Macce diagnostic method of patient having digestive tract surgery

Abstract

To provide a method of prognosis and diagnosis of major adverse cardiovascular and cerebrovascular events (MACCE) in a patient who has taken a major surgery of the digestive tract.SOLUTION: A method of prognosis and / or risk assessment and / or diagnosis of MACCE in a patient who has taken a digestive tract surgery includes: i) a step for providing a sample of body fluid from the patient; ii) a step for determining the level of a biomarker selected from a group comprising copeptin, troponin, and cerebral sodium diuretic peptide in the sample; iii) a step for determining at least one additional parameter of the patient; iv) a step for combining the biomarker level determined at step ii) and the additional parameter determined at step iii) and performing combination assessment; and v) a step for correlating the combination assessment with at least one of prognosis, risk assessment, and diagnosis of the MACCE in the patient.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a method for the prognosis and diagnosis of major adverse cardiovascular or cerebrovascular events (MACCE) in patients undergoing major gastrointestinal surgery. The present invention also relates to a kit for carrying out said method. [Background technology]

[0002] Globally, over 200 million adults aged 45 years or older undergo major noncardiac surgery each year [Alonso-Coello et al., Polskie Archiwum Medycyny Wewnetrznej.118(11),pp.616-618]. Of these, millions die from complications within 30 days [Botto et al., Anesthesiology,120(3),pp.564-578.doi:10.1097 / ALN.0000000000000113] and a significant proportion of patients suffer major cardiac complications during the first year after surgery [Ekeloef et al., British Journal of Anaesthesia,117(5),pp.559-568.doi:10.1093 / bja / aew321]. The main cause of postoperative mortality is cardiac complications due to ischemic insult to the myocardium causing cellular damage and uncontrolled cell death [Botto et al.,Anesthesiology,120(3),pp.564-578.doi:10.1097 / ALN.0000000000000113,Sessler and Khanna;Intensive Care Med(2018)44:811-822,https: / / doi.org / 10.1007 / s00134-018-5224-7,Landesberg et al.,Circulation,119(22),pp.2936-2944.doi:10.1161 / CIRCULATIONAHA.108.828228]. In addition to mortality, postoperative cardiac injury causes a significant number of postoperative complications, prolonging recovery and hospital stays, resulting in patient suffering and increased healthcare costs [Devereaux and Sessler, New England journal of medicine, p. 2258, 2015].

[0003] MACCE is the most common cause of serious perioperative morbidity and mortality, with incidence rates ranging from 1 to 7%, depending on the population studied. 10% of patients who develop MACCE die during hospitalization. Several independent preoperative and intraoperative risk factors for MACCE have been identified, including coronary artery disease, chronic congestive heart failure, intraoperative hypotension, and blood transfusion. These suggest that patients may be stratified according to their risk of MACCE. However, current risk stratification systems have limited sensitivity and specificity. Thus, further research is needed to identify better predictive models and risk stratification scores [Sabate et al., British Journal of Anaesthesia, p.879,2011].

[0004] Perioperative myocardial infarction (PMI) is a common cardiovascular complication and is associated with poor outcomes. 12% of patients with PMI die within 30 days, with the majority of deaths occurring within 48 hours [Hanson et al.,Catheterization and Cardiovascular Interventions,82(4),pp.622-628.doi:10.1002 / ccd.24626]. However, 58.2% of patients with ischemic myocardial injury do not meet the universal definition of myocardial infarction (MI), even though these cardiac injuries are independently associated with 30-day mortality [Botto et al., Anesthesiology, 120(3), pp. 564-578. doi:10.1097 / ALN.0000000000000113; Noordzij et al., British Journal of Anaesthesia, 114(6), pp. 909-918. doi:10.1093 / bja / aev027, 2015].

[0005] The third universal definition of MI is myocardial necrosis caused by prolonged ischemia and is a common cause of death and disability. This definition was established by the European Society of Cardiology, the American College of Cardiology Foundation, the American Heart Association, and the World Heart Federation. Two different mechanisms may cause MI, both of which are seen after non-cardiac surgery. Type I MI is caused by acute coronary syndrome (ACS). Myocardial blood flow is reduced due to rupture, ulceration, erosion, or detachment of unstable atherosclerotic plaques in one or more coronary vessels, followed by intraluminal thrombosis. Type II MI is caused by a long-term imbalance between myocardial oxygen supply and demand and may result from conditions such as cardiac arrhythmias, anemia, respiratory failure, hypotension, hypertension, or by direct toxic effects of high levels of endogenous or exogenous circulating cortisol and catecholamines [Landesberg et al., Circulation, 119(22), pp. 2936-2944. doi:10.1161 / CIRCULATIONAHA.108.828228, Thygesen et al., Circulation, 126(16), p.2020.doi:10.1161 / CIR.0b013e31826e1058].

[0006] The diagnostic criteria for MI consist of a new elevation of the cardiac biomarker troponin, three-fold above the upper level of the reference range in the background of suspicious myocardial ischemia accompanied by either ischemic symptoms or ischemic electrocardiogram (ECG) findings. At least 2-4 hours are required for myocardial cell necrosis due to ischemia, depending on, for example, collateral circulation to the ischemic area, myocyte susceptibility to ischemia, previous myocardial necrosis, and individual differences in coronary artery size and occlusion. These variations may also affect the ECG signs of ischemia, so the ECG should always be compared with a previous ECG, if available. Acute or ongoing ECG abnormalities may enable the clinician to identify the location of the infarction and the amount of myocardium at risk. The earliest symptoms of myocardial ischemia are typically T-wave and ST-segment changes. More severe shifts or inversions involving multiple leads / myocardial territories are associated with more severe myocardial ischemia and a worse prognosis. The ECG by itself is often insufficient to diagnose myocardial ischemia and infarction, as ischemic patterns can be caused by other conditions, such as ST deviations in acute pericarditis, left bundle branch block (LBBB), left ventricular hypertrophy (LVH), and abnormal Q waves, for example, in cardiac amyloidosis, acute cor pulmonale, and hyperkalemia [Thygesen et al., Circulation, 126(16), p. 2020. doi:10.1161 / CIR.0b013e31826e1058].

[0007] Ischemic symptoms of MI include various combinations of non-specific symptoms such as chest, upper limb, mandibular pain, and dyspnea. In many cases, symptoms last more than 20 minutes and are diffuse, not focal, positional, or influenced by motion. Patients with MI may also be asymptomatic, which is most common in women, elderly, diabetic, postoperative, and critically ill patients [Thygesen et al.,Circulation,126(16),p.2020.doi:10.1161 / CIR.0b013e31826e1058]. Most postoperative myocardial injury occurs within 48 hours after noncardiac surgery. A possible explanation for the lack of symptoms during this period is that patients are taking pain medications that usually mask the symptoms. This is thought to partially explain why 65% ​​of PMIs are asymptomatic [Devereaux and Sessler, New England journal of medicine, p. 2258, 2015; Devereaux et al., JAMA, 317(16), pp. 1642-1651. doi:10.1001 / jama.2017.4360, 2017].

[0008] Myocardial injury after noncardiac surgery (MINS) is an ischemic myocardial injury associated with adverse outcomes that occurs in 8% of surgical patients [Botto et al., Anesthesiology, 120(3), pp.564-578. doi:10.1097 / ALN.0000000000000113]. Ten percent of patients with MINS die within 30 days, and MINS patients have a higher 1-year and greater than 1-year mortality rate, as well as a higher incidence of nonfatal cardiac arrest, congestive heart failure, and stroke [Botto et al., Anesthesiology,120(3),pp.564-578.doi:10.1097 / ALN.0000000000000113; Mauermann et al.,Current Opinion in Anaesthesiology,29(3),pp.403-412.doi:10.1097 / ACO.0000000000000336]. Furthermore, local myocardial injury can cause myocardial stunning, leading to diastolic dysfunction and reduced cardiac output, resulting in reduced peripheral blood supply, impaired tissue healing, and increased risk of wound infection [Noordzij et al., British Journal of Anaesthesia, 114(6), pp. 909-918. doi:10.1093 / bja / aev027, 2015].

[0009] The diagnostic criterion for MINS is a postoperative troponin elevation determined to be due to myocardial ischemia (without evidence of a nonischemic etiology), with or without ischemic symptoms. MINS does not include perioperative myocardial injury resulting from etiologies other than ischemia, e.g., sepsis or pulmonary embolism. The postoperative threshold for MINS depends on the type of troponin assay. For fifth-generation cTnT, the threshold is >20 ng / L, an increase of at least 5 ng / L or >65 ng / L from baseline [Sessler and Khanna; Intensive Care Med (2018) 44: 811-822, https: / / doi.org / 10.1007 / s00134-018-5224-7]. The criteria for MINS cover a broader range of myocardial injury than MI, from reversible myocardial injury to necrosis. This broader concept includes several signs of myocardial injury, making MINS a more appropriate term for surgical patients and reducing the risk of underestimating the extent of myocardial damage seen after non-cardiac surgery [Mauermann et al., Current Opinion in Anaesthesiology, 29(3), pp. 403-412. doi:10.1097 / ACO.0000000000000336].

[0010] 93.6% of MINS cases occur within 3 days after surgery, and MINS patients have mild troponin elevations and often lack ischemic features [Noordzij et al.,British Journal of Anaesthesia,114(6),pp.909-918.doi:10.1093 / bja / aev027,2015]. 84% of patients with MINS do not experience ischemic symptoms, and only 34.9% show signs of ischemia on ECG [Botto et al.,Anesthesiology,120(3),pp.564-578.doi:10.1097 / ALN.0000000000000113]. These findings indicate that reliable diagnosis of perioperative myocardial injury is possible in most cases only by continuous postoperative troponin measurements. Alternatively, it has been reported that 93.1% of MINS and 68% of PMI may go undetected [Devereaux et al., JAMA, 317(16), pp. 1642-1651. doi:10.1001 / jama.2017.4360, 2017].

[0011] The mechanism of MINS remains unclear, but it has been suggested to be similar to that behind PMI [Mauermann et al.,Current Opinion in Anaesthesiology,29(3),pp.403-412.doi:10.1097 / ACO.0000000000000336]. Although several trials have been conducted to combat MINS, it remains unknown how to safely and efficiently prevent myocardial injury [Sessler and Khanna;Intensive Care Med(2018)44:811-822,https: / / doi.org / 10.1007 / s00134-018-5224-7]. As an example, the POISE study, a large randomized trial of perioperative and postoperative beta-blockers, reduced the incidence of major cardiovascular events by 30%, but at the same time increased the incidence of severe hypotension, stroke, and death [Devereaux et al., Lancet, 371(9627), pp.1839-1847. doi:10.1016 / S0140-6736(08)60601-7].

[0012] In addition, the development of infection after surgery is one of the major postoperative complications, causing pain, poor wound healing, the need for further treatment including antibiotics, prolonged hospital stay, and increased medical costs. Postoperative infections can cause serious problems including failure of the surgical procedure, sepsis, organ failure, and in some cases, ultimately death. Postoperative infection may be defined as any infection that occurs within 30 days of surgery and may be related to the surgery itself or the postoperative course. The incidence of postoperative infections can vary widely and depends on the type of procedure performed and the patient's specific risk factors for the development of infection. Postoperative infections may involve, for example, the wound itself, or deeper infections within the body cavity, or systemic infections, but may also include more distal infections such as pulmonary infections (e.g., pneumonia) or catheter-associated urinary tract infections.

[0013] Postoperative wound infections, also known as surgical site infections (SSIs), complicate the recovery process for many patients. As defined by the Centers for Disease Control and Prevention (CDC), these infections typically occur within 30 days of surgery at the site or portion of the body where surgery was performed. SSIs may be classified as superficial / incisional if limited to the skin and subcutaneous tissue, deep incisional if involving fascia and muscle, or organ space if involving a body cavity (e.g., the peritoneal cavity after gastrointestinal surgery; Horan et al., Am J Infect Control.; 36(5):309-332, 2008). Deep tissue and organ space SSIs are less frequent than superficial SSIs, but are associated with increased morbidity / mortality, readmission rates, prolonged length of stay, and overall hospital-related costs when compared to superficial SSIs. While the majority of SSIs are uncomplicated, others may be severe and more challenging, often requiring extensive surgical debridement, multiple reoperations, and may be life-threatening.

[0014] Postoperative infections can result from several factors in addition to infection at the surgical site. Postoperative pneumonia, and airway infections, for example, are generally considered signs of physiological and immunological disorders that occur after major surgery. Postoperative pulmonary infections are associated with cough, phlegm, shortness of breath, chest pain, temperature above 38°C, and pulse rates above 100 beats per minute. Up to half of people have asymptomatic chest signs after surgery, and up to a quarter may develop symptomatic disease. The incidence of postoperative pulmonary complications in major surgery ranges from less than 1% to 23%. Several studies have shown that pulmonary complications are more common than cardiac complications, and postoperative respiratory failure is a common postoperative complication (Miskovic at al., British Journal of Anaesthesia, 118(3):317-34, 2017).

[0015] Diagnosis of surgical site infections can be difficult because signs and symptoms are often nonspecific and may lack sensitivity in some clinical scenarios. However, early diagnosis of postoperative infections is crucial to initiating appropriate treatment, such as antibiotic therapy.

[0016] Particularly serious postoperative infections are associated with blood infections or sepsis. Despite significant improvements in diagnostic and preventive measures, the incidence of sepsis continues to grow rapidly in hospitalized patients (Martin et al. 2003), with mortality ranging from 10% to 54% depending on the disease severity level, the definition of organ dysfunction used, and country-specific incidence (Kaukonen et al. 2014., Vincent et al. 2006). For any postoperative disease, but especially for sepsis, early and accurate assessment of both the infection burden and disease severity in terms of the overall pathophysiological host response is crucial to make rapid and reliable decisions regarding diagnostic tests and treatment strategies.

[0017] Previous studies have investigated the use of biomarkers in predicting postoperative outcomes in patients. For example, it was possible to show a correlation between the expression of arginine vasopressin (AVP) and copeptin with the severity of systemic inflammatory response syndrome (SIRS) with and without shock in patients after noncardiac surgery [Jochberger et al., SHOCK, Vol. 31, No. 2, pp. 132-138, 2009]. Copeptin is even more highly elevated in SIRS patients after cardiac surgery [Jochberger et al., J Clin Endocrinol Metab 91: 4381-4386, 2006]. Another study showed that copeptin is increased in patients with inflammatory bowel disease (IBD) and further increased in IBD patients who underwent intestinal resection [Ohlsson and Melander, Drug Target Insights 2015: 9, 21-27 DOI: 10.4137 / DTI.S26589]. Copeptin, as a general stress biomarker, is known to be elevated in response to surgical trauma, but no differences were found between minimally invasive and conventional surgical techniques [Netto et al.,Acta Chirurgica Belgica,DOI:10.1080 / 00015458.2018.1482698,2018]. Preoperative copeptin and NT-proBNP levels have been investigated to improve risk stratification of patients undergoing major vascular surgery, showing that increased biomarker levels are predictive of outcome in this patient population [Jarai et al.,Am J Cardiol 2011;108:1188-1195,2011]. However, another study showed that copeptin lost its predictive quality for major adverse cardiac events when evaluating patients undergoing vascular surgery in the severe stage of chronic kidney disease (CKD) [Schrimpf et al.,PLoS ONE 10(4):e0123093.DOI:10.1371 / journal.pone.0123093,2015]. In summary, although there have been indications of a possible predictive value of biomarkers for postoperative patient health outcomes, there is no clear method allowing an objective assessment of the patient's situation.Therefore, there is a need for methods that allow rapid and early assessment of possible MACCE and MINS as well as postoperative infections in patients undergoing abdominal surgery, particularly gastrointestinal surgery, to reduce postoperative complications that prolong recovery and hospital stay and increase mortality. Summary of the Invention

[0018] It is therefore a primary object of the present invention to provide a method and kit that allows for the rapid and reliable diagnosis, prognosis and exclusion of MACCE and / or MINS and / or post-operative infections in patients undergoing major gastrointestinal surgery. Further objects will become apparent from the following description.

[0019] This object is achieved by a method and a kit according to the independent claims. Preferred embodiments are set forth in the respective dependent claims.

[0020] Specifically, the present invention relates to a method for at least one of prognosis, risk assessment, and diagnosis of major adverse cardiovascular or cerebrovascular events (MACCE) in patients undergoing major gastrointestinal surgery, the method comprising: i) providing a sample of bodily fluid from a patient; ii) determining in the sample the level of a biomarker selected from the group consisting of copeptin, troponin, and brain natriuretic peptide (BNP); iii) determining at least one additional parameter of the patient; iv) combining the biomarker levels determined in step ii) with the additional parameters determined in step iii) into a combined evaluation; and v) correlating the combination assessment with at least one of a prognosis, a risk assessment, and a diagnosis of MACCE in the patient.

