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Abstract The incidence of heat-related illnesses and heatstroke continues to rise amidst global warming. Hyperthermia triggers inflammation, coagulation, and progressive multiorgan dysfunction, and, at levels above 40 °C, can even lead to cell death. Blood cells, particularly granulocytes and platelets, are highly sensitive to heat, which promotes proinflammatory and procoagulant changes. Key factors in heatstroke pathophysiology involve mitochondrial thermal damage and excessive oxidative stress, which drive apoptosis and necrosis. While the kinetics of cellular damage from heat have been extensively studied, the mechanisms driving heat-induced organ damage and death are not yet fully understood. Converse to hyperthermia, hypothermia is generally protective, as seen in therapeutic hypothermia. However, accidental hypothermia presents another environmental threat due to arrhythmias, cardiac arrest, and coagulopathy. From a cellular physiology perspective, hypothermia generally supports mitochondrial homeostasis and enhances cell preservation, aiding whole-body recovery following resuscitation. This review summarizes recent findings on temperature-related cellular damage and preservation and suggests future research directions for understanding the tempo-physiologic axis.

Abstract Diagnosing coagulopathy in septic patients remains challenging in intensive care. Disseminated intravascular coagulation (DIC) indeed presents with complex pathophysiology, complicating timely diagnosis. Epidemiological data indicate a significant prevalence of DIC in septic patients, with mortality rates up to 60%. Despite advances, current biomarker-based diagnostic tools often fail to provide early and accurate detection. This review evaluates the utility and limitations of traditional and emerging biomarkers for diagnosing sepsis-induced coagulopathy (SIC) and DIC. We also assess the effectiveness of anticoagulant therapy guided by biomarker-based diagnostic criteria.

Abstract In sepsis, inflammation, and nutrient deficiencies endanger cellular homeostasis and survival. Autophagy is primarily a mechanism of cellular survival under fasting conditions. However, autophagy-dependent cell death, known as autophagic cell death, is proinflammatory and can exacerbate sepsis. Autophagy also regulates various types of non-inflammatory and inflammatory cell deaths. Non-inflammatory apoptosis tends to suppress inflammation, however, inflammatory necroptosis, pyroptosis, ferroptosis, and autophagic cell death lead to the release of inflammatory cytokines and damage-associated molecular patterns (DAMPs) and amplify inflammation. The selection of cell death mechanisms is complex and often involves a mixture of various styles. Similarly, protective autophagy and lethal autophagy may be triggered simultaneously in cells. How cells balance the regulatory mechanisms of these processes is an area of interest that is still under investigation. Therapies aimed at modulating autophagy are considered promising. Enhancing autophagy helps clear and recycle damaged organelles and reduce the burden of inflammatory processes while inhibiting excessive autophagy, which could prevent autophagic cell death. In this review, we introduce recent advances in research and the complex regulatory system of autophagy in sepsis.

Abstract The mortality rate of sepsis remains high and further increases when complicated by disseminated intravascular coagulation (DIC). Consequently, early detection and appropriate management of DIC will be helpful for the management of sepsis. Although overt DIC criteria are often used for diagnosing definitive DIC, it was not designed to detect early-phase DIC. The criteria and scoring system for sepsis-induced coagulopathy (SIC) were developed and introduced in 2017 to detect early-stage DIC, and they were subsequently adopted by the International Society on Thrombosis and Haemostasis in 2019. The objective of detecting SIC was not to miss the patients at high risk of developing overt DIC at an earlier time. Although anticoagulant therapies are potential options for the treatment of sepsis-associated DIC, their effectiveness has not been established, and further research is warranted. For that purpose, an international collaborative platform is required for future clinical trials, and SIC criteria have been suggested for such studies. Calculating the SIC score is straightforward and suitable for use in clinical settings. This review aims to introduce SIC criteria and its scoring system for better management of sepsis-associated DIC. We also intended to update the current knowledge regarding this novel diagnostic criterion.

Abstract Introduction Although largely used, the place of oxygen therapy and its devices in patients with acute hypoxemic respiratory failure (ARF) deserves to be clarified. The French Intensive Care Society (Société de Réanimation de Langue Française, SRLF) and the French Emergency Medicine Society (Société Française de Médecine d’Urgence, SFMU) organized a consensus conference on oxygen therapy in ARF (excluding acute cardiogenic pulmonary oedema and hypercapnic exacerbation of chronic obstructive diseases) in December 2023. Methods A committee without any conflict of interest (CoI) with the subject defined 7 generic questions and drew up a list of sub questions according to the population, intervention, comparison and outcomes (PICO) model. An independent work group reviewed the literature using predefined keywords. The quality of the data was assessed using the GRADE methodology. Fifteen experts in the field from both societies proposed their own answers in a public session and answered questions from the jury (a panel of 16 critical-care and emergency medicine physicians, nurses and physiotherapists without any CoI) and the public. The jury then met alone for 48 h to write its recommendations. Results The jury provided 22 statements answering 11 questions: in patients with ARF (1) What are the criteria for initiating oxygen therapy? (2) What are the targets of oxygen saturation? (3) What is the role of blood gas analysis? (4) When should an arterial catheter be inserted? (5) Should standard oxygen therapy, high-flow nasal cannula oxygen therapy (HFNC) or continuous positive airway pressure (CPAP) be preferred? (6) What are the indications for non-invasive ventilation (NIV)? (7) What are the indications for invasive mechanical ventilation? (8) Should awake prone position be used? (9) What is the role of physiotherapy? (10) Which criteria necessarily lead to ICU admission? (11) Which oxygenation device should be preferred for patients for whom a do-not-intubate decision has been made? Conclusion These recommendations should optimize the use of oxygen during ARF.

