CN103893205B - A kind ofly comprise cardioplegic solution of lignocaine and adenosine and preparation method thereof - Google Patents

Abstract

The invention relates to the technical field of cardioplegia, in particular to a cardioplegia containing lidocaine and adenosine and a preparation method thereof. In 1000ml organ preservation solution, the components are: sodium chloride 5.0-7.0g; potassium chloride 2.0-3.0g; magnesium sulfate 0.3-0.5g; calcium chloride 0.05-0.1g; glucose 5-8g; Adenosine 0.3-0.6g; Adenosine 100-200mg; Astragaloside 4 10-20mg; Coenzyme Q10? 50-80mg; Double distilled water balance.

Description

A cardioplegia solution containing lidocaine and adenosine and its preparation method

technical field

The invention relates to the technical field of cardioplegia, in particular to a cardioplegia containing lidocaine and adenosine and a preparation method thereof.

Background technique

Since the beginning of heart surgery in the 1960s, pioneers in cardiac surgery have attempted several ways to support the patient's circulation on the one hand and protect the heart on the other. The protective effect of hypothermia has been recognized not only locally in the heart but also in systemic applications. The subsequent development of cardiac surgery has mainly utilized the gradual improvement of extracorporeal circulation components, allowing more and more complex and longer operations to be performed, but unfortunately, the myocardial protection effect has not reached the ideal state, and cardiac arrest still exists after surgery - Reperfusion injury. Therefore, it is necessary to provide a measure of myocardial protection that is better than merely cooling the myocardium.

Cardioplegia is an important guarantee for the completion of cardiac surgery. It can be divided into the following three categories according to the principle of action: depolarizing cardioplegia, hyperpolarizing cardioplegia and polarizing cardioplegia. Depolarizing cardioplegia is the most commonly used cardioplegia in clinical practice, and commonly used depolarizing cardioplegia includes STH-2 solution and LA solution. However, some studies have shown that low cardiac output after cardiovascular surgery may be related to the poor myocardial protection of high potassium depolarizing cardioplegia. The possible reasons are as follows: ① Depolarizing cardioplegia reduces the myocardial cell membrane potential to below -50mv, but the cell membrane potential is between -60 and -15mv, and there is an inward steady-state sodium window current, which can cause myocardial cell sodium overload ;② When the membrane potential is between -40 and -15mv, there is an inward calcium current in the cell membrane, and the calcium in the sarcoplasmic reticulum is easy to flow out in the depolarized state, which aggravates the intracellular calcium overload, and the transmembrane flow of sodium and calcium will aggravate myocardial injury , is not conducive to the recovery of myocardial function; ③ high potassium in depolarization cardioplegia can directly damage coronary endothelial cells, resulting in damage to the autoregulatory function of vascular endothelial cells and blood vessels. Hyperpolarized cardioplegia was first proposed by Cohn et al. in 1993, using KATP channel opener to hyperpolarize the membrane potential of myocardial cells (about -110mv) and arrest in diastole. Among them, the commonly used potassium channel openers reported in the literature include adenosine, nicorandil, pinacidil, etc. Hyperpolarized cardioplegia has been studied in the laboratory for a long time, but because of its poor myocardial protection Indeed, it has not yet been applied clinically. Similar to depolarizing cardioplegia, hyperpolarized cardioplegia also has the problem of transmembrane ion and energy imbalance.

Through research, it is found that the defects of the above-mentioned cardioplegia still need to be further improved, especially the time for inducing cardioplegia must be shortened as much as possible, and it is also appropriate to use the minimum effective volume of cardioplegia to obtain cardiac arrest. Traditional myocardial protection uses chemical cardiac arrest plus local hypothermia to reduce myocardial energy consumption, and various additives are added to minimize the degree of ischemia and hypoxia damage during cardiac arrest. In recent years, more research focuses on how to reduce ischemic injury during cardiac arrest and reperfusion injury after reperfusion. The myocardium is in an anaerobic metabolic state after blocking the circulation. When the tissue is hypoxic, because intracellular glucose is converted into lactic acid under anaerobic conditions, a large amount of lactic acid is produced, and it is prefilled with lactated Ringer's solution in cardiopulmonary bypass cardiac surgery. They are also prone to hyperlactic acidosis, leading to severe lactic acidosis. Although the low temperature reduces the metabolic state of the cells, the utilization of sugar and the storage of ATP are greatly reduced, and the cardiomyocytes have a negative energy balance when the metabolism is not completely stopped.

