Plasma concentrations of copeptin, C-reactive protein and procalcitonin are positively correlated with APACHE II scores in patients with sepsis

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1 Research Report Plasma concentrations of copeptin, C-reactive protein and procalcitonin are positively correlated with APACHE II scores in patients with sepsis Journal of International Medical Research 2015, Vol. 43(2) ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalspermissions.nav DOI: / imr.sagepub.com Li Jiang, Bing Feng, Dongna Gao and Yu Zhang Abstract Objective: To evaluate the correlation between Acute Physiology and Chronic Health Evaluation II (APACHE II) score and plasma concentrations of copeptin, C-reactive protein (CRP) and procalcitonin in patients with sepsis. Methods: Patients with sepsis were prospectively enrolled. APACHE II scores were determined during the first 24 h after admission to the intensive care unit. Plasma copeptin, CRP and procalcitonin were quantified at admission, 24 h, 48 h, and 72 h. Survival at 28 days after admission was recorded. Results: APACHE II score was significantly positively correlated with plasma copeptin, CRP and procalcitonin concentrations. Survivors (n ¼ 15) had significantly lower APACHE II scores and copeptin, CRP and procalcitonin concentrations than nonsurvivors (n ¼ 26). APACHE II score, copeptin at 72 h, CRP at 48 h and procalcitonin at 24 h were independent risk factors for death. Conclusion: Plasma copeptin, CRP and procalcitonin concentrations were positively correlated with APACHE II score in patients with sepsis, and reflected disease severity. Keywords Sepsis, APACHE II, copeptin, C-reactive protein, procalcitonin Date received: 14 July 2014; accepted: 2 November 2014 Introduction Sepsis has a mortality rate of 25% 1 globally and its clinical management presents an important medical challenge. The rapid progression of sepsis requires correspondingly swift adjustments in therapy, and accurate evaluation of disease severity is Emergency Department, The first affiliated Hospital of DaLian Medical University, DaLian, China Corresponding author: Li Jiang, Emergency Department, The first affiliated Hospital of DaLian Medical University, 222 Zhongshan Road, XiGang District, DaLian, China. fangrong928@163.com Creative Commons CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License ( which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (

2 Jiang et al. 189 therefore important for predicting prognosis, preventing complications and reducing mortality. The Acute Physiology and Chronic Health Evaluation II (APACHE II) is the standard method for evaluating sepsis, 2 but other diagnostic and prognostic biomarkers are being investigated. Copeptin, a short peptide derived from a preprohormone consisting of vasopressin, neurophysin II and copeptin, is one possible sepsis biomarker. Vasopressin is released on exposure to stress such as severe infection and sepsis, but its small molecular size and short half-life make detection impractical. 3 Copeptin is a useful surrogate for vasopressin because it is stable in plasma and is released in similar quantities. 4 Plasma copeptin concentrations were found to be significantly higher in patients with septic shock than in healthy control subjects ( pmol/l vs pmol/l). 5 C-reactive protein (CRP) is an acutephase protein synthesized by the liver in response to inflammation. Normal plasma CRP concentrations (<8 mg/l) rise significantly during the early phase of sepsis. 6 Procalcitonin is a 116 amino acid precursor of calcitonin. Plasma procalcitonin concentrations are below the limits of detection in healthy individuals (0.5 ng/ml), and can rise to 1000 ng/ml in severe bacterial infection or sepsis. 7 Procalcitonin has a half-life of h in the blood, 8 and concentrations are correlated with severity of sepsis in patients in the intensive care unit (ICU). 9 The aim of this study was to determine plasma concentrations of copeptin, CRP and procalcitonin in patients with sepsis, and evaluate their correlations with APACHE II scores. The diagnostic and prognostic value of these biomarkers is discussed. Patients and methods Study population This prospective study included patients with sepsis who were treated in the ICU of Dalian Medical University First Hospital, Dalian, Liaoning, China between May 2012 and December Sepsis was diagnosed according to guidelines of the Surviving Sepsis Campaign Exclusion criteria were: (i) cardiovascular disease (e.g. acute coronary syndrome, rheumatic heart disease, congenital heart disease); (ii) multiple trauma with injury severity score >15; (iii) heart failure; (iv) death within 72 h of admission; (v) incomplete clinical data. This study was approved by the ethics committee of DaLian Medical University First Hospital, and written informed consent was obtained from each patient or their next-of-kin. Data collection Venous blood (10 ml) was collected on admission to ICU, and at 24 h, 48 h and 72 h after admission. Uncoagulated blood was centrifuged at 2500 g for 15 min at 4 C and the resulting plasma was analysed. Copeptin, CRP and procalcitonin were quantified using enzyme linked immunosorbent assay kits (Phoenix Pharmaceuticals, Burlingame, CA, USA; Roche, Basel, Switzerland; and BRAHMS Diagostica GmbH, Germany, respectively), according to the manufacturers instructions. APACHE II scores were assigned, based on the most pessimistic clinical and laboratory data obtained during the first 24 h following admission. Patients were followed-up for 28 days after admission, and the 28-day mortality rate was calculated. Statistical analyses Continuous data were expressed as mean SD and compared using Kruskal Wallis or Mann Whitney U-test. Categorical data were expressed as n (%) and compared using 2 -test. Spearman s rank correlation coefficient was used to evaluate associations between APACHE II score and plasma concentrations of copeptin, CRP