Abstract Background The underrepresentation of women in leadership remains a pervasive issue, prompting a critical examination of support mechanisms within professional settings. Previous studies have identified challenges women face, ranging from limited visibility to barriers to career advancement. This survey aims to investigate perceptions regarding the effectiveness of women’s leadership programs, mentoring initiatives, and a specialized communication course. Particularly it specifically targets addressing the challenges encountered by professional women. Methods This multi-center, observational, international online survey was developed in partnership between ESICM NEXT and the ESICM Diversity and Inclusiveness Monitoring Group for Healthcare. Invitations to participate were distributed to both females and men through emails and social networks. Data were collected from April 1, 2023, through October 1, 2023. Results Out of 354 respondents, 90 were men (25.42%) and 264 were women (74.58%). Among them, 251 completed the survey, shedding light on the persistent challenges faced by women in leadership roles, with 10%-50% of respondents holding such positions. Women’s assertiveness is viewed differently, with 65% recognizing barriers such as harassment. Nearly half of the respondent’s experience interruptions in meetings. Only 47.4% receiving conference invitations, with just over half accepting them. A mere 12% spoke at ESICM conferences in the last three years, receiving limited support from directors and colleagues, indicating varied obstacles for female professionals. Encouraging family participation, reducing fees, providing childcare, and offering economic support can enhance conference involvement. Despite 55% applying for ESICM positions, barriers like mobbing, harassment, lack of financial support, childcare, and language barriers were reported. Only 14% had access to paid family leave, while 32% benefited from subsidized childcare. Participation in the Effective Communication Course on Career Advancement Goals and engagement in women’s leadership and mentoring programs could offer valuable insights and growth opportunities. Collaborating with Human Resources and leadership allies is crucial for overcoming barriers and promoting women’s career growth. Conclusions The urgency of addressing identified barriers to female leadership in intensive care medicine is underscored by the survey’s comprehensive insights. A multifaceted and intersectional approach, considering sexism, structural barriers, and targeted strategies, is essential.

Abstract Background There is no reliable indicator that can assess the treatment effect of anticoagulant therapy for sepsis-associated disseminated intravascular coagulation (DIC) in the short term. The aim of this study is to develop and validate a prognostic index identifying 28-day mortality in septic DIC patients treated with antithrombin concentrate after a 3-day treatment. Methods The cohort for derivation was established utilizing the dataset from post-marketing surveys, while the cohort for validation was acquired from Japan’s nationwide sepsis registry data. Through univariate and multivariate analyses, variables that were independently associated with 28-day mortality were identified within the derivation cohort. Risk variables were then assigned a weighted score based on the risk prediction function, leading to the development of a composite index. Subsequently, the area under the receiver operating characteristic curve (AUROC). 28-day survival was compared by Kaplan–Meier analysis. Results In the derivation cohort, 252 (16.9%) of the 1492 patients deceased within 28 days. Multivariable analysis identified DIC resolution (hazard ratio [HR]: 0.31, 95% confidence interval [CI]: 0.22–0.45, P

Abstract Maintaining tissue perfusion in sepsis depends on vascular integrity provided by the endothelial glycocalyx, the critical layer covering the luminal surface of blood vessels. The glycocalyx is composed of proteoglycans, glycosaminoglycans, and functional plasma proteins that are critical for antithrombogenicity, regulating tone, controlling permeability, and reducing endothelial interactions with leukocytes and platelets. Degradation of the glycocalyx in sepsis is substantial due to thromboinflammation, and treatments for sepsis and septic shock may exacerbate endotheliopathy via additional glycocalyx injury. As a result, therapeutic strategies aimed at preserving glycocalyx integrity should be considered, including modifications in fluid volume resuscitation, minimizing catecholamine use, controlling hyperglycemia, and potential use of corticosteroids and anticoagulants. In this review, we explore treatment strategies aligned with the recommendations outlined in the Surviving Sepsis Campaign Guidelines 2021 with a special emphasis on evidence regarding glycocalyx protection.

Abstract Background Disseminated intravascular coagulation (DIC) worsens the prognosis of septic shock and contributes to multiple organ failure. To date, no data linking DIC and acute kidney injury (AKI) occurrence, severity, and evolution in this setting are available. We aimed at analyzing the association between AKI occurrence, severity and evolution in patients with septic shock-induced DIC. In a prospective monocentric cohort study, consecutive patients, 18 years and older, admitted in the ICU of Strasbourg University Hospital in the setting of systemic hypotension requiring vasopressor related to an infection, without history of terminal chronic kidney disease were eligible. AKI was defined according to the KDIGO classification. DIC diagnosis was based on the International Society on Thrombosis and Haemostasis (ISTH) score. Evolution of AKI was evaluated through the composite endpoint of major adverse kidney events. Only patients with DIC that occurred before or at the time of AKI diagnosis were considered. Univariate and multivariate analysis were performed to determine factors associated with renal outcomes. Results 350 patients were included, of whom 129 experienced DIC. Patients with DIC were more seriously ill (median SAPS II 64 vs. 56, p

Objectives: Staphylococcus epidermidis (SE) is a supposedly low-virulence agent, which may cause proven bloodstream infections (BSIs), with little-known consequences on intensive care unit (ICU) patients. We aimed at studying ICU patients diagnosed with BSIs caused by SE (SE-BSIs). Methods: We constituted a retrospective cohort in two medical ICUs. SE-BSIs were defined by two or more independent SE-positive blood cultures of the same strain, within 48 hours, without concurrent infection. Results: We included 59 patients; 58% were men (n = 34), with median age of 67 (interquartile range 60-74) years and a simplified acute physiology score II of 59 (36-74) points, and 56% were immunocompromised (n = 33). Among the 37 (63%) patients requiring norepinephrine initiation or increase at the onset of SE-BSI versus patients not requiring vasopressors (37%; n = 22), concomitant arterial lactate levels reached 2.8 (1.9-5.8) versus 1.5 (1.3-2.2) mmol/l (P

