RU2523450C1 - Method for prevention of early postoperative cognitive dysfunction in patients following complete coronary bypass surgery - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention can be used for preventing developing cognitive disorders in patients suffering from ischemic heart disease (IHD) after complete coronary bypass surgery. For this purpose, 10-14 days before the planned surgery with underlying standard drug therapy containing ACE inhibitors, beta-blockers, nitrates, calcium antagonists and acetylsalicylic acid, rosuvastatin is additionally prescribed in a daily dose of 20 mg nocte. After the coronary bypass surgery, taking the preparation is continued for the whole hospital period, taking continuously after discharge from the hospital is recommended.

EFFECT: method enables preventing developing early postoperative cognitive dysfunction in the patients following the cardiosurgical complete bypass procedures.

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Description

The invention relates to medicine, namely to cardiology and neurology, and can be used to prevent the development of cognitive impairment in patients with coronary heart disease (CHD) who underwent coronary artery bypass grafting (CABG) in cardiopulmonary bypass (IR).

CABG surgery, especially performed under IR conditions, in 20-90% of patients can lead to the development of early postoperative cognitive dysfunction (POCD). The etiology of cognitive dysfunction after open heart surgery is multifactorial and includes cerebral embolism, global cerebral hypoperfusion, systemic and cerebral inflammatory response, damage to the blood-brain barrier.

There is a method of preventing POCD in elderly patients after surgery on the abdominal organs using a drug of the cerebroactive drug group - thiocetam (Usenko L.V. Prevention and correction of postoperative cognitive dysfunctions in elderly patients. / Usenko L.V., Rizk Shadi Eid , Krishtafor A.A., Kanyuk G.S., Kushch I.P. Methodological recommendations. - Dnepropetrovsk, 2007. - 60 p.). The use of thiocetam at the beginning and throughout the postoperative period helps to increase the indicators of higher mental functions in the immediate postoperative period, while maintaining this cognitive-restoring effect up to the 30th day after the operation. This method contributes to the prevention of early POKD, however, it is shown only to patients who underwent surgery on the abdominal organs. In addition, the method provides for the initiation of therapy immediately after surgery, which is not acceptable for cardiac surgery, such as CABG, which are performed under IR conditions.

Closest to the proposed invention is a method for the treatment and prevention of POKD in patients undergoing cardiac surgery, including CABG under conditions of IR. The method is based on the use of a neuroprotective drug with antioxidant activity - cytoflavin (Suslina Z.A. Neuroprotection in cardiac surgery / Z.A.Suslina, L.A. Bokeria, M.A.Piradov, A.I. Malashenkov and others. // Annals of Clinical and Experimental Neurology. - 2009. - T. 3. - No. 1. - P. 4-8). At the same time, cytoflavin is administered dropwise at a dosage of 20 ml per 200 ml of a 0.9% sodium chloride solution within 3 days before and 3 days after KS operation. The method gives a positive clinical effect, which is manifested in the improvement of long-term and operational memory, as well as the dynamic component of mental activity.

The disadvantage of this method is that the constituent substances that make up cytoflavin are rapidly metabolized in the body and have a half-life of about 2 hours, which gives a short-term effect and does not maintain a constant concentration of the drug in the blood. The indicated drawback raises doubts about the prophylactic effect of cytoflavin on the development of POKD in the early stages in patients undergoing CABG under IR conditions. At the same time, the drug used does not affect the performance of the systemic inflammatory response and requires an intravenous route of administration.

The technical result of the invention is to increase the effectiveness of preventing the development of early POKD in patients after cardiac surgery performed under infrared conditions due to the use of a lipid-lowering drug, rosuvastatin, in the perioperative period.

It is known that IR, under which most cardiosurgical interventions are currently being performed, causes a systemic inflammatory response (SVR) of the body, while the resulting cytokines are a direct factor in aggression against the blood-brain barrier and cellular components of the brain. Due to pleiotropic effects, statins are known to have beneficial effects on endothelial function, increase the stability of atherosclerotic plaques, limit platelet aggregation and reduce vascular inflammation. The presence of favorable therapeutic effects of rosuvastatin, not associated with their lipid-lowering effect, suggests their mediated cerebroprotective effect and the possibility of using it for the prevention of POKD.

