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

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.

Long-term effects of restriction of intravenous fluid in adult ICU patients with septic shock.

PURPOSE: To assess long-term outcomes of restrictive versus standard intravenous (IV) fluid therapy in adult intensive care unit (ICU) patients with septic shock included in the European Conservative versus Liberal Approach to Fluid Therapy in Septic Shock in Intensive Care (CLASSIC) trial. METHODS: We conducted the pre-planned analyses of mortality, health-related quality of life (HRQoL) using EuroQol (EQ)-5D-5L index values and EQ visual analogue scale (VAS), and cognitive function using Mini Montreal Cognitive Assessment (Mini MoCA) test at 1 year. Deceased patients were assigned numerical zero for HRQoL as a state equal to death and zero for cognitive function outcomes as worst possible score, and we used multiple imputation for missing data on HRQoL and cognitive function. RESULTS: Among 1554 randomized patients, we obtained 1-year data on mortality in 97.9% of patients, HRQoL in 91.3%, and cognitive function in 86.3%. One-year mortality was 385/746 (51.3%) in the restrictive-fluid group versus 383/767 (49.9%) in the standard-fluid group, absolute risk difference 1.5%-points [99% confidence interval (CI) - 4.8 to 7.8]. Mean differences were 0.00 (99% CI - 0.06 to 0.05) for EQ-5D-5L index values, - 0.65 for EQ VAS (- 5.40 to 4.08), and - 0.14 for Mini MoCA (- 1.59 to 1.14) for the restrictive-fluid group versus the standard-fluid group. The results for survivors only were similar in both groups. CONCLUSIONS: Among adult ICU patients with septic shock, restrictive versus standard IV fluid therapy resulted in similar survival, HRQoL, and cognitive function at 1 year, but clinically important differences could not be ruled out.

The effects of preoperative focused cardiac ultrasound in high-risk patients: A randomised controlled trial (PREOPFOCUS).

BACKGROUND: Surgery is the third most common cause of mortality worldwide. Focused cardiac ultrasound (FOCUS) yields information on cardiac status and discloses the presence of unknown pathology. Preoperative FOCUS changes patient treatment, allowing for a patient-tailored anaesthesia. We hypothesised that preoperative FOCUS would reduce the proportion of patients who were either admitted to hospital for more than 10 days or who were dead within 30 days after high-risk, non-cardiac surgery. METHODS: This was a randomised, controlled, multi-center study. Patients ≥65 years of age, admitted for urgent orthopaedic- or abdominal surgery, scheduled for general- or neuraxial anaesthesia and with ASA 3/4 were eligible for inclusion. Patients were randomised in a 1:1 ratio to preoperative FOCUS or no preoperative FOCUS performed in accordance with a predefined protocol. Primary endpoint was the proportion of patients admitted more than 10 days or who were dead within 30 days. Secondary endpoints included major complications, days of admission and changes in anaesthesia handling. RESULTS: During the second COVID-19 wave the study monitoring committee terminated the study prematurely. We included 338 patients of which 327 were included in the final analysis. In the FOCUS group, 41/163 (25%) patients met the criteria for the primary endpoint versus 35/164 (21%) for the control group, adjusted odds ratio 1.37 (95% CI 0.86-2.30), p = .36. The proportions of patients who developed major complications did not differ significantly between groups. Length of hospital stay was 4 (3-8) days in the FOCUS group and 4 (3-7) days on the control group (adjusted p = .24). CONCLUSION: The routine availability of preoperative FOCUS assessment in this cohort does not appear to reduce the risk for hospitalisation exceeding 10 days or 30-day mortality, although study enrolment was prematurely terminated.

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).

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.

Restriction of Intravenous Fluid in ICU Patients with Septic Shock.

