High levels of soluble VEGF receptor 1 early after trauma are associated with shock, sympathoadrenal activation, glycocalyx degradation and inflammation in severely injured patients: a prospective study

<p>Abstract</p> <p>Background</p> <p>The level of soluble vascular endothelial growth factor receptor 1 (sVEGFR1) is increased in sepsis and strongly associated with disease severity and mortality. Endothelial activation and damage contribute to both sepsis and trauma pathology. Therefore, this study measured sVEGFR1 levels in trauma patients upon hospital admission hypothesizing that sVEGFR1 would increase with higher injury severity and predict a poor outcome.</p> <p>Methods</p> <p>Prospective observational study of 80 trauma patients admitted to a Level I Trauma Centre. Data on demography, biochemistry, Injury Severity Score (ISS), transfusions and 30-day mortality were recorded and plasma/serum (sampled a median of 68 min (IQR 48-88) post-injury) was analyzed for sVEGFR1 and biomarkers reflecting sympathoadrenal activation (adrenaline, noradrenaline), tissue injury (histone-complexed DNA fragments, hcDNA), endothelial activation and damage (von Willebrand Factor Antigen, Angiopoietin-2, soluble endothelial protein C receptor, syndecan-1, soluble thrombomodulin (sTM)), coagulation activation/inhibition and fibrinolysis (prothrombinfragment 1 + 2, protein C, activated Protein C, tissue-type plasminogen activator, plasminogen activator inhibitor-1, D-dimer) and inflammation (interleukin-6). Spearman correlations and regression analyses to identify variables associated with sVEGFR1 and its predictive value.</p> <p>Results</p> <p>Circulating sVEGFR1 correlated with injury severity (ISS, rho = 0.46), shock (SBE, rho = -0.38; adrenaline, rho = 0.47), tissue injury (hcDNA, rho = 0.44) and inflammation (IL-6, rho = 0.54) (all p < 0.01) but by multivariate linear regression analysis only lower SBE and higher adrenaline and IL-6 were independent predictors of higher sVEGFR1. sVEGFR1 also correlated with biomarkers indicative of endothelial glycocalyx degradation (syndecan-1, rho = 0.67), endothelial cell damage (sTM, rho = 0.66) and activation (Ang-2, rho = 0.31) and hyperfibrinolysis (tPA, rho = 0.39; D-dimer, rho = 0.58) and with activated protein C (rho = 0.31) (all p < 0.01). High circulating sVEGFR1 correlated with high early and late transfusion requirements (number of packed red blood cells (RBC) at 1 h (rho = 0.27, p = 0.016), 6 h (rho = 0.27, p = 0.017) and 24 h (rho = 0.31, p = 0.004) but was not associated with mortality.</p> <p>Conclusions</p> <p>sVEGFR1 increased with increasing injury severity, shock and inflammation early after trauma but only sympathoadrenal activation, hypoperfusion, and inflammation were independent predictors of sVEGFR1 levels. sVEGFR1 correlated strongly with other biomarkers of endothelial activation and damage and with RBC transfusion requirements. Sympathoadrenal activation, shock and inflammation may be critical drivers of endothelial activation and damage early after trauma.</p

A descriptive study of the surge response and outcomes of ICU patients with COVID-19 during first wave in Nordic countries

Abstract Background We sought to provide a description of surge response strategies and characteristics, clinical management and outcomes of patients with severe COVID-19 in the intensive care unit (ICU) during the first wave of the pandemic in Denmark, Finland, Iceland, Norway and Sweden. Methods Representatives from the national ICU registries for each of the five countries provided clinical data and a description of the strategies to allocate ICU resources and increase the ICU capacity during the pandemic. All adult patients admitted to the ICU for COVID-19 disease during the first wave of COVID-19 were included. The clinical characteristics, ICU management and outcomes of individual countries were described with descriptive statistics. Results Most countries more than doubled their ICU capacity during the pandemic. For patients positive for SARS-CoV-2, the ratio of requiring ICU admission for COVID-19 varied substantially (1.6-6.7%). Apart from age (proportion of patients aged 65 years or over between 29-62%), baseline characteristics, chronic comorbidity burden and acute presentations of COVID-19 disease were similar among the five countries. While utilization of invasive mechanical ventilation was high (59-85%) in all countries, the proportion of patients receiving renal replacement therapy (7-26%) and various experimental therapies for COVID-19 disease varied substantially (e.g. use of hydroxychloroquine 0-85%). Crude ICU mortality ranged from 11% to 33%. Conclusion There was substantial variability in the critical care response in Nordic ICUs to the first wave of COVID-19 pandemic, including usage of experimental medications. While ICU mortality was low in all countries, the observed variability warrants further attention.Peer reviewe

