Publications by authors named "Nicholas Heming"

41 Publications

Valproic Acid as an Adjuvant Treatment for Generalized Convulsive Status Epilepticus in Adults Admitted to Intensive Care Units: Protocol for a Double-Blind, Multicenter Randomized Controlled Trial.

JMIR Res Protoc 2021 Feb 24;10(2):e22511. Epub 2021 Feb 24.

Centre Hospitalier Poissy Saint Germain en Laye, Poissy, France.

Background: Generalized convulsive status epilepticus (GCSE) is a frequent medical emergency. GCSE treatment focuses on the administration of benzodiazepines followed by a second-line antiepileptic drug (AED). Despite this stepwise strategy, GCSE is not controlled in one-quarter of patients and is associated with protracted hospitalization, high mortality, and long-term disability. Valproic acid (VPA) is an AED with good tolerability and neuroprotective properties.

Objective: This study aims to demonstrate that administration of VPA as an adjuvant for first- and second-line treatment in GCSE can improve outcomes.

Methods: A multicenter, double-blind, randomized controlled trial was conducted, comparing VPA with a placebo in adults admitted to intensive care units (ICUs) for GCSE in France. GCSE was diagnosed by specifically trained ICU physicians according to standard criteria. All patients received standard of care, including a benzodiazepine and a second-line AED (not VPA), at the discretion of the treating medical team. In the intervention arm, VPA was administered intravenously at a loading dose of 30 mg/kg over 15 minutes, followed by a continuous infusion of 1 mg/kg/hour over the next 12 hours. In the placebo group, an identical intravenous administration of 0.9% saline was used. The primary outcome was the proportion of patients discharged alive from the hospital by day 15. Secondary outcomes were frequency of refractory and super refractory GCSE, ICU-related morbidity, adverse events related to VPA, and cognitive dysfunction at 3 months. Statistical analyses will be performed according to the intent-to-treat principle.

Results: The first patient was randomized on February 18, 2013, and the last patient was randomized on July 7, 2018. Of 248 planned patients, 98.7% (245/248) were enrolled across 20 ICUs. At present, data management is still ongoing, and all parties involved in the trial remain blinded.

Conclusions: The Valproic Acid as an Adjuvant Treatment for Generalized Convulsive Status Epilepticus (VALSE) trial will evaluate whether the use of VPA as an adjuvant for first- and second-line treatment in GCSE improves outcomes.

Trial Registration: ClinicalTrials.gov NCT01791868; https://clinicaltrials.gov/ct2/show/NCT01791868.

International Registered Report Identifier (irrid): DERR1-10.2196/22511.
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http://dx.doi.org/10.2196/22511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946594PMC
February 2021

Prevalence of pressure injuries among critically ill patients and factors associated with their occurrence in the intensive care unit: The PRESSURE study.

Aust Crit Care 2021 Jan 19. Epub 2021 Jan 19.

CERC, SRLF, France. Electronic address:

Background: The prevalence of pressure injuries (PIs) in critically ill patients has been extensively studied, but there is uncertainty regarding the risk factors. The main objective of this study was to describe the prevalence of PIs in critically ill patients. Secondary objectives were to describe PI, use of preventive measures for PI, and factors associated with occurrence of PI in the intensive care unit (ICU).

Material And Methods: This was a 1-day point-prevalence study performed on a weekday in June 2017 in ICUs in France. On the same day, we noted the presence or absence of PI in all hospitalised patients of the participating ICUs, data on the ICUs, and the characteristics of patients and of PI.

Results: Eighty-six participating ICUs allowed the inclusion of 1228 patients. The prevalence of PI on the study day was 18.7% (95% confidence interval: 16.6-21.0). PIs acquired in the ICU were observed in 12.5% (95% confidence interval: 10.6-14.3) of critically ill patients on the study day. The most frequent locations of PI were the sacrum (57.4%), heel (35.2%), and face (8.7%). Severe forms of PI accounted for 40.8% of all PIs. Antiulcer mattresses were used in 91.5% of the patients, and active and/or passive mobilisation was performed for all the patients. Multiple logistic regression analysis identified longer length of stay in the ICU, a higher Simplified Acute Physiology Score, higher body weight, motor neurological disorder, high-dose steroids, and absence of oral nutrition on the study day as factors independently associated with occurrence of PI in the ICU.

