Pro-adrenomedullin Levels Research Articles

Primary Graft Dysfunction and Mortality Following Lung Transplantation: A Role for Proadrenomedullin Plasma Levels

Primary graft dysfunction (PGD) after lung transplantation (LT) is a heterogeneous syndrome that comprises clinical presentations with diverse grades of severity. Proadrenomedullin (proADM) levels may be associated with PGD and may enhance its relationship with outcomes. We prospectively included 100 LT recipients. Plasma levels of proADM were measured at 24, 48 and 72 h after admission to the intensive care unit (ICU). We assessed their relationship with PGD grade and ICU mortality. Fifty patients (50%) presented grade 3 PGD at ICU admission. Twenty-two patients (22%) developed grade 3 PGD at 72 h, the only grade associated with higher mortality (odds ratio 6.84, 95% confidence interval [CI] 1.47-38.44). ProADM levels measured at 24 h (3.25 vs. 1.61 nmol/L; p = 0.016) and 72 h (2.17 vs. 1.35 nmol/L; p = 0.011) were higher in these patients than the rest of the population. When we added the individual predictive utility of grade 3 PGD at 72 h for ICU mortality (area under the curve [AUC] 0.72, 95% CI 0.53-0.90) to that of ProADM at 72 h, the predictive value of the model improved (AUC 0.81, 95% CI 0.65-0.97). Higher levels of proADM measured following LT are associated with grade 3 PGD at 72 h. ProADM enhances the association of this entity with mortality.

Diagnostic and prognostic usefulness of mid-regional pro-adrenomedullin levels in patients with severe sepsis

Mid-regional pro-adrenomedullin (MR-proADM) is a fragment of 48 amino acids which splits from the final proADM molecule in a ratio of 1:1 with ADM. It is essentially irrelevant, but proportionally represents the levels and activity of ADM. Its half-life is several hours longer, and its plasma concentrations can be determined in clinical practice. It has been identified as a prognostic marker, stratifying the mortality risk in patients with sepsis.

Plasma mid-regional pro-adrenomedullin levels are inversely associated with anxiety but unrelated to depression: Results from the observational DIAST-CHF study in patients with cardiovascular risk factors

ObjectivesIt has been postulated that patients with heart failure have a high risk of ventricular arrhythmias and sudden cardiac death resulting from anxiety-induced autonomic arousal. In the prospective and multicenter DIAST-CHF (Diagnostic Trial on Prevalence and Clinical Course of Diastolic Dysfunction and Heart Failure) study, we therefore, tested the hypothesis that adrenomedullin (ADM), a well-established predictor for cardiovascular outcome, is associated with self-rated anxiety symptoms in patients at risk of suffering from or actually with overt heart failure. Participants and measuresStudy participants with risk factors for diastolic dysfunction were requested to complete the Hospital Anxiety and Depression Scale (HADS), and plasma mid-regional pro-adrenomedullin (MR-proADM) concentrations were measured. ResultsIn bivariate analysis, we found significantly lower plasma MR-proADM levels in patients with elevated HADS-anxiety scores above the clinically relevant cut-off level of ≥11 (n=118, 536pmol/l, interquartile range [IQR] 449–626) as compared to non-anxious study participants (n=1,292, 573pmol/l, IQR 486–702, p=0.001). A set of multivariate models adjusted for potential confounders confirmed the negative association between self-rated anxiety symptoms and plasma MR-proADM. In similar models, no significant association was detected between HADS-depression scores and MR-proADM. ConclusionsThe inverse relationship between plasma MR-proADM and anxiety observed in patients with cardiovascular risk factors supports a previous experimental study using a mutant mouse line with a brain-specific loss of ADM expression which displayed hyperactive and over-anxious behavior. Further experimental and clinical studies are warranted to test the hypothesis that also in humans ADM acts as a neuromodulator with anxiolytic properties.

