An extracellular fluid-type blood-containing cardioplegic solution

Abstract

The invention discloses a crystalloid cardioplegia solution, which contains the following proportioning raw materials in every 1000mL crystalloid cardioplegia solution: 6-18g of mannitol, 3.75-11.25g of magnesium sulfate, 2.5-7.5g of sodium bicarbonate, 3.2-9.6g of potassium chloride, 0.24-0.72g of lidocaine, 4.5-13.5g of sodium chloride, 1.25-3.75g of glucose, 6-18 units of insulin, and the remainder is water. The crystalloid cardioplegia solution of the present invention can be used as an intracellular liquid liquid to form an extracellular fluid type blood-containing cardioplegia solution with blood for clinical use, and is flexible in method; the blood after perfusion can directly enter the blood without causing electrolyte imbalance and blood loss; it can be used for antegrade perfusion of the heart, or retrograde perfusion; myocardial edema can be reduced; it has little effect on blood dilution, and a single perfusion can provide a safe arrest time of> 40 minutes; it is convenient to store without a cold chain. The solution of the present invention has superior performance that is unmatched by commercially available cardioplegia solutions in the market.

Description

Technical Field

[0001] The present invention particularly relates to an extracellular fluid type blood-containing cardioplegia solution. Background Art

[0002] Cardioplegic solution (abbreviated as "cardioplegic solution") is a fluid that is injected into the heart through the coronary artery during open-heart surgery, inducing low-temperature chemical arrest and rapidly stopping the heart to protect the myocardium. Cardioplegic solutions can be divided into crystalloid solutions (a low-molecular-weight solution composed of multiple components such as potassium and magnesium ions that has myocardial protective properties) and hemolytic solutions (a mixture of crystalloid and blood). The former, represented by HTK solution, is an intracellular fluid.

[0003] Large amounts of HTK fluid entering the bloodstream not only lead to severe blood dilution and myocardial edema, but also cause severe electrolyte imbalances, such as hyponatremia and hypochloremia. To prevent this from happening, aspiration is typically used to prevent it from entering the bloodstream. This leads to blood loss, and the fluid is unstable, requiring cold chain transportation, making its clinical use extremely inconvenient.

[0004] Currently, the formulations of blood-containing cardioplegic solutions used in clinical practice vary, resulting in varying myocardial protective effects and making quality control difficult during clinical use. For example, ① their physical and chemical properties are unstable and unsuitable for long-term storage; ② there is insufficient evidence to support the use of Del-Nido solution in adults, and there is no evidence to prove its safety for single-dose perfusion in patients with ischemic cardiomyopathy and coronary artery stenosis; ③ they are easily contaminated during the preparation process; ④ the ions in the prepared liquid cannot be detected, which may lead to extremely different ion concentrations; ⑤ due to formulation issues, the rate of ventricular fibrillation during re-cardioplegia is high; and ⑥ the "safe" cardioplegic arrest time reported by different companies varies. Summary of the Invention

[0005] To solve the above problems, the present invention provides a crystalloid cardioplegia solution, wherein each 1000 mL of crystalloid cardioplegia solution contains the following raw materials:

[0006] Mannitol 6-18g, magnesium sulfate 3.75-11.25g, sodium bicarbonate 2.5-7.5g, potassium chloride 3.2-9.6g, lidocaine 0.24-0.72g, sodium chloride 4.5-13.5g, glucose 1.25-3.75g, insulin 6-18 units, and the balance is water.

[0007] Furthermore, each 1000 mL of crystalloid cardioplegia solution contains the following raw materials:

[0008] Mannitol 12g, magnesium sulfate 7.5g, sodium bicarbonate 5g, potassium chloride 6.4g, lidocaine 0.48g, sodium chloride 6.48g, glucose 2.5g, insulin 12 units, and the balance is water.

[0009] Furthermore, the water is water for injection.

[0010] The present invention also provides an extracellular fluid type blood-containing cardioplegic solution, which comprises the aforementioned crystalloid cardioplegic solution and autologous oxygenated blood.

[0011] Furthermore, the volume ratio of the crystalloid cardioplegia solution to autologous oxygenated blood is 1:3-5, preferably 1:4.

[0012] Furthermore, it also includes compound electrolyte injection.

[0013] Furthermore, the volume ratio of the crystalloid cardioplegia solution, compound electrolyte injection and autologous oxygenated blood is 1:2 to 4:1, preferably 1:3:1.

