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BackgroundThere is increasing evidence regarding the association between endotoxemia and the pathogenesis of atherosclerosis and myocardial infarction (MI). During the acute phase of MI, endotoxemia might increase inflammation and drive adverse cardiovascular (CV) outcomes. We aimed to explore the risk factors and prognostic value of endotoxemia in patients admitted for acute MI.MethodsPatients admitted to the coronary care unit of Dijon University Hospital for type 1 acute MI between 2013 and 2015 were included. Endotoxemia, assessed by plasma lipopolysaccharide (LPS) concentration, was measured by mass spectrometry. Major adverse CV events were recorded in the year following hospital admission.ResultsData from 245 consecutive MI patients were analyzed. LPS concentration at admission markedly increased with age and diabetes. High LPS concentration was correlated with metabolic biomarkers (glycemia, triglyceride, and total cholesterol) but not with CV (troponin Ic peak and N-terminal pro-brain natriuretic peptide) or inflammatory biomarkers (C-reactive protein, IL6, IL8, and TNFα). LPS concentration was not associated with in-hospital or 1-year outcomes.ConclusionsIn patients admitted for MI, higher levels of endotoxins were related to pre-existing conditions rather than acute clinical severity. Therefore, endotoxins measured on the day of MI could reflect metabolic chronic endotoxemia rather than MI-related acute gut translocation.

Abstract Background Left ventricular ejection fraction (LVEF) is inconsistently associated with poor outcomes in patients with sepsis. Newer parameters such as LV longitudinal strain (LVLS), mitral annular plane systolic excursion (MAPSE) and LV longitudinal wall fractional shortening (LV-LWFS) may be more sensitive indicators of LV dysfunction, but are sparsely investigated. Our objective was to evaluate the association between five traditional and novel echocardiographic parameters of LV systolic function (LVEF, peak tissue Doppler velocity at the mitral valve (s´), LVLS, MAPSE and LV-LWFS) and outcomes in patients admitted to the Intensive Care Unit (ICU) with septic shock. Methods A total of 152 patients admitted to the ICU with septic shock from two data repositories were included. Transthoracic echocardiograms were performed within 24 h of ICU admission. The primary outcome was myocardial injury, defined as high-sensitivity troponin T ≥ 45 ng/L on ICU admission. Secondary outcomes were organ support-free days (OSFD) and 30-day mortality. We also tested for the prognostic value of the systolic function parameters using multivariable analysis. Results LVLS, MAPSE and LV-LWFS, but not LVEF and s´, differed between patients with and without myocardial injury. After adjustment for age, pre-existing cardiac disease, Simplified Acute Physiology (SAPS3) score, Sequential Organ Failure Assessment (SOFA) score, plasma creatinine and presence of right ventricular dysfunction, only MAPSE and LV-LWFS were independently associated with myocardial injury. None of the systolic function parameters were associated with OSFD or 30-day mortality. Conclusions MAPSE and LV-LWFS are independently associated with myocardial injury and outperform LVEF, s´ and LVLS. Whether these parameters are associated with clinical outcomes such as the need for organ support and short-term mortality is still unclear. Trial registration NCT01747187 and NCT04695119.

Objective: We investigated the effects of the maintenance of angiotensin-converting enzyme inhibitors (ACE inhibitors) the day of the surgery on the incidence of postoperative acute kidney injury (AKI) and cardiac events in patients undergoing cardiac surgery.Methods: We performed a multicentric observational study with propensity matching on 1,072 patients treated with ACE inhibitors. We collected their baseline demographic data, comorbidities, and operative and postoperative outcomes. AKI was defined by KDIGO (Kidney Disease: Improving Global Outcome).Results: Maintenance of an ACE inhibitor was not associated with an increased risk of AKI (OR: 1.215 (CI95%:0.657–2.24), p = 0.843, 71 patients (25.1%) vs. 68 patients (24%)). Multivariate logistic regression and sensitive analysis did not demonstrate any association between ACE inhibitor maintenance and AKI, following cardiac surgery (OR: 1.03 (CI95%:0.81–1.3)). No statistically significant difference occurs in terms of incidence of cardiogenic shock (OR: 1.315 (CI95%:0.620–2.786)), stroke (OR: 3.313 (CI95%:0.356–27.523)), vasoplegia (OR: 0.741 (CI95%:0.419–1.319)), postoperative atrial fibrillation (OR: 1.710 (CI95%:0.936–3.122)), or mortality (OR: 2.989 (CI95%:0.343–26.034)). ICU and hospital length of stays did not differ (3 [2; 5] vs. 3 [2; 5] days, p = 0.963 and 9.5 [8; 12] vs. 10 [8; 14] days, p = 0.638).Conclusion: Our study revealed that maintenance of ACE inhibitors on the day of the surgery was not associated with increased postoperative AKI. ACE inhibitor maintenance was also not associated with an increased rate of postoperative major cardiovascular events (arterial hypotension, cardiogenic shock, vasopressors use, stroke and death).

