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.

Invasive group A streptococcal infections requiring admission to ICU: a nationwide, multicenter, retrospective study (ISTRE study).

BACKGROUND: Group A Streptococcus is responsible for severe and potentially lethal invasive conditions requiring intensive care unit (ICU) admission, such as streptococcal toxic shock-like syndrome (STSS). A rebound of invasive group A streptococcal (iGAS) infection after COVID-19-associated barrier measures has been observed in children. Several intensivists of French adult ICUs have reported similar bedside impressions without objective data. We aimed to compare the incidence of iGAS infection before and after the COVID-19 pandemic, describe iGAS patients' characteristics, and determine ICU mortality associated factors. METHODS: We performed a retrospective multicenter cohort study in 37 French ICUs, including all patients admitted for iGAS infections for two periods: two years before period (October 2018 to March 2019 and October 2019 to March 2020) and a one-year after period (October 2022 to March 2023) COVID-19 pandemic. iGAS infection was defined by Group A Streptococcus isolation from a normally sterile site. iGAS infections were identified using the International Classification of Diseases and confirmed with each center's microbiology laboratory databases. The incidence of iGAS infections was expressed in case rate. RESULTS: Two hundred and twenty-two patients were admitted to ICU for iGAS infections: 73 before and 149 after COVID-19 pandemic. Their case rate during the period before and after COVID-19 pandemic was 205 and 949/100,000 ICU admissions, respectively (p < 0.001), with more frequent STSS after the COVID-19 pandemic (61% vs. 45%, p = 0.015). iGAS patients (n = 222) had a median SOFA score of 8 (5-13), invasive mechanical ventilation and norepinephrine in 61% and 74% of patients. ICU mortality in iGAS patients was 19% (14% before and 22% after COVID-19 pandemic; p = 0.135). In multivariate analysis, invasive mechanical ventilation (OR = 6.08 (1.71-21.60), p = 0.005), STSS (OR = 5.75 (1.71-19.22), p = 0.005), acute kidney injury (OR = 4.85 (1.05-22.42), p = 0.043), immunosuppression (OR = 4.02 (1.03-15.59), p = 0.044), and diabetes (OR = 3.92 (1.42-10.79), p = 0.008) were significantly associated with ICU mortality. CONCLUSION: The incidence of iGAS infections requiring ICU admission increased by 4 to 5 after the COVID-19 pandemic. After the COVID-19 pandemic, the rate of STSS was higher, with no significant increase in ICU mortality rate.

[Visibility of patients and respect for their privacy: reconciling apparently contrary imperatives in the intensive care unit]. / Visibilité des patients et respect de leur intimité : concilier des impératifs apparemment contraires en service de réanimation.

Rigorous monitoring of vital functions in intensive care requires optimal visibility of patients and their environment. Conversely, respect for privacy is an ethical imperative to respect. Liquid crystal electrical film is a device that can be applied to windows and can take opaque or transparent form on demand. Its use could satisfy the visibility of patients and respect for their privacy.

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.

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.

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.

Hydrocortisone plus Fludrocortisone for Adults with Septic Shock.

