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
  • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
  • A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
• • 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
  • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
  • A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
  • A61M1/3479—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate by dialysing the filtrate
• • 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
  • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
  • A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
  • A61M1/3482—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate by filtrating the filtrate using another cross-flow filter, e.g. a membrane filter
• • 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
  • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
  • A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
  • A61M1/3486—Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents

Definitions

• the present invention relates to removal of harmful components from the blood for therapeutic purposes including treatment of renal failure, liver failure, sepsis, multiple organ failure, and other diseases.
• Blood purification techniques may have utility in the treatment of acute and chronic liver failure, hepato-renal syndrome, renal failure, trauma (the crush syndrome), congestive heart failure, rheumatoid arthritis, infection, sepsis, hyperlipidemia, acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction syndrome (MODS).
• trauma the crush syndrome
• congestive heart failure the congestive heart failure
• rheumatoid arthritis infection
• sepsis hyperlipidemia
• ARDS acute respiratory distress syndrome
• SIRS systemic inflammatory response syndrome
• MODS multiorgan dysfunction syndrome
• Blood/plasma toxins which may contribute to these conditions may include: urea, creatinine, ammonia, bile acids, bilirubin, short-chain fatty acids, phenols, interleukins IL-6, IL-I, and IL- 18; tumor necrosis factor alpha - TNF ⁇ , chemokines (IL-8), leukotrienes, platelet activating factor (PAF), thromboxane A2, interferon gamma (INF ⁇ ), bacterial toxins, lipid A, anaphylatoxins (C3a), reactive oxygen species, vasoactive mediators such as nitric oxide (NO), certain prostaglandins, and other biologically active components.
• urea creatinine, ammonia, bile acids, bilirubin, short-chain fatty acids, phenols, interleukins IL-6, IL-I, and IL- 18
• tumor necrosis factor alpha - TNF ⁇ chemokines (IL-8), le
• a semipermeable membrane In hemofiltration or plasmafiltration techniques, a semipermeable membrane, often a hollow-fiber filter, may be used to remove molecular weight components that, by virtue of low molecular weight and hydrodynamic radius, are small enough to permeate the membrane. Since these membranes are generally permeable to water, hemofiltration will generally remove liquid from the blood. To prevent dehydration of the patient, the removed liquid is replaced with electrolyte solution, plasma, albumin, other fluid, or a combination thereof. The fraction of blood, plasma or other body fluid that permeates the membrane is called the "ultrafiltrate". Examples of hemofiltration techniques designed to remove inflammatory mediators are described in U.S. Patents No. 6,287,516, 6,730,266; 6,736,972; 6,787,404; and U.S. Published Patent Application No. 20060129082, all of which are hereby incorporated by reference.
• HVHF High- Volume Hemofiltration
• a secondary hollow-fiber filtration cartridge removes fluid and low molecular weight components from the ultrafiltrate for return to the patient, thereby reducing the quantity of replacement fluid needed. Accordingly, the quantity of waste generated is reduced. To accomplish this, the molecular weight cutoff value for the secondary filter must be less than for primary filter. Examples of hemofiltration systems with coupled filters include those described in US Patent, 6,198,681,
• a blood purification apparatus includes a primary purification device that receives a primary input fluid at an input via a primary inlet line.
• the primary purification device is adapted to partition the input fluid into a first output stream that is enriched in larger components and a second output stream that is enriched in smaller components.
• the first output stream is returnable to the patient via a primary outlet line.
• a reservoir stores reservoir fluid and is positioned to accept the second output stream.
• a secondary purification device is in fluid communication with the reservoir, receives reservoir fluid from the reservoir and partitions the reservoir fluid into a third output stream enriched in larger components and a fourth output stream enriched in smaller components.
• the fourth output stream is coupled to a position selected from the first output stream and the primary inlet line, and the third output stream is coupled to the reservoir.
• 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 favoring larger components and the second filter may have a sieving distribution favoring smaller components, thereby retaining intermediately-sized components 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 cutoffs of the primary and secondary purification devices may be selected to cause retention of a toxin binding protein in the reservoir.
