A method for preventing reocclusion operations in the great vessels


(57) Abstract:

The invention relates to medicine, namely to vascular surgery, and is intended to prevent reocclusion operations in the great vessels. Surface vessels treated with 1% aqueous solution of methylene blue for 5-7 minutes Then put a solution atselizina with a concentration of 0.1 g/ml for 8-10 minutes Then treated with heparin at a concentration of 5000 IU/ml for 3-5 minutes Method allows you to give a surface vessels thrombopenia and anti-inflammatory properties. This prevents reocclusion after surgery on the great vessels. table 1.

The present invention relates to the field of medicine and can be used in vascular surgery.

Reconstructive surgery on the blood vessels is always associated with the release of vessels from the surrounding tissues, opening the lumen of the vessel, removing the diseased inner lining, implantation of foreign tel. no doubt, It is accompanied by the destruction of the natural ways to supply and innervation of the vascular wall, a violation of the regeneration of the arterial wall and the emergence of aseptic inflammation in the area of reconstruction. [Riles Th.S. et al. Longterm results following implantation of a new small diameter bovine vessel xenograft. // International Congress of Angiology. - 1985. - P. 60-66]. There is every reason to believe that induced by surgical treatment of degenerative and inflammatory processes in the vascular wall play an important role in the Genesis of restenosis and reocclusion blood vessels. It is especially relevant to the arteries of small and medium caliber [A. marcinkevičius, Tripolis Century , Ikelite R., Treponema Etc. Influence the progression of atherosclerosis in long-term results of reconstruction of the aorta and peripheral arteries. // Cardiology. - 1988. - So 28. - 6. - S. 12-16, Taylor L. M., Loboa L., Porter J. M. The clinical course of carotid bifurcation stenosis as determined by duplex scanning. // J. Vas. Surg. - 1988. - V. 8. - N 3. - P. 255-261]. Significantly reduce the effectiveness of the operations thrombosis of blood vessels that occur in both the near and long-term postoperative periods. Traditional methods of prevention of early thrombosis and inflammatory processes in the vascular wall designed to eliminate all possible postoperative complications. Work is conducted in several directions:

1. the control of blood coagulation system, and timely correction;

2. intraoperative creating atrombogennoe surface area reconstru occlusive disease;

5. treatment of accompanying diseases.

Intraoperative formation atrombogennoe surface in the area of reconstruction performed with the use of heparin solution. This measure is short-term: most of the anticoagulant is not delayed when restoring blood flow [Operative surgery./Under the editorship of L. Littmann. - Budapest: Publishing house of the Academy of Sciences of Hungary, 1985. - 1175 C.]. There is also known a method of fixation of heparin by means of ultrasound: the surface of the artery after removal of the intima is exposed to ultrasound in the presence of heparin for 30 seconds. Heparin retained in the vessel wall is not more than 12 hours [Antushev A. F. Prevention of infection of vascular prostheses and thrombosis endarterectomies arteries. // The Diss. for obtaining the academic degree of Cand. the honey. Sciences. - 1985]. The umbilical vein or the carotid artery of dogs, pigs, proposed for use as vascular grafts, chemically modified heparin using carbodiimide for at least 5 hours. The concentration of heparin on the surface is 31.5 µg/cm2[E. S. Venkataramani, Senatore F., M. Feola, et al. Nonthrombogenic small-caliber human umbilical vein vascular prosthesis // Surgery. - 1986. - V. 6. - P. 735-741].

To eliminate postoperative onlinelicensing mixtures intraarterially to relieve peripheral angiospasm. They also desegregate therapy with the use of acetylsalicylic acid (ASA) or its water-soluble form atselizina (salt ASC with lysine and glycine).

