KR20230104212A - Process for calculating the set flow rate in devices for extracorporeal treatment of blood and in medical devices for extracorporeal treatment of blood - Google Patents

Abstract

A CRRT device is provided that includes a control unit configured to execute a flow setup procedure that determines a set value for a prescribed dialysis dose to be delivered (D _set ), and a steady state in the blood of a patient subject to CRRT blood therapy. receiving a patient prescription including clinical prescription parameters by allowing input of a target value for a parameter representing acid-base balance (nNBL; Cp _{HCO3_pat} ), and fluid flow rate through an anticoagulant infusion line (Q _cit ); Fluid flow through the PBP infusion line (Q _PBP ), fluid flow through the pre-dilution infusion line (Q _rep.pre ), fluid flow through the post-dilution infusion line (Q _rep.post ), fluid through the post-dilution bicarbonate infusion line flow rate (Q _HCO3 ), fluid flow rate through the ion balancing infusion line (Q _ca ), blood fluid flow rate through the extracorporeal blood circuit (Q _b ), fluid flow rate through the dialysis fluid supply line (Q _dial ), and effluent fluid line determining operating parameters that calculate a set value of the relevant fluid flow rate comprising one or more of the fluid flow rates (Q _eff ) through It is based on the set value of (D _set ) and the target value for the parameter (nNBL; Cp _{HCO3_pat} ) representing the steady-state acid-base balance in the blood.

Description

Process for calculating the set flow rate in devices for extracorporeal treatment of blood and in medical devices for extracorporeal treatment of blood

The present invention relates to a medical device for the extracorporeal treatment of blood. The invention also relates to a process for calculating a set flow rate in a medical device for extracorporeal fluid treatment.

More specifically, the present invention relates to continuous renal replacement therapy (CRRT) with or without an anticoagulant, eg CRRT with or without a systemic anticoagulant (eg heparin) / local anticoagulant (eg eg, CRRT with or without citrate). In particular, the present invention may advantageously be used to administer a topical citrate anticoagulant (RCA) during continuous renal replacement therapy (CRRT).

The kidneys control the elimination of water, excretion of catabolites (or waste products of metabolism such as urea and creatinine), and concentration of electrolytes (eg, sodium, potassium, magnesium, calcium, bicarbonate, phosphate, chloride) in the blood. It performs many functions, including the regulation of acid/base balance in the body, and especially the regulation of the acid/base balance obtained by the elimination of weak acids and the production of ammonium salts. In individuals who have lost the use of the kidneys (temporarily or permanently), since these excretion and regulatory mechanisms are no longer functioning, the body accumulates water and waste products from metabolism, as well as excess electrolytes, as well as general blood pressure. Acidosis is also indicated where the pH drops below 7.35 (blood pH usually varies within a narrow range of 7.35 to 7.45). As mentioned, to overcome renal dysfunction, conventionally, a patient's blood is circulated on one side of a semipermeable membrane and a dialysis liquid containing the major electrolytes of the blood in concentrations close to those in the blood of healthy subjects is circulated on the other side. Recourse has been made to blood therapy involving extracorporeal circulation through an exchanger (dialyzer) with a semipermeable membrane. In addition, a pressure difference is created between the two compartments of the dialyzer, which are bounded by a semi-permeable membrane, so that a portion of the plasma fluid passes by ultrafiltration through the membrane into the compartment containing the dialysis liquid. The blood treatment that takes place in the dialysis machine with respect to waste products of metabolism and electrolytes originates from two mechanisms of molecular transport across the membrane. On the one hand, molecules move from a liquid with a higher concentration to a liquid with a lower concentration. This is diffuse transport. On the other hand, certain catabolites and certain electrolytes are entrained by the plasma fluid filtered through the membrane under the influence of the pressure difference created between the two compartments of the exchanger. This is convective transport. Therefore, three of the kidney functions mentioned above, i.e., removal of water, excretion of catabolites, and regulation of the blood's electrolyte concentration, are performed in conventional blood treatment devices by a combination of dialysis and hemofiltration. called hemodiafiltration). To perform one or more of the treatments described above, the extracorporeal blood treatment equipment may include a plurality of lines for delivering fluid directly to the patient or into the extracorporeal blood circuit.

When setting up the machine, the operator typically imposes the blood pump flow rate, separate flow rates for each infusion line, dialysis line and effluent line (in practice this latter is alternatively based on a set patient fluid removal rate). can be calculated). A set value for the flow rate of each line is used to control each pump: that is, a plurality of pumps are used, wherein each pump sucks fluid from each fluid container according to the set flow rate value of each line. or supply fluid to each fluid container. Accordingly, the setup of the machine is cumbersome as it involves defining and entering on the operator side a relatively high number of flow rates. In addition, the independent setting of each one of the flow rates does not provide intuitive information to the operator in terms of medically related prescription parameters. Finally, the need to independently set a plurality of parameters can be error-prone and does not allow to optimize fluid consumption.

WO 2013/030642 deals with a process of setting up a blood treatment device and a medical device for the delivery or collection of fluids, wherein a control unit controls two or more fluid flow rates of a fluid based on a prescribed volume value and a fluid flow rate set by an operator. It is configured to calculate the set value of the flow rate. However, WO 2013/030642 does not focus on the acid-base balance management aspect and does not specifically address acid-base balance issues in topical anticoagulants in relation to CRRT.

Regarding the regulation of the acid/base balance in the body, the approach adopted to overcome renal deficiency is to act on the mechanisms by which the acid/base balance in the body is regulated, which consists of the buffer system of the blood, the main of which is It includes carbonic acid as a weak acid related to bicarbonate related alkali salts. This is why bicarbonate is administered via the vascular route either directly or indirectly during a hemodialysis session to correct acidosis in patients suffering from renal failure. In the field of renal therapy, continuous renal replacement therapy (CRRT) has been widely used for critically ill patients with acute renal injury, and anticoagulation of extracorporeal blood is required to maintain circuit patency. In recent decades, different anticoagulation strategies have been used in clinical settings, with heparin being the most commonly used anticoagulant. Heparin has the advantages of being inexpensive, easy to monitor, and simple to reverse, but it can increase bleeding. Additionally, there is a risk of heparin-induced thrombocytopenia type II, which can lead to life-threatening complications. First introduced into clinical use in the early 1980s, topical citrate anticoagulant (RCA) has been recommended as the most appropriate form of CRRT local circuit anticoagulant and has been used safely in patients with severe hepatic dysfunction. However, citrate infusion in critically ill patients can affect various metabolic systems, leading to metabolic alkalosis, hypocalcemia and citrate overload/toxicity. These potential disturbances can be partially addressed through careful monitoring, adherence to treatment protocols, and supervision by staff trained in clinical practice. Despite the above importance, citrate anticoagulants have become the preferred anticoagulant choice for continuous renal replacement therapy (CRRT) because they minimize patient bleeding risk (local anticoagulant effect) and increase extracorporeal blood circuit lifespan. RCA has some limitations regarding compatibility with 'large' blood flow rates, but this is not an issue for CRRT, where efficiency is primarily driven by fluid exchange rate and most treatments are delivered at blood flow rates below 200 ml/min. don't The rapid metabolism of citrate injected into the patient is part of the key mechanism that makes RCA successful. Citrate metabolism releases complex calcium while producing bicarbonate and _CO2 as well as energy. In situations where large amounts of citrate are infused into the patient, large amounts of bicarbonate are produced, to the point where metabolic alkalosis occurs. Citrate accumulation is consistent with a scenario in which systemic citrate concentrations increase significantly. This can occur in two situations: 'normal' citrate load combined with poor citrate metabolism, and 'normal' citrate metabolism combined with large citrate load. Scenario 1 is likely to lead to metabolic acidosis due to the low production rate of bicarbonate from citrate. A second scenario is specifically considered and addressed in this application in relation to CRRT therapy in the context of RCA. The result of citrate accumulation is the need to increase total calcium concentration to keep (whole body) ionized calcium within the physiological range. This can be achieved by increasing the rate of calcium infusion. This problem is temporary during initiation of therapy, as a safe steady state can be reached after systemic citrate concentrations have stabilized (6-8 hours). However, discontinuation of therapy can lead to the development of hypercalcemia (citrate is metabolized and complex bound calcium is released). In the clinical setting, citrate accumulation is diagnosed through monitoring of the ratio of total to ionized whole body calcium (a ratio >2.5 indicating potential for citrate accumulation). In addition, once citrate enters the patient's systemic circulation, it is metabolized to bicarbonate on a 1:3 basis; Thus, 1 mmol citrate produces 3 mmol bicarbonate. When the citrate load is high, large amounts of bicarbonate are produced with a risk of metabolic alkalosis. Thus, although topical anticoagulants can greatly alleviate the side effects of heparin, RCA needs to properly monitor the acid-base balance of the patient's blood to avoid the risk of severe alkalosis.

EP0678301 relates to an artificial kidney for intensive care, particularly suitable for treating people suffering from renal failure temporarily after an accident or surgical operation. As is evident in the prior art literature, in addition to purifying plasma waste products (eg urea) and removing excess water, the kidneys play an important role in maintaining the acid-base balance of the blood. Since the final concentration of bicarbonate in the blood depends on the concentration of bicarbonate in the perfusion solution or dialysis liquid, the respective flow rate, and the flow rate of the patient's blood through the membrane exchanger, the main problem based on document EP0678301 is the concentration of bicarbonate in the patient's blood. is seldom exactly the desired concentration. EP0678301 describes a blood treatment device comprising a dialyzer with two chambers separated by a membrane. A container of dialysis fluid (not containing any bicarbonate) is connected to the fluid pump through a duct leading to the second chamber of the dialyzer. An electromagnetic clamp is provided to connect the vessel to the dialyzer or blood circuit. A bubble trap is provided in the return line of the blood circuit. A bubble trap is connected to the injection vessel containing the bicarbonate solution. According to EP0678301, the flow rate of the circulation pump (Q _HCO3 ) is given by the following formula:

or expression:

Controlled as a function of the flow rate of the dialysate pump (Q _OUT ), regardless of the type of treatment delivered to the patient by

here:

Q _HCO3 is the flow rate of the circulation pump;

Q _OUT is the flow rate of the dialysate pump (Q _OUT );

[HCO ₃ ] _DES is the desired bicarbonate concentration in the patient's blood;

[HCO ₃ ] _SOL is the concentration of the solution in the vessel;

Cl is the clearance of the dialyzer for bicarbonate.

In particular, this prior art relates to the proper adjustment of the patient's blood acid-base balance by using specific control of postinfusion of bicarbonate solution based on clearance/dialysate flow rate that operates exclusively in the following dialysis machine configuration: postdilution HF with and HD(F) with postdilution. Thus, the problem of proper acid-base management remains unresolved in configurations in which citrate is infused prior to the blood pump (eg, a topical anticoagulant system) and/or a bicarbonate-containing solution is pre-injected.

Regarding adaptation to specific patient conditions, protocols may include instructions for adjusting citrate infusions or dialysis fluid/replacement flow rates if patient monitoring data demonstrate alkalosis or acidosis problems (previously unsystematic). ). Where such guidance exists, it appears to be largely empirical. In case of acidosis, some literature reports on bicarbonate 'bolus' infusion. Some published protocols derive from some upstream modeling, but cannot explicitly use parameters representative of the buffer balance expected from the regimen, whatever 'original' protocol parameters are used or after they are further adjusted to patient monitoring data. . To date, the prediction and control of acid-base balance during CRRT, especially when using topical citrate anticoagulants (RCAs), remains a difficult question, particularly when attempting to use unproven regimens.

In this situation, the general purpose of the present embodiments is to provide a technical solution that can overcome one or more of the above disadvantages.

More specifically, it is an object of the present embodiments to provide a CRRT medical device and assist prescription for extracorporeal treatment of blood and at the same time to make available a process configured to take into account proper acid-base blood balance, especially with respect to topical anticoagulants. . Specifically, it is an object of the present embodiments to allow acid-balance control/management, where the system is also designed to change the buffer balance of the extracorporeal blood circuit in an easy but safe and controlled manner.

It is an object of the present invention to provide an apparatus and method capable of properly calculating the set flow rate while keeping an eye on the proper buffer balance and reducing the measures required for equipment set-up as much as possible.

Another object of aspects of the present invention is to define an apparatus and process that allows an operator to set up a CRRT blood treatment device using medically meaningful parameters, thereby making the user interface easier to use. In particular, it is an object of the present invention to provide an assistive regimen in situations where the regimen includes a parameter specifying the steady-state acid-base balance target, a parameter of particular importance in the case of citrate anticoagulants.

A secondary object of the present invention is to provide a medical device for fluid treatment and a set flow rate in the device which can facilitate setting the flow rate before and during treatment and optimize the consumption of the fluid with respect to prescription goals and system limitations. It is to provide a process for calculating.

Another ancillary object is a device capable of controlling operating parameters in a safe manner.

At least one of the above objects is substantially achieved by a device according to one or more of the appended device claims. One or more of the above objects are also achieved substantially by a method according to any one of the appended method claims.

Devices and processes according to aspects of the present invention are described herein below.

