Treatment of positive catheter tip culture without bloodstream infections in critically ill patients. A case-cohort study from the OUTCOMEREA network.

PURPOSE: This study aimed to evaluate the impact on subsequent infections and mortality of an adequate antimicrobial therapy within 48 h after catheter removal in intensive care unit (ICU) patients with positive catheter tip culture. METHODS: We performed a retrospective analysis of prospectively collected data from 29 centers of the OUTCOMEREA network. We developed a propensity score (PS) for adequate antimicrobial treatment, based on expert opinion of 45 attending physicians. We conducted a 1:1 case-cohort study matched on the PS score of being adequately treated. A PS-matched subdistribution hazard model was used for detecting subsequent infections and a PS-matched Cox model was used to evaluate the impact of antibiotic therapy on mortality. RESULTS: We included 427 patients with a catheter tip culture positive with potentially pathogenic microorganisms. We matched 150 patients with an adequate antimicrobial therapy with 150 controls. In the matched population, 30 (10%) subsequent infections were observed and 62 patients died within 30 days. Using subdistribution hazard models, the daily risk to develop subsequent infection up to Day-30 was similar between treated and non-treated groups (subdistribution hazard ratio [sHR] 1.08, 95% confidence interval [CI] 0.62-1.89, p = 0.78). Using Cox proportional hazard models, the 30-day mortality risk was similar between treated and non-treated groups (HR 0.89, 95% CI 0.45-1.74, p = 0.73). CONCLUSIONS: Antimicrobial therapy was not associated with decreased risk of subsequent infection or death in short-term catheter tip colonization in critically ill patients. Antibiotics may be unnecessary for positive catheter tip cultures.

Single-drug versus combination antimicrobial therapy in critically ill patients with hospital-acquired pneumonia and ventilator-associated pneumonia due to Gram-negative pathogens: a multicenter retrospective cohort study.

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.

Non-ventilator-associated ICU-acquired pneumonia (NV-ICU-AP) in patients with acute exacerbation of COPD: From the French OUTCOMEREA cohort.

BACKGROUND: Non-ventilator-associated ICU-acquired pneumonia (NV-ICU-AP), a nosocomial pneumonia that is not related to invasive mechanical ventilation (IMV), has been less studied than ventilator-associated pneumonia, and never in the context of patients in an ICU for severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD), a common cause of ICU admission. This study aimed to determine the factors associated with NV-ICU-AP occurrence and assess the association between NV-ICU-AP and the outcomes of these patients. METHODS: Data were extracted from the French ICU database, OutcomeRea™. Using survival analyses with competing risk management, we sought the factors associated with the occurrence of NV-ICU-AP. Then we assessed the association between NV-ICU-AP and mortality, intubation rates, and length of stay in the ICU. RESULTS: Of the 844 COPD exacerbations managed in ICUs without immediate IMV, NV-ICU-AP occurred in 42 patients (5%) with an incidence density of 10.8 per 1,000 patient-days. In multivariate analysis, prescription of antibiotics at ICU admission (sHR, 0.45 [0.23; 0.86], p = 0.02) and no decrease in consciousness (sHR, 0.35 [0.16; 0.76]; p < 0.01) were associated with a lower risk of NV-ICU-AP. After adjusting for confounders, NV-ICU-AP was associated with increased 28-day mortality (HR = 3.03 [1.36; 6.73]; p < 0.01), an increased risk of intubation (csHR, 5.00 [2.54; 9.85]; p < 0.01) and with a 10-day increase in ICU length of stay (p < 0.01). CONCLUSION: We found that NV-ICU-AP incidence reached 10.8/1000 patient-days and was associated with increased risks of intubation, 28-day mortality, and longer stay for patients admitted with AECOPD.

Corticosteroids for severe acute exacerbations of chronic obstructive pulmonary disease in intensive care: From the French OUTCOMEREA cohort.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Outcomes in critically Ill HIV-infected patients between 1997 and 2020: analysis of the OUTCOMEREA multicenter cohort.

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.

