Effects of Losartan on Patients Hospitalized for Acute COVID-19: A Randomized Controlled Trial.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) down-regulates angiotensin-converting enzyme 2, potentially increasing angiotensin II. We hypothesized that losartan compared to usual care decreases mortality and is safe in patients hospitalized with coronavirus disease 2019 (COVID-19). We aimed to evaluate the effect of losartan versus usual care on 28-day mortality in patients hospitalized for acute COVID-19. METHODS: Eligibility criteria included adults admitted for acute COVID-19. Exclusion criteria were hypotension, hyperkalemia, acute kidney injury, and use of angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors within 7 days. Participants were randomized to losartan 25-100 mg/day orally for the hospital duration or 3 months or the control arm (usual care) in 29 hospitals in Canada and France. The primary outcome was 28-day mortality. Secondary outcomes were hospital mortality, organ support, and serious adverse events (SAEs). RESULTS: The trial was stopped early because of a serious safety concern with losartan. In 341 patients, any SAE and hypotension were significantly higher in the losartan versus usual care groups (any SAE: 39.8% vs 27.2%, respectively, P = .01; hypotension: 30.4% vs 15.3%, respectively, P < .001) in both ward and intensive care patients. The 28-day mortality did not differ between losartan (6.5%) versus usual care (5.9%) (odds ratio, 1.11 [95% confidence interval, .47-2.64]; P = .81), nor did organ dysfunction or secondary outcomes. CONCLUSIONS: Caution is needed in deciding which patients to start or continue using ARBs in patients hospitalized with pneumonia to mitigate risk of hypotension, acute kidney injury, and other side effects. ARBs should not be added to care of patients hospitalized for acute COVID-19. CLINICAL TRIALS REGISTRATION: NCT04606563.

Fibrinolysis as a Causative Mechanism for Bleeding Complications on Extracorporeal Membrane Oxygenation: A Pilot Observational Prospective Study.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is associated with a high risk of bleeding complications. The specific impact of ECMO on fibrinolysis remains unexplored. The objective of the current pilot observational prospective study was to investigate the longitudinal dynamics of fibrinolytic markers-i.e., changes over time-in the context of bleeding events in patients on ECMO. METHODS: Longitudinal dynamics of contact phase components (kininogen and bradykinin) and fibrinolysis markers (tissue plasminogen activator [tPA], plasminogen activator inhibitor-1 [PAI-1], their complexes [tPA•PAI-1], plasmin-antiplasmin complexes, plasminogen, and D-dimer) were measured in patients undergoing venovenous and venoarterial ECMO, before implantation, at 0, 6, and 12 h after implantation, and daily thereafter. RESULTS: The cohort consisted of 30 patients (214 ECMO days). The concentrations of tPA, D-dimer, plasmin-antiplasmin complexes, PAI-1, and tPA•PAI-1 complexes were increased, whereas plasminogen decreased compared to normal values. A noteworthy divergence was observed between hemorrhagic and nonhemorrhagic patients: in bleeding patients, D-dimer, plasmin-antiplasmin, tPA, PAI-1, and tPA•PAI-1 followed an increasing kinetics before hemorrhage and then decreased to their baseline level; conversely, nonbleeding patients showed a decreasing kinetics in these markers. Also, D-dimer and tPA followed an increasing kinetics in bleeding patients compared to nonbleeding patients (median values for D-dimer dynamics: 1,080 vs. -440 ng/ml, P = 0.05; tPA dynamics: 0.130 vs. 0.100 nM, P = 0.038), and both markers significantly increased the day before hemorrhage. A tPA concentration above 0.304 nM was associated with bleeding events (odds ratio, 4.92; 95% CI, 1.01 to 24.08; P = 0.049). CONCLUSIONS: Contact activation induces fibrinolysis in ECMO patients, especially in patients experiencing bleeding. This finding supports the role of this mechanism as a possible causal factor for hemorrhages during ECMO and open new avenues for novel therapeutic perspectives.

TLRs1-10 Protein Expression in Circulating Human White Blood Cells during Bacterial and COVID-19 Infections.

