Abstract:
A method and device for renal replacement therapy is described that sterile-filters solution that can subsequently be used as a replacement fluid in the same unit. The devices and methods include a pump that can be reversed from its normal forward-pumping direction to sterilize a container of replacement fluid to produce sterile replacement fluid. The sterile replacement fluid is captured in a fluid bag. Upon sterilization of the contents of the container, the pump switches to run in its normal forward-pumping direction. The sterile replacement fluid produced by the previous process is now injected into a patient to perform renal replacement therapy. The waste produced during the renal replacement therapy can be trapped in the container that previously held the non-sterile solution. Systems for sterile filtration and subsequent renal replacement therapy that include pre-connected, sterilized, disposable kits for fluid management and batch collection of sterilized fluid are also described.

Description:
FIELD OF THE INVENTION 
     The present invention relates generally to medical devices and methods useful for batch sterile-filtering fluid prior to use as a replacement fluid in renal replacement therapies. More particularly, the devices and methods include using a filter such as a hemofilter first for sterile filtration of a replacement fluid to render the fluid sterile, followed by a renal replacement therapy that uses the sterilized fluid for infusion into a patient. 
     BACKGROUND OF THE INVENTION 
     Patients undergoing hemofiltration, hemodialysis, hemodiafiltration, ultrafiltration, or other form of renal replacement therapy need replacement fluid, dialysate, or infusate which is free of biological contaminants. Given the large amount of sterile fluid needed by such therapies and the current method of spiking multiple bags of replacement fluid, dialysate, or infusate, there is a risk of touch contamination resulting in the introduction of biological contaminants into the fluids. Making the appropriate connections, then filtering the fluid greatly reduces this risk to the patient. It would be advantageous if the same equipment used in renal replacement therapy, such as hemofiltration, could be reconfigured for on-line decontamination of prepackaged solutions such as dialysate to produce the large volumes of sterilized replacement fluid required for the therapy. 
     Presently methods to produce volumes of dialysate from tap water are known, but require complex water purification/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 sterile replacement fluid, is not deemed to be sufficiently free of pathogenic contaminants to allow the injection of such a fluid into a patient. In hemodialysis, the dialysate never enters the patient&#39;s body, but instead flows past a semipermeable membrane that permits impurities in the blood to osmose through the membrane from the higher concentration blood to the lower concentration dialysate. Thus dialysate, intended for extracorporeal use only, is less expensive than solutions prepared as replacement fluids, which will be injected into a patient. 
     Attempts to render dialysate sufficiently sterile for use as a replacement fluid in hemofiltration and hemodiafiltration have focused on a continuous sterilization process that requires 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. 
     However, if dialysate or other fluid of similar physiological make up could be converted to sterile replacement fluid in the same filter used for hemofiltration or hemodiafiltration, utilizing the same pumps, and without the need for periodic quality-controlled filter purging, a renal replacement therapy unit could be made significantly more simple for reconfiguration to a hemofiltration process to produce low cost sterile replacement fluid in situ. Moreover, the ready availability of pre-connected, disposable filtration and fluid pathway kits that have been sterilized and sealed by the manufacturer would significantly reduce the opportunity for touch contamination during the preparation of sterile replacement fluid. 
     SUMMARY OF THE INVENTION 
     The present invention provides devices and methods for producing sterile replacement fluid in a unit that is subsequently used for renal replacement therapy on a patient. The system can be used both to sterilize non-sterile fluid and to sterilize sterile fluid contaminated (e.g., by touch contamination) during connection due to improper technique. In a first embodiment, a system is provided to perform a method that includes the steps of providing a renal replacement therapy unit that has a filter with a membrane separating a waste side of the filter from a clean side. The membrane has a pore size smaller than the non-sterile and pyrogenic material to be filtered. The renal replacement therapy unit also includes a first container of a solution of suitable concentration for use as a replacement fluid that may include the non-sterile and/or pyrogenic material, or sterile fluid contaminated (e.g., by touch contamination) during connection due to improper technique. The first container is in fluid communication with the waste side of the filter. The unit also includes a second container that is adapted to hold sterile replacement fluid. The second container is in fluid communication with the clean side of the filter. A pump, generally the ultrafiltrate pump, is in fluid communication with the first container and the second container. The pump is capable of switching between a first direction that pumps fluid out of the first container and a second direction that removes waste from blood. A second pump, called a replacement fluid pump, pumps fluid out of the second container. The method further includes the step of running the pump in the first (reverse) direction to pump the solution of suitable concentration from the first container into the waste side of the filter. The solution from the first container is filtered through the membrane of the filter to trap the non-sterile and pyrogenic material on the waste side of the filter and produce sterile replacement fluid in the clean side of the filter. The sterile replacement fluid that flows from the clean side of the filter is collected in the second container. During therapy the pump switches to run in the second (forward) direction to pump waste from the blood. The sterile replacement fluid is pumped from the second container into the blood by a second pump. The sterile replacement fluid is used to perform renal replacement therapy on a patient. 