Conclusion: This large point-prevalence study shows that PIs are found in about one of five critically ill patients despite extensive use of devices for preventing PI. Acquisition of PI in the ICU is strongly related to the patient's severity of illness on admission to the ICU and length of stay in the ICU.
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http://dx.doi.org/10.1016/j.aucc.2020.12.001DOI Listing
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

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

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

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

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 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 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Ruzena Uddin Alastair Somerville Kate Colette Tatham Shaman Jhanji Ethel Black Arnold Dela Rosa Ryan Howle Redmond Tully Andrew Drummond Joy Dearden Jennifer Philbin Sheila Munt Alain Vuylsteke Charles Chan Saji Victor Ramprasad Matsa Minerva Gellamucho Ben Creagh-Brown Joe Tooley Laura Montague Fiona De Beaux Laetitia Bullman Ian Kersiake Carrie Demetriou Sarah Mitchard Lidia Ramos Katie White Phil Donnison Maggie Johns Ruth Casey Lehentha Mattocks Sarah Salisbury Paul Dark Andrew Claxton Danielle McLachlan Kathryn Slevin Stephanie Lee Jonathan Hulme Sibet Joseph Fiona Kinney Ho Jan Senya Aneta Oborska Abdul Kayani Bernard Hadebe Rajalakshmi Orath Prabakaran Lesley Nichols Matt Thomas Ruth Worner Beverley Faulkner Emma Gendall Kati Hayes Colin Hamilton-Davies Carmen Chan Celina Mfuko Hakam Abbass Vineela Mandadapu Susannah Leaver Daniel Forton Kamal Patel Elankumaran Paramasivam Matthew Powell Richard Gould Elizabeth Wilby Clare Howcroft Dorota Banach Ziortza Fernández de Pinedo Artaraz Leilani Cabreros Ian White Maria Croft Nicky Holland Rita Pereira Ahmed Zaki David Johnson Matthew Jackson Hywel Garrard Vera Juhaz Alistair Roy Anthony Rostron Lindsey Woods Sarah Cornell Suresh Pillai Rachel Harford Tabitha Rees Helen Ivatt Ajay Sundara Raman Miriam Davey Kelvin Lee Russell Barber Manish Chablani Farooq Brohi Vijay Jagannathan Michele Clark Sarah Purvis Bill Wetherill Ahilanandan Dushianthan Rebecca Cusack Kim de Courcy-Golder Simon Smith Susan Jackson Ben Attwood Penny Parsons Valerie Page Xiao Bei Zhao Deepali Oza Jonathan Rhodes Tom Anderson Sheila Morris Charlotte Xia Le Tai Amy Thomas Alexandra Keen Stephen Digby Nicholas Cowley Laura Wild David Southern Harsha Reddy Andy Campbell Claire Watkins Sara Smuts Omar Touma Nicky Barnes Peter Alexander Tim Felton Susan Ferguson Katharine Sellers Joanne Bradley-Potts David Yates Isobel Birkinshaw Kay Kell Nicola Marshall Lisa Carr-Knott Charlotte Summers

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

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

Thiamine status and lactate concentration in sepsis: A prospective observational study.

Medicine (Baltimore) 2020 Feb;99(7):e18894

General Intensive Care Unit, Raymond Poincaré Hospital, Garches, France and U1173 Lab Inflammation & Infection, University of Versailles SQY-Paris Saclay - INSERM, Montigny-Le-Bretonneux.

Thiamine is an essential co-factor for aerobic metabolism. Both thiamine deficiency and sepsis may be associated with hyperlactatemia and hypotension. We assessed the relationship between thiamine compounds, lactate concentrations and clinical outcomes in septic patients.We undertook a prospective observational single-center study. Erythrocyte levels of total thiamine, free thiamine, thiamine mono, di and triphosphate (TMP, TDP, and TTP respectively), the erythrocyte transketolase activity (ETKA) and the effect of thiamine diphosphate on ETKA were measured in septic patients by high performance liquid chromatography and correlated with arterial lactate. Vital status at the end of intensive care unit stay was recorded.Overall, 28 patients suffering from sepsis were included. Median (interquartile range [IQR]) age was 60 [44-77.3] years, 15 (53.6%) patients were male, median [IQR] simplified acute physiology score II was 40 [27-50]. There was no correlation between total thiamine and lactate levels (P = .33). There was no correlation between free thiamine (P = .81), TMP (P = .71), TDP (P = .31), TTP (P = .86), and lactate levels in our population. There was no correlation between ETKA (P = .58) or the effect of TDP on ETKA (P = .40) and lactate concentration. Total thiamine and TDP concentration were significantly higher in intensive care unit (ICU) survivors than in nonsurvivors (P = .03 and P = .03). The effect of TDP on ETKA was significantly higher in nonsurvivors compared to survivors (P = .04).We found no correlation between thiamine compounds and lactate concentration in sepsis. Thiamine deficiency in sepsis may be associated with ICU-mortality.
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http://dx.doi.org/10.1097/MD.0000000000018894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035069PMC
February 2020

Vasopressor Therapy and the Brain: Dark Side of the Moon.

Front Med (Lausanne) 2019 10;6:317. Epub 2020 Jan 10.

General Intensive Care Unit, Raymond Poincaré Hospital, Garches, France.

