There was no significant interaction between fluid type and infusion rate (P = .98).

Conclusions And Relevance: Among patients in the intensive care unit requiring fluid challenges, infusing at a slower rate compared with a faster rate did not reduce 90-day mortality. These findings do not support the use of a slower infusion rate.

Trial Registration: ClinicalTrials.gov Identifier: NCT02875873.
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http://dx.doi.org/10.1001/jama.2021.11444DOI Listing
September 2021

The association of the COVID-19 pandemic and short-term outcomes of non-COVID-19 critically ill patients: an observational cohort study in Brazilian ICUs.

Intensive Care Med 2021 Sep 13. Epub 2021 Sep 13.

D'Or Research and Educational Institute, Rio de Janeiro, Brazil.

Purpose: To assess whether intensive care unit (ICU) outcomes for patients not affected by coronavirus disease 2019 (COVID-19) worsened during the COVID-19 pandemic.

Methods: Retrospective cohort study including prospectively collected information of patients admitted to 165 ICUs in a hospital network in Brazil between 2011 and 2020. Association between admission in 2020 and worse hospital outcomes was performed using different techniques, including assessment of changes in illness severity of admitted patients, a variable life-adjusted display of mortality during 2020, a multivariate mixed regression model with admission year as both fixed effect and random slope adjusted for SAPS 3 score, an analysis of trends in performance using standardized mortality ratio (SMR) and standardized resource use (SRU), and perturbation analysis.

Results: A total of 644,644 admissions were considered. After excluding readmissions and patients with COVID-19, 514,219 patients were available for analysis. Non-COVID-19 patients admitted in 2020 had slightly lower age and SAPS 3 score but a higher mortality (6.4%) when compared with previous years (2019: 5.6%; 2018: 6.1%). Variable-adjusted life display (VLAD) in 2020 increased but started to decrease as the number of COVID-19 cases increased; this trend reversed as number of COVID cases reduced but recurred on the second wave. After logistic regression, being admitted in 2020 was associated with higher mortality when compared to previous years from 2016 and 2019. Individual ICUs standardized mortality ratio also increased during 2020 (higher SMR) while resource use remained constant, suggesting worsening performance. A perturbation analysis further confirmed changes in ICU outcomes for non-COVID-19 patients.

Conclusion: Hospital outcomes of non-COVID-19 critically ill patients worsened during the pandemic in 2020, possibly resulting in an increased number of deaths in critically ill non-COVID patients.
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http://dx.doi.org/10.1007/s00134-021-06528-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437089PMC
September 2021

Effect of Intravenous Fluid Treatment With a Balanced Solution vs 0.9% Saline Solution on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial.

JAMA 2021 Aug 10. Epub 2021 Aug 10.

HCor Research Institute, São Paulo, Brazil.

Importance: Intravenous fluids are used for almost all intensive care unit (ICU) patients. Clinical and laboratory studies have questioned whether specific fluid types result in improved outcomes, including mortality and acute kidney injury.

Objective: To determine the effect of a balanced solution vs saline solution (0.9% sodium chloride) on 90-day survival in critically ill patients.

Design, Setting, And Participants: Double-blind, factorial, randomized clinical trial conducted at 75 ICUs in Brazil. Patients who were admitted to the ICU with at least 1 risk factor for worse outcomes, who required at least 1 fluid expansion, and who were expected to remain in the ICU for more than 24 hours were randomized between May 29, 2017, and March 2, 2020; follow-up concluded on October 29, 2020. Patients were randomized to 2 different fluid types (a balanced solution vs saline solution reported in this article) and 2 different infusion rates (reported separately).

Interventions: Patients were randomly assigned 1:1 to receive either a balanced solution (n = 5522) or 0.9% saline solution (n = 5530) for all intravenous fluids.

Main Outcomes And Measures: The primary outcome was 90-day survival.

Results: Among 11 052 patients who were randomized, 10 520 (95.2%) were available for the analysis (mean age, 61.1 [SD, 17] years; 44.2% were women). There was no significant interaction between the 2 interventions (fluid type and infusion speed; P = .98). Planned surgical admissions represented 48.4% of all patients. Of all the patients, 60.6% had hypotension or vasopressor use and 44.3% required mechanical ventilation at enrollment. Patients in both groups received a median of 1.5 L of fluid during the first day after enrollment. By day 90, 1381 of 5230 patients (26.4%) assigned to a balanced solution died vs 1439 of 5290 patients (27.2%) assigned to saline solution (adjusted hazard ratio, 0.97 [95% CI, 0.90-1.05]; P = .47). There were no unexpected treatment-related severe adverse events in either group.

Conclusion And Relevance: Among critically ill patients requiring fluid challenges, use of a balanced solution compared with 0.9% saline solution did not significantly reduce 90-day mortality. The findings do not support the use of this balanced solution.

Trial Registration: ClinicalTrials.gov Identifier: NCT02875873.
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http://dx.doi.org/10.1001/jama.2021.11684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356144PMC
August 2021

Disparity in the access to kidney transplantation for sensitized patients in the state of Sao Paulo-Brazil.

Transpl Immunol 2021 Oct 3;68:101441. Epub 2021 Aug 3.

Insper Institute of Education and Research, Statistics and Data Science, Brazil.

