JPH03294201A - Cardiac muscle-protective solution - Google Patents

Abstract

PURPOSE:To provide the title solution capable of suppressing to the utmost the myocardiopathy in case of ischemia along with suppressing reperfusion disorder leading to enhanced restoration of cardiac function, containing succinate ion. restoration of cardiac function after operation. CONSTITUTION:The objective solution can be obtained by adding succinate ion at a concentration of 3-30mmol/l to a cardiac muscleprotective solution containing (A) sodium ion, (B) potassium ion, (C) calcium ion and, where appropriate, (D) glucose, at concentrations of 50-200mmol/l, 10-50mmol/l, 0.02-1mmol/l, and <=10%(w/v), respectively. For the present solution, the succinic acid reduces ubiquinone and suppresses enzyme radical generation, thereby mitigating mitochondria injury, leading to having the above-mentioned effects. And for the present solution, it is preferable that, as a cardiac muscleprotective solution kit made up of the present solution and an alkaline buffer solution (pref. an aqueous solution containing bicarbonate ion at a concentration of 100-1100mmol/l), an appropriate amount of the latter be added to the former immediately before use.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a cardioplegia solution. More specifically, the present invention relates to a cardioplegia solution characterized by adding succinate ions.

(Prior Art and Problems to be Solved by the Invention) Aortic occlusion is an essential means in open heart surgery, especially in left heart surgery. On the other hand, in other open heart surgeries, the bloodless and static field of view resulting from aortic blockade provides an extremely favorable surgical environment of safety and reliability. Myocardial protection, which aims to prevent ischemic damage when coronary blood flow is disrupted during surgery, has made great progress in elucidating the pathogenesis of myocardial ischemia. Myocardial protection methods based on this theoretical basis have led to dramatic improvements in surgical outcomes in the field of cardiac surgery, and have come to be an indispensable auxiliary tool for cardiac surgery, along with hypothermia and extracorporeal circulation.

Due to disruption of coronary blood flow, the myocardium rapidly shifts to anaerobic metabolism, which is extremely inefficient in energy production. Accumulation of lactic acid and hydrogen ions as metabolites leads to a decrease in tissue pH, while mitochondria are damaged due to accumulation of fatty acid esters resulting from suppression of fatty acid oxidation, suppressing energy production and shifting to depletion. do. Eventually, energy-dependent cell membrane damage occurs, ie, the cell membrane's ion balance ability and cell volume maintenance ability are impaired, and along with the abnormal influx of calcium ions into the cells, sodium ions and water enter the cells, resulting in irreversible ischemic damage.

The core concept of the myocardial protection method for preventing myocardial ischemic damage mentioned above is "preservation of high-energy substances in the myocardium during ischemia"
Currently, the myocardial protection methods currently in use mainly involve the combination of myocardial local cooling and multidose cardioplegia, in which cardioplegia is intermittently administered. The purpose is to rapidly activate electromechanical activity (electrog+) under aortic occlusion.
The aim is to build the myocardium and conserve energy by eliminating the mechanical activity and achieving a state of cardiac arrest at low temperatures.

Cardiopulgating fluid (cardioplectic fluid) is a drug mainly containing potassium ions, which is used to achieve electrical and mechanical arrest of the heart.
It is one of the myocardial protection methods that protect the myocardium in anoxic conditions during aortic blockage. This allows for bloodless surgery during heart surgery.
As mentioned above, a static field of view is obtained, which enables finer and more accurate surgical operations, leading to improved surgical outcomes.

The first cardioplegia solution was Merlose (Melr.
After 955 months, 2xf2 of 25% potassium citrate was diluted 10 times on the extracorporeal circulation surface (final potassium concentration: 245 sEq/l) and injected from the aortic root to block the aorta for 15 minutes at room temperature and mild cold. It all started with the announcement that it was possible. Representative cardioplegia solutions developed subsequently include the following.

B retschneider
) Liquid sodium chloride 0.709/(112.0 mmol/a Potassium chloride 0.75 1Q, 0 Magnesium chloride 0.i12.

