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Background As of mid-June 2020, 7,500,000 people were infected with SARS-CoV-2 worldwide and 420,000 people died, mainly from coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome (ARDS). COVID-19-related ARDS is subject to a mortality rate of 50% and prolonged period of mechanical ventilation, with no specific pharmacological treatment currently available (Infection au nouveau Coronavirus (SARS-CoV-2), COVID-19, France et Monde. https://www.santepubliquefrance.fr/dossiers/coronavirus-covid-19). Because of its immunomodulatory action, we propose to evaluate the efficacy and safety of intravenous immunoglobulin (IVIG) administration in patients developing COVID-19-related ARDS. Methods The trial is a phase III double-blind, randomized, multicenter, parallel group, concurrent, controlled study in hospitalized participants with COVID-19 requiring mechanical ventilation using a sequential design. Participants in the treatment group will receive infusions of polyvalent immunoglobulin for 4 consecutive days, and the placebo group will receive an equivalent volume of sodium chloride 0.9% for the same duration. The primary outcome is the number of ventilator-free days up to the 28th day. Secondary objectives are to evaluate the effect of IVIG on (1) organ failure according to the Sequential Organ Failure Assessment (SOFA) score at 14 and 28 days, (2) lung injury score at 14 and 28 days, (3) the occurrence of grade 3 or 4 adverse events of IVIG, (4) length of intensive care unit (ICU) stay, (5) length of hospital stay, (6) functional outcomes at day 90 defined by the activities of daily living and instrumental activities of the daily living scales, and (7) 90-day survival. One hundred thirty-eight subjects will be randomized in a 1:1 ratio to IVIG or placebo groups (69 in each group), considering 90% power, alpha level 0.05 (two sides), and 0.67 effect size level. Discussion The ICAR trial investigates the effect of IVIG in COVID-19-related ARDS. We expect an increase in the survival rate and a reduction in the duration of mechanical ventilation, which is associated with significant morbidity. Trial registration EudraCT 2020-001570-30. ClinicalTrials.gov NCT04350580. Registered on 17 April 2020

Lower sepsis mortality rates imply that more patients are discharged from the hospital, but sepsis survivors often experience sequelae, such as functional disability, cognitive impairment, and psychiatric morbidity. Nevertheless, the mechanisms underlying these long-term disabilities are not fully understood. Considering the extensive use of animal models in the study of the pathogenesis of neuropsychiatric disorders, it seems adopting this approach to improve our knowledge of postseptic psychiatric symptoms is a logical approach. With the purpose of gathering and summarizing the main findings of studies using animal models of sepsis-induced psychiatric symptoms, we performed a systematic review of the literature on this topic. Thus, 140 references were reviewed, and most of the published studies suggested a time-dependent recovery from behavior alterations, despite the fact that some molecular alterations persist in the brain. This review reveals that animal models can be used to understand the mechanisms that underlie anxiety and depression in animals recovering from sepsis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-020-00981-9.

International audience; Rationale: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown.Objectives: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2

Decisions of withdrawal of life-sustaining therapy for patients with severe brain injury are often based on prognostic evaluations such as analysis of electroencephalography (EEG) reactivity (EEG-R). However, EEG-R usually relies on visual assessment, which requires neurophysiological expertise and is prone to inter-rater variability. We hypothesised that quantitative analysis of EEG-R obtained 3 days after patient admission can identify new markers of subsequent awakening and consciousness recovery.In this prospective observational study of patients with severe brain injury requiring mechanical ventilation, quantitative EEG-R was assessed using standard 11-lead EEG with frequency-based (power spectral density) and functional connectivity-based (phase-lag index) analyses. Associations between awakening in the intensive care unit (ICU) and reactivity to auditory and nociceptive stimulations were assessed with logistic regression. Secondary outcomes included in-ICU mortality and 3-month Coma Recovery Scale-Revised (CRS-R) score.Of 116 patients, 86 (74%) awoke in the ICU. Among quantitative EEG-R markers, variation in phase-lag index connectivity in the delta frequency band after noise stimulation was associated with awakening (adjusted odds ratio=0.89, 95% confidence interval: 0.81-0.97, P=0.02 corrected for multiple tests), independently of age, baseline severity, and sedation. This new marker was independently associated with improved 3-month CRS-R (adjusted β=-0.16, standard error 0.075, P=0.048), but not with mortality (adjusted odds ratio=1.08, 95% CI: 0.99-1.18, P=0.10).An early-stage quantitative EEG-R marker was independently associated with awakening and 3-month level of consciousness in patients with severe brain injury. This promising marker based on functional connectivity will need external validation before potential integration into a multimodal prognostic model.

Sepsis is a life-threatening condition induced by a deregulated host response to severe infection. Post-sepsis syndrome includes long-term psychiatric disorders, such as persistent anxiety and post-traumatic stress disorder, whose neurobiological mechanisms remain unknown. Using a reference mouse model of sepsis, we showed that mice that recovered from sepsis further developed anxiety-related behaviours associated with an exaggerated fear memory. In the brain, sepsis induced an acute pathological activation of a specific neuronal population of the central nucleus of the amygdala, which projects to the ventral bed nucleus of the stria terminalis. Using viral-genetic circuit tracing and in vivo calcium imaging, we observed that sepsis induced persistent changes in the connectivity matrix and in the responsiveness of these central amygdala neurons projecting to the ventral bed nucleus of the stria terminalis. The transient and targeted silencing of this subpopulation only during the acute phase of sepsis with a viral pharmacogenetic approach, or with the anti-epileptic and neuroprotective drug levetiracetam, prevented the subsequent development of anxiety-related behaviours. Specific inhibition of brain anxiety and fear circuits during the sepsis acute phase constitutes a preventive approach to preclude the post-infection psychiatric outcomes.

