Fosfomycin-induced agranulocytosis: a case report and review of the literature.

BACKGROUND: The intravenous form of fosfomycin, a bactericide antibiotic used to treat multiresistant bacterial infections is little prescribed. The most common reported adverse effects are hypokaliemia and hypernatremia. We describe a case of agranulocytosis, a rarely described side effect that may be fatal. CASE PRESENTATION: A 45 year-old woman was admitted to the intensive care unit for post-surgical meningitis following meningioma resection. Meropenem and vancomycin were first introduced. A DRESS-syndrom with meropenem was suspected. Neutropenia was diagnosed three days after the introduction of parenteral fosfomycin and agranulocytosis four days later. Eosinophilia was also observed. A bone marrow aspiration was performed showing a disappearance of the neutrophil granulocyte line and a significant eosinophilia. Meropenem was discontinued. Fosfomycin was maintained and filgrastim was added. As filgrastim had no effect, the relationship with fosfomycin was suspected, so it was then withheld. An increase of the neutrophil count was observed. Because of the complexity of the case, the unfavorable course of the illness and the urgent need for revision surgery, a rechallenge with fosfomycin was done followed by a decrease of the neutrophil count. CONCLUSION: This is the third paper reporting agranulocytosis induced by fosfomycin, and the first detailed description of a case. Based on chronological and semiological criteria and bibliographic data, the event was qualified as probable with the Naranjo adverse drug probability scale. Literature data is scarce. The summary of product characteristics mentions that only a few cases of transient neutropenia and agranulocytosis have been reported. An analysis of the FDA Adverse Event Reporting System Database highlighted a higher than expected frequency of agranulocytosis in patients treated with fosfomycin. Parenteral fosfomycin is often used in patients receiving other medications, so that it is rarely the only suspect. In our case, the results of the bone marrow aspiration, the sudden drop of the neutrophil count with concomitant eosinophilia and the absence of improvement despite the dose decrease, point towards an immuno-allergic mechanism. However, the overlap between the suspected DRESS induced by meropenem and the agranulocytosis do not allow to conclude with certainty on the causality. Awareness should be raised about this side effect.

Insulin therapy and blood glucose management in critically ill patients: a 1-day cross-sectional observational study in 69 French intensive care units.

BACKGROUND: Hyperglycaemia is common in critically ill patients, but blood glucose and insulin management may differ widely among intensive care units (ICUs). We aimed to describe insulin use practices and the resulting glycaemic control in French ICUs. We conducted a multicentre 1-day observational study on November 23, 2021, in 69 French ICUs. Adult patients hospitalized for an acute organ failure, severe infection or post-operative care were included. Data were recorded from midnight to 11:59 p.m. the day of the study by 4-h periods. RESULTS: Two ICUs declared to have no insulin protocol. There was a wide disparity in blood glucose targets between ICUs with 35 different target ranges recorded. In 893 included patients we collected 4823 blood glucose values whose distribution varied significantly across ICUs (P < 0.0001). We observed 1135 hyperglycaemias (> 1.8 g/L) in 402 (45.0%) patients, 35 hypoglycaemias (≤ 0.7 g/L) in 26 (2.9%) patients, and one instance of severe hypoglycaemia (≤ 0.4 g/L). Four hundred eight (45.7%) patients received either IV insulin (255 [62.5%]), subcutaneous (SC) insulin (126 [30.9%]), or both (27 [6.6%]). Among patients under protocolized intravenous (IV) insulin, 767/1681 (45.6%) of glycaemias were above the target range. Among patients receiving insulin, short- and long-acting SC insulin use were associated with higher counts of hyperglycaemias as assessed by multivariable negative binomial regression adjusted for the propensity to receive SC insulin: incidence rate ratio of 3.45 (95% confidence interval [CI] 2.97-4.00) (P < 0.0001) and 3.58 (95% CI 2.84-4.52) (P < 0.0001), respectively. CONCLUSIONS: Practices regarding blood glucose management varied widely among French ICUs. Administration of short or long-acting SC insulin was not unusual and associated with more frequent hyperglycaemia. The protocolized insulin algorithms used failed to prevent hyperglycaemic events.