BACKGROUND: Intravenous fluids are recommended for the treatment of patients who are in septic shock, but higher fluid volumes have been associated with harm in patients who are in the intensive care unit (ICU). METHODS: In this international, randomized trial, we assigned patients with septic shock in the ICU who had received at least 1 liter of intravenous fluid to receive restricted intravenous fluid or standard intravenous fluid therapy; patients were included if the onset of shock had been within 12 hours before screening. The primary outcome was death from any cause within 90 days after randomization. RESULTS: We enrolled 1554 patients; 770 were assigned to the restrictive-fluid group and 784 to the standard-fluid group. Primary outcome data were available for 1545 patients (99.4%). In the ICU, the restrictive-fluid group received a median of 1798 ml of intravenous fluid (interquartile range, 500 to 4366); the standard-fluid group received a median of 3811 ml (interquartile range, 1861 to 6762). At 90 days, death had occurred in 323 of 764 patients (42.3%) in the restrictive-fluid group, as compared with 329 of 781 patients (42.1%) in the standard-fluid group (adjusted absolute difference, 0.1 percentage points; 95% confidence interval [CI], -4.7 to 4.9; P = 0.96). In the ICU, serious adverse events occurred at least once in 221 of 751 patients (29.4%) in the restrictive-fluid group and in 238 of 772 patients (30.8%) in the standard-fluid group (adjusted absolute difference, -1.7 percentage points; 99% CI, -7.7 to 4.3). At 90 days after randomization, the numbers of days alive without life support and days alive and out of the hospital were similar in the two groups. CONCLUSIONS: Among adult patients with septic shock in the ICU, intravenous fluid restriction did not result in fewer deaths at 90 days than standard intravenous fluid therapy. (Funded by the Novo Nordisk Foundation and others; CLASSIC ClinicalTrials.gov number, NCT03668236.).

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.

Long-term patient-important outcomes after septic shock: A protocol for 1-year follow-up of the CLASSIC trial.

BACKGROUND: In patients with septic shock, mortality is high, and survivors experience long-term physical, mental and social impairments. The ongoing Conservative vs Liberal Approach to fluid therapy of Septic Shock in Intensive Care (CLASSIC) trial assesses the benefits and harms of a restrictive vs standard-care intravenous (IV) fluid therapy. The hypothesis is that IV fluid restriction improves patient-important long-term outcomes. AIM: To assess the predefined patient-important long-term outcomes in patients randomised into the CLASSIC trial. METHODS: In this pre-planned follow-up study of the CLASSIC trial, we will assess all-cause mortality, health-related quality of life (HRQoL) and cognitive function 1 year after randomisation in the two intervention groups. The 1-year mortality will be collected from electronic patient records or central national registries in most participating countries. We will contact survivors and assess EuroQol 5-Dimension, -5-Level (EQ-5D-5L) and EuroQol-Visual Analogue Scale and Montreal Cognitive Assessment 5-minute protocol score. We will analyse mortality by logistic regression and use general linear models to assess HRQoL and cognitive function. DISCUSSION: With this pre-planned follow-up study of the CLASSIC trial, we will provide patient-important data on long-term survival, HRQoL and cognitive function of restrictive vs standard-care IV fluid therapy in patients with septic shock.

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.

Conservative vs liberal fluid therapy in septic shock (CLASSIC) trial-Protocol and statistical analysis plan.

INTRODUCTION: Intravenous (IV) fluid is a key intervention in the management of septic shock. The benefits and harms of lower versus higher fluid volumes are unknown and thus clinical equipoise exists. We describe the protocol and detailed statistical analysis plan for the conservative versus liberal approach to fluid therapy of septic shock in the Intensive Care (CLASSIC) trial. The aim of the CLASSIC trial is to assess benefits and harms of IV fluid restriction versus standard care in adult intensive care unit (ICU) patients with septic shock. METHODS: CLASSIC trial is an investigator-initiated, international, randomised, stratified, and analyst-blinded trial. We will allocate 1554 adult patients with septic shock, who are planned to be or are admitted to an ICU, to IV fluid restriction versus standard care. The primary outcome is mortality at day 90. Secondary outcomes are serious adverse events (SAEs), serious adverse reactions (SARs), days alive at day 90 without life support, days alive and out of the hospital at day 90 and mortality, health-related quality of life (HRQoL), and cognitive function at 1 year. We will conduct the statistical analyses according to a pre-defined statistical analysis plan, including three interim analyses. For the primary analysis, we will use logistic regression adjusted for the stratification variables comparing the two interventions in the intention-to-treat (ITT) population. DISCUSSION: The CLASSIC trial results will provide important evidence to guide clinicians' choice regarding the IV fluid therapy in adults with septic shock.