BACKGROUND: Septic shock is characterized by dysregulation of the host response to infection, with circulatory, cellular, and metabolic abnormalities. We hypothesized that therapy with hydrocortisone plus fludrocortisone or with drotrecogin alfa (activated), which can modulate the host response, would improve the clinical outcomes of patients with septic shock. METHODS: In this multicenter, double-blind, randomized trial with a 2-by-2 factorial design, we evaluated the effect of hydrocortisone-plus-fludrocortisone therapy, drotrecogin alfa (activated), the combination of the three drugs, or their respective placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included mortality at intensive care unit (ICU) discharge and hospital discharge and at day 28 and day 180 and the number of days alive and free of vasopressors, mechanical ventilation, or organ failure. After drotrecogin alfa (activated) was withdrawn from the market, the trial continued with a two-group parallel design. The analysis compared patients who received hydrocortisone plus fludrocortisone with those who did not (placebo group). RESULTS: Among the 1241 patients included in the trial, the 90-day mortality was 43.0% (264 of 614 patients) in the hydrocortisone-plus-fludrocortisone group and 49.1% (308 of 627 patients) in the placebo group (P=0.03). The relative risk of death in the hydrocortisone-plus-fludrocortisone group was 0.88 (95% confidence interval, 0.78 to 0.99). Mortality was significantly lower in the hydrocortisone-plus-fludrocortisone group than in the placebo group at ICU discharge (35.4% vs. 41.0%, P=0.04), hospital discharge (39.0% vs. 45.3%, P=0.02), and day 180 (46.6% vs. 52.5%, P=0.04) but not at day 28 (33.7% and 38.9%, respectively; P=0.06). The number of vasopressor-free days to day 28 was significantly higher in the hydrocortisone-plus-fludrocortisone group than in the placebo group (17 vs. 15 days, P<0.001), as was the number of organ-failure-free days (14 vs. 12 days, P=0.003). The number of ventilator-free days was similar in the two groups (11 days in the hydrocortisone-plus-fludrocortisone group and 10 in the placebo group, P=0.07). The rate of serious adverse events did not differ significantly between the two groups, but hyperglycemia was more common in hydrocortisone-plus-fludrocortisone group. CONCLUSIONS: In this trial involving patients with septic shock, 90-day all-cause mortality was lower among those who received hydrocortisone plus fludrocortisone than among those who received placebo. (Funded by Programme Hospitalier de Recherche Clinique 2007 of the French Ministry of Social Affairs and Health; APROCCHSS ClinicalTrials.gov number, NCT00625209 .).

Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis.

BACKGROUND: Acute kidney injury is the most frequent complication in patients with septic shock and is an independent risk factor for death. Although renal-replacement therapy is the standard of care for severe acute kidney injury, the ideal time for initiation remains controversial. METHODS: In a multicenter, randomized, controlled trial, we assigned patients with early-stage septic shock who had severe acute kidney injury at the failure stage of the risk, injury, failure, loss, and end-stage kidney disease (RIFLE) classification system but without life-threatening complications related to acute kidney injury to receive renal-replacement therapy either within 12 hours after documentation of failure-stage acute kidney injury (early strategy) or after a delay of 48 hours if renal recovery had not occurred (delayed strategy). The failure stage of the RIFLE classification system is characterized by a serum creatinine level 3 times the baseline level (or ≥4 mg per deciliter with a rapid increase of ≥0.5 mg per deciliter), urine output less than 0.3 ml per kilogram of body weight per hour for 24 hours or longer, or anuria for at least 12 hours. The primary outcome was death at 90 days. RESULTS: The trial was stopped early for futility after the second planned interim analysis. A total of 488 patients underwent randomization; there were no significant between-group differences in the characteristics at baseline. Among the 477 patients for whom follow-up data at 90 days were available, 58% of the patients in the early-strategy group (138 of 239 patients) and 54% in the delayed-strategy group (128 of 238 patients) had died (P=0.38). In the delayed-strategy group, 38% (93 patients) did not receive renal-replacement therapy. Criteria for emergency renal-replacement therapy were met in 17% of the patients in the delayed-strategy group (41 patients). CONCLUSIONS: Among patients with septic shock who had severe acute kidney injury, there was no significant difference in overall mortality at 90 days between patients who were assigned to an early strategy for the initiation of renal-replacement therapy and those who were assigned to a delayed strategy. (Funded by the French Ministry of Health; IDEAL-ICU ClinicalTrials.gov number, NCT01682590 .).

Association Between Anxiety and New Organ Failure, Independently of Critical Illness Severity and Respiratory Status: A Prospective Multicentric Cohort Study.

