Diagnosis of cognitive function changes in patients with abdominal neoplasms occurring in the early postsurgery period and management of those with neuroprotective drug

РЕЗЮМЕ Актуальність. Проблема аналізу діагностичних критеріїв та адекватної нейропротекторної корекції післяопераційної когнітивної дисфункції при абдомінальній онкохірургії в залежності від ступеня та структури порушень, залишається невирішеною повною мірою, чим і визначається її актуальність. Мета роботи – оцінка стану післяопераційної когнітивної дисфункції у хворих з новоутвореннями черевної порожнини та корекція цитиколіном можливих порушень залежно від рівня показника загального когнітивного дефіциту. Матеріали та методи. Дослідження було проведено на базі відділень для пацієнтів хірургічного профілю комунального закладу «Харківська міська клінічна лікарня швидкої та невідкладної медичної допомоги імені професора О.І. Мещанінова». Для досягнення мети дослідження було обстежено 80 пацієнтів з новоутвореннями черевної порожнини, яким проводили оперативне втручання під загальною анестезією з використанням пропофолу та фентанілу. Результати та їх обговорення. На основі проведеного комплексного клінічного дослідження й аналізу механізмів формувань післяопераційної когнітивної дисфункції у пацієнтів онкохірургічного профілю після операції з використанням загальної анестезії нами запропоновано напрямок та схема корекції післяопераційної когнітивної дисфункції з використанням розробленого клініко-діагностичного критерію, який є основним у формуванні індивідуального алгоритму ведення пацієнтів у післяопераційному періоді. Висновки. На підставі проведеного аналізу даних про стан змін когнітивної функції, в порівнянні післяопераційного періоду з доопераційним станом, було вироблено диференційований підхід до інтенсивної нейропротекторної терапії післяопераційної когнітивної дисфункції. Запропоновано метод інтенсивної нейропротекторної терапії післяопераційної когнітивної дисфункції у пацієнтів з новоутвореннями черевної порожнини, яким проводиться хірургічне втручання з використанням загальної анестезії. Ключові слова: онкохірургія, анестезія, когнітивна функція, нейропротекторна терапія, хірургічний струс.


INTRODUCTION
Annually, lots of patients of all ages worldwide need surgery with the use of general anesthesia drugs. The corresponding human response to general anesthesia, surgical trauma and surgical concussion represents a universal comprehensive response [4,23,29].
The convincing data were obtained via a prospective randomized study of the International Study of Post-Operative Cognitive Dysfunction -ISPOCD1 (1998) and ISPOCD2 (2000), which made it possible to reveal persistent manifestations of POCD in 6.2% of middle-aged and 14% of elderly patients [45,55,57].
The risk factors of cognitive dysfunction in this group of patients include: a patient's attitude to his/her underlying disease, impact of general anesthesia, surgical stress and trauma, concomitant chronic cerebrovascular disease in a patient, duration of general anesthesia while surgery, age and education of a patient [6,41,47,48,62]. Thus, the author (Bunyatyan A.A., 1995) defined the concept of "Surgical stress" as a set of pathophysiological changes in the human body caused by changes in metabolism and inflammatory, immune reactions induced by surgical trauma. The systemic response of the human body to surgical trauma is activating the sympathetic nervous system, secretion of pituitary hormones, insulin resistance, cytokine production, acute phase reaction, neutrophilic leukocytosis, lymphocyte proliferation [3,30].
The occurrence of cognitive disorders in these patients is influenced by many biochemical and pathophysiological mechanisms: metabolic, hemorheological, hypoxic, toxic, leading to damage of the cerebral vessel walls at microcirculation level [29,50,54,61]. By themselves, drugs for general anesthesia cause changes in brain perfusion, which subsequently result in various disorders of the higher nervous system in the postoperative period in patients [4,5,18,26,52]. Postoperative changes in cognitive function are explained by a number of authors as a consequence of apoptosis, under the influence of drugs for general anesthesia, especially at high doses and long operations [42,22,31,38].
Postoperative cognitive dysfunction varies in clinical manifestations and significantly affects the outcomes of each operation. Unfortunately, at the present stage, the issues of etiology, pathogenesis, diagnosis, prevention and treatment of postoperative cognitive dysfunction are still far from being completely solved [8,23,26,30,32,51].
