Beneficial effects of citrulline enteral administration on sepsis-induced T cell mitochondrial dysfunction.

Severe sepsis induces a sustained immune dysfunction associated with poor clinical behavior. In particular, lymphopenia along with increased lymphocyte apoptosis and decreased lymphocyte proliferation, enhanced circulating regulatory T cells (Treg), and the emergence of myeloid-derived suppressor cells (MDSCs) have all been associated with persistent organ dysfunction, secondary infections, and late mortality. The mechanisms involved in MDSC-mediated T cell dysfunction during sepsis share some features with those described in malignancies such as arginine deprivation. We hypothesized that increasing arginine availability would restore T cell function and decrease sepsis-induced immunosuppression. Using a mouse model of sepsis based on cecal ligation and puncture and secondary pneumonia triggered by methicillin-resistant Staphylococcus aureus inoculation, we demonstrated that citrulline administration was more efficient than arginine in increasing arginine plasma levels and restoring T cell mitochondrial function and proliferation while reducing sepsis-induced Treg and MDSC expansion. Because there is no specific therapeutic strategy to restore immune function after sepsis, we believe that our study provides evidence for developing citrulline-based clinical studies in sepsis.

Enteral citrulline supplementation versus placebo on SOFA score on day 7 in mechanically ventilated critically ill patients: the IMMUNOCITRE randomized clinical trial.

BACKGROUND: Restoring plasma arginine levels through enteral administration of L-citrulline in critically ill patients may improve outcomes. We aimed to evaluate whether enteral L-citrulline administration reduced organ dysfunction based on the Sequential Organ Failure Assessment (SOFA) score and affected selected immune parameters in mechanically ventilated medical intensive care unit (ICU) patients. METHODS: A randomized, double-blind, multicenter clinical trial of enteral administration of L-citrulline versus placebo for critically ill adult patients under invasive mechanical ventilation without sepsis or septic shock was conducted in four ICUs in France between September 2016 and February 2019. Patients were randomly assigned to receive enteral L-citrulline (5 g) every 12 h for 5 days or isonitrogenous, isocaloric placebo. The primary outcome was the SOFA score on day 7. Secondary outcomes included SOFA score improvement (defined as a decrease in total SOFA score by 2 points or more between day 1 and day 7), secondary infection acquisition, ICU length of stay, plasma amino acid levels, and immune biomarkers on day 3 and day 7 (HLA-DR expression on monocytes and interleukin-6). RESULTS: Of 120 randomized patients (mean age, 60 ± 17 years; 44 [36.7%] women; ICU stay 10 days [IQR, 7-16]; incidence of secondary infections 25 patients (20.8%)), 60 were allocated to L-citrulline and 60 were allocated to placebo. Overall, there was no significant difference in organ dysfunction as assessed by the SOFA score on day 7 after enrollment (4 [IQR, 2-6] in the L-citrulline group vs. 4 [IQR, 2-7] in the placebo group; Mann‒Whitney U test, p = 0.9). Plasma arginine was significantly increased on day 3 in the treatment group, while immune parameters remained unaffected. CONCLUSION: Among mechanically ventilated ICU patients without sepsis or septic shock, enteral L-citrulline administration did not result in a significant difference in SOFA score on day 7 compared to placebo. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02864017 (date of registration: 11 August 2016).

Tolerance and complications of therapeutic plasma exchange by centrifugation: A single center experience.

