Plasmapheresis and plasma exchange techniques

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

Plasma exchange is a one-step procedure in which plasma is filtered through a highly porous filter or centrifuged to remove high molecular weight substances or protein-bound molecules. The plasma filtrate is in turn replaced by albumin (20% of the volume) and fresh frozen plasma (80% of the volume).

Plasmapheresis is a two-step procedure in which the filtered plasma is further processed using an adsorption technique and then returned to the patient's bloodstream. Therapeutic plasma exchange and plasmapheresis are recommended for the filtration of substances with a molecular weight >15,000 Daltons. These substances are more difficult to remove using traditional RRT methods: hemodialysis or hemofiltration. Examples of such substances are immune complexes (molecular weight >300 kD); immunoglobulins (eg, IgG with a molecular weight of 160 kD); cryoglobulins; endotoxin (molecular weight from 100 to 2400 x 103 Daltons) and lipoproteins (molecular weight 1.3 x 106 Daltons).

The amount of planned plasma exchange is calculated based on the expected volume of the patient's circulating plasma: [volume of circulating plasma = (0.065 x body weight in kg) x (1 - hematocrit in vol.%)]. It is advisable to exchange at least one volume of circulating plasma per procedure, with the obligatory replacement of the filtrate with freshly frozen donor plasma.

Plasma exchange therapy is indicated for post-transfusion or post-perfusion hemolysis, post-ischemic syndrome (myoglobinemia), and rejection crisis with high antibody titers in the post-transplant period. In addition, it is applicable in complex intensive therapy of 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 systemic inflammatory response syndrome and significantly improve hemodynamic parameters in the absence of any changes in pre- and postload. Despite the positive aspects of plasma exchange therapy, this technique 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 patient mortality rates, but stabilizes blood circulation parameters and reduces intracranial pressure. Therapeutic plasma exchange is capable of removing albumin-bound macromolecular substances, such as endotoxins, benzodiazepines, indoles, phenols, bilirubin, aromatic amino acids, bile acids, etc. However, high-volume plasmapheresis is not without side effects, which primarily include the development of anaphylactoid reactions and the risk of potential infection of the patient through donor plasma. In addition, serious disadvantages of the technique include non-selectivity and the ability to remove substances with only a small distribution volume in the body.

Treatment usually includes 1-4 procedures. Sessions are held daily or every 1-2 days. During plasmapheresis, 700-2500 ml of plasma are usually replaced in one procedure. A 5 or 10% albumin solution, as well as FFP, colloids are used as a replacement solution. FFP is considered the best replacement medium, as it completely retains its therapeutic properties after thawing. Intravenous administration of special solutions begins before plasmapheresis and continues during the procedure. Upon completion of plasmapheresis, the volume of solutions administered should be no less than the volume of plasma removed, and in terms of the amount of proteins administered, it should exceed it by at least 10 g, which corresponds to approximately 200 ml of plasma.

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Mechanism of action

Removal of plasma containing a wide range of toxic metabolites from the patient's body has a beneficial effect on the function of all vital organs and systems. The detoxifying effect depends on the volume of replaced plasma. Plasmapheresis achieves the greatest elimination of substances concentrated mainly in the vascular bed, i.e. those substances whose physicochemical properties only weakly or do not allow them to penetrate into the intracellular sector at all. This is primarily characteristic of large-molecular metabolites such as myoglobin, proteins, and also for most medium-weight molecules, especially polypeptides.

Expected effect of plasmapheresis

Removal of a wide range of toxic substances from the blood, primarily large-molecular ones, is a powerful means of preventing and treating acute renal failure and MOF. 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 insignificant. Detoxification of the body and intravenous administration of therapeutic protein solutions stabilize homeostasis, normalize the transport function of the blood and its aggregate state, improve intraorgan microcirculation and intracellular metabolism. Removal of fibrinolytically active substances from the body with plasma and intravenous administration of FFP are considered an effective means of combating fibrinolytic bleeding.

