Daily Ards Research Analysis

BACKGROUND: The COVID-19 pandemic has resulted in a critical shortage of respiratory ventilators, highlighting the urgent need to explore alternative treatment options for patients with acute respiratory distress syndrome (ARDS) caused by respiratory viruses, as an alternative to invasive mechanical ventilation (IMV) in future pandemics. OBJECTIVES: The objective of this study was to assess the effectiveness of alternative noninvasive oxygenation and ventilation strategies in comparison to invasive mechanical ventilation (IMV) in patients with virus-induced acute respiratory failure (ARF). The primary outcome was the all-cause ICU mortality rate. METHODS: A systematic review was conducted following the Cochrane guidelines and PRISMA reporting guidelines. The search encompassed databases such as Medline, Cochrane CENTRAL, and Embase to identify relevant indexed literature. Additionally, gray literature was included by consulting regulatory agencies. The included studies compared various oxygenation and ventilatory alternatives, such as high-flow nasal cannula (HFNC), continuous positive airway pressure (CPAP), or noninvasive mechanical ventilation (NIMV) with IMV. An exploratory meta-analysis was performed by calculating the risk ratio (RR) by random effects and meta-regression to explore possible sources of heterogeneity and to compare ventilatory alternatives against IMV to reduce mortality, length of stay (LOS) days in ICU, nosocomial infection, and barotrauma. RESULTS: A total of forty-seven studies were included in this systematic review. NIMV had an RR of 0.70 (0.58-0.85), HFNC had an RR of 0.54 (0.42-0.71), and CPAP had an RR of 0.80 (0.71-0.90), with meta-regression models that reduced heterogeneity to 0%. For LOS days in ICU, NIMV had 0.38 (- 0.69: - 0.08) lower days and HFNC 0.29 (- 0.64: 0.06) lower days with meta-regression models that reduction heterogeneity to 0% for HFNC and 50% for NIMV. Not enough studies reported nosocomial infection or barotrauma to evaluate them in a meta-analysis. The overall quality of evidence, as assessed by GRADE evaluation, was determined to be from very low to medium certainty depending on the ventilatory strategy and outcome. CONCLUSIONS: The findings of this systematic review support the use of alternative noninvasive oxygenation and ventilation strategies as viable alternatives to conventional respiratory ventilation for managing viral-induced ARF. Although it is essential to interpret these findings with caution given the overall low to medium certainty of the evidence, the integration of these modalities as part of the management strategies of these patients could help reduce the utilization of ICU beds, invasive ventilators, and costs in both developed and developing countries.

BACKGROUND: The application of sepsis subtypes to enhance personalized medicine in critically ill patients is hindered by the lack of validation across diverse cohorts and the absence of a simple classification model. We aimed to validate the previously identified SENECA clinical sepsis subtypes in multiple large ICU cohorts, and to develop parsimonious classifier models for δ-type adjudication in clinical practice. METHODS: Data from four cohorts between 2008 and 2023 were used to assign α, β, γ and δ-type in patients fulfilling the Sepsis-3 criteria using clinical variables: (I) The Molecular diAgnosis and Risk stratification of Sepsis (MARS, n = 2449), (II) a contemporary continuation of the MARS study (MARS2, n = 2445) (III) the Dutch National Intensive Care Evaluation registry (NICE, n = 28,621) and (IV) the Medical Information Mart for Intensive Care including (MIMIC-IV, n = 18,661). K-means clustering using clinical variables was conducted to assess the optimal number of classes and compared to the SENECA subtypes. Parsimonious models were built in the SENECA derivation cohort to predict subtype membership using logistic regression, and validated in MARS and MIMIC-IV. RESULTS: Among 52.226 patients with sepsis, the subtype distribution in MARS, MARS2 and NICE was 2-6% for the α-type, 1-5% for the β-type, 49-65% for the γ-type and 26-48% for the δ-type compared to 33%, 27%, 27% and 13% in the original SENECA derivation cohort, whereas subtype distribution in MIMIC-IV was more similar at 25%, 24%, 27% and 25%, respectively. In-hospital mortality rates were significantly different between the four cohorts for α, γ and δ-type (p < 0.001). Method-based validation showed moderate overlap with the original subtypes in both MARS and MIMIC-IV. A parsimonious model for all four subtypes had moderate to low accuracy (accuracy 62.2%), while a parsimonious classifier model with 3 variables (aspartate aminotransferase, serum lactate, and bicarbonate) had excellent accuracy in predicting the δ-type patients from all other types in the derivation cohort and moderate accuracy in the validation cohorts (MARS: area under the receiver operator characteristic curve (AUC) 0.93, 95% CI [0.92-0.94], accuracy 85.5% [84.0-86.8%]; MIMIC-IV: AUC 0.86 [0.85-0.87], accuracy 82.9% [82.4-83.4%]). CONCLUSIONS: The distribution and mortality rates of clinical sepsis subtypes varied between US and European cohorts. A three-variable model could accurately identify the δ-type sepsis patients.

BACKGROUND: Cytokine release triggered by a hyperactive immune response is thought to contribute to severe acute respiratory syndrome coronavirus 2019 (SARS-CoV-2)-related respiratory failure. Bruton tyrosine kinase (BTK) is involved in innate immunity, and BTK inhibitors block cytokine release. We assessed the next-generation BTK inhibitor zanubrutinib in SARS-CoV-2-infected patients with respiratory distress. METHOD: Cohort 1 had a prospective, randomized, double-blind, placebo-controlled design; cohort 2 had a single-arm design. Adults with SARS-CoV-2 requiring hospitalization (without mechanical ventilation) were randomized in cohort 1. Those on mechanical ventilation ≤24 hours were enrolled in cohort 2. Patients were randomized 1:1 to zanubrutinib 320 mg once daily or placebo (cohort 1), or received zanubrutinib 320 mg once daily (cohort 2). Co-primary endpoints were respiratory failure-free survival rate and time to return to breathing room air at 28 days. Corollary studies to assess zanubrutinib's impact on immune response were performed. RESULTS: Sixty-three patients in cohort 1 received zanubrutinib (n=30) or placebo (n=33), with median treatment duration of 8.5 and 7.0 days, respectively. The median treatment duration in cohort 2 (n=4) was 13 days; all discontinued treatment early. In cohort 1, respiratory failure-free survival and the estimated rates of not returning to breathing room air by day 28 were not significantly different between treatments. Importantly, serological response to coronavirus disease 2019 (COVID-19) was not impacted by zanubrutinib. Lower levels of granulocyte colony-stimulating factor, interleukin (IL)-10, monocyte chemoattractant protein-1, IL-4, and IL-13 were observed in zanubrutinib-treated patients. Moreover, single-cell transcriptome analysis showed significant downregulation of inflammatory mediators (IL-6, IL-8, macrophage colony-stimulating factor, macrophage inflammatory protein-1α, IL-1β) and signaling pathways (JAK1, STAT3, TYK2), and activation of gamma-delta T cells in zanubrutinib-treated patients. CONCLUSIONS: Marked reduction in inflammatory signaling with preserved SARS-CoV-2 serological response was observed in hospitalized patients with COVID-19 respiratory distress receiving zanubrutinib. Despite these immunological findings, zanubrutinib did not show improvement over placebo in clinical recovery from respiratory distress. Concurrent administration of steroids and antiviral therapy to most patients may have contributed to these results. Investigation of zanubrutinib may be warranted in other settings where cytokine release and immune cell exhaustion are important. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov/study/NCT04382586, identifier NCT04382586.