Publications by authors named "Djillali Annane"

360 Publications

Corticosteroids for treating sepsis in children and adults.

Emergencias 2021 Abr;33(2):137-138

Division of Critical Care, Department of Medicine, McMaster University, Hamilton, Canadá.

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March 2021

Association between prophylactic angiotensin-converting enzyme inhibitors and overall survival in Duchenne muscular dystrophy-analysis of registry data.

Eur Heart J 2021 Mar 22. Epub 2021 Mar 22.

APHP, Cochin Hospital, Cardiology Department, FILNEMUS, Paris-Descartes, Sorbonne Paris Cité University, Paris, France.

Aims: To estimate the effect of prophylactic angiotensin-converting enzyme inhibitors (ACEi) on survival in Duchenne muscular dystrophy (DMD).

Methods And Results: We analysed the data from the French multicentre DMD Heart Registry (ClinicalTrials.gov: NCT03443115). We estimated the association between the prophylactic prescription of ACEi and event-free survival in 668 patients aged 8 to 13 years, with normal left ventricular function, using (i) a Cox model with intervention as a time-dependent covariate, (ii) a propensity-based analysis comparing ACEi treatment vs. no treatment, and (iii) a set of sensitivity analyses. The study outcomes were overall survival and hospitalizations for heart failure (HF) or acute respiratory failure. Among the 668 patients included in the DMD Heart Registry, 576 (mean age 6.1 ± 2.8 years) were eligible for this study, of whom 390 were treated with ACEi prophylactically. Death occurred in 53 patients (13.5%) who were and 60 patients (32.3%) who were not treated prophylactically with ACEi, respectively. In a Cox model with intervention as a time-dependent variable, the hazard ratio (HR) associated with ACEi treatment was 0.49 [95% confidence interval (CI) 0.34-0.72] and 0.47 (95% CI 0.31-0.17) for overall mortality after adjustment for baseline variables. In the propensity-based analysis, 278 patients were included in the treatment group and 834 in the control group, with 18.5% and 30.4% 12-year estimated probability of death, respectively. ACEi were associated with a lower risk of death (HR 0.39; 95% CI 0.17-0.92) and hospitalization for HF (HR 0.16; 95% CI 0.04-0.62). All other sensitivity analyses yielded similar results.

Conclusion: Prophylactic ACEi treatment in DMD was associated with a significantly higher overall survival and lower rates of hospitalization for HF.
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http://dx.doi.org/10.1093/eurheartj/ehab054DOI Listing
March 2021

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

N Engl J Med 2021 Feb 25. 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.).
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http://dx.doi.org/10.1056/NEJMoa2100433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953461PMC
February 2021

Impact of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Hypertensive Patients with COVID-19 (COVIDECA Study).

Am J Cardiol 2021 Feb 20. Epub 2021 Feb 20.

Department of Cardiology, Ambroise Paré Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Centre de référence des cardiomyopathies et des troubles du rythme cardiaque héréditaires ou rares, Université de Versailles-Saint Quentin (UVSQ), Boulogne-Billancourt, France; INSERM U-1018, CESP, Epidémiologie clinique, UVSQ, Université de Paris Saclay, Villejuif, France. Electronic address:

Effect of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) among hypertensive patients with coronavirus disease 2019 (COVID-19) is debated. The aim of the COVIDECA study was to assess the outcome of ACEI and ARB among hypertensive patients presenting with COVID-19. We reviewed from the Assistance Publique-Hôpitaux de Paris healthcare record database all patients presenting with confirmed COVID-19 by RT-PCR. We compared hypertensive patients with ACEI or ARB and hypertensive patients without ACEI and ARB. Among 13,521 patients presenting with confirmed COVID-19 by RT-PCR, 2,981 hypertensive patients (mean age: 78.4 ± 13.6 years, 1,464 men) were included. Outcome of hypertensive patients was similar whatever the use or non-use of ACEI or ARB: admission in ICU (13.4% in patients with ACEI or ARB versus 14.8% in patients without ACEI/ARB, p = 0.35), need of mechanical ventilation (5.5% in patients with ACEI or ARB vs 6.3% in patients without ACEI/ARB, p = 0.45), in-hospital mortality (27.5% in patients with ACEI or ARB vs 26.7% in patients without ACEI/ARB, p = 0.70). In conclusion, the use of ACEI and ARB remains safe and can be maintained in hypertensive patients presenting with COVID-19.
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http://dx.doi.org/10.1016/j.amjcard.2021.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895710PMC
February 2021

Impact of Coronavirus Disease 2019 in a French Cohort of Myasthenia Gravis.

Neurology 2021 Feb 10. Epub 2021 Feb 10.

Referral Center for Neuromuscular Diseases and ALS, Timone University Hospital, Aix-Marseille University, Marseille, France.

Objective: To describe the clinical characteristics and outcomes of COVID-19 among patients with MG and identify factors associated with COVID-19 severity in MG patients.

Methods: The CO-MY-COVID registry was a multicenter, retrospective, observational cohort study conducted in neuromuscular referral centers and general hospitals of the FILNEMUS network (between March 1, 2020, and June 8, 2020), including MG patients with a confirmed or highly-suspected diagnosis of COVID-19. COVID-19 was diagnosed based on a polymerase chain reaction (PCR) test from a nasopharyngeal swab and/or SARS-CoV-2 serology, thoracic computed tomography (CT-scan), or typical symptoms. The main outcome was COVID-19 severity based on location of treatment/management (home, hospitalized in a medical unit, or in an intensive care unit). We collected information on demographic variables, general history, and risk factors for severe COVID-19. Multivariate ordinal regression models were used to identify factors associated with severe COVID-19 outcomes.

Results: Among 3,558 MG patients registered in the French database for rare disorders, 34 (0.96%) had COVID-19. The mean age at COVID-19 onset was 55.0 ±19.9 years (mean MG duration: 8.5 ± 8.5 years). By the end of the study period, 28 patients recovered from COVID-19, 1 remained affected, and 5 died. Only high Myasthenia Gravis Foundation of America (MGFA) class (≥IV) before COVID-19 was associated with severe COVID-19 (p=0.004); factors that were not associated included gender, MG duration, and medium MGFA classes (≤IIIb). The type of MG treatment had no independent effect on COVID-19 severity.

Conclusions: This registry-based cohort study shows that COVID-19 had a limited effect on most patients, and immunosuppressive medications and corticosteroids used for MG management are not risk factors for poorer outcomes. However, the risk of severe COVID-19 is elevated in patients with high MGFA classes [odds ratio: 102.6 (4.4; 2,371.9)]. These results are important for establishing evidence-based guidelines for the management of MG patients during the COVID-19 pandemic.
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http://dx.doi.org/10.1212/WNL.0000000000011669DOI Listing
February 2021

Current use of inotropes in circulatory shock.

Ann Intensive Care 2021 Jan 29;11(1):21. Epub 2021 Jan 29.

Medical Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Paris-Saclay University Hospitals, Bicêtre hospital, Le Kremlin-Bicêtre, France.

Background: Treatment decisions on critically ill patients with circulatory shock lack consensus. In an international survey, we aimed to evaluate the indications, current practice, and therapeutic goals of inotrope therapy in the treatment of patients with circulatory shock.

Methods: From November 2016 to April 2017, an anonymous web-based survey on the use of cardiovascular drugs was accessible to members of the European Society of Intensive Care Medicine (ESICM). A total of 14 questions focused on the profile of respondents, the triggering factors, first-line choice, dosing, timing, targets, additional treatment strategy, and suggested effect of inotropes. In addition, a group of 42 international ESICM experts was asked to formulate recommendations for the use of inotropes based on 11 questions.

Results: A total of 839 physicians from 82 countries responded. Dobutamine was the first-line inotrope in critically ill patients with acute heart failure for 84% of respondents. Two-thirds of respondents (66%) stated to use inotropes when there were persistent clinical signs of hypoperfusion or persistent hyperlactatemia despite a supposed adequate use of fluids and vasopressors, with (44%) or without (22%) the context of low left ventricular ejection fraction. Nearly half (44%) of respondents stated an adequate cardiac output as target for inotropic treatment. The experts agreed on 11 strong recommendations, all of which were based on excellent (> 90%) or good (81-90%) agreement. Recommendations include the indications for inotropes (septic and cardiogenic shock), the choice of drugs (dobutamine, not dopamine), the triggers (low cardiac output and clinical signs of hypoperfusion) and targets (adequate cardiac output) and stopping criteria (adverse effects and clinical improvement).

Conclusion: Inotrope use in critically ill patients is quite heterogeneous as self-reported by individual caregivers. Eleven strong recommendations on the indications, choice, triggers and targets for the use of inotropes are given by international experts. Future studies should focus on consistent indications for inotrope use and implementation into a guideline for circulatory shock that encompasses individualized targets and outcomes.
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http://dx.doi.org/10.1186/s13613-021-00806-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846624PMC
January 2021

Early abolition of cough reflex predicts mortality in deeply sedated brain-injured patients.

