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TBILISI STATE MEDICAL UNIVERSITY

ANNALS OF BIOMEDICAL RESEARCH AND EDUCATION

2001 October/December, Volume 1, Issue 4

Lymfhogenic Pharmacotherapy in the Treatment of Pyo-inflamatory Processes


Tengiz Akhmeteli, Nodar Lomidze, Guram Gvasalia, Lali Ahmeteli
Department of Surgery #1, Tbilisi State Medical University, Georgia

Abstract
Lymphatic system plays the leading role in the pathogenesis of any infectious process and endogenous toxemia. We considered this fact and studied experimentally and clinically opportunities of endolymphatic antibacterial, detoxification and immunomodulational therapy. Afferent antibacterial and detoxification therapy is carried out through the catheter in the lymphatic duct of foot or calf region. Antibiotic, fluid for dialysis, bacteriophag and placental interferon were injected endolymphaticaly. At first, kinetics of bacteriophag and the opportunities of antibacterial irrigation were confirmed experimentally in healthy dogs with peritonitis. On the strength of this experiment endolymphatic phagotherapy was used in the treatment of 26 patients with peritonitis. Endolymphatic antibiotic therapy, detoxification and immunomodulation with Plaferon, were used in patients with local and generalized peritonitis, destructional appendicitis, appendicular infiltrate, periappendicular abscess, acute pancreatitis, gynecologic suppurative diseases and acute paraproctitis. Analysis of the results from the control group shows that the lymphogenic therapy of pyo-inflamatory diseases is very effective, which is proved by the results of bacteriologic, endogenous toxemia and immune status studies

Keywords: pyo-inflamatory diseases, lymphogenic antoboiticotherapy, immunomodulation, detoxification, EPR Introduction Material and Methods
Our experiment was held in the presence of the following generalized pyo-inflamatory diseases: suppurative peritonitis (diffuse and universal, 139 patients), destructional appendicitis (149 patients), periappendicular infiltrate (11 patients), acute suppurative pancreatitis (14 patients), gynecologic suppurative diseases 15 patients), abdominal abscesses (17 patients), putrid-necrotic and anaerobic paraproctitis (38 patients). For direct endolymphatic therapy, catheterization of the lymphatic vessel was carried out from the dorsal surface of the foot; indirect endolymphatic - lymphotropic therapy was held from the calf level (systemic lymphotrofic) and from the Brun's point (regional lymphotropic). Lymphostimulationwas done by injection of Lidaza in cases of the last two methods. For acute

ithout doubt, lymphatic system plays very important role in the pathogenesis of any pioinflamatory diseases and endogenous toxemia. With the help of specific barrier, draining, transport and immunologic function it plays an important role in the hard process of localization, neutralization and elimination of microbes and toxins of different genesis. Without functions of lymphatic system body defenses against infectious processes or just its risk factors are so weakened that there arises a real danger of generalized inflamatoryreaction, sepsis and multiorgan failure. Proceeding from this, we can conclude, that in case of pyo-inflamatory diseases, lymphatic system must by all means, in the list of defenses and the body's endoecologic rehabilitation must be carried out purposefully (2).

TBILISI STATE MEDICAL UNIVERSITY

ANNALS OF BIOMEDICAL RESEARCH AND EDUCATION

2001 October/December, Volume 1, Issue 4


pancreatitis we catheterized round ligament of liver surgically or laparoscopicaly. For antibacterial therapy we injected Gentamicin, Ampicillin, Claforan and Cefataxime into the lymfhatic system once a day with 1/2 or 1/3 of the 24-hour therapeutic dose. We were pioneers in performing endolymphatic injection of Bacteriophag and phagotherapy of suppurative peritonitis. Before establishment of this method, the kinetics of Bacteriophag in the lymphatic system was studied in dogs. Catheterization of peripheral limphatic vessel for afferent therapy was conducted from the hind paw. For studies of the central lymph we drained thoracic lymphatic duct in the neck. During experimental Staphilococcal peritonitis we studied staphylococci in the central lymph and endolymphatically injected phag particles in the periphery. For clinically verified staphylococcal peritonitis, endolymphatic phagotherapy was used in 26 cases. For endogenous detoxification, lavage of the lymphatic system was conducted by NaCl isotonic solution or Hemodez (400-500 ml) infused into the lymphatic vessel during 6-8 hours. To these solutions we added spasmolitic, disagragative preparations and inhibitors of proteolysis (No-spa, Trental, Kontrical). As one of the objective criteria of effectiveness of the treatment, we measured degree of endogenous toxemia, which was estimated dynamically by specific enzymatic markers (Alaninaminotransferase, Aspartataminotransferase, Creatinaze, Lactatdehidrogenaze, Base phosphatase), we calculated number of medium molecular oligopeptides (1), index of leukocyte intoxication (ILI) was calculated by Calf-Calif formula (1941), the degree of toxicity of plazma was measured by biotest of the live organism-test of Paramecia. In the same plane we studied clinically highly informative specific markers pro- and antioxidative systemic components of superoxidative oxidation of lipids by the electronic paramagnetic resonance spectrometry of the blood. Activity of the antioxidant enzymes was measured by biochemical method with spectrophotometry. To estimate the status of the organism's immune system, we measured percentage of B and T lymphocytes and their subpopulations (T-active, Thelper, T-suppressors, index of immunomodulation), quantity of immunoglobulins of 3 classes: G, A and M in the blood. Activity of neutrophiles was discussed according to 3 criteria: phagocyte number, index and percent of digestion. Activity of a and g interferon was measured by in vitro productive ability of leukocytes. For lymphogenic immunocorrection we used production of our home country, immunomodulator Plaferon-LB, which was injected endolymphaticaly and lymphotropicaly once a day during the postoperative period (36 patients). Patients of the control group were followed only by systemic immunocorrection with plaferon intramuscularly or sublingually.