As noted by some researchers, on the background of systemic treatment atselizina clinically observed favorable for wound healing: less pronounced pain and swelling of the soft tissues after surgery for head and neck, there are no clinical and radiographic signs of anastomosis after operations on the stomach and intestines. But the systematic use of drugs, especially long-term, often accompanied by side effects. For example, the use of atselizina can cause allergic reactions, to increase the effects of anticoagulants, ulcerogenic effects of other non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. In addition, drugs ASA is contraindicated in bronchial asthma, peptic ulcer, bleeding, gipokoagulyatsii. There are also ambiguous shifts of blood coagulation, depending on the dose atselizina [Lenkowski F., Neyrinck N. G., Glaser, S. C. Application of acetylsalicylic acid in coronary artery disease. // Therapeutic. Archive. - 1996. - 8. - S. 79-83].

As a local Pro ASC (atselizina) is unknown.

Closest to the proposed invention is a method including the processing of the intima of a blood vessel dye methylene blue and the anticoagulant heparin to prevent reocclusion in reconstructive operations on the vessels [Izhboldin R. I. "Local prevention early reocclusion when performing an open operation of the main arteries." Abstract. Kida. Diss., Ufa, 1998. - 21 S.]. The intimal surface acquires anti-platelet properties, but this method of prevention of early thrombosis does not provide for the possible treatment of the disease in the form of local inflammatory process.

The authors propose a method for preventing reocclusion vessels using intraoperative surface processing vessels (media) or autovenous graft by atselizina and heparin in order to give the surface thrombogenic and anti-inflammatory properties. Soluble in water aalisin and heparin are not able to stay on the surface of the tissue (table), so fixing directly in the vascular wall using the vital dye methylene blue (MTB). [Mashkovsky M. D. Medicines. - Kharkov: Torsing, 1997. - T. 2. - 590 C.]. Immobilization of Svoistva dye: first, closely associated with elements of the connective tissue collagen and glycosaminoglycans; secondly, the ability of the molecules of the MS to associate among themselves with the formation of di-, tri-. . . multimers (the phenomenon of metachromasia) [Ghosh A. K., Mukeree P. Multiple association equilibria in the self association of methylene blue and other dyes. // JACS. - 1970. - V. 92. - N 22. - R. 6408-6412]; third, to interact with anionic substances of the nature of the formation of complexes are less soluble in water than the original reactants.

Aggregated dye molecules is partially associated with the surface of the biomaterial, have the ability to attach an additional number of other molecules with a negative charge, for example, the ASC as anion and heparin [Lawton J. B., Phillips G. O. Polyanions and their complexes. Part 10. Mechanism of dye binding to chemically different sites. // J. Chem. Soc. Perkin II. - 1977. - P. 38-44].

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The advantages of this method are speed and ease of intraoperative formation using dye MS surface with anticoagulant, but also with anti-inflammatory properties, which helps for a short time to create in the reconstruction zone of high concentration effective medicines.

The invention is illustrated by the following example.

The amount of immobilized ASC on the surface of biomaterials is determined as follows. Fragments of cadaver tissues of large blood vessels and autovenous graft with the measured area is treated with dyes and drugs in the sequence described in the example. If the application of the drugs produced on the surface of the media, washing fabrics provide running water if the fabric is treated by adventitia, they are immersed in the saline solution for a certain time, thus approximately simulating the conditions in which blood vessels are. To retrieve the ASC from complexes with MS fragments of vessels is placed in a known volume of a 10% solution of HCI and make extraction of the ASC in the form of the free acid in diethyl ether. After several extraction of the ether extracts are combined ether is evaporated, the ASC is avodat similarly, using ether extract not treated with drugs fragment tissue. The result of the control experiment is subtracted from the experimental results. The concentration of ASA on 1 cm2surface calculated according to equation

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where TNaOHthe alkali titer (mg/ml, VNaOH- the amount of alkali consumed in the titration ASC; 180,16 and 40 - molecular weight ASC and NaOH, respectively; S is a square piece of cloth.

