Copeptin combined with National Early Warning Score for predicting survival in elderly patients with acute and critical illness

Purpose Copeptin, reecting vasopressin release, as well as the National Early Warning Score (NEWS), reecting the severity of critical illness, might qualify for survival prediction in elderly patients with acute and critical illness. This prospective observational study aimed at assessing the predictive value of copeptin combined with NEWS on the prognosis of elderly patients with acute and critical illness. We analyzed serum copeptin levels and the NEWS at admission to the emergency department (ED) in a prospective, single-center and observational study comprising 205 elderly patients with acute and critical illness. Death within 30 days after admission to the ED was the primary end point. of elderly patients with acute and critical illness, comparing to either factor individually. signicantly copeptin levels to survivors. levels of copeptin ICU 30-day in our of copeptin as a short-term prognostic biomarker in copeptin signicantly in non-survivors as compared with survivors. Multivariate logistic regression analysis showed that copeptin an independent risk factor for 30-day mortality in patients with critical may be a clinically useful non-specic reecting severity


Introduction
Vasopressin, also known as arginine vasopressin (AVP) or anti-diuretic hormone (ADH), plays a key role in many physiologic and pathologic processes, such as hypovolemia, hypoxia, acidosis, and changes in plasma osmolality. Copeptin, a 39-aminoacid glycopeptide, is a C-terminal part of the precursor preprovasopressin (pre-proAVP), which secretes into the circulation from the posterior pituitary gland in equimolar amounts with vasopressin [1,2]. Vasopressin, which has a short half-life in blood, is bound to platelets to a great extent and biochemically instable. In contrast, copeptin is stable, easily measured and reliably mirrors biologically functionality of vasopressin in both healthy and acutely ill individuals [2][3][4][5].
In fact, accurate diagnosis could be delayed in elderly patients with acute and critical illness in emergency department (ED) because of atypical signs and symptoms, which make early evaluation important. Back in 2012, the UK Royal College of Physicians developed the National Early Warning Score (NEWS), which has become a common tool for predicting deterioration in the emergency patients, and commonly used internationally [12,13]. In this study, we observed whether copeptin combined with NEWS have a stronger predictive power on the prognosis of elderly patients with critical illness in ED, which was never reported previously.

Subjects and study design
We conducted a prospective observational study of consecutive patients admitted to the ED of a single academic tertiary hospital between January 2017 and November 2018. We included patients aged over 60 at admission to the ED who had NEWS of 5 points or more. The following patients were excluded: patients with immunode ciency or autoimmune diseases; pregnant women; patients with end-stage renal disease and end-stage liver disease; patients with advanced malignant tumor; family members of patients to give up for further treatment; patients who disagreed to join this study; patients with poor compliance; patients could not be followed up. The study was approved by the ethical review board at Beijing Hospital. A written informed consent was obtained from all participants.

Baseline assessment and follow-up
On admission to the ED, patients' demographic data, medical/medication history and vital signs were recorded, and the NEWS were calculated. A separate blood tube for copeptin analysis was included in the standardized laboratory panel, routinely collected within few minutes from ED admission. Routine laboratory tests include complete blood count, creatinine, urea nitrogen, aminotransferase, procalcitonin, cardiac troponin I and N-terminal pro-B-type natriuretic peptide.
Follow-up was performed for 30 days or until death, whichever occurred rst. Patients alive at day 30 were classi ed as survivors; all others were classi ed as non-survivors. No patient was lost to follow-up.

Copeptin measurements
Venous blood samples were collected at the time of admission, centrifuged, and serum samples were stored at − 80 °C. Copeptin concentrations were analyzed by enzyme-linked immunosorbent assay (ELISA) using commercial kits (Beijing Solarbio Science & Technology Co., Ltd, Beijing, China) in accordance with the manufactures' instructions.