A first independent aspect relates to a continuous renal replacement therapy (CRRT) device comprising:

a filtration unit (2) having a primary chamber (3) and a secondary chamber (4) separated by a semipermeable membrane (5);

An extracorporeal blood circuit 17 having a blood withdrawal line 6 connected to the inlet of the primary chamber 3 and a blood return line 7 connected to the outlet of the primary chamber 3 - said extracorporeal blood circuit 17 comprising: - configured to be connected to the patient's cardiovascular system;

a blood pump 21 configured to control the flow of blood through the extracorporeal blood circuit 17;

an effluent fluid line 13 connected to the outlet of the secondary chamber 4;

One or more of the additional fluid lines selected from the group comprising:

a pre-dilution infusion line 29 connected at one end to the blood withdrawal line 6;

a post-dilution infusion line 63 having one end connected to the blood return line 7;

a post-diluted bicarbonate infusion line (23), one end of which is connected to the blood return line (7);

an ion balancing infusion line (74) connected at one end to a blood return line (7) or a patient catheter;

A dialysis liquid supply line (8), one end of which is connected to the inlet of the secondary chamber (4);

A pre-blood pump - PBP - infusion line 52, one end of which is connected to the blood withdrawal line in the region of the blood withdrawal line located upstream of the blood pump 21 during use;

An anticoagulant infusion line 51 having one end connected to the blood withdrawal line in the region of the blood withdrawal line located upstream of the blood pump 21 during use, and

a syringe fluid line (22) connected at one end to a blood draw line;

an actuator for regulating the flow of fluid (24, 25, 26, 31, 53, 54, 65, 75) through the fluid line (23, 8, 13, 29, 52, 51, 63, 74);

memory 16 for storing one or more mathematical relationships; and

a control unit 12 connected to a memory 16 and an actuator;

The control unit is configured to execute a flow setup procedure, the flow setup procedure comprising:

- Receiving a patient prescription including clinical prescription parameters - This receiving step comprises:

o Allowing input of a target value for a parameter (nNBL; Cp _{HCO3_pat} ) representing the steady-state acid-base balance in the blood of a patient who needs to receive CRRT blood treatment - ,

- determining one or more operational parameters using the one or more mathematical relationships, wherein determining the operational parameters comprises calculating a set value of one or more fluid flow rates selected from the group comprising:

Fluid flow rate through the anticoagulant infusion line 51 (Q _cit ),

Fluid flow rate through the PBP injection line 52 (Q _PBP );

Fluid flow rate (Q _rep.pre ) through the pre-dilution injection line 29,

Fluid flow rate (Q _rep.post ) through the post-dilution injection line 63,

Fluid flow rate (Q _HCO3 ) through the post-diluted bicarbonate inlet line 23;

Fluid flow rate through the ion balancing implant line 74 (Q _ca ),

blood fluid flow rate (Q _b ) through the extracorporeal blood circuit (17);

Fluid flow rate through the syringe fluid line 22 (Q _syr ),

Fluid flow rate (Q _dial ) through the dialysis fluid supply line (8), and

- fluid flow rate through the effluent fluid line (13) (Q _eff );

Here, the step of calculating the set value of one or more fluid flow rates is based on the target value for at least a parameter (nNBL; Cp _{HCO3_pat} ) representing the steady-state acid-base balance in the blood.

In an aspect according to the previous aspect, receiving the patient prescription includes accepting input of a set value (D _set ) for the prescribed dialysis dose to be delivered, and determining the one or more operating parameters comprises at least two determining operating parameters, wherein determining the operating parameters comprises calculating set values of at least two fluid flow rates selected from the group, and calculating set values of at least two fluid flow rates comprises at least Based on the set value of the prescribed dialysis dose (D _set ) and the target value for the parameter representing the steady-state acid-base balance in the blood (nNBL; Cp _{HCO3_pat} ).

A further independent aspect relates to the process of setting up a continuous renal replacement therapy (CRRT) device,

This device:

a filtration unit (2) having a primary chamber (3) and a secondary chamber (4) separated by a semipermeable membrane (5);

An extracorporeal blood circuit 17 having a blood withdrawal line 6 connected to the inlet of the primary chamber 3 and a blood return line 7 connected to the outlet of the primary chamber 3 - said extracorporeal blood circuit 17 comprising: - configured to be connected to the patient's cardiovascular system;

a blood pump 21 configured to control the flow of blood through the extracorporeal blood circuit 17;

an effluent fluid line 13 connected to the outlet of the secondary chamber 4;

One or more of the additional fluid lines selected from the group comprising:

a pre-dilution infusion line 29 connected at one end to the blood withdrawal line 6;

Post-dilution infusion line 63, one end of which is connected to the blood return line 7;

Post-diluted bicarbonate infusion line (23), one end of which is connected to the blood return line (7);

an ion balancing infusion line 74 connected at one end to the blood return line 7 or the patient catheter;

A dialysis liquid supply line (8), one end of which is connected to the inlet of the secondary chamber (4);

In use, in the region of the blood withdrawal line located upstream of the blood pump 21, before the blood pump - PBP - infusion line 52, one end of which is connected to the blood withdrawal line;

In use, an anticoagulant infusion line 51 having one end connected to the blood withdrawal line in the blood withdrawal line region located upstream of the blood pump 21, and

a syringe fluid line 22 connected at one end to a blood withdrawal line;

an actuator for regulating the flow of fluid (24, 25, 26, 31, 53, 54, 65, 75) through the fluid line (23, 8, 13, 29, 52, 51, 63, 74);

memory 16 for storing one or more mathematical relationships; and

a control unit 12 connected to a memory 16 and an actuator;

The method comprises the following steps executable by the control unit, which steps include:

- Receiving a patient prescription including clinical prescription parameters - This receiving step comprises:

o allowing input of a set value (D _set ) for the prescribed dialysis dose to be delivered;

o Allowing input of a target value for a parameter (nNBL; Cp _{HCO3_pat} ) representing the steady-state acid-base balance in the blood of a patient who needs to receive CRRT blood treatment - ,

- determining an operating parameter using the one or more mathematical relationships, wherein determining the operating parameter comprises calculating set values of at least two fluid flow rates selected from a group comprising:

Fluid flow rate through the anticoagulant infusion line 51 (Q _cit ),

Fluid flow rate through the PBP injection line 52 (Q _PBP );

Fluid flow rate (Q _rep.pre ) through the pre-dilution injection line 29,

Fluid flow rate (Q _rep.post ) through the post-dilution injection line 63,

Fluid flow rate (Q _HCO3 ) through the post-diluted bicarbonate inlet line 23;

Fluid flow rate through the ion balancing implant line 74 (Q _ca ),

blood fluid flow rate (Q _b ) through the extracorporeal blood circuit (17);

Fluid flow rate (Q _dial ) through the dialysis fluid supply line (8), and

- fluid flow rate through the effluent fluid line (13) (Q _eff );

Here, the step of calculating the set values of the at least two fluid flow rates includes at least the set values of the prescribed dialysis volume (D _set ) and the target values for the parameter representing the steady-state acid-base balance in the blood (nNBL; Cp _{HCO3_pat} ). is based on

In another independent aspect, a continuous renal replacement therapy (CRRT) device is provided:

a filtration unit (2) having a primary chamber (3) and a secondary chamber (4) separated by a semipermeable membrane (5);

An extracorporeal blood circuit 17 having a blood withdrawal line 6 connected to the inlet of the primary chamber 3 and a blood return line 7 connected to the outlet of the primary chamber 3 - said extracorporeal blood circuit 17 comprising: - configured to be connected to the patient's cardiovascular system;

a blood pump 21 configured to control the flow of blood through the extracorporeal blood circuit 17;

an effluent fluid line 13 connected to the outlet of the secondary chamber 4;

One or more of the additional fluid lines selected from the group comprising:

a pre-dilution infusion line 29 connected at one end to the blood withdrawal line 6;

a post-dilution infusion line 63 having one end connected to the blood return line 7;

a post-diluted bicarbonate infusion line (23), one end of which is connected to the blood return line (7);

an ion balancing infusion line (74) connected at one end to a blood return line (7) or a patient catheter;

A dialysis liquid supply line (8), one end of which is connected to the inlet of the secondary chamber (4);

In use, in the region of the blood withdrawal line located upstream of the blood pump 21, before the blood pump - PBP - infusion line 52, one end of which is connected to the blood withdrawal line;

An anticoagulant infusion line 51 having one end connected to the blood withdrawal line in the region of the blood withdrawal line located upstream of the blood pump 21 during use, and

a syringe fluid line (22) connected at one end to a blood draw line;

an actuator for regulating the flow of fluid (24, 25, 26, 31, 53, 54, 65, 75) through the fluid line (23, 8, 13, 29, 52, 51, 63, 74);

memory 16 for storing one or more mathematical relationships; and

a control unit 12 connected to a memory 16 and an actuator;

The control unit is configured to execute a flow setup procedure, the flow setup procedure comprising:

- Receiving a patient prescription including clinical prescription parameters - This receiving step comprises:

o allowing input of a set value (D _set ) for the prescribed dialysis dose to be delivered;

o Allowing input of a target value for a parameter (nNBL; Cp _{HCO3_pat} ) representing the steady-state acid-base balance in the blood of a patient who needs to receive CRRT blood treatment - ,

- determining an operating parameter using the one or more mathematical relationships, wherein determining the operating parameter comprises calculating set values of at least two fluid flow rates selected from a group comprising:

Fluid flow rate through the anticoagulant infusion line 51 (Q _cit ),

Fluid flow rate through the PBP injection line 52 (Q _PBP );

Fluid flow rate (Q _rep.pre ) through the pre-dilution injection line 29,

Fluid flow rate (Q _rep.post ) through the post-dilution injection line 63,

Fluid flow rate (Q _HCO3 ) through the post-diluted bicarbonate inlet line 23;

Fluid flow rate through the ion balancing implant line 74 (Q _ca ),

blood fluid flow rate (Q _b ) through the extracorporeal blood circuit (17);

Fluid flow rate (Q _dial ) through the dialysis fluid supply line (8), and

- fluid flow rate through the effluent fluid line (13) (Q _eff );

Here, the step of calculating the set values of the at least two fluid flow rates includes at least the set values of the prescribed dialysis volume (D _set ) and the target values for the parameter representing the steady-state acid-base balance in the blood (nNBL; Cp _{HCO3_pat} ). is based on

In particular, according to the foregoing aspects, the step of calculating each of the set values of the at least two fluid flow rates includes at least said set values of the prescribed dialysis dose (D _set ) and the parameter representing the steady-state acid-base balance in the blood (nNBL; Based on the target value for Cp _{HCO3_pat} ). For example, the first fluid flow rate from the above list (eg, the fluid flow rate Q _rep.post through the postdilution infusion line 63) is the set value of the prescribed dialysis volume (D _set ) and the blood The second fluid flow rate from the list (e.g., the fluid flow _rate through the dialysis liquid supply line 8 ( Q _dial )) is calculated based on both the set value of the prescribed dialysis dose (D _set ) and the target value for the parameter representing the steady-state acid-base balance in the blood (nNBL; Cp _{HCO3_pat} ).

In a further independent aspect, a continuous renal replacement therapy (CRRT) device is provided:

a filtration unit (2) having a primary chamber (3) and a secondary chamber (4) separated by a semipermeable membrane (5);

An extracorporeal blood circuit 17 having a blood withdrawal line 6 connected to the inlet of the primary chamber 3 and a blood return line 7 connected to the outlet of the primary chamber 3 - said extracorporeal blood circuit 17 comprising: - configured to be connected to the patient's cardiovascular system;

a blood pump 21 configured to control the flow of blood through the extracorporeal blood circuit 17;

an effluent fluid line 13 connected to the outlet of the secondary chamber 4;

One or more of the additional fluid lines selected from the group comprising:

a pre-dilution infusion line 29 connected at one end to the blood withdrawal line 6;

a post-dilution infusion line 63 having one end connected to the blood return line 7;

a post-diluted bicarbonate infusion line (23), one end of which is connected to the blood return line (7);

an ion balancing infusion line (74) connected at one end to a blood return line (7) or a patient catheter;

A dialysis liquid supply line (8), one end of which is connected to the inlet of the secondary chamber (4);

In use, in the region of the blood withdrawal line located upstream of the blood pump 21, before the blood pump - PBP - infusion line 52, one end of which is connected to the blood withdrawal line;

An anticoagulant infusion line 51 having one end connected to the blood withdrawal line in the region of the blood withdrawal line located upstream of the blood pump 21 in use, and

a syringe fluid line (22) connected at one end to a blood draw line;

an actuator for regulating the flow of fluid (24, 25, 26, 31, 53, 54, 65, 75) through the fluid line (23, 8, 13, 29, 52, 51, 63, 74);

memory 16 for storing one or more mathematical relationships; and

a control unit 12 connected to a memory 16 and an actuator;

The control unit is configured to execute a flow setup procedure, the flow setup procedure comprising:

- Receiving a patient prescription including clinical prescription parameters - This receiving step comprises:

o allowing input of a set value (D _set ) for the prescribed dialysis dose to be delivered;

o Allowing input of a target value for a parameter (nNBL; Cp _{HCO3_pat} ) representing the steady-state acid-base balance in the blood of a patient who needs to receive CRRT blood treatment - ,

- determining one or more operational parameters using the one or more mathematical relationships, wherein determining the operational parameters comprises calculating set values of at least two fluid flow rates selected from a group comprising:

Fluid flow rate through the anticoagulant infusion line 51 (Q _cit ),

Fluid flow rate through the PBP injection line 52 (Q _PBP );

Fluid flow rate (Q _rep.pre ) through the pre-dilution injection line 29,

Fluid flow rate (Q _rep.post ) through the post-dilution injection line 63,

Fluid flow rate (Q _HCO3 ) through the post-diluted bicarbonate inlet line 23;

Fluid flow rate through the ion balancing implant line 74 (Q _ca ),

blood fluid flow rate (Q _b ) through the extracorporeal blood circuit (17);

Fluid flow rate through the syringe fluid line 22 (Q _syr ),

Fluid flow rate (Q _dial ) through the dialysis fluid supply line (8), and

- fluid flow rate through the effluent fluid line (13) (Q _eff );

where the following, i.e.

Fluid flow rate through the anticoagulant infusion line 51 (Q _cit ),

Fluid flow rate through the PBP injection line 52 (Q _PBP );

The step of calculating the set value of any one of the fluid flow rates (Q _rep.pre ) through the pre-dilution injection line 29 is:

at least based on both the set value of the prescribed dialysis dose (D _set ) and the target value for the parameter representing the steady-state acid-base balance in the blood (nNBL; Cp _{HCO3_pat} ) (this flow rate as mentioned in the previous aspects It is noted that one of at least two flow rates), and

Here, the step of calculating the set value of at least another fluid flow rate includes at least the set value of the prescribed dialysis volume (D _set ) and the target value for the parameter representing the steady-state acid-base balance in the blood (nNBL; Cp _{HCO3_pat} ). is based on

In a further aspect according to any of the previous aspects, the at least another fluid flow rate (or one of the at least two flow rates) is:

• Fluid flow through the dialysis liquid supply line (8) (Q _dial ); or

The fluid flow rate (Q _eff ) through the effluent fluid line 13 is either:

Here, the step of calculating the set value of the other fluid flow rate includes at least the target value for the parameter (nNBL; Cp _{HCO3_pat} ) representing the steady-state acid-base balance in the blood and the set value (D _set ) of the prescribed dialysis dose. is based on

In a second aspect according to any one of the previous aspects, the anticoagulant infusion line 51 has one end connected to the blood draw line in a blood draw line region located upstream of the blood pump 21 in use, and the anticoagulant source ( 10) is connected to the opposite end of the anticoagulant infusion line 51, where the step of receiving the patient prescription allows input of a set value for the local anticoagulant dose (D _cit ), in particular the citrate dose, representing the strength of the local anticoagulant. Include more steps.

In a third aspect according to the preceding aspect, the local anticoagulant dose (D _cit ) has units equal to the concentration, more particularly the infused amount of anticoagulant per liter of blood treated (mmol/L blood).

