Experimental and Clinical Rationale for Enteroprotective Therapy in Various Forms of Acute Pancreatitis

The dissertation is devoted to the experimental and clinical rationale for enteroprotective therapy in various forms of acute pancreatitis. The study investigates morphofunctional changes in the intestine, microcirculation, lipid metabolism, and hypoxia indicators in intestinal tissues in the dynamics of acute biliary pancreatitis. Special attention is given to the role of endogenous intoxication and enteral insufficiency in the pathogenesis of the disease.

Based on experimental and clinical data, it has been established that the effectiveness of mexidol therapy depends on the severity of acute pancreatitis. In the edematous form, the drug demonstrates high effectiveness in correcting enteral insufficiency through antioxidant and antihypoxic effects, whereas in destructive forms (pancreatonecrosis), the positive effect is less pronounced and appears later.

Relevance of the study. Acute pancreatitis is currently considered one of the most frequently encountered surgical diseases. Over the past 20 years, an increase in the incidence of acute pancreatitis has been observed (Saveliev V.S. 1993; Manuilov A.M., 2001).

One of the leading roles in the pathogenesis of homeostasis disorders in acute pancreatitis is played by endogenous intoxication, which largely determines the severity and outcome of the disease. The development of the endogenous intoxication syndrome is based on the intensification of free radical lipid peroxidation processes, an increase in phospholipase activity, and a decrease in the antioxidant defense of the organism (Belyavsky L.D. et al., 1993; Petrosyan A. et al. 1998; Vlasov A.P. et al., 2004; Rykov A.V. 2006; Cuzzocrea S. et al. 1999; Fukuhara K. et al. 1999; Tokyay R. et al. 1999). In the progression of entotoxicosis, highly toxic products accumulate, which act as triggers initiating mechanisms of autodestruction in various organs, leading to the development of the multiple organ failure syndrome, which is the universal pathogenetic basis of any critical condition (Buranashvili Z.A. et al., 2001). A special place in the complex of visceral disorders is given to enteral insufficiency (Saveliev V.S. et al. 2004). The multidirectional impact of numerous pathogenic factors on the structural formations of the intestinal mucosa leads to a sharp change in its properties (especially barrier) and to the entry of toxins and pathogenic microflora into the lymphatic system, portal circulation, and abdominal cavity (Eryukhin I.A., I. Pakhkon B.V., 1995). Currently, this pathogenetic syndrome is considered to play a leading role in the saturation of the organism with endotoxin, which is the main inducer of the development of the systemic inflammatory response syndrome, abdominal sepsis, and multiple organ failure in acute pancreatitis. The development of bacterial translocation against the background of enteral insufficiency determines the degree of endogenous intoxication (Gelfand et al. 1999), determining the severity of the disease course and prognosis in acute pancreatitis (Saveliev V.S. et al., 2002).

Thus, the problem of scientific search for new methods of pharmacological correction of enteral insufficiency in acute pancreatitis in the context of preventing entotoxicosis and multiple organ failure, and improving the overall treatment efficacy, remains highly relevant.

Goal of the study

To assess morphofunctional changes in the intestine in various forms of acute pancreatitis: to study the effects of the antioxidant mexidol in the correction of enteral insufficiency in this pathology in experiments and clinical practice.

Main objectives

1. In the dynamics of acute experimental pancreatitis of the edematous and destructive forms, to study morphological changes in the intestine; to determine their relationship with clinical and laboratory manifestations of enteral insufficiency.

2. In various forms of acute pancreatitis, to investigate intestinal microcirculation and lipid metabolism. To establish their relationship with the intensity of lipid peroxidation processes, phospholipase activity, and the degree of hypoxia.

3. To study the effects of the antioxidant mexidol in the correction of enteral insufficiency in acute experimental pancreatitis of varying severity.

4. To identify the main components of the pathogenetic direction of the enteroprotective action of the drug in acute pancreatitis, and to determine the features of its influence in various forms of this pathology.

5. To determine the effect of mexidol on a range of clinico-laboratory indicators in patients with acute pancreatitis of the edematous form.

Scientific novelty

In various forms of acute experimental biliary pancreatitis, a range of morphofunctional changes in the intestine have been studied. It has been established that in acute pancreatitis of varying severity, the development of the endogenous intoxication syndrome is accompanied by the formation of morphological changes in the small intestine in the form of point hemorrhages, erosions, and ulcers, disruption of lipid metabolism, histohematological permeability, and electrogenesis of tissue structures of the organ.

It has been shown that the basis of membrane-destructive processes in the intestinal wall lies the development of hypoxia, the progression of lipid peroxidation processes, and phospholipase activity. In the destructive form of acute pancreatitis, the significant degree of enteral insufficiency is determined by the depth of pathomorphological and dysfunctional phenomena in the intestine, which is associated with generalized damage to the biomembranes of cellular structures of the intestine.

