adrenomedullin and Shock--Septic

The early diagnosis of sepsis is hampered by the lack of reliable laboratory measures. There is growing evidence that presepsin and Mid-regional pro-adrenomedullin (MR-proADM) are promising biomarkers in the diagnosis of sepsis. This study was conducted to evaluate and compare the diagnostic value of MR-proADM and presepsin in sepsis patients.. We searched Web of Science, PubMed, Embase, China national knowledge infrastructure, and Wanfang up to 22th July, 2022, for studies evaluating the diagnosis performance of presepsin and MR-proADM in adult sepsis patients. Risk of bias was assessed using quadas-2. Pooled sensitivity and specificity were calculated using bivariate meta-analysis. Meta-regression and subgroup analysis were used to find source of heterogeneity.. A total of 40 studies were eventually selected for inclusion in this meta-analysis, including 33 for presepsin and seven for MR-proADM. Presepsin had a sensitivity of 0.86 (0.82-0.90), a specificity of 0.79 (0.71-0.85), and an AUC of 0.90 (0.87-0.92). The sensitivity of MR-proADM was 0.84 (0.78-0.88), specificity was 0.86 (0.79-0.91), and AUC was 0.91 (0.88-0.93). The profile of control group, population, and standard reference may be potential sources of heterogeneity.. This meta-analysis demonstrated that presepsin and MR-proADM exhibited high accuracy (AUC ≥ 0.90) in the diagnosis of sepsis in adults, with MR-proADM showing significantly higher accuracy than presepsin.

Topics: Adrenomedullin; Adult; Biomarkers; Humans; Lipopolysaccharide Receptors; Peptide Fragments; Prognosis; Protein Precursors; Sepsis; Shock, Septic

Sepsis and septic shock represent a leading cause of mortality in the Emergency Department (ED) and in the Intensive Care Unit (ICU). For these life-threating conditions, different diagnostic and prognostic biomarkers have been studied. Proadrenomedullin (MR-proADM) is a biomarker that can predict organ damage and the risk of imminent death in patients with septic shock, as shown by a large amount of data in the literature. The aim of our narrative review is to evaluate the role of MR-proADM in the context of Emergency Medicine and to summarize the current knowledge of MR-proADM as a serum indicator that is useful in the Emergency Department (ED) to determine an early diagnosis and to predict the long-term mortality of patients with sepsis and septic shock. We performed an electronic literature review to investigate the role of MR-proADM in sepsis and septic shock in the context of ED. We searched papers on PubMed

Topics: Adrenomedullin; Biomarkers; Emergency Service, Hospital; Humans; Prognosis; Protein Precursors; Sepsis; Shock, Septic

Sepsis represents one of the major medical challenges of the 21st century. Despite substantial improvements in the knowledge on pathophysiological mechanisms, this has so far not translated into novel adjuvant treatment strategies for sepsis. In sepsis, both vascular tone and vascular integrity are compromised, and contribute to the development of shock, which is strongly related to the development of organ dysfunction and mortality. In this review, we focus on dipeptidyl peptidase 3 (DPP3) and adrenomedullin (ADM), two molecules that act on the vasculature and are involved in the pathophysiology of sepsis and septic shock. DPP3 is an ubiquitous cytosolic enzyme involved in the degradation of several important signalling molecules essential for regulation of vascular tone, including angiotensin II. ADM is a key hormone involved in the regulation of vascular tone and endothelial barrier function. Previous studies have shown that circulating concentrations of both DPP3 and ADM are independently associated with the development of organ failure and adverse outcome in sepsis. We now discuss new evidence illustrating that these molecules indeed represent two distinct pathways involved in the development of septic shock. Recently, both ADM-enhancing therapies aimed at improving endothelial barrier function and vascular tone and DPP3-blocking therapies aimed at restoring systemic angiotensin responses have been shown to improve outcome in various preclinical sepsis models. Given the current lack of effective adjuvant therapies in sepsis, additional research on the therapeutic application of these peptides in humans is highly warranted.

Topics: Adrenomedullin; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Humans; Sepsis; Shock, Septic

Topics: Adrenomedullin; Arteriosclerosis; Diagnostic Techniques, Endocrine; Heart Failure; Humans; Hypertension; Immunoradiometric Assay; Kidney Failure, Chronic; Peptides; Radioimmunoassay; Reference Values; Shock, Septic; Specimen Handling; Systemic Inflammatory Response Syndrome

Adrenomedullin (AM), inducing a potent and powerful hypotensive activity caused by dilatation of resistance vessels, has elicited interest for its cardiovascular actions. AM is secreted from various cell type, including vascular endothelial and smooth muscle cell. AM plasma levels are increased in various cardiovascular diseases as heart failure and hypertension and may be involved in pathophysiological changes in cardiovascular diseases.

Topics: Adrenomedullin; Animals; Cardiovascular Diseases; Chronic Disease; Glomerulonephritis; Heart Failure; Homeostasis; Humans; Hypertension; Hypertension, Pulmonary; Myocardial Infarction; Peptides; Rats; Shock, Septic

Adrenomedullin is a 52-amino acid peptide that was first isolated from human pheochromocytoma. Subsequently, it was found to be distributed widely in the body, including throughout the cardiovascular system. It belongs to a family of peptides that include calcitonin gene-related peptide and amylin. Adrenomedullin causes vasorelaxation and influences vascular proliferation and interacts closely with nitric oxide, and it may have a role in the pathophysiology of hypertension, ischemic heart disease, and cardiac and renal failure. Nonpeptide agonists or antagonists of adrenomedullin may have potential therapeutic application. The role of adrenomedullin in septicemic shock also merits further investigation.

Topics: Adrenomedullin; Animals; Calcitonin Gene-Related Peptide; Cardiovascular Physiological Phenomena; Humans; Peptides; Receptors, Calcitonin Gene-Related Peptide; Shock, Septic; Signal Transduction; Tissue Distribution; Vasodilation

Topics: Adrenomedullin; Animals; Biomarkers; Blood Pressure; Complement Factor H; Hemodynamics; Humans; Peptide Fragments; Peptides; Shock, Septic; Vasodilation

Adrenomedullin (AM) is a vasodilator peptide first identified in pheochromocytoma tissue, but endothelial cells and vascular smooth muscle cells actively secrete AM in addition to expressing AM receptors. AM dilates blood vessels through its direct action on the smooth muscle and the endothelial cell-mediated nitric oxide pathway. We have further demonstrated that AM is synthesized and secreted from macrophages, fibroblasts, cardiomyocytes and many other types of cells. AM secretion from these cells as well as the vascular wall cells are commonly stimulated with inflammatory cytokines and lipopolysaccharide. AM receptor is also widely distributed, and AM is shown to regulate production of inflammatory cytokines and cell growth. Based on these data, AM is deduced to be a multi-functional peptide participating in the regulation of vascular tone, inflammation and other physiologic events of the vasculature.

Topics: Adrenal Gland Neoplasms; Adrenomedullin; Amino Acid Sequence; Animals; Blood Pressure; Cell Division; Cytokines; Endothelium, Vascular; Fibroblasts; Humans; Inflammation; Lipopolysaccharides; Mice; Mice, Transgenic; Molecular Sequence Data; Muscle, Smooth, Vascular; Neoplasm Proteins; Nitric Oxide; Organ Specificity; Peptides; Pheochromocytoma; Rats; Receptors, Adrenomedullin; Receptors, Peptide; Shock, Septic; Vasodilation

Topics: Adrenomedullin; Animals; Humans; Peptides; Sepsis; Shock, Septic

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Blood Glucose; Bronchodilator Agents; Cardiotonic Agents; Cardiovascular Diseases; Humans; Hyperaldosteronism; Kidney Failure, Chronic; Peptides; Reference Values; Shock, Septic; Tumor Cells, Cultured

Investigate safety and tolerability of adrecizumab, a humanized monoclonal adrenomedullin antibody, in septic shock patients with high adrenomedullin.. Phase-2a, double-blind, randomized, placebo-controlled biomarker-guided trial with a single infusion of adrecizumab (2 or 4 mg/kg b.w.) compared to placebo. Patients with adrenomedullin above 70 pg/mL, < 12 h of vasopressor start for septic shock were eligible. Randomization was 1:1:2. Primary safety (90-day mortality, treatment emergent adverse events (TEAE)) and tolerability (drug interruption, hemodynamics) endpoints were recorded. Efficacy endpoints included the Sepsis Support Index (SSI, reflecting ventilator- and shock-free days alive), change in Sequential-related Organ Failure Assessment (SOFA) and 28-day mortality.. 301 patients were enrolled (median time of 8.5 h after vasopressor start). Adrecizumab was well tolerated (one interruption, no hemodynamic alteration) with no differences in frequency and severity in TEAEs between treatment arms (TEAE of grade 3 or higher: 70.5% in the adrecizumab group and 71.1% in the placebo group) nor in 90-day mortality. Difference in change in SSI between adrecizumab and placebo was 0.72 (CI -1.93-0.49, p = 0.24). Among various secondary endpoints, delta SOFA score (defined as maximum versus minimum SOFA) was more pronounced in the adrecizumab combined group compared to placebo [difference at 0.76 (95% CI 0.18-1.35); p = 0.007]. 28-day mortality in the adrecizumab group was 23.9% and 27.7% in placebo with a hazard ratio of 0.84 (95% confidence interval 0.53-1.31, log-rank p = 0.44).. Overall, we successfully completed a randomized trial evaluating selecting patients for enrolment who had a disease-related biomarker. There were no overt signals of harm with using two doses of the adrenomedullin antibody adrecizumab; however, further randomized controlled trials are required to confirm efficacy and safety of this agent in septic shock patients.

Topics: Adrenomedullin; Antibodies, Monoclonal, Humanized; Biomarkers; Double-Blind Method; Humans; Shock, Septic; Treatment Outcome

Sepsis remains a major health problem with an increasing incidence, high morbidity and high mortality. Apart from treatment with antibiotics and organ support, no approved specific adjunct therapies currently exist. Adrenomedullin (ADM) is a vasoactive peptide. High plasma concentrations of ADM correlate with worse outcome in sepsis patients. Preclinical work with the non-neutralising ADM-binding antibody adrecizumab showed promising effects in animal models of septic shock, including improved vascular barrier function, reduced vasopressor demand and organ dysfunction and increased survival. Therapeutic use of adrecizumab may therefore improve outcome in critically ill patients with septic shock and high ADM plasma concentrations. Phase I studies in healthy volunteers did not reveal any safety concerns. In this biomarker-guided trial, the safety and efficacy of adrecizumab will be investigated in patients with septic shock.. We describe a phase II, randomised, double-blind, placebo-controlled, biomarker-guided, proof-of-concept and dose-finding clinical trial in patients with early septic shock and high concentration of circulating ADM. A total of 300 patients will be enrolled at approximately 30 sites within the European Union. Patients are randomised to receive active treatment (2 and 4 mg/kg adrecizumab) or placebo, in a 1:1:2 ratio. Patient selection is guided by clinical parameters, and biomarker-guided by measurement of circulating biologically active ADM concentration at admission. Primary endpoint is safety and tolerability of adrecizumab over a 90-day period. A key secondary endpoint is the Sepsis Severity Index over a 14-day period.. This study is approved by relevant institutional review boards/independent ethics committees and is conducted in accordance with the ethical principles of the Declaration of Helsinki, the European Medicines Agency guidelines of Good Clinical Practice and all other applicable regulations. Results of this study will be published in a peer-reviewed scientific journal.. NCT03085758; Pre-results.