Abstract Background Type 2 diabetes mellitus (T2DM) is a major global health issue and a significant risk factor for atherosclerosis. Atherosclerosis in T2DM patients has been associated with inflammation, insulin resistance, hyperglycemia, dyslipidemia, and oxidative stress. Identifying molecular features of atherosclerotic plaques in T2DM patients could provide valuable insights into the pathogenesis of the disease. Methods The MASCADI (Arachidonic Acid Metabolism in Carotid Stenosis Plaque in Diabetic Patients) study aimed to investigate the increase of 2-arachidonoyl-lysophatidylcholine (2-AA-LPC) in carotid plaques from T2DM and control patients and to explore its association with plaque vulnerability as well as with blood and intra-plaque biomarkers altered during diabetes. Results In a population of elderly, polymedicated patients with advanced stage of atherosclerosis, we found that T2DM patients had higher systemic inflammation markers, such as high-sensitivity C-reactive protein (hsCRP) and IL-1β, higher levels of oxysterols, increased triglyceride levels, and decreased HDL levels as compared to control patients. Furthermore, 2-AA-LPC was significantly enriched in plaques from diabetic patients, suggesting its potential role in diabetic atherosclerosis. Interestingly, 2-AA-LPC was not associated with systemic markers related to diabetes, such as hsCRP, triglycerides, or HDL cholesterol. However, it was significantly correlated with the levels of inflammatory markers within the plaques such as lysophospholipids and 25-hydroxycholesterol, strengthening the link between local inflammation, arachidonic acid metabolism and diabetes. Conclusion Our study is in line with a key role for inflammation in the pathogenesis of diabetic atherosclerosis and highlights the involvement of 2-AA-LPC. Further research is needed to better understand the local processes involved in the alteration of plaque composition in T2DM and to identify potential therapeutic targets. Trial registration The MASCADI was registered on ClinicalTrials.gov (clinical registration number: NCT03202823).

Abstract Background Norepinephrine is a commonly used drug for treating vasoplegic acute circulatory failure in ICU. The prediction of norepinephrine macro- and micro-circulatory response is complicated by its uneven receptors’ distribution between the arterial and the venous structures, and by the presence of a physiological vascular waterfall (VW) that disconnects the arterial and the venous circulation in two pressure systems. The objectives of this study were to describe the VW in patients with arterial hypotension due to vasodilatory circulatory shock, and its behavior according to its response to norepinephrine infusion. Methods A prospective, observational, bi-centric study has included adult patients, for whom the physician decided to initiate norepinephrine during the six first hours following admission to the ICU after cardiac surgery, and unresponsive to a fluid challenge. The mean systemic pressure (MSP) and the critical closing pressure (CCP) were measured at inclusion and after norepinephrine infusion. Results Thirty patients were included. Norepinephrine increased arterial pressure and total peripheral resistances in all cohort. The cohort was dichotomized as VW responders (patients with a change of VW over the least significant change (≥ 93% increase in VW)), and as VW non-responders. In 19 (63%) of the 30 patients, VW increased from 3.47 [− 14.43;7.71] mmHg to 43.6 [25.8;48.1] mmHg, p

Abstract 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, CI95% 0.21–1.17, p = 0.109) nor 28-day mortality (OR 0.75, CI95% 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.

Abstract 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, CI95%:0.70–0.92, p = 0.001), followed by the renal venous impedance index (AUC = 0.72, CI95% 0.61–0.84, p = 0.001). The baseline VEXUS score (AUC of 0.66 CI95% 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.

