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Ahuja N, Mishra A, Gupta R, Ray S. Biomarkers in sepsis-looking for the Holy Grail or chasing a mirage! World J Crit Care Med 2023; 12:188-203. [PMID: 37745257 PMCID: PMC10515097 DOI: 10.5492/wjccm.v12.i4.188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 05/12/2023] [Accepted: 06/12/2023] [Indexed: 09/05/2023] Open
Abstract
Sepsis is defined as a life-threatening organ dysfunction caused by the dysregulated host response to infection. It is a complex syndrome and is characterized by physiologic, pathologic and biochemical abnormalities in response to an infection. Diagnosis of sepsis is based on history, physical examination and other investigations (including biomarkers) which may help to increase the certainty of diagnosis. Biomarkers have been evaluated in the past for many diseases and have been evaluated for sepsis as well. Biomarkers may find a possible role in diagnosis, prognostication, therapeutic monitoring and anti-microbial stewardship in sepsis. Since the pathophysiology of sepsis is quite complex and is incompletely understood, a single biomarker that may be robust enough to provide all information has not been found as of yet. However, many biomarkers have been studied and some of them have applications at the bedside and guide clinical decision-making. We evaluated the PubMed database to search for sepsis biomarkers for diagnosis, prognosis and possible role in antibiotic escalation and de-escalation. Clinical trials, meta-analyses, systematic reviews and randomized controlled trials were included. Commonly studied biomarkers such as procalcitonin, Soluble urokinase-type plasminogen activator (Supar), presepsin, soluble triggering receptor expressed on myeloid cells 1, interleukin 6, C-reactive protein, etc., have been described for their possible applications as biomarkers in septic patients. The sepsis biomarkers are still an area of active research with newer evidence adding to the knowledge base continuously. For patients presenting with sepsis, early diagnosis and prompt resuscitation and early administration of anti-microbials (preferably within 1 h) and source control are desired goals. Biomarkers may help us in the diagnosis, prognosis and therapeutic monitoring of septic patients. The marker redefining our view on sepsis is yet a mirage that clinicians and researchers continue to chase.
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Affiliation(s)
- Neelmani Ahuja
- Department of Critical Care Medicine, Holy Family Hospital, Delhi 110025, India
| | - Anjali Mishra
- Department of Critical Care Medicine, Holy Family Hospital, Delhi 110025, India
| | - Ruchi Gupta
- Department of Critical Care Medicine, Holy Family Hospital, Delhi 110025, India
| | - Sumit Ray
- Department of Critical Care Medicine, Holy Family Hospital, Delhi 110025, India
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Procalcitonin and Adrenomedullin in Infectious Diseases. MICROBIOLOGY RESEARCH 2023. [DOI: 10.3390/microbiolres14010016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Calcitonin (CT) and adrenomedullin (ADM) are members of the CT family. Procalcitonin (PCT) is a prohormone of CT. Elevations in serum PCT and ADM levels are associated with severe sepsis and coronavirus disease 2019 (COVID-19). PCT enhances sepsis mortality and it binds to the CGRP receptor, which is a heterodimer of CT receptor-like receptor and receptor activity-modifying protein 1. The N-terminal truncated form of PCT, PCT3-116, is produced by the cleavage of PCT by dipeptidyl peptidase 4 (DPP-4) and is the main form of PCT in serum during sepsis, inducing microvascular permeability. Mid-regional pro-adrenomedullin (MR-proADM) is used instead of ADM as a biological indicator because ADM is rapidly degraded, and MR-proADM is released at the same rate as ADM. ADM reduces endothelial permeability and promotes endothelial stability. Endothelial dysfunction is responsible for multiple organ failure in sepsis and COVID-19 patients. Therefore, ADM may be an important molecule for improving the severity associated with sepsis and COVID-19. This review focuses on the current knowledge of PCT and ADM in sepsis and COVID-19.
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Hill A, Bergmann D, Schulte J, Zayat R, Marx G, Simon TP, Mossanen J, Brücken A, Stoppe C. Proenkephalin A and bioactive adrenomedullin are useful for risk prognostication in cardiac surgery. Front Cardiovasc Med 2023; 9:1017867. [PMID: 36756642 PMCID: PMC9900105 DOI: 10.3389/fcvm.2022.1017867] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 12/28/2022] [Indexed: 01/24/2023] Open
Abstract
Introduction Various clinical scores have been developed to predict organ dysfunction and mortality in patients undergoing cardiac surgery, but outcome prediction may be inaccurate for some patient groups. Proenkephalin A (penKid) and bioactive adrenomedullin (bio-ADM) have emerged as promising biomarkers correlating with shock and organ dysfunction. This imposes the question of whether they can be used as prognostic biomarkers for risk stratification in the perioperative setting of cardiac surgery. Methods Patients undergoing cardiac surgery were prospectively enrolled in this observational study. PenKid and bio-ADM plasma levels, as well as markers evaluating inflammation and organ dysfunction, were measured at five perioperative time points from before the induction of anesthesia to up to 48 h postoperatively. Clinical data regarding organ dysfunction and patient outcomes were recorded during the intensive care unit (ICU)-stay with a special focus on acute kidney injury (AKI). Results In 136 patients undergoing cardiac surgery, the bio-ADM levels increased and the penKid levels decreased significantly over time. PenKid was associated with chronic kidney disease (CKD), the incidence of AKI, and renal replacement therapy (RRT). Bio-ADM was associated with lactate and the need for vasopressors. PenKid was useful to predict an ICU-length of stay (LOS)>1 day and added prognostic value to the European System for Cardiac Operative Risk Evaluation Score (EuroSCORE) II when measured after the end of cardiopulmonary bypass and 24 h after cardiac surgery. For bio-ADM, the same was true when measured 24 h after surgery. PenKid also added prognostic value to the EuroSCORE II for the combined outcome "ICU length of stay >1 day and in-hospital mortality." Conclusion The combination of preoperative EuroSCORE II and intraoperative measurement of penKid may be more useful to predict a prolonged ICU LOS and increased mortality than EuroSCORE II alone. Bio-ADM correlates with markers of shock. More research is encouraged for early risk stratification and validation of penKid and bio-ADM as a tool involved in clinical decisions, which may enable the early initiation of organ protective strategies.
