Performance monitoring of regional citrate anticoagulation

A monitoring device operates to monitor regional citrate anticoagulation (RCA) in a blood treatment system which is configured to administrate citrate to an extracorporeal blood circuit (10) upstream of a dialyzer (11) during a treatment session. At consecutive time steps during the treatment session, the monitoring device obtains a current measurement value of systemic ionized calcium (iCaSYS) or systemic total calcium (CaSYS), operates a predefined algorithm on the current measurement value to generate a current computation value that represents ionized calcium (iCa2, iCa3) in blood at a selected location (loc2, loc3) downstream or upstream of the dialyzer (11) in the extracorporeal blood circuit (10), and presents and/or evaluates the current computation value for assessment of the regional citrate anticoagulation. The need for conventional blood sampling and blood analysis upstream and/or downstream of the dialyzer, e.g. during CRRT, is thereby reduced significantly.

PRIORITY CLAIM

The present application is a National Phase of International Application No. PCT/EP2019/079721, filed Oct. 30, 2019, which claims priority to Swedish Application No. 1851551-0, filed Dec. 11, 2018. The entire contents of each application are incorporated herein by reference and relied upon.

TECHNICAL FIELD

The present invention relates to regional citrate anticoagulation (RCA) during blood treatment, and in particular to a technique for performance monitoring during a blood treatment that involves RCA, e.g. a continuous or semi-continuous renal replacement therapy.

BACKGROUND ART

Continuous or semi-continuous renal replacement therapies have become established as the treatment of choice for supporting critically ill patients with acute kidney injury. Continuous renal replacement therapy (CRRT) is typically a 24-hour treatment, whereas semi-continuous therapy may be performed daily with a duration of 6-12 hours or more. There are many different forms or “modalities” of continuous or semi-continuous renal replacement therapies, including but not limited to CVVH (continuous veno-venous hemofiltration), CVVHD (continuous veno-venous hemodialysis), CVVHDF (continuous veno-venous hemodiafiltration), SLEF (slow extended hemofiltration), SLED (sustained low-efficiency dialysis), and SCUF (slow continuous ultrafiltration). Common to these therapies is that they operate with a relatively low blood flow rate in the extracorporeal blood circuit, typically less than 200 ml/min. Renal replacement therapy involves passing the patient's blood through plastic tubings and membranes (e.g. in a dialyzer), which triggers clotting as well as complement cascade. Continuous and semi-continuous therapies usually require some degree of anticoagulation to prevent clotting in the extracorporeal blood circuit. Without anticoagulation, the survival of tubings and membranes is diminished and therapy becomes less effective.

Citrate or citric acid (C6H8O7) is present in the human plasma, among other forms, as a trivalent negative citrate anion. This ion chelates ionized calcium (Ca2+) in the plasma resulting in a single negative calcium-citrate complex and in low levels of free ionized calcium. Since the coagulation cascade requires free ionized calcium for optimal function, blood clotting in the extracorporeal blood circuit may be prevented by infusion of citrate into the withdrawal (arterial) limb of the extracorporeal blood circuit. As citrate is a small molecule, a majority of the calcium-citrate complex is moved across the membrane of the dialyzer and is lost in the dialysate effluent. To replace lost calcium, a local infusion of free ionized calcium is made into the return (venous) limb of the extracorporeal blood circuit or directly into the patient. Theoretically, this type of Regional Citrate Anticoagulation, commonly abbreviated RCA or CRA, is both very powerful and fully reversible without systemic (intra-patient) bleeding tendencies.

However, RCA has a potential for causing electrolyte abnormalities. Reported derangements by RCA include metabolic alkalosis and acidosis, hypernatremia and hyponatremia, and hypocalcemia. Such abnormalities are detected with proper monitoring and the local treatment protocol should describe how to adjust fluid flows under different conditions to counteract or prevent the abnormalities. The incidence of metabolic complications depends on the amount of citrate administered, the design, rules and flexibility of the protocol, and its proper use.

During RCA, it is common practice to measure the calcium blood status in two locations; a first location representing the blood in the patient and a second location with the highest risk of clotting. Depending on the local treatment protocol, the first location may be in the patient or at an upstream end of the extracorporeal blood circuit, resulting in “systemic” measurement values, and the second location may be upstream or downstream the dialyzer in the extracorporeal blood circuit, resulting in “pre-dialyzer” and “post-dialyzer” measurement values, respectively. The concentration of ionized calcium at the second location is monitored to ensure a low risk for coagulation in the extracorporeal blood circuit and may be used for modifying citrate dose accordingly. The level of systemic ionized calcium (at the first location) is monitored to ensure that the calcium infusion is capable of maintaining systemic ionized calcium levels within physiological range and may be used for modifying calcium infusion rate accordingly. For example, a target value for post-dialyzer ionized calcium may be in the range 0.3-0.5 mmol/L and a target value for systemic ionized calcium may be in the range 1.1-1.25 mmol/L.

One serious and potentially life-threatening complication of RCA is citrate accumulation in the patient. In clinical practice, the total-to-ionized calcium ratio (aka calcium ratio), which is related to the blood citrate concentration, is commonly accepted as an indirect index of citrate accumulation during RCA. For example, a calcium ratio≥2.5 may imply an increased risk of metabolic complications. To enable evaluation of the calcium ratio, the total calcium in the patient (aka total systemic calcium or systemic total calcium) is monitored together with the systemic ionized calcium.

Thus, protocols for RCA typically prescribe monitoring of at least three calcium values, namely ionized calcium at the first and second locations and total calcium at the first location, and often one or more additional systemic blood parameters, such as pH, bicarbonate, potassium, serum sodium, etc. Ionized calcium may be measured by sampling and subsequent sample analysis, e. g. by a blood gas analyzer, where the sampling and sample analysis may be performed every 20 minutes at startup of RCA and then at least every 6 hours when stable conditions are attained. Systemic total calcium may be measured by a laboratory test of a blood sample and may be performed at least once daily.

Further details regarding RCA and its implementations and complications are found in the articles “Citrate anticoagulation for continuous renal replacement therapy(CRRT)inpatients with acute kidney injury admitted to the intensive care unit”, by Davenport and Tolwani, published in NDT Plus (2009) 2:439-447, and “Complication of regional citrate anticoagulation: accumulation or overload?”, by Schneider et al., published in Critical Care (2017) 21:281.

RCA is known to be laborious, costly and complex, partly because of the need for frequent measurements of blood parameters, including ionized calcium. Further, conventional blood gas analyzers are typically not approved for typical concentrations of post-dialyzer ionized calcium (e.g. 0.2-0.5 mmol/L), nor for samples having high levels of citrate. Thus, it has been shown that the current practice of performing sampling and blood gas analysis may be afflicted by measurement errors, e.g. in the article “Discrepant post filter ionized calcium concentrations by common blood gas analyzers in CRRT using regional citrate anticoagulation” by Schwarzer et al., published in Critical Care (2015) 19:321.

There is a general need to improve the practice of using RCA during renal replacement therapy, with respect to at least one of simplicity, cost and accuracy.

The prior art comprises US2008/0015487 which proposes to install an online clearance monitor (OCM) for precise measurement of the delivered small solute clearance, and an online sensor system (OSS) for measuring free ionized levels of calcium, magnesium and citrate in the effluent fluid. It is further proposed to use the measurement values provided by the OSS to back-calculate the corresponding values in the patient's plasma. Allegedly, it is possible to mathematically derive the patient's plasma citrate and total calcium and magnesium level and thereby eliminate the need for laboratory monitoring of the patient's systemic total and ionized calcium and magnesium levels during RCA. However, the proposed use of an OCM and an OSS will not only add significant cost but also considerable complexity to the therapy, e.g. with respect to calibration and maintenance of the OCM and OSS.

WO2010/029401 presents a method for controlling, in continuous dialysis using RCA, the local infusion of calcium by calculations based on modeling of the reactions in the blood circulation, or by approximation of calcium clearance, in accordance with the actual flow rates and the mode of treatment. Specifically, it is proposed to control a pump for local infusion of a calcium solution as a function of the flow rate of blood entering the arterial line, the flow rate of effluent fluid from the dialyzer and the flow rate of citrate, while presuming a known concentration of the infused calcium solution and a fixed value of the systemic total calcium.

