Characterising biological mechanisms underlying ethnicity-associated outcomes in COVID-19 through biomarker trajectories: a multicentre registry analysis

Background Differences in routinely collected biomarkers between ethnic groups could reflect dysregulated host responses to disease and to treatments, and be associated with excess morbidity and mortality in COVID-19. Methods A multicentre registry analysis from patients aged ≥16 yr with SARS-CoV-2 infection and emergency admission to Barts Health NHS Trust hospitals during 01/01/2020-13/05/2020 (wave 1) and 01/09/2020-17/02/2021 (wave 2) was subjected to unsupervised longitudinal clustering techniques to identify distinct phenotypic patient clusters based on trajectories of routine blood results over the first 15 days of hospital admission. Distribution of trajectory clusters across ethnic categories was determined, and associations between ethnicity, trajectory clusters, and 30-day survival were assessed using multivariable Cox proportional hazards modelling. Secondary outcomes were intensive care unit admission, survival to hospital discharge, and long-term survival to 640 days. Results We included 3237 patients with hospital length of stay ≥7 days. In patients who died, there was greater representation of Black and Asian ethnicity in trajectory clusters for C-reactive protein (CRP) and urea-to-creatinine ratio (UCR) associated with increased risk of death. Inclusion of trajectory clusters in survival analyses attenuated or abrogated the higher risk of death in Asian and Black patients. Inclusion of CRP went from hazard ratio (HR) 1.36 [0.95-1.94] to HR 0.97 [0.59-1.59] (wave 1), and from HR 1.42 [1.15-1.75]) to HR 1.04 [0.78-1.39] (wave 2) in Asian patients. Trajectory clusters associated with reduced 30-day survival were similarly associated with worse secondary outcomes. Conclusions Clinical biochemical monitoring of COVID-19 and progression and treatment response in SARS-CoV-2 infection should be interpreted in the context of ethnic background.

Novel nutritional strategies to prevent muscle wasting.

PURPOSE OF REVIEW: Muscle wasting in critical illness has proven to be refractory to physical rehabilitation, and to conventional nutritional strategies. This presents one of the central challenges to critical care medicine in the 21st century. Novel strategies are needed that facilitate nutritional interventions, identify patients that will benefit and have measurable, relevant benefits. RECENT FINDINGS: Drug repurposing was demonstrated to be a powerful technique in the coronavirus disease 2019 pandemic, and may have similar applications to address the metabolic derangements of critical illness. Newer biological signatures may aid the application of these techniques and the association between changes in urea:creatinine ratio and the development of skeletal muscle wasting is increasing. A core outcome set for nutrition interventions in critical illness, supported by multiple international societies, was published earlier this year should be adopted by future nutrition trials aiming to attenuate muscle wasting. SUMMARY: The evidence base for the lack of efficacy for conventional nutritional strategies in preventing muscle wasting in critically ill patients continues to grow. Novel strategies such as metabolic modulators, patient level biological signatures of nutritional response and standardized outcome for measurements of efficacy will be central to future research and clinical care of the critically ill patient.

Physical and psychological impairment in survivors of acute respiratory distress syndrome: a systematic review and meta-analysis.

BACKGROUND: Survivors of acute respiratory distress syndrome (ARDS) are at risk of long-term comorbidities. This systematic review and meta-analysis evaluated health-related quality of life (HRQoL), and physical and psychological impairments in ARDS survivors from 3 months to 5 yr follow-up after ICU discharge. METHODS: Systematic search of PubMed, AMED, BNI, and CINAHL databases from January 2000 to date. The primary outcome was HRQoL. Secondary outcomes included physical, pulmonary, and cognitive function, mental health, and return to work. A secondary analysis compared classical ARDS with severe acute respiratory syndrome coronavirus disease-2 (SARS-CoV-2) ARDS. RESULTS: Forty-eight papers met inclusion criteria including 11 693 patients; of those 85% (n=9992) had classical ARDS and 14% (n=1632) had SARS-CoV-2 ARDS. The 36-Item Short Form Health Survey (SF-36) physical component summary score mean (95% confidence interval [CI]) was 46 (41-50) at 3 months, 39 (36-41) at 6 months, and 40 (38-43) at 12 months. The SF-36 mental component summary mean score was 53 (48-57) at 3 months, 45 (40-50) at 6 months, and 44 (42-47) at 12 months. SF-36 values were lower than those found in the normal population up to 5 yr. The predictive distance walked in 6 min was 57% (45-69), 63% (56-69), and 66% (62-70) at 3, 6, and 12 months, respectively. Classical ARDS and SARS-CoV-2 ARDS showed no difference in HRQoL and physical function; however, patients with classical ARDS had higher incidence of anxiety and depression (P<0.001). CONCLUSION: ARDS survivors can experience reduced HRQoL and physical and mental health impairment. These symptoms might not recover completely up to 5 yr after ICU discharge. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42021296506.

