Patent Publication Number: US-8535258-B2

Title: Hemofiltration methods for treatment of diseases in a mammal

Description:
RELATED APPLICATIONS 
     This application is a Continuation-In-Part of U.S. patent application Ser. No. 11/934,978, which is now U.S. Pat. No. 7,758,533, filed, Nov. 5, 2007, which is a continuation of U.S. patent application Ser. No. 10/843,933, filed May 12, 2004, which is now U.S. Pat. No. 7,291,122, which is a continuation-in-part of U.S. patent application Ser. No. 09/815,675 filed Mar. 23, 2001, which is now U.S. Pat. No. 6,736,972, and which claims the benefit under 35 U.S.C. §119(e), to Provisional Patent Application Ser. No. 60/191,788 filed Mar. 24, 2000. All the above-noted applications are incorporated herein by reference for all purposes. 
    
    
     BACKGROUND 
     The present disclosure relates generally to systems, methods and devices using hemofiltration for treatment of both chronic and acute Inflammatory Mediator Related Diseases. More specifically, but not by way of limitation, the present invention relates to use of hemofiltration techniques, including adsorptive devices and therapeutic agents to treat such diseases. 
     Inflammatory Mediator Related Diseases often result from 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., cytokines, 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 are known collectively as inflammatory mediators. Inflammatory mediators include various cytokines (e.g., tumor necrosis factor (“TNF”); the interleukins; interferon, etc.), various prostaglandins (e.g., PG I.sub.2, E.sub.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 (e.g., myocardial depressant factor (“MDF”)). These compounds interact as a network with the characteristics of network preservation and self-amplification. Some of these compounds, such as MDF and peptidases, are directly injurious to tissue; other compounds, such as cytokines, coordinate destructive inflammation. 
     The systemic inflammatory response with its network of systems (e.g., monocytes/macrophages, complement, antibody production, coagulation, kallikrein, neutrophil activation, etc.) is initiated and regulated through the cytokine system and other inflammatory mediators. (Cytokines are generally thought of as a subgroup of inflammatory mediators.) The cytokine system consists of more than 200 known molecules each of which activates or suppresses one or more components of the immune system or one or more other cytokines in the network. The cytokine network is the dominant control system of the immune response. The primary sources of cytokines are monocytes/macrophages, endothelial cells, and similar cells. 
     Key characteristics of the cytokine system are as follows: (i) cytokines are chemical signals coordinating immune system and associated systemic activities; (ii) commonly, two or more cytokines 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 individual&#39;s survival; these redundant control signals assure a systemic response which does not falter); (iii) cytokine and inflammatory mediator 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. Therefore, high concentrations of cytokines and inflammatory mediators measured in the patient&#39;s blood that are sustained over time correlate with the patient&#39;s risk of death. 
     The general strategy of most treatments is to identify what is conceived to be a key or pivotal single cytokine or inflammatory mediators This single target cytokine or inflammatory mediator is then inactivated in an attempt to abate the inflammatory response. The most widely applied technologies used to inactivate cytokines or inflammatory mediators is binding with monoclonal antibodies or specific antagonists. Monoclonal antibodies and specific antagonists are used because they effectively bind the target cytokines or inflammatory mediators, or their receptors, usually in an “all or none” blockade. 
     This strategy is problematic for two reasons. First, the cytokine system is essential to mobilize the inflammatory response, and through it, the host immune response. If the cytokine system were blocked, death would ensue from unhealed injury or infection. Second, the cytokine and inflammatory mediator 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. Such a redundant, self-amplifying system is generally not effectively controlled by blocking one point, such as one cytokine or inflammatory mediator. 
     Patients with life threatening illness are cared for in hospitals in the intensive care unit (ICU). These patients may be seriously injured from automobile accidents, etc., have had major surgery, have suffered a heart attack, or may be under treatment for serious infection, cancer, or other major disease. While medical care for these primary conditions is sophisticated and usually effective, a significant number of patients in the ICU will not die of their primary disease. Rather, a significant number of patients in the ICU die from a secondary complication known commonly as sepsis or septic shock. Medically, sepsis and septic shock and their effects are sometimes referred to as Systemic Inflammatory Response Syndrome, Multiple Organ System Dysfunction Syndrome, Multiple Organ System Failure, and Compensatory Anti-inflammatory Response Syndrome. 
     In short, medical illness, trauma, complication of surgery, and any human disease state, if sufficiently injurious to the patient, may elicit Systemic Inflammatory Response Syndrome/Multiple Organ System Dysfunction Syndrome/Multiple Organ System Failure or Compensatory Anti-inflammatory Response Syndrome. The systemic inflammatory response within certain physiologic limits is beneficial. As part of the immune system, the systemic inflammatory response promotes the removal of dead tissue, healing of injured tissue, detection and destruction of cancerous cells as they form, and mobilization of host defenses to resist or to combat infection. 
     When stimulated by injury or infection, the systemic inflammatory response may cause symptoms which include fever, increased heart rate, and increased respiratory rate. This symptomatic response constitutes Systemic Inflammatory Response Syndrome. If the stimulus to the systemic inflammatory response is very potent, such as massive tissue injury or major microbial infection, then the inflammatory response can be excessive. This excessive response can cause injury or destruction to vital organ tissue and may result in vital organ dysfunction, which may be manifested in many ways, including a drop in blood pressure, deterioration in lung function, reduced kidney function, and other vital organ malfunction. This condition is known as Multiple Organ System Dysfunction Syndrome. With very severe or life threatening injury or infection, the inflammatory response is extreme and can cause extensive tissue damage with vital organ damage and failure. These patients will usually die promptly without the use of ventilators to maintain lung ventilation, drugs to maintain blood pressure and strengthen the heart, and, in certain circumstances, artificial support for the liver, kidneys, coagulation, brain and other vital systems. This condition is known as Multiple Organ System Failure. These support measures partially compensate for damaged and failed organs, they do not cure the injury or infection or control the extreme inflammatory response that causes vital organ failures. 
     In recent years, it has been increasingly recognized that Systemic Inflammatory Response Syndrome/Multiple Organ System Dysfunction Syndrome/Multiple Organ System Failure/Compensatory Anti-inflammatory Response Syndrome exists in phases. In particular, an early pro-inflammatory phase, which is recognized as Systemic Inflammatory Response Syndrome, usually occurs within hours or a very few days of significant injury or infection; Compensatory Anti-inflammatory Response Syndrome occurs later. Systemic Inflammatory Response Syndrome and Compensatory Anti-inflammatory Response Syndrome may also appear in repeating and alternate cycles, or concurrently. 
     As noted previously, the pro-inflammatory response is critical to host recovery and survival (by healing injury and eliminating infection), but when extreme this response causes vital organ dysfunction or failure. In biology, it is common for one response to be counter balanced by another response; these compensatory responses or systems allow restoration of balance and return the organism (e.g., the patient) to homeostasis. Compensatory Anti-inflammatory Response Syndrome is associated with the abatement of the excesses inflammatory mediators characteristic of Systemic Inflammatory Response Syndrome, however Compensatory Anti-inflammatory Response Syndrome itself is often extreme and results in immune suppression. Systemic Inflammatory Response Syndrome and Compensatory Anti-inflammatory Response Syndrome are each associated with respective characteristic inflammatory mediators. The immune suppression of Compensatory Anti-inflammatory Response Syndrome is very commonly associated with secondary infection. This secondary infection then elicits another Systemic Inflammatory Response Syndrome, often worse and more destructive than the first. In patients, it is commonly this second episode of Systemic Inflammatory Response Syndrome that is lethal. 
     Both Systemic Inflammatory Response Syndrome and Compensatory Anti-inflammatory Response Syndrome are mediated by excesses of either pro-inflammatory and anti-inflammatory mediators, respectively. Hemofiltration may be as beneficial to Compensatory Anti-inflammatory Response Syndrome as to Systemic Inflammatory Response Syndrome. However, in Systemic Inflammatory Response Syndrome the improvement may be affirmatively observed by improvement in pulmonary and cardio-circulatory function and survival, whilst in Compensatory Anti-inflammatory Response Syndrome it may be observed negatively, by non-occurrence of secondary infection and secondary Systemic Inflammatory Response Syndrome. Both Systemic Inflammatory Response Syndrome and Compensatory Anti-inflammatory Response Syndrome may be monitored in a limited way, by monitoring their respective inflammatory mediators in blood, lung fluid or other body fluid. Systemic Inflammatory Response Syndrome and Compensatory Anti-inflammatory response Syndrome may occur concurrently as a mixed or an overlapping disorder. 