WO2010/148194 relates to conventional intermittent hemodialysis for patients suffering from chronic kidney disease (CKD) and proposes to perform RCA by combining infusion of citrate with the use of a dialysate containing both citrate and calcium, to thereby reduce or eliminate the need for post-dialyzer calcium infusion. A method is also proposed for blind prediction of the concentration of systemic ionized calcium at any point during the dialysis treatment or after completed dialysis treatment (“post-dialysis”), by use of a time-dependent mathematical model that includes processes in the patient affecting both calcium and citrate. The blind prediction implies that the systemic ionized calcium is blindly calculated as a function of time based solely on an initial measurement, e.g. at the start of dialysis treatment. There is no indication about the parameters that are measured in the initial measurement. The blind prediction involves computation of predicted concentrations of citrate and ionized calcium at various locations in the extracorporeal blood circuit. Since the mathematical model represents processes in the patient affecting calcium, it is further proposed to statistically correct the predicted concentration of post-dialysis systemic ionized calcium by accounting for the patient's parathyroid hormone (PTH) and/or alkaline phosphatase (AP) level. The correction is determined by employing a multivariate linear regression model including a category of the PTH or AP level of the patient, dialysis treatment time and the predicted concentration of post-dialysis systemic ionized calcium. A corresponding disclosure is found in the article “A Mathematical Model of Regional Citrate Anticoagulation in Hemodialysis”, by Thijssen et al., published in Blood Purif 2010; 29:197-203.

SUMMARY

It is an objective of the invention to at least partly overcome one or more limitations of the prior art.

A further objective is to improve the practice of using RCA during renal replacement therapy, with respect to at least one of simplicity, cost and accuracy.

One or more of these objectives, as well as further objectives that may appear from the description below, are at least partly achieved by a monitoring device, a blood treatment system, a method of monitoring, and a computer-readable medium, embodiments thereof being defined by the dependent claims.

A first aspect of the invention is a monitoring device for a blood treatment system. The blood treatment system comprises an extracorporeal blood circuit which comprises a blood withdrawal line and a blood return line for connection to a vascular system of subject and a dialyzer intermediate the blood withdrawal and blood return lines. The blood treatment system is configured for regional citrate anticoagulation, RCA, by administration of citrate to the extracorporeal blood circuit upstream of the dialyzer during a treatment session. The monitoring device is configured to, at consecutive time steps during the treatment session: obtain a current measurement value of systemic ionized calcium or systemic total calcium; operate a predefined algorithm on the current measurement value to generate a current computation value that represents ionized calcium in blood at a selected location downstream or upstream of the dialyzer in the extracorporeal blood circuit; and present and/or evaluate the current computation value for assessment of the regional citrate anticoagulation.

The first aspect makes it possible to dispense with or at least significantly reduce the need for the conventional procedure of taking and analyzing blood samples upstream and/or downstream of the dialyzer in the extracorporeal blood circuit. Instead, by the first aspect, corresponding information is obtained by algorithmic computations based on a measurement value of systemic ionized calcium or systemic total calcium. Such a measurement value may be obtained in accordance with conventional practice. Thus, the first aspect may serve to reduce the number blood samples that need to be taken and analyzed for monitoring the performance of the regional citrate anticoagulation. The complexity of performing blood treatment in combination with RCA is thereby reduced. Further, lowering the number of blood samples will free time for clinical staff as well as save expenditure for blood sample analysis. Although it may seem counter-intuitive, the accuracy of the computation value, at least when representing post-dialyzer ionized calcium, may even be better than the accuracy of the corresponding measurement value obtained by the conventional approach of performing blood sampling and subsequent blood sample analysis. As noted above, conventional blood gas analyzers are not optimized for blood that is sampled downstream of the dialyzer in the extracorporeal blood circuit and the resulting measurement value lacks in both accuracy and precision. On the other hand, there are established procedures and devices for measuring ionized and total calcium in the blood of the patient, i.e. systemic values, with high accuracy. Thus, by starting from a relatively accurate measurement value of systemic ionized calcium or systemic total calcium, it is not unlikely that the computation value produced by the first aspect is more accurate than the conventionally measured value.

The ability of the first aspect to provide a sufficient accuracy is also due to the fact that the current computation value is generated by operating the predefined algorithm on a current measurement value of systemic ionized calcium or systemic total calcium, e.g. a measurement value that is obtained anew to be relevant at the respective time step. Thereby, the computation starts from the actual level of ionized or total calcium in the subject's blood at each time step. Compared to using predicted levels of calcium in the extracorporeal blood circuit or the subject, the use of actual levels is more likely to render accurate results.

In the following, various embodiments of the first aspect are defined. These embodiments provide at least some of the technical effects and advantages described in the foregoing, as well as additional technical effects and advantages as readily understood by the skilled person, e.g. in view of the following detailed description.

In one embodiment, the monitoring device is further configured to obtain input data comprising current values of operation parameters of the blood treatment system, and optionally one or more of system configuration data for the blood treatment system, chemical parameter data for substances in the blood, and physiological parameter data for the subject, and the monitoring device is configured to operate the predefined algorithm on the input data and the current computation value to generate the current computation value.

In one embodiment, the predefined algorithm comprises a first function configured to estimate the ionized calcium in the blood at the selected location in the extracorporeal blood circuit, said first function being linearly dependent on total calcium at the selected location and total citrate at the selected location.

In one embodiment, the first function is obtained by linearization of a non-linear function with respect to each of total calcium and total citrate, wherein the non-linear function is a solution to a system of equations representing chemical reactions of calcium in free form and bound to other substances in blood, including citrate, while assuming predefined amounts of other substances than calcium and citrate.

In one embodiment, the linearization is performed with respect to reference values of total calcium and total citrate, said reference values corresponding to expected values of total calcium and total citrate, respectively, at the selected location.

In one embodiment, the predefined algorithm comprises a second function configured to estimate the total calcium in the blood at the selected location.

In one embodiment, the selected location is downstream of the dialyzer, and the second function depends on the systemic total calcium and represents a mass balance of total calcium that enters the extracorporeal blood circuit in the blood from the subject and total calcium in the blood at an intermediate location in the extracorporeal blood circuit upstream of the dialyzer, while accounting for fluid infusion into the extracorporeal blood circuit intermediate the subject and the intermediate location, wherein the second function further accounts for a loss of total calcium from the blood in the dialyzer.

In one embodiment, the predefined algorithm comprises a third function configured to estimate the total citrate in the blood at the selected location in the extracorporeal blood circuit.

In one embodiment, the selected location is downstream of the dialyzer, and the third function depends on systemic total citrate and represents a mass balance of total citrate that enters the extracorporeal blood circuit in the blood from the subject and total citrate at an intermediate location in the extracorporeal blood circuit upstream of the dialyzer, while accounting for fluid infusion into the extracorporeal blood circuit intermediate the subject and the intermediate location, wherein the third function further accounts for a loss of total citrate from the blood in the dialyzer.

In one embodiment, the predefined algorithm further comprises a fourth function configured to estimate systemic total citrate as a function of time from start of the regional citrate anticoagulation.

In one embodiment, the fourth function represents a metabolic generation rate of citrate in the subject and further accounts for the administration of citrate into the extracorporeal blood circuit upstream of the dialyzer and a loss of total citrate from the blood in the dialyzer.

In one embodiment, the predefined algorithm further comprises at least one fifth function configured to estimate a clearance of total citrate and a clearance of total calcium from the blood in the dialyzer, wherein the monitoring device is configured to compute a loss of total citrate and a loss of total calcium in the dialyzer based on the clearance of total citrate and the clearance of total calcium, respectively.

In one embodiment, the predefined algorithm comprises a sixth function configured to estimate systemic total calcium as a function of the systemic ionized calcium.

In one embodiment, the predefined algorithm comprises a seventh function configured to estimate the systemic ionized calcium as a function of the systemic total calcium.

In one embodiment, the current measurement value represents the systemic ionized calcium in the blood of the subject, and the monitoring device is further configured to operate the predefined algorithm on the current measurement value to generate a further current computation value representing the systemic total calcium.

In an alternative embodiment, the current measurement value represents the systemic total calcium, and the monitoring device is further configured to operate the predefined algorithm on the current measurement value to generate a further current computation value representing the systemic ionized calcium.

In one embodiment, the monitoring device is further configured to operate the predefined algorithm to generate a further current computation value representing systemic total citrate.

In one embodiment, the monitoring device is further configured to evaluate at least the further current computation value for assessment of accumulation of citrate in the subject.

In one embodiment, the monitoring further comprises an interface for signal communication with a blood analysis apparatus, wherein the monitoring device is further configured to, at the respective consecutive time step, obtain the measurement value from a signal received over the interface from the blood analysis apparatus.

In one embodiment, the monitoring device is further configured to output the current computation value for presentation on a display device.

In one embodiment, the monitoring device is further configured to evaluate the current computation value for detection of an alarm situation, and cause an alarm to be generated when the alarm situation is detected.

In one embodiment, the monitoring device further comprises a decision support module, which is configured to evaluate the current computation value in relation to a clinically proven protocol for the regional citrate anticoagulation, obtain a recommendation for operation of the blood treatment system based on the protocol, and output the recommendation for presentation on a display device.

In one embodiment, the monitoring device further comprises an interface for signal communication with a set of pumping devices in the blood treatment system, wherein the monitoring device is further configured to generate one or more control signals for the set of pumping devices as a function of the current computation value, and provide the one of more control signals to the interface.