Nutritional priorities in patients with severe COVID-19.

PURPOSE OF REVIEW: The COVID-19 pandemic has altered the profile of critical care services internationally, as professionals around the globe have struggled to rise to the unprecedented challenge faced, both in terms of individual patient management and the sheer volume of patients that require treatment and management in intensive care. This review article sets out key priorities in nutritional interventions during the patient journey, both in the acute and recovery phases. RECENT FINDINGS: The current review covers the care of the acutely unwell patient, and the evidence base for nutritional interventions in the COVID-19 population. One of the biggest differences in caring for critically ill patients with acute respiratory failure from COVID-19 is often the time prior to intubation. This represents specific nutritional challenges, as does nursing patients in the prone position or in the setting of limited resources. This article goes on to discuss nutritional support for COVID-19 sufferers as they transition through hospital wards and into the community. SUMMARY: Nutritional support of patients with severe COVID-19 is essential. Given the longer duration of their critical illness, combined with hypermetabolism and energy expenditure, patients with COVID-19 are at increased risk for malnutrition during and after their hospital stay.

Case presentation and panel discussion: Critical illness.

Despite a mounting evidentiary base, controversies surrounding critical care nutrition support persist. Anchored by a case of a 60-year-old male with esophageal cancer who develops acute hypoxemic respiratory failure and septic shock, five panelists from the American Society of Parenteral and Enteral Nutrition (ASPEN) 2021 Pre-Conference discuss key clinical dilemmas in critical care nutrition, including hierarchy of evidence, bedside evaluation of malnutrition, optimal protein dose, use of fiber, and therapies targeting gut function and gut microbiota .

Prone positioning for non-intubated spontaneously breathing patients with acute hypoxaemic respiratory failure: a systematic review and meta-analysis.

BACKGROUND: Prone positioning in non-intubated spontaneously breathing patients is becoming widely applied in practice alongside noninvasive respiratory support. This systematic review and meta-analysis evaluates the effect, timing, and populations that might benefit from awake proning regarding oxygenation, mortality, and tracheal intubation compared with supine position in hypoxaemic acute respiratory failure. METHODS: We conducted a systematic literature search of PubMed/MEDLINE, Cochrane Library, Embase, CINAHL, and BMJ Best Practice until August 2021 (International Prospective Register of Systematic Reviews [PROSPERO] registration: CRD42021250322). Studies included comprise least-wise 20 adult patients with hypoxaemic respiratory failure secondary to acute respiratory distress syndrome or coronavirus disease (COVID-19). Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed, and study quality was assessed using the Newcastle-Ottawa Scale and the Cochrane risk-of-bias tool. RESULTS: Fourteen studies fulfilled the selection criteria and 2352 patients were included; of those patients, 99% (n=2332/2352) had COVID-19. Amongst 1041 (44%) patients who were placed in the prone position, 1021 were SARS-CoV-2 positive. The meta-analysis revealed significant improvement in the PaO2/FiO2 ratio (mean difference -23.10; 95% confidence interval [CI]: -34.80 to 11.39; P=0.0001; I2=26%) after prone positioning. In patients with COVID-19, lower mortality was found in the group placed in the prone position (150/771 prone vs 391/1457 supine; odds ratio [OR] 0.51; 95% CI: 0.32-0.80; P=0.003; I2=48%), but the tracheal intubation rate was unchanged (284/824 prone vs 616/1271 supine; OR 0.72; 95% CI: 0.43-1.22; P=0.220; I2=75%). Overall proning was tolerated for a median of 4 h (inter-quartile range: 2-16). CONCLUSIONS: Prone positioning can improve oxygenation amongst non-intubated patients with acute hypoxaemic respiratory failure when applied for at least 4 h over repeated daily episodes. Awake proning appears safe, but the effect on tracheal intubation rate and survival remains uncertain.