INTRODUCTION: Toll-like receptors play crucial roles in the sepsis-induced systemic inflammatory response. Septic shock mortality correlates with overexpression of neutrophilic TLR2 and TLR9, while the role of TLR4 overexpression remains a debate. In addition, TLRs are involved in the pathogenesis of viral infections such as COVID-19, where the single-stranded RNA of SARS-CoV-2 is recognized by TLR7 and TLR8, and the spike protein activates TLR4. METHODS: In this study, we conducted a comprehensive analysis of TLRs 1-10 expressions in white blood cells from 71 patients with bacterial and viral infections. Patients were divided into 4 groups based on disease type and severity (sepsis, septic shock, moderate, and severe COVID-19) and compared to 7 healthy volunteers. RESULTS: We observed a significant reduction in the expression of TLR4 and its co-receptor CD14 in septic shock neutrophils compared to the control group (p < 0.001). Severe COVID-19 patients exhibited a significant increase in TLR3 and TLR7 levels in neutrophils compared to controls (p < 0.05). Septic shock patients also showed a similar increase in TLR7 in neutrophils along with elevated intermediate monocytes (CD14+CD16+) compared to the control group (p < 0.005 and p < 0.001, respectively). However, TLR expression remained unchanged in lymphocytes. CONCLUSION: This study provides further insights into the mechanisms of TLR activation in various infectious conditions. Additional analysis is needed to assess their correlation with patient outcome and to evaluate the impact of TLR-pathway modulation during septic shock and severe COVID-19.

Clinician-Reported Physical and Cognitive Impairments After Convulsive Status Epilepticus: Post Hoc Study of a Randomized Controlled Trial.

BACKGROUND: Clinician-reported outcome (ClinRO) measures are emerging as useful contributors to assessments of treatment benefits. The objective of this study was to collect ClinRO measures of physical and cognitive impairments after convulsive status epilepticus (CSE) requiring intensive care unit admission. METHODS: We conducted a post hoc analysis of the data from HYBERNATUS, a multicenter open-label controlled trial that randomized 270 critically ill patients with CSE requiring mechanical ventilation in 11 French intensive care units to therapeutic hypothermia (32-34 °C for 24 h) plus standard care or standard care alone. We included all patients who attended a day 90 in-person neurologist visit with measurement of the functional independence measure (FIM) score (range from 18 [total assistance] to 126 [total independence]), Mini-Mental State Examination (MMSE) score (range 0-30), and Glasgow outcome scale (GOS) score (1, death; 2, vegetative state; 3, severe disability; 4, moderate disability; and 5, mild or no disability). These three scores were compared across groups defined by several patient and CSE characteristics. RESULTS: Of 229 patients with GOS scores ≥ 3 on day 90 (male sex, 58.2%; median age, 56 years [47-67]), 67 (29%) attended an in-person neurologist visit. Twenty-nine (43%) patients had a previous history of epilepsy, and 16 (24%) patients had a primary brain insult. CSE was refractory in 22 (33%) patients. On day 90 after CSE onset, median FIM and MMSE scores were 121 (112-125) and 26.0 (24.0-28.8), respectively. The GOS score was 3 in 16 (33.8%) patients, 4 in 9 (13.4%) patients, and 5 in 42 (62.7%) patients. Worse GOS score values were significantly associated with worse FIM and MMSE scores. CONCLUSIONS: In patients attending the in-person neurologist visit on day 90 after CSE onset, ClinRO measures indicated that the main impairments were cognitive. FIM and MMSE scores were associated with GOS scores. Further studies are needed to evaluate the possible impact of neuroprotective and rehabilitation strategies on disability and cognitive impairments in survivors of CSE. Clinical trial registration NCT01359332.

Disseminated intravascular coagulation is strongly associated with severe acute kidney injury in patients with septic shock.