     In the United States of America each year, Systemic Inflammatory Response Syndrome/Multiple Organ System Dysfunction Syndrome/Multiple Organ System Failure is believed to afflict approximately 700,000 patients and results in about 200,000 deaths. Overall, depending on the number of organ systems failing, the mortality rate of Multiple Organ System Failure ranges generally from 40 to 100%. For instance, if three or more vital organs fail, death results in about 90% of cases. Systemic Inflammatory Response Syndrome/Multiple Organ System Dysfunction Syndrome/Multiple Organ System Failure and Compensatory Anti-inflammatory Response Syndrome are the most common cause of death in intensive care units and are the thirteenth most common cause of death in the United States of America. Systemic Inflammatory Response Syndrome/Multiple Organ System Dysfunction Syndrome/Multiple Organ System Failure and Compensatory Anti-inflammatory Response Syndrome cost at least $15 billion yearly for supportive care. In addition, the incidence of Systemic Inflammatory Response Syndrome/Multiple Organ System Dysfunction Syndrome/Multiple Organ System Failure and Compensatory Anti-inflammatory Response Syndrome are on the rise; reported cases increased about 139% between 1979 and 1987. This increase is due to an aging population, increased utilization of invasive medical procedures, immuno-suppressive therapies (e.g. cancer chemotherapy), and transplantation procedures. Inflammatory Mediator Related Diseases include both acute problems, as well as chronic problems. 
     Chronic inflammatory diseases of the joints and skin such as lupus, fibromyalgia, pemphigoid and rheumatoid arthritis and other rheumatoid conditions generally result from chromic inflammation. These diseases may therefore benefit from ultrafiltration to remove their inflammatory mediators. Removal of redundant mediators may be particularly helpful. 
     Chronic degenerative disease of the nervous system may be mediated by abnormal levels of serum and cerebrospinal fluid antibodies. For example, abnormal levels of antibodies have been detected in multifocal motor neuropathy and chronic inflammatory demyelinating polyneuropathy. The immune response has also been implicated in multiple sclerosis, Guillain-Barre syndrome, systemic lupus erythematosis, and cryobulinemic vasculitis. Patients with chronic degenerative diseases of the nervous system may, therefore, benefit from ultrafiltration of the blood to lower antibody levels, control inflammation or lower levels of other abnormal proteins or substances correlated with a particular degenerative neuromuscular disease. 
     Existing techniques of hemofiltration have been developed as a technique to control overhydration and acute renal failure in unstable ICU patients. Existing hemofiltration techniques may use a hemofilter of various designs and materials. For example, the material may consist of a cellulose derivative or synthetic membrane (e.g., polysulfone, polyamide, etc.) fabricated as either a parallel plate or hollow fiber filtering surface. Because the blood path to, through, and from the membrane is low resistance, the patient&#39;s own blood pressure drives blood through the filter circuit. In these hemofiltration applications, the hemofilter is part of a blood circuit. In passive flow hemofiltration, arterial blood flows through a large bore cannula, into plastic tubing leading to the filter and blood returns from the filter through plastic tubing to a vein. This is known as arteriovenous hemofiltration. Alternatively 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. This is known as pumped arteriovenous hemofiltration or pumped venovenous hemofiltration. 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. In order to prevent lethal volume depletion, a physiologic and isotonic replacement fluid is infused into the patient concurrently with hemofiltration 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. 
     Treatment of certain diseases by filtration of blood is well established medical practice. Dialysis, using dialysis filters, which remove molecules with molecular weights up to 5,000 to 10,000 Dalton, is used to treat chronic and some acute renal failure. Conventional hemofiltration, discussed below, is used to treat acute renal failure, and in some cases, chronic renal failure. Plasmapheresis, using plasma filters or centrifuge techniques which remove molecules with molecular weights of 1,000,000 to 5,000,000 Dalton or more, is used to treat diseases associated with high molecular weight pathologic immunoglobulins or immune complexes, (e.g., multiple myeloma, lupus vasculitis, etc.). 
     During filtration of protein-containing solutions, colloids or suspensions, or blood, the accumulation of protein as a gel or polarization layer occurs on the membrane surface. This gel layer typically reduces effective pore size, reducing the filterable molecular weights by roughly 10-40%. Therefore, pore sizes selected are somewhat larger than needed, anticipating a reduction in effective size. Thus, present membranes allow filtration and removal of excess water, electrolytes, small molecules and nitrogenous waste while avoiding loss of albumin or larger proteins. These membranes are well-suited to their accepted uses, that is, treatment of overhydration and acute renal failure in unstable ICU patients. 
     Observations in ICU patients indicate that hemofiltration, in addition to controlling overhydration and acute renal failure, is associated with improvements in lung function and cardiovascular function. None of these improvements has been associated with shortened course of ventilator therapy, shortened ICU stay, or improved survival. The usual amount of ultrafiltrate taken in the treatment of overhydration and acute renal failure is 250 to 2000 ml/hour, 24 hours a day. A few published observations have suggested that higher amounts of ultrafiltrate brought about greater improvements in pulmonary and cardiovascular status; these have resulted in the development of a technique known as high volume hemofiltration. In high volume hemofiltration, from 2 to 9 liters/hour of ultrafiltrate are taken for periods of from 4 to 24 hours or more. 
     There is however great hesitance to use high volume hemofiltration for the following reasons: (i) 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; (ii) the high volume of ultrafiltrate removed could filter out of the blood desirable compounds from the patient resulting in dangerous deficiencies; (iii) 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 (iv) high volumes of replacement fluid add considerable expense to the therapy. 
     High volume hemofiltration, as currently practiced, uses conventional hemofilters with pore sizes which provide a molecular weight cut off of 30,000 Daltons and occasionally of 50,000 Daltons. The device and process described in U.S. Pat. No. 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 inflammatory mediators. These large pore membranes should remove excess amounts of all known inflammatory mediators. These large pore hemofiltration membranes have been demonstrated in animal studies to be superior to conventional hemofilter membranes in improving survival time in a swine model of lethal Staphylococcus aureus infection (Lee, P A et al. Critical Care Medicine April 1998). However, it may be anticipated that in high volume hemofiltration, the large pore membranes may also remove more desirable compounds thus increasing the risk of the negative side effects of high volume hemofiltration. 
     Other techniques used in the past to treat inflammatory diseases include hemodialysis and plasmapheresis. Hemodialysis is well suited to fluid and small solute (less the 10,000 Daltons) removal. However hemodialysis membranes remove very few inflammatory mediators (only those smaller than 5000 to 10,000 Daltons) and so have been ineffective in improving patient condition in Systemic Inflammatory Response Syndrome/Multiple Organ Dysfunction Syndrome/Multiple Organ System Failure. In the unstable ICU patient, 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 Systemic Inflammatory Response Syndrome/Multiple Organ Dysfunction Syndrome/Multiple Organ System Failure. Hemofiltration was specifically developed 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 inflammatory mediators. However all desirable substances, many adapted to the patient&#39;s current condition, are also removed, often with injurious or lethal effects. 
     Consequently, the additional methods for treatment of Inflammatory Mediator Related Diseases are needed. Furthermore, while high volume hemofiltration holds some promises, it seems to be unworkable and overly dangerous in present form. 
     SUMMARY 
     To provide improvements to treatment systems and methods for patients experiencing Inflammatory Mediator Related Diseases and the like, the illustrative, non-limiting embodiments described herein are directed to systems, methods, and apparatuses for treating Inflammatory Mediator Related Diseases and the like. According to one illustrative, non-limiting embodiment, a method for treating a patient experiencing Inflammatory Mediator Related Diseases includes providing a network of medical tubing, fluidly coupling the network of medical tubing to the patient for removal of blood and delivery of fluids, and fluidly coupling a hemofilter to the network of medical tubing. The hemofilter has a molecular weight exclusion limit equal to or greater than approximately 69,000 Daltons and is operable to remove an ultrafiltrate from the blood stream in a portion of the network of medical tubing and to create a filtered blood stream for return to the patient through a portion of the network of medical tubing and an ultrafiltrate stream. The method further includes fluidly coupling a waste reservoir to the network of medical tubing and fluidly coupling an adsorptive device to a portion of the network of medical tubing. The adsorptive device contains at least one adsorbent material operable to receive the ultrafiltrate stream from the hemofilter and to remove an inflammatory mediator therefrom to create a post adsorption ultrafiltrate routable to at least one of the patient or to the waste reservoir. The method also include administering a therapeutic agent to the patient for treating Inflammatory Mediator Related disease. 