PeerJ 2020 26;8:e10326. Epub 2020 Nov 26.

Laboratory of Human Histopathology and Animal Models, Institut Pasteur, Paris, France.

Background: Deep sedation may hamper the detection of neurological deterioration in brain-injured patients. Impaired brainstem reflexes within the first 24 h of deep sedation are associated with increased mortality in non-brain-injured patients. Our objective was to confirm this association in brain-injured patients.

Methods: This was an observational prospective multicenter cohort study involving four neuro-intensive care units. We included acute brain-injured patients requiring deep sedation, defined by a Richmond Assessment Sedation Scale (RASS) < -3. Neurological assessment was performed at day 1 and included pupillary diameter, pupillary light, corneal and cough reflexes, and grimace and motor response to noxious stimuli. Pre-sedation Glasgow Coma Scale (GCS) and Simplified Acute Physiology Score (SAPS-II) were collected, as well as the cause of death in the Intensive Care Unit (ICU).

Results: A total of 137 brain-injured patients were recruited, including 70 (51%) traumatic brain-injured patients, 40 (29%) vascular (subarachnoid hemorrhage or intracerebral hemorrhage). Thirty patients (22%) died in the ICU. At day 1, the corneal (OR 2.69, = 0.034) and cough reflexes (OR 5.12, = 0.0003) were more frequently abolished in patients that died in the ICU. In a multivariate analysis, abolished cough reflex was associated with ICU mortality after adjustment to pre-sedation GCS, SAPS-II, RASS (OR: 5.19, 95% CI [1.92-14.1], = 0.001) or dose of sedatives (OR: 8.89, 95% CI [2.64-30.0], = 0.0004).

Conclusion: Early (day 1) cough reflex abolition is an independent predictor of mortality in deeply sedated brain-injured patients. Abolished cough reflex likely reflects a brainstem dysfunction that might result from the combination of primary and secondary neuro-inflammatory cerebral insults revealed and/or worsened by sedation.
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http://dx.doi.org/10.7717/peerj.10326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700733PMC
November 2020

Assessment of Machine Learning to Estimate the Individual Treatment Effect of Corticosteroids in Septic Shock.

JAMA Netw Open 2020 12 1;3(12):e2029050. Epub 2020 Dec 1.

Saclay and Paris Seine Nord Endeavour to Personalize Interventions for Sepsis, Rapid Recognition of Corticosteroid Resistant or Sensitive Sepsis, Department of Intensive Care, Hôpital Raymond Poincaré Groupes Hospitalo-Universitaires Assistance Publique-Hôpitaux de Paris, Université Paris Saclay, Laboratory of Infection and Inflammation, School of Medicine Simone Veil, University Versailles Saint Quentin, University Paris Saclay, Institut national de la santé et de la recherche médicale, Garches, France.

Importance: The survival benefit of corticosteroids in septic shock remains uncertain.

Objective: To estimate the individual treatment effect (ITE) of corticosteroids in adults with septic shock in intensive care units using machine learning and to evaluate the net benefit of corticosteroids when the decision to treat is based on the individual estimated absolute treatment effect.

Design, Setting, And Participants: This cohort study used individual patient data from 4 trials on steroid supplementation in adults with septic shock as a training cohort to model the ITE using an ensemble machine learning approach. Data from a double-blinded, placebo-controlled randomized clinical trial comparing hydrocortisone with placebo were used for external validation. Data analysis was conducted from September 2019 to February 2020.

Exposures: Intravenous hydrocortisone 50 mg dose every 6 hours for 5 to 7 days with or without enteral 50 μg of fludrocortisone daily for 7 days. The control was either the placebo or usual care.

Main Outcomes And Measures: All-cause 90-day mortality.

Results: A total of 2548 participants were included in the development cohort, with median (interquartile range [IQR]) age of 66 (55-76) years and 1656 (65.0%) men. The median (IQR) Simplified Acute Physiology Score (SAPS II) was 55 [42-69], and median (IQR) Sepsis-related Organ Failure Assessment score on day 1 was 11 (9-13). The crude pooled relative risk (RR) of death at 90 days was 0.89 (95% CI, 0.83 to 0.96) in favor of corticosteroids. According to the optimal individual model, the estimated median absolute risk reduction was of 2.90% (95% CI, 2.79% to 3.01%). In the external validation cohort of 75 patients, the area under the curve of the optimal individual model was 0.77 (95% CI, 0.59 to 0.92). For any number willing to treat (NWT; defined as the acceptable number of people to treat to avoid 1 additional outcome considering the risk of harm associated with the treatment) less than 25, the net benefit of treating all patients vs treating nobody was negative. When the NWT was 25, the net benefit was 0.01 for the treat all with hydrocortisone strategy, -0.01 for treat all with hydrocortisone and fludrocortisone strategy, 0.06 for the treat by SAPS II strategy, and 0.31 for the treat by optimal individual model strategy. The net benefit of the SAPS II and the optimal individual model treatment strategies converged to zero for a smaller number willing to treat, but the individual model was consistently superior than model based on the SAPS II score.

Conclusions And Relevance: These findings suggest that an individualized treatment strategy to decide which patient with septic shock to treat with corticosteroids yielded positive net benefit regardless of potential corticosteroid-associated side effects.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.29050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729430PMC
December 2020

Metabolomics of exhaled breath in critically ill COVID-19 patients: A pilot study.

EBioMedicine 2021 Jan 4;63:103154. Epub 2020 Dec 4.

Université Paris-Saclay, UVSQ, INSERM, Infection et inflammation, Montigny le Bretonneux, France (S.G.D., P.M., N.H., D.A.); Intensive Care Unit, Raymond Poincaré Hospital, Assistance Publique-Hôpitaux de Paris, Garches, France (P.M., G.S., S.C., N.H., J.F., D.A.); FHU SEPSIS (Saclay and Paris Seine Nord Endeavour to PerSonalize Interventions for Sepsis) (S.G.D., H.S., E.N., L-J.C., P.D., E.T., D.A.).

Background: Early diagnosis of coronavirus disease 2019 (COVID-19) is of the utmost importance but remains challenging. The objective of the current study was to characterize exhaled breath from mechanically ventilated adults with COVID-19.

Methods: In this prospective observational study, we used real-time, online, proton transfer reaction time-of-flight mass spectrometry to perform a metabolomic analysis of expired air from adults undergoing invasive mechanical ventilation in the intensive care unit due to severe COVID-19 or non-COVID-19 acute respiratory distress syndrome (ARDS).

Findings: Between March 25 and June 25, 2020, we included 40 patients with ARDS, of whom 28 had proven COVID-19. In a multivariate analysis, we identified a characteristic breathprint for COVID-19. We could differentiate between COVID-19 and non-COVID-19 ARDS with accuracy of 93% (sensitivity: 90%, specificity: 94%, area under the receiver operating characteristic curve: 0·94-0·98, after cross-validation). The four most prominent volatile compounds in COVID-19 patients were methylpent-2-enal, 2,4-octadiene 1-chloroheptane, and nonanal.

Interpretation: The real-time, non-invasive detection of methylpent-2-enal, 2,4-octadiene 1-chloroheptane, and nonanal in exhaled breath may identify ARDS patients with COVID-19.

Funding: The study was funded by Agence Nationale de la Recherche (SoftwAiR, ANR-18-CE45-0017 and RHU4 RECORDS, Programme d'Investissements d'Avenir, ANR-18-RHUS-0004), Région Île de France (SESAME 2016), and Fondation Foch.
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http://dx.doi.org/10.1016/j.ebiom.2020.103154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714658PMC
January 2021

Effects of low-dose hydrocortisone and hydrocortisone plus fludrocortisone in adults with septic shock: a protocol for a systematic review and meta-analysis of individual participant data.

BMJ Open 2020 12 2;10(12):e040931. Epub 2020 Dec 2.

The George Institute for Global Health, Newtown, New South Wales, Australia.

Introduction: The benefits and risks of low-dose hydrocortisone in patients with septic shock have been investigated in numerous randomised controlled trials and trial-level meta-analyses. Yet, the routine use of this treatment remains controversial. To overcome the limitations of previous meta-analyses inherent to the use of aggregate data, we will perform an individual patient data meta-analysis (IPDMA) on the effect of hydrocortisone with or without fludrocortisone compared with placebo or usual care on 90-day mortality and other outcomes in patients with septic shock.