Biomarkers of hemodynamic stress and aortic stiffness post-STEMI: a cross-sectional analysis

Methods Fifty-four patients four months after acute STEMI were enrolled in this cross-sectional, single-center study. Nterminal pro B-type natriuretic peptide (NT-proBNP), mid-regional pro-A-type natriuretic peptide (MR-proANP) and mid-regional pro-adrenomedullin (MR-proADM) levels were measured by established assays. Aortic stiffness was assessed by the measurement of pulse wave velocity using velocity-encoding, phase-contrast cardiovascular magnetic resonance imaging.

Postoperative pro-adrenomedullin levels predict mortality in thoracic surgery patients: comparison with Acute Physiology and Chronic Health Evaluation IV Score*.

Risk assessment in ICU patients using commonly used prognostic models may be influenced using different data definitions and by errors in data collection. We investigated whether a set of biomarkers (procalcitonin, MR-pro-adrenomedullin, CT-pro-endothelin-1, CT-pro-arginine vasopressin, and MR-pro-atrial natriuretic peptide), alone or as a panel, could be useful in postoperative risk assessment for hospital mortality in comparison with the Acute Physiology and Chronic Health Evaluation IV score. In a prospective observational cohort study, we analyzed 800 consecutive patients undergoing elective cardiac surgery. We assessed biomarker levels on admission to the ICU and every 6 hours thereafter for 24 hours. For every postoperative time point and for every biomarker, we determined the predictive value for hospital mortality and made a comparison with the Acute Physiology and Chronic Health Evaluation IV score. Intensive care of an academic referral hospital. A total of 800 consecutive patients undergoing elective cardiac surgery. None. MR-pro-adrenomedullin is a good predictor of mortality (c-statistic at time point 6 hr after admission to the ICU, 0.940; 95% CI, 0.918-0.956) and performed better than the Acute Physiology and Chronic Health Evaluation IV score (c-statistic, 0.842; 95% CI, 0.811-0.868). The c-statistic did not change significantly on the time points 6, 12, and 18 hours after admission. Using a cutoff value for proadrenomedullin taken 6 hours after admission on ICU (time point 2) of 3.2 nmol/L sensitivity was 81.8% and specificity 93.9%, the positive likelihood ratio was 13.3, positive predictive value was 31.0%, and negative predictive value was 99.4%. Patients with a MR-pro-adrenomedullin above this cutoff level had an odds ratio of 68.9 (95% CI, 22.2-213.1) for not surviving their hospital stay. The other biomarkers had less predictive power. In elective cardiac surgery, MR-pro-adrenomedullin measured between 6 and 18 hours after admission to the ICU is a better predictor of hospital mortality in comparison with the Acute Physiology and Chronic Health Evaluation IV score.

Abstract T P184: The Importance of Blood Biomarkers in Penetrating Artery Territory Infarction; A Prospective Multicenter Observational Study

Objective: Neurological deterioration in penetrating artery territory infarction (PATI) is unpredictable and associated with a worse clinical outcome. This study aimed to determine the importance of blood biomarkers to predict neurological deterioration and long-term clinical outcome. Methods: From November 2012 to December 2013, we performed a prospective multicenter observational study of PATI patients presenting within 2 days of stroke onset. Blood samples were obtained within 24h after admission (1st point) and on a day between 6th and 8th hospitalization (2nd point) for several biomarkers. Symptomatic progression (SP) was defined as the increase of at least one point on the National Institutes of Health Stroke Scale. Favorable outcome was defined as modified Rankin Scale score≤2 at 90 days after ictus. Results: 25 patients (28%) showed SP in evaluated 90 patients (35 men with a mean age of 70.4 years). The patients with SP were significantly (p<0.05) more elderly, hypertensive, clinically severed than those without SP on admission. At 1st point, the patients with SP had significantly higher serum IL-6 and lower CD34 levels as compared to those without SP (IL-6: 4.8 [2.3-7.95] vs 2.4[1.3-4.1] pg/ml (p=0.007) and CD34: 0.5 [0.31-0.88] vs 0.8[0.49-1.08] /μL (p=0.002)). Moreover, the patients with poor outcome at 90 days had significantly higher serum IL-6 levels, higher TNF-alpha levels and lower CD34 levels as compared to those with favorable outcome. At 2nd point, the patients with poor outcome had significantly higher serum IL-6 levels, higher TNF-alpha levels, higher pro-adrenomedullin levels, and lower ADAMTS13 levels compared to those with favorable outcome . Comparing the change of biomarker levels between two-point measurements, the significant increases of pro-adrenomedullin and oxidized LDL receptor-1, and decrease of ADAMTS13 were correlated with SP. Conclusions: Blood biomarkers of inflammatory and endothelial function might be valuable to predict symptomatic progression and poor long-term outcome in PATI, meaning the surrogate markers for treatment evaluation in future stroke trials.

