The surviving sepsis campaign: basic/translational science research priorities

Deutschman, Clifford S.; Hellman, Judith; Ferrer, Ricard; Backer, Daniel De; Coopersmith, Craig M.

doi:10.1186/s40635-020-00312-4

Cited by 18 publications

(18 citation statements)

References 230 publications

(296 reference statements)

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“…The metabolic response to sepsis has long been studied and is still of great interest for guiding therapeutic management of critical illness and long-term morbidity 1 . However, many previously investigated pathways have not led to practice-changing clinical trials, and thus the field is at a stage where many of the well-studied metabolic pathways including glucose production [28][29][30][31] , lactate production 32,33 , and muscle proteolysis 34,35 require greater insight and may require pivoting to the exploration of new metabolic pathways, to translate to standard-of-care precision medicine.…”

Section: Discussionmentioning

confidence: 99%

“… Summary Reprogramming metabolism is of great therapeutic interest for reducing morbidity and mortality during sepsis-induced critical illness 1 . Disappointing results from randomized controlled trials targeting glutamine and antioxidant metabolism in patients with sepsis have begged for both identification of new metabolic targets, and a deeper understanding of the metabolic fate of glutamine at the systemic and tissue-specific manner 2–4 .…”

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confidence: 99%

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Tissue-Specific and Interorgan Metabolic Reprogramming Maintains Tolerance to Sepsis

Leitner

Lee

Zhu

et al. 2022

Preprint

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Reprogramming metabolism is of great therapeutic interest for reducing morbidity and mortality during sepsis-induced critical illness. Disappointing results from randomized controlled trials targeting glutamine and antioxidant metabolism in patients with sepsis have begged for both identification of new metabolic targets, and a deeper understanding of the metabolic fate of glutamine at the systemic and tissue-specific manner. In critically ill patients versus elective surgical controls, skeletal muscle transcriptional metabolic reprogramming is comprised of reduced expression of genes involved in mitochondrial metabolism, electron transport, and glutamate transport, with concomitant increases in glutathione cycling, glutamine, branched chain, and aromatic amino acid transport. To analyze putative interorgan communications during sepsis, we performed systemic and tissue specific metabolic phenotyping in a murine polymicrobial sepsis model, cecal ligation and puncture. In the setting of drastically elevated inflammatory cytokines, we observed >10% body weight loss, >50% reductions in oxygen consumption and carbon dioxide production, and near full suppression of voluntary activity for the 48 hours following sepsis as compared to sham-operated controls. We found increased correlations in the metabolome between liver, kidney, and spleen, with drastic loss of correlations between the heart and quadriceps metabolome and all other organs, pointing to a shared metabolic signature within vital abdominal organs, and unique metabolic signatures for skeletal and cardiac muscle during sepsis. A lowered GSH:GSSG and elevated AMP:ATP ratio in the liver underlie the significant upregulation of isotopically labeled glutamine's contribution to TCA anaplerosis and glutamine-derived glutathione biosynthesis; meanwhile, the skeletal muscle and spleen were the only organs where glutamine's contribution to the TCA cycle was significantly suppressed. These results highlight tissue-specific mitochondrial reprogramming, rather than global mitochondrial dysfunction, as a mechanistic consequence of sepsis. Using a multi-omic approach, we demonstrate a model by which sepsis-induced proteolysis fuels the liver's production of anaplerotic substrates and the antioxidant glutathione to sustain tolerance to sepsis.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Tissue-Specific and Interorgan Metabolic Reprogramming Maintains Tolerance to Sepsis

Leitner

Lee

Zhu

et al. 2022

Preprint

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“…An initial 88 questions were reduced to 22 final clinical questions. Subcommittees were tasked with elaborating on their initial contributions, and are previously published [3,4]. Another document specifically addresses research priorities for Coronavirus Disease 2019 [5].…”

Section: Methodsmentioning

confidence: 99%

The Surviving Sepsis Campaign: research priorities for the administration, epidemiology, scoring and identification of sepsis

Nunnally

Ferrer

Martin

et al. 2021

ICMx

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Objective To identify priorities for administrative, epidemiologic and diagnostic research in sepsis. Design As a follow-up to a previous consensus statement about sepsis research, members of the Surviving Sepsis Campaign Research Committee, representing the European Society of Intensive Care Medicine and the Society of Critical Care Medicine addressed six questions regarding care delivery, epidemiology, organ dysfunction, screening, identification of septic shock, and information that can predict outcomes in sepsis. Methods Six questions from the Scoring/Identification and Administration sections of the original Research Priorities publication were explored in greater detail to better examine the knowledge gaps and rationales for questions that were previously identified through a consensus process. Results The document provides a framework for priorities in research to address the following questions: (1) What is the optimal model of delivering sepsis care?; (2) What is the epidemiology of sepsis susceptibility and response to treatment?; (3) What information identifies organ dysfunction?; (4) How can we screen for sepsis in various settings?; (5) How do we identify septic shock?; and (6) What in-hospital clinical information is associated with important outcomes in patients with sepsis? Conclusions There is substantial knowledge of sepsis epidemiology and ways to identify and treat sepsis patients, but many gaps remain. Areas of uncertainty identified in this manuscript can help prioritize initiatives to improve an understanding of individual patient and demographic heterogeneity with sepsis and septic shock, biomarkers and accurate patient identification, organ dysfunction, and ways to improve sepsis care.

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“…Advances in metabolomics enable profiling of a much greater proportion of human plasma metabolites at decreasing cost. Recently, the task force for the Research Committee of the Surviving Sepsis Campaign identified five key basic and translational science research priorities (16). The first two priorities include: 1) elucidating mechanisms that underlie sepsis and 2) how sepsis alters metabolism.…”

mentioning

confidence: 99%

Plasma Metabolites in Early Sepsis Identify Distinct Clusters Defined by Plasma Lipids

Rogers

Leligdowicz

Contrepois

et al. 2021

Critical Care Explorations

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The surviving sepsis campaign: basic/translational science research priorities

Cited by 18 publications

References 230 publications

Tissue-Specific and Interorgan Metabolic Reprogramming Maintains Tolerance to Sepsis

Tissue-Specific and Interorgan Metabolic Reprogramming Maintains Tolerance to Sepsis

The Surviving Sepsis Campaign: research priorities for the administration, epidemiology, scoring and identification of sepsis

Plasma Metabolites in Early Sepsis Identify Distinct Clusters Defined by Plasma Lipids

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