OBJECTIVES: Anxiety results from the anticipation of a threat and might be associated with poor outcome in the critically ill. This study aims at showing that anxiety at admission in critically ill patients is associated with new organ failure over the first 7 days of ICU hospitalization independently of baseline organ failure at admission. DESIGN: Prospective multicenter cohort study. SETTING: Three mixed ICU from April 2014 to December 2017. PATIENTS: Coma-, delirium-, and invasive mechanical ventilation-free patients admitted to the ICU were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: "State anxiety" was assessed using the state component of the State-Trait Anxiety Inventory State. Severity of illness was measured using Simplified Acute Physiology Score II and Sequential Organ Failure Assessment scores. Primary endpoint was a composite of occurrence of death or new organ failure in the first 7 days after admission. Three hundred ninety-one patients were included; 159 of 391 women (40.7%); median age 63 years (49-74 yr); median Simplified Acute Physiology Score II 28 (19-37). Two hundred three out of 391 patients (51.9%) reported moderate to severe anxiety (State-Trait Anxiety Inventory State ≥ 40). One hundred two out of 391 patients (26.1%) developed a new organ failure. After adjustment to Simplified Acute Physiology Score II and Sequential Organ Failure Assessment, State-Trait Anxiety Inventory State greater than or equal to 40 was associated with the primary endpoint (odds ratio, 1.94; 95% CI, 1.18-3.18; p = 0.009) and respiratory failure. In post hoc analysis, State-Trait Anxiety Inventory State greater than or equal to 40 was associated with new organ failure independently and notably of respiratory status at admission (dyspnea-Visual Analogic Scale and PaCO2 ≥ 45 mm Hg). CONCLUSIONS: Moderate to severe anxiety at ICU admission is associated with early occurrence of new organ failure in critically ill patients, independently of respiratory status and severity of critical illness. The causality link could be addressed in an interventional trial.

A Comparison of the Mortality Risk Associated With Ventilator-Acquired Bacterial Pneumonia and Nonventilator ICU-Acquired Bacterial Pneumonia.

OBJECTIVES: To investigate the respective impact of ventilator-associated pneumonia and ICU-hospital-acquired pneumonia on the 30-day mortality of ICU patients. DESIGN: Longitudinal prospective studies. SETTING: French ICUs. PATIENTS: Patients at risk of ventilator-associated pneumonia and ICU-hospital-acquired pneumonia. INTERVENTIONS: The first three episodes of ventilator-associated pneumonia or ICU-hospital-acquired pneumonia were handled as time-dependent covariates in Cox models. We adjusted using the case-mix, illness severity, Simplified Acute Physiology Score II score at admission, and procedures and therapeutics used during the first 48 hours before the risk period. Baseline characteristics of patients with regard to the adequacy of antibiotic treatment were analyzed, as well as the Sequential Organ Failure Assessment score variation in the 2 days before the occurrence of ventilator-associated pneumonia or ICU-hospital-acquired pneumonia. Mortality was also analyzed for Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species(ESKAPE) and P. aeruginosa pathogens. MEASUREMENTS AND MAIN RESULTS: Of 14,212 patients who were admitted to the ICUs and who stayed for more than 48 hours, 7,735 were at risk of ventilator-associated pneumonia and 9,747 were at risk of ICU-hospital-acquired pneumonia. Ventilator-associated pneumonia and ICU-hospital-acquired pneumonia occurred in 1,161 at-risk patients (15%) and 176 at-risk patients (2%), respectively. When adjusted on prognostic variables, ventilator-associated pneumonia (hazard ratio, 1.38 (1.24-1.52); p < 0.0001) and even more ICU-hospital-acquired pneumonia (hazard ratio, 1.82 [1.35-2.45]; p < 0.0001) were associated with increased 30-day mortality. The early antibiotic therapy adequacy was not associated with an improved prognosis, particularly for ICU-hospital-acquired pneumonia. The impact was similar for ventilator-associated pneumonia and ICU-hospital-acquired pneumonia mortality due to P. aeruginosa and the ESKAPE group. CONCLUSIONS: In a large cohort of patients, we found that both ICU-hospital-acquired pneumonia and ventilator-associated pneumonia were associated with an 82% and a 38% increase in the risk of 30-day mortality, respectively. This study emphasized the importance of preventing ICU-hospital-acquired pneumonia in nonventilated patients.

