Plasmapheresis for critically ill patients

Efferent therapy is intended to eliminate fr om the organism various pathological products (the Latin efferens – elimination). In the past, rather popular was such a form of efferent therapy as bloodletting which apart fr om eliminating excessive circulating blood volume (CBV) released the organism from toxic elements. Even barbers were allowed to perform it. However, even in hands of experienced doctors this method was not deprived of hazards, so much the more the history knows the cases of failures of such procedure. 

More safe method of efferent therapy is the removal of not the whole blood, but of its liquid part – plasma, components of which are the main carriers of pathological products in the organism, what’s more, it is restored much quicker than blood formed elements. This particular method is called plasmapheresis (from the Greek πλάσμα - plasma, liquid part of blood, and ἀφαίρεσις - aphairesis, taking away). In this context "apheiresis" is from the Greek “removal” either. 


Hippocrates himself wrote that “medicine is addition and withdrawal. Withdrawal of everything that is superfluous; addition of the missing. And the one, who does this best, is the best doctor”.

Nevertheless, the most popular methods of contemporary medicine are intended mainly to introduce into the organism of various drug preparations that are far from being harmless, but the number of which is continuously growing. Development of efferent therapy methods was hindered by lack of simple, cheap and accessible devices, and only during the last decade successes of membrane technology allowed to draw them nearer to the wide medical practice. What contributed most to it in Russia was creation of plasmafilter “ROSA” and device for membrane plasmapheresis “HEMOFENIX” developed by the Russian company “TRACKPORE TECHNOLOGY Corporation” and produced in Dubna, Moscow region.  
The work aims to give more complete substantiation of efferent therapy indications in various acute diseases and critically conditions based on own experience and modern literature reports.

INTERNAL ENVIRONMENT OF THE HUMAN AND MECHANISMS OF ITS REGULATIONS

Human, like any biological entity, is in constant contact and interaction with the environment. Life is a constant process of metabolism both within the body, and with environment, absorption of oxygen and release of carbon dioxide, water and food intake and excretion of end products of metabolism. The very existence of the organism depends on the ability of constancy maintaining within certain limits of its internal environment.
During thousands of years of evolution there were perfected mechanisms of autoregulation of internal environment – homeostasis and protection against aggressive influences both from outside, and from poisonous and toxic substances, and microbial-viral contamination. But during the process of own metabolism as well, there are formed relatively toxic intermediate and final products of metabolism, which are subject to slow inactivation or removal. Therefore, formed a complex and multi-stage system of protection and correction of the internal environment. It consists of three main components:

1. Microsomal monooxygenase system of liver detoxification. 
2. Immune system 
3. Excretory system.

Hundreds of thousands of foreign compounds – xenobiotics –always get to the body from outside. The main liposoluble toxic substances undergo biotransformation during the process of digestion in intestine, from which by portal vein they can not bypass liver, wh ere due to oxidation and enzymatic processes they finally convert into non-toxic water-soluble compounds, which are further metabolized in all organs and tissues.

Liver is a barrier not only for exogenous, but also for endogenous toxic compounds, constantly arising during the process of metabolism – synthesis of some and decay of other substances: lactate and pyruvate, urea and creatinine, ammonia and fatty acids, aromatic amino acids, alcohols and aldehydes, phenols and ketones, products of proteolysis and hydrolysis, activity of automicroflora and viruses, etc.

Immune system, in its turn, consists of three components: the central organs (thymus and bone marrow), lymphoid structures scattered over the body (spleen, lymph nodes), and immunocompetent cells.

There are the following parts of the immune system: recognition of foreign substances – antigens, phagocytosis, a cooperative function of T-lymphocytes and antibody production, interaction of antibodies with antigen and of complement with immunoglobulins and target cells. There are physical and chemical processes occuring: reception, immune adhesion and adsorption.

