Plasmapheresis and plasma exchange techniques

Therapeutic plasma exchange and plasmapheresis are effective methods of extracorporeal detoxification and the recognized methods of treating toxin-related diseases.

Plasma exchange is a one-stage procedure in which the plasma is filtered through a high porous filter or subjected to centrifugation to remove substances with a large molecular weight or molecules associated with the protein. In turn, the plasma filter is replaced by albumin (20% by volume) and freshly frozen plasma (80% of the volume).

Plasmapheresis is a two-stage procedure, during which the filtered plasma is subjected to further processing with the help of adsorption techniques, and then returns to the bloodstream of the patient. Therapeutic plasma exchange and plasmapheresis is recommended for the filtration of substances with a molecular weight> 15 000 daltons. These substances are more difficult to remove by traditional methods of PTA: hemodialysis or hemofiltration. Examples of such substances are immune complexes (molecular weight> 300kD); immunoglobulins (for example, IgG with a molecular weight of 160 kD); cryoglobulins; endotoxin (molecular weight from 100 to 2400x103 daltons) and lipoproteins (molecular weight 1.3 x 106 dalton).

The planned plasma exchange rate is calculated on the basis of the estimated volume of circulating plasma of the patient: [volume of circulating plasma = (0,065 mass of body in kg) x (1-hematocrit in%)]. It is advisable to exchange at least one volume of circulating plasma for the procedure, with an indispensable replacement of the filtrate with freshly frozen donor plasma.

Plasma exchange therapy is indicated for posttransfusion or postperfusion hemolysis, post-ischemic syndrome (myoglobinemia), with a crisis of rejection with a high antibody titer in the posttransplant period. In addition, it is applicable in complex intensive care for severe sepsis and liver failure. This technique can effectively reduce the concentration of a wide range of proinflammatory mediators in the plasma of patients with the syndrome of a systemic inflammatory response and significantly improve hemodynamic parameters in the absence of any changes in pre- and post-loading. Despite the positive aspects of plasma exchange therapy, this method does not lead to a significant reduction in mortality in patients with sepsis.

The use of high-volume plasma exchange in liver failure does not affect the mortality rates of patients, but stabilizes blood circulation parameters and reduces intracranial pressure. The therapeutic plasma exchange is capable of removing macromolecular substances bound to albumin, such as endotoxins, benzodiazepines, indoles, phenols, bilirubin, aromatic amino acids, bile acids, etc. However, the high-volume plasmapheresis is not devoid of side effects, which include, first of all, the development of anaphylactoid reactions and the danger of potential infection of the patient through donor plasma. In addition, the serious drawbacks of the technique are nonselectivity and the possibility of removing substances with only a small amount of distribution in the body.

Treatment, as a rule, includes 1-4 procedures. Sessions are held daily or after 1-2 days. In plasmapheresis, as a rule, 700-2500 ml of plasma is substituted for one procedure. As a replacement solution, 5 or 10% albumin solution, and also FFP, colloids are used. The best replacing medium is FFP, which completely retains its healing properties after thawing. Enter intravenously, special solutions begin before plasmapheresis and continue during the procedure. At the end of plasmapheresis, the volume of injected solutions should not be less than the volume of the removed plasma, and by the number of injected proteins - exceed not less than 10 g, which corresponds to approximately 200 ml of plasma.

[1], [2], [3], [4], [5]

Mechanism of action

Removal from the body of a patient with a plasma containing a wide range of toxic metabolites, has a beneficial effect on the function of all vital organs and systems. The detoxification effect depends on the volume of the substituted plasma. With plasmapheresis, the elimination of substances concentrated mainly in the vascular bed, those substances whose physical and chemical properties only slightly or do not allow them to penetrate into the intracellular sector, is achieved to the greatest extent. This is primarily characteristic of large-molecule metabolites such as myoglobin, proteins, as well as for most middle-weight molecules, especially polypeptides.

Expected effect of plasmapheresis

Removal from the blood of a wide range of toxic substances, primarily large-molecule ones, is a powerful tool for the prevention and treatment of acute renal and PON. Toxic metabolites of low molecular weight are evenly distributed in the extracellular (vascular and interstitial) and cellular sectors, so a decrease in their concentration in the blood is negligible. Detoxification of the body and intravenous administration of therapeutic protein solutions stabilize homeostasis, normalize the transport function of blood and its aggregate state, improve intraorganic microcirculation and intracellular metabolism. Excretion from the body with plasma fibrinolytically active substances and intravenous injection of FFP are considered an effective means of fighting fibrinolytic bleeding.

In connection with these features, plasmapheresis is used mainly in the somatogenic phase of acute poisoning for the treatment of endotoxicosis. In the toxicogenic phase, plasmapheresis is not suitable as a universal method of detoxification (like DG or hemosorption [GS]), since many exotoxicants are adsorbed by blood cells and therefore remain in the patient's body after plasmapheresis.