Biomarkers of hemodynamic stress and aortic stiffness after STEMI: a cross-sectional analysis.

Aim. Increased aortic stiffness might adversely affect cardiac structure, function, and perfusion. Release of biomarkers of hemodynamic stress is thought to be enhanced by these alterations. We aimed to evaluate the association between biomarkers of hemodynamic stress and aortic stiffness assessed at a chronic stage after ST-segment elevation myocardial infarction (STEMI). Methods. Fifty-four patients four months after STEMI were enrolled in this cross-sectional, single-center study. N-terminal pro–B-type natriuretic peptide (NT-proBNP), mid-regional pro–A-type natriuretic peptide (MR-proANP), and mid-regional proadrenomedullin (MR-proADM) levels were measured by established assays. Aortic stiffness was assessed by the measurement of pulse wave velocity using phase-contrast cardiovascular magnetic resonance. Results. NT-proBNP, MR-proANP, and MR-proADM concentrations were all correlated with aortic stiffness in univariate analysis (r = 0.378, r = 0.425, and r = 0.532; all P < 0.005, resp.). In multiple linear regression analysis, NT-proBNP (β = 0.316, P = 0.005) and MR-proADM (β = 0.284, P < 0.020) levels were associated with increased aortic stiffness independently of age, blood pressure, and renal function. NT-proBNP was the strongest predictor for high aortic stiffness (area under the curve: 0.82, 95% CI 0.67–0.96). Conclusion. At a chronic stage after STEMI, concentrations of biomarkers for hemodynamic stress, especially NT-proBNP, are positively correlated with aortic stiffness. These biomarkers might also be useful as predictors of high aortic stiffness after STEMI.

Mid-regional proadrenomedullin levels predict recurrence of atrial fibrillation after catheter ablation

BackgroundWe evaluated the prognostic value of mid-regional proadrenomedullin (MR-proADM) in atrial fibrillation (AF) patients undergoing radiofrequency ablation. MethodsPlasma concentrations of MR-proADM were measured at baseline and after 12months in 87 AF patients in whom radiofrequency ablation was performed. The association between MR-proADM and AF recurrence was tested by univariable and multivariable Cox models. ResultsIn all 87 patients radiofrequency ablation was successfully performed. Of the total population 54% had paroxysmal AF. The mean left ventricular ejection fraction was 54% (minimum 25%). After 12months of follow-up, 71% of the patients were free of AF recurrence. At baseline, mean MR-proADM in the total population was 0.72nmol/l±0.22. Patients with AF recurrence had significantly higher baseline MR-proADM (0.89nmol/l±0.29) as compared with patients without AF recurrence (0.65nmol/l±0.14; p<0.001). After 12months, mean MR-proADM plasma concentration remained higher in patients with AF recurrence (0.81nmol/l±0.22 as compared with patients free of AF 0.54nmol/l±0.20; p<0.001). Receiver operating characteristic (ROC) curve analysis for MR-proADM yields a specificity of 98% and a sensitivity of 64% with an optimal cut-off value of 0.82nmol/l to predict recurrence of AF after catheter ablation. In the logistic regression analysis only MR-proADM remained independently predictive for AF recurrence. ConclusionThis is the first study revealing the association between MR-proADM elevation before ablation and poor outcomes after ablation of AF. Larger studies are needed to validate these results.