INTRODUCTION: Therapeutic plasma exchange (TPE) constitutes an important therapy for hematological, neurological, immunological, and nephrological diseases. Most studies have focused on efficacy, whereas tolerance and complications during sessions have been less well studied and not recently. MATERIAL AND METHODS: We conducted a single center retrospective study of all patients who underwent TPE between 2011 and 2018. TPE sessions using the centrifugation technique were performed by dedicated trained nurses. Specific side effects were identified through surveillance forms completed contemporaneously. The primary outcome was the rate of all-type adverse effects that occurred during the TPE sessions. RESULTS: In total, 1895 TPE sessions performed on 185 patients were analyzed. At least one adverse effect was reported for 805 sessions (42.5% [29.9%-70.1%]), corresponding to 171 patients (92.4% [87.6%-95.8%]). Hypotension occurred during 288 sessions (15.2%), was asymptomatic in 95.8% of cases, and more frequent with the use of 4% albumin than fresh frozen plasma (FFP) (19.8 vs 8.9%, P <.0001). Hypocalcemia occurred during 370 sessions (19.6%) and was more frequent with the use of FFP than with the use of albumin alone (FFP alone: 28.0%, albumin + FFP: 26%, albumin alone: 11.7%; P <.0001). Allergic reactions occurred during 56 sessions (3%), exclusively with FFP. Severe adverse effects were reported for 0.3% of sessions and 5.4% of patients. CONCLUSIONS: TPE is a safe therapy when performed by a trained team. Adverse effects were frequent but mostly not serious. The replacement fluid was the main determinant of the occurrence of complications. (ClinicalTrials.gov ID: NCT03888417).

SARS-CoV-2-Induced ARDS Associates with MDSC Expansion, Lymphocyte Dysfunction, and Arginine Shortage.

PURPOSE: The SARS-CoV-2 infection can lead to a severe acute respiratory distress syndrome (ARDS) with prolonged mechanical ventilation and high mortality rate. Interestingly, COVID-19-associated ARDS share biological and clinical features with sepsis-associated immunosuppression since lymphopenia and acquired infections associated with late mortality are frequently encountered. Mechanisms responsible for COVID-19-associated lymphopenia need to be explored since they could be responsible for delayed virus clearance and increased mortality rate among intensive care unit (ICU) patients. METHODS: A series of 26 clinically annotated COVID-19 patients were analyzed by thorough phenotypic and functional investigations at days 0, 4, and 7 after ICU admission. RESULTS: We revealed that, in the absence of any difference in demographic parameters nor medical history between the two groups, ARDS patients presented with an increased number of myeloid-derived suppressor cells (MDSC) and a decreased number of CD8pos effector memory cell compared to patients hospitalized for COVID-19 moderate pneumonia. Interestingly, COVID-19-related MDSC expansion was directly correlated to lymphopenia and enhanced arginase activity. Lastly, T cell proliferative capacity in vitro was significantly reduced among COVID-19 patients and could be restored through arginine supplementation. CONCLUSIONS: The present study reports a critical role for MDSC in COVID-19-associated ARDS. Our findings open the possibility of arginine supplementation as an adjuvant therapy for these ICU patients, aiming to reduce immunosuppression and help virus clearance, thereby decreasing the duration of mechanical ventilation, nosocomial infection acquisition, and mortality.

Prior Exposure to Angiotensin II Receptor Blockers in Patients With Septic Shock to Individualize Mean Arterial Pressure Target? A Post Hoc Analysis of the Sepsis and Mean Arterial Pressure (SEPSISPAM) Trial.

OBJECTIVES: Individualizing a target mean arterial pressure is challenging during the initial resuscitation of patients with septic shock. The Sepsis and Mean Arterial Pressure (SEPSISPAM) trial suggested that targeting high mean arterial pressure might reduce the occurrence of acute kidney injury among those included patients with a past history of chronic hypertension. We investigated whether the class of antihypertensive medications used before the ICU stay in chronic hypertensive patients was associated with the severity of acute kidney injury occurring after inclusion, according to mean arterial pressure target. DESIGN: Post hoc analysis of the SEPSISPAM trial. SETTING: The primary outcome was the occurrence of severe acute kidney injury during the ICU stay defined as kidney disease improving global outcome stage 2 or higher. Secondary outcomes were mortality at day 28 and mortality at day 90. PATIENTS: All patients with chronic hypertension included in SEPSISPAM with available antihypertensive medications data in the hospitalization report were included. MEASUREMENTS AND MAIN RESULTS: We analyzed 297 patients. Severe acute kidney injury occurred in 184 patients, without difference according to pre-ICU exposure to antihypertensive medications. Patients with pre-ICU exposure to angiotensin II receptor blockers had significantly less severe acute kidney injury in the high mean arterial pressure target group (adjusted odd ratio 0.24 with 95% CI [0.09-0.66]; p = 0.006). No statistically significant association was found after adjustment for pre-ICU exposure to antihypertensive medications and survival. CONCLUSIONS: Our results suggest that patients with septic shock and chronic hypertension treated with angiotensin II receptor blocker may benefit from a high mean arterial pressure target to reduce the risk of acute kidney injury occurrence.

