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

Monti G. Carta S. Kotani Y. Bruni A. Konkayeva M. Guarracino F. Yakovlev A. Cucciolini G. Shemetova M. Scapol S. Momesso E. Garofalo E. Brizzi G. Baldassarri R. Ajello S. Isirdi A. Meroi F. Baiardo Redaelli M. Boffa N. Votta C.D. Borghi G. Montrucchio G. Rauch S. DAmico F. Pace M.C. Paternoster G. Vitale F. Giardina G. Labanca R. Lembo R. Marmiere M. Marzaroli M. Nakhnoukh C. Plumari V. Scandroglio A.M. Scquizzato T. Sordoni S. Valsecchi D. Agrò F.E. Finco G. Bove T. Corradi F. Likhvantsev V. Longhini F. Konkayev A. Landoni G. Bellomo R. Zangrillo A. Belletti A. Monaco F. Nuzzi M. Oriani A. Panozzo G. Pasculli N. Pieri M. Pontillo D. Turi S. Calabrò M.G. Fominskiy E. Ortalda A. Sacchi S. Pazzanese V. Peveri B. Furlan F. Pruna A. Sgobba S.P. Maltese M. Neri G. Corea A. Bosco V. Bertini P. Amitrano D. Doroni L. Villano M. Taddei E. Bologna M.L. Brizzi V. Orso D. Sartori M. Brussa A. Guarino M.C. Salvini A. Kadantseva K. Redkin I. Banova Z. Formicola G.L. De Cesaris E. Mattei A. Seraglio P.M.E. Leggieri C. Kadralinova A. Zhanarystan N. Abdirakhym G. Sardo S. Pota V. Vignale R. Greco M. Ajello V. Benedetto U. Dascenzo F. Yavorovsky A.
2025 Lippincott Williams and Wilkins

Critical Care Medicine
2025

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. Copyright

critical care , esomeprazole , proton pump inhibitors , sepsis , septic shock

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Department of Anaesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
IRCCS Ospedale Policlinico San Martino, UO Medicina Nucleare, Genova, Italy
Department of Intensive Care Medicine, Kameda Medical Center, Kamogawa, Japan
Department of Medical and Surgical Sciences, Anaesthesia and Intensive Care Unit, Magna Graecia University of Catanzaro, Catanzaro, Italy
Department of Anaesthesiology and Intensive Care, National Scientific Center of Traumatology and Orthopedics Named after N. Batpenov, Astana Medical University, Astana, Kazakhstan
Department of Cardiothoracic Anaesthesia and ICU, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
Federal Research and Clinical Centre of Resuscitation and Rehabilitation, Moscow, Russian Federation
Department of Surgical Medical, Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy
V. Negovsky Reanimatology Research Institute FRCC RR, Moscow, Russian Federation
Moscow Healthcare Department, Moscow State Budgetary Healthcare Institution, Moscow City Oncological Hospital No.1, Moscow, Russian Federation
Department of Emergency Santa Maria della Misericordia, Udine University Hospital, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), Udine, Italy
UOC Anestesia e Rianimazione, AULSS 4 Veneto Orientale, (VE), San Donà di Piave, Italy
Emergency and Critical Care Department, Anesthesia and Intensive Care Unit, Maggiore Hospital, ASST Lodi, Lodi, Italy
Department of Surgical Sciences, University of Turin, Turin, Italy
Department of Anaesthesia Intensive Care and Emergency, Città della Salute E della Scienza Hospital, Turin, Italy
Department of Anaesthesiology and Intensive Care Medicine, Hospital of Merano (SABES-ASDAA), Merano, Italy
Department of Women Child and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Napoli, Italy
Department of Health Sciences, University of Basilicata; Anaesthesia and ICU, San Calo Hospital, Potenza, Italy
Emergency Department, IRCCS San Raffaele Scientific Institute, Milan, Italy
Fondazione Policlinico Campus Bio-Medico di Roma, Rome, Italy
Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
Department of Medicine (DMED), University of Udine, Udine, Italy
First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
Department of Critical Care, The University of Melbourne, Melbourne, VIC, Australia
Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, VIC, Australia
IRCCSs San Raffaele Scientific Institute, Milan, Italy
Department of Medical and Surgical Sciences, Magna GraeciaUniversity of Catanzaro,, Anesthesia and ICU, Catanzaro, Italy
Department of Cardiothoracic Anesthesia and ICU, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
Federal Research and Clinical Center of Resuscitation and Rehabilitation, Moscow, Russian Federation
Emergency and Critical Care Department, Anaesthesia and Intensive Care Unit, Maggiore Hospital, ASST Lodi, Lodi, Italy
Department of Anesthesia Intensive Care and Emergency, Città della Salute E della Scienza Hospital, Turin, Italy
Astana Medical University, Astana, Kazakhstan
Università della Campania Luigi Vanvitelli,, Napoli, Italy
San Calo Hospital, Cardiovascular Anesthesia and ICU, Potenza, Italy
Humanitas University, Milan, Italy
IRCCS Humanitas Research Hospital, Milan, Italy
Department of Cardiothoracic Anesthesia and Intensive Care, Hospital Tor Vergata Roma, Rome, Italy
University of G. DAnnunzio Chieti and Pescara, Chieti, Italy
University of Turin, Turin, Italy
Città della Salute E della Scienza Hospital, Turin, Italy
IM Sechenov First Moscow State Medical University, Ministry of Public Health of Russia, Moscow, Russian Federation

Department of Anaesthesia and Intensive Care
School of Medicine
IRCCS Ospedale Policlinico San Martino
Department of Intensive Care Medicine
Department of Medical and Surgical Sciences
Department of Anaesthesiology and Intensive Care
Department of Cardiothoracic Anaesthesia and ICU
Federal Research and Clinical Centre of Resuscitation and Rehabilitation
Department of Surgical Medical
V. Negovsky Reanimatology Research Institute FRCC RR
Moscow Healthcare Department
Department of Emergency Santa Maria della Misericordia
UOC Anestesia e Rianimazione
Emergency and Critical Care Department
Department of Surgical Sciences
Department of Anaesthesia Intensive Care and Emergency
Department of Anaesthesiology and Intensive Care Medicine
Department of Women Child and General and Specialized Surgery
Department of Health Sciences
Emergency Department
Fondazione Policlinico Campus Bio-Medico di Roma
Department of Medical Sciences and Public Health
Department of Medicine (DMED)
First Moscow State Medical University (Sechenov University)
Department of Critical Care
Australian and New Zealand Intensive Care Research Centre
IRCCSs San Raffaele Scientific Institute
Department of Medical and Surgical Sciences
Department of Cardiothoracic Anesthesia and ICU
Federal Research and Clinical Center of Resuscitation and Rehabilitation
Emergency and Critical Care Department
Department of Anesthesia Intensive Care and Emergency
Astana Medical University
Università della Campania Luigi Vanvitelli
San Calo Hospital
Humanitas University
IRCCS Humanitas Research Hospital
Department of Cardiothoracic Anesthesia and Intensive Care
University of G. DAnnunzio Chieti and Pescara
University of Turin
Città della Salute E della Scienza Hospital
IM Sechenov First Moscow State Medical University

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