JP2009120592A - Colloidal infusion preparation with reduced lactic acid - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a novel colloidal infusion preparation containing no lactic acid. <P>SOLUTION: The colloidal infusion preparation contains an organic carboxylate salt and is used in infusion therapy to bleeding or shock under operation, and when the colloidal infusion preparation is administered to a mammalian including human, the amount of a lactate salt as the organic carboxylate salt is reduced to the amount which does not affect a blood lactic acid value in the mammalian concerned. The colloidal infusion preparation substantially contains no lactate salt, therefore, evaluation of oxygen demand-and-supply balance using the lactic acid value as an index under operation can be performed more accurately by using the colloidal infusion preparation instead of infusion preparations by conventional techniques. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention is a colloidal infusion preparation comprising a salt of an organic carboxylic acid for use in infusion therapy for bleeding during surgery or for shock, wherein the colloidal infusion preparation is administered to a mammal including a human, The present invention relates to the above-mentioned colloidal infusion preparation, wherein the amount of lactate as a salt of the organic carboxylic acid is reduced to an amount that does not affect the endogenous blood lactic acid level in the mammal.

  Some infusions are called plasma augmentation and extracorporeal circulation perfusates. This plasma augmentation and extracorporeal circulation perfusate is (1) used as a surrogate plasma in the treatment of acute bleeding, especially in the case of acute massive bleeding, and (2) prevention of surgical shock based on trauma, burns, bleeding, etc. And (3) used to reduce blood transfusion volume during surgery, and (4) used as an extracorporeal circulation perfusate to facilitate perfusion and reduce the risk of complications during surgery. Is done. Among such plasma augmentation and extracorporeal circulation perfusates, those containing artificial polymer compounds are referred to as “cold infusion” or artificial blood substitute plasma.

  For hemorrhage during surgery, infusion therapy using colloidal infusion, which is artificial blood substitute plasma, is usually performed first, and the start time of transfusion is determined while monitoring an oxygen supply-demand balance index. Negative factors such as GVHD (Graft Versus Host Disease) due to blood transfusions are stochastically very low, but they are still at risk, so we should refrain from easy blood transfusions. In addition, the use of blood for blood transfusion should not be easily judged because the blood donation uses valuable blood donations that are well-funded. Therefore, it is an important procedure in clinical practice to first perform infusion therapy using colloidal infusion, which is artificial plasma substitute, and determine the start time of blood transfusion while monitoring the oxygen supply-demand balance index.

  Examples of the oxygen supply-demand balance include hemoglobin levels, arterial oxygen partial pressure, arterial blood pH, base excess, and blood lactate levels. Among these indicators, blood lactic acid level is the most important and reliable indicator for assessing the oxygen supply-demand balance because lactic acid is produced by anaerobic metabolism, and is also a prognostic indicator in severe cases It is extremely useful.

In addition, “shock”, a syndrome that occurs acutely due to large invasion of the living body and can lead to death if left untreated, is necessary for the cells that make up tissues and organs to function normally. It is a condition that usually causes a decrease in arterial pressure that occurs when blood is insufficient. Anaerobic respiration, in which more lactic acid is produced and accumulated as a result of the decrease in blood perfusion to the main tissues due to hypotension, resulting in insufficient transport and uptake of O ₂ and aerobic metabolism. Transitioning to is the pathological condition underlying the shock. Therefore, the importance of monitoring the blood lactate level as an index in the diagnosis of shock has also been suggested (see Non-Patent Document 1 below).

  By the way, the conventional colloidal infusion used in the clinic currently has only a lactate salt, specifically, one containing sodium lactate. However, when such prior art colloid infusions are perfused, the endogenous blood lactate levels may be significantly higher due to the exogenous lactate contained in the colloid infusion. Therefore, in order to accurately monitor the blood lactate level as an important indicator in the determination of the start of blood transfusion and the diagnosis of shock in the above-mentioned fluid therapy, the endogenous blood lactate level must be affected during colloidal infusion. It should be free from any ingredients that affect it.