Background Respiratory complications are frequently reported after aneurismal subarachnoid hemorrhage (aSAH), even if their association with outcome remains controversial. Acute respiratory distress syndrome (ARDS) is one of the most severe pulmonary complications after aSAH, with a reported incidence ranging from 11 to 50%. This study aims to assess in a large cohort of aSAH patients, during the first week after an intensive care unit (ICU) admission, the incidence of ARDS defined according to the Berlin criteria and its effect on outcome. Methods This is a multicentric, retrospective cohort study in 3 European intensive care units. We collected data between January 2009 and December 2017. We included adult patients (≥ 18 years) with a diagnosis of aSAH admitted to the ICU. Results A total of 855 patients fulfilled the inclusion criteria. ARDS was assessable in 851 patients. The cumulative incidence of ARDS was 2.2% on the first day since ICU admission, 3.2% on day three, and 3.6% on day seven. At the univariate analysis, ARDS was associated with a poor outcome (p = 0.005) at ICU discharge, and at the multivariable analysis, patients with ARDS showed a worse neurological outcome (Odds ratio = 3.00, 95% confidence interval 1.16–7.72; p = 0.023). Conclusions ARDS has a low incidence in the first 7 days of ICU stay after aSAH, but it is associated with worse outcome.

Resume L’encephalopathie liee au sepsis (EAS) est une complication des infections severes. Son diagnostic repose sur l’examen clinique et est formalise par des check-lists ou des algorithmes. Son incidence est estimee a 20–40 % des patients admis en reanimation pour une infection. Elle se traduit par des anomalies de l’examen clinique, telles que des troubles de la conscience ou de la vigilance, associes a des anomalies electroencephalographiques ou radiologiques. La survenue de crises convulsives generalisees est rare, bien que les anomalies epileptiques soient frequentes a l’EEG. Des signes neurologiques de localisation sont parfois observes, souvent en rapport avec des accidents ischemiques ou hemorragiques intracrâniens. L’EAS est pourvoyeuse de troubles psychologiques (anxiete, depression, suicide) et cognitifs a long terme, alterant la qualite de vie des patients, mais egalement d’une surmortalite probablement en rapport avec la persistance de troubles de la deglutition. Sa physiopathologie implique des processus neuro-inflammatoires ischemiques, associes a des perturbations metaboliques, conduisant a une crise metabolique et a une mort cellulaire. Des perturbations de l’autoregulation cerebrale ont recemment ete mises en evidence. A ce jour, il n’existe pas de strategie pharmacologique ciblant la neuro-inflammation, ni la neuro-transmission (y compris une strategie de sedation) permettant de reduire l’incidence, la duree ou la severite de l’EAS. Les interventions non pharmacologiques proposees pour la prevention ou le traitement du delirium doivent etre appliquees chez les patients septiques, notamment la mobilisation precoce, l’arret de la sedation et la rehydratation, la prise en charge des inconforts physiques et psychologiques et le retrait des medicaments pro-delirants.

While the coronavirus disease 2019 (COVID-19) pandemic placed a heavy burden on healthcare systems worldwide, it also induced urgent mobilisation of research teams to develop treatments preventing or curing the disease and its consequences. It has, therefore, challenged critical care research to rapidly focus on specific fields while forcing critical care physicians to make difficult ethical decisions. This narrative review aims to summarise critical care research -from organisation to research fields- in this pandemic setting and to highlight opportunities to improve research efficiency in the future, based on what is learned from COVID-19. This pressure on research revealed, i.e., i/ the need to harmonise regulatory processes between countries, allowing simplified organisation of international research networks to improve their efficiency in answering large-scale questions; ii/ the importance of developing translational research from which therapeutic innovations can emerge; iii/ the need for improved triage and predictive scores to rationalise admission to the intensive care unit. In this context, key areas for future critical care research and better pandemic preparedness are artificial intelligence applied to healthcare, characterisation of long-term symptoms, and ethical considerations. Such collaborative research efforts should involve groups from both high and low-to-middle income countries to propose worldwide solutions. As a conclusion, stress tests on healthcare organisations should be viewed as opportunities to design new research frameworks and strategies. Worldwide availability of research networks ready to operate is essential to be prepared for next pandemics. Importantly, researchers and physicians should prioritise realistic and ethical goals for both clinical care and research. Copyright © 2022. Published by Elsevier Masson SAS.

Acute respiratory distress syndrome (ARDS) is a major complication of COVID-19 and is associated with high mortality and morbidity. We aimed to assess whether intravenous immunoglobulins (IVIG) could improve outcomes by reducing inflammation-mediated lung injury.In this multicentre, double-blind, placebo-controlled trial, done at 43 centres in France, we randomly assigned patients (1:1) receiving invasive mechanical ventilation for up to 72 h with PCR confirmed COVID-19 and associated moderate-to-severe ARDS to receive either IVIG (2 g/kg over 4 days) or placebo. Random assignment was done with a web-based system and was stratified according to the participating centre and the duration of invasive mechanical ventilation before inclusion in the trial (12 h, 12-24 h, and24-72 h), and treatment was administered within the first 96 h of invasive mechanical ventilation. To minimise the risk of adverse events, the IVIG administration was divided into four perfusions of 0·5 g/kg each administered over at least 8 hours. Patients in the placebo group received an equivalent volume of sodium chloride 0·9% (10 mL/kg) over the same period. The primary outcome was the number of ventilation-free days by day 28, assessed according to the intention-to-treat principle. This trial was registered on ClinicalTrials.gov, NCT04350580.Between April 3, and October 20, 2020, 146 patients (43 [29%] women) were eligible for inclusion and randomly assigned: 69 (47%) patients to the IVIG group and 77 (53%) to the placebo group. The intention-to-treat analysis showed no statistical difference in the median number of ventilation-free days at day 28 between the IVIG group (0·0 [IQR 0·0-8·0]) and the placebo group (0·0 [0·0-6·0]; difference estimate 0·0 [0·0-0·0]; p=0·21). Serious adverse events were more frequent in the IVIG group (78 events in 22 [32%] patients) than in the placebo group (47 events in 15 [20%] patients; p=0·089).In patients with COVID-19 who received invasive mechanical ventilation for moderate-to-severe ARDS, IVIG did not improve clinical outcomes at day 28 and tended to be associated with an increased frequency of serious adverse events, although not significant. The effect of IVIGs on earlier disease stages of COVID-19 should be assessed in future trials.Programme Hospitalier de Recherche Clinique.

