System and method for delivery of regional citrate anticoagulation to extracorporeal blood circuits   

Abstract: The present invention includes a comprehensive replacement fluid system and method for the delivery of regional citrate anticoagulation (RCA) to extracorporeal blood circuits, wherein the system may include an online clearance monitor (OCM) and a circuit effluent online sensor system (OSS) for the continuous determination of patient plasma content of ultrafilterable solutes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 12/280,450 filed Dec. 16, 2008, now U.S. Pat. No. 8,211,048, issued Jul. 3, 2012, which is the National Stage Entry of PCT/US2007/062589 filed Feb. 22, 2007, which, in turn, claims the benefit of U.S. provisional application Ser. No. 60/775,729 filed Feb. 22, 2006; U.S. provisional application Ser. No. 60/775,728 filed Feb. 22, 2006; U.S. provisional application Ser. No. 60/790,882 filed Apr. 11, 2006; U.S. provisional application Ser. No. 60/791,055 filed Apr. 11, 2006; and U.S. provisional application Ser. No. 60/845,646 filed Sep. 19, 2006, each of which is incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a system and method for the delivery of regional citrate anticoagulation (RCA) to extracorporeal blood circuits.

2. Background Art

Continuous renal replacement therapy (CRRT) is a form of extracorporeal blood treatment (EBT) that is performed in the intensive care unit (ICU) for patients with acute renal failure (ARF) or end-stage renal disease (ESRD), who are often hemodynamically unstable with multiple co-morbidities. In a specific form of CRRT, continuous veno-venous hemofiltration (CVVH) (FIG. 1), blood is pumped through a hemofilter and uremic toxin-laden plasma ultrafiltrate is discarded at a rate of 1-10 liters per hour (convective removal of solutes). An equal amount of sterile crystalloid solution (replacement fluid, CRRT fluid) with physiological electrolyte and base concentrations is simultaneously infused into the blood circuit either before the hemofilter (pre-dilution) or after the hemofilter (post-dilution) to avoid volume depletion and hemodynamic collapse. From a theoretical and physiological point of view, when run continuously for 24 hours per day, CVVH is the closest of all available renal replacement therapy (RRT) modalities today to replicating the function of the native kidneys. Most experts in the field believe that it should be the preferred treatment modality for unstable patients with renal failure. Nevertheless, 90% of RRT in the ICU is performed as intermittent hemodialysis (IHD), sustained low efficiency dialysis (SLED), or sometimes as continuous veno-venous hemo-diafiltration (CVVHDF). Common to all of these latter methods of RRT is that the removal of most solutes is predominantly by the process of diffusion from blood plasma through the membrane of the hemofilter into the dialysis fluid. Diffusion is less efficient in the removal of larger solutes than convection and therefore, from a theoretical standpoint, CVVH is a superior method of RRT.

The most important reason for the limited use of CVVH in the ICU is that anticoagulation is mandatory to prevent clotting of the extracorporeal circuit in 24-hour treatments. Systemic anticoagulation has an unacceptable rate of major bleeding complications and cannot be done safely. Similarly, extracorporeal blood treatments including plasmapheresis, plasma adsorption on specialized columns, blood banking procedures, lipid apheresis systems, plasma adsorption-based endotoxin removal, treatment with a bioartificial kidney device that contains live renal tubular cells, or with a liver replacement therapy circuit also require powerful regional anticoagulation. Regional citrate anticoagulation has emerged as a possible solution to the clinical problem of circuit clotting.

Citrate (or the quickly buffered citric acid) is present in the human plasma as the trivalent negative citrate anion. This ion chelates ionized calcium in the plasma resulting in a single negative Ca-citrate complex and in low free ionized calcium levels. Since the coagulation cascade requires free ionized calcium for optimal function, blood clotting in the extracorporeal blood circuit (EBC) can be completely prevented by an infusion of citrate into the arterial (incoming) limb of the EBC. When the blood is passed through the extracorporeal processing unit, the anticoagulant effect can be fully reversed by the local infusion of free ionized calcium into the venous (return) limb of the EBC. Therefore, theoretically, regional citrate anticoagulation can be both very powerful and fully reversible without systemic (intra-patient) bleeding tendencies.

Regional citrate anticoagulation has been performed for more than 20 years. Nevertheless, all currently described regional citrate anticoagulation methods are labor intensive and complex with the ICU nurse administering several potentially very dangerous IV infusions in the circuit and/or in central venous lines with frequent laboratory measurements and prescription adjustments. Physician errors in prescription and nursing errors in administration can quickly lead to major complications, and even to death. Due to its well-documented dangers, regional citrate anticoagulation has not gained wide use in clinical practice. The recognized dangers of RCA include hypernatremia; metabolic alkalosis; metabolic acidosis; hypocalcemia 1 (due to net calcium loss from the patient); hypocalcemia 2 (due to systemic citrate accumulation); rebound hypercalcemia (due to release of calcium from citrate after CVVH is stopped); hypophosphatemia; fluctuating levels of anticoagulation; nursing and physician errors; ionized hypomagnesemia; declining filter performance; trace metal depletion; access disconnection; wrong connection of citrate, calcium infusions, and/or of the blood circuit to the patient; and accidental disconnection of the citrate or calcium infusion.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a prior art system for continuous veno-venous hemofiltration (CVVH) or CVVH with dialysis (CVVHDF);

