WO2003009885A2 - Systemes d'hemofiltration, procedes et dispositifs utilises dans le traitement de maladies liees aux mediateurs de l'inflammation - Google Patents

Systemes d'hemofiltration, procedes et dispositifs utilises dans le traitement de maladies liees aux mediateurs de l'inflammation Download PDF

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Publication number
WO2003009885A2
WO2003009885A2 PCT/US2002/023603 US0223603W WO03009885A2 WO 2003009885 A2 WO2003009885 A2 WO 2003009885A2 US 0223603 W US0223603 W US 0223603W WO 03009885 A2 WO03009885 A2 WO 03009885A2
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Prior art keywords
ultrafiltrate
stream
blood
mammal
hemofilter
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PCT/US2002/023603
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English (en)
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WO2003009885A3 (fr
Inventor
James R. Matson
Patrice A. Lee
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Immunocept, L.L.C.
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Priority claimed from US09/912,904 external-priority patent/US6730266B2/en
Application filed by Immunocept, L.L.C. filed Critical Immunocept, L.L.C.
Priority to AU2002319690A priority Critical patent/AU2002319690A1/en
Priority to EP02750294A priority patent/EP1409041A4/fr
Publication of WO2003009885A2 publication Critical patent/WO2003009885A2/fr
Publication of WO2003009885A3 publication Critical patent/WO2003009885A3/fr

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    • 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
    • A61M1/3486—Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents

Definitions

  • the present invention relates generally to systems, methods, and devices used for hemofiltration. More specifically, the present invention relates to novel systems, methods, and devices for hemofiltration for inflammatory mediator-related diseases (IMRD) , which include systemic inflammatory response syndrome ("SIRS”) , multiorgan system dysfunction syndrome (“MODS”) , and multiorgan system failure (“MOSF”) (collectively "SIRS/MODS/MOSF”) .
  • IMRD inflammatory mediator-related diseases
  • SIRS systemic inflammatory response syndrome
  • MODS multiorgan system dysfunction syndrome
  • MOSF multiorgan system failure
  • ICU intensive care unit
  • SIRS systemic inflammatory response syndrome
  • MODS multiorgan system dysfunction syndrome
  • MOSF multiorgan system failure
  • SIRS/MODS/MOSF systemic inflammatory response syndrome
  • SIRS systemic inflammatory response syndrome
  • SIRS/MODS/MOSF afflicts approximately 400,000-600,000 patients and results in about 150,000 deaths. Overall, depending on the number of organ systems failing, the mortality rate of MOSF ranges generally from 40 to 100%. For instance, if three (3) or more vital organs fail, death results in more the 90% of cases. SIRS/MODS/ MOSF is the most common cause of death in intensive care units and is the thirteenth most common cause of death in the United States of America. SIRS/MODS/MOSF costs about $5 to $10 billion yearly for supportive care. In addition, the incidence of SIRS/MODS/MOSF is on the rise; reported cases increased about 139% between 1979 and 1987.
  • the detrimental mechanism of SIRS/MODS/MOSF is the excessive activation of the inflammatory response.
  • the inflammatory response consists of the interaction of various cell systems (e.g., monocyte/macrophage, neutrophil, and lymphocytes) and various humoral systems (e.g., cytokine, coagulation, complement, and kallikrein/kinin) .
  • Each component of each system may function as an effector (e.g., killing pathogens, destroying tissue, etc.), a signal (e.g., most cytokines) , or both.
  • Humoral elements of the inflammatory response were known as- toxic mediators, but are now known collectively as inflammatory mediators ("IM”) .
  • IM include various cytokines (e.g., tumor necrosis factor (“TNF”) ; the interleukins; interferon, etc.), various prostaglandins (e.g., PG I 2 , E 2 , Leukotrienes) , various clotting factors (e.g., platelet activating factor (“PAF”) ) , various peptidases, reactive oxygen metabolites, and various poorly understood peptides which cause organ dysfunction (myocardial depressant factor (“MDF”) ) .
  • TNF tumor necrosis factor
  • PAF platelet activating factor
  • MDF myocardial depressant factor
  • Infection e.g., abscesses and sepsis
  • Infection is a common complication of critical illness.
  • Certain bacterial exotoxins, endotoxins or enterotoxins are extremely potent stimuli to SIRS/MODS/MOSF.
  • Infection is the single most common cause of SIRS leading to MODS/MOSF.
  • the development and use of effective antibiotics and other supportive measures have not had a significant effect on the death rate from MOSF.
  • the systemic inflammatory response with its network of systems is initiated and regulated through the cytokine ("CK") system and IM' s .
  • the CK system consists of more than thirty known molecules each of which activates or suppresses one or more components of the immune system and one or more CK in the network.
  • the CK network is the dominant control system of the immune response.
  • the sources of CK' s are monocyte/macrophages and endothelial cells and they are produced in every tissue in the body.
  • CK are chemical signals coordinating immune system and associated system activities; (ii) commonly, two or more CK will trigger the same action providing a "fail safe" response to a wide variety of different stimuli (the systemic inflammatory response is critical to the individuals survival; these redundant control signals assure a system response which does not falter.); (iii) CK and IM concentrations (usually measured in blood) therefore increase in order to stimulate, control, and maintain the inflammatory response proportionally to the severity of the injury or infection; and (iv) as severity of injury or infection increases, the cytodestructive activity of the system increases resulting in MODS/MOSF.
  • CK and IM signals which make up the control network of the immune response consist of many redundant control loops to assure the "fail safe" initiation and continuation of this critical response.
  • control theory indicates that a redundant, self amplifying system will not be effectively controlled by blocking one point, such as one CK or IM (Mohler, 1995) .
  • HF hemofiltration
  • a hemofilter of some sort which consists of a cellulose derivatives or synthetic membrane (e.g., polysulfone, polyamide, etc.) fabricated as either a parallel plate or hollow fiber filtering surface. Since the blood path to, through, and from the membrane is low resistance, the patients' own blood pressure drives blood through the filter circuit. In these HF applications, the hemofilter is part of a blood circuit. In passive flow HF, arterial blood flows through a large bore cannula, into plastic tubing leading to the filter; blood returns from the filter through plastic tubing to a vein.
