Long COVID is frequently associated with persistent autonomic dysfunction, cognitive impairment, and psychological distress, reflecting sustained neuroimmune and autonomic dysregulation. Effective disease-modifying therapies remain scarce. To evaluate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on autonomic symptoms, post-traumatic stress symptoms, and cognitive performance in patients with long COVID. In this open-label, single-arm prospective pilot study, seventeen patients with long COVID underwent weekly one-hour taVNS sessions for eight consecutive weeks. Autonomic symptoms were assessed using the Composite Autonomic Symptom Score-31 (COMPASS-31), psychological symptoms using the PTSD Checklist for DSM-5 (PCL-5), and cognitive function using a standardized attention and executive function battery (COGBAT). Outcomes were evaluated at baseline and post-intervention. Paired non-parametric analyses were performed. Following taVNS, autonomic symptoms improved significantly, with mean COMPASS-31 scores decreasing from 33.71 ± 16.81 to 13.78 ± 9.38 (p < 0.0001). Post-traumatic stress symptoms were significantly reduced (PCL-5: 25.76 ± 14.99 to 19.47 ± 14.63; p = 0.028). Cognitive performance improved, with COGBAT scores increasing from 37.71 ± 25.75 to 49.41 ± 26.79 (p = 0.011). No adverse events were reported. taVNS appears to be a safe and promising non-pharmacological intervention for improving autonomic dysfunction, cognitive impairment, and psychological symptoms in long COVID. These findings warrant confirmation in randomized, sham-controlled trials.

Background and objectives – Absent cough reflex is associated with mortality intensive care unit (ICU) patients requiring deep sedation, suggesting that lower brainstem dysfunction contributed to adverse outcomes. We conducted a multicenter observational cohort study to confirm this hypothesis by assessing the peak latency (PL) of the lower brainstem-generated P14 evoked potential (EP), which is slightly increased by sedatives. We aimed to demonstrate that a P14-PL> 16 ms is independently associated with day-28 mortality. Patients and methods - Mechanically ventilated adult patients, comatose or deeply sedated, brain-injured or not, were included. At day 3, EPs were performed in patients remaining unconscious. The Simplified Acute Physiological Score (SAPSII), initial Glasgow Coma Scale (GCS), sedation depth and brainstem reflexes were collected. The primary outcome was 28-day mortality. The secondary outcomes were delayed awakening and delirium after sedation discontinuation. Results - Between 2015 and 2019, 322 patients were included. EPs were performed in 264 (82%) patients, including 140 (53%) brain-injured and 251 (95%) deeply sedated patients. The median age, SAPSII and initial GCS were 62 years [50; 71], 49 [40; 62] and 11 [6; 15], respectively. A P14-PL > 16ms was found in 76 (29%) patients and was associated with day-28 mortality (adjusted hazard ratio, 3.0; 95% confidence interval, [1.7-5.2]). Absent cough and pupillary light reflexes were associated with death. Only absent oculocephalogyre reflex was associated with delayed awakening (adjusted odds ratio, 2.1, 95%CI, [1.1 - 3.7]). Interpretation – Impaired neurological and neurophysiological lower brainstem responses are associated with mortality in deeply sedated patients. Funded by the French Ministry of Health; PRORETRO; n° P120915; ClinicalTrials.gov registry: NCT02395861; date: 24 March 2015

