Mortality, incidence, and microbiological documentation of ventilated acquired pneumonia (VAP) in critically ill patients with COVID-19 or influenza.

BACKGROUND: Data on ventilator associated pneumonia (VAP) in COVID-19 and influenza patients admitted to intensive care units (ICU) are scarce. This study aimed to estimate day-60 mortality related to VAP in ICU patients ventilated for at least 48 h, either for COVID-19 or for influenza, and to describe the epidemiological characteristics in each group of VAP. DESIGN: Multicentre retrospective observational study. SETTING: Eleven ICUs of the French OutcomeRea™ network. PATIENTS: Patients treated with invasive mechanical ventilation (IMV) for at least 48 h for either COVID-19 or for flu. RESULTS: Of the 585 patients included, 503 had COVID-19 and 82 had influenza between January 2008 and June 2021. A total of 232 patients, 209 (41.6%) with COVID-19 and 23 (28%) with influenza, developed 375 VAP episodes. Among the COVID-19 and flu patients, VAP incidences for the first VAP episode were, respectively, 99.2 and 56.4 per 1000 IMV days (p < 0.01), and incidences for all VAP episodes were 32.8 and 17.8 per 1000 IMV days (p < 0.01). Microorganisms of VAP were Gram-positive cocci in 29.6% and 23.5% of episodes of VAP (p < 0.01), respectively, including Staphylococcus aureus in 19.9% and 11.8% (p = 0.25), and Gram-negative bacilli in 84.2% and 79.4% (p = 0.47). In the overall cohort, VAP was associated with an increased risk of day-60 mortality (aHR = 1.77 [1.36; 2.30], p < 0.01), and COVID-19 had a higher mortality risk than influenza (aHR = 2.22 [CI 95%, 1.34; 3.66], p < 0.01). VAP was associated with increased day-60 mortality among COVID-19 patients (aHR = 1.75 [CI 95%, 1.32; 2.33], p < 0.01), but not among influenza patients (aHR = 1.75 [CI 95%, 0.48; 6.33], p = 0.35). CONCLUSION: The incidence of VAP was higher in patients ventilated for at least 48 h for COVID-19 than for influenza. In both groups, Gram-negative bacilli were the most frequently detected microorganisms. In patients ventilated for either COVID-19 or influenza VAP and COVID-19 were associated with a higher risk of mortality.

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.

Unchanged Characteristics and Survival among Critically Ill COVID-19 Patients during First, Second, and Third Waves: A Prospective Observational Cohort.

BACKGROUND: This study was carried out to compare characteristics and outcomes in patients with acute respiratory failure related to COVID-19 during first, second, and third waves. METHODS: We included consecutive adults admitted to the intensive care unit between March 2020 and July 2021. We compared three groups defined by the epidemic intake phase: waves 1 (W1), 2 (W2), and 3 (W3). RESULTS: We included 289 patients. Two hundred and eight (72%) patients were men with a median age of 63 years (IQR: 54-72), of whom 68 (23.6%) died in hospital. High-flow nasal oxygen (HFNO) was inversely associated with the need for invasive mechanical ventilation (MV) in multivariate analysis (p = 0.003) but not dexamethasone (p = 0.25). The day-90 mortality rate did not vary from W1 (27.4%) to W2 (23.9%) and W3 (22%), p = 0.67. By multivariate analysis, older age (odds ratio [OR]: 0.94/year, p < 0.001), immunodeficiency (OR: 0.33, p = 0.04), acute kidney injury (OR: 0.26, p < 0.001), and invasive MV (OR: 0.13, p < 0.001) were inversely associated with higher day-90 survival as opposed to the use of intermediate heparin thromboprophylaxis dose (OR: 3.21, p = 0.006). HFNO use and dexamethasone were not associated with higher day-90 survival (p = 0.24 and p = 0.56, respectively). CONCLUSIONS: In patients with acute respiratory failure due to COVID-19, survival did not change between first, second, and third waves while the use of invasive MV decreased. HFNO or intravenous steroids were not associated with better outcomes, whereas the use of intermediate dose of heparin for thromboprophylaxis was associated with higher day-90 survival. Larger multicentric studies are needed to confirm our findings.