3 190 Journal of International Medical Research 43(2) and procalcitonin. Prognostic factors were analysed using multivariate logistic regression analysis. Receiver operating characteristic (ROC) curves of copeptin, CRP and procalcitonin were generated and the area under the curve (AUC) was calculated. All statistical analyses were performed using SPSS Õ version 17.0 (SPSS Inc., Chicago, IL, USA) for Windows Õ. P-values <0.05 were considered statistically significant. Results The study included 41 patients (25 male/16 female; mean age years, range years). Mortality rates were 11.1% (1/9), 62.5% (5/8), and 83.3% (20/24) for patients with APACHE II scores 15, 15 to 25, and 25, respectively (P < 0.05). The mean APACHE II score was significantly higher in patients who died within 28 days of admission (n ¼ 26) compared with survivors (n ¼ 15; vs ; P < 0.01). There were significant positive correlations between APACHE II score and plasma copeptin, CRP and procalcitonin concentrations at all timepoints (Table 1). Data regarding plasma concentrations of copeptin, CRP and procalcitonin in patients stratified according to APACHE II scores are given in Table 2. Concentrations of copeptin and procalcitonin were significantly higher in patients with APACHE II scores 25 than those with scores <25 (15 or 15 25) at all timepoints (P < 0.05 for each comparison). CRP concentrations were significantly higher in patients with APACHE II scores 25 than those with scores <25 (15 or 15 25) at 24 h, 48 h and 72 h after admission (P < 0.05 for each comparison). Plasma concentrations of copeptin, CRP and procalcitonin were significantly higher in patients who died within 28 days of admission compared with survivors (P < 0.05, Table 3). Significant risk factors for death in patients with sepsis were APACHE II score (odds ratio [OR] 1.09, 95% confidence intervals [CI] 1.054, 1.128), copeptin at 72 h (OR 1.508, 95% CI 1.161, 1.958), CRP at 48 h (OR 1.009, 95% CI 1.003, 1.015), and procalcitonin at 24 h (OR 1.085, 95% CI 1.036, 1.108). The AUC of the ROC curves were 0.951, and for copeptin at 72 h, procalcitonin at 24 h and CRP at 48 h, respectively (P < 0.05; Figure 1). Discussion Plasma copeptin, CRP and procalcitonin concentrations were positively correlated with APACHE II score in patients with sepsis, in the present study. These three Table 1. Correlations between Acute Physiology and Chronic Health Evaluation II (APACHE II) 2 score and plasma concentrations of copeptin, CRP and procalcitonin in patients with sepsis (n ¼ 41). Time after admission to ICU, h Parameter r P r P r P r P Copeptin < < < <0.01 CRP < < < <0.01 Procalcitonin < < < <0.01 Spearman s rank correlation coefficient analysis. ICU, intensive care unit.

4 Jiang et al. 191 Table 2. Plasma concentrations of copeptin, C-reactive protein and prolactin in patients with sepsis, stratified according to Acute Physiology and Chronic Health Evaluation II (APACHE II) 2 score. APACHE II score Parameter 15 n¼ n¼8 >25 n¼24 Plasma copeptin, ng/ml Admission to ICU a,b 24 h a,b 48 h a,b 72 h a,b Plasma C-reactive protein, mg/l Admission to ICU h a,b 48 h a a,b 72 h a,b Plasma prolactin, ng/ml Admission to ICU a,b 24 h a,b 48 h a,b 72 h a,b Data presented as meansd. a P < 0.05 vs APACHE II score 15 at same timepoint; b P < 0.05 vs APACHE II score at same timepoint; Kruskal Wallis or Mann Whitney U-test. ICU, intensive care unit. biomarkers reflected disease severity and could be used to predict outcome. Vasopressin is released by the hypothalamic pituitary adrenal axis that also produces adrenocorticotropic hormone and cortisol. Serum cortisol concentrations have been shown to reflect an individual s stress levels and can be used to predict the outcome of patients with sepsis or pneumonia. 11 Copeptin concentrations provide a more accurate reflection of stress severity than cortisol levels. 12 Copeptin concentration can independently predict the survival of critically ill patients with haemorrhagic and septic shock, 13 and is significantly elevated in patients with lower respiratory tract infections compared with healthy controls. 14 Additionally, copeptin concentration has been shown to be associated with the severity of pneumonia, as based on a pneumonia severity index. Plasma copeptin concentrations increased significantly with higher APACHE II scores in the present study, reflecting the severity of sepsis. In addition, plasma copeptin concentrations were significantly higher in patients who died within 28 days of admission than in patients who survived. In accordance with previous findings, 8,13,15 18 our study showed that plasma copeptin could be used to evaluate the severity of sepsis. In addition, the present finding that elevated copeptin concentration at 72 h after admission was associated with increased mortality suggests that this parameter could be used to predict sepsis-related patient death. Elevated CRP concentrations represent an acute-phase response to acute tissue injuries such as those produced by surgery, infection or acute inflammation, and signify the body s attempt to neutralize the inflammatory agent and promote healing of the injured tissue. 18,19 Plasma CRP can