Venoarterial extracorporeal membrane oxygenation induces early immune alterations.

BACKGROUND: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) provides heart mechanical support in critically ill patients with cardiogenic shock. Despite important progresses in the management of patients under VA-ECMO, acquired infections remain extremely frequent and increase mortality rate. Since immune dysfunctions have been described in both critically ill patients and after surgery with cardiopulmonary bypass, VA-ECMO initiation may be responsible for immune alterations that may expose patients to nosocomial infections (NI). Therefore, in this prospective study, we aimed to study immune alterations induced within the first days by VA-ECMO initiation. METHODS: We studied immune alterations induced by VA-ECMO initiation using cytometry analysis to characterize immune cell changes and enzyme-linked immunosorbent assay (ELISA) to explore plasma cytokine levels. To analyze specific changes induced by VA-ECMO initiation, nine patients under VA-ECMO (VA-ECMO patients) were compared to nine patients with cardiogenic shock (control patients). RESULTS: Baseline immune parameters were similar between the two groups. VA-ECMO was associated with a significant increase in circulating immature neutrophils with a significant decrease in C5a receptor expression. Furthermore, we found that VA-ECMO initiation was followed by lymphocyte dysfunction along with myeloid-derived suppressor cells (MDSC) expansion. ELISA analysis revealed that VA-ECMO initiation was followed by an increase in pro-inflammatory cytokines such as IL-6, IL-8 and TNF-α along with IL-10, a highly immunosuppressive cytokine. CONCLUSION: VA-ECMO is associated with early immune changes that may be responsible for innate and adaptive immune alterations that could confer an increased risk of infection.

Incidence and risk factors for acquired colonization and infection due to extended-spectrum beta-lactamase-producing Gram-negative bacilli: a retrospective analysis in three ICUs with low multidrug resistance rate.

The purpose of this study is to assess risk factors for the acquisition of extended-spectrum ß-lactamase-producing Gram-negative bacilli (ESBL-GNB) colonization and infection (AI) in ICUs with low ESBL-GNB prevalence rate. We conducted a retrospective observational study in three ICUs in Bretagne, France. All patients admitted from January 2016 to September 2017 with a length of stay of 2 days or more were included. Universal screening for ESBL-GNB colonization was performed in all participating ICUs. Of the 3250 included patients, 131 (4.0%) were colonized at admission, 59 acquired colonization while hospitalized (1.9%; 95% CI [1.5-2.5%]), and 15 (0.5%; 95% CI [0.3-0.8%]) acquired ESBL-GNB infections. In the case of infection, the specificity and the negative predictive values of preexistent colonization for the ESBL-GNB etiology were 93.2% [91.5-95.1%] and 95.2% [93.5-97.1%], respectively. Colonization was the main risk factor for ESBL-GNB AI (OR = 9.61; 95% CI [2.86-32.29]; p < 0.001). Antimicrobial susceptibility of non-ESBL-GNB isolates responsible for AI was similar for any non-carbapenem ß-lactam (95%) and imipenem (94%). ESBL-GNB AIs were rare in ICUs with low ESBL-GNB prevalence rate. Prior colonization was the main risk factor for subsequent infection. Empirical carbapenem therapy could be avoided in non ESBL-GNB colonized patients with suspected AI.

Acute Neurologic Disorder from an Inhibitor of Fatty Acid Amide Hydrolase.