Low versus standard calorie and protein feeding in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group trial (NUTRIREA-3).

BACKGROUND: The optimal calorie and protein intakes at the acute phase of severe critical illness remain unknown. We hypothesised that early calorie and protein restriction improved outcomes in these patients, compared with standard calorie and protein targets. METHODS: The pragmatic, randomised, controlled, multicentre, open-label, parallel-group NUTRIREA-3 trial was performed in 61 French intensive care units (ICUs). Adults (≥18 years) receiving invasive mechanical ventilation and vasopressor support for shock were randomly assigned to early nutrition (started within 24 h after intubation) with either low or standard calorie and protein targets (6 kcal/kg per day and 0·2-0·4 g/kg per day protein vs 25 kcal/kg per day and 1·0-1·3 g/kg per day protein) during the first 7 ICU days. The two primary endpoints were time to readiness for ICU discharge and day 90 all-cause mortality. Key secondary outcomes included secondary infections, gastrointestinal events, and liver dysfunction. The trial is registered on ClinicalTrials.gov, NCT03573739, and is completed. FINDINGS: Of 3044 patients randomly assigned between July 5, 2018, and 8 Dec 8, 2020, eight withdrew consent to participation. By day 90, 628 (41·3%) of 1521 patients in the low group and 648 (42·8%) of 1515 patients in the standard group had died (absolute difference -1·5%, 95% CI -5·0 to 2·0; p=0·41). Median time to readiness for ICU discharge was 8·0 days (IQR 5·0-14·0) in the low group and 9·0 days (5·0-17·0) in the standard group (hazard ratio [HR] 1·12, 95% CI 1·02 to 1·22; p=0·015). Proportions of patients with secondary infections did not differ between the groups (HR 0·85, 0·71 to 1·01; p=0·06). The low group had lower proportions of patients with vomiting (HR 0·77, 0·67 to 0·89; p<0·001), diarrhoea (0·83, 0·73 to 0·94; p=0·004), bowel ischaemia (0·50, 0·26 to 0·95; p=0·030), and liver dysfunction (0·92, 0·86-0·99; p=0·032). INTERPRETATION: Compared with standard calorie and protein targets, early calorie and protein restriction did not decrease mortality but was associated with faster recovery and fewer complications. FUNDING: French Ministry of Health.

Relationship between corticosteroid use and incidence of ventilator-associated pneumonia in COVID-19 patients: a retrospective multicenter study.

BACKGROUND: Ventilator-associated pneumonia (VAP) is common in patients with severe SARS-CoV-2 pneumonia. The aim of this ancillary analysis of the coVAPid multicenter observational retrospective study is to assess the relationship between adjuvant corticosteroid use and the incidence of VAP. METHODS: Planned ancillary analysis of a multicenter retrospective European cohort in 36 ICUs. Adult patients receiving invasive mechanical ventilation for more than 48 h for SARS-CoV-2 pneumonia were consecutively included between February and May 2020. VAP diagnosis required strict definition with clinical, radiological and quantitative microbiological confirmation. We assessed the association of VAP with corticosteroid treatment using univariate and multivariate cause-specific Cox's proportional hazard models with adjustment on pre-specified confounders. RESULTS: Among the 545 included patients, 191 (35%) received corticosteroids. The proportional hazard assumption for the effect of corticosteroids on the incidence of VAP could not be accepted, indicating that this effect varied during ICU stay. We found a non-significant lower risk of VAP for corticosteroid-treated patients during the first days in the ICU and an increased risk for longer ICU stay. By modeling the effect of corticosteroids with time-dependent coefficients, the association between corticosteroids and the incidence of VAP was not significant (overall effect p = 0.082), with time-dependent hazard ratios (95% confidence interval) of 0.47 (0.17-1.31) at day 2, 0.95 (0.63-1.42) at day 7, 1.48 (1.01-2.16) at day 14 and 1.94 (1.09-3.46) at day 21. CONCLUSIONS: No significant association was found between adjuvant corticosteroid treatment and the incidence of VAP, although a time-varying effect of corticosteroids was identified along the 28-day follow-up.

