Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
  • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
  • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
  • A61M1/1654—Dialysates therefor
  • A61M1/1676—Dialysates therefor containing proteins, e.g. albumin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/38—Albumins
  • A61K38/385—Serum albumin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
  • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
  • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
  • A61M1/1654—Dialysates therefor
  • A61M1/1656—Apparatus for preparing dialysates
  • A61M1/166—Heating
  • A61M1/1664—Heating with temperature control
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
  • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
  • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
  • A61M1/1694—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes with recirculating dialysing liquid
  • A61M1/1696—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes with recirculating dialysing liquid with dialysate regeneration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
  • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
  • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
  • A61M1/1698—Blood oxygenators with or without heat-exchangers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
  • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
  • A61M1/3621—Extra-corporeal blood circuits
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M2202/00—Special media to be introduced, removed or treated
  • A61M2202/02—Gases
  • A61M2202/0225—Carbon oxides, e.g. Carbon dioxide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M2230/00—Measuring parameters of the user
  • A61M2230/20—Blood composition characteristics
  • A61M2230/202—Blood composition characteristics partial carbon oxide pressure, e.g. partial dioxide pressure (P-CO2)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M2230/00—Measuring parameters of the user
  • A61M2230/20—Blood composition characteristics
  • A61M2230/208—Blood composition characteristics pH-value

Definitions

• the present invention generally relates to a process suitable for extracorporeal lung support.
• a dialysis liquid is used, and carbon dioxide, bicarbonate and hydrogen cations can be efficiently transported from blood across a semipermeable membrane to the dialysis liquid.
• the present invention is suitable for treating or preventing a variety of conditions associated with the presence of undesired substances in the blood and/or with undesired blood pH, such as malfunction of the lungs, kidneys and /or liver.
• CO 2 carbon dioxide
• the vertebrate (human or animal) body carbon dioxide
• carbon dioxide is produced in peripheral tissues as a result of metabolic activity.
• carbon dioxide produced in the tissues diffuses down its partial pressure gradient into the blood, mainly into the erythrocyte.
• protein-bound carbon dioxide reversibly binds to blood proteins, such as hemoglobin and plasma proteins, by associating with amino groups of blood proteins, e.g. hemoglobin, to form carbamino proteins, e.g. carbaminohemoglobin.
• blood proteins such as hemoglobin and plasma proteins
• carbamino proteins e.g. carbaminohemoglobin.
• Carbon dioxide does not typically bind to iron, as oxygen does, but to amino groups of the hemoglobin protein and to amino groups on the polypeptide chains of other blood proteins, particularly plasma proteins.
• Bicarbonate ions (c) originate from carbon dioxide which, following its entry into red blood cel ls (erythrocytes), combi nes with water to form carbonic acid (H2CO 3 ).
• Addition or removal of one or more reactants (be it in vivo or in vitro) causes, by Le Chatelier's principle, a shift of the reaction, in accordance with the equi librium.
• Carbonic anhydrase is not strictly required for this reaction to occur as such; however, it is important for efficient conversion.
• the human or animal body also produces not only carbon dioxide, but also acidic organic molecules.
• the acidic organic molecules are a further source of H + ions.
• the presence of H + ions influences the blood pH.
• fluids such as blood must be maintai ned within the narrow pH range, e.g. i n the human body in the range of pH 7.35 to 7.45, i.e. slightly alkaline. Buffering of the blood is therefore important.
• the buffering capacity of the blood is usually i nsufficient to maintain the blood within that pH range.
• the hydrogen cations which are formed when carbonic acid dissociates into hydrogen cations and bicarbonate ions, can bind to proteins in the blood, particularly in the erythrocyte.
• the major intracel lular hydrogen cation acceptor, or buffer for binding of hydrogen cations is the protein hemoglobin.
• the hydrogen cations primari ly bind to the histidine side chains of hemoglobin.
• Bicarbonate serves a crucial biochemical role in the physiological pH buffering system.
• acidosis refers to an increased acidity in the mammalian body. Acidosis can be determined by measuring the pH of a subject's bodily fluids, particularly blood plasma, more particularly arterial blood plasma. In mammals, particularly humans, acidosis is characterized by a pH of arterial blood plasma of below 7.35. Blood pH values of below 6.8 are usually not tolerated by a human or animal body since a pH outside this range usually results in irreversible cell damage. Thus, acidosis is characterized by a pH of arterial blood plasma of 6.8 to less than 7.35. Hemoglobin, and to a lesser extent plasma proteins, are capable of buffering the pH of the blood, e.g. an excess of hydrogen cations. The buffering of hydrogen cations minimizes the pH change of the blood as the blood traverses the tissue capillaries. However, the buffering capacity is not unlimited, and thus, acidosis can occur.
• subjects suffering from acidosis can be grouped into two major subgroups, based on the molecular causes of acidity in blood plasma: respiratory acidosis and metabolic acidosis.
• respiratory acidosis In practice, patients exhibiting features of both conditions.
• a given subject may suffer from any one of (i) metabolic acidosis, or (ii) respiratory acidosis, or (iii) a combination of metabolic and respiratory acidosis.
• symptoms of acidosis include headache, confusion, tiredness, sleepiness, tremors, and dysfunction of the central nervous system, which may progress to coma if there is no intervention. There is therefore a need for treatment of subjects suffering from acidosis.
• Metabolic acidosis on a molecular level, is caused by an increased amount of acidic organic molecules, caused by increased production of organic acids (e.g. lactic acid) as a result of increased metabolic activity and/or by disturbances in the ability to excrete acid via the kidneys.
• Metabolic acidosis in chronic renal failure (CRF) is the result of a decreased ability to excrete nonvolatile acid and the reduced renal synthesis of bicarbonate, and thus an increase in hydrogen cations in the body.
• organic acids can originate for example from amino acid residues of protein catabolism or from accumulation of ketoacids (ketosis) during starvation or in diabetic acidosis.
• kidney dialysis A particular format of kidney dialysis is termed hemodialysis, and is based on a device that filters wastes, salts and fluid from body fluids. Hemodialysis is the most common way to treat advanced kidney fai lure.
• Respiratory acidosis on a molecular level, results from a bui ld-up of carbon dioxide in the blood due to decreased venti lation (hypoventilation). It is most often caused by malfunction of the lungs. However, head injuries, drugs (especial ly anaesthetics and sedatives), and abnormalities of the central nervous system, such as brain tumors, can be causative for this condition as wel l. It can also occur as a compensatory response to chronic metabolic alkalosis. If respiratory acidosis persists, e.g. in cases of i l lnesses that compromise pulmonary function, such as late-stage emphysema and muscular dystrophy, such compensatory mechanisms, i.e. extraneous bicarbonate i nfusion, cannot efficiently reverse the buildup of carbon dioxide associated with uncompensated respiratory acidosis. In these cases, the use of a lung support may be indicated.
• Mechanical venti lation is a method to mechanical ly assist or replace spontaneous breathing.
• Mechanical venti lation may involve a machine (ventilator), or the breathing may be assisted by a healthcare professional, such as a nurse or a physician.
• mechanical ventilation may involve a device penetrating into the subject's body ("i nvasive mechanical venti lation"), i.e. either penetrati ng through the mouth (such as an endotracheal tube) or penetrati ng through the skin (such as a tracheostomy tube).
• i nvasive mechanical venti lation i.e. either penetrati ng through the mouth (such as an endotracheal tube) or penetrati ng through the skin (such as a tracheostomy tube).
• positive pressure venti lation where a gas (e.g. air) is pushed into the trachea
• negative pressure venti lation e.g.
• extracorporeal membrane oxygenation is one of the most common treatments for extracorporeal lung support, used to assist or lung replace the function of the lungs.
• Blood is removed from the body and introduced into a device having a membrane (porous membrane for short term treatments or a non-porous membrane for long term treatments) separating the blood from a gas phase (oxygen, or gas mixture comprising oxygen, e.g. air or oxygen-seep gas mixture), which allows for oxygenation of the blood.
• extracorporeal blood flow rates during ECMO are similar to the cardiac output of up to about 7 l/min, it is possible to combine ECMO with heart support, by including a pump in the system (ECLS, extracorporeal life support).
• ECLS extracorporeal life support
• oxygen can be introduced directly into extracorporeal blood, e.g. by means of an oxygen (super)saturated liquid, as described in US 6,344,489 B1 (Wayne State University) and US 6,607,698 B1 (Therox/Wayne State University).
• the extracorporeal introduction of a liquid typically increases the volume of the blood; therefore volume reduction prior to re- introduction of the gas-enriched blood into the human or animal body is required.
• a gas-saturated or gas-supersaturated liquid increases the risk of bubble formation.
• bubbles particularly oxygen bubbles
• the presence of bubbles, particularly oxygen bubbles can cause undesired denaturation of blood proteins, and therefore, application of these methods and systems requires utmost care in order to minimize bubble formation.
• blood may be oxygenated directly, i.e. without a gas exchange membrane, e.g. by injecting oxygen into the blood by means of a bubble oxygenator. This method is associated with undesired foam formation and with the risk of gas embolism. This method is not suitable to treat acidosis.
• ECCO2R extracorporeal CO 2 removal
• Such treatment can be indicated e.g. in case of respiratory acidosis.
• ECCO 2 R systems typically rely on the use of a gas exchange membrane, across which carbon dioxide diffuses out of the extracorporeal blood into a gas chamber.
• the AV-ECCO 2 R system (Novalung, Germany) is by far the most widely used ECCO2R technique.
• WO 201 0/091 867 A1 describes an apparatus for treatment of a biological liquid in a three-chamber-system.
• a first chamber is suitable for receiving a biological liquid such as blood, and a second chamber, separated from the first chamber by a gas-permeable but liquid-impermeable membrane, is capable of optionally receiving a gas such as oxygen.
• a lower blood flow rate than for ECMO i.e. about 2 l/min or less
• Such blood flow rates are realized e.g. in the commonly used pECLA (pump-less extracorporeal lung assist).
• the efficiency of both blood oxygenation and blood carbon dioxide removal is dependent to the blood flow rate, and the following holds: the higher the blood flow rate, the better the oxygenation for the subject (e.g. patient), and the lower the blood flow rate, the better the carbon dioxide removal from the blood (ECCO 2 R).
• high-flow refers to > 2400 ml/min
• mid-flow refers to 800-2400 ml/min
• low flow refers to ⁇ 800 ml/min.
• Liquid breathing is an alternative form of lung support in which a normally air-breathing organism breathes an oxygen-rich liquid (such as a perfluorocarbon), rather than breathing air, in methods of TLV (total liquid ventilation) or PLV (partial liquid ventilation), whereby PFC (perfluorocarbon) containing l iquid is flooded into the lungs by a mechanical venti lator for transporting breathing gases such as oxygen and carbon dioxide (Lachmann et al., Intensivmed. und Notfal lmed., vol. 34, pp. 51 3-526 (1 997).
• a standard mode of appl ication for l iquid breathing has not been establ ished yet.
• the object of the present i nvention is to provide a novel method suitable for treating acidosis. It is also desired to provide a versati le method which is suitable for adaptation to treatment of subjects suffering from respi ratory acidosis, metabolic acidosis or any mixed forms of respiratory acidosis and metabol ic acidosis. It is a further object to provide an improved method of metabolite removal, particularly carbon dioxide removal, from a biological liquid such as blood i n general, and from the human or animal body i n particular. It is also an object to provide an improved method for carbon dioxide removal, aimi ng to overcome the disadvantages associated with blood air contact in traditional ECCO 2 .
• the present invention al lows to correct or treat or prevent acidosis, to reduce the work of breathing, and to al low the patient time to recover from acute decompensation. Further advantages of the present invention are associated with elements of the i nvention which are described i n the detai led description below.
• Acidosis refers to an increased acidity (i.e. an increased hydrogen cation concentration) in the blood and other body tissue. If not further specified, it typically refers to increased acidity of the blood plasma. Increased acidity typically means that the pH of arterial blood plasma is lower than 7.35, typically 6.8 to less than 7.35.