In one embodiment, the monitoring device is further configured, during the treatment session, to obtain measurement data representing at least one of calcium and citrate in the blood of the subject and/or the extracorporeal blood circuit, and adjust the predefined algorithm based on the measurement data.

A second aspect is a blood treatment system comprising an extracorporeal blood circuit for connection to a vascular system of a subject. The extracorporeal blood circuit comprises a blood withdrawal line and a blood return line for connection to the vascular system, and a dialyzer intermediate the blood withdrawal and blood return lines. The blood treatment system further comprises a pumping device for pumping blood from the subject through the blood withdrawal line, the dialyzer and the blood return line back to the subject. The blood treatment system further comprises a sub-system which is operable to perform regional citrate anticoagulation, RCA, in relation to the extracorporeal blood circuit and the subject, and a monitoring device in accordance the first aspect or any of its embodiments.

A third aspect of the invention is a method of monitoring a blood treatment system comprising an extracorporeal blood circuit which is configured for connection to a vascular system of a subject and comprises a dialyzer, wherein the blood treatment system is configured for regional citrate anticoagulation, RCA, by administration of citrate to the extracorporeal blood circuit upstream of the dialyzer during a treatment session. The method comprises, at consecutive time steps during the treatment session: obtaining a current measurement value of systemic ionized calcium or systemic total calcium; operating a predefined algorithm on the current measurement value to generate a current computation value representing ionized calcium in blood at a selected location downstream or upstream of the dialyzer in the extracorporeal blood circuit; and presenting and/or evaluating the current computation value for assessment of the regional citrate anticoagulation.

Any one of the embodiments of the first aspect may be adapted and implemented as an embodiment of the third aspect.

A fourth aspect of the invention is a computer-readable medium comprising computer instructions which, when executed by a processor, cause the processor to perform the method of the third aspect and any of its embodiments.

Still other objectives, features, embodiments, aspects and advantages of the present invention may appear from the following detailed description, from the attached claims as well as from the drawings.

DETAILED DESCRIPTION OF EXAMPLE EMBODIMENTS

Also, it will be understood that, where possible, any of the advantages, features, functions, devices, and/or operational aspects of any of the embodiments of the present invention described and/or contemplated herein may be included in any of the other embodiments of the present invention described and/or contemplated herein, and/or vice versa. In addition, where possible, any terms expressed in the singular form herein are meant to also include the plural form and/or vice versa, unless explicitly stated otherwise. As used herein, “at least one” shall mean “one or more” and these phrases are intended to be interchangeable. Accordingly, the terms “a” and/or “an” shall mean “at least one” or “one or more”, even though the phrase “one or more” or “at least one” is also used herein. As used herein, except where the context requires otherwise owing to express language or necessary implication, the word “comprise” or variations such as “comprises” or “comprising” is used in an inclusive sense, that is, to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.

Embodiments of the invention are applicable to all forms of extracorporeal blood treatment or processing that may be combined with regional citrate anticoagulation (RCA), including acute dialysis therapies such as the continuous or semi-continuous renal replacement therapies discussed in the Background section, as well as chronic dialysis therapies such as intermittent hemodialysis, hemofiltration, hemodiafiltration and ultrafiltration etc, and hybrid dialysis therapies such as prolonged intermittent renal replacement therapy (PIRRT), sustained low-efficiency dialysis (SLED), and extended daily dialysis (EDD) etc. Conventionally, the different types of dialysis therapy are referred to as “modalities”.

In the following, without limitation, embodiments will be described with reference to Continuous Renal Replacement Therapy (CRRT) and modalities thereof.

FIG.1is a schematic view of a blood treatment system1for performing CRRT in combination with RCA when connected to a human subject100, denoted “patient” in the following. The system1comprises an extracorporeal blood circuit (“EC circuit”)10which is connected to the vascular system of the patient100at a blood withdrawal end and a blood return end. The connections may be performed by any conventional device, such as a needle or catheter. Blood lines or tubings are arranged to define a blood withdrawal path or limb10aand a blood return path or limb10bof the EC circuit10. A blood filtration unit11, denoted “dialyzer” herein, is connected between the withdrawal and return paths10a,10b. The dialyzer11comprises a semi-permeable membrane11a, which is arranged to separate the dialyzer11into a blood compartment, which is fluidly connected to the withdrawal and return paths10a,10b, and a dialysis fluid compartment. A blood pump12is arranged in the withdrawal path10aand is operable to draw blood from the patient100and pump the blood via the blood compartment of the dialyzer11and through the return path10bback to the patient100. The system1further comprises a source13of dialysis fluid. A dialysis fluid path or line13aconnects the source13to the dialysis fluid compartment of the dialyzer11. Similarly, an effluent path or line14aconnects the dialysis fluid compartment of the dialyzer11to a sink14for spent dialysis fluid (denoted “effluent” in the following). A dialysis fluid pump13bis arranged in the dialysis fluid path13a, and an effluent pump14bis arranged in the effluent path14a.

In the illustrated example, the system1further comprises a first source20of replacement fluid which is connected by a first replacement fluid line20ato the withdrawal path10aintermediate the blood pump12and the dialyzer11. A first replacement fluid pump20bis arranged in the first replacement fluid line20a. The system1further comprises a second source21of replacement fluid which is connected by a second replacement fluid line21ato the return path11a. A second replacement fluid pump21bis arranged in the second replacement fluid line21a.

The system1further comprises an arrangement for pre-dialyzer infusion of citrate into the EC circuit10. The citrate infusion arrangement includes a source22of a citrate-containing fluid. A citrate fluid line22aconnects the source22to the withdrawal path10aupstream of the blood pump12. A citrate pump22bis arranged in the citrate fluid line22a.

The system1further comprises an arrangement for post-dialyzer infusion of ionized calcium into the EC circuit10. The calcium infusion arrangement includes a source23of a calcium-containing fluid. In the illustrated example, a calcium fluid line23aconnects the source23to the return path10bintermediate the dialyzer11and the second replacement fluid line21a. In other examples, the line23amay be connected to the return path10bdownstream of the second replacement fluid line21a, or directly to the vascular system of the patient100. In the illustrated example, the source23is a syringe pump which is operable to infuse the calcium-containing fluid. In an alternative, a separate calcium pump is arranged in the calcium fluid line23adownstream of the source23.

The system1is operated by a control device40, which is configured to generate control signals S1-S7for the pumps12,13b,14b,20b,21b,22band23at least partly in accordance with a control program comprising computer instructions. The control program may also operate based on measurement signals received by the control device40from sensors (not shown) in the system1. The control device40comprises a processor41and computer memory42. The control program is stored in the memory42and executed by the processor41. The control program may be supplied to the control device40on a computer-readable medium, which may be a tangible (non-transitory) product (e.g. magnetic medium, optical disk, read-only memory, flash memory, etc) or a propagating signal. In the illustrated example, the control device40comprises a control signal interface43afor providing the control signals S1-S7to the pumps in the system1. The control device40also comprises an input interface43bfor connection to one or more input devices44that enables an operator to input control data, as well as an output interface43cfor connection to one or more output devices45for providing feedback data to the operator. For example, the input device(s)44may comprise a keyboard, keypad, computer mouse, control button, touch screen, printer, etc, and the output device(s)45, may comprises a display device, an indicator lamp, an alarm device, etc. The operator may be a clinically experienced person, such as a physician or a nurse.

The control device40is operable to effect blood treatment in the system1by operating, in accordance with the control program, the pump12to circulate blood through the EC circuit10, the pump13bto supply dialysis fluid to the dialyzer11, the pump14bto remove effluent from the dialyzer11, and the pumps20a,20bto infuse replacement fluid before the dialyzer11(“pre-infusion”) and after the dialyzer11(“post-infusion”). The control device40is also operable to effect RCA in the system1by operating, in accordance with the control program, the pump22bto infuse the citrate-containing fluid and the pump23to infuse the calcium-containing fluid. The underlying rationale for RCA and the infusion of citrate and calcium is described in the Background section and is also well-known to the person skilled in the art and will not be repeated here.

Although the system1inFIG.1is described for a modality that involves both dialysis, pre-infusion and post-infusion of replacement fluid, the system1may be modified into other modalities, e.g. by refraining from either of pre-infusion and post-infusion of replacement fluid, or both, and/or by performing pure ultrafiltration in the dialyzer11instead of dialysis. Further, embodiments of the invention are applicable to any clinically proven composition of the dialysis fluid, the replacement fluid, the citrate-containing fluid and the calcium-containing fluid, respectively.

