Acute encephalopathy in the ICU: a practical approach.

PURPOSE OF REVIEW: Acute encephalopathy (AE) - which frequently develops in critically ill patients with and without primary brain injury - is defined as an acute process that evolves rapidly and leads to changes in baseline cognitive status, ranging from delirium to coma. The diagnosis, monitoring, and management of AE is challenging. Here, we discuss advances in definitions, diagnostic approaches, therapeutic options, and implications to outcomes of the clinical spectrum of AE in ICU patients without primary brain injury. RECENT FINDINGS: Understanding and definitions of delirium and coma have evolved. Delirium is a neurocognitive disorder involving impairment of attention and cognition, usually fluctuating, and developing over hours to days. Coma is a state of unresponsiveness, with absence of command following, intelligible speech, or visual pursuit, with no imaging or neurophysiological evidence of cognitive motor dissociation. The CAM-ICU(-7) and the ICDSC are validated, guideline-recommended tools for clinical delirium assessment, with identification of clinical subtypes and stratification of severity. In comatose patients, the roles of continuous EEG monitoring and neuroimaging have grown for the early detection of secondary brain injury and treatment of reversible causes. SUMMARY: Evidence-based pharmacologic treatments for delirium are limited. Dexmedetomidine is effective for mechanically ventilated patients with delirium, while haloperidol has minimal effect of delirium but may have other benefits. Specific treatments for coma in nonprimary brain injury are still lacking.

Increased levels of GM-CSF and CXCL10 and low CD8+ memory stem T Cell count are markers of immunosenescence and severe COVID-19 in older people.

BACKGROUND: Ageing leads to altered immune responses, resulting in higher susceptibility to certain infections in the elderly. Immune ageing is a heterogeneous process also associated with inflammaging, a low-grade chronic inflammation. Altered cytotoxic T cell responses and cytokine storm have previously been described in severe COVID-19 cases, however the parameters responsible for such immune response failures are not well known. The aim of our study was to characterize CD8+ T cells and cytokines associated with ageing, in a cohort of patients aged over 70 years stratified by COVID-19 severity. RESULTS: One hundred and four patients were included in the study. We found that, in older people, COVID-19 severity was associated with (i) higher level of GM-CSF, CXCL10 (IP-10), VEGF, IL-1ß, CCL2 (MCP-1) and the neutrophil to lymphocyte ratio (NLR), (ii) increased terminally differentiated CD8+T cells, and (ii) decreased early precursors CD8+ T stem cell-like memory cells (TSCM) and CD27+CD28+. The cytokines mentioned above were found at higher concentrations in the COVID-19+ older cohort compared to a younger cohort in which they were not associated with disease severity. CONCLUSIONS: Our results highlight the particular importance of the myeloid lineage in COVID-19 severity among older people. As GM-CSF and CXCL10 were not associated with COVID-19 severity in younger patients, they may represent disease severity specific markers of ageing and should be considered in older people care.

Quantitative analysis of early-stage EEG reactivity predicts awakening and recovery of consciousness in patients with severe brain injury.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 ß=-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). CONCLUSIONS: 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.

Early Clinical and Electrophysiological Brain Dysfunction Is Associated With ICU Outcomes in COVID-19 Critically Ill Patients With Acute Respiratory Distress Syndrome: A Prospective Bicentric Observational Study.