Beta-lactam dosing during continuous renal replacement therapy: a survey of practices in french intensive care units.

BACKGROUND: Little information is available on current practice in beta-lactam dosing during continuous renal replacement therapy (CRRT). Optimized dosing is essential for improving outcomes, and there is no consensus on the appropriate dose regimens. The objective of the present study was to describe current practice for beta-lactam dosing during CRRT in intensive care units (ICUs). METHODS: We conducted a nationwide survey by e-mailing an online questionnaire to physicians working in ICUs in France. The questionnaire included three sections: demographic characteristics, CRRT practices, and beta-lactam dosing regimens during CRRT. RESULTS: 157 intensivists completed the questionnaire. Continuous venovenous hemofiltration was the most frequently used CRRT technique, and citrate was the most regularly used anticoagulant. The median prescribed dose at baseline was 30 mL/kg/h. The majority of prescribers (57%) did not reduce beta-lactam dosing during CRRT. The tools were used to adapt dosing regimens during CRRT included guidelines, therapeutic drug monitoring (TDM), and data from the literature. When TDM was used, 100% T > 4 time the MIC was the most common mentioned pharmacokinetic/pharmacodynamic target (53%). Pharmacokinetic software tools were rarely used. Prolonged or continuous infusions were widely used during CRRT (88%). Institutional guidelines on beta-lactam dosing during CRRT were rare. 41% of physicians sometimes consulted another specialist before adapting the dose of antibiotic during CRRT. CONCLUSIONS: Our present results highlight the wide range of beta-lactam dosing practices adopted during CRRT. Personalized TDM and the implementation of Bayesian software appear to be essential for optimizing beta-lactam dosing regimens and improving patient outcomes.

Invasive pulmonary aspergillosis among intubated patients with SARS-CoV-2 or influenza pneumonia: a European multicenter comparative cohort study.

BACKGROUND: Recent multicenter studies identified COVID-19 as a risk factor for invasive pulmonary aspergillosis (IPA). However, no large multicenter study has compared the incidence of IPA between COVID-19 and influenza patients. OBJECTIVES: To determine the incidence of putative IPA in critically ill SARS-CoV-2 patients, compared with influenza patients. METHODS: This study was a planned ancillary analysis of the coVAPid multicenter retrospective European cohort. Consecutive adult patients requiring invasive mechanical ventilation for > 48 h for SARS-CoV-2 pneumonia or influenza pneumonia were included. The 28-day cumulative incidence of putative IPA, based on Blot definition, was the primary outcome. IPA incidence was estimated using the Kalbfleisch and Prentice method, considering extubation (dead or alive) within 28 days as competing event. RESULTS: A total of 1047 patients were included (566 in the SARS-CoV-2 group and 481 in the influenza group). The incidence of putative IPA was lower in SARS-CoV-2 pneumonia group (14, 2.5%) than in influenza pneumonia group (29, 6%), adjusted cause-specific hazard ratio (cHR) 3.29 (95% CI 1.53-7.02, p = 0.0006). When putative IPA and Aspergillus respiratory tract colonization were combined, the incidence was also significantly lower in the SARS-CoV-2 group, as compared to influenza group (4.1% vs. 10.2%), adjusted cHR 3.21 (95% CI 1.88-5.46, p < 0.0001). In the whole study population, putative IPA was associated with significant increase in 28-day mortality rate, and length of ICU stay, compared with colonized patients, or those with no IPA or Aspergillus colonization. CONCLUSIONS: Overall, the incidence of putative IPA was low. Its incidence was significantly lower in patients with SARS-CoV-2 pneumonia than in those with influenza pneumonia. Clinical trial registration The study was registered at ClinicalTrials.gov, number NCT04359693 .

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).

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.

Early Bacterial Identification among Intubated Patients with COVID-19 or Influenza Pneumonia: A European Multicenter Comparative Clinical Trial.