Influence of dyskalemia at admission and early dyskalemia correction on survival and cardiac events of critically ill patients.

OBJECTIVES: Our objectives were (1) to characterize the distribution of serum potassium levels at ICU admission, (2) to examine the relationship between dyskalemia at ICU admission and occurrence of cardiac events, and (3) to study both the association between dyskalemia at ICU admission and dyskalemia correction by day 2 on 28-day mortality. DESIGN: Inception cohort study from the longitudinal prospective French multicenter OUTCOMEREA database (1999-2014) SETTING: 22 French OUTCOMEREA network ICUs PATIENTS: Patients were classified into six groups according to their serum potassium level at admission: three groups of hypokalemia and three groups of hyperkalemia defined as serious hypokalemia [K+] < 2.5 and serious hyperkalemia [K+] > 7 mmol/L, moderate hypokalemia 2.5 ≤ [K+] < 3 mmol/L and moderate hyperkalemia 6 < [K+] ≤ 7 mmol/L, and mild hypokalemia 3 ≤ [K+] < 3.5 mmol/L and mild hyperkalemia 5 < [K+] ≤ 6 mmol/L. We sorted evolution at day 2 of dyskalemia into three categories: balanced, not-balanced, and overbalanced. INTERVENTION: None MEASUREMENTS AND MAIN RESULTS: Of 12,090 patients, 2108 (17.4%) had hypokalemia and 1445 (12%) had hyperkalemia. Prognostic impact of dyskalemia and its correction was assessed using multivariate Cox models. After adjustment, hypokalemia and hyperkalemia were independently associated with a greater risk of 28-day mortality. Mild hyperkalemic patients had the highest mortality (hazard ratio (HR) 1.29, 95% confidence interval (CI) [1.13-1.47], p < 0.001). Adjusted 28-day mortality was higher if serum potassium level was not-balanced at day 2 (aHR = 1.51, 95% CI [1.30-1.76], p < 0.0001) and numerically higher but not significantly different if serum potassium level was overbalanced at day 2 (aHR = 1.157, 95% CI [0.84-1.60], p = 0.38). Occurrence of cardiac events was evaluated by logistic regression. Except for patients with serious hypokalemia at admission, the depth of dyskalemia was associated with increased risk of cardiac events. CONCLUSIONS: Dyskalemia is common at ICU admission and associated with increased mortality. Occurrence of cardiac events increased with dyskalemia depth. A correction of serum potassium level by day 2 was associated with improved prognosis.

Association Between Body Weight Variation and Survival and Other Adverse Events in Critically Ill Patients With Shock: A Multicenter Cohort Study of the OUTCOMEREA Network.

OBJECTIVES: This study in critically ill patients with shock assessed the prognostic value of body weight variations occurring each day from day 3 to day 7 on the 30-day outcome in terms of mortality, occurrence of ventilator-associated pneumonia and of bedsore, and occurrence of length of stay. DESIGN: Retrospective analysis of data. Multivariate subdistribution survival models were used at each day, from day 3 to day 7. The impact of body weight variations on length of stay was estimated through a multivariate negative binomial regression model. SETTING: Prospective multicenter cohort study. PATIENTS: Critically ill patients admitted in ICU with shock and requiring mechanical ventilation within 48 hours. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Two-thousand three-hundred seventy-four patients were included. Their median body weight variations increased from 0.4 kg (interquartile range, 0-4.8 kg) on day 3 to 3 kg (interquartile range, -0.4 to 8.2 kg) on day 7. Categories of body weight variations were defined depending on body weight variations interquartiles: weight loss, no weight gain, moderate and severe weight gain. A severe weight gain tended to be associated with death at days 5 and 6 (day 5: subdistribution hazard ratio, 1.27; 95% CI, 0.99-1.63; p = 0.06 and day 6: subdistribution hazard ratio, 1.43; 95% CI, 1.08-1.89; p = 0.01), a weight loss tended to be associated with bedsore, and a severe gain between at days 5 and 6 was associated with ventilator-associated pneumonia. Any body weight variations were associated with an increased length of stay. CONCLUSIONS: In survivors at day 3, body weight variations during the first days of ICU stay might be a clinically relevant tool to prevent weight gain but also for prognostication of 30-day mortality, occurrence of ventilator-associated pneumonia, and occurrence of prolonged ICU stay.