Understanding the main mechanisms occurring after general anesthesia during surgery and the state of cognitive function makes it possible to form pharmacological directions to support the cognitive function in patients which can deteriorate after surgery. The study conducted by scientists indicates that the mechanisms leading to neuronal damage and providing neuronal plasticity have a certain sequence. Such knowledge indicates the possibility of providing adequate neuroprotection and stimulation of plasticity with the use of drugs of the cytocolin group. The authors emphasize the use of citicoline and choline among other neuroprotective drugs in this category of patients. At the present stage, there is no single approach to the management of patients with cognitive changes in the postoperative period [1,20,21,23,29,36,38,53]. Thus, the issue of diagnosis and adequate neuroprotective correction by cytocolines of postoperative cognitive dysfunction in patients remains unresolved, determining its relevance.
Purpose -assessing the postsurgery cognitive dysfunction in patients with neoplasms of the abdominal cavity and management of possible disorders with citicoline depending on the level of general cognitive deficit.

MATERIAL AND METHODS
The study is a fragment of the research project of Emergency Medicine, Anesthesiology and Intensive Care Department of Kharkiv National Medical University of the Ministry of Health of Ukraine.
The study was conducted at the premises of departments for patients of surgical profile of Municipal Institution "Kharkov City Clinical Hospital of Ambulance and Emergency Care named after Professor O.I. Meshchaninov" (2009-2019). To achieve the aim of the study, 80 patients with abdominal neoplasms who underwent surgery under general anesthesia using propofol and fentanyl were examined.
Surgical intervention in the studied patients was performed for acute intestinal obstruction caused by malignant tumors of the colon of various localizations. In this regard, palliative and radical surgical interventions were performed urgently.
Inclusion criteria were the age 50 to 80, regardless of gender, the presence of oncological surgery using analgesia -general multicomponent anesthesia with artificial ventilation and total myoplegia, the possibility of productive contact at the time of hospitalization, obtaining informed consent, no history of blood disease mental disorders, allergic reactions. Criteria for non-inclusion were reoperation, diagnosed disorders of the central nervous system disease, addiction to drugs, narcotics, alcohol, and refusal of the patient or his relatives to participate in the study.
All patients were divided into 2 groups depending on the age of patients on the WHO scale, who underwent surgery using general anesthesia: Group 1 (n = 39) represented by middle-aged patients (50-59 years); Group 2 (n = 41) include elderly and senile patients (60-80 years).
Patients were prescribed a neuroprotective drug according to the scheme, as indicated in our patent. Dissolved in 200 ml of 0.9% sodium chloride solution, citicoline was administered intravenously in a dose of 1000 mg, 30 minutes before the end of the operation, within 12 hours after the operation and daily for 5 days [12,13,14].
The assessment of patients' condition before surgery was ASA II, according to the American Society of Anesthesiologists' Classification of the Physical Status of Patients (ASA, 1941). According to the classification of surgical-anesthesiological risk (V.A. Gologorsky, 1982) the patients' condition was assessed as 2 B. The control points of the examination were the day before surgery and the 1st, 7th, 30th day after surgery.

Study design
To assess the state of cognitive function in patients with abdominal neoplasms by conducting five neuropsychological tests. To figure out the changes in the function at selected control points, paying attention to the structure of violations, over time. To calculate the rate of ISSN 2708-7166 (Print) ISSN 2708-7174 (Online)
total cognitive deficit to determine the feasibility of neuroprotective correction. To manage cognitive impairment with citicoline and diagnose cognitive changes in control points that occurred under the influence of treatment.
Our patented calculation method, that is an indicator of total cognitive deficit, was used. Assessing this indicator makes it possible to obtain a quantitative description of the state of the cognitive sphere. The total cognitive deficit is calculated from the average sum of the percentage deviations from the norm of the results of the study of five tests of cognitive impairment. The percentage deviations of each test result from the norm for each of the five neuropsychological tests were determined. From the sum of the obtained test results, the arithmetic mean value, which is an indicator of total cognitive deficit, is obtained. Given the range of normal values of neuropsychological tests, which mainly has a 20% deviation, we indicated the range of changes in the total cognitive deficit of 20% as a criterion for the need for therapeutic correction in each patient at each stage of research [12,13,14,15].
All values are given as M ± m. To assess the significance of differences Student's t-test was used, at p = 0.05 differences were considered statistically significant. The presence of correlations between the obtained indicators was determined by Pearson's test. All mathematical operations and graphical constructions were performed using the software packages Microsoft Office XP: Microsoft XP Home and Microsoft Excel XP (license: 00049153409442 and 74017640000010657664, respectively).

RESULTS OF THE RESEARCH
In the preoperative period in the study of cognitive function using the MMSE test, the results in all patients were lower by 9.7% of the maximum probable value of the test. Patients of Group 1 by 9.6%, Group 2 -by 15.4%. The changes in the MMSE over time depended on the age of patients.
