Abstract:
Blood treatment system and method for high rate hemofiltration ensures against pyrogenic patient reaction by providing various mechanisms for filtering replacement fluid to remove endotoxins and other safety features including detecting incorrect fluid administration.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application is a divisional of U.S. patent application Ser. No. 10/513,693, filed on Nov. 8, 2004, which claims the benefit of U.S. Provisional Patent Application No. 60/386,483, filed on Jun. 6, 2002, now expired, and U.S. Provisional Patent Application No. 60/438,567, filed on Jan. 7, 2003, now expired, and International Application No. PCT/US03/17743, filed on Jun. 5, 2003, all of which are incorporated herein by reference in their entireties. 
     
    
     BACKGROUND OF THE INVENTION 
       [0002]    During hemofiltration, hemodialysis, hemodiafiltration, ultrafiltration, and other forms of renal replacement therapy, blood is drawn from a patient, passed through a filter, and returned to the patient. Depending on the type of treatment, fluids and electrolytes are exchanged in the filter between a dialysate and/or extracted from the blood by filtration. One effect may be a net loss of fluid and electrolytes from the patient and/or exhaustion of dialysate, with a concomitant need for its replenishment, again depending on the type of treatment. To replace fluid lost from the patient and keep the patient from dehydrating, replacement fluid may be injected into the patient at a rate that matches a rate of loss, with an adjustment for a desired net change in the patient&#39;s fluid complement. To replace exhausted dialysate, fresh dialysate is continuously circulated through the filter. 
         [0003]    Presently methods to produce large volumes of dialysate from tap water are known, but each requires complex water purification and standardization equipment, since impurities and cleaning additives such as chlorine vary greatly in tap water from municipality to municipality and within a municipality over time. (See Twardowski U.S. Pat. Nos. 6,146,536 and 6,132,616.) Moreover, dialysate solution, whether prepared online or prepackaged, while of the proper concentration for use as a replacement fluid, is not directly infused into the patient&#39;s body. Instead, dialysate flows past a semipermeable membrane that permits ions and water to be exchanged across the membrane until a balance between their concentrations in blood and their concentrations in the dialysis is achieved. This is effective to remove impurities from the blood and to add missing electrolytes to the blood, but the volume of fluid that is infused is not as great as with hemofiltration. 
         [0004]    Conventionally, dialysate and/or replacement fluid is supplied from either of two sources: batches of fluid, typically in multiple bags, or a continuous sources of water that is sterile-filtered and added to concentrated electrolytes to achieve the required dilution level. Because replacement fluid is injected directly into the patient, replacement fluid is required to be sterile and is recommended to have limited levels of pyrogens, particularly endotoxins, which are quantified in endotoxin units (EU). The maximum amount of endotoxin allowed in a parenteral product or medical device set by the US Food and Drug Administration (FDA) and United States Pharmacopoeia (USP) for drugs is 5.0 EU/Kg/hr, a rate taking into account the weight of the patient (in Kg.) and the rate of infusion. Currently, however, replacement fluid packaged such that it is regulated as a drug may have an endotoxin load of up to 0.5 EU/ml. This would limit the replacement fluid exchange rate for a 72 Kg. patient to less than 12 ml./min. To be safely infused, per these specifications, at higher rates, the fluid must be further filtered of endotoxins. Filtering to 0.03 EU/ml., a level that may be identified as “ultrapure,” allows an infusion rate of 200 ml./min., which may be sufficient for high rate continuous hemofiltration therapy of the type described in the following pending US patent applications each of which is hereby incorporated by reference as fully set forth in its entirety herein. 
         [0005]    Ser. No. 08/800,881, filed Feb. 14, 1997 for Hemofiltration System; 
         [0006]    Ser. No. 09/451,238 for Nov. 29, 1999 for Systems and Methods for Performing Frequent Hemofiltration; 
         [0007]    Ser. No. 09/512,929, filed Feb. 25, 2000 for Fluid Replacement systems &amp; Methods for Use in Hemofiltration; 
         [0008]    Ser. No. 09/513,564, filed Feb. 25, 2000 for Systems and Methods for Detecting Air in an Arterial Blood Line of a Blood Processing Circuit; 
         [0009]    No. 60/438,567, filed Jan. 30, 2003 for Preparing Replacement Fluid by Means of Batch Filtration Prior to Treatment; 
         [0010]    Ser. No. 09/513,910, filed Feb. 25, 2000 for Systems and Methods that Maintain Sterile Extracorporeal Processing Conditions; 
         [0011]    Ser. No. 09/513,911, filed Feb. 25, 2000 for Synchronized Volumetric Fluid Balancing Systems and Methods; 
         [0012]    Ser. No. 09/513,915, filed Feb. 25, 2000 for Systems and Methods for Controlling Blood Flow &amp; Waste Fluid Removal During Hemofiltration; 
         [0013]    Ser. No. 09/862,207, filed May 21, 2001 for Methods, Systems and Kits for the Extracorporeal Processing of Blood; 
         [0014]    Ser. No. 09/865,905, filed May 24, 2001 for Fluid Processing Systems and Methods Using Extracorporeal Fluid Flow Panels Oriented Within a Cartridge; 
         [0015]    Ser. No. 09/894,236, filed Jun. 27, 2001 for Hemofiltration System; 
         [0016]    Ser. No. 09/900,362, filed Jul. 7, 2001 for Method and Apparatus for Leak Detection in a Fluid Line (Disconnect Sensor—Reverse Lines to Use Air Sensor on Arterial Line (Leak)); 
         [0017]    Ser. No. 09/905,246, filed Jul. 12, 2001 for Devices and Methods for Sterile Filtering; 
         [0018]    Ser. No. 09/907,872, filed Jul. 17, 2001 for Hermetic Flow Selector Valve; 
         [0019]    Ser. No. 60/324,437 filed Sep. 24, 2001 for Device and Method for Enhancing Performance of Membranes. 