A plasma-like solution that can contain acetic acid as an organic carboxylic acid is known (see Patent Document 1 below). The plasma-like solution is composed of potassium ion, magnesium ion, sodium ion, calcium ion, chloride ion, high molecular swelling agent, organic carboxylic acid (which can be lactic acid, acetic acid, pyruvic acid or citric acid) or a salt thereof. , And sugar. However, the plasma solution is mainly a preservation solution for the purpose of preserving the transplanted organ at the time of organ transplantation, etc., and is not a colloidal infusion for use in infusion therapy for bleeding or shock during surgery. In addition to lactic acid being not actively excluded as an organic carboxylic acid contained in sodium, sodium lactate is used in the examples. Furthermore, acetic acid is only mentioned as an example of an organic carboxylic acid. For example, in Patent Document 1 (Japanese Patent No. 3715312), page 6, lines 18 to 26, “The solution of the present invention contains an organic carboxylic acid or a salt therein.” “Salts” include any carboxylic acid or carboxylic acid derivative that can be metabolized to a mammal. Examples of carboxylic acids and carboxylates suitable for the solutions of the present invention include lactic acid and sodium lactate, citric acid and sodium citrate, gluconic acid and sodium gluconate, pyruvate and sodium pyruvate, succinic acid and sodium succinate, Acetic acid and sodium acetate are included. In the example illustrating the use of the HLB solution that follows, sodium lactate is used. When metabolized in vivo, lactic acid serves as a component of the kinetic buffer system of the solution to help maintain bicarbonate levels and thus maintain biological pH in vivo. Is described.
Japanese Patent No. 3715312 General supervision of Masanori Fukushima "Merck Manual 17th edition Japanese version" Nikkei Business Publications, December 10, 1999, p1709-1716

  As described above, when a large amount of colloidal infusion is used as an alternative blood during surgery, exogenous lactic acid contained in the colloidal infusion evaluates the oxygen supply-demand balance using the blood lactic acid level as an index (i.e., There is a potential problem that makes it difficult to evaluate the degree of increase in endogenous lactic acid alone, and as a result, misjudgment of the determination of the start time of blood transfusion therapy is exacerbated by the patient's condition to be treated. In addition, there is a clinical problem that shock diagnosis performed by evaluating the oxygen supply-demand balance using blood lactate level as an index cannot be accurately performed due to the presence of lactate in the colloidal infusion.

  An object of the present invention is to solve the above-mentioned problems, that is, in order to accurately monitor blood lactate level as an important indicator in determination of blood transfusion start time and shock diagnosis in infusion therapy. When administered to mammals including humans, the amount of lactate as a salt of organic carboxylic acid is reduced to an amount that does not affect endogenous blood lactate levels in the mammal. Is to provide.

  As a result of eager search for a novel colloidal infusion that can be used in place of a colloidal infusion containing lactate as an alkalizing agent, the present inventor, for example, has a structure different from the conventional plasma-like solution described in Patent Document 1. From the point of view that the colloidal infusion containing, for example, acetate instead of lactate accurately monitors the blood lactate level as an important indicator in the determination of transfusion initiation time and shock diagnosis in infusion therapy It has been found that it is excellent, and the present invention has been completed.

  Specifically, the problems of the present invention are solved by the solving means shown in the following [1] to [7]:

  [1] A colloidal infusion preparation containing an organic carboxylic acid salt for use in infusion therapy for bleeding during surgery or for shock, when the colloid infusion preparation is administered to a mammal including a human, The colloidal infusion preparation, wherein the amount of lactate as a salt of the organic carboxylic acid is reduced to an amount that does not affect the endogenous blood lactic acid level in mammals.

  [2] The colloidal infusion preparation according to the above [1], wherein the amount that does not affect the blood lactate level in the mammal is less than 0.15% by weight.

  [3] The colloidal infusion preparation according to [2], wherein the amount that does not affect blood lactate level in the mammal is less than 0.1% by weight.

  [4] The colloidal infusion preparation according to [3], wherein the amount that does not affect blood lactate level in the mammal is less than 0.05% by weight.

  [5] The colloidal infusion preparation according to the above [4], wherein the amount that does not affect the blood lactate level in the mammal is substantially zero.

  [6] The colloidal infusion preparation according to [1] or [2], wherein the organic carboxylic acid is acetic acid.

  [7] The colloidal infusion preparation according to [6], wherein the salt of acetic acid is sodium acetate.

  The colloidal infusion preparation according to the present invention can evaluate the oxygen supply-demand balance using the endogenous blood lactic acid level as an index without being affected by exogenous lactic acid. It is extremely useful as a colloidal infusion preparation used for infusion therapy. That is, in the colloidal infusion preparation according to the present invention, when the colloidal infusion preparation is administered to mammals including humans, the organic carboxylic acid is reduced to an amount that does not affect the endogenous blood lactate level in the mammals. By reducing the amount of lactate as an acid salt, it is possible to accurately monitor the blood lactate level as an important indicator in the determination of the start of transfusion in fluid therapy and the diagnosis of shock.

