Publications by authors named "Antoine Roquilly"

116 Publications

Effect of dexamethasone on complications or all cause mortality after major non-cardiac surgery: multicentre, double blind, randomised controlled trial.

BMJ 2021 06 2;373:n1162. Epub 2021 Jun 2.

CHU Nantes, Université de Nantes, Pôle Anesthésie-Réanimation, Service d'Anesthésie Réanimation Chirurgicale, Hôtel Dieu, Nantes, France.

Objective: To assess the effect of dexamethasone on complications or all cause mortality after major non-cardiac surgery.

Design: Phase III, randomised, double blind, placebo controlled trial.

Setting: 34 centres in France, December 2017 to March 2019.

Participants: 1222 adults (>50 years) requiring major non-cardiac surgery with an expected duration of more than 90 minutes. The anticipated time frame for recruitment was 24 months.

Interventions: Participants were randomised to receive either dexamethasone (0.2 mg/kg immediately after the surgical procedure, and on day 1) or placebo. Randomisation was stratified on the two prespecified criteria of cancer and thoracic procedure.

Main Outcomes Measures: The primary outcome was a composite of postoperative complications or all cause mortality within 14 days after surgery, assessed in the modified intention-to-treat population (at least one treatment administered).

Results: Of the 1222 participants who underwent randomisation, 1184 (96.9%) were included in the modified intention-to-treat population. 14 days after surgery, 101 of 595 participants (17.0%) in the dexamethasone group and 117 of 589 (19.9%) in the placebo group had complications or died (adjusted odds ratio 0.81, 95% confidence interval 0.60 to 1.08; P=0.15). In the stratum of participants who underwent non-thoracic surgery (n=1038), the primary outcome occurred in 69 of 520 participants (13.3%) in the dexamethasone group and 93 of 518 (18%) in the placebo group (adjusted odds ratio 0.70, 0.50 to 0.99). Adverse events were reported in 288 of 613 participants (47.0%) in the dexamethasone group and 296 of 609 (48.6%) in the placebo group (P=0.46).

Conclusions: Dexamethasone was not found to significantly reduce the incidence of complications and death in patients 14 days after major non-cardiac surgery. The 95% confidence interval for the main result was, however, wide and suggests the possibility of important clinical effectiveness.

Trial Registration: ClinicalTrials.gov NCT03218553.
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http://dx.doi.org/10.1136/bmj.n1162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171383PMC
June 2021

Distinct immunological signatures discriminate severe COVID-19 from non-SARS-CoV-2-driven critical pneumonia.

Immunity 2021 May 9. Epub 2021 May 9.

Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland. Electronic address:

Immune profiling of COVID-19 patients has identified numerous alterations in both innate and adaptive immunity. However, whether those changes are specific to SARS-CoV-2 or driven by a general inflammatory response shared across severely ill pneumonia patients remains unknown. Here, we compared the immune profile of severe COVID-19 with non-SARS-CoV-2 pneumonia ICU patients using longitudinal, high-dimensional single-cell spectral cytometry and algorithm-guided analysis. COVID-19 and non-SARS-CoV-2 pneumonia both showed increased emergency myelopoiesis and displayed features of adaptive immune paralysis. However, pathological immune signatures suggestive of T cell exhaustion were exclusive to COVID-19. The integration of single-cell profiling with a predicted binding capacity of SARS-CoV-2 peptides to the patients' HLA profile further linked the COVID-19 immunopathology to impaired virus recognition. Toward clinical translation, circulating NKT cell frequency was identified as a predictive biomarker for patient outcome. Our comparative immune map serves to delineate treatment strategies to interfere with the immunopathologic cascade exclusive to severe COVID-19.
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http://dx.doi.org/10.1016/j.immuni.2021.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106882PMC
May 2021

Effect of Continuous Infusion of Hypertonic Saline vs Standard Care on 6-Month Neurological Outcomes in Patients With Traumatic Brain Injury: The COBI Randomized Clinical Trial.

JAMA 2021 05;325(20):2056-2066

Université de Nantes, CHU Nantes, Pôle anesthésie réanimations, Service d'Anesthésie Réanimation chirurgicale, Hôtel Dieu, Nantes, France.

Importance: Fluid therapy is an important component of care for patients with traumatic brain injury, but whether it modulates clinical outcomes remains unclear.

Objective: To determine whether continuous infusion of hypertonic saline solution improves neurological outcome at 6 months in patients with traumatic brain injury.

Design, Setting, And Participants: Multicenter randomized clinical trial conducted in 9 intensive care units in France, including 370 patients with moderate to severe traumatic brain injury who were recruited from October 2017 to August 2019. Follow-up was completed in February 2020.

Interventions: Adult patients with moderate to severe traumatic brain injury were randomly assigned to receive continuous infusion of 20% hypertonic saline solution plus standard care (n = 185) or standard care alone (controls; n = 185). The 20% hypertonic saline solution was administered for 48 hours or longer if patients remained at risk of intracranial hypertension.

Main Outcomes And Measures: The primary outcome was Extended Glasgow Outcome Scale (GOS-E) score (range, 1-8, with lower scores indicating worse functional outcome) at 6 months, obtained centrally by blinded assessors and analyzed with ordinal logistic regression adjusted for prespecified prognostic factors (with a common odds ratio [OR] >1.0 favoring intervention). There were 12 secondary outcomes measured at multiple time points, including development of intracranial hypertension and 6-month mortality.

Results: Among 370 patients who were randomized (median age, 44 [interquartile range, 27-59] years; 77 [20.2%] women), 359 (97%) completed the trial. The adjusted common OR for the GOS-E score at 6 months was 1.02 (95% CI, 0.71-1.47; P = .92). Of the 12 secondary outcomes, 10 were not significantly different. Intracranial hypertension developed in 62 (33.7%) patients in the intervention group and 66 (36.3%) patients in the control group (absolute difference, -2.6% [95% CI, -12.3% to 7.2%]; OR, 0.80 [95% CI, 0.51-1.26]). There was no significant difference in 6-month mortality (29 [15.9%] in the intervention group vs 37 [20.8%] in the control group; absolute difference, -4.9% [95% CI, -12.8% to 3.1%]; hazard ratio, 0.79 [95% CI, 0.48-1.28]).

Conclusions And Relevance: Among patients with moderate to severe traumatic brain injury, treatment with continuous infusion of 20% hypertonic saline compared with standard care did not result in a significantly better neurological status at 6 months. However, confidence intervals for the findings were wide, and the study may have had limited power to detect a clinically important difference.

Trial Registration: ClinicalTrials.gov Identifier: NCT03143751.
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http://dx.doi.org/10.1001/jama.2021.5561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150692PMC
May 2021

Circulating Treg cells expressing TNF receptor type 2 contributes to sepsis-induced immunosuppression in patients during sepsis shock.

