Article

Clinical relevance of copeptin plasma levels as a biomarker of disease severity and mortality in critically ill patients

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Abstract

Background Copeptin, also termed C‐terminal pre‐pro‐vasopressin or CTproAVP, mirrors endogenous vasopressin (anti‐diuretic hormone, ADH) activity and might thereby serve as a biomarker reflecting the biological stress level. We therefore hypothesized that copeptin plasma concentrations are associated with disease severity in critically ill patients and could predict mortality. Methods We analyzed plasma copeptin levels in a prospective, single‐center, observational study comprising 218 critically ill patients at admission to the medical intensive care unit (ICU). Mortality was assessed during a 2‐year observational follow‐up period. Results Copeptin plasma levels were significantly elevated in critically ill patients (n = 218) at ICU admission, as compared with 66 healthy controls. Neither sepsis as the cause of critical illness nor pre‐existing metabolic disorders (type 2 diabetes, obesity) were found to influence copeptin levels. On the contrary, plasma copeptin was closely associated with disease severity (eg APACHE‐II score) and correlated with biomarkers of inflammation, renal failure, metabolism, vascular tone, and tissue perfusion. Elevated copeptin levels at ICU admission predicted short‐term and long‐term mortality. Conclusions Copeptin plasma concentrations are significantly elevated in critically ill patients, correlate with disease severity and predict ICU and long‐term outcome. Thus, copeptin could be a promising tool for prognostication and management of critically ill patients.

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... More recently, with the development of a reliable copeptin assay [14], the C-terminal part of the AVP precursor has been used as a surrogate marker of circulating AVP in clinical practice [15][16][17][18]. Plasma copeptin levels are elevated in several acute clinical scenarios, both in the adult [19][20][21][22] and in the pediatric population [23][24][25]. Of note, plasma copeptin levels may predict disease severity in critically ill patients [20,26,27], posing the question whether AVP activation could also be associated with a pro-inflammatory state. ...
... Plasma copeptin levels are elevated in several acute clinical scenarios, both in the adult [19][20][21][22] and in the pediatric population [23][24][25]. Of note, plasma copeptin levels may predict disease severity in critically ill patients [20,26,27], posing the question whether AVP activation could also be associated with a pro-inflammatory state. Significant copeptin increment in response to the acute hypoglycemic stress has been well documented in adult healthy subjects, whereas the copeptin response to hypoglycemia in individuals with anterior and/or posterior pituitary hormone deficiencies was significantly reduced [28,29]. ...
... Both AVP and prolactin carry pro-inflammatory properties [50,56,57]. The interplay between the activation of the inflammatory system and AVP secretion in response to acute stress may partially explain the well described association between high copeptin levels and worse prognosis in critically ill patients [19,20,27]. In the current study we showed, for the first time, that acute hypoglycemia elicits an increase of IL-6 plasma levels in children and adolescents, which is in line with previous data in the adult population [58]. ...
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PurposeThe physiological role of arginine vasopressin (AVP) in the acute stress response in humans and especially in children is unclear. The aim of this study was to explore the interaction between copeptin, a well-established surrogate marker of AVP release, and anterior pituitary hormone activation in response to acute hypoglycemic stress in children and adolescents.Methods We conducted an exploratory single center study involving 77 children and adolescents undergoing insulin-induced hypoglycemia. Blood levels of copeptin, ACTH, cortisol, GH, prolactin, interleukin-6 (IL-6), adrenaline and noradrenaline were determined at baseline and after insulin-induced hypoglycemia.ResultsBasal plasma levels of copeptin (median: 5.2 pmol/L) increased significantly after hypoglycemia (median 9.7 pmol/L; P < 0.0001). Subjects with insufficient HPA axis response or severe GH deficiency had lower hypoglycemia-induced copeptin increase (median: 2.3 pmol/L) compared with individuals with intact pituitary response (median: 5.2 pmol/L, P = 0.02). Copeptin increase correlated significantly with the maximal increase of ACTH (rs = 0.30; P = 0.010), cortisol (rs = 0.33; P = 0.003), prolactin (rs = 0.25; P = 0.03), IL-6 (rs = 0.35; P = 0.008) and with BMI-SDS (rs = − 0.28, P = 0.01). In multivariate regression analysis, prolactin increase was the only independent variable associated with copeptin increase (P = 0.0004).Conclusion Our data indicate that: (1) hypoglycemic stress elicits a marked copeptin response in children and adolescents, pointing out its role as an acute stress marker in this population; (2) stress-induced AVP/copeptin release is associated with anterior pituitary activation, mainly a prolactin response.
... Jochberger et al. showed plasma concentrations of copeptin to be significantly higher in critically ill patients compared to healthy individuals [8]. Studies suggest that copeptin levels are related to higher mortality in critically ill patients [9]. In addition, an association between copeptin levels and the severity of critical illness is suggested, especially in patients with sepsis or hemorrhagic shock [10]. ...
