Automation of intraoperative analysis of indicators the inflammatory response of neurosurgical patients undergoing brain tumors removal

. The data of the study of indicators of the inflammatory response, hormonal status, biochemical blood parameters in the perioperative period in neurosurgical patients undergoing surgery for tumors of the posterior cranial fossa are presented. This study included 65 patients. The surgery was performed under anesthesia with fentanyl (3-5 µg / kg-hour), clonidine (1-2 µg / kg-hour), and propofol (3-5 mg / kg-hour). A significant increase in the level of interleukin 10 was observed at the level of hemostasis. The day after surgery, the level of Interleukin 6 increased significantly. During hemostasis, there was a temporary increase in ACTH, cortisol, and prolactin levels. The day after the surgery, rates returned to their original levels. Under conditions of persistent neurovegetative, a sufficient humoral response to surgical trauma was noted.


Introduction
The digitization of the medical sector in the Russian Federation is now systematic, mainly at the level of federal documents, and is usually concentrated in specific areas rather than inclusive. At the same time, some processes that are not on the priority list are to ensure timeliness, use information to control the integrity of operations, optimize time costs and minimize human factors. In addition, it needs to be automated gradually. An example in this field is the intraoperative management of neurosurgery patients. At Armazov National Medical Research Center, the research area of the designated subject area is the control of perioperative inflammation, during which the brain tumor has been cleared.
Significant research and hands-on testing of the developed methods to collaborate with patients can already produce enough data samples. On this basis, based on the basic principles of establishing a distributed information system, it is expected to develop to the level of big data. Admiral Makarov State University of Maritime and Inland Shipping has developed an information system called " Automated system of intraoperative monitoring of homeostasis index of neurosurgical patients" (Sokolov, Lesteva, Musin, 2014).
Since computerized systems is now widely used in today world, we cannot exclude important areas of human life such as health care. The latest digital development has had a positive effect on the development of the most promising ways to organize the delivery of healthcare to people around the world. At the same time, the efficient construction of an IT infrastructure is becoming increasingly important. Many states have long innovated in the medical field.
The organization of the rest of the paper is as follows-Section 2 'Subject of the study' contains information about a certain set of body reactions in which the functional state called the "surgical stage of anesthesia" is reflected and to which the anesthesiologist most often draws attention and tries to correct. Section 3 'Materials and methods' contains information about histological variants of tumors of the posterior cranial fossa. Section 3.1 Automation of the study-basic information contains information about structure of the indicator accounting system. Section 3.2 Automation of the study-Practical use contains information about developed software. Section 4 Results of the study presents experimental results of the proposed system. Section 5 conclusion concludes the work.