  • arteriovenous HF This is known as arteriovenous HF.
  • a blood pump is used, so that blood is pumped from either an artery or a vein to the filter and returned to a vein.
  • Ultrafiltrate collects in the filter jacket and is drained through the ultrafiltrate line and discarded. Ultrafiltrate flow rates are usually 250 ml - 2000 ml/hour.
  • a physiologic and isotonic replacement fluid is infused into the patient concurrently with HF at a flow rate equal to or less than the ultrafiltrate flow rate. The balance of replacement fluid and ultrafiltrate is determined by the fluid status of the patient .
  • the pores of most filter membranes allow passage of molecules up to 30,000 Daltons with very few membranes allowing passage of molecules up to 50,000 Daltons.
  • the membranes used to treat renal failure were generally designed to achieve the following specific goals: (i) to permit high conductance of the aqueous phase of blood plasma water needed to permit the formation of ultrafiltrate at a fairly low transmembrane pressure (typically 20-40 mm Hg) , which requires a relatively large pore size that incidentally passes molecules of up to 30,000 to 50,000 Daltons; and (ii) to avoid passage of albumin (e.g., 68,000 Daltons).
  • the ultrafiltrate contains electrolytes and small molecules (e.g., urea, creatinine, and uric acid), but no cells and only peptides and proteins smaller than the membrane pore size.
  • the composition of the ultrafiltrate is very similar to plasma water. Loss of albumin, and subsequently, oncotic pressure, could cause or aggravate tissue edema and organ dysfunction (e.g., pulmonary edema) , so hemofilters are designed to avoid this by having molecular weight exclusion limits well below the molecular weight of albumin (e.g., 68,000 Daltons).
  • HVHF high volume HF
  • HVHF improves survival in patients with SIRS/MODS/MOSF; there is growing interest in the use of HVHF in SIRS/MODS/MOSF .
  • HVHF high volumes
  • the high volumes (currently 24 - 144 liters/day) of ultrafiltrate require equally high volumes of sterile, pharmaceutical grade replacement fluid; at these high volumes, errors in measuring ultrafiltrate coming out and replacement fluid flowing into the patient could cause injurious or lethal fluid overload or volume depletion;
  • the high volume of ultrafiltrate removed could filter out of the blood desirable compounds from the patient resulting in dangerous deficiencies; this is currently theoretical, but should be taken seriously;
  • large volumes of warm (body temperature) ultrafiltrate flowing out of the patient, and large volumes of cool (room temperature) replacement fluid flowing into the patient can cause thermal stress or hypothermia; and
  • high volumes of replacement fluid add considerable expense to the therapy.
  • HVHF as currently practiced, uses conventional hemofilters with pore sizes which provide a molecular weight cut of 30,000 Daltons and occasionally of 50,000 Daltons.
  • the device and process described in United States Patent Number 5,571,418 generally contemplates the use of large pore hemofiltration membranes with pore sizes to provide molecular weight exclusion limits of 100,000 to 150,000 Daltons. With these higher molecular weight cutoffs, these membranes are designed to remove a wider range of different IM's; these large pore membranes should remove excess amounts of all known IM's.
  • hemodialysis membranes remove very few IM (only those smaller than 5000 to 10,000 Daltons) and so have been ineffective in improving patient condition in SIRS/MODS/MOSF.
  • hemodialysis commonly results in rapid deterioration of cardiovascular function and pulmonary function requiring premature termination of the dialysis procedure.
  • Hemodialysis has also been associated with increasing the occurrence of chronic renal failure in survivors of SIRS/MODS/MOSF. HF was specifically developed (Kramer, 1997) to avoid these complications of hemodialysis and has been very successful in doing so.
  • Plasmapheresis can be done with both membrane based and centrifugation based techniques. Plasmapheresis separates plasma and all that plasma contains from blood, leaving only formed elements. The removed plasma is usually replaced by either albumin solution or fresh frozen plasma. The removed plasma would contain all IM's.
  • Studies of plasmapheresis in animal models of SIRS/MODS/MOSF have shown increased mortality with plasmapheresis compared to untreated control animals. No controlled study of plasmapheresis in humans with SIRS/MODS/MOSF has ever been done. The expense of albumin and fresh frozen plasma, and the risk of transmission of serious or deadly viral disease with fresh frozen plasma are serious draw backs to the use of plasmapheresis in SIRS/MODS/MOSF.
  • IM related disease e.g., SIRS/MODS/MOSF
  • SIRS/MODS/MOSF IM related disease
  • high volume hemofiltration holds some promises, it is unworkable in its present form and is overly dangerous.
  • the present invention fulfills this longstanding need and desire in this art .
  • SUMMARY Preferred embodiments of the process and system treat inflammatory mediator-related disease, such as sepsis or SIRS/MODS/MOSF.
  • preferred embodiments of the hemofiltration system are used in mammals.
  • Preferred embodiments are generally comprised of a hemofilter, blood and ultrafiltrate lines, and an adsorptive device of one or more chambers containing adsorbent material of one or more types .
  • the hemofilter receives a stream of blood removed from the mammal and removes ultrafiltrate from the stream of blood from the mammal and thereby creates a stream of filtered blood, which is eventually returned to the mammal, and a stream of ultrafiltrate.
  • the hemofilter sieves the ultrafiltrate, the ultrafiltrate comprised of a fraction of plasma water, electrolytes, and peptides and small proteins.
  • the sieved blood peptides and proteins have a molecular size smaller than the pore size of the membrane; IM are included in this group.
  • the hemofilter is comprised of a biocompatible material.
  • the hemofilter is comprised of a membrane and a jacket, wherein the membrane is selected from the group of biocompatible materials (e.g., polysulfone, polyacrylonitrile, polymethylmethacrylate, polyvinyl-alcohol, polyamide, polycarbonate, etc.) and cellulose derivatives, and the jacket is comprised of polycarbonate or some other suitable biocompatible material.
  • the adsorptive device is comprised of an encasement jacket.
  • the adsorptive device incorporates one or more chambers containing adsorbent material of one or more types in the chamber or chambers.