Rationale: Intensity of anxiety at admission in intensive care unit (ICU) is associated with subsequent deterioration.Objective: The primary aim of this study was to assess predictive value of stressful fears and feelings to predict new organ failure within the first seven days after ICU admission.Methods: We conducted a prospective three-center cohort study of non-comatose patients without delirium or invasive mechanical ventilation. A twelve-item questionnaire was developed to assess stressful fears and feelings. Illness severity was assessed using SAPS-II and SOFA scores. Intensity of chronic and acute anxiety was assessed with the ‘Trait’ and ‘State’ forms of the State-Trait Anxiety Inventory (STAI). Patients were followed-up for seven days. Results: From April 2014 to December 2017, 373 patients (median age, 63y.o. [49-74]; 159 [40.7%] women; SAPS-II 28 [19-37]) were included. Feeling of vulnerability and fear of dying was reported in 209 (54.4%) and 178 (46.4%) patients, respectively. STAI was equal or above 40 in 192 (51.5%) patients. Ninety-four (25.2%) patients developed a new organ failure. Feeling of vulnerability (OR=1.96, 95%CI:1.12-3.43], p=0.01) and absence of fear of dying (OR=2.38, 95%CI:1.37-4.17], p=0.002) were associated with occurrence of a new organ failure after adjustment on STAI ≥40, SAPS-II and SOFA. Conclusion: Absence of fear of dying is associated with occurrence of new organ failure within the seven post-ICU admission days. We hypothesize that fear of dying might be protective for subsequent deterioration by mobilizing patient’s homeostatic resources. Trial registration: NCT02355626

Coronary angiography is a procedure in which patients tend to present with a moderately high level of stress and anxiety. The present investigation sought to examine the impact of a patient controlled music listening intervention by mobile application (Music-Care) on sedative consumption as primary endpoint, and on pain, anxiety and satisfaction levels. This is a prospective non-randomized controlled clinical study. Patients scheduled to undergo coronary angioplasty under local anesthesia and sedation were recruited. A 76 patients were included, 54 were assigned under the music arm and 22 under the control arm. Medication intake during the procedure has been reported as well as anxiety as measured by numeric rating score and APAIS, pain and satisfaction scores. Music group was administered "U" sequence during the procedure. Patients under music took significantly less midazolam medication (median 1 vs 3 mg in control, p

Background Generalized convulsive status epilepticus (GCSE) is a frequent medical emergency. GCSE treatment focuses on the administration of benzodiazepines followed by a second-line antiepileptic drug (AED). Despite this stepwise strategy, GCSE is not controlled in one-quarter of patients and is associated with protracted hospitalization, high mortality, and long-term disability. Valproic acid (VPA) is an AED with good tolerability and neuroprotective properties. Objective This study aims to demonstrate that administration of VPA as an adjuvant for first- and second-line treatment in GCSE can improve outcomes. Methods A multicenter, double-blind, randomized controlled trial was conducted, comparing VPA with a placebo in adults admitted to intensive care units (ICUs) for GCSE in France. GCSE was diagnosed by specifically trained ICU physicians according to standard criteria. All patients received standard of care, including a benzodiazepine and a second-line AED (not VPA), at the discretion of the treating medical team. In the intervention arm, VPA was administered intravenously at a loading dose of 30 mg/kg over 15 minutes, followed by a continuous infusion of 1 mg/kg/hour over the next 12 hours. In the placebo group, an identical intravenous administration of 0.9% saline was used. The primary outcome was the proportion of patients discharged alive from the hospital by day 15. Secondary outcomes were frequency of refractory and super refractory GCSE, ICU-related morbidity, adverse events related to VPA, and cognitive dysfunction at 3 months. Statistical analyses will be performed according to the intent-to-treat principle. Results The first patient was randomized on February 18, 2013, and the last patient was randomized on July 7, 2018. Of 248 planned patients, 98.7% (245/248) were enrolled across 20 ICUs. At present, data management is still ongoing, and all parties involved in the trial remain blinded. Conclusions The Valproic Acid as an Adjuvant Treatment for Generalized Convulsive Status Epilepticus (VALSE) trial will evaluate whether the use of VPA as an adjuvant for first- and second-line treatment in GCSE improves outcomes. Trial Registration ClinicalTrials.gov NCT01791868; https://clinicaltrials.gov/ct2/show/NCT01791868. International Registered Report Identifier (IRRID) DERR1-10.2196/22511