Rationale: Early empirical antimicrobial treatment is frequently prescribed to critically ill patients with coronavirus disease (COVID-19) based on Surviving Sepsis Campaign guidelines.Objectives: We aimed to determine the prevalence of early bacterial identification in intubated patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia, as compared with influenza pneumonia, and to characterize its microbiology and impact on outcomes.Methods: A multicenter retrospective European cohort was performed in 36 ICUs. All adult patients receiving invasive mechanical ventilation >48 hours were eligible if they had SARS-CoV-2 or influenza pneumonia at ICU admission. Bacterial identification was defined by a positive bacterial culture within 48 hours after intubation in endotracheal aspirates, BAL, blood cultures, or a positive pneumococcal or legionella urinary antigen test.Measurements and Main Results: A total of 1,050 patients were included (568 in SARS-CoV-2 and 482 in influenza groups). The prevalence of bacterial identification was significantly lower in patients with SARS-CoV-2 pneumonia compared with patients with influenza pneumonia (9.7 vs. 33.6%; unadjusted odds ratio, 0.21; 95% confidence interval [CI], 0.15-0.30; adjusted odds ratio, 0.23; 95% CI, 0.16-0.33; P < 0.0001). Gram-positive cocci were responsible for 58% and 72% of coinfection in patients with SARS-CoV-2 and influenza pneumonia, respectively. Bacterial identification was associated with increased adjusted hazard ratio for 28-day mortality in patients with SARS-CoV-2 pneumonia (1.57; 95% CI, 1.01-2.44; P = 0.043). However, no significant difference was found in the heterogeneity of outcomes related to bacterial identification between the two study groups, suggesting that the impact of coinfection on mortality was not different between patients with SARS-CoV-2 and influenza.Conclusions: Bacterial identification within 48 hours after intubation is significantly less frequent in patients with SARS-CoV-2 pneumonia than patients with influenza pneumonia.Clinical trial registered with www.clinicaltrials.gov (NCT04359693).

Saving lives by ventilating two patients with specific pressure-controlled ventilation from a single ICU-ventilator during the COVID-19 pandemic.

In late December 2019, SARS-CoV-2 was discovered, which is responsible for a new human disease called COVID-19. Among all laboratory-confirmed COVID-19 cases, 14% were hospitalized, with 2% admitted to intensive care units (ICU) with acute respiratory distress syndrome (ARDS) requiring mechanical ventilation [1]. SARS-CoV-2 has spread quickly across the world, with more than one hundred million confirmed cases and more than 2,500,000 dead. In March 2020, the Hospital of Valenciennes had to admit hundreds of COVID-19 patients, and its capacity was almost exceeded [2]. More recently, in France, thousands of critically ill patients had to be admitted to ICUs. In Europe, the next wave of COVID-19 pandemic could be more severe than the first one, and we already know that, in the case of increasing numbers of critically ill, some of them will die as a result of the unavailability of mechanical ventilators [3]. This shortage may be lessened if one ventilator could service more than one patient. The main worry is that this concept could be not useful and systematically deleterious for the patient. Some concepts have already been proposed to ventilate differently two circuits with a single ventilator, with several limitations like the lack of individualization of ventilation of each circuit [4-6]. More recently, in the face of the COVID-19 pandemic, Clarke et al. [7] described a new concept able to deliver specific ventilation for two different lung tests with a single ventilator. Again, Levin et al. [8] have recently shown that a similar concept of differential ventilation using a single ventilator with flow control valves is feasible in humans.

Relationship between ventilator-associated pneumonia and mortality in COVID-19 patients: a planned ancillary analysis of the coVAPid cohort.