  • the adsorptive device receives the stream of ultrafiltrate and selectively or nonselectively removes IM that cause inflammatory mediator-related disease, such as sepsis and SIRS/MODS/MOSF, from the ultrafiltrate removed from the blood of the mammal to create a stream of post adsorption ultrafiltrate.
  • the adsorptive device is preferably comprised of an encasement jacket comprised of polycarbonate or other suitable biocompatible material and may be configured as having one or more chambers.
  • Each chamber may contain an adsorbent material or a combination of adsorbent materials.
  • the adsorptive device is designed to be placed in the line transferring ultrafiltrate removed by the hemofilter and adsorbs IM from the ultrafiltrate producing " post adsorption ultrafiltrate.”
  • the stream of post adsorption ultrafiltrate is eventually combined or reinfused, in whole or in part, with the stream of filtered blood and returned to the mammal .
  • the adsorbent material may be comprised of a host of materials, including, but not limited to, activated charcoal, uncharged resins, charged resins, silica, immobilized polymyxin B, anion exchange resin, cation exchange resin, neutral exchange resin, polysulfone, polyacrylonitrile, polymethylmethacrylate, polyvinyl-alcohol, polyamide, polycarbonate, cellulose derivatives, immobilized monoclonal antibodies, immobilized IM receptors, and immobilized specific antagonists.
  • the adsorbent material may also be organized in a number of ways, including a matrix of rods, a porous sieve, a matrix of porous material which conveniently presents adsorbent materials to ultrafiltrate, and beads. Each adsorbent material may be uncoated or coated; the adsorbent material and/or the adsorbent device should prevent or contain dissolution and fragmentation of adsorbent material.
  • preferred embodiments may also be comprised of a blood pump to pump the blood from the mammal, an ultrafiltrate waste pump to pump a portion of the ultrafiltrate to the waste reservoir, an ultra iltrate return pump to pump ultrafiltrate back into the blood circuit returning the ultrafiltrate to the patient, a three-way stop cock or a first three-way joint, and a second three-way joint.
  • First tubing transfers the blood from the mammal to the blood pump; second tubing transfers the blood from the blood pump to hemofilter; third tubing transfers the filtered blood filtered by the hemofilter to the three-way joint or three-way stop cock; fourth tubing transfers the filtered blood along with the post adsorption ultrafiltrate to the mammal; fifth tubing transfers the ultrafiltrate to the adsorptive device; sixth tubing transfers the post adsorption ultrafiltrate to second three-way joint; seventh tubing transfers post adsorption ultrafiltrate to the first ultrafiltrate return pump; eighth tubing transfers post adsorption ultrafiltrate from the first ultrafiltrate return pump to three-way joint or three-way stop cock joining fourth tubing which transfers filtered blood along with the post adsorption ultrafiltrate to the mammal; ninth tubing transfers post adsorption ultrafiltrate to second ultrafiltrate waste pump; and tenth tubing transfers post adsorption ultrafiltrate from second ultra filtrate waste pump to waste reservoir
  • alternative preferred embodiments may utilize a single filter, which would be a "two-stage" filter, that incorporates both the hemofilter and the adsorptive device containing the adsorbent material (s) .
  • a second ultrafiltrate pump can be used along with associated changes to the necessary tubing.
  • Preferred processes to treat IM related diseases and SIRS/MODS/MOSF in a mammal are comprised of the following steps: (a) removing blood from the mammal to create a blood stream; (b) filtering the blood stream to remove ultrafiltrate from the blood to create an ultrafiltrate stream and a filtered blood stream; (c) circulating the ultrafiltrate stream to the adsorptive device to remove IM that cause IM related disease and SIRS/MODS/MOSF to create a post adsorption ultrafiltrate stream; (d) combining the post adsorption ultrafiltrate stream with the filtered blood stream to create a post adsorption ultrafiltrate/filtered blood stream; and (e) returning the post adsorption ultrafiltrate/ filtered blood stream to the mammal.
  • Additional steps may include after step (a) , (al) pumping the blood stream; and after step (b) , (bl) circulating ultrafiltrate to the ultrafiltrate waste pump and on to the waste reservoir and after step (c) , (cl) pumping the post adsorption ultrafiltrate stream circulating the post adsorption ultrafiltrate stream to the post hemofilter blood line, or alternatively, to any convenient tubing or vascular canula which returns post adsorption ultrafiltrate stream to the mammal's vascular system.
  • Preferred embodiments provide a number of advantages, important functions and key features.
  • the use of preferred embodiments allows the safe use of two stage high volume hemofiltration ("HVHF”) with its improved patient survival, avoids dangerous fluid balance errors inherent to conventional HVHF, avoids the risk of depletion of desirable humoral compounds, avoids or minimizes thermal stress and hypothermia, and avoids the cost of excessive amounts of replacement fluid.
  • the immune system has many, redundant CK and IM control loops; several of these loops must be down regulated if system wide control is to be achieved and death from SIRS/MODS/MOSF prevented. The preferred embodiments address this task.
  • the use of the adsorptive device comprised of adsorbent material (s) provides additional advantages.
  • Conventional hemofiltration i.e., hemofiltration performed to treat acute renal failure
  • Conventional hemofiltration usually requires the production of and discard of from about 200 ml to 2,000 ml of ultra filtrate per hour. In patients, if this volume were not replaced, the loss of fluid would soon lead to dehydration, shock and death.
  • some or all of this hourly loss is replaced each hour as either medicinal or nutrient solutions, or, in whole or in part, with an isotonic, physiologic, sterile, pharmaceutical grade intravenous solution known as replacement fluid.
  • the pumps used to control ultrafiltrate and replacement fluid flow are either intravenous fluid pumps or roller pumps adapted for this purpose.
  • Criticisms of HVHF include: (i) the risk of fluid balance errors with high fluid flux; (ii) the risk of depletion of desirable compounds; (iii) the risk of hypothermia; and (iv) expense.
  • the risk of high fluid flux the high volumes of ultrafiltrate (about 48 to 150 liters/day) and replacement fluid (about 48 to 150 liters/day) , being pumped on current equipment, could result in large and dangerous fluid imbalances .