OBJECTIVES: Describe the prevalence of acute cerebral dysfunction and assess the prognostic value of an early clinical and electroencephalography (EEG) assessment in ICU COVID-19 patients. DESIGN: Prospective observational study. SETTING: Two tertiary critical care units in Paris, France, between April and December 2020. PATIENTS: Adult critically ill patients with COVID-19 acute respiratory distress syndrome. INTERVENTIONS: Neurologic examination and EEG at two time points during the ICU stay, first under sedation and second 4-7 days after sedation discontinuation. MEASUREMENTS AND MAIN RESULTS: Association of EEG abnormalities (background reactivity, continuity, dominant frequency, and presence of paroxystic discharges) with day-28 mortality and neurologic outcomes (coma and delirium recovery). Fifty-two patients were included, mostly male (81%), median (interquartile range) age 68 years (56-74 yr). Delayed awakening was present in 68% of patients (median awakening time of 5 d [2-16 d]) and delirium in 74% of patients who awoke from coma (62% of mixed delirium, median duration of 5 d [3-8 d]). First, EEG background was slowed in the theta-delta range in 48 (93%) patients, discontinuous in 25 patients (48%), and nonreactive in 17 patients (33%). Bifrontal slow waves were observed in 17 patients (33%). Early nonreactive EEG was associated with lower day-28 ventilator-free days (0 vs 16; p = 0.025), coma-free days (6 vs 22; p = 0.006), delirium-free days (0 vs 17; p = 0.006), and higher mortality (41% vs 11%; p = 0.027), whereas discontinuous background was associated with lower ventilator-free days (0 vs 17; p = 0.010), coma-free days (1 vs 22; p < 0.001), delirium-free days (0 vs 17; p = 0.001), and higher mortality (40% vs 4%; p = 0.001), independently of sedation and analgesia. CONCLUSIONS: Clinical and neurophysiologic cerebral dysfunction is frequent in COVID-19 ARDS patients. Early severe EEG abnormalities with nonreactive and/or discontinuous background activity are associated with delayed awakening, delirium, and day-28 mortality.

Circulating Von Willebrand factor and high molecular weight multimers as markers of endothelial injury predict COVID-19 in-hospital mortality.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a respiratory disease associated with endotheliitis and microthrombosis. OBJECTIVES: To correlate endothelial dysfunction to in-hospital mortality in a bi-centric cohort of COVID-19 adult patients. METHODS: Consecutive ambulatory and hospitalized patients with laboratory-confirmed COVID-19 were enrolled. A panel of endothelial biomarkers and von Willebrand factor (VWF) multimers were measured in each patient ≤ 48 h following admission. RESULTS: Study enrolled 208 COVID-19 patients of whom 23 were mild outpatients and 189 patients hospitalized after admission. Most of endothelial biomarkers tested were found increased in the 89 critical patients transferred to intensive care unit. However, only von Willebrand factor antigen (VWF:Ag) scaled according to clinical severity, with levels significantly higher in critical patients (median 507%, IQR 428-596) compared to non-critical patients (288%, 230-350, p < 0.0001) or COVID-19 outpatients (144%, 133-198, p = 0.007). Moreover, VWF high molecular weight multimers (HMWM) were significantly higher in critical patients (median ratio 1.18, IQR 0.86-1.09) compared to non-critical patients (0.96, 1.04-1.39, p < 0.001). Among all endothelial biomarkers measured, ROC curve analysis identified a VWF:Ag cut-off of 423% as the best predictor for in-hospital mortality. The accuracy of VWF:Ag was further confirmed in a Kaplan-Meier estimator analysis and a Cox proportional Hazard model adjusted on age, BMI, C-reactive protein and D-dimer levels. CONCLUSION: VWF:Ag is a relevant predictive factor for in-hospital mortality in COVID-19 patients. More than a biomarker, we hypothesize that VWF, including excess of HMWM forms, drives microthrombosis in COVID-19.

Habituation of auditory startle reflex is a new sign of minimally conscious state.

