Randomized Controlled Trial

. 2025 Aug 1;53(8):e1554-e1566.

doi: 10.1097/CCM.0000000000006720. Epub 2025 May 29.

A Multinational Randomized Trial of Mega-Dose Esomeprazole as Anti-Inflammatory Agent in Sepsis

Giacomo Monti^{1

2}, Sonia Carta³, Yuki Kotani^{1

2

4}, Andrea Bruni⁵, Maiya Konkayeva⁶, Fabio Guarracino⁷, Aleksey Yakovlev⁸, Giada Cucciolini⁹, Maria Shemetova^{10

11}, Sara Scapol¹², Elena Momesso¹³, Eugenio Garofalo⁵, Giulia Brizzi⁷, Rubia Baldassarri⁷, Silvia Ajello¹, Alessandro Isirdi⁹, Francesco Meroi¹², Martina Baiardo Redaelli¹, Nicoletta Boffa¹³, Carmine Domenico Votta¹⁴, Giovanni Borghi¹, Giorgia Montrucchio^{15

16}, Simon Rauch¹⁷, Filippo D'Amico¹, Maria Caterina Pace¹⁸, Gianluca Paternoster¹⁹, Francesca Vitale³, Giuseppe Giardina¹, Rosa Labanca¹, Rosalba Lembo¹, Marilena Marmiere¹, Matteo Marzaroli¹, Cristina Nakhnoukh¹, Valentina Plumari¹, Anna Mara Scandroglio¹, Tommaso Scquizzato¹, Stella Sordoni¹, Davide Valsecchi²⁰, Felice Eugenio Agrò²¹, Gabriele Finco²², Tiziana Bove^{12

23}, Francesco Corradi⁹, Valery Likhvantsev^{10

24}, Federico Longhini⁵, Aidos Konkayev⁶, Giovanni Landoni^{1

2}, Rinaldo Bellomo^{25

26}, Alberto Zangrillo^{1

2}; PPI-SEPSIS Study Group

Collaborators, Affiliations

Collaborators

PPI-SEPSIS Study Group:
Alessandro Belletti²⁷, Fabrizio Monaco²⁷, Massimiliano Nuzzi²⁷, Alessandro Oriani²⁷, Gloria Panozzo²⁷, Nicola Pasculli²⁷, Marina Pieri²⁷, Domenico Pontillo²⁷, Stefano Turi²⁷, Maria Grazia Calabrò²⁷, Evgeny Fominskiy²⁷, Alessandro Ortalda²⁷, Stefania Sacchi²⁷, Vittorio Pazzanese²⁷, Beatrice Peveri²⁷, Federico Furlan²⁷, Alessandro Pruna²⁷, Stefano Pietro Sgobba²⁷, Michele Maltese²⁷, Giuseppe Neri²⁸, Angela Corea²⁸, Vincenzo Bosco²⁸, Pietro Bertini²⁹, Daniele Amitrano²⁹, Luca Doroni²⁹, Michela Villano²⁹, Erika Taddei⁹, Erika Taddei⁹, Maria Lidia Bologna⁹, Virginia Brizzi⁹, Daniele Orso³⁰, Marco Sartori³⁰, Alessandro Brussa³⁰, Maria Carmen Guarino³¹, Adelasia Salvini³¹, Kristina Kadantseva¹⁰, Ivan Redkin³², Zhanna Banova¹¹, Giuseppe Luca Formicola³³, Enrico De Cesaris³⁴, Alessia Mattei²¹, Paolo Mario Enrico Seraglio³⁵, Carlo Leggieri³⁵, Asiya Kadralinova³⁶, Nazerke Zhanarystan³⁶, Gaziza Abdirakhym³⁶, Salvatore Sardo²², Vincenzo Pota³⁷, Rosaria Vignale³⁸, Massimiliano Greco³⁹, Valentina Ajello⁴⁰, Umberto Benedetto⁴¹, Fabrizio D'Ascenzo⁴², Andrey Yavorovsky⁴³