Lidocaine is a commonly used clinical drug, often used in nerve block, treatment of arrhythmia, organ protection and so on. Studies have found that lidocaine concentration ≥ 0.6mmol/L can quickly arrest the myocardium, and retain its anti-inflammatory and antioxidant effects, and can quickly re-beat after reperfusion, and the incidence of arrhythmia after reperfusion is significantly reduced.

Adenosine is an intermediate product of myocardial energy metabolism and plays an important pathophysiological role in maintaining the homeostasis of the cardiovascular system and various injury mechanisms. Adenosine has the function of regulating coronary circulation. Adenosine improves myocardial oxygen supply and promotes glucose inflow through persistent dilation of coronary arteries. It replenishes the high-energy phosphate bond pool in cells, enhances heart function, and antagonizes the action of catecholamines, restoring the unbalanced oxygen supply and demand and energy metabolism. In addition, adenosine also has the functions of inhibiting the release of endothelin, preventing the aggregation of platelets in the microcirculation and increasing the content of Mn-SOD in cardiomyocytes.

Contents of the invention

The present invention provides a cardioplegia containing lidocaine and adenosine and a preparation method thereof, which overcomes the above-mentioned deficiencies in the prior art, and can effectively solve the problem that the traditional cardioplegia has induced cardiac arrest for too long, Reperfusion is required, arrhythmia is prone to occur after re-beating, myocardial damage is likely to occur, inflammatory reactions are prone to occur, and oxygen cannot be carried.

A cardioplegia solution containing lidocaine and adenosine, in 1000ml organ preservation solution, the components are respectively:

Sodium chloride 5.0-7.0g; Potassium chloride 2.0-3.0g; Magnesium sulfate 0.3-0.5g;

Calcium chloride 0.05-0.1g; Glucose 5-8g; Lidocaine 0.3-0.6g;

Adenosine 100-200mg; Astragaloside IV 10-20mg; Coenzyme Q1050-80mg;

Tetrandrine 5-10mg; higinaconine 5-10mg; histidine 5-8g; the balance of double distilled water.

In one embodiment of the present invention, in the 1000ml organ preservation solution, the components are preferably:

Sodium chloride 6.5g; Potassium chloride 2.3g; Magnesium sulfate 0.35g;

Calcium chloride 0.07g; Glucose 6g; Lidocaine 0.5g;

Adenosine 130mg; Astragaloside IV 15mg; Coenzyme Q1075mg;

Tetrandrine 7mg; higenamine 8mg; histidine 6g; the balance of double distilled water.

In another embodiment of the present invention, in the 1000ml organ preservation solution, the components are preferably:

Sodium chloride 6g; Potassium chloride 2.5g; Magnesium sulfate 0.4g;

Calcium chloride 0.07g; Glucose 7g; Lidocaine 0.4g;

Adenosine 150mg; Astragaloside IV 17mg; Coenzyme Q1060mg;

Tetrandrine 9mg; higenamine 6mg; histidine 7g; the rest of double distilled water.

Another object of the present invention is to provide a kind of method for preparing described cardioplegic solution, concrete steps are as follows:

(1) Add 800ml of double-distilled water into a container larger than 1000ml, then add sodium chloride, potassium chloride, magnesium sulfate, and calcium chloride in sequence, and stir until the color becomes clear; then add glucose, lidocaine, adenosine, and astragalus Aside, tetrandrine, histidine and higenamine, stir until the color becomes clear; then add coenzyme Q10, stir until the color becomes clear;

(2) Adjust the pH of the solution to 7.65, adjust the osmotic pressure to 350-385mOsm/L, adjust the volume to 1000ml with double-distilled water, and store at 4°C for later use.