Neurological examination of non-communicating patients relies on a few decisive items that enable the crucial distinction between vegetative state (VS)-also coined unresponsive wakefulness syndrome (UWS)-and minimally conscious state. Over the past 10 years, this distinction has proven its diagnostic value as well as its important prognostic value on consciousness recovery. However, clinicians are currently limited by three factors: (i) the current behavioural repertoire of minimally conscious state items is limited and restricted to a few cognitive domains in the goldstandard revised version of the Coma Recovery Scale; (ii) a proportion of ∼15-20% clinically VS/UWS patients are actually in a richer state than VS/UWS as evidenced by functional brain imaging; and (iii) the neurophysiological and cognitive interpretation of each minimally conscious state item is still unclear and debated. In the current study we demonstrate that habituation of the auditory startle reflex (hASR) tested at bedside constitutes a novel, simple and powerful behavioural sign that can accurately distinguish minimally conscious state from VS/UWS. In addition to enlarging the minimally conscious state items repertoire, and therefore decreasing the low sensitivity of current behavioural measures, we also provide an original and rigorous description of the neurophysiological basis of hASR through a combination of functional (high density EEG and 18F-fluorodeoxyglucose PET imaging) and structural (diffusion tensor imaging MRI) measures. We show that preservation of hASR is associated with the functional and structural integrity of a brain-scale fronto-parietal network, including prefrontal regions related to control of action and inhibition, and meso-parietal areas associated with minimally conscious and conscious states. Lastly, we show that hASR predicts 6-month improvement of consciousness. Taken together, our results show that hASR is a cortically-mediated behaviour, and suggest that it could be a new clinical item to clearly and accurately identify non-communicating patients who are in the minimally conscious state.

Epidemiology and Predictors of Long-Stays in Medical ICU: A Retrospective Cohort Study.

INTRODUCTION: Prolonged stays in ICU have been associated with overconsumption of resources but little is known about their epidemiology. We aimed to identify predictors and prognostic factors of extended stays, studying a long-stay population. METHODS: We present a retrospective cohort study between July 2000 and December 2013 comparing patients hospitalized in a medical ICU for ≥30 days (long-stay patients-LSP) with patients hospitalized for <30 days (short-stay patients-SSP). Admission characteristics were collected from the local database for every patient and evolution during the ICU stay was retrieved from LSP files. RESULTS: Among 8906 patients hospitalized in the ICU, 417 (4.7%) were LSP. At admission, male sex (adjusted odds-ratio (aOR) 1.4 [1.1; 1.7]), inpatient (aOR 2.0 [1.6; 2.4]) and in-ICU hospitalizations for respiratory (aOR 2.9 [1.6; 3.5]) or infectious diseases (aOR 1.6 [1.1; 2.5]) were all independently associated with a long stay in the ICU, while hospitalizations for metabolic (aOR 0.2 [0.1; 0.5]) or cardiovascular diseases (aOR 0.3 [0.2; 0.5]) were in favor of a short stay. In-ICU and in-hospital LSP mortality were 38.8% and 48.2%. Age (aOR 1.02 [1.00-1.04]), catecholamines (aOR 3.9 [1.9; 8.5]), renal replacement therapy (aOR 2.4 [1.3; 4.3]), primary disease-related complications (aOR 2.5 [1.4; 4.6]) and nosocomial infections (aOR 4.1 [1.8; 10.1]) were independently associated with mortality in LSP. CONCLUSION: LSP were highly comorbid patients mainly hospitalized for respiratory diseases. Their mortality was mostly related to nosocomial infections but the majority were discharged alive from the hospital.

EEG evidence of compensatory mechanisms in preclinical Alzheimer's disease.