FIG.1also indicates a conventional configuration of the system1for obtaining blood samples. As described in the Background section, in accordance with certain protocols, blood samples may be routinely taken to measure the level of systemic total calcium and systemic ionized calcium, as well as post-dialyzer ionized calcium. As used herein, “systemic” refers to the blood in the patient100and “ionized calcium” refers to the free calcium ions, Ca2+. Further, the term “level” may be any type of relative or absolute measure, such as a concentration or an amount. In one non-limiting example, the post-dialyzer ionized calcium may be measured to monitor proper performance of anticoagulation, systemic ionized calcium may be measured to monitor proper performance of the calcium infusion, and the systemic total calcium may be monitored to evaluate citrate accumulation in the patient100. The systemic ionized calcium and post-dialyzer ionized calcium are conventionally measured in blood samples that are taken by connecting a respective sampling device30a,30bto the EC circuit10at a respective designated location. Specifically, systemic ionized calcium is measured at the upstream end of the withdrawal path10a, i.e. close to the connection to the patient100where fresh blood enters the EC circuit10. Post-dialyzer ionized calcium is measured in the return path10b, downstream of the dialyzer11and upstream of the calcium infusion. When the sampling device30a,30bhas been operated to obtain a blood sample, the sampling device30a,30bis disconnected from the EC circuit10and connected to a blood analysis apparatus50, which is separate from the system1and configured to analyze the blood sample for determination of the level of ionized calcium, and possibly other blood parameters such as level of pH, bicarbonate, magnesium, sodium, potassium, chloride, hematocrit, oxygenation, etc. Any suitable blood analysis apparatus50may be used, e.g. a so-called blood gas analyzer (BGA).

Alternatively, the systemic ionized calcium may be measured by BGA analysis of a blood sample which is taken from the patient.

The systemic total calcium is conventionally measured by laboratory analysis of a blood sample which is taken from the patient or at a location in the EC circuit10close to the connection to the patient100, e.g. by use of the sampling device30a. The apparatus50may present the result of the analysis of the respective blood sample to the operator on a display device51, whereupon the operator may evaluate the measurement values based on clinical experience and practice to decide if any setting needs to be changed. If so, the operator may change the setting(s) via the input device44. Alternatively, as indicated by a dashed line inFIG.1, the blood analysis apparatus50may be connected to transfer the measurement values over a wired or wireless connection52to the control device40via its input interface43b, whereby the control device40may show the measurement values to the operator on the display45.

FIG.2corresponds toFIG.1and shows the EC circuit10in linear outline, with blood from the patient entering at the left end and treated blood leaving at the right end.FIG.2also indicates parameters that may be used in computations in accordance with embodiments of the invention. The level of total calcium in the patient100is designated CaSYS(“systemic total calcium”), and the level of total citrate in the patient100is designated CITSYS(“total systemic citrate” or “systemic total citrate”). A first location at the upstream end of the EC circuit10is designated loc1 and the level of ionized calcium at loc1 is designated iCaSYS(“systemic ionized calcium”). A second location downstream of the dialyzer11is designated loc2 and the level of ionized calcium at loc2 is designated iCa2(“post-dialyzer ionized calcium”). Further, the level of total citrate and total calcium at loc2 is designated CIT2(“post-dialyzer total citrate”) and Ca2(“post-dialyzer total calcium”), respectively. A third location upstream of the dialyzer11and downstream of the citrate administration and the pre-infusion (if present) is designated loc3. It should be realized that loc1 and loc2 correspond to the sampling locations inFIG.1. The flow rate of blood taken from the patient is designated by QB. Further, the flow rates of pumps in the system is designated by QDfor the dialysis fluid pump13b, QEfor the effluent pump14b, QPREfor the first replacement fluid pump20b, QPOSTfor the second replacement fluid pump21b, QPBPfor the citrate pump22b, and QSYRfor the calcium pump23.

If the total or ionized calcium is measured at loc1, the measured values may differ slightly from the actual values in the patient, e.g. as a result of so-called access recirculation at the connection site where the arterial path10ais connected to the vascular system. To compensate for the difference, a correction factor may be empirically or theoretically determined and applied to the measured values.

By insightful reasoning and thorough simulation and experimentation, the inventors have found that it is possible to replace at least the measurement of post-dialyzer ionized calcium, iCa2, by a computation of a corresponding parameter value based on a measurement value of either systemic total calcium, CaSYS, or systemic ionized calcium, iCaSYS. Embodiments of the invention are based on this insight. The computation of iCa2will greatly reduce both cost and complexity of performing blood treatment in combination with RCA, since it obviates or at least reduces the need to regularly take blood samples downstream of the dialyzer11during blood treatment. As a conservative estimate, it takes at least 5 minutes for clinical staff to manually take the blood sample, transport the sampling device (30binFIG.1) to the blood analysis apparatus50and wait for the blood analysis. Assuming that 6-10 such samples are taken each day for each blood treatment machine, this corresponds to 30-50 minutes of qualified staff time. Further, the analysis of blood samples by the apparatus50also comes with an operational cost. Thus, for a clinic that operates a plurality of machines that perform blood treatment combined with RCA, considerable savings in both time and operational cost are enabled by embodiments of the invention.

FIG.3is a flow chart of a method300for performance monitoring of RCA during a blood treatment session in accordance with an embodiment. As used herein, a “blood treatment session” involves pumping blood through the EC circuit11when the latter has been arranged in fluid communication with the vascular system of the patient100. The method300may be performed by the control program in the control device40(FIG.1). Alternatively, the device40may be a dedicated monitoring device, whereas the control signals S1-S7may be generated by a separate control device (not shown). In step301, a current measurement value of systemic ionized calcium, iCaSYS, or systemic total calcium, CaSYS, is obtained. With reference to the device40inFIG.1, a current measurement value of iCaSYSmay be obtained either by electronic transfer from the blood analysis apparatus50over communication line52or by the operator manually entering the measurement value through use of the input device44. A current measurement value of CaSYS, which conventionally is given by a laboratory test, may be entered manually by the operator through use of the input device44. In step302, a current value of the post-dialyzer ionized calcium at loc2, i.e. iCa2(FIG.2), is computed as a function of the current measurement value. Step302may involve operating a predefined algorithm on the current measurement value. It may be noted that step301may involve obtaining current measurement values of both iCaSYSand CaSYS, and that step302may involve computing the current value of iCa2as a function of these current measurement values.

In step303, the current value of iCa2is presented and/or evaluated for assessment of the RCA performance. For example, step303may involve presenting the current value of iCa2on a display device (cf.45inFIG.1) or otherwise, to allow the operator to assess the RCA performance and take corrective action if deemed necessary. Alternatively or additionally, step303may involve a machine-implemented evaluation of the current value of iCa2for assessment of the RCA performance, which may result in, e.g., an alarm signal or a recommendation to the operator to change one or more settings of the system1. Further examples of step303are given below with reference toFIG.4. The method300then proceeds to step304, in which it waits before returning to step301. For example, step304may wait for a predefined time period, e.g. in accordance with a predefined sampling scheme as exemplified in the Background section. Alternatively, step304may proceed to step301whenever a new current measurement value of iCaSYSor CaSYSis received by method300.

From the flow chart inFIG.3, it is seen that the computation of the current value of iCa2is based on a measurement value which is obtained anew for each repetition of steps301-303. Thus, the computation of the current value of iCa2does not require the level of ionized or total calcium in the patient or in the EC circuit10to be projected over time. The skilled person realizes that the accuracy of the computed value is likely to increase when it is based on actual measurements rather than projections.

FIG.4is a block diagram of a system for RCA monitoring in accordance with an embodiment. Blocks400-401represent preparatory modeling and analysis for determining the predefined algorithm to be used in the RCA monitoring. Blocks402-407represent input data, and block408represents output data. Blocks410and421-423represent functional modules or processes that may be implemented in a monitoring device (cf.40inFIG.1). In the following description ofFIG.4, reference is made to parameters that are defined in the nomenclature list at the end of the detailed description.

Block400involves defining an extended model of the system1and the patient100for the purpose of deriving an algorithm that defines the level of post-dialyzer ionized calcium. Such an extended model comprises a model of the relevant blood chemistry, including the interactions of calcium with other substances in the blood. The interactions are defined by a number of chemical reactions. The outcome of these reactions is determined by the local concentration of the reactants and chemical equilibrium constants together with the total amounts of calcium and other substances. The total of a substance is the sum of all its forms. The total concentrations depend on the composition of the blood that is pumped from the patient100, the fluids that are mixed into the EC circuit10, and the transport of substances over the membrane11a. The blood chemistry includes calcium, both in free form and bound to other substances. In one example, the model of blood chemistry includes calcium in free form and calcium binding to citrate, albumin, bicarbonate, phosphate and carbonate, as well as substances that are competing to bind to citrate, albumin, bicarbonate, phosphate and carbonate, such as magnesium, sodium, and hydrogen. In embodiments of the invention, the concentration of calcium in the patient100is measured as total concentration (CaSYS) or as ionized (free) concentration (iCaSYS). In one example, the model of blood chemistry assumes that the amount/concentration of the modeled substances other than calcium and citrate are known (e.g. measured or estimated) with the exception of citrate which is modeled over treatment time based on the known addition of citrate for anticoagulation (by pump22binFIG.2). For example, the modeled substances other than calcium and citrate may be assumed to be constant over time.