An analysis of the concentration of inflammation markers performed in patients with coronary heart disease (IHD), conducted at the FSBI “Research Institute of the CPSU” SB RAMS, showed that in the group of patients who did not take rosuvastatin in preparation for surgery, the levels of pro-inflammatory cytokines were higher compared to patients who in the preoperative period took this drug for 10-14 days (see table. 1).

Table 1 The dynamics of the concentration of ititerleukins and CRP depending on the intake of rosuvastatin in patients in the preoperative period Index, Log 10 ng / ml prior to randomization 2-3 days before school R Patients with rosuvastatin (1) Patients without rosuvastatin (2) Rosuvastatin Patients (3) Patients without rosuvastatin (4) IL-1β 0.62 ± 0.25 0.62 ± 0.27 0.36 ± 0.19 0.62 ± 0.16 p _3-4 = 0,00063 IL-6 1.79 ± 0.4 1.78 ± 0.2 1.5 ± 0.2 1.8 ± 0.31 p _3-4 = 0.0001 IL-8 0.65 ± 0.2 0.62 ± 0.23 0.62 ± 0.25 0.36 ± 0.01 p _3-4 = 0.004 IL-10 0.46 ± 0.02 0.47 ± 0.1 0.6 ± 0.2 0.46 ± 0.2 p _3-4 = 0.0042 TNF-α 0.62 ± 0.1 0.64 ± 0.2 0.36 ± 0.14 0.62 ± 0.1 p _3-4 = 0,00034 CRP 0.63 ± 0.3 0.62 ± 0.21 0.36 ± 0.1 0.62 ± 0.15 p _3-4 = 0,0005

Note: p is the significance level of the difference between the groups, p _3-4 is the significant difference in the indicators of inflammatory markers in patients 2 days before CABG in the group taking rosuvastatin (3) and patients without rosuvastatin (4), CRP - C-reactive protein, TNF -α - tumor necrosis factor α, IL - interleukin.

So, 2 days before surgery, the level of C-reactive peptide (hsCRP) in the group of patients not taking rosuvastatin was 2 times higher (p = 0,0005), the level of interleukin (IL) -1β was 1.7 times higher (p = 0.00063), IL-8 and IL-6 - 1.2 times (p = 0.004 and p = 0.0001, respectively), tumor necrosis factor a (TNF-α) - 2 times (p = 0.00034 ) Moreover, prior to the appointment of rosuvastatin, no intergroup differences in the concentration of inflammatory markers were detected.

On the 2nd day after surgery in both groups of patients revealed an increase in plasma concentrations of hsCRP, IL-1β, 6, 8, TNF-α compared with preoperative indicators. However, in the group of patients who did not take rosuvastatin, these indicators were higher compared to patients who took it: hsCRP and IL-6 - 2 times (p = 0.000001 and p = 0.0001, respectively), IL-1β - 1.4 times (p = 0.0012), IL-8 - 1.2 times (p = 0.037), TNF-α - 2.7 times (p = 0.0032) (see table. 2).

table 2 The dynamics of the concentration of interleukins and CRP depending on the intake of rosuvastatin in patients in the postoperative period Index, Log10ng / ml 2-3rd day after CABG 7-10th day after CABG R Patients with rosuvastatin (1) Patients without rosuvastatin (2) Rosuvastatin Patients (3) Patients without rosuvastatin (4) IL-1β 0.57 ± 0.25 1.58 ± 0.16 0.37 ± 0.12 1.37 ± 0.2 p _1-2 = 0.0012 p _3-4 = 0.003 IL-6 15.0 ± 0.2 28.4 ± 1.6 4.36 ± 0.4 5.27 ± 0.24 p _1-2 = 0,0001 IL-8 0.57 ± 0.2 1.58 ± 0.12 0.37 ± 0.03 1.37 ± 0.06 p _1-2 = 0,037 p _3-4 = 0,043 IL-12 1.34 ± 0.22 1.35 ± 0.29 1.65 ± 0.35 1.74 ± 0.3 p≥0.05 IL-10 0.57 ± 0.02 0.73 ± 0.2 0.54 ± 0.3 0.65 ± 0.1 p _1-2 = 0.003 TNF-α 0.57 ± 0.2 1.58 ± 0.2 0.57 ± 0.3 1.37 ± 0.2 p _1-2 = 0,0032 p _3-4 = 0,0003 CRP 0.57 ± 0.25 1.58 ± 0.16 0.43 ± 0.17 1.33 ± 0.31 p _1-2 = 0.000001 P _3-4 = 0.000003