Acute kidney injury in COVID-19: multicentre prospective analysis of registry data.

BACKGROUND: Acute kidney injury (AKI) is a common and important complication of coronavirus disease 2019 (COVID-19). Further characterization is required to reduce both short- and long-term adverse outcomes. METHODS: We examined registry data including adults with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection admitted to five London Hospitals from 1 January to 14 May 2020. Prior end-stage kidney disease was excluded. Early AKI was defined by Kidney Disease: Improving Global Outcomes creatinine criteria within 7 days of admission. Independent associations of AKI and survival were examined in multivariable analysis. Results are given as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals. RESULTS: Among 1855 admissions, 455 patients (24.5%) developed early AKI: 200 (44.0%) Stage 1, 90 (19.8%) Stage 2 and 165 (36.3%) Stage 3 (74 receiving renal replacement therapy). The strongest risk factor for AKI was high C-reactive protein [OR 3.35 (2.53-4.47), P < 0.001]. Death within 30 days occurred in 242 (53.2%) with AKI compared with 255 (18.2%) without. In multivariable analysis, increasing severity of AKI was incrementally associated with higher mortality: Stage 3 [HR 3.93 (3.04-5.08), P < 0.001]. In 333 patients with AKI surviving to Day 7, 134 (40.2%) recovered, 47 (14.1%) recovered then relapsed and 152 (45.6%) had persistent AKI at Day 7; an additional 105 (8.2%) patients developed AKI after Day 7. Persistent AKI was strongly associated with adjusted mortality at 90 days [OR 7.57 (4.50-12.89), P < 0.001]. CONCLUSIONS: AKI affected one in four hospital in-patients with COVID-19 and significantly increased mortality. Timing and recovery of COVID-19 AKI is a key determinant of outcome.

Mixed methods evaluation of the impact of the COVID-19 ICU remote-learning rehabilitation course for frontline health professionals during the COVID-19 pandemic in the UK.

Background: Optimising outcomes for critically ill patients with COVID-19 patients requires early interdisciplinary rehabilitation. As admission numbers soared through the pandemic, the redeployed workforce needed rapid, effective training to deliver these rehabilitation interventions. Methods: The COVID-19 ICU Remote-Learning Rehab Course (CIRLC-rehab) is a one-day interdisciplinary course developed after the success of CIRLC-acute. The aim of CIRLC-rehab was to rapidly train healthcare professionals to deliver physical, nutritional and psychological rehabilitation strategies in the ICU/acute setting. The course used blended learning with interactive tutorials delivered by shielding critical care professionals. CIRLC-rehab was evaluated through a mixed-methods approach, including questionnaires, and follow-up semi-structured interviews to evaluate perceived impact on clinical practice. Quantitative data are reported as n (%) and means (SD). Inductive descriptive thematic analysis with methodological triangulation was used to analyse the qualitative data from the questionnaires and interviews. Results: 805 candidates completed CIRLC-rehab. 627 (78.8%) completed the post-course questionnaire. 95% (n = 596) found CIRLC-rehab extremely or very useful and 96.0% (n = 602) said they were very likely to recommend the course to colleagues. Overall confidence rose from 2.78/5 to 4.14/5. The course promoted holistic and humanised care, facilitated informal networks, promoted interdisciplinary working and equipped the candidates with practical rehabilitation strategies that they implemented into clinical practice. Conclusion: This pragmatic solution to educating redeployed staff during a pandemic increased candidates' confidence in the rehabilitation of critically ill patients. There was also evidence of modifications to clinical care utilising learning from the course that subjectively facilitated holistic and humanised rehabilitation, combined with the importance of recognising the humanity, of those working in ICU settings themselves. Whilst these data are self-reported, we believe that this work demonstrates the real-term benefits of remote, scalable and rapid educational delivery.

Natural history, trajectory, and management of mechanically ventilated COVID-19 patients in the United Kingdom.