Heparin determine from the aqueous phase, in which, after carrying out extraction with ether is added zinc dust. Hydrogen at the time of allocation restores dye MS before leucosolenia that is not painted, not able to form complexes with heparin and does not interfere with the determination of heparin carbazolyl method in 87% sulfuric acid by the reaction of the DISHA on uronic acid. From the solution select a sample volume of 0.5 ml, poured 3 ml of concentrated H2SO4containing borax (0.25 mol/l), heated in a boiling water bath for 10 minutes, cool, add 0.1 ml of 0.1% alcohol solution of carbazole and again heated for 15 minutes Develops a pink-violet color. As the reference solution is prepared under the same conditions, the control sample (10% solution model HC1), not containing CNOMO schedule dependence of optical density on the concentration of heparin. From the calculation of the surface concentration of immobilized using dye MS heparin exclude the results of the reaction the DISHA control tissue sample, i.e. all endogenous glycosaminoglycans, including heparin contained in the tissues and giving in the reaction of the DISHA additional colouring solutions.

Changing the order of application of drugs on the painted surface of the biomaterial: first, heparin, then aalisin - leads to a decrease of the surface concentration and the ASC.

As follows from the results given in the table, the strength of binding of ASA and heparin and, therefore, their concentration on the surface depend on the type of biomaterial and the sequence of application of medicinal substances.

Morphological picture of the results of the intraoperative use of complex MS-aalisin-heparin for the prevention of aseptic inflammation during operations on the great vessels.

This method was studied in experiments on mongrel dogs of both sexes. Were formed 4 groups of 10 animals in each group. Animals of the 1st group in the position of the carotid artery were sewn autovenous shunts processing MS-aalisin-heparin. The 2nd group consisted of animals with bodabodas MS-aalisin-heparin. In the 4th group consisted of animals with a similar operation without processing. In each group of animals biopsy specimens for histological studies were performed on 40-th and 90 th day after the operation. The material was fixed in 10% buffered formalin for Lilly. The sections were stained with hematoxylin and eosin, toluidine blue van gieson, conducted a silver impregnation method for Gugino.

In groups of animals, where the operation was performed without processing autograft, much more often met parietal thrombi in the area of anastomosis compared with groups where handled MS-aalisin-heparin. 40 days was observed active thrombus formation with erythrocyte aggregation on fresh fibrin masses, under which was placed a layer of degraded fibrin with mononuclear cells (macrophages, monocytes, lymphocytes). Next was located immature granulation tissue growing into media. On the 90th day was celebrated organized thrombi containing Mature vessels, and from the surface of the vascular lumen is covered with the intima of the artery. The intima of the artery in the area of anatomosis in groups of animals without treatment on the 40th day was characterized by a marked Rosvodokanal and animation reticle glycosaminoglycans compared with those after treatment MS-aalisin-heparin. On the 90 day these differences were leveled. Intima during this period had formed a network of reticular fibers having a predominantly longitudinal orientation. Acidic glycosaminoglycans were observed mainly on the surface. The medial shell of the arteries in the groups of animals without treatment on the 40th day characteristies pronounced proliferation of smooth muscle cells, which to a 90-day was focused on the background of sclerotic changes in the media. After processing MS-aalisin-heparin sclerosis media at 90 days was not observed. In the field of suture material on the 40th day was still seeing pockets of fibrinoidnogo necrosis, and often they were observed in the anastomoses without treatment. State autotransplants in the studied groups, specific features had not. On the 40th and 90th day they had a thin intima decorated with the underlying connective tissue elements.

As follows from histological studies, processing autotransplants complex MS-aalisin-heparin stabilizes tissue homeostasis in the anastomosis, which subsequently can significantly reduce restenosis and reocclusion in the postoperative period.

The way to prevent reocclusion blue for 5-7 min, then heparin with a concentration of 5000 IU/ml for 3-5 min, characterized in that after treatment with methylene blue put a solution atselizina with a concentration of 0.1 g/ml for 8-10 min, and then heparin.


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