Rationale: Sepsis induces a sustained immune dysfunction responsible for poor outcome and nosocomial infections. Myeloid-derived suppressor cells (MDSCs) described in cancer and inflammatory processes may be involved in sepsis-induced immune suppression but their clinical impact remains poorly defined. Objectives: To clarify phenotype, suppressive activity, origin, and clinical impact of MDSCs in septic patients. Methods: Peripheral blood transcriptomic analysis was performed on 29 septic patients and 15 healthy donors. A second cohort of 94 consecutive septic patients, 11 severity-matched intensive care patients and 67 healthy donors was prospectively enrolled for flow cytometry and functional experiments. Measurements and Main Results: Genes involved in MDSC suppressive functions, including S100A12, S100A9, MMP8 and ARG1, were upregulated in the peripheral blood of septic patients. CD14^posHLA-DR^low/neg monocytic (M)-MDSCs were expanded in intensive care septic and non-septic patients and CD14^negCD15^pos low-density granulocytes/ granulocytic (G)-MDSCs were more specifically expanded in septic patients (p<.001). Plasma levels of MDSC mediators S100A8/A9, S100A12, and Arginase 1 were significantly increased. In vitro, CD14^pos- and CD15^pos-cell depletion increased T-cell proliferation in septic patients. G-MDSCs, made of immature and mature granulocytes expressing high levels of degranulation markers, were specifically responsible for arginase 1 activity. High initial levels of G-MDSCs, arginase 1, and S100A12 but not M-MDSCs were associated with subsequent occurrence of nosocomial infections. Conclusions: M-MDSCs and G-MDSCs strongly contribute to T-cell dysfunction in septic patients. More specifically, G-MDSCs producing arginase 1 are associated with a higher incidence of nosocomial infections and appear to be major actors of sepsis-induced immune suppression.

Exaggerated release of neutrophil extracellular traps (NETs) along with decreased NET clearance and inability to remove apoptotic cells (efferocytosis) may contribute to sustained inflammation in acute respiratory distress syndrome (ARDS). Recent studies in experimental models of ARDS have revealed the crosstalk between AMP-activated protein kinase (AMPK) and high-mobility group box 1 (HMGB1), which may contribute to effectiveness of efferocytosis, thereby reducing inflammation and ARDS severity.We investigated neutrophil and NET clearance by macrophages from control and ARDS patients and examined how bronchoalveolar lavage (BAL) fluid from control and ARDS patients could affect NET formation and efferocytosis. Metformin (an AMPK activator) and neutralising antibody against HMGB1 were applied to improve efferocytosis and NET clearance.Neutrophils from ARDS patients showed significantly reduced apoptosis. Conversely, NET formation was significantly enhanced in ARDS patients. Exposure of neutrophils to ARDS BAL fluid promoted NET production, while control BAL fluid had no effect. Macrophage engulfment of NETs and apoptotic neutrophils was diminished in ARDS patients. Notably, activation of AMPK in macrophages or neutralisation of HMGB1 in BAL fluid improved efferocytosis and NET clearance.In conclusion, restoration of AMPK activity with metformin or specific neutralisation of HMGB1 in BAL fluid represent promising therapeutic strategies to decrease sustained lung inflammation during ARDS.

Introduction: Ventilator-associated pneumonia (VAP) may contribute to the mortality associated with acute respiratory distress syndrome (ARDS). We aimed to determine the incidence, outcome, and risk factors of bacterial VAP complicating severe ARDS in patients ventilated by using a strictly standardized lung-protective strategy. Methods: This prospective epidemiologic study was done in all the 339 patients with severe ARDS included in a multicenter randomized, placebo-controlled double-blind trial of cisatracurium besylate in severe ARDS patients. Patients with suspected VAP underwent bronchoalveolar lavage to confirm the diagnosis. Results: Ninety-eight (28.9%) patients had at least one episode of microbiologically documented bacterial VAP, including 41 (41.8%) who died in the ICU, compared with 74 (30.7%) of the 241 patients without VAP (P = 0.05). After adjustment, age and severity at baseline, but not VAP, were associated with ICU death. Cisatracurium besylate therapy within 2 days of ARDS onset decreased the risk of ICU death. Factors independently associated with an increased risk to develop a VAP were male sex and worse admission Glasgow Coma Scale score. Tracheostomy, enteral nutrition, and the use of a subglottic secretion-drainage device were protective. Conclusions: In patients with severe ARDS receiving lung-protective ventilation, VAP was associated with an increased crude ICU mortality which did not remain significant after adjustment.