Sepsis, a leading cause of morbidity and mortality, is caused by a deregulated host response to pathogens, and subsequent life-threatening organ dysfunctions. All major systems, including the cardiovascular, respiratory, renal, hepatic, hematological, and the neurological system may be affected by sepsis. Sepsis associated neurological dysfunction is triggered by multiple factors including neuro-inflammation, excitotoxicity, and ischemia. Ischemia results from reduced cerebral blood flow, caused by extreme variations of blood pressure, occlusion of cerebral vessels, or more subtle defects of the microcirculation. International guidelines comprehensively describe the initial hemodynamic management of sepsis, revolving around the normalization of systemic hemodynamics and of arterial lactate. By contrast, the management of sepsis patients suffering from brain dysfunction is poorly detailed, the only salient point being mentioned is that sedation and analgesia should be optimized. However, sepsis and the hemodynamic consequences thereof as well as vasopressors may have severe untoward neurological consequences. The current review describes the general neurological complications, as well as the consequences of vasopressor therapy on the brain and its circulation and addresses methods for cerebral monitoring during sepsis.
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http://dx.doi.org/10.3389/fmed.2019.00317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966606PMC
January 2020

CD89 Is a Potent Innate Receptor for Bacteria and Mediates Host Protection from Sepsis.

Cell Rep 2019 04;27(3):762-775.e5

INSERM U1149, Centre de Recherche sur l'Inflammation, Paris, France; CNRS ERL8252, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Faculté de Médecine, Site Xavier Bichat, Paris, France; Inflamex Laboratory of Excellence, Paris, France. Electronic address:

Direct bacterial recognition by innate receptors is crucial for bacterial clearance. Here, we show that the IgA receptor CD89 is a major innate receptor that directly binds bacteria independently of its cognate ligands IgA and c-reactive protein (CRP). This binding is only partially inhibited by serum IgA and induces bacterial phagocytosis by CD11c dendritic cells and monocytes and/or macrophages, suggesting a physiological role in innate host defense. Blood phagocytes from common variable immunodeficiency patients bind, internalize, and kill bacteria in a CD89-dependent manner, confirming the IgA independence of this mechanism. In vivo, CD89 transgenic mice are protected in two different models of sepsis: a model of pneumonia and the cecal ligation and puncture (CLP) polymicrobial model of infection. These data identify CD89 as a first-line innate receptor for bacterial clearance before adaptive responses can be mounted. Fc receptors may emerge as a class of innate receptors for various bacteria with pleiotropic roles.
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http://dx.doi.org/10.1016/j.celrep.2019.03.062DOI Listing
April 2019

Dysglycemia and Neurologic Outcome in Mechanically Ventilated Patients With Guillain-Barré Syndrome.

Crit Care Med 2019 03;47(3):e227-e233

Department of neuro-anesthesiology and intensive care medicine, Sainte-Anne teaching hospital, Paris-Descartes University, Paris, France.

Objectives: Acute respiratory failure is a frequent complication of Guillain-Barré syndrome, associated with high morbidity and mortality. Adjuvant treatments are needed to improve the outcome of Guillain-Barré syndrome. Since dysglycemia is a risk factor for development of axonal polyneuropathy in critically ill patients and since insulin therapy may be neuroprotective, we sought to explore the association between dysglycemia and neurologic status in Guillain-Barré syndrome patients.

Design: Retrospective study.

Setting: Single-center study.

Interventions: All plasma levels of glycemia measured by enzymatic technique as well as capillary glycemia were collected in a cohort of mechanically ventilated Guillain-Barré syndrome patients. Insulin administration and dysglycemia were correlated to neurologic status at discharge defined by disability grade and arm grade.

Measurements And Main Results: In a multivariate analysis, disability grade and arm grade at ICU discharge were independently and inversely correlated with mean blood glucose. Disability grade and arm grade did not correlate with any other dysglycemic variables or with insulin administration or length of stay.

Conclusions: In the present study, we found that neurologic disability at ICU discharge correlated with dysglycemia in mechanically ventilated Guillain-Barré syndrome patients. These finding indicates that dysglycemia may delay motor recovery and impact the functional outcome of Guillain-Barré syndrome. Blood glucose control might be an adjuvant therapy for improving Guillain-Barré syndrome recovery.
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http://dx.doi.org/10.1097/CCM.0000000000003635DOI Listing
March 2019

Morbidity and Mortality of Crystalloids Compared to Colloids in Critically Ill Surgical Patients: A Subgroup Analysis of a Randomized Trial.

Anesthesiology 2018 12;129(6):1149-1158

From the General Intensive Care Unit, Raymond Poincaré Hospital, Garches, France (N.H., L.L., D.A.) U1173 Lab Inflammation and Infection, University of Versailles SQY-Paris Saclay - INSERM, Montigny-le-Bretonneux, France (N.H., L.L., D.A.) Department of Anesthesiology and Critical Care Medicine B, Saint Eloi Hospital, Montpellier, France (S.J.) Intensive Care Unit, Institute of Cardiology, Pitié Salpêtrière Hospital, Paris, France (J.L.T.) Anaesthesiology-Emergency-Intensive Care Unit Department, AP-HM North Hospital, Marseille, France (C.M.) Biostatistical Unit, Saint Louis Hospital, Paris, France (S.C.).