In a fourth aspect according to the preceding two aspects, the control unit 12 is configured to, in particular, calculate a set value for the fluid flow rate (Q _cit ) as a function of a set value for the local anticoagulant dose (D _cit ). It is configured to mathematically relate a set value for the fluid flow rate (Q _cit ) through the anticoagulant infusion line 51 to a set value for the local anticoagulant dose (D _cit ) using the flow rate mathematical relationship.

In a fifth aspect according to any of the preceding three aspects, the control unit 12 controls, in particular the blood flow rate Q _b and/or the fluid flow rate Q b as a function of the anticoagulant, in particular citrate concentration, of the anticoagulant source 10 . In order to calculate the set value for _cit ), the set value for the fluid flow rate (Q _cit ) through the anticoagulant infusion line (51) is calculated using the citrate flow rate mathematical relationship as the blood flow rate (Q _b ) and/or the anticoagulant source (10 ) of the anticoagulant, in particular citrate, is configured to mathematically relate.

In a 6 aspect according to any of the preceding 4 aspects, said at least one mathematical relationship comprises a citrate flow rate mathematical relationship, wherein the fluid flow rate Q _cit through the anticoagulant infusion line (51) is stored in said memory (16). The stored citrate flow rate is calculated based on the mathematical relationship:

The meanings of the marks here are given in the glossary.

In a 7th aspect according to any of the preceding aspects the control unit (12) is configured to drive the anticoagulant pump (54) to infuse the anticoagulant into the blood draw line at the fluid flow rate (Q _cit ) calculated for the anticoagulant. do.

In an eighth aspect according to any of the preceding aspects 2 or 3, the local anticoagulant dose (D _cit ) is the fluid flow rate (Q _cit ) through the anticoagulant infusion line 51 .

In a ninth aspect according to any one of the preceding seven aspects, calculating the setpoint value comprises calculating at least three fluid flow rates, in particular using at least one of said one or more mathematical relations, to determine at least a local Further based on said set value of anticoagulant dose (D _cit ).

In a tenth aspect according to any one of the preceding aspects the CRRT device comprises an ion balancing infusion line 74 having one end connected to the blood return line 7 or the patient catheter and at the opposite end of the ion balancing infusion line 74. A connected ion balancing solution source 11 , wherein the step of receiving the patient prescription sets an ion reestablishment solution parameter (CaComp; D _ca ), in particular a calcium compensation parameter representing the strength of ion balancing, in particular calcium ion balancing. A step of allowing input of a value is further included.

In an eleventh aspect according to the preceding aspect, the ion reestablishment solution parameter CaComp is a compensation value or percentage compensation of calcium removed in the filtration unit 2, for example comprised between 0.05 and 2 or between 5% and 200%. indicates

In a twelfth aspect according to the preceding aspect 10, the ion-reestablishment solution parameter (D _ca ) is eg calcium, the ion equivalent capacity, eg calcium, concentration, in particular the calcium capacity is the total calcium concentration of the effluent.

In a thirteenth aspect according to any of the preceding three aspects, the control unit 12 provides, in particular, a set value for the fluid flow rate Q _ca as a function of a set value for the ion reestablishment solution parameter CaComp; D _ca . To calculate the value, the set value for the fluid flow rate through the ion balancing injection line 74 (Q _ca ) is the set value for the ion re-establishment solution parameter (CaComp; D _ca ), using the calcium flow mathematical relationship. It is constructed to relate mathematically.

In a fourteenth aspect according to any of the preceding four aspects, the control unit 12 calculates a set value for the fluid flow rate Q _ca , in particular as a function of the effluent flow rate Q _eff , to calculate the calcium flow rate It is configured to mathematically relate a set value for the fluid flow rate (Q _ca ) through the ion balancing implant line 74 to the effluent flow rate (Q _eff ) using a mathematical relationship.

In a fifteenth aspect according to any one of the preceding five aspects, the control unit 12 provides a function of the calcium concentration C _ca , in particular in the ion balancing solution source 11 and/or the postdilution injection line 63 Fluid flow rate as a function of the calcium concentration (C _carep.post ) in the auxiliary vessel 64 connected to and/or as a function of the calcium concentration (Cca HCO3) in the bicarbonate vessel 28 connected to the post-dilution bicarbonate infusion line 23 (Cca _HCO3 ). Calcium concentration _{of the} ion balancing solution source 11 (C _ca ) and/or calcium concentration (C _carep.post ) of the auxiliary container 64 connected to the post-dilution infusion line 63, and/or of the bicarbonate container 28 connected to the post-dilution bicarbonate infusion line 23 It is configured to relate mathematically to calcium concentration (Cca _HCO3 ).

In a sixteenth aspect according to any of the preceding six aspects, said one or more mathematical relationships comprises a calcium flow rate mathematical relationship, wherein the set value for the fluid flow rate (Q _ca ) through the ion balancing implant line (74) is calculated based on the calcium flow mathematical relationship stored in memory 16:

The meanings of the marks here are given in the glossary.

In a 17th aspect according to the preceding 12th aspect, the one or more mathematical relationships comprises a calcium flow rate mathematical relationship, wherein the set value for the fluid flow rate (Q _ca ) through the ion balancing implant line (74) is stored in the memory (16) ) is calculated based on the stored calcium flux mathematical relationship:

The meanings of the indications herein are given in the glossary; If any of the infusion lines are missing, the corresponding flow rate is not mathematically related, or the corresponding flow rate is set to zero.

In an eighteenth aspect according to any of the preceding aspects, the control unit 12 drives the ion balancing pump 75 to pump the ion re-establishment solution into blood at a calculated fluid flow rate Q _ca for the ion-reestablishment solution. It is configured for injection into the return line (7) or the patient (P).

In a 19th aspect according to any one of the preceding 9 aspects, calculating the setpoint value comprises calculating at least three fluid flow rates, in particular using at least one of said one or more mathematical relations, to calculate at least ion Based on the set value for the reestablishment solution parameter (CaComp; D _ca ).

In a twentieth aspect according to any one of the preceding aspects, receiving the patient prescription further comprises allowing input of a set value for the blood flow rate Q _b , wherein calculating the set value comprises at least Comprising the step of calculating the three fluid flow rates, the step of calculating one or more (two or all) set values of the at least three fluid flow rates, in particular using at least one of the one or more mathematical relations, at least the blood flow rate Further based on the set value for (Q _b ).

In a 21st aspect according to any of the preceding aspects, receiving the patient prescription further comprises accepting input from the patient of at least a set value for the fluid removal rate (Q _PFR ), calculating the set value The step of doing comprises calculating at least three fluid flow rates, and calculating one or more (two or all) set values of the at least three fluid flow rates, in particular using at least one of said one or more mathematical relations. , at least based on the above set value for the rate of fluid removal from the patient (Q _PFR ).

In a twenty-second aspect according to any of the preceding aspects, the control unit 12 controls, in particular, the fluid flow rate through the effluent fluid line 13 (Q _eff ) based on the set value for the fluid removal rate (Q _PFR ). configured to mathematically relate the fluid flow rate through the effluent fluid line 13 (Q _eff ) to a set value for the fluid removal rate (Q _PFR ), using the mathematical relationship of the effluent flow rate to calculate do.

In a twenty-third aspect according to any of the preceding two aspects, the control unit 12 determines the fluid flow rate Q through the effluent fluid line 13 based on the effluent flow rate mathematical relationship included in said one or more mathematical relationships. _eff ) is mathematically related, in particular configured to compute:

The meanings of the indications herein are given in the glossary; If any of the infusion line or dialysis liquid supply line is missing, the corresponding flow rate is not mathematically related, or the corresponding flow rate is set to zero.

In a twenty-fourth aspect according to any of the preceding aspects the CRRT device comprises a fluid source of a solution supplying fluid to one of said one or more additional fluid lines, said solution comprising at least one in the form of bicarbonate or bicarbonate precursors. contains a buffer of

In a twenty-fifth aspect according to the preceding aspect, the bicarbonate precursor comprises citrate, lactate and/or acetate.

In a 26 aspect according to any one of the preceding aspects the parameter indicative of the steady state acid-base balance in the blood of the patient receiving CRRT treatment (nNBL) is a parameter of the patient's expected net buffer load (NBL) at steady state where the net buffer load is a function of bicarbonate precursor metabolism, such as citrate or lactate metabolism, bicarbonate balance in the extracorporeal blood circuit 17, and/or acid to the extracorporeal blood circuit 17, such as bicarbonate infusion and/or citric acid infusion to the patient. is the sum of bicarbonate production due to injection.

In a 27 aspect according to the preceding aspect, the net buffer load is the patient's normalized net buffer load (nNBL) load expected at steady state, in particular normalized for the patient's body weight (BW), and more particularly for CRRT treatment The parameter representing the steady-state acid-base balance (nNBL) in the recipient patient's blood is the net buffer load (NBL) or normalized net buffer load (nNBL):

In a 28 aspect according to any one of the preceding aspects the parameter indicative of the steady state acid-base balance in the patient's blood (nNBL) is based on one or more of the following, in particular 4 of the following:

Estimates of the amount per unit time of bicarbonate produced from the metabolism of bicarbonate precursors, particularly citrate (J _{met_cit} ) and/or lactate (J _{met_lact} ), injected into the patient;

· Bicarbonate balance from CRRT blood treatment to be delivered in amount per unit time (J _{HCO3_bal} );

· Lactate balance from CRRT blood treatment to be delivered in amount per unit time (J _{lact_bal} );

· Acid injection from citric acid contained in the fluid source in quantity per unit time (J _H+ ).

In a 29 aspect according to the preceding aspect, the parameter representing the steady state acid-base balance in the blood of the patient (nNBL) is an estimate of bicarbonate form precursor metabolism (J _{met_cit} ; J _lact ), bicarbonate balance (J _{HCO3_bal} ), and acid is the algebraic sum of infusions (J _H+ ), especially acid infusion (J _H+ ) is the negative term giving the loss of the patient buffer.

In a 30th aspect according to the preceding aspect, the parameter representing the steady state acid-base balance in the patient's blood (nNBL) is defined as:

Alternatively, when lactate balance is also considered, the parameter representing the steady-state acid-base balance in the patient's blood (nNBL) is defined as:

In a 31 aspect according to any one of the preceding aspects the parameter representing the steady state acid-base balance in the blood of the patient (nNBL; Cp _{HCO3_pat} ) is an acid infusion from citric acid contained in the fluid source in amount per unit time (J _H+ ), where the acid feed (J _H+ ) is a function of the citric acid concentration (C _{citric_pbp} ) and the feed rate of citric acid (Q _cit ), in particular the acid feed (J _H+ ) is the citric acid concentration (C _{citric_pbp} ) times the amount of citric acid. equal to three times the infusion rate (Q _cit ).

In a 32 aspect according to any one of the preceding aspects, the parameter representing the steady state acid-base balance in the blood of a patient receiving CRRT treatment (nNBL) assumes a constant value for the patient plasma bicarbonate concentration (Cp _{HCO3_pat} 0). , and the constant value is, for example, 25 mM.

In a 33rd aspect according to any of the preceding aspects the parameter representing the steady-state bicarbonate concentration in the patient's blood (Cp _{HCO3_pat} ) is an estimated net buffer load (J _{buffer_load} ) representing the steady-state acid-base balance in the patient's blood /BW).

In a further aspect according to any of the preceding aspects, the parameter representing the steady state bicarbonate concentration in the patient's blood (Cp _{HCO3_pat} ) imposes a constant value on the normalized net buffer load (NBL) for the patient at steady state. It is defined so that the constant value is, for example, NBL = nNBL0 · BW = 0,1 mmol / h / kg.

In a 34 aspect according to any of the preceding aspects the parameter representing the steady state bicarbonate concentration in the blood of the patient (Cp _{HCO3_pat} ) imposes a constant value on the normalized net buffer load (NBL) for the patient at steady state. It is defined so that the constant value is, for example, nNBL0 BW = 0,1 mmol/h/kg.

In a 35 aspect according to any one of the preceding aspects the one or more mathematical relationships comprises a steady state bicarbonate indicator mathematical relationship, wherein the steady state bicarbonate indicator mathematical relationship is a parameter indicative of a steady state bicarbonate concentration in the blood of the patient ( Cp _{HCO3_pat} ) with the at least two flow rates of the group.

In a 36 aspect according to any one of the preceding aspects the one or more mathematical relationships comprises a steady state bicarbonate indicator mathematical relationship, wherein the steady state bicarbonate indicator mathematical relationship is a parameter indicative of a steady state bicarbonate concentration in the blood of the patient ( Cp _{HCO3_pat} ), the fluid flow rate through the predilution infusion line 29 (Q _rep.pre ), the fluid flow rate through the dialysis liquid supply line 8 (Q _dial ), the fluid flow rate through the anticoagulant infusion line 51 ( Q _cit ), the fluid flow rate (Q _PBP ) through the PBP injection line 52, and in particular, the parameter (Cp _{HCO3_pat} ) of the fluid flowing in each line (Q _rep.pre ; Q _dial ; Q _cit ; Q _PBP ) x the respective bicarbonate concentration (C _HCO3rep.pre ; C _HCO3dial ; C _HCO3cit ; C _HCO3PBP ).

In a 37 aspect according to any of the preceding aspects the one or more mathematical relationships comprises a steady state bicarbonate indicator mathematical relationship, wherein the steady state bicarbonate indicator mathematical relationship is a parameter indicative of a steady state bicarbonate concentration in the blood of the patient ( Cp _{HCO3_pat} ) is connected to the blood flow rate (Q _b ), in particular to the blood water flow rate (Q _bw ) and/or to the blood water flow rate at the inlet of the filtration unit (2) (Qbw _inlet ).

In a 38 aspect according to any one of the preceding aspects the one or more mathematical relationships comprises a steady state bicarbonate indicator mathematical relationship, wherein the steady state bicarbonate indicator mathematical relationship is a parameter indicative of a steady state bicarbonate concentration in the blood of the patient ( Cp _{HCO3_pat} ) is connected to the bicarbonate concentration of the fluid flowing in the dialysis liquid supply line (8) (C _HCO3dial ) and/or the bicarbonate clearance of the filtration unit (2) (K _HCO3 ).

In a 39 aspect according to any one of the preceding aspects the one or more mathematical relationships comprises a steady state bicarbonate indicator mathematical relationship, wherein the steady state bicarbonate indicator mathematical relationship is a parameter indicative of a steady state bicarbonate concentration in the blood of the patient ( Cp _{HCO3_pat} ) is connected to the bicarbonate plasma water concentration at the inlet of the filtration unit (Cpw _{HCO3_inlet} ).