Procaine hydrochloride 2.00 7.4 Mannitol 43.50 239.0 (pH 5.5-7.0
, fi transmissive pressure 320trOstr/9) St. Thomas Hospital (S L, Thotaas Ho5p
ital) Liquid sodium chloride 5.359/(1
91,6E remol/a Sodium hydrogen carbonate 2.10
25.0 Potassium chloride 1.10
14.8 Magnenium sulfate 0.30 1
．． Magnesium dichloride 3.05 15.0 Potassium dihydrogen phosphate 0.16 1.2 Calcium chloride O, L8 1.2 Procaine hydrochloride 0.27 1.0 (pH 7, 4: osmotic pressure 300 so sm/kg) used At that time, add the drug and cool to around 4℃ before using chlorpromazine.
5x9/(IATP 40 β-methacin 4 Heparin 25 Regular insulin 50 units Glucose-insulino potassium solution CGTK solution) 5%
Glucose solution 1000zi + regular insulin 20 units Potassium chloride 20IIEq 7% sodium bicarbonate 1oz9 (pH 7, 8; osmotic pressure 334 ll1osffi/kg
) By using such myocardial protection methods and cardioplegia solutions, it has become possible to perform operations with relative safety even when the aorta is occluded for three hours or more. However, in patients with severe myocardial damage before surgery or with disease in multiple organs due to long-term heart failure, postoperative low output syndrome (low output 5 yndr syndrome) may occur.
o@e: L OS ) and multiple organ failure (multior
The occurrence of cancer failure is often a problem. Therefore, it is desired to develop a more complete myocardial protection method, that is, to extend the safe time for myocardial ischemia and to develop a cardioplegia solution that does not cause a decrease in cardiac function after surgery.

On the other hand, after cardiac surgery, the ischemic myocardium recovers by releasing the aortic blockage, but reperfusion after myocardial ischemia sometimes causes even stronger damage (reperfusion injury). This is mainly caused by membrane changes during ischemia, and with the inadvertent start of reperfusion, abnormal calcium influx into cells occurs within 2 to 3 minutes.
It is said to cause sodium and water influx, resulting in reperfusion injury. Furthermore, it is said that membranes that have been damaged by ischemia are also damaged by oxygen radicals during reperfusion. For this reason, careful blood flow resumption methods that require a high degree of care have been developed to prevent reperfusion injury.

Based on the above, there is a strong demand for the development of a cardioplegic solution that suppresses myocardial damage during ischemia as much as possible, suppresses reperfusion damage, and enhances recovery of cardiac function after surgery.

(Means for solving the problem) Under such circumstances, as a result of intensive research by the present inventors,
The present inventors have discovered that the above problems can be solved by adding succinate ions to the cardioplegia solution, and have completed the present invention. That is, the present invention provides a cardioplegia solution characterized by adding succinate ions to a cardioplegia solution containing sodium ions, potassium ions, calcium ions, and optionally glucose; ~200 mmol/l, potassium ions ~50 mmol/l,
The concentration of sium ions is 0.02 to 1 mmol/l, glucose is 10% (w/v) or less, and succinate ions are 3 to 1 mmol/l.
The present invention provides a cardioplegia solution kit comprising a cardioplegia solution containing 30 mmol/Q; and the above-mentioned cardioplegia solution and an alkaline buffer.

Examples of the alkaline buffer used in the cardioplegia kit include carbonate buffer, tromethamine (TRAM) buffer, and the like. Preferred alkaline buffers include:
hydrogen carbonate ion at 100 to 1100 mI)%/(1
, preferably an aqueous solution containing 500 to 1000 mmol/Q (for example, an 8° 4% aqueous sodium bicarbonate solution)
When added to a cardioplegia solution before use, the bicarbonate ion content is adjusted to 1 to 50 mmol/Q.

Among the components of the cardioplegia solution described above, components other than succinate ions are commonly used in conventional cardioplegia solutions. For example, sodium chloride is commonly used as a sodium ion source, potassium chloride or potassium dihydrogen phosphate is commonly used as a potassium ion source, and calcium chloride is commonly used as a calcium ion source.

In addition, metal ions of succinate, which provide the succinate ions described below, may also constitute a part of these ion sources.