Objectif Les patients atteints d’un SJSR présentent des symptômes moteurs. Notre objectif est d’évaluer objectivement la plainte moteur par actimétrie. Méthodes Étude observationnelle incluant tout patient participant à une étude de stimulation du nerf vague par voie transauriculaire (taSNV) pour un SJSR sévère et pharmacorésistant. Un actimètre au poignet et au pied a été porté de 20h00 à 08h00 pendant 7jours semaine 1 et 8. L’actimétrie au poignet identifie la période de la soirée et la nuit (après l’endormissement). L’actimétrie au pied détermine : le nombre, le temps de mouvement (%) et les mouvements périodiques des membres en soirée et pendant le sommeil. La sévérité du SJSR a été évaluée avec l’IIRLS et la qualité de vie par le RLS QOL. Résultats Au total, 29 patients ont été inclus dont 48 % d’hommes, d’âge moyenne (63,4±10,3), IRLS (32,4±4,2). Les mouvements des jambes ont été très fréquents avant l’endormissement : temps de mouvement (11,5 %±6 %), mouvements périodiques à l’éveil (42±22,3), mouvements/h (70,6±32,3) et pendant le sommeil : temps de mouvements (10,9 %±5,7 %), mouvements périodiques pendant le sommeil (16,7±10,5), mouvements/h (27,5±13,2) avec des variations très importantes intra-nuit et inter-individu. Aucune corrélation n’a été trouvée entre l’IRLS initial et les paramètres d’actimétrie de sommeil ou du mouvement. La taSNV a améliorée la sévérité (IRLS [25,6±6,4] vs [32,4±4,2] p<0,0001) et la qualité de vie (RLS QOL [47,6±13,3] vs [63,4±17,5] p=0,001). Aucune différence significative n’a été trouvé pour les paramètres aux MI dans le groupe total et chez les répondeurs (52 %) avec une tendance à une diminution dans le temps de mouvement chez les répondeurs. Un temps de mouvements faible a été associé à une réponse au taSNV. Conclusion Les mouvements des jambes sont très fréquents chez les patients atteints d’un SJSR, ne sont pas corrélé avec la sévérité mesurée par l’IRLS mais sont un facteur prédicteur de réussite d’un taSNV. Des nouveaux indices sont en développement pour mieux évaluer la plainte moteur chez les patients atteints d’un SJSR.

INTRODUCTION:Acute encephalopathy in the ICU poses significant diagnostic, therapeutic, and prognostic challenges. Standardized expert guidelines on acute encephalopathy are needed to improve diagnostic methods, therapeutic decisions, and prognostication. METHODS:The experts conducted a review of the literature, analysed it according to the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) methodology and made proposals for guidelines, which were rated by other experts. Only expert opinions with strong agreement were selected. RESULTS:The synthesis of expert work and the application of the GRADE method resulted in 39 recommendations. Among the 39 formalized recommendations, 1 had a high level of evidence (GRADE 1 +) and 10 had a low level of evidence (GRADE 2 + or 2-). These recommendations describe indication for ICU admission, use of clinical scores and EEG for diagnosis, detection of complications, and prognostication. The remaining 28 recommendations were based on expert consensus. These recomandations describe common indications for blood and CSF studies, neuroimaging, use of neuromonitoring, and provide guidelines for management in the acute phase. CONCLUSION:This expert consensus statement aims to provide a structured framework to enhance the consistency and quality of care for ICU patients presenting with acute encephalopathy. By integrating high-quality evidence with expert opinion, it offers a pragmatic approach to addressing the complex nature of acute encephalopathy in the ICU, promoting best practices in patient care and facilitating future research in the field.

Absent cough reflex is associated with mortality in intensive care unit (ICU) patients requiring deep sedation, suggesting that lower brainstem dysfunction contributes to adverse outcomes. We conducted a multicenter observational cohort study to confirm this hypothesis by assessing the peak latency (PL) of the lower brainstem-generated P14 evoked potential (EP), which is slightly increased by sedatives. We aimed to demonstrate that a P14-PL > 16 ms is independently associated with day-28 mortality. Mechanically ventilated adult patients, comatose or deeply sedated, brain injured or not, were included. At day 3, EPs were performed in patients remaining unconscious. The Simplified Acute Physiological Score (SAPSII), initial Glasgow Coma Scale (GCS), sedation depth, and brainstem reflexes were collected. The primary outcome was day-28 mortality. The secondary outcomes were delayed awakening and delirium after sedation discontinuation. Between 2015 and 2019, 322 patients were included. EPs were performed in 264 (82