In a 40 aspect according to any one of the preceding aspects the one or more mathematical relationships comprises a steady state bicarbonate indicator mathematical relationship, wherein the steady state bicarbonate indicator mathematical relationship is a parameter indicative of a steady state bicarbonate concentration in the blood of the patient ( Cp _{HCO3_pat} ) is connected to the ultrafiltration flow rate (Q _fil ) in the filtration unit (2), in particular to the ultrafiltration flow rate (Q _fil ) × bicarbonate concentration of the fluid flowing in the dialysis liquid supply line (8) (C _HCO3dial ) let it

In a 41 aspect according to any one of the preceding aspects the one or more mathematical relationships comprises a steady state bicarbonate indicator mathematical relationship, wherein the steady state bicarbonate indicator mathematical relationship is a parameter indicative of a steady state bicarbonate concentration in the blood of the patient ( Cp _{HCO3_pat} ) is coupled with bicarbonate removal (J _{HCO3_eff} ) to spent dialysate flowing in the effluent line (13).

In a 42 aspect according to any one of the preceding aspects the one or more mathematical relationships comprises a steady state bicarbonate indicator mathematical relationship, wherein the steady state bicarbonate indicator mathematical relationship is:

The meanings of the indications herein are given in the glossary; If any of the infusion line or dialysis liquid supply line is missing, the corresponding flow rate is not mathematically related, or the corresponding flow rate is set to zero.

It should be noted that if Cp _{HCO3_pat} is taken as a parameter representing the steady-state acid-base balance in the patient's blood, in this case nNBL would have to be taken as a constant (implicitly), ie nNBL0; Conversely, if nNBL is taken as a parameter representing the steady-state acid-base balance in the patient's blood, in this case Cp _{HCO3_pat} would (implicitly) have to be taken as a constant, ie Cp _{HCO3_pat} 0.

In a 43rd aspect according to any of the preceding aspects the target value for the parameter (nNBL; Cp _{HCO3_pat} ) representing the steady state acid-base balance in the patient's blood is the fluid flow rate through the predilution infusion line (29) ( The set value of the fluid flow rate Q _rep.pre through the pre-dilution injection line 29 , which affects the set value of Q _rep.pre , is an operating parameter calculated by the control unit 12 . In particular, it is one of at least two flow rates calculated based on the set value of the prescribed dialysis dose (D _set ) and said target value for a parameter representing the steady-state acid-base balance in the blood (nNBL; Cp _{HCO3_pat} ).

In a 44 aspect according to any of the preceding aspects the target value for the parameter (nNBL; Cp _{HCO3_pat} ) representing the steady state acid-base balance in the patient's blood is the fluid flow rate through the postdilution infusion line (63) ( Q _rep.post ) and influences the set value of the fluid flow rate (Q _rep.post ) through the post-dilution injection line 63 , which is the operating parameter calculated by the control unit 12 . In particular, it is one of at least two flow rates calculated based on the set value of the prescribed dialysis dose (D _set ) and said target value for a parameter representing the steady-state acid-base balance in the blood (nNBL; Cp _{HCO3_pat} ).

In a 45 aspect according to any of the preceding aspects the target value for the parameter (nNBL; Cp _{HCO3_pat} ) representing the steady state acid-base balance in the patient's blood is the fluid flow rate through the post-dilution bicarbonate infusion line (23) The set value of the fluid flow rate (Q _HCO3 ) through the post-dilution bicarbonate injection line 23 , which affects the set value of (Q _HCO3 ), is an operating parameter calculated by the control unit 12 . In particular, it is one of at least two flow rates calculated based on the set value of the prescribed dialysis dose (D _set ) and said target value for a parameter representing the steady-state acid-base balance in the blood (nNBL; Cp _{HCO3_pat} ).

In a 46 aspect according to any of the preceding aspects the target value for the parameter (nNBL; Cp _{HCO3_pat} ) representing the steady state acid-base balance in the patient's blood is the fluid flow rate through the ion balancing infusion line (74) ( The set value of the fluid flow rate (Q _ca ) through _the ion balancing injection line 74 is an operating parameter calculated by the control unit 12 . In particular, it is one of at least two flow rates calculated based on the set value of the prescribed dialysis dose (D _set ) and said target value for a parameter representing the steady-state acid-base balance in the blood (nNBL; Cp _{HCO3_pat} ).

In a 47 aspect according to any of the preceding aspects, the target value for the parameter (nNBL; Cp _{HCO3_pat} ) representing the steady state acid-base balance in the patient's blood is the fluid flow rate through the dialysis liquid supply line (8) ( The set value of the fluid flow rate (Q _dial ) through the dialysis liquid supply line 8 is an operating parameter calculated by the control unit 12 _. In particular, it is one of at least two flow rates calculated based on the set value of the prescribed dialysis dose (D _set ) and said target value for a parameter representing the steady-state acid-base balance in the blood (nNBL; Cp _{HCO3_pat} ).

In a 48 aspect according to any of the preceding aspects, the target value for the parameter (nNBL; Cp _{HCO3_pat} ) representing the steady state acid-base balance in the patient's blood is in particular blood fluid through the extracorporeal blood circuit (17). influencing the set value of the fluid flow rate Q _cit through the anticoagulant infusion line 51 if the set value for the flow rate Q _b is determined as an operating parameter by the control unit 12;

The set value of the fluid flow rate Q _cit through the anticoagulant infusion line 51 is an operating parameter calculated by the control unit 12 . In particular, it is one of at least two flow rates calculated based on the set value of the prescribed dialysis dose (D _set ) and said target value for a parameter representing the steady-state acid-base balance in the blood (nNBL; Cp _{HCO3_pat} ).

In a 49 aspect according to any of the preceding aspects the target value for the parameter (nNBL; Cp _{HCO3_pat} ) representing the steady state acid-base balance in the patient's blood is the fluid flow rate through the PBP infusion line (52) (Q _PBP ), the set value of the fluid flow rate through the PBP injection line 52 (Q _PBP ) is an operating parameter calculated by the control unit 12 . In particular, it is one of at least two flow rates calculated based on the set value of the prescribed dialysis dose (D _set ) and said target value for a parameter representing the steady-state acid-base balance in the blood (nNBL; Cp _{HCO3_pat} ).

In a 50th aspect according to any one of the preceding aspects, the target value for the parameter (nNBL; Cp _{HCO3_pat} ) representing the steady state acid-base balance in the patient's blood is the blood fluid flow rate through the extracorporeal blood circuit (17) ( The set value of the blood fluid flow rate (Q _b ) through _the extracorporeal blood circuit 17 is an operating parameter calculated by the control unit 12 . In particular, it is one of at least two flow rates calculated based on the set value of the prescribed dialysis dose (D _set ) and said target value for a parameter representing the steady-state acid-base balance in the blood (nNBL; Cp _{HCO3_pat} ).

In a 51 aspect according to any of the preceding aspects, the target value for the parameter (nNBL; Cp _{HCO3_pat} ) representing the steady state acid-base balance in the patient's blood is the fluid flow rate through the effluent fluid line (13) ( The set value of the fluid flow rate (Q _eff ) through the effluent fluid line 13 , which affects the set value of Q _eff , is an operating parameter calculated by the control unit 12 . In particular, it is one of at least two flow rates calculated based on the set value of the prescribed dialysis dose (D _set ) and said target value for a parameter representing the steady-state acid-base balance in the blood (nNBL; Cp _{HCO3_pat} ).

In particular, the target value for the parameter representing the steady-state acid-base balance in the patient's blood (nNBL; Cp _{HCO3_pat} ) is relevant (ie, the use of the line at a set flow rate where the line is present and the applied treatment is not zero). is required), most and specifically all of the above are used for the calculation of all fluid flow rates.

In a 52nd aspect according to any one of the preceding aspects, at least a number of said one or more mathematical relationships are based on a parameter (nNBL; Cp _{HCO3_pat} ) indicative of a steady-state acid-base balance in the blood of a patient amenable to CRRT blood therapy. Correlate with at least two fluid flow rates selected from the group.

In a 53 aspect according to any one of the preceding aspects, the step of calculating the set value of the fluid flow rate Q _cit through the anticoagulant infusion line 51 is, in particular, the blood fluid flow rate through the extracorporeal blood circuit 17 ( If the set value for Q _b ) is determined by the control unit 12 as an operating parameter, at least said target value for the parameter representing the steady-state acid-base balance in the blood (nNBL; Cp _{HCO3_pat} ) and/or prescribed Based on the set value (D _set ) of the dialysis dose,

In particular here, the control unit 12 calculates the set value of the fluid flow rate Q _cit through the anticoagulant infusion line 51 using the above mathematical relationship.

In a 54 aspect according to any of the preceding aspects, calculating the set value of the fluid flow rate (Q _PBP ) through the PBP infusion line ( 52 ) comprises at least a parameter indicative of the steady-state acid-base balance in the blood (nNBL ; Cp _{HCO3_pat} ) and/or based on the set value (D _set ) of the prescribed dialysis dose, in particular wherein the control unit 12 utilizes the above mathematical relationship to control PBP through the infusion line 52. Calculate the set value of the fluid flow rate (Q _PBP ).

In a 55 aspect according to any of the preceding aspects the step of calculating the set value of the fluid flow rate Q _rep.pre through the predilution infusion line 29 is indicative of a steady state acid-base balance in at least the blood. based on the set value (D _set ) of the prescribed dialysis dose and/or the target value for the parameter (nNBL; Cp _{HCO3_pat} ), in particular wherein the control unit 12 uses the above mathematical relationship to determine the pre-dilution infusion line ( 29) to calculate the set value of the fluid flow rate (Q _rep.pre ).

In a 56 aspect according to any of the preceding aspects the step of calculating the set value of the fluid flow rate Q _rep.post through the postdilution infusion line 63 is indicative of a steady state acid-base balance in at least the blood. based on the set value (D _set ) of the prescribed dialysis dose and/or the target value for the parameter (nNBL; Cp _{HCO3_pat} ), in particular wherein the control unit 12 uses the above mathematical relationship to determine the post-dilution infusion line ( 63) to calculate the set value of the fluid flow rate (Q _rep.post ).

In a 57 aspect according to any of the preceding aspects the step of calculating the set value of the fluid flow rate (Q _HCO 3 ) through the post-dilution bicarbonate infusion line (23) comprises at least a parameter indicative of the steady state acid-base balance in the blood. based on the set value (D _set ) of the prescribed dialysis dose and/or the target value for (nNBL; Cp _{HCO3_pat} ), in particular wherein the control unit 12 uses the above mathematical relationship to determine the post-dilution bicarbonate infusion line ( 23) to calculate the set value of the fluid flow rate (Q _HCO3 ).

In a 58 aspect according to any of the preceding aspects, calculating the set value of the fluid flow rate Q _ca through the ion balancing infusion line 74 comprises at least a parameter indicative of the steady-state acid-base balance in the blood ( based on the target value for nNBL; Cp _{HCO3_pat} ) and/or the set value (D _set ) of the prescribed dialysis dose, in particular wherein the control unit 12 uses the above mathematical relationship to adjust the ion balancing infusion line 74 Calculate the set value of the fluid flow rate (Q _ca ) through

In a 59 aspect according to any of the preceding aspects, the step of calculating the set value of the blood fluid flow rate (Q _b ) through the extracorporeal blood circuit ( 17 ) comprises at least a parameter indicative of the steady-state acid-base balance in the blood ( _{nNBL ;} Calculate the set value of the fluid flow rate (Q _b ) through

In a 60 aspect according to any of the preceding aspects, the step of calculating the set value of the fluid flow rate (Q _dial ) through the dialysis liquid supply line (8) comprises at least a parameter indicative of the steady-state acid-base balance in the blood ( based on the target value for nNBL; Cp _{HCO3_pat} ) and/or the set value (D _set ) of the prescribed dialysis dose, in particular wherein the control unit 12 uses the above mathematical relationship to adjust the dialysis liquid supply line 8 Calculate the set value of the fluid flow rate (Q _dial ) through

In a 61 aspect according to any of the preceding aspects, calculating the set value of the fluid flow rate Q _eff through the effluent fluid line 13 comprises at least a parameter indicative of the steady-state acid-base balance in the blood ( based on the target value for nNBL; Cp _{HCO3_pat} ) and/or the set value (D _set ) of the prescribed dialysis dose, in particular wherein the control unit 12 uses the above mathematical relationship to determine the effluent fluid line 13 Calculate the set value of the fluid flow rate (Q _eff ) through

In a 62 aspect according to any one of the preceding aspects, said one or more mathematical relationships relate a parameter indicative of the steady state acid-base balance in blood (nNBL; Cp _{HCO3_pat} ) to at least one, particularly all of the following: Include the load mathematical relationship:

o bicarbonate balance (J _{HCO3_bal} );

o bicarbonate produced from the metabolism of citrate (J _{met_cit} ), or citrate load (J _{cit_load} ), in particular where the metabolism of citrate load leads to 3 moles of bicarbonate per mole of citrate at steady state, i.e. J _{met_cit} = 3 J _{cit_load} ,

o bicarbonate resulting from the metabolism of lactate (J _{met_lact} ), or lactate balance (J _{lact_bal} ), in particular where the metabolism of lactate leads to 1 mole of bicarbonate per mole of lactate at steady state, i.e. J _{met_lact} = J _{lact_bal} ;

o acid injection (J _H+ );

where optionally the net buffer load mathematical relationship is:

The meanings of the indications herein are given in the Glossary; If any of the mass transfer rates are missing, the corresponding mass transfer term is not mathematically related, or its value is set to zero.

In a 63rd aspect according to any one of the preceding aspects, said one or more mathematical relationships comprises a bicarbonate balance mathematical relationship based on bicarbonate balance from CRRT blood treatment to be delivered in amount per unit time (J _{HCO3_bal} ), in particular wherein bicarbonate The balance (J _{HCO3_bal} ) is the difference between the bicarbonate infusion rate (J _{HCO3_inf} ) from the dialysis liquid supply line 8 and/or the infusion line and the bicarbonate removal into the dialysate (J _{HCO3_dial} ), in particular the bicarbonate balance mathematical relationship is: :

The meanings of the indications herein are given in the Glossary; If any of the mass transfer rates are missing, the corresponding mass transfer term is not mathematically related, or its value is set to zero.

In a 64 aspect according to the preceding aspect, the bicarbonate infusion rate from the dialysis liquid supply line (8) (J _{HCO3_inf} ) is a function of the fluid flow rate (Q _dial ) through the dialysis liquid supply line (8) and the dialysis liquid supply line (8). It is a function of the bicarbonate concentration (C _HCO3dial ) in the dialysis fluid flowing through the dialysis fluid, specifically the fluid flow rate (Q _dial ) times the bicarbonate concentration (C _HCO3dial ).