[0021] In particular, the present invention relates to a method for the diagnosis of major adverse cardiovascular or cerebrovascular events (MACCE) in patients undergoing gastrointestinal surgery, step v) relates to correlating the combined evaluation with the presence or absence of MACCE in said patients. It is emphasized that the present invention relates to an in vitro method. The present invention is not performed on a human or animal body, but is separated from these bodies and is performed entirely in vitro. Thus, the step of providing a patient sample is not intended to be performed on either a human or animal body, but relates to providing an in vitro assay with the sample, for example by removing the sample from a refrigerator. The actual sample extraction from the human or animal body is not part of the method of the present invention. [Brief description of the drawings]

[0022] [Figure 1] Determined levels of the biomarkers copeptin (marked COP or COPAVP), cTnT (marked hsTnT for the high sensitivity assay used, see below), NT-proBNP, MR-proADM, CT-proET-1, and PCT are shown in a patient population at different sampling times, separated into patients who developed MACCE and those who did not. [Diagram 2] Determined levels of the biomarkers copeptin (marked COP or COPAVP), cTnT (marked hsTnT for the high sensitivity assay used, see below), NT-proBNP, MR-proADM, CT-proET-1, and PCT are shown in a patient population at different sampling times, separated into patients who developed MACCE and those who did not. [Diagram 3] Determined levels of the biomarkers copeptin (marked COP or COPAVP), cTnT (marked hsTnT for the high sensitivity assay used, see below), NT-proBNP, MR-proADM, CT-proET-1, and PCT are shown in a patient population at different sampling times, separated into patients who developed MACCE and those who did not. [Figure 4]Determined levels of the biomarkers copeptin (marked COP or COPAVP), cTnT (marked hsTnT for the high sensitivity assay used, see below), NT-proBNP, MR-proADM, CT-proET-1, and PCT are shown in a patient population at different sampling times, separated into patients who developed MACCE and those who did not. [Diagram 5] Determined levels of the biomarkers copeptin (marked COP or COPAVP), cTnT (marked hsTnT for the high sensitivity assay used, see below), NT-proBNP, MR-proADM, CT-proET-1, and PCT are shown in a patient population at different sampling times, separated into patients who developed MACCE and those who did not. [Figure 6] Determined levels of the biomarkers copeptin (marked COP or COPAVP), cTnT (marked hsTnT for the high sensitivity assay used, see below), NT-proBNP, MR-proADM, CT-proET-1, and PCT are shown in a patient population at different sampling times, separated into patients who developed MACCE and those who did not. [Figure 7] As in Figures 1-6, the determined levels of biomarkers are shown and the patient population is divided into those who developed MINS and those who did not. [Figure 8] As in Figures 1-6, the determined levels of biomarkers are shown and the patient population is divided into those who developed MINS and those who did not. [Figure 9] As in Figures 1-6, the determined levels of biomarkers are shown and the patient population is divided into those who developed MINS and those who did not. [Figure 10] As in Figures 1-6, the determined levels of biomarkers are shown and the patient population is divided into those who developed MINS and those who did not. [Figure 11]As in Figures 1-6, the determined levels of biomarkers are shown and the patient population is divided into those who developed MINS and those who did not. [Figure 12] As in Figures 1-6, the determined levels of biomarkers are shown and the patient population is divided into those who developed MINS and those who did not. [Figure 13] Similar to Figures 1-6, the determined levels of biomarkers are shown, with the patient population divided into those who developed infection in addition to MACCE and those who did not. [Figure 14] Similar to Figures 1-6, the determined levels of biomarkers are shown, with the patient population divided into those who developed infection in addition to MACCE and those who did not. [Figure 15] Similar to Figures 1-6, the determined levels of biomarkers are shown, with the patient population divided into those who developed infection in addition to MACCE and those who did not. [Figure 16] Similar to Figures 1-6, the determined levels of biomarkers are shown, with the patient population divided into those who developed infection in addition to MACCE and those who did not. [Figure 17] Similar to Figures 1-6, the determined levels of biomarkers are shown, with the patient population divided into those who developed infection in addition to MACCE and those who did not. [Figure 18] Similar to Figures 1-6, the determined levels of biomarkers are shown, with the patient population divided into those who developed infection in addition to MACCE and those who did not. [Figure 19] Determined levels of MR-proADM, PCT and CT-proET-1 are shown and the patient population is divided into those who developed infection and those who did not. [Figure 20] Determined levels of MR-proADM, PCT and CT-proET-1 are shown and the patient population is divided into those who developed infection and those who did not. [Figure 21]Determined levels of MR-proADM, PCT and CT-proET-1 are shown and the patient population is divided into those who developed infection and those who did not. [Figure 22] The determined levels of MR-proADM, PCT and CT-proET-1 are shown, with the patient population divided into those who developed blood infections and those who did not.The determined levels of MR-proADM, PCT and CT-proET-1 are shown at different time points, distinguishing between different combinations of MACCE and infections. [Figure 23] The determined levels of MR-proADM, PCT and CT-proET-1 are shown, with the patient population divided into those who developed blood infections and those who did not.The determined levels of MR-proADM, PCT and CT-proET-1 are shown at different time points, distinguishing between different combinations of MACCE and infections. [Figure 24] The determined levels of MR-proADM, PCT and CT-proET-1 are shown, with the patient population divided into those who developed blood infections and those who did not.The determined levels of MR-proADM, PCT and CT-proET-1 are shown at different time points, distinguishing between different combinations of MACCE and infections. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] It has been found that certain biomarkers copeptin, troponin and BNP allow for a rapid and early diagnosis of whether a patient undergoing gastrointestinal surgery has MACCE. Furthermore, it has been found that certain biomarkers can provide important prognostic information by identifying patients at risk for MACCE before surgery. It has been shown that the combination of the level of at least one of these biomarkers with at least one additional parameter improves the results, so that the evaluation obtained is superior to the evaluation of each biomarker alone. Although the present invention relates to the field of clinical diagnosis, the determination of the biomarker level is performed on a sample obtained from the patient and is therefore not performed in the patient's body.

[0024] In a preferred embodiment, the method is a method for at least one of prognosis, risk assessment, and diagnosis of major adverse cardiovascular or cerebrovascular events (MACCE) combined with infection in patients undergoing gastrointestinal surgery, preferably a method for risk classification of patients, classifying them into a group that is likely to develop both MACCE and infection and another group that is unlikely to develop both MACCE and infection. It is completely unexpected that based on the measurement of the biomarkers described herein, accurate and reliable conclusions can be drawn about whether a patient will suffer from cardiovascular or cerebrovascular events such as MINS or MACCE, and infections such as blood infections after surgery. This prognostic ability of copeptin, troponin, and / or BNP in the specific context described herein is novel and surprising, allowing for improved detection, prediction, and management of adverse events surrounding surgery. The combined evaluation of these possible adverse events is also particularly clinically relevant. Optimal treatment guidelines may depend a lot on such evaluation, since measures or medications to treat infections may be unfavorable to cardiovascular or cerebrovascular events and vice versa. By providing a diagnosis or prognosis for both adverse events, clinicians may select the best possible treatment approach. For example, when predicting or diagnosing MACCE, PMI, or MINS, subsequent clinical procedures such as bypass surgery or angioplasty increase the risk of worsening a possible infection. Early upfront anti-infective therapy, such as antibiotic therapy, may be critical to overall positive patient outcomes.

[0025] As used herein, "infection" within the scope of the present invention refers to a pathological process caused by the invasion of normally sterile tissues or body fluids by a pathogenic or potentially pathogenic agent / pathogen, organism and / or microorganism, and preferably relates to bacterial, viral, fungal and / or parasitic infection(s). Thus, the infection may be a bacterial infection, a viral infection and / or a fungal infection. The infection may be a local or systemic infection. For the purposes of the present invention, a viral infection may be considered as an infection by a microorganism.

[0026] Furthermore, a subject suffering from an infectious disease may suffer from two or more sources of infection at the same time.For example, a subject suffering from an infectious disease may suffer from bacterial infection and viral infection, viral infection and fungal infection, bacterial infection and fungal infection, bacterial infection, fungal infection and viral infection, or may suffer from a mixed infection comprising one or more of the infections listed herein, including potential superinfection, for example one or more viral infections and / or one or more fungal infections plus one or more bacterial infections.

[0027] As used herein, "infectious disease" includes all diseases or disorders associated with bacterial and / or viral and / or fungal infection.

[0028] In one embodiment, the infection to be detected or tested for is Bordetella, such as Bordetella pertussis, Borrelia, such as Borrelia burgdorferi, Brucella, such as Brucella abortus, Brucella canis, Brucella melitensis or Brucella suis, Campylobacter, such as Campylobacter jejuni, Chlamydia, such as Chlamydia pneumonia, Chlamydia trachomatis, Chlamydophila psittaci and Chlamydophila, Clostridium, such as Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium tetani, Corynebacterium, such as Corynebacterium diphtheria, Enterococcus, such as Enterococcus faecalis, Enterococcus faecium, Escherichia, such as Escherichia coli, Francisella Francisella such as Haemophilus influenzae, Helicobacter such as Helicobacter pylori, Legionella such as Legionella pneumophila, Leptospira such as Leptospira interrogans, Listeria such as Listeria monocytogenes, Mycobacterium such as Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium ulcerans, Mycoplasma such as Mycoplasma pneumonia, Neisseria such as Neisseria gonorrhoeae, Neisseria meningitides, Pseudomonas such as Pseudomonas aeruginosa, RickettsiaThe bacterial strain may be selected from a species of Rickettsia such as rickettsia, Salmonella such as Salmonella typhi, Salmonella typhimurium, Shigella such as Shigella sonnei, Staphylococcus such as Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus such as Streptococcus agalactiae, Streptococcus pneumonia, Streptococcus pyogenes, Treponema such as Treponema pallidum, Vibrio such as Vibrio cholera, Yersinia such as Yersinia pestis, Yersinia enterocolitica or Yersinia pseudotuberculosis.

[0029] Pathogenic fungi are fungi that cause disease in humans or other organisms. Candida species are important human pathogens best known for causing opportunistic infections in immunocompromised hosts (e.g., transplant patients, AIDS patients, cancer patients). Infections are difficult to treat and can be very serious, with 30-40% of systemic infections resulting in death. Aspergillosis is another possible fungal pathogen. Aspergillus can cause disease in three major ways: through the production of mycotoxins, through the induction of an allergic response, and via local or systemic infection. In the latter two classifications, the immune status of the host is important. The most common pathogenic species are Aspergillus fumigatus and Aspergillus flavus. Aspergillus flavus can produce aflatoxins, both toxins and carcinogens, that can contaminate food. Aspergillus fumigatus and Aspergillus clavatus can cause disease. Cryptococcus neoformans can cause disease in humans. Cryptococcus neoformans is a major pathogen of humans and animals. Cryptococcus laurentii and Cryptococcus albidus are known to occasionally cause moderate to severe disease in immunocompromised human patients. Cryptococcus gattii is endemic to tropical regions of the African and Australian continents and can cause disease. Histoplasma capsulatum can cause histoplasmosis in humans, dogs, and cats. Pneumocystis jirovecii (or Pneumocystis carinii) can cause a type of pneumonia in people with weakened immune systems, such as premature infants, the elderly, and AIDS patients. Stachybotrys chartarum or "black mold" can cause respiratory damage and severe headaches.

[0030] In one embodiment, the infection detected or tested is Acinetobacter baumannii, Klebsiella pneumoniae, Acinetobacter lwoffii, Listeria monocytogenes, Aeromonas caviae, Morganella morganii, Aeromonas hydrophila, Neisseria gonorrhoeae, Aspergillus flavus, Neisseria meningitidis, Aspergillus nidulans, Pasteurella multocida, Aspergillus niger, Pasteurella pneumotropica, Aspergillus terreus, Propionibacterium acnes, Bacillus anthracis, Proteus mirabilis, Bacillus cereus, Providencia rettgeri, Bacillus subtilis, Pseudomonas aeruginosa, Bacteroides fragilis, Salmonella choleraesuis, Brucella melitensis, Serratia liquefaciens, Burkholderia cepacia, Serratia marcescens, Candida albicans, Staphylococcus aureus, Candida dubliniensis, Staphylococcus epidermidis, Candida glabrata, Staphylococcus haemolyticus, Candida krusei, Staphylococcus hominis, Candida parapsilosis、Staphylococcus saccharolyticus、Candida tropicalis、Staphylococcus warneri、Capnocytophaga canimorsus、Stenotrophomonas maltophilia、Citrobacter braakii、Streptococcus agalactiae、Citrobacterfreundii, Streptococcus anginosus, Clostridium perfringens, Streptococcus bovis, Corynebacterium jeikeium, Streptococcus constellatus, Enterobacter aerogenes, Streptococcus dysgalactiae, Enterobacter cloacae, Streptococcus mutans, Enterobacter sakazakii, Streptococcus pneumoniae, Enterococcus faecalis, Streptococcus pyogenes, Enterococcus faecium, Streptococcus salivarius, Escherichia coli, Streptococcus sanguinis, Shigella sp., Streptococcus suis, Gemella haemolysans, Vibrio vulnificus, Gemella morbillorum, Yersinia enterocolitica, Haemophilus influenzae, Yersinia pestis, Kingella The host may be selected from the group consisting of: Yersinia kingae, Yersinia pseudotuberculosis, and Klebsiella oxytoca.

[0031] As used herein, the term "bloodborne infection" may include systemic bloodstream infection, sepsis, severe sepsis, and / or septic shock.

[0032] "Sepsis" in the context of the present invention refers to a systemic response to infection. Alternatively, sepsis may be viewed as a combination of SIRS and a confirmed infectious process or infection. Sepsis may be characterized as a clinical syndrome defined by the presence of both infection and a systemic inflammatory response (Levy et al., Crit Care Med.;31(4):1250-6,2003). The term "sepsis" as used herein includes, but is not limited to, sepsis, severe sepsis, and septic shock.

[0033] The term "sepsis" as used herein includes, but is not limited to, sepsis, severe sepsis, and septic shock. Severe sepsis refers to sepsis associated with organ dysfunction, hypoperfusion abnormalities, or sepsis-induced hypotension. Hypoperfusion abnormalities include lactic acidosis, oliguria, and sudden changes in mental status. Sepsis-induced hypotension is defined by the presence of systolic blood pressure less than about 90 mm Hg or its reduction from baseline by about 40 mm Hg or more in the absence of other causes of hypotension (e.g., cardiogenic shock). Septic shock is defined as severe sepsis with sepsis-induced hypotension that persists despite adequate fluid resuscitation, together with the presence of hypoperfusion abnormalities or organ dysfunction (Bone et al., CHEST 101(6):1644-55, 1992).

[0034] Alternatively, the term sepsis may be defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. In clinical operationalism, organ dysfunction can be represented preferably by an increase of 2 or more points in the Sequential Organ Failure Assessment (SOFA) score and is associated with an in-hospital mortality rate of more than 10%. Septic shock may be defined as a subset of sepsis, in which particularly severe cardiovascular, cellular, and metabolic abnormalities are associated with a higher risk of death than sepsis alone. Patients with septic shock can be clinically identified by the need for vasopressors to maintain a mean arterial pressure of 65 mm Hg or higher and serum lactate levels of more than 2 mmol / L (>18 mg / dL) in the absence of hypovolemia.

[0035] The term "sepsis" as used herein relates to all possible stages in the development of sepsis.

[0036] The term "sepsis" also includes severe sepsis or septic shock based on the definition of SEPSIS-2 (Bone et al., 2009). The term "sepsis" also includes subjects that fall within the definition of SEPSIS-3 (Singer et al., JAMA; 315(8): 801-810, 2016). As used herein, the term "sepsis" refers to all possible stages in the development of sepsis.

[0037] At least one additional parameter can be selected from the group consisting of at least one additional biomarker level and patient clinical parameter.When more than one additional parameter is used in the combined evaluation, the additional parameters can be of the same category or different categories.For example, in the case of two additional parameters, the additional parameters can be both additional biomarker levels, two clinical parameters, or additional biomarker levels and clinical parameters.The additional biomarker level can be the level of one of the remaining two biomarkers mentioned in step ii) that are not used in this step to determine the biomarker level.For example, when the biomarker level determined in step ii) is the level of copeptin, the additional parameter can be the level of troponin or BNP.

[0038] More generally, determining the at least one additional parameter preferably comprises determining the level of at least one additional biomarker, which is selected from the group consisting of copeptin, troponin, BNP, mid-regional pro-adrenomedullin (MR-proADM), C-terminal proendothelin-1 (CT-proET-1), procalcitonin (PCT), MR-proANP (mid-regional pro-atrial natriuretic peptide), creatine kinase, creatine kinase-MB, myoglobin, lactate, and CRP (C-reactive protein).

[0039] In a preferred embodiment, the levels of all three biomarkers copeptin, troponin, and brain natriuretic peptide (BNP) are determined and used in steps iv) and v) below. Optionally, at least one of MR-proADM, CT-proET-1, and PCT can be additionally determined and combined into a combined assessment.

[0040] The sequence of the 164 amino acid precursor peptide of vasopressin (preprovasopressin) is given in SEQ ID NO:1. Provasopressin relates to amino acid residues 19-164 of the sequence of preprovasopressin. The amino acid sequence of provasopressin is given in SEQ ID NO:2. Provasopressin is cleaved into mature vasopressin, neurophysin II, and C-terminal provasopressin (CT-proAVP or copeptin). Copeptin relates to amino acid residues 126-164 of preprovasopressin. The amino acid sequence of copeptin is provided in SEQ ID NO:3. Neurophysin II comprises amino acid residues 32-124 of preprovasopressin, and its sequence is shown in SEQ ID NO:4.

[0041] Troponin is a protein found in muscle that facilitates contraction by sliding of actin and myosin filaments. It is composed of three subunits: C, I, and T. Troponin T isoform cTnT is found exclusively in cardiomyocytes and is the most important cardiac biomarker due to its myocardial specificity and high clinical sensitivity. However, troponin levels typically increase slowly after surgery, and therefore their usefulness for early diagnosis of MACCE and MINS in postoperative patients has typically been considered limited. The sequence of subunit C is given in SEQ ID NO: 7. The sequence of subunit I is given in SEQ ID NO: 6. The sequence of subunit T is given in SEQ ID NO: 5.

[0042] The sequence of the 134 amino acid precursor peptide of brain natriuretic peptide (preproBNP) is given in SEQ ID NO: 8. ProBNP relates to amino acid residues 27-134 of preproBNP. The sequence of proBNP is shown in SEQ ID NO: 9. ProBNP is cleaved into N-terminal proBNP (NT-pro-BNP) and mature BNP. NT-pro-BNP comprises amino acid residues 27-102 and its sequence is shown in SEQ ID NO: 10. SEQ ID NO: 11 shows the sequence of BNP comprising amino acid residues 103-134 of the preproBNP peptide.

[0043] Clinical parameters in the sense of the present invention generally refer to any parameter that indicates the health and / or physical condition of a patient. The clinical parameters are preferably selected from important parameters of cardiac or cerebrovascular conditions or events. Preferably, the clinical parameters are selected from the group consisting of age, abnormal ECG (especially pathological Q waves), LBBB (appearance of left bundle branch block), ST elevation (more than 2 mm in V1, V2, V3 or more than 1 mm in other leads), ST depression (appearance of ST segment depression of more than 1 mm), T wave inversion (symmetric inversion of T waves of more than 1 mm in at least two consecutive leads), intraoperative hypotension, intraoperative tachycardia, intraoperative bradycardia, hyperlipidemia, smoking status, anemia, functional capacity (MET), red blood cell transfusion, arrhythmia, non-sinus rhythm, duration and size of said gastrointestinal surgery, medical history of the patient (especially with regard to cardiac and cerebrovascular events), and liver disease. The present invention also includes any of the parameters mentioned herein, alone or in any combination with any number of other parameters.

