Age-related changes in plasma biomarkers and their association with mortality in COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19)-induced mortality occurs predominantly in older patients. Several immunomodulating therapies seem less beneficial in these patients. The biological substrate behind these observations is unknown. The aim of this study was to obtain insight into the association between ageing, the host response and mortality in patients with COVID-19. METHODS: We determined 43 biomarkers reflective of alterations in four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, and cytokine and chemokine release. We used mediation analysis to associate ageing-driven alterations in the host response with 30-day mortality. Biomarkers associated with both ageing and mortality were validated in an intensive care unit and external cohort. RESULTS: 464 general ward patients with COVID-19 were stratified according to age decades. Increasing age was an independent risk factor for 30-day mortality. Ageing was associated with alterations in each of the host response domains, characterised by greater activation of the endothelium and coagulation system and stronger elevation of inflammation and organ damage markers, which was independent of an increase in age-related comorbidities. Soluble tumour necrosis factor receptor 1, soluble triggering receptor expressed on myeloid cells 1 and soluble thrombomodulin showed the strongest correlation with ageing and explained part of the ageing-driven increase in 30-day mortality (proportion mediated: 13.0%, 12.9% and 12.6%, respectively). CONCLUSIONS: Ageing is associated with a strong and broad modification of the host response to COVID-19, and specific immune changes likely contribute to increased mortality in older patients. These results may provide insight into potential age-specific immunomodulatory targets in COVID-19.

Prognostication using SpO2/FiO2 in invasively ventilated ICU patients with ARDS due to COVID-19 - Insights from the PRoVENT-COVID study.

BACKGROUND: The SpO2/FiO2 is a useful oxygenation parameter with prognostic capacity in patients with ARDS. We investigated the prognostic capacity of SpO2/FiO2 for mortality in patients with ARDS due to COVID-19. METHODS: This was a post-hoc analysis of a national multicenter cohort study in invasively ventilated patients with ARDS due to COVID-19. The primary endpoint was 28-day mortality. RESULTS: In 869 invasively ventilated patients, 28-day mortality was 30.1%. The SpO2/FiO2 on day 1 had no prognostic value. The SpO2/FiO2 on day 2 and day 3 had prognostic capacity for death, with the best cut-offs being 179 and 199, respectively. Both SpO2/FiO2 on day 2 (OR, 0.66 [95%-CI 0.46-0.96]) and on day 3 (OR, 0.70 [95%-CI 0.51-0.96]) were associated with 28-day mortality in a model corrected for age, pH, lactate levels and kidney dysfunction (AUROC 0.78 [0.76-0.79]). The measured PaO2/FiO2 and the PaO2/FiO2 calculated from SpO2/FiO2 were strongly correlated (Spearman's r = 0.79). CONCLUSIONS: In this cohort of patients with ARDS due to COVID-19, the SpO2/FiO2 on day 2 and day 3 are independently associated with and have prognostic capacity for 28-day mortality. The SpO2/FiO2 is a useful metric for risk stratification in invasively ventilated COVID-19 patients.

Outcome in patients undergoing postponed elective surgery during the COVID-19 pandemic (TRACE II): study protocol for a multicentre prospective observational study.

INTRODUCTION: During the COVID-19 pandemic many non-acute elective surgeries were cancelled or postponed around the world. This has created an opportunity to study the effect of delayed surgery on health conditions prior to surgery and postsurgical outcomes in patients with postponed elective surgery. The control group of the Routine Postsurgical Anesthesia Visit to Improve Patient Outcome (TRACE I) study, conducted between 2016 and 2019, will serve as a control cohort. METHODS AND ANALYSIS: TRACE II is an observational, multicentre, prospective cohort study among surgical patients with postponed surgery due to COVID-19 in academic and non-academic hospitals in the Netherlands. We aim to include 2500 adult patients. The primary outcome will be the 30-day incidence of major postoperative complications. Secondary outcome measures include the 30-day incidence of minor postoperative complications, 1 year mortality, length of stay (in hospital, medium care and intensive care), quality of recovery 30 days after surgery and postoperative quality of life up to 1 year following surgery. Multivariable logistic mixed-effects regression analysis with a random intercept for hospital will be used to test group differences on the primary outcome. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Institutional Review Board of Maastricht University Medical Centre+ and Amsterdam UMC. Findings will be presented at national and international conferences, as well as published in peer-reviewed scientific journals, with a preference for open access journals. Data will be made publicly available after publication of the main results. TRIAL REGISTRATION NUMBER: NL8841.