Topics: Adrenomedullin; Antibodies; Double-Blind Method; Humans; Proof of Concept Study; Shock, Septic

The biological role of adrenomedullin (ADM), a hormone involved in hemodynamic homeostasis, is controversial in sepsis because administration of either the peptide or an antibody against it may be beneficial.. Plasma biologically active ADM (bio-ADM) was assessed on days 1, 2, and 7 after randomization of 956 patients with sepsis or septic shock to albumin or crystalloids for fluid resuscitation in the multicenter Albumin Italian Outcome Sepsis trial. We tested the association of bio-ADM and its time-dependent variation with fluid therapy, vasopressor administration, organ failures, and mortality.. Plasma bio-ADM on day 1 (median [Q1-Q3], 110 [59-198] pg/mL) was higher in patients with septic shock, associated with 90-day mortality, multiple organ failures and the average extent of hemodynamic support therapy (fluids and vasopressors), and serum lactate time course over the first week. Moreover, it predicted incident cardiovascular dysfunction in patients without shock at enrollment (OR [95% CI], 1.9 [1.4-2.5]; P < .0001, for an increase of 1 interquartile range of bio-ADM concentration). bio-ADM trajectory during the first week of treatment clearly predicted 90-day mortality after adjustment for clinically relevant covariates (hazard ratio [95% CI], 1.3 [1.2-1.4]; P < .0001), and its reduction below 110 pg/mL at day 7 was associated with a marked reduction in 90-day mortality. Changes over the first 7 days of bio-ADM concentrations were not dependent on albumin treatment.. In patients with sepsis, the circulating, biologically active form of ADM may help individualizing hemodynamic support therapy, while avoiding harmful effects. Its possible pathophysiologic role makes bio-ADM a potential candidate for future targeted therapies.. ClinicalTrials.gov; No.: NCT00707122.

Topics: Adrenomedullin; Aged; Albumins; Biomarkers; Crystalloid Solutions; Female; Fluid Therapy; Hemodynamics; Humans; Isotonic Solutions; Male; Middle Aged; Multiple Organ Failure; Resuscitation; Sepsis; Shock, Septic; Treatment Outcome

The aims of the present study were to evaluate the prognostic value of adrenomedullin (AM) in septic patients in the emergency department (ED) and to compare it with procalcitonin (PCT) and Mortality in Emergency Department Sepsis (MEDS) score.. We enrolled 837 consecutive patients who fulfilled the systemic inflammatory response syndrome criteria and were admitted to the ED of Beijing Chaoyang Hospital and 100 age-matched healthy controls. Serum AM and PCT were determined, and MEDS score was calculated at enrollment. The prognostic value of AM was compared with PCT and MEDS score. Primary outcome was in-hospital mortality.. On admission, mean levels of AM were 28.66 ± 6.05 ng/L in 100 healthy controls, 31.65 ± 6.47 ng/L in 153 systemic inflammatory response syndrome patients, 33.24 ± 8.59 ng/L in 376 sepsis patients, 34.81 ± 8.33 ng/L in 210 severe sepsis patients, and 45.15 ± 9.87 ng/L in 98 septic shock patients. The differences between the 2 groups were significant. Adrenomedullin level was higher in nonsurvivors than in survivors in every group. The area under receiver operating characteristic curve of AM for predicting in-hospital mortality in septic patients was 0.773, which was better than PCT (0.701) and MEDS score (0.721). Combination of AM and MEDS score improved the accuracy of AM and MEDS score in predicting the risk of in-hospital mortality (area under receiver operating characteristic curve, 0.817). In logistic regression analysis, AM and MEDS score were independent predictors of in-hospital mortality.. Adrenomedullin is valuable for prognosis in septic patients in the ED.

Topics: Adrenomedullin; Aged; Biomarkers; Calcitonin; Calcitonin Gene-Related Peptide; Case-Control Studies; Emergency Service, Hospital; Female; Hospital Mortality; Humans; Kaplan-Meier Estimate; Logistic Models; Male; Middle Aged; Prognosis; Protein Precursors; ROC Curve; Sepsis; Severity of Illness Index; Shock, Septic; Systemic Inflammatory Response Syndrome

Information about biologically active adrenomedullin (mature AM), a potential new biomarker for sepsis and septic shock, is limited. Here, we investigated the value of mature AM for diagnosis and outcome prediction in sepsis.. Patients admitted to the intensive care unit (ICU) were retrospectively cate-gorised into non-sepsis or sepsis groups, according to the Sepsis-3 definitions. Plasma levels of mature and total (the sum of the levels of intermediate and mature forms) AM were measured, and their usefulness was compared with that of other sepsis biomarkers, such as procalcitonin and presepsin.. Of the 98 patients analysed, 42 were assigned to the non-sepsis and 56 to the sepsis group. Mature and total AM levels on admission were significantly higher in patients with than in those without sepsis. The areas under the receiver operating characteristic curves (AUCs) of mature and total AM for diagnosing sepsis were 0.85 and 0.88, whereas those of procalcitonin and presepsin were 0.83 and 0.68, respectively. AUCs of mature and total AM for predicting 28-day mortality in patients with sepsis became significant on day 3 after admission. A good correlation between the AM forms was found, indicating that changes in their plasma levels may directly reflect each other.. Because mature and total AM levels increased significantly in patients with sepsis on admission, both forms may be used as reliable and early biomarkers for diagnosing sepsis according to the Sepsis-3 definitions. However, prediction of 28-day mortality in such patients would require several days of ICU stay.

Topics: Adrenomedullin; Biomarkers; Humans; Intensive Care Units; Lipopolysaccharide Receptors; Peptide Fragments; Prognosis; Retrospective Studies; ROC Curve; Sepsis; Shock, Septic

Topics: Adrenomedullin; Heart Failure; Humans; Inflammation; Sepsis; Shock, Septic

Topics: Adrenomedullin; Heart Failure; Humans; Inflammation; Sepsis; Shock, Septic

Stratification of the severity of infection is currently based on the Sequential Organ Failure Assessment (SOFA) score, which is difficult to calculate outside the ICU. Biomarkers could help to stratify the severity of infection in surgical patients.. Levels of ten biomarkers indicating endothelial dysfunction, 22 indicating emergency granulopoiesis, and six denoting neutrophil degranulation were compared in three groups of patients in the first 12 h after diagnosis at three Spanish hospitals.. There were 100 patients with infection, 95 with sepsis and 57 with septic shock. Seven biomarkers indicating endothelial dysfunction (mid-regional proadrenomedullin (MR-ProADM), syndecan 1, thrombomodulin, angiopoietin 2, endothelial cell-specific molecule 1, vascular cell adhesion molecule 1 and E-selectin) had stronger associations with sepsis than infection alone. MR-ProADM had the highest odds ratio (OR) in multivariable analysis (OR 11·53, 95 per cent c.i. 4·15 to 32·08; P = 0·006) and the best area under the curve (AUC) for detecting sepsis (0·86, 95 per cent c.i. 0·80 to 0·91; P < 0·001). In a comparison of sepsis with septic shock, two biomarkers of neutrophil degranulation, proteinase 3 (OR 8·09, 1·34 to 48·91; P = 0·028) and lipocalin 2 (OR 6·62, 2·47 to 17·77; P = 0·002), had the strongest association with septic shock, but lipocalin 2 exhibited the highest AUC (0·81, 0·73 to 0·90; P < 0·001).. MR-ProADM and lipocalin 2 could be alternatives to the SOFA score in the detection of sepsis and septic shock respectively in surgical patients with infection.. La estratificación de la gravedad de una infección se basa actualmente en la puntuación SOFA (Sequential Organ Failure Assessment), que es difícil de calcular fuera de la unidad de cuidados intensivos. Los biomarcadores podrían ayudar a estratificar la gravedad de la infección en pacientes quirúrgicos. MÉTODOS: Se compararon las concentraciones de 10 biomarcadores que denotan disfunción endotelial, 22 que indican granulopoyesis de emergencia y 6 que expresan la degranulación de neutrófilos en tres grupos de pacientes de tres hospitales españoles (100 con infección, 95 con sepsis y 57 con shock séptico) en las primeras doce horas después del diagnóstico.. Siete biomarcadores que expresan disfunción endotelial (proadrenomedulina, sindecan-1, trombomodulina, angiopoyetina-2, endocan-1, molécula de adhesión endotelial 1 y E-selectina) mostraron una fuerte asociación con la sepsis en comparación con la infección aislada. La proadrenomedulina presentó el valor más alto de la razón de oportunidades (odds ratio, OR) en el análisis multivariable (OR 11,53, i.c. del 95% 4,15-32,08, P = 0,006) y la mejor área bajo la curva para detectar sepsis (AUC 0,86, i.c. del 95% 0,80-0,91, P < 0,001). En la comparación entre sepsis y shock séptico, los biomarcadores que mostraron la asociación más estrecha con el shock séptico fueron dos biomarcadores de degranulación de neutrófilos (proteinasa-3 y lipocalina-2) (OR 8,09, i.c. del 9% 1,34-48,91, P = 0,028; OR 6.62, i.c. del 95% 2,47-17,77, P = 0,002), pero la lipocalina-2 presentó la mejor AUC (0,81, i.c. del 95% 0,73-0,90, P < 0,001). CONCLUSIÓN: la proadrenomedulina y la lipocalina-2 podrían representar alternativas a la puntuación SOFA para detectar sepsis y shock séptico en pacientes quirúrgicos con infección.

