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Trials
Published in: Trials 1/2022

Open Access 01-12-2022 | Antibiotic | Study protocol

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

Authors: David J. Gagnon, Sergey V. Ryzhov, Meghan A. May, Richard R. Riker, Bram Geller, Teresa L. May, Sarah Bockian, Joanne T. deKay, Ashley Eldridge, Thomas Van der Kloot, Patricia Lerwick, Christine Lord, F. Lee Lucas, Patrick Mailloux, Barbara McCrum, Meghan Searight, Joel Wirth, Jonathan Zuckerman, Douglas Sawyer, David B. Seder

Published in: Trials | Issue 1/2022

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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.
Literature
1.
2.
Perbet S, Mongardon N, Dumas F, et al. Early-onset pneumonia after cardiac arrest: characteristics, risk factors and influence on prognosis. Am J Respir Crit Care Med. 2011;184:1048–54.PubMedCrossRef
3.
Gajic O, Festic E, Afessa B. Infectious complications in survivors of cardiac arrest admitted to the medical intensive care unit. Resuscitation. 2004;60:65–9.PubMedCrossRef
4.
Rello J, Vallés J, Jubert P, et al. Lower respiratory tract infections following cardiac arrest and cardiopulmonary resuscitation. Clin Infect Dis. 1995;21:310–4.PubMedCrossRef
5.
Gaussorgues P, Gueugniaud PY, Vedrinne JM, Salord F, Mercatello A, Robert D. Bacteremia following cardiac arrest and cardiopulmonary resuscitation. Intensive Care Med. 1988;14:575–7.PubMedCrossRef
6.
Kim YM, Youn CS, Kim SH, et al. Adverse events associated with poor neurological outcome during targeted temperature management and advanced critical care after out-of-hospital cardiac arrest. Crit Care. 2015;19:283.PubMedPubMedCentralCrossRef
7.
Bjork RJ, Snyder BD, Campion BC, Loewenson RB. Medical complications of cardiopulmonary arrest. Arch Intern Med. 1982;142:500–3.PubMedCrossRef
8.
Voorhees WD, Babbs CF, Tacker WA Jr. Regional blood flow during cardiopulmonary resuscitation in dogs. Crit Care Med. 1980;8(3):134–6.PubMedCrossRef
9.
Grimaldi D, Guivarch E, Neveux N, et al. Markers of intestinal injury are associated with endotoxemia in successfully resuscitated patients. Resuscitation. 2013;84(1):60–5.PubMedCrossRef
10.
Grimaldi D, Sauneuf B, Guivarch E, et al. High level of endotoxemia following out-of-hospital cardiac arrest is associated with severity and duration of postcardiac arrest shock. Crit Care Med. 2015;43:2597–04.PubMedCrossRef
11.
Adrie C, Laurent I, Monchi M, Cariou A, Dhainaou JF, Spaulding C. Postresuscitation disease after cardiac arrest: a sepsis-like syndrome? Curr Opin Crit Care. 2004;10:208–12.PubMedCrossRef
12.
Adrie C, Adib-Conquy M, Laurent I, et al. Successful cardiopulmonary resuscitation after cardiac arrest as a "sepsis-like" syndrome. Circulation. 2002;106:562–8.PubMedCrossRef
13.
Soppi E, Lindroos M, Nikoskelainen J, Kalliomäki JL. Effect of cardiopulmonary resuscitation-induced stress on cell-mediated immunity. Intensive Care Med. 1984;10:287–92.PubMedCrossRef
14.
Beurskens CJ, Horn J, de Boer AM, Schultz MJ, van Leeuwen EM, Vroom MB, et al. Cardiac arrest patients have an impaired immune response, which is not influenced by induced hypothermia. Crit Care. 2014;18:R162.PubMedPubMedCentralCrossRef
15.
Sirvent JM, Torres A, El-Ebiary M, Castro P, de Batlle J, Bonet A. Protective effect of intravenously administered cefuroxime against nosocomial pneumonia in patients with structural coma. Am J Respir Crit Care Med. 1997;155:1729–34.PubMedCrossRef
16.
Acquarolo A, Urli T, Perone G, Giannotti C, Candiani A, Latronico N. Antibiotic prophylaxis of early onset pneumonia in critically ill comatose patients. A randomized study. Intensive Care Med. 2005;31:510–6.PubMedCrossRef
17.
Vallés J, Peredo R, Burgueño MJ, et al. Efficacy of single-dose antibiotic against early-onset pneumonia in comatose patients who are ventilated. Chest. 2013;143:1219–25.PubMedCrossRef
18.
François B, Cariou A, Clere-Jehl R, et al. Prevention of early ventilator-associated pneumonia after cardiac arrest. N Engl J Med. 2019;381:1831–42.PubMedCrossRef
19.
20.
Ceftriaxone [package insert]. Weston, FL: Apotex Corporation; 2011.
21.
Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33 °C vs. 36 °C after cardiac arrest. N Engl J Med. 2013;369:2197–206.PubMedCrossRef
22.
Dankiewicz J, Cronberg T, Lilja G, et al. Hypothermia versus normothermia after out-of-hospital cardiac arrest. N Engl J Med. 2021;384:2283–94.PubMedCrossRef
23.