[0044] Since there is no unique, explicit and exclusive definition of MACCE and what conditions this term includes in the art, MACCE as used herein is defined as the occurrence of at least one condition selected from the following group of conditions: - Non-fatal cardiac arrest (absence of cardiac rhythm or presence of a disordered rhythm requiring any part of basic or advanced cardiopulmonary resuscitation), - acute myocardial infarction (increase and gradual decrease in troponin levels or, in the case of creatine kinase isoenzymes as a marker of myocardial necrosis, decrease accompanied by at least one of the following: ischemic symptoms, abnormal Q waves on the ECG, ST-segment elevation or depression, coronary intervention (e.g., coronary angioplasty), or an irregular decrease in an elevated troponin level detected at its peak after surgery in a patient in whom no alternative explanation for the troponin elevation has been identified), - congestive heart failure (new in-hospital signs or symptoms of dyspnea or fatigue, orthopnea, paroxysmal nocturnal dyspnea, elevated jugular venous pressure, pulmonary rales on physical examination, cardiac enlargement or pulmonary vascular congestion), - new cardiac arrhythmias (atrial flutter, atrial fibrillation, or ECG evidence of second- or third-degree atrioventricular conduction block), - angina pectoris (dull diffuse substernal chest discomfort brought on by exertion or emotion and relieved by rest or nitroglycerin), - Stroke (embolic, thrombotic, or hemorrhagic event lasting at least 30 minutes with or without persistent residual motor, sensory, or cognitive impairment; if neurological symptoms persist for more than 24 hours, a person is diagnosed with a stroke; if they persist for less than 24 hours, the event is defined as a transient ischemic attack), - Transient ischemic attack (an embolic, thrombotic, or hemorrhagic event lasting at least 30 minutes with or without persistent residual motor, sensory, or cognitive impairment; if neurological symptoms persist for more than 24 hours, a person is diagnosed with a stroke; if they persist for less than 24 hours, the event is defined as a transient ischemic attack), - Myocardial injury after non-cardiac surgery (MINS; postoperative troponin elevation judged to be due to myocardial ischemia (without evidence of non-ischemic etiology) with or without ischemic symptoms. Thus, other conditions not listed above, such as circulatory shock, are not considered MACCEs as used herein and are expressly excluded.

[0045] "Diagnosis" in the context of the present invention relates to the recognition and early detection of a disease or clinical condition or its absence in a subject, and may also include differential diagnosis and exclusion. Early in this context is intended to mean the earliest possible time point for diagnosis. This includes patients with and without symptoms related to the disease. Diagnosis is achieved by the measurement of biomarkers with or without the addition of further clinical parameters, scores, or medical procedures known in the art. Again, the present invention relates to in vitro diagnosis. Diagnosis is performed on a patient sample, but not on the human or animal body.

[0046] In the present invention, the term "risk assessment" refers to assigning a probability of experiencing a certain adverse event to an individual. This allows the individual to be preferably assigned to a certain risk category, where the category includes, for example, high risk vs. low risk, or risk categories based on numerical values, such as risk categories 1, 2, 3, etc. In the present invention, the term "risk stratification" refers to dividing subjects into different risk groups according to their further prognosis. Risk assessment also relates to stratification for applying preventive and / or therapeutic measures.

[0047] In the present invention, the term "prognosis" refers to a prediction of how a subject's (e.g., patient's) condition will progress. It may also include a prediction of the subject's chance of recovery or chance of adverse outcome (e.g., occurrence of MACCE with or without infection or death).

[0048] The term "sample" as used herein refers to a sample of bodily fluid obtained for the purpose of diagnosis, prognosis, or evaluation of a subject of interest, such as a patient. Preferred test samples include blood, serum, plasma, cerebrospinal fluid, urine, saliva, sputum, and pleural effusion. In addition, those skilled in the art will understand that some test samples can be more easily analyzed after fractionation or purification procedures, such as separation of whole blood into serum or plasma components.

[0049] Thus, in a preferred embodiment of the invention, the sample is selected from the group comprising a blood sample, a serum sample, a plasma sample, a cerebrospinal fluid sample, a saliva sample and a urine sample, or an extract of any of the aforementioned samples. Preferably, the sample is a blood sample, most preferably a serum sample or a plasma sample.

[0050] The term "level" in the context of the present invention relates to the concentration (preferably expressed as weight / volume or molar amount / volume) of the marker peptide obtained from a patient sample.

[0051] The term "patient" as used herein refers to a living human or non-human organism that is receiving medical care or should be receiving medical care for a disease. This includes individuals without a defined disease who are being investigated for signs of pathology, specifically individuals who are being investigated for possible MACCE or MINS, preferably combined with an infection. Thus, the methods and assays described herein are applicable to both human and veterinary diseases. Specifically, patients evaluated with the methods of the present invention are preferably undergoing elective gastrointestinal surgery. Patients may also suffer from other comorbidities such as hypertension, diabetes, COPD (chronic obstructive pulmonary disease), metabolic syndrome, obesity (BMI (body mass index) of at least 30), non-cardiovascular chronic diseases, pain, fever, infection, sepsis, or SIRS (systemic inflammatory response syndrome).

[0052] The term "combining" as used herein to provide a combined evaluation refers to assigning an index value to the measured or calculated results and combining values ​​from different results into a combined evaluation. This may include selecting a certain number of parameters and arranging these parameters into a designated group using a mathematical algorithm (e.g., deviation or ratio). For example, the measured biomarker level may be above or below a predefined threshold, which the skilled person can translate into an index value by evaluating whether an increase in the biomarker value compared to the reference data is considered to indicate the presence of a disease or condition. Different thresholds may provide different index strengths. The same applies to the calculation results, such as an increase or decrease in the ratio, the ratio between different biomarker levels, etc. Thus, the term "combined evaluation" refers to the overall index value of all the measured or calculated results provided by the present invention, which can then be correlated to the patient's condition.

[0053] The term "correlate" as used herein with respect to combination evaluation refers to comparing the totality of all measured or calculated index values ​​(combined evaluation) with those values ​​of patients known to suffer from or known to be at risk of a given condition. The evaluation in the patient sample can be compared with a value known to be associated with a particular diagnosis. The evaluation of the sample is said to be correlated with the diagnosis, which means that a person skilled in the art can use this evaluation to determine that a patient suffers from a particular type of disease and respond accordingly. Alternatively, the evaluation can be compared with an evaluation known to be associated with a good outcome (such as, for example, the absence of disease). In a preferred embodiment, the panel of marker levels and their combined index values ​​are correlated with a global probability or a particular outcome.

[0054] In the present invention, all of the patients on whom the method of the present invention is carried out undergo gastrointestinal surgery. The purpose of the method of the present invention is to determine whether these patients have or are at risk of having MACCE, preferably MACCE combined with infection. Therefore, the correlation of step iv) of the method of the present invention preferably includes providing reference data on patients who have undergone gastrointestinal surgery and patients who have and / or have not had MACCE or MINS, preferably MACCE or MINS combined with infection. The patient's combined evaluation is then compared with this reference data to determine whether the patient has or is at risk of having MACCE or MINS, preferably MACCE or MINS combined with infection. A reference group consisting of patients who have also undergone gastrointestinal surgery is more suitable for the present invention than, for example, a reference group of healthy patients.

[0055] To further increase the performance of the method of the present invention, in a preferred embodiment, the level of at least one additional biomarker is determined in the sample, the additional biomarker being selected from the group consisting of copeptin, troponin, BNP, mid-regional pro-adrenomedullin (MR-proADM), C-terminal proendothelin-1 (CT-proET-1), procalcitonin (PCT), MR-proANP (mid-regional pro-atrial natriuretic peptide), creatine kinase, creatine kinase-MB, myoglobin, lactate, and CRP (C-reactive protein). The level of at least one additional biomarker is combined into a combined evaluation. In a particularly preferred embodiment, the levels of all of the biomarkers copeptin, troponin, BNP, MR-proADM, CT-proET-1, and PCT are determined and combined into a combined evaluation. The use of a combination of biomarkers increases the diagnostic performance of the method and makes the method less susceptible to the variation of a single biomarker.

[0056] The sequence of the 153 amino acid preproANP is shown in SEQ ID NO: 21. Upon cleavage of the N-terminal signal peptide (25 amino acids) and the two C-terminal amino acids, proANP (SEQ ID NO: 22) is released. "Pro-atrial natriuretic peptide" or "proANP" refers to a prohormone containing 126 amino acids. As used herein, the peptide containing 28 amino acids (99-126) of the C-terminal section of the 126 amino acid prohormone (proANP) is referred to as the actual hormone ANP. When ANP is released from its prohormone proANP, an equimolar amount of the remaining larger partial peptide of proANP consisting of 98 amino acids, N-terminal proANP (NT-proANP; proANP(1-98); shown as SEQ ID NO: 23), is released into the circulation. NT-proANP has a significantly superior half-life and stability, allowing NT-proANP to be used as a test parameter for diagnosis, follow-up, and treatment management. See, for example, Lothar Thomas (Editor), Labor und Diagnose, 5th expanded ed., Chapter 2, section 2.14, Kardiale Diagnostik, pages 116-118, and WO2008 / 135571. The level of proANP is preferably measured in the plasma or serum of the subject.

[0057] Atrial natriuretic peptide (ANP), a member of the natriuretic peptide family, regulates several physiological parameters, including diuresis and natriuresis, as well as the reduction of arterial blood pressure (BP). It is produced primarily in the atria of the heart and constitutes 98% of the circulating natriuretic peptides (Vesely DL. Life 2002;53:153-159). ANP is derived from the cleavage of its precursor prohormones, which are significantly more stable in the circulation than the mature peptides. A mid-region fragment of the precursor hormone (amino acids 53-90 of NT-proANP; SEQ ID NO: 24), termed mid-region proANP (MR-proANP), may be relatively resistant to degradation by exoproteases, unlike epitopes at the N- or C-terminus of proANP used in previous immunoassays (Morgenthaler NG et al. Clin Chem 2004;50:234-236; Gerszten RE et al. 2008. Am J Physiol Lung Cell Mol Physiol). We have previously noted that in adults with essential hypertension, higher plasma levels of MR-proANP are associated with higher systolic blood pressure (SBP), greater arterial stiffness, and greater severity of hypertension (unpublished data). Based on these findings, we hypothesized that plasma MR-proANP may be relevant as a measure of target organ damage in adults with hypertension.

[0058] As used herein, "lactate" refers to the lactate concentration measured in blood. Usually, lactate concentration is evaluated daily or even more frequently. Blood lactate concentration can be determined by lactate oxidase spectrophotometry. With regard to clinical applications, it is well known in the art that lactate can identify patients at high risk of morbidity and mortality (Broder G, Weil MH. Excess lactate: An index of reversibility of shock in human patients. Science 1964; 143: 1457-59; Manikis P, Jankowski S, Zhang H, Kahn RJ, Vincent JL. Correlation of serial blood lactate levels to organ failure and mortality after trauma. Am J Emerg Med 1995; 13, 6: 619-22).

[0059] "Myoglobin" is a single-chain globular protein of 153 amino acids (SEQ ID NO: 26) that contains a central heme (iron-containing porphyrin) prosthetic group around which the rest of the apoprotein folds. Its sequence is shown in SEQ ID NO: 25. Myoglobin is a susceptibility marker for muscle injury and therefore a possible marker for heart attack in patients with chest pain (Weber et al. 2005. Clinical Biochemistry 38:1027-30). CK-MB and cardiac troponin T, cTnT, are used in combination with ECG and clinical signs to diagnose acute myocardial infarction (AMI). Cardiac troponin is a protein complex consisting of three subunits, T (cTcT), I (cTcI), and C, of ​​which T and I are present only in thermal muscle tissue and are used as markers for diagnostic purposes (Rottbauer W et al., Eur Heart J 1996;17:3-8).

[0060] "Creatine kinase" is an enzyme and is represented by different isoforms that can have B- (brain type) or M- (muscle type) subunits. Creatine kinase is composed of isoforms CK-MM, CK-MB, and CK-BB that can have distinct expression patterns based on tissue type (Schlattner U, Tokarska-Schlattner M, Wallimann T (February 2006). "Mitochondrial creatine kinase in human health and disease". Biochimica et Biophysica Acta. 1762(2):164-80). This enzyme plays a functional role in adenosine triphosphate (ATP) metabolism and is therefore present in organs with a high demand for ATP, such as muscle, retina, brain, heart, or kidney. Creatine kinase blood levels are detected to detect tissue damage, for example, in myocardial infarction, muscular dystrophy, or related diseases such as acute kidney injury. (Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM (January 1992). "Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the 'phosphocreatine circuit' for cellular energy homeostasis". The Biochemical Journal. 281 (Pt 1)(1):21-40, Moghadam-Kia S, Oddis CV, Aggarwal R (January 2016). "Approach to asymptomatic creatine kinase elevation". Cleveland Clinic Journal of Medicine. 83(1):37-42).

[0061] "C-reactive protein (CRP)" is an acute phase protein that is physiologically induced during inflammatory conditions (Thompson D, Pepys MB, Wood SP (1999). "The physiological structure of human C-reactive protein and its complex with phosphocholine". Structure. 7(2): 169-77). The sequence of CRP is given in SEQ ID NO: 27. CRP is part of the complement system by promoting phagocytosis in macrophages. In addition, CRP can also activate the innate immune response to infection (Bray C, Bell LN, Liang H, Haykal R, Kaiksow F, Mazza JJ, Yale SH (December 2016). "Erythrocyte Sedimentation Rate and C-reactive Protein Measurements and Their Relevance in Clinical Medicine". Wisconsin Medical Journal (WMJ). 115(6): 317-21.). CRP is a known and widely used marker for inflammation. In healthy adults, normal concentrations of CRP vary between 0.8 mg / L and 3.0 mg / L, and rarely up to 10 mg / L. Pathological levels can be defined as mild inflammation and viral infections (10-40 mg / L), active inflammation, bacterial infections (40-200 mg / L), and severe bacterial infections and burns (>200 mg / L) (Chew KS (April 2012). "What's new in Emergencies Trauma and Shock? C-reactive protein as a potential clinical biomarker for influenza infection: More questions than answers". Journal of Emergencies, Trauma, and Shock. 5(2):115-7.).

[0062] The amino acid sequence of the precursor peptide of Adrenomedullin (preproAdrenomedullin) is given in SEQ ID NO: 12. ProAdrenomedullin relates to amino acid residues 22-185 of the sequence of preproAdrenomedullin. The amino acid sequence of proAdrenomedullin (proADM) is given in SEQ ID NO: 13. MR-proAdrenomedullin (MR-proADM) relates to amino acid residues 45-92 of pre-proADM. The amino acid sequence of MR-proADM is provided in SEQ ID NO: 14.

[0063] The sequence of the 212 amino acid precursor peptide of endothelin-1 (preproendothelin-1) is given in SEQ ID NO: 15. Pro-ET-1 relates to amino acid residues 18-212 of the sequence of pre-pro-ET-1. The amino acid sequence of pro-ET-1 is given in SEQ ID NO: 16. Pro-ET-1 is cleaved into mature ET-1, big-ET-1, and C-terminal proET-1 (CT-proET-1). ET-1 relates to amino acid residues 53-73 of pre-pro-ET-1. The amino acid sequence of ET-1 is given in SEQ ID NO: 17. CT-proET-1 relates to amino acid residues 168-212 of pre-pro-ET-1. The amino acid sequence of CT-proET-1 is provided in SEQ ID NO: 18. Big-ET-1 comprises amino acid residues 53-90 of pre-pro-ET-1, the sequence of which is given in SEQ ID NO: 19.

[0064] Procalcitonin is the precursor of calcitonin and katacalcin. The amino acid sequence of PCT1-116 is given in SEQ ID NO:20.

[0065] Generally, the level of the biomarkers mentioned can be measured by directly determining the biomarker itself. However, in a preferred embodiment, the level of at least one of the biomarkers is determined by determining the level of at least one of the precursors, precursor fragments, and fragments of the biomarker. In other words, the level of the biomarker is indirectly determined by determining the level of the precursor, precursor fragment, or fragment of the biomarker. The advantage lies in the fact that these indirect peptide targets are often more easily measured or more stable in either the patient's body fluid or the assay environment. Since the ratio of the indirect peptide target to the biomarker of interest is known, the level of the indirect peptide target can be easily used to determine the level of the biomarker of interest.

[0066] As described herein in the context of proteins and other peptides, the term "fragment" refers to a smaller protein or peptide that can be derived from a larger protein or peptide and thus includes a subsequence of the larger protein or peptide. The fragment can be derived from the larger protein or peptide by saponification of one or more of its peptide bonds. A "fragment" of a biomarker preferably relates to a fragment that is at least 6 amino acids in length, most preferably at least 12 amino acid residues in length. Such fragments are preferably detectable by immunological assay.

[0067] For example, in a preferred embodiment, determining the level of troponin comprises determining the level of subunit cardiac troponin T (cTnT), preferably isoform 6 of cTnT (SEQ ID NO: 5), or a homologous peptide having at least 75% amino acid sequence identity with isoform 6 of cTnT. More preferably, the amino acid sequence identity with isoform 6 of cTnT is at least 80%, at least 85%, at least 90%, and most preferably at least 95%. Cardiac troponin T is used as a biomarker for MI because it is released from myocardium upon tissue injury. There are several isoforms of cTnT, and the present invention is not limited to any of them, but isoform 6 is preferred. However, any of the other isoforms can be used in the present invention.

[0068] In another preferred embodiment, determining the level of BNP comprises determining the level of the precursor fragment NT-proBNP (SEQ ID NO: 10).

[0069] Since the risk of postoperative complications increases with the age of the patient, the method of the present invention is preferably performed on patients who are at least 50 years old. Restricting the patient population on which the method is performed allows the cut-off value to be specifically selected for the biomarker levels commonly found in the target population. By evaluating patients who are at least 50 years old, the method of the present invention can be tailored to the physiological parameters of this group.

[0070] The present invention is directed to the diagnosis of serious complications after gastrointestinal surgery. Therefore, it is preferred that patients stay in hospital for at least one day after undergoing gastrointestinal surgery, since serious complications are more prominent after serious surgical procedures. The length of hospital stay reflects the severity of the surgical procedure and therefore the general risk of complications. The present invention can also be carried out on samples of patients who are being treated with analgesics or pain treatments. By targeting this group of patients with the method, the diagnosis of the present invention will be targeted to patients who may be most in need.

[0071] Eligible gastrointestinal surgical procedures can be either laparoscopic or open (conventional). Specifically, gastrointestinal surgery includes: -gastric surgery, -Small bowel surgery, especially duodenal surgery, -Colon surgery, especially rectal surgery, - reproductive system surgery, especially hysterectomy or salpingo-oophorectomy, -kidney surgery, especially nephrectomy, - Bladder surgery, especially cystectomy, - Gallbladder surgery, especially cholecystectomy, and -surgery for gastrointestinal cysts.

[0072] Since the method of the present invention is intended for the diagnosis of MACCE resulting from gastrointestinal surgery, preferably combined with infection, it is preferable that the patient does not have cardiovascular comorbidities.Such comorbidities also often lead to non-physiological levels of the biomarkers described herein, and therefore can be masked or misinterpreted as newly acquired MACCE as a result of gastrointestinal surgery.Therefore, the diagnostic value of the method is higher in patients without pre-existing conditions that can be misinterpreted as MACCE.

[0073] Thus, in a preferred embodiment, a patient is excluded if the patient has an exclusion condition, which is selected from the group consisting of organ transplantation, traumatic injury, endocrine disease, endocrine surgery, vascular disease, vascular surgery (e.g., aneurysm surgery), intravascular disease, intravascular surgery, acute coronary syndrome (ACS), heart failure, decompensated congestive heart failure, aortic valve stenosis, reduced left ventricular ejection fraction (LVEF), and circulatory shock. The exclusion condition can be either present or diagnosed in the patient's recent past, or diagnosed immediately after gastrointestinal surgery. The main criterion is that the exclusion condition present in the patient affects the level of biomarkers by the method at the time of sampling the patient. If this is the case and these situations are identified in a timely manner, the patient is excluded. In this way, the detrimental effect of the exclusion condition on the diagnostic performance of the present invention can be prevented. Otherwise, the method of the present invention may cause a false diagnosis of MACCE in patients under the influence of one or more of the exclusion conditions.

