Ceftriaxone to PRevent pneumOnia and inflammaTion aftEr Cardiac arresT (PROTECT): study protocol for a randomized, placebo-controlled trial

Abstract

Background: Pneumonia is the most common infection after out-of-hospital cardiac arrest (OHCA) occurring in up to 65% of patients who remain comatose after return of spontaneous circulation. Preventing infection after OHCA may (1) reduce exposure to broad-spectrum antibiotics, (2) prevent hemodynamic derangements due to local and systemic inflammation, and (3) prevent infection-associated morbidity and mortality.

Methods: The ceftriaxone to PRevent pneumOnia and inflammaTion aftEr Cardiac arrest (PROTECT) trial is a randomized, placebo-controlled, single-center, quadruple-blind (patient, treatment team, research team, outcome assessors), non-commercial, superiority trial to be conducted at Maine Medical Center in Portland, Maine, USA. Ceftriaxone 2 g intravenously every 12 h for 3 days will be compared with matching placebo. The primary efficacy outcome is incidence of early-onset pneumonia occurring < 4 days after mechanical ventilation initiation. Concurrently, T cell-mediated inflammation bacterial resistomes will be examined. Safety outcomes include incidence of type-one immediate-type hypersensitivity reactions, gallbladder injury, and Clostridioides difficile-associated diarrhea. The trial will enroll 120 subjects over approximately 3 to 4 years.

Discussion: The PROTECT trial is novel in its (1) inclusion of OHCA survivors regardless of initial heart rhythm, (2) use of a low-risk antibiotic available in the USA that has not previously been tested after OHCA, (3) inclusion of anti-inflammatory effects of ceftriaxone as a novel mechanism for improved clinical outcomes, and (4) complete metagenomic assessment of bacterial resistomes pre- and post-ceftriaxone prophylaxis. The long-term goal is to develop a definitive phase III trial powered for mortality or functional outcome.

Trial registration: ClinicalTrials.gov NCT04999592 . Registered on August 10, 2021.

Keywords: Antibiotics; Cardiac arrest; Ceftriaxone; Hypothermia; Inflammation; Metagenomics; Microbiome; Pneumonia; Targeted temperature management.

Fig. 1

Ceftriaxone increases CD73 on T lymphocytes, and CD73 levels correlate with IFN-γ. A T cells were purified from peripheral blood from pre-operative coronary artery bypass patients and incubated in the absence (control) or presence of 50 μg/ml ceftriaxone for 24 h. B CD73 was measured in viable CD3 T cells gated as shown (red gate). C Quantification of flow cytometric data showing CD73 in total CD3 T cells and subpopulations of CD4+ and CD8+ unpaired t test, n=4. D Subpopulations of peripheral blood cells. E CD3+ T lymphocytes were gated and subpopulations of CD4+ (blue gate) and CD8+ (red gate) identified (F). G, H The expression of CD73 and production of IFN-γ in subpopulations of CD4+ (blue gate) and CD8+ (red gate) T lymphocytes