In-hospital mortality during the wild-type, alpha, delta, and omicron SARS-CoV-2 waves: a multinational cohort study in the EuCARE project.

Background: Investigating outcomes of hospitalised COVID-19 patients throughout the pandemic is crucial to understand the impact of different SARS-CoV-2 variants. We compared 28-day in-hospital mortality of Wild-type, Alpha, Delta, and Omicron variant infections. Whether the difference in risk by variant varied by age was also evaluated. Methods: We conducted a cohort study including patients ≥18 years, hospitalised between 2020 and 02-01 and 2022-10-15 with a SARS-CoV-2 positive test, from nine countries. Variant was classified based on sequenced viruses or from national public metadata. Mortality was compared using the cumulative incidence function and subdistribution hazard ratios (SHR) adjusted for age, sex, calendar time, and comorbidities. Results were shown age-stratified due to effect measure modification (P < 0.0001 for interaction between age and variant). Findings: We included 38,585 participants: 19,763 Wild-type, 6387 Alpha, 3640 Delta, and 8795 Omicron. The cumulative incidence of mortality decreased throughout the study period. Among participants ≥70 years, the adjusted SHR (95% confidence interval) for Delta vs. Omicron was 1.66 (1.29-2.13). This estimate was 1.66 (1.17-2.36) for Alpha vs. Omicron, and 1.34 (0.92-1.95) for Wild-type vs. Omicron. These were 1.21 (0.81-1.82), 1.21 (0.68-2.17), and 0.98 (0.53-1.82) among unvaccinated participants. When comparing Omicron sublineages, the aSHR for BA.1 was 1.92 (1.43-2.58) compared to BA.2 and 1.52 (1.11-2.08) compared to BA.5. Interpretation: The herein observed decrease in in-hospital mortality seems to reflect a combined effect of immunity from vaccinations and previous infections, although differences in virulence between SARS-CoV-2 variants may also have contributed. Funding: European Union's Horizon Europe Research and Innovation Programme.

Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study).

PURPOSE: The CIGMA study investigated a novel human polyclonal antibody preparation (trimodulin) containing ~ 23% immunoglobulin (Ig) M, ~ 21% IgA, and ~ 56% IgG as add-on therapy for patients with severe community-acquired pneumonia (sCAP). METHODS: In this double-blind, phase II study (NCT01420744), 160 patients with sCAP requiring invasive mechanical ventilation were randomized (1:1) to trimodulin (42 mg IgM/kg/day) or placebo for five consecutive days. Primary endpoint was ventilator-free days (VFDs). Secondary endpoints included 28-day all-cause and pneumonia-related mortality. Safety and tolerability were monitored. Exploratory post hoc analyses were performed in subsets stratified by baseline C-reactive protein (CRP; ≥ 70 mg/L) and/or IgM (≤ 0.8 g/L). RESULTS: Overall, there was no statistically significant difference in VFDs between trimodulin (mean 11.0, median 11 [n = 81]) and placebo (mean 9.6; median 8 [n = 79]; p = 0.173). Twenty-eight-day all-cause mortality was 22.2% vs. 27.8%, respectively (p = 0.465). Time to discharge from intensive care unit and mean duration of hospitalization were comparable between groups. Adverse-event incidences were comparable. Post hoc subset analyses, which included the majority of patients (58-78%), showed significant reductions in all-cause mortality (trimodulin vs. placebo) in patients with high CRP, low IgM, and high CRP/low IgM at baseline. CONCLUSIONS: No significant differences were found in VFDs and mortality between trimodulin and placebo groups. Post hoc analyses supported improved outcome regarding mortality with trimodulin in subsets of patients with elevated CRP, reduced IgM, or both. These findings warrant further investigation. TRIAL REGISTRATION: NCT01420744.

Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis.

BACKGROUND: Levosimendan is a calcium-sensitizing drug with inotropic and other properties that may improve outcomes in patients with sepsis. METHODS: We conducted a double-blind, randomized clinical trial to investigate whether levosimendan reduces the severity of organ dysfunction in adults with sepsis. Patients were randomly assigned to receive a blinded infusion of levosimendan (at a dose of 0.05 to 0.2 µg per kilogram of body weight per minute) for 24 hours or placebo in addition to standard care. The primary outcome was the mean daily Sequential Organ Failure Assessment (SOFA) score in the intensive care unit up to day 28 (scores for each of five systems range from 0 to 4, with higher scores indicating more severe dysfunction; maximum score, 20). Secondary outcomes included 28-day mortality, time to weaning from mechanical ventilation, and adverse events. RESULTS: The trial recruited 516 patients; 259 were assigned to receive levosimendan and 257 to receive placebo. There was no significant difference in the mean (±SD) SOFA score between the levosimendan group and the placebo group (6.68±3.96 vs. 6.06±3.89; mean difference, 0.61; 95% confidence interval [CI], -0.07 to 1.29; P=0.053). Mortality at 28 days was 34.5% in the levosimendan group and 30.9% in the placebo group (absolute difference, 3.6 percentage points; 95% CI, -4.5 to 11.7; P=0.43). Among patients requiring ventilation at baseline, those in the levosimendan group were less likely than those in the placebo group to be successfully weaned from mechanical ventilation over the period of 28 days (hazard ratio, 0.77; 95% CI, 0.60 to 0.97; P=0.03). More patients in the levosimendan group than in the placebo group had supraventricular tachyarrhythmia (3.1% vs. 0.4%; absolute difference, 2.7 percentage points; 95% CI, 0.1 to 5.3; P=0.04). CONCLUSIONS: The addition of levosimendan to standard treatment in adults with sepsis was not associated with less severe organ dysfunction or lower mortality. Levosimendan was associated with a lower likelihood of successful weaning from mechanical ventilation and a higher risk of supraventricular tachyarrhythmia. (Funded by the NIHR Efficacy and Mechanism Evaluation Programme and others; LeoPARDS Current Controlled Trials number, ISRCTN12776039 .).

