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Background Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. Methods AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. Results Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5–148.1 pg/ml]. Initial SOFA score was 7 [IQR 5–10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9–2.9]; adjusted HR 1.6 [CI 1.1–2.5]) and between bio-ADM levels and SOFA score ( p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5–9.8). Conclusions AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. Trial registration ClinicalTrials.gov, NCT02393781 . Registered on March 19, 2015.

Background This study assessed the ability of mid-regional proadrenomedullin (MR-proADM) in comparison to conventional biomarkers (procalcitonin (PCT), lactate, C-reactive protein) and clinical scores to identify disease severity in patients with sepsis. Methods This is a secondary analysis of a randomised controlled trial in patients with severe sepsis or septic shock across 33 German intensive care units. The association between biomarkers and clinical scores with mortality was assessed by Cox regression analysis, area under the receiver operating characteristic and Kaplan-Meier curves. Patients were stratified into three severity groups (low, intermediate, high) for all biomarkers and scores based on cutoffs with either a 90% sensitivity or specificity. Results 1089 patients with a 28-day mortality rate of 26.9% were analysed. According to the Sepsis-3 definition, 41.2% and 58.8% fulfilled the criteria for sepsis and septic shock, with respective mortality rates of 20.0% and 32.1%. MR-proADM had the strongest association with mortality across all Sepsis-1 and Sepsis-3 subgroups and could facilitate a more accurate classification of low (e.g. MR-proADM vs. SOFA: N = 265 vs. 232; 9.8% vs. 13.8% mortality) and high (e.g. MR-proADM vs. SOFA: N = 161 vs. 155; 55.9% vs. 41.3% mortality) disease severity. Patients with decreasing PCT concentrations of either ≥ 20% (baseline to day 1) or ≥ 50% (baseline to day 4) but continuously high MR-proADM concentrations had a significantly increased mortality risk (HR (95% CI): 19.1 (8.0–45.9) and 43.1 (10.1–184.0)). Conclusions MR-proADM identifies disease severity and treatment response more accurately than established biomarkers and scores, adding additional information to facilitate rapid clinical decision-making and improve personalised sepsis treatment.

Background A reduction in duration of antibiotic therapy is crucial in minimizing the development of antimicrobial resistance, drug-related side effects and health care costs. The minimal effective duration of antimicrobial therapy for febrile urinary tract infections (fUTI) remains a topic of uncertainty, especially in male patients, those of older age or with comorbidities. Biomarkers have the potential to objectively identify the optimal moment for cessation of therapy. Methods A secondary analysis of a randomized placebo-controlled trial among 35 primary care centers and 7 emergency departments of regional hospitals in the Netherlands. Women and men aged ≥18 years with a diagnosis of fUTI were randomly assigned to receive antibiotic treatment for 7 or 14 days. Patients indicated to receive antimicrobial treatment for more than 14 days were excluded from randomization. The biomarkers procalcitonin (PCT), mid-regional proadrenomedullin (MR-proADM), and C-reactive protein (CRP) were compared in their ability to predict clinical cure or failure through the 10–18 day post-treatment visit. Results Biomarker concentrations were measured in 249 patients, with a clinical cure rate of 94% in the 165 randomized and 88% in the 84 non-randomized patients. PCT, MR-proADM and CRP concentrations did not differ between patients with clinical cure and treatment failure, and did not predict treatment outcome, irrespective of 7 or 14 day treatment duration (ROC AUC 0.521; 0.515; 0.512, respectively). PCT concentrations at presentation were positively correlated with bacteraemia (τ = 0.33, p  < 0.001) and presence of shaking chills (τ = 0.25, p  < 0.001), and MR-proADM levels with length of hospital stay (τ = 0.40, p  < 0.001), bacteraemia (τ = 0.33, p  < 0.001), initial intravenous treatment (τ = 0.22, p  < 0.001) and time to defervescence (τ = 0.21, p  < 0.001). CRP did not display any correlation to relevant clinical parameters. Conclusions Although the biomarkers PCT and MR-proADM were correlated to clinical parameters indicating disease severity, they did not predict treatment outcome in patients with community acquired febrile urinary tract infection who were treated for either 7 or 14 days. CRP had no added value in the management of patients with fUTI. Trial registration The study was registered at ClinicalTrials.gov [ NCT00809913 ; December 16, 2008] and trialregister.nl [ NTR1583 ; December 19, 2008].