     According to another illustrative, non-limiting embodiment, a hemofiltration system for treating a patient includes a network of medical tubing, a hemofilter fluidly coupled to the network of medical tubing, at least one therapeutic agent for administering to the patient, and an adsorptive device fluidly coupled to the network of medical tubing. The hemofilter may have a molecular weight exclusion limit equal to or greater than approximately 69,000 Daltons. The hemofilter is operable to remove an ultrafiltrate from a blood stream extracted from the patient and to create a filtered blood stream in a return flow path to the patient and an ultrafiltrate stream. The adsorptive device contains at least one adsorbent material and is operable to receive the ultrafiltrate stream from the hemofilter and to create a post adsorption ultrafiltrate routable to at least one of the return flow path and a waste reservoir. 
     According to another illustrative, non-limiting embodiment, a hemofiltration system for treating an Inflammatory Mediator Related Disease in a mammal includes a plurality of medical tubes forming a network of medical tubes, a hemofilter fluidly coupled to the network of medical tubes, and at least one therapeutic agent used to treat the Inflammatory Mediator Related Disease. The hemofilter has a molecular weight exclusion limit equal to or greater than approximately 69,000 Daltons and is operable to receive blood from a mammal and to selectively remove an inflammatory mediator from the blood, and to create a filtered blood stream in a return flow path to the mammal. The therapeutic agent is operable to reduce adverse effects of the inflammatory mediator. 
     Other features and advantages of the illustrative, non-limiting embodiments will become apparent with reference to the drawings and detailed description that follow. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       A more complete understanding of specific embodiments of the present invention and advantages thereof may be acquired by referring to the following description taken in conjunction with the accompanying drawings, in which like reference numbers indicate like features, and wherein: 
         FIG. 1A  is a schematic diagram of the physical layout of various components of a specific, illustrative, non-limiting embodiment, including a patient, which may be any mammal  100 , such as a human, a hemofilter  102 , a blood pump  104 , a first ultrafiltrate pump  106   a  and a second ultrafiltrate pump  106   b , an adsorptive device  108  having one or more chambers containing adsorbent material of one or more types, a three-way stop cock or first three-way joint  110 , a second three-way joint  125 , and associated tubing; 
         FIG. 1B  is a schematic of the physical layout of various components of a specific, illustrative, non-limiting embodiment, including mammal  100 , such as a human, 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; 
         FIG. 2  is a schematic diagram of an alternate physical layout of various components of a specific, illustrative, non-limiting embodiment, including mammal  200 , such as a human, hemofilter  202 , blood pump  204 , first ultrafiltrate pump  206   a  and second ultrafiltrate pump  206   b , 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; 
         FIG. 3  is a diagram showing the system flow of a specific, illustrative, non-limiting embodiment using the system of  FIG. 1A ; 
         FIG. 4  is a diagram showing the system flow of a specific, illustrative, non-limiting embodiment using the system shown in  FIG. 2 ; 
         FIGS. 5A ,  5 B, and  5 C are diagrams showing alternate, specific, illustrative, non-limiting embodiments of adsorbent device  108  (in  FIGS. 1A and 1B ) and adsorptive device  208  (in  FIG. 2 ); 
         FIG. 6  illustrates a method for providing therapeutic agents with hemofiltration according to one illustrative, non-limiting embodiment; and 
         FIG. 7  illustrates a system for providing therapeutic agents and hemofiltration according to one illustrative, non-limiting embodiment. 
     
    
    
     DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS 
     In the following detailed description of illustrative, non-limiting embodiments, reference is made to the accompanying drawings that form a part hereof. These embodiments are described in sufficient detail to enable those skilled in the art to practice the inventions, and it is understood that other embodiments may be utilized and that logical structural, mechanical, electrical, and chemical changes may be made without departing from the spirit or scope of the invention. To avoid detail not necessary to enable those skilled in the art to practice the embodiments described herein, the description may omit certain information known to those skilled in the art. The following detailed description is not to be taken in a limiting sense, and the scope of the illustrative embodiments are defined only by the appended claims. 
     As a point of reference, the following terms and definitions are provided. Although definitions are provided herein, one skilled in the art may understand the various terms, based on further information provided herein or background knowledge, to encompass subject matter beyond that set forth in these definitions. 
     The term “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 from ultrafiltrate. Blood components not part of the ultrafiltrate are normally returned to the mammal. 
     The term “ultrafiltrate” refers to the filtered plasma water, solute, molecules and other materials, including target peptides and proteins containing inflammatory mediators and smaller than effective pore size of the membrane in a hemofilter. 
     The term “Systemic Inflammatory Response Syndrome” refers to the excessive and dysfunctional elaboration of inflammatory mediators in a mammal, which results in an excessive and injurious inflammatory response. 
     The term “Multiple Organ Dysfunction Syndrome” refers to Systemic Inflammatory Response Syndrome causing injury or destruction to vital organ tissue and resulting in vital organ dysfunction, which may be manifested in many ways, including a drop in blood pressure, deterioration in lung function, reduced kidney function, and other vital organ malfunction. 
     The term “Multiple Organ System Failure” refers to the clinical syndrome of vital organ dysfunction or failure due to tissue injury resulting from Systemic Inflammatory Response Syndrome. Its mortality rate is approximately 40-100%. 
     The term “Inflammatory Mediator Related Disease” refers to any disease state characterized by injurious or lethal excess production of inflammatory mediators. Diseases commonly included in this category include lupus erythematosis, hemolytic uremic syndrome, bullous pemphigoid, pemphigus vulgaris, sepsis, Systemic Inflammatory Response Syndrome/Multiple Organ Dysfunction Syndrome/Multiple Organ System Failure, Compensatory Anti-inflammatory Response Syndrome, fibromyalgia, rheumatoid conditions, chronic neuromuscular disease such as multiple sclerosis, Guillain-Barre syndrome, cryobulinemic vasculitis, chronic inflammatory demyelinating polyneuropathy, macular degeneration, chronic neuromuscular and multifocal motor neuropathy, and certain coagulation disorders. Various other diseases presently known or discovered in the future may also fall within the category of Inflammatory Mediator Related Diseases. 
     The term “Compensatory Anti-inflammatory Response Syndrome” refers to the clinical condition which occurs in association with or in response to Systemic Inflammatory Response Syndrome, which is a reduction, compensatory or otherwise, of the immune responsiveness of the host. If the reduced immune responsiveness of Compensatory Anti-inflammatory Response Syndrome is sufficiently severe, then anergy and increased susceptibility to infection may lead to complicating new infections in the host. Compensatory Anti-inflammatory Response Syndrome is associated with circulating anti-inflammatory mediators including interleukins-4, -10, -11, and -13, soluble receptors of TNF, and the like. Concentration of these anti-inflammatory inflammatory mediators in the blood of the host may correlate with the severity of Compensatory Anti-inflammatory Response Syndrome. 
     The term “inflammatory mediators” refers to a heterogeneous group of chemicals synthesized and released by human tissue. Inflammatory mediators 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 inflammatory mediators is typically between 1,000-500,000 Daltons. Inflammatory mediators may include both pro-inflammatory and anti-inflammatory mediators. 
     The term “hemofilter” refers to a filter used in hemofiltration. It may 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 typically 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 may accumulate inside the body of the filter enclosed by the filter jacket. This jacket typically has an ultrafiltrate drainage port. 
     The term “large pore hemofiltration” refers to the use of a membrane or other types of filtration media which may remove albumin from a mammal&#39;s blood stream. For some applications, a large pore hemofilter may have molecular weight exclusion limits equal to or greater than approximately 69,000 Daltons and may be used to treat Inflammatory Mediator Related Diseases in accordance with teachings of the present invention. For some applications, large pore hemofiltration, performed in accordance with teachings of the present invention, may permit removal of more albumin from a mammal&#39;s blood stream than some previous hemofiltration techniques and devices. However, teachings of the present invention may be used to substantially reduce or eliminate negative effects from removing increased amounts of albumin or other desirable compounds from a mammal&#39;s blood stream during large pore hemofiltration. In some uses, large pore hemofiltration may treat liver failure using a hemofilter of up to 500-1 million kD. In some illustrative, non-limiting embodiments, the hemofilter is a 100 kiloDalton to 150 kiloDalton hemofilter. In some illustrative, non-limiting embodiments, the hemofilter has a molecular weight exclusion limit of up to 500,000 to 1,000,000 Daltons. 
     The term “large pore hemofilter” refers to a hemofilter satisfactory for use in providing large pore hemofiltration in accordance with teachings of the present invention. “High Volume hemofiltration” includes hemofiltration in which from 2 to 9 liters/hour of ultrafiltrate are taken for periods of from 4 to 24 hours or more. 