Clinical examination, critical care ultrasonography and outcomes in the critically ill : cohort profile of the Simple Intensive Care Studies-I

Purpose In the Simple Intensive Care Studies-I (SICS-I), we aim to unravel the value of clinical and haemodynamic variables obtained by physical examination and critical care ultrasound (CCUS) that currently guide daily practice in critically ill patients. We intend to (1) measure all available clinical and haemodynamic variables, (2) train novices in obtaining values for advanced variables based on CCUS in the intensive care unit (ICU) and (3) create an infrastructure for a registry with the flexibility of temporarily incorporating specific (haemodynamic) research questions and variables. The overall purpose is to investigate the diagnostic and prognostic value of clinical and haemodynamic variables. Participants The SICS-I includes all patients acutely admitted to the ICU of a tertiary teaching hospital in the Netherlands with an ICU stay expected to last beyond 24 hours. Inclusion started on 27 March 2015. Findings to date On 31 December 2016, 791 eligible patients fulfilled our inclusion criteria of whom 704 were included. So far 11 substudies with additional variables have been designed, of which six were feasible to implement in the basic study, and two are planned and awaiting initiation. All researchers received focused training for obtaining specific CCUS images. An independent Core laboratory judged that 632 patients had CCUS images of sufficient quality. Future plans We intend to optimise the set of variables for assessment of the haemodynamic status of the critically ill patient used for guiding diagnostics, prognosis and interventions. Repeated evaluations of these sets of variables are needed for continuous improvement of the diagnostic and prognostic models. Future plans include: (1) more advanced imaging; (2) repeated clinical and haemodynamic measurements; (3) expansion of the registry to other departments or centres; and (4) exploring possibilities of integration of a randomised clinical trial superimposed on the registry. Study registration number NCT02912624; Pre-results.Peer reviewe

Goal directed fluid removal with furosemide versus placebo in intensive care patients with fluid overload:A trial protocol for a randomised, blinded trial (GODIF trial)

Funding Information: SW has received a grant from Merchant Jakob Ehrenreich and wife Grete Ehrenreich's Foundation to production of trial drug for the GODIF trial. AP has received research funding from the Novo Nordisk Foundation, Health Insurance Denmark (Sygeforsikringen Danmark), Fresenius Kabi, Denmark, and Pfizer, Denmark. MO has received research funding from Fresenius Medical Care, Baxter and Biomerieux. MHB has received research funding for the GODIF trial from Novo Nordisk Foundation, Jakob Madsen's and wife Olga Madsen's Foundation, Svend Andersen's Foundation, and Health Insurance Denmark (Sygeforsikringen Danmark). No authors received any financial gain. All other authors declared no conflicts of interest. Publisher Copyright: © 2022 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.Background: Fluid overload is a risk factor for mortality in intensive care unit (ICU) patients. Administration of loop diuretics is the predominant treatment of fluid overload, but evidence for its benefit is very uncertain when assessed in a systematic review of randomised clinical trials. The GODIF trial will assess the benefits and harms of goal directed fluid removal with furosemide versus placebo in ICU patients with fluid overload. Methods: An investigator-initiated, international, randomised, stratified, blinded, parallel-group trial allocating 1000 adult ICU patients with fluid overload to infusion of furosemide versus placebo. The goal is to achieve a neutral fluid balance. The primary outcome is days alive and out of hospital 90 days after randomisation. Secondary outcomes are all-cause mortality at day 90 and 1-year after randomisation; days alive at day 90 without life support; number of participants with one or more serious adverse events or reactions; health-related quality of life and cognitive function at 1-year follow-up. A sample size of 1000 participants is required to detect an improvement of 8% in days alive and out of hospital 90 days after randomisation with a power of 90% and a risk of type 1 error of 5%. The conclusion of the trial will be based on the point estimate and 95% confidence interval; dichotomisation will not be used. ClinicalTrials.gov identifier: NCT04180397. Perspective: The GODIF trial will provide important evidence of possible benefits and harms of fluid removal with furosemide in adult ICU patients with fluid overload.Peer reviewe

The diagnostic accuracy of clinical examination for estimating cardiac index in critically ill patients:the Simple Intensive Care Studies-I