FIG. 2 illustrates a system according to the present invention for using citrate in the pre-dilution solution and infusion of a post-dilution solution to enhance removal of citrate in the hemofilter;

FIG. 3 illustrates use of a regional citrate anticoagulation (RCA) system according to the present invention to anticoagulate the extracorporeal circuit of applications other than CRRT;

FIGS. 4a-4b illustrate a continuous renal replacement therapy (CRRT) circuit based on pre- and post-dilution hemofiltration with an integrated online sensor system (OSS) and hematocrit sensors according to the present invention;

FIG. 5a illustrates a hemodialysis system which may be used for 24-hour sustained low efficiency dialysis (SLED) or 4-5 hour intermittent hemodialysis (IHD) with RCA according to the present invention;

FIG. 5b illustrates a conductivity-based online clearance monitor (OCM) according to the present invention for 24-hour SLED or IHD with online-generated dialysis fluid and automated RCA;

FIG. 6a illustrates a hemodialysis system which may be used for continuous veno-venous hemodialysis with pre-dilution hemofiltration (CVVHDF or c-SLEDF) with RCA according to the present invention;

FIG. 6b illustrates a conductivity-based OCM according to the present invention for pre-dilution CVVHDF with online-generated therapy fluid and automated RCA;

FIG. 7a illustrates a hemodialysis system which may be used for 4-5-hour post-dilution hemodiafiltration (intermittent post-HDF) with RCA according to the present invention;

FIG. 7b illustrates a conductivity-based OCM according to the present invention for post-dilution hemodiafiltration (HDF) with online-generated therapy fluid and automated RCA;

FIG. 8a illustrates a hemodialysis system which may be used for simultaneous pre- and post-dilution continuous veno-venous hemofiltration (CVVH) or 4-6 hour intermittent high volume hemofiltration (HVHF) with RCA according to the present invention;

FIG. 8b illustrates a conductivity-based OCM according to the present invention for pre- and post-dilution CVVH or HVHF with online-generated replacement fluid and automated RCA;

FIGS. 9a and 9b illustrate a triple lumen venous catheter with an infusion pathway according to the present invention;

FIGS. 10a and 10b illustrate a quadruple lumen catheter with an infusion pathway according to the present invention;

FIG. 10c illustrates a quadruple lumen vascular access catheter according to another aspect of the present invention with connection lines of different lengths and colors;

FIG. 10d illustrates a quadruple lumen vascular access catheter according to another aspect of the present invention with the male and female line connectors reversed and of different colors;

FIG. 11a illustrates connectors according to the present invention used to attach standard dialysis blood lines (independent arterial and venous blood circuit ends) for dialysis using separate arterial and venous needles;

FIG. 11b illustrates connectors according to the present invention used to attach a citrate-dedicated dialysis blood tubing (different arterial and venous blood circuit ends) for dialysis using separate arterial and venous needles;

FIG. 12a illustrates an arterial infusion line connector according to the present invention which may be used to attach a citrate-dedicated dialysis arterial blood line using separate arterial and venous needles;

FIG. 12b illustrates a venous infusion line connector according to the present invention which may be used to attach a standard or citrate-dedicated dialysis venous blood line using separate arterial and venous needles;

FIG. 13 illustrates citrate-dedicated blood circuit tubing with integrated arterial and venous medication infusion line connectors according to the present invention which may be used to connect the extracorporeal circuit to the patient using separate arterial and venous access needles or a double lumen hemodialysis catheter;

FIGS. 14a-14b illustrates a triple lumen vascular access catheter according to the present invention for use with single needle dialysis operational mode;

FIGS. 14c-14d illustrates a triple lumen vascular access catheter according to the present invention for use with single needle dialysis operational mode that accommodates citrate-dedicated blood tubing and medication infusion lines with different arterial and venous connectors;

FIG. 15a illustrates a connector according to the present invention for circuit priming and for attachment to a single vascular access needle from a dialysis blood line set and medication infusion lines for use with single needle dialysis operational mode;

FIG. 15b illustrates a connector according to the present invention for circuit priming and for attachment to a single vascular access needle from a dialysis blood line set for use with single needle dialysis operational mode;

FIGS. 15c and 15d illustrate a connector according to the present invention for circuit priming and for attachment to a single vascular access needle from a citrate-dedicated dialysis blood line for use with single needle dialysis operational mode;

FIG. 16a illustrates a connector according to the present invention for attachment to a single vascular access needle or to a single lumen catheter from a dialysis blood line for use with single needle dialysis operational mode;

FIG. 16b illustrates a connector according to the present invention for attachment to a single vascular access needle or to a single lumen catheter from a citrate-dedicated dialysis blood line for use with single needle dialysis operational mode;

FIG. 17a illustrates a hemodialysis system which may be used for 24-hour sustained low efficiency dialysis (SLED) or 4-5 hour intermittent hemodialysis (IHD) with RCA according to the present invention;