Abstract Background Anticoagulants are widely used but can lead to iatrogenic events such as bleeding. Limited data exists regarding the characteristics and management of patients admitted to intensive care units (ICU) for severe anticoagulant-related extracranial bleeding. Methods A retrospective observational study was conducted in five French ICUs. From January 2007 to December 2018, all patients aged over 18 years admitted to ICU for extracranial bleeding while receiving therapeutic anticoagulation were included. Results 486 patients were included, mainly male (61%) with an average age of 73 ± 13 years. Most patients had comorbidities, including hypertension (68%), heart disease (49%) and diabetes (33%). Patients were treated by vitamin K antagonists (VKA, 54%), heparins (25%) and direct oral anticoagulants (DOAC, 7%). The incidence of patients admitted to ICU for anticoagulant-related bleeding increased from 3.2/1000 admissions in 2007 to 5.8/1000 in 2018. This increase was particularly high for DOAC class. Upon admission, patients exhibited severe organ failure, as evidenced by a high SOFA score (7 ± 4) and requirement for organ support therapies such as vasopressors (31.5%) and invasive mechanical ventilation (34%). Adherence to guidelines for the specific treatment of anticoagulant-related bleeding was generally low. ICU mortality was 27%. In multivariate analysis, five factors were independently associated with mortality: chronic hypertension, need for vasopressors, impaired consciousness, hyperlactatemia and prolonged aPTT > 1.2. Conclusion Anticoagulant-related extracranial bleeding requiring ICU admission is a serious complication responsible for organ failure and significant mortality. Its incidence is rising. The therapeutic management is suboptimal and could be improved by educational programs.

Abstract Background The International Society on Thrombosis and Haemostasis (ISTH) released overt disseminated intravascular coagulation (DIC) diagnostic criteria in 2001. Since then, DIC has been understood as the end-stage consumptive coagulopathy and not the therapeutic target. However, DIC is not merely a decompensated coagulation disorder, but also includes early stages with systemic activation in coagulation. Thus, the ISTH has recently released sepsis-induced coagulopathy (SIC) criteria that can diagnose compensated-phase of coagulopathy with readily available biomarkers. Main body DIC is a laboratory-based diagnosis due to various critical conditions, although sepsis is the most common underlying disease. The pathophysiology of sepsis-associated DIC is multifactorial, and in addition to coagulation activation with suppressed fibrinolysis, multiple inflammatory responses are initiated by activated leukocytes, platelets, and vascular endothelial cells as part of thromboinflammation. Although overt DIC diagnostic criteria were established by ISTH to diagnose the advanced stage of DIC, additional criteria that can detect an earlier stage of DIC were needed for potential therapeutic considerations. Accordingly, the ISTH introduced SIC criteria in 2019 that are easy to use and require only platelet count, prothrombin time-international normalized ratio, and Sequential Organ Failure Assessment Score. SIC score can be used to evaluate disease severity and determine the timing of potential therapeutic interventions. One of the major disadvantages in treating sepsis-associated DIC is the lack of availability of specific therapeutic approaches beyond treating the underlying infection. Clinical trials to date have failed because included patients who were not coagulopathic. Nevertheless, in addition to infection control, anticoagulant therapy will be the choice for sepsis-associated DIC. Therefore, the efficacy of heparin, antithrombin, and recombinant thrombomodulin has to be proven in future clinical studies. Conclusion It is necessary to develop a novel therapeutic strategy against sepsis-associated DIC and improve the outcomes. Consequently, we recommend screening and monitoring DIC using SIC scoring system.

Abstract Background Timely management of acute myocardial infarction (AMI) and acute stroke has undergone impressive progress during the last decade. However, it is currently unknown whether both sexes have profited equally from improved strategies. We sought to analyze sex-specific temporal trends in intensive care unit (ICU) admission and mortality in younger patients presenting with AMI or stroke in Switzerland. Methods Retrospective analysis of temporal trends in 16,954 younger patients aged 18 to ≤ 52 years with AMI or acute stroke admitted to Swiss ICUs between 01/2008 and 12/2019. Results Over a period of 12 years, ICU admissions for AMI decreased more in women than in men (− 6.4% in women versus − 4.5% in men, p

Introduction: Toll-like receptors play crucial roles in the sepsis-induced systemic inflammatory response. Septic shock mortality correlates with overexpression of neutrophilic TLR2 and TLR9, while the role of TLR4 overexpression remains a debate. In addition, TLRs are involved in the pathogenesis of viral infections such as COVID-19, where the single-stranded RNA of SARS-CoV-2 is recognized by TLR7 and TLR8, and the spike protein activates TLR4. Methods: In this study, we conducted a comprehensive analysis of TLRs 1–10 expressions in white blood cells from 71 patients with bacterial and viral infections. Patients were divided into 4 groups based on disease type and severity (sepsis, septic shock, moderate, and severe COVID-19) and compared to 7 healthy volunteers. Results: We observed a significant reduction in the expression of TLR4 and its co-receptor CD14 in septic shock neutrophils compared to the control group (p < 0.001). Severe COVID-19 patients exhibited a significant increase in TLR3 and TLR7 levels in neutrophils compared to controls (p < 0.05). Septic shock patients also showed a similar increase in TLR7 in neutrophils along with elevated intermediate monocytes (CD14+CD16+) compared to the control group (p < 0.005 and p < 0.001, respectively). However, TLR expression remained unchanged in lymphocytes. Conclusion: This study provides further insights into the mechanisms of TLR activation in various infectious conditions. Additional analysis is needed to assess their correlation with patient outcome and to evaluate the impact of TLR-pathway modulation during septic shock and severe COVID-19.

