The choice of methods of therapeutic apheresis in multiple organ failure

Extracorporeal detoxification methods, immuno- and reocorrection are an integral part of therapeutic measures in the broadest range of diseases associated with severe endogenous intoxication .

In acute inflammatory diseases of the thoracic and abdominal cavities – severe pneumonia, abscesses and gangrene of the lung, mediastinitis, acute pancreatitis, peritonitis of different etiology, infectious diseases, as well as extensive burns and severe trauma, "crush syndrome", sepsis and eclampsia accumulation of endogenous toxins largely determines the severity of pathology and general outcome of disease. Thus even timely surgical intervention and the most modern medicines and broad-spectrum antibiotics are not able to eliminate the severe endotoxemia and restore immune defense system in such patients.

The diverse nature of the accumulating slag metabolites and endotoxins defines an integrated approach to the selection of efferent therapy optimum tactics consisting of two main groups of methods. The first of them is based on the possibility of using sorbents for medical purposes for fixation of different substances in the circulating blood and their subsequent disposal. Another group includes methods of withdrawal of harmful substances along with some part of the blood – plasma.

Efficacy sorption methods depends on the properties of sorbents and the characteristics of the absorbed substances, including molecular weight, charge, degree of hydrophobicity or hydrophilicity, the presence of free radicals, etc. Passing the blood through a column of adsorbents (activated carbons, neutral and charged resin immune hemosorbent) called direct hemoperfusion (Direct HemoPerfusion, DHP). In the CIS countries, these methods traditionally called hemosorption [1, 2]. Applied to hemosorption on activated charcoal is also used the term "hemocarboperfusion" [3]. If sorption cleaning undergoes a blood plasma only, they talk about a specific or non-specific plasma adsorption.

Detoxification using hemosorption stabilize the patient's condition in the critical status [4]. With this sorbent can be detained both living and dead microorganisms already. We were convinced of their own experience, spending hemosorption in victims of mines and explosive wounds and patients at the height of "Pseudomonas" sepsis. Blood culture fr om blood flowing into the sorbent, and the sorbent itself after the procedure, identify the abundant growth of this pathogen, while the blood flowing fr om the sorbent caused growth only single colonies. Simultaneously, increased sensitivity of the blood cultures to used antibiotics. For complete elimination of purulent resorptive fever or sepsis deployed traditionally required from 2 to 7 sessions of hemosorption [3, 5].

Apart from the usual non-selective hemoperfusion increasingly used selective adsorption methods endotoxins and cytokines [6, 7]. In particular, it was possible endotoxin removal by selective absorption fixation on the fibers of polymyxin-B in the case of sepsis and septic shock caused by Gram-negative bacteria [8]. Selective sorbents based on polymyxin "Liposorb" created in Belarus, also showed its effectiveness in Gram-negative sepsis [9].

It should be noted that practically all selective hemo- and plasmasorbents consist of biospecific component (proteins, peptides, amino acids, nucleic acids, antibiotics, etc.) immobilized on neutral polymer matrix, which certainly limits the range pathochemical products removed they from blood. In particular, anti- endotoxin hemo- and plasma sorbents are indifferent to other endogenous toxins that accumulate in Gram-negative sepsis, for example, the products of lipid peroxidation, serine protease components of the kallikrein-kinin system, "middle molecules " and a variety of other substances hydrophobic and hydrophilic nature.

Moreower, during such endotoxin adsorption techniques blood usually stabilizes using heparin. Therefore I.N.Soloveva and A.A. Ragimov [10] believe that the high risk of bleeding due to heparinization is contraindicated for selective sorption of endotoxin .

In this regard, the use of non-selective sorbentswith their widest range of phagocytic activity has been, is and will be one of the main approaches in the extracorporeal therapy of critical states. First of all, it refers to the so-called deligand hemosorbents derived from various carbon materials and known under the brand name HSGD (Hemosorbents granulated deligand, Kiev).Due to the nature of its porous structure, these hemosorbents ten times better than a conventional activated carbons in capacity in relation to the protein-bound and membrane-acting toxins, proinflammatory cytokines, bacterial poisons, including lipopolysaccharide of gram-negative bacteria, "middle molecules," some hydrolases and a variety of pathochemical other component [11].
          These sorbents as synthetic hemosorbents previous generation (SKN, SUGS) can serve as a matrix for the immobilization of various biologically active molecules, including proteins, nucleic acid, heparin and other sulfated polysaccharides [12]. HSGD type sorbents can be used in both in the form of coated and uncoated, and in the latter case, their capacity is still sufficient for multifactor cleaning, especially since some types of coatings, so-called "diffusely transparent" and "superclear" not only reduce, but can even improve absorbency deligand hemosorbents [13] .