Background and Objectives: Procalcitonin (PCT), presepsin (PSEP), interferon-λ3 (IFN-λ3), and bioactive adrenomedullin (bio-ADM) are promising sepsis biomarkers. We explored the clinical utility of a multi-marker approach using these four biomarkers in patients with suspected sepsis. Materials and Methods: In a total of 248 patients, the biomarkers were evaluated with the sequential organ failure assessment (SOFA) score. Receiver operating characteristic curves with area under the curve (AUC) were analyzed to diagnose sepsis and predict in-hospital mortality. Survival and reclassification analyses were also used to predict in-hospital mortality. Results: The four biomarkers showed comparable diagnostic performance (AUC = 0.61–0.95, p < 0.001–0.003), and sepsis proportion increased significantly as the number of biomarkers used in the multi-marker approach increased (7.7–91.7%, p < 0.001). The proportion of biomarker quartiles (Q1–Q4) differed significantly according to SOFA score (p < 0.001). The four biomarkers predicted in-hospital mortality (AUC = 0.63–0.84, p < 0.001–0.004). The multi-marker approach performed better than the SOFA score (mortality rate, 58.3% vs. 31.3%; adjusted hazard ratio [HR], 14.7 vs. 4.6), and the addition of biomarkers to the SOFA score increased the performance. The multi-marker approach resulted in a higher HR in patients aged ≥75 years than in the overall population (9.2 vs. 4.2). Conclusions: Each biomarker showed clinical utility in patients with suspected sepsis. The multi-marker approach showed complementary clinical utility in addition to the SOFA score and better prognostic performance in patients aged ≥75 years. The use of biomarkers, alone or in combination, would be a valuable tool in combination with the SOFA score.

Background The performance of blood biomarkers (mid-regional proadrenomedullin (MR-proADM), procalcitonin (PCT), C-reactive protein (CRP), and lactate) and clinical scores (Sequential Organ Failure Assessment (SOFA), National Early Warning Score (NEWS), and quick SOFA) was compared to identify patient populations at risk of delayed treatment initiation and disease progression after presenting to the emergency department (ED) with a suspected infection. Methods A prospective observational study across three EDs. Biomarker and clinical score values were calculated upon presentation and 72 h, and logistic and Cox regression used to assess the strength of association. Primary outcomes comprised of 28-day mortality prediction and delayed antibiotic administration or intensive care (ICU) admission, whilst secondary outcomes identified subsequent disease progression. Results Six hundred eighty-four patients were enrolled with hospitalisation, ICU admission, and infection-related 28-day mortality rates of 72.8%, 3.4%, and 4.4%, respectively. MR-proADM and NEWS had the strongest association with hospitalisation and the requirement for antibiotic administration, whereas MR-proADM alone had the strongest association with ICU admission (OR [95% CI]: 5.8 [3.1 - 10.8]) and mortality (HR [95% CI]: 3.8 [2.2 - 6.5]). Patient subgroups with high MR-proADM concentrations (≥ 1.77 nmol/L) and low NEWS (< 5 points) values had significantly higher rates of ICU admission (8.1% vs 1.6%; p  < 0.001), hospital readmission (18.9% vs. 5.9%; p  < 0.001), infection-related mortality (13.5% vs. 0.2%; p  < 0.001), and disease progression (29.7% vs. 4.9%; p  < 0.001) than corresponding patients with low MR-proADM concentrations. ICU admission was delayed by 1.5 [0.25 – 5.0] days in patients with high MR-proADM and low NEWS values compared to corresponding patients with high NEWS values, despite similar 28-day mortality rates (13.5% vs. 16.5%). Antibiotics were withheld in 17.4% of patients with high MR-proADM and low NEWS values, with higher subsequent rates of ICU admission (27.3% vs. 4.8%) and infection-related hospital readmission (54.5% vs. 14.3%) compared to those administered antibiotics during ED treatment. Conclusions Patients with low severity signs of infection but high MR-proADM concentrations had an increased likelihood of subsequent disease progression, delayed antibiotic administration or ICU admission. Appropriate triage decisions and the rapid use of antibiotics in patients with high MR-proADM concentrations may constitute initial steps in escalating or intensifying early treatment strategies.