BACKGROUND: Disseminated intravascular coagulation (DIC) worsens the prognosis of septic shock and contributes to multiple organ failure. To date, no data linking DIC and acute kidney injury (AKI) occurrence, severity, and evolution in this setting are available. We aimed at analyzing the association between AKI occurrence, severity and evolution in patients with septic shock-induced DIC. In a prospective monocentric cohort study, consecutive patients, 18 years and older, admitted in the ICU of Strasbourg University Hospital in the setting of systemic hypotension requiring vasopressor related to an infection, without history of terminal chronic kidney disease were eligible. AKI was defined according to the KDIGO classification. DIC diagnosis was based on the International Society on Thrombosis and Haemostasis (ISTH) score. Evolution of AKI was evaluated through the composite endpoint of major adverse kidney events. Only patients with DIC that occurred before or at the time of AKI diagnosis were considered. Univariate and multivariate analysis were performed to determine factors associated with renal outcomes. RESULTS: 350 patients were included, of whom 129 experienced DIC. Patients with DIC were more seriously ill (median SAPS II 64 vs. 56, p < 0.001), and had higher 28-day mortality (43.3% vs. 26.2%, p < 0.001). AKI was more frequent in patients with DIC (86.8% vs. 74.2%, p < 0.005), particularly for the more severe stage of AKI [KDIGO 3 in 58.1% of patients with DIC vs. 30.8% of patients without DIC, p < 0.001, AKI requiring renal replacement therapy (RRT) in 47.3% of patients with DIC vs. 21.3% of patients without DIC, p < 0.001]. After adjustment for confounding factors, DIC occurrence remained associated with the risk of having the more severe stage of AKI with an odds ratio (OR) of 2.74 [IC 95% (1.53-4.91), p < 0.001], and with the risk of requiring RRT during the ICU stay [OR 2.82 (1.53-5.2), p < 0.001]. CONCLUSION: DIC appears to be strongly associated with the risk of developing the more severe form of AKI (stage 3 of the KDIGO classification, RRT requirement), even after adjustment for severity and other relevant factors.

Inhaled Amikacin to Prevent Ventilator-Associated Pneumonia.

BACKGROUND: Whether preventive inhaled antibiotics may reduce the incidence of ventilator-associated pneumonia is unclear. METHODS: In this investigator-initiated, multicenter, double-blind, randomized, controlled, superiority trial, we assigned critically ill adults who had been undergoing invasive mechanical ventilation for at least 72 hours to receive inhaled amikacin at a dose of 20 mg per kilogram of ideal body weight once daily or to receive placebo for 3 days. The primary outcome was a first episode of ventilator-associated pneumonia during 28 days of follow-up. Safety was assessed. RESULTS: A total of 850 patients underwent randomization, and 847 were included in the analyses (417 assigned to the amikacin group and 430 to the placebo group). All three daily nebulizations were received by 337 patients (81%) in the amikacin group and 355 patients (83%) in the placebo group. At 28 days, ventilator-associated pneumonia had developed in 62 patients (15%) in the amikacin group and in 95 patients (22%) in the placebo group (difference in restricted mean survival time to ventilator-associated pneumonia, 1.5 days; 95% confidence interval [CI], 0.6 to 2.5; P = 0.004). An infection-related ventilator-associated complication occurred in 74 patients (18%) in the amikacin group and in 111 patients (26%) in the placebo group (hazard ratio, 0.66; 95% CI, 0.50 to 0.89). Trial-related serious adverse effects were seen in 7 patients (1.7%) in the amikacin group and in 4 patients (0.9%) in the placebo group. CONCLUSIONS: Among patients who had undergone mechanical ventilation for at least 3 days, a subsequent 3-day course of inhaled amikacin reduced the burden of ventilator-associated pneumonia during 28 days of follow-up. (Funded by the French Ministry of Health; AMIKINHAL ClinicalTrials.gov number, NCT03149640; EUDRA Clinical Trials number, 2016-001054-17.).

Mottling as a prognosis marker in cardiogenic shock.

AIMS: Impact of skin mottling has been poorly studied in patients admitted for cardiogenic shock. This study aimed to address this issue and identify determinants of 30-day and 1-year mortality in a large cardiogenic shock cohort of all etiologies. METHODS AND RESULTS: FRENSHOCK is a prospective multicenter observational registry conducted in French critical care units between April and October, 2016. Among the 772 enrolled patients (mean age 65.7 ± 14.9 years; 71.5% male), 660 had skin mottling assessed at admission (85.5%) with almost 39% of patients in cardiogenic shock presenting mottling. The need for invasive respiratory support was significantly higher in patients with mottling (50.2% vs. 30.1%, p < 0.001) and likewise for the need for renal replacement therapy (19.9% vs. 12.4%, p = 0.09). However, the need for mechanical circulatory support was similar in both groups. Patients with mottling at admission presented a higher length of stay (19 vs. 16 days, p = 0.033), a higher 30-day mortality rate (31% vs. 23.3%, p = 0.031), and also showed significantly higher mortality at 1-year (54% vs. 42%, p = 0.003). The subgroup of patients in whom mottling appeared during the first 24 h after admission had the worst prognosis at 30 days. CONCLUSION: Skin mottling at admission in patients with cardiogenic shock was statistically associated with prolonged length of stay and poor outcomes. As a perfusion-targeted resuscitation parameter, mottling is a simple, clinical-based approach and may thus help to improve and guide immediate goal-directed therapy to improve cardiogenic shock patients' outcomes.