Effects of Peritoneal Sepsis on Rat Central Osmoregulatory Neurons Mediating Thirst and Vasopressin Release.

Sepsis is a life-threatening condition caused by the systemic inflammatory response to a bacterial infection. Although much is known about the cellular and molecular changes that characterize the peripheral inflammatory response to sepsis, almost nothing is known of the neuronal changes that cause associated perturbations in the central control of homeostasis. Osmoregulation is one of the key homeostatic systems perturbed during sepsis. In healthy subjects, systemic hypertonicity normally excites osmoreceptor neurons in the organum vasculosum laminae terminalis (OVLT), which then activates downstream neurons that induce a parallel increase in water intake and arginine vasopressin (AVP) secretion to promote fluid expansion and maintain blood pressure. However, recent studies have shown that the early phase of sepsis is associated with increased AVP levels and suppressed thirst. Here we examined the electrophysiological properties of OVLT neurons and magnocellular neurosecretory cells (MNCs) in acute in vitro preparations obtained from rats subjected to sham surgery or cecal ligation and puncture (CLP). We found that the intrinsic excitability of OVLT neurons was not affected significantly 18-24 h after CLP. However, OVLT neurons in CLP rats were hyperpolarized significantly compared with shams. Moreover, a reduced proportion of these cells displayed spontaneous electrical activity and osmoresponsiveness in septic animals. In contrast, the osmoresponsiveness of MNCs was only attenuated by CLP, and a larger proportion of these neurons displayed spontaneous electrical activity in septic animals. These results suggest that acute sepsis disrupts centrally mediated osmoregulatory reflexes through differential effects on the properties of neurons in the OVLT and supraoptic nucleus. SIGNIFICANCE STATEMENT: Sepsis is a life-threatening condition caused by the systemic inflammatory response to bacterial infection. Although the early phase of sepsis features impaired thirst and enhanced vasopressin release, the basis for these defects is unknown. Here, we show that cecal ligation and puncture (CLP) in rats impairs the osmoresponsiveness of neurons in the organum vasculosum lamina terminalis (OVLT; which drives thirst) and attenuates that of neurosecretory neurons in the supraoptic nucleus (SON; which secrete oxytocin and vasopressin). Notably, we found that OVLT neurons are hyperpolarized and electrically silenced. In contrast, CLP increased the proportion of SON neurons displaying spontaneous electrical activity. Therefore, CLP affects the properties of osmoregulatory neurons in a manner that can affect systemic osmoregulation.

Recombinant human activated protein C for adults with septic shock: a randomized controlled trial.