[0014] Furthermore, the compound electrolyte injection is Bomel A.

[0015] Furthermore, the temperature of the extracellular fluid-containing cardioplegia solution is 4°C. 8℃.

[0016] The present invention also provides a method for preparing the aforementioned crystalloid cardioplegia solution, which comprises the following steps:

[0017] Weigh the raw materials according to the ratio, mix them together and you'll get the product.

[0018] The present invention also provides a method for preparing the extracellular fluid-type blood-containing cardioplegia solution, which comprises the following steps:

[0019] Add the ingredients according to the proportions to the heart cold filling device to obtain the product.

[0020] Finally, the present invention provides a use of the aforementioned crystalloid cardioplegia solution, an extracellular fluid type blood-containing cardioplegia solution, in the preparation of a drug for cardiac arrest.

[0021] The crystalloid cardioplegia solution of the present invention is an intracellular fluid-type liquid that can be combined with blood to form an extracellular fluid-type blood-containing cardioplegia solution for clinical use. Compared with the prior art, it has the following advantages: (1) flexible usage: it can be combined with blood to form an extracellular fluid-type blood-containing cardioplegia solution in a ratio of 1:4 (crystalloid 1:blood 4); it can be mixed with normal saline (compound electrolyte solution), blood or lactated Ringer's solution to synthesize an extracellular fluid-type blood-containing cardioplegia solution, for example, normal saline (compound electrolyte solution) and blood can be combined in a ratio of 1:3:1 to synthesize an extracellular fluid-type blood-containing cardioplegia solution; (2) the blood after perfusion can be directly injected into the bloodstream without causing electrolyte disturbance or blood loss; (3) it can be used for antegrade or retrograde perfusion of the heart; (4) the osmotic pressure slightly higher than that of blood can reduce myocardial edema; (5) less crystalloid is used for perfusion, which has little effect on blood dilution; (6) one perfusion can provide a safe arrest time of more than 40 minutes; and (7) it is convenient to store without the need for a cold chain. Clinical trials have shown that the solution of the present invention has incomparable superior performance than the cardioplegic solutions commonly used in clinical practice. For example, it is more effective than Del-nido cardioplegic solution in maintaining human electrolyte balance and plasma crystal osmotic pressure, and is more stable than St. Thomas cardioplegic solution in maintaining blood potassium levels and preventing the occurrence of hyperkalemia.

[0022] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0023] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. DETAILED DESCRIPTION

[0024] Example 1 Crystalloid cardioplegia solution of the present invention

[0025] Formula: mannitol 12g, magnesium sulfate 7.5g, sodium bicarbonate 5g, potassium chloride 6.4g, lidocaine 0.48g, sodium chloride 6.48g, glucose 2.5g, insulin 12 units, water for injection 1000ml.

[0026] Preparation method: Take the above substances, mix and dissolve them, and filter them with a 0.22μm sterilizing filter to obtain the product.

[0027] Example 2 Extracellular fluid type blood-containing cardioplegia solution of the present invention

[0028] Formula: crystalloid cardioplegia solution prepared in Example 1 and autologous oxygenated blood in a volume ratio of 1:4;

[0029] Preparation method: Crystalloid cardioplegia solution and autologous oxygenated blood are mixed in a cardiac cold perfusion device and cooled to 4°C. 8°C to obtain extracellular fluid-type blood-containing cardioplegic solution.

[0030] Example 3 Extracellular fluid type blood-containing cardioplegia solution of the present invention

[0031] Formula: crystalloid cardioplegia solution prepared in Example 1, BP-A, and autologous oxygenated blood in a volume ratio of 1:3:1;

[0032] Preparation method: Crystalloid cardioplegia solution, BP-A and autologous oxygenated blood are mixed in a cardiac cold perfusion device according to the ratio and cooled to 4°C. 8°C to obtain extracellular fluid-type blood-containing cardioplegic solution.

[0033] Example 4 Crystalloid cardioplegia solution of the present invention

[0034] Formula: mannitol 6g, magnesium sulfate 3.75g, sodium bicarbonate 2.5g, potassium chloride 3.2g, lidocaine 0.24g, sodium chloride 3.24g, glucose 1.25g, insulin 6 units, water for injection 1000ml.