         [0020]    Ser. No. 10/040,659, filed Jan. 7, 2002 for Blood Treatment Replacement Fluid Using Infusible Fluids in Combination; 
         [0021]    No. 60/346,458 filed Jan. 7, 2002 for Hemofiltration Filter with High Membrane Utilization Effectiveness; and 
         [0022]    No. 60/346,403 filed Jan. 7, 2002 for Hemofiltration System Method of Use and Associated Control System. 
         [0023]    In many instances, blood treatment therapies may require a large quantity of sterile fluid. A typical way to provide the large quantity of replacement fluid is to provide multiple bags of replacement fluid, dialysate, or infusate. The connection of these bags of fluid to an extracorporeal blood circuit creates a risk of touch contamination resulting in the introduction of contaminants into the fluids. Contamination may occur, for example, at the point where bags of fluid are accessed (“spiked”) or at other times during preparation for infusion such as when the patient is accessed. 
         [0024]    Attempts to render dialysate suitable for use as a replacement fluid in hemofiltration and hemodiafiltration have focused on continuous sterilization processes that require a separate dialysate filtration/purification apparatus that must be periodically purged and verified to provide sufficient constant flow of sterile replacement fluid required for hemofiltration. (See Chavallet U.S. Pat. Nos. 6,039,877 and 5,702,597.) Such devices are necessarily complicated and require separate pumping systems for the sterilization process. In addition, the rate of supply of dialysate for such systems is very high, requiring an expensive filter to be used. The same high-rate problem exists for the generation of replacement fluid for hemofiltration, and therefore also requires an expensive filter. 
         [0025]    There is a need for improved mechanisms for providing safe economic replacement fluid for use in various blood therapies. 
       SUMMARY OF THE INVENTION 
       [0026]    In the present invention, sterile, and preferably substantially non-pyrogenic (e.g., including endotoxin-free) replacement fluid or dialysate may be generated in batch form by filtering. According to various embodiments of inventions disclosed, 
         [0027]    1. raw fluid is passed through a filter prior to treatment to prepare a batch of infusible replacement fluid; 
         [0028]    2. raw fluid is passed by gravity feed during treatment through filters attached to infusion lines from each of one or more batch containers; 
         [0029]    3. raw or prefiltered fluid according to either or both of the previous methods is passed through a last-chance filter immediately prior to injection into the patient. 
         [0030]    Preferably, the filter has a pore size and quality effective to block endotoxins such that the replacement ultimately infused that is substantially less than 5 EU/Kg./hr (based on the rate of treatment), the limit set by the USP for parenteral drugs and no more than 0.5 EU/ml. Preferably the filter provides this degree of filtration with minimal pressure drop, for example by means of a relatively large pore size (e.g., 0.2 Micron) in combination with a charged nylon membrane which attracts endotoxins and helps to ensure against their passage. Filters are available with smaller pore sizes and may be used rather than relying on adsorption as with the nylon membrane example. For example pores sizes of 0.005 micron and somewhat larger will block most endotoxins. But small pore size implies high pressure drop and generates inefficiencies for production. 
         [0031]    The raw (source) replacement fluid may be industry standard quantities of pyrogens and labeled as suitable for injection, the inventive method providing a higher degree of purity than is currently allowed for infusible fluids regulated either as medical devices or drugs. 
         [0032]    The batch filtration process may be permitted to take any length of time because the rate of flow of raw replacement fluid (or components thereof) through the filter is completely independent of the rate of consumption by the renal therapy. Because the filters used for such filtering tend to be expensive, it may be desirable for such a batch process to employ a small pyrogen filter for such filtration. Such a filter can have a flow capacity that is much lower than that required for real-time filtering of the replacement fluid (or components). Alternatively, the fluid may be passed under pressure for a suitably supported membrane or strong membrane material adequate to permit real-time filtration as discussed elsewhere in the present specification. In addition to preparation of low pyrogen (preferably at least with low levels of endotoxins) fluid from sterile or non-sterile and/or pyrogen-purified fluid, embodiments of inventions disclosed may be used to ensure against touch contamination. 
         [0033]    Treatment by hemofiltration requires the extraction from patients of a large volume of fluid compared to hemodialysis, although both perform similar functions. In hemodialysis, fluid and electrolytes cross a filter membrane into and out of the blood of the patient in response to a difference in concentration of electrolytes. Some net quantity of fluid may be taken from the patient if there is an excess in the patient&#39;s blood and some net quantity of replacement fluid may be infused directly if there is a paucity in the patient&#39;s blood. In hemofiltration, fluid is drawn out of the patient continuously and replaced with electrolytically-proper fluid. As a result, the quantity of fluid infused in the patient tends to be much greater than with hemodialysis and, coincidentally, most other types of infusion therapies including parental infusion therapies. In addition, new hemofiltration therapies have been developed which permit very fast continuous treatment, which may involve the infusion of replacement fluid at a very high rate. The risk of adverse reactions due to the infusion of pyrogens into patients increases with the dose and the period of time over which the infusion takes place. As a consequence, the allowed concentration of pyrogens in replacement fluid for hemofiltration should be substantially lower than for other treatments, for example for hemodialysis or other infusion therapies. 
         [0034]    While low pyrogen levels may be achieved using sterilization and filtration techniques that are known, there are also a number of practical matters that are well to combine in addressing the problem of pyrogen infusion in hemofiltration. For example, even when highly purified replacement fluid is used for replacement fluid, touch-contamination can cancel any benefit of starting with a highly purified fluid. 
