Background: The pathophysiology of COVID-19 includes immune-mediated hyperinflammation, which could potentially lead to respiratory failure and death. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is among cytokines that contribute to the inflammatory processes. Lenzilumab, a GM-CSF neutralising monoclonal antibody, was investigated in the LIVE-AIR trial to assess its efficacy and safety in treating COVID-19 beyond available treatments. Methods: In LIVE-AIR, a phase 3, randomised, double-blind, placebo-controlled trial, hospitalised adult patients with COVID-19 pneumonia not requiring invasive mechanical ventilation were recruited from 29 sites in the USA and Brazil and were randomly assigned (1:1) to receive three intravenous doses of lenzilumab (600 mg per dose) or placebo delivered 8 h apart. All patients received standard supportive care, including the use of remdesivir and corticosteroids. Patients were stratified at randomisation by age and disease severity. The primary endpoint was survival without invasive mechanical ventilation to day 28 in the modified intention-to-treat population (mITT), comprising all randomised participants who received at least one dose of study drug under the documented supervision of the principal investigator or sub-investigator. Adverse events were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04351152, and is completed. Findings: Patients were enrolled from May 5, 2020, until Jan 27, 2021. 528 patients were screened, of whom 520 were randomly assigned and included in the intention-to-treat population. 479 of these patients (n=236, lenzilumab; n=243, placebo) were included in the mITT analysis for the primary outcome. Baseline demographics were similar between groups. 311 (65%) participants were males, mean age was 61 (SD 14) years at baseline, and median C-reactive protein concentration was 79 (IQR 41–137) mg/L. Steroids were administered to 449 (94%) patients and remdesivir to 347 (72%) patients; 331 (69%) patients received both treatments. Survival without invasive mechanical ventilation to day 28 was achieved in 198 (84%; 95% CI 79–89) participants in the lenzilumab group and in 190 (78%; 72–83) patients in the placebo group, and the likelihood of survival was greater with lenzilumab than placebo (hazard ratio 1·54; 95% CI 1·02–2·32; p=0·040). 68 (27%) of 255 patients in the lenzilumab group and 84 (33%) of 257 patients in the placebo group experienced at least one adverse event that was at least grade 3 in severity based on CTCAE criteria. The most common treatment-emergent adverse events of grade 3 or higher were related to respiratory disorders (26%) and cardiac disorders (6%) and none led to death. Interpretation: Lenzilumab significantly improved survival without invasive mechanical ventilation in hospitalised patients with COVID-19, with a safety profile similar to that of placebo. The added value of lenzilumab beyond other immunomodulators used to treat COVID-19 alongside steroids remains unknown. Funding: Humanigen.
Fluid resuscitation is one of the most frequent and necessary practices in clinical medicine and is an integral part of the initial stabilization of critically ill, hypovolemic patients. Longstanding debate and conflicting evidence surround the use of both colloid and crystalloid fluid resuscitation in these patients. The basis of this debate is heavily rooted in the physiological understanding of Starlings forces. In this review, we aim to highlight the ongoing debate of albumin venus crystalloid resuscitation both broadly and as it relates to lung function, and will discuss the current state-of-the-art, starting from an historic perspective and progressing through a review of both physiologic and clinical evidence. Despite the biologic and physiologic plausibility of therapeutic benefit, the current evidence base does not support the routine use of albumin administration to improve patient survival or prevent respiratory dysfunction.
SARS-CoV-2 vaccines confer great protection against COVID-19 in healthy adults, but it is unknown how patients with severe asthma and atopic dermatitis on biologic therapies respond despite animal data suggesting a lower response.
Objective: To characterize variation in the institutional review board application process of a multicenter, observational critical care study.
Design, Setting,and Subjects: Survey analysis of 36 investigators who applied for participation in the United States Critical Illness and Injury Trials Group: Critical Illness and Outcomes Study, an observational study of 69 adult ICUs.
Interventions: None.
Measurements and Main Results: Analysis of investigator-specific characteristics, institutional review board process, application and approval dates, and level of difficulty in obtaining approval. Surveys were analyzed from 36 sites (95%) that applied for institutional review board approval. Level of review ranged from full board, expedited, to exempt. Seventy-five percent of applications were submitted by an experienced investigator while 25% were submitted by a less experienced investigator. Median time to institutional review board approval was 30 days (interquartile range, 14-54) and ranged from 5 days to 5.5 months. Time to approval was 29 days (interquartile range, 17-48) for applications submitted by an experienced investigator compared with 97 days (interquartile range, 25-159) for those submitted by a less experienced investigator (p = 0.08). Subjective level of difficulty was significantly higher for less experienced investigators (4 of 10; interquartile range, 2-8) vs experienced investigators (2 of 10; interquartile range, 1-3) (p = 0.04). Four sites cited institutional review board concern regarding waiver of consent as a major barrier to approval and were required to perform revisions or participate in board meetings regarding this concern.
Conclusions: In a multicenter, observational critical care study, significant variation was observed between sites in all aspects of the institutional review board evaluation and approval process. The level of difficulty was significantly higher for less experienced investigators with a trend toward longer time to institutional review board approval. Variation in institutional review board interpretation of waiver of informed consent regulations was cited as a major barrier to approval. Copyright
Objective
To derive and validate a predictive model and novel emergency medical services (EMS) screening tool for severe sepsis (SS).
Design
Retrospective cohort study.
Setting
A single EMS system and an urban, public hospital.
Patients
Sequential adult, nontrauma, nonarrest, at-risk, EMS-transported patients between January 1, 2011, and December 31, 2012 were included in the study. At-risk patients were defined as having all 3 of the following criteria present in the EMS setting: (1) heart rate greater than 90 beats/min, (2) respiratory rate greater than 20 beats/min, and (3) systolic blood pressure less than 110 mm Hg.
Interventions
None.
Measurements and Main Results
Among 66,439 EMS encounters, 555 met the criteria for analysis. Fourteen percent (n = 75) of patients had SS, of which 19% (n = 14) were identified by EMS clinical judgment. In-hospital mortality for patients with SS was 31% (n = 23). Six EMS characteristics were found to be predictors of SS: older age, transport from nursing home, Emergency Medical Dispatch (EMD) 9-1-1 chief concern category of "sick person," hot tactile temperature assessment, low systolic blood pressure, and low oxygen saturation. The final predictive model showed good discrimination in derivation and validation subgroups (areas under curves, 0.843 and 0.820, respectively). Sensitivity of the final model was 91% in the derivation group and 78% in the validation group. At a predefined threshold of 2 or more points, prehospital severe sepsis (PRESS) score sensitivity was 86%.
Conclusions
The PRESS score is a novel EMS screening tool for SS that demonstrates a sensitivity of 86% and a specificity of 47%. Additional validation is needed before this tool can be recommended for widespread clinical use.