J Infect Dis 2021 May 21. Epub 2021 May 21.

Nantes Université, Thérapeutiques Anti-Infectieuses, Nantes, France.

Background: Septic shock remains a major cause of death that can be complicated by a long-term impairment in immune function defining immunosuppression induced by sepsis (IS). Among Treg cells, the tumor necrosis factor receptor 2 positive (TNFR2 pos) Treg cell subset endorses significant immunosuppressive functions in human tumors and in a sepsis mouse model but have not been investigated during septic shock in humans.

Methods: We prospectively enrolled patients with septic shock hospitalized in Intensive Care Unit (ICU). We performed immunophenotyping and functional tests of CD4+T cells, Treg cells and TNFR2 posTregcells, on blood samples collected at 1, 4 and 7 days after admission in ICU.

Results: We investigated 10 patients with septic shock and compared to 10 healthy controls. Although the proportions of circulating Tregcells and TNFR2 posTregcells subsets were not increased, their CTLA-4 expression and suppressive functions in vitro were increased at 4 days of septic shock. Also, PBMC from healthy donors cultured with serum from septic shock patients had increased CTLA4 expression in TNFR2 pos Treg cells compared to TNFR2 neg Treg cells.

Conclusion: In patients with septic shock, CTLA-4 expression and suppressive function were increased in circulating TNFR2 posTreg cells. We identify TNFR2 posTreg cells as a potential attractive target for therapeutic intervention.
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http://dx.doi.org/10.1093/infdis/jiab276DOI Listing
May 2021

Reply to Author.

Clin Infect Dis 2021 May 16. Epub 2021 May 16.

MRL, Merck & Co., Inc., Kenilworth, New Jersey, USA.

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http://dx.doi.org/10.1093/cid/ciab391DOI Listing
May 2021

Antibiotic resistance heterogeneity and LasR diversity within Pseudomonas aeruginosa populations from pneumonia in intensive care unit patients.

Int J Antimicrob Agents 2021 Jun 20;57(6):106341. Epub 2021 Apr 20.

Laboratoire UPRES EA3826, IRS2 - Nantes Biotech, Université de Nantes, Nantes, France.

This study investigated within-host heterogeneity of 66 Pseudomonas aeruginosa populations from pneumonia in 51 critically ill ventilated patients by examining 30 colonies per bronchoalveolar lavage (BAL). Differences in antibiotic susceptibility and quorum-sensing (QS) phenotypes were observed between the members of 14 (21.2%) and 10 (15.2%) populations, respectively. A significant association was found between QS deficiency and ceftazidime resistance. QS deficiency was associated with various lasR modifications, and was observed in 25 of 51 (49.0%) patients, including seven patients who received ≤48 h of ventilation. This study confirms the need to examine diverse colonies when analysing BAL cultures, particularly in β-lactam-exposed patients, to avoid missing ceftazidime- or imipenem-resistant isolates.
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http://dx.doi.org/10.1016/j.ijantimicag.2021.106341DOI Listing
June 2021

Could Azithromycin Be Part of Acute Pneumonia Treatment?

Front Microbiol 2021 16;12:642541. Epub 2021 Mar 16.

Laboratoire EA 3826 "Thérapeutiques cliniques et expérimentales des infections", IRS2-Nantes Biotech, Université de Nantes, Nantes, France.

Azithromycin (AZM) is a 15-membered-ring macrolide that presents a broad-spectrum antimicrobial activity against Gram-positive bacteria and atypical microorganisms but suffers from a poor diffusion across the outer-membrane of Gram-negative bacilli, including (PA). However, AZM has demonstrated clinical benefits in patients suffering from chronic PA respiratory infections, especially cystic fibrosis patients. Since the rise of multidrug-resistant PA has led to a growing need for new therapeutic options, this macrolide has been proposed as an adjunctive therapy. Clinical trials assessing AZM in PA acute pneumonia are scarce. However, a careful examination of the available literature provides good rationales for its use in that context. In fact, 14- and 15-membered-ring macrolides have demonstrated immunomodulatory and immunosuppressive effects that could be of major interest in the management of acute illness. Furthermore, growing evidence supports a downregulation of PA virulence dependent on direct interaction with the ribosomes, and based on the modulation of several key regulators from the Quorum Sensing network. First highlighted , these interesting properties of AZM have subsequently been confirmed in the animal models. In this review, we systematically analyzed the literature regarding AZM immunomodulatory and anti-PA effects. and studies, as well as clinical trials were reviewed, looking for rationales for AZM use in PA acute pneumonia.
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http://dx.doi.org/10.3389/fmicb.2021.642541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008145PMC
March 2021

Assessment of remifentanil for rapid sequence induction and intubation in patients at risk of pulmonary aspiration of gastric contents compared to rapid-onset paralytic agents: study protocol for a non-inferiority simple blind randomized controlled trial (the REMICRUSH study).

Trials 2021 Mar 30;22(1):237. Epub 2021 Mar 30.

Université de Nantes, CHU Nantes, Pôle Anesthésie-Réanimation, Service d'Anesthésie Réanimation Chirurgicale, Hôtel Dieu, Nantes, F-44093, France.

Background: Rapid-onset paralytic agents are recommended to achieve muscle relaxation and facilitate tracheal intubation during rapid sequence induction in patients at risk of pulmonary aspiration of gastric contents. However, opioids are frequently used in this setting. The study's objective is to demonstrate the non-inferiority of remifentanil compared to rapid-onset paralytic agents, in association with an hypnotic drug, for tracheal intubation in patients undergoing  procedure under general anesthesia and at risk of pulmonary aspiration of gastric contents.

Methods: The REMICRUSH (Remifentanil for Rapid Sequence Induction of Anaesthesia) study is a multicenter, single-blinded, non-inferiority randomized controlled trial comparing remifentanil (3 to 4 μg/kg) with rapid-onset paralytic agents (succinylcholine or rocuronium 1 mg/kg) for rapid sequence induction in 1150 adult surgical patients requiring tracheal intubation during general anesthesia. Enrolment started in October 2019 in 15 French anesthesia units. The expected date of the final follow-up is October 2021. The primary outcome is the proportion of successful tracheal intubation without major complications. A non-inferiority margin of 7% was chosen. Analyses of the intent-to-treat and per-protocol populations are planned.

Discussion: The REMICRUSH trial protocol has been approved by the ethics committee of The Comité de Protection des Personnes Sud-Ouest et Outre-Mer II and will be carried out according to the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines. The results of this study will be disseminated through presentations at scientific conferences and publications in peer-reviewed journals. The REMICRUSH trial is the first randomized controlled trial powered to investigate whether remifentanil with hypnotics is non-inferior to rapid-onset paralytic agents with hypnotic in rapid sequence induction of anesthesia for full stomach patients considering successful tracheal intubation without major complication.

