Publications by authors named "Carole Schwebel"

120 Publications

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

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

Preemptive ganciclovir for mechanically ventilated patients with cytomegalovirus reactivation.

Ann Intensive Care 2021 Feb 11;11(1):33. Epub 2021 Feb 11.

Sorbonne Université, INSERM, Médecine Intensive Réanimation, Institut de Cardiologie, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Assistance Publique-Hôpitaux de Paris, Paris, France.

Background: The effect of cytomegalovirus (CMV) reactivation on the length of mechanical ventilation and mortality in immunocompetent ICU patients requiring invasive mechanical ventilation remains controversial. The main objective of this study was to determine whether preemptive intravenous ganciclovir increases the number of ventilator-free days in patients with CMV blood reactivation.

Methods: This double-blind, placebo-controlled, randomized clinical trial involved 19 ICUs in France. Seventy-six adults ≥ 18 years old who had been mechanically ventilated for at least 96 h, expected to remain on mechanical ventilation for ≥ 48 h, and exhibited reactivation of CMV in blood were enrolled between February 5th, 2014, and January 23rd, 2019. Participants were randomized to receive ganciclovir 5 mg/kg bid for 14 days (n = 39) or a matching placebo (n = 37).

Results: The primary endpoint was ventilator-free days from randomization to day 60. Prespecified secondary outcomes included day 60 mortality. The trial was stopped for futility based on the results of an interim analysis by the DSMB. The subdistribution hazard ratio for being alive and weaned from mechanical ventilation at day 60 for patients receiving ganciclovir (N = 39) compared with control patients (N = 37) was 1.14 (95% CI from 0.63 to 2.06; P = 0.66). The median [IQR] numbers of ventilator-free days for ganciclovir-treated patients and controls were 10 [0-51] and 0 [0-43] days, respectively (P = 0.46). Mortality at day 60 was 41% in patients in the ganciclovir group and 43% in the placebo group (P = .845). Creatinine levels and blood cells counts did not differ significantly between the two groups.

Conclusions: In patients mechanically ventilated for ≥ 96 h with CMV reactivation in blood, preemptive ganciclovir did not improve the outcome.
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http://dx.doi.org/10.1186/s13613-020-00793-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876264PMC
February 2021

Neglecting Plasma Protein Binding in COVID-19 Patients Leads to a Wrong Interpretation of Lopinavir Overexposure.

Clin Pharmacol Ther 2021 04 9;109(4):1030-1033. Epub 2021 Mar 9.

INTHERES, Université de Toulouse, INRA, ENVT, Toulouse Cedex 3, France.

Boffito et al. recalled the critical importance to correctly interpret protein binding. Changes of lopinavir pharmacokinetics in coronavirus disease 2019 (COVID-19) are a perfect illustration. Indeed, several studies described that total lopinavir plasma concentrations were considerably higher in patients with severe COVID-19 than those reported in patients with HIV. These findings have led to a reduction of the dose of lopinavir in some patients, hypothesizing an inhibitory effect of inflammation on lopinavir metabolism. Unfortunately, changes in plasma protein binding were never investigated. We performed a retrospective cohort study. Data were collected from the medical records of patients hospitalized for COVID-19 treated with lopinavir/ritonavir in intensive care units or infectious disease departments of Toulouse University Hospital (France). Total and unbound concentrations of lopinavir, C reactive protein, albumin, and alpha-1-acid glycoprotein (AAG) levels were measured during routine care on the same samples. In patients with COVID-19, increased total lopinavir concentration is the result of an increased AAG-bound lopinavir concentration, whereas the unbound concentration remains constant, and insufficient to reduce the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral load. Although international guidelines have recently recommended against using lopinavir/ritonavir to treat severe COVID-19, the description of lopinavir pharmacokinetics changes in COVID-19 is a textbook case of the high risk of misinterpretation of a total drug exposure when changes in protein binding are not taken into consideration.
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http://dx.doi.org/10.1002/cpt.2196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013748PMC
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

Ventilation Management and Outcomes for Subjects With Neuromuscular Disorders Admitted to ICUs With Acute Respiratory Failure.

Respir Care 2021 Apr 29;66(4):669-678. Epub 2020 Dec 29.

Médecine Intensive - Réanimation, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.

Background: Patients with neuromuscular disorders (NMD) share the risk of acute respiratory failure (ARF) leading to ICU admissions. Noninvasive ventilation (NIV) is often proposed as an alternative to invasive ventilation. This study describes clinical features, ventilation management, and outcomes of subjects with NMD admitted to ICU and managed for ARF.

Methods: We performed a multicenter retrospective study in 7 adult ICUs in the Auvergne-Rhone-Alpes area in France involving subjects with NMD admitted to the ICU for ARF. The primary end point was ICU mortality. Secondary end points were NIV failure, weaning from invasive ventilation, and long-term mortality. We hypothesized a poorer outcome in the case of bulbar musculature involvement.

Results: A total of 242 subjects were included; 142 subjects had nonhereditary NMD (58.7%), and 100 had hereditary NMD (41.3%). Eleven subjects had home ventilation through a tracheostomy. While 112 were intubated at admission, 119 initially underwent NIV. NIV was successful in avoiding orotracheal intubation in 78 subjects (65.5%). ICU mortality was 13.6%. Factors associated with ICU mortality were nonhereditary NMD and requirement for invasive ventilation. The involvement of bulbar musculature in ARF and hereditary NMD were associated with NIV failure. After a median follow-up of 1.2 y, 53 of 209 subjects had died.

Conclusions: The ICU mortality of NMD subjects with ARF was low, with no impact of bulbar muscles involvement. NIV was proposed for approximately half of the subjects, and it was more effective when ARF was not attributed to bulbar musculature involvement. The long-term outcome was good.
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http://dx.doi.org/10.4187/respcare.08362DOI Listing
April 2021

Local signs at insertion site and catheter-related bloodstream infections: an observational post hoc analysis using individual data of four RCTs.

Crit Care 2020 12 14;24(1):694. Epub 2020 Dec 14.

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

Background: Little is known on the association between local signs and intravascular catheter infections. This study aimed to evaluate the association between local signs at removal and catheter-related bloodstream infections (CRBSI), and which clinical conditions may predict CRBSIs if inflammation at insertion site is present.