• Bicarbonate equilibrium refers to the equilibrium of carbonic acid and bicarbonate/ hydrogen cation:
• the term buffering agent can be used for solid or dissolved compounds alike. Buffering agents are typically soluble in solution, preferably aqueous solution. The function of a buffering agent is to prevent an undesired change in pH when an acidic or basic compound is added to said solution. Salts of the weak acid or base which is suitable to maintain the acidity (pH) of a solution near a certain value can also be referred to as buffering agents.
• Carboanhydrase refers to an enzyme which catalyzes the reversible conversion of dissolved carbon dioxide to carbonic acid: CO2 + H 2 0 ⁇ H2CO3 (i.e. carbonic acid)
• Carboanhydrase is naturally present in red blood cells (erythrocytes) and at other sites of the human or animal body.
• Dialysis liquid and dialysis liquid are used interchangeably herein.
• Erythrocytes or red blood cells or RBCs refer synonymously to blood cells of the vertebrate organism characterized by presence of hemoglobin in the cytoplasm. RBCs take up oxygen in the lungs and release it into peripheral tissues, and take up undesired substances such as hydrogen cations and carbon dioxide in peripheral tissues and release them in the lungs. The release/uptake in peripheral tissues mainly occurs while erythrocytes pass through the capillaries of these tissues.
• Extracorporeal refers to any process, activity, substance or device which is present or performed outside the body of a human or animal. If a process, activity, substance or device which is present or performed partially outside the body of a human or animal, the term refers to the part outside the body.
• Fluid generally refers to a non-solid state of matter.
• a fluid is either a liquid or a gas.
• Hemoglobin is a protein typically present in red blood cells of the vertebrate organism.
• the peptide chains of hemoglobin contain numerous amino and carboxyl groups.
• the hemoglobin molecule is comprised of four globular protein subunits. Each subunit is composed of a protein chain (globin) which is associated with a non-protein heme group.
• Hemoglobin is capable of reversibly binding small molecules such as metabolites, most notably oxygen (O2), hydrogen cations (H + ) and carbon dioxide (C0 2 ) or solvates of any of these.
• oxygen can reversibly bind to the heme group.
• carbaminohemoglobin having one or more carbamino groups is termed carbaminohemoglobin.
• carbaminohemoglobin is the major contributor to the Haldane effect.
• carbaminohemoglobin is thought to account for about 1 0 % of carbon dioxide transport in mammals.
• carboxyl groups of hemoglobin are capable of binding, and hence buffering, hydrogen cations (such hydrogen cations are formed typically as a result of CO2 dissociation and the bicarbonate equilibrium).
• hemoglobin Over the normal physiological pH range, much of the binding of hydrogen cations by hemoglobin occurs at 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.
• Hydrogen carbonate or bicarbonate are used interchangeably to refer to an anion with the chemical formula HCCV. Hydrogen carbonate is an intermediate form in the deprotonation of carbonic acid. It is a polyatomic anion. Unless the context dictates otherwise, the term is used herein to the hydrogen anion (HCO 3 " ), and to any salt of bicarbonate, such as e.g. sodium bicarbonate.
• Hydrogen cation or hydrogen ion or H + are used interchangeably herein to refer to a cationic form of atomic hydrogen. All these terms include collectively cations of all isotopes of hydrogen, particularly proton, deuteron, and triton.
• hydrogen cations typically form solvates by addition of one or more water molecules. Such solvates are called hydroxonium ions and can be described by the general formula H + (H 2 0) n ; n being an integer such as 0, 1 , 2, 3, 4, or more than 4; most typically 1 or 4.
• the term hydrogen cation can also be used herein to refer to a hydrogen cation in solution or to solvated states a hydrogen cation.
• Metabolite as used herein, refers to any intermediate or product of the human or animal metabolism. Particular metabolites of importance in the present invention are carbon dioxide, hydrogen carbonate and hydrogen cation.
• Oxygen refers herein to molecular dioxygen (O2) unless the context dictates otherwise. Oxygen is essential for cellular respiration in all aerobic organisms, including mammals. Oxygenated/deoxygenated hemoglobin refer to the oxygenation state of hemoglobin. Since hemoglobin is typically comprised of four hemoglobin protein subunits, each of which can be oxygenated/deoxygenated reversibly, five states of oxygenation are possible: the fully deoxygenated form (all four subunits deoxygenated) is always referred to as "deoxygenated"; the fully oxygenated form (all four subunits oxygenated) is always referred to as "oxygenated”.
• oxygenated and deoxygenated are also used as relative terms herein: for example, relative to a form of hemoglobin having one subunit oxygenated, the forms having two or three or four subunits oxygenated can all be referred to as “oxygenated” hemoglobin. Conversely, the same form having one subunit oxygenated can be referred to as “oxygenated” hemoglobin relative to a form having no subunit oxygenated (i.e. all subunits deoxygenated).
• Deoxygenated hemoglobin is also referred to as deoxyhemoglobin.
• Oxygenated hemoglobin is also referred to as oxyhemoglobin.
• hemoglobin is used simultaneously for oxyhemoglobin and deoxyhemoglobin, unless the context dictates otherwise.
• oxyhemoglobin/deoxyhemoglobin do not particularly require a specific quantity of hydrogen cations being bound to the oxyhemoglobin/deoxyhemoglobin protein.
• p_CO_2 refers to the partial pressure of carbon dioxide (CO2) in a fluid, e.g. in blood plasma or dialysis liquid.
• Peripheral tissue refers herein to any non-lung tissue (non-gill tissue) of a vertebrate, particularly to non-lung tissue of a mammal.
• Plasma refers herein to blood plasma, i.e. the extracellular intravascular liquid fraction of the blood.
• pH or pH value refers to the negative of the logarithm to base 1 0 of the activity of the hydrogen ion.
• Solutions with a pH less than 7 are acidic and solutions with a pH greater than 7 are alkaline or basic.
• Sodium bicarbonate or sodium hydrogen carbonate refer interchangeably to the (water-soluble) chemical compound with the formula NaHCC>3 (also known as baking soda or soda or bicarbonate of soda) in any form, e.g. crystalline (e.g. anhydrous or any hydrate), or dissolved in solution, e.g. aqueous solution.
• Sodium carbonate refers to the (water-soluble) disodium salt of carbonic acid (Na 2 C03, also known as washing soda or soda ash) in any form, e.g. crystalline (e.g. anhydrous or any hydrate such as heptahydrate or decahydrate), or dissolved in solution, e.g. aqueous solution.
• Solvate refers to a solute being surrounded or complexed by solvent molecules. Solvation is an interaction of a solute (e.g. an ion such as hydrogen cation (H + ), hydrogen carbonate (HCO3 " )) with the solvent (e.g. water). In the solvated state, the solvate is typically stabilized (as opposed to a non-solvated state). Unless the context dictates otherwise, solvate preferably refers herein to a solute being solvated in water.
• Subject or patient refers to an individual human or animal, preferably human.
• a subject can be healthy or suffering from at least one medical condition, disease or illness.
• a patient is a subject suffering from at least one medical condition, disease or illness.
• the term patient can designate an individual suffering from any one or more of the specific conditions disclosed herein.
• Figure 1 Results of buffering capacity of solutions comprising bicarbonate and/or albumin (for details, Example 1 )
• the i nventors invented a method or process which addresses the objects of this i nvention and the shortcomings of prior art methods or processes.
• the i nventors found that advantages over conventional methods or processes for extracorporeal carbon dioxide removal, which rely on gas as a dialysis liquid, can be achieved by using a liquid dialysis l iquid (dialysis l iquid) in a method for extracorporeal carbon dioxide removal.
• This method al lows to effectively remove carbon dioxide from the blood and/or to adjust the blood pH to a desired or normal value and/or to adjust (increase or decrease) the bicarbonate concentration in the blood.
• the method enables a versati le organ support based on the needs of individual subjects: for example, it provides lung support and/or kidney support, dependent on the function of the kidney, and to stabi lize the blood pH in the case of subjects suffering from respiratory acidosis, e.g. by increasing the body's production of bicarbonate.
• a desired or normal value of blood pH lies in the range of pH 7.35 to 7.45, preferably 7.36 to 7.44, more preferably 7.37 to 7.43, more preferably 7.38 to 7.42, more preferably 7.39 to 7.41 , and most preferably about 7.40. More general ly, the blood pH range of pH 6.8 to pH 8.0 may be acceptable.
• a suitable dialysis liquid is characterized as follows:
• (i i) comprising at least one buffering agent, wherein the buffering agent is characterized by at least one pKa value in the range from 7.0 to 1 1 .0; and (i i i) having a buffering capacity for H + ions which is 1 2 mmol/l H + ions or more.
• Suitable buffering agents to be comprised in the dialysis l iquid include in particular any one or more of the fol lowi ng: Tris(hydroxymethyl)aminomethane (Tris, THAM); carbonate/bicarbonate; water-soluble proteins, preferably albumin.
• the present invention thus provides (i) a process for removal of at least one undesired substance from blood, comprising the step of exposing blood to a dialysis liquid, whereby blood and dialysis l iquid are separated by a semipermeable membrane, wherein the dialysis liquid has the properties or preferred properties defined herein; and (b) a process for removal of at least one undesired substance from blood, comprisi ng the steps: (i) i ntroducing blood into a first chamber of a device, said device comprising a first chamber and a second chamber, wherein the first chamber and the second chamber are separated by a semipermeable membrane, (i i) introducing a dialysis liquid into a second chamber of said device, wherein the dialysis liquid being introduced into the second chamber is characterized by the properties as defined herein.
• the present invention thus provides an improved method suitable for extracorporeal carbon dioxide removal and/or for adjusting the pH and/or for adjusting the buffering capacity of the blood.
• Particular, preferred and advantageous embodiments of the present invention are provided in this description and in the enclosed claims.
• first chamber is generally used to refer to a chamber configured or suitable to receive blood
• second chamber is generally used to refer to a chamber configured or suitable to receive a dialysis liquid; typically, the first and second chamber are separated from each other by a semipermeable membrane as defined herein.
• no direct connection exists for the first chamber and the second chamber.
• only those substances which are capable of traversing the semipermeable membrane can migrate from the first chamber into the second chamber and/or from the second chamber into the first chamber.
• Blood and the dialysis liquid are aqueous fluids.
• aqueous is generally used herein to refer to water or water-containing fluids, particularly but without limitation to the liquid state thereof.
• the term aqueous is used herein to refer to fluids, particularly liquids or liquid phases, comprising water.
• aqueous liquids comprise more than 50 % (vol./vol.) water, and are hydrophilic.
• Blood and the dialysis liquid are such aqueous fluids.
• ECO2R extracorporeal carbon dioxide removal methods of the prior art
• kidney support dialysis therapies are, however, generally unsuitable for aiding or substituting liver functions, i.e. for removing certain substances (particularly toxins), such as protein-bound substances (particularly toxins) from the blood.
• WO 03/094998 A1 (HepaWash) describes an apparatus and a method for the removal of protein-bound substances (particularly toxins) from blood, which relies on an absorber liquid which is suitable as dialysis liquid for liver dialysis, wherein the dialysis liquid comprises albumin, and may optionally comprise caffeine. This allows for binding of protein-bound toxins to the carrier albumin.
• albumin has the capacity to buffer aqueous liquids, and it is thought that certain amino acid residues of albumin (e.g. imidazole group of histidine, thiol group of cysteine) are important (Caironi et al., Blood Transfus., 2009; 7(4): 259-267), and at more elevated pH values, the amino groups of lysine side chains and of the N-termini may contribute to buffering.
• the buffering capacity of albumin has traditionally been exploited in blood (where it occurs naturally in the human or animal body), and the suitability of albumin-containing liquids for extracorporeal lung support, or extracorporeal carbon dioxide removal in particular, has not been recognized or exploited in the art.
• Bicarbonate is e.g. known to provide physiological pH buffering system. Bicarbonate containing dialysis liquids, without albumin, have been previously described in the art. Typical bicarbonate concentrations in such previous dialysis liquids range from 32 to 40 mmol/l.
• the present invention is advantageous compared to such previous uses, inter alia because the buffering capacity of buffering agents with a pKa in the above-specified range, such as albumin, carbonate/bicarbonate, or Tris, respectively, may be employed.
• other inorganic or organic buffering agents are present.
• such buffering agents have at least one pKa value in the range from 7.0 to 9.0.