Introduction Corticosteroids affect variably survival in sepsis trials, suggesting heterogeneity in patients’ response to corticosteroids. The RECORDS (Rapid rEcognition of COrticosteRoiD resistant or sensitive Sepsis) trial aimed at defining endotypes associated with adults with sepsis responsiveness to corticosteroids.Methods and analysis RECORDS, a multicentre, placebo-controlled, biomarker-guided, adaptive Bayesian design basket trial, will randomly assign to a biomarker stratum 1800 adults with community-acquired pneumonia, vasopressor-dependent sepsis, septic shock or acute respiratory distress syndrome. In each stratum, patients will be randomly assigned to receive a 7-day course of hydrocortisone and fludrocortisone or their placebos. Patients with COVID-19 will be treated with a 10-day standard course of dexamethasone and randomised to fludrocortisone or its placebo. Primary outcome will be 90-day death or persistent organ dysfunction. Large simulation study will be performed across a range of plausible scenarios to foresee power to detect a 5%–10% absolute difference with corticosteroids. We will assess subset-by-treatment interaction by estimating in a Bayesian framework two quantities: (1) measure of influence, relying on the value of the estimation of corticosteroids’ effect in each subset, and (2) measure of interaction.Ethics and dissemination The protocol was approved by the Ethics Committee (Comité de Protection des Personnes, Dijon, France), on 6 April 2020. Trial results will be disseminated at scientific conferences and results will be published in peer-reviewed journals.Trial registration number ClinicalTrials.gov Registry (NCT04280497).

Abstract Background In comatose patients receiving oro-tracheal intubation for mechanical ventilation (MV), the risk of aspiration is increased. Aspiration can lead to chemical pneumonitis (inflammatory reaction to the gastric contents), or aspiration pneumonia (infection caused by inhalation of microorganisms). Distinguishing between the two types is challenging. We tested the interest of using a decisional algorithm based on procalcitonin (PCT) values to guide initiation and discontinuation of antibiotic therapies in intubated patients. Methods The PROPASPI (PROcalcitonin Pneumonia/pneumonitis Associated with ASPIration) trial is a multicenter, prospective, randomized, controlled, single-blind, superiority study comparing two strategies: (1) an intervention group where threshold PCT values were used to guide initiation and discontinuation of antibiotics (PCT group); and (2) a control group, where antibiotic therapy was managed at the physician’s discretion. Patients aged 18 years or over, intubated for coma (Glasgow score ≤ 8), with MV initiated within 48 h after admission, were eligible. The primary endpoint was the duration of antibiotic treatment during the first 15 days after admission to the ICU. Results From 24/2/2015 to 28/8/2019, 1712 patients were intubated for coma in the 5 participating centers, of whom 166 were included in the study. Data from 159 were available for intention-to-treat analysis: 81 in the PCT group, and 78 in the control group. Overall, 67 patients (43%) received antibiotics in the intensive care unit (ICU); there was no significant difference between groups (37 (46%) vs 30 (40%) for PCT vs control, p = 0.432). The mean duration of antibiotic treatment during the first 15 days in the ICU was 2.7 ± 3.8 days; there was no significant difference between groups (3.0 ± 4.1 days vs 2.3 ± 3.4 days for PCT vs control, p = 0.311). The mean number of days under MV was significantly higher in the PCT group (3.7 ± 3.6 days) than in controls (2.7 ± 2.5 days, p = 0.033). The duration of ICU stay was also significantly longer in the PCT group: 6.4 ± 6.5 days vs 4.6 ± 3.5 days in the control group (p = 0.043). After adjustment for SAPS II score, the difference in length of stay and duration of mechanical ventilation between groups was no longer significant. Conclusion The use of PCT values to guide therapy, in comparison to the use of clinical, biological (apart from PCT) and radiological criteria, does not modify exposure to antibiotics in patients intubated for coma. Trial registration Clinicaltrials.gov Identifier NCT02862314.

Abstract Background Differences in physiology of ARDS have been described between COVID-19 and non-COVID-19 patients. This study aimed to compare initial values and longitudinal changes in respiratory system compliance (C RS), oxygenation parameters and ventilatory ratio (VR) in patients with COVID-19 and non-COVID-19 pulmonary ARDS matched on oxygenation. Methods 135 patients with COVID-19 ARDS from two centers were included in a physiological study; 767 non-COVID-19 ARDS from a clinical trial were used for the purpose of at least 1:2 matching. A propensity-matching was based on age, severity score, oxygenation, positive end-expiratory pressure (PEEP) and pulmonary cause of ARDS and allowed to include 112 COVID-19 and 198 non-COVID pulmonary ARDS. Results The two groups were similar on initial oxygenation. COVID-19 patients had a higher body mass index, higher C RS at day 1 (median [IQR], 35 [28–44] vs 32 [26–38] ml cmH2O−1, p = 0.037). At day 1, C RS was correlated with oxygenation only in non-COVID-19 patients; 61.6% and 68.2% of COVID-19 and non-COVID-19 pulmonary ARDS were still ventilated at day 7 (p = 0.241). Oxygenation became lower in COVID-19 than in non-COVID-19 patients at days 3 and 7, while C RS became similar. VR was lower at day 1 in COVID-19 than in non-COVID-19 patients but increased from day 1 to 7 only in COVID-19 patients. VR was higher at days 1, 3 and 7 in the COVID-19 patients ventilated using heat and moisture exchangers compared to heated humidifiers. After adjustment on PaO2/FiO2, PEEP and humidification device, C RS and VR were found not different between COVID-19 and non-COVID-19 patients at day 7. Day-28 mortality did not differ between COVID-19 and non-COVID-19 patients (25.9% and 23.7%, respectively, p = 0.666). Conclusions For a similar initial oxygenation, COVID-19 ARDS initially differs from classical ARDS by a higher C RS, dissociated from oxygenation. C RS become similar for patients remaining on mechanical ventilation during the first week of evolution, but oxygenation becomes lower in COVID-19 patients. Trial registration: clinicaltrials.gov NCT04385004

