JP2010507464A - Liquid-saving cascade hemofiltration - Google Patents

Abstract

The present invention provides a method and apparatus for efficiently purifying blood or blood-derived fluid in a manner that reduces waste fluid. The blood purification apparatus has a primary purification device and receives a primary influent from a liquid supply at the inlet through a primary infusion line. The primary purification device distributes the influent into two effluent streams. The first effluent is concentrated with larger components and the second effluent is concentrated with smaller components. The first effluent can be returned to the source via the primary discharge line. The reservoir is positioned to store reservoir fluid and receive a second effluent. A secondary purification device coupled to the reservoir receives the reservoir fluid from the reservoir and passes the reservoir fluid into two additional streams: a third effluent stream enriched in a larger component and a fourth fluid enriched in a smaller component. Distribute to effluent. The fourth effluent is connected to merge with either the primary injection line or the first effluent. The third effluent is connected to the reservoir. As a result, albumin or other intermediate molecular weight molecules are concentrated in the reservoir over time. Optionally, the device may include a dialysis module or an adsorption module for removing low molecular weight toxins.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This patent application is a US Provisional Application No. 60 on “Liquid-Saving Cascade Blood Filtration Methods” filed on 23 October 2006, the entire contents of which are incorporated herein by reference. Claim priority to / 862,508.

TECHNICAL FIELD The present invention relates to the removal of harmful components from blood for therapeutic purposes including the treatment of renal failure, liver failure, sepsis, multiple organ failure, and other diseases.

Background Patients with diseases and other pathological conditions in which harmful components accumulate in the circulating blood may benefit from removing such substances through blood or plasma purification treatment . Examples of such treatments include blood / plasma adsorption therapy, hemodialysis, albumin dialysis, hemofiltration, cascade hemofiltration, plasma filtration, split plasma therapy (may include filtration, adsorption, and fluid exchange), Cell based therapy, total plasma exchange therapy, and selective blood or plasma filtration are included.

  Blood purification technology includes acute and chronic liver failure, hepatorenal syndrome, renal failure, trauma (crash syndrome), congestive heart failure, rheumatoid arthritis, infection, sepsis, hyperlipidemia, acute respiratory distress syndrome (ARDS), whole body May have utility in the treatment of multiple inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). Blood / plasma toxins that may be involved in these conditions include: urea, creatinine, ammonia, bile acids, bilirubin, short chain fatty acids, phenol, interleukins IL-6, IL-1, and IL-18; Tumor necrosis factor α-TNFα, chemokine (IL-8), leukotriene, platelet activating factor (PAF), thromboxane A2, interferon gamma (IFNγ), bacterial toxin, lipid A, anaphylatoxin (C3a), reactive oxygen species , Vasoactive mediators such as nitric oxide (NO), certain prostaglandins, and other bioactive ingredients.

  In hemofiltration or plasma filtration techniques, semi-permeable membranes, often hollow fiber filters, may be used to remove small molecular weight components sufficiently to permeate the membrane with low molecular weight and hydrodynamic radius . Because these membranes are generally permeable to water, hemofiltration is generally considered to remove fluid from the blood. To prevent patient dehydration, the removed fluid is replaced with electrolyte solution, plasma, albumin, other fluids, or combinations thereof. The fraction of blood, plasma, or other body fluid that passes through the membrane is called "ultrafiltrate". Examples of hemofiltration techniques designed to remove inflammatory mediators are US Pat. Nos. 6,287,516, 6,730,266, all of which are incorporated herein by reference, Nos. 6,736,972 (Patent Document 3), 6,787,404 (Patent Document 4), and US Patent Application No. 20060129082 (Patent Document 5).

  Scientific evidence that further increasing the filtration rate in hemofiltration may be beneficial for many patients with conditions including sepsis, SIRS, MODS, acute renal failure, and catecholamine-refractory septic shock Is increasing. This type of treatment is called high-volume hemodialysis (“HVHF”). The ultrafiltrate production rate used herein is “ultrafiltration rate” and is expressed in milliliters / minute.

Despite the potential advantages of HVHF, problems with HVHF that may limit its clinical use include the following:
(I) risk of fluid balance error;
(Ii) deleterious depletion of desirable blood components (eg, nutrients, hormones, medications used by patients, vitamins, and certain blood clotting factors);
(Iii) risk of hypothermia; and (iv) high cost of treatment due to consumption of albumin, fresh frozen plasma, and large amounts (within 200 L / day) of sterile hemofiltration solution.

  By using cascade hemofiltration, the amount of liquid that is discarded (and necessarily replaced) can be reduced. In cascade hemofiltration, a secondary hollow fiber filtration cartridge removes liquid and low molecular weight components from the ultrafiltrate for return to the patient, thereby reducing the amount of replacement fluid required. Therefore, the amount of waste produced is reduced. To achieve this, the molecular weight cutoff value of the secondary filter must be smaller than the cutoff value of the primary filter. Examples of blood filtration systems having a pair of filters include US Pat. No. 6,198,681 (US Pat. No. 6,099,086), US Pat. No. 2,0040,182787 (US Pat. No. 5,677,097), all of which are incorporated herein by reference; Ho , et al, Gut, 2002, 50, 869-876 (Non-patent Document 1); and Bruni, et al., Transfusion Sci. 1999, 21, 193-199 (Non-patent Document 2). It is.

  Despite the advantages of cascade hemofiltration in saving liquids, when used for HVHF, the above example still produces far more waste and responds than if it is economical, convenient or safe Requires administration of a large amount of replacement fluid. For example, the process described in US Patent Application No. 20040182787 is expected to produce as much as about 70 L / day of waste under HVHF conditions. In addition, such treatments include amino acids included in medications that may be administered in clinical settings such as antibiotics, diuretics, cardiotropes, pressors, sedatives, and analgesics. It is thought to cause loss of hormones, and other beneficial molecules.