Specific examples of compounds that provide succinate ions include, but are not limited to, succinic acid, sodium succinate, potassium succinate, calcium succinate, and magnenoum succinate. The succinate ion is
By having the above composition, during myocardial ischemia, coenzyme Qlo is reduced and intracellular antioxidant action is enhanced, thereby suppressing reperfusion injury and exhibiting the effect of preventing a decline in cardiac function.

The preferred composition range of the cardioplegia solution of the present invention is 60 to 140 mmol/l of sodium ions, 15 to 40 mmol/l of potassium ions, 5 to 05 mmol/l of carnoum ions, and 2 to 5 mmol/l of glucose. %(
★/V>, and succinate ion is 5 to 20 mmol/
I! Preferably, bicarbonate ions are included in the kit of the present invention at a concentration of 500 to 1000 mmol/Q.

The cardioplegia solution of the present invention is prepared as a solution containing the above-mentioned glucose and each electrolyte ion within the above-mentioned specific range, and can be prepared using the same method as general injections. That is, for example, precisely weighed amounts of glucose, sodium chloride, potassium chloride,
Calcium gluconate (or calcium chloride) and sodium succinate are dissolved in distilled water for injection, and a small amount of distilled water for injection is added thereto to make a predetermined liquid volume. Then, an appropriate amount of activated carbon is added and stirred for 10 to 30 minutes.

After the activated carbon is filtered off using a filter paper, it is purified and filtered using a 0.45μ true membrane filter. Fill the obtained filtrate into a container,
Close it and heat sterilize it with high pressure steam at 100-120°C for 10-60 minutes. Immediately before use, add an appropriate amount of an alkaline buffer solution, such as a sodium bicarbonate solution, to the solution thus obtained to adjust the pH to 7.0 to 8.5, preferably 7.4 to 8.0. adjust. The osmotic pressure at this time is 300-500 so sm/Qs, preferably 330
~400aksl/Q.

The cardioplegia solution of the present invention can be used alone, or
If necessary, other drugs with cardioprotective effects include lidocaine, procaine, steroids, magnesium ions, calcium antagonists (fezibin, verapamil hydrochloride, diltiazem hydrochloride, etc.), anti-proteases, coenzyme Q, etc. , insulin that increases the utilization of glucose, prostaglandin E that has a membrane stabilizing effect, etc. may be added and used.

Administration (or perfusion) of cardioplegia fluid cooled to below 4°C
Regarding the method, as soon as possible after occluding the aorta, inject l in an amount according to body weight into the aortic root proximal to the aortic occlusion site.
O~+5zQ/9 (for children, 15-201Q/9)
injected using a cannula or after an incision in the right shoulder.
A catheter with a balloon is placed in the coronary sinus and injected. At present, a method in which the drug is administered only for the first time when the aorta is blocked is rarely used, and an intermittent coronary perfusion method in which the drug is administered at fixed intervals is widely used. Therefore, in the present invention, 5 to 8 zQ/kg (7 to 10 x f2/kg for children) is administered at intervals of 20 to 30 minutes after the first administration.
) is preferably administered. It can also be administered by continuous perfusion at a low flow rate. According to the cardioplegia solution of the present invention, which is obtained by adding succinate ions to a conventional cardioplegia solution, succinic acid acts on ubiquinone in the mitochondrial electron transport chain to reduce ubiquinone, thereby suppressing the production of oxygen radicals. By alleviating mitochondrial damage, ATP, creatine phosphate (CP) and other high-energy phosphate compounds (HE) in myocardial tissue can be reduced.
It is possible to promote recovery after reperfusion of P) and increase the recovery rate of cardiac function after surgery.

Next, the present invention will be explained in more detail based on Examples, but the present invention is not limited thereto.

Example 1 Glucose (272,79), sodium succinate (16
4g), sodium chloride (29,59), potassium chloride (+5.19) and carunium gluconate (045g)
) was dissolved in approximately 9.5Q of distilled water for injection. After completely dissolving, add more distilled water for injection to make the total volume exactly 10
c. Activated carbon (lOg) was added to this aqueous solution, and 20
After stirring for a minute, the activated carbon was filtered off using a filter paper, and the filtrate was filtered through a membrane filter with a pore size of 045 μl. Filtered. This purified filtrate was accurately filled into a vial of 495 zQ each, sealed, and heat sterilized with high pressure steam at 100° C. for 40 minutes. In this way, the cardioplegia solution (495zQ) of the present invention was obtained, and at the time of use, 8.4% Na HCOs aqueous solution (Tyrone 84, manufactured by Otsuka Pharmaceutical Co., Ltd.) 51 was added thereto.