         [0035]    In disclosed embodiments of blood treatments systems, including hemofiltration systems generally as well as high flow-rate hemofiltration systems particularly, the low pyrogen concentrations may be achieved by one or more features, including: 
         [0036]    1. batch filtration of raw replacement fluid at the site of use and in a manner that minimizes risk of touch-contamination or other sources of recontamination; 
         [0037]    2. filtration of raw replacement fluid at the site of use at the rate of consumption in real time during treatment, preferably with a filter located close to the point of injection so as to minimize the risk of downstream contamination; 
         [0038]    3. filtration using filters that permit the passage of no more than 0.03 endotoxin units per ml.; and 
         [0039]    4. filtration using filters using a combination of adsorption and blocking mechanisms to provide an optimal balance between pressure drop across the filter media and the need to block pyrogen particles, preferably with a charged nylon membrane, which attracts endotoxins thereby helping to block them and having an approximately 0.2 micron pore size. 
         [0040]    Generally replacement fluid is heated before being infused into a patient. This is often accomplished by passing the fluid through a heater with enough heating capacity to heat the fluid as it is being infused. The capacity of the heater must be matched to the mass flow of the fluid and the temperature rise required. In a batch preparation process, where a batch of fluid is prepared over a substantial period before use, a small heater may heat the replacement fluid over a long period of time. Insulation may be provided to prevent heat loss. An insulating outer container for the source replacement fluid may be provided. For example, the container may be an insulated box with room for one or more large disposable sterile bags of the type normally used for infusible fluids. 
         [0041]    The preparation of warm replacement fluid may be automated by a control process that permits a user to set up the fluids and other materials well in advance of a scheduled treatment. The process would ensure that the replacement fluid is treated to remove pyrogens and heated to the proper temperature when the treatment is to begin. The automation process may be permit the user to select how far in advance of the treatment the preparation should be performed. This may be useful, for example, where a particular source of replacement fluid has proved to release more than a usual quantity of dissolved gases upon heating. Heating the replacement fluid and permitting it to settle for a time before it is used may allow gases to come out of solution and settle at the top of the batch vessel or vessels. The automation process may be incorporated in the control functions of renal therapy machine. 
         [0042]    The invention or inventions will be described in connection with certain preferred embodiments, with reference to the following illustrative figures so that it may be more fully understood. With reference to the figures, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention or inventions only, and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention or inventions. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention or inventions, the description taken with the drawings making apparent to those skilled in the art how the several forms of the invention or inventions may be embodied in practice. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0043]      FIG. 1  is a schematic illustration of a standalone/retrofit apparatus system for batch filtration of a sterile, endotoxin-purified, or pyrogen-purified replacement fluid. 
           [0044]      FIG. 2  is a flow chart illustrating an exemplary control procedure applicable to various embodiments of the invention including those of  FIGS. 1 and 3 . 
           [0045]      FIG. 3  is a schematic illustration of a blood treatment machine with an attached subsystem for batch preparation of infusible replacement fluid. 
           [0046]      FIGS. 4A and 4B  are illustrations of fluid filters that may be used in various embodiments of the invention. 
           [0047]      FIG. 5  illustrates an exemplary blood treatment system with a filter used to filter gas, pyrogens, endotoxins, or pyrogens from replacement fluid during treatment. 
           [0048]      FIGS. 6-8  illustrate a blood treatment machine and cartridge providing various supporting mechanical features for the embodiment of  FIG. 5  and further embodiments, including one in which a quality of replacement fluid is sensed before infusion. 
           [0049]      FIG. 9  illustrates a disposable fluid circuit kit which may support various embodiments of the invention. 
           [0050]      FIG. 10  illustrates a set up for priming a blood treatment process, which components of the invention may be used to support. 
           [0051]      FIG. 11  illustrates a portion of a blood treatment machine that allows a pump used as part of the blood treatment to also be used to control the filtering of fluid to provide a batch of infusible replacement fluid. 
           [0052]      FIG. 12  illustrates a patient undergoing treatment. 
           [0053]      FIGS. 13 and 14  illustrate embodiments of a filtering manifold for filtering of infusible fluids. 
       
    
    
     DETAILED DESCRIPTION 
       [0054]    Referring to  FIG. 1 , a filter  160  filters fluid from a source of fluid  150  to generate a batch of infusible replacement fluid  130 . The filter  160  may be, and preferably is, a microporous filter that blocks pyrogens and allows the passage of dissolved electrolytes and water. The latter may provide an infusible fluid free of all pyrogens, however, in practice, the pyrogen concentration must be reduced, but not necessarily eliminated since total elimination is not practical. The most common type of pyrogen is endotoxins, which may be present even in sterilized fluids. 
         [0055]    In hemofiltration, a large quantity of fluid is drawn from the patient and replaced with replacement fluid. Compared to dialysis, the quantity actually removed and replaced with replacement fluid tends to be high. As a consequence, it is desirable to provide replacement fluid that has a lower concentration of pyrogens than may be allowed in other infusible fluids and what may cross the membrane of a dialysis system. Thus, a filter effective to reduce endotoxins to levels at least as low as 0.03 endotoxin units per 25 ml. should be provided for the filter  160 . 
         [0056]    The result of the filtration process is the sterilization and cleansing of endotoxins and particulate pyrogens in the raw fluid from the source of fluid  150 . The source of fluid  150  may be a container  196  of fluid approved for injection or non-sterile replacement fluid. It may also be one or more containers of constituents which, when combined, form a proper replacement fluid (not shown) or a continuous source such as a tap water that is combined or has been combined with electrolyte concentrate (not shown). The starting fluid may be a function of the type of filter  160  used. For example, when processing fluid with a relatively large concentration of particulate pyrogens, for example bacteria, it is desirable to use a very large filter to ensure that its filtering performance is not compromised. In a preferred embodiment, a small replacement filter is used (since they tend to be costly) and the source fluid is fluid that has already been filtered to achieve low levels of pyrogens. 