Due to the above-mentioned 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 HD or hemosorption [HS]), since many exotoxicants are adsorbed by blood cells and therefore remain in the patient's body after plasmapheresis.

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Sorbent-based therapy

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

Sorbents are divided into two large groups: specific and non-specific. Sorbents of the first group use specially selected ligands or antibodies that provide high target specificity. Non-specific adsorption is based on the use of charcoal and ion-exchange resins that 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 at first the clinical use of sorbents was hampered by the frequent occurrence of leukopenia and thrombocytopenia, recent design improvements and the emergence of biocompatible coatings have revived interest in this auxiliary blood purification technique.

The emergence of new molecules capable of attaching sepsis mediators to their surface has led to the development of extracorporeal 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 cartridge with synthetic resin, which has increased adsorption properties, before returning to the bloodstream. Experimental studies have shown the possibility of significantly reducing the concentration of inflammation mediators using this technique, increasing the immunomodulatory effect and survival rate. The use of the technique in the clinic is still very limited, but preliminary research results are quite encouraging.

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

The use of specific sorbents is intended for special treatment methods. Polymyxin-B coated resins can effectively bind lipopolysaccharides - mediators of the septic process. The use of resins significantly reduces the content of lipopolysaccharides in plasma, improves hemodynamics, and also affects the reduction of mortality. For this method, the moment of the beginning of therapy plays a significant role. Since it is impossible to determine the onset of septic syndrome before the appearance of clinical symptoms, the "time factor" significantly affects the results of 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 therapy of multiple organ failure syndrome and sepsis. The method is based on a combination of all physical mechanisms of extracorporeal blood purification: convection, adsorption and diffusion. The effectiveness of this combined method is significantly increased by the elimination of albumin-bound hydrophobic and hydrophilic toxins directly from the plasma, due to sequential processes in the extracorporeal circuit, and not from whole blood.

Treatment of liver failure

Evidence of the involvement of albumin-bound metabolites in the pathogenesis of multiple organ failure in patients with liver disease and the need for a safe and biocompatible treatment technique led to the development of the concept of albumin dialysis - molecular adsorbing 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 a sorbent used to eliminate albumin-bound molecules and biocompatible modern dialysis membranes. Protein-bound molecules are removed selectively by using albumin as a specific carrier of toxins in human blood. Thus, albumin dialysis is an extracorporeal system for replacing the liver's detoxification function, based on the concept of dialysis using a specific membrane and albumin as a dialysate. The protein acts as a molecular sorbent that is continuously restored by recirculation in the extracorporeal circuit. Due to the "attracting" effect of albumin, the system achieves a high level of elimination of albumin-bound substances, such as bile acids and bilirubin, which are not removed during hemofiltration. The filter membrane used in the albumin dialysis process, due to its physicochemical characteristics (ability to interact with lipophilic-bound domains), allows the release of albumin ligand complexes present in the blood. The membrane itself is impermeable to albumin and other valuable proteins, such as hormones, blood coagulation factors, antithrombin III. Two columns with activated carbon and anion-exchange resin as sorbents and a dialyzer allow the removal of both protein-bound and water-soluble metabolic products, thus making the system suitable for use in patients with hepatorenal syndrome.

Blood perfusion through the MARS filter is provided by the peristaltic pump of the artificial kidney apparatus. Albumin dialysate saturated with protein-bound and low-molecular water-soluble substances is directed in the MARS filter to a low-permeability dialyzer, where water-soluble substances are removed by using a bicarbonate dialysate. Ultrafiltration and correction of the acid-base and electrolyte balance of the patient's plasma can be performed through this element. Next, the albumin dialysate is purified from protein-bound molecules by passing through columns with activated carbon and anion-exchange resin, after which the regenerated albumin solution again enters the MARS filter. The flow in the albumin circuit is provided by the peristaltic pump of the MARS monitor. Venovenous access is required for blood perfusion. The duration of treatment depends on the patient's body weight, the size of the MARS membrane used (adult or child) and the indications for therapy. On average, its duration does not exceed 6-8 hours.