Methods: We used individual data from four multicenter randomized controlled trials in intensive care units (ICUs) that evaluated various prevention strategies for arterial and central venous catheters. We used multivariate logistic regressions in order to evaluate the association between ≥ 1 local sign, redness, pain, non-purulent discharge and purulent discharge, and CRBSI. Moreover, we assessed the probability for each local sign to observe CRBSI in subgroups of clinically relevant conditions.

Results: A total of 6976 patients and 14,590 catheters (101,182 catheter-days) and 114 CRBSI from 25 ICUs with described local signs were included. More than one local sign, redness, pain, non-purulent discharge, and purulent discharge at removal were observed in 1938 (13.3%), 1633 (11.2%), 59 (0.4%), 251 (1.7%), and 102 (0.7%) episodes, respectively. After adjusting on confounders, ≥ 1 local sign, redness, non-purulent discharge, and purulent discharge were associated with CRBSI. The presence of ≥ 1 local sign increased the probability to observe CRBSI in the first 7 days of catheter maintenance (OR 6.30 vs. 2.61 [> 7 catheter-days], p = 0.02).

Conclusions: Local signs were significantly associated with CRBSI in the ICU. In the first 7 days of catheter maintenance, local signs increased the probability to observe CRBSI.
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http://dx.doi.org/10.1186/s13054-020-03425-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737269PMC
December 2020

Chlorhexidine-impregnated sponge versus chlorhexidine gel dressing for short-term intravascular catheters: which one is better?

Crit Care 2020 07 23;24(1):458. Epub 2020 Jul 23.

University of Paris, INSERM IAME, U1137, Team DesCID, Paris, France.

Background: Chlorhexidine-gluconate (CHG) impregnated dressings may prevent catheter-related bloodstream infections (CRBSI). Chlorhexidine-impregnated sponge dressings (sponge-dress) and gel dressings (gel-dress) have never been directly compared. We used the data collected for two randomized-controlled trials to perform a comparison between sponge-dress and gel-dress.

Methods: Adult critically ill patients who required short-term central venous or arterial catheter insertion were recruited. Our main analysis included only patients with CHG-impregnated dressings. The effect of gel-dress (versus sponge-dress) on major catheter-related infections (MCRI) and CRBSI was estimated using multivariate marginal Cox models. The comparative risks of dressing disruption and contact dermatitis were evaluated using logistic mix models for clustered data. An explanatory analysis compared gel-dress with standard dressings using either CHG skin disinfection or povidone iodine skin disinfection.

Results: A total of 3483 patients and 7941 catheters were observed in 16 intensive care units. Sponge-dress and gel-dress were utilized for 1953 and 2108 catheters, respectively. After adjustment for confounders, gel-dress showed similar risk for MCRI compared to sponge-dress (HR 0.80, 95% CI 0.28-2.31, p = 0.68) and CRBSI (HR 1.13, 95% CI 0.34-3.70, p = 0.85), less dressing disruptions (OR 0.72, 95% CI 0.60-0.86, p < 0.001), and more contact dermatitis (OR 3.60, 95% CI 2.51-5.15, p < 0.01). However, gel-dress increased the risk of contact dermatitis only if CHG was used for skin antisepsis (OR 1.94, 95% CI 1.38-2.71, p < 0.01).

Conclusions: We described a similar infection risk for gel-dress and sponge-dress. Gel-dress showed fewer dressing disruptions. Concomitant use of CHG for skin disinfection and CHG-impregnated dressing may significantly increase contact dermatitis.

Trials Registration: These studies were registered within ClinicalTrials.gov (numbers NCT01189682 and NCT00417235 ).
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http://dx.doi.org/10.1186/s13054-020-03174-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376730PMC
July 2020

Ultrasound guidance and risk for intravascular catheter-related infections among peripheral arterial catheters: a post-hoc analysis of two large randomized-controlled trials.

Ann Intensive Care 2020 Jul 8;10(1):89. Epub 2020 Jul 8.

University of Paris, INSERM IAME, U1137, Team DeSCID, Paris, France.

Background: The impact on infectious risk of ultrasound guidance at insertion remains controversial in short-term arterial catheters (ACs). The present study investigated the association between ultrasound guidance (US) during AC insertion and major catheter-related infections (MCRI), catheter-related bloodstream infections (CR-BSI) or colonization, using univariate and multivariate marginal Cox model for clustered data. The skin colonization at catheter removal was evaluated to explain our results.

Results: We used individual data from two multicenter randomized-controlled trials (RCTs) that included a total of 3029 patients, 10 ICUs and 3950 ACs. US guidance was used for 386 (9.8%) catheter placements. In the univariate Cox model analysis, AC insertion with US versus without US exhibited similar risks for MCRI (HR 0.86, CI 95% 0.27-2.72, p = 0.79), CR-BSI (HR 0.87, CI 95% 0.20-3.72, p = 0.85) and catheter colonization (HR 1.31, CI 95% 0.92-1.86, p = 0.13). After adjustment on confounders, risks associated with US guidance remained similar versus non-US for MCRI (HR 0.71, CI 95% 0.23-2.24, p = 0.56), CR-BSI (HR 0.71, CI 95% 0.17-3.00, p = 0.63) and catheter colonization (HR 0.92, CI 95% 0.63-1.34, p = 0.67). No differences between US and non-US for MCRI, CR-BSI and colonization were observed according to the insertion site, radial or femoral. At catheter removal, the skin colonization was similar between US and non-US groups (p = 0.69).

Conclusions: Using the largest dataset ever collected from large multi-centric RCTs conducted with relatively consistent insertion and maintenance catheter protocols, we showed that the risk of infectious complications for ACs inserted under US guidance is not superior compared to those inserted without US guidance. Trial registration These studies were registered within ClinicalTrials.gov (numbers NCT01629550 and NCT01189682).
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http://dx.doi.org/10.1186/s13613-020-00705-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343671PMC
July 2020

A Comprehensive Bench Assessment of Automatic Tube Compensation in ICU Ventilators for Better Clinical Management.

Respir Care 2020 Dec 30;65(12):1864-1873. Epub 2020 Jun 30.

Institut Mondor de Recherche Biomédicale, Université Paris Est Créteil, INSERM 955, Créteil, France.