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Affiliation(s)
- Aileen Hill
- Department of Intensive Care and Intermediate Care, Medical Faculty RWTH Aachen, Aachen, Germany
- Department of Anesthesiology, Medical Faculty RWTH Aachen, Aachen, Germany
| | | | | | - Rashad Zayat
- Department of Cardiothoracic Surgery, Medical Faculty RWTH Aachen, Aachen, Germany
| | - Gernot Marx
- Department of Intensive Care and Intermediate Care, Medical Faculty RWTH Aachen, Aachen, Germany
| | - Tim-Philipp Simon
- Department of Intensive Care and Intermediate Care, Medical Faculty RWTH Aachen, Aachen, Germany
| | - Jana Mossanen
- Department of Intensive Care and Intermediate Care, Medical Faculty RWTH Aachen, Aachen, Germany
| | - Anne Brücken
- Department of Intensive Care and Intermediate Care, Medical Faculty RWTH Aachen, Aachen, Germany
| | - Christian Stoppe
- Department of Anesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Würzburg, Würzburg, Germany
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Jailani ABA, Bigos KJA, Avgoustou P, Egan JL, Hathway RA, Skerry TM, Richards GO. Targeting the adrenomedullin-2 receptor for the discovery and development of novel anti-cancer agents. Expert Opin Drug Discov 2022; 17:839-848. [PMID: 35733389 DOI: 10.1080/17460441.2022.2090541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Adrenomedullin (AM) is a peptide responsible for many physiological processes including vascular health and hormone regulation. Dysregulation of AM signaling can stimulate cancers by promoting proliferation, angiogenesis and metastasis. Two AM receptors contribute to tumor progression in different ways. Adrenomedullin-1 receptor (AM1R) regulates blood pressure and blocking AM signaling via AM1R would be clinically unacceptable. Therefore, antagonizing adrenomedullin-2 receptor (AM2R) presents as an avenue for anti-cancer drug development. AREAS COVERED We review the literature to highlight AM's role in cancer as well as delineating the specific roles AM1R and AM2R mediate in the development of a pro-tumoral microenvironment. We highlight the importance of exploring the residue differences between the receptors that led to the development of first-in-class selective AM2R small molecule antagonists. We also summarize the current approaches targeting AM and its receptors, their anti-tumor effects and their limitations. EXPERT OPINION As tool compounds, AM2R antagonists will allow the dissection of the functions of CGRPR (calcitonin gene-related peptide receptor), AM1R and AM2R, and has considerable potential as a first-in-class oncology therapy. Furthermore, the lack of detectable side effects and good drug-like pharmacokinetic properties of these AM2R antagonists support the promise of this class of compounds as potential anti-cancer therapeutics.
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Affiliation(s)
- Ameera B A Jailani
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - Kamilla J A Bigos
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - Paris Avgoustou
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - Joseph L Egan
- Department of Chemistry, University of Sheffield, Sheffield, UK
| | | | - Timothy M Skerry
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - Gareth O Richards
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
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Di Somma S, Crisanti L. Can Acute Care Biomarkers Change Patient’s Management in Sepsis? EURASIAN JOURNAL OF EMERGENCY MEDICINE 2022. [DOI: 10.4274/eajem.galenos.2022.21.2.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
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Corr MP, Fairley D, McKenna JP, Shields MD, Waterfield T. Diagnostic value of mid-regional pro-Adrenomedullin as a biomarker of invasive bacterial infection in children: a systematic review. BMC Pediatr 2022; 22:176. [PMID: 35379203 PMCID: PMC8977188 DOI: 10.1186/s12887-022-03255-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 03/28/2022] [Indexed: 11/10/2022] Open
Abstract
Background Invasive bacterial infections (IBI) in children present a difficult clinical challenge. They are often life-threatening, however in the early stages they can be hard to differentiate from benign viral infections. This leaves clinicians with the risk of missing a serious IBI diagnosis or inappropriately using antimicrobials in a child with a viral infection- contributing to the ongoing development of increased antimicrobial resistance. Hence, biomarkers which could aid in early detection of IBI and differentiation from viral infections are desirable. Mid-Regional pro-Adrenomedullin (MR-proADM) is a biomarker which has been associated with IBI. The aim of this systematic review was to determine its diagnostic accuracy in identifying children with IBI. Methods A strategy was devised to search online databases MEDLINE, Embase, Web of Science and Scopus for human clinical trials reporting the accuracy of MR-proADM in children. Against predesigned inclusion and exclusion criteria full texts were selected for inclusion and data extraction. True positives, false positives, true negatives and false negatives were extracted from each included study to fill 2 × 2 tables. Using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool methodological quality of each study was assessed. Results A total of 501 articles were initially identified. After the removal of duplicates and abstract screening 11 texts were fully reviewed and four texts (totaling 1404 patients) were included in the systematic analysis. Only one study was of a high quality and that study accounted for the vast majority of patients. A single study reported the diagnostic accuracy of MR-proADM for invasive bacterial infection reporting an Area under the Curve of 0.69. The paucity of available studies made meta-analysis and studies of heterogeneity impossible. Conclusion There is a paucity of research regarding the diagnostic accuracy of MR-proADM in the diagnosis of invasive bacterial infections in children. Initial results would suggest that MR-proADM testing alone is poor at identifying IBI in young children. It remains unclear if MR-proADM performs differently in older children or in children with signs and symptoms of IBI. Trial registration PROSPERO CRD42018096295. Supplementary Information The online version contains supplementary material available at 10.1186/s12887-022-03255-9.