[0035] Preparation method: Take the above substances, mix and dissolve them, and filter them with a 0.22μm sterilizing filter to obtain the product.

[0036] Example 5 Extracellular fluid type blood-containing cardioplegia solution of the present invention

[0037] Formula: crystalloid cardioplegia solution prepared in Example 4 and autologous oxygenated blood in a volume ratio of 1:4;

[0038] Preparation method: Crystalloid cardioplegia solution and autologous oxygenated blood are mixed in a cardiac cold perfusion device and cooled to 4°C. 8°C to obtain extracellular fluid-type blood-containing cardioplegic solution.

[0039] Example 6 Crystalloid cardioplegia solution of the present invention

[0040] Formula: mannitol 18g, magnesium sulfate 11.25g, sodium bicarbonate 7.5g, potassium chloride 9.6g, lidocaine 0.72g, sodium chloride 9.72g, glucose 3.75g, insulin 18 units, water for injection 1000ml.

[0041] Preparation method: Take the above substances, mix and dissolve them, and filter them with a 0.22μm sterilizing filter to obtain the product.

[0042] Example 7 Extracellular fluid type blood-containing cardioplegia solution of the present invention

[0043] Formula: crystalloid cardioplegia solution prepared in Example 6 and autologous oxygenated blood in a volume ratio of 1:4;

[0044] Preparation method: Crystalloid cardioplegia solution and autologous oxygenated blood are mixed in a cardiac cold perfusion device according to the ratio and cooled to 4°C. 8°C to obtain extracellular fluid-type blood-containing cardioplegic solution.

[0045] The beneficial effects of the present invention are described below through test examples.

[0046] Application of Experimental Example 1 in Aortic Dissection

[0047] Subject: A 70 kg male patient underwent aortic arch replacement.

[0048] Methods and results: Preoperative serum potassium was 3.49 mmol / L. 1200 mL of the extracellular solution containing blood prepared in Example 2 was injected at 4°C. 8℃.

[0049] The perfusion flow rate was 240mL / min, and the heart stopped beating after 30 seconds of perfusion. The perfusion was completed after 5 minutes. At this time, the artificial heart and lungs completely replaced the patient's heart and lung work. Blood gas was rechecked 5 minutes after perfusion, and the blood potassium was 4.39mmol / L. 39 minutes after the heart perfusion stopped beating, blood gas was rechecked again, and the blood potassium was 4.13mmol / L and the blood sodium was 141mmol / L. After 142 minutes of heart perfusion stopped beating (a total of 3 perfusions, and the two perfusions after the operation were half-volume perfusions, that is, 600ml each time, and each myocardial ischemia lasted about 47 minutes), the heart resumed blood supply. One minute after the blood supply was restored, the heart automatically resumed beating. 9 minutes after the resumption of beating, the electrocardiogram and heart function returned to normal, the extracorporeal circulation was successfully stopped, and the patient's heart and lungs worked independently.

[0050] Conclusion: After infusion of the extracellular fluid-based blood-containing cardioplegia solution of the present invention, blood potassium levels fluctuated little, without causing hyperkalemia (typically, potassium ion concentrations exceeding 5.5 mmol / L). Furthermore, the solution was able to maintain cardiac arrest for more than 40 minutes, resolving the trade-off between achieving cardiac arrest and preventing hyperkalemia. Furthermore, the patient's internal environment remained stable, with no hyponatremia and normal blood electrolyte levels.

[0051] Application of Experimental Example 2 in Multiple Types of Heart Diseases

[0052] Subjects: 26 cardiac surgery patients weighing over 40 kg, aged 17 to 78 years (15 males and 11 females). Three underwent aortic valve replacement with mitral valvuloplasty, two underwent coronary artery bypass grafting, six underwent mitral valve replacement with tricuspid valvuloplasty, six underwent aortic valve replacement / valvuloplasty, two underwent pulmonary valve replacement, one underwent tricuspid valve replacement (reoperation), two underwent ventricular septal defect repair, one underwent cardiac tumor removal, one underwent pulmonary artery stenosis correction, and two underwent complete endocardial cushion defect repair.

[0053] Methods: An observational study was conducted to investigate the myocardial protective effects of this cardioplegic solution (the extracellular fluid-based blood-containing cardioplegic solution of Example 2). 1 mL of blood was drawn from patients before, after, and before CPB was initiated and discontinued for blood gas analysis and to assess the patient's internal environment. After patency of the ascending aorta, the occurrence of spontaneous cardiac resuscitation, arrhythmias, and the use of vasoactive drugs during CPB were observed.

