Ceftriaxone to Prevent Pneumonia and Inflammation after Cardiac Arrest (PROTECT): study protocol for a randomized, placebo-controlled trial

David J. Gagnon, Maine Medical Center
Sergey V. Ryzhov, Maine Medical Center Research Institute, Scarborough, ME, USA.
Meghan A. May, University of New England College of Osteopathic Medicine, Biddeford, ME, USA.
Richard R. Riker, Tufts University School of Medicine, Boston, MA, USA.
Bram Geller, Tufts University School of Medicine, Boston, MA, USA.
Teresa L. May, Maine Medical Center Research Institute, Scarborough, ME, USA.
Sarah Bockian, Maine Medical Center Neuroscience Institute, Maine Medical Center, Portland, ME, USA.
Joanne T. deKay, Maine Medical Center Research Institute, Scarborough, ME, USA.
Ashley Eldridge, Maine Medical Center Neuroscience Institute, Maine Medical Center, Portland, ME, USA.
Thomas Van der Kloot, Department of Critical Care Services, Maine Medical Center, Portland, ME, USA.
Patricia Lerwick, Department of Critical Care Services, Maine Medical Center, Portland, ME, USA.
Christine Lord, Maine Medical Center Neuroscience Institute, Maine Medical Center, Portland, ME, USA.
F Lee Lucas, Maine Medical Center Research Institute, Scarborough, ME, USA.
Patrick Mailloux, Department of Critical Care Services, Maine Medical Center, Portland, ME, USA.
Barbara McCrum, Maine Medical Center Neuroscience Institute, Maine Medical Center, Portland, ME, USA.
Meghan Searight, Maine Medical Center Neuroscience Institute, Maine Medical Center, Portland, ME, USA.
Joel Wirth, Department of Critical Care Services, Maine Medical Center, Portland, ME, USA.
Jonathan Zuckerman, Tufts University School of Medicine, Boston, MA, USA.
Douglas Sawyer, Maine Medical Center Research Institute, Scarborough, ME, USA.
David B. Seder, Maine Medical Center Research Institute, Scarborough, ME, USA.

Document Type

Article

Publication Date

3-4-2022

Institution/Department

Pharmacy; Pulmonology; MaineHealth Institute for Research

Journal Title

Trials

MeSH Headings

Ceftriaxone (adverse effects); Double-Blind Method; Humans; Inflammation; Out-of-Hospital Cardiac Arrest (diagnosis, drug therapy); Pneumonia; Randomized Controlled Trials as Topic; Treatment Outcome

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.

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197

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