RU2783826C2 - Methods and systems for removal of carbon dioxide - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine, namely to a method for removal of hydrogen cations (H⁺) from biological fluid in a dialysis system, a method for extracorporeal treatment of blood of a subject – a human or an animal in the dialysis system, as well as to a method for the treatment of a subject suffering from an acid-base balance disorder. Methods include impact on biological fluid through semipermeable membrane of dialysis fluid in a dialyzer, in which dialysis fluid includes (I) pH value in the range from 8.0 to 11.0, (II) at least one buffer agent with pKa value in the range from 7.0 to 11.0, and (III) buffer capacity for H⁺ ions of at least 12 mmol/l, wherein the method additionally includes automatic determination of a number of hydrogen cations (H⁺) removed from biological fluid, where the number of hydrogen cations (H⁺) removed from biological fluid is calculated based on the buffer capacity of dialysis fluid and the difference between pH value of dialysis fluid coming into the dialyzer and pH value of dialysis fluid coming out of the dialyzer.

EFFECT: above-described methods allow for effective removal of hydrogen cations from biological fluid.

19 cl, 7 dwg, 4 tbl, 4 ex

Description

The field of technology to which the invention belongs

The present invention relates to systems and methods used for extracorporeal lung support. The inventive dialysis solution provides efficient transport of carbon dioxide, bicarbonate, and hydrogen cations from a biological fluid, such as blood, through a semi-permeable membrane into the dialysis fluid. The proposed systems and methods are useful for the treatment or prevention of various conditions associated with the presence of undesirable substances in the blood and/or with an undesirable blood pH, such as dysfunction of the lungs, kidneys or liver.

State of the art

Transport of metabolites in the blood

One of the metabolites in the body of vertebrates (humans or animals), formed mainly as a result of cellular respiration, is carbon dioxide (CO ₂ ). The formation of carbon dioxide in the body of vertebrates (humans or animals) occurs in peripheral tissues as a result of metabolic activity. Carbon dioxide formed in the tissues diffuses in their capillaries in the direction of reducing its partial pressure into the blood, mainly into erythrocytes. In vertebrates, there are three main ways of transporting carbon dioxide in the blood: (a) dissolution of CO ₂ (carbon dioxide is much more soluble in the blood than oxygen), (b) attachment to blood proteins such as hemoglobin and plasma proteins, and (c ) the formation of ion pairs, namely bicarbonate ions and H ⁺ ions. An adult at rest produces approximately 10 mmol CO ₂ per minute. In addition, approximately 8 mmol (approximately 15,000 mmol/day) of H ⁺ ions are formed in erythrocytes every minute. According to calculations, the kidneys usually excrete approximately 100 mmol of H ⁺ ions per day. These calculations are based on the amount of blood (5 l) in the body of an adult: per minute, 10 mmol of CO ₂ enters 5 l of blood, that is, 2 mmol of H ⁺ ions per 1 l of blood.

At the molecular level, protein-bound carbon dioxide (b) reversibly attaches to blood proteins, such as hemoglobin and plasma proteins, by combining with the amino groups of blood proteins, such as hemoglobin, and forming carbaminoproteins, such as carbaminohemoglobin. Carbon dioxide usually attaches not to iron, like oxygen, but to the amino groups of hemoglobin and the amino groups of the polypeptide chains of other blood proteins, in particular plasma proteins. Bicarbonate ions (c) result from the entry of carbon dioxide into red blood cells (erythrocytes) and react with water to form carbon dioxide (H ₂ CO ₃ ^- ). This reaction is catalyzed mainly by the enzyme carbonic anhydrase, found among other things in red blood cells. This enzyme is also present in the endothelium of the lungs and other parts of the body. Then carbon dioxide dissociates to form bicarbonate ions (HCO ₃ ) and hydrogen cations:

Добавление или удаление (будь то in vivo или in vitro) одного или более веществ, участвующих в реакции, вызывает, согласно принципу Ле Шателье, смещение реакции в соответствии с равновесием. Присутствие карбоангидразы не является строго обязательным для протекания этой реакции, хотя оно важно для эффективной конверсии.The initial and resulting substances (reagents and products) in this reaction are in dynamic equilibrium, which is qualitatively reflected in the above equation by arrows

The addition or removal (whether in vivo or in vitro) of one or more substances involved in a reaction causes, according to Le Chatelier's principle, a shift of the reaction in accordance with equilibrium. The presence of carbonic anhydrase is not strictly required for this reaction to take place, although it is essential for efficient conversion.

In addition, as a result of metabolic activity in the human or animal body, organic acid molecules are formed. Molecules of organic acids are another source of H ⁺ ions. The presence of H ⁺ ions affects the pH of the blood. However, in the human or animal body, the pH value of fluids such as blood must be within a narrow range; for example, in the human body, these pH values are in the range from 7.35 to 7.45, which corresponds to a slightly alkaline environment. Therefore, the functioning of blood buffer systems is of great importance. If a subject suffers from a condition associated with an excess of H ⁺ ions, this usually means that the capacity of the buffer system is insufficient to maintain the pH of the blood within the specified range.

In the general case, hydrogen cations formed during the dissociation of carbon dioxide into these cations and bicarbonate ions can attach to proteins in the blood, in particular in erythrocytes. The main intracellular acceptor of hydrogen cations, or a buffer for the addition of the latter, is the hemoglobin protein. Basically, hydrogen cations are attached to the histidine side chains of hemoglobin.

Bicarbonate plays an extremely important biochemical role in the physiological buffer system that maintains a normal pH level. In healthy vertebrates (humans or animals) (a) about 5% of carbon dioxide is transported unchanged, being dissolved in plasma, (b) about 10% of carbon dioxide is transported, being attached to blood proteins , in particular to hemoglobin and plasma proteins, and (c) most of the carbon dioxide is transported in the form of bicarbonate ions and hydrogen cations, the latter being bound mainly to proteins.

In the respiratory organs, namely in the lungs, of a healthy human or animal organism, carbon dioxide is released and, as a result, its partial pressure (pCO ₂ ) decreases. Normal values of pCO ₂ in the arterial blood of a subject (human) are in the range of 35-45 mmHg (Hg). Values of pCO ₂ greater than 45 mmHg are referred to as "high pCO ₂ " or "elevated pCO ₂ ". One of the possible causes of high pCO ₂ is hypoventilation. If pCO ₂ in the arterial blood of the subject exceeds 45 mm Hg. Art., then this subject requires treatment to reduce pCO ₂ .

- Acidosis

The term "acidosis" refers to hyperacidity in the body of mammals. The presence of acidosis can be determined by measuring the pH of the subject's physiological fluids, in particular blood plasma, more specifically arterial blood plasma. In mammals, in particular humans, acidosis is characterized by an arterial plasma pH of less than 7.35. pH values below 6.8 are usually unacceptable for the human or animal body, since the pH outside the specified range leads, as a rule, to an irreversible disruption of cell activity. Thus, acidosis is characterized by an arterial plasma pH ranging from 6.8 to less than 7.35. Hemoglobin and, to a lesser extent, plasma proteins are able to act as a buffer against blood pH, for example, in the case of an excess of hydrogen cations. The counteraction of the buffer system to the change in the concentration of hydrogen cations minimizes the change in the pH of the blood as it passes through the capillaries of the tissues. However, the buffer capacity is not unlimited, which creates the possibility for acidosis to occur.

In general, subjects suffering from acidosis can be divided, based on the molecular causes of the increase in acidity in the blood plasma, into two main subgroups, namely the subgroups of respiratory acidosis and metabolic acidosis. In practice, there are cases of overlap between these two conditions, that is, a given subject may suffer from (I) metabolic acidosis or (II) respiratory acidosis or (III) a combination of metabolic and respiratory acids.

In each case, the symptoms of acidosis include headache, malaise, fatigue, drowsiness, tremors, and central nervous system dysfunction that may progress to coma if left untreated. Therefore, subjects suffering from acidosis require treatment.

Metabolic acidosis, considered at the molecular level, arises from an increase in the number of organic acid molecules due to an increase in the production of these acids (for example, lactic acid) as a result of increased metabolic activity and / or impaired ability of the kidneys to excrete acids. Metabolic acidosis in chronic renal failure (CRF) is a consequence of a decrease in the ability to excrete non-volatile acids and a decrease in bicarbonate synthesis in the kidneys, resulting in an increase in the amount of hydrogen cations in the body. Organic acids can be formed, for example, from amino acid residues of protein catabolism or as a result of the accumulation of keto acids (ketosis) during fasting or diabetic acidosis. In many cases, the body attempts to compensate for the metabolic acidosis with respiration (respiratory compensation), however, non-volatile metabolites are not eliminated in this way, so that affected subjects are at risk of exhaustion leading to respiratory failure. Severe metabolic acidosis no longer adequately compensated by the lungs may require treatment by infusion into the body of a buffer drug such as bicarbonate. Symptomatic treatment of metabolic acidosis in chronic renal failure (CRF) can also be done through kidney dialysis. One form of kidney dialysis, called hemodialysis, is based on a device that filters out toxins, salts, and certain fluids from bodily fluids. Hemodialysis is the most common treatment for progressive kidney failure. However, long-term dialysis-based therapies often fail to completely eliminate the base deficiency in metabolic acidosis, as shown, for example, in a review published by Kopple et al. (Kidney International, 2005, 67, S95, pp. 21-27).

Respiratory acidosis, considered at the molecular level, occurs due to the accumulation of carbon dioxide in the blood due to insufficient ventilation (hypoventilation). The most common cause of this condition is lung dysfunction, although it can also occur due to traumatic brain injury, drugs (especially anesthetics and sedatives), and disorders of the central nervous system due to, for example, brain tumors. It may also occur as a compensatory response to chronic metabolic alkalosis. In the presence of respiratory acidosis, such as diseases that cause lung dysfunction such as advanced emphysema and muscular dystrophy, a compensatory mechanism such as exogenous bicarbonate infusion cannot effectively reverse the accumulation of carbon dioxide associated with uncompensated respiratory acidosis. In such cases, the use of lung support may be indicated.

- Systems for lung support and treatment of respiratory acidosis

One of the most important advances in medicine was the invention and then use of artificial, or mechanical, ventilation in the case of patients suffering from respiratory failure. In Germany, artificial lung ventilation is used annually for more than 240,000 patients with an average duration of therapy equal to 10 days. The average mortality rate for these patients is about 35%. If, along with respiratory failure, dysfunction of any other organ occurs, then mortality rises to approximately 75%.

Artificial lung ventilation is a method of mechanical support or replacement of spontaneous breathing. Mechanical ventilation may involve the use of a device (ventilator) or the provision of respiratory support by a healthcare worker. In any case, mechanical ventilation (ALV) may involve the use of a device inserted inside the patient's body ("invasive ventilation"), namely through the mouth (eg, endotracheal tube) or through the skin (eg, tracheostomy tube). There are two main types of mechanical ventilation, namely positive pressure ventilation, in which a gas (such as air) is forced into the trachea, and negative pressure ventilation, in which the patient's chest is placed in a low-pressure envelope, causing the chest to expands and draws air into the patient's lungs. Along with all the advantages of artificial lung ventilation, it also has disadvantages, such as a decrease, up to 30%, of blood flow (perfusion) through internal organs, such as the liver, a decrease in blood pressure, an increase in intra-abdominal pressure, a deterioration in the excretory function of the kidneys, and ventilator-induced damage. lungs (HIPL), barotrauma, volutrauma, atelectrauma and biotrauma, acute respiratory failure syndrome (ARF), pneumonia, dyspnea in patients under sedation during procedures in the intensive care unit (ICU), weaning from the ventilator after approximately 48 hours ventilation (see, for example, Larsen and Ziegenfuss, "Artificial Lung Ventilation", Springer, Berlin, Heidelberg, 2013; Schmidt et al., Intensive Care Med., 2014, 40, pp. 1-10).

Some of the problems associated with the unwanted effects of mechanical ventilation can be resolved with the help of extracorporeal lung support systems. These systems are designed to provide extracorporeal oxygenation (oxygenation) or extracorporeal removal of carbon dioxide from the blood. Today, extracorporeal membrane oxygenation (ECMO) is one of the most common methods of extracorporeal lung support and is used as an adjuvant or replacement therapy in relation to lung function. The blood is removed from the body and introduced into a device containing a membrane (a porous membrane for short-term treatment and a non-porous membrane for long-term treatment) separating the blood from a gas phase (oxygen or an oxygen-containing gas mixture, such as a mixture of air or oxygen and a propellant gas), which allows you to saturate the blood with oxygen. Since the extracorporeal blood flow during ECMO is close to the heart's flow rate of up to approximately 7 L/min, it is possible to combine ECMO with cardiac support by including a pump (extracorporeal life support - ECLS) in the system. As an alternative to membrane oxygenation, oxygen can be injected directly into the blood in an extracorporeal circuit, for example with a (super)oxygenated fluid, as described in US Pat. However, extracorporeal fluid administration generally increases blood volume, which makes it necessary to reduce this volume before re-introducing gas-enriched blood into the human or animal body. The introduction of a liquid saturated or supersaturated with gas increases the risk of bubble formation. In general, the presence of bubbles, in particular oxygen bubbles, can cause unwanted denaturation of blood proteins, so these methods and systems require extreme care in use to minimize bubble formation. Alternatively, oxygenation of the blood can be performed directly without a gas exchange membrane, for example by introducing oxygen into the blood using a bubble oxygenator. This method is associated with undesirable foam formation and the risk of gas embolism. This method is not suitable for the treatment of acidosis.

Another priority for extracorporeal lung support is extracorporeal CO2 removal ( _ECCO2R ). This therapy may be indicated, for example, in cases of respiratory acidosis. In a review published by Baker et al. (J. Mens. Care Soc, 2012, 13, pp. 232-236), ECCO2R systems typically use a gas exchange membrane through which carbon dioxide diffuses from the blood into the extracorporeal circuit to the gas chamber. According to Baker et al., the most widely used system based on the ECCO2R technique is undoubtedly the AV-ECCO2R system manufactured by Novalung (Germany). The operation of this system is based on the entry of blood in the extracorporeal circuit into contact with a gas-permeable membrane, on the other side of which there is a gas (oxygen or an oxygen-containing gas mixture) acting as a "displacement gas", as a result of which gaseous carbon dioxide passes through the membrane and is removed from the gas chamber by the flow of displacing gas.

In the publication WO 2010/091867 (Novalung), incorporated into the present application by reference, a device for treating biological fluid in a three-chamber system is described. The first chamber is intended to receive a biological fluid such as blood, and the second chamber, separated from the first chamber by a gas-permeable but not liquid-permeable membrane, serves, in this embodiment, to receive a gas such as oxygen. Due to the fact that the membrane is gas permeable, gaseous carbon dioxide can diffuse from the first chamber into the second, which implements the ECCO2R mechanism, and oxygen can diffuse, in this embodiment, from the second chamber into the first. This provides extracorporeal lung support. Small molecules, such as water molecules, can be removed from the first chamber through a liquid-permeable membrane located in the third chamber.

Thus, existing methods and devices developed for the extracorporeal removal of carbon dioxide are based on the gas used as the dialysis fluid. The mentioned three-chamber system is relatively complex, and its use may be associated with an unfavorable factor in the form of a high resistance to blood flow. As one alternative, the Respiratory Dialysis® system from ALung Technologies is on the market. Its technique is based on the use of propellant gas instead of dialysis fluid. This technique is not suitable for regulating acid-base balance and/or blood electrolyte homeostasis and is not suitable for use in traditional dialysis devices (Cove et al., Critical Care, 2012, 16:232).

In publications on this topic (Aucella et al., Contrib. Nephrol., 2007, 156, pp. 287-296; Vigano et al., ed. Ronco/Cruz, "Hemodialysis - from basic scientific research to clinical practice") describes dialysis fluids containing carbonate/bicarbonate. However, the fluids described are characterized by relatively high bicarbonate concentrations ranging from 35 to 48 mmol. Such dialysis fluids are unsuitable or not applicable for removing excess bicarbonate from the blood. These dialysis fluids use acetic acid as an additional ingredient.

For prior art ECCO2R systems, a flow rate that is lower than that of ECMO (ie, approximately 2 L/min or less) is appropriate. Such a blood flow velocity is realized, for example, in widely used pumpless extracorporeal lung support systems (pECLA). In general, the effectiveness of both blood oxygenation and removal of carbon dioxide from it depends on the blood flow rate in accordance with the following principles: the higher the blood flow rate, the better the oxygenation of the subject (for example, the patient) as a whole, and the lower the blood flow rate, the more effective removal of carbon dioxide from the blood (ECCO2R). Generally, high speed (suitable for ECMO) is considered to be above 2400 ml/min, medium speed (suitable for ECMO and ECCO2R) is values in the range of 800-2400 ml/min, and low speed (suitable for ECCO2R) is values below 800 ml/min.

An alternative form of lung support is fluid breathing, in which a normally air-breathing organism inhales an oxygen-enriched fluid (such as perfluorocarbon) for breathing, rather than air, in accordance with a total fluid ventilation (FLV) or partial fluid ventilation (PLV) technique. when the lungs are filled with fluid containing perfluorocarbon (PFC) using a mechanical ventilator to move inhaled and exhaled gases such as oxygen and carbon dioxide (see Lachmann et al., Intensivmed. und Notfallmed, 1997, 34, 513 -526). The standard for the use of liquid breathing has not yet been approved.

In accordance with the prior art, the withdrawal of the subject's blood into the extracorporeal circuit is carried out not only to support the lungs (oxygenation and/or removal of CO ₂ ), but, alternatively, to support other organs, such as the liver or kidneys. In many cases, patients suffer from multi-organ dysfunction, and combination therapy with lung (eg, ventilator), liver, and kidney (particularly dialysis, such as hemodialysis) support may be indicated. Due to the number of devices used, such combination therapy is relatively complex and therefore difficult to implement in daily clinical practice.

Setting goals

One of the objectives of the present invention is to provide new systems and methods suitable for the treatment of acidosis. It is preferred to provide a generic method suitable for the treatment of subjects suffering from respiratory acidosis, metabolic acidosis, or any combination of forms of respiratory and metabolic acidosis. Another object of the invention is to provide an improved method for removing metabolites, in particular carbon dioxide, in general from a biological fluid such as blood, and in particular from a human or animal body. Another object of the invention is to provide an improved method for removing carbon dioxide, which eliminates the disadvantages associated with the contact of blood and air in the traditional ECCO2R technique.

Furthermore, it is an object of the invention to provide lung support that is quantitatively superior in CO ₂ removal (or, alternatively or in addition, H ⁺ /bicarbonate removal) in the millimolar range. Another objective is to provide combined removal of H ⁺ and bicarbonate in the largest possible quantities, ie in the millimolar range. Finally, another object is to provide a method suitable for the treatment of disorders of the normal functioning of several organs, including the lungs, liver and kidneys in any combination, preferably with a single device. These and other objects of the invention can be solved using the systems and methods presented in the present description and designed to remove carbon dioxide from a biological fluid, in particular from the blood.

The systems and methods provided herein can correct, treat, or prevent acidosis, facilitate breathing, and provide time to recover from acute decompensation. Other advantages of the invention are related to elements of the described systems and methods.

Brief summary of the invention

Systems and methods are described below to solve the above problems and overcome the shortcomings of the methods and methods of the prior art. In particular, the systems and methods described herein offer advantages over existing methods or methods for extracorporeal carbon dioxide removal based on dialysis fluid gas. For the purpose of extracorporeal removal of carbon dioxide in the systems and methods presented in the present description, a liquid (dialysis fluid, or dialysis fluid) is used. This effectively removes carbon dioxide from the blood, adjusts the blood pH to a desired or normal value, and regulates (by increasing or decreasing) the concentration of bicarbonate in the blood. The measurement and monitoring of the pH values of the dialysis fluid can be performed automatically and substantially continuously. Similarly, the amount of carbon dioxide or hydrogen ions or bicarbonate removed from the blood can be easily, substantially automatically and substantially continuously monitored and measured, thereby providing a relatively smooth and simple optimization of the systems and methods described herein. This information can be shared with primary care professionals to optimize patient care. Therefore, the systems and methods provided herein allow for adaptive organ support based on the needs of individual patients. For example, the systems and methods provided herein provide support for the lungs and, in many cases, the liver and kidneys, depending on their function. In addition, the systems and methods provided herein provide stabilization or normalization of blood pH in the case of patients suffering from acid-base imbalance, such as metabolic or respiratory acidosis. Generally, the desired or normal blood pH is in the range of 7.35 to 7.45, more preferably 7.36 to 7.44, even more preferably 7.37 to 7.43, even more preferably from 7.38 to 7.42, even more preferably from 7.39 to 7.41, and most preferably about 7.40. In general, acceptable blood pH values are in the range of 6.8 to 8.0.