The present invention has carried out in-depth research on the dosage of lidocaine and adenosine, combined with the advantages of traditional medicine of the motherland, carried out a large number of complicated screening tests on Chinese medicine extracts and their monomers related to heart protection, and determined the best Chinese medicine Monomer components and their weight ratios, thereby obtaining a cardioplegia prescription that reaches the best effect, using a small amount of cardioplegia prepared by the present invention can effectively make cardiac arrest, avoiding cardiac arrest due to myocardial ischemia The damage to the myocardium caused by reperfusion can improve the success rate of a re-beat and reduce the incidence of arrhythmia after re-beat, and effectively reduce the inflammatory response and effectively protect the cardiomyocytes.

detailed description

The present invention will be illustrated below with reference to the accompanying drawings and further detailed description. It should be pointed out that the following description is only an illustration of the technical solutions claimed in the present invention, and is not any limitation to these technical solutions. The protection scope of the present invention shall be determined by the contents described in the appended claims.

Example 1

Accurately weigh the following ingredients:

Sodium chloride 6.5g; Potassium chloride 2.3g; Magnesium sulfate 0.35g;

Calcium chloride 0.07g; Glucose 6g; Lidocaine 0.5g;

Adenosine 130mg; Astragaloside IV 15mg; Coenzyme Q1075mg;

Tetrandrine 9mg; higenamine 6mg; histidine 7g.

(1) Add 800ml of double-distilled water into a container larger than 1000ml, then add sodium chloride, potassium chloride, magnesium sulfate, and calcium chloride in sequence, and stir until the color becomes clear; then add glucose, lidocaine, adenosine, and astragalus Aside, tetrandrine, histidine and higenamine, stir until the color becomes clear; then add coenzyme Q10, stir until the color becomes clear;

(2) Adjust the pH of the solution to 7.65, the osmotic pressure to 370mOsm/L, distill the volume to 1000ml with double-distilled water, and store it at 4°C for later use.

Example 2

Accurately weigh the following ingredients:

Sodium chloride 6g; Potassium chloride 2.5g; Magnesium sulfate 0.4g;

Calcium chloride 0.07g; Glucose 7g; Lidocaine 0.4g;

Adenosine 150mg; Astragaloside IV 17mg; Coenzyme Q1060mg;

9 mg of tetrandrine; 6 mg of higenamine; 7 g of histidine; other preparation methods are the same as in Example 1.

Example 3

Accurately weigh the following ingredients:

Sodium chloride 5.0g; Potassium chloride 3.0g; Magnesium sulfate 0.5g;

Calcium chloride 0.05g; Glucose 8g; Lidocaine 0.6g;

Adenosine 200mg; Astragaloside IV 10mg; Coenzyme Q1050mg;

10 mg of tetrandrine; 5 mg of higenamine; 5 g of histidine; other preparation methods are the same as in Example 1.

Example 4

Using the non-circulatory Langendorff perfusion function test model of isolated mouse heart, compared with three commonly used donated heart preservation solutions (Thomas solution, Stanford solution, UW solution), to study the long-term (10 hours) preservation of isolated mice at 4°C Heart preservation effect.