Methods And Analysis: To assess the benefits and risks of hydrocortisone, with or without fludrocortisone for adults with septic shock, we will search major electronic databases from inception to September 2020 (Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and Latin American Caribbean Health Sciences Literature), complimented by a search for unpublished trials. The primary analysis will compare hydrocortisone with or without fludrocortisone to placebo or no treatment in adult patients with septic shock. Secondary analyses will compare hydrocortisone to placebo (or usual care), hydrocortisone plus fludrocortisone to placebo (or usual care), and hydrocortisone versus hydrocortisone plus fludrocortisone. The primary outcome will be all cause mortality at 90 days. We will conduct both one-stage IPDMA using mixed-effect models and machine learning with targeted maximum likelihood analyses. We will assess the risk of bias related to unshared data and related to the quality of individual trial.

Ethics And Dissemination: This IPDMA will use existing data from completed randomised clinical trials and will comply with the ethical and regulatory requirements regarding data sharing for each of the component trials. The findings of this study will be submitted for publication in a peer-review journal with straightforward policy for open access.

Prospero Registration Number: CRD42017062198.
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http://dx.doi.org/10.1136/bmjopen-2020-040931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713227PMC
December 2020

Eculizumab as an emergency treatment for adult patients with severe COVID-19 in the intensive care unit: A proof-of-concept study.

EClinicalMedicine 2020 Nov 5;28:100590. Epub 2020 Nov 5.

Department of Intensive Care, Hôpital Raymond Poincaré (APHP), Laboratory of Infection & Inflammation - U1173, School of Medicine Simone Veil, University Versailles Saint Quentin - University Paris Saclay, INSERM, Garches, France.

Background: Complement pathway inhibition may provide benefit for severe acute respiratory illnesses caused by viral infections such as COVID-19. We present results from a nonrandomized proof-of-concept study of complement C5 inhibitor eculizumab for treatment of severe COVID-19.

Methods: All patients ( = 80) with confirmed SARS-CoV-2 infection and severe COVID-19 admitted to our intensive care unit between March 10 and May 5, 2020 were included. Forty-five patients were treated with standard care and 35 with standard care plus eculizumab through expanded-access emergency treatment. The prespecified primary outcome was day-15 survival. Clinical laboratory values and biomarkers, complement levels, and treatment-emergent serious adverse events (TESAEs) were also assessed.

Findings: At day 15, estimated survival was 82.9% (95% CI: 70.4%‒95.3%) with eculizumab and 62.2% (48.1%‒76.4%) without eculizumab (log-rank test,  = 0.04). Patients treated with eculizumab experienced a significantly more rapid decrease in lactate, blood urea nitrogen, total and conjugated bilirubin levels and a significantly more rapid increase in platelet count, prothrombin time, and in the ratio of arterial oxygen tension over fraction of inspired oxygen versus patients treated without eculizumab. Eculizumab-associated changes in complement levels, laboratory values, and biomarkers were consistent with terminal complement inhibition, reduced hypoxia, and decreased inflammation. TESAEs of special interest occurring in >5% of patients treated with/without eculizumab were ventilator-associated pneumonia (51%/24%), bacteremia (11%/2%), gastroduodenal hemorrhage (14%/16%), and hemolysis (3%/18%).

Interpretation: Findings from this proof-of-concept study suggest eculizumab may improve survival and reduce hypoxia in patients with severe COVID-19. Randomized studies evaluating the efficacy and safety of this treatment approach are needed.

Funding: Programme d'Investissements d'Avenir: ANR-18-RHUS60004.
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http://dx.doi.org/10.1016/j.eclinm.2020.100590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644240PMC
November 2020

Myorelaxants in ARDS patients.

Intensive Care Med 2020 Dec 7;46(12):2357-2372. Epub 2020 Nov 7.

Assistance Publique - Hôpitaux de Marseille, Hôpital Nord, Médecine Intensive Réanimation, 13015, Marseille, France.

Neuromuscular blocking agents (NMBAs) inhibit patient-initiated active breath and the risk of high tidal volumes and consequent high transpulmonary pressure swings, and minimize patient/ ventilator asynchrony in acute respiratory distress syndrome (ARDS). Minimization of volutrauma and ventilator-induced lung injury (VILI) results in a lower incidence of barotrauma, improved oxygenation and a decrease in circulating proinflammatory markers. Recent randomized clinical trials did not reveal harmful muscular effects during a short course of NMBAs. The use of NMBAs should be considered during the early phase of severe ARDS for patients to facilitate lung protective ventilation or prone positioning only after optimising mechanical ventilation and sedation. The use of NMBAs should be integrated in a global strategy including the reduction of tidal volume, the rational use of PEEP, prone positioning and the use of a ventilatory mode allowing spontaneous ventilation as soon as possible. Partial neuromuscular blockade should be evaluated in future trials.
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http://dx.doi.org/10.1007/s00134-020-06297-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648542PMC
December 2020

Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS.

Intensive Care Med 2020 Dec 4;46(12):2284-2296. Epub 2020 Nov 4.

Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA.

Current literature addressing the pharmacological principles guiding glucocorticoid (GC) administration in ARDS is scant. This paucity of information may have led to the heterogeneity of treatment protocols and misinterpretation of available findings. GCs are agonist compounds that bind to the GC receptor (GR) producing a pharmacological response. Clinical efficacy depends on the magnitude and duration of exposure to GR. We updated the meta-analysis of randomized trials investigating GC treatment in ARDS, focusing on treatment protocols and response. We synthesized the current literature on the role of the GR in GC therapy including genomic and non-genomic effects, and integrated current clinical pharmacology knowledge of various GCs, including hydrocortisone, methylprednisolone and dexamethasone. This review addresses the role dosage, timing of initiation, mode of administration, duration, and tapering play in achieving optimal response to GC therapy in ARDS. Based on RCTs' findings, GC plasma concentration-time profiles, and pharmacodynamic studies, optimal results are most likely achievable with early intervention, an initial bolus dose to achieve close to maximal GRα saturation, followed by a continuous infusion to maintain high levels of response throughout the treatment period. In addition, patients receiving similar GC doses may experience substantial between-patient variability in plasma concentrations affecting clinical response. GC should be dose-adjusted and administered for a duration targeting clinical and laboratory improvement, followed by dose-tapering to achieve gradual recovery of the suppressed hypothalamic-pituitary-adrenal (HPA) axis. These findings have practical clinical relevance. Future RCTs should consider these pharmacological principles in the study design and interpretation of findings.
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http://dx.doi.org/10.1007/s00134-020-06289-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641258PMC
December 2020

Corticosteroid treatment in severe COVID-19 patients with acute respiratory distress syndrome.

J Clin Invest 2020 12;130(12):6417-6428

Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

BACKGROUNDCorticosteroids are widely used in patients with COVID 19, although their benefit-to-risk ratio remains controversial.METHODSPatients with severe COVID-19-related acute respiratory distress syndrome (ARDS) were included from December 29, 2019 to March 16, 2020 in 5 tertiary Chinese hospitals. Cox proportional hazards and competing risks analyses were conducted to analyze the impact of corticosteroids on mortality and SARS-CoV-2 RNA clearance, respectively. We performed a propensity score (PS) matching analysis to control confounding factors.RESULTSOf 774 eligible patients, 409 patients received corticosteroids, with a median time from hospitalization to starting corticosteroids of 1.0 day (IQR 0.0-3.0 days) . As compared with usual care, treatment with corticosteroids was associated with increased rate of myocardial (15.6% vs. 10.4%, P = 0.041) and liver injury (18.3% vs. 9.9%, P = 0.001), of shock (22.0% vs. 12.6%, P < 0.001), of need for mechanical ventilation (38.1% vs. 19.5%, P < 0.001), and increased rate of 28-day all-cause mortality (44.3% vs. 31.0%, P < 0.001). After PS matching, corticosteroid therapy was associated with 28-day mortality (adjusted HR 1.46, 95% CI 1.01-2.13, P = 0.045). High dose (>200 mg) and early initiation (≤3 days from hospitalization) of corticosteroid therapy were associated with a higher 28-day mortality rate. Corticosteroid use was also associated with a delay in SARS-CoV-2 coronavirus RNA clearance in the competing risk analysis (subhazard ratio 1.59, 95% CI 1.17-2.15, P = 0.003).CONCLUSIONAdministration of corticosteroids in severe COVID-19-related ARDS is associated with increased 28-day mortality and delayed SARS-CoV-2 coronavirus RNA clearance after adjustment for time-varying confounders.FUNDINGNone.
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http://dx.doi.org/10.1172/JCI140617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685724PMC
December 2020

Sepsis in the critically ill patient: current and emerging management strategies.

Expert Rev Anti Infect Ther 2020 Nov 23:1-13. Epub 2020 Nov 23.

Department of Intensive Care, Raymond Poincaré Hospital, GHU APHP Université Paris Saclay , Garches, France.

