Proadrenomedullin for Early Risk Assessment in the Emergency Department
Proadrenomedullin for Early Risk Assessment in the Emergency Department
The study ia aiming to the assessment of Mid-Regional proadrenomedullin (MR-proADM) as a
 novel biomarker that can provide accurate short-, mid- and long term prognostic information
 in the triage and multi-dimensional risk assessment of patients in the Emergency Department
 (ED). A clinical algorithm with predefined MR-proADM cut-off values: <0.75 nmol/L (low risk),
 0.75 nmol/L≥ and ≤ 1.5 nmol/L (intermediate risk); >1.5 nmol/L is pre-defined. Based on these
 cut-off values, a prespecified algorithm aiming to predict i) reduction of hospitalization in
 the ward/ICU and increase of out-patient treatment (rule-out of risk); and ii) reduce adverse
 complications (identify patients at risk) will be applied and compared with the initial
 clinical decision.
Emergency departments (ED) are becoming increasingly over-crowded, with patients facing
 prolonged waiting times. This is further aggravated by the shortage of available hospital
 space. Therefore, a safe and rapid triaging of patients is essential in improving the
 workflow within the ED, maximizing patient safety and comfort, and alleviating any
 unnecessary financial burden from the healthcare provider.

 Adrenomedullin (ADM), a 52 amino acid peptide, is a member of the calcitonin peptide family
 and is widely expressed in many tissues and organs. It has been shown to have a variety of
 physiological functions, including immune-modulating, direct bactericidal, diuretic and
 potent vasodilatory activity. In healthy subjects, ADM circulates at low picomolar
 concentrations. In many pathological states such as hypertension, renal failure, lower
 respiratory diseases and septic shock, plasma levels of adrenomedulin are significantly
 up-regulated in proportion to disease severity. These unique properties makes it a
 potentially useful marker in determination of the patients most at risk of developing
 complications on admission to the ED, in order to rapidly triage and administer the most
 effective treatment in the shortest possible time.

 However, reliable measurement of ADM is challenging due to a number of issues, such as: a
 short half time of 22 minutes; rapid degradation by proteases; and binding to complement
 factor H. Therefore, the increased stability of its precursor molecule,
 Mid-Regional(MR)-proADM, allows it to be reliably measured as a surrogate biomarker for the
 unstable ADM in a 1:1 ratio. The aim of this study is the assessment of MR-proADM as a novel
 biomarker that can provide accurate short-, mid- and long term prognostic information in the
 triage and multi-dimensional risk assessment of patients in the ED setting.

 ADM, present mainly in endothelial and vascular smooth muscle cells, can act as both a
 hormone and cytokine (often termed a "hormokine) in an autocrine and paracrine manner. 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 ADM 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 tumor necrosis factor-alpha
 (TNFα) are two of the most potent triggers for ADM production. It is also up-regulated by
 hypoxia, bacterial products, such as lipopolysaccharide (LPS), and shear stress. Moreover,
 ADM has potent antimicrobial actions through membrane channel formation and lysis, and
 anti-apoptotic properties, it enhances renal excretion of sodium, decreases aldosterone
 synthesis and increases renal blood flow and urine volume. The ubiquitous and important
 functional role of ADM results in its clinical use in many diverse indications. Its precursor
 molecule, MR-proADM, has been shown to be a powerful risk assessment marker in sepsis and
 lower respiratory tract infections with the ability to predict 30 day mortality regardless of
 the underlying diagnosis. Plasma concentrations of MR-proADM have been also shown to be
 elevated in myocardial infarction, and to correlate with the severity of acute and chronic
 heart failure. Furthermore, it has been shown that it outperforms BNP and NT-BNP in
 predicting mortality in ED patients with dyspnea after 30 days8-12. MR-proADM is also
 elevated in various types of glomerulonephritis and progressively increased in patients with
 chronic renal failure (CKD) and has greater predictive accuracy in determining risk of CKD
 progression, compared to standard GFR measurements.

 MR-proADM is determined in plasma EDTA samples by an automated immunofluorescent assay
 (Thermo ScientificTM BRAHMSTM MR-proADM KRYPTORTM). Healthy individuals have detectable
 levels of MR-proADM of approximately 0.4nmol/L. The functional assay sensitivity has been
 assessed as being 0.25 nmol/L. Levels of MR-proADM are not influenced by food or water intake
 and there are no significant gender-related differences, which optimize its use in risk
 assessment. Furthermore, it remains stable up to 72 hours in EDTA plasma at room temperature
 and over four freeze/ thaw cycles.

 In a previous study, an algorithm has been validated using MR-proADM cut-off values together
 with clinical risk assessment by the ED physician. The application of this model could
 potentially lead to an increase of patients safely discharged from the hospital falling into
 the low risk category. It has been shown that the prognostic information of this model could
 enhance the appropriateness of disposition decisions of patients presenting to the ED with
 non-specific complaints (NSC).
Inclusion Criteria:

 -  Age more than or equal to 18 years

 -  Written informed consent provided by the patient

 Exclusion Criteria:

 High-risk for death the first 24 hours post admission i.e. moribund patients unlikely to
 thrive as defined by the attending physicians