         [0057]    One or more conduit elements form a line  120  to convey the source fluid  150  through the filter  160  and into a batch container  147 . The latter may be any type of sterile, preferably disposable container, for example, a large IV bag. It may also include a number of such containers appropriately interconnected to permit flow into and out of them in the fashion of container  147 . 
         [0058]    Included in the conveyance from source fluid  150  to infusible replacement fluid  130  may be a pump  190 , such as a peristaltic pump. The pressure at an outlet of the filter  160  may be sensed by a pressure sensor  162  and the pump  190  controlled by a controller  170  to insure a predefined transmembrane pressure (TMP) threshold of the filter  160  is not breached. The TMP may be maintained at a maximum safe level to maximize throughput. Note that complexity may be avoided if the source fluid  150  is arranged such as to maintain a desired TMP at the filter  160  without the need of a pump  190  or pressure sensor  162 . For example, the source fluid  150  may be provided by a batch container elevated at a certain height to provide a desired head. Note that a control valve  165  or a speed of the pump  190  may be used to regulate the flow rate to maintain desired TMP limits. 
         [0059]    A control/shutoff valve  180  may provide the controller  170  the ability to stop the flow of fluid through the filter  160  once a desired volume is reached. A heater  185  may be provided to warm the filtered replacement fluid  130  to prepare it for use. An insulated container  145  may be used to reduce heat loss so that heater  185  can be a relatively low power type. The heater  185  may be controlled by the controller  170  to ensure the replacement fluid  130  is at a desired temperature when required to be used. Alternatively the heater  185  can be controlled by an independent device actuated by, for example, a pressure sensor (for example as shown at  186  in  FIG. 1 ) triggered by the flow of fluid into the batch container  147 , a timer (not shown) settable to trigger based on a predefined treatment time, or some other means. Preferably, in either case, a temperature regulator (e.g., a temperature sensor  183  combined with logic in controller  170 ) regulates power to the heater to ensure a required temperature is maintained and not exceeded. The temperature sensor  183  may be used to sense the quantity of filtered replacement fluid by the rate of detected temperature increase versus heater output. The temperature sensor  183 , heater  185 , and filtered replacement fluid  130  can be modeled in any desired fashion. For example one may neglect all but the thermal mass of the RF, assume perfect heat transfer (including assuming the RF fluid to be isothermal). Then, the mass is given by the product of the temperature change, the thermal capacitance of the fluid, and the heat output rate of the heater. More complex theoretical or empirical algorithms would be a simple matter to derive and implement, for example the temperature variation can be fitted to the transient exponential that governs for instantaneous uniform heating from a plane source as the heater is started, taking temperature data points before substantial convection starts. The mass may also be determined by means of a contact-type pressure sensor  186  (e.g., strain gage attached to a bendable plate and calibrated against mass). Once the mass of fluid is calculated to be below a certain level, the controller  170  may be programmed to respond in accord with the assumption the filtered replacement fluid is exhausted. Equivalently, the controller  170  may simply respond to some predefined rate of temperature rise of the temperature sensor  183 . 
         [0060]    When the temperature of the filtered replacement fluid  130  is raised, dissolved gas may come out of solution. This may cause bubbles to accumulate inside the replacement fluid container  147 , which is undesirable because of the risk of infusing bubbles into the patient&#39;s bloodstream. To help ameliorate that problem, a vibrator or ultrasonic transducer  184  may be provided to cause bubbles to coalesce and rise to a top of the container  147 . As a result, bubble-free replacement fluid may be drawn through the outlet  148 . 
         [0061]    A connector  195  may be provided for connecting the source fluid to the line  120 . The connector may be a luer, spike, threaded adapter, or any other suitable type. Although the various controls indicated above are shown to be controlled an automatic controller  170 , each may be controlled also by manual mechanisms. 
         [0062]    The  FIG. 1  embodiment allows replacement fluid to be prepared in batch for later use. Thus, the rate of filtration of replacement fluid need not match the requirements of the treatment process or preparatory steps such as priming. As a result, a low capacity filter may be used for the filter  160 . For example, typically only a small quantity of expensive media is required to make a small-capacity filter and as such, the cost of a low capacity filter can be much smaller than a high capacity filter. Also, other features found in high capacity filters, such as a large ratio of media surface to volume of the filter module are achievable only by means of folding or forming media into shapes that can be difficult to manufacture, such as tubes. Thus, savings can be achieved in simplification of the configuration of the filter as well. Relatively small filters with simple planar media held in plastic casings are available and suitable for this purpose. 
         [0063]    The configuration of  FIG. 1  may be retrofitted for use with an existing treatment system. For this purpose, the outlet  148  may be provided with any required connection adapter. A user interface  175  for entering data into the controller  170  may be provided as well. 
         [0064]    Referring now also to  FIG. 2 , a control algorithm for controlling the heater  185 , pump  190 , valves  165 / 180 , etc. begins with the a setting of a time for treatment S 10 , for example by entering a time into the controller  170  via a user interface (UI)  175 . The time can be entered manually or automatically by means of, for example, a data signal from a remote source via a switched or network circuit. The time for treatment may be obtained from a treatment calendar entered into the controller  170 , which also may be obtained from a remote source. In the present simple algorithm, first and second time intervals T 1  and T 2  are defined representing the interval required for filtration of RF and the interval required for heating of RF, respectively. These values may be obtained from any of the above means (e.g., local manual or remote entry via UI/interface  175 ) or from data encoded on one of the consumables involved in the process. For example, the filter  160 , the RF fluid container  147 , the source fluid  150  container(s), or any other consumable may be provided with one or more bar-codes, RFID tags, or other suitable encoding device. Such devices may provide values for T 1  and T 2 , tables of values that depend upon other factors, or other data from which T 1  and T 2  may be derived. 