In all patients in the preoperative period, the results of the FAB test were 7.5% lower than the maximum probable value of the test. In patients of Group 1 -by 3.8%, Group 2 -by 16.1%. FAB test results also varied depending on the age of the patients.
In all patients, the results of the clock drawing test were 4.0% lower than the maximum probable value. Patients of Group 1 are 2.0% lower than the maximum probable value on the test, patients of Group 2 -by 8.0%. The results of the clock drawing test depended on the age of the patients, especially in patients of Group 2.
The Schulte test results obtained by us were significantly (p <0.01) 5.5% lower than the maximum probable test value. In patients of Group 1 -8.2% lower, Group 2 -18.3% lower. The Schulte test data obtained depended on the age of the patients.
In all patients in the preoperative period, the result of the total cognitive deficit was 9.68%. In patients of Group 1 it was equal to 8.52%, in patients of Group 2 -19.38% The analysis of the results of postoperative cognitive function in groups after surgery ( Table 1).
On the 1st day after the operation, the results of the MMSE test values significantly deteriorated from the values before the operation. Significant (p <0.01) deterioration was in patients of Group 2 -by 23.3% of the values before surgery. Within 30 days, the MMSE test significantly improved (p <0.01), but did not fully recover (5.92% of preoperative values). The smallest decrease in MMSE test values on the 1st day was observed in patients of Group 1 (1.4% of the values before surgery) and completely recovered within 30 days after surgery.
After the operation on the 1st day, the results of the FAB test values significantly (p <0.01) worsened from the values before the operation, more significantly in patients of Group 2 (25.8% of the level before the operation). Within 30 days, the condition of the FAB test significantly (p <0.01) improved (4.63% of preoperative values). But a faster improvement was observed on the 7th day and persisted for 30 days (1.15% of preoperative values). On the 30th day of the study, the best recovery of the test level to the level before surgery was in patients of Group 1. Deterioration of FAB test scores from day 1 gradually recovered in each group, with almost complete recovery to preoperative values in patients of Group 1. FAB test scores after surgery were proportional to age in all periods of the study, on the 1st day: 10.0% and 37.7% -respectively, on the 7th day: 5.0%, 30.5% and through 30 days: 5.0%, 20.0%, respectively.
On the 1st day after surgery, the results of the clock drawing test deteriorated from the values before surgery, more significantly in patients of Group 2 -22.8%. Deterioration of the clock drawing test from the 1st day was gradually restored in each group, but almost complete recovery to the values that were before surgery in patients did not occur. Indicators of the test of drawing the clock after surgery from the maximum probable result in all terms of the study were proportional to age on the 1st day: 14.0%, 29.0%, respectively, by groups, on the 7th day: 12.0%, 19 , 0%, after 30 days: 7.0%, 10.0%, respectively. In patients of all groups at all times of observation, no significant difference in the rate of recovery was observed, recovery was gradual but not complete.
According to the results A.R. Luria 10 words test on the 1st day there is a significant (p <0.01) deterioration of the results from the values of the test before surgery, more significantly in patients of Group 2 (19.8% of the level before surgery). On the 30th day of the study, significant (p <0.01) recovery was in patients of the 1st and 2nd groups.
In the study on the 1st day after surgery, the results of Schulte test can be found significant (p <0,01) deterioration of the results from the values before surgery, more pronounced in patients of Group 2 (51.2% of the level before surgery). Deterioration of Schulte test from the 1st day was gradually restored in each group, but almost completely (p <0.01) was restored in patients of Group 2. The parameters of Schulte test after surgery differed from the maximum probable test result in all periods of the study and had a proportional dependence on the age of patients on the 1st day (40.2%, 78.8%, respectively, groups), on the 7th day (24, 8%, 64.8%), on the 30th day -(7.8%, 38.2%, respectively). In patients of all groups in the short-term observations, there was no significant difference in the rate of recovery of Schulte test; it was gradual, with complete recovery to the level of cognitive impairment in this test to the level of values before surgery.
The analysis of the results of the effectiveness of citicoline treatment of postoperative cognitive function in groups of patients after surgery (Table 2).
In patients on the background of the treatment regimen on the 1st day after surgery, the results of MMSE test values deteriorated from pre-surgery values. Significant (p <0.013) deterioration of test values was in patients of Group 2 (14.2% of pre-surgery values). Already on the 7th day, the condition of the MMSE test in patients improved, but did not fully recover in patients of Group 2 (4.7% of pre-surgery values). In patients of Group 1 the result was better from the values before surgery by 1.8%. On the 30th day, the condition of MMSE test indicators improved, which should be noted, in patients of Group 1 and Group 2 it became higher than the values before surgery (2.6% and 6.3%, respectively, by groups).