: Sepsis, a dysregulated host response to infection, is a major cause of morbidity and mortality worldwide. Early identification and evidence-based treatment of sepsis are associated with improved outcomes. : This narrative review was undertaken following a PubMed search for English language reports published before July 2020 using the terms 'sepsis,' 'septic shock,' 'fluids,' 'fluid therapy,' 'albumin,' 'corticosteroids,' 'vasopressor.' Emerging management strategies were identified following a search of the ClinicalTrails.gov database using the term 'sepsis.' Additional reports were identified by examining the reference lists of selected articles and based on personnel knowledge of the field of sepsis. : The core treatment of sepsis relies on source control, early antibiotics, and organ support. The main emerging strategies focus on immunomodulation, artificial intelligence, and on multi-omics approaches for a personalized therapy.
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http://dx.doi.org/10.1080/14787210.2021.1846522DOI Listing
November 2020

Population pharmacokinetics of lopinavir/ritonavir in Covid-19 patients.

Eur J Clin Pharmacol 2021 Mar 13;77(3):389-397. Epub 2020 Oct 13.

APHM, INSERM, IRD, SESSTIM, Hop Sainte Marguerite, Service de Pharmacologie clinique, CAP-TV, Aix-Marseille University, Marseille, France.

Objective: To develop a population pharmacokinetic model for lopinavir boosted by ritonavir in coronavirus disease 2019 (Covid-19) patients.

Methods: Concentrations of lopinavir/ritonavir were assayed by an accredited LC-MS/MS method. The population pharmacokinetics of lopinavir was described using non-linear mixed-effects modeling (NONMEM version 7.4). After determination of the base model that better described the data set, the influence of covariates (age, body weight, height, body mass index (BMI), gender, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), C reactive protein (CRP), and trough ritonavir concentrations) was tested on the model.

Results: From 13 hospitalized patients (4 females, 9 males, age = 64 ± 16 years), 70 lopinavir/ritonavir plasma concentrations were available for analysis. The data were best described by a one-compartment model with a first-order input (KA). Among the covariates tested on the PK parameters, only the ritonavir trough concentrations had a significant effect on CL/F and improved the fit. Model-based simulations with the final parameter estimates under a regimen lopinavir/ritonavir 400/100 mg b.i.d. showed a high variability with median concentration between 20 and 30 mg/L (C/C) and the 90% prediction intervals within the range 1-100 mg/L.

Conclusion: According to the estimated 50% effective concentration of lopinavir against SARS-CoV-2 virus in Vero E6 cells (16.7 mg/L), our model showed that at steady state, a dose of 400 mg b.i.d. led to 40% of patients below the minimum effective concentration while a dose of 1200 mg b.i.d. will reduce this proportion to 22%.
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http://dx.doi.org/10.1007/s00228-020-03020-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552959PMC
March 2021

Early mechanical ventilation in patients with Guillain-Barré syndrome at high risk of respiratory failure: a randomized trial.

Ann Intensive Care 2020 Sep 30;10(1):128. Epub 2020 Sep 30.

Medical Intensive Care Unit, Raymond Poincaré Teaching Hospital, 104 boulevard Raymond Poincaré, 92380, Garches, France.

Introduction: About 30% of patients with Guillain-Barré syndrome become ventilator dependent, of whom roughly 75% develop pneumonia. This trial aimed at assessing the impact of early mechanical ventilation (EMV) on pneumonia occurrence in GBS patients. We hypothesize that EMV will reduce the incidence of pneumonia.

Methods: This was a single centre, open-label, randomized controlled trial performed on two parallel groups. 50 intensive care unit adults admitted for Guillain-Barré syndrome and at risk for acute respiratory failure. Patients were randomized to early mechanical ventilation via face-mask or endotracheal intubation owing to the presence or absence of impaired swallowing (experimental arm), or to conventional care (control arm). The primary outcome was the incidence of pneumonia up to intensive care unit discharge (or 90 days, pending of which occurred first).

Findings: Twenty-five patients were randomized in each group. There was no significant difference between groups for the incidence of pneumonia (10/25 (40%) vs 9/25 (36%), P = 1). There was no significant difference between groups for the time to onset of pneumonia (P = 0.50, Gray test). During follow-up, there were 16/25 (64%) mechanically ventilated patients in the control group, and 25/25 (100%) in the experimental arm (P < 000·1). The time on ventilator was non-significantly shorter in the experimental arm (14 [7; 29] versus 21.5 [17.3; 35.5], P = 0.10). There were no significant differences between groups for length of hospital stay, neurological scores, the proportion of patients who needed tracheostomy, in-hospital death, or any serious adverse events.

Conclusions: In the present study including adults with Guillain-Barré syndrome at high risk of respiratory failure, we did not observe a prevention of pneumonia with early mechanical ventilation.

Trial Registration: ClinicalTrials.gov under the number NCT00167622. Registered 9 September 2005, https://clinicaltrials.gov/ct2/show/NCT00167622?cond=Guillain-Barre+Syndrome&cntry=FR&draw=2&rank=1.
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http://dx.doi.org/10.1186/s13613-020-00742-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525233PMC
September 2020

Association of kidney function with effectiveness of procalcitonin-guided antibiotic treatment: a patient-level meta-analysis from randomized controlled trials.

Clin Chem Lab Med 2020 Sep 28;59(2):441-453. Epub 2020 Sep 28.

Medical University Department, Kantonsspital Aarau, Aarau, Switzerland.

Objectives: Patients with impaired kidney function have a significantly slower decrease of procalcitonin (PCT) levels during infection. Our aim was to study PCT-guided antibiotic stewardship and clinical outcomes in patients with impairments of kidney function as assessed by creatinine levels measured upon hospital admission.

Methods: We pooled and analyzed individual data from 15 randomized controlled trials who were randomly assigned to receive antibiotic therapy based on a PCT-algorithms or based on standard of care. We stratified patients on the initial glomerular filtration rate (GFR, ml/min/1.73 m2) in three groups (GFR >90 [chronic kidney disease; CKD 1], GFR 15-89 [CKD 2-4] and GFR<15 [CKD 5]). The main efficacy and safety endpoints were duration of antibiotic treatment and 30-day mortality.

Results: Mean duration of antibiotic treatment was significantly shorter in PCT-guided (n=2,492) compared to control patients (n=2,510) (9.5-7.6 days; adjusted difference in days -2.01 [95% CI, -2.45 to -1.58]). CKD 5 patients had overall longer treatment durations, but a 2.5-day reduction in treatment duration was still found in patients receiving in PCT-guided care (11.3 vs. 8.6 days [95% CI -3.59 to -1.40]). There were 397 deaths in 2,492 PCT-group patients (15.9%) compared to 460 deaths in 2,510 control patients (18.3%) (adjusted odds ratio, 0.88 [95% CI 0.78 to 0.98)]. Effects of PCT-guidance on antibiotic treatment duration and mortality were similar in subgroups stratified by infection type and clinical setting (p interaction >0.05).

Conclusions: This individual patient data meta-analysis confirms that the use of PCT in patients with impaired kidney function, as assessed by admission creatinine levels, is associated with shorter antibiotic courses and lower mortality rates.
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http://dx.doi.org/10.1515/cclm-2020-0931DOI Listing
September 2020

Aspirin for the primary prevention of sepsis.

Authors:
Djillali Annane

Lancet Respir Med 2021 02 17;9(2):121-122. Epub 2020 Sep 17.

Service de médecine intensive réanimation, Hôpital Raymond Poincaré, Laboratory of infection and inflammation U1173 Université Paris Saclay-UVSQ, INSERM, RHU-RECORDS, FHU-SEPSIS, 92380 Garches, France. Electronic address:

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http://dx.doi.org/10.1016/S2213-2600(20)30410-0DOI Listing
February 2021

Teaching NeuroImages: Cytotoxic lesions of the corpus callosum in encephalopathic patients with COVID-19.

Neurology 2020 12 16;95(22):1021-1022. Epub 2020 Sep 16.

From the Department of Radiology (M.E., C.D., R.-Y.C.), APHP, Hôpitaux R. Poincaré-A Paré, DMU Smart Imaging, GH Université Paris-Saclay; Department of Neuroradiology (M.E.), Université Paris-Descartes-Sorbonne-Paris-Cité, IMABRAIN-INSERM-UMR1266, DHU-Neurovasc, Centre Hospitalier Sainte-Anne, Paris; Department of Internal Medecine (A.L.G., M.M.), APHP, Hôpitaux R. Poincaré-A Paré, DMU Smart Imaging, GH Université Paris-Saclay; Department of Imaging (M.L., C.L.), Hôpital Privé de Parly II, Le Chesnay; and FHU SEPSIS (Saclay and Paris Seine Nord Endeavour to PerSonalize Interventions for Sepsis) (D.O., D.A.), RHU RECORDS (Rapid rEcognition of CORticosteroiD resistant or sensitive Sepsis), Department of Intensive Care, Hôpital Raymond Poincaré (GHU APHP Université Paris Saclay), Laboratory of Infection & Inflammation-U1173, School of Medicine Simone Veil, University Versailles Saint Quentin-University Paris Saclay, INSERM, Garches, France.