      When hemosorption circulation derived from leukocytes overloaded with microbes that prevents their adhesion to the vascular endothelium, especially in the affected areas last circulating toxic products, with subsequent decay and further destruction of endothelial (syndrome of "WBC regional standing"). Special studies show an increase in the number of dead white blood cells as increasing severity of septic complications [14]. Furthermore, the sorbent and the retained most adhesion-active platelets that when returning into the bloodstream may be nuclei for formation of platelet aggregates with induction of consecutive stages of DIC.

        Recently, of particular interest are some nonspecific effects hemosorption promoting acceleration of reparative processes in the affected organs and tissues [15].

       Sorption method of extraction of toxic products from the body can be also implemented entirely bloodless method. We are talking about enterosorption [16, 17], using, in particular, the physiological process of filtration and reabsorption of fluid from the bloodstream to the intestinal lumen and back.

     Thus, biologically active substances permeant from the liquid portion of blood are contacted with enterosorbent taken inside it and fixed on it and together with them excreted. Given that the intestinal villi are able to pass all of the ingredients, the molecular weight is lower than the weight of albumin, it becomes clear enterosorption effectiveness in eliminating endogenous intoxication, although the efficiency and yield of adsorption of toxic substances directly from the blood flowing through the column hemosorption [18]. Moreover, given the intense processes of decay and fermentation paresis of bowel and peritonitis, it is also desirable intestinal lavage with addition enterosorbents that should prevent the entry of toxic substances into the bloodstream.
   Moreover, given the intense processes of decay and fermentation paresis bowel and peritonitis, it is desirable intestinal lavage also with addition enterosorbents that should prevent the entry of toxic substances into the bloodstream.

Among the many mechanisms of therapeutic action enterosorption one of the most important is its beneficial effect on the intestinal biocenosis [19], in violation of which currently is associated with a wide array of serious diseases and progression of pathological conditions. It should also be emphasized that the above thesis about the positive influence on the sorption methods reparatory potential of affected organs and tissues [15] is fully valid for enterosorption. This effect is realized at the level of deep restructuring of epigenetic activity synthesis vast ensemble of cellular proteins [20].

Nevertheless, it should be noted that many of the critical state and, in particular, sepsis develop against the initial immunosuppression and emerging endotoxemia contributes to further oppression of immune protection. Therefore, even against active sorption detoxification body is unprotected against the possibility of activation of a secondary infection, such as fungal or viral.
From this viewpoint, the pathogenetic most justified is to use plasma exchange when leaving the plasma composition derived products are not only toxic, but also components compromised humoral immunity. At the same time it should be noted that virtually all available in this plasma is active antibodies are usually associated with pathological antigens entered in the respective immune complexes. Similarly, all available opsonins and complement are already spent in the preceding reactions phagocytosis, making it impossible to capture pathogens even quite normal phagocytes. Replacement of removable plasma with fresh frozen donor plasma can quickly restore these natural defense mechanisms, without which the most powerful broad-spectrum antibiotics are powerless, and they are often hepato- or nephrotoxicity may exacerbate the patient's condition.

After the massive plasma exchange in the amount of 0.7-1.5 of circulating plasma volume (CHV), often comes a quick change in the course of the disease and reverse the development of organ disorders [21, 22]. V.Yu.Pronin et al. [23] emphasized that in all cases of septic complications and septic shock as early as possible is necessary to carry out therapeutic plasmapheresis. Enabling courses of plasmapheresis in patients with abdominal sepsis in 50% -100% CPV in the early postoperative period, not only reduced the toxemia, but also effectively stimulated immunity, stopped manifestations of DIC with the restoration of the affected parenchymal organs and 19.5% reduced mortality [10, 24]. The courses of plasmapheresis proved useful and at septic complications after surgery with remove a brain tumor [25]. Using plasmaphersis showed its usefulness in the treatment of acute purulent mediastinitis [26, 27]. Plasmapheresis was efficient also at concomitant renal disease, when in addition to the partial replacement of their functions ensured also immunomodulatory effects, as well as in children with sepsis-induced multiple organ failure [28] .
Positive results were achieved also with the use of plasmapheresis in the complex treatment of obstetric sepsis and septic shock, especially in the early stages of the process. The level of mortality can be reduced from 80% to 15%, and postpartum women stay in the hospital is reduced from 42.4 to 24.6 bed days [29, 30, 31].