Definition of Terms In the present specification, the term “colloidal infusion” refers to a plasma augmentation / extracorporeal circulation perfusate containing an artificial polymer compound, and is also referred to as “artificial substitute plasma”.

  In the present specification, “the amount that does not affect the endogenous blood lactate level in mammals when administered to mammals including humans” is less than 0.20 g per 100 mL of colloidal infusion ( Less than 0.20 wt%), preferably less than 0.15 wt%, more preferably less than 0.1 wt%, even more preferably less than 0.05 wt%, most preferably substantially zero. Say quantity.

  The colloidal infusion preparation according to the present invention is a salt of an organic carboxylic acid that is an alkalinizing agent, and lactic acid as a salt of the organic carboxylic acid when the colloidal infusion preparation is administered to a mammal including a human. To an amount that does not affect endogenous blood lactate levels in the mammal, ie, to an amount of less than 0.20 g (less than 0.20 wt%) per 100 mL of colloidal infusion, preferably 0.15 Instead of prior art colloidal infusions, since it has been reduced to less than wt%, more preferably less than 0.1 wt%, even more preferably less than 0.05 wt%, most preferably substantially zero. By using the colloidal infusion preparation according to the present invention, it is possible to more accurately evaluate the balance between oxygen supply and demand using the blood lactic acid level during surgery as an index, compared to the prior art colloidal infusion containing lactate. so That.

  The organic carboxylate other than lactate used in the colloidal infusion preparation according to the present invention may be any one as long as it can act as an alkalizing agent as an infusion component. From the viewpoint, acetate used as a component of the crystalline infusion is preferable, and sodium acetate is particularly preferable.

  In the colloidal infusion preparation according to the present invention, an electrolyte used in a general electrolyte solution can be used in combination with the sodium acetate. For example, sodium sources include sodium chloride, sodium citrate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium sulfate and the like, and these may be hydrates.

  Examples of the potassium source include potassium chloride, potassium acetate, potassium citrate, potassium hydrogen phosphate, potassium dihydrogen phosphate, potassium sulfate and the like, and these may be hydrates. Furthermore, examples of the calcium source include calcium chloride, calcium acetate, calcium pantothenate and the like, and these may be hydrates.

  Examples of the chlorine source include sodium chloride, potassium chloride, calcium chloride and the like.

  The dose and administration rate of the colloidal infusion preparation according to the present invention are not particularly limited. For example, 500 to 1000 mL is gradually instilled intravenously per adult.

  The following examples specifically illustrate the present invention, and the scope of the present invention should be defined by the appended claims and should not be limited by the examples.

Example 1 Preparation of Acetic Acid Containing Colloid Infusion (Low Molecular Dextran Acetic Ringer Solution) Components other than dextran 40 (Nagoya Sangyo Co., Ltd.) were dissolved in water for injection, and then dextran 40 was added in small portions and dissolved. After making up with water for injection, the solution was sterilized by filtration with a 0.22 μm filter, dispensed into ampoules and melted. The prepared solution had a pH of 6.8 and an osmotic pressure ratio of 1 with respect to physiological saline.
The composition of the prepared acetic acid-containing colloidal infusion (low molecular dextran-added acetic acid Ringer solution) is shown in Table 1 below together with the composition of the low molecular dextran-added lactic acid Ringer solution (commercially available low molecular dextran L injection, Otsuka Pharmaceutical).

Example 2: Measurement of blood lactic acid level using autologous blood storage model Rats (350-400 g, male) were used for tracheostomy under 3% sevoflurane anesthesia (pure oxygen administration, inhaled sevoflurane concentration 3%), and artificial respiration was performed. Initiated (pure oxygen ventilation, respiratory sevoflurane concentration 3%, arterial blood carbon dioxide concentration was set at 35 ± 5 mmHg), and the left jugular vein and carotid artery were cannulated.
After closing the neck, the inhaled sevoflurane concentration was changed to 2%, and arterial blood was collected 10 minutes later to obtain the value before the start of the experiment.

