Sepsis has a well-studied inflammatory phase, with a less-understood secondary immunosuppressive phase. Elevated blood lactate and slow lactate clearance are associated with mortality; however, regulatory roles are unknown. We hypothesized that lactic acid (LA) contributes to the late phase and is not solely a consequence of bacterial infection. No studies have examined LA effects in sepsis models in vivo or a mechanism by which it suppresses LPS-induced activation in vitro. Because mast cells can be activated systemically and contribute to sepsis, we examined LA effects on the mast cell response to LPS. LA significantly suppressed LPS-induced cytokine production and NF-kB transcriptional activity in mouse bone marrow-derived mast cells and cytokine production in peritoneal mast cells. Suppression was MCT-1 dependent and reproducible with sodium lactate or formic acid. Further, LA significantly suppressed cytokine induction following LPS-induced endotoxemia in mice. Because glycolysis is linked to inflammation and LA is a byproduct of this process, we examined changes in glucose metabolism. LA treatment reduced glucose uptake and lactate export during LPS stimulation. LA effects were mimicked by glycolytic inhibitors and reversed by increasing ATP availability. These results indicate that glycolytic suppression and ATP production are necessary and sufficient for LA effects. Our work suggests that enhancing glycolysis and ATP production could improve immune function, counteracting LA suppressive effects in the immunosuppressive phase of sepsis.

Cellular metabolism and energy sensing pathways are closely linked to inflammation, but there is little understanding of how these pathways affect mast cell function. Mast cells are major effectors of allergy and asthma, and can be activated by the alarmin IL-33, which is linked to allergic disease. Therefore, we investigated the metabolic requirements for IL-33-induced mast cell function, to identify targets for controlling inflammation. We found that IL-33 increases glycolysis, glycolytic protein expression, and oxidative phosphorylation (OX PHOS). Inhibiting OX PHOS had little effect on cytokine production, but antagonizing glycolysis with 2-deoxyglucose or oxamate suppressed inflammatory cytokine production in vitro and in vivo. ATP reversed this suppression. Glycolytic blockade suppressed IL-33 signaling, including ERK phosphorylation, NFκB transcription, and ROS production in vitro, and suppressed IL-33-induced neutrophil recruitment in vivo. To test a clinically relevant way to modulate these pathways, we examined the effects of the FDA-approved drug metformin on IL-33 activation. Metformin activates AMPK, which suppresses glycolysis in immune cells. We found that metformin suppressed cytokine production in vitro and in vivo, effects that were reversed by ATP, mimicking the actions of the glycolytic inhibitors we tested. These data suggest that glycolytic ATP production is important for IL-33-induced mast cell activation, and that targeting this pathway may be useful in allergic disease.

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Clinical guidelines are evidence‐based clinician decision‐support tools that improve health outcomes, reduce patient harm, and decrease healthcare costs, but are often underused in emergency departments (EDs). This article describes a replicable, evidence‐based design‐thinking approach to developing best practices for guideline design that improves clinical satisfaction and usage. We used a 5‐step process to enhance guideline usability in our ED. First, we conducted end‐user interviews to identify barriers to guideline usage. Second, we reviewed the literature to identify key principles in guideline design. Third, we applied our findings to create a standardized guideline format, incorporating rapid cycle learning and iterative improvements. Fourth, we ensured the clinical validity of our updated guidelines by using a rigorous process for peer review. Lastly, we evaluated the impact of our guideline conversion process by tracking clinical guidelines access per day from October 2020 to January 2022. Our end‐user interviews and review of the design literature revealed several barriers to guideline use, including lack of readability, design inconsistencies, and guideline complexity. Although our previous clinical guideline system averaged 0.13 users per day, >43 users per day accessed the clinical guidelines on our new digital platform in January 2022, representing an increase in access and use exceeding 33,000%. Our replicable process using open‐access resources increased clinician access to and satisfaction with clinical guidelines in our ED. Design‐thinking and use of low‐cost technology can significantly improve clinical guideline visibility and has the potential to increase guideline use.

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