[0074] Since the present invention is aimed at the rapid diagnosis of MACCE, preferably combined with infection, following gastrointestinal surgery, the sample is preferably taken immediately before and / or immediately after gastrointestinal surgery or within the first 3 days after surgery. In particular, the sample is preferably taken from the patient within 24 hours before gastrointestinal surgery, within 24 hours after gastrointestinal surgery, the first day after gastrointestinal surgery, the second day after gastrointestinal surgery, or the third day after gastrointestinal surgery. Taking a sample after gastrointestinal surgery is of course suitable for monitoring the impact of the gastrointestinal surgery itself on the levels of biomarkers, but taking a sample immediately before gastrointestinal surgery has two main applications. First of all, it helps to establish a baseline of the levels of the biomarkers described herein in a particular patient. Thus, the levels of the biomarkers obtained at a later time point can be compared to these baselines. Secondly, even in patients who do not have one of the aforementioned exclusion conditions, a higher level of the biomarkers mentioned herein compared to a healthy control group may indicate an increased risk of this particular patient developing MACCE, preferably combined with infection, following gastrointestinal surgery. Therefore, measuring the level of the biomarker before gastrointestinal surgery can help to increase the diagnostic value of the method of the present invention.The control group can also be a group of patients who have undergone gastrointestinal surgery and have developed or preferably have not developed MACCE or MINS, preferably combined with infection.

[0075] The method of the present invention provides valuable results even when only one patient sample taken at one of the aforementioned time points is evaluated. However, the performance of the method of the present invention increases when multiple patient samples taken at different time points are evaluated. Thus, in a preferred embodiment, the method comprises providing 2-5 samples from the patient, the samples being taken at different times before and / or after the gastrointestinal surgery, and steps ii), iv), and v) are performed for all said samples. In a most preferred embodiment, the 5 samples are taken from the patient at different time points immediately before and after the gastrointestinal surgery. Preferably, the different times at which the 2-5 samples are said to be taken are selected from the group consisting of within 24 hours before the gastrointestinal surgery, within 24 hours after the gastrointestinal surgery, the first day after the gastrointestinal surgery, the second day after the gastrointestinal surgery, and the third day after the gastrointestinal surgery. In an embodiment in which 5 samples are taken, each sample is taken at one of these time points. The determination of the biomarker levels in these samples can be performed sequentially, for example, each sample can be measured on the day it is taken. Alternatively, samples from all time points can be collected and measured simultaneously, for example after the last sample has been taken. Different assays or one multimarker joint assay can be used for the different biomarkers.

[0076] In embodiments of the method in which more than one patient sample is provided, the development of the level of the biomarker in the sample, for example, the increase or decrease of the biomarker level between the time points when the samples are taken, can be used to increase the diagnostic value of the present invention. For example, in a preferred embodiment, the level of the biomarker in samples taken at different times is determined and then compared, and the difference in the level of the biomarker at different times is combined into a combined evaluation. By comparing the levels in samples taken at different times, additional information about the patient's condition can be obtained beyond the level of the biomarker at a particular time. As already mentioned, this additional information can be the increase or decrease of a particular biomarker over the period when the samples were taken. However, additional information can also be obtained by more complex evaluation of the relationship of each of the biomarkers to the other biomarkers. For example, the importance of a high level of copeptin on the first day after gastrointestinal surgery to be generally indicative of MACCE is either increased if the patient shows high levels of troponin and / or BNP on the second and / or third days, or decreased if the levels of troponin and / or BNP do not show an increase at these times. In this way, the levels of biomarkers measured in samples taken at different times create a synergistic effect in the diagnostic value of the methods of the invention, far exceeding the level of the biomarker simply at one or more time points (i.e., information about the level of a biomarker that has decreased by a certain value from one sampling time to another is of greater diagnostic value than information about the level of the biomarker at these sampling times alone).

[0077] In a preferred embodiment, a biomarker level determined to exceed a certain threshold is indicative of MACCE in the patient, preferably in combination with an infection. The value of this particular threshold must take into account several factors, as explained below.

[0078] First of all, the sensitivity and specificity of a diagnostic and / or prognostic test depends not only on the analytical "quality" of the test, but also on the definition of what constitutes an abnormal result. In practice, receiver operating characteristic curves (ROC curves) are typically calculated by plotting the value of a variable against its relative frequency in a "normal" population (i.e., apparently healthy patients, specifically herein, with or without infection, undergoing gastrointestinal surgery and not developing MACCE) and a "disease" population (i.e., patients suffering from diabetes, insulin resistance, and / or metabolic syndrome; specifically herein, patients undergoing gastrointestinal surgery and also developing MACCE and possibly infection). For any particular marker, the distributions of marker levels for subjects with and without disease are likely to overlap. Under such conditions, the test will not completely distinguish normal from disease with 100% accuracy, and the area of ​​overlap indicates where the test cannot distinguish normal from disease. A threshold is selected above which (or below which, depending on how the marker is altered by the disease) the test is considered abnormal, and below which the test is considered normal. The horizontal axis of the ROC curve represents (1-specificity), which increases with the false positive rate. The vertical axis of the curve represents sensitivity, which increases with the true positive rate. Thus, for a particular cutoff selected, the value of (1-specificity) may be determined and the corresponding sensitivity may be obtained. The area under the ROC curve (AUC) is a measure of the probability that the measured marker level will allow for the correct identification of a disease or condition. Thus, the area under the ROC curve can be used to determine the validity of the test. ROC curves can be used even when the test results do not necessarily provide an exact number. As long as the results can be ranked, a ROC curve can be created. For example, the results of a test on a "disease" sample can be ranked according to degree (e.g., 1=low, 2=normal, and 3=high). This ranking can be correlated with the results in a "normal" population, and a ROC curve is created.These methods are well known in the art (see, for example, Hanley et al. 1982. Radiology 143:29-36). Preferably, the ROC curve produces an AUC of greater than about 0.5, more preferably greater than about 0.7, even more preferably greater than about 0.8, even more preferably greater than about 0.85, and most preferably greater than about 0.9. The term "about" in this context refers to + / - 5% of a given measurement. In certain embodiments, the markers and / or marker panels are selected to exhibit at least about 70% sensitivity, more preferably at least about 80% sensitivity, even more preferably at least about 85% sensitivity, even more preferably at least about 90% sensitivity, and most preferably at least about 95% sensitivity, in combination with at least about 70% specificity, more preferably at least about 80% specificity, even more preferably at least about 85% specificity, even more preferably at least about 90% specificity, and most preferably at least about 95% specificity. In particularly preferred embodiments, both the sensitivity and specificity are at least about 75%, more preferably at least about 80%, even more preferably at least about 85%, even more preferably at least about 90%, and most preferably at least about 95%. The term "about" in this context refers to + / - 5% of a given measurement.

[0079] Therefore, it is important to note that the specific threshold value used in the method of the present invention must be adapted to the actual use of the present invention. Different threshold values ​​will result in different sensitivity and specificity of the present invention, which should be adapted by the clinician using the present invention, taking into account the specific situation. Thus, the threshold value may be adapted depending on whether it is considered more appropriate to identify the majority of subjects at risk, at the expense of identifying "false positives", or whether it is considered more appropriate to mainly identify subjects at high risk, at the expense of missing a few subjects at moderate risk. These decisions must be made by the clinician who implements the present invention, and are accomplished by modifying the threshold value. Therefore, the threshold values ​​given herein are exemplary, and should not be understood as limiting the present invention in any way.

[0080] Another thing to consider is that different assays may require different thresholds if these assays are calibrated differently. Thus, the above thresholds must be applied to such differently calibrated assays accordingly, taking into account the calibration differences. One possibility to quantify the calibration differences is a method comparison analysis (correlation) of the assay in question (e.g., copeptin assay) with each biomarker assay used in the present invention (e.g., Thermo Scientific B·R·A·H·M·S Kryptor Compact plus) by measuring the respective biomarker (e.g., copeptin) in the sample using both methods. Another possibility is to determine the median biomarker level of a representative normal population using the assay in question, assuming that this test has sufficient analytical sensitivity, compare the results with the median biomarker level as described in the literature, and recalculate the calibration based on the difference obtained by this comparison.

[0081] Overall, the specific thresholds used in the present invention must be determined individually whenever the present invention is used. As exemplary values, and in preferred embodiments of the present invention, the specific thresholds are selected from the group consisting of the following, above which the biomarker levels indicate a MACCE in the patient, preferably combined with an infection: for copeptin, 25 pmol / L, preferably 75 pmol / L, more preferably 125 pmol / L, even more preferably 175 pmol / L, most preferably 225 pmol / L; for cTnT, 15 ng / L, preferably 20 ng / L, more preferably 25 ng / L, even more preferably 30 ng / L, most preferably 35 ng / L, 45 ng / L or 65 ng / L; for NT-proBNP, 500 ng / L, preferably 900 ng / L, more preferably 1300 ng / L, even more preferably 1700 ng / L, most preferably 2100 ng / L or 2800 ng / L; for MR-proADM, 0.8 nmol / L or 1.0 nmol / L, preferably 1.25 nmol / L, more preferably 1.5 nmol / L, even more preferably 1.75 nmol / L, most preferably 2.0 nmol / L or 2.4 nmol / L; - 80 pmol / L, preferably 90 pmol / L, more preferably 100 pmol / L, even more preferably 110 pmol / L, most preferably 120 pmol / L for CT-proET-1; - for PCT, 0.5 μg / L, preferably 1.0 μg / L, more preferably 1.5 μg / L, even more preferably 2.0 μg / L, most preferably 2.5 μg / L or 3.0 μg / L. In another specific embodiment, the threshold value is within a margin of plus or minus 10% of any of the above threshold values. Thus, the threshold value for copeptin can be, for example, anywhere between 22.5 pmol / L and 27.5 pmol / L (e.g., a range of 25 pmol / L plus or minus 10%). This applies to all exemplary threshold values ​​given herein.

[0082] In a further particular embodiment, the risk of MACCE, preferably combined with infection, in a patient relates to the risk of MACCE, preferably combined with infection, in a patient within at least one of 30 days and 12 months after gastrointestinal surgery, these periods having been proven to be of greatest importance in clinical prognosis.

[0083] Apart from the mere occurrence of MACCE, preferably in combination with an infection, the present invention may also be used to assess the risk of patient death, in particular death due to the development of MACCE, preferably in combination with an infection, after gastrointestinal surgery. Thus, the prognosis includes the risk of death within 30 days and / or within 12 months after gastrointestinal surgery.

[0084] An important subgroup of MACCE, myocardial injury after non-cardiac surgery (MINS), has already been mentioned. Since MINS is the cause of numerous complications, including increased patient mortality, and prolonged hospitalization, in a preferred embodiment of the present invention, the MACCE is MINS, and the method is a method for the diagnosis of MINS, preferably combined with infection, in patients who have undergone gastrointestinal surgery. In other words, the method of the present invention may target a specific diagnosis and / or prognosis related to MINS, preferably combined with infection, in patients who have undergone gastrointestinal surgery. Since MINS typically does not show any specific symptoms well in other clinical tests, including ECG, the present invention is of high practical value because patients who develop MINS may not be detected and therefore not treated otherwise.

[0085] Thus, in a preferred embodiment of the present invention, a biomarker level determined to exceed a certain threshold is indicative of MINS in a patient, preferably in combination with an infection. Needless to say, the general remarks regarding the definition and determination of a certain threshold mentioned above also apply to this particular threshold, preferably in relation to MINS in combination with an infection.

[0086] In another preferred embodiment of the invention, the determined biomarker level above a particular threshold is indicative of perioperative myocardial injury in the patient. Of course, the general caution regarding the definition and determination of a particular threshold mentioned above also applies to this particular threshold in the context of perioperative myocardial injury.

[0087] As exemplary values, and in preferred embodiments of the present invention, specific threshold values ​​are selected from the group consisting of the following, above which the biomarker levels are indicative of MINS in a patient, preferably in combination with an infection: for copeptin, 25 pmol / L, preferably 50 pmol / L or 75 pmol / L, more preferably 125 pmol / L, even more preferably 175 pmol / L, most preferably 225 pmol / L; for cTnT, 10 ng / L, preferably 20 ng / L, more preferably 30 ng / L, even more preferably 40 ng / L, most preferably 50 ng / L or 60 ng / L; for NT-proBNP, 250 ng / L or 500 ng / L, preferably 750 ng / L, more preferably 1250 ng / L or 1500 ng / L, even more preferably 1750 ng / L, most preferably 2250 ng / L; - for MR-proADM, 0.8 nmol / L or 1.0 nmol / L, preferably 1.25 nmol / L, more preferably 1.5 nmol / L, even more preferably 1.75 nmol / L, most preferably 2.0 nmol / L; - for CT-proET-1, 65 pmol / L or 75 pmol / L or 80 pmol / L, preferably 90 pmol / L, more preferably 100 pmol / L, even more preferably 110 pmol / L, most preferably 120 pmol / L; - for PCT, 0.2 μg / L or 0.5 μg / L, preferably 0.75 μg / L or 0.8 μg / L, more preferably 1.0 μg / L, even more preferably 1.25 μg / L, most preferably 1.5 μg / L. In another specific embodiment, the threshold value is within a margin of plus or minus 10% of any of the above threshold values. Thus, the threshold value for copeptin can be, for example, anywhere between 22.5 pmol / L and 27.5 pmol / L (e.g., a range of 25 pmol / L plus or minus 10%). This applies to all exemplary threshold values ​​given herein.

[0088] Another option in determining the specific threshold above which the level of the biomarker indicates MACCE and / or MINS is to also consider the time point at which the sample in question was taken from the patient, preferably in combination with infection. For example, the level of a certain biomarker, for example copeptin, is elevated immediately after gastrointestinal surgery, both in patients with MACCE and / or MINS and in those without such complications. However, this increase quickly falls off again. Therefore, when assessing the level of copeptin, it is necessary to select a higher specific threshold for samples taken up to 24 hours after gastrointestinal surgery compared to any other time point. This can be done for any of the biomarkers mentioned herein. Thus, in a preferred embodiment of the present invention, the determined biomarker levels obtained at different times are preferably evaluated using different thresholds. In this way, the physiological baseline of the determined biomarker levels in patients without MACCE and / or MINS with or without infection can be considered and taken into account in the method of the present invention.

[0089] Another increase in the diagnostic performance of the present invention may be achieved when the determined biomarker levels obtained at different times are weighted differently. For example, an increase in troponin levels in samples taken on the second and / or third day after gastrointestinal surgery is more important than an increase in troponin levels in samples taken before gastrointestinal surgery. Thus, the increase in levels on the second and / or third day after gastrointestinal surgery can be given a greater diagnostic weight in the combined evaluation, meaning that the increase in these levels at these specific time points will have more impact on the combined evaluation than less important measurements at other time points. The different weights assigned to the biomarker levels obtained at different times may also relate to different biomarkers. For example, an increase in troponin levels in samples taken on the second and / or third day after gastrointestinal surgery may be more important than an increase in copeptin levels on the first and / or second and / or third day after gastrointestinal surgery. The performance of the present invention can be increased by weighting the determined biomarker levels according to the diagnostic value at the specific time point of each measurement.

[0090] By providing multiple samples from different time points from a patient, these samples and their importance to the diagnosis and / or prognosis of the patient can be evaluated in many different ways. For example, the relative change in biomarker level between two samples taken at different times can be combined into said combined evaluation. The relative change is measured as a decrease or increase in the level of a particular biomarker, expressed, for example, as a percentage, compared to a previous level. This can be determined, for example, by how much the biomarker has increased or decreased considering one or more previous measurements. These measurements do not have to be consecutive. For example, the increase or decrease in the level of a biomarker can be determined from a measurement before the gastrointestinal surgery to the first and / or second and / or third and / or fourth postoperative measurement. In this way, each sample taken at a particular time point can be compared to any other sample from any other time point. This can be different for each biomarker. For example, the method can include using the relative change in BNP from samples taken on the second and third days after surgery, and in addition the relative change in copeptin between a sample taken up to 24 hours after gastrointestinal surgery and a sample taken on the first day after surgery. Any such combination is possible.

[0091] In another preferred embodiment of the present invention, the ratio between the levels of at least two biomarkers in a sample is determined and the ratios are combined into a combined assessment, where the biomarkers for determining the ratio are preferably selected from the copeptin / troponin pair, the copeptin / BNP pair, and the BNP / troponin pair. The levels of the at least two biomarkers may be from one sample or from different samples, in particular different samples taken at different time points. The ratio can be calculated directly between the measured levels of the biomarkers or between parameters derived from the levels of the biomarkers, such as the relative change in the biomarker levels. In a preferred embodiment, the ratio between the relative change of the at least two biomarkers is determined and combined into a combined assessment. In another preferred embodiment, the ratios determined from samples taken at different times are compared to obtain the relative change in the ratio over time, preferably expressed as a percentage, which is then also combined into a combined assessment.

[0092] For example, the method also includes providing reference data for the determined biomarkers, and in particular for the parameters determined as described above, such as the difference between the biomarker levels at two different time points, the relative change in the biomarker levels, or the ratio of the biomarker levels. This reference data can then be used to compare the measurement results and determine the patient's condition. In this preferred embodiment, step iv) includes providing reference data for the determined biomarkers, - A determined level of at least one of the biomarkers, - A difference in the level of at least one of the biomarkers obtained at different times, - the relative change in the level of one of the biomarkers determined in two samples obtained at different times, - the ratio between the levels of at least two biomarkers obtained simultaneously or at different times, and - a relative change in the ratio of at least two biomarkers determined in at least two samples obtained at different times; The difference between the determined values ​​and the reference data is calculated in comparison with the reference data, the calculated difference being preferably expressed in the form of a score, in particular as a numerical value.

[0093] Reference data are preferably also provided for clinical parameters as additional parameters. Reference data are again preferably provided from a reference group of patients who have also undergone gastrointestinal surgery, although reference data from a reference group of healthy patients are also suitable in principle. As mentioned before, the clinical parameters determined in the patient are preferably compared with the reference data and the results are converted into a score, in particular a numerical value. The clinical parameters can be determined at the same time(s) as the biomarker level(s), although it would only make sense to take more than one value if significant changes in the clinical parameters are expected in the time frame in question. Clinical parameters such as age, smoking habits, patient medical history, etc. need only be taken once of course. Other clinical parameters such as ECG may be taken at several time points. The relative changes in the values ​​thus obtained can be evaluated in a similar manner as described for the biomarker levels.

