Therapeutic apheresis for sepsis

Despite all the advances in the treatment of infections and critical states, purulent- septic complications in surgery is one of the common causes of deaths. With considerable frequency of septic shock (in the U.S. - up to 500,000 patients per year, of which 100,000 die), this problem is extremely important. Mortality rate is 28.6%, and the cost per patient – $ 22.100. The general costs of caring for these patients in the United States account for 16.7 billion dollars [1].  In pediatric patients with sepsis number of such patients reaches 42,364 with case fatality rate of 10.3%. Treatment costs of one such child reach $ 40.600, and the total cost to 1.96 billion dollars a year [2]. In Western Europe, the cost of treating one patient with sepsis constitute 23.000-29.000 Euro [3].

 All this underscores the importance and urgency of this problem, still waiting for their decision.
Sepsis, obviously, is more common than it documented in the laboratory detection of various microorganisms in blood cultures. This is largely due to the early onset of antibiotic therapy in the event of inflammatory diseases and complications. Back in the 80s when studying acute pneumonia in animal experiments, we have found that within 15 minutes after intratracheal administration in healthy animals culture pathogenic pneumococci their ever found blood cultures or smears of slices of liver, kidney and spleen [4]. Therefore, almost any particularly severe, inflammatory complications can assume the presence of pathogens not only in wounds or damaged organs, but also in circulation.

It should be noted that the very development of an acute infectious process could be due to the initial immunodeficiency that developed as a result of recently transferred other diseases (even the common respiratory viral infections), adverse environmental or social factors, chronic intoxications (alcohol, drugs, etc.), not to mention the classical HIV. Proof of this is often observed at the initial stage of the disease both leuko-.and lymphopenia,

Further is developing chain mutual aggravated events. Immune system mobilizes all its reserves to combat infectious and other agents that are not unlimited, and eventually they comes exhaustion. Increase endotoxemia acts overwhelmingly all components of cellular and humoral immunity leading to an even more profound immunosuppression, which may be described as "immune distress syndrome."

The development of endotoxemia in critical conditions often described as "systemic inflammatory response syndrome," (SIRS) which may be the answer not only to infection and sepsis, but also to any aggression and traumatic stress. Thus the fore pro-inflammatory mediators, primarily cytokines, such as IL-1 and TNF-a, as well as degradation products of neutrophils, platelets and coagulation factors, complement fragments, derivatives of arachidonic acid, "granulocyte-colony stimulating factor" [5]. Yet it is not clear what causes circulating cells (macrophages, neutrophils, platelets) sent to places of injury or infection and how they interact with the vascular endothelium. It is not clear and escalating this, in general, positive biological response, in a state of shock and subsequent multiple organ failure and death.

Such excessive reactions are often counterproductive and themselves contribute to the development of septic shock, adult respiratory distress syndrome (RDS) and multiple organ failure. In the blood plasma increases rapidly content acute phase proteins synthesized mainly in the liver. They affect blood coagulation (fibrinogen), phagocytosis and bactericidal (complement, C-reactive protein). They may be anti-thrombogenic (a-1-acid glycoprotein), anti-protease (a-1-anti-trypsin, a-1- chymotrypsin), antioxidants (ceruloplasmin, glutathione). The concentration of C-reactive protein, normally extremely low, with such systemic inflammatory response rapidly increases by 10-100 times, which often reflects the scale of the manifestations of this disease. Since more than 50% of cases in the genesis of septic complications plays a significant role Gram-negative bacteria, the leading role played by lipopolysaccharide, which are permanent structural components of the cell membrane of these bacteria [6].

However, the body in response to such aggression forms also anti-inflammatory response, as a compensatory. This generates another class of biologically active substances as interleukins 4, 10, 11 and 13, growth factor-b, colony-stimulating factor, circulating  receptors-antagonists of TNF and IL-1. These mediators are still poorly understood, however, proven by their inhibition of monocytes, T- and B-lymphocytes, including proliferation of antigen-specific T-lymphocytes. As a result, developing immunosuppression, which sometimes can be very deep. This is especially dangerous, given both as previous immunosuppression, and increases with the severity of patients with septic complications. Moreover, these mediators may even suppress their own synthesis, thereby providing a restoration of homeostasis. These reactions are characterized as "compensatory anti-inflammatory reaction." The interaction between these pro-inflammatory and anti-inflammatory mediators is presented as a battle of opposing forces. If there is a balance of these forces, the homeostasis is restored. If not – then develops one or the other reaction. At the same time, and in both cases it is possible dramatic developments fatal.

