|Publication number||US20050209547 A1|
|Application number||US 10/513,693|
|Publication date||Sep 22, 2005|
|Filing date||Jun 5, 2003|
|Priority date||Jun 6, 2002|
|Also published as||EP1531894A2, EP1531894A4, EP1531894B1, US8192387, US20080203023, US20130032537, WO2003103533A2, WO2003103533A3|
|Publication number||10513693, 513693, PCT/2003/17743, PCT/US/2003/017743, PCT/US/2003/17743, PCT/US/3/017743, PCT/US/3/17743, PCT/US2003/017743, PCT/US2003/17743, PCT/US2003017743, PCT/US200317743, PCT/US3/017743, PCT/US3/17743, PCT/US3017743, PCT/US317743, US 2005/0209547 A1, US 2005/209547 A1, US 20050209547 A1, US 20050209547A1, US 2005209547 A1, US 2005209547A1, US-A1-20050209547, US-A1-2005209547, US2005/0209547A1, US2005/209547A1, US20050209547 A1, US20050209547A1, US2005209547 A1, US2005209547A1|
|Inventors||Jeffrey Burbank, James Brugger|
|Original Assignee||Burbank Jeffrey H, Brugger James M|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (22), Referenced by (22), Classifications (13), Legal Events (1)|
|External Links: USPTO, USPTO Assignment, Espacenet|
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's fluid complement. To replace exhausted dialysate, fresh dialysate is continuously circulated through the filter.
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'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.
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.
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.
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.
There is a need for improved mechanisms for providing safe economic replacement fluid for use in various blood therapies.
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,
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., 02. 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.
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.
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.
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's blood and some net quantity of replacement fluid may be infused directly if there is a paucity in the patient'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.
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.
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:
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.
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.
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.
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 ml. should be provided for the filter 160.
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.
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.
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.
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
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'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.
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.
The configuration of
Referring now also to
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 T1, which represents the lead time (ahead of the scheduled treatment) required for the filtering process. A loop through step S20 is exited to step S30 when the clock reaches the treatment time minus T1. At step S30, 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.
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 S40 which is exited to step S50 only when the treatment time minus the predefined interval T2 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
Once the heater is started, the controller 170 may wait for the source fluid to be exhausted at step S60. Step S60 exits to step S70 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 S70, 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 S70.
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
The controller 170 pauses again at step S80 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 S80 is exited to step S90 where power to the heater 185 is terminated.
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
Referring now to
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.
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
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
The benefits of the
In the embodiment of
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.
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.
Referring now to
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.
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.
An alternative to the gas relief gasket 428 is a gas relief valve 426 as shown in
Referring now to
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'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.
Although the embodiment of
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.
Referring now to
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.
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
Referring now also to
Disposable components, such as the circuit sets of
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
Referring now to
Referring now to
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'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.
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
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.
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|International Classification||C02F1/44, A61F, A61M37/00, A61M1/34|
|Cooperative Classification||B01D61/32, A61M1/3455, A61M2205/75, A61M1/1656, A61L2/0017|
|European Classification||B01D61/32, A61L2/00P2A, A61M1/34E4|
|Nov 8, 2004||AS||Assignment|
Owner name: NXSTAGE MEDICAL, INC., MASSACHUSETTS
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BURBANK, JEFFREY H.;BRUGGER, JAMES;REEL/FRAME:016692/0567;SIGNING DATES FROM 20041103 TO 20041104