• buffering agents may be employed, each having a pKa value in the range of 7.0 to 9.0.
• Suitable additional organic buffering agents include proteins, particularly water-soluble proteins, or amino acids, or Tris; and suitable additional inorganic buffering molecules include HP04 2 7H 2 P0 4 " .
• a further advantage of the present process is its versatility: Depending on the blood flow rates (up to 600 ml/min, or in case of two parallel devices up to 1200 ml/min), dialysis liquid flow rates (up to 2000 ml/min) and the exact dialysis liquid composition it is possible to remove from 0 to 1 0 mmol/min of carbon dioxide from the blood. Blood
• blood In the vertebrate (human or animal) body, blood is composed of blood cells and blood plasma (also referred to as "plasma"), so that the blood cells are suspended in the plasma.
• plasma blood plasma
• the major component of plasma is water, and the major type of blood cells are erythrocytes.
• the methods of the present invention are suitable for being applied to all types of blood from humans or animals, preferably vertebrates, preferably mammals, and most preferably humans, and are suitable for the purposes herein as long as at least one undesired substance, as defined herein, is contained therein.
• blood can refer to a mixture of blood, as taken from the human or animal body, and an acceptable additive in an acceptable amount.
• An additive is acceptable if the function of the blood is not significantly negatively affected.
• the amount of the additive is acceptable, if addition of the additive does not result in a significant volume increase of the blood, as taken from the human or animal body, so that the volume of the blood increases by not more than 50 %, preferably not more than 40 %, not more than 30 %, not more than 20 %, not more than 1 0 %, not more than 5 %.
• the process of the present invention comprises exclusively to in vitro activities.
• the process is exploited to address medical needs of a living subject, as described in detail below; in these alternative embodiments, the contacting of blood via a semipermeable membrane with a dialysis liquid also occurs in vitro, (i.e. outside the body of a human or animal), or extracorporeal. Additionally, interaction with the human or animal body occurs, as described below.
• a suitable blood flow rate is up to 600 ml/min, or in case of two parallel devices up to 1200 ml/min, but usually much lower.
• the at least one undesired substance to be removed is a substance resulting from metabolic activity.
• the at least one undesired substance is selected from the group consisting of carbon dioxide (CO 2 ), hydrogen cation (H + ), hydrogen carbonate (HCCV), carbonic acid (H2CO 3 ), and solvates of any one thereof, and any combinations of these.
• CO 2 carbon dioxide
• H + hydrogen cation
• HCCV hydrogen carbonate
• H2CO 3 carbonic acid
• H2CO3 ⁇ CO2 + H 2 0 is typically catalyzed or aided by the enzyme carboanhydrase which is present in erythrocytes.
• carboanhydrase which is present in erythrocytes.
• the removal of one reactant causes, by Le Chatelier's principle, a shift of the reaction.
• ECCO 2 R systems of the prior art rely on the use of a gas exchange membrane, across which one reactant, carbon dioxide, diffuses from the extracorporeal blood into a gas chamber.
• the present invention enables the removal of at least one undesired substance from one liquid (blood) directly into another liquid (dialysis liquid).
• the present invention is not limited to the removal of gaseous undesired substances (such as CO 2 ), and does not require the transfer of undesired substances into the gas phase. It is thus contemplated that carbon dioxide is not transferred into the gas phase in the process of the present invention.
• gaseous undesired substances such as CO 2
• one of the forms in which CO 2 is transported in the blood is in the form of carbamino groups, wherein carbon dioxide is attached to the terminal amine groups of proteins in the blood, primarily hemoglobin (then termed carbaminohemoglobin).
• carbaminohemoglobin a protein that influences the formation of carbamino groups.
• carbaminohemoglobin a protein that influences the formation of carbamino groups.
• carbon dioxide in the carbamino form is also rapidly released from the amino group of blood proteins such as hemoglobin when the carbon dioxide concentration decreases in its surrounding as a result of diffusion into the dialysis liquid, so that, in accordance with Le Chatelier's principle, a new equilibrium is established.
• carbaminohemoglobin and dissolved carbon dioxide are also in equilibrium with the bicarbonate (HCO 3 )/ H + -ion pair, but rapid conversion via H 2 CO 3 requires the enzyme carbonic anhydrase. Carbonic anhydrase is naturally present in erythrocytes.
• all three major forms of carbonate present in blood can be removed, directly or indirectly, across the semipermeable membrane. While free CO 2 and bicarbonate ions can cross the semipermeable membrane along the concentration gradient into the dialysis liquid, hemoglobin-bound C0 2 becomes preferentially released from hemoglobin when e.g.
• the concentration of free CO 2 decreases as a result of diffusion into the dialysis liquid, so that, in accordance with Le Chatelier's principle, a new equilibrium is established for the three major forms of carbonate present in blood (transportation forms).
• the different molecular entities for carbon dioxide transport do not have to be transferred to the gas phase to be removed.
• blood-gas contact is not required, and preferably not foreseen.
• the present invention enables removing all major transportation forms of carbon dioxide from the blood completely in a liquid medium.
• bicarbonate (HCCV) concentration of the dialysis liquid and of the blood bicarbonate can be removed from the blood along the concentration gradient for the dialysis liquid on the one side and blood on the other side of the semipermeable membrane.
• these undesired substances can be removed directly by transfer into the dialysis liquid along the concentration gradient (direct removal).
• the undesired substances can be removed i ndirectly by reaction with substances transferred from the dialysis liquid into the blood, which also results in a net removal of the undesired substance from the blood (indirect removal): for example, hydrogen cations can be i ndirectly removed from the blood by transferring OH " ions from the dialysis liquid i nto the blood, which is achieved because the pH of the dialysis liquid used in the present invention is typical ly more alkali ne than the pH of the blood to be treated.
• the present i nvention enables the removal of substances which are soluble i n liquids. These substances i nclude ions of any type, as long as they are soluble i n water, and hydrogen cations and bicarbonate anions i n particular.
• the present invention therefore al lows for more complete, and thus more efficient, removal of metabolites from the blood than the ECCO2R methods of the state of the art.
• the mechanism of carbon dioxide removal according to the present i nvention allows that the dissolved gas diffuses from one l iquid phase to another liquid phase.
• a dialysis unit comprising two chambers, as described in detail below, can suitably be used in the process of the present invention.
• the fi rst chamber is suitable for receivi ng the blood.
• the first chamber suitably has an inlet (for enteri ng blood) and an outlet (for exiting blood). It is desired that the blood, when a dialysis unit used in the process of the present invention, exits the first chamber (outlet) when its pH l ies in the range of pH 7.35 to 7.45, preferably 7.36 to 7.44, more preferably 7.37 to 7.43, more preferably 7.38 to 7.42, more preferably 7.39 to 7.41 , and most preferably about 7.40.
• the blood is returned into the human or animal body after exiting the first chamber (outlet).
• Suitable tubing and connections are known in the art and can be employed in the context of the present invention.
• one or at least one bubble trap can be placed behi nd the first chamber. This is particularly suitable if blood is also exposed to a gas or to a gas-saturated or gas-supersaturated l iquid, during at least part of the process.
• the dialysis liquid of the present invention is an aqueous liquid, i.e. a liquid comprising water.
• the dialysis liquid suitable for the present invention is characterized as follows:
• buffering agent a buffering agent that influences buffering capacity
• pH a buffering capacity
• specific conditions may be appropriately selected, as described below.
• a buffering capacity for H + ions which is 12 mmol/l H + ions or more, is typically a buffering capacity, which exceeds the buffering of blood plasma (pH 7.45; see Example 1 ).
• the buffering capacity of the dialysis liquid typically exceeds the buffering of blood plasma (pH 7.45).
• the buffering capacity of the dialysis liquid is typically a buffering capacity for 12 mmol/l or more H + ions.
• the dialysis liquid comprises at least one buffering agent(s), typically at least two buffering agents.
• a buffered dialysis liquid in general, or more preferably, the dialysis liquid, as specifically defined by the present invention allows to perform the carbon dioxide removal in a pH range, which is not detrimental to blood. That holds, as the actual capacity of the dialysis liquid for ions is much higher than it would be if the buffering agent(s) were not contained.
• Said at least one buffering agent(s) provides, or contributes to, the buffer capacity of the dialysis liquid.
• the present inventors found that the use of a dialysis liquid (as opposed to a sweep gas as in conventional CO 2 removal systems) is suitable for maintaining the pH of the dialysis liquid within an acceptable pH range. Buffering capacity for H + ions
• buffering capacity for H + ions or “buffering capacity” is an abstract value expressing the capacity of a given liquid to buffer the addition of H + ions.
• the term “buffering capacity for H + ions” is an inherent property of a respective liquid (aqueous solution).
• Blood plasma is e.g. such a liquid.
• the determination of buffering capacity of blood plasma requires a step of centrifugation; the centrifugation results in pelleting of blood cells including platelets, and the supernatant is termed plasma. Such centrifugation is described in example 1 . Suitable conditions for centrifugation of blood, and thus for the preparation of blood plasma are known in the art.
• the term “buffering capacity for H + ions” refers to the capacity to buffer a certain amount of H + ions, without reaching a pH lower than 6.5. "Without reaching a pH lower than 6.5” means that the pH of a properly mixed liquid does not reach a value of lower than pH 6.5. Thus, adequate mixing is important in practical assessment of the buffering capacity.
• the term “buffering capacity for H + ions” can be used solely for liquids having a pH of 6.5 or more. As defined herein, a solution having a pH of 6.5 would have a buffering capacity for H + ions of zero mmol/l (0 mmol/l).
• the dialysis liquids of the present invention all have a pH much higher than 6.5, i.e. as defined herein; and therefore, they do have a buffering capacity for H + ions. If the buffering capacity is 12 mmol/l H + ions or more, the respective liquid (dialysis liquid) has a buffering capacity for H + ions according to the invention. More preferred are buffering capacities higher than that, i.e.
• H + ions 12 mmol/l or more, 14 mmol/l or more, 1 6 mmol/l or more, 1 8 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.
• the dialysis liquid according to the present invention typically has a buffering capacity for H + ions of 12 or more mmol/l, such as more than 12 mmol/l.
• Preferred buffering capacities lie in the range from 1 2 to 50 mmol/l, more than 1 2 to 40 mmol/, 1 3 to 30 mmol/l, 14 to 25 mmol/l, 1 5 to 24 mmol/l, 1 6 to 23 mmol/l, 1 7 to 22 mmol/l, 1 8 to 21 mmol/l, 19 to 20 mmol/l.
• the buffering capacity is not solely dependent on the pH of the respective liquid, but influenced by the composition of the liquid (presence and concentration of buffering compounds in the said liquid).
• Buffering capacity for H + ions is indicated as a number value, with the unit "mmol/l".
• the buffering capacity for H + ions (buffering capacity in mmol/l) is determined by the following four-step assay:
• the assay is suitable for determining the buffering capacity for H + ions of a given liquid (dialysis liquid or candidate dialysis liquid) that has a pH in the pH range of the dialysis liquids of the present invention, i.e. pH 8.0 to pH 1 1 .0, or subrange thereof.
• a first step it is tested whether the given liquid has a pH within that range. If that is not the case, the given liquid is not a dialysis liquid according to the present invention (no further testing necessary). If that is, however, the case, then the buffering capacity of the given liquid is determined by means of the following steps 2 and 3 : 2.
• the liquid is subjected to titration with HCI.
• 0.1 M HCI is added, the solutions are agitated to ensure mixing, the pH is continuously monitored, and titration is terminated exactly when the pH of the liquid subject to titration reaches a final value of pH 6.5. In other words, titration is stopped when the pH reaches a value of 6.5.
• the buffering capacity H + -ion in mmol/l
• HCI is a strong acid which, according to the common general knowledge, dissolves completely in aqueous solution.
• 0.1 HCI (0.1 mol/l) contains 0.1 mol/l dissolved CI " ions and 0.1 mol/l dissolved H + ions. Based on the volume of HCI required for a given liquid to reach a pH of 6.5 upon titration, the amount of H + ions can be calculated that is buffered by said volume of dialysis liquid.