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Affiliation(s)
| | - Derek Fairley
- Department of Microbiology, Belfast Health and Social Care Trust, Belfast, UK
| | - James P McKenna
- Department of Microbiology, Belfast Health and Social Care Trust, Belfast, UK
| | - Michael D Shields
- Centre for Experimental Medicine, Wellcome Wolfson Institute of Experimental Medicine, Queen's University Belfast, Belfast, UK
| | - Thomas Waterfield
- Centre for Experimental Medicine, Wellcome Wolfson Institute of Experimental Medicine, Queen's University Belfast, Belfast, UK
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Kita T, Kitamura K. Translational studies of adrenomedullin and related peptides regarding cardiovascular diseases. Hypertens Res 2022; 45:389-400. [PMID: 34992239 PMCID: PMC8732970 DOI: 10.1038/s41440-021-00806-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/24/2021] [Accepted: 10/28/2021] [Indexed: 12/11/2022]
Abstract
Adrenomedullin (AM) is a vasodilative peptide with various physiological functions, including the maintenance of vascular tone and endothelial barrier function. AM levels are markedly increased during severe inflammation, such as that associated with sepsis; thus, AM is expected to be a useful clinical marker and therapeutic agent for inflammation. However, as the increase in AM levels in cardiovascular diseases (CVDs) is relatively low compared to that in infectious diseases, the value of AM as a marker of CVDs seems to be less important. Limitations pertaining to the administrative route and short half-life of AM in the bloodstream (<30 min) restrict the therapeutic applications of AM for CVDs. In early human studies, various applications of AM for CVDs were attempted, including for heart failure, myocardial infarction, pulmonary hypertension, and peripheral artery disease; however, none achieved success. We have developed AM as a therapeutic agent for inflammatory bowel disease in which the vasodilatory effect of AM is minimized. A clinical trial evaluating this AM formulation for acute cerebral infarction is ongoing. We have also developed AM derivatives that exhibit a longer half-life and less vasodilative activity. These AM derivatives can be administered by subcutaneous injection at long-term intervals. Accordingly, these derivatives will reduce the inconvenience in use compared to that for native AM and expand the possible applications of AM for treating CVDs. In this review, we present the latest translational status of AM and its derivatives.
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Affiliation(s)
- Toshihiro Kita
- Department of Projects Research, Frontier Science Research Center, University of Miyazaki, Miyazaki, Japan.
| | - Kazuo Kitamura
- Department of Projects Research, Frontier Science Research Center, University of Miyazaki, Miyazaki, Japan
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Kita T, Kitamura K. Adrenomedullin Therapy in Moderate to Severe COVID-19. Biomedicines 2022; 10:biomedicines10030533. [PMID: 35327335 PMCID: PMC8945653 DOI: 10.3390/biomedicines10030533] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 02/19/2022] [Accepted: 02/21/2022] [Indexed: 12/15/2022] Open
Abstract
The 2019 coronavirus (COVID-19) pandemic is still in progress, and a significant number of patients have presented with severe illness. Recently introduced vaccines, antiviral medicines, and antibody formulations can suppress COVID-19 symptoms and decrease the number of patients exhibiting severe disease. However, complete avoidance of severe COVID-19 has not been achieved, and more importantly, there are insufficient methods to treat it. Adrenomedullin (AM) is an endogenous peptide that maintains vascular tone and endothelial barrier function. The AM plasma level is markedly increased during severe inflammatory disorders, such as sepsis, pneumonia, and COVID-19, and is associated with the severity of inflammation and its prognosis. In this study, exogenous AM administration reduced inflammation and related organ damage in rodent models. The results of this study strongly suggest that AM could be an alternative therapy in severe inflammation disorders, including COVID-19. We have previously developed an AM formulation to treat inflammatory bowel disease and are currently conducting an investigator-initiated phase 2a trial for moderate to severe COVID-19 using the same formulation. This review presents the basal AM information and the most recent translational AM/COVID-19 study.
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van Lier D, Kox M, Pickkers P. Promotion of vascular integrity in sepsis through modulation of bioactive adrenomedullin and dipeptidyl peptidase 3. J Intern Med 2021; 289:792-806. [PMID: 33381880 PMCID: PMC8246835 DOI: 10.1111/joim.13220] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 11/07/2020] [Accepted: 11/10/2020] [Indexed: 12/19/2022]
Abstract
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.
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Affiliation(s)
- D van Lier
- From the, Department of Intensive Care Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands
| | - M Kox
- From the, Department of Intensive Care Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands
| | - P Pickkers
- From the, Department of Intensive Care Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands
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10
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Circulating biomarkers to assess cardiovascular function in critically ill. Curr Opin Crit Care 2021; 27:261-268. [PMID: 33899816 DOI: 10.1097/mcc.0000000000000829] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW Circulatory shock is one of the most common reasons for ICU admission. Mortality rates in excess of 40% necessitate the rapid identification of high-risk patients, as well as the early assessment of effects of initiated treatments. There is an unmet medical need for circulating biomarkers that may improve patient stratification, predict responses to treatment interventions and may even be a target for novel therapies, enabling a better biological rationale to personalize therapy. RECENT FINDINGS Apart from established biomarkers such as lactate, ScvO2 or NT-pro-BNP, novel biomarkers, including adrenomedullin, angiopoietins, angiotensin I/II ratios, renin and DPP3 show promise, as they are all associated with well defined, therapeutically addressable molecular pathways that are dysregulated during circulatory shock. Although some of the therapies related to these biomarkers are still in preclinical stages of development, they may represent personalized treatment opportunities for patients in circulatory shock. SUMMARY From a molecular perspective, shock represents a highly heterologous syndrome, in which multiple unique pathways are dysregulated. Assessment of the status of these pathways with circulating biomarkers may provide a unique opportunity to detect specific phenotypes and implement personalized medicine in the treatment of circulatory shock.
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Malinina DA, Shlyk IV, Polushin YS, Аfanasiev AA, Stanevich OV, Bakin EA. The informative value of proadrenomedullin in patients with severe COVID-19. MESSENGER OF ANESTHESIOLOGY AND RESUSCITATION 2020. [DOI: 10.21292/2078-5658-2020-17-6-31-38] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
| | - I. V. Shlyk
- Pavlov First Saint Petersburg State Medical University
| | | | | | - O. V. Stanevich
- Pavlov First Saint Petersburg State Medical University; Smorodintsev Research Institute of Influenza
| | - E. A. Bakin
- Pavlov First Saint Petersburg State Medical University
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Deniau B, Takagi K, Asakage A, Mebazaa A. Adrecizumab: an investigational agent for the biomarker-guided treatment of sepsis. Expert Opin Investig Drugs 2020; 30:95-102. [PMID: 33256482 DOI: 10.1080/13543784.2021.1857365] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Introduction: Sepsis is a major health problem with a high incidence and mortality. ADM, a free-circulating peptide mainly expressed and secreted by vascular endothelial cells, shows vasodilatory properties and causes hypotension when present in higher concentrations during sepsis. Areas covered: Adrecizumab (ADZ) (HAM 8101) is a humanized targeted therapy directed against the N-terminus of adrenomedullin (ADM). ADZ inhibits excessive circulating sepsis-induced ADM and stimulates protective effects on the endothelial barrier, and decreases interstitial vasodilatory effects. ADZ demonstrated a promising safety profile in healthy subjects in phase I studies. According to these results, a phase II proof of concept study enrolling 300 septic patients is currently in course (NCT03085758). Expert opinion: ADZ is the first humanized antibody directed against ADM. The main interest of ADZ is its potential use as a 'biomarker-guided therapy' in septic patients with high circulating ADM. ADZ is increasingly seen as a potential adjunct therapy to restore endothelial function in septic shock. A positive pivotal phase III trial is indeed needed to convince the intensive care community to prescribe ADZ in septic shock patients. Further, it would be of interest to see whether ADZ might also benefit other critical diseases such as cardiogenic shock where endothelial dysfunction has also been described.
