Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

(1,3)-β-D-glucan-based diagnosis of invasive Candida infection versus culture-based diagnosis in patients with sepsis and with an increased risk of invasive Candida infection (CandiSep): study protocol for a randomized controlled trial

Abstract Background The time to diagnosis of invasive Candida infection (ICI) is often too long to initiate timely antifungal therapy in patients with sepsis. Elevated serum (1,3)-β-D-glucan (BDG) concentrations have a high diagnostic sensitivity for detecting ICI. However, the clinical significance of elevated BDG concentrations is unclear in critically ill patients. The goal of this study is to investigate whether measurement of BDG in patients with sepsis and a high risk for ICI can be used to decrease the time to empiric antifungal therapy and thus, increase survival. Methods/design This prospective multicenter open randomized controlled trial is being conducted in 19 German intensive care units. All adult patients with severe sepsis or septic shock and an increased risk for ICI are eligible for enrolment. Risk factors are total parenteral nutrition, previous abdominal surgery, previous antimicrobial therapy, and renal replacement therapy. Patients with proven ICI or those already treated with systemic antifungal substances are excluded. Patients are allocated to a BDG or standard care group. The standard care group receives targeted antifungal therapy as necessary. In the BDG group, BDG serum samples are taken after randomization and 24 h later. Antifungal therapy is initiated if BDG is ≥80 pg/ml in at least one sample. We plan to enroll 312 patients. The primary outcome is 28-day mortality. Other outcomes include antifungal-free survival within 28 days after enrolment, time to antifungal therapy, and the diagnostic performance of BDG compared to other laboratory tests for early ICI diagnosis. The statistical analysis will be performed according to the intent-to-treat principle. Discussion Because of the high risk of death, American guidelines recommend empiric antifungal therapy in sepsis patients with a high risk of ICI despite the limited evidence for such a recommendation. In contrast, empiric antifungal therapy is not recommended by European guidelines. BDG may offer a way out of this dilemma since BDG potentially identifies patients in need of early antifungals. However, the evidence for such an approach is inconclusive. This clinical study will generate solid evidence for health-care providers and authors of guidelines for the use of BDG in critically ill patients. Trial registration Clinicaltrials.gov, NCT02734550. Registered 12 April 2016

Effect of acyclovir therapy on the outcome of mechanically ventilated patients with lower respiratory tract infection and detection of herpes simplex virus in bronchoalveolar lavage: protocol for a multicentre, randomised controlled trial (HerpMV)

Introduction Herpes simplex virus (HSV) is frequently detected in the respiratory tract of mechanically ventilated patients and is associated with a worse outcome. The aim of this study is to determine whether antiviral therapy in HSV-positive patients improves outcome.Methods and analysis Prospective, multicentre, open-label, randomised, controlled trial in parallel-group design. Adult, mechanically ventilated patients with pneumonia and HSV type 1 detected in bronchoalveolar lavage (≥105 copies/mL) are eligible for participation and will be randomly allocated (1:1) to receive acyclovir (10 mg/kg body weight every 8 hours) for 10 days (or until discharge from the intensive care unit if earlier) or no intervention (control group). The primary outcome is mortality measured at day 30 after randomisation (primary endpoint) and will be analysed with Cox mixed-effects model. Secondary endpoints include ventilator-free and vasopressor-free days up to day 30. A total of 710 patients will be included in the trial.Ethics and dissemination The trial was approved by the responsible ethics committee and by Germany’s Federal Institute for Drugs and Medical Devices. The clinical trial application was submitted under the new Clinical Trials Regulation through CTIS (The Clinical Trials Information System). In this process, only one ethics committee, whose name is unknown to the applicant, and Germany’s Federal Institute for Drugs and Medical Devices are involved throughout the entire approval process. Results will be published in a journal indexed in MEDLINE and CTIS. With publication, de-identified, individual participant data will be made available to researchers.Trial registration number NCT06134492

Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19

International audienc