Background: To date, 750 000 patients with COVID-19 worldwide have required mechanical ventilation and thus are at high risk of acute brain dysfunction (coma and delirium). We aimed to investigate the prevalence of delirium and coma, and risk factors for delirium in critically ill patients with COVID-19, to aid the development of strategies to mitigate delirium and associated sequelae. Methods: This multicentre cohort study included 69 adult intensive care units (ICUs), across 14 countries. We included all patients (aged ≥18 years) admitted to participating ICUs with severe acute respiratory syndrome coronavirus 2 infection before April 28, 2020. Patients who were moribund or had life-support measures withdrawn within 24 h of ICU admission, prisoners, patients with pre-existing mental illness, neurodegenerative disorders, congenital or acquired brain damage, hepatic coma, drug overdose, suicide attempt, or those who were blind or deaf were excluded. We collected de-identified data from electronic health records on patient demographics, delirium and coma assessments, and management strategies for a 21-day period. Additional data on ventilator support, ICU length of stay, and vital status was collected for a 28-day period. The primary outcome was to determine the prevalence of delirium and coma and to investigate any associated risk factors associated with development of delirium the next day. We also investigated predictors of number of days alive without delirium or coma. These outcomes were investigated using multivariable regression. Findings: Between Jan 20 and April 28, 2020, 4530 patients with COVID-19 were admitted to 69 ICUs, of whom 2088 patients were included in the study cohort. The median age of patients was 64 years (IQR 54 to 71) with a median Simplified Acute Physiology Score (SAPS) II of 40·0 (30·0 to 53·0). 1397 (66·9%) of 2088 patients were invasively mechanically ventilated on the day of ICU admission and 1827 (87·5%) were invasively mechanical ventilated at some point during hospitalisation. Infusion with sedatives while on mechanical ventilation was common: 1337 (64·0%) of 2088 patients were given benzodiazepines for a median of 7·0 days (4·0 to 12·0) and 1481 (70·9%) were given propofol for a median of 7·0 days (4·0 to 11·0). Median Richmond Agitation–Sedation Scale score while on invasive mechanical ventilation was –4 (–5 to –3). 1704 (81·6%) of 2088 patients were comatose for a median of 10·0 days (6·0 to 15·0) and 1147 (54·9%) were delirious for a median of 3·0 days (2·0 to 6·0). Mechanical ventilation, use of restraints, and benzodiazepine, opioid, and vasopressor infusions, and antipsychotics were each associated with a higher risk of delirium the next day (all p≤0·04), whereas family visitation (in person or virtual) was associated with a lower risk of delirium (p

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

BACKGROUND Generalized convulsive status epilepticus (GCSE) is a frequent medical emergency. GCSE treatment focuses on the administration of benzodiazepines followed by a second-line antiepileptic drug (AED). Despite this stepwise strategy, GCSE is not controlled in one-quarter of patients and is associated with protracted hospitalization, high mortality, and long-term disability. Valproic acid (VPA) is an AED with good tolerability and neuroprotective properties. OBJECTIVE This study aims to demonstrate that administration of VPA as an adjuvant for first- and second-line treatment in GCSE can improve outcomes. METHODS A multicenter, double-blind, randomized controlled trial was conducted, comparing VPA with a placebo in adults admitted to intensive care units (ICUs) for GCSE in France. GCSE was diagnosed by specifically trained ICU physicians according to standard criteria. All patients received standard of care, including a benzodiazepine and a second-line AED (not VPA), at the discretion of the treating medical team. In the intervention arm, VPA was administered intravenously at a loading dose of 30 mg/kg over 15 minutes, followed by a continuous infusion of 1 mg/kg/hour over the next 12 hours. In the placebo group, an identical intravenous administration of 0.9% saline was used. The primary outcome was the proportion of patients discharged alive from the hospital by day 15. Secondary outcomes were frequency of refractory and super refractory GCSE, ICU-related morbidity, adverse events related to VPA, and cognitive dysfunction at 3 months. Statistical analyses will be performed according to the intent-to-treat principle. RESULTS The first patient was randomized on February 18, 2013, and the last patient was randomized on July 7, 2018. Of 248 planned patients, 98.7% (245/248) were enrolled across 20 ICUs. At present, data management is still ongoing, and all parties involved in the trial remain blinded. CONCLUSIONS The Valproic Acid as an Adjuvant Treatment for Generalized Convulsive Status Epilepticus (VALSE) trial will evaluate whether the use of VPA as an adjuvant for first- and second-line treatment in GCSE improves outcomes. CLINICALTRIAL ClinicalTrials.gov NCT01791868; https://clinicaltrials.gov/ct2/show/NCT01791868. INTERNATIONAL REGISTERED REPORT DERR1-10.2196/22511

Objectives Apoptosis-Inducing Factor (AIF) is a protein involved in mitochondrial electron transport chain assembly/stability and programmed cell death. The relevant role of this protein is underlined because mutations altering mitochondrial AIF properties result in acute pediatric mitochondriopathies and tumor metastasis. By generating an original AIF-deficient mouse strain, this study attempted to analyze, in a single paradigm, the cellular and developmental metabolic consequences of AIF loss and the subsequent oxidative phosphorylation (OXPHOS) dysfunction. Methods We developed a novel AIF-deficient mouse strain and assessed, using molecular and cell biology approaches, the cellular, embryonic, and adult mice phenotypic alterations. Additionally, we conducted ex vivo assays with primary and immortalized AIF knockout mouse embryonic fibroblasts (MEFs) to establish the cell death characteristics and the metabolic adaptive responses provoked by the mitochondrial electron transport chain (ETC) breakdown. Results AIF deficiency destabilized mitochondrial ETC and provoked supercomplex disorganization, mitochondrial transmembrane potential loss, and high generation of mitochondrial reactive oxygen species (ROS). AIF-/Y MEFs counterbalanced these OXPHOS alterations by mitochondrial network reorganization and a metabolic reprogramming toward anaerobic glycolysis illustrated by the AMPK phosphorylation at Thr172, the overexpression of the glucose transporter GLUT-4, the subsequent enhancement of glucose uptake, and the anaerobic lactate generation. A late phenotype was characterized by the activation of P53/P21-mediated senescence. Notably, approximately 2% of AIF-/Y MEFs diminished both mitochondrial mass and ROS levels and spontaneously proliferated. These cycling AIF-/Y MEFs were resistant to caspase-independent cell death inducers. The AIF-deficient mouse strain was embryonic lethal between E11.5 and E13.5 with energy loss, proliferation arrest, and increased apoptotic levels. Contrary to AIF-/Y MEFs, the AIF KO embryos were unable to reprogram their metabolism toward anaerobic glycolysis. Heterozygous AIF+/- females displayed progressive bone marrow, thymus, and spleen cellular loss. In addition, approximately 10% of AIF+/- females developed perinatal hydrocephaly characterized by brain development impairment, meningeal fibrosis, and medullar hemorrhages; those mice died 5 weeks after birth. AIF+/- with hydrocephaly exhibited loss of ciliated epithelium in the ependymal layer. This phenotype was triggered by the ROS excess. Accordingly, it was possible to diminish the occurrence of hydrocephalus AIF+/- females by supplying dams and newborns with an antioxidant in drinking water. Conclusions In a single knockout model and at 3 different levels (cell, embryo, and adult mice) we demonstrated that by controlling the mitochondrial OXPHOS/metabolism, AIF is a key factor regulating cell differentiation and fate. Additionally, by providing new insights into the pathological consequences of mitochondrial OXPHOS dysfunction, our new findings pave the way for novel pharmacological strategies., Highlights • Mitochondrial AIF loss triggers OXPHOS/metabolism impairment. • AIF-/Y MEFs reprogram their metabolism by enabling an AMPK/GLUT-4 glycolytic pathway. • OXPHOS dysfunction associated with AIF loss generates a P53/P21 senescent phenotype. • The lack of metabolic plasticity provokes embryonic lethality in the AIF KO animals. • AIF+/- females develop immune cell exhaustion and perinatal hydrocephaly.