Deterioration of MMSE test scores from day 1 gradually recovered in each group, with improvement from preoperative values in both groups of patients. The indicators of the MMSE test after surgery differed from the maximum probable result of this test on the 7th day by: 8.0%, 19.6%, respectively, by groups and on the 30th day by: 7.3%, 10.3%, after surgery, they were proportional to the age of the patients, and on the 1st day they were not proportional to the age of the patients. In patients of Group 1 against the background of the treatment regimen, the dynamics of deterioration of cognitive function was observed to a lesser extent, with rapid recovery and improvement.
In the study in patients on the background of the treatment regimen on the 1st day after surgery, the results of the FAB test significantly (p <0.01) deteriorated from pre-surgery values, more significantly in patients of Group 2 (9.2% of pre-surgery levels), on the 7th day significantly (p <0.01) improved (3.3% of preoperative values). In patients of Group 1, the improvement on the 7th day after surgery was maintained on the 30th day. FAB test scores after surgery on the background of neuroprotective therapy differed from the maximum probable test result in all periods of the study and had a proportional dependence on the age of patients on the 1st day by: 6.1%, 23.8% lower, respectively, by groups, on On the 7th day by: 4.4%, 18.8%, on the 30th day by: 4.4%, 12.7%, respectively.
The obtained changes in cognitive function on the background of neuroprotective therapy according to the results of this test may be associated with age-related features of the plasticity of cognitive function and the depletion of compensatory capacity.
On the 1st day after surgery on the background of neuroprotective therapy, the results of the clock drawing test deteriorated from the values before surgery, significantly (p <0.01) more in patients of Group 2 (22.0% of the level before surgery), by 30-th day significantly (p <0,01) values were restored to the level before surgery. The indicators of the test of drawing the clock after surgery on the background of the appointment of a neuroprotective drug differed from the maximum probable result in all periods of the study and had a proportional dependence on the age of patients on day 1 by: 6.0%, 22.0%, respectively, groups on the 7th days by: 5.0%, 18.0% and on the ISSN 2708-7166 (Print) ISSN 2708-7174 (Online)
On the 1st day after surgery on the background of the appointment to the standard scheme of postoperative neuroprotective therapy, the results of A.R. Luria 10 words test deteriorated from the values before surgery, significantly (p <0.01) more in patients of Group 2 (9.8% of the level before surgery) with a significant (p <0.01) improvement on the 30th day. In patients of Group 1 there was a faster improvement from the values before surgery and complete recovery to the level before surgery on the 7th day in patients of Group 2. On day 30 of the study, patients in all groups had improved test performance. Test scores A.R. Luria 10 words test after surgery on the background of neuroprotective therapy differed from the most probable test result in all periods of the study and had a proportional dependence on the age of patients on the 1st day by: 21.0%, 45.0%, respectively, by groups on the 7th day by: 13.0%, 40.0%, on the 30th day by: 9.0%, 31.0%, respectively. According to the results of A.R. Luria 10 words test in patients in a short time there was a recovery to the values before surgery: in patients of Group 2.
On the 1st day after surgery, the results of Schulte test significantly (p <0.01) deteriorated from pre-surgery values, more significantly in patients of Group 2 (41.6% of the level before surgery) and on the 30th day significantly p <0.01) gradually improved. The indicators of Schulte test on the background of the inclusion of neuroprotective therapy after surgery differed from the maximum probable result in all periods of the study and had a proportional dependence on the age of patients on the 1st day by: 39.2%, 67.4%, respectively, by groups on the 7th day in patients of the 2nd -55.0% and on the 30th day in patients of the 1st and 2nd groups by: 8.4%, 20.6%, respectively.
During all periods of the study, on the background of neuroprotective therapy, there was a change in the overall cognitive deficit with improvement in patients of Group 1 by 21.3% from pre-surgery, and in patients of Group 2 improved by 17.4% from values before surgery.
Thus, the indicator of total cognitive deficit was developed as the only generalized quantitative indicator of changes in cognitive function in patients of different ages, at different stages of the study. The indicator of general cognitive deficit makes it possible to assess the adequacy of drug tactics and compare the changes over time with the state of cognitive function before surgery and at different stages after surgery in each case. This indicator is the only criterion for the appointment of adequate individual treatment to correct possible cognitive i mpairments that occur or worsen after general anesthesia during surgery in patients with oncosurgical profile.