  • imbalances of as much as 30 liters of excess fluid delivered to the patient, or 30 liters of excess fluid removed from the patient could occur. Any error approaching this magnitude in either direction would be very injurious or lethal to the patient.
  • HVHF is considered by many to be dangerous and potentially deadly.
  • the high volumes of ultrafiltrate (about 48 to 150 liters/day) removed from the patient do remove large amounts of IM with resulting improvements in SIRS/MODS/MOSF. However, these high volumes may also remove desirable compounds with deleterious effects. This criticism is theoretical at this time but should be taken seriously.
  • the risk of hypothermia about 48 to 150 liters of warm (body temperature) ultrafiltrate are removed from the patient causing heat loss, and about 48 to 150 liters of cool (room temperature) replacement fluid is infused into the patient causing cooling. This flux causes thermal stress and may cause hypothermia.
  • the use of the adsorbent device by preferred embodiments addresses these concerns.
  • the adsorbent device adsorbs IM from the ultrafiltrate thus removing them from the ultrafiltrate; the post adsorption ultrafiltrate may then be reinfused, in whole or in part, back into the patient . Since post adsorption ultrafiltrate is returned to the patient, in whole or in part, the amount of replacement fluid needed to preserve fluid balance in the patient is sharply reduced (to the amount of ultrafiltrate discarded) , or eliminated entirely.
  • the volumes of ultrafiltrate discarded and replacement fluid infused will need to be only those indicated by the patients state of edema (over hydration) and/or needs to accommodate medicinal or nutrient solutions; typically 2 to 6 liters per day. These lower volumes of fluid flux (about 2 to 6 liters per day) can be safely managed by existing pump technology, pumping errors on these small volumes are well tolerated.
  • HVHF is a technique which may significantly improve survival in SIRS/MODS/MOSF, however, HVHF creates new and substantial risks and expenses. Preferred embodiments eliminate or sharply reduce these risks and expenses, and make HVHF much safer and more cost effective in patients suffering from SIRS/MODS/MOSF.
  • FIGURE 1A is a schematic of the physical layout of various components of a preferred embodiment, including mammal 100, hemofilter 102, blood pump 104, first ultrafiltrate pump 106a and second ultrafiltrate pump 106b, adsorptive device 108 having one or more chambers containing adsorbent material of one or more types, three-way stop cock or first three-way joint 110, second three-way joint 125, and associated tubing;
  • FIGURE IB is a schematic of the physical layout of various components of a preferred embodiment, including mammal 100, hemofilter 102, blood pump 104, single ultrafiltrate pump 106, adsorptive device 108 having one or more chambers containing adsorbent material of one or more types, three-way stop cock or first three-way joint 110, second three-way joint 125, and associated tubing;
  • FIGURE 2 is a schematic of an alternate physical layout of various components of a preferred embodiment, including mammal 200, hemofilter 202, blood pump 204, first ultra-filtrate pump 206a and second ultra-filtrate pump 206b, adsorptive device 208 having one or more chambers containing adsorbent material of one or more types, three-way stop cock or first three-way joint 210, second three-way joint 225, and associated tubing;
  • FIGURE 3A is a diagram showing the system flow of a preferred embodiment shown in FIGURE 1A;
  • FIGURE 3B is a diagram showing the system flow of a preferred embodiment shown in FIGURE IB
  • FIGURE 4 is a diagram showing the system flow of a preferred embodiment shown in FIGURE 2 ;
  • FIGURES 5A, 5B, and 5C are diagrams showing alternate preferred embodiments of adsorbent device 108 (in FIGURES 1A and IB) and adsorptive device 208 (in FIGURE 2) .
  • hemofiltration refers to a process of filtering blood by a membrane with separation of all formed elements, all proteins larger than effective pore size of the membrane, and retained plasma water and solute (these return to the patient) from ultrafiltrate.
  • ultrafiltration rate refers to the filtered plasma water and solute and molecules (including target peptides and proteins containing IM) smaller than effective pore size of the membrane.
  • SIRS Inflammatory Response Syndrome
  • IM inflammatory mediators
  • MODS refers to SIRS causing injury or destruction to vital organ tissue and resulting in vital organ dysfunction, which is manifested in many ways, including a drop in blood pressure, deterioration in lung function, reduced kidney function, and other vital organ malfunction.
  • MOSF Multiple Organ System Failure
  • IMRD Inflammatory Mediator Related Disease
  • IM Inflammatory Mediators
  • IM include cytokines, prostaglandins, oxygen metabolites, kinins, complement factors, various clotting factors, various peptidases, various peptides, various proteins, and various toxic peptides.
  • the molecular weight range of known IM is 1,000-100,000 Daltons.
  • Hemofilter refers to the filter used in hemofiltration. It can be configured in a number of ways, such as a series of parallel plates or as a bundle of hollow fibers.
  • the blood path is from a blood inlet port, through the fibers or between the plates, then to a blood outlet port. Filtration of blood occurs at the membrane with ultrafiltrate forming on the side of the membrane opposite the blood. This ultrafiltrate accumulates inside the body of the filter contained and embodied by the filter jacket. This jacket has an ultrafiltrate drainage port.
  • large pore hemofiltration refers to the use of a membrane or other types of filtration media which may remove albumin from a patient's blood stream.
  • a large pore hemofilter may have molecular weight exclusion limits equal to or greater than approximately 69,000 Daltons to treat SIRS, MODS, MOSF and IMRD in accordance with teachings of the present invention.
  • large pore hemofiltration performed in accordance with teachings of the present invention, may permit removal of more albumin from a patient's blood stream than some previous hemofiltration techniques.
  • teachings of the present invention substantially reduce or eliminate negative effects from removing increased amounts of albumin or other desirable compounds from a patient ' s blood stream during large pore hemofiltration.
  • the term "large pore hemofilter” refers to a hemofilter satsifactory for use in providing large pore hemofiltration in accordance with teachings of the present invention.
