; for the CORIMUNO-19 Collaborative Group IMPORTANCE Severe pneumonia with hyperinflammation and elevated interleukin-6 is a common presentation of coronavirus disease 2019 (COVID-19). OBJECTIVE To determine whether tocilizumab (TCZ) improves outcomes of patients hospitalized with moderate-to-severe COVID-19 pneumonia. DESIGN, SETTING, AND PARTICPANTS This cohort-embedded, investigator-initiated, multicenter, open-label, bayesian randomized clinical trial investigating patients with COVID-19 and moderate or severe pneumonia requiring at least 3 L/min of oxygen but without ventilation or admission to the intensive care unit was conducted between March 31, 2020, to April 18, 2020, with follow-up through 28 days. Patients were recruited from 9 university hospitals in France. Analyses were performed on an intention-to-treat basis with no correction for multiplicity for secondary outcomes. INTERVENTIONS Patients were randomly assigned to receive TCZ, 8 mg/kg, intravenously plus usual care on day 1 and on day 3 if clinically indicated (TCZ group) or to receive usual care alone (UC group). Usual care included antibiotic agents, antiviral agents, corticosteroids, vasopressor support, and anticoagulants. MAIN OUTCOMES AND MEASURES Primary outcomes were scores higher than 5 on the World Health Organization 10-point Clinical Progression Scale (WHO-CPS) on day 4 and survival without need of ventilation (including noninvasive ventilation) at day 14. Secondary outcomes were clinical status assessed with the WHO-CPS scores at day 7 and day 14, overall survival, time to discharge, time to oxygen supply independency, biological factors such as C-reactive protein level, and adverse events. RESULTS Of 131 patients, 64 patients were randomly assigned to the TCZ group and 67 to UC group; 1 patient in the TCZ group withdrew consent and was not included in the analysis. Of the 130 patients, 42 were women (32%), and median (interquartile range) age was 64 (57.1-74.3) years. In the TCZ group, 12 patients had a WHO-CPS score greater than 5 at day 4 vs 19 in the UC group (median posterior absolute risk difference [ARD] −9.0%; 90% credible interval [CrI], −21.0 to 3.1), with a posterior probability of negative ARD of 89.0% not achieving the 95% predefined efficacy threshold. At day 14, 12% (95% CI −28% to 4%) fewer patients needed noninvasive ventilation (NIV) or mechanical ventilation (MV) or died in the TCZ group than in the UC group (24% vs 36%, median posterior hazard ratio [HR] 0.58; 90% CrI, 0.33-1.00), with a posterior probability of HR less than 1 of 95.0%, achieving the predefined efficacy threshold. The HR for MV or death was 0.58 (90% CrI, 0.30 to 1.09). At day 28, 7 patients had died in the TCZ group and 8 in the UC group (adjusted HR, 0.92; 95% CI 0.33-2.53). Serious adverse events occurred in 20 (32%) patients in the TCZ group and 29 (43%) in the UC group (P = .21). CONCLUSIONS AND RELEVANCE In this randomized clinical trial of patients with COVID-19 and pneumonia requiring oxygen support but not admitted to the intensive care...

In volume-responders, unlike markers of anaerobic metabolism, central venous oxygen saturation did not allow the prediction of whether a fluid-induced increase in oxygen delivery would result in an increase in oxygen consumption. This suggests that along with indicators of volume-responsiveness, the indicators of anaerobic metabolism should be considered instead of central venous oxygen saturation for starting hemodynamic resuscitation.

Extravascular lung water index and pulmonary vascular permeability index measured by transpulmonary thermodilution are independent risk factors of day-28 mortality in patients with acute respiratory distress syndrome.

Background Patients with COVID-19 pneumonia have an excess of inflammation and increased concentrations of cytokines including interleukin-1 (IL-1). We aimed to determine whether anakinra, a recombinant human IL-1 receptor antagonist, could improve outcomes in patients in hospital with mild-to-moderate COVID-19 pneumonia.Methods In this multicentre, open-label, Bayesian randomised clinical trial (CORIMUNO-ANA-1), nested within the CORIMUNO-19 cohort, we recruited patients from 16 University hospitals in France with mild-to-moderate COVID-19 pneumonia, severe acute respiratory syndrome coronavirus 2 infection confirmed by real-time RT-PCR, requiring at least 3 L/min of oxygen by mask or nasal cannula but without ventilation assistance, a score of 5 on the WHO Clinical Progression Scale (WHO-CPS), and a C-reactive protein serum concentration of more than 25 mg/L not requiring admission to the intensive care unit at admission to hospital. Eligible patients were randomly assigned (1:1) using a web-based secure centralised system, stratified by centre and blocked with varying block sizes (randomly of size two or four), to either usual care plus anakinra (200 mg twice a day on days 1-3, 100 mg twice on day 4, 100 mg once on day 5) or usual care alone. Usual care was provided at the discretion of the site clinicians. The two coprimary outcomes were the proportion of patients who had died or needed non-invasive or mechanical ventilation by day 4 (ie, a score of >5 on the WHO-CPS) and survival without need for mechanical or non-invasive ventilation (including high-flow oxygen) at day 14. All analyses were done on an intention-to-treat basis. The trial is registered with ClinicalTrials.gov, NCT04341584, and is now closed to accrual. FindingsBetween April 8 and April 26, 2020, we screened 153 patients. The study was stopped early following the recommendation of the data and safety monitoring board, after the recruitment of 116 patients: 59 were assigned to the anakinra group, and 57 were assigned to the usual care group. Two patients in the usual care group withdrew consent and were not analysed. In the analysable population, the median age was 66 years (IQR 59 to 76) and 80 (70%) participants were men. In the anakinra group, 21 (36%) of 59 patients had a WHO-CPS score of more than 5 at day 4 versus 21 (38%) of 55 in the usual care group (median posterior absolute risk difference [ARD] -2•5%, 90% credible interval [CrI] -17•1 to 12•0), with a posterior probability of ARD of less than 0 (ie, anakinra better than usual care) of 61•2%. At day 14, 28 (47%; 95% CI 33 to 59) patients in the anakinra group and 28 (51%; 95% CI 36 to 62) in the usual care group needed ventilation or died, with a posterior probability of any efficacy of anakinra (hazard ratio [HR] being less than 1) of 54•5% (median posterior HR 0•97; 90% CrI 0•62 to 1•52). At day 90, 16 (27%) patients in the anakinra group and 15 (27%) in the usual care group had died. Serious adverse events occurred in 27 (46%) patients in the anakinra group and 21 (38%) in the usu...