Topics: Adrenomedullin; Adult; Aged; Angiopoietin-2; Area Under Curve; Biomarkers; Female; Hospital Mortality; Humans; Intensive Care Units; Lipocalin-2; Male; Middle Aged; Multivariate Analysis; Neutrophils; Organ Dysfunction Scores; Prognosis; Protein Precursors; ROC Curve; Sepsis; Shock, Septic; Spain; Thrombomodulin; Vascular Cell Adhesion Molecule-1

Topics: Adrenomedullin; Humans; Intensive Care Units; Lactic Acid; Prognosis; Prospective Studies; Sepsis; Shock, Septic

Following the SEPSIS-3 consensus, detection of organ failure as assessed by the SOFA (Sequential Organ Failure Assessment) score, is mandatory to detect sepsis. Calculating SOFA outside of the Intensive Care Unit (ICU) is challenging. The alternative in this scenario, the quick SOFA, is very specific but less sensible. Biomarkers could help to detect the presence of organ failure secondary to infection either in ICU and non-ICU settings.. We evaluated the ability of four biomarkers (C-Reactive protein (CRP), lactate, mid-regional proadrenomedullin (MR-proADM) and procalcitonin (PCT)) to detect each kind of organ failure considered in the SOFA in 213 patients with infection, sepsis or septic shock, by using multivariate regression analysis and calculation of the area under the receiver operating curve (AUROC).. In the multivariate analysis, MR-proADM was an independent predictor of five different failures (respiratory, coagulation, cardiovascular, neurological and renal). In turn, lactate predicted three (coagulation, cardiovascular and neurological) and PCT two (cardiovascular and renal). CRP did not predict any of the individual components of SOFA. The highest AUROCs were those of MR-proADM and PCT to detect cardiovascular (AUROC, CI95%): MR-proADM (0.82 [0.76-0.88]), PCT (0.81 [0.75-0.87] (P < .05) and renal failure: MR-proADM (0.87 [0.82-0.92]), PCT (0.81 [0.75-0.86]), (P < .05). None of the biomarkers tested was able to detect hepatic failure.. In patients with infection, MR-proADM was the biomarker detecting the largest number of SOFA score components, with the exception of hepatic failure.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Area Under Curve; Blood Coagulation Disorders; C-Reactive Protein; Cardiovascular Diseases; Female; Heart Failure; Humans; Infections; Intensive Care Units; Lactic Acid; Liver Failure; Male; Middle Aged; Multivariate Analysis; Nervous System Diseases; Organ Dysfunction Scores; Peptide Fragments; Procalcitonin; Protein Precursors; Renal Insufficiency; Respiratory Insufficiency; ROC Curve; Sepsis; Shock, Septic

Biomarkers can be of help to understand critical illness and to identify and stratify sepsis. Adrenomedullin is a vasoactive hormone, with reported prognostic and potentially therapeutic value in sepsis. The primary aim of this study was to investigate the association of circulating bioactive adrenomedullin (bio-ADM) levels at intensive care unit (ICU) admission with mortality in sepsis patients and in a general ICU population. Secondary aims included the association of bio-ADM with organ failure and the ability of bio-ADM to identify sepsis.. In this retrospective observational study, adult patients admitted to one of four ICUs during 2016 had admission bio-ADM levels analysed. Age-adjusted odds ratios (OR) with 95% CI for log-2 transformed bio-ADM, and Youden's index derived cut-offs were calculated. The primary outcome was 30-day mortality, and secondary outcomes included the need for organ support and the ability to identify sepsis.. Bio-ADM in 1867 consecutive patients were analysed; 632 patients fulfilled the sepsis-3 criteria of whom 267 had septic shock. The median bio-ADM in the entire ICU population was 40 pg/mL, 74 pg/mL in sepsis patients, 107 pg/mL in septic shock and 29 pg/mL in non-septic patients. The association of elevated bio-ADM and mortality in sepsis patients and the ICU population resulted in ORs of 1.23 (95% CI 1.07-1.41) and 1.22 (95% CI 1.12-1.32), respectively. The association with mortality remained after additional adjustment for lactate in sepsis patients. Elevated bio-ADM was associated with an increased need for dialysis with ORs of 2.28 (95% CI 2.01-2.59) and 1.97 (95% CI 1.64-2.36) for the ICU population and sepsis patients, respectively, and with increased need of vasopressors, OR 1.33 (95% CI 1.23-1.42) (95% CI 1.17-1.50) for both populations. Sepsis was identified with an OR of 1.78 (95% CI 1.64-1.94) for bio-ADM, after additional adjustment for severity of disease. A bio-ADM cut-off of 70 pg/mL differentiated between survivors and non-survivors in sepsis, but a Youden's index derived threshold of 108 pg/mL performed better.. Admission bio-ADM is associated with 30-day mortality and organ failure in sepsis patients as well as in a general ICU population. Bio-ADM may be a morbidity-independent sepsis biomarker.

Topics: Adrenomedullin; Aged; Biomarkers; Critical Illness; Electronic Health Records; Female; Humans; Logistic Models; Male; Middle Aged; Odds Ratio; Organ Dysfunction Scores; Prognosis; Retrospective Studies; Sepsis; Shock, Septic; Sweden

Procalcitonin and Mid-regional pro Adrenomedullin have been proposed for sepsis diagnosis, antibiotic therapy guidance and prognosis. A retrospective analysis of PCT and MR-proADM on 571 consecutive patients with sepsis diagnosis was performed. Median values were compared using the non-parametric Mann-Whitney's test. Receiver operating characteristic analysis was performed to define cutoff points for sepsis diagnosis. Pretest odds, posttest odds, and posttest probability have been calculated. Data were analyzed using Med-Calc 11.6.1.0 software. PCT resulted excellent in gram-negative, but less performant in gram-positive and fungal etiologies. MR-proADM values resulted homogenously distributed within the different microbial classes and increased significantly in septic shock. PCT highest PPV value was found to distinguish gram-negative from fungal sepsis and septic shock (>3. 57 ng/mL, PPV 0.96 and > 8.77 ng/mL, PPV 0.96, respectively). Good diagnostic accuracy was evidenced to discriminate gram-negative from gram-positive septic shock (>3.88 ng/mL PPV 0.89). Lower diagnostic accuracy was evidenced to discriminate gram-negative and gram-positive sepsis (>0.80 ng/mL, PPV 0.78) and gram-positive from fungal septic shock (>1.74 ng/mL PPV 0.75). The lowest PCT PPV (0.28) was found in gram-positive and fungal sepsis distinction. MR-proADM discriminating cut-offs were homogeneously distributed in Gram-negative and Gram-positive sepsis and were higher in septic shock, but not influenced by pathogen etiologies. MR-proADM cut-off values > 3.39 nmol/L in sepsis and >4.33 nmol/L in septic shock were associated with significant higher risk of 90-days mortality. In conclusion, PCT and MR-proADM combination represents an advantage for sepsis diagnosis and for 90-days mortality risk stratification.

Topics: Adrenomedullin; Adult; Aged; Anti-Bacterial Agents; Bacteria; Drug Combinations; Female; Fungi; Humans; Italy; Male; Middle Aged; Procalcitonin; Prognosis; Protein Precursors; Retrospective Studies; ROC Curve; Sepsis; Shock, Septic

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Biologically active adrenomedullin (bio-ADM) is an emerging biomarker for sepsis. We explored whether bio-ADM concentration could predict severity, organ failure, and 30-day mortality in septic patients.. In 215 septic patients (109 patients with sepsis; 106 patients with septic shock), bio-ADM concentration was measured at diagnosis of sepsis, using sphingotest bio-ADM (Sphingotec GmbH, Hennigsdorf, Germany) and analyzed in terms of sepsis severity, vasopressor use, and 30-day mortality. The number of organ failures, sequential (sepsis-related) organ failure assessment (SOFA) score, and 30-day mortality were compared according to bio-ADM quartiles.. Bio-ADM concentration was significantly higher in patients with septic shock, vasopressor use, and non-survivors than in patients with solitary sepsis, no vasopressor use, and survivors, respectively (all. Bio-ADM could serve as a useful and objective biomarker to predict severity, organ failure, and 30-day mortality in septic patients.

Topics: Adrenomedullin; Aged; Area Under Curve; Female; Humans; Male; Middle Aged; Multiple Organ Failure; Proportional Hazards Models; ROC Curve; Sepsis; Severity of Illness Index; Shock, Septic; Survival Rate

The third Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defined sepsis as an organ dysfunction consequent to infection. A Sequential Organ Failure Assessment (SOFA) score at least 2 identifies sepsis. In this study, procalcitonin (PCT) and midregional pro-adrenomedullin (MR-proADM) were evaluated along with SOFA and quick SOFA (qSOFA) scores in patients with sepsis or septic shock.. A total of 109 septic patients and 50 patients with noninfectious disease admitted at the Department of Internal Medicine and General Surgery of the University Hospital Campus Bio-Medico of Rome were enrolled. PCT and MR-proADM were measured with immunoluminometric assays (Brahms, Hennigsdorf, Germany). Data were analyzed with receiver-operating characteristic (ROC) curve analysis, likelihood ratios, and Mann-Whitney U test using MedCalc 11.6.1.0 package.. At ROC curve analysis, PCT showed the highest area under the curve and positive likelihood ratio values of 27.42 in sepsis and 43.62 in septic shock. MR-proADM and SOFA score showed a comparable performance. In septic shock, lactate showed the most accurate diagnostic ability. In sepsis, the best combination was PCT with MR-proADM with a posttest probability of 0.988. Based upon these results, an algorithm for sepsis and septic shock diagnosis has been developed. MR-proADM, SOFA, and qSOFA scores significantly discriminated survivors from nonsurvivors.. PCT and MR-proADM test combination represent a good tool in sepsis diagnosis and prognosis suggesting their inclusion in the diagnostic algorithm besides SOFA and qSOFA scores. Furthermore, MR-proADM as marker of organ dysfunction, with a turn around time of about 30 min, has the advantage to be more objective and rapid than SOFA score.

Topics: Adrenomedullin; Aged; Algorithms; Female; Humans; Male; Organ Dysfunction Scores; Procalcitonin; Prospective Studies; Protein Precursors; ROC Curve; Sepsis; Shock, Septic

To investigate the protective effect of intermedin1-53 (IMD1-53) on cardiac function in rats with septic shock and its underlying mechanism.. Twenty-four male Sprague-Dawley (SD) rats were randomly assigned into three groups, namely the control group (NC group), septic shock group (ET group) and IMD1-53 treatment group (IMD group), with 8 rats in each group. Levels of hemodynamic indicators, blood glucose, lactate acid, CK-MB (creatine kinase-MB) and cTnI (cardiac troponin I) in rats were determined. Cardiac tissues of rats were collected for TUNEL (terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling) staining. Protein levels of caspase-3, caspase-9, Bax, Bcl2, iNOS (inducible nitric oxide synthase) and COX-2 (cyclooxygenase-2) in cardiac tissues were detected by Western blot. Moreover, activities of SOD (superoxide dismutase), CAT (catalase) and MDA (malondialdehyde) in myocardial homogenate were determined, thereby exploring the effect of IMD1-53 on oxidative stress and cardiomyocyte apoptosis in rats with septic shock induced by endotoxin.. Lower levels of mean arterial blood pressure (MABP), maximum rate of left ventricular diastolic pressure (+LVdp/dtmax) and left ventricular systolic pressure (LVSP) were observed in ET group than those of NC group (p < 0.05). Levels of lactic acid, blood glucose, CK-MB and cTnI in ET group were remarkably increased than those of NC group (p < 0.05). Moreover, activities of SOD and CAT in myocardial homogenate of ET group were remarkably reduced in comparison with those of NC group (p < 0.05). Protein levels of caspase-3, caspase-9, Bcl-2, Bax, iNOS and COX-2 in ET group were all remarkably elevated than those of NC group (p < 0.05). The above indicators were all significantly improved in IMD group than those of ET group (p < 0 05).. IMD1-53 can protect cardiac function in rats with septic shock via inhibiting oxidative stress and cardiomyocyte apoptosis.