Dialysis fluid suitable for use in the systems and methods described herein may be characterized as follows:

(I) have a pH value in the range of 8.0 to 11.0,

(II) contain at least one buffering agent having a pKa value in the range of 7.0 to 11.0,

(III) have an H ⁺ ion buffer capacity of approximately 12 mmol/L H ⁺ ions or more.

This description provides details of buffer capacity, pH and other parameters, and also provides a quantitative analysis to determine the buffer capacity in accordance with the invention. Suitable dialysis fluid buffering agents include, for example, tris(hydroxymethyl)aminomethane (Tris, TGAM), carbonate/bicarbonate, and water-soluble proteins such as albumin.

In general, the systems and methods provided herein provide a technique for removing at least one unwanted substance from a biological fluid, such as blood, by exposing the biological fluid, such as blood, to a dialysis fluid having the preferred properties, given in the present description, through a semi-permeable membrane. Further, in general, the systems and methods provided herein provide a technique for removing at least one unwanted substance from a biological fluid, such as blood, by (i) introducing the biological fluid into a first chamber of a device comprising a first chamber, and a second chamber separated by a semi-permeable membrane; and (ii) introducing into the second chamber of the device a dialysis fluid having the preferred properties described herein. Thus, the systems and methods provided herein provide an improved means of extracorporeal carbon dioxide removal and regulation of blood pH and buffering capacity. In the present description and the attached claims are, in particular, the preferred and useful implementations of these systems and methods.

The first object of the invention is a method for removing at least one undesirable substance from a biological fluid, comprising (a) exposing the biological fluid through a semipermeable membrane to a dialysis fluid characterized by (I) a pH value ranging from 8.0 to 11, 0, (II) at least one buffering agent having a pKa value ranging from 7.0 to 11.0, and (III) a buffering capacity of at least 12 mmol/L for H ⁺ ions. The at least one undesirable substance may be one or more of the following: carbon dioxide (CO ₂ ), hydrogen cation (H ⁺ ), hydrogen carbonate (HCO ₃ ^- ), and solvates thereof. The method also includes (b) automatically determining the amount of one or more undesirable substances selected from the group consisting of carbon dioxide (CO ₂ ), hydrogen cation (H ⁺ ), hydrogen carbonate (HCO ₃ ^- ) and their solvates removed from the biological fluid . Automatic determination of the amount of one or more undesirable substances selected from the group consisting of carbon dioxide (CO ₂ ), hydrogen cation (H ⁺ ), hydrogen carbonate (HCO ₃ ^- ) and their solvates removed from the biological fluid, includes the measurement of the difference in pH value dialysis fluid before the latter is exposed to the biological fluid through the semi-permeable membrane and the pH value of the dialysis fluid after the latter comes into contact with the biological fluid through the semi-permeable membrane in accordance with the buffer capacity and flow rate. The biological fluid may be blood.

The dialysis fluid may contain at least one buffering agent, which may be tris(hydroxymethyl)aminomethane (Tris, TGAM), carbonate/bicarbonate, and albumin. In addition, the dialysis fluid may have a pH value in the range of 8.0 to 9.0 and contain (I) 10 to 40 mmol/l carbonate/bicarbonate and (II) 10 to 60 g/l albumin. The method may also include (c) treating the dialysis fluid, during which the dialysis fluid may be exposed to one or more of the following: (I) an adsorbent, (II) a membrane, (III) an acidic medium at an appropriate pH, and (IV) alkaline environment with an appropriate pH level. In addition, treatment of the dialysis fluid may include removal of carbon dioxide therefrom. The method may also further include (d) recycling the dialysis fluid.

The second object of the invention is a method of extracorporeal treatment of blood of a human or animal subject by (a) drawing blood from a vein or artery of the subject, (b) exposing the blood through a semi-permeable membrane to a dialysis fluid characterized by (i) a pH value ranging from 8, 0 to 11.0, (II) at least one buffering agent having a pKa value in the range from 7.0 to 11.0, and (III) a buffering capacity of at least 12 mmol/l for H ⁺ ions, (c) removing at least one unwanted substance from the blood; and (d) returning the blood to the subject's body. The at least one undesirable substance may be one or more of the following: carbon dioxide (CO ₂ ), hydrogen cation (H ⁺ ), hydrogen carbonate (HCO ₃ ^- ), and solvates thereof. The method may also include (e) automatically determining the amount of one or more undesirable substances selected from the group consisting of carbon dioxide (CO ₂ ), hydrogen cation (H ⁺ ), hydrogen carbonate (HCO ₃ ^- ) and their solvates removed from the blood, and automatic determination of the amount of one or more undesirable substances selected from the group consisting of carbon dioxide (CO ₂ ), hydrogen cation (H ⁺ ), bicarbonate (HCO ₃ ^- ) and their solvates removed from the blood, may include measuring the difference in pH value dialysis fluid before exposure of the latter to the blood through the semipermeable membrane and the pH value of the dialysis fluid after contact with the latter with blood through the semipermeable membrane. The dialysis fluid may contain at least one buffering agent, including tris(hydroxymethyl)aminomethane (tris, TGAM), carbonate/bicarbonate, and albumin. In addition, the dialysis fluid may have a pH value in the range of 8.0 to 9.0 and contain (I) 10 to 40 mmol/l carbonate/bicarbonate and (II) 10 to 60 g/l albumin. The method may also include (e) treating the dialysis fluid, during which the dialysis fluid may be exposed to one or more of the following: (I) an adsorbent, (II) a membrane, (III) an acidic medium with an appropriate pH, and (IV) alkaline environment with an appropriate pH level. In addition, treatment of the dialysis fluid may include removal of carbon dioxide therefrom. The method may also include (g) recycling the dialysis fluid.

The third object of the invention is a method of treating a subject suffering from an acid-base imbalance by (a) taking a biological fluid from the body of the subject, (b) exposing the biological fluid through a semi-permeable membrane to a dialysis fluid characterized by (I) a pH value that is in the range from 8.0 to 11.0, (II) at least one buffering agent having a pKa value in the range from 7.0 to ^11.0 , and (III) a buffer capacity of at least 12 mmol/L, (c) removing at least one unwanted substance from the biological fluid and (d) returning the biological fluid to the subject's body. The at least one undesirable substance may be one or more of the following: carbon dioxide (CO ₂ ), hydrogen cation (H ⁺ ), hydrogen carbonate (HCO ₃ ^- ), and solvates thereof. The method may also include (e) automatically quantifying one or more undesirable substances selected from the group consisting of carbon dioxide (CO ₂ ), hydrogen cation (H ⁺ ), hydrogen carbonate (HCO ₃ ^- ) and their solvates removed from the biological fluid. environment. Automatic determination of the amount of one or more undesirable substances selected from the group consisting of carbon dioxide (CO ₂ ), hydrogen cation (H), hydrogen carbonate (HCO ₃ ^- ) and their solvates removed from the biological fluid may include measuring the difference in pH value dialysis fluid prior to exposing the latter to the biological fluid through the semipermeable membrane and the pH value of the dialysis fluid after contacting the latter with the biological fluid through the semipermeable membrane. The dialysis fluid may contain at least one buffering agent from the group of such agents, including tris(hydroxymethyl)aminomethane (tris, TGAM), carbonate/bicarbonate and albumin. In addition, the dialysis fluid may have a pH value in the range of 8.0 to 9.0 and contain (I) 10 to 40 mmol/l carbonate/bicarbonate and (II) 10 to 60 g/l albumin. The method may also include (e) treating the dialysis fluid, during which the dialysis fluid may be exposed to one or more of the following: (I) an adsorbent, (II) a membrane, (III) an acidic medium at an appropriate pH, and (IV) alkaline environment with an appropriate pH level. In addition, treatment of the dialysis fluid may include removal of carbon dioxide therefrom. The method may also include (g) recycling the dialysis fluid. A subject suffering from acid-base imbalance may also suffer from one or more of the following: respiratory acidosis, metabolic acidosis, pulmonary insufficiency, hepatic insufficiency, and renal insufficiency.

The fourth object of the invention is a dialysis fluid intended for use in one of the methods presented in the present description, or for use in the treatment of humans or animals, and characterized by (I) a pH value in the range from 8.0 to 11.0, (II ) at least one buffering agent having a pKa value in the range of 7.0 to 11.0, and (III) a buffering capacity of 12 mmol/l or more for H ⁺ ions. The dialysis fluid may contain at least one buffer agent from the group of such agents including tris(hydroxymethyl)aminomethane (Tris, TGAM), carbonate/bicarbonate, and albumin. In addition, the dialysis fluid may have a pH value in the range of 8.0 to 9.0 and contain (I) 10 to 40 mmol/l carbonate/bicarbonate and (II) 10 to 60 g/l albumin.

A fifth aspect of the invention is a method for determining the buffer capacity of a dialysis fluid, comprising substantially continuously titrating the dialysis fluid with an acid or alkali solution to obtain a desired or optimum pH value of the dialysis fluid.

A sixth aspect of the invention is a method for substantially continuous and substantially automatic calculation of the pCO _{2 of} a biological fluid, comprising determining the pH and bicarbonate concentration for a dialysis fluid present in a dialysis circuit, performed by substantially continuous titration of the dialysis fluid with an acid or alkali solution to obtain the desired or optimal pH value of the dialysis fluid.

Brief description of the drawings

The drawings show:

in fig. 1 diagram of the dialysis system presented in the present description and connected to a human patient for therapy in accordance with the method presented in the present description,

in fig. 2 diagram of the dialysis system presented in the present description,

in fig. 3 - buffer capacity of solutions containing bicarbonate and/or albumin in accordance with the description given in example 1,

in fig. 4 illustrates the comparison of the methods presented in the present description, with the reference method in accordance with the description given in example 2,

in fig. 5 - Ca ²⁺ levels in dialysis fluid and blood versus time as described in Example 3.

In FIG. 6 shows the pH values of blood and dialysate during therapy using the dialysis system presented in the present description of the modified HepaWash® LK2001 dialysis device manufactured by HepaWash (Munich, Germany). During the passage of blood through the dialysis device (dialyzer), its pH may change. There is a direct correlation between the pH values of blood and dialysis fluid. The dialyzer can adjust the pH of the dialysis fluid entering it in accordance with the flow rates of both fluids entering the dialyzer.

In FIG. 7, the volume flow through the dialysis system described herein is shown as a function of HCO ₃ ⁻ concentration. The flow rate (in ml/min) decreases with increasing concentration of HCO ₃ ^- (in mmol/l).

Detailed description of the preferred embodiments of the invention

Terms and Definitions

"Containing": in the context of the present description means the possibility of having more positions or elements than actually listed. However, in the context of some embodiments of the invention, the term "comprising" should be interpreted in a narrower sense as synonymous with the terms "consisting essentially of" or "consisting of".

"Acidosis": hyperacidity (that is, an increased concentration of hydrogen cations) in the blood and other tissues of the body. Unless otherwise specified, this term generally refers to hyperacidity in blood plasma. The term "hyperacidity" generally means that the arterial plasma pH is less than 7.35, typically 6.8 to less than 7.35.

"Carbonate equilibrium": the equilibrium between carbonic acid and bicarbonate/hydrogen cation:

This equilibrium is dynamic and dissociation is spontaneous (i.e., occurs independently of a catalytic reaction involving an enzyme such as carbonic anhydrase).

"Buffer": in the context of the present description means a weak acid or alkali suitable for maintaining a certain acidity (pH) value of the solution (for example, close to the pKa value of a weak acid or alkali, for example pH = pKa ± 1), even when an acid or alkaline compound. The term "buffering agent" can be used for both solids and solutes. Buffer agents are usually soluble in solutions, preferably in aqueous solution. The function of a buffering agent is to prevent an undesirable change in pH when an acidic or alkaline compound is added to the solution. Buffer agents may also be referred to as salts of a weak acid or alkali, suitable for maintaining a certain value of acidity (pH) of the solution.

"Carboanhydrase": as used herein, refers to an enzyme that catalyzes the reversible conversion of dissolved carbon dioxide to carbonic acid:

(то есть углекислота)

(i.e. carbonic acid)

Carbonic anhydrase is commonly found in red blood cells (erythrocytes) and other parts of the human or animal body.

"dialysis fluid" and "dialysis fluid": in the context of the present description are used interchangeably.

"Erythrocytes", or red blood cells (RBCs): synonymous names for the blood cells of the vertebrate body, characterized by the presence of hemoglobin in the cytoplasm. CCPs capture oxygen in the lungs and release it in peripheral tissues, and also capture unwanted substances such as hydrogen cations and carbon dioxide in peripheral tissues and release them in the lungs. Release/uptake in peripheral tissues occurs when erythrocytes pass through the capillaries of these tissues.

"Extracorporeal": refers to any process, procedure, substance or device that is located or performed outside the human or animal body. When processes, procedures, substances or devices are located or performed partly outside the human or animal body, this term refers to the part outside the body.

"Fluid": refers generally to the non-solid state of matter. The fluid is usually either a liquid or a gas.

"Hemoglobin", abbreviated as Hb: a protein normally found in the red blood cells of vertebrates. Peptide chains of hemoglobin contain many amino groups and carboxyl groups. Typically, a hemoglobin molecule contains four spherical protein subunits. Each subunit consists of a protein chain (globin) linked to a non-protein heme group. Hemoglobin is capable of reversibly attaching small molecules such as metabolites, primarily oxygen (O ₂ ), hydrogen cations (H ⁺ ) and carbon dioxide (CO ₂ ) or solvates of any of the above. As a rule, oxygen can reversibly attach to the heme group. In contrast, carbon dioxide can usually reversibly add to amino groups (typically the N-terminus and side chains of arginine and lysine residues in hemoglobin), leading to the formation of carbamine groups. Hemoglobin containing one or more carbamin groups is called carbaminohemoglobin. Carbaminohemoglobin is the main contributor to the Haldane effect. It is generally believed that carbaminohemoglobin is responsible for approximately 10% of carbon dioxide transport in mammals. Finally, hemoglobin carboxyl groups are capable of attaching hydrogen cations, thereby providing a buffering effect (such hydrogen cations are usually formed as a result of CO ₂ dissociation and the occurrence of carbonate equilibrium). Within the normal physiological pH range, the attachment of most hydrogen cations by hemoglobin occurs with the participation of the imidazole group of the amino acid histidine present in the globin chain. Deoxygenated hemoglobin is a better acceptor for hydrogen cations than oxygenated hemoglobin.

"Hydrocarbonate" or "bicarbonate": used interchangeably to refer to an anion with the chemical formula HCO ₃ ^- . Bicarbonate is an intermediate form in the deprotonation of carbon dioxide. It is a polyatomic anion. In the present description, this term is used, unless the context requires otherwise, to the bicarbonate anion (HCO ₃ ^- ) and to any bicarbonate salt, such as, for example, sodium bicarbonate.

"Hydrogen cation" or hydrogen ion (H ⁺ ): are used interchangeably to refer to the cationic form of a hydrogen atom. All these terms collectively include cations of all hydrogen isotopes, in particular protium, deuterium and tritium. In aqueous solution, hydrogen cations usually form solvates by adding one or more water molecules. These solvates are called hydronium ions and can be described by the general formula H ⁺ (H ₂ O) _n where n is an integer equal to 0, 1, 2, 3, 4 or greater than 4, most typically 1 or 4. In the context of this description, the term "hydrogen cation" can also be used to refer to a hydrogen cation in solution or in a solvated state.

"Metabolite": as used herein, refers to any intermediate or end product of human or animal metabolism. Specific metabolites of importance to the present invention are carbon dioxide, hydrogen carbonate and hydrogen cations.

"Oxygen": as used herein, unless the context dictates otherwise, refers to a dioxygen (O ₂ ) molecule. Oxygen plays an important role in the cellular respiration of all aerobic organisms, including mammals.

"Oxygenated/deoxygenated hemoglobin": refers to the oxygenated state of hemoglobin. Since hemoglobin is usually composed of four protein subunits, each of these subunits can be reversibly oxygenated/deoxygenated, with five oxygenation states possible: the fully deoxygenated form (all four subunits are deoxygenated) is always referred to as "deoxygenated", and the fully oxygenated form (all four subunits are oxygenated) is always referred to as "oxygenated". In the context of the present description, the terms "oxygenated" and "deoxygenated" are also used as relative concepts: for example, forms of hemoglobin containing two, three or four oxygenated subunits may be referred to as oxygenated hemoglobin compared to a form containing one oxygenated subunit. Conversely, the same form containing one oxygenated subunit may be referred to as oxygenated hemoglobin compared to a form containing no oxygenated subunits (i.e., all subunits are deoxygenated). Deoxygenated hemoglobin is also called deoxyhemoglobin. Oxygenated hemoglobin is also called oxyhemoglobin. Unless the context implies otherwise, in the present description, the term "hemoglobin" is used simultaneously for oxyhemoglobin and deoxyhemoglobin. In the context of the present description, the terms "oxyhemoglobin/deoxyhemoglobin" do not specifically require the presence of a specific number of hydrogen cations attached to the oxyhemoglobin/deoxyhemoglobin protein.

"pCO ₂ ": refers to the partial pressure of carbon dioxide (CO ₂ ) in a fluid, such as blood plasma or dialysis fluid.

"Peripheral tissue": in the context of the present description refers to any non-lung tissue (non-gill tissue) of vertebrates, in particular non-lung tissue of mammals.

"Plasma": in the context of the present description refers to blood plasma, that is, the extracellular intravascular fluid fraction of blood.

"pH", or pH value: refers to the negative base 10 logarithm of hydrogen ion activity. Solutions with a pH less than 7 are acidic, and solutions with a pH greater than 7 are alkaline or basic.

"pKa": an indicator expressing the degree of acidity of weak acids and determined as described below. In general, weak acids are present in partially dissociated form in aqueous solution according to the following equation:

This equation defines the pKa value as follows:

In general, the lower the pKa value, the stronger the acid.

"Sodium bicarbonate", or sodium bicarbonate: used interchangeably to refer to a (water-soluble) chemical

a compound having the formula NaHCO ₃ (also known as baking powder, baking soda, or simply soda) and present in any form, such as crystalline (for example, in anhydrous form or in the form of any hydrate) or dissolved in solution, for example, in an aqueous solution.

"Sodium carbonate": refers to a (water-soluble) disodium salt of carbonic acid (Na ₂ CO ₃ , also known as washing or soda ash) present in any form, such as crystalline (for example, in anhydrous form or in the form of any hydrate, such as a heptahydrate or decahydrate) or dissolved in a solution, such as an aqueous solution.

"Solvate": refers to a solute surrounded by or complexed with solvent molecules. Solvation is the interaction of a solute (eg an ion such as the hydrogen cation H ⁺ , hydrogen carbonate HCO ₃ ) with a solvent (eg water). In the solvated state, the solvate is usually stabilized (as opposed to the unsolvated state). Unless the context implies otherwise, in the present description, the term "solvate" refers primarily to a substance dissolved in water.

"Subject" or patient: refers to an individual person or animal, preferably a human. The subject may be healthy or may be suffering from at least one health disorder, ailment, or disease. A patient is a subject suffering from at least one health disorder, ailment, or disease. In the context of the present description, the term "patient" may refer to an individual suffering from one or more of the specific conditions mentioned in the present description.

The systems and methods presented in the present description are aimed at solving the problems and eliminating the shortcomings of the methods and procedures mentioned above, corresponding to the prior art. In particular, the systems and methods described herein offer advantages over existing extracorporeal carbon dioxide removal techniques or procedures based on the use of gas as the dialysis fluid by using a liquid fluid (dialysis fluid) to perform dialysis in method of extracorporeal removal of carbon dioxide. These systems and methods effectively remove carbon dioxide from the blood, adjust the pH of the blood to a desired or normal value, and regulate (by increasing or decreasing) the concentration of bicarbonate in the blood. Therefore, these systems and methods provide adaptive organ support based on the needs of individual patients. For example, these systems and methods provide support to the lungs and/or kidneys, depending on the functioning of the latter, and stabilize blood pH in the case of subjects suffering from respiratory acidosis, for example, by increasing the production of bicarbonate in the body. Generally, the desired or normal blood pH is in the range of 7.35 to 7.45, more preferably 7.36 to 7.44, even more preferably 7.37 to 7.43, even more preferably from 7.38 to 7.42, even more preferably from 7.39 to 7.41, and most preferably about 7.40. In general, acceptable blood pH values may be in the range of 6.8 to 8.0.