Management of Acute Exacerbations of Chronic Obstructive Pulmonary Disease in the ICU: An Observational Study From the OUTCOMEREA Database, 1997-2018.

OBJECTIVES: Our aim was to describe changes in the management of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) by ICUs and patient outcomes. DESIGN: We extracted data from the OutcomeRea database concerning patients admitted for AECOPD between 1997 and 2018. We analyzed trends in the use of ventilatory support, corticosteroid therapy, antibiotic therapy, and patient survival. SETTING: ICUs at 32 French sites. PATIENTS: One thousand eight hundred sixteen patients in the database had a diagnosis of AECOPD. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Over time, there was a reduction in the prescription of corticosteroids and antibiotics. In a time-series analysis, these changes in practice were not linked with ICU mortality. The proportion of patients treated with invasive mechanical ventilation (IMV) also gradually declined (from 51% between 1997 and 2002 to 35% between 2013 and 2018) with an association between decrease in IMV use and reduction in ICU mortality in a time series analysis. Rates of noninvasive ventilation (NIV) failure decreased with an increase in NIV use to support weaning from IMV. There was a reduction in the median ICU length of stay (from 8 d in 1997-2002 to 4 d in 2013-2018) and in the median total duration of hospitalization (from 23 d in 1997-2002 to 14 d in 2013-2018). We observed an improvement in prognosis, with decreases in overall hospital mortality (from 24% between 1997 and 2002 to 15% between 2013 and 2018), ICU mortality (from 14% between 1997 and 2002 to 10% between 2013 and 2018), and 90-day mortality (from 41% between 1997 and 2002 to 22% between 2013 and 2018). CONCLUSIONS: The length of stay and mortality of patients with AECOPD admitted to ICUs has decreased over the last 20 years, with a wider use of NIV and a reduction in antibiotic and corticosteroid prescriptions.

Clinical and biological clusters of sepsis patients using hierarchical clustering.

BACKGROUND: Heterogeneity in sepsis expression is multidimensional, including highly disparate data such as the underlying disorders, infection source, causative micro-organismsand organ failures. The aim of the study is to identify clusters of patients based on clinical and biological characteristic available at patients' admission. METHODS: All patients included in a national prospective multicenter ICU cohort OUTCOMEREA and admitted for sepsis or septic shock (Sepsis 3.0 definition) were retrospectively analyzed. A hierarchical clustering was performed in a training set of patients to build clusters based on a comprehensive set of clinical and biological characteristics available at ICU admission. Clusters were described, and the 28-day, 90-day, and one-year mortality were compared with log-rank rates. Risks of mortality were also compared after adjustment on SOFA score and year of ICU admission. RESULTS: Of the 6,046 patients with sepsis in the cohort, 4,050 (67%) were randomly allocated to the training set. Six distinct clusters were identified: young patients without any comorbidities, admitted in ICU for community-acquired pneumonia (n = 1,603 (40%)); young patients without any comorbidities, admitted in ICU for meningitis or encephalitis (n = 149 (4%)); elderly patients with COPD, admitted in ICU for bronchial infection with few organ failures (n = 243 (6%)); elderly patients, with several comorbidities and organ failures (n = 1,094 (27%)); patients admitted after surgery, with a nosocomial infection (n = 623 (15%)); young patients with immunosuppressive conditions (e.g., AIDS, chronic steroid therapy or hematological malignancy) (n = 338 (8%)). Clusters differed significantly in early or late mortality (p < .001), even after adjustment on severity of organ dysfunctions (SOFA) and year of ICU admission. CONCLUSIONS: Clinical and biological features commonly available at ICU admission of patients with sepsis or septic shock enabled to set up six clusters of patients, with very distinct outcomes. Considering these clusters may improve the care management and the homogeneity of patients in future studies.

Life Support Limitations in Mechanically Ventilated Stroke Patients.

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, n = 167 [45%]; hemorrhagic, n = 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; p < 0.01). Limitation of life support preceded ICU death in 70% of ischemic strokes and 45% of hemorrhagic strokes (p < 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.

One-year survival in acute stroke patients requiring mechanical ventilation: a multicenter cohort study.

