Publications by authors named "Jean-Francois Timsit"

407 Publications

Simplified frontal EEG in adults under veno-arterial extracorporeal membrane oxygenation.

Ann Intensive Care 2021 May 13;11(1):76. Epub 2021 May 13.

Laboratory for Vascular Translational Science, INSERM UMR1148, Team 6, Université de Paris, 75018, Paris, France.

Background: EEG-based prognostication studies in intensive care units often rely on a standard 21-electrode montage (EEG) requiring substantial human, technical, and financial resources. We here evaluate whether a simplified 4-frontal electrode montage (EEG) can detect EEG patterns associated with poor outcomes in adult patients under veno-arterial extracorporeal membrane oxygenation (VA-ECMO).

Methods: We conducted a reanalysis of EEG data from a prospective cohort on 118 adult patients under VA-ECMO, in whom EEG was performed on admission to intensive care. EEG patterns of interest included background rhythm, discontinuity, reactivity, and the Synek's score. They were all reassessed by an intensivist on a EEG montage, whose analysis was then compared to an expert's interpretation made on EEG recordings. The main outcome measure was the degree of correlation between EEG and EEG montages to identify EEG patterns of interest. The performance of the Synek scores calculated on EEG and EEG montage to predict outcomes (i.e., 28-day mortality and 90-day Rankin score [Formula: see text]) was investigated in a secondary exploratory analysis.

Results: The detection of EEG patterns using EEG was statistically similar to that of EEG for background rhythm (Spearman rank test, ρ = 0.66, p < 0.001), discontinuity (Cohen's kappa, [Formula: see text] = 0.955), reactivity ([Formula: see text] = 0.739) and the Synek's score (ρ = 0.794, p < 0.001). Using the Synek classification, we found similar performances between EEG and EEG montages in predicting 28-day mortality (AUC EEG 0.71, AUC EEG 0.68) and for 90-day poor neurologic outcome (AUC EEG 0.71, AUC EEG 0.66). An exploratory analysis confirmed that the Synek scores determined by 4 or 21 electrodes were independently associated with 28-day mortality and poor 90-day functional outcome.

Conclusion: In adult patients under VA-ECMO, a simplified 4-frontal electrode EEG montage interpreted by an intensivist, detected common EEG patterns associated with poor outcomes, with a performance similar to that of a standard EEG montage interpreted by expert neurophysiologists. This simplified montage could be implemented as part of a multimodal evaluation for bedside prognostication.
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http://dx.doi.org/10.1186/s13613-021-00854-0DOI Listing
May 2021

Impact of early low-calorie low-protein versus standard-calorie standard-protein feeding on outcomes of ventilated adults with shock: design and conduct of a randomised, controlled, multicentre, open-label, parallel-group trial (NUTRIREA-3).

BMJ Open 2021 May 11;11(5):e045041. Epub 2021 May 11.

Service de Médecine Intensive Réanimation, Centre Hospitalier de Valenciennes, Valenciennes, France.

Introduction: International guidelines include early nutritional support (≤48 hour after admission), 20-25 kcal/kg/day, and 1.2-2 g/kg/day protein at the acute phase of critical illness. Recent data challenge the appropriateness of providing standard amounts of calories and protein during acute critical illness. Restricting calorie and protein intakes seemed beneficial, suggesting a role for metabolic pathways such as autophagy, a potential key mechanism in safeguarding cellular integrity, notably in the muscle, during critical illness. However, the optimal calorie and protein supply at the acute phase of severe critical illness remains unknown. NUTRIREA-3 will be the first trial to compare standard calorie and protein feeding complying with guidelines to low-calorie low-protein feeding. We hypothesised that nutritional support with calorie and protein restriction during acute critical illness decreased day 90 mortality and/or dependency on intensive care unit (ICU) management in mechanically ventilated patients receiving vasoactive amine therapy for shock, compared with standard calorie and protein targets.

Methods And Analysis: NUTRIREA-3 is a randomised, controlled, multicentre, open-label trial comparing two parallel groups of patients receiving invasive mechanical ventilation and vasoactive amine therapy for shock and given early nutritional support according to one of two strategies: early calorie-protein restriction (6 kcal/kg/day-0.2-0.4 g/kg/day) or standard calorie-protein targets (25 kcal/kg/day, 1.0-1.3 g/kg/day) at the acute phase defined as the first 7 days in the ICU. We will include 3044 patients in 61 French ICUs. Two primary end-points will be evaluated: day 90 mortality and time to ICU discharge readiness. The trial will be considered positive if significant between-group differences are found for one or both alternative primary endpoints. Secondary outcomes include hospital-acquired infections and nutritional, clinical and functional outcomes.

Ethics And Dissemination: The NUTRIREA-3 study has been approved by the appropriate ethics committee. Patients are included after informed consent. Results will be submitted for publication in peer-reviewed journals.

Trial Registration Number: NCT03573739.
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http://dx.doi.org/10.1136/bmjopen-2020-045041DOI Listing
May 2021

Distribution of pathogens and antimicrobial resistance in bacteremia according to hospitalization duration: A nationwide surveillance study in Switzerland.

Clin Microbiol Infect 2021 Apr 29. Epub 2021 Apr 29.

Department of Infectious Diseases, Bern University Hospital and University of Bern, Switzerland; Infectious Diseases and Hospital Epidemiology, Hirslanden Central Switzerland, Lucerne, Switzerland.

Objectives: Changing microorganism distributions and decreasing antibiotic susceptibility with increasing length of hospital stay have been demonstrated for the colonization or infection of selected organ systems. We wanted to describe microorganism distribution or antibiotic resistance in bacteremia according to duration of the hospitalization using a large national epidemiological/microbiological database (ANRESIS) in Switzerland.

