Adrenomedullin in Sepsis

The key mediator in sepsis

The key mediator in sepsisAdrenomedullin plays a key role in initiating the inflammatory response observed in the early stages of septic onset, as well as in its progression from sepsis to septic shock. The strength of MR-proADM measurements lie in its ability to accurately assess the immediate clinical risk of the microbial infection, as well as an accurate prediction of organ dysfunction, failure and overall mortality.

 

Sepsis: Background, incidence and the importance of Adrenomedullin

adrenomedullin-sepsis-high-risk

Sepsis, severe sepsis, and septic shock are the increasingly severe stages of an uncontrolled, systemic inflammatory host response to a bloodstream infection, whilst the standard host response to a non-infectious insult is commonly known as SIRS (systemic inflammatory response syndrome) . The increasing severity and progression to septic shock is not thought to be a linear development2; on the contrary, sepsis can be viewed as a pathophysiological process rather than a specific syndrome3, where approximately 9 % of patients with sepsis progress to severe sepsis, and 3 % progress to septic shock4.

Studies have shown the most common sites of infection to include the lung (68 %), abdomen (22 %), blood (20 %) and urinary tract (14 %)5, with organs such as the lungs (18 %), kidneys (15 %) and the cardiovascular system (7 %)6 contributing towards multiple organ dysfunction and failure, and ultimately death, in over 65 % of cases5, 6.

However, despite significant improvements in diagnosis, treatment, care, and preventative measures, the incidence of sepsis continues to increase by as much as 8.7 % per year6. During the early stages of infection, proper triage, management, and disposition of patients with sepsis are associated with improved outcomes7, and the early identification of patients at high risk of cardiovascular and organ dysfunction can lead to a reduction in the number of clinical complications and overall mortality8.

It is therefore of extreme importance to accurately diagnose and determine the risk of septic progression at the earliest opportunity, and in this respect, the blood biomarker, adrenomedullin, plays a key role.

 

Adrenomedullin plays a pivotal role in initiating the pro-inflammatory response

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The early phase of sepsis results from either a severe infection and/or large-scale tissue damage, resulting in an excessive activation of the host immune system. Thus, responses that are normally beneficial for fighting infections are turned into a multitude of excessive, damaging pro-inflammatory stimuli.

It has been proposed that increased adrenomedullin production plays a pivotal role in initiating the pro-inflammatory, hyperdynamic response in sepsis9-11, where key inflammatory cytokines such as TNF-α and IL-1β, in addition to bacterial endotoxin, strongly stimulate its synthesis and secretion12-14 predominantly from endothelial15 and vascular smooth muscle cells12, but also from the small intestine, which has been shown to be a major source of production during polymicrobial sepsis16.

The vasodilatory properties of adrenomedullin are of significant importance during the pathophysiology of sepsis, and can be initiated by either a direct effect on vascular smooth muscle cells to increase cyclic AMP production17, or an indirect effect on vascular endothelial cell nitric oxide production18. Consequently, increased adrenomedullin levels can lead to decreased vascular resistance and significantly increased microvascular blood flow in the liver, small intestine, kidney and spleen10, which can be crucial in maintaining blood flow to individual organs in need. Indeed, studies have shown specific adrenomedullin binding sites on many organs, including the intestine, heart, lungs, spleen and liver19, and increased circulatory adrenomedullin levels have been shown to increase heart rate, cardiac output and stroke volume, similar to characteristics of the hyperdyanamic stage of sepsis itself.

 

The immunosuppressive response is characterised by a reduced vascular responsiveness to adrenomedullin

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The failure of numerous anti-inflammatory therapies raises the question of whether mortality in sepsis actually derives from the uncontrolled, pro-inflammatory response. Indeed, while some patients die during this phase, many succumb at later time points that are associated with a prolonged immunosuppressive state.

Whilst adrenomedullin levels remain elevated during late immunosuppressive stage20, potentially due to diminished clearance by the lungs21, studies have indicated that vascular endothelial cell function, which is responsible for a significant proportion of adrenomedullin production, is depressed22, can undergo apoptosis due to increased pro-inflammatory mediator levels, and may be partially detached from the base membrane23, thus playing an important role in any subsequent development of multiple organ failure24, 25.

However, the defining characteristic of the immunosuppressive stage is a reduced vascular responsiveness and immune paralysis, and thus, adrenomedullin is thought to play a significant role in the transition between the early, hyperdynamic phase, and the late, immunosuppressive phase10.

Indeed, vascular responsiveness to adrenomedullin is decreased at both the macro- and microcirculatory levels during the immunosuppressive stage, despite up-regulated adrenomedullin levels, and this reduction can lead to a deterioration in haemodynamics and provide the stimulus for the transition between the hyperdynamic and immunosuppressive stages26. It is also thought that alterations and disruptions in membrane bound adrenomedullin receptors, signal transduction, adenylate cyclase sensitization27, the down-regulation of adrenomedullin binding sites, the internalization of adrenomedullin receptors or in a decrease in adrenomedullin binding proteins may play a role in altering adrenomedullin activity at this stage9, 28.

 

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