It should be recognized that the deterioration of the socio-demographic indicators, with increased number of patients with an impaired immune system, until the acquired immunodeficiency syndrome, do not allow to reduce mortality in sepsis, carrying up to 1,400 people every day, despite the introduction of new therapeutic technologies [7].
Thus, septic complications develop as severe endotoxemia on the background of increasing immunosuppression, resulting in a vicious cycle to break that neither the body nor the most intensive medical therapy is not able to.

Detoxificationusinghemosorptioncan stabilizethe patient's condition[8].Whileon the sorbentmay be delayedboth livinganddeadmicroorganismsalready. It derived fromcirculating alsoleukocytesoverloaded withmicrobes,thatprevents theiradhesion tovascular endothelium, particularly in the areas ofits defeat of circulatingtoxic products, withsubsequent decayandfurtherdestruction ofendothelial (syndrome of "WBC regionalstanding.") Specialstudies showan increase inthe number of deadwhite blood cellsasincreasing severityof septic complications[9].Furthermore,the sorbentare retainedmost adhesively active platelets thatwhen returninginto the bloodstreammay be as nucleifor formation ofplatelet aggregateswiththe excitationof successive stagesof DIC.

We were convinced of their own experience, spending 80 years hemosorption patients at the height of "Pseudomonas" sepsis. Sowing of blood flowing into the sorbent, and the sorbent itself after the procedure, to identify the abundant growth of this pathogen, while the blood flowing fr om the sorbent caused growth only single colonies. Thus for the total elimination of sepsis sometimes required to 5-7 sessions hemosorption [10].

Nevertheless, even after the most active sorption detoxification body is unprotected against microbes. Perhaps the development and secondary fungal or viral organisms, against which antibiotics may be powerless and the patient's condition deteriorates again.

Therefore, the most pathogenetic justified the use of plasma exchange when removed from plasma derived products not only toxic, but also all the components of the immune system are incompetent. In this case all the available active antibodies already are associated with pathological antigens in the form of inactive immune complexes. All available opsonins and complement already had been used in previous reactions phagocytosis, making it impossible to capture pathogens even quite normal phagocytes. Fresh frozen donor plasma replacement removed plasma allows you to quickly restore the natural protective mechanisms, without which the most powerful super-wide spectrum antibiotics are powerless, and their hepato- or nephrotoxicity may exacerbate the patient's condition.
After the massive plasma exchange occurs faster turning point in a course of diseases and reverse the development of organ disorders [9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23].

V.Yu.Pronin et al. [24] emphasize that in all cases of septic complications and septic shock as early as possible is necessary to carry out therapeutic plasmapheresis. Enablingcoursesof plasmapheresisin patients with abdominalsepsisin 50%-100% CPVinthe early postoperative period, not only reduced thetoxemia, but also effectivelystimulatedimmunity,stop manifestationsof DICwith the restorationof the affectedparenchymal organsand19.5%reducedmortality[14, 25].

The coursesof plasmapheresisproved usefulandseptic complicationsafter surgeryremovalof brain tumors[11, 15]. Usingplasmapheresisshowedtheir effectivenessin the treatmentof acutesuppurativemediastinitis[26, 27, 13]. Plasmapheresiswas efficient andwith concomitantrenal disease, whenin addition totheirfunction providessubstitutionthere was also immunomodulatoryeffects[28].Plasma exchangewas effective alsoin children withsepsis-induced multiple organ failure[29].

Over the past 10 years and abroad has increased dramatically the frequency of use of active methods of extracorporeal correction of sepsis, especially in Japan, wh ere the payment for such procedures provided by the state. Besides conventional nonselective plasmapheresis increasingly used selective adsorption methods endotoxins and cytokines [30, 31, 32]. In particular, it was possible endotoxin removal by selective absorption on the toner fixation on the fibers of polymyxin-B in the case of sepsis and septic shock caused by Gram-negative bacteria [33, 34]. Selective sorbentsbased onpolymyxin"Liposorb" created inBelarus,also showedits effectiveness inGram-negativesepsis[35].However, the high risk of bleedingdue toheparinizationiscontraindicated forselective sorption ofendotoxin[20].