Background: Automatic tube compensation (ATC) unloads endotracheal tube (ETT) resistance. We conducted a bench assessment of ATC functionality in ICU ventilators to improve clinical management.

Methods: This study had 2 phases. First, we performed an international survey on the use of ATC in clinical practice, hypothesizing a rate of ATC use of 25%. Second, we tested 7 modern ICU ventilators in a lung model mimicking a normal subject (Normal), a subject with ARDS, and a subject with COPD. Inspiratory effort consisted of esophageal pressure over 30 consecutive breaths obtained in a real patient under weaning. A brand new 8-mm inner diameter ETT was attached to the lung model, and ATC was set at 100% compensation for the ETT. The 30 breaths were first run with ATC off and no ETT (ie, reference period), and then with ATC on and ETT (ie, active period). The primary end point was the difference in tidal volume (V) between reference and active periods. We hypothesized that the V difference should be equal to 0 in an ideally functioning ATC. V difference was compared across ventilators and respiratory mechanics conditions using a linear mixed-effects model.

Results: The clinical use of ATC was 64% according to 644 individuals who responded to the international survey. The V difference varied significantly across ventilators in all respiratory mechanics configurations. The divergence between V difference and 0 was small but significant: the extreme median (interquartile range) values were -0.013 L (-0.019 to -0.002) in the COPD model and 0.056 L (0.051-0.06) in the Normal model. V difference for all ventilators was 0.015 L (95% CI 0.013-0.018) in the ARDS model, which was significantly different from 0.021 L (95% CI 0.018-0.024) in the Normal model ( < .001) and 0.010 L (0.007-0.012) in the COPD model ( = .003).

Conclusions: ATC is used more frequently in clinical practice than expected. In addition, V delivery by ATC differed slightly though significantly between ventilators.
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http://dx.doi.org/10.4187/respcare.07608DOI Listing
December 2020

Mucormycosis in intensive care unit: surgery is a major prognostic factor in patients with hematological malignancy.

Ann Intensive Care 2020 Jun 8;10(1):74. Epub 2020 Jun 8.

Université Grenoble Alpes, Grenoble, France.

Background: Mucormycosis is an invasive fungal infection, with an increasing incidence especially in patients with hematological malignancies. Its prognosis is poor because of its high invasive power and its intrinsic low susceptibility to antifungal agents. We aimed to describe the epidemiology of mucormycosis in intensive care units (ICU) and evaluate the outcomes. We performed a retrospective multi-center study in 16 French ICUs between 2008 and 2017. We compared the patients who survived in ICU and the patients who did not to identify factors associated with ICU survival. Then, we focused on the subgroup of patients with hematological malignancies.

Results: Mucormycosis was diagnosed in 74 patients during the study period. Among them, 60 patients (81%) were immunocompromised: 41 had hematological malignancies, 9 were solid organ transplant recipients, 31 received long-term steroids, 11 had diabetes, 24 had malnutrition. Only 21 patients survived to ICU stay (28.4%) with a median survival of 22 days (Q1-Q3 = 9-106) and a survival rate at day 28 and day 90, respectively, of 35.1% and 26.4%. Survivors were significantly younger (p = 0.001), with less frequently hematological malignancies (p = 0.02), and less malnutrition (p = 0.05). Median survival in patients with hematological malignancies (n = 41) was 15 days (Q1-Q3 = 5-23.5 days). In this subgroup, curative surgery was a major factor associated with survival in multivariate analysis (odds ratio = 0.71, [0.45-0.97], p < 0.001).

Conclusion: Overall prognosis of mucormycosis in ICU remains poor, especially in patients with hematological malignancies. In this subgroup of patients, a therapeutic strategy including curative surgery was the main factor associated with survival.
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http://dx.doi.org/10.1186/s13613-020-00673-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280386PMC
June 2020

Impact of take-home messages written into slide presentations delivered during lectures on the retention of messages and the residents' knowledge: a randomized controlled study.

BMC Med Educ 2020 Jun 3;20(1):180. Epub 2020 Jun 3.

Biostatistics unit, Delegation à la Recherche Clinique (DRCI), University Hospital of Clermont-Ferrand, Clermont-Ferrand, France.

Background: Lectures with slide presentations are widely used to teach evidence-based medicine to large groups. Take-home messages (THMs) are poorly identified and recollected by students. We investigated whether an instruction to list THMs in written form on slides would improve the retention thereof by residents, and the residents' level of knowledge, 1 month after lectures.

Methods: Prospective blinded randomized controlled study was conducted. Twelve lectures (6 control and 6 intervention lectures) were delivered to 73 residents. For the intervention lectures, the lecturers were instructed to incorporate clear written THMs into their slide presentations. The outcomes were ability of resident to recollect THMs delivered during a lecture (as assessed by accordance rate between the lecturers' and residents' THMs) and knowledge (as assessed by multiple choice questions (MCQs)).

Results: Data for 3738 residents' THMs and 3410 MCQs were analyzed. The intervention did not significantly increase the number of THMs written on slides (77% (n = 20/26), 95% CI 56-91 vs 64% (n = 18/28), 95% CI 44-81, p = 0.31) nor THMs retention (13% (n = 238/1791), 95% CI 12-15 vs 17% (n = 326/1947), 95% 15-18, p = 0.40) nor knowledge (63.8 ± 26.2 vs 61.1 ± 31.4 /100 points, p = 0.75). In multivariable analyses performed with all THMs written on slides from the two groups, a superior knowledge was associated with notetaking during lectures (OR 1.88, 95% CI 1.41-2.51) and THMs retention (OR 2.17, 95% CI 1.54-3.04); and THMs retention was associated with written THMs (OR 2.94, 95% CI 2.20-3.93).

Conclusions: In lectures delivered to residents, a third of the THMs were not in written form. An intervention based on an explicit instruction to lecturers to provide THMs in written form in their slide presentations did not result in increased use of written THMs into the slide presentation or improvement of the THMs retention or level of knowledge. However, we showed that there was a strong positive association between writing THMs on a slide, retention of THMs and residents' knowledge. Further researches are needed to assess interventions to increase written THMs in lectures by faculty.

