Respiratory drive heterogeneity associated with systemic inflammation and vascular permeability in acute respiratory distress syndrome.

BACKGROUND: In acute respiratory distress syndrome (ARDS), respiratory drive often differs among patients with similar clinical characteristics. Readily observable factors like acid-base state, oxygenation, mechanics, and sedation depth do not fully explain drive heterogeneity. This study evaluated the relationship of systemic inflammation and vascular permeability markers with respiratory drive and clinical outcomes in ARDS. METHODS: ARDS patients enrolled in the multicenter EPVent-2 trial with requisite data and plasma biomarkers were included. Neuromuscular blockade recipients were excluded. Respiratory drive was measured as PES0.1, the change in esophageal pressure during the first 0.1 s of inspiratory effort. Plasma angiopoietin-2, interleukin-6, and interleukin-8 were measured concomitantly, and 60-day clinical outcomes evaluated. RESULTS: 54.8% of 124 included patients had detectable respiratory drive (PES0.1 range of 0-5.1 cm H2O). Angiopoietin-2 and interleukin-8, but not interleukin-6, were associated with respiratory drive independently of acid-base, oxygenation, respiratory mechanics, and sedation depth. Sedation depth was not significantly associated with PES0.1 in an unadjusted model, or after adjusting for mechanics and chemoreceptor input. However, upon adding angiopoietin-2, interleukin-6, or interleukin-8 to models, lighter sedation was significantly associated with higher PES0.1. Risk of death was less with moderate drive (PES0.1 of 0.5-2.9 cm H2O) compared to either lower drive (hazard ratio 1.58, 95% CI 0.82-3.05) or higher drive (2.63, 95% CI 1.21-5.70) (p = 0.049). CONCLUSIONS: Among patients with ARDS, systemic inflammatory and vascular permeability markers were independently associated with higher respiratory drive. The heterogeneous response of respiratory drive to varying sedation depth may be explained in part by differences in inflammation and vascular permeability.

Frequency of screening and SBT Technique Trial-North American Weaning Collaboration (FAST-NAWC): an update to the protocol and statistical analysis plan.

BACKGROUND: This update summarizes key changes made to the protocol for the Frequency of Screening and Spontaneous Breathing Trial (SBT) Technique Trial-North American Weaning Collaborative (FAST-NAWC) trial since the publication of the original protocol. This multicenter, factorial design randomized controlled trial with concealed allocation, will compare the effect of both screening frequency (once vs. at least twice daily) to identify candidates to undergo a SBT and SBT technique [pressure support + positive end-expiratory pressure vs. T-piece] on the time to successful extubation (primary outcome) in 760 critically ill adults who are invasively ventilated for at least 24 h in 20 North American intensive care units. METHODS/DESIGN: Protocols for the pilot, factorial design trial and the full trial were previously published in J Clin Trials ( https://doi.org/10.4172/2167-0870.1000284 ) and Trials (https://doi: 10.1186/s13063-019-3641-8). As planned, participants enrolled in the FAST pilot trial will be included in the report of the full FAST-NAWC trial. In response to the onset of the coronavirus disease of 2019 (COVID-19) pandemic when approximately two thirds of enrollment was complete, we revised the protocol and consent form to include critically ill invasively ventilated patients with COVID-19. We also refined the statistical analysis plan (SAP) to reflect inclusion and reporting of participants with and without COVID-19. This update summarizes the changes made and their rationale and provides a refined SAP for the FAST-NAWC trial. These changes have been finalized before completion of trial follow-up and the commencement of data analysis. TRIAL REGISTRATION: Clinical Trials.gov NCT02399267.

ESICM guidelines on acute respiratory distress syndrome: definition, phenotyping and respiratory support strategies.