  • FIGURE 1A is a schematic of the physical layout of various components of a preferred embodiment, including mammal 100, hemofilter 102, blood pump 104, first ultrafiltrate pump 106a, second ultrafiltrate pump 106b, adsorptive device 108 having one or more chambers containing adsorbent material of one or more types, three-way stop cock or first three-way joint 110, second three-way joint 125, and associated tubing.
  • FIGURE IB is similar to FIGURE 1A, except that single ultrafiltrate pump 106 is used in lieu of first ultrafiltrate pump 106a and second ultrafiltrate pump 106b.
  • FIGURES 1A and IB position three-way stop cock or first three-way joint 110 in such a manner that it divides ultrafiltrate stream downstream from adsorptive device 108.
  • FIGURE 2 is an alternate schematic of the physical layout of various components of a preferred embodiment shown in FIGURES 1A and IB, except that three-way stop cock or first three- way joint 210 divides ultrafiltrate stream before adsorptive device '208.
  • FIGURES 3A and 3B are diagrams showing the system flow of a preferred embodiment shown in FIGURES 1A and IB, respectively.
  • FIGURE 4 is a diagram showing the system flow of a preferred embodiment shown in FIGURE 2.
  • Steps 301 and 302 (in FIGURES 3A and 3B) and steps 401 and 402 (in FIGURE 4) show blood being continuously withdrawn from mammal 100 (in FIGURES 1A and IB) and mammal 200 (in FIGURE 2) and directed to blood pump 104 (in FIGURES 1A and IB) and blood pump 204 (in FIGURE 2) via first tubing 101 (in FIGURES 1A and IB) and first tubing 201 (in FIGURE 2) .
  • step 303 (in FIGURE 3A and 3B) and step 403 (in FIGURE 4) show the continuous pumping of blood by blood pump 104 into hemofilter 102 via second tubing 103 (in FIGURES 1A and IB) and by blood pump 204 into hemofilter 202 via second tubing 203 (in FIGURE 2) .
  • Mammal 100 (in FIGURES 1A and IB) and mammal 200 (in FIGURE 2) preferably have a major blood vessel cannulated allowing for the continuous withdrawal of blood by blood pump 104 (in FIGURES 1A and IB) and blood pump 204 (in FIGURE 2) .
  • hemofilter 102 ultra- filtrates blood extracted from mammal 100 (in FIGURES 1A and IB) and hemofilter 202 ultra-filtrates blood extracted from mammal 200 (in FIGURE 2) .
  • step 305 As shown in steps 304 and 306 (in FIGURES 3A and 3B) and steps 404 and 406 (in FIGURE 4) , hemofilter 102 ultra- filtrates blood extracted from mammal 100 (in FIGURES 1A and IB) and hemofilter 202 ultra-filtrates blood extracted from mammal 200 (in FIGURE 2) . And, step 305
  • step 405 returns blood filtered by hemofilter 102 to mammal 100 via third tubing 105 and fourth tubing 107 in FIGURES 1A and IB and by hemofilter 202 to mammal 200 via third tubing 205 and fourth tubing 207 in FIGURE 2.
  • ultrafiltration is a filtration process in which blood cells and blood proteins with a molecular size larger than the pore size of hemofilter membrane 109 (in FIGURES 1A and IB) and hemofilter membrane 209 (in FIGURE 2) are retained in the blood path.
  • the composition of hemofilter membrane 109 (in FIGURES 1A and IB) and hemofilter membrane 209 (in FIGURE 2) are preferably comprised of biocompatible material, such as polysulfone, polyacrylonitrile, polymethylmethacrylate, polyvinyl-alcohol, polyamide, polycarbonate, cellulose derivatives, etc., but is not limited to these materials.
  • the jacket of the hemofilter will be preferably comprised of a biocompatible material, such as polycarbonate, but not limited to, polycarbonate.
  • Hemofilter membrane 109 (in FIGURES 1A and IB) and hemofilter membrane 209 (in FIGURE 2) are preferably organized as a parallel plate membrane or as a membrane hollow fiber.
  • Preferred embodiments use a hemofilter incorporating the techniques and materials discussed in United States Patent Number 5,571,418, which is herein incorporated by reference, which discusses the use of large pore hemofiltration membranes for hemofiltration processes.
  • Hemofilter membrane 109 in FIGURES 1A and IB and hemofilter membrane 209 in FIGURE 2 are preferably comprised of large pore hemofiltration membranes, which are preferably fabricated from any biocompatible material suitable for the purpose such as polysulfone, polyacrylonitrile, polymethylmethacrylate, polyvinyl- alcohol, polyamide, polycarbonate, cellulose derivatives, etc., but, of course, without limitation to these materials .
  • hemofilter membrane 109 (in FIGURES 1A and IB) sieves a fraction of plasma water, electrolytes, blood peptides and proteins with a molecular size smaller than the pore size of the membrane to form ultrafiltrate stream 111 (in FIGURES 1A and IB) , which is directed to adsorptive device 108 (in FIGURES 1A and IB) , which has one or more chambers containing adsorbent material of one or more types, via fifth tubing 112 (in FIGURES 1A and IB) .
  • adsorptive device 108 is perfused by ultrafiltrate stream 111.
  • hemofilter membrane 209 (in FIGURE 2) sieves a fraction of plasma water, electrolytes, blood peptides and proteins with a molecular size smaller than the pore size of the membrane to form ultrafiltrate stream 211 (in FIGURE 2) , which is directed to adsorptive device 208 (in FIGURE 2) , which has one or more chambers containing adsorbent material of one or more types, via fifth tubing 212, and sixth tubing 215 (in FIGURE 2) .
  • adsorptive device 208 is perfused by ultrafiltrate stream 211.
  • ultrafiltrate stream 115 (in FIGURES 1A and IB) is divided at three-way stop cock or first three-way joint 110 (in FIGURES 1A and IB) , after adsorptive device 108 in FIGURES 1A and IB.
  • ultrafiltrate stream 211 (in FIGURE 2) is divided at three-way stop cock or first three-way joint 210 (in FIGURE 2), before adsorptive device 208 in FIGURE 2.