A dialysis fluid suitable for use in the systems and methods described herein is characterized by the following:

(I) has a pH value in the range of 8.0 to 11.0,

(II) contains at least one buffer agent, characterized by at least one pKa value in the range from 7.0 to 11.0,

(III) has a buffer capacity for H ⁺ ions of about 12 mmol/l of H ⁺ ions or more.

Below are the details of buffer capacity, pH and other parameters. In addition, below is a quantitative analysis to determine the buffer capacity in accordance with the invention.

Suitable dialysis fluid buffering agents include, in particular, one or more of the following: tris(hydroxymethyl)aminomethane (tris, TGAM), carbonate/bicarbonate, and water-soluble proteins, preferably albumin.

Thus, the systems and methods provided herein provide for (a) a technique for removing at least one unwanted substance from the blood, characterized by exposing the blood through a semi-permeable membrane to a dialysis fluid having the properties or preferred properties described herein, and (b) a technique for removing at least one unwanted substance from the blood, characterized by (i) introducing blood into the first chamber of a device comprising a first chamber and a second chamber separated by a semi-permeable membrane, and (ii) introducing into the second chamber of the device a dialysis fluid having the properties or the preferred properties described in the present description.

The systems and methods provided herein are useful for extracorporeal carbon dioxide removal and/or pH adjustment and/or regulation of blood buffering capacity. In the present description and the appended claims are, in particular, the preferred and useful implementations of these systems and methods.

The term "first chamber" generally refers to a chamber capable of or suitable for receiving blood, and the term "second chamber" generally refers to a chamber capable of or suitable for receiving dialysis fluid; in a typical embodiment of the invention presented in the present description, the first and second chambers are separated from each other by a semi-permeable membrane. In a typical embodiment of the invention, no direct connection (tubes, etc.) is provided between the first and second chambers. Consequently, only substances capable of passing through the semi-permeable membrane can pass from the first chamber to the second and/or from the second chamber to the first.

Blood and dialysis fluid are aqueous fluids. In the context of the present description, the term "aqueous" refers generally to water or water-containing fluids, in particular and without limitation, in a liquid state. In the context of the present description, the term "aqueous" is used to refer to fluids, in particular liquids or liquid phases containing water. Generally, aqueous liquids contain more than 50% by volume (vol.) water and are hydrophilic. Blood and dialysis fluid are such aqueous fluids. Thus, the fundamental difference between the systems and methods presented herein and the prior art extracorporeal carbon dioxide removal (ECCO2R) methods is that the present invention uses a dialysis fluid in a liquid state.

The use of liquid dialysis fluids in other technical fields or for other purposes (ie, other than the task of extracorporeal removal of carbon dioxide in accordance with the ECCO2R methodology) is described in publications reflecting the state of the art. In the systems presented in these publications, the dialysis fluid is delivered to the area immediately adjacent to the blood, located in the extracorporeal circuit and separated by a semipermeable membrane, thereby ensuring the transfer of unwanted substances along the concentration gradient from the blood to the dialysis fluid and, in some cases, the desired substances. in the opposite direction. These prior art systems are intended for other purposes, namely kidney and/or liver support. For example, dialysis to support the kidneys may be indicated for acidosis, which may be due to chronic renal failure (CRF). Such dialysis therapy for kidney support is, however, generally unacceptable for use as an adjuvant or replacement therapy in relation to liver function, i.e. to remove certain substances (in particular toxins) from the blood, such as protein-bound substances (in particular toxins ). WO 03/094998 A1 (HepaWash) describes a device and method for removing protein-bound substances (particularly toxins) from the blood based on the use of an absorbent liquid suitable for use as a dialysis liquid in liver dialysis, the dialysis liquid containing albumin. and may optionally contain caffeine. This allows protein-bound toxins to be attached to the albumin carrier. However, these prior art systems do not aim to provide lung support, let alone effective removal of carbon dioxide (CO ₂ ), hydrogen cation (H ⁺ ) and bicarbonate (HCO ₃ ^- ). It has been surprisingly found that dialysis fluid in general, and the specific dialysis fluid described herein in particular, is useful for extracorporeal carbon dioxide removal and bicarbonate control. These goals can be achieved through individually tailored therapy, that is, based on the needs of a particular patient.

In general, albumin has properties that allow it to act as a buffer for aqueous fluids, and it is believed that certain amino acid residues of albumin (for example, the histidine imidazole group, the cysteine thiol group) are important in this (Caironi et al., Blood Transfus., 2009, 7(4), 259-267), and at elevated pH values, the amino groups of the side chains of lysine and the N-termini may contribute to the buffering action. However, the buffering properties of albumin find their traditional use in the blood (where it is formed naturally in the human or animal body), and the effectiveness of albumin-containing fluids for extracorporeal lung support and, in particular, for extracorporeal carbon dioxide removal is not recognized and is not used. in this area. In addition, it is known that bicarbonate is the basis of a physiological buffer system that maintains a normal pH level. Dialysis fluids containing bicarbonate, although not containing albumin, have been described previously. The typical concentration of bicarbonate in these dialysis fluids is in the range of 32 to 40 mmol/L. The systems and methods presented herein are also advantageous over those previously used in that they take advantage of the buffering capacity of buffering agents with a pKa value in the above range, namely albumin, carbonate/bicarbonate or tris. Other inorganic or organic buffering agents may be used as an addition. Such buffering agents have at least one pKa value, preferably in the range between 7.0 and 9.0. Suitable additional organic buffering agents include proteins, in particular water-soluble proteins, amino acids and tris, and suitable additional inorganic buffer molecules include HPO ₄ ^2- /H ₂ PO ₄ ^- .

Another advantage of the systems and methods presented in the present description is their adaptability. Depending on the blood flow rate (up to 600 ml/min or, in the case of two parallel devices, up to 1200 ml/min), the dialysis fluid flow rate (up to 2000 ml/min) and the exact composition of the dialysis fluid, the blood can be removed from 0 up to 10 mmol/min carbon dioxide.

Schematic representation of the system presented in the present description

In FIG. 1 and 2 show a flow 1 of a treated fluid, eg blood, entering the inlet of a dialysis system, and a flow 2 of a treated fluid, eg blood, entering the outlet of the dialysis system. Also shown is an incoming regenerated liquid stream 3 intended for exchange and containing a known buffer, and an outgoing liquid stream 4 intended for exchange and subjected to analysis and regeneration. The dialysis system includes a two-chamber device, such as a dialyzer 5, and a semi-permeable membrane 6. One or more pumps 7, 8, 17, 18 are provided at various locations in the system to obtain and maintain the required fluid flows. One or more sensors 9, 10 are provided to measure or monitor one or more parameters including pH, temperature, pCO ₂ , hemoglobin concentration, oxygen saturation, and flow rate. Similarly, one or more sensors 11, 12, 13, 14, 15 are provided to measure or monitor one or more parameters including pH, pCO ₂ , cCO ₂ , flow rate, electrical conductivity, and temperature. In addition, a junction point 16 is provided from which two separate lines exit for the passage of dialysis fluid flows into them. In each of these separate lines leaving the branching point 16 there is provided a source or reservoir 19, 20 of reverse osmosis treated water (osmosis water). One of these separate lines is fed with an acidic concentrate 21, such as HCl, the stream 23 of which is mixed with osmotic water from a source or reservoir 20 to form an acidic mixed feed solution 25 with a known concentration of H ⁺ . A second separate line is fed with an alkaline concentrate 22, such as NaOH, whose stream 24 is mixed with osmotic water from a source or reservoir 19 to form an alkaline mixed feed solution 26 with a known concentration of OH. There are two points 27, 28 (one in each of two separate lines) for mixing the fresh feed solution and the recycle solution. In addition, a neutralization or mixing zone 29 is provided downstream of the two separate lines. Two filters 30, 31 are provided, one in each individual line. There are two waste disposal pumps 32, 33 (one in each separate line) and one or more respective sensors 34, 35 downstream of the waste disposal pumps 32, 33 to measure one or more parameters including pH, pCO ₂ , CCO ₂ , flow rate, electrical conductivity and temperature, and acting as a titrator. One or more waste containers 36, 37 may also be provided. The dialysis system comprises a reservoir/buffer container/mixing zone 38 and a circuit 39 for the fluid to be treated. Similarly, the dialysis system includes a circuit 40 for exchange and differential measurement of exchange along with a circuit 41 for titration and fluid control. In some cases, one or more additional solutions 42, 43 may be provided, as needed or desired and optional.

In FIG. 1 shows a dialysis system 44 as described herein. This dialysis system may also include a control unit, such as an electronic control unit 45, which may be located either inside or outside the dialysis system 44 shown, one or more additional sensors 46 designed to measure or monitor one or more parameters, including partial pressure or volume percentage CO ₂ , capnography or infrared spectroscopy, which can also be located outside the system 44 shown, and one or more additional sensors 47 designed to measure one or more parameters, including pCO ₂ , tcpCO ₂ , SpCO ₂ , pO ₂ , tcpO ₂ , SpO ₂ , pulses or temperature, and also can be located outside the shown dialysis system 44. In addition, connection ports 48 can be provided to effectively connect the dialysis system 44 to the patient 49.

Blood

The blood present in the body of vertebrates (humans or animals) consists of the cellular elements of blood and blood plasma (also called plasma), the cellular elements being suspended in the plasma. The main component of plasma in the body of vertebrates is water, and the main type of cellular elements in the blood are erythrocytes. The systems and methods provided herein can be used in all blood types of humans or animals, preferably vertebrates, preferably mammals, most preferably humans, and are suitable for the above tasks when at least one undesirable substance is present in the blood as defined by this description.

Whether the term "blood" is used in reference to a first chamber, a dialysis unit, a dialyzer, or in any other context related to extracorporeal techniques, the term does not necessarily mean pure blood taken from a human or animal body. In some embodiments of the invention, the term "blood" may refer to a mixture of blood taken from a human or animal body and an acceptable supplement in an acceptable amount. An additive is acceptable if it does not have a significant negative effect on blood function. The amount of the additive is acceptable if the introduction of this additive does not lead to a significant increase in the volume of blood taken from the human or animal body, that is, if the blood volume increases by no more than 50%, preferably no more than 40%, no more than 30%, no more than 20%, no more than 10%, no more than 5%.

In some embodiments of the invention, the systems and methods presented in the present description are used exclusively for in vitro procedures. In alternative embodiments, the systems and methods provided herein are applied to medical problems in living subjects, as detailed below. In these alternative embodiments of the invention, the contact of blood with dialysis fluid through a semi-permeable membrane also occurs in vitro (that is, outside the human or animal body), or extracorporeally. In addition, there is an interaction with the human or animal body, described below.

A suitable blood flow rate is up to 600 ml/min, and in the case of two parallel devices up to 1200 ml/min, but usually much lower.

Unwanted substances in the blood and their removal

In the broadest sense, at least one unwanted substance to be removed is a substance formed as a consequence of metabolic activity. This at least one undesirable substance is one or more of the following: carbon dioxide (CO ₂ ), hydrogen cation (H ⁺ ), hydrogen carbonate (HCO ₃ ^- ), carbonic acid (H ₂ CO ₃ ) and solvates of any of the above or any combination of them. It is known that in aqueous media (for example, in an aqueous solution or aqueous suspension, such as, for example, blood or dialysis fluid), the relationship of these undesirable substances to each other is expressed by the following equilibrium equation:

Диссоциацию углекислоты

обычно катализирует или облегчает фермент карбоангидраза, присутствующий в эритроцитах. Согласно общему принципу динамического равновесия (принципу Ле Шателье), удаление одного вещества, участвующего в реакции, вызывает смещение реакции. Системы ECCO2R, соответствующие уровню техники, основываются на использовании газообменной мембраны, через которую одно из участвующих в реакции веществ, двуокись углерода, диффундирует из крови в экстракорпоральном контуре в газовую камеру. В отличие от этого, настоящее изобретение позволяет осуществить непосредственный вывод по меньшей мере одного нежелательного вещества из одной жидкости (крови) в другую жидкость (диализная жидкость). Следовательно, системы и способы, представленные в настоящем описании, не ограничиваются удалением газообразных нежелательных веществ (таких как CO₂) и не требуют перехода нежелательных веществ в газовую фазу. Таким образом, предполагается, что в системах и способах, представленных в настоящем описании, двуокись углерода не переходит в газовую фазу.The initial and resulting substances (reagents and products) in this reaction are in dynamic equilibrium, which is qualitatively reflected in the above equation by arrows

dissociation of carbon dioxide

usually catalyzes or facilitates the enzyme carbonic anhydrase present in erythrocytes. According to the general principle of dynamic equilibrium (Le Chatelier's principle), the removal of one substance involved in the reaction causes a shift in the reaction. Prior art ECCO2R systems rely on the use of a gas exchange membrane through which one of the reactants, carbon dioxide, diffuses from the blood in the extracorporeal circuit into the gas chamber. In contrast, the present invention allows for the direct removal of at least one unwanted substance from one fluid (blood) to another fluid (dialysis fluid). Therefore, the systems and methods presented herein are not limited to the removal of gaseous unwanted substances (such as CO ₂ ) and do not require the transition of unwanted substances into the gas phase. Thus, it is assumed that in the systems and methods presented in the present description, carbon dioxide does not go into the gas phase.

In general, one of the modes of transport of CO ₂ in the blood is transport in the form of carbamin groups, during which carbon dioxide is attached to the terminal amino groups of proteins in the blood, primarily hemoglobin (called in this case carbaminohemoglobin). Generally speaking, it has been found that the formation of carbamic groups is rapid and reversible and does not need to be catalyzed by any enzyme. Therefore, carbon dioxide bound in carbamic compounds is also rapidly released from the amino group of blood proteins such as hemoglobin when the concentration of carbon dioxide in the environment decreases due to diffusion into the dialysis fluid, resulting in, in accordance with Le Chatelier's principle, new balance. As mentioned above, carbaminohemoglobin and dissolved carbon dioxide are also in equilibrium with the bicarbonate (HCO ₃ ⁻ )/H ⁺ ion pair, but rapid conversion by H ₂ CO ₃ requires the presence of the carbonic anhydrase enzyme. Carbonic anhydrase is found naturally in red blood cells.

Therefore, in the systems and methods presented herein, direct or indirect removal through a semi-permeable membrane of all three major carbonate forms present in the blood can be performed: (i) CO ₂ bound to a protein (hemoglobin) and present in the form of carbaminohemoglobin, (II) free CO ₂ and (III) bicarbonate (HCO ₃ ^- ) / H ⁺ . As free CO ₂ and bicarbonate ions pass through the membrane into the dialysis fluid along the concentration gradient, there is preferential release from hemoglobin of its associated CO ₂ when, for example, the concentration of free CO ₂ decreases due to diffusion into the dialysis fluid, so that there is , according to Le Chatelier's principle, a new balance between the three main carbonate (transport) forms present in the blood. It is important to note that in the systems and methods described herein, the various transport forms of carbon dioxide do not need to go into the gas phase to be removed. Therefore, blood-gas contact is not required and is preferably not provided. The systems and methods presented herein allow the removal of all major transport forms of carbon dioxide from the blood, performed entirely in a liquid medium. Depending on the concentration of bicarbonate (HCO ₃ ^- ) in the dialysis fluid and blood, bicarbonate can be removed from the blood along the concentration gradient between the dialysis fluid on one side of the semipermeable membrane and the blood on the other side of this membrane.

In the case of the systems and methods presented herein, these unwanted substances can be removed by passing directly into the dialysis fluid along a concentration gradient (direct removal). Alternatively or additionally, unwanted substances can be removed indirectly by reacting with substances transferred from the dialysis fluid into the blood, which also results in the actual removal of unwanted substances from the blood (indirect removal): for example, hydrogen cations can be indirectly removed from the blood as a result of the transfer of OH ^- ions from the dialysis fluid to the blood, which is achieved due to the fact that the pH of the dialysis fluid used in the invention usually corresponds to a more alkaline environment than the pH of the blood to be treated. It is also possible to indirectly remove other unwanted substances, such as carbon dioxide, carbonate, bicarbonate, as a result of the transfer of substances from the dialysis fluid into the blood, affecting the carbonate balance.

Unlike prior art systems that remove dioxide in the gas phase, the systems and methods presented herein allow the removal of substances soluble in liquids. These substances include ions of any type, provided they are soluble in water, in particular hydrogen cations and bicarbonate anions. Therefore, the systems and methods provided herein allow for a more complete and therefore more efficient removal of metabolites from the blood than the prior art ECCO2R techniques. The carbon dioxide removal mechanism underlying the systems and methods described herein allows diffusion of dissolved gas from one liquid phase to another liquid phase.

The systems and methods described herein can suitably use a dialysis device comprising two chambers and described in detail below. The first chamber is configured to receive blood. The first chamber respectively contains an inlet (for incoming blood) and an outlet (for outgoing blood).

Desirably, in the dialysis device used in the systems and methods provided herein, the blood exiting the first chamber (outlet) has a pH value in the range of 7.35 to 7.45, preferably 7.36 to 7. .44, more preferably 7.37 to 7.43, even more preferably 7.38 to 7.42, even more preferably 7.39 to 7.41 and most preferably a pH of about 7.40 . After leaving the first chamber (exhaust), the blood is preferably returned to the human or animal body. Suitable tubing and connectors are known in the art and can be used with the systems and methods described herein.

Optionally, measures can be provided to remove bubbles from the blood (if any), namely after the blood has exited the first chamber (exhaust) and before it is reintroduced into the human or animal body. To this end, one or at least one bubble trap can be placed behind the first chamber. This is particularly applicable when the blood is exposed to a saturated or supersaturated gas liquid during at least part of the process.

dialysis fluid

The dialysis fluid in the systems and methods described herein is an aqueous fluid, that is, a fluid containing water. A dialysis fluid suitable for use in the systems and methods described herein is characterized by the following:

(I) has a pH value in the range of 8.0 to 11.0,

(II) contains at least one buffer agent, characterized by at least one pKa value in the range from 7.0 to 11.0,

(III) has an H ⁺ ion buffer capacity of 12 mmol/L H ⁺ ions or more.

These buffering agent, buffering capacity, and pH conditions are also referred to herein as "base conditions". Within these base conditions, more specific conditions may be appropriately selected as described below.

The buffer capacity for H ⁺ ions, which is 12 mmol/l of H ⁺ ions or more, usually exceeds the buffer capacity of blood plasma (pH 7.45; see Example 1). Therefore, in the systems and methods described herein, the buffering capacity of dialysis fluid typically exceeds the buffering capacity of blood plasma (pH 7.45). In other words, the buffer capacity of the dialysis fluid is usually a buffer capacity for 12 mmol/l H ⁺ ions or more.

In the systems and methods described herein, the dialysis fluid contains generally at least one buffering agent, in a typical embodiment of the invention, at least two buffering agents. The use of buffered dialysis fluid in general, and the specific dialysis fluid used in the systems and methods described herein, in particular, allows removal of carbon dioxide in a pH range that does not adversely affect the blood, since the actual ionic capacity of the dialysis fluid is much higher, than in the absence of buffer(s) agent(s). The at least one buffering agent provides or contributes to the buffering capacity of the dialysis fluid. It has been found surprisingly that the use of dialysis fluid (as opposed to the use of propellant in existing systems to remove CO ₂ ) maintains blood pH at an acceptable level.

Buffer tank for H ⁺ ions

As used herein, the term "H ⁺ ion buffer capacity", or simply "buffer capacity", refers to an abstract meaning expressing the ability of a given fluid to buffer the addition of H ⁺ ions. The buffer capacity for H ⁺ ions is an inherent property of the corresponding liquid (aqueous solution). Blood plasma is also such a liquid. Determination of the buffer capacity of blood plasma requires a centrifugation procedure (step), which results in the precipitation of blood cells, including platelets, and the supernatant (supernatant) is called plasma. Such centrifugation is described in Example 1. Suitable conditions for the centrifugation of blood and hence the preparation of blood plasma are known in the art.