BACKGROUND: Most prognostic studies in acute stroke patients requiring invasive mechanical ventilation are outdated and have limitations such as single-center retrospective designs. We aimed to study the association of ICU admission factors, including the reason for intubation, with 1-year survival of acute stroke patients requiring mechanical ventilation. METHODS: We conducted a secondary data use analysis of a prospective multicenter database (14 ICUs) between 1997 and 2016 on consecutive ICU stroke patients requiring mechanical ventilation at admission. We excluded patients with stroke of traumatic origin, subdural hematoma or cerebral venous thrombosis. The primary outcome was survival 1 year after ICU admission. Factors associated with the primary outcome were identified using a multivariable Cox model stratified on inclusion center. RESULTS: We identified 419 patients (age 68 [58-76] years, males 60%) with a Glasgow coma score (GCS) of 4 [3-8] at admission. Stroke subtypes were acute ischemic stroke (AIS, 46%), intracranial hemorrhage (ICH, 42%) and subarachnoid hemorrhage (SAH, 12%). At 1 year, 96 (23%) patients were alive. Factors independently associated with decreased 1-year survival were ICH and SAH stroke subtypes, a lower GCS score at admission, a higher non-neurological SOFA score. Conversely, patients receiving acute-phase therapy had improved 1-year survival. Intubation for acute respiratory failure or coma was associated with comparable survival hazard ratios, whereas intubation for seizure was not associated with a worse prognosis than for elective procedure. Survival did not improve over the study period, but patients included in the most recent period had more comorbidities and presented higher severity scores at admission. CONCLUSIONS: In acute stroke patients requiring mechanical ventilation, the reason for intubation and the opportunity to receive acute-phase stroke therapy were independently associated with 1-year survival. These variables could assist in the decision process regarding the initiation of mechanical ventilation in acute stroke patients.

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

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.

Diabetes was the only comorbid condition associated with mortality of invasive pneumococcal infection in ICU patients: a multicenter observational study from the Outcomerea research group.

PURPOSES: Streptococcus 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. METHODS: Multicenter 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. RESULTS: Of 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). CONCLUSIONS: Diabetes 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.

Respective impact of implementation of prevention strategies, colonization with multiresistant bacteria and antimicrobial use on the risk of early- and late-onset VAP: An analysis of the OUTCOMEREA network.

RATIONALE: The impact of prevention strategies and risk factors for early-onset (EOP) versus late-onset (LOP) ventilator-associated pneumonia (VAP) are still debated. OBJECTIVES: To evaluate, in a multicenter cohort, the risk factors for EOP and LOP, as the evolution of prevention strategies. METHODS: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSION: VAP risk factors are mostly different according to the pneumonia time of onset, which should lead to differentiated prevention strategies.

Effect of Transfusion on Mortality and Other Adverse Events Among Critically Ill Septic Patients: An Observational Study Using a Marginal Structural Cox Model.

OBJECTIVES: RBC transfusion is often required in patients with sepsis. However, adverse events have been associated with RBC transfusion, raising safety concerns. A randomized controlled trial validated the 7 g/dL threshold, but previously transfused patients were excluded. Cohort studies led to conflicting results and did not handle time-dependent covariates and history of treatment. Additional data are thus warranted to guide patient's management. DESIGN: To estimate the effect of one or more RBC within 1 day on three major outcomes (mortality, ICU-acquired infections, and severe hypoxemia) at day 30, we used marginal structural models. A trajectory modeling, based on hematocrit evolution pattern, allowed identification of subgroups. Secondary analyses were performed into each of them. SETTING: A prospective French multicenter database. PATIENTS: Patients with sepsis at admission. Patients with hemorrhagic shock at admission were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Overall, in our cohort of 6,016 patients, RBC transfusion was not associated with death (hazard ratio, 1.07; 95% CI, 0.88-1.30; p = 0.52). However, RBC transfusion was associated with increased occurrence of ICU-acquired infections (hazard ratio, 2.77; 95% CI, 2.33-3.28; p < 0.01) and of severe hypoxemia (hazard ratio, 1.29; 95% CI, 1.14-1.47; p < 0.01). A protective effect from death by the transfusion was found in the subgroup with the lowest hematocrit level (26 [interquartile range, 24-28]) (hazard ratio, 0.72; 95% CI, 0.55-0.95; p = 0.02). CONCLUSIONS: RBC transfusion did not affect overall mortality in critically ill patients with sepsis. Increased occurrence rate of ICU-acquired infection and severe hypoxemia are expected outcomes from RBC transfusion that need to be weighted with its benefits in selected patients.

