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
  • A61M1/1698—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
  • A61M1/14—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
  • 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
  • A61M1/32—Oxygenators without membranes
• • 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
  • A61M1/3666—Cardiac or cardiopulmonary bypass, e.g. heart-lung machines
• • 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
  • A61M1/369—Temperature treatment
• • 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
  • A61M2202/0208—Oxygen
• • 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
  • A61M2202/00—Special media to be introduced, removed or treated
  • A61M2202/03—Gases in liquid phase, e.g. cryogenic liquids
• • 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
  • A61M2202/04—Liquids
  • A61M2202/0468—Liquids non-physiological
  • A61M2202/0476—Oxygenated solutions
• • 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
  • A61M2202/06—Solids
• • 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
  • A61M2230/205—Blood composition characteristics partial oxygen pressure (P-O2)
• • 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.
• the process comprises contacting blood with a dialysis liquid via a semipermeable membrane. Either the blood or the dialysis liquid, or both, become oxygen-enriched, prior, after or simultaneously to said contacting step.
• a net transfer of oxygen from the dialysis liquid to blood occurs across the semipermeable membrane.
• the step of contacting further allows for removal of undesired substances from blood directly to the dialysis liquid across the semipermeable membrane. Thereby, an efficient extracorporeal lung support is provided.
• red blood cells erythrocytes
• the chemical entity in red blood cells that binds oxygen in the lungs is the protein hemoglobin, particularly the heme moieties of hemoglobin.
• the human or animal body produces carbon dioxide, H + ions and other metabolites.
• carbon dioxide is produced in peripheral tissues as a result of metabolic activity.
• the kidney typically accounts for a removal of approximately 100 mmol H + ions/day.
• 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 cells (erythrocytes), combines with water to form carbonic acid (H 2 CO 3 ).
• fluids such as blood must be maintained within the narrow pH range, e.g. in the human body preferably in the range of pH 7.35 to 7.45, i.e. slightly alkaline.
• the metabolites transported in the blood such as carbon dioxide (CO2), can influence the blood pH.
• 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 maintained within the narrow pH range, e.g. in 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 insufficient to maintain the blood within that pH range.
• Bicarbonate serves a crucial biochemical role i n the physiological pH buffering system.
• the healthy vertebrate (human or animal) body (a) about 5 % of carbon dioxide is transported unchanged, dissolved in the plasma; (b) about 1 0 % of carbon dioxide is transported bound to blood proteins, particularly hemoglobin and plasma proteins; and (c) the majority of carbon dioxide is transported in the form of bicarbonate ions and hydrogen cations; the hydrogen cations are mainly bound to protei ns.
• the respiratory organs of the healthy human or animal body the lungs, carbon dioxide is released; thereby the partial pressure of CO2 (pC0 2 ) is decreased.
• Normal values of pC0 2 in a (human) subject's arterial blood are in the range 35-45 mmHg.
• a pC0 2 of more than 45 mmHg is referred to herein as "high pC0 2 " or "increased pC0 2 ".
• Hypoventi lation is one possible cause of high pCC>2. If the pC0 2 in a subject's arterial blood is higher than 45 mmHg, the subject may need a treatment in order to reduce pC0 2 .
• acidosis refers to an increased acidity in the mammalian body. Acidosis can be determined by measuri ng the pH of a subject's bodi ly 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.
• subjects suffering from acidosis can be grouped i nto two major subgroups, based on the molecular causes of acidity in the blood plasma: respiratory acidosis and metabolic acidosis.
• Metabolic acidosis on a molecular level, is caused by an i ncreased amount of acidic organic molecules, caused by increased production of organic acids (e.g. lactic acid) as a result of increased metabol ic activity and/or by disturbances in the ability to excrete acid via the kidneys.
• Respiratory acidosis on a molecular level, results from a build-up of carbon dioxide in the blood due to decreased venti lation (hypoventi lation). It is usually caused by malfunction of the lungs.
• 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.
• Mechanical ventilation is a method to mechanically assist or replace spontaneous breathing, i.e. a method of lung support.
• Mechanical ventilation 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 ("invasive mechanical ventilation"), i.e. either penetrating through the mouth (such as an endotracheal tube) or penetrating through the skin (such as a tracheostomy tube).
• invasive mechanical ventilation a device penetrating into the subject's body
• penetrating through the mouth such as an endotracheal tube
• penetrating through the skin such as a tracheostomy tube.
• positive pressure ventilation where a gas (e.g. air) is pushed into the trachea
• negative pressure ventilation e.g.
• undesired consequences can include, without limitation, the following: reduction in blood perfusion of internal organs, e.g.
• liver by up to 30 %, decrease in blood pressure, increase in intra-abdominal pressure, decrease in the excretory renal function, ventilator-induced lung injury (VILI), barotrauma, volutrauma, atelectrauma, and biotrauma, acute respiratory distress syndrome (ARDS), pneumonia, dyspnea of sedated subjects treated in an intensive care unit (ICU), weaning after about 48h ventilation (see e.g. Larsen and ZiegenfuB, Beatmung, Springer, Berlin Heidelberg, 2013; and Schmidt et al., Intensive Care Med., vol. 40, , pp. 1 -10, 2014).
• 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), which al lows for oxygenation of the blood.
• a membrane porous membrane for short term treatments or a non-porous membrane for long term treatments
• gas phase oxygen, or gas mixture comprising oxygen
• 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 i ncluding a pump in the system (ECLS, extracorporeal life support).
• ECLS extracorporeal life support
• oxygen can be i ntroduced directly into extracorporeal blood, e.g. by means of an oxygen (super)saturated liquid, as described i n US 6,344,489 ⁇ (Wayne State University) and US 6,607,698 B1 (Therox/Wayne State University).
• ECCO 2 R extracorporeal carbon dioxide removal
• Such treatment can be indicated e.g. in case of respiratory acidosis.