In a 65 aspect according to any of the two preceding aspects the bicarbonate injection rate from the injection line (J _{HCO3_inf} ) is equal to the fluid flow rate(s) (Q _rep.pre ; Q _rep.post ; Q _cit ; Q _PBP ; Q _HCO3 ; Q _ca ) and the respective bicarbonate concentrations (C _HCO3rep.pre ; C _HCO3rep.post ; C _HCO3cit ; C _HCO3PBP ; C _HCO3HCO3 ; C _HCO3ca ), in particular the fluid flow rate(s) (Q _rep.pre ; Q _rep.post ; Q _cit ; Q _PBP ; Q _HCO3 ; Q _ca ) x the respective bicarbonate concentrations (C _HCO3rep.pre ; C _HCO3rep.post ; C _HCO3cit ; C _HCO3PBP ; C _HCO3HCO3 ; C _HCO3ca ).

In a 66 aspect according to any of the three preceding aspects said one or more mathematical relations comprises a bicarbonate infusion mathematical relation, wherein the bicarbonate infusion rate from the dialysis liquid supply line (8) and infusion line (J _{HCO3_inf} ) is In particular, according to the bicarbonate injection mathematical relationship:

The meanings of the indications herein are given in the glossary; If any of the infusion line or dialysis liquid supply line is missing, the corresponding flow rate is not mathematically related, or the corresponding flow rate is set to zero.

In a 67 aspect according to any of the preceding four aspects the removal of bicarbonate into the spent dialysate in the effluent line (13) (J _{HCO3_eff} ) is dependent on the fluid flow rate (Q _dial ) through the dialysis liquid supply line (8) and It is a function of the bicarbonate concentration (C _HCO3dial ) of the dialysis fluid flowing in the dialysis fluid supply line 8, in particular the fluid flow rate (Q _dial ) times the bicarbonate concentration (C _HCO3dial ).

In a 68 aspect according to any of the preceding five aspects the bicarbonate removal into the spent dialysate in the effluent line 13 (J _{HCO3_eff} ) is a function of the bicarbonate concentration in the dialysis fluid (C _HCO3dial ), in particular the filter inlet It is a function of the difference between the concentration of bicarbonate in plasma (Cpw _{HCO3_inlet} ) and the concentration of bicarbonate in the dialysis fluid (C _HCO3dial ).

In a 69 aspect according to any of the preceding six aspects, bicarbonate removal into the spent dialysate in the effluent line 13 (J _{HCO3_eff} ) is dependent on the ultrafiltration flow rate of the filtration unit 2 (Q _fil ) and the dialysate liquid It is a function of the bicarbonate concentration (C _HCO3dial ) of the dialysis fluid flowing in the supply line 8, in particular the ultrafiltration flow rate (Q _fil ) times the bicarbonate concentration (C _HCO3dial ).

In a 70 aspect according to any of the preceding seven aspects, the bicarbonate removal (J _{HCO3_eff} ) into the spent dialysate in the effluent line (13) is a function of the bicarbonate clearance (K _HCO3 ).

In a 71 aspect according to any of the preceding eight aspects the bicarbonate removal from the effluent line (13) to the spent dialysate (J _{HCO3_eff} ) is a function of the fluid flow rate (Q _eff ) through the effluent line (13). , in particular where the bicarbonate clearance (K _HCO3 ) is assumed equal to the effluent fluid flow rate (Q _eff ).

In a 72 aspect according to any one of the preceding aspects the bicarbonate removal into the spent dialysate in the effluent line 13 (J _{HCO3_eff} ) is a function of the bicarbonate clearance (K _HCO3 ), wherein the bicarbonate clearance (K _HCO3 ) is one or more flow rates, particularly including one or more of a fluid flow rate through the dialysis liquid supply line 8 (Q _dial ), an ultrafiltration rate in the filtration unit 2 (Q _fil ), and a blood water flow rate (Qbw _inlet ); is a function of

In a 73 aspect according to the preceding aspect, the bicarbonate clearance (K _HCO3 ) is a function of the filtration unit 2 intended for CRRT treatment, in particular the sieving coefficient for bicarbonate (SC _HCO3 ) and/or bicarbonate is a function of the ratio of the filtration unit surface area to the diffusive mass transfer resistance (S/RT _HCO3 ).

In a 74 aspect according to any one of the preceding aspects, the one or more mathematical relationships comprise the following bicarbonate clearance mathematical relationship:

The meanings of the indications herein are given in the Glossary; If any of the infusion line or dialysis liquid supply line is missing, the corresponding flow rate is not mathematically related, or the corresponding flow rate is set to zero.

It should be noted that the above formula does not work for Q _dial = 0 or Q _fil = 0; In this situation, the infinite value can be removed by (artificially) replacing the zero value for one or both of Q _dial and/or Q _fil with, for example, 1 or 0.1 ml/h. Otherwise, pure CVVHD or specific formulas for pure CVVH may alternatively be used.

In a 75 aspect according to any of the preceding aspects the one or more mathematical relationships relate the ultrafiltration flow rate (Q fil ) through the filtration unit (2) to the fluid removal rate (Q _fil ) from the patient, in particular according to the following equation: _PFR ) and the ultrafiltration flow rate(s) (Q _PBP , Q _cit , Q _rep.pre , Q _rep.post , Q _{HCO 3} , Q _ca ) in the extracorporeal blood circuit 17; :

The meanings of the indications herein are given in the glossary; If any of the infusion lines are missing, the corresponding flow rate is not mathematically related, or the corresponding flow rate is set to zero.

In a 76 aspect according to any one of the preceding aspects, said one or more mathematical relationships are the relationship between blood water flow rate (Q _bw ), blood fluid flow rate (Q _b ) and haematocrit (Hct), in particular according to the following formula: and a blood-moisture flow rate mathematical relationship that relates to:

The meanings of the marks here are given in the glossary.

In a 77 aspect according to any one of the preceding aspects the one or more mathematical relationships comprises the blood water flow rate at the filtration unit inlet (Qbw _inlet ) as the blood water flow rate (Q _bw ), the fluid through the anticoagulant infusion line (51) at the filtration unit inlet coupled to one or more of the flow rate Q _cit , the fluid flow rate through the PBP injection line 52 (Q _PBP ), and the fluid flow rate through the pre-dilution injection line 29 (Q _rep.pre ). It includes the blood-moisture flow rate mathematical relationship, in particular the blood-moisture flow rate mathematical relationship at the inlet of the filtration unit is as follows:

The meanings of the marks here are given in the glossary.

In a 78 aspect according to any of the preceding aspects the one or more mathematical relationships comprise a bicarbonate removal mathematical relationship, in particular wherein the bicarbonate removal mathematical relationship is:

The meanings of the marks here are given in the glossary.

In a 79 aspect according to any one of the preceding aspects the one or more mathematical relationships are blood water flow rate (Q _bw ), blood water flow rate at the filter inlet (Qbw _inlet ), fluid flow rate through the anticoagulant infusion line (51) as a function of flow rate including one or more of (Q _cit ), fluid flow rate through PBP infusion line 52 (Q _PBP ) and fluid flow rate through pre-dilution infusion line 29 (Q _rep.pre ); and/or at the filter inlet that correlates the bicarbonate plasma water concentration at the filter inlet (Cpw _{HCO3_inlet} ) as a function of the bicarbonate concentration of the fluid flowing from the corresponding infusion line (C _HCO3cit ; C _HCO3PBP ; C _HCO3rep.pre ) and the patient plasma bicarbonate concentration (CpHCO3pat). contains the mathematical relationship between plasma number and concentration of

In an 80 aspect according to the preceding aspect, the plasma number concentration mathematical relationship at the filter inlet is:

The meanings of the indications herein are given in the Glossary; If any of the infusion lines are missing, the corresponding flow rate is not mathematically related, or the corresponding flow rate is set to zero.

In a 81 aspect according to any one of the preceding aspects the one or more mathematical relationships comprises a bicarbonate balance mathematical relationship based on the bicarbonate balance from CRRT blood treatment to be delivered in amount per unit time (J _{HCO3_bal} ), in particular bicarbonate balance The mathematical relationship is:

The meanings of the indications herein are given in the Glossary; If any of the infusion line or dialysis liquid supply line is missing, the corresponding flow rate is not mathematically related, or the corresponding flow rate is set to zero.

It should be noted that the above equation assumes that no bicarbonate is present in the ion replacement (Ca) solution.

In a 82 aspect in accordance with any one of the preceding aspects the net buffer load mathematical relationship of aspect 62 and the bicarbonate balance mathematical relationship of aspect 81 (or alternatively aspect 63+66+78) are the steady state acid-base in the blood The net buffer load mathematical relationship of aspect 62 to link a parameter representing the balance (nNBL; Cp _{HCO3_pat} ) with the flow rates of at least two fluids selected from the group, and the control unit 12 calculates the set values of the flow rates of the at least two fluids. and the bicarbonate balance mathematical relationship of Embodiment 81 (or alternatively Embodiment 63+66+78).

In an 83 aspect according to the preceding aspect, the mathematical relationships of aspects 75, 76, 77 and 78 are further used by the control unit 12 to calculate set values of said at least two flow rates.

In a 84 aspect according to any one of the preceding aspects the one or more mathematical relationships comprises a citrate load mathematical relationship based on a citrate load (J _{cit_load} ) for the patient in amount per unit time, in particular wherein the citrate load (J _{cit_load} ) is the difference between the rate of citrate injection through the anticoagulant infusion line 51 (J _{cit_PBP} ) and the rate of citrate removal from the effluent line 13 to the effluent (J _{cit_dial} ), in particular the citrate load mathematical relationship is:

The meanings of the indications herein are given in the Glossary; If any of the mass transfer rates are missing, the corresponding mass transfer term is not mathematically related, or its value is set to zero.

In a 85 aspect according to the preceding aspect, the citrate load (J _{cit_load} ), in particular the rate of citrate removal into the effluent (J _{cit_dial} ), is a function of the patient's citrate metabolic clearance (K _{cit_met} ), in particular the metabolic clearance is for example Based on body weight (BW), e.g. directly proportional, e.g. determined as follows:

Here, patient citrate metabolic clearance (K _{cit_met} ) is measured in [ml/min] and body weight (BW) is measured in [kg].

In a 86 aspect, in accordance with any of the two preceding aspects, the citrate load (J _{cit_load} ) is a function of the citrate clearance (K _cit ).

In a 87 aspect according to any of the three preceding aspects the citrate load (J _{cit_load} ) is a function of the fluid flow rate (Q _eff ) through the effluent fluid line ( 13 ), in particular wherein the citrate clearance (K _cit ) is It is estimated equal to the effluent fluid flow rate (Q _eff ).

In a 88 aspect according to any one of the preceding aspects the citrate load (J _{cit_load} ) is a function of citrate clearance (K _cit ) and according to the citrate clearance mathematical relationship of said one or more mathematical relationships: citrate clearance (K _cit ) In particular, one or more of the fluid flow rate through the dialysis liquid supply line 8 (Q _dial ), the ultrafiltration rate in the filtration unit 2 (Q _fil ), and the plasma water flow rate at the inlet to the filtration unit (Q _{pw_inlet} ) is a function of one or more flow rates including

In a 89 aspect according to the preceding aspect, the citrate load (J _{cit_load} ) is in particular the ratio of the filtration unit surface area to the sieving modulus for citrate (SC _cit ) and/or the diffusion mass transfer resistance to citrate (S/RT _cit ). As a function of , CRRT is a function of the filtration unit 2 intended for CRRT treatment.

In a 90 aspect according to any of the preceding aspects, the one or more mathematical relationships comprise the following citrate clearance mathematical relationship:

The meanings of the indications herein are given in the Glossary; If any of the infusion line or dialysis liquid supply line is missing, the corresponding flow rate is not mathematically related, or the corresponding flow rate is set to zero.

In a 91 aspect according to any one of the preceding aspects, said one or more mathematical relationships comprises a plasma flow rate mathematical relationship linking plasma flow rate (Q _p ) to blood fluid flow rate (Q _b ) and hematocrit (Hct), In particular, it follows:

The meanings of the marks here are given in the glossary.

In a 92 aspect according to any one of the preceding aspects, said one or more mathematical relationships comprises a plasma number flow rate mathematical relationship linking plasma number flow rate (Qpw) to blood fluid flow rate (Q _b ) and hematocrit (Hct), and , in particular according to:

The meanings of the marks here are given in the glossary.

In a 93 aspect according to any one of the preceding aspects, said one or more mathematical relationships comprises the plasma water flow rate at the filtration unit inlet (Q _{pw_inlet} ) as the plasma water flow rate (Qpw), the fluid flow rate through the anticoagulant infusion line (51) plasma at the filtration unit inlet coupled to one or more of (Q _cit ), a fluid flow rate through PBP infusion line 52 (Q _PBP ), and a fluid flow rate through predilution infusion line 29 (Q _rep.pre ). Including the water flow rate mathematical relationship, in particular the blood water flow rate mathematical relationship at the inlet of the filtration unit is as follows:

The meanings of the indications herein are given in the Glossary; If any of the infusion line or dialysis liquid supply line is missing, the corresponding flow rate is not mathematically related, or the corresponding flow rate is set to zero.

In a 94 aspect according to any of the preceding aspects, the citrate load (J _{cit_load} ) is alternatively a function of citrate dose (D _cit ) and blood flow (Q _b ), ie D _cit Q _b , or Or according to the function of the citrate flow rate (Q _cit ) and the total citrate concentration (C _{cit_pbp} ) of the anticoagulant line 51, that is, Q _cit ·C _citPBP .

In a 95 aspect according to any one of the preceding aspects, the one or more mathematical relationships is a function of citrate load (J _{cit_load} ) as citrate dose (D _cit ) and/or blood flow rate (Q _b ) and/or citrate clearance (K _{cit )} . ) and/or the plasma water flow rate at the inlet of the filtration unit 2 (Q _{pw_inlet} ), in particular wherein the citrate load mathematical relationship is one of:

or:

The meanings of the marks here are given in the glossary.

In a 96 aspect according to any one of the preceding aspects, the net buffer load mathematical relationship of aspect 67 and the citrate load mathematical relationship of aspect 95 form a parameter representing steady-state acid-base balance in blood (nNBL; Cp _{HCO3_pat} ) as a group and the control unit 12 uses the net buffer loading mathematical relationship of aspect 67 and the citrate loading mathematical relationship of aspect 95 to calculate the set values of the at least two fluid flow rates.

