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Background The importance of assessing venous congestion in ICU patients is widely acknowledged, but its study is hampered by the lack of a practical evaluation tool. The Venous Excess Ultrasound Grading System (VExUS), based on a semi-quantitative combined ultrasound assessment, has been associated with acute kidney injury (AKI) in cardiac ICU patients. The objectives of this study were to assess the prevalence of congestion using VExUS in general ICU patients, and to evaluate the association between VExUS, AKI and death. Methods This prospective, observational study included adult patients within 24 h of ICU admission. VExUS and hemodynamic parameters were measured four times during the ICU stay: within 24 h of ICU admission, after day 1 (between 24 and 48 h), after day 2 (between 48 and 72 h), and last day of ICU stay. The prevalence of AKI during the first week in ICU and 28-day mortality were assessed. Results Among the 145 patients included, the percentage of patients with a VExUS score of 2 (moderate congestion) and 3 (severe congestion) was 16% and 6%, respectively. The prevalence did not change over the study period. There was no significant association between admission VExUS scores and AKI ( p  = 0.136) or 28-day mortality ( p  = 0.594). Admission VExUS ≥ 2 was not associated with AKI (OR 0.499, CI 95% 0.21–1.17, p  = 0.109) nor 28-day mortality (OR 0.75, CI 95% 0.2–2.8, p  = 0.669). The results were similar for VExUS scores measured at day 1 and day 2. Conclusions In general ICU cohort the prevalence of moderate to severe venous congestion was low. Early assessment of systemic venous congestion using VExUS scores was not associated with the development of AKI or with 28-day mortality.

Mitochondria have emerged as key actors of innate and adaptive immunity. Mitophagy has a pivotal role in cell homeostasis, but its contribution to macrophage functions and host defense remains to be delineated. Here, we showed that lipopolysaccharide (LPS) in combination with IFN-γ inhibited PINK1-dependent mitophagy in macrophages through a STAT1-dependent activation of the inflammatory caspases 1 and 11. In addition, we demonstrated that the inhibition of mitophagy triggered classical macrophage activation in a mitochondrial ROS-dependent manner. In a murine model of polymicrobial infection (cecal ligature and puncture), adoptive transfer of Pink1-deficient bone marrow or pharmacological inhibition of mitophagy promoted macrophage activation, which favored bactericidal clearance and led to a better survival rate. Reciprocally, mitochondrial uncouplers that promote mitophagy reversed LPS/IFN-γ-mediated activation of macrophages and led to immunoparalysis with impaired bacterial clearance and lowered survival. In critically ill patients, we showed that mitophagy was inhibited in blood monocytes of patients with sepsis as compared with nonseptic patients. Overall, this work demonstrates that the inhibition of mitophagy is a physiological mechanism that contributes to the activation of myeloid cells and improves the outcome of sepsis.

Background Fluid overload and venous congestion are associated with morbi-mortality in the ICU (intensive care unit). Administration of diuretics to correct the fluid balance is common, although there is no strong relationship between the consequent fluid loss and clinical improvement. The aim of the study was to evaluate the ability of the portal pulsatility index, the renal venous impedance index, and the VEXUS score (venous ultrasound congestion score) to predict appropriate diuretic-induced fluid depletion. Methods The study had a prospective, observational, single-center observational design and was conducted in a university-affiliated medico-surgical ICU. Adult patients for whom the clinician decided to introduce loop diuretic treatment were included. Hemodynamic and ultrasound measurements (including the portal pulsatility index, renal venous impedance index and VEXUS score) were performed at inclusion and 2 hours after the initiation of the diuretics. The patients’ characteristics were noted at inclusion, 24 h later, and at ICU discharge. The appropriate diuretic-induced fluid depletion was defined by a congestive score lower than 3 after diuretic fluid depletion. The congestive score included clinical and biological parameters of congestion. Results Eighty-one patients were included, and 43 (53%) patients presented with clinically significant congestion score at inclusion. Thirty-four patients (42%) had an appropriate response to diuretic-induced fluid depletion. None of the left- and right-sided echocardiographic parameters differed between the two groups. The baseline portal pulsatility index was the best predictor of appropriate response to diuretic-induced fluid depletion (AUC = 0.80, CI 95% :0.70–0.92, p  = 0.001), followed by the renal venous impedance index (AUC = 0.72, CI 95% 0.61–0.84, p  = 0.001). The baseline VEXUS score (AUC of 0.66 CI 95% 0.53–0.79, p  = 0.012) was poorly predictive of appropriate response to diuretic-induced fluid depletion. Conclusion The portal pulsatility index and the renal venous impedance index were predictive of the appropriate response to diuretic-induced fluid depletion in ICU patients. The portal pulsatility index should be evaluated in future randomized studies.