What We Already Know About This Topic: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: The multicenter randomized Colloids versus Crystalloids for the Resuscitation of the Critically Ill (CRISTAL) trial was designed to test whether colloids altered mortality compared to crystalloids in the resuscitation of intensive care unit patients with hypovolemic shock. This preplanned analysis tested the same hypothesis in the subgroup of surgical patients.

Methods: The CRISTAL trial prospectively defined patients as critically ill surgical patients whenever they underwent emergency or scheduled surgery immediately before or within 24 h of intensive care unit admission and had hypovolemic shock. The primary outcome measure was death by day 28. Secondary outcome measures included death by day 90, the need for renal replacement therapy, or the need for fresh frozen plasma transfusion.

Results: There were 741 critically ill surgical patients, 356 and 385 in the crystalloid and colloid arm, respectively. Median (interquartile range) age was 66 (52 to 76) yr, and 484 (65.3%) patients were male. Surgery was unscheduled in 543 (73.3%) cases. Mortality by day 28 did not significantly differ for crystalloids 84 (23.6%) versus colloids 100 (26%; adjusted odds ratio, 0.86; 95% CI, 0.61 to 1.21; P = 0.768). Death by day 90 (111 [31.2%] vs. 122 [31.7%]; adjusted odds ratio, 0.97; 95% CI, 0.70 to 1.33; P = 0.919) did not significantly differ between groups. Renal replacement therapy was required for 42 (11.8%) patients in the crystalloids arm versus 49 (12.7%) in the colloids arm (P = 0.871).

Conclusions: The authors found no survival benefit when comparing crystalloids to colloids in critically ill surgical patients.
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http://dx.doi.org/10.1097/ALN.0000000000002413DOI Listing
December 2018

Immune Effects of Corticosteroids in Sepsis.

Front Immunol 2018 30;9:1736. Epub 2018 Jul 30.

General Intensive Care Unit, Raymond Poincaré Hospital, Garches, France.

Sepsis, a life-threatening organ dysfunction, results from a dysregulated host response to invading pathogens that may be characterized by overwhelming systemic inflammation or some sort of immune paralysis. Sepsis remains a major cause of morbidity and mortality. Treatment is nonspecific and relies on source control and organ support. Septic shock, the most severe form of sepsis is associated with the highest rate of mortality. Two large multicentre trials, undertaken 15 years apart, found that the combination of hydrocortisone and fludrocortisone significantly reduces mortality in septic shock. The corticosteroids family is composed of several molecules that are usually characterized according to their glucocorticoid and mineralocorticoid power, relative to hydrocortisone. While the immune effects of glucocorticoids whether mediated or not by the intracellular glucocorticoid receptor have been investigated for several decades, it is only very recently that potential immune effects of mineralocorticoids non-renal mineralocorticoid receptors have gained popularity. We reviewed the respective role of glucocorticoids and mineralocorticoids in counteracting sepsis-associated dysregulated immune systems.
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http://dx.doi.org/10.3389/fimmu.2018.01736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077259PMC
September 2019

Value and mechanisms of EEG reactivity in the prognosis of patients with impaired consciousness: a systematic review.

Crit Care 2018 08 2;22(1):184. Epub 2018 Aug 2.

Department of Neuro-Intensive Care Medicine, Sainte-Anne Hospital, Paris-Descartes University, Paris, France.

Background: Electroencephalography (EEG) is a well-established tool for assessing brain function that is available at the bedside in the intensive care unit (ICU). This review aims to discuss the relevance of electroencephalographic reactivity (EEG-R) in patients with impaired consciousness and to describe the neurophysiological mechanisms involved.

Methods: We conducted a systematic search of the term "EEG reactivity and coma" using the PubMed database. The search encompassed articles published from inception to March 2018 and produced 202 articles, of which 42 were deemed relevant, assessing the importance of EEG-R in relationship to outcomes in patients with impaired consciousness, and were therefore included in this review.

Results: Although definitions, characteristics and methods used to assess EEG-R are heterogeneous, several studies underline that a lack of EEG-R is associated with mortality and unfavorable outcome in patients with impaired consciousness. However, preserved EEG-R is linked to better odds of survival. Exploring EEG-R to nociceptive, auditory, and visual stimuli enables a noninvasive trimodal functional assessment of peripheral and central sensory ascending pathways that project to the brainstem, the thalamus and the cerebral cortex. A lack of EEG-R in patients with impaired consciousness may result from altered modulation of thalamocortical loop activity by afferent sensory input due to neural impairment. Assessing EEG-R is a valuable tool for the diagnosis and outcome prediction of severe brain dysfunction in critically ill patients.

Conclusions: This review emphasizes that whatever the etiology, patients with impaired consciousness featuring a reactive electroencephalogram are more likely to have a favorable outcome, whereas those with a nonreactive electroencephalogram are prone to having an unfavorable outcome. EEG-R is therefore a valuable prognostic parameter and warrants a rigorous assessment. However, current assessment methods are heterogeneous, and no consensus exists. Standardization of stimulation and interpretation methods is needed.
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http://dx.doi.org/10.1186/s13054-018-2104-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6091014PMC
August 2018

Efficacy of Rituximab in Refractory Generalized anti-AChR Myasthenia Gravis.

