RU2425684C1 - Method of preparing dialysis fluid - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: preparation of a dialysis fluid including provided physiological pH, electrolytes, osmolarity values differing by the fact that a lipid-containing dialysis fluid is prepared by diffusion and dialysis membrane convection of 20% officinal emulsified solution of essential lipids - Lipofundin MCT/LCT in countercurrent to a standard dialysis fluid for 2 hours.

EFFECT: effectiveness of the invention consists in preparing the dialysis fluid to be used for lipid-bound toxins and metabolites excretion from an organism, reduced time of staying in hospital and number of fatal outcomes.

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Description

The present invention relates to medicine, namely to substitution and intensive care, toxicology, and can be used to provide transmembrane mass transfer of fat-soluble substances from the blood.

The problem of removing fat-soluble (associated with lipids and lipoproteins) toxic substances (dichloroethane, carbon tetrachloride, benzene, etc.), drugs (propranolol, digoxin, diazepam, etc.), as well as fat-soluble metabolites that become high in concentration toxic, lead to damage to the functions of various organs, tissues or important regulatory mechanisms (bile acids, prostacyclins, nitric oxide, indole and phenolic metabolites, thiols, etc.) is still far from resolving Eden. Of the existing extracorporeal methods, only high-volume plasmapheresis and, to some extent, hemosorption can be mentioned, but these methods are not selective, and their effectiveness is insufficient.

Fat-soluble (lipophilic) lipid / lipoprotein-related substances are not eliminated by the use of widespread replacement therapy methods (hemodialysis, hemodiafiltration, peritoneal dialysis, etc.) (Stetsyuk EA, Lebedev SV, 1997; Gurevich K.Ya . et al., 2003), since the dialysis fluid used in the above methods does not contain lipids per se, which would allow ligand substances to bind to the lipid molecules of the dialysis fluid. We could not find descriptions of the dialysing fluid containing lipids in the available literature.

Analogue

The dialysis solutions used for hemodialysis and hemodiafiltration on devices operating without water purification and, accordingly, without a dilution unit for concentrated salt solutions (concentrates of dialysis solutions) are analogous. These solutions contain the necessary and corresponding physiological plasma concentrations of salt ions, osmolarity, pH. In addition to water, salt samples are used for cooking. After mixing in certain quantities of samples of salts and water, the resulting dialysis solution is packaged in containers, which are subsequently used during the procedure (Stetsyuk EA, Lebedev SV Classical hemodialysis. M., 1997. - P.22-29 )

One of these analogues is the Duosol® bicarbonate buffer (B.Braun) dialysis and substitution solution in two-chamber bags. The large chamber has a volume of 4445 ml, the small chamber 555 ml. There are three types of this solution, depending on the content of potassium chloride in the small chamber.

Active ingredients
g / liter Duosol® with potassium
0 mmol / l Duosol® with potassium
2 mmol / l Duosol® with potassium
4 mmol / l big camera small camera big camera small camera big camera small camera Sodium chloride 6.18 4.21 6.18 4.21 6.18 4.21 Potassium chloride - - - 1.34 - 2.68 Calcium chloride two-water - 1.98 - 1.98 - 1.98 Magnesium chloride hexahydrate - 0.91 - 0.91 - 0.91 Glucose monohydrate - 9.90 - 9.90 - 9.90 Sodium bicarbonate 3,59 - 3,59 - 3,59 -

Other components contained in the small chamber - hydrochloric acid 25% for pH correction and water for injection, in the large chamber - carbon dioxide for pH adjustment and water for injection. As you can see, the developers were not able to produce a solution with the necessary bicarbonate content, since at physiological pH values, calcium will precipitate over time. Hydrochloric acid, combining with carbon dioxide (after rupture of the septum separating the two packets), forms the required amount of bicarbonate. Since the solution is prepared "ex tempore", calcium simply does not have time to form a precipitate.

The disadvantage of the analogue is the impossibility of elimination of protein-bound molecules and fat-soluble substances - toxic metabolites, xenobiotics, poisons.

The closest analogue is getting Albumin 20% (Plazbumin-20, USA). It is produced from human plasma using the Cohn cold ethanol fractionation process (http://www.solucionestraumatologicas.com/MFT/PRODUCTO/P899.HTM). Plazbumin-20 is a 20% sterile albumin solution containing 200 g / l of total protein, of which 192 g / l of albumin, the remaining components are thermostable alpha and beta globulins. The drug is stabilized with 0.016 M sodium caprylate and 0.016 M acetyl tryptophan. The sodium content in the product is 145 meq / l. The drug does not contain preservatives. Each bottle of Plazbumin-20 undergoes heat treatment at a temperature of 60 ° C for 10 hours, which prevents the possibility of transfusion transmission of hepatitis viruses. Plasbumin-20 is used both for intravenous administration and as a dialysis solution (Mitzner SR, Stange J., Klammt S. et al. Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: Results of a prospective, randomized, controlled clinical trial. Liver Transplantation. - 2000. - Vol.6. - No. 3. P.277-286) on the procedure of molecular adsorption-recirculation system (MARS) - albumin dialysis.

