Publications by authors named "Hamid Merdji"

23 Publications

  • Page 1 of 1

A Translational Investigation of Interferon-α and STAT1 Signaling in Endothelial Cells during Septic Shock Provides Therapeutic Perspectives.

Am J Respir Cell Mol Biol 2021 Apr 2. Epub 2021 Apr 2.

Strasbourg 1 University, 27083, Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM (French National Institute of Health and Medical Research), UMR_S1109, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Strasbourg, France;

Septic shock and disseminated intravascular coagulation (DIC) are knowingly characterized by an endothelial cell dysfunction. The molecular mechanisms underlying this relationship are, however, poorly understood. In this work, me aimed at investigating human circulating interferon-α (IFN-α) in septic shock-induced DIC patients and tested the potential role of endothelial Stat1 as a therapeutic target in a mouse model of sepsis. For this, circulating type I, II and III IFNs and procoagulant microvesicles were quantified in a prospective cohort of septic shock patients. Next, we used a septic shock model induced by cecal ligation and puncture (CLP) in wild-type (WT) mice, in Ifnar1 (type I IFN receptor subunit 1)-knockout (KO) mice, as well as in Stat1 (Signal transducer and activator of transcription 1) conditional KO mice. In humans samples, we observed higher levels of circulating IFN-α and IFN-α1 in DIC compared to non-DIC patients, while levels of IFN-β, IFN-γ, IFN-λ1, IFN-λ2, IFN-λ3 were not different. IFN-α level was positively correlated with CD105-microvesicle levels, reflecting endothelial injury. In Ifnar1-/- mice, CLP did not induce septic shock and was characterized by lesser endothelial cell injury, with lower aortic inflammatory cytokine expression, endothelial inflammatory-related genes expression and fibrinolysis. In mice in which Stat1 was specifically ablated in endothelial cells, a marked protection against sepsis was also observed, suggesting the relevance of an endothelium-targeted strategy. Our work highlights the key roles of type I interferons as pathogenic players in septic shock-induced DIC and the potential pertinence of endothelial STAT1 as a therapeutic target.
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http://dx.doi.org/10.1165/rcmb.2020-0401OCDOI Listing
April 2021

Kinetic Glomerular Filtration Rate Equations in Patients With Shock: Comparison With the Iohexol-Based Gold-Standard Method.

Crit Care Med 2021 Mar 12. Epub 2021 Mar 12.

CHRU Tours, Médecine Intensive Réanimation, CIC INSERM 1415, CRICS-TriggerSEP research network, Tours, France. CHR Orléans, Médecine Intensive Réanimation, CRICS-TriggerSEP research network, Orléans, France. Université de Strasbourg (UNISTRA), Faculté de Médecine, Hôpitaux universitaires de Strasbourg, Nouvel Hôpital Civil, Service de Médecine Intensive-Réanimation, Strasbourg, France. INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine (RNM), FMTS, Strasbourg, France. CHRU Tours, Biochimie et Biologie Moléculaire, Tours, France. INSERM, Individual Profiling and Prevention of Risks with Immunosuppressive Therapies, U1248, Limoges, France. Service de Néphrologie, Hôpital Bretonneau, CHU Tours et EA4245, Université de Tours, Tours, France. INSERM, Centre d'étude des pathologies respiratoires, U1100, Université de Tours, Tours, France.

Objectives: Static glomerular filtration rate formulas are not suitable for critically ill patients because of nonsteady state glomerular filtration rate and variation in the volume of distribution. Kinetic glomerular filtration rate formulas remain to be evaluated against a gold standard. We assessed the most accurate kinetic glomerular filtration rate formula as compared to iohexol clearance among patients with shock.

Design: Retrospective multicentric study.

Setting: Three French ICUs in tertiary teaching hospitals.

Patients: Fifty-seven patients within the first 12 hours of shock.

Measurements And Main Results: On day 1, we compared kinetic glomerular filtration rate formulas with iohexol clearance, with or without creatinine concentration correction according to changes in volume of distribution and ideal body weight. We analyzed three static glomerular filtration rate formulas (Cockcroft and Gault, modification of diet in renal disease, and Chronic Kidney Disease-Epidemiology Collaboration), urinary creatinine clearance, and seven kinetic glomerular filtration rate formulas (Jelliffe, Chen, Chiou and Hsu, Moran and Myers, Yashiro, Seelhammer, and Brater). We evaluated 33 variants of these formulas after applying corrective factors. The bias ranged from 12 to 47 mL/min/1.73 m2. Only the Yashiro equation had a lower bias than urinary creatinine clearance before applying corrective factors (15 vs 20 mL/min/1.73 m2). The corrected Moran and Myers formula had the best mean bias, 12 mL/min/1.73 m2, but wide limits of agreement (-50 to 73). The corrected Moran and Myers value was within 30% of iohexol-clearance-measured glomerular filtration rate for 27 patients (47.4%) and was within 10% for nine patients (15.8%); other formulas showed even worse accuracy.

Conclusions: Kinetic glomerular filtration rate equations are not accurate enough for glomerular filtration rate estimation in the first hours of shock, when glomerular filtration rate is greatly decreased. They can both under- or overestimate glomerular filtration rate, with a trend to overestimation. Applying corrective factors to creatinine concentration or volume of distribution did not improve accuracy sufficiently to make these formulas reliable. Clinicians should not use kinetic glomerular filtration rate equations to estimate glomerular filtration rate in patients with shock.
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http://dx.doi.org/10.1097/CCM.0000000000004946DOI Listing
March 2021

Higher anticoagulation targets and risk of thrombotic events in severe COVID-19 patients: bi-center cohort study.

Ann Intensive Care 2021 Jan 25;11(1):14. Epub 2021 Jan 25.

Service de Médecine Intensive Réanimation, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, 1, Place de l'Hôpital, 67091, Strasbourg Cedex, France.

Background: Thromboprophylaxis of COVID-19 patients is a highly debated issue. We aimed to compare the occurrence of thrombotic/ischemic events in COVID-19 patients with acute respiratory distress syndrome (ARDS) treated with either prophylactic or therapeutic dosage of heparin. All patients referred for COVID-19 ARDS in two intensive care units (ICUs) from two centers of a French tertiary hospital were included in our cohort study. Patients were compared according to their anticoagulant treatment to evaluate the risk/benefit of prophylactic anticoagulation versus therapeutic anticoagulation. Medical history, symptoms, biological data and imaging were prospectively collected.