FIG. 17b illustrates a hemodialysis system which may be used for simultaneous pre- and post-dilution continuous veno-venous hemofiltration (CVVH) or 4-6 hour intermittent high volume hemofiltration (HVHF) with RCA according to the present invention;

FIG. 17c illustrates a hemodialysis system with sensors and online generation of fluid for continuous SLED with RCA according to the present invention;

FIG. 17d illustrates a hemodialysis system with sensors and online generation of fluid for pre-dilution CVVH with RCA according to the present invention;

FIG. 18 depicts a calculation according to the present invention of the maximum possible systemic citrate level during RCA;

FIG. 19 depicts a calculation according to the present invention of the conductivity of plasma (Cpin) in the arterial limb of the extracorporeal circuit entering the hemodialyzer;

FIG. 20a illustrates an OCM in accordance with the present invention;

FIG. 20b illustrates an OCM in accordance with another aspect of the present invention;

FIG. 21 depicts a comparison according to the present invention of the effects of permanent access recirculation on the fresh dialysis fluid conductivity bolus-based online dialysance measurement (Deffective) versus the circuit arterial limb blood conductivity bolus-based online dialysance measurement (DBolus);

FIG. 22 illustrates a basic hemofiltration circuit according to the present invention which may be used to extract a small amount of ultrafiltrate for chemical analysis;

FIG. 23 illustrates a complete hemofiltration circuit according to the present invention which may be used to extract a small amount of ultrafiltrate for chemical analysis;

FIG. 24 illustrates a hemofiltration circuit according to the present invention which may be used for priming and initial testing of pumps and pressure transducers;

FIG. 25 illustrates a complete hemofiltration circuit according to the present invention which may used to extract a small amount of ultrafiltrate for chemical analysis;

FIG. 26 illustrates a hemofiltration circuit according to the present invention showing the location of the triple lumen venous catheter with an infusion port at the tip of the withdrawal lumen;

FIG. 27a illustrates an air gap backflow prevention device which may be used to isolate ultrafiltrate from the patient circuit according to the present invention;

FIG. 27b illustrates a backflow prevention device comprising a series of one way valves which may be used to isolate ultrafiltrate from the patient circuit according to the present invention;

FIG. 27c illustrates a reduced pressure zone backflow prevention device which may be used to isolate ultrafiltrate from the patient circuit according to the present invention;

FIG. 28a illustrates a hemofiltration circuit according to the present invention showing a possible location for a reduced pressure zone backflow prevention device;

FIG. 28b illustrates a hemofiltration circuit according to the present invention showing a possible location for an air gap backflow prevention device;

FIG. 29a depicts a configuration according to the present invention for deriving the patient systemic solute level (Csys) by measuring the ultrafiltrate solute concentration CUF and dividing by the hemofilter sieving coefficient S for the specific solute;

FIG. 29b depicts a configuration according to the present invention for deriving the patient systemic citrate level CSys by measuring the ultrafiltrate citrate concentration CUF;

FIG. 29c depicts a configuration according to the present invention for deriving the patient systemic citrate level CSys by measuring the ultrafiltrate citrate concentration CUF;

FIG. 30a is a schematic illustration of a citrate, calcium and magnesium sensor according to the present invention for use in a continuously flowing fluid circuit;

FIG. 30b is a schematic illustration of a citrate sensor according to the present invention for use in a continuously flowing fluid circuit;

FIG. 31 is a schematic illustration of systemic citrate kinetics during citrate anticoagulation including citrate generation, citrate body clearance and citrate filter clearance in accordance with the present invention;

FIG. 32 is a schematic illustration of solute fluxes in the extracorporeal circuit during CRRT according to the present invention using citrate as a small solute example;

FIG. 33 is a graph depicting plasma citrate concentration in the patient during RCA in accordance with the present invention;

FIG. 34a is a graph depicting citrate concentration measured by a citrate sensor in the drain circuit of a renal replacement therapy machine utilizing RCA with fixed CRRT prescription settings according to the present invention that result in the development of a citrate steady state determined by the CRRT settings and the patient\'s citrate metabolism;

FIG. 34b is a graph depicting citrate concentration measured by a citrate sensor in the drain circuit of a dialysis machine utilizing RCA according to the present invention; and

FIG. 34c is a graph depicting the effluent citrate concentration as measured by an online filter clearance and patency monitor according to the present invention.

DETAILED DESCRIPTION

As required, detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the invention that may be embodied in various and alternative forms. The figures are not necessarily to scale, some features may be exaggerated or minimized to show details of particular components. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a representative basis for teaching one skilled in the art to variously employ the present invention.

The present invention includes a comprehensive, two replacement fluid system and method for the delivery of regional citrate anticoagulation (RCA) to extracorporeal blood circuits, wherein the system may include an online clearance monitor (OCM) and a circuit effluent online sensor system (OSS) for the continuous determination of patient plasma content of ultrafilterable solutes. It is understood that components described for one system according to the present invention can be implemented within other systems according to the present invention as well.