Abstract Background The phase 3 multinational SCARLET study evaluated the efficacy and safety of a recombinant human soluble thrombomodulin (ART-123) for treatment of sepsis-associated coagulopathy (SAC), which correlates with increased mortality risk in patients with sepsis. Although no significant reduction in mortality was observed with ART-123 compared with placebo in the full analysis set (FAS), an efficacy signal of ART-123 was observed in subgroups of patients who sustained coagulopathy until the first treatment and those not administered concomitant heparin. Post hoc analysis was performed of patients treated in France, the country with the largest enrollment (19% of the FAS) and consistent patient enrollment throughout the study duration. Methods Adult patients with SAC (international normalized ratio > 1.4; platelets > 30 × 109/L to 30% within 24 h) and evidence of bacterial infection were included. The primary efficacy outcome was 28-day all-cause mortality. Safety outcomes included adverse, serious adverse, and major bleeding events. This analysis assessed patient characteristics and efficacy and safety outcomes in France compared with the rest of the world (ROW; excluding France). Mortality rates were assessed in patients in France or the ROW with characteristics previously associated with ART-123 efficacy. Results Baseline characteristics were similar between France and the ROW, but some measurements of disease severity were higher in patients in France. The 28-day all-cause mortality absolute risk reductions (ARRs) with ART-123 were 8.3% in France and 1.1% in the ROW. The greater ARR in France may be related to a higher rate of sustained coagulopathy and lower rate of heparin use. In France and the ROW, 84.6% and 78.0% of patients sustained coagulopathy from the time of initial SAC diagnosis to first treatment with the study drug, and 65.8% and 43.9% did not receive heparin, respectively. The ARRs for these subgroups of patients in France were 13.4% and 16.6%, respectively. Safety of ART-123 was comparable between France and the ROW. Conclusions Results from this exploratory analysis suggest that patients with sustained SAC not receiving concomitant heparin may benefit from ART-123, a fact that should be confirmed in future studies with more restrictive inclusion criteria.

In this paper, we propose to account for the blame addressed to vaccine skeptics and “anti-vax” (VS and AV) by considering their attitude as the result of the psychological mechanism of denial, understood in a psychodynamic manner. To that effect, we draw on a secondary account of our clinical experience in two hospital units (psychiatry and intensive care unit), and on openly available media material. First, we lay out how VS and AV can be understood as the result from fetishist risk denial, a specific psychological transaction with an object by which VS and AV people feel intimately protected; this object is viewed as so powerful that its protection makes the vaccine appear irrelevant. Second, we show how this mechanism can explain the specific content of the blame frequently addressed to VS and AV, who are reproached with being selfish by vaccinated people and caregivers. We contend that, contrary to common belief, they are thus blamed because they force others (and especially caregivers) to compensate their lack of self-protection and preservation, which derives from their exclusive relation to an almighty object. While such a relation accounts for the unwillingness to consider vaccination, it also explains the harshness of the blame voiced by caregivers, who feel helpless in most situations as they cannot effectively force VS and AV to take care of themselves and others.

Abstract Background Thromboprophylaxis of COVID-19 patients is a highly debated issue. We aimed to compare the occurrence of thrombotic/ischemic events in COVID-19 patients with acute respiratory distress syndrome (ARDS) treated with either prophylactic or therapeutic dosage of heparin. All patients referred for COVID-19 ARDS in two intensive care units (ICUs) from two centers of a French tertiary hospital were included in our cohort study. Patients were compared according to their anticoagulant treatment to evaluate the risk/benefit of prophylactic anticoagulation versus therapeutic anticoagulation. Medical history, symptoms, biological data and imaging were prospectively collected. Results One hundred and seventy-nine patients (73% men) were analyzed: 108 in prophylactic group and 71 in therapeutic group. Median age and SAPS II were 62 [IQR 51; 70] years and 47 [IQR 37; 63] points. ICU mortality rate was 17.3%. Fifty-seven patients developed clinically relevant thrombotic complications during their ICU stay, less frequently in therapeutic group (adjusted OR 0.38 [0.14–0.94], p = 0.04). The occurrences of pulmonary embolism (PE), deep vein thrombosis (DVT) and ischemic stroke were significantly lower in the therapeutic group (respective adjusted OR for PE: 0.19 [0.03–0.81]; DVT: 0.13 [0.01–0.89], stroke: 0.06 [0–0.68], all p

Abstract Background During COVID-19 pandemic, visits have been prohibited in most French ICUs. Psychological effects, for reference persons (RPs), of remote-only communication have been assessed. Methods All RPs of patients referred to ICU for COVID-19 were included. HADS, IES-R, and satisfaction were evaluated at admission, discharge/death, and 3 months. At 3 months, a psychologist provided a qualitative description of RPs’ psychological distress. Results Eighty-eight RPs were included. Prevalence of anxiety and depression was 83% and 73% respectively. At 3 months, lower HADS decrease was associated with patient death/continued hospitalization, and/or sleeping disorders in RPs (p

Abstract Background Neurotropism of SARS-CoV-2 and its neurological manifestations have now been confirmed. We aimed at describing delirium and neurological symptoms of COVID-19 in ICU patients. Methods We conducted a bicentric cohort study in two French ICUs of Strasbourg University Hospital. All the 150 patients referred for acute respiratory distress syndrome due to SARS-CoV-2 between March 3 and May 5, 2020, were included at their admission. Ten patients (6.7%) were excluded because they remained under neuromuscular blockers during their entire ICU stay. Neurological examination, including CAM-ICU, and cerebrospinal fluid analysis, electroencephalography, and magnetic resonance imaging (MRI) were performed in some of the patients with delirium and/or abnormal neurological examination. The primary endpoint was to describe the incidence of delirium and/or abnormal neurological examination. The secondary endpoints were to describe the characteristics of delirium, to compare the duration of invasive mechanical ventilation and ICU length of stay in patients with and without delirium and/or abnormal neurological symptoms. Results The 140 patients were aged in median of 62 [IQR 52; 70] years old, with a median SAPSII of 49 [IQR 37; 64] points. Neurological examination was normal in 22 patients (15.7%). One hundred eighteen patients (84.3%) developed a delirium with a combination of acute attention, awareness, and cognition disturbances. Eighty-eight patients (69.3%) presented an unexpected state of agitation despite high infusion rates of sedative treatments and neuroleptics, and 89 (63.6%) patients had corticospinal tract signs. Brain MRI performed in 28 patients demonstrated enhancement of subarachnoid spaces in 17/28 patients (60.7%), intraparenchymal, predominantly white matter abnormalities in 8 patients, and perfusion abnormalities in 17/26 patients (65.4%). The 42 electroencephalograms mostly revealed unspecific abnormalities or diffuse, especially bifrontal, slow activity. Cerebrospinal fluid examination revealed inflammatory disturbances in 18/28 patients, including oligoclonal bands with mirror pattern and elevated IL-6. The CSF RT-PCR SARS-CoV-2 was positive in one patient. The delirium/neurological symptoms in COVID-19 patients were responsible for longer mechanical ventilation compared to the patients without delirium/neurological symptoms. Delirium/neurological symptoms could be secondary to systemic inflammatory reaction to SARS-CoV-2. Conclusions and relevance Delirium/neurological symptoms in COVID-19 patients are a major issue in ICUs, especially in the context of insufficient human and material resources. Trial registration NA.