... There is no single clear-cut pathophysiological explanation for stress-induced hyperglycemia in ICU patients as many inflammatory and hormonal factors seem to contribute, but our results suggest copeptin is not a part of it. In contrast to previous studies [9,[29][30][31][32], our results did not show an association between copeptin levels on ICU admission and mortality. However, we did find copeptin levels at ICU day 3 to be higher in survivors than in non-survivors, which suggests that a sustained increase in copeptin levels might be necessary to recover from acute stress, as well as from the higher catabolic demands of critical illness. ...
... One possible explanation for this difference is the severity of disease, since our sample included a heterogeneous population of very sick patients, as demonstrated by high SAPS 3 scores (Table 1). While our cohort had miscellaneous reasons for ICU admission, Koch et al. [9] included patients with or without sepsis, Ristagno et al. [30] restricted their population to survivors of out-of-hospital cardiac arrest, and Seligman et al. [31] studied patients with ventilator-associated pneumonia. This is reassured by the fact that copeptin at all time points (T1, T2 and T3) were higher in survivals when the subset of patients surveying until T3 were analyzed. ...
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Objectives: Copeptin, an equimolar indicator of serum antidiuretic hormone levels, has been associated with higher mortality in critically ill patients and with the development of diabetes in the general population. The aim of the present study was to investigate the association of copeptin levels with glycemic parameters in critically ill patients and to compare the time-course of copeptin in survivors and non-survivors. Design: Prospective cohort study. Patients: From June to October 2019, critically ill patients were prospectively enrolled and followed for 90 days. Measurements: Plasma copeptin levels were determined at intensive care unit (ICU) admission (copeptin T1), 24 h (copeptin T2), and 48 h (copeptin T3) after study entry. Blood glucose and glycated hemoglobin levels were measured. ICU, in-hospital, and 90-day mortality, and length of stay in the ICU and hospital were evaluated. Results: 104 patients were included. No significant correlation was detected between copeptin levels and blood glucose (r = -0.17, p = 0.09), HbA1c (r = 0.01, p = 0.9), glycemic gap (r = -0.16, p = 0.11), and stress hyperglycemia ratio (r = -0.14, p = 0.16). Copeptin T3 levels were significantly higher in survivors than in non-survivors at hospital discharge (561 [370-856] vs 300 [231-693] pg/mL, p = 0.015) and at 90 days (571 [380-884] vs 300 [232-698] pg/mL, p = 0.03). Conclusions: No significant correlations were found between copeptin levels and glycemic parameters, suggesting that copeptin is not a relevant factor in the induction of hyperglycemia during critical illness. Copeptin levels at ICU day 3 were higher in survivors than in non-survivors.
... 7 The prognostic and, in some cases, diagnostic value of copeptin has been documented in clinical conditions like sepsis and septic shock, 8 community-acquired and ventilator-associated pneumonia 9,10 and other critical illnesses. 11 Only one study has investigated the prognostic role of copeptin in COVID- 19, showing a significant association with all-cause 30-day mortality. 12 Mid-regional proadrenomedullin (MR-proADM) is one of the peptides released from pre-proadrenomedullin and commonly assessed as a surrogate marker of adrenomedullin. ...
... The median length of stay was 14 days (IQR [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. Twenty-one patients (18%) died during hospitalization, and 8 were transferred to ICU. ...
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Background: Biomarkers are used for diagnosis, risk stratification and medical decisions. Copeptin and mid-regional proadrenomedullin (MR-proADM) are markers of stress and endothelial function, respectively, which have been studied in pneumonia, sepsis and septic shock. This study aimed to assess whether copeptin and MR-proADM could predict coronavirus disease 2019 (COVID-19) in-hospital outcomes, that is multi-system complications, length of stay and mortality. Methods: Copeptin and MR-proADM were assessed at admission in 116 patients hospitalized with COVID-19. Data were retrospectively extracted from an online database. The primary endpoint was in-hospital mortality. The secondary endpoints were in-hospital complications, the composite outcome 'death, or admission to intensive care unit, or in-hospital complications', and length of stay. The predictive power was expressed as area under the receiver operator characteristic curve (AUROC). Results: Copeptin was increased in non-survivors (median 29.7 [interquartile range 13.0-106.2] pmol/L) compared to survivors (10.9 [5.9-25.3] pmol/L, p < 0.01). The AUROC for mortality was 0.71, with a hazard ratio of 3.67 (p < 0.01) for copeptin values > 25.3 pmol/L. MR-proADM differentiated survivors (0.8 [0.6-1.1] nmol/L) from non-survivors (1.5 [1.1-2.8] nmol/L, p < 0.001) and yielded a AUROC of 0.79 and a hazard ratio of 7.02 (p < 0.001) for MR-proADM values > 1.0 nmol/L. Copeptin and MR-proADM predicted sepsis (AUROC 0.95 and 0.96 respectively), acute kidney injury (0.87 and 0.90), the composite outcome (0.69 and 0.75) and length of stay (r = 0.42, p < 0.001, and r = 0.46, p < 0.001). Conclusions: Admission MR-proADM and copeptin may be implemented for early risk stratification in COVID-19-hospitalized patients to help identify those eligible for closer monitoring and care intensification.