The composition of the obtained cardioplegia solution is shown in Table 1.

Example 2 Glucose (254, 29), sodium succinate (21
,079), sodium chloride (29,519), potassium chloride (11,309), and calcium chloride (dihydrate) (0.15 g), and the amount of distilled water for injection used was
A cardioplegia solution of the present invention was obtained in the same manner as in Example 1, except that C was used. In addition, 8.4%N per 495xQ immediately before use.
a HCOs aqueous solution (Meiron 84: manufactured by Otsuka Pharmaceutical Co., Ltd. > 5 t (l) was added and used. The composition of the obtained cardioplegia solution is shown in Table 2.

Example 3 Glucose (181.8g), sodium succinate (32g)
, 7g), sodium chloride (59°Og), potassium chloride (22.6g) and calcium chloride (dihydrate) (0
, 74 g) to obtain a cardioplegia solution of the present invention in the same manner as in Example 1. In addition, 7% per 495m1 immediately before use
NaHCOs aqueous solution (manufactured by Meiron Ni Otsuka Pharmaceutical Co., Ltd.)
5+al was added and used. The composition of the obtained cardioplegia solution is shown in Table 3.

Example 4 Glucose (363.6g), sodium succinate (40g)
, 9g), sodium chloride (17,7g), potassium chloride (15,1g) and calcium chloride (dihydrate) (0
A cardioplegia solution of the present invention was obtained in the same manner as in Example 1 using 15 g) of the present invention. In addition, 8.4% per 495m1 for direct sailing
5 ml of NaHCOz aqueous solution (Meiron 84: manufactured by Otsuka Pharmaceutical Co., Ltd.) was added thereto. The composition of the obtained cardioplegia solution is shown in Table 4.

Test Example The cardioplegia solution prepared in Example 1 above was used as the test solution, and the cardioplegia solution prepared in the same manner as in Example 1 using the composition shown in Table 5 below was used as the comparison solution. The comparison solution did not contain sodium succinate, so the amount of sodium chloride was increased to make the sodium ion concentration the same as the test solution, and the amount of glucose was reduced to adjust the osmotic pressure.

[Test method] The above test solution, comparative solution, and Krebs-Henseleit CK
After preparing 4 liquids, a test was conducted using the method described below. In addition, WKA male rats (body weight 250 to 350 g) were used in the test.

Anesthetize the patient by intraperitoneally injecting bentoparbital sodium (100 u). After anesthesia, heparin sulfate (2x9)
was injected intravenously through the femoral vein. The chest was opened through a median sternotomy, and the heart was quickly removed and immersed in Krebs-Henseleit buffer that had been previously cooled with water.

After making an incision in the main pulmonary artery to facilitate coronary perfusion outflow, a fluid flow device [To*inag
a) et al., J. Surg, Res., 34, t t l,
(t983)] and immediately attach it to the Langendorff (L
angendorfD perfusion (coronary perfusion is performed from the aorta side, and the left ventricle is essentially not working; in other words, the left ventricle is not functioning as a pump and is in the state of a non-working heart!!
started. Thereafter, a left shoulder cannula was inserted into the left atrium from the right pulmonary vein. After 10 minutes of Langendorff perfusion, release the left shoulder line and switch to working mode.
mode) perfusion (perfusion fluid flows from the left shoulder through the left ventricle, part of it perfuses the coronary vessels, and part of the perfusion fluid is pumped out by a pump function against the aortic perfusion amount). An additional 10 minutes of preischemic perfusion was performed. Thereafter, both the aorta and left shoulder lines were closed, and a cardioplegia solution (61C) was immediately injected into the aortic root from a side branch over a period of 1 minute, followed by complete global ischemia of the heart for 25 minutes. Reperfusion started with Langendorff immersion, and after 5 minutes, the operating mode was changed to perfusion, and 2
Working mode perfusion was performed for 5 minutes. In addition, the left shoulder front load is 1
6ciHtO1 aortic afterload was 80czH,o.