• the toxin-binding protein may be albumin.
• the molecular weight cutoff of the primary purification device may be selected to direct immunoglobulins and molecules larger than immunoglobulins to the first output stream.
• the effective or nominal molecular weight cutoffs of the primary purification device may be between 50,000 and 2,000,000 daltons.
• the apparatus may also include an optional tertiary purification device adapted to remove toxins that are normally removed by the kidney or liver.
• the tertiary purification device may be a dialysis device or an adsorption device.
• the apparatus may include a pumping system that is coupled to cause flow through the primary purification device and through the secondary purification device.
• the pumping system may include at least one centrifugal pump.
• the apparatus may be configured so that the flow rates of the second and the fourth output streams may be approximately equal.
• the pumping system may operate to induce a fluid flow through the primary purification device at the rate that is between 10 ml/min and 5000 ml/min.
• the pumping system may operate to induce a flow of the second output stream at the rate that is between 1 ml/min and 1500 ml/min.
• the pumping system may operate to induce a fluid flow through the second purification device at a rate that is between 10 ml/min and
• a method for removing a component species from a source includes receiving a primary input fluid via an inlet line.
• the primary input fluid contains components of the blood.
• the input fluid is partitioned into a first output stream that is enriched in larger components and a second output stream that is enriched in smaller components.
• the first output stream is returned to the blood source and the second output stream is collected in a reservoir.
• Fluid is obtained from the reservoir and partitioned into a third output stream that is enriched in larger components and a fourth output stream that is enriched in smaller components.
• the fourth output stream is directed to merge with a fluid the input fluid stream or the first output stream.
• the third output stream is returned to the reservoir.
• the reservoir may be filled with a replacement fluid.
• the replacement fluid may include an effective does of a therapeutic agent.
• the replacement fluid may include a toxin- binding molecule.
• the toxin-binding molecule may be, for example, albumin. At least some of the fluid in the reservoir may be replaced with a substantially toxin-free replacement fluid.
• the flow rates in the respective streams are controlled so that no additional replacement fluid need be provided to the patient.
• the flow rate of the second stream and the fourth stream may be about equal so that the fluid enters the reservoir at about the same rate as fluid is removed from the reservoir.
• toxins may be removed from a fluid derived from the reservoir with a toxin-binding stationary phase.
• Toxin molecules in the fourth output stream may be removed by dialysis.
• the fluid source may be a patient and the input fluid drawn from the patient through the inlet line.
• the first output stream returns to the patient via an outlet line.
• the patient, inlet line, and outlet line form a circuit.
• the partitioning of the input fluid includes causing albumin to enter the second output stream and the partitioning of the reservoir fluid causes the return of albumin to the reservoir in the third output stream.
• albumin concentrates in the reservoir over time.
• the bodily fluid may be blood in a patient or in a reservoir or may be a non-blood fluid or blood fraction such as plasma, serum, cerebro-spinal fluid, or ascitic fluid.
• fluid maybe recovered from the reservoir (e.g., after treatment).
• a valuable biological component may be extracted from the fluid and used for research or therapeutic uses including administering the component to a patient.
• 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. Fluid is induced to flow from the source through the primary circuit and primary purification device to generate an output stream containing intermediate weight molecules from the blood.
• a reservoir collects the output stream containing intermediate weight molecules.
• a fluid fraction is extracted from the reservoir in a manner that leaves the intermediate weight molecules in the reservoir. As a result, the concentration of intermediate weight molecules in the reservoir will increase over time.
• the extracted fluid fraction may be returned to the source.
• the extracted fluid fraction may be returned to the source via the primary purification device.
• the extraction may be accomplished using a secondary purification device.
• a dialysis or adsorption device may be used to remove low molecular weight toxins.
• a method for purifying a first fluid includes removing a quantity of the first fluid from a source, selectively extracting toxin-carrying molecules from the first fluid to generate an extract fluid enriched in the toxin-carrying molecules, storing the extract fluid, recovering molecules of a lower molecular weight than the extracted toxin-carrying molecules from the extract fluid; and returning the molecules of a lower molecular weight to the source.