Affiliations

¹ Department of Anaesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy.
² School of Medicine, Vita-Salute San Raffaele University, Milan, Italy.
³ UO Medicina Nucleare, IRCCS Ospedale Policlinico San Martino, Genova, Italy.
⁴ Department of Intensive Care Medicine, Kameda Medical Center, Kamogawa, Japan.
⁵ Anaesthesia and Intensive Care Unit, Department of Medical and Surgical Sciences, "Magna Graecia" University of Catanzaro, Catanzaro, Italy.
⁶ Department of Anaesthesiology and Intensive Care, Astana Medical University, National Scientific Center of Traumatology and Orthopedics named after N. Batpenov, Astana, Kazakhstan.
⁷ Department of Cardiothoracic Anaesthesia and ICU, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy.
⁸ Federal Research and Clinical Centre of Resuscitation and Rehabilitation, Moscow, Russia.
⁹ Department of Surgical, Medical, Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy.
¹⁰ V. Negovsky Reanimatology Research Institute FRCC RR, Moscow, Russia.
¹¹ Moscow State Budgetary Healthcare Institution, "Moscow City Oncological Hospital No.1, Moscow Healthcare Department," Moscow, Russia.
¹² Department of Emergency "Santa Maria della Misericordia", Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), Udine University Hospital, Udine, Italy.
¹³ UOC Anestesia e Rianimazione, AULSS 4 Veneto Orientale, San Donà di Piave (VE), Italy.
¹⁴ Emergency and Critical Care Department, Anesthesia and Intensive Care Unit, Maggiore Hospital, ASST Lodi, Lodi, Italy.
¹⁵ Department of Surgical Sciences, University of Turin, Turin, Italy.
¹⁶ Department of Anaesthesia, Intensive Care and Emergency, "Città della Salute e della Scienza" Hospital, Turin, Italy.
¹⁷ Department of Anaesthesiology and Intensive Care Medicine, Hospital of Merano (SABES-ASDAA), Merano, Italy.
¹⁸ Department of Women, Child and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Napoli, Italy.
¹⁹ Department of Health Sciences, School of Medicine, University of Basilicata; Anaesthesia and ICU, San Calo Hospital, Potenza, Italy.
²⁰ Emergency Department, IRCCS San Raffaele Scientific Institute, Milan, Italy.
²¹ Fondazione Policlinico Campus Bio-Medico di Roma, Rome, Italy.
²² Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
²³ Department of Medicine (DMED), University of Udine, Udine, Italy.
²⁴ First Moscow State Medical University (Sechenov University), Moscow, Russia.
²⁵ Department of Critical Care, The University of Melbourne, Melbourne, VIC, Australia.
²⁶ Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, VIC, Australia.
²⁷ IRCCSs San Raffaele Scientific Institute, Milan, Italy.
²⁸ Anesthesia and ICU, Department of Medical and Surgical Sciences, "Magna Graecia" University of Catanzaro, Catanzaro, Italy.
²⁹ Department of Cardiothoracic Anesthesia and ICU, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy.
³⁰ Department of Emergency "Santa Maria della Misericordia", Azienda Sanitaria Universitaria Friuli Centrale [ASUFC], Udine University Hospital, Udine, Italy.
³¹ UOC Anestesia e Rianimazione, AULSS 4 Veneto Orientale, San Donà di Piave [VE], Italy.
³² Federal Research and Clinical Center of Resuscitation and Rehabilitation, Moscow, Russia.
³³ Emergency and Critical Care Department, Anaesthesia and Intensive Care Unit, Maggiore Hospital, ASST Lodi, Lodi, Italy.
³⁴ Department of Anesthesia, Intensive Care and Emergency, "Città della Salute e della Scienza" Hospital, Turin, Italy.
³⁵ Department of Anaesthesiology and Intensive Care Medicine, Hospital of Merano [SABES-ASDAA], Merano, Italy.
³⁶ Astana Medical University, Astana, Kazakhstan.
³⁷ Università della Campania "Luigi Vanvitelli," Napoli, Italy.
³⁸ Cardiovascular Anesthesia and ICU, San Calo Hospital, Potenza, Italy.
³⁹ Humanitas University, Milan, Italy; IRCCS Humanitas Research Hospital, Milan, Italy.
⁴⁰ Department of Cardiothoracic Anesthesia and Intensive Care, Hospital Tor Vergata Roma, Rome, Italy.
⁴¹ University of G. d'Annunzio Chieti and Pescara, Chieti, Italy.
⁴² University of Turin, Turin, Italy; Città Della Salute e Della Scienza Hospital, Turin, Italy.
⁴³ IM Sechenov First Moscow State Medical University, Ministry of Public Health of Russia, Moscow, Russia.

