Background. Given the rapidly evolving pandemic of COVID-19 in 2020, authorities focused on the r... more Background. Given the rapidly evolving pandemic of COVID-19 in 2020, authorities focused on the repurposing of available drugs to develop timely and cost-effective therapeutic strategies. Evidence suggested the potential utility of remdesivir in the framework of an early access program. REMDECO-19 is a multicenter national cohort study assessing the ability of remdesivir to improve the outcome of patients hospitalized with COVID-19. Methods. We conducted a retrospective real-life study that included all patients from the early access program of remdesivir in France. The primary endpoint was the clinical course evolution of critically ill and hospitalized COVID-19 patients treated with remdesivir. Secondary endpoints were the SOFA score evolution within 29 days following the admission and mortality at 29 and 90 days. Results. Eighty-five patients were enrolled in 22 sites from January to April 2020. The median WHO and SOFA scores were respectively reduced by two and six points betwee...
Polyvalent 23 epitope polysaccharide pneumonia vaccine induced effective protection through strai... more Polyvalent 23 epitope polysaccharide pneumonia vaccine induced effective protection through strain-adapted effector mechanisms as demonstrated by the different cytokine responses in mice challenged with two different strains
Dear Editor, Corticosteroids are recommended for complicated sepsis [1]. However, their positive ... more Dear Editor, Corticosteroids are recommended for complicated sepsis [1]. However, their positive average effects demonstrated in trials translates into individual effects ranging from harm to survival benefit [2]. Biomarkers preventing unsafe corticosteroids exposure are needed. Owing to the role of monocyte in corticosteroids effects [3], we hypothesized that monocyte distribution width (MDW) may identify corticosteroids-resistance in sepsis. We prospectively categorized consecutive hospitalized adults according to the presence of infection, sepsis or septic shock, and corticotherapy [4] (Supplementary material). Ethics Committee and Commission Nationale de l’Informatique et des Libertés approved waiver of consent. The study protocol and statistical analysis plan are available at https:// www. fhusepsis. uvsq. fr/ sepsis, and registered at ClinicalTrials.gov under NCT04292431. Corticosteroids-resistance was defined by day-7 death, vasopressors or mechanical ventilation-dependency, or sequential organ failure assessment (SOFA) score > 6. Data were abstracted weekly from the electronic health record, deidentified, and stored for subsequent analysis. Researchers remained blinded to participants’ identity. At routine blood sampling, MDW, the index test, was analysed (Unicell DxH 900 analyzer, Beckman Coulter, USA) and results were kept undisclosed. This exploratory study had no formal sample size calculation. Evaluation of biomarkers performance to identify the corticosteroids-resistance used analysis of receiver operating characteristic (ROC) and decision curves, i.e. estimates of standardized net benefit by probability threshold categorizing observations as corticosteroids-resistance, and logistic regression models with odds ratio (OR). Of 1676 patients, 1496 had measurements of MDW (Supplementary material, Fig. 1). There were 197 patients with infection, 89 with sepsis, and 40 with septic shock (Supplementary material, Table 1). Age was not significantly different between groups (P = 0.16). Patients with sepsis or septic shock were more likely male (P = 0.018), mechanically ventilated (P < 0.0001), ICU-dependent (P < 0.0001). Of 191 corticosteroids-treated patients, 67 had corticosteroidsresistance (Supplementary material, Table 2). MDW increased gradually from no infection to septic shock (Fig. 1A). Median MDW was 24.5 (IQR, 22.2–27.9) and 21.7 (19.9–25.5) in patients with versus without corticosteroids-resistance (P = 0.0004) (Fig. 1B, Supplementary material, Table 3 and Fig. 2). Figure 1C displayed ROC curves analysis for corticosteroids-resistance. Sensitivity analyses by individual criteria and excluding one criteria of the definition of corticosteroids-resistance, yielded consistent AUC (Supplementary material, Figs. 3, 4). When MDW > 25, the OR for corticosteroids-resistance was 2.33 (95% CI 1.33–4.44, P = 0.0098) and outperforming other laboratory tests (Supplementary material, Tables 3, 4). By multivariate analysis, corticosteroids-resistance was associated with higher MDW (P = 0.0082), and lower neutrophil mean volume (P = 0.0094) and lymphocytes count (P = 0.0017) (Table 1). After adjusting for baseline requirement of vasopressor, mechanical ventilation and SOFA score, corticosteroids-resistance remained associated with higher MDW (P = 0.035, Table 1). There was no interaction between MDW effect on corticosteroids-resistance, *Correspondence: Djillali.annane@aphp.fr Department of Intensive Care, Hôpital Raymond Poincaré (APHP), 104 Boulevard Raymond Poincaré, 92380 Garches, France
