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High morbidity and mortality are linked to CNS dysfunction, excessive inflammation, immune compromise, coagulopathy and multiple organ dysfunction. Males appear to have a higher risk of mortality than females. Currently, there are few or no effective drug therapies to protect the brain, maintain the blood brain barrier, resolve excessive inflammation and reduce secondary injury in other vital organs. We propose a major reason for lack of progress is a consequence of the treat-as-you-go, single-nodal target approach, rather than a more integrated, systems-based approach. A new revolution is required to better understand how the body responds to an infection, identify new markers to detect its progression and discover new system-acting drugs to treat it. In this review, we present a brief history of sepsis followed by its pathophysiology from a systems\u2019 perspective and future opportunities. We argue that targeting the body\u2019s early immune-driven CNS-response may improve patient outcomes. If the barrage of PAMPs and DAMPs can be reduced early, we propose the multiple CNS-organ circuits (or axes) will be preserved and secondary injury will be reduced. We have been developing a systems-based, small-volume, fluid therapy comprising adenosine, lidocaine and magnesium (ALM) to treat sepsis and endotoxemia. Our early studies indicate that ALM therapy shifts the CNS from sympathetic to parasympathetic dominance, maintains cardiovascular-endothelial glycocalyx coupling, reduces inflammation, corrects coagulopathy, and maintains tissue O<jats:sub>2<\/jats:sub>supply. Future research will investigate the potential translation to humans.<\/jats:p>","DOI":"10.1186\/s12929-024-01043-4","type":"journal-article","created":{"date-parts":[[2024,5,30]],"date-time":"2024-05-30T02:01:44Z","timestamp":1717034504000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Revolution in sepsis: a symptoms-based to a systems-based approach?"],"prefix":"10.1186","volume":"31","author":[{"given":"Geoffrey P.","family":"Dobson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayley L.","family":"Letson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jodie L.","family":"Morris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,30]]},"reference":[{"key":"1043_CR1","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1016\/j.cell.2006.02.015","volume":"124","author":"S Akira","year":"2006","unstructured":"Akira S, Uematsu S, Takeuchi O. 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