Results and Discussions


Most frequent (68% cause of inflammation in patients with peritonitis is colonic bacteria, but among them E.Coli mentioned above is characterized by high firstline resistance to many antibiotics. Studies of sensitivity showed that so widely used antibiotics as are Cefataxime, Amikacin, are effective only if used in high concentrations (32 mg/ml), which is impossible to achieve when injected systemically. Selective endolymphatic injection increases effectiveness of the preparations mentioned, because by this route concentration is for several times higher, than that achieved in plazma. Sensitivity of microflora regarding Bacteriophag was too low and no more than 53%, but after the adaptation of Bacteriophag in respect to species of bacteria in the hospital the sensitivity could be increased up to 80%, which enabled us to use endolymphatic phagotherapy for suppurative peritonitis. The experiments, held previously, showed that endolymphatically injected Bacteriophag in intact animals cannot cross lymphatic barrier. Bacteriophag can overcome lymphatic barrier and enter systemic lymph only if injected with Hialuronidase endolymphatically. During pyo-inflamatory diseases, e.g. suppurative peritonitis, the lymphatic barrier is open for Bacteriophag and afferently injected phag particles enter central lymph in high concentrations and eradicate bacteria that cause infection. This effectively increases main functions of lymphatic system: to localize, inhibit and eliminate the microflora, to prevent spread of bacteria and their toxins. Besides, as during pyoinflamatory processes the antibacterial agents spread retrogradely- from lymphatic flow to the inflammatory tissue (unlike the norm), the prospects of the endolymphatic phagotherapy becomes more and more reliable. The aforementioned effect is achieved only while infusing Bacteriophag endolymphaticaly. In a short period, after the infusion is completed, phag particles disappear from the central lymph. It leads to the need of monitorial infusion of bacteriophag. During treatment of generalized peritonitis, while performing endolymphatic detoxification and irrigation of the lymphatic pool, we take into account the fact, that in case of nondrained thoracic duct and inhibited detoxification by the liver, massive amount of toxins may enter blood from the lymph and there arises a real danger of iatrogenic endotoxic generalized reaction, even endotoxic shock may develop. Because of the

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TBILISI STATE MEDICAL UNIVERSITY