Methods: We conducted a nationwide, observational study on bacteremia using ANRESIS data from 1 January 2008 to 31 December 2017. We analyzed data on bacteremia from those Swiss hospitals that sent information on a regular basis during the entire study period. We described the pathogen distribution and specific trends of resistance during the hospitalization for E. coli, K. pneumoniae, P. aeruginosa, S. marcescens and S. aureus.

Results: We included 28,318 bacteremia isolates from 90 Swiss hospitals. The most common etiology was E. coli (33.4%, 9,459), followed by S. aureus (16.7%, 4,721), K. pneumoniae (7.1%, 2,005), E. faecalis (5.2%, 1,473), P. aeruginosa (4.3%, 1,228), S. pneumoniae (4.3%, 1,208) and E. faecium (3.9%, 1,101). We observed 489 (1.73%) Serratia marcescens isolates. We observed an increasing trend for Enterococcus faecium (from 1.5% at day 0 to 13.7% at day 30; p<0.001), K. pneumoniae (from 6.1% to 7.8%, p<0.001) and P. aeruginosa (from 2.9% to 13.7%, p<0.001) with increasing duration of hospitalization; and a decreasing trends for E. coli (from 41.6% at day 0 to 21.6% at day 30; p<0.001) and S. aureus (from 14.4% to 14.7%; p<0.001). Ceftriaxone resistance among E. coli remained stable for the first 15 days of hospitalization and then increased. Ceftriaxone resistance among K. pneumoniae and S. marcescens and oxacillin resistance among S. aureus increased linearly during the hospitalization. Cefepime resistance among P. aeruginosa remained stable during the hospitalization.

Conclusions: We showed that hospitalization duration is associated with a species- and antibiotic class-dependent pattern of antimicrobial resistance.
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http://dx.doi.org/10.1016/j.cmi.2021.04.025DOI Listing
April 2021

Two original observations concerning bacterial infections in COVID-19 patients hospitalized in intensive care units during the first wave of the epidemic in France.

PLoS One 2021 29;16(4):e0250728. Epub 2021 Apr 29.

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

Among 197 COVID-19 patients hospitalized in ICU, 88 (44.7%) experienced at least one bacterial infection, with pneumonia (39.1%) and bloodstream infections (15,7%) being the most frequent. Unusual findings include frequent suspicion of bacterial translocations originating from the digestive tract as well as bacterial persistence in the lungs despite adequate therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250728PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084132PMC
May 2021

Ventilator-associated pneumonia in the era of COVID-19 pandemic: How common and what is the impact?

Crit Care 2021 04 21;25(1):153. Epub 2021 Apr 21.

Medical and Infectious Diseases ICU (MI2), AP-HP, Bichat Hospital, 75018, Paris, France.

We reviewed similarities and differences of ventilator associated pneumonia in Sars-Cov2 infection and with other ARDS. The differences in epidemiology and outcome will be detailed. Possible explanations of differences in pathophysiology of VAP in Sarscov2 infections will be cited and discussed.
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http://dx.doi.org/10.1186/s13054-021-03571-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059113PMC
April 2021

Viral epidemiology and SARS-CoV-2 co-infections with other respiratory viruses during the first COVID-19 wave in Paris, France.

Influenza Other Respir Viruses 2021 Apr 4. Epub 2021 Apr 4.

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

Objectives: Our work assessed the prevalence of co-infections in patients with SARS-CoV-2.

Methods: All patients hospitalized in a Parisian hospital during the first wave of COVID-19 were tested by multiplex PCR if they presented ILI symptoms.

Results: A total of 806 patients (21%) were positive for SARS-CoV-2, 755 (20%) were positive for other respiratory viruses. Among the SARS-CoV-2-positive patients, 49 (6%) had viral co-infections. They presented similar age, symptoms, except for fever (P = .013) and headaches (P = .048), than single SARS-CoV-2 infections.

Conclusions: SARS-CoV-2-infected patients presenting viral co-infections had similar clinical characteristics and prognosis than patients solely infected with SARS-CoV-2.
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http://dx.doi.org/10.1111/irv.12853DOI Listing
April 2021

Performance of Repeated Measures of (1-3)-β-D-Glucan, Mannan Antigen, and Antimannan Antibodies for the Diagnosis of Invasive Candidiasis in ICU Patients: A Preplanned Ancillary Analysis of the EMPIRICUS Randomized Clinical Trial.

Open Forum Infect Dis 2021 Mar 2;8(3):ofab080. Epub 2021 Mar 2.

UMR1137-IAME Inserm, Paris Diderot University, Paris, France.

Background: We aimed to assess the prognostic value of repeated measurements of serum (1-3)-β-D-glucan (BDG), mannan-antigen (mannan-Ag), and antimannan antibodies (antimannan-Ab) for the occurrence of invasive candidiasis (IC) in a high-risk nonimmunocompromised population.

Methods: This was a preplanned ancillary analysis of the EMPIRICUS Randomized Clinical Trial, including nonimmunocompromised critically ill patients with intensive care unit-acquired sepsis, multiple colonization, and multiple organ failure who were exposed to broad-spectrum antibacterial agents. BDG (>80 and >250 pg/mL), mannan-Ag (>125 pg/mL), and antimannan-Ab (>10 AU) were collected repeatedly. We used cause-specific hazard models. Biomarkers were assessed at baseline in the whole cohort (cohort 1). Baseline covariates and/or repeated measurements and/or increased biomarkers were then studied in the subgroup of patients who were still alive at day 3 and free of IC (cohort 2).

Results: Two hundred thirty-four patients were included, and 215 were still alive and free of IC at day 3. IC developed in 27 patients (11.5%), and day 28 mortality was 29.1%. Finally, BDG >80 pg/mL at inclusion was associated with an increased risk of IC (CSHR[IC], 4.67; 95% CI, 1.61-13.5) but not death (CSHR[death], 1.20; 95% CI, 0.71-2.02).