BACKGROUND: A decrease in fatty acid amide hydrolase (FAAH) activity increases the levels of endogenous analogues of cannabinoids, or endocannabinoids. FAAH inhibitors have shown analgesic and antiinflammatory activity in animal models, and some have been tested in phase 1 and 2 studies. In a phase 1 study, BIA 10-2474, an orally administered reversible FAAH inhibitor, was given to healthy volunteers to assess safety. METHODS: Single doses (0.25 to 100 mg) and repeated oral doses (2.5 to 20 mg for 10 days) of BIA 10-2474 had been administered to 84 healthy volunteers in sequential cohorts; no severe adverse events had been reported. Another cohort of participants was then assigned to placebo (2 participants) or 50 mg of BIA 10-2474 per day (6 participants). This report focuses on neurologic adverse events in participants in this final cohort. A total of 4 of the 6 participants who received active treatment consented to have their clinical and radiologic data included in this report. RESULTS: An acute and rapidly progressive neurologic syndrome developed in three of the four participants starting on the fifth day of drug administration. The main clinical features were headache, a cerebellar syndrome, memory impairment, and altered consciousness. Magnetic resonance imaging showed bilateral and symmetric cerebral lesions, including microhemorrhages and hyperintensities on fluid-attenuated inversion recovery and diffusion-weighted imaging sequences predominantly involving the pons and hippocampi. One patient became brain dead; the condition of two patients subsequently improved, but one patient had residual memory impairment, and the other patient had a residual cerebellar syndrome. One patient remained asymptomatic. CONCLUSIONS: An unanticipated severe neurologic disorder occurred after ingestion of BIA 10-2474 at the highest dose level used in a phase 1 trial. The underlying mechanism of this toxic cerebral syndrome remains unknown.

At-Risk Drinking Is Independently Associated With Acute Kidney Injury in Critically Ill Patients.

OBJECTIVES: Unhealthy use of alcohol and acute kidney injury are major public health problems, but little is known about the impact of excessive alcohol consumption on kidney function in critically ill patients. We aimed to determine whether at-risk drinking is independently associated with acute kidney injury in the ICU and at ICU discharge. DESIGN: Prospective observational cohort study. SETTING: A 21-bed polyvalent ICU in a university hospital. PATIENTS: A total of 1,107 adult patients admitted over a 30-month period who had an ICU stay of greater than or equal to 3 days and in whom alcohol consumption could be assessed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We assessed Kidney Disease Improving Global Outcomes stages 2-3 acute kidney injury in 320 at-risk drinkers (29%) and 787 non-at-risk drinkers (71%) at admission to the ICU, within 4 days after admission and at ICU discharge. The proportion of patients with stages 2-3 acute kidney injury at admission to the ICU (42.5% vs 18%; p < 0.0001) was significantly higher in at-risk drinkers than in non-at-risk drinkers. Within 4 days and after adjustment on susceptible and predisposing factors for acute kidney injury was performed, at-risk drinking was significantly associated with acute kidney injury for the entire population (odds ratio, 2.15; 1.60-2.89; p < 0.0001) in the subgroup of 832 patients without stages 2-3 acute kidney injury at admission to the ICU (odds ratio, 1.44; 1.02-2.02; p = 0.04) and in the subgroup of 971 patients without known chronic kidney disease (odds ratio, 1.92; 1.41-2.61; p < 0.0001). Among survivors, 22% of at-risk drinkers and 9% of non-at-risk drinkers were discharged with stages 2-3 acute kidney injury (p < 0.001). CONCLUSIONS: Our results suggest that chronic and current alcohol misuse in critically ill patients is associated with kidney dysfunction. The systematic and accurate identification of patients with alcohol misuse may allow for the prevention of acute kidney injury.

Impaired efferocytosis and neutrophil extracellular trap clearance by macrophages in ARDS.

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.

Early Expansion of Circulating Granulocytic Myeloid-derived Suppressor Cells Predicts Development of Nosocomial Infections in Patients with Sepsis.