  • FIGURE 1A after three-way stop cock or first three-way joint 110 divides post-adsorptive ultrafiltrate stream 115, discard ultrafiltrate stream 127 is directed toward second ultra-filtrate pump 106b and to waste reservoir 119 and return ultrafiltrate stream 131 is directed toward first ultra-filtrate pump 106a and on to mammal 100.
  • ultrafiltrate stream 115 is directed toward single ultrafiltrate pump 106 and discard ultrafiltrate stream 121 is directed to waste reservoir 119 and return ultrafiltrate stream 129 is returned to mammal 100.
  • ultrafiltrate stream 211 is directed toward three stop cock 210 and discard ultrafiltrate stream 221 is directed toward second ultrafiltrate pump 206b and then onto waste reservoir 219 and return ultrafiltrate stream 229 is directed toward first ultrafiltrate pump 206a and eventually returned to mammal 200.
  • Adsorptive device 108 (in FIGURES 1A and IB) and adsorptive device 208 (in FIGURE 2) have one or more chambers containing adsorbent material (s) .
  • the adsorbent material (s) is (are) preferably fixed or contained within the respective adsorbent device and none will pass into the ultrafiltrate stream or return to mammal 100 (in FIGURES 1A and IB) and mammal 200 (in FIGURE 2) .
  • the adsorbent materials used in the preferred embodiment may be coated or uncoated. The nature of the adsorbent materials used in the preferred embodiment is such that solutes to be adsorbed will be bound to the adsorbent materials.
  • adsorbent material is presented to ultrafiltrate flow by structures such as rods or plates, or flows through structures such as beads or porous matrix of any configuration effective in presentation of adsorptive material (s) to ultrafiltrate stream, or flows through one or more chambers containing immobilized particulate, beaded or fragmented adsorbent material .
  • Adsorbent materials may include, but are not limited to: silica, activated charcoal, nonionic resins, ionic resins, immobilized polymyxin B, anion exchange resin, cation exchange resin, neutral exchange resin, immobilized monoclonal antibodies, immobilized IM receptors, immobilized specific antagonists, cellulose and its derivatives, synthetic materials (e.g., polysulfone, polyacrylonitrile, polymethylmethacrylate, polyvinyl- alcohol, polyamide, polycarbonate, etc.) and the like or any combination thereof.
  • synthetic materials e.g., polysulfone, polyacrylonitrile, polymethylmethacrylate, polyvinyl- alcohol, polyamide, polycarbonate, etc.
  • the selection of adsorbent materials depends on the inflammatory mediators to be removed.
  • Preferred embodiment uses polymyxin to remove endotoxin, anti-TNF antibody to remove TNF, polyacrylonitrile to remove interleukin 1-beta and TNF, among other adsorbents, both specific and nonspecific.
  • Adsorbents may also be used in various combinations as the patients condition and stage of disease warrant.
  • FIGURES 5A, 5B, and 5C are diagrams showing preferred embodiments of adsorptive device 108 (in FIGURE 1A and IB) and adsorptive device 208 (in FIGURE 2) , both of which have one or more chambers containing adsorbent material of one or more types .
  • Adsorbent materials vary widely in their adsorptive capacity, and types and conditions of substances adsorbed.
  • IM are of many different chemical types (e.g. peptides, lipids) and each IM's charge and plasma binding (e.g., specific or nonspecific circulating soluble receptors) will vary the characteristics of how they may be adsorbed during the course of any inflammatory mediator related disease ("IMRD”) or episode of SIRS/MODS/MOSF.
  • IMRD inflammatory mediator related disease
  • adsorbent materials are of different chemical and physical types.
  • Particulate adsorbent materials e.g. charcoal; beads of polysulfone, polyacrylonitrile, polymethylmethacrylate, polyvinyl- alcohol, polyamide, polycarbonate, cellulose derivatives, and similar materials; liposomes, etc.
  • Particulate adsorbent materials may be coated or uncoated, but are usually encased in a porous flexible mesh sac or rigid porous containment jacket which allows free access of perfusing fluid (e.g.
  • ultrafiltrate but contains the particles and prevents them from being carried back to the mammal in the ultrafiltrate stream.
  • Some adsorbents e.g. silica gel
  • Some adsorbents lend themselves to being cast or otherwise fabricated in various rigid or semirigid configurations (e.g. rods, plates etc.) which allow for effective and convenient presentation of ultrafiltrate containing IM to the adsorbent material .
  • Some adsorbents e.g. monoclonal antibodies, IM receptors, specific antagonists, polymyxin B
  • the matrix of biocompatible material will be configured to allow effective and convenient presentation of ultrafiltrate containing IM to the affixed adsorbent material.
  • adsorbent device 108 in FIGURES 1A and IB
  • adsorbent device 208 in FIGURE 2
  • Adsorbent devices 508 in FIGURE 5A
  • 510 in FIGURE 5B
  • 512 in FIGURE 5C
  • Adsorbent devices 508 have an inlet port to which the ultrafiltrate tubing which carries the ultrafiltrate from hemofilter 108 (in FIGURES 1A and IB) and hemofilter 208 (in FIGURE 2) will be attached to provide ultrafiltrate flow to adsorbent devices 508, 510, or 512.
  • Ultrafiltrate flow through adsorbent device 508 (in FIGURE 5A) , 510 (in FIGURE 5B) , and 512 (in FIGURE 5C) perfuses the adsorbent materials allowing for adsorption of IM, and flows out of the adsorbent device through an outlet port .
  • FIGURE 5C where a multiple chamber configuration is used for adsorptive device 512, the chambers will be separated by a screen or other porous barrier which retains the adsorbent materials or combinations of adsorbent materials in their separate compartments and allows free flow of ultrafiltrate through adsorptive device 512.
  • An alternative embodiment utilizes separate, exchangeable modules each containing an adsorbent material or adsorbent materials. A module or a combination of modules may be inserted into the adsorbent device to provide for the adsorption of different types of IM as the condition of the mammal may require.
  • adsorbent device 108 in FIGURES 1A and IB
  • adsorptive device 208 in FIGURE 2
  • hemofilter 102 in FIGURES 1A and IB
  • hemofilter 202 in FIGURE 2
  • ultrafiltrate formed at the hemofilter membrane will pass into the hemofilter jacket
  • the hemofilter jacket will incorporate the adsorptive materials in one or more chambers and ultrafiltrate will flow through the adsorbent materials.