U.S. Pat.No. 6,287,516 U.S. Patent No. 6,730,266 U.S. Patent No. 6,736,972 U.S. Patent No. 6,787,404 US Patent Application No. 20060129082 U.S. Patent No. 6,198,681 U.S. Patent Application No. 200040182787

Ho, et al, Gut, 2002, 50, 869-876 Bruni, et al., Transfusion Sci. 1999, 21, 193-199

  In an exemplary embodiment of the invention, the blood purification apparatus includes a primary purification device that receives a primary influent at the input via a primary infusion line. The primary purification device is adapted to distribute the influent into a first effluent stream enriched in larger components and a second effluent stream enriched in smaller components. The first effluent can be returned to the patient via the primary drain line. The reservoir is positioned to store the reservoir fluid and receive the second effluent. The secondary purification device is in fluid communication with the reservoir and receives reservoir fluid from the reservoir, and passes the reservoir fluid into a third effluent stream enriched in a larger component and a fourth fluid enriched in a smaller component. Distribute to the effluent stream. The fourth effluent is connected to a location selected from the first effluent and the primary injection line, and the third effluent is connected to the reservoir.

  Optionally or additionally, the first and second purification devices may be a first hollow fiber filter and a second hollow fiber filter. The first filter may have a sieving distribution that sorts the larger components, and the second filter may have a sieving distribution that sorts the smaller components, thereby Intermediate sized components are retained in the reservoir. The nominal molecular weight cutoff of the first filter may be less than about 4,000,000 daltons, and the nominal molecular weight cutoff of the second filter may be less than about 2,000,000 daltons. The molecular weight cut-off of the primary and secondary purification devices may be selected so that the toxin binding protein is stored in the reservoir. The toxin binding protein may be albumin. The molecular weight cut-off of the primary purification device may be selected to direct immunoglobulins and larger molecules than immunoglobulins to the first effluent. The effective or nominal molecular weight cutoff of the primary purification device may be between 50,000 and 2,000,000 daltons.

  The apparatus may also include any tertiary purification device adapted to remove toxins normally removed by the kidney or liver. For example, the tertiary purification device may be a dialysis device or an adsorption device.

  Optionally or in addition, the apparatus may include a pumping system coupled to flow through the primary purification device and the secondary purification device. The pumping system may include at least one centrifugal pump. The apparatus may be configured such that the flow rates of the second and fourth effluent streams are approximately equal. The pumping system may operate to induce liquid flow through the primary purification device at a rate of 10 ml / min to 5000 ml / min. The pumping system may be operated to induce the flow of the second effluent at a rate of 1 ml / min to 1500 ml / min. The pumping system may operate to induce a liquid flow through the second purification device at a rate of 10 ml / min to 5,000 ml / min. The pumping system may operate to induce a fourth effluent stream having a rate of 1 ml / min to 1500 ml / min. The pumping system may operate to maintain the liquid in the reservoir at a substantially constant level. The reservoir may include an inlet port and an outlet port. The liquid source may be a patient's vasculature or a liquid source reservoir.

  According to another aspect of the invention, a method for removing component species from a source (eg, blood or other body fluid in a reservoir) receives a primary influent via an infusion line. Stages are included. The primary influent contains blood components. The influent is distributed into a first effluent stream enriched in larger components and a second effluent stream enriched in smaller components. The first effluent is returned to the blood source and the second effluent is collected in the reservoir. Liquid is obtained from the reservoir and distributed into a third effluent stream enriched in larger components and a fourth effluent stream enriched in smaller components. The fourth effluent stream is directed to merge with the influent stream or the first effluent stream. The third effluent is returned to the reservoir.

  Optionally or in addition, the reservoir may be filled with a replacement solution prior to initiating the liquid flow. The replacement fluid may contain an effective amount of the therapeutic substance. Optionally or in addition, the replacement fluid may include a toxin binding molecule. The toxin binding molecule may be albumin, for example. At least a portion of the liquid in the reservoir may be replaced by a replacement solution that is substantially free of toxins.

  Optionally or additionally, the flow rate in each stream is controlled so that no additional replacement fluid need be provided to the patient. The flow rates of the second and fourth streams may be approximately equal so that the liquid enters the reservoir at approximately the same rate that the liquid is removed from the reservoir.

  Optionally or in addition, the toxin may be removed from the liquid originating from the reservoir by a toxin-binding stationary phase. Toxin molecules in the fourth effluent may be removed by dialysis.

  Optionally or additionally, the liquid source may be a patient or an influent collected from the patient through an infusion line. The first effluent is returned to the patient via the drain line. The patient, infusion line and drain line form a circuit.

  Optionally or in addition, the distribution of the influent includes the steps of placing albumin in the second effluent and returning the albumin to the reservoir in the third effluent by distribution of the reservoir. As a result, albumin is concentrated over time in the reservoir. The body fluid may be blood in a patient or reservoir, or it may be a non-blood body fluid or a blood fraction such as plasma, serum, cerebrospinal fluid, or ascites.

  Optionally or in addition, liquid may be collected from the reservoir (eg, after treatment). Useful biological components may be extracted from the liquid and used for research applications or therapeutic applications including administering the components to a patient.

  According to yet another aspect of the present invention, a method for purifying a source of blood or blood-derived fluid includes creating a primary circuit coupled to the source. The primary circuit includes a primary purification device. The liquid is directed to flow from the source through the primary circuit and the primary purification device, producing an effluent containing intermediate molecular weight molecules from the blood. The reservoir collects an effluent stream containing intermediate molecular weight molecules. The liquid fraction is extracted from the reservoir to leave an intermediate molecular weight molecule in the reservoir. As a result, the concentration of intermediate molecular weight molecules in the reservoir is thought to increase over time.

  Optionally or in addition, the extracted liquid fraction may be returned to the source. The extracted liquid fraction may be returned to the source via the primary purification device. Extraction may be accomplished using a secondary purification device.

  Optionally or in addition, dialysis devices or adsorption devices may be used to remove low molecular weight toxins.

  According to another aspect of the present invention, a method for purifying a first liquid includes removing an amount of the first liquid from a source, selectively extracting toxin-bearing molecules from the first liquid. Generating an extract enriched with toxin-carrying molecules, storing the extract, recovering molecules having a lower molecular weight than the extracted toxin-carrying molecules from the extract, and supplying a low molecular weight to the source The step of returning the molecule is included.