         [0065]    The controller  170  waits until it is time to start the flow of raw RF fluid from source fluid  150  toward container  147  by comparing a current time (indicated by a clock internal to the controller  170 , which is not shown) to a difference between a scheduled treatment time and T 1 , which represents the lead time (ahead of the scheduled treatment) required for the filtering process. A loop through step S 20  is exited to step S 30  when the clock reaches the treatment time minus T 1 . At step S 30 , the flow of source fluid  150  through the filter  160  is initiated. If the pump  190  is present, it may be started and regulated according to a specified TMP. The latter may be provided to the controller  170  manually or automatically through UI/interface  175 . Automatic entry may be by way of a data store such as bar-code or RFID attached to the filter, for example which may be read when the filter  160  is installed in a chassis with a corresponding reader device (not shown). Note, as mentioned above, the source fluid may be sterile and the filtration process provided as a guarantee against contamination, for example by accidental touching. 
         [0066]    Once the flow of source fluid  150  is initiated, the controller waits for the required time for applying power to the heater  185 . The delay and the initiation are controlled by step S 40  which is exited to step S 50  only when the treatment time minus the predefined interval T 2  is reached. Note that the delay may also be zero. As mentioned above, alternatively, the heater may be triggered by detecting fluid such as by means of a sensor  186  of  FIG. 1  (not shown) triggered by the presence of filtered replacement fluid  130  in the container  147 . The sensor  186  may be any of a variety of types, such as an ultrasonic sensor, capacitance sensor, mass sensor, optical sensor, etc. 
         [0067]    Once the heater is started, the controller  170  may wait for the source fluid to be exhausted at step S 60 . Step S 60  exits to step S 70  when the source fluid is determined to be exhausted. The latter may be detected by integrating the flow rate to measure the total volume (the rate may be determined by the pumping rate, for example, or by a flow meter (not shown)). The exhaustion of the source fluid  150  may also be indicated by a quantity indicator (e.g., a level indicator) in the filtered replacement fluid container  147  or an intermediate container supplied through a drip chamber, for example. Alternatively, the exhaustion of the source fluid  150 , if supplied from a fixed-volume container, may be indicated by a sensor such as an ultrasonic sensor, capacitance sensor, mass sensor, optical sensor, a scale, etc. Yet another alternative is to sense gas or a precipitous rise in negative pressure (sensed by a pressure sensor which is not shown) at the pump  190  inlet. At step S 70 , the line  120  may be clamped by actuating shutoff/control valve  180 . Additionally, if appropriate, the pump  190  may be deactivated at the point where the exhaustion of the source fluid  150  is detected at step S 70 . 
         [0068]    According to an embodiment, as the fluid is pumped, the TMP of the filter, as indicated by pressure sensors  162 , may be monitored. If the TMP is determined by the controller  170  to be, at any point, below a predetermined nominal value or to have changed precipitously during filtration, the controller  170  may trigger an alarm or take some other action to insure that the resulting replacement fluid is handled appropriately. For example, a back-up filter could be added during treatment as discussed with respect to  FIG. 5 . The TMP results could trigger an alarm at any point during filtration or could be assessed and reported at step S 70 , before treatment would begin. 
         [0069]    The controller  170  pauses again at step S 80  to wait for the sterile fluid to be exhausted. This may be indicated by a signal from the treatment machine (e.g., received via UI/interface  175 ) or by direct measurement by a sensor, such as an ultrasonic sensor, capacitance sensor, mass sensor, optical sensor, a scale, etc. As mentioned above, the controller  170 , or the heater  185  itself, may be provided with a threshold temperature-rise rate that indicates the mass of fluid in the replacement fluid container  147  has fallen below a minimum level. The loop of step S 80  is exited to step S 90  where power to the heater  185  is terminated. 
         [0070]    Note that all the functionality of the controller  170  may be provided, via a control interface, by a controller (not shown) internal to a treatment machine. For example, the apparatus of  FIG. 1  could be provided as an optional module for such a treatment machine rather than a retrofit module. 
         [0071]    Referring now to  FIG. 3 , a combination blood treatment system and filtered replacement fluid device  310  has a replacement fluid preparation subsystem  305  configured substantially as the device of  FIG. 1 . A filter  260  filters fluid from a source of fluid  250  to generate a batch of filtered replacement fluid  230  as in the embodiment of  FIG. 1 . Again, the source of fluid  150  may be a container of purified or unpurified replacement fluid, one or more containers of constituents which, when combined, form a proper replacement fluid and any of the latter may include a continuous source such as a water tap. A line  320  conveys the source fluid  250  through the filter  260  and into a batch container  247 , which may be any type of sterile, preferably disposable container, for example, a large IV bag. It may also include a number of such containers appropriately interconnected to permit flow into and out of them in the fashion of container  247 . 
         [0072]    Again, a pump  290  may be provided and pressure at an outlet of the filter  260  may be sensed by a pressure sensor  262 . The pump  290  may be controlled by a controller  270  to insure a maximum safe TMP to maximize throughput. Again, the pump  290  is not required and the source fluid  250  may be arranged such as to maintain a desired TMP at the filter  260  without the need of the pump  290  or pressure sensor  262  by elevation. A control valve  265  or a speed of the pump  290  may be used to regulate the flow rate to maintain desired TMP limits. 
         [0073]    A control/shutoff valve  280  may provide the controller  270  the ability to stop the flow of fluid through the filter  260  once a desired volume is reached. A heater  285  may be provided to warm the filtered replacement fluid  230  to prepare it for use. An insulated container  245  may be used and the heater controlled using a temperature sensor  283  as discussed with respect to the  FIG. 1  embodiment. Bubbles may be controlled, as discussed above, by means of a vibration or ultrasonic transducer  284  and remaining fluid by means of pressure sensor  286 . 