Trial Registration: ClinicalTrials.gov NCT03960801. Registered on May 23, 2019.
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http://dx.doi.org/10.1186/s13063-021-05192-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009075PMC
March 2021

A Phase 3, Randomized, Double-Blind Study Comparing Tedizolid Phosphate and Linezolid for Treatment of Ventilated Gram-Positive Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia.

Clin Infect Dis 2021 Mar 15. Epub 2021 Mar 15.

Merck Research Laboratories, Merck & Co, Inc, Kenilworth, New Jersey, USA.

Background: Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are associated with high mortality rates. We evaluated the efficacy and safety of tedizolid (administered as tedizolid phosphate) for treatment of gram-positive ventilated HABP/VABP.

Methods: In this randomized, noninferiority, double-blind, double-dummy, global phase 3 trial, patients were randomized 1:1 to receive intravenous tedizolid phosphate 200 mg once daily for 7 days or intravenous linezolid 600 mg every 12 hours for 10 days. Treatment was 14 days in patients with concurrent gram-positive bacteremia. The primary efficacy end points were day 28 all-cause mortality (ACM; noninferiority margin, 10%) and investigator-assessed clinical response at test of cure (TOC; noninferiority margin, 12.5%) in the intention-to-treat population.

Results: Overall, 726 patients were randomized (tedizolid, n = 366; linezolid, n = 360). Baseline characteristics, including incidence of methicillin-resistant Staphylococcus aureus (31.3% overall), were well balanced. Tedizolid was noninferior to linezolid for day 28 ACM rate: 28.1% and 26.4%, respectively (difference, -1.8%; 95% confidence interval [CI]: -8.2 to 4.7). Noninferiority of tedizolid was not demonstrated for investigator-assessed clinical cure at TOC (tedizolid, 56.3% vs linezolid, 63.9%; difference, -7.6%; 97.5% CI: -15.7 to 0.5). In post hoc analyses, no single factor accounted for the difference in clinical response between treatment groups. Drug-related adverse events occurred in 8.1% and 11.9% of patients who received tedizolid and linezolid, respectively.

Conclusions: Tedizolid was noninferior to linezolid for day 28 ACM in the treatment of gram-positive ventilated HABP/VABP. Noninferiority of tedizolid for investigator-assessed clinical response at TOC was not demonstrated. Both drugs were well tolerated.

Clinical Trials Registration: NCT02019420.
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http://dx.doi.org/10.1093/cid/ciab032DOI Listing
March 2021

Diuretics decrease fluid balance in patients on invasive mechanical ventilation: the randomized-controlled single blind, IRIHS study.

Crit Care 2021 03 10;25(1):98. Epub 2021 Mar 10.

Médecine Intensive et Réanimation, Hôtel Dieu, University Hospital of Nantes, 1 place Alexis Ricordeau, 44093, Nantes, France.

Background: Fluid overload has been associated with increased morbidity and mortality in critically ill patients. The goal of this study was to assess the efficacy and safety of a diuretic strategy to overcome positive fluid balance in patients on invasive mechanical ventilation.

Methods: Design: Multicenter, single-blind, randomized-controlled study. Patients were randomized into a diuretic (furosemide) or a control group. Patients were eligible in case of fluid overload defined as in-ICU weight increase ≥ 3%, invasive mechanical ventilation (FiO ≤ 60% and PEEP ≤ 10 cm HO on inclusion) and hemodynamic stabilization. The primary outcome was fluid balance, defined as weight variation from reference weight to successful extubation. The main secondary outcome was the safety of diuretic.

Results: 171 patients were randomized. After 5 exclusions, 166 patients were included in the analysis: 77 in the diuretic and 89 in the control group. Fluid balance was 1.4 [- 2.5 to 4.5] kg in the diuretic and 6.4 [0.5-11.2] kg in the control group (p < 0.001). In the multiple imputation analysis, fluid balance was significantly decreased in the diuretic group (mean difference = - 4.8 95% CI [- 7.3 to - 2.5], p < 0.001). Eleven (14%) patients died in the diuretic group and 16 (18%) patients in the control group (p = 0.5). There was a worsening of Acute Kidney Injury in 67 (75.3%) patients of the control group versus 46 (59.7%) patients in the diuretic group (p = 0.03).

Conclusions: In this multicenter randomized-controlled study, protocolized diuretic therapy reduced fluid accumulation in patients receiving mechanical ventilation and was well tolerated with a favorable safety profile. Trial registration NCT02345681, Registered January 26 2015, Prospectively registered, https://clinicaltrials.gov/ct2/show/NCT02345681?term=02345681&draw=2&rank=1 .
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http://dx.doi.org/10.1186/s13054-021-03509-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943707PMC
March 2021

Balanced Opioid-free Anesthesia with Dexmedetomidine versus Balanced Anesthesia with Remifentanil for Major or Intermediate Noncardiac Surgery.

Anesthesiology 2021 04;134(4):541-551

Background: It is speculated that opioid-free anesthesia may provide adequate pain control while reducing postoperative opioid consumption. However, there is currently no evidence to support the speculation. The authors hypothesized that opioid-free balanced anesthetic with dexmedetomidine reduces postoperative opioid-related adverse events compared with balanced anesthetic with remifentanil.

Methods: Patients were randomized to receive a standard balanced anesthetic with either intraoperative remifentanil plus morphine (remifentanil group) or dexmedetomidine (opioid-free group). All patients received intraoperative propofol, desflurane, dexamethasone, lidocaine infusion, ketamine infusion, neuromuscular blockade, and postoperative lidocaine infusion, paracetamol, nefopam, and patient-controlled morphine. The primary outcome was a composite of postoperative opioid-related adverse events (hypoxemia, ileus, or cognitive dysfunction) within the first 48 h after extubation. The main secondary outcomes were episodes of postoperative pain, opioid consumption, and postoperative nausea and vomiting.

Results: The study was stopped prematurely because of five cases of severe bradycardia in the dexmedetomidine group. The primary composite outcome occurred in 122 of 156 (78%) dexmedetomidine group patients compared with 105 of 156 (67%) in the remifentanil group (relative risk, 1.16; 95% CI, 1.01 to 1.33; P = 0.031). Hypoxemia occurred 110 of 152 (72%) of dexmedetomidine group and 94 of 155 (61%) of remifentanil group patients (relative risk, 1.19; 95% CI, 1.02 to 1.40; P = 0.030). There were no differences in ileus or cognitive dysfunction. Cumulative 0 to 48 h postoperative morphine consumption (11 mg [5 to 21] versus 6 mg [0 to 17]) and postoperative nausea and vomiting (58 of 157 [37%] versus 37 of 157 [24%]; relative risk, 0.64; 95% CI, 0.45 to 0.90) were both less in the dexmedetomidine group, whereas measures of analgesia were similar in both groups. Dexmedetomidine patients had more delayed extubation and prolonged postanesthesia care unit stay.