Treatment of severe hospital-acquired and ventilator-associated pneumonia: a systematic review of inclusion and judgment criteria used in randomized controlled trials.

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.

Persistent lymphopenia is a risk factor for ICU-acquired infections and for death in ICU patients with sustained hypotension at admission.

BACKGROUND: Severely ill patients might develop an alteration of their immune system called post-aggressive immunosuppression. We sought to assess the risk of ICU-acquired infection and of mortality according to the absolute lymphocyte count at ICU admission and its changes over 3 days. METHODS: Adults in ICU for at least 3 days with a shock or persistent low blood pressure were extracted from a French ICU database and included. We evaluated the impact of the absolute lymphocyte count at baseline and its change at day 3 on the incidence of ICU-acquired infection and on the 28-day mortality rate. We categorized lymphocytes in 4 groups: above 1.5 × 103 cells/µL; between 1 and 1.5 × 103 cells/µL; between 0.5 and 1 × 103 cells/µL; and below 0.5 × 103 cells/µL. RESULTS: A total of 753 patients were included. The median lymphocyte count was 0.8 × 103 cells/µL [0.51-1.29]. A total of 174 (23%) patients developed infections; the 28-day mortality rate was 21% (161/753). Lymphopenia at admission was associated with ICU-acquired infection (p < 0.001) but not with 28-day mortality. Independently of baseline lymphocyte count, the absence of lymphocyte count increase at day 3 was associated with ICU-acquired infection (sub-distribution hazard ratio sHR: 1.37 [1.12-1.67], p = 0.002) and with 28-day mortality (sHR: 1.67 [1.37-2.03], p < 0.0001). CONCLUSION: Lymphopenia at ICU admission and its persistence at day 3 were associated with an increased risk of ICU-acquired infection, while only persisting lymphopenia predicted increased 28-day mortality. The lymphocyte count at ICU admission and at day 3 could be used as a simple and reproductive marker of post-aggressive immunosuppression.

Impact of transfusion on patients with sepsis admitted in intensive care unit: a systematic review and meta-analysis.

Red blood cell transfusion (RBCT) threshold in patients with sepsis remains a matter of controversy. A threshold of 7 g/dL for stabilized patients with sepsis is commonly proposed, although debated. The aim of the study was to compare the benefit and harm of restrictive versus liberal RBCT strategies in order to guide physicians on RBCT strategies in patients with severe sepsis or septic shock. Four outcomes were assessed: death, nosocomial infection (NI), acute lung injury (ALI) and acute kidney injury (AKI). Studies assessing RBCT strategies or RBCT impact on outcome and including intensive care unit (ICU) patients with sepsis were assessed. Two systematic reviews were achieved: first for the randomized controlled studies (RCTs) and second for the observational studies. MEDLINE, EMBASE, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and Clinical Trials.gov were analyzed up to March 01, 2015. Der Simonian and Laird random-effects models were used to report pooled odds ratios (ORs). Subgroup analyses and meta-regressions were performed to explore studies heterogeneity. One RCT was finally included. The restrictive RBCT strategy was not associated with harm or benefit compared to liberal strategy. Twelve cohort studies were included, of which nine focused on mortality rate. RBCT was not associated with increased mortality rate (overall pooled OR was 1.10 [0.75, 1.60]; I 2 = 57%, p = 0.03), but was associated with the occurrence of NI (2 studies: pooled OR 1.25 [1.04-1.50]; I 2 = 0%, p = 0.97), the occurrence of ALI (1 study: OR 2.75 [1.22-6.37]; p = 0.016) and the occurrence of AKI (1 study: OR 5.22 [2.1-15.8]; p = 0.001). Because there was only one RCT, the final meta-analyses were only based on the cohort studies. As a result, the safety of a RBCT restrictive strategy was confirmed, although only one study specifically focused on ICU patients with sepsis. Then, RBCT was not associated with increased mortality rate, but was associated with increased in occurrence of NI, ALI and AKI. Nevertheless, the data on RBCT in patients with sepsis are sparse and the high heterogeneity between studies prevents from drawing any definitive conclusions.