Conclusions: Among high-risk patients, a first measurement of BDG >80 pg/mL was strongly associated with the occurrence of IC. Neither a cutoff of 250 pg/mL nor repeated measurements of fungal biomarkers seemed to be useful to predict the occurrence of IC. The cumulative risk of IC in the placebo group if BDG >80 pg/mL was 25.39%, which calls into question the efficacy of empirical therapy in this subgroup.
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http://dx.doi.org/10.1093/ofid/ofab080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002176PMC
March 2021

Ultrasound-guided catheterization and infectious risk in obese ICU patients.

Intensive Care Med 2021 Mar 27. Epub 2021 Mar 27.

INSERM, IAME, University of Paris, 75006, Paris, France.

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http://dx.doi.org/10.1007/s00134-021-06382-6DOI Listing
March 2021

Survival in Immunocompromised Patients Ultimately Requiring Invasive Mechanical Ventilation: .

Am J Respir Crit Care Med 2021 Mar 22. Epub 2021 Mar 22.

Hôpital Saint Louis Paris - APHP, France, Paris, France;

Rationale: Acute respiratory failure (ARF) is associated with high mortality in immunocompromised patients, particularly when invasive mechanical ventilation is needed. Therefore, noninvasive oxygenation/ventilation strategies have been developed to avoid intubation, with uncertain impact on mortality, especially when intubation is delayed.

Objectives: We sought to report trends of survival over time in immunocompromised patients receiving invasive mechanical ventilation. The impact of delayed intubation after failure of noninvasive strategies was also assessed.

Methods: Systematic review and meta-analysis using individual data (IPD) of studies which focused on immunocompromised adult patients with ARF requiring invasive mechanical ventilation. Studies published in English were identified through PubMed, Web of science, and Cochrane Central (2008-2018). IPD were requested to corresponding authors for all identified studies. We used mixed-effect models to estimate the effect of delayed intubation on hospital mortality and described mortality rates over time.

Measurements And Main Results: 11087 patients were included (24 studies, 3 controlled trials and 21 cohorts), of whom 7736 (74%) were intubated within 24h of ICU admission (early intubation). Crude mortality rate was 53.2%. Adjusted survivals improved over time (from 1995 to 2017, OR for hospital mortality per year: 0.96[0.95-0.97]). For each elapsed day between ICU admission and intubation, mortality was higher (OR:1.38[1.26-1.52], p<0.001). Early intubation was significantly associated with lower mortality (OR: 0.83[0.72-0.96]), regardless of initial oxygenation strategy. These results persisted after propensity score analysis (matched OR associated with delayed intubation :1.56[1.44-1.70]).

Conclusion: In immunocompromised intubated patients, survival has improved over time. Time between ICU admission and intubation is a strong predictor of mortality, suggesting a detrimental effect of late initial oxygenation failure.
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http://dx.doi.org/10.1164/rccm.202009-3575OCDOI Listing
March 2021

Impact of rapid multiplex PCR on management of antibiotic therapy in COVID-19-positive patients hospitalized in intensive care unit.

Eur J Clin Microbiol Infect Dis 2021 Mar 17. Epub 2021 Mar 17.

Université de Paris, INSERM, IAME, F-75006, Paris, France.

Because the diagnosis of co/superinfection in COVID-19 patients is challenging, empirical antibiotic therapy is frequently initiated until microbiological analysis results. We evaluated the performance and the impact of the BioFire® FilmArray® Pneumonia plus Panel on 112 respiratory samples from 67 COVID-19 ICU patients suspected of co/superinfections. Globally, the sensitivity and specificity of the test were 89.3% and 99.1%, respectively. Positive tests led to antibiotic initiation or adaptation in 15% of episodes and de-escalation in 4%. When negative, 28% of episodes remained antibiotic-free (14% no initiation, 14% withdrawal). Rapid multiplex PCRs can help to improve antibiotic stewardship by administering appropriate antibiotics earlier and avoiding unnecessary prescriptions.
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http://dx.doi.org/10.1007/s10096-021-04213-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968559PMC
March 2021

Life Support Limitations in Mechanically Ventilated Stroke Patients.

Crit Care Explor 2021 Feb 22;3(2):e0341. Epub 2021 Feb 22.

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

Objectives: The determinants of decisions to limit life support (withholding or withdrawal) in ventilated stroke patients have been evaluated mainly for patients with intracranial hemorrhages. We aimed to evaluate the frequency of life support limitations in ventilated ischemic and hemorrhagic stroke patients compared with a nonbrain-injured population and to determine factors associated with such decisions.

Design: Multicenter prospective French observational study.

Setting: Fourteen ICUs of the French OutcomeRea network.

Patients: From 2005 to 2016, we included stroke patients and nonbrain-injured patients requiring invasive ventilation within 24 hours of ICU admission.

Intervention: None.

Measurements And Main Results: We identified 373 stroke patients (ischemic, = 167 [45%]; hemorrhagic, = 206 [55%]) and 5,683 nonbrain-injured patients. Decisions to limit life support were taken in 41% of ischemic stroke cases (vs nonbrain-injured patients, subdistribution hazard ratio, 3.59 [95% CI, 2.78-4.65]) and in 33% of hemorrhagic stroke cases (vs nonbrain-injured patients, subdistribution hazard ratio, 3.9 [95% CI, 2.97-5.11]). Time from ICU admission to the first limitation was longer in ischemic than in hemorrhagic stroke (5 [3-9] vs 2 d [1-6] d; < 0.01). Limitation of life support preceded ICU death in 70% of ischemic strokes and 45% of hemorrhagic strokes ( < 0.01). Life support limitations in ischemic stroke were increased by a vertebrobasilar location (vs anterior circulation, subdistribution hazard ratio, 1.61 [95% CI, 1.01-2.59]) and a prestroke modified Rankin score greater than 2 (2.38 [1.27-4.55]). In hemorrhagic stroke, an age greater than 70 years (2.29 [1.43-3.69]) and a Glasgow Coma Scale score less than 8 (2.15 [1.08-4.3]) were associated with an increased risk of limitation, whereas a higher nonneurologic admission Sequential Organ Failure Assessment score was associated with a reduced risk (per point, 0.89 [0.82-0.97]).