Results: One hundred and seventy-nine patients (73% men) were analyzed: 108 in prophylactic group and 71 in therapeutic group. Median age and SAPS II were 62 [IQR 51; 70] years and 47 [IQR 37; 63] points. ICU mortality rate was 17.3%. Fifty-seven patients developed clinically relevant thrombotic complications during their ICU stay, less frequently in therapeutic group (adjusted OR 0.38 [0.14-0.94], p = 0.04). The occurrences of pulmonary embolism (PE), deep vein thrombosis (DVT) and ischemic stroke were significantly lower in the therapeutic group (respective adjusted OR for PE: 0.19 [0.03-0.81]; DVT: 0.13 [0.01-0.89], stroke: 0.06 [0-0.68], all p < 0.05). The occurrence of bleeding complications was not significantly different between groups, neither were ICU length of stay or mortality rate. D-dimer levels were significantly lower during ICU stay, and aPTT ratio was more prolonged in the therapeutic group (p < 0.05).

Conclusion: Increasing the anticoagulation of severe COVID-19 patients to a therapeutic level might decrease thrombotic complications without increasing their bleeding risk.
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http://dx.doi.org/10.1186/s13613-021-00809-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829649PMC
January 2021

SARS-CoV-2 viral load in nasopharyngeal swabs in the emergency department does not predict COVID-19 severity and mortality.

Acad Emerg Med 2021 03 5;28(3):306-313. Epub 2021 Feb 5.

INSERM (French National Institute of Health and Medical Research, UMR 1260, Regenerative NanoMedicine (RNM), Fédération de Médecine Translationnelle (FMTS), University of Strasbourg, Strasbourg, France.

Introduction: The ongoing COVID-19 pandemic has led to devastating repercussions on health care systems worldwide. This viral infection has a broad clinical spectrum (ranging from influenza-like disease, viral pneumonia, and hypoxemia to acute respiratory distress syndrome requiring prolonged intensive care unit stays). The prognostic impact of measuring viral load on nasopharyngeal swab specimens (by reverse transcriptase polymerase chain reaction [RT-PCR]) is yet to be elucidated.

Methods: Between March 3 and April 5, 2020, we conducted a retrospective study on a cohort of COVID-19 patients (mild or severe disease) who were hospitalized after presenting to the emergency department (ED) and had at least one positive nasopharyngeal swab during their hospital stay. We led our study at the University Hospitals of Strasbourg in the Greater East region of France, one of the pandemic's epicenters in Europe.

Results: We have collected samples from a cohort of 287 patients with a confirmed diagnosis of COVID-19 who were included in our study. Nearly half of them (50.5%) presented a mild form of the disease, while the other half (49.5%) presented a severe form, requiring mechanical ventilation. Median (interquartile range) viral load on the initial upper respiratory swab at admission was 4.76 (3.29-6.06) log copies/reaction. When comparing survivors and nonsurvivors, this viral load measurement did not differ according to subgroups (p = 0.332). Additionally, we have found that respiratory viral load measurement was predictive of neither in-hospital mortality (adjusted odds ratio [AOR] = 1.05, 95% confidence interval [CI] = 0.85 to 1.31, p = 0.637) nor disease severity (AOR = 0.88, 95% CI = 0.73 to 1.06, p = 0.167).

Conclusion: Respiratory viral load measurement on the first nasopharyngeal swab (by RT-PCR) during initial ED management is neither a predictor of severity nor a predictor of mortality in SARS-CoV-2 infection. Host response to this viral infection along with the extent of preexisting comorbidities might be more foretelling of disease severity than the virus itself.
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http://dx.doi.org/10.1111/acem.14217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014851PMC
March 2021

Psychological effects of remote-only communication among reference persons of ICU patients during COVID-19 pandemic.

J Intensive Care 2021 Jan 9;9(1). Epub 2021 Jan 9.

Service de Médecine Intensive-Réanimation, Nouvel Hôpital Civil, Hôpitaux universitaires de Strasbourg, Strasbourg, France.

Background: During COVID-19 pandemic, visits have been prohibited in most French ICUs. Psychological effects, for reference persons (RPs), of remote-only communication have been assessed.

Methods: All RPs of patients referred to ICU for COVID-19 were included. HADS, IES-R, and satisfaction were evaluated at admission, discharge/death, and 3 months. At 3 months, a psychologist provided a qualitative description of RPs' psychological distress.

Results: Eighty-eight RPs were included. Prevalence of anxiety and depression was 83% and 73% respectively. At 3 months, lower HADS decrease was associated with patient death/continued hospitalization, and/or sleeping disorders in RPs (p < 0.01). Ninety-nine percent RPs felt the patient was safe (9 [7; 10]/10 points, Likert-type scale), confident with caregivers (10 [9; 10]/10 points), and satisfied with information provided (10 [9; 10]/10 points). All RPs stressed the specific-type of "responsibility" associated with being an RP in a remote-only context, leading RPs to develop narrow diffusion strategies (67%) and restrict the array of contacted relatives to a very few and/or only contacting them rarely. 10 RPs (30%) related the situation to a prior traumatic experience.

Conclusion: RPs experienced psychological distress and reported that being an RP in a remote-only communication context was a specific responsibility and qualified it as an overall negative experience.

Trial Registration: NCT04385121 . Registered 12 May 2020. https://clinicaltrials.gov/ .
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http://dx.doi.org/10.1186/s40560-020-00520-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794617PMC
January 2021

Prognostic Value of Troponin Elevation in COVID-19 Hospitalized Patients.

J Clin Med 2020 Dec 17;9(12). Epub 2020 Dec 17.

Department of Hypertension, Vascular Disease and Clinical Pharmacology, Strasbourg Regional University Hospital, 67091 Strasbourg, France.