In one example, the extended model quantifies each included reaction by its equilibrium constant (EQ), giving the equation: ([AB])/([A]·[B])=EQ, where the complex AB is formed by A and B, and [ ] denotes concentration.

The extended model accounts for the addition of fluids into the EC circuit10by considering the mass balance of each substance. Thus, the concentration of substance at loc3 (FIG.2) is given by the mass flow of the substance at loc1 and considering any mass flow of the substance into the EC circuit10upstream of loc3.

The concentration of post-filter total calcium is dependent on the amount of the total calcium that is free for transport over the membrane11aand the amount of protein-bound calcium that cannot pass the membrane11a. When using RCA, a relatively large portion of free calcium will bind citrate, and citrate-calcium complexes will be lost through the membrane11a. In one example, the extended model involves computing the clearance for different solutes in the dialyzer11as a function of the flow rates and the concentrations of the solute at the inlets of the dialyzer. The term “clearance” is well-known to the skilled person and is defined as the mass transfer rate for a solute divided by its plasma concentration or by the concentration gradient if the solute is present on both sides of the membrane11a. In the present disclosure, no distinction is made between clearance and dialysance. The clearance depends on the flow rates of blood and dialysis fluid, the applied ultrafiltration rate (QFIL), and characteristics of the membrane11a. There are established equations for computing clearance for small uncharged water soluble substances, both under pure diffusive conditions and with significant convective transport across the membrane11a. In one example, the extended model may be based on the principles disclosed in the article “Diffusive-convective mass transfer rates for solutes present on both sides of a dialyzer membrane” by Sternby et al, published in ASAIO J 51(3):246-251, 2005. The equations in the article are given for uncharged substances, and thus the mass transport rate is assumed to be a linear function of the inlet concentrations, since the driving forces for diffusion and convection are linear. For charged solutions, equations for clearance may also consider the electrical potential across the membrane. If required, such a membrane potential arises to maintain electro-neutrality. Since all of the charged solutes act together, a calculation of the transportation of one ion may, to be reasonably accurate, consider other relevant ions in the solution. Further, calculation of solute transportation may also consider complex binding between ions. When a complex transfers across the membrane11a, its concentration will change on both sides of the membrane11aand affect the equilibrium between the complex and its individual components. Since, these changes affect the concentration gradient and the transport rate for these components across the membrane11a, equilibrium equations may be included in the calculation of the mass transfers. The calculation of mass transfer rates involves the mass transfer area coefficients of the various solutes, which are available in handbooks or may be estimated. In one example, the extended model considers complexes formed with albumin, which is a major component of blood and is known to bind a variety of charged solutes like sodium, calcium, magnesium and hydrogen ions. The extended model may also consider that each albumin molecule may bind a large number of these ions with different equilibrium constants and that this binding is pH dependent. In a further example, the extended model may consider complexes formed when calcium and magnesium bind to bicarbonate and citrate.

For the transport algorithm, the membrane11amay be considered to be composed of a number of serial segments. For each membrane segment, the transport of each solute and each complex may be calculated separately, taking the membrane potential into account. With the given inlet concentration for each solute, the outlet concentrations for a membrane segment may be calculated from the transports. The total concentration of each compound may be calculated by summing the free concentration and the concentrations of all complexes where they appear. From the total concentration, a new distribution between free concentration and relevant complexes may be calculated. The recalculated concentration may be used as input to the next membrane segment. This calculation is done iteratively along the whole membrane11auntil a steady state situation is reached.

The skilled person understands that the extended model may be derived in many different ways and the foregoing is merely to be regarded as guiding principles. In any event, the extended model results in a non-linear system of equations, which may be numerically solved to render an extended function ƒ_iCaextthat gives ionized calcium at any location in the EC circuit10as a function of modeled substances at this location.

In one example, the extended model is configured to handle26chemical reactions and, after adding equations for totals of involved substances including calcium and electro-neutrality, the extended model results in a non-linear system of37equations. The extended function ƒ_iCaextmay be a function of variables such as totals of calcium, magnesium, sodium, chloride, potassium, bicarbonate, hydrogen phosphate, sulfate, citrate, acetate, lactate and albumin.

The extended model may also result in an equation for the total calcium at loc2, i.e. Ca2, e.g. by considering mass flow balance between loc1 and loc3, and losses in the dialyzer11between loc3 and loc2. In one example, such an equation is given by:

where KCais the clearance of calcium in the dialyzer11, FCALmay be approximated by a constant number (e.g. in range 0.8-1), and

where

Thus, in this example, an equation for the total calcium at loc2 may be given as a second function Ca2=ƒ0,2(CaSYS, H, fpw, KCa, FCAL, QB, QPRE, QE, QD, QPBP).

The extended model may also result in an equation for the total citrate at loc2, i.e. CIT2, e.g. by considering mass flow balance between loc1 and loc3, and losses in the dialyzer11between loc3 and loc2. In one example, such an equation is given by:

In this example, citrate dose DCITis given in mmol/L and defined by the equation:

where CITPBPis the citrate concentration in source22.

It is understood that CIT2may be obtained from CITPW2by straight-forward conversion:
CIT2=CITPW2·fpw2

Thus, in this example, an equation for the total citrate at loc2 may be given as a third function CIT2=ƒ0,3(CITsys, H, fpw, KCIT, DCIT, QB, QPRE, QE, QD, QPBP).

As seen, ƒ0,3depends on the total citrate in the patient's blood, CITSYS. In one embodiment, CITSYSmay be set to a fixed value. However, it has been found that improved results may be achieved by instead modeling CITSYSas a function of treatment time. Such modeling may be performed in many different ways. One example is described in the article “Citrate Pharmacokinetics in Critically Ill Patients with Acute Kidney Injury”, by Zheng et al., published in PLoS One Vol. 8,6 (2013). An equation for the systemic total citrate as a function of time may be given by:

where CIT0is the level of systemic total citrate at the start of RCA and may be set to a predefined or measured value, and t is the time from start of RCA, and JCITLOAD=DCIT*QB*60*10−3. This equation accounts for the rate of body metabolism of citrate (GMET) and also accounts for the infusion of citrate into the EC circuit10and the loss (clearance) of total citrate in the dialyzer11.

Although not shown herein, the model may be modified to account for an abnormal metabolic rate in the patient, e.g. by modifying the parameter GMET.

Thus, in this example, an equation for the systemic total citrate may be given as a fourth function CITSYS=ƒ0.4(CIT0, VD, KBODY, GMET, DCIT, QB, KCIT, t)

As understood from the foregoing, the extended model may also include one or more equations for calculation of the clearance of total citrate and total calcium in the dialyzer. Such equations are well-known in the art and the clearance for substance Y may be represented as a fifth function KY=ƒ0,5(k0AY, αY, QB, QD, QFIL).

The extended model may also comprise an equation for conversion of systemic ionized calcium, iCaSYS, to systemic total calcium, CaSYS. Such an equation may be derived by considering CaSYSas the sum of the different forms of calcium in plasma, e.g. iCa, CaAlb, CaHCO3, CaPO4, CaCit and CaCit2. The model may quantify each form by considering its chemical equilibrium. For example, CaCit=iCasSYS·iCIT·EQCacit, where CaCit and iCIT are the concentration of CaCit and ionized citrate, respectively, and EQCacitis the equilibrium association constant for CaCit. Further, the model may account for the fact that albumin has 12 binding sites that may be occupied by free calcium, and that the number of occupied binding sites (nCaREF) is dependent on pH:
nCaREF=1.58+0.907·(pH−7.4)

In one example, an equation for the systemic total calcium may be given by:

Thus, in this example, an equation for the systemic total calcium may be given as a sixth function CaSYS=ƒ0,6(iCaSYS, Alb, HCO3, pH, EQCaX, iCIT, iCaREF, iP), where EQCaXrepresents the equilibrium association constants EQCa, EQCaHCO3, EQCaCO3, EQCaPO4, EQCaCIT, EQCaCIT2.

Reverting now toFIG.4, it is seen that the extended computation function ƒ_iCaextand the second to sixth computation functions ƒ0,2, ƒ0,3, ƒ0,4, ƒ0,5, ƒ0,6are provided to block401, in which a reduced model is determined to define the predefined algorithm for use in the RCA monitoring.