PurposeCardiac 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.MethodsThis 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).ResultsData 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

BackgroundHyperlactatemia is a biological marker of tissue hypoperfusion with well-known diagnostic, prognostic, and therapeutic implications in shock states. In daily clinical practice, it is difficult to find out the exact mechanism underlying hyperlactatemia. Central venous to arterial CO2 difference (pCO2 gap) is a better parameter of tissue hypoperfusion than the usual ones (clinical examination and mixed venous saturation). Furthermore, the ratio between the pCO2 gap and p(v–a)CO2/C(a–v)O2 may be a promising indicator of anaerobic metabolism, allowing for the identification of different causes of tissue hypoxia and hyperlactatemia. The main aim of the study is to demonstrate that initial hemodynamic resuscitation based on an algorithm integrating the pCO2 gap and p(v–a)CO2/C(a–v)O2 ratio vs. usual clinical practice in acute circulatory failure improves lactate clearance.MethodsLACTEL is a randomized, prospective, multicentric, controlled study. It compares the treatment of hyperlactatemia using an algorithm based on the pCO2 gap and P(v–a)CO2/C(a–v)O2 ratio vs. usual clinical practice in acute circulatory failure. A total of 90 patients were enrolled in each treatment group. The primary endpoint is the number of patients with a lactate clearance of more than 10% 2 h after inclusion. Lactate levels were monitored during the first 48 h of treatment as hemodynamic parameters, biological markers of organ failure, and 28-day mortality.DiscussionpCO2 derivate indices may be of better interest than routine clinical indices to differentiate causes of hyperlactatemia and diagnose anaerobiosis. LACTEL results will provide clinical insights into the role of these indices in the early hemodynamic management of acute circulatory failure in the ICU.Clinical Trial Registrationwww.clinicaltrials.gov; identifier: NCT05032521.

IntroductionTwo parallel paradigms of cardiovascular efficiency and haemodynamic optimisation coexist in haemodynamic research. Targeting ventriculo-arterial (VA) coupling [i.e., the ratio between arterial and ventricular elastance (EV)] and electromechanical coupling are two promising approaches in acute circulatory failure. However, validation of the parameters of electromechanical coupling in critically ill patients is ongoing. Furthermore, a unifying link between VA and electromechanical coupling may exist, as EV is correlated with different times of the cardiac cycle.Materials and MethodsThis study was a retrospective analysis of a prospectively collected observational database from one tertiary center ICU. We analyzed the relationship between electromechanical dyssynchrony and acute circulatory failure hemodynamics before and after treatment (i.e., fluid expansion, dobutamine, or norepinephrine infusion). The relationship between electromechanical coupling and VA coupling was also investigated. Adult patients with haemodynamic instability were included. Haemodynamic parameters, including arterial pressure, cardiac index, VA coupling, stroke work index/pressure–volume area (SWI/PVA), t-IVT, and Tei's index, were collected before and after treatment. A t-IVT of >12 s/min was classified as intraventricular dyssynchrony.ResultsWe included 54 patients; 39 (72.2%) were classified as having intraventricular dyssynchrony at baseline. These patients with baseline dyssynchrony showed a statistically significant amelioration of t-IVT (from 18 ± 4 s to 14 ± 6 s, p = 0.001), left ventricular EV [from 1.1 (0.72–1.52) to 1.33 (0.84–1.67) mmHg mL−1, p = 0.001], VA coupling [from 2 (1.67–2.59) to 1.80 (1.40–2.21), p = 0.001], and SWI/PVA [from 0.58 (0.49–0.65) to 0.64 (0.51–0.68), p = 0.007]. Patients without baseline dyssynchrony showed no statistically significant results. The improvement in VA coupling was mediated by an amelioration of EV. All patients improved their arterial pressure and cardiac index with treatment. The haemodynamic treatment group exhibited no effect on changing t-IVT.ConclusionAcute circulatory failure is associated with electromechanical dyssynchrony. Cardiac electromechanical coupling was improved by haemodynamic treatment only if altered at baseline. The improvement of cardiac electromechanical coupling was associated with the improvement of markers of cardiocirculatory efficacy and efficiency (i.e., SWI/PVA and VA coupling). This study was the first to demonstrate a possible link between cardiac electromechanical coupling and VA coupling in patients with acute circulatory failure.