Conclusions: This trial refuted the hypothesis that balanced opioid-free anesthesia with dexmedetomidine, compared with remifentanil, would result in fewer postoperative opioid-related adverse events. Conversely, it did result in a greater incidence of serious adverse events, especially hypoxemia and bradycardia.

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http://dx.doi.org/10.1097/ALN.0000000000003725DOI Listing
April 2021

Effect of High-Dose Baclofen on Agitation-Related Events Among Patients With Unhealthy Alcohol Use Receiving Mechanical Ventilation: A Randomized Clinical Trial.

JAMA 2021 02;325(8):732-741

Centre Hospitalo-Universitaire de Nantes, Service d'Anesthésie Réanimation Chirurgicale, France.

Importance: Unhealthy alcohol use can lead to agitation in the intensive care unit (ICU).

Objective: To assess whether high-dose baclofen reduces agitation-related events compared with placebo in patients with unhealthy alcohol use receiving mechanical ventilation.

Design, Settings, And Participants: This phase 3, double-blind, placebo-controlled, randomized clinical trial conducted in 18 ICUs in France recruited adults receiving mechanical ventilation who met criteria for unhealthy alcohol use. Patients were enrolled from June 2016 to February 2018; the last follow-up was in May 2019.

Interventions: Baclofen (n = 159), adjusted from 50 to 150 mg per day based on estimated glomerular filtration rate, or placebo (n = 155) during mechanical ventilation up to a maximum of 15 days before gradual dose reduction over 3 to 6 days.

Main Outcomes And Measures: The primary end point was the percentage of patients with at least 1 agitation-related event over the treatment period. Secondary outcomes included duration of mechanical ventilation, length of ICU stay, and 28-day mortality.

Results: Among 314 patients who were randomized (mean age, 57 years; 60 [17.2%] women), 313 (99.7%) completed the trial. There was a statistically significant decrease in the percentage of patients who experienced at least 1 agitation-related event in the baclofen group vs the placebo group (31 [19.7%] vs 46 [29.7%]; difference, -9.93% [95% CI, -19.45% to -0.42%]; adjusted odds ratio, 0.59 [95% CI, 0.35-0.99]). Of 18 prespecified secondary end points, 14 were not significantly different. Compared with the placebo group, the baclofen group had a significantly longer median length of mechanical ventilation (9 vs 8 days; difference, 2.00 [95% CI, 0.00-3.00]; hazard ratio [HR] for extubation, 0.76 [95% CI, 0.60-0.97]) and stay in the ICU (14 vs 11 days; difference, 2.00 [95% CI, 0.00-4.00]; HR for discharge, 0.70 [95% CI, 0.54-0.90]). At 28 days, there was no significant difference in mortality in the baclofen vs placebo group (25.3% vs 21.6%; adjusted odds ratio, 1.24 [95% CI, 0.72-2.13]). Delayed awakening (no eye opening at 72 hours after cessation of sedatives and analgesics) occurred in 14 patients (8.9%) in the baclofen group vs 3 (1.9%) in the placebo group.

Conclusions And Relevance: Among patients with unhealthy alcohol use receiving mechanical ventilation, treatment with high-dose baclofen, compared with placebo, resulted in a statistically significant reduction in agitation-related events. However, considering the modest effect and the totality of findings for the secondary end points and adverse events, further research is needed to determine the possible role of baclofen in this setting and to potentially optimize dosing.

Trial Registration: ClinicalTrials.gov Identifier: NCT02723383.
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http://dx.doi.org/10.1001/jama.2021.0658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903253PMC
February 2021

Study protocol for a multicentre, 2×2 factorial, randomised, controlled trial evaluating the interest of intravenous iron and tranexamic acid to reduce blood transfusion in hip fracture patients (the HiFIT study).

BMJ Open 2021 01 17;11(1):e040273. Epub 2021 Jan 17.

Département Anesthésie Réanimation, Centre Hospitalier Universitaire d'Angers, Angers, France.

Introduction: Blood transfusion and anaemia are frequent and are associated with poor outcomes in patients with hip fracture (HF). We hypothesised that preoperative intravenous iron and tranexamic acid (TXA) may reduce the transfusion rate in these patients.

Methods And Analysis: The HiFIT study is a multicentre, 2×2 factorial, randomised, double-blinded, controlled trial evaluating the effect of iron isomaltoside (IIM) (20 mg/kg) vs placebo and of TXA (intravenously at inclusion and topically during surgery) versus placebo on transfusion rate during hospitalisation, in patients undergoing emergency surgery for HF and having a preoperative haemoglobin between 95 and 130 g/L. 780 patients are expected. The primary endpoint is the proportion of patients receiving an allogenic blood transfusion of packed red blood cells from the day of surgery until hospital discharge (or until D30 if patient is still hospitalised). Enrolment started on March 2017 in 11 French hospitals. The study was stopped between July 2017 and August 2018 (because of investigation of serious AEs with IIM in Spain) and slowed down since March 2020 (COVID-19 crisis). The expected date of final follow-up is May 2022. Analyses of the intent-to-treat and per-protocol populations are planned.

Ethics And Dissemination: The HiFIT trial protocol has been approved by the Ethics Committee of Comité de Protection des Personnes Ouest II and the French authorities (ANSM). It will be carried out according to the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines. The results will be disseminated through presentation at scientific conferences and publication in peer-reviewed journals. The HiFIT trial will be the largest study evaluating iron and TXA in patients with HF.

Trial Registration Number: clinicalTrials.gov identifier: NCT02972294; EudraCT Number 2016-003087-40.
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http://dx.doi.org/10.1136/bmjopen-2020-040273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813351PMC
January 2021

The A2B trial, antibiotic prophylaxis for excision-graft surgery in burn patients: a multicenter randomized double-blind study.

Trials 2020 Nov 25;21(1):973. Epub 2020 Nov 25.

Department of Anaesthesiology, Critical Care Medicine and Burn unit, AP-HP, Saint Louis and Lariboisière University Hospitals, 1 Avenue Claude Vellefaux, 75010, Paris, France.

Background: The indication for antibiotic prophylaxis in burn patients remains highly controversial, with no consensus having been reached. The objective of antibiotic prophylaxis is to reduce the risk of postoperative local and systemic infections. Burn surgery is associated with a high incidence of bacteremia, postoperative infections, and sepsis. However, antibiotic prophylaxis exposes patients to the risk of selecting drug-resistant pathogens as well as to the adverse effects of antibiotics (i.e., Clostridium difficile colitis). The lack of data precludes any strong international recommendations regarding perioperative prophylaxis using systemic antibiotics in this setting. The goal of this project is therefore to determine whether perioperative systemic antibiotic prophylaxis can reduce the incidence of postoperative infections in burn patients.