         [0074]    A connector  295  may be provided for connecting the source fluid to the line  320 . The connector may be a luer, spike, threaded adapter, or any other suitable type. Although the various controls indicated above are shown to be controlled an automatic controller  270 , each may be controlled also by manual mechanisms. Other aspects of the control mechanisms for the embodiment of  FIG. 3  may be provided as discussed with respect to  FIGS. 1 and 2 . 
         [0075]    The benefits of the  FIG. 3  embodiment are similar to those of the  FIG. 1  embodiment in that it allows replacement fluid over a time period that is not driven by the speed of supply to the treatment process. As a result, a low capacity filter may be used for the filter  260  with the attendant benefits identified above. Note that the UI/interface  275  and controller  270  are shared in the present embodiment by the treatment machine. Thus, any information required for control of both the treatment and preparation of filtered replacement fluid  230  would not need to be communicated to a separate controller such as controller  270 . Note also that the communications among the illustrated components is provided by a channel  202  which may be wire harness, separate wires, a bus, a wireless channel or any suitable communications/power transmission device. 
         [0076]    In the embodiment of  FIG. 3 , a predicted quantity of replacement fluid may be filtered and stored for use during treatment. If, however, for some reason, more is required, the treatment machine controller  270  could be configured to identify that situation and control the subsystem  305  components to provide it. Many blood treatment process employ a filter  220  to filter blood and into which replacement fluid is supplied to a patient  225 . More details on preferred embodiments of the treatment machine are discussed below. 
         [0077]    In either of the above embodiments, the rate of flow of fluid during preparation of the batch of replacement fluid may be substantially less than the rate of consumption during treatment. In an exemplary embodiment of an application for hemofiltration, the amount of replacement fluid consumed is between 9 and 18 l. and the rate of consumption is approximately 200 ml./min. For daily treatment, a higher quantity of fluid is required. Also, the media used for sterile filtration may be any suitable media that insures the quality of the replacement fluid is as desired. In the embodiments discussed above, it was assumed that the end sought was preparation of filtered replacement fluid employed microfiltration to prevent the passage of pyrogens including endotoxins and any other pyrogens. However, the invention could be used with other types of filtration or treatment processes to produce a batch of fluid consumed by a medical treatment process, for example, dialysate for hemodialysis treatment. The benefits accrue in particular when the time scale of preparation may be longer than the time scale of consumption. Moreover, the benefits are more appreciable when some sort of energy-consuming process is required, such as heating, before consumption. Here, not only is the time scale of preparation compatible with a small inexpensive filter, but the long time scale permits heating of the replacement fluid over a long interval. To support this benefit, the batch container may be insulated to minimize heat loss so a small heater will be adequate. Also, the preferred application for the present invention is in the context of hemofiltration because the quantity of fluid required for such treatment is relatively small. 
         [0078]    Note that other motivations for filtering the fluid, in addition to or as an alternative to sterilization of a non-sterile fluid, is (1) removal of air bubbles and/or (2) as a safety net for ensuring against accidental contamination. If bubble removal is the only concern, a drip chamber may be used instead of a filter. For removing bubbles, the filter preferably is of a type that permits the passage of fluid, but which blocks the passage of bubbles, for example due to its media pore size and the surface tension of the fluid. 
         [0079]    Referring now to  FIG. 4A , a preferred type of filter  400  for some of the present embodiments has an inlet port  415  providing an inlet channel  410  communicating with an inlet chamber  440 . An outlet leading port  405  provides an outlet channel  420  communicating with an outlet chamber  445 . A piece of filter media  425  separates the inlet and outlet chambers  440  and  445 . The fluid to be sterilized enters the inlet chamber  440 , is sterilized by passing through the filter media  425 , and exits via the outlet chamber  445 . A gas relief gasket  428  allows gas accumulating in the inlet chamber  440  to be released to the ambient atmosphere. Internal supports and structural details are not shown in the illustration for clarity, but a practical embodiment of the filter of  FIG. 4  may have ribs for strength and internal supports for the media  425  and gasket  428  so that the filter  400  may be capable of tolerating a substantial TMP. 
         [0080]    An integrated contact sensor  412  may be incorporated in the filter to sense the quality of the fluid such as its salinity. The illustration shows a pair of conductive contacts which, as will be understood by those of skill in the art, may be connected to a conductivity measuring device to generate a signal. Note that the sensor  412  could also include a non-contact type sensor such as an induction type device. 
         [0081]    The gas relief gasket  428  may be of a porous hydrophobic material such as PTFE. Air bubbles trapped in the inlet chamber  440  can coalesce in the inlet chamber  440  and exit via the gas relief gasket  428 . It may be, depending on the type of gas relief gasket  428  used, that a substantial TMP will be required to eliminate air. 
         [0082]    An alternative to the gas relief gasket  428  is a gas relief valve  426  as shown in  FIG. 4B . Since the inlet chamber  440  is connected to the non-sterile side of the filtration system, there is little risk of contamination if microbes were to enter through a mechanical device such as the gas relief valve  426 . The latter is illustrated figuratively and allows only gas to escape. Other features of the embodiment of  FIG. 4B  are labeled with the same numerals as features of the embodiment of  FIG. 4A  where they serve substantially identical functions and, thus, their descriptions are not repeated here. 