Trial Registration: ClinicalTrials.gov NCT01795651 (Fev 21, 2013).
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http://dx.doi.org/10.1186/s12909-020-02092-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271544PMC
June 2020

Screening of hepatitis E in patients presenting for acute neurological disorders.

J Infect Public Health 2020 Jul 26;13(7):1047-1050. Epub 2020 Mar 26.

Department of Internal Medicine, Grenoble University Hospital, Grenoble, France; Univ. Grenoble Alpes, Department of Internal Medicine CHU Grenoble, Inserm (U1036), CEA, BIG-BCI, France.

Introduction: Hepatitis E virus (HEV) infection has been reported to be associated with neurological disorders. However, the real prevalence of acute hepatitis E in those diseases is still unknown. We determined the prevalence of anti-HEV IgM antibody in a population with acute non-traumatic, non-metabolic, non-vascular neurological injury.

Method: A registry was created in Grenoble Hospital University from 2014 to 2018 to collect data on patients with acute (<3 months) non-traumatic, non-metabolic, non-vascular neurological injuries. Acute hepatitis E was defined as anti-HEV IgM-positive serum in immunocompetent patient, and as anti-HEV IgM-positive serum or HEV RNA-positive serum in immunocompromised patients.

Results: One hundred fifty-nine patients were included. Anti-HEV IgM seroprevalence in our cohort of non-traumatic, non-metabolic, non-vascular neurological injuries was 6.9% (eleven patients, including 4 Parsonage-Turner syndrome (PTS) and 2 Guillain-Barré syndrome (GBS)). Elevated transaminases were observed in only 64% of hepatitis E patients and cholestasis in 64%.

Conclusion: In this study, 6·9% of patients with acute non-traumatic, non-metabolic, non-vascular neurological injuries had a probable recent HEV infection. HEV serology should be systematically performed in this population, even in patients with normal transaminase level.
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http://dx.doi.org/10.1016/j.jiph.2019.12.012DOI Listing
July 2020

Does endo-tracheal tube clamping prevent air leaks and maintain positive end-expiratory pressure during the switching of a ventilator in a patient in an intensive care unit? A bench study.

PLoS One 2020 11;15(3):e0230147. Epub 2020 Mar 11.

Médecine Intensive-Réanimation, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France.

Objectives: When patients with acute respiratory distress syndrome are moved out of an intensive care unit, the ventilator often requires changing. This procedure suppresses positive end expiratory pressure and promotes lung derecruitment. Clamping the endotracheal tube may prevent this from occurring. Whether or not such clamping maintains positive end-expiratory pressure has never been investigated. We designed a bench study to explore this further.

How The Study Was Done: We used the Elysee 350 ventilator in 'volume controlled' mode with a positive end-expiratory pressure of 15 cmH2O, connected to an endotracheal tube with an 8 mm internal diameter inserted into a lung model with 40 ml/cmH2O compliance and 10 cmH2O/L/s resistance. We measured airway pressure and flow between the distal end of the endotracheal tube and the lung model. We tested a plastic, a metal, and an Extra Corporeal Membrane Oxygenation clamp, each with an oral/nasal, a nasal, and a reinforced endotracheal tube. We performed an end-expiratory hold then clamped the endotracheal tube and disconnected the ventilator. We measured the change in airway pressure and volume for 30 s following the disconnection of the ventilator.

Results: Airway pressure decreased thirty seconds after disconnection with all combinations of clamp and endotracheal tube. The largest fall in airway pressure (-17.486 cmH2O/s at 5 s and -18.834 cmH2O/s at 30 s) was observed with the plastic clamp combined with the reinforced endotracheal tube. The smallest decrease in airway pressure (0 cmH2O/s at 5 s and -0.163 cmH2O/s at 30 s) was observed using the Extra Corporeal Membrane Oxygenation clamp with the nasal endotracheal tube.

Conclusions: Only the Extra Corporeal Membrane Oxygenation clamp was efficient. Even with an Extra Corporeal Membrane Oxygenation clamp, it is important to limit the duration the ventilator is disconnected to a few seconds (ideally 5 s).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230147PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065807PMC
June 2020

Impact of obstructive sleep apnea on the obesity paradox in critically ill patients.

J Crit Care 2020 04 20;56:120-124. Epub 2019 Dec 20.

INSERM U1137, Université Paris Diderot, Sorbonne Paris Cite, Paris, France; Medical and Infectious Intensive Care Unit, Bichat Claude Bernard University Hospital, AP-HP, Paris, France.

Objective: Patients admitted to an intensive care unit (ICU) frequently suffer from multiple chronic diseases, including obstructive sleep apnea (OSA). Until recently OSA was not considered as a key determinant in an ICU patient's prognosis. The objective of this study was to document the impact of OSA on the prognosis of ICU patients.

Methods: Data were retrospectively collected concerning adult patients admitted to ICU at two university hospitals. In a nested study OSA status was checked using the hospital electronic medical records to identify exposed and unexposed cases. The following outcomes were considered: length of stay in the ICU, ICU mortality, in-hospital mortality, ventilator-associated pneumonia (VAP).

Results: Out of 5146 patients included in the study, 289 had OSA at ICU admission (5.6%). After matching, the overall impact of OSA on length of ICU stay was not significant (p = .24). In a predefined subgroup analysis, there was a significant impact of OSA on the length of ICU stay for patients with BMI over 40 kg/m (IRR: 1.56 [1.05; 2.32], p = .03). OSA status had no impact on ICU or hospital mortality and VAP.

Conclusion: In general, known OSA did not increase the ICU stay except for patients with both OSA and morbid obesity.
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http://dx.doi.org/10.1016/j.jcrc.2019.12.016DOI Listing
April 2020

Influence of dyskalemia at admission and early dyskalemia correction on survival and cardiac events of critically ill patients.

Crit Care 2019 Dec 19;23(1):415. Epub 2019 Dec 19.

UMR 1137, IAME, Université Paris Diderot, F75018, Paris, France.

Objectives: Our objectives were (1) to characterize the distribution of serum potassium levels at ICU admission, (2) to examine the relationship between dyskalemia at ICU admission and occurrence of cardiac events, and (3) to study both the association between dyskalemia at ICU admission and dyskalemia correction by day 2 on 28-day mortality.