The system and method according to the present invention is capable of delivering RCA to an extracorporeal system requiring anticoagulation. The system addresses the difficulties and risks to patients associated with extracorporeal anticoagulation methods and CRRT devices currently in use for continuous veno-venous hemofiltration (CVVH). The system may include a combination of various CRRT and dialysis machine hardware components, a software control module, and a sensor module to measure citrate or other solute levels online to ensure the maximum accuracy and safety of treatment prescriptions, and the use of replacement fluids designed to fully exploit the design of the system according to the present invention.

With reference first to FIG. 2, a system for CRRT according to the present invention is illustrated and designated generally by reference numeral 10. System 10 includes a CRRT circuit 12 including an arterial blood line 14, a hemofilter 16 in fluid communication with arterial blood line 14, and a venous blood line 18 in fluid communication with hemofilter 16. Arterial and venous blood lines 14, 18 are arranged to be connected to an access catheter 20 in order to withdraw blood from and return blood to a patient. A blood pump 22 is operably connected to arterial blood line 14 in order to facilitate movement of blood from access catheter 20 through CRRT circuit 12. According to one aspect of the present invention, blood pump 22 may be precise, with pumping speeds which may be adjustable in 5 ml/min or finer increments. An effluent line 24 is also in fluid communication with hemofilter 16 for carrying effluent fluid to a drain to be discarded. An ultrafiltration pump 26 may be operably connected to effluent line 24 to facilitate this process, wherein ultrafiltration pump 26 may be an overall ultrafiltration pump that may be non-volumetric in a scale-based system, or a net ultrafiltration pump which may be volumetric.

While CRRT circuit 12 is shown and described, it is understood that the system according to the present invention may comprise any extracorporeal circuit, either wholly or only partially outside the body. Furthermore, it is understood that “patient” as used herein is not limited to human beings, but may comprise other species as well.

With continuing reference to FIG. 2, system 10 further comprises a pre-filter infusion line 28 having a pre-dilution connection 30 to arterial blood line 14 upstream from hemofilter 16. Pre-filter infusion line 28 may supply a pre-dilution solution, such as a citrate-containing anticoagulation solution as described below, from a pre-filter source (e.g., bag 32). A pre-filter replacement fluid pump 34 may be operably connected to pre-filter infusion line 28 to facilitate infusion of the pre-dilution solution, wherein pre-filter pump 34 may be implemented as a volumetric pump. A non-volumetric pump may be acceptable with scale-based balancing. Hemofilter 16 may then be used to remove the citrate anticoagulant (and the bound calcium) from the blood before it is returned to the patient. System 10 may also include a post-filter infusion line 36 having a post-dilution connection 38 to venous blood line 18 downstream from hemofilter 16 for restoring the so processed anticoagulated blood to normal volume. Post-filter infusion line 36 may supply a post-dilution solution, such as an essentially calcium-free, bicarbonate solution as described below, from a post-filter source (e.g., bag 40). A post-filter replacement fluid pump 41 may be operably connected to post-filter infusion line 36 to facilitate infusion of the post-dilution solution, wherein post-filter pump 41 may be implemented as a volumetric pump, although a non-volumetric pump may be acceptable with scale-based balancing.

In accordance with the present invention, an additional IV infusion line 42 and associated IV infusion pump 44 may be utilized for an IV solution infusion into venous blood line 18 downstream from post-dilution connection 38. In particular, IV infusion pump 44 may be used to administer a pre-mixed calcium and magnesium-containing infusion from an IV infusion source (e.g., bag 46) in coordination with the CVVH prescription (described below) and patient chemistry values. Patients will differ in their need for calcium supplementation to reverse the citrate anticoagulation as they will have different albumin and steady state citrate levels. There may also be differences in calcium release from or uptake into the bones. Finally, one may have to administer extra calcium and magnesium in the initial few-hour “loading” phase of RCA to saturate the expanding systemic citrate pool until the steady state is reached. As depicted in FIG. 3, the anticoagulated blood restored to normal volume with the post-filter replacement fluid infusion can be perfused into any secondary extracorporeal blood treatment (EBT) device 48.

FIG. 4a illustrates additional components which may be included in system 10 according to the present invention. System 10 may integrate online (e.g., optical) hematocrit sensors 50 and/or 52 operably connected to arterial blood line 14 to determine the dilution of the incoming blood and in communication with an associated display 54. Hematocrit sensors 50, 52 may be deployed in duplicate, one before (sensor 50) and one after (sensor 52) pre-dilution connection 30. First hematocrit sensor 50 may be used to determine arterial plasma flow in real time. Second hematocrit sensor 52 may allow for checking the reliability of the two sensors 50, 52 against each other when the pre-dilution fluid is not running When the pre-dilution fluid is running at a known (machine settings and volumetric pump defined) rate, the readout from hematocrit sensors 50, 52 may allow for the determination of the degree of hemodilution with the pre-filter infusion, and thereby for the calculation of the delivered blood flow to the dialyzer 16. Online hematocrit sensors 50 and/or 52 allow minute-to-minute calculation of the plasma volume in the blood flowing into the dialyzer 16. This ensures the most accurate and possibly continuously-adjusted dosing of citrate-containing pre-filter fluid to achieve the target citrate to plasma flow ratio. Hematocrit sensors 50 and/or 52 can also be used to detect access recirculation. Finally, the readout from first hematocrit sensor 50 (before the pre-dilution infusion) allows for monitoring the patient\'s blood volume and will detect excessive net ultrafiltration leading to intravascular volume depletion with concomitant hemoconcentration in the patient before hemodynamic compromise could result. Doppler based fluid flow, hematocrit monitors, and volumetric fluid pumps may be used on arterial and venous blood lines 14, 18 as well as the replacement fluid lines 28, 36 and effluent fluid line 24 for maximal precision in ensuring that the set blood flow rate on blood pump 22 matches the actual blood flow delivered by the action of blood pump 22, and that all other fluid flows (pre-filter fluid flow, effluent flow, venous blood flow and net ultrafiltration amount) are all the same as defined by the machine settings.