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.

Ventilator-Associated Pneumonia in COVID-19 Patients Admitted in Intensive Care Units: Relapse, Therapeutic Failure and Attributable Mortality-A Multicentric Observational Study from the OutcomeRea Network.

Introduction: Ventilator-associated pneumonia (VAP) incidence is high among critically ill COVID-19 patients. Its attributable mortality remains underestimated, especially for unresolved episodes. Indeed, the impact of therapeutic failures and the determinants that potentially affect mortality are poorly evaluated. We assessed the prognosis of VAP in severe COVID-19 cases and the impact of relapse, superinfection, and treatment failure on 60-day mortality. Methods: We evaluated the incidence of VAP in a multicenter prospective cohort that included adult patients with severe COVID-19, who required mechanical ventilation for ≥48 h between March 2020 and June 2021. We investigated the risk factors for 30-day and 60-day mortality, and the factors associated with relapse, superinfection, and treatment failure. Results: Among 1424 patients admitted to eleven centers, 540 were invasively ventilated for 48 h or more, and 231 had VAP episodes, which were caused by Enterobacterales (49.8%), P. aeruginosa (24.8%), and S. aureus (22%). The VAP incidence rate was 45.6/1000 ventilator days, and the cumulative incidence at Day 30 was 60%. VAP increased the duration of mechanical ventilation without modifying the crude 60-day death rate (47.6% vs. 44.7% without VAP) and resulted in a 36% increase in death hazard. Late-onset pneumonia represented 179 episodes (78.2%) and was responsible for a 56% increase in death hazard. The cumulative incidence rates of relapse and superinfection were 45% and 39.5%, respectively, but did not impact death hazard. Superinfection was more frequently related to ECMO and first episode of VAP caused by non-fermenting bacteria. The risk factors for treatment failure were an absence of highly susceptible microorganisms and vasopressor need at VAP onset. Conclusions: The incidence of VAP, mainly late-onset episodes, is high in COVID-19 patients and associated with an increased risk of death, similar to that observed in other mechanically ventilated patients. The high rate of VAP due to difficult-to-treat microorganisms, pharmacokinetic alterations induced by renal replacement therapy, shock, and ECMO likely explains the high cumulative risk of relapse, superinfection, and treatment failure.

Bacterial Pulmonary Co-Infections on ICU Admission: Comparison in Patients with SARS-CoV-2 and Influenza Acute Respiratory Failure: A Multicentre Cohort Study.

BACKGROUND: Few data are available on the impact of bacterial pulmonary co-infection (RespCoBact) during COVID-19 (CovRespCoBact). The aim of this study was to compare the prognosis of patients admitted to an ICU for influenza pneumonia and for SARS-CoV-2 pneumonia with and without RespCoBact. METHODS: This was a multicentre (n = 11) observational study using the Outcomerea© database. Since 2008, all patients admitted with influenza pneumonia or SARS-CoV-2 pneumonia and discharged before 30 June 2021 were included. Risk factors for day-60 death and for ventilator-associated-pneumonia (VAP) in patients with influenza pneumonia or SARS-CoV-2 pneumonia with or without RespCoBact were determined. RESULTS: Of the 1349 patients included, 157 were admitted for influenza and 1192 for SARS-CoV-2. Compared with the influenza patients, those with SARS-CoV-2 had lower severity scores, were more often under high-flow nasal cannula, were less often under invasive mechanical ventilation, and had less RespCoBact (8.2% for SARS-CoV-2 versus 24.8% for influenza). Day-60 death was significantly higher in patients with SARS-CoV-2 pneumonia with no increased risk of mortality with RespCoBact. Patients with influenza pneumonia and those with SARS-CoV-2 pneumonia had no increased risk of VAP with RespCoBact. CONCLUSIONS: SARS-CoV-2 pneumonia was associated with an increased risk of mortality compared with Influenza pneumonia. Bacterial pulmonary co-infections on admission were not associated with patient survival rates nor with an increased risk of VAP.

