Prognosis value of pupillometry in COVID-19 patients admitted in intensive care unit.

INTRODUCTION: ICU patients with SARS-CoV-2-related pneumonia are at risk to develop a central dysautonomia which can contribute to mortality and respiratory failure. The pupillary size and its reactivity to light are controlled by the autonomic nervous system. Pupillometry parameters (PP) allow to predict outcomes in various acute brain injuries. We aim at assessing the most predictive PP of in-hospital mortality and the need for invasive mechanical ventilation (IV). MATERIAL AND METHODS: We led a prospective, two centers, observational study. We recruited adult patients admitted to ICU for a severe SARS-CoV-2 related pneumonia between April and August 2020. The pupillometry was performed at admission including the measurement of baseline pupillary diameter (PD), PD variations (PDV), pupillary constriction velocity (PCV) and latency (PDL). RESULTS: Fifty patients, 90 % males, aged 66 (60-70) years were included. Seven (14 %) patients died in hospital. The baseline PD (4.1 mm [3.5; 4.8] vs 2.6 mm [2.4; 4.0], P = 0.009), PDV (33 % [27; 39] vs 25 % [15; 36], P = 0.03) and PCV (3.5 mm.s-1 [2.8; 4.4] vs 2.0 mm.s-1 [1.9; 3.8], P = 0.02) were significantly lower in patients who will die. A PD value <2.75 mm was the most predictive parameter of in-hospital mortality, with an AUC = 0.81, CI 95 % [0.63; 0.99]. Twenty-four (48 %) patients required IV. PD and PDV were significantly lower in patients who were intubated (3.5 mm [2.8; 4.4] vs 4.2 mm [3.9; 5.2], P = 0.03; 28 % [25; 36 %] vs 35 % [32; 40], P = 0.049, respectively). CONCLUSIONS: A reduced baseline PD is associated with bad outcomes in COVID-19 patients admitted in ICU. It is likely to reflect a brainstem autonomic dysfunction.

Incidence and prevalence of coma in the UK and the USA.

The epidemiology of coma is unknown because case ascertainment with traditional methods is difficult. Here, we used crowdsourcing methodology to estimate the incidence and prevalence of coma in the UK and the USA. We recruited UK and US laypeople (aged ≥18 years) who were nationally representative (i.e. matched for age, gender and ethnicity according to census data) of the UK and the USA, respectively, utilizing a crowdsourcing platform. We provided a description of coma and asked survey participants if they-'right now' or 'within the last year'-had a family member in coma. These participants (UK n = 994, USA n = 977) provided data on 30 387 family members (UK n = 14 124, USA n = 16 263). We found more coma cases in the USA (n = 47) than in the UK (n = 20; P = 0.009). We identified one coma case in the UK (0.007%, 95% confidence interval 0.00-0.04%) on the day of the survey and 19 new coma cases (0.13%, 95% confidence interval 0.08-0.21%) within the preceding year, resulting in an annual incidence of 135/100 000 (95% confidence interval 81-210) and a point prevalence of 7 cases per 100 000 population (95% confidence interval 0.18-39.44) in the UK. We identified five cases in the USA (0.031%, 95% confidence interval 0.01-0.07%) on the day of the survey and 42 new cases (0.26%, 95% confidence interval 0.19-0.35%) within the preceding year, resulting in an annual incidence of 258/100 000 (95% confidence interval 186-349) and a point prevalence of 31 cases per 100 000 population (95% confidence interval 9.98-71.73) in the USA. The five most common causes were stroke, medically induced coma, COVID-19, traumatic brain injury and cardiac arrest. To summarize, for the first time, we report incidence and prevalence estimates for coma across diagnosis types and settings in the UK and the USA using crowdsourcing methods. Coma may be more prevalent in the USA than in the UK, which requires further investigation. These data are urgently needed to expand the public health perspective on coma and disorders of consciousness.

Upcoming and urgent challenges in critical care research based on COVID-19 pandemic experience.

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.

Intravenous immunoglobulins in patients with COVID-19-associated moderate-to-severe acute respiratory distress syndrome (ICAR): multicentre, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: 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. METHODS: 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, and >24-72 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: Programme Hospitalier de Recherche Clinique.

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.

Neurologic Outcomes of Survivors of COVID-19-Associated Acute Respiratory Distress Syndrome Requiring Intubation.