Topics: Adrenomedullin; Animals; Apoptosis; Cardiotonic Agents; Male; Myocytes, Cardiac; Neuropeptides; Oxidative Stress; Random Allocation; Rats; Rats, Sprague-Dawley; Shock, Septic

Patients with catheter-related bloodstream infection (CRBSI) have a poor prognosis. Proadrenomedullin (pro-ADM) has emerged as a valuable marker of sepsis. The potential role of pro-ADM in predicting the prognosis of CRBSI was evaluated. We enrolled 25 CRBSI patients and pro-ADM level was measured within 24 hours after each admission. Survival was assessed after 28 days. Among 25 patients with CRBSI, 14 patients survived. Pro-ADM in survivors was significantly lower than that in non-survivors (3.71 ± 1.30 vs 5.58 ± 1.18 nmol/L). The area under the curve (AUC) for pro-ADM was 0.87 (95% CI 0.68-0.97) with a cut-off value of 4.67 nmol/L, providing sensitivity of 85.7% and specificity of 81.8%. The AUCs for PCT, WBC, and CRP were 0.76 (95% CI 0.55-0.90), 0.72 (95% CI 0.50-0.88), and 0.69 (95% CI 0.48-0.86), respectively. Kaplan-Meier survival curves showed pro-ADM ≥ 4.67 nmol/L was associated with higher mortality (log-rank p = 0.001). Moreover, the pro-ADM level was significantly higher in patients with septic shock than those without shock (5.44 ± 1.17 vs 3.54 ± 1.18nmol/L). The mortality of patients with septic shock was higher than that of patients without shock (69.2% vs 16.7%, P = .008). In conclusion, pro-ADM could be used as a prognostic marker of CRBSI in critically ill patients.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Area Under Curve; Biomarkers; Catheter-Related Infections; Female; Humans; Intensive Care Units; Male; Middle Aged; Prognosis; Prospective Studies; Protein Precursors; Risk Factors; Sensitivity and Specificity; Shock, Septic; Survival Rate

Fungi are of increasing importance in sepsis. However, culture-based diagnostic procedures are associated with relevant weaknesses. Therefore, culture- and next-generation sequencing (NGS)-based fungal findings as well as corresponding plasma levels of β-d-glucan, interferon gamma (INF-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-2, -4, -6, -10, -17A, and mid-regional proadrenomedullin (MR-proADM) were evaluated in 50 septic patients at six consecutive time points within 28 days after sepsis onset. Furthermore, immune-response patterns during infections with

Topics: Adrenomedullin; Aged; Biomarkers; Candida; Female; High-Throughput Nucleotide Sequencing; Host-Pathogen Interactions; Humans; Immune System; Interleukin-17; Male; Middle Aged; Mycoses; Protein Precursors; Shock, Septic; Time Factors

Adrenomedullin is released by different tissues in hypoxia, oxidative stress, and inflammation and is found in general and medical patients and, recently, in sepsis patients in emergency departments. The aim of this study was to evaluate biologically active adrenomedullin that mirrors directly the active peptide levels in plasma of surgical intensive care unit (ICU) patients with sepsis.. In this single-center observational pilot trial, 42 ICU patients with sepsis and 14 patients after major surgery were included after sepsis diagnosis or ICU admission.. This is the first study investigating adrenomedullin in patients with sepsis following major surgery. Higher adrenomedullin on admission is associated with increased vasopressor need and mortality after 90 days. Thus, adrenomedullin may be a useful additional parameter in surgical patients with sepsis.

Topics: Adrenomedullin; Adult; Aged; Biomarkers; Case-Control Studies; Critical Care; Emergency Service, Hospital; Female; Humans; Intensive Care Units; Length of Stay; Male; Middle Aged; Pilot Projects; Postoperative Complications; Predictive Value of Tests; Prospective Studies; Shock, Septic

Our objective is to analyze whether the combination of C-reactive protein (CRP), procalcitonin (PCT), presepsin or SCD14-ST and mid-regional pro-adrenomedullin (MR-proADM) measured in the first 24 h from ICU admission allowing a better management of septic patients (diagnostic and prognostic) both in severe sepsis (SS) and septic shock (SSh).. Cohort study of 388 patients admitted in the ICU during 12 months of whom 142 were controls. Biomarkers were measured through immunoluminometric assays in samples of serum or plasma within the first 24 h after admission. Data were evaluated with non-parametric statistics bivariant, ROC curve analysis for diagnostic evaluation and multivariate analyses for survival analysis.. In the analyzed cohort, 61.8% of patients were males, mean age: 63 years range (18-90) and 67.8% in controls mean age: 63 years, range (39-91). PCT showed the highest area under the curve (AUC) (0.989) as compared with the rest of biomarkers (p<0.01). PCT also enabled the difference between Gram-positive or Gram-negative bacteria to be determined. The AUCs for CRP (0.922) and presepsin (0.948) showed a similar diagnostic value. In cases of SSh, the AUC of presepsin experienced a noticeable increase (p<0.0001). MR-proADM showed a better prognostic value (p=0.00022) particularly in cases of SSh (p=0.00001) increasing along with the APACHE-II score.. PCT, MR-proADM and presepsin are complementary markers that could be of great help in the management of septic patients when they are measured in the first 24 h after ICU admission.

Topics: Adolescent; Adrenomedullin; Adult; Aged; Aged, 80 and over; Biomarkers; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Cohort Studies; Female; Humans; Immunologic Techniques; Lipopolysaccharide Receptors; Luminescent Measurements; Male; Middle Aged; Multivariate Analysis; Peptide Fragments; Protein Precursors; ROC Curve; Sepsis; Shock, Septic; Survival Analysis; Young Adult

The aim was to ascertain the prognostic value of mid-regional pro-adrenomedullin (MR-proADM), measured within 24 hours from the onset of septic shock (SS).. We performed a prospective, observational study on all patients admitted to our hospital's Intensive Care Unit with SS over a one year period from January to December 2011 to examine the outcomes in 100 consecutive SS cases. Demographic data and severity score (APACHEII and SOFA) were recorded. MR-proADM, C-reactive protein and procalcitonin were measured within the first 24 hours from SS onset. The outcome variable studied was 28-day mortality. Data were evaluated with non-parametric statistics bivariant and multivariate analyses for survival analysis.. In patients who died within 28 days (36%), MR-proADM, Lactate, APACHE II as well as SOFA were significantly higher compared with survivors. MR-proADM showed the best association with 28-day mortality, as well as a prognostic value (logrank test: P=0.0012). Statistical significance was also seen in the Cox regression analysis (P=0.0004) for all patients with a Relative Risk of 1.26 times that of the baseline for each mmol/L of increase in MR-proADM.. In our study MR-proADM levels measured on admission correlates with 28-day mortality in patients with septic shock.

Topics: Adrenomedullin; APACHE; Biomarkers; C-Reactive Protein; Calcitonin; Humans; Organ Dysfunction Scores; Prognosis; Prospective Studies; Shock, Septic; Survival Analysis; Time Factors

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.. 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.. 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.. 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.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Biomarkers; Cardiomyopathies; Cohort Studies; Endothelin-1; Female; Humans; Intensive Care Units; Male; Middle Aged; Prognosis; Shock, Septic; Survival Analysis; Sweden

Intermedin (IMD) is a calcitonin gene-related peptide shown to have a protective effect on myocardial function in ischemia-reperfusion injury. Whether IMD has beneficial effect in severe sepsis and septic shock (and its underlying mechanisms) is not known.. We induced septic shock using cecal ligation and puncture (CLP). We focused on the potential beneficial effect of IMD1-53 on cardiac papillary muscle and cardiomyocytes against septic shock and its relationship with the protection of cardiac function.. Early (immediately after CLP) and late (12 h after CLP) administration of IMD1-53 (0.5 μg/kg) improved animal survival significantly, increased cardiac contractility and function, and improved tissue perfusion and oxygen delivery. The effect of early administration of IMD1-53 was better than that of late administration. The Rho kinase/TnI and BKCa pathways participated in the protective effect of IMD1-53 on cardiac function in septic rats. An inhibitor of Rho kinase (Y-27632) or a BKCa opener (NS1619) abolished the protective effect of IMD1-53 on cardiac function. IMD1-53 increased expression of Rho kinase in cardiac muscle and inhibited TnI phosphorylation. IMD1-53 inhibited currents in BKCa channels and intracellular calcium concentration in cardiomyocytes.. IMD1-53 is beneficial against severe sepsis/septic shock. IMD1-53 can improve cardiac contractility and cardiac function significantly, and then improve tissue perfusion and oxygen delivery. Rho kinase and the BKCa pathways have important roles in these effects. These findings provide a new treatment strategy for severe sepsis with cardiac dysfunction.

Topics: Adrenomedullin; Animals; Female; Large-Conductance Calcium-Activated Potassium Channels; Male; Myocardium; Myocytes, Cardiac; Neuropeptides; Peptide Hormones; Phosphorylation; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; Shock, Septic

BACKGROUND The aim of this study was to investigate the value of plasma intermedin (IMD) in assessing severity and treatment efficacy of septic shock. MATERIAL AND METHODS Healthy male Sprague-Dawley (SD) rats were chosen and divided into a normal control group (n=15) and a shock model group (n=27) that received intravenous injection of lipopolysaccharide (LPS). Then, 3 specimens were taken from each group. The shock model group rats were divided into an LPS group and a treatment group with 12 rats each. The treatment group received intravenous injection of compound sodium lactate solution. Plasma IMD and IMD1-47 mRNA expressions were compared and analyzed. RESULTS Mean arterial pressure (MAP) was lower while white blood cell count and TNF-α were higher in the shock model group than in the normal control group (P<0.05). After 10 h and 20 h, the treatment group had lower plasma IMD and IMD1-47 mRNA expressions compared with the LPS group (P<0.05). Plasma IMD and IMD1-47 mRNA expressions in the LPS group after 20 h were significantly higher than after 10 h (P<0.05). IMD was positively correlated with interleukins (IL-3, IL-6, and IL-8), white blood cell count, and body temperature (all P<0.05), but were negatively correlated with systolic pressure (r=-0.8474, P=0.0040). CONCLUSIONS Plasma IMD level can effectively reflect the severity of septic shock and can be used as an important indicator of septic shock treatment effectiveness.

