There will be our usual mix of major trial result presentations, reviews of the best trials of the past year and panel discussions of various aspects of clinical trials.
These are the first presentations of the results of major critical care trials and usually occur in conjunction with a simultaneous publication in a major general medical journal. Each results session lasts 90 minutes, including time for the results presentation, independent editorial, questions and a panel discussion.
The MERCY trial is a multicenter, randomized, double-blind study aiming to optimize meropenem use in ICU patients with gram-negative infections. With a sample size of 607 participants, the trial compares continuous infusion (3g/day or 2g/day based on renal function) with intermittent bolus administration (1g every 6-8 hours or 12 hours) of meropenem in patients with sepsis or septic shock.
The primary outcome is a composite of 28-day mortality and the emergence of new extended drug-resistant (XDR) or pan drug-resistant (PDR) bacteria. Secondary outcomes include 90-day mortality, antibiotic-free days, ICU-free days, and cumulative SOFA-free points.
The study started in June 2018 and completed in December 2022. Participants were adults in ICU with sepsis or septic shock requiring meropenem treatment, and were not already on carbapenem or had contraindications to the drug.
The MERCY trial seeks to determine if continuous meropenem infusion can reduce mortality and the emergence of drug-resistant pathogens compared to intermittent bolus administration.
Around 11,000 of the most seriously ill children are referred to intensive care as an emergency in the UK each year, of whom at least 7,500 receive both invasive mechanical ventilation and supplemental oxygen. The administration of oxygen is a fundamental part of care in paediatric critical illness with supplemental oxygen offered to nearly every acutely unwell child. However, the optimal targets for systemic oxygenation are unknown.
OXY-PICU is a multi-centre, randomised controlled trial in 2040 critically ill children, comparing oxygen targets of SpO2 88-92% with >94%. The primary outcome is a cComposite of mortality and duration of organ support at 30 days.
CRYOSTAT-2 is a multicenter, randomised controlled clinical trial aimed at evaluating the efficacy and safety of early fibrinogen concentrate administration in adult patients with major traumatic hemorrhage. The study population consists of trauma patients presenting with active bleeding and clinical signs of shock, requiring a massive transfusion protocol. In the intervention group, patients receive a dose of 6 grams of fibrinogen concentrate (3 pools), administered intravenously as soon as possible after randomization. The control group receives standard major haemorrhage protocol only. The primary outcome is mortality at 28 days. 1568 patients will provide 90% power to detect a 7% absolute risk reduction for mortality at 28 days, from 26% in the control group to 19% in the intervention group, at the 5% significance level.
The TAME trial is an international, randomized controlled trial investigating the efficacy of targeted therapeutic mild hypercapnia in improving functional outcomes in 1700 comatose adults after out-of-hospital cardiac arrest (OHCA). Participants are randomised to be managed with either targeted therapeutic mild hypercapnia (PaCO2 range of 50-55 mmHg), or targeted normocapnia (PaCO2 range of 35-45 mmHg). The primary outcome measure is the proportion of participants with favorable neurological outcomes at six months, assessed using the Glasgow Outcome Scale-Extended (GOSE). Favorable GOSE outcomes are scores ≥5. The TAME trial requires 812 patients per arm (total of 1624 patients) to achieve 90% power to detect an 8% absolute increase in the primary outcome at an α of 0.05 with an expected 50% incidence in the control arm. The sample size was increased to 1700 patients (850 per arm) to account for a 5% loss to follow-up and withdrawal of consent rate.
The Pre-hospital Anti-fibrinolytics for Traumatic Coagulopathy and Haemorrhage (The PATCH-Trauma study) compared TXA, initiated prehospital and continued in hospital over 8 hours, with placebo in patients with severe trauma at risk of acute traumatic coagulopathy being treated in advanced trauma systems. 1316 patients were recruited by prehospital clinicians in Australia, New Zealand and Germany. The primary outcome was the eight-level Glasgow Outcome Scale Extended (GOS-E) at 6 months after injury, dichotomised to favourable (GOSE 5–8) and unfavourable (GOSE 1–4) outcomes, analysed using an intention-to-treat (ITT) approach. Secondary outcomes included mortality at 24 hours, 28 days and at 6 months, vascular occlusive events, sepsis, coagulation status, blood product usage, and other measures of quality of life.