Abstract Background There is no gold standard to diagnose septic shock-induced disseminated intravascular coagulation (DIC). The objective of our multicenter prospective study was to assess the performances of the different major scoring systems in terms of mortality prediction and DIC diagnosis. The JAAM-DIC 2016 score, the ISTH overt-DIC 2001 score, the associations of sepsis-induced coagulopathy (SIC) score with JAAM-DIC 2016 or ISTH overt-DIC scores were tested in patients within 12 h of their admission in ICU for septic shock (day 1) and at day 2. Results 582 patients were enrolled in the study. 182/567 (32.1%) were diagnosed with DIC according to ISTH overt-DIC score, and 193/561 (34.4%) according to JAAM-DIC score; 486/577 patients (84.2%) were diagnosed with a coagulopathy according to SIC score. A moderate concordance was observed between ISTH overt-DIC and JAAM-DIC [κ = 0.67 (0.60, 0.73), p

Abstract Background The influence of socioeconomic status on patient outcomes is unclear. We assessed the impact of socioeconomic deprivation on severity of illness at intensive care unit (ICU) admission, and on the risk of death at 3 months after ICU admission. Methods The IVOIRE study was a prospective, observational, multicentre cohort study in the ICU of 8 participating hospitals in France, including patients aged ≥ 18 years admitted to the ICU and receiving at least one life support therapy for organ failure. The primary outcomes were severity at admission (assessed by SAPSII score), and mortality at 3 months. Socioeconomic data were obtained from interviews with patients or family. Deprivation was assessed using the EPICES score. Results Among 1294 patents included between 2013 and 2016, 629 (48.6%) were classed as deprived and differed significantly from non-deprived subjects in terms of sociodemographic characteristics and pre-existing conditions. The mean SAPS II score at admission was 50.1 ± 19.4 in deprived patients and 52.3 ± 17.3 in non-deprived patients, with no significant difference by multivariable analysis (β = − 1.85 [95% CI − 3.86; + 0.16, p = 0.072]). The proportion of death was 31.1% at 3 months, without significant differences between deprived and non-deprived patients, even after adjustment for confounders. Conclusions Deprivation is frequent in patients admitted to the ICU and is not associated with disease severity at admission, or with mortality at 3 months between deprived and non-deprived patients. Trial registration The IVOIRE cohort is registered with ClinicalTrials.gov under the identifier NCT01907581, registration date 17/7/2013

Biological rhythms are important regulators of immune functions. In intensive care unit (ICU), sepsis is known to be associated with rhythm disruption. Our objectives were to determine factors associated with rhythm disruption of the body temperature and to assess the relationship between temperature and mortality in septic shock patients; In a cohort of septic shock, we recorded body temperature over a 24-h period on day 2 after ICU admission. For each patient, the temperature rhythmicity was assessed by defining period and amplitude, and the adjusted average (mesor) of the temperature by sinusoidal regression and cosinor analysis. Analyses were performed to assess factors associated with the three temperature parameters (period, amplitude, and mesor) and mortality. 162 septic shocks were enrolled. The multivariate analysis demonstrates that the period of temperature was associated with gender (women, coefficient −2.2 h, p = 0.031) and acetaminophen use (coefficient −4.3 h, p = 0.002). The mesor was associated with SOFA score (coefficient −0.05 °C per SOFA point, p = 0.046), procalcitonin (coefficient 0.001 °C per ng/mL, p = 0.005), and hydrocortisone use (coefficient −0.5 °C, p = 0.002). The amplitude was associated with the dialysis (coefficient −0.5 °C, p = 0.002). Mortality at day 28 was associated with lower mesor (adjusted hazard ratio 0.50, 95% CI 0.28 to 0.90; p = 0.02), and higher amplitude (adjusted hazard ratio 5.48, 95% CI 1.66 to 18.12; p = 0.005) of temperature. Many factors, such as therapeutics, influence the body temperature during septic shock. Lower mesor and higher amplitude were associated with mortality and could be considered prognostic markers in ICU. In the age of artificial intelligence, the incorporation of such data in an automated scoring alert could compete with physicians to identify high-risk patients during septic shock.

Introduction Pre-emptive inhaled antibiotics may be effective to reduce the occurrence of ventilator-associated pneumonia among critically ill patients. Meta-analysis of small sample size trials showed a favourable signal. Inhaled antibiotics are associated with a reduced emergence of antibiotic resistant bacteria. The aim of this trial is to evaluate the benefit of a 3-day course of inhaled antibiotics among patients undergoing invasive mechanical ventilation for more than 3 days on the occurrence of ventilator-associated pneumonia.Methods and analysis Academic, investigator-initiated, parallel two group arms, double-blind, multicentre superiority randomised controlled trial. Patients invasively ventilated more than 3 days will be randomised to receive 20 mg/kg inhaled amikacin daily for 3 days or inhaled placebo (0.9% Sodium Chloride). Occurrence of ventilator-associated pneumonia will be recorded based on a standardised diagnostic framework from randomisation to day 28 and adjudicated by a centralised blinded committee.Ethics and dissemination The protocol and amendments have been approved by the regional ethics review board and French competent authorities (Comité de protection des personnes Ouest I, No.2016-R29). All patients will be included after informed consent according to French law. Results will be disseminated in international scientific journals.Trial registration numbers EudraCT 2016-001054-17 and NCT03149640.