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 patients with sepsis. METHODS: Peripheral blood transcriptomic analysis was performed on 29 patients with sepsis and 15 healthy donors. A second cohort of 94 consecutive patients with sepsis, 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 up-regulated in the peripheral blood of patients with sepsis. CD14posHLA-DRlow/neg monocytic (M)-MDSCs were expanded in intensive care unit patients with and without sepsis and CD14negCD15pos low-density granulocytes/granulocytic (G)-MDSCs were more specifically expanded in patients with sepsis (P < 0.001). Plasma levels of MDSC mediators S100A8/A9, S100A12, and arginase 1 were significantly increased. In vitro, CD14pos- and CD15pos-cell depletion increased T-cell proliferation in patients with sepsis. 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 patients with sepsis. More specifically, G-MDSCs producing arginase 1 are associated with a higher incidence of nosocomial infections and seem to be major actors of sepsis-induced immune suppression.

High versus low blood-pressure target in patients with septic shock.

BACKGROUND: The Surviving Sepsis Campaign recommends targeting a mean arterial pressure of at least 65 mm Hg during initial resuscitation of patients with septic shock. However, whether this blood-pressure target is more or less effective than a higher target is unknown. METHODS: In a multicenter, open-label trial, we randomly assigned 776 patients with septic shock to undergo resuscitation with a mean arterial pressure target of either 80 to 85 mm Hg (high-target group) or 65 to 70 mm Hg (low-target group). The primary end point was mortality at day 28. RESULTS: At 28 days, there was no significant between-group difference in mortality, with deaths reported in 142 of 388 patients in the high-target group (36.6%) and 132 of 388 patients in the low-target group (34.0%) (hazard ratio in the high-target group, 1.07; 95% confidence interval [CI], 0.84 to 1.38; P=0.57). There was also no significant difference in mortality at 90 days, with 170 deaths (43.8%) and 164 deaths (42.3%), respectively (hazard ratio, 1.04; 95% CI, 0.83 to 1.30; P=0.74). The occurrence of serious adverse events did not differ significantly between the two groups (74 events [19.1%] and 69 events [17.8%], respectively; P=0.64). However, the incidence of newly diagnosed atrial fibrillation was higher in the high-target group than in the low-target group. Among patients with chronic hypertension, those in the high-target group required less renal-replacement therapy than did those in the low-target group, but such therapy was not associated with a difference in mortality. CONCLUSIONS: Targeting a mean arterial pressure of 80 to 85 mm Hg, as compared with 65 to 70 mm Hg, in patients with septic shock undergoing resuscitation did not result in significant differences in mortality at either 28 or 90 days. (Funded by the French Ministry of Health; SEPSISPAM ClinicalTrials.gov number, NCT01149278.).

Extracorporeal Membrane Oxygenation in Pregnancy.

AIM: Adult respiratory distress syndrome (ARDS) may pose specific challenges in pregnant women, including the need for prone decubitus ventilation and extracorporeal membrane oxygenation (ECMO). We present our experience with ECMO during pregnancy and review the literature on this topic. METHODS: We performed a systematic literature review using the MEDLINE-NIH database. Papers describing single cases or clinical series of pregnant women treated with veno-venous ECMO for ARDS were retrieved; the clinical features and maternal and infant outcomes were presented in aggregate form. RESULTS: We describe the case of a 32-year-old primigravida who received ECMO starting at the 28th gestation week due to A/H1N1 influenza-related ARDS. This strategy allowed saving both mother and child; normal recovery without sequelae was evident at one year. The systematic review included 29 reported cases of ECMO employment during pregnancy; A/H1N1 influenza was the etiology of ARDS in 79% of cases. Maternal and infant mortality may reach 28%, while the rate of complications during ECMO support reaches 57%. CONCLUSIONS: ECMO is a viable treatment for severe ARDS during pregnancy, after failure of other therapeutic strategies; the risk of spontaneous gynecological bleeding is limited. Issues remain about the timing of ECMO implantation and the management of gestation. Close fetal assessment and multidisciplinary discussion are pivotal for decision-making.

Diagnosis of Pneumocystis jirovecii pneumonia in immunocompromised patients by real-time PCR: a 4-year prospective study.