As shown in FIG. 4b, a total of four hematocrit sensors 50, 51, 52, 53 may be used to determine the dilution of the blood hemoglobin in the arterial limb 14 as well as the venous limb 18 of the extracorporeal circuit 12. FIG. 4b depicts a comprehensive battery of four online hematocrit sensors 50-53 deployed in close physical proximity to each other, at strategic points of the extracorporeal blood circuit 12 for a single modular implementation integrated into system 10 according to the present invention. Such integration is fully possible and is contemplated in all other systems described herein. In addition to sensors 50, 52 described above, sensors 51, 53 may be deployed in duplicate, one before and one after the post-dilution connection 38. The venous limb hemoglobin concentration, which may be determined using sensor 51, may be temporarily increased by increased ultrafiltration on the hemofilter 16 with or without a simultaneous decrease in the rate of infusion of one or more of the crystalloid fluids used by the system. Conversely, the circuit venous limb hemoglobin concentration (sensor 51) can be temporarily decreased by faster infusion of one or more of the crystalloid fluids used by the system with or without a simultaneous decrease in ultrafiltration. The effect on the arterial limb hemoglobin concentration (sensor 50) of such programmed, intermittent, temporary changes in the venous limb hemoglobin concentration allow the precise, automated, intermittent calculation of access recirculation, R as apparent to those skilled in the art.

System 10 may further include an integrated online sensor system (OSS) comprising a solute sensor or sensor array 56 operably connected to effluent fluid line 24 for determining the solute concentration of the ultrafiltrate, and in communication with an associated display 58. In one embodiment, solute sensor 56 may comprise an online citrate sensor which may be used to eliminate the risk of undetected citrate accumulation and may double as an online delivered clearance and liver function monitor. Solute sensor 56 may also function as an online calcium and magnesium sensor. The current clinical practice of monitoring laboratory parameters every six hours to detect citrate accumulation is not applicable to the new treatment protocols with higher clearance goals and a concomitant more rapid citrate accumulation that would occur with a sudden decline in liver function. More frequent laboratory testing is clinically not practical. Solute sensor 56 according to the present invention allows for the derivation of the citrate, calcium and magnesium level in the patient\'s systemic plasma. Under such monitoring, RCA may be performed with complete safety. The post-filter fluid summary bicarbonate content could also be adjusted and the liver function monitored in real time through observing the metabolism of citrate. Solute sensor 56 may also serve as an online clearance module.

All of these elements may be coordinated and monitored by a control program, which may be utilized to determine the optimal ratio of pre- and post-dilution fluids and the fluid flow rates required to reach treatment goals while minimizing citrate load into the patient.

Disposable, sterile fluid circuits may be utilized according to the present invention. System 10 may work with, but is not limited to, blood flows in the range of 50-450 ml/min with flows optimally around the 75 to 200 ml/min range (for 24-hour CVVH versus high volume hemofiltration (HVHF) operational mode). This is a benefit, as even the least optimally performing catheter access will deliver such flows. According to one aspect of the present invention, hemofilter 16 may be removable from system 10, so that an appropriate size filter could be used for the prescribed blood flow and hourly ultrafiltration goals, and also so that elective filter changes could be performed every 24 hours because of predictable protein fouling even in the absence of clotting. More frequent filter changes may also be needed for the clinical application (e.g. cytokine removal).

Since only convective clearance may be used according to the present invention (no diffusive or dialytic component is required), the anticoagulation achieved remains uniform along the axis of hemofilter 16, promising superior results when compared with other protocols using CVVH with simultaneous dialysis (CVVHDF). The amount of middle molecular weight uremic toxin clearance including inflammatory cytokines will also be predictably greater than in any prior CRRT implementations. System 10 according to the present invention running on a CVVH machine or a dedicated device with the necessary pumps and controls may be used to safely provide citrate anticoagulation to any extracorporeal blood circuit, wherein the maximum operational blood flow may be, but is not limited to, 450 ml/minute.

