Sepsis cascade

In the present manuscript, we will discuss the mechanism by which endotoxin initiates the sepsis cascade, the rationale for targeting LPS, and the most significant treatments that have been studied antibodies, vaccines, binding peptides, lipid A analog, phospholipids, and polymyixin B hemoperfusion. 

With one exception sepsis therapy focusing primarily on the pro-inflammatory mediators has not produced positive results (Zeni et al., 1997). Hence, targeting the sepsis cascade at earlier steps may yield better outcomes. 

The initiating event in the sepsis cascade is the release of endotoxin, which prompts the release of tumor necrosis factor alpha, interleukin-1, interleukin-6, interleukin-8, and platelet-activating factor from mononuclear phagocytes and endothelial cells. 

The Role of Plasma Cascade Systems in Sepsis 4.1.1. The Coagulation System... 

There are various inhibitors within the coagulation system that counterregulate activation of the coagulation cascade. Among them, antithrombin III (AT-III) and protein C (PC) are the most important (SI). AT-III binds in the presence of heparin the activated factors F-IXa, F-Xa, and F-IIa (thrombin). PC is activated by a complex formed between thrombin and thrombomodulin, a surface protein of endothelial cells. Once activated, PC in the presence of protein S (PS) specifically degrades activated factors F-Va and F-VIIIa. PC decreases in the course of sepsis in relation to the severity of the condition (L15). Experimental studies have... 

With respect to both the coagulation and fibrinolytic cascade systems, in 28 patients who developed septic shock a relation was found between lowered plasma levels of F-XII and antithrombin III and elevated levels of PAI-1 and thrombin-antithrombin III complexes at the diagnosis of sepsis and the severity of disease, expressed according to the APACHE II scoring system (L7). Nevertheless, administration of inhibitors of coagulation or enhancement of fibrinolysis did not improve the outcome in patients with sepsis (B35). 

Interaction with Other Cascade Systems. Interactions between the complement system, the kinin, and the coagulation and fibrinolytic systems have repeatedly been reported (S37, PI9). Activation of one system induces activation of the other systems. The reciprocal activation of the various cascade systems may have an important role in the pathogenesis of ARDS and MODS as complications of sepsis. Nevertheless, until now no convincing prophylactic or therapeutic effects of intervention in the complement cascade system on the severity of septic complications have been reported. 

Sepsis represents a complex pathophysiology characterized by the activation of multiple overlapping and interacting cascades leading to systemic inflammation, a procoagulant state, and decreased fibrinolysis. 

FIGURE 117-3. Cascades of sepsis. ACTH = adrenocorticotropic hormone. 

The corticosteroids have been the subject of much controversy in the management of septic patients. Corticosteroids suppress the activation of polymorphonuclear leukocytes, complement activation, release of TNF, and activation of the coagulation system involved in the cascades of sepsis. A recent study demonstrated a decrease in mortality (absolute reduction of 10%) with lower doses of hydrocortisone and fludrocortisone in patients with adrenal insufficiency requiring high-dose or increasing vasopressor therapy within the first 8 hours of septic shock. There was no benefit for those patients without adrenal insufficiency. In summary, routine use of corticosteroids in patients with sepsis or septic shock is not recommended until further study. 

Observational study A prospective, randomised controlled experimental study and observational clinical cohort analysis involving 870 septic patients concluded that calcium supplementation does not provide benefit in the clinical management of septic patients and may rather be harmful. During sepsis, derangements in calcium homeostasis occur through altered calcium signalling, transduced by the calmodulin-dependent protein kinase cascade. This increases inflammation and vascular leak that culminates in elevated organ dysfunction and mortality [68 ]. 

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