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Review
. 2024 May 30;31(1):57.
doi: 10.1186/s12929-024-01043-4.

Revolution in sepsis: a symptoms-based to a systems-based approach?

Geoffrey P Dobson  1 , Hayley L Letson  2 , Jodie L Morris  2
Affiliations
Review

Revolution in sepsis: a symptoms-based to a systems-based approach?

Geoffrey P Dobson et al. J Biomed Sci. .

Abstract

Severe infection and sepsis are medical emergencies. 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' perspective and future opportunities. We argue that targeting the body's 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 O2 supply. Future research will investigate the potential translation to humans.

Keywords: ALM; Coagulopathy; Infection; Inflammation; Intra-abdominal; Sepsis.

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Conflict of interest statement

GPD is the sole inventor of the ALM concept for cardiac surgery, trauma and sepsis. JLM and HLL have no conflicts to declare.

Figures

Fig. 1
Fig. 1
Brief history of infection and sepsis from the Renaissance to the present. Note the advances in the 19th century when asepsis, surgical practice and research were rapidly being developed for major diseases and trauma. The timeline provides a perspective of the changing ideas, practices, and outcomes from which the current thinking and treatments have developed (See text). CNS, central nervous system; MgSO4, magnesium sulfate
Fig. 2
Fig. 2
Schematic of CNS-control linked complications following a major infection and sepsis. Excessive inflammation and tissue damage can lead to CNS dysfunction, pulmonary injury, cardiovascular uncoupling, endothelial activation, tissue ischemia, microbiome composition changes, mitochondrial dysfunction, multiple organ failure, and ultimately death. Mortality rates are from Skei and colleagues [155]. Hyperinflammation, immune dysfunction, endotheliopathy, coagulopathy and multiple organ dysfunction are all under the control of the CNS. CNS, central nervous system; BBB, blood–brain barrier; NTS, nucleus tractus solitarius; HPA, hypothalamic-pituitary axis; LV, left ventricle; DAMPs, damage-associated molecular patterns; PAMPs, pathogen-associated molecular patterns
Fig. 3
Fig. 3
A schematic of the source of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) in response to an infection, sepsis or the trauma of surgery. The immune-driven inflammatory response is determined by the mix of cytokines and other neural and inflammatory mediators that determine the selection, activation, recruitment and fate of immune effector cells. Secondary injury is defined as a progressive process that begins with a pathogen or injury and leads to CNS dysfunction, excessive inflammation, immune dysfunction, coagulopathy, oxidative stress and mitochondrial energy deficit. Sepsis progresses in the setting of hyperinflammation, immune dysfunction, oxidative stress and redox imbalance. TLR, toll-like receptor; NLR, NOD-like receptor; RAGE, receptor for advanced glycation end products; CLR, C-type lectin-like receptor; RLR, RIG-I-like receptor; NK cell, natural killer cell; ILC, innate lymphoid cell; ARDS, acute respiratory distress syndrome; PIICS, Persistent Inflammation, Immunosuppression, and Catabolism Syndrome; MODS, multiple organ dysfunction syndrome
Fig. 4
Fig. 4
Coagulopathy is a systemic pathological condition in which the blood’s ability to clot is impaired with varying degrees of fibrinolysis. The schematic illustrates the different sepsis-induced phenotypes around the Thrombomodulin (TM)-thrombin switch (1) [47, 48]. The TM-thrombin “switch” regulates coagulation and fibrinolysis in both directions depending on different activators and inhibitors at the thrombin-TM active sites (EFF-like domains) [47, 48]. During an early infection, patients appear to have a procoagulable phenotype which may form from activation of Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) (2), which decreases plasmin levels (3) and increases fibrinogen to form a stronger a stronger clot. As infection progresses the phenotype may change to a more hypocoagulable state where fibrinogen is decreased, D-dimers increase (fibrinolysis), and in extreme cases progresses to a specific hypocoagulation dominated by hyperfibrinolysis with microvascular fibrin deposits (DIC). The phenotypic change from a hyper- to hypo-coagulable state to disseminated intravascular coagulopathy (DIC) appears to be associated with a transition from a TF-dominated inflammatory microenvironment, favoring EGF-like Domain 3–6), to a non-TF dominated environment, favoring EGF-like Domain 4–6, with high mortality. This hypothesis requires knowledge of cytokines, immune cells, tPA, PAI-1, α2-antiplasmin, fibrinogen, TAFI levels and remains to be tested. Drugs to modulate the thrombin-TM “switch” following infection and sepsis are urgently required. TPA: tissue plasminogen activator; PAI-1: plasminogen activator inhibitor-1; WVF: Von Willebrand factor; S100A10: S100 calcium binding protein A10; FVIII: Factor VIII; EPCR: endothelial protein C receptor; FDP: FDP: fibrin degradation product
Fig. 5
Fig. 5
Schematic of 2016–2021 Surviving Sepsis Campaign guidelines that suggest initial resuscitation of at least 30 mL/kg of isotonic crystalloid fluid within the first 3 h of sepsis identification to restore circulating fluid volume and optimize stroke volume. However, there is a paucity of high-quality data to support this clinical practice. The significant heterogeneity of sepsis and the reports that ~ 50% are non-responders makes the recommendation highly problematic. Current evidence indicates that administration of large fluid volumes to the critically ill may cause harm by exacerbating secondary injury (see text). IV, intravenous; CNS, central nervous system; ADP, adenosine triphosphate; ATP, adenosine triphosphate
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