Quality of life after acute kidney injury.

PURPOSE OF REVIEW: Deciphering the effect of acute kidney injury (AKI) during critical illness on long-term quality of life versus the impact of conditions that brought on critical illness is difficult. RECENT FINDINGS: Reports on patient-centred outcomes such as health-related quality of life (HRQOL) have provided insight into the long-lasting impact of critical illness complicated by AKI. However, these data stem from observational studies and randomized controlled trials, which have been heterogeneous in their patient population, timing, instruments used for assessment and reporting. Recent studies have corroborated these findings including lack of effect of renal replacement therapy compared to severe AKI on outcomes and worse physical compared to cognitive dysfunction. SUMMARY: In adults, more deficits in physical than mental health domains are found in survivors of AKI in critical care, whereas memory deficits and learning impairments have been noted in children. Further study is needed to understand and develop interventions that preserve or enhance the quality of life for individual patients who survive AKI following critical illness, across all ages.

Awake prone positioning in acute hypoxaemic respiratory failure.

Awake prone positioning (APP) of patients with acute hypoxaemic respiratory failure gained considerable attention during the early phases of the coronavirus disease 2019 (COVID-19) pandemic. Prior to the pandemic, reports of APP were limited to case series in patients with influenza and in immunocompromised patients, with encouraging results in terms of tolerance and oxygenation improvement. Prone positioning of awake patients with acute hypoxaemic respiratory failure appears to result in many of the same physiological changes improving oxygenation seen in invasively ventilated patients with moderate-severe acute respiratory distress syndrome. A number of randomised controlled studies published on patients with varying severity of COVID-19 have reported apparently contrasting outcomes. However, there is consistent evidence that more hypoxaemic patients requiring advanced respiratory support, who are managed in higher care environments and who can be prone for several hours, benefit most from APP use. We review the physiological basis by which prone positioning results in changes in lung mechanics and gas exchange and summarise the latest evidence base for APP primarily in COVID-19. We examine the key factors that influence the success of APP, the optimal target populations for APP and the key unknowns that will shape future research.

A new multiplex SARS-CoV-2 antigen microarray showed correlation of IgG, IgA, and IgM antibodies from patients with COVID-19 disease severity and maintenance of relative IgA and IgM antigen binding over time.

Zoonotic spillover of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to humans in December 2019 caused the coronavirus disease 2019 (COVID-19) pandemic. Serological monitoring is critical for detailed understanding of individual immune responses to infection and protection to guide clinical therapeutic and vaccine strategies. We developed a high throughput multiplexed SARS-CoV-2 antigen microarray incorporating spike (S) and nucleocapsid protein (NP) and fragments expressed in various hosts which allowed simultaneous assessment of serum IgG, IgA, and IgM responses. Antigen glycosylation influenced antibody binding, with S glycosylation generally increasing and NP glycosylation decreasing binding. Purified antibody isotypes demonstrated a binding pattern and intensity different from the same isotype in whole serum, probably due to competition from the other isotypes present. Using purified antibody isotypes from naïve Irish COVID-19 patients, we correlated antibody isotype binding to different panels of antigens with disease severity, with binding to the S region S1 expressed in insect cells (S1 Sf21) significant for IgG, IgA, and IgM. Assessing longitudinal response for constant concentrations of purified antibody isotypes for a patient subset demonstrated that the relative proportion of antigen-specific IgGs decreased over time for severe disease, but the relative proportion of antigen-specific IgA binding remained at the same magnitude at 5 and 9 months post-first symptom onset. Further, the relative proportion of IgM binding decreased for S antigens but remained the same for NP antigens. This may support antigen-specific serum IgA and IgM playing a role in maintaining longer-term protection, important for developing and assessing vaccine strategies. Overall, these data demonstrate the multiplexed platform as a sensitive and useful platform for expanded humoral immunity studies, allowing detailed elucidation of antibody isotypes response against multiple antigens. This approach will be useful for monoclonal antibody therapeutic studies and screening of donor polyclonal antibodies for patient infusions.

Epidemiology and outcomes of early-onset AKI in COVID-19-related ARDS in comparison with non-COVID-19-related ARDS: insights from two prospective global cohort studies.