Advanced respiratory mechanics assessment in mechanically ventilated obese and non-obese patients with or without acute respiratory distress syndrome.

BACKGROUND: Respiratory mechanics is a key element to monitor mechanically ventilated patients and guide ventilator settings. Besides the usual basic assessments, some more complex explorations may allow to better characterize patients' respiratory mechanics and individualize ventilation strategies. These advanced respiratory mechanics assessments including esophageal pressure measurements and complete airway closure detection may be particularly relevant in critically ill obese patients. This study aimed to comprehensively assess respiratory mechanics in obese and non-obese ICU patients with or without ARDS and evaluate the contribution of advanced respiratory mechanics assessments compared to basic assessments in these patients. METHODS: All intubated patients admitted in two ICUs for any cause were prospectively included. Gas exchange and respiratory mechanics including esophageal pressure and end-expiratory lung volume (EELV) measurements and low-flow insufflation to detect complete airway closure were assessed in standardized conditions (tidal volume of 6 mL kg-1 predicted body weight (PBW), positive end-expiratory pressure (PEEP) of 5 cmH2O) within 24 h after intubation. RESULTS: Among the 149 analyzed patients, 52 (34.9%) were obese and 90 (60.4%) had ARDS (65.4% and 57.8% of obese and non-obese patients, respectively, p = 0.385). A complete airway closure was found in 23.5% of the patients. It was more frequent in obese than in non-obese patients (40.4% vs 14.4%, p < 0.001) and in ARDS than in non-ARDS patients (30% vs. 13.6%, p = 0.029). Respiratory system and lung compliances and EELV/PBW were similarly decreased in obese patients without ARDS and obese or non-obese patients with ARDS. Chest wall compliance was not impacted by obesity or ARDS, but end-expiratory esophageal pressure was higher in obese than in non-obese patients. Chest wall contribution to respiratory system compliance differed widely between patients but was not predictable by their general characteristics. CONCLUSIONS: Most respiratory mechanics features are similar in obese non-ARDS and non-obese ARDS patients, but end-expiratory esophageal pressure is higher in obese patients. A complete airway closure can be found in around 25% of critically ill patients ventilated with a PEEP of 5 cmH2O. Advanced explorations may allow to better characterize individual respiratory mechanics and adjust ventilation strategies in some patients. Trial registration NCT03420417 ClinicalTrials.gov (February 5, 2018).

Staphylococcus epidermidis bloodstream infections are a cause of septic shock in intensive care unit patients.

OBJECTIVES: Staphylococcus epidermidis (SE) is a supposedly low-virulence agent, which may cause proven bloodstream infections (BSIs), with little-known consequences on intensive care unit (ICU) patients. We aimed at studying ICU patients diagnosed with BSIs caused by SE (SE-BSIs). METHODS: We constituted a retrospective cohort in two medical ICUs. SE-BSIs were defined by two or more independent SE-positive blood cultures of the same strain, within 48 hours, without concurrent infection. RESULTS: We included 59 patients; 58% were men (n = 34), with median age of 67 (interquartile range 60-74) years and a simplified acute physiology score II of 59 (36-74) points, and 56% were immunocompromised (n = 33). Among the 37 (63%) patients requiring norepinephrine initiation or increase at the onset of SE-BSI versus patients not requiring vasopressors (37%; n = 22), concomitant arterial lactate levels reached 2.8 (1.9-5.8) versus 1.5 (1.3-2.2) mmol/l (P <0.01), whereas the mean blood pressure was 49 (42-54) versus 61 (56-65) mm Hg (P = 0.01) and the mortality was 46% (n = 17) vs 14% (n = 3) at day 28 (P = 0.01), respectively. Regarding antibiotics, the susceptibility rates toward linezolid and vancomycin were 71% (n = 41/58) and 100% (n = 54/54), respectively. At the time of SE-BSI, all but one patient had a central venous access device. CONCLUSION: This work highlights SE-BSIs as a cause of septic shock, mostly in immunocompromised ICU patients, with increasing concerns about resistance to antibiotics and central line management.