Prognostication using SpO2/FiO2 in invasively ventilated ICU patients with ARDS due to COVID-19 – Insights from the PRoVENT-COVID study☆

Background The SpO2/FiO2 is a useful oxygenation parameter with prognostic capacity in patients with ARDS. We investigated the prognostic capacity of SpO2/FiO2 for mortality in patients with ARDS due to COVID–19. Methods This was a post-hoc analysis of a national multicenter cohort study in invasively ventilated patients with ARDS due to COVID–19. The primary endpoint was 28–day mortality. Results In 869 invasively ventilated patients, 28–day mortality was 30.1%. The SpO2/FiO2 on day 1 had no prognostic value. The SpO2/FiO2 on day 2 and day 3 had prognostic capacity for death, with the best cut-offs being 179 and 199, respectively. Both SpO2/FiO2 on day 2 (OR, 0.66 [95%–CI 0.46–0.96]) and on day 3 (OR, 0.70 [95%–CI 0.51–0.96]) were associated with 28–day mortality in a model corrected for age, pH, lactate levels and kidney dysfunction (AUROC 0.78 [0.76–0.79]). The measured PaO2/FiO2 and the PaO2/FiO2 calculated from SpO2/FiO2 were strongly correlated (Spearman's r = 0.79). Conclusions In this cohort of patients with ARDS due to COVID–19, the SpO2/FiO2 on day 2 and day 3 are independently associated with and have prognostic capacity for 28–day mortality. The SpO2/FiO2 is a useful metric for risk stratification in invasively ventilated COVID–19 patients.

Early warning scores to assess the probability of critical illness in patients with COVID-19.

OBJECTIVE: Validated clinical risk scores are needed to identify patients with COVID-19 at risk of severe disease and to guide triage decision-making during the COVID-19 pandemic. The objective of the current study was to evaluate the performance of early warning scores (EWS) in the ED when identifying patients with COVID-19 who will require intensive care unit (ICU) admission for high-flow-oxygen usage or mechanical ventilation. METHODS: Patients with a proven SARS-CoV-2 infection with complete resuscitate orders treated in nine hospitals between 27 February and 30 July 2020 needing hospital admission were included. Primary outcome was the performance of EWS in identifying patients needing ICU admission within 24 hours after ED presentation. RESULTS: In total, 1501 patients were included. Median age was 71 (range 19-99) years and 60.3% were male. Of all patients, 86.9% were admitted to the general ward and 13.1% to the ICU within 24 hours after ED admission. ICU patients had lower peripheral oxygen saturation (86.7% vs 93.7, p≤0.001) and had a higher body mass index (29.2 vs 27.9 p=0.043) compared with non-ICU patients. National Early Warning Score 2 (NEWS2) ≥ 6 and q-COVID Score were superior to all other studied clinical risk scores in predicting ICU admission with a fair area under the receiver operating characteristics curve of 0.740 (95% CI 0.696 to 0.783) and 0.760 (95% CI 0.712 to 0.800), respectively. NEWS2 ≥6 and q-COVID Score ≥3 discriminated patients admitted to the ICU with a sensitivity of 78.1% and 75.9%, and specificity of 56.3% and 61.8%, respectively. CONCLUSION: In this multicentre study, the best performing models to predict ICU admittance were the NEWS2 and the Quick COVID-19 Severity Index Score, with fair diagnostic performance. However, due to the moderate performance, these models cannot be clinically used to adequately predict the need for ICU admission within 24 hours in patients with SARS-CoV-2 infection presenting at the ED.

Assessment of Lung Reaeration at 2 Levels of Positive End-expiratory Pressure in Patients With Early and Late COVID-19-related Acute Respiratory Distress Syndrome.