National survey and point prevalence study of sedation practice in UK critical care.

BACKGROUND: The present study was designed to (1) establish current sedation practice in UK critical care to inform evidence synthesis and potential future primary research and (2) to compare practice reported via a survey with actual practice assessed in a point prevalence study (PPS). METHODS: UK adult general critical care units were invited to participate in a survey of current sedation practice, and a representative sample of units was invited to participate in a PPS of sedation practice at the patient level. Survey responses were compared with PPS data where both were available. RESULTS: Survey responses were received from 214 (91 %) of 235 eligible critical care units. Of these respondents, 57 % reported having a written sedation protocol, 94 % having a policy of daily sedation holds and 94 % using a sedation scale to assess depth of sedation. In the PPS, across units reporting a policy of daily sedation holds, a median of 50 % (IQR 33-75 %) of sedated patients were considered for a sedation hold. A median of 88 % (IQR 63-100 %) of patients were assessed using the same sedation scale as reported in the survey. Both the survey and the PPS indicated propofol as the preferred sedative and alfentanil, fentanyl and morphine as the preferred analgesics. In most of the PPS units, all patients had received the unit's reported first-choice sedative (median across units 100 %, IQR 64-100 %), and a median of 80 % (IQR 67-100 %) of patients had received the unit's reported first-choice analgesic. Most units (83 %) reported in the survey that sedatives are usually administered in combination with analgesics. Across units that participated in the PPS, 69 % of patients had received a combination of agents - most frequently propofol combined with either alfentanil or fentanyl. CONCLUSIONS: Clinical practice reported in the national survey did not accurately reflect actual clinical practice at the patient level observed in the PPS. Employing a mixed methods approach provided a more complete picture of sedation practice in terms of breadth and depth of information.

Validation of a classification system for causes of death in critical care: an assessment of inter-rater reliability.

OBJECTIVE: Trials in critical care have previously used unvalidated systems to classify cause of death. We aimed to provide initial validation of a method to classify cause of death in intensive care unit patients. DESIGN, SETTING AND PARTICIPANTS: One hundred case scenarios of patients who died in an ICU were presented online to raters, who were asked to select a proximate and an underlying cause of death for each, using the ICU Deaths Classification and Reason (ICU-DECLARE) system. We evaluated two methods of categorising proximate cause of death (designated Lists A and B) and one method of categorising underlying cause of death. Raters were ICU specialists and research coordinators from Australia, New Zealand and the United Kingdom. MAIN OUTCOME MEASURES: Inter-rater reliability, as measured by the Fleiss multirater kappa, and the median proportion of raters choosing the most likely diagnosis (defined as the most popular classification choice in each case). RESULTS: Across all raters and cases, for proximate cause of death List A, kappa was 0.54 (95% CI, 0.49-0.60), and for proximate cause of death List B, kappa was 0.58 (95% CI, 0.53-0.63). For the underlying cause of death, kappa was 0.48 (95% CI, 0.44-0.53). The median proportion of raters choosing the most likely diagnosis for proximate cause of death, List A, was 77.5% (interquartile range [IQR], 60.0%-93.8%), and the median proportion choosing the most likely diagnosis for proximate cause of death, List B, was 82.5% (IQR, 60.0%-92.5%). The median proportion choosing the most likely diagnosis for underlying cause was 65.0% (IQR, 50.0%-81.3%). Kappa and median agreement were similar between countries. ICU specialists showed higher kappa and median agreement than research coordinators. CONCLUSIONS: The ICU-DECLARE system allowed ICU doctors to classify the proximate cause of death of patients who died in the ICU with substantial reliability.

Critical care research in a district general hospital: the first year.

Until recently, research in critical care units has usually taken place in university teaching hospitals. The 'general' critical care unit patient population is broader than this and the research needs to reflect this. As a general critical care unit in a district general hospital we wanted to set-up research within our own department, as part of the critical care team and part of our culture. With extensive background communication, drive and hard work, the support of the hospital Research and Development department was gained and Comprehensive Local Research Network funding successfully applied for. A research team was established and a model for the Research Nurse role was developed and implemented. This model is described. Participation in national trials commenced and the research portfolio is growing. Networking with other teams also proved valuable. Research has been established as part of the 'culture' of the day-to-day work and the staff have embraced this. Dedicated Research Nurse posts and education of the whole team have ensured successful implementation and recruitment of the studies. Experiences of the first year are shared and discussed here. Sharing experience of developing research within a critical care unit in a district general hospital, and a suggested model for a new Research Nurse role, may benefit other similar units in their efforts to establish research.

Sedation practice in the intensive care unit: a UK national survey.

INTRODUCTION: The purpose of this study was to evaluate sedation practice in UK intensive care units (ICUs), particularly the implementation of daily sedation holding, written sedation guidelines, sedation scoring tools and choice of agents. METHODS: A national postal survey was conducted in all UK ICUs. RESULTS: A total of 192 responses out of 302 addressed units were received (63.5%). Of the responding ICUs, 88% used a sedation scoring tool, most frequently the Ramsey Sedation Scale score (66.4%). The majority of units have a written sedation guideline (80%), and 78% state that daily sedation holding is practiced. A wide variety of sedating agents is used, with the choice of agent largely determined by the duration of action rather than cost. The most frequently used agents were propofol and alfentanil for short-term sedation; propofol, midazolam and morphine for longer sedation; and propofol for weaning purposes. CONCLUSIONS: Most UK ICUs use a sedation guideline and sedation scoring tool. The concept of sedation holding has been implemented in the majority of units, and most ICUs have a written sedation guideline.