... Several studies suggest that increased copeptin serum concentrations can be detected in chronic kidney disease and that its level may predict future development of chronic kidney failure in a population free from kidney disease at baseline [32,33]. A correlation between copeptin and creatinine levels was found also in severely-ill patients with acute kidney injury, even if evidence is still scarce [34]. Looking at our data, while we confirm that a weak but positive correlation exists even in our trauma cohort between these two biomarkers (Spearman's rho 0.297; 95%CI 0.129-0.450, ...
... Our data and studies in the literature suggest the increased copeptin and creatinine concentrations in adult trauma patients might share only some pathophysiological stimuli (e.g. hypoperfusion), while copeptin may possibly contribute to further development of acute kidney failure by enhancing endothelial dysfunction and increasing systemic vascular tone [34]. ...
Article
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Background: Early prognostication in trauma patients is challenging, but particularly important. We wanted to explore the ability of copeptin, the C-terminal fragment of arginine vasopressin, to identify major trauma, defined as Injury Severity Score (ISS) > 15, in a heterogeneous cohort of trauma patients and to compare its performances with lactate. We also evaluated copeptin performance in predicting other clinical outcomes: mortality, hospital admission, blood transfusion, emergency surgery, and Intensive Care Unit (ICU) admission. Methods: This single center, pragmatic, prospective observational study was conducted at Arcispedale Santa Maria Nuova, a level II trauma center in Reggio Emilia, Italy. Copeptin determination was obtained on Emergency Department (ED) arrival, together with venous lactate. Different outcomes were measured including ISS, Revised Trauma Score (RTS), hospital and ICU admission, blood transfusion, emergency surgery, and mortality. Results: One hundred and twenty five adult trauma patients admitted to the ED between June 2017 and March 2018. Copeptin showed a good ability to identify patients with ISS > 15 (AUC 0.819). Similar good performances were recorded also in predicting other outcomes. Copeptin was significantly superior to lactate in identifying patients with ISS > 15 (P 0.0015), and in predicting hospital admission (P 0.0002) and blood transfusion (P 0.016). Comparable results were observed in a subgroup of patients with RTS 7.84. Conclusions: In a heterogeneous group of trauma patients, a single copeptin determination at the time of ED admission proved to be an accurate biomarker, statistically superior to lactate for the identification of major trauma, hospital admission, and blood transfusion, while no statistical difference was observed for ICU admission and emergency surgery. These results, if confirmed, may support a role for copeptin during early management of trauma patients.
... In the critical care setting, a prospective, observational study of 218 patients showed that high copeptin concentrations on admission to ICU was a predictor of short and long-term mortality. 32 Inflammatory cytokines, key mediators of the stress response, such as IL-1, TNF-α stimulate vasopressin secretion and plasma copeptin is elevated in sepsis compared to patients with infections without systemic inflammation. 33 Further supporting this relationship is a prospective, observational study of 50 critically ill patients that found an association between elevated plasma copeptin levels and advanced vasodilatory shock due to sepsis or systemic inflammatory response syndrome. ...
Article
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Direct measurement of the nonapeptide vasopressin has been limited by analyte instability ex vivo and in vivo rapid degradation, low serum concentrations requiring a sensitive assay and inherent secretory pulsatility. Copeptin is a 39 amino acid glycopeptide cleavage product of vasopressin synthesis with high stability, providing a marker of vasopressin secretion. Copeptin measurement has applications in diagnosis of diabetes insipidus and other diseases with altered vasopressin secretion. This review summarises our current understanding of serum copeptin measurement in diabetes insipidus and possible future applications of copeptin assays. As vasopressin is a stress hormone, there is emerging evidence on the use of copeptin for diagnosis and prognostication of disorders such as syndrome of inappropriate anti-diuretic hormone secretion, diabetes mellitus, critical illness, stroke, cardiovascular disease, respiratory disease, renal disease and thermal stress. Copeptin concentration measurement is likely to improve the diagnostic reliability of diabetes insipidus and, as a marker of stress, may have diagnostic or prognostic utility in specific clinical circumstances. Further studies are needed to determine if goal-directed therapy using plasma copeptin concentrations may improve patient outcomes.
... N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a well-established diagnostic marker of heart failure [13] and an important predictor of mortality in patients with heart failure [13] or ACS [14]. Both NT-proBNP [15,16] and copeptin [17,18] have been found to predict mortality in critically ill patients admitted to a medical intensive care unit (ICU). ...