[0054] Results: The heart stopped beating after the cardioplegia solution was perfused for 30 seconds. The average heart block time was 108 minutes.

[0055] Note: Clamping time refers to the time from the moment the ascending aorta is clamped with a clamp, cardioplegic solution is infused from the aortic root to arrest the heart, to the moment the clamp is released after the intracardiac procedure, allowing the heart to regain blood supply and resume beating. Simply put, the time the heart is stopped is the clamping time. The average clamping time for the 26 surgeries was 108 minutes. During the clamping period, the heart was perfused with cardioplegic solution an average of three times, with the last two perfusions being half-dose. After opening the ascending aorta, all patients spontaneously resumed beating. One patient experienced ventricular fibrillation 3 minutes after closure, but sinus rhythm was restored after 150J surface defibrillation. All patients were extubated the next day and discharged successfully 5-7 days later.

[0056] The trends of serum potassium and blood glucose before, after, and before stopping extracorporeal circulation are shown in Table 1 .

[0057] Table 1 Trends in blood potassium and blood glucose

[0058]

[0059] Conclusion: The cardioplegic solution of the present invention has a good effect on cardiac arrest and has little impact on the internal environment. It is suitable for cardiac arrest and protection in various cardiovascular surgeries.

[0060] Comparison of Comparative Example 1 and Intracellular Cardioplegia Solution - HTK Solution in Cardiac Surgery

[0061] A 57-year-old male patient weighing 69 kg underwent mitral valve replacement, tricuspid valvuloplasty, and radiofrequency ablation. During the procedure, he received a single bolus of cold (4-8°C) HTK solution. After cardiopulmonary bypass and occlusion of the ascending aorta, the HTK group received a single antegrade perfusion of 2000 ml of HTK solution through the aortic root at a pressure of 100-120 mmHg (1 mmHg = 133.3 Pa). After cardiac arrest, the perfusion pressure was increased to 40-50 mmHg for 6-8 minutes. Preoperatively, his serum potassium was 4.65 mmol / L, his sodium was 138 mmol / L, and his hemoglobin was 163 g / L, indicating a generally stable internal environment. However, 10 minutes after perfusion, blood gas analysis revealed serum potassium of 2.94 mmol / L, sodium of 98 mmol / L, and hemoglobin of 5.3 g / L, indicating severe hemodilution, hyponatremia, and a disturbed internal environment. At this point, the blood reservoir volume increased significantly, indicating severe hemodilution. A hemoconcentrator was immediately installed to filter out the excess cardioplegic solution. Potassium was supplemented 1g and 3g of concentrated sodium chloride in divided doses. Ten minutes later, a blood gas analysis revealed potassium at 3.65mmol / l, sodium at 131mmol / l, and hemoglobin at 7.1g.

[0062] Comparison of Comparative Example 2 with Extracellular Fluid Cardioplegia Solutions - Del-nido Solution and St. Thomas Solution in Cardiac Surgery

[0063] Subjects: A 59-year-old female patient weighing 50 kg received Del-nido solution perfusion; a 62-year-old male patient weighing 68 kg received St. Thomas solution perfusion.

[0064] Planned surgery: Female patients will undergo pulmonary valve replacement + tricuspid valvuloplasty; male patients will undergo aortic valve replacement + mitral valve replacement.

[0065] Methods: Two patients received an initial intraoperative perfusion of cold (4-8°C) blood-containing solution at 20 ml / kg for cardioplegic arrest. Both solutions were freshly prepared. After cardioplegic bypass and cooling to 31-33°C, the ascending aorta was clamped. The Del-nido solution group received a single antegrade perfusion of 1000 ml of blood-containing solution in a 1:4 ratio (1 part blood: 4 parts crystalloid) via the aortic root. The St. Thomas solution group received 1300 ml of a 4:1 ratio (4 parts blood: 1 part crystalloid) via the left and right coronary arteries, with perfusions occurring every 20 minutes. In both groups, perfusion pressures were maintained at 100-120 mmHg (1 mmHg = 133.3 Pa). Post-cardioplegic perfusion pressures were maintained at 40-50 mmHg, and perfusion durations were 6-8 minutes.