Abstract Background Nephrotoxic drug prescription may contribute to acute kidney injury (AKI) occurrence and worsening among critically ill patients and thus to associated morbidity and mortality. The objectives of this study were to describe nephrotoxic drug prescription in a large intensive-care unit cohort and, through a case–control study nested in the prospective cohort, to evaluate the link of nephrotoxic prescription burden with AKI. Results Six hundred and seventeen patients (62%) received at least one nephrotoxic drug, among which 303 (30%) received two or more. AKI was observed in 609 patients (61%). A total of 351 patients were considered as cases developing or worsening AKI a given index day during the first week in the intensive-care unit. Three hundred and twenty-seven pairs of cases and controls (patients not developing or worsening AKI during the first week in the intensive-care unit, alive the case index day) matched on age, chronic kidney disease, and simplified acute physiology score 2 were analyzed. The nephrotoxic burden prior to the index day was measured in drug.days: each drug and each day of therapy increasing the burden by 1 drug.day. This represents a semi-quantitative evaluation of drug exposure, potentially easy to implement by clinicians. Nephrotoxic burden was significantly higher among cases than controls: odds ratio 1.20 and 95% confidence interval 1.04–1.38. Sensitivity analysis showed that this association between nephrotoxic drug prescription in the intensive-care unit and AKI was predominant among the patients with lower severity of disease (simplified acute physiology score 2 below 48). Conclusions The frequently observed prescription of nephrotoxic drugs to critically ill patients may be evaluated semi-quantitatively through computing drug.day nephrotoxic burden, an index significantly associated with subsequent AKI occurrence, and worsening among patients with lower severity of disease.

Abstract Background Non-tunneled hemodialysis catheters are currently used for critically ill patients with acute kidney injury requiring extracorporeal renal replacement therapy. Strategies to prevent catheter dysfunction and infection with catheter locks remain controversial. Methods In a multicenter, randomized, controlled, double-blind trial, we compared two strategies for catheter locking of non-tunneled hemodialysis catheters, namely trisodium citrate at 4% (intervention group) versus unfractionated heparin (control group), in patients aged 18 years or older admitted to the intensive care unit and in whom a first non-tunneled hemodialysis catheter was to be inserted by the jugular or femoral vein. The primary endpoint was length of event-free survival of the first non-tunneled hemodialysis catheter. Secondary endpoints were: rate of fibrinolysis, incidence of catheter dysfunction and incidence of catheter-related bloodstream infection (CRBSI), all per 1000 catheter-days; number of hemorrhagic events requiring transfusion, length of stay in intensive care and in hospital; 28-day mortality. Results Overall, 396 randomized patients completed the trial: 199 in the citrate group and 197 in the heparin group. There was no significant difference in baseline characteristics between groups. The duration of event-free survival of the first non-tunneled hemodialysis catheter was not significantly different between groups: 7 days (IQR 3–10) in the citrate group and 5 days (IQR 3–11) in the heparin group (p = 0.51). Rates of catheter thrombosis, CRBSI, and adverse events were not statistically different between groups. Conclusions In critically ill patients, there was no significant difference in the duration of event-free survival of the first non-tunneled hemodialysis catheter between trisodium citrate 4% and heparin as a locking solution. Catheter thrombosis, catheter-related infection, and adverse events were not statistically different between the two groups. Trial registration Registered with Clinicaltrials.gov under the number NCT01962116. Registered 14 October 2013.

The protein Z (PZ)-dependent plasma protease inhibitor (ZPI) is a glycoprotein that inhibits factor XIa and, in the presence of PZ, FXa. Recently, ZPI has been shown to be an acute-phase protein (APP). As usually APPs downregulate the harmful effects of inflammation, we tested whether ZPI could modulate the increase of cytokines observed in inflammatory states. We observed that recombinant human ZPI (rhZPI) significantly decreases the levels of interleukin (IL)-1, IL-6, and tumor necrosis factor- α (TNF-α) induced by lipopolysaccharide (LPS) in a whole blood model. This inhibitory effect was unaffected by the presence of PZ or heparin. A ZPI mutant within the reactive loop center ZPI (Y387A), lacking anticoagulant activity, still had an anti-inflammatory activity. Surprisingly, rhZPI did not inhibit the synthesis of IL-6 or TNF-α when purified monocytes were stimulated by LPS, whereas the inhibitory effect was evidenced when lymphocytes were added to monocytes. The requirement of lymphocytes could be due to the synthesis of CCL5 (RANTES), a chemokine mainly produced by activated lymphocytes which is induced by rhZPI, and which can reduce the production of proinflammatory cytokines in whole blood. Lastly, we observed that the intraperitoneal injection of rhZPI significantly decreased LPS-induced IL-6 and TNF-α production in mouse plasma.

Background and Objectives: Cerebral complications related to the COVID-19 were documented by brain MRIs during the acute phase. The purpose of the present study was to describe the evolution of these neuroimaging findings (MRI and FDG-PET/CT) and describe the neurocognitive outcomes of these patients. Methods: During the first wave of the COVID-19 outbreak between 1 March and 31 May 2020, 112 consecutive COVID-19 patients with neurologic manifestations underwent a brain MRI at Strasbourg University hospitals. After recovery, during follow-up, of these 112 patients, 31 (initially hospitalized in intensive care units) underwent additional imaging studies (at least one brain MRI). Results: Twenty-three men (74%) and eight women (26%) with a mean age of 61 years (range: 18–79) were included. Leptomeningeal enhancement, diffuse brain microhemorrhages, acute ischemic strokes, suspicion of cerebral vasculitis, and acute inflammatory demyelinating lesions were described on the initial brain MRIs. During follow-up, the evolution of the leptomeningeal enhancement was discordant, and the cerebral microhemorrhages were stable. We observed normalization of the vessel walls in all patients suspected of cerebral vasculitis. Four patients (13%) demonstrated new complications during follow-up (ischemic strokes, hypoglossal neuritis, marked increase in the white matter FLAIR hyperintensities with presumed vascular origin, and one suspected case of cerebral vasculitis). Concerning the grey matter volumetry, we observed a loss of volume of 3.2% during an average period of approximately five months. During follow-up, the more frequent FDG-PET/CT findings were hypometabolism in temporal and insular regions. Conclusion: A minority of initially severe COVID-19 patients demonstrated new complications on their brain MRIs during follow-up after recovery.