       FIG. 1A  is a schematic diagram of the physical layout of various components of an illustrative, non-limiting embodiment, including a patient, e.g., a mammal  100 , such as a human, a hemofilter  102 , a blood pump  104 , a first ultrafiltrate pump  106   a , a second ultrafiltrate pump  106   b , an adsorptive device  108  having one or more chambers containing adsorbent material of one or more types, a three-way stop cock or first three-way joint  110 , a second three-way joint  125 , and associated tubing.  FIG. 1B  is similar to  FIG. 1A , except that a single ultrafiltrate pump  106  is used in lieu of the first ultrafiltrate pump  106   a  and the second ultrafiltrate pump  106   b . Both  FIGS. 1A and 1B  position the three-way stop cock or first three-way joint  110  in such a manner that it divides the ultrafiltrate stream downstream from the adsorptive device  108 .  FIG. 2  is an alternative, schematic diagram of a physical layout of various components of a specific illustrative, non-limiting embodiment shown in  FIGS. 1A and 1B , except that the three-way stop cock or first three-way joint  210  divides the ultrafiltrate stream before the adsorptive device  208 .  FIG. 3  is a diagram showing the system flow of a specific, non-limiting embodiment using the embodiment shown in  FIG. 1A .  FIG. 4  is a schematic diagram that shows the system flow of a specific, non-limiting embodiment using the embodiment shown in  FIG. 2 . 
     Steps  301  and  302  (in  FIG. 3 ) and steps  401  and  402  (in  FIG. 4 ) show blood being continuously withdrawn from the mammal  100 ,  200  (in  FIGS. 1A ,  1 B, and  2 ) and directed to blood pump  104  (in  FIGS. 1A and 1B ) and blood pump  204  (in  FIG. 2 ), such as a human via first tubing  101  (in  FIGS. 1A and 1B ) and first tubing  201  (in  FIG. 2 ). Specifically, step  303  (in  FIG. 3 ) and step  403  (in  FIG. 4 ) show the continuous pumping of blood by the blood pump  104  into the hemofilter  102  via the second tubing  103  (in  FIGS. 1A and 1B ) and by the blood pump  204  into the hemofilter  202  via the second tubing  203  (in  FIG. 2 ). The mammal  100 ,  200  may have a major blood vessel cannulated allowing for the continuous withdrawal of blood by the blood pump  104  (in  FIGS. 1A and 1B ) and the blood pump  204  (in  FIG. 2 ). As shown in steps  304  and  306  (in  FIG. 3 ) and steps  404  and  406  (in  FIG. 4 ), the hemofilter  102  ultra-filtrates blood extracted from mammal  100 , such as a human (in  FIGS. 1A and 1B ), and the hemofilter  202  ultra-filtrates blood extracted from the mammal  200 , such as a human (in  FIG. 2 ). And, step  305  (in  FIG. 3 ) and step  405  (in  FIG. 4 ) return blood filtered by the hemofilter  102  to the mammal  100  via the third tubing  105  and the fourth tubing  107  in  FIGS. 1A and 1B  and by the hemofilter  202  to the mammal  200  via the third tubing  205  and the fourth tubing  207  in  FIG. 2 . 
     Referring to  FIGS. 1A ,  1 B, and  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  FIGS. 1A and 1B ) and hemofilter membrane  209  (in  FIG. 2 ) are retained in the blood path and pass the hemofilter membrane while other portions may be sieved into a separate fluid path. The composition of the hemofilter membrane  109  (in  FIGS. 1A and 1B ) and the hemofilter membrane  209  (in  FIG. 2 ) may include 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 may include a biocompatible material, such as polycarbonate, but is not limited to polycarbonate. Hemofilter membrane  109  (in  FIGS. 1A and 1B ) and hemofilter membrane  209  (in  FIG. 2 ) may be organized as a parallel plate membrane or as a membrane hollow fiber. 
     Some illustrative embodiments may use a hemofilter incorporating the techniques and materials discussed in U.S. Pat. No. 5,571,418, which is herein incorporated by reference for all purposes, and which discusses the use of large pore hemofiltration membranes for hemofiltration processes. Hemofilter membrane  109  in  FIGS. 1A and 1B  and hemofilter membrane  209  in  FIG. 2  may include large pore hemofiltration membranes, which may be fabricated from any biocompatible material suitable for the purpose such as polysulfone, polyacrylonitrile, polymethylmethacrylate, polyvinyl-alcohol, polyamide, polycarbonate, cellulose derivatives, etc., but without limitation to these materials. 
     As shown in step  304  in  FIG. 3 , the hemofilter membrane  109  (in  FIGS. 1A and 1B ) 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  FIGS. 1A and 1B ), which is directed to adsorptive device  108  (in  FIGS. 1A and 1B ), which has one or more chambers containing adsorbent material of one or more types, via fifth tubing  112  (in  FIGS. 1A and 1B ). As shown in step  307  in  FIG. 3 , adsorptive device  108  is perfused by ultrafiltrate stream  111 . Similarly, as shown in step  404  in  FIG. 4 , the hemofilter membrane  209  (in  FIG. 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  FIG. 2 ), which is directed to adsorptive device  208  (in  FIG. 2 ), which has one or more chambers containing adsorbent material of one or more types, via fifth tubing  212 , and sixth tubing  215  (in  FIG. 2 ). As shown in step  407  in  FIG. 4 , the adsorptive device  208  is perfused by ultrafiltrate stream  211 . 
     As shown in steps  308  in  FIG. 3 , the ultrafiltrate stream  115  (in  FIGS. 1A and 1B ) is divided at three-way stop cock or first three-way joint  110  (in  FIGS. 1A and 1B ), after adsorptive device  108  in  FIGS. 1A and 1B . As shown by step  408  in  FIG. 4 , the ultrafiltrate stream  211  (in  FIG. 2 ) is divided at three-way stop cock or first three-way joint  210  (in  FIG. 2 ), before adsorptive device  208  in  FIG. 2 . 
     Specifically, in  FIG. 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 ultrafiltrate pump  106   b  and to waste reservoir  119 , and return ultrafiltrate stream  131  is directed toward first ultrafiltrate pump  106   a  and on to mammal  100 , such as a human. In  FIG. 1B , the 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 , such as a human. In  FIG. 2 , the ultrafiltrate stream  211  is directed toward three-way joint stop cock  210  and discard ultrafiltrate stream  221  is directed toward second ultrafiltrate pump  206   b  and then onto waste reservoir  219  and return ultrafiltrate stream  229  is directed toward first ultrafiltrate pump  206   a  and eventually returned to mammal  200 , such as human. 
     Adsorptive device  108  (in  FIGS. 1A and 1B ) and adsorptive device  208  (in  FIG. 2 ) have one or more chambers containing adsorbent material(s). The adsorbent material(s) may be fixed or contained within the respective adsorbent device. Typically none will pass into the ultrafiltrate stream or return to mammal  100  (in  FIGS. 1A and 1B ) and mammal  200  (in  FIG. 2 ), such as a human. The adsorbent materials used in specific embodiments may be coated or uncoated. The nature of the adsorbent materials used in specific embodiments is such that solutes to be adsorbed may be bound to the adsorbent materials. As shown in  FIGS. 5A ,  5 B, and  5 C, the adsorbent material is presented to ultrafiltrate flows by structures such as rods or plates, or through structures such as beads or porous matrix of any configuration effective in presentation of adsorptive material(s) to ultrafiltrate stream, or 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 or uncharged resins or polymers, ionic or charged resins or polymers, immobilized polymyxin B, anion exchange resin or polymer, cation exchange resin or polymer, neutral exchange resin or polymer, immobilized monoclonal antibodies, immobilized inflammatory mediators receptors, immobilized specific antagonists, cellulose and its derivatives, synthetic materials, polysulfone, polyacrylonitrile, polymethylmethacrylate, polyvinyl-alcohol, polyamide, polycarbonate, polystyrene-derivative fibers, Xigris® and the like or any combination thereof. 
     The selection of adsorbent materials may depend on the inflammatory mediators to be removed. Specific embodiments may use polymyxin to remove endotoxin, anti-TNF antibody to remove TNF, or polyacrylonitrile to remove interleukin 1-beta and TNF, among other adsorbents. Adsorbents may be both specific and nonspecific. Adsorbents may also be used in various combinations as the mammal&#39;s condition and stage of disease warrant. 