Pneumocystis jirovecii pneumonia (PCP) is a life-threatening infection in immunocompromised patients. Quantitative real-time PCR (qPCR) is more sensitive than microscopic examination for the detection of P. jirovecii but also detects colonized patients. Hence, its positive predictive value (PPV) needs evaluation. In this 4-year prospective observational study, all immunocompromised patients with acute respiratory symptoms who were investigated for PCP were included, totaling 659 patients (814 bronchoalveolar lavage fluid samples). Patients with negative microscopy but positive qPCR were classified through medical chart review as having retained PCP, possible PCP, or colonization, and their clinical outcomes were compared to those of patients with microscopically proven PCP. Overall, 119 patients were included for analysis, of whom 35, 41, and 43 were classified as having retained PCP, possible PCP, and colonization, respectively. The 35 patients with retained PCP had clinical findings similar to those with microscopically proven PCP but lower fungal loads (P < 0.001) and were mainly non-HIV-infected patients (P < 0.05). Although the mean amplification threshold was higher in colonized patients, it was not possible to determine a discriminant qPCR cutoff. The PPV of qPCR in patients with negative microscopy were 29.4% and 63.8% when considering retained PCP and retained plus possible PCP, respectively. Patients with possible PCP had a higher mortality rate than patients with retained PCP or colonization (63% versus 3% and 16%, respectively); patients who died had not received co-trimoxazole. In conclusion, qPCR is a useful tool to diagnose PCP in non-HIV patients, and treatment might be better targeted through a multicomponent algorithm including both clinical/radiological parameters and qPCR results.

Short-term decline in all-cause acquired infections with the routine use of a decontamination regimen combining topical polymyxin, tobramycin, and amphotericin B with mupirocin and chlorhexidine in the ICU: a single-center experience.

OBJECTIVES: In a multicenter, placebo-controlled, randomized, double-blind trial, we showed that acquired infections in intubated patients were reduced by the combination of topical polymyxin plus tobramycin and nasal mupirocin plus chlorhexidine body wash. Because intubated patients are particularly at risk for acquired infections, we reassessed the impact of this protocol as a routine procedure to control acquired infections in the ICU. DESIGN: Nonrandomized study comparing acquired infections in ICU patients during two 1-year periods: the last year before (group A, n = 925) and the first year after the implementation of the protocol (group B, n = 1,022). Acquired infections were prospectively recorded. SETTING: Polyvalent medical ICU at a university-affiliated hospital. PATIENTS: All patients admitted to the ICU. INTERVENTIONS: Administration of polymyxin/tobramycin/amphotericin B in the oropharynx and the gastric tube plus a mupirocin/chlorhexidine regimen in intubated patients and standard care in the other patients. MEASUREMENTS AND MAIN RESULTS: The comparison of acquired infection rates between groups was adjusted for differences at baseline. Infection rates were lower in group B compared with group A (5.3% vs 11.0%; p < 0.001), as were the incidence rates of total acquired infections (9.4 vs 23.6 per 1,000 patient-days; p < 0.001), intubation-related pneumonia (5.1 vs 17.1 per 1,000 ventilator-days; p < 0.001), and catheter-related bloodstream infections (1.0 vs 3.5 per 1,000 catheter-days; p = 0.03). There were fewer acquired infections caused by ceftazidime-resistant Enterobacteriaceae (0.8‰ vs 3.6‰; p < 0.001), ciprofloxacin-resistant Enterobacteriaceae (0.8‰ vs 2.5‰; p = 0.02), ciprofloxacin-resistant Pseudomonas aeruginosa (0.5‰ vs 1.6‰; p = 0.05), and colistin-resistant Gram-negative bacilli (0.7‰ vs 1.9‰; p = 0.04). Fewer patients got acquired infections due to multidrug-resistant aerobic Gram-negative bacilli (p = 0.008). CONCLUSIONS: In intubated patients, the use of topical polymyxin/tobramycin/amphotericin B plus mupirocin/chlorhexidine was associated with the reduction of all-cause ICU-acquired infections. Long-term emergence of multidrug-resistant organisms deserves further investigation.

At-risk drinking is independently associated with ICU and one-year mortality in critically ill nontrauma patients*.