In its precise meaning, the term "buffering capacity for H ⁺ ions" refers to the ability to buffer a certain amount of H ⁺ ions without reaching a pH value below 6.5. The expression "without reaching a pH value below 6.5" means that the pH of the properly mixed liquid does not reach a value below 6.5. Therefore, good mixing is essential in the practical evaluation of buffer capacity. Thus, in the context of this specification and in relation to the dialysis fluid used in the systems and methods presented in this specification, the term "H ⁺ ion buffer capacity" can only be used for fluids having a pH value of 6.5 or greater. As defined herein, a solution having a pH value of 6.5 would have zero (0 mmol/l) buffer capacity for H ⁺ ions. All dialysis fluids used in the systems and methods described herein have a pH value well above 6.5, i.e., in accordance with the foregoing, have a buffering capacity for H ⁺ ions. If the buffer capacity of the dialysis fluid is 12 mmol/l of H ⁺ ions or more, then this fluid corresponds to the systems and methods presented in the present description. Higher (i.e. above 12 mmol/L) buffer capacity values for H ⁺ ions are more preferred, namely 14 mmol/L or more, 16 mmol/L or more, 18 mmol/L or more, 20 mmol/L or more, 22 mmol/l or more, 24 mmol/l or more, 26 mmol/l or more, 28 mmol/l or more, 30 mmol/l or more, 32 mmol/l or more, 34 mmol/l or more , 36 mmol/l or more, 38 mmol/l or more, 40 mmol/l or more, 42 mmol/l or more, 44 mmol/l or more, 46 mmol/l or more, 48 mmol/l or more, 50 mmol/l or more. Thus, dialysis fluid according to the systems and methods described herein typically has an H ⁺ ion buffering capacity of 12 mmol/l or more, in particular more than 12 mmol/l. Preferred buffer capacity values are in the range of 12 to 50 mmol/L, more than 12 to 40 mmol/L, 13 to 30 mmol/L, 14 to 25 mmol/L, 15 to 24 mmol/L, 16 up to 23 mmol/l, from 17 to 22 mmol/l, from 18 to 21 mmol/l, from 19 to 20 mmol/l.

The buffer capacity depends not only on the pH of the respective liquid, but also on its composition (on the presence of buffer compounds in this liquid and their concentration). The buffer capacity for H ⁺ ions is indicated as a numerical value with the unit "mmol/l". According to the invention, the buffer capacity for H ⁺ ions (buffer capacity in mmol/l) is determined by carrying out the following quantitative analysis, which includes four steps:

1. This quantitative analysis is applicable to determine the buffer capacity for H ⁺ ions of a given fluid (dialysis fluid or fluid intended for use as a dialysis fluid) having a pH value in the range corresponding to the pH range of dialysis fluids used in the systems and methods presented in the present description, that is, the pH value in the range from 8.0 to 11.0 or in a subrange of this range. Thus, in the first step, it is checked whether the pH value of the given liquid is within the specified range. If this is not the case, then the fluid is not a dialysis fluid according to the invention (no further testing is necessary). If, however, this is the case, then determine the buffer capacity of this liquid by performing the following steps 2 and 3.

2. The liquid is titrated with HCl. In particular, 0.1 M HCl is added, shaken to ensure mixing, continuously monitor the pH, and complete the titration at the exact moment when the pH of the titrated liquid reaches a final value of 6.5. In other words, the titration is stopped when the pH reaches 6.5. From the amount of HCl added up to reaching a pH value of 6.5, calculate the buffer capacity (H ⁺ ions in mmol/l). This possibility is due to the fact that HCl is a strong acid, completely soluble, according to well-known knowledge, in an aqueous solution. Thus, 0.1 M (0.1 mol/l) HCl contains 0.1 mol/l of dissolved Cl ^- ions and 0.1 mol/l of dissolved H ⁺ ions. From the volume of HCl required to reach a pH of 6.5 for a given fluid by titration, the amount of H ⁺ ions buffered by said volume of dialysis fluid can be calculated. If the amount of this fluid used in the analysis is 1 litre, this directly yields the amount of H ⁺ ions buffered by one liter of dialysis fluid (buffer capacity in mmol/l). If the amount of this fluid used in the analysis is greater than or less than 1 liter, then the amount of H ⁺ ions buffered by one liter of dialysis fluid (buffer capacity in mmol/l) can be obtained by a simple mathematical calculation.

3. The buffer capacity determined in step 2 (in mmol/l) is compared with the reference value. Suitable reference values are 10 mmol/l, 11 mmol/l, 12 mmol/l, 13 mmol/l, 14 mmol/l, with 12 mmol/l being strongly preferred. Alternatively, the buffer capacity of human or animal blood (pigs, mice) is used as a reference value; in this case, the buffering capacity of the blood plasma is determined as described in step 2 above.

4. If the buffer capacity value of a given solution (in mmol/L) exceeds the reference value (in mmol/L), then the solution is defined as having a buffer capacity consistent with the systems and methods presented herein.

When performing a quantitative analysis to determine the buffer capacity, all pH measurements, as well as titration, are performed at room temperature (the temperature of all solutions and equipment; ambient temperature). The quantitative analysis described above is straightforward and can be performed by one of ordinary skill in the art with minimal effort and based on the guidance provided herein and common knowledge. Therefore, the buffer capacity of a given liquid can be determined quickly and reliably without undue effort.

An exemplary determination of buffering capacity according to the procedure adopted in the systems and methods provided herein is given in Example 1 below. As shown in this example, blood plasma having a pH of 7.45 typically has a buffering capacity of 12 mmol/L. However, it can be assumed that blood plasma obtained from other sources (other species and/or individuals) has a different buffering capacity. Other possible values for the buffering capacity of blood plasma are in the range from 3 to 30 mmol/l, preferably from 4 to 25 mmol/l, preferably from 5 to 20 mmol/l, preferably from 6 to 19 mmol/l, preferably from 7 to 18 mmol/l, preferably 8 to 17 mmol/l, preferably 9 to 16 mmol/l, preferably 10 to 15 mmol/l, preferably 11 to 14 mmol/l, preferably 12 to 13 mmol/l.

The dialysis fluid used in the systems and methods described herein preferably and typically has a buffer capacity greater than that of blood plasma. When treating the blood of an individual, such as a patient, in accordance with the method of the invention, the buffering capacity for H ⁺ ions is preferably chosen such that it exceeds the buffering capacity of the blood of this individual, such as this patient.

dialysis fluid pH

Preferred dialysis fluid pH ranges include pH 8.0 to 11, 8.0 to 10.0, 8.0 to 9.5, and preferably 8.0 to 9.0. Hence, at least one pKa value of at least one buffering agent present in the dialysis fluid is in the pH range of 7.0 to 11.0, 8.0 to 10.5, 8.0 to 10.0 , from 8.0 to 9.5 and preferably from 8.0 to 9.0. If more than one buffering agent is present, it is preferred that each of them has a pKa value within the range or subrange indicated above. If at least one buffering agent has more than one pKa value, then at least one of said pKa values, preferably more than one of said pKa values, is(are) within the range or subrange indicated above. Any buffering agent having at least one pKa value in the range of 7.0 to 11.0 is theoretically suitable for buffering within the desired pH range. However, with respect to the systems and methods described herein, the buffering agent must be chosen so that it is not toxic or causes undesirable side effects in the human or animal being dialyzed. In particular, suitable buffering agents are, as mentioned above, the carbonate/bicarbonate system, tris and water-soluble proteins (preferably albumin). Another suitable dialysis fluid pH is in the range of 7.75 to 9.0. In general, preferred pH values are in the range of 7.75 to 9.0, preferably 8.0 to 9.0, preferably 8.1 to 8.9, preferably 8.2 to 8.8, preferably 8.3 to 8.7, more preferably 8.4 to 8.6, and most preferably 8.5 or so. It is important to emphasize that these ranges and subranges are generally preferred. For specific cases, for example for processing the blood of a particular subgroup of patients, alternative, different or overlapping ranges, as described below, may be preferred. The pH value can be adjusted by changing the amount or concentration of buffer substances, such as bicarbonate and hemoglobin, within the ranges specified in the present description, and/or by adding an acid or alkali, such as hydrochloric acid or sodium hydroxide.

Bicarbonate and hydrogen cations, as well as other small molecules, including ions or substances that can affect the pH of an aqueous liquid, can pass through a semi-permeable membrane during the process of the invention. Therefore, the pH value of the dialysis fluid does not necessarily remain constant throughout the step of this process involving contact of the blood with the dialysis fluid. Therefore, the pH of the dialysis fluid is preferably determined, exactly as described herein, in the step immediately preceding contact with blood, for example, in the step where the dialysis fluid enters the second chamber of the dialysis device as described herein.

Buffer Agent in Dialysis Fluid

Suitable buffering agents present in the dialysis fluid include, in particular, one or more of the following: tris(hydroxymethyl)aminomethane (tris, TGAM), carbonate/bicarbonate, and water-soluble proteins, preferably albumin.

Bicarbonate has a pH value (pKa) of 10.3 (conjugated basic carbonate). Therefore, in an aqueous solution containing bicarbonate, depending on the pH of this solution, a carbonate may also be present. The expression "carbonate/bicarbonate" is used here for the sake of convenience in relation to bicarbonate and its corresponding basic carbonate, the expression "carbonate/bicarbonate concentration" or "(total) carbonate/bicarbonate concentration", and the like. refers in the context of the present description to the total concentration of carbonate and bicarbonate. For example, "20 mM carbonate/bicarbonate" refers to a formulation with a combined concentration of bicarbonate and its corresponding basic carbonate equal to 20 mM. The ratio of bicarbonate to carbonate usually depends on the pH of a given composition.

Bicarbonate and hydrogen cations, as well as other small molecules, including ions or substances that can affect the pH of an aqueous liquid, can pass through a semi-permeable membrane during the process of the invention. Therefore, the (total) concentration of carbonate/bicarbonate in the dialysis fluid is preferably determined, exactly as described herein, in the step immediately preceding contact with blood, for example, in the step where the dialysis fluid enters the second chamber of the dialysis device as described herein. .

Tris(hydroxymethyl)aminomethane is commonly referred to as tris. Tris(hydroxymethyl)aminomethane is also known as THAM. Tris is an organic compound having the formula (HOCH ₂ ) ₃ CNH ₂ . The acidity index (pKa) of Tris is 8.07. Tris is non-toxic and has previously been used to treat acidosis in vivo (e.g., Kallet et al., Am. J. of Resp. and Crit. Care Med., 161, 1149-1153; Hoste et al., J Nephrol, 18, 303-7.). In an aqueous solution containing Tris, the corresponding base may also be present, depending on the pH of the solution. Unless the context dictates otherwise, the term "tris" is used herein, for the sake of convenience, to refer to both tris(hydroxymethyl)aminomethane and its corresponding base. For example, the expression "20 mM Tris" refers to a formulation with a total concentration of Tris and its corresponding base equal to 20 mM. The ratio of tris(hydroxymethyl)aminomethane to its corresponding base depends on the pH of the given composition. Tris and its conjugate base, as well as other small molecules, including ions or substances that can affect the pH of an aqueous liquid, can pass through a semi-permeable membrane during the implementation of the methods proposed in the invention. Therefore, the concentration of Tris in the dialysis fluid is preferably determined, exactly as described herein, in the step immediately preceding contact with blood, for example, in the step where the dialysis fluid enters the second chamber of the dialysis device as described herein.

A water-soluble protein is applicable for use in the systems and methods provided herein if it contains at least one imidazole chain (histidine side chain) and/or at least one amino side chain (lysine) or at least one sulfhydryl side chain (cysteine). These side chains typically have pKa values ranging from 7.0 to 11.0. A protein falls under the definition of "water soluble" if at least 10 g/l of this protein can be dissolved in an aqueous solution having a pH value within the dialysis fluid range used in the present invention, for example pH 8.0. As follows from the following, the strongly preferred water-soluble protein used in the present invention is albumin.

Albumin is the preferred water soluble protein for use in the systems and methods described herein. In general, albumin has good buffering capacity in the desired pH range, usually due to the presence of several amino acid side chains with corresponding pKa values. The albumin used in the systems and methods provided herein is preferably human or animal serum albumin (eg, bovine serum albumin), or alternatively, albumin obtained through genetic engineering or a mixture of the above. It is also possible to use mixtures containing albumin and at least one other carrier substance. In any event, the concentration of albumin referred to herein is its total concentration, regardless of whether a single type of albumin (eg, human serum albumin) or a mixture of different types of albumin is used. The dialysis fluid used in the systems and methods described herein contains 10 to 60 g/L, preferably 15 to 30 g/L, preferably 20 to 25 g/L, most preferably 30 or about 30 g/l albumin. The albumin concentration can also be indicated as a percentage: 20 g/l of albumin corresponds to a value of 2% w/v - 2% (w/v). According to the invention, albumin is the second buffering agent in the dialysis fluid. The albumin present in the dialysis fluid contributes to its buffering capacity and adds carbonate in the form of carbamic groups. The pH range in which albumin can buffer fluids well, such as blood, is well known in the art, such as from biochemistry textbooks. The presence of albumin in the dialysis fluid facilitates the removal of protein-bound substances from the blood. Due to its ability to adsorb or attach substances such as hydrogen cations, carbon dioxide and toxins, albumin can also be referred to more generally as an adsorbent or adsorbent molecule.

In addition to the ability of albumin to attach undesirable substances of the types described above, and therefore its utility in extracorporeal carbon dioxide removal and blood pH regulation techniques, the presence of albumin in the dialysis fluid used in the systems and methods presented herein also provides or facilitates removal of protein-bound toxins. One of the properties of albumin present in the dialysis fluid can be used for this: in general, albumin is known to attach itself to unbound toxins, and this can be beneficial when albumin is present in the dialysis fluid, as it will allow the toxins to pass through the semi-permeable membrane to bind. from blood to dialysis fluid. This method is called albumin dialysis (see, for example, WO 2009/071103 A1, incorporated herein by reference in its entirety).

A suitable total concentration of carbonate/bicarbonate (the combined concentration of both substances) is between 0 and 40 mmol/l. The presence of carbonate/bicarbonate in the dialysis fluid contributes to the buffering capacity of that dialysis fluid. However, the lower the concentration of carbonate/bicarbonate, the better the removal of CO ₂ from the blood. Therefore, it may be preferable to use a dialysis fluid that does not contain or does not contain carbonate/bicarbonate. The pH range in which bicarbonate can be a good buffer in fluids such as blood is well known in the art, for example from biochemistry textbooks. During the preparation of the dialysis fluid used in the systems and methods described herein, the bicarbonate may be added in the form of any of its salts such as sodium bicarbonate, potassium bicarbonate, and others, or alternatively added directly by introducing carbon dioxide, in some cases in the presence of carbonic anhydrase, and adjusting the pH as necessary by adding a suitable base such as sodium hydroxide or potassium hydroxide, the use of sodium hydroxide being strongly preferred. When added in the form of a salt, the use of sodium bicarbonate or sodium carbonate is strongly preferred. Alternatively, potassium salts or mixtures of sodium and potassium salts may be added. In particular, sodium carbonate or potassium carbonate is suitable for addition to dialysis fluid at high pH (eg up to pH 11). In general, the preferred (cumulative) concentrations of carbonate/bicarbonate in the dialysis fluid at the step of introducing into the second chamber during the process proposed in the systems and methods presented in the present description, are in the range from 10 to 40 mmol/l, more preferred - from 15 to 35 mmol/l, even more preferably from 20 to 30 mmol/l, and most preferably 30 or about 30 mmol/l. It is important to emphasize that these ranges and subranges are generally preferred. For specific cases, for example for processing the blood of a particular subgroup of patients, alternative, different or overlapping ranges, as described below, may be preferred. Alternative suitable (cumulative) concentrations of carbonate/bicarbonate are in the range of 0 to 40 mmol/l or more, preferred 5 to 35 mmol/l, even more preferred 10 to 30 mmol/l, even more preferred 15 to 25 mmol/l, and the most preferred are 25 or about 25 mmol/l. In the case of dialysis fluid recirculation, the (cumulative) carbonate/bicarbonate concentration is determined and adjusted as necessary prior to introducing the dialysis fluid into the second chamber. Due to possible side effects, the use of (cumulative) carbonate/bicarbonate concentrations in excess of 40 mmol/l is generally undesirable.

Suitable Tris concentrations range from 0 to 40 mmol/l or up to more than 30 mmol/l, preferred is from 5 to 25 mmol/l, more preferred is from 10 to 20 mmol/l, even more preferred is about 15 mmol/l l. Alternative suitable Tris concentrations are in the range of 0 to 38 mmol/L or 0 to 20 mmol/L.

A suitable albumin concentration is 10 to 60 g/l (ie 1 to 6 g/100 ml). In the present description, g/l and g/100 ml means the ratio of the amount in grams to the volume (final volume of the albumin-containing liquid). Albumin is preferably not the only buffering agent present in the dialysis fluid. Thus, the presence, along with albumin, of a carbonate/bicarbonate or tris is preferred. The dialysis fluid according to the systems and methods described herein preferably contains (I) carbonate/bicarbonate and (II) albumin, or (I) tris and (II) albumin. In particular, in the absence of carbonate/bicarbonate additive in the dialysis fluid (i.e., the concentration of carbonate/bicarbonate in the dialysis fluid is 0 mmol/l or close to 0 mmol/l), the presence of both tris and albumin in the dialysis fluid is preferred. Alternatively, Tris is the only buffering agent contained in the dialysis fluid.

In the systems and methods provided herein, all of the above ranges and concentrations of tris, carbonate/bicarbonate, and albumin are combinable.

Other Properties of the Dialysis Fluid

The dialysis fluid typically contains water. Typically more than 50% (V/V), more than 60% (V/V), more than 70% (V/V), more than 80% (V/V), or more than 90% (V/V). v/v) of the dialysis fluid is water. The dialysis fluid may also contain other fluids that are miscible with it.

The systems and methods presented herein provide not only a process for removing unwanted substances, but also a proper dialysis fluid suitable for this purpose. Any and every specific dialysis fluid mentioned in the present description is the subject of the present invention.

Albumin is preferably not the only buffering agent present in the dialysis fluid. Thus, the presence, along with albumin, of a carbonate/bicarbonate or tris is preferred. The dialysis fluid according to the systems and methods described herein preferably contains (I) carbonate/bicarbonate and (II) albumin, or (I) tris and (II) albumin. In an alternative preferred embodiment, Tris is the only buffering agent contained in the dialysis fluid, ie the latter does not contain carbonate/bicarbonate or albumin additives. In general, carbonate/bicarbonate, albumin and tris are buffering agents and hence can all contribute to keeping the pH within the desired range. These buffering agents may have at least one pKa value within the pH range indicated above.

There is no need to constantly maintain the pH value of the dialysis fluid at the required level from the very beginning of its exposure to the blood (entering the second chamber). In particular, in the case of dialysis fluid recirculation, the pH and (cumulative) carbonate/bicarbonate concentrations may change over time, as described below. However, during the step of introduction into the second chamber, the pH levels and bicarbonate/albumin concentrations in the dialysis fluid are adjusted to match the desired values. For example, pH can be measured using at least one device designed for this purpose, before the dialysis fluid enters the second chamber. Optionally, an additional pH measurement can be carried out using at least one device designed for this purpose.

The first particular dialysis fluid used in the invention contains 0 to 40 mmol/l (preferably 10 to 40 mmol/l) carbonate/bicarbonate, 10 to 60 g/l (i.e. 1 to 6 g/100 ml) albumin and has a pH value in the range of 7.75 to 11.0, preferably 8.0 to 10.0, more preferably 8.0 to 9.0. Preferred carbonate/bicarbonate concentrations have been indicated above.

The second particular dialysis fluid used in the systems and methods provided herein contains 0 to 40 mmol/L (preferably 1 to 20 mmol/L) Tris, 10 to 60 g/L (i.e. 1 to 6 g/100 ml) of albumin and has a pH value in the range of 7.75 to 11.0, preferably 8.0 to 10.0, more preferably 8.0 to 9.0. Preferred Tris concentrations have been indicated above.

The third specific dialysis fluid used in the systems and methods presented in the present description, contains from 0 to 40 mmol/l (preferably from 1 to 20 mmol/l) Tris. Preferred Tris concentrations have been indicated above. A suitable buffer capacity is generally provided for a dialysis fluid having Tris as a buffer at a relatively high pH. Therefore, in the absence of additional buffering agents such as carbonate/bicarbonate and albumin, the pH value of the dialysis fluid is in particular suitably high, for example 8.5 to 11.0 or 9.0 to 10.5, preferably 9 .0 to 10.0.