Background Mid-Regional pro-Adrenomedullin (MR-proADM) is an inflammatory biomarker that improves the prognostic assessment of patients with sepsis, septic shock and organ failure. Previous studies of MR-proADM have primarily focussed on bacterial infections. A limited number of small and monocentric studies have examined MR-proADM as a prognostic factor in patients infected with SARS-CoV-2, however there is need for multicenter validation. An evaluation of its utility in predicting need for hospitalisation in viral infections was also performed. Methods An observational retrospective analysis of 1861 patients, with SARS-CoV-2 confirmed by RT-qPCR, from 10 hospitals across Europe was performed. Biomarkers, taken upon presentation to Emergency Departments (ED), clinical scores, patient demographics and outcomes were collected. Multiclass random forest classifier models were generated as well as calculation of area under the curve analysis. The primary endpoint was hospital admission with and without death. Results Patients suitable for safe discharge from Emergency Departments could be identified through an MR-proADM value of ≤ 1.02 nmol/L in combination with a CRP (C-Reactive Protein) of ≤ 20.2 mg/L and age ≤ 64, or in combination with a SOFA (Sequential Organ Failure Assessment) score < 2 if MR-proADM was ≤ 0.83 nmol/L regardless of age. Those at an increased risk of mortality could be identified upon presentation to secondary care with an MR-proADM value of > 0.85 nmol/L, in combination with a SOFA score ≥ 2 and LDH > 720 U/L, or in combination with a CRP > 29.26 mg/L and age ≤ 64, when MR-proADM was > 1.02 nmol/L. Conclusions This international study suggests that for patients presenting to the ED with confirmed SARS-CoV-2 infection, MR-proADM in combination with age and CRP or with the patient’s SOFA score could identify patients at low risk where outpatient treatment may be safe.

Background Older patients presenting to the emergency department (ED) after falling are increasingly prevalent. Falls are associated with functional decline and death. Biomarkers predicting short-term mortality might facilitate decisions regarding resource allocation and disposition. D-dimer levels are used to rule out thromboembolic disease, while copeptin and adrenomedullin (MR-proADM) may be used as measures of the patient`s stress level. These nonspecific biomarkers were selected as potential predictors for mortality. Methods Prospective, international, multicenter, cross-sectional observation was performed in two tertiary and two regional hospitals in Germany and Switzerland. Patients aged 65 years or older presenting to the ED after a fall were enrolled. Demographic data, Activities of Daily Living (ADL), and D-dimers were collected upon presentation. Copeptin and MR-proADM levels were determined from frozen samples. Primary outcome was 30-day mortality; and secondary outcomes were mortality at 90, 180, and 365 days. Results Five hundred and seventy-two patients were included. Median age was 83 [IQR 78, 89] years, 236 (67.7%) were female. Mortality overall was 3.1% (30 d), 5.4% (90 d), 7.5% (180 d), and 13.8% (365 d), respectively. Non-survivors were older, had a lower ADL index and higher levels of all three biomarkers. Elevated levels of MR-proADM and D-dimer were associated with higher risk of mortality. MR-proADM and D-dimer showed high sensitivity and low negative likelihood ratio regarding short-term mortality, whereas copeptin did not. Conclusion D-dimer and MR-proADM levels might be useful as prognostic markers in older patients presenting to the ED after a fall, by identifying patients at low risk of short-term mortality. Trial registration ClinicalTrials.gov Identifier: NCT02244983.