Exertional Hypoxemia in Stable COPD Is Common and Predicted by Circulating Proadrenomedullin

The prevalence of exertional hypoxemia in unselected patients with COPD is unknown. Intermittent hypoxia leads to adrenomedullin (ADM) upregulation through the hypoxia-inducible factor-1 pathway. We aimed to assess the prevalence and the annual probability to develop exertional hypoxemia in stable COPD. We also hypothesized that increased ADM might be associated with exertional hypoxemia and envisioned that adding ADM to clinical variables might improve its prediction in COPD. A total of 1,233 6-min walk tests and circulating proadrenomedullin (proADM) levels from 574 patients with clinically stable, moderate to very severe COPD enrolled in a multinational cohort study and followed up for 2 years were concomitantly analyzed. The prevalence of exertional hypoxemia was 29.1%. In a matrix derived from a fitted-multistate model, the annual probability to develop exertional hypoxemia was 21.6%. Exertional hypoxemia was associated with greater deterioration of specific domains of health-related quality of life, higher severe exacerbation, and death annual rates. In the logistic linear and conditional Cox regression multivariable analyses, both FEV1% predicted and proADM proved independent predictors of exertional hypoxemia (P < .001 for both). Adjustment for comorbidities, including cardiovascular disorders, and exacerbation rate did not influence results. Relative to using FEV1% predicted alone, adding proADM resulted in a significant improvement of the predictive properties (P = .018). Based on the suggested nonlinear nomogram, patients with moderate COPD (FEV1% predicted = 50%) but high proADM levels (> 2 nmol/L) presented increased risk (> 30%) for exertional desaturation. Exertional desaturation is common and associated with poorer clinical outcomes in COPD. ADM improves prediction of exertional desaturation as compared with the use of FEV1% predicted alone. ISRCTN Register; No.: ISRCTN99586989; URL: www.controlled-trials.com.

Biomarker-guided clinical decisions: for patients, health economists or neither?

In this issue of the European Respiratory Journal , Albrich et al. [1] report on a randomised trial. Their hypothesis is that triage decisions in patients with respiratory infections, guided by adding measurements of the calcitonin-superfamily gene derived peptide, mid-regional proadrenomedullin, are more effective than if guided according to clinical assessment alone. Length of hospital stay is, amongst other end-points, compared between the groups. The authors should be commended for their effort in conducting a randomised trial with a biomarker-strategy; this implies a much increased workload when compared to epidemiological studies. Adrenomedullin is a 52 amino acid polypeptide. It is formed by amino acids 95–146 of “pre-proadrenomedullin” and is involved in multiple effects, which include vasodilation [2, 3], osteoblast activity [4], renoprotection [5] and angiogenesis [6]. Mid-regional proadrenomedullin (amino acids 45–92 of “pre-proadrenomedullin”) is produced in 1:1 ratio with adrenomedullin and is not a pro-hormone of adrenomedullin. The physiological role, if any, of mid-regional proadrenomedullin is largely unknown. Mid-regional proadrenomedullin levels in blood have been shown to be related to the prognosis of the patient. In a study of 228 patients with community acquired pneumonia, a high ability to predict a Pneumonia Severity Index score of 4–5 ( versus 1–3), was reported (area under the curve of the receiver operating characteristic curve: mid-regional proadrenomedullin 0.81, procalcitonin 0.62, C-reactive protein 0.59) [7]. However, knowledge of prognosis indicated by a biomarker is not always translated into …

Clinical outcome in cardiorenal patients related to coronary computed tomography angiography and serum adrenomedullin