     Another embodiment is a pre-connected, sterilized fluid management kit for use in presterilizing replacement fluids prior to renal replacement therapy. The kit includes various disposable components of a renal replacement therapy unit. In one embodiment, the kit includes a fluid pumping and balancing system, a sterile fluid reservoir, a plurality of tubes conventionally used in a renal replacement therapy, and a replacement fluid container. Each of the plurality of tubes has a first end in fluid communication with the fluid pumping and balancing system and a second end releasably coupled to and in fluid communication with the sterile fluid reservoir. The replacement fluid container tube has a first end coupled to the fluid pumping and balancing system and a second end adapted to couple to a replacement fluid container. The kit is sterilized and packaged in a container at the time of manufacturing to prevent contamination prior to use in a renal replacement therapy unit. 
     Another embodiment is a system for batch sterilization of replacement fluid and renal replacement therapy using the sterilized fluid. The system includes a renal replacement therapy unit adapted to releasably receive a sterilized kit and a sterilized kit having preconnected disposable elements of the renal replacement therapy unit. The kit includes a fluid pumping and balancing system, a plurality of connectors, each having a first end coupled to the fluid pumping and balancing system and a second end adapted to releasably couple to the renal replacement therapy unit, a sterile replacement fluid container releasably coupled to the fluid pumping and balancing system through a plurality of tubes, and a tube having a first end coupled to the fluid pumping and balancing system and a second end adapted to releasably couple to a container of solution to be sterilized. 
     Another embodiment is a method for producing sterile replacement fluid in a renal replacement therapy unit. The method includes the steps of providing a renal replacement therapy unit, a sterilized kit that includes certain disposable elements of the unit, and a container of solution of suitable concentration for use as a replacement fluid. The unit is adapted to releasably receive the sterilized kit. The kit includes a plurality of tubes adapted to releasably couple to the renal replacement therapy unit, a preconnected sterile replacement fluid container and a tube having an end adapted to releasably couple to the solution container. The method further includes the steps of releasably coupling the sterilized kit to the renal replacement therapy unit, releasably coupling the tube to the container of a solution of suitable concentration for use as a replacement fluid, pumping the solution through the renal replacement therapy unit to sterilize it, and capturing the sterilized solution in the sterile replacement fluid container for use in renal replacement therapy. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1 depicts an embodiment of a hemofiltration unit performing the therapy. 
     FIG. 2A is a schematic of the embodiment of FIG. 1, performing hemofiltration therapy. 
     FIG. 2B is a schematic of the embodiment of FIG. 3 performing solution sterilization. 
     FIG. 3 is an embodiment of a hemofiltration unit operating in the reverse pumping mode used for solution sterilization 
     FIG. 3A depicts an embodiment of a hemofiltration unit used to mix dialysate. 
     FIG. 4 is another embodiment of a disposable unit adapted to couple to a hemofiltration unit for solution sterilization, priming, and subsequent hemofiltration therapy. 
     FIG. 5 is an embodiment of a hemofiltration unit performing solution sterilization demonstrating the fluid flow paths. 
     FIG. 6 is an embodiment of a hemofiltration unit in priming mode. 
     FIG. 7A is an embodiment of a renal replacement therapy system (without tubing) showing the installation of a fluid management kit in a hemofiltration unit adapted to receive the kit. 
     FIG. 7B shows the embodiment of the system of FIG. 7A with the kit fully installed (without tubing). 