The RCA system according to the present invention eliminates the risks associated with a separate concentrated citrate infusion for anticoagulation in CVVH and other extracorporeal circuits. Citrate removal by hemofilter 16 is important for safe operation of a CVVH system using citrate anticoagulation. If hemofiltration is stopped and blood continues to flow through the circuit 12 to prevent coagulation, the separate infusion of citrate has to be stopped immediately or the patient will receive an excess amount of citrate which could be life threatening. In RCA system 10, if for any reason hemofiltration stops and blood continues to flow through circuit 12 to prevent coagulation (e.g., replacement solution bags 32, 40 are empty), the delivery of citrate with the pre-dilution fluid and also the delivery of calcium with the post-dilution fluid are immediately aborted to protect the patient from an infusion of excess citrate and calcium.

The RCA system according to the present invention markedly reduces the need for health care personnel to monitor and adjust CRRT based on hemofiltration. The use of the post-filter fluid provides for enhanced clearance and variability in the treatment prescription with the varying potassium and alkali content depending on the fluid selected as described below. Finally, the RCA system according to the present invention greatly reduces the risk of citrate accumulation in the patient associated with RCA during hemofiltration or any other extracorporeal blood processing intervention. The specific dangers of RCA as addressed by the RCA system according to the present invention are explained below: 1) Hypernatremia: Only isonatric solutions may be used including the calcium solution. Clinically significant hypernatremia (or hyponatremia) due to the treatment cannot occur. 2) Metabolic alkalosis: The sum of bicarbonate and anions metabolizable to bicarbonate (in mEq) may be kept between 25-50 mEq bicarbonate equivalents per liter of replacement fluid. This is in keeping with fluid alkali content per liter prescribed in most CVVH protocols in the literature. Mild metabolic alkalosis with systemic plasma bicarbonate in the range of 25-30 is possible with high clearance goals but it is not likely to occur or be clinically highly relevant. Changing the ratio of the 25 and 50 bicarbonate bags on the scales (2:0, 1:1, 0:2) and/or supplementing any post-dilution fluid bag with up to 5 mEq/L NaHCO3 (from standard IV push bicarbonate ampoules) will allow flexible adjustment of the overall post-dilution fluid bicarbonate content from 25 to 55 in about 5 mEq/L increments. 3) Metabolic acidosis: With the above flexibility in fluid alkali content, it could only develop if citrate were not metabolized. Even so, if the post-dilution fluid is bicarbonate based, life-threatening wash out of bicarbonate could not occur with prescriptions with >=50% citrate extraction. Citrate sensor 56 may detect the lack of liver metabolism of citrate and may alert the operator to change to a pair of replacement fluids and treatment settings specifically designed for anhepatic patients. The additional citric acid in the pre-filter fluid is not an effective acid from the standpoint of the patient, as the bicarbonates that it consumes are regenerated through the metabolism of the citrate anion in the liver without any net acid generation (analogous to the course diabetic ketoacidosis in a Type 1 diabetic ESRD patient). In the near anhepatic patient, bicarbonate lost through ultrafiltration will not be regenerated by citrate metabolism. However, even such patients can continue on RCA with CVVH, provided that the citrate extraction is >=60%, 50 bicarbonate post-dilution fluid is used, and the calcium homeostasis is adequately managed with a carefully selected (and higher) dose of the calcium and magnesium infusion. 4) Hypocalcemia 1 (due to net calcium loss from the patient): The ultrafiltrate total calcium and magnesium losses are easily calculable in the RCA system according to the present invention. Calcium and magnesium supplements needed in the form of the dedicated infusion regulated by the system may be calculated by a dosing program also taking into account any ongoing citrate accumulation predicted by kinetic modeling and measured by citrate sensor 56. The patient\'s systemic total and ionized calcium levels may be measured every 6 hours as well as calcium volume of distribution determined by anthropomorphic and citrate sensor data. Magnesium may be dosed to maintain a total plasma Ca:Mg=2:1 mM ratio (as ionized magnesium measurements are not routinely available and all chelators of calcium (albumin, citrate, etc) also chelate magnesium. 5) Hypocalcemia 2 (due to citrate accumulation): Citrate will be given in the pre-dilution fluid. This eliminates the risk of nursing errors with a separate citrate infusion. This protocol achieves equally or more efficient anti-coagulation than any previous protocol with 30-40% less net citrate load into the patient. Careful selection of the pre-filter fluid citrate content and keeping the citrate extraction >=50-66% will eliminate the risk of citrate accumulation beyond 3.75-5 mM. Finally, marked citrate accumulation due to lack of metabolism when it occurs, may also be detected accurately by citrate sensor 56 before the ionized calcium could drop by more than 0.25 mmol/L. This may be accomplished by analyzing the sensor-measured systemic plasma levels of citrate by a kinetic modeling program according to the present invention. The kinetic program analyzes the CVVH prescription (fluid compositions and flow rates as well as blood flow rate) and the sensor data when available. It also utilizes anthropomorphic data to predict the citrate volume of distribution in the patient. Finally the patient\'s citrate clearance in L/minute may be calculated and subsequently used to generate the expected citrate accumulation curve and guide calcium and magnesium replacement to saturate the retained citrate. In citrate non-metabolizers (patients with liver failure), RCA with CVVH will be either terminated or carefully continued