During MARS therapy, significant clinical changes are observed in most patients with both fulminant and decompensated chronic liver failure. First of all, this concerns the reversal of hepatic encephalopathy, stabilization of systemic hemodynamics, and improvement of liver and kidney function. A decrease in the intensity of skin itching in primary biliary cirrhosis is also observed. 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 liver failure. It can be assumed that comparative studies of the effectiveness of MARS therapy and the new Prometheus technology, which has recently appeared on the medical equipment market and is based on the principle of plasma fractionation using a membrane highly permeable to albumin molecules with subsequent perfusion of the filtrate through exchange resins, may be extremely interesting. Publications on the first results of using Prometheus technology in the treatment of liver failure show a fairly high attractiveness of the method.

Technical aspects of detoxification

Vascular access for continuous renal replacement therapy

The success of any technology of extracorporeal blood purification and, above all, continuous RRT largely depends on adequate vascular access. When performing continuous arteriovenous hemofiltration, catheters of the largest diameter are used for artery and vein catheterization to ensure a sufficient gradient facilitating blood movement through the extracorporeal circuit. The problem of vascular access is most acute when it is necessary to perform the procedure in newborns and children of the first year of life due to the small caliber of the artery and vein. In children weighing up to 5 kg, catheterization of the femoral or umbilical arteries and veins is performed using single-lumen probes of 3.5 to 5 Fr. The use of double-lumen venous catheters has facilitated vascular access in patients in intensive care units during both intermittent and continuous venovenous procedures. However, when using double-lumen catheters, blood recirculation is likely, which, if exceeding 20% of the blood flow volume in the extracorporeal circuit, can lead to significant hemoconcentration in it, increased blood viscosity, filter thrombosis, and inadequate blood purification. Given the tendency of blood recirculation to increase as the blood flow rate increases, intensive care units do not recommend performing the procedure with a blood flow rate of more than 180-200 ml/min.

Configuration of hemofilters for continuous renal replacement therapy

To reduce arteriovenous gradient losses during continuous arteriovenous hemofiltration, short filters of small size with a large sectional area are used. To prevent hemodynamic disturbances, especially at the beginning of the procedure, it is necessary to strictly take into account the volume of the primary filling of the hemofilter. In newborns and children with low body weight, filters with a primary volume of 3.7 ml to 15 ml are usually used, while the effective membrane area does not exceed 0.042-0.08 m2.

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Hemofilters with highly permeable membranes

In order to increase the clearance of "medium" molecules during extracorporeal detoxification procedures in patients with multiple organ failure and sepsis, hemofilters with highly permeable membranes (up to 100 kDa) are used. The results of the first experimental and clinical studies indicate a reliable increase in the elimination of inflammation mediators, and the clearances of these substances when using highly permeable membranes are similar for convection and diffusion principles of mass transfer. A randomized prospective study comparing the effectiveness of using highly permeable and standard hemofilter membranes in patients with acute renal failure and sepsis showed no decrease in albumin concentration 48 hours after the start of the procedure in both groups of patients. A significantly better clearance of IL-6 and IL-1 was also observed by the end of the first day in the group of patients treated with highly porous filters.

To draw final conclusions about the advisability of using hemofiltration with high-permeability filters, it is necessary to comprehensively evaluate the results of clinical trials and the first randomized prospective studies that are currently being conducted in leading clinics in Western Europe.