It has been found that the effectiveness of mexidol in the therapy of acute experimental pancreatitis is due to the reduction of altering processes in the intestine. The basis of the pathogenetic action of the drug lies in its antioxidant and antihypoxic effects, manifested by a decrease in the intensity of lipid peroxidation, depression of phospholipase A, and correction of tissue hypoxia. Another mechanism of the enteroprotective effect of mexidol is its ability to reduce the degree of endogenous intoxication by eliminating both its initiating and prolonging factors.

It has been experimentally confirmed that the effectiveness of therapy is determined by the degree of enteral insufficiency, which depends on the severity of acute pancreatitis. It has been shown that in acute edematous pancreatitis, the positive effect of mexidol is clearly evident from the first three days of therapy. The timely inclusion of the drug in the complex of therapeutic measures leads to rapid restoration of transcapillary exchange, electrogenesis of intestinal tissue structures, correction of lipid destabilizations and structural damage to tissue structures of the organ, preventing the progression of membrane-destructive phenomena of intestinal cellular structures. It has been found that in the destructive form of the disease, the positive effect of the drug is less noticeable and begins to manifest only by the fifth day of therapy in the form of stabilization of circulatory-metabolic disorders of intestinal tissues, which is due to deep pathomorphological and functional phenomena in the small intestine in pancreatonecrosis, and is characterized only by a slowing of the progression of enteral insufficiency and the pathological process as a whole.

Clinico-laboratory studies have shown that the inclusion of mexidol in the therapy of patients with acute edematous pancreatitis, compared with the control, contributes to the correction of enteral insufficiency, which was manifested by relatively rapid restoration of intestinal peristalsis, reduction of the severity of the toxic syndrome, decrease in the intensity of lipid peroxidation and phospholipase A activity in blood plasma.

Practical significance

The use of mexidol in acute edematous pancreatitis has demonstrated high effectiveness of this therapy scheme in the correction of enteral insufficiency through reduction of the severity of the endogenous intoxication syndrome and restoration of the structural-functional status of the intestine, which indicates the advisability of using mexidol in clinical practice and determines the value of the work in the practical aspect.

The effectiveness of mexidol therapy is determined by the degree of enteral insufficiency, which depends on the severity of acute pancreatitis. It has been proven that the use of mexidol in destructive forms of acute pancreatitis is of low effectiveness.

The study of some molecular and cellular mechanisms of mexidol action in enteral insufficiency against the background of acute pancreatitis significantly expands the understanding of the pathogenesis of this pathology, making it possible to develop a pathogenetic scheme of membrane-protective therapy aimed at correcting the arising dysregulatory disorders of the gastrointestinal tract and preventing the progression of the pathological process in the organism.

Positions for defense

1. The basis of morphofunctional disorders of the intestine in acute pancreatitis lies membrane-destructive processes of its tissue structures, determined by the intensity of lipid peroxidation, phospholipase activity, and the degree of tissue hypoxia. The degree of the indicated disorders correlates with the severity of the pathology and justifies the use of the antioxidant mexidol in the therapy of enteral insufficiency in acute pancreatitis.

2. The inclusion of the drug in the complex of therapeutic measures for the edematous form of acute pancreatitis leads to rapid restoration of the morphofunctional status of the intestine, preventing the progression of membrane-destructive phenomena of intestinal cellular structures already from the first days of therapy. In the destructive form of the disease, the positive effect of the drug is less significant and begins to manifest only after the fifth injection of the drug.

3. The use of mexidol in the treatment of patients with the edematous form of acute pancreatitis contributes to the correction of enteral insufficiency, manifested by rapid positive clinico-laboratory dynamics, which proves the high effectiveness of the drug in the therapy of this pathology.

Implementation into practice

The developed dissertation positions have been implemented in the practical activities of the clinical hospital of emergency medical care in the city of Saransk, and included in the educational program for students at the Department of Faculty Surgery, Medical Faculty of Mordovia State University named after N.P. Ogaryov.

Personal works

The main results of the work were reported and discussed at the Ogaryov Readings — scientific-practical conference of Mordovia State University (Saransk, 2003–2006), the VII International Conference «Bioantioxidants» (M., 2006), the Scientific Conference of Young Scientists of Mordovia State University (Saransk, 2005–2006), the XII International Scientific-Practical Conference «Health and Education in the 21st Century» (M., 2006).

Publications. Eight scientific works have been published on the topic of the dissertation.

The dissertation was carried out in accordance with the research plan on the topic of Mordovia State University named after N.P. Ogaryov «New methods of intensive therapy and resuscitation in surgery and experiments» (state registration number 019900137470).