Estimating the attributable fraction of mortality from acute respiratory distress syndrome to inform enrichment in future randomised clinical trials.

BACKGROUND: Efficiency of randomised clinical trials of acute respiratory distress syndrome (ARDS) depends on the fraction of deaths attributable to ARDS (AFARDS) to which interventions are targeted. Estimates of AFARDS in subpopulations of ARDS could improve design of ARDS trials. METHODS: We performed a matched case-control study using the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE cohort. Primary outcome was intensive care unit mortality. We used nearest neighbour propensity score matching without replacement to match ARDS to non-ARDS populations. We derived two separate AFARDS estimates by matching patients with ARDS to patients with non-acute hypoxaemic respiratory failure (non-AHRF) and to patients with AHRF with unilateral infiltrates only (AHRF-UL). We also estimated AFARDS in subgroups based on severity of hypoxaemia, number of lung quadrants involved and hyperinflammatory versus hypoinflammatory phenotypes. Additionally, we derived AFAHRF estimates by matching patients with AHRF to non-AHRF controls, and AFAHRF-UL estimates by matching patients with AHRF-UL to non-AHRF controls. RESULTS: Estimated AFARDS was 20.9% (95% CI 10.5% to 31.4%) when compared with AHRF-UL controls and 38.0% (95% CI 34.4% to 41.6%) compared with non-AHRF controls. Within subgroups, estimates for AFARDS compared with AHRF-UL controls were highest in patients with severe hypoxaemia (41.1% (95% CI 25.2% to 57.1%)), in those with four quadrant involvement on chest radiography (28.9% (95% CI 13.4% to 44.3%)) and in the hyperinflammatory subphenotype (26.8% (95% CI 6.9% to 46.7%)). Estimated AFAHRF was 33.8% (95% CI 30.5% to 37.1%) compared with non-AHRF controls. Estimated AFAHRF-UL was 21.3% (95% CI 312.8% to 29.7%) compared with non-AHRF controls. CONCLUSIONS: Overall AFARDS mean values were between 20.9% and 38.0%, with higher AFARDS seen with severe hypoxaemia, four quadrant involvement on chest radiography and hyperinflammatory ARDS.

A critical care outreach team under strain - Evaluation of the service provided to patients with haematological malignancy during the Covid-19 pandemic.

PURPOSE: Critical Care Outreach Teams (CCOTs) have been associated with improved outcomes in patients with haematological malignancy (HM). This study aims to describe CCOT activation by patients with HM before and during the Covid-19 pandemic, assess amny association with worse outcomes, and examine the psychological impact on the CCOT. MATERIALS AND METHODS: A retrospective, mixed-methods analysis was performed in HM patients reviewed by the CCOT over a two-year period, 01 July 2019 to 31 May 2021. RESULTS: The CCOT increased in size during the surge period and reviewed 238 HM patients, less than in the pre- and post-surge periods. ICU admission in the baseline, surge and the non-surge periods were 41.7%, 10.4% and 47.9% respectively. ICU mortality was 22.5%, 0% and 21.7% for the same times. Time to review was significantly decreased (p = 0.012). Semi-structured interviews revealed four themes of psychological distress: 1) time-critical work; 2) non-evidence based therapies; 3) feelings of guilt; 4) increased decision-making responsibility. CONCLUSIONS: Despite the increase in total hospital referrals, the number of patients with HM that were reviewed during the surge periods decreased, as did their ICU admission rate and mortality. The quality of care provided was not impaired, as reflected by the number of patients receiving bedside reviews and the shorter-than-pre-pandemic response time.

The Impact of Sample Size Misestimations on the Interpretation of ARDS Trials: Systematic Review and Meta-analysis.

BACKGROUND: Indeterminate randomized controlled trials (RCTs) in ARDS may arise from sample size misspecification, leading to abandonment of efficacious therapies. RESEARCH QUESTIONS: If evidence exists for sample size misspecification in ARDS RCTs, has this led to rejection of potentially beneficial therapies? Does evidence exist for prognostic enrichment in RCTs using mortality as a primary outcome? STUDY DESIGN AND METHODS: We identified 150 ARDS RCTs commencing recruitment after the 1994 American European Consensus Conference ARDS definition and published before October 31, 2020. We examined predicted-observed sample size, predicted-observed control event rate (CER), predicted-observed average treatment effect (ATE), and the relationship between observed CER and observed ATE for RCTs with mortality and nonmortality primary outcome measures. To quantify the strength of evidence, we used Bayesian-averaged meta-analysis, trial sequential analysis, and Bayes factors. RESULTS: Only 84 of 150 RCTs (56.0%) reported sample size estimations. In RCTs with mortality as the primary outcome, CER was overestimated in 16 of 28 RCTs (57.1%). To achieve predicted ATE, interventions needed to prevent 40.8% of all deaths, compared with the original prediction of 29.3%. Absolute reduction in mortality ≥ 10% was observed in 5 of 28 RCTs (17.9%) but was predicted in 21 of 28 RCTs (75.0%). For RCTs with mortality as the primary outcome, no association was found between observed CER and observed ATE (pooled OR: ß = -0.04; 95% credible interval, -0.18 to 0.09). We identified three interventions that are not currently standard of care with a Bayesian-averaged effect size of > 0.20 and moderate strength of existing evidence: corticosteroids, airway pressure release ventilation, and noninvasive ventilation. INTERPRETATION: Reporting of sample size estimations was inconsistent in ARDS RCTs, and misspecification of CER and ATE was common. Prognostic enrichment strategies in ARDS RCTs based on all-cause mortality are unlikely to be successful. Bayesian methods can be used to prioritize interventions for future effectiveness RCTs.