In patients with acute respiratory distress syndrome under protective ventilation and maximal alveolar recruitment, prone positioning increased the cardiac index only in patients with preload reserve, emphasizing the important role of preload in the hemodynamic effects of prone positioning.

IntroductionWe wanted to determine the number of cold bolus injections that are necessary for achieving an acceptable level of precision for measuring cardiac index (CI), indexed global end-diastolic volume (GEDVi) and indexed extravascular lung water (EVLWi) by transpulmonary thermodilution.MethodsWe included 91 hemodynamically stable patients (age 59 (25% to 75% interquartile range: 39 to 79) years, simplified acute physiologic score (SAPS)II 59 (53 to 65), 56% under norepinephrine) who were monitored by a PiCCO2 device. We performed five successive cold saline (15 mL, 6°C) injections and recorded the measurements of CI, GEDVi and EVLWi.ResultsConsidering five boluses, the coefficient of variation (CV, calculated as standard deviation divided by the mean of the five measurements) was 7 (5 to 11)%, 7 (5 to 12)% and 7 (6 to 12)% for CI, GEDVi and EVLWi, respectively. If the results of two bolus injections were averaged, the precision (2 × CV/√ number of boluses) was 10 (7 to 15)%, 10 (7 to 17)% and 8 (7 to 14)% for CI, GEDVi and EVLWi, respectively. If the results of three bolus injections were averaged, the precision dropped below 10%, that is, the cut-off that is generally considered as acceptable (8 (6 to 12)%, 8 (6 to 14)% and 8 (7 to 14)% for CI, GEDVi and EVLWi, respectively). If two injections were performed, the least significant change, that is, the minimal change in value that could be trusted to be significant, was 14 (10 to 21)%, 14 (10 to 24)% and 14 (11 to 23)% for CI, GEDVi and EVLWi, respectively. If three injections were performed, the least significant change was 12 (8 to 17)%, 12 (8 to 19)% and 12 (9 to 19)% for CI, GEDVi and EVLWi, respectively, that is, below the 15% cut-off that is usually considered as clinically relevant.ConclusionsThese results support the injection of at least three cold boluses for obtaining an acceptable precision when transpulmonary thermodilution is used for measuring CI, GEDVi and EVLWi.

Extravascular lung water (EVLW) is the amount of fluid that is accumulated in the interstitial and alveolar spaces. In lung oedema, EVLW increases either because of increased lung permeability or because of increased hydrostatic pressure in the pulmonary capillaries, or both. Increased EVLW is always potentially life-threatening, mainly because it impairs gas exchange and reduces lung compliance. The only technique that provides an easy measurement of EVLW at the bedside is transpulmonary thermodilution. The validation of EVLW measurements by thermodilution was based on studies showing reasonable correlations with gravimetry or thermo-dye dilution in experimental and clinical studies. EVLW should be indexed to predicted body weight. This indexation reduces the proportion of ARDS patients for whom EVLW is in the normal range. Compared to non-indexed EVLW, indexed EVLW (EVLWI) is better correlated with the lung injury score and the oxygenation and it is a better predictor of mortality of patients with acute lung injury or acute respiratory distress syndrome (ARDS). Transpulmonary thermodilution also provides the pulmonary vascular permeability index (PVPI), which is an indirect reflection of the integrity of the alveolocapillary barrier. As clinical applications, EVLWI and PVPI may be useful to guide fluid management of patients at risk of fluid overload, as during septic shock and ARDS. High EVLWI and PVPI values predict mortality in several categories of critically ill patients, especially during ARDS. Thus, fluid administration should be limited when EVLWI is already high. Whatever the value of EVLWI, PVPI may indicate that fluid administration is particularly at risk of aggravating lung oedema. In the acute phase of haemodynamic resuscitation during septic shock and ARDS, high EVLWI and PVPI values may warn of the risk of fluid overload and prevent excessive volume expansion. At the post-resuscitation phase, they may prompt initiation of fluid removal thereby achieving a negative fluid balance.

In septic shock patients, decreasing the dose of norepinephrine decreased the mean systemic pressure and, to a lesser extent, the resistance to venous return. As a result, venous return decreased.