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http://dx.doi.org/10.1212/WNL.0000000000010880DOI Listing
December 2020

Association Between Anxiety and New Organ Failure, Independently of Critical Illness Severity and Respiratory Status: A Prospective Multicentric Cohort Study.

Crit Care Med 2020 10;48(10):1471-1479

1General Intensive Care Unit, APHP, Raymond Poincaré Hospital, University of Versailles Saint-Quentin en Yvelines, Garches, France. 2Perception and Memory Laboratory, Neuroscience Department, Institut Pasteur, Paris, France. 3General Intensive Care Unit, Sud-Essonne Hospital, Étampes, France. 4Centre d'Epidémiologie Clinique, Assistance Publique Hôpitaux de Paris, Hôtel Dieu Hospital, University Paris Descartes, Paris, France. 5General Intensive Care Unit, Institut Gustave Roussy Hospital, Villejuif, France. 6Department of Psychiatry, Sainte-Anne Hospital, Paris-Descartes University, Paris, France. 7Centre Hospitalier Sainte-Anne, Service Hospitalo-Universitaire, Faculté de Médecine Paris Descartes, Paris, France. 8Université Paris Descartes, Inserm Centre de Psychiatrie et Neurosciences, Laboratoire de Physiopathologie des maladies Psychiatriques, Paris, France. 9CNRS, GDR 3557, Institut de Psychiatrie, Paris, France. 10Department of Neuropathology, Sainte-Anne Hospital, Université de Paris, Paris, France. 11Laboratory of Critical Care, National Institute of Infectious Disease Evandro Chagas, Oswaldo Cruz Foundation, Ministry of Health, Rio de Janeiro, Brazil. 12D'Or Institute of Research and Education (IDOR), Rio de Janeiro, Brazil.

Objectives: Anxiety results from the anticipation of a threat and might be associated with poor outcome in the critically ill. This study aims at showing that anxiety at admission in critically ill patients is associated with new organ failure over the first 7 days of ICU hospitalization independently of baseline organ failure at admission.

Design: Prospective multicenter cohort study.

Setting: Three mixed ICU from April 2014 to December 2017.

Patients: Coma-, delirium-, and invasive mechanical ventilation-free patients admitted to the ICU were included.

Interventions: None.

Measurements And Main Results: "State anxiety" was assessed using the state component of the State-Trait Anxiety Inventory State. Severity of illness was measured using Simplified Acute Physiology Score II and Sequential Organ Failure Assessment scores. Primary endpoint was a composite of occurrence of death or new organ failure in the first 7 days after admission. Three hundred ninety-one patients were included; 159 of 391 women (40.7%); median age 63 years (49-74 yr); median Simplified Acute Physiology Score II 28 (19-37). Two hundred three out of 391 patients (51.9%) reported moderate to severe anxiety (State-Trait Anxiety Inventory State ≥ 40). One hundred two out of 391 patients (26.1%) developed a new organ failure. After adjustment to Simplified Acute Physiology Score II and Sequential Organ Failure Assessment, State-Trait Anxiety Inventory State greater than or equal to 40 was associated with the primary endpoint (odds ratio, 1.94; 95% CI, 1.18-3.18; p = 0.009) and respiratory failure. In post hoc analysis, State-Trait Anxiety Inventory State greater than or equal to 40 was associated with new organ failure independently and notably of respiratory status at admission (dyspnea-Visual Analogic Scale and PaCO2 ≥ 45 mm Hg).

Conclusions: Moderate to severe anxiety at ICU admission is associated with early occurrence of new organ failure in critically ill patients, independently of respiratory status and severity of critical illness. The causality link could be addressed in an interventional trial.
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http://dx.doi.org/10.1097/CCM.0000000000004495DOI Listing
October 2020