• ECCO2R systems typically rely on the use of a gas exchange membrane, across which carbon dioxide diffuses from the extracorporeal blood into a gas chamber.
• the AV-ECCO 2 R system (Novalung, Germany) is by far the most widely used ECCO 2 R technique.
• WO 2010/091 867 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.
• the efficiency of both blood oxygenation and blood carbon dioxide removal is dependent on the blood flow rate, and the following holds: the higher the blood flow rate, the better the oxygenation for the whole 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 (suitable for ECMO) refers to > 2400 ml/min
• mid-flow (suitable for both ECMO and ECCO2R) refers to 800- 2400 ml/min
• low flow (suitable for ECC0 2 R) refers to ⁇ 800 ml/min.
• a lower blood flow rate than for ECMO i.e.
• Liquid breathing is an alternative form of lung support in the state of the art.
• an organism e.g. human
• breathes an oxygen-rich liquid such as a perfluorocarbon
• TLV total liquid ventilation
• PLV partial liquid ventilation
• PFC perfluorocarbon
• the withdrawal of a subject's blood into an extracorporeal circuit is practiced not only for the purposes of lung support (oxygenation and/or CO 2 removal), but alternatively for the purpose of supporting other organs, such as liver or kidney.
• Such methods typically involve the contacting of blood with a dialysis liquid across a semipermeable membrane, thus allowing the transfer of the undesired substances from the blood along the concentration gradient to the dialysis liquid, and optionally of desired substances in the opposite direction.
• kidney support and/or liver support are directed at other purposes, i.e. kidney support and/or liver support.
• dialysis for kidney support can be indicated in case of acidosis, which can result from chronic renal failure (CRF).
• WO 03/094998 A1 (Hepa Wash) 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, both for the purpose of binding of toxins to albumin.
• These prior art methods are, however, not directed at an efficient removal of carbon dioxide (C0 2 ), hydrogen cation (H + ) and hydrogen carbonate (HC0 3 ⁇ ), nor at oxygenating blood.
• C0 2 carbon dioxide
• H + hydrogen cation
• HC0 3 ⁇ hydrogen carbonate
• the object of the present invention is to provide a novel method suitable for extracorporeal lung support, which provides for oxygenation as well as carbon dioxide removal (ECCO2R). It is also desired to overcome the disadvantages associated with blood air contact in traditional membrane gas exchange devices (e.g. ECCO 2 R and ECMO). It is also an object of the invention to provide a lung support with superior quantitative capabilities: for lung support, the removal of CO 2 (or alternatively or additionally the removal of the HVbicarbonate ion pair) has to be in the mmol range. It is thus an object to achieve combined removal of H + ions and bicarbonate in superior quantities, i.e. in that range. It is yet a further object to provide a single device capable of solving these objects.
• the present invention provides a superior method for extracorporeal lung support. Further advantages of the present invention are associated with elements of the invention which are described in the detailed 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:
• Bohr effect In general, the binding affinity of oxygen to hemoglobin is influenced by the pH (and thus by the concentration of hydrogen cations) and by the partial pressure of carbon dioxide (pC0 2 ). Thus, oxygenation of hemoglobin and carbon dioxide removal from hemoglobin mutually influence each other. This phenomenon is referred to as Bohr effect.
• Bohr effect For reference, as well as for further aspects of the Bohr effect, see R. F. Schmidt, F. Lang, and M. Heckmann, Eds., Physiologie desteil. Berlin, Heidelberg: Springer Berlin Heidelberg, 201 1 ; and J. B. West, Respiratory Physiology: The Essentials. Lippincott Williams & Wilkins, 2012.
• the process of the present invention requires at least a chamber for blood (first chamber) and a chamber for dialysis l iquid (second chamber). Specific embodiments are provided in the detailed description.
• No. 1 2-1 5 or one of these into No. 1 6 may be realized.
• No. 1 2-14 can be combined by one unit or realized separately.
• No. 6-8 and 1 0-1 2 can be realized or just one, two or any combination of these.
• No. 5 can precede No. 1 0, positioned in between No. 1 0 and No. 1 , in between No. 1 and No. 1 1 and fol lowing No. 1 1 .
• No. 4 can be located i n between No. 2, No. 3 and No. 12-1 6.
• No. 1 2 can be located ahead of or fol lowing No. 1 3 in the dialysis liquid flow path, but is located preferably fol lowing No. 14.
• No. 14 preferably follows No. 1 3 in the dialysis liquid flow path.
• the present i nventors found that advantages over conventional methods or processes for extracorporeal lung support, which rely on a gas phase for lung support, can be achieved by using a l iquid dialysis fluid (dialysis liquid) in a method for extracorporeal lung support.
• This method al lows to effectively oxygenate blood, to remove carbon dioxide from the blood and/or to adjust the blood pH to a desi red or normal value and/or to adjust (increase or decrease) the bicarbonate concentration in the blood. Therefore the method enables an efficient and versatile lung support, and can support further organs, based on the needs of individual subjects.
• the present invention is, however, not limited to a particular choice effect or to a particular theory for explaini ng any of these effects. More general ly speaking, the i nvention is based inter alia on the discovery that the binding of certain substances to hemoglobin can be favorably exploited when blood is contacted with a dialysis liquid as defined herein and blood is directly or indirectly oxygenated as described herein.
• the dissociated hydrogen cation reacts with bicarbonate (HCO 3 ) to form carbonic acid (H2CO3), and said carbonic acid further reacts - typical ly aided by the enzyme carboanhydrase which is present in erythrocytes - to water and CO 2 , the binding of oxygen to hemoglobin favors the shifting of the bicarbonate buffer equilibrium towards CO 2 formation.
• CO2 is then typical ly released from the red blood cells as a consequence of oxygenation of hemoglobin.