• the amount of the given liquid used in the assay is 1 liter, the amount of H + ions that is buffered by 1 I dialysis liquid (buffering capacity in mmol/l) is directly obtained. If the amount of the given liquid used in the assay is a defined amount which is more than 1 liter or less than 1 liter, the amount of H + ions that can be buffered by 1 I dialysis liquid (buffering capacity in mmol/l)) is obtainable by simple mathematical calculation.
• the buffering capacity as determined in step 2 (mmol/l) is compared to a reference value.
• Suitable reference values are 10 mmol/l; 1 1 mmol/l, 12 mmol/l, 1 3 mmol/l, 14, mmol/l; whereby 12mmmol/l is strongly preferred.
• the reference value is represented by the buffering capacity of human or animal (pork, mouse) blood; in that case, the buffering capacity of blood plasma is determined as described in above step 2.
• the given solution is determined to have a buffering capacity according to the present invention.
• blood plasma buffering capacities lie in the range of 3 to 30 mmol/l, preferably 4 to 25 mmol/l, preferably 5 to 20 mmol/l, preferably 6 to 1 9 mmol/l, preferably 7 to 1 8 mmol/l, preferably 8 to 1 7 mmol/l, preferably 9 to 1 6 mmol/l, preferably 1 0 to 1 5 mmol/l, preferably 1 1 to 14 mmol/l, preferably 12 to 13 mmol/l.
• the dialysis liquid according to the present invention typically has a buffering capacity which exceeds the buffering capacity of blood plasma.
• the buffering capacity for H + ions is preferably selected such that it exceeds the buffering capacity of blood of that individual, e.g. that patient. pH of the dialysis liquid
• Preferred pH ranges of the dialysis liquid include pH 8.0 to pH 1 0.5, pH 8.0 to pH 10.0, pH 8.0 to pH 9.5, and preferably pH 8.0 to pH 9.0.
• the at least one pKa value of the at least one buffering agent present in the dialysis liquid is in the range from pH 7.0 to pH 1 1 .0; pH 8.0 to 1 0.5, 8.0 to 10.0, 8.0 to 9.5, and preferably 8.0 to 9.0. If more than one buffering agent is present, it is preferably that each of them has a pKa value in the above range or subrange.
• the at least one buffering agent has more than one pKa value, at least one said pKa value, preferably more than one said pKa values, lie(s) is in the above range or subrange.
• Any buffering agent having at least one pKa value in the range from 7.0 to 1 1 .0 is theoretically suitable for buffering in the desired pH range.
• the buffering agent must be selected such that it is not toxic or does not cause undesired side effects in the human or animal being that is subject to dialysis.
• Particularly suitable buffering agents are the carbonate/bicarbonate system, Tris, and water-soluble proteins (preferably albumin), all as defined herein above.
• pH 7.75 to pH 9.0 Another suitable pH value of the dialysis liquid is the range from pH 7.75 to pH 9.0.
• preferred pH values lie in the range from pH 7.75 to pH 9.0, preferably from pH 8.0 to pH 9.0, preferably from pH 8.1 to pH 8.9, preferably from pH 8.2 to pH 8.8, preferably from pH 8.3 to pH 8.7, more preferably from pH 8.4 to pH 8.6, and most preferably at or around pH 8.5. It is important to note that these are general preferred ranges and subranges. For specific purposes, such as for treating blood from a specific patient subgroup, alternative, different or partially diverging ranges may be preferable, as described below.
• the pH can be adjusted by the amount or concentration of buffering substances, such as bicarbonate and hemoglobin, within the ranges contemplated herein, and/or adjusted by addition of an acid or base, such as hydrochloric acid or sodium hydroxide.
• the pH of the dialysis liquid does not necessarily remain constant throughout the process step of contacting blood with the dialysis liquid. Therefore, in a precise sense, the pH of the dialysis liquid, as defined in this specification, is preferably defined for the dialysis liquid at the stage immediately preceding the contacting of blood, e.g. at the stage wherein the dialysis liquid enters the second chamber of a dialysis unit as described herein.
• Buffering agent comprised in the dialysis liquid
• Suitable buffering agents to be comprised in the dialysis liquid include in particular any one or more of the following: Tris(hydroxymethyl)aminomethane (Tris, THAM); carbonate/bicarbonate; water-soluble proteins, preferably albumin.
• Bicarbonate is characterized by an acidity (pKa) of 10.3 (conjugate base carbonate).
• pKa acidity
• carbonate may be present as well, depending on the pH of the solution.
• carbonate/bicarbonate is used herein to refer to both bicarbonate and its corresponding base carbonate.
• carbonate/bicarbonate concentration or “(combined) carbonate/bicarbonate concentration”, or the like, refers herein to the total concentration of carbonate and bicarbonate.
• “20 mM carbonate/bicarbonate” refers to a composition having a 20 mM total concentration of bicarbonate and its corresponding base carbonate. The ratio of bicarbonate to carbonate will typically be dictated by the pH of the composition.
• the (combined) carbonate/bicarbonate concentration of the dialysis liquid is preferably defined for the dialysis liquid at the stage immediately preceding the contacting of blood, e.g. at the stage wherein the dialysis liquid enters the second chamber of a dialysis unit as described herein.
• Tris(hydroxymethyl)aminomethane usually called “Tris”.
• Tris(hydroxymethyl)aminomethane is also known as "THAM". Tris is an organic compound with the formula (HOCH 2 )3CNH 2 . The acidity (pKa) of Tris is 8.07. Tris is nontoxic and has previously been used to treat acidosis in vivo (e.g. Kallet et al., Am. J. of Resp. and Crit. Care Med. 161 : 1 149-1 153; Hoste et al., J. Nephrol. 18: 303-7.). In an aqueous solution comprising Tris, the corresponding base may be present as well, depending on the pH of the solution.
• Tris is used herein to refer to both Tris(hydroxymethyl)aminomethane and its corresponding base, unless the context dictates otherwise.
• 20 mM Tris refers to a composition having a 20 mM total concentration of Tris and its corresponding base.
• the ratio of Tris(hydroxymethyl)aminomethane to its corresponding base will be dictated by the pH of the composition.
• Tris and its conjugate base, as well as other smal l molecules, including ions or substances which can influence the pH of an aqueous liquid, can traverse the semipermeable membrane during the process of the present invention.
• the Tris concentration of the dialysis liquid is preferably defined for the dialysis liquid at the stage immediately preceding the contacting of blood, e.g. at the stage wherein the dialysis liquid enters the second chamber of a dialysis unit as described herein.
• a water-soluble protein is suitable for the purposes of the present invention if it has at least one imidazole (histidi ne side) chain and/or at least one amino group (lysine) side chai n or at least one sulfhydryl (cysteine) side chain. These side chains typically have pKa values in the range from 7.0 to 1 1 .0.
• a protein falls under the definition water-soluble if at least 1 0 g/l of the protein is soluble in aqueous solution having a pH within the range of the dialysis l iquid of the present invention, e.g. pH 8.0.
• a strongly preferred water- soluble protein in the context of the present invention is albumin, as defined in the fol lowing.
• Albumin is a preferred water-soluble protein in the context of the present invention.
• albumi n has good buffering capacity i n the desired pH range, typical ly, owing to several amino acid side chains with respective pKa values.
• albumin is preferably serum albumin of a human or animal, such as human serum albumin, animal albumin (e.g. bovine serum albumin), or alternatively genetically engineered albumin, or mixtures of any one or more of these. Mixtures containing albumin and at least one further carrier substance are also possible.
• the albumin concentration specified herein refers to the total concentration of albumin, no matter if one si ngle type of albumin (e.g.
• the dialysis liquid used in the present invention comprises 1 0 to 60 g/l albumin, preferably 1 5 to 30 g/l albumin, preferably 20 to 25 g/l albumin, and most preferably 30 or about 30 g/l albumin.
• the concentration of albumin can also be indicated as % value; i.e. 20 g/l albumin corresponds to 2 % albumin (wt./vol).
• Albumi n is a second buffering agent i n the dialysis l iquid according to the present i nvention.
• the albumin in the dialysis liquid contributes to its buffering capacity, and bi nds carbonate i n the form of carbamino groups.
• the pH range i n which albumin can suitably buffer liquids, such as blood, is wel l known i n the art, e.g. from biochemistry textbooks.
• the presence of albumin i n the dialysis liquid faci l itates the removal of protein- bound substances from blood.
• albumin can also be more generally referred to as an adsorber, or adsorber molecule.
• albumin dialysis liquid In addition to albumin's suitability for binding an undesired substance of the type described above, and thus its suitability in methods for extracorporeal carbon dioxide removal and of blood pH adjustment, the presence of albumin in the dialysis liquid, as in the present invention, further enables or enhances the removal of the protein-bound toxins.
• albumin is known to bind to the unbound toxins, and this property can be taken advantage of when albumin is present in the dialysis liquid, thus enabling the binding of toxins traversing the semipermeable membrane from blood into the dialysis liquid. This method is called "albumin dialysis” (see e.g. WO 2009/071 103 A1 , incorporated herein by reference in its entirety).
• a suitable total concentration of carbonate/bicarbonate is 0 to 40 mmol/l.
• the presence of carbonate/bicarbonate in the dialysis liquid contributes to buffering capacity of the dialysis liquid.
• the lower the concentration of carbonate/bicarbonate the better the removal of CO 2 from the blood. Therefore, it can be desired to use a dialysis liquid devoid of carbonate/bicarbonate, or without addition of carbonate/bicarbonate.
• the pH range in which bicarbonate can suitably buffer liquids, such as blood is well known in the art, e.g. from biochemistry textbooks.
• bicarbonate can be added in the form of any of its salts, such as sodium bicarbonate, potassium bicarbonate, and others, or alternatively be added indirectly by introducing carbon dioxide, optionally in the presence of carbonic anhydrase, and adjusting the pH as required by addition of a suitable base, such as sodium hydroxide or potassium hydroxide, sodium hydroxide being strongly preferred.
• a suitable base such as sodium hydroxide or potassium hydroxide, sodium hydroxide being strongly preferred.
• sodium bicarbonate or sodium carbonate is strongly preferred.
• potassium salts, or mixtures of sodium and potassium salts can be used. Salts particularly useful to be added to dialysis liquid at high pH (e.g. up to pH 1 1 ) are sodium carbonate or potassium carbonate.
• preferred (combined) carbonate/bicarbonate concentrations in the dialysis liquid lie in the range from 1 0 to 40 mmol/l, preferably 1 5 to 35 mmol/l, more preferably 20 to 30 mmol/l, and most preferably at or about 30 mmol/l. It is important to note that these are general preferred ranges and subranges. For specific purposes, such as for treating blood from a specific patient subgroup, alternative, different or partially diverging ranges may be preferable, as described below.
• Alternative suitable (combined) carbonate/bicarbonate concentrations lie in the range from 0 to 40 mmol/l, or more than 0 to 40 mmol/l, preferably 5 to 35 mmol/l, preferably 10 to 30 mmol/l, more preferably 1 5 to 25 mmol/l, and most preferably at or about 25 mmol/l.
• the (combined) carbonate/bicarbonate concentration is determined, and adjusted if required, prior to entering of the dialysis liquid into the second chamber.
• (combined) carbonate/bicarbonate concentrations above 40 mmol/l are not desired in view of possible side effects.
• Suitable Tris concentrations are in the range from 0 to 40 mmol/l, or more than 0 to 30 mmol/l, preferably 5 to 25 mmol/l, preferably 1 0 to 20 mmol/l, more preferably about 1 5 mmol/l.
• Alternative suitable Tris concentrations are in the range from 0-38 mmol/l, or 0-20 mmol/l.
• a suitable concentration of albumin is 1 0 to 60 g/l (i.e. 1 to 6 g/1 00 ml).
• g/l, and g/1 00 ml refers to the grams per volume (final volume of the albumi n-containing liquid).
• albumin is not the only buffering agent present in the dialysis liquid.
• carbonate/bicarbonate or Tris is present in addition to albumi n.
• a preferred dialysis liquid according to the present invention comprises both (i) carbonate/bicarbonate and (ii) albumin; or both (i) Tris and (i i) albumin.
• no carbonate/bicarbonate is added to the dialysis l iquid (i.e. the carbonate/bicarbonate concentration i n the dialysis liquid is 0 mmol/l or near 0 mmol/l)
• Tris is the only bufferi ng agent comprised in the dialysis liquid.