Design: Inception cohort study from the longitudinal prospective French multicenter OUTCOMEREA database (1999-2014) SETTING: 22 French OUTCOMEREA network ICUs PATIENTS: Patients were classified into six groups according to their serum potassium level at admission: three groups of hypokalemia and three groups of hyperkalemia defined as serious hypokalemia [K+] < 2.5 and serious hyperkalemia [K+] > 7 mmol/L, moderate hypokalemia 2.5 ≤ [K+] < 3 mmol/L and moderate hyperkalemia 6 < [K+] ≤ 7 mmol/L, and mild hypokalemia 3 ≤ [K+] < 3.5 mmol/L and mild hyperkalemia 5 < [K+] ≤ 6 mmol/L. We sorted evolution at day 2 of dyskalemia into three categories: balanced, not-balanced, and overbalanced.

Intervention: None MEASUREMENTS AND MAIN RESULTS: Of 12,090 patients, 2108 (17.4%) had hypokalemia and 1445 (12%) had hyperkalemia. Prognostic impact of dyskalemia and its correction was assessed using multivariate Cox models. After adjustment, hypokalemia and hyperkalemia were independently associated with a greater risk of 28-day mortality. Mild hyperkalemic patients had the highest mortality (hazard ratio (HR) 1.29, 95% confidence interval (CI) [1.13-1.47], p < 0.001). Adjusted 28-day mortality was higher if serum potassium level was not-balanced at day 2 (aHR = 1.51, 95% CI [1.30-1.76], p < 0.0001) and numerically higher but not significantly different if serum potassium level was overbalanced at day 2 (aHR = 1.157, 95% CI [0.84-1.60], p = 0.38). Occurrence of cardiac events was evaluated by logistic regression. Except for patients with serious hypokalemia at admission, the depth of dyskalemia was associated with increased risk of cardiac events.

Conclusions: Dyskalemia is common at ICU admission and associated with increased mortality. Occurrence of cardiac events increased with dyskalemia depth. A correction of serum potassium level by day 2 was associated with improved prognosis.
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http://dx.doi.org/10.1186/s13054-019-2679-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921444PMC
December 2019

Acyclovir for Mechanically Ventilated Patients With Herpes Simplex Virus Oropharyngeal Reactivation: A Randomized Clinical Trial.

JAMA Intern Med 2020 02;180(2):263-272

Médecine Intensive Réanimation, Aix-Marseille Université, Hôpital Nord, Assistance Publique-Hôpitaux de Marseille, Marseille, France.

Importance: The role of herpes simplex virus (HSV) reactivation on morbidity and mortality in patients in the intensive care unit requiring mechanical ventilation remains unknown.

Objective: To determine whether preemptive treatment with intravenous acyclovir reduces the duration of mechanical ventilation in patients with HSV oropharyngeal reactivation.

Design, Setting, And Participants: A double-blind, placebo-controlled randomized clinical trial was conducted in 16 intensive care units in France. Participants included 239 adults (age, >18 years) who received mechanical ventilation for at least 96 hours and continued to receive mechanical ventilation for 48 hours or more, with HSV oropharyngeal reactivation. Patients were enrolled between February 2, 2014, and February 22, 2018.

Interventions: Participants were randomized to receive intravenous acyclovir, 5 mg/kg, 3 times daily for 14 days or a matching placebo.

Main Outcomes And Measures: The primary end point was ventilator-free days from randomization to day 60. Prespecified secondary outcomes included mortality at 60 days. Main analyses were conducted on an intention-to-treat basis.

Results: Of 239 patients enrolled and randomized, 1 patient withdrew consent, leaving 238 patients, with 119 patients in both the acyclovir and placebo (control) groups (median [IQR] age, 61 [50-70] years; 76 [32%] women) available for primary outcome measurement. On day 60, the median (IQR) numbers of ventilator-free days were 35 (0-53) for acyclovir recipients and 36 (0-50]) for controls (P = .17 for between-group comparison). Among secondary outcomes, 26 patients (22%) and 39 patients (33%) had died at day 60 (risk difference, 0.11, 95% CI, -0.004 to 0.22, P = .06). The adverse event frequency was similar for both groups (28% in the acyclovir group and 23% in the placebo group, P = .40), particularly acute renal failure post randomization affecting 3 acyclovir recipients (3%) and 2 controls (2%). Four patients (3%) in the acyclovir group vs none in the placebo group stopped the study drug for treatment-related adverse events.

Conclusions And Relevance: In patients receiving mechanical ventilation for 96 hours or more with HSV reactivation in the throat, use of acyclovir, 5 mg/kg, 3 times daily for 14 days, did not increase the number of ventilator-free days at day 60, compared with placebo. These findings do not appear to support routine preemptive use of acyclovir in this setting.

Trial Registration: ClinicalTrials.gov identifier: NCT02152358.
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http://dx.doi.org/10.1001/jamainternmed.2019.5713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990840PMC
February 2020

Reverse Triggering: Sometimes It Is Not Only the Diaphragm.

Am J Respir Crit Care Med 2020 04;201(7):e24-e25

Medical Intensive Care Unit, University Hospital, Grenoble, France.

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http://dx.doi.org/10.1164/rccm.201907-1358IMDOI Listing
April 2020

Ventilator-associated pneumonia due to Stenotrophomonas maltophilia: Risk factors and outcome.

J Infect 2020 03 2;80(3):279-285. Epub 2019 Nov 2.

UMR 1137, IAME, Université Paris Diderot, Paris, France; Outcomerea Research Network, Aulnay sous Bois, France; Medical and Infectious diseases ICU (MI2), APHP, Bichat Hospital, Paris, France. Electronic address:

Background: Stenotrophomonas maltophilia (SM) is increasingly identified in intensive care unit (ICU). This study aim to identify risk factors for SM ventilator-associated pneumonia (VAP) and whether it affects ICU mortality METHODS: Two nested matched case-control studies were performed based in OUTCOMEREA database. The first episodes of SM-VAP patients were matched with two different control groups: VAP due to other micro-organisms (VAP-other) and Pseudomonas aeruginosa VAP (Pyo-VAP). Matching criteria were the hospital, the SAPS II, and the previous duration of mechanical ventilation (MV).