Early biomarkers are needed to identify individuals at high risk of preclinical Alzheimer's disease and to better understand the pathophysiological processes of disease progression. Preclinical Alzheimer's disease EEG changes would be non-invasive and cheap screening tools and could also help to predict future progression to clinical Alzheimer's disease. However, the impact of amyloid-ß deposition and neurodegeneration on EEG biomarkers needs to be elucidated. We included participants from the INSIGHT-preAD cohort, which is an ongoing single-centre multimodal observational study that was designed to identify risk factors and markers of progression to clinical Alzheimer's disease in 318 cognitively normal individuals aged 70-85 years with a subjective memory complaint. We divided the subjects into four groups, according to their amyloid status (based on 18F-florbetapir PET) and neurodegeneration status (evidenced by 18F-fluorodeoxyglucose PET brain metabolism in Alzheimer's disease signature regions). The first group was amyloid-positive and neurodegeneration-positive, which corresponds to stage 2 of preclinical Alzheimer's disease. The second group was amyloid-positive and neurodegeneration-negative, which corresponds to stage 1 of preclinical Alzheimer's disease. The third group was amyloid-negative and neurodegeneration-positive, which corresponds to 'suspected non-Alzheimer's pathophysiology'. The last group was the control group, defined by amyloid-negative and neurodegeneration-negative subjects. We analysed 314 baseline 256-channel high-density eyes closed 1-min resting state EEG recordings. EEG biomarkers included spectral measures, algorithmic complexity and functional connectivity assessed with a novel information-theoretic measure, weighted symbolic mutual information. The most prominent effects of neurodegeneration on EEG metrics were localized in frontocentral regions with an increase in high frequency oscillations (higher beta and gamma power) and a decrease in low frequency oscillations (lower delta power), higher spectral entropy, higher complexity and increased functional connectivity measured by weighted symbolic mutual information in theta band. Neurodegeneration was associated with a widespread increase of median spectral frequency. We found a non-linear relationship between amyloid burden and EEG metrics in neurodegeneration-positive subjects, either following a U-shape curve for delta power or an inverted U-shape curve for the other metrics, meaning that EEG patterns are modulated differently depending on the degree of amyloid burden. This finding suggests initial compensatory mechanisms that are overwhelmed for the highest amyloid load. Together, these results indicate that EEG metrics are useful biomarkers for the preclinical stage of Alzheimer's disease.

Aberrant brain-heart coupling is associated with the severity of post cardiac arrest brain injury.

OBJECTIVE: To investigate autonomic nervous system activity measured by brain-heart interactions in comatose patients after cardiac arrest in relation to the severity and prognosis of hypoxic-ischemic brain injury. METHODS: Strength and complexity of bidirectional interactions between EEG frequency bands (delta, theta, and alpha) and ECG heart rate variability frequency bands (low frequency, LF and high frequency, HF) were computed using a synthetic data generation model. Primary outcome was the severity of brain injury, assessed by (i) standardized qualitative EEG classification, (ii) somatosensory evoked potentials (N20), and (iii) neuron-specific enolase levels. Secondary outcome was the 3-month neurological status, assessed by the Cerebral Performance Category score [good (1-2) vs. poor outcome (3-4-5)]. RESULTS: Between January 2007 and July 2021, 181 patients were admitted to ICU for a resuscitated cardiac arrest. Poor neurological outcome was observed in 134 patients (74%). Qualitative EEG patterns suggesting high severity were associated with decreased LF/HF. Severity of EEG changes were proportional to higher absolute values of brain-to-heart coupling strength (p < 0.02 for all brain-to-heart frequencies) and lower values of alpha-to-HF complexity (p = 0.049). Brain-to-heart coupling strength was significantly higher in patients with bilateral absent N20 and correlated with neuron-specific enolase levels at Day 3. This aberrant brain-to-heart coupling (increased strength and decreased complexity) was also associated with 3-month poor neurological outcome. INTERPRETATION: Our results suggest that autonomic dysfunctions may well represent hypoxic-ischemic brain injury post cardiac arrest pathophysiology. These results open avenues for integrative monitoring of autonomic functioning in critical care patients.

Barriers to research findings utilization amongst critical care nurses and allied health professionals: An international survey.

