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Key messages In this study including 391 critically ill patients with nosocomial pneumonia due to Gram-negative pathogens, combination therapy was not associated with a reduced hazard of death at Day 28 or a greater likelihood of clinical cure at Day 14. No over-risk of AKI was observed in patients receiving combination therapy. Background The benefits and harms of combination antimicrobial therapy remain controversial in critically ill patients with hospital-acquired pneumonia (HAP), ventilated HAP (vHAP) or ventilator-associated pneumonia (VAP) involving Gram-negative bacteria. Methods We included all patients in the prospective multicenter OutcomeRea database with a first HAP, vHAP or VAP due to a single Gram-negative bacterium and treated with initial adequate single-drug or combination therapy. The primary endpoint was Day-28 all-cause mortality. Secondary endpoints were clinical cure rate at Day 14 and a composite outcome of death or treatment-emergent acute kidney injury (AKI) at Day 7. The average effects of combination therapy on the study endpoints were investigated through inverse probability of treatment-weighted regression and multivariable regression models. Subgroups analyses were performed according to the resistance phenotype of the causative pathogens (multidrug-resistant or not), the pivotal (carbapenems or others) and companion (aminoglycosides/polymyxins or others) drug classes, the duration of combination therapy (< 3 or ≥ 3 days), the SOFA score value at pneumonia onset (< 7 or ≥ 7 points), and in patients with pneumonia due to non-fermenting Gram-negative bacteria, pneumonia-related bloodstream infection, or septic shock. Results Among the 391 included patients, 151 (38.6%) received single-drug therapy and 240 (61.4%) received combination therapy. VAP (overall, 67.3%), vHAP (16.4%) and HAP (16.4%) were equally distributed in the two groups. All-cause mortality rates at Day 28 (overall, 31.2%), clinical cure rate at Day 14 (43.7%) and the rate of death or AKI at Day 7 (41.2%) did not significantly differ between the groups. In inverse probability of treatment-weighted analyses, combination therapy was not independently associated with the likelihood of all-cause death at Day 28 (adjusted odd ratio [aOR], 1.14; 95% confidence interval [CI] 0.73–1.77; P  = 0.56), clinical cure at Day 14 (aOR, 0.79; 95% CI 0.53–1.20; P  = 0.27) or death or AKI at Day 7 (aOR, 1.07; 95% CI 0.71–1.63; P  = 0.73). Multivariable regression models and subgroup analyses provided similar results. Conclusions Initial combination therapy exerts no independent impact on Day-28 mortality, clinical cure rate at Day 14, and the hazard of death or AKI at Day 7 in critically ill patients with mono-bacterial HAP, vHAP or VAP due to Gram-negative bacteria.

Whether diabetes mellitus increases the risk of acute kidney injury (AKI) during sepsis is controversial. We used a case-control design to compare the frequency of AKI, use of renal replacement therapy (RRT), and renal recovery in patients who had severe sepsis or septic shock with or without diabetes. The data were from the Outcomerea prospective multicenter database, in which 12 French ICUs enrolled patients admitted between January 1997 and June 2009. First, we compared 451 patients with severe sepsis or septic shock and diabetes to 3,277 controls with severe sepsis or septic shock and without diabetes. Then, we compared 318 cases (with diabetes) to 746 matched controls (without diabetes). Diabetic patients did not have a higher frequency of AKI (hazard ratio [HR], 1.18; P = 0.05]) or RRT (HR, 1.09; P = 0.6). However, at discharge, diabetic patients with severe sepsis or septic shock who experienced acute kidney injury during the ICU stay and were discharged alive more often required RRT (9.5% vs. 4.8%; P = 0.02), had higher serum creatinine values (134 vs. 103 µmoL/L; P<0.001) and had less often recovered a creatinine level less than 1.25 fold the basal creatinine (41.1% vs. 60.5%; P<0.001). In patients with severe sepsis or septic shock, diabetes is not associated with occurrence of AKI or need for RRT but is an independent risk factor for persistent renal dysfunction in patients who experience AKI during their ICU stay.