(1) Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) penetrates the respiratory epithelium through angiotensin-converting enzyme-2 (ACE2) binding. Myocardial and endothelial expression of ACE2 could account for the growing body of reported evidence of myocardial injury in severe forms of Human Coronavirus Disease 2019 (COVID-19). We aimed to provide insight into the impact of troponin (hsTnI) elevation on SARS-CoV-2 outcomes in patients hospitalized for COVID-19. (2) Methods: This was a retrospective analysis of hospitalized adult patients with the SARS-CoV-2 infection admitted to a university hospital in France. The observation period ended at hospital discharge. (3) Results: During the study period, 772 adult, symptomatic COVID-19 patients were hospitalized for more than 24 h in our institution, of whom 375 had a hsTnI measurement and were included in this analysis. The median age was 66 (55-74) years, and there were 67% of men. Overall, 205 (55%) patients were placed under mechanical ventilation and 90 (24%) died. A rise in hsTnI was noted in 34% of the cohort, whereas only three patients had acute coronary syndrome (ACS) and one case of myocarditis. Death occurred more frequently in patients with hsTnI elevation (HR 3.95, 95% CI 2.69-5.71). In the multivariate regression model, a rise in hsTnI was independently associated with mortality (OR 3.12, 95% CI 1.49-6.65) as well as age ≥ 65 years old (OR 3.17, 95% CI 1.45-7.18) and CRP ≥ 100 mg/L (OR 3.62, 95% CI 1.12-13.98). After performing a sensitivity analysis for the missing values of hsTnI, troponin elevation remained independently and significantly associated with death (OR 3.84, 95% CI 1.78-8.28). (4) Conclusion: Our study showed a four-fold increased risk of death in the case of a rise in hsTnI, underlining the prognostic value of troponin assessment in the COVID-19 context.
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http://dx.doi.org/10.3390/jcm9124078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766903PMC
December 2020

Outcomes of COVID-19 Hospitalized Patients Previously Treated with Renin-Angiotensin System Inhibitors.

J Clin Med 2020 Oct 28;9(11). Epub 2020 Oct 28.

Department of Hypertension, Vascular Disease and Clinical Pharmacology, Strasbourg Regional University Hospital, 67091 Strasbourg, France.

(1) Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) penetrates respiratory epithelium through angiotensin-converting enzyme-2 binding, raising concerns about the potentially harmful effects of renin-angiotensin system inhibitors (RASi) on Human Coronavirus Disease 2019 (COVID-19) evolution. This study aimed to provide insight into the impact of RASi on SARS-CoV-2 outcomes in patients hospitalized for COVID-19. (2) Methods: This was a retrospective analysis of hospitalized adult patients with SARS-CoV-2 infection admitted to a university hospital in France. The observation period ended at hospital discharge. (3) Results: During the study period, 943 COVID-19 patients were admitted to our institution, of whom 772 were included in this analysis. Among them, 431 (55.8%) had previously known hypertension. The median age was 68 (56-79) years. Overall, 220 (28.5%) patients were placed under mechanical ventilation and 173 (22.4%) died. According to previous exposure to RASi, we defined two groups, namely, "RASi" ( = 282) and "RASi-free" ( = 490). Severe pneumonia (defined as leading to death and/or requiring intubation, high-flow nasal oxygen, noninvasive ventilation, and/or oxygen flow at a rate of ≥5 L/min) and death occurred more frequently in RASi-treated patients (64% versus 53% and 29% versus 19%, respectively). However, in a propensity score-matched cohort derived from the overall population, neither death (hazard ratio (HR) 0.93 (95% confidence interval (CI) 0.57-1.50), = 0.76) nor severe pneumonia (HR 1.03 (95%CI 0.73-1.44), = 0.85) were associated with RASi therapy. (4) Conclusion: Our study showed no correlation between previous RASi treatment and death or severe COVID-19 pneumonia after adjustment for confounders.
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http://dx.doi.org/10.3390/jcm9113472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692895PMC
October 2020

A Machine Learning Approach to Estimate the Glomerular Filtration Rate in Intensive Care Unit Patients Based on Plasma Iohexol Concentrations and Covariates.

Clin Pharmacokinet 2021 Feb;60(2):223-233

INSERM, IPPRITT, U1248, 87000, Limoges, France.

Objective: This work aims to evaluate whether a machine learning approach is appropriate to estimate the glomerular filtration rate in intensive care unit patients based on sparse iohexol pharmacokinetic data and a limited number of predictors.

Methods: Eighty-six unstable patients received 3250 mg of iohexol intravenously and had nine blood samples collected 5, 30, 60, 180, 360, 540, 720, 1080, and 1440 min thereafter. Data splitting was performed to obtain a training (75%) and a test set (25%). To estimate the glomerular filtration rate, 37 candidate potential predictors were considered and the best machine learning approach among multivariate-adaptive regression spline and extreme gradient boosting (Xgboost) was selected based on the root-mean-square error. The approach associated with the best results in a ten-fold cross-validation experiment was then used to select the best limited combination of predictors in the training set, which was finally evaluated in the test set.

Results: The Xgboost approach yielded the best performance in the training set. The best combination of covariates comprised iohexol concentrations at times 180 and 720 min; the relative deviation from these theoretical times; the difference between these two concentrations; the Simplified Acute Physiology Score II; serum creatinine; and the fluid balance. It resulted in a root-mean-square error of 6.2 mL/min and an r of 0.866 in the test set. Interestingly, the eight patients in the test set with a glomerular filtration rate < 30 mL/min were all predicted accordingly.

Conclusions: Xgboost provided accurate glomerular filtration rate estimation in intensive care unit patients based on two timed blood concentrations after iohexol intravenous administration and three additional predictors.
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http://dx.doi.org/10.1007/s40262-020-00927-6DOI Listing
February 2021

Delirium and encephalopathy in severe COVID-19: a cohort analysis of ICU patients.

Crit Care 2020 08 8;24(1):491. Epub 2020 Aug 8.

Hôpitaux Universitaires de Strasbourg, Service de Médecine Intensive-Réanimation, Nouvel Hôpital Civil, 1, place de l'Hôpital, F-67091, Strasbourg, Cedex, France.

Background: Neurotropism of SARS-CoV-2 and its neurological manifestations have now been confirmed. We aimed at describing delirium and neurological symptoms of COVID-19 in ICU patients.

Methods: We conducted a bicentric cohort study in two French ICUs of Strasbourg University Hospital. All the 150 patients referred for acute respiratory distress syndrome due to SARS-CoV-2 between March 3 and May 5, 2020, were included at their admission. Ten patients (6.7%) were excluded because they remained under neuromuscular blockers during their entire ICU stay. Neurological examination, including CAM-ICU, and cerebrospinal fluid analysis, electroencephalography, and magnetic resonance imaging (MRI) were performed in some of the patients with delirium and/or abnormal neurological examination. The primary endpoint was to describe the incidence of delirium and/or abnormal neurological examination. The secondary endpoints were to describe the characteristics of delirium, to compare the duration of invasive mechanical ventilation and ICU length of stay in patients with and without delirium and/or abnormal neurological symptoms.