COVID-19-related acute kidney injury; incidence, risk factors and outcomes in a large UK cohort.

BACKGROUND: Acute kidney injury (AKI) is common among patients hospitalised with COVID-19 and associated with worse prognosis. The aim of this study was to investigate the epidemiology, risk factors and outcomes of AKI in patients with COVID-19 in a large UK tertiary centre. METHODS: We analysed data of consecutive adults admitted with a laboratory-confirmed diagnosis of COVID-19 across two sites of a hospital in London, UK, from 1st January to 13th May 2020. RESULTS: Of the 1248 inpatients included, 487 (39%) experienced AKI (51% stage 1, 13% stage 2, and 36% stage 3). The weekly AKI incidence rate gradually increased to peak at week 5 (3.12 cases/100 patient-days), before reducing to its nadir (0.83 cases/100 patient-days) at the end the study period (week 10). Among AKI survivors, 84.0% had recovered renal function to pre-admission levels before discharge and none required on-going renal replacement therapy (RRT). Pre-existing renal impairment [odds ratio (OR) 3.05, 95%CI 2.24-4,18; p <  0.0001], and inpatient diuretic use (OR 1.79, 95%CI 1.27-2.53; p <  0.005) were independently associated with a higher risk for AKI. AKI was a strong predictor of 30-day mortality with an increasing risk across AKI stages [adjusted hazard ratio (HR) 1.59 (95%CI 1.19-2.13) for stage 1; p < 0.005, 2.71(95%CI 1.82-4.05); p < 0.001for stage 2 and 2.99 (95%CI 2.17-4.11); p < 0.001for stage 3]. One third of AKI3 survivors (30.7%), had newly established renal impairment at 3 to 6 months. CONCLUSIONS: This large UK cohort demonstrated a high AKI incidence and was associated with increased mortality even at stage 1. Inpatient diuretic use was linked to a higher AKI risk. One third of survivors with AKI3 exhibited newly established renal impairment already at 3-6 months.

Impact of differences in acute respiratory distress syndrome randomised controlled trial inclusion and exclusion criteria: systematic review and meta-analysis.

BACKGROUND: Control-arm mortality varies between acute respiratory distress syndrome (ARDS) RCTs. METHODS: We systematically reviewed ARDS RCTs that commenced recruitment after publication of the American-European Consensus (AECC) definition (MEDLINE, Embase, and Cochrane central register of controlled trials; January 1994 to October 2020). We assessed concordance of RCT inclusion criteria to ARDS consensus definitions and whether exclusion criteria are strongly or poorly justified. We estimated the proportion of between-trial difference in control-arm 28-day mortality explained by the inclusion criteria and RCT design characteristics using meta-regression. RESULTS: A literature search identified 43 709 records. One hundred and fifty ARDS RCTs were included; 146/150 (97.3%) RCTs defined ARDS inclusion criteria using AECC/Berlin definitions. Deviations from consensus definitions, primarily aimed at improving ARDS diagnostic certainty, frequently related to duration of hypoxaemia (117/146; 80.1%). Exclusion criteria could be grouped by rationale for selection into strongly or poorly justified criteria. Common poorly justified exclusions included pregnancy related, age, and comorbidities (infectious/immunosuppression, hepatic, renal, and human immunodeficiency virus/acquired immunodeficiency syndrome). Control-arm 28-day mortality varied between ARDS RCTs (mean: 29.8% [95% confidence interval: 27.0-32.7%; I2=88.8%; τ2=0.02; P<0.01]), and differed significantly between RCTs with different Pao2:FiO2 ratio inclusion thresholds (26.6-39.9 kPa vs <26.6 kPa; P<0.01). In a meta-regression model, inclusion criteria and RCT design characteristics accounted for 30.6% of between-trial difference (P<0.01). CONCLUSIONS: In most ARDS RCTs, consensus definitions are modified to use as inclusion criteria. Between-RCT mortality differences are mostly explained by the Pao2:FiO2 ratio threshold within the consensus definitions. An exclusion criteria framework can be applied when designing and reporting exclusion criteria in future ARDS RCTs.

Provision of acute renal replacement therapy, using three separate modalities, in critically ill patients during the COVID-19 pandemic. An after action review from a UK tertiary critical care centre.