with special consideration of the risk of rebound hypercalcemia at the cessation of RCA and metabolic acidosis from bicarbonate wash-out. 6) Rebound hypercalcemia (due to release of calcium from citrate after CVVH is stopped): The RCA prescription will ensure that systemic citrate levels stay <=3-5 mM corresponding to about maximum 0.6-1 mM chelated calcium that could be released after RCA is stopped in all patients who can metabolize citrate. Most patients will have 1 mM citrate and about 0.25 mM Ca chelated by citrate in the steady state. The RCA system and method according to the present invention may be designed to keep systemic ionized Ca levels around 1-1.25 and therefore the highest calcium level after RCA is stopped will be <=1.6-1.85 mM and most patients will rebound to <=1.5 mM Ca levels after treatment. If a patient with liver failure is treated with RCA for CVVH, the prescription may be modified so that the steady state citrate level does not exceed 4 mM and the ionized calcium will be maintained at 1.0. A 35 ml/kg/hour treatment goal may still be achieved for any patient size. Total magnesium will be kept at 50% of total calcium (mM/mM). This will require large doses of the additional calcium and magnesium infusions, as there will be more calcium and magnesium in the ultrafiltrate. If the liver function improves the values will gradually normalize with ongoing CVVH and a reduction in the calcium and magnesium infusion without rebound hypercalcemia. If the liver does not improve, rebound hypercalcemia will not occur as the citrate will not be metabolized. Finally, prior to a liver transplant, high volume hemofiltration without citrate anticoagulation can be rendered for a few hours to wash out all citrate and chelated extra calcium and magnesium before the new liver (with good metabolic function) is put in. This way even the anhepatic patient will be able to receive high dose RCA for CVVH. 7) Hypophosphatemia: Because of the lack of calcium or magnesium, the pre-filter and post-filter solutions both can also be supplemented with phosphate by the manufacturer without the risk of calcium- or magnesium-phosphate precipitation. The phosphate-containing fluids can be used even when the serum phosphorus is high as the large filtration goals will allow significant net phosphate removal. Conversely, the fluids may also serve to correct hypophosphatemia towards normal when needed. 8) Fluctuating levels of anticoagulation: The fixed composition of the pre-filter fluid and the blood plasma flow to pre-filter fluid ratio that is kept fixed during a treatment ensures predictable citrate levels and very effective anticoagulation in the circuit as well as a clearly defined hourly citrate load into the patient. Since only convective clearance is used, the concentrations of ionized calcium and citrate remain unchanged and uniform along the axis of hemofilter 16, quite different from other protocols using CVVHDF. The consideration of the patient\'s hemoglobin, and total plasma protein level allows for maximizing the post-dilution ultrafiltration without inducing excessive hemoconcentration. 9) Nursing and physician errors: These are near completely eliminated by the system and method according to the present invention, as the nurse\'s role is mainly to obtain blood samples for total and ionized calcium at specified intervals and notify nephrology of the results. The nurse may also make the needed changes to the mixed calcium and magnesium infusion based on the dosing program (may be provided as a web application or integrated into the RCA for CVVH system according to the present invention). Since the control program may write the entire prescription and continuously monitor the machine settings, physician errors are eliminated. Citrate sensor 56 may obviate the need for any laboratory monitoring. 10) Ionized hypomagnesemia: Since clinical monitoring of ionized magnesium is usually not possible, the protocol will aim to maintain a 2:1 mM/mM ratio between total plasma calcium and total plasma magnesium. To achieve this, the mM ratio of calcium and magnesium may be fixed at 2:1 in the regulated calcium/magnesium infusion. Such dosing ensures that total and ionized magnesium levels will be appropriate for the steady state plasma citrate levels. 11) Declining filter performance: Due to the purely convective nature of small solute removal, this is not expected to be a problem before transmembrane pressure alarms are generated. Elective filter changes every 24 hours may be recommended due to the predictable protein fouling of the filters even in the absence of clotting. 12) Trace metal depletion: Cationic trace metal supplementation may be provided with the calcium infusion to restore precise mass balance for these trace solutes. Should any trace metal be incompatible with chloride as an anion, it can be provided in a higher concentration in the pre-filter solution. 13) Access disconnection: Most patients treated will have catheter access with a low risk of accidental disconnection. 14) Wrong connection of citrate, calcium, or blood circuit to patient: These errors are prevented by the hardware and disposable tubing set design of the system as explained herein. 15) Disconnection of the citrate, post-filter or calcium infusion: This can be completely prevented by appropriate circuit tubing design (contiguous connection to the blood line, air in-line detection plus scale based monitoring).

The various solutions and fluids which may be utilized according to the system and method of the present invention explained above are now described. For any description of solutions and fluids herein, except where expressly indicated, all numerical quantities in this description indicating amounts of material or conditions of reaction and/or use are to be understood as modified by the word “about” in describing the broadest scope of the present invention. Practice within the numerical limits stated is generally preferred. Furthermore, the phrase “essentially free” is understood to mean that only trace amounts of a material, compound, or constituent may be present.