Septic-associated encephalopathy (SAE) is a key manifestation of sepsis, ranging from delirium to coma and occurring in up to 70% of patients admitted to the ICU. SAE is associated with higher ICU and hospital mortality, and also with poorer long-term outcomes, including cognitive and functional outcomes. The pathophysiology of SAE is complex, and it may involve neurotransmitter dysfunction, inflammatory and ischemic lesions to the brain, microglial activation, and blood–brain barrier dysfunction. Delirium (which is included in the SAE spectrum) is mostly diagnosed with validated scales in the ICU population. There is no established treatment for SAE; benzodiazepines should generally be avoided in this setting. Nonpharmacological prevention and management is key for treating SAE; it includes avoiding oversedation (mainly with benzodiazepines), early mobilization, and sleep promotion. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-020-00862-1) contains supplementary material, which is available to authorized users.

The brainstem conveys sensory and motor inputs between the spinal cord and the brain, and contains nuclei of the cranial nerves. It controls the sleep-wake cycle and vital functions via the ascending reticular activating system and the autonomic nuclei, respectively. Brainstem dysfunction may lead to sensory and motor deficits, cranial nerve palsies, impairment of consciousness, dysautonomia, and respiratory failure. The brainstem is prone to various primary and secondary insults, resulting in acute or chronic dysfunction. Of particular importance for characterizing brainstem dysfunction and identifying the underlying etiology are a detailed clinical examination, MRI, neurophysiologic tests such as brainstem auditory evoked potentials, and an analysis of the cerebrospinal fluid. Detection of brainstem dysfunction is challenging but of utmost importance in comatose and deeply sedated patients both to guide therapy and to support outcome prediction. In the present review, we summarize the neuroanatomy, clinical syndromes, and diagnostic techniques of critical illness-associated brainstem dysfunction for the critical care setting.

Background Microglia function is essential to maintain the brain homeostasis. Evidence shows that aged microglia are primed and show exaggerated response to acute inflammatory challenge. Systemic inflammation signals to the brain inducing changes that impact cognitive function. However, the mechanisms involved in age-related cognitive decline associated to episodic systemic inflammation are not completely understood. The aim of this study was to identify neuropathological features associated to age-related cognitive decline in a mouse model of episodic systemic inflammation. Methods Young and aged Swiss mice were injected with low doses of LPS once a week for 6 weeks to induce episodic systemic inflammation. Sickness behavior, inflammatory markers, and neuroinflammation were assessed in different phases of systemic inflammation in young and aged mice. Behavior was evaluated long term after episodic systemic inflammation by open field, forced swimming, object recognition, and water maze tests. Results Episodic systemic inflammation induced systemic inflammation and sickness behavior mainly in aged mice. Systemic inflammation induced depressive-like behavior in both young and aged mice. Memory and learning were significantly affected in aged mice that presented lower exploratory activity and deficits in episodic and spatial memories, compared to aged controls and to young after episodic systemic inflammation. Systemic inflammation induced acute microglia activation in young mice that returned to base levels long term after episodic systemic inflammation. Aged mice presented dystrophic microglia in the hippocampus and entorhinal cortex at basal level and did not change morphology in the acute response to SI. Regardless of their dystrophic microglia, aged mice produced higher levels of pro-inflammatory (IL-1β and IL-6) as well as pro-resolution (IL-10 and IL-4) cytokines in the brain. Also, higher levels of Nox2 expression, oxidized proteins and lower antioxidant defenses were found in the aged brains compared to the young after episodic systemic inflammation. Conclusions Our data show that aged mice have increased susceptibility to episodic systemic inflammation. Aged mice that showed cognitive impairments also presented higher oxidative stress and abnormal production of cytokines in their brains. These results indicate that a neuroinflammation and oxidative stress are pathophysiological mechanisms of age-related cognitive impairments. Electronic supplementary material The online version of this article (10.1186/s12974-018-1059-y) contains supplementary material, which is available to authorized users.