BACKGROUND: Patients with SARS-CoV-2 infection are at higher risk for ventilator-associated pneumonia (VAP). No study has evaluated the relationship between VAP and mortality in this population, or compared this relationship between SARS-CoV-2 patients and other populations. The main objective of our study was to determine the relationship between VAP and mortality in SARS-CoV-2 patients. METHODS: Planned ancillary analysis of a multicenter retrospective European cohort. VAP was diagnosed using clinical, radiological and quantitative microbiological criteria. Univariable and multivariable marginal Cox's regression models, with cause-specific hazard for duration of mechanical ventilation and ICU stay, were used to compare outcomes between study groups. Extubation, and ICU discharge alive were considered as events of interest, and mortality as competing event. FINDINGS: Of 1576 included patients, 568 were SARS-CoV-2 pneumonia, 482 influenza pneumonia, and 526 no evidence of viral infection at ICU admission. VAP was associated with significantly higher risk for 28-day mortality in SARS-CoV-2 (adjusted HR 1.70 (95% CI 1.16-2.47), p = 0.006), and influenza groups (1.75 (1.03-3.02), p = 0.045), but not in the no viral infection group (1.07 (0.64-1.78), p = 0.79). VAP was associated with significantly longer duration of mechanical ventilation in the SARS-CoV-2 group, but not in the influenza or no viral infection groups. VAP was associated with significantly longer duration of ICU stay in the 3 study groups. No significant difference was found in heterogeneity of outcomes related to VAP between the 3 groups, suggesting that the impact of VAP on mortality was not different between study groups. INTERPRETATION: VAP was associated with significantly increased 28-day mortality rate in SARS-CoV-2 patients. However, SARS-CoV-2 pneumonia, as compared to influenza pneumonia or no viral infection, did not significantly modify the relationship between VAP and 28-day mortality. CLINICAL TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov, number NCT04359693.

Invasive pulmonary aspergillosis in COVID-19 critically ill patients: Results of a French monocentric cohort.

INTRODUCTION: Coronavirus disease 2019 or COVID-19 is a new infectious disease responsible for potentially severe respiratory impairment associated with initial immunosuppression. Similarly to influenza, several authors have described a higher risk of fungal infection after COVID-19, in particular for invasive pulmonary aspergillosis. The main objective here is to define the prevalence of invasive pulmonary aspergillosis (IPA) in a cohort of COVID-19 patients with moderate to severe acute respiratory disease syndrome (ARDS). MATERIAL AND METHODS: We conducted a large monocentric retrospective study investigating all the ventilated COVID-19 patients with ARDS hospitalized at Valenciennes' general hospital, France, between March 15, 2020 and April 30, 2020. In the center a systematic IPA screening strategy was carried out for all ARDS patients, with weekly tests of serum galactomannan and beta-D-glucan. Bronchoalveolar lavage with culture and chest CT scan were performed when the serum assays were positives. RESULTS: A total of 54 patients were studied. Their median age was 65 years, and 37 of the patients (71%) were male. Two patients had chronic immunosuppression and among all the patients, only 2 non-immunocompromised presented a putative IPA during their stay. CONCLUSION: The prevalence of IPA in this cohort of COVID-19 patients (3.7%) is not higher than what is described in the other ARDS populations in the literature. These results are however different from the previous publications on COVID-19 patients and must therefore be confirmed by larger and multicentric studies.

Relationship between SARS-CoV-2 infection and the incidence of ventilator-associated lower respiratory tract infections: a European multicenter cohort study.

PURPOSE: Although patients with SARS-CoV-2 infection have several risk factors for ventilator-associated lower respiratory tract infections (VA-LRTI), the reported incidence of hospital-acquired infections is low. We aimed to determine the relationship between SARS-CoV-2 pneumonia, as compared to influenza pneumonia or no viral infection, and the incidence of VA-LRTI. METHODS: Multicenter retrospective European cohort performed in 36 ICUs. All adult patients receiving invasive mechanical ventilation > 48 h were eligible if they had: SARS-CoV-2 pneumonia, influenza pneumonia, or no viral infection at ICU admission. VA-LRTI, including ventilator-associated tracheobronchitis (VAT) and ventilator-associated pneumonia (VAP), were diagnosed using clinical, radiological and quantitative microbiological criteria. All VA-LRTI were prospectively identified, and chest-X rays were analyzed by at least two physicians. Cumulative incidence of first episodes of VA-LRTI was estimated using the Kalbfleisch and Prentice method, and compared using Fine-and Gray models. RESULTS: 1576 patients were included (568 in SARS-CoV-2, 482 in influenza, and 526 in no viral infection groups). VA-LRTI incidence was significantly higher in SARS-CoV-2 patients (287, 50.5%), as compared to influenza patients (146, 30.3%, adjusted sub hazard ratio (sHR) 1.60 (95% confidence interval (CI) 1.26 to 2.04)) or patients with no viral infection (133, 25.3%, adjusted sHR 1.7 (95% CI 1.2 to 2.39)). Gram-negative bacilli were responsible for a large proportion (82% to 89.7%) of VA-LRTI, mainly Pseudomonas aeruginosa, Enterobacter spp., and Klebsiella spp. CONCLUSIONS: The incidence of VA-LRTI is significantly higher in patients with SARS-CoV-2 infection, as compared to patients with influenza pneumonia, or no viral infection after statistical adjustment, but residual confounding may still play a role in the effect estimates.