• the dialysis liquid typical ly comprises water. Typical ly more than 50 % (vol./vol.), more than more than 60 % (vol. /vol.), more than 70 % (vol./vol.), more than 80 % (vol./vol.), or more than 90 % (vol./vol.), of the dialysis liquid is water. Other water-miscible liquids can also be comprised in the dialysis liquid.
• the present invention not only provides a process for removing an undesired substance, but also a dialysis liquid as such, which is suitable for said purpose. Any and al l specific dialysis l iquid described herein is a subject of the present invention.
• albumin is not the only buffering agent present in the dialysis liquid.
• carbonate/bicarbonate or Tris is present in addition to albumin.
• a preferred dialysis liquid according to the present invention comprises both (i) carbonate/bicarbonate and (ii) albumi n; or both (i) Tris and (ii) albumi n.
• An alternative preferred dialysis l iquid comprises Tris as the only bufferi ng agent, i .e. does not contain added carbonate/bicarbonate or albumin.
• carbonate/bicarbonate, albumin and Tris are buffering agents, and thus can all contribute to maintenance of the pH within a desired range. These buffering agents have at least one pKa value in the pH range defined above.
• the dialysis liquid is adjusted to comply with the specified pH and bicarbonate/albumin concentrations.
• the pH can be measured by at least one pH measuring device before the dialysis liquid enters the second chamber.
• the pH can additionally be measured by at least one pH measuring device.
• a first particular dialysis liquid useful in the present invention comprises 0 to 40 mmol/l carbonate/bicarbonate (preferably 10 to 40 mmol/l carbonate/bicarbonate), 10 to 60 g/l albumin (i.e. 1 to 6 g/100 ml albumin), and has a pH the range from pH 7.75 to pH 1 1 .0, preferably pH 8.0 to pH 10.0, and more preferably pH 8.0 to pH 9.0.
• Preferred carbonate/bicarbonate concentrations are as specified above.
• a second particular dialysis liquid useful in the present invention comprises 0 to 40 mmol/l Tris (preferably 1 to 20 mmol/l Tris), 1 0 to 60 g/l albumin (i.e. 1 to 6 g/100 ml albumin), and has a pH the range from pH 7.75 to pH 1 1 .0, preferably pH 8.0 to pH 10.0, and more preferably pH 8.0 to pH 9.0.
• Preferred Tris concentrations are as specified above.
• a third particular dialysis liquid useful in the present invention comprises 0 to 40 mmol/l Tris (preferably 1 to 20 mmol/l Tris). Preferred Tris concentrations are as specified above.
• a suitable buffering capacity is generally provided for Tris-buffered dialysis liquids when the pH is relatively high.
• the pH of the dialysis liquid is suitably particularly high, e.g. 8.5 to 1 1 .0, or 9.0 to 1 0.5, preferably 9. 0 to 10.0.
• the dialysis liquid can also comprise other membrane-permeable small molecules for transfer into blood, if desired, e.g. glucose.
• the dialysis liquid comprises calcium (Ca 2+ ) ions.
• the calcium ions are at least partially bound to albumin for the dialysis liquid of the present invention.
• the albumin- containing dialysis liquid according to the present invention contains higher calcium concentrations than what is known from dialysis liquids according to the state of the art.
• the calcium ion concentration of albumin-containing dialysis liquid is 1 .7 mmol/l or higher. This is desired in order to provide sufficient free calcium available, i.e.
• the dialysis liquid comprises 2 to 4 mmol/l calcium (Ca 2+ ) ions, more preferably 2.4 - 2.6 mmol/l calcium ions.
• Calcium ions can be added in the form of any suitable salt, e.g. calcium chloride. Addition of calcium into the dialysis liquid is beneficial because blood also comprises calcium; the presence of calcium in the dialysis liquid prevents undesired net flux (leaking) of calcium ions from the blood to the dialysis liquid. It is known that calcium ions can precipitate at (very) basic pH.
• the presence of calcium is, however, not incompatible with the present invention in view of the maximum pH value of 9.0 of the dialysis liquid when being brought in contact with blood separated from the dialysis liquid by the semipermeable membrane.
• the dialysis liquid has a pH of more than 10, some ions such as calcium ions (and others) become insoluble. Therefore, if the dialysis liquid has a pH of more than 9, it is preferable that no calcium ions (and/or other insoluble ions) are present. In order not to deplete a patient of such ions, they should be infused directly into the blood of the patient, if the dialysis liquid has a pH of that range.
• the dialysis liquid is characterized by an osmolarity, which is substantially identical to the osmolarity of blood being dialyzed.
• the enzyme carbonic anhydrase may be added to the dialysis liquid, or may be present in the dialysis liquid.
• Carbonic anhydrases are enzymes, which promote the reversible reaction from carbon dioxide to bicarbonate (HCCV) and H + -ions. Carbonic anhydrases can be added to the extracorporeal blood circuit. It is also possible to coat the inside surface of the first or second chamber with carbonic anhydrases.
• a dialysis liquid suitable for the physiological purposes of the present invention preferably comprises the desired electrolytes, nutrients and buffers in adequate concentrations, so that their levels in the patient's blood can be adjusted, e.g. brought to normal physiological values, or to any otherwise desired or indicated values.
• Optional constituents of the dialysis liquid according to the present invention include electrolytes, preferably selected from sugars and/or salts (anions/cations/zwitterions).
• Typical cations include calcium, magnesium, potassium and sodium ions; typical anions include chloride, HCO 3 " , H 2 CO 3 , HPCV " , H 2 PO4 " ;
• typical zwitterions include amino acids (e.g.
• the dialysis liquid contains no added acetic acid and no added acetate.
• the combined concentration of acetic acid in the dialysis liquid is 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.
• the dialysis liquid can be designed to specifically or primarily address a particular goal.
• the dialysis liquid may be designed to the goal of adjusting the blood pH, or to the goal of removing carbon dioxide - directly or indirectly.
• the terms design and adaptation of the dialysis liquid are used interchangeably and refer to the dialysis liquid immediately prior to exposure to blood via the semipermeable membrane, i.e. at the stage of entering the second chamber.
• the dialysis liquid used in the present invention can be adapted to such purposes, within the general framework of the dialysis liquid as described herein.
• bicarbonate can be removed from the blood along the concentration gradient for the dialysis liquid on the one side and blood on the other side of the semipermeable membrane.
• bicarbonate will be removed from the blood into the dialysis liquid along the concentration gradient.
• the (combined) carbonate/bicarbonate concentration of the dialysis liquid is selected such that it is not lower than the (combined) carbonate/bicarbonate concentration of the blood, "not lower”, in this context, means equal or higher, such as slightly higher, but typically means roughly equal or equal.
• a dialysis liquid adjusted for treating blood from a subject suffering from metabolic acidosis comprises bicarbonate preferably in the concentration range from 1 6 to 40 mmol/l.
• the concentration is increased slowly during the course of treatment, so as to avoid acidosis of the cells.
• Preferred embodiments of the (combi ned) carbonate/bicarbonate concentration for such purposes include the range from 25 to 35 mmol/l, or (about) 30 mmol/l.
• a dialysis liquid adjusted for treating blood from a subject suffering from respiratory acidosis comprises bicarbonate preferably in the concentration range from 0 to 40 mmol/l, or alternatively 5 to 40 mmol/l or 1 0 to 40 mmol/l.
• Preferred embodiments of the (combined) carbonate/bicarbonate concentration for such purposes include the range from 1 5 to 35 mmol/l, from 20 to 30 mmol/l, or (about) 25 mmol/l.
• the process of the present invention also allows for adjusting the pH of the blood to a desired level.
• This is suitable e.g. for the treatment of acidic blood, e.g. blood from acidosis patients.
• the blood pH is adjusted to a predetermined value or a predetermined range within the range of pH 6.8 to pH 8.5. Blood pH values outside that range are not desired in view of undesired side effects, such as denaturation of blood proteins and/or precipitation of blood components.
• adjusti ng the blood pH value or range means that the blood is characterized by said adjusted value or range at the stage of exit from the first chamber.
• physiological blood of a healthy human subject typically has a pH i n the range of 7.35 to 7.45, i .e. around 7.40
• the present invention is particularly suitable for treating subjects suffering from acidosis (acidosis patients), i .e. subjects suffering from metabolic and/or respiratory acidosis.
• acidosis acidosis patients
• the present i nvention directed at, or suitable for, treating blood from acidosis patients, it can be desired to adjust the blood pH to a range or value that is more alkaline than 7.40, more than 7.40 to 8.0, 7.5 to 7.9, or 7.6 to 7.8, preferably within the range of pH 7.65 to 7.75, e.g. 7.7.
• Adjustment of the blood pH in the method of the present invention is technically feasible because of the buffering capacity of the dialysis liquid used, and because of the permeability of the semipermeable membrane of H + and OH " ions.
• pH adjustment of the blood can be achieved.
• H + and OH " ions can cross the semipermeable membrane, and wi l l do so along the respective concentration gradient.
• H + -ions are eliminated from the blood mainly in view of the excellent buffering capacity of the dialysis liquid of the present invention.
• the dialysis liquid used in the present invention can be adjusted based on the needs, e.g. based on the needs of a patient being subjected to treatment by dialysis.
• the present invention thus allows for preferential removal of carbon dioxide, or for preferential Adjustment of the blood pH, or both.
• This versatility is provided by the possibilities to adjust the pH of the dialysis liquid and to adjust the concentration of buffering substances (particularly albumin and bicarbonate) in the dialysis liquid, each independently from each other, within the general ranges as defined herein.
• a further undesired substance can be removed from the blood.
• a further undesired substance is a toxin, e.g. a protein-bound toxin.
• it is intended to remove at least two undesired substances from the blood, e.g. at least one undesired substance as specified above, and additionally a toxin.
• the term toxin, as used herein, is not particularly limited and refers to any substance which is toxic to the human or animal body, including metabolites, e.g. bilirubin, bile acids; copper; other substances like hormones or drugs accumulating in hepatic failure.
• said toxin is protein-bound in the blood of the human or animal body.
• protein-bound toxins are hardly removed by hemodialysis.
• albumin in the dialysis liquid, as in the present invention, enables or enhances the removal of the protein-bound toxins: in the blood, a small proportion of the protein-binding toxins is in the free form in solution and this proportion can diffuse through the semipermeable membrane in the dialyser and bind to the free binding sites of the adsorber (albumin) in the dialysis liquid.
• a device suitable for the present invention comprises a first chamber, suitable for receiving blood, and a second chamber, suitable for receiving the dialysis liquid.
• the first chamber and the second chamber are separated by at least one semipermeable membrane.
• the first chamber is divided into a multitude of first chambers.
• a multitude refers to any integer more than one.
• a multitude of first chamber is present in the device.
• each first chamber is in contact with the second chamber separated by a semipermeable membrane.
• Said first chambers are preferably present in the form of capillaries. This enables that the blood flows through the capillaries while being in contact with the dialysis liquid by the semipermeable membrane.
• each second chamber is in contact with the first chamber by a semipermeable membrane.
• the ratio of total volume of the (multitude of) second chambers to total volume of the (multitude of) first chambers can be in the range of 10:1 to 1 :10.
• the total volume of the (multitude of) second chambers is larger than the total volume of the (multitude of) first chambers.
• a preferred ratio is about 2:1 .
• the transfer of the at least one undesired substance from the blood into the dialysis liquid occurs across a semipermeable membrane.
• the membrane is ideally permeable to oxygen, carbon dioxide, bicarbonate, H + ions and liquids.
• the semipermeable membrane separates the first chamber and the second chamber. This enables the transfer of membrane-permeable substances from the first chamber to the second chamber or from the second chamber to the first chamber.
• such substances being membrane permeable, will preferentially migrate along their concentration gradient.
• the semipermeable membrane is not permeable for proteins of the size or properties of albumin.