[0094] The term "score" in the context of the present invention refers to a rating, especially expressed as a numerical value, based on a particular outcome or the extent of a certain quality or condition (e.g., biomarker level or derived parameter) present in the patient.

[0095] It is further preferred that at least two different scores are determined, and the combined evaluation comprises a combined score determined from said at least two different scores, which indicates the presence or absence of MACCE, preferably combined with infection, in the patient.In other words, the method represents each of the determined parameters, i.e. at least one biomarker level and at least one additional parameter, as a score representing an intermediate result, which can then be combined into a combined evaluation from which the desired diagnosis and / or prognosis can be derived.For example, the reference data is divided into groups of values, which preferably increase or decrease linearly. The increase or decrease is preferably consistent with the severity of the outcome of the patient from which the reference data was obtained. Each group is associated with a respective score, for example, such that the number increases with severity.The values ​​determined for the patient according to steps ii) and iii) are then compared with the reference values ​​associated with the predefined groups.The score of the appropriate group is then assigned to the determined parameters and used to evaluate the combined score, which will form the basis of the final evaluation. This evaluation is performed for each of the parameters determined in steps ii) and iii), i.e. the level of at least one biomarker and at least one additional parameter. In the same manner, the biomarker levels or their differences or their relative changes or their proportions at said specific time points can be evaluated and expressed as scores, which are then used in the combined score.

[0096] These scores and combination scores can be expressed numerically, and therefore can also be graded according to their degree of difference with respect to reference data.This results in a graded combination score that can be useful for stratifying patients into specific risk groups related to the diagnosis and / or prognosis of patients with or developing MACCE or MINS, preferably combined with infection.Such risk groups can relate, for example, to low, medium or high risk of having or developing MACCE or MINS, preferably combined with infection, in the time frame specifically mentioned above.Stratification can also relate to risk of death, again in the time frame specifically mentioned above.The scores described can also be used for treatment guidance, with different risk groups indicating that certain patients require different treatment approaches.

[0097] Reference data can be data obtained from healthy subjects. These subjects can be those who have no known pathology and do not undergo gastrointestinal surgery. However, reference data is preferably related to patients who have undergone gastrointestinal surgery, and patients who have and / or have not had MACCE or MINS with or without infection. It is particularly meaningful to compare the data obtained from patients as described above with reference data from patients who have undergone gastrointestinal surgery but have not developed MACCE or MINS with or without infection, which is why this is the most preferred embodiment.

[0098] In the following, embodiments are described relating to determining the level of at least one of the biomarkers copeptin, troponin, and BNP in combination with the level of at least one of the biomarkers proADM, PCT, and proET-1, or fragment(s) thereof, for diagnosing or predicting MACCE in combination with an infection.

[0099] ADM / any infection: In one embodiment, determining the level of at least one additional biomarker includes determining the level of proADM or a fragment(s) thereof, wherein a level of proADM or a fragment(s) thereof above a threshold indicates a high likelihood of infection.

[0100] In one embodiment, the sample is isolated preoperatively, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment(s) thereof, wherein a level of proADM or a fragment(s) thereof above a threshold value selected from a range of values ​​between 0.7 nmol / L and 0.8 nmol / L ±20% or more indicates a high probability of infection. Any value within this range may be considered as a suitable threshold value. For example, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8 nmol / L.

[0101] In one embodiment, the sample is isolated within 12 hours, preferably within 6 hours, after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment(s) thereof, wherein a level of proADM or a fragment(s) thereof above a threshold value selected from a range of values ​​between 1.0 nmol / L and 1.2 nmol / L ±20% or more indicates a high probability of infection. Any value within this range may be considered as a suitable threshold value. For example, 1.0, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2 nmol / L.

[0102] In one embodiment, the sample is isolated postoperatively, one day after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment(s) thereof, wherein a level of proADM or a fragment(s) thereof above a threshold value selected from a range of values ​​between 1.3 nmol / L and 1.5 nmol / L ±20% or more indicates a high probability of infection. Any value within this range may be considered as a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5 nmol / L.

[0103] In one embodiment, the sample is isolated postoperatively, 2 days after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment(s) thereof, wherein a level of proADM or a fragment(s) thereof above a threshold value selected from a range of values ​​between 1.3 nmol / L and 1.5 nmol / L ±20% or more indicates a high probability of infection. Any value within this range may be considered as a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5 nmol / L.

[0104] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment(s) thereof, wherein a level of proADM or a fragment(s) thereof above a threshold value selected from a range of values ​​between 1.1 nmol / L and 1.5 nmol / L ±20% or more indicates a high likelihood of infection. Any value within this range may be considered a suitable threshold value. For example, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5 nmol / L.

[0105] In one embodiment, the sample is isolated after surgery and determining the level of at least one biomarker comprises determining the level of proADM or a fragment(s) thereof, wherein a level of proADM or a fragment(s) thereof above a threshold value selected from a range of values ​​between 1.1 nmol / L and 1.5 nmol / L ±20% or more indicates a high likelihood of infection. Any value within this range may be considered a suitable threshold value. For example, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5 nmol / L.

[0106] In one embodiment, the sample is isolated postoperatively, 1, 2, 3 or more days after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment(s) thereof, wherein a level of proADM or a fragment(s) thereof above a threshold value selected from a range of values ​​between 1.3 nmol / L and 1.5 nmol / L ±20% or more indicates a high probability of infection. Any value within this range may be considered as a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5 nmol / L.

[0107] In one embodiment, a first sample is isolated from the patient post-operatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient post-operatively at a subsequent second time point, preferably with at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining a level of proADM or a fragment(s) thereof, and an increase or plateauing in the level of proADM or a fragment(s) thereof indicates a high likelihood of infection.

[0108] In one embodiment, a first sample is isolated from the patient at a first time point, preferably postoperatively, one or more days after surgery, and a second sample is isolated from the patient at a subsequent second time point, preferably at least 12, 24, 36, 48 hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining the level of proADM or fragment(s) thereof, wherein an increase in the level of proADM or fragment(s) thereof above a threshold value selected from a range of values ​​between 0.01 nmol / L and 0.4 nmol / L ±20% or more indicates a high likelihood of infection. Any value within this range may be considered as a suitable threshold value for the increase in proADM or fragment(s) between the first and second time points. For example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4 nmol / L.

[0109] ADM / Blood-borne diseases: In one embodiment, determining the level of at least one additional biomarker includes determining the level of proADM or a fragment(s) thereof, wherein a level of proADM or a fragment(s) thereof above a threshold indicates a high likelihood of a blood-borne infection.

[0110] In one embodiment, the sample is isolated preoperatively, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment(s) thereof, wherein a level of proADM or a fragment(s) thereof above a threshold value selected from a range of values ​​between 0.7 nmol / L and 0.9 nmol / L ±20% or more indicates a high probability of blood-borne infection. Any value within this range may be considered as a suitable threshold value. For example, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.84, 0.85, 0.86, 0.87, 0.88.0.89, 0.9 nmol / L.

[0111] In one embodiment, the sample is isolated within 12 hours, preferably within 6 hours, after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment(s) thereof, wherein a level of proADM or a fragment(s) thereof above a threshold value selected from a range of values ​​between 1.0 nmol / L and 1.3 nmol / L ±20% or more indicates a high probability of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 1.0, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3 nmol / L.

[0112] In one embodiment, the sample is isolated post-operatively, one day after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment(s) thereof, wherein a level of proADM or a fragment(s) thereof above a threshold value selected from a range of values ​​between 1.2 nmol / L and 1.8 nmol / L ±20% or more indicates a high likelihood of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5 , 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1. 66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8nmol / L.

[0113] In one embodiment, the sample is isolated post-operatively, 2 days after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment(s) thereof, wherein a level of proADM or a fragment(s) thereof above a threshold value selected from a range of values ​​between 1.2 nmol / L and 1.8 nmol / L ±20% or more indicates a high likelihood of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5 , 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1. 66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8nmol / L.

[0114] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment(s) thereof, wherein a level of proADM or a fragment(s) thereof above a threshold value selected from a range of values ​​between 1.2 nmol / L and 1.8 nmol / L ±20% or more indicates a high likelihood of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5 , 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1. 66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8nmol / L.

[0115] In one embodiment, the sample is isolated after surgery and determining the level of at least one biomarker comprises determining the level of proADM or a fragment(s) thereof, wherein a level of proADM or a fragment(s) thereof above a threshold value selected from a range of values ​​between 1.1 nmol / L and 1.5 nmol / L ±20% or more indicates a high likelihood of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5 nmol / L.

[0116] In one embodiment, the sample is isolated postoperatively, 1, 2, 3 or more days after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment(s) thereof, wherein a level of proADM or a fragment(s) thereof above a threshold value selected from a range of values ​​between 1.3 nmol / L and 1.8 nmol / L ±20% or more indicates a high likelihood of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.60, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.70, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.80, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.90, 1.91, 1.92, 1.93 .55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.6 8, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8nmol / L.

[0117] In one embodiment, a first sample is isolated from the patient post-operatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient post-operatively at a subsequent second time point, preferably with at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining a level of proADM or a fragment(s) thereof, and an increase or plateauing in the level of proADM or a fragment(s) thereof indicates a high likelihood of a blood infection.

[0118] In one embodiment, a first sample is isolated from the patient postoperatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient postoperatively at a subsequent second time point, preferably at least 12, 24, 36, 48 or more hours having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining the level of proADM or fragment(s) thereof, wherein an increase in the level of proADM or fragment(s) thereof above a threshold value selected from a range of values ​​between 0.01 nmol / L and 0.4 nmol / L ±20% or more indicates a high likelihood of blood infection. Any value within this range may be considered as a suitable threshold value for the increase in proADM or fragment(s) between the first and second time points. For example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4 nmol / L.

[0119] PCT / any infection: In one embodiment, determining the level of the at least one additional biomarker comprises determining the level of PCT or a fragment(s) thereof, wherein a level of PCT or a fragment(s) thereof above a threshold indicates an increased likelihood of infection.

[0120] In one embodiment, the sample is isolated within 12 hours, preferably within 6 hours, after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment(s) thereof, wherein a level of PCT or a fragment(s) thereof above a threshold value selected from a range of values ​​between 0.2 μg / L and 0.3 μg / L ±20% or more indicates a high probability of infection. Any value within this range may be considered as a suitable threshold value. For example, 0.1, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3 μg / L.

[0121] In one embodiment, the sample is isolated post-operatively, one day after surgery, and determining the level of the at least one biomarker comprises determining the level of PCT or a fragment(s) thereof, wherein a level of PCT or a fragment(s) thereof above a threshold value selected from a range of values ​​between 0.6 μg / L and 0.9 μg / L ±20% or more indicates a high likelihood of infection. Any value within this range may be considered a suitable threshold value. For example, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9 μg / L.

[0122] In one embodiment, the sample is isolated postoperatively, 2 days after surgery, and determining the level of at least one biomarker includes determining the level of PCT or a fragment(s) thereof, wherein a level of PCT or a fragment(s) thereof above a threshold value selected from a range of values ​​between 0.7 μg / L and 1.3 μg / L ±20% or more indicates a high likelihood of infection. Any value within this range may be considered a suitable threshold value. For example, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1. , 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1 .16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3μg / L.

[0123] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining a level of PCT or a fragment(s) thereof, wherein a level of PCT or a fragment(s) thereof above a threshold value selected from a range of values ​​between 0.6 μg / L and 1.3 μg / L ±20% or more indicates a high likelihood of infection. Any value within this range may be considered a suitable threshold value. For example, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0 .95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.1 3, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3μg / L.

[0124] In one embodiment, the sample is isolated postoperatively, one or more days after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment(s) thereof, wherein a level of PCT or a fragment(s) thereof above a threshold value selected from a range of values ​​between 0.6 μg / L and 1.1 μg / L ±20% or more indicates a high likelihood of infection. Any value within this range may be considered a suitable threshold value. For example, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.9 ... .85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0 .98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1μg / L.

[0125] In one embodiment, the sample is isolated postoperatively, 2, 3 or more days after surgery, and determining the level of the at least one biomarker comprises determining a level of PCT or a fragment(s) thereof, wherein a level of PCT or a fragment(s) thereof above a threshold value selected from a range of values ​​between 0.7 μg / L and 1.3 μg / L ±20% or more indicates a high likelihood of infection. Any value within this range may be considered a suitable threshold. For example, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1 , 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1 .16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3μg / L.

[0126] In one embodiment, a first sample is isolated from the patient post-operatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient post-operatively at a subsequent second time point, preferably with at least 12, 24, 36, 48 or more hours having elapsed between the first and second time points, and determining the level of the at least one biomarker comprises determining a level of PCT or a fragment(s) thereof, wherein an increased level of PCT or a fragment(s) thereof indicates an increased likelihood of infection.

[0127] In one embodiment, a first sample is isolated from the patient at a first time point, preferably postoperatively, one or more days after surgery, and a second sample is isolated from the patient at a subsequent second time point, preferably at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more elapsed between the first and second time points, and determining the level of at least one biomarker includes determining the level of PCT or a fragment(s) thereof, wherein an increase in the level of PCT or a fragment(s) thereof above a threshold value selected from a range of values ​​between 0.1 μg / L and 0.6 μg / L ±20% or more indicates a high likelihood of infection. Any value within this range may be considered a suitable threshold value for the increase in PCT or a fragment(s) thereof between the first and second time points. For example, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0. 35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0. 48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.6μg / L.

[0128] PCT / Blood-borne diseases: In one embodiment, determining the level of the at least one additional biomarker comprises determining the level of PCT or a fragment(s) thereof, wherein a level of PCT or a fragment(s) thereof above a threshold indicates a high likelihood of a blood-borne infection.

[0129] In one embodiment, the sample is isolated within 12 hours, preferably within 6 hours, after surgery, and determining the level of at least one biomarker includes determining the level of PCT or a fragment(s) thereof, wherein a level of PCT or a fragment(s) thereof above a threshold value selected from a range of values ​​between 0.1 μg / L and 0.3 μg / L ±20% or more indicates a high probability of blood-borne infection. Any value within this range may be considered as a suitable threshold value. For example, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3 μg / L.

[0130] In one embodiment, the sample is isolated postoperatively, one day after surgery, and determining the level of at least one biomarker includes determining the level of PCT or a fragment(s) thereof, wherein a level of PCT or a fragment(s) thereof above a threshold value selected from a range of values ​​between 0.6 μg / L and 1.8 μg / L ±20% or more indicates a high likelihood of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89 ,0.9,0.91,0.92,0.93,0.94,0.95,0.96,0.97,0.98,0.99,1,1.01,1.02,1.03,1.04,1.05,1.06,1.07,1.08,1.09,1.1,1.11,1.12,1.13,1.14,1.15,1.16,1.17,1.18,1.19,1.2,1 .21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1 .66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8μg / L.

[0131] In one embodiment, the sample is isolated post-operatively, 2 days after surgery, and determining the level of the at least one biomarker comprises determining the level of PCT or a fragment(s) thereof, wherein a level of PCT or a fragment(s) thereof above a threshold value selected from a range of values ​​between 0.7 μg / L and 2.3 μg / L ±20% or more indicates a high likelihood of blood-borne infection. Any value within this range may be considered a suitable threshold. For example, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1 .1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.9 , 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2, 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.1, 2. 11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.2, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.3μg / L.

[0132] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment(s) thereof, wherein a level of PCT or a fragment(s) thereof above a threshold value selected from a range of values ​​between 0.7 μg / L and 2.3 μg / L ±20% or more indicates a high likelihood of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1. 1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1. 5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8, 1.8, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1. 9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2, 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.1, 2. 11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.2, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.3μg / L.

[0133] In one embodiment, the sample is isolated postoperatively, one or more days after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment(s) thereof, wherein a level of PCT or a fragment(s) thereof above a threshold value selected from a range of values ​​between 0.7 μg / L and 1.8 μg / L ±20% or more indicates a high likelihood of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89 ,0.9,0.91,0.92,0.93,0.94,0.95,0.96,0.97,0.98,0.99,1,1.01,1.02,1.03,1.04,1.05,1.06,1.07,1.08,1.09,1.1,1.11,1.12,1.13,1.14,1.15,1.16,1.17,1.18,1.19,1.2,1 .21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1 .66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8μg / L.

[0134] In one embodiment, the sample is isolated postoperatively, 2, 3 or more days after surgery, and determining the level of the at least one biomarker comprises determining a level of PCT or a fragment(s) thereof, wherein a level of PCT or a fragment(s) thereof above a threshold value selected from a range of values ​​between 1 μg / L and 2.3 μg / L ±20% or more indicates a high likelihood of blood-borne infection. Any value within this range may be considered a suitable threshold. For example, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32 ,1.33,1.34,1.35,1.36,1.37,1.38,1.39,1.4,1.41,1.42,1.43,1.44,1.45,1.46,1.47,1.48,1.49,1.5,1.5,1.5,1.51,1.52,1.53,1.54,1.55,1.56,1.57,1.58,1.59,1.6,1.61,1.62,1.63,1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2, 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.1, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.2, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.3μg / L.

[0135] In one embodiment, a first sample is isolated from the patient post-operatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient post-operatively at a subsequent second time point, preferably with at least 12, 24, 36, 48 or more hours having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining a level of PCT or a fragment(s) thereof, wherein an increased level of PCT or a fragment(s) thereof indicates a high likelihood of a blood infection.

[0136] In one embodiment, a first sample is isolated from the patient at a first time point, preferably postoperatively, one or more days after surgery, and a second sample is isolated from the patient at a subsequent second time point, preferably at least 12 hours, 24 hours, 36 hours, 48 ​​hours, or more elapsed between the first and second time points, and determining the level of at least one biomarker includes determining the level of PCT or a fragment(s) thereof, wherein an increase in the level of PCT or a fragment(s) thereof above a threshold value selected from a range of values ​​between 0.1 μg / L and 1 μg / L ±20% or more indicates a high likelihood of blood infection. Any value within this range may be considered a suitable threshold value for the increase in PCT or a fragment(s) thereof between the first and second time points. For example, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.54, 0 .55, 0.56, 0.57, 0.58, 0.59, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0 .78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1μg / L.

[0137] proET-1 / any infection: In one embodiment, determining the level of at least one additional biomarker includes determining the level of proET-1 or a fragment(s) thereof, wherein a level of proET-1 or a fragment(s) thereof above a threshold indicates a high likelihood of infection.

[0138] In one embodiment, the sample is isolated postoperatively, 2 days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment(s) thereof, wherein a level of proET-1 or a fragment(s) thereof above a threshold value selected from a range of values ​​between 85 pmol / L and 95 pmol / L ±20% or more indicates a high probability of infection. Any value within this range may be considered a suitable threshold value. For example, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 pmol / L.

