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Extracorporeal Detoxification in Abdominal Sepsis in Cancer Patients

The purpose is to evaluate the detoxification effects of the polymyxin sorption columns and filtration detoxification using polymethyl methacrylate membranes in abdominal sepsis in cancer patients. respectively, as determined 60 minutes after completion of filtration detoxification procedure ( P <0.05). The SOFA index decreased by 4.1±1.1 points ( P <0.05). Conclusion. The use of polymyxin column sorption and filtration detoxification using a polymethyl metacrylate membrane improves the results of treatment of abdominal sepsis in cancer patients.


Introduction
«Sepsis is a life-threatening organ dysfunction caused by the body's disregulatory response to infection...» [1]. The development of sepsis is accompanied by an uncontrolled cascade of changes in the systems of inflammation, coagulation and fibrinolysis occurring simultaneously as a cycle of automatic overlapping of interdependent processes with subsequent disorders of microcirculation and tissue oxygenation, development of mitochondrial dysfunction and metabolic disorders. Multiple organ failure develops as a result of a combination of cellular, vascular, and metabolic disorders [2,3]. Under these conditions, when the functions of physiological protective systems of the organism are suppressed, the extracorporeal detoxification becomes one of the main components of the intensive care of sepsis [4][5][6].
Lipopolysaccharide (LPS) is an important infectious trigger of inflammation. The correlation between the concentration of LPS in the systemic circulation, the incidence and severity of organ dysfunctions, as well as the mortality rate in Gram-negative sepsis have been confirmed [7,8]. Over recent years, in order to inhibit the systemic effects of LPS, methods of its selective extracorporeal removal are used including polymyxin sorption [9][10][11][12]. Various multicenter studies have shown that the inclusion of the polymyxin sorption in the complex treatment of abdominal sepsis contributes to a decrease of the activity of endotoxininduced inflammation, and an increase in the survival rate in these patients. However, in different studies, there were discrepancies in the evaluation of clinical effects of column sorption presumably due to heterogeneity of patient groups [13,14].
Цель исследования -оценить детоксикационные эффекты использования колонок с полимик-PMMA membrane in sepsis and septic shock was reported in a number of studies. For example, O.  presented the results of the use of filtration detoxification using the PMMA membrane in 55 patients. A decrease in the IL-6 level after perfusion of one volume of circulating blood through the filter, a significant reduction in the dose of pressor amines in cases of septic shock, an increase in PaO 2 /FiO 2 in sepsis-induced acute respiratory distress syndrome (ARDS) were demonstrated [16]. Taka-aki Nakadaet et al. (2011) reported a decrease of IL-6 concentration in blood, improvement of hemodynamic parameters, relief of dysoxia, and an increase of the urine output when PMMA membrane was used in patients with sepsis [17]. A number of studies had shown the effectiveness of removal of (a) proinflammatory cytokines from the systemic blood flow, which led to early recovery of homeostasis in septic shock, and (b) anti-inflammatory cytokines (IL-10), which contributed to the optimization of the cytokine balance including «immune paralysis» associated with a decrease in monocytic HLA-DR. These data have a rational explanation from the point of view of «peak concentration hypothesis», «cytokine sepsis theory», and «damage chain reaction» [16,18,19].
Currently, sepsis is considered the most common cause of nosocomial ARI. The hospital mortality in sepsis and ARI reaches 70%, which is almost twice as high as in patients without ARI [20,21]. Over recent years, on the basis of experimental and clinical studies, pathogenetic mechanisms of ARI in sepsis have been specified. The development of ARI is the consequence of impairment of renal haemodynamics with the formation of cortical hypoperfusion and medullary overflow; direct interaction of LPS with cellular structures of the kidney; the activation of immune cells, accompanied by a massive release of inflammatory cytotoxic molecules; endocrine dysregulation; mutually complicating cross-effects of the systemic inflammation, multiple organ disorders and ARI [22][23][24][25][26]. This determines the pathogenetic validity of the initiation of the application of the detoxification by filtration in the early stages of sepsis-associated ARI, as well as the choice of the method and dialysis membrane, taking into account the pathogenetic mechanisms of its development. However, at present, these issues remain the subject of scientific discussions and their solution requires further scientific research.
The purpose of the study was to evaluate the detoxification effects of the polymyxin column sorption and filtration detoxification using polymethyl methacrylate membranes in abdominal sepsis in cancer patients.
Дополнительно в целях изучения детоксикационных эффектов диализной мембраны РММА серии «BK-1,6 F» In 173 patients, acute renal injury (ARI) was diagnosed in the structure of organ impairment, in 61 patients it was diagnosed in a combination with acute respiratory distress syndrome (ARDS). The baseline severity was 26.3±3.3 points according to the APACHE-II scale, 10.2±2.5 points according to the SOFA scale, and 4.3±1.8 points according to the qSOFA scale.