Interaction of antibodies with antigen is an adsorption process of forming the immune complex "antigen + antibody + complement". It is retained in the lymphoid tissue, phagocytized and degraded by lysosomal enzymes. Natural serum factors – opsonins – promote adherence of microorganisms, dead cells and their fragments ("detritus") to the plasma membrane of phagocytes (monocytes, neutrophils), increase the velocity of phagocytosis. It should be borne in mind that in case of depletion or absence of opsonins of complement, even normal phagocyte is not capable of capturing the bacteria, so defects in humoral immunity entails failure and cell-phagocytic defense mechanism.
But humoral immunity depends on the cell immunity as well, since T-cells are required for both, start of antibody forming by B-lymphocytes, and regulation of this process. In particular, T-helper cells (CD4) stimulate production of antibodies, and T-suppressor (CD8) inhibit this process, and, depending on the relations between the two subclasses (CD4/CD8), there are possible hyperimmune reactions and immunosuppression.

The task of the immune system also includes a struggle not only with food of foreign origin, but also with those arising within the body, including ever-emerging abnormal cells, which include tumor ones. Here also works a mechanism of a "friend or foe" reaction, and own cell with anomalous properties is destroyed along with the foreign ones by natural killer cells (T-killers) and other macrophages.

All final products of own metabolism and degradation of foreign substances, require removal from the body. The structure of excretory system consists of four components: kidneys, gastrointestinal tract, lungs, sweat and sebaceous glands of skin.

Kidneys remove water (1.5-2 liters a day) and dissolved urea, creatinine, potassium, sodium, chloride, calcium, magnesium, sulfates, phosphates. In addition, kidneys eliminate water-soluble products of biotransformation xenobiotics, products of proteolysis of immune complexes, remains of bacteria, viruses, protozoa, fungi digested by phagocytes, and substances spontaneously transformed into foreign substances.

Gastrointestinal tract eliminates lipids, cholesterol, bile acids, steroids, bilirubin, water, food debris, nonviable microbial body unabsorbed xenobiotics.

Through lungs there are removed carbon dioxide, water, volatile xenobiotics (ethanol, ether, etc.).

Sweat and sebaceous glands of skin derive water (400-600 ml), sodium, potassium, calcium, magnesium, phosphorus, chloride. Also urea, creatinine in case of uremia; in diabetes – glucose; in hepatic failure – ammonia, bile acids; in poisonings – mercury, arsenic, iron, iodine, bromine, quinine, benzoic acid, succinic and hippuricacid, salicylates, salol, antipyrine, methylene blue, etc. 
                                   
                                   Mechanisms of homeostasis disorders 

In addition to the direct toxic effects of a number of xenobiotics, perversions of metabolic processes occur in the body. For example, penetration of oxidants stimulates lipid peroxidation with depletion, and then depression of antioxidant defense system. Final products of peroxidation, as malondialdehyde, diene conjugates, Schiff bases are accumulated. Increase of concentration of these natural metabolites leads to disorders and other metabolic processes, in particular, to excitation of proteolysis.

Another big disorder of homeostasis occurs in certain diseases. Thus, in acute inflammatory processes an important role play mediators of inflammatory with increase of kininogenase-kinin cascade products in blood – biogenic amines (serotonin, histamine, kallikrein) contributing to worsening of shock-producing reactions.

Upcoming biochemical disorders of internal environment can not affect the protection system – organs of detoxification, immunity, excretion. Developing "toxic press" causes a cascade of subsequent disorders with the emergence of a number of vicious circles that the body itself is no longer able to break, even with the help of various drug therapies. 

Traditional approaches to treatment in most cases have symptomatic nature, such as the use of antibiotics for infections. If kidneys are not able to eliminate some products, then diuretics are not able to restore this function.

Without liquidating the reasons of depression or distortion of immune responses it is difficult to rely on a persistent immune correction. Without sanation of internal environment, excretion of pathological products, restoration of the normal course of metabolic processes, including lipid peroxidation and proteolysis, i.e., without liquidation of the "toxic press" on immunity, it is difficult to count on its recovery with only medical stimulation, without which it is impossible to achieve a breakthrough in the disease course. Excretion of abnormal substances and sanation of the internal environment are the aims of a variety of efferent therapy methods.

It should be noted that the concept of "pathological products" presupposes not so much toxic substances of exogenous or endogenous origin, as autoantibodies, immune complexes and other practical natural metabolites whose concentration exceeds physiological limits, which has pathological effects on organs and body systems.