J Neuromuscul Dis 2018 ;5(2):241-249

AP-HP, Hôpital Pitié-Salpêtrière, Department of Internal Medicine and ClinicalImmunology, Inflammation-Immunopathology-Biotherapy Department (I2B), East Paris Neuromuscular Diseases Reference Center, Inserm U974, Sorbonne Université, Paris 6, Paris, France.

Background: Several retrospective case series have suggested rituximab (RTX) might improve patients with refractory Myasthenia Gravis (MG).

Objective: In this study, we aimed to evaluate prospectively the efficacy of RTX on muscle function in refractory generalized anti-acetylcholine receptor (AChR) MG patients.

Methods: Enrolled patients received 1 g of RTX at day 0, day 14, and 6-month follow-up (M6). The primary endpoint was improvement of muscle function at 12-month (M12) based on myasthenic muscle score (MMS). Secondary endpoints were an improvement of the MG Foundation of America Postintervention Status (MGFA-PIS), respiratory forced vital capacity, occurrences of acute MG exacerbation and requirement of associated immunosuppressants and immunomodulatory agents.

Results: Twelve patients were enrolled, and 11 completed the study. Only a single patient presented an improvement of at least 20 points on MMS at M12, although 2 patients displayed an increase of at least 18 points at M12. MGFA-PIS had improved in 55% of patients by M12. The clinical improvement was not associated with a reduction of immunosuppressant burden.

Conclusions: These results provide data on the effect of RTX in patients with severe, refractory anti-AChR Abs generalized MG. Even though primary outcome was only reached in a single patient at M12, a beneficial effect of RTX on muscle function was seen in half of the patients at M12 and persisted in a third of patients at M18.
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http://dx.doi.org/10.3233/JND-180300DOI Listing
November 2018

Haemodynamic response to crystalloids or colloids in shock: an exploratory subgroup analysis of a randomised controlled trial.

BMJ Open 2017 Oct 6;7(10):e016736. Epub 2017 Oct 6.

General Intensive Care Unit, Raymond Poincaré Hospital, Garches, France.

Objective: To compare the haemodynamic effect of crystalloids and colloids during acute severe hypovolaemic shock.

Design: Exploratory subgroup analysis of a multicentre randomised controlled trial (Colloids Versus Crystalloids for the Resuscitation of the Critically Ill, CRISTAL, ClinicalTrials.gov NCT00318942).

Setting: CRISTAL was conducted in intensive care units in Europe, North Africa and Canada.

Participants: Current analysis included all patients who had a pulmonary artery catheter in place at randomisation. 220 patients (117 received crystalloids vs 103 colloids) underwent pulmonary artery catheterisation.

Intervention: Crystalloids versus colloids for fluid resuscitation in hypovolaemic shock.

Outcome Measures: Haemodynamic data were collected at the time of randomisation and subsequently on days 1, 2, 3, 4, 5, 6 and 7.

Results: Median cumulative volume of fluid administered during the first 7 days was higher in the crystalloids group than in the colloids group (3500 (2000-6000) vs 2500 (1000-4000) mL, p=0.01). Patients in the colloids arm exhibited a lower heart rate over time compared with those allocated to the crystalloids arm (p=0.014). There was no significant difference in Cardiac Index (p=0.053), mean blood pressure (p=0.4), arterial lactates (p=0.9) or global Sequential Organ Failure Assessment score (p=0.3) over time between arms.

Conclusions: During acute severe hypovolaemic shock, patients monitored by a pulmonary artery catheter achieved broadly similar haemodynamic outcomes, using lower volumes of colloids than crystalloids. The heart rate was lower in the colloids arm.
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http://dx.doi.org/10.1136/bmjopen-2017-016736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640079PMC
October 2017

Early impairment of intracranial conduction time predicts mortality in deeply sedated critically ill patients: a prospective observational pilot study.

Ann Intensive Care 2017 Dec 12;7(1):63. Epub 2017 Jun 12.

General Intensive Care Unit - Assistance Publique Hôpitaux de Paris, Raymond-Poincaré Hospital, INSERM U 1173, University of Versailles Saint-Quentin en Yvelines, Garches, France.

Background: Somatosensory (SSEP) and brainstem auditory (BAEP) evoked potentials are neurophysiological tools which, respectively, explore the intracranial conduction time (ICCT) and the intrapontine conduction time (IPCT). The prognostic values of prolonged cerebral conduction times in deeply sedated patients have never been assessed. Sedated patients are at risk of developing new neurological complications, undetected. In this prospective observational bi-center pilot study, we investigated whether early impairment of SSEP's ICCT and/or BAEP's IPCT could predict in-ICU mortality or altered mental status (AMS), in deeply sedated critically ill patients.