Results: The 140 patients were aged in median of 62 [IQR 52; 70] years old, with a median SAPSII of 49 [IQR 37; 64] points. Neurological examination was normal in 22 patients (15.7%). One hundred eighteen patients (84.3%) developed a delirium with a combination of acute attention, awareness, and cognition disturbances. Eighty-eight patients (69.3%) presented an unexpected state of agitation despite high infusion rates of sedative treatments and neuroleptics, and 89 (63.6%) patients had corticospinal tract signs. Brain MRI performed in 28 patients demonstrated enhancement of subarachnoid spaces in 17/28 patients (60.7%), intraparenchymal, predominantly white matter abnormalities in 8 patients, and perfusion abnormalities in 17/26 patients (65.4%). The 42 electroencephalograms mostly revealed unspecific abnormalities or diffuse, especially bifrontal, slow activity. Cerebrospinal fluid examination revealed inflammatory disturbances in 18/28 patients, including oligoclonal bands with mirror pattern and elevated IL-6. The CSF RT-PCR SARS-CoV-2 was positive in one patient. The delirium/neurological symptoms in COVID-19 patients were responsible for longer mechanical ventilation compared to the patients without delirium/neurological symptoms. Delirium/neurological symptoms could be secondary to systemic inflammatory reaction to SARS-CoV-2.

Conclusions And Relevance: Delirium/neurological symptoms in COVID-19 patients are a major issue in ICUs, especially in the context of insufficient human and material resources.

Trial Registration: NA.
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http://dx.doi.org/10.1186/s13054-020-03200-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414289PMC
August 2020

Delirium and encephalopathy in severe COVID-19: a cohort analysis of ICU patients.

Crit Care 2020 08 8;24(1):491. Epub 2020 Aug 8.

Hôpitaux Universitaires de Strasbourg, Service de Médecine Intensive-Réanimation, Nouvel Hôpital Civil, 1, place de l'Hôpital, F-67091, Strasbourg, Cedex, France.

Background: Neurotropism of SARS-CoV-2 and its neurological manifestations have now been confirmed. We aimed at describing delirium and neurological symptoms of COVID-19 in ICU patients.

Methods: We conducted a bicentric cohort study in two French ICUs of Strasbourg University Hospital. All the 150 patients referred for acute respiratory distress syndrome due to SARS-CoV-2 between March 3 and May 5, 2020, were included at their admission. Ten patients (6.7%) were excluded because they remained under neuromuscular blockers during their entire ICU stay. Neurological examination, including CAM-ICU, and cerebrospinal fluid analysis, electroencephalography, and magnetic resonance imaging (MRI) were performed in some of the patients with delirium and/or abnormal neurological examination. The primary endpoint was to describe the incidence of delirium and/or abnormal neurological examination. The secondary endpoints were to describe the characteristics of delirium, to compare the duration of invasive mechanical ventilation and ICU length of stay in patients with and without delirium and/or abnormal neurological symptoms.

Results: The 140 patients were aged in median of 62 [IQR 52; 70] years old, with a median SAPSII of 49 [IQR 37; 64] points. Neurological examination was normal in 22 patients (15.7%). One hundred eighteen patients (84.3%) developed a delirium with a combination of acute attention, awareness, and cognition disturbances. Eighty-eight patients (69.3%) presented an unexpected state of agitation despite high infusion rates of sedative treatments and neuroleptics, and 89 (63.6%) patients had corticospinal tract signs. Brain MRI performed in 28 patients demonstrated enhancement of subarachnoid spaces in 17/28 patients (60.7%), intraparenchymal, predominantly white matter abnormalities in 8 patients, and perfusion abnormalities in 17/26 patients (65.4%). The 42 electroencephalograms mostly revealed unspecific abnormalities or diffuse, especially bifrontal, slow activity. Cerebrospinal fluid examination revealed inflammatory disturbances in 18/28 patients, including oligoclonal bands with mirror pattern and elevated IL-6. The CSF RT-PCR SARS-CoV-2 was positive in one patient. The delirium/neurological symptoms in COVID-19 patients were responsible for longer mechanical ventilation compared to the patients without delirium/neurological symptoms. Delirium/neurological symptoms could be secondary to systemic inflammatory reaction to SARS-CoV-2.

Conclusions And Relevance: Delirium/neurological symptoms in COVID-19 patients are a major issue in ICUs, especially in the context of insufficient human and material resources.

Trial Registration: NA.
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http://dx.doi.org/10.1186/s13054-020-03200-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414289PMC
August 2020

Neurologic and neuroimaging findings in patients with COVID-19: A retrospective multicenter study.

Neurology 2020 09 17;95(13):e1868-e1882. Epub 2020 Jul 17.