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Affiliation(s)
- Benjamin Deniau
- Department of Anesthesiology and Critical Care and Burn Unit, Assistance Publique - Hôpitaux De Paris (AP-HP), Groupe Hospitalier St Louis-Lariboisière , Paris, France.,Université de Paris, FHU PROMICE , Paris, France.,INSERM UMR-S 942 MASCOT, Lariboisière Hospital, Institut National de la Santé et de la Recherche Médicale , Paris, France
| | - Koji Takagi
- INSERM UMR-S 942 MASCOT, Lariboisière Hospital, Institut National de la Santé et de la Recherche Médicale , Paris, France
| | - Ayu Asakage
- INSERM UMR-S 942 MASCOT, Lariboisière Hospital, Institut National de la Santé et de la Recherche Médicale , Paris, France
| | - Alexandre Mebazaa
- Department of Anesthesiology and Critical Care and Burn Unit, Assistance Publique - Hôpitaux De Paris (AP-HP), Groupe Hospitalier St Louis-Lariboisière , Paris, France.,Université de Paris, FHU PROMICE , Paris, France.,INSERM UMR-S 942 MASCOT, Lariboisière Hospital, Institut National de la Santé et de la Recherche Médicale , Paris, France
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Pierrakos C, Velissaris D, Bisdorff M, Marshall JC, Vincent JL. Biomarkers of sepsis: time for a reappraisal. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2020; 24:287. [PMID: 32503670 PMCID: PMC7273821 DOI: 10.1186/s13054-020-02993-5] [Citation(s) in RCA: 350] [Impact Index Per Article: 70.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 05/14/2020] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Sepsis biomarkers can have important diagnostic, therapeutic, and prognostic functions. In a previous review, we identified 3370 references reporting on 178 different biomarkers related to sepsis. In the present review, we evaluate the progress in the research of sepsis biomarkers. METHODS Using the same methodology as in our previous review, we searched the PubMed database from 2009 until September 2019 using the terms "Biomarker" AND "Sepsis." There were no restrictions by age or language, and all studies, clinical and experimental, were included. RESULTS We retrieved a total of 5367 new references since our previous review. We identified 258 biomarkers, 80 of which were new compared to our previous list. The majority of biomarkers have been evaluated in fewer than 5 studies, with 81 (31%) being assessed in just a single study. Apart from studies of C-reactive protein (CRP) or procalcitonin (PCT), only 26 biomarkers have been assessed in clinical studies with more than 300 participants. Forty biomarkers have been compared to PCT and/or CRP for their diagnostic value; 9 were shown to have a better diagnostic value for sepsis than either or both of these biomarkers. Forty-four biomarkers have been evaluated for a role in answering a specific clinical question rather than for their general diagnostic or prognostic properties in sepsis. CONCLUSIONS The number of biomarkers being identified is still increasing although at a slower rate than in the past. Most of the biomarkers have not been well-studied; in particular, the clinical role of these biomarkers needs to be better evaluated.
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Affiliation(s)
- Charalampos Pierrakos
- Intensive Care Department, Brugmann University Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | | | - Max Bisdorff
- Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium
| | - John C Marshall
- Surgery/Critical Care Medicine, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Jean-Louis Vincent
- Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium.
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Corr M, Waterfield T, Fairley D, McKenna J, Shields MD. A protocol for a systematic review and meta-analysis of the diagnostic accuracy of mid-regional pro-adrenomedullin in predicting invasive bacterial infection in children. Syst Rev 2020; 9:69. [PMID: 32241288 PMCID: PMC7119004 DOI: 10.1186/s13643-020-01338-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 03/19/2020] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND The early recognition of invasive bacterial infections (IBI) in children can be difficult. Clinically it is often challenging to differentiate between the early stages of an IBI and a benign self-limiting viral infection. These challenges mandate a cautious approach resulting in the overuse of antimicrobial drugs with resultant antimicrobial resistance. Due to these challenges, there is growing research into the role of biomarkers for the early identification of children with IBI. Earlier and more accurate diagnoses may lead to improved clinical outcomes for children and reduced antimicrobial resistance. Mid-regional pro-adrenomedullin (MR-proADM) is a biomarker that has been shown to be elevated in patients with IBI. The aim of this systematic review is to determine the diagnostic accuracy of MR-proADM at identifying children with IBI. METHODS To identify relevant studies we will search MEDLINE, Embase, Web of Science and Scopus from 1980 to the present day for all human clinical trials involving children that report the test accuracy of MR-proADM. We will include case-control studies, cohort studies and randomised control trials reported in any language. In addition, we will hand-search reference lists and grey literature including conference abstracts and web searches. Two reviewers will independently screen study titles and abstracts for eligibility followed by full-text assessment and data extraction including population, setting, timing and use of index test and reference standard used. Methodological quality will be assessed, by two authors, according to the revised tool for the quality assessment of diagnostic accuracy studies (QUADAS-2), any discrepancies will be resolved by a third author. The following test characteristics will be extracted into 2 × 2 tables for all included studies: true positives, false positives, true negatives and false negatives. Study-specific estimates of sensitivity and specificity with 95% confidence intervals will be displayed in forest plots. DISCUSSION This review will report the normal ranges for MR-proADM in health and the diagnostic accuracy of MR-proADM at identifying children with IBI. The review will help to define where in the diagnostic pathway MR-proADM could be useful including potential as a point-of-care test for children at first presentation with IBI. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42018096295.