Highly sensitized (HS) patients accumulate on deceased donor kidney transplantation (DDKT) waitlists worldwide due to matching difficulty and inequity of allocation policies. Current situation of HS patients on KT waitlist in Brazil has not been published. All patients enrolled on the KT waitlist of the State of São Paulo from 2002 to 2017 were retrospectively assessed. Patients were divided into eight groups according to their degree of sensitization, PRA of 0%, >0-40%, >40-80%, >80-85%, >85-90%, >90-95%, >95-98% and > 98%. Cumulative incidence curves for transplantation or mortality/removal from waitlist were estimated by competing risk. Among 50,249 waitlisted candidates, 1247 prioritized, 2467 with age < 18 or > 75 years and 4152 submitted to living-donor KT were excluded from the analysis, remaining 42,383 patients. There were 29,664(70%) PRA 0%, 5611(13.2%) PRA > 0-40%, 3442(8.2%) PRA > 40-80%, 507(1.2%) PRA > 80-85%, 564(1.3%) PRA > 85-90%, 825(1.9%) PRA >90-95%, 859(2%) PRA > 95-98% and 911(2.2%) PRA > 98%. There was a progressive increase in the need of prioritization, waiting time for KT or on waitlist and time on dialysis as PRA increased (p < 0.001). Probability of DDKT clearly increased as PRA decreased so that PRA 0% candidates were much more likely to be transplanted compared to PRA > 98% patients(HR:13.02, p < 0.001). Waiting list mortality/removal was higher among PRA > 0-40%(HR1.05,p = 0.03), PRA > 90-95%(HR:1.10,p = 0.05), PRA > 95-98%(HR:1.26,p < 0.001) and PRA > 98%(HR:1.09,p = 0.05) patients compared to PRA zero candidates. HS patients in Sao Paulo-Brazil required greater prioritization due to lack of venous access, longer dialysis and waitlist times, lower probability of DDKT and higher rates of waitlist mortality/removal. We confirmed the disparity of access to KT among HS patients in Sao Paulo-Brazil, indicating the need of new strategies that optimize transplantation for this subcategory of patients.
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http://dx.doi.org/10.1016/j.trim.2021.101441DOI Listing
October 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.).
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http://dx.doi.org/10.1056/NEJMoa2105911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362594PMC
August 2021

The Limitations of Standardized Mortality Ratios for Coronavirus Disease 2019 ICU Patients.

Crit Care Med 2021 Jul 29. Epub 2021 Jul 29.

Critical Care Department, D'Or Institute for Research and Education, Rio de Janeiro, Brazil Department of Critical and Intensive Care Medicine, Academic Hospital Fundación Santa Fe de Bogota, Bogota, Colombia HCor Research Institute, São Paulo, Brazil.

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http://dx.doi.org/10.1097/CCM.0000000000005245DOI Listing
July 2021

Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials.

Nat Commun 2021 04 15;12(1):2349. Epub 2021 Apr 15.

Infectious and Tropical Diseases Department, Angers University Hospital, Angers, France.

Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.
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http://dx.doi.org/10.1038/s41467-021-22446-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050319PMC
April 2021

Evolving changes in mortality of 13,301 critically ill adult patients with COVID-19 over 8 months.

Intensive Care Med 2021 05 14;47(5):538-548. Epub 2021 Apr 14.

D'Or Institute for Research and Education (IDOR), Rio de Janeiro, RJ, Brazil.

Purpose: Clinical characteristics and management of COVID-19 patients have evolved during the pandemic, potentially changing their outcomes. We analyzed the associations of changes in mortality rates with clinical profiles and respiratory support strategies in COVID-19 critically ill patients.

Methods: A multicenter cohort of RT-PCR-confirmed COVID-19 patients admitted at 126 Brazilian intensive care units between February 27 and October 28, 2020. Assessing temporal changes in deaths, we identified distinct time periods. We evaluated the association of characteristics and respiratory support strategies with 60-day in-hospital mortality using random-effects multivariable Cox regression with inverse probability weighting.

Results: Among the 13,301 confirmed-COVID-19 patients, 60-day in-hospital mortality was 13%. Across four time periods identified, younger patients were progressively more common, non-invasive respiratory support was increasingly used, and the 60-day in-hospital mortality decreased in the last two periods. 4188 patients received advanced respiratory support (non-invasive or invasive), from which 42% underwent only invasive mechanical ventilation, 37% only non-invasive respiratory support and 21% failed non-invasive support and were intubated. After adjusting for organ dysfunction scores and premorbid conditions, we found that younger age, absence of frailty and the use of non-invasive respiratory support (NIRS) as first support strategy were independently associated with improved survival (hazard ratio for NIRS first [95% confidence interval], 0.59 [0.54-0.65], p < 0.001).

Conclusion: Age and mortality rates have declined over the first 8 months of the pandemic. The use of NIRS as the first respiratory support measure was associated with survival, but causal inference is limited by the observational nature of our data.
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http://dx.doi.org/10.1007/s00134-021-06388-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044656PMC
May 2021

Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial.

BMJ 2021 01 20;372:n84. Epub 2021 Jan 20.

Hospital Alemão Oswaldo Cruz, São Paulo, Brazil.

Objective: To determine whether tocilizumab improves clinical outcomes for patients with severe or critical coronavirus disease 2019 (covid-19).

Design: Randomised, open label trial.

Setting: Nine hospitals in Brazil, 8 May to 17 July 2020.

Participants: Adults with confirmed covid-19 who were receiving supplemental oxygen or mechanical ventilation and had abnormal levels of at least two serum biomarkers (C reactive protein, D dimer, lactate dehydrogenase, or ferritin). The data monitoring committee recommended stopping the trial early, after 129 patients had been enrolled, because of an increased number of deaths at 15 days in the tocilizumab group.

Interventions: Tocilizumab (single intravenous infusion of 8 mg/kg) plus standard care (n=65) versus standard care alone (n=64).

Main Outcome Measure: The primary outcome, clinical status measured at 15 days using a seven level ordinal scale, was analysed as a composite of death or mechanical ventilation because the assumption of odds proportionality was not met.

