Effect of Selepressin vs Placebo on Ventilator- and Vasopressor-Free Days in Patients With Septic Shock: The SEPSIS-ACT Randomized Clinical Trial.

IMPORTANCE: Norepinephrine, the first-line vasopressor for septic shock, is not always effective and has important catecholaminergic adverse effects. Selepressin, a selective vasopressin V1a receptor agonist, is a noncatecholaminergic vasopressor that may mitigate sepsis-induced vasodilatation, vascular leakage, and edema, with fewer adverse effects. OBJECTIVE: To test whether selepressin improves outcome in septic shock. DESIGN, SETTING, AND PARTICIPANTS: An adaptive phase 2b/3 randomized clinical trial comprising 2 parts that included adult patients (n = 868) with septic shock requiring more than 5 µg/min of norepinephrine. Part 1 used a Bayesian algorithm to adjust randomization probabilities to alternative selepressin dosing regimens and to trigger transition to part 2, which would compare the best-performing regimen with placebo. The trial was conducted between July 2015 and August 2017 in 63 hospitals in Belgium, Denmark, France, the Netherlands, and the United States, and follow-up was completed by May 2018. INTERVENTIONS: Random assignment to 1 of 3 dosing regimens of selepressin (starting infusion rates of 1.7, 2.5, and 3.5 ng/kg/min; n = 585) or to placebo (n = 283), all administered as continuous infusions titrated according to hemodynamic parameters. MAIN OUTCOMES AND MEASURES: Primary end point was ventilator- and vasopressor-free days within 30 days (deaths assigned zero days) of commencing study drug. Key secondary end points were 90-day mortality, kidney replacement therapy-free days, and ICU-free days. RESULTS: Among 868 randomized patients, 828 received study drug (mean age, 66.3 years; 341 [41.2%] women) and comprised the primary analysis cohort, of whom 562 received 1 of 3 selepressin regimens, 266 received placebo, and 817 (98.7%) completed the trial. The trial was stopped for futility at the end of part 1. Median study drug duration was 37.8 hours (IQR, 17.8-72.4). There were no significant differences in the primary end point (ventilator- and vasopressor-free days: 15.0 vs 14.5 in the selepressin and placebo groups; difference, 0.6 [95% CI, -1.3 to 2.4]; P = .30) or key secondary end points (90-day mortality, 40.6% vs 39.4%; difference, 1.1% [95% CI, -6.5% to 8.8%]; P = .77; kidney replacement therapy-free days: 18.5 vs 18.2; difference, 0.3 [95% CI, -2.1 to 2.6]; P = .85; ICU-free days: 12.6 vs 12.2; difference, 0.5 [95% CI, -1.2 to 2.2]; P = .41). Adverse event rates included cardiac arrhythmias (27.9% vs 25.2% of patients), cardiac ischemia (6.6% vs 5.6%), mesenteric ischemia (3.2% vs 2.6%), and peripheral ischemia (2.3% vs 2.3%). CONCLUSIONS AND RELEVANCE: Among patients with septic shock receiving norepinephrine, administration of selepressin, compared with placebo, did not result in improvement in vasopressor- and ventilator-free days within 30 days. Further research would be needed to evaluate the potential role of selepressin for other patient-centered outcomes in septic shock. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02508649.

The effects of preoperative point-of-care focused cardiac ultrasound in high-risk patients: study protocol for a prospective randomised controlled trial.

INTRODUCTION: Perioperative mortality and morbidity remain substantial in acute surgery. Risk factors include known cardiovascular disease, but preoperative screening is insensitive to occult cardiopulmonary conditions. Focused cardiac ultrasound (FOCUS) can disclose both structural and functional cardiac disease and provides insight into the patient's haemodynamic status. This study aims to clarify whether preoperative FOCUS changes clinical outcomes in high-risk patients. METHODS: This is a multi-centre, randomised, controlled, prospective study including patients ≥ 65 years of age scheduled for acute/emergency abdominal- or orthopaedic surgery. A total of 800 patients will be randomised to ± application of preoperative FOCUS. The primary endpoint is the proportion of patients admitted to hospital > 10 days or death within 30 days of surgery. The secondary endpoints include changes in the anaesthesia approach facilitated by FOCUS, biomarkers of organ function and perioperative complications. CONCLUSIONS: The knowledge generated from this study may facilitate changes in the anaesthesia evaluation and decision process and, consequently, in the entire perioperative anaesthesia clinical practice. The study has the potential to reduce the risk of perioperative cardiopulmonary complications which directly implies improved patient outcome and reduced hospital costs. FUNDING: The Research Fund of the Department of Anaesthesiology, Randers Regional Hospital, The Central Denmark Region's Medical Research Fund and the Hospital of Southern Jutland. TRIAL REGISTRATION: NCT03501927.

[Monitoring options and reversal agents for oral anticoagulants].

The approval of the oral direct thrombin inhibitor dabigatranetexilat and the oral factor Xa inhibitors rivaroxaban and apixaban as thromboprophylaxis challenges the position of the vitamin K antagonists (VKA). Predictable pharmacodynamics gives the new oral anticoagulants an advantageous profile. Unlike VKAs there is no specific reversal agent available for the new oral anticoagulants. Experience with haemostatic products for the emergency management of critical bleeding caused by these agents is limited.