The acute respiratory distress syndrome (ARDS) is a common cause of acute respiratory failure, and is associated with substantial mortality and morbidity. Dozens of clinical trials targeting ARDS ...have failed, with no drug specifically targeting lung injury in widespread clinical use. Thus, the need for drug development in ARDS is great. Targeted proteomic studies in ARDS have identified many key pathways in the disease, including inflammation, epithelial injury, endothelial injury or activation, and disordered coagulation and repair. Recent studies reveal the potential for proteomic changes to identify novel subphenotypes of ARDS patients who may be most likely to respond to therapy and could thus be targeted for enrollment in clinical trials. Nontargeted studies of proteomics in ARDS are just beginning and have the potential to identify novel drug targets and key pathways in the disease. Proteomics will play an important role in phenotyping of patients and developing novel therapies for ARDS in the future.
Microvascular injury, inflammation, and coagulation play critical roles in the pathogenesis of acute lung injury (ALI). Plasma protein C levels are decreased in patients with acute lung injury and ...are associated with higher mortality and fewer ventilator-free days.
To test the efficacy of activated protein C (APC) as a therapy for patients with ALI.
Eligible subjects were critically ill patients who met the American/European consensus criteria for ALI. Patients with severe sepsis and an APACHE II score of 25 or more were excluded. Participants were randomized to receive APC (24 microg/kg/h for 96 h) or placebo in a double-blind fashion within 72 hours of the onset of ALI. The primary endpoint was ventilator-free days.
APC increased plasma protein C levels (P = 0.002) and decreased pulmonary dead space fraction (P = 0.02). However, there was no statistically significant difference between patients receiving placebo (n = 38) or APC (n = 37) in the number of ventilator-free days (median 25-75% interquartile range: 19 0-24 vs. 19 14-22, respectively; P = 0.78) or in 60-day mortality (5/38 vs. 5/37 patients, respectively; P = 1.0). There were no differences in the number of bleeding events between the two groups.
APC did not improve outcomes from ALI. The results of this trial do not support a large clinical trial of APC for ALI in the absence of severe sepsis and high disease severity.
Background: Despite being a focus of intensive investigation, acute lung injury (ALI) remains a major cause of morbidity and mortality.
However, the current consensus definition impedes ...identification of patients with ALI before they require mechanical ventilation.
To establish a definition of early ALI (EALI), we carried out a prospective cohort study to identify clinical predictors of
progression to ALI.
Methods: Potential cases of EALI were identified by daily screening of chest radiographs (CXRs) for all adult emergency department
and new medicine service admissions at Stanford University Hospital.
Results: Of 1,935 screened patients with abnormal CXRs, we enrolled 100 patients admitted with bilateral opacities present < 7 days
and not due exclusively to left atrial hypertension. A total of 33 of these 100 patients progressed to ALI requiring mechanical
ventilation during their hospitalization. Progression to ALI was associated with immunosuppression, the modified Rapid Emergency
Medicine Score, airspace opacities beyond the bases, systemic inflammatory response syndrome, and the initial oxygen requirement
(> 2 L/min). On multivariate analysis, only an initial oxygen requirement > 2 L/min predicted progression to ALI (odds ratio,
8.1; 95% confidence interval, 2.7 to 24.5). A clinical diagnosis of EALI, defined by hospital admission with bilateral opacities
on CXR not exclusively due to left atrial hypertension and an initial oxygen requirement of > 2 L/min, was 73% sensitive and
79% specific for progression to ALI.
Conclusions: A new clinical definition of EALI may have value in identifying patients with ALI early in their disease course.
The aim is to provide a narrative review of the role of corticosteroids, with and without inhaled beta agonist, in communityacquired pneumonia. Community and health-care associated pneumonia remain ...leading causes of morbidity and mortality despite appropriate antibiotic therapy. The pneumonia-associated adverse outcomes are not only related to the infectious organism, but also to a dysfunctional host-immune response resulting in overwhelming inflammation. Use of systemic corticosteroids as adjuvant therapy in pneumonia remains controversial. Multiple randomized clinical trials evaluating corticosteroids in patients with community acquired pneumonia have found discrepant results in terms of benefits and adverse effects. Inhaled delivery of corticosteroids offer the potential advantage of providing therapeutic benefits directly to the lung, with minimal to no adverse systemic effects.Conclusion. Although meta-analyses suggest potential benefits in a select group of patients with more severe pneumonia, the ideal timing, dose, route of delivery, duration, and patient selection remain to be established. A smaller body of literature suggests benefit of inhaled corticosteroids, with or without inhaled beta agonists, but future large scale clinical trials are needed to establish clinical benefit with inhaled delivery.