Methods: The A2B trial is a multicenter (10 centers), prospective, randomized, double-blinded, placebo-controlled study. The trial will involve the recruitment of 506 adult burn patients with a total body surface area (TBSA) burn of between 5 and 40% and requiring at least one excision-graft surgery for deep burn injury. Participants will be randomized to receive antibiotic prophylaxis (antibiotic prophylaxis group) or a placebo (control group) 30 min before the incision of the first two surgeries. The primary outcome will be the occurrence of postoperative infections defined as postoperative sepsis and/or surgical site infection and/or graft lysis requiring a new graft within 7 days after surgery. Secondary outcomes will include mortality at day 90 postrandomization, skin graft lysis requiring a new graft procedure, postoperative bacteremia (within 48 h of surgery), postoperative sepsis, postoperative surgical site infection, number of hospitalizations until complete healing (> 95% TBSA), number of hospitalization days living without antibiotic therapy at day 28 and day 90, and multiresistant bacterial colonization or infection at day 28 and day 90.

Discussion: The trial aims to provide evidence on the efficacy and safety of antibiotic prophylaxis for excision-graft surgery in burn patients.

Trial Registration: ClinicalTrials.gov NCT04292054 . Registered on 2 March 2020.
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http://dx.doi.org/10.1186/s13063-020-04894-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687822PMC
November 2020

Pulmonary infections complicating ARDS.

Intensive Care Med 2020 12 11;46(12):2168-2183. Epub 2020 Nov 11.

IAME 1137, INSERM, Université de Paris, Paris, France.

Pulmonary infection is one of the main complications occurring in patients suffering from acute respiratory distress syndrome (ARDS). Besides traditional risk factors, dysregulation of lung immune defenses and microbiota may play an important role in ARDS patients. Prone positioning does not seem to be associated with a higher risk of pulmonary infection. Although bacteria associated with ventilator-associated pneumonia (VAP) in ARDS patients are similar to those in patients without ARDS, atypical pathogens (Aspergillus, herpes simplex virus and cytomegalovirus) may also be responsible for infection in ARDS patients. Diagnosing pulmonary infection in ARDS patients is challenging, and requires a combination of clinical, biological and microbiological criteria. The role of modern tools (e.g., molecular methods, metagenomic sequencing, etc.) remains to be evaluated in this setting. One of the challenges of antimicrobial treatment is antibiotics diffusion into the lungs. Although targeted delivery of antibiotics using nebulization may be interesting, their place in ARDS patients remains to be explored. The use of extracorporeal membrane oxygenation in the most severe patients is associated with a high rate of infection and raises several challenges, diagnostic issues and pharmacokinetics/pharmacodynamics changes being at the top. Prevention of pulmonary infection is a key issue in ARDS patients, but there is no specific measure for these high-risk patients. Reinforcing preventive measures using bundles seems to be the best option.
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http://dx.doi.org/10.1007/s00134-020-06292-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656898PMC
December 2020

COVID-19, steroids and other immunomodulators: The jigsaw is not complete.

Anaesth Crit Care Pain Med 2020 12 25;39(6):699-701. Epub 2020 Oct 25.

CHU Nantes, Université de Nantes, Pôle Anesthésie Réanimations, Service d'anesthésie Réanimation Chirurgicale, Hôtel Dieu, 44093 Nantes, France. Electronic address:

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http://dx.doi.org/10.1016/j.accpm.2020.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585715PMC
December 2020

Choice of fluid for critically ill patients: An overview of specific situations.

Anaesth Crit Care Pain Med 2020 12 19;39(6):837-845. Epub 2020 Oct 19.

Aix Marseille Université, Assistance Publique Hôpitaux de Marseille, Service d'Anesthésie et de Réanimation, Hôpital Nord, 13005 Marseille, France.

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http://dx.doi.org/10.1016/j.accpm.2020.10.003DOI Listing
December 2020

Evaluation of the FilmArray Pneumonia Panel for Rapid Diagnosis of Hospital-Acquired Pneumonia in Intensive Care Unit Patients.

Front Microbiol 2020 25;11:2080. Epub 2020 Aug 25.

Service de Bactériologie-Hygiène, Pôle de Biologie, CHU Nantes, Nantes, France.

The FilmArray Pneumonia Panel (FAPP) is a new multiplex molecular test for hospital-acquired pneumonia (HAP), which can rapidly detect 18 bacteria, 9 viruses, and 7 resistance genes. We aimed to compare the diagnosis performance of FAPP with conventional testing in 100 intensive care unit (ICU) patients who required mechanical ventilation, with clinically suspected HAP. A total of 237 samples [76 bronchoalveolar lavages (BAL) and 82 endotracheal aspirates (ETA) obtained at HAP diagnosis, and 79 ETA obtained during follow-up (ETA)], were analyzed independently by routine microbiology testing and FAPP. 58 patients had paired BAL and ETA. The positivity thresholds of semi-quantified bacteria were 10-10 CFUs/mL or 10 copies/mL for BAL, and 10 CFUs/mL or copies/mL for ETA. Respiratory commensals (, , , ) were the most common pathogens. Discordant results for bacterial identification were observed in 33/76 (43.4%) BAL and 36/82 (43.9%) ETA, and in most cases, FAPP identified one supplemental bacteria (23/33 BAL and 21/36 ETA). An absence of growth, or polybacterial cultures, explained almost equally the majority of the non-detections in culture. No linear relationship was observed between bin and CFUs/mL variables. Concordant results between paired BAL and ETA were obtained in 46/58 (79.3%) patients with FAPP. One of the 17 resistance genes detected with FAPP ( and MREJ) was not confirmed by conventional testing. Overall, FAPP enhanced the positivity rate of diagnostic testing, with increased recognition of coinfections. Implementing this strategy may allow clinicians to make more timely and informed decisions.
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http://dx.doi.org/10.3389/fmicb.2020.02080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477898PMC
August 2020

Implementation of French recommendations for the prevention and the treatment of hospital-acquired pneumonia: a cluster-randomized trial.

Clin Infect Dis 2020 Sep 24. Epub 2020 Sep 24.

Neuro-Intensive Care Unit, Centre Hospitalier Universitaire, Poitiers, France.

Background: We determined whether an audit on the adherence to guidelines for hospital-acquired pneumonia (HAP) for can improve the outcomes of patients in intensive care units (ICUs).

Methods: This study was conducted at 35 ICUs in 30 hospitals. We included consecutive adult patients hospitalized in ICUs for three days or more. After a three-month baseline period followed by the dissemination of recommendations, an audit on the compliance to recommendations (audit period) was followed by a three-month cluster-randomized trial. We randomly assigned ICUs to either audit and feedback (intervention group) or participation to a national registry (control group). The primary outcome was the duration of ICU stay.