Results: A total of 129 patients were enrolled (mean age 57 (SD 14) years; 68% men) and all completed follow-up. All patients in the tocilizumab group and two in the standard care group received tocilizumab. 18 of 65 (28%) patients in the tocilizumab group and 13 of 64 (20%) in the standard care group were receiving mechanical ventilation or died at day 15 (odds ratio 1.54, 95% confidence interval 0.66 to 3.66; P=0.32). Death at 15 days occurred in 11 (17%) patients in the tocilizumab group compared with 2 (3%) in the standard care group (odds ratio 6.42, 95% confidence interval 1.59 to 43.2). Adverse events were reported in 29 of 67 (43%) patients who received tocilizumab and 21 of 62 (34%) who did not receive tocilizumab.

Conclusions: In patients with severe or critical covid-19, tocilizumab plus standard care was not superior to standard care alone in improving clinical outcomes at 15 days, and it might increase mortality.

Trial Registration: ClinicalTrials.gov NCT04403685.
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http://dx.doi.org/10.1136/bmj.n84DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815251PMC
January 2021

Postcardiac Arrest Neuroprognostication Practices: A Survey of Brazilian Physicians.

Crit Care Explor 2021 Jan 11;3(1):e0321. Epub 2021 Jan 11.

Department of Neurology, Yale University School of Medicine, New Haven, CT.

End-of-life care and decisions on withdrawal of life-sustaining therapies vary across countries, which may affect the feasibility of future multicenter cardiac arrest trials. In Brazil, withdrawal of life-sustaining therapy is reportedly uncommon, allowing the natural history of postcardiac arrest hypoxic-ischemic brain injury to present itself. We aimed to characterize approaches to neuroprognostication of cardiac arrest survivors among physicians in Brazil.

Design: Cross-sectional study.

Setting: Between August 2, 2019, and July 31, 2020, we distributed a web-based survey to physicians practicing in Brazil.

Subjects: Physicians practicing in Brazil and members of the Brazilian Association of Neurointensive Care, who care for patients resuscitated following cardiac arrest.

Interventions: Not applicable.

Measurements And Main Results: Responses from 185 physicians were obtained. Pupillary reflexes, corneal reflexes, and motor responses were considered critical to prognostication, whereas neuroimaging and electroencephalography were also regarded as important. For patients without targeted temperature management, absent pupillary and corneal reflexes at 24 hours postarrest were considered strongly predictive of poor neurologic outcome by 31.8% and 33.0%, respectively. For targeted temperature management-treated patients, absent pupillary and corneal reflexes at 24-hour postrewarming were considered prognostic by 22.9% and 20.0%, respectively. Physicians felt comfortable making definitive prognostic recommendations at day 6 postarrest or later (34.2%) for nontargeted temperature management-treated patients, and at day 6 postrewarming (20.4%) for targeted temperature management-treated patients. Over 90% believed that improving neuroprognostic accuracy would affect end-of-life decision-making.

Conclusions: There is significant variability in neuroprognostic approaches to postcardiac arrest patients and timing of prognostic studies among Brazilian physicians, with practices frequently deviating from current guidelines, underscoring a need for greater neuroprognostic accuracy. Nearly all physicians believed that improving neuroprognostication will impact end-of-life decision-making. Given the tendency to delay prognostic recommendations while using similar neuroprognostic tools, Brazil offers a unique cohort in which to examine the natural history of hypoxic-ischemic brain injury in future studies.
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http://dx.doi.org/10.1097/CCE.0000000000000321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803669PMC
January 2021

Using Bayesian Methods to Augment the Interpretation of Critical Care Trials. An Overview of Theory and Example Reanalysis of the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial.

Am J Respir Crit Care Med 2021 03;203(5):543-552

PAIR (Palliative and Advanced Illness Research) Center Clinical Trials Methods and Outcomes Lab.

Most randomized trials are designed and analyzed using frequentist statistical approaches such as null hypothesis testing and values. Conceptually, values are cumbersome to understand, as they provide evidence of data incompatibility with a null hypothesis (e.g., no clinical benefit) and not direct evidence of the alternative hypothesis (e.g., clinical benefit). This counterintuitive framework may contribute to the misinterpretation that the absence of evidence is equal to evidence of absence and may cause the discounting of potentially informative data. Bayesian methods provide an alternative, probabilistic interpretation of data. The reanalysis of completed trials using Bayesian methods is becoming increasingly common, particularly for trials with effect estimates that appear clinically significant despite values above the traditional threshold of 0.05. Statistical inference using Bayesian methods produces a distribution of effect sizes that would be compatible with observed trial data, interpreted in the context of prior assumptions about an intervention (called "priors"). These priors are chosen by investigators to reflect existing beliefs and past empirical evidence regarding the effect of an intervention. By calculating the likelihood of clinical benefit, a Bayesian reanalysis can augment the interpretation of a trial. However, if priors are not defined , there is a legitimate concern that priors could be constructed in a manner that produces biased results. Therefore, some standardization of priors for Bayesian reanalysis of clinical trials may be desirable for the critical care community. In this Critical Care Perspective, we discuss both frequentist and Bayesian approaches to clinical trial analysis, introduce a framework that researchers can use to select priors for a Bayesian reanalysis, and demonstrate how to apply our proposal by conducting a novel Bayesian trial reanalysis.
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http://dx.doi.org/10.1164/rccm.202006-2381CPDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924582PMC
March 2021

Hydroxychloroquine with or without Azithromycin in Covid-19. Reply.

N Engl J Med 2021 01 2;384(2):191. Epub 2020 Dec 2.

HCor Research Institute, São Paulo, Brazil.