Natraemia variations induced by acute dialysis in critically ill patients: a database study.

Natraemia is often abnormal in critically ill patients and may change rapidly during renal replacement therapy (RRT). This database study in a single intensive care unit (ICU) evaluated natraemia before and after the first RRT session for acute kidney injury. Of 252 patients who required RRT in 2018-2020, 215 were included. Prevalences were 53.9% for hyponatraemia (≤ 135 mmol/L) and 3.7% for hypernatraemia (> 145 mmol/L). Dialysate sodium was ≥ 145 mmol/L in 83% of patients. Median dialysis sodium gradient was 12 mmol/L, with a value above 16 mmol/L in 25% of patients. Median natraemia increased from 135 before to 140 mmol/L after RRT, the median hourly increase being faster than recommended, at 1.0 mmol/L [0.2-1.7]. By multivariate analysis, the only variable significantly associated with the RRT-induced natraemia change was the dialysis sodium gradient [odds ratio, 1.66; 95% confidence interval 1.39-2.10]. Pearson's correlation coefficient between the gradient and the natraemia change was 0.57. When performing RRT in ICU patients, in addition to the haemodynamic considerations put forward in recommendations, the dialysis sodium gradient deserves careful attention in order to control natraemia variations. Studies to devise a formula for predicting natraemia variations might prove helpful to confirm our results.

Auricular Acupuncture for Preoperative Anxiety in Parturient Women with Scheduled Cesarean Section: A Randomized Placebo-Controlled Blind Study.

Introduction: Preoperative anxiety before cesarean section is a major issue. Nonpharmacologic anxiety control is believed to be more suitable in pregnant women. Auricular acupuncture (AA) is an inexpensive, easy-to-use, and validated intervention to reduce anxiety in different surgical settings. We evaluated the effect of AA on preoperative cesarean section anxiety. Methods: In a prospective, blind, controlled trial, pregnant women with a scheduled cesarean section under spinal anesthesia were randomized to receive AA with needle, AA without needle (sham), or usual care (no intervention). Anxiety level was assessed by using a visual analogue scale for anxiety (VAS-A; 0-minimal anxiety, 100-maximal anxiety) at three time points: inclusion (pre-induction room-T0), when entering the operating room (T1), and before incision (T2). The primary outcome was the VAS-A variation (percentage changes) between T0 and T1 in the AAe group compared with that in the sham AA group. The secondary outcomes were the VAS-A variation between T0 and T1 in the AA group compared with that in the control group, and the variation between T0 and T2 compared between the three groups, the effect of AA on parasympathetic tone, and the incidence of adverse effects. Results: In women immediately before anesthesia for cesarean section, the AA produced a 19% decrease of anxiety, compared with a 21% anxiety increase in sham AA, which is significantly different. The effect of AA was more present in women with low initial anxiety. The proportion of patients reaching clinically significant anxiety reduction (>33% from the initial level) was 2.5 times higher in the AA group (p = 0.02) compared with the sham group. No differences in anxiety variations were found compared with the no-intervention group. No effect of AA was noted on parasympathetic tone. Conclusion: Compared with sham, AA decreased maternal anxiety level when arriving in the operation room and just before the beginning of the cesarean section, with a trend toward improvement compared with usual care.

Association of ventilator type with hospital mortality in critically ill patients with SARS-CoV2 infection: a prospective study.