PURPOSE: The trajectory of mechanically ventilated patients with coronavirus disease 2019 (COVID-19) is essential for clinical decisions, yet the focus so far has been on admission characteristics without consideration of the dynamic course of the disease in the context of applied therapeutic interventions. METHODS: We included adult patients undergoing invasive mechanical ventilation (IMV) within 48 h of intensive care unit (ICU) admission with complete clinical data until ICU death or discharge. We examined the importance of factors associated with disease progression over the first week, implementation and responsiveness to interventions used in acute respiratory distress syndrome (ARDS), and ICU outcome. We used machine learning (ML) and Explainable Artificial Intelligence (XAI) methods to characterise the evolution of clinical parameters and our ICU data visualisation tool is available as a web-based widget ( https://www.CovidUK.ICU ). RESULTS: Data for 633 adults with COVID-19 who underwent IMV between 01 March 2020 and 31 August 2020 were analysed. Overall mortality was 43.3% and highest with non-resolution of hypoxaemia [60.4% vs17.6%; P < 0.001; median PaO2/FiO2 on the day of death was 12.3(8.9-18.4) kPa] and non-response to proning (69.5% vs.31.1%; P < 0.001). Two ML models using weeklong data demonstrated an increased predictive accuracy for mortality compared to admission data (74.5% and 76.3% vs 60%, respectively). XAI models highlighted the increasing importance, over the first week, of PaO2/FiO2 in predicting mortality. Prone positioning improved oxygenation only in 45% of patients. A higher peak pressure (OR 1.42[1.06-1.91]; P < 0.05), raised respiratory component (OR 1.71[ 1.17-2.5]; P < 0.01) and cardiovascular component (OR 1.36 [1.04-1.75]; P < 0.05) of the sequential organ failure assessment (SOFA) score and raised lactate (OR 1.33 [0.99-1.79]; P = 0.057) immediately prior to application of prone positioning were associated with lack of oxygenation response. Prone positioning was not applied to 76% of patients with moderate hypoxemia and 45% of those with severe hypoxemia and patients who died without receiving proning interventions had more missed opportunities for prone intervention [7 (3-15.5) versus 2 (0-6); P < 0.001]. Despite the severity of gas exchange deficit, most patients received lung-protective ventilation with tidal volumes less than 8 mL/kg and plateau pressures less than 30cmH2O. This was despite systematic errors in measurement of height and derived ideal body weight. CONCLUSIONS: Refractory hypoxaemia remains a major association with mortality, yet evidence based ARDS interventions, in particular prone positioning, were not implemented and had delayed application with an associated reduced responsiveness. Real-time service evaluation techniques offer opportunities to assess the delivery of care and improve protocolised implementation of evidence-based ARDS interventions, which might be associated with improvements in survival.

The post-ICU presentation screen (PICUPS) and rehabilitation prescription (RP) for intensive care survivors part I: Development and preliminary clinimetric evaluation.

Background: Patients who have had prolonged stays in intensive care have ongoing rehabilitation needs. This is especially true of COVID-19 ICU patients, who can suffer diverse long-term ill effects. Currently there is no systematic data collection to guide the needs for therapy input for either of these groups nor to inform planning and development of rehabilitation services. These issues could be resolved in part by the systematic use of a clinical tool to support decision-making as patients progress from the Intensive Care Unit (ICU), through acute hospital care and onwards into rehabilitation. We describe (i) the development of such a tool (the Post-ICU Presentation Screen (PICUPS)) and (ii) the subsequent preparation of a person-centred Rehabilitation Prescription (RP) to travel with the patient as they continue down the care pathway. Methods: PICUPS development was led by a core group of experienced clinicians representing the various disciplines involved in post-ICU rehabilitation. Key constructs and item-level descriptors were identified by group consensus. Piloting was performed as part of wider clinical engagement in 26 acute hospitals across England. Development and validation of such a tool requires clinimetric analysis, and this was based on classical test theory. Teams also provided feedback about the feasibility and utility of the tool. Results: Initial PICUPS design yielded a 24-item tool. In piloting, a total of 552 records were collated from 314 patients, of which 121 (38.5%) had COVID-19. No obvious floor or ceiling effects were apparent. Exploratory factor analysis provided evidence of uni-dimensionality with strong loading on the first principal component accounting for 51% of the variance and Cronbach's alpha for the full-scale score 0.95 - although a 3-factor solution accounted for a further 21%. The PICUPS was responsive to change both at full scale- and item-level. In general, positive responses were seen regarding the tool's ability to describe the patients during their clinical course, engage and flag the relevant professionals needed, and to inform what should be included in an RP. Conclusions: The PICUPS tool has robust scaling properties as a clinical measure and is potentially useful as a tool for identifying rehabilitation needs as patients step down from ICU and acute hospital care.