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http://dx.doi.org/10.1056/NEJMc2031780DOI Listing
January 2021

Preferences for the measurement and supplementation of magnesium, phosphate and zinc in ICUs: The international WhyTrace survey.

Acta Anaesthesiol Scand 2021 03 25;65(3):390-396. Epub 2020 Nov 25.

Department of Intensive Care, Rigshospitalet University of Copenhagen, Copenhagen, Denmark.

Background: Patients admitted to the Intensive Care Unit (ICU) often have low magnesium, phosphate and zinc levels. Monitoring of serum concentrations and supplementation may be important, but there is no consensus on optimal practice. The objective of the WhyTrace survey was to describe current practice regarding the measurement and supplementation of magnesium, phosphate and zinc in ICUs.

Methods: A 54-item electronic questionnaire was developed in accordance with SURGE, SUrvey Reporting GuidelinE, to address international clinical practice in the ICU. National investigators recruited ICUs in ten countries with one physician responding per ICU using a unique e-mail distributed survey-link.

Results: The questionnaire was sent to clinicians in 336 ICUs of whom 283 (84%) responded. In 62% of the ICUs, a standard procedure was in place regarding the measurement of serum magnesium levels, in 58% for phosphate and in 9% for zinc. Zinc was never or rarely measured in 64% of ICUs. The frequency of requesting serum levels varied from twice daily to once weekly. Regarding supplementation, 66% of ICUs had a standard procedure for magnesium, 63% for phosphate and 15% for zinc. Most procedures recommended supplementation when serum levels were below the lower reference level, but some used the upper reference levels as the threshold for supplementation and others decided on a case-by-case basis.

Conclusion: The practice of measuring and supplementing magnesium, phosphate and zinc differed substantially between ICUs. Our findings indicate that there is a need for high-quality prospective data on frequencies of measurements, treatment goals and effects of supplementation on patient-important outcomes.
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http://dx.doi.org/10.1111/aas.13738DOI Listing
March 2021

Reductio ad absurdum in critical care trials.

J Crit Care 2021 02 8;61:71-72. Epub 2020 Oct 8.

HCor Research Institute, Rua Abílio Soares, 250, 12th Floor, São Paulo, Brazil. Electronic address:

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http://dx.doi.org/10.1016/j.jcrc.2020.10.001DOI Listing
February 2021

Intensive care accessibility and outcomes in pandemics.

Intensive Care Med 2020 11 14;46(11):2064-2066. Epub 2020 Oct 14.

Intensive Care Unit, Royal Melbourne Hospital, Parkville, VIC, Australia.

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http://dx.doi.org/10.1007/s00134-020-06264-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556548PMC
November 2020

Guiding Principles for the Conduct of Observational Critical Care Research for Coronavirus Disease 2019 Pandemics and Beyond: The Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study Registry.

Crit Care Med 2020 11;48(11):e1038-e1044

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Mayo Clinic, Rochester, MN.

Objectives: Use of observational data to inform the response and care of patients during a pandemic faces unique challenges.

Design: The Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study COVID 2019 Registry Core data and research methodology team convened over virtual meetings throughout March to June 2020 to determine best practice goals for development of a pandemic disease registry to support rapid data collection and analysis.

Setting: International, multi-center registry of hospitalized patients.

Patients: None.

Interventions: None.

Measurements And Main Results: Large-scale observational data collection requires: 1) quality assurance and harmonization across many sites; 2) a transparent process for selecting from among many potential research questions; 3) the use of best practices in design of descriptive, predictive, and inferential studies; (4) innovative approaches to characterize random error in the setting of constantly updated data; (5) rapid peer-review and reporting; and (6) transitions from a focus on discovery to implementation. Herein, we describe the guiding principles to best practices and suggestions for innovations to study design and reporting within the coronavirus disease 2019 Viral Infection and Respiratory Illness Universal Study pandemic registry.

Conclusions: Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study coronavirus disease 2019 registry sought to develop and implement prespecified best practices combined with grassroots efforts from clinical sites worldwide in order to develop clinically useful knowledge in response to a pandemic.
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http://dx.doi.org/10.1097/CCM.0000000000004572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540620PMC
November 2020

Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial.

Lancet 2020 10 5;396(10256):959-967. Epub 2020 Sep 5.

Hospital Israelita Albert Einstein, São Paulo, Brazil.

Background: The efficacy and safety of azithromycin in the treatment of COVID-19 remain uncertain. We assessed whether adding azithromycin to standard of care, which included hydroxychloroquine, would improve clinical outcomes of patients admitted to the hospital with severe COVID-19.

Methods: We did an open-label, randomised clinical trial at 57 centres in Brazil. We enrolled patients admitted to hospital with suspected or confirmed COVID-19 and at least one additional severity criteria as follows: use of oxygen supplementation of more than 4 L/min flow; use of high-flow nasal cannula; use of non-invasive mechanical ventilation; or use of invasive mechanical ventilation. Patients were randomly assigned (1:1) to azithromycin (500 mg via oral, nasogastric, or intravenous administration once daily for 10 days) plus standard of care or to standard of care without macrolides. All patients received hydroxychloroquine (400 mg twice daily for 10 days) because that was part of standard of care treatment in Brazil for patients with severe COVID-19. The primary outcome, assessed by an independent adjudication committee masked to treatment allocation, was clinical status at day 15 after randomisation, assessed by a six-point ordinal scale, with levels ranging from 1 to 6 and higher scores indicating a worse condition (with odds ratio [OR] greater than 1·00 favouring the control group). The primary outcome was assessed in all patients in the intention-to-treat (ITT) population who had severe acute respiratory syndrome coronavirus 2 infection confirmed by molecular or serological testing before randomisation (ie, modified ITT [mITT] population). Safety was assessed in all patients according to which treatment they received, regardless of original group assignment. This trial was registered at ClinicalTrials.gov, NCT04321278.