• the steps of removing, extracting, storing, recovering and returning are performed concurrently.
• the toxin-carrying molecule is a protein.
• the toxin-carrying molecule may be albumin.
• Fig. 1 is a flow diagram showing a general method for purifying a fluid in accordance with an embodiment of the present invention
• FIG. 2 is a flow diagram of a specific embodiment in accordance with the method of Fig. 1;
• Fig. 3 is a flow diagram of a further specific embodiment in accordance with the method of Fig. 1;
• Fig. 4a is a block diagram showing a fluid-conserving cascade hemofiltration system, in a pre-dilution configuration, in accordance with an embodiment of the invention
• Fig. 4b is a block diagram showing a fluid-conserving cascade hemofiltration system in a post-dilution configuration, in accordance with an embodiment of the invention
• Fig. 5 is a schematic of a cascade hemofiltration system in accordance with the embodiment of Fig. 1;
• Fig. 6a is a block diagram showing a fluid-conserving cascade hemofiltration system with an adsorptive column, in a pre-dilution configuration, in accordance with an embodiment of the invention
• Fig. 6b is a block diagram showing a fluid-conserving cascade hemofiltration system with an adsorptive column, in a post-dilution configuration, in accordance with an embodiment of the invention
• Fig. 7 is a schematic of a cascade hemofiltration system with an adsorptive column in accordance with the embodiment of Fig. 3;
• Fig. 8 is a block diagram showing a fluid-conserving cascade hemofiltration system with a dialysis cartridge, in accordance with an embodiment of the invention.
• Fig. 9 is a schematic of a cascade hemofiltration system with a dialysis cartridge in accordance with the embodiment of Fig. 5. Detailed Description of Specific Embodiments
• Toxins means components, which due to a detrimentally high concentration in the body, may be beneficially removed from a patient.
• Examples of toxins include any of a variety of such molecules, which due to a detrimentally high concentration in the body, play a role in the pathophysiology of specific diseases or failure of one or more body organs.
• Such toxins include ammonia, urea, creatinine, free bile acids, bilirubin, phenols, inflammatory mediators ("IMs”; typically cytokines, interleukins and chemokines), and other molecules normally removed by the liver, lungs, gastrointestinal tract, kidneys, and other tissues and organs.
• IMs inflammatory mediators
• a "toxin-binding molecule” is a molecule, typically a macromolecule such as a protein that binds toxins.
• Albumin is used throughout as an exemplary toxin-binding molecule, but other proteins or non-protein macromolecules may be used as toxin-binding molecules as well.
• Components means molecules, ions, macromolecular complexes, cells, aggregates, fragments or portions thereof, or other species that are dissolved or suspended in a fluid.
• a “purification device” means a device that partitions components in an input fluid into a plurality of output streams, each containing a distribution of components that is a proper subset of the input stream components.
• purification devices include hemofilters, hollow-fiber hemofilters, dialysis cartridges, centrifuges and systems based on gradient centrifugation with or without use of substances such as ficoll.
• An "output stream enriched in smaller components”, in the context of a purification device, means a fluid stream, resulting from passage of an input fluid through the purification device, having a distribution of components that is, by a statistical measure, of lower molecular weight or hydrodynamic radius than the distribution of components in the input fluid. Examples of such statistical measures include the mean, median, mode, and range.
• An "output stream enriched in larger components”, in the context of a purification device, means a fluid stream, resulting from passage of an input fluid through the purification device, having a distribution of components that is, by a statistical measure, of higher molecular weight or hydrodynamic radius than the distribution of components in the input fluid. Examples of such statistical measures include the mean, median, mode, and range.
• a "nominal molecular weight cutoff means the mean pore size of a semipermeable membrane (e.g., as stated by the manufacturer).
• a "90% effective molecular weight cutoff of a purification device means the molecular weight of components of an input fluid at which the purification device will act to direct at least 90% of those components to the output stream enriched in larger components.
• a "sieving coefficient” is a measure predictive of the fractional permeation of a given blood component placed on one side of a semipermeable membrane.