Topics: Adrenomedullin; Animals; Biomarkers, Pharmacological; Injections, Intravenous; Interleukins; Lipopolysaccharides; Male; Neuropeptides; Rats; Rats, Sprague-Dawley; RNA, Messenger; Shock, Septic; Sodium Lactate; Treatment Outcome

To explore the early diagnostic value of pro-adrenomedullin (pro-ADM) in sepsis.. A prospective study was conducted. Eighty-two patients with acute infection admitted to Department of Emergency of Shanxi Medical University Second Hospital from April 2013 to March 2014 were enrolled. According to the diagnostic criteria of sepsis, the patients with acute infection were divided into ordinary infection group [infection without systemic inflammatory response syndrome (SIRS), n = 25] and sepsis group (infection combined with SIRS, n = 57). According to degree of severity of sepsis, the latter group was subdivided into three subgroups: sepsis group (n = 22), severe sepsis group (n = 27) and septic shock group (n = 8). Twenty-four healthy persons were included to serve as healthy control group. The venous blood from all the research objects in hospital was collected within 24 hours. The levels of pro-ADM and procalcitonin ( PCT ) were determined by enzyme linked immunosorbent assay (ELISA), and acute physiology and chronic health evaluation II (APACHE II ) score was recorded. The relationship between pro-ADM and PCT and also APACHE II score was analyzed with Pearson correlation analysis. The receiver-operating characteristic curve (ROC) of pro-ADM and PCT were used to evaluate the diagnostic acuity of sepsis.. The plasma levels of pro-ADM, PCT and APACHE II score in sepsis group were significantly higher than those in ordinary infection group and healthy control group [pro-ADM (ng/L): 66.69 ± 1.73 vs. 53.43 ± 2.70, 45.87 ± 1.43; PCT (ng/L): 1 336.49 ± 40.26 vs. 1 083.09 ± 47.99, 959.04 ± 37.53; APACHE II score: 14.60 ± 0.81 vs. 8.10 ± 1.14, 3.00 ± 1.15, all P < 0.01]. With the aggravation of sepsis, the levels of pro-ADM, PCT and APACHE II score were gradually increased, and there were significant differences among sepsis, severe sepsis, and septic shock groups [pro-ADM (ng/L): 64.91 ± 2.50, 73.56 ± 2.80, 84.67 ± 4.52; PCT (ng/L): 1 152.65 ± 48.62, 1 233.93 ± 63.06, 1 475.71 ± 109.93; APACHE II score: 12.91 ± 1.15, 14.55 ± 1.14, 19.37 ± 2.40, P < 0.05 or P < 0.01]. Pearson correlation analysis results showed that the level of pro-ADM was positively related with PCT (r = 0.473, P = 0.006), and it was also positively correlated with APACHE II score (r = 0.707, P = 0.008). ROC curve analysis showed that area under the ROC curve (AUC) of pro-ADM for diagnosis of sepsis was 0.823 (P = 0.003). When the cutoff value was 59.40 ng/L, the sensitivity was 80.7%, the specificity was 68.0%, the positive predictive value was 85.2%, and the negative predictive value was 60.7%. AUC of the PCT for diagnosis of sepsis was 0.653 (P = 0.043). When the cutoff value was 1 194.67 ng/L, the sensitivity was 68.4%, the specificity was 64.0%, the positive predictive value was 81.8%, and the negative predictive value was 44.7%. It was proved that the pro-ADM had a higher diagnostic value for sepsis than PCT.. The plasma levels of pro-ADM can be used as an early indicator in diagnosis and severity evaluation and prognosis in patients with sepsis.

Topics: Adrenomedullin; APACHE; Biomarkers; Calcitonin; Calcitonin Gene-Related Peptide; Case-Control Studies; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Humans; Prognosis; Prospective Studies; Protein Precursors; ROC Curve; Sensitivity and Specificity; Sepsis; Shock, Septic; Systemic Inflammatory Response Syndrome

The aim of the study was to assess adrenomedullin (AM) as a predictor for development of severe sepsis and septic shock in emergency department (ED).. From December 2011 to October 2012, 372 consecutive septic patients admitted to ED were enrolled. AM was examined in every patient. All patients were followed up for 3 days. The outcome variable was development of severe sepsis or septic shock. The predictive ability of AM was evaluated by binary logistic regression analysis and receiver operating characteristic (ROC) curve.. On admission, the differences of AM among patients with different comorbidities, infections, and culture results were not significant. AM level was higher in patients who progressed than in who did not (41.63 ± 6.55 versus 31.31 ± 7.71 ng/L, P < 0.001). AM was the only independent predictor of outcome. The area under ROC curve of AM was 0.847. With a cutoff value of 41.24 ng/L, the sensitivity was 67.6%, the specificity was 90.0%, the positive predictive value was 61.5%, the negative predictive value was 92.2%, the positive likelihood ratio was 6.78, and the negative likelihood ratio was 0.36.. Adrenomedullin is valuable for predicting development of severe sepsis and septic shock in ED.

Topics: Adrenomedullin; Aged; China; Comorbidity; Emergency Service, Hospital; Female; Humans; Male; Middle Aged; Predictive Value of Tests; ROC Curve; Shock, Septic; Treatment Outcome

Risk stratification could represent a major improvement in critically ill patients' management. The objective of this study is to evaluate the association between concentrations of four circulating prohormones (C-terminal-provasopressin, midregional-proadrenomedullin (MR-proADM), midregional-proatrial natriuretic peptide, and C-terminal- proendothelin-1) and the occurrence of nosocomial infections (NIs) in septic shock patients.. We performed an observational, clinical study with septic shock patients (n = 98) recruited from adult intensive care units in a university hospital. Prohormone concentrations were assessed three times within the first week after the onset of septic shock using an immunoluminometric assay.. Significantly elevated plasmatic MR-proADM concentrations were measured in patients who went on to develop NIs in comparison with patients who remain infection free (p = 0.043). No differences were observed for the other three prohormone concentrations.. Elevated plasmatic MR-proADM concentration is associated with the development of secondary NIs after septic shock. This information, if confirmed in a larger group of patients, could represent a major advance in the monitoring of intensive care unit patient infectious risk.

Topics: Adrenomedullin; Aged; Atrial Natriuretic Factor; Cohort Studies; Cross Infection; Endothelin-1; Female; Glycopeptides; Humans; Male; Middle Aged; Peptide Fragments; Protein Precursors; Risk Factors; Severity of Illness Index; Shock, Septic

Midregional proadrenomedullin (proADM) is a novel biomarker with potential prognostic utility in patients with community-acquired pneumonia. The aim of this study was to investigate the value of proADM levels for severity assessment and outcome prediction in severe sepsis and septic shock due to CAP.. Prospective observational study including 49 patients admitted to ICU with both a clinical and radiologic diagnosis of pneumonia and fulfilling criteria for severe sepsis or septic shock. The prognostic accuracy of proADM levels was compared with those of pneumonia severity index and of procalcitonin (PCT) and C-reactive protein (CRP).. 49 patients with severe sepsis or septic shock due to CAP were included in the study. Mortality was 24.5% for ICU and 34.7% for hospital mortality. In all cases proADM values at ICU admission were pathological (considering normal proADM levels <4 nmol/L). ProADM consistently rose as PSI class advanced from II to V (p = 0.02). Median proADM levels were higher (p <0.01) in hospital non-survivors 5.0 (1.9-10.1) nmol/L vs. survivors 1.7 (1.3-3.1) nmol/L. These differences were also significant with respect to ICU mortality. The receiver-operating characteristic curve for proADM yielded an AUC of 0.72; better than the AUC for PCT and CRP (0.40 and 0.44 respectively) and similar to PSI (0.74).. In our study MR-proADM levels correlate with increasing severity of illness and death. High MR-proADM levels offer additional risk stratification in high-risk CAP patients.

Topics: Adrenomedullin; Biomarkers; Community-Acquired Infections; Female; Follow-Up Studies; Humans; Immunoassay; Intensive Care Units; Male; Middle Aged; Pneumonia, Bacterial; Predictive Value of Tests; Prognosis; Prospective Studies; Protein Precursors; Reproducibility of Results; Severity of Illness Index; Shock, Septic

It has been shown that pro-adrenomedullin is a good marker of the severity of septic shock but there are no data on the early changes in serum pro-adrenomedullin concentrations in patients with shock.. Twenty-one patients with septic shock and 21 healthy subjects studied as controls. Serum concentrations of pro-adrenomedullin, procalcitonin, ferritin, CRP and IL-6 were determined in all subjects at the initial observation. Patients with septic shock were also studied after 24 and 48 hours.. The concentrations of the acute phase proteins were significantly higher in patients with septic shock than in the control subjects during the entire study period (P<0.001). Only procalcitonin significantly decreased on the third day of observation with respect to both the first day (P=0.002) and the second day (P=0.006). Proadrenomedullin (P=0.017) and IL-6 (P=0.001) showed an AUC significantly different from the null hypothesis in differentiating the patients who survived and those who did not. The sensitivity and specificity of pro-adrenomedullin in the assessment of death were 71.4% and 72.7%, respectively, while IL-6 had a sensitivity of 92.9% and a specificity of 60.6%.. Proadrenomedullin is a reliable prognostic marker in patients with shock; further studies on a more consistent number of septic patients will definitively assess whether proadrenomedullin may replace the current prognostic markers in critically ill patients with shock due to sepsis.

Topics: Acute-Phase Proteins; Adrenomedullin; Adult; Aged; Aged, 80 and over; Area Under Curve; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Female; Ferritins; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Prognosis; Protein Precursors; Sensitivity and Specificity; Shock, Septic; Time Factors

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.. 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.. 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 less than 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 APACHE II scores.. Pro-ANP and pro-ADM are valuable biomarkers for prediction of severity of septic patients.

Topics: Adolescent; Adrenomedullin; Adult; Aged; APACHE; Atrial Natriuretic Factor; C-Reactive Protein; Female; Humans; Male; Middle Aged; Protein Precursors; Sepsis; Shock, Septic

Topics: Adrenomedullin; Cardiovascular Diseases; Humans; Immunoradiometric Assay; Shock, Septic

Leakage of the gut mucosal barrier in the critically ill patient may allow translocation of bacteria and their virulence factors, thereby perpetuating sepsis and inflammation. Present evidence suggests that adrenomedullin (AM) improves endothelial barrier function and stabilizes circulatory function in systemic inflammation. We tested the hypothesis that exogenously applied AM stabilizes gut epithelial barrier function. Infusion of Staphylococcus aureus alpha-toxin induced septic shock in rats. AM infusion in a therapeutic setting reduced translocation of labeled dextran from the gut into the systemic circulation in this model. AM also reduced alpha-toxin and hydrogen peroxide (H2O2)-related barrier disruption in Caco-2 cells in vitro and reduced H2O2-related rat colon barrier malfunction in Ussing chamber experiments. AM was shown to protect endothelial barrier function via cAMP elevation, but AM failed to induce cAMP accumulation in Caco-2 cells. cAMP is degraded via phosphodiesterases (PDE), and Caco-2 cells showed high activity of cAMP-degrading PDE3 and 4. However, AM failed to induce cAMP accumulation in Caco-2 cells even in the presence of sufficient PDE3/4 inhibition, whereas adenylyl cyclase activator forskolin induced strong cAMP elevation. Furthermore, PDE3/4 inhibition neither amplified AM-induced epithelial barrier stabilization nor affected AM cAMP-related rat colon short-circuit current, furthermore indicating that AM may act independently of cAMP in Caco-2 cells. Finally, experiments using chemical inhibitors indicated that PKC, phosphatidylinositide 3-kinase, p38, and ERK did not contribute to AM-related stabilization of barrier function in Caco-2 cells. In summary, during severe inflammation, elevated AM levels may substantially contribute to the stabilization of gut barrier function.