       FIGS. 5A ,  5 B, and  5 C are diagrams showing selected embodiments of adsorptive device  108  (in  FIGS. 1A and 1B ) and adsorptive device  208  (in  FIG. 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 as well as types and conditions of substances adsorbed. Inflammatory mediators are of many different chemical types (e.g. peptides, lipids) and each inflammatory mediator&#39;s charge and plasma binding (e.g., specific or nonspecific circulating soluble receptors) may vary and affect characteristics of how they may be adsorbed during the course of any Inflammatory Mediator Related Disease. For this reason, various adsorbent materials may be used in a single adsorptive device in order to provide the range of chemical binding characteristics and capacity needed for removal of many inflammatory mediators from the ultrafiltrate. 
     Adsorbent materials may be 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.) 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) 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 inflammatory mediators to the adsorbent material. 
     Other adsorbents (e.g. monoclonal antibodies, inflammatory mediators receptors, specific antagonists, polymyxin B) may best be affixed to a supporting matrix of biocompatible material (e.g. polycarbonate and the like) for presentation of adsorbent material to the ultrafiltrate stream containing inflammatory mediators. The matrix of biocompatible material may be configured to allow effective and convenient presentation of ultrafiltrate containing inflammatory mediators to the affixed adsorbent material. 
     Depending on physical and chemical compatibilities of the adsorbent materials, and the requirements of adequate ultrafiltrate flow, the adsorbent device  108  (in  FIGS. 1A and 1B ) and the adsorbent device  208  (in  FIG. 2 ) may be configured as one chamber containing one or more adsorbent materials, as shown in adsorptive device  508  in  FIG. 5A  and adsorptive device  510  in  FIG. 5B , or separated into multiple chambers each containing one or more adsorbent materials, as shown in adsorptive device  512  in  FIG. 5C . The adsorbent devices  508  (in  FIG. 5A ),  510  (in  FIG. 5B ), and  512  (in  FIG. 5C ) have an inlet port to which the ultrafiltrate tubing, which carries the ultrafiltrate from hemofilter  108  (in  FIGS. 1A and 1B ) and hemofilter  208  (in  FIG. 2 ), may be attached to provide ultrafiltrate flow to the adsorbent devices  508 ,  510 , or  512 . Ultrafiltrate flow through the adsorbent device  508  (in  FIG. 5A ),  510  (in  FIG. 5B ), and  512  (in  FIG. 5C ), perfuses the adsorbent materials allowing for adsorption of inflammatory mediators, and flows out of the adsorbent device through an outlet port. 
     Referring to  FIG. 5C , where a multiple chamber configuration is used for adsorptive device  512 , the chambers may 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 inflammatory mediators as the condition of the mammal may require. Although not shown, the adsorbent device  108  (in  FIGS. 1A and 1B ) and the adsorptive device  208  (in  FIG. 2 ) may be incorporated into or combined with hemofilter  102  (in  FIGS. 1A and 1B ) and hemofilter  202  (in  FIG. 2 ), respectively. In this embodiment ultrafiltrate formed at the hemofilter membrane passes into the hemofilter jacket, the hemofilter jacket incorporates the adsorptive materials in one or more chambers and ultrafiltrate flows through the adsorbent materials. Ultrafiltrate transfers from the combined hemofilter/adsorbent device through an outlet port to post adsorbent ultrafiltrate tubing. 
     The amount of blood continuously pumped may be operator determined and may depend on the condition of mammal  100  (in  FIGS. 1A and 1B ) and mammal  200  (in  FIG. 2 ), such as a human, and the needs of effective hemofiltration. The amount of blood continuously removed may be determined on a case by case basis. The flow rate, the amount of blood removed and the duration of the hemofiltration therapy may be determined by the weight, the age and the nature and severity of the illness in the mammal. Typically, but without limitation, blood flow rates may range from 100 to 200 ml/minute. The rate of ultrafiltration may depend on the nature and severity of illness and may be indexed to body weight, total body water and/or clinical indices of disease management (e.g., pulmonary function, cardiovascular status, etc.). Typically, total ultrafiltrate flow rate is 1 to 9 liters/hour of which from 0 to 2 liters/hour may be discarded. The discard rate may be determined by the fluid balance requirements of the mammal. The amount of ultrafiltrate discarded may be determined by the operator as the operator judges the needs of mammal  100  and mammal  200 , such as a human, for fluid removal. All ultrafiltrate not discarded may returned to the mammal  100  (in  FIGS. 1A and 1B ) and the mammal  200  (in  FIG. 2 ), such as a human. 
     With respect to the tubing used in specific embodiments, e.g., the blood pump tubing, ultrafiltrate tubing, etc., may be made of a biocompatible material, such as polyvinylchloride, but is not limited to this material. The tubing may be flexible and have outside or inside diameters complementary to the appropriate hemofilter connections, adsorptive device connections, joints, stop cocks, or pump heads. 
     With respect to the tubing in  FIG. 1A , the first tubing  101  transfers blood from the mammal  100 , such as a human, to the blood pump  104 ; the second tubing  103  transfers blood from the blood pump  104  to the hemofilter  102 ; the third tubing  105  transfers the filtered blood filtered by the hemofilter  102  to the second three-way joint  125 ; the fourth tubing  107  transfers the filtered blood along with the post adsorption ultrafiltrate to the mammal  100 , such as a human; the fifth tubing  112  transfers the ultrafiltrate to adsorptive device  108 ; the sixth tubing  123  transfers the post adsorption ultrafiltrate to the three-way stop cock or first three-way joint  110 ; the seventh tubing  131  transfers post adsorption ultrafiltrate to the first ultrafiltrate pump  106   a ; the eighth tubing  129  transfers post adsorption ultrafiltrate from the first ultrafiltrate pump  106   a  to the second three-way joint  125  joining the fourth tubing  107 , which transfers filtered blood along with the post adsorption ultrafiltrate to the mammal; the ninth tubing  127  transfers post adsorption ultrafiltrate to the second ultrafiltrate pump  106   b ; and the tenth tubing  121  transfers post adsorption ultrafiltrate from the second ultra filtrate pump  106   b  to the waste reservoir  119 . It should be apparent that the tubes, e.g., tubes  101 ,  103 ,  105 ,  107 ,  112 ,  123 , etc., may take numerous configurations as needed to transports fluids and that together the plurality of fluidly coupled tubes form a network of medical tubes. According to one illustrative, non-limiting embodiment, the first ultrafiltrate pump  106   a  and associated tubing implement steps  311  and  312  in  FIG. 3 . According to one illustrative, non-limiting embodiment, the second ultrafiltrate pump  106   b , waste reservoir  119 , and associated tubing implement steps  309  and  310  in  FIG. 3 . It should be apparent that while peristaltic pumps are shown, the various pumps may be any device that provides motive force to a fluid stream. 
     With respect to the tubing in  FIG. 1B , the first tubing  101  transfers blood from the mammal  100 , such as a human, to the blood pump  104 ; the second tubing  103  transfers blood from the blood pump  104  to the hemofilter  102 ; the third tubing  105  transfers the filtered blood filtered by hemofilter  102  to the second three-way joint  125 ; the fourth tubing  107  transfers the filtered blood along with the post adsorption ultrafiltrate to the mammal  100 , such as a human; the fifth tubing  112  transfers the ultrafiltrate to the adsorptive device  108 ; the sixth tubing  123  transfers the post adsorption ultrafiltrate or ultrafiltrate stream  115  to a single ultrafiltrate pump  106 ; the seventh tubing  127  transfers post adsorption ultrafiltrate from the ultrafiltrate pump  106  to the three-way stop cock or first three-way joint  110 ; the eighth tubing  129  transfers post adsorption ultrafiltrate from the three-way stop cock or first three-way joint  110  to the second three-way joint  125  joining the fourth tubing  107 , which transfers filtered blood along with the post adsorption ultrafiltrate to mammal  100 , such as a human; and the ninth tubing  121  transfers post adsorption ultrafiltrate from the three-way stop cock or first three-way joint  110  to the waste reservoir  119 . According to one illustrative, non-limiting embodiment, the single ultrafiltrate pump  106  and associated tubing implement step  351  in  FIG. 3 . Accordingly to one illustrative, non-limiting embodiment, the waste reservoir  119  and associated tubing implement step  310  in  FIG. 3 . Accordingly to one illustrative, non-limiting embodiment, the second three-way joint  125  and associated tubing implement step  312  in  FIG. 3 . 