• Bohr effect The fact that the binding affinity of oxygen to hemoglobin is influenced by the pH (and thus by the concentration of hydrogen cations) and by the partial pressure of carbon dioxide (pCCh) is also referred to as Bohr effect.
• the process of the invention does not require a gas exchange membrane (i.e. a membrane having on at least one side blood and on the other side a gas phase). Instead, the removal of the undesired substance occurs across a semipermeable membrane having a liquid on both sides of the semipermeable membrane, i.e. blood on one side and a dialysis liquid on the respective other side.
• the present invention enables separate regulation and control of the oxygenation and of removal of the at least one undesired substance.
• the present invention enables to adjust a specific carbon dioxide removal rate, oxygenation or (over)oxygenation rate of the blood and to adjust the blood pH to a desired level.
• the present invention thus provides (i) a process oxygenating blood, comprising the step of exposing blood to a dialysis liquid separated by a semipermeable membrane, wherein the dialysis liquid has the properties or preferred properties defined herein; and (b) a process oxygenating blood, comprising the steps: (i) introducing 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, (ii) introducing a dialysis liquid into a second chamber of said device, wherein the dialysis liquid being introduced into the second chamber.
• 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 liquids.
• step (i) precedes step (ii).
• steps (i) and (ii) are carried out simultaneously.
• either the blood or the dialysis liquid, or both become oxygen- enriched in step (i).
• a net transfer of oxygen from the dialysis liquid to blood occurs across the semipermeable membrane during the step of contacting.
• the step of contacting further allows for the removal of undesired substances from blood directly into the dialysis liquid.
• the flow of blood and the flow of dialysis liquid are preferably not realized in counter-current mode; i.e. blood and dialysis liquids do not flow in opposite directions to each other.
• dialysis liquid and blood flow in the same direction through the device of the present invention (co-current).
• the co-current mode is particularly preferably when the blood is cooled to a temperature below 37 °C.
• the blood plasma concentration of carbonate, the blood plasma concentration of bicarbonate, and the ratio of carbonate to bicarbonate in the blood plasma are also possible to adjust the blood plasma concentration of carbonate, the blood plasma concentration of bicarbonate, and the ratio of carbonate to bicarbonate in the blood plasma, (a) by using an appropriate dialysis liquid within the framework of the present invention, and (b) by oxygenating blood, thereby causing removal of an undesired substance from blood.
• the ratio of carbonate to bicarbonate in the blood plasma is dependent on pH and can be influenced by choosing a dialysis liquid with an appropriate pH.
• 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.
• the process of the present invention comprises the step of introducing oxygen into blood and/or into the dialysis liquid according to the present invention. If oxygen is introduced into the dialysis liquid, it is typical that the oxygen is introduced into the dialysis liquid in a step preceding or parallel to the step of exposing blood to the dialysis liquid separated by the semipermeable membrane. Thereby, a net transfer of at least a fraction of said oxygen occurs from the dialysis liquid to the blood.
• the step of introducing oxygen into (said deoxygenated) blood and/or into a dialysis liquid is followed by - or concurrent with - a step of contacting blood and dialysis liquid via a semipermeable membrane, allows transfer of small molecules including oxygen across the semipermeable membrane.
• Either location of the oxygenation step may result in oxygenated blood, i.e. blood having an increased oxygen concentration.
• a step of "direct" oxidation of blood is provided; for introduction of oxygen into the dialysis liquid, a step of "indirect” oxidation of blood is provided.
• at least one site for oxygen to be introduced is typically provided along the flow path of e.g. dialysis liquid or blood.
• Introduction preferably infusion of gaseous oxygen into blood and/or dialysis liquid, respectively.
• the introduction can be implemented e.g. by means of a bubble oxygenator.
• infusion generally refers to the i ntroduction of a fluid (l iquid or gas, as the case may be) i nto another fluid, i.e. i nto dialysis liquid or into blood.
• oxygen-enriched liquid of a desired degree of oxygenation can be prepared and provided. Said liquid can subsequently be used for oxygenating blood and/or dialysis liquid. It is possible to use an oxygen-super-saturated or oxygen-over-saturated liquid, havi ng increased oxygen partial pressure.
• Such liquid is prepared at high pressure, typically significantly higher than normal atmospheric pressure.
• oxygen supersaturated liquid can be passed through one or more capillaries.
• Suitable capillaries have an inner diameter (ID) of 0.012 - 1000 ⁇ and a length of 0.1 mm - 1 100 mm.
• ID inner diameter
• any capillary has its specific flow rate of oxygen supersaturated liquid, as a function of its inner diameter, length, pressure difference and the liquid, the total flow rate can be increased by using several capillaries in parallel.
• Flow rate, and thus oxygenation can preferably be adjusted by varying the pressure of the oxygen-enriched liquid. This influences concentration of dissolved oxygen in the respective liquid.
• the oxygen solubility in a liquid is preferably increased by increasing the gas pressure, increasing or decreasing the temperature, decreasing the ion concentration and ionization of the used gas.
• the volume of extracorporeal blood typically increases. It is typically not desired to increase the total amount of blood of a human or animal that is being treated. Therefore, subsequent reduction of blood volume is desired under such circumstances. Thus, reduction of the blood volume at any stage before re-introducing blood into the subject is typically implemented under such circumstances. Reduction of blood volume can be achieved e.g. by filtration. Thereby, it is possible to not enrich the human or animal subject with liquid, i.e. not to hyper-hydrate or not to overwater the human or animal subject. This is particularly important during long term treatment.
• liquid oxygen is preferably directly introduced into the dialysis liquid. It is conceivable that such introduction contributes to cooling of the dialysis liquid. This can be preferred for such embodiments.
• the oxygen can be passed through one or more fine tubes or capillaries.
• oxygen is typically in gaseous form.