The resulting albumin has advantages: it allows you to remove albumin-bound xenobiotics, metabolites and toxins when using it as a dialysis fluid during the albumin dialysis procedure from the patient’s blood. The most significant drawback is the inability to use albumin-containing dialysis fluid to eliminate fat-soluble and water-soluble metabolites, xenobiotics, poisons.

Tasks:

- to ensure compatibility and safety of the use of a modified lipid solution as a lipid dialysis solution in clinical practice;

- to provide a change in the composition of the solution due to changes in the concentration of electrolytes and removal of non-emulsified triglycerides from it to ensure physiological concentrations of the ingredients (except the actual emulsified lipids), pH, osmolality;

- to obtain the composition of a dialysis fluid containing lipid molecules in high concentration and, accordingly, allowing the elimination of substances associated with lipids and lipoproteins from human blood (fat-soluble and water-soluble metabolites, xenobiotics and poisons).

The essence of the invention is to obtain a dialysis fluid, including the provision of physiological pH values, electrolytes, osmolarity, characterized in that the lipid-containing dialysis fluid is obtained by diffusion and convection through the dialysis membrane of a 20% offsinal emulsified solution of essential lipids - Lipofundin MCT / LST in countercurrent with standard dialysis solution for 2 hours.

The technical result of the invention is the manufacture of a dialysis fluid containing emulsified essential lipids. Ensuring the compatibility and safety of using a modified lipid solution as a lipid dialysis solution in clinical practice by changing the composition of the solution by changing the concentration of electrolytes and removing non-emulsified triglycerides from it to ensure physiological concentrations of the ingredients (except for the actually emulsified lipids), pH, osmolarity.

The medical and social effectiveness of the invention consists in the manufacture of dialysis fluid for use in order to remove lipid-bound toxins and metabolites from the body, shorten the patient’s hospital stay and reduce fatalities.

A method of manufacturing a dialysis fluid.

To obtain lipid-containing dialysis fluid, pharmacopoeial 20% Lipofundin MCT / LST (B. Braun, Germany) is used - a fat emulsion for intravenous administration and a lactate dialysis and substitution solution.

The “artificial” kidney apparatus is prepared for the hemodialysis procedure according to the instructions for use. A high-flow dialyzer and a set of highways are loaded into the device, it is tested for the dialysis procedure. Substitutional solution in 4.5 liter packets is used to fill the pipelines, which ensures the entire cycle of preparation of a lipid-containing dialysis fluid. After filling the lines with a substitutional solution and passing the test for dialysis, an excess of the substitute is drained, leaving 2 liters of solution in the bag. Then, 2 liters of 20% Lipofundin MCT / LST are added to the solution, filling the “blood cavity” of the dialyzer and highways. We get a solution containing Lipofundin and substitute in equal proportions.

Example 1

The parameters of the procedure are set on the “artificial kidney” apparatus: the flow rate of the lipofundin-substitutional mixture is 200 ml per minute, the flow rate of the bicarbonate dialysis fluid is 500 ml per minute, the temperature is 36.5 ° C, the procedure takes 2 hours. The conductivity of the dialysis solution is 138-142 mS, ultrafiltration is 1000 ml / h (due to the substitutional solution remaining in the packet). At the end of the procedure, the solution in the bag is used as a lipid dialysis fluid.

In a series of benchmark studies of the modification of the official 20% Lipofundin MCT / LST (a series of 7 dialyses) before the procedure and every 30 minutes of the dialysis procedure for preparing a lipid-containing dialysis fluid, a modified lipofundin is taken for laboratory studies. Investigate the level of sodium, potassium, pH, the content of free non-emulsified triglycerides, osmolality. The data obtained are presented in table 1.