                                    Methods of efferent therapy

There are two groups of such methods. One of them is based on the possibility of applying sorption methods of fixation of various substances circulating in blood, and their subsequent removal. Another group includes methods of removing harmful substances together with a part of the blood – plasma. 
Hemodialysis is also one of efferent therapy types. Clinical indications to it are limited mainly to acute and chronic nephropathy and some kinds of poisoning [Gotloib L., 1996]. These issues were rather fully described in a special literature and thus not included in the aims of this work.
In the intensive therapy practice more popular are methods of hemofiltration – hemodiafiltration and ultrafiltration. They are based on removal of liquid part of blood except for proteins, what makes them close to hemodialysis, but water exudation mechanism is based on filtration through microporous membranes. In this mode, can operate both conventional dialyzers and special hemofilters that allow to perform relatively long sessions for up to 180 hours with removal of up to 20-40 liters of liquid a day. Such intensive removal of the liquid needs special polyionic and buffer substitute solutions under the control of acid-base balance and ionogram. 

Sorption methods are based on such peculiarity of many harmful products, as presence of the charge in these molecules or free radicals in their structure that in contact with the sorbent, consisting of activated carbon or other surface structures (sometimes coated with enzymes or ion exchange resins), are able to be adsorbed to the latter. Transmission of blood through the columns with sorbents is called hemosorption (hemocarboperfusion) [Ostapenko V.A., 1995].

It should be noted that many natural metabolites – protein molecules, lipids, mucopolysaccharides – have “closed” molecular structures electrically and, therefore, biologically inert.  That is why “normal” metabolites can contact with active sorbents –  they easily pass them by and remain in circulation, thus minimizing the possible harmful effects of the procedure.Despite the common alienation of specialists, such nonspecific hemosorption still finds its application in the treatment of patients with sepsis, allergic and autoimmune diseases.

It is possible to apply sorption method without removal of pathological products and without elimination from the organism of any internal environment elements. This is an enterosorption. There is used a process of physiological filtration and reabsorption of liquid from the bloodstream into the intestine glimpse by its villi. The products that were removed with the liquid part of blood contact with enterosorbent taken beforehand, fix on it and together with it are removed from the body. Considering that the intestinal villi are able to pass all of the ingredients, the molecular weight of which is lower than the mass of albumin, and toxic substances at their core are of medium-molecular mass, the effectiveness of enterosorption in eliminating endotoxicosis becomes clear. The advantage of this method is the possibility of its use in ambulatory (home) conditions, although its efficiency yields to a direct adsorption of these substances directly from the blood flowing through the column during hemosorption [Nikolaev V.G. et al, 2005].

However far not all substances, subject to elimination from the organism, can be captured and fixed on sorbents. Electro-chemically inert molecules are incapable of adhesion and remain in circulation, which makes hemosorption procedure inadequate. In such cases the elimination effect of such substances can be obtained during plasmapheresis, when some part of plasma is completely removed together with all the pathological products that were there. 

Removed volume of plasma is completed with plasma-substituting solutions, albumin and donor plasma. In the latter case, especially when the removed plasma is completely substituted with donor plasma, the operation is called plasma exchange. Unlike hemosorption, plasmapheresis has more or less universalcharacter, when all the pathological elements are removed irrespective of presence and amount of electrostatic charge of their molecules. 

There are two main methods of plasmapheresis – gravitational and filtrational. The first one is performed by centrifugation of blood with constant or intermittent flow in special devices produced by Gambro, Fresenius, Cobe, Dideco, Terumo or in bags in ordinary centrifuges. 

The second method is based on blood filtration in special plasma filters. As a rule, there are produced filters, wh ere filtration if performed through hollow porous fibers. In Russia there has been organised production of plasma filters PFM-800 containing flathollow “track” porous membranes (“Plasmofilter”, Saint-Petersburg). In 2001 appeared a filter of new generation PFM-TT “Rosa”, developed by “TRACKPORE TECHNOLOGY Corporation” and produced in Dubna, Moscow region. Description of peculiarities of the latter as well as different techniques of its application will be detailed below in the conclusion of the work. 