However,P.Toftet al.[36] in theanimal experimentshave shown thatnon-selectiveandconventionalplasmapheresissufficientlyeffective in preventingoxidativestress andthe accumulation ofgranulocytesin the lungsafter administration ofEscherichia coliendotoxinin a dose of30mcg/kg. Especially becauseifgram-negativefloraselective adsorptionof endotoxinwas quite effective, then the significant increaseof mixedflora ofsurvivalwere observed[37, 38], and in fact oftenoccursjustmixedflora. Furthermore, sorption of endotoxinhas no directeffect on thelevelof common intoxication[39].Moreover,S.V.Chermnyh[40]showed that even in ordinaryplasmapheresisendotoxin content ofgram-negative bacteriais reducedby 3.4 times.
Attempts to usehemodialysis orhemofiltrationin the treatment ofsepsisshowedtheir lowefficiency,because itremovesonly a smallpart of the poolof lowmolecular weightendotoxins. However, both asintermittently, and continuoushemofiltrationgives no significant reduction inmortality[41].Moreover, in isolatedrenal-replacement therapy does not occuradequatelyrestoreimmune defensesystems[42,43].

Of course, the presence of acute renal failureassociatedwith decreasedrate ofdiuresisuntilanuriamay justifythe use of suchfiltrationmethods for removingexcessfluid, but it is notthe recovery ofits ownrenal excretory function. On the otherhand, afterhemosorptionorplasma exchange, whenremoved"toxic news" from the kidneys, already at the next dayyou can get500-700ml of urinewith a furtherpositive dynamics.

Larger molecules up to 10-30 kDa, play an equally important role in the physiopathology of sepsis and multiple organ failure, and removing them is possible only when hemosorption or plasmapheresis with replacement removed in donor plasma. Thus toxic products displayed more fully, which allows a more favorable outcome in 80% of these patients [44, 45, 46, 47, 48, 49].
Positive results were achieved and the use of plasmapheresis in the complex treatment of obstetric sepsis and septic shock, especially in the early stages of the process, when the mortality rate can be reduced from 80% to 15%, and postpartum women stay in the hospital decreased from 42.4 to 24.6 days [50,51,53].

Plasmapheresis in obstetric sepsis is often performed in partial plasma exchange in two stages. For preoperative preparation after hemodynamic stabilization and elimination of hypovolemia held therapeutic plasmapheresis with removal of 50% CPV with 100% reimbursement with donor fresh frozen plasma. In the early postoperative period after stabilization of circulatory dynamics, 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 [52, 53].
It must be borne in mind that in septic shock develops extremely critical condition with severe hemodynamic instability. But even in these cases, detoxification without break the vicious circle of complications can not be, and the very perform of this procedure is high risk. Experience in the use of the domestic apparatus "Hemofeniks" with membrane plasma filter "Rosa" when the amount of the priming volume of system does not exceed 70 ml and variable blood volume of about 9 ml, demonstrated the possibility of success of membrane plasmapheresis even when systolic blood pressure is maintained only sympathomimetics at least 90 mm Hg. At the same timecould be observedevensome stabilizationof circulatory dynamicswas allowed toreduce thedoses ofsympathomimeticevenduring theprocedureas theelimination of toxicsubstances.This makes it possibleto hold such aplasma exchange, even infants.

Thus,in the treatment ofseptic conditionsmust consider all ofthe pathogenic mechanismsof their development.At the same time, does notbelittling the importance ofcausalantibioticnecessarymeasures to eliminateendotoxemiaand restoreimmune defensesystems. Andthe mostreasonableis to useashemosorptionandplasma exchangewith replacementplasmaremovedwith an equal volumeof fresh frozenplasma donation. Usingaso-calledrenalreplacement therapyorselective adsorptionof endotoxinis not able toprovide eithera fulldetoxificationorimmune correction. In addition,suchextracorporealdetoxificationshould beginat the first signof septic complications, without waiting for a comprehensive picture ofmultiple organ failure.

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