• a "sieving distribution" of a semipermeable membrane is the set of sieving coefficients corresponding to a plurality of components found in a fluid sample exposed to the membrane.
• a "sieving distribution favoring larger components" in the context of a purification device means that the purification device produces an output stream enriched in larger components.
• a "sieving distribution favoring smaller components" in the context of a purification device means that the purification device produces an output stream enriched in smaller components.
• a purification system removes toxins from a biological fluid without discarding a large portion of the fluid. As a result, large amounts of replacement fluid need not be administered to the patient.
• Embodiments may be used to treat acute and chronic liver failure, hepato-renal syndrome, renal failure, trauma (the crush syndrome), congestive heart failure, rheumatoid arthritis, infection, sepsis, hyperlipidemia, acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction syndrome (MODS), burns, certain congenital disorders (e.g., the Guillain-Barre syndrome, Goddpasture's syndrome, anti-GMB nephritis, Waldenstrom's macroglobulinemia, systemic lupus erythematosus) and other diseases or conditions resulting in accumulation of toxins, including mediators of inflammation and other harmful components in the blood.
• congenital disorders e.g., the Guillain-Barre syndrome, Goddpasture's syndrome, anti-GMB nephritis, Waldenstrom's macroglobulinemia, systemic lupus erythematosus
• Embodiments remove inflammatory mediators from bodily fluids.
• Other embodiments may include the use of complementary purification elements to remove toxins that are normally excreted, metabolized, or otherwise processed by the liver or kidneys.
• Examples of complementary purification elements include absorptive filters, adsorptive columns, dialysis cartridges, affinity columns, columns loaded with particles with specific antibodies attached to them, and cell-based artificial organs (including artificial livers).
• certain illustrative embodiments described herein relate to the purification of blood, but could also be used to purify blood plasma, blood serum, other blood fractions, or non-blood complex body fluids such as ascitic fluid and cerebro-spinal fluid.
• Fig. 1 shows a flow diagram of a method in accordance with an embodiment of the invention.
• a fluid such as blood, blood plasma or other blood-derived fluid, is withdrawn from a source, such as a reservoir or human patient (step 100).
• a toxin-carrying molecule is extracted from the fluid (step 110).
• the toxin-carrying molecule maybe, for instance, albumin.
• the so-formed extract fluid is stored in a reservoir (step 120).
• Lower molecular weight molecules e.g., water, salts, antibiotics, nutrients, small molecule drugs, etc.
• the lower molecular weight molecules are recycled by returning them to the source (step 140). This process (steps 100-140) may be repeated or performed continuously.
• Fig. 2 shows a flow diagram for another a method in accordance with an embodiment of the present invention.
• a primary circuit is created (step 200).
• the primary circuit includes an in-line primary purification device. Fluid is caused to flow from the source and through the primary circuit (step 210). The fluid flow may be induced by pumping, force of gravity, centrifugation, or other suitable method.
• the action of the primary purification device results in the generation of an output stream that contains intermediate weight molecules (step 220).
• the intermediate weight molecules are larger than the low molecular weight molecules of step 130 of Fig. 1, but are smaller than molecules such as antibodies or cellular components such as red blood cells that are to be retained in the fluid source.
• Albumin is a specific example of an intermediate weight molecule that also happens to be a toxin-binding protein molecule.
• the output stream is collected in a reservoir (step 230). Fluid containing lower molecular weight molecules is extracted from the reservoir (step 240) in a manner that leaves the intermediate weight molecules in the reservoir.
• the reservoir may be thought of as a sink for intermediate-weight molecules.
• Fig. 3 shows another flow diagram for yet another method in accordance with an embodiment of the invention.
• An input fluid is received (step 300).
• the input fluid is partitioned into two output streams (step 310).
• a first output stream is relatively enriched in larger components derived from the source fluid and a second output stream is relatively enriched in smaller components derived from the source fluid.
• the first stream (with the larger components) is returned to the blood source (step 320).
• the second stream is collected in a reservoir (step 330). Fluid collected in the reservoir is obtained and partitioned into two further streams, one containing fluid enriched in relatively larger components and the other containing fluid enriched in relatively smaller components (step 340).