[6], [7], [8]

Therapy based on sorbents

In recent years, interest has increased in the use of sorbents in the extracorporeal treatment of severe hepatic renal failure and sepsis. Since many toxins that accumulate in organs and tissues in these pathological conditions (for example, bile acids, bilirubin, aromatic amino acids, fatty acids), although they are substances of average molecular weight, have hydrophobic properties and circulate in the blood as a complex with albumin. These protein-related metabolic products cause the development and maintenance of organ dysfunction observed in liver failure. The use of traditional methods of dialysis therapy does not make it possible to remove toxin-related toxins from the plasma, since these techniques provide control of only water-soluble molecules, and the use of sorption techniques, especially in combination with PTA methods, is fully justified for the removal of albumin-bound hydrophobic complexes, as well as water-soluble substances.

Sorbents are divided into two large groups: specific and nonspecific. In the sorbents of the first group, specially selected ligands or antibodies are used, which ensure high target specificity. Nonspecific adsorption is based on the use of charcoal and ion-exchange resins, which have the ability to bind toxins and hydrophilic properties. These substances are characterized by high adsorption capacity (> 500 m2 / g) and their production is less expensive. Although initially the clinical use of sorbents was hampered by the often occurring leukopenia and thrombocytopenia, recent improvements in the design and the appearance of biocompatible coatings have revived interest in this supplementary blood purification technique.

The appearance of new molecules capable of attaching sepsis mediators to their surface led to the development of extracorporal techniques based on the principle of combined plasma filtration and adsorption. For this purpose, a plasma filter is used, then the plasma is passed through a synthetic resin cartridge prior to being returned to the bloodstream, which has increased adsorption properties. Experimental studies have shown the possibility of a significant reduction in the concentration of inflammatory mediators with the help of this technique, an increase in the immunomodulatory effect and a survival rate. The use of the technique in the clinic is very limited, but the preliminary results of the research are quite encouraging.

Another technology based on sorbents is hemolipodialysis, which uses dialysating solution saturated with liposomes and consisting of a double layer of phospholipids with a spherical structure and inclusions of the molecules of vitamin E. The solution that surrounds the liposomes contains vitamin C and electrolytes. This technique is used experimentally to remove fat-soluble, hydrophobic and albumin-bound toxins diagnosed in sepsis.

The use of specific sorbents is intended for special methods of treatment. Resins coated with polymyxin-B can effectively bind lipopolysaccharides - mediators of the septic process. The use of resins significantly reduces the lipopolysaccharide content in plasma, improves hemodynamics, and also affects the reduction of lethality. For this technique, the moment of the beginning of therapy plays an essential role. Since it is impossible to determine the onset of a septic syndrome before the onset of clinical symptoms, the "time factor" has a significant effect on the outcome of the treatment.

In 2006, K. Ronco and his colleagues proposed a new combined method - plasma filtration + adsorption + dialysis, which, according to the authors, can be of great practical importance in the complex treatment of multiple organ dysfunction syndrome and sepsis. The method is based on a combination of all the physical mechanisms of extracorporeal blood purification: convection, adsorption and diffusion. Significantly increases the effectiveness of this combined method of eliminating albumin-bound hydrophobic and hydrophilic toxins directly from the plasma, due to sequential processes in the extracorporeal circuit, rather than from whole blood.

Treatment of liver failure

Evidence of the involvement of albumin-related metabolites in the pathogenesis of multiple organ failure in patients with liver disease and the need for safe and biocompatible treatment techniques led to the development of the concept of albumin dialysis, the molecular adsorption recirculating system (MARS-therapy). The aim of the method is the effective removal of albumin-bound hydrophobic toxins and water-soluble substances.

The MARS system is a method that combines the effectiveness of the sorbent used to eliminate molecules bound to albumin and the biocompatible modern dialysis membranes. Removal of protein-bound molecules occurs selectively through the use of albumin as a specific carrier of toxins in human blood. Thus, albumin dialysis is an extracorporeal system to replace the detoxification function of the liver, which is based on the concept of dialysis using a specific membrane and albumin as a dialysate. The protein acts as a molecular sorbent, which is restored in a continuous mode by recirculation in the extracorporeal circle. Due to the "attracting" effect of albumin, the system achieves a high level of elimination of albumin-related substances, such as bile acids and bilirubin, which are not removed during hemofiltration. The membrane filter used in the albumin dialysis process, thanks to its physico-chemical characteristics (the ability to interact with lipophilically bound domains), allows the release of albumin ligand complexes found in the blood. The membrane itself is impermeable to albumin and other valuable proteins, such as hormones, clotting factors, antithrombin III. Two columns with activated carbon and anion exchange resin as sorbents and a dialyzer allow to remove both protein-bound and water-soluble metabolic products, thereby making the system suitable for use in patients with hepatorenal syndrome.