OBJECTIVES: To determine the perceived barriers to the implementation of research findings in clinical practice among critical care nurses and allied health professionals. METHODS: A cross-sectional study was conducted using an online questionnaire sent to critical care nurses and allied health professionals in French-speaking countries. The primary objective was the identification and grading of perceived barriers to implementation of research findings into clinical practice, using a previously validated tool (French version of the BARRIERS scale). The scale is divided into 4 dimensions, each containing 6 to 7 questions to be answered using a 4-point Likert scale (1: no barrier, 4: great barrier). Descriptive statistics were performed and weighted score per dimensions were compared. Univariate and multivariate linear regressions were performed to identify factors associated with the total score by dimension. RESULTS: A total of 994 nurses and allied health professionals (85.1 % of ICU nurses) from 5 countries (71.8 % from France) responded to the survey. Main reported barriers to research findings utilization were "Statistical analyses are not understandable" (54.5 %), "Research articles are not readily available" (54.3 %), and "Implications for practice are not made clear" (54.2 %). Weighted scores differed between dimensions, with the "communication" and "organization" dimensions being the greatest barriers (median [IQR]: 2.3 [1.8-2.7] and 2.0 [1.6-2.4], while the "adopter" and "innovation" dimensions having lower scores (1.5 [1.2-1.8] and 1.5 [1.0-1.8] (all pairwise comparisons p-value < 0.0001, except for the adopter vs. innovation comparison, p > 0.05). CONCLUSIONS: Accessibility and understanding of research results seem to be the main barriers to research utilization in practice by respondents. A large number of the reported barriers could be overcome through education and organizational change. IMPLICATIONS FOR PRACTICE: Promoting a research culture among nurses and allied health professionals is an issue that needs investment. This should include training in critical reading of scientific articles and statistics.

Heart rate variability for neuro-prognostication after CA: Insight from the Parisian registry.

BACKGROUND: Hypoxic ischemic brain injury (HIBI) induced by cardiac arrest (CA) seems to predominate in cortical areas and to a lesser extent in the brainstem. These regions play key roles in modulating the activity of the autonomic nervous system (ANS), that can be assessed through analyses of heart rate variability (HRV). The objective was to evaluate the prognostic value of various HRV parameters to predict neurological outcome after CA. METHODS: Retrospective monocentric study assessing the prognostic value of HRV markers and their association with HIBI severity. Patients admitted for CA who underwent EEG for persistent coma after CA were included. HRV markers were computed from 5 min signal of the ECG lead of the EEG recording. HRV indices were calculated in the time-, frequency-, and non-linear domains. Frequency-domain analyses differentiated very low frequency (VLF 0.003-0.04 Hz), low frequency (LF 0.04-0.15 Hz), high frequency (HF 0.15-0.4 Hz), and LF/HF ratio. HRV indices were compared to other prognostic markers: pupillary light reflex, EEG, N20 on somatosensory evoked potentials (SSEP) and biomarkers (neuron specific enolase-NSE). Neurological outcome at 3 months was defined as unfavorable in case of best CPC 3-4-5. RESULTS: Between 2007 and 2021, 199 patients were included. Patients were predominantly male (64%), with a median age of 60 [48.9-71.7] years. 76% were out-of-hospital CA, and 30% had an initial shockable rhythm. Neurological outcome was unfavorable in 73%. Compared to poor outcome, patients with a good outcome had higher VLF (0.21 vs 0.09 ms2/Hz, p < 0.01), LF (0.07 vs 0.04 ms2/Hz, p = 0.003), and higher LF/HF ratio (2.01 vs 1.01, p = 0.008). Several non-linear domain indices were also higher in the good outcome group, such as SD2 (15.1 vs 10.2, p = 0.016) and DFA α1 (1.03 vs 0.78, p = 0.002). These indices also differed depending on the severity of EEG pattern and abolition of pupillary light reflex. These time-frequency and non-linear domains HRV parameters were predictive of poor neurological outcome, with high specificity despite a low sensitivity. CONCLUSION: In comatose patients after CA, some HRV markers appear to be associated with unfavorable outcome, EEG severity and PLR abolition, although the sensitivity of these HRV markers remains limited.

Severe asthma exacerbation: Changes in patient characteristics, management, and outcomes from 1997 to 2016 in 40 ICUs in the greater Paris area.