     With respect to the tubing in  FIG. 2 , the first tubing  201  transfers blood from the mammal  200 , such as a human, to the blood pump  204 ; the second tubing  203  transfers blood from the blood pump  204  to the hemofilter  202 ; the third tubing  205  transfers the filtered blood filtered by hemofilter  202  to the second three-way joint  225 ; the fourth tubing  207  transfers the filtered blood along with the post adsorption ultrafiltrate to the mammal  200 , such as a human; the fifth tubing  212  transfers the ultrafiltrate to the three-way stop cock or first three-way joint  210 ; the sixth tubing  215  transfers the ultrafiltrate from three-way stop cock or first three-way joint  210  to the adsorptive device  208 ; the seventh tubing  229  transfers the post adsorption ultrafiltrate or ultrafiltrate stream  215  to the first ultrafiltrate pump  206   a ; the eighth tubing  223  transfers post adsorption ultrafiltrate from the first ultrafiltrate pump  206   a  to second three-way joint  225  joining the fourth tubing  207 , which transfers filtered blood along with the post adsorption ultrafiltrate to mammal  200 , such as a human; the ninth tubing  225  transfers ultrafiltrate from the three-way stop cock or first three-way joint  210  to the second ultrafiltrate pump  206   b ; and the tenth tubing  233  transfers ultrafiltrate from second ultrafiltrate pump  206   b  to waste reservoir  219 . It should be apparent that the various tubes may be arranged in different combinations to move fluids as desired and together form a network of medical tubes. According to one illustrative, non-limiting embodiment, the first ultrafiltrate pump  206   a  and associated tubing implement steps  411  and  412  in  FIG. 4 . According to one illustrative, non-limiting embodiment, the second ultrafiltrate pump  206   b  and waste reservoir  219  and associated tubing implement steps  409  and  410  in  FIG. 4 . 
     Referring now primarily to  FIG. 6 ,  FIG. 6  illustrates an illustrative method for providing therapeutic agents with hemofiltration according to some embodiments of the present invention. The method may be used with one of the systems disclosed in  FIGS. 1A ,  1 B,  2 , and  7 , or other systems configurable to provide therapeutic agents and hemofiltration. 
     The method begins at step  600  where a system receives blood from a mammal, such as a human. In one illustrative, non-limiting embodiment, blood is continuously withdrawn from a mammal, preferably from a major blood vessel cannulated thereby allowing continuous withdrawal of blood from a mammal. A pump may also be provided for continuous withdrawal and transfer of blood from a mammal. The method then proceeds to step  601  where a hemofilter filters the blood. 
     In a specific illustrative, non-limiting embodiment, the hemofilter used to filter blood may include a large pore hemofiltration membrane configured to provide molecular weight exclusion limits of 100,000 to 150,000 Daltons. In this manner, a wide range of different immune mediators may be removed from the blood. 
     Other embodiments may include incorporating an adsorptive device at step  601 . Adsorptive devices, such as those disclosed above, may be provided for adsorbing additional inflammatory mediators. An adsorptive device may be configured with one or more chambers and may be included within a hemofilter or provided as an additional component within a hemofiltration system. The adsorption device&#39;s chambers may include selective adsorbent materials having adsorptive characteristics and capacities for adsorbing during the course of any Inflammatory Mediator Related Disease. Therefore, various adsorbent materials may be used in order to provide a range of chemical binding characteristics and capacities needed for removal of many inflammatory mediators from the ultrafiltrate. 
     Upon filtering the blood, the method may proceed to step  602  where a therapeutic agent is provided to the filtered blood. The therapeutic agent may be provided or integrated into the blood in certain dose adjusted amounts thereby providing a therapeutic agent in association with hemofiltration of blood. In another illustrative, non-limiting embodiment, the therapeutic agent may be administered to the mammal independently from, but in conjunction with, a hemofiltration system, such as the large pore hemofiltration systems shown in  FIG. 1A ,  1 B,  2  or  7 . 
     In one illustrative, non-limiting embodiment, a therapeutic agent may be a pharmaceutical agent for treating an Inflammatory Mediator Related Disease. Pharmaceutical agents may include, but are not limited to, venerable allopurinol, elastase inhibitors, and prostaglandin inhibitors. Other pharmaceutical agents may be used as they are developed and become available. The pharmaceutical agent may be provided in a predetermined dosage amount such that, upon providing the pharmaceutical agent an effective amount of therapy is provided to a specimen or mammal. In this manner, hemofiltration used in conjunction with a pharmaceutical agent may reduce undesirable effects or disorders in an inflammatory response of a mammal. 
     In another illustrative, non-limiting embodiment, the therapeutic agent may be directed towards alleviation of a coagulation disorder. For example, the therapeutic agent may be activated protein C, sometimes referred to as recombinant activated protein C. The therapeutic agent may also be full length protein C or other species and derivatives having full protein C proteolytic, amidolytic, esterolytic and biological (anticoagulant or profibrinolytic) activities. See U.S. Pat. No. 6,008,199 entitled “Methods For Treating Hypercoagulable States Or Acquired Protein C Deficiency” for examples of protein C variants usable in treating coagulation disorders. Human protein C and its derivatives and variants may be used in many embodiments of the invention. In some embodiments of the invention, protein C may be used for treatment of problems other than coagulation disorders, or to treat the effects of coagulation disorders. 
     In still another illustrative, non-limiting embodiment, the therapeutic agent may be a biological agent developed to treat Systemic Inflammatory Response Syndrome/Multiple Organ System Dysfunction Syndrome/Multiple Organ System Failure or Compensatory Anti-inflammatory Response Syndrome. Biological agents may include, but are not limited to, monoclonal antibodies or receptor antagonists such as anti-tumor necrosis factor, interleukin 1 receptor antagonist, and various endotoxin antibodies. Other biological agents may be used as they are developed and become available. The biological agent may be provided in a predetermined dosage amount such that, upon providing the biological agent, an effective amount of therapy is provided to a mammal. In this manner, hemofiltration used in conjunction with a biological agent may reduce undesirable effects or disorders in an inflammatory response of a mammal. 
     Accordingly to some illustrative, non-limiting embodiments, upon providing a therapeutic agent to the blood, the method then proceeds to step  603  where the blood is returned to the mammal. Therefore, the method of  FIG. 6  provides hemofiltration of blood received from a mammal, such as a human. The hemofiltration may be used in conjunction with a therapeutic agent, such as a pharmaceutical agent and/or a biological agent, thereby providing enhanced therapy of an Inflammatory Mediator Related Disease. In this manner, excessive and destructive inflammatory activity may be abated allowing the inflammatory system of the mammal to return to a more physiologic level. 
     Referring now primarily to  FIG. 7 ,  FIG. 7  illustrates a system for providing hemofiltration with therapeutic agents according to one illustrative, non-limiting embodiment of the present invention. The system illustrated in  FIG. 7  is similar to the systems illustrated in  FIGS. 1A ,  1 B, and  2  and may include like or similar components or features.  FIG. 7  illustrates one configuration of providing a hemofiltration system incorporating therapeutic agents for an Inflammatory Mediator Related Disease. 
     During operation, blood may be continuously withdrawn from mammal  700 , such as a human, into a tube  701  via a cannulated major blood vessel allowing continuous withdrawal of blood by a blood pump  704 . The amount of blood continuously pumped may depend on the condition of mammal  700  and may be determined on a case by case basis. 
     Blood is transferred from the mammal  700  to a hemofilter  702  via a tube  701 , the blood pump  704  and the tube  703 . A tube  705  transfers the filtered blood to a first three-way joint  725 . A tube  712  coupled to the hemofilter  702  transfers an ultrafiltrate  711  to an adsorptive device  708  where, via a tube  723 , the adsorptive device  708  transfers the post adsorptive ultrafiltrate  715  to a three-way stop cock  710 . The three-way stopcock  710  allows transfer of the post absorption ultrafiltrate  715  to first ultrafiltrate pump  706   a  via a tube  731  and a second ultrafiltrate pump  706   b  via a tube  727 . The second ultrafiltrate pump  706   b  and the tube  721  transfer post adsorption ultrafiltrate from the second ultrafiltrate pump  706   b  to a waste reservoir  719 . 
     The first ultrafiltrate pump  706   a  pumps the post adsorption ultrafiltrate  715  to the first three-way joint  725  via the tube  731  and the tube  729 . The first three-way joint  725  transfers the filtered blood and post adsorption filtrate  715  to the second three-way joint  734 . A therapeutic agent  730  is transferred to the second three-way joint via a tube  732  where the tube  707  transfers the therapeutic agent  730 , post adsorption ultrafiltrate  715  and blood to mammal  700 . In this manner, the system illustrated in  FIG. 7  provides hemofiltration of blood from a mammal in conjunction with a therapeutic agent, thereby providing enhanced therapy of an Inflammatory Mediator Related Disease. 