One reason for block401is that full solving of ƒ_iCaextrequires significant computing capacity. In an attempt to reduce the complexity of ƒ_iCaext, the inventors have made computer simulations which indicate that the extended function has a major dependence on the totals for calcium and citrate, and a smaller dependence on other variables. Therefore, to simplify computations, ƒ_iCaextmay be linearized with respect to the variables of total calcium (Cax) and total citrate (CITx), where subscript x denotes an arbitrary location in the EC circuit10:

The linearization is further illustrated inFIG.5which schematically depicts a three-dimensional space which is spanned by the dimensions iCax, Cax, and CITx, and where different evaluation points piare indicated by open circles. Each evaluation point pi is given by a pair of coordinates in the Caxand CITxdimensions. Specifically, the extended function ƒ_iCaextis evaluated at evaluation points piselected around and including a reference point pREF, which is given by reference values for total calcium (CaREF) and total citrate (CITREF). The reference values are selected to be relevant at the post-dialyzer location, loc2, and may be nominal (desired) values at this location. As indicated inFIG.5, the derivative of ƒ_iCaextin the Caxdimension (δƒ_iCaext/δCax) and in the CITxdimension (δƒ_iCaext/δCITx) at the reference point pREFmay be estimated based on the evaluated values of ƒ_iCaextat a number of evaluation points piin the Caxdimension and the CITxdimension, respectively. The linearized function ƒ0,1makes it possible to compute ionized calcium at loc2, i.e. iCa2, based on current values of total citrate, CIT2, and total calcium, Ca2, at loc2, represented by P2inFIG.5. The linearization may also involve comparing the outputs of ƒ0,1and ƒ_iCaextto verify that a sufficient agreement is achieved within a region of interest500, i.e. for all relevant values of total calcium and total citrate at loc2.

The values of parameters included in the extended function, ƒiCaext, other than the modeled parameters may be estimated based on experience and/or be taken from literature and handbooks and/or be obtained for a relevant population of patients. In the latter example, at least some of the parameter values may be obtained as an average of a respective machine setting or measured physiological parameter, e.g. for a specific clinic, group of clinics, etc. Thereby, the extended function may be tailored to a specific environment.

To summarize, and as indicated in block401inFIG.4, the linearization may be seen to result in a linear function for calculating iCa based on Ca and CIT in loc2:
iCa2=ƒ0,1(Ca2,CIT2)=β0+β1·(Ca2−CaREF)+β2·(CIT2−CITREF)
where β0, β1and β2are constants given by the linearization. In one example, iCa2is calculated in mmol/L and the parameters of ƒ0,1are given by β0=[0.32, 0.45], β1=[0.29, 0.41], β2=[−0.15, −0.05], CaREF=[1.15,1.55] and CITREF=[2.00, 2.80], where the respective pair of brackets defines an interval which is inclusive of the start and end values.

FIG.10contains a summary overview of the functions ƒ0,1-ƒ0,6as well additional functions described further below.

Block401may also involve defining one or more final functions to be used in the algorithmic computations by block410. For example, as indicated in block401, the computation functions ƒ0,1, ƒ0, 2, ƒ0,3, ƒ0,5, ƒ0,6may be combined into an aggregated computation function that directly outputs post-dialyzer ionized calcium, iCa2, based on measured values of systemic ionized calcium and systemic total citrate: iCa2=ƒ1(iCaSYS, CITSYS). The use of an aggregated function is optional; post-dialyzer ionized calcium, iCa2may instead be computed by evaluating ƒ0,1, ƒ0,2, ƒ0,3, ƒ0,5, ƒ0,6in suitable sequence based on measured values of iCaSYS. Thus, any reference to ƒ1in the following may imply the aggregated function or the sequence of functions ƒ0,1, ƒ0,2, ƒ0,3, ƒ0,5, ƒ0,6or any composite functions formed therefrom.

Block401may also involve assigning one or more fixed generic values, which are presumed valid for the relevant systems1, modalities and patients, to one more parameters that are used in the above-mentioned functions. Such parameter(s) may be constant and, e.g., include one or more of FCAL, H, fpw, CIT0, GMET, KBODY, VD, k0AY, αy, Alb, HCO3, pH, EQCax, iCIT, iCaREFand iP. It is also conceivable that block401involves defining one or more approximation functions for estimating one or more parameters in dependence of a measurable property of the patient100. Such approximation function(s) may, e.g., include one or more of: GMET=0.0167·W, VD=(29/72)·W and KBODY=7.79·W·60·10−3, where W is the weight of the patient.

In the example ofFIG.4, block401also involves defining (e.g., based on ƒ0,6) a final function for computing systemic total calcium based on systemic ionized calcium: CaSYS=ƒ2(iCaSYS), and defining (e.g., based on ƒ0,4) a final function for estimating systemic total citrate as a function of time: CITSYS=ƒ3(t).

As shown inFIG.4, block401provides a set of computation functions ƒ1, ƒ2, ƒ3to the computation module410, in which the set of functions ƒ1, ƒ2, ƒ3forms the core of a predefined algorithm for computation of post-dialyzer ionized calcium, iCa2, and optionally further parameters. In the illustrated example, the predefined algorithm comprises the functions:

where RCais the calcium ratio which is conventionally used for evaluating citrate accumulation during RCA, as explained in the Background section. It should be noted that the dependence of the respective function on various parameters is not exhaustive. For example, as understood from the foregoing, the function ƒ1depends on several additional parameters, such as flow rates, clearances, etc. Likewise, function ƒ2several additional parameters, such as concentrations of albumin and bicarbonate in the patient's blood, pH of the patient's blood, etc.

The computation module401operates the predefined algorithm on current measurement data402. In the illustrated example the measurement data402is a measured value of iCaSYS, which is typically measured at loc1 inFIG.2. The computation block410also operates on further input data, which includes one or more current values of machine settings (MS)403of the blood treatment system1, and may also include one or more physiological parameters (PP)404of the patient100, one or more system parameters (SP)405relating to the configuration of the system1, and one or more chemical parameters (CP)406. Examples of such parameters are given in the table ofFIG.6. As used herein, “machine settings” are current values of operation parameters for the blood treatment system1, “physiological parameters” define the physiological state of the patient100or a group of representative patients, “system parameters” define the current structural configuration of the blood treatment system1, and “chemical parameters” define chemical characteristics of blood.

Some of the parameters inFIG.6may be considered as constants. Generic values of such constants may be pre-stored in memory (cf.42inFIG.1) for retrieval by the module410. Alternatively, as explained above, generic values of one or more constants may instead be embedded in the set of functions ƒ1, ƒ2, ƒ3.

The values of at least some of the parameters inFIG.6may be entered by the operator of the system1before start-up of a blood treatment session or, depending on implementation, may be calculated by the control device (40inFIG.1) before and/or during the blood treatment session. Such parameters may include one or more machine settings (MS), e.g. one or more of treatment time, total fluid to be removed from the patient, blood flow rate (QB), dialysis fluid flow rate (QD), effluent flow rate (QE), flow rate of replacement fluid upstream of dialyzer (QPRE), flow rate of replacement fluid downstream of dialyzer (QPOST), ultrafiltration rate (QFIL), flow rate of citrate-containing fluid (QPBP), citrate dose (DCIT), etc. It is also conceivable that block410obtains one or more machine settings from sensor(s) in the system1, e.g. flow rate sensor(s), pump speed sensor(s), etc. It should be noted that one or more of the machine settings (MS) may be changed, by the operator or the control device, during the treatment session and that the computation block410is configured to account for such changes by entering the changed parameter values into the predefined computation algorithm.

The operator may also enter current values of patient parameters (PP), such as hematocrit (H), albumin concentration (Alb), bicarbonate concentration (HCO3), weight (W), blood pH (pH), etc. Concentration values and pH may be given by laboratory analysis of the patient's blood and may alternatively pre-stored in the memory (42inFIG.1) for subsequent retrieval.

With respect to the examples of system parameters (SP) inFIG.6, it may be noted that the clearance parameters KCa, KCITmay be included in input data in so far as they are fixed values rather than calculated by the function ƒ0,5. In addition to the parameter examples inFIG.6, the operator may also indicate the type of fluid within one or more of the sources13,20,21,22,23(FIG.2), so that the composition of the fluid is known to block410. For example, the predefined algorithm may be configured to account for the concentration of calcium or citrate, if present in any of the fluids.

The system inFIG.4may implement the RCA monitoring300ofFIG.3. Thus, the computation module410may be configured to obtain the current measurement data402, which represents a current measured value of systemic ionized calcium (iCaSYS) in accordance with step301. Module410may be further configured to compute and output one or more current computation values, including a current value of post-dialyzer ionized calcium (iCa2), by operating the predefined algorithm on the measurement data402and the further input data403-406. As indicated inFIG.4, output data from the module410may additionally include one or more of a current value of systemic total calcium (CaSYS), a current value of systemic total citrate (CITSYS), a current value of the calcium ratio (RCa), and the current measured value of systemic ionized calcium (iCaSYS).