ObjectifLa stimulation du nerf vague transauriculaire (tVNS) a démontré un intérêt potentiel dans le syndrome des jambes sans repos (SJSR) sévère et pharmaco-résistant. L’objectif de notre étude était d’identifier les facteurs associés à une réponse à la tVNS.MéthodesÉtude observationnelle de patients atteints d’un SJSR sévère (IRLS>20), pharmaco-résistant et traités par tVNS à hauteur d’une séance par semaine en hôpital de jour pendant 8 semaines. Les échelles validées de sévérité du SJSR (IRLS), de dépression (HADD), d’anxiété (HADA), et de qualité de vie (RLS QOL) initiales, les données sociodémographiques et de la maladie (âge de début, traitement et polypharmacie) ont été analysées. Les patients ont été divisés en répondeurs R (IRLS>20 ou amélioration>5 sur l’IRLS) ou non répondeurs NR.RésultatsCinquante et un patients ont été inclus, 58 % hommes d’âge moyen 64,3±11,5 avec un IRLS initial de 31,1±4,3 et après 8 semaines de 25,3±6,4, p<0,0001. 57 % ont été des répondeurs (R) et 43 % des non-répondeurs (NR). Dans une analyse bivariée, seul l’âge (R 61,5±12,1 vs NR 68,4±9,7, p=0,016) et l’IRLS initial (R 32,6±3,5 vs NR 29,1±4,5, p=0,002) sont significativement associé au profil R. Un modelé mixte incluant le sexe, l’âge au début, l’heure de démarrage des symptômes, l’utilisation d’agonistes dopaminergiques, la polypharmacie, l’HADD initial confirme le rôle de l’âge (OR 0,9 IC 95 % 0,85–1,021, p=0,046) et de l’IRLS initial (OR 1,278 IC 95 % 1,004–1,628, p=0,009).ConclusionLes patients SJSR plus jeunes et ceux avec un IRLS plus élevé auraient plus de probabilité de répondre positivement aux traitements par tVNS.

Aims: This work aimed to study the effect of noninvasive vagus nerve stimulation on severe restless legs syndrome (RLS) resistant to pharmacotherapy.Materials and Methods: Patients with severe pharmacoresistant RLS were recruited from a tertiary care sleep center. Inter-vention was one-hour weekly sessions of transauricular vagus nerve stimulation (tVNS) in the left cymba concha, for eight weeks. The primary outcome measure was the score on the International Restless Legs Rating Scale (IRLS); secondary outcome measures were quality of life (Restless Legs Syndrome Quality of Life scale [RLSQOL]), mood disorders using the Hospital Anxiety and Depression scale subscale for depression (HADD) and Hospital Anxiety and Depression scale subscale for anxiety (HADA), and objective sleep latency, sleep duration, efficiency, and leg movement time measured by actigraphy.Results: Fifteen patients, 53% male, aged mean 62.7 +/- 12.3 years with severe RLS, reduced quality of life, and symptoms of anxiety and depression, were included. The IRLS improved from baseline to session eight: IRLS 31.9 +/- 2.9 vs 24.6 +/- 5.9 p = 0.0003. Of these participants, 27% (4/15) had a total response with a decrease below an IRLS score of 20; 40% (6/15) a partial response with an improvement in the IRLS > 5 but an IRLS above 20; and 33% (5/15) were nonresponders. After tVNS, quality of life improved (RLSQOL 49.3 +/- 18.1 vs 80.0 +/- 19.6 p = 0.0005), as did anxiety (HADA 8.9 +/- 5.4 vs 6.2 +/- 5.0 p = 0.001) and depression (HADD 5.2 +/- 4.5 vs 4.0 +/- 4.0 p = 0.01). No significant change was found in actigraphic outcome measures.Conclusions: In this pilot study, tVNS improved the symptoms of RLS in 66% of participants (10/15) with severe pharmacor-esistant RLS, with concomitant improvements in quality of life and mood. Randomized controlled trials evaluating therapeutic efficacy of tVNS in RLS are needed to confirm these promising findings.

