Dynamics of Cognitive Functions and Proinflammatory Cytokines in Different Variants of Coronary Artery Bypass Surgery

Цель исследования. Изучить показатели когнитивного потенциала и провоспалительного звена системного ответа организма при проведении операций прямой реваскуляризации миокарда на работающем сердце и в условиях различных видов искусственного кровообращения (классическое искусственное кровообращение и минимизированный экстракорпоральный контур). Материалы и методы. Обследовали 205 пациентов в возрасте 41—76 лет (56,16±2,91 лет). Всех пациентов оценивали по Монреальской шкале когнитивных функций и проводили перфузионную томографию головного мозга с контрастом. Исследовали концентрацию фактора некроза опухоли, интерлейкинов-6 и 8, нейроспецифической енолазы в периоперационном периоде. Всех больных оперировали в условиях общей сбалансированной анестезии на основе севофлюрана. Всех пациентов случайным образом разделили на три группы: пациенты, оперированные на работающем сердце; больные, оперированные с использованием классического контура искусственного кровообращения; пациенты, оперированные с использованием минимизированного экстракорпорального контура. Операции на работающем сердце выполняли с использованием аппарата стабилизатора миокарда. Искусственное кровообращение с использованием мембранных оксигенаторов проводили в непульсирующем режиме с перфузионным индексом 2,4 л/(мин•м2) в условиях умеренной гипотермии (34—35°С). Защиту миокарда в период пережатия аорты осуществляли методом фармако-холодовой кардиоплегии. Результаты. Через 7 суток после операции наименьшее количество баллов по Монреальской шкале когнитивных функций выявили в группе пациентов, оперированных с использованием классического контура искусственного кровообращения. В данной группе снижение показателя составило почти 23% (p=0,0202) по сравнению с исходным значением. В этой же группе прирост значения нейроспецифической енолазы составил 43,19% (p=0,0047). Через сутки после операции наибольшие значения (p<0,05) фактора некроза опухолей, интерлейкина-6 и интерлейкина-8 выявили в группе с классическоим контуром искусственного кровообращения. Показатели кортизола через 24 часа после операции также выросли во всех группах, но наименьший прирост зарегистрировали в группе пациентов, оперированных на работающем сердце. Заключение. Проведение операции на работающем сердце или использование минимизированного экстракорпорального контура с биосовместимым покрытием, центрифужным насосом и отсутствием контакта крови с воздухом минимально влияет на когнитивный потенциал пациентов, снижает проявления системного воспалительного ответа, что, в свою очередь, позволяет снизить количество послеоперационных осложнений и улучшить результаты лечения.


Introduction
Surgical myocardial revascularization is known to be the most effective way of treatment of patients with ischemic heart disease (IHD) [1].The current level of coronary surgery allows direct myocardial revascularization to be safe enough with hospital mortality not exceeding 1-3% [1,2].The overwhelming number of surgeries on the cardiac arteries in the international practice is performed using the cardiopulmonary bypass (CPB) with a temporary cardiac arrest [3,4].Despite the perfection of the modern technical support, extracorporeal circulation is significantly different from the physiological one [1,5,6].
The effect of prolonged use of extracorporeal circulation on cerebral perfusion has not been fully studied [7][8][9].The main complications in patients with cardiovascular diseases due to inadequate protection of the brain within the early post-operative period include impaired short-term and long-term memory, concentration, and thinking [10][11][12].Cognitive impairment occurs in 30-80% of patients who have undergone heart surgery using extracorporeal circulation [13][14][15][16].
Systemic inflammatory response (SIR), which develops during the extracorporeal circulation, contributes to the development of many adverse reactions in the post-operative period [17][18][19].There are a number of specific factors having systemic influence, which are characteristic of cardiac surgery: blood contact with the foreign surface of the contours of the extracorporeal circulation apparatus, surgical trauma, and reperfusion injury.They cause the development of a systemic inflammatory response (activation of the complement system, cytokine release, WBC activation, expression of adhesion molecules, endothelins, excessive formation of oxygen radicals and nitric oxide), hypothermia, hemodilution due to the use of solutions for cardioplegia and primary filling of the CPB circuit, as well as disorders in vascular tone [20][21][22][23].

Materials and Methods
The inclusion criteria were the following: elective surgery, age over 18 years, the informed consent, absence of intraoperative surgical complications.
A total of 205 patients (141 men and 64 women) aged 41-76 years (56.16±2.91 years) were examined.The clinical severity of the initial condition of patients corresponded to the II-IV functional class of IHD according to the NYHA classification.121 patients (59.02%) had a history of myocardial infarction.
All patients were assessed according to the Montreal Cognitive Assessment (MoCA test) three days before surgery and on the seventh day of the post-operative period.Different cognitive spheres were evaluated: attention and its concentration, executive functions, memory, speech, visual and constructive skills, abstract thinking, counting and orientation.The duration of the MoCA test was approximately 10 minutes.All patients underwent enhanced CT perfusion imaging of the brain three days before surgery and on the seventh day of the post-operative period to exclude organic brain damage.
Blood sampling for proinflammatory cytokines assays (tumor necrosis factor, TNFα; interleukin-6,IL-6; interleukin-8, IL-8; cortisol) were performed from the superior vena cava before surgery and a day after surgery.For neuron specific enolase (NSE) assay, venous blood sampling was performed from the superior vena cava three days before surgery and one week after surgery.The concentration of biomarkers was determined by ELISA using a BioHimMak reagent kit on a BioChem biochemical analyzer.
Surgery in all patients was performed under general balanced anesthesia based on sevoflurane.Patients underwent bypass grafting surgery of 1-4 (2.63±0.74)coronary arteries.
All the patients were randomly divided into three groups: BH -patients operated on a beating heart (67 people), CCPB -patients operated with classical CPB (79 people), MECC -patients operated using minimized extracorporeal circuit (59 people
All data obtained during the study were statistically processed using StatPlus Pro software.The arithmetic mean and the error off the mean were calculated.The significance of differences between groups was determined by nonparametric Mann-Whitney test.Differences between groups were considered significant at a probability level of more than 95% (P<0.05).