Statistical analysis
Normally distributed continuous variables were described using mean ± standard deviation (SD), nonnormally distributed continuous variables as median and interquartile range (IQR). Categorical variables were described as frequency or percentage and tested by Chi-squared test. The relation of predictors with survival was investigated using logistic regression models. The prognostic values of copeptin, NEWS and copeptin combined with NEWS on the outcome were evaluated by (Receiver Operating Characteristic) ROC curve which compared by Z-test, and the Youden index was used to identify the optimal cut-off points for risk strati cation. The area under the ROC curve (AUC) values were reported with corresponding 95% (con dence intervals) CIs. All tests were 2-tailed; P 0.05 was de ned as signi cant. Data were analyzed using statistical softwares (SPSS, Ver. 23.0; MedCalc, Ver. 18.0).

Baseline characteristics
A total of 205 patients were included in the study, 128 patients with cardiovascular critical illness, 39 patients with respiratory critical illness, 26 patients with sepsis (except for severe pneumonia), 12 patients with other critical illness (including gastrointestinal bleeding, rhabdomyolysis, organophosphorus poisoning and anaphylactic shock). Within 30 days after admission, 159 patients (77.6%) alive at day 30 were classi ed as survivors, 46 patients (22.4%) were classi ed as non-survivors.
Baseline characteristics serum copeptin levels and the NEWS were compared between survivor group and non-survivor group ( Table 1). The serum copeptin levels and the NEWS in the non-survivor group were higher than those in the survivor group (30.35 (14.20, 38.91), 17.53 (13.01, 25.20), P = 0.001; 9.0 (7.0-10.0), 7.0 (6.0-8.0), P = 0.001)). Table 1 Clinical and demographic baseline characteristics of the study population 3.2 Copeptin, NEWS and copeptin combined with NEWS were all independent risk factors for 30-day mortality in elderly patients with critical illness Multivariate logistic regression analyses were performed using variables including copeptin, NEWS, MBP, ALT, AST, CRE, cTNI and NT-proBNP, showed that copeptin and NEWS were both independent predictors of 30-day survival in elderly patients with critical illness (Table 2). In further analysis, copeptin combined with NEWS was also an independent predictor of 30-day survival in elderly patients with critical illness.  (Fig. 1, Table 3). Using Z-test to compare the above three curves, copeptin combined with NEWS performed a higher predictive value for 30-day survival (P < 0.05) ( Table 4). The optimal cut-off values of copeptin and NEWS for Risk strati cation were calculated by Youden index, were 19.78 pg/ml and 8.5 points, respectively. Risk strati cation analyses showed that patients with higher copeptin levels and higher NEWS points had the highest risk of death (Fig. 2). Copeptin combined with NEWS have a stronger predictive power on the prognosis of elderly patients with critical illness.