Changes in Body Temperature Patterns Are Predictive of Mortality in Septic Shock: An Observational Study.

Biological rhythms are important regulators of immune functions. In intensive care unit (ICU), sepsis is known to be associated with rhythm disruption. Our objectives were to determine factors associated with rhythm disruption of the body temperature and to assess the relationship between temperature and mortality in septic shock patients; In a cohort of septic shock, we recorded body temperature over a 24-h period on day 2 after ICU admission. For each patient, the temperature rhythmicity was assessed by defining period and amplitude, and the adjusted average (mesor) of the temperature by sinusoidal regression and cosinor analysis. Analyses were performed to assess factors associated with the three temperature parameters (period, amplitude, and mesor) and mortality. 162 septic shocks were enrolled. The multivariate analysis demonstrates that the period of temperature was associated with gender (women, coefficient -2.2 h, p = 0.031) and acetaminophen use (coefficient -4.3 h, p = 0.002). The mesor was associated with SOFA score (coefficient -0.05 °C per SOFA point, p = 0.046), procalcitonin (coefficient 0.001 °C per ng/mL, p = 0.005), and hydrocortisone use (coefficient -0.5 °C, p = 0.002). The amplitude was associated with the dialysis (coefficient -0.5 °C, p = 0.002). Mortality at day 28 was associated with lower mesor (adjusted hazard ratio 0.50, 95% CI 0.28 to 0.90; p = 0.02), and higher amplitude (adjusted hazard ratio 5.48, 95% CI 1.66 to 18.12; p = 0.005) of temperature. Many factors, such as therapeutics, influence the body temperature during septic shock. Lower mesor and higher amplitude were associated with mortality and could be considered prognostic markers in ICU. In the age of artificial intelligence, the incorporation of such data in an automated scoring alert could compete with physicians to identify high-risk patients during septic shock.

Microcirculatory dysfunction in cardiogenic shock.

Cardiogenic shock is usually defined as primary cardiac dysfunction with low cardiac output leading to critical organ hypoperfusion, and tissue hypoxia, resulting in high mortality rate between 40% and 50% despite recent advances. Many studies have now evidenced that cardiogenic shock not only involves systemic macrocirculation, such as blood pressure, left ventricular ejection fraction, or cardiac output, but also involves significant systemic microcirculatory abnormalities which seem strongly associated with the outcome. Although microcirculation has been widely studied in the context of septic shock showing heterogeneous alterations with clear evidence of macro and microcirculation uncoupling, there is now a growing body of literature focusing on cardiogenic shock states. Even if there is currently no consensus regarding the treatment of microcirculatory disturbances in cardiogenic shock, some treatments seem to show a benefit. Furthermore, a better understanding of the underlying pathophysiology may provide hypotheses for future studies aiming to improve cardiogenic shock prognosis.

Rapid rEcognition of COrticosteRoiD resistant or sensitive Sepsis (RECORDS): study protocol for a multicentre, placebo-controlled, biomarker-guided, adaptive Bayesian design basket trial.

INTRODUCTION: Corticosteroids affect variably survival in sepsis trials, suggesting heterogeneity in patients' response to corticosteroids. The RECORDS (Rapid rEcognition of COrticosteRoiD resistant or sensitive Sepsis) trial aimed at defining endotypes associated with adults with sepsis responsiveness to corticosteroids. METHODS AND ANALYSIS: RECORDS, a multicentre, placebo-controlled, biomarker-guided, adaptive Bayesian design basket trial, will randomly assign to a biomarker stratum 1800 adults with community-acquired pneumonia, vasopressor-dependent sepsis, septic shock or acute respiratory distress syndrome. In each stratum, patients will be randomly assigned to receive a 7-day course of hydrocortisone and fludrocortisone or their placebos. Patients with COVID-19 will be treated with a 10-day standard course of dexamethasone and randomised to fludrocortisone or its placebo. Primary outcome will be 90-day death or persistent organ dysfunction. Large simulation study will be performed across a range of plausible scenarios to foresee power to detect a 5%-10% absolute difference with corticosteroids. We will assess subset-by-treatment interaction by estimating in a Bayesian framework two quantities: (1) measure of influence, relying on the value of the estimation of corticosteroids' effect in each subset, and (2) measure of interaction. ETHICS AND DISSEMINATION: The protocol was approved by the Ethics Committee (Comité de Protection des Personnes, Dijon, France), on 6 April 2020. Trial results will be disseminated at scientific conferences and results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04280497).

