Method for protecting ischemized liver

FIELD: experimental medicine.

SUBSTANCE: in rabbits one should induce hepatic ischemia due to occlusion of hepato-duodenal ligament for 30 min. Moreover, reamberin should be introduced at the dosage of 35 ml/kg during the whole period of occlusion, and at the dosage of 5 ml/kg for 10 min after removing the above-mentioned occlusion. The method provides preventing the death of experimental animals in case of ischemic exposure being harmful for this type of animals.

EFFECT: higher efficiency of protection.

2 tbl

 

The invention relates to medicine and can be used in hepatobiliary surgery, in particular for liver resections.

In a similar experimental and clinical works temporary ischemia of the liver is achieved by compression of the hepato-duodenal ligament (MPD). For anti-ischemic protection of the liver is vnutriaortalina hypothermic perfusion of the standard polygon solutions, in some studies with oxygenation of the solution and the addition of colloidal plasma substitutes [2, 7].

The disadvantages of transfused environments depending on the quality of the infusion solution should be attributed to the lack of a comprehensive anti-ischemic actions, involving simultaneous antihypoxic, anti-oxidant, energymetabolism and detoxification properties. In addition, conducting regional hypothermic perfusion of the liver polygon solutions during ischemia has its methodological features and is used to narrow the field of liver surgery for certain types of operations associated with total vascular exclusion of the body.

For the prevention and cessation of bleeding in surgical interventions and injuries of the liver is widely used receiving temporary full pinched PDS. Bleeding and blood loss are one of the main problems surgical is th Hepatology. Therefore, temporary (for the period of implementation of the surgical hemostasis) clamping of the PDS refers to the number of common techniques used in the resection and liver injury. However, even short-term clamping of the MPD is a dangerous admission, causing severe ischemic liver damage, stagnation of blood in the portal system with the buildup of stagnant toxemia in the portal vein, the emergence of the phenomenon of reperfusion liver injury excessive inflow mycotoxins stagnant blood CNC bed at eliminating the occlusion ELVs rough systemic hemodynamic [5]. This causes, according to most authors, to limit the time safe pinched MPD 15-20 minutes.

One of the main causes of adverse postoperative period when clamped MPD is encountered when carrying out this technique ischemic liver damage. The basis of this damage is the reduction of the level of energy metabolism in the ischemic liver tissue, respectively, the improvement of energy products in the liver cells reduces the degree of liver damage. Key moments in the onset and progression of disorders during ischemia and reperfusion of the liver tissue are hypoxia, activation of lipid peroxidation (LPO) (stimulation of free radical processes),inhibition of the antioxidant system, endotoxicosis [1].

The above suggests that an effective method of preventing ischemic liver damage during temporary occlusion of ELVs will be the treatment having antihypoxic and antioxidant effect, reducing the activity of lipid peroxidation, significantly increasing the energy potential of cells and has a detoxifying effect. These actions, according to Savalanche, (2002) [3], have infusion reamberine - balanced isotonic polygon infusion solution, with the main active component of 1.5% sodium succinate (manufacturing LLC NTFP "Polysan", St. Petersburg). In the basis of the pharmacological effects of reamberine lies that succinate is an energy metabolite product of the fifth and sixth substrate reactions of the Krebs cycle. The oxidation of succinate is carried out by the enzyme succinate dehydrogenase, the activity of which does not depend on the concentration of NAD/NADH+that hypoxia promotes the synthesis of ATP when disturbed OVER-dependent cellular respiration. Conservation of energy products is the basis for the occurrence of volatile metabolic processes in the cell, which allows the fabric to resist ischemic effects. It is logical that to be most effective solution should be to bring the right near St is significant to the liver, bypassing fabric filters and creating in the liver the greatest concentration of active substance [4].

Closest to the proposed development is a method of applying reamberine in patients with mechanical jaundice of non-neoplastic origin [6]. Hypertension in the bile ducts causes a lack of blood supply to the liver with the development of ischemia and hypoxia liver cells. The solution reamberine applied 400.0Hz in units of ml / day drip into a peripheral vein for 7 days after surgery for decompression of the biliary tract.