The aim of these guidelines is to update the 2017 clinical practice guideline (CPG) of the European Society of Intensive Care Medicine (ESICM). The scope of this CPG is limited to adult patients and to non-pharmacological respiratory support strategies across different aspects of acute respiratory distress syndrome (ARDS), including ARDS due to coronavirus disease 2019 (COVID-19). These guidelines were formulated by an international panel of clinical experts, one methodologist and patients' representatives on behalf of the ESICM. The review was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement recommendations. We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence and grade recommendations and the quality of reporting of each study based on the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) network guidelines. The CPG addressed 21 questions and formulates 21 recommendations on the following domains: (1) definition; (2) phenotyping, and respiratory support strategies including (3) high-flow nasal cannula oxygen (HFNO); (4) non-invasive ventilation (NIV); (5) tidal volume setting; (6) positive end-expiratory pressure (PEEP) and recruitment maneuvers (RM); (7) prone positioning; (8) neuromuscular blockade, and (9) extracorporeal life support (ECLS). In addition, the CPG includes expert opinion on clinical practice and identifies the areas of future research.

Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial.

BACKGROUND: There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure. METHODS: TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2-4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761. FINDINGS: Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80-1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77-1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94-2·08; p=0·10). INTERPRETATION: Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy. FUNDING: National Institutes of Health.

Use of N-Acetylcysteine for Clozapine-Induced Acute Liver Injury: A Case Report and Literature Review.

Purpose: To report a case of clozapine-induced hepatotoxicity managed with intravenous (IV) N-acetylcysteine (NAC) and summarize the available literature. Summary: A 46-year-old woman with history of bipolar disorder with psychotic features presented to the intensive care unit with asterixis and elevations in liver enzymes. The patient had been initiated on risperidone, clozapine, and lithium approximately 1 month prior to admission. After ruling out other possible non-drug etiologies, clozapine was suspected as the likeliest cause of the acute liver injury. Her acute liver injury was managed with the discontinuation of all antipsychotics, administration of IV NAC, and other standard of care supportive measures. Conclusion: Although clozapine has been associated with hepatitis and acute liver failure, there are no reports of NAC used in the management of clozapine-induced hepatotoxicity. NAC was used in our patient after considering the potential benefit and limited adverse effects. The role of NAC in non-acetaminophen-induced acute liver failure remains promising, but more research is warranted.

I-SPY COVID adaptive platform trial for COVID-19 acute respiratory failure: rationale, design and operations.

INTRODUCTION: The COVID-19 pandemic brought an urgent need to discover novel effective therapeutics for patients hospitalised with severe COVID-19. The Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis (ISPY COVID-19 trial) was designed and implemented in early 2020 to evaluate investigational agents rapidly and simultaneously on a phase 2 adaptive platform. This manuscript outlines the design, rationale, implementation and challenges of the ISPY COVID-19 trial during the first phase of trial activity from April 2020 until December 2021. METHODS AND ANALYSIS: The ISPY COVID-19 Trial is a multicentre open-label phase 2 platform trial in the USA designed to evaluate therapeutics that may have a large effect on improving outcomes from severe COVID-19. The ISPY COVID-19 Trial network includes academic and community hospitals with significant geographical diversity across the country. Enrolled patients are randomised to receive one of up to four investigational agents or a control and are evaluated for a family of two primary outcomes-time to recovery and mortality. The statistical design uses a Bayesian model with 'stopping' and 'graduation' criteria designed to efficiently discard ineffective therapies and graduate promising agents for definitive efficacy trials. Each investigational agent arm enrols to a maximum of 125 patients per arm and is compared with concurrent controls. As of December 2021, 11 investigational agent arms had been activated, and 8 arms were complete. Enrolment and adaptation of the trial design are ongoing. ETHICS AND DISSEMINATION: ISPY COVID-19 operates under a central institutional review board via Wake Forest School of Medicine IRB00066805. Data generated from this trial will be reported in peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: NCT04488081.

Association of Positive End-Expiratory Pressure and Lung Recruitment Selection Strategies with Mortality in Acute Respiratory Distress Syndrome: A Systematic Review and Network Meta-analysis.