Table 1 The study of a 20% solution of Lipofundin MCT / LST during its dialysis modification options before in 30 minutes After 1 hour after 1 h 30 min after 2 hours Osmolarity, mosm / l 388.25 ± 16.42 295.43 ± 5.03 293.43 ± 3.87 293.29 ± 3.87 292.29 ± 4.39 Triglycerides, mmol / L 586.23 ± 30.89 1.51 ± 0.64 0.55 ± 0.53 0.21 ± 0.14 0.13 ± 0.02 pH * 7.41 ± 0.08 7.41 ± 0.08 7.38 ± 0.11 Potassium, mmol / L 0.62 ± 0.12 1.95 ± 0.38 1.91 ± 0.56 1.94 ± 0.56 1.92 ± 0.57 Sodium, mmol / L 15.53 ± 0.82 137.6 ± 4.52 138.26 ± 4.46 137.99 ± 4.67 137.76 ± 4.86 Ionized calcium, mmol / l 0.60 ± 0.12 1.30 ± 0.11 1.36 ± 0.21 1.41 ± 0.14 1.39 ± 0.16 Chlorides, mmol / L - 119.5 ± 2.12 121.2 ± 1.21 ^* - the pH of a 20% solution of lipofundin MCT / LST according to the manufacturer varies from 6.8 to 8.0

As can be seen from table 1, by the 30th minute of the procedure, all the studied parameters of the modified 20% Lipofundin MCT / LST solution corresponded to physiological norms. Thus, a solution of 20% Lipofundin MCT / LST, which is practically free of free triglycerides, is modified; its osmolarity, electrolyte concentration, and pH are normalized. After 2 hours of dialysis modification, a solution of essential lipids is ready for use as a dialysis solution.

To objectify the possibility of using the obtained dialysis solution, a comparative analysis of the properties of the well-known serial 20% Lipofundin MCT / LST and the dialysis fluid we offer is carried out.

Example 2

In order to identify the effect of a factory 20% Lipofundin MCT / LST solution used as a dialysis fluid on citrated donor blood, a series of bench tests were carried out. Dialyzed citrated donor blood using a high-flow dialyzer in a closed loop. As a dialysis fluid, a 20% Lipofundin MCT / LST solution was used in the recirculation mode with a second peristaltic pump in countercurrent with dialyzed blood. The total procedure time is 2 hours. Blood samples were taken initially, after 15, 30 minutes, 1 and 2 hours. The data obtained are shown in table 2.

As follows from table 2, after 15 minutes of the procedure in the blood, a decrease in the concentration of hemoglobin and hematocrit was noted. Moreover, an increase in the concentration of free hemoglobin by more than 50 times from the original figures was noted in parallel. This is probably due to a critical decrease in the concentration of sodium, calcium and, accordingly, chlorine. We believe that a very significant, almost two-fold increase in the concentration of triglycerides that diffuse from the lipofundin solution into the blood also makes a certain contribution to the hemolysis process.

The growth of osmolarity, which significantly exceeded the upper normal values, also looks rather problematic. A critical increase in potassium concentration was noted at the 15th minute of the procedure (from 7.08 ± 0.43 to 10.70 ± 2.36 mmol / L), which remains throughout the procedure (up to 12.52 ± 2.27), which if used in vivo would inevitably lead to cardiac arrest.

table 2 Parameters of donated canned citrated blood during dialysis with 20% solution of lipofundin MCT / LST options before the procedure 15 minutes 30 minutes 1 hour 2 hours Red blood cells, × 10 ¹² / l 4.23 ± 0.73 3.82 ± 0.78 3.31 ± 0.75 3.28 ± 0.46 3.07 ± 0.40 Hemoglobin, g / l 117.71 ± 2.66 106.57 ± 6.03 96.86 ± 14.69 91.86 ± 10.29 81.43 ± 8.68 Hematocrit% 0.39 ± 0.07 0.36 ± 0.08 0.34 ± 0.1 0.32 ± 0.06 0.28 ± 0.05 Free hemoglobin, g / l 1.05 ± 0.61 50.38 ± 3.86 54.45 ± 9.23 62.59 ± 3.22 67.99 ± 14.67 Osmolarity, mosm / l 324.29 ± 27.19 347.14 ± 20.22 346.14 ± 21.72 352.43 ± 18.42 354.17 ± 17.92 Cholesterol, mmol / L 2.64 ± 0.44 5.00 ± 2.5 5.55 ± 3.45 5.79 ± 2.28 5.83 ± 1.59 Triglycerides, mmol / L 0.79 ± 0.16 157.11 ± 51.1 125.19 ± 59.64 131.83 ± 39.4 137.48 ± 43.99 pH 7.26 ± 0.22 7.19 ± 0.10 7.12 ± 0.12 7.10 ± 0.09 7.12 ± 0.11 Potassium, mmol / L 7.08 ± 0.43 10.70 ± 2.36 11.81 ± 2.13 12.13 ± 2.01 12.52 ± 2.27 Sodium, mmol / L 130.23 ± 8.72 78.11 ± 10.23 71.28 ± 9.87 64.42 ± 8.93 63.71 ± 9.12 Ionized calcium, mmol / l 0.66 ± 0.02 0.33 ± 0.03 0.33 ± 0.02 0.28 ± 0.03 0.30 ± 0.02 Chlorides, mmol / L 102.09 ± 7.01 63.04 ± 1.89 63.90 ± 1.97 62.69 ± 2.01 63.21 ± 2.03