  Optionally or in addition, the steps of removing, extracting, storing, recovering, and returning are performed simultaneously.

  Optionally or in addition, the toxin-carrying molecule is a protein. For example, the toxin-carrying molecule may be albumin.

  The foregoing features of the invention will be more readily understood by reference to the following detailed description, taken in conjunction with the accompanying drawings, in which:

FIG. 3 is a flow diagram illustrating a general method for purifying liquid according to an aspect of the present invention. FIG. 2 is a flow diagram of a particular embodiment, according to the method of FIG. FIG. 2 is a flow diagram of a further specific embodiment according to the method of FIG. FIG. 4a is a block diagram illustrating a liquid-saving cascade hemofiltration system in a pre-dilution configuration, according to an embodiment of the present invention. FIG. 4b is a block diagram of a liquid-saving cascade hemofiltration system in a post-dilution configuration, according to an embodiment of the present invention. 2 is an illustration of a cascade hemofiltration system according to the embodiment of FIG. FIG. 6a is a block diagram illustrating a liquid-saving cascade hemofiltration system having an adsorption column in a pre-dilution configuration, according to an embodiment of the present invention. FIG. 6b is a block diagram illustrating a liquid-saving cascade hemofiltration system having an adsorption column in a post-dilution configuration, according to an embodiment of the present invention. FIG. 4 is an illustration of a cascade hemofiltration system having an adsorption column according to the embodiment of FIG. 1 is a block diagram illustrating a liquid-saving cascade hemofiltration system having a dialysis cartridge, according to aspects of the present invention. FIG. FIG. 6 is an illustration of a cascade hemofiltration system having a dialysis cartridge according to the embodiment of FIG.

Detailed Description of Specific Aspects Definitions The following terms used in the description and appended claims have the meanings indicated, unless the context requires otherwise.

  “Toxin” means an ingredient that may be beneficially removed from a patient due to deleteriously high concentrations in the body. Examples of toxins include any of a variety of such molecules that play a role in the pathophysiology of a particular disease or failure of one or more body organs due to harmfully high concentrations in the body. included. Such toxins include ammonia, urea, creatinine, free bile acids, bilirubin, phenol, inflammatory mediators (“IM”; typically cytokines, interleukins, and chemokines), and liver, lung, gastrointestinal tract, kidney And other molecules normally removed by other tissues and organs.

  A “toxin binding molecule” is a molecule, typically a macromolecule such as a protein that binds to a toxin. Albumin is used throughout as an exemplary toxin-binding molecule, although other proteins or non-protein macromolecules may be used as toxin-binding molecules as well.

  “Component” means a molecule, ion, macromolecular complex, cell, aggregate, fragment, or part thereof, or other species dissolved or suspended in a liquid.

  “Purification device” means a device that distributes components in an influent into a plurality of effluent streams, each containing a distribution of components that are a suitable subset of the influent components. Examples of purification devices include hemofilters, hollow fiber hemofilters, dialysis cartridges, centrifuges, and systems based on gradient centrifugation with or without the use of substances such as Ficoll.

  In the context of a purification device, “smaller component-concentrated effluent” is a statistical measure that purifies an influent that has a distribution of components that have a lower molecular weight or hydrodynamic radius than the distribution of the components in the influent. By liquid flow caused by passing through the device. Examples of such statistical measures include mean, median, mode, and range.

  “Large component concentrated effluent” in the context of a purification device purifies an influent that has a higher molecular weight or hydrodynamic radius distribution of components in a statistical measure than the distribution of components in the influent. By liquid flow caused by passing through the device. Examples of such statistical measures include mean, median, mode, and range.

  “Nominal molecular weight cut-off” means the average pore size of the semipermeable membrane (eg, as described by the manufacturer).

  The “90% effective molecular weight cut-off” of a purification device refers to the molecular weight of the components of the influent that the purification device acts to direct at least 90% of the components of the influent to the effluent stream where the larger components are concentrated. means.

  The “sieving coefficient” is a scale for predicting permeation of a fraction of a predetermined blood component placed on one surface of a semipermeable membrane.

  A “sieving distribution” of a semipermeable membrane is a set of sieving coefficients corresponding to a plurality of components found in a liquid sample exposed to the membrane.

  “Sieving distribution that sorts larger components” in the context of a purification device means that the purification device produces an effluent stream enriched in larger components.

  “Sieving distribution that sorts smaller components” in the context of a purification device means that the purification device produces an effluent stream enriched in smaller components.

  In an exemplary embodiment of the invention, the purification system removes toxins from biological fluids without discarding most of the liquid. As a result, there is no need to administer a large amount of replacement fluid to the patient. Aspects include acute and chronic liver failure, hepatorenal syndrome, renal failure, trauma (crash syndrome), congestive heart failure, rheumatoid arthritis, infection, sepsis, hyperlipidemia, acute respiratory distress syndrome (ARDS), systemic inflammation Reaction syndrome (SIRS), and multiple organ dysfunction syndrome (MODS), burns, certain congenital disorders (eg, Giant-Barre syndrome, Goodpasture syndrome, anti-GMB nephritis, Waldenstrom macroglobulinemia, systemic erythema Lupus) and other diseases or conditions resulting from the accumulation of toxins including inflammatory mediators and other harmful components in the blood may be used.

  Embodiments remove inflammatory mediators from body fluids. Other embodiments may include the use of an auxiliary purification element to remove toxins normally excreted, metabolized, or otherwise processed by the liver or kidney. Examples of auxiliary purification elements include adsorption filters, adsorption columns, dialysis cartridges, affinity columns, columns loaded with particles to which specific antibodies are attached, and cell-based artificial organs (eg, artificial livers). For simplicity, certain exemplary embodiments described herein relate to blood purification, but also plasma, serum, other blood fractions, or non-blood such as ascites and cerebrospinal fluid Sex complex fluids can be used for purification. Related aspects of the present invention include minimal waste fluids, hormones, electrolytes, nutrients, and administered nutrients and medications (eg, antibiotics, antiviral agents, diuretics, cardiac stimulants, pressors, steroids, sedatives) And a method and apparatus for efficiently purifying blood using ultrafiltration with minimal or no loss of beneficial molecules, including

  FIG. 1 shows a flow diagram of a method according to an embodiment of the invention. A liquid, such as blood, plasma, or other liquid derived from blood, is collected from a source, such as a reservoir or a human patient (step 100). Toxin-carrying molecules are extracted from the liquid (step 110). The toxin-carrying molecule can be, for example, albumin. The extract thus formed is stored in a reservoir (step 120). Low molecular weight molecules (eg, water, salts, antibiotics, nutrients, small molecule drugs, etc.) are extracted from the liquid (step 130). The low molecular weight molecules are reused by returning them to the source (step 140). This process (stages 100-140) may be repeated or performed continuously.