5 192 Journal of International Medical Research 43(2) Figure 1. Receiver operating characteristic curves for plasma concentrations of copeptin, procalcitonin (PTC) and C-reactive protein (CRP) in predicting survival of patients with sepsis. Times shown are after admission to intensive care unit reach 1000-fold normal concentrations during the acute-phase response, 20 and CRP has therefore been used to monitor disease activity in conditions including sepsis. Plasma CRP concentrations were positively correlated with APACHE II scores and reflected the severity of sepsis in the present study, in accordance with the findings of others. 21 Animal studies indicate that procalcitonin plays a pathophysiological role in the development of severe sepsis and is associated with mortality. Treatment with procalcitonin was shown to double the death rate in animals, 21 whereas injection with an antiprocalcitonin antibody increased the survival of animals with sepsis Procalcitonin is an accurate biomarker for severe infection, 25,26 and for the diagnosis of bacterial sepsis and bacteraemia. 27 Procalcitonin concentration has also been used to guide the empirical antibiotic treatment of sepsis patients, 28 and, in accordance with our findings, is known to reflect the severity of infection as well as having prognostic implications for critically ill patients. 29 An advantage of procalcitonin over other biomarkers is that its production is not significantly affected by nonsteroidal or steroidal anti-inflammatory drugs Our study has several limitations. The sample size was small and caution should be used when interpreting the results. In

6 Jiang et al. 193 Table 3. Plasma concentrations of copeptin, C-reactive protein and prolactin in patients with sepsis, stratified according to survival at 28 days after admission to intensive care unit (ICU). Parameter Survivors n¼15 Nonsurvivors n¼26 Statistical significance a Copeptin, ng/ml Admission to ICU P < h P < h P < h P < 0.05 C-reactive protein, mg/l Admission to ICU P < h P < h P < h P <0.05 Prolactin, ng/ml Admission to ICU P < h P < h P < h P <0.05 Data presented as meansd. a Kruskal Wallis or Mann Whitney U-test. addition, copeptin concentrations at 72 h after admission were a less-useful predictive factor for death compared with procalcitonin at 24 h, since patients may have already died by 72 h after admission. In conclusion, plasma copeptin, CRP and procalcitonin concentrations were positively correlated with APACHE II score in patients with sepsis, and therefore reflected disease severity. APACHE II score, copeptin concentration at 72 h, CRP concentration at 48 h and procalcitonin concentration at 24 h were independent risk factors for death in patients with sepsis. Declaration of conflicting interest The authors declare that there are no conflicts of interest. Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors. References 1. Linde-Zwirble WT and Angus DC. Severe sepsis epidemiology: sampling, selection, and society. Crit Care 2004; 8: Knaus WA, Draper EA, Wagner DP, et al. APACHE II: a severity of disease classification system. Crit Care Med 1985; 13: Katan M, Morgenthaler NG, Dixit KC, et al. Anterior and posterior pituitary function testing with simultaneous insulin tolerance test and a novel copeptin assay. J Clin Endocrinol Metab 2007; 92: Katan M and Christ-Crain M. The stress hormone copeptin: a new prognostic biomarker in acute illness. Swiss Med Wkly 2010; 140: w Jochberger S, Do rler J, Luckner G, et al. The vasopressin and copeptin response to infection, severe sepsis, and septic shock. Crit Care Med 2009; 37: Grigoras I, Branisteanu DD, Ungureanu D, et al. Early dynamics of leptin plasma level in surgical critically ill patients. a prospective comparative study. Chirurgia (Bucur) 2014; 109:

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