Mechanisms of sepsis and insights from clinical trials

Abstract

Multiple clinical trials of adjunctive therapy for sepsis and septic shock have been conducted to neutralize bacterial components or to modulate host inflammatory responses to infection but with limited success. Many therapies are only beneficial only in patients with a high severity of illness and have minimal or harmful effects in patients that are less severely ill. Improved measures of severity of illness and discovery of biomarkers to help identify these high-risk patients are needed.

Figure 1. Pathogenesis and therapy of sepsis and septic shock

Outline of the sequence of events that occur during the pathogenesis of sepsis and septic shock including examples of standard therapy.

Figure 2. Toll-like Receptor 4 signaling, NF-κB activation and corticosteroid effects

Schematic representation of TLR4 signaling (adapted from references 3 and 4). Lipopolysaccharide (LPS) binding to TLR4 stimulates both myeloid differentiation factor 88 (MyD88)-dependent and -independent pathways. The MyD88-dependent pathway involves activation of the IκB kinase (IKK) complex, which degrades the inhibitor of NF-κB IκB, allowing translocation of the NF-κB transcription factor to the nucleus. NF-κB binds to specific κB recognition sites and to coactivators, such as cAMP-response-element-binding-protein-binding-protein (CBP), that have intrinsic histone acetyltransferase (HAT) activity. The end result is acetylation of core histone H4, causing activation of gene transcription encoding multiple inflammatory proteins. The MyD88-independent pathway starts with engagement of Toll / IL-1 receptor domain (TIR) domain containing adaptor-inducing interferon-beta (TRIF) and TRIF-related adaptor molecule (TRAM), which activates TANK-binding-kinase-1 (TBK1). TBK1 phosphorylates interferon response factor 3 (IRF3), resulting in its translocation to the nucleus and subsequent activation of interferon-beta and other genes. Corticosteroids decrease inflammation by two mechanisms: 1). activation of glucocorticoid receptors (GR), resulting in translocation to the nucleus and binding to coactivators that inhibit HAT, 2). binding to glucocorticoid-response elements (GREs) in the promoter region of steroid-sensitive genes, resulting in increased transcription of anti-inflammatory genes.

Figure 3. Relationship between the severity of illness and treatment effects of mediator-specific anti-inflammatory agents in preclinical and clinical trials of sepsis

The relationship between the control odds of dying (risk of death) on the X axis and the odds ratio of survival (Y axis) in 95 experiments (open circles) from 38 published animal studies cited in 22 clinical trials (open circles) of mediator specific anti-inflammatory agents in sepsis. The line is a weighted linear regression that shows that the treatment effect of these agents is significantly related to severity of illness as represented by the control odds of dying (p < 0.0001); these agents are beneficial in populations with a high severity of illness at a high risk of death and have minimal effect or are harmful in populations that are less severely ill with a low risk of death (Reproduced with permission).

Figure 4. The effects of steroids on survival in sepsis: an analysis of clinical sepsis trials using high and low doses of corticosteroids

Relative survival benefits (closed boxes) are shown with 95% confidence intervals (horizontal lines). Meta-analysis of 13 trials (9 trials pre-1989 and 4 trials post-1997) demonstrated significant variability with no overall improvement in relative survival benefit (fixed-effects estimate, 1.01 [95% CI, 0.94 to 1.09]. The effect of steroids in the trials published before 1989 (high dose steroids) compared with those published after 1997 (low dose steroids) differed significantly (P = 0.02). One significant outlier trial was removed and the remaining, 8 pre-1989 trials had a consistent harmful effect of steroids on survival [fixed-effects estimate, 0.89 [CI, 0.82 to 0.97]. In the 4 trials published after 1997, the effect of low dose steroids on the relative survival benefit was consistently beneficial (fixed-effects estimate, 1.23 [CI, 1.01 to 1.50] (Reproduced with permission) .