Attributable mortality of ICU-acquired bloodstream infections: Impact of the source, causative micro-organism, resistance profile and antimicrobial therapy.

OBJECTIVES: ICU-acquired bloodstream infection (ICUBSI) in Intensive Care unit (ICU) is still associated with a high mortality rate. The increase of antimicrobial drug resistance makes its treatment increasingly challenging. METHODS: We analyzed 571 ICU-BSI occurring amongst 10,734 patients who were prospectively included in the Outcomerea Database and who stayed at least 4 days in ICU. The hazard ratio of death associated with ICU-BSI was estimated using a multivariate Cox model adjusted on case mix, patient severity and daily SOFA. RESULTS: ICU-BSI was associated with increased mortality (HR, 1.40; 95% CI, 1.16-1.69; p = 0.0004). The relative increase in the risk of death was 130% (HR, 2.3; 95% CI, 1.8-3.0) when initial antimicrobial agents within a day of ICU-BSI onset were not adequate, versus only 20% (HR, 1.2; 95% CI, 0.9-1.5) when an adequate therapy was started within a day. The adjusted hazard ratio of death was significant overall, and even higher when the ICU-BSI source was pneumonia or unknown origin. When treated with appropriate antimicrobial agents, the death risk increase was similar for ICU-BSI due to multidrug resistant pathogens or susceptible ones. Interestingly, combination therapy with a fluoroquinolone was associated with more favorable outcome than monotherapy, whereas combination with aminoglycoside was associated with similar mortality than monotherapy. CONCLUSIONS: ICU-BSI was associated with a 40% increase in the risk of 30-day mortality, particularly if the early antimicrobial therapy was not adequate. Adequacy of antimicrobial therapy, but not pathogen resistance pattern, impacted attributable mortality.

Continuous renal replacement therapy versus intermittent hemodialysis in intensive care patients: impact on mortality and renal recovery.

PURPOSE: The best renal replacement therapy (RRT) modality remains controversial. We compared mortality and short- and long-term renal recovery between patients treated with continuous RRT and intermittent hemodialysis. METHODS: Patients of the prospective observational multicenter cohort database OUTCOMEREA™ were included if they underwent at least one RRT session between 2004 and 2014. Differences in patients' baseline and daily characteristics between treatment groups were taken into account by using a marginal structural Cox model, allowing one to substantially reduce the bias resulting from confounding factors in observational longitudinal data analysis. The composite primary endpoint was 30-day mortality and dialysis dependency. RESULTS: Among 1360 included patients with RRT, 544 (40.0 %) and 816 (60.0 %) were initially treated by continuous RRT and intermittent hemodialysis, respectively. At day 30, 39.6 % patients were dead. Among survivors, 23.8 % still required RRT. There was no difference between groups for the primary endpoint in global population (HR 1.00, 95 % CI 0.77-1.29; p = 0.97). In patients with higher weight gain at RRT initiation, mortality and dialysis dependency were significantly lower with continuous RRT (HR 0.54, 95 % CI 0.29-0.99; p = 0.05). Conversely, this technique appeared to be deleterious in patients without shock (HR 2.24, 95 % CI 1.24-4.04; p = 0.01). Six-month mortality and persistent renal dysfunction were not influenced by the RRT modality in patients with dialysis dependence at ICU discharge. CONCLUSION: Continuous RRT did not appear to improve 30-day and 6-month patient outcomes. It seems beneficial for patients with fluid overload, but might be deleterious in the absence of hemodynamic failure.