    
    
     DETAILED DESCRIPTION 
     A hemofiltration device  1  is depicted in FIG.  1 . In a conventional forward pumping hemofiltration mode, a draw blood line  20  carries blood, for example arterial blood, from the patient  92  to a filter  30 . A membrane in the filter  30  allows waste products such as urea and other undesirable metabolic byproducts that are blood contaminants together with water to pass through the filter membrane to the waste side of the filter  30  and out a side port  40  into a waste line  50 . The waste line  50  drains the waste filtrate  61  into a waste container  60 . The filter membrane does not permit blood cells and higher molecular weight proteins to pass through with the waste filtrate and thus concentrated, purified blood passes out the filter top port  70 . The fluid volume lost as waste filtrate during the hemofiltration process must now be replaced in the concentrated, purified blood to return the blood to its proper physiologic concentration. Accordingly, a measured volume of sterile replacement fluid  81  from a sterile fluid reservoir  80  is added to the filtered blood in an amount equal to the volume of waste filtrate removed during the hemofiltration process. A fluid balancing system (not shown in FIG. 1) that measures the waste filtrate removed and then dispenses the proper volume of replacement fluid needed is located inside the hemofiltration unit  1 . Systems and devices for fluid balancing have been described in U.S. patent application Ser. No. 09/513,773, filed Feb. 25, 2000, U.S. Pat. No. 6,579,258,the contents of which are incorporated herein in their entirety by reference. The replacement fluid flows from the replacement sterile fluid reservoir  80 , through the replacement fluid line  10 , to the balancing system in the hemofiltration unit  1 . The reconstituted blood, now consisting of the concentrated, purified blood and the measured amount of replacement fluid, is returned via the return blood line  90 , for instance a venous line, to the patient  92 . 
     FIG. 2A shows a schematic representation of the hemofiltration process. A draw blood line  20  carries blood from the patient to the filter  30 . The blood pump  25  pushes the blood through the filter, and the pressure differential due to the positive pressure of the blood drives the blood across the membrane. A balancing system  48  meters the waste or blood, water, and contaminants through the membrane  35  of the filter  30 , metering out the blood, water, and contaminants into the waste side  33  of the filter and allowing concentrated purified blood to pass out the clean side  37  of the filter and into the filter top port.  70 . The waste filtrate exits the waste port  40  of the filter  30  and passes into the balancing system  48 . Sterile replacement fluid flows from the sterile replacement fluid reservoir  80  through the replacement fluid line  10  to the balancing system  48  where a measured amount of sterile replacement fluid equal to the amount of waste filtrate passed through the balancing system  48  is allowed to combine with the concentrated blood in the return line  90  and return to the patient. The waste filtrate that has passed through the balancing system passes through the waste line  50  and into the waste container  60 . 
     If the therapy requires hemofiltration and ultrafiltration, then an ultrafiltration pump  45  removes excess fluid from the patient&#39;s blood and dumps the excess fluid into the waste container  60 . This excess fluid removed by the ultrafiltration pump  45  does not pass through the balancing system and thus is not matched by an equal amount of replacement fluid. The system may use additional pumps such as a waste pump and a replacement fluid pump as part of the fluid balancing system to assist the proper fluid flow through the system. 
     FIG. 3 shows an embodiment of the present invention prior to connection to the patient  92  to perform therapy. The hemofiltration unit  1  is configured to convert a solution of suitable electrolyte concentration for use as a replacement fluid  82 , for example dialysate, in a container  62  to sterile replacement fluid  81  that is pumped to a container adapted to hold the sterile fluid, such as a sterile fluid reservoir  80 , via a filtration sterilization process. While the solution  82  to be converted will have the proper electrolyte concentration required of replacement fluids, there is a concern that the solution will include non-sterile and/or pyrogenic material, for example pathogens such as bacteria, and thus not be sufficiently sterile to be injected into a patient as a replacement fluid. Thus, the hemofiltration unit can be used to filter the solution to remove bacteria and other pathogens and to prepare sterile replacement fluid for a subsequent hemofiltration procedure by running the appropriate pump in the hemofiltration unit in reverse of the pumping mode used for conventional hemofiltration. In a preferred embodiment, the hemofiltration unit is adapted to receive certain disposable components including a fluid pumping and balancing system as more fully explained herein. 
     FIG. 2B shows the fluid sterilization process schematically. A pump in fluid communication with the fluid container  62 , for instance an ultrafiltration pump  45 , is run in reverse of the direction that the pump is conventionally run during ultrafiltration therapy to draw fluid from the container  62  up through the waste line  50  and into the waste side  33  of the filter  30  via the waste port  40 . The pump  45  forces the fluid through the filter membrane  35  into the clean side  37  of the filter. Because the non-sterile material in the fluid, for instance bacteria or pyrogen, is larger than the pore size of the filter membrane  35 , bacteria in the fluid remain on the waste side  33  of the filter. The filtered fluid, now rendered sterile, emerges as sterile replacement fluid from the top port  70  of the filter and flows through the return blood line  90  into the sterile replacement fluid reservoir  80 . 