  After 1 mL of blood was collected from the artery using a syringe pump, 1 mL of infusion was performed from the vein using a syringe pump, and this was repeated 10 times. The rate of blood collection and infusion was 1 mL / min. The Acetate group was transfused using the acetic acid-containing colloidal infusion prepared in Example 1, and the Lactate group was a commercially available low-molecular dextran L injection (Otsuka Pharmaceutical) as a control. When 10 mL of autologous blood storage and 10 mL of infusion were completed, blood was collected for data acquisition. The lactic acid level in the collected blood is shown in Table 2 below.

  From the blood lactate level shown in Table 2, it can be seen that the lactate group significantly increased the blood lactate level compared to the acetate group. This shows that the exogenous lactate in the colloidal infusion formulation infused in the Lactate group affected the endogenous blood lactate level in rats in the Lactate group. That is, sodium lactate is said to be rapidly degraded in the liver in vivo, but experimental facts indicate that such degradation is not complete and affects blood lactic acid levels.

Example 3: Measurement of blood lactic acid level and pH due to bleeding while blocking hepatic hilar blood flow Using rats (350-450 g, male), under 3% sevoflurane anesthesia (pure oxygen administration, inhaled sevoflurane concentration 3%) Tracheotomy and artificial respiration are started (tidal volume 2.5 mL, respiratory rate 65-75 times / min), common carotid artery (for arterial pressure measurement and blood removal), internal jugular vein (for infusion or transfusion) cannulated Was enforced. After closing the neck, the abdomen was opened and the hepatic artery and portal vein were secured with sutures at the hepatic hilar region. The sevoflurane concentration was changed to 2%, 100 units of heparin were intravenously administered, and arterial blood gas analysis was performed. The results of blood gas analysis of arterial blood are shown in Table 3 below.

  Hepatic artery and portal vein were ligated and blocked, and 1 mL blood was removed from the catheter placed in the common carotid artery at a rate of 1 mL / min, and 1 mL was returned from the catheter placed in the internal jugular vein at a rate of 1 mL / min (transfusion group, n = 8), or 1 mL infusion (Acetate group: 10% dextran-added acetic Ringer solution, n = 8, Lactate group: 10% dextran-added lactated Ringer solution, n = 8), and this operation was repeated 10 times for a total of 10 mL of blood removal After a total of 10 mL of blood was returned or infused, arterial blood gas analysis was performed. Furthermore, blood was collected from the portal vein on the intestinal tract side from the ligation blocker, and blood gas analysis was performed. The blood gas analysis results of portal vein blood are shown in Table 4 below.

  In hepatectomy, hepatic hilar blood flow is cut for the purpose of reducing blood loss. Lack of hepatic hilar blood flow prevents lactic acid metabolism in the liver, and lactic acid production increases due to breakdown of the oxygen supply-demand balance in the intestinal tract due to stagnation of the intestinal circulation. It has been. From the results shown in Table 3, it can be seen that the Acetate group has a significantly lower blood lactic acid level than the Lactate group. Further, from the results shown in Table 4, the Lactate group shows a significant decrease in pH compared to the transfusion group, but the Acetate group does not show a significant decrease in pH compared to the transfusion group. I understand that.

  From the above results, the colloidal infusion preparation according to the present invention was compared with the prior art colloidal infusion preparation containing lactate, using the endogenous blood lactic acid level as an index without being affected by exogenous lactic acid. Since the oxygen supply-demand balance can be more accurately evaluated, the usefulness as a colloidal infusion preparation for use in infusion therapy for bleeding during surgery or for shock is extremely high.

Claims (7)

  A colloidal infusion preparation comprising a salt of an organic carboxylic acid for use in infusion therapy for bleeding during surgery or for shock, wherein the colloid infusion preparation is administered to a mammal, including a human, in the mammal The above-mentioned colloidal infusion preparation, wherein the amount of lactate as a salt of the organic carboxylic acid is reduced to an amount that does not affect the endogenous blood lactic acid level.   The colloidal infusion preparation according to claim 1, wherein the amount that does not affect blood lactate level in the mammal is less than 0.15 wt%.   The colloidal infusion preparation according to claim 2, wherein the amount that does not affect blood lactate level in the mammal is less than 0.1 wt%.   The colloidal infusion preparation according to claim 3, wherein the amount that does not affect blood lactate level in the mammal is less than 0.05% by weight.   The colloidal infusion preparation according to claim 4, wherein the amount that does not affect the blood lactate level in the mammal is substantially zero.   The colloidal infusion preparation according to claim 1 or 2, wherein the organic carboxylic acid is acetic acid.   The colloidal infusion preparation according to claim 6, wherein the salt of acetic acid is sodium acetate.