Skrupky LP, McConnell K, Dallas J, Kollef MH. A comparison of ventilator-associated pneumonia rates as identified according to the National Healthcare Safety Network and American College of Chest Physicians Criteria. Crit Care Med. 2012;40:281–4.PubMedCrossRef
24.
American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388–416.CrossRef
25.
McDonald CL, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66:e1–e48.PubMedPubMedCentralCrossRef
26.
Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary report--Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117:391–7.PubMedCrossRef
27.
Harmon MBA, Hodiamont CJ, Dankiewicz J, et al. Microbiological profile of nosocomial infections following cardiac arrest: Insights from the targeted temperature management (TTM) trial. Resuscitation. 2020;148:227–33.PubMedCrossRef
28.
29.
Russell JA, Epstein LG, Greer DM, et al. Brain death, the determination of brain death, and member guidance for brain death accommodation requests. Neurology. 2019;92:228–304.CrossRef
30.
31.
Gibson MK, Forsberg KJ, Dantas G. Improved annotation of antibiotic resistance determinants reveals microbial resistomes cluster by ecology. ISME J. 2015;9:207–16.PubMedCrossRef
32.
Kaminski J, Gibson MK, Franzosa EA, et al. High-specificity targeted functional profiling in microbial communities with ShortBRED. PLoS Comput Biol. 2015;11:e1004557.PubMedPubMedCentralCrossRef
33.
Ryzhov SV, Pickup MW, Chytil A, et al. Role of TGF-beta signaling in generation of CD39+CD73+ myeloid cells in tumors. J Immunol. 2014;193:3155–64.PubMedCrossRef
34.
Wei J, Pan X, Pei Z, et al. The beta-lactam antibiotic, ceftriaxone, provides neuroprotective potential via anti-excitotoxicity and anti-inflammation response in a rat model of traumatic brain injury. The J Trauma Acute Care Surg. 2012;73:654–60.PubMedCrossRef
35.
Melzer N, Meuth SG, Torres-Salazr D, et al. A beta-lactam antibiotic dampens excitotoxic inflammatory CNS damage in a mouse model of multiple sclerosis. PLoS One. 2008;3:e3149.PubMedPubMedCentralCrossRef
36.
Hameed MQ, Hsieh TH, Morales-Quezada L, et al. Ceftriaxone treatment preserves cortical inhibitory interneuron function via transient salvage of GLT-1 in a rat traumatic brain injury model. Cereb Cortex. 2019;29:4506–18.PubMedCrossRef
37.
Krzyzanowska W, Pomierny B, Bystrowska B, et al. Ceftriaxone- and N-acetylcysteine-induced brain tolerance to ischemia: Influence on glutamate levels in focal cerebral ischemia. PLoS One. 2017;12:e0186243.PubMedPubMedCentralCrossRef
38.
Jagadapillai R, Mellen NM, Sachleben LR Jr, Gozal E. Ceftriaxone preserves glutamate transporters and prevents intermittent hypoxia-induced vulnerability to brain excitotoxic injury. PLoS One. 2014;9:e100230.PubMedPubMedCentralCrossRef
39.
Hu YY, et al. Ceftriaxone modulates uptake activity of glial glutamate transporter-1 against global brain ischemia in rats. J Neurochem. 2015;132:194–205.PubMedCrossRef
40.
Tai CH, Bellesi M, Chen AC, et al. A new avenue for treating neuronal diseases: Ceftriaxone, an old antibiotic demonstrating behavioral neuronal effects. Behav Brain Res. 2019;364:149–56.PubMedCrossRef
41.
Gonzalez H, Pacheco R. T-cell-mediated regulation of neuroinflammation involved in neurodegenerative diseases. Journal of Neuroinflammation. 2014;11:201.PubMedPubMedCentralCrossRef
42.
Daglas M, Draxler DF, Ho H, et al. Activated CD8+ T cells cause long-term neurological impairment after traumatic brain injury in mice. Cell Reports. 2019;29:1178–1191.e1176.PubMedCrossRef
43.
Clemenzi MN, Wellhauser L, Aljghami ME, Belsham DD. Tumour necrosis factor α induces neuroinflammation and insulin resistance in immortalised hypothalamic neurones through independent pathways. J Neuroendocrinol. 2019;31:e12678.PubMedCrossRef
44.
Van Puyvelde S, Deborggraeve S, Jacobs J. Why the antibiotic resistance crisis requires a One Health approach. Lancet Infect Dis. 2018;18:132–4.PubMedCrossRef
Metadata
Title
Ceftriaxone to PRevent pneumOnia and inflammaTion aftEr Cardiac arresT (PROTECT): study protocol for a randomized, placebo-controlled trial
Authors
David J. Gagnon
Sergey V. Ryzhov
Meghan A. May
Richard R. Riker
Bram Geller
Teresa L. May
Sarah Bockian
Joanne T. deKay
Ashley Eldridge
Thomas Van der Kloot
Patricia Lerwick
Christine Lord
F. Lee Lucas
Patrick Mailloux
Barbara McCrum
Meghan Searight
Joel Wirth
Jonathan Zuckerman
Douglas Sawyer
David B. Seder
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Trials / Issue 1/2022
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-022-06127-w

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