Combination Therapy with Aminoglycoside in Bacteremiasdue to ESBL-Producing Enterobacteriaceae in ICU.

OBJECTIVES: Evaluation of the efficacy of empirical aminoglycoside in critically ill patients with bloodstream infections caused by extended-spectrum ß-lactamase producing Enterobacteriaceae (ESBL-E BSI). METHODS: Patients treated between 2011 and 2018 for ESBL-E BSI in the ICU of six French hospitals were included in a retrospective observational cohort study. The primary endpoint was mortality on day 30. RESULTS: Among 307 patients, 169 (55%) were treated with empirical aminoglycoside. Death rate was 40% (43% with vs. 39% without aminoglycoside, p = 0.55). Factors independently associated with death were age ≥70 years (OR: 2.67; 95% CI: 1.09-6.54, p = 0.03), history of transplantation (OR 5.2; 95% CI: 1.4-19.35, p = 0.01), hospital acquired infection (OR 8.67; 95% CI: 1.74-43.08, p = 0.008), vasoactive drugs >48 h after BSI onset (OR 3.61; 95% CI: 1.62-8.02, p = 0.001), occurrence of acute respiratory distress syndrome (OR 2.42; 95% CI: 1.14-5.16, p = 0.02), or acute renal failure (OR 2.49; 95% CI: 1.14-5.47, p = 0.02). Antibiotherapy appropriateness was more frequent in the aminoglycoside group (91.7% vs. 77%, p = 0.001). Rate of renal impairment was similar in both groups (21% vs. 24%, p = 0.59). CONCLUSIONS: In intensive care unit (ICU) patients with ESBL-E BSI, empirical treatment with aminoglycoside was frequent. It demonstrated no impact on mortality, despite increasing treatment appropriateness.

Severe leptospirosis in non-tropical areas: a nationwide, multicentre, retrospective study in French ICUs.

PURPOSE: To report the incidence, risk factors, clinical presentation, and outcome predictors of severe leptospirosis requiring intensive care unit (ICU) admission in a temperate zone. METHODS: LEPTOREA was a retrospective multicentre study conducted in 79 ICUs in metropolitan France. Consecutive adults admitted to the ICU for proven severe leptospirosis from January 2012 to September 2016 were included. Multiple correspondence analysis (MCA) and hierarchical classification on principal components (HCPC) were performed to distinguish different clinical phenotypes. RESULTS: The 160 included patients (0.04% of all ICU admissions) had median values of 54 years [38-65] for age, 40 [28-58] for the SAPSII, and 11 [8-14] for the SOFA score. Hospital mortality was 9% and was associated with older age; worse SOFA score and early need for endotracheal ventilation and/or renal replacement therapy; chronic alcohol abuse and worse hepatic dysfunction; confusion; and higher leucocyte count. Four phenotypes were identified: moderately severe leptospirosis (n = 34, 21%) with less organ failure and better outcomes; hepato-renal leptospirosis (n = 101, 63%) with prominent liver and kidney dysfunction; neurological leptospirosis (n = 8, 5%) with the most severe organ failures and highest mortality; and respiratory leptospirosis (n = 17, 11%) with pulmonary haemorrhage. The main risk factors for leptospirosis contamination were contact with animals, contact with river or lake water, and specific occupations. CONCLUSIONS: Severe leptospirosis was an uncommon reason for ICU admission in metropolitan France and carried a lower mortality rate than expected based on the high severity and organ-failure scores. The identification in our population of several clinical presentations may help clinicians establish an appropriate index of suspicion for severe leptospirosis.