PURPOSE: Patients with novel coronavirus disease (COVID-19) frequently develop acute respiratory distress syndrome (ARDS) and need invasive ventilation. The potential to reaerate consolidated lung tissue in COVID-19-related ARDS is heavily debated. This study assessed the potential to reaerate lung consolidations in patients with COVID-19-related ARDS under invasive ventilation. MATERIALS AND METHODS: This was a retrospective analysis of patients with COVID-19-related ARDS who underwent chest computed tomography (CT) at low positive end-expiratory pressure (PEEP) and after a recruitment maneuver at high PEEP of 20 cm H2O. Lung reaeration, volume, and weight were calculated using both CT scans. CT scans were performed after intubation and start of ventilation (early CT), or after several days of intensive care unit admission (late CT). RESULTS: Twenty-eight patients were analyzed. The median percentages of reaerated and nonaerated lung tissue were 19% [interquartile range, IQR: 10 to 33] and 11% [IQR: 4 to 15] for patients with early and late CT scans, respectively (P=0.049). End-expiratory lung volume showed a median increase of 663 mL [IQR: 483 to 865] and 574 mL [IQR: 292 to 670] after recruitment for patients with early and late CT scans, respectively (P=0.43). The median decrease in lung weight attributed to nonaerated lung tissue was 229 g [IQR: 165 to 376] and 171 g [IQR: 81 to 229] after recruitment for patients with early and late CT scans, respectively (P=0.16). CONCLUSIONS: The majority of patients with COVID-19-related ARDS undergoing invasive ventilation had substantial reaeration of lung consolidations after recruitment and ventilation at high PEEP. Higher PEEP can be considered in patients with reaerated lung consolidations when accompanied by improvement in compliance and gas exchange.

Study protocol for the TRUSt trial: a pragmatic randomised controlled trial comparing the standard of care with a transitional pain service for patients at risk of chronic postsurgical pain undergoing surgery.

INTRODUCTION: Patients with either surgery-related or patient-related risk factors are at an increased risk of acute and chronic postsurgical pain (CPSP) and long-term opioid use. To improve recovery, prevent CPSP and decrease opioid use, we need to identify these patients before surgery and provide a multidisciplinary pain management strategy throughout hospital admission and follow-up in the postdischarge period. We hypothesise that a multidisciplinary transitional pain service (TPS) improves quality of recovery and reduce the incidence of CPSP and opioid consumption. METHODS AND ANALYSIS: We aim to investigate the effectiveness of implementation of a TPS for patients at risk of developing CPSP. The trial design is a pragmatic, open-label, randomised controlled trial (RCT). After stratification for sex, patients are randomly assigned to the TPS or standard of care (SOC) group. Our primary outcome is the quality of recovery, measured at the morning of the third postoperative day, employing the quality of recovery (QoR)-15 questionnaire. Secondary outcomes are the incidence of CPSP, opioid consumption and patient-reported outcome measures at 3 and 6 months postoperatively. We need to enrol 176 patients to detect a minimal clinical important difference of 8 points on the QoR-15 score. ETHICS AND DISSEMINATION: Ethics approval was obtained by the accredited medical research ethics committee of the Academic Medical Center in Amsterdam (2020_211) on 15 October 2020. Protocol version 3.2 was approved on 25 January 2020. The trial is registered with the Netherlands Trial Register, NL9115. The results will be disseminated by open access publication in a peer-reviewed journal.Trial registration number NL9115.

Practice of adjunctive treatments in critically ill COVID-19 patients-rational for the multicenter observational PRoAcT-COVID study in The Netherlands.