Conclusions: In ventilated stroke patients, decisions to limit life support are more than three times more frequent than in nonbrain-injured patients, with different timing and associated risk factors between ischemic and hemorrhagic strokes.
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http://dx.doi.org/10.1097/CCE.0000000000000341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901798PMC
February 2021

How the COVID-19 pandemic will change the future of critical care.

Intensive Care Med 2021 Mar 22;47(3):282-291. Epub 2021 Feb 22.

School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.

Coronavirus disease 19 (COVID-19) has posed unprecedented healthcare system challenges, some of which will lead to transformative change. It is obvious to healthcare workers and policymakers alike that an effective critical care surge response must be nested within the overall care delivery model. The COVID-19 pandemic has highlighted key elements of emergency preparedness. These include having national or regional strategic reserves of personal protective equipment, intensive care unit (ICU) devices, consumables and pharmaceuticals, as well as effective supply chains and efficient utilization protocols. ICUs must also be prepared to accommodate surges of patients and ICU staffing models should allow for fluctuations in demand. Pre-existing ICU triage and end-of-life care principles should be established, implemented and updated. Daily workflow processes should be restructured to include remote connection with multidisciplinary healthcare workers and frequent communication with relatives. The pandemic has also demonstrated the benefits of digital transformation and the value of remote monitoring technologies, such as wireless monitoring. Finally, the pandemic has highlighted the value of pre-existing epidemiological registries and agile randomized controlled platform trials in generating fast, reliable data. The COVID-19 pandemic is a reminder that besides our duty to care, we are committed to improve. By meeting these challenges today, we will be able to provide better care to future patients.
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http://dx.doi.org/10.1007/s00134-021-06352-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898492PMC
March 2021

Association of Standard Electroencephalography Findings With Mortality and Command Following in Mechanically Ventilated Patients Remaining Unresponsive After Sedation Interruption.

Crit Care Med 2021 04;49(4):e423-e432

Department of Intensive Care Medicine, AP-HP, Bichat-Claude Bernard University Hospital, Paris, France.

Context: Delayed awakening after sedation interruption is frequent in critically ill patients receiving mechanical ventilation.

Objectives: We aimed to investigate the association of standard electroencephalography with mortality and command following in this setting.

Design, Setting, And Patients: In a single-center study, we retrospectively analyzed standard electroencephalography performed in consecutive mechanically ventilated patients remaining unresponsive (comatose/stuporous or unable to follow commands) after sedation interruption. Standard electroencephalography parameters (background activity, continuity, and reactivity) were reassessed by neurophysiologists, blinded to patients' outcome. Patients were categorized during follow-up into three groups based on their best examination as: 1) command following, 2) unresponsive, or 3) deceased. Cause-specific models were used to identify independent standard electroencephalography parameters associated with main outcomes, that is, mortality and command following. Follow-up was right-censored 30 days after standard electroencephalography.

Measurements And Main Results: Main standard electroencephalography parameters recorded in 121 unresponsive patients (median time between sedation interruption and standard electroencephalography: 2 d [interquartile range, 1-4 d]) consisted of a background frequency greater than 4 Hz in 71 (59%), a discontinuous background in 19 (16%), and a preserved reactivity in 98/120 (82%) patients. At 30 days, 66 patients (55%) were command following, nine (7%) were unresponsive, and 46 (38%) had died. In a multivariate analysis adjusted for nonneurologic organ failure, a reactive standard electroencephalography with a background frequency greater than 4 Hz was independently associated with a reduced risk of death (cause-specific hazard ratio, 0.38; CI 95%, 0.16-0.9). By contrast, none of the standard electroencephalography parameters were independently associated with command following. Sensitivity analyses conducted after exclusion of 29 patients with hypoxic brain injury revealed similar findings.

Conclusions: In patients remaining unresponsive after sedation interruption, a pattern consisting of a reactive standard electroencephalography with a background frequency greater than 4 Hz was associated with decreased odds of death. None of the standard electroencephalography parameters were independently associated with command following.
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http://dx.doi.org/10.1097/CCM.0000000000004874DOI Listing
April 2021

The Impact of Carbapenem Resistance on Mortality in Patients With Klebsiella Pneumoniae Bloodstream Infection: An Individual Patient Data Meta-Analysis of 1952 Patients.

Infect Dis Ther 2021 Mar 14;10(1):541-558. Epub 2021 Feb 14.

Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy.

Introduction: Available evidence from observational studies and meta-analyses has highlighted an increased mortality in patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream infections (BSI) compared with their carbapenem-susceptible (CSKP) counterparts, but the exact reasons for this outcome difference are still to be determined.

Methods: We updated the search of a previous meta-analysis through four databases up to April 2018. A two-stage individual-patient data (IPD) meta-analysis was conducted, building an adjusting model to account for age, comorbidities and activity of empirical and targeted antimicrobial therapy. The protocol was registered on PROSPERO (identifier: CRD42018104256).

Results: IPD data were obtained from 14 out of 28 eligible observational studies. A total of 1952 patients were investigated: 1093 in the CRKP group and 859 in the CSKP group. Patients with CRKP-BSI had a twofold risk of death compared with CSKP-infected patients [adjusted odds ratio (aOR) 2.17; 95% confidence interval (CI) 1.56-3.04; I = 44.1%]. Mortality was higher in patients with CRKP BSI, in both the subgroup of absent/inactive (aOR 1.75; 95% CI 1.24-2.47; I = 0) and of active initial therapy (aOR 2.66; 95% CI 1.70-4.16; I = 16%) as well as in case of active targeted therapy (aOR 2.21; 95% CI 1.36-3.59; I = 58%).