International audience; Sepsis, a leading cause of morbidity and mortality, is caused by a deregulated host response to pathogens, and subsequent life-threatening organ dysfunctions. All major systems, including the cardiovascular, respiratory, renal, hepatic, hematological, and the neurological system may be affected by sepsis. Sepsis associated neurological dysfunction is triggered by multiple factors including neuro-inflammation, excitotoxicity, and ischemia. Ischemia results from reduced cerebral blood flow, caused by extreme variations of blood pressure, occlusion of cerebral vessels, or more subtle defects of the microcirculation. International guidelines comprehensively describe the initial hemodynamic management of sepsis, revolving around the normalization of systemic hemodynamics and of arterial lactate. By contrast, the management of sepsis patients suffering from brain dysfunction is poorly detailed, the only salient point being mentioned is that sedation and analgesia should be optimized. However, sepsis and the hemodynamic consequences thereof as well as vasopressors may have severe untoward neurological consequences. The current review describes the general neurological complications, as well as the consequences of vasopressor therapy on the brain and its circulation and addresses methods for cerebral monitoring during sepsis. © Copyright © 2020 Heming, Mazeraud, Azabou, Moine and Annane.

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease, caused by absence of functional dystrophin and inevitably leading to death. A variable proportion of women carriers (2.5 to 19%) can also manifest symptoms ranging from myalgia to cardiomyopathy, and pathophysiological mechanisms are still not completely understood. Our study focused on 12 month-old female mdx mice, displaying marked chronic muscle lesions, similar to the lesions observed in human DMD. Our aim was to focus on the alterations of the vascular network organisation, and functional repercussions using a combination of histology/morphometry techniques and totally non-invasive functional approach (multiparametric and functional nuclear magnetic resonance), clearly relevant for clinical diagnosis and research, combining arterial spin labeling imaging of perfusion, and 31P-spectroscopy of phosphocreatine kinetics. Collectively, our results demonstrate that the vasculature, both in its steady state organisation and dynamic behaviour after an ischemia-reperfusion stress, is altered in the 12 month-old female mdx mouse: increased density of vascular sections in histology, modification of the post-ischemic hyperemia profile, increase in mitochondrial oxidative rephosphorylation capacity, in striking opposition to what was observed in age-matched male mdx mice. We believe the apparent discordance between vascular and muscular features in the female mdx mouse make it an interesting tool to decipher further dystrophinopathy pathophysiological mechanisms.

Background Skeletal muscle has the capacity to adapt to environmental changes and regenerate upon injury. To study these processes, most experimental methods use quantification of parameters obtained from images of immunostained skeletal muscle. Muscle cross-sectional area, fiber typing, localization of nuclei within the muscle fiber, the number of vessels, and fiber-associated stem cells are used to assess muscle physiology. Manual quantification of these parameters is time consuming and only poorly reproducible. While current state-of-the-art software tools are unable to analyze all these parameters simultaneously, we have developed MuscleJ, a new bioinformatics tool to do so. Methods Running on the popular open source Fiji software platform, MuscleJ simultaneously analyzes parameters from immunofluorescent staining, imaged by different acquisition systems in a completely automated manner. Results After segmentation of muscle fibers, up to three other channels can be analyzed simultaneously. Dialog boxes make MuscleJ easy-to-use for biologists. In addition, we have implemented color in situ cartographies of results, allowing the user to directly visualize results on reconstituted muscle sections. Conclusion We report here that MuscleJ results were comparable to manual observations made by five experts. MuscleJ markedly enhances statistical analysis by allowing reliable comparison of skeletal muscle physiology-pathology results obtained from different laboratories using different acquisition systems. Providing fast robust multi-parameter analyses of skeletal muscle physiology-pathology, MuscleJ is available as a free tool for the skeletal muscle community. Electronic supplementary material The online version of this article (10.1186/s13395-018-0171-0) contains supplementary material, which is available to authorized users.

Background: Anxiety results from the anticipation of a future threat. Anxiety is associated with poor outcomes following acute myocardial infarction, surgery, or Guillain-Barre Syndrome. Objective: To assess anxiety in critically ill patients in association with organ dysfunction. Methods: Prospective multicenter cohort study of adult ICU patients who were spontaneously breathing and had normal mental status. Upon ICU admission, intensity of anxiety was assessed using the State-Trait Anxiety Inventory-State (STAI-State) instrument and a visual analogue scale (VAS). Causes of anxiety were investigated by asking patients whether they feared death, believed to be vulnerable and believed to be in a serious condition. Severity of illness was assessed using SAPS-II and SOFA scores. Patients were followed-up for seven days. Main outcome measures: Primary endpoint was a composite outcome of mortality, persistence or worsening of organ dysfunction, unplanned surgery, coronary-angiography or transfusion, or readmission to the ICU in the first week following discharge; secondary outcomes were the duration of mechanical ventilation, hospital and ICU length of stay and mortality. Findings: From April 2015 to December 2017, 391 patients (median age, 63yo [49-74]; 159 (40.7%) women; SAPS-II 28 [19-37]) were included. 203/391 (51.9%) patients reported moderate to severe anxiety (STAI-State ≥40), 262/391 (67.9%) patients believed to be in a severe condition, 209/391 (54.4%) reported feeling vulnerable, and 178/391 (46.4%) patients feared death. Out of 391, 175 (44.8%) patients met the primary endpoint. After adjustment to SAPS-II and SOFA, STAI-State ≥40 (OR, 2.49; 95%CI, [1.56-3.98], p=0.0001) and absence of fear of death (OR, 0.53; 95%CI, [0.33-0.85]; p=0.008) were associated with the primary endpoint, especially in patients without organ dysfunction at admission (OR, 3.80; 95%CI, [1.99-7.25] p

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2017. Other selected articles can be found online at http://ccforum.com/series/annualupdate2017 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901 .Originally published in the Annual Update in Intensive Care and Emergency Medicine 2017. The number of authors differs in the two versions due to constraints regarding the number of authors in the Annual Update in Intensive Care and Emergency Medicine. In the Annual Update version of the review, the three senior authors appear in the acknowledgement section. In the Critical Care version, these three senior authors appear as full authors of the manuscript. All authors helped draft and revise the manuscript for critical intellectual content.