OBJECTIVES: The impact of at-risk drinking on the outcomes of nontrauma patients is not well characterized. The aim of this study was to determine whether at-risk drinking is independently associated with the survival of nontrauma patients in an ICU and within 1 year following ICU discharge. DESIGN: Observational cohort study. SETTING: A 21-bed mixed ICU in a university hospital. PATIENTS: A total of 662 patients who experienced an ICU stay of 3 days or more and for whom alcohol consumption could be assessed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: ICU-related variables were collected prospectively, and a 1-year follow-up was determined retrospectively. Analyses were adjusted based on prognostic determinants of short- and long-term outcomes, as previously described in ICU patients and alcohol abusers. Two hundred and eight patients (33%) were identified as at-risk drinkers according to the National Institute on Alcohol Abuse and Alcoholism criteria. Additionally, 111 patients (17%) died in the ICU, and 97 (15%) died after ICU discharge. From the ICU admission until the end of the 1-year follow-up period, the at-risk drinkers exhibited poorer survival than the non-at-risk drinkers (p = 0.0004, as determined by the log-rank test). More specifically, 50 at-risk drinkers (24%) versus 61 non-at-risk drinkers (13%) died in the ICU (p = 0.0009 for the comparison). After adjustment, at-risk drinking remained independently associated with mortality in the ICU (adjusted odds ratio of 1.83; 95% CI of 1.16-2.89; p = 0.01) and with mortality within the year following ICU discharge (adjusted hazard ratio of 1.70; 95% CI of 1.15-2.52; p = 0.008). The causes of death in the at-risk and non-at-risk drinkers were similar. CONCLUSIONS: In this population of critically ill nontrauma patients, at-risk drinking was independently associated with death in the ICU and within the year following ICU discharge.

Can we predict poor hemodynamic tolerance of intermittent hemodialysis with echocardiography in intensive care patients?

OBJECTIVES: Tolerance of intermittent hemodialysis is potentially poor for patients hospitalized in the intensive care unit, particularly those in shock. The aim of this study was to determine whether an evaluation of the hemodynamic state by echocardiography before an intermittent hemodialysis session could predict tolerance during the session. METHODS: Before an intermittent hemodialysis session, transesophageal echocardiography was performed on sedated patients, and transthoracic echocardiography was performed on nonsedated patients. Poor tolerance during intermittent hemodialysis was defined by the following criteria: greater than 20% decrease in mean arterial pressure, need for fluid loading (≥500 mL), a 15% increase in catecholamine if the dose was stable before the session or doubling the speed of catecholamine infusion if necessary, arrhythmia, and the necessity to stop the session before its prescribed end. RESULTS: A total of 54 patients were included: 20 (37%) were intubated under controlled mechanical ventilation (group 1) and underwent transesophageal echocardiography; 14 (26%) were intubated under pressure support ventilation (group 2) and underwent transthoracic echocardiography; and 20 (37%) had no ventilation support (group 3). Twenty-four patients (46%) had poor tolerance criteria. A comparison of groups showed no significant difference in tolerance. Similarly, there was no difference with and without ultrafiltration. Increased respiratory variation of the vena cava was not predictive of poor tolerance in groups 1 and 2. In group 3, there was greater variation in patients with poor tolerance. In patients receiving mechanical ventilation, greater respiratory variability of the maximum velocity measured in the pulmonary artery was predictive of poor tolerance. CONCLUSIONS: The hemodynamic profile of patients receiving mechanical ventilation was unable to predict tolerance of an intermittent hemodialysis session. In patients without mechanical ventilation, hypovolemia before the session appeared to be predictive of poor tolerance.

Induced hypothermia in severe bacterial meningitis: a randomized clinical trial.