BACKGROUND: To evaluate the association between ventilator type and hospital mortality in patients with acute respiratory distress syndrome (ARDS) related to COVID-19 (SARS-CoV2 infection), a single-center prospective observational study in France. RESULTS: We prospectively included consecutive adults admitted to the intensive care unit (ICU) of a university-affiliated tertiary hospital for ARDS related to proven COVID-19, between March 2020 and July 2021. All patients were intubated. We compared two patient groups defined by whether an ICU ventilator or a less sophisticated ventilator such as a sophisticated turbine-based transport ventilator was used. Kaplan-Meier survival curves were plotted. Cox multivariate regression was performed to identify associations between patient characteristics and hospital mortality. We included 189 patients (140 [74.1%] men) with a median age of 65 years [IQR, 55-73], of whom 61 (32.3%) died before hospital discharge. By multivariate analysis, factors associated with in-hospital mortality were age ≥ 70 years (HR, 2.11; 95% CI, 1.24-3.59; P = 0.006), immunodeficiency (HR, 2.43; 95% CI, 1.16-5.09; P = 0.02) and serum creatinine ≥ 100 µmol/L (HR, 3.01; 95% CI, 1.77-5.10; P < 0.001) but not ventilator type. As compared to conventional ICU (equipped with ICU and anesthesiology ventilators), management in transient ICU (equipped with non-ICU turbine-based ventilators) was associated neither with a longer duration of invasive mechanical ventilation (18 [IQR, 11-32] vs. 21 [13-37] days, respectively; P = 0.39) nor with a longer ICU stay (24 [IQR, 14-40] vs. 27 [15-44] days, respectively; P = 0.44). CONCLUSIONS: In ventilated patients with ARDS due to COVID-19, management in transient ICU equipped with non-ICU sophisticated turbine-based ventilators was not associated with worse outcomes compared to standard ICU, equipped with ICU ventilators. Although our study design is not powered to demonstrate any difference in outcome, our results after adjustment do not suggest any signal of harm when using these transport type ventilators as an alternative to ICU ventilators during COVID-19 surge.

Impact of early corticosteroids on 60-day mortality in critically ill patients with COVID-19: A multicenter cohort study of the OUTCOMEREA network.

OBJECTIVES: In severe COVID-19 pneumonia, the appropriate timing and dosing of corticosteroids (CS) is not known. Patient subgroups for which CS could be more beneficial also need appraisal. The aim of this study was to assess the effect of early CS in COVID-19 pneumonia patients admitted to the ICU on the occurrence of 60-day mortality, ICU-acquired-bloodstream infections(ICU-BSI), and hospital-acquired pneumonia and ventilator-associated pneumonia(HAP-VAP). METHODS: We included patients with COVID-19 pneumonia admitted to 11 ICUs belonging to the French OutcomeReaTM network from January to May 2020. We used survival models with ponderation with inverse probability of treatment weighting (IPTW). RESULTS: The study population comprised 303 patients having a median age of 61.6 (53-70) years of whom 78.8% were male and 58.6% had at least one comorbidity. The median SAPS II was 33 (25-44). Invasive mechanical ventilation was required in 34.8% of the patients. Sixty-six (21.8%) patients were in the Early-C subgroup. Overall, 60-day mortality was 29.4%. The risks of 60-day mortality (IPTWHR = 0.86;95% CI 0.54 to 1.35, p = 0.51), ICU-BSI and HAP-VAP were similar in the two groups. Importantly, early CS treatment was associated with a lower mortality rate in patients aged 60 years or more (IPTWHR, 0.53;95% CI, 0.3-0.93; p = 0.03). In contrast, CS was associated with an increased risk of death in patients younger than 60 years without inflammation on admission (IPTWHR = 5.01;95% CI, 1.05, 23.88; p = 0.04). CONCLUSION: For patients with COVID-19 pneumonia, early CS treatment was not associated with patient survival. Interestingly, inflammation and age can significantly influence the effect of CS.

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.

Association Between Early Invasive Mechanical Ventilation and Day-60 Mortality in Acute Hypoxemic Respiratory Failure Related to Coronavirus Disease-2019 Pneumonia.