PURPOSE: The aim of this study is to describe the incidence of Acute Kidney Injury (AKI) amongst patients admitted to the Intensive Care Unit (ICU) with COVID-19. In addition we aim to detail the range of Renal Replacement Therapy (RRT) modalities offered to these patients (including peritoneal dialysis - PD - and intermittent haemodialysis - IHD) in order to meet demand during pandemic conditions. MATERIALS AND METHODS: Single-centre retrospective case note review of adult patients with confirmed COVID-19 admitted to ICU. RESULTS: Amongst 136 patients without a prior history of End Stage Kidney Disease (ESKD), 108 (79%) developed AKI and 63% of admitted patients received RRT. Due to resource limitations the range of RRT options were expanded from solely Continuous Veno-Venous HaemoDiaFiltration (CVVHDF - our usual standard of care) to include PD (in 35 patients) and IHD (in 15 patients). During the study period the proportion of RRT provided within ICU as CVVHDF fell from 100% to a nadir of 39%. There were no significant complications of either PD or IHD. CONCLUSIONS: During periods of resource limitations PD and IHD can safely be used to reduce dependence on CVVHDF in select patients with AKI secondary to COVID-19.

An image dataset of cleared, x-rayed, and fossil leaves vetted to plant family for human and machine learning.

Leaves are the most abundant and visible plant organ, both in the modern world and the fossil record. Identifying foliage to the correct plant family based on leaf architecture is a fundamental botanical skill that is also critical for isolated fossil leaves, which often, especially in the Cenozoic, represent extinct genera and species from extant families. Resources focused on leaf identification are remarkably scarce; however, the situation has improved due to the recent proliferation of digitized herbarium material, live-plant identification applications, and online collections of cleared and fossil leaf images. Nevertheless, the need remains for a specialized image dataset for comparative leaf architecture. We address this gap by assembling an open-access database of 30,252 images of vouchered leaf specimens vetted to family level, primarily of angiosperms, including 26,176 images of cleared and x-rayed leaves representing 354 families and 4,076 of fossil leaves from 48 families. The images maintain original resolution, have user-friendly filenames, and are vetted using APG and modern paleobotanical standards. The cleared and x-rayed leaves include the Jack A. Wolfe and Leo J. Hickey contributions to the National Cleared Leaf Collection and a collection of high-resolution scanned x-ray negatives, housed in the Division of Paleobotany, Department of Paleobiology, Smithsonian National Museum of Natural History, Washington D.C.; and the Daniel I. Axelrod Cleared Leaf Collection, housed at the University of California Museum of Paleontology, Berkeley. The fossil images include a sampling of Late Cretaceous to Eocene paleobotanical sites from the Western Hemisphere held at numerous institutions, especially from Florissant Fossil Beds National Monument (late Eocene, Colorado), as well as several other localities from the Late Cretaceous to Eocene of the Western USA and the early Paleogene of Colombia and southern Argentina. The dataset facilitates new research and education opportunities in paleobotany, comparative leaf architecture, systematics, and machine learning.

Rate and risk factors for rehospitalisation in sepsis survivors: systematic review and meta-analysis.

PURPOSE: Sepsis survivors have a higher risk of rehospitalisation and of long-term mortality. We assessed the rate, diagnosis, and independent predictors for rehospitalisation in adult sepsis survivors. METHODS: We searched for non-randomized studies and randomized clinical trials in MEDLINE, Cochrane Library, Web of Science, and EMBASE (OVID interface, 1992-October 2019). The search strategy used controlled vocabulary terms and text words for sepsis and hospital readmission, limited to humans, and English language. Two authors independently selected studies and extracted data using predefined criteria and data extraction forms. RESULTS: The literature search identified 12,544 records. Among 56 studies (36 full and 20 conference abstracts) that met our inclusion criteria, all were non-randomised studies. Studies most often report 30-day rehospitalisation rate (mean 21.4%, 95% confidence interval [CI] 17.6-25.4%; N = 36 studies reporting 6,729,617 patients). The mean (95%CI) rehospitalisation rates increased from 9.3% (8.3-10.3%) by 7 days to 39.0% (22.0-59.4%) by 365 days. Infection was the most common rehospitalisation diagnosis. Risk factors that increased the rehospitalisation risk in sepsis survivors were generic characteristics such as older age, male, comorbidities, non-elective admissions, hospitalisation prior to index sepsis admission, and sepsis characteristics such as infection and illness severity, with hospital characteristics showing inconsistent associations. The overall certainty of evidence was moderate for rehospitalisation rates and low for risk factors. CONCLUSIONS: Rehospitalisation events are common in sepsis survivors, with one in five rehospitalisation events occurring within 30 days of hospital discharge following an index sepsis admission. The generic and sepsis-specific characteristics at index sepsis admission are commonly reported risk factors for rehospitalisation. REGISTRATION: PROSPERO CRD 42016039257, registered on 14-06-2016.