IMPORTANCE: Despite advances in care, mortality and morbidity remain high in adults with acute bacterial meningitis, particularly when due to Streptococcus pneumoniae. Induced hypothermia is beneficial in other conditions with global cerebral hypoxia. OBJECTIVE: To test the hypothesis that induced hypothermia improves outcome in patients with severe bacterial meningitis. DESIGN, SETTING, AND PATIENTS: An open-label, multicenter, randomized clinical trial in 49 intensive care units in France, February 2009-November 2011. In total, 130 patients were assessed for eligibility and 98 comatose adults (Glasgow Coma Scale [GCS] score of ≤8 for <12 hours) with community-acquired bacterial meningitis were randomized. INTERVENTIONS: Hypothermia group received a loading dose of 4°C cold saline and were cooled to 32°C to 34°C for 48 hours. The rewarming phase was passive. Controls received standard care. MAIN OUTCOMES AND MEASURES: Primary outcome measure was the Glasgow Outcome Scale score at 3 months (a score of 5 [favorable outcome] vs a score of 1-4 [unfavorable outcome]). All patients received appropriate antimicrobial therapy and vital support. Analyses were performed on an intention-to-treat basis. The data and safety monitoring board (DSMB) reviewed severe adverse events and mortality rate every 50 enrolled patients. RESULTS: After inclusion of 98 comatose patients, the trial was stopped early at the request of the DSMB because of concerns over excess mortality in the hypothermia group (25 of 49 patients [51%]) vs the control group (15 of 49 patients [31%]; relative risk [RR], 1.99; 95% CI, 1.05-3.77; P = .04). Pneumococcal meningitis was diagnosed in 77% of patients. Mean (SD) temperatures achieved 24 hours after randomization were 33.3°C (0.9°C) and 37.0°C (0.9°C) in the hypothermia and control group, respectively. At 3 months, 86% in the hypothermia group compared with 74% of controls had an unfavorable outcome (RR, 2.17; 95% CI, 0.78-6.01; P = .13). After adjustment for age, score on GCS at inclusion, and the presence of septic shock at inclusion, mortality remained higher, although not significantly, in the hypothermia group (hazard ratio, 1.76; 95% CI, 0.89-3.45; P = .10). Subgroup analysis on patients with pneumococcal meningitis showed similar results. Post hoc analysis showed a low probability to reach statistically significant difference in favor of hypothermia at the end of the 3 planned sequential analyses (probability to conclude in favor of futility, 0.977). CONCLUSIONS AND RELEVANCE: Moderate hypothermia did not improve outcome in patients with severe bacterial meningitis and may even be harmful. Careful evaluation of safety issues in future trials on hypothermia are needed and may have important implications in patients presenting with septic shock or stroke. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00774631.

Cardiac output monitoring in septic shock: evaluation of the third-generation Flotrac-Vigileo.

Continuous cardiac index (CI) monitoring is frequently used in critically ill patients. Few studies have compared the pulse contour-based device FloTrac/Vigileo to pulmonary artery thermodilution (PAC) in terms of accuracy for CI monitoring in septic shock. The aim of our study was to compare the third-generation FloTrac/Vigileo to PAC in septic shock. Eighteen patients with septic shock requiring monitoring by PAC were included in this study. We monitored CI using both FloTrac/Vigileo and continuous thermodilution (PAC-CI). Hemodynamic data were recorded every hour or every 2 min during fluid challenges. The primary endpoint was the global agreement of all CI-paired measurements determined using the Bland-Altman method adapted to replicated data. We tested the linearity of the bias by regression analysis, and compared the reactivity of the 2 techniques during fluid challenges. A receiver operating characteristic (ROC) curve analysis tested the ability of FloTrac/Vigileo to detect concordant and significative CI changes, using PAC-CI as the reference method. Overall, 1,201 paired CI measurements were recorded. The Bland-Altman analysis for global agreement of the 2 techniques showed a bias of -0.1 ± 2.1 L min(-1) m(-2) and a percentage error of 64 %. The overall correlation coefficient between PAC-CI and FloTrac/Vigileo CI was 0.47 (p < 0.01), with r(2) = 0.22. The area under the curve of the ROC curve for detecting concordant and significant changes in CI was 0.72 (0.53; 0.87). In our study, third-generation Flowtrac-Vigileo appears to be too inaccurate to be recommended for CI monitoring in septic shock.