Note: p - level of significance of differences between groups, p _1-2 - significant differences in indicators of markers of inflammation in patients 2-3 days after CABG in groups taking rosuvastatin (1) and patients without rosuvastatin (2), p _3-4 - significant differences in indicators on days 7-10, CRP - C-reactive protein, TNF-α - tumor necrosis factor α, IL - interleukin.

By the 7-10th day of the postoperative period, a decrease in the concentration of proinflammatory cytokines was observed in both groups, however, in the group of patients who did not take rosuvastatin, their level was still higher: hsCRP and TNF-α - 3.7 times (p = 0.000003 and p = 0.0003, respectively), IL-1β - 1.3 times (p = 0.003), IL-8 - 1.25 times (p = 0.043).

Subsequent correlation analysis between the level of pro-inflammatory cytokines and indicators of patient cognitive function showed that an increase in the concentration of TNF-α, IL-1β on the 2nd day and IL-12 on the 10th day after CABG was associated with a decrease in the reaction rate in neurodynamic tests. Large concentrations of IL-6, IL-12 on the 2nd day after CABG were associated with fewer memorized words. In addition, a high concentration of IL-8 on the 10th day after CABG was associated with fewer processed characters in the Bourdon Proof Test test on the 10th day after CG. For the group taking rosuvastatin, no reliable correlation between these indicators was found.

Table 3 Correlation between pro-inflammatory cytokines and indicators of cognitive function in patients in the postoperative period of CABG in conditions of IR Indicators of neuropsychological status Pro-inflammatory cytokines FHO-α, IL-1β IL-12 IL-6 IL-8 IL-10 Reaction rate in the test of the level of functional mobility of nervous processes r = + 0.61 p = 0.01 r = + 0.6 p = 0.035 r = + 0.8 p = 0.003 Bourdon Proof Test r = -0.67 p = 0.04 r = -0.8 p = 0.04 Test "remembering 10 words" r = -0.62 p = 0.01 r = -0.61 p = 0.01

Note: p - significance level, r - Spearman's rank correlation coefficient, TNF-α - tumor necrosis factor α, IL - interleukin.

Thus, in patients taking rosuvastatin, in the postoperative period of CABG, the indicators of neuropsychological status were better in comparison with patients who did not take it. In the rosuvastatin group, the worst neuropsychological parameters were associated with a higher concentration of pro-inflammatory cytokines.

The method is as follows: for patients with coronary artery disease 10 days before the expected surgical intervention, against the background of standard drug therapy, including ACE inhibitors (enalapril maleate 5-15 mg per day), beta-blockers (bisoprolol 2.5-5 mg per day), nitrates (isosorbide dinitrate 40-80 mg per day), calcium antagonists (amlodipine 2.5-10 mg), acetylsalicylic acid (100 mg at lunch after meals), rosuvastatin is additionally prescribed in a daily dose of 20 mg at night. After CABG, administration of the drug continues throughout the hospital period, followed by the recommendation of continuous administration after discharge from the hospital.

The proposed method was used in the clinic of the FSBI “Research Institute of the CPSU” of the RAMS in 180 patients with coronary artery disease who underwent CABG under conditions of infrared.

The drug rosuvastatin for the prevention of the development of early POKD in patients undergoing CABG under IR conditions has not been previously used.

Application examples

Example 1

Patient M., born in 1954, was admitted to the cardiology department of the Research Institute for Complex Problems of Cardiovascular Diseases SB RAMS with a diagnosis of Coronary Heart Disease. Angina pectoris FC II. Postinfarction cardiosclerosis (07.10.2010). Hypertension stage III, risk 4. CHF I (FC II). EuroSCORE 2 (1.5). Scheduled operation of CABG under conditions of infrared. The duration of the IR is 102 minutes, the time of clamping the aorta is 84 minutes. There were no complications in the intraoperative and early postoperative period.