From the Hôpitaux Universitaires de Strasbourg (S.K., F.L., S.B., F.-D.A., T.W.), Service d'imagerie 2, Hôpital de Hautepierre; Engineering Science, Computer Science and Imaging Laboratory (S.K., N.M.), UMR 7357, University of Strasbourg-CNRS; Service de Neurologie (M. Anheim), Hôpitaux Universitaires de Strasbourg; Institut de Génétique et de Biologie Moléculaire et Cellulaire (M. Anheim), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Illkirch; Fédération de Médecine Translationnelle de Strasbourg (M. Anheim), Université de Strasbourg; Hôpitaux universitaires de Strasbourg (H.M., F.M., J.H.), Service de Médecine Intensive Réanimation, Nouvel Hôpital Civil; INSERM (French National Institute of Health and Medical Research) (H.M., F.M.), UMR 1260, Regenerative Nanomedicine, Fédération de Médecine Translationnelle de Strasbourg; Médecine Intensive-Réanimation (M.S., F.S.), Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg; Service de Neuroradiologie (H.O., F.B., J.M.), Hôpitaux Civils de Colmar; Service d'Imagerie (A. Khalil, A.G.), Unité de Neuroradiologie, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat Claude Bernard; Université Paris Diderot (A. Khalil), Paris; Service de Neurologie (S. Carré, C.L.), Centre Hospitalier de Haguenau; Service de Radiologie (M. Alleg), Centre Hospitalier de Haguenau; Service de Neuroradiologie, (E.S., R.A., F.Z.) Hôpital Central, CHU de Nancy; CHIC Unisanté (L.J., P.N., Y.T.M.), Hôpital Marie Madeleine, Forbach; Neuroimaging Department (G.H., J. Benzakoun, C.O., G. Boulouis, M.E.-G., B.K.), GHU Paris Psychiatrie et Neurosciences, Hôpital Sainte-Anne, Université de Paris, INSERM U1266, F-75014; CHU Rennes (J.-C.F., B.C.-N.), Department of Neuroradiology; CHU Rennes (A.M.), Medical Intensive Care Unit; Department of Neuroradiology (P.-O.C., F.R., P.T.), University Hospital of Dijon, Hôpital François Mitterrand; Service de Radiologie (C.B.), CHU de Saint-Etienne; Service de Réanimation (X.F.), CH de Roanne; Service de Neuroradiologie (G.F., S.S.), CHU de Limoges; Radiology Department (I.d.B., G. Bornet), Hôpital Privé d'Antony; Department of Diagnostic and Interventional Neuroradiology (H.D.), University Hospital, Nantes; Neuroradiology Department (J. Berge), CHU de Bordeaux; Service de Neuroradiologie (A. Kazémi), CHU de Lille; Assistance Publique Hôpitaux de Paris (N.P.), Service de Neuroradiologie, Hôpital Pitié-Salpêtrière; Sorbonne Université (N.P.), Univ Paris 06, UMR S 1127, CNRS UMR 7225, ICM, F-75013; Service de Neuroradiologie Diagnostique (A.L.), Foundation A. Rothschild Hospital, Paris; EA CHIMERE 7516 (J.-M.C.), Université de Picardie Jules Verne; Service de NeuroRadiologie, pôle Imagerie Médicale, Centre Hospitalo-Universitaire d'Amiens; Hôpitaux Universitaires de Strasbourg (P.-E.Z., M.M.), UCIEC, Pôle d'Imagerie, Strasbourg; Observatoire Français de la Sclérose en Plaques (J.-C.B.), Lyon; Nephrology and Transplantation Department (S. Caillard), Hôpitaux Universitaires de Strasbourg; Inserm UMR S1109 (S. Caillard), LabEx Transplantex, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg; Hôpitaux Universitaires de Strasbourg (O.C., P.M.M.), Service d'Anesthésie-Réanimation, Nouvel Hôpital Civil; Hôpitaux Universitaires de Strasbourg (S.F.-K.), Laboratoire de Virologie Médicale; Radiology Department (M.O.), Nouvel Hôpital Civil, Strasbourg University Hospital; CHU de Strasbourg (N.M.), Service de Santé Publique, GMRC, F-67091 Strasbourg; Immuno-Rhumatologie Moléculaire (S.F.-K., J.H.), INSERM UMR_S1109, LabEx TRANSPLANTEX, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg; MRI Center (F.C.), Centre Hospitalier Lyon Sud, Hospices Civils de Lyon; and Université Lyon 1 (F.C.), CREATIS-LRMN, CNRS/UMR/5220-INSERM U630, Villeurbanne, France.

Objective: To describe neuroimaging findings and to report the epidemiologic and clinical characteristics of patients with coronavirus disease 2019 (COVID-19) with neurologic manifestations.

Methods: In this retrospective multicenter study (11 hospitals), we included 64 patients with confirmed COVID-19 with neurologic manifestations who underwent a brain MRI.

Results: The cohort included 43 men (67%) and 21 women (33%); their median age was 66 (range 20-92) years. Thirty-six (56%) brain MRIs were considered abnormal, possibly related to severe acute respiratory syndrome coronavirus. Ischemic strokes (27%), leptomeningeal enhancement (17%), and encephalitis (13%) were the most frequent neuroimaging findings. Confusion (53%) was the most common neurologic manifestation, followed by impaired consciousness (39%), presence of clinical signs of corticospinal tract involvement (31%), agitation (31%), and headache (16%). The profile of patients experiencing ischemic stroke was different from that of other patients with abnormal brain imaging: the former less frequently had acute respiratory distress syndrome ( = 0.006) and more frequently had corticospinal tract signs ( = 0.02). Patients with encephalitis were younger ( = 0.007), whereas agitation was more frequent for patients with leptomeningeal enhancement ( = 0.009).

Conclusions: Patients with COVID-19 may develop a wide range of neurologic symptoms, which can be associated with severe and fatal complications such as ischemic stroke or encephalitis. In terms of meningoencephalitis involvement, even if a direct effect of the virus cannot be excluded, the pathophysiology seems to involve an immune or inflammatory process given the presence of signs of inflammation in both CSF and neuroimaging but the lack of virus in CSF.

Clinicaltrialsgov Identifier: NCT04368390.
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http://dx.doi.org/10.1212/WNL.0000000000010112DOI Listing
September 2020

Performances of disseminated intravascular coagulation scoring systems in septic shock patients.

Ann Intensive Care 2020 Jul 10;10(1):92. Epub 2020 Jul 10.

Hôpitaux Universitaires de Strasbourg, Service de Médecine Intensive Réanimation, Nouvel Hôpital Civil, 1, Place de l'Hôpital, 67091, Strasbourg Cedex, France.

Background: There is no gold standard to diagnose septic shock-induced disseminated intravascular coagulation (DIC). The objective of our multicenter prospective study was to assess the performances of the different major scoring systems in terms of mortality prediction and DIC diagnosis. The JAAM-DIC 2016 score, the ISTH overt-DIC 2001 score, the associations of sepsis-induced coagulopathy (SIC) score with JAAM-DIC 2016 or ISTH overt-DIC scores were tested in patients within 12 h of their admission in ICU for septic shock (day 1) and at day 2.

Results: 582 patients were enrolled in the study. 182/567 (32.1%) were diagnosed with DIC according to ISTH overt-DIC score, and 193/561 (34.4%) according to JAAM-DIC score; 486/577 patients (84.2%) were diagnosed with a coagulopathy according to SIC score. A moderate concordance was observed between ISTH overt-DIC and JAAM-DIC [κ = 0.67 (0.60, 0.73), p < 0.001]. The delay of positivity of the scores for early DIC patients was not different between JAAM-DIC and ISTH overt-DIC scores. Although it was positive earlier, SIC score had worse diagnosis specificity, as 84.2% of the patients with septic shock were diagnosed with "coagulopathy". The specificity of SIC score alone to predict mortality was very low [0.18 (0.15; 0.22)], compared to the ones of JAAM-DIC score [0.71 (0.67; 0.75)], and of ISTH overt-DIC score [0.76 (0.72; 0.80)], p < 0.001. The sensitivity of SIC score to predict mortality was 0.95 [0.89; 0.98], and the ones of JAAM-DIC score and ISTH overt-DIC score were 0.61 [0.50; 0.70] and 0.68 [0.58; 0.77], respectively. There was no benefit in sensitivity and specificity in combining SIC score to JAAM-DIC score or to ISTH overt-DIC score, compared to JAAM-DIC score or ISTH overt-DIC score alone.