• bicarbonate and hydrogen cations as well as other small molecules, including ions or substances, which can influence the pH of an aqueous liquid, can traverse the semipermeable membrane during the process of the present invention. Therefore, the pH of the dialysis liquid does not necessarily remain constant throughout the process step of contacting blood with the dialysis liquid. Therefore, in a precise sense, the pH and the (combined) carbonate/bicarbonate concentration of the dialysis liquid, as defined in this specification, are preferably defined for the dialysis liquid at the stage immediately preceding said contacting, i.e. the stage wherein the dialysis liquid enters the second chamber. In other words, the dialysis liquid, when entering the second chamber, has a pH the range from pH 8.0 to pH 1 1 .0 (or any preferred value or subrange thereof, as defined in this specification).
• the blood/and/or the dialysis liquid are preferentially moved, e.g. by a constant flow of these liquids through the respective chamber, and optionally by stirring, shaking, pressure gradient (causing convection) or other suitable mechanical activity.
• Such mechanical activity is believed to contribute to efficient exposure of the substances to the surface of the semipermeable membrane, and thus to the efficiency of migration across the membrane.
• the exposed surface area of the semipermeable membrane can be in the range from 0.01 m 2 to 6 m 2 .
• a (combi ned) surface area of up to 6 m 2 is typically present when two dialysis units are being used in parallel. Such parallel use of two dialysis units is contemplated in one embodiment of the present invention.
• the exposed surface area of any one dialysis unit is in the range from 0.01 m 2 to 3 m 2 , such as from 0.1 m 2 to 2.2 m 2 . In general, surface areas in the lower part of these ranges are particularly suitable for the treatment of children.
• Exposed surface area refers to the area of the semipermeable membrane exposed to the first chamber on the one side, and simultaneously exposed to the second chamber on the other side. Any additional sections of the membrane, which are not exposed to both chambers simultaneously, but e.g.
• the process of the present i nvention uses more than one such membrane, either in the same dialysis unit, or i n more than one dialysis unit. If more than one dialysis unit is used, such more than one dialysis units can be present in a row, or in paral lel, from the perspective of the extracorporeal blood stream. Preferably, there are two devices for dialysis, each with an exposed surface area as disclosed above.
• the process of the present invention thus al lows for a transfer of carbon dioxide and other compounds, such as hydrogen cation and bicarbonate, to pass (through the dialysis membrane) i nto the dialysis liquid.
• the process of the present invention can be referred to as liquid/liquid dialysis method suitable for CO 2 removal .
• the semipermeable membrane contains carbonic anhydrase activity. This can be achieved by coati ng the membrane, on the blood-facing side and/or on the side facing the dialysis l iquid, with carbonic anhydrase.
• one chamber is provided on either side of the semipermeable membrane, i.e. a first chamber on one side of the semipermeable membrane, and a second chamber on the other side of the semipermeable membrane.
• a device is suitably used which comprises two compartments, divided by a semipermeable membrane.
• the fi rst chamber, the semipermeable membrane and the second chamber are comprised by one device.
• blood is present in the first chamber, and the dialysis liquid is present in the second chamber, the chambers being separated by said semipermeable membrane.
• the semipermeable membrane with the enzyme carbonic anhydrase.
• multiple first chambers are present, each in contact with the second chamber via or across a semipermeable membrane. Such multiple first chambers can have the form of capillaries; thus, in the process of that embodiment, blood streams through capillaries.
• Embodiments in which only one of these liquids flows through its respective chamber, while the other one is steadily present in its respective other chamber, i.e. without flowing (entering, passing through and exiting) of the respective other liquid through that respective other chamber, are termed semi-static.
• the blood flows through the first chamber and the dialysis liquid simultaneously flows through the second chamber.
• blood is passed through the blood compartment (first chamber) and that the dialysis liquid is passed through the dialysis liquid compartment (second chamber).
• the process of the present invention makes it possible to efficiently remove one or more undesired substance as defined above, including CO2, without requiring a gas stream (sweep gas) as in the prior art.
• a gas stream e.g. gas exchange membrane
• the dialysis unit used in the present invention does not comprise a chamber having gas (sweep gas) in contact with blood separated by a membrane (e.g. gas exchange membrane).
• the device comprising the first chamber, second chamber and the semipermeable membrane is a dialysis unit, optionally comprised in a dialyzer.
• a dialysis unit is a unit comprising a first chamber as defined herein, a second chamber as defined herein, and a semipermeable membrane, as well as means for entering and removing a fluid (e.g. blood) into and from the first chamber (inlet and outlet), and means for entering and removing a fluid (e.g. dialysis liquid) into and from the second chamber (inlet and outlet).
• a fluid e.g. blood
• the first chamber comprises and inlet and an outlet
• the second chamber comprises an inlet and an outlet.
• the dialysis unit comprises a biological fluid compartment (first chamber) that is part of the biological fluid circuit, a dialysis liquid compartment (second chamber) that is part of the dialysis liquid circuit, and a semipermeable membrane separating the biological fluid compartment and the dialysis liquid compartment.
• first chamber biological fluid compartment
• second chamber dialysis liquid compartment
• semipermeable membrane separating the biological fluid compartment and the dialysis liquid compartment.
• the device is a device for ultrafiltration (ultrafiltration device).
• the second chamber does substantially not comprise any gas phase, i.e. is filled substantially solely with dialysis liquid in the liquid phase.
• gas contact of the blood may be entirely excluded, or limited to a minimum, required under the circumstances, e.g. a bubble catcher or a similar device.
• the semipermeable membrane used in the present invention is not particularly limited, as long as it is permeable for water and inorganic molecules solubilized in water.
• a suitable semipermeable membrane for the present invention allows for transfer of the at least one undesired substance across the semipermeable membrane.
• the membrane can e.g. be selected among conventional semipermeable membranes as currently used e.g. for hemodialysis. It is also conceivable, however, to consider membranes with larger pores than those presently used for dialysis.
• the diffusion through the membrane can optionally be supported by convective transport by means of filtration.
• a dialyzer comprises a dialysis unit as described, and additionally tubing (inlet and outlet) connected with the respective means for entering and removing a fluid into and from said first and second chamber, respectively: the tubing connected to the first chamber (inlet and outlet) is suitable to be connected to the blood system of a human or animal.
• the dialyzer essentially comprises two chambers separated by a dialysis membrane, to each of which is connected a tubing system for the fluids to be used.
• the tubing connected to the second chamber (inlet and outlet) is suitable to be connected to a regeneration unit.
• the latter setting allows for regeneration (recirculation, recycling) of the dialysis liquid, as described herein below, as well as in WO 03/094998 A1 and WO 2009/071 1 03 A1 , both incorporated herein by reference in their entirety.
• the dialyzers used in the present invention are not particularly limited, and can be conventional dialysers currently used e.g. for haemodialysis.
• the HepaWash ® system (Example 2) is used in the present invention.
• dialyzer Conventional components of a dialyzer, such as manometers, air detectors, pumping devices like heparin pumps, blood pumps, etc., form part of the means or device according to the invention.
• the dialysis liquid can also be recycled (“recycling” or "multi use” or “multi pass”).
• dialysis liquid (“used dialysis liquid”) exiting from the second chamber (outlet) is collected and returned into the second chamber (inlet).
• Albumin is relatively costly. It is therefore generally desi red to recycle albumin-containi ng dialysis liquid. In other words, the recycl i ng can result in major cost savings.
• the recycling enables also having a high dialysis l iquid flow rate of up to 4000 ml/min.
• Typical ly, recycli ng of the dialysis liquid requires the cleani ng or regeneration of the dialysis liquid.
• Such cleaning or regeneration is achieved by at least one type of treatment step in order to remove undesired substances from the dialysis l iquid (i.e. used dialysis liquid) prior to re-entry i nto the second chamber.
• Said step occurs outside the second chamber, i .e. at a site different from the site of blood contact.
• Said at least one treatment step is selected from exposure to an (i) adsorber and/or (ii) diafiltration and/or (i i i) acidic pH and/or basic pH (iv) and/or exposure to a permeable or semipermeable membrane (i.e.
• Said adsorber is usually an entity different from albumin; i .e. in the case of albumin-containing dialysate, said adsorber is a further or additional adsorber.
• said adsorber is capable of binding sodium ions (Na + ) and/or chloride ions (CI " ).
• any one or more of such treatment steps can be conducted in row or i n parallel (i.e. upon splitting the dialysis liquid). It is possible to foresee that the dialysis l iquid is subjected to treatment or purification after being exposed to the blood by exchange of molecules across the semipermeable membrane, i .e. after exiti ng from the second chamber.
• Suitable means for treatment or purification of the dialysis liquid include one or more adsorber unit(s), one or more pH change unit(s) and/or one or more diafi ltration unit(s). Such units are not mutually exclusive and may be present in row or in paral lel .
• the recycling of the dialysis liquid of the present i nvention can also require, and thus involve, an adjustment of the (combi ned) carbonate/bicarbonate concentration and/or of the pH, so as to ensure that the pH of the dialysis liquid, when being (re)introduced into the first chamber, complies with the properties desired in the context of the present invention, as defined herein, (re)introduced refers to the introduction after recycling.
• the blood is passed through the first chamber, and the dialysis liquid is passed through the second chamber.
• the flow rate, or speed of the blood and of the dialysis liquid may selected from constant or varying (changing) over time.
• the blood flow rate in the extracorporeal blood circuit is adjustable within the range from 50 ml/min to 7000 ml/min.
• the blood flow rate is about 2 l/min or less, e.g. 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 typically controlled and regulated and may be adjusted to the treatment conditions and to the dialysis liquid flow rate.
• the present invention makes it possible that the lungs can be supported up to 100% with maximum mid-flow blood flow rates, without using another ventilation device.
• conventional extracorporeal lung support devices which are mid-flow-treatments cannot support the lungs equally well. This means that the invented lung support functions sufficiently well at mid-flow conditions, which means, that it is easy to handle for the operator and less hazardous for the patient.
• an additional lung protective ventilation (LPV) which is common for other mid-flow devices, is dispensable.
• the dialysis liquid flow rate can be in the range from 1 0 ml/min to 1 1000 ml/min (i.e. 0.1 667 ml/h to 183.333 ml/h). More typically, the dialysis liquid flow rate is selected among the following: slow dialysis liquid flow rates (1 -2 l/h) and normal dialysis liquid flow rates (25-60 l/h)/dialyzer, as well as intermediate rates (more than 2 l/h to less than 25 l/h). The flow rate can thus be adapted as required.
• the flow rate of the blood is lower than the flow rate of the dialysis liquid. Therefore, an efficient treatment of the blood can be achieved.
• the blood and the dialysis liquid are conventionally conveyed in counter-current, but they can also be conveyed in co-current.
• blood and dialysis liquid can be passed through the device for dialysis in the same direction or counter-current.
• a possibility is foreseen to remove carbon dioxide, and/or carbonic acid and/or its dissociation products (HVHCO3 ) from the dialysis liquid ("removal").
• This is ideal ly foreseen in a discrete step, i .e. a step after the dialysis l iquid exits the second chamber (outlet).
• the means for these purposes are not particularly l imited, as long as they are suitable.
• carbon dioxide, and/or carbonic acid and/or its dissociation products are suitably removed from the dialysis l iquid by degasification (pressure reduction, heating or cool i ng, ultrasonic, membrane degasification, substitution by inert gas, addition of reductant, freeze-pump-thaw cycling, pH decrease, centrifugal force or addition of degasification additives), fi ltration, sorption or chemical bonding.
• degasification pressure reduction, heating or cool i ng, ultrasonic, membrane degasification, substitution by inert gas, addition of reductant, freeze-pump-thaw cycling, pH decrease, centrifugal force or addition of degasification additives
• fi ltration e.g.
• the process according to the present i nvention is conducted such that the recycl i ng i ncludes acidification of the dialysis l iquid to acidic pH, for formation of carbon dioxide, and removal of carbon dioxide from the dialysis liquid across a carbon dioxide-permeable membrane.
• the membrane is gas-permeable, and carbon dioxide is removed in the gas phase.
• Albumi n is commercial ly available, but relatively expensive. Therefore, albumin-based dialysis l iquids can incur high process costs.
• albumin-containing dialysis l iquid has been described for the case of liver dialysis, e.g. i n WO 03/094998 A1 , incorporated herein by reference in its entirety.
• albumin can be recycled based on the principle that the bi nding affi nity of carrier proteins (such as albumin) towards bound substances, such as toxins, can be influenced by certain measures, such as pH- changes.