Le sepsis est un problème de santé publique majeur, associé à une morbi-mortalité conséquente. La... more Le sepsis est un problème de santé publique majeur, associé à une morbi-mortalité conséquente. La forme la plus sévère du sepsis, le choc septique, a une physiopathologie complexe, associant entre autres anomalies une insuffisance corticotrope et une réponse inflammatoire exagérée. Les corticoïdes, médicaments aux effets pléiotropes, corrigent cette insuffisance corticotrope et exhibent un effet anti-inflammatoire. Les corticoïdes sont à l’heure actuelle un des rares médicaments possiblement capables de réduire la mortalité dans le choc septique. S’ajoute à cet effet bénéfique sur la mortalité un effet hémodynamique favorable. L’administration de corticoïdes à faibles doses et sur une courte période est associée à remarquablement peu d’effets secondaires. Un traitement par hydrocortisone 200mg/j peut être administré chez les patients en choc septique. Nous suggérons l’administration de ce traitement en bolus intraveineux intermittent pendant sept jours sans sevrage progressif à la f...
The authors have withdrawn this manuscript and do not wish it to be cited. Because of controversy... more The authors have withdrawn this manuscript and do not wish it to be cited. Because of controversy about hydroxychloroquine and the retrospective nature of their study, they intend to revise the manuscript after peer review.
Recent studies show that intraoperative mechanical ventilation using low tidal volumes (VT) can p... more Recent studies show that intraoperative mechanical ventilation using low tidal volumes (VT) can prevent postoperative pulmonary complications (PPCs). The aim of this individual patient data meta-analysis is to evaluate the individual associations between VT size and positive end-expiratory pressure (PEEP) level and occurrence of PPC. Randomized controlled trials comparing protective ventilation (low VT with or without high levels of PEEP) and conventional ventilation (high VT with low PEEP) in patients undergoing general surgery. The primary outcome was development of PPC. Predefined prognostic factors were tested using multivariate logistic regression. Fifteen randomized controlled trials were included (2,127 patients). There were 97 cases of PPC in 1,118 patients (8.7%) assigned to protective ventilation and 148 cases in 1,009 patients (14.7%) assigned to conventional ventilation (adjusted relative risk, 0.64; 95% CI, 0.46 to 0.88; P < 0.01). There were 85 cases of PPC in 957 p...
International Journal of Antimicrobial Agents, 2013
Surgical-site infections are the leading cause of post-operative morbidity and mortality as well ... more Surgical-site infections are the leading cause of post-operative morbidity and mortality as well as increased costs following colorectal surgery. The purpose of this study was to evaluate different β-lactam antimicrobial dosing regimens currently used for prophylaxis in elective colorectal procedures with the aim of identifying optimal antibiotics and dosing regimens. Serum pharmacokinetic (PK) parameters specific to each drug for use in pharmacodynamic (PD) modelling were obtained from the published literature. Susceptibility data for Escherichia coli, Bacteroides fragilis and Staphylococcus aureus for use in modelling simulations were obtained from the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Monte Carlo simulation was used to evaluate the influence of dose and dosing frequency of tested antibiotics to achieve a prophylaxis target fT&gt;MIC (time during which the free drug concentration exceeds the pathogen minimum inhibitory concentration) of 100% for up to 4h. Ertapenem 1g, cefuroxime 1.5 g and cefazolin 2 g were the only antibiotic regimens that consistently yielded target fT&gt;MIC of 100% for the entire 4-h post-dose interval and against all targeted organisms more than 90% of the time. In contrast, cefoxitin, cefotetan and ampicillin/sulbactam yielded very poor predicted PK/PD performances. In conclusion, this study demonstrates the value of, and need for, applied PD research in the area of surgical prophylaxis. Whether cefoxitin, cefotetan or ampicillin/sulbactam should continue to be advocated as first-line agents for prophylaxis during elective colorectal surgery, particularly at the standard doses currently being used, is debatable.