     In other methods, the user mixes the dialysate and then sterilizes it as shown in FIG. 3A. A first container  82  of concentrated electrolytes, e.g., any one or more of sodium lactate, potassium, calcium, magnesium chloride, sodium chloride, bicarbonate, and/or other appropriate salts, and/or other elements, is connected to Y-connector  84 . A second container  83  of water, ringers lactate, or saline is also connected to the Y-connector. The two solutions are then mixed as they pass through Y-connector  84  and then pass through the filter. 
     The hemofiltration unit automatically primes the remainder of the fluid pathway when all of the replacement fluid is transformed into sterile replacement fluid. The priming process is described more fully herein. 
     Once the fluid pathway is primed, the hemofiltration unit is ready to be connected to the patient for renal replacement therapy. Referring again to FIGS. 1 and 2A, the blood pump  25  pumps the patient&#39;s blood through the filter  30 , the balancing system  48  meters fluid from the sterile fluid reservoir  80 , and the trapped bacteria on the waste side  33  of the filter pass into the container  60  along with waste blood water. In a preferred embodiment, the now-empty container  60  previously containing the solution  82  can now be used as a waste container for the hemofiltration therapy. A system using more than one filter can also be employed. Further, the system can be used to mix a concentrate solution with another solution. 
     While the embodiments shown are described for hemofiltration therapy, the devices and methods can be used for blood processing, infusive therapies, or any renal replacement therapy, for instance hemodiafiltration, and can also be used for hemodialysis. Moreover, while the hemofiltration unit described is a volumetric system, this method can be readily employed with a mass-metric hemofiltration system that uses scales instead of balance chambers or flow meters to balance flows. 
     In a preferred embodiment, the fluid pumping and balancing system and optionally other elements may be preconnected, prepackaged, sterilized and sealed by the manufacturer into a disposable unit such as a kit to reduce touch contamination that can be introduced during set-up of the fluid sterilization process. A renal therapy unit is adapted to receive the kit, which is releasably coupled to the unit, to form a system for batch sterilization of replacement fluid and subsequent renal replacement therapy using the sterilized fluid. Following therapy, the kit may be removed and discarded and a new kit can be installed for a subsequent fluid sterilization and therapy procedure. 
     FIG. 4 shows an embodiment of a pre-connected, disposable fluid management kit  100 . The embodiment includes a filter  300 , for example a hemofilter, and a sterile fluid reservoir  800  connected to a fluid pumping and balancing system  12  through various tubes or lines  900 ,  10 ,  200 . A first end  901 ,  101 ,  201  of each tube  900 ,  10 ,  200  is coupled to the fluid pumping and balancing system  12  and a second end  902 ,  102 ,  202  of each tube  900 ,  10 ,  200  is releasably coupled to the sterile fluid reservoir  800  via connectors  93 ,  11 ,  21 . Manual clamps  94  may also be used to control fluid flow when disconnecting lines. A waste line  500  has a first end  501  coupled to the fluid pumping and balancing system  12  and a second end  502  removably sealed by a cap  52 . In the embodiment of FIG. 4, the fluid management kit includes a filter  300  in fluid communication with the pumping and balancing system  12 . The pre-coupled, disposable components of the fluid management kit are sterilized by the manufacturer and sealed in a suitable container  130  to guard against contamination. The container  130  may be a poly bag, Tyvek®, paper or other suitable material. The sterilization process used by the manufacturer may be of any conventional method used for sterilizing medical equipment such as gamma irradiation, chemical sterilant such as ethylene oxide, steam, e-beam or the like. The fluid pumping and balancing system  12  of the embodiment of FIG. 4 includes a blood pump  250 , an ultrafiltrate pump  450 , a fluid balancing system  480 , and a venous air detector  515 . The fluid balancing system  480  illustrated in the embodiment is a volumetric system, however it could also be gravimetric flow meters or other means of fluid balancing. The components of the fluid management kit may be connected to form a fluid pathway in any conventional structure used for hemofiltration and ultrafiltration such as the structures shown in the embodiments of FIGS. 1-3. Similarly, the hemofiltration filter  300  may be integrated into the fluid pathway in any conventional structure. In certain embodiment, the hemofiltration filter is not part of the disposable kit. 
     In the embodiment of FIG. 4, the sterile fluid reservoir  800  is releasably coupled to the fluid pumping and balancing system  12  through a blood return line  900 , a sterile replacement fluid line  10  and a draw blood line  200  through connectors  93 ,  11 , and  21 . The connectors  93 ,  11 , and  21  can be Luer connectors, proprietary connectors or any other connectors that will provide a hermetic seal that can be decoupled by a user. The sterile fluid reservoir  800  may be of any size required by the therapy, but preferably between 1 and 75 liters and most preferably between 5 and 50 liters, generally approximately 20 liters. The replacement fluid container line  500  can later be used as a waste line during hemofiltration. 