[0066] Results: Five minutes after extracorporeal perfusion, the patient's internal environment was checked. The main items are shown in Table 2.

[0067] Table 2 Trends of serum potassium, serum sodium and hemoglobin

[0068]

[0069] As shown in Table 2, the Del-nido solution group experienced a certain degree of hemodilution, a decrease in serum sodium levels, and a decrease in plasma crystalloid osmotic pressure, due to the cardioplegia ratio of 4 parts crystalloid in the cardioplegia solution. Although the St. Thomas solution group did not experience hemodilution, its reperfusion frequency was higher (119 minutes of extracorporeal circulation, 4 perfusions in total), resulting in hyperkalemia of 5.8 mmol / l during blood gas analysis after the ascending aorta was opened.

[0070] Situation after opening of the ascending aorta: In the Del-nido solution group, heart beat was resumed 2 minutes after opening. After the additional installation of a blood concentrator to filter out excess water, the hemoglobin returned to 7.5g, but this increased the financial burden on the patients. After 0.03ug / kg / min of epinephrine was infused, extracorporeal circulation was stopped 17 minutes after opening. In the St. Thomas solution group, heart beat was resumed 13 minutes after opening. The blood potassium level was rechecked and was 5.8mmol / l. After 0.08ug / kg / min of epinephrine was infused, extracorporeal circulation was stopped 33 minutes after opening.

[0071] Comparison of Experimental Examples 1-2 and Comparative Examples 1-2 shows that the solution of the present invention has incomparable superior performance compared to the cardioplegic solutions commonly used in clinical practice. For example, it is more effective than Del-nido cardioplegic solution in maintaining human electrolyte balance and plasma crystal osmotic pressure, and maintains blood potassium levels more stably than St. Thomas cardioplegic solution, thereby preventing the occurrence of hyperkalemia.

[0072] In summary, the crystalloid cardioplegia solution of the present invention, as an intracellular fluid-type liquid, can be combined with blood in various forms to form an extracellular fluid-type blood-containing cardioplegia solution for clinical use. Clinical trials have shown that the cardioplegia solution of the present invention does not cause blood loss, can reduce myocardial edema, maintain electrolyte balance in the human body, and has the prospect of expanding clinical application.

Claims

1. An extracellular fluid-type blood-containing cardioplegic solution, characterized in that: It consists of crystalloid cardioplegia and autologous oxygenated blood; The raw material composition of each 1000 mL of the crystalloid cardioplegia solution is: Mannitol 6-18 g, magnesium sulfate 3.75-11.25 g, sodium bicarbonate 2.5-7.5 g, potassium chloride 3.2-9.6 g, lidocaine 0.24-0.72 g, sodium chloride 4.5-13.5 g, glucose 1.25-3.75 g, insulin 6-18 units, and the balance is water.

2. The extracellular fluid-type blood-containing cardioplegia solution according to claim 1, characterized in that: The raw material composition of each 1000 mL of the crystalloid cardioplegia solution is: Mannitol 12 g, magnesium sulfate 7.5 g, sodium bicarbonate 5 g, potassium chloride 6.4 g, lidocaine 0.48 g, sodium chloride 6.48 g, glucose 2.5 g, insulin 12 units, and the balance is water for injection.

3. The extracellular fluid-type blood-containing cardioplegia solution according to claim 1, characterized in that: The water is water for injection.

4. The extracellular fluid-type blood-containing cardioplegia solution according to claim 1, characterized in that: The volume ratio of the crystalloid cardioplegia solution to autologous oxygenated blood is 1:3-5.

5. The extracellular fluid-type blood-containing cardioplegia solution according to claim 4, characterized in that: The volume ratio of the crystalloid cardioplegia solution to autologous oxygenated blood is 1:

4.

6. The extracellular fluid-type blood-containing cardioplegia solution according to any one of claims 1 to 5, characterized in that: The temperature of the extracellular fluid type blood-containing cardioplegia solution is 4°C to 8°C.

7. The method for preparing the crystalloid cardioplegia solution according to any one of claims 1 to 6, characterized in that: It includes the following steps: Weigh the raw materials according to the ratio, mix them together and you'll get the product.

8. Use of the extracellular fluid-type blood-containing cardioplegic solution according to any one of claims 1 to 6 in the preparation of a medicament for cardiac arrest.

Images