The DEVICE trial is a prospective, multicentre, non-blinded, randomised trial being conducted in 7 EDs and 10 ICUs in the USA. The trial plans to enrol up to 2000 critically ill adults undergoing orotracheal intubation with a laryngoscope. Eligible patients are randomised 1:1 to the use of a video laryngoscope or a direct laryngoscope for the first intubation attempt. The primary outcome is successful intubation on the first attempt. The secondary outcome is the incidence of severe complications between induction and 2 min after intubation, defined as the occurrence of one or more of the following: severe hypoxaemia (lowest oxygen saturation <80%); severe hypotension (systolic blood pressure <65 mm Hg or new or increased vasopressor administration); cardiac arrest or death.
The UK REBOA Trial is a pragmatic, Bayesian, group-sequential, randomised controlled trial, performed in 16 major trauma centres in England. It aim's to randomise 120 injured patients with suspected exsanguinating haemorrhage to either standard major trauma centre care plus REBOA device (resuscitative endovascular balloon occlusion of the aorta) or standard major trauma centre care alone. The primary clinical outcome is 90-day mortality. Secondary clinical outcomes include 3-h, 6-h, and 24-h mortality; in-hospital mortality; 6-month mortality; length of stay (in hospital and intensive care unit); 24-h blood product use; need for haemorrhage control procedure (operation or angioembolisation); and time to commencement of haemorrhage control procedure (REBOA, operation, or angioembolisation). The primary economic outcome is lifetime incremental cost per QALY gained, from a health and personal social services perspective.
These presentations are of some of the best critical care trials published over the past 12 months. These last 40 minutes and include the trial presentation, editorial and questions.
In this bayesian adaptive randomized clinical platform trial that included 4869 critically ill patients with COVID-19, the probability was high that IL-6 receptor antagonists and antiplatelet agents improved survival at 6 months (posterior probabilities of superiority of >99.9% and 95.0%, respectively). Long-term outcomes were not improved with therapeutic anticoagulation (11.5%), convalescent plasma (54.7%), or lopinavir-ritonavir (31.9%) and were worsened with hydroxychloroquine (posterior probability of harm, 96.8%). Corticosteroids did not improve long-term outcomes, although enrollment was terminated early in response to external evidence.
In a cluster-randomized trial, adults receiving mechanical ventilation were assigned to lower (90%; 88-92% range), intermediate (94%; 92-96% range), or higher (98%; 96-100% range) oxygen saturation targets. The primary outcome was ventilator-free days through day 28, and the secondary outcome was death by day 28. A total of 2541 patients were included, with no significant difference in ventilator-free days among the groups (P=0.81). In-hospital death by day 28 was similar across groups. Incidences of cardiac arrest, arrhythmia, myocardial infarction, stroke, and pneumothorax were also comparable. No significant difference in outcomes was observed among the different oxygen saturation target groups.
Critically ill patients frequently lose muscle mass and develop weakness whilst in the ICU. While it's intuitive to think physical activity may reduce muscle loss, improve strength and ultimately patient outcomes, the trials to date have been inconclusive. Is (very) early mobilisation beneficial? Or could it even be harmful? Join Chief Investigator Prof Carol Hodgson to find out.
Despite being a prevalent complication of critical illness, no specific therapy has been identified for delirium. To date, management largely consists of treating the underlying disorder and optimising the patient's drug therapies, nursing care, mobilisation and environment. Can haloperidol improve outcomes for patients with delirium? Nina Christine Andersen-Ranberg, the Coordinating Investigator of AID-ICU, will present the trial, with an idependent editorial to follow.
Whether to use early vasopressor instead of fluids has been a hot question in critical care. The PETAL group recently reported the results of the long awaited CLOVERS trial addressing this issue. How do we interpret this trial and what does it mean for management of the septic patient? Ivor Douglas, the co-chief investigator, will present the trial, with an independent editorial to follow.
This double-blind, randomized, placebo-controlled superiority trial investigated the efficacy and safety of 4-factor prothrombin complex concentrate (4F-PCC) in patients with trauma at risk of massive transfusion. The study took place across 12 French level I trauma centers and involved 324 patients. The primary outcome was 24-hour blood product consumption, and secondary outcomes included thromboembolic events. Results showed no significant difference in blood product consumption between the 4F-PCC and placebo groups, with 12 and 11 units consumed, respectively. However, 35% of patients in the 4F-PCC group experienced at least one thromboembolic event, compared to 24% in the placebo group. The findings do not support the systematic use of 4F-PCC for patients at risk of massive transfusion due to the increased risk of thromboembolic events.