Post-sepsis syndrome - an evolving entity that afflicts survivors of sepsis

Abstract

Background: The sequelae of sepsis were once thought to be independent of sepsis itself and assumed to be either comorbid to sick patients or complications of critical illness. Recent studies have reported consistent patterns of functional disabilities in sepsis survivors that can last from months to years after symptoms of active sepsis had resolved. BODY: Post-sepsis syndrome is an emerging pathological entity that has garnered significant interest amongst clinicians and researchers over the last two decades. It is marked by a significantly increased risk of death and a poor health-related quality of life associated with a constellation of long-term effects that persist following the patient's bout with sepsis. These include neurocognitive impairment, functional disability, psychological deficits, and worsening medical conditions.

Conclusion: This "post-sepsis syndrome" has been the subject of active preclinical and clinical research providing new mechanistic insights and approaches linked to survivor well-being. Here we review important aspects of these research efforts and goals of care for patients who survive sepsis.

Keywords: HMGB1; Post-sepsis syndrome; Sepsis sequelae; Sepsis survivors.

Fig. 1

Sepsis incidence trends. Figure adapted with supplementary data and used with permission by authors (Rhee et al. 2017)

Fig. 2

Septicemia mortality in the United States 2004–2017. a Total Deaths in the U.S. b Average Mortality Rate. Original figure based on data from the Center for Disease Control and Prevention. Septicemia Mortality by State: 2004–2017. National Center for Health Statistics 2017 January 11, 2019; Available from:https://www.cdc.gov/nchs/pressroom/sosmap/septicemia_mortality/septicemia.htm

Fig. 3

Patient outcomes following sepsis. Original figure. Approximately half of patients who survived a hospitalization for sepsis achieved a complete or near complete recovery at 2 years after discharge; one third of total patients died during this period; and one sixth of these patients remained with one or more of the serious, lasting complications of post-sepsis syndrome

Fig. 4

Mechanisms of cognitive decline after sepsis. The neurocognitive effects of sepsis are caused by a combination of cerebral ischemia, neuronal dysfunction, and neuroinflammation. These three contributory pathways are associated with persistently elevated levels of HMGB1, a cytokine secreted by immune cells (e.g. monocytes, macrophages, and dendritic cells) during the late stages of sepsis. Systemic endothelial dysfunction and variations in blood pressure lead to poor blood flow to the brain and contribute to cerebral ischemia. Cholinergic dysfunction is related to increased acetylcholinesterase activity and a decrease in receptor density in the hippocampus; this pathophysiology is a major contributor to impaired neurotransmission. Activation of microglia and astroglia produce increased inflammatory mediators (tumor necrosis factor, interleukin-6, and interleukin-12) and is associated with compromised blood-brain barrier integrity that allows for the passage of neurotoxic factors (cytokines, reactive oxygen species, and glutamate) and sustained neuroinflammation

Fig. 5

MECO-1 and α-MSH as anti-HMGB1 corticotropic peptides. Figure used with permission from authors (Qiang et al. 2017). Melanocortin-like peptide of E. coli-1 (MECO-1) has anti-inflammatory effects similar to α-melanocyte-stimulating hormone (α-MSH) and adrenocorticotropin (ACTH), two prominent mammalian melanocortin hormones. HMGB1, the proposed major inflammatory mediator of the post-sepsis syndrome, remained elevated in septic mice treated with saline alone. MECO-1 and α-MSH were equally effective in attenuating the release of HMGB1 from macrophage-like cells in septic mice. The model for sepsis used was cecal ligation and puncture (CLP)