Background COVID-19-related ARDS has unique features when compared with ARDS from other origins, suggesting a distinctive inflammatory pathogenesis. Data regarding the host response within the lung are sparse. The objective is to compare alveolar and systemic inflammation response patterns, mitochondrial alarmin release, and outcomes according to ARDS etiology (i.e., COVID-19 vs. non-COVID-19). Methods Bronchoalveolar lavage fluid and plasma were obtained from 7 control, 7 non-COVID-19 ARDS, and 14 COVID-19 ARDS patients. Clinical data, plasma, and epithelial lining fluid (ELF) concentrations of 45 inflammatory mediators and cell-free mitochondrial DNA were measured and compared. Results COVID-19 ARDS patients required mechanical ventilation (MV) for significantly longer, even after adjustment for potential confounders. There was a trend toward higher concentrations of plasma CCL5, CXCL2, CXCL10, CD40 ligand, IL-10, and GM-CSF, and ELF concentrations of CXCL1, CXCL10, granzyme B, TRAIL, and EGF in the COVID-19 ARDS group compared with the non-COVID-19 ARDS group. Plasma and ELF CXCL10 concentrations were independently associated with the number of ventilator-free days, without correlation between ELF CXCL-10 and viral load. Mitochondrial DNA plasma and ELF concentrations were elevated in all ARDS patients, with no differences between the two groups. ELF concentrations of mitochondrial DNA were correlated with alveolar cell counts, as well as IL-8 and IL-1β concentrations. Conclusion CXCL10 could be one key mediator involved in the dysregulated immune response. It should be evaluated as a candidate biomarker that may predict the duration of MV in COVID-19 ARDS patients. Targeting the CXCL10-CXCR3 axis could also be considered as a new therapeutic approach. Trial registration ClinicalTrials.gov, NCT03955887

Background Although immune modulation is a promising therapeutic avenue in coronavirus disease 2019 (COVID-19), the most relevant targets remain to be found. COVID-19 has peculiar characteristics and outcomes, suggesting a unique immunopathogenesis. Methods Thirty-six immunocompetent non-COVID-19 and 27 COVID-19 patients with severe pneumonia were prospectively enrolled in a single center, most requiring intensive care. Clinical and biological characteristics (including T cell phenotype and function and plasma concentrations of 30 cytokines) and outcomes were compared. Results At similar baseline respiratory severity, COVID-19 patients required mechanical ventilation for significantly longer than non-COVID-19 patients (15 [7–22] vs. 4 (0–15) days; p = 0.0049). COVID-19 patients had lower levels of most classical inflammatory cytokines (G-CSF, CCL20, IL-1β, IL-2, IL-6, IL-8, IL-15, TNF-α, TGF-β), but higher plasma concentrations of CXCL10, GM-CSF and CCL5, compared to non-COVID-19 patients. COVID-19 patients displayed similar T-cell exhaustion to non-COVID-19 patients, but with a more unbalanced inflammatory/anti-inflammatory cytokine response (IL-6/IL-10 and TNF-α/IL-10 ratios). Principal component analysis identified two main patterns, with a clear distinction between non-COVID-19 and COVID-19 patients. Multivariate regression analysis confirmed that GM-CSF, CXCL10 and IL-10 levels were independently associated with the duration of mechanical ventilation. Conclusion We identified a unique cytokine response, with higher plasma GM-CSF and CXCL10 in COVID-19 patients that were independently associated with the longer duration of mechanical ventilation. These cytokines could represent the dysregulated immune response in severe COVID-19, as well as promising therapeutic targets. ClinicalTrials.gov: NCT03505281.