This dynamics was studied basic biochemical blood indicators of endogenous intoxication, the state of the antioxidant system. Determined that use of the drug Reamberin in mechanical jaundice and related partial liver ischemia provides detoxification, antihypoxic, anti-oxidant and cytoprotective actions.

The disadvantage of the prototype is that Reamberin is injected into a peripheral vein and enters the liver after passing through a powerful fabric filters (muscles, lungs, intestines and other), which is accompanied by the disposal of a significant part of our preparation, leading to a decrease in their income in the liver, with a corresponding reduction therapeutic hepatotropic actions.

The invention conclusion is moved in that infusion of reamberine held in the proximal part iriatai portal vein during temporary occlusion hepato-duodenal ligament. Infusion reamberine in the portal vein proximal to the site of occlusion VCP inhibits excessive activation of processes of lipid peroxidation, activates the antioxidant system has antihypoxia and membrane-stabilizing effect on liver cells.

Before the operation, during which it is assumed temporary clamping of the hepato-duodenal ligament, first a bunch of lead round nipple rubber tube, after which the free ends of the tubes pass through a wide and short rubber tube. Clamping of the hepato-duodenal ligament carry out the tension until the complete cessation of blood flow to the liver) coming out of the pipe ends curled a bunch of tubes and their fixation on the pipe surgical clip. After that kateteriziruyut one of the branches of the portal vein (usually the right gastroepiploic vein) and within the vein down the end of the catheter close to the liver. When clamped MPD internal lumen of the catheter in the portal vein within the ligament, not clamped, which allows for the infusion of reamberine in the proximal relative to the location pinched ligament area of the portal vein. Infusion of reamberine spent is during pinched ligaments and in the next 10 minutes after its removal.

To prove the effectiveness of the invention experiments were carried out in 20 anesthetized rabbits. In rabbits at 30 minutes was perikli hepato-duodenal ligament. In earlier studies performed by us [5] it was shown that clamping of the tie-in at this time is absolutely fatal to rabbits. In this experiment 10 rabbits during occlusion ligaments and in the next 10 minutes after removal of the occlusion was poured vnutriaortalina directly to the liver isotonic sodium chloride solution (control group animals), other 10 rabbits was poured into an experience Reamberin (experimental group of animals). The total volume transfused solutions in all experiments was the same: 35 ml/kg during occlusion ligaments and 5 ml/kg after removal of the occlusion of the binding.

Analyzed the course and outcomes of the experiments, the data of biochemical blood tests, which were taken from the femoral vein before occlusion of the hepato-duodenal ligament and 15 minutes after its removal. The total amount withdrawn in each experiment blood was approximately 20 ml. Differences between the assessed indicators were considered to be statistically significant at p<0,05.

In the control group experimental animals one animal died during occlusion ligament, another 5 minutes after removal of the occlusion ligaments, Stalin the e eight animals lived upon removal of the occlusion ligaments 40± 2.9 minutes.

In the experimental group the experimental animals showed a significant positive effect of infusion of reamberine: none of the animals of this group were not lost during occlusion ligaments, and after resolving occlusion in experimental rabbits lived an average of 11 minutes longer than in the control group (the lifespan of rabbits after eliminating occlusion ligament was 51±3.7 minutes, the difference with the control group significantly - p<0,05).

In the control group animals according to serum chemiluminescence of peripheral venous blood, determination of the content in the serum malondialdehyde and ceruloplasmin marked increase in the intensity of lipid peroxidation and the tendency to decrease of antioxidant activity (P(Imax)/∑). Especially significantly (162,5%) increased the content of serum malondialdehyde content of ceruloplasmin remained virtually unchanged.

In the experimental group of animals, the intensity of lipid peroxidation was decreased, the trend towards reduction of antioxidant activity, but the content in the serum malondialdehyde statistically remained unchanged and 15% had a higher content of ceruloplasmin (see table 1).

Table 1.