Enalapril maleate 10 mg, bisoprolol 5 mg, acetylsalicylic acid 100 mg in the afternoon after meals, isosorbide dinitrate 80 mg per day were prescribed to the patient as preoperative preparation. For 10 days before surgery and throughout the hospital postoperative period, the patient took rosuvastatin 20 mg in one dose at night.

Before the appointment of rosuvastatin, as well as on the 7-10th day after CABG, the patient underwent neuropsychological testing: MMSE scale, tests of complex visual-motor reaction (SPMR), mobility of nervous processes (UVP), brain performance (RGM), and proof-reading Bourdon (KP), memorizing 10 numbers, syllables and words (see table 4).

Table 4 Dynamics of individual neuropsychological parameters of patient M. Indicator To school 7-10 days after CABG MMSE, points 29th 29th SPMR reaction rate, ms 675 582 The number of MPSR errors 2 0 UVP reaction rate, ms 499 472 Number of Missed UVP Signals 12 9 The number of processed signals RGM 452 487 RGM reaction rate, ms 486 461 The number of errors RGM 118 114 The number of memorized numbers 6 5 Number of syllables memorized 3 four The number of memorized words four 5 KP attention rate 35.81 45.85 The number of errors KP 12 9

Based on the testing performed on the 7-10th day after the operation, it was reliably shown that the patient’s cognitive function improved, the reaction rate increased in the MTCM, UVP, RGM tests, the number of errors and missed signals in the MLCP, UVP and CP tests decreased, the number of memorized syllables increased and words, the attention ratio has increased.

Example 2

Patient I., born in 1953, was admitted to the cardiology department of the Research Institute of Complex Problems of Cardiovascular Diseases SB RAMS with a diagnosis of coronary heart disease. Angina pectoris FC III. Hypertension III stage, risk 4. CHF I (FC III). EuroSCORE 0 (0.88). A planned operation of coronary bypass surgery in cardiopulmonary bypass was performed. Duration of IK-99 min, aortic clamping time - 68 min. There were no complications in the intraoperative and early postoperative period.

Enalapril maleate 10 mg, bisoprolol 5 mg, acetylsalicylic acid 100 mg in the afternoon after meals, isosorbide dinitrate 80 mg per day were prescribed to the patient as preoperative preparation. Throughout the hospital period, rosuvastatin was not prescribed.

Neuropsychological testing was carried out in the same volume as the patient in example 1. (see table 5)

Table 5 Dynamics of individual neuropsychological parameters of patient I. Indicator Before surgery 7-10 days after CABG MMSE, points 28 28 SPMR reaction rate, ms 580 597 The number of MPSR errors 0 one UVP reaction rate, ms 625 646 Number of Missed UVP Signals thirty 45 The number of signals RGM, 232 230 RGM reaction rate, ms 652 668 The number of errors RGM 122 128 The number of memorized numbers 6 6 Number of syllables memorized 3 four The number of memorized words 7 5 KP attention rate 38,4 29.2 The number of errors KP 3 5

On the 7-10th day after the operation, the majority of the cognitive functions assessed worsened, the reaction rate decreased in the tests of SZMR, UFP, RGM, the number of errors and missed signals in the tests of SZMR, UFP and KP increased, the number of memorized words decreased, the attention coefficient decreased.

When analyzing changes in neuropsychological parameters in groups of patients depending on the presence or absence of rosuvastatin in therapy, it was found that early POKD developed in 81% of patients in the group without rosuvastatin (N = 40) and 55% in the group with rosuvastatin (N = 69) , (p = 0.000001).

The proposed method of prevention is effective in reducing the incidence of early POKD in patients after coronary artery bypass grafting under conditions of cardiopulmonary bypass. The method is affordable, easily reproducible and does not require special equipment.

Claims (1)

A method for the prevention of early postoperative cognitive dysfunction in patients after coronary artery bypass grafting under cardiopulmonary bypass, including the appointment in the preoperative period of standard drug therapy using ACE inhibitors, beta-blockers, nitrates, calcium antagonists and acetylsalicylic acid, characterized in that 10-14 days before surgery, patients are prescribed rosuvastatin in a daily dose of 20 mg at night, and after coronary bypass surgery, the drug is continued s hospital period followed the recommendation of admission after discharge from hospital.