Methods: SSEP by stimulation of the median nerve and BAEP were assessed in critically ill patients receiving deep sedation on day 3 following ICU admission. Deep sedation was defined by a Richmond Assessment sedation Scale (RASS) <-3. Mean left- and right-side ICCT and IPCT were measured for each patient. Primary and secondary outcomes were, respectively, in-ICU mortality and AMS defined as the occurrence of delirium and/or delayed awakening after discontinuation of sedation.

Results: Eighty-six patients were studied of which 49 (57%) were non-brain-injured and 37 (43%) were brain-injured. Impaired ICCT was a predictor of in-ICU mortality after adjustment on the global Sequential Organ Failure Assessment score (SOFA) [OR (95% CI) = 2.69 (1.05-6.85); p = 0.039] and on the non-neurological SOFA components [2.67 (1.05-6.81); p = 0.040]. IPCT was more frequently delayed in the subgroup of patients who developed post-sedation AMS (24%) compared those without AMS (0%). However, this difference did not reach statistical significance (p = 0.053). Impairment rates of ICCT and IPCT were not found to be significantly different between non-brain- and brain-injured subgroups of patients.

Conclusion: In critically ill patients receiving deep sedation, early ICCT impairment was associated with mortality. Somatosensory and brainstem auditory evoked potentials may be useful early warning indicators of brain dysfunction as well as prognostic markers in deeply sedated critically ill patients.
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http://dx.doi.org/10.1186/s13613-017-0290-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5468361PMC
December 2017

Brainstem response patterns in deeply-sedated critically-ill patients predict 28-day mortality.

PLoS One 2017 25;12(4):e0176012. Epub 2017 Apr 25.

General Intensive Care Unit, AP-HP, Raymond Poincaré Hospital, University of Versailles Saint-Quentin en Yvelines, Garches, France.

Background And Purpose: Deep sedation is associated with acute brain dysfunction and increased mortality. We had previously shown that early-assessed brainstem reflexes may predict outcome in deeply sedated patients. The primary objective was to determine whether patterns of brainstem reflexes might predict mortality in deeply sedated patients. The secondary objective was to generate a score predicting mortality in these patients.

Methods: Observational prospective multicenter cohort study of 148 non-brain injured deeply sedated patients, defined by a Richmond Assessment sedation Scale (RASS) <-3. Brainstem reflexes and Glasgow Coma Scale were assessed within 24 hours of sedation and categorized using latent class analysis. The Full Outline Of Unresponsiveness score (FOUR) was also assessed. Primary outcome measure was 28-day mortality. A "Brainstem Responses Assessment Sedation Score" (BRASS) was generated.

Results: Two distinct sub-phenotypes referred as homogeneous and heterogeneous brainstem reactivity were identified (accounting for respectively 54.6% and 45.4% of patients). Homogeneous brainstem reactivity was characterized by preserved reactivity to nociceptive stimuli and a partial and topographically homogenous depression of brainstem reflexes. Heterogeneous brainstem reactivity was characterized by a loss of reactivity to nociceptive stimuli associated with heterogeneous brainstem reflexes depression. Heterogeneous sub-phenotype was a predictor of increased risk of 28-day mortality after adjustment to Simplified Acute Physiology Score-II (SAPS-II) and RASS (Odds Ratio [95% confidence interval] = 6.44 [2.63-15.8]; p<0.0001) or Sequential Organ Failure Assessment (SOFA) and RASS (OR [95%CI] = 5.02 [2.01-12.5]; p = 0.0005). The BRASS (and marginally the FOUR) predicted 28-day mortality (c-index [95%CI] = 0.69 [0.54-0.84] and 0.65 [0.49-0.80] respectively).

Conclusion: In this prospective cohort study, around half of all deeply sedated critically ill patients displayed an early particular neurological sub-phenotype predicting 28-day mortality, which may reflect a dysfunction of the brainstem.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176012PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404790PMC
September 2017

Neuroanatomy of sepsis-associated encephalopathy.

Crit Care 2017 Mar 21;21(1):65. Epub 2017 Mar 21.

General ICU, Raymond Poincaré Hospital, Garches, France.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2017. Other selected articles can be found online at http://ccforum.com/series/annualupdate2017 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901 .Originally published in the Annual Update in Intensive Care and Emergency Medicine 2017. The number of authors differs in the two versions due to constraints regarding the number of authors in the Annual Update in Intensive Care and Emergency Medicine. In the Annual Update version of the review, the three senior authors appear in the acknowledgement section. In the Critical Care version, these three senior authors appear as full authors of the manuscript. All authors helped draft and revise the manuscript for critical intellectual content.
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http://dx.doi.org/10.1186/s13054-017-1643-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360026PMC
March 2017

Prognostic value of nocturnal hypoventilation in neuromuscular patients.

Neuromuscul Disord 2017 Apr 21;27(4):326-330. Epub 2016 Dec 21.