SD rats were weighed, and 0.5-0.7 ml of 2% pentobarbital sodium was injected intraperitoneally. After anesthesia, the patient was fixed in the supine position, heparin (3 mg/Kg) was injected through the left femoral vein, the chest was quickly opened, the aorta was cut off at the junction of the aorta and the right subclavian artery, and the heart was removed. Immediately put the heart into a plate containing cold KHB solution (4°C), wash off the residual blood in the aorta with cold KHB solution, insert the aortic perfusion tube and fix it (the end of the perfusion tube should not touch the aortic valve) , quickly move the heart to the Langendorff perfusion apparatus and start perfusion. The perfusion pressure is 90cmH2O (8.32Kpa). From thoracotomy to perfusion, it should be completed quickly within 50-70 seconds, and give up if it exceeds 80 seconds. 3 minutes after the heart beat back, the heart was paced with an electric stimulator (the anode was placed in the right atrial appendage, and the cathode was fixed in the right ventricle. The stimulation frequency was 5Hz (300 times/min), and the stimulation waveform was a square wave (40mv). Cut the right The atrial appendage, through the right atrium and mitral valve, sends a balloon with a pressure-measuring catheter into the left ventricle, and the other end of the pressure-measuring tube is connected to a pressure sensor, which is connected to an electrophysiological multiconductor recorder. It is used to measure heart function and observe Metrics once, including:

①.Left ventricular end-diastolic pressure (LVEDP)

②. Left Ventricular Pressure (LVDP)

③.Left ventricular pressure differential (+dp/dt)

④. Coronary flow (CF)

Measurement of coronary flow: collect the fluid flowing out from the right atrium, and the amount of fluid collected per minute is the coronary flow (ml/min). When the perfusion lasted for 30 minutes, if the mouse heart contraction was weak and there was ventricular fibrillation, the pressure of the left ventricle was <70mmHg, then it was abandoned.

At 30 minutes, stop the cardiac perfusion, and immediately change to perfusing cardioplegia, the pressure is 75cmH ₂ O (7.36Kpa), the temperature of the cardioplegia is 4°C, and the heart surface is cooled at the same time (4°C). After 3 minutes of perfusion, Place the heart in the corresponding preservation solution. Constant temperature 4°C. After 10 hours of storage, the heart was restored to perfusion (the perfusion method was the same as that before the arrest), and after 30 minutes of reperfusion, the heart function was measured, and the left ventricular wall tissue was cut out, and 2 parts were cut evenly and quickly stored in liquid nitrogen for energy storage. Determination of metabolic indicators.

The specific results are as follows:

Cardiac function of isolated SD rat hearts preserved for 10 hours and reperfused for 30 minutes

LVEDP (mmHg) LVDP(mmHg) +dp/dt CF Stanford solution 53.2±11.6 21.3±5.4 478±187 5.2±0.7 UW liquid 59.5±13.3 25.8±4.8 534±162 5.5±0.8 Thomas liquid 48.2±12.7 29.5±5.2 567±175 5.7±0.8 Example 1 21.4±11.3 57.8±6.7 1772±365 7.4±0.9 Example 2 22.7±10.5 59.4±5.8 1838±297 7.8±0.7 Example 3 24.6±11.5 53.4±5.2 1674±288 7.0±0.4 Comparative example 1 39.2±10.1 34.5±4.6 978±262 6.1±0.4 Comparative example 2 41.6±12.2 31.3±4.8 931±224 6.3±0.5 Comparative example 3 40.9±12.4 33.9±4.5 953±281 6.4±0.6

Compared with before preservation, the recovery rate of cardiac function after 10 hours of preservation and reperfusion for 30 minutes (%)

LVDP +dp/dt Stanford solution 41.5% 43.7% UW liquid 44.2% 43.8%

Thomas liquid 45.3% 46.2% Example 1 71.1% 73.6% Example 2 75.4% 76.5% Example 3 69.8% 70.4% Comparative example 1 54.7% 53.5% Comparative example 2 51.2% 52.8% Comparative example 3 53.6% 54.4%

Myocardial high-energy phosphate content when stored for 10 hours and reperfused for 30 minutes

(μmol/g) ATP ADP AMP Stanford solution 1.42±0.11 0.73±0.17 0.71±0.15 UW liquid 1.53±0.06 0.77±0.15 0.65±0.17 Thomas liquid 1.58±0.08 0.81±0.18 0.81±0.16 Example 1 3.24±0.14 1.86±0.22 0.93±0.20 Example 2 3.42±0.18 1.94±0.24 0.98±0.24 Example 3 2.95±0.15 1.79±0.21 0.89±0.18 Comparative example 1 1.92±0.09 0.93±0.12 0.63±0.17 Comparative example 2 2.05±0.08 1.14±0.15 0.75±0.18 Comparative example 3 1.95±0.08 1.06±0.14 0.74±0.16