ANNALS OF BIOMEDICAL RESEARCH AND EDUCATION

2001 October/December, Volume 1, Issue 4


above mentioned, me don't perform endolymphatic detoxification during the postoperative 24 hours. The contraindication is also nonstabile hemodynamics, especially due to infectious-toxic shock. To decrease the iatrogenic toxic effects (result of entolymphatic detoxification) endolymphatic procedure was carried in conjunction with forceful diuresis or plasmapheresis. The importance of the lymphomicricirculation failure in the pathogenesis of acute pancreatitis is well known, toxolymphy in acute pancreatitis is reported, besides, the level of toxins in lymph exceeds the level of toxemia. So, influence on the lymphatic system, improvement of lymphatic microcirculation in acute pancreatitis is pathogeneticaly approved. To have an influence on the lymphatic system in acute pancreatitis we catheterized tissue, rich of lymphatic vessels, around the round ligament of liver. In some cases laparoscopy was used for control. Trough the catheter we injected solution, which contained Novocain, Platifillin, Papaverin, or Nospa, Kontrical. One dose of injected solution is 200-300 ml., which is needed for spreading over the entire length of the pancreas. Small number of studies doesn't allow us to make the last conclusion, but we can say, that the general impression is hopeful. This method also was effectively used in acute cholecistitis. 149 patients operated on the destructional appendicitis were followed by lymphogenic antibioticitherapy. Endolymphatic, systemic lymphotropic and regional lymphotropic antibioticotherapy was used. Metronidazole was added in the form of either pills irrigational preparation. The comparison with the control group of patients confirmed the superiority of lymphogenic antibioticotherapy, included in the complex of treatment. In the main group of patients the following was observed: general condition improved faster, sleep normalized, body temperature returned to normal levels 1-2 days earlier, the peripheral blood analysis shoved decreased leucocytosis with decreased numbers of immature cells, peristaltic regenerated faster. Postoperative wound complications were relatively rare - the incidents of suppuration decreased more than twice (from 7,4% to 3,0%). For the periappendicular infiltrate endolymphatic antibioticotherapy was used without systemic antibioticotherapy in 11 patients. The results were evaluated according to the temperature reaction, symptoms of intoxication and rate of diminution of the size of the infiltrate. The results were compared to those of the control group (11 patients) who received standard treatment. It appeared that the positive dynamics of the process was two days ahead the control group. The infiltrate did not suppurate in any case. As for the control group, abscess formed in one case and a surgical intervention was needed. The results of endolymphatic antibioticotherapy in acute paraproctitis show that endolymphatic monotherapy with third generation cephalosporins is sufficient and markedly decreases the rates of infiltrate absorption on the stage of infiltrate or postoperative patients with mild to moderate disease course. For the severe paraproctitis, particularly nonclostridial and clostridial anaerobic paraproctitis and ascending lymphangitis, endolymphatic antibacterial therapy must be used in conjunction with the systemic massive antibioticotherapy. Metronidazole preparations must be injected endolymphaticaly. Endolymphatic and systemic therapy with Penicillin is indicated for anaerobic clostridial paraproctitis. For the gynecologic suppurative processes (salinities, salpingooophoritis, pelvioperitonitis) endolymphatic antibioticotherapy was conducted effectively. In case of the encircled process endolymphatic monotherapy gives desirable results. The same refers to the pyoinflamatory diseases of soft tissue (post-injection abscesses and infiltrates of buttocks, etc.). We have established new method of immunocorrection in peritonitis: lymphogenic injection of Plaferon LB (endolymphaticaly and lymphotropicaly). The comparison with the results of sublingual and intramuscular Plaferonotherapy showed significantly higher activation of the studied immunologic indicators, especially with endolymphatically injected Plaferon. The action of endogenic interferon g obviously increased, higher was the percent of T lymphocytes, active and helper fractions (p<0,05), phagocytic index (p<0,001) and the end of phagocytosis (p<0,005). The results of lymphoplaferonotherapy on 5th day were the same as those got on the 8-10th day of intramuscular and sublingual therapy with Plaferon. It confirms that the activation of the immune system with lymphogenic Plaferonotherapy is faster and more effective. The studies of pro and antioxidant system show that intensification of the oxidative process, increased production of nitrogen oxide and failure of the antioxidative system take place in suppurative diffuse and universal peritonitis. All of the aforementioned assists to the imbalance between pro- and antioxidative systems, inhibition of organism's compensative reactions, and development of proliferative processes and appears with the development of hypoxia and oxidative stress. The bases of positive clinical results after the endolymphatic as well as lymphotropic therapy, is the regeneration of dysfunctions on the molecular level, normalization of the oxidative processes. So, with the use of lymphogenic methods of therapy, the activation of the peroxidative system decreases, which

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TBILISI STATE MEDICAL UNIVERSITY

ANNALS OF BIOMEDICAL RESEARCH AND EDUCATION

2001 October/December, Volume 1, Issue 4


predisposes to the development of compensationalregenerative reactions in the organism. Also must be noted, that the Fe+3 transferin system is the least sensitive to this treatment, which points to the low level of proliferative processes in the organism. Thus, the barrier, drainage and immunomodulation functions of lymphatic system were chosen as the "targets" therapeutic action in the complex medical treatment of suppurative inflammatory diseases. By the application op lymphogenic methods at hospital conditions, the control of major functions of lymphatic system was provided, which enables us to achieve high concentration of antibacterial preparations in inflammation sources, the localization, suppression and elimination of the pathogenic microbes at the level of lymphatic barrier, the mobilization of immunity and effective detoxification at the cell-systemic level. Endolymphatic phagotherapy of suppurative peritonitis, which was applied by us for the first time in practice, has real perspectives of future application.

References
1. Gabrielian N.I., Dmitriev A.A., Kulakov G.P. - The diagnostic value of middle molecule determination in blood plazma in nephritic diseases. // Klin. Med. 1981. 10.38-42. Levin I.M. 35 year of practical lymphology. - Collected materials from the congress of Russian lymphologists. Moscow. 2000. 11-11.

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