  FIG. 2 shows a flow diagram of another method according to an embodiment of the invention. A primary circuit is created (step 200). The primary circuit includes an in-line primary purification device. Liquid is flowed from the source through the primary circuit (step 210). The liquid flow may be induced by pumping, gravity, centrifugation, or other suitable method. The action of the primary purification device produces an effluent containing intermediate molecular weight molecules (stage 220). The intermediate molecular weight is larger than the low molecular weight molecule in step 130 of FIG. 1, but smaller than molecules such as antibodies or cellular components such as red blood cells that are retained in the liquid source. Albumin is a specific example of an intermediate molecular weight molecule that can also be a toxin-binding protein molecule. The effluent is collected in a reservoir (stage 230). The liquid containing the low molecular weight molecule is extracted from the reservoir to leave an intermediate molecular weight molecule in the reservoir (step 240). As a result, if the volume of liquid in the reservoir is constant or only slightly increased, the intermediate molecular weight molecules retained in the reservoir will increase in concentration over time. Thus, the reservoir can be thought of as a sink for intermediate molecular weight molecules.

  FIG. 3 shows another flow diagram of yet another method according to an embodiment of the invention. Inflow liquid is received (step 300). The influent is distributed into two effluent streams (step 310). The first effluent is relatively concentrated with larger components from the source liquid, and the second effluent is relatively concentrated with smaller components from the source liquid. The first stream (having a larger component) is returned to the blood source (stage 320). The second stream is collected in a reservoir (stage 330). Obtain the liquid collected in the reservoir and distribute it into two further streams, one containing the concentrated liquid with a relatively large component and the other containing the concentrated liquid with a relatively small component ( Stage 340). A stream enriched in larger components (but also containing smaller components) is returned to the reservoir where it is retained (stage 360). The stream enriched in smaller components is recycled (step 350), for example, by returning the stream to the source.

  FIG. 4a shows a block diagram of a cascade hemofiltration system according to an embodiment of the present invention. Liquid (eg, blood or plasma) travels from a liquid source (eg, a patient or a reservoir of blood collected from the patient) via the primary infusion line 31 to the inlet of the primary purification device 30. Primary purification device 30 distributes blood into two streams, a first effluent ("primary return stream") and a second effluent ("primary ultrafiltration stream"). Due to the action of the primary purification device, the primary return flow contains larger components (as measured by hydrodynamic radius or mass) and the primary ultrafiltration flow contains more toxins and other molecular components to be removed. It is thought to contain small components as well as components that are returned to the patient. Larger components (eg, blood cells, antibodies, and other large proteins) in the return flow are returned to the liquid source through the primary return drain line 32. The primary purification device 30 provides a primary ultrafiltration flow through a second outlet, which flows through the primary ultrafiltration line 33 to the reservoir 50. Infusion line 31, primary purification device 30, and primary discharge line 32, when connected to a liquid supply, define a primary circuit with the liquid supply. Lines 31-33 and other lines described herein may be implemented as standard medical grade tubing or other suitable conduit structures that are well known in the art.

  The secondary purification device 40 receives the toxin-containing liquid from the reservoir 50 and has two effluents from this liquid, i.e., relatively small molecules to return to the patient (e.g., nutrients, medication, electrolytes, water, and hormones). And a liquid to be returned to the reservoir 50 containing a relatively large toxin and a relatively large toxin (eg, albumin-binding toxin, and inflammatory mediators such as cytokines). In addition to ions, sugars, nutrients, hormones, and medications, the returned liquid may contain relatively smaller toxins such as urea, creatinine and ammonia, as well as other small toxin components. As described below, smaller toxins may be removed or inactivated using various techniques, or returned to the patient for metabolism and excretion. Extracting liquid containing only low molecular toxins and other low molecular components from the liquid maintained in reservoir 50, and returning larger concentrated toxin liquid back to reservoir 50 Toxins may be accumulated in reservoir 50. At the same time, by returning the liquid containing water and small molecule solutes back to the liquid source (eg, the patient's blood circulation), replacement of the liquid and the accompanying molecules is minimally or not necessary.

  The secondary purification device 40 can operate in the same manner as the primary purification device 30, but selects and releases ultrafiltrate having a smaller component than that selected by the primary filtration device 30. The secondary purification device 40 takes the liquid with toxins from the reservoir 50 through the secondary infusion line 41 and draws the liquid into two streams, a third stream containing a relatively large component (the first two The flow relates to the primary purification device already discussed, and in this specification we will refer to the third flow as the “secondary return flow”) and the fourth flow containing a relatively small component ( In the present specification we will refer to the “secondary ultrafiltration stream”). The secondary return flow flows back to the reservoir via the secondary discharge line 42, and the secondary ultrafiltration flow flows back to the primary circuit via the secondary ultrafiltration line 43. In this embodiment, the secondary ultrafiltration line 43 connects to the primary circuit at the inlet of the primary purification device 30 or upstream of the inlet (a “pre-dilution” arrangement). The intermediate sized toxin exits the primary purification device 30 in the primary ultrafiltration flow and enters the reservoir 50, but is returned to the reservoir in the secondary return flow that exits the secondary purification device 40, so that the reservoir 50 It is believed that the concentration of intermediate sized toxins such as IM within increases as a function of the cumulative liquid flow through the primary purification device 30.