Service de Réanimation médicale et unité de ventilation à domicile, CHU Raymond Poincaré, 92380 Garches, France; INSERM CIC 14.29, CHU Raymond Poincaré, 92380 Garches, France. Electronic address:

In neuromuscular disease (NMD) patients, current guidelines recommend the initiation of home mechanical ventilation (HMV) in case of daytime hypercapnia or nocturnal desaturation as an indirect sign of hypoventilation. Transcutaneous capno-oximetry (TcCO) enables the direct assessment of nocturnal hypercapnia; however the best cut-off value remains to be defined. We aimed to compare the prognostic value of several published definitions of nocturnal hypercapnia in a cohort of NMD patients. All consecutive TcCO recordings performed between 2010 and 2014 in unventilated adult NMD patients in a tertiary reference centre were retrospectively collected. Initiation of HMV and mortality were collected as outcomes of interest. 124 patients with normal daytime blood gazes were analysed (median age 39 [IQR 31-55] years; vital capacity 61% [43-82] of predicted). The prevalence of nocturnal hypercapnia ranged from 3% to 44%, depending on the definition. Over a median follow-up duration of 2.5 years [IQR 1.6-4.1], HMV was initiated for 51 patients, whilst 4 patients died. Nocturnal peak TcCO ≥49 mmHg was the best predictor of HMV initiation in the follow-up, being associated with a hazard ratio of 2.6 [95% CI 1.4-4.6] in a multivariate analysis adjusting for lung function parameters. Nocturnal TcCO identifies NMD patients at risk for subsequent need for HMV in the following few years, who were not identified by daytime blood gases or nocturnal oximetry. As a consequence, peak nocturnal TcCO ≥49 mmHg should be considered as one of the criteria to start HMV in patients with NMDs, along with symptoms of hypoventilation, daytime hypercapnia, abnormal nocturnal oximetry results, and a diminished level of forced vital capacity.
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http://dx.doi.org/10.1016/j.nmd.2016.12.006DOI Listing
April 2017

Acetazolamide and Invasive Mechanical Ventilation for Patients With COPD--Reply.

JAMA 2016 Jul;316(1):100-1

Assistance Publique-Hôpitaux de Paris, Paris, France.

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http://dx.doi.org/10.1001/jama.2016.4625DOI Listing
July 2016

Neuroanatomy and Physiology of Brain Dysfunction in Sepsis.

Clin Chest Med 2016 06;37(2):333-45

Institut Pasteur - Unité Histopathologie Humaine et Modèles Animaux, Département Infection et Épidémiologie, Rue du docteur roux, Paris 75724 Cedex 15, France; General Intensive Care, Assistance Publique Hopitaux de Paris, Raymond Poincaré Teaching Hosptal, Garches 92380, France; Versailles-Saint Quentin University, Avenue de Paris, Versailles 78000, France. Electronic address:

Sepsis-associated encephalopathy (SAE), a complication of sepsis, is often complicated by acute and long-term brain dysfunction. SAE is associated with electroencephalogram pattern changes and abnormal neuroimaging findings. The major processes involved are neuroinflammation, circulatory dysfunction, and excitotoxicity. Neuroinflammation and microcirculatory alterations are diffuse, whereas excitotoxicity might occur in more specific structures involved in the response to stress and the control of vital functions. A dysfunction of the brainstem, amygdala, and hippocampus might account for the increased mortality, psychological disorders, and cognitive impairment. This review summarizes clinical and paraclinical features of SAE and describes its mechanisms at cellular and structural levels.
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http://dx.doi.org/10.1016/j.ccm.2016.01.013DOI Listing
June 2016

Effect of Acetazolamide vs Placebo on Duration of Invasive Mechanical Ventilation Among Patients With Chronic Obstructive Pulmonary Disease: A Randomized Clinical Trial.

JAMA 2016 Feb;315(5):480-8

European Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.

Importance: Acetazolamide has been used for decades as a respiratory stimulant for patients with chronic obstructive pulmonary disease (COPD) and metabolic alkalosis, but no large randomized placebo-controlled trial is available to confirm this approach.

Objective: To determine whether acetazolamide reduces mechanical ventilation duration in critically ill patients with COPD and metabolic alkalosis.

Design, Setting, And Participants: The DIABOLO study, a randomized, double-blind, multicenter trial, was conducted from October 2011 through July 2014 in 15 intensive care units (ICUs) in France. A total of 382 patients with COPD who were expected to receive mechanical ventilation for more 24 hours were randomized to the acetazolamide or placebo group and 380 were included in an intention-to treat analysis.

Interventions: Acetazolamide (500-1000 mg, twice daily) vs placebo administered intravenously in cases of pure or mixed metabolic alkalosis, initiated within 48 hours of ICU admission and continued during the ICU stay for a maximum of 28 days.

Main Outcomes And Measures: The primary outcome was the duration of invasive mechanical ventilation via endotracheal intubation or tracheotomy. Secondary outcomes included changes in arterial blood gas and respiratory parameters, weaning duration, adverse events, use of noninvasive ventilation after extubation, successful weaning, the duration of ICU stay, and in-ICU mortality.