Findings: 447 patients were enrolled from March 28 to May 19, 2020. COVID-19 was confirmed in 397 patients who constituted the mITT population, of whom 214 were assigned to the azithromycin group and 183 to the control group. In the mITT population, the primary endpoint was not significantly different between the azithromycin and control groups (OR 1·36 [95% CI 0·94-1·97], p=0·11). Rates of adverse events, including clinically relevant ventricular arrhythmias, resuscitated cardiac arrest, acute kidney failure, and corrected QT interval prolongation, were not significantly different between groups.

Interpretation: In patients with severe COVID-19, adding azithromycin to standard of care treatment (which included hydroxychloroquine) did not improve clinical outcomes. Our findings do not support the routine use of azithromycin in combination with hydroxychloroquine in patients with severe COVID-19.

Funding: COALITION COVID-19 Brazil and EMS.
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http://dx.doi.org/10.1016/S0140-6736(20)31862-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836431PMC
October 2020

Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial.

JAMA 2020 10;324(13):1307-1316

Aché Laboratórios Farmacêuticos, São Paulo, Brazil.

Importance: Acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) is associated with substantial mortality and use of health care resources. Dexamethasone use might attenuate lung injury in these patients.

Objective: To determine whether intravenous dexamethasone increases the number of ventilator-free days among patients with COVID-19-associated ARDS.

Design, Setting, And Participants: Multicenter, randomized, open-label, clinical trial conducted in 41 intensive care units (ICUs) in Brazil. Patients with COVID-19 and moderate to severe ARDS, according to the Berlin definition, were enrolled from April 17 to June 23, 2020. Final follow-up was completed on July 21, 2020. The trial was stopped early following publication of a related study before reaching the planned sample size of 350 patients.

Interventions: Twenty mg of dexamethasone intravenously daily for 5 days, 10 mg of dexamethasone daily for 5 days or until ICU discharge, plus standard care (n =151) or standard care alone (n = 148).

Main Outcomes And Measures: The primary outcome was ventilator-free days during the first 28 days, defined as being alive and free from mechanical ventilation. Secondary outcomes were all-cause mortality at 28 days, clinical status of patients at day 15 using a 6-point ordinal scale (ranging from 1, not hospitalized to 6, death), ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, and Sequential Organ Failure Assessment (SOFA) scores (range, 0-24, with higher scores indicating greater organ dysfunction) at 48 hours, 72 hours, and 7 days.

Results: A total of 299 patients (mean [SD] age, 61 [14] years; 37% women) were enrolled and all completed follow-up. Patients randomized to the dexamethasone group had a mean 6.6 ventilator-free days (95% CI, 5.0-8.2) during the first 28 days vs 4.0 ventilator-free days (95% CI, 2.9-5.4) in the standard care group (difference, 2.26; 95% CI, 0.2-4.38; P = .04). At 7 days, patients in the dexamethasone group had a mean SOFA score of 6.1 (95% CI, 5.5-6.7) vs 7.5 (95% CI, 6.9-8.1) in the standard care group (difference, -1.16; 95% CI, -1.94 to -0.38; P = .004). There was no significant difference in the prespecified secondary outcomes of all-cause mortality at 28 days, ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, or the 6-point ordinal scale at 15 days. Thirty-three patients (21.9%) in the dexamethasone group vs 43 (29.1%) in the standard care group experienced secondary infections, 47 (31.1%) vs 42 (28.3%) needed insulin for glucose control, and 5 (3.3%) vs 9 (6.1%) experienced other serious adverse events.

Conclusions And Relevance: Among patients with COVID-19 and moderate or severe ARDS, use of intravenous dexamethasone plus standard care compared with standard care alone resulted in a statistically significant increase in the number of ventilator-free days (days alive and free of mechanical ventilation) over 28 days.

Trial Registration: ClinicalTrials.gov Identifier: NCT04327401.
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http://dx.doi.org/10.1001/jama.2020.17021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489411PMC
October 2020

Trends in clinical profiles, organ support use and outcomes of patients with cancer requiring unplanned ICU admission: a multicenter cohort study.

Intensive Care Med 2021 Feb 7;47(2):170-179. Epub 2020 Aug 7.

Department of Critical Care and Graduate Program in Translational Medicine, D'Or Institute for Research and Education, Rio de Janeiro, Brazil.

Purpose: To describe trends in outcomes of cancer patients with unplanned admissions to intensive-care units (ICU) according to cancer type, organ support use, and performance status (PS) over an 8-year period.

Methods: We retrospectively analyzed prospectively collected data from all cancer patients admitted to 92 medical-surgical ICUs from July/2011 to June/2019. We assessed trends in mortality through a Bayesian hierarchical model adjusted for relevant clinical confounders and whether there was a reduction in ICU length-of-stay (LOS) over time using a competing risk model.

Results: 32,096 patients (8.7% of all ICU admissions; solid tumors, 90%; hematological malignancies, 10%) were studied. Bed/days use by cancer patients increased up to more than 30% during the period. Overall adjusted mortality decreased by 9.2% [95% credible interval (CI), 13.1-5.6%]. The largest reductions in mortality occurred in patients without need for organ support (9.6%) and in those with need for mechanical ventilation (MV) only (11%). Smallest reductions occurred in patients requiring MV, vasopressors, and dialysis (3.9%) simultaneously. Survival gains over time decreased as PS worsened. Lung cancer patients had the lowest decrease in mortality. Each year was associated with a lower sub-hazard for ICU death [SHR 0.93 (0.91-0.94)] and a higher chance of being discharged alive from the ICU earlier [SHR 1.01 (1-1.01)].