Solutions for continuous renal replacement therapy

The technology of continuous RRT requires the mandatory use of balanced replacement electrolyte solutions in order to fully or partially compensate for the volume of the removed ultrafiltrate. In addition, when performing continuous hemodialysis and hemodiafiltration, it is necessary to use dialysing solutions. Currently, two-component bicarbonate solutions are used for replacement, taking into account possible violations of hemodynamics and metabolic parameters when using acetate or lactate buffers. To achieve specific metabolic goals (correction of acidosis or electrolyte imbalance), the composition of replacement solutions varies significantly. However, factory-made bicarbonate-containing solutions have not yet become widespread in our country, and with certain rules and caution, one-component, lactate replacement and dialysing 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 initially leads 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 filter thrombosis, leading to unwanted blood loss, an increase in the time of RRT, and a significant increase in the cost of treatment. On the other hand, excessive anticoagulant therapy can cause serious complications, primarily bleeding, the frequency of which reaches 25%.

In clinical conditions, unfractionated heparin is the most widely used anticoagulant. The advantages of using this drug include the standardization of the method, ease of use, relative cheapness and the possibility of adequately monitoring the dose of the anticoagulant using available tests. One of the important advantages of heparin is the possibility of rapid neutralization of its action with 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. Moreover, the absence of a direct relationship between the frequency of its development and the absolute amount of the administered anticoagulant has been proven. The frequency of hemorrhagic complications is largely determined by the balance of the coagulation and anticoagulation systems in patients of different groups, as well as the variability of the half-life of heparin.

The ability to quickly bind heparin and neutralize its activity with protamine sulfate formed the basis of the regional anticoagulation method. During the RRT procedure, heparin is administered before the filter to prevent its thrombosis, and the required dose of protamine is administered after the filter, with strict control of anticoagulation in the extracorporeal circuit. This method reduces the risk of hemorrhagic complications. However, when using it, one cannot exclude heparin-induced thrombocytopenia, as well as allergic reactions to the administration of protamine sulfate and the development of hypotension, bronchospasm and other manifestations that are extremely dangerous for patients in intensive care units.

Regional citrate anticoagulation reduces the risk of bleeding, but requires a special method of extracorporeal therapy and monitoring of ionized calcium concentration. This technique allows for effective anticoagulation, but requires continuous addition of calcium to the extracorporeal circuit. In addition, since citrate metabolism 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 enoxaparin sodium, nadroparin calcium, etc., has become widespread. Although the use of low-molecular-weight heparins (molecular weight of about 5 kDa) somewhat reduces the risk of developing hemorrhagic complications, their cost is significantly higher compared to heparin, and their use requires special, more expensive monitoring. These drugs have a pronounced cumulative effect, and they should be used with great caution, especially with continuous RRT.

A new method that allows to reliably reduce the doses of anticoagulants during RRT in patients with a high risk of bleeding is a modification of the extracorporeal circuit using the technique developed at the A.N. Bakulev Scientific Center for Cardiovascular Surgery of the Russian Academy of Medical Sciences. The use of an extracorporeal circuit with intravenous catheters treated with heparin using a special technology makes it possible not to use systemic anticoagulation during the procedure. At the same time, the effective operation of the filter is maintained, the thromboresistance of the circuit increases, and the risk of hemorrhagic complications in patients with multiple organ failure syndrome is reduced.

Currently, scientists are working on creating athrombogenic hemofilter membranes, blood lines and catheters coated with heparin.

Patients with severe thrombocytopenia and coagulopathy undergo RRT without systemic anticoagulation, but the duration of continuous procedures is limited to 12-18 hours.

Over the past few decades, there have been enormous changes in the approach to detoxification methods in the postoperative period in surgical patients. This is due to the proven effectiveness of efferent methods in a number of pathological conditions, the emergence of many new, including hybrid, treatment technologies, and the emerging progress in the outcomes of complex intensive care. Of course, in the near future, we should expect new multicenter randomized studies aimed at determining the types of extracorporeal detoxification, the use of which will be most effective for solving specific problems in certain clinical situations. This will open the way to a wider use of detoxification methods in accordance with both "renal" and "extrarenal" indications. The results of such studies will help determine the most justified time to start using extracorporeal blood purification, its "dose" and effectiveness depending on a specific method of therapy in critically ill patients, including those who have undergone major reconstructive surgeries.

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