BACKGROUND: Acute kidney injury (AKI) is a frequent and severe complication of both COVID-19-related acute respiratory distress syndrome (ARDS) and non-COVID-19-related ARDS. The COVID-19 Critical Care Consortium (CCCC) has generated a global data set on the demographics, management and outcomes of critically ill COVID-19 patients. The LUNG-SAFE study was an international prospective cohort study of patients with severe respiratory failure, including ARDS, which pre-dated the pandemic. METHODS: The incidence, demographic profile, management and outcomes of early AKI in patients undergoing invasive mechanical ventilation for COVID-19-related ARDS were described and compared with AKI in a non-COVID-19-related ARDS cohort. RESULTS: Of 18,964 patients in the CCCC data set, 1699 patients with COVID-19-related ARDS required invasive ventilation and had relevant outcome data. Of these, 110 (6.5%) had stage 1, 94 (5.5%) had stage 2, 151 (8.9%) had stage 3 AKI, while 1214 (79.1%) had no AKI within 48 h of initiating invasive mechanical ventilation. Patients developing AKI were older and more likely to have hypertension or chronic cardiac disease. There were geo-economic differences in the incidence of AKI, with lower incidence of stage 3 AKI in European high-income countries and a higher incidence in patients from middle-income countries. Both 28-day and 90-day mortality risk was increased for patients with stage 2 (HR 2.00, p < 0.001) and stage 3 AKI (HR 1.95, p < 0.001). Compared to non-COVID-19 ARDS, the incidence of shock was reduced with lower cardiovascular SOFA score across all patient groups, while hospital mortality was worse in all groups [no AKI (30 vs 50%), Stage 1 (38 vs 58%), Stage 2 (56 vs 74%), and Stage 3 (52 vs 72%), p < 0.001]. The time profile of onset of AKI also differed, with 56% of all AKI occurring in the first 48 h in patients with COVID-19 ARDS compared to 89% in the non-COVID-19 ARDS population. CONCLUSION: AKI is a common and serious complication of COVID-19, with a high mortality rate, which differs by geo-economic location. Important differences exist in the profile of AKI in COVID-19 versus non-COVID-19 ARDS in terms of their haemodynamic profile, time of onset and clinical outcomes.

The CHARTER-Ireland trial: can nebulised heparin reduce acute lung injury in patients with SARS-CoV-2 requiring advanced respiratory support in Ireland: a study protocol and statistical analysis plan for a randomised control trial.

BACKGROUND: COVID-19 pneumonia is associated with the development of acute respiratory distress syndrome (ARDS) displaying some typical histological features. These include diffuse alveolar damage with extensive pulmonary coagulation activation. This results in fibrin deposition in the microvasculature, leading to the formation of hyaline membranes in the air sacs. Well-conducted clinical trials have found that nebulised heparin limits pulmonary fibrin deposition, attenuates progression of ARDS, hastens recovery and is safe in non-COVID ARDS. Unfractionated heparin also inactivates the SARS-CoV-2 virus and prevents entry into mammalian cells. Nebulisation of heparin may therefore limit fibrin-mediated lung injury and inhibit pulmonary infection by SARS-CoV-2. Based on these findings, we designed the CHARTER-Ireland Study, a phase 1b/2a randomised controlled study of nebulised heparin in patients requiring advanced respiratory support for COVID-19 pneumonia. METHODS: This is a multi-centre, phase 1b/IIa, randomised, parallel-group, open-label study. The study will randomise 40 SARs-CoV-2-positive patients receiving advanced respiratory support in a critical care area. Randomisation will be via 1:1 allocation to usual care plus nebulised unfractionated heparin 6 hourly to day 10 while receiving advanced respiratory support or usual care only. The study aims to evaluate whether unfractionated heparin will decrease the procoagulant response associated with ARDS up to day 10. The study will also assess safety and tolerability of nebulised heparin as defined by number of severe adverse events; oxygen index and respiratory oxygenation index of intubated and unintubated, respectively; ventilatory ratio; and plasma concentration of interleukin (IL)-1ß, IL6, IL-8, IL-10 and soluble tumour necrosis factor receptor 1, C-reactive protein, procalcitonin, ferritin, fibrinogen and lactate dehydrogenase as well as the ratios of IL-1ß/IL-10 and IL-6/IL-10. These parameters will be assessed on days 1, 3, 5 and 10; time to separation from advanced respiratory support, time to discharge from the intensive care unit and number tracheostomised to day 28; and survival to days 28 and 60 and to hospital discharge, censored at day 60. Some clinical outcome data from our study will be included in the international meta-trials, CHARTER and INHALE-HEP. DISCUSSION: This trial aims to provide evidence of potential therapeutic benefit while establishing safety of nebulised heparin in the management of ARDS associated with SARs-CoV-2 infection. TRIAL REGISTRATION: ClinicalTrials.gov NCT04511923 . Registered on 13 August 2020. Protocol version 8, 22/12/2021 Protocol identifier: NUIG-2020-003 EudraCT registration number: 2020-003349-12 9 October 2020.