Results and Discussion
Evaluation of dynamics by MoCA test revealed no significant changes before surgery and 7 days after surgery in the BH and MECC groups of patients (table 1).CCPB group of patients, however, experienced y significantly decreased MoCA test values byto 23% compared to the baseline values (P=0.0202).
The increase of NSE level after 7 days after surgery (table 1) did not exceed 7 % and was statistically insignificant in the BH and MECC groups of patients.In the CCPB group of patients, a significant (P=0.0047)increase in the level of neuron specific enolase reached 43.19%.
A day after the surgery, all groups showed an increase in the concentration of cytokines (table 2).The highest levels of TNFα after surgery were found in the MECC group, where its level was 39.17±4.59pg/ml.The level of IL-6 in this group of patients increased 70-fold a day after the surgery, while the increase in this parameter in other groups did not exceed 330%.The maximum level of IL-8 a day after surgery was 301.18±34.48pg/ml in the MECC group of patients.Cortisol levels 24 hours after surgery were also in- Повышенные концентрации цитокинов являлись причиной более высоких дозировок адреномиметиков, продленной искусственной вентиляции легких (ИВЛ) в послеоперационном периоде в группе пациентов КИК (табл.3).Соответственно время госпитализации данной группы пациентов в отделении реанимации превышало аналогичный показатель в других группах почти в два раза.Также в группе КИК частота возникновения тахиа-creased in all groups; the smallest increase (1.9 times) was recorded in the group of patients operated on a beating heart.Elevated levels of cytokines caused higher dosages of adrenergic agonists, prolonged mechanical ventilation (MV) in the post-operative period in the CCPB patient group (table 3).The duration of the hospital stay in CCPB group of patients in the intensive care unit exceeded almost twice the same parameter in other groups.Also in the MECC group, the incidence of tachyarrhythmias (paroxysmal atrial fibrillation) within the post-operative period significantly exceeded the same criterion in the reference groups 0.84-2.42-fold(P=0.0054).
In order to develop an optimal strategy for extracorporeal circulation, before the main stage of the surgery, we chose two parameters: estimated volumetric perfusion rate (VPR) and cardiac index (CI).The mean values of these parameters in the statistical population were 5 l/min and 2.5 l/(min•m 2 ), respectively.
In our clinic, in patients with an estimated volumetric perfusion rate of more than 5 l/min and the technical ability to perform off-pump bypass surgery, we try to perform beating heart surgery (fig.a).If there is no such technical possibility, we carry out minimally invasive cardiopulmonary bypass.
Using the MECC systems, the surgery was performed in patients with low cardiac output of less than 2.5 l/(min•m 2 ) and VPR of less than 5 l/min (fig.b).In patients with satisfactory cardiac output of more than 2.5 l/(min•m 2 ) and VPR of less than 5 l/min, the surgery using standard CPB was performed (fig.b).

Conclusion
The results of the clinical studyedemonstrate that cardiac surgery using extracorporeal circulation activates inflammatory cascades and serves as Таблица 3. Результаты лечения.Table 3.The results of treatment in the groups.В целом, проведение операции на работающем сердце или использование минимизированного экстракорпорального контура минимально влияет на когнитивный потенциал пациентов, снижает проявления системного воспалительного ответа, что, в свою очередь, позволяет снизить количество послеоперационных осложнений и улучшить результаты лечения.a trigger for a systemic inflammatory response In a post-operative period, this may lead to the development of a systemic inflammatory response.Next day after the surgery, patients in all groups experienced the increase in levels of cytokines, however, the highest levels were recorded in the group with classical cardiopulmonary bypass.Incerase in inflammatory mediators might result in prolongation of hospitalization, longer post-operative MV, greater need in adrenergic agonists, and the occurrence of paroxysms of atrial fibrillation.Assessing the dynamics of the Montreal Cognitive Assessment scoring, it was found that the off-pump coronary artery bypass grafting was the most favorable for the preservation of cognitive functions of patients.

Parameters
The data obtained allowed us to develop an optimal strategy for CABG surgery.Evaluation of the volume rate of perfusion and cardiac index before the main stage of the operation allows selection of the safest algorithm for surgery.
Thereby, the off-pump surgery or minimized extracorporeal circuit minimally affects the cognitive potential of patients, reduces manifestations of the systemic inflammatory response associated with a number of postoperative complications, and improves the results of treatment.