A prospective study of 132 patients with severe community-acquired pneumonia (CAP) treated in the... more A prospective study of 132 patients with severe community-acquired pneumonia (CAP) treated in the ICU was carried out to determine the causative agents, the value of the clinical, biological, and radiologic features in predicting the etiology, and to define prognostic factors. The study group included 98 men and 34 women (mean age: 58 +/- 18 years). The most frequent underlying condition was COPD (51 patients, 39 percent). On admission, 35 patients were in shock, 71 were mentally confused, and 81 (61 percent) required mechanical ventilation during their hospitalization. The clinical, laboratory, and radiologic parameters were of little value for predicting the etiology in patients with severe CAP. An etiologic diagnosis was made in 95 (72 percent) patients. The most frequent pathogens were Streptococcus pneumoniae (43 cases [45 percent]), Gram-negative bacilli (14 cases [15 percent]), and Haemophilus influenzae (14 cases [15 percent]) Mortality was 24 percent. It was significantly associated with a age more than 60 years, septic shock, impairment of alertness, mechanical ventilation requirement, bacteremic pneumonia, and S pneumoniae or Enterobacteriaceae as the causes of the pneumonia. Recommendations for antibiotic chemotherapy in patients with severe CAP admitted to the ICU are included.
Background Delaying time to prone positioning (PP) may be associated with higher mortality in acu... more Background Delaying time to prone positioning (PP) may be associated with higher mortality in acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19). We evaluated the use and the impact of early PP on clinical outcomes in intubated patients hospitalized in intensive care units (ICUs) for COVID-19.Methods All intubated patients with ARDS due to COVID-19 were involved in a secondary analysis from a prospective multicenter cohort study of COVID-ICU network including 149 ICUs across France, Belgian and Switzerland. Patients were followed-up until Day-90. The primary outcome was survival at Day-60. Analysis used a Cox proportional hazard model including a propensity score. Results Among 2137 intubated patients, 1504 (70.4%) were placed in PP during their ICU stay, and 491 (23%) during the first 24 hrs following ICU admission. One hundred and eighty-one patients (36.9%) of the early PP group had a PaO2/FiO2 ratio > 150 mmHg when prone positioning was init...
Background. Given the rapidly evolving pandemic of COVID-19 in 2020, authorities focused on the r... more Background. Given the rapidly evolving pandemic of COVID-19 in 2020, authorities focused on the repurposing of available drugs to develop timely and cost-effective therapeutic strategies. Evidence suggested the potential utility of remdesivir in the framework of an early access program. REMDECO-19 is a multicenter national cohort study assessing the ability of remdesivir to improve the outcome of patients hospitalized with COVID-19. Methods. We conducted a retrospective real-life study that included all patients from the early access program of remdesivir in France. The primary endpoint was the clinical course evolution of critically ill and hospitalized COVID-19 patients treated with remdesivir. Secondary endpoints were the SOFA score evolution within 29 days following the admission and mortality at 29 and 90 days. Results. Eighty-five patients were enrolled in 22 sites from January to April 2020. The median WHO and SOFA scores were respectively reduced by two and six points betwee...