RATIONALE: A decade after drotrecogin alfa (activated) (DAA) was released on the market worldwide, its benefit-to-risk ratio remains a matter of debate. OBJECTIVES: The current investigator-led trial was designed to evaluate the efficacy and safety of DAA, in combination with low-dose steroids, in adults with persistent septic shock. METHODS: This was a multicenter (24 intensive care units), placebo-controlled, double-blind, 2 × 2 factorial design trial in which adults with persistent septic shock and no contraindication to DAA were randomly assigned to DAA alone (24 µg/kg/h for 96 h), hydrocortisone and fludrocortisone alone, their respective combinations, or their respective placebos. Primary outcome was mortality rate on Day 90. MEASUREMENTS AND MAIN RESULTS: On October 25, 2011, the trial was suspended after the withdrawal from the market of DAA. The Scientific Committee decided to continue the trial according to a two parallel group design comparing low-dose steroids with their placebos and to analyze the effects of DAA on patients included before trial suspension. At the time trial was suspended, 411 patients had been recruited, 208 had received DAA, and 203 had received its placebo. There was no significant interaction between DAA and low-dose steroids (P = 0.47). On Day 90, there were 99 deaths (47.6%) among the 208 patients receiving DAA and 94 deaths (46.3%) among the 203 patients receiving placebo (P = 0.79). There was no evidence of a difference between DAA and its placebo for any secondary outcomes or serious adverse events. CONCLUSIONS: In adults with established and severe septic shock, DAA showed no evidence of benefit or harm. Clinical trial registered with www.clinicaltrials.gov (NCT00625209).

Association of Lack of Fear of Dying With New Organ Failure: Results of a Multicenter Prospective Cohort Study.

BACKGROUND: Patients' anxiety on intensive care unit (ICU) admission is associated with subsequent deterioration. OBJECTIVE: To assess whether patients' fears/anxiety are predictive of new organ failure within 7 days of ICU admission. METHODS: In a prospective 3-center cohort study of non-comatose patients without delirium or invasive mechanical ventilation, 9 specific fears were evaluated through yes/no questions. Illness severity was assessed using the Simplified Acute Physiology Score II (SAPS II) and the Sequential Organ Failure Assessment (SOFA). Intensity of acute and chronic anxiety was assessed with the state and trait components of the State-Trait Anxiety Inventory (STAI). Patients were followed up for 7 days. RESULTS: From April 2014 to December 2017, 373 patients (median [IQR] age, 63 [48-74] years; 152 [40.8%] women; median (IQR) SAPS II, 27 [19-37]) were included. Feelings of vulnerability and fear of dying were reported by 203 (54.4%) and 172 (46.1%) patients, respectively. The STAI-State score was 40 or greater in 192 patients (51.5%). Ninety-four patients (25.2%) had new organ failure. Feelings of vulnerability (odds ratio, 1.96 [95% CI, 1.12-3.43]; P=.02) and absence of fear of dying (odds ratio, 2.38 [95% CI, 1.37-4.17]; P=.002) were associated with new organ failure after adjustment for STAI-State score (≥40), SAPS II, and SOFA score. CONCLUSION: Absence of fear of dying is associated with new organ failure within the first 7 days after ICU admission. Fear of dying may protect against subsequent deterioration by mobilizing patients' homeostatic resources. ClinicalTrials.gov Identifier: NCT02355626.

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.

A randomized clinical trial to evaluate the effect of post-intensive care multidisciplinary consultations on mortality and the quality of life at 1 year.

PURPOSE: Critical illness is associated with long-term increased mortality and impaired quality of life (QoL). We assessed whether multidisciplinary consultations would improve outcome at 12 months (M12) after intensive care unit (ICU) discharge. METHODS: We performed an open, multicenter, parallel-group, randomized clinical trial. Eligible are patients discharged alive from ICU in 11 French hospitals between 2012 and 2018. The intervention group had a multidisciplinary face-to-face consultation involving an intensivist, a psychologist, and a social worker at ICU discharge and then at M3 and M6 (optional). The control group had standard post-ICU follow-up. A consultation was scheduled at M12 for all patients. The QoL was assessed using the EuroQol-5 Dimensions-5 Level (Euro-QoL-5D-5L) which includes five dimensions (mobility, self-care, usual activities, pain, and anxiety/depression), each ranging from 1 to 5 (1: no, 2: slight, 3: moderate, 4: severe, and 5: extreme problems). The primary endpoint was poor clinical outcome defined as death or severe-to-extreme impairment of at least one EuroQoL-5D-5L dimension at M12. The information was collected by a blinded investigator by phone. Secondary outcomes were functional, psychological, and cognitive status at M12 consultation. RESULTS: 540 patients were included (standard, n = 272; multidisciplinary, n = 268). The risk for a poor outcome was significantly greater in the multidisciplinary group than in the standard group [adjusted odds ratio 1.49 (95% confidence interval, (1.04-2.13)]. Seventy-two (13.3%) patients died at M12 (standard, n = 32; multidisciplinary, n = 40). The functional, psychological, and cognitive scores at M12 did not statistically differ between groups. CONCLUSIONS: A hospital-based, face-to-face, intensivist-led multidisciplinary consultation at ICU discharge then at 3 and 6 months was associated with poor outcome 1 year after ICU.