PMID: 40439536
DOI: 10.1097/CCM.0000000000006720

Randomized Controlled Trial

A Multinational Randomized Trial of Mega-Dose Esomeprazole as Anti-Inflammatory Agent in Sepsis

Giacomo Monti et al. Crit Care Med. 2025.

. 2025 Aug 1;53(8):e1554-e1566.

doi: 10.1097/CCM.0000000000006720. Epub 2025 May 29.

Authors

Collaborators

PPI-SEPSIS Study Group:
Alessandro Belletti²⁷, Fabrizio Monaco²⁷, Massimiliano Nuzzi²⁷, Alessandro Oriani²⁷, Gloria Panozzo²⁷, Nicola Pasculli²⁷, Marina Pieri²⁷, Domenico Pontillo²⁷, Stefano Turi²⁷, Maria Grazia Calabrò²⁷, Evgeny Fominskiy²⁷, Alessandro Ortalda²⁷, Stefania Sacchi²⁷, Vittorio Pazzanese²⁷, Beatrice Peveri²⁷, Federico Furlan²⁷, Alessandro Pruna²⁷, Stefano Pietro Sgobba²⁷, Michele Maltese²⁷, Giuseppe Neri²⁸, Angela Corea²⁸, Vincenzo Bosco²⁸, Pietro Bertini²⁹, Daniele Amitrano²⁹, Luca Doroni²⁹, Michela Villano²⁹, Erika Taddei⁹, Erika Taddei⁹, Maria Lidia Bologna⁹, Virginia Brizzi⁹, Daniele Orso³⁰, Marco Sartori³⁰, Alessandro Brussa³⁰, Maria Carmen Guarino³¹, Adelasia Salvini³¹, Kristina Kadantseva¹⁰, Ivan Redkin³², Zhanna Banova¹¹, Giuseppe Luca Formicola³³, Enrico De Cesaris³⁴, Alessia Mattei²¹, Paolo Mario Enrico Seraglio³⁵, Carlo Leggieri³⁵, Asiya Kadralinova³⁶, Nazerke Zhanarystan³⁶, Gaziza Abdirakhym³⁶, Salvatore Sardo²², Vincenzo Pota³⁷, Rosaria Vignale³⁸, Massimiliano Greco³⁹, Valentina Ajello⁴⁰, Umberto Benedetto⁴¹, Fabrizio D'Ascenzo⁴², Andrey Yavorovsky⁴³

