Enhancement of the haemostatic effect of platelets in the presence of high normal concentrations of von Willebrand factor for critically ill patients needing platelet transfusion-a protocol for the will-plate randomised controlled trial.

INTRODUCTION: von Willebrand Factor (vWF) is a key protein mediating platelet adhesion on the surface of damaged endothelia. To the best of our knowledge, no trial exists that investigated the effect of platelet transfusion in combination with the administration of balanced vWF in severe blood loss, despite being widely used in clinical practice. The Basel Will-Plate study will investigate the impact of the timely administration of balanced vWF (1:1 vWF and FVIII) in addition to platelet transfusion on the need for blood and coagulation factor transfusion in patients admitted to the intensive care unit (ICU) who suffer from severe bleeding. The study hypothesis is based on the assumption that adding balanced vWF to platelets will reduce the overall need for transfusion of blood products compared to the transfusion of platelets alone. METHODS AND ANALYSIS: The Will-Plate study is an investigator-initiated, single-centre, double-blinded randomised controlled clinical trial in 120 critically ill patients needing platelet transfusion. The primary outcome measure will be the number of fresh frozen plasma (FFP) and red blood cell (RBC) transfusions according to groups. Secondary outcome measures include the number of platelet concentrates transfused within the first 48 h after treatment of study medication, quantity of blood loss in the first 48 h after treatment with the study medication, length of stay in ICU and hospital, number of revision surgeries for haemorrhage control, ICU mortality, hospital mortality, 30-day mortality and 1-year mortality. Patients will be followed after 30 days and 1 year for activities of daily living and mortality assessment. The sample size was calculated to detect a 50% reduction in the number of blood products subsequently transfused within 2 days in patients with Wilate® compared to placebo. ETHICS AND DISSEMINATION: This study has been approved by the Ethics Committee of Northwestern and Central Switzerland and will be conducted in compliance with the protocol, the current version of the Declaration of Helsinki, the ICH-GCP or ISO EN 14155 (as far as applicable) and all national legal and regulatory requirements. The study results will be presented at international conferences and published in a peer-reviewed journal. TRIALS REGISTRATION: ClinicalTrials.gov NCT04555785. PROTOCOL VERSION: Clinical Study Protocol Version 2, 01.11.2020. Registered on Sept. 21, 2020.

Low-Dose Radiation Therapy for Severe COVID-19 Pneumonia: A Randomized Double-Blind Study.

PURPOSE: The morbidity and mortality of patients requiring mechanical ventilation for coronavirus disease 2019 (COVID-19) pneumonia is considerable. We studied the use of whole-lung low-dose radiation therapy (LDRT) in this patient cohort. METHODS AND MATERIALS: Patients admitted to the intensive care unit and requiring mechanical ventilation for COVID-19 pneumonia were included in this randomized double-blind study. Patients were randomized to 1 Gy whole-lung LDRT or sham irradiation (sham-RT). Treatment group allocation was concealed from patients and intensive care unit clinicians, who treated patients according to the current standard of care. Patients were followed for the primary endpoint of ventilator-free days at day 15 postintervention. Secondary endpoints included overall survival, as well as changes in oxygenation and inflammatory markers. RESULTS: Twenty-two patients were randomized to either whole-lung LDRT or sham-RT between November and December 2020. Patients were generally elderly and comorbid, with a median age of 75 years in both arms. No difference in 15-day ventilator-free days was observed between groups (P = 1.00), with a median of 0 days (range, 0-9) in the LDRT arm and 0 days (range, 0-13) in the sham-RT arm. Overall survival at 28 days was identical at 63.6% (95% confidence interval, 40.7%-99.5%) in both arms (P = .69). Apart from a more pronounced reduction in lymphocyte counts after LDRT (P < .01), analyses of secondary endpoints revealed no significant differences between the groups. CONCLUSIONS: Whole-lung LDRT failed to improve clinical outcomes in critically ill patients requiring mechanical ventilation for COVID-19 pneumonia.

Low dose radiation therapy for severe COVID-19 pneumonia: a randomized double-blind study.