Background: Adrenomedullin is present in numerous human body tissues and its powerful vasodilatatory activity is thought to play role in cardiovascular/renal homeostasis and possibly in atherosclerosis. We conducted a prospective 2-year study of one hundred twenty-three patients with chronic kidney disease (CKD). Clinical outcome was analyzed to coronary computed tomography angiography (CCTA) findings and serum adrenomedullin levels. Methods: We determined plasma mid-regional pro-adrenomedullin (MR-proADM) levels using sandwich immunoassay in patients (pts) on stage 2 to 5 CKD (glomerular filtration rate - GFR < 90 ml/min/1.73 m2). Coronary artery calcification (CAC) and noninvasive coronary angiograms were performed by 64-multi-detector computed tomography (Siemens, Germany). The presence of stenosis ≥ 50% during CCTA was considered as significant. The degree of coronary artery calcification was assessed using the Agatston calcium score method. Results: We studied consecutive 123 pts with suspected coronary artery disease (mean age 62.5±10.7 years, 57.7% male, arterial hypertension 89.2%, type 2 diabetes 25.2%, 29.0% had a history of tobacco use and 38.2% were on regular haemodialysis- mean 51.7 months, ranging from 3 to 252 months). On CCTA, 76 pts (65.0%) had no coronary artery disease (CAD),in 29 pts (24.8%) one significant epicardial stenosis and in 12 (10.3%) multivessel disease were documented. The mean MR-proADM plasma levels and CAC score were 1.4 nmol/l and 472.8, respectively. MR-proADM correlated with CAC (r=0.20; p=0.02), GFR (r=-0.75; p<0.001), total cholesterol and LDL-cholesterol (r=-0.36; p=0.02 and r=-0.34; p= 0.001). During follow-up period (18.4±6.2 months) 7 cardiovascular deaths were occurred and 1 patient underwent percutaneous coronary intervention for unstable angina. The main characteristics in pts with cardiac events or eventfree survival were the following: serum MR-proADM (2.5 vs 1.3 nmol/l), CAC (663.7 vs 462.5). When we compared these variables to cardiac events only significant difference was documented in MR-proADM levels (p=0,04). Otherwise, areas under receiver operating characteristic curve (AUC) for prediction of cardiovascular mortality were 0.82 (95% CI 0.67-0.97), 0.75 (95% CI 0.50-0.99) and 0.64 (95% CI 0.29-0.99) for MR-proADM vs duration of hemodialysis and CAC. Conclusions: Coronary computed tomography angiography and serum adrenomedullin represent new alternative diagnostic tools for risk stratification in special group of cardiorenal patients.

Associations of mid-regional pro-adrenomedullin levels to cardiovascular and metabolic abnormalities, and mortality in an elderly population from the community

The mid-regional part of the prohormone of adrenomedullin (MR-proADM) is emerging as a novel risk indicator in patients with cardiac disease. We investigated MR-proADM levels and their changes over 5 years in elderly community-dwellers, together with the underlying cardiovascular and metabolic conditions, and the prognostic implications of these measurements. MR-proADM was analyzed using a sandwich immunoassay (Thermo Fisher Scientific) in participants from the PIVUS study. Measurements were performed at 70 (n=1002) and 75 years of age (n=795) together with various measurements of other markers of cardiovascular function. In cross-sectional analyses, MR-proADM was independently related to current smoking, renal dysfunction, obesity, lower left-ventricular ejection fraction, and higher levels of N-terminal pro-B-type natriuretic peptide and C-reactive protein. There were no independent associations to other cardiovascular risk factors or vascular pathologies. MR-proADM levels predicted all-cause mortality during 8.0 years of follow-up independent of cardiovascular risk indicators (adjusted HR 5.1 [95% CI 2.8-9.5]; p<0.001) using results obtained at 70 and 75 years as updated covariates. Baseline MR-proADM levels improved prognostic discrimination (IDI=0.018 [p=0.001]). Also the change in MR-proADM levels over time independently predicted all-cause mortality occurring after 75 years (adjusted HR 13.4 [95% CI 3.5-50.5]; p<0.001). MR-proADM levels in the elderly integrate information on several relevant aspects in cardiovascular disease, namely cardiovascular risk factors including obesity, low-grade inflammation, renal dysfunction and left-ventricular abnormalities. Furthermore, MR-proADM and its changes over time predicted mortality, and might provide utility as an indicator of the overall cardiovascular risk burden.

Can procalcitonin differentiate Staphylococcus aureus from coagulase-negative staphylococci in clustered gram-positive bacteremia?