Background: Despite advances in asthma treatments, severe asthma exacerbation (SAE) remains a life-threatening condition in adults, and there is a lack of data derived from adult patients admitted to intensive care units (ICUs) for SAE. The current study investigated changes in adult patient characteristics, management, and outcomes of SAE over a 20-year period in 40 ICUs in the greater Paris area. Methods: In this retrospective observational study, admissions to 40 ICUs in the greater Paris area for SAE from January 1, 1997, to December 31, 2016 were analyzed. The primary outcome was the proportion of ICU admissions for SAE during 5-year periods. Secondary outcomes were ICU and hospital mortality, and the use of mechanical ventilation and catecholamine. Multivariate analysis was performed to assess factors associated with ICU mortality. Results: A total of 7049 admissions for SAE were recorded. For each 5-year period, the proportion decreased over time, with SAE accounting for 2.84% of total ICU admissions (n=2841) between 1997 and 2001, 1.76% (n=1717) between 2002 and 2006, 1.05% (n=965) between 2007 and 2011, and 1.05% (n=1526) between 2012 and 2016. The median age was 46 years (interquartile range [IQR]: 32-59 years), 55.41% were female, the median Simplified Acute Physiology Score II was 20 (IQR: 13-28), and 19.76% had mechanical ventilation. The use of mechanical ventilation remained infrequent throughout the 20-year period, whereas the use of catecholamine decreased. ICU and hospital mortality rates decreased. Factors associated with ICU mortality were renal replacement therapy, catecholamine, cardiac arrest, pneumothorax, acute respiratory distress syndrome, sepsis, and invasive mechanical ventilation (IMV). Non-survivors were older, had more severe symptoms, and were more likely to have received IMV. Conclusion: ICU admission for SAE remains uncommon, and the proportion of cases decreased over time. Despite a slight increase in symptom severity during a 20-year period, ICU and hospital mortality decreased. Patients requiring IMV had a higher mortality rate.

The positive impact of COVID-19 on critical care: from unprecedented challenges to transformative changes, from the perspective of young intensivists.

Over the past 2 years, SARS-CoV-2 infection has resulted in numerous hospitalizations and deaths worldwide. As young intensivists, we have been at the forefront of the fight against the COVID-19 pandemic and it has been an intense learning experience affecting all aspects of our specialty. Critical care was put forward as a priority and managed to adapt to the influx of patients and the growing demand for beds, financial and material resources, thereby highlighting its flexibility and central role in the healthcare system. Intensivists assumed an essential and unprecedented role in public life, which was important when claiming for indispensable material and human investments. Physicians and researchers around the world worked hand-in-hand to advance research and better manage this disease by integrating a rapidly growing body of evidence into guidelines. Our daily ethical practices and communication with families were challenged by the massive influx of patients and restricted visitation policies, forcing us to improve our collaboration with other specialties and innovate with new communication channels. However, the picture was not all bright, and some of these achievements are already fading over time despite the ongoing pandemic and hospital crisis. In addition, the pandemic has demonstrated the need to improve the working conditions and well-being of critical care workers to cope with the current shortage of human resources. Despite the gloomy atmosphere, we remain optimistic. In this ten-key points review, we outline our vision on how to capitalize on the lasting impact of the pandemic to face future challenges and foster transformative changes of critical care for the better.

Discrepancies in the late auditory potentials of post-anoxic patients: Watch out for focal brain lesions, a pilot retrospective study.

