Assessment of Disease Severity, Progression and Treatment in Infected Patients Presenting to the Emergency Department

Despite significant improvements in diagnostic and preventative measures, the incidence of sepsis has continued to escalate rapidly in hospitalized patients, with mortality rates ranging between 10 - 54%, depending on the level of severity. The earliest possible identification and assessment of sepsis patients entering the Emergency Department (ED) is therefore crucial in providing the patient with the most appropriate management and treatment strategy at the earliest time point possible. Indeed, an early identification of patients with an infection and at a high risk of cardiovascular and organ dysfunction can lead to an earlier individualised treatment, a potential reduction in the number of clinical complications, and an overall decrease in hospital mortality.

Adrenomedullin (ADM), a 52 amino acid peptide, is a member of the calcitonin peptide family and is widely expressed in many tissues and organs, although its main sources of production include the endothelial and vascular smooth muscle cells. Adrenomedullin can act as both a hormone and cytokine (often termed a "hormokine") in an autocrine and paracrine manner, and its potent vasodilatory and hypotensive response is elicited through an initial increase in cyclic adenosine monophosphate levels, and a subsequent production of nitric oxide.

The importance of adrenomedullin in homeostasis is illustrated by its central role in the up- and down-regulation of cytokines and other mediators, as well as its own stimulatory and inhibitory effect on cytokine production. Indeed, Interleukin (IL)-1β and tumour necrosis factor (TNF) are two of the most potent stimulators for adrenomedullin production and adrenomedullin itself is up-regulated by hypoxia, bacterial products and shear stress, amongst many other factors.

Finally, adrenomedullin has been shown to have a variety of physiological functions, including immune-modulating, direct bactericidal, diuretic and potent vasodilatory activity, and in healthy conditions, circulates at low picomolar concentrations. However, plasma levels are significantly up-regulated in many diseased states in proportion to disease severity such as hypertension, renal failure, lower respiratory diseases and septic shock, due to either damage to the endothelial cells or microvascular and microcirculatory impairment.

This allows clinicians to determine the patients most at risk of developing complications upon their admission to the ED or ICU, in order to rapidly triage and administer the most effective treatment, in the shortest space of time.

However, reliable measurement of ADM is challenging due to a number of issues, such as a short half life of 22 minutes, rapid degradation by proteases and binding to complement factor H. The measurement of its stable precursor molecule, MR-proADM, provides a solution to these problems, since reliable measurements in relation to adrenomedullin can be made in a 1:1 ratio, thus allowing changes in protein concentrations to be determined.

The majority of deaths in patients suffering from sepsis occur due to multiple organ failure, related to the primary infection. However, complications leading up to initial organ dysfunction and failure include factors such as an impaired microcirculation, enhanced microvascular permeability, a decrease in the number of perfused capillaries, endothelial cell apoptosis and an abnormal systemic blood flow to organ systems. Few tools currently available have the ability to accurately assess these early physiological changes.

The vasodilatory and microcirculatory properties of adrenomedullin are therefore of significant importance during the pathophysiology and progression of sepsis, with increased levels being shown to lead to a decreased vascular resistance and a significantly increased microvascular blood flow in the liver, small intestine, kidney and spleen. Indeed, the production of adrenomedullin has been shown to have:

• protective properties against endothelial permeability and consequent organ damage
• protective effects in organs in response to bacterial induced shock
• the ability to stabilize the microcirculation in inflammation - a hallmark of organ failure
• the ability to restore endothelial stability in infected organs due to prevention of undesired inflammatory decompartmentalization.

Crucially, the body can facilitate the localized cellular production and release of adrenomedullin in order to meet the specific perfusion requirements of individual organs, which can be crucial in maintaining blood supply.

Whilst current benchmarks of sepsis which include lactate and SOFA scores can accurately assess the degree of tissue hypoxia and organ dysfunction at any given time point, elevated MR-proADM levels can accurately reflect the early microvascular changes that occur in the build up to subsequent organ damage and dysfunction, the majority of which are extremely difficult to detect using standard clinical techniques, biomarkers or severity scores.

The clinical use of MR-proADM

Thus, MR-proADM levels can provide the treating physician with an accurate reflection of abnormalities in the microcirculation before the patient develops any form of organ dysfunction or adverse clinical signs become apparent, thus providing an earlier warning of any developing complications associated with the infectious condition. Indeed, even when diagnostic biomarkers such as PCT, CRP or lactate are either initially low or decreasing satisfactorily, patients might still be at considerable risk of further complications, which can be highlighted through elevated MR-proADM values. In these cases, an immediate transfer to a more intensive ward or department and an early, rapid and goal directed therapeutic treatment would most likely be required in order to achieve the best possible clinical outcome for the patient.

On the other hand, resolving issues in the microcirculation/endothelium can be indicative of an improvement in clinical status, and illustrated by low MR-proADM values. Accordingly, even in the presence of elevated laboratory or other biomarker values and poor clinical signs, the patient in question may develop no further physiological complications apart from the pre-existing microbial infection itself, which when treatment is correctly initiated, can facilitate an earlier transfer onto a less acute ward, consequently saving the healthcare provider valuable resources such as physician time, hospital beds and overall financial budget.

The results of the SIDED study (doi: 10.1186 / s13054-019-2329-5) showed that MR-proADM measurement at presentation could accurately assess disease severity and identify specific patient populations based on the likelihood of subsequent disease progression. This was of particular importance in patients with few pathophysiological signs and symptoms, as indicated by low SOFA, qSOFA or NEWS scores, where initial treatment may either be withheld, delayed or insufficient. Our study therefore, for the first time, highlights the use of MR-proADM in potentially identifying this patient population in order to initiate appropriate treatment strategies at the earliest opportunity.

Based on the results of this study, two clinically important uses for MR-proADM can be proposed: (i) an early escalation of treatment in patients with MR-proADM concentrations ≥1.5 nmol/L, thus identifying an already high level of disease severity or a high potential for further development and progression, and (ii) a decreased number of hospital admissions allowing a safe increase in out-patient treatment in patients with MR-proADM concentrations <0.9 nmol/L.

Samples of the biomarkers were in SIDED study retrospectively analyzed in a device that is not routinely used in the ED (Kryptor, Thermo Fisher, Germany). The availability of MR-proADM at the point of care could facilitate its widespread use in all EDs. This study is conducted to confirm the results of the SIDED study by using a device at the patient's bedside (Samsung IB10 platforms) that allows the quantitative determination of the MR-proADM and procalcitonin biomarkers, instead of using a Kryptor platform, and obtaining the biomarkers results in no more than 20 minutes.