The system inFIG.4further comprises a monitoring module420, which is configured to receive the output data from the computation module410and perform one or more monitoring operations based thereon, e.g. in accordance with step303inFIG.3. In the illustrated example, the monitoring module420comprises a decision support sub-module421, a presentation sub-module422and a safety check module423.

The decision support module421is configured to obtain a predefined and clinically proven protocol407for blood treatment combined with RCA. The protocol407may be tailored to the current blood treatment system1, such as its modality and the compositions of the fluids, and may define the type of dialyzer(s) that may be used, allowable ranges of individual machine settings, etc. Further, the protocol407may define acceptable range(s) for the output data from the module410, as well as corrective measures to be taken when the output data falls outside the acceptable range(s). Protocols for blood treatment combined with RCA are defined based on experience and extensive testing. There are many available treatment protocols, including universal protocols such as the so-called Kalmar protocol, e.g. described in the article “Regional Citrate Anticoagulation in Continuous Renal Replacement Therapies”, by Daga-Ruiz et al, published in Int J Crit Care Emerg Med 2018, 4:054, or local protocols defined by or for a specific clinic or clinic provider. The decision support module421comprises logic which is configured to process the protocol407to define a set of rules that associates ranges of output values, such as one or more of iCa2, CaSYS, iCaSYS, RCaand CITSYSwith corrective measures to be taken. The logic is further configured to compare the output data from the module410with the set of rules and, based on the comparison, determine if and how any settings of the system1should be modified to improve the performance of the RCA. Based thereon, the module421may output one or more operational recommendations408for presentation to the operator, e.g. on the display device45. The recommendation(s)408may, e.g., indicate one or more machine settings to be changed and a desired direction or amount of change.

The presentation sub-module422is configured to format and provide the output data for presentation on a display device45. For example, the output data may be presented to show current values and/or trends to the operator.

The safety check module423is configured to compare the output data to one or more operational limits, which may be predefined and stored in memory or given by the protocol407, and to cause an alarm device430to generate an audible and/or visible alarm signal whenever a deviation between the output data and the operational limit(s) is detected. Concurrently, the safety check module423may cause the system1to enter a safe operational mode, which is configured to safeguard the patient's health.

It is also conceivable to combine the monitoring module420with a control module so that the system inFIG.4is also configured to automatically determine suitable changes to machine settings based on the output data, e.g. in view of the protocol407, and modify one or more of control signals for the blood treatment system1accordingly (cf. signals S1-S7inFIG.1), possibly subject to confirmation by the operator through use of the input device44.

FIG.7is a flow chart of a computation method that may be performed by the computation module410inFIG.4, e.g. when implemented on the device40inFIG.1. In steps701-704, chemical parameters CP, physiological parameters PP, system parameters SP and machine settings MS are initialized, in which corresponding variables are instantiated and assigned a value. In the illustrated example, the values have been entered via the input device44and stored in the memory42, from which the values are read in steps701-704. As understood from the foregoing discussion, some values may be entered well ahead of blood treatment, e.g. during configuration of the device40, while other values may be entered by the operator in preparation for a specific treatment session. In step705, the clearances of calcium and citrate (KCa, KCIT) are calculated, e.g. by use of function ƒ0,5or any equivalent function. In a variant, these clearances are set equal and calculated for one of calcium and citrate. In yet another variant, fixed values of KCa, KCITare included among the system parameters. In step706, the systemic total citrate CITSYSis set to CIT0. The computation method is now prepared for performing computations as part of the RCA monitoring during a blood treatment session.

After being notified that RCA has started (step707), a counter of the treatment time (t) is set to zero in step708. In step709, the computation method waits until the treatment time equals a sampling time point (tS). At this time, the method proceeds to step710which computes a predicted value of systemic total citrate at the sampling time point, by evaluating function ƒ3at t=tS. In step711, a measured value of systemic ionized calcium iCaSYSis obtained, either by user input via the input device44, or from the blood analysis apparatus50over the connection52(FIG.1). In step712, a value of post-dialyzer ionized calcium iCa2is computed by operating the function ƒ1on the measured iCaSYSvalue and the predicted CITSYSvalue (given by step710). In step713, a current value of systemic total calcium CaSYSis computed by operating function ƒ2on the measured iCaSYSvalue. In step714, the calcium ratio RCais computed based on the current values of iCaSYSand CITSYS. In step715, the current values of iCaSYS, iCa2, CaSYS, RCaand CITSYSare output, whereupon the method returns to step709, to wait for the next sampling time point. In one embodiment, the sampling time points are predefined and, e.g., given by a data structure stored in the memory42. Alternatively or additionally, the next sampling time point may be implied whenever a measured iCaSYSvalue is obtained (cf. step711).

FIG.8Agraphically depicts the sequence of calculations that may be performed during execution of the computation method inFIG.7. Open circles represent measured values, filled circles represent computed values, and arrows indicate the values used in the respective calculation. The graph inFIG.7Apresumes that measurements are taken every hour for the first three hours and then every fourth hour. At each such measurement (sampling time point), a current value of CITSYSis projected and used, together with the measured value of iCaSYS, for computing a current value of iCa2. The measured value of iCaSYSis further used for computing a current value of CaSYSwhich is used, together with measured value of iCaSYS, for computing a current value of RCa. In the illustrated example, it is presumed that the current value of CITSYSis projected based on the preceding value of CITSYS. In an alternative, using function ƒ3, current values of CITSYSare projected based on the value of CITSYSat time t=t0(CIT0).

As explained with reference toFIG.3, steps301-302may alternatively obtain a measured value of systemic total calcium, CaSYS, and compute a current value of post-dialyzer ionized calcium, iCa2, based on the measured value of CaSYS. Such an embodiment may be implemented by modification of the system inFIG.4, in which the measurement data402is CaSYSinstead of iCaSYS. The computation of a current value of iCa2based on a measured value of CaSYSmay be implemented in different ways. A few non-limiting examples are given below.

In a first example, a seventh function ƒ0,7is provided to generate iCaSYSas a function of CaSYS, by straight-forward re-arrangement of variables in function ƒ0,6:
iCaSYS=ƒ0,7(CaSYS,Alb,HCO3,pH,EQCaX,iCIT,iCaREF,iP)

In the first example, with reference toFIG.4, block401may be seen to involve defining, based on ƒ0,7, a final function for computing systemic ionized calcium based on systemic total calcium: iCaSYS=ƒ4(CaSYS) and providing the set of functions ƒ1, ƒ3, ƒ4to the computation module410. The computation method inFIG.7may be modified accordingly, by step711obtaining a measured value of CaSYS, step712computing a value of iCaSYSby operating the function ƒ4on the measured value of CaSYS, and step713computing a value of iCa2operating the function ƒ1on the computed value of iCaSYSand the predicted value of CITSYS(given by step710).FIG.8Bgraphically depicts the sequence of calculations that may be performed during execution of such a modified computation method.

In a second example, with reference toFIG.4, block401may be seen to involve combining functions ƒ0,1, ƒ0,2, ƒ0,3, ƒ0,5into a final function for computing post-dialyzer ionized calcium based on systemic total calcium and systemic total citrate: iCa2=ƒ1*(CaSYS, CITSYS) and to provide the set of functions ƒ1*, ƒ3, ƒ4to the computation module410.

In a third example, block401may be seen to involve a further linearization of function ƒ_iCaextto derive a linear function ƒ0,7* for calculating systemic iCa based on systemic Ca and systemic CIT. The linearization may be performed as exemplified with reference toFIG.5but at a reference point PREF_2given by reference values for total calcium (CaREF_2) and total citrate (CITREF_2) in the blood of the patient. Such a linear function may be given by:

where β0_2, β1_2and β2_2are constants given by the linearization. By analogy with function ƒ1, functions ƒ0,2, ƒ0,3, ƒ0,4, ƒ0,5, ƒ0,7* may be seen to form a final function iCaSYS=ƒ4*(CaSYS, CITSYS). Thus, in the third example, block401may provide the set of functions ƒ1, ƒ3ƒ4* or ƒ1*, ƒ3, ƒ4* to the computation module410.

The utility of the computation method inFIG.7has been evaluated based on measurement data obtained for a plurality of patients when subjected to blood treatment by CRRT machines (Prismaflex® from Baxter Corporation) equipped with ST150 sets and operated predominantly in modality CVVHDF. Values of post-dialyzer ionized calcium, iCa2, were computed based on measured values of systemic ionized calcium, iCaSYS, and compared to measured values of post-dialyzer ionized calcium. The measured values were obtained by blood sampling and BGA analysis as described with reference toFIG.1.FIG.9Ais a comparison of average computed iCa2values versus average measured iCa2values, where each data point inFIG.9Arepresents time averages of computed and measured values, respectively, for a respective patient.FIG.9Bshows an example of the difference between individual computed and measured iCa2values during a treatment session.FIG.9Cis a graph of the average difference between computed and measured iCa2values for a plurality of patients. The average of the data points inFIG.9Cis 0.013 mmol/L with a standard deviation of 0.019 mmol/L.FIG.9Dis a graph of the standard deviation of the difference between computed and measured iCa2values for the plurality of patients inFIG.9C. Considering that a standard BGA typically has an nominal accuracy of ±7.5% and that BGAs are not certified for measurements of ionized calcium in the range of 0.2-0.5 mmol/L or for blood samples with high concentration of citrate, the results inFIGS.9A-9Dindicate that the computation method is useful for replacing measurements of post-dialyzer ionized calcium in systems for blood treatment that involves RCA.