• oversatu rating blood with oxygen is usually not envisaged because oxygen gas diffusion is driven by the concentration gradient.
• the oxygen concentration of the dialysis liquid and/or of any oxygen-enriched liquid (e.g. blood plasma) other than blood, which is brought into contact with blood in the process of the present invention is preferably at least as high as the desired oxygen concentration of the blood plasma.
• introduction of oxygen is preferably realized prior to the step of contacting the dialysis l iquid with blood via the semipermeable membrane, i.e. be fore the dialysis l iquid is passed through the device for dialysis.
• introduction of oxygen is realized in parallel to the step of contacting the dialysis liquid with blood via the semipermeable membrane. In that case, introduction of oxygen across an oxygen- permeable membrane according to (3) above is most preferred.
• a separate (third) chamber may preferably be provided in the device for dialysis.
• the device of the present invention preferably comprises - in addition to the first chamber for receiving blood and the second chamber for receivi ng dialysis liquid - a third chamber for receivi ng oxygen (e.g. oxygen gas, gaseous mixture comprising oxygen, oxygen-enriched l iquid or oxygen dissolved in a l iquid).
• a third chamber for receivi ng oxygen e.g. oxygen gas, gaseous mixture comprising oxygen, oxygen-enriched l iquid or oxygen dissolved in a l iquid.
• the i ntroduction of oxygen into the extracorporeal blood should be adjusted, i .e. preferably adjusted to the extracorporeal blood flow rate. If the oxygen is introduced into the dialysis liquid, the dialysis l iquid flow rate and the amount of oxygen introduced should be adjusted, i.e. preferably adjusted to the extracorporeal blood flow rate.
• the step of contacting blood and dialysis liquid via the semipermeable membrane is typically not foreseen at all, or foreseen only as an additional measure, i.e. in addition to introduction foreseen in addition to in a step before the step of contacting blood and dialysis l iquid via the semipermeable membrane.
• oxygen is introduced in at least two sites, i .e. one preceding the step of blood/dialysis liquid contact, and one following the step of blood/dialysis l iquid contact.
• an oxygen-enriched dialysis liquid can be prepared prior to contacting of blood via the semipermeable membrane (introduction of oxygen at position no. 1 0 in Fig. 2, see also Example 3), or oxygen-enriched blood can be prepared prior to contacting of dialysis l iquid via the semipermeable membrane (introduction of oxygen at position no. 1 2 in Fig. 2).
• the introduction of oxygen after said contacting step is possible, but preferably not as the only site of oxygenation.
• no gas bubbles e.g.
• the dialysis liquid is passed through or passed along at least one bubble trap upon said step of introducing oxygen, but preceding the step of contacting blood and dialysis l iquid via the semipermeable membrane.
• the bubble trap is suitably local ized at a position in the extracorporeal blood flow path, which is behind (after) the place where oxygen is introduced into the dialysis liquid, but ahead of (before) the device for dialysis.
• a bubble trap may be dispensable because, typical ly, oxygen dissolves sufficiently wel l or sufficiently quickly in the blood.
• the blood is preferably passed through or passed along at least one bubble trap before the blood is reintroduced into the patient.
• the bubble trap is suitably local ized at a site of the extracorporeal blood flow path, which fol lows the device for dialysis and is also localized past (after) the site where oxygen is introduced.
• the dialysis liquid is characterized by a pH the range from pH 6.8 to pH 1 1 ; and comprises albumin, preferably 10 to 60 g/l 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
• 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 has not been recognized or exploited in the art.
• 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 single type of albumin (e.g. human serum albumin) or a mixture of various types of albumin is being employed.
• the dialysis liquid used in the present invention comprises 10 to 60 g/l albumin, preferably 10 to 40 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.
• concentration of albumin can also be indicated as % value; i.e. 2 g/100 ml albumin corresponds to 2 % albumin (wt./vol).
• Albumin is a second buffering agent in the dialysis liquid according to the present invention.
• the albumin in the dialysis liquid contributes to its buffering capacity, and binds carbonate in the form of carbamino groups.
• the dialysis liquid typically comprises water. Typically 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 liquid described herein is a subject of the present invention. Buffering agent comprised in the dialysis liquid
• albumin is not the only buffering agent present in the dialysis liquid.
• the dialysis liquid comprises at least one additional buffering agent, wherein the buffering agent is characterized by at least one pKa value in the range from 7.0 to 1 1 .0.
• the use of a buffered dialysis liquid in general, and of the specific dialysis liquid of the present invention in particular, allows to perform carbon dioxide removal in a pH range which is not detrimental to blood, while 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.
• Suitable buffering agents to be comprised in the dialysis liquid include i n particular any one or more of the fol lowing: Tris(hydroxymethyl)aminomethane (Tris, THAM) and carbonate/bicarbonate.
• 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 wi l l typically be dictated by the pH of the composition.
• Carbonate/bicarbonate is a suitable additional buffering agent.
• the carbonate/bicarbonate pair is known to provide physiological pH bufferi ng system.
• Bicarbonate-containing dialysis liquids, without albumin, have been previously described in the art.
• the (combined) carbonate/bicarbonate concentration of the dialysis liquid is preferably defined for the dialysis liquid at the stage immediately preceding the contacti ng of blood, e.g. at the stage wherein the dialysis liquid enters the second chamber of a dialysis unit as described herein.
• a suitable total concentration of carbonate/bicarbonate (combi ned concentration of both substances together) is 0 to 40 mmol/l.
• bicarbonate can be added i n the form of any of its salts, such as sodium bicarbonate, potassium bicarbonate, and others, or alternatively be added indirectly by introducing carbon dioxide, optional ly in the presence of carbonic anhydrase, and adjusti ng 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.