Conclusion: Resistance to carbapenem is associated with worse outcome in patients with BSI by Klebsiella pneumoniae even adjusting for comorbidities and treatment appropriateness according to in vitro activity of empirical and targeted therapy. This applies to a scenario dominated by colistin-based therapies for CRKP. Further studies are needed to compare the mortality difference between CRKP and CSKP cases in the light of new anti-CRKP antimicrobials.
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http://dx.doi.org/10.1007/s40121-021-00408-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954918PMC
March 2021

Intensified thromboprophylaxis in COVID-19 critically ill patients: Is it enough?

J Infect 2021 05 5;82(5):e20-e22. Epub 2021 Feb 5.

APHP, Medical and Infectious Diseases ICU, Bichat-Claude Bernard Hospital, APHP, 46 rue Henri Huchard, Paris 75018, France; Université de Paris, UMR 1137, IAME, Paris, France.

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http://dx.doi.org/10.1016/j.jinf.2021.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862021PMC
May 2021

Arterial Thrombotic Events in Adult Inpatients With COVID-19.

Mayo Clin Proc 2021 02 27;96(2):295-303. Epub 2020 Nov 27.

Département Pneumologie A, Hôpital Bichat, Assistance Publique Hôpitaux de Paris, Université de Paris, France.

Objective: To evaluate the clinical course of and risk factors for arterial thrombotic events in adult inpatients with coronavirus disease 2019 (COVID-19).

Methods: All consecutive adult patients admitted for COVID-19 infection in a referral center in France and discharged from the hospital between April 1 and April 30, 2020, were included. All arterial thrombotic events that occurred through discharge were considered for analysis. Epidemiologic, demographic, clinical, laboratory, treatment, and outcome data were extracted from electronic medical records with use of a standardized data collection form.

Results: Overall, 531 COVID-19+ patients were analyzed. Among them, 30 (5.6%) experienced arterial thrombotic events. Arterial thrombotic events in the setting of COVID-19 infection happened at a median of 11 (5-20) days after the first symptoms of infection; occurred in high-risk patients according to traditional cardiovascular risk factors; had an atypical pattern, such as thrombosis of the aorta, upper limb, or renal arteries or cerebral microvasculopathy in 7 (23.3%) cases; and were associated with an in-hospital mortality rate of 40%. Arterial thrombotic events increased the risk of death by 3-fold in COVID-19+ patients (hazard ratio, 2.96; 95% CI, 1.4 to 4.7; P=.002). A subdistribution survival hazard model showed that a concentration of D-dimer above 1250 ng/mL increased the risk of arterial thrombotic events in COVID-19+ patients by more than 7 (subdistribution hazard ratio, 7.68; 95% CI, 2.9 to 20.6; P<.001).

Conclusion: A dramatically high rate of in-hospital death was observed in patients who suffered arterial thrombotic events in the setting of COVID-19 infection. A D-dimer level above 1250 ng/mL at entry may identify COVID-19+ patients at risk for arterial thrombotic events.
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http://dx.doi.org/10.1016/j.mayocp.2020.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691140PMC
February 2021

Multistate Modeling of COVID-19 Patients Using a Large Multicentric Prospective Cohort of Critically Ill Patients.

J Clin Med 2021 Feb 2;10(3). Epub 2021 Feb 2.

Inserm U 1137, Université de Paris, Sorbonne Paris Cite, 75870 Paris, France.

The mortality of COVID-19 patients in the intensive care unit (ICU) is influenced by their state at admission. We aimed to model COVID-19 acute respiratory distress syndrome state transitions from ICU admission to day 60 outcome and to evaluate possible prognostic factors. We analyzed a prospective French database that includes critically ill COVID-19 patients. A six-state multistate model was built and 17 transitions were analyzed either using a non-parametric approach or a Cox proportional hazard model. Corticosteroids and IL-antagonists (tocilizumab and anakinra) effects were evaluated using G-computation. We included 382 patients in the analysis: 243 patients were admitted to the ICU with non-invasive ventilation, 116 with invasive mechanical ventilation, and 23 with extracorporeal membrane oxygenation. The predicted 60-day mortality was 25.9% (95% CI: 21.8%-30.0%), 44.7% (95% CI: 48.8%-50.6%), and 59.2% (95% CI: 49.4%-69.0%) for a patient admitted in these three states, respectively. Corticosteroids decreased the risk of being invasively ventilated (hazard ratio (HR) 0.59, 95% CI: 0.39-0.90) and IL-antagonists increased the probability of being successfully extubated (HR 1.8, 95% CI: 1.02-3.17). Antiviral drugs did not impact any transition. In conclusion, we observed that the day-60 outcome in COVID-19 patients is highly dependent on the first ventilation state upon ICU admission. Moreover, we illustrated that corticosteroid and IL-antagonists may influence the intubation duration.
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http://dx.doi.org/10.3390/jcm10030544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867229PMC
February 2021

Modeling SARS-CoV-2 viral kinetics and association with mortality in hospitalized patients from the French COVID cohort.

Proc Natl Acad Sci U S A 2021 02;118(8)

Université de Paris, INSERM, IAME, F-75018 Paris, France.