The dialysis fluid may also contain other small molecules, such as glucose, which can pass through the membrane into the blood. The dialysis fluid preferably contains calcium ions (Ca ²⁺ ). Unlike the dialysis fluid of the prior art, which contains only free calcium ions, the typical dialysis fluid used in the systems and methods presented herein is characterized in that the calcium ions are at least partially bound to albumin. In general, at high pH values, most of the calcium is attached to albumin, while the smaller part remains free to participate in the exchange with the blood. Therefore, the total calcium content of the albumin-containing dialysis fluid used in the systems and methods described herein has higher calcium concentrations than prior art dialysis fluids. Specifically, the concentration of calcium ions in the albumin-containing dialysis fluid is 1.7 mmol/L or more. This is required to ensure that there is sufficient free calcium, ie that there is no decrease in the concentration of free calcium ions in the blood (see Example 3).

The dialysis fluid preferably contains 2 to 4 mmol/l, more preferably 2.4 to 2.6 mmol/l calcium ions (Ca ²⁺ ). The calcium ions may be added in the form of any suitable salt such as calcium chloride. Adding calcium to the dialysis fluid is useful because the blood also contains calcium. The presence of calcium in the dialysis fluid prevents the unwanted net flow (flow) of calcium ions from the blood into the dialysis fluid. Although it is known that calcium ions can precipitate at a pH corresponding to a highly alkaline environment, the presence of calcium is not incompatible with the systems and methods presented in the present description, taking into account the maximum pH of the dialysis fluid of 9.0 at the step of introducing it into contact with blood through a semipermeable membrane. If the pH of the dialysis fluid exceeds 10, then some ions, such as calcium ions (and others), are insoluble. Therefore, if the dialysis fluid has a pH greater than 9, then the absence of calcium ions (and other insoluble ions) is preferred. If the dialysis fluid has a pH in this range, then in order not to deprive the patient of such ions, they should be injected directly into the patient's blood by infusion.

The dialysis fluid preferably has an osmolarity substantially identical to that of the blood being dialyzed.

In addition to the above, the enzyme carbonic anhydrase may be added to or present in the dialysis fluid. Carbonic anhydrase is an enzyme that accelerates a reversible reaction involving carbon dioxide and the formation of bicarbonate (HCO ₃ ^- ) and hydrogen ions H ⁺ . Carbonic anhydrase can be added to the blood in an extracorporeal circuit. Carbonic anhydrase can also be applied as a coating to the inner surface of the first or second chamber. In general, and in addition to the above: dialysis fluid suitable for physiological procedures using the systems and methods presented in the present description, preferably contains the required electrolytes, nutrients and buffering agents in sufficient concentrations to adjust their levels in the patient's blood , bringing them, for example, to normal physiological, required or specified values. Additional dialysis fluid components used in the systems and methods presented herein include electrolytes, preferably selected from sugars and/or salts (anions/cations/zwitterions). Typical cations include calcium, magnesium, potassium and sodium ions, typical chloride anions, HCO ₃ ^- , H ₂ CO ₃ , HPO ₄ ^2- , H ₂ PO ₄ ^- , typical zwitter ions - amino acids (for example, histidine) and peptides or salts of fruit acids.

The dialysis fluid is preferably free of acetic acid and acetate additives. The total concentration of acetic acid in the dialysis fluid is preferably less than 4 mmol/L, less than 3 mmol/L, less than 2 mmol/L, less than 1 mmol/L, most preferably 0 mmol/L.

Adapting Dialysis Fluid to Methods

In terms of the overall adaptability of the dialysis fluid used in the systems and methods presented herein, i.e. its applicability to regulate blood pH and directly or indirectly remove carbon dioxide from it, as well as combinations of the above, the dialysis fluid can be designed for solution, mainly or primarily, of a particular problem. For example, the dialysis fluid may be designed for the task of regulating the pH of the blood or the task of removing, directly or indirectly, carbon dioxide. As used herein, the terms "designed" and "adapted" are used interchangeably and refer to the dialysis fluid just prior to its exposure to the blood through the semi-permeable membrane, i.e. at the step of its introduction into the second chamber.

For example, in the case where the blood of a subject suffering from metabolic acidosis is to be subjected to the process of the present invention, pH adjustment will typically be necessary, while removal of carbon dioxide may be undesirable or not indicated. In the case of preferential removal of H ⁺ CO ₂ ions, it serves as a source of bicarbonate production. In another example, when the blood of a subject suffering from respiratory acidosis is required to be exposed using the systems and methods provided herein, pH adjustment and carbon dioxide removal are typically required. The dialysis fluid used in the proposed systems and methods can be adapted to such tasks within the framework of the general principles set forth in relation to this fluid in the present description.

Depending on the concentration of bicarbonate (HCO ₃ ^- ) in the dialysis fluid and blood, bicarbonate can be removed from the blood along the concentration gradient between the dialysis fluid on one side of the semipermeable membrane and the blood on the other side of this membrane. In other words, as long as the (cumulative) concentration of carbonate/bicarbonate in the dialysis fluid is lower than the (cumulative) concentration of carbonate/bicarbonate in the blood, bicarbonate will move from the blood into the dialysis fluid along the concentration gradient. If the removal of bicarbonate from the blood is not required or indicated, then the (cumulative) concentration of carbonate/bicarbonate in the dialysis fluid is chosen so that it is not lower than the (cumulative) concentration of carbonate/bicarbonate in the blood, and in the context of the present description "not lower" means "equal to or higher", e.g. "slightly higher", but usually means "approximately equal to" or "equal to".

In general, dialysis fluid prepared to treat the blood of a subject suffering from metabolic acidosis contains bicarbonate in the preferred concentration range of 16 to 40 mmol/L. During treatment, the concentration is preferably slowly increased to avoid acidosis of the cells. The preferred (cumulative) concentration of carbonate/bicarbonate for this purpose is in the range of 25 to 35 mmol/l, or (approximately) 30 mmol/l.

On the other hand, dialysis fluid prepared for treating the blood of a subject suffering from respiratory acidosis generally contains bicarbonate in the preferred concentration range of 0 to 40 mmol/L or alternatively 5 to 40 mmol/L or 10 to 10 40 mmol/l. The preferred (cumulative) concentration of carbonate/bicarbonate for this purpose is in the range of 15 to 35 mmol/L, 20 to 30 mmol/L, or (approximately) 25 mmol/L.

Applicability for pH regulation

In addition to efficient removal of metabolites such as CO ₂ and bicarbonate ions from the blood, the systems and methods provided herein allow the blood pH to be adjusted to the desired level. This applies, for example, in the case of treating "acidic" blood, such as the blood of patients suffering from acidosis. At the same time, it is desirable that the blood pH be adjusted to a predetermined value or a predetermined range of values from 6.8 to 8.5. pH values outside this range are unacceptable due to undesirable side effects such as protein denaturation and/or precipitation of blood components. In general, regulation of the pH value or range of blood means that the blood is characterized by this adjusted value or range of values at the step of leaving the first chamber.

Given that blood in a healthy human body typically has a pH value in the range of 7.35 to 7.45, i.e. approximately 7.40, in some embodiments of the invention it is desirable to adjust the pH of the blood to a range of values covering the specified range, that is, 7 to 8.5, 7.0 to 7.8, 7.2 to 7.6, or 7.3 to 7.5. In preferred embodiments of the invention, if it is necessary to bring the blood pH to a value close to the level characteristic of blood in a healthy person, it is desirable to adjust the blood pH to a value or range of values from 7.35 to 7.45, preferably from 7.36 up to 7.44, more preferably from 7.37 to 7.43, even more preferably from 7.38 to 7.42, even more preferably from 7.39 to 7.41, and most preferably up to a value equal to approximately 7.40.

As detailed below, the systems and methods provided herein are applicable in particular to the treatment of patients suffering from acidosis, namely metabolic and/or respiratory acidosis. In embodiments intended or suitable for treating the blood of such patients, it may be desirable to adjust the blood pH to a range or value greater than 7.40 (corresponding to a more alkaline environment) and greater than 7.40 to 8.0, from 7.5 to 7.9 or 7.6 to 7.8, preferably within the range of 7.65 to 7.75, such as 7.7.

The regulation of blood pH in the systems and methods presented herein is technically feasible due to the buffering capacity of the dialysis fluid used and the permeability of the semi-permeable membrane to H ⁺ and OH ^- ions. Thus, regulation of blood pH can be accomplished with buffered dialysis fluid. Ions H ⁺ and OH ^- can pass through the semi-permeable membrane along the corresponding concentration gradient.

Without wishing to be bound by any particular theory, it can be assumed that H ⁺ ions are removed from the blood mainly due to the excellent buffering capacity of the dialysis fluid used in the systems and methods presented herein. In addition, there is reason to believe that minor amounts of H ⁺ ions are removed by reaction with OH ^- ions present in the dialysis fluid on either side or both sides of the semipermeable membrane. Removal from the blood of not only carbon dioxide, but also H ⁺ ions (as a result of reaction with OH ^- ions), allows the regulation of the acid-base balance of the blood. As detailed below, the dialysis fluid used in the systems and methods described herein can be tailored to the needs, for example, the needs of the patient being treated with dialysis. Thus, the systems and methods provided herein allow for preferential removal of carbon dioxide or preferential regulation of blood pH, or both. This adaptability makes it possible to control the pH of the dialysis fluid and control the concentration of buffer substances (in particular, albumin and bicarbonate) in it independently of each other and within the general ranges specified in the present description.

Applicability for removing toxins

Some embodiments of the invention provide the ability to remove other or additional unwanted substances from the blood. In these embodiments, such unwanted substances are toxins, such as protein-bound toxins. These embodiments of the invention are aimed at removing at least two undesirable substances from the blood, for example at least one undesirable substance from those mentioned above and additionally any toxin. In the context of the present description, the term "toxin" does not imply any particular limitation and refers to any substance that is toxic to the human or animal body, including metabolites, such as bilirubin, bile acids, copper; other substances such as hormones or drugs that accumulate in liver failure. Toxins in the blood of a person or animal are usually associated with proteins. In general, protein-bound toxins are poorly removed by hemodialysis. The presence of albumin in the dialysis fluid used in the systems and methods provided herein allows for or improved removal of protein-bound toxins: a small proportion of dissolved protein-bound toxins present in the blood in free form can diffuse across the semi-permeable membrane into the dialysis device and attach to free binding sites. in the adsorbent (albumin) contained in the dialysis fluid.

Semi-permeable membrane and a device containing such a membrane

An apparatus suitable for use in the systems and methods described herein comprises a first chamber suitable for receiving dialysis fluid. The first and second chambers are separated by at least one semi-permeable membrane.

The first chamber is suitably divided into several first chambers. The term "several" means any integer greater than one. Thus, in a typical embodiment of the invention, the device comprises a plurality of first chambers. Each first chamber is preferably in contact with the second chamber through a semi-permeable membrane. The first chambers are preferably in the form of capillaries. This allows blood to pass through the capillaries while in contact with the dialysis fluid through a semi-permeable membrane.

In some embodiments, the invention provides for the presence of multiple second cameras in the device. Every second chamber is preferably in contact with the first chamber through a semi-permeable membrane.

The ratio of the total volume of the second chamber (multiple second chambers) to the total volume of the first chamber (multiple first chambers) in the device may range from 10:1 to 1:10. The total volume of the second chamber (multiple second chambers) preferably exceeds the total volume of the first chamber (multiple first chambers). The preferred ratio is approximately 2:1.

Thus, in the systems and methods described herein, the passage of at least one unwanted substance from the blood into the dialysis fluid occurs through a semi-permeable membrane. This membrane is ideally permeable to oxygen, carbon dioxide, bicarbonate, H ⁺ ions and liquids. In a device containing a first chamber for receiving blood and a second chamber for receiving dialysis fluid, a semi-permeable membrane is located between the first and second chambers. This allows substances capable of passing through the membrane to pass from the first chamber to the second or from the second chamber to the first. As a rule, such substances capable of passing through the membrane preferentially move along their concentration gradient.

A semi-permeable membrane is impermeable to proteins whose size or properties are characteristic of albumin. However, bicarbonate and hydrogen cations, as well as other small molecules, including ions or substances capable of affecting the pH of an aqueous liquid, can pass through a semi-permeable membrane during the process of the invention. Therefore, the pH of the dialysis fluid does not necessarily remain constant throughout the step of this process characterized by blood coming into contact with the dialysis fluid. Therefore, more specifically, the pH and the (total) carbonate/bicarbonate concentration of the dialysis fluid are preferably determined, in accordance with the above, in the step immediately preceding this contact, i.e. in the step of entering the dialysis fluid into the second chamber. In other words, upon entering the second chamber, the dialysis fluid has a pH value in the range of 8.0 to 11.0 (or, as described herein, in any preferred sub-range of this range).

Since the passage (transport) of substances across a semipermeable membrane is passive, i.e. occurs along a concentration gradient, the blood and/or dialysis fluid is preferably set in motion, for example by passing a constant stream of each of these fluids through a respective chamber and, optionally, by agitation, shaking, creating a pressure difference (causing convection) or by other suitable mechanical action. It is believed that such mechanical actions increase the efficiency of substances coming into contact with the surface of a semi-permeable membrane and, therefore, passing through this membrane.

In an exemplary embodiment, a device suitable for use in the systems and methods described herein may have an exposed (open) surface area of the semi-permeable membrane between 0.01 and 6 m ² . In the case of parallel use of two dialysis modules, the (cumulative) surface area is typically up to 6 m ² . Such parallel use of two dialysis modules is provided in one of the embodiments of the invention for the systems and methods presented in the present description. The open surface area in any of the dialysis modules is typically in the range between 0.01 and 3 m ² , for example between 0.1 and 2.2 m ² . In general, surface areas in the lower part of these ranges are particularly suitable for treating children. The expression "open surface area" refers to the area of the semi-permeable membrane opening on one side into the first chamber and simultaneously on the other side into the second chamber. Any additional areas of the membrane that do not open simultaneously into both chambers, but, for example, are fixed in any fastener or otherwise overlap, are not considered part of the open surface area. In the systems and methods described herein, it is possible to use more than one such membrane in the same dialysis module or in more than one dialysis module. If the number of dialysis modules exceeds one, then these dialysis modules may be arranged in series or in parallel with respect to the flow of blood in the extracorporeal circuit. Preferably, two dialysis devices are used, each having an open surface area as described above.

Thus, the systems and methods provided herein allow carbon dioxide and other substances such as hydrogen cations and bicarbonate to pass into the dialysis fluid (by passing through the dialysis membrane). Therefore, the systems and methods presented herein may be referred to as liquid-liquid dialysis systems and methods suitable for removing CO ₂ . They make it possible to remove metabolites, such as CO ₂ , from the blood more efficiently than existing methods.

Although carbaminohemoglobin and dissolved carbon dioxide are in equilibrium with the bicarbonate (HCO ₃ ^- )/H ⁺ ion pair, the presence of the enzyme carbonic anhydrase is required for rapid conversion. In some embodiments, the semipermeable membrane may be configured as a source of carbonic anhydrase activity. This can be achieved by applying carbonic anhydrase as a coating to the side of the membrane facing the blood and/or dialysis fluid.

One chamber may be provided on each side of the semi-permeable membrane, ie a first chamber on one side of the semi-permeable membrane and a second chamber on the other side of the membrane. In other words, the device used contains two compartments separated by a semi-permeable membrane. The first chamber, the semi-permeable membrane and the second chamber are preferably provided in one device. Thus, the blood is in the first chamber, and the dialysis fluid is in the second chamber, separated from the first chamber by said semi-permeable membrane. It may also be envisaged to coat the semi-permeable membrane with the enzyme carbonic anhydrase.

Several first chambers may be provided, each of which is in contact with the second chamber through a semi-permeable membrane. These first chambers may be in the form of capillaries through which blood flows during the process of this embodiment.

Although the use of the systems and methods presented herein is in a static mode, that is, when blood is constantly present in the first chamber without flowing (entering, passing and exiting) through this chamber, and dialysis fluid is constantly present in the second chamber without flowing (entering passing and exiting) through this chamber is not impossible, embodiments of the invention providing for semi-static and non-static modes are preferred. In non-static mode, blood flows (enters, passes, and exits) through the first chamber, and dialysis fluid flows (enters, passes, and exits) through the second chamber. Semi-static mode refers to the mode provided in embodiments of the invention in which only one of these fluids flows through its respective chamber, while the other fluid is constantly present in its respective second chamber, without flowing (entering, passing and exiting) through this chamber. Thus, in the systems and methods described herein, blood preferably flows through the first chamber and dialysis fluid simultaneously flows through the second chamber. Therefore, it is preferred that the blood passes through the blood compartment (first chamber) and the dialysis fluid through the dialysis fluid compartment (second chamber).

The systems and methods provided herein effectively remove one or more of the undesirable substances mentioned above, including CO ₂ , without the need for a gas stream (propellant gas) provided in the prior art. In particular, they do not provide for and do not require the conversion of unwanted CO ₂ into the gas phase. A typical dialysis module used in the systems and methods described herein does not include a chamber with a gas (propellant gas) in contact with blood through a membrane (eg, a gas exchange membrane).

The device containing the first chamber, the second chamber and a semi-permeable membrane is a dialysis module included in different versions of the dialyzer. The dialysis module contains a first chamber according to the present description, a second chamber according to the present description and a semi-permeable membrane, as well as a means for introducing fluid (for example, blood) into the first chamber (inlet) and withdrawing it from the first chamber (outlet) and a means for introducing fluid ( e.g., dialysis fluid) into the second chamber (inlet) and out of the second chamber (outlet). Thus, the first chamber contains an inlet and outlet and the second chamber contains an inlet and outlet. Therefore, in the systems and methods described herein, the dialysis module comprises a biological fluid compartment (first chamber) that is part of the biological fluid circuit, a dialysis fluid compartment (second chamber) that is part of the dialysis fluid circuit, and a semi-permeable membrane. separating the biological fluid compartment and the dialysis fluid compartment. When using a dialysis module, blood passes through the first chamber and dialysis fluid passes through the second chamber. Alternatively, the device is an ultrafiltration device (ultrafiltration device). During the implementation of the methods presented in the present description, the second chamber does not contain, preferably and essentially, no gas phase, that is, filled essentially only dialysis fluid in the liquid phase. Therefore, the contact of gas with blood can be completely eliminated or minimized, and the need for it may arise only in certain circumstances, for example, when using a bubble trap or similar device.

The semi-permeable membrane used in the systems and methods described herein is not particularly limited as long as it is permeable to water and water-soluble inorganic molecules. A suitable semi-permeable membrane allows at least one unwanted substance to pass through. The membrane can be selected, for example, from conventional semi-permeable membranes currently used, for example for hemodialysis. One can, however, also consider using membranes with larger pores than those currently used for dialysis. Diffusion through the membrane can in some cases be supported by convective transport provided by filtration.

The dialyzer contains, as mentioned above, a dialysis module and additional tubes (inlet and outlet) connected to the corresponding means for supplying fluid to the first and second chambers and removing this medium from these chambers: tubes connected to the first chamber (with inlet and outlet) , applicable for connection with the circulatory system of a human or animal. Essentially, the dialyzer comprises two chambers, which are separated by a dialysis membrane, and to each of which is connected a tubing system for the fluids to be used. The pipes connected to the second chamber (with inlet and outlet) can optionally be connected to a regeneration module. The latter allows for the regeneration (recirculation, reuse) of the dialysis fluid as described below, as well as in publications WO 03/094998 A1 and WO 2009/071103 A1, each of which is fully incorporated into this application by reference. The dialyzers used in the systems and methods described herein are not particularly limited and may be conventional dialyzers currently used, for example for hemodialysis. In one embodiment of the present invention, the ^HepaWash® system is used (Example 2).

Other features and process parameters

Other features and parameters described below relate to the use of a dialysis module, ie a device comprising a first chamber, a second chamber and a semi-permeable membrane. Conventional dialyzer components such as pressure gauges, air detectors, pumping devices such as heparin pumps, infusion pumps, etc. form part of the tool or device of the invention.

One time use

After leaving the second chamber (outlet), the dialysis fluid can be disposed of. The process of its use in such embodiments of the invention is called "one-time" or "single pass". Single use requires the addition of fresh dialysis fluid (to the inlet of the second chamber) throughout essentially the entire process. Although the possibility of a single use is implied in the context of the present description, such a use is not applicable to the same extent as the recycling described below. Therefore, in the context of the present invention, single use is less preferred.

recycling

In contrast to disposable use, dialysis fluid can also be recycled ("repeated or multiple or multiple use"). To this end, the dialysis fluid ("waste dialysis fluid") exiting the second chamber (outlet) is collected and returned to the second chamber (inlet). Albumin has a relatively high cost. Therefore, it is generally desirable to recirculate the albumin-containing dialysis fluid. In other words, recycling can provide significant cost savings. In addition, recirculation allows you to maintain a high flow rate of dialysis fluid, reaching up to 4000 ml/min.