Insights Regarding the Berlin Definition of ARDS from Prospective Observational Studies.

The definition of acute respiratory distress syndrome (ARDS), has evolved since it was first described in 1967 by Ashbaugh and Petty to the current "Berlin" definition of ARDS developed in 2012 by an expert panel, that provided clarification on the definition of "acute," and on the cardiac failure criteria. It expanded the definition to include patients receiving non-invasive ventilation, and removed the term "acute lung injury" and added a requirement of patients to be receiving a minimum 5 cmH2O expiratory pressure.Since 2012, a series of observational cohort studies have generated insights into the utility and robustness of this definition. This review will examine novel insights into the epidemiology of ARDS, failures in ARDS diagnosis, the role of lung imaging in ARDS, the novel ARDS cohort that is not invasively ventilated, lung compliance profiles in patients with ARDS, sex differences that exist in ARDS management and outcomes, the progression of ARDS following initial diagnosis, and the clinical profile and outcomes of confirmed versus resolved ARDS. Furthermore, we will discuss studies that challenge the utility of distinguishing ARDS from other causes of acute hypoxemic respiratory failure (AHRF) and identify issues that may need to be addressed in a revised definition.

Presence of comorbidities alters management and worsens outcome of patients with acute respiratory distress syndrome: insights from the LUNG SAFE study.

BACKGROUND: The impact of underlying comorbidities on the clinical presentation, management and outcomes in patients with ARDS is poorly understood and deserves further investigation. OBJECTIVES: We examined these issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. METHODS: In this secondary analysis of the patient cohort enrolled in the LUNG SAFE study, our primary objective was to determine the frequency, and impact of comorbidities on the management and ICU survival of patients with ARDS. Secondary outcomes relating to comorbidities included their impact on ventilatory management, the development of organ failures, and on end-of-life care. RESULTS: Of 2813 patients in the study population, 1692 (60%) had 1 or more comorbidities, of whom 631 (22.4%) had chronic respiratory impairment, 290 (10.3%) had congestive heart failure, 286 (10.2%) had chronic renal failure, 112 (4%) had chronic liver failure, 584 (20.8%) had immune incompetence, and 613 (21.8%) had diabetes. Multiple comorbidities were frequently present, with 423 (25%) having 2 and 182 (11%) having at least 3 or more comorbidities. The use of invasive ventilation (1379 versus 998, 82 versus 89%), neuromuscular blockade (301 versus 249, 18 versus 22%), prone positioning (97 versus 104, 6 versus 9%) and ECMO (32 versus 46, 2 versus 4%) were each significantly reduced in patients with comorbidities as compared to patients with no comorbidity (1692 versus 1121, 60 versus 40%). ICU mortality increased from 27% (n = 303) in patients with no comorbidity to 39% (n = 661) in patients with any comorbidity. Congestive heart failure, chronic liver failure and immune incompetence were each independently associated with increased ICU mortality. Chronic liver failure and immune incompetence were independently associated with more decisions to limitation of life supporting measures. CONCLUSIONS: Most patients with ARDS have significant comorbidities, they receive less aggressive care, and have worse outcomes. Enhancing the care of these patients must be a priority for future clinical studies. Trial registration LUNG-SAFE is registered with ClinicalTrials.gov, number NCT02010073.

Unraveling Structural Rearrangements of the CFH Gene Cluster in Atypical Hemolytic Uremic Syndrome Patients Using Molecular Combing and Long-Fragment Targeted Sequencing.

