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.

Electroencephalography (EEG) is a well-established tool for assessing brain function that is available at the bedside in the intensive care unit (ICU). This review aims to discuss the relevance of electroencephalographic reactivity (EEG-R) in patients with impaired consciousness and to describe the neurophysiological mechanisms involved. We conducted a systematic search of the term “EEG reactivity and coma” using the PubMed database. The search encompassed articles published from inception to March 2018 and produced 202 articles, of which 42 were deemed relevant, assessing the importance of EEG-R in relationship to outcomes in patients with impaired consciousness, and were therefore included in this review. Although definitions, characteristics and methods used to assess EEG-R are heterogeneous, several studies underline that a lack of EEG-R is associated with mortality and unfavorable outcome in patients with impaired consciousness. However, preserved EEG-R is linked to better odds of survival. Exploring EEG-R to nociceptive, auditory, and visual stimuli enables a noninvasive trimodal functional assessment of peripheral and central sensory ascending pathways that project to the brainstem, the thalamus and the cerebral cortex. A lack of EEG-R in patients with impaired consciousness may result from altered modulation of thalamocortical loop activity by afferent sensory input due to neural impairment. Assessing EEG-R is a valuable tool for the diagnosis and outcome prediction of severe brain dysfunction in critically ill patients. This review emphasizes that whatever the etiology, patients with impaired consciousness featuring a reactive electroencephalogram are more likely to have a favorable outcome, whereas those with a nonreactive electroencephalogram are prone to having an unfavorable outcome. EEG-R is therefore a valuable prognostic parameter and warrants a rigorous assessment. However, current assessment methods are heterogeneous, and no consensus exists. Standardization of stimulation and interpretation methods is needed.

Animal experiments are widely used in preclinical medical research with the goal of disease modeling and exploration of novel therapeutic approaches. In the context of sepsis and septic shock, the translation into clinical practice has been disappointing. Classical animal models of septic shock usually involve one-sex-one-age animal models, mostly in mice or rats, contrasting with the heterogeneous population of septic shock patients. Many other factors limit the reliability of preclinical models and may contribute to preclinical research failure in critical care, including the host specificity of several pathogens, the fact that laboratory animals are raised in pathogen-free facilities and that organ support techniques are either absent or minimal. Advanced animal models have been developed with the aim of improving the clinical translatability of experimental findings. So-called animal ICUs refer to the preclinical investigation of adult or even aged animals of either sex, using—in case of rats and mice—miniaturized equipment allowing for reproducing an ICU environment at a small animal scale and integrating chronic comorbidities to more closely reflect the clinical conditions studied. Strength and limitations of preclinical animal models designed to decipher the mechanisms involved in septic cardiomyopathy are discussed. This article reviews the current status and the challenges of setting up an animal ICU.

Background: Neurofeedback (NF) training, as a method of self-regulation of brain activity, may be beneficial in elderly patients with mild cognitive impairment (MCI). In this pilot study, we investigated whether a sensorimotor (SMR)/theta NF training could improve cognitive performance and brain electrical activity in elderly patients with MCI. Methods: Twenty elderly patients with MCI were assigned to 20 consecutive sessions of sensorimotor (SMR)/theta NF training, during 10 weeks, on a basis of two sessions each week. Neuropsychological assessments and questionnaires, as well as electroencephalogram (EEG), were performed and compared between baseline (T0), after the last NF training session at 10 weeks (T1), and 1-month follow-up (T2). Results: Repeated measures ANOVA revealed that from baseline to post-intervention, participants showed significant improvement in the Montreal cognitive assessment (MoCa, F = 4.78; p = 0.012), the delayed recall of the Rey auditory verbal learning test (RAVLT, F = 3.675; p = 0.032), the Forward digit span (F = 13.82; p < 0.0001), the Anxiety Goldberg Scale (F = 4.54; p = 0.015), the Wechsler Adult Intelligence Score–Fourth Edition (WAIS-IV; F = 24.75; p < 0.0001), and the Mac Nair score (F = 4.47; p = 0.016). EEG theta power (F = 4.44; p = 0.016) and alpha power (F = 3.84; p = 0.027) during eyes-closed resting-state significantly increased after the NF training and showed sustained improvement at a 1-month follow-up. Conclusion: Our results suggest that NF training could be effective to reduce cognitive deficits in elderly patients with MCI and improve their EEG activity. If these findings are confirmed by randomized controlled studies with larger samples of patients, NF could be seen as a useful non-invasive, non-pharmacological tool for preventing further decline, rehabilitation of cognitive function in the elderly. Clinical Trial Registration: This pilot study was a preliminary step before the trial registered in www.ClinicalTrials.gov, under the number of NCT03526692.

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.

We prospectively studied early bedside standard EEG characteristics in 61 acute postanoxic coma patients. Five simple EEG features, namely, isoelectric, discontinuous, nonreactive to intense auditory and nociceptive stimuli, dominant delta frequency, and occurrence of paroxysms were classified yes or no. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating characteristic curve (AUC) of each of these variables for predicting an unfavorable outcome, defined as death, persistent vegetative state, minimally conscious state, or severe neurological disability, as assessed 1 year after coma onset were computed as well as Synek’s score. The outcome was unfavorable in 56 (91.8%) patients. Sensitivity, specificity, PPV, NPV, and AUC of nonreactive EEG for predicting an unfavorable outcome were 84%, 80%, 98%, 31%, and 0.82, respectively; and were all very close to the ones of Synek score >3, which were 82%, 80%, 98%, 29%, and 0.81, respectively. Specificities for predicting an unfavorable outcome were 100% for isoelectric, discontinuous, or dominant delta activity EEG. These 3 last features were constantly associated to unfavorable outcome. Absent EEG reactivity strongly predicted an unfavorable outcome in postanoxic coma, and performed as accurate as a Synek score >3. Analyzing characteristics of some simple EEG features may easily help nonneurophysiologist physicians to investigate prognostic issue of postanoxic coma patient. In this study (a) discontinuous, isoelectric, or delta-dominant EEG were constantly associated with unfavorable outcome and (b) nonreactive EEG performed prognostic as accurate as a Synek score >3.