Recirculation of dialysis fluid usually requires its purification or regeneration. Purification or regeneration is performed within at least one type of treatment step to remove unwanted substances from the dialysis fluid (ie dialysis waste fluid) prior to its re-entry into the second chamber. This step is usually performed outside the second chamber, i.e. at a site other than the blood contact site. At least one treatment step may include one or more exposures by (I) an adsorbent and/or (II) diafiltration and/or (III) an acidic medium with an appropriate pH level and/or an alkaline medium with an appropriate pH level and/or (IV) a permeable or semi-permeable membrane (ie, a membrane other than the membrane located in the dialysis module between the first and second chambers). The adsorbent is usually a substance other than albumin, ie, in the case of an albumin-containing dialysate, a different or additional adsorbent is used. In some embodiments of the invention, the adsorbent is capable of attaching sodium ions (Na ⁺ ) or chloride ions (Cl ^- ).

One or more of these processing steps may be performed sequentially or in parallel (ie, by splitting the dialysis fluid stream). It can be envisaged that the dialysis fluid is treated or purified after contact with blood through the semi-permeable membrane, ie after leaving the second chamber. Suitable means for treating or purifying the dialysis fluid include one or more adsorption modules, one or more pH change modules, and/or one or more diafiltration modules. These modules are not incompatible and can be placed in series or in parallel. In particular, dialysis fluid recycling in the systems and methods described herein may also include, as a necessary step, adjusting the (cumulative) carbonate/bicarbonate concentration and/or pH to match the pH of the dialysis fluid being reintroduced into the first chamber. , the values required as set forth in the present description. The expression "re-introduced" means the introduction after recycling.

Flow rates

The blood passes through the first chamber and the dialysis fluid through the second chamber. The selected flow rate of blood and dialysis fluid can be constant or vary (change) over time.

In general, the blood flow rate in the extracorporeal circuit can be adjusted between 50 and 7000 ml/min. However, in the systems and methods provided herein, the blood flow rate is typically about 2 L/min or less, such as about 1 L/min or less, about 0.5 L/min or less, and in any case at least 50 ml/min. The blood flow rate is usually monitored and regulated so that it can be adjusted according to the processing conditions and the flow rate of the dialysis fluid. Thus, the systems and methods provided herein provide the ability to support the lungs up to 100% at maximum blood flow rates in the middle of the respiratory movement without the use of another ventilation device. However, conventional extracorporeal lung support devices operating in support mode in the middle of the respiratory movement cannot provide the same good lung support. This means that the lungs are sufficiently well supported in the middle of the respiratory movement, which simplifies the work of the specialist performing the procedure and is less dangerous for the patient. In addition, this avoids the use of protective mechanical ventilation (protective ventilation), which is a common practice for other devices operating in support mode in the middle of the respiratory movement.

In the systems and methods described herein, the dialysis fluid flow rate can range between 10 and 11,000 ml/min (ie, 0.1667 to 183.333 ml/hour). In more typical cases, the flow rate of dialysis fluid in the dialyzer is selected from the following values: low (1-2 l/h), normal (25-60 l/h) and medium (greater than 2 to less than 25 l/h). The flow rate can thus be adapted to the needs. In general, the blood flow rate is preferably lower than the dialysis fluid flow rate. Due to this, an efficient blood treatment can be performed.

In a dialysis module, that is, in a device containing a first chamber, a second chamber and a semi-permeable membrane, blood and dialysis fluid usually move in countercurrent, but cocurrent movement is also possible. However, it is generally assumed that blood and dialysis fluid can flow through the dialysis device in the same direction or in countercurrent.

Removal of CO ₂ from dialysis fluid

In the systems and methods described herein and in accordance with a preferred embodiment of the invention, carbon dioxide and/or carbon dioxide and/or dissociation products of the latter (H ⁺ /HCO ₃ ^- ) can be removed ("removal") from the dialysis fluid. Ideally, this occurs within a separate step, namely the step following the exit of the dialysis fluid from the second chamber (outlet). The means used for these purposes are not subject to special restrictions other than applicability. From this point of view, carbon dioxide and/or carbon dioxide and/or dissociation products of the latter (H ⁺ /HCO ₃ ^- ) can be properly removed from the dialysis fluid by degassing (pressure reduction, heating or cooling, ultrasonic treatment, membrane degassing, replacement with an inert gas, reducing agent addition, cool-pump-heat cycling, pH reduction, centrifugation or use of degassing agents), filtration, sorption or chemical bonding. For example, removal can be accomplished by degassing (e.g., depressurization, heating or cooling, sonication, membrane degassing, inert gas displacement, addition of a reducing agent, cool-pump-heat cycling, pH reduction, centrifugation, or the use of degassing additives) , filtration, sorption or chemical bonding and/or combinations of the above. This provides an ideal opportunity to measure the concentration of carbon dioxide and/or carbonic acid and/or bicarbonate and/or measure the pH in the dialysis fluid after the latter has left the second chamber. Removal of carbon dioxide and/or carbon dioxide and/or dissociation products of the latter is particularly effective in embodiments of the invention involving recycling of dialysis fluid as described below.

In a particularly preferred embodiment of the invention, the process proposed therein proceeds in such a way that recycling comprises acidification (acidification) of the dialysis fluid to an acidic pH to form carbon dioxide and removal of the latter from the dialysis fluid through a carbon dioxide-permeable membrane. This membrane is gas permeable and carbon dioxide is removed in the gas phase.

Acid/alkaline treatment

Albumin can be purchased on the market, but is relatively expensive. Therefore, the use of albumin-based dialysis fluid can be expensive. In publications reflecting the state of the art, the recycling of albumin-containing dialysis fluid is described for the case of dialysis in relation to the liver, for example in the publication WO 2003/094998, incorporated herein by reference in its entirety. As stated in WO 2003/094998, albumin recycling can be based on the principle that the binding capacity of carrier proteins (such as albumin) to attachable substances, such as toxins, can be influenced in certain ways, such as by changing the pH. Selectively lowering and then raising (or vice versa) the pH of a dialysis fluid containing albumin promotes efficient removal of attached substances by dialysis (diffusion) or filtration (convection) or a combination of both processes, referred to below as diafiltration. In general, diafiltration is a dilution process involving the removal or separation, depending on the size of the molecules, of the components (penetrating molecules such as salts, small proteins, solvents, etc.) of a solution using filters that are permeable to these components. Removal of such components by diafiltration allows subsequent recycling of the albumin. As stated in the publications reflecting the prior art, albumin regeneration can be effectively carried out in a dialysis regeneration module, providing for the separation of the dialysis fluid into two parallel streams, namely acid and alkaline streams, the flow paths of which are parallel (see publication WO 2009/071103, in full incorporated into this application by reference). The process and apparatus (eg, dialysis fluid regeneration module, dialysis module) described in WO 2009/071103 are also applicable to the recycling of albumin-containing dialysis fluid in the systems and methods described herein.

At the step of processing (purification, regeneration) of the dialysis fluid at a changed pH, it is possible to remove toxins attached, for example, to albumin. To efficiently remove such toxins, the dialysis fluid recovery module (corresponding to the systems and methods described herein) has two flow paths arranged parallel to each other and in fluid communication. The dialysis fluid to be regenerated is divided into two streams moving through these channels. In the first flow path, an acidic fluid is added to the dialysis fluid (from a suitable fluid delivery device). In the case of toxins soluble in an acidic solution, the concentration of free toxins in the solution increases. The detoxification device downstream of the acidic fluid supply device removes free toxins from the acidified dialysis fluid flowing through the first flow path. The addition of an acidic fluid to the dialysis fluid facilitates the removal of toxins soluble in the fluid. In addition, as a result of lowering the pH, for example, precipitation of toxins soluble in an alkaline medium can occur, and therefore their removal from the dialysis fluid. In a second flow channel extending parallel to the first channel, an alkaline fluid (from a suitable feeder) is added to the dialysis fluid flowing through this channel. Due to the increase in pH, the concentration of free toxins that are soluble in an alkaline environment increases, thereby facilitating the removal of such toxins. These toxins are removed by a second detoxification device located downstream of the alkaline fluid supply device. The second detoxification device is configured to remove toxins from the alkalized dialysis fluid moving through the second flow path. In addition, as a result of the increase in pH, for example, the precipitation of acid-soluble toxins can occur, and hence their removal from the dialysis fluid. The presence of an acidic flow path and an alkaline flow path arranged in parallel makes it possible to efficiently remove acid-soluble toxins and alkali-soluble toxins from the dialysis fluid. Therefore, the dialysis fluid regeneration module used in the systems and methods described herein provides efficient removal of protein-bound toxins. In the context of the present description, the term "toxin" has a very broad meaning and covers all protein-bound substances, even if they are not usually referred to directly as toxins, for example, drugs, electrolytes, H ⁺ , hormones, fats, vitamins, gases and metabolic breakdown products. such as bilirubin. At the outlet of the acid treatment device and the alkaline treatment device, collectively referred to as "pH-corrected treatment devices" (or detoxification devices), the regenerated acidified dialysis fluid from the first flow path is merged with the regenerated alkalized dialysis fluid from the second flow path, whereby the acidified the dialysis fluid from the first flow path and the alkalized dialysis fluid from the second flow path at least partially neutralize each other. Thus, by fusing the acidified dialysis fluid stream from the first flow path with the alkalized dialysis fluid stream from the second flow path, a regenerated dialysis fluid stream with physiological pH can be obtained.

According to a preferred embodiment of the invention, the acidic fluid added from the first feeder contains at least one of the following: hydrochloric acid, sulfuric acid, and acetic acid. In a preferred embodiment of the invention, the first delivery device is configured to adjust the pH value of the dialysis fluid in the first flow path between 1 and 7, preferably between 2.5 and 5.5.

The alkaline fluid added from the second feeder preferably contains at least one of sodium hydroxide solution and potassium hydroxide solution. In a preferred embodiment of the invention, the second supply device is configured to adjust the pH value of the dialysis fluid in the second flow path between 7 and 13, preferably between 8 and 13, more preferably between 8 and 11.

In addition, the acidic fluid and the alkaline fluid are preferably chosen such that the corresponding "physiological" products are formed during the neutralization process. For example, the resulting neutralization products may already somehow be present in a certain concentration in the corresponding biological fluid. For example, when using an aqueous solution of hydrochloric acid and an aqueous solution of sodium hydroxide, NaCl is formed in a certain concentration in the process of neutralizing acidified and alkalized streams. NaCl is usually also present in a biological fluid such as blood or blood serum.

According to one of the preferred embodiments of the invention, as a result of lowering the pH of the dialysis fluid in the first flow path, the concentration ratio of the toxin-carrier complex and free toxin and free carrier substance shifts towards free toxin for at least some of the toxins present in the dialysis fluid, as a result, the concentration of free toxins in the dialysis fluid increases. By lowering the pH of the dialysis fluid in the first flow path, the solubility of acid-soluble toxins (such as, for example, magnesium or copper) increases, while the binding capacity of acid-soluble toxins and carrier substances decreases. This leads to a corresponding increase in the concentration of free toxins in the solution.

In addition, the detoxification device is preferably configured to at least partially remove said free toxins. With an increase in the concentration of free toxins, the degree of removal of these toxins can also increase.

Further, as a result of lowering the pH value of the dialysis fluid in the first flow path, for example, some alkali-soluble toxins can precipitate and then be removed from the dialysis fluid.

In a preferred embodiment of the invention, as a result of an increase in the pH of the dialysis fluid in the second flow path, the concentration ratio of the toxin-carrier complex and free toxin and free carrier substance shifts towards free toxin for at least some of the toxins present in the dialysis fluid, whereby the concentration free toxins in the dialysis fluid increases. By increasing the pH of the dialysis fluid in the second flow path, the solubility of alkaline soluble toxins (such as, for example, bilirubin) increases, while the binding capacity of alkaline soluble toxins and carrier substances decreases. This leads to a corresponding increase in the concentration of free toxins in the solution.

In addition, another detoxification device is preferably configured to at least partially remove said free toxins. With an increase in the concentration of free toxins, the degree of removal of these toxins can also increase.

Further, as a result of lowering the pH value of the dialysis fluid in the second flow path, for example, some acid-soluble toxins can precipitate and then be removed from the dialysis fluid.

According to another preferred embodiment of the invention, as a result of an increase in the temperature of the dialysis fluid, the concentration ratio of the toxin-carrier complex and free toxin and free carrier substance shifts towards free toxin for at least some of the toxins present in the dialysis fluid, whereby the concentration of free toxins in dialysis fluid increases. Accordingly, the degree of removal of free toxins by detoxification devices also increases.

Other aspects of the recycling of albumin-containing dialysis fluid are described in WO 2009/071103, which is hereby incorporated in its entirety, together with the illustrations, by reference. In addition to what is stated in WO 2009/071103, the present disclosure also highlights the contribution of albumin to the superior buffering capacity of the dialysis fluid of the invention.

Adsorption treatment/Adsorption

To perform extraction, or removal, of unwanted substances such as electrolytes (eg, cations such as potassium, sodium and calcium cations, or anions such as chloride, carbonate or bicarbonate anions), an adsorbent may be brought into contact with the dialysis fluid. In general, the adsorbent is capable of adsorbing at least one undesirable substance present in the patient's blood (eg, urea, uric acid, electrolytes, sodium, calcium or potassium cations, chloride anions). The adsorbent is usually placed in an adsorption module, that is, in a stationary device through which the dialysis fluid passes. The type, composition or material of the adsorbent is not associated with any particular restrictions, as long as this adsorbent is capable of binding at least one substance to be removed from the dialysis fluid. Various types of adsorbents are known in the art. The described process can be adapted to the actual needs of, for example, an individual patient by selecting the appropriate adsorbent. The use of an adsorbent is particularly advantageous in embodiments of the invention involving recirculation of dialysis fluid.

Features of dialysis fluid regeneration

Excess unwanted substances can be removed from the dialysis fluid (waste dialysis fluid) through the membrane, namely through a permeable or semi-permeable membrane. For example, gases and/or substances/ions dissolved in the dialysis fluid can be removed by such a membrane treatment. In a preferred embodiment of the invention, carbon dioxide can be removed either as a gas or dissolved in a liquid. One particularly suitable method of removing carbon dioxide is by contacting the dialysis fluid with a carbon dioxide permeable membrane. The dialysis fluid has a certain pressure p ₁ which is higher than the pressure p _{2 of} the fluid (liquid or gas) on the other side of said membrane, ie p ₂ <p ₁ . The goal of removing CO ₂ from the spent dialysis fluid can also be achieved (alternatively) if the CO ₂ partial pressure is lower for the fluid on the other side of the membrane. Similarly, it is possible to remove bicarbonate along a concentration gradient, namely by bringing the spent dialysis fluid into contact with a bicarbonate-permeable membrane, provided that the (cumulative) concentration of carbonate/bicarbonate in the fluid (liquid) on the other side of the membrane is lower (cumulative) the carbonate/bicarbonate concentration of the spent dialysis fluid. In all cases, the membrane used is impermeable to albumin. This can be achieved by selecting a membrane with an appropriate pore size. Such membrane treatment is particularly useful in recirculating embodiments of the invention.

Dialysis modules

The dialysis is preferably performed with two devices, or dialysis modules, used in a parallel configuration. This allows for an increase in the exposed surface area of the membrane and therefore allows more efficient exchange of one or more unwanted substances across the semi-permeable membrane.

Therapeutic use

The systems and methods presented in this trial can and should be used for medical purposes to achieve beneficial results. Any action aimed at healing the human or animal body by surgical or therapeutic intervention and aiming, in particular, at preventing the deterioration of the condition of a living subject or improving this condition, that is, having a medical purpose, can be called a medical method or medical use. In the context of the present description, the terms "method" and "process" are generally used interchangeably. However, in some cases, the term "method" is used to refer to specific medical methods that are offered in the present invention and which may include, in all aspects, the process described above for removing any unwanted substance from the blood. In particular, the invention provides a method for the extracorporeal treatment of the blood of a patient in need of such treatment. The blood in the extracorporeal circuit is subjected to the dialysis process described herein, that is, exposure to dialysis fluid through a semi-permeable membrane. To this end, blood is withdrawn from the subject exposed using the systems and methods presented in the present description, and appropriately re-introduced to this subject. In general, the process according to the invention draws venous blood from the patient and injects it into the first chamber. This allows the processing of blood in accordance with all aspects specific to the systems and methods presented in the present description. The blood ("processed blood") then exits the first chamber and can be reintroduced to the patient. Most typically, treated blood is injected into a patient's vein, but alternatively, it can be injected into an artery, although the latter is accordingly limited to processes in which the blood is also oxygenated. All of these aspects, covering the process from the moment the blood is taken from the patient's body to the moment the patient's treated blood is introduced back into the patient's body, are general in relation to all the indications mentioned in the present description, and the corresponding methods of conservative treatment for these indications.

The systems and methods provided herein are applicable to the implementation of a therapeutic effect on the human or animal body (commonly referred to as medical use). The therapeutic effect of the invention can be adapted to the specific and actual needs of the respective patient. Although the process of gas exchange in nature is not limited to organisms that have lungs, but also occurs in organisms that have gills, such as fish, the therapeutic use of the invention is focused on the task of supporting the lungs, that is, the treatment or prevention of certain conditions of organisms that have lungs, preferably mammals. , more preferably people. Therefore, gills and organisms having gills are not the subject of detailed discussion in the present description.

In therapeutic methods, the dialysis fluid preferably has an osmolarity substantially identical to that of the blood of the biological subject (eg, human) being dialyzed in the dialysis device.

Although the systems and methods presented herein are applicable to extracorporeal blood processing, in some cases they do not include a step that is an invasive procedure (invasive step), a step that involves significant physical intervention in the body, a step that requires professional medical competence when it is performed, and a step that carries a significant risk to health, even if performed with due professional care and competence. The systems and methods provided herein preferably do not include an invasive step that involves a significant physical intervention in the body, requires professional medical competence in its implementation and carries a significant risk to health, even if it is performed with due professional care and competence. For example, the systems and methods provided herein, in some cases, do not include the invasive step of connecting the dialysis system to the human or animal body, or correspondingly disconnecting it. In another example, the introduction of an extracorporeal device into contact with the venous blood of a living subject and, therefore, the implementation of the corresponding medical method does not entail a significant risk to health.

The therapeutic methods of the invention are applicable or suitable for the treatment of at least one of the conditions, including respiratory acidosis, metabolic acidosis, pulmonary insufficiency, renal insufficiency, multiple organ failure, and any combination of the above. These therapeutic methods can be optimized according to the condition or the specific patient to be treated (personalized medicine). While the following sections describe the treatment of these conditions, the methods presented equally cover appropriate preventive measures.

All of these treatments involve drawing venous blood from a subject into an extracorporeal circuit in which, as described herein, the blood is brought into contact with dialysis fluid through a semi-permeable membrane, after which the thus treated blood is injected back into the body of the same subject, preferably into vein, less preferably - in the artery of the latter. The individual configurations are described below.

Treatment of respiratory acidosis

The systems and methods provided herein are applicable to the treatment of patients suffering from acute or chronic respiratory acidosis. Such patient populations include subjects suffering from hypoventilation, lung tumors, asthma, muscular dystrophy, or emphysema, especially advanced emphysema. For the treatment of subjects suffering from respiratory acidosis, the dialysis fluid has a (cumulative) carbonate/bicarbonate concentration in the second chamber inlet in the range of 0 to 40 mmol/L. It is known that in the case of respiratory acidosis, the (cumulative) carbonate/bicarbonate concentration is preferably as low as possible, ie 0 mmol/l or higher. Subranges include 1 to 35 mmol/L, 2 to 30 mmol/L, 3 to 25 mmol/L, 4 to 20 mmol/L, 5 to 15 mmol/L, such as 10 mmol/L.

In general, the (cumulative) concentration of carbonate/bicarbonate at the lower end of the specified range or subrange provides effective removal of undesirable substances such as bicarbonate, CO ₂ and carbonate from the blood.