     Use of the pre-packaged, sterilized fluid management kit greatly reduces the risk of touch contamination. For instance, in the embodiment of FIG. 4, the only connection that must be made by the user during set up is the connection of the replacement fluid container to the waste line  500 . Replacement fluid is commonly provided in one-liter bags, thus requiring up to 50 of more connections to sterilize a sufficient amount of fluid depending on the prescribed therapy. In the embodiment of FIG. 4, all of these connections are made on the waste side of the filter, and accordingly any contamination introduced by the connection procedure is filtered out as the solution moves through the system to the sterile fluid reservoir  800  during batch sterilization. 
     FIG. 5 shows a schematic of the fluid flow of the fluid management kit  100  of the embodiment of FIG. 4 in use in a system for batch sterilization of replacement fluid and subsequent renal replacement therapy, where the system includes the hemofiltration unit fitted with a disposable fluid management kit. The system is best seen in FIGS. 7A and 7B, where the system  1000  for batch sterilization of replacement fluid and renal replacement therapy using the sterilized fluid includes a renal replacement therapy unit  1100  adapted to releasably receive a sterilized fluid management kit and a sterile fluid management kit  1200  (tubing and bags not shown). FIG. 7A shows the installation of the kit  1200  into the unit  1100 . Returning now to FIG. 5, the fluid flow illustrates the batch sterilization process. The second end  502  of the waste line  500  has been releasably coupled to the replacement fluid containers  600 . All of the other fluid connectors  93 ,  11 ,  21  have been preconnected by the manufacturer and thus are not a source of touch contamination during set-up. Only one pump  450  runs during sterile filtration. All other pumps and the balancing system are dormant during sterile filtration. Sterile filtration continues until the entire batch has been processed. 
     During replacement fluid sterilization, the pump  450 , which in this embodiment is the ultrafiltration pump, runs in reverse (a second direction) of its conventional therapeutic pumping direction (a first direction) through filter  300  until the containers  600  of replacement fluid are empty. The emptying of the container results in air pumped into the filter, which is sensed by the venous air detector  515 , best seen in FIG.  4 . When the venous air detector  515  senses the presence of air, software in the hemofiltration system triggers the pump  450  to reverse the pumping direction to the first direction and to prime the system including the filter. This first direction pumps fluid from the sterile fluid replacement reservoir  800 . This priming process is shown in FIG.  6 . Since the blood return line  900 , the draw line  200  and the replacement fluid line  10  are all connected to the sterile replacement fluid reservoir  800 , fluid can be drawn out and air pushed into the reservoir  800  where it floats out of solution. The pump  450  rotates in the forward, or first, pumping direction, metering fluid from the bag  800  and forcing air into the bag  800  from the return line  900 . Fluid is drawn through the replacement fluid line  10  and into the fluid balancing system  480  forcing air out into the venous return line  900 . Sterile replacement fluid is pushed back across the filter  300  priming the waste side of the filter and dumping air into the former replacement fluid containers, now the waste containers  570 . Because the reservoir  800  of sterile replacement fluid acts as a bubble trap, the hemofiltration system, exclusive of the bag, is primed and free of air. 
     An integrity test can be performed on the filter to verify that the replacement fluid was properly filtered during sterilization. The test, substantially similar to that used in manufacture of the filter itself, measures the partial pressure of the wet filter using the air from the arterial line as the test medium. The replication of the manufacturer&#39;s test assures that the filter is leak free and thus the filtered fluid is sterile and safe to use as a replacement fluid. 
     In certain embodiments, a blood leak detector  516  can be incorporated into the fluid pumping and balancing system and used as a redundant test of filter integrity. If the filter demonstrates a leak after the patient has been connected, the blood leak detector will alarm. 
     Once a test of filter integrity is successfully performed and the system has been primed as previously described, the unit is ready for renal replacement therapy, for instance hemofiltration or hemodiafiltration. The second end of each of the draw and return lines is decoupled from the sterile replacement fluid reservoir and each is releasably coupled to the appropriate vascular access of the patient and renal replacement therapy is initiated. The vascular access can be a native fistula, a synthetic graft, a catheter a subcutaneous port or other conventionally used method. 
     Although the foregoing invention has, for the purposes of clarity and understanding, been described in some detail 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.