Results: Of the 102 SM-VAP patients (6.2% of all VAP patients), 92 were matched with 375 controls for the SM-VAP/other-VAP matching and 84 with 237 controls for the SM-VAP/Pyo-VAP matching. SM-VAP risk factors were an exposition to ureido/carboxypenicillin or carbapenem during the week before VAP, and respiratory and coagulation components of SOFA score upper to 2 before VAP. SM-VAP received early adequate therapy in 70 cases (68.6%). Risk factors for Day-30 were age (OR = 1.03; p < 0.01) and Chronic heart failure (OR = 3.15; p < 0.01). Adequate treatment, either monotherapy or combination of antimicrobials, did not modify mortality. There was no difference in 30-day mortality, but 60-day mortality was higher in patients with SM-VAP compared to Other-VAP (P = 0.056).

Conclusions: In a large series, independent risk factors for the SM-VAP were ureido/carboxypenicillin or carbapenem exposure the week before VAP, and respiratory and coagulation components of the SOFA score > 2 before VAP. Mortality risk factors of SM-VAP were age and chronic heart failure. Adequate treatment did not improve SM-VAP prognosis.
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http://dx.doi.org/10.1016/j.jinf.2019.10.021DOI Listing
March 2020

Impact of species and antibiotic therapy of enterococcal peritonitis on 30-day mortality in critical care-an analysis of the OUTCOMEREA database.

Crit Care 2019 09 6;23(1):307. Epub 2019 Sep 6.

Medical and Infectious Diseases ICU, Bichat University Hospital, AP-HP, Paris, France.

Introduction: Enterococcus species are associated with an increased morbidity in intraabdominal infections (IAI). However, their impact on mortality remains uncertain. Moreover, the influence on outcome of the appropriate or inappropriate status of initial antimicrobial therapy (IAT) is subjected to debate, except in septic shock. The aim of our study was to evaluate whether an IAT that did not cover Enterococcus spp. was associated with 30-day mortality in ICU patients presenting with IAI growing with Enterococcus spp.

Material And Methods: Retrospective analysis of French database OutcomeRea from 1997 to 2016. We included all patients with IAI with a peritoneal sample growing with Enterococcus. Primary endpoint was 30-day mortality.

Results: Of the 1017 patients with IAI, 76 (8%) patients were included. Thirty-day mortality in patients with inadequate IAT against Enterococcus was higher (7/18 (39%) vs 10/58 (17%), p = 0.05); however, the incidence of postoperative complications was similar. Presence of Enterococcus spp. other than E. faecalis alone was associated with a significantly higher mortality, even greater when IAT was inadequate. Main risk factors for having an Enterococcus other than E. faecalis alone were as follows: SAPS score on day 0, ICU-acquired IAI, and antimicrobial therapy within 3 months prior to IAI especially with third-generation cephalosporins. Univariate analysis found a higher hazard ratio of death with an Enterococcus other than E. faecalis alone that had an inadequate IAT (HR = 4.4 [1.3-15.3], p = 0.019) versus an adequate IAT (HR = 3.1 [1.0-10.0], p = 0.053). However, after adjusting for confounders (i.e., SAPS II and septic shock at IAI diagnosis, ICU-acquired peritonitis, and adequacy of IAT for other germs), the impact of the adequacy of IAT was no longer significant in multivariate analysis. Septic shock at diagnosis and ICU-acquired IAI were prognostic factors.

Conclusion: An IAT which does not cover Enterococcus is associated with an increased 30-day mortality in ICU patients presenting with an IAI growing with Enterococcus, especially when it is not an E. faecalis alone. It seems reasonable to use an IAT active against Enterococcus in severe postoperative ICU-acquired IAI, especially when a third-generation cephalosporin has been used within 3 months.
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http://dx.doi.org/10.1186/s13054-019-2581-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731585PMC
September 2019

Pneumonia in acute ischemic stroke patients requiring invasive ventilation: Impact on short and long-term outcomes.

J Infect 2019 09 22;79(3):220-227. Epub 2019 Jun 22.

UMR 1137, IAME, Paris Diderot University, Sorbonne Paris Cité, 16 rue Henri Huchard, 75018 Paris, France; Medical and Infectious Diseases Intensive Care Unit, AP-HP, Bichat-Claude Bernard Hospital, 46 rue Henri Huchard, 75018 Paris, France.

Objectives: To describe the epidemiology and prognostic impact of pneumonia in acute ischemic stroke patients requiring invasive mechanical ventilation.

Methods: Retrospective analysis from a prospective multicenter cohort study of critically ill patients with acute ischemic stroke requiring invasive mechanical ventilation at admission. Impact of pneumonia was investigated using Cox regression for 1-year mortality, and competing risk survival models for ICU mortality censored at 30-days.

Results: We included 195 patients. Stroke was supratentorial in 62% and 64% of patients had a Glasgow coma scale score <8 on admission. Mortality at day-30 and 1 year were 56%, and 70%, respectively. Post-stroke pneumonia was identified in 78 (40%) patients, of which 46/78 (59%) episodes were present at ICU admission. Post-stroke pneumonia was associated with an increase in 1-year mortality (adjusted HR 1.49, 95%CI [1.01-2.20]). Post-stroke pneumonia was not associated with ICU mortality but was associated with a 1.6-fold increase in ICU length of stay (CSHR 0.62 [0.39-0.99], p = 0.06).

Conclusions: In ischemic stroke patients requiring invasive ventilation, pneumonia occurred in 40% of cases and was associated with a 49% increase in 1-year mortality. Post-stroke pneumonia did not impact day-30 mortality but increased ICU length of stay.
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http://dx.doi.org/10.1016/j.jinf.2019.06.012DOI Listing
September 2019

Remote ischemic conditioning in septic shock (RECO-Sepsis): study protocol for a randomized controlled trial.

Trials 2019 May 22;20(1):281. Epub 2019 May 22.

Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Médecine Intensive-Réanimation, 5, place d'Arsonval, 69437, Lyon Cedex 03, France.

Background: Septic shock is a major public health problem that is associated with up to 50% mortality. Unfavorable outcomes are mainly attributed to multiple organ failure (MOF) resulting from an uncontrolled inflammatory response and ischemia-reperfusion processes. REmote ischemic COnditioning (RECO) is a promising intervention to prevent ischemia-reperfusion injury. We hypothesize that RECO would reduce the severity of septic shock-induced MOF.