OBJECTIVES: To describe 3-6-month neurologic outcomes of survivors of COVID-19-associated acute respiratory distress syndrome, invasively ventilated in the ICU. DESIGN: A bicentric prospective study during the two first waves of the pandemic (March to May and September to December, 2020). SETTING: Two academic hospital ICUs, Paris, France. PATIENTS: Adult COVID-19-associated acute respiratory distress syndrome survivors, invasively ventilated in the ICU, were eligible for a neurologic consultation between 3 and 6 months post ICU discharge. INTERVENTIONS: Follow-up by face-to-face neurologic consultation. MEASURES AND MAIN RESULTS: The primary endpoint was favorable functional outcome defined by a modified Rankin scale score less than 2, indicating survival with no significant disability. Secondary endpoints included mild cognitive impairment (Montreal Cognitive Assessment score < 26), ICU-acquired weakness (Medical Research Council score < 48), anxiety and depression (Hospital Anxiety and Depression score > 7), and posttraumatic stress disorder (posttraumatic stress disorder checklist for Diagnostic and Statistical Manual of Mental Disorders 5 score > 30). Of 54 eligible survivors, four non-French-speaking patients were excluded, eight patients were lost-to-follow-up, and one died during follow-up. Forty-one patients were included. Time between ICU discharge and neurologic consultation was 3.8 months (3.6-5.9 mo). A favorable functional outcome was observed in 16 patients (39%) and mild cognitive impairment in 17 of 33 patients tested (52%). ICU-acquired weakness, depression or anxiety, and posttraumatic stress disorder were reported in six of 37 cases (16%), eight of 31 cases (26%), and two of 27 cases (7%), respectively. Twenty-nine patients (74%) required rehabilitation (motor, cognitive, or psychologic). ICU and hospital lengths of stay, tracheostomy, and corticosteroids were negatively associated with favorable outcome. By contrast, use of alpha-2 agonists during ICU stay was associated with favorable outcome. CONCLUSIONS: COVID-19-associated acute respiratory distress syndrome requiring intubation led to slight-to-severe functional disability in about 60% of survivors 4 months after ICU discharge. Cognitive impairment, muscle weakness, and psychologic symptoms were frequent. A large multicenter study is warranted to allow identification of modifiable factors for improving long-term outcome.

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.

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.

Randomized Controlled Study Evaluating Efficiency of Low Intensity Transcranial Direct Current Stimulation (tDCS) for Dyspnea Relief in Mechanically Ventilated COVID-19 Patients in ICU: The tDCS-DYSP-COVID Protocol.

The severe respiratory distress syndrome linked to the new coronavirus disease (COVID-19) includes unbearable dyspneic suffering which contributes to the deterioration of the prognosis of patients in intensive care unit (ICU). Patients are put on mechanical ventilation to reduce respiratory suffering and preserve life. Despite this mechanical ventilation, most patients continue to suffer from dyspnea. Dyspnea is a major source of suffering in intensive care and one of the main factors that affect the prognosis of patients. The development of innovative methods for its management, especially non-drug management is more than necessary. In recent years, numerous studies have shown that transcranial direct current stimulation (tDCS) could modulate the perception of acute or chronic pain. In the other hand, it has been shown that the brain zones activated during pain and dyspnea are close and/or superimposed, suggesting that brain structures involved in the integration of aversive emotional component are shared by these two complex sensory experiences. Therefore, it can be hypothesized that stimulation by tDCS with regard to the areas which, in the case of pain have activated one or more of these brain structures, may also have an effect on dyspnea. In addition, our team recently demonstrated that the application of tDCS on the primary cortical motor area can modulate the excitability of the respiratory neurological pathways. Indeed, tDCS in anodal or cathodal modality reduced the excitability of the diaphragmatic cortico-spinal pathways in healthy subjects. We therefore hypothesized that tDCS could relieve dyspnea in COVID-19 patients under mechanical ventilation in ICU. This study was designed to evaluate effects of two modalities of tDCS (anodal and cathodal) vs. placebo, on the relief of dyspnea in COVID-19 patients requiring mechanical ventilation in ICU. Trial Registration: This protocol is derived from the tDCS-DYSP-REA project registered on ClinicalTrials.gov NCT03640455. It will however be registered under its own NCT number.