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Authors:
Derek C Angus Lennie Derde Farah Al-Beidh Djillali Annane Yaseen Arabi Abigail Beane Wilma van Bentum-Puijk Lindsay Berry Zahra Bhimani Marc Bonten Charlotte Bradbury Frank Brunkhorst Meredith Buxton Adrian Buzgau Allen C Cheng Menno de Jong Michelle Detry Lise Estcourt Mark Fitzgerald Herman Goossens Cameron Green Rashan Haniffa Alisa M Higgins Christopher Horvat Sebastiaan J Hullegie Peter Kruger Francois Lamontagne Patrick R Lawler Kelsey Linstrum Edward Litton Elizabeth Lorenzi John Marshall Daniel McAuley Anna McGlothin Shay McGuinness Bryan McVerry Stephanie Montgomery Paul Mouncey Srinivas Murthy Alistair Nichol Rachael Parke Jane Parker Kathryn Rowan Ashish Sanil Marlene Santos Christina Saunders Christopher Seymour Anne Turner Frank van de Veerdonk Balasubramanian Venkatesh Ryan Zarychanski Scott Berry Roger J Lewis Colin McArthur Steven A Webb Anthony C Gordon Farah Al-Beidh Derek Angus Djillali Annane Yaseen Arabi Wilma van Bentum-Puijk Scott Berry Abigail Beane Zahra Bhimani Marc Bonten Charlotte Bradbury Frank Brunkhorst Meredith Buxton Allen Cheng Menno De Jong Lennie Derde Lise Estcourt Herman Goossens Anthony Gordon Cameron Green Rashan Haniffa Francois Lamontagne Patrick Lawler Edward Litton John Marshall Colin McArthur Daniel McAuley Shay McGuinness Bryan McVerry Stephanie Montgomery Paul Mouncey Srinivas Murthy Alistair Nichol Rachael Parke Kathryn Rowan Christopher Seymour Anne Turner Frank van de Veerdonk Steve Webb Ryan Zarychanski Lewis Campbell Andrew Forbes David Gattas Stephane Heritier Lisa Higgins Peter Kruger Sandra Peake Jeffrey Presneill Ian Seppelt Tony Trapani Paul Young Sean Bagshaw Nick Daneman Niall Ferguson Cheryl Misak Marlene Santos Sebastiaan Hullegie Mathias Pletz Gernot Rohde Kathy Rowan Brian Alexander Kim Basile Timothy Girard Christopher Horvat David Huang Kelsey Linstrum Jennifer Vates Richard Beasley Robert Fowler Steve McGloughlin Susan Morpeth David Paterson Bala Venkatesh Tim Uyeki Kenneth Baillie Eamon Duffy Rob Fowler Thomas Hills Katrina Orr Asad Patanwala Steve Tong Mihai Netea Shilesh Bihari Marc Carrier Dean Fergusson Ewan Goligher Ghady Haidar Beverley Hunt Anand Kumar Mike Laffan Patrick Lawless Sylvain Lother Peter McCallum Saskia Middeldopr Zoe McQuilten Matthew Neal John Pasi Roger Schutgens Simon Stanworth Alexis Turgeon Alexandra Weissman Neill Adhikari Matthew Anstey Emily Brant Angelique de Man Francois Lamonagne Marie-Helene Masse Andrew Udy Donald Arnold Phillipe Begin Richard Charlewood Michael Chasse Mark Coyne Jamie Cooper James Daly Iain Gosbell Heli Harvala-Simmonds Tom Hills Sheila MacLennan David Menon John McDyer Nicole Pridee David Roberts Manu Shankar-Hari Helen Thomas Alan Tinmouth Darrell Triulzi Tim Walsh Erica Wood Carolyn Calfee Cecilia O’Kane Murali Shyamsundar Pratik Sinha Taylor Thompson Ian Young Shailesh Bihari Carol Hodgson John Laffey Danny McAuley Neil Orford Ary Neto Michelle Detry Mark Fitzgerald Roger Lewis Anna McGlothlin Ashish Sanil Christina Saunders Lindsay Berry Elizabeth Lorenzi Eliza Miller Vanessa Singh Claire Zammit Wilma van Bentum Puijk Wietske Bouwman Yara Mangindaan Lorraine Parker Svenja Peters Ilse Rietveld Kik Raymakers Radhika Ganpat Nicole Brillinger Rene Markgraf Kate Ainscough Kathy Brickell Aisha Anjum Janis-Best Lane Alvin Richards-Belle Michelle Saull Daisy Wiley Julian Bion Jason Connor Simon Gates Victoria Manax Tom van der Poll John Reynolds Marloes van Beurden Evelien Effelaar Joost Schotsman Craig Boyd Cain Harland Audrey Shearer Jess Wren Giles Clermont William Garrard Kyle Kalchthaler Andrew King Daniel Ricketts Salim Malakoutis Oscar Marroquin Edvin Music Kevin Quinn Heidi Cate Karen Pearson Joanne Collins Jane Hanson Penny Williams Shane Jackson Adeeba Asghar Sarah Dyas Mihaela Sutu Sheenagh Murphy Dawn Williamson Nhlanhla Mguni Alison Potter David Porter Jayne Goodwin Clare Rook Susie Harrison Hannah Williams Hilary Campbell Kaatje Lomme James Williamson Jonathan Sheffield Willian van’t Hoff Phobe McCracken Meredith Young Jasmin Board Emma Mart Cameron Knott Julie Smith Catherine Boschert Julia Affleck Mahesh Ramanan Ramsy D’Souza Kelsey Pateman Arif Shakih Winston Cheung Mark Kol Helen Wong Asim Shah Atul Wagh Joanne Simpson Graeme Duke Peter Chan Brittney Cartner Stephanie Hunter Russell Laver Tapaswi Shrestha Adrian Regli Annamaria Pellicano James McCullough Mandy Tallott Nikhil Kumar Rakshit Panwar Gail Brinkerhoff Cassandra Koppen Federica Cazzola Matthew Brain Sarah Mineall Roy Fischer Vishwanath Biradar Natalie Soar Hayden White Kristen Estensen Lynette Morrison Joanne Smith Melanie Cooper Monash Health Yahya Shehabi Wisam Al-Bassam Amanda Hulley Christina Whitehead Julie Lowrey Rebecca Gresha James Walsham Jason Meyer Meg Harward Ellen Venz Patricia Williams Catherine Kurenda Kirsy Smith Margaret Smith Rebecca Garcia Deborah Barge Deborah Byrne Kathleen Byrne Alana Driscoll Louise Fortune Pierre Janin Elizabeth Yarad Naomi Hammond Frances Bass Angela Ashelford Sharon Waterson Steve Wedd Robert McNamara Heidi Buhr Jennifer Coles Sacha Schweikert Bradley Wibrow Rashmi Rauniyar Erina Myers Ed Fysh Ashlish Dawda Bhaumik Mevavala Ed Litton Janet Ferrier Priya Nair Hergen Buscher Claire Reynolds John Santamaria Leanne Barbazza Jennifer Homes Roger Smith Lauren Murray Jane Brailsford Loretta Forbes Teena Maguire Vasanth Mariappa Judith Smith Scott Simpson Matthew Maiden Allsion Bone Michelle Horton Tania Salerno Martin Sterba Wenli Geng Pieter Depuydt Jan De Waele Liesbet De Bus Jan Fierens Stephanie Bracke Brenda Reeve William Dechert Michaël Chassé François Martin Carrier Dounia Boumahni Fatna Benettaib Ali Ghamraoui David Bellemare Ève Cloutier Charles Francoeur François Lamontagne Frédérick D’Aragon Elaine Carbonneau Julie Leblond Gloria Vazquez-Grande Nicole Marten Maggie Wilson Martin Albert Karim Serri Alexandros Cavayas Mathilde Duplaix Virginie Williams Bram Rochwerg Tim Karachi Simon Oczkowski John Centofanti Tina Millen Erick Duan Jennifer Tsang Lisa Patterson Shane English Irene Watpool Rebecca Porteous Sydney Miezitis Lauralyn McIntyre Laurent Brochard Karen Burns Gyan Sandhu Imrana Khalid Alexandra Binnie Elizabeth Powell Alexandra McMillan Tracy Luk Noah Aref Zdravko Andric Sabina Cviljevic Renata Đimoti Marija Zapalac Gordan Mirković Bruno Baršić Marko Kutleša Viktor Kotarski Ana Vujaklija Brajković Jakša Babel Helena Sever Lidija Dragija Ira Kušan Suvi Vaara Leena Pettilä Jonna Heinonen Anne Kuitunen Sari Karlsson Annukka Vahtera Heikki Kiiski Sanna Ristimäki Amine Azaiz Cyril Charron Mathieu Godement Guillaume Geri Antoine Vieillard-Baron Franck Pourcine Mehran Monchi David Luis Romain Mercier Anne Sagnier Nathalie Verrier Cecile Caplin Shidasp Siami Christelle Aparicio Sarah Vautier Asma Jeblaoui Muriel Fartoukh Laura Courtin Vincent Labbe Cécile Leparco Grégoire Muller Mai-Anh Nay Toufik Kamel Dalila Benzekri Sophie Jacquier Emmanuelle Mercier Delphine Chartier Charlotte Salmon PierreFrançois Dequin Francis Schneider Guillaume Morel Sylvie L’Hotellier Julio Badie Fernando Daniel Berdaguer Sylvain Malfroy Chaouki Mezher Charlotte Bourgoin Bruno Megarbane Sebastian Voicu Nicolas Deye Isabelle Malissin Laetitia Sutterlin Christophe Guitton Cédric Darreau Mickaël Landais Nicolas Chudeau Alain Robert Pierre Moine Nicholas Heming Virginie Maxime Isabelle Bossard Tiphaine Barbarin Nicholier Gwenhael Colin Vanessa Zinzoni Natacham Maquigneau André Finn Gabriele Kreß Uwe Hoff Carl Friedrich Hinrichs Jens Nee Mathias Pletz Stefan Hagel Juliane Ankert Steffi Kolanos Frank Bloos Sirak Petros Bastian Pasieka Kevin Kunz Peter Appelt Bianka Schütze Stefan Kluge Axel Nierhaus Dominik Jarczak Kevin Roedl Dirk Weismann Anna Frey Vivantes Klinikum Neukölln Lorenz Reill Michael Distler Astrid Maselli János Bélteczki István Magyar Ágnes Fazekas Sándor Kovács Viktória Szőke Gábor Szigligeti János Leszkoven Daniel Collins Patrick Breen Stephen Frohlich Ruth Whelan Bairbre McNicholas Michael Scully Siobhan Casey Maeve Kernan Peter Doran Michael O’Dywer Michelle Smyth Leanne Hayes Oscar Hoiting Marco Peters Els Rengers Mirjam Evers Anton Prinssen Jeroen Bosch Ziekenhuis Koen Simons Wim Rozendaal F Polderman P de Jager M Moviat A Paling A Salet Emma Rademaker Anna Linda Peters E de Jonge J Wigbers E Guilder M Butler Keri-Anne Cowdrey Lynette Newby Yan Chen Catherine Simmonds Rachael McConnochie Jay Ritzema Carter Seton Henderson Kym Van Der Heyden Jan Mehrtens Tony Williams Alex Kazemi Rima Song Vivian Lai Dinu Girijadevi Robert Everitt Robert Russell Danielle Hacking Ulrike Buehner Erin Williams Troy Browne Kate Grimwade Jennifer Goodson Owen Keet Owen Callender Robert Martynoga Kara Trask Amelia Butler Livia Schischka Chelsea Young Eden Lesona Shaanti Olatunji Yvonne Robertson Nuno José Teodoro Amaro dos Santos Catorze Tiago Nuno Alfaro de Lima Pereira Lucilia Maria Neves Pessoa Ricardo Manuel Castro Ferreira Joana Margarida Pereira Sousa Bastos Simin Aysel Florescu Delia Stanciu Miahela Florentina Zaharia Alma Gabriela Kosa Daniel Codreanu Yaseen Marabi Eman Al Qasim Mohamned Moneer Hagazy Lolowa Al Swaidan Hatim Arishi Rosana Muñoz-Bermúdez Judith Marin-Corral Anna Salazar Degracia Francisco Parrilla Gómez Maria Isabel Mateo López Jorge Rodriguez Fernandez Sheila Cárcel Fernández Rosario Carmona Flores Rafael León López Carmen de la Fuente Martos Angela Allan Petra Polgarova Neda Farahi Stephen McWilliam Daniel Hawcutt Laura Rad Laura O’Malley Jennifer Whitbread Olivia Kelsall Laura Wild Jessica Thrush Hannah Wood Karen Austin Adrian Donnelly Martin Kelly Sinéad O’Kane Declan McClintock Majella Warnock Paul Johnston Linda Jude Gallagher Clare Mc Goldrick Moyra Mc Master Anna Strzelecka Rajeev Jha Michael Kalogirou Christine Ellis Vinodh Krishnamurthy Vashish Deelchand Jon Silversides Peter McGuigan Kathryn Ward Aisling O’Neill Stephanie Finn Barbara Phillips Dee Mullan Laura Oritz-Ruiz de Gordoa Matthew Thomas Katie Sweet Lisa Grimmer Rebekah Johnson Jez Pinnell Matt Robinson Lisa Gledhill Tracy Wood Matt Morgan Jade Cole Helen Hill Michelle Davies David Antcliffe Maie Templeton Roceld Rojo Phoebe Coghlan Joanna Smee Euan Mackay Jon Cort Amanda Whileman Thomas Spencer Nick Spittle Vidya Kasipandian Amit Patel Suzanne Allibone Roman Mary Genetu Mohamed Ramali Alison Ghosh Peter Bamford Emily London Kathryn Cawley Maria Faulkner Helen Jeffrey Tim Smith Chris Brewer Jane Gregory James Limb Amanda Cowton Julie O’Brien Nikitas Nikitas Colin Wells Liana Lankester Mark Pulletz Patricia Williams Jenny Birch Sophie Wiseman Sarah Horton Ana Alegria Salah Turki Tarek Elsefi Nikki Crisp Louise Allen Iain McCullagh Philip Robinson Carole Hays Maite Babio-Galan Hannah Stevenson Divya Khare Meredith Pinder Selvin Selvamoni Amitha Gopinath Richard Pugh Daniel Menzies Callum Mackay Elizabeth Allan Gwyneth Davies Kathryn Puxty Claire McCue Susanne Cathcart Naomi Hickey Jane Ireland Hakeem Yusuff Graziella Isgro Chris Brightling Michelle Bourne Michelle Craner Malcolm Watters Rachel Prout Louisa Davies Suzannah Pegler Lynsey Kyeremeh Gill Arbane Karen Wilson Linda Gomm Federica Francia Stephen Brett Sonia Sousa Arias Rebecca Elin Hall Joanna Budd Charlotte Small Janine Birch Emma Collins Jeremy Henning Stephen Bonner Keith Hugill Emanuel Cirstea Dean Wilkinson Michal Karlikowski Helen Sutherland Elva Wilhelmsen Jane Woods Julie North Dhinesh Sundaran Laszlo Hollos Susan Coburn Joanne Walsh Margaret Turns Phil Hopkins John Smith Harriet Noble Maria Theresa Depante Emma Clarey Shondipon Laha Mark Verlander Alexandra Williams Abby Huckle Andrew Hall Jill Cooke Caroline Gardiner-Hill Carolyn Maloney Hafiz Qureshi Neil Flint Sarah Nicholson Sara Southin Andrew Nicholson Barbara Borgatta Ian Turner-Bone Amie Reddy Laura Wilding Loku Chamara Warnapura Ronan Agno Sathianathan David Golden Ciaran Hart Jo Jones Jonathan Bannard-Smith Joanne Henry Katie Birchall Fiona Pomeroy Rachael Quayle Arystarch Makowski Beata Misztal Iram Ahmed Thyra KyereDiabour Kevin Naiker Richard Stewart Esther Mwaura Louise Mew Lynn Wren Felicity Willams Richard Innes Patricia Doble Joanne Hutter Charmaine Shovelton Benjamin Plumb Tamas Szakmany Vincent Hamlyn Nancy Hawkins Sarah Lewis Amanda Dell Shameer Gopal Saibal Ganguly Andrew Smallwood Nichola Harris Stella Metherell Juan Martin Lazaro Tabitha Newman Simon Fletcher Jurgens Nortje Deirdre Fottrell-Gould Georgina Randell Mohsin Zaman Einas Elmahi Andrea Jones Kathryn Hall Gary Mills Kim Ryalls Helen Bowler Jas Sall Richard Bourne Zoe Borrill Tracey Duncan Thomas Lamb Joanne Shaw Claire Fox Jeronimo Moreno Cuesta Kugan Xavier Dharam Purohit Munzir Elhassan Dhanalakshmi Bakthavatsalam Matthew Rowland Paula Hutton Archana Bashyal Neil Davidson Clare Hird Manish Chhablani Gunjan Phalod Amy Kirkby Simon Archer Kimberley Netherton Henrik Reschreiter Julie Camsooksai Sarah Patch Sarah Jenkins David Pogson Steve Rose Zoe Daly Lutece Brimfield Helen Claridge Dhruv Parekh Colin Bergin Michelle 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JAMA 2020 10;324(13):1317-1329

