A randomised controlled trial of an open lung strategy with staircase recruitment, titrated PEEP and targeted low airway pressures in patients with acute respiratory distress syndrome

INTRODUCTION: Tidal volume and plateau pressure minimisation are the standard components of a protective lung ventilation strategy for patients with acute respiratory distress syndrome (ARDS). Open lung strategies, including higher positive end-expiratory pressure (PEEP) and recruitment manoeuvres to date have not proven efficacious. This study examines the effectiveness and safety of a novel open lung strategy, which includes permissive hypercapnia, staircase recruitment manoeuvres (SRM) and low airway pressure with PEEP titration. METHOD: Twenty ARDS patients were randomised to treatment or ARDSnet control ventilation strategies. The treatment group received SRM with decremental PEEP titration and targeted plateau pressure < 30 cm H2O. Gas exchange and lung compliance were measured daily for 7 days and plasma cytokines in the first 24 hours and on days 1, 3, 5 and 7 (mean ± SE). Duration of ventilation, ICU stay and hospital stay (median and interquartile range) and hospital survival were determined. RESULTS: There were significant overall differences between groups when considering plasma IL-8 and TNF-α. For plasma IL-8, the control group was 41% higher than the treatment group over the seven-day period (ratio 1.41 (1.11 to 1.79), P = 0.01), while for TNF-α the control group was 20% higher over the seven-day period (ratio 1.20 (1.01 to 1.42) P = 0.05). PaO2/FIO2 (204 ± 9 versus 165 ± 9 mmHg, P = 0.005) and static lung compliance (49.1 ± 2.9 versus 33.7 ± 2.7 mls/cm H2O, P < 0.001) were higher in the treatment group than the control group over seven days. There was no difference in duration of ventilation (180 (87 to 298) versus 341 (131 to 351) hrs, P = 0.13), duration of ICU stay (9.9 (5.6 to 14.8) versus 16.0 (8.1 to 19.3) days, P = 0.19) and duration of hospital stay (17.9 (13.7 to 34.5) versus 24.7 (20.5 to 39.8) days, P = 0.16) between the treatment and control groups. CONCLUSIONS: This open lung strategy was associated with greater amelioration in some systemic cytokines, improved oxygenation and lung compliance over seven days. A larger trial powered to examine clinically-meaningful outcomes is warranted. TRIAL REGISTRATION: ACTRN12607000465459

Effects of brain tissue oxygen (PbtO2) guided management on patient outcomes following severe traumatic brain injury: A systematic review and meta-analysis.

Monitoring and optimisation of brain tissue oxygen tension (PbtO2) has been associated with improved neurological outcome and survival in observational studies of severe traumatic brain injury (TBI). We carried out a systematic review of randomized controlled trials to determine if PbtO2-guided management is associated with differential neurological outcomes, survival, and adverse events. Searches were carried out to 10 February 2022 in Medline (OvidSP), 11 February in EMBASE (OvidSP) and 8 February in Cochrane library. Randomized controlled trials comparing PbtO2 and ICP-guided management to ICP-guided management alone were included. The primary outcome was survival with favourable neurological outcome at 6-months post injury. Data were extracted by two independent authors and GRADE certainty of evidence assessed. There was no difference in the proportion of patients with favourable neurological outcomes with PbtO2-guided management (relative risk [RR] 1.42, 95% CI 0.97 to 2.08; p = 0.07; I2 = 0%, very low certainty evidence) but PbtO2-guided management was associated with reduced mortality (RR 0.54, 95% CI 0.31 to 0.93; p = 0.03; I2 = 42%; very low certainty evidence) and ICP (mean difference (MD) - 4.62, 95% CI - 8.27 to - 0.98; p = 0.01; I2 = 63%; very low certainty evidence). There was no significant difference in the risk of adverse respiratory or cardiovascular events. PbtO2-guided management in addition to ICP-based care was not significantly associated with increased favourable neurological outcomes, but was associated with increased survival and reduced ICP, with no difference in respiratory or cardiovascular adverse events. However, based on GRADE criteria, the certainty of evidence provided by this meta-analysis was consistently very low. MESH: Brain Ischemia; Intensive Care; Glasgow Outcome Scale; Randomized Controlled Trial; Craniocerebral Trauma

Expert consensus and recommendations on safety criteria for active mobilization of mechanically ventilated critically ill adults

Introduction: The aim of this study was to develop consensus recommendations on safety parameters for mobilizing adult, mechanically ventilated, intensive care unit (ICU) patients. Methods: A systematic literature review was followed by a meeting of 23 multidisciplinary ICU experts to seek consensus regarding the safe mobilization of mechanically ventilated patients. Results: Safety considerations were summarized in four categories: respiratory, cardiovascular, neurological and other. Consensus was achieved on all criteria for safe mobilization, with the exception being levels of vasoactive agents. Intubation via an endotracheal tube was not a contraindication to early mobilization and a fraction of inspired oxygen less than 0.6 with a percutaneous oxygen saturation more than 90% and a respiratory rate less than 30 breaths/minute were considered safe criteria for in- and out-of-bed mobilization if there were no other contraindications. At an international meeting, 94 multidisciplinary ICU clinicians concurred with the proposed recommendations. Conclusion: Consensus recommendations regarding safety criteria for mobilization of adult, mechanically ventilated patients in the ICU have the potential to guide ICU rehabilitation whilst minimizing the risk of adverse events

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial

Importance: The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive. Objective: To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. Design, Setting, and Participants: The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. Interventions: The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). Main Outcomes and Measures: The primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, -1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority &gt;99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility &gt;95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events. Results: Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (O

Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials.

Funder: laura and john arnold foundationBACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. CONCLUSIONS: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Taxonomy of the order Mononegavirales: update 2017.

In 2017, the order Mononegavirales was expanded by the inclusion of a total of 69 novel species. Five new rhabdovirus genera and one new nyamivirus genus were established to harbor 41 of these species, whereas the remaining new species were assigned to already established genera. Furthermore, non-Latinized binomial species names replaced all paramyxovirus and pneumovirus species names, thereby accomplishing application of binomial species names throughout the entire order. This article presents the updated taxonomy of the order Mononegavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV)

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570