Conclusions: Our data suggest that the added value of SIC score alone or combined with other scores is limited, and that both JAAM-DIC score and ISTH overt-DIC score can be used in septic shock patients. Trial registration clinicaltrial; Trial registration number: NCT02391792; Date of registration: 18/03/2015; URL of trial registry record: https://clinicaltrials.gov/ct2/show/NCT02391792?term=meziani&draw=4&rank=1.
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http://dx.doi.org/10.1186/s13613-020-00704-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352012PMC
July 2020

Prothrombotic phenotype in COVID-19 severe patients.

Intensive Care Med 2020 07 20;46(7):1502-1503. Epub 2020 May 20.

Hôpitaux Universitaires de Strasbourg, Service de Médecine Intensive Réanimation, Nouvel Hôpital Civil, 1, place de l'Hôpital, 67091, Strasbourg cedex, France.

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http://dx.doi.org/10.1007/s00134-020-06082-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237619PMC
July 2020

High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study.

Intensive Care Med 2020 06 4;46(6):1089-1098. Epub 2020 May 4.

Service de Médecine Intensive Réanimation, Nouvel Hôpital Civil, Hôpitaux universitaires de Strasbourg, 1, Place de l'Hôpital, 67091, Strasbourg Cedex, France.

Purpose: Little evidence of increased thrombotic risk is available in COVID-19 patients. Our purpose was to assess thrombotic risk in severe forms of SARS-CoV-2 infection.

Methods: All patients referred to 4 intensive care units (ICUs) from two centers of a French tertiary hospital for acute respiratory distress syndrome (ARDS) due to COVID-19 between March 3rd and 31st 2020 were included. Medical history, symptoms, biological data and imaging were prospectively collected. Propensity score matching was performed to analyze the occurrence of thromboembolic events between non-COVID-19 ARDS and COVID-19 ARDS patients.

Results: 150 COVID-19 patients were included (122 men, median age 63 [53; 71] years, SAPSII 49 [37; 64] points). Sixty-four clinically relevant thrombotic complications were diagnosed in 150 patients, mainly pulmonary embolisms (16.7%). 28/29 patients (96.6%) receiving continuous renal replacement therapy experienced circuit clotting. Three thrombotic occlusions (in 2 patients) of centrifugal pump occurred in 12 patients (8%) supported by ECMO. Most patients (> 95%) had elevated D-dimer and fibrinogen. No patient developed disseminated intravascular coagulation. Von Willebrand (vWF) activity, vWF antigen and FVIII were considerably increased, and 50/57 tested patients (87.7%) had positive lupus anticoagulant. Comparison with non-COVID-19 ARDS patients (n = 145) confirmed that COVID-19 ARDS patients (n = 77) developed significantly more thrombotic complications, mainly pulmonary embolisms (11.7 vs. 2.1%, p < 0.008). Coagulation parameters significantly differed between the two groups.

Conclusion: Despite anticoagulation, a high number of patients with ARDS secondary to COVID-19 developed life-threatening thrombotic complications. Higher anticoagulation targets than in usual critically ill patients should therefore probably be suggested.
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http://dx.doi.org/10.1007/s00134-020-06062-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197634PMC
June 2020

Evaluation of anti-Xa activity after injection of a heparin lock for dialysis catheters in intensive care: A prospective observational study.

Thromb Res 2020 04 11;188:82-84. Epub 2020 Feb 11.

Service de Médecine Intensive-Réanimation, CHRU Strasbourg, Faculté de Médecine, Strasbourg, France; ImmunoRhumatologie Moléculaire, INSERM UMR_S1109, LabEx TRANSPLANTEX, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France.

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http://dx.doi.org/10.1016/j.thromres.2020.02.006DOI Listing
April 2020

Influence of deprivation on initial severity and prognosis of patients admitted to the ICU: the prospective, multicentre, observational IVOIRE cohort study.

Ann Intensive Care 2020 Feb 11;10(1):20. Epub 2020 Feb 11.

INSERM, CIC 1432, Module Epidémiologie Clinique, Dijon, France.

Background: The influence of socioeconomic status on patient outcomes is unclear. We assessed the impact of socioeconomic deprivation on severity of illness at intensive care unit (ICU) admission, and on the risk of death at 3 months after ICU admission.

Methods: The IVOIRE study was a prospective, observational, multicentre cohort study in the ICU of 8 participating hospitals in France, including patients aged ≥ 18 years admitted to the ICU and receiving at least one life support therapy for organ failure. The primary outcomes were severity at admission (assessed by SAPSII score), and mortality at 3 months. Socioeconomic data were obtained from interviews with patients or family. Deprivation was assessed using the EPICES score.

Results: Among 1294 patents included between 2013 and 2016, 629 (48.6%) were classed as deprived and differed significantly from non-deprived subjects in terms of sociodemographic characteristics and pre-existing conditions. The mean SAPS II score at admission was 50.1 ± 19.4 in deprived patients and 52.3 ± 17.3 in non-deprived patients, with no significant difference by multivariable analysis (β = - 1.85 [95% CI - 3.86; + 0.16, p = 0.072]). The proportion of death was 31.1% at 3 months, without significant differences between deprived and non-deprived patients, even after adjustment for confounders.

Conclusions: Deprivation is frequent in patients admitted to the ICU and is not associated with disease severity at admission, or with mortality at 3 months between deprived and non-deprived patients. Trial registration The IVOIRE cohort is registered with ClinicalTrials.gov under the identifier NCT01907581, registration date 17/7/2013.
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http://dx.doi.org/10.1186/s13613-020-0637-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013026PMC
February 2020

Sepsis inhibits tumor growth in mice with cancer through Toll-like receptor 4-associated enhanced Natural Killer cell activity.

Oncoimmunology 2019;8(11):e1641391. Epub 2019 Jul 19.

Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.