Example 5

Collect 100 examples of cases, be divided into 6 groups on average, apply cardioplegia prepared by the present invention in operation (all extracorporeal circulation cardiac operations complete the intracardiac operation within 2h of stopping), before perfusing the cardioplegia, treat the patient's heart Labeled with markers, after infusion of cardioplegia solution, the release of biochemical markers of myocardial injury, cardiac output, lactic acid production and other indicators were measured in each group after re-beating.

The specific results are as follows:

cTnI(ng/ml) measurement results

base value 2 hours after cardiac resumption Stanford solution 0.03±0.01 11.8±3.8 UW liquid 0.04±0.01 10.5±2.7 Thomas liquid 0.04±0.01 9.9±3.4 Example 1 0.03±0.01 5.3±1.9 Example 2 0.04±0.01 4.9±1.6 Example 3 0.03±0.01 5.4±1.8

Changes in cardiac output (L/min)

base value heart beat heart beat 2h Stanford solution 3.4±0.7 1.8±0.6 2.2±0.5 UW liquid 3.3±0.5 1.9±0.5 2.3±0.7 Thomas liquid 3.4±0.6 1.8±0.5 2.3±0.6 Example 1 3.4±0.7 2.3±0.4 2.8±0.7 Example 2 3.3±0.4 2.4±0.5 2.9±0.6 Example 3 3.4±0.5 2.3±0.4 2.8±0.6

Lactic acid production (mmol/L)

base value heart beat 2h Stanford solution 0.8±0.3 1.9±0.6 UW liquid 0.7±0.2 1.7±0.5 Thomas liquid 0.8±0.3 1.8±0.7 Example 1 0.8±0.4 1.3±0.5

Example 2 0.8±0.2 1.2±0.4 Example 3 0.8±0.3 1.3±0.5

In addition, the present invention also separately detects and counts the cardiac arrest time, one-time re-beating success rate, and arrhythmia occurrence rate.

The specific results are as follows:

Cardiac induced arrest time One-time re-jump success rate Arrhythmia incidence Stanford solution 67±23s 83% twenty three% UW liquid 53±25s 90% 31% Thomas liquid 58±24s 87% 28% Example 1 42±18s 100% 12% Example 2 39±14s 100% 10% Example 3 43±15s 100% 13%

The content of the present invention only exemplifies some specific embodiments of the claims, wherein the technical features recorded in one or more technical solutions can be combined with any one or more technical solutions, and the technical solutions obtained by these combinations It is also within the scope of protection of the present application, just as these combined technical solutions have been specifically recorded in the disclosure content of the present invention.

Claims (2)

1. a cardioplegic solution comprising lidocaine and adenosine, is characterized in that, in the 1000ml organ preservation solution, the components are respectively: Sodium chloride 6.5g; Potassium chloride 2.3g; Magnesium sulfate 0.35g; Calcium chloride 0.07g; Glucose 6g; Lidocaine 0.5g; Adenosine 130mg; Astragaloside IV 15mg; Coenzyme Q1075mg; Tetrandrine 7mg; higenamine 8mg; histidine 6g; the balance of double distilled water. 2. a method for preparing cardioplegia solution according to claim 1, is characterized in that, concrete steps are as follows: (1) Add 800ml of double-distilled water into a container larger than 1000ml, then add sodium chloride, potassium chloride, magnesium sulfate, and calcium chloride in sequence, and stir until the color becomes clear; then add glucose, lidocaine, adenosine, and astragalus Aside, tetrandrine, histidine and higenamine, stir until the color becomes clear; then add coenzyme Q10, stir until the color becomes clear; (2) Adjust the pH of the solution to 7.65, adjust the osmotic pressure to 350-385mOsm/L, adjust the volume to 1000ml with double-distilled water, and store at 4°C for later use.