  Thus, compared to prior art systems and methods that involve discarding much or all of the primary ultrafiltration stream, the system of the present invention requires water and low molecular weight components to be reused. The volume of replacement fluid is reduced or eliminated altogether. Similar to the prior art blood filtration method, the system of FIG. 4a uses a toxin sink, or reservoir 50. However, unlike prior art methods where the amount of liquid contained in the toxin sink increases indefinitely with use, the concentration of toxin in reservoir 50 increases over time, so reservoir 50 has a limited volume. Can have. By initiating a blood purification technique on the patient with a replacement fluid in the reservoir 50 (e.g., electrolyte or albumin solution 0.1 L to 10 L), it may be possible to perform the technique without an additional source of replacement fluid There is sex. Alternatively, it may be desirable or more effective to manually or automatically discard or replace all or part of the toxin-containing solution in reservoir 50 after prolonged use. To increase convenience and therapeutic utility, the replacement fluid added to the reservoir may also contain drugs, adsorbents, or other therapeutic substances.

  In another embodiment, the flow of secondary ultrafiltrate flows back to the primary circuit downstream of the primary purification device 30 via the secondary ultrafiltration line 43, for example by coupling to the primary discharge line 32. . Such a “post-dilution” configuration is shown in FIG. 4b. Alternatively, the secondary ultrafiltration stream may be returned directly to the liquid source.

  As an example, the primary purification device 30 may be a selective permeation hemofiltration cartridge with an effective molecular weight cutoff value (eg, 90% effective molecular weight cutoff) of 5000-100,000 daltons, and the secondary purification device 40 is effective molecular weight. It may be a selectively permeable plasma filtration cartridge with a cut-off value of 100 to 5000 daltons. In a further example, if the primary purification device 30 has an effective cutoff value of 150,000 daltons and the secondary purification device 40 has an effective cutoff value of about 500 daltons, a molecular weight of about 500-150,000 daltons (69,000 daltons) Are likely to be concentrated in the reservoir 50, but these ranges depend on which components you want to remove from the blood and the effective molecular weight cutoff as a function of the liquid flux. May change with change. These changes include make-up flow, ultrafiltration rate, semipermeable membrane composition and structure, liquid viscosity, liquid osmotic pressure, membrane hydrophilicity, presence of antifouling membrane coating, membrane polarity, and other factors It may be a function of As many inflammatory mediators fall within this range, IM is concentrated in the reservoir 50 and removed from the blood. In addition, toxins bound to toxin binding molecules, including molecules bound to albumin, can accumulate in reservoir 50 if present. The effective cut-off value and sieving factor for individual blood / plasma components and the nominal cut-off value for a given permselective membrane (relative to the average pore size before use) are determined by chemical and mechanical characteristics (eg, , Type of polymer and porous material used, porous wetting properties, charge, symmetry, resistance to contamination, surface exchange area, thickness), operating characteristics (replenishment flow rate, speed, ultrafiltration speed, transmembrane pressure), As well as a function of the interaction between blood or plasma components and the filtration membrane. For example, when selecting a membrane with an effective molecular weight cut-off that allows permeation of albumin, a polysulfone membrane may require a nominal cut-off value of 400 kDa, but a nominal cut that requires a polyethersulfone or cellulose acetate membrane. The off value may be only 100 kDa. In addition, the effective molecular weight cut-off of the primary purification device is selected to be low enough to retain immunoglobulins and return them to the blood source, thereby retaining the beneficial effects of these molecules. In general, the molecular weight cutoff will be chosen to be less than about 1,000,000 daltons for this purpose.

  The secondary injection line 41, the secondary purification device 40, and the secondary discharge line 42 together constitute a secondary fluid circuit. In this way, the primary ultrafiltration line 33 and the secondary ultrafiltration line 43 serve to move the ultrafiltrate between the primary circuit and the secondary circuit. In the embodiment shown in FIGS. 4 a and 4 b, the secondary ultrafiltrate is returned to the primary fluid circuit either upstream or downstream of the primary purification device 30. These arrangements are referred to as pre-dilution and post-dilution arrangements, respectively, because they dilute the blood before they enter the primary clarification device or return directly to the patient after leaving the primary clarification device. Pre-dilution may prevent side effects such as protein aggregation and blood clotting in the primary purification device 30 that may occur due to blood concentration by the primary purification device. Post-dilution may enhance blood / plasma purification in such embodiments because the secondary effluent (primary ultrafiltrate) is not diluted.

  FIG. 5 shows a particular hemofiltration system arrangement according to the more general embodiment of FIG. 4a. The system is connected to the vasculature of patient 10 by a venous-venous connection. The primary circuit pump 51 pushes blood through the primary circuit.

  Pumping blood through the primary circuit induces the production of primary ultrafiltrate, which is pushed through the primary ultrafiltration line 33 by the primary ultrafiltration pump 52 to the reservoir 50. The secondary circuit pump 53 induces liquid to flow from the reservoir through the secondary circuit. The secondary ultrafiltration pump 54 pushes the secondary ultrafiltrate into the primary circuit in the predilution arrangement. (Collectively, pumps 51, 52, 53 and 54 constitute the pumping system of this embodiment.) Any of a variety of commercially available pumps may be used. For effective filtration, it may be desirable to use one or more pumps that can produce high flow rates. However, when choosing a pump and flow rate combination, care should be taken to avoid hemolysis due to pumping; for example, by using a centrifugal pump in the primary circuit pump 51, 0.2 to 5 without causing hemolysis. A flow rate as high as L / min may be possible.