We aimed to evaluate the prognostic value of octanoyl-carnitine in patients undergoing surgical myocardial revascularization for coronary artery disease. We conducted a retrospective analysis of an existing prospective cohort aimed at studying risk factors for vasoplegia in patients undergoing cardiac surgery with cardiopulmonary bypass. We conducted our study exclusively on patients included in the prospective cohort at Dijon University Hospital in 2021. We included 42 adult patients undergoing coronary artery bypass grafting, either alone or combined with another surgical procedure. We collected plasma samples for each patient from EDTA-anticoagulated tubes, taken as part of routine biological check-ups according to the department protocol, at three time points: preoperatively, immediately postoperatively in the intensive care unit, and on the first postoperative day. Liquid chromatography coupled with tandem mass spectrometry was used to determine plasma levels of acyl-carnitines, including octanoyl-carnitine. The primary endpoint was the occurrence of major postoperative complications (stroke, atrial fibrillation, acute kidney injury, and/or death). Fourteen patients (33%) had major postoperative complications. Octanoyl-carnitine plasma concentration significantly increased during the perioperative period and was significantly associated with major postoperative complications at all three time points in coronary artery bypass grafting patients (T1: 14.2 [11.6; 18.6] vs 21.1 [14.8; 28.0], T2: 20.9 [16.4;27.9] vs 34.8 [21.2;37.2], T3: 22.8 [13.7;30.9] vs 34.4 [30.2;41.2]; p  < 0.05; in nmol/l). At baseline, octanoyl-carnitine levels were higher in patients with complications, while other acyl-carnitines showed no significant differences. Octanoyl-carnitine is associated with mitochondrial metabolism and could be evaluated alone or in conjunction with clinical scores.

Cardiac surgery with cardiopulmonary bypass triggers sterile inflammation that is responsible for post-operative morbidity. Automated flow cytometry devices used for leucocyte count provide cell population data (CPD) regarding fluorescence intensity, size and granularity of leukocytes that have never been studied in the context of sterile inflammation. Our objective was to explore leukocyte cell population data in patients undergoing cardiac surgery with cardiopulmonary bypass in order to determine whether CPD could be used to monitor immune cell activation. This is an ancillary study of a cohort of patients undergoing cardiac surgery with cardiopulmonary bypass. Cell population data (CPD) extracted from a routine automated flow cytometer were analyzed (Fluorescence targeted to nucleic acids). The time points of interest were: pre-operative, postoperative and 5 days after surgery. The variations in those parameters were studied. Data were then compared between patients according to the occurrence of a composite criteria (supra-ventricular arrythmia, stroke, acute renal failure, and/or death). Data from 1453 patients were analyzed. The neutrophil count, fluorescence granularity (NE-SCC), intensity (NE-SFL) and size (NE-FSC) increased with surgery. Heterogeneity of neutrophils decreased in terms of fluorescence granularity (NE-WX) and size (NE-WZ) but increased in terms of intensity (NE-WY). The lymphocyte count decreased with surgery. While fluorescence granularity (LY-X) and size increased (LY-Z), Lymphocyte intensity decreased (LY-Y). Lymphocytes were less heterogeneous in terms of their granularity, size and intensity after surgery (LY-WX, LY-WY, LY-WZ). Patients who developed the composite complication criteria had a higher pre-operative neutrophil count (5.08 [3.89;6.95] vs 4.76 [3.60;6.13], p = 0.02; AUC = 0.56 [0.51;0.60]), and more heterogeneous neutrophils in terms of fluorescence granularity (NE-WX, AUC = 0.57 [0.52;0.62]) and intensity (NE-WY, AUC 0.61 [0.56;0.65]). Those patients also had lower pre-operative lymphocyte count (1.49 [1.10;1.14] vs 1.81 [1.39;2.39], p<0.01, AUC = 0.61 [0.57;0.66]) and fluorescence granularity (LY-X, AUC = 0.57 [0.53;0.62]). NE-WX, NE-WY and LY-X were associated with post-operative complications after adjustment on the EuroSCORE 2 (adjusted odd ratio of 1.01 [1.00;1.02]; 1.01 [1.00;1.01] and 1.08 [1.02;1.15] respectively). Cardiac surgery with cardiopulmonary bypass was associated with substantial alterations of CPD probably reflecting leukocytes activation in sterile inflammation. Pre-operative NE-WX, NE-WY and LY-X biomarkers levels were associated with post-operative complications, independently of the EuroSCORE 2. Such routine, unexploited and low cost parameters might represent useful tools likely to monitor immune function and predict outcomes for patients undergoing cardiac surgery. Our findings requires validation on a larger external cohort.