Methods/design: RECO in septic shock patients (RECO-Sepsis study) is an ongoing, prospective, multicenter, randomized, open-label trial, testing whether RECO, as an adjuvant therapy to conventional treatment in septic shock, decreases the severity of MOF as assessed by the Sequential Organ Failure Assessment (SOFA) score. Adult patients admitted to an intensive care unit with documented or suspected infection, lactatemia > 2 mmol/l, and treated with norepinephrine for less than 12 h are potentially eligible for the study. Non-inclusion criteria are: having expressed the wish not to be resuscitated, contraindication for the use of a brachial cuff on both arms, intercurrent disease with an expected life expectancy of less than 24 h, cardiac arrest, and pregnant or breastfeeding women. After enrollment, patients are randomized (n = 180) 1:1 to receive RECO or no adjunctive intervention. RECO consists of four cycles of cuff inflation to 200 mmHg for 5 min and then deflation to 0 mmHg for another 5 min. RECO is performed at inclusion and repeated 12 and 24 h later. The primary endpoint is the mean daily SOFA score up to day 4 after inclusion. Secondary outcomes include the need for organ support, hospital length of stay, and 90-day mortality.

Discussion: Results of this proof-of-concept trial should provide information on the efficacy of RECO in patients with septic shock.

Trial Registration: ClinicalTrials.gov, ID: identifier: NCT03201575 . Registered on 28 June 2017.
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http://dx.doi.org/10.1186/s13063-019-3406-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532140PMC
May 2019

Interprofessional safety reporting and review of adverse events and medication errors in critical care.

Ther Clin Risk Manag 2019 2;15:549-556. Epub 2019 Apr 2.

Université Grenoble Alpes, Grenoble 38000, France.

Background: The intensive care unit (ICU) environment is prone to the risk of adverse events (AEs) and medication errors (MEs). The objective of this work was to describe a multidisciplinary safety program focused on AE and ME reporting and review in an ICU over a 7-year period.

Methods: The program was implemented in an 18-bed medical ICU of a 2,200-bed university hospital. A multidisciplinary steering committee (intensivist, clinical pharmacist, nurses, and research assistants) met monthly. The first part of the meeting was dedicated to the review of events targeted through an internal voluntary reporting system, and the second part concerned the analysis of the previous month's events, according to a standardized method called Orion, inspired by the aeronautic industry.

Results: A total of 808 AEs were reported, mostly related to medication processes (30.3% and 33.4% for prescription and administration, respectively). Among these, 526 AEs were related to medications (65.1%), of which 464 were MEs (88.2%). These MEs concerned mostly anti-infective drugs (23.5%) and related to wrong doses (35.8%). Among all AEs reported, 58 (43 MEs [74.1%]) were analyzed further and found to be associated with anti-infective (16.1%) and vasoactive drugs (16.1%). According to National Coordinating Council for Medication Error Reporting and Prevention classification, most AEs caused no harm to patients (category A-D: 38 events, 65.5%). Nurses were most often involved in the analysis (50.7%), along with pharmacists (37.5%). Training was identified as the most frequent corrective action (45.1%).

Conclusion: This program dedicated to AE and ME reporting, review, and analysis in ICU showed long-term engagement of the health care team in AE surveillance and helped in targeting measures for education, organization, and promoting teamwork and safety.
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http://dx.doi.org/10.2147/TCRM.S188185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450184PMC
April 2019

Impact of bronchial colonization with Candida spp. on the risk of bacterial ventilator-associated pneumonia in the ICU: the FUNGIBACT prospective cohort study.

Intensive Care Med 2019 06 24;45(6):834-843. Epub 2019 Apr 24.

Medical ICU, Gabriel-Montpied University Hospital,, Clermont-Ferrand,, France.

Introduction: Respiratory tract Candida spp. colonization is associated with more frequent bacterial ventilator-associated pneumonia (VAP). However, this colonization could be causally related to VAP or simply reflect the immune paralysis associated with multiple organ failure.

Objective: To prospectively evaluate the relationship between Candida spp. colonization and bacterial VAP in mechanically ventilated patients with multiple organ failure.

Inclusion: Patients receiving mechanical ventilation for > 4 days and presenting multiple organ failure were included. Tracheal colonization with Candida spp. was evaluated at inclusion (day 0, D0) and every 4 days until extubation. Quantitative proximal and tracheal cultures were performed at each VAP episode. Monocyte human leukocyte antigen-DR isotype (mHLA-DR) expression and the ratio of polymononuclear leukocytes to lymphocytes were used to evaluate immunoparalysis at D0 and D7. The relationship between fungal colonization and VAP was modelled using cause-specific models for repeated events with adjustment for time-dependent confounders and immune factors.

Results: A total of 213 patients, with a median age of 64, simplified acute physiology score II (SAPS II) score 55 and sequential organ failure assessment (SOFA) score 10, mainly admitted for medical reasons (n = 197, 92%), were enrolled in 2012-2015. The median ICU stay was 24 days and the mortality rate was 32% (69 cases). Median mHLA-DR was 5916 Ab-bound/cell [3863-8934]; median lymphocyte count, 0.9Giga/L [0.6-1.3]; neutrophil-to-lymphocyte ratio, 10.9 [6.5-19.7]. Overall, 146 cases (68.5%) had tracheal colonization with Candida spp. An episode of VAP occurred (either for the first or only time) in 62 (29.1%) cases 5.5 days (median) after D0; a second episode occurred in 12 (5.6%) cases, 15.5 days (median) after D0. After adjustment, bronchial colonization with Candida was not associated with VAP [adjusted cause-specific hazard ratio = 0.98 (0.59-1.65), p = 0.95].

Conclusion: In patients with mechanical ventilation for more than 4 days and multiple organ failure, bronchial colonization with Candida spp. was not associated with VAP, even after adjustment for immune function.
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http://dx.doi.org/10.1007/s00134-019-05622-0DOI Listing
June 2019

Medicine and Intensive Care Training: The Search for the Holy Grail of Diversity Within Harmonization.