  As an alternative to or as an aid to using an additional replacement fluid reservoir 49 (eg, an intravenous bag individually connected to the patient), reservoir 50 may be filled with replacement fluid prior to the start of treatment. Optionally, the replacement fluid may contain therapeutic substances for adsorption and retention of specific molecules in reservoir 50 or for delivery to the patient, such as small molecule antibiotics, anticoagulants, and anti-inflammatory compounds. . If the reservoir 50 is pre-filled with the replacement fluid and the primary ultrafiltration flow rate and the secondary ultrafiltration flow rate are equal or nearly equal, additional replacement fluid may not be necessary. By setting the ultrafiltration pumps 52 and 54 to similar levels of flow, approximately equal flow rates may be achieved. However, slight flow at the reservoir fluid level may be tolerated depending on the size of the reservoir and the duration of treatment. Alternatively, the production of primary and / or secondary ultrafiltrate may be altered by adjusting the pump to increase or decrease the liquid level in the reservoir 50. The liquid may be periodically removed from the reservoir 50, discarded, and replaced with a replacement solution that does not contain toxins. Liquid replacement can be particularly advantageous during bulk blood filtration or blood filtration that lasts more than 8 hours. For example, biochemical non-ideal properties can change the binding capacity of toxin-binding molecules at high concentrations, or secondary purification can be performed when proteins in the secondary circuit reach a certain concentration. Then there is a tendency to get dirty.

  The range of flow rates can generally be 10-5000 ml / min in the primary and secondary circuits, which is about 1 to 1500 ml / min of primary and secondary ultrafiltrate. To produce. Since the liquid maintained in the reservoir 50 is released from the primary circuit, the flow rate of the liquid through the secondary purification device 40 is used to maintain the patency of the hollow fiber lumen and soil (e.g., protein May be chosen to be very high to protect the permselective membrane from (by pore closure by protein fragments, and other components). For example, the flow rate of liquid entering the secondary purification device 40 may be about 10 times greater than the flow rate of liquid entering the primary purification device 30.

  In an exemplary embodiment, the liquid flow through the primary purification device 30 may be about 10-5000 ml / min. The second effluent flow rate (primary ultrafiltration rate) may be about 1 to 500 or about 1 to 1500 ml / min.

  Various control schemes may ensure desirable system performance. For example, flow rate and / or reservoir level sensors may be used with a microcontroller to adjust the pump speed to ensure an appropriate liquid level in the reservoir 50. Additional sensors, such as blood-chemical sensors, may also be incorporated into the system to further improve safety, efficacy, or convenience.

  In operation, the pressure generated by the pumping system in the infusion line 31 and the ultrafiltration line 43 causes the blood from the patient to enter the secondary purification device 40 via the retrograde flow from the infusion line 31 to the ultrafiltration line 43. Balance it so that it does not enter or enter the patient through reverse flow. Alternatively or additionally, one or more active or passive valves (eg, check valves) may be used to prevent such undesirable flow.

  The primary purification device 30 in FIG. 5 is a hollow fiber hemofilter with a membrane having a nominal molecular weight cut-off of 1 to 4,000,000 daltons. The secondary purification device 40 is a hollow fiber plasma filter having a nominal molecular weight cut-off of 1 to 2,000,000 daltons. The primary purification device 30 has a sieving distribution that sorts out larger components, while the secondary purification device 40 has a sieving distribution that sorts out smaller components. As a result, intermediate sized components such as immunomodulators or toxin-binding molecules will be collected in reservoir 50.

  The primary filter 30 has a sufficiently high molecular weight cutoff to pass albumin through the reservoir 50 (eg, about 100,000 to 800,000 daltons depending on the type of selective permeation filter used) and the secondary filter 40 If it has a molecular weight cut-off that is low enough to prevent passage of albumin (eg, less than about 70,000 daltons), it is believed that albumin is retained in reservoir 50 and concentrated in the reservoir. Removal of albumin from the blood has the advantage of removing albumin-bound toxins, but albumin may need to be replaced.

  The reservoir 50 in FIG. 5 includes an injection port for filling the reservoir 50 with liquid and an exhaust port for draining the liquid maintained in the reservoir 50. Alternatively, the reservoir may be disposable. The disposable reservoir may be secured to the secondary circuit using a quick disconnect to quickly remove or replace the reservoir fluid. Although shown as a bowl without a lid in the illustration of FIG. 6a, the reservoir keeps the blood of the patient out of particular biologically hazardous substances and maintains the sterility of the system In order to be closed or otherwise sealed. The replacement fluid introduced into the reservoir includes blood filtrate, dialysate, electrolyte solution, amino acid solution, albumin solution, human serum, the aforementioned combination, or any other solution that may be administered intravenously to the patient. May be.

  Figures 6a to 9 show embodiments utilizing at least one additional tertiary purification device. FIGS. 6a to 7 show an embodiment in which an adsorption device is included, and FIGS. 8 to 9 show an embodiment in which a dialysis unit is included. The purification device operates to remove these toxins as a result of washing low molecular weight toxins from the blood supply, mimicking the action of a healthy liver or kidney. These arrangements may replace or supplement liver or kidney function in patients with septic shock or multiple organ dysfunction syndrome. Embodiments that combine adsorption and dialysis are also within the scope of the present invention.

  FIGS. 6a-7 show an embodiment of the invention that includes an adsorption device 60 located in the secondary ultrafiltration line 43. FIG. The adsorption device 60 includes a casing that defines one or more chambers that hold adsorbent material (ie, a toxin-binding stationary phase) for removing specific toxins. Adsorbent materials include activated carbon, resin (eg, uncharged, neutral, anion exchange, or cation exchange resin), silica, albumin, immobilized antibody, immobilized receptor, immobilized specific antagonist, Polymers, cellulose derivatives, and immobilized antibiotics, or combinations thereof may be included. The adsorbent material may be organized in a variety of ways, such as beads, rods, porous granules, sieves, matrices with anchored molecules, and the like. Adsorption device accepts secondary ultrafiltrate flow and contains liver failure, renal failure, or ammonia, phenol, mercaptan, aromatic amino acids, urea, creatinine, oxygen reactive species, nitric oxide, and vasoactive agents Components that cause or exacerbate any other disease or condition associated with accumulation of toxic substances in the blood circulation are selectively or non-selectively removed. Some commercial or preclinical systems utilizing adsorption device technology that may be used with the embodiments of FIGS. 6 and 7 include (1) Adsorba columns containing activated carbon as an adsorbent (Gambro, Hechingen, Germany) (2) BioLogic-DT system (HaemoCleanse, West Lafayette, IN) containing a mixture of charcoal, silica, and exchange resin as adsorbent, (3) MARS (Molecular Adsorbent Recirculating System using charcoal and resin as adsorbent) Gambro GmbH, Hechingene, Germany), and (4) Prometheus (Fresenius, Germany) using two types of ion exchange resins as adsorbents. FIG. 6b shows a post-dilution arrangement in which an adsorption device is included.