Results: Among 1,856 patients enrolled, 602, 669, and 585 were recruited in the baseline, audit, and intervention periods, respectively. The composite measure of compliance was 47(38-56)% in the intervention group and 42(25-53)% in the control group (p=0.001). As compared to the baseline period, the ICU length of stay was reduced by 3.2 days in the intervention group (p=0.07) and by 2.8 days in the control group (p=0.02). The duration of ICU stay was 7 (5-14) in the control group and 9 (5-20) days in the intervention group (p=0.10). After adjustment for unbalanced baseline characteristics, the hazard ratio for being discharged alive from ICU in the control group was 1.17 (95% CI, 0.69 to 2.01; p=0.10).

Conclusions: The publication of French guidelines for HAP was associated with a reduction of the ICU length of stay. However, the realization of an audit to improve their application did not further improve outcomes.
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http://dx.doi.org/10.1093/cid/ciaa1441DOI Listing
September 2020

Pseudomonas aeruginosa Infection Impairs NKG2D-Dependent NK Cell Cytotoxicity through Regulatory T-Cell Activation.

Infect Immun 2020 11 16;88(12). Epub 2020 Nov 16.

Université de Nantes, Thérapeutiques Cliniques et Expérimentales des Infections, EA 3826, Institut de Recherche en Santé 2 Nantes Biotech, Nantes, France

Natural killer (NK) cells play a key role in both antibacterial and antitumor immunity. infection has already been reported to alter NK cell functions. We studied the effect of on NK cell cytotoxic response (CD107a membrane expression) to a lymphoma cell line. Through positive and negative cell sorting and adoptive transfer, we determined the influence of monocytes, lymphocytes, and regulatory T cells (Treg) on NK cell function during infection. We also studied the role of the activating receptor natural killer group 2D (NKG2D) in NK cell response to B221. We determined that significantly altered both cytotoxic response to B221 and NKG2D expression on NK cells in a Treg-dependent manner and that the NKG2D receptor was involved in NK cell cytotoxic response to B221. Our results also suggested that during infection, monocytes participated in Treg-mediated NK cell alteration. In conclusion, infection impairs NK cell cytotoxicity and alters antitumor immunity. These results highlight the strong interaction between bacterial infection and immunity against cancer.
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http://dx.doi.org/10.1128/IAI.00363-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671885PMC
November 2020

A Randomized, Double-blind, Multicenter Trial Comparing Efficacy and Safety of Imipenem/Cilastatin/Relebactam Versus Piperacillin/Tazobactam in Adults With Hospital-acquired or Ventilator-associated Bacterial Pneumonia (RESTORE-IMI 2 Study).

Clin Infect Dis 2020 Aug 12. Epub 2020 Aug 12.

Merck Research Laboratories, Merck & Co, Inc, Kenilworth, New Jersey, USA.

Background: Imipenem combined with the β-lactamase inhibitor relebactam has broad antibacterial activity, including against carbapenem-resistant gram-negative pathogens. We evaluated efficacy and safety of imipenem/cilastatin/relebactam in treating hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP).

Methods: This was a randomized, controlled, double-blind phase 3 trial. Adults with HABP/VABP were randomized 1:1 to imipenem/cilastatin/relebactam 500 mg/500 mg/250 mg or piperacillin/tazobactam 4 g/500 mg, intravenously every 6 hours for 7-14 days. The primary endpoint was day 28 all-cause mortality in the modified intent-to-treat (MITT) population (patients who received study therapy, excluding those with only gram-positive cocci at baseline). The key secondary endpoint was clinical response 7-14 days after completing therapy in the MITT population.

Results: Of 537 randomized patients (from 113 hospitals in 27 countries), the MITT population comprised 264 imipenem/cilastatin/relebactam and 267 piperacillin/tazobactam patients; 48.6% had ventilated HABP/VABP, 47.5% APACHE II score ≥15, 24.7% moderate/severe renal impairment, 42.9% were ≥65 years old, and 66.1% were in the intensive care unit. The most common baseline pathogens were Klebsiella pneumoniae (25.6%) and Pseudomonas aeruginosa (18.9%). Imipenem/cilastatin/relebactam was noninferior (P < .001) to piperacillin/tazobactam for both endpoints: day 28 all-cause mortality was 15.9% with imipenem/cilastatin/relebactam and 21.3% with piperacillin/tazobactam (difference, -5.3% [95% confidence interval {CI}, -11.9% to 1.2%]), and favorable clinical response at early follow-up was 61.0% and 55.8%, respectively (difference, 5.0% [95% CI, -3.2% to 13.2%]). Serious adverse events (AEs) occurred in 26.7% of imipenem/cilastatin/relebactam and 32.0% of piperacillin/tazobactam patients; AEs leading to treatment discontinuation in 5.6% and 8.2%, respectively; and drug-related AEs (none fatal) in 11.7% and 9.7%, respectively.

Conclusions: Imipenem/cilastatin/relebactam is an appropriate treatment option for gram-negative HABP/VABP, including in critically ill, high-risk patients.

Clinical Trials Registration: NCT02493764.
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http://dx.doi.org/10.1093/cid/ciaa803DOI Listing
August 2020

Regulatory T Cells Expressing Tumor Necrosis Factor Receptor Type 2 Play a Major Role in CD4+ T-Cell Impairment During Sepsis.

J Infect Dis 2020 09;222(7):1222-1234

EA3826 Thérapeutiques Anti-Infectieuses, Institut de Recherche en Santé 2 Nantes Biotech, Université de Nantes, Nantes, France.

Sepsis causes inflammation-induced immunosuppression with lymphopenia and alterations of CD4+ T-cell functions that renders the host prone to secondary infections. Whether and how regulatory T cells (Treg) are involved in this postseptic immunosuppression is unknown. We observed in vivo that early activation of Treg during Staphylococcus aureus sepsis induces CD4+ T-cell impairment and increases susceptibility to secondary pneumonia. The tumor necrosis factor receptor 2 positive (TNFR2pos) Treg subset endorsed the majority of effector immunosuppressive functions, and TNRF2 was particularly associated with activation of genes involved in cell cycle and replication in Treg, probably explaining their maintenance. Blocking or deleting TNFR2 during sepsis decreased the susceptibility to secondary infection. In humans, our data paralleled those in mice; the expression of CTLA-4 was dramatically increased in TNFR2pos Treg after culture in vitro with S. aureus. Our findings describe in vivo mechanisms underlying sepsis-induced immunosuppression and identify TNFR2pos Treg as targets for therapeutic intervention.
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http://dx.doi.org/10.1093/infdis/jiaa225DOI Listing
September 2020

Monocytic Human Leukocyte Antigen DR Expression in Young Infants Undergoing Cardiopulmonary Bypass.