Affiliations

¹ Department of Anaesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy.
² School of Medicine, Vita-Salute San Raffaele University, Milan, Italy.
³ UO Medicina Nucleare, IRCCS Ospedale Policlinico San Martino, Genova, Italy.
⁴ Department of Intensive Care Medicine, Kameda Medical Center, Kamogawa, Japan.
⁵ Anaesthesia and Intensive Care Unit, Department of Medical and Surgical Sciences, "Magna Graecia" University of Catanzaro, Catanzaro, Italy.
⁶ Department of Anaesthesiology and Intensive Care, Astana Medical University, National Scientific Center of Traumatology and Orthopedics named after N. Batpenov, Astana, Kazakhstan.
⁷ Department of Cardiothoracic Anaesthesia and ICU, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy.
⁸ Federal Research and Clinical Centre of Resuscitation and Rehabilitation, Moscow, Russia.
⁹ Department of Surgical, Medical, Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy.
¹⁰ V. Negovsky Reanimatology Research Institute FRCC RR, Moscow, Russia.
¹¹ Moscow State Budgetary Healthcare Institution, "Moscow City Oncological Hospital No.1, Moscow Healthcare Department," Moscow, Russia.
¹² Department of Emergency "Santa Maria della Misericordia", Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), Udine University Hospital, Udine, Italy.
¹³ UOC Anestesia e Rianimazione, AULSS 4 Veneto Orientale, San Donà di Piave (VE), Italy.
¹⁴ Emergency and Critical Care Department, Anesthesia and Intensive Care Unit, Maggiore Hospital, ASST Lodi, Lodi, Italy.
¹⁵ Department of Surgical Sciences, University of Turin, Turin, Italy.
¹⁶ Department of Anaesthesia, Intensive Care and Emergency, "Città della Salute e della Scienza" Hospital, Turin, Italy.
¹⁷ Department of Anaesthesiology and Intensive Care Medicine, Hospital of Merano (SABES-ASDAA), Merano, Italy.
¹⁸ Department of Women, Child and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Napoli, Italy.
¹⁹ Department of Health Sciences, School of Medicine, University of Basilicata; Anaesthesia and ICU, San Calo Hospital, Potenza, Italy.
²⁰ Emergency Department, IRCCS San Raffaele Scientific Institute, Milan, Italy.
²¹ Fondazione Policlinico Campus Bio-Medico di Roma, Rome, Italy.
²² Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy.
²³ Department of Medicine (DMED), University of Udine, Udine, Italy.
²⁴ First Moscow State Medical University (Sechenov University), Moscow, Russia.
²⁵ Department of Critical Care, The University of Melbourne, Melbourne, VIC, Australia.
²⁶ Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, VIC, Australia.
²⁷ IRCCSs San Raffaele Scientific Institute, Milan, Italy.
²⁸ Anesthesia and ICU, Department of Medical and Surgical Sciences, "Magna Graecia" University of Catanzaro, Catanzaro, Italy.
²⁹ Department of Cardiothoracic Anesthesia and ICU, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy.
³⁰ Department of Emergency "Santa Maria della Misericordia", Azienda Sanitaria Universitaria Friuli Centrale [ASUFC], Udine University Hospital, Udine, Italy.
³¹ UOC Anestesia e Rianimazione, AULSS 4 Veneto Orientale, San Donà di Piave [VE], Italy.
³² Federal Research and Clinical Center of Resuscitation and Rehabilitation, Moscow, Russia.
³³ Emergency and Critical Care Department, Anaesthesia and Intensive Care Unit, Maggiore Hospital, ASST Lodi, Lodi, Italy.
³⁴ Department of Anesthesia, Intensive Care and Emergency, "Città della Salute e della Scienza" Hospital, Turin, Italy.
³⁵ Department of Anaesthesiology and Intensive Care Medicine, Hospital of Merano [SABES-ASDAA], Merano, Italy.
³⁶ Astana Medical University, Astana, Kazakhstan.
³⁷ Università della Campania "Luigi Vanvitelli," Napoli, Italy.
³⁸ Cardiovascular Anesthesia and ICU, San Calo Hospital, Potenza, Italy.
³⁹ Humanitas University, Milan, Italy; IRCCS Humanitas Research Hospital, Milan, Italy.
⁴⁰ Department of Cardiothoracic Anesthesia and Intensive Care, Hospital Tor Vergata Roma, Rome, Italy.
⁴¹ University of G. d'Annunzio Chieti and Pescara, Chieti, Italy.
⁴² University of Turin, Turin, Italy; Città Della Salute e Della Scienza Hospital, Turin, Italy.
⁴³ IM Sechenov First Moscow State Medical University, Ministry of Public Health of Russia, Moscow, Russia.