• the stream enriched in the larger components (but also including smaller components) is returned to the reservoir and retained in it (step 360).
• the stream enriched in the smaller components is recycled (step 350); for example, by returning the stream to the source.
• Fig. 4a shows a block-diagram for a cascade hemofiltration system in accordance with an embodiment of the present invention.
• Fluid e.g., blood or plasma
• a fluid source e.g., a patient, or reservoir of blood collected from a patient
• the primary purification device 30 partitions the blood into two streams: a first output stream ("a primary return stream") and a second output stream ("a primary ultrafiltrate stream").
• the primary return stream will contain larger components (as measured by hydrodynamic radius or mass) and the primary ultrafiltrate stream will contain smaller components including toxins and other molecular components that are to be removed, as well as components that are to be returned to the patient.
• the larger components e.g., blood cells, antibodies and other large proteins
• the primary purification device 30 provides the primary ultrafiltrate stream via a second outlet, which flows a through primary ultrafiltrate line 33, into a reservoir 50.
• the inlet line 31, primary purification device 30, and primary outlet line 32 together with the fluid source define a primary circuit when connected with a fluid source.
• the lines 31-33 and other lines described herein may be implemented, as is well known in the art, as standard medical-grade tubing or other suitable conduit structure.
• a secondary purification device 40 accepts the toxin-containing fluid from the reservoir 50, and creates two output streams from this fluid; a fluid having relatively smaller molecules (e.g., nutrients, medications, electrolytes, water and hormones) for return to the patient and a fluid for return to the reservoir 50 that contains relatively larger toxins (e.g., albumin-bound toxins, and mediators of inflammation such as cytokine).
• the returned fluid in addition to ions, sugars, nutrients, hormones and medications may include relatively smaller toxins such as urea, creatinine and ammonia, and other small toxic components. As described below, the smaller toxins maybe removed or inactivated using various techniques, or may be returned to the patient for metabolism and excretion.
• the larger toxins may thereby accumulate in the reservoir 50.
• the fluid source e.g., patient's blood circulation
• the secondary purification device 40 may operate much like the primary purification device 30, but selects for and emits an ultrafiltrate with components smaller than those selected by the primary filtration device 30.
• the secondary purification device 40 draws toxin-laden fluid from the reservoir 50 through a secondary inlet line 41 and partitions the fluid into two streams: a third stream (the first two streams are associated with the primary purification device discussed previously, and we here call the third stream a "secondary return stream”) containing relatively large components, and a fourth stream (which we here call the "secondary ultrafiltrate stream”) containing relatively small components.
• the secondary return stream flows back to the reservoir via secondary outlet line 42, and the secondary ultrafiltrate stream flows, via secondary ultrafiltrate line 43, back to the primary circuit.
• the secondary ultraf ⁇ ltrate line 43 connects to the primary circuit at or upstream of an inlet of the primary purification device 30 (a "pre-dilution" configuration). Because intermediate-sized toxins will exit the primary purification device 30 in the primary ultraf ⁇ ltrate stream and enter the reservoir 50, yet will be returned to the reservoir in the secondary return stream emanating from the secondary purification device 40, the concentration of intermediate-sized toxins, such as IMs, in the reservoir 50 will increase as a function of cumulative fluid flow through the primary purification device 30.
• the volume of replacement fluid needed is reduced or completely eliminated because the system of the present embodiment recycles water and lower molecular weight components.
• the system of Fig. 4a employs a toxin-sink - the reservoir 50.
• the reservoir 50 may have a limited volume because the concentration of toxins in the reservoir 50 will increase over time.
• the replacement fluid added to the reservoir may also contain drugs, sorbents, or other therapeutic substances.
• the secondary ultrafiltrate stream flows, via the secondary ultrafiltrate line 43, back to the primary circuit downstream of the primary purification device 30, e.g., by joining with the primary outlet line 32.
• Such a "post- dilution" configuration is shown in Fig. 4b.
• the secondary ultrafiltrate stream may be returned directly to the fluid source.