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Background: Early risk stratification applying cardiac biomarkers may prove useful in sudden cardiac arrest patients. We investigated the prognostic utility of early-on levels of high sensitivity cardiac troponin-T (hs-cTnT), copeptin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with out-of-hospital cardiac arrest (OHCA). Methods: We conducted a prospective observational unicenter study, including patients with OHCA of assumed cardiac origin from the southwestern part of Norway from 2007 until 2010. Blood samples for later measurements were drawn during cardiopulmonary resuscitation or at hospital admission. Results: A total of 114 patients were included, 37 patients with asystole and 77 patients with VF as first recorded heart rhythm. Forty-four patients (38.6 %) survived 30-day follow-up. Neither hs-cTnT (p = 0.49), nor copeptin (p = 0.39) differed between non-survivors and survivors, whereas NT-proBNP was higher in non-survivors (p < 0.001) and significantly associated with 30-days all-cause mortality in univariate analysis, with a hazard ratio (HR) for patients in the highest compared to the lowest quartile of 4.6 (95% confidence interval (CI), 2.1 – 10.1), p < 0.001. This association was no longer significant in multivariable analysis applying continuous values, [HR 0.96, (95% CI, 0.64 - 1.43), p = 0.84]. Similar results were obtained by dividing the population by survival at hospital admission, excluding non-ROSC patients on-scene [HR 0.93 (95% CI, 0.50 - 1.73), P = 0.83]. We also noted that NT-proBNP was significantly higher in asystole- as compared to VF-patients, p < 0.001. Conclusions: Early-on levels of hs-cTnT, copeptin and NT-proBNP did not provide independent prognostic information following OHCA. Prediction was unaffected by excluding on-scene non-ROSC patients in the multivariable analysis. Clinical Trial Registration: ClinicalTrials. gov, NCT02886273.
... Recently, in 2018, Koch et al. [40] reported significantly elevated plasma Cp levels in critically ill patients at ICU admission than control levels, and were closely associated with disease severity judged by APACHE-II score, correlated with biomarkers of inflammation and tissue perfusion and could predict short-term and long-term mortality, so concluded that Cp could be a promising tool for prognostication and management of critically ill patients. ...
... CoP is the C-terminal cleavage part of the precursor pre-proAVP and is co-released in an equimolar ratio to AVP, thus closely mirroring AVP secretion, without a specific physiological function of its own (i.e., analogous to C-peptide for insulin) (32,33). CoP has therefore emerged as a promising biomarker in several AVP-associated endocrine, cardiovascular, pulmonary, and renal disorders, as well as other acute medical stress states (e.g., sepsis) (30,(34)(35)(36)(37)(38). ...
Article
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Background Major depressive disorder (MDD) constitutes the leading cause of disability worldwide. Although efficacious antidepressant pharmacotherapies exist for MDD, only about 40–60% of the patients respond to initial treatment. However, there is still a lack of robustly established and applicable biomarkers for antidepressant response in everyday clinical practice.Objective This study targets the assessment of the vasopressin (AVP) surrogate marker Copeptin (CoP), as a potential peripheral hypothalamic-level biomarker of antidepressant treatment response in MDD.Methods We measured baseline and dynamic levels of plasma CoP along with plasma ACTH and cortisol (CORT) in drug-naive outpatients with MDD before and after overnight manipulation of the hypothalamic-pituitary-adrenal (HPA) axis [i.e., stimulation (metyrapone) and suppression (dexamethasone)] on three consecutive days and their association with treatment response to 4 weeks of escitalopram treatment.ResultsOur findings suggest significantly higher baseline and post-metyrapone plasma CoP levels in future non-responders, a statistically significant invert association between baseline CoP levels and probability of treatment response and a potential baseline plasma CoP cut-off level of above 2.9 pmol/L for future non-response screening. Baseline and dynamic plasma ACTH and CORT levels showed no association with treatment response.Conclusions This pilot study provide first evidence in humans that CoP may represent a novel, clinically easily applicable, endocrine biomarker of antidepressant response, based on a single-measurement, cut-off level. These findings, underline the role of the vasopressinergic system in the pathophysiology of MDD and may represent a significant new tool in the clinical and biological phenotyping of MDD enhancing individual-tailored therapies.
... N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a well-established diagnostic marker of heart failure [13] and an important predictor of mortality in patients with heart failure [13] or ACS [14]. Both NT-proBNP [15,16] and copeptin [17,18] have been found to predict mortality in critically ill patients admitted to a medical intensive care unit (ICU). ...
Preprint
Full-text available
Background Early risk stratification applying cardiac biomarkers may prove useful in sudden cardiac arrest patients. We investigated the prognostic utility of early-on levels of high sensitivity cardiac troponin-T (hs-cTnT), copeptin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with out-of-hospital cardiac arrest (OHCA). Methods We conducted a prospective observational unicenter study, including patients with OHCA of assumed cardiac origin from the southwestern part of Norway from 2007 until 2010. Blood samples for later measurements were drawn during cardiopulmonary resuscitation or at hospital admission. Results A total of 114 patients were included, 37 patients with asystole and 77 patients with VF as first recorded heart rhythm. Forty-four patients (38.6%) survived 30-day follow-up. Neither hs-cTnT (p = 0.49), nor copeptin (p = 0.39) differed between non-survivors and survivors, whereas NT-proBNP was higher in non-survivors and significantly associated with time to death, with a hazard ratio (HR) for patients in the highest compared to the lowest quartile of 4.6 (95% CI 2.1–10.1), p < 0.001. This association was attenuated in the multivariable analysis [HR 2.18 (95% CI 0.83–5.72)], p = 0.11. NT-proBNP was significantly higher in asystole- as compared to VF-patients, p < 0.001. Conclusions In OHCA, NT-proBNP was significantly associated with 30-day survival in univariate analysis, but associations were attenuated after multivariable adjustment. Hs-cTnT and copeptin did not provide prognostic information following OHCA. Clinical Trial Registration ClinicalTrials. gov, NCT02886273.