Topics: Adrenomedullin; Animals; Bacterial Toxins; Bacterial Translocation; Caco-2 Cells; Colon; Cyclic AMP; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 4; Dextrans; Disease Models, Animal; Enzyme Activators; Extracellular Signal-Regulated MAP Kinases; Fluorescein-5-isothiocyanate; Fluorescent Dyes; Hemolysin Proteins; Humans; Hydrogen Peroxide; Ileum; Infusions, Intravenous; Intestinal Mucosa; Male; p38 Mitogen-Activated Protein Kinases; Permeability; Phosphatidylinositol 3-Kinases; Phosphodiesterase Inhibitors; Protein Kinase C; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Shock, Septic; Signal Transduction; Time Factors

Topics: Adrenomedullin; Biomarkers; Glycopeptides; Hospital Mortality; Humans; Predictive Value of Tests; Prognosis; Protein Precursors; Shock, Septic; Up-Regulation; Vasopressins

Improvements in survival after septic shock will most likely rely on our capacity to manage individualized therapies based on the measurement of rapidly accessible biomarkers. As the early phase of septic shock is dominated by severe alterations of the cardiovascular system, the predictive value for mortality of pro-vasopressin (pro-AVP) and pro-adrenomedullin (pro-ADM), two vasoactive pro-hormones, was assessed.. In 99 consecutive patients, pro-hormone concentrations were measured (immunoluminometric assay) three times within the first week after the onset of septic shock.. Pro-AVP and pro-ADM concentrations were significantly increased in non-survivors in comparison with survivors and were significantly associated with mortality after both univariate and multivariate analysis. Importantly, when assessed as a pair, pro-ADM and pro-AVP were even more informative.. Both Pro-ADM and pro-AVP appear to be good biomarkers for the prediction of 28-day mortality after septic shock. However, their association in a single variable tends to improve their predictive capacity.

Topics: Adrenomedullin; Aged; Analysis of Variance; Biomarkers; Female; France; Glycopeptides; Humans; Immunoassay; Kaplan-Meier Estimate; Logistic Models; Luminescent Measurements; Male; Middle Aged; Predictive Value of Tests; Prognosis; Protein Precursors; Risk Assessment; ROC Curve; Severity of Illness Index; Shock, Septic; Statistics, Nonparametric

To assess the clinical value of pro-adrenomedullin (pro-ADM) in the prognosis and risk stratification in sepsis.. Fifty-one critically ill patients admitted to the intensive care unit (ICU) were prospectively stratified into four groups according to internationally recognized criteria: systemic inflammatory response syndrome (SIRS, 25 cases), sepsis (12 cases), severe sepsis (9 cases) and septic shock (5 cases). The levels of plasma pro-ADM was determined in every patient using a new sandwich immunoassay, and compared with procalcitonin (PCT), C-reactive protein (CRP) and interleukin-6 (IL-6), and the acute physiology and chronic health evaluation II (APACHE II) score.. (1) Median pro-ADM concentration was 0.34 microg/L for SIRS, 2.23 microg/L for sepsis, 4.57 microg/L for severe sepsis and 8.21 microg/L for septic shock. The plasma concentration of pro-ADM exhibited a gradual increase, and the median pro-ADM value was highest in the septic shock group (all P<0.05). (2) Compared with the other biomarkers, in the sepsis, severe sepsis and septic shock groups, the plasma concentration of pro-ADM and APACHE II score in the non-survivors was significantly higher than in the survivors (pro-ADM: 2.01 microg/L vs. 9.75 microg/L, APACHE II score: 23.44 scores vs. 38.21 scores, both P<0.05). (3) By the receiver operating characteristic (ROC) curve plot analysis of pro-ADM in sepsis, the area under the ROC curve for pro-ADM (0.87) in survivors was similar to the area under the ROC curve for PCT (0.81) and APACHE II score (0.81), and was significantly higher than the area under the ROC curve for CRP (0.53) and IL-6 (0.71).. The measurement of pro-ADM is a new and useful marker in sepsis prognosis and risk stratification.

Topics: Adrenomedullin; Adult; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Critical Illness; Female; Humans; Intensive Care Units; Interleukin-6; Male; Middle Aged; Peptide Fragments; Postoperative Complications; Protein Precursors; Risk Assessment; Sepsis; Shock, Septic; Systemic Inflammatory Response Syndrome

Topics: Adrenomedullin; Atrial Natriuretic Factor; Biomarkers; Endotoxemia; Glucocorticoids; Hormones; Humans; Inflammation Mediators; Neurophysins; Prednisolone; Protein Precursors; Shock, Septic; Vasopressins

Current therapies of sepsis and septic shock require administration of a large volume of fluid to maintain hemodynamic stability. The vasoregulatory peptide adrenomedullin has been shown to prevent the transition to the fatal hypocirculatory septic state by poorly understood mechanisms. We tested the hypothesis that therapeutic administration of adrenomedullin would reduce vascular hyperpermeability, thereby contributing to improved hemodynamics and survival.. Prospective randomized controlled animal study.. Male Sprague-Dawley rats (270 g).. We used 4.8 x 10(3) U/kg of Staphylococcus aureus alpha-toxin, a pore-forming exotoxin, to induce vascular leakage and circulatory shock in rats. The infusion rate was 24 microg/kg per hour. Adrenomedullin was started 1 h after alpha-toxin administration.. Infusion of alpha-toxin in rats induced cardiocirculatory failure resulting in a 6-h mortality of 53%. alpha-Toxin provoked massive vascular hyperpermeability, which was indicated by an enrichment of Evans blue dye albumin in the tissues of lung, liver, ileum and kidney. Plasma fluid loss led to a significant hemoconcentration. Hemodynamic impairment observed after alpha-toxin infusion was closely correlated to vascular hyperpermeability. Therapeutic administration of 24 microg/kg per hour adrenomedullin reduced 6-h mortality from 53% to 7%. Stabilization of the endothelial barrier by adrenomedullin was indicated by reduced extravasation of albumin and plasma fluid and may have contributed to hemodynamic improvement.. These data suggest that adrenomedullin-related reduction of vascular hyperpermeability might represent a novel and important mechanism contributing to the beneficial effects of this endogenous vasoregulatory peptide in sepsis and septic shock.

Topics: Adrenomedullin; Animals; Capillary Permeability; Male; Rats; Rats, Sprague-Dawley; Shock, Septic; Type C Phospholipases; Vasodilator Agents

Adrenomedullin (ADM) is upregulated in cardiac tissue under various pathophysiological conditions, particularly in septic shock. The intracellular mechanisms involved in the effect of ADM on adult rat ventricular myocytes are still to be elucidated. Ventricular myocytes were isolated from adult rats 4 h after an intraperitoneal injection of lipopolysaccharide (LPS, 10 mg/kg). Membrane potential and L-type calcium current (I(Ca,L)) were determined using whole cell patch-clamp methods. APD in LPS group was significantly shorter than control values (time to 50% repolarization: LPS, 169 +/- 2 ms; control, 257 +/- 2 ms, P < 0.05; time to 90% repolarization: LPS, 220 +/- 2 ms; control, 305 +/- 2 ms, P < 0.05). I(Ca,L) density was significantly reduced in myocytes from the LPS group (-3.2 +/- 0.8 pA/pF) compared with that of control myocytes (-6.7 +/- 0.3 pA/pF, P < 0.05). The ADM antagonist ADM-(22-52) reversed the shortened APD and abolished the reduction of I(Ca,L) in shock myocytes. In myocytes from control rats, incubating with ADM for 1 h induced a marked decrease in peak I(Ca,L) density. This effect was reversed by ADM-(22-52). The G(i) protein inhibitor, pertussis toxin (PTX), the protein kinase A (PKA) inhibitor, KT-5720, and the specific cyclooxygenase 2 (COX-2) inhibitor, nimesulide, reversed the LPS-induced reduction in peak I(Ca,L). The results suggest a COX-2-involved PKA-dependent switch from G(s) coupled to PTX-sensitive G(i) coupling by ADM in adult rat ventricular myocytes. The present study delineates the intracellular pathways involved in ADM-mediated effects on I(Ca,L) in adult rat ventricular myocytes and also suggests a role of ADM in sepsis.

Topics: Adrenomedullin; Animals; Calcium; Calcium Channels, L-Type; Cells, Cultured; Dose-Response Relationship, Drug; Ion Channel Gating; Male; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Shock, Septic; Signal Transduction

Adrenomedullin (AM) is a highly conserved peptide that can act as a potent vasodilator, anti-microbial factor and anti-inflammatory factor. Several studies have implicated diverse roles for AM in regulating the inflammatory and hemodynamic responses to septic shock. Moreover, during sepsis the receptors that mediate AM signaling [calcitonin receptor-like receptor (calcrl) and receptor activity modifying proteins (RAMP) 2 and 3] undergo dynamic and robust changes in their expression. Although numerous studies have used animal models to study the role of administered or increased AM in septic animals, genetic studies to determine the consequences of reduced AM during septic shock have not yet been performed. Here, we used a murine model of lipopolysaccharide (LPS)-induced septic shock to assess the inflammatory response in mice heterozygous for the AM gene. Following LPS challenge, AM(+/-) mice had higher expression of TNF-alpha and IL-1beta than LPS-treated wild-type (WT) controls. Consequently, serum TNF-alpha was also significantly elevated in LPS-treated AM(+/-) mice compared to WT LPS-treated mice. We also observed higher serum levels of liver enzymes, suggesting more advanced end-organ damage in mice with genetically reduced AM. Finally, we found that RAMP2 and calcrl expression levels were markedly reduced in LPS-treated mice, whereas RAMP3 expression was significantly elevated. Importantly, these changes in receptor gene expression were conserved in AM(+/-) mice, demonstrating that AM peptide itself does not impact directly on the expression of the genes encoding its receptors. We, therefore, conclude that during septic shock the dynamic modulation of AM and its receptors primarily functions to dampen the inflammatory response.