When the (cumulative) concentration of carbonate/bicarbonate in the dialysis fluid is at a low level (e.g., 0 or 0 to 10 mmol/L), proper buffering is achieved by the presence of sufficient other buffering agents, usually albumin, in the dialysis fluid. and/or trisa. In particular, in the absence of carbonate/bicarbonate additives in the dialysis fluid (i.e., when the concentration of carbonate/bicarbonate in the dialysis fluid is equal to or close to 0 mmol/l), the presence of both tris and albumin in the dialysis fluid is preferred. The concentrations of these buffering agents are chosen such that the buffering capacity is higher than the buffering capacity of the blood plasma. This allows you to effectively regulate the pH of the blood.

It is also possible to increase the (cumulative) concentration of carbonate/bicarbonate during treatment. This allows treatment to be tailored to the needs of the individual patient (personalized medicine).

Blood exposed to such a dialysis fluid through a semi-permeable membrane typically has a pH in the range of 7.40 to no more than 8.0, 7.5 to 7.9, 7.6 to 7.8, or 7. 65 to 7.75, for example 7.7. Such blood is injected back into the subject's body.

The dialysis fluid is disposed of or preferably recycled. In the latter case, the dialysis fluid is preferably subjected to a membrane treatment. Membrane treatment can completely or partially remove carbon dioxide and/or bicarbonate and/or carbonate and/or carbonic acid. This allows the dialysis fluid to be recirculated. To remove carbon dioxide, the membrane treatment is preferably performed at low pH, ie after acidification of the dialysate.

It is known that in subjects suffering from respiratory acidosis (ie, excess dissolved CO ₂ in body fluids due to insufficient removal in the lungs), the kidneys often respond with some delay, for example 3 weeks, producing increased amounts of bicarbonate. The systems and methods provided herein allow for the care of subjects suffering from respiratory acidosis throughout the course of the disease, that is, in the early stages, when removal of excess CO ₂ from body fluids is mainly required, and in the later stages, when it is necessary (additional) removal of excess bicarbonate from body fluids. In addition, at all stages of the disease, it is possible to remove excess H ⁺ ions from physiological fluids. During treatment, the physician may change the composition and pH of the dialysis fluid in accordance with the recommendations given in this description.

Treatment of metabolic acidosis

For the treatment of subjects suffering from acute or chronic metabolic acidosis, in the case of normal functioning of the lungs, the dialysis fluid has a (cumulative) carbonate/bicarbonate concentration in the second chamber inlet in the range of 20 to 40 mmol/l, preferably 25 to 35 mmol/l , more preferably is exactly or approximately 30 mmol/L.

For the treatment of subjects suffering from acute or chronic metabolic acidosis in the event of impaired lung function, the dialysis fluid preferably does not contain carbonate/bicarbonate additives. A dialysis fluid suitable for this type of patient has a (cumulative) carbonate/bicarbonate concentration in the range of 0 to 5 mmol/l (preferably 0 mmol/l) and the buffering capacity is contributed by albumin and tris having a concentration in the ranges indicated above. For example, if the (cumulative) concentration of carbonate/bicarbonate in the dialysis fluid is identical to the (cumulative) concentration of carbonate/bicarbonate in the patient's blood, then this does not imply a net conversion of bicarbonate.

Desirably, the pH of the dialysis fluid is high, eg in the range of 8.0 to 11.0, preferably 9.0 to 10.0. The buffer capacity of dialysis fluid is higher than the buffer capacity of blood plasma. The combination of the high pH value of the dialysis fluid and the high buffering capacity of this fluid makes it possible to effectively regulate the blood pH and ensure a minimal net exit from the blood (in whole or in part) of substances such as bicarbonate, CO ₂ and carbonate. In particular, this flow can be increased compared to standard dialysis techniques.

Blood exposed to such a dialysis fluid through a semi-permeable membrane will typically have a pH in the range resulting from regulation of blood pH and covering the desired ranges or values, namely 7.0 to 7.8, 7.2 to 7.6, 7.3 to 7.5, 7.35 to 7.45, most preferably exactly or about 7.40.

The systems and methods provided herein also allow treatment of a condition characterized by a combination of respiratory and metabolic acidosis. This is ensured by the possibility of adjusting, according to individual needs, the parameters of the dialysis fluid, in particular its pH and its (cumulative) concentration of carbonate/bicarbonate.

Treatment of pulmonary insufficiency

The systems and methods provided herein are applicable to the treatment of patients suffering from acute or chronic respiratory (pulmonary) insufficiency. Subjects suffering from pulmonary insufficiency, but not usually accompanied by insufficiency of other organs, such as kidneys or liver, develop respiratory acidosis or are at risk of developing respiratory acidosis. This is due to the fact that the excretion of carbon dioxide does not proceed as efficiently as in healthy subjects, or does not occur at all. This group of patients includes those suffering from asthma, hypoventilation, lung diseases such as lung cancer, complications associated with smoking and exposure to other toxins or particles present in the air, or muscular dystrophy or emphysema, especially advanced emphysema. Many patients suffering from these lung diseases have fully functioning kidneys (fully efficient renal function). The systems and methods provided herein provide lung support. With their help, subjects suffering from the above conditions receive the required treatment, described in the section on the treatment of respiratory acidosis.

Treatment of combined organ failure: combined lung, liver and kidney support

In many cases, subjects suffering from pulmonary insufficiency also present with impaired liver or kidney function. These subjects are also applicable to the methods of treatment proposed in the invention and providing support for these organs.

Лечение комбинированной недостаточности легких и почек Системы и способы, представленные в настоящем описании, также позволяют обеспечить лечение субъектов, страдающих острой или хронической (ренальной) почечной недостаточностью (ХПН). Почки играют важную роль в поддержании кислотно-щелочного гомеостаза здоровых субъектов путем регулирования рН плазмы крови: основные функции включают реабсорбцию бикарбоната из мочи и выведение в мочу катионов водорода. Эти функции почек имеют важное значение для поддержания кислотно-щелочного баланса и могут также вносить вклад в контроль рН крови. У пациентов, страдающих почечной недостаточностью, нормальное функционирование почек нарушается. Данная группа пациентов включает пациентов, страдающих почечными заболеваниями, такими как рак почек, а также осложнениями, связанными с интоксикацией и воздействием некоторых лекарственных препаратов.

Treatment of Combined Lung and Kidney Insufficiency The systems and methods provided herein also allow for the treatment of subjects suffering from acute or chronic (renal) renal insufficiency (CRF). The kidneys play an important role in maintaining acid-base homeostasis in healthy subjects by regulating blood plasma pH: the main functions include the reabsorption of bicarbonate from the urine and the excretion of hydrogen cations into the urine. These kidney functions are essential for maintaining acid-base balance and may also contribute to blood pH control. In patients suffering from renal insufficiency, the normal functioning of the kidneys is impaired. This group of patients includes patients suffering from kidney diseases such as kidney cancer, as well as complications associated with intoxication and exposure to certain drugs.

Renal replacement therapy (RRT) is widely used to treat these patients in modern intensive care units (ICUs). Patients in the intensive care unit (ICU) in the postoperative state and after an interventional study, that is, who are already sensitive to risk factors, often develop acute renal failure (ARF) as part of the multiple organ failure syndrome (MOS). In general, ICU patients require various organ support, such as continuous renal replacement therapy (CRRT), liver dialysis, and mechanical ventilation. In contrast to prior art techniques that traditionally require the use of at least three different devices for the treatment of renal, hepatic and pulmonary insufficiency in such patients (or the use, in addition to the device for the treatment of liver failure, of a combined three-chamber device for the treatment of renal/pulmonary insufficiency - PrismaLung™, DE 102009 008601 Al; Novalung, WO 2010/091867; these publications are incorporated herein by reference in their entirety), the systems and methods presented herein are substantially improved.

Parameters to be selected for the situations described above for cases of respiratory or metabolic acidosis (preferably) include the (cumulative) concentration of carbonate/bicarbonate in the dialysis fluid entering the second chamber, the pH of the blood leaving the first chamber, etc. . These parameters additionally and preferably include, as generally described above, adsorbent parameters. The adsorbent is used to bind or adsorb at least one unwanted substance present in the patient's blood in order to extract liquid or dissolved substances (urea, uric acid, electrolytes, sodium, calcium or potassium cations, chloride anions). For example, in patients suffering from renal insufficiency, it is common to impair the ability of the kidneys to maintain physiological concentrations of sodium, calcium or potassium cations and/or chloride anions in the blood. These violations are eliminated using the systems and methods presented in the present description.

Лечение комбинированной недостаточности почек, печени и легких Системы и способы, представленные в настоящем описании, также позволяют обеспечить лечение субъектов, страдающих острой или хронической печеночной недостаточностью в дополнение к легочной недостаточности, почечной недостаточности либо того и другого. Типичная методика лечения с помощью систем и способов, представленных в настоящем описании, включает экстракорпоральное удаление токсинов. Для лечения таких субъектов способы, описанные в публикациях WO 2009/071103 и/или WO 03/094998, целиком включенных в настоящую заявку посредством ссылок, или способы, разработанные компанией HepaWash^® GmbH (Мюнхен, Германия), можно модифицировать таким образом, чтобы диализная жидкость соответствовала основным требованиям, предъявляемым к диализной жидкости в системах и способах, представленных в настоящем описании, или в любом варианте осуществления настоящего изобретения. В этих способах альбумин выполняет двойную, или синергичную, функцию: он не только связывает токсины (что способствует устранению причин печеночной недостаточности), но и оказывает буферное воздействие на диализную жидкость наряду с карбонатом (что способствует устранению причин легочной недостаточности). Это означает, что дополнительно к функциональным возможностям, описанным в WO 2009/071103 и WO 03/094998, можно осуществить поддержку легких и/или коррекцию рН крови до физиологического или иного желаемого уровня. Эта методика позволяет объединить в одном устройстве диализ почек, диализ печени и поддержку легких, включающую удаление двуокиси углерода и оксигенацию крови. Модификации или конфигурации, описанные выше применительно к лечению почечной недостаточности (например, присутствие адсорбента), равным образом применимы и к данному варианту осуществления изобретения.

Treatment of Combined Renal, Hepatic, and Lung Insufficiency The systems and methods provided herein also allow for the treatment of subjects suffering from acute or chronic liver failure in addition to pulmonary insufficiency, renal insufficiency, or both. A typical method of treatment using the systems and methods presented in the present description, includes extracorporeal removal of toxins. For the treatment of such subjects, the methods described in publications WO 2009/071103 and/or WO 03/094998, incorporated herein by reference in their entirety, or methods developed by HepaWash ^® GmbH (Munich, Germany), can be modified so that the dialysis the fluid met the basic requirements for dialysis fluid in the systems and methods presented in the present description, or in any embodiment of the present invention. In these methods, albumin performs a dual, or synergistic, function: it not only binds toxins (which helps to eliminate the causes of liver failure), but also buffers the dialysis fluid along with carbonate (which helps to eliminate the causes of pulmonary insufficiency). This means that, in addition to the functionality described in WO 2009/071103 and WO 03/094998, lung support and/or blood pH adjustment to a physiological or other desired level can be performed. This technique allows you to combine kidney dialysis, liver dialysis and lung support, including removal of carbon dioxide and oxygenation of the blood, in one device. The modifications or configurations described above in relation to the treatment of renal failure (eg, the presence of an adsorbent) are equally applicable to this embodiment of the invention.

The (cumulative) concentration of carbonate/bicarbonate can also be gradually increased during treatment within the range specified in the present description (from 0 to 40 mmol/l).

Automatic and patient-adapted CO2 _removal

The systems and methods provided herein can be adapted to automatically measure certain values for a gas present in a biological fluid, such as blood, such as the pH, pCO _{2 of} the blood, and its bicarbonate concentration, without coming into contact with that biological fluid. environment. Accordingly, the composition of the dialysate fluid can be adapted to the needs in a simple, quick and automatic manner.

The transport of CO ₂ in the blood occurs mainly in the form of H ⁺ + HCO ₃ ^- . To remove CO ₂ or eliminate the problem of lack or imbalance of acid-base balance completely in the liquid phase, it is necessary to remove H ⁺ and HCO ₃ ^- from the biological fluid, such as the patient's blood, by means of the dialysis fluid itself. The pH value of the dialysis fluid must be higher than the pH value of the blood, and the concentration of HCO ₃ in ^the dialysis fluid must be lower than the corresponding concentration in the blood. The presence of OH in the dialysate excludes the presence of protons in the blood. As shown in FIG. 1 and 2, the concentration of bicarbonate in the dialysis system can be controlled by adding different amounts of bicarbonate to the fluid streams, for example at points 21 and 22, or by removing liquid (such as dissolved bicarbonate) or gas (bicarbonate H ⁺ → CO ₂ , so that at bicarbonate can be removed by venting) through filters 30 and 31 using pumps 32 and 33 into drain bags 36 and 37.

With known values for the blood gas of a subject being treated, the systems and methods provided herein allow automatic adjustment of dialysis fluid parameters, such as pH and bicarbonate concentration, in accordance with the goals of treatment and to meet the needs of that subject. Therefore, the systems and methods described herein can provide a relatively continuous display of values for a patient's blood gas. This effectively eliminates the need for a second blood draw to determine the patient's blood gas values.

The composition of the dialysis fluid and preferred values are given in the present description. For dialysis fluid according to the systems and methods presented herein, the following values are actually known at the start of this procedure: pH, pCO ₂ , HCO ₃ ^- , bicarbonate concentration, and buffer capacity. Other values can be easily calculated by those of ordinary skill in the art using the Henderson-Hasselbach equation.

As shown in FIG. 1 and 2, the pH of the fluid from the body of the subject can be measured using various pH meters 11, 12, 13, 14 and 15. The bicarbonate concentration can be measured by back titration of the dialysis fluid. Bicarbonate acts as an important buffer in the dialysate along with albumin. The concentration of albumin and its buffering capacity at different pH values are known values, since the dialysis system presented in the present description is a closed system, and the concentration of albumin is already known at the beginning of the procedures in accordance with the dialysis technique.

As shown in FIG. 1 and 2, fluid removal can be carried out through filters 30 and 31. Albumin cannot pass through either the semi-permeable membrane of these filters or through membrane 6. The flow 4 of dialysate from dialyzer 5 with a known pH (sensors 12, 13) passes to point 16, where it splits into two streams. The prepared acidic solution 21 is mixed with osmotic water 20, resulting in the formation of a fluid 25 with a certain and known concentration of H ⁺ , which at point 27 is mixed with the dialysis fluid. The known flow rate of the fluid 25 is determined in accordance with the desired pH value for the liquid in section 3, measured by the pH sensor 11. The pH value measured by the pH sensor 14 must necessarily be maintained at a relatively constant level (for example, pH 3) in order to ensure proper removal of toxins. The desired pH value is achieved by changing the flow rate using pump 17. Thus, it is possible to adjust the flow to reach a certain pH and add 25 protons at a known concentration in the area by measuring the flow rate using sensor 14 and making adjustments if necessary using the pump 17. The buffer capacity of the dialysis fluid can be calculated since the only unknown buffer in the fluid is bicarbonate. The calculation includes determining the decrease in pH from the values measured by sensors 12 and 13 to the value measured by sensor 14, determining the volume of liquid supplied by pump 17, and determining the concentration of H ⁺ in section 25.

The dialysate stream 4 from the dialyzer 5 with a known pH (sensors 12, 13) passes to point 16 where it splits into two streams. The prepared alkaline solution 22 is mixed with osmotic water 19, resulting in the formation of a fluid 26 with a certain and known concentration of OH, which at point 28 is mixed with the dialysis fluid. The known flow rate of the fluid 26 is determined in accordance with the desired pH value for the liquid in section 3, measured by the pH sensor 11. The pH value measured by the pH sensor 15 must necessarily be maintained at a relatively constant level (for example, pH 11) in order to ensure proper removal of toxins. The desired pH value is achieved by changing the flow rate using the pump 18. Thus, it is possible to adjust the flow to reach a certain pH and add a known concentration of protons in the area 26 by measuring the flow rate using the sensor 15 and making adjustments, if necessary, using the pump 18. The buffer capacity of the dialysis fluid can be calculated because the only unknown buffer in the fluid is bicarbonate. The calculation includes determining the decrease in pH from the values measured by the sensors 12 and 13 to the value measured by the sensor 15, determining the volume of liquid supplied by the pump 18, and determining the concentration of OH in section 26.

The systems and methods provided herein allow a relatively continuous bidirectional titration to be performed to calculate the concentration of bicarbonate in the dialysis fluid. This concentration of bicarbonate is its concentration in fluids 2 and 4 (see FIGS. 1 and 2). Essentially, the entire buffer capacity of the dialysate is a known value. H ⁺ , HCO ₃ ^- and OH can diffuse and participate in the exchange through the semipermeable membrane 6. If streams 1 and 3 move simultaneously and at the same speed or the ratio of both streams and the exchange rate are known, then a complete exchange or adjustment of concentrations can take place . Therefore, the pH value measured by sensor 12 and the calculated bicarbonate concentration will be the same as liquid 2.

Known pH and bicarbonate concentrations for liquid 2 can be used to calculate the pCO _{2 of} this liquid according to the Henderson-Hasselbach equation. This equation for blood is as follows:

It is also possible to duplicate the measurement of pCO ₂ using sensor 12. The bicarbonate concentration can then be easily calculated according to the Henderson-Hasselbach equation.

If the buffering capacity of the dialysate is too high or the flow rates are too different, then the pH values of the fluids 4 and 2 may not match each other. However, the concentrations of bicarbonate in fluids 2 and 4 will then be the same (flow rate from 2 to 4, maximum from 1 to 12). Therefore, the pH value of fluid 2 can be easily calculated from the above equation, where the pCO ₂ value is measured by sensor 12 or sensor 10. Sensor 10 can be integrated into this system or into an external analytical device, the values of which are entered into the dialysis system by the user.

An important task of the dialysis systems and methods presented in the present description is the regulation of the acid-base balance of fluids 1 and 2, such as blood taken from the patient's body. The protons present in liquids 1, 2 can be considered as toxins. It is desirable to obtain a quantitative value for the amount of toxins removed. If there is an exchange between the fluids on both sides of the semi-permeable membrane, then the ΔpH between sensors 11 and 12 can be measured. the fluid entering the dialyzer (pH meter 11) and the fluid leaving the dialyzer (pH meter 12), the amount of protons removed from the blood can be easily calculated. Thus, a continuous measurement of the proton load of the blood and the patient is carried out. Once the proton load has been determined, the pH of the dialysate can be adjusted to remove more or less protons from the blood as desired or needed.

A high (eg pH 9) or low (eg pH 7.4) dialyzer inlet 11 pH obtained in a relatively short time determines the potential to remove more or less protons from the blood. Therefore, if the amount of removed protons or the value of ΔpH between the inlet stream 11 and the outlet stream 12 is small, then the pH of the dialysate must be lowered to prevent an undesirably high pH value of the outward stream 2 of the physiological fluid detected by the sensor 10. If the number of removed protons or the value of ΔpH between the inlet stream 11 and the outflow 12 of the dialyzer is large, the pH of fluid 3 can be raised to remove more protons from the blood. These high and low pH testing procedures can be performed substantially continuously over a very short time, such as 1 minute, 10 minutes, or 30 minutes, to adjust the pH of the dialysate. To adjust the pH or calculate the amount of protons (proton load) to be removed from one side of the membrane 6, the flow rate of the dialysate through both chambers of the dialyzer 5 on each side of the membrane 6 and the buffer capacity of the dialysate must be taken into account.

The systems and methods provided herein also provide the ability to calculate base excess in a patient. Comparison of the base excess with the reference range helps to determine whether the acid-base imbalance is caused by respiratory, metabolic, or mixed metabolic-respiratory pathology. Assessment of acid-base status and blood gases in metabolic and respiratory disorders provides valuable information for diagnosing, for example, circulatory disorders, shock, ventilation disorders, lung perfusion disorders, renal failure, comatose conditions, diabetic complications, intoxication, and adrenal cortical dysfunction. .

As shown in FIG. 1 and 2, the pH of dialysate 3 is adjusted by changing the ratio between the H ⁺ /OH concentrations in fluids 25 and 26. The processing in this procedure is preferably performed in parallel with the measurement and calculation of the pH of the fluids. These calculations, however, can also be done in reverse, which is more common for dialysis. In this case, the pH and bicarbonate concentrations of the fluids at each outlet do not match because the flows are moving in opposite directions. However, it is still possible to calculate the proton load taken from the patient. Due to the risk of obtaining a high pH value for the outgoing stream 2, for example for blood injected back into the patient's body, at least one parameter (pH, pCO ₂ , HCO ₃ bicarbonate concentration) ^is measured by the sensor 10 before the blood is injected back into the patient's body.