Background Hospital-acquired and ventilator-associated pneumonia (HAP/VAP) are often selected for randomized clinical trials (RCTs) aiming at new drug approval. Guidelines for the design of such RCTs have been repeatedly updated by regulatory agencies. We hypothesized that large variability in the enrolled populations, the endpoints assessed and the HAP/VAP definition criteria may impact the results of these studies, and addressed this through a systematic review of HAP/VAP RCTs. Methods A search (Pubmed-Embase-ICAAC-ECCMID) of all RCTs published between 1994 and 2016 comparing antimicrobial treatment for HAP/VAP in the intensive care unit was conducted. The populations enrolled, inclusion/exclusion criteria, statistical design and endpoints assessed were recorded. All unpublished RCTs recorded on the ClinicalTrials.gov registry were also screened. Results From the 93 abstracts reviewed, 39 potentially relevant studies were inspected, leading to 27 studies being included. As expected, illness severity or the proportion with VAP (27–100%) differed greatly among the enrolled populations. The HAP/VAP definition used various clinical and biological criteria, and only 55% of studies required a microbiological sample. The mandatory duration of prior hospital stay was variable; the mechanical ventilation duration was an inclusion criterion in only 41% of VAP studies. Nine studies had non-inferiority design, but nine studies (33%) did not have a pre-specified statistical hypothesis. Clinical cure was the primary endpoint in 24 studies, but was recorded in several populations or as the co-primary endpoint in 13 studies. The definition of clinical cure and the timing of its assessment greatly differed. This variability slightly improved over time but remained significant in the 13 registered but currently unpublished RCTs that we screened. Conclusion Our study provides a description of populations and endpoints of RCTs evaluating antimicrobials for treatment of HAP/VAP in the ICU. There was significant heterogeneity in enrollment criteria, endpoints and statistical design, which may influence the ability of studies to demonstrate differences between studied drugs.

Abstract Purpose Despite antiviral therapy (ART), 800,000 deaths still occur yearly and globally due to HIV infection. In parallel with the good virological control and the aging of this population, multiple comorbidities [HIV-associated-non-AIDS (HANA) conditions] may now be observed. Methods HIV adult patients hospitalized in intensive care unit (ICU) from all the French region from university and non-university hospital who participate to the OutcomeRea™ database on a voluntary basis over a 24-year period. Results Of the 24,298 stays registered, 630 (2.6%) were a first ICU stay for HIV patients. Over time, the mean age and number of comorbidities (diabetes, renal and respiratory history, solid neoplasia) of patients increased. The proportion of HIV diagnosed on ICU admission decreased significantly, while the median duration of HIV disease as well as the percentage of ART-treated patients increased. The distribution of main reasons for admission remained stable over time (acute respiratory distress > shock > coma). We observed a significant drop in the rate of active opportunistic infection on admission, while the rate of active hemopathy (newly diagnosed or relapsed within the last 6 months prior to admission to ICU) qualifying for AIDS increased—nonsignificantly—with a significant increase in the anticancer chemotherapy administration in ICU. Admissions for HANA or non-HIV reasons were stable over time. In multivariate analysis, predictors of 60-day mortality were advanced age, chronic liver disease, past chemotherapy, sepsis-related organ failure assessment score > 4 at admission, hospitalization duration before ICU admission > 24 h, AIDS status, but not the period of admission. Conclusion Whereas the profile of ICU-admitted HIV patients has evolved over time (HIV better controlled but more associated comorbidities), mortality risk factors remain stable, including AIDS status.

Purpose Noninvasive ventilation (NIV) had proven benefits in clinical trials that included selected patients admitted to highly skilled centers. Whether these benefits apply to every patient and in everyday practice deserves appraisal. The aim of the study was to assess the use and outcomes of NIV over the last 15 years. Methods Multicenter database study of critically ill patients who required ventilatory support for acute respiratory failure between 1997 and 2011. The impact of first-line NIV on 60-day mortality was evaluated using a marginal structural model. Follow-up was censored on day 60. Results Of 3,163 patients, 1,232 (39 %) received NIV. Over the study period, first-line NIV increased from 29 to 42 %, and NIV success rates increased from 69 to 84 %. NIV decreased 60-day mortality [adjusted hazard ratio (aHR), 0.75; 95 % confidence interval (95 % CI), 0.68–0.83; P  < 0.0001]. This protective effect was observed in patients with acute-on-chronic respiratory failure (aHR, 0.71; 95 % CI, 0.57–0.90; P  = 0.004), but not in patients with cardiogenic pulmonary edema (aHR, 0.85; 95 % CI, 0.70–1.03; P  = 0.10) or in patients with hypoxemic ARF, either immunocompetent (aHR, 1.18; 95 % CI, 0.87–1.59; P  = 0.30) or immunocompromised (aHR, 0.89; 95 % CI, 0.70–1.13; P  = 0.35). NIV failure was an independent time-dependent risk factor for mortality (aHR, 4.2; 95 % CI, 2.8–6.2; P  < 0.0001). Conclusions The use of NIV increased steadily over the study period. First-line NIV was associated with better 60-day survival and fewer ICU-acquired infections compared to first-line intubation. Survival benefits from NIV occurred only in patients with acute-on-chronic respiratory failure and immunocompromised patients.