[0139] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment(s) thereof, wherein a level of proET-1 or a fragment(s) thereof above a threshold value selected from a range of values ​​between 80 pmol / L and 95 pmol / L ±20% or more indicates a high probability of infection. Any value within this range may be considered a suitable threshold value. For example, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 pmol / L.

[0140] In one embodiment, the sample is isolated postoperatively, 2, 3 or more days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment(s) thereof, wherein a level of proET-1 or a fragment(s) thereof above a threshold value selected from a range of values ​​between 80 pmol / L and 95 pmol / L ±20% or more indicates a high probability of infection. Any value within this range may be considered a suitable threshold value. For example, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95 pmol / L.

[0141] proET-1 / blood infections: In one embodiment, determining the level of at least one additional biomarker includes determining the level of proET-1 or a fragment(s) thereof, wherein a level of proET-1 or a fragment(s) thereof above a threshold indicates a high likelihood of a blood-borne infection.

[0142] In one embodiment, the sample is isolated postoperatively, 2 days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment(s) thereof, wherein a level of proET-1 or a fragment(s) thereof above a threshold value selected from a range of values ​​between 85 pmol / L and 105 pmol / L ±20% or more indicates a high probability of blood-borne infection. Any value within this range may be considered a suitable threshold value. For example, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105 pmol / L.

[0143] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment(s) thereof, wherein a level of proET-1 or a fragment(s) thereof above a threshold value selected from a range of values ​​between 80 pmol / L and 110 pmol / L ±20% or more indicates a high probability of blood-borne infection. Any value within this range may be considered as a suitable threshold value. For example, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110 pmol / L.

[0144] In one embodiment, the sample is isolated postoperatively, 2, 3 or more days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment(s) thereof, wherein a level of proET-1 or a fragment(s) thereof above a threshold value selected from a range of values ​​between 80 pmol / L and 110 pmol / L ±20% or more indicates a high probability of blood-borne infection. Any value within this range may be considered as a suitable threshold value. For example, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110 pmol / L.

[0145] ADM / Infectious Diseases and MACCE / MINS: In one embodiment, determining the level of at least one additional biomarker includes determining the level of proADM or a fragment(s) thereof, wherein a level of proADM or a fragment(s) thereof above a threshold indicates an increased likelihood of infection, preferably a blood infection, and a cardiovascular or cerebrovascular adverse event, preferably MACCE and / or MINS.

[0146] In one embodiment, the sample is isolated before surgery, and determining the level of at least one biomarker comprises determining the level of proADM or its fragment(s), wherein a level of proADM or its fragment(s) above a threshold value selected from a range of values ​​between 0.7 nmol / L and 0.9 nmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9 nmol / L.

[0147] In one embodiment, the sample is isolated within 12 hours, preferably within 6 hours, after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or its fragment(s), wherein a level of proADM or its fragment(s) above a threshold value selected from the range of values ​​between 1.0 nmol / L and 1.6 nmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1. 46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6nmol / L.

[0148] In one embodiment, the sample is isolated postoperatively, one day after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or its fragment(s), wherein a level of proADM or its fragment(s) above a threshold value selected from a range of values ​​between 1.3 nmol / L and 2.2 nmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1. 75,1.76,1.77,1.78,1.79,1.8,1.81,1.82,1.83,1.84,1.85,1.86,1.87,1.88,1.89,1.9,1.91,1.92,1.93,1.94,1.95,1.96,1.97,1. 98, 1.99, 2, 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.1, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.2nmol / L.

[0149] In one embodiment, the sample is isolated postoperatively, 2 days after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment(s) thereof, wherein a level of proADM or a fragment(s) thereof above a threshold value selected from a range of values ​​between 1.3 nmol / L and 2.3 nmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54 ,1.55,1.56,1.57,1.58,1.59,1.6,1.61,1.62,1.63,1.64,1.65,1.66,1.67,1.68,1.69,1.7,1.71,1.72,1.73,1.74,1.75,1.76,1.77,1.78,1.79,1. 8, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2, 2.01, 2.02, 2.03, 2.04, 2.05, 2. 06, 2.07, 2.08, 2.09, 2.1, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2 .19, 2.2, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.3nmol / L.

[0150] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment(s) thereof, wherein a level of proADM or a fragment(s) thereof above a threshold value selected from a range of values ​​between 1.3 nmol / L and 2.3 nmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54 ,1.55,1.56,1.57,1.58,1.59,1.6,1.61,1.62,1.63,1.64,1.65,1.66,1.67,1.68,1.69,1.7,1.71,1.72,1.73,1.74,1.75,1.76,1.77,1.78,1.79,1. 8, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2, 2.01, 2.02, 2.03, 2.04, 2.05, 2. 06, 2.07, 2.08, 2.09, 2.1, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2 .19, 2.2, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.3nmol / L.

[0151] In one embodiment, the sample is isolated after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or its fragment(s), wherein a level of proADM or its fragment(s) above a threshold value selected from a range of values ​​between 1.3 nmol / L and 2 nmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1. 65, 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8, 1.81, 1.82, 1.8 3, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2nmol / L.

[0152] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment(s) thereof, wherein a level of proADM or a fragment(s) thereof above a threshold value selected from a range of values ​​between 1.3 nmol / L and 2.3 nmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54 ,1.55,1.56,1.57,1.58,1.59,1.6,1.61,1.62,1.63,1.64,1.65,1.66,1.67,1.68,1.69,1.7,1.71,1.72,1.73,1.74,1.75,1.76,1.77,1.78,1.79,1. 8, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2, 2.01, 2.02, 2.03, 2.04, 2.05, 2. 06, 2.07, 2.08, 2.09, 2.1, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2 .19, 2.2, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.3nmol / L.

[0153] In one embodiment, a first sample is isolated from the patient post-operatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient post-operatively at a subsequent second time point, preferably with at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining the level of proADM or a fragment(s) thereof, and an increased level of proADM or a fragment(s) thereof indicates an increased likelihood of infection, preferably a blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS.

[0154] In one embodiment, a first sample is isolated from the patient postoperatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient postoperatively at a subsequent second time point, preferably at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining the level of proADM or its fragment(s), and an increase in the level of proADM or its fragment(s) above a threshold value selected from a range of values ​​between 0.01 nmol / L and 1 nmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value for the increase in proADM or fragment(s) between the first and second time points. For example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0. 29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58 0.59, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0 .8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1nmol / L.

[0155] PCT / Infectious Diseases and MACCE / MINS: In one embodiment, determining the level of the at least one additional biomarker comprises determining the level of PCT or a fragment(s) thereof, wherein a level of PCT or a fragment(s) thereof above a threshold indicates an increased likelihood of infection, preferably a blood infection, and a cardiovascular or cerebrovascular adverse event, preferably MACCE and / or MINS.

[0156] In one embodiment, the sample is isolated within 12 hours, preferably within 6 hours, after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment(s) thereof, wherein a level of PCT or a fragment(s) thereof above a threshold value selected from a range of values ​​between 0.1 μg / L and 0.4 μg / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4 μg / L.

[0157] In one embodiment, the sample is isolated postoperatively, one day after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment(s) thereof, wherein a level of PCT or a fragment(s) thereof above a threshold value selected from a range of values ​​between 0.6 μg / L and 1.8 μg / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.8 9, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1. 2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.291.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1 .51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1. 66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8μg / L.

[0158] In one embodiment, the sample is isolated postoperatively, 2 days after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment(s) thereof, wherein a level of PCT or a fragment(s) thereof above a threshold value selected from a range of values ​​between 0.6 μg / L and 3 μg / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.291.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1. 37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1 .76, 1.77, 1.78, 1.79, 1.8, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2, 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.1, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.2, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.3, 2.31, 2.32, 2.33, 2.34, 2.35, 2.36, 2.37, 2.38, 2.39, 2.4, 2.41, 2.42, 2.43, 2.44, 2.45, 2.46, 2.47, 2.48, 2.49, 2.5, 2.51, 2.52, 2.53, 2.54, 2.55, 2.56, 2.57, 2. 58, 2.59, 2.6, 2.61, 2.62, 2.63, 2.64, 2.65, 2.66, 2.67, 2.68, 2.69, 2.7, 2.71, 2.72, 2.73, 2.74, 2.75, 2.76, 2.77, 2.78, 2.79, 2.8, 2.81, 2.82, 2.83, 2.84, 2.85, 2.86, 2.87, 2.88, 2.89, 2.9, 2.91, 2.92, 2.93, 2.94, 2.95, 2.96, 2.97, 2.98, 2.99, 3μg / L.

[0159] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment(s) thereof, wherein a level of PCT or a fragment(s) thereof above a threshold value selected from a range of values ​​between 0.6 μg / L and 3 μg / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.291.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1. 37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1 .76, 1.77, 1.78, 1.79, 1.8, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2, 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.1, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.2, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.3, 2.31, 2.32, 2.33, 2.34, 2.35, 2.36, 2.37, 2.38, 2.39, 2.4, 2.41, 2.42, 2.43, 2.44, 2.45, 2.46, 2.47, 2.48, 2.49, 2.5, 2.51, 2.52, 2.53, 2.54, 2.55, 2.56, 2.57, 2. 58, 2.59, 2.6, 2.61, 2.62, 2.63, 2.64, 2.65, 2.66, 2.67, 2.68, 2.69, 2.7, 2.71, 2.72, 2.73, 2.74, 2.75, 2.76, 2.77, 2.78, 2.79, 2.8, 2.81, 2.82, 2.83, 2.84, 2.85, 2.86, 2.87, 2.88, 2.89, 2.9, 2.91, 2.92, 2.93, 2.94, 2.95, 2.96, 2.97, 2.98, 2.99, 3μg / L.

[0160] In one embodiment, the sample is isolated after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment(s) thereof, wherein a level of PCT or a fragment(s) thereof above a threshold value selected from a range of values ​​between 0.7 μg / L and 3 μg / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08 ,1.09,1.1,1.11,1.12,1.13,1.14,1.15,1.16,1.17,1.18,1.19,1.2,1.21,1.22,1.23,1.24,1.25,1.26,1.27,1.28,1.291.3,1.31,1.32,1.33,1.34,1.35,1.36,1.37,1.38,1.39,1.4,1.41,1.42,1.43,1.44,1.45,1.46,1.47,1. 48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.8 7, 1.88, 1.89, 1.9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2, 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.1, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.2, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.3, 2.31, 2.32, 2.33, 2.34, 2.35, 2.36, 2.37, 2.38, 2.39, 2.4, 2.41, 2.42, 2.43, 2.44, 2.45, 2.46, 2.47, 2.48, 2.49, 2.5, 2.51, 2.52, 2.53, 2.54, 2.55, 2.56, 2.57, 2.58, 2.59, 2.6, 2.61, 2.62, 2.63, 2. 64, 2.65, 2.66, 2.67, 2.68, 2.69, 2.7, 2.71, 2.72, 2.73, 2.74, 2.75, 2.76, 2.77, 2.78, 2.79, 2.8, 2.81, 2.82, 2.83, 2.84, 2.85, 2.86, 2.87, 2.88, 2.89, 2.9, 2.91, 2.92, 2.93, 2.94, 2.95, 2.96, 2.97, 2.98, 2.99, 3μg / L.

[0161] In one embodiment, the sample is isolated postoperatively, 1, 2, 3 or more days after surgery, and determining the level of at least one biomarker comprises determining the level of PCT or a fragment(s) thereof, wherein a level of PCT or a fragment(s) thereof above a threshold value selected from a range of values ​​between 1 μg / L and 3 μg / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value.For example, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.291.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1 .75, 1.76, 1.77, 1.78, 1.79, 1.8, 1.81, 1.82, 1.83, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2 , 2.01, 2.02, 2.03, 2.04, 2.05, 2.06, 2.07, 2.08, 2.09, 2.1, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19, 2.2, 2.21, 2.22, 2.23, 2.24, 2.25 ,2.26,2.27,2.28,2.29,2.3,2.31,2.32,2.33,2.34,2.35,2.36,2.37,2.38,2.39,2.4,2.41,2.42,2.43,2.44,2.45,2.46,2.47,2.48,2.49,2.5, 2.51, 2.52, 2.53, 2.54, 2.55, 2.56, 2.57, 2.58, 2.59, 2.6, 2.61, 2.62, 2.63, 2.64, 2.65, 2.66, 2.67, 2.68, 2.69, 2.7, 2.71, 2.72, 2.73, 2.74, 2.75, 2.76, 2.77, 2.78, 2.79, 2.8, 2.81, 2.82, 2.83, 2.84, 2.85, 2.86, 2.87, 2.8 8, 2.89, 2.9, 2.91, 2.92, 2.93, 2.94, 2.95, 2.96, 2.97, 2.98, 2.99, 3 μg / L.

[0162] In one embodiment, a first sample is isolated from the patient post-operatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient post-operatively at a subsequent second time point, preferably with at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining a level of PCT or a fragment(s) thereof, and an increase or plateauing in the level of PCT or a fragment(s) thereof indicates an increased likelihood of infection, preferably a blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS.

[0163] In one embodiment, a first sample is isolated from the patient at a first time point, preferably one or more days after surgery, postoperatively, and a second sample is isolated from the patient at a subsequent second time point, preferably at least 12 hours, 24 hours, 36 hours, 48 ​​hours, or more elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining the level of PCT or its fragment(s), and an increase in the level of PCT or its fragment(s) above a threshold value selected from a range of values ​​between 0.1 μg / L and 2 μg / L ± 20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value for the increase in PCT or fragment(s) between the first and second time points.For example, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58 0.59, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0. 94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, 1.11, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.30, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.40, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.50, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.60, 1.61, 1.62, 1.63, 1.64, 1.65, 1.66, 1.67, 1.68, 1.69, 1.70, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1 3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.41, 1.42, 1.43, 1.44, 1.45, 1.46, 1.47, 1.48, 1.49, 1.5, 1.51, 1.52, 1.53, 1.54, 1.55, 1.56, 1.57, 1.58, 1.59, 1.6, 1.61, 1.62, 1.63, 1.64, 1.65 , 1.66, 1.67, 1.68, 1.69, 1.7, 1.71, 1.72, 1.73, 1.74, 1.75, 1.76, 1.77, 1.78, 1.79, 1.8, 1.81, 1.82, 1.8 3, 1.84, 1.85, 1.86, 1.87, 1.88, 1.89, 1.9, 1.91, 1.92, 1.93, 1.94, 1.95, 1.96, 1.97, 1.98, 1.99, 2μg / L.

[0164] proET-1 / infection and MACCE / MINS: In one embodiment, determining the level of at least one additional biomarker comprises determining the level of proET-1 or a fragment(s) thereof, wherein a level of proET-1 or a fragment(s) thereof above a threshold indicates an increased likelihood of infection, preferably a blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS.

[0165] In one embodiment, the sample is isolated before surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or its fragment(s), wherein a level of proET-1 or its fragment(s) above a threshold value selected from a range of values ​​between 60 pmol / L and 85 pmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85 pmol / L.

[0166] In one embodiment, the sample is isolated within 12 hours, preferably within 6 hours, after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or its fragment(s), wherein a level of proET-1 or its fragment(s) above a threshold value selected from a range of values ​​between 80 pmol / L and 110 pmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110 pmol / L.

[0167] In one embodiment, the sample is isolated postoperatively, one day after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment(s) thereof, wherein a level of proET-1 or a fragment(s) thereof above a threshold value selected from a range of values ​​between 80 pmol / L and 120 pmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120 pmol / L.

[0168] In one embodiment, the sample is isolated postoperatively, 2 days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or its fragment(s), wherein a level of proET-1 or its fragment(s) above a threshold value selected from a range of values ​​between 80 pmol / L and 120 pmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120 pmol / L.

[0169] In one embodiment, the sample is isolated postoperatively, 3 days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or its fragment(s), wherein a level of proET-1 or its fragment(s) above a threshold value selected from a range of values ​​between 80 pmol / L and 120 pmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120 pmol / L.

[0170] In one embodiment, the sample is isolated after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or its fragment(s), wherein a level of proET-1 or its fragment(s) above a threshold value selected from a range of values ​​between 80 pmol / L and 110 pmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110 pmol / L.

[0171] In one embodiment, the sample is isolated postoperatively, 1, 2, 3 or more days after surgery, and determining the level of at least one biomarker comprises determining the level of proET-1 or its fragment(s), wherein a level of proET-1 or its fragment(s) above a threshold value selected from a range of values ​​between 80 pmol / L and 120 pmol / L ±20% or more indicates a high probability of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value. For example, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120 pmol / L.

[0172] In one embodiment, a first sample is isolated from the patient post-operatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient post-operatively at a subsequent second time point, preferably with at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining the level of proET-1 or a fragment(s) thereof, and an increase or plateauing in the level of proET-1 or a fragment(s) thereof indicates an increased likelihood of infection, preferably a blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS.

[0173] In one embodiment, a first sample is isolated from the patient postoperatively at a first time point, preferably one or more days after surgery, and a second sample is isolated from the patient postoperatively at a subsequent second time point, preferably at least 12 hours, 24 hours, 36 hours, 48 ​​hours or more having elapsed between the first and second time points, and determining the level of at least one biomarker comprises determining the level of proET-1 or its fragment(s), wherein an increase in the level of proET-1 or its fragment(s) above a threshold value selected from a range of values ​​between 1 pmol / L and 40 pmol / L ±20% or more indicates a high likelihood of infection, preferably blood infection, and cardiovascular or cerebrovascular adverse events, preferably MACCE and / or MINS. Any value within this range may be considered as a suitable threshold value for the increase in proET-1 or fragment(s) between the first and second time points. For example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 pmol / L.

[0174] Some embodiments relate to determining the level of proET-1, PCT, or proADM, or a fragment(s) thereof, as an additional biomarker to diagnose or predict cardiovascular or cerebrovascular events, such as perioperative myocardial injury (PMI), and infections, such as blood infections.

[0175] In one embodiment, determining the level of at least one additional biomarker comprises determining the level of proET-1, PCT, and / or proADM, or fragment(s) thereof, wherein a level of proET-1, PCT, and / or proADM, or fragment(s) thereof above a threshold indicates a high likelihood of a cardiovascular or cerebrovascular adverse event, preferably perioperative myocardial injury (PMI), and the presence of an infection, preferably a blood infection. Samples may be taken preoperatively or intraoperatively in some embodiments.

[0176] The present invention also relates to a kit for carrying out the method described herein. All the features, effects and advantages of the method of the present invention also apply to the kit of the present invention and vice versa. Therefore, to avoid repetition, reference is made to the previous description. In particular, the kit of the present invention comprises at least one detection reagent for determining the level of at least one of the biomarkers copeptin, troponin and brain natriuretic peptide (BNP) in a sample of body fluid from a patient, and reference data, in particular reference levels, from a patient who has undergone gastrointestinal surgery corresponding to at least one of the copeptin, troponin and BNP levels, said reference data being preferably stored in a computer-readable medium and / or used in the form of a computer executable code configured to compare the determined level of at least one of copeptin, troponin and BNP with said reference data. Particularly preferably, the detection reagent comprises a reagent for determining the level of the biomarkers copeptin, troponin and brain natriuretic peptide (BNP) in a sample of body fluid from the patient, and the reference data comprises data corresponding to said biomarkers from a patient who has undergone gastrointestinal surgery.