Lower versus higher hemoglobin threshold for transfusion in septic shock.

BACKGROUND: Blood transfusions are frequently given to patients with septic shock. However, the benefits and harms of different hemoglobin thresholds for transfusion have not been established. METHODS: In this multicenter, parallel-group trial, we randomly assigned patients in the intensive care unit (ICU) who had septic shock and a hemoglobin concentration of 9 g per deciliter or less to receive 1 unit of leukoreduced red cells when the hemoglobin level was 7 g per deciliter or less (lower threshold) or when the level was 9 g per deciliter or less (higher threshold) during the ICU stay. The primary outcome measure was death by 90 days after randomization. RESULTS: We analyzed data from 998 of 1005 patients (99.3%) who underwent randomization. The two intervention groups had similar baseline characteristics. In the ICU, the lower-threshold group received a median of 1 unit of blood (interquartile range, 0 to 3) and the higher-threshold group received a median of 4 units (interquartile range, 2 to 7). At 90 days after randomization, 216 of 502 patients (43.0%) assigned to the lower-threshold group, as compared with 223 of 496 (45.0%) assigned to the higher-threshold group, had died (relative risk, 0.94; 95% confidence interval, 0.78 to 1.09; P=0.44). The results were similar in analyses adjusted for risk factors at baseline and in analyses of the per-protocol populations. The numbers of patients who had ischemic events, who had severe adverse reactions, and who required life support were similar in the two intervention groups. CONCLUSIONS: Among patients with septic shock, mortality at 90 days and rates of ischemic events and use of life support were similar among those assigned to blood transfusion at a higher hemoglobin threshold and those assigned to blood transfusion at a lower threshold; the latter group received fewer transfusions. (Funded by the Danish Strategic Research Council and others; TRISS ClinicalTrials.gov number, NCT01485315.).

[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.

Transfusion requirements in septic shock (TRISS) trial - comparing the effects and safety of liberal versus restrictive red blood cell transfusion in septic shock patients in the ICU: protocol for a randomised controlled trial.

BACKGROUND: Transfusion of red blood cells (RBC) is recommended in septic shock and the majority of these patients receive RBC transfusion in the intensive care unit (ICU). However, benefit and harm of RBCs have not been established in this group of high-risk patients. METHODS/DESIGN: The Transfusion Requirements in Septic Shock (TRISS) trial is a multicenter trial with assessor-blinded outcome assessment, randomising 1,000 patients with septic shock in 30 Scandinavian ICUs to receive transfusion with pre-storage leuko-depleted RBC suspended in saline-adenine-glucose and mannitol (SAGM) at haemoglobin level (Hb) of 7 g/dl or 9 g/dl, stratified by the presence of haematological malignancy and centre. The primary outcome measure is 90-day mortality. Secondary outcome measures are organ failure, ischaemic events, severe adverse reactions (SARs: anaphylactic reaction, acute haemolytic reaction and transfusion-related circulatory overload, and acute lung injury) and mortality at 28 days, 6 months and 1 year.The sample size will enable us to detect a 9% absolute difference in 90-day mortality assuming a 45% event rate with a type 1 error rate of 5% and power of 80%. An interim analysis will be performed after 500 patients, and the Data Monitoring and Safety Committee will recommend the trial be stopped if a group difference in 90-day mortality with P ≤0.001 is present at this point. DISCUSSION: The TRISS trial may bridge the gap between clinical practice and the lack of efficacy and safety data on RBC transfusion in septic shock patients. The effect of restrictive versus liberal RBC transfusion strategy on mortality, organ failure, ischaemic events and SARs will be evaluated.