In the No NV-ICU-AP population, the number of patients with No decrease in consciousness Day 1–Day 2 (Glasgow Coma Scale = 15) is 312 (38.9%) In the NV-ICU-AP population, the number of patients with No decrease in consciousness Day 1–Day 2 (Glasgow Coma Scale = 15) is 28 (66.7%) The correct Table 1 values are: In the No NV-ICU-AP population, the number of patients with No decrease in consciousness Day 1–Day 2 (Glasgow Coma Scale = 15) is 490 (61.1%) In the NV-ICU-AP population, the number of patients with No decrease in consciousness Day 1–Day 2 (Glasgow Coma Scale = 15) is 14 (33.1%) Table 1 has been updated in this correction article and the original article [1] has been corrected. Table 1 Baseline characteristics and mortality rate for patients with non-ventilator-associated ICU-acquired pneumonia admitted to an ICU for severe acute exacerbation of chronic obstructive pulmonary disease Full size table The incorrect Table 1 values are: In the No NV-ICU-AP population, the number of patients with No decrease in consciousness Day 1–Day 2 (Glasgow Coma Scale = 15) is 312 (38.9%) In the NV-ICU-AP population, the number of patients with No decrease in consciousness Day 1–Day 2 (Glasgow Coma Scale = 15) is 28 (66.7%) The correct Table 1 values are: In the No NV-ICU-AP population, the number of patients with No decrease in consciousness Day 1–Day 2 (Glasgow Coma Scale = 15) is 490 (61.1%) In the NV-ICU-AP population, the number of patients with No decrease in consciousness Day 1–Day 2 (Glasgow Coma Scale = 15) is 14 (33.1%) Table 1 has been updated in this correction article and the original article [1] has been corrected.

Acute exacerbation of chronic obstructive pulmonary disease (COPD) is a frequent cause of intensive care unit (ICU) admission. However, data are scarce and conflicting regarding the impact of systemic corticosteroid treatment in critically ill patients with acute exacerbation of COPD. The aim of the study was to assess the impact of systemic corticosteroids on the occurrence of death or need for continuous invasive mechanical ventilation at day 28 after ICU admission. In the OutcomeReaTM prospective French national ICU database, we assessed the impact of corticosteroids at admission (daily dose ≥ 0.5 mg/kg of prednisone or equivalent during the first 24 hours ICU stay) on a composite outcome (death or invasive mechanical ventilation) using an inverse probability treatment weighting. Between January 1, 1997 and December 31, 2018, 391 out of 1,247 patients with acute exacerbations of COPDs received corticosteroids at ICU admission. Corticosteroids improved the main composite endpoint (OR = 0.70 [0.49; 0.99], p = 0.044. However, for the subgroup of most severe COPD patients, this did not occur (OR = 1.12 [0.53; 2.36], p = 0. 770). There was no significant impact of corticosteroids on rates of non-invasive ventilation failure, length of ICU or hospital stay, mortality or on the duration of mechanical ventilation. Patients on corticosteroids had the same prevalence of nosocomial infections as those without corticosteroids, but more glycaemic disorders. Using systemic corticosteroids for acute exacerbation of COPD at ICU admission had a positive effect on a composite outcome defined by death or need for invasive mechanical ventilation at day 28.

