Experimental and Clinical Justification of the Use of Ozone-Modified Sorbents in the Intensive Therapy of Mechanical Jaundice

The dissertation is dedicated to the experimental and clinical justification of the use of ozone-modified sorbents in the intensive therapy of mechanical jaundice. The research was conducted at the Nizhny Novgorod State Medical Academy and is aimed at addressing the relevant problem of reducing postoperative mortality in patients with obstructive jaundice of extrahepatic origin, the main cause of which is progressive hepatocellular insufficiency against the background of cholestatic endogenous intoxication. The study developed a technology for stabilizing ozonized physiological solution, a technique for oxidative modification of carbon hemosorbents with ozone, and conducted a comprehensive assessment of the detoxifying and hemodynamic-regulating effects of ozone-modified hemosorbent TETRA both in vitro and in clinical conditions of the postoperative period.

Relevance of the Topic. The number of patients with diseases of the pancreatoduodenal zone, extrahepatic bile ducts, requiring surgical treatment, increases year by year [137,146,235,259,262]. The most common complication encountered in diseases of the hepatopancreatobiliary zone is mechanical jaundice [114,222]. Despite the successes achieved in biliary surgery, the postoperative mortality among patients with obstructive cholestasis, both of benign and malignant genesis, remains high to date and ranges from 12 to 49% [68,101,112,227].

The main cause worsening the prognosis of surgical treatment of patients with mechanical jaundice is progressive hepatocellular insufficiency. Mortality in developing hepatorenal insufficiency and pronounced hepatoencephalic insufficiency reaches 90% [125]. This is facilitated by the circumstance that hepatic insufficiency (HI), not completely eliminated in the preoperative period, is often complicated by severe purulent cholangitic intoxication with kidney damage (hepatorenal syndrome) and (or) brain damage (hepatoencephalic insufficiency) [244]. Additional causes contributing to the progression of acute hepatic insufficiency after surgery are the narcosis leading to disruption of intracellular hepatocyte metabolism and the operative trauma causing systemic and portal hemodynamic disturbances [230].

The leading manifestation of progressive HI in mechanical jaundice is high cholestatic endotoxemia of the body [114,277,244,318,360]. Endogenous intoxication is caused, in particular, by ammonia, unsaturated fatty acids, lactate and pyruvate, bilirubin, bile acids, products of enzymatic and autolytic tissue breakdown, proteolytic enzymes, aromatic amino acids and hydrocarbons, uremic toxins, indirectly activated cascades of cellular and humoral immunity, excessive accumulation of other products of normal and disturbed metabolism [157,230,333]. The increasing endotoxemia influences the further progression of hepatocellular insufficiency and the development of hepatic encephalopathy [214,215,306].

Based on the leading role of progressive endotoxemia in the formation of organ dysfunctions and postoperative complications, an important role is assigned to detoxification therapy. In this connection, methods of extracorporeal sorption detoxification — lymphosorption, lymphoplasmasorption, plasmasorption, and hemosorption — are traditionally used in the complex treatment of patients with cholemic endotoxemia [41,114,149, 159,227,277].

The method of hemosorption, introduced by Yu.M. Lopukhin and his school in mechanical jaundice, is considered the optimal detoxification technique, which was preferred by other authors [159,230]. Its main advantage is the ability to quickly and effectively reduce the concentration of toxic metabolites in the blood of the patient [59,64,157,186,300]. Moreover, hemocarboperfusion itself is not technically complex and does not require expensive equipment or special conditions [27,174,187,230].

The application of various sorption techniques in the postoperative period has demonstrated high efficiency [27,64,116,157,186,277]. However, the sorbents currently used are still far from the clinical optimum, and the search for ways to improve both the carbons and the procedure as a whole appears sufficiently promising to researchers [108,197,199,202,203,204,206,207,208,209].

One of the possible directions for increasing the efficiency of sorption detoxification is the oxidative modification of carbon sorbents [164,173,231,256,273,347,381,394,412]. The method of ozone modification of hemosorbents, which allows a significant increase in the clearance of most clinical toxins, appears quite promising [30,44,231,345,394].

However, despite the unquestionable technological and organizational simplicity of the method, its accessibility, and the possibility of wide practical use, a number of questions related to the technique of sorbent oxidation, the tactics of their safe and effective use in mechanical jaundice, remain open. Thus, to date, there are no sufficiently effective approaches in ozone therapy to stabilize the concentration of dissolved ozone over a practically significant time interval that would allow dose-controlled ozone modification of hemosorbents [92,142,218]. In connection with this, the difficulty of expecting predictable therapeutic effects becomes objective [92,119,275].

Goal of the Scientific Research. To improve the results of treatment of patients with mechanical jaundice based on the use of ozone-modified hemosorption in the postoperative period.

Tasks of the Research:

1. To evaluate the dynamics of ozone decay in ozonized physiological solution located in a flask and in an infusion system depending on the conditions of bubbling and storage, and to determine intervals of its stability for accurate dosing during ozone modification of a sorbent.