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Affiliation(s)
- Michael Corr
- Centre for Experimental Medicine, Wellcome Wolfson Institute of Experimental Medicine, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7AE UK
| | - Thomas Waterfield
- Centre for Experimental Medicine, Wellcome Wolfson Institute of Experimental Medicine, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7AE UK
| | | | | | - Michael D. Shields
- Centre for Experimental Medicine, Wellcome Wolfson Institute of Experimental Medicine, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7AE UK
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Effects of the Humanized Anti-Adrenomedullin Antibody Adrecizumab (HAM8101) on Vascular Barrier Function and Survival in Rodent Models of Systemic Inflammation and Sepsis. Shock 2019; 50:648-654. [PMID: 29324627 DOI: 10.1097/shk.0000000000001102] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE Adrenomedullin (ADM) is an important regulator of endothelial barrier function during sepsis. Administration of a murine antibody targeted against the N-terminus of ADM (HAM1101) resulted in improved outcome in models of murine sepsis. We studied the effects of a humanized form of this antibody (HAM8101, also known as Adrecizumab) on vascular barrier dysfunction and survival in rodent models of systemic inflammation and sepsis. METHODS Rats (n=48) received different dosages of HAM8101 or placebo (n = 8 per group), directly followed by administration of lipopolysaccharide (5 mg/kg). Twenty-four hours later, Evans Blue dye was administered to assess vascular leakage in kidney and liver tissue. Furthermore, mice (n = 24) were administered different dosages of HAM8101 or placebo (n = 6 per group), immediately followed by cecal ligation and puncture (CLP). Eighteen hours later, albumin, vascular endothelial growth factor (VEGF), and angiopoietin-1 were analyzed in the kidney. Finally, effects of single and repeated dose administration of HAM1101, HAM8101 and placebo on survival were assessed in CLP-induced murine sepsis (n = 60, n = 10 per group). RESULTS Dosages of 0.1 and 2.5 mg/kg HAM8101 attenuated renal albumin leakage in endotoxemic rats. Dosages of 0.1, 2.0, and 20 mg/kg HAM8101 reduced renal concentrations of albumin and the detrimental protein VEGF in septic mice, whereas concentrations of the protective protein angiopoietin-1 were augmented. Both single and repeated administration of both HAM1101 and HAM8101 resulted in improved survival during murine sepsis. CONCLUSIONS Pretreatment with the humanized anti-ADM antibody HAM8101 improved vascular barrier function and survival in rodent models of systemic inflammation and sepsis.
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Abstract
Sepsis remains a major scientific and medical challenge, for which, apart from significant refinements in supportive therapy, treatment has barely changed over the last few decades. During sepsis, both vascular tone and vascular integrity are compromised, and contribute to the development of shock. The free circulating peptide adrenomedullin (ADM) is involved in the regulation of the endothelial barrier function and tone of blood vessels. Several animal studies have shown that ADM administration improves outcome of sepsis. However, in higher dosages, ADM administration may cause hypotension, limiting its clinical applicability. Moreover, ADM has a very short half-life and easily adheres to surfaces, further hampering its clinical use. The non-neutralizing anti-ADM antibody Adrecizumab (HAM8101) which causes a long-lasting increase of plasma ADM has shown promising results in animal models of systemic inflammation and sepsis; it reduced inflammation, attenuated vascular leakage, and improved hemodynamics, kidney function, and survival. Combined with an excellent safety profile derived from animal and phase I human studies, Adrecizumab represents a promising candidate drug for the adjunctive treatment of sepsis. In this review, we first provide a brief overview of the currently available data on the role of adrenomedullin in sepsis and describe its effects on endothelial barrier function and vasodilation. Furthermore, we provide a novel hypothesis concerning the mechanisms of action through which Adrecizumab may exert its beneficial effects in sepsis.
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Li Q, Wang B, Yang L, Peng C, Ma L, Chai C. Assessment of adrenomedullin and proadrenomedullin as predictors of mortality in septic patients: A systematic review and meta-analysis. ACTA ACUST UNITED AC 2018. [DOI: 10.1016/j.medine.2017.10.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Geven C, Kox M, Pickkers P. Adrenomedullin and Adrenomedullin-Targeted Therapy As Treatment Strategies Relevant for Sepsis. Front Immunol 2018; 9:292. [PMID: 29520277 PMCID: PMC5827550 DOI: 10.3389/fimmu.2018.00292] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 02/01/2018] [Indexed: 12/29/2022] Open
Abstract
Sepsis remains a major medical challenge, for which, apart from improvements in supportive care, treatment has not relevantly changed over the last few decades. Vasodilation and vascular leakage play a pivotal role in the development of septic shock, with vascular leakage being caused by disrupted endothelial integrity. Adrenomedullin (ADM), a free circulating peptide involved in regulation of endothelial barrier function and vascular tone, is implicated in the pathophysiology of sepsis. ADM levels are increased during sepsis, and correlate with extent of vasodilation, as well as with disease severity and mortality. In vitro and preclinical in vivo data show that administration of ADM exerts anti-inflammatory, antimicrobial, and protective effects on endothelial barrier function during sepsis, but other work suggests that it may also decrease blood pressure, which could be detrimental for patients with septic shock. Work has been carried out to negate ADMs putative negative effects, while preserving or even potentiating its beneficial actions. Preclinical studies have demonstrated that the use of antibodies that bind to the N-terminus of ADM results in an overall increase of circulating ADM levels and improves sepsis outcome. Similar beneficial effects were obtained using coadministration of ADM and ADM-binding protein-1. It is hypothesized that the mechanism behind the beneficial effects of ADM binding involves prolongation of its half-life and a shift of ADM from the interstitium to the circulation. This in turn results in increased ADM activity in the blood compartment, where it exerts beneficial endothelial barrier-stabilizing effects, whereas its detrimental vasodilatory effects in the interstitium are reduced. Up till now, in vivo data on ADM-targeted treatments in humans are lacking; however, the first study in septic patients with an N-terminus antibody (Adrecizumab) is currently being conducted.