Conclusion: Outcomes in critically ill cancer patients improved in the past 8 years, with reductions in both mortality and ICU LOS, suggesting improvements in overall care. However, outcomes remained poor in patients with lung cancer, requiring multiple organ support and compromised PS.
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http://dx.doi.org/10.1007/s00134-020-06184-2DOI Listing
February 2021

Deploying Randomized Controlled Trials during the COVID-19 Pandemic: Reason and Bayesian Designs.

Ann Am Thorac Soc 2020 08;17(8):937-938

Research Institute, HCor, São Paulo, Brazil, and Center for Epidemiological Research, Southern Denmark University, Odense, Denmark.

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http://dx.doi.org/10.1513/AnnalsATS.202005-463EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393781PMC
August 2020

Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19.

N Engl J Med 2020 11 23;383(21):2041-2052. Epub 2020 Jul 23.

From HCor Research Institute (A.B.C., F.G.Z., L.P.D., A.M., L.K.-D., T.L., D.L.M.J., P.G.M.B.S., L.T., E.O.A.-S., L.N.L., I.S.M.), Brazilian Research in Intensive Care Network (A.B.C., F.G.Z., R.G.R., L.C.P.A., V.C.V., T.L., F.G.R.F., A.S.-N., F.R.M.), Hospital Sírio Libanês Research and Education Institute (L.C.P.A.), BP-A Beneficência Portuguesa de São Paulo (V.C.V.), International Research Center, Hospital Alemão Oswaldo Cruz (A.A.), Brazilian Clinical Research Institute (P.G.M.B.S., R.D.L.), Hospital São Camilo (A.T.S.), Hospital Moriah (L.S.E.), Academic Research Organization of Hospital Israelita Albert Einstein (R.H.M.F., O.B.), Hospital Israelita Albert Einstein (L.S.E., A.J.P., A.S.-N.), Hospital Sepaco (F.G.R.F.), and Hospital Santa Paula (O.C.E.G.), São Paulo, Hospital Moinhos de Vento, Porto Alegre (R.G.R., M.F.), Hospital Naval Marcílio Dias, Rio de Janeiro (V.C.S.D.), Hospital Giselda Trigueiro, Natal (E.P.M.), Instituto Tacchini de Pesquisa em Saúde, Hospital Tacchini, Bento Gonçalves (N.A.G.), Hospital Bruno Born, Lajeado (F.F.C.), Hospital Baia Sul, Florianópolis (I.S.M.), Hospital Regional Hans Dieter Schmidt, Joinville (C.R.H.F.); Angiocor Blumenau, Blumenau (A.P.M.K.), and EMS Pharma, Hortolândia (R.B.A., M.F.B.O.) - all in Brazil; and Duke Clinical Research Institute, Duke University Medical Center, Durham, NC (R.D.L.).

Background: Hydroxychloroquine and azithromycin have been used to treat patients with coronavirus disease 2019 (Covid-19). However, evidence on the safety and efficacy of these therapies is limited.

Methods: We conducted a multicenter, randomized, open-label, three-group, controlled trial involving hospitalized patients with suspected or confirmed Covid-19 who were receiving either no supplemental oxygen or a maximum of 4 liters per minute of supplemental oxygen. Patients were randomly assigned in a 1:1:1 ratio to receive standard care, standard care plus hydroxychloroquine at a dose of 400 mg twice daily, or standard care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for 7 days. The primary outcome was clinical status at 15 days as assessed with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition) in the modified intention-to-treat population (patients with a confirmed diagnosis of Covid-19). Safety was also assessed.

Results: A total of 667 patients underwent randomization; 504 patients had confirmed Covid-19 and were included in the modified intention-to-treat analysis. As compared with standard care, the proportional odds of having a higher score on the seven-point ordinal scale at 15 days was not affected by either hydroxychloroquine alone (odds ratio, 1.21; 95% confidence interval [CI], 0.69 to 2.11; P = 1.00) or hydroxychloroquine plus azithromycin (odds ratio, 0.99; 95% CI, 0.57 to 1.73; P = 1.00). Prolongation of the corrected QT interval and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent.

Conclusions: Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care. (Funded by the Coalition Covid-19 Brazil and EMS Pharma; ClinicalTrials.gov number, NCT04322123.).
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http://dx.doi.org/10.1056/NEJMoa2019014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397242PMC
November 2020

Structure and process associated with the efficiency of intensive care units in low-resource settings: An analysis of the CHECKLIST-ICU trial database.

J Crit Care 2020 10 18;59:118-123. Epub 2020 Jun 18.

D'Or Institute for Research and Education (IDOR), Rio de Janeiro, RJ, Brazil; Brazilian Research in Intensive Care Network (BRICNet), Brazil; Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, RJ, Brazil. Electronic address:

Purpose: Characteristics of structure and process impact ICU performance and the outcomes of critically ill patients. We sought to identify organizational characteristics associated with efficient ICUs in low-resource settings.

Materials And Methods: This is a secondary analysis of a multicenter cluster-randomized clinical trial in Brazil (CHECKLIST-ICU). Efficient units were defined by standardized mortality ratio (SMR) and standardized resource use (SRU) lower than the overall medians and non-efficient otherwise. We used a regularized logistic regression model to evaluate associations between organizational factors and efficiency.