• preferred (combined) carbonate/bicarbonate concentrations in the dialysis liquid lie in the range from more than 0 (e.g. 1 ) to 40 mmol/l, preferably 1 0 to 35 mmol/l, more preferably 1 5 to 30 mmol/l, and most preferably at or about 20 to 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 1 0 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.
• Tris(hydroxymethyl)aminomethane usually called “Tris”.
• Tris(hydroxymethyl)aminomethane is also known as "THAM". Tris is an organic compound with the formula (HOCH 2 ) 3 CNH 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. 1 61 : 1 149-1 1 53; Hoste et al., J. Nephrol. 1 8: 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 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.
• 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.
• 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 10 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 water-soluble protein in addition to albumin, is suitable for the purposes of the present invention if it has at least one imidazole (histidine side) chain and/or at least one amino group (lysine) side chain 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 10 g/l of the protein is soluble in aqueous solution having a pH within the range of the dialysis liquid 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 following.
• a preferred dialysis liquid according to the present invention comprises both (i) carbonate/bicarbonate and (ii) albumin; or both (i) Tris and (ii) albumin. Particularly, when no carbonate/bicarbonate is added to the dialysis liquid
• Tris is the only buffering agent comprised in the dialysis liquid.
• a preferred dialysis liquid according to the present invention comprises both (i) carbonate/bicarbonate and (ii) albumin; or both (i) Tris and (ii) albumin.
• An alternative preferred dialysis liquid comprises Tris as the only buffering agent, i.e. does not contain added carbonate/bicarbonate or albumin.
• the present invention is advantageous compared to previous uses of carbonate-containing dialysis liquids, inter alia because the buffering capacity albumin can be taken advantage of.
• 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), 10 to 60 g/l albumin (i.e. 1 to 6 g/1 00 ml albumin), and has a pH the range from pH 7.75 to pH 1 1 .0, preferably pH 8.0 to pH 1 0.0, and more preferably pH 8.0 to pH 9.0.
• Preferred Tris concentrations are as specified above.
• 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 i n include proteins, particularly water-soluble proteins, or amino acids, or Tris; and suitable additional i norganic buffering molecules include H PO 4 2 7H 2 PO 4 -.
• the dialysis liquid used in the present i nvention has a high buffering capacity for H + ions, e.g. a buffering capacity for H + ions which is 1 2 mmol/l H + ions or more.
• a buffering capacity for H + ions which is 1 2 mmol/l H + ions or more is typical ly a buffering capacity which exceeds the buffering of blood plasma (pH 7.45; see Example 1 ).
• the buffering capacity of the dialysis liquid typical ly exceeds the buffering of blood plasma (pH 7.45).
• the bufferi ng capacity of the dialysis liquid is typically a buffering capacity for 1 2 mmol/l or more H + ions.
• buffering capacity for H + ions or simply “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 such a liquid.
• the determination of buffering capacity of blood plasma requires a step of centrifugation; the centrifugation results in pel leting 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 reachi ng 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 i n 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.
• a solution havi ng a pH of 6.5 would have a bufferi ng capacity for H + ions of zero mmol/l (0 mmol/).
• the dialysis liquids of the present invention typically have a pH higher than 6.5, i.e. as defi ned herein; and therefore, they do have a bufferi ng capacity for H + ions.
• the bufferi ng capacity is 1 2 mmol/l H + ions or more. Even more preferred are buffering capacities higher than that, i.e.
• H + ions 12 mmol/l or more, 1 4 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 12 to 50 mmol/l, more than 12 to 40 mmol/, 1 3 to 30 mmol/l, 14 to 25 mmol/l, 1 5 to 24 mmol/l, 16 to 23 mmol/l, 1 7 to 22 mmol/l, 18 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 6.8 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:
• the liquid is subjected to titration with HCI.
• HCI 0.1 M HCI
• 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
• 0.1 M 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. If 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.
• 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 i n step 2 (mrnol/1) is compared to a reference value. Suitable reference values are 1 0 mmol/l; 1 1 mmol/l, 1 2 mmol/l, 1 3 mmol/l, 1 4 mmol/l; whereby 1 2 mmol/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 determi ned as described in above step 2.
• the present invention thus allows for preferential removal of carbon dioxide, or for preferential adjustment of the blood pH, or both.
• This versati lity 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.
• 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 exposed surface area of the semipermeable membrane can be in the range from 0.01 m 2 to 6 m 2 .
• a (combined) 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 semipermeable membrane contains carbonic anhydrase activity. This can be achieved by coating the membrane, on the blood-facing side and/or on the side facing the dialysis liquid, 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, separated by a semipermeable membrane.
• the first 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 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 second chamber does substantial ly not comprise any gas phase, i.e. is fil led substantially solely with dialysis l iquid in the l iquid 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 simi lar device.
• the semipermeable membrane used in the present invention is not particularly l imited, as long as it is permeable for water and inorganic molecules solubi lized 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 from 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.
• the following further features and parameters are suitable for use in connection with the dialysis unit, i.e. in the device comprising the first chamber, the second chamber and the semipermeable membrane.
• 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 desired to recycle albumin-containing dialysis liquid. In other words, the recycling can result in major cost savings.
• the recycling enables also having a high dialysis liquid flow rate of up to 4000 ml/min.
• recycling of the dialysis liquid requires the cleaning or regeneration of the dialysis liquid.
• cleaning or regeneration is achieved by at least one type of treatment step in order to remove undesired substances from the dialysis liquid (i.e. used dialysis liquid) prior to re-entry into 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 (iii) acidic pH and/or basic pH (iv) and/or exposure to a permeable or semipermeable membrane (i.e.
• any one or more of such treatment steps can be conducted in series or in parallel (i.e. upon dividing the dialysis liquid). It is possible to foresee that the dialysis liquid is subjected to treatment or purification after being exposed to the blood separated by the semipermeable membrane, i.e. after exiting 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 i n row or in paral lel.