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Affiliation(s)
- Christopher Geven
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, Netherlands
- Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands
| | - Matthijs Kox
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, Netherlands
- Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands
| | - Peter Pickkers
- Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, Netherlands
- Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands
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Assessment of adrenomedullin and proadrenomedullin as predictors of mortality in septic patients: A systematic review and meta-analysis. Med Intensiva 2017; 42:416-424. [PMID: 29246418 DOI: 10.1016/j.medin.2017.10.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 10/16/2017] [Accepted: 10/26/2017] [Indexed: 12/25/2022]
Abstract
OBJECTIVE To ascertain the ability of adrenomedullin (ADM) and proadrenomedullin (proADM) to predict mortality in sepsis patients. DESIGN A systematic literature search was made of the PubMed, EMBASE, Cochrane and China National Knowledge Infrastructure (CNKI) databases before May 2017, supplemented by manual searches of references. A meta-analysis of high-quality clinical studies was subsequently performed to assess the association between ADM/proADM and mortality risk among patients with sepsis. PATIENTS Thirteen studies involving 2556 patients were included in the study. INTERVENTIONS Two reviewers independently identified articles, extracted data, assessed quality and cross-checked the results. The predictive values of ADM and proADM referred to mortality were assessed by relative risk (RR). The overall diagnostic accuracy of ADM and proADM in application to sepsis was pooled according to a bivariate model. Publication bias was assessed using Deek's funnel plot asymmetry test. RESULTS Elevated ADM or proADM levels were associated with increased mortality (pooled RR=3.31; 95%CI 2.31-4.75). Subgroup analyses indicated the pooled RRs were 3.12 (95%CI 1.75-5.56) and 3.43 (95%CI 2.21-5.31) for ADM and proADM, respectively. The pooled sensitivity and specificity were 0.72 (95%CI 0.64-0.78) and 0.77 (95%CI 0.69-0.83), respectively. The overall area under the summary receiver operating characteristic (SROC) curve was 0.80 (95%CI 0.77-0.84). Publication bias was not statistically significant. CONCLUSIONS Both ADM and proADM might serve as useful markers for predicting the prognosis of sepsis.
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Caironi P, Latini R, Struck J, Hartmann O, Bergmann A, Maggio G, Cavana M, Tognoni G, Pesenti A, Gattinoni L, Masson S, Masson S, Caironi P, Spanuth E. Circulating Biologically Active Adrenomedullin (bio-ADM) Predicts Hemodynamic Support Requirement and Mortality During Sepsis. Chest 2017; 152:312-320. [DOI: 10.1016/j.chest.2017.03.035] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Revised: 01/30/2017] [Accepted: 03/20/2017] [Indexed: 12/29/2022] Open
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Simon TP, Martin L, Doemming S, Humbs A, Bruells C, Kopp R, Hartmann O, Struck J, Bergmann A, Marx G, Schuerholz T. Plasma adrenomedullin in critically ill patients with sepsis after major surgery: A pilot study. J Crit Care 2016; 38:68-72. [PMID: 27865148 DOI: 10.1016/j.jcrc.2016.10.017] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Revised: 07/30/2016] [Accepted: 10/21/2016] [Indexed: 11/18/2022]
Abstract
PURPOSE 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. MATERIALS AND METHODS 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. RESULTS Patients (66% male) were 70 (median) (interquartile range [IQR], 61-77]) years old and had a body mass index of 26.2 (24.2-29.4) kg/m2. The ICU and hospital length of stay was 8 (1-22) and 17 (8-21) days, respectively. Eight patients had sepsis, 19 developed severe sepsis, and 15 suffered from septic shock. Adrenomedullin increased with severity (sepsis: 25.8 pg/mL [IQR 20.3-40.2], severe sepsis: 84.2 pg/mL [IQR 42.7-118.5], septic shock: 119.7 pg/mL [IQR 83.8-172.6]; P<.0001). Higher adrenomedullin was associated with poor 90-day outcomes (P=.019) and more frequent vasopressor use (P=.001). CONCLUSIONS 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.
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Affiliation(s)
- Tim-Philipp Simon
- Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany
| | - Lukas Martin
- Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany
| | - Sabine Doemming
- Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany
| | - Andreas Humbs
- Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany
| | - Christian Bruells
- Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany
| | - Ruedger Kopp
- Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany
| | - Oliver Hartmann
- Sphingotec GmbH, Neuendorfstraße 15A, 16761, Hennigsdorf, Germany
| | - Joachim Struck
- Sphingotec GmbH, Neuendorfstraße 15A, 16761, Hennigsdorf, Germany
| | - Andreas Bergmann
- Sphingotec GmbH, Neuendorfstraße 15A, 16761, Hennigsdorf, Germany
| | - Gernot Marx
- Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany
| | - Tobias Schuerholz
- Department of Intensive Care and Intermediate Care, University Hospital RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany.
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Severity Scores in Emergency Department Patients With Presumed Infection: A Prospective Validation Study. Crit Care Med 2016; 44:539-47. [PMID: 26901543 DOI: 10.1097/ccm.0000000000001427] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVES The objectives of this study were to 1) validate a number of severity of illness scores in a large cohort of emergency department patients admitted with presumed infection and 2) compare the performance of scores in patient subgroups with increasing mortality: infection without systemic inflammatory response syndrome, sepsis, severe sepsis, and septic shock. DESIGN Prospective, observational study. SETTING Adult emergency department in a metropolitan tertiary, university-affiliated hospital. PATIENTS Emergency department patients admitted with presumed infection. INTERVENTIONS None. METHODS Consecutive emergency department patients admitted with presumed infection were identified over 160 weeks in two periods between 2007 and 2011. Clinical and laboratory data sufficient to calculate Mortality in Emergency Department Sepsis score, Acute Physiology and Chronic Health Evaluation II, Simplified Acute Physiology Score II, Sequential Organ Failure Assessment, and the Severe Sepsis Score were entered into a database. Model discrimination was quantified using area under the receiver operating curve. Calibration was assessed using visual plots, Hosmer-Lemeshow statistics, and linear regressions of observed and predicted values. MEASUREMENTS AND MAIN RESULTS A total of 8,871 patients were enrolled with 30-day mortality of 3.7%. Area under the receiver operating curve values for the entire cohort were: Mortality in Emergency Department Sepsis score of 0.92, Simplified Acute Physiology Score II and Acute Physiology and Chronic Health Evaluation II scores of 0.90, Sequential Organ Failure Assessment score of 0.86, and Severe Sepsis Score of 0.82. Discrimination decreased in subgroups with greater mortality for each score. All scores overestimated mortality, but closest concordance between predicted and observed mortality was seen with Mortality in Emergency Department Sepsis score. CONCLUSIONS The decrease in area under the receiver operating curve seen in subgroups with increasing mortality may explain some variation in results seen in previous validation studies. Scores developed in intensive care settings overestimated mortality in the emergency department. Our results underscore the importance of employing predictive models developed in similar patient populations. The Mortality in Emergency Department Sepsis score outperformed more complex predictive models and would be the most appropriate scoring system for use in similar emergency department populations with a wide spectrum of mortality risk.