At obstetric sepsis plasmapheresis there is often performed as partial plasma exchange in two stages. For preoperative preparation after hemodynamic stabilization and elimination of hypovolemia held therapeutic plasmapheresis with removal of 50% CPV and wholly refund donor fresh frozen plasma. In the early postoperative period after stabilization of hemodynamics, gas exchange and renal excretory function held repeated sessions of plasmapheresis with removal of up to 70% CPV and also with the absolute recovery of fresh frozen donor plasma [32].
It must be borne in mind is quite a high risk of bleeding from acute gastric ulcers and erosions. Mucous membranes of the gastrointestinal tract, wh ere they begin to form so-called stressors ulcers are among the most "weak" and fragile sites of the body. For example, such an ulcer with a frequency of up to 15-40% are formed after heavy operations and trauma, shock and stress [33].
The mechanism of acute ulcers of the gastrointestinal tract also associated with the effects of local microcirculatory disorders occurring in sepsis and septic shock circulatory. Occurrence of vasospasm and the deterioration of the blood supply to the intestines, not in this situation relating to the number of vital organs, first is physiologically justified. However, full recovery of the microcirculation is often delayed, which leads to the development of hypoxic and ischemic tissue damage.

Specific clinical studies of L.Oud and M.T.Haupt [34], 12 patients undergoing septic shock, showed that the pH in the bulk of the gastric mucosa is reduced from 7.33 after stabilization state to a total of 7.26 at 24 hours, 7 20 - 36 hours and remained reduced (7.24) after 48 hours. Thus, gastro-intramucous acidosis requiring probably use enterosorption, arose and persisted for at least 48 hours in patients, even derived from septic shock, regardless of the normalization of hemodynamics, gas exchange and CBS in the bloodstream. All this undoubtedly contributed to the development of destructive processes in the mucous membranes, until the appearance of acute erosions and ulcers. The severity of these processes is confirmed by the fact that, despite the restoration of central hemodynamics and gas exchange, 10 (83%) of the 12 patients examined in the future still died.
DIC syndrome almost naturally accompanies critical condition. In this phase of 2-4 days hypercoagulable DIC replaced anticoagulation and local destruction of the mucous membranes with denudation and erosion of vessels, which creates prerequisites for the emergence of bleeding, which due to systemic anticoagulation may take profuse character, giving the high (up to 40-60 %) mortality.

Gastroscopy gives a picture with multiple surfaces of mucosal erosions. Sometimes it is possible to note the signs of the syndrome Mallory-Weiss, ie cracking of the gastric mucosa. In the rest of the digestive tract can also attack autolysis with massive rejection of the villi, leading to an increase in toxicity.
 For prevention and treatment of DIC used moderate systemic heparinization (up to 40-50 thousand units a day), glucocorticoids, and other infusion dextrans or   hydro-ethyl starch solutions, introduction trental and curantylum. During profuse bleeding therapy of fresh frozen plasma, in subacute and chronic forms of DIC they held plasmapheresis also [35]. Plasmapheresis removes activators of blood hemostasis products paracoagulation microparticles destroyed platelets, activated blood factors [10, 36, 37].

Carrying a massive plasma exchange, when along with the removal of toxic products and the replacement is carried out fresh frozen donor plasma containing all the normal components of the blood coagulation system, allows to break the vicious circle formed without giving opportunity to eradicate manifestations of DIC. We note here that the donor plasma, as well as whole blood donation, with the infusion of this parallel without prior removal of the factors that led to the DIC will be subjected to the same exposure to toxic substances, which resulted in the emergence of the DIC, and therefore such tactics can only certain way postpone the inevitable adverse outcome.
On the other hand, a few hours after plasma exchange we can observe a tendency to normalization of coagulation and bleeding stops. In this case, plasma exchange should be resorted to, without waiting for the deployment of the full picture of DIC with profuse bleeding, ie, such therapy should be preventive in nature and start at the first signs of impending complications – increased bleeding, identifying erosive changes of gastric mucosa and signs of coagulopathy, detected by laboratory study [38].