High-flow nasal cannula therapy: clinical practice in intensive care units.

BACKGROUND: Despite the extensive use of high-flow nasal cannula (HFNC) therapy in intensive care units (ICU) for acute respiratory failure (ARF), its daily clinical practice has not been assessed. We designed a regional survey in ICUs in North-west France to evaluate ICU physicians' clinical practice with HFNC. MATERIALS AND METHODS: We sent an observational survey to ICU physicians from 34 French ICUs over a 6-month period in 2016-2017. The survey included questions regarding the indications and expected efficiency of HFNC, practical aspects of use (initiation, weaning) and satisfaction. Comparisons between junior and senior ICU physicians were performed using a Fischer exact test. RESULTS: Among the 235 ICU physicians contacted, 137 responded (58.3%) all of whom regularly used HFNC. Hypoxemic ARF was considered a good indication for HFNC by all 137, but only 30% expected HFNC success (i.e., avoiding intubation in at least 60% of cases). Among hypoxemic indications, 30% of juniors considered acute pulmonary edema a good indication versus 74% of seniors (p < 0.0001). Hypercapnic ARF was considered a good indication by 33% with only 2% expecting HFNC success. A need for conventional oxygen therapy ≥ 6 L/min justified HFNC therapy for 40% and ≥ 9 L/min for 39% of responders. 58% of ICU physicians started HFNC therapy with a FiO2 ≥ 50% and 28% with a gas flow ≥ 50 L/min. Practices for HFNC weaning were heterogeneous: 48% considered a FiO2 ≤ 30%; whereas, 30% considered a FiO2 ≤ 30% with a high flow ≤ 20 L/min. Criteria for HFNC failure (i.e., need for intubation) were ventilatory pauses or arrest (97%), persistent hypoxemia (95%), respiratory acidosis (81%), worsening of breathing (95%, 100% of seniors and 86% of juniors, p = 0.003), bronchial congestion (75%) and circulatory failure (61%, 72% of seniors and 44% of juniors, p = 0.007). CONCLUSION: HFNC is used by ICU physicians in many situations of ARF, despite their relatively low expectations of success, especially in cases of hypercapnia. Clinical practices appear somewhat heterogeneous. Despite the physiological benefit of HFNC, further prospective observational studies are still required on HFNC outcomes and daily practices.

One-year mortality in patients requiring prolonged mechanical ventilation: multicenter evaluation of the ProVent score.

INTRODUCTION: Current severity-of-illness indexes are unable to assess the long-term prognosis of patients requiring prolonged mechanical ventilation. A prognostic scoring system (Prognosis for Prolonged Ventilation score - ProVent - score) seems able to evaluate one-year mortality of such patients. However, testing of the model outside the developers' centers has not been reported. So, it is unclear how the ProVent score performs in non-US and non-tertiary ICUs. The goal of our study was to evaluate its performances in a French multicenter, community hospital-based setting. METHODS: In three primary ICUs, 201 patients requiring mechanical ventilation for at least 21 days were enrolled in a retrospective cohort study. ICU mortality was abstracted from medical records and, for patients discharged alive from the ICU, one-year mortality was determined by telephone calls to patients' general practitioners. RESULTS: One-year mortality was 60% (n = 120). On day 21 of ventilation, ProVent score value was 0 in 19 patients (9%), 1 in 63 patients (31%), 2 in 64 patients (32%), 3 in 37 patients (18%), and ≥4 in 18 patients (9%), respectively. For ProVent score values ranging from 0 to ≥4, one-year mortality rates were 21%, 43%, 67%, 78%, and 94%, respectively. The area under the curve (AUC) of the receiver operator characteristic (ROC) curve for the ProVent score was 0.74 (95% confidence interval 0.671 to 0.809). Stepwise logistic regression analysis showed that only three variables (age ≥65 years, vasopressors, and hemodialysis) were independently associated with one-year mortality in our population. In assigning one point to each variable, we created a French ProVent score. The Hosmer-Lemeshow goodness-of-fit statistic was 1.36 (DF = 6, P = 0.857) and the AUC of the ROC curve was 0.742 (95% confidence interval 0.673 to 0.810). One-year mortality rates for French ProVent score ranging from 0 to 3 were 34.6%, 70.9%, 83.3% and 100%, respectively (P <0.0001). CONCLUSIONS: The ProVent score is able, even in non-US ICUs and in community hospitals, to accurately identify among patients requiring prolonged mechanical ventilation those who are at high risk of one-year mortality. Its simplification appears possible. However, further validation of this French ProVent score in a larger external sample is indicated.