Sepsis-induced immune dysfunctions are likely to impact on malignant tumor growth. Sequential sepsis-then-cancer models of tumor transplantation in mice recovering from sepsis have shown that the post-septic immunosuppressive environment was able to promote tumor growth. We herein addressed the impact of sepsis on pre-established malignancy in a reverse cancer-then sepsis experimental model. Mice previously inoculated with MCA205 fibrosarcoma cells were subjected to septic challenges by polymicrobial peritonitis induced by cecal ligation and puncture or endotoxinic shock. The anti-tumoral immune response was assessed through the distribution of tumor-infiltrating immune cells, as well as the functions of cytotoxic cells. As compared to sham surgery, polymicrobial sepsis dampened malignant tumor growth in wild-type (WT) mice, but neither in ( nor in mice. Similar tumor growth inhibition was observed following a LPS challenge in WT mice, suggesting a regulatory role of Tlr4 in this setting. The low expression of MHC class 1 onto MCA205 cells suggested the involvement of Natural Killer (NK) cells in sepsis-induced tumor inhibition. Septic insults applied to mice with cancer promoted the main anti-tumoral NK functions of IFNγ production and degranulation. The anti-tumoral properties of NK cells obtained from septic mice were exacerbated when cultured with MHC1 MCA205 or YAC-1 cells. These results suggest that sepsis may harbor dual effects on tumor growth depending on the sequential experimental model. When applied in mice with cancer, sepsis prevents tumor growth in a Tlr4-dependent manner by enhancing the anti-tumoral functions of NK cells.
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http://dx.doi.org/10.1080/2162402X.2019.1641391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791422PMC
July 2019

Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm.

N Engl J Med 2019 12 2;381(24):2327-2337. Epub 2019 Oct 2.

From Médecine Intensive Réanimation, University Hospital Center, Nantes (J.-B.L., N.B., J.R.), the Paris Cardiovascular Research Center, INSERM Unité 970 (J.-B.L., A.C.), the Medical Intensive Care Unit, Cochin University Hospital Center (A.C.), and the AfterROSC Network (J.-B.L., A.C., N.P., S.L.), Paris, Université de Strasbourg, Faculté de Médecine (H.M.), Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Service de Médecine Intensive Réanimation (H.M.), and Unité Mixte de Recherche (UMR) 1260, Regenerative Nano Medecine, INSERM, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg (H.M.), Strasbourg, INSERM Centres d'Investigation Clinique (CIC) 1415, Centre Hospitalier Régional Universitaire de Tours (A.L.G., B.G.), the Medical Intensive Care Unit, University Hospital Center (P.-F.D.), INSERM UMR 1100-Centre d'Etude des Pathologies Respiratoires, Tours University (P.-F.D.), and Université de Tours (B.G.), Tours, the Medical-Surgical Intensive Care Unit, District Hospital Center, La Roche-sur-Yon (G.C.), the Medical Intensive Care Unit, South Brittany General Hospital Center, Lorient (G.G.), Médecine Intensive Réanimation, Centre Hospitalier Universitaire Lille, and Université de Lille, Faculté de Médicine, Lille (P.G.), the Medical Intensive Care Unit, University Hospital Center, Clermond-Ferrand (E.C.), the Medical Intensive Care Unit, Regional Hospital Center, Orleans (T.B.), the Medical Intensive Care Unit, University Hospital Center, INSERM CIC 1402, Équipe ALIVE, and Université de Poitiers, Faculté de Médecine et de Pharmacie de Poitiers, Poitiers (J.-P.F.), the Medical Intensive Care Unit, University Hospital Center, Angers (P.A.), Service de Réanimation Polyvalente, University Hospital Center, and CIC 1435, University Hospital Center, Limoges (N.P.), the Medical-Surgical Intensive Care Unit, General Hospital Center, Le Mans (M.L.), the Medical-Surgical Intensive Care Unit, General Hospital Center, Argenteuil (G.P.), the Medical Intensive Care Unit, University Hospital Center, Dijon (J.-P.Q.), the Medical-Surgical Intensive Care Unit, General Hospital Center, Roanne (J.-C.C.), the Medical-Surgical Intensive Care Unit, General Hospital Center, Annecy (M.S.), the Medical-Surgical Intensive Care Unit, Versailles Hospital, Versailles (S.L.), the Medical-Surgical Intensive Care Unit, General Hospital Center, Saint Brieuc (J.L.), the Medical-Surgical Intensive Care Unit, General Hospital Center, Lens (D.T.), the Medical-Surgical Intensive Care Unit, General Hospital Center, Angouleme (A. Desachy), the Medical-Surgical Intensive Care Unit, General Hospital Center, Rodez (A. Delahaye), the Medical-Surgical Intensive Care Unit, General Hospital Center, Saint Malo (V.B.), the Medical-Surgical Intensive Care Unit, General Hospital Center, Montauban (S.V.), and the Medical Intensive Care Unit, University Hospital Center, Point-a-Pitre (F.M.) - all in France.

Background: Moderate therapeutic hypothermia is currently recommended to improve neurologic outcomes in adults with persistent coma after resuscitated out-of-hospital cardiac arrest. However, the effectiveness of moderate therapeutic hypothermia in patients with nonshockable rhythms (asystole or pulseless electrical activity) is debated.

Methods: We performed an open-label, randomized, controlled trial comparing moderate therapeutic hypothermia (33°C during the first 24 hours) with targeted normothermia (37°C) in patients with coma who had been admitted to the intensive care unit (ICU) after resuscitation from cardiac arrest with nonshockable rhythm. The primary outcome was survival with a favorable neurologic outcome, assessed on day 90 after randomization with the use of the Cerebral Performance Category (CPC) scale (which ranges from 1 to 5, with higher scores indicating greater disability). We defined a favorable neurologic outcome as a CPC score of 1 or 2. Outcome assessment was blinded. Mortality and safety were also assessed.

Results: From January 2014 through January 2018, a total of 584 patients from 25 ICUs underwent randomization, and 581 were included in the analysis (3 patients withdrew consent). On day 90, a total of 29 of 284 patients (10.2%) in the hypothermia group were alive with a CPC score of 1 or 2, as compared with 17 of 297 (5.7%) in the normothermia group (difference, 4.5 percentage points; 95% confidence interval [CI], 0.1 to 8.9; P = 0.04). Mortality at 90 days did not differ significantly between the hypothermia group and the normothermia group (81.3% and 83.2%, respectively; difference, -1.9 percentage points; 95% CI, -8.0 to 4.3). The incidence of prespecified adverse events did not differ significantly between groups.