         [0083]    Referring now to  FIG. 5 , the filters of  FIGS. 4A and 4B  may be used for filtration of replacement fluid in the embodiment of  FIG. 5  as discussed presently. Replacement fluid  360 , which may or may not be sterile, is supplied to a hemofiltration machine  490 . A replacement fluid pump  350  pumps the replacement fluid into a balancing mechanism  330  which meters the replacement fluid before it is introduced, via a junction  485 , into the venous (return) line  480  and ultimately into the blood stream of a patient  225 . Note that a common alternative configuration dilutes the arterial blood at  480 B before it enters the filter  395 . Waste fluid is drawn through a waste line  470  from a filter  395  and pumped via a waste pump  365  through the fluid balancing mechanism  330 . The fluid balancing mechanism  330  meters the replacement fluid to match the rate of withdrawal of waste fluid so that the patient&#39;s fluid balance is maintained during treatment. Actually, the rate of withdrawal of waste fluid may be greater than the rate of metering of replacement fluid by pumping waste fluid through a bypass pump called an ultrafiltration pump  339 . The latter sends some of the waste fluid directly to a waste fluid sump  380 , thereby bypassing the fluid balancing mechanism  330 . The fluid balancing mechanism is depicted figuratively and may operate in accord with any suitable control device. Preferably it meters replacement fluid on an equal-volume or equal-mass basis. A preferred mechanism is described in U.S. patent application Ser. No. 09/513,911, filed on Feb. 25, 2000, entitled: “Synchronized Volumetric Fluid Balancing Systems and Methods,” which is hereby incorporated by reference as if fully set forth in its entirety herein. Various sensors and line clamps, indicated figuratively at  335 ,  355 ,  320 ,  385 , and  390 , may be provided to control flow and ensure safe operation. 
         [0084]    A filter  337  is provided in the replacement fluid line  338  just upstream of the junction  485 . The filter  337  may serve as a last chance safety net for ensuring that replacement fluid is sterile and/or that all bubbles are removed before flowing into the venous line  480 . To ensure that air is not infused into the patient&#39;s body, an air sensor  390  is often provided in hemofiltration systems, but detection of air normally triggers an alarm, automatic shutdown, and skilled intervention to restart the hemofiltration treatment. Obviously, this is undesirable so the system should, as effectively as possible, insure that air or other gas is not injected into the venous line  480  without requiring interruption. 
         [0085]    Although the embodiment of  FIG. 5  includes a hemofiltration machine, other types of treatment processes may be provided a last-chance filter similar to filter  337  and air sensor  390 . For example, hemodiafiltration, hemodialysis, or other treatments may require the infusion of replacement fluid and thereby benefit from a filter such as filter  337 . Preferably, the filter  337  is substantially as in the embodiment of  FIG. 4A . Thus, the filter  337  removes both air and pyrogens. 
         [0086]    Instead of employing a filter at the location indicated at  337 , a drip chamber may be used. Suitable drip chambers are currently available with air vents and microfilters effective to remove pyrogens, so they may be substituted for the filter  337 . Also, in some cases, it may be that there is very little risk that the replacement fluid is contaminated with pyrogens, the filter  337  may serve as a mechanism for removing only air or other gases. In such cases, drip chambers which remove gas (either with or without a vent), could be employed at the above location in the fluid circuit. 
         [0087]    Referring now to  FIGS. 6 ,  7 , and  8  the last chance filter or drip chamber (or combination device)  510  may be installed in a cartridge  520  that holds and orients blood and fluid circuits for a hemofiltration machine  540 . In the embodiment shown, which is described substantially in U.S. patent application Ser. No. 09/513,773, filed Feb. 25, 2000 and entitled: “Fluid Processing Systems and Methods Using Extracorporeal Fluid Flow Panels Oriented Within A Cartridge,” hereby incorporated by reference in its entirety as if fully set forth herein, fluid circuit components may be held in a cartridge  520  and clamped (as shown in  FIG. 8  with the machine closing as illustrated by the arrow  665 ) within a receiving gap  530  in a blood treatment machine such as hemofiltration machine  540 . The cartridge  520  may have a preferred orientation which may insure a correct orientation for the last chance filter or drip chamber (or combination device)  510  if required by the particular device chosen. To insure orientation of the last chance filter or drip chamber (or combination device)  510 , the latter is preferably held by the cartridge  520  in a fixed orientation with respect to the cartridge  520 . 
         [0088]    In an alternative embodiment, the last chance filter or drip chamber (or combination device)  520  may be accompanied by a device  660  for measuring the quality of the replacement fluid, such as conductivity or density. This may provide a last-chance check that the replacement fluid is of the correct type. For example, where such fluids are derived from mixtures, if the proportion is not exactly what is required, infusion could be harmful to the patient  225 . An example of a device  660  to test the fluid could be a wettable pair of contacts (not shown) formed in a tubing set  650  of the cartridge may be used in conjunction with a resistance measurement device to measure the ion concentration of the fluid. Alternatively, a non-wettable sensor, such as an inductive conductivity cell could be used. Other kinds of fluid quality sensors could be employed such as specific-molecule detectors built on silicon wafers and temperature sensors. 
         [0089]    Preferably, the tubing set  650  and cartridge  620  of which it is a part form a disposable component that is used for one treatment and disposed of. Note that the fluid quality sensor  660  may used alone or together with the last chance filter or drip chamber (or combination device)  510 . Note, although  FIGS. 6 and 7  are detailed, they are intended to show various components figuratively and do not reveal the details of the routing necessary to achieve the flow paths discussed with respect to them or as illustrated elsewhere. 