The description of a single material, compound or constituent or a group or class of materials, compounds or constituents as suitable for a given purpose in connection with the present invention implies that mixtures of any two or more single materials, compounds or constituents and/or groups or classes of materials, compounds or constituents are also suitable. Also, unless expressly stated to the contrary, percent, “parts of,” and ratio values are by weight. Description of constituents in chemical terms refers to the constituents at the time of addition to any combination specified in the description, and does not necessarily preclude chemical interactions among constituents of the mixture once mixed.

The replacement solutions that may be used by the system according to the present invention include solutions which are referred to below as “CitrateEasy” and “BicarbEasy” solutions for CVVH and which may be provided in two formulations each, described in detail below. Using the system and method according to the present invention, the citrate solution may be introduced into extracorporeal circuit 12 before the blood enters hemofilter 16. The system and method of the present invention may utilize a combination of pre-dilution and post-dilution hemofiltration, wherein the pre-dilution solution may be CitrateEasy and the post-dilution fluid may be BicarbEasy.

CitrateEasy is a near isonatric (to physiologic human plasma) and isoalkalic (to other commercial CRRT fluids and in terms of metabolizable bicarbonate equivalent anions per liter) citrate anticoagulant-containing hemofiltration solution. BicarbEasy is a bicarbonate-based hemofiltration fluid that may be essentially calcium and magnesium free and contains phosphate. BicarbEasy may be manufactured in a single chamber bag 40, allowing for ease of use and significant cost savings in the process. The post-dilution ultrafiltration provides for maximal fractional extraction of the citrate load from extracorporeal circuit 12 and for maximal uremic clearance achieved for a given rate of extracorporeal circuit blood flow. Since CitrateEasy and BicarbEasy are essentially free of calcium and magnesium, phosphate can be added to both for physiologic phosphate balance. The composition of both the pre-filter and post-filter fluids and the control algorithm of the system and method according to the present invention allows for high blood flows and high per hour clearance rates to be accomplished with the special requirements of twelve hour daily CVVH and high volume hemofiltration (HVHF), without overloading the patient with citrate or inducing undue acid-base or electrolyte changes.

The use of the CitrateEasy fluid with the system of the present invention eliminates the need for and all the associated risks of a separate concentrated citrate infusion. Citrate removal by hemofilter 16 is important for safe operation of a CVVH system using citrate anticoagulation. The separate infusion of citrate in a traditional set-up will have to be stopped immediately when solute clearance is aborted or the patient will receive an excess amount of citrate which could be life threatening. In the system using CitrateEasy, if for any reason hemofiltration stops, the delivery of citrate with the pre-dilution fluid is immediately aborted.

Further, while calcium and magnesium are essentially completely eliminated from the replacement fluids, the net balance of these divalent cations in the CVVH circuit may be kept zero in the individual patient by careful and strictly machine-regulated and coordinated dosing of a combined calcium and magnesium supplement infusion. Nursing errors with the calcium and magnesium infusion may be eliminated by physically integrating this infusion pump 44 with system 10 for the delivery of additional mixed calcium and magnesium into venous blood line 18 of circuit 12, ensuring maintenance of physiologic ionized calcium and free magnesium levels in the patient. The system according to the present invention may monitor the rate settings of this pump 44 and may alert the operator if the value detected is unusual in the light of other treatment and patient parameters. Finally, the mandatory addition of phosphate to the pre-filter and post-filter replacement fluid by the manufacturer will eliminate the need for separate intravenous phosphate administration to prevent hypophosphatemia due to removal by CVVH. The pre-filter phosphate may yield a further (minor) Ca chelation and anticoagulation as well.

It is understood that the fluids may be provided in a 1×, 5×, 10×, 50×, or any other concentrated or diluted ratio of the fluid components described herein. In addition, citrate could be replaced by isocitrate or another non-toxic, metabolizable calcium chelator. Any such variations of the following fluids are fully contemplated.

mmol/L mEq/L Sodium (Na+) 135-150   135-150 Potassium (K+) 0-4   0-4 Citrate (Cit3−)  8-16.67 24-50 Acid citrate (CitH3) 0-10   0-30 Chloride (Cl−) 95-120   95-120 Calcium (Ca2+) 0-4.0   0-8.0 Magnesium (Mg2+) 0-2.0   0-4.0 Dextrose 5.5-11.0   5.5-11.0 Phosphate 0.0-5.0   0.0-5.0 Inulin    0-few mM     0-few mM PAH    0-few mM     0-few mM Trace metals Only if incompatible with the Ca infusion

Inulin and PAH may be introduced in their usual, fluoroprobe-, or biotin-labeled form here to allow online monitoring of glomerular filtration rate and renal tubular secretory function as described with reference to the online sensor system. In addition, the above solution may be provided consisting essentially of all components except for inulin, PAH, and trace metals.

This is a high citrate fluid with phosphorus added, wherein one preferred mode of operation is simultaneous pre- and post dilution CVVH. This solution may not be advised for patients with liver failure and inability to attain >=66% citrate extraction and/or preexisting severe metabolic acidosis. This solution works with BicarbEasy25/50Ca0K2/4P1.

mmol/L mEq/L

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