On the other hand, has already arrived in hemorrhagic complications plasma exchange performing is often pulled out of fear of increased bleeding during heparinization. This tactic is very dangerous, because without addressing the causes of DIC syndrome it is almost impossible to stop, and temporizing with the only threatens the development of irreversible multiple organ disorders.
In such cases, plasma exchange should be carried out without any use of heparin using conventional blood anticoagulant based solution of sodium citrate (ACD-A, CPD). We use such tactics as early as possible is present only when the threat of bleeding. It should be recalled, and the high risk of hemorrhagic complications during hemodialysis or hemofiltration, which is also used in heparin. Fraxiparin and other low molecular weight heparins in this sense are less dangerous, but they do not always allow to achieve adequate anticoagulation, which leads to a rapid thrombosis of the extracorporeal circuit [39].

Attempts to use hemodialysis or hemofiltration in the treatment of sepsis showed their low efficiency. However, as intermittently, and in the extended, hemofiltration does not provide significant reduction in mortality [39]. This is due to the fact that larger molecules, ranging in size from 10 to 50 kDa and the protein-bound toxins, which play a vital role in the biochemistry of sepsis and multiple organ failure are not removed by dialysis and hemofiltration. You can get them only if hemosorption on deligand hemosorbents or by plasmapheresis with replacement donor plasma volume removed, to achieve favorable outcomes in 80% of these patients [40, 41, 42, 43, 44, 45].

Moreover, in isolated renal-replacement therapy does not occur adequately restore immune defense systems [46, 47].

Of course, the presence of acute renal failure associated with decreased rate of diuresis until anuria justifies the use of such methods are dialysis-filtration removing excess fluid and electrolytes, but by themselves they are not very effective in restoring its own renal excretory function. On the other hand, after hemosorption or plasma exchange, when removed "toxic pressure" from the kidneys, the next day can be obtained over 700 ml of urine and with further positive diuresis dynamic. Only in combination with a special application schema deligand hemosorbents dialysis may be used in the treatment of various embodiments of liver and multi-organ failure [11].
Additionally, we note that in septic shock develops extremely critical condition with severe hemodynamic instability, in which the absence of an effective detoxification break the vicious circle of possible complications is virtually impossible, despite the fact that the performing of the procedure itself is associated with some risk. It should be noted that the use of the Russian devices "Hemofenix" with membrane plasma filter "Rosa" when the priming volume of the system does not exceed 70 ml and variable blood volume will be only about 9 ml, demonstrates the feasibility of a membrane plasmapheresis successful even in cases wh ere systolic blood pressure is only supported sympathomimetics at about 90 mm Hg. At the same time, some stabilization of hemodynamics, makes it possible to reduce the doses of sympathomimetics observed as elimination of toxic substances directly during the procedure [38].

Note also that the combined use of specialized laser irradiation of blood, its ozonation and indirect electrochemical oxidation contributes to our opinion the development of more persistent therapeutic effect.

Thus, the data can justify the optimal algorithm efferent therapy in critical conditions. As a first step, especially in cases of infectious and inflammatory diseases and their etiology of systemic complications, the most justified holding hemosorption using conventional non-selective sorbents (VNIITU-1, SKN and especially HSGD) with possible application in the perfusion circuit laser irradiation of blood or adding sodium hypochlorite as an agent for the indirect electrochemical oxidation.

In the second stage, the next day, in the amount of plasma exchange expedient 1.5-2.5 liters of plasma, as a parallel laser irradiation of blood with the aim of deepening detoxification and immune correction. Often these two sessions is enough to achieve a stable positive effect with the restoration of the liver, kidneys, lungs, brain. Later the body, relying on additional enterosorbtion support, it will be able to independently ensure a favorable outcome.

With such tactics in patients with acute pneumonia were able to reduce the time of their stay in a hospital bed from 24.1 to 19.9 days, increase the frequency of complete recovery from 21.6 to 42.9% and to prevent deaths [48, 49 Voinov V.A. et al., 2007, 2013]. In severe multiple organ failure, which develops in acute inflammatory diseases of the chest and abdomen, sepsis and eclampsia, mortality rate was reduced from 74% to 31% [5]. Similar data on mortality reduction from 59 to 11% in children with multiple organ failure caused by a pale toadstool poisoning were obtained using hemosorbents HSGD combined with massive transfusion highly refined human serum albumin [11].

Summarizing, we note that plasma exchange, which removes the totality present in the liquid portion of blood and toxic immunosuppressive factors in the treatment of critical conditions naturally complemented by modern technology hemosorption. Enterosorption with its features continuous detoxifying action and correction of intestinal biocenosis makes this list exhaustive efferent methods.

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