Procalcitonin (PCT) and pro-adrenomedullin (ProADM) have been proposed as diagnostic and prognostic biomarkers of infection. Between July 2009 and January 2012, we studied the role of these biomarkers in 163 patients with clustered gram-positive and gram-negative bacteremia. PCT levels were significantly higher in patients with Staphylococcus aureus and gram-negative bacteremia than those with coagulase-negative staphylococci (CoNS) isolated from blood cultures (P = 0.29 and <0.001, respectively). ProADM levels were only significantly higher in patients with gram-negative bacteremia (median 1.46 nmol/L) than those with CoNS (median 1.01 nmol/L) (P = 0.04). Among patients with CoNS, PCT, and ProADM, levels failed to differentiate blood contamination (medians 0.24 ng/mL and 0.97 nmol/L) from true bacteremia (medians 0.26 ng/mL and 1.14 nmol/L) (P = 0.51 and 0.57, respectively). In cancer patients, PCT (and to a lesser extent, ProADM) was useful in differentiating CoNS from S. aureus and gram-negative bacteremia.

Optimised patient transfer using an innovative multidisciplinary assessment in Kanton Aargau (OPTIMA I) - an observational survey in lower respiratory tract infections

Current medical scores have limited efficiency and safety profiles to enable assignment to the most appropriate treatment site in patients with lower respiratory tract infections (LRTIs). We describe our current triage practice and assess the potential of a combination of CURB65 with proadrenomedullin (ProADM) levels for triage decisions. Consecutive patients with LRTIs presenting to our emergency department were prospectively followed and retrospectively classified according to CURB65 and ProADM levels (CURB65-A). Low medical risk patients were further subgrouped according to biopsychosocial and functional risks. We compared the proportion of patients virtually allocated to triage sites with actual triage decisions and assessed the added impact of ProADM in a subgroup. Overall, 93% of 146 patients were hospitalised. Among the 138 patients with available CURB65-A, 17.4% had a low medical risk indicating possible treatment in an outpatient or non-acute medical setting; 34.1% had an intermediate medical risk (short-hospitalisation); and 48.6% had a high medical risk (hospitalisation). Fewer patients were in a low CURB65-A class (I) than a low CURB65 class (0,1) (17.4% vs. 46.3%, p <0.001). Mean length of hospitalisation was 9.8 days including 3.6 days after reaching medical stability. In 60.3% of patients, hospitalisation was prolonged after medical stability mainly for medical reasons. Current rates of hospitalisation are high in patients with LRTI and length of stay frequently extended beyond time of medical stabilization. The lower proportion of patients reclassified as low risk by adding ProADM to the CURB65 score might improve confidence in the triage algorithm.

Optimized patient transfer using an innovative multidisciplinary assessment in the Kanton Aargau (OPTIMA I): an observational survey in lower respiratory tract infections

Current medical scores have limited efficiency and safety profiles to enable assignment to the most appropriate treatment site in patients with lower respiratory tract infections (LRTIs). We describe our current triage practice and assess the potential of a combination of CURB65 with proadrenomedullin (ProADM) levels for triage decisions.Consecutive patients with LRTIs presenting to our emergency department were prospectively followed and retrospectively classified according to CURB65 and ProADM levels (CURB65-A). Low medical risk patients were further subgrouped according to biopsychosocial and functional risks. We compared the proportion of patients virtually allocated to triage sites with actual triage decisions and assessed the added impact of ProADM in a subgroup.Overall, 93% of 146 patients were hospitalised. Among the 138 patients with available CURB65-A, 17.4% had a low medical risk indicating possible treatment in an outpatient or non-acute medical setting; 34.1% had an intermediate medical risk (short-hospitalisation); and 48.6% had a high medical risk (hospitalisation). Fewer patients were in a low CURB65-A class (I) than a low CURB65 class (0,1) (17.4% vs. 46.3%, p <0.001). Mean length of hospitalisation was 9.8 days including 3.6 days after reaching medical stability. In 60.3% of patients, hospitalisation was prolonged after medical stability mainly for medical reasons.Current rates of hospitalisation are high in patients with LRTI and length of stay frequently extended beyond time of medical stabilization. The lower proportion of patients reclassified as low risk by adding ProADM to the CURB65 score might improve confidence in the triage algorithm.