Conclusions: Among patients with coma who had been resuscitated from cardiac arrest with nonshockable rhythm, moderate therapeutic hypothermia at 33°C for 24 hours led to a higher percentage of patients who survived with a favorable neurologic outcome at day 90 than was observed with targeted normothermia. (Funded by the French Ministry of Health and others; HYPERION ClinicalTrials.gov number, NCT01994772.).
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http://dx.doi.org/10.1056/NEJMoa1906661DOI Listing
December 2019

Spontaneous ilio-psoas hematomas complicating intensive care unit hospitalizations.

PLoS One 2019 22;14(2):e0211680. Epub 2019 Feb 22.

Université de Strasbourg (UNISTRA), Faculté de Médecine, Hôpitaux universitaires de Strasbourg, Service de Réanimation Médicale, Nouvel Hôpital Civil, Strasbourg, France.

Background: Ilio-psoas hematoma is a potentially lethal condition that can arise during hospital stay. However, neither the incidence nor the prognosis of patients whose stay in intensive care units (ICU) is complicated by a iatrogenic ilio-psoas hematoma is known.

Methods: A bicentric retrospective study was conducted to compile the patients who developed an ilio-psoas hematoma while they were hospitalized in ICU between January 2009 and December 2016. Their biometric characteristics, pre-existing conditions, the circumstances in which the hematoma was diagnosed, the treatments they received and their prognosis were recorded.

Results: Forty patients were diagnosed with an ilio-psoas hematoma during their ICU stay. The incidence of this complication was 3.8 cases for 1000 admissions, taking into account only patients who stayed more than three days in ICU. The median age of patients was 74 years old and the median time between admission and the diagnosis of ilio-psoas hematoma was 12.6 days. A large proportion of them was obese (42.5%) and/or under dialysis (50%) prior to developing their hematoma. Ninety-five percent of the patients had heparin at prophylactic or therapeutic doses. Only 10% of them were above the therapeutic range of anticoagulation. The ICU mortality rate was of 50% following this complication (versus a general mortality rate of 22% for the patients without IPH over the same period of time). Patients with IPH that were complicated by disseminated intravascular coagulopathy had a significantly higher mortality rate than those with IPH and no disseminated intravascular coagulopathy (OR 6.91, 95% CI [1.28; 58.8], p = 0.04).

Conclusion: Age, anticoagulation, a high body mass index and dialysis seem to be risk factors of developing an ilio-psoas hematoma in ICU. Iatrogenic ilio-psoas hematomas complicated by disseminated intravascular coagulopathies are more at risk of leading to death. It is noteworthy that activated partial thromboplastin time above the therapeutic range was not a good predictor of developing a hematoma for patients who received unfractioned heparin therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211680PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386274PMC
November 2019

Docosahexaenoic acid, but not eicosapentaenoic acid, improves septic shock-induced arterial dysfunction in rats.

PLoS One 2017 20;12(12):e0189658. Epub 2017 Dec 20.

INSERM (French National Institute of Health and Medical Research), UMR 1260, Regenerative Nanomedicine (RNM), FMTS, Strasbourg, France.

Introduction: Long chain n-3 fatty acid supplementation may modulate septic shock-induced host response to pathogen-induced sepsis. The composition of lipid emulsions for parenteral nutrition however remains a real challenge in intensive care, depending on their fatty acid content. Because they have not been assessed yet, we aimed at determining the respective effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) during septic shock-induced vascular dysfunction.

Methods: In a peritonitis-induced septic shock model, rats were infused with EPA, DHA, an EPA/DHA mixture or 5% dextrose (D5) during 22 hours. From H18, rats were resuscitated and monitored during 4 hours. At H22, plasma, aorta and mesenteric resistance arteries were collected to perform ex vivo experiments.

Results: We have shown that septic rats needed an active resuscitation with fluid challenge and norepinephrine treatment, while SHAM rats did not. In septic rats, norepinephrine requirements were significantly decreased in DHA and EPA/DHA groups (10.6±12.0 and 3.7±8.0 μg/kg/min respectively versus 17.4±19.3 μg/kg/min in D5 group, p<0.05) and DHA infusion significantly improved contractile response to phenylephrine through nitric oxide pathway inhibition. DHA moreover significantly reduced vascular oxidative stress and nitric oxide production, phosphorylated IκB expression and vasodilative prostaglandin production. DHA also significantly decreased polyunsaturated fatty acid pro-inflammatory mediators and significantly increased several anti-inflammatory metabolites.

Conclusions: DHA infusion in septic rats improved hemodynamic dysfunction through decreased vascular oxidative stress and inflammation, while EPA infusion did not have beneficial effects.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189658PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738044PMC
January 2018

Yellow urticaria following plasma transfusion.

Intensive Care Med 2018 01 11;44(1):100-101. Epub 2017 Sep 11.

Hopitaux Universitaires de Strasbourg, Strasbourg, France.

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http://dx.doi.org/10.1007/s00134-017-4931-9DOI Listing
January 2018

Sepsis-induced expansion of granulocytic myeloid-derived suppressor cells promotes tumour growth through Toll-like receptor 4.

J Pathol 2016 08 23;239(4):473-83. Epub 2016 Jun 23.

Institut Cochin, INSERM U1016, CNRS UMR8104, Paris, France.

Severe sepsis remains a frequent and dreaded complication in cancer patients. Beyond the often fatal short-term outcome, the long-term sequelae of severe sepsis may also impact directly on the prognosis of the underlying malignancy in survivors. The immune system is involved in all stages of tumour development, in the detection of transforming and dying cells and in the prevention of tumour growth and dissemination. In fact, the profound and sustained immune defects induced by sepsis may constitute a privileged environment likely to favour tumour growth. We investigated the impact of sepsis on malignant tumour growth in a double-hit animal model of polymicrobial peritonitis, followed by subcutaneous inoculation of MCA205 fibrosarcoma cells. As compared to their sham-operated counterparts, post-septic mice exhibited accelerated tumour growth. This was associated with intratumoural accumulation of CD11b(+) Ly6G(high) polymorphonuclear cells (PMNs) that could be characterized as granulocytic myeloid-derived suppressor cells (G-MDSCs). Depletion of granulocytic cells in post-septic mice inhibited the sepsis-enhanced tumour growth. Toll-like receptor (TLR)-4 (Tlr4) and Myd88 deficiencies prevented sepsis-induced expansion of G-MDSCs and tumour growth. Our results demonstrate that the myelosuppressive environment induced by severe bacterial infections promotes malignant tumour growth, and highlight a critical role of CD11b(+) Ly6G(high) G-MDSCs under the control of TLR-dependent signalling. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4744DOI Listing
August 2016