PURPOSE: The morbidity and mortality of patients requiring mechanical ventilation for coronavirus disease 2019 (COVID-19) pneumonia is considerable. We studied the use of whole-lung low dose radiation therapy (LDRT) in this patient cohort. METHODS AND MATERIALS: Patients admitted to the intensive care unit (ICU) and requiring mechanical ventilation for COVID-19 pneumonia were included in this randomized double-blind study. Patients were randomized to 1 Gy whole-lung LDRT or sham irradiation (sham-RT). Treatment group allocation was concealed from patients and ICU clinicians, who treated patients according to the current standard of care. Patients were followed for the primary endpoint of ventilator-free days (VFDs) at day 15 post-intervention. Secondary endpoints included overall survival, as well as changes in oxygenation and inflammatory markers. RESULTS: Twenty-two patients were randomized to either whole-lung LDRT or sham-RT between November and December 2020. Patients were generally elderly and comorbid, with a median age of 75 years in both arms. No difference in 15-day VFDs was observed between groups (p = 1.00), with a median of 0 days (range, 0-9) in the LDRT arm, and 0 days (range, 0-13) in the sham-RT arm. Overall survival at 28 days was identical at 63.6% (95%CI, 40.7-99.5%) in both arms (p = 0.69). Apart from a more pronounced reduction in lymphocyte counts following LDRT (p < 0.01), analyses of secondary endpoints revealed no significant differences between the groups. CONCLUSIONS: Whole-lung LDRT failed to improve clinical outcomes in critically ill patients requiring mechanical ventilation for COVID-19 pneumonia.

Cardiovascular Biomarkers in the Early Discrimination of Type 2 Myocardial Infarction.

Importance: Rapid and accurate noninvasive discrimination of type 2 myocardial infarction (T2MI), which is because of a supply-demand mismatch, from type 1 myocardial infarction (T1MI), which arises via plaque rupture, is essential, because treatment differs substantially. Unfortunately, this is a major unmet clinical need, because even high-sensitivity cardiac troponin (hs-cTn) measurement provides only modest accuracy. Objective: To test the hypothesis that novel cardiovascular biomarkers quantifying different pathophysiological pathways involved in T2MI and/or T1MI may aid physicians in the rapid discrimination of T2MI vs T1MI. Design, Setting, and Participants: This international, multicenter prospective diagnostic study was conducted in 12 emergency departments in 5 countries (Switzerland, Spain, Italy, Poland, and the Czech Republic) with patients presenting with acute chest discomfort to the emergency departments. The study quantified the discrimination of hs-cTn T, hs-cTn I, and 17 novel cardiovascular biomarkers measured in subsets of consecutively enrolled patients against a reference standard (final diagnosis), centrally adjudicated by 2 independent cardiologists according to the fourth universal definition of MI, using all information, including cardiac imaging and serial measurements of hs-cTnT or hs-cTnI. Results: Among 5887 patients, 1106 (18.8%) had an adjudicated final diagnosis of MI; of these, 860 patients (77.8%) had T1MI, and 246 patients (22.2%) had T2MI. Patients with T2MI vs those with T1MI had lower concentrations of biomarkers quantifying cardiomyocyte injury hs-cTnT (median [interquartile range (IQR)], 30 (17-55) ng/L vs 58 (28-150) ng/L), hs-cTnI (median [IQR], 23 [10-83] ng/L vs 115 [28-576] ng/L; P < .001), and cardiac myosin-binding protein C (at presentation: median [IQR], 76 [38-189] ng/L vs 257 [75-876] ng/L; P < .001) but higher concentrations of biomarkers quantifying endothelial dysfunction, microvascular dysfunction, and/or hemodynamic stress (median [IQR] values: C-terminal proendothelin 1, 97 [75-134] pmol/L vs 68 [55-91] pmol/L; midregional proadrenomedullin, 0.97 [0.67-1.51] pmol/L vs 0.72 [0.53-0.99] pmol/L; midregional pro-A-type natriuretic peptide, 378 [207-491] pmol/L vs 152 [90-247] pmol/L; and growth differentiation factor 15, 2.26 [1.44-4.35] vs 1.56 [1.02-2.19] ng/L; all P < .001). Discrimination for these biomarkers, as quantified by the area under the receiver operating characteristics curve, was modest (hs-cTnT, 0.67 [95% CI, 0.64-0.71]; hs-cTn I, 0.71 [95% CI, 0.67-0.74]; cardiac myosin-binding protein C, 0.67 [95% CI, 0.61-0.73]; C-terminal proendothelin 1, 0.73 [95% CI, 0.63-0.83]; midregional proadrenomedullin, 0.66 [95% CI, 0.60-0.73]; midregional pro-A-type natriuretic peptide, 0.77 [95% CI, 0.68-0.87]; and growth differentiation factor 15, 0.68 [95% CI, 0.58-0.79]). Conclusions and Relevance: In this study, biomarkers quantifying myocardial injury, endothelial dysfunction, microvascular dysfunction, and/or hemodynamic stress provided modest discrimination in early, noninvasive diagnosis of T2MI.