Topics: Adrenomedullin; Alanine Transaminase; Animals; Aspartate Aminotransferases; Endotoxins; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression; Heterozygote; Inflammation Mediators; Interleukin-1beta; Lipopolysaccharides; Liver; Lung; Male; Mice; Mice, Inbred Strains; Mice, Knockout; Receptors, Adrenomedullin; Receptors, Peptide; Reverse Transcriptase Polymerase Chain Reaction; Shock, Septic; Tumor Necrosis Factor-alpha

Hypodynamic septic shock is associated with a poor prognosis. The present randomized-controlled laboratory experiment was designed to test the hypothesis that the vasodilatory peptide hormone adrenomedullin (ADM) is a useful agent to prevent and reverse the development of hypodynamic circulation in ovine endotoxaemia.. Twenty-four healthy ewes were chronically instrumented for haemodynamic monitoring and randomly allocated to either the control, treatment, or prophylaxis group (n = 8 each). After a baseline (BL) measurement in the healthy state, all sheep were subjected to a continuous endotoxin infusion started at 10 ng kg(-1) min(-1) and doubled every hour six times. After 4 h of endotoxin challenge, the treatment group received ADM (50 ng kg(-1) min(-1)) for the remaining 3 h of the experiment. The prophylaxis group received a simultaneous infusion of endotoxin and ADM (50 ng kg(-1) min(-1)) from the beginning to the end of the 7 h intervention period.. In the control and treatment groups, the ewes exhibited a hypodynamic circulation at 4 h (>20% reduction in cardiac index, both P < 0.01 vs BL). Endotoxin also increased mean pulmonary arterial pressure (MPAP) and arterial lactate concentrations. Prophylactic infusion of ADM prevented the occurrence of pulmonary hypertension and hypodynamic circulation and thereby blunted the increase in arterial lactate concentrations. In the treatment group, ADM administration increased CI (P < 0.001) and reduced both MPAP (P = 0.023) and arterial lactate concentrations (P < 0.001 each at 7 h) when compared with the control group.. This study demonstrates that exogenous ADM prevents and reverses hypodynamic circulation, attenuates pulmonary hypertension, and limits lactic acidosis in ovine endotoxaemia.

Topics: Acidosis, Lactic; Adrenomedullin; Animals; Cardiac Output; Drug Evaluation, Preclinical; Endotoxemia; Female; Hypertension, Pulmonary; Lactic Acid; Sheep, Domestic; Shock, Septic; Vasodilator Agents

Adrenomedullin (ADM) acts as an autocrine or a paracrine factor in the regulation of cardiac function. The intracellular mechanisms involved in the direct effect of ADM on adult rat ventricular myocytes (ARVMs) are still to be elucidated. In ARVMs from normal rats, ADM produced an initial (< 30 min) increase in cell shortening and Ca2+ transients and a marked decrease in both on prolonged incubation (> 1 h). Both effects were sensitive to ADM antagonist ADM-(22-52). Treatment with SQ-22536, an inhibitor of adenylate cyclase, blocked the positive inotropic effect of ADM and potentiated its negative inotropic effect. The negative inotropic effect was sensitive to inhibition by pertussis toxin (PTX), an inhibitor of Gi proteins and KT-5720, an inhibitor of PKA. The observations suggest a switch from Gs-coupled to PTX-sensitive, PKA-dependent Gi coupling by ADM in ARVMs. The ADM-mediated Gi-signaling system involves cAMP-dependent pathways because SQ-22536 further increased the negative inotropic actions of ADM. Also, because ADM is overproduced by ARVMs in our rat model of septic shock, ARVMs from LPS-treated rats were subjected to treatment with ADM-(22-52) and PTX. The decrease in cell shortening and Ca2+ transients in LPS-treated ARVMs could be reversed back with ADM-(22-52) and PTX. This indicates that ADM plays a role in mediating the negative inotropic effect in LPS-treated ARVM through the activation of Gi signaling. This study delineates the intracellular pathways involved in ADM-mediated direct inotropic effects on ARVMs and also suggests a role of ADM in sepsis.

Topics: Adrenomedullin; Animals; Calcium Signaling; Cells, Cultured; GTP-Binding Protein alpha Subunits, Gi-Go; GTP-Binding Protein alpha Subunits, Gs; Heart Ventricles; Lipopolysaccharides; Male; Myocardial Contraction; Myocytes, Cardiac; Peptides; Rats; Rats, Sprague-Dawley; Shock, Septic

Urocortin 1 (UCN) and adrenomedullin (AM) are two neuropeptides that have emerged as potential endogenous anti-inflammatory factors based on their production by and binding to immune cells. Because human septic shock involves excessive inflammatory cytokine production, we investigated the effect of UCN and AM in the production of inflammatory mediators and their therapeutic actions in two models of septic shock. Both peptides down-regulated the production of inflammatory mediators by endotoxin-activated macrophages. The administration of UCN or AM protected against lethality after cecal ligation and puncture or after injection of bacterial endotoxin and prevented septic shock-associated histopathology, such as infiltration of inflammatory cells and intravascularly disseminated coagulation in various target organs. The therapeutic effect of UCN and AM was mediated by decreasing the local and systemic levels of a wide spectrum of inflammatory mediators, including cytokines, chemokines, and the acute phase protein serum amyloid A. Importantly, UCN or AM treatment was therapeutically effective in established endotoxemia. In conclusion, UCN and AM could represent two multistep therapeutic agents for human septic shock to be used in combination with other immunomodulatory agents or complementary as anti-inflammatory factors to other therapies.

Topics: Adrenomedullin; Amyloid; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Corticotropin-Releasing Hormone; Down-Regulation; Endotoxemia; Inflammation; Macrophages; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Nitric Oxide; Peptides; Peroxidase; Shock, Septic; Urocortins

Adrenomedullin (ADM), a multifunction peptide with important roles in regulating cardiovascular homeostasis, has the vasodilatory properties and is of particular interest in the pathophysiology of sepsis. ADM levels in plasma and tissues are regulated by the proteolysis of neutral endopeptidase (NEP), the major enzyme of ADM degradation. We observed the NEP activity in the plasma, the activity and distribution of NEP and its mRNA expression in the tissues of rats in septic shock to study the possible role of NEP in elevating tissue ADM concentration during sepsis. ADM level increases progressively during sepsis except in the jejunum. Rats in early phase of shock (ES) showed diverse changes in tissue NEP activity. Plasma NEP activity, tissue NEP activity and its protein and mRNA expression in the left ventricle, aorta, jejunum and lung in the late phase of shock (LS) rats were lower than those in ES and the control, but no statistical change of NEP activity in the kidney was observed. The level of ADM was inversely correlated with NEP activity in the plasma, ventricle and aorta and positively correlated with NEP activity in the jejunum. Thus, in sepsis, the local concentration and action of ADM in tissues may be differentially regulated by NEP.

Topics: Adrenomedullin; Animals; Aorta; Blood Glucose; Blood Pressure; Cecal Diseases; Cecum; Chromatography, High Pressure Liquid; Gene Expression; Heart Ventricles; Immunohistochemistry; Jejunum; Kidney; Lactic Acid; Ligation; Linear Models; Lung; Male; Neprilysin; Peptides; Punctures; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Shock, Septic

To determine the role of adrenomedullin (AM) in the fluid electrolyte homeostasis and endotoxin shock, cerebral spinal fluid (CSF) and plasma were sampled from rats after respective challenges. The AM levels were measured by a highly sensitive immunoassay. The AM levels in the CSF of the rats anesthetized with ether (10.7 +/- 0.60 fmol/ml) were significantly higher than those with isoflurane 5.17 +/- 0.70 fmol/ml, P < 0.01), while the plasma level did not differ significantly. The CSF levels of the rats received 2% saline drinking increased to 3 and 4 folds at day 5 and day 7, respectively, while the plasma levels did not differ from controls at both time points. The AM levels in CSF or plasma increased to 1.5 and 3 folds at 1.5 h after intraperitoneal (i.p.) administration of lipopolysaccharide (LPS, 5 mg/kg), reached 6.5 and 30 folds at 6 h, respectively, while no change was observed in the controls. The present findings suggest that AM in the CSF is regulated independently from that in the plasma, the centrally synthesized AM plays and important role in the regulation of the fluid electrolyte homeostasis. Furthermore, the circulatory AM plays an important role in the endotoxin shock.

Topics: Adrenomedullin; Animals; Lipopolysaccharides; Male; Peptides; Rats; Rats, Wistar; Shock, Septic; Sodium Chloride, Dietary; Water-Electrolyte Balance

Adrenomedullin and PAMP are potent vasodilatory peptides derived from a common larger precursor peptide. Elevation of circulating levels of both peptides has been described for diseases involving dysfunction of the cardiovascular system. However, the reliable quantification has been hampered by their short half-life times and - as known for Adrenomedullin -- the existence of a binding protein. Here we report the identification of another peptide derived from the Adrenomedullin precursor, termed proADM 45-92, which is present in large concentrations in plasma of septic shock patients. This peptide is produced in stoichiometric amounts to Adrenomedullin and PAMP, but -- contrary to them -- is apparently non-functional and stable. Thus, proADM 45-92 represents a suitable diagnostic target which could be used to assess the concentrations of Adrenomedullin gene products released into the bloodstream.

Topics: Adrenomedullin; Amino Acid Sequence; Chromatography, High Pressure Liquid; Enzyme-Linked Immunosorbent Assay; Humans; Molecular Sequence Data; Peptide Fragments; Protein Precursors; Proteins; Reference Values; Shock, Septic; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

A clinical hallmark of sepsis is an early, hyperdynamic cardiac phase (increased cardiac output) that degrades to a hypodynamic phase, which results in poor gut perfusion and subsequent gastrointestinal (GI) hypoxemia, tissue ischemia, necrosis and loss of gut barrier function. Studies in rat cecal-ligation and puncture suggest that the potent vasodilator adrenomedullin (AM) might initiate or maintain the hypodynamic phase. We hypothesize that AM expression is increased in acute Escherichia coli bacteremia and chronic E coli-Bacteroides fragilis sepsis.. Acute bacteremia: male Sprague-Dawley rats were anesthetized (urethane/alpha-chloralose), tracheotomized, and cannulated for monitoring blood pressure (MABP) and heart rate (HR) and for infusion of E coli (10(9) colony-forming units [CFU] E coli per 1 mL normal saline) and blood sampling. Arterial blood was withdrawn for arterial blood gas (ABG) measurements every 60 minutes. After 6 hours, we harvested lung, liver, kidney, spleen, and small intestine tissue samples and drew arterial and portal blood for AM enzyme-linked immunosorbent assay (ELISA). Chronic sepsis: a sterile gauze pad was implanted and animals recovered for 5 days. Twenty-four hours (10(9) CFU E coli and 10(9) CFU B fragilis per 1 mL normal saline; 1 injection) or 72 hours (2 injections) after the inoculation of the back sponge, rats were anesthetized, intubated, and cannulated as above. MABP, HR, and ABG were measured for 1 hour before tissue and serum harvest for AM ELISA.. Sepsis increased HR and MABP in all groups. Acute sepsis caused a respiratory alkalosis and pH was also elevated in chronic sepsis. Serum AM levels were increased in all groups compared with baseline and remained elevated at every time point, but were not different between saline controls and septic animals at any time point, except for the portal serum from the 72-hour chronic sepsis, which was elevated.. These data suggest that surgical manipulation alone is sufficient to stimulate AM secretion, most probably from endothelial cells. While the AM levels were decreasing at 72 hours compared with 6 hours or 24 hours in the arterial blood and the saline control portal blood, it remained elevated in the septic portal samples, suggesting that the sepsis-induced increase of AM was derived from the gut by a different mechanism than that which elevated arterial serum levels.