PMID: 40439536
DOI: 10.1097/CCM.0000000000006720

Abstract

Objectives: Proton pump inhibitors have dose-dependent immunomodulatory effects. We tested the hypothesis that mega-dose esomeprazole therapy would reduce organ dysfunction in patients with sepsis or septic shock.

Design: A multinational, randomized, double-blind, placebo-controlled clinical trial.

Setting: Seventeen ICUs or emergency departments in three countries.

Patients: Adult patients with sepsis or septic shock.

Interventions: Mega-dose (1024 mg) esomeprazole or placebo over a 72-hour period.

Measurements and main results: The primary outcome was mean daily Sequential Organ Failure Assessment (SOFA) score to day 10. Secondary outcomes included antibiotics-free days, ICU-free days at day 28, and all-cause mortality. We also conducted a mechanistic study of the in vitro effects of esomeprazole in sepsis. We randomized 307 patients and assigned 148 to esomeprazole and 159 to placebo. Mean age was 71 years; 166 patients (54%) had septic shock and median SOFA score at randomization was 7. The median mean daily SOFA score in the first 10 days post-randomization was 5 (interquartile range [IQR], 3-9) in the esomeprazole group and 5 (IQR, 3-8) in the placebo group (risk difference, 0.1; 95% CI, -0.8 to 1.0; p > 0.99). No differences were observed in secondary outcomes. Monocytes isolated from patients' peripheral blood and activated with a toll-like receptor agonist exhibited a pro-inflammatory phenotype, which was not affected by esomeprazole therapy.

Conclusions: Among patients with sepsis or septic shock, mega-dose esomeprazole did not reduce organ dysfunction or other patient-related or biological secondary outcomes.

Trial registration: ClinicalTrials.gov NCT03452865.

Keywords: critical care; esomeprazole; proton pump inhibitors; sepsis; septic shock.

PubMed Disclaimer

Conflict of interest statement

Dr. Guarracino received funding from Abbott, Chiesi, Edwards, Masimo, Orion, Orphan, Viatris, and Vygon. Drs. Isirdi, Meroi, Corradi, and Bellomo disclosed off-label use of Esomeprazole. Drs. Borghi’s, Marmiere’s, and Landoni’s institutions received funding from the Italian Ministry of Health. Dr. Montrucchio received funding from 3M and Thermofisher. Dr. Vitale received support for article research from the National Institutes of Health. Drs. Marmiere and Landoni received support for article research from the Italian Ministry of Health. Dr. Sordoni received support for article research from the Italian Ministry of Health (Progetto di Ricerca Finalizzata Ordinaria, GR-2016- 02363630). The remaining authors have disclosed that they do not have any potential conflicts of interest.

References

1. Singer M, Deutschman CS, Seymour CW, et al.: The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016; 315:801–810
1. Fleischmann-Struzek C, Mellhammar L, Rose N, et al.: Incidence and mortality of hospital- and ICU-treated sepsis: Results from an updated and expanded systematic review and meta-analysis. Intensive Care Med 2020; 46:1552–1562
1. Angus DC, van der Poll T: Severe sepsis and septic shock. N Engl J Med 2013; 369:840–851
1. Chousterman BG, Swirski FK, Weber GF: Cytokine storm and sepsis disease pathogenesis. Semin Immunopathol 2017; 39:517–528
1. Neumann I, Letelier LM, Rada G, et al.: Comparison of different regimens of proton pump inhibitors for acute peptic ulcer bleeding. Cochrane Database Syst Rev 2013; 2013:CD007999

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A Multinational Randomized Trial of Mega-Dose Esomeprazole as Anti-Inflammatory Agent in Sepsis

Collaborators

Affiliations

A Multinational Randomized Trial of Mega-Dose Esomeprazole as Anti-Inflammatory Agent in Sepsis

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Associated data

LinkOut - more resources

Full Text Sources

Medical