AIMS: Late auditory evoked potentials, and notably mismatch negativity (MMN) and P3 responses, can be used as part of the multimodal prognostic evaluation in post-anoxic disorders of consciousness (DOC). MMN response preferentially stems from the temporal cortex and the arcuate fasciculus. Situations with discrepant evaluations, for example MMN absent but P3 present, are frequent and difficult to interpret. We hypothesize that discrepant MMN-/P3+ results could reflect a higher prevalence of lesions in MMN generating regions. This study presents correlations between neurophysiological and neuroradiological results. METHODS: This retrospective study was conducted on 38 post-anoxic DOC patients. Brain lesions were analyzed on 3T MRI both anatomically and through computation of the local arcuate fasciculus fractional anisotropy values on Diffusion Tensor Imaging sequences. Neurophysiological data and outcome were also analyzed. RESULTS: Our cohort included 8 MMN-/P3+, 7 MMN+/P3+, 21 MMN-/P3- and 2 MMN-/P3+ patients, assessed at a median delay of 20.5 days since cardiac arrest. Our results show that MMN-/P3+ patients tended to have fewer temporal and basal ganglia lesions than MMN-/P3- patients, and more than MMN+/P3+ patients (p-values for trend: p = 0.02 for temporal and p = 0.02 for basal ganglia lesions). There was a statistical difference across groups for mean fractional anisotropy values in the arcuate fasciculus (p = 0.008). The percentage of patients regaining consciousness at three months in MMN-/P3+ patients was higher than in MMN-/P3- patients and lower than in MMN+/P3+ patients. CONCLUSION: This study suggests that discrepancies in late auditory evoked potentials may be linked to focal post-anoxic brain lesions, visible on brain MRI.

PupillOmetry for preDIction of DeliriUM in ICU (PODIUM): protocol for a prospective multicentre cohort study.

INTRODUCTION: Delirium is a severe complication that is associated with short-term adverse events, prolonged hospital stay and neurological sequelae in survivors. Automated pupillometry is an easy-to-use device that allows for accurate objective assessment of the pupillary light responses in comatose patients in the intensive care unit (ICU). Whether automated pupillometry might predict delirium in critically ill patients is not known. We hypothesise that automated pupillometry could predict the occurrence of delirium in critically ill patients without primary brain injury, requiring more than 48 hours of invasive mechanical ventilation in the ICU. METHODS AND ANALYSIS: The PupillOmetry for preDIction of DeliriUM in ICU (PODIUM) study is a prospective cohort study, which will be conducted in eight French ICUs in the Paris area. We aim to recruit 213 adult patients requiring invasive mechanical ventilation for more than 48 hours. Automated pupillometry (Neurological Pupil Index; NPi-200, Neuroptics) will be assessed two times per day for 7 days. Delirium will be assessed using the Confusion Assessment Method in ICU two times per day over 14 days in non-comatose patients (Richmond Agitation and Sedation Scale ≥-3).The predictive performances of the seven automated pupillometry parameters (ie, pupillary diameter, variation of the pupillary diameter, pupillary constriction speed, pupillary dilatation speed, photomotor reflex latency, NPi and symmetry of pupillary responses) measured to detect the delirium occurrence within 14 days will be the main outcomes. Secondary outcomes will be the predictive performances of the seven automated pupillometry parameters to detect complications related to delirium, ICU length of stay, mortality, functional and cognitive outcomes at 90 days. ETHICS AND DISSEMINATION: The PODIUM study has been approved by an independent ethics committee, the Comité de Protection des Personnes (CPP) OUEST IV-NANTES (CPP21.02.15.45239 32/21_3) on 06 April 2021). Participant recruitment started on 15 April 2022. Results will be published in international peer-reviewed medical journals and presented at conferences. TRIAL REGISTRATION NUMBER: NCT05248035; clinicaltrials.gov.

In-hospital cardiac arrests admitted alive in intensive care units: Insights from the CubRéa database.

BACKGROUND: In-hospital cardiac arrest(IHCA) has received little attention compared with out-of-hospital cardiac arrest. AIM: To address the paucity of data on IHCA patients, we examined key features, variations in mortality and predictors of death among patients admitted in French intensive care units(ICUs) from 1997 to 2015. METHODS: Using the database of the Collège des Utilisateurs de Bases de données en Réanimation(CUB-Réa) that prospectively collects data from ICUs in the greater Paris area, we determined temporal trends in the incidence of IHCA, patients' outcomes, crude and Simplified Acute Physiology Score(SAPS)-II Standardized mortality and predictors of in-ICU mortality. RESULTS: Of the 376,325 ICU admissions, 15,324(4.08%) had IHCA, with incidence increasing from 2.78% to 3.83%(p < 0.001). Over time, the patient age increased by 0.7 years(p = 0.04) and SAPS-II increased by 2.3%(p < 0.001). Crude in-ICU mortality decreased from 78% to 62.5% over the past 18 years(p < 0.001). The SAPS-II-standardized mortality also decreased over time from 78.4% to 68.3%(p < 0.001) representing a 10.1% relative decrease from 1997 to 2015. In multivariate analysis, admission in a more recent time-period was an independent correlate of decreased mortality(OR 0.40, 95%CI 0.35-0.46). CONCLUSION: Occurrence of IHCA increased over time but remains an uncommon reason for being admitted to ICU. From 1997 to 2015, we observed a change in patient profile, with older and more critically ill patients, despite which in-ICU mortality has substantially decreased in IHCA patients, likely resulting from a global improvement in the process of care and more widespread implementation of rapid response teams.