Ann Thorac Surg 2021 05 8;111(5):1636-1642. Epub 2020 Jul 8.

CHU Nantes, Pôle Anesthésie Réanimations, Service d'Anesthésie Réanimation Chirurgicale, Hôtel Dieu, Nantes, France.

Background: Monocytic human leukocyte antigen DR (mHLA-DR) expression levels have been reported to be a marker of immunosuppression and a predictor of sepsis and mortality. There are, however, scant data regarding mHLA-DR monitoring in young infants after cardiopulmonary bypass. Our objectives were to investigate the kinetics of mHLA-DR expression and to determine whether mHLA-DR levels are associated with healthcare-associated infection (HAI) after cardiopulmonary bypass in young infants.

Methods: mHLA-DR levels were analyzed by flow cytometry using a standardized method in 49 infants (<3 months old) with congenital heart disease before and after cardiopulmonary bypass. Results are expressed as the number of anti-HLA-DR antibodies per cell (AB/c).

Results: Postoperative mHLA-DR expression was reduced in all infants. Eleven patients (22%) developed HAI, and 4 patients (8%) died during the 30-day follow-up. mHLA-DR expression was significantly lower on postoperative day 4 in the HAI group compared with those who without HAI (3768 AB/c [range, 1938-6144] vs 13,230 AB/c [range, 6152-19,130], P = .014). Although mHLA-DR expression was associated with postoperative severity, mHLA-DR ≤4500 AB/c in the first 72 hours among patients with higher postoperative severity (extracorporeal membrane oxygenation and/or corticoids and/or delayed closure of sternum) was associated with occurrence of HAI in the univariate analysis (odds ratio, 6.3; 95% confidence interval, 1.0-38.7; P = .037).

Conclusions: Cardiopulmonary bypass induces a profound decrease in mHLA-DR expression in young infants. Among patients with higher postoperative severity, low level of mHLA-DR in the early postoperative period is associated with the development of HAI.
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http://dx.doi.org/10.1016/j.athoracsur.2020.05.071DOI Listing
May 2021

Author Correction: Alveolar macrophages are epigenetically altered after inflammation, leading to long-term lung immunoparalysis.

Nat Immunol 2020 Aug;21(8):962

Université de Nantes, EA3826 Thérapeutiques Anti-Infectieuses, Institut de Recherche en Santé 2 Nantes Biotech, Nantes, France.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41590-020-0739-9DOI Listing
August 2020

Alveolar macrophages are epigenetically altered after inflammation, leading to long-term lung immunoparalysis.

Nat Immunol 2020 06 18;21(6):636-648. Epub 2020 May 18.

Université de Nantes, EA3826 Thérapeutiques Anti-Infectieuses, Institut de Recherche en Santé 2 Nantes Biotech, Nantes, France.

Sepsis and trauma cause inflammation and elevated susceptibility to hospital-acquired pneumonia. As phagocytosis by macrophages plays a critical role in the control of bacteria, we investigated the phagocytic activity of macrophages after resolution of inflammation. After resolution of primary pneumonia, murine alveolar macrophages (AMs) exhibited poor phagocytic capacity for several weeks. These paralyzed AMs developed from resident AMs that underwent an epigenetic program of tolerogenic training. Such adaptation was not induced by direct encounter of the pathogen but by secondary immunosuppressive signals established locally upon resolution of primary infection. Signal-regulatory protein α (SIRPα) played a critical role in the establishment of the microenvironment that induced tolerogenic training. In humans with systemic inflammation, AMs and also circulating monocytes still displayed alterations consistent with reprogramming six months after resolution of inflammation. Antibody blockade of SIRPα restored phagocytosis in monocytes of critically ill patients in vitro, which suggests a potential strategy to prevent hospital-acquired pneumonia.
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http://dx.doi.org/10.1038/s41590-020-0673-xDOI Listing
June 2020

Nationwide Analysis of Urinary Retention Following Inguinal Hernia Repair: Results from the National Prospective Hernia Registry.

World J Surg 2020 08;44(8):2638-2646

Clinique de Chirurgie Digestive et Endocrinienne (CCDE), Institut des Maladies de l'Appareil Digestif (IMAD), University Hospital of Nantes, 1, Place Alexis Ricordeau, 44093, Nantes, France.

Background: Urinary retention is one of the most common early postoperative complications following inguinal hernia repair (IHR). The aim of this study was to assess the incidence of postoperative urinary retention (POUR) and to identify associated risk factors.

Method: Data of consecutive patients undergoing IHR from 2011 to 2017 were collected from a national multicenter cohort. POUR was defined as the inability to void requiring urinary catheterization. A multivariate analysis was conducted to identify independent risk factors for POUR.

Results: Of 13,736 patients, 109 (0.8%) developed POUR. Patients with POUR had longer hospital length of stay (p < 0.001). IHR was performed by a laparoscopic or an open approach in 7012 (51.3%) and 6655 (48.7%) patients, respectively, and spinal anesthesia was realized in 591 (4.3%) patients. Ambulatory surgery was performed in 10,466 (76.6%) patients. Multivariate analysis identified preoperative dysuria (0R 3.73, p < 0.001), diabetes mellitus (OR 1.98, p = 0.029) and spinal anesthesia (OR 7.56, p < 0.001) as independent preoperative risk factors associated with POUR. POUR was the cause of ambulatory failure in 35 (10.2%) patients who required unanticipated admission.

Conclusion: The incidence of POUR following IHR remains low but impacts hospitalization settings. Preoperative risk factors for POUR should be considered for the choice of the anesthetic technique.
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http://dx.doi.org/10.1007/s00268-020-05538-7DOI Listing
August 2020

Feasibility and impact of the implementation of a clinical scale-based sedation-analgesia protocol in severe burn patients undergoing mechanical ventilation. A before-after bi-center study.

Burns 2020 09 8;46(6):1310-1317. Epub 2020 Mar 8.

Anesthesia and Critical Care, University Hospital of Nantes, Hôtel Dieu, 1 place Alexis Ricordeau, Nantes 44093, France; Laboratoire UPRES EA 3826 «Thérapeutiques cliniques et expérimentales des infections». University hospital of Nantes, 22 boulevard Benoni-Goullin, Nantes 44200, France.

Background: Severe burn patients undergo prolonged administration of sedatives and analgesics for burn care. There are currently no guidelines for the dose adaptation of sedation-analgesia in severe burn patients.

Methods: We performed a before-after 2-center study to demonstrate the feasibility and efficacy of a sedation-analgesia scale-based protocol in severely burned patients receiving ≥24h of invasive mechanical ventilation. Before the intervention, continuous infusion of hypnotic and morphine derivatives was continued. During the Intervention phase, general anesthesia was relayed from day 1 by RASS/BPS-titrated continuous infusion of hypnotic and morphine derivatives and with short half-life drugs adminstered for daily burn dressings. The primary outcome was the duration of invasive mechanical ventilation in the ICU.