Hydrocortisone plus fludrocortisone for community acquired pneumonia-related septic shock: a subgroup analysis of the APROCCHSS phase 3 randomised trial.

BACKGROUND: Glucocorticoids probably improve outcomes in patients hospitalised for community acquired pneumonia (CAP). In this a priori planned exploratory subgroup analysis of the phase 3 randomised controlled Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial, we aimed to investigate responses to hydrocortisone plus fludrocortisone between CAP and non-CAP related septic shock. METHODS: APROCCHSS was a randomised controlled trial that investigated the effects of hydrocortisone plus fludrocortisone, drotrecogin-alfa (activated), or both on mortality in septic shock in a two-by-two factorial design; after drotrecogin-alfa was withdrawn on October 2011, from the market, the trial continued on two parallel groups. It was conducted in 34 centres in France. In this subgroup study, patients with CAP were a preselected subgroup for an exploratory secondary analysis of the APROCCHSS trial of hydrocortisone plus fludrocortisone in septic shock. Adults with septic shock were randomised 1:1 to receive, in a double-blind manner, a 7-day treatment with daily administration of intravenous hydrocortisone 50 mg bolus every 6h and a tablet of 50 µg of fludrocortisone via the nasogastric tube, or their placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included all-cause mortality at intensive care unit (ICU) and hospital discharge, 28-day and 180-day mortality, the number of days alive and free of vasopressors, mechanical ventilation, or organ failure, and ICU and hospital free-days to 90-days. Analysis was done in the intention-to-treat population. The trial was registered at ClinicalTrials.gov (NCT00625209). FINDINGS: Of 1241 patients included in the APROCCHSS trial, CAP could not be ruled in or out in 31 patients, 562 had a diagnosis of CAP (279 in the placebo group and 283 in the corticosteroid group), and 648 patients did not have CAP (329 in the placebo group and 319 in the corticosteroid group). In patients with CAP, there were 109 (39%) deaths of 283 patients at day 90 with hydrocortisone plus fludrocortisone and 143 (51%) of 279 patients receiving placebo (odds ratio [OR] 0·60, 95% CI 0·43-0·83). In patients without CAP, there were 148 (46%) deaths of 319 patients at day 90 in the hydrocortisone and fludrocortisone group and 157 (48%) of 329 patients in the placebo group (OR 0·95, 95% CI 0·70-1·29). There was significant heterogeneity in corticosteroid effects on 90-day mortality across subgroups with CAP and without CAP (p=0·046 for both multiplicative and additive interaction tests; moderate credibility). Of 1241 patients included in the APROCCHSS trial, 648 (52%) had ARDS (328 in the placebo group and 320 in the corticosteroid group). There were 155 (48%) deaths of 320 patients at day 90 in the corticosteroid group and 186 (57%) of 328 patients in the placebo group. The OR for death at day 90 was 0·72 (95% CI 0·53-0·98) in patients with ARDS and 0·85 (0·61-1·20) in patients without ARDS (p=0·45 for multiplicative interaction and p=0·42 for additive interaction). The OR for observing at least one serious adverse event (corticosteroid group vs placebo) within 180 days post randomisation was 0·64 (95% CI 0·46-0·89) in the CAP subgroup and 1·02 (0·75-1·39) in the non-CAP subgroup (p=0·044 for multiplicative interaction and p=0·042 for additive interaction). INTERPRETATION: In a pre-specified subgroup analysis of the APROCCHSS trial of patients with CAP and septic shock, hydrocortisone plus fludrocortisone reduced mortality as compared with placebo. Although a large proportion of patients with CAP also met criteria for ARDS, the subgroup analysis was underpowered to fully discriminate between ARDS and CAP modifying effects on mortality reduction with corticosteroids. There was no evidence of a significant treatment effect of corticosteroids in the non-CAP subgroup. FUNDING: Programme Hospitalier de Recherche Clinique of the French Ministry of Health, by Programme d'Investissements d'Avenir, France 2030, and IAHU-ANR-0004.

Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial.

IMPORTANCE: Evidence supporting the choice of intravenous colloid vs crystalloid solutions for management of hypovolemic shock remains unclear. OBJECTIVE: To test whether use of colloids compared with crystalloids for fluid resuscitation alters mortality in patients admitted to the intensive care unit (ICU) with hypovolemic shock. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, randomized clinical trial stratified by case mix (sepsis, trauma, or hypovolemic shock without sepsis or trauma). Therapy in the Colloids Versus Crystalloids for the Resuscitation of the Critically Ill (CRISTAL) trial was open label but outcome assessment was blinded to treatment assignment. Recruitment began in February 2003 and ended in August 2012 of 2857 sequential ICU patients treated at 57 ICUs in France, Belgium, North Africa, and Canada; follow-up ended in November 2012. INTERVENTIONS: Colloids (n = 1414; gelatins, dextrans, hydroxyethyl starches, or 4% or 20% of albumin) or crystalloids (n = 1443; isotonic or hypertonic saline or Ringer lactate solution) for all fluid interventions other than fluid maintenance throughout the ICU stay. MAIN OUTCOMES AND MEASURES: The primary outcome was death within 28 days. Secondary outcomes included 90-day mortality; and days alive and not receiving renal replacement therapy, mechanical ventilation, or vasopressor therapy. RESULTS: Within 28 days, there were 359 deaths (25.4%) in colloids group vs 390 deaths (27.0%) in crystalloids group (relative risk [RR], 0.96 [95% CI, 0.88 to 1.04]; P = .26). Within 90 days, there were 434 deaths (30.7%) in colloids group vs 493 deaths (34.2%) in crystalloids group (RR, 0.92 [95% CI, 0.86 to 0.99]; P = .03). Renal replacement therapy was used in 156 (11.0%) in colloids group vs 181 (12.5%) in crystalloids group (RR, 0.93 [95% CI, 0.83 to 1.03]; P = .19). There were more days alive without mechanical ventilation in the colloids group vs the crystalloids group by 7 days (mean: 2.1 vs 1.8 days, respectively; mean difference, 0.30 [95% CI, 0.09 to 0.48] days; P = .01) and by 28 days (mean: 14.6 vs 13.5 days; mean difference, 1.10 [95% CI, 0.14 to 2.06] days; P = .01) and alive without vasopressor therapy by 7 days (mean: 5.0 vs 4.7 days; mean difference, 0.30 [95% CI, -0.03 to 0.50] days; P = .04) and by 28 days (mean: 16.2 vs 15.2 days; mean difference, 1.04 [95% CI, -0.04 to 2.10] days; P = .03). CONCLUSIONS AND RELEVANCE: Among ICU patients with hypovolemia, the use of colloids vs crystalloids did not result in a significant difference in 28-day mortality. Although 90-day mortality was lower among patients receiving colloids, this finding should be considered exploratory and requires further study before reaching conclusions about efficacy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00318942.