OBJECTIVES: About 5% of patients with coronavirus disease-2019 are admitted to the ICU for acute hypoxemic respiratory failure. Opinions differ on whether invasive mechanical ventilation should be used as first-line therapy over noninvasive oxygen support. The aim of the study was to assess the effect of early invasive mechanical ventilation in coronavirus disease-2019 with acute hypoxemic respiratory failure on day-60 mortality. DESIGN: Multicenter prospective French observational study. SETTING: Eleven ICUs of the French OutcomeRea network. PATIENTS: Coronavirus disease-2019 patients with acute hypoxemic respiratory failure (Pao2/Fio2 ≤ 300 mm Hg), without shock or neurologic failure on ICU admission, and not referred from another ICU or intermediate care unit were included. INTERVENTION: We compared day-60 mortality in patients who were on invasive mechanical ventilation within the first 2 calendar days of the ICU stay (early invasive mechanical ventilation group) and those who were not (nonearly invasive mechanical ventilation group). We used a Cox proportional-hazard model weighted by inverse probability of early invasive mechanical ventilation to determine the risk of death at day 60. MEASUREMENT AND MAIN RESULTS: The 245 patients included had a median (interquartile range) age of 61 years (52-69 yr), a Simplified Acute Physiology Score II score of 34 mm Hg (26-44 mm Hg), and a Pao2/Fio2 of 121 mm Hg (90-174 mm Hg). The rates of ICU-acquired pneumonia, bacteremia, and the ICU length of stay were significantly higher in the early (n = 117 [48%]) than in the nonearly invasive mechanical ventilation group (n = 128 [52%]), p < 0.01. Day-60 mortality was 42.7% and 21.9% in the early and nonearly invasive mechanical ventilation groups, respectively. The weighted model showed that early invasive mechanical ventilation increased the risk for day-60 mortality (weighted hazard ratio =1.74; 95% CI, 1.07-2.83, p=0.03). CONCLUSIONS: In ICU patients admitted with coronavirus disease-2019-induced acute hypoxemic respiratory failure, early invasive mechanical ventilation was associated with an increased risk of day-60 mortality. This result needs to be confirmed.

Multistate Modeling of COVID-19 Patients Using a Large Multicentric Prospective Cohort of Critically Ill Patients.

The mortality of COVID-19 patients in the intensive care unit (ICU) is influenced by their state at admission. We aimed to model COVID-19 acute respiratory distress syndrome state transitions from ICU admission to day 60 outcome and to evaluate possible prognostic factors. We analyzed a prospective French database that includes critically ill COVID-19 patients. A six-state multistate model was built and 17 transitions were analyzed either using a non-parametric approach or a Cox proportional hazard model. Corticosteroids and IL-antagonists (tocilizumab and anakinra) effects were evaluated using G-computation. We included 382 patients in the analysis: 243 patients were admitted to the ICU with non-invasive ventilation, 116 with invasive mechanical ventilation, and 23 with extracorporeal membrane oxygenation. The predicted 60-day mortality was 25.9% (95% CI: 21.8%-30.0%), 44.7% (95% CI: 48.8%-50.6%), and 59.2% (95% CI: 49.4%-69.0%) for a patient admitted in these three states, respectively. Corticosteroids decreased the risk of being invasively ventilated (hazard ratio (HR) 0.59, 95% CI: 0.39-0.90) and IL-antagonists increased the probability of being successfully extubated (HR 1.8, 95% CI: 1.02-3.17). Antiviral drugs did not impact any transition. In conclusion, we observed that the day-60 outcome in COVID-19 patients is highly dependent on the first ventilation state upon ICU admission. Moreover, we illustrated that corticosteroid and IL-antagonists may influence the intubation duration.

Photoperiod integration in C3H rd1 mice.

In mammals, the suprachiasmatic nuclei (SCN) constitute the main circadian clock, receiving input from the retina which allows synchronization of endogenous biological rhythms with the daily light/dark cycle. Over the year, the SCN encodes photoperiodic variations through duration of melatonin secretion, with abundant nocturnal levels in winter and lower levels in summer. Thus, light information is critical to regulate seasonal reproduction in many species and is part of the central photoperiodic integration. Since intrinsically photosensitive retinal ganglion cells (ipRGCs) are vital for circadian photoentrainment and other nonvisual functions, we studied the contribution of ipRGCs in photoperiod integration in C3H retinal degeneration 1 (rd1) mice. We assessed locomotor activity and melatonin secretion in mice exposed to short or long photoperiods. Our results showed that rd1 mice are still responsive to photoperiod variations in term of locomotor activity, melatonin secretion, and regulation of the reproductive axis. In addition, retinas of animals exposed to short photoperiod exhibit higher melanopsin labeling intensity compared with the long photoperiod condition, suggesting seasonal-dependent changes within this photoreceptive system. These results show that ipRGCs in rd1 mice can still measure photoperiod and suggest a key role of melanopsin cells in photoperiod integration and the regulation of seasonal physiology.