In any of these methods after plasma removal, concentrated cell mass of blood (“erythromass”) is diluted with sodium chloride isotonic solution or other plasma substitute and returned to a patient. During one session it is possible to remove from 1/3 to ½ of circulating plasma volume (CPV). In case of donor plasma or albumine substitution, up to 1 or 2 CPV can be removed [Gurevich K.J. at al., 1993; Sokolov A.A., Bel’skich 2003].     

CPV of an adult person with an average weight is 2.0–2.5 l. It is easy enough to calculate knowing the circulating blood volume (CBV), which makes about 7% from body weight and hematocrit index (Ht). Then there is elementary calculation:

                                                                                       CPV = CBV -  Ht  х  CBV  , 
                                                          100

Where – hematocrit index is percentage, and circulating blood and plasma volume – in milliliters.   
If hematocrit was not measured directly​​, then it can be roughly calculated from the number of erythrocytes, which multiplied by 10 approximately corresponds to hematocrit (3,6×1012/l erythrocytes correspond to hematocrit 36%), or from hemoglobin content divided into three (hemoglobin 120 g/l - approximately 40% hematocrit).

After plasmapheresis session a significant decrease in the concentration of pathological products can be observed, but after a few hours their content in the blood is close to the original level. This suggests that substances, which before had been in the interstitium, or even in the cells, penetrated to the bloodstream. Subsequent sessions of plasmapheresis promote removal of these substances, which leads to a more complete sanation of the whole internal environment, given that most of the harmful products are in extravascular space. It should be borne in mind that there is a "moving equilibrium" of concentrations of various substances in intracellular, extracellular (interstitial) and intravascular spaces of the organism. Change of their content in one of these spaces (in this case – intravascular) leads to redistribution in the others.

More selective methods of plasmapheresis are also used, when received plasma is subjected to cooling, which promotes the precipitation of some proteins and immune complexes, lipoproteins and triglycerides, fibrinogen, and other "acute phase" proteins, which in the future (after thawing) can be removed again by centrifugation or by sorption, and the remaining components of the plasma can be returned to the patient.

This method is called "cryoprecipitation", "cryosorption" or "cryosorption modification of autoplasma". Cold precipitation is enhanced in the presence of heparin, therefore one of such methods is known as heparin-induced extracorporeal precipitation of cholesterol (Heparin-induced extracorporeal LDL precipitation - HELP-apheresis. However, in the Technical Manual of the American Association of Blood Banks (2000) it is emphasized that by means of adsorption or cryopheresis it is possible to remove only a part of the pathological component, so the expected efficiency of these methods is lower than of those for which plasma is removed entirely.

Another method of selective plasmapheresis is cascade plasmafiltration when plasma obtained with one of the methods re-passes through a special microporous filter that passes only low molecular weight proteins (albumins) and holds those with high molecular weight, including immunoglobulins and atherogenic lipoproteins [Valbonesi M. et al., 2001; Hanafusa N. et al., 2006]. For the first time cascade plasmafiltration was performed by T. Agishi et al. in 1980 [Agishi T. et al., 2000]. As a secondary cascade plasmafilters there are used Albusave (Dideco, Italy), EVA-Flux EVAL 2-5A (Kawasumi, Japan), EC-20W (Asahi, Japan), Kuraray Evaflux 4 (Kuraray, Japan), etc.

Nevertheless, despite its importance, efferent therapy intended to remove pathological products of the internal environment, is only the first step in correcting its violations. The second one is elimination of secondary effects of these disorders – restoration of natural protective systems, mainly immunity.

In this book we use somewhat expansive notion of efferent therapy, including in it not only the removal of harmful substances from the body, but other methods of correcting defects of internal environment by physico-chemical influence on its individual components (blood, plasma, lymph) outside the body (extracorporally), or even inside it.

The basis of extracorporeal methods of immune correction is photo-hemotherapy (blood photomodification) – blood irradiation with ultraviolet or laser beams. There are many reports of favorable effects of such therapy: in patients with immunosuppression effect of immune stimulation is revealed, and with various allergies – immune correction, that is, reducing pathological allergic reactions. In patients with inflammatory diseases of lungs after ultraviolet irradiation of blood electron microscopy indicates restoration of specific intracellular organelles in neutrophil leukocytes, suggesting an increase of their phagocytic ability. Also increases the number of immunoglobulins, T- and B-lymphocytes, reduces leukocytic index of intoxication (LII) [Nazarov I.P., Vinnik Y.S., 2002].