Abstract COVID-19 pneumonia has specific features and outcomes that suggests a unique immunopathogenesis. Severe forms of COVID-19 appear to be more frequent in obese patients, but an association with metabolic disorders is not established. Here, we focused on lipoprotein metabolism in patients hospitalized for severe pneumonia, depending on COVID-19 status. Thirty-four non-COVID-19 and 27 COVID-19 patients with severe pneumonia were enrolled. Most of them required intensive care. Plasma lipid levels, lipoprotein metabolism, and clinical and biological (including plasma cytokines) features were assessed. Despite similar initial metabolic comorbidities and respiratory severity, COVID-19 patients displayed a lower acute phase response but higher plasmatic concentrations of non-esterified fatty acids (NEFAs). NEFA profiling was characterised by higher level of polyunsaturated NEFAs (mainly linoleic and arachidonic acids) in COVID-19 patients. Multivariable analysis showed that among severe pneumonia, COVID-19-associated pneumonia was associated with higher NEFAs, lower apolipoprotein E and lower high-density lipoprotein cholesterol concentrations, independently of body mass index, sequential organ failure (SOFA) score, and C-reactive protein levels. NEFAs and PUFAs concentrations were negatively correlated with the number of ventilator-free days. Among hospitalized patients with severe pneumonia, COVID-19 is independently associated with higher NEFAs (mainly linoleic and arachidonic acids) and lower apolipoprotein E and HDL concentrations. These features might act as mediators in COVID-19 pathogenesis and emerge as new therapeutic targets. Further investigations are required to define the role of NEFAs in the pathogenesis and the dysregulated immune response associated with COVID-19. Trial registration: NCT04435223.

Abstract The purpose of this study was to determine whether dynamic elastance EAdyn derived from echocardiographic measurements of stroke volume variations can predict the success of a one-step decrease of norepinephrine dose. In this prospective single-center study, 39 patients with vasoplegic syndrome treated with norepinephrine and for whom the attending physician had decided to decrease norepinephrine dose and monitored by thermodilution were analyzed. EAdyn is the ratio of pulse pressure variation to stroke volume variation and was calculated from echocardiography stroke volume variations and from transpulmonary thermodilution. Pulse pressure variation was obtained from invasive arterial monitoring. Responders were defined by a decrease in mean arterial pressure (MAP) > 10% following norepinephrine decrease. The median decrease in norepinephrine was of 0.04 [0.03–0.05] µg kg−1 min−1. Twelve patients (31%) were classified as pressure responders with a median decrease in MAP of 13% [12–15%]. EAdyn was lower in pressure responders (0.40 [0.24–0.57] vs 0.95 [0.77–1.09], p

Abstract 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.

Abstract 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

BackgroundThe optimal management of hypotensive patients during norepinephrine weaning is unclear. The primary study aim was to assess the ability of preload dependence to predict hypotension following norepinephrine weaning. The secondary aims were to describe the effect of norepinephrine weaning on preload dependence, and the cardiovascular effects of fluid expansion in hypotensive patients following norepinephrine weaning.Materials and MethodsThis was a prospective observational monocentric study. We included PiCCO®-monitored patients with norepinephrine-treated septic shock, for whom the physician decided to decrease the norepinephrine dosage during the de-escalation phase. Three consecutive steps were evaluated with hemodynamic measurements: baseline, after norepinephrine decrease, and after 500 mL fluid expansion.ResultsForty-five patients were included. Preload dependence assessed by stroke volume changes following passive leg raising was not predictive of pressure response to norepinephrine weaning [AUC of 0.42 (95%CI: 0.25–0.59, p = 0.395)]. After fluid expansion, there was no difference in the prior preload dependence between pressure-responders and non-pressure-responders (14 vs. 13%, p = 1). The pressure response to norepinephrine decrease was not associated with pressure response after fluid expansion (40 vs. 23%, p = 0.211).ConclusionHypotension following norepinephrine decrease was not predicted by preload dependence, and there was no association between arterial hypotension after norepinephrine decrease and fluid response.