... N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a well-established diagnostic marker of heart failure [13] and an important predictor of mortality in patients with heart failure [13] or ACS [14]. Both NT-proBNP [15,16] and copeptin [17,18] have been found to predict mortality in critically ill patients admitted to a medical intensive care unit (ICU). ...
Preprint
Full-text available
Background: Early risk stratification applying cardiac biomarkers may prove useful in sudden cardiac arrest patients. We investigated the prognostic utility of early-on levels of high sensitivity cardiac troponin-T (hs-cTnT), copeptin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with out-of-hospital cardiac arrest (OHCA). Methods: We conducted a prospective observational unicenter study, including patients with OHCA of assumed cardiac origin from the Southwestern part of Norway from 2007 until 2010. Blood samples for later measurements were drawn during cardiopulmonary resuscitation or at hospital admission. Results: A total of 114 patients were included, 37 patients with asystole and 77 patients with VF as first recorded heart rhythm. Forty-four patients (38.6%) survived 30-day follow-up. Neither hs-cTnT (p = 0.49), nor copeptin (p = 0.39) differed between non-survivors and survivors, whereas NT-proBNP was higher in non-survivors and significantly associated with time to death, with a hazard ratio (HR) for patients in the highest compared to the lowest quartile of 4.6 (95% CI 2.1 – 10.1), p < 0.001. This association was attenuated in the multivariable analysis [HR 2.18 (95% CI 0.83 – 5.72)], p = 0.11. NT-proBNP was significantly higher in asystole- as compared to VF-patients, p < 0.001. Conclusions: In OHCA, NT-proBNP was significantly associated with 30-day survival in univariate analysis, but associations were attenuated after multivariable adjustment. Hs-cTnT and copeptin did not provide prognostic information following OHCA. Clinical Trial Registration: ClinicalTrials. gov, NCT02886273.
... N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a well-established diagnostic marker of heart failure [13] and an important predictor of mortality in patients with heart failure [13] or ACS [14]. Both NT-proBNP [15,16] and copeptin [17,18] have been found to predict mortality in critically ill patients admitted to a medical intensive care unit (ICU). ...
Article
Full-text available
Background: Early risk stratification applying cardiac biomarkers may prove useful in sudden cardiac arrest patients. We investigated the prognostic utility of early-on levels of high sensitivity cardiac troponin-T (hs-cTnT), copeptin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with out-of-hospital cardiac arrest (OHCA). Methods: We conducted a prospective observational unicenter study, including patients with OHCA of assumed cardiac origin from the southwestern part of Norway from 2007 until 2010. Blood samples for later measurements were drawn during cardiopulmonary resuscitation or at hospital admission. Results: A total of 114 patients were included, 37 patients with asystole and 77 patients with VF as first recorded heart rhythm. Forty-four patients (38.6%) survived 30-day follow-up. Neither hs-cTnT (p = 0.49), nor copeptin (p = 0.39) differed between non-survivors and survivors, whereas NT-proBNP was higher in non-survivors (p < 0.001) and significantly associated with 30-days all-cause mortality in univariate analysis, with a hazard ratio (HR) for patients in the highest compared to the lowest quartile of 4.6 (95% confidence interval (CI), 2.1-10.1), p < 0.001. This association was no longer significant in multivariable analysis applying continuous values, [HR 0.96, (95% CI, 0.64-1.43), p = 0.84]. Similar results were obtained by dividing the population by survival at hospital admission, excluding non-return of spontaneous circulation (ROSC) patients on scene [HR 0.93 (95% CI, 0.50-1.73), P = 0.83]. We also noted that NT-proBNP was significantly higher in asystole- as compared to VF-patients, p < 0.001. Conclusions: Early-on levels of hs-cTnT, copeptin and NT-proBNP did not provide independent prognostic information following OHCA. Prediction was unaffected by excluding on-scene non-ROSC patients in the multivariable analysis. Trial registration: ClinicalTrials. gov, NCT02886273 .
... The DeLong method was used to compare AUCs [27]. The Youden index (the sum of sensitivity and specificity minus one) was used to calculate optimum cut-offs [28]. Statistical analyses were carried out with SPSS version 23 (SPSS, Chicago, IL, USA), and MedCalc version 19 was used for DeLong testing (MedCalc Software, Ostend, Belgium). ...