OBJECTIVES Reperfusion pulmonary edema is a specific complication of pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. Extravascular lung water measurement may be valuable for diagnosing reperfusion pulmonary edema. The primary objective of this study was to describe and assess the clinical significance of extravascular lung water variations after pulmonary endarterectomy. DESIGN Prospective observational study. SETTING Nineteen-bed cardiothoracic ICU. PATIENTS Consecutive patients who were hemodynamically stable after pulmonary endarterectomy were divided into two groups based on whether their preoperative pulmonary vascular resistance indicated severe or nonsevere chronic thromboembolic pulmonary hypertension (> 900 or ≤ 900 dynes·s/cm, respectively). INTERVENTIONS Hemodynamic variables obtained by right heart catheterization and transpulmonary thermodilution measurements were recorded 1 hour, 1 day, and 2 days after pulmonary endarterectomy. Extravascular lung water was indexed to predicted body weight (EVLWPBW). MEASUREMENTS AND MAIN RESULTS We studied 31 patients. Overall, 26 patients (84%) experienced reperfusion pulmonary edema during the first 72 hours after pulmonary endarterectomy. EVLWPBW significantly increased between the first hour after pulmonary endarterectomy and day 2 (10.2 ± 2.6 vs 11.4 ± 3.6; p = 0.03). EVLWPBW measured at the first hour after pulmonary endarterectomy is closely associated with reperfusion pulmonary edema occurrence in the next 48 hours (area under the receiver-operating characteristics curve = 0.88 ± 0.07). EVLWPBW correlated with duration of mechanical ventilation (ρ = 0.59; p < 0.0001) and ICU stay (ρ = 0.52; p < 0.0001). Patients with severe chronic thromboembolic pulmonary hypertension (n = 15) had higher EVLWPBW values at day 2 compared with those without (n = 16) (13.2 ± 3.6 vs 9.7 ± 2.7 mL/kg; p = 0.004). Cardiac output was measured simultaneously by pulmonary artery catheter and aortic transpulmonary thermodilution on 92 occasions; agreement was good, with a bias of 0.50 ± 0.95 L/min (95% CI, -1.36-2.36). CONCLUSIONS Accurate extravascular lung water measurements were obtained after pulmonary endarterectomy. Extravascular lung water may prove valuable for diagnosing reperfusion pulmonary edema after pulmonary endarterectomy and had prognostic value. Extravascular lung water values were significantly higher in patients with severe compared with nonsevere chronic thromboembolic pulmonary hypertension.

Objet La dystrophie musculaire de Duchenne (DMD) est une maladie neuromusculaire progressivement letale touchant principalement les garcons, et se caracterisant par une absence de dystrophine [1] . Une proportion variable de femmes porteuses de la mutation (2,5 a 19 %) peut egalement manifester des symptomes allant de la myalgie a la cardiomyopathie [2] , [3] . Les mecanismes physiopathologiques sous-jacents ne sont pas completement elucides mais une des hypotheses emises recemment propose une alteration conjointe du tissu musculaire et du reseau vasculaire [4] . Ce projet de recherche se concentre sur des souris mdx femelles vieillissantes (12 mois), presentant des lesions musculaires marquees, similaires a celles observees chez l’homme lors de DMD. Notre objectif est de caracteriser les alterations de l’organisation du reseau vasculaire musculaire et son expression fonctionnelle. Materiel et methode Utilisation des techniques d’histologie/morphometrie combinees a une approche fonctionnelle non invasive (la resonance magnetique nucleaire multi-parametrique et fonctionnelle), pertinente pour la recherche et le diagnostic clinique, combinant a la fois une imagerie de perfusion par marquage du spin arteriel, et l’evaluation du metabolisme energetique par spectroscopie du phosphore. Resultats Les souris femelles mdx vieillissantes presentent, comme les souris mâles mdx vieillissants, des lesions musculaires marquees (atrophie des myofibres, inflammation chronique, fibrose…). Mais malgre ces atteintes du tissu musculaire, notre analyse du reseau vasculaire a quant a elle mis en evidence une augmentation de la perfusion et du metabolisme oxydatif du tissu musculaire apres un stress, ainsi qu’une augmentation de la densite vasculaire musculaire, contrairement a nos precedents resultats obtenus chez les mâles mdx vieillissants [5] . Conclusion De facon surprenante, les femelles mdx presentent une rupture du couplage myogenese–angiogenese. Ces resultats apportent un nouvel eclairage sur la physiopathologie des dystrophinopathies et notamment sur le role du reseau vasculaire et du sexe dans l’expression de la maladie.

Very scarce data is available on histological and molecular methods used by neuropathologists for the diagnosis of brain tumors. We performed a survey on this subject, addressed to neuropathologists worldwide and answered through an online form. There were responses from 314 centers from 49 countries. The great majority of neuropathologists systematically use the world health organization pathology guidelines [1] , [2] and around 20% use it mostly with rare exceptions. Immunohistochemistry is available in practically all centers, and around 75% of all centers use some form of molecular technique for the diagnosis of brain tumors, of which 69% FISH or CISH, and 62% techniques other than FISH/CISH. Molecular techniques are more available in countries with highest human development index and in centers with highest number of cases diagnosed. Most pediatric brain tumors are diagnosed by centers also diagnosing adult cases. Most pathologists have access to relevant clinical data and imaging exams from their patients. This survey confirms that most pathologists often perform at least some molecular techniques for the diagnosis of brain tumors. Techniques and availability are heterogeneous worldwide and access to them could be largely improved through collaboration.