Severe pharmacoresistant restless legs syndrome (RLS) is difficult to manage and a source of suffering to patients. We studied the effectiveness at 6 months of an innovative treatment: transauricular vagus nerve stimulation (taVNS) in the left cymba concha in a case series of 15 patients, 53% male, mean (SD) age 62.7 (12.3) years with severe pharmacoresistant RLS (mean [SD] International Restless Legs Rating Scale [IRLS] score of 31.9 [2.9]) at baseline. Following an 8-week non-randomised hospital-based study with eight 1-h sessions of taVNS, patients were trained to administer taVNS at home and were followed up for 6 months. The primary outcome measure was the IRLS score, secondary outcome measures were quality of life, mood disorders using the Hospital Anxiety and Depression scale (HAD) subscales for depression (HADD) and anxiety (HADA). At the 6-month follow-up 13/15 patients continued to use weekly taVNS. Symptom severity decreased (mean [SD] IRLS score 22.2 [9.32] at 6 months, p = 0.0005). Four of the 15 patients had an IRLS score of <20 at 6 months and two an IRLS score of 5. Quality of life significantly improved compared to baseline (mean [SD] score at baseline 49.3 [18.1] versus 65.66 [22.58] at 6 months, p = 0.0005) as did anxiety and depression symptoms (mean [SD] HADA score at baseline 8.9 [5.4] versus 7.53 [4.42] at 6 months, p = 0.029; and HADD score at baseline 5.2 [4.5] versus 4.73 [4.44] at 6 months, p = 0.03). Treatment was well tolerated, and no adverse events were reported. Our case series shows a potential role for self-administered taVNS in patients with severe pharmacoresistant RLS. Randomised controlled trials are needed to confirm the utility of taVNS.

Le syndrome des jambes sans repos (SJSR) reste parfois difficile à contrôler malgré un traitement pharmacologique optimisé, et constitue une souffrance importante pour les patients. La stimulation du nerf vague (SNV) module l’activité des aires sensorimotrices, limbiques et des noyaux monoaminergiques impliqués dans la physiopathologie du SJSR. Nous avons évalué la sévérité des symptômes (IRLSS), la qualité de vie (RLSQOL), et l’humeur (HAD) avant et après 8 semaines de traitement par SNV trans-auriculaire à raison d’une séance d’une heure par semaine, chez 15 patients (46 % femmes), moyenne d’âges : 62,7 ± 12.3 ans, ayant un SJSR sévère malgré un traitement optimisé, sans syndrome d’augmentation. Une actimétrie est posée à la cheville afin de mesurer les mouvements des jambes et au poignet pour évaluer le sommeil pendant 7 jours au début et pendant 7 jours à la fin du traitement. Le score IRLSS moyen des patients à l’inclusion était de 31,9 ± 2,9. Le score de l’IRLSS a été significativement amélioré entre S1 et S8 : 31,9 ± 2,9 vs 24,6 ± 5,9 (p < 0,0003). Une amélioration significative a été également trouvée entre S1 et S8 pour les symptômes d’anxiété (8,9 ± 5,4 vs 6,2 ± 5 p = 0,001) et de dépression (5,2 ± 4,5 vs 4 ± 4 p = 0,01), de même que la qualité de vie (49,3 ± 18,1 vs 80 ± 19,6 p = 0,0005). L’analyse des données de l’actimétrie n’a pas montré de différence significative. La prise en charge par traitement SNV semble très prometteuse sur l’amélioration des symptômes chez les patients souffrant de SJSR pharmaco résistant. De larges études randomisées et contrôlées sont nécessaires.