While the psychiatric disorders are conditions frequently encountered in hospitalized patients, there are little or no data regarding the characteristics and short- and long-term outcomes in patients with preexisting psychiatric disorders in ICU. Such assessment may provide the opportunity to determine the respective impact on mortality in the ICU and after ICU discharge with reasons for admission, including modalities of self-harm, of underlying psychiatric disorders and prior psychoactive medications. ICU and 1-year survival analysis performed on a retrospective cohort of patients with preexisting psychiatric disorders admitted from 2000 through 2013 in a 21-bed polyvalent ICU in a university hospital. Among the 1751 patients of the cohort, 1280 (73%) were admitted after deliberate self-harm. Psychiatric diagnoses were: schizophrenia, n = 97 (6%); non-schizophrenia psychotic disorder, n = 237 (13%); depression disorder, n = 1058 (60%), bipolar disorder, n = 172 (10%), and anxiety disorder, n = 187 (11%). ICU mortality rate was significantly lower in patients admitted after self-harm than in patients admitted for other reasons than self-harm [38/1288 patients (3%) vs. 53/463 patients (11%), respectively, p < 0.0001]. Compared with patients admitted for deliberate self-poisoning with psychoactive medications, patients admitted for self-harm by hanging, drowning, jumping from buildings, or corrosive chemicals ingestion had a significantly higher ICU mortality rate. In the ICU, SAPS II score [adjusted odds ratio (OR) 1.061, 95% CI 1.041–1.079, p < 0.0001], use of vasopressors (adjusted OR 7.40, 95% CI 2.94–18.51, p < 0.001), out-of-hospital cardiac arrest (adjusted OR 14.70, 95% CI 3.86–38.51, p < 0.001), and self-harm by hanging, drowning, jumping from buildings, or corrosive chemicals ingestion (adjusted OR 11.49, 95% CI 3.76–35.71, p < 0.001) were independently associated with mortality. After ICU discharge SAPS II score [adjusted hazard ratio (HR) 1.023, 95% CI 1.010–1.036, p < 0.01], age (adjusted HR 1.030, 95% CI 1.016–1.044, p < 0.0001), admission for respiratory failure (adjusted HR 2.23, 95% CI 1.19–4.57, p = 0.01), and shock (adjusted HR 3.72, 95% CI 1.97–6.62, p < 0.001) were independently associated with long-term mortality. Neither psychiatric diagnoses nor psychoactive medications received before admission to the ICU were independently associated with mortality. The study provides data on the short- and long-term outcomes of patients with prepsychiatric disorders admitted to the ICU that may guide decisions when considering ICU admission and discharge in these patients.

To characterize the factors associated with delayed defecation in long-term ventilated patients and to examine the relationship between delayed defecation and logistic organ dysfunction scores, acquired bacterial infections, and mortality in the intensive care unit. Prospective observational cohort study. A 21-bed polyvalent intensive care unit in a university hospital. A total of 609 adult patients admitted over a 41-month period who underwent mechanical ventilation for ≥ 6 days. None. Three hundred fifty-three patients (58%) passed stools ≥ 6 days after they were admitted to the intensive care unit ("late" defecation). Patients with early and late defecation had similar general characteristics when admitted to the intensive care unit and had similar logistic organ dysfunction scores on the first day of mechanical ventilation. Several variables were independently associated with a delay in defecation: a Pao2/Fio2 ratio of less than 150 mm Hg (adjusted hazard ratio 1.40; 95% confidence interval: 1.06-1.60; p = .0073), a systolic blood pressure between 70 and 89 mm Hg (adjusted hazard ratio 1.48; 95% confidence interval: 1.17-1.79; p = .002), and systolic blood pressure < 68 mm Hg (adjusted hazard ratio 1.29; 95% confidence interval: 1.01-1.60; p = .03). Logistic organ dysfunction scores were significantly higher on the fourth and ninth days of mechanical ventilation in patients with late defecation than in those with early defecation. The crude intensive care unit mortality rate was 18% in patients with early defecation and 30% in patients with late defecation (p < .001). Acquired bacterial infections at any site occurred in 34% of patients with early defecation and 66% of patients with late defecation (p < .001). A Pao2/Fio2 ratio of < 150 mm Hg and systolic blood pressure of < 90 mm Hg during the first 5 days of mechanical ventilation were independently associated with a delay in defecation. Our results suggest that constipation is associated with adverse outcomes in long-term ventilated patients.