[0177] The detection reagents may, for example, include capture molecules. They may, for example, be designed for use in an assay system such as Thermo Scientific B·R·A·H·M·S Kryptor Compact plus. In a preferred embodiment of the kit, the detection reagents also include reagents for determining the level of at least one of the biomarkers midregional pro-adrenomedullin (MR-proADM), C-terminal proendothelin-1 (CT-proET-1), and procalcitonin (PCT) in a sample of body fluid from the patient, and the reference data includes data corresponding to the at least one biomarker from patients who have undergone gastrointestinal surgery.

[0178] As used herein, the term "capture molecule" includes molecules that may be used to bind target molecules or molecules of interest, i.e., analytes (e.g., biomarkers), from a sample. Thus, the capture molecule must be appropriately shaped, both spatially and with respect to surface features such as surface charge, hydrophobicity, hydrophilicity, the presence or absence of Lewis donors and / or acceptors, to specifically bind to the target molecule or molecule of interest. Thereby, the binding may be mediated, for example, by ionic, van der Waals forces, pi-pi, sigma-pi, hydrophobic or hydrogen bond interactions, or a combination of two or more of the aforementioned interactions, or by covalent interactions between the capture molecule and the target molecule or molecule of interest. In the context of the present invention, the capture molecule may be selected, for example, from the group consisting of nucleic acid molecules, carbohydrate molecules, PNA molecules, proteins, peptides, and glycoproteins. Capture molecules include, for example, antibodies, aptamers, DAR pins (Designed Ankyrin Repeat Proteins), affimers, and the like.

[0179] The term "antibody" as used herein is used broadly to refer to both antibody molecules, such as monoclonal antibodies, polyclonal antisera, enriched or purified polyclonal antibodies, recombinant antibodies, and various antibody-derived molecules, particularly functional derivatives, unless otherwise indicated. Such antibody-derived molecules include at least one variable region (either heavy chain variable region or light chain variable region), as well as individual antibody light chains, individual antibody heavy chains, chimeric fusions between antibody chains and other molecules, and the like. Functional immunoglobulin fragments according to the present invention may be Fv, scFv, disulfide-linked Fv, Fab, and F(ab')2. The term "antibody" also encompasses polyclonal antibodies, monoclonal antibodies, preferably IgG1 antibodies, chimeric monoclonal antibodies, humanized antibodies, genetically engineered monoclonal antibodies. Functional derivatives are chemically and / or biochemically modified variants of antibodies / antisera with similar functionality / binding capabilities.

[0180] The reference data provided in the kit of the present invention is preferably designed to distinguish at least one of the pairs of patients with / without MACCE or MINS and with / without MACCE or MINS after gastrointestinal surgery.Therefore, the reference data is preferably designed to be compared with the biomarker level determined in the sample taken from the patient at a specific time point as described above.By using the kit of the present invention, clinicians can obtain a quick and easy diagnosis and / or prognosis of the patients undergoing gastrointestinal surgery, taking into account the risk of having and / or developing MACCE or MINS.

[0181] The present invention also encompasses a computer executing a computer executable code, the computer executable code being configured to execute step iv) and / or v) of the method of the present invention. For example, the computer executable code is designed to generate a combination assessment from input data, e.g., determined biomarker levels. In a preferred embodiment, the computer executing the code is also connected to an assay system, the assay system being configured to execute step ii) and optionally step iii) of the method of the present invention. The assay system can be, for example, Thermo Scientific B·R·A·H·M·S Kryptor Compact plus. In this way, the assay system can provide the computer with input data for executing step iv) and / or v). The computer can also be provided with the aforementioned reference data. Optimally, the user only needs to execute step i), and the computer with the assay system executes the remaining method and presents the user with the resulting diagnosis and / or prognosis, or at least a score(s) on which the diagnosis and / or prognosis can be made.

[0182] Finally, the present invention also relates to a computer program product comprising a set of computer instructions stored on at least one computer readable medium, said set of computer instructions further comprising instructions executable by one or more processors for executing steps iv) and / or v) of the method of the present invention. The computer readable medium may be any kind of computer storage means, such as a USB stick, an external or internal hard disk, a diskette, a tape storage device, an external mobile terminal, e.g. a mobile phone, a tablet or the like. EXAMPLES

[0183] A multicenter prospective cohort study was conducted in several hospitals in Sweden. Subjects were recruited consecutively from April 2017 to October 2018. Patients aged 50 years or older undergoing elective abdominal surgery graded as major or major / complex by the Surgical Outcome Risk Tool, SORT [Protopapa et al., British Journal of Surgery, 101(13), pp.1774-1783. doi:10.1002 / bjs.9638,2014] were eligible. In addition, the procedure had to be performed under general anesthesia and required at least one night of hospitalization. Eligible patients were identified by daily screening of the patient list at the preoperative assessment clinic. Before agreeing to participate, patients were informed of the study's aims, methods, expected benefits, possible risks, and the possibility of withdrawal at any time. Written informed consent was obtained from all patients before inclusion. Participants could only be included once and were excluded if they were unable to provide informed consent or if they underwent one of the following types of abdominal surgery: transplant, trauma, endocrine, vascular, or endovascular. Included patients were excluded if their elective surgery was cancelled due to patient death or if another non-elective surgery was performed before this elective surgery. The predefined study outcome was MACCE (as defined above) within 30 days. Overall patient characteristics are given in Table 1. [Table 1]

[0184] Five sampling points were defined: preoperative (less than 24 hours before anesthesia), postoperative (within 24 hours of surgery), and days 1, 2, and 3 after surgery. At these time points, arterial or venous blood samples were obtained using 8.5 ml EDTA Vacutainers. Blood samples were sent to a local clinical chemistry laboratory where the samples were centrifuged and the plasma was frozen in aliquots at -80°C and stored until batch analysis of plasma concentrations of biomarkers was performed. Concurrently, ECGs were obtained from each patient at each sampling point.

[0185] The occurrence of MACCE was reviewed through charts on days 1, 2, and 3, and 30 days after surgery via telephone interview and / or by reviewing the patients' medical records. The incidence of MINS was calculated from the analyzed cTnT plasma levels [according to Sessler and Khanna; Intensive Care Med (2018) 44: 811-822, https: / / doi.org / 10.1007 / s00134-018-5224-7]. Mortality was assessed using the Swedish population registry. If a patient was discharged, dropped out, or died before all samples were obtained, they were not excluded and the collected samples were analyzed, unless the patient asked not to be included in the data analysis.

[0186] Copeptin, MR-proADM, CT-proET-1, and PCT were measured using a Thermo Scientific B·R·A·H·M·S Kryptor Compact plus according to the manufacturer's instructions (B·R·A·H·M·S GmbH, Hennigsdorf, Germany). Cardiac troponin T (cTnT) and NT-proBNP were measured using Cobas e 602 / Cobas e 601 / Cobas e 411 assays according to the manufacturer's instructions (Roche Diagnostics, Mannheim, Germany).

[0187] Data analysis was performed using Graphpad PRISM 8. Data distribution was examined using the D'Agostino & Parson test. Comparisons between different groups were performed using Fisher's exact test and Kruskal-Wallis test. A p value of less than 0.05 was considered significant.

[0188] Patient and clinical characteristics are shown in Table 2. Here, ASA stands for the American Society of Anesthesiologists (ASA) physical status classification system. 387 surgical patients were recruited and included in the analysis. It is noteworthy that only 43% of patients who had MACCE were classified as high-risk patients (ASA III-IV) and only 38% were classified as having MINS. [Table 2]

[0189] The collected data did not pass the D'Agostino-Parson normality test, so nonparametric tests were used for analysis. The Kruskal-Wallis test was used to compare how the plasma levels of the measured biomarkers differed between patients affected and unaffected by MACCE. Figures 1-6 show the plasma levels of the measured biomarkers copeptin, cTnT, NT-proBNP, MR-proADM, CT-proET-1, and PCT in patients with and without MACCE at all sampling points / times. In the figures, PreOp refers to the preoperative sampling point, PACU (Postanesthesia Care Unit) refers to the postoperative sampling point, POD1 refers to the sampling point on the 1st day after surgery, POD2 refers to the sampling point on the 2nd day after surgery, and POD3 refers to the sampling point on the 3rd day after surgery.

[0190] As can be seen from Figures 1 - 6 , biomarker levels of all measured biomarkers are increased in the group of patients who suffered from MACCE within 30 days of gastrointestinal surgery compared to the group of patients who did not suffer from MACCE.

[0191] The variation in biomarker levels was also compared between patients with and without MINS using the Kruskal-Wallis test. Similar to Figures 1-6, Figures 7-12 show the plasma levels of the measured biomarkers copeptin, cTnT, NT-proBNP, MR-proADM, CT-proET-1, and PCT in patients with and without MINS at all sampling points / times. Again, as can be seen in Figures 7-12, the biomarker levels of all measured biomarkers are increased in the group of patients with MINS within 30 days of gastrointestinal surgery compared to the group of patients without MINS.

[0192] Regarding infections as postoperative adverse events, 105 (27%) patients developed infections, of which 11 had blood infections. Overall mortality was 1.3% (5 deaths). Table 2 summarizes patient characteristics with regard to the occurrence of infections. Biomarker levels were determined for all patients preoperatively (preOP), in the postanesthesia care unit (PACU), and on days 1 (POD1), 2 (POD2), and 3 (POD3) after surgery. [Table 3]

[0193] Figures 13-18 show biomarker levels in MACCE patients with or without additional infection. All of the biomarkers show significantly higher levels in patients with a combination of MACCE and infection, except for PCT before surgery. For the biomarkers troponin (Figure 14), BNP (Figure 15), proADM (Figure 16), proET-1 (Figure 17), and PCT (Figure 18), the increase in biomarker levels becomes even more pronounced at later time points (i.e., POD2 and POD3), whereas copeptin (Figure 13) shows a more constant increase compared to patients without infection at all time points analyzed. Thus, all of the biomarkers are suitable to distinguish patients with only MACCE from those with both MACCE and infection. The basic data are shown in Table 4. [Table 4]

[0194] From the values ​​given in Table 4, a person skilled in the art can easily deduce which test parameters, such as cut-off values, should be used in the method of the present invention. These can then be selected with respect to the practical application at hand. It is also clear that the measured biomarker levels should be evaluated expediently with respect to the time point when the sample is taken. For example, copeptin levels of more than 15 pmol / L, preferably more than 20 pmol / L, or more than 25 pmol / L in the sample taken before surgery (PreOP) indicate that the patient is at high risk of developing both MACCE and infection after surgery. At other time points of sampling, these values ​​may vary, for example, in PACU, greater than 195 pmol / L, or greater than 200 pmol / L, or greater than 205 pmol / L, or greater than 210 pmol / L, or greater than 215 pmol / L, or greater than 220 pmol / L, or greater than 225 pmol / L, or greater than 230 pmol / L; on POD1, greater than 30 pmol / L, or greater than 35 pmol / L, or greater than 40 pmol / L, or greater than 45 pmol / L; on POD2, greater than 20 pmol / L, or greater than 25 pmol / L, or greater than 30 pmol / L, or greater than 35 pmol / L; on POD3, greater than 15 pmol / L, or greater than 20 pmol / L, or greater than 25 pmol / L. Of course, for any biomarker, an assessment value other than a cutoff value can be calculated, whereby the measured biomarker level is related to a biomarker level established for patients with MACCE without infection and / or without any symptoms. For example, a factor may be established by which the measured biomarker level differs from the level of a patient with MACCE but without infection.

[0195] For hsTnT, levels of more than 8ng / L, or more than 9ng / L, or more than 10ng / L, or more than 11ng / L, or more than 12ng / L in samples taken in PreOP and / or PACU indicate that the patient is at high risk of developing both MACCE and infection after surgery. At other time points of sampling, these values ​​may vary, for example, more than 10ng / L, or more than 15ng / L, or more than 20ng / L, or more than 25ng / L, or more than 30ng / L on POD1 and / or POD2 and / or POD3. A global cut-off value for all time points may be selected, for example, more than 10ng / L or more than 15ng / L, depending on the desired sensitivity and specificity, as well as other factors of the application at hand.

[0196] For NT-proBNP, levels of more than 260ng / L, or more than 280ng / L, or more than 300ng / L, or more than 320ng / L in samples taken in PreOP and / or PACU indicate that the patient is at high risk of developing both MACCE and infection after surgery. At other sampling times, these values ​​may vary, for example, at POD1 and / or POD2 and / or POD3, more than 500ng / L, or more than 550ng / L, or more than 600ng / L, or more than 650ng / L, or more than 700ng / L, or more than 750ng / L, or more than 800ng / L, or more than 850ng / L. The global cut-off value for all time points may be selected, for example, at more than 300ng / L or more than 500ng / L, depending on the desired sensitivity and specificity, as well as other factors of the application at hand.

[0197] For MR-proADM, a level of more than 0.70 nmol / L, or more than 0.75 nmol / L, or more than 0.80 nmol / L in the sample taken at PreOP indicates that the patient is at high risk of developing both MACCE and infection after surgery. At other time points of sampling, these values ​​may vary, for example, in PACU and / or POD1 and / or POD2 and / or POD3, it may be more than 1.00 nmol / L, or more than 1.10 nmol / L, or more than 1.20 nmol / L, or more than 1.30 nmol / L, or more than 1.40 nmol / L, or more than 1.50 nmol / L, or more than 1.60 nmol / L. The global cut-off value for all time points may be selected, for example, at more than 0.8 nmol / L or more than 1.5 nmol / L, depending on the desired sensitivity and specificity, as well as other factors of the current application.

[0198] For CT-proET-1, levels of more than 65 pmol / L, or more than 70 pmol / L, or more than 75 pmol / L, or more than 80 pmol / L in samples taken at PreOP indicate that the patient is at high risk of developing both MACCE and infection after surgery. At other time points of sampling, these values ​​may vary, for example, in PACU and / or POD1 and / or POD2 and / or POD3, more than 85 pmol / L, or more than 90 pmol / L, or more than 95 pmol / L, or more than 100 pmol / L, or more than 105 pmol / L, or more than 110 pmol / L, or more than 115 pmol / L, or more than 120 pmol / L, or more than 125 pmol / L. A global cut-off value for all time points may be selected, for example, at 80 pmol / L or more than 100 pmol / L, depending on the desired sensitivity and specificity, as well as other factors of the application at hand.

[0199] For PCT, levels of 0.06 μg / L or greater than 0.08 μg / L, or greater than 0.10 μg / L, or greater than 0.12 μg / L in samples taken in PreOP and / or PACU indicate that the patient is at high risk of developing both MACCE and infection postoperatively. At other times of sampling, these values ​​may vary, for example, on POD1 and / or POD2 and / or POD3, the levels may be greater than 0.8 μg / L, or greater than 0.9 μg / L, or greater than 1.0 μg / L, or greater than 1.1 μg / L, or greater than 1.2 μg / L, or greater than 1.3 μg / L, or greater than 1.4 μg / L, or greater than 1.5 μg / L. A global cutoff value for all time points may be selected, for example, at greater than 0.1 μg / L, or greater than 1.0 μg / L, or greater than 1.5 μg / L, depending on the desired sensitivity and specificity, as well as other factors of the application at hand.

[0200] Figures 19-21 summarize the results regarding infection for MR-proADM, PCT, and CT-proET-1. The levels of all biomarkers, especially MR-proADM and PCT, were higher in the group of patients who suffered from infection after surgery. This trend is evident at all sample points: preOP, PACU, and POD1-3.

[0201] The levels of MR-proADM in patients developing infections after surgery were higher for early PACU sample points and even mildly preoperatively compared to those in patients without infection. This difference becomes more pronounced postoperatively, starting on POD1, and especially on POD2 and POD3 (Figure 19). The levels of MR-proADM in patients without any infections drop from about 1.25 nmol / L after POD1 to less than 1.2 nmol / L on POD3. In patients with infections, the levels remain robustly above 1.5 nmol / L on all PODs 1-3.

[0202] In the case of PCT as a marker of infection development, strikingly significant differences are seen from POD1 through POD3 postoperatively (Figure 20). While postoperative patients without infection have PCT levels that remain around or below 0.75 μg / L, those with infection have PCT levels that continuously rise from POD1 (~1.0 μg / L) to above ~1.25 μg / L on PODs 2 and 3. Notably, milder differences are also evident preoperatively and early in the PACU.

[0203] In the case of CT-proET-1, the difference between patients with and without infection is less pronounced than in the case of the markers PCT and MR-proADM. However, clear differences allow a reliable discrimination, especially at the later sample points, 2-3 days after surgery (Figure 21).

[0204] These results indicate that MR-proADM and PCT in particular, and to a lesser extent CT-proET-1, can be used to provide a reliable prediction or diagnosis of the incidence of infection in postoperative patients and can therefore be advantageously combined with measurements of copeptin, troponin, and BNP. Predictions or diagnoses can be established using a single threshold for all sample points or at individual sample points (e.g., preOP, PACU, POD1-3) by comparison with sample point-specific values.

[0205] In addition, the different time courses of biomarker levels in patients with and without any infection allow for a more reliable prognosis or diagnosis when samples are taken at least at two time points and the percentages or absolute differences for the different sample points are analyzed.

[0206] Table 5 summarizes patient characteristics with respect to the occurrence of blood infections. Biomarker levels were determined for all patients preoperatively (preOP), in the postanesthesia care unit (PACU), and on days 1 (POD1), 2 (POD2), and 3 (POD3) after surgery. [Table 5]

[0207] Figures 22-24 summarize the results for MR-proADM, PCT, and CT-proET-1. The levels of all biomarkers, especially MR-proADM and PCT, were higher in the group of patients who suffered from blood infections after surgery. This trend is evident at all sample points: preOP, PACU, and PODs 1-3.

[0208] The levels of MR-proADM in patients who develop blood infections postoperatively are significantly higher for the early PACU sample points and even preoperatively compared to the levels in patients without infections. This difference becomes more pronounced postoperatively from POD1 to POD3 (Figure 22). The levels of MR-proADM in patients without any infections drop from about 1.3 nmol / L after POD1 to less than 1.2 nmol / L on POD3. For patients with blood infections, the levels remain robustly above about 1.75 nmol / L all POD1-3.

[0209] A particularly striking difference in PCT levels is seen postoperatively from POD1 through POD3, as well as in the incidence of infection versus the incidence of blood infection (Figure 23). While the levels of PCT in postoperative patients without blood infection remain around or below 0.75 μg / L, those with blood infections continually increase from POD1 (approximately 2.0 μg / L) to above approximately 2.5 μg / L on PODs 2 and 3. Notably, mild differences are also evident preoperatively and early in the PACU.