Results: Among 382 randomized patients, 380 (mean age, 69 years; 272 men [71.6%]; 379 [99.7%] with endotracheal intubation) completed the study. For the acetazolamide group (n = 187), compared with the placebo group (n = 193), no significant between-group differences were found for median duration of mechanical ventilation (-16.0 hours; 95% CI, -36.5 to 4.0 hours; P = .17), duration of weaning off mechanical ventilation (-0.9 hours; 95% CI, -4.3 to 1.3 hours; P = .36), daily changes of minute-ventilation (-0.0 L/min; 95% CI, -0.2 to 0.2 L/min; P = .72), or partial carbon-dioxide pressure in arterial blood (-0.3 mm Hg; 95% CI, -0.8 to 0.2 mm Hg; P = .25), although daily changes of serum bicarbonate (between-group difference, -0.8 mEq/L; 95% CI, -1.2 to -0.5 mEq/L; P < .001) and number of days with metabolic alkalosis (between-group difference, -1; 95% CI, -2 to -1 days; P < .001) decreased significantly more in the acetazolamide group. Other secondary outcomes also did not differ significantly between groups.

Conclusions And Relevance: Among patients with COPD receiving invasive mechanical ventilation, the use of acetazolamide, compared with placebo, did not result in a statistically significant reduction in the duration of invasive mechanical ventilation. However, the magnitude of the difference was clinically important, and it is possible that the study was underpowered to establish statistical significance.

Trial Registration: clinicaltrials.gov Identifier: NCT01627639.
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http://dx.doi.org/10.1001/jama.2016.0019DOI Listing
February 2016

Emerging drugs for the treatment of sepsis.

Expert Opin Emerg Drugs 2016 11;21(1):27-37. Epub 2016 Jan 11.

a General intensive care unit , Raymond Poincaré Hospital (APHP), Laboratory of Inflammation and Infection U1173, University of Versailles SQY/INSERM , Garches , France.

Introduction: The incidence of sepsis, the systemic inflammatory response of the host to an infectious insult, has steadily increased over past decades. This trend is expected to continue. Sepsis is a leading cause of death and disability worldwide. Treatment relies on antibiotics associated to source control and supportive care. Major progress has been made in the understanding and overall management of sepsis. However, there is no specific treatment for sepsis.

Areas Covered: We searched PubMed and the ClinicalTrials.gov site for English language reports of phase II and III clinical trials pertaining to the field of sepsis. The current review provides a summary of promising candidate treatments for sepsis. We broadly separated candidate drugs into three distinct categories: Blood purification techniques, immunomodulatory drugs and treatments targeting other systems including the heart, the endothelium or coagulation.

Expert Opinion: Efforts to identify an efficient treatment for sepsis are hampered by the broad definition of the syndrome associated with major heterogeneity between patients affected by sepsis. The characterization of homogeneous groups of patients, through biological or clinical markers is unfortunately lacking. Current research remains active. Candidate drugs for sepsis include hemoperfusion with polymyxin B coated fibre devices, modulation of the immune system with treatments such as hydrocortisone, intravenous immunoglobulins, mesenchymal stem cells, GM-CSF or interferon gamma. Candidate drugs acting on the cardiovascular system include short acting beta 1 blockers, levosimendan or selepressin. Finally, promising strategies, involving monoclonal antibodies or protein antagonists, which selectively inhibit bacterial virulence factors are being assessed at the bedside. A much awaited and needed specific treatment for sepsis will hopefully soon emerge.
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http://dx.doi.org/10.1517/14728214.2016.1132700DOI Listing
October 2016

Modeling for critically ill patients: An introduction for beginners.

J Crit Care 2015 Dec 4;30(6):1287-94. Epub 2015 Sep 4.

Medical Intensive Care Unit, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes Sorbonne Paris Cité, Paris, France. Electronic address:

Models are mathematical tools used to describe real-world features. Therapeutic interventions in the field of critical care medicine may easily be translated into such models. Indeed, numerous variables influencing drug pharmacokinetics and pharmacodynamics are systematically documented in the intensive care unit over time. Organ failure, fluid shifts, other drug administration, and renal replacement therapy may cause changes in physiological values, such as body weight and composition, temperature, serum protein levels, arterial pH, and renal or hepatic function. Trials assessing the efficacy and safety of novel drugs usually exclude critically ill patients, and guidelines regarding drug dosage rarely apply to such patients. Modeling in the critically ill may allow physicians to inform decisions related to therapeutic interventions, particularly relating to infectious diseases. However, few clinicians are familiar with these methods. Here, we present a current overview of population pharmacokinetic and pharmacodynamic models applicable in critically ill patients aimed at nonspecialists and then emphazize recent potential of modeling for optimizing treatments and care in the intensive care unit.
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http://dx.doi.org/10.1016/j.jcrc.2015.09.002DOI Listing
December 2015