Division of Anaesthetics, Pain Medicine and Intensive Care Medicine, Department of Surgery and Cancer, Imperial College London and Imperial College Healthcare NHS Trust, London, United Kingdom.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited.

Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19.

Design, Setting, And Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020.

Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108).

Main Outcomes And Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%).

Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively.

Conclusions And Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.

Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.
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http://dx.doi.org/10.1001/jama.2020.17022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489418PMC
October 2020

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis.

JAMA 2020 10;324(13):1330-1341

Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.

Importance: Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support.

Objective: To estimate the association between administration of corticosteroids compared with usual care or placebo and 28-day all-cause mortality.

Design, Setting, And Participants: Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The trials were conducted in 12 countries from February 26, 2020, to June 9, 2020, and the date of final follow-up was July 6, 2020. Pooled data were aggregated from the individual trials, overall, and in predefined subgroups. 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-effect meta-analysis of overall mortality, with the association between the intervention and mortality quantified using odds ratios (ORs). Random-effects meta-analyses also were conducted (with the Paule-Mandel estimate of heterogeneity and the Hartung-Knapp adjustment) and an inverse variance-weighted fixed-effect analysis using risk ratios.

Exposures: Patients had been randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or to receive usual care or placebo (1025 patients).

Main Outcomes And Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. A secondary outcome was investigator-defined serious adverse events.

Results: A total of 1703 patients (median age, 60 years [interquartile range, 52-68 years]; 488 [29%] women) were included in the analysis. Risk of bias was assessed as "low" for 6 of the 7 mortality results and as "some concerns" in 1 trial because of the randomization method. Five trials reported mortality at 28 days, 1 trial at 21 days, and 1 trial at 30 days. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53-0.82]; P < .001 based on a fixed-effect meta-analysis). There was little inconsistency between the trial results (I2 = 15.6%; P = .31 for heterogeneity) and the summary OR was 0.70 (95% CI, 0.48-1.01; P = .053) based on the random-effects meta-analysis. The fixed-effect summary OR for the association with mortality was 0.64 (95% CI, 0.50-0.82; P < .001) for dexamethasone compared with usual care or placebo (3 trials, 1282 patients, and 527 deaths), the OR was 0.69 (95% CI, 0.43-1.12; P = .13) for hydrocortisone (3 trials, 374 patients, and 94 deaths), and the OR was 0.91 (95% CI, 0.29-2.87; P = .87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Among the 6 trials that reported serious adverse events, 64 events occurred among 354 patients randomized to corticosteroids and 80 events occurred among 342 patients randomized to usual care or placebo.

Conclusions And Relevance: In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.
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http://dx.doi.org/10.1001/jama.2020.17023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489434PMC
October 2020

Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial.

JAMA 2020 10;324(13):1298-1306

INSERM CIC1415, CHU de Tours, Tours, France.

Importance: Coronavirus disease 2019 (COVID-19) is associated with severe lung damage. Corticosteroids are a possible therapeutic option.

Objective: To determine the effect of hydrocortisone on treatment failure on day 21 in critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute respiratory failure.

Design, Setting, And Participants: Multicenter randomized double-blind sequential trial conducted in France, with interim analyses planned every 50 patients. Patients admitted to the intensive care unit (ICU) for COVID-19-related acute respiratory failure were enrolled from March 7 to June 1, 2020, with last follow-up on June 29, 2020. The study intended to enroll 290 patients but was stopped early following the recommendation of the data and safety monitoring board.

Interventions: Patients were randomized to receive low-dose hydrocortisone (n = 76) or placebo (n = 73).

Main Outcomes And Measures: The primary outcome, treatment failure on day 21, was defined as death or persistent dependency on mechanical ventilation or high-flow oxygen therapy. Prespecified secondary outcomes included the need for tracheal intubation (among patients not intubated at baseline); cumulative incidences (until day 21) of prone position sessions, extracorporeal membrane oxygenation, and inhaled nitric oxide; Pao2:Fio2 ratio measured daily from day 1 to day 7, then on days 14 and 21; and the proportion of patients with secondary infections during their ICU stay.

Results: The study was stopped after 149 patients (mean age, 62.2 years; 30.2% women; 81.2% mechanically ventilated) were enrolled. One hundred forty-eight patients (99.3%) completed the study, and there were 69 treatment failure events, including 11 deaths in the hydrocortisone group and 20 deaths in the placebo group. The primary outcome, treatment failure on day 21, occurred in 32 of 76 patients (42.1%) in the hydrocortisone group compared with 37 of 73 (50.7%) in the placebo group (difference of proportions, -8.6% [95.48% CI, -24.9% to 7.7%]; P = .29). Of the 4 prespecified secondary outcomes, none showed a significant difference. No serious adverse events were related to the study treatment.

Conclusions And Relevance: In this study of critically ill patients with COVID-19 and acute respiratory failure, low-dose hydrocortisone, compared with placebo, did not significantly reduce treatment failure (defined as death or persistent respiratory support) at day 21. However, the study was stopped early and likely was underpowered to find a statistically and clinically important difference in the primary outcome.