Topics: Acute Disease; Adrenomedullin; Animals; Bacteremia; Bacteroides fragilis; Bacteroides Infections; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Escherichia coli Infections; Male; Multiple Organ Failure; Peptides; Portal System; Rats; Rats, Sprague-Dawley; Shock, Septic; Time Factors; Vasodilator Agents

Plasma level of adrenomedullin (AM), a potent vasodilator peptide, is increased in patients with sepsis. AM was also found to be present in cerebrospinal fluid (CSF) of humans, and intracerebroventricular injection of AM resulted in elevated systemic blood pressure in rats. In the present study, we measured AM levels in CSF and plasma of 7 patients with septic shock who had severe hypotension, and compared with those of 10 control patients receiving primary transurethral resection of bladder tumor. CSF samples were obtained through the procedure of lumbar puncture and AM levels were measured by radioimmunoassay. AM concentration in CSF of the septic patients was increased to a level 35 times higher than that of control group (35 +/- 21 vs. 0.9 +/-0 .3 pmol/L, mean +/- S .D., p < 0.01). Similarly, plasma AM concentration was increased by 27 times compared with control group (176 +/- 71 vs. 6.5+/-1.8 pmol/L, p < 0.01). Despite the similar increase in CSF and plasma AM, no significant correlation was found between the AM concentrations in the CSF and plasma (r = 0.01 P = 0.95). Taken together with the central actions of AM, these findings suggest that AM of the central nervous system may be involved in pathophysiology of sepsis of humans.

Topics: Adolescent; Adrenomedullin; Adult; Aged; Aged, 80 and over; Case-Control Studies; Female; Humans; Male; Middle Aged; Shock, Septic

To study the biosyntheses and pathophysiological roles of adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) in septic shock, we compared the time course of plasma concentrations of these peptides and blood pressure in rats injected with either 0.9% saline (control group) or lipopolysaccharide (LPS group). The plasma AM concentration in the LPS group did not increase 30 and 60 min after LPS injection, at which time points the blood pressure remained low. Thereafter, AM rapidly increased, and it amounted to 35 times the basal value 4 h after injection, when the blood pressure returned to the basal level. The increment of plasma PAMP in the LPS group was lower than that of AM. We also examined the tissue concentration of AM and PAMP--as well as the tissue expression of proadrenomedullin (proAM) mRNA--in the LPS and control groups. LPS significantly increased the tissue concentrations of AM and PAMP in the lung, but decreased them in the adrenal gland and cardiac atrium. The LPS injection augmented proAM gene transcription in the lung, adrenal gland and aorta. In an immunohistochemical examination, AM staining was intense in alveolar endothelial cells of the lung in the LPS group. Thus, this septic shock model had high plasma levels of PAMP as well as AM, while the biosynthesis and secretion of the two peptides may have been differentially regulated in various tissues of rats injected with LPS. The present results suggest that these two bioactive peptides may play different roles in the pathophysiology of septic shock.

Topics: Adrenomedullin; Animals; Blood Pressure; Disease Models, Animal; Gene Expression; Lipopolysaccharides; Lung; Male; Peptide Fragments; Peptides; Proteins; Rats; Rats, Wistar; RNA, Messenger; Shock, Septic

Immunostimulants increase nitric oxide (NO) and tetrahydrobiopterin (BH4) synthesis in vascular smooth muscle cells (VSMC) by coinducing expression of an isoform of NO synthase (iNOS) and GTP cyclohydrolase I (GTPCH). GTPCH is the first and rate-limiting enzyme in the synthesis of BH4, a cofactor of NO synthases. Given the adrenomedullin (AM) increases NO production, this effect of AM may involve modulation of BH4 synthesis in cytokine-stimulated VSMC.. We investigated the effects of AM on the synthesis of NO and BH4, the expression of iNOS and GTPCH mRNA, and the promoter activity of iNOS and GTPCH genes in rat VSMC stimulated with interleukin-1 (IL-1).. IL-1 increased both NO and BH4 synthesis as well as the abundance of iNOS and GTPCH mRNA. AM significantly increased both NO and BH4 synthesis caused by IL-1 stimulation. AM also augmented the IL-1-induced increase in the abundance of iNOS and GTPCH mRNA. IL-1 activated the iNOS promoter activity as well as the GTPCH promoter activity in VSMC. AM alone had no effect on the activity of either the iNOS or the GTPCH promoter, nor did it potentiate the activation by IL-1 of either of these promoters.. These results suggest that AM increases IL-1-induced NO and BH4 synthesis by enhancing the expression of iNOS and GTPCH genes at the post-transcriptional level. Thus, the potentiating effect of AM on NO synthesis appears to be associated with an increased expression of both genes necessary for cellular NO synthesis in VSMC.

Topics: Adrenomedullin; Analysis of Variance; Animals; Antioxidants; Biopterins; Cells, Cultured; Enzyme Activation; Gene Expression; GTP Cyclohydrolase; Interleukin-1; Male; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Peptides; Polymerase Chain Reaction; Promoter Regions, Genetic; Rats; Rats, Wistar; RNA, Messenger; Shock, Septic; Vasodilator Agents

Wistar rats were injected intravenously with bacterial lipopolysaccharide (LPS) and developed endotoxic shock with severe hypotension. This was accompanied by significantly elevated concentrations of adrenomedullin (AM) in the plasma and expression of high levels of AM mRNA in the lung. Pretreatment of the rats with dexamethasone (DEX) prevented hypotension caused by LPS administration, but plasma AM concentrations and AM mRNA levels in the lung remained elevated. Adrenalectomized (ADX) rats developed a more severe form of circulatory shock in response to a low-dose of LPS. This was accompanied by only a slight increase in circulating AM in the plasma. However, pretreatment of ADX rats with DEX caused substantial elevations of plasma AM concentrations and expression of AM mRNA in the lung. Our studies demonstrate that glucocorticoid upregulates the expression and secretion of AM in vivo, and endogenous glucocorticoid is required for increased AM secretion under certain conditions such as endotoxic shock.

Topics: Adrenal Glands; Adrenalectomy; Adrenomedullin; Animals; Dexamethasone; Disease Models, Animal; Dose-Response Relationship, Drug; Glucocorticoids; Lipopolysaccharides; Lung; Male; Peptides; Rats; Rats, Wistar; RNA, Messenger; Shock, Septic

Septic shock is a life-threatening disorder caused by lipopolysaccharide (LPS) and other bacterial products. Accumulating evidence indicates a role for vasoactive substances and cytokines in this disease process. In this study we examined the effect of LPS on the gene expression of endothelin-1 (ET-1) and adrenomedullin (AM), two major vasoactive peptides predominantly produced by vascular endothelial cells, to investigate their role in the pathophysiology of septic shock. LPS induced ET-1 and AM gene expression in the heart, lung, kidney, liver, and aorta within 6 h. In the liver, whereas basal ET-1 and AM mRNA were hardly detectable, ET-1 and AM gene expression and peptide production were markedly increased by LPS. This LPS-induced upregulation of ET-1 and AM expression is greatly potentiated by D-galactosamine (D-GalN), although D-GalN alone could not induce ET-1 and AM gene expression. These results, together with the previous findings that liver injury induced by LPS and D-GalN is mainly mediated by tumor necrosis factor-alpha (TNF-alpha), suggest that the LPS-cytokine pathway may cause upregulation of ET-1 and AM production, leading to dysregulation of systemic and regional vascular tone.

Topics: Adrenomedullin; Animals; Blotting, Northern; Endothelin-1; Endotoxins; Enzyme-Linked Immunosorbent Assay; Galactosamine; Lipopolysaccharides; Liver; Male; Mice; Mice, Inbred C57BL; Peptides; RNA; Shock, Septic; Up-Regulation

Adrenomedullin (AM) is a potent vasorelaxing peptide isolated from human pheochromocytoma. It is proposed that AM dilates the blood vessels by autocrine or paracrine mechanisms. Our investigation concerned whether the vasodilating function of AM accounts for the hypotension occurring in endotoxin shock. The effect of endotoxin shock on AM gene expression in the cardiovascular system was probed using a canine model. The cDNA encoding the AM precursor in dogs was isolated from cDNA libraries of the adrenal gland and was sequenced. The canine AM precursor is constituted of 188 amino acids and its AM consists of 52 amino acids, similar to human and porcine AM. The dogs were injected intravenously with 2 mg/kg of lipopolysaccharide (LPS) after being anesthetized and intubated. After 4 h, we collected whole blood, the large and small blood vessels, and the heart from our canine model of endotoxin shock, and extracted RNA from those tissues for Northern blot analysis. In the endotoxin shock model, the mRNA levels of the AM had increased in almost all of the blood vessels. These results suggest that AM may dilate the blood vessels systemically, even if AM acts as a local modulator of vascular tone. In addition, the plasma concentrations of the AM were high enough to allow for AM to act as a vasodilating hormone. Consequently, AM may be one of the factors facilitating severe hypotension complicated with endotoxin shock.

Topics: Adrenomedullin; Amino Acid Sequence; Animals; Base Sequence; Blood Vessels; Cloning, Molecular; DNA, Complementary; Dogs; Female; Gene Expression Regulation; Humans; Molecular Sequence Data; Myocardium; Peptides; Sequence Analysis, DNA; Sequence Homology, Amino Acid; Shock, Septic

To investigate plasma concentrations of adrenomedullin in patients with septic shock and the potential association of these concentrations with relaxation of vascular tone.. Prospective, case series.. Department of Emergency and Critical Care Medicine, Nara Medical University.. Twelve patients who fulfilled the clinical criteria for severe sepsis or septic shock (as defined by the Members of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee) and 13 healthy volunteers.. Arterial blood samples were obtained via a 20-gauge cannula inserted into each patient's radial artery.. After extraction and purification, plasma adrenomedullin was measured by radioimmunoassay. Systemic vascular resistance index, pulmonary vascular resistance, cardiac index, and stroke volume index were determined with a thermodilution catheter. The mean plasma concentration of adrenomedullin was markedly higher in patients than in controls (226.1 +/- 66.4 [SEM] vs. 5.05 +/- 0.21 fmol/mL, p < .01). Moreover, these concentrations correlated significantly with cardiac index, stroke volume index, and heart rate values, and correlated significantly with decreases in diastolic blood pressure, systemic vascular resistance index, and pulmonary vascular resistance index values.. Enhanced production of adrenomedullin in patients with septic shock may contribute to reduced vascular tone, hypotension, or both. More data are needed to clarify the role of adrenomedullin in the regulation of vascular tone in this patient population.

Topics: Adrenomedullin; Adult; Aged; Aged, 80 and over; Female; Hemodynamics; Humans; Male; Middle Aged; Peptides; Prospective Studies; Sepsis; Shock, Septic; Vasodilation