2. To develop a technique for ozone modification of carbon hemosorbents and to investigate their detoxification efficiency and hemocompatibility in vitro.

3. To study the effect of the use of ozone-modified hemosorbents in patients with mechanical jaundice on endotoxemia indicators, lipid metabolism, systems of lipid peroxidation and antioxidant protection, hemostasis, immunity, formed elements of blood, and the course of the postoperative period.

Scientific Novelty of the Research. For the first time, based on the study of the dependence of ozone decay in solution on the conditions of preparation and storage, intervals of relative stability of therapeutically significant concentrations of ozone in ozonized physiological solution have been determined.

The effectiveness and predictability of ozone modification of domestic carbon hemosorbents with ozonized physiological solution compared to treatment of the sorption column with an ozone-oxygen gas mixture has been substantiated.

For the first time, in vitro, the effect of ozone modification of hemosorbent TETRA on indicators of general substrate endotoxemia and formed elements during perfusion of blood from patients with mechanical jaundice through a sorption column has been evaluated.

For the first time, it has been shown that performing ozone-modified hemosorption with sorbent TETRA in the early postoperative period in patients with mechanical jaundice increases detoxification efficiency, restores altered indicators of acid-base state, hemostasis, lipid peroxidation, antioxidant activity, immunity, protein and lipid fractions, general and substrate toxicity, reduces the number of postoperative complications, patient bed-days, and hospital mortality.

Practical Significance of the Research. A technology for increasing the stability of ozonized physiological solution has been developed.

A mathematical assessment of the processes of inactivation of ozonized physiological solution in a flask and in an intravenous infusion system has been provided, allowing more accurate calculation of the ozone dose, both in parenteral and combined application of ozone therapy.

A technique for oxidative modification of various carbon sorbents with ozone has been developed. The optimal ratio of ozone dose and amount of sorbent during treatment has been identified, and the effectiveness of various methods of sorbent treatment in the process of oxidative modification has been evaluated.

The advisability of using ozonized carbon hemosorbents as an alternative to standard ones in the postoperative period in patients with obstructive jaundice of extrahepatic origin has been demonstrated.

Introduction into Practice. The results of the dissertation work have been introduced into the practice of resuscitation and surgical departments of medical institutions of Nizhny Novgorod and are used in conducting lectures at the Department of Anesthesiology, Resuscitation and Transfusiology of the Military Medical Institute of the FSB of Russia.

Positions for Defense.

1. Ozonized physiological solution obtained by bubbling 200 ml of 0.9% NaCl solution with an ozone-oxygen mixture at an ozone concentration of 60 mg/l, a flow rate of 0.4 l/min, for 30 minutes under standard external conditions, has a decay dynamics with a significant period of ozone stability in the solution, which allows accurate dosing of ozone therapy methods.

2. Treatment of hemosorbents with ozonized physiological solution significantly increases their sorption capacity compared to bubbling an ozone-oxygen mixture through the sorption column. The sorption indicators of ozone-modified hemosorbent TETRA exceed the analogous values of hemosorbents FAS and VNIITU. Ozone modification of hemosorbent TETRA does not affect its hemoresistance.

3. In patients with mechanical jaundice in the early postoperative period, pronounced endotoxemia with predominance of the high-molecular-weight catabolic pool of VNIISM, disturbances of the LOA-ROS systems, immunity, hemostasis, acid-base state, electrolyte balance, biochemical indicators, and cellular blood composition are determined.

4. Ozone-modified hemosorption, compared to standard hemosorption, has a more pronounced corrective influence on changes in homeostasis and the course of the postoperative period in patients with mechanical jaundice.

Presentation of the Work. The materials of the dissertation were reported at the XXXVI, XXXVII final scientific-practical conferences of the Military Medical Institute of the Federal Border Service of Russia at the Nizhny Novgorod State Medical Academy (Nizhny Novgorod, 2002, 2003); the VIII Nizhny Novgorod session of young scientists (Nizhny Novgorod, 2003); the International Scientific Seminar "High-Intensity Physical Factors in Medicine, Biology, Agriculture, and Ecology" (Sarov, 2004); the II Ukrainian-Russian Scientific-Practical Conference "Ozone in Biology and Medicine" (Odessa, 2004); the VI All-Russian Scientific-Practical Conference with international participation "Ozone in Biology and Medicine" (Nizhny Novgorod, 2005).

Publications. Seven scientific works on the topic of the dissertation have been published, and three rationalization proposals have been registered.

Structure and Volume of the Dissertation. The dissertation is presented on 222 pages of typed text and consists of an introduction, a literature review, three chapters of original research, a conclusion, conclusions, practical recommendations, and a list of references including 421 sources (of which 280 are domestic and 141 are foreign). The work contains 42 tables and is illustrated with 36 figures.