Multimodal FDG-PET and EEG assessment improves diagnosis and prognostication of disorders of consciousness.

INTRODUCTION: Functional brain-imaging techniques have revealed that clinical examination of disorders of consciousness (DoC) can underestimate the conscious level of patients. FDG-PET metabolic index of the best preserved hemisphere (MIBH) has been reported as a promising measure of consciousness but has never been externally validated and compared with other brain-imaging diagnostic procedures such as quantitative EEG. METHODS: FDG-PET, quantitative EEG and cognitive evoked potential using an auditory oddball paradigm were performed in minimally conscious state (MCS) and vegetative state (VS) patient. We compared out-sample diagnostic and prognostic performances of PET-MIBH and EEG-based classification of conscious state to the current behavioral gold-standard, the Coma Recovery Scale - revised (CRS-R). RESULTS: Between January 2016 and October 2019, 52 patients were included: 21 VS and 31 MCS. PET-MIBH had an AUC of 0.821 [0.694-0.930], sensitivity of 79% [62-91] and specificity of 78% [56-93], not significantly different from EEG (p = 0.628). Their combination accurately identified almost all MCS patients with a sensitivity of 94% [79-99%] and specificity of 67% [43-85]. Multimodal assessment also identified VS patients with neural correlate of consciousness (4/7 (57%) vs. 1/14 (7%), p = 0.025) and patients with 6-month recovery of command-following (9/24 (38%) vs. 0/16 (0%), p = 0.006), outperforming each technique taken in isolation. CONCLUSION: FDG-PET MIBH is an accurate and robust procedure across sites to diagnose MCS. Its combination with EEG-based classification of conscious state not only optimizes diagnostic performances but also allows to detect covert cognition and to predict 6-month command-following recovery demonstrating the added value of multimodal assessment of DoC.

Importance, limits and caveats of the use of "disorders of consciousness" to theorize consciousness.

The clinical and fundamental exploration of patients suffering from disorders of consciousness (DoC) is commonly used by researchers both to test some of their key theoretical predictions and to serve as a unique source of empirical knowledge about possible dissociations between consciousness and cognitive and/or neural processes. For instance, the existence of states of vigilance free of any self-reportable subjective experience [e.g. "vegetative state (VS)" and "complex partial epileptic seizure"] originated from DoC and acted as a cornerstone for all theories by dissociating two concepts that were commonly equated and confused: vigilance and conscious state. In the present article, we first expose briefly the major achievements in the exploration and understanding of DoC. We then propose a synthetic taxonomy of DoC, and we finally highlight some current limits, caveats and questions that have to be addressed when using DoC to theorize consciousness. In particular, we show (i) that a purely behavioral approach of DoC is insufficient to characterize the conscious state of patients; (ii) that the comparison between patients in a minimally conscious state (MCS) and patients in a VS [also coined as unresponsive wakefulness syndrome (UWS)] does not correspond to a pure and minimal contrast between unconscious and conscious states and (iii) we emphasize, in the light of original resting-state positron emission tomography data, that behavioral MCS captures an important but misnamed clinical condition that rather corresponds to a cortically mediated state and that MCS does not necessarily imply the preservation of a conscious state.