BACKGROUND: Patients with coronavirus disease 2019 (COVID-19) may need hospitalization for supplemental oxygen, and some need intensive care unit (ICU) admission for escalation of care. Practice of adjunctive and supportive treatments remain uncertain and may vary widely between countries, within countries between hospitals, and possibly even within ICUs. We aim to investigate practice of adjunctive and supportive treatments, and their associations with outcome, in critically ill COVID-19 patients. METHODS: The 'PRactice of Adjunctive Treatments in Intensive Care Unit Patients with Coronavirus Disease 2019' (PRoAcT-COVID) study is a national, observational study to be undertaken in a large set of ICUs in The Netherlands. The PRoAcT-COVID includes consecutive ICU patients, admitted because of COVID-19 to one of the participating ICUs during a 3-month period. Daily follow-up lasts 28 days. The primary endpoint is a combination of adjunctive treatments, including types of oxygen support, ventilation, rescue therapies for hypoxemia refractory to supplementary oxygen or during invasive ventilation, other adjunctive and supportive treatments, and experimental therapies. We will also collect tracheostomy rate, duration of invasive ventilation and ventilator-free days and alive at day 28 (VFD-28), ICU and hospital length of stay, and the mortality rates in the ICU, hospital and at day 90. DISCUSSION: The PRoAcT-COVID study is an observational study combining high density treatment data with relevant clinical outcomes. Information on treatment practices, and their associations with outcomes in COVID-19 patients in highly and urgently needed. The results of the PRoAcT-COVID study will be rapidly available, and circulated through online presentations, such as webinars and electronic conferences, and publications in peer-reviewed journals-findings will also be presented at a dedicated website. At request, and after agreement of the PRoAcT-COVID steering committee, source data will be made available through local, regional and national anonymized datasets. TRIAL REGISTRATION: The PRoAcT-COVID study is registered at clinicaltrials.gov (study identifier NCT04719182).

PRactice of VENTilation in Patients with Novel Coronavirus Disease (PRoVENT-COVID): rationale and protocol for a national multicenter observational study in The Netherlands.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is rapidly expanding across the world, with more than 100,000 new cases each day as of end-June 2020. Healthcare workers are struggling to provide the best care for COVID-19 patients. Approaches for invasive ventilation vary widely between and within countries and new insights are acquired rapidly. We aim to investigate invasive ventilation practices and outcome in COVID-19 patients in the Netherlands. METHODS: PRoVENT-COVID ('study of PRactice of VENTilation in COVID-19') is an investigator-initiated national, multicenter observational study to be undertaken in intensive care units (ICUs) in The Netherlands. Consecutive COVID-19 patients aged 18 years or older, who are receiving invasive ventilation in the participating ICUs, are to be enrolled during a 10-week period, with a daily follow-up of 7 days. The primary outcome is ventilatory management (including tidal volume expressed as mL/kg predicted body weight and positive end-expiratory pressure expressed as cmH2O) during the first 3 days of ventilation. Secondary outcomes include other ventilatory variables, use of rescue therapies for refractory hypoxemia such as prone positioning and extracorporeal membrane oxygenation, use of sedatives, vasopressors and inotropes; daily cumulative fluid balances; acute kidney injury; ventilator-free days and alive at day 28 (VFD-28), duration of ICU and hospital stay, and ICU, hospital and 90-day mortality. DISCUSSION: PRoVENT-COVID will be the largest observational study to date, with high density ventilatory data and major outcomes. There is urgent need for a better understanding of ventilation practices, and the effects of ventilator settings on outcomes in COVID-19 patients. The results of PRoVENT-COVID will be rapidly disseminated through electronic presentations, such as webinars and electronic conferences, and publications in international peer-reviewed journals. Access to source data will be made available through local, regional and national anonymized datasets on request, and after agreement of the PRoVENT-COVID steering committee. TRIAL REGISTRATION: PRoVENT-COVID is registered at clinicaltrials.gov (identifier NCT04346342).

Second Update for Anaesthetists on Clinical Features of COVID-19 Patients and Relevant Management.

The COVID-19 pandemic poses great challenges for healthcare workers around the world, including perioperative specialists. Previously, we provided a first overview of available literature on SARS-CoV-2 and COVID-19, relevant for anaesthetists and intensivists. In the current review, we provide an update of this topic, after a literature search current through May 2020. We discuss the evidence on perioperative risk for COVID-19 patients presenting for surgery, the risk of transmission of SARS-CoV-2 in the operating room, and the current literature on laboratory diagnostics. Furthermore, cardiovascular and nervous system involvement in COVID-19 are discussed, as well as considerations in diabetic patients. Lastly, the latest evidence on pharmacological treatment is summarised.