IntroductionThe determination of ventriculo-arterial coupling is gaining an increasing role in cardiovascular and sport medicine. However, its relevance in critically ill patients is still under investigation. In this study we measured the association between ventriculo-arterial coupling and oxygen consumption (VO2) response after hemodynamic interventions in cardiac surgery patients with acute circulatory instability.Material and MethodsSixty-one cardio-thoracic ICU patients (67 ± 12 years, 80% men) who received hemodynamic therapeutic interventions (fluid challenge or norepinephrine infusion) were included. Arterial pressure, cardiac output, heart rate, arterial (EA), and ventricular elastances (EV), total indexed peripheral resistances were assessed before and after hemodynamic interventions. VO2 responsiveness was defined as VO2 increase >15% following the hemodynamic intervention. Ventriculo-arterial coupling was assessed measuring the EA/EV ratio by echocardiography. The left ventricle stroke work to pressure volume area ratio (SW/PVA) was also calculated.ResultsIn the overall cohort, 24 patients (39%) were VO2 responders, and 48 patients had high ventriculo-arterial (EA/EV) coupling ratio with a median value of 1.9 (1.6–2.4). Most of those patients were classified as VO2 responders (28 of 31 patients, p = 0.031). Changes in VO2 were correlated with those of indexed total peripheral resistances, EA, EA/EV and cardiac output. EA/EV ratio predicted VO2 increase with an AUC of 0.76 [95% CI: 0.62–0.87]; p = 0.001. In principal component analyses, EA/EV and SW/PVA ratios were independently associated (p < 0.05) with VO2 response following interventions.ConclusionsVO2 responders were characterized by baseline high ventriculo-arterial coupling ratio due to high EA and low EV. Baseline EA/EV and SW/PVA ratios were associated with VO2 changes independently of the hemodynamic intervention used. These results underline the pathophysiological significance of measuring ventriculo-arterial coupling in patients with hemodynamic instability, as a potential therapeutic target.

Aim: Little is known about the cardiovascular effects of oral water intake in shock patients. This study was designed to assess the effect of oral water on stroke volume and blood pressure during a 1-h time period.Method and Results: This open-label, randomized clinical trial included patients admitted to intensive care with acute circulatory failure. Three ICU units at the anesthesia and critical care department of the Dijon Bourgogne University Hospital. Patients were randomized 1:1 to an intervention or standard care group. The intervention group received 500 ml of oral water while the standard care group received intravenous administration of 500 ml of physiological saline solution. Baseline SV did not differ between the two groups (36 ml [28;51] vs. 38 ml [30;51], p = 0.952). The number of patients who were fluid responders did not differ between the two groups [n = 19 (76%) vs. n = 18 (72%), p = 1]. The median change in stroke volume during the three time points did not differ between the two groups (p < 0.05). In the intervention group, blood pressure increased up to 60 min. In the control group, blood pressure quickly increased at the end of fluid expansion, then returned close to baseline value at 60 min.Conclusion: Shock patients who were administered oral water experienced improvements in blood pressure and blood flow up to 60 min when compared with patients who received intravenous saline solution. Further studies are warranted to confirm these effects.Clinical Trial Registration:www.clinicaltrials.gov, identifier: NCT03951519.

Background: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is the rescue treatment proposed to patients with refractory cardiogenic shock. The VA-ECMO implantation promotes inflammation and ischemia-reperfusion injuries through the VA-ECMO flow, causing digestive mucosa barrier disrupture and inducing translocation of bacterial wall components—Lipopolysaccharides (LPS) with further inflammation and circulatory impairment. LPS is a well-studied surrogate indicator of bacterial translocation. Oxiris membrane is a promising and well-tolerated device that can specifically remove LPS. The main study aim is to compare the LPS elimination capacity of Oxiris membrane vs. a non-absorbant classical renal replacement (RRT) membrane in patients with cardiogenic shock requiring VA-ECMO.Methods: ECMORIX is a randomized, prospective, single-center, single-blind, parallel-group, controlled study. It compares the treatment with Oxiris membrane vs. the standard continuous renal replacement therapy care in patients with cardiogenic shock support by peripheral VA-ECMO. Forty patients will be enrolled in both treatment groups. The primary endpoint is the value of LPS serum levels after 24 h of treatment. LPS serum levels will be monitored during the first 72 h of treatment, as clinical and cardiac ultrasound parameters, biological markers of inflammation and 30-day mortality.Discussion: Oxiris membrane appears to be beneficial in controlling the VA-ECMO-induced ischemia-reperfusion inflammation by LPS removal. ECMORIX results will be of major importance in the management of severe cases requiring VA-ECMO and will bring pathophysiological insights about the LPS role in this context.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT04886180.