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Adrenomedullin (ADM) is a peptide with pleiotropic effects in systemic inflammation. Its more stable precursor protein midregional proadrenomedullin (MRproADM) can be measured more reliably compared to ADM. Our objective was to investigate the potential role of MRproADM as a diagnostic and prognostic biomarker in critically ill patients at the intensive care unit (ICU). We therefore measured MRproADM in 203 ICU patients and 66 healthy controls. We found that MRproADM levels are significantly increased in critically ill patients as compared to healthy controls. MRproADM levels are significantly increased in patients with sepsis, but its diagnostic value for identifying sepsis is numerically lower than that of established markers (e.g., interleukin-6, C-reactive protein, and procalcitonin). MRproADM levels are closely correlated to endothelial and organ dysfunction, inflammation, and established clinical scores (APACHE II, SOFA, and SAPS2). MRproADM concentrations correlate with vasopressor use but not fluid balance. Increased MRproADM levels (cut - off > 1.4 nmol/L) in critically ill patients are independent predictors of ICU and overall mortality during a follow-up of up to 26 months (OR 3.15 for ICU mortality, 95% CI 1.08-9.20, p = 0.036; OR for overall mortality 2.4, 95% CI 1.12-5.34, p = 0.026). Our study demonstrates the potential of MRproADM serum levels as a prognostic biomarker in critical illness for ICU mortality and long-term survival during follow-up.
... The COVID-19-induced lung injury may affect the cardiopulmonary hemodynamics and left atrial underfilling with subsequent activation of renin-angiotensin-aldosterone system and AVP/copeptin release. This could happen from either the direct viral-induced injury or the cytokines storm-induced injury [19,[25][26][27]. ...
Article
Aim: To investigate the change in a serum level of copeptin, a neuroendocrine biomarker, in differentiating grades of COVID-19 severity on admission time and to find its diagnostic potential. Materials & Methods: 160 COVID-19 patients were classified according to disease severity into 80 mild to moderate and 80 severe patients. Serum copeptin level was assessed by ELISA on their admission time. Besides, serum CRP, ferritin and D-dimer were estimated. Results: Severe COVID-19 patients showed higher serum copeptin level in comparison to mild to moderate cases, with diagnostic potential to distinguish disease severity with 93.33% sensitivity and 100% specificity at cut-off value >18.5 Pmol/l. Conclusion: Serum copeptin was remarkably increased with COVID-19 severity with reasonable differentiation potential for recently admitted patients.
... This is in part due to altered vascular permeability and hypoalbuminemia, both of which contribute to increased leak of fluid from the intravascular to the interstitial space. Additionally, critically ill patients frequently experience increased ADH secretion, resulting in fluid retention (101). In human patients with sepsis, net positive fluid balance is common and each 1L of cumulative fluids at 72 h of hospitalization has been associated with an increased odds of mortality (102). ...
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Sepsis is currently defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis may occur secondary to infection anywhere in the body, and its pathogenesis is complex and not yet fully understood. Variations in the host immune response result in diverse clinical manifestations, which complicates clinical recognition and fluid therapy both in humans and veterinary species. Septic shock is a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone. Although septic shock is a form of distributive shock, septic patients frequently present with hypovolemic and cardiogenic shock as well, further complicating fluid therapy decisions. The goals of this review are to discuss the clinical recognition of sepsis in dogs and cats, the basic mechanisms of its pathogenesis as it affects hemodynamic function, and considerations for fluid therapy. Important pathophysiologic changes, such as cellular interaction, microvascular alterations, damage to the endothelial glycocalyx, hypoalbuminemia, and immune paralysis will be also reviewed. The advantages and disadvantages of treatment with crystalloids, natural and synthetic colloids, and blood products will be discussed. Current recommendations for evaluating fluid responsiveness and the timing of vasopressor therapy will also be considered. Where available, the veterinary literature will be used to guide recommendations.
... The relationship between copeptin levels and renal failure is well known [23] and due to the Zn deficiency in dialysis patients [24]. Koch et al. conducted a large observational study, and they demonstrated that copeptin serum concentrations were associated with the inflammatory markers, metabolic disorders, and renal failure in critically ill patients [25]. In line with this, other studies have shown that increased concentrations of copeptin are related to renal insufficiency, and copeptin is inversely related to estimated glomerular filtration rate (eGFR) [22,26]. ...
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We aimed to investigate the association between zinc (Zn) supplementation and serum levels of copeptin, high-sensitive C-reactive protein (hs-CRP), glycemic control, anthropometric parameters and renal function in Zn -deficient diabetic hemodialysis patients (DHPs). This randomized, double-blind, placebo-controlled trial (RCT) was conducted on 46 DHPs with Zn-deficiency. The Zn supplement group (n = 21) received a 220-mg/day Zn sulfate capsule (containing 50 mg Zn), and the control group (n = 25) received a placebo capsule (220 mg corn starch), for 8 weeks. Fasting, predialysis blood samples were taken at baseline and after 8 weeks to assess fasting blood glucose (FBG), serum insulin, copeptin, high-sensitive C-reactive protein (hs-CRP), blood urea nitrogen (BUN), creatinine (Cr) concentrations, and homoeostatic model assessment (HOMA-IR) and quantitative insulin-sensitivity check index (QUICKI). Compared to controls, serum copeptin (P < 0.001), hs-CRP (P < 0.001), BUN (P < 0.001), Cr (P < 0.001), Zn (P < 0.001), FBG (P < 0.001) levels, BMI (P < 0.001), and body weight (P < 0.001) were significantly affected following ZnSO4 supplementation for 8 weeks. In contrast, QUICKI (P = 0.57), HOMA-IR (P = 0.60), and serum insulin (P = 0.55) were not affected following Zn supplementation in comparison with patients receiving placebo. Zn sulfate supplementation appears to have favorable effects on serum copeptin and hs-CRP, FBG, and renal function in Zn-deficient DHPs. Iranian Registry of Clinical Trials Identifier: IRCT20190806044461N1
... Due to the instability of vasopressin in human plasma and serum, copeptin, the C-terminal fragment of the vasopressin precursor, has emerged as a surrogate marker of vasopressin as it is released in equimolar amounts [7]. Copeptin has been reported to be of prognostic value in a variety of clinical conditions, including infectious and cardiovascular disease [8][9][10][11][12]. Since SARS-CoV-2 infection has been associated with myocardial injury, endothelial dysfunction and coagulopathy, we hypothesized that copeptin may add prognostic information in COVID-19 as an additional marker of cardiovascular disease [13]. ...