In a 97 aspect according to the preceding aspect, the mathematical relationships of aspects 85, 90, 91, 92 and 83 are further used by the control unit 12 to calculate set values of said at least two fluid flow rates.

In a 98 aspect according to any of the preceding aspects the control unit 12 is configured to calculate flow rates of two or more fluids selected from the group.

In a 99th aspect according to any of the preceding aspects the control unit 12 is configured to calculate the flow rate of at least three fluids selected from the group.

In a 100 aspect according to any of the preceding aspects the control unit 12 is configured to calculate flow rates of at least four fluids selected from the group.

In a 101 aspect according to any one of the preceding aspects the control unit 12 is configured to receive 'n' number of clinical prescription parameters and calculate fluid flow rates of 'm' plurality of selected from the group, wherein the plurality of The fluid flow rate is greater than or equal to the number of clinical prescription parameters, i.e., m≥n.

In a 102 aspect according to any of the preceding aspects the control unit 12 controls the prescribed dialysis dose D _set and the parameter indicative of the steady state acid-base balance in the patient's blood (nNBL; Cp _{HCO3_pat} ). and the following, i.e.

o topical anticoagulant, eg citrate, capacity (D _cit ) + ion, eg calcium, reestablishment solution parameters (CaComp; D _ca );

o rate of fluid removal from the patient (Q _pfr ); and

o is configured to receive 'n' number of clinical prescription parameters including one or more of blood flow rates (Q _b ):

Here, the control unit 12 is further configured to calculate the 'm' plurality of fluid flow rates selected from the group, where the plurality of fluid flow rates is greater than or equal to the number of clinical prescription parameters, ie m≥n.

In a 103 aspect according to any of the two preceding aspects, if m>n, the control unit 12 provides a selectable additional regimen configuration parameter, said additional regimen configuration parameter calculating 'm' fluid flow rate In particular, if m=n+1, one additional regimen configuration parameter is selectable, and if m=n+2, two additional regimen configuration parameters are selectable. do.

In a 104 aspect according to any of the preceding aspects, said additional mathematical relationship comprises one or more of a convection-diffusion relationship, a blood predilution relationship, and a pre-postinfusion relationship.

In a 105 aspect according to any one of the preceding aspects the device is configured to perform topical anticoagulant treatment:

- an anticoagulant infusion line 51 connected at one end to the blood withdrawal line in the area of the blood withdrawal line located upstream of the blood pump 21 in use;

- a topical anticoagulant source (10) providing anticoagulant to the anticoagulant infusion line (51), said source especially comprising citrate;

- an ion balancing infusion line 74 connected at one end to the blood return line 7 or to the patient catheter, and

- an ion balancing solution source (11) providing an ion balancing solution to the ion balancing implantation line (74), said source comprising in particular calcium ions;

Here the control unit 12 is configured to execute a flow setup procedure, which flow setup procedure:

- Receiving a patient prescription - This receiving step comprises:

o including allowing input of a set value for the prescribed anticoagulant dose to be delivered (D _cit ),

- set values for at least two fluid flow rates, at least the fluid flow rate (Q _cit ) through the anticoagulant infusion line (51) and the fluid flow rate (Q _ca ) through the ion balancing infusion line (74) using the above one or more mathematical relationships. Determining operating parameters including calculating .

In a 106 aspect according to the preceding aspect, calculating set values for at least the fluid flow rate through the anticoagulant infusion line (51) (Q _cit ) and/or the fluid flow rate (Q _ca ) through the ion balancing infusion line (74) The step is carried out, in particular if the set value for the blood fluid flow rate Q _b through the extracorporeal blood circuit 17 is determined by the control unit 12 as an operating parameter, said set value D _set of at least the prescribed dialysis dose ) is based on

In a 107 aspect according to the preceding aspect, calculating set values for at least the fluid flow rate through the anticoagulant infusion line (51) (Q _cit ) and/or the fluid flow rate (Q _ca ) through the ion balancing infusion line (74) The step is carried out, in particular when the set value for the blood fluid flow rate _Qb through the extracorporeal blood circuit 17 is determined by the control unit 12 as an operating parameter, at least a parameter representing the steady-state acid-base balance in the blood ( based on the above target values for nNBL; Cp _{HCO3_pat} ).

In a 108 aspect according to any one of the preceding aspects, one or more of said mathematical relationships derives a parameter (nNBL; Cp _{HCO3_pat} ) indicative of the steady state acid-base balance in the patient's blood from metabolism of citrate infused to the patient. Correlate with an estimate of the amount per unit time of bicarbonate produced (J _{met_cit} ), in particular where the metabolism of citrate load leads to 3 moles of bicarbonate per mole of citrate at steady state, i.e.:

In a 109 aspect according to any of the preceding aspects the control unit (12) is further configured to control the actuator to regulate the flow of fluid based on the set value and the calculated value(s) of fluid flow rate It consists of

In a 110 aspect according to any of the preceding aspects the actuator for regulating the flow of fluid (24, 25, 26, 31, 53, 54, 65, 75) is a pump, for example a rotary and/or peristaltic pumps, and/or valves.

In a 111 aspect according to any one of the preceding aspects, the one or more mathematical relationships are selected from the group, wherein the one or more mathematical relationships represent a steady-state acid-base balance in the blood of a patient subject to CRRT blood therapy (nNBL; Cp _{HCO3_pat} ). Correlate with at least two fluid flow rates.

In a 112 aspect according to any of the preceding aspects, control unit 12 relates the prescribed dose value (D _set ) and a target value for a parameter representing the steady state acid-base balance in the blood to the mathematical relationship. It is further configured to calculate set values of the at least two fluid flow rates by applying.

In a 113 aspect according to any of the preceding two aspects the control unit 12 is further configured to calculate the at least two set values of the fluid flow rates by applying clinical prescription parameters to said mathematical relationship.

In a 114 aspect according to any of the preceding three aspects the clinical prescription parameter further comprises a body fluid removal rate for said mathematical relation from the patient (Q _pfr ).

In aspect 115 according to any of the preceding four aspects, the clinical prescription parameter further includes the blood flow rate Q _b of the extracorporeal blood circuit 17 .

In a 116 aspect according to any one of the preceding 5 aspects, the clinical prescription parameters further include a prescribed dialysis dose (D _set ) and a parameter representing a steady-state acid-base balance in the patient's blood (nNBL; Cp _{HCO3_pat} ). do.

In a 117 aspect according to any one of the preceding six aspects the clinical prescription parameters further include a local anticoagulant dose (D _cit ) and/or an ion reestablishment solution parameter (CaComp; D _ca ).

In a 118 aspect according to any of the preceding aspects the memory 16 stores a plurality of additional mathematical relationships correlating together the flow rates of at least two fluids selected from said group.

In a 119 aspect according to the preceding aspect, the CRRT device comprises

- the pre-dilution infusion line 29, one end of which is connected to the blood withdrawal line 6, before the blood pump, one end of which is connected to the blood withdrawal line in the area of the blood withdrawal line located upstream of the blood pump 21 when in use - PBP - selected from the group comprising an infusion line 52 and the anticoagulant infusion line 51 connected at one end to the blood withdrawal line in the region of the blood withdrawal line located upstream of the blood pump 21 when in use. pre-dilution lines of a preset number;

- the postdilution infusion line 63 having one end connected to the blood return line 7, the postdilution bicarbonate infusion line 23 having one end connected to the blood return line 7, and having one end connected to the blood return line ( 7) or a preset number of post-dilution lines selected from the group comprising the ion balancing infusion line 74 connected to the patient catheter;

wherein the additional mathematical relationship stored in the memory includes one or more of:

- the total fluid flow rate (Q _rep.pre + Q _rep.post + Q _pbp + Q _HCO3 + Q _ca + Q _cit ) through the pre-dilution and post-dilution lines of the preset number through the dialysis liquid supply line (8) a convection-diffusion relationship relating the fluid flow rate through (Q _dial );

- Blood relating the blood flow rate (Q _b ) or plasma flow rate (Q _p ) to the total fluid flow rate (Q _rep.pre + Q _pbp + Q _cit ) injected into the blood withdrawal line through the pre-set number of pre-dilution lines. pre-dilution relationship,

- The total fluid flow rate (Q _rep.pre + Q _pbp + Q _cit ) through the preset number of pre-dilution lines is converted into the total fluid flow rate (Q _rep.post + Q _{HCO 3} + Q cit ) through the preset number of post-dilution lines. _ca ) before-after relationship.

In a 120 aspect according to the preceding aspect, the convection-diffusion relationship is the total fluid flow rate through the preset number of pre-dilution and post-dilution lines (Q _rep.pre + Q _rep.post + Q _pbp + Q _HCO3 + Q _ca + Q _cit ) and the fluid flow rate (Q _dial ) through the dialysis liquid supply line 8 , and in particular the convection-diffusion relationship is defined as the total fluid flow through the preset number of pre-dilution and post-dilution lines A first percentage division or a first percentage division of the flow rate (Q _rep.pre + Q _rep.post + Q _pbp + Q _HCO3 + Q _ca + Q _cit ) divided by the fluid flow rate (Q _dial ) through the dialysis liquid supply line (8). Define the ratio (R1).

In a 121st aspect according to any one of the two preceding aspects, the blood pre-dilution relationship is the total fluid flow rate injected into the blood withdrawal line 6 via the preset number of pre-dilution lines (Q _rep.pre + Q _pbp + Q _cit ) divided by the blood flow rate (Q _b ) or plasma flow rate (Q _p ) to define a second ratio (R2).

In a 122 aspect according to any one of the three preceding aspects, the before-after relationship is the total fluid flow rate through the preset number of pre-dilution lines (Q _rep.pre + Q _pbp + Q _cit ) and the preset number Defines a third division between the total fluid flow rate (Q _rep.post + Q _HCO3 + Q _ca ) through the post-dilution line of the pre-dilution line, in particular, the before-post relationship is the total fluid flow rate through the preset number of pre-dilution lines ( A third percentage division or third ratio (R3) divided by Q _rep.pre + Q _pbp + Q _cit ) by the total fluid flow rate (Q _rep.post + Q _HCO3 + Q _ca ) through the preset number of post-dilution lines. ) is defined.

In a 123 aspect according to any one of the preceding three aspects the control unit 12 controls a preset value for each one of said first, second and third split/ratio R1, R2, R3; or It is further configured to store preset ranges.

In a 124 aspect according to any of the preceding four aspects the control unit 12 provides a set value or setting for each one of said first, second and third division/ratio R1, R2, R3. It is further configured to accept input by the operator of the range.

In a 125 aspect according to any of the preceding 7 aspects the control unit 12 is further configured to allow a user to select one or more regimen configurations, said regimen configurations comprising: at least one of said additional mathematical relations; and optionally two or three of said additional mathematical relationships, wherein the steady state acid-base balance in the patient's blood is entered by the operator for both the mathematical relationship and the additional mathematical relationship(s) selected by the user. It is configured to calculate at least two set values of the fluid flow rate by applying a target value for a parameter (nNBL; Cp _{HCO3_pat} ) representing , and a set value (D _set ) of a prescribed capacity.

In a 126 aspect according to any of the preceding aspects the control unit 12 is further configured to allow a user to select one or more regimen configurations, wherein selecting the regimen configuration comprises a net buffer load (nNBL; NBL) and steady-state patient bicarbonate (Cp _{HCO3_pat} ) CRRT blood selecting a parameter (nNBL; Cp _{HCO3_pat} ) representing a steady-state acid-base balance in the blood of a patient who is to be treated.

In a 127 aspect according to any of the preceding aspects the control unit 12 is further configured to allow a user to select one or more regimen regimens, wherein selecting the regimen regimen determines the prescribed dialysis dose (D _set ).

In a 128 aspect according to any of the preceding aspects the control unit 12 is further configured to allow a user to select one or more regimen configurations, wherein the step of selecting the regimen configurations is a clinical regimen parameter or operational parameter. and selecting the blood flow rate as .

In a 129 aspect according to any of the preceding aspects the control unit 12 is further configured to allow a user to enter treatment configuration values including receiving input for one or more of the following.

- patient weight (BW);

- patient hematocrit (Hct);

- a filter unit such as filter mass transfer coefficient by surface area (K0.A), sieving coefficient (SC), solute removal rate (K _sol ), filtration unit surface (S), diffusion mass transfer resistance (RT), or a combination thereof parameter;

- a substance concentration, in particular a bicarbonate concentration and/or a lactate concentration and/or a citrate concentration and/or a calcium concentration, to one or more vessels supplying said lines (29, 63, 23, 74, 8, 52, 51).

In a 130 aspect according to the preceding aspect, the control unit 12 is further configured to calculate set values of the at least two fluid flow rates by applying treatment configuration values to said mathematical relationship.

In a 131 aspect according to any of the two preceding aspects the substance concentration for one or more vessels is entered by an operator for each individual vessel via a user interface (15) connected to the control unit (12), and/or the substance concentration in the fluid is determined by the control unit 12 associating the identification code on each individual container with the respective substance concentration.

In a 132 aspect according to any of the preceding three aspects, said filtration unit parameters for a filtration unit are entered by an operator, and/or said filtration unit parameters transmit an identification code on filtration unit 2 to said filtration unit. determined by the control unit 12 associating it with parameters.

In a 133 aspect according to any one of the preceding aspects the apparatus comprises a dialysis liquid supply line 8 connected to the inlet of the secondary chamber, wherein the control unit controls at least some of the clinical prescription parameters, in particular set by the operator. of the dialysis liquid supply line 8 not set by the operator based on the target value for the parameter representing the steady-state acid-base balance (nNBL; Cp _{HCO3_pat} ) and/or the prescribed dialysis volume value (D _set ). It is configured to calculate a set value for the fluid flow rate (Q _dial ).

In a 134 aspect according to any of the preceding aspects the device comprises a pre-dilution infusion line (29) connected at one end to the blood draw line (6), in particular the blood pump (21) is connected to the blood draw line ( 6) and the pre-dilution infusion line 29 connected to the blood withdrawal line 6 downstream of the blood pump 21, wherein the control unit controls at least some of the clinical prescription parameters, in particular set by the operator. of the pre-dilution infusion line 29 not set by the operator based on the target value for the parameter representing the steady-state acid-base balance (nNBL; Cp _{HCO3_pat} ) and/or the prescribed dialysis dose value (D _set ). It is configured to calculate a set value for the fluid flow rate (Q _rep.pre ).