Introduction: Lipopolysaccharide (LPS) is a component of gram-negative bacteria, known for its ability to trigger inflammation. The main pathway of LPS clearance is the reverse lipopolysaccharide transport (RLT), with phospholipid transfer protein (PLTP) and lipoproteins playing central roles in this process in experimental animal models. To date, the relevance of this pathway has never been studied in humans. Cardiac surgery with cardiopulmonary bypass is known to favor LPS digestive translocation. Our objective was to determine whether pre-operative PLTP activity and triglyceride or cholesterol-rich lipoprotein concentrations were associated to LPS concentrations in patients undergoing cardiac surgery with cardiopulmonary bypass.Methods: A post-hoc analysis was conducted on plasma samples obtained from patients recruited in a randomized controlled trial.Total cholesterol, high density lipoprotein cholesterol (HDLc), low density lipoprotein cholesterol (LDLc), triglyceride and PLTP activity were measured before surgery. LPS concentration was measured by mass spectrometry before surgery, at the end of cardiopulmonary bypass and 24 h after admission to the intensive care unit.Results: High PLTP activity was associated with lower LPS concentration but not with inflammation nor post-operative complications. HDLc, LDLc and total cholesterol were not associated with LPS concentration but were lower in patients developing post-operative adverse events. HDLc was negatively associated with inflammation biomarkers (CRP, PCT). Triglyceride concentrations were positively correlated with LPS concentration, PCT and were higher in patients with post-operative complications.Conclusion: Our study supports the role of PLTP in LPS elimination and the relevance of RLT in human. PLTP activity, and not cholesterol rich lipoproteins pool size seemed to be the limiting factor for RLT. PLTP activity was not directly related to post-operative inflammation and adverse events, suggesting that LPS clearance is not the main driver of inflammation in our patients. However, HDLc was associated with lower inflammation and was associated with favorable outcomes, suggesting that HDL beneficial anti-inflammatory effects could be, at least in part independent of LPS clearance.

Bacterial lipopolysaccharides (LPS, endotoxins) are found in high amounts in the gut lumen. LPS can cross the gut barrier and pass into the blood (endotoxemia), leading to low-grade inflammation, a common scheme in metabolic diseases. Phospholipid transfer protein (PLTP) can transfer circulating LPS to plasma lipoproteins, thereby promoting its detoxification. However, the impact of PLTP on the metabolic fate and biological effects of gut-derived LPS is unknown. This study aimed to investigate the influence of PLTP on low-grade inflammation, obesity and insulin resistance in relationship with LPS intestinal translocation and metabolic endotoxemia. Wild-type (WT) mice were compared with Pltp-deficient mice (Pltp-KO) after a 4-month high-fat (HF) diet or oral administration of labeled LPS. On a HF diet, Pltp-KO mice showed increased weight gain, adiposity, insulin resistance, lipid abnormalities and inflammation, together with a higher exposure to endotoxemia compared to WT mice. After oral administration of LPS, PLTP deficiency led to increased intestinal translocation and decreased association of LPS to lipoproteins, together with an altered catabolism of triglyceride-rich lipoproteins (TRL). Our results show that PLTP, by modulating the intestinal translocation of LPS and plasma processing of TRL-bound LPS, has a major impact on low-grade inflammation and the onset of diet-induced metabolic disorders.