High plasma mid-regional pro-adrenomedullin levels in children with severe dengue virus infections

Background Dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) is characterized by hemorrhage, plasma leakage and shock. Adrenomedullin and vasopressin are vaso-active hormones that mediate endothelial permeability, vascular tone and water balance and may therefore play a role during DHF/DSS. Adrenomedullin reduces endothelial permeability and has vasodilatory properties, while vasopressin is a potent vasoconstrictor with anti-diuretic effects. Objectives To determine mid-regional pro-adrenomedullin (MR-proADM) and copeptin, which are reliable and stable markers for adrenomedullin and vasopressin response, respectively, and relate their plasma concentrations to outcome and markers of plasma leakage in Indonesian children with DHF and DSS. Study design In this observational cohort study Indonesian children with DHF/DSS were enrolled. On study days 0 and 2, plasma MR-proADM and copeptin concentrations as well as parameters of plasma leakage were determined. Plasma MR-proADM and copeptin concentrations were compared to values of healthy controls. Results MR-proADM was increased in both DHF ( n = 43) and DSS ( n = 28) vs. controls ( n = 17), with median (IQR) values of 0.47 (0.40–0.68), 0.56 (0.44–1.00) vs. 0.22 (0.19–0.29) nmol/L, respectively. Additionally, MR-proADM correlated with signs of increased vascular leakage such as low albumin and increased pleural effusion. Copeptin concentrations showed no significant changes as compared to controls. Conclusions MR-proADM concentrations are elevated in children with DHF and DSS and correlate with the severity of plasma leakage, in contrast to copeptin concentrations. We speculate that adrenomedullin has a functional role in limiting endothelial hyperpermeability during DHF/DSS. Finally, MR-proADM may be a candidate biomarker to predict development of DHF/DSS.

Prognostic Value of Mid-Regional Pro-Adrenomedullin Levels Taken on Admission and Discharge in Non–ST-Elevation Myocardial Infarction: The LAMP (Leicester Acute Myocardial Infarction Peptide) II Study

The purpose of this study was to assess the prognostic value of admission and discharge mid-regional pro-adrenomedullin (sAM) levels in non-ST-elevation myocardial infarction (MI) and identify values to aid clinical decision making. N-terminal pro-B-type natriuretic peptide and GRACE (Global Registry of Acute Coronary Events) score were used as comparators. sAM is a stable precursor of adrenomedullin. We measured plasma sAM on admission and discharge in 745 non-ST-elevation MI patients (514 men, median age 70.0 +/- 12.7 years). The primary end point was a composite of death, heart failure, hospitalization, and recurrent acute MI over mean follow-up of 760 days (range 150 to 2,837 days), with each event assessed individually as secondary end points. During follow-up, 120 (16.1%) patients died, and there were 65 (8.7%) hospitalizations for heart failure and 77 (10.3%) recurrent acute MIs. Both admission and discharge levels were increased (median 0.81 nmol/l [range 0.06 to 5.75 nmol/l] and 0.76 nmol/l [range 0.25 to 6.95 nmol/l], respectively) compared with established normal ranges. Multivariate adjusted Cox regression models revealed that both were associated with the primary end point (hazard ratio: 9.75 on admission and 7.54 on discharge; both p < 0.001). Admission sAM was particularly associated with early (<30 days) mortality (c-statistic = 0.90, p < 0.001), and when compared with N-terminal pro-B-type natriuretic peptide and GRACE score, it was the only independent predictor of this end point. Admission sAM >1.11 nmol/l identified those at highest risk of death (p < 0.001). Patients with above-median admission sAM may benefit from revascularization. sAM level is prognostic for death or heart failure. Admission levels are a strong predictor of early mortality and, when >1.11 nmol/l, complements the GRACE score to improve risk stratification.

Prediction about severity and outcome of sepsis by pro-atrial natriuretic peptide and pro-adrenomedullin