Abstract Background Septic shock-induced disseminated intravascular coagulation is responsible for increased occurrence of multiple organ dysfunction and mortality. Immunothrombosis-induced coagulopathy may contribute to hypercoagulability. We aimed at determining whether recombinant human thrombomodulin (rhTM) could control exaggerated immunothrombosis by studying procoagulant responses, fibrinolysis activity borne by microvesicles (MVs) and NETosis in septic shock. Methods In a septic shock model after a cecal ligation and puncture-induced peritonitis (H0), rats were treated with rhTM or a placebo at H18, resuscitated and monitored during 4 h. At H22, blood was sampled to perform coagulation tests, to characterize MVs and to detect neutrophils extracellular traps (NETs). Lungs were stained with hematoxylin–eosin for inflammatory injury assessment. Results Coagulopathy was attenuated in rhTM-treated septic rats compared to placebo-treated rats, as attested by a significant decrease in procoagulant annexin A5+-MVs and plasma procoagulant activity of phospholipids and by a significant increase in antithrombin levels (84 ± 8 vs. 64 ± 6%, p

Abstract Host infection by a micro-organism triggers systemic inflammation, innate immunity and complement pathways, but also haemostasis activation. The role of thrombin and fibrin generation in host defence is now recognised, and thrombin has become a partner for survival, while it was seen only as one of the “principal suspects” of multiple organ failure and death during septic shock. This review is first focused on pathophysiology. The role of contact activation system, polyphosphates and neutrophil extracellular traps has emerged, offering new potential therapeutic targets. Interestingly, newly recognised host defence peptides (HDPs), derived from thrombin and other “coagulation” factors, are potent inhibitors of bacterial growth. Inhibition of thrombin generation could promote bacterial growth, while HDPs could become novel therapeutic agents against pathogens when resistance to conventional therapies grows. In a second part, we focused on sepsis-induced coagulopathy diagnostic challenge and stratification from “adaptive” haemostasis to “noxious” disseminated intravascular coagulation (DIC) either thrombotic or haemorrhagic. Besides usual coagulation tests, we discussed cellular haemostasis assessment including neutrophil, platelet and endothelial cell activation. Then, we examined therapeutic opportunities to prevent or to reduce “excess” thrombin generation, while preserving “adaptive” haemostasis. The fail of international randomised trials involving anticoagulants during septic shock may modify the hypothesis considering the end of haemostasis as a target to improve survival. On the one hand, patients at low risk of mortality may not be treated to preserve “immunothrombosis” as a defence when, on the other hand, patients at high risk with patent excess thrombin and fibrin generation could benefit from available (antithrombin, soluble thrombomodulin) or ongoing (FXI and FXII inhibitors) therapies. We propose to better assess coagulation response during infection by an improved knowledge of pathophysiology and systematic testing including determination of DIC scores. This is one of the clues to allocate the right treatment for the right patient at the right moment.

BackgroundIlio-psoas hematoma is a potentially lethal condition that can arise during hospital stay. However, neither the incidence nor the prognosis of patients whose stay in intensive care units (ICU) is complicated by a iatrogenic ilio-psoas hematoma is known.MethodsA bicentric retrospective study was conducted to compile the patients who developed an ilio-psoas hematoma while they were hospitalized in ICU between January 2009 and December 2016. Their biometric characteristics, pre-existing conditions, the circumstances in which the hematoma was diagnosed, the treatments they received and their prognosis were recorded.ResultsForty patients were diagnosed with an ilio-psoas hematoma during their ICU stay. The incidence of this complication was 3.8 cases for 1000 admissions, taking into account only patients who stayed more than three days in ICU. The median age of patients was 74 years old and the median time between admission and the diagnosis of ilio-psoas hematoma was 12.6 days. A large proportion of them was obese (42.5%) and/or under dialysis (50%) prior to developing their hematoma. Ninety-five percent of the patients had heparin at prophylactic or therapeutic doses. Only 10% of them were above the therapeutic range of anticoagulation. The ICU mortality rate was of 50% following this complication (versus a general mortality rate of 22% for the patients without IPH over the same period of time). Patients with IPH that were complicated by disseminated intravascular coagulopathy had a significantly higher mortality rate than those with IPH and no disseminated intravascular coagulopathy (OR 6.91, 95% CI [1.28; 58.8], p = 0.04).ConclusionAge, anticoagulation, a high body mass index and dialysis seem to be risk factors of developing an ilio-psoas hematoma in ICU. Iatrogenic ilio-psoas hematomas complicated by disseminated intravascular coagulopathies are more at risk of leading to death. It is noteworthy that activated partial thromboplastin time above the therapeutic range was not a good predictor of developing a hematoma for patients who received unfractioned heparin therapy.

Long chain n-3 fatty acid supplementation may modulate septic shock-induced host response to pathogen-induced sepsis. The composition of lipid emulsions for parenteral nutrition however remains a real challenge in intensive care, depending on their fatty acid content. Because they have not been assessed yet, we aimed at determining the respective effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) during septic shock-induced vascular dysfunction.In a peritonitis-induced septic shock model, rats were infused with EPA, DHA, an EPA/DHA mixture or 5% dextrose (D5) during 22 hours. From H18, rats were resuscitated and monitored during 4 hours. At H22, plasma, aorta and mesenteric resistance arteries were collected to perform ex vivo experiments.We have shown that septic rats needed an active resuscitation with fluid challenge and norepinephrine treatment, while SHAM rats did not. In septic rats, norepinephrine requirements were significantly decreased in DHA and EPA/DHA groups (10.6±12.0 and 3.7±8.0 μg/kg/min respectively versus 17.4±19.3 μg/kg/min in D5 group, p