Rationale: COVID-19 displays distinct characteristics that suggest a unique pathogenesis. The objective of this study was to compare biomarkers of coagulopathy and outcomes in COVID-19 and non-COVID-19 patients with severe pneumonia.Methods: Thirty-six non-COVID-19 and 27 COVID-19 non-immunocompromised patients with severe pneumonia were prospectively enrolled, most requiring intensive care. Clinical and biological characteristics (including plasma biomarkers of coagulopathy) were compared.Results: At similar baseline severity, COVID-19 patients required mechanical ventilation (MV) for significantly longer than non-COVID-19 patients (p = 0.0049) and more frequently developed venous thrombotic complications (p = 0.031). COVID-19 patients had significantly higher plasma concentrations of soluble VCAM1 (sVCAM1) (5,739 ± 3,293 vs. 3,700 ± 2,124 ng/ml; p = 0.009), but lower levels of D-dimers, vWF-A2, sICAM1, sTREM1, VEGF, and P-selectin, compared to non-COVID-19 patients. Principal component analysis identified two main patterns, with a clear distinction between non-COVID-19 and COVID-19 patients. Multivariable regression analysis confirmed that sVCAM1 rising levels were independently associated with a longer duration of MV. Finally, we identified close correlations between sVCAM1 and some features of COVID-19 immune dysregulation (ie. CXCL10, GM-CSF, and IL-10).Conclusion: We identified specific features of the coagulopathy signature in severe COVID-19 patients, with higher plasma sVCAM1 levels, that were independently associated with the longer duration of mechanical ventilation.Clinical Trial Registration:ClinicalTrials.gov, identifier: NCT03505281.

BackgroundFluid responsiveness has been extensively studied by using the preload prism. The arterial load might be a factor modulating the fluid responsiveness. The norepinephrine (NE) administration increases the arterial load and modifies the vascular properties. The objective of the present study was to determine the relationship between fluid responsiveness, preload, arterial load, and NE use. We hypothesized that as a preload/arterial load, NE use may affect fluid responsiveness.MethodsThe retrospective multicentered analysis of the pooled data from 446 patients monitored using the transpulmonary thermodilution before and after fluid expansion (FE) was performed. FE was standardized between intensive care units (ICUs). The comparison of patients with and without NE at the time of fluid infusion was performed. Stroke volume (SV) responsiveness was defined as an increase of more than 15% of SV following the FE. Pressure responsiveness was defined as an increase of more than 15% of mean arterial pressure (MAP) following the FE. Arterial elastance was used as a surrogate for the arterial load.ResultsA total of 244 patients were treated with NE and 202 were not treated with NE. By using the univariate analysis, arterial elastance was correlated to SV variations with FE. However, the SV variations were not associated with NE administration (26 [15; 46]% vs. 23 [10; 37]%, p = 0.12). By using the multivariate analysis, high arterial load and NE administration were associated with fluid responsiveness. The association between arterial elastance and fluid responsiveness was less important in patients treated with NE. Arterial compliance increased in the absence of NE, but it did not change in patients treated with NE (6 [−8; 19]% vs. 0 [−13; 15]%, p = 0.03). The changes in total peripheral and arterial elastance were less important in patients treated with NE (−8 [−17; 1]% vs. −11 [−20; 0]%, p < 0.05 and −10 [−19; 0]% vs. −16 [−24; 0]%, p = 0.01).ConclusionThe arterial load and NE administration were associated with fluid responsiveness. A high arterial load was associated with fluid responsiveness. In patients treated with NE, this association was lower, and the changes of arterial load following FE seemed to be driven mainly by its resistive component.

Abstract 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.

Introduction: It has been suggested that dynamic arterial elastance (Eadyn) can predict decreases in arterial pressure in response to changing norepinephrine levels. The objective of this study was to determine whether Eadyn is correlated with determinants of the vascular waterfall [critical closing pressure (CCP) and systemic arterial resistance (SARi)] in patients treated with norepinephrine.Materials and Methods: Patients treated with norepinephrine for vasoplegia following cardiac surgery were studied. Vascular and flow parameters were recorded immediately before the norepinephrine infusion and then again once hemodynamic parameters had been stable for 15 min. The primary outcomes were Eadyn and its associations with CCP and SARi. The secondary outcomes were the associations between Eadyn and vascular/flow parameters.Results: At baseline, all patients were hypotensive with Eadyn of 0.93 [0.47;1.27]. Norepinephrine increased the arterial blood pressure, cardiac index, CCP, total peripheral resistance (TPRi), arterial elastance, and ventricular elastance and decreased Eadyn [0.40 (0.30;0.60)] and SARi. Eadyn was significantly associated with arterial compliance (CA), CCP, and TPRi (p < 0.05).Conclusion: In patients with vasoplegic syndrome, Eadyn was correlated with determinants of the vascular waterfall. Eadyn is an easy-to-read functional index of arterial load that can be used to assess the patient’s macro/microcirculatory status.Clinical Trial Registration:ClinicalTrials.gov #NCT03478709.