• the primary purification device 30 may be a permselective hemofiltration cartridge with an effective molecular weight cutoff value (e.g., a 90% effective molecular cutoff) of between 5000 and 100,000 daltons and the secondary purification device 40 may be a permselective plasmafiltration cartridge with an effective molecular weight cutoff value of between 100 and 5000 daltons.
• an effective molecular weight cutoff value e.g., a 90% effective molecular cutoff
• 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
• molecules with a molecular weight of between about 500 and 150,000 daltons will tend to concentrate in the reservoir 50, although these ranges may change depending on which components one wishes to remove from the blood and changes in the effective molecular weight cutoffs as a function of fluid flux.
• These changes maybe a function of feed flow, ultrafiltration rate, composition and structure of the semipermeable membrane, fluid viscosity, fluid osmolarity, membrane hydrophilicity, presence or lack of an anti-fouling membrane coating, membrane polarity, and other factors.
• the effective cutoff value and sieving coefficients for individual blood/plasma components and the nominal cutoff value (related to the average pore size before use) of a given permselective membrane may differ as a function of chemical and mechanical characteristics of the permselective membrane (e.g., type of polymer and porophores used, porosity wetting properties, charge, symmetry, resistance to fouling, surface exchange area, thickness), operational characteristics (feed flow rate, velocity, ultrafiltration rate, transmembrane pressure), and interactions between blood or plasma components and the filter membrane.
• a polysulfone membrane may require a nominal cutoff value of 400 kDa, while a polyethersulfone or cellulose acetate membrane may require a nominal cutoff value of only 100 kDa.
• the effective molecular weight cutoff of the primary purification device may be selected to be low enough to retain immunoglobulins and return them to the blood source, thereby retaining the beneficial effects of these molecules. Generally, the molecular weight cutoff will be selected to be below about 1,000,000 daltons for this purpose.
• the secondary inlet line 41, secondary purification device 40, and secondary outlet line 42 together constitute a secondary fluidic circuit.
• the primary ultrafiltrate line 33, and the secondary ultrafiltrate line 43 serve to transfer ultrafiltrate fluid between the primary and secondary circuits.
• the secondary ultraf ⁇ ltrate is returned to the primary fluidic circuit either upstream or downstream of the primary purification device 30.
• These configurations are referred to as pre-dilution and post- dilution configurations, respectively, since they dilute the blood before it enters the primary purification device or after it exits the primary purification device and before it is directly returned to the patient.
• Pre-dilution may prevent adverse effects, such as protein aggregation and blood coagulation in the primary purification device 30, that may occur due to concentration of the blood by the primary purification device.
• Post-dilution may enhance blood/plasma purification because in such an embodiment, the secondary output stream (primary ultrafiltrate) is not diluted.
• Fig. 5 shows a specific hemofiltration system configuration in accordance with the more general embodiment of Fig 4a.
• the system is connected to the vasculature of a patient 10 by veno-venous attachment.
• a primary circuit pump 51 urges blood through the primary circuit. Pumping of blood through the primary circuit induces production of primary ultraf ⁇ ltrate, which is urged by a primary ultraf ⁇ ltrate pump 52 through the primary ultraf ⁇ ltrate line 33 to the reservoir 50.
• a secondary circuit pump 53 induces fluid to flow from the reservoir through the secondary circuit.
• a secondary ultraf ⁇ ltrate pump 54 urges the secondary ultraf ⁇ ltrate to the primary circuit in pre-dilution configuration.
• pumps 51, 52, 53, and 54 constitute a pumping system for the embodiment.
• Any of a variety of commercially available pumps may be used.
• the reservoir 50 may be filled with replacement fluid prior to the start of therapy.
• the replacement fluid may contain therapeutic agents for adsorption and retention of specific molecules in the reservoir 50 or for delivery to a patient such as small-molecule antibiotics, anti-coagulant and anti-inflammatory compounds.
• No additional replacement fluid may be needed if the reservoir 50 is pre-filled with replacement fluid and the primary ultraf ⁇ ltrate flow rate and the secondary ultraf ⁇ ltrate flow rate are equal or nearly equal. Approximately equal flow may be achieved by setting the ultraf ⁇ ltrate pumps 52 and 54 to similar levels of flow.