Hydrocortisone in Severe Community-Acquired Pneumonia.

BACKGROUND: Whether the antiinflammatory and immunomodulatory effects of glucocorticoids may decrease mortality among patients with severe community-acquired pneumonia is unclear. METHODS: In this phase 3, multicenter, double-blind, randomized, controlled trial, we assigned adults who had been admitted to the intensive care unit (ICU) for severe community-acquired pneumonia to receive intravenous hydrocortisone (200 mg daily for either 4 or 7 days as determined by clinical improvement, followed by tapering for a total of 8 or 14 days) or to receive placebo. All the patients received standard therapy, including antibiotics and supportive care. The primary outcome was death at 28 days. RESULTS: A total of 800 patients had undergone randomization when the trial was stopped after the second planned interim analysis. Data from 795 patients were analyzed. By day 28, death had occurred in 25 of 400 patients (6.2%; 95% confidence interval [CI], 3.9 to 8.6) in the hydrocortisone group and in 47 of 395 patients (11.9%; 95% CI, 8.7 to 15.1) in the placebo group (absolute difference, -5.6 percentage points; 95% CI, -9.6 to -1.7; P = 0.006). Among the patients who were not undergoing mechanical ventilation at baseline, endotracheal intubation was performed in 40 of 222 (18.0%) in the hydrocortisone group and in 65 of 220 (29.5%) in the placebo group (hazard ratio, 0.59; 95% CI, 0.40 to 0.86). Among the patients who were not receiving vasopressors at baseline, such therapy was initiated by day 28 in 55 of 359 (15.3%) of the hydrocortisone group and in 86 of 344 (25.0%) in the placebo group (hazard ratio, 0.59; 95% CI, 0.43 to 0.82). The frequencies of hospital-acquired infections and gastrointestinal bleeding were similar in the two groups; patients in the hydrocortisone group received higher daily doses of insulin during the first week of treatment. CONCLUSIONS: Among patients with severe community-acquired pneumonia being treated in the ICU, those who received hydrocortisone had a lower risk of death by day 28 than those who received placebo. (Funded by the French Ministry of Health; CAPE COD ClinicalTrials.gov number, NCT02517489.).

How to manage coagulopathies in critically ill patients.

Coagulopathy is a severe and frequent complication in critically ill patients, for which the pathogenesis and presentation may be variable depending on the underlying disease. Based on the dominant clinical phenotype, the current review differentiates between hemorrhagic coagulopathies, characterized by a hypocoagulable and hyperfibrinolysis state, and thrombotic coagulopathies with a systemic prothrombotic and antifibrinolytic phenotype. We discuss the differences in pathogenesis and treatment of the common coagulopathies.

Fluid balance control in critically ill patients: results from POINCARE-2 stepped wedge cluster-randomized trial.

BACKGROUND: In critically ill patients, positive fluid balance is associated with excessive mortality. The POINCARE-2 trial aimed to assess the effectiveness of a fluid balance control strategy on mortality in critically ill patients. METHODS: POINCARE-2 was a stepped wedge cluster open-label randomized controlled trial. We recruited critically ill patients in twelve volunteering intensive care units from nine French hospitals. Eligible patients were ≥ 18 years old, under mechanical ventilation, admitted to one of the 12 recruiting units for > 48 and ≤ 72 h, and had an expected length of stay after inclusion > 24 h. Recruitment started on May 2016 and ended on May 2019. Of 10,272 patients screened, 1361 met the inclusion criteria and 1353 completed follow-up. The POINCARE-2 strategy consisted of a daily weight-driven restriction of fluid intake, diuretics administration, and ultrafiltration in case of renal replacement therapy between Day 2 and Day 14 after admission. The primary outcome was 60-day all-cause mortality. We considered intention-to-treat analyses in cluster-randomized analyses (CRA) and in randomized before-and-after analyses (RBAA). RESULTS: A total of 433 (643) patients in the strategy group and 472 (718) in the control group were included in the CRA (RBAA). In the CRA, mean (SD) age was 63.7 (14.1) versus 65.7 (14.3) years, and mean (SD) weight at admission was 78.5 (20.0) versus 79.4 (23.5) kg. A total of 129 (160) patients died in the strategy (control) group. Sixty-day mortality did not differ between groups [30.5%, 95% confidence interval (CI) 26.2-34.8 vs. 33.9%, 95% CI 29.6-38.2, p = 0.26]. Among safety outcomes, only hypernatremia was more frequent in the strategy group (5.3% vs. 2.3%, p = 0.01). The RBAA led to similar results. CONCLUSION: The POINCARE-2 conservative strategy did not reduce mortality in critically ill patients. However, due to open-label and stepped wedge design, intention-to-treat analyses might not reflect actual exposure to this strategy, and further analyses might be required before completely discarding it. Trial registration POINCARE-2 trial was registered at ClinicalTrials.gov (NCT02765009). Registered 29 April 2016.