Fast and reliable assays to precisely define the nature of the infectious agents causing sepsis are eagerly anticipated. New molecular biology techniques are now available to define the presence of bacterial or fungal DNA within the bloodstream of sepsis patients. We have used a new technique (VYOO®) that allows the enrichment of microbial DNA before a multiplex polymerase chain reaction (PCR) for pathogen detection provided by SIRS-Lab (Jena, Germany). We analyzed 72 sepsis patients and 14 non-infectious systemic inflammatory response syndrome (SIRS) patients. Among the sepsis patients, 20 had a positive blood culture and 35 had a positive microbiology in other biological samples. Of these, 51.4% were positive using the VYOO® test. Among the sepsis patients with a negative microbiology and the non-infectious SIRS, 29.4% and 14.2% were positive with the VYOO® test, respectively. The concordance in bacterial identification between microbiology and the VYOO® test was 46.2%. This study demonstrates that these new technologies offer great hopes, but improvements are still needed.

The impact of prevention strategies and risk factors for early-onset (EOP) versus late-onset (LOP) ventilator-associated pneumonia (VAP) are still debated. To evaluate, in a multicenter cohort, the risk factors for EOP and LOP, as the evolution of prevention strategies. 7,784 patients with mechanical ventilation (MV) for at least 48 hours were selected into the multicenter prospective OUTCOMEREA database (1997-2016). VAP occurring between the 3rd and 6th day of MV defined EOP, while those occurring after defined LOPs. We used a Fine and Gray subdistribution model to take the successful extubation into account as a competing event. Overall, 1,234 included patients developed VAP (EOP: 445 (36%); LOP: 789 (64%)). Male gender was a risk factor for both EOP and LOP. Factors specifically associated with EOP were admission for respiratory distress, previous colonization with multidrug-resistant Pseudomonas aeruginosa, chest tube and enteral feeding within the first 2 days of MV. Antimicrobials administrated within the first 2 days of MV were all protective of EOP. ICU admission for COPD exacerbation or pneumonia were early risk factors for LOP, while imidazole and vancomycin use within the first 2 days of MV were protective factors. Late risk factors (between the 3rd and the 6th day of MV) were the intra-hospital transport, PAO2-FIO2<200 mmHg, vasopressor use, and known colonization with methicillin-resistant Staphylococcus aureus. Among the antimicrobials administered between the 3rd and the 6th day, fluoroquinolones were the solely protective one.Contrarily to LOP, the risk of EOP decreased across the study time periods, concomitantly with an increase in the compliance with bundle of prevention measures. VAP risk factors are mostly different according to the pneumonia time of onset, which should lead to differentiated prevention strategies.

PurposesStreptococcus pneumoniae is a leading pathogen of severe community, hospital or nursing facility infections. We sought to describe characteristics of invasive pneumococcal infection (IPI) and pneumonia (due to the high mortality of intensive care-associated pneumonia) and to report outcomes according to various types of comorbidity.MethodsMulticenter observational cohort study on the prospective Outcomerea database, including adult patients, with a hospital stay < 48 h before ICU admission and a documented IPI within the first 72 h of ICU admission. Comorbid conditions were defined according to the Knaus and Charlson classification.ResultsOf the 20,235 patients, 5310 (26.4%) had an invasive infection, including 560/5,310 (10.6%) who had an IPI. The ICU 28-day mortality was 109/560 (19.8%). Four factors were independently associated with mortality: SOFA day 1–2: [hazard ratio (HR) 1.21; 95% confidence interval (95% CI) 1.15–1.27, p < 0.001]; maximum lactate level day 1–2: (HR 1.07, 95% CI 1.02–1.12, p = 0.006); diabetes mellitus: (HR 1.91, 95% CI 1.23–3.03, p = 0.006) and appropriate antibiotics (HR 0.28, 95% CI 0.15–0.50, p < 0.001). Comparable results were obtained when other comorbid conditions were forced into the model. Diabetes impact was more pronounced in case of micro- or macro-angiopathy (HR 4.17, 95%CI 1.68–10.54, p = 0.003), in patients ≥ 65 years old (HR 2.59, 95% CI 1.56–4.28, < 0.001) and in those with body mass index (BMI) < 25 kg/m2 (HR 2.11, 95% CI 1.10–4.06, p = 0.025).ConclusionsDiabetes mellitus was the only comorbid condition which independently influenced mortality in patients with IPI. Its impact was more pronounced in patients with complications, aged ≥ 65 years and with BMI < 25 kg/m2.