Rationale: The most beneficial positive end-expiratory pressure (PEEP) selection strategy in patients with acute respiratory distress syndrome (ARDS) is unknown, and current practice is variable. Objectives: To compare the relative effects of different PEEP selection strategies on mortality in adults with moderate to severe ARDS. Methods: We conducted a network meta-analysis using a Bayesian framework. Certainty of evidence was evaluated using grading of recommendations assessment, development and evaluation methodology. Measurements and Main Results: We included 18 randomized trials (4,646 participants). Compared with a lower PEEP strategy, the posterior probability of mortality benefit from a higher PEEP without lung recruitment maneuver (LRM) strategy was 99% (risk ratio [RR], 0.77; 95% credible interval [CrI], 0.60-0.96, high certainty), the posterior probability of benefit of the esophageal pressure-guided strategy was 87% (RR, 0.77; 95% CrI, 0.48-1.22, moderate certainty), the posterior probability of benefit of a higher PEEP with brief LRM strategy was 96% (RR, 0.83; 95% CrI, 0.67-1.02, moderate certainty), and the posterior probability of increased mortality from a higher PEEP with prolonged LRM strategy was 77% (RR, 1.06; 95% CrI, 0.89-1.22, low certainty). Compared with a higher PEEP without LRM strategy, the posterior probability of increased mortality from a higher PEEP with prolonged LRM strategy was 99% (RR, 1.37; 95% CrI, 1.04-1.81, moderate certainty). Conclusions: In patients with moderate to severe ARDS, higher PEEP without LRM is associated with a lower risk of death than lower PEEP. A higher PEEP with prolonged LRM strategy is associated with increased risk of death when compared with higher PEEP without LRM.

Risks and Benefits of Ultra-Lung-Protective Invasive Mechanical Ventilation Strategies with a Focus on Extracorporeal Support.

Lung-protective ventilation strategies are the current standard of care for patients with acute respiratory distress syndrome in an effort to provide adequate ventilatory requirements while minimizing ventilator-induced lung injury. Some patients may benefit from ultra-lung-protective ventilation, a strategy that achieves lower airway pressures and Vt than the current standard. Specific physiological parameters beyond severity of hypoxemia, such as driving pressure and respiratory system elastance, may be predictive of those most likely to benefit. Because application of ultra-lung-protective ventilation is often limited by respiratory acidosis, extracorporeal membrane oxygenation or extracorporeal carbon dioxide removal, which remove carbon dioxide from blood, is an attractive option. These strategies are associated with hematological complications, especially when applied at low blood-flow rates with devices designed for higher blood flows, and a recent large randomized controlled trial failed to show a benefit from an extracorporeal carbon dioxide removal-facilitated ultra-lung-protective ventilation strategy. Only in patients with very severe forms of acute respiratory distress syndrome has the use of an ultra-lung-protective ventilation strategy-accomplished with extracorporeal membrane oxygenation-been suggested to have a favorable risk-to-benefit profile. In this critical care perspective, we address key areas of controversy related to ultra-lung-protective ventilation, including the trade-offs between minimizing ventilator-induced lung injury and the risks from strategies to achieve this added protection. In addition, we suggest which patients might benefit most from an ultra-lung-protective strategy and propose areas of future research.