Results: From 118 ICUs (13,635 patients), 47 units were considered efficient and 71 non-efficient. Efficient units presented lower incidence rates (median[IQR]) of central line-associated bloodstream infections (4.95[0.00-22.0] vs 6.29[0.00-25.6], p = .04), utilization rates of mechanical ventilation (0.41[0.07-0.73] vs 0.58[0.19-0.82], p < .001), central venous catheter (0.67[0.15-0.98] vs 0.78[0.33-0.98], p = .04), and indwelling urinary catheter (0.62[0.22-0.95] vs 0.76[0.32-0.98], p < .01) than non-efficient units. The reported active surveillance of ventilator-associated pneumonia (OR = 1.72; 95%CI, 1.16-2.57) and utilization of central venous catheters (OR = 1.94; 95%CI, 1.32-2.94) were associated with efficient ICUs.

Conclusions: In low-resource settings, active surveillance of nosocomial infections and the utilization of invasive devices were associated with efficiency, supporting the management and evaluation of performance indicators as a starting point for improvement in ICU.
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http://dx.doi.org/10.1016/j.jcrc.2020.06.008DOI Listing
October 2020

Customization and external validation of the Simplified Mortality Score for the Intensive Care Unit (SMS-ICU) in Brazilian critically ill patients.

J Crit Care 2020 10 29;59:94-100. Epub 2020 May 29.

Graduate Program in Translational Medicine, Department of Critical Care, D'Or Institute for Research and Education, Rio de Janeiro, Brazil.

Purpose: To customize and externally validate the recently proposed Simplified Mortality Score for the ICU (SMS-ICU, a simple score for 90-day mortality that has no need for ancillary testing results) for in-hospital mortality and to compare its performance to SAPS 3.

Material And Methods: We used data from two distinct large cohorts of adult Brazilian patients with unplanned ICU admissions to perform a first-level customization (43,017 patients admitted to 78 ICUs) of the original SMS-ICU score for in-hospital mortality and, sequentially, externally validate it (313,365 patients admitted to 99 ICUs). Performance of SMS-ICU was assessed through measurements of discrimination and calibration and compared with SAPS 3.

Results: In the validation cohort, median SMS-ICU was 13 (IQR 8-16) points and median SAPS 3 was 44 (IQR 36-51). Discrimination of SMS-ICU was good (AUC 0.817; 95% CI 0.814-0.819) but slightly lower than of SAPS 3 (AUC 0.845; 95% CI 0.843-0.848;). The customized SMS-ICU predictions were comparable to SAPS 3 in terms of calibration.

Conclusion: In this external validation of the SMS-ICU in a large Brazilian cohort, we observed good discrimination of SMS-ICU and acceptable calibration after first-level customization. SMS-ICU can be used as a measure of illness severity for acutely admitted ICU patients in clinical studies.
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http://dx.doi.org/10.1016/j.jcrc.2020.05.016DOI Listing
October 2020

Bundle of Coated Devices to Reduce Nosocomial Infections in the Intensive Care Unit. CRITIC Pilot Randomized Controlled Trial.

Ann Am Thorac Soc 2020 10;17(10):1257-1263

Instituto de Pesquisa, Hospital do Coração, São Paulo, Brazil.

Coated devices may reduce biofilm formation and reduce the occurrence of device-related infections in critically ill patients. A bundle of coated devices (an endotracheal tube [ETT], central venous catheter [CVC], and urinary catheter [UC]) simultaneously inserted may optimize benefits of coated devices in patients with the most severe illness. To assess the feasibility of a randomized controlled trial on simultaneous insertion of gold/silver/palladium-coated devices versus uncoated devices in severely ill patients, which required sequential insertion of all three devices (an ETT, CVC, and UC) for support in the intensive care unit (ICU). This was a multicenter randomized controlled pilot trial. Patients who required simultaneous insertion of an ETT, CVC, and UC were randomized to treatment with coated versus uncoated devices, which were used as necessary for up to 28 days. The primary endpoint was feasibility, defined as the trial being able to enroll enough participants to have the sample size necessary for its secondary primary endpoint (estimating sepsis incidence in this population) in less than 1 year and for estimating the number of admitted patients who require simultaneous insertion of all three devices. Secondary endpoints included the incidence of sepsis and device-associated infections (ventilator-associated pneumonia, catheter-related bloodstream infection, and catheter-related urinary-tract infection) within each group as well as the number of days alive and free of antibiotics during the ICU stay. All events were adjudicated. One hundred and three patients (48 in the coated-device group and 55 in the uncoated-device group) were included in the per-protocol analysis. The inclusion period was 8 months. There were 13 septic events in each group (26 in total), with an approximate incidence of sepsis of 32.3 (95% credible interval [CrI], 22.4-44.9) per 100 patient-days. The overall incidences of ventilator-associated pneumonia, catheter-related urinary-tract infection, and catheter-related bloodstream infection were 15.2 (95% CrI, 7.8-26.4), 6.3 (95% CrI, 2.4-13.7), and 7.9 (95% CrI, 3.6-15.1) per 1,000 patient-days, and incidence rates were not statistically different between groups. Patients in the coated-device group had more days alive and free of antibiotics in the ICU (28.97 d vs. 19.62 d per 100 patient-days; mean ratio, 1.48; 95% CrI, 1.16-1.89). Use of a bundle of coated devices as the initial treatment for of severely ill patients is feasible. Coated devices may be associated with more days alive and free of antibiotics.Clinical trial registered with www.clinicaltrials.gov (NCT03868241).
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http://dx.doi.org/10.1513/AnnalsATS.202003-206OCDOI Listing
October 2020

Contributing factors to the plasma albumin level at diagnosis of hematological malignancy.

Hosp Pract (1995) 2020 Oct 2;48(4):223-229. Epub 2020 Jun 2.

Department of Haematology, Odense University Hospital, and the Research Unit of Haematology, Department of Clinical Research, University of Southern Denmark , Odense C, Denmark.

