Corticosteroids in Generalized Autoimmune Myasthenia Gravis: A Narrative Review

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Brainstem dysfunction in critically ill patients

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

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

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 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Why the application of IVIG might be beneficial in patients with COVID-19 – Authors' reply

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Vasopressor Therapy and the Brain: Dark Side of the Moon

International audienceSepsis, 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

Neuro-Inflammatory Response and Brain-Peripheral Crosstalk in Sepsis and Stroke

International audienceDespite recent therapeutic advances, ischemic stroke is still a leading cause of death and disability. There is renewed attention on peripheral inflammatory signaling as a way of modulating the post-ischemic neuro-inflammatory process. The immune-brain crosstalk has long been the focus for understanding the mechanisms of sickness behavior, which is an adaptive autonomic, neuroendocrine, and behavioral response to a peripheral inflammation. It is mediated by humoral and neural pathways that mainly involve the circumventricular organs and vagal nerve, respectively. In this review we address the question of how sepsis and stroke can dysregulate this adaptive response, notably by impairing the central integration of peripheral signaling, but also by efferent control of the immune response. We highlight the potential role of gut–brain and brain–spleen signaling in stroke

Brainstem dysfunction in critically ill patients

International audienceThe 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

The Sarcoglycan complex is expressed in the cerebrovascular system and is specifically regulated by astroglial Cx30 channels

International audienceAstrocytes, the most prominent glial cell type in the brain, send specialized processes called endfeet, around blood vessels and express a large molecular repertoire regulating the cerebrovascular system physiology. One of the most striking properties of astrocyte endfeet is their enrichment in gap junction proteins Connexin 43 and 30 (Cx43 and Cx30) allowing in particular for direct intercellular trafficking of ions and small signaling molecules through perivascular astroglial networks. In this study, we addressed the specific role of Cx30 at the gliovascular interface. Using an inactivation mouse model for Cx30 (Cx30 ∆/∆ ; ∆ means deleted allele) we showed that absence of Cx30 does not affect blood-brain barrier (BBB) organization and permeability. However, it results in the cerebrovascular fraction, in a strong upregulation of Sgcg encoding γ-Sarcoglycan (γ-SG), a member of the Dystrophin-associated protein complex (DAPC) connecting cytoskeleton and the extracellular matrix. The same molecular event occurs in Cx30 T5M/T5M mutated mice, where Cx30 channels are closed, demonstrating that Sgcg regulation relied on Cx30 channel functions. We further characterized the expression of other Sarcoglycan complex (SGC) molecules in the cerebrovascular system and showed the presence of α-, β-, δ-, γ-, ε-and ζ-SG, as well as Sarcospan. Their expression was however not modified in Cx30 ∆/∆. These results suggest that a full SGC might be present in the cerebrovascular system, and that expression of one of its member, γ-SG, depends on Cx30 channels. As described in skeletal muscles, the SGC may contribute to membrane stabilization and signal transduction in the cerebrovascular system, which may therefore be regulated by Cx30 channel-mediated functions

Effect of early treatment with polyvalent immunoglobulin on acute respiratory distress syndrome associated with SARS-CoV-2 infections (ICAR trial): study protocol for a randomized controlled trial

International audienceBackground: 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