Crit Care Med 2019 05;47(5):e428-e429

INSERM, IAME, UMR 1137, Paris, France, and Univ Paris Diderot, Sorbonne Paris Cité, Paris, France, and AP-HP, Hôpital Louis Mourier, service de Médecine intensive Réanimation, Colombes, France Medical Intensive Care Unit and Department of Biostatistics, APHP, Hôpital St-Louis, Paris, France, and Univ Paris Diderot, Sorbonne Paris Cité, Paris, France Medical Intensive care unit, Grenoble University Hospital, Grenoble 1 University, U823, La Tronche, France Medical Intensive care unit, Grenoble University Hospital, Grenoble 1 University, U823, La Tronche, France, and INSERM, Université Grenoble-Alpes, U1042, HP2, 38000, Grenoble, France Sorbonne Université INSERM Unité Mixte de Recherche, Institute of Cardiometabolism and Nutrition, Paris, France, and AP-HP, Hôpital Pitié-Salpêtrière, Institut de Cardiologie, Service de Médecine Intensive-Réanimation, Paris, France Médecine Intensive Réanimation, CHRU de Tours, Tours, France.

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http://dx.doi.org/10.1097/CCM.0000000000003643DOI Listing
May 2019

Multi-organ failure induced by Nivolumab in the context of allo-stem cell transplantation.

Exp Hematol Oncol 2019 28;8. Epub 2019 Mar 28.

1Institute for Advanced Biosciences, Université Grenoble Alpes, INSERM 1209, UMR CNRS 5309, Grenoble, France.

Background: Immune checkpoint inhibitors have radically changed the landscape of anti-tumor therapies in several malignancies. However the adverse events associated with immune checkpoint blockade in combination with other treatments remains to be thoroughly documented. Here we report the case of a 33-year-old male with classical Hodgkin lymphoma who was successfully treated for lymphoma but experienced serious and eventually fatal multisystem organ failure following nivolumab administration and allogeneic stem cell transplantation.

Case Presentation: The patient was diagnosed with stage IIIa nodular sclerosing Hodgkin lymphoma. Originally treated by chemotherapy and autologous stem cell transplantation, he subsequently received two allogeneic stem cell transplants from matched and haplo-identical siblings upon successive disease recurrences. Nivolumab treatment was administered prior to the second allograft, after which complete remission of lymphoma was achieved (year 10), as evidenced by clinical and radiographic examination. However within the next 3 months, the patient went on to develop a constellation of symptoms affecting multiple organs, including acute pneumonia with no evidence of bacterial infection, widespread cutaneous eruptions on trunk and lower limbs, mucosal ulcerations, myositis, diarrhea and colitis. Further complications included hepatic cytolysis, acute renal failure, pancreatitis, as well as complete heart block. Some of these injuries being suggestive of graft-versus-host disease, the patient was administered immunosuppressive therapy (mycophenolate, steroids and polyvalent immunoglobulins), but died shortly afterwards. Tissue biopsies revealed extensive lymphocytic infiltration (mostly CD3 + T cells) in skin, liver, and most peculiarly in muscles, including the myocardium. Massive lymphoid-histiocytic infiltration of muscle fibers was accompanied by acute necrotizing myositis and endomysial inflammation.

Conclusions: Multi-organ failure represents a rare but potentially fatal outcome of immune checkpoint blockade in patients receiving allogeneic stem cell grafts. Nivolumab may induce atypical immune-mediated tissue inflammation and damage, such as the extensive muscular polymyositis described here in a patient with Hodgkin lymphoma. Nivolumab might also worsen GVHD symptoms in the context of allogeneic stem cell transplantation. Irrespective of the actual pathological mechanisms, clinicians should be alerted to these fatal drug-related toxicities.
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http://dx.doi.org/10.1186/s40164-019-0132-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437980PMC
March 2019

A Comparison of the Mortality Risk Associated With Ventilator-Acquired Bacterial Pneumonia and Nonventilator ICU-Acquired Bacterial Pneumonia.

Crit Care Med 2019 03;47(3):345-352

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

Objectives: To investigate the respective impact of ventilator-associated pneumonia and ICU-hospital-acquired pneumonia on the 30-day mortality of ICU patients.

Design: Longitudinal prospective studies.

Setting: French ICUs.

Patients: Patients at risk of ventilator-associated pneumonia and ICU-hospital-acquired pneumonia.

Interventions: The first three episodes of ventilator-associated pneumonia or ICU-hospital-acquired pneumonia were handled as time-dependent covariates in Cox models. We adjusted using the case-mix, illness severity, Simplified Acute Physiology Score II score at admission, and procedures and therapeutics used during the first 48 hours before the risk period. Baseline characteristics of patients with regard to the adequacy of antibiotic treatment were analyzed, as well as the Sequential Organ Failure Assessment score variation in the 2 days before the occurrence of ventilator-associated pneumonia or ICU-hospital-acquired pneumonia. Mortality was also analyzed for Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species(ESKAPE) and P. aeruginosa pathogens.

Measurements And Main Results: Of 14,212 patients who were admitted to the ICUs and who stayed for more than 48 hours, 7,735 were at risk of ventilator-associated pneumonia and 9,747 were at risk of ICU-hospital-acquired pneumonia. Ventilator-associated pneumonia and ICU-hospital-acquired pneumonia occurred in 1,161 at-risk patients (15%) and 176 at-risk patients (2%), respectively. When adjusted on prognostic variables, ventilator-associated pneumonia (hazard ratio, 1.38 (1.24-1.52); p < 0.0001) and even more ICU-hospital-acquired pneumonia (hazard ratio, 1.82 [1.35-2.45]; p < 0.0001) were associated with increased 30-day mortality. The early antibiotic therapy adequacy was not associated with an improved prognosis, particularly for ICU-hospital-acquired pneumonia. The impact was similar for ventilator-associated pneumonia and ICU-hospital-acquired pneumonia mortality due to P. aeruginosa and the ESKAPE group.

Conclusions: In a large cohort of patients, we found that both ICU-hospital-acquired pneumonia and ventilator-associated pneumonia were associated with an 82% and a 38% increase in the risk of 30-day mortality, respectively. This study emphasized the importance of preventing ICU-hospital-acquired pneumonia in nonventilated patients.
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http://dx.doi.org/10.1097/CCM.0000000000003553DOI Listing
March 2019