The characterization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral kinetics in hospitalized patients and its association with mortality is unknown. We analyzed death and nasopharyngeal viral kinetics in 655 hospitalized patients from the prospective French COVID cohort. The model predicted a median peak viral load that coincided with symptom onset. Patients with age ≥65 y had a smaller loss rate of infected cells, leading to a delayed median time to viral clearance occurring 16 d after symptom onset as compared to 13 d in younger patients ( < 10). In multivariate analysis, the risk factors associated with mortality were age ≥65 y, male gender, and presence of chronic pulmonary disease (hazard ratio [HR] > 2.0). Using a joint model, viral dynamics after hospital admission was an independent predictor of mortality (HR = 1.31, < 10). Finally, we used our model to simulate the effects of effective pharmacological interventions on time to viral clearance and mortality. A treatment able to reduce viral production by 90% upon hospital admission would shorten the time to viral clearance by 2.0 and 2.9 d in patients of age <65 y and ≥65 y, respectively. Assuming that the association between viral dynamics and mortality would remain similar to that observed in our population, this could translate into a reduction of mortality from 19 to 14% in patients of age ≥65 y with risk factors. Our results show that viral dynamics is associated with mortality in hospitalized patients. Strategies aiming to reduce viral load could have an effect on mortality rate in this population.
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http://dx.doi.org/10.1073/pnas.2017962118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929555PMC
February 2021

Outcome of SARS-CoV-2 infection is linked to MAIT cell activation and cytotoxicity.

Nat Immunol 2021 03 2;22(3):322-335. Epub 2021 Feb 2.

Université de Paris, Infections Antimicrobials Modelling Evolution UMR 1137, Paris, France.

Immune system dysfunction is paramount in coronavirus disease 2019 (COVID-19) severity and fatality rate. Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in mucosal immunity and protection against viral infections. Here, we studied the immune cell landscape, with emphasis on MAIT cells, in cohorts totaling 208 patients with various stages of disease. MAIT cell frequency is strongly reduced in blood. They display a strong activated and cytotoxic phenotype that is more pronounced in lungs. Blood MAIT cell alterations positively correlate with the activation of other innate cells, proinflammatory cytokines, notably interleukin (IL)-18, and with the severity and mortality of severe acute respiratory syndrome coronavirus 2 infection. We also identified a monocyte/macrophage interferon (IFN)-α-IL-18 cytokine shift and the ability of infected macrophages to induce the cytotoxicity of MAIT cells in an MR1-dependent manner. Together, our results suggest that altered MAIT cell functions due to IFN-α-IL-18 imbalance contribute to disease severity, and their therapeutic manipulation may prevent deleterious inflammation in COVID-19 aggravation.
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http://dx.doi.org/10.1038/s41590-021-00870-zDOI Listing
March 2021

Obesity and risk of catheter-related infections in the ICU. A post hoc analysis of four large randomized controlled trials.

Intensive Care Med 2021 Apr 1;47(4):435-443. Epub 2021 Feb 1.

University of Paris, INSERM, IAME, 75006, Paris, France.

Purpose: Obesity increases the risk of nosocomial infection, but data regarding the role of body mass index (BMI) in catheter related infections are scarce. We used the data gathered from four randomized, controlled trials (RCTs) to investigate the association between body mass index (BMI) and intravascular catheter infections in critically ill obese patients.

Methods: Adult obese patients who required short-term central venous, arterial or dialysis catheter insertion in the intensive care unit (ICU) were analyzed. The association between BMI and major catheter-related infection (MCRI), catheter-related bloodstream infection (CRBSI) and catheter tip colonization was estimated using univariate and multivariate marginal Cox models. Exploratory analysis using dressing disruptions was added.

Results: A total of 2282 obese patients and 4275 catheters from 32 centers were included in this post-hoc analysis. Overall, 66 (1.5%) MCRI, 43 (1%) CRBSI and 399 (9.3%) catheter colonizations were identified. The hazard ratio (HR) for MCRI, CRBSI and colonization increased with BMI. After adjustment for well-known infection risk factors, the BMI ≥ 40 group had an increased risk for MCRI (HR 1.88, 95% CI 1.13-3.12, p = 0.015), CRBSI (HR 2.19, 95% CI 1.19-4.04, p = 0.012) and colonization (HR 1.44, 95% CI 1.12-1.84, p = 0.0038) compared to the BMI < 40 group. The mean dressing disruption per catheter was increased in the BMI ≥ 40 group (2.03 versus 1.68 in the BMI < 40 group, p = 0.05).

Conclusions: Using the largest dataset ever collected from large multicentric RCTs, we showed that patients with BMI ≥ 40 had an increased risk for intravascular catheter infections. Targeted prevention measures should focus on this population with a particular attention to catheter care and dressing disruption.
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http://dx.doi.org/10.1007/s00134-020-06336-4DOI Listing
April 2021

Association Between Early Invasive Mechanical Ventilation and Day-60 Mortality in Acute Hypoxemic Respiratory Failure Related to Coronavirus Disease-2019 Pneumonia.

Crit Care Explor 2021 Jan 22;3(1):e0329. Epub 2021 Jan 22.

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

Objectives: About 5% of patients with coronavirus disease-2019 are admitted to the ICU for acute hypoxemic respiratory failure. Opinions differ on whether invasive mechanical ventilation should be used as first-line therapy over noninvasive oxygen support. The aim of the study was to assess the effect of early invasive mechanical ventilation in coronavirus disease-2019 with acute hypoxemic respiratory failure on day-60 mortality.

Design: Multicenter prospective French observational study.

Setting: Eleven ICUs of the French OutcomeRea network.

Patients: Coronavirus disease-2019 patients with acute hypoxemic respiratory failure (Pao/Fio ≤ 300 mm Hg), without shock or neurologic failure on ICU admission, and not referred from another ICU or intermediate care unit were included.

Intervention: We compared day-60 mortality in patients who were on invasive mechanical ventilation within the first 2 calendar days of the ICU stay (early invasive mechanical ventilation group) and those who were not (nonearly invasive mechanical ventilation group). We used a Cox proportional-hazard model weighted by inverse probability of early invasive mechanical ventilation to determine the risk of death at day 60.