Changes of some indicators of activity GENDER and ceruloplasmin in the serum of rabbits in the dynamics of the experiment (M±m)
Groups of ANIMALSCHEMILUMINESCENCE (Crotone)MALONIC DIALDEHYDE (Ámol/l)CPU (mg/l)
P
TOAFTERTOAFTERTOAFTERtoAFTER
A (n=10)104,5±6,4115,9±7,61234,9±61,21499,4±45,31,6±0,24,2±0,4593,3±51,9636,6±49,4
In (n=10)118,6±8,791,8±3,91193,9±for 95.31053,9±107,33,1±0,23,3±0,2to 158.4±10,3181,9±12,5
Note: A group of animals who were the infusion of saline; group of animals who were infusion reamberine; P(Imax) - peak luminescence; Σ - sutasoma luminescence (60 sec.); CPU - ceruloplasmin; pre - baseline; after - indicators che the ez for 15 min after removal of the occlusion MPD.

In the control group animals at the end of the experience dramatically increased the activity of transaminases (AST 4.4 times; Alat 4.0 times) and lactate dehydrogenase - 3.3 times.

In the experimental group of animals increased in the end of the experiment the enzyme activity was much smaller: the activity of AST was increased by 2.9 times, Alat - 2.1 times, lactate dehydrogenase - 1.7 times (see table 2).

Table 2.

Changes in the activity of transaminases (Alt and AST) and lactate dehydrogenase (LDH) in the serum of rabbits in the dynamics of the experiment (M±m)
Groups of ANIMALSAlat (U/l)AST (IU/l)LDH (IU/l)
toafterToAftertoafter
A (n=10)65,7±9,2AZN 264.2±15,548,8±7,3215,1±16,1612,6±82,32031±70
In (n=10)41,7±8,589,3±8,539,5±8,7or 115.1±37,7550,6±35,1939,9±146,6
Note: A group of animals who were the infusion of saline; the group of animals, which was conducted infusion reamberine; pre - baseline; after-figures in 15 min after removal of the occlusion CDS.

Thus, the data of experiments convincingly demonstrate the effectiveness of the invention, its ability to improve the body's resistance to acute temporary occlusion hepato-duodenal ligament, with the most important mechanisms of this favorable effect is the inhibition of lipid peroxidation and membrane-stabilizing effect on liver cells during ischemia and reperfusion.

Literature

1. Bilenko MV Ischemic and reperfusion injury of organs (molecular mechanisms, ways of prevention and treatment). - M.: Medicine, 1989. - 368 S.: ill.

2. Kardovsky A.G. Perfusion of the liver as a method of preventing ischemic damage in the termination of the afferent blood supply: Dis.(Kida. the honey. Sciences. - Kirov, 1984. - 146 S.: ill.

3. Obolensky SV Reamberin - a new tool for infusion therapy in the practice of medicine critical States: Methodological recommendations. - SPb.: Saint-Petersburg medical Academy of postgraduate education, 2002. - 24 S.

4. Ostroverkhov G. Transumbilical therapy of inflammatory diseases of the liver and biliary tract, " Vestn. Acad. the honey. of Sciences of the USSR. - 1971. No. 9. - P.57-62.

5. Sukhorukov the VP Transfusiology the economical provision of large and extremely large liver resections: Diss. Dr. med. Sciences. - Kirov, 1990. - 451 S.: ill.

6. Topuzov EG, Kovalenko A.L., Drohomyretska H., Balashov VK Belyakova NV Applied reamberine in patients with mechanical jaundice // Attending physician. - 1999. No. 7. - S.43-46.

7. Sauvanet A., Century is of particular interest, Belghiti J. A simplified technique of ex situ hepatic surgical treatment // J. of the American College of surgeons. - 1994. - Vol.178. - P.79-81.

The way to protect the ischemic liver induced by 30-min occlusion of the hepato-duodenal ligament in the experiment in rabbits by vnutripocherngo introduction of reamberine at a dose of 35 ml/kg during the period of occlusion, and at a dose of 5 ml/kg over 10 min after removal of the occlusion.



 

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