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BackgroundCOVID-19 has been associated with a high prevalence of myocardial injury and increased cardiovascular morbidity. Copeptin, a marker of vasopressin release, has been previously established as a risk marker in both infectious and cardiovascular disease.Methods This prospective, observational study of patients with laboratory-confirmed COVID-19 infection was conducted from June 6th to November 26th, 2020 in a tertiary care hospital. Copeptin and high-sensitive cardiac troponin I (hs-cTnI) levels on admission were collected and tested for their association with the primary composite endpoint of ICU admission or 28-day mortality.ResultsA total of 213 eligible patients with COVID-19 were included of whom 55 (25.8%) reached the primary endpoint. Median levels of copeptin and hs-cTnI at admission were significantly higher in patients with an adverse outcome (Copeptin 29.6 pmol/L, [IQR, 16.2–77.8] vs 17.2 pmol/L [IQR, 7.4–41.0] and hs-cTnI 22.8 ng/L [IQR, 11.5–97.5] vs 10.2 ng/L [5.5–23.1], P < 0.001 respectively). ROC analysis demonstrated an optimal cut-off of 19.3 pmol/L for copeptin and 16.8 ng/L for hs-cTnI and an increase of either biomarker was significantly associated with the primary endpoint. The combination of raised hs-cTnI and copeptin yielded a superior prognostic value to individual measurement of biomarkers and was a strong prognostic marker upon multivariable logistic regression analysis (OR 4.274 [95% CI, 1.995–9.154], P < 0.001). Addition of copeptin and hs-cTnI to established risk models improved C-statistics and net reclassification indices.Conclusion The combination of raised copeptin and hs-cTnI upon admission is an independent predictor of ICU admission or 28-day mortality in hospitalized patients with COVID-19.Graphical abstract
... • BNP > 500 ngL −1 consistent with the diagnosis of CHF [59]. • Values of ≈500ngL −1 reported in critically ill patients without diagnosis of cardiac complication [24,58] NT-proBNP Cardiomyocytes of the ventricles • NICE guidance recommends NT-pro-BNP for early rule out of NSTEMI [60] • NT-proBNP is considered the gold standard biomarker in HF diagnosis and management [61] and is recommended as part of diagnostic workup in the [73][74][75], and can rapidly identify left ventricular systolic dysfunction in sepsis patients [76] • MR-proANP is superior to BNP and pro-BNP in predicting death in CF patients [77] • It has shown strong prognostic utility in AIS, independently predicting post-stroke mortality and functional outcome [78] • It has shown diagnostic value for AHF in patients with acute dyspnoea [67] • In response to increased tension of the atrial wall, the active hormone ANP is secreted by splitting of its precursor into NT-proANP, and an active hormone ANP Copeptin • Useful in combination with cTn to safely and effectively ruleout AMI on admission with the first blood sample [80] • However, since the introduction of hs-cTn, copeptin has been shown to provide very little additive value [81] • Circulating levels of copeptin at ICU admission independently predict mortality in critically ill patients [82,83] • Copeptin levels correlate with markers of renal failure and metabolic disturbances in ICU patients [84] and correlate with severity of sepsis [85] and traumatic brain injury [86] • Copeptin assays are of extremely limited application diagnostically or prognostically for cardiac dysfunction [87] [85] Inflammatory markers IL-6 ...
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Purpose The significance of the validated biomarkers of sepsis Mid-regional pro-atrial natriuretic peptide (MR-proANP) and copeptin have not been tested in a burn injury setting. Materials and methods 42 consecutive patients were included in a prospective observational study. Daily blood specimens collected over the initial 20 days of treatment were quantitatively analysed by immunoluminometric sandwich assay (Kryptor, BRAHMS, Berlin, Germany) for MR-proANP, copeptin and procalcitonin (PCT). Results In patients with absence of sepsis, copeptin levels initially increased post-burn injury and thereafter rapidly declined. In contrast, MR-proANP was only slightly elevated within the first few days. MR-proANP [199.8 (115.6; 399.5) vs 160.1 (93.7; 280.6), P < .007] and PCT [1.12 (0.32; 2.22) vs 0.32 (0.16; 0.53), P < .001] levels were significantly higher on days of sepsis. Copeptin, however, showed no significant differences [20.7 (11.8; 42.2) vs 16.8 (11.0; 30.6), P = .11]. Both, MR-proANP and PCT level increases were noted upon the first day of sepsis. Conclusion Burn injury itself maybe associated with copeptin and to a lesser degree MR-proANP level increases. Subsequent increases in MR-proANP may be considered diagnostic for sepsis but demonstrated no advantages over PCT. The role of copeptin remains inappropriate for diagnosing sepsis after burn injury (ClinicalTrials.gov number, NCT01055587).