In some cases, the fluid 3 may be provided with a channel that bypasses the dialyzer 5. This bypass channel may be connected from time to time. The purpose of this bypass channel is to recheck the readings of both sensors 11 and 12 if they repeat each other. This is possible in the absence of exchange through the membrane 6, the absence of bicarbonate, with the exception of the latter additives contained in fluids 19, 20, 21, 22, 42, 43, or in any other solution added to the dialysate. In this case, the concentration of bicarbonate in the dialysate can be corrected to a certain and known level, for example to zero. Therefore, during processing, there is also the possibility of controlling the buffer capacity of the dialysate, related primarily to albumin and excluding bicarbonate.

Temperature and flow

Sensors 9 and 10 shown in FIG. 1 and 2 may also be flow sensors. These flow sensors provide better processing performance and more precise control of parameters. The exact flow rates of the biological fluid, or fluids 1 and 2, in the extracorporeal circuit are not known. Due to the use, in most cases, of peristaltic or centrifugal pumps, flow rates are not very accurate and depend on pressure. Sensors 9 and 10 may also be temperature sensors. pH values, chemical reactions and the amount of dissolved gases depend on temperature.

Liquid Waste Measurement

The systems and methods presented in the present description are characterized by the presence of a closed recirculation loop. It is a continuous partial replacement of the dialysis fluid. Fresh dialysis fluids are introduced into the dialysis circuit (for example, as shown in Figs. 1 and 2, pos. 19, 20, 21, 22), while at the same time, partial removal of the recirculating dialysis fluid is carried out through, for example, filters 30, 31 The advantage of using such filters is the pore size of the filter membrane 30, 31. A membrane that is impermeable to albumin is preferred. Such waste fluids can be measured by sensors 34 and 35. Therefore, pH and pCO ₂ measurement or titration is essential to determine the bicarbonate concentration because the other major buffer, albumin, is not present in the fluid. It is also advantageous that the measured fluid is not re-introduced into the circuit, so that it can be subjected to some other treatment that is not allowed for fluids re-introduced into contact with blood.

Capnography / Skin measurement

As shown in FIG. 1, using the sensor 46 can measure the level of CO ₂ in the gases exhaled by the patient. Thus, the partial pressure or volume of CO ₂ as a percentage can be measured using capnography, performed on the basis of infrared spectroscopy. Using the sensor 47 it is possible to measure the level of CO ₂ in the body of the patient, for example on the skin. In addition, you can measure pCO 2 , tcpCO ₂ , SpCO ₂ , pO ₂ , tcpO ₂ , _{SpO 2 ,} pulse and temperature. Such a skin sensor, or exhalation sensor, can be used to measure pCO ₂ in a patient. These values can be analyzed by the dialysis system controller 45 . Absent in the exhalation, for example due to pulmonary insufficiency, carbon dioxide can be released in the extracorporeal dialysis circuit. Knowing the buffer capacity of the dialysis fluid, the flow rates of blood and dialysate through the dialyzer, and the magnitude of the difference between the pH value of the dialysis fluid entering the dialyzer and the pH value of the dialysis fluid leaving the dialyzer, it is possible to obtain, by regulation, the pH values necessary to remove the exact amount of acid in the blood.

Examples

The following examples are provided for illustrative purposes. These examples do not limit the scope of the invention.

Example 1: Determination of the Buffer Capacity of Aqueous Solutions Containing Buffer Agents

Tests were carried out to experimentally determine the buffering capacity of various aqueous solutions containing one or more buffering agents. These aqueous solutions were model fluids, the buffer capacity of which corresponded to the dialysis fluids (dialysates) proposed in the present invention, or the dialysis fluids (dialysates) used as reference.

1A: preparation of liquids

The above model fluids were generally prepared as follows. For the preparation of model fluids corresponding to the systems and methods presented in the present description, and reference liquids, pure water (osmotic quality) was used as a basis and one or more buffering agents were added corresponding to the systems and methods presented in this description, namely albumin and /or sodium bicarbonate ("soda") and/or tris(hydroxymethyl)aminomethane (tris, TGAM). In particular, albumin (at the concentration below) and/or bicarbonate (at the concentration below) and/or Tris (at the concentration below) were dissolved in water. Thereafter, or at the same time, the pH was adjusted to obtain the values indicated below. If necessary, albumin addition and pH adjustment can be performed simultaneously. As shown in the table below, in some cases, albumin dissolves faster at or near the required pH values. The pH was checked at any speed and adjusted if necessary after dissolving all buffering agents. The pH adjustment is usually performed by adding a strong acid (HCl aqueous solution) and/or a strong alkali (NaOH aqueous solution).

As reference liquids, solutions were prepared without the addition of buffer agents (albumin, carbonate/bicarbonate, Tris). The pH of these solutions was adjusted as indicated in the table below to 7.45 and 9, respectively. As other reference liquids, two model acetate-containing liquids were prepared, additionally containing sodium bicarbonate in the range indicated in publications reflecting the state of the art . This is shown in more detail in the table below.

In addition, four Tris-containing model liquids were prepared. For this, two Tris solutions were prepared:

- Tris 38 mmol/l: initial pH value after dissolution - 10.45,

- Tris 20 mmol/l: initial pH value after dissolution - 10.14.

HCl (0.1 M or 0.2 M) was added until the pH value indicated in the table below was obtained (7.45 or 9.0, respectively). Tris-containing model liquids were prepared in this way.

Generally speaking, no carbonate (for example, sodium carbonate) was added during the preparation of model liquids. However, it is clear that carbonate and bicarbonate are in dynamic equilibrium as a function of pH. Therefore, a model fluid made by adding a certain amount of bicarbonate (e.g. 20 mmol/L) and adjusting the pH to a certain value (e.g. pH 9) will contain bicarbonate and carbonate at a certain combined concentration (e.g., in this case 20 mmol /l).

The following model liquids were prepared:

In FIG. 3, all of these fluids are labeled "dialysate". The appropriate buffering agents and pH values are also indicated there.

The reference value (corresponding to the international standard) of the buffering capacity of blood plasma ("plasma") was determined. For this purpose, the following study of pig blood was carried out. First, the bicarbonate concentration and pH were determined, whereby the average bicarbonate concentration was 24.2 mmol/L and the pH was 7.45. Secondly, this blood was subjected to centrifugation to obtain a cell-free supernatant. The cell-free supernatant was determined to be plasma. In FIG. 3 it is designated as "blood plasma".

1B: definition of buffer capacity

An experimental study was made of the buffer capacity for H ⁺ ions of all liquids described in section 1A (model liquids according to the table in section 1A; plasmas described in section 1A). To this end, all fluids (reference model fluids, model fluids according to the present invention, and blood plasma) were titrated with HCl. In particular, 0.1 M HCl was added, continuously monitoring the pH, shaking the solutions to ensure mixing, and completing the titration when a final pH of 6.5 was reached. In other words, the titration was stopped when the pH value became equal to 6.5. Buffer capacity (number of H ⁺ ions in mmol/l) was calculated from the amount of HCl added until a pH of 6.5 was reached.

The buffer capacity determined by such assay is shown in FIG. 3. The buffer capacity value obtained for blood plasma was 12.00 mmol/l H ⁺ ions. As shown by this quantitative analysis, the model fluids of the invention preferably have a buffering capacity (in mmol/L) that is greater than that of blood plasma. Thus, the model fluid according to the systems and methods provided herein exhibits excellent buffering capacity, particularly in embodiments where the pH of the model fluid is higher than the pH of normal human blood.

Example 2: comparison of systems and methods presented in the present description, with a reference process

Dialysis fluid was tested according to the systems and methods described herein using the ^HepaWash® LK2001 dialysis device manufactured by ^HepaWash®® (Munich, Germany). A Nikkiso DBB-03 dialysis device offered on the market by Nikkiso (Japan) was used as a reference device.

The ^HepaWash® dialysis device has been described previously, but not in conjunction with the systems and methods described herein, and not in relation to the task of removing carbon dioxide from the blood.

The reference device marketed by Nikkiso is a conventional hemodialysis system. This device is of the countercurrent type and is therefore intended to provide support to the kidneys (hemodialysis) and to remove unwanted urea from the blood. The device is connected directly to the reverse osmosis machine to supply osmotic water. The dialysis fluid is used to perform a one-pass process, that is, after one pass through the dialyzer, the dialysis fluid is discarded.

These devices ( ^HepaWash® and Nikkiso) used two different dialysis fluids. In the case of the Nikkiso hemodialysis system, a dialysis fluid with a pH of 7.45 was used with the following characteristics:

In the case of the ^HepaWash® device, a dialysis fluid with a pH of 9 was used with the following characteristics:

The purpose of this experiment was to compare the two indicated dialysis devices. In particular, it was required to determine which device is capable of effectively removing added carbon dioxide from the blood. To do this, 110 standard cubic centimeters of CO ₂ per minute (110 cm/min CO ₂ ) were continuously added to pig blood. Blood containing CO ₂ was subjected to dialysis under the following conditions:

^HepaWash® :

- blood flow: 400 ml/min

- dialysis fluid flow: 800 ml/min.

Nikkiso:

- blood flow: 350 ml/min

- dialysis fluid flow: 500 ml/min.

The blood was recirculated in both cases.

The result of the experiment is shown in Fig. 4. The graph shows a comparison of blood pH values during treatment with the different devices indicated (Nikkiso and HepaWash ^® ). It can be seen that only the HepaWash ^® system maintains the blood pH between 7.3 and 7.4, but not the Nikkiso hemodialysis system, in which the pH of the blood treated by it quickly drops to 6.65.

As follows from FIG. 4, kidney dialysis (hemodialysis) systems, such as the system offered by Nikkiso, fail to solve the problem of excessive blood acidification. Without being limited by any particular theory, it can be assumed that this system removes from the blood not only H ⁺ ions, but also a buffering agent - bicarbonate. The removal of H ⁺ and bicarbonate is similar to the removal of CO ₂ in the lungs.

The HepaWash ^® system provides the ability to remove excess H ⁺ ions (appearing due to the dissociation of carbon dioxide into bicarbonate and H ⁺ ions). Therefore, this system is able to effectively prevent excessive blood acidification. As mentioned above and known to those skilled in the art, it is necessary to rule out a situation where the blood pH falls below 6.8 (excessive acidification of the blood). The HepaWash ^® system provides the solution to this problem. On the other hand, this example shows that the dialysis device offered by Nikkiso is not suitable for removing CO ₂ from the blood while maintaining its pH value.

Example 3: Calcium Concentrations

The dialysis fluid used contained calcium (Ca ^{2+ ions} ) and its pH was changed between 7.45 and 9 (FIG. 5). The dialysis fluid was in contact with the blood through a semi-permeable membrane. The concentration of calcium in the blood was determined. As shown in FIG. 5, even if the calcium concentration in the dialysis fluid exceeds 1.70 mmol/l, the concentration of calcium ions in the blood remains within the required range of 1.00-1.70 mmol/l. This indicates that the concentration of calcium ions in the dialysis fluid used in the systems and methods presented in the present description is acceptable and in the range of values above 1.70 mmol/l.

Example 4: Materials and Method

As mentioned above, the dialysis system was used, which is a modified dialysis device HepaWash ^® LK2001 manufactured by HepaWash ^® (Munich, Germany). The ^HepaWash® dialysis device has been previously described, but not with regard to both the objectives of the present invention and the removal of lactic acid from the blood.

A dialysis fluid with the following characteristics was used with the ^HepaWash® device:

The purpose of this experiment was to compare the pH of inlet dialysate 11, outlet dialysate 12, inlet blood 9 and outlet blood 10. In particular, the aim was to demonstrate the correlation of different pH values with changes in the amount of added lactic acid and the pH of the dialysate.

For this, five liters of porcine blood were processed in the extracorporeal circuit 39 (see FIGS. 1 and 2). The blood was subjected to dialysis under the following conditions:

- blood flow: 400 ml/min,

- dialysis fluid flow: 800 ml/min.

The blood was subjected to continuous recirculation at a temperature of 37°C.

Five minutes later, 3 mmol lactic acid per minute (that is, 3 mmol lactic acid/min.) was continuously added to the pig blood. This means that 3 mmol of lactic acid was continuously added to the pig blood every minute. After 20 minutes, the pH value of the blood in the tank, measured with a pH meter 9 (see Fig. 1 and 2), was about 7.0. Then the pH value of the dialysis fluid entering the dialyzer was adjusted to 9. The value for the dialysis fluid at the inlet was measured by the sensor 11 (see Fig. 1 and 2).

After 55 minutes, the amount of lactic acid was reduced to 1 mmol. 1 mmol of lactic acid per minute (that is, 1 mmol of lactic acid/min.) was continuously added to pig blood. This means that 1 mmol of lactic acid was continuously added to the pig blood every minute.

As the pH of the dialysis fluid leaving the dialyzer 5, measured by the sensor 12, increased, the pH of the dialysis fluid entering the dialyzer decreased (see FIGS. 1 and 2).

results

The results are shown in FIG. 6, which shows the pH values of blood and dialysate during treatment with a dialysis system, which is a modified HepaWash ^® LK2001 dialysis device manufactured by HepaWash ^® (Munich, Germany). As shown in FIG. 6, the pH of the blood may change as it passes through the dialyzer. There is a direct correlation between the pH values of blood and dialysis fluid. The difference between the pH value of the fluid entering the dialyzer and the pH value of the fluid leaving the dialyzer is also in direct correlation with the corresponding value for the fluid in contact with the former through the membrane 6 (see Fig. 1 and 2).

Knowing the buffer capacity of the dialysis fluid, one can also calculate the number of removed protons. A low concentration of protons in the blood results in a smaller difference between the dialysis fluid inlet and outlet values. Therefore, the dialysis system can adjust the pH of the dialysis fluid entering the dialyzer according to the flow rates of both fluids entering it. If the pH of the dialysis fluid leaving the dialyzer is less than or close to the pH of the dialysis fluid entering the dialyzer, then an algorithm can be applied to lower the pH of the dialysis fluid entering the dialyzer according to the flow rates.

The dialysis system provided herein (such as the ^HepaWash® system) allows excess acid to be removed. Therefore, the dialysis system provided herein (such as the ^HepaWash® system) is able to effectively prevent excessive blood acidification. As mentioned above and known to those skilled in the art, the situation of lowering the pH of the blood to values below 6.8 (excessive acidification of the blood) is fraught with negative consequences and should be avoided. The dialysis system provided herein (such as the ^HepaWash® system) also provides the ability to prevent blood pH from rising to an undesirable level, such as above about 8.2. As is known to those of ordinary skill in the art, exceeding a blood pH of about 8.2 causes irreparable damage to the blood.

Claims (29)

1. A method for removing hydrogen (H ⁺ ) cations from a biological fluid in a dialysis system comprising a dialyzer, comprising (a) exposing the biological fluid through a semi-permeable membrane to a dialysis fluid in the dialyzer, wherein the dialysis fluid comprises (I) a pH value , ranging from 8.0 to 11.0, (II) at least one buffering agent having a pKa value in the range from 7.0 to 11.0, and (III) a buffer capacity for H ⁺ ions of at least measure of 12 mmol/l, wherein the method further comprises (b) automatically determining the amount of hydrogen cations (H ⁺ ) removed from the biological fluid, in which the amount of hydrogen cations (H ⁺ ) removed from the biological fluid is calculated based on the buffer the capacity of the dialysis fluid; and the difference between the pH value of the dialysis fluid entering the dialyzer and the pH value of the dialysis fluid leaving the dialyzer. 2. The method of claim 1, wherein automatically determining the amount of hydrogen cations (H ⁺ ) removed from the biological fluid comprises measuring the pH value of the dialysis fluid prior to exposing the biological fluid through the semi-permeable membrane and the pH value of the dialysis fluid after contacting the latter with a biological fluid through a semi-permeable membrane. 3. The method of claim 1, wherein the dialysis fluid contains at least one buffering agent selected from the group consisting of tris(hydroxymethyl)aminomethane (Tris, TGAM), carbonate/bicarbonate, and albumin. 4. The method of claim 1, further comprising (c) treating the dialysis fluid by exposing the dialysis fluid to one or more of the following: (I) an adsorbent, (II) a membrane, (III) an acidic medium at an appropriate pH, and ( IV) alkaline environment with an appropriate pH level. 5. The method of claim 4 wherein treating the dialysis fluid in step (c) comprises removing carbon dioxide, H ⁺ or HCO ₃ ^- from the dialysis fluid. 6. The method of claim 1 further comprising (d) recirculating the dialysis fluid. 7. A method for extracorporeal processing of blood of a subject - a human or an animal in a dialysis system, including a dialyzer, including: (a) drawing blood from a vein or artery of the subject, (b) exposing the blood through a semi-permeable membrane to a dialysis fluid in a dialyzer, wherein the dialysis fluid comprises (i) a pH value ranging from 8.0 to 11.0, (ii) at least one buffering agent having a pKa value in the range from 7.0 to 11.0 and (III) a buffer capacity for H ⁺ ions of at least 12 mmol/l, (c) removal of hydrogen cations (H ⁺ ) from the blood, (d) returning blood to the subject's body, and (e) automatically determining the amount of hydrogen cations (H ⁺ ) removed from the blood, in which the amount of hydrogen cations (H ⁺ ) removed from the biological fluid is calculated based on the buffer capacity of the dialysis fluid and the difference between the pH value of the dialysis fluid entering into the dialyzer, and the pH value of the dialysis fluid leaving the dialyzer. 8. The method of claim 7 wherein automatically determining the amount of hydrogen cations (H ⁺ ) removed from the blood comprises measuring the pH value of the dialysis fluid prior to exposure of the latter to the blood through the semi-permeable membrane and the pH value of the dialysis fluid after contact with the blood. through a semipermeable membrane. 9. The method of claim 7, wherein the dialysis fluid contains at least one buffering agent selected from the group consisting of tris(hydroxymethyl)aminomethane (tris, TGAM), carbonate/bicarbonate, and albumin. 10. The method of claim 7, further comprising (e) treating the dialysis fluid by exposing the dialysis fluid to one or more of the following: (i) 10 adsorbent, (ii) a membrane, (iii) an acidic medium with an appropriate pH, and (IV) alkaline environment with an appropriate pH level. 11. The method of claim 10 wherein treating the dialysis fluid in step (e) comprises removing carbon dioxide, H ⁺ or HCO ₃ ^- from the dialysis fluid. 12. The method of claim 7, comprising (g) recirculating the dialysis fluid. 13. A method of treating a subject suffering from an acid-base balance disorder, comprising: (a) withdrawing a biological fluid from the subject's body, (b) exposing the biological fluid through the semi-permeable membrane to dialysis fluid in the dialyzer, wherein the dialysis fluid comprises (i) a pH value ranging from 8.0 to 11.0, (ii) at least one buffering agent having a pKa value in the range of 7.0 to 11.0 and (III) a buffer capacity of at least 12 mmol/l for H ⁺ ions, (c) removing hydrogen cations (H ⁺ ) from the biological fluid, (d) returning the biological fluid to the subject's body, and (e) automatically determining the amount of hydrogen cations (H ⁺ ) removed from the blood, in which the amount of hydrogen cations (H ⁺ ) removed from the biological fluid is calculated based on the buffer capacity of the dialysis fluid and the difference between the pH value of the dialysis fluid entering into the dialyzer, and the pH value of the dialysis fluid leaving the dialyzer. 14. The method of claim 13, wherein automatically determining the amount of hydrogen cations (H ⁺ ) removed from the biological fluid comprises measuring the pH value of the dialysis fluid prior to exposing the biological fluid through the semi-permeable membrane and the pH value of the dialysis fluid after contacting the latter with a biological fluid through a semi-permeable membrane. 15. The method of claim 13, wherein the dialysis fluid contains at least one buffering agent selected from the group consisting of tris(hydroxymethyl)aminomethane (tris, TGAM), carbonate/bicarbonate, and albumin. 16. The method of claim 13, further comprising (e) treating the dialysis fluid by exposing the dialysis fluid to one or more of the following: (I) an adsorbent, (II) a membrane, (III) an acidic medium at an appropriate pH, and ( IV) alkaline environment with an appropriate pH level. 17. The method of claim 16 wherein treating the dialysis fluid in step (e) comprises removing carbon dioxide, H ⁺ or HCO ₃ ^- from the dialysis fluid. 18. The method of claim 13, also comprising (g) recycling the dialysis fluid. 19. The method of claim. 1, in which the buffer capacity of the dialysis fluid is determined by continuous titration of the dialysis fluid with an acid or alkali solution.

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