Thus, the use of an officinal emulsified solution of essential lipids - 20% Lipofundin MCT / LST as a dialysis solution is impossible, since this leads to the development of blood hemolysis, "life-incompatible" changes in the concentrations of potassium, sodium, calcium, osmolarity, pH and triglycerides.

Example 3

In a series of studies, the effect of dialysis-modified 20% Lipofundin MCT / LST solution on donated canned blood was studied. Citrate donated blood was perfused using a high-flux dialyzer in a closed loop. As a dialysis fluid, a modified 20% Lipofundin MCT / LST solution was used, which was supplied in a recirculation mode with an additional peristaltic pump in countercurrent with dialyzed blood. The total procedure time is 2 hours. Blood samples were taken initially, after 15, 30 minutes, 1 and 2 hours. The data obtained are shown in table 3.

Table 3 Parameters of perfused citrated blood with prepared dialysis solution options before the procedure 15 minutes 30 minutes 1 hour 2 hours Red blood cells, × 10 ¹² / l 4.24 ± 0.32 4.24 ± 0.65 4.34 ± 0.55 4.43 ± 0.55 4.44 ± 0.79 Hemoglobin, g / l 132.08 ± 8.93 135.86 ± 18.92 133.57 ± 16.8 135.14 ± 15.16 138.14 ± 15.12 Hematocrit% 0.40 ± 0.03 0.41 ± 0.06 0.40 ± 0.04 0.40 ± 0.04 0.41 ± 0.07 Free hemoglobin, g / l 2.57 ± 1.13 2.68 ± 1.18 2.87 ± 1.42 2.96 ± 1.22 3.16 ± 1.74 Osmolarity, mosm / l 316.43 ± 11.18 299.29 ± 10.64 295.86 ± 6.91 295.57 ± 7.74 295.14 ± 7.71 Cholesterol, mmol / L 3.96 ± 1.33 4.09 ± 0.84 4.01 ± 1.12 4.11 ± 1.12 4.14 ± 1.07 Triglycerides, mmol / L 0.82 ± 0.24 1.38 ± 0.15 1.39 ± 0.15 1.41 ± 0.17 1.44 ± 0.18 pH 7.06 ± 0.11 7.31 ± 0.15 7.33 ± 0.15 7.37 ± 0.1 7.32 ± 0.11 Potassium, mmol / L 11.31 ± 2.21 6.40 ± 2.29 5.21 ± 2.23 5.02 ± 2.15 5.15 ± 2.13 Sodium, mmol / L 156.14 ± 13.67 149.37 ± 11.49 143.33 ± 12.14 144.2 ± 12.17 143.3 ± 12.84 Ionized calcium, mmol / l 0.06 ± 0.02 0.31 ± 0.04 0.36 ± 0.04 0.46 ± 0.05 0.60 ± 0.04 Chlorides, mmol / L 92.00 ± 6.22 96.71 ± 2.56 98.14 ± 2.48 98.07 ± 2.71 98.71 ± 2.63

As follows from table 3, as a result of the use of an offsinal emulsified solution of essential lipids modified with dialysis, 20% Lipofundin MCT / LCT as a dialysis solution, exclusively positive changes in pH, osmolarity and electrolytes were revealed. The concentrations of triglycerides, cholesterol, free hemoglobin remained within physiological values, and the concentrations of hemoglobin, erythrocytes and, accordingly, hematocrit slightly increased, due to a slight excess ultrafiltration during the dialysis procedure. Thus, a series of studies proved the absolute safety of using the modified 20% Lipofundin MCT / LST solution as a lipid-containing dialysis fluid modified by the proposed method.

Claims (1)

A method of obtaining a dialysis fluid, including the provision of physiological pH values, electrolytes, osmolarity, characterized in that the lipid-containing dialysis fluid is obtained by diffusion and convection through the dialysis membrane of a 20% offsinal emulsified solution of essential lipids - Lipofundin MCT / LST in countercurrent with a standard dialysis solution within 2 hours