Advancing precision medicine for acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a heterogeneous clinical syndrome. Understanding of the complex pathways involved in lung injury pathogenesis, resolution, and repair has grown considerably in recent decades. Nevertheless, to date, only therapies targeting ventilation-induced lung injury have consistently proven beneficial, and despite these gains, ARDS morbidity and mortality remain high. Many candidate therapies with promise in preclinical studies have been ineffective in human trials, probably at least in part due to clinical and biological heterogeneity that modifies treatment responsiveness in human ARDS. A precision medicine approach to ARDS seeks to better account for this heterogeneity by matching therapies to subgroups of patients that are anticipated to be most likely to benefit, which initially might be identified in part by assessing for heterogeneity of treatment effect in clinical trials. In October 2019, the US National Heart, Lung, and Blood Institute convened a workshop of multidisciplinary experts to explore research opportunities and challenges for accelerating precision medicine in ARDS. Topics of discussion included the rationale and challenges for a precision medicine approach in ARDS, the roles of preclinical ARDS models in precision medicine, essential features of cohort studies to advance precision medicine, and novel approaches to clinical trials to support development and validation of a precision medicine strategy. In this Position Paper, we summarise workshop discussions, recommendations, and unresolved questions for advancing precision medicine in ARDS. Although the workshop took place before the COVID-19 pandemic began, the pandemic has highlighted the urgent need for precision therapies for ARDS as the global scientific community grapples with many of the key concepts, innovations, and challenges discussed at this workshop.

Promises and challenges of personalized medicine to guide ARDS therapy.

Identifying new effective treatments for the acute respiratory distress syndrome (ARDS), including COVID-19 ARDS, remains a challenge. The field of ARDS investigation is moving increasingly toward innovative approaches such as the personalization of therapy to biological and clinical sub-phenotypes. Additionally, there is growing recognition of the importance of the global context to identify effective ARDS treatments. This review highlights emerging opportunities and continued challenges for personalizing therapy for ARDS, from identifying treatable traits to innovative clinical trial design and recognition of patient-level factors as the field of critical care investigation moves forward into the twenty-first century.

Latent Class Analysis Reveals COVID-19-related Acute Respiratory Distress Syndrome Subgroups with Differential Responses to Corticosteroids.

Rationale: Two distinct subphenotypes have been identified in acute respiratory distress syndrome (ARDS), but the presence of subgroups in ARDS associated with coronavirus disease (COVID-19) is unknown. Objectives: To identify clinically relevant, novel subgroups in COVID-19-related ARDS and compare them with previously described ARDS subphenotypes. Methods: Eligible participants were adults with COVID-19 and ARDS at Columbia University Irving Medical Center. Latent class analysis was used to identify subgroups with baseline clinical, respiratory, and laboratory data serving as partitioning variables. A previously developed machine learning model was used to classify patients as the hypoinflammatory and hyperinflammatory subphenotypes. Baseline characteristics and clinical outcomes were compared between subgroups. Heterogeneity of treatment effect for corticosteroid use in subgroups was tested. Measurements and Main Results: From March 2, 2020, to April 30, 2020, 483 patients with COVID-19-related ARDS met study criteria. A two-class latent class analysis model best fit the population (P = 0.0075). Class 2 (23%) had higher proinflammatory markers, troponin, creatinine, and lactate, lower bicarbonate, and lower blood pressure than class 1 (77%). Ninety-day mortality was higher in class 2 versus class 1 (75% vs. 48%; P < 0.0001). Considerable overlap was observed between these subgroups and ARDS subphenotypes. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RT-PCR cycle threshold was associated with mortality in the hypoinflammatory but not the hyperinflammatory phenotype. Heterogeneity of treatment effect to corticosteroids was observed (P = 0.0295), with improved mortality in the hyperinflammatory phenotype and worse mortality in the hypoinflammatory phenotype, with the caveat that corticosteroid treatment was not randomized. Conclusions: We identified two COVID-19-related ARDS subgroups with differential outcomes, similar to previously described ARDS subphenotypes. SARS-CoV-2 PCR cycle threshold had differential value for predicting mortality in the subphenotypes. The subphenotypes had differential treatment responses to corticosteroids.

Effect of Esophageal Pressure-guided Positive End-Expiratory Pressure on Survival from Acute Respiratory Distress Syndrome: A Risk-based and Mechanistic Reanalysis of the EPVent-2 Trial.