  In another embodiment, the adsorption device may be located at other locations in the fluid system, such as at the secondary filter inlet line 41 or the secondary filter discharge line 42. The adsorbent may also be included in the reservoir 50 and the reservoir 50 agitated or shaken to promote toxin binding to the adsorbent.

  FIGS. 8-9 illustrate embodiments of the present invention that include further purification by dialysis of the secondary ultrafiltrate. This embodiment includes a dialysis cartridge 70 that is incorporated into the secondary ultrafiltrate line 43 and connected to a dialysate source. Similar to the adsorption filter, the dialysis cartridge 70 may be incorporated into other fluid locations in the system, such as in the secondary filter inlet line 41 or the secondary filter discharge line 42. Toxins in the secondary ultrafiltrate that are small enough to pass through the dialysis membrane of the cartridge 70 are thus removed and do not reenter the patient 10. In a further related aspect of the invention, any previously described aspect further includes a cell-based device for providing a particular biological function (eg, metabolism and / or synthesis of a particular blood component). May be. For example, a HepatAssist-2 cartridge (Arbios Systems, Inc.) loaded with viable hepatocytes may be included in the system fluid line to provide metabolic detoxification. In addition, various combinations of dialysis, adsorption, and cell-based purification may be used.

  In a further related aspect, in any of the previously described aspects, a digital control system may be utilized to adjust the flow rate within the above parameters and maintain acceptable operating conditions.

  In further embodiments, the liquid may be recovered from the reservoir 50 and used for research or therapeutic purposes (biomedical or otherwise). It is believed that the reservoir fluid tends to concentrate useful biological components. These components can be recovered by various processing and purification techniques known in the art (fractionation, chromatography, etc.) for sale and use in research or for administration to patients as therapeutic agents It may be formulated and packaged. Examples of useful components include cytokines, chemokines, and immunomodulators.

  The described aspects of the invention are intended to be examples only, and many variations and modifications will be apparent to those skilled in the art. All such changes and modifications are intended to be included within the scope of the present invention as defined in the appended claims. For example, the purification device described herein may be combined with equipment for gas exchange (including oxygenation), pathogen sterilization, temperature control, gamma irradiation, ultraviolet treatment, and the like. The purification device is not limited to hollow fiber filters and may operate on other principles including centrifugation and gradient centrifugation.

Claims (60)