• 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 be selected from constant or varying (changing) over time.
• the flow-rate is not generally limited.
• the blood flows through the first chamber at a low-flow flow-rate (less than 800 ml/min; preferably 1 00 to 800 ml/min), at a mid-flow flow-rate (800 to 2400 ml/min), or at a high-flow flow-rate (more than 2400 ml/min).
• the blood flow rate is typically controlled and regulated and may be adjusted to the treatment conditions and to the dialysis liquid.
• mid-flow is most preferred.
• a low-flow and/or mid-flow treatment is easier to handle for the operator than high- flow, and is less risky for the patient than high-flow.
• additional lung protective venti lation is dispensable; this is a major advantage compared to state of the art mid-flow devices, which usually require additional LPV.
• the high rate of oxygenation at mid-flow flow rate according to the present invention is possible due to the transfer of undesired substances, such as carbon dioxide to the liquid phase, and due to potential i ntroduction of excess oxygen to blood (to supersaturate blood with oxygen).
• Such prior art mid-flow systems are disadvantageous firstly because they usually have to be used in combination with lung protective ventilation (LPV).
• Mechanical ventilation methods are, however, associated with the risk of activation of platelets, inflammation, blood clotting and through so might lead to lethality (Assmann et al., Zeitschrift fur Herz-,Thorax- und GefaB composition, vol. 23, no. 4, pp. 229-234, Jul. 2009).
• Another disadvantage of combination of prior art systems with LPV is the limited staff and space capacity at hospitals and care providers; however, the combination of protective ventilation and extracorporeal lung support would require at least two devices in parallel.
• the process of the present invention is advantageously carried out without parallel LPV.
• an additional lung protective ventilation (LPV) which is common for prior art mid-flow devices, is dispensable.
• High-flow flow rates are also possible in the present invention.
• a cannulation of larger vessels is necessary, which has to be conducted by a specialist and is associated with certain health risks. That is one of the reasons, why mid- flow flow-rates are considered advantageous in the present invention.
• a pump may be provided to direct or control the flow rate of blood.
• a pump is typically provided to direct or control the flow rate of the dialysis liquid.
• 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 from 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. Higher flow rates of the dialysis liquid generally enable efficient transfer of bicarbonate/carbonate.
• 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 preferably not conveyed in counter-current, i.e. are preferably 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 ( Figure 2C no. 1 5).
• This is ideally foreseen in a discrete step, i.e. a step after the dialysis liquid exits the second chamber (outlet).
• the means for these purposes are not particularly limited, as long as they are suitable.
• the process according to the present invention is conducted such that the recycling includes acidification of the dialysis liquid to acidic pH, for formation of carbon dioxide, and removal of carbon dioxide from the dialysis liquid across a carbon dioxide-permeable membrane by means of a bubble trap.
• the membrane is gas- permeable, and carbon dioxide is removed in the gas phase.
• albumin is commercially available, but relatively expensive. Therefore, albumin-based dialysis liquids can incur high process costs.
• recycling of albumin-containing dialysis liquid has been described for the case of liver dialysis, e.g. in WO 03/094998 A1 , incorporated herein by reference in its entirety.
• albumin can be recycled based on the principle that the binding affinity 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 usi ng fi lters permeable of said components. Diafi ltration-mediated removal of such components al lows for subsequent recycling of the albumin.
• albumi n can be efficiently regenerated in a dialysis regeneration unit having two parallel dialysis l iquid flow paths, i .e. an acidic flow path and an alkaline flow path in paral lel (WO 09/071 1 03 A1 ).
• the process and device (e.g. dialysis l iquid regeneration unit, dialysis unit) described in WO 09/071 1 03 A1 are also suitable for recycling albumin-containing dialysis l iquid i n the process of the present invention; WO 09/071 1 03 A1 is therefore i ncorporated herein by reference in its entirety 1 .
• the free toxins are removed from the acidified dialysis l iquid flowing in the first flow path.
• an acidic fluid to the dialysis l iquid
• removal of acidic soluble toxins is enabled.
• 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 l iquid flowi ng in the second flow path.
• the dialysis l iquid regeneration unit is capable of efficiently removing protein-bindi ng toxins.
• toxi n is understood very broadly herein and encompasses all protei n-binding substances, even if they are usual ly not directly toxic (causi ng health issues) as such, such as drugs, electrolytes, H + , hormones, fats, vitamins, gases, and metabol ic degradation products l ike bi lirubi n.
• 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 liquid from the first flow path and the alkal ized dialysis liquid from the second flow path may neutral ize one another at least partially.
• a flow of regenerated dialysis l iquid 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, and acetic acid.
• the first supply unit is adapted for adjusti ng the pH of the dialysis l iquid 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, and 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 from 7 to 1 3, preferably from 8 to 1 3, more preferably from 8 to 1 1 .
• the acidic fluid and the alkali ne fluid are chosen such that "physiological" neutralization products are generated during neutral ization.
• a certain concentration of the formed neutralization products might already be present in the respective biological fluid anyway.
• amounts of NaCl occur by neutralization of the acidified flow and the alkalized flow.
• NaCI is typically also present in a biological fluid, like e.g. blood or blood serum.
• a concentration ratio of toxi n-carrier-complex to free toxin and free carrier substance is shifted i n favour of the free toxin for at least some of the toxins in the dialysis liquid, thereby increasing a concentration of free toxi ns i n the dialysis liquid.
• the detoxification unit is adapted for at least partially removing said free toxins. Due to the i ncreased concentration of free toxins, said toxins may be removed at an increased rate. Furthermore, by decreasing the pH value of the dialysis liquid in the first flow path, some of 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 l imited, 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.
• carbon dioxide is removed, either as a gas or in the state of being dissolved in a l iquid.