In a 135 aspect according to any one of the preceding aspects the device comprises a post-dilution infusion line (63) connected at one end to the blood return line (7), wherein the control unit controls at least some of the clinical regimen parameters, in particular Post-dilution infusion line not set by the operator, based on the prescribed dialysis dose value (D _set ) and/or the target value for the parameter representing the steady-state acid-base balance (nNBL; Cp _{HCO3_pat} ) set by the operator. It is configured to calculate the set value for the fluid flow rate (Q _rep.post ) of (63).

In a 136 aspect according to any of the preceding aspects the device comprises a post-diluted bicarbonate infusion line (23) connected at one end to a blood return line (7), wherein the control unit controls at least some of the clinical prescription parameters; In particular, post-diluted bicarbonate not set by the operator based on the target value for the parameter representing the steady-state acid-base balance (nNBL; Cp _{HCO3_pat} ) set by the operator and/or the prescribed dialysis dose value (D _set ). It is configured to calculate a set value for the fluid flow rate Q _HCO3 of the infusion line 23 .

In a 137 aspect according to any of the preceding aspects the device comprises an ion balancing infusion line (74) connected at one end to a blood return line (7) or a patient catheter, wherein the control unit controls at least one of the clinical prescription parameters. Some, in particular, ions not set by the operator, based on the prescribed dialysis dose value (D _set ) and/or a target value for a parameter representing steady-state acid-base balance (nNBL; Cp _{HCO3_pat} ) set by the operator. It is configured to calculate a set value for the fluid flow rate Q _ca of the balancing infusion line 74 .

In a 138 aspect according to any one of the preceding aspects the device is provided in use in the region of the blood draw line located upstream of the blood pump 21 before the blood pump - PBP - infusion line connected at one end to the blood draw line. 52, in particular the blood pump 21 is activated corresponding to a segment of the blood withdrawal line 6, wherein the control unit controls at least some of the clinical prescription parameters, in particular the steady state acid-base balance set by the operator. Before the blood pump - PBP - fluid flow rate in the infusion line 52, which is not set by the operator, based on the target value for the parameter (nNBL; Cp _{HCO3_pat} ) and/or the prescribed dialysis dose value (D _set ) representing It is configured to calculate a set value for (Q _PBP ).

In a 139 aspect according to any of the preceding aspects the device comprises an anticoagulant infusion line (51) connected at one end to the blood draw line in the region of the blood draw line located upstream of the blood pump (21) in use. And, in particular, the blood pump 21 is at least some of the clinical prescription parameters, in particular, a target value for a parameter representing a steady-state acid-base balance (nNBL; Cp _{HCO3_pat} ) set by the operator and/or the prescribed dialysis dose value ( Based on D _set ), the corresponding segment of the blood withdrawal line 6 is activated, where the control unit calculates a set value for the fluid flow rate Q _cit of the anticoagulant infusion line 51 not set by the operator. is configured to

In a 140 aspect according to any of the preceding aspects the operating parameter further comprises the blood flow rate Q _b of the extracorporeal blood circuit 17 , wherein the control unit controls at least some of the clinical prescription parameters, in particular by the operator. of the extracorporeal blood circuit 17, which is not set by the operator, based on the target value for the set steady-state acid-base balance parameter (nNBL; Cp _{HCO3_pat} ) and/or the prescribed dialysis dose value (D _set ). It is configured to calculate a set value for the blood flow rate (Q _b ).

In a 141st aspect according to any of the preceding aspects the control unit 12 is configured to calculate at least three, in particular at least four set values of the fluid flow rate selected from the group.

In a 142 aspect according to any of the preceding aspects the control unit 12 is configured to calculate a set value for a rate of patient fluid removal from the patient (Q _PFR ).

In a 143 aspect according to any of the preceding aspects the prescribed dialysis dose value (D _set ) comprises a prescribed value for a flow rate or combination of flow rates.

In a 144 aspect according to any of the preceding aspects the prescribed dialysis dose value (D _set ) comprises a prescribed value for one selected from the group comprising:

- the effluent capacity flow rate D _{eff_set} , which is the prescribed value of the flow rate through the effluent line 13;

- the convective capacity flow rate (D _{conv_set} ), which is the prescribed value of the sum of the flow rates through all infusion lines (Q _rep.pre , Q _rep.post , Q _PBP , Q _cit , Q _ca , Q _HCO3 ) and the patient fluid removal rate (Q _pfr ) - optionally the convective capacity flow rate value prescribed here is corrected for pre-dilution -,

- the diffusion capacity flow rate (D _{dial_set} ), which is the prescribed value of the flow rate (Q _dial ) through the dialysis fluid line;

- urea dose (D _{urea_set} ), which is the value prescribed for the estimated urea clearance;

- The clearance capacity (K _{solute_set} ), which is the prescribed value for the estimated clearance for a given solute.

In a 145 aspect according to the preceding aspect, the control unit 12, when the infusion line 29, 51, 52 is present and delivers fluid upstream from the treatment unit 2, according to the formula: In this case, by multiplying by a dilution factor (F _dilution ) less than 1, it is configured to correct the selected one of the above-defined doses to take into account the pre-dilution effect:

Dose _{corr_xxx} = F _dilution x Dose _{_xxx} (xxx = eff, conv, dial).

In a 146 aspect according to any of the preceding aspects the control unit 12 is configured to control the blood pump 21 using the entered or calculated set value for the blood flow Q _b .

In a 147 aspect according to any of the preceding aspects the CRRT device further comprises a graphical user interface (15) connected to said control unit (12), said control unit comprising:

- display on a graphical user interface an indication prompting the user to enter or select a set value (D _set ) for the prescribed dialysis dose;

- display on a graphical user interface an indication prompting the user to enter or select a target value for said parameter (nNBL; Cp _{HCO3_pat} ) representative of the steady-state acid-base balance in the patient's blood;

- displaying an indication that allows the user to enter or select a set value for the mathematical relationship(s), in particular one or more of the first, second and third ratios. including, displaying an indication on the graphical user interface that may allow a user to select one or more additional mathematical relationships he or she intends to select;

- detect a selection of further mathematical relationships, and

- configured to use said further mathematical relationship to calculate set values of the flow rates of at least two fluids selected from the group.

In a 148 aspect according to any of the preceding aspects the actuator for regulating the flow of fluid through the fluid line comprises a pre-infusion pump (31) for regulating the flow through the pre-dilution infusion line (29) and and/or a post-infusion pump 65 for regulating flow through the post-dilution infusion line 63.

In a 149 aspect according to any one of the preceding aspects a dialysis liquid supply line (8) is connected to the inlet of the secondary chamber (4) and an actuator for regulating the flow of fluid through said fluid lines is provided for said dialysis fluid. and at least a dialysis fluid pump (25) for regulating the flow through the fluid supply line (8).

In a 150 aspect according to any of the preceding aspects the actuator for regulating the flow of fluid through the fluid line is before the blood pump - the PBP - the PBP infusion pump for regulating the flow through the infusion line (52). 53 and/or an anticoagulant pump 54 for regulating flow through the anticoagulant infusion line 51 .

In a 151 aspect according to any of the preceding aspects the actuator for regulating the flow of fluid through the fluid line comprises a bicarbonate pump (24) for regulating the flow through the post-diluted bicarbonate infusion line (23) and and/or an ion balancing pump 75 for regulating the flow through the ion balancing implant line 74.

In a 152 aspect according to any of the preceding aspects the CRRT device further comprises a collection vessel (62) connected to the end of the effluent fluid line (13) for collecting spent dialysate.

In a 153 aspect according to any of the preceding aspects the CRRT device further comprises a fresh fluid replacement vessel 30 connected to the end of the pre-dilution infusion line 29, in particular said vessel 30 containing the replacement solution It is a bag containing

In a 154 aspect according to any of the preceding aspects the CRRT device further comprises an auxiliary container 64 of fresh fluid connected to the end of the postinfusion line 63, in particular wherein said container 64 contains a replacement solution. It is a bag containing

In a 155 aspect according to any of the preceding aspects the CRRT apparatus further comprises a liquid container 14 of fresh fluid connected to the end of the dialysis fluid supply line 8, in particular said container 14 comprising a fresh dialysis liquid It is a bag containing fluid.

In a 156 aspect according to any of the preceding aspects the CRRT device further comprises a fresh fluid PBP container 18 connected to the end of the infusion line 52 prior to the blood pump, in particular said container 18 replacing It is a bag containing a solution.

In a 157 aspect according to any of the preceding aspects the CRRT device further comprises a container (10) for a topical anticoagulant connected to the end of the anticoagulant infusion line (51), in particular wherein said container (10) is a bag , citrate and optionally citric acid.

In a 158 aspect according to any of the preceding aspects the CRRT device further comprises a bicarbonate container (24) connected to the end of the post-diluted bicarbonate infusion line (23), in particular wherein said container (24) contains a bicarbonate solution, optionally It is a bag containing a concentrated bicarbonate solution.

In a 159 aspect according to any of the preceding aspects the CRRT apparatus further comprises an ion balancing solution vessel (11) connected to the end of the ion balancing injection line (74), in particular wherein said vessel (11) contains a calcium concentrated solution is a bag or syringe containing

In a 160 aspect according to any one of the preceding aspects the CRRT device further comprises one or more scales for weighing one or more of said containers, in particular the device comprising a scale corresponding to each individual container of said containers. and wherein the at least one scale is connected to a control unit and transmits a corresponding weight signal to the control unit.

In a 161 aspect according to any of the preceding aspects the memory (16) stores one or a plurality of optimization criteria, and the control unit (12) applies the optimization criteria to obtain a set value for the fluid flow rate(s) is configured to calculate

In a 162 aspect according to the preceding aspect the optimization criterion is the emptying time of at least one of the containers 10; 18; 30; 64; 28; 11; 14 of the fresh fluid and/or of the collection container 62. and a first optimization criterion that imposes that the filling time be substantially equal to or a multiple of the emptying time of one or more of the other containers of fresh fluid.

In a 163 aspect according to any of the two preceding aspects the optimization criterion comprises a second optimization criterion imposing such that fluid consumption through said fluid line is minimized.

In a 164 aspect according to any of the preceding three aspects the optimization criterion comprises a third optimization criterion imposed such that the lifetime of said filtration unit 2 is maximized.

In a 165 aspect according to any of the preceding four aspects, the optimization criterion comprises a fourth optimization criterion imposing such that the urea clearance or dialysance of a given solute is maximized.

In a 166 aspect according to any of the preceding five aspects the control unit 12 is configured to enable a user to select one or more of said criteria and to calculate said at least one flow rate using said selected criterion. .

In a 167 aspect according to any of the preceding six aspects the control unit 12 enables a user to select one or more of said criteria and one or more mathematical relations of said further mathematical relations and determines whether said selected criterion and said and calculate at least three flow rates using the selected additional mathematical relationships.

In a 168 aspect according to any of the preceding aspects the control unit 12 determines whether the selected further mathematical relations are compatible or conflicting with each other, and then:

If the selected additional mathematical relationship is compatible, calculate the flow rate(s) based on the selected additional mathematical relationship and the clinical prescription parameters;

If one or more of the selected additional mathematical relationships conflict with each other, one or more of the following sub-steps are configured:

Steps to notify the user;

allowing the user to assign a priority to each of the selected additional mathematical relationships;

assigning a priority order to the selected further mathematical relation, wherein the priority order is either pre-determined or user adjustable, and thereafter disregarding the further mathematical relation as soon as the flow rate is calculated from the prioritized further mathematical relation. step to do,

• Defining a compromise between additional mathematical relations using pre-established rules.

In a 169 aspect according to any of the preceding aspects the control unit 12 is directed to each container 10; 18; 30; 64; 28; 11; 14 of fresh fluid and optionally to the collection container 62. It is configured to store the volume or weight of the fluid contained in the memory 16.

In a 170 aspect according to the preceding aspect, said volume or weight of fluid is detected by a sensor associated with each individual container and connected to the control unit 12 .

In a 171 aspect according to the preceding aspect the volume of fluid is determined based on a signal associated with a corresponding pump acting on an infusion line fluidly coupled to each vessel, for example a signal from a Hall sensor associated with a peristaltic pump. based or based on the plunger position of the syringe pump.

In a 172 aspect according to the preceding aspect, the volume of fluid is detected based on a signal associated with the pump in question in one or more of the following.

- an ion balancing implant line 74;

- syringe fluid line 22;

- anticoagulant infusion line (51).

In a 173 aspect according to the preceding aspect 170, the sensor is a weigh scale that weighs at least one of the containers.

In a 174 aspect according to the preceding aspect 170, the sensor is a drop counter that determines weight and/or volume based on drop count.

In a 175 aspect according to any of the preceding aspects, the method comprising, when executed by a control unit of an apparatus according to any of the preceding apparatus aspects, causing the control unit to execute each step described in the preceding aspects. A data carrier containing instructions to cause configuration is provided.

Aspects of the present invention are illustrated in the accompanying drawings, which serve as non-limiting examples:
1 illustrates a CRRT extracorporeal blood treatment device according to aspects of the present disclosure.
2-6 show schematic representations of a blood treatment device according to aspects of the present disclosure.
7 is a flow diagram illustrating calculation of a set flow rate in a CRRT extracorporeal blood treatment device of the type, eg, of FIGS. 1-6, in accordance with aspects of the present invention.

As mentioned, extracorporeal hemotherapy (dialysis) may be used in patients with rapidly progressive loss of kidney function, referred to as acute renal failure, or with slowly worsening kidney function, referred to as stage 5 chronic kidney disease (or end-stage renal disease). In the following description, some embodiments of an extracorporeal blood treatment device will first be described as being suitable or designed primarily for intensive care procedures. Then, after introduction of the citrate topical anticoagulant, the definition of the steady-state acid-base balance parameter(s) follows. Methods for simplifying and/or supporting CRRT prescriptions based on meaningful clinical parameters are hereinafter described and, as will be apparent from the following description, can be implemented in any of the described embodiments.

Justice

Unless defined otherwise, all technical and scientific terms used have the same meaning as commonly understood by one of skill in the art.

The term “downstream” refers to the position of a first component relative to a second component in a flow path, where fluid will pass through the second component before the first component during normal operation. A first element may be said to be "downstream" of a second element, while a second element may be said to be "upstream" of the first element. 1 shows the direction of fluid circulation (indicated by numeral 200) during normal operation of the device 1.

“Dialysis fluid” is defined as the treatment liquid introduced into the second chamber of the filtration unit 2 . Dialysis fluid can be prepared online or prepackaged in sterile bags. Typically in CRRT devices/applications, dialysis fluid as well as replacement fluids (possibly topical anticoagulant fluids and/or ion re-establishment solution fluids) are included in the (disposable) bag.