Perfusion of blood through the MARS-filter provides a peristaltic pump of the artificial kidney apparatus. The albumin dialysis solution saturated with protein-bound and low molecular weight water-soluble substances is sent to the low-permeability dialyzer in the MAPC filter, where water-soluble substances are removed by the use of the bicarbonate dialysis solution. Through this element, it is possible to perform ultrafiltration, as well as correction of the acid-base and electrolyte balance of the patient's plasma. Further, the albumin dialysis solution is purified from protein-bound molecules as it passes through the columns with activated carbon and anion exchange resin, after which the regenerated albumin solution is again fed into the MAPC filter. The flow in the albumin circuit provides the peristaltic pump of the MARS monitor. Perfusion of blood requires veno-venous access. The duration of treatment depends on the patient's body weight, the size of the MARS membrane used (adult or pediatric) and on indications for therapy. On average, its duration does not exceed 6-8 hours.

When conducting MAP-therapy, significant clinical changes are noted in the majority of patients with both fulminant and decompensated chronic hepatic insufficiency. First of all, it concerns reversion of liver encephalopathy, stabilization of systemic hemodynamics, improvement of liver and kidney function. There is also a decrease in the intensity of skin pruritus in primary biliary cirrhosis. According to research, the synthetic functions of the liver improve after the use of albumin dialysis.

The first results on the use of albumin dialysis indicate the possibility of its use in patients (including children) with hepatic insufficiency. It can be assumed that comparative studies of the effectiveness of MARS therapy and the new Prometheus technology, recently appeared on the market of medical equipment, based on the principle of plasma fractionation using a membrane highly permeable for albumin molecules, followed by perfusion of the filtrate through exchange resins, are extremely interesting. Publications about the first results of using Prometheus technology in the treatment of liver failure show a sufficiently high attractiveness of the technique.

Technical Aspects of Detoxification

Vascular access for permanent renal replacement therapy

The success of any technology of extracorporeal cleansing of blood and, above all, constant PTA largely depends on adequate vascular access. With continuous arteriovenous hemofiltration, catheters of the largest diameter are used to catheter arteries and veins to provide a sufficient gradient that promotes blood flow through the extracorporeal circuit. The problem of vascular access is most acute when it is necessary to carry out the procedure for newborns and children of the first year of life due to the small caliber of the artery and vein. Children with a body weight of up to 5 kg perform catheterization of the femoral or umbilical arteries and veins, using single-lumen probes ranging in size from 3.5 to 5 Fr. The use of double-lumen venous catheters facilitated vascular access in patients in intensive care units for both intermittent and permanent veno-venous procedures. However, when using double-lumen catheters, recirculation of blood is likely, which, if the amount of blood flow in the extracorporeal circuit exceeds 20%, can lead to significant hemoconcentration in it, increased blood viscosity, filter thrombosis and inadequate blood purification. Given the tendency of blood recirculation to increase with increasing blood flow velocity, intensive care units are not recommended to perform a procedure with a blood flow rate of more than 180-200 ml / min.

Configuration of hemofilters for permanent renal replacement therapy

To reduce the loss of an arteriovenous gradient with continuous arteriovenous hemofiltration, short filters with a small sectional area are used. To prevent hemodynamic disorders, especially at the beginning of the procedure, it is necessary to strictly consider the volume of primary hemofiltration. In newborns and children with a low body weight, filters with a primary volume of 3.7 ml to 15 ml are usually used, while the effective area of the membrane does not exceed 0.042-0.08 m2.

[9], [10], [11], [12], [13], [14], [15], [16]

Hemofilters with high permeability membranes

To increase the clearance of "medium" molecules, when performing procedures for extracorporeal detoxification, patients with polyorganic insufficiency and sepsis use haemofilters with high-permeability membranes (up to 100 kD). The results of the first experimental and clinical studies indicate a significant increase in the elimination of inflammatory mediators, and the clearance of these substances when using highly permeable membranes is similar in the convection and diffusion principles of mass transfer. A randomized prospective study compared with the efficacy of using high-permeability and standard hemofiltration membranes in patients with acute renal failure and sepsis showed no reduction in albumin concentrations 48 hours after the start of the procedure in both groups of patients. Also, significantly better clearance of IL-6 and IL-1 was observed by the end of the first day in the group of patients for which high-porosity filters were used.

For final conclusions on the advisability of using hemofiltration using high-permeability filters, the results of clinical trials and the first randomized prospective studies that are currently conducted in leading clinics in Western Europe should be comprehensively evaluated.