Discussion
Hypothalamic-pituitary-adrenal (HPA) axis is an important part of the neuroendocrine system that responds to stressors which disrupt the homeostatic balance [14]. AVP is one of the key hormones of the HPA axis, and copeptin, a peptide consisting of 39 amino acids, is released together with AVP during processing of the precursor peptide [15,16]. In contrast to the biochemically instable AVP, which has a short half-life in blood and is bound to a great extent to platelets, copeptin is a stable protein in the circulation and reliably mirrors biologically functional vasopressin in both healthy and acutely ill patients [17][18][19][20].
Of note, the spectrum of diseases underlying non-speci c complaints is extremely broad in the ED. When the diagnosis is unclear, risk strati cation and early prognostication become challenging correspondingly, but are still of particularly importance. The Basel Non-speci c Complaints (BANC) study [21] was a delayed type cross-sectional diagnostic study with a prospective 30-day follow-up showed that sensitive risk strati cation tools were needed to identify whether the patients with nonspeci c complaints presenting to the ED had potentially adverse health outcomes.
Copeptin is triggered by many diseases, not limited to one single organ system. Its non-speci city, with respect to a precise diagnostic role, is its strength as a more generalized marker for acute critical illness [22]. In a prospective observational single-center study including 225 critically ill patients admitted to a medical ICU [23], non-survivors within 30 days after ICU admittance showed signi cantly higher circulating copeptin levels as compared to survivors. Circulating levels of copeptin at ICU admission independently predict 30-day mortality in patients admitted to a medical ICU. In our study, we con rmed the value of copeptin as a short-term prognostic biomarker in elderly patients with critical illness. The serum copeptin levels were signi cantly higher in non-survivors as compared with survivors. Multivariate logistic regression analysis showed that copeptin was an independent risk factor for 30-day mortality in elderly patients with critical illness. Therefore, copeptin may well be a clinically useful non-speci c prognostic marker re ecting disease severity and survival.
Back in 2012, the UK Royal College of Physicians developed the National Early Warning Score (NEWS), a simple and easy to use tool at the bedside, which has become a common tool for predicting deterioration in acute critical illness patients [12,13]. NEWS can be used to standardize the assessment of acuteillness severity not only when acute ill patients present to the hospital or as a surveil-lance system for all patients in hospitals, but potentially also in the pre-hospital assessment [24]. Through its use, clinical staff has a better indication whether a patient is more at risk, which make it possible to timely intervene and stabilize a patient before further deterioration occurs. Thus far the NEWS is the most sensitive Early Warning Score available [25].
A retrospective cohort study by Pirneskoski J et al. [26] including 35800 patients, showed that prehospital NEWS score had a good speci city and sensitivity for prediction of death within 1 day of emergency medical services dispatch. Another retrospective observational cohort study [27] with 81,520 consecutive ED patients concluded that the NEWS could predict in-hospital mortality within 24 h, 48 h, 7 days, and 30 days for patients arriving at the ED. In our study, median NEWS points were signi cantly higher in non-survivors as compared with survivors. Multivariate logistic regression analysis showed that NEWS was independent risk factors for 30-day mortality in elderly patients with critical illness. NEWS showed a good performance for predicting 30-day survival in elderly patients with critical illness, the same with copeptin.
As has been mentioned above, copeptin and NEWS both showed a good performance for predicting 30day survival in elderly patients with critical illness. However, it was never reported whether copeptin combined with NEWS have a stronger predictive power on the prognosis of elderly patients with critical illness comparting to both factors independently.
From our multivariate logistic regression analysis, copeptin combined with NEWS were also an independent risk factor for 30-day mortality in elderly patients with critical illness. In the further study, we concluded that copeptin combined with NEWS performed a much higher predictive value for 30-day survival using the Z test to compare the areas under the ROC curves. Importantly, we also calculated the optimal cut-off value of copeptin and NEWS using the Youden index. Risk strati cation analysis showed that the high-risk group with both higher copeptin levels and higher NEWS points had the highest risk of death. Therefore, our study concluded that copeptin combined with NEWS have a stronger predictive power on the prognosis of elderly patients with critical illness.

Conclusions
Copeptin combined with NEWS have a stronger predictive power on the prognosis of elderly patients with critical illness.

Declarations
Ethics approval and consent to participate The study protocol was approved by Beijing Hospital Ethics Committee. A written informed legal consent to participate was obtained at the time of enrollment from all the patients, or from a family member if the patient was unable to provide consent due to his/her medical condition.

Consent for publication
Not applicable.

Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
This study was supported by Special Fund for Health Science Research (201002011). This funding source did not have any role in the design of this study and collection, analysis, and interpretation of data and in writing the manuscript.
Authors' contributions FW and XCZ designed the trial and obtained institutional approval and research funding. FW and WA supervised the conduct of the trial and data collection. WA undertook recruitment of patients and managed the data. FW, WA and XCZ provided statistical advice on study design and analyzed the data. FW drafted the manuscript, and all authors contributed substantially to its revision. All authors have read and approved the manuscript. Figure 1 The ROC curve of copeptin, NEWS and copeptin combined with NEWS