IntroductionDuring peritonitis, lipopolysaccharides (LPS) cross the peritoneum and pass through the liver before reaching the central compartment. The aim of the present study was to investigate the role of lipoproteins and phospholipid transfer protein (PLTP) in the early stages of LPS detoxification.Material and MethodsPeritonitis was induced by intra-peritoneal injection of LPS in mice. We analyzed peritoneal fluid, portal and central blood. Lipoprotein fractions were obtained by ultracentrifugation and fast protein liquid chromatography. LPS concentration and activity were measured by liquid chromatography coupled with mass spectrometry and limulus amoebocyte lysate. Wild-type mice were compared to mice knocked out for PLTP.ResultsIn mice expressing PLTP, LPS was able to bind to HDL in the peritoneal compartment, and this was maintained in plasma from portal and central blood. A hepatic first-pass effect of HDL-bound LPS was observed in wild-type mice. LPS binding to HDL resulted in an early arrival of inactive LPS in the central blood of wild-type mice.ConclusionPLTP promotes LPS peritoneal clearance and neutralization in a model of peritonitis. This mechanism involves the early binding of LPS to lipoproteins inside the peritoneal cavity, which promotes LPS translocation through the peritoneum and its uptake by the liver.

Background: Ultrasound-guided axillary brachial plexus block (ABPB) is a technique of choice for regional anesthesia during hand and forearm surgery. Intravenous sedation may facilitate this procedure, particularly for those suffering from anxiety; however, it can also be associated with respiratory, cardiovascular, and neurological side effects. The objective of this study was to evaluate the effect of intravenous sedation on perioperative respiratory depression for patients undergoing day-case hand surgery under ABPB. Methods: A prospective, observational, single-center study was conducted between 1 May and 1 November 2016. Results: A total of 2318 patients were included, with 501 patients in the group with IV sedation and 1817 in the group without. A multivariable propensity-score matched analysis showed that the variables associated with the number of desaturation were: (i) sedation (aRR 1.534 [95% CI: 1.283 to 1.836]), (ii) age and sex, (iii) type of surgery, and iv) Body Mass Index (BMI). Conclusions: Supplementing ABPB with IV sedation was associated with an increased rate of respiratory depression (episodes of desaturation) compared to fully awakened patients. The rate of oxygen administration was also higher in sedated patients even though they had fewer cases of chronic respiratory diseases and fewer were active smokers than non-sedated patients. Future research should consider precisely evaluating patient satisfaction, as well as the differences between sedation and drug-free approaches.

Abstract Background Minimal invasive heart surgery (MIHS) presents several benefits, but provides intense and prolonged post-operative pain. Our objective was to compare efficacy of serratus anterior plane block (SAPB) with continuous wound infiltration (CWI) for management of post-operative pain following MIHS. Methods It’s retrospective, monocentric study between November 2016 to April 2017. The study was performed at the University hospital of Dijon, Burgundy, France. All patients scheduled for MIHS was included. Data was collected retrospectively. During this period, 20 patients had SAPB and 26 had CWI. SAPB was performed before extubation with a single injection of 0.5 mg/kg of ropivacaïne (5 mg/ml). In the CWI group, catheter was inserted in the subcutaneous space by the surgeon at the end of the procedure. A 10 ml bolus of ropivacaïne (7.5 mg/mL) was followed by a continuous infusion (2 mg/ml) between 7 and 12 ml/h for 48 h. Morphine consumption and visual analog score (VAS) were recorded for 48 h. Length of stay in intensive care unit and hospital was also collected. Results Morphine consumption and VAS score were significantly lower in SAPB group (p

An amendment to this paper has been published and can be accessed via the original article.

An amendment to this paper has been published and can be accessed via the original article.

We describe here an unusual case of brain death following cardiac arrest. Brain electric activity had totally ceased, allowing the confirmation of brain death, despite normal cerebral blood flow (assessed by both transcranial doppler and tomodensitometry) and no evidence of intracranial hypertension. In our case, a residual electric activity was assessed at admission and lesions worsened on imaging during ICU stay, suggesting that part of the neuronal damage occurred after brain reperfusion. All these elements suggest BD rather by cellular toxicity than intracranial pressure elevation.