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Martínez-Herrero S, Martínez A. Adrenomedullin regulates intestinal physiology and pathophysiology. Domest Anim Endocrinol 2016; 56 Suppl:S66-83. [PMID: 27345325 DOI: 10.1016/j.domaniend.2016.02.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 02/11/2016] [Accepted: 02/15/2016] [Indexed: 02/08/2023]
Abstract
Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are 2 biologically active peptides produced by the same gene, ADM, with ubiquitous distribution and many physiological functions. Adrenomedullin is composed of 52 amino acids, has an internal molecular ring composed by 6 amino acids and a disulfide bond, and shares structural similarities with calcitonin gene-related peptide, amylin, and intermedin. The AM receptor consists of a 7-transmembrane domain protein called calcitonin receptor-like receptor in combination with a single transmembrane domain protein known as receptor activity-modifying protein. Using morphologic techniques, it has been shown that AM and PAMP are expressed throughout the gastrointestinal tract, being specially abundant in the neuroendocrine cells of the gastrointestinal mucosa; in the enterochromaffin-like and chief cells of the gastric fundus; and in the submucosa of the duodenum, ileum, and colon. This wide distribution in the gastrointestinal tract suggests that AM and PAMP may act as gut hormones regulating many physiological and pathologic conditions. To date, it has been proven that AM and PAMP act as autocrine/paracrine growth factors in the gastrointestinal epithelium, play key roles in the protection of gastric mucosa from various kinds of injury, and accelerate healing in diseases such as gastric ulcer and inflammatory bowel diseases. In addition, both peptides are potent inhibitors of gastric acid secretion and gastric emptying; they regulate the active transport of sugars in the intestine, regulate water and ion transport in the colon, modulate colonic bowel movements and small-intestine motility, improve endothelial barrier function, and stabilize circulatory function during gastrointestinal inflammation. Furthermore, AM and PAMP are antimicrobial peptides, and they contribute to the mucosal host defense system by regulating gut microbiota. To get a formal demonstration of the effects that endogenous AM and PAMP may have in gut microbiota, we developed an inducible knockout of the ADM gene. Using this model, we have shown, for the first time, that lack of AM/PAMP leads to changes in gut microbiota composition in mice. Further studies are needed to investigate whether this lack of AM/PAMP may have an impact in the development and/or progression of intestinal diseases through their effect on microbiota composition.
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Affiliation(s)
- S Martínez-Herrero
- Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), Logroño, La Rioja 26006, Spain
| | - A Martínez
- Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), Logroño, La Rioja 26006, Spain.
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Prognostic Value of Adrenomedullin and Natriuretic Peptides in Uroseptic Patients Induced by Ureteroscopy. Mediators Inflamm 2016; 2016:9743198. [PMID: 26880865 PMCID: PMC4736384 DOI: 10.1155/2016/9743198] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Revised: 11/21/2015] [Accepted: 11/25/2015] [Indexed: 11/29/2022] Open
Abstract
The aim of this paper is to investigate whether urosepsis is related to irrigation pressure of ureteroscopy (URS) and evaluate the prognostic value of adrenomedullin (ADM) and atrial and brain natriuretic peptides (ANP and BNP) in URS-induced uroseptic patients. From July 2008 to October 2013, we enrolled 332 patients with untreated unilateral ureteral obstruction (UUO). The UUO group included three subgroups of, respectively, 118, 132, and 82 patients who underwent URS under intermittent stable irrigation pressure of, respectively, 80, 120, and 160 mmHg. The plasma concentrations of ADM, ANP, and BNP were measured in all subjects. URS was performed for all UUO patients; the values of the three peptides were measured again after URS. Irrigation pressure and stone size were independent risk factors of urosepsis. After URS, the plasma concentrations of ADM, ANP, and BNP were significantly higher in uroseptic patients. Moreover, the concentrations were significantly higher depending on the disease severity. Plasma concentrations of the three peptides were correlated with plasma ET concentration in the uroseptic patients. The areas under receiver operating characteristic (ROC) curve of ADM, ANP, and BNP for predicting urosepsis were 0.811, 0.728, and 0.764, respectively. In conclusion, ADM, along with ANP and BNP, is valuable for prognosis in urosepsis secondary to URS which is associated with irrigation pressure.
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Simon TP, Doemming S, Humbs A, Martin L, Bruells C, Hartmann O, Struck J, Bergmann A, Marx G, Schuerholz T. Adrenomedullin in plasma of surgical ICU-patients with sepsis - a pilot study. Intensive Care Med Exp 2015. [PMCID: PMC4797814 DOI: 10.1186/2197-425x-3-s1-a302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Sehgal V, Bajwa SJS, Consalvo JA, Bajaj A. Clinical conundrums in management of sepsis in the elderly. J Transl Int Med 2015; 3:106-112. [PMID: 27847897 PMCID: PMC4936459 DOI: 10.1515/jtim-2015-0010] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
In 2012, surviving sepsis campaign came out with updated international guidelines for management of severe sepsis and septic shock. Paradoxically, there are no specific guidelines for management of sepsis in the elderly, although the elderly are more predisposed to sepsis, and morbidity and mortality related to sepsis. Sepsis in the elderly is, more often than not, complicated by clinical conundrums such as congestive heart failure (CHF), atrial fibrillation (AF), chronic kidney disease (CKD), acute kidney injury (AKI), delirium, dementia, ambulatory dysfunction, polypharmacy, malglycemia, nutritional deficiencies, and antibiotic resistance. Also, with recurrent admissions to the hospital and widespread use of antibiotics, the elderly are more susceptible to Clostridium difficile colitis.