• One particularly suitable way of removi ng carbon dioxide consists of bri nging the dialysis liquid into contact with a membrane which is permeable for carbon dioxide.
• the dialysis l iquid has a certai n pressure pi, and the pressure of the fluid (liquid or gas) on the other side of said membrane, p 2 , is lower, i.e. p 2 ⁇ pi -
• the object of CO 2 removal from the used dialysis liquid can also, or alternatively, be achieved if the partial pressure of CO 2 is lower in the fluid on the other side of said membrane. Simi larly, it is possible to remove hydrogen carbonate along a concentration gradient, i.e.
• 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 livi ng subject, i.e. serving a medical purpose, may be referred to as a medical method or medical use.
• 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 i nvention can involve any and al l 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 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.
• the present invention enables extracorporeal oxygenation as wel l as extracorporeal removal of at least one undesired substance, such as carbon dioxide or bicarbonate or hydrogen cations. Therefore, the present invention provides a ful l lung support and it particularly suites for that patient group.
• the present invention provides a significant improvement.
• the proper functioning of the kidneys is affected in patients suffering from kidney failure.
• the present invention also enables the treatment of kidney failure, and of multi-organ failure.
• the present invention provides a further advantage over the prior art because, instead of two separate devices, one for treating lung failure and one for treating kidney failure, only one single device is used.
• the single device comprises the first and second chamber for contacting blood and dialysis liquid separated by the semipermeable membrane in the process of the present invention.
• the conditions are suitably selected from the conditions described herein for any of respiratory or metabol ic acidosis, preferably those described for metabolic acidosis.
• an adsorber which is suitable for bindi ng or 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).
• the dialysis liquid can be adapted specifical ly to in order to maintain desired levels of the respective solute(s).
• the dialysis liquid contains either (i) more or (ii) less of the respective solute(s) than the desired blood concentration of the respective solute(s), depending on whether it is desired to (i) i ncrease or to (i i) decrease the concentration of the respective solute(s) i n blood of the subject being treated.
• the dialysis liquid is preferably selected such that its pH and/or buffering capacity is/are adapted to such goal: for example, the pH may be in the range of pH 8.0 to 1 1 .0, and/or the buffering capacity for H + ions may be 12 mmol/l or more. Further aspects of treating acidosis are described in the following.
• the present invention also al lows for treating subjects suffering from acute or chronic liver failure in addition to lung failure and/or kidney failure.
• Typical treatment in accordance with the present i nvention involves extracorporeal toxin removal .
• the methods described i n WO 2009/071 1 03 A1 and/or WO 03/094998 A1 or the methods made avai lable through the company Hepa Wash (Munich, Germany), can be modified such that the dialysis l iquid compl ies 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 l iver insufficiency) but also buffers the dialysis liquid, together with carbonate (which addresses lung i nsufficiency). That means, that in addition to the functionalities described in WO 2009/071 1 03 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 si ngle 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.
• 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 l iquid at the stage of entering the second chamber, suitably contains a low (combined) carbonate/bicarbonate concentration, in the range from 0 to maximally 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 i n include 1 to 35 mmol/l, 2 to 30 mmol/l, 3 to 25 mmol/l, 4 to 20 mmol/l, 5 to 1 5 mmol/l, e.g. 1 0 mmol/l .
• I n general, a (combined) carbonate/bicarbonate concentration at the lower end of the above range or subrange allows for efficient removal of withdrawal of undesired substances, such as bicarbonate, CO2 and carbonate, from the blood.
• the dialysis l iquid for treatment of that patient group is suitably adjusted to have a buffering capacity of at least 1 2 mmol/l, as defined herein.
• the treatment of acidosis patients together with blood oxygenation typical ly requires addition of 2,3-DPC to the dialysis liquid, as described above. This is because acidosis patients typical ly produce less 2,3-DPG than healthy subjects.
• the blood typically 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 kidney oftentimes reacts, with some delay of e.g. 3 weeks, by production of i ncreased amounts of bicarbonate.
• the present invention allows to treat subjects suffering from respiratory acidosis during the entire course of the disease, i.e. at early stages when mai nly the removal of excess CO2 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. It is also possible to gradually increase the (combined) carbonate/bicarbonate concentration over the course of treatment, within the range of the present invention (0 to 40 mmol/l).
• the oxygenation of step of the process of the present i nvention contributes to the release of H + ions and of CO 2 from hemoglobi n.
• the molecular reason is the extracorporeal exploitation of the Haldane effect, as described above.
• the oxygenation step renders the removal of these undesired substances from blood very efficient. This is a major improvement over prior art methods.
• organic acids can originate for example from amino acid residues of protein catabol ism or from accumulation of ketoacids (ketosis) during starvation or in diabetic acidosis.
• ketoacids ketoacids
• Whi le in many instances, the affected body attempts compensating metabolic acidosis by respiration (respiratory compensation), non-volati le metabol ites are not excreted by this route, and affected subjects are at risk for exhaustion leadi ng to respiratory fai lure.
• the present invention provides a solution: Either as a preventive measure, or as a therapeutic measure, i.e.
• a treatment by the method of the present invention may be i ndicated:
• a high pH of the dialysis liquid is desired, e.g. pH 8.0 to 1 1 .0, preferably pH 8.0 to 9.0 for the treatment of subjects suffering from metabolic acidosis.
• the buffering capacity of the dialysis l iquid is higher than the bufferi ng capacity of blood plasma.
• the combi nation of high pH of the dialysis liquid and high bufferi ng capacity of the dialysis l iquid allows 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. In particular, the flux can be increased compared to standard dialysis methods.
• the treatment of acidosis patients together with blood oxygenation typically requires addition of 2,3-DPG to the dialysis liquid, as described above. This is because acidosis patients typical ly produce less 2,3-DPG than healthy subjects.