[0210] For CT-proET-1, the difference between patients with and without blood infection is less pronounced than for the markers PCT and MR-proADM. However, clear differences allow differentiation, especially at the later sample points, 2-3 days after surgery. The levels of CT-proET-1 in patients with blood infection on POD 2 and 3 were above 100 pmol / L, while the levels in patients without blood infection on POD 2 and POD 3 were around or below 0.75 pmol / L (Figure 24).

[0211] These results indicate that MR-proADM and PCT in particular, and to a lesser extent CT-proET-1, may be useful for reliable prediction or diagnosis of the incidence of blood infections in postoperative patients and may therefore be advantageously combined with measurements of copeptin, troponin, and BNP. Prediction or diagnosis may be established using a single threshold for all sample points or at individual sample points (e.g., preOP, PACU, POD1-3) by comparison with sample point-specific values.

[0212] In addition, the different time courses of biomarker levels in patients with and without blood infections allow for more reliable prognosis or diagnosis when samples are taken at two or more time points and the percentages or absolute differences for the different sample points are analyzed.

[0213] Table 6 summarizes patient characteristics with regard to the postoperative occurrence of infection and MACCE. Biomarker levels were determined for all patients preoperatively (preOP), in the postanesthesia care unit (PACU), and on days 1 (POD1), 2 (POD2), and 3 (POD3) after surgery. [Table 6]

[0214] Figures 25-27 summarize the results for MR-proADM, PCT, and CT-proET-1.

[0215] Notably, levels of all biomarkers were particularly high in the group of patients who had both infection and MACCE, and this trend was evident at all sample points: preOP, PACU, and PODs 1-3.

[0216] For MR-proADM, levels in patients who suffered from infection and MACCE exhibit clear differences compared to patients who suffered from neither of these events or only one of the adverse events across all sample points (Figure 25). The differences are particularly pronounced postoperatively. Patients who did not develop infection and did not experience MACCE postoperatively had MR-proADM levels below 1 nmol / L in the PACU or on PODs 1-3, whereas patients who suffered from both adverse events had a steady increase in MR-proADM levels from approximately 1.5 nmol / L in the PACU to approximately 2.3 nmol / L on POD 3.

[0217] PCT appears to be a particularly valuable marker for the combined prognosis or diagnosis of infection and MACCE. This is especially true for postoperative sample points from POD1 to POD3 (Figure 26). Patients who developed infection and suffered MACCE events from POD1 to POD3 had PCT levels consistently above 2 μg / L, and even averaged about 3.5 μg / L on POD3. On the contrary, for patients who did not experience either MACCE or infection after surgery, PCT levels were determined to be around or below 0.5 μg / L. The difference of more than 4-fold on POD1 and more than 7-fold on POD3 indicates a strong synergistic effect for the combined diagnosis or prediction of infection and MACCE using PCT as a marker.

[0218] Similarly, it was determined that for CT-proET-1 across all sample points, levels in patients who suffered both infection and MACCE postoperatively were significantly higher than those who experienced neither of these adverse events (Figure 27). For the former group, CT-proET-1 levels remained at or below approximately 80 pmol / L, whereas in the latter group, postoperative levels of CT-proET-1 from PACU to POD3 were at or above approximately 125 pmol / L.

[0219] This data shows that the prognosis and / or diagnosis of infection and MACCE using one of the described biomarkers can be achieved with particularly high accuracy and reliability.Therefore, these biomarkers can be advantageously combined with the measurement of copeptin, troponin and BNP.Such a strong predictive power cannot be expected from the predictability of the marker for one of adverse events, which shows the functional synergy of these biomarkers for the diagnosis or prediction of these prominent adverse events.

[0220] A prediction or diagnosis can be established using a single threshold for all sample points or at individual sample points (eg, preOP, PACU, POD1-3) by comparison to sample point-specific values.

[0221] In addition, the different time courses of biomarker levels in patients with and without infection and MACCE allow for more reliable prognosis or diagnosis when samples are taken at two or more time points and the percentages or absolute differences for the different sample points are analyzed. array SEQ ID NO:1 (amino acid sequence of pre-pro-AVP): TIFF2025013795000008.tif18133 SEQ ID NO:2 (amino acid sequence of pro-AVP): TIFF2025013795000009.tif14133 SEQ ID NO:3 (amino acid sequence of CT-pre-proAVP copeptin): TIFF2025013795000010.tif5107 SEQ ID NO: 4 (amino acid sequence of Neurophysin II): TIFF2025013795000011.tif10134 SEQ ID NO:5 (amino acid sequence of cTnT (isoform-6)): TIFF2025013795000012.tif25134 SEQ ID NO:6 (amino acid sequence of cTnI): TIFF2025013795000013.tif21133 SEQ ID NO:7 (amino acid sequence of TnC): TIFF2025013795000014.tif18133 SEQ ID NO:8 (amino acid sequence of pre-pro-BNP): TIFF2025013795000015.tif12133 SEQ ID NO:9 (amino acid sequence of pro-BNP): TIFF2025013795000016.tif12134 SEQ ID NO: 10 (amino acid sequence of NT-pro-BNP): TIFF2025013795000017.tif9135 SEQ ID NO:11 (amino acid sequence of BNP): TIFF2025013795000018.tif595 SEQ ID NO: 12 (amino acid sequence of pre-pro-ADM): TIFF2025013795000019.tif18133 SEQ ID NO: 13 (amino acid sequence of pro-ADM): TIFF2025013795000020.tif16133 SEQ ID NO: 14 (amino acid sequence of MR-pro-ADM): TIFF2025013795000021.tif6129 SEQ ID NO: 15 (amino acid sequence of pre-pro-ET-1): TIFF2025013795000022.tif21133 SEQ ID NO: 16 (amino acid sequence of pro-ET-1): TIFF2025013795000023.tif18132 SEQ ID NO: 17 (amino acid sequence of ET-1): TIFF2025013795000024.tif566 SEQ ID NO: 18 (amino acid sequence of CT-pro-ET-1): TIFF2025013795000025.tif5122 SEQ ID NO: 19 (amino acid sequence of Big-ET-1): TIFF2025013795000026.tif4107 SEQ ID NO: 20 (amino acid sequence of PCT): TIFF2025013795000027.tif14131 SEQ ID NO: 21 (amino acid sequence of pre-pro-ANP (Homo sapiens)): TIFF2025013795000028.tif17132 SEQ ID NO: 22 (amino acid sequence of pro-ANP (Homo sapiens)): TIFF2025013795000029.tif13132 SEQ ID NO: 23 (amino acid sequence of NT-proANP): TIFF2025013795000030.tif10133 SEQ ID NO: 24 (MR-proANP = amino acid sequence of amino acids 53 to 90 of proANP): TIFF2025013795000031.tif4108 SEQ ID NO:25 (Myoglobin (Homo sapiens)) TIFF2025013795000032.tif18167 SEQ ID NO: 26 (Creatine kinase (Homo sapiens)) TIFF2025013795000033.tif34168 SEQ ID NO: 27 (C-reactive protein (Homo sapiens)) TIFF2025013795000034.tif22168

Claims

1. 1. A method for at least one of prognosis, risk assessment, and diagnosis of major adverse cardiovascular or cerebrovascular events (MACCE) in patients undergoing gastrointestinal surgery, comprising: i) providing a sample of a bodily fluid from said patient; ii) determining in said sample the level of a biomarker selected from the group consisting of copeptin, troponin, and brain natriuretic peptide (BNP); iii) determining at least one additional parameter of the patient; iv) combining the biomarker levels determined in step ii) with the additional parameters determined in step iii) into a combined assessment; and v) correlating said combination assessment with at least one of a prognosis, a risk assessment, and a diagnosis of MACCE in said patient.

2. 2. The method of claim 1, wherein the method is for at least one of prognosis, risk assessment, and diagnosis of major adverse cardiovascular or cerebrovascular events (MACCE) in combination with infection in patients who have undergone gastrointestinal surgery, preferably for risk stratification of the patients into a group that is likely to develop both MACCE and infection and another group that is unlikely to develop both MACCE and infection.

3. The method according to any one of claims 1 to 2, wherein said additional parameter is selected from the group consisting of the level of at least one additional biomarker and a clinical parameter of the patient.

4. 4. The method of claim 3, wherein the additional biomarkers are selected from the group consisting of copeptin, troponin, BNP, proadrenomedullin (proADM), preferably its fragment mid-region proadrenomedullin (MR-proADM), proendothelin-1 (proET-1), preferably its fragment C-terminal proendothelin-1 (CT-proET-1), procalcitonin (PCT), MR-proANP (mid-region pro-atrial natriuretic peptide), creatine kinase, creatine kinase-MB, myoglobin, lactate, and CRP (C-reactive protein).

5. 5. The method of claim 3 or 4, wherein the levels of the biomarkers copeptin, troponin, and brain natriuretic peptide (BNP), and optionally at least one of proADM, MR-proADM, proET-1, CT-proET-1, and PCT are determined and combined into a combined assessment.

6. 6. The method according to any one of claims 3 to 5, wherein the clinical parameters are selected from the group consisting of age, abnormal ECG, in particular pathological Q waves, LBBB, ST elevation, ST depression, T wave inversion, intraoperative hypotension, intraoperative tachycardia, intraoperative bradycardia, hyperlipidemia, smoking status, anemia, functional capacity (MET), red blood cell transfusion, arrhythmia, non-sinus rhythm, duration and size of the gastrointestinal surgery, patient medical history, and liver disease.

7. 7. The method of any one of claims 1 to 6, wherein the level of at least one of the biomarkers is determined by determining the level of at least one of a precursor, a precursor fragment, and a fragment of the biomarker.

8. 8. The method of any one of claims 1 to 7, wherein determining the level of the troponin comprises determining the level of the subunit cardiac troponin T (cTnT), preferably isoform 6 of cTnT, or a homologous peptide having at least 75% amino acid sequence identity with isoform 6 of cTnT.

9. The method according to any one of claims 1 to 8, wherein determining the level of BNP comprises determining the level of the precursor fragment NT-proBNP.

10. The method of any one of claims 1 to 9, wherein the patient is at least 50 years old.

11. The method of any one of claims 1 to 10, wherein the patient is treated with an analgesic or pain medication.

12. The method of any one of claims 1 to 11, wherein the patient is hospitalized for at least one day after undergoing the gastrointestinal surgery.

13. the gastrointestinal surgery is one of laparoscopic surgery and open surgery; - gastric surgery, - small intestinal surgery, especially duodenal surgery, - Colon surgery, especially rectal surgery, - surgery on the reproductive system, in particular hysterectomy or salpingo-oophorectomy, - kidney surgery, especially nephrectomy, - bladder surgery, especially cystectomy, - gallbladder surgery, especially cholecystectomy, and - surgery of gastrointestinal cysts.

14. The method of any one of claims 1 to 13, wherein the patient is free of cardiovascular comorbidities.

15. 15. The method of any one of claims 1 to 14, wherein the patient is excluded if the patient has an exclusion condition selected from the group consisting of organ transplantation, traumatic injury, endocrine disease, endocrine surgery, vascular disease, vascular surgery, endovascular disease, endovascular surgery, acute coronary syndrome (ACS), heart failure, decompensated congestive heart failure, aortic stenosis, reduced left ventricular ejection fraction (LVEF), and circulatory shock.

16. 16. The method of any one of claims 1 to 15, wherein the sample is taken from the patient within 24 hours prior to, within 24 hours after, the first day after, the second day after, or the third day after the gastrointestinal surgery.

17. 17. The method according to any one of claims 1 to 16, wherein the method comprises providing between 2 and 5 samples from the patient, said samples being taken at different times before and / or after the gastrointestinal surgery, and steps ii), iv) and v) are performed for all said samples.

18. 18. The method of claim 17, wherein the different times at which the two to five samples are said to be taken are selected from the group consisting of within 24 hours prior to the gastrointestinal surgery, within 24 hours after the gastrointestinal surgery, the first day after the gastrointestinal surgery, the second day after the gastrointestinal surgery, and the third day after the gastrointestinal surgery.

19. 19. The method of any one of claims 17 to 18, wherein the levels of said biomarkers in samples taken at said different times are determined and then compared, and said differences in the levels of biomarkers at said different times are combined into said combined assessment.

20. The method of any one of claims 1 to 19, wherein a biomarker level determined to be above a particular threshold is indicative of MACCE in said patient.

21. The particular threshold value is for copeptin, 25 pmol / L, preferably 75 pmol / L, more preferably 125 pmol / L, even more preferably 175 pmol / L, most preferably 225 pmol / L; for cTnT, 15 ng / L, preferably 20 ng / L, more preferably 25 ng / L, even more preferably 30 ng / L, most preferably 35 ng / L, 45 ng / L, or 65 ng / L; - for NT-proBNP 500 ng / L, preferably 900 ng / L, more preferably 1300 ng / L, even more preferably 1700 ng / L, most preferably 2100 ng / L or 2800 ng / L; - for MR-proADM, 0.8 nmol / L or 1.0 nmol / L, preferably 1.25 nmol / L, more preferably 1.5 nmol / L, even more preferably 1.75 nmol / L, most preferably 2.0 nmol / L or 2.4 nmol / L; - 80 pmol / L, preferably 90 pmol / L, more preferably 100 pmol / L, even more preferably 110 pmol / L, most preferably 120 pmol / L for CT-proET-1; - for PCT, 0.5 μg / L, preferably 1.0 μg / L, more preferably 1.5 μg / L, even more preferably 2.0 μg / L, most preferably 2.5 μg / L or 3.0 μg / L.

22. The method of any one of claims 1 to 21, wherein the method comprises correlating the combination assessment with the risk of MACCE in a patient within at least one of 30 days and 12 months after the gastrointestinal surgery.

23. The method of any one of claims 18 to 19, wherein the prognosis comprises the risk of death within at least one of 30 days and 12 months after the gastrointestinal surgery.

24. The method according to any one of claims 1 to 23, wherein said MACCE is myocardial injury after non-cardiac surgery (MINS) and said method is for the diagnosis of MINS in patients who have undergone gastrointestinal surgery.

25. 22. The method of claim 21, wherein a biomarker level determined to exceed a particular threshold is indicative of MINS in the patient.

26. The particular threshold value is for copeptin, 25 pmol / L, preferably 50 pmol / L or 75 pmol / L, more preferably 125 pmol / L, even more preferably 175 pmol / L, most preferably 225 pmol / L; for cTnT, 10 ng / L, preferably 20 ng / L, more preferably 30 ng / L, even more preferably 40 ng / L, most preferably 50 ng / L or 60 ng / L; for NT-proBNP, 250 ng / L or 500 ng / L, preferably 750 ng / L, more preferably 1250 ng / L or 1500 ng / L, even more preferably 1750 ng / L, most preferably 2250 ng / L; - for MR-proADM, 0.8 nmol / L or 1.0 nmol / L, preferably 1.25 nmol / L, more preferably 1.5 nmol / L, even more preferably 1.75 nmol / L, most preferably 2.0 nmol / L; - for CT-proET-1, 65 pmol / L or 75 pmol / L or 80 pmol / L, preferably 90 pmol / L, more preferably 100 pmol / L, even more preferably 110 pmol / L, most preferably 120 pmol / L; - for PCT, 0.2 μg / L or 0.5 μg / L, preferably 0.75 μg / L or 0.8 μg / L, more preferably 1.0 μg / L, even more preferably 1.25 μg / L, most preferably 1.5 μg / L.

27. The method according to any one of claims 17 to 26, wherein the determined biomarker levels obtained at different times are evaluated using different thresholds.

28. The method according to any one of claims 17 to 27, wherein the determined biomarker levels obtained at different times are weighted differently.

29. The method of any one of claims 17 to 28, wherein the relative changes in biomarker levels between the two samples taken at different times are combined into said combined assessment.

30. 30. The method of any one of claims 1 to 29, wherein a ratio between levels of at least two biomarkers in said samples is determined and said ratios are combined into said combined assessment, said biomarkers for determining said ratio being preferably selected from copeptin / troponin, copeptin / BNP, and BNP / troponin.

31. Step iv) comprises providing reference data for the determined biomarkers, - said determined level of at least one of said biomarkers, - said difference in the level of at least one of said biomarkers obtained at different times, - the relative change in the level of one of the biomarkers determined in two samples obtained at different times, - said ratio between levels of at least two biomarkers obtained simultaneously or at different times, and - the relative change in the ratio of at least two biomarkers determined in at least two samples obtained at different times; The method according to any one of claims 1 to 30, wherein the difference of the determined value and the reference data compared with the reference data is calculated, and the calculated difference is preferably expressed in the form of a score, in particular as a numerical value.

32. 32. The method of claim 31 , wherein at least two different scores are determined and the combination assessment comprises a combined score determined from the at least two different scores indicative of the presence or absence of MACCE in the patient.

33. The method according to any one of claims 31 to 32, wherein said reference data concerns patients who have undergone gastrointestinal surgery and who have and / or have not had MACCE or MINS.

34. The method of any one of claims 2 to 33, wherein the infection is selected from the group consisting of a fungal, bacterial, or viral infection.

35. 35. The method of any one of claims 2 to 34, wherein the infection is selected from the group consisting of a blood infection, a respiratory infection, a urinary tract infection, a skin infection, or an abdominal infection.

36. The method of any one of claims 2 to 35, wherein the infection is selected from the group consisting of bloodstream infection, sepsis, severe sepsis, and / or septic shock.

37. A kit comprising: at least one detection reagent for determining the level of at least one of the biomarkers copeptin, troponin, and brain natriuretic peptide (BNP) in a sample of bodily fluid from a patient; A kit for performing the method according to any one of claims 1 to 36, comprising reference data, in particular reference levels, from patients who have undergone gastrointestinal surgery corresponding to at least one of copeptin, troponin and BNP levels, said reference data preferably being stored on a computer readable medium and / or in the form of a computer executable code configured to compare the determined levels of at least one of copeptin, troponin and BNP with said reference data.

38. 38. The kit of claim 37, wherein the at least one detection reagent comprises reagents for determining the level of at least one of the biomarkers copeptin, troponin, and brain natriuretic peptide (BNP), and optionally MR-proADM, CT-proET-1, and PCT, in a sample of body fluid from the patient, and wherein the reference data comprises data corresponding to the biomarkers in patients who have undergone gastrointestinal surgery.

39. A computer comprising means for executing computer executable code, said computer executable code being arranged to carry out steps iv) and / or v) of the method according to any one of claims 1 to 36.

40. 40. The computer of claim 39, wherein the computer is connected to an assay system, the assay system being configured to carry out step ii) of the method of any one of claims 1 to 36.

41. 37. A computer program product comprising a set of computer instructions stored on at least one computer readable medium, said set of computer instructions further comprising instructions executable by one or more processors to perform steps iv) and / or v) of the method of any one of claims 1 to 36.

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