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Background Endothelin 1 (ET-1) is a strong vasoconstrictor, which is involved in inflammation and reduced tissue perfusion. C-terminal proendothelin-1 (CT-proET-1) is the stable circulating precursor protein of ET-1. We hypothesized that CT-proET-1, reflecting ET-1 activation, is involved in the pathogenesis of critical illness and associated with its prognosis. Methods Two hundred seventeen critically ill patients (144 with sepsis, 73 without sepsis) were included prospectively upon admission to the medical intensive care unit (ICU), in comparison to 65 healthy controls. CT-proET-1 serum concentrations were correlated with clinical data and extensive laboratory parameters. Overall survival was followed for up to 3 years. ResultsCT-proET-1 serum levels at admission were significantly increased in critically ill patients compared to controls. CT-proET-1 serum levels showed significant correlations to systemic inflammation as well as multiple markers of organ dysfunction (kidney, liver, heart). Patients with sepsis displayed higher circulating CT-proET-1 than ICU patients with non-septic diseases. CT-proET-1 levels >74 pmol/L at ICU admission independently predicted ICU death (adjusted hazard ratio (HR) 2.66, 95% confidence interval (CI) 1.30–5.47) and overall mortality during follow-up (adjusted HR 2.19, 95%-CI 1.21–3.98). ConclusionsCT-proET-1 serum concentrations at admission are increased in critically ill patients and associated with sepsis, disease severity, organ failure, and mortality.
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Objective: To characterize copeptin levels and to explore its prognostic importance in patients with acute myocardial infarction with newly detected glucose abnormalities. Methods: Copeptin was measured in 166 patients with acute myocardial infarction without known diabetes and in 168 age- and gender-matched controls. Participants were classified as having normal glucose tolerance or abnormal glucose tolerance (impaired glucose tolerance + type 2 diabetes mellitus) by oral glucose tolerance test. Study participants were followed over a decade for major cardiovascular event (acute myocardial infarction/stroke/congestive heart failure/cardiovascular death), cardiovascular and total death. Results: Median copeptin level was higher in patients (10.5 pmol/L) than controls (5.9 pmol/L; p < 0.01). Patients with abnormal glucose tolerance had higher copeptin (12.2 pmol/L) than those with normal glucose tolerance (7.9 pmol/L; p < 0.01) but levels of copeptin did not differ in controls with abnormal glucose tolerance or normal glucose tolerance. Copeptin predicted major cardiovascular events [ n = 64; hazard ratio = 1.15 (1.01-1.32; p = 0.04)], cardiovascular mortality [ n = 29; hazard ratio = 1.24 (1.06-1.46; p = 0.01)] and total death [ n = 51; hazard ratio = 1.21 (1.05-1.40; p = 0.01)] in unadjusted Cox regression analyses in the patient cohort. In controls, copeptin predicted major cardiovascular events [ n = 26; hazard ratio = 1.17 (1.01-1.36; p = 0.03)]. Conclusion: Copeptin levels are highest among acute myocardial infarction patients with glucose disturbances and predict an adverse prognosis in unadjusted analyses. These findings imply that raised copeptin reflects stress rather than acting as a pathogenic factor for glucose abnormalities.
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Arginine vasopressin (AVP) is a key regulator of water balance, but its instability makes reliable measurement difficult and precludes routine use. We present a method for quantifying AVP release by use of copeptin, a glycopeptide comprising the C-terminal part of the AVP prohormone. We measured copeptin in 50-microL serum and plasma samples from healthy individuals and from critically ill patients with sepsis. Our sandwich immunoluminometric assay used 2 polyclonal antibodies to amino acids 132-164 of pre-provasopressin. The assay yielded results within 3 h. The analytical detection limit was 1.7 pmol/L, and the interlaboratory CV was <20% for values >2.25 pmol/L. The assay was linear on dilution of the analyte. Ex vivo copeptin stability (<20% loss of analyte) for at least 7 days at room temperature and 14 days at 4 degrees C was shown for serum and EDTA-, heparin-, and citrate plasma. Copeptin (median, 4.2 pmol/L; range, 1-13.8 pmol/L) was detectable in 97.5% of 359 healthy individuals and was not associated with age. Median concentrations were considerably higher in men than women, increased significantly after exercise, and were influenced by fasting and water load. Copeptin was significantly (P <0.001) increased in 60 critically ill patients with sepsis (median, 79.5 pmol/L; range, 10.6-228.0 pmol/L). The correlation between copeptin and AVP for 110 samples was r = 0.78 (P <0.0001). Copeptin is stable for days after blood withdrawal and can be quickly and easily measured. The copeptin assay may be a useful alternative to direct measurement of AVP concentration.