Background No study has been conducted to demonstrate the feasibility of an opioid-free anesthesia (OFA) protocol in cardiac surgery to improve patient care. The aim of the present study was to evaluate the effect of OFA on post-operative morphine consumption and the post-operative course. Methods After retrospectively registering to clinicaltrial.gov (NCT03816592), we performed a retrospective matched cohort study (1:1) on cardiac surgery patients with cardiopulmonary bypass between 2018 and 2019. Patients were divided into two groups: OFA (lidocaine, dexamethasone and ketamine) or opioid anaesthesia (OA) (sufentanil). The main outcome was the total postoperative morphine consumption in the 48 h after surgery. Secondary outcomes were rescue analgesic use, a major adverse event composite endpoint, and ICU and hospital length of stay (LOS). Results One hundred ten patients were matched (OFA: n  = 55; OA: n = 55). On inclusion, demographic and surgical data for the OFA and OA groups were comparable. The total morphine consumption was higher in the OA group than in the OFA group (15 (6–34) vs 5 mg (2–18), p  = 0.001). The pain score during the first 48 post-operative hours did not differ between the two groups. Creatinine values did not differ on the first post-operative day (80 (IQR: 66–115) vs 77 mmol/l (IQR: 69–95), p  = 0.284). Incidence of the composite endpoint was lower in the OFA group (25 patients (43%) vs 38 patients (68%), p  = 0.021). The time to extubation and the ICU stays were shorter in the OFA group (3 (1–5) vs 5 (3–6) hours, p = 0.001 and 2 (1–3) vs 3 (2–5) days, p  = 0.037). Conclusion The use of OFA was associated with lower morphine consumption. OFA might be associated with shorter intubation time and ICU stays. Further randomized studies are needed to confirm these results. Trial registration This study was retrospectively registered to ct2 (identifier: NCT03816592 ) on January 25, 2019.

Background In intensive care unit (ICU) settings, venous excess ultrasound (VExUS) score has gained attention for predicting Acute Kidney Injury (AKI). This led to the identification that venous congestion via VExUS should prompt diuretic therapy. However, in acute heart failure (AHF), a share of the literature considers creatinine elevation as a sign of efficient decongestion. Thus, the relationship between VExUS, diuretic response, and renal outcomes remains unclear in ICU patients. Methods Secondary analysis of a prospective observational study conducted in a cardiovascular ICU (2019–2022). Adult patients with clinical signs of fluid overload receiving loop diuretic treatment were included. Patients were divided into two groups based on their highest VExUS score severity over 24 h: congestive (VExUS ≥ 2) versus non-congestive (VExUS < 2). The primary outcome was WRF at ICU discharge. Secondary outcomes included diuretic response parameters, hemoconcentration, and distinction between \"pseudo-WRF\" (WRF with hemoconcentration) and \"true-WRF\" (WRF without hemoconcentration). Results Seventy-seven patients were analyzed (37 with VExUS < 2, 40 with VExUS ≥ 2). WRF occurred in 14 patients (37.8%) in the non-congestive group versus 8 patients (20.0%) in the congestive group (p = 0.139). No significant differences were observed between groups for diuretic response parameters: loop diuretic-adjusted diuresis at 2 h (545 vs 600 mL/40 mg, p = 0.950), natriuresis (104 vs 93.0 mmol/L, p = 0.355), cumulative fluid removal (−685 vs −1141 mL, p = 0.895), or cumulative loop diuretic prescription (120 vs 100 mg, p = 0.303). Hemoconcentration rates were similar between groups (48.6% vs 32.5%, p = 0.226), as were pseudo-WRF rates (16.2% vs 7.5%, p = 0.241). Conclusions In critically ill patients systematically treated with loop diuretics, VExUS score was not significantly associated with worsening renal function or diuretic response parameters. These preliminary findings suggest that larger studies may be needed to better understand the potential relationship between VExUS and renal outcomes in this patient population.