Further, while operations are depicted in the drawings in a particular order, this should not be understood as requiring that such operations be performed in the particular order shown or in sequential order, or that all illustrated operations be performed, to achieve desirable results. In certain circumstances, multitasking and parallel processing may be advantageous. Moreover, the separation of various system components in the embodiments described above should not be understood as requiring such separation in all embodiments. Reverting toFIG.4, block400may not only represent a preparatory step for defining the extended model, but may be an operative module which is configured to adapt the extended model based on measurement data M, as indicated by dashed lines inFIG.4, where the measurement data M is obtained at considerably lower rate than the input data402. The measurement data M may comprise measured amounts of one or more forms of calcium, total calcium, or total citrate in the blood of the patient and/or in the blood at any location in the EC circuit10. In one example, the measurement data M may include measured CaSYSvalues, and block400may adjust the function ƒ0,6by comparing the measured CaSYSvalues to computed CaSYSvalues, which are obtained by operating ƒ0,6on measured iCaSYSvalues (cf. input data402). In another example, the measurement data M may include measured CITSYSvalues, and block400may adjust the function ƒ0,4by comparing the measured CITSYSvalues to computed CaSYSvalues given by ƒ0,4as a function of treatment time. In yet another example, the measurement data M may include measured iCa2values and measured Ca2values, and block400may adjust the extended function ƒ_iCaext, by comparing the measured iCa2values to computed iCa2values, which are obtained by operating ƒ_iCaexton the measured Ca2values.

Correspondingly, as also indicated inFIG.4, block401may be an operative module which is configured to adapt the reduced model based on measurement data M, e.g. by adjusting any one of functions ƒ1, ƒ1*, ƒ2, ƒ3, ƒ4, ƒ4*.

It may also be noted that the linear function ƒ0,1need not be derived, in block401, by linearization of an extended function given by theoretical modeling of the system1but may instead be derived by linear regression analysis of time-coordinated measurement values of iCa2, Ca2and CIT2. Correspondingly, the linear function ƒ0,7* may be derived by linear regression analysis of time-coordinated measurement values of iCaSYS, CaSYSand CITSYS. In a further variant, the extended model includes a respective extended function for each relevant form of calcium in the blood, including ionized calcium and one or more of CaAlb, CaHCO3, CaPO4, CaCit and CaCit2. Correspondingly, the reduced model may include a respective linear function for each relevant form, where the respective linear function is obtained by linearization of the respective extended function with respect to variables Ca and CIT (cf.FIG.5). The reduced model may also include a function for computing the total calcium and total citrate at loc3 (FIG.2), by considering mass flow balance between loc1 and loc3. The reduced model may further comprise one or more functions for computing the loss (clearance) of the respective form of calcium through the dialyzer membrane, as well as a function for predicting CITSYSin the patient (cf. ƒ3). Based on the linear functions, the computation module410may be configured to compute, based on a measured value of CaSYS, the amount of the respective form of calcium in the patient's blood. Further, the module410may be configured to compute the amount of the respective form of calcium at loc3, compute and remove the respective loss through the dialyzer membrane, and sum the remaining amounts of the different forms of calcium to obtain the total calcium at loc2, i.e. Ca2. The module410may also be configured to compute a current value of systemic total citrate (CITSYS), compute a corresponding amount of total citrate at loc3, compute and remove the loss of total citrate through the dialyzer membrane, to obtain the total citrate at loc2, i.e. CIT2. The module410may then be configured to operate the linear function for ionized calcium on Ca2and CIT2to obtain iCa2. If the measured value (402) instead represents iCaSYS, the module410may be configured to operate the function ƒ2on the measured iCaSYSvalue to obtain a computed CaSYSvalue for use in the further computations.

The foregoing description is based on the assumption that the treatment protocol prescribes monitoring of ionized calcium downstream of the dialyzer, at loc2 inFIG.2(post-dialyzer ionized calcium). As mentioned in the Background section, the treatment protocol may alternatively, or additionally, prescribe that ionized calcium should be monitored upstream of the dialyzer, at loc3 inFIG.2(pre-dialyzer ionized calcium). As understood from the description of block400hereinabove (FIG.4), the analysis for obtaining computation functions relevant to loc3 is a subset of the analysis for obtaining computation functions relevant to loc2. Thus, the foregoing teachings readily enable the skilled person to modify the predefined algorithm (used in computation block410) to yield a computation value that represents ionized calcium, iCa3, in blood at loc3, e.g. based on total calcium Ca3and total citrate CIT3at loc3, as indicated by a dashed box inFIG.2. For example, with reference toFIG.10, ƒ0,1may be modified to define a functional relation between iCa3and Ca3, CIT3; ƒ0,2may be modified to define a functional relation between Ca3and CaSYS; and ƒ0,3may be modified to define a functional relation between CIT3and CITSYS.FIG.11is a flow chart of an example method300′ for performance monitoring of RCA during a blood treatment session based on pre-dialyzer ionized calcium. Steps301′-304′ correspond to steps301-304inFIG.3and need not be described in further detail.

Nomenclature

Alb: albumin concentration (mmol/L)HCO3: bicarbonate concentration (mmol/L)CaREF: total calcium concentration at linearization reference point for loc2 (mmol/L)CaREF_2: total calcium concentration at linearization reference point for loc1 (mmol/l)Cax: total calcium concentration at location x (mmol/L)CaSYS: total calcium concentration in blood of patient (mmol/L)Ca2: total calcium concentration in blood at loc2 (mmol/L)Ca3: total calcium concentration in blood at loc3 (mmol/L)CaPW2: total calcium concentration in plasma water at loc2 (mmol/L)CITREF: total citrate concentration at linearization reference point for loc2 (mmol/L)CITREF_2: total citrate concentration at linearization reference point for loc1 (mmol/L)CITx: total citrate concentration in blood at location x (mmol/L)CIT2: total citrate concentration in blood at loc2 (mmol/L)CIT3: total citrate concentration in blood at loc3 (mmol/L)CITPBP: citrate concentration in citrate-containing fluid (mmol/L)CITPW2: total citrate concentration in plasma water at loc2 (mmol/L)iCaSYS: ionized calcium concentration in blood of patient (mmol/L)iCa2: ionized calcium concentration in blood at loc2 (mmol/L)iCa3: ionized calcium concentration in blood at loc3 (mmol/L)iCIT: ionized citrate concentration in blood of patient (mmol/L)iP: ionized phosphate concentration in blood of patient (mmol/L)DCIT: citrate dose (mmol/L of blood)EQCaHCO3: equilibrium association constant for CaHCO3 (L/mmol)EQCaCO3: equilibrium association constant for CaCO3 (L/mmol)EQCaP: equilibrium association constant for CaP (L/mmol)EQCaCIT: equilibrium association constant for CaCit (L/mmol)EQCaCIT2: equilibrium association constant for CaCit2 (L2/mmol2)fwp: plasma water fractionFDIL: dilution ratio for plasma water when reaching dialyzerFCAL: fraction of patient plasma total calcium made available in plasma water for transfer through dialyzer membrane after citrate infusion.GMET: metabolic generation rate of citrate in the body of the patient (mmol/h)H: hematocrit of patient blood as fraction of 1k0AY: mass transfer area coefficient of dialyzer for substance Y (mL/h)KBODY: plasma clearance of citrate in the body of the patient (L/h)KY: plasma clearance of substance Y in the dialyzer (L/h)KCa: plasma clearance of calcium in the dialyzer (L/h)KCITplasma clearance of citrate in dialyzer (L/h)QB: blood flow rate from patient (mL/min)QD. flow rate of dialysis fluid (mL/h)QE: flow rate of effluent (mL/h)QPW: plasma water flow rate (mL/h)QPWI: plasma water flow rate at dialyzer inlet (mL/h)QPOST: flow rate of replacement fluid downstream of dialyzer (mL/h)QPRE: flow rate of replacement fluid upstream of dialyzer (mL/h)QPBP: flow rate of citrate-containing fluid (mL/h)QFIL: ultrafiltration rate (mL/h)t: time from start of RCA (h)VD: volume of citrate distribution (L)W: weight of patient (kg)αY: Donnan factor