As an evaluation index of the myocardial protective effect, the cardiac function recovery rate (aortic flow rate, cardiac output) after 30 minutes of reperfusion relative to the pre-ischemic value
and myocardial tissue adenine nucleotide content.

Cardiac function was measured immediately before the onset of ischemia and 30 minutes after reperfusion (
Figure 1). The aortic flow rate was determined by measuring the flow rate flowing out from the aortic reservoir over time. Cardiac output was calculated as the sum of coronary perfusion and aortic perfusion.

Sampling of myocardial tissue adenine nucleotides and high-energy phosphate compounds was performed immediately before the onset of ischemia, after the end of ischemia, and 30 minutes after reperfusion (FIGS. 2 and 3). The tissue was clamped with Wollenberger forceps previously cooled to -196° C. in liquid nitrogen, immersed in liquid nitrogen, rapidly cooled, and crushed. Quantification of adenine nucleotides was performed by high-performance liquid chromatography [Kamiike et al., J.B.
1ochet I 982.91.1349]. TAN
indicates the sum of ATP, ADP and AMP. Creatine phosphate (cp) was measured by an enzymatic method [Methods
ds or enzymatic analysis),
New York, Academic Press, +9751° High energy phosphate compound (HEP) is represented by the following formula! HEP=2ATP+ADP+CP The results are shown in FIGS. 1, 2, and 3.

In the figure, the test group indicates a group in which a test solution was injected as a myocardial protection solution during cardiac ischemia, and the comparison group indicates a group in which a comparison solution was also injected. Regarding the recovery rate of cardiac function 30 minutes after reperfusion, as is clear from Figure 1, the test group showed a significantly better recovery rate than the comparison group in terms of aortic flow rate and cardiac output.

As for ATP and TAN, as is clear from FIG. 2, the test group showed significantly higher values than the comparison group 30 minutes after reperfusion. Comparing TAN 30 minutes after reperfusion, the comparison group had a further decrease than at the end of ischemia, whereas it did not decrease in the test group.

Regarding creatine phosphate (cp) and high energy phosphate compound (HEP), as is clear from FIG. 3, the test group showed significantly higher values than the comparison group 30 minutes after reperfusion.

[Brief explanation of drawings]

Figure 1 shows the aortic flow rate and heart rate 30 minutes after reperfusion when the cardioplegia solution of the present invention (test group) and the conventional cardioplegia solution (comparison group) were injected during ischemia in isolated rat hearts. Figure 2 is a graph showing the amount of ATP and TAN immediately before the start of ischemia, at the end of ischemia, and 30 minutes after reperfusion in the test group and the comparison group, showing the recovery rate of output.
Figure 3 shows creatine phosphate <cp> and high-energy phosphate compound () (EP) immediately before the start of ischemia, at the end of ischemia, and 30 minutes after reperfusion in the test group and comparison group.
It is a graph showing the amount. Muscle Figure Comparison Group (n/Riro: Sengensei (n=6) Figure 2◆ ◇ -Hemata # (+1=41

Claims (6)

[Claims] (1) A cardioplegia solution characterized by adding succinate ions. (2) A claim characterized in that succinate ions are added to a cardioplegia solution containing sodium ions, potassium ions, calcium ions, and optionally glucose.
The cardioplegia solution described in 1). (3) 50 to 200 mmol/l of sodium ions,
Potassium ion 10-50 mmol/l, calcium ion 0.02-1 mmol/l, glucose 10%
(w/v) or less and 3 to 30 mmol/l of succinate ions. (4) A cardioplegia kit comprising the cardioplegia solution according to claim (1), (2) or (3) and an alkaline buffer. (5) The kit according to claim (4), wherein the alkaline buffer is an aqueous solution containing bicarbonate ions. (6) The bicarbonate ion concentration of the alkaline buffer is 100~
The kit according to claim 5, which has a concentration of 1100 mmol/l.