         [0090]    Referring now also to  FIG. 9 , the tubing set and cartridge assembly  610 , discussed previously, may incorporate the batch replacement fluid container  625  as part of a sterile replaceable set  690 . The filter  615  may have a tube  622  with a connector  620  for attachment to a source fluid  250 . A tube  635  may connect the filter to the batch replacement fluid container  625 , which may be fitted with another tube  630  connected by a connector  648 , which may be permanent or removable, to convey fluid to the tubing set and cartridge assembly  610 . Referring now also to  FIG. 10 , the batch replacement fluid container  625  may also be fitted with additional connectors  670  and/or extensions (not shown) to permit the batch replacement fluid container to be used for priming blood, replacement fluid, and/or waste lines. For example, as discussed in U.S. patent application Ser. No. 09/905,246, filed Jul. 12, 2001, entitled: “Devices and Methods For Sterile Filtering of Dialysate,” which is hereby incorporated by reference as if fully set forth in its entirety herein, replacement fluid is circulated through a replacement fluid container  740  to flush air out of all the fluid circuiting (not all shown) of a blood treatment apparatus  710 . As described in detail in the &#39;246 application incorporated by reference above, the venous (return) and arterial (supply) blood lines  725  and  730  may be temporarily connected via connectors  750  to the replacement fluid container  740  and fluid circulated through the container  740  until gas bubbles are substantially purged from the corresponding circuits. Note, the replacement fluid container  740  corresponds to the containers  147  ( FIG. 1 ),  247  ( FIG. 3 ), and  625  ( FIG. 9 ) in the foregoing figures and to respective containers in the application incorporated by reference immediately above. The air and other gases may settle in the replacement fluid container  740  as the fluid circulates. Liberation of the gases would ordinarily be promoted by the application of heat from a heater  775  (with power source  770 ), which may be employed as discussed with regard to the embodiments of  FIGS. 1-3  or in any suitable way to bring the temperature of the replacement fluid to body temperature. Replacement fluid circuits including line  735 , blood circuits including lines  725  and  730 , and waste fluid circuits including line  780  may all be flushed with fluid from the container  740 . The details of the blood treatment apparatus and its internal plumbing can vary. Replacement fluid may be transferred from the replacement fluid line  735  or from the blood line  735  to the waste line, for example through a filter, to flush the waste portion of the circuit including the waste line  780 . Replacement fluid may circulate through the blood circuit including lines  725  and  730  as indicated to flush the blood circuit, at least a portion of which may be closed as indicated by the arterial and venous lines  730  and  735 . 
         [0091]    Disposable components, such as the circuit sets of  FIGS. 8 and 9  or the batch replacement fluid container  625  alone, or other components that may be used with the embodiments disclosed may be packaged with instructions for preparing infusible replacement fluid. For example, the source fluid  150 / 250  or a concentrate which may be mixed to make the same ( FIGS. 1 and 3 ) may be supplied with instructions for sterile filtering the fluid as described in the instant specification. Such may constitute packages of consumables or reusable components. 
         [0092]    Note that benefits of the filtering method and apparatus discussed above may best be achieved by performing the filtration just prior to treatment, although this is not required. The filtering method may be performed at the treatment site. For example, non-sterile concentrate may be stored at the residence of a patient. The concentrate may be diluted with distilled water in a source fluid container (e.g.,  196  of  FIG. 1 ) at the residence and processed as discussed in the instant application. Because the infusible fluid is generated at the treatment site, the need for regulatory-cleared fluids, such as might be obtained from a manufacturer, is not avoided. Cost savings and storage-space economies can thus be realized by the patient. This is particularly important in view of the fact that renal replacement therapies are often administered many times per week and storage and cost of consumables can present a serious problem in a residence or any other facility. 
         [0093]    Referring now to  FIG. 11 , a blood treatment machine, a portion of which is illustrated figuratively at  810 , may permit a pump  845  that, during treatment, conveys replacement fluid to a patient, to be used for sterile filtering a non-sterile source fluid. Here, the machine  810  has a common guide  850  that accommodates a fluid line  815  through which fluid is conveyed by the pump  845 , for example a peristaltic pump. During treatment, the line  815 - 825  may be guided by a first selected guide  830  in a first direction toward other components of an internal fluid circuit (not shown) as indicated at  825 . During sterile-filtering, fluid may be pumped by the same pump  845  through a line  815 - 820  that is allowed to pass out of the blood treatment machine  810  via a different guide  835 . This allows the line  815 - 820  to be fed to an external connection to the sterile fluid container (not shown) as indicated at  820 . 
         [0094]    Referring now to  FIGS. 12-14 , a patient  640  receives a blood treatment by a continuous process performed by a blood treatment machine  610 . The process extracts fluid from the blood of the patient  640  which must be replaced to prevent the patient  640  from dehydrating. For example, the treatment process may be hemofiltration or hemodiafiltration. In such processes, blood may be drawn from the patient  640  through an access  650  and returned to the patient  640  through the same access  650 . 
         [0095]    As is known in the art, the treatment process provided by the blood treatment machine  610  may remove substantial quantities of fluids including electrolytes from the patent&#39;s  640  blood. As part of the process, as is also known, fluid may be provided to the patient  640  during treatment. During hemofiltration, for example, multiple liters of fluid may be required to replace what is withdrawn from the patient during treatment. Such fluid may require multiple standard containers  10 - 30  to make up a sufficient quantity to treat the patient  640 . 
         [0096]    The desired low levels of endotoxins discussed above may be provided by means of a manifold  683  having inline filters  681  on each arm  665  of the manifold  683 . The manifold  683  has a header  655  connecting each arm  665  to a common feed line  645 . Referring to  FIGS. 13 and 14 , filters may be located on each arm  740  of a manifold  770  as indicated at  776  or on a common feed line  790  as indicated at  779 . Either embodiment may include spikes  778  or other suitable connectors for connecting to the source containers  10 - 30 . Again, the filters  681 ,  776 , and  779  are preferably configured to ensure levels of endotoxins in the filtered product are lower than 5 EU/Kg./hr. of treatment time and no more than 0.03 EU/ml. 
         [0097]    Although the foregoing invention has been described by way of illustration and example, it will be obvious that certain changes and modifications may be practiced that will still fall within the scope of the appended claims. For example, the devices and methods of each embodiment can be combined with or used in any of the other embodiments.