The widespread presence of autoantibodies in acute infection with SARS-CoV-2 is increasingly recognized, but the prevalence of autoantibodies in non-SARS-CoV-2 infections and critical illness has not ...yet been reported. We profiled IgG autoantibodies in 267 patients from 5 independent cohorts with non-SARS-CoV-2 viral, bacterial, and noninfectious critical illness. Serum samples were screened using Luminex arrays that included 58 cytokines and 55 autoantigens, many of which are associated with connective tissue diseases (CTDs). Samples positive for anti-cytokine antibodies were tested for receptor blocking activity using cell-based functional assays. Anti-cytokine antibodies were identified in > 50% of patients across all 5 acutely ill cohorts. In critically ill patients, anti-cytokine antibodies were far more common in infected versus uninfected patients. In cell-based functional assays, 11 of 39 samples positive for select anti-cytokine antibodies displayed receptor blocking activity against surface receptors for Type I IFN, GM-CSF, and IL-6. Autoantibodies against CTD-associated autoantigens were also commonly observed, including newly detected antibodies that emerged in longitudinal samples. These findings demonstrate that anti-cytokine and autoantibodies are common across different viral and nonviral infections and range in severity of illness.
Due to the errors occurred in the originally published version, this article is being reprinted in its entirety as Correction. All errors have been corrected. It is the correct version.
Fifty years ago, the Food and Drug Administration (FDA) began implementing new provisions of the Federal Food, Drug, and Cosmetic Act aimed at assuring the safety of new food additives before they ...enter the marketplace. Today, the agency's procedures for premarket evaluation of food additive safety have evolved into a scientifically rigorous, sound and dependable system whose objective and independent evaluations by FDA scientists assure that new food additives are safe for their intended uses before they arrive on the consumer's plate. Although controversy often surrounds food additives in the popular media and culture, and science-based challenges to FDA's decisions do arise, the agency's original safety judgments successfully withstand these challenges time and again. This article reviews the basic components of the FDA's decision-making process for evaluating the safety of new food additives, and identifies characteristics of this process that are central to assuring that FDA's decisions are marked by scientific rigor and high integrity, and can continue to be relied on by consumers.
The acute respiratory distress syndrome (ARDS) was first described by Ashbaugh and colleagues in 1967. However, despite considerable efforts, early progress in treatment was slowed by lack of ...consistent definitions and appropriately powered clinical trials. In 1994, the American-European Consensus Conference on ARDS established criteria defining ARDS as well as acute lung injury (ALI). Additionally, the conference established research directives and international coordination of clinical studies. Current incidence of ALI in the United States is estimated at 200,000 cases per year with a mortality rate approaching 40%. Mechanical ventilation, using positive end-expiratory pressure and reduced tidal volumes and inspiratory pressures, along with improved supportive care has increased survival rates. However, to date, pharmacological therapies have failed to improve survival in multicenter clinical trials. This article focuses on clinical treatments for ALI that have been tested in phase II and III clinical trials as well as a discussion of potential future therapies.
Objectives
Patients hospitalized for COVID‐19 frequently develop hypoxemia and acute respiratory distress syndrome (ARDS) after admission. In non‐COVID‐19 ARDS studies, admission to hospital wards ...with subsequent transfer to intensive care unit (ICU) is associated with worse outcomes. We hypothesized that initial admission to the ward may affect outcomes in patient with COVID‐19 ARDS.
Methods
This was a retrospective study of consecutive adults admitted for COVID‐19 ARDS between March 2020 and March 2021 at Stanford Health Care. Mortality scores at hospital admission (Coronavirus Clinical Characterization Consortium Mortality Score 4C score) and ICU admission (Simplified Acute Physiology Score III SAPS‐III) were calculated, as well as ROX index for patients on high flow nasal oxygen. Patients were classified by emergency department (ED) disposition (ward‐first vs. ICU‐direct), and 28‐ and 60‐day mortality and highest level of respiratory support within 1 day of ICU admission were compared. A second cohort (April 2021‒July 2022, n = 129) was phenotyped to validate mortality outcome.
Results
A total of 157 patients were included, 48% of whom were first admitted to the ward (n = 75). Ward‐first patients had more comorbidities, including lung disease. Ward‐first patients had lower 4C and similar SAPS‐III score, yet increased mortality at 28 days (32% vs. 17%, hazard ratio HR 2.0, 95% confidence interval 95% CI 1.0‒3.7, p = 0.039) and 60 days (39% vs. 23%, HR 1.83, 95% CI 1.04‒3.22, p = 0.037) compared to ICU‐direct patients. More ward‐first patients escalated to mechanical ventilation on day 1 of ICU admission (36% vs. 14%, p = 0.002) despite similar ROX index. Ward‐first patients who upgraded to ICU within 48 h of ED presentation had the highest mortality. Mortality findings were replicated in a sensitivity analysis.
Conclusion
Despite similar baseline risk scores, ward‐first patients with COVID‐19 ARDS had increased mortality and escalation to mechanical ventilation compared to ICU‐direct patients. Ward‐first patients requiring ICU upgrade within 48 h were at highest risk, highlighting a need for improved identification of this group at ED admission.
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