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 Growing evidence associates organ dysfunction(s) with impaired metabolism in sepsis. Recent research has increased our understanding of the role of substrate utilization and mitochondrial dysfunction in the pathophysiology of sepsis-related organ dysfunction. The purpose of this review is to present this evidence as a coherent whole and to highlight future research directions. Main text Sepsis is characterized by systemic and organ-specific changes in metabolism. Alterations of oxygen consumption, increased levels of circulating substrates, impaired glucose and lipid oxidation, and mitochondrial dysfunction are all associated with organ dysfunction and poor outcomes in both animal models and patients. The pathophysiological relevance of bioenergetics and metabolism in the specific examples of sepsis-related immunodeficiency, cerebral dysfunction, cardiomyopathy, acute kidney injury and diaphragmatic failure is also described. Conclusions Recent understandings in substrate utilization and mitochondrial dysfunction may pave the way for new diagnostic and therapeutic approaches. These findings could help physicians to identify distinct subgroups of sepsis and to develop personalized treatment strategies. Implications for their use as bioenergetic targets to identify metabolism- and mitochondria-targeted treatments need to be evaluated in future studies.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) through excessive end organ inflammation. Despite improved understanding of the pathophysiology, management, and the great efforts worldwide to produce effective drugs, death rates of COVID-19 patients remain unacceptably high, and effective treatment is unfortunately lacking. Pharmacological strategies aimed at modulating inflammation in COVID-19 are being evaluated worldwide. Several drug therapies targeting this excessive inflammation, such as tocilizumab, an interleukin (IL)-6 inhibitor, corticosteroids, programmed cell death protein (PD)-1/PD-L1 checkpoint inhibition, cytokine-adsorption devices, and intravenous immunoglobulin have been identified as potentially useful and reliable approaches to counteract the cytokine storm. However, little attention is currently paid for non-drug therapeutic strategies targeting inflammatory and immunological processes that may be useful for reducing COVID-19-induced complications and improving patient outcome. Vagus nerve stimulation attenuates inflammation both in experimental models and preliminary data in human. Modulating the activity of cholinergic anti-inflammatory pathways (CAPs) described by the group of KJ Tracey has indeed become an important target of therapeutic research strategies for inflammatory diseases and sepsis. Non-invasive transcutaneous vagal nerve stimulation (t-VNS), as a non-pharmacological adjuvant, may help reduce the burden of COVID-19 and deserve to be investigated. VNS as an adjunct therapy in COVID-19 patients should be investigated in clinical trials. Two clinical trials on this topic are currently underway (NCT04382391 and NCT04368156). The results of these trials will be informative, but additional larger studies are needed.

The Translational Research Committee of the French Intensive Care Society organized the first Young Investigator’s Day on October 18th 2019. This seminar gave young Intensive Care students the opportunity to present their Master’s or PhD research work to a college of expert researchers. For this first event, Professors Jean-Marc Cavaillon (Paris), Laurent Papazian (Marseille), Peter Radermacher (Ulm) et Hafid Ait-Oufella (Paris) kindly accepted to give young candidates their critical support. The subjects of presentations, covering the fields of neuroscience, immunology, hemodynamics and pharmacology illustrated the richness and diversity of translational research in Intensive Care Medicine.

Axial spondyloarthritis (SpA), is a major cause of chronic pain and disability that profoundly alters the quality of life of patients. Nearly half of patients with SpA usually develop drug resistance. Non-pharmacological treatments targeting inflammation are an attractive alternative to drug administration. Vagus nerve stimulation (VNS), by promoting a cholinergic anti-inflammatory reflex holds promise for treating inflammatory disease. Inflammatory reflex signaling, which is enhanced by electrically stimulating the vagus nerve, significantly reduces cytokine production and attenuates disease severity in animal models of endotoxemia, sepsis, colitis, and other preclinical models of inflammatory diseases. It has been proposed that vagal efferent fibers release acetylcholine (Ach), which can interact with α7-subunit-containing nicotinic receptors expressed by tissue macrophages and other immune cells to rapidly inhibit the synthesis/release of pro-inflammatory cytokines such as TNFα, IL-1β, IL-6, and IL-18. External vagal nerve stimulation devices are now available that do not require surgery nor implantation to non-invasively stimulate the vagal nerve. This double-blind randomized cross-over clinical trial aims to study the change in SpA disease activity, according to Assessment in Ankylosing Spondylitis 20 (ASAS20) definition, after 12 weeks of non-invasive VNS treatment vs. non-specific dummy stimulation (control group). One hundred and twenty adult patients with drug resistant SpA, meeting the ASAS classification criteria, will be included in the study. Patients will be randomized into two parallel groups according to a cross over design: either active VNS for 12 weeks, then dummy stimulation for 12 weeks, or dummy stimulation for 12 weeks, then active VNS for 12 weeks. The two stimulation periods will be separated by a 4 weeks wash-out period. A transcutaneous auricular vagus nerve stimulator Tens Eco Plus SCHWA MEDICO TM France will be used in this study. The active VNS stimulation will be applied in the cymba conchae of the left ear upon the auricular branch of the vagus nerve, using low intensity (2–5 mA), once à week, during 1 h. Dummy stimulation will be performed under the same conditions and parameters as active VNS stimulation, but at an irrelevant anatomical site: the left ear lobule. This multicenter study was registered on ClinicalTrials.gov : NCT04286373.