Subject of the study
There is a certain set of body reactions in which the functional state called the "surgical stage of anesthesia" is reflected and to which the anesthesiologist most often draws attention and tries to correct. These are indicators of systemic hemodynamics, changes in spontaneous and induced bioelectric activity of the brain, deviations in the level of various hormones and other biologically active substances in the blood.
In neurosurgery, the concept of the adequacy of anesthesia is interpreted more broadly. So, the criteria of adequacy in neuroanesthesiology depending on the stage of the operation, can be (i) before decompression of the brain -maintaining perfusion pressure (ii) after decompression -preservation of elasticity, suppleness of the brain, assessment and the maximum possible limitation of centrogenic reactions (iii) at the stage of removal of the tumor and hemostasis -normal indicators of vascular-platelet and coagulation hemostasis in the wound.
In addition, an adequate anesthetic benefit is the key to a smooth, harmonious exit of the patient from the anesthetized state. In the postoperative period after surgery on the brain, the clinical manifestations of inadequacy of anesthesia can be excessive inhibition of central nervous system functions, multiple organ dysfunction. Apparently, an overly expressed systemic inflammatory response may be the background, and in some cases, the main cause of this symptomatology. For cognitive impairment, this relationship is well established by Sokolov Lesteva and Musin, (2014).
Inflammation is both a pathological and adaptive process caused by the reaction of the body's defense mechanisms to local damage. Inflammation triggers tissue degradation products, immune complexes -activate several basic components of the inflammation program at once. Moreover, the initial activation of even one link can "turn on" the entire system of inflammatory reactivity as a whole. The regulatory intermediaries for this mutual activation are cytokines, hemostatic activation products, biogenic amines, and many other inflammatory mediators. A key role in coordinating the mechanisms of inflammation belongs to cytokines. The main producers of cytokines are T cells and activated macrophages, as well as other types of leukocytes, postcapillary venule endotheliocytes, platelets and various types of stromal cells. Initially, a local inflammatory response is controlled by proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-12, TNF, interferons, as well as their endogenous antagonists, especially IL-10. Subsequently, with the prevalence of the inflammatory component over the anti-inflammatory one and damage to the primary barrier structures in the area of inflammation, a "breakthrough" of inflammatory mediators into the systemic circulation occurs. At the same time, the main function of pro-inflammatory mediators in the circulating blood is to attract white blood cells, coagulation and complement factors, acute phase proteins to the area of inflammation in order to perform a protective and then recovery function of the inflammatory process (Konsman, Luheshi, Bluthe, & Dantzer, 2000).
Non-infectious reasons for the manifestation of a systemic inflammatory response can include ischemia, reperfusion (after hemorrhagic shock), the use of VAD in cardiac surgery, severe pancreatitis, intestinal ischemia (mesenteric vascular thrombosis), but the most common causes are severe trauma or extensive surgery (Savel'ev & Gel'fand, 2013). There are neuro-reflex (realized by the sympathetic nervous system) and humoral ways of informing the central nervous system about inflammation. The humoral chain is as follows. The antigen initiates the synthesis of pro-inflammatory cytokines by peripheral macrophages, then the synthesis of pro-inflammatory cytokines in the choroid plexuses of the ventricles begins. A cytokine-mediated effect on the neuroregulatory centers of the brain occurs both through the microglia of afferent pathways of cranial nerves (mainly n.vagus) and through the cerebrospinal fluid. The efferent effects of this cascade of reactions are realized through the neuroendocrine response, fever, various disorders of behavior, consciousness, etc. Thus, the adaptive effect of the systemic inflammatory response to surgical damage is realized (Konsman Luheshi Bluthe, and Dantzer, 2000).
Adaptive reactions are a chain of neuro-humoral changes that lead to the mobilization of the hypothalamic-pituitary system and the release of catecholamines, ACTH, ADH, and TSH into the blood. The purpose of these reactions is to quickly protect the body from pathological effects. Most neuroregulatory systems that play a role in adapting the body to various environmental influences are in the brain stem. Opioid and adrenergic antinociceptive systems are integral parts of the neuroregulatory systems of the brain stem. They contribute to the functional integration of numerous compensation and adaptation mechanisms (Divya & Singh, 2019). The introduction of opioids in combination with clonidine forms a sufficient level of neurovegetative stability due to the modulating effect of drugs on the neuroregulatory structures of the brain stem (Savel'ev & Gel'fand, 2013). Under the conditions of an anaesthetic support based on the use of such a combination of drugs, an adequate intraoperative assessment of both hemodynamic reactions and electrophysiological parameters and determination of the indications for continued neurovegetative stabilization in the postoperative period based on this assessment are possible.
The aim of the research was to study biochemical, coagulation indicators, systemic inflammatory response data (including cytokine levels), hormonal status in patients who had surgery for tumors of the posterior cranial fossa under conditions of neuro-vegetative stabilization based on the combined administration of fentanyl and clonidine.

Materials and methods
The study sample included 65 patients (42 women, 23 men). The average age of the studied patients was 50.5 ± 5.2 years. All patients had surgery for tumors of the posterior cranial fossa. The operations were performed as planned. The following histological variants of tumors of the posterior cranial fossa were distinguished: meningiomas, neuromas of the VIII nerve, ependymomas, astrocytomas. The preoperative condition of all patients was assessed as severe due to the underlying disorder, compensated for by vital functions and corresponding to classes III -IV of the physical condition of patients according to the Laboratory studies included: analysis of blood biochemical parameters, coagulogram data, hormonal status indicators (TSH, T3, T4, ACTH, Cortisol, STH, Prolactin), cytokine levels (IL-8, IL-6, IL-10, TNF). Studies of blood biochemical parameters and hormone levels were carried out using an Integra 400 plus biochemical analyzer (Roche, Switzerland, Germany, USA). Studies of cytokine levels were carried out using an Immuite 1000 immunochemiluminescent analyzer (DPC, USA). Analysis of blood samples was carried out in five stages: a day before surgery, on the day of surgery before induction of anesthesia, after induction of anesthesia, after removal of the tumor (at the stage of hemostasis), on the first day after surgery. These stages were chosen in order to assess the influence of various factors of the perioperative period on the neurohumoral indicators of adaptive reactions of the body.

Automation of the study-Basic information
The developed automated system allows processing the results of the study. The system has the following scheme (Fig. 1). The reference system for accounting indicators includes 3 main subsystems, 2 of which also include a certain number of modules. The main subsystems: "Data viewing"; "Add new data"; "Data analysis". The data viewing subsystem includes the following modules: "Search for necessary data"; "Change of data"; "Data removal". The data analysis subsystem has 2 modules: "Comparison of indicators" and "Plotting".
The interface of the developed automated system reflects all the necessary subsystems and modules of the developed reference system. For information processing, a table with general data is used. MS Excel is used to work with it. Due to that it was possible to plot graphs using one of various types of interpolation and approximation to obtain forecasts. To build the forecast curves, approximation and interpolation methods are used. Interpolation in computational mathematics, a way of finding intermediate values of a quantity from an available discrete set of known values.
The constructed function is discontinuous, which limits its application. For left piecewise linear interpolation, we have a graphical representation ( fig.2):
To calculate the value of S(x) at an arbitrary point of the segment z‫[א‬a, b], it is necessary to solve the system of equations for the coefficients ci, i = 1,2, ..., N-1, then find all the coefficients bi, di. Next, it is necessary to determine what interval [xi0, xi0-1] this point falls into, and, knowing the number i0, calculate the value of the spline and its derivatives at the point z Approximation is a scientific method that consists in replacing some objects with others, in one sense or another, close to the original, but simpler (Kondratyev, 2008).
Approximation allows one to study the numerical characteristics and qualitative properties of an object, reducing the problem to the study of simpler or more convenient objects (for example, those whose characteristics are easily calculated or whose properties are already known). In the theory of numbers, Diophantine approximations are studied, in particular, the approximations of irrational numbers by rational ones. In geometry, approximations of curves by broken lines are considered. Some sections of mathematics are entirely devoted to approximations, for example, the theory of approximation of functions, numerical methods of analysis (Lesteva, 2009.).