Measurement And Main Results: The 245 patients included had a median (interquartile range) age of 61 years (52-69 yr), a Simplified Acute Physiology Score II score of 34 mm Hg (26-44 mm Hg), and a Pao/Fio of 121 mm Hg (90-174 mm Hg). The rates of ICU-acquired pneumonia, bacteremia, and the ICU length of stay were significantly higher in the early ( = 117 [48%]) than in the nonearly invasive mechanical ventilation group ( = 128 [52%]), < 0.01. Day-60 mortality was 42.7% and 21.9% in the early and nonearly invasive mechanical ventilation groups, respectively. The weighted model showed that early invasive mechanical ventilation increased the risk for day-60 mortality (weighted hazard ratio =1.74; 95% CI, 1.07-2.83, p=0.03).

Conclusions: In ICU patients admitted with coronavirus disease-2019-induced acute hypoxemic respiratory failure, early invasive mechanical ventilation was associated with an increased risk of day-60 mortality. This result needs to be confirmed.
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http://dx.doi.org/10.1097/CCE.0000000000000329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838010PMC
January 2021

COVID-19 increased the risk of ICU-acquired bloodstream infections: a case-cohort study from the multicentric OUTCOMEREA network.

Intensive Care Med 2021 02 27;47(2):180-187. Epub 2021 Jan 27.

UMR 1137, IAME, INSERM, Université de Paris, 75018, Paris, France.

Purpose: The primary objective of this study was to investigate the risk of ICU bloodstream infection (BSI) in critically ill COVID-19 patients compared to non-COVID-19 patients. Subsequently, we performed secondary analyses in order to explain the observed results.

Methods: We conducted a matched case-cohort study, based on prospectively collected data from a large ICU cohort in France. Critically ill COVID-19 patients were matched with similar non-COVID-19 patients. ICU-BSI was defined by an infection onset occurring > 48 h after ICU admission. We estimated the effect of COVID-19 on the probability to develop an ICU-BSI using proportional subdistribution hazards models.

Results: We identified 321 COVID-19 patients and 1029 eligible controls in 6 ICUs. Finally, 235 COVID-19 patients were matched with 235 non-COVID-19 patients. We observed 43 ICU-BSIs, 35 (14.9%) in the COVID-19 group and 8 (3.4%) in the non-COVID-19 group (p ≤ 0.0001), respectively. ICU-BSIs of COVID-19 patients were more frequently of unknown source (47.4%). COVID-19 patients had an increased probability to develop ICU-BSI, especially after 7 days of ICU admission. Using proportional subdistribution hazards models, COVID-19 increased the daily risk to develop ICU-BSI (sHR 4.50, 95% CI 1.82-11.16, p = 0.0012). Among COVID-19 patients (n = 235), a significantly increased risk for ICU-BSI was detected in patients who received tocilizumab or anakinra (sHR 3.20, 95% CI 1.31-7.81, p = 0.011) but not corticosteroids.

Conclusions: Using prospectively collected multicentric data, we showed that the ICU-BSI risk was higher for COVID-19 than non-COVID-19 critically ill patients after seven days of ICU stay. Clinicians should be particularly careful on late ICU-BSIs in COVID-19 patients. Tocilizumab or anakinra may increase the ICU-BSI risk.
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http://dx.doi.org/10.1007/s00134-021-06346-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839935PMC
February 2021

Burden of pneumococcal pneumonia requiring ICU admission in France: 1-year prognosis, resources use, and costs.

Crit Care 2021 01 10;25(1):24. Epub 2021 Jan 10.

AP-HP, Medical and Infectious Diseases Intensive Care Unit (MI2), Bichat-Claude Bernard University Hospital, 46 rue Henri Huchard, 75018, Paris, France.

Background: Community-acquired pneumonia (CAP), especially pneumococcal CAP (P-CAP), is associated with a heavy burden of illness as evidenced by high rates of intensive care unit (ICU) admission, mortality, and costs. Although well-defined acutely, determinants influencing long-term burden are less known. This study assessed determinants of 28-day and 1-year mortality and costs among P-CAP patients admitted in ICUs.

Methods: Data regarding all hospital and ICU stays in France in 2014 were extracted from the French healthcare administrative database. All patients admitted in the ICU with a pneumonia diagnosis were included, except those hospitalized for pneumonia within the previous 3 months. The pneumococcal etiology and comorbidities were captured. All hospital stays were included in the cost analysis. Comorbidities and other factors effect on the 28-day and 1-year mortality were assessed using a Cox regression model. Factors associated with increased costs were identified using log-linear regression models.

Results: Among 182,858 patients hospitalized for CAP in France for 1 year, 10,587 (5.8%) had a P-CAP, among whom 1665 (15.7%) required ICU admission. The in-hospital mortality reached 22.8% at day 28 and 32.3% at 1 year. The mortality risk increased with age > 54 years, malignancies (hazard ratio (HR) 1.54, 95% CI [1.23-1.94], p = 0.0002), liver diseases (HR 2.08, 95% CI [1.61-2.69], p < 0.0001), and the illness severity at ICU admission. Compared with non-ICU-admitted patients, ICU survivors remained at higher risk of 1-year mortality. Within the following year, 38.2% (516/1350) of the 28-day survivors required at least another hospital stay, mostly for respiratory diseases. The mean cost of the initial stay was €19,008 for all patients and €11,637 for subsequent hospital stays within 1 year. One-year costs were influenced by age (lower in patients > 75 years old, p = 0.008), chronic cardiac (+ 11% [0.02-0.19], p = 0.019), and respiratory diseases (+ 11% [0.03-0.18], p = 0.006).

Conclusions: P-CAP in ICU-admitted patients was associated with a heavy burden of mortality and costs at one year. Older age was associated with both early and 1-year increased mortality. Malignant and chronic liver diseases were associated with increased mortality, whereas chronic cardiac failure and chronic respiratory disease with increased costs.

Trial Registration: N/A (study on existing database).
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http://dx.doi.org/10.1186/s13054-020-03442-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798246PMC
January 2021

Factors associated with survival of patients with solid Cancer alive after intensive care unit discharge between 2005 and 2013.