Objective Measurement of biomarkers is a potential approach to early prediction of the risk of mortality in patients with sepsis. The aim of the present study was to evaluate the prognostic value of pro-atrial natriuretic peptide (pro-ANP) and pro-adrenomedullin (pro-ADM) levels in a cohort of medical intensive care patients and to compare it with that of other known biomarkers and physiological scores. Methods Blood samples of 51 consecutive critically ill patients admitted to the intensive care unit and 53 age-matched healthy control people were evaluated in this prospective study. The prognostic value of pro-ANP and pro-ADM levels was compared with that of acute physiology and chronic health evaluation (APACHE) II scores and various biomarkers such as C-reactive protein, interleukin-6 and procalcitonin. Pro-ANP and pro-ADM were detected by a new sandwich immunoassay. Results On admission, 25 patients had systemic inflammatory response syndrome (SIRS), 12 sepsis, 9 severe sepsis and 5 septic shock. At that time, the median levels (ng/ml) of pro-ANP and pro-ADM were 87.22 and 0.34 respectively in patients with SIRS, 1533.30 and 2.23 in those with sepsis, 1098.73 and 4.57 in those with severe sepsis, and 1933.94 and 8.21 in those with septic shock. With the increasing severity of disease, the levels of pro-ANP and pro-ADM were gradually increased. On admission, the circulating levels of pro-ANP and pro-ADM in patients with sepsis, severe sepsis, or septic shock were significantly higher in non-survivors than in survivors (P<0.05). In a receiver operating characteristic curve analysis for the survival of patients with sepsis, the areas under the curve (AUCs) for pro-ANP and pro-ADM were 0.89 and 0.87 respectively, which was similar to the AUCs for procalcitonin and AP ACHE II scores. Conclusion Pro-ANP and pro-ADM are valuable biomarkers for prediction of severity of septic patients.

Biomarkers in lower respiratory tract infections

This review aims to provide physicians with an overview of the potential of biomarkers to complement existing clinical severity scores and in conjunction with clinical parameters to improve the diagnosis, risk-stratification and management of lower respiratory tract infections (LRTIs). The usefulness of biomarkers for diagnosing LRTIs is still unclear. However, the specificity of pneumonia diagnosis is high when high sensitivity C-reactive protein (CRP) and procalcitonin (PCT) are used. PCT, CRP and particularly pro-atrial natriuretic peptide (MR-proANP), pro-vasopressin (CT-proAVP) and proadrenomedullin (proADM) levels can reliably predict LRTIs mortality. These markers do not significantly improve the severity scores predictive values, confirming that biomarkers are meant to complement, rather than supersede, clinician’s judgment and validated severity scores. Biomarkers, and particularly PCT, are useful tools as antibiotic treatment duration indicators both in pneumonia and exacerbations of chronic obstructive pulmonary disease (COPD). Even if more data are required to fully appreciate the role of biomarkers in LRTIs management, there is emerging evidence that biomarkers have the potential to improve the daily clinical management of LRTIs.

Mid‐regional pro‐adrenomedullin as a novel predictor of mortality in patients with chronic heart failure

Adrenomedullin (ADM) is a vasodilatory peptide. Its plasma levels or its precursors have not been evaluated in large populations of patients with chronic heart failure (CHF). We sought to explore mid-regional proADM (MR-proADM). We assessed MR-proADM in 501 CHF patients [age 63 +/- 11 years, New York Heart Association (NYHA) class I/II/III/IV 9/44/39/8%, median N-terminal pro-B-type natriuretic peptide (NT-proBNP) 878 pg/mL (interquartile range-IQR 348-2480 pg/mL), median left ventricular ejection fraction (LVEF) 31% (IQR 25-37%)]. Mid-regional pro-adrenomedullin levels (median 0.64 nmol/L, IQR 0.49-0.87 nmol/L) increased with NYHA class (P < 0.0001). During 1-year follow-up, 70 patients (14%) died. Increasing MR-proADM was a predictor of poor survival at 12 months (hazard ratio 1.82, 95% confidence interval 1.24-2.66, P = 0.002) after multivariable adjustment. In receiver-operating characteristic curve analysis of 12-month survival, the area under the curve for MR-proADM and NT-proBNP was similar (P = 0.3). Comparison of Cox proportional hazard models using the likelihood ratio chi(2) statistic showed that both NT-proBNP and MR-proADM added prognostic value to a base model of LVEF, age, creatinine, and NYHA class. Adding MR-proADM to the base model had stronger prognostic power than adding NT-proBNP (both P < 0.01). Mid-regional pro-adrenomedullin is an independent predictor of mortality in CHF patients, which adds prognostic information to NT-proBNP.