• diafi ltration is a di lution process that involves removal or separation of components (permeable molecules like salts, small proteins, solvents etc.,) of a solution based on their molecular size by using filters permeable of said components. Diafiltration-mediated removal of such components allows for subsequent recycling of the albumin.
• albumin can be efficiently regenerated in a dialysis regeneration unit having two parallel dialysis liquid streams, i.e. an acidic flow path and an alkaline flow path in parallel (WO 09/071 103 A1 ).
• the process and device (e.g. dialysis liquid regeneration unit, dialysis unit) described in WO 09/071 103 A1 are also suitable for recycling albumin-containing dialysis liquid in the process of the present invention; WO 09/071 103 A1 is therefore incorporated herein by reference in its entirety 1 .
• toxins bound e.g. to albumin can be removed.
• the dialysis liquid regeneration unit For efficiently removing said toxins, the dialysis liquid regeneration unit according to embodiments of the present invention comprises two flow paths that are fluidically connected in parallel.
• the dialysis liquid to be regenerated is split up and conveyed through the two flow paths.
• an acidic fluid is added (from an acidic fluid supply unit) to the dialysis liquid.
• the concentration of free toxins in solution is increased.
• a detoxification unit which is located downstream of the acidic fluid supply unit, the free toxins are removed from the acidified dialysis liquid flowing in the first flow path.
• alkaline soluble toxins may e.g. be precipitated and thereby removed from the dialysis liquid fluid.
• an alkaline fluid is added (from an alkaline fluid supply unit) to the dialysis liquid flowing in the second flow path. Due to the increase of the pH, the concentration of free alkaline soluble toxins is increased, and thus, removal of alkaline soluble toxins is facilitated.
• These toxins are removed by a further detoxification unit, which is located downstream of the alkaline fluid supply unit.
• the further detoxification unit is adapted for removing toxins from the alkalized dialysis liquid flowing in the second flow path.
• the dialysis liquid regeneration unit is capable of efficiently removing protein-binding toxins.
• toxins is understood very broadly herein and encompasses all protein-binding substances, even if they normally not directly referred to as toxins, such as drugs, electrolytes, H + , hormones, fats, vitamins, gases, and metabolic degradation products like bilirubin.
• the regenerated acidified dialysis liquid from the first flow path may be merged with the regenerated alkalized dialysis liquid from the second flow path, whereby the acidified dialysis fluid from the first flow path and the alkalized dialysis fluid from the second flow path may neutralize one another at least partially.
• a flow of regenerated dialysis liquid at a physiological pH value may be provided.
• the acidic fluid added by the first supply unit comprises at least one of: hydrochloric acid, sulfuric acid, acetic acid.
• the first supply unit is adapted for adjusting the pH of the dialysis liquid in the first flow path to a pH from 1 to 7, preferably from 2.5 to 5.5.
• the alkaline fluid added by the second supply unit comprises at least one of: sodium hydroxide solution, potassium hydroxide solution.
• the second supply unit is adapted for adjusting the pH of the dialysis liquid in the second flow path to a pH in the range from 7 to 1 3, preferably from 8 to 13, more preferably from 8 to 1 1 .
• the acidic fluid and the alkaline fluid are chosen such that "physiological" neutralization products are generated during neutralization.
• a certain concentration of the formed neutralization products might already be present in the respective biological fluid anyway.
• a certain concentration of NaCl is produced during neutralization of the acidified flow and the alkalized flow.
• NaCl is typically also present in a biological fluid, like e.g. blood or blood serum.
• a concentration ratio of toxin-carrier-complex to free toxin and free carrier substance is shifted in favour of the free toxin for at least some of the toxins in the dialysis liquid, thereby increasing a concentration of free toxins in the dialysis liquid.
• the solubility of acidic soluble toxins like e.g. magnesium or copper
• the binding affinity of the acidic soluble toxins to the carrier substances is reduced. Accordingly, the concentration of free toxins in solution is increased.
• the detoxification unit is adapted for at least partially removing said free toxins. Due to the increased concentration of free toxins, said toxins may be removed at an increased rate.
• the alkaline soluble toxins may e.g. be precipitated and thereby removed from the dialysis liquid fluid.
• a concentration ratio of toxin-carrier-complex to free toxin and free carrier substance is shifted in favour of the free toxin for at least some of the toxins in the dialysis liquid, thereby increasing a concentration of free toxins in the dialysis liquid.
• the further detoxification unit is adapted for at least partially removing said free toxins. Due to the increased concentration of free toxins, said toxins may be removed at an increased rate.
• some of the acidic soluble toxins may e.g. be precipitated and thereby removed from the dialysis liquid fluid.
• the concentration ratio of toxin-carrier-complex to free toxin and free carrier substance is shifted in favour of the free toxin for at least some of the toxins in the dialysis liquid, thereby increasing a concentration of free toxins in the dialysis liquid. Accordingly, the free toxins may be removed at an increased rate by the detoxification units.
• albumin has also contributes to the excellent buffering capacity of dialysis liquids according to the present invention.
• an adsorber can be brought in contact with the dialysis liquid.
• the adsober is capable of adsorbing at least one undesired substance present in the patient's blood (e.g. urea, uric acid, electrolytes, sodium, calcium or potassium cations; chloride anions).
• an adsorber is present in an adsorber unit, i.e. a stationary unit through which the dialysis liquid is passed.
• the type or composition or material of the adsorber is not particularly limited, as long as it has the capacity to bind at least one of the substances to be removed from the dialysis liquid.
• Different adsorber types are known in the art. By appropriate choice of the adsorber, the process can be adjusted to the actual needs, e.g. needs of an individual patient.
• An adsorber is particularly useful in recycling embodiments, i.e. when it is intended to recycle the dialysis liquid.
• Excess or undesired substances can be removed from the dialysis liquid (used dialysis liquid) across a membrane, i.e. a permeable or semipermeable membrane.
• gases and/or solutes/ions dissolved in the dialysis liquid can be removed by such a membrane treatment or membrane contact.
• carbon dioxide is removed, either as a gas or in the state of being dissolved in a liquid.
• One particularly suitable way of removing carbon dioxide consists of bringing the dialysis liquid into contact with a membrane which is permeable for carbon dioxide.
• the dialysis liquid has a certain pressure pi, and the pressure of the fluid (liquid or gas) on the other side of said membrane, p 2/ is lower, i.e.
• the object of C0 2 removal from the used dialysis liquid can also, or alternatively, be achieved if the partial pressure of CO2 is lower in the fluid on the other side of said membrane.
• it is possible to remove hydrogen carbonate along a concentration gradient i.e. by bringing the used dialysis liquid into contact with a bicarbonate-permeable membrane, as long as the (combined) carbonate/bicarbonate concentration in the fluid (liquid) on the other side of the membrane is lower than the (combined) carbonate/bicarbonate concentration of the used dialysis liquid.
• the membrane used is not permeable for albumin. This can be realized by selecting a membrane with an appropriate pore size. Such membrane treatment is particularly useful for recycling embodiments.
• any activity directed at treatment of the human or animal body by surgery or therapy particularly those aiming at preventing or improving a condition in a living subject, i.e. serving a medical purpose, may be referred to as a medical method or medical use.
• a medical method or medical use In general, the terms method and process are used interchangeably herein.
• the term method is used to refer particularly to medical methods; the medical methods of the present invention can involve any and all aspects of the above described process for removal of an undesired substance from blood.
• this invention provides a method for extracorporeal treatment of blood from a patient in need of such treatment.
• the extracorporeal blood is subjected to dialysis process as described herein, i.e. - generally speaking - is being exposed to a dialysis liquid by a semipermeable membrane.
• blood is removed from a subject, subjected to the process of the present invention, and suitably returned to the subject.
• venous blood from a patient is removed and entered into the first chamber of the process of the present invention. This allows for treatment of the blood in the process of the present invention, in any and all aspects described herein. Subsequently, the blood (“treated blood”) exits the first chamber and can be returned to the patient.
• the treated blood most typically is entered into a vein of the patient, but can alternatively be returned into an artery, however the latter is suitably limited to processes wherein the blood is also subjected to oxygenation. All these aspects spanning the process from removal of patient blood from the body until returning treated patient blood into the body are common to medical the methods for all indications described herein.
• the findings of the present invention enable its exploitation in the treatment of the human or animal body by therapy (generally referred to as medical uses). It is possible to customize the medical uses of the present invention specifically to the actual needs of the respective patient.
• gas-exchange is not limited to organisms having lungs. Gas exchange also occurs in organisms having gills, such as fish.
• Medical use according to the present invention is focused on support of the lung function, i.e. for treating or preventing certain conditions in organisms having lungs, such as preferably mammals, and more preferably humans. Therefore, gills, and/or organisms having gills, are not discussed in detail in this specification.
• the dialysis liquid is characterized by an osmolarity, which is substantially identical to the osmolarity of blood, i.e. of the blood of the species (e.g. human) being dialyzed in the dialysis unit.
• the method of the invention does not (or at least not necessarily) comprise an invasive step and/or does not comprise a step representing a substantial physical intervention on the body and/or does not comprise a step which requires professional medical expertise to be carried out and/or does not comprise a step which entails a substantial health risk even when carried out with professional care and expertise.
• the method of the invention does not comprise an invasive step representing a substantial physical intervention on the body which requires professional medical expertise to be carried out and which entails a substantial health risk even when carried out with the required professional care and expertise.
• All these treatment methods involve the removing, preferably venous, blood from a subject, thus yielding extracorporeal blood; exposing the extracorporeal blood to contact with the dialysis liquid as described herein by means of a semipermeable membrane, as described in the context of the process of the present invention, thus yielding treated blood, and returning the treated blood into the same subject, preferably into the vein of the subject, and in a less preferred embodiment into the artery of the subject.
• a semipermeable membrane as described in the context of the process of the present invention
• the methods of the present invention are suitable for treating patients suffering from acute or chronic respiratory acidosis.
• Patient groups include subjects suffering from hypoventilation, lung tumors, asthma, muscular dystrophy or emphysema, particularly late-stage emphysema.
• the dialysis liquid at the stage of entering the second chamber, suitably contains a (combined) carbonate/bicarbonate concentration in the range from 0 to 40 mmol/l.
• the preferred (combined) carbonate/bicarbonate concentration is as low as possible, i.e. 0 mmol/l or more than 0 mmol/l.
• 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, e.g. 10 mmol/l.
• a (combined) carbonate/bicarbonate concentration at the lower end of the above range or subrange allows for efficient removal or withdrawal of undesired substances, such as bicarbonate, CO 2 and carbonate, from the blood.
• the buffering is suitably achieved by sufficient amount of other buffering agents in the dialysis liquid, typically albumin and/or Tris.
• other buffering agents typically albumin and/or Tris.
• the concentrations of these buffering agents are selected such that the buffering capacity exceeds the buffering capacity of blood plasma. This allows for efficient adjustment of the blood pH. It is also possible to increase the (combined) carbonate/bicarbonate concentration over the course of treatment. This al lows to adapt the treatment to the needs of an individual (personalized medicinal ne).
• the blood typically ly has a pH in the range of 7.40 or more; such as higher than 7.40 but not higher than 8.0, such as pH 7.5 to 7.9, or pH 7.6 to 7.8, or pH 7.65 to 7.75, e.g. 7.7.
• 8.0 such as pH 7.5 to 7.9, or pH 7.6 to 7.8, or pH 7.65 to 7.75, e.g. 7.7.
• pH 7.40 or more such as higher than 7.40 but not higher than 8.0, such as pH 7.5 to 7.9, or pH 7.6 to 7.8, or pH 7.65 to 7.75, e.g. 7.7.
• the dialysis l iquid is either discarded, or, preferably, recycled. I n the latter case it is preferable to subject the dialysis liquid to a membrane treatment.
• a membrane treatment By the membrane treatment, carbon dioxide and/or bicarbonate and/or carbonate and/or carbonic acid may be removed, or partial ly removed. This allows for recycling of the dialysis liquid.
• the membrane treatment is preferably carried out at low pH, i.e. following acidification of the diaiysate.