     In a specific illustrative, non-limiting embodiment, the hemofilter  702  may include a large pore hemofiltration membrane configured to provide molecular weight exclusion limits of 100,000 to 150,000 Daltons. In this manner, a wide range of different immune mediators may be removed from the blood. 
     Additionally, in a specific illustrative, non-limiting embodiment, a therapeutic agent  730  may provide variable dose adjusted pharmaceutical agents and/or biological agents as needed by mammal  700  as desired by the healthcare provider, such as a human. In one illustrative, non-limiting embodiment, a therapeutic agent may be a pharmaceutical agent developed to treat an Inflammatory Mediator Related Disease. Pharmaceutical agents may include, but are not limited to, venerable allopurinol, elastase inhibitors, prostaglandin inhibitors, and protein C. Other pharmaceutical agents may be used as they are developed and become available. The pharmaceutical agent may be provided in a predetermined dosage amount such that, upon providing the pharmaceutical agent an effective amount of therapy is provided to a mammal. 
     In another illustrative, non-limiting embodiment, the therapeutic agent may be a biological agent developed to treat an Inflammatory Mediator Related Disease. Biological agents may include, but are not limited to, monoclonal antibodies or receptor antagonists such as anti-tumor necrosis factor, interleukin 1 receptor antagonist, and various endotoxin antibodies. Other biological agents may be used as they are developed and become available. The biological agent may be provided in a predetermined dosage amount such that, upon providing the biological agent, an effective amount of therapy is provided to a mammal. Therefore, as different types or new therapeutic agents become available, the system illustrated in  FIG. 7  may be configured to provide the newly available therapeutic agents with hemofiltration thereby providing an enhanced therapy of an Inflammatory Mediator Related Disease. 
     In one illustrative, non-limiting embodiment, a therapeutic agent may be provided to mammal  700 , without the use of therapeutic agent  730 , tube  732 , second three-way joint  734 , and tube  707 . For example, a predetermined dosage amount of a therapeutic agent may be intravenously provided to the mammal  700 , using an separate therapeutic agent system (not shown) configured to provide therapeutic agents in association with hemofiltered blood. In this embodiment, the mammal  700  may receive hemofiltered blood via the tube  707  and variable dose adjusted therapeutic agents via a separate tube (not shown). In this manner, a hemofiltration system may be provided in addition to a therapeutic agent system for providing enhanced therapy of an Inflammatory Mediator Related Disease. 
     In one illustrative, non-limiting embodiment, therapeutic agents may be delivered to the patient or mammal directly or using an aspect of a hemofiltration system and may include agents interfering or addressing inflammation, antimalarials, antiobiotics or other agents. Accordingly a number of categories of agent may be used. For example, toll-like receptor (TLR) antagonists may be used, e.g., chloroquine, ketamine, nicotinic acid and analogues, statins, Vitamin D3, lidocaine, glycine, or the like. Other toll-like receptor (TLR) antagonists may include toll-like receptor (TLR) intracellular signaling pathway interference agents, e.g., eritoran, restotrvid, ketamine, opioids, Vitamin D3, lansoprazole, and the like. 
     On the occasion with antimalarials are desired for use with hemofiltration, the agent supplied may be any antimalarial agent, e.g., non-artemisinin combinations (such as amodiaquinine with sulphadoxine-pyrimethamine); artemisinin combinations (such as artesunate with amodiaquine, artesunate with sulphadoxine-pyrimethamine, artemether with lumefantrine, artesunate with mefloquine, dihydroartemisinin with piperaquine, artesunate with chlorproquanildapsone, artesunate with pyronaridine, artesunate with atovaquone-proguanil, etc.); mono-therapy agents (such as chloroquine, amodiaquine, sulphadoxine-pyrimethamine), or other agents (such as primaquine, artemether-lumefantrine, artemisinin with naphthoquine). 
     Still other agents may be used. For example, other agents may include statin drugs (such as, lovastatin, atorvastatin, fluvastatin, pravastatin, ulinastatin, simvastatin, rosuvastin, and the like), T-cell function augmenting drugs (such as thymosin alpha1), non-steroidal anti-inflammatory drugs, resolvins (such as resolvin D2), N-acetylcysteine, pentoxifylline, antioxidants (such as alpha-lipoic acid, ascorbate, magnolol, ethyl pyruvate, vitamin E, selenium, glutamine, omega-3 fatty acids, melatonin, vitamin C), Inducible nitric oxide synthase (iNOS) inhibitors (such as, propofol, simendans (levo- and dextrosimendan)), calcium activated potassium channel inhibitors, histone deacetylase inhibitors, peroxynitrite inhibitors, proteasome inhibitors (such as lactacystin), dimemorfan, activators for antioxidant response elements (such as NF-ET-related factor-2 (Nrf2)), stabilizers of antioxidant elements (such as superoxide dismutase), and antioxidant inflammation modulators (such as flavonoids or polyphenols). 
     Various modifications of the systems and methods described above are also included within the scope of the present invention. For instance, structural modifications may include the integration of the hemofilter  102  in  FIGS. 1A and 1B  and the hemofilter  202  in  FIG. 2  with the adsorptive device  108  (in  FIGS. 1A and 1B ) and the adsorptive device  208  (in  FIG. 2 ), both of which have one or more chambers containing adsorbent material of one or more types, with elimination of the additional tubing. In this illustrative, non-limiting embodiment, ultrafiltrate formed in the jacket of the hemofilter  102  (in  FIGS. 1A and 1B ) and the hemofilter  202  (in  FIG. 2 ) may be presented directly to adsorbent material contained with in the hemofilter jacket or in a chamber or chambers directly contiguous with the hemofilter jacket. The chamber containing ultrafiltrate may be drained by the ultrafiltrate line. Ultrafiltrate may be continuously pumped and apportioned for discard or returned to the mammal  100  (in  FIGS. 1A and 1B ),  200  (in  FIG. 2 ), such as a human. In addition, the configuration of the ultrafiltrate lines may be modified to provide for infusion of ultrafiltrate into the mammal  100  (in  FIGS. 1A and 1B ),  200  (in  FIG. 2 ), via a vascular cannula in a blood vessel and separate from the hemofiltration circuit. Furthermore, the ultrafiltrate return pump and the ultrafiltrate discard pump in the embodiments shown and discussed above may be combined into a single two head ultrafiltrate pump system. While the 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. 
     Hemofiltration, particularly with a 100 to 150 kD filter, removes many excess circulating inflammatory mediators that respectively characterize Systemic Inflammatory Response Syndrome/Multiple Organ System Dysfunction Syndrome/Multiple Organ System Failure, or Compensatory Anti-inflammatory Response Syndrome. During either condition, it may be desirable to actually supplement inflammatory mediators or provide some other therapeutic agent to augment the system in abatement. In particular, during Systemic Inflammatory Response Syndrome/Multiple Organ System Dysfunction Syndrome/Multiple Organ System Failure when pro-inflammatory inflammatory mediators are in excess, in addition to performance of hemofiltration to remove excess pro-inflammatory inflammatory mediators, the administration of anti-inflammatory inflammatory mediators or therapeutic agents may be useful to additionally abate or otherwise modulate the pro-inflammatory systemic inflammatory response. Similarly, during Compensatory Anti-inflammatory Response Syndrome hemofiltration may remove many excess anti-inflammatory inflammatory mediators that may ameliorate immune suppression, in addition, administration of pro-inflammatory inflammatory mediators or other therapeutic agents to promote immune responsiveness, may ameliorate immune suppression of Compensatory Anti-inflammatory Response Syndrome. 
     Modifications of the adsorptive device may be determined by the Inflammatory Mediator Related Disease to be treated and the phase of the disease. Various regions of the inflammatory mediator network are dominant at different phases of an Inflammatory Mediator Related Disease and different Inflammatory Mediator Related Diseases exhibit different patterns of inflammatory mediator networking. Thus a different adsorbent material or materials, or different groupings of adsorbent materials may be needed for different Inflammatory Mediator Related Diseases in their different phases. Thus different adsorptive devices may be developed as more is learned of Inflammatory Mediator Related Diseases and their phases. Adsorptive devices may contain a fixed adsorbent material or a fixed combination of adsorbent materials. Alternatively, an adsorptive device may be configured with different, interchangeable modules of adsorbent materials to be adapted to the changing dominance of the inflammatory mediator network. The modules may consist of one or more chambers containing adsorbent material of one or more types. The adsorptive device may be designed to accept modules of adsorptive materials inserted in place as dictated by mammal need and operator assessment. Alternatively, a multiple module adsorbent may have a selector to select different chambers. 