Among methods of laser irradiation of blood the most common is a helium-neon (He-Ne) laser as a light source of red light (l = 0,633 µm). In case of coincidence of the enzymes absorption spectrum in a cell or in its membrane with energy spectrum of laser radiation, they are activated. In particular, catalase is activated, which has the same spectrum (0.633 µm), as He-Ne laser. Copper-containing redox enzymes – cytochrome oxidase and ceruloplasmin – may be acceptors. Activation of these enzymes is enhanced in the presence of singlet oxygen, which emphasizes the combination of this method with addition of substances containing free oxygen. It is possible a selective absorption of red quanta by oxygen with its transition to the singlet state. In such cases, it is justified to add substances containing singlet oxygen, for example – sodium hypochlorite.

Enzymes, such as superoxide dismutase, lactate dehydrogenase, phosphatase, can be acceptors of such irradiation. The red light of He-Ne laser influences hemoglobin molecules with decrease of its affinity for oxygen, which increases its impaction on tissues in hypoxia. This irradiation has a favorable effect on the lipid composition of erythrocyte membranes, normalizing their aggregation properties, deformability, which improves rheological properties and oxygen-transport function of blood.

 When combined with efferent therapy, it is always possible to use extracorporeal circuit of perfusion and to perform more dosing irradiation. Eases the situation a good permeability for laser beams of the walls of PVC blood lines. A particular area of ​​such tube can be placed inside a mirror sphere in which the tangential beam creates the effect of "inner lights shining" and irradiation of blood passing from all directions, which makes it possible to dispense irradiation with regard to the speed of blood flow and body weight. Combined application of laser irradiation of blood with hemosorption and plasmapheresis significantly potentiates their immuno- and rheologic impact, significantly increases efficacy of treating.

External irradiation of separate parts of the skin with He-Ne laser is also possible, but penetration of these rays is limited to only a few millimeters, which allows to irradiate superficial wounds or trophic ulcers. More deeply (up to 8 cm) penetrates radiation of infrared lasers with emission spectrum of 0.89 µm, which allows to use them in irradiation of both superficial large blood vessels and some of internal organs (liver, kidneys, heart, joints).

But in any case, plasmapheresis is associated with a temporary, renewable, but still lost of certain part of immunoglobulins, complement, opsonins, which, undoubtedly, at some time weakens immune protection capability of a patient. Thus, almost every operation of plasmapheresis (as well as hemosorption) must be accompanied by a quantum immunocorrection.

 On the other hand, in almost all cases when quantum photo-hemotherapy is performed for immunocorrection, it is meaningless without parallel efferent therapy. This also can be said about different types of drug immunomodulation – without efferent therapy its effect will not be stable and long enough.

Efferent therapy can also be combined with methods of "oxidative detoxification" – low-flow membrane oxygenation and indirect electrochemical oxidation and ozonation of blood.

For the electrochemical oxidation it is used effect of electrolytic decomposition of usual isotonic sodium chloride solution with the device EDO-4 with formation of the above sodium hypochlorite (NaClO). Active radical ("singlet oxygen") of the latter in addition to bactericidal activity has the ability to rapidly oxidize hydrophobic toxic substances, such as bilirubin, creatinine, urea, fatty acids and other substances in the blood, which potentiates the detoxication process. Pre-treatment of hemosorbents with sodium hypochlorite increases their sorption capacity.

For ozonation of blood most commonly it’s used ozonation of isotonic solutions of sodium chloride with subsequent intravenous infusion. In such ozonization of blood there are reached effects of immunomodulatory, anti-inflammatory, anti-allergic. Decrease of concentrations of LDL, triglycerides, and glucose is also possible. Effect on the immune system manifests itself by activation of lymphocytes and macrophages with increased production of cytokines (interleukin-2), g-interferon, β2-microglobulin. Apart from that, in introduction of ozonated solutions there is observed an effect of microcirculation improvement.

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