Early recognition and timely treatment of sepsis and septic shock is vital. Despite appropriate management, mortality and morbidity rates remain high. In recent years, many of the research efforts have been directed towards finding novel biomarkers that would rapidly identify, classify and risk-stratify the severity of sepsis in order to achieve prompt and targeted treatment of patients with sepsis and septic shock. Among these biomarkers, adrenomedullin (ADM) in the form of the biologically active fragment (bio-ADM) and dipeptidyl peptidase 3 (DPP3) have recently been in the spotlight. The aim of this narrative review is to summarize current evidence on these two novel biomarkers regarding their clinical utility in diagnosis, prognosis, treatment monitoring and therapy guidance of sepsis and septic shock in the emergency department (ED) and in the intensive care unit (ICU) setting. Bio-ADM seems to be a promising biomarker with respect to the overall management of sepsis (diagnosis, severity prediction, prognosis and treatment monitoring and guidance). On the other hand, DPP3 appears to be useful mainly for sepsis prognosis and for predicting sepsis-induced acute kidney injury. Given their potential clinical utility in sepsis management, the use of these two novel biomarkers, in conjunction with established biomarkers and clinical scores, could lead to the application of refined integrated protocols in the ED and the ICU, which could promptly and effectively inform clinical decision-making in patients presenting with sepsis or septic shock.

AimsThere is a lack of biomarkers validated for assessing clinical deterioration in patients with COVID-19 on presentation to secondary or tertiary care. This evaluation looked at the potential clinical application of C reactive protein (CRP), procalcitonin, mid-regional proadrenomedullin (MR-proADM) and white cell count to support prediction of clinical outcomes.Methods135 patients presenting to Hampshire Hospitals NHS Foundation Trust between April and June 2020 confirmed to have COVID-19 via reverse-transcription-qPCR were included. Biomarkers from within 24 hours of presentation were used to predict disease progression by Cox regression and area under the receiver operating characteristic curves. The endpoints assessed were 30-day all-cause mortality, intubation and ventilation, critical care admission and non-invasive ventilation (NIV) use.ResultsElevated MR-proADM was shown to have the greatest ability to predict 30-day mortality adjusting for age, cardiovascular disease, renal disease and neurological disease. A significant association was also noted between raised MR-proADM and CRP concentrations and the requirement for critical care admission and NIV.ConclusionsThe measurement of MR-proADM and CRP in patients with confirmed COVID-19 infection on admission shows significant potential to support clinicians in identifying those at increased risk of disease progression and need for higher level care, subsequently enabling prompt escalation in clinical interventions.

Background Adrenomedullin and endothelin-1 are hormones with opposing effects on the cardiovascular system. Adrenomedullin acts as a vasodilator and seems to be important for the initiation and continuation of the hyperdynamic circulatory response in sepsis. Endothelin-1 is a vasoconstrictor and has been linked to decreased cardiac performance. Few studies have studied the relationship between adrenomedullin and endothelin-1, and morbidity and mortality in septic shock patients. High-sensitivity troponin T (hsTNT) is normally used to diagnose acute cardiac injury but is also prognostic for outcome in intensive care. We investigated the relationship between mid-regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), and myocardial injury, measured using transthoracic echocardiography and hsTNT in septic shock patients. We were also interested in the development of different biomarkers throughout the ICU stay, and how early measurements were related to mortality. Further, we assessed if a positive biomarker panel, consisting of MR-proADM, CT-proET-1, and hsTNT changed the odds for mortality. Methods A cohort of 53 consecutive patients with septic shock had their levels of MR-proADM, CT-proET-1, hsTNT, and left ventricular systolic functions prospectively measured over 7 days. The relationship between day 1 levels of MR-proADM/CT-proET-1 and myocardial injury was studied. We also investigated the relationship between biomarkers and early (7-day) and later (28-day) mortality. Likelihood ratios, and pretest and posttest odds for mortality were calculated. Results Levels of MR-proADM and CT-proET-1 were significantly higher among patients with myocardial injury and were correlated with left ventricular systolic dysfunction. MR-proADM and hsTNT were significantly higher among 7-day and 28-day non-survivors. CT-proET-1 was also significantly higher among 28-day but not 7-day non-survivors. A positive biomarker panel consisting of the three biomarkers increased the odds for mortality 13-fold to 20-fold. Conclusions MR-proADM and CT-proET-1 are associated with myocardial injury. A biomarker panel combining MR-proADM, CT-proET-1, and hsTNT increases the odds ratio for death, and may improve currently available scoring systems in critical care.