Complement factor H (CFH) and its related proteins have an essential role in regulating the alternative pathway of the complement system. Mutations and structural variants (SVs) of the CFH gene cluster, consisting of CFH and its five related genes (CFHR1-5), have been reported in renal pathologies as well as in complex immune diseases like age-related macular degeneration and systemic lupus erythematosus. SV analysis of this cluster is challenging because of its high degree of sequence homology. Following first-line next-generation sequencing gene panel sequencing, we applied Genomic Vision's Molecular Combing Technology to detect and visualize SVs within the CFH gene cluster and resolve its structural haplotypes completely. This approach was tested in three patients with atypical hemolytic uremic syndrome and known SVs and 18 patients with atypical hemolytic uremic syndrome or complement factor 3 glomerulopathy with unknown CFH gene cluster haplotypes. Three SVs, a CFH/CFHR1 hybrid gene in two patients and a rare heterozygous CFHR4/CFHR1 deletion in trans with the common CFHR3/CFHR1 deletion in a third patient, were newly identified. For the latter, the breakpoints were determined using a targeted enrichment approach for long DNA fragments (Samplix Xdrop) in combination with Oxford Nanopore sequencing. Molecular combing in addition to next-generation sequencing was able to improve the molecular genetic yield in this pilot study. This (cost-)effective approach warrants validation in larger cohorts with CFH/CFHR-associated disease.

Factors for success of awake prone positioning in patients with COVID-19-induced acute hypoxemic respiratory failure: analysis of a randomized controlled trial.

BACKGROUND: Awake prone positioning (APP) improves oxygenation in coronavirus disease (COVID-19) patients and, when successful, may decrease the risk of intubation. However, factors associated with APP success remain unknown. In this secondary analysis, we aimed to assess whether APP can reduce intubation rate in patients with COVID-19 and to focus on the factors associated with success. METHODS: In this multicenter randomized controlled trial, conducted in three high-acuity units, we randomly assigned patients with COVID-19-induced acute hypoxemic respiratory failure (AHRF) requiring high-flow nasal cannula (HFNC) oxygen to APP or standard care. Primary outcome was intubation rate at 28 days. Multivariate analyses were performed to identify the predictors associated to treatment success (survival without intubation). RESULTS: Among 430 patients randomized, 216 were assigned to APP and 214 to standard care. The APP group had a lower intubation rate (30% vs 43%, relative risk [RR] 0.70; CI95 0.54-0.90, P = 0.006) and shorter hospital length of stay (11 interquartile range [IQR, 9-14] vs 13 [IQR, 10-17] days, P = 0.001). A respiratory rate ≤ 25 bpm at enrollment, an increase in ROX index > 1.25 after first APP session, APP duration > 8 h/day, and a decrease in lung ultrasound score ≥ 2 within the first 3 days were significantly associated with treatment success for APP. CONCLUSION: In patients with COVID-19-induced AHRF treated by HFNC, APP reduced intubation rate and improved treatment success. A longer APP duration is associated with APP success, while the increase in ROX index and decrease in lung ultrasound score after APP can also help identify patients most likely to benefit. TRIAL REGISTRATION: This study was retrospectively registered in ClinicalTrials.gov at July 20, 2021. Identification number NCT04477655. https://clinicaltrials.gov/ct2/show/NCT04477655?term=PRO-CARF&draw=2&rank=1.

Public opinion of the Irish "COVID Tracker" digital contact tracing App: A national survey.

Objective: This study aims to gather public opinion on the Irish "COVID Tracker" digital contact tracing (DCT) App, with particular focus on App usage, usability, usefulness, technological issues encountered, and potential changes to the App. Methods: A 35-item online questionnaire was deployed for 10 days in October 2020, 3 months after the launch of the Irish DCT App. Results: A total of 2889 completed responses were recorded, with 2553 (88%) respondents currently using the App. Although four in five users felt the App is easy to download, is easy to use and looks professional, 615 users (22%) felt it had slowed down their phone, and 757 (28%) felt it had a negative effect on battery life. Seventy-nine percent of respondents reported the App's main function is to aid contact tracing. Inclusion of national COVID-19 trends is a useful ancillary function according to 87% of respondents, and there was an appetite for more granular local data. Overall, 1265 (44%) respondents believed the App is helping the national effort, while 1089 (38%) were unsure. Conclusions: DCT Apps may potentially augment traditional contact tracing methods. Despite some reports of negative effects on phone performance, just 7% of users who have tried the App have deleted it. Ancillary functionality, such as up-to-date regional COVID-19, may encourage DCT App use. This study describes general positivity toward the Irish COVID Tracker App among users but also highlights the need for transparency on effectiveness of App-enabled contact tracing and for study of non-users to better establish barriers to use.

Awake prone positioning for non-intubated patients with COVID-19-related acute hypoxaemic respiratory failure: a systematic review and meta-analysis.