Automation of the study-Practical use
In the proposed system, the data processed during the program cannot get to the local network or the Internet without the knowledge of the employees working with the system. This ensures the security of data, the distribution of which entails liability, in accordance with Federal Law No. 152 of July 27, 2006 "On Personal Data". The underlying distributed architecture can be implemented in case of compliance with information security requirements, in particular, the use of certified cryptographic tools (Nagpal & Singh, 2019).
The initial form allows going to one of three main actions - Figure 4. On the plotting form, there are four fields to fill in with those parameters that need to be displayed on the graph. Upon activation of each of the four fields, a drop-down list of parameters opens, the indicators for which are presented in the general table.
After filling in the appropriate fields and clicking the "Build chart" button, the graph is built (fig.5).

Fig. 5. Examples of built graphs.
For convenience, it is possible to close any of the provided forms using the standard button to close the window. The initial form is called up using the keyboard shortcut Ctrl + Q. The ability to build forecasts on the schedule is carried out using standard MS Excel tools. To do this, go to the "Work with charts: Layout" tab ( fig.6). Adding a new patient is carried out using the form for adding new data, which opens after clicking the "Add client" button on the main form ( fig.7). The form for adding new data works with the same elements as the form for displaying information. Data is also saved using the "Save changes" button. Comparison of client indicators. Clicking on the "Compare client indicators" button on the initial form will open the Client Comparison form. There are four fields in the form for filling with the names of patients whose indicators need to be compared and a field for filling with the name of the indicator, according to which the comparison will be made (Kondratyev, Dryagina, Zhulev & Nikishchenkova, 2012).

Results of the study
The automated system can set thresholds for timely notification of the user about the deviation of the current indicator from the norm. In general, indicators of hormonal status, blood coagulation, and biochemical parameters remained relatively stable at all stages of the perioperative period. When studying the levels of cytokines, a significant increase in the level of Interleukin 10 at the stage of hemostasis was noted. On the next day after the operation, the level of Interleukin 6 was significantly increased. Table 1. Dynamics of cytokine levels at various stages of the perioperative period. In addition, at the stage of hemostasis, a transient increase in the levels of ACTH, Cortisol, Prolactin was noted, the rate of which returned to the initial values on the next day after the operation. These changes fit into the standard picture of changes in hormonal status in response to surgical trauma. Currently, medical information systems (information systems) are developing more and more actively, which helps healthcare institutions to work more efficiently and quickly. For obvious reasons, informatization of the healthcare sector in Russia is currently experiencing an increased level of government attention (Zhilenkov & Chernyi, 2019). Financial investments in the creation of new medical technologies have a positive effect on this process and the improvement of existing services. This primarily refers to the development of unified systems, the creators of which are constantly trying to optimize the work of this software for clinics. Periodic updates provide product users with the ability to use all available IT in medicine. Also in our country, an urgent need is also being fixed for the prompt implementation of effective innovations in the domestic health care system. In this regard, the issue of ensuring the most effective protection of information becomes especially important. For this reason, systems are currently being actively developed to block the threat of external intrusion to confidential medical data (Chernyi & Budnik, 2017).

Conclusions
Automation of regional problems in the medical field not only solves the problems, but also establishes a systematic research base and forms a national-level production application software base to ensure stable and rapid development. Regarding issues to be solved in the current study: Analysis results and prognosis graphs show that changes in the systemic inflammatory response that occur in the body in response to surgery are essentially transient in direct contact with the brain. was.
There is no relationship between the level of various indicators of homeostasis and the frequency of postoperative complications. It is noted that under the conditions of neurovegetative stabilization with fentanyl, clonidine and propofol, the body has a sufficient humoral response to operating pressure while maintaining the appropriateness of anesthesia. There is no "criteria" for indicators of systemic inflammatory response during surgery. There is an example of an indirect assessment of systemic inflammatory response associated with catecholamines. This is the reason and consequences of the development of systemic inflammatory response It is one of. It seems interesting to further analyze these changes and compare them with the clinical features of the postoperative period, especially consciousness disorder, neurodystrophic syndrome, and other symptoms of central nervous system pathology.