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Affiliation(s)
- Vishal Sehgal
- Department of Internal Medicine, The Common Wealth Medical College, Scranton, PA 18510, USA
| | - Sukhminder Jit Singh Bajwa
- Department of Anaesthesiology and Intensive Care Medicine, Gian Sagar Medical College, Banur, Patiala, Punjab, India
| | - John A Consalvo
- Chairman Emergency Medicine, Regional hospital of Scranton, PA, USA
| | - Anurag Bajaj
- Department of Internal Medicine, WCGME, SCRANTON, PA, USA
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Parlato M, Cavaillon JM. Host response biomarkers in the diagnosis of sepsis: a general overview. Methods Mol Biol 2015; 1237:149-211. [PMID: 25319788 DOI: 10.1007/978-1-4939-1776-1_15] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Critically ill patients who display a systemic inflammatory response syndrome (SIRS) are prone to develop nosocomial infections. The challenge remains to distinguish as early as possible among SIRS patients those who are developing sepsis. Following a sterile insult, damage-associated molecular patterns (DAMPs) released by damaged tissues and necrotic cells initiate an inflammatory response close to that observed during sepsis. During sepsis, pathogen-associated molecular patterns (PAMPs) trigger the release of host mediators involved in innate immunity and inflammation through identical receptors as DAMPs. In both clinical settings, a compensatory anti-inflammatory response syndrome (CARS) is concomitantly initiated. The exacerbated production of pro- or anti-inflammatory mediators allows their detection in biological fluids and particularly within the bloodstream. Some of these mediators can be used as biomarkers to decipher among the patients those who developed sepsis, and eventually they can be used as prognosis markers. In addition to plasma biomarkers, the analysis of some surface markers on circulating leukocytes or the study of mRNA and miRNA can be helpful. While there is no magic marker, a combination of few biomarkers might offer a high accuracy for diagnosis.
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Affiliation(s)
- Marianna Parlato
- Unit of Cytokines and Inflammation, Institut Pasteur, 28 rue du Dr Roux, 75724, Paris Cedex 15, France
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Larráyoz IM, Martínez-Herrero S, García-Sanmartín J, Ochoa-Callejero L, Martínez A. Adrenomedullin and tumour microenvironment. J Transl Med 2014; 12:339. [PMID: 25475159 PMCID: PMC4272513 DOI: 10.1186/s12967-014-0339-2] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Accepted: 11/21/2014] [Indexed: 01/03/2023] Open
Abstract
Adrenomedullin (AM) is a regulatory peptide whose involvement in tumour progression is becoming more relevant with recent studies. AM is produced and secreted by the tumour cells but also by numerous stromal cells including macrophages, mast cells, endothelial cells, and vascular smooth muscle cells. Most cancer patients present high levels of circulating AM and in some cases these higher levels correlate with a worst prognosis. In some cases it has been shown that the high AM levels return to normal following surgical removal of the tumour, thus indicating the tumour as the source of this excessive production of AM. Expression of this peptide is a good investment for the tumour cell since AM acts as an autocrine/paracrine growth factor, prevents apoptosis-mediated cell death, increases tumour cell motility and metastasis, induces angiogenesis, and blocks immunosurveillance by inhibiting the immune system. In addition, AM expression gets rapidly activated by hypoxia through a HIF-1α mediated mechanism, thus characterizing AM as a major survival factor for tumour cells. Accordingly, a number of studies have shown that inhibition of this peptide or its receptors results in a significant reduction in tumour progression. In conclusion, AM is a great target for drug development and new drugs interfering with this system are being developed.
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Affiliation(s)
- Ignacio M Larráyoz
- Oncology Area, Center for Biomedical Research of La Rioja CIBIR, C/Piqueras 98, Logroño, 26006, Spain.
| | - Sonia Martínez-Herrero
- Oncology Area, Center for Biomedical Research of La Rioja CIBIR, C/Piqueras 98, Logroño, 26006, Spain.
| | - Josune García-Sanmartín
- Oncology Area, Center for Biomedical Research of La Rioja CIBIR, C/Piqueras 98, Logroño, 26006, Spain.
| | - Laura Ochoa-Callejero
- Oncology Area, Center for Biomedical Research of La Rioja CIBIR, C/Piqueras 98, Logroño, 26006, Spain.
| | - Alfredo Martínez
- Oncology Area, Center for Biomedical Research of La Rioja CIBIR, C/Piqueras 98, Logroño, 26006, Spain.
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Chen YX, Li CS. Arterial lactate improves the prognostic performance of severity score systems in septic patients in the ED. Am J Emerg Med 2014; 32:982-6. [PMID: 25059886 DOI: 10.1016/j.ajem.2014.05.025] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Revised: 05/19/2014] [Accepted: 05/19/2014] [Indexed: 10/25/2022] Open
Abstract
OBJECTIVE To evaluate the prognostic performance of lactate in septic patients in the emergency department (ED) and investigate how to add lactate to the traditional score systems. METHODS This was a single-centered, prospective, observational cohort study conducted in ED of Beijing Chao-Yang Hospital. The study enrolled adult septic patients admitted to the ED. Arterial lactate was measured in every patient. Acute Physiology and Chronic Health Evaluation (APACHE) II, Sequential Organ Failure Assessment (SOFA), and Mortality in Emergency Department Sepsis (MEDS) scores were calculated on ED arrival. The primary outcome was 28-day mortality. RESULTS The average levels of lactate, MEDS, APACHE II, and SOFA were much higher in nonsurvivors than in survivors (P < .001), and they were the independent predictors of 28-day mortality. Area under receiver operating characteristic (AUC) curves of MEDS, APACHE II, SOFA, and lactate were 0.74, 0.74, 0.75, and 0.79, respectively. The AUCs of combination lactate and MEDS, APACHE II, and SOFA were 0.81, 0.81, and 0.82, respectively and were much higher than that of score systems alone (P < .05). The AUCs of modified MEDS, APACHE II, and SOFA were 0.80, 0.80, and 0.81, respectively. The prognostic value of the modified score systems was superior to the original score systems and similar to the combination of the lactate and original score systems. CONCLUSIONS Lactate is a prognostic predictor in septic patients in the ED, and it may improve the performance of APACHE II, SOFA, and MEDS scores in predicting mortality.
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Affiliation(s)
- Yun-Xia Chen
- Emergency Department of Beijing Chao-Yang Hospital, Affiliated to Capital Medical University, Chaoyang District, Beijing 100020, China.
| | - Chun-Sheng Li
- Emergency Department of Beijing Chao-Yang Hospital, Affiliated to Capital Medical University, Chaoyang District, Beijing 100020, China.
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