• the kidney in subjects suffering from respiratory acidosis (i .e. excess dissolved C0 2 in the body fluids due to i nefficient removal in the lungs), the kidney oftentimes reacts, with some delay of e.g. 3 weeks, by production of increased amounts of bicarbonate.
• the present invention al lows to treat subjects suffering from respiratory acidosis during the entire course of the disease, i .e. at early stages when mainly the removal of excess CO 2 from the body fluids is desired, as well as at later stages, when (additional ly) the removal of excess bicarbonate from the body fluids is desired. Further, the removal of excess H + ions from the body fluids is possible at all stages of the disease.
• the physician can alter the composition and pH of the dialysis liquid based on the guidance provided herein.
• the dialysis liquid at the stage of entering the second chamber, suitably contains a (combined) carbonate/bicarbonate concentration in the range from 20 to 40 mmol/l, preferably 25 to 35 mmol/l, more preferably exactly or about 30 mmol/l.
• the dialysis l iquid preferably does not contain added carbonate/bicarbonate.
• a suitable dialysis liquid for that type of patients suitably contains a (combined) carbonate/bicarbonate concentration in the range from 0 to 5 mmol/l (preferably 0 mmol/l), and the buffering capacity is contributed by albumin and Tris, both within the concentration ranges defi ned above.
• a high pH of the dialysis l iquid is desired, e.g. pH 8.0 to 1 1 .0, preferably pH 9.0 to 1 0.0.
• the buffering capacity of the dialysis liquid is higher than the buffering capacity of blood plasma.
• the combination of high pH of the dialysis l iquid and high buffering capacity of the dialysis l iquid al lows for efficient adjustment of the blood pH, and minimal net flux (addition or removal) of substances of bicarbonate, C0 2 and carbonate from the blood.
• the flux can be i ncreased compared to standard dialysis methods.
• the blood typically has a pH i n the range of desired to adjust the blood pH to a range or value encompassing that range, i.e. 7.0 to 7.8, 7.2 to 7.6, or 7.3 to 7.5, 7.35 to 7.45, and most preferably exactly or about 7.40.
• the present invention also al lows for the treatment of a condition characterized by a combi nation of respiratory acidosis and metabol ic acidosis. This is possible because the dialysis liquid, particularly the pH and the (combi ned) carbonate/bicarbonate concentration in the dialysis l iquid, can be adjusted to individual needs.
• the methods of the present invention are suitable for treating patients suffering from acute or chronic respiratory fai lure (lung failure).
• This patient group includes patients suffering from asthma, hypoventilation, lung diseases such as lung cancer, complications associated with smoking and with exposure to other air-born toxins or particles, or muscle dystrophy, or emphysema, particularly late-stage emphysema. Many patients suffering from such lung diseases have a completely working kidney (full renal function).
• the present invention provides a lung support. Subjects suffering from such conditions are suitably treated by the method of the invention as described for the treatment of respiratory acidosis.
• lung fai lure In many cases subjects suffering from lung fai lure are also affected by a liver and/or kidney dysfunction.
• the methods of the present invention are also suitable for treating such subjects, and thus to support these organs: Treatment of combined lung failure/kidney failure
• the present invention also allows for treating subjects suffering inter alia from acute or chronic kidney (renal) insufficiency, or chronic renal failure (CRF).
• the kidneys play an important role in maintaining acid-base homeostasis of healthy individuals by regulating the pH of the blood plasma: main functions include reabsorption of bicarbonate from urine, and excretion of hydrogen cations into urine. These functions of the kidneys are important for maintaining acid-base balance, and can also contribute to controlling blood pH.
• the proper functioning of the kidneys is affected in patients suffering from kidney failure.
• This patient group includes patients suffering from kidney diseases such as kidney cancer, as well as complications associated with intoxication and with exposure to certain medicaments.
• Renal replacement therapy is being widely used in modern intensive care settings/intensive care unit (ICU) for treating such subjects.
• ICU subjects In subjects in the intensive care unit (ICU subjects), acute renal failure (ARF) is frequent, as a part of multiple organ dysfunction syndrome (MODS), in postoperative states and after interventional studies, in already susceptible individuals.
• ICU subjects In general, ICU subjects are in need of different organ support such as continuous renal replacement therapy (CRRT), liver dialysis and mechanical ventilation.
• CRRT continuous renal replacement therapy
• liver dialysis liver dialysis and mechanical ventilation.
• the present invention provides a significant improvement.
• the conditions are suitably selected among the conditions described above for any of respiratory or metabolic acidosis, preferably those described for metabolic acidosis.
• an adsorber as generally described above.
• the adsorber is suitable for binding or adsorbing at least one undesired substance present in the patient's blood.
• To extract liquid or dissolved substances urea, uric acid, electrolytes, sodium, calcium or potassium cations; chloride anions).
• urea, uric acid, electrolytes, sodium, calcium or potassium cations; chloride anions For example, in patients suffering from kidney failure, it is typical that the kidney fai ls to maintain physiological concentrations of sodium, calcium or potassium cations; and/or of chloride anions, in the blood.
• the present invention also allows for treating subjects suffering from acute or chronic liver failure in addition to lung failure and/or kidney fai lure.
• Typical treatment in accordance with the present invention involves extracorporeal toxin removal.
• the methods described in WO 2009/071 1 03 A1 and/or WO 03/094998 A1 can be modified such that the dialysis liquid complies with the framework dialysis liquid of the present invention, or with any embodiments thereof.
• albumin has a dual or synergistic function: it not only binds toxins (which addresses liver insufficiency) but also buffers the dialysis liquid, together with carbonate (which addresses lung insufficiency). That means, that in addition to the functionalities described in WO 2009/071 103 A1 and/or WO 03/094998 A1 , it is possible to perform a lung support and/or to correct the blood pH to a physiological level or otherwise desired level.
• This treatment allows to combine a kidney dialysis, liver dialysis and a lung support comprising a carbon dioxide removal and blood oxygenation in one single device. Modifications or configurations described above for the treatment of kidney failure, such as presence of an adsorber, are suitably employed also in this embodiment.
• fol lowi ng examples are provided for illustrative purposes. These examples do not limit the invention.
• Example 1 bufferi ng capacity of solutions comprisi ng one or more buffering agents
• exemplary liquids 1 and 2 refer to dialysis liquids (dialysates without buffering agents).
• Exemplary liquids 3 to 8 of table 1 refer to dialysis liquids (dialysates with various buffering agents exemplary liquids).
• Dialysis l iquids 9 and 1 0 of table 1 refer to dialysis liquids (dialysates) as described in the prior art.
• Exemplary liquids 1 1 to 14 refer to Tris solution only.
• the buffering capacity of exemplary dialysis l iquids (dialysates 5 to 8) correspond to dialysis liquids (dialysates) according to the present i nvention.
• exemplary liquids were generally prepared as follows: For the preparation of exemplary liquids according to the present invention and of exemplary l iquids as outlined in table 1 , pure water (osmosis qual ity) was used as a basis, and one or more buffering agents according to the present invention (albumin and/or sodium bicarbonate ("soda”) and/or Tris(hydroxymethyl)ami nomethane (Tris/THAM) was added. In particular, albumin (at the concentration indicated below) and/or bicarbonate (at the concentration indicated below) and/or Tris (at the concentration i ndicated below) was dissolved in water. Subsequently or simultaneously, the pH was adjusted to the values indicated below.
• albumin dissolves more rapidly at or near the desired pH values as indicated in the Table below.
• Adjustment of the pH is typical ly done by addition of an acidic concentrate (aqueous HCl) and/or by addition of a basic concentrate (aqueous NaOH).
• Tris-containing exemplary liquids were prepared.
• a exemplary liquid made by addition of a certain amount of bicarbonate (e.g. 20 mmol/l) and adjustment to a certain pH (e.g. pH 9) will comprise a certain combined concentration of bicarbonate and carbonate (e.g. in that case 20 mmol/l).
• the buffering capacity of blood plasma was determined.
• pig blood was tested as follows. First, the bicarbonate concentration and pH were determined, and it was found that the mean bicarbonate concentration was 24.2 mmol/l and the pH was 7.45. Second, said blood was subjected to centrifugation in order to obtain a cell free supernatant. The cell free supernatant was designated plasma. In Figure 1 , this is referred to as "blood plasma”. 1 B: Determination of buffering capacity
• the buffering capacity for H + ions of all liquids described in section 1 A was experimentally tested. To that end, all liquids (comparative exemplary liquids and exemplary liquids according to the present invention, and blood plasma) were subjected to titration with HCI. In particular, 0.1 M HCI was added, the pH was continuously monitored, the solutions were agitated to ensure mixing, and titration was terminated when the pH reached a final value of pH of 6.5. In other words, titration was stopped when the pH reached a value of 6.5. Based on the amount of HCI added until pH 6.5 was reached, the buffering capacity (H + -ion in mmol/l) was calculated. The buffering capacity determined by this assay is shown in Figure 1 .
• the buffering capacity of blood plasma was determined to be 12.00 mmol/l H + -ions.
• exemplary liquids according to the present invention are characterized by a buffering capacity (in mmol/l) superior to the buffering capacity of blood plasma, as determined by this assay.
• the exemplary liquid according to the present invention provides excellent buffering capacity, particularly in embodiments wherein the exemplary liquid has a pH above the pH of normal human blood.
• Example 2 Comparison of the process according to the present invention to a reference process A dialysis liquid according to the present invention was tested by using a HepaWash ® (Munich, Germany) dialysis device (Hepa Wash LK2001 dialysis device).
• Hepa Wash LK2001 dialysis device Hepa Wash LK2001 dialysis device.
• a dialysis device Nikkiso DBB-03 dialysis device commercially offered by Nikkiso (Japan) was used.
• the HepaWash ® dialysis device was described previously, but not in combination with the process according to the present invention, nor in combination with the purpose of carbon dioxide removal from blood.
• the reference device commercially offered by Nikkiso is a conventional hemodialysis system. That device uses a counter-current and is thus specifically designed to provide a renal support (hemodialysis), and to remove the undesired substance urea from the blood.
• the device is connected directly to osmosis apparatus for supply of osmosis water.
• the dialysis liquid is used in a single pass process; i.e. after a single pass through the dialyzer, the dialysis liquid is discarded.
• the C02-containing blood was subjected to dialysis under the following conditions:
• Dialysis liquid flow 800 ml/min.
• Dialysis liquid flow 500 ml/min.
• FIG. 2 The result is shown in Figure 2.
• the figure compares blood pH values during treatment with these different devices (Nikkiso and Hepa Wash ® ). As can be taken from the figure, that only the Hepa Wash ® system, but not the Nikkiso system (Hemodialysis System), can maintain the blood pH from 7.3 to 7.4, while the pH value of the blood treated with the Nikkiso machine (Hemodialysis System) rapidly fell to 6.65.
• renal dialysis (hemodialysis) machines such as the one offered by Nikkiso, are incapable of preventing the problem of over-acidification of the blood. Without wishing to be bound to a particular theory, it is thought that this system removes not only H + ions, but also the buffering agent bicarbonate, from the blood. Removing H + and bicarbonate resembles the removal of CO2 in the lung.
• the Hepa Wash ® system makes it possible to remove excess H + ions (present due to dissociation of carbonic acid into bicarbonate and H + ions). This system is therefore capable to efficiently prevent over-acidification of the blood. As indicated above, and as known to the skilled person, a blood pH values below 6.8 (over-acidification of blood) is to be avoided. This goal can be achieved with the Hepa Wash ® system. On the other hand, as also shown in this example, the dialysis device by Nikkiso is not suitable for CO 2 removal from blood upon maintenance of blood pH.
• Dialysis liquid comprisi ng calcium (Ca 2+ ions) was used, and the pH of the dialysis l iquid was altered in the range of pH 7.45 to pH 9 (see Figure 3).
• the dialysis liquid was in contact with blood via a semipermeable membrane.
• the calcium concentration in blood was determined. As can be taken from Figure 3, even in the case of a calcium concentration above 1 .70 mmol/l in the dialysis liquid, the calcium ion concentration in the blood remains within the desired range of 1 .00 - 1 .70 mmol/l. This demonstrates that the calcium ion concentration in the dialysis liquid according to the present invention is suitably in a range above 1 .70 mmol/l.

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