• the production of primary and/or secondary ultraf ⁇ ltrate may be altered to increase or decrease the level of fluid in the reservoir 50.
• Fluid may be periodically removed from the reservoir 50, discarded, and replaced with toxin-free replacement fluid. Replacing the fluid may be especially advantageous during high-volume hemof ⁇ ltration or hemofiltration lasting for more than 8 hours.
• biochemical non-idealities may alter the binding capacity of toxin-binding molecules at high concentrations, or the secondary purification may tend to foul above a certain concentration of proteins in the secondary circuit is reached.
• the range of flow rates may generally be between 10 and 5000 ml/min in the primary and secondary circuits, which will allow production of between about 1 and 1500 ml/min of primary and secondary ultraf ⁇ ltrate.
• the fluid flow rate through the secondary purification device 40 may be chosen to be very high so as to maintain the patency of the hollow fiber lumens and to protect the permselective membrane against fouling (e.g., due to occlusion of pores by proteins, protein fragments and other components).
• the flow rate of fluid entering the secondary purification device 40 may be about 10 times greater than then the rate at which fluid enters the primary purification device 30.
• the fluid flow through the primary purification device 30 may be about between 10 and 5000 ml/min.
• the flow rate of the second output stream (the primary ultrafiltration rate) may be about 1 to 500 or about 1 to 1500 ml/min.
• Various control schemes may ensure the desired system performance.
• flow-rate and/or reservoir level sensors may be employed along with a microcontroller to adjust the pumping rates so as to ensure a proper fluid level in the reservoir 50.
• additional sensors such as blood-chemistry sensors, may also be incorporated into the system.
• the pressure generated by pumping system in the inlet line 31 and ultrafiltrate line 43 will balance so that blood from the patient does not enter the secondary purification device 40 via retrograde flow from the inlet line 31 to the ultrafiltrate line 43, or to the patient via flow in the reverse direction.
• one or more active valve or passive valves e.g., check-valves may be used to prevent such unwanted flows.
• the primary purification device 30 of Fig. 5 is a hollow-fiber hemo filter with a membrane having a nominal molecular weight cutoff of between 1 and 4,000,000 daltons.
• the secondary purification device 40 is a hollow-fiber plasmafilter having a nominal molecular weight cutoff of between 1 and 2,000,000 daltons.
• the primary purification device 30 has a sieving distribution favoring larger components, while the secondary purification device 40 has a sieving distribution favoring smaller components.
• intermediately-sized components such as immune modulators or toxin-binding molecules, will collect in the reservoir 50.
• the primary filter 30 has a molecular weight cutoff that is sufficiently high to allow the passage of albumin to the reservoir 50 (e.g., about 100,000 to 800,000 dalton, depending on the type of permselective filter used), and the secondary filter 40 has a molecular weight cutoff that is sufficiently low to prevent the passage of albumin (e.g., less than about 70,000 daltons), then albumin will be retained in, and concentrate within, the reservoir 50. Removal of albumin from the blood has the benefit of removing albumin-bound toxins, but may necessitate albumin replacement.
• the reservoir 50 of Fig. 5 includes an inlet port for filling the reservoir 50 with fluid, and an outlet port for draining the fluid held within the reservoir 50.
• the reservoir may be disposable.
• a disposable reservoir may be secured to the secondary circuit using quick-disconnects for rapidly removing or changing the reservoir fluid.
• the reservoir should be closed, or otherwise sealed to prevent, among other things, biohazard danger from the patient's blood and to maintain sterility of the system.
• Replacement fluid introduced into the reservoir may include hemofiltration fluid, a dialysate, electrolyte solution, amino acid solution, albumin solution, human serum, combinations of the foregoing, or any other solution that might be intravenously administered to a patient.
• Figs 6a-9 show embodiments which utilize at least one additional, tertiary, purification devices; Figs. 6a-7 show an embodiment which includes an adsorptive device, and Figs. 8-9 show an embodiment which includes a dialysis unit.