Cerebral perfusion using ASL in patients with COVID-19 and neurological manifestations: A retrospective multicenter observational study.

BACKGROUND AND PURPOSE: Cerebral hypoperfusion has been reported in patients with COVID-19 and neurological manifestations in small cohorts. We aimed to systematically assess changes in cerebral perfusion in a cohort of 59 of these patients, with or without abnormalities on morphological MRI sequences. METHODS: Patients with biologically-confirmed COVID-19 and neurological manifestations undergoing a brain MRI with technically adequate arterial spin labeling (ASL) perfusion were included in this retrospective multicenter study. ASL maps were jointly reviewed by two readers blinded to clinical data. They assessed abnormal perfusion in four regions of interest in each brain hemisphere: frontal lobe, parietal lobe, posterior temporal lobe, and temporal pole extended to the amygdalo-hippocampal complex. RESULTS: Fifty-nine patients (44 men (75%), mean age 61.2 years) were included. Most patients had a severe COVID-19, 57 (97%) needed oxygen therapy and 43 (73%) were hospitalized in intensive care unit at the time of MRI. Morphological brain MRI was abnormal in 44 (75%) patients. ASL perfusion was abnormal in 53 (90%) patients, and particularly in all patients with normal morphological MRI. Hypoperfusion occurred in 48 (81%) patients, mostly in temporal poles (52 (44%)) and frontal lobes (40 (34%)). Hyperperfusion occurred in 9 (15%) patients and was closely associated with post-contrast FLAIR leptomeningeal enhancement (100% [66.4%-100%] of hyperperfusion with enhancement versus 28.6% [16.6%-43.2%] without, p = 0.002). Studied clinical parameters (especially sedation) and other morphological MRI anomalies had no significant impact on perfusion anomalies. CONCLUSION: Brain ASL perfusion showed hypoperfusion in more than 80% of patients with severe COVID-19, with or without visible lesion on conventional MRI abnormalities.

A randomised trial of anti-GM-CSF otilimab in severe COVID-19 pneumonia (OSCAR).

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) and dysregulated myeloid cell responses are implicated in the pathophysiology and severity of COVID-19. METHODS: In this randomised, sequential, multicentre, placebo-controlled, double-blind study, adults aged 18-79 years (Part 1) or ≥70 years (Part 2) with severe COVID-19, respiratory failure and systemic inflammation (elevated C-reactive protein/ferritin) received a single intravenous infusion of otilimab 90 mg (human anti-GM-CSF monoclonal antibody) plus standard care (NCT04376684). The primary outcome was the proportion of patients alive and free of respiratory failure at Day 28. RESULTS: In Part 1 (n=806 randomised 1:1 otilimab:placebo), 71% of otilimab-treated patients were alive and free of respiratory failure at Day 28 versus 67% who received placebo; the model-adjusted difference of 5.3% was not statistically significant (95% CI -0.8-11.4%, p=0.09). A nominally significant model-adjusted difference of 19.1% (95% CI 5.2-33.1%, p=0.009) was observed in the predefined 70-79 years subgroup, but this was not confirmed in Part 2 (n=350 randomised) where the model-adjusted difference was 0.9% (95% CI -9.3-11.2%, p=0.86). Compared with placebo, otilimab resulted in lower serum concentrations of key inflammatory markers, including the putative pharmacodynamic biomarker CC chemokine ligand 17, indicative of GM-CSF pathway blockade. Adverse events were comparable between groups and consistent with severe COVID-19. CONCLUSIONS: There was no significant difference in the proportion of patients alive and free of respiratory failure at Day 28. However, despite the lack of clinical benefit, a reduction in inflammatory markers was observed with otilimab, in addition to an acceptable safety profile.