BACKGROUND: Awake prone positioning has been broadly utilised for non-intubated patients with COVID-19-related acute hypoxaemic respiratory failure, but the results from published randomised controlled trials (RCTs) in the past year are contradictory. We aimed to systematically synthesise the outcomes associated with awake prone positioning, and evaluate these outcomes in relevant subpopulations. METHODS: In this systematic review and meta-analysis, two independent groups of researchers searched MEDLINE, Embase, PubMed, Web of Science, Scopus, MedRxiv, BioRxiv, and ClinicalTrials.gov for RCTs and observational studies (with a control group) of awake prone positioning in patients with COVID-19-related acute hypoxaemic respiratory failure published in English from Jan 1, 2020, to Nov 8, 2021. We excluded trials that included patients intubated before or at enrolment, paediatric patients (ie, younger than 18 years), or trials that did not include the supine position in the control group. The same two independent groups screened studies, extracted the summary data from published reports, and assessed the risk of bias. We used a random-effects meta-analysis to pool individual studies. We used the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the certainty and quality of the evidence. The primary outcome was the reported cumulative intubation risk across RCTs, and effect estimates were calculated as risk ratios (RR;95% CI). The analysis was primarily conducted on RCTs, and observational studies were used for sensitivity analyses. No serious adverse events associated with awake prone positioning were reported. The study protocol was prospectively registered with PROSPERO, CRD42021271285. FINDINGS: A total of 1243 studies were identified, we assessed 138 full-text articles and received the aggregated results of three unpublished RCTs; therefore, after exclusions, 29 studies were included in the study. Ten were RCTs (1985 patients) and 19 were observational studies (2669 patients). In ten RCTs, awake prone positioning compared with the supine position significantly reduced the need for intubation in the overall population (RR 0·84 [95% CI 0·72-0·97]). A reduced need for intubation was shown among patients who received advanced respiratory support (ie, high-flow nasal cannula or non-invasive ventilation) at enrolment (RR 0·83 [0·71-0·97]) and in intensive care unit (ICU) settings (RR 0·83 [0·71-0·97]) but not in patients receiving conventional oxygen therapy (RR 0·87 [0·45-1·69]) or in non-ICU settings (RR 0·88 [0·44-1·76]). No obvious risk of bias and publication bias was found among the included RCTs for the primary outcome. INTERPRETATION: In patients with COVID-19-related acute hypoxaemic respiratory failure, awake prone positioning reduced the need for intubation, particularly among those requiring advanced respiratory support and those in ICU settings. Awake prone positioning should be used in patients who have acute hypoxaemic respiratory failure due to COVID-19 and require advanced respiratory support or are treated in the ICU. FUNDING: OpenAI, Rice Foundation, National Institute for Health Research, and Oxford Biomedical Research Centre.

Can nebulised HepArin Reduce morTality and time to Extubation in patients with COVID-19 Requiring invasive ventilation Meta-Trial (CHARTER-MT): Protocol and statistical analysis plan for an investigator-initiated international meta-trial of prospective randomised clinical studies.

There is significant interest in the potential for nebulised unfractionated heparin (UFH), as a novel therapy for patients with COVID-19 induced acute hypoxaemic respiratory failure requiring invasive ventilation. The scientific and biological rationale for nebulised heparin stems from the evidence for extensive activation of coagulation resulting in pulmonary microvascular thrombosis in COVID-19 pneumonia. Nebulised delivery of heparin to the lung may limit alveolar fibrin deposition and thereby limit progression of lung injury. Importantly, laboratory studies show that heparin can directly inactivate the SARS-CoV-2 virus, thereby prevent its entry into and infection of mammalian cells. UFH has additional anti-inflammatory and mucolytic properties that may be useful in this context. METHODS AND INTERVENTION: The Can nebulised HepArin Reduce morTality and time to Extubation in Patients with COVID-19 Requiring invasive ventilation Meta-Trial (CHARTER-MT) is a collaborative prospective individual patient data analysis of on-going randomised controlled clinical trials across several countries in five continents, examining the effects of inhaled heparin in patients with COVID-19 requiring invasive ventilation on various endpoints. Each constituent study will randomise patients with COVID-19 induced respiratory failure requiring invasive ventilation. Patients are randomised to receive nebulised heparin or standard care (open label studies) or placebo (blinded placebo-controlled studies) while under invasive ventilation. Each participating study collect a pre-defined minimum dataset. The primary outcome for the meta-trial is the number of ventilator-free days up to day 28 day, defined as days alive and free from invasive ventilation.