• the purification devices may operate to remove low molecular weight toxins with the result of clearing these toxins from the blood supply, thus mimicking the action of a healthy liver or kidney. These configurations may replace or supplement the liver or kidney function of a patient in septic shock or with multiorgan dysfunction syndrome. Embodiments that combine sorption and dialysis are also within the scope of the present invention.
• Figs. 6a-7 show an embodiment of the present invention that includes an adsorptive device 60 positioned in the secondary ultrafiltrate line 43.
• the adsorptive device 60 includes a casing defining one or more chambers, which hold adsorptive material (i.e., a toxin-binding stationary phase) to remove specific toxins.
• the adsorbent material may include activated charcoal, resins (e.g., uncharged, neutral, anion exchange or cation exchange resins), silica, albumin, immobilized antibodies, immobilized receptors, immobilized specific antagonists, polymers, cellulose derivatives, and immobilized antibiotics, or combinations thereof.
• the adsorbent material may be organized in a number of ways, e.g., as beads, rods, porous granules, a sieve, a matrix with anchored molecules, etc.
• the adsorptive device receives the stream of secondary ultrafiltrate and selectively or non-selective Iy removes components that cause or aggravate liver failure, renal failure or any other disease or pathological condition associated with accumulation in the blood circulation of toxic substances, including: ammonia, phenols, mercaptans, aromatic amino acids, urea, creatinine, oxygen reactive species, nitric oxide, and vasoactive substances.
• Adsorba columns (Gambro, Hechingen, Germany) which contains activated charcoal as the sorbent
• BioLogic-DT System HaemoCleanse, West Lafayette, IN
• MARS Molecular Adsorbent Recirculating System; Gambro GmbH, Hechingene, Germany
• Prometheus Fresenius
• Fig. 6b shows a post- dilution configuration for an embodiment that includes an adsorptive device.
• the adsorptive device may be positioned at other points in the fluidic system, e.g., the secondary filter inlet line 41 or the secondary filter outlet line 42.
• the sorbent may also be included in the reservoir 50 and the reservoir 50 stirred or shaken to encourage toxin binding to the sorbent.
• Figs. 8-9 show an embodiment of the present invention that includes further purification of the secondary ultrafiltrate by dialysis. This embodiment includes a dialysis cartridge 70 incorporated into the secondary ultrafiltrate line 43 and connected to a source of dialysis fluid.
• the dialysis cartridge 70 may be incorporated at other fluidic positions within the system, e.g., positioned in the secondary filter inlet line 41 or the secondary filter outlet line 42. Toxins in the secondary ultrafiltrate that are small enough to cross the dialysis membrane of the cartridge 70 are thus removed and prevented from re-entering the patient 10.
• any of the embodiments previously described may additionally include a cell-based device to provide specific biologic function (e.g., metabolism and/or synthesis of specific blood components).
• a HepatAssist-2 cartridge loaded with viable liver cells (Arbios Systems, Inc.) may be included in a fluidic line of the system to provide metabolic detoxification.
• various combinations of dialysis, sorption, and cell-based purification may be used.
• any of the embodiments previously described may utilize a digital control system for regulating flow within parameters as described above and for maintaining acceptable operating conditions.
• fluid may be recovered from the reservoir 50 and used for research (biomedical or otherwise) or for therapeutic purposes.
• the reservoir fluid will tend to be enriched in valuable biological components.
• These components may be recovered by various processing and purification procedures that are known in the art (fractionation, chromatography, etc.) and formulated and packaged for sale and use in research or for administration to patients as therapeutic agents.
• Example of valuable components include cytokines, chemokines, and immunomodulators.
• the purification devices described herein may be combined with instrumentation for gas exchange (including oxygenation), pathogen sterilization, temperature control, gamma irradiation, ultraviolet light treatment, etc.
• instrumentation for gas exchange including oxygenation
• pathogen sterilization including oxygenation
• temperature control including temperature control
• gamma irradiation including temperature control
• ultraviolet light treatment etc.
• the purification devices are not limited to hollow fiber filters, but may operate on other principles, including centrifugation and gradient centrifugation.

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