Association of infection with systemic inflammation defines sepsis. It affects 950,000 patients per year in Europe and the mortality varies from 26% to 60%. In 60% of cases, sepsis induces acute brain dysfunction (SIBD) clinically characterized by altered consciousness ranging from confusion to coma. SIBD is correlated with long-term psycho-cognitive dysfunctions and dementia, and represents a major public health issue. Interestingly, SIBD is not due to direct brain infection, but rather driven by peripheral inflammatory mediators. These mediators affect primarily blood-brain barrier functions causing endothelial activation and microvascular dysfunctions, leading then to intraparenchymal glial dysfunctions and ultimately neurotoxicical effects. However, neither a clear scenario of these events nor molecular key drivers of SIBD have been defined, compromising the design of targeted therapies. Our project is to define key pathophysiological targets of SIBD. We focused on Lipocalin2 (Lcn2), a protein recently found to be upregulated in several neuroinflammatory contexts. Here, we studied the expression of Lcn2 in the brain during sepsis. Experiments were performed in the cecal ligation and puncture (CLP) mouse model for sepsis, which consists of an induced fecal peritonitis. Control mice (Sham) were submitted to skin incision only. In the cortex, hippocampus, and cerebellum, we found a 1000-fold increase in Lcn2 mRNA in CLP mice compared to Sham, associated to the upregulation of inflammatory cytokines TNF-alpha and IL-1beta. We localized Lcn2 upregulation by in situ hybridization and immunohistochemistry mostly in endothelial cells. We confirmed the Lcn2 upreglation performing qPCR on purified brain vessels 4 h post-CLP, which paralleled the upregulation of ICAM, an endothelial activation marker. Altogether, these results suggest that endothelial activation is probably one of the earliest mechanisms induced by peritonitis in the brain, and that Lcn2 upregulation may participate to this regulation. Together, they might therefore be instrumental in neuroinflammatory processes leading to SIBD.

Stress-induced hyperglycemia has been considered an adaptive mechanism to stress up to the first intensive insulin therapy trial, which showed a 34% reduction in relative risk of in-hospital mortality when normalizing blood glucose levels. Further trials had conflicting results and, at present, stress-induced hyperglycemia management remains non-consensual. These findings could be explained by discrepancies in trials, notably regarding the approach to treat hyperglycemia: high versus restrictive caloric intake. Stress-induced hyperglycemia is a frequent complication during intensive care unit stay and is associated with a higher mortality. It results from an imbalance between insulin and counter-regulatory hormones, increased neoglucogenesis, and the cytokine-induced insulin-resistant state of tissues. In this review, we summarize detrimental effects of hyperglycemia on organs in the critically ill (peripheric and central nervous, liver, immune system, kidney, and cardiovascular system). Finally, we show clinical and experimental evidence of potential benefits from glucose and insulin administration, notably on metabolism, immunity, and the cardiovascular system.

Background Generalised convulsive status epilepticus (GCSE) is a medical emergency. Guidelines recommend a stepwise strategy of benzodiazepines followed by a second-line anti-seizure medicine (ASM). However, GCSE is uncontrolled in 20–40% patients and is associated with protracted hospitalisation, disability, and mortality. The objective was to determine whether valproic acid (VPA) as complementary treatment to the stepwise strategy improves the outcomes of patients with de novo established GCSE. Methods This was a multicentre, double-blind, randomised controlled trial in 244 adults admitted to intensive care units for GCSE in 16 French hospitals between 2013 and 2018. Patients received standard care of benzodiazepine and a second-line ASM (except VPA). Intervention patients received a 30 mg/kg VPA loading dose, then a 1 mg/kg/h 12 h infusion, whilst the placebo group received an identical intravenous administration of 0.9% saline as a bolus and continuous infusion. Primary outcome was proportion of patients discharged from hospital by day 15. The secondary outcomes were seizure control, adverse events, and cognition at day 90. Results A total of 126 (52%) and 118 (48%) patients were included in the VPA and placebo groups. 224 (93%) and 227 (93%) received a first-line and a second-line ASM before VPA or placebo infusion. There was no between-group difference for patients hospital-discharged at day 15 [VPA, 77 (61%) versus placebo, 72 (61%), adjusted relative risk 1.04; 95% confidence interval (0.89–1.19); p = 0.58]. There were no between-group differences for secondary outcomes. Conclusions VPA added to the recommended strategy for adult GCSE is well tolerated but did not increase the proportion of patients hospital-discharged by day 15. Trial registration No. NCT01791868 (ClinicalTrials.gov registry), registered: 15 February 2012.

International audience; Abstract Background The COVID-19 pandemic is a heavy burden in terms of health care resources. Future decision-making policies require consistent data on the management and prognosis of the older patients (> 70 years old) with COVID-19 admitted in the intensive care unit (ICU). Methods Characteristics, management, and prognosis of critically ill old patients (> 70 years) were extracted from the international prospective COVID-ICU database. A propensity score weighted-comparison evaluated the impact of intubation upon admission on Day-90 mortality. Results The analysis included 1199 (28% of the COVID-ICU cohort) patients (median [interquartile] age 74 [72–78] years). Fifty-three percent, 31%, and 16% were 70–74, 75–79, and over 80 years old, respectively. The most frequent comorbidities were chronic hypertension (62%), diabetes (30%), and chronic respiratory disease (25%). Median Clinical Frailty Scale was 3 (2–3). Upon admission, the PaO 2 /FiO 2 ratio was 154 (105–222). 740 (62%) patients were intubated on Day-1 and eventually 938 (78%) during their ICU stay. Overall Day-90 mortality was 46% and reached 67% among the 193 patients over 80 years old. Mortality was higher in older patients, diabetics, and those with a lower PaO 2 /FiO 2 ratio upon admission, cardiovascular dysfunction, and a shorter time between first symptoms and ICU admission. In propensity analysis, early intubation at ICU admission was associated with a significantly higher Day-90 mortality (42% vs 28%; hazard ratio 1.68; 95% CI 1.24–2.27; p