Evaluation of "Candida score" in critically ill patients: a prospective, multicenter, observational, cohort study.

INTRODUCTION: Although prompt initiation of appropriate antifungal therapy is essential for the control of invasive Candida infections and an improvement of prognosis, early diagnosis of invasive candidiasis remains a challenge and criteria for starting empirical antifungal therapy in ICU patients are poorly defined. Some scoring systems, such as the "Candida score" could help physicians to differentiate patients who could benefit from early antifungal treatment from those for whom invasive candidiasis is highly improbable. This study evaluated the performance of this score in a cohort of critically ill patients. METHODS: A prospective, observational, multicenter, cohort study was conducted from January 2010 to March 2011 in five intensive care units in Nord-Pas de Calais, an area from North of France. All patients exhibiting, on ICU admission or during their ICU stay, a hospital-acquired severe sepsis or septic shock could be included in this study. The data collected included patient characteristics on ICU admission and at the onset of severe sepsis or septic shock. The "Candida score" was calculated at the onset of sepsis or shock. The incidence of invasive candidiasis was determined and its relationship with the value of the "Candida score" was studied. RESULTS: Ninety-four patients were studied. When severe sepsis or shock occurred, 44 patients had a score = 2, 29 patients had a score = 3, 17 patients had a score = 4, and 4 patients had a score = 5. Invasive candidiasis was observed in five (5.3%) patients. One patient had candidemia, three patients had peritonitis, and one patient had pleural infection. The rates of invasive candidiasis was 0% in patients with score = 2 or 3, 17.6% in patients with score = 4, and 50% in patients with score = 5 (p < 0.0001). CONCLUSIONS: Our results confirm that the "Candida score" is an interesting tool to differentiate among ICU patients who exhibit hospital-acquired severe sepsis or septic shock those would benefit from early antifungal treatment (score > 3) from those for whom invasive candidiasis is highly improbable (score ≤ 3).

Dimethylformamide metabolism following self-harm using a veterinary euthanasia product.

BACKGROUND: A veterinary euthanasia drug containing embutramide, mebezonium, tetracaine, and dimethylformamide (DMF; T-61® or Tanax®) may cause serious manifestations or even fatalities after self-poisoning. Immediate toxicity is mainly due to a general anesthetic and due to a neuromuscular blocking agent, while delayed hepatotoxicity seems related to the solvent DMF. The protective role of N-acetylcysteine (NAC) administration remains debatable. MATERIAL AND METHODS: Two male veterinarians (50- and 44-year-old) attempted suicide by injecting T-61 in the precordial area for the first one, and by ingesting 50 mL for the second. Both received NAC (for 14 days in the first case and only for 20 h in the second). Urine was collected for the serial determination of DMF, N-methylformamide (NMF), and N-acetyl-S-(N-methylcarbamoyl)cysteine (AMCC). RESULTS: Both patients developed only mild signs of liver injury. The metabolite of DMF, NMF, appeared rapidly in the urine, while a further delay was necessary for AMCC excretion. The kinetics of elimination of DMF and DMF metabolites were slightly slower than those reported in exposed workers. CONCLUSIONS: While both patients had a favorable outcome, there is no clear evidence that NAC could directly influence NMF and AMCC excretion. Further investigations of NMF and AMCC excretion, with and without NAC, would be indicated.