The first effluent can be returned to the patient via the primary drain line into an influent that is a first effluent enriched with a larger component and a second effluent enriched with a smaller component. A primary purification device for receiving the primary influent at the input via the primary injection line, adapted to dispense;
A reservoir for storing reservoir fluid, positioned to receive a second effluent;
A fourth effluent is connected to a location selected from the first effluent and the primary injection line, and a third effluent is connected to the reservoir, receiving reservoir fluid from the reservoir, A blood purification apparatus comprising: a secondary purification device in fluid communication with the reservoir for distributing a third effluent stream enriched in a larger component and a fourth effluent stream enriched in a smaller component; .   2. The apparatus of claim 1, wherein the first and second purification devices are a first hollow fiber filter and a second hollow fiber filter.   The first filter has a sieving distribution that sorts out larger components, and the second filter has a sieving distribution that sorts out smaller components, thereby increasing the size of the medium 3. The device of claim 2, wherein the component is retained in the reservoir.   4. The apparatus of claim 3, wherein the nominal molecular weight cutoff of the first filter is less than about 4,000,000 daltons and the nominal molecular weight cutoff of the second filter is less than about 2,000,000 daltons.   The apparatus of claim 1, further comprising a tertiary purification device adapted to remove toxins normally removed by the kidney or liver.   The apparatus according to claim 6, wherein the tertiary purification device is one of a dialysis device and an adsorption device.   The apparatus of claim 1, further comprising a pumping system coupled to produce a flow through the primary purification device and a flow through the secondary purification device.   8. The apparatus of claim 7, wherein the pumping system includes at least one centrifugal pump.   8. The apparatus of claim 7, wherein the flow rates of the second and fourth effluent streams are approximately equal.   8. The apparatus of claim 7, wherein the pumping system is operative to induce a liquid flow through the primary purification device at a rate of 10 ml / min to 5000 ml / min.   8. The apparatus of claim 7, wherein the pumping system is operative to induce a second effluent stream at a rate of 1 ml / min to 1500 ml / min.   8. The apparatus of claim 7, wherein the pumping system is operative to induce a liquid flow through the second purification device at a rate of 10 ml / min to 5,000 ml / min.   8. The apparatus of claim 7, wherein the pumping system is operative to induce a fourth effluent stream having a rate of 1 ml / min to 1500 ml / min.   8. The apparatus of claim 7, wherein the pumping system operates in a manner that maintains the liquid in the reservoir at a substantially constant level.   The apparatus of claim 1, wherein the reservoir includes an inlet port and an outlet port.   The apparatus of claim 1, wherein the molecular weight cutoff of the primary and secondary purification devices is selected to store the toxin binding protein in the reservoir.   17. The device of claim 16, wherein the toxin binding protein is albumin.   The apparatus of any one of the preceding claims, wherein the molecular weight cutoff of the primary purification device is selected to direct immunoglobulins and molecules larger than immunoglobulins to the first effluent.   19. An apparatus according to any one of claims 16-18, wherein one of the effective and nominal molecular weight cutoffs of the primary purification device is 50,000-2,000,000 daltons.   The apparatus of any one of the preceding claims, further comprising a liquid source selected from one of a patient's vasculature and a liquid source reservoir. Receiving a primary influent containing at least a component of a source liquid via an injection line;
Distributing the influent into a first effluent stream enriched in larger components and a second effluent stream enriched in smaller components;
Returning the first effluent to the liquid source;
Collecting a second effluent stream in a reservoir;
Obtaining a liquid from the reservoir and distributing the resulting liquid into a third effluent stream enriched in larger components and a fourth effluent stream enriched in smaller components;
Directing a fourth effluent stream to join a liquid stream selected from the group consisting of an influent or a first effluent stream; and returning a third effluent stream to the reservoir A method for removing component species from a plant.   24. The method of claim 21, further comprising the step of filling the reservoir with a replacement fluid prior to initiating liquid flow.   24. The method of claim 22, wherein the replacement fluid comprises a toxin binding molecule.   24. The method of claim 23, wherein the toxin binding molecule is albumin.   23. The method of claim 22, wherein the replacement fluid comprises an effective amount of a therapeutic substance.   24. The method of claim 21, further comprising controlling the flow rate in each stream so that no additional replacement fluid needs to be provided to the patient.   27. A method according to any one of claims 21 to 26, wherein the flow rates of the second and fourth streams are approximately equal so that the liquid enters the reservoir at approximately the same rate at which the liquid is removed from the reservoir.   23. The method of claim 21, further comprising replacing at least a portion of the liquid in the reservoir liquid with a replacement liquid that is substantially free of toxins.   24. The method of claim 21, further comprising removing toxins in the fluid from the reservoir with a toxin-binding stationary phase.   30. A method according to any one of claims 21 to 29, wherein the liquid source is a blood source.   24. The method of claim 21, wherein the liquid source is a reservoir.   32. The method of claim 31, wherein the reservoir contains patient fluid.   35. The method of claim 32, wherein the body fluid is selected from the group consisting of blood, plasma, serum, cerebrospinal fluid, or ascites.   24. The method of claim 21, further comprising using dialysis to remove toxin molecules from the fourth effluent stream.   A method in which the liquid source is a patient, an influent is collected from the patient through an infusion line, and a first effluent is returned to the patient through the drain line, the patient, the infusion line, and the drain line being 24. The method of claim 21, forming a circuit.   Distributing the influent includes allowing albumin to enter the second effluent, and distributing the reservoir liquid includes albumin in the third effluent such that albumin concentrates in the reservoir over time. 36. A method according to any one of claims 21 to 35, wherein the is returned to the reservoir.   27. A method according to any one of claims 21 to 26, further comprising the step of recovering a liquid from the reservoir.   38. The method of claim 37, further comprising extracting useful biological components.   40. The method of claim 38, further comprising administering the extracted useful biological component to the patient.   40. The method of claim 38 or 39, wherein the useful organism comprises a component selected from the group consisting of cytokines, chemokines, and immunomodulators.   41. The method of claim 37 or 40, further comprising using a useful biological component for research. The first effluent stream can be returned to the source via the primary discharge line, to receive the primary influent from the source at the inlet via the primary injection line, and the influent is larger components. A primary purification means for distributing the concentrated first effluent to a second effluent enriched with smaller components;
A reservoir for storing reservoir fluid, positioned to receive a second effluent;
A fourth effluent is connected to the inlet or output of the primary purification means, and a third effluent is connected to the reservoir, for receiving reservoir fluid from the reservoir, and more A blood purification device comprising: a secondary purification means coupled to a reservoir for distributing a third effluent stream enriched in a larger component and a fourth effluent stream enriched in a smaller component.   43. The blood purification apparatus according to claim 42, comprising tertiary purification means for adsorbing toxins.   43. The blood purification apparatus according to claim 42, comprising tertiary purification means for removing toxins by dialysis. Creating a primary circuit coupled to a source including a primary purification device;
Flowing a liquid from a source through a primary circuit and a primary purification device to produce an effluent containing intermediate molecular weight molecules from the blood;
Collecting an effluent stream containing molecules of intermediate molecular weight in a reservoir;
Purifies the source of blood or blood-derived fluid, including extracting a liquid fraction from the reservoir in a manner that leaves the intermediate molecular weight molecules in the reservoir to increase the concentration of the intermediate molecular weight molecule over time How to do.   46. The method of claim 45, wherein the extracted liquid fraction is returned to the source.   48. The method of claim 46, wherein the extracted liquid fraction is returned to the source via a primary purification device.   46. The method of claim 45, wherein extraction is accomplished using a secondary purification device.   49. The method of any one of claims 45 to 48, further comprising using a dialysis device or an adsorption device to remove low molecular weight toxins. Means for creating a primary circuit coupled to a source;
Means for flowing liquid from a source through a primary circuit containing a primary purification device that removes an effluent stream containing molecules of intermediate molecular weight from the blood;
Means for collecting in the reservoir an effluent stream containing molecules of intermediate molecular weight;
A source of blood or blood-derived fluid, including means for extracting fluid from the reservoir in a manner that leaves the intermediate molecular weight molecules in the reservoir to increase the concentration of the intermediate molecular weight molecules over time. System for purifying.   51. The system of claim 50, further comprising means for returning the extracted liquid to the source.   52. The system of claim 51, further comprising means for returning the extracted liquid to the source via the primary purification device.   51. The system of claim 50, further comprising secondary purification means for effecting extraction.   54. The system according to any one of claims 50 to 53, further comprising a dialysis means or an adsorption means for removing low molecular weight toxins. Removing an amount of the first liquid from the source;
Selectively extracting the toxin-carrying molecule from the first liquid to produce an extract enriched in the toxin-carrying molecule;
Storing the extract;
A method for purifying a first liquid, comprising: recovering a lower molecular weight molecule from the extracted liquid than the extracted toxin-carrying molecule; and returning the lower molecular weight molecule to the source.   56. The method of claim 55, wherein the steps of removing, extracting, storing, recovering, and returning are performed simultaneously.   57. The method of claim 55 or 56, wherein the toxin-carrying molecule is a protein.   58. The method of claim 57, wherein the protein is albumin. Means for removing an amount of the first liquid from the source;
Means for selectively extracting toxin-carrying molecules from the liquid to produce an extract containing the extracted protein molecules;
Means for storing the extract;
Means for recovering from the extract a molecule having a lower molecular weight than the extracted toxin-carrying molecule;
And a means for purifying the first liquid comprising means for returning low molecular weight molecules back to the liquid source.   60. The system of claim 59, further comprising means for simultaneously removing, extracting, storing, retrieving and returning.

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