  • Ultrafiltrate will transfer from the combined hemofilter/adsorbent device through an outlet port to post adsorbent ultrafiltrate tubing.
  • the amount of blood continuously pumped will be operator determined and depend on the condition of mammal 100 (in FIGURES 1A and IB) and mammal 200 (in FIGURE 2) and the needs of effective HF.
  • the amount of blood continuously removed must be determined on a case by case basis.
  • the flow rate, the amount of blood removed and the duration of the HF therapy are determined by the weight, the age and the nature and severity of illness of mammal.
  • blood flow rates range from 100 to 200 ml/minute.
  • the rate of ultrafiltration depends on the nature and severity of illness and is indexed to body weight, total body water and/or clinical indices of disease management (e.g., pulmonary function, cardiovascular status, etc.).
  • total ultrafiltrate flow rate is 1 to 9 liters/hour of which from 0 to 2 liters/hour may be discarded.
  • the discard rate will be determined by the fluid balance requirements of the mammal.
  • the amount of ultrafiltrate discarded will be determined by operator as operator judges the needs of mammal 100 and mammal 200 for fluid removal.
  • the composition of the material making up the blood pump tubing, ultrafiltrate tubing, etc is preferably of a biocompatible material, such as polyvinylchloride, but not limited to this material.
  • the tubing will be flexible and have outside diameters complementary to the appropriate hemofilter connections, adsorptive device connections, joints, stop cocks, or pump heads .
  • first tubing 101 transfers blood from mammal 100 to blood pump 104; second tubing 103 transfers blood from blood pump 104 to hemofilter 102; third tubing 105 transfers the filtered blood filtered by hemofilter 102 to second three-way joint 125; fourth tubing 107 transfers the filtered blood along with the post adsorption ultrafiltrate to mammal 100; fifth tubing 112 transfers the ultrafiltrate to adsorptive device 108; sixth tubing 123 transfers the post adsorption ultrafiltrate to three-way stop cock or second three-way joint 110; seventh tubing 131 transfers post adsorption ultrafiltrate to first ultrafiltrate pump 106a; eighth tubing 129 transfers post adsorption ultrafiltrate from first ultrafiltrate pump 106a to second three-way joint 125 joining fourth tubing 107 which transfers filtered blood along with the post adsorption ultrafiltrate to the mammal; ninth tubing 127 transfers post adsorption ultra
  • First ultrafiltrate pump 106a and associated tubing implement steps 311 and 312 in FIGURE 3A; second ultrafiltrate pump 106b, waste reservoir 119, and associated tubing implement steps 309 and 310 in FIGURE 3A.
  • first tubing 101 transfers blood from mammal 100 to blood pump 104; second tubing 103 transfers blood from blood pump 104 to hemofilter 102; third tubing 105 transfers the filtered blood filtered by hemofilter 102 to second three-way joint 125; fourth tubing 107 transfers the filtered blood along with the post adsorption ultrafiltrate to mammal 100; fifth tubing 112 transfers the ultrafiltrate to adsorptive device 108; sixth tubing 123 transfers the post adsorption ultrafiltrate or ultrafiltrate stream 115 to single ultrafiltrate pump 106; seventh tubing 127 transfers post adsorption ultrafiltrate from ultrafiltrate pump 106 to three-way stop cock or first three-way joint 110; eighth tubing 129 transfers post adsorption ultrafiltrate from three-way stop cock or first three-way joint 110 to second three- way joint 125 joining fourth tubing 107 which transfers filtered blood along with the post adsorption ultrafiltrate to ma
  • first tubing 201 transfers blood from mammal 200 to blood pump 204; second tubing 203 transfers blood from blood pump 204 to hemofilter 202; third tubing 205 transfers the filtered blood filtered by hemofilter 202 to second three-way joint 225; fourth tubing 207 transfers the filtered blood along with the post adsorption ultrafiltrate to mammal 200; fifth tubing 212 transfers the ultrafiltrate to three-way stop cock or first three-way joint 210; sixth tubing 215 transfers the ultrafiltrate from three-way stop cock or first three-way joint 210 to adsorptive device 208; seventh tubing 229 transfers the post adsorption ultrafiltrate or ultrafiltrate stream 215 to first ultrafiltrate pump 204;
  • structural modification could include the integration of hemofilter 102 in FIGURES 1A and IB and hemofilter 202 in FIGURE 2 with adsorptive device 108 (in FIGURES 1A and IB) and adsorptive device 208 (in FIGURE 2) , both of which have one or more chambers containing adsorbent material of one or more types, with elimination of the additional tubing.
  • ultrafiltrate formed in jacket of hemofilter 102 (in FIGURES 1A and IB) and hemofilter 202 (in FIGURE 2) would be presented directly to adsorbent material contained with in hemofilter j cket or in a chamber or chambers directly contiguous with hemofilter jacket.
  • the chamber containing ultrafiltrate would be drained by ultrafiltrate line.
  • Ultrafiltrate would be continuously pumped and apportioned for discard or returned to mammal 100 (in FIGURES 1A and IB) and mammal 200 (in FIGURE 2) .
  • the ultrafiltrate return pump and the ultrafiltrate discard pump in the preferred embodiment shown and discussed above may be combined into a single two head ultrafiltrate pump system.
  • ultrafiltrate return pump and the ultrafiltrate discard pump are shown in the figures as two separate pumps, it is within the scope of the invention to combine two pumps into a single pump, and thus, the separate pumps may be interpreted as two parts of a single pump.
  • adsorbent device Modifications of adsorbent device will be determined by the inflammatory mediator related disease (IMRD) to be treated and the phase of the disease.
  • IMRD inflammatory mediator related disease
  • Various regions of the IM network are dominant at different phases of an IMRD and different IMRD exhibit different patterns of IM networking.
  • a different adsorbent material or materials, or different groupings of adsorbent materials will be needed for different IMRD' s in their different phases.
  • Adsorbent devices may contain a fixed adsorbent material or a fixed combination of adsorbent materials.