Dexmedetomidine in prevention and treatment of postoperative and intensive care unit delirium: a systematic review and meta-analysis.

BACKGROUND: To determine the preventive and therapeutic effect of dexmedetomidine on intensive care unit (ICU) delirium. METHODS: The literature search using PubMed and the Cochrane Central Register of Controlled Trials was performed (August 1, 2018) to detect all randomized controlled trials (RCTs) of adult ICU patients receiving dexmedetomidine. Articles were included if they assessed the influence of dexmedetomidine compared to a sedative agent on incidence of ICU delirium or treatment of this syndrome. Accordingly, relevant articles were allocated to the following two groups: (1) articles that assessed the delirium incidence (incidence comparison) or articles that assessed the treatment of delirium (treatment comparison). Incidence of delirium and delirium resolution were the primary outcomes. We combined treatment effects comparing dexmedetomidine versus (1) placebo, (2) standard sedatives, and (3) opioids in random-effects meta-analyses. Risk of bias for each included RCT was assessed following Cochrane standards. RESULTS: The literature search resulted in 28 articles (25 articles/4975 patients for the incidence comparison and three articles/166 patients for the treatment comparison). In the incidence comparison, heterogeneity was present in different subgroups. Administration of dexmedetomidine was associated with significantly lower overall incidence of delirium when compared to placebo (RR 0.52; 95% CI 0.39-0.70; I2 = 37%), standard sedatives (RR 0.63; 95% CI 0.46-0.86; I2 = 69%), as well as to opioids (RR 0.61; 95% CI 0.44-0.83; I2 = 0%). Use of dexmedetomidine significantly increased the risks of bradycardia and hypotension. Limited data were available on circulatory insufficiency and mortality. In the treatment comparison, the comparison drugs in the three RCTs were placebo, midazolam, and haloperidol. The resolution of delirium was measured differently in each study. Two out of the three studies indicated clear favorable effects for dexmedetomidine (i.e., compared to placebo and midazolam). The study comparing dexmedetomidine with haloperidol was a pilot study (n = 20) with high variability in the results. CONCLUSION: Findings suggest that dexmedetomidine reduces incidence and duration of ICU delirium. Furthermore, our systematic searches show that there is limited evidence if a delirium shall be treated with dexmedetomidine.

Baden Prevention and Reduction of Incidence of Postoperative Delirium Trial (PRIDe): a phase IV multicenter, randomized, placebo-controlled, double-blind clinical trial of ketamine versus haloperidol for prevention of postoperative delirium.

BACKGROUND: Delirium is a neurobehavioural syndrome that frequently develops in the postoperative setting. The incidence of elderly patients who develop delirium during hospital stay ranges from 10-80%. Delirium was first described more than half a century ago in the cardiac surgery population, where it was already discovered as a state that might be accompanied by serious complications such as prolonged ICU and hospital stay, reduced quality of life and increased mortality. Furthermore, the duration of delirium is associated with worse long-term cognitive function in the general ICU population. This long-term experience with delirium suggests a high socioeconomic burden and has been a focus of many studies. Due to the multifactorial origin of delirium, we have several but no incontestable options for prevention and symptomatic treatment. Overall, delirium represents a high burden not only for patient and family members, but also for the medical care team that aims to prevent postoperative delirium to avoid serious consequences associated with it. The purpose of this study is to determine whether postoperative delirium can be prevented by the combination of established preventive agents. In addition, measured levels of pre- and postoperative cortisol, neuron specific enolase (NSE) and S-100ß will be used to investigate dynamics of these parameters in delirious and non-delirious patients after surgery. METHODS/DESIGN: The Baden PRIDe Trial is an investigator-initiated, phase IV, two-centre, randomised, placebo-controlled, double-blind clinical trial for the prevention of delirium with haloperidol, ketamine, and the combination of both vs. placebo in 200 patients scheduled for surgery. We would like to investigate superiority of one of the three treatment arms (i.e., haloperidol, ketamine, combined treatment) to placebo. DISCUSSION: There is limited but promising evidence that haloperidol and ketamine can be used to prevent delirium. Clinical care for patients might improve as the results of this study may lead to better algorithms for the prevention of delirium. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02433041 . Registered on 7 April 2015. Swiss National Clinical Trial Portal, SNCTP000001628. Registered on 9 December 2015.