Trial Registration: ClinicalTrials.gov Identifier: NCT02517489.
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http://dx.doi.org/10.1001/jama.2020.16761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489432PMC
October 2020

Corticosteroid therapy for critically ill patients with COVID-19: A structured summary of a study protocol for a prospective meta-analysis of randomized trials.

Trials 2020 Aug 24;21(1):734. Epub 2020 Aug 24.

Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Canada.

Objectives: Primary objective: To estimate the effect of corticosteroids compared with usual care or placebo on mortality up to 28 days after randomization. Secondary objectives: To examine whether the effect of corticosteroids compared with usual care or placebo on mortality up to 28 days after randomization varies between subgroups related to treatment characteristics, disease severity at the time of randomization, patient characteristics, or risk of bias. To examine the effect of corticosteroids compared with usual care or placebo on serious adverse events.

Study Design: Prospective meta-analysis of randomized controlled trials. Both placebo-controlled and open-label trials are eligible.

Participants: Hospitalised, critically ill patients with suspected or confirmed COVID-19.

Intervention And Comparator: Intervention groups will have received therapeutic doses of a steroid (dexamethasone, hydrocortisone or methylprednisolone) with IV or oral administration immediately after randomization. The comparator groups will have received standard of care or usual care or placebo.

Main Outcome: All-cause mortality up to 28 days after randomization.

Search Methods: Systematic searching of clinicaltrials.gov , EudraCT, the WHO ISRCTN registry, and the Chinese clinical trials registry. Additionally, research and WHO networks will be asked for relevant trials.

Risk Of Bias Assessments: These will be based on the Cochrane RoB 2 tool, and will use structured information provided by the trial investigators on a form designed for this prospective meta-analysis. We will use GRADE to assess the certainty of the evidence.

Statistical Analyses: Trial investigators will provide data on the numbers of participants who did and did not experience each outcome according to intervention group, overall and in specified subgroups. We will conduct fixed-effect (primary analysis) and random-effects (Paule-Mandel estimate of heterogeneity and Hartung-Knapp adjustment) meta-analyses. We will quantify inconsistency in effects between trials using I statistics. Evidence for subgroup effects will be quantified by ratios of odds ratios comparing effects in the subgroups, and corresponding interaction p-values. Comparisons between subgroups defined by trial characteristics will be made using random-effects meta-regression. Comparisons between subgroups defined by patient characteristics will be made by estimating trial-specific ratios of odds ratios comparing intervention effects between subgroups then combining these using random-effects meta-analysis. Steroid interventions will be classified as high or low dose according to whether the dose is greater or less than or equal to 400 mg hydrocortisone per day or equivalent. We will use network meta-analysis methods to make comparisons between the effects of high and low dose steroid interventions (because one trial randomized participants to both low and high dose steroid arms).

Prospero Registration Number: CRD42020197242 FULL PROTOCOL: The full protocol for this prospective meta-analysis is attached as an additional file, accessible from the Trials website (Additional file 1). To expedite dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol for the systematic review.
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http://dx.doi.org/10.1186/s13063-020-04641-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443535PMC
August 2020

Impact of medical care, including use of anti-infective agents, on prognosis of COVID-19 hospitalized patients over time.

Int J Antimicrob Agents 2020 Oct 2;56(4):106129. Epub 2020 Aug 2.

Maladies Infectieuses, Université Paris-Saclay, AP-HP Hôpital Raymond Poincaré, Garches, France.

Introduction: The effect of anti-infective agents in COVID-19 is unclear. The impact of changes in practice on prognosis over time has not been evaluated.

Methods: Single center, retrospective study in adults hospitalized in a medicine ward for COVID-19 from March 5 to April 25 2020. Patient characteristics were compared between two periods (before/after March 19) considering French guidelines. The aim of the study was to evaluate how medical care impacted unfavorable outcome, namely admission to intensive care unit (ICU) and/or death.

Results: A total of 132 patients were admitted: mean age 59.0±16.3 years; mean C-reactive protein (CRP) level 84.0±71.1 mg/L; 46% had a lymphocyte count <1000/mm. Prescribed anti-infective agents were lopinavir-ritonavir (n=12), azithromycin (AZI) (n=28) and AZI combined with hydroxychloroquine (HCQ) (n=52). There was a significant decrease in ICU admission, from 43% to 12%, between the two periods (P<0.0001). Delays until transfer to ICU were similar between periods (P=0.86). Pulmonary computerized tomography (CT)-scans were performed significantly more often with time (from 50% to 90%, P<0.0001), and oxygen-dependency (53% vs 80%, P=0.001) and prescription of AZI±HCQ (from 25% to 76%, P<0.0001) were also greater over time. Multivariate analyses showed a reduction of unfavorable outcome in patients receiving AZI±HCQ (hazard ratio [HR]=0.45, 95% confidence interval [CI: 0.21-0.97], P=0.04), particularly among an identified category of individuals (lymphocyte ≥1000/mm or CRP ≥100 mg/L).

Conclusion: The present study showed a significant decrease in admission to ICU over time, which was probably related to multiple factors, including a better indication of pulmonary CT-scan, oxygen therapy, and a suitable prescription of anti-infective agents.
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http://dx.doi.org/10.1016/j.ijantimicag.2020.106129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396133PMC
October 2020

Randomized Controlled Study Evaluating Efficiency of Low Intensity Transcranial Direct Current Stimulation (tDCS) for Dyspnea Relief in Mechanically Ventilated COVID-19 Patients in ICU: The tDCS-DYSP-COVID Protocol.

Front Med (Lausanne) 2020 26;7:372. Epub 2020 Jun 26.

General Intensive Care Unit-Assistance Publique Hôpitaux de Paris, Raymond Poincaré Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Inserm UMR 1173, Infection and Inflammation (2I), University of Versailles Saint-Quentin en Yvelines (UVSQ), Paris-Saclay University, Paris, France.

The severe respiratory distress syndrome linked to the new coronavirus disease (COVID-19) includes unbearable dyspneic suffering which contributes to the deterioration of the prognosis of patients in intensive care unit (ICU). Patients are put on mechanical ventilation to reduce respiratory suffering and preserve life. Despite this mechanical ventilation, most patients continue to suffer from dyspnea. Dyspnea is a major source of suffering in intensive care and one of the main factors that affect the prognosis of patients. The development of innovative methods for its management, especially non-drug management is more than necessary. In recent years, numerous studies have shown that transcranial direct current stimulation (tDCS) could modulate the perception of acute or chronic pain. In the other hand, it has been shown that the brain zones activated during pain and dyspnea are close and/or superimposed, suggesting that brain structures involved in the integration of aversive emotional component are shared by these two complex sensory experiences. Therefore, it can be hypothesized that stimulation by tDCS with regard to the areas which, in the case of pain have activated one or more of these brain structures, may also have an effect on dyspnea. In addition, our team recently demonstrated that the application of tDCS on the primary cortical motor area can modulate the excitability of the respiratory neurological pathways. Indeed, tDCS in anodal or cathodal modality reduced the excitability of the diaphragmatic cortico-spinal pathways in healthy subjects. We therefore hypothesized that tDCS could relieve dyspnea in COVID-19 patients under mechanical ventilation in ICU. This study was designed to evaluate effects of two modalities of tDCS (anodal and cathodal) vs. placebo, on the relief of dyspnea in COVID-19 patients requiring mechanical ventilation in ICU. This protocol is derived from the tDCS-DYSP-REA project registered on ClinicalTrials.gov NCT03640455. It will however be registered under its own NCT number.
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http://dx.doi.org/10.3389/fmed.2020.00372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332773PMC
June 2020

[From sepsis to septic shock].

Rev Infirm 2020 Apr - May;69(260-261):16-18

Service de médecine intensive réanimation, hôpital Raymond-Poincaré, GHU, AP-HP université Paris-Saclay, 104, boulevard Raymond-Poincaré, 92380 Garches, France; UFR Simone-Veil Santé, université de Versailles - Saint-Quentin-en-Yvelines, université Paris-Saclay, 2, avenue de la Source-de-la-Bièvre, 78180 Montigny-le-Bretonneux, France. Electronic address:

Septic shock, defined as the combination of sepsis, a requirement for catecholamines to maintain systolic blood pressure above 65 mmHg and a serum lactate level above 2 mmol/L despite adequate volume resuscitation is a life-threatening condition. The Quick Sepsis-related Organ Failure Assessment (qSOFA), which can be used by all nurses with a high-risk patient presenting with infection, enables the patient to be transferred rapidly to specialist care units.
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http://dx.doi.org/10.1016/S1293-8505(20)30144-5DOI Listing
July 2020