Polyvalent 23 epitope polysaccharide pneumonia vaccine induced effective protection through strai... more Polyvalent 23 epitope polysaccharide pneumonia vaccine induced effective protection through strain-adapted effector mechanisms as demonstrated by the different cytokine responses in mice challenged with two different strains
Dear Editor, Corticosteroids are recommended for complicated sepsis [1]. However, their positive ... more Dear Editor, Corticosteroids are recommended for complicated sepsis [1]. However, their positive average effects demonstrated in trials translates into individual effects ranging from harm to survival benefit [2]. Biomarkers preventing unsafe corticosteroids exposure are needed. Owing to the role of monocyte in corticosteroids effects [3], we hypothesized that monocyte distribution width (MDW) may identify corticosteroids-resistance in sepsis. We prospectively categorized consecutive hospitalized adults according to the presence of infection, sepsis or septic shock, and corticotherapy [4] (Supplementary material). Ethics Committee and Commission Nationale de l’Informatique et des Libertés approved waiver of consent. The study protocol and statistical analysis plan are available at https:// www. fhusepsis. uvsq. fr/ sepsis, and registered at ClinicalTrials.gov under NCT04292431. Corticosteroids-resistance was defined by day-7 death, vasopressors or mechanical ventilation-dependency, or sequential organ failure assessment (SOFA) score > 6. Data were abstracted weekly from the electronic health record, deidentified, and stored for subsequent analysis. Researchers remained blinded to participants’ identity. At routine blood sampling, MDW, the index test, was analysed (Unicell DxH 900 analyzer, Beckman Coulter, USA) and results were kept undisclosed. This exploratory study had no formal sample size calculation. Evaluation of biomarkers performance to identify the corticosteroids-resistance used analysis of receiver operating characteristic (ROC) and decision curves, i.e. estimates of standardized net benefit by probability threshold categorizing observations as corticosteroids-resistance, and logistic regression models with odds ratio (OR). Of 1676 patients, 1496 had measurements of MDW (Supplementary material, Fig. 1). There were 197 patients with infection, 89 with sepsis, and 40 with septic shock (Supplementary material, Table 1). Age was not significantly different between groups (P = 0.16). Patients with sepsis or septic shock were more likely male (P = 0.018), mechanically ventilated (P < 0.0001), ICU-dependent (P < 0.0001). Of 191 corticosteroids-treated patients, 67 had corticosteroidsresistance (Supplementary material, Table 2). MDW increased gradually from no infection to septic shock (Fig. 1A). Median MDW was 24.5 (IQR, 22.2–27.9) and 21.7 (19.9–25.5) in patients with versus without corticosteroids-resistance (P = 0.0004) (Fig. 1B, Supplementary material, Table 3 and Fig. 2). Figure 1C displayed ROC curves analysis for corticosteroids-resistance. Sensitivity analyses by individual criteria and excluding one criteria of the definition of corticosteroids-resistance, yielded consistent AUC (Supplementary material, Figs. 3, 4). When MDW > 25, the OR for corticosteroids-resistance was 2.33 (95% CI 1.33–4.44, P = 0.0098) and outperforming other laboratory tests (Supplementary material, Tables 3, 4). By multivariate analysis, corticosteroids-resistance was associated with higher MDW (P = 0.0082), and lower neutrophil mean volume (P = 0.0094) and lymphocytes count (P = 0.0017) (Table 1). After adjusting for baseline requirement of vasopressor, mechanical ventilation and SOFA score, corticosteroids-resistance remained associated with higher MDW (P = 0.035, Table 1). There was no interaction between MDW effect on corticosteroids-resistance, *Correspondence: Djillali.annane@aphp.fr Department of Intensive Care, Hôpital Raymond Poincaré (APHP), 104 Boulevard Raymond Poincaré, 92380 Garches, France
Le sepsis est un problème de santé publique majeur, associé à une morbi-mortalité conséquente. La... more Le sepsis est un problème de santé publique majeur, associé à une morbi-mortalité conséquente. La forme la plus sévère du sepsis, le choc septique, a une physiopathologie complexe, associant entre autres anomalies une insuffisance corticotrope et une réponse inflammatoire exagérée. Les corticoïdes, médicaments aux effets pléiotropes, corrigent cette insuffisance corticotrope et exhibent un effet anti-inflammatoire. Les corticoïdes sont à l’heure actuelle un des rares médicaments possiblement capables de réduire la mortalité dans le choc septique. S’ajoute à cet effet bénéfique sur la mortalité un effet hémodynamique favorable. L’administration de corticoïdes à faibles doses et sur une courte période est associée à remarquablement peu d’effets secondaires. Un traitement par hydrocortisone 200mg/j peut être administré chez les patients en choc septique. Nous suggérons l’administration de ce traitement en bolus intraveineux intermittent pendant sept jours sans sevrage progressif à la f...
The authors have withdrawn this manuscript and do not wish it to be cited. Because of controversy... more The authors have withdrawn this manuscript and do not wish it to be cited. Because of controversy about hydroxychloroquine and the retrospective nature of their study, they intend to revise the manuscript after peer review.