All patients received a standard sepsis therapy [1]. Additionally, polymyxin column sorption using the Toraymyxin PMX-20 R column with immobilized polymyxin B («Toray Industries», Japan) was additionally included in the complex treatment of 86 patients. The polymyxin sorption was carried out for 2-6 hours after sepsis was diagnosed at EAA values greater than 0.5. The blood flow rate was 80-150 ml/min; the duration was 120-240 min; the frequency was 2-3 sessions with a 24 hour interval.
With the development of ARI and ARDS, filtration detoxification (hemodialysis, hemofiltration, hemodiafiltration) using a dialyzer with a BK-1.6F polymethyl methacrylate membrane, pore diameter is 100A («Toray Industries», Japan) was included in the complex treatment of 144 patients. Detoxification was carried out using the Multifiltrate apparatus («Fresenius», Germany). The vascular access was via V. subclavia/ V. femoralis. The perfusion rate was 150 ml/h. The flow rates of the substituate and dialysate were 1000-1200 ml/h. Heparinization is an unfractionated heparin at a dose calculated taking into account the parameters of activated partial thromboplastin time. Detoxification was carried out for 8 -12 hours with a change of the dialyzer once every 4 hours, which was due to a high but tied for time sorption activity and the appearance of signs of thrombosis in the dialyzer.
Along with a general clinical examination, procalcitonin (PCT) levels and endotoxin activity in the blood were studied. Procalcitonin was determined by a quantitative method (Brahms Diagnostica GmbH, Germany). The endotoxin activity assay (EAA) was performed by a chemiluminescence technique on a luminometer Smart Line Tube Illuminometer («Berthold Detection Systems GmbH», Germany) using an EAA TM immunodiagnostic reagent kit. The tests were carried out while diagnosing sepsis, before extracorporeal detoxification, and 1 and 24 hours after detoxification treatment.
In addition, a retrospective analysis of filtration detoxification of ascitic fluid of patients with ovarian cancer performed to obtain its protein concentrate as a biological medium for the intraperitoneal chemotherapy was carried out to determine the detoxification effects of the «BK-1.6 F» PMMA dialysis membrane. The results of biochemical and immunological investigations of ascitic fluid and its components (protein concentrate and filtrate obtained by its filtration detoxification) and the morphological structure of protein film-like structures of ascitic fluid and its protein concentrate were also studied [27][28][29].
Анализ клинических результатов свидетельствовал о положительном воздействии полимиксиновой сорбции на течение генерализованного [30]. The total (TAC) and effective albumin concentration (EAC) with the calculation of reserve binding capacity of albumin (EAC/TAC • 100%), which allows to conclude on the degree of sorption of toxic ligands, was determined by a fluorimetric method. The intoxication coefficient reflecting the balance between accumulation and binding of toxic ligands was calculated using the following formula: ICMMM/EAC = (МMМ 254 /EAC) • 1000 [31]. The concentration of cytokines IL-1α, IL-6, TNF-α, IL-10, and IFN-γ was determined by ELISA using test-systems («Cytokine», St. Petersburg). The total amount of protein was determined by the biuret test. Cytokines are substances of a protein nature with a molecular weight lower than that of albumin and globulins and are contained in biological fluids in much smaller quantities (measured in pg/ml, whereas albumin and globulins are measured in g/l). Taking into account the fact that the total amount of protein in the ascetic fluid of patients is largely individual and can vary widely, in each sample of ascetic fluid, protein concentrate and filtrate, the cytokine concentration was recalculated by the total amount of protein and the values of their specific content were obtained.
The morphological study of solid-state film-like structures was performed by wedge-shaped dehydration [32]. The microscopy was carried out in the light and polarization modes by the Leica DMLS2 microscope.
The statistical processing of the results was carried out using the Statistica 6.0 software and Student's t-test. The difference at P<0.05 was considered significant.

Results and Discussion
Polymyxin column sorption was included in the complex intensive care in 86 patients. The method is based on neutralization of endotoxin biological activity during the polymyxin sorption by binding lipid A, which is an obligatory component of the LPS molecule, as well as sorption of activated neutrophils and proapoptotic factors. In 78 patients, 2 sorption sessions were conducted at intervals of 24 hours, in 8 cases 3 sessions were performed, which was due to the persistence of endotoxemia.
Analysis of clinical results showed a positive effect of polymyxin sorption on the course of generalized inflammation in abdominal sepsis in cancer patients. When it was included in the main treatment, in 68 (79.1%) cases, a decreases in the daily febril state from 38.7±0.3°C to 37.4±0.4°C, WBC count from 18.9±8.3•10 9 /l to 11.2±2.4•10 9 /l, neutrophil blood count from 88.1±3.2 % to 74.1±3.2 %, and SOFA index by 5.6±2.1 points (P<0.05) were observed in 24 hours after the completion of the procedure. At that timepoint, there was a decrease in the PCT level from 7.1±2.6 ng/ml to 2.2±0.4 ng/ml and EAA from 0.62±0.10 to 0.36±0.01 (P<0.05).