BMC Cancer 2021 Jan 5;21(1). Epub 2021 Jan 5.

Department of Pneumology and Physiology, Grenoble-Alpes University Hospital, BP217, FR-38043, Grenoble Cedex 9, France.

Background: At intensive care unit (ICU) admission, the issue about prognosis of critically ill cancer patients is of clinical interest, especially after ICU discharge. Our objective was to assess the factors associated with 3- and 6-month survival of ICU cancer survivors.

Methods: Based on the French OutcomeRea™ database, we included solid cancer patients discharged alive, between December 2005 and November 2013, from the medical ICU of the university hospital in Grenoble, France. Patient characteristics and outcome at 3 and 6 months following ICU discharge were extracted from available database.

Results: Of the 361 cancer patients with unscheduled admissions, 253 (70%) were discharged alive from ICU. The main primary cancer sites were digestive (31%) and thoracic (26%). The 3- and 6-month mortality rates were 33 and 41%, respectively. Factors independently associated with 6-month mortality included ECOG performance status (ECOG-PS) of 3-4 (OR,3.74; 95%CI: 1.67-8.37), metastatic disease (OR,2.56; 95%CI: 1.34-4.90), admission for cancer progression (OR,2.31; 95%CI: 1.14-4.68), SAPS II of 45 to 58 (OR,4.19; 95%CI: 1.76-9.97), and treatment limitation decision at ICU admission (OR,4.00; 95%CI: 1.64-9.77). Interestingly, previous cancer chemotherapy prior to ICU admission was independently associated with lower 3-month mortality (OR, 0.38; 95%CI: 0.19-0.75). Among patients with an ECOG-PS 0-1 at admission, 70% (n = 66) and 61% (n = 57) displayed an ECOG-PS 0-2 at 3- and 6-months, respectively. At 3 months, 74 (55%) patients received anticancer treatment, 13 (8%) were given exclusive palliative care.

Conclusions: Factors associated with 6-month mortality are almost the same as those known to be associated with ICU mortality. We highlight that most patients recovered an ECOG-PS of 0-2 at 3 and 6 months, in particular those with a good ECOG-PS at ICU admission and could benefit from an anticancer treatment following ICU discharge.
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http://dx.doi.org/10.1186/s12885-020-07706-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786972PMC
January 2021

Molecular diagnostic methods for pneumonia: how can they be applied in practice?

Curr Opin Infect Dis 2021 Apr;34(2):118-125

Université de Paris, IAME, INSERM.

Purpose Of Review: Pneumonia represents a major burden in clinical practice. A rapid etiological diagnosis is critical for optimizing the antibiotic use. Owing to the variety of possible pathogens and the time needed for bacterial cultures or usual polymerase chain reaction (PCR) assays, timely and precise diagnosis is a huge challenge. Several new rapid multiplex assays have been developed in the last decade to resolve these issues. This review aims to provide an overview of recent evidence on improvements and limitations of new rapid molecular assays for pneumonia.

Recent Findings: Several rapid multiplex-PCR assays are commercially available for upper or lower respiratory tract samples, allowing detection of a wide range of respiratory viruses, bacteria, and, in some cases, of several antibiotic resistance genes. Clinical evaluations demonstrated their good correlation with gold-standard assays but their lack of exhaustiveness, especially for hospital-acquired pneumonia. Studies that evaluated their potential benefits on antibiotic use suffered from important weaknesses with conflicting and limited results.

Summary: New molecular assays may enable improvements in patient management and antibiotic use. Available studies highlight several benefits and the strong interrelations needed between microbiologists and physicians for their implementation and interpretation according to the clinical and epidemiological context.
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http://dx.doi.org/10.1097/QCO.0000000000000713DOI Listing
April 2021

Glucocorticoids with low-dose anti-IL1 anakinra rescue in severe non-ICU COVID-19 infection: A cohort study.

PLoS One 2020 16;15(12):e0243961. Epub 2020 Dec 16.

Pulmonology Department, Kremlin-Bicêtre University Hospital, AP-HP, Paris-Saclay University, Kremlin-Bicêtre, France.

Background: The optimal treatment for patients with severe coronavirus-19 disease (COVID-19) and hyper-inflammation remains debated.

Material And Methods: A cohort study was designed to evaluate whether a therapeutic algorithm using steroids with or without interleukin-1 antagonist (anakinra) could prevent death/invasive ventilation. Patients with a ≥5-day evolution since symptoms onset, with hyper-inflammation (CRP≥50mg/L), requiring 3-5 L/min oxygen, received methylprednisolone alone. Patients needing ≥6 L/min received methylprednisolone + subcutaneous anakinra daily either frontline or in case clinical deterioration upon corticosteroids alone. Death rate and death or intensive care unit (ICU) invasive ventilation rate at Day 15, with Odds Ratio (OR) and 95% CIs, were determined according to logistic regression and propensity scores. A Bayesian analysis estimated the treatment effects.

Results: Of 108 consecutive patients, 70 patients received glucocorticoids alone. The control group comprised 63 patients receiving standard of care. In the corticosteroid±stanakinra group (n = 108), death rate was 20.4%, versus 30.2% in the controls, indicating a 30% relative decrease in death risk and a number of 10 patients to treat to avoid a death (p = 0.15). Using propensity scores a per-protocol analysis showed an OR for COVID-19-related death of 0.9 (95%CI [0.80-1.01], p = 0.067). On Bayesian analysis, the posterior probability of any mortality benefit with corticosteroids+/-anakinra was 87.5%, with a 7.8% probability of treatment-related harm. Pre-existing diabetes exacerbation occurred in 29 of 108 patients (26.9%).

Conclusion: In COVID-19 non-ICU inpatients at the cytokine release phase, corticosteroids with or without anakinra were associated with a 30% decrease of death risk on Day 15.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243961PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743937PMC
December 2020