Recent studies show that intraoperative mechanical ventilation using low tidal volumes (VT) can p... more Recent studies show that intraoperative mechanical ventilation using low tidal volumes (VT) can prevent postoperative pulmonary complications (PPCs). The aim of this individual patient data meta-analysis is to evaluate the individual associations between VT size and positive end-expiratory pressure (PEEP) level and occurrence of PPC. Randomized controlled trials comparing protective ventilation (low VT with or without high levels of PEEP) and conventional ventilation (high VT with low PEEP) in patients undergoing general surgery. The primary outcome was development of PPC. Predefined prognostic factors were tested using multivariate logistic regression. Fifteen randomized controlled trials were included (2,127 patients). There were 97 cases of PPC in 1,118 patients (8.7%) assigned to protective ventilation and 148 cases in 1,009 patients (14.7%) assigned to conventional ventilation (adjusted relative risk, 0.64; 95% CI, 0.46 to 0.88; P < 0.01). There were 85 cases of PPC in 957 p...
International Journal of Antimicrobial Agents, 2013
Surgical-site infections are the leading cause of post-operative morbidity and mortality as well ... more Surgical-site infections are the leading cause of post-operative morbidity and mortality as well as increased costs following colorectal surgery. The purpose of this study was to evaluate different β-lactam antimicrobial dosing regimens currently used for prophylaxis in elective colorectal procedures with the aim of identifying optimal antibiotics and dosing regimens. Serum pharmacokinetic (PK) parameters specific to each drug for use in pharmacodynamic (PD) modelling were obtained from the published literature. Susceptibility data for Escherichia coli, Bacteroides fragilis and Staphylococcus aureus for use in modelling simulations were obtained from the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Monte Carlo simulation was used to evaluate the influence of dose and dosing frequency of tested antibiotics to achieve a prophylaxis target fT&gt;MIC (time during which the free drug concentration exceeds the pathogen minimum inhibitory concentration) of 100% for up to 4h. Ertapenem 1g, cefuroxime 1.5 g and cefazolin 2 g were the only antibiotic regimens that consistently yielded target fT&gt;MIC of 100% for the entire 4-h post-dose interval and against all targeted organisms more than 90% of the time. In contrast, cefoxitin, cefotetan and ampicillin/sulbactam yielded very poor predicted PK/PD performances. In conclusion, this study demonstrates the value of, and need for, applied PD research in the area of surgical prophylaxis. Whether cefoxitin, cefotetan or ampicillin/sulbactam should continue to be advocated as first-line agents for prophylaxis during elective colorectal surgery, particularly at the standard doses currently being used, is debatable.
A prospective study of 132 patients with severe community-acquired pneumonia (CAP) treated in the... more A prospective study of 132 patients with severe community-acquired pneumonia (CAP) treated in the ICU was carried out to determine the causative agents, the value of the clinical, biological, and radiologic features in predicting the etiology, and to define prognostic factors. The study group included 98 men and 34 women (mean age: 58 +/- 18 years). The most frequent underlying condition was COPD (51 patients, 39 percent). On admission, 35 patients were in shock, 71 were mentally confused, and 81 (61 percent) required mechanical ventilation during their hospitalization. The clinical, laboratory, and radiologic parameters were of little value for predicting the etiology in patients with severe CAP. An etiologic diagnosis was made in 95 (72 percent) patients. The most frequent pathogens were Streptococcus pneumoniae (43 cases [45 percent]), Gram-negative bacilli (14 cases [15 percent]), and Haemophilus influenzae (14 cases [15 percent]) Mortality was 24 percent. It was significantly associated with a age more than 60 years, septic shock, impairment of alertness, mechanical ventilation requirement, bacteremic pneumonia, and S pneumoniae or Enterobacteriaceae as the causes of the pneumonia. Recommendations for antibiotic chemotherapy in patients with severe CAP admitted to the ICU are included.
Background Delaying time to prone positioning (PP) may be associated with higher mortality in acu... more Background Delaying time to prone positioning (PP) may be associated with higher mortality in acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19). We evaluated the use and the impact of early PP on clinical outcomes in intubated patients hospitalized in intensive care units (ICUs) for COVID-19.Methods All intubated patients with ARDS due to COVID-19 were involved in a secondary analysis from a prospective multicenter cohort study of COVID-ICU network including 149 ICUs across France, Belgian and Switzerland. Patients were followed-up until Day-90. The primary outcome was survival at Day-60. Analysis used a Cox proportional hazard model including a propensity score. Results Among 2137 intubated patients, 1504 (70.4%) were placed in PP during their ICU stay, and 491 (23%) during the first 24 hrs following ICU admission. One hundred and eighty-one patients (36.9%) of the early PP group had a PaO2/FiO2 ratio > 150 mmHg when prone positioning was init...
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