Objectives: Many factors contribute to the plasma albumin (PA) level. We aimed to quantify different factors' relative contribution to the PA level when diagnosing hematological malignancy (HM).

Methods: The study was a population-based registry study including patients with HM in a Danish region. We applied multivariate linear regression analyses with C-reactive protein (CRP), WHO performance score (WHO-PS), age, sex, comorbidity, and HM type as exposures and the PA level on the day of the HM diagnosis (DX) as the outcome. The relative contribution of each exposure was determined as a percentage of the models' coefficient of determination (R).

Results: In total, 2528 patients with HM had PA measured on DX. In the model comprising all exposures, CRP contributed with 65.8% to the R of 0.389 whereas 3 variables (CRP, WHO-PS, HM type) together contributed with 96.1%. When CRP was excluded from the model, R declined to 0.215 and the WHO-PS contributed with 96%. Other models, including separate analyses for each HM type, corroborated these results, except in myeloma patients where WHO-PS contributed with 61.1% to the R of 0.234.

Conclusion: The inflammation biomarker CRP was the main predictor of the PA level on DX. The WHO-PS also contributed to the PA level on DX whereas the remaining factors (HM type, age, sex, and comorbidity) were of much less importance.
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http://dx.doi.org/10.1080/21548331.2020.1770511DOI Listing
October 2020

Hydroxyethyl Starch for Fluid Replacement Therapy in High-Risk Surgical Patients: Context and Caution.

JAMA 2020 01;323(3):217-218

Research Institute, HCor (Hospital do Coração), São Paulo, Brazil.

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http://dx.doi.org/10.1001/jama.2019.20141DOI Listing
January 2020

Heterogeneity of treatment effect of prophylactic pantoprazole in adult ICU patients: a post hoc analysis of the SUP-ICU trial.

Intensive Care Med 2020 04 14;46(4):717-726. Epub 2020 Jan 14.

Department of Intensive Care 4131, Copenhagen University Hospital - Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.

Purpose: The Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial compared prophylactic pantoprazole with placebo in 3291 adult ICU patients at risk of clinically important gastrointestinal bleeding (CIB). As a predefined subgroup analysis suggested increased 90-day mortality with pantoprazole in the most severely ill patients, we aimed to further explore whether heterogenous treatment effects (HTE) were present.

Methods: We assessed HTE in subgroups defined according to illness severity by SAPS II quintiles and the total number of risk factors for CIB using Bayesian hierarchical models, and on the continuous scale using Bayesian logistic regression models with interactions. Estimates were presented as posterior probability distributions of odds ratios (ORs), probabilities of different effect sizes, and marginal effects plots.

Results: We observed potential HTE for 90-day mortality according to illness severity (median subgroup OR range 0.90-1.09) with higher risk in the most severely ill, but not with different numbers of risk factors (1.00-1.02). We observed potential HTE of pantoprazole for clinically important events (0.86-1.18) and infectious adverse events (0.88-1.27) with higher risk in patients with greater illness severity and in those with more risk factors for CIB. Pantoprazole substantially and consistently reduced the risk of CIB with no indications of HTE (0.53-0.63).

Conclusions: In this post hoc analysis of the SUP-ICU trial, we found indications of HTE with increased risks of serious adverse events in patients with greater illness severity or more risk factors for CIB allocated to pantoprazole. These findings are hypothesis-generating and warrant further prospective investigation. CLINICALTRIALS.

Gov Identifier: NCT02467621.
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http://dx.doi.org/10.1007/s00134-019-05903-8DOI Listing
April 2020

The association of cardiovascular failure with treatment for ventilator-associated lower respiratory tract infection.

Intensive Care Med 2019 12 16;45(12):1753-1762. Epub 2019 Oct 16.

Critical Care Department, Hospital Universitario Joan XXIII, URV/IISPV/CIBERES, Tarragona, Spain.

Purpose: Ventilator associated-lower respiratory tract infections (VA-LRTIs), either ventilator-associated pneumonia (VAP) or tracheobronchitis (VAT), accounts for most nosocomial infections in intensive care units (ICU) including. Our aim was to determine if appropriate antibiotic treatment in patients with VA-LRTI will effectively reduce mortality in patients who had cardiovascular failure.

Methods: This was a pre-planned subanalysis of a large prospective cohort of mechanically ventilated patients for at least 48 h in eight countries in two continents. Patients with a modified Sequential Organ Failure Assessment (mSOFA) cardiovascular score of 4 (at the time of VA-LRTI diagnosis and needed be present for at least 12 h) were defined as having cardiovascular failure.

Results: VA-LRTI occurred in 689 (23.2%) out of 2960 patients and 174 (25.3%) developed cardiovascular failure. Patients with cardiovascular failure had significantly higher ICU mortality than those without (58% vs. 26.8%; p < 0.001; OR 3.7; 95% CI 2.6-5.4). A propensity score analysis found that the presence of inappropriate antibiotic treatment was an independent risk factor for ICU mortality in patients without cardiovascular failure, but not in those with cardiovascular failure. When the propensity score analysis was conducted in patients with VA-LRTI, the use of appropriate antibiotic treatment conferred a survival benefit for patients without cardiovascular failure who had only VAP.

Conclusions: Patients with VA-LRTI and cardiovascular failure did not show an association to a higher ICU survival with appropriate antibiotic treatment. Additionally, we found that in patients without cardiovascular failure, appropriate antibiotic treatment conferred a survival benefit for patients only with VAP.

Trial Registry: ClinicalTrials.gov, number NCT01791530.
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http://dx.doi.org/10.1007/s00134-019-05797-6DOI Listing
December 2019
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