Rationale: In acute respiratory distress syndrome (ARDS), the effect of positive end-expiratory pressure (PEEP) may depend on the extent to which multiorgan dysfunction contributes to risk of death, and the precision with which PEEP is titrated to attenuate atelectrauma without exacerbating overdistension. Objectives: To evaluate whether multiorgan dysfunction and lung mechanics modified treatment effect in the EPVent-2 (Esophageal Pressure-guided Ventilation 2) trial, a multicenter trial of esophageal pressure (Pes)-guided PEEP versus empirical high PEEP in moderate to severe ARDS. Methods: This post hoc reanalysis of the EPVent-2 trial evaluated for heterogeneity of treatment effect on mortality by baseline multiorgan dysfunction, determined via Acute Physiology and Chronic Health Evaluation II (APACHE-II). It also evaluated whether PEEP titrated to end-expiratory transpulmonary pressure near 0 cm H2O was associated with survival. Measurements and Main Results: All 200 trial participants were included. Treatment effect on 60-day mortality differed by multiorgan dysfunction severity (P = 0.03 for interaction). Pes-guided PEEP was associated with lower mortality among patients with APACHE-II less than the median value (hazard ratio, 0.43; 95% confidence interval, 0.20-0.92) and may have had the opposite effect in patients with higher APACHE-II (hazard ratio, 1.69; 95% confidence interval, 0.93-3.05). Independent of treatment group or multiorgan dysfunction severity, mortality was lowest when PEEP titration achieved end-expiratory transpulmonary pressure near 0 cm H2O. Conclusions: The effect on survival of Pes-guided PEEP, compared with empirical high PEEP, differed by multiorgan dysfunction severity. Independent of multiorgan dysfunction, PEEP titrated to end-expiratory transpulmonary pressure closer to 0 cm H2O was associated with greater survival than more positive or negative values. These findings warrant prospective testing in a future trial.

Discordance Between Respiratory Drive and Sedation Depth in Critically Ill Patients Receiving Mechanical Ventilation.

OBJECTIVES: In mechanically ventilated patients, deep sedation is often assumed to induce "respirolysis," that is, lyse spontaneous respiratory effort, whereas light sedation is often assumed to preserve spontaneous effort. This study was conducted to determine validity of these common assumptions, evaluating the association of respiratory drive with sedation depth and ventilator-free days in acute respiratory failure. DESIGN: Prospective cohort study. SETTING: Patients were enrolled during 2 month-long periods in 2016-2017 from five ICUs representing medical, surgical, and cardiac specialties at a U.S. academic hospital. PATIENTS: Eligible patients were critically ill adults receiving invasive ventilation initiated no more than 36 hours before enrollment. Patients with neuromuscular disease compromising respiratory function or expiratory flow limitation were excluded. INTERVENTIONS: Respiratory drive was measured via P0.1, the change in airway pressure during a 0.1-second airway occlusion at initiation of patient inspiratory effort, every 12 ± 3 hours for 3 days. Sedation depth was evaluated via the Richmond Agitation-Sedation Scale. Analyses evaluated the association of P0.1 with Richmond Agitation-Sedation Scale (primary outcome) and ventilator-free days. MEASUREMENTS AND MAIN RESULTS: Fifty-six patients undergoing 197 bedside evaluations across five ICUs were included. P0.1 ranged between 0 and 13.3 cm H2O (median [interquartile range], 0.1 cm H2O [0.0-1.3 cm H2O]). P0.1 was not significantly correlated with the Richmond Agitation-Sedation Scale (RSpearman, 0.02; 95% CI, -0.12 to 0.16; p = 0.80). Considering P0.1 terciles (range less than 0.2, 0.2-1.0, and greater than 1.0 cm H2O), patients in the middle tercile had significantly more ventilator-free days than the lowest tercile (incidence rate ratio, 0.78; 95% CI, 0.65-0.93; p < 0.01) or highest tercile (incidence rate ratio, 0.58; 95% CI, 0.48-0.70; p < 0.01). CONCLUSIONS: Sedation depth is not a reliable marker of respiratory drive during critical illness. Respiratory drive can be low, moderate, or high across the range of routinely targeted sedation depth.