  • an adsorbent device may be configured with different, interchangeable modules of adsorbent materials to be adapted to the changing dominance of the IM network.
  • the modules may consist of one or more chambers containing adsorbent material of one or more types .
  • the adsorbent device may be designed to accept modules of adsorbent materials inserted in place as dictated by patient need and operator assessment .
  • Adsorbent materials exhibit chemical characteristics which determine what physical form will provide the greatest stability in flowing ultrafiltrate.
  • Adsorbent material must remain irreversibly bound to its supporting matrix, or in the case of beads (e.g. polysulfone, polyacrylonitrile, etc) or particulates (e.g. charcoal) inescapably contained in mesh or other containment device.
  • Adsorbent material, matrix, and containment material can not be allowed to dissolve, dissociate or fragment into the ultrafiltrate to be infused into the mammal.
  • Adsorbent material, matrix, and containment material must be configured to provide physical durability, and adequate porosity and configuration for optimal presentation of adsorbent material to flowing ultrafiltrate.
  • Adsorbent devices of one or more chambers containing adsorbent material of one or more types could be used in series, in which ultrafiltrate flows from the first to subsequent adsorbent devices.
  • the sequence, number and type of adsorbent devices would be determined by operator to meet the needs of mammal .
  • the ultrafiltrate stream could be divided by a manifold with distribution of ultrafiltrate to adsorbent devices arranged in a parallel configuration, with each line from each adsorbent device either returned to a manifold and reunited into a single ultrafiltrate line, or each line individually apportioned for return to mammal and discard.

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  • Biomedical Technology (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Hematology (AREA)
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Abstract

L'invention se rapporte à un système d'hémofiltration pour mammifères. Ce système comporte un hémofiltre et un dispositif d'absorption. Cet hémofiltre enlève l'ultrafiltrat d'un flux sanguin issu d'un mammifère afin de créer un flux sanguin et un flux d'ultrafiltrat. Le dispositif d'absorption est constitué de un ou plusieurs matériaux absorbants et sert à absorber des médiateurs d'inflammation du flux d'ultrafiltrat issu de l'hémofiltre, et à ôter les médiateurs d'inflammation entraînant des maladies liées aux médiateurs de l'inflammation, des sepsis, et des SIRS/MODS/MOSF afin de créer un flux d'ultrafiltrat après l'absorption. Ce flux est combiné de manière sélective avec le flux sanguin filtré et, ensemble, ces deux flux sont renvoyés vers le mammifère.
PCT/US2002/023603 2001-07-25 2002-07-24 Systemes d'hemofiltration, procedes et dispositifs utilises dans le traitement de maladies liees aux mediateurs de l'inflammation WO2003009885A2 (fr)

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AU2002319690A AU2002319690A1 (en) 2001-07-25 2002-07-24 Hemofiltration systems, methods and devices used to treat inflammatory mediator related disease
EP02750294A EP1409041A4 (fr) 2001-07-25 2002-07-24 Systemes d'hemofiltration, procedes et dispositifs utilises dans le traitement de maladies liees aux mediateurs de l'inflammation

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EP1944046A1 (fr) * 2007-01-12 2008-07-16 Sorin Group Italia S.r.l. Utilisation de résines polymères pour l'élimination adsorptive extracorporelle de médiateurs inflammatoires dans le traitement de maladies liées à l'inflammation systémique
WO2010040086A1 (fr) 2008-10-02 2010-04-08 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Administration d'un polymère adsorbant pour le traitement d'une inflammation systémique
US8038638B2 (en) 2004-02-23 2011-10-18 Hemolife Medical, Inc. Plasma detoxification and volume control system and methods of use
US8339447B2 (en) 2004-10-21 2012-12-25 Truevision Systems, Inc. Stereoscopic electronic microscope workstation
WO2016030357A1 (fr) 2014-08-26 2016-03-03 3M Innovative Properties Company Système d'élimination des médiateurs pro-inflammatoires ainsi que des granulocytes et des monocytes du sang

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8038638B2 (en) 2004-02-23 2011-10-18 Hemolife Medical, Inc. Plasma detoxification and volume control system and methods of use
US8339447B2 (en) 2004-10-21 2012-12-25 Truevision Systems, Inc. Stereoscopic electronic microscope workstation
EP1944046A1 (fr) * 2007-01-12 2008-07-16 Sorin Group Italia S.r.l. Utilisation de résines polymères pour l'élimination adsorptive extracorporelle de médiateurs inflammatoires dans le traitement de maladies liées à l'inflammation systémique
WO2008084111A1 (fr) * 2007-01-12 2008-07-17 Sorin Group Italia S.R.L. Utilisation de résines polymériques pour l'élimination extracorporelle par adsorption de médiateurs inflammatoires dans le traitement des maladies liées à une inflammation systémique
WO2010040086A1 (fr) 2008-10-02 2010-04-08 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Administration d'un polymère adsorbant pour le traitement d'une inflammation systémique
EP2352568A1 (fr) * 2008-10-02 2011-08-10 University of Pittsburgh - Of the Commonwealth System of Higher Education Administration d'un polymère adsorbant pour le traitement d'une inflammation systémique
EP2352568A4 (fr) * 2008-10-02 2013-04-17 Univ Pittsburgh Administration d'un polymère adsorbant pour le traitement d'une inflammation systémique
US8647666B2 (en) 2008-10-02 2014-02-11 University of Pittsburgh—of the Commonwealth System of Higher Education Administration of an adsorbent polymer for treatment of systemic inflammation
US9603807B2 (en) 2008-10-02 2017-03-28 University of Pittsburgh—of the Commonwealth System of Higher Education Enteral administration of sorbent polymer for treatment and prophylaxis of inflammation
WO2016030357A1 (fr) 2014-08-26 2016-03-03 3M Innovative Properties Company Système d'élimination des médiateurs pro-inflammatoires ainsi que des granulocytes et des monocytes du sang

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AU2002319690A1 (en) 2003-02-17
EP1409041A2 (fr) 2004-04-21
WO2003009885A3 (fr) 2003-07-03
EP1409041A4 (fr) 2007-05-16

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