Results: Eighty-seven (46.2%) patients were included in the Control phase and 101 (53.7%) in the Intervention phase. The median burned cutaneous surface was 20% [11%-38%] and median ABSI was 7 [5-9]. The durations of hypnotic and opioid infusions were not statistically different between the 2 phases (8 days [2-24] vs. 6 days [2-17] (P=0.3) and 17 days [4-32] vs. 8 days [3-23] (P=0.06), respectively). The duration of mechanical ventilation was 14 days [3-29] in the Control phase and 7 days [2-24] in the Intervention phase (P=0.7). When taking into account the competition between mortality and weaning from mechanical ventilation, we found no significant difference between the 2 phases (Gray test, P=0.4). The time-series analysis showed no difference for the duration of mechanical ventilation in the Intervention phase (P=0.6). Eighteen (20.7%) patients died in the Control phase, and 18 (18%) in the Intervention phase (P=0.6).

Conclusion: Scale-based lightening of continuous sedation-analgesia with repeated short general anesthesia for dressing is feasible in severe burn patients but failed to demonstrate a decrease in the duration of invasive mechanical ventilation.
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http://dx.doi.org/10.1016/j.burns.2020.02.009DOI Listing
September 2020

Management of severe thermal burns in the acute phase in adults and children.

Anaesth Crit Care Pain Med 2020 04 5;39(2):253-267. Epub 2020 Mar 5.

Department of Anaesthesiology, Critical Care and Burn Centre, Lariboisière-Saint-Louis Hospitals, DMU Parabol, AP-HP Nord, University of Paris, Paris, France; Inserm UMR-S 942, Cardiovascular Markers in Stress Conditions (MASCOT), University of Paris, Paris, France; Department of Research, University of Ottawa Heart Institute, Ottawa, ON, Canada.

Objectives: To provide recommendations to facilitate the management of severe thermal burns during the acute phase in adults and children.

Design: A committee of 20 experts was asked to produce recommendations in six fields of burn management, namely, (1) assessment, admission to specialised burns centres, and telemedicine; (2) haemodynamic management; (3) airway management and smoke inhalation; (4) anaesthesia and analgesia; (5) burn wound treatments; and (6) other treatments. At the start of the recommendation-formulation process, a formal conflict-of-interest policy was developed and enforced throughout the process. The entire process was conducted independently of any industry funding. The experts drew up a list of questions that were formulated according to the PICO model (Population, Intervention, Comparison, and Outcomes). Two bibliography experts per field analysed the literature published from January 2000 onwards using predefined keywords according to PRISMA recommendations. The quality of data from the selected literature was assessed using GRADE® methodology. Due to the current paucity of sufficiently powered studies regarding hard outcomes (i.e. mortality), the recommendations are based on expert opinion.

Results: The SFAR guidelines panel generated 24 statements regarding the management of acute burn injuries in adults and children. After two scoring rounds and one amendment, strong agreement was reached for all recommendations.

Conclusion: Substantial agreement was reached among a large cohort of experts regarding numerous strong recommendations to optimise the management of acute burn injuries in adults and children.
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http://dx.doi.org/10.1016/j.accpm.2020.03.006DOI Listing
April 2020

About prevention of early ventilator-associated pneumonia after cardiac arrest.

Anaesth Crit Care Pain Med 2020 02 7;39(1):9-10. Epub 2020 Jan 7.

Anaesthesiology and Intensive Care Unit, Hôtel-Dieu, CHU Nantes, Nantes, France. Electronic address:

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http://dx.doi.org/10.1016/j.accpm.2020.01.002DOI Listing
February 2020

Effect of Hydroxyethyl Starch vs Saline for Volume Replacement Therapy on Death or Postoperative Complications Among High-Risk Patients Undergoing Major Abdominal Surgery: The FLASH Randomized Clinical Trial.

JAMA 2020 01;323(3):225-236

CHU Montpellier, Département Anesthésie et Réanimation B (DAR B), Hôpital Saint-Eloi, and Inserm U-1046, Montpellier, France.

Importance: It is not known if use of colloid solutions containing hydroxyethyl starch (HES) to correct for intravascular deficits in high-risk surgical patients is either effective or safe.

Objective: To evaluate the effect of HES 130/0.4 compared with 0.9% saline for intravascular volume expansion on mortality and postoperative complications after major abdominal surgery.

Design, Setting, And Participants: Multicenter, double-blind, parallel-group, randomized clinical trial of 775 adult patients at increased risk of postoperative kidney injury undergoing major abdominal surgery at 20 university hospitals in France from February 2016 to July 2018; final follow-up was in October 2018.

Interventions: Patients were randomized to receive fluid containing either 6% HES 130/0.4 diluted in 0.9% saline (n = 389) or 0.9% saline alone (n = 386) in 250-mL boluses using an individualized hemodynamic algorithm during surgery and for up to 24 hours on the first postoperative day, defined as ending at 7:59 am the following day.

Main Outcomes And Measures: The primary outcome was a composite of death or major postoperative complications at 14 days after surgery. Secondary outcomes included predefined postoperative complications within 14 days after surgery, durations of intensive care unit and hospital stays, and all-cause mortality at postoperative days 28 and 90.

Results: Among 826 patients enrolled (mean age, 68 [SD, 7] years; 91 women [12%]), 775 (94%) completed the trial. The primary outcome occurred in 139 of 389 patients (36%) in the HES group and 125 of 386 patients (32%) in the saline group (difference, 3.3% [95% CI, -3.3% to 10.0%]; relative risk, 1.10 [95% CI, 0.91-1.34]; P = .33). Among 12 prespecified secondary outcomes reported, 11 showed no significant difference, but a statistically significant difference was found in median volume of study fluid administered on day 1: 1250 mL (interquartile range, 750-2000 mL) in the HES group and 1500 mL (interquartile range, 750-2150 mL) in the saline group (median difference, 250 mL [95% CI, 83-417 mL]; P = .006). At 28 days after surgery, 4.1% and 2.3% of patients had died in the HES and saline groups, respectively (difference, 1.8% [95% CI, -0.7% to 4.3%]; relative risk, 1.76 [95% CI, 0.79-3.94]; P = .17).

Conclusions And Relevance: Among patients at risk of postoperative kidney injury undergoing major abdominal surgery, use of HES for volume replacement therapy compared with 0.9% saline resulted in no significant difference in a composite outcome of death or major postoperative complications within 14 days after surgery. These findings do not support the use of HES for volume replacement therapy in such patients.

Trial Registration: ClinicalTrials.gov Identifier: NCT02502773.
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http://dx.doi.org/10.1001/jama.2019.20833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990683PMC
January 2020