PurposeClinical examination is often the first step to diagnose shock and estimate cardiac index. In the Simple Intensive Care Studies-I, we assessed the association and diagnostic performance of clinical signs for estimation of cardiac index in critically ill patients.MethodsIn this prospective, single-centre cohort study, we included all acutely ill patients admitted to the ICU and expected to stay>24h. We conducted a protocolised clinical examination of 19 clinical signs followed by critical care ultrasonography for cardiac index measurement. Clinical signs were associated with cardiac index and a low cardiac index (4.5s, or skin mottling over the knee.ConclusionsSeven out of 19 clinical examination findings were independently associated with cardiac index. For estimation of cardiac index, clinical examination was found to be insufficient in multivariable analyses and in diagnostic accuracy tests. Additional measurements such as critical care ultrasonography remain necessary

Influenza and associated co-infections in critically ill immunosuppressed patients

Abstract Background It is unclear whether influenza infection and associated co-infection are associated with patient-important outcomes in critically ill immunocompromised patients with acute respiratory failure. Methods Preplanned secondary analysis of EFRAIM, a prospective cohort study of 68 hospitals in 16 countries. We included 1611 patients aged 18 years or older with non-AIDS-related immunocompromise, who were admitted to the ICU with acute hypoxemic respiratory failure. The main exposure of interest was influenza infection status. The primary outcome of interest was all-cause hospital mortality, and secondary outcomes ICU length of stay (LOS) and 90-day mortality. Results Influenza infection status was categorized into four groups: patients with influenza alone (n = 95, 5.8%), patients with influenza plus pulmonary co-infection (n = 58, 3.6%), patients with non-influenza pulmonary infection (n = 820, 50.9%), and patients without pulmonary infection (n = 638, 39.6%). Influenza infection status was associated with a requirement for intubation and with LOS in ICU (P < 0.001). Patients with influenza plus co-infection had the highest rates of intubation and longest ICU LOS. On crude analysis, influenza infection status was associated with ICU mortality (P < 0.001) but not hospital mortality (P = 0.09). Patients with influenza plus co-infection and patients with non-influenza infection alone had similar ICU mortality (41% and 37% respectively) that was higher than patients with influenza alone or those without infection (33% and 26% respectively). A propensity score-matched analysis did not show a difference in hospital mortality attributable to influenza infection (OR = 1.01, 95%CI 0.90–1.13, P = 0.85). Age, severity scores, ARDS, and performance status were all associated with ICU, hospital, and 90-day mortality. Conclusions Category of infectious etiology of respiratory failure (influenza, non-influenza, influenza plus co-infection, and non-infectious) was associated with ICU but not hospital mortality. In a propensity score-matched analysis, influenza infection was not associated with the primary outcome of hospital mortality. Overall, influenza infection alone may not be an independent risk factor for hospital mortality in immunosuppressed patients

Furosemide versus placebo for fluid overload in intensive care patients—The randomised GODIF trial second version : Statistical analysis plan

Publisher Copyright: © 2023 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.Background: Fluid overload is associated with increased mortality in intensive care unit (ICU) patients. The GODIF trial aims to assess the benefits and harms of fluid removal with furosemide versus placebo in stable adult patients with moderate to severe fluid overload in the ICU. This article describes the detailed statistical analysis plan for the primary results of the second version of the GODIF trial. Methods: The GODIF trial is an international, multi-centre, randomised, stratified, blinded, parallel-group, pragmatic clinical trial, allocating 1000 adult ICU patients with moderate to severe fluid overload 1:1 to furosemide versus placebo. The primary outcome is days alive and out of hospital within 90 days post-randomisation. With a power of 90% and an alpha level of 5%, we may reject or detect an improvement of 8%. The primary analyses of all outcomes will be performed in the intention-to-treat population. For the primary outcome, the Kryger Jensen and Lange method will be used to compare the two treatment groups adjusted for stratification variables supplemented with sensitivity analyses in the per-protocol population and with further adjustments for prognostic variables. Secondary outcomes will be analysed with multiple linear regressions, logistic regressions or the Kryger Jensen and Lange method as suitable with adjustment for stratification variables. Conclusion: The GODIF trial data will increase the certainty about the effects of fluid removal using furosemide in adult ICU patients with fluid overload. Trial Registrations: EudraCT identifier: 2019-004292-40 and ClinicalTrials.org: NCT04180397.Peer reviewe