     Different configurations of adsorbent materials may be used. Adsorbent materials exhibit chemical characteristics that determine what physical form will provide the greatest stability in flowing ultrafiltrate. Adsorbent material may 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 are preferably not allowed to dissolve, dissociate or fragment into the ultrafiltrate to be infused into the mammal. Adsorbent material, matrix, and containment material may be configured to provide physical durability, and adequate porosity and configuration for optimal presentation of adsorbent material to flowing ultrafiltrate. Some illustrative configurations of a matrix are shown in  FIGS. 5A ,  5 B, and  5 C. Adsorptive devices of one or more chambers containing adsorbent material of one or more types may be used in series, in which ultrafiltrate flows from the first to subsequent adsorptive devices. The sequence, number and type of adsorptive devices may be determined by the operator to meet the needs of the mammal. Alternatively, the ultrafiltrate stream may be divided by a manifold with distribution of ultrafiltrate to adsorptive devices arranged in a parallel configuration, with each line from each adsorptive device either returned to a manifold and reunited into a single ultrafiltrate line, or each line individually apportioned for return to mammal and discard. 
     In accordance with some teachings of the illustrative, non-limiting embodiments, methods and systems for treating Inflammatory Mediator Related Diseases in mammals using a hemofilter are disclosed. In selected illustrative, non-limiting embodiments, the treatment of acute or chronic problems may be addressed. A therapeutic agent may be used in connection with the hemofilter. An adsorptive device may also be included. Illustrative embodiments may be particularly beneficial when used in large pore hemofiltration systems. 
     According to illustrative, non-limiting embodiment, a hemofiltration system for treating Inflammatory Mediator Related Diseases is disclosed. The system includes a hemofilter to receive blood and remove inflammatory mediators from the blood. The system may further include at least one therapeutic agent used in association with the hemofilter to reduce adverse inflammatory mediator effects. In a particular illustrative, non-limiting embodiment, the system may further include a 100 to 150 kiloDalton hemofilter. In a particular illustrative, non-limiting embodiment the system may include an adsorptive device associated with the hemofilter. In a particular illustrative, non-limiting embodiment, the system may include a therapeutic or biological agent to reduce adverse inflammatory mediator effects, or reduce other adverse effects. In a particular illustrative, non-limiting embodiment, the system may include a pharmaceutical agent to reduce adverse inflammatory mediator effects. 
     According to another illustrative, non-limiting embodiments, a method for treating inflammatory mediator related diseases is disclosed. The method includes receiving blood from a mammal and filtering the blood using a hemofilter wherein the hemofilter removes inflammatory mediators from the blood. The method may further include providing at least one therapeutic agent wherein the therapeutic agent reduces adverse inflammatory mediator effects. In a particular illustrative, non-limiting embodiment, the therapeutic agent may include a biological agent. In a particular illustrative, non-limiting embodiment, the therapeutic agent may include a pharmaceutical agent. In a particular illustrative, non-limiting embodiment, the hemofilter may be configured as a 100 to 150 kiloDalton hemofilter. In a particular illustrative, non-limiting embodiment, an adsorptive device associated with the hemofilter may be provided. 
     According to another illustrative, non-limiting embodiment, a system and method are provided for hemofiltration of blood from mammals having a chronic inflammatory disease, such as chronic inflammatory skin and joint disease and chronic neuromuscular disease, especially those with debilitating diseases refractory to existing medical therapies. 
     Specific embodiments include a hemofilter, blood and ultrafiltrate lines, and an adsorptive device having 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 and thereby creates a stream of filtered blood, which is eventually returned to the mammal, and a stream of ultrafiltrate. The ultrafiltrate typically includes plasma water, electrolytes, peptides and small proteins. The blood peptides and proteins removed from the blood by the hemofilter and found in the ultrafiltrate have a molecular size smaller than the pore size of the hemofilter. Most inflammatory mediators are included in this group. The ultrafiltrate is then provided to the adsorptive device. 
     The hemofilter may be made of a biocompatible material. In particular, the hemofilter may include a membrane and a jacket. In specific embodiments, the membrane and jacket may include biocompatible materials. 
     The adsorptive device may incorporate an encasement jacket along with one or more chambers containing adsorbent material of one or more types. The adsorptive device may receive the stream of ultrafiltrate and selectively or nonselectively remove inflammatory mediators that cause Inflammatory Mediator Related Diseases from the ultrafiltrate to create a stream of post adsorption ultrafiltrate. 
     The adsorptive device may be designed to be placed in the line transferring ultrafiltrate removed by the hemofilter to adsorb inflammatory mediators from the ultrafiltrate, producing post adsorption ultrafiltrate. The stream of post adsorption ultrafiltrate may eventually be combined or reinfused, in whole or in part, with the stream of filtered blood and returned to the mammal. The above systems and methods may be used with acute or chronic diseases, as appropriate. 
     Some embodiments allow for the rapid stabilization of mammals undergoing septic shock and increase survival rate of the mammal. Some embodiments abate excessive and destructive inflammatory activity that characterizes septic shock or other Inflammatory Mediator Related Diseases. 
     The immune system has many redundant cytokine and inflammatory mediator control loops; several of these loops must be down-regulated to achieve systemwide disease control and to see improvement in the symptoms of various diseases including chronic skin, joint and neuromuscular disease. Various embodiments of the present invention address this task. 
     Some illustrative embodiments may increase the effectiveness of therapeutic agents as adjunctive therapy to hemofiltration. Certain illustrative, non-limiting embodiments of the invention allow the safe use of two-stage high volume hemofiltration, which may result in improved mammal survival. These embodiments may avoid or minimize dangerous fluid balance errors inherent to conventional high volume hemofiltration, avoid or minimize the risk of depletion of desirable humoral compounds, avoid or minimize thermal stress and hypothermia, and avoid or minimize the cost of excessive amounts of replacement fluid. 
     Moreover, the use of an adsorptive device including adsorbent material(s) in selected embodiments provides a number of advantages. First, with respect to the risk of high fluid flux in high volume hemofiltration, the adsorbent device adsorbs inflammatory mediators 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 mammal. Because post adsorption ultrafiltrate may be returned to the mammal, in whole or in part, the amount of replacement fluid needed to preserve fluid balance in the mammal may be sharply reduced (to the amount of ultrafiltrate discarded), or eliminated entirely. The volumes of ultrafiltrate discarded and replacement fluid infused may be limited to those indicated by the mammal&#39;s 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) may be safely managed by existing pump technology. Pumping errors with these small volumes are well tolerated. 
     With respect to the risk of depletion of desirable compounds in high volume hemofiltration, because all or most of the ultrafiltrate may be returned to the mammal (as post adsorption ultrafiltrate), and because adsorbent material may be selected with as narrow a range of adsorbed substances as possible and focused on inflammatory mediators, the loss of desirable substances may be minimized. 
     With respect to the risk of hypothermia in high volume hemofiltration, because warm (body temperature) ultrafiltrate may be returned to the mammal, the amount of cool (room temperature) replacement fluid needed may be sharply reduced. This may control or eliminate the heat loss that would otherwise occur with discard of ultrafiltrate and also control or eliminate the cooling that would occur by the infusion of cool replacement fluid. In this way, the stress of hypothermia may be controlled or eliminated. With respect to the expense, the cost of replacement fluid varies widely depending on markets, contract arrangements and other considerations. However, $2 to $10 per liter are typical costs. Thus, high volume hemofiltration could create an incremental cost of from $96 to $1,500 per day. By reinfusion of post adsorption ultrafiltrate following adsorption of inflammatory mediators, and thereby reducing the need for all or most replacement fluid, this incremental cost may be reduced or eliminated. 
     High volume hemofiltration is a technique that may significantly improve symptoms and survival in chronic disease, however, high volume hemofiltration creates new and substantial risks and expenses. Various embodiments of the present invention may eliminate or sharply reduce some or all of these risks and expenses, and make high volume hemofiltration, as well as low volume hemofiltration, much safer and more cost effective in mammals suffering from Inflammatory Mediator Related Diseases 
     Although the present invention and its advantages have been disclosed in the context of certain illustrative, non-limiting embodiments, it should be understood that various changes, substitutions, permutations, and alterations can be made without departing from the scope of the invention as defined by the appended claims. It will be appreciated that any feature that is described in a connection to any one embodiment may also be applicable to any other embodiment. Various components described specifically for the systems and methods described above may be used with other systems and methods, including those described specifically herein and other systems and methods not specifically described. Appropriate uses will be apparent to one skilled in the art.