The Post-ICU presentation screen (PICUPS) and rehabilitation prescription (RP) for intensive care survivors part II: Clinical engagement and future directions for the national Post-Intensive care Rehabilitation Collaborative.

Background: Many Intensive Care Unit (ICU) survivors suffer from a multi- system disability, termed the post-intensive care syndrome. There is no current national coordination of either rehabilitation pathways or related data collection for them. In the last year, the need for tools to systematically identify the multidisciplinary rehabilitation needs of severely affected COVID-19 survivors has become clear. Such tools offer the opportunity to improve rehabilitation for all critical illness survivors through provision of a personalised Rehabilitation Prescription (RP). The initial development and secondary refinement of such an assessment and data tools is described in the linked paper. We report here the clinical and workforce data that was generated as a result. Methods: Prospective service evaluation of 26 acute hospitals in England using the Post-ICU Presentation Screen (PICUPS) tool and the RP. The PICUPS tool comprised items in domains of a) Medical and essential care, b) Breathing and nutrition; c) Physical movement and d) Communication, cognition and behaviour. Results: No difference was seen in total PICUPS scores between patients with or without COVID-19 (77 (IQR 60-92) vs. 84 (IQR 68-97); Mann-Whitney z = -1.46, p = 0.144. A network analysis demonstrated that requirements for physiotherapy, occupational therapy, speech and language therapy, dietetics and clinical psychology were closely related and unaffected by COVID-19 infection status. A greater proportion of COVID-19 patients were referred for inpatient rehabilitation (13% vs. 7%) and community-based rehabilitation (36% vs.15%). The RP informed by the PICUPS tool generally specified a greater need for multi-professional input when compared to rehabilitation plans instituted. Conclusions: The PICUPS tool is feasible to implement as a screening mechanism for post-intensive care syndrome. No differences are seen in the rehabilitation needs of patients with and without COVID-19 infection. The RP could be the vehicle that drives the professional interventions across the transitions from acute to community care. No single discipline dominates the rehabilitation requirements of these patients, reinforcing the need for a personalised RP for critical illness survivors.

Ethnicity and outcomes in patients hospitalised with COVID-19 infection in East London: an observational cohort study.

OBJECTIVE: To describe outcomes within different ethnic groups of a cohort of hospitalised patients with confirmed COVID-19 infection. To quantify and describe the impact of a number of prognostic factors, including frailty and inflammatory markers. SETTING: Five acute National Health Service Hospitals in east London. DESIGN: Prospectively defined observational study using registry data. PARTICIPANTS: 1737 patients aged 16 years or over admitted to hospital with confirmed COVID-19 infection between 1 January and 13 May 2020. MAIN OUTCOME MEASURES: The primary outcome was 30-day mortality from time of first hospital admission with COVID-19 diagnosis during or prior to admission. Secondary outcomes were 90-day mortality, intensive care unit (ICU) admission, ICU and hospital length of stay and type and duration of organ support. Multivariable survival analyses were adjusted for potential confounders. RESULTS: 1737 were included in our analysis of whom 511 had died by day 30 (29%). 538 (31%) were from Asian, 340 (20%) black and 707 (40%) white backgrounds. Compared with white patients, those from minority ethnic backgrounds were younger, with differing comorbidity profiles and less frailty. Asian and black patients were more likely to be admitted to ICU and to receive invasive ventilation (OR 1.54, (95% CI 1.06 to 2.23); p=0.023 and OR 1.80 (95% CI 1.20 to 2.71); p=0.005, respectively). After adjustment for age and sex, patients from Asian (HR 1.49 (95% CI 1.19 to 1.86); p<0.001) and black (HR 1.30 (95% CI 1.02 to 1.65); p=0.036) backgrounds were more likely to die. These findings persisted across a range of risk factor-adjusted analyses accounting for major comorbidities, obesity, smoking, frailty and ABO blood group. CONCLUSIONS: Patients from Asian and black backgrounds had higher mortality from COVID-19 infection despite controlling for all previously identified confounders and frailty. Higher rates of invasive ventilation indicate greater acute disease severity. Our analyses suggest that patients of Asian and black backgrounds suffered disproportionate rates of premature death from COVID-19.