• the blood typically has a pH in the range of desired to adjust the blood pH to a range or value encompassi ng 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 dialysis liquid at the stage of enteri ng the second chamber, suitably contains carbonate as an additional buffering agent.
• the present invention also allows for the treatment of a condition characterized by a combination of respiratory acidosis and metabol ic acidosis. This is possible because the dialysis liquid, particularly the pH and the (combined) carbonate/bicarbonate concentration in the dialysis l iquid, can be adjusted to individual needs.
• the dialysis liquid preferably does not contain any added carbonate/bicarbonate.
• a suitable dialysis l iquid for that type of patients suitably contains a (combined) carbonate/bicarbonate concentration i n the range from 0 to 5 mmol/l (preferably 0 mmol/l).
• the buffering capacity is provided by albumin alone; or by albumin and a further suitable non-carbonate/non-bicarbonate bufferi ng agent, e.g. Tris, within the concentration range defined above.
• subjects suffering from lung failure and/or from inefficient gas exchange in the lungs are also affected by dysfunction of other organs.
• the methods of the present invention are also suitable for treating such subjects, and thus to support these organs.
• cardiovascular disease particularly impaired function of the heart and thus impaired blood flow
• the blood transport to the lungs is oftentimes inefficient.
• suffering from such a cardiovascular condition as a consequence of said cardiovascular condition, also suffer from impaired gas exchange in the lungs, i.e. impaired carbon dioxide release in the lungs and/or impaired blood oxygenation in the lungs.
• the present invention allows to treat not only the consequence (impaired gas exchange in the lungs), but also the reason (cardiovascular disease, e.g. impaired function of the heart and thus impaired blood flow).
• a pump is provided either before the first chamber or after the first chamber. The pump moves the blood through the extracorporeal circuit and thus at least partially substitutes the impaired function of the heart.
• Example 1 buffering capacity of solutions comprising one or more buffering agents
• aqueous solutions comprising one or more buffering agents. These aqueous solutions are exemplary liquids, the buffering capacity of which corresponds either to dialysis liquids (dialysates) according to the present invention or to dialysis liquids (dialysates) for comparative purposes.
• exemplary dialysis liquids For the preparation of exemplary dialysis liquids according to the present invention and of reference liquids, pure water (osmosis quality) 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)aminomethane (TrisATHAM)) was added.
• albumin and/or sodium bicarbonate (“soda") and/or Tris(hydroxymethyl)aminomethane (TrisATHAM) was added.
• albumin and/or sodium bicarbonate (“soda") and/or Tris(hydroxymethyl)aminomethane (TrisATHAM) was added.
• albumin and/or sodium bicarbonate (“soda”) and/or Tris(hydroxymethyl)aminomethane (TrisATHAM) Tris(hydroxymethyl)aminomethane
• TrisATHAM Tris(hydroxymethyl)aminomethane
• the buffering capacity determined by this assay is shown in Figure 1 .
• the buffering capacity of blood plasma was determined to be 1 2.00 mmol/l H + ions.
• exemplary l iquids accordi ng to the present i nvention are characterized by a buffering capacity (in mmol/l) superior to the buffering capacity of blood plasma, as determined by this assay.
• the dialysis liquid according to the present invention provides excellent buffering capacity, particularly in embodiments wherein the inventive dialysis liquid has a pH above the pH of normal human blood.
• Dialysis liquid comprising calcium (Ca 2+ ions) was used, and the pH of the dialysis liquid was altered from pH 7.45 to pH 9 (see Figure 3).
• the dialysis liquid was i n contact with blood via a semipermeable membrane.
• the calcium concentration in blood was determined.
• the calcium ion concentration in the blood remai ns within the desi red range of 1 .00 - 1 .70 mmol/l.
• the calcium ion concentration in the dialysis liquid according to the present invention is suitably i n a range above 1 .70 mmol/l.
• hepari nized pig blood Five liters of hepari nized pig blood were conti nuously pumped through a model extracorporeal blood circuit (Hepa Wash LK2001 dialysis device) at a blood flow rate of 200 ml/min. Schematically, the blood passed through the first chamber (represented by no. 1 i n Figure 2A). The blood was i n contact to a dialysis liquid over a semipermeable membrane.
• the blood was recycled. However, i n order to mimic deoxygenated blood from a patient in need of lung support, and in order to keep the oxygen saturation of hemoglobin of the blood entering the first chamber constant, the blood was continuously deoxygenated. This ensured that the blood entering the first chamber had an oxygen saturation (0 2 Hb pre) of about 60 to 70 % (see Figure 4).
• the dialysis liquid had a pH of 7.45.
• the dialysis liquid flow rate was set at 1 000 ml/min.
• the dialysis liquid passed through the second chamber (represented by no. 2 in Figure 2A).
• the dialysis liquid entering the second chamber was composed as follows:
• oxygen-enriched osmosis water was constantly initiated into the dialysis liquid before the dialysis liquid entered the second chamber (at a position schematically represented by no. 12 in Figure 2A).
• the oxygen concentration and the initiation rate were adjusted to achieve target oxyhemoglobin saturation of about 99%.
• Oxygen enrichment of the osmosis water can be achieved by any one of the methods described herein.
• the oxygen enrichment of the osmosis water was achieved by exposure to oxygen at increased pressure, followed by releasing the so-enriched osmosis water through capi llaries into the dialysis liquid at a position schematically represented by no. 12 in Figure 2A.
• Oxygen saturation of hemoglobin (in %) was measured (indicated as 0 2 Hb [%] in Fig. 4).
• 02Hb pre oxygen saturation of hemoglobin, measured before entry of the blood into the first chamber.
• This example shows that the method of the present invention enables very efficient and continuous oxygenation of blood.
• the oxygen saturation of hemoglobin in blood exiting from the first chamber was constantly above 95 %, typically around 99 %.

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