Only in 5 patients, inotropic / vasoactive support was carried out as previously.
The inclusion of the polymyxin column sorption into the complex intensive treatment provided a positive effect on the state of metabolism. In 63 (73.3%) patients, the normalization of lactate, blood pH and blood BE values was observed indicating the improvement of cellular oxygenation and normalization of cellular metabolism.
After extracorporeal elimination of endotoxin, improvement of lung oxygenation function was observed. Increased oxygenation index (РаО 2 /FiO 2 ) from 239.3±46.2 to 317.3±14 (P<0.05) was diagnosed. In 23 (37.7%) of 61 cases, patients on mechanical ventilation were transferred to spontaneous breathing after the completion of the sorption treatment.
The use of the polymyxin sorption in the complex of treatment of abdominal sepsis led to an improvement in the functional state of the kidneys. For example, in 49 of 53 patients (92.5%) with initial oligoanuria for more than 6 hours and an increased blood creatinine level up to an average of 246 μmol/l (210-270), the recovery of hourly urine output followed by a decreased creatinine level was observed. Only in 4 cases (7.5%), the progression of ARI and the need for renal replacement therapy was found. The obtained results correspond to the literature data indicating the significant nephroprotective effect of the polymyxin column sorption associated with the abrogation of systemic proapoptotic activity through removing the lipopolysaccharide of Gram-negative bacteria [31].
PCT and IL-6 blood levels decreased from 6.7±2.7 ng/ml to 2.3±0.6 ng/ml and from 7300±7700 pg/ml to 860±180 pg/ml, respectively were registered 60 minutes after completion of filtration detoxification (P<0.05). The parameters of the EAA test did not undergo statistically significant changes. There was a decrease in the blood lactate level from 5.6±2.3 mg/ml to 1.9±0.9 mg/ml (P<0.05). The SOFA index in these patients decreased by 4.1±1.1 points (P<0.05).
While diagnosing septic shock, in 22 (73.3%) of 30 patients, values of catecholamine index decreased from 5.2±1.2 to 2.1±0.6 after the filtration detoxification. At the same time, in 12 cases (40.0%), normalization of hemodynamics was observed and the administration of pressor amines was canceled. In 123 (85.4%) of 144 patients, the frequency of filtration detoxification was from 1 to 4 sessions. Only in 21 (14.6%) cases, the course of ARI required a long-term dialysis treatment.
The content of cytokines in the ascetic fluid of patients with ovarian cancer and its components, protein concentrate and filtrate obtained during filtration, is presented in Table. Significantly lower concentrations of IFN-γ, IL-1α, IL-6, IL-10 and the absence of TNF-α were found in the protein concentrate as compared to ascitic fluid and filtrate. In the filtrate, the content of IFN-γ, IL-6, IL-10 was significantly lower than that in the ascetic fluid, and IL-1α was not determined. At the same time, the total concentration of cytokines in the protein concentrate and filtrate obtained during filtration was significantly lower than those in the ascitic fluid, which indirectly confirms the presence of the mechanism of their sorption by a dializer membrane.
The morphological structure of film-like structures (facies) of the ascitic fluid and its protein concentrate obtained after the filtration detoxification using PMMA membranes was studied in 15 samples.
The study of the morphological pattern of solidstate facies makes it possible to make the molecular organization of biological fluids visible and to detect conformational changes in albumin in various pathological conditions. During the transition of biological liquids into the solid phase, a dry film, facies, is formed (Fig. a). Evaporation of protein-bound water leads to the coagulation of protein molecules, stretching, compression of the film and the formation of «cracks». In biological fluids of healthy people, the formation of «cracks» occurs at regular intervals from the periphery to the center, and the ends of radial «cracks» are rounded and form «arcades» and «sec- Показатели эндогенной интоксикации и содержание цитокинов в биологической среде, полученной при фильтрационной детоксикации у больных раком яичников (n=30).
Morphological changes in facies of ascetic fluid were characterized by pronounced disorders of the system and subsystem structure, accumulation of pathological proteins, toxic metabolic products. After filtration in the protein concentrate of the ascitic fluid, the restorative dynamics in both system types of film-like structures and stability of the physiological rhythm of self-recovery (recovery of circular autorhythms, radial or partially radial symmetry of «cracks») were observed (Fig. b, c). These data clearly show the detoxification effects of the PMMA membrane.

Conclusion
Inclusion of polymyxin column sorption in the complex treatment of abdominal sepsis in cancer patients contributes to prevention of the hyperactivation of immune responses at an early stage of the development, which determines the need for its timely application immediately after surgical debridement and initiation of antibiotic therapy. In the development of multiple organ failure, the polymyxin column sorption should be combined with the filtration detoxification providing extracorporeal removal of excessively produced inflammatory reaction mediators and endogenous toxic substances.