Solutions for chronic renal replacement therapy

The technology of constant PTA requires the obligatory use of balanced replacement electrolyte solutions in order to completely or partially compensate the volume of the removed ultrafiltrate. In addition, with the implementation of continued hemodialysis and hemodiafiltration, the use of dialysis solutions is necessary. Currently, two-component bicarbonate solutions are used to replace, taking into account possible violations of hemodynamics and metabolic parameters with the use of acetate or lactate buffers. To achieve specific metabolic goals (correction of acidosis or electrolyte imbalance), the composition of substitution solutions is significantly different. However, factory-made bicarbonate-containing solutions have not yet received a sufficiently wide distribution in our country, and with certain rules and caution, one-component, lactate replacement and dialysis solutions can be successfully used.

Anticoagulation

Any methods of extracorporeal blood purification require the use of anticoagulant therapy to prevent thrombus formation in the circuit. Inadequate anticoagulation leads first to a decrease in the effectiveness of therapy, which is associated with a decrease in the rate of ultrafiltration and clearance of substances, and subsequently - to thrombosis of the filter, leading to unwanted blood loss, increased time of PTA, and a significant increase in the cost of treatment. On the other hand, excessive anticoagulant therapy can be the cause of serious complications, especially bleeding, whose frequency reaches 25%.

In clinical settings, unfractionated heparin was most widely used as an anticoagulant. Advantages of using this drug are the standard of the technique, ease of use, relative cheapness and the possibility of adequate monitoring of the dose of anticoagulant with available tests. One of the important advantages of heparin is the possibility of rapid neutralization of its action by protamine sulfate. Despite the fact that heparin continues to be the most frequently used anticoagulant, its use is often associated with a high risk of bleeding. And it was proved the absence of a direct relationship between the frequency of its development and the absolute amount of the injected anticoagulant. The frequency of hemorrhagic complications is largely determined by the balance of the coagulating and anticoagulant systems in patients of different groups, as well as by the variability of the half-life of heparin.

The possibility of rapid binding of heparin and neutralization of its activity with protamine sulfate formed the basis for the method of regional anticoagulation. During the procedure of PTA, heparin is injected before the filter to prevent its thrombosis, and the necessary dose of protamine - after the filter, with a clear control of anticoagulation in the extracorporeal circuit. This method reduces the risk of hemorrhagic complications. However, it can not exclude heparin-induced thrombocytopenia, as well as allergic reactions to the introduction of protamine sulfate and the development of hypotension, bronchospasm and other manifestations, which are extremely dangerous for patients in intensive care units.

Regional citrate anticoagulation reduces the risk of bleeding, but requires the use of a special method for performing extracorporeal therapy and controlling the concentration of ionized calcium. This technique allows to achieve effective anticoagulation, but requires the constant addition of calcium in the extracorporeal circuit. In addition, since the metabolism of citrate in the liver, kidneys and skeletal muscles is accompanied by the production of bicarbonate, one of the side effects of this technique is the development of metabolic alkalosis.

In recent years, the use of low molecular weight heparins, in particular sodium enoxaparin, calcium suparaparin, etc., has spread. Although the use of low molecular weight heparins (molecular weight about 5 kDa) slightly reduces the risk of hemorrhagic complications, their cost compared with heparin is much higher, and the application requires special more expensive monitoring. These drugs have a pronounced cumulative effect, and use them especially with a constant PTA should be done with great caution.

A new method that allows to reliably reduce doses of anticoagulants during PTA in patients with a high risk of bleeding is a modification of the extracorporeal contour according to the method developed at the Vavilov Scientific Center of Cardiovascular Surgery. A.N. Bakulev RAMS. The use of an extracorporeal contour with intravenous catheters treated with heparin by special technology makes it possible not to use systemic anticoagulation during the procedure. At the same time, the effective work of the filter is preserved, the thrombus resistance of the contour increases and the risk of hemorrhagic complications in patients with multiorgan insufficiency syndrome decreases.

Currently, scientists are working on the creation of atrombogenic membranes of hemofilters, blood lines and catheters covered with heparin.

Patients with severe thrombocytopenia and coagulopathy are treated with PTA without systemic anticoagulation, but at the same time limit the duration of permanent procedures to 12-18 hours.

Over the past few decades, there have been huge changes in the approach to methods of detoxification in the postoperative period in surgical patients. This is due to the proven efficacy of efferent methods in a number of pathological conditions, the emergence of many new, including hybrid, treatment technologies and a definite progress in the outcomes of complex intensive therapy. Of course, in the near future we should expect to conduct new multicenter randomized trials aimed at identifying types of extracorporeal detoxification, the use of which will be most effectively used to solve specific problems in certain clinical situations. This will open the way to wider application of detoxification methods in accordance with both "renal" and "non-adrenal" indications. The results of such studies will allow to determine the most justified time of the beginning of the use of extracorporeal cleansing of blood, its "dose" and effectiveness depending on the specific method of therapy in critically ill patients who have suffered including large reconstructive surgical interventions.

[17], [18], [19], [20], [21], [22], [23], [24]