Dopamine 2 Receptor Signaling Controls the Daily Burst in Phagocytic Activity in the Mouse Retinal Pigment Epithelium.

Purpose: A burst in phagocytosis of spent photoreceptor outer fragments by RPE is a rhythmic process occurring 1 to 2 hours after the onset of light. This phenomenon is considered crucial for the health of the photoreceptors and RPE. We have recently reported that dopamine, via dopamine 2 receptor (D2R), shifts the circadian rhythm in the RPE. Methods: Here, we first investigated the impact of the removal of D2R on the daily peak of phagocytosis by RPE and then we analyzed the function and morphology of retina and RPE in the absence of D2R. Results: D2R knockout (KO) mice do not show a daily burst of phagocytic activity after the onset of light. RNA sequencing revealed a total of 394 differentially expressed genes (DEGs) between ZT 23 and ZT 1 in the control mice, whereas in D2R KO mice, we detected 1054 DEGs. Pathway analysis of the gene expression data implicated integrin signaling to be one of the upregulated pathways in control but not in D2R KO mice. Consistent with the gene expression data, phosphorylation of focal adhesion kinase (FAK) did not increase significantly in KO mice at ZT 1. No difference in retinal thickness, visual function, or morphology of RPE cells was observed between wild-type (WT) and D2R KO mice at the age of 3 and 12 months. Conclusions: Our data suggest that removal of D2R prevents the burst of phagocytosis and a related increase in the phosphorylation of FAK after light onset. The pathway analysis points toward a putative role of D2R in controlling integrin signaling, which is known to play an important role in the control of the daily burst of phagocytosis by the RPE. Our data also indicate that the absence of the burst of phagocytic activity in the early morning does not produce any apparent deleterious effect on the retina or RPE up to 1 year of age.

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.

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.

Hypothermia for Neuroprotection in Convulsive Status Epilepticus.

BACKGROUND: Convulsive status epilepticus often results in permanent neurologic impairment. We evaluated the effect of induced hypothermia on neurologic outcomes in patients with convulsive status epilepticus. METHODS: In a multicenter trial, we randomly assigned 270 critically ill patients with convulsive status epilepticus who were receiving mechanical ventilation to hypothermia (32 to 34°C for 24 hours) in addition to standard care or to standard care alone; 268 patients were included in the analysis. The primary outcome was a good functional outcome at 90 days, defined as a Glasgow Outcome Scale (GOS) score of 5 (range, 1 to 5, with 1 representing death and 5 representing no or minimal neurologic deficit). The main secondary outcomes were mortality at 90 days, progression to electroencephalographically (EEG) confirmed status epilepticus, refractory status epilepticus on day 1, "super-refractory" status epilepticus (resistant to general anesthesia), and functional sequelae on day 90. RESULTS: A GOS score of 5 occurred in 67 of 138 patients (49%) in the hypothermia group and in 56 of 130 (43%) in the control group (adjusted common odds ratio, 1.22; 95% confidence interval [CI], 0.75 to 1.99; P=0.43). The rate of progression to EEG-confirmed status epilepticus on the first day was lower in the hypothermia group than in the control group (11% vs. 22%; odds ratio, 0.40; 95% CI, 0.20 to 0.79; P=0.009), but there were no significant differences between groups in the other secondary outcomes. Adverse events were more frequent in the hypothermia group than in the control group. CONCLUSIONS: In this trial, induced hypothermia added to standard care was not associated with significantly better 90-day outcomes than standard care alone in patients with convulsive status epilepticus. (Funded by the French Ministry of Health; HYBERNATUS ClinicalTrials.gov number, NCT01359332 .).