“Dialysate” or “effluent” is defined as the fluid discharged from the second chamber of the filtration unit 2 . Dialysate or effluent is a spent dialysis fluid that contains uremic toxins removed from the blood, and may include ultrafiltration fluid.

A “topical anticoagulant” is defined as a substance that, when mixed with extracorporeal blood, substantially prevents blood coagulation in the extracorporeal blood circuit and is rapidly metabolized by the patient to avoid systemic anticoagulation.

During extracorporeal blood therapy (eg, CRRT), the "net buffer load" is the bicarbonate produced from the metabolism of bicarbonate precursors such as citrate and/or lactate infused into the patient (J _{met_cit} ; J _{met_lact} ), the patient's net loss or net loss. It is defined as a combination of bicarbonate balance from extracorporeal blood therapy (J _{HCO3_bal} ), which may be consistent with a benefit, and, where relevant, acid infusion, eg from the citric acid content of an anticoagulant solution. From a mathematical point of view, the general definition of net buffer load (mmol/h) used hereafter is:

“Citrate dose” is defined as the infused amount of citrate per liter of blood treated (mmol/L blood); This defines the strength of citrate anticoagulation.

A patient's “citrate load” is defined as the rate at which citrate is returned to the patient in mmol/h.

"Bicarbonate balance" is defined as the rate of net infusion or loss of bicarbonate in an extracorporeal blood treatment that is equal to the difference between the rate of infusion from the dialysate and/or replacement fluid and the rate of removal of bicarbonate from the dialysate.

"Calcium compensation" (or calcium compensation parameter) is defined as the relative dose of calcium infusion to compensate for the expected calcium loss in the dialysate, expressed as a percentage.

In particular, the "total calcium concentration" of an effluent is defined as the total amount of calcium per unit liquid volume of the effluent, including both ionized and bound calcium.

“K ₀ A” is defined as the mass transfer area coefficient of the filtration unit, where K ₀ is the clearance at infinite blood and dialysis fluid flow rates and A is the filtration unit surface area. “K ₀ A” varies with a given solute, and thus varies with the specifically contemplated solute.

In this application, the term "citrate" means that the ingredient is in the form of a salt of citric acid, such as a sodium, magnesium, calcium, or potassium salt. Citric acid (denoted by C ₆ H ₈ O ₇ ) deprotonates stepwise, so “citrate” includes all the different forms of citrate (denoted by C ₆ H ₅ O ₇ ^3- ), hydrogen citrate (denoted by C ₆ H ₆ O ₇ ^2- ), and dihydrogen citrate (represented by C ₆ H ₇ O ^7- ).

The term "citrate" or "total citrate" refers to the total amount of citric acid and any salts thereof, such as its sodium, magnesium, calcium or potassium salts. In other words, “total citrate” is the sum of free citrate ions and citrate-containing complexes and ion pairs.

The term “buffer agent” means a bicarbonate or bicarbonate precursor such as lactate, citrate or acetate.

"Number of degrees of freedom" is defined as the difference between the number of operating flow rates to be calculated minus the number of prescription parameters.

glossary

The following terms/parameters are used consistently throughout the equations provided in the following detailed operational description of the extracorporeal blood therapy device.

parameter

BW Patient weight (kg)

C Solute concentration (mM)

Total citrate concentration in C _{cit_PBP} citrate anticoagulant solution (sodium citrate + citric acid) - (mM)

C_ca Calcium concentration of ion balancing solution (mmol/l)

Calcium concentration of C _carep.post post-dilution replacement solution (mmol/l)

Cca _HCO3 Calcium concentration in bicarbonate container/infusion line (mmol/l)

Cp Plasma concentration (mM)

Cpw Plasma number concentration (mM)

Cpw _{cit_inlet} Citrate concentration in plasma water at filter inlet (mM)

Cp _{cit_pat} patient systemic citrate concentration (mM)

Bicarbonate concentration in C _HCO3cit citrate solution (mM)

C _{HCO PBP} Bicarbonate concentration of PBP solution (mM)

C _HCO3dial bicarbonate concentration in dialysis fluid (mM)

C Bicarbonate concentration in _HCO3rep.pre pre-dilution line (mM)

C _HCO3rep.post postdilution line bicarbonate concentration (mM)

Bicarbonate concentration (mM) in C _HCO3HCO3post post-dilution bicarbonate line

Cp _{HCO3_pat} Patient systemic bicarbonate plasma concentration (mM) (↔ [HCO ₃ ^- ] _pat.eq )

Cpw _{HCO3_pat} patient systemic bicarbonate plasma concentration (mM)

Bicarbonate plasma water concentration at Cpw _{HCO3_inlet} filter inlet (mM)

C _{lact_dial} Concentration of lactate in dialysis fluid (mM)

C _lactrep.pre pre-dilution line lactate concentration (mM)

C _lactrep.post postdilution line lactate concentration (mM)

Cp _{lact_pat} patient systemic lactate plasma concentration (mM)

Lactate Plasma Water Concentration at Cpw _{lact_inlet} filter inlet (mM)

D_CRRT CRRT Dialysis Volume (ml/h)

D_eff Effluent volume (ml/h)

D_conv Convection capacity (ml/h)

D_dial Diffusion capacity (ml/h)

D_urea Urea capacity (ml/h)

D_sol Clearance capacity (ml/h)

NDose _xxx normalized dose (ml/kg/h)

D_cit Citrate dose (mmol/L blood)

D_ca calcium dose; Calcium concentration in effluent (mmol/l)

Hct Hematocrit (dimensionless, ∈ [0; 1])

J_xxx Mass transfer rate of 'xxx' solute (amount per unit time) - (mmol/h)

J _{HCO3_bal} bicarbonate balance from extracorporeal blood therapy - (mmol/h)

J _{HCO3_inf} Bicarbonate infusion rate from dialysis and/or all replacement fluids - (mmol/h)

J _{HCO3_eff} Bicarbonate removal rate to effluent - (mmol/h)

J_H+ Acid infusion in extracorporeal hemotherapy - (mmol/h)

J _{citrate_load} citrate load or net infusion rate of citrate to patient - (mmol/h)

J _{cit_PBP} Citrate infusion rate of anticoagulant circuit before blood pump - (mmol/h)

J _{cit_dial} effluent citrate loss - (mmol/h)

J _{met_cit} Bicarbonate from metabolism of infused citrate - (mmol/h)

J _{lact_bal} lactate balance from extracorporeal blood therapy - (mmol/h)

J _{lact_inf} Lactate infusion rate from dialysis and/or all replacement fluids - (mmol/h)

J _{lact_eff} Lactate removal rate to effluent - (mmol/h)

J _{met_lact} bicarbonate produced from metabolism of lactate injected into patients - (mmol/h)

J _{buffer_load} net buffer load during extracorporeal therapy - (mmol/h)

SC_urea Filter sieving factor for urea

SC_cit Filter sieving factor for citrate

SC_HCO3 Filter sieving factor for bicarbonate

PRE Total injection rate of alternative fluid flow (dimensionless, ∈ [0; 1])

Q Flow rate (ml/min)

Q_b Blood flow (ml/min)

Q_PBP Flow rate before blood pump (ml/min)

Q_cit Citrate solution flow rate (ml/min)

Q_HCO3 Bicarbonate postinjection solution flow rate (ml/min)

Q _rep.pre Alternate flow rate/before filter (ml/min)

Q _rep.post alternate flow rate/after filter (ml/min)

Q_PFR Patient fluid clearance (PFR) rate (ml/min)

Q_rep Total replacement flow (Q_rep.pre+Q_{rep. post}) (ml/min)

Q_pre Total pre-dilution injection flow (ml/min)

Q_syr Syringe flow (ml/min)

Q_bw Blood water flow (ml/min)

Q _{bw_inlet} Blood water flow rate at filter inlet (ml/min)

Qp Plasma flow (ml/min)

Qpw Plasma water flow rate (ml/min)

Q Plasma water flow rate at _pw-inlet filter inlet (ml/min)

Q_eff Effluent flow (ml/min)

Q_fil Ultrafiltration rate in CRRT filter (ml/min)

Q_dial Dialysis flow (ml/min)

Q_ca Calcium solution flow rate (ml/min)

S/RT _xxx Ratio of filter surface area to diffusion mass transfer resistance (ml/min) for solute 'xxx'(↔'K0.A _xxx ')

CaComp Calcium compensation parameter (dimensionless, ∈ [5%; 200%])

F _{dilutionblood} blood dilution factor (dimensionless)

F _{dilutionplasma} plasma dilution factor (dimensionless)

F _dilutionpw Plasma number dilution factor (dimensionless)

index

cit citrate

HCO₃ bicarbonate

lact lactate

Ca calcium

inlet filter blood inlet

PBP before blood pump

dial dialysis fluid

rep how

rep.pre Pre-dilution alternative injection

rep. post Post-dilution alternative injection

eff effluent or dialysate

Fixed values indicated below constants may be changed according to specific needs

Cp _HCO3 0 = 25 mM patient plasma bicarbonate concentration (mM)

Cp _lact 0 = 1.5 mM patient plasma lactate concentration (mM)

nNBL0=0,1 m mol/h/kg Establish normalized net buffer load under patient steady state

F _cal* = 0.92 Fraction of patient plasma total calcium available in plasma for delivery through the filter membrane after citrate infusion (dimensionless)

Fp=0.95 Plasma number volume fraction

F _rbc =0.85 Volume fraction of water in red blood cells

F_cal=F_cal*/F_p Fraction of patient plasma total calcium available in plasma water for delivery through the filter membrane after citrate infusion (dimensionless)

It should be noted that the values for the above constants are exemplary. For example, patient plasma bicarbonate concentrations may be set at other levels, for example 27 mM, based on the physician's decision; The same is true for normalized net buffer loading where other values such as 0.15 mmol/h/kg can be assumed. Also, other constants can be more accurately estimated without affecting other parts of this description.

Extracorporeal blood therapy device, especially for CRRT treatment

Referring to Fig. 1, numeral 1 generally refers to an extracorporeal blood treatment device specifically for intensive care therapy. The extracorporeal blood treatment device 1 is designed to deliver any one of treatments such as hemodialysis, hemofiltration, hemodiafiltration, and ultrafiltration. The device according to FIG. 1 is specifically designed for continuous renal replacement therapy (CRRT). The CRRT system is configured to provide very specific treatment designed for patients who are in acute disease and have temporarily lost complete renal function. In this respect, CRRT systems may differ structurally and/or operationally from extracorporeal blood therapy systems designed for chronic patient treatment. Unlike chronic patients, acute patients usually suffer complete loss of kidney function either temporarily due to co-occurring severe damage or during post-surgery recovery. As a result, acute patients are often extremely frail and generally not in a condition to receive regular dialysis treatment, which can further aggravate their condition and lead to serious and possibly life-threatening complications. In the situation as described, the CRRT system treats patients in very poor health individually, without inducing additional stress on the patient's body and, in particular, without causing important parameters related to the patient's blood to deviate from ideal or near-ideal values. designed to do Thus, within the scope of this document, a CRRT system is essentially characterized by one or more of the following characteristics. CRRT includes renal replacement therapy, which refers to adjuvant therapy primarily aimed at facilitating sustained fluid clearance in patients with diuretic resistance or acute renal failure. Thus, CRRT systems essentially require continuous net fluid removal from the patient. That is, the CRRT system controls fluid balance, such as a weight loss control system configured to produce a sustained rate of net weight loss (as opposed to simply controlling parameters to achieve a desired target weight loss as commonly found in chronic patient care). system is needed In addition, acute patients can be safely removed in a short period of time (eg, within hours of chronic treatment) without causing potentially serious consequences (eg, hypovolemic shock, arrhythmia, hypoxemia, hypoventilation, etc.). experience no extravascular fluid overload. Thus, CRRT systems inherently have system parameters, particularly flow rates, to ensure that the necessary low flow rates for both blood circulating outside the body and therapeutic fluids (either injected into the extracorporeal circuit or diffused through the dialysis machine) are used. A more precise control of should be included. In addition, CRRT treatment is administered continuously (eg, for days or weeks, without interruption/with minimal interruption, eg with interruption time for bag change). Thus, treatment settings in CRRT are based on flow rate settings rather than settings related to some specific treatment time (an unknown as an acute patient may require treatment for an unknown amount of time). As a result, operation of the CRRT system cannot be based on some predefined achieved absolute weight loss, but rather on the patient's carefully controlled fluid balance, and therefore, based on a set rate of weight loss, the overall (and Continuous adjustments are required to a number of operating parameters that must be controlled and maintained over the course of treatment (which are not known a priori). Additionally, CRRT renal replacement therapy involves therapy that replaces renal function for a relatively long period of time, and therefore, the CRRT system (to remove unwanted substances from the blood and add desired substances to the blood by diffusion) is used at least in the dialysis machine. Fresh infusion fluid combined with fresh dialysis fluid exchange and/or ultrafiltration (to remove unwanted substances from the blood and add desired substances to the blood by convection) is required.

For at least the reasons described above, a CRRT system needs to exhibit certain technical characteristics that enable the system to:

- allow setting of weight loss rate;

- Excess moisture is continuously removed according to the set weight loss rate,

- continuous operation at relatively low flow rates compatible with CRRT, and

- Balancing the ionic equilibrium through appropriate dialysis performed and/or replacement fluid continuously delivered at a controlled flow rate.

Finally, in order to prepare the CRRT device as quickly as possible in the urgent situation of a patient in need of treatment and in the absence of prior notification of an emergency requiring treatment, the CRRT machine is worn using an integrated disposable set, where all lines and The filtration units are grouped together and already suitably connected to the disposable set. Additionally, all fluids are contained in pre-packaged bags (eg 2, 5 or 10 liters each of dialysis fluid or replacement fluid) or pre-packaged syringes (heparin and/or concentrated calcium replacement solution).

The device 1 of FIG. 1 has an extracorporeal blood circuit 17 , which can be eg a needle or catheter or implanted port or other access device (not shown) introduced into a vein or artery of the patient. The blood is taken from the patient P via , and the blood is brought to the filtration unit 2 , for example continuously, via the blood withdrawal line 6 . The filtration unit 2 has a primary chamber 3 and a secondary chamber 4 separated by a semi-permeable membrane 5; Depending on the treatment, the membrane of the filtration unit may be selected to have different properties and performance.

The blood passes through the primary chamber 3 of the filtration unit 2, and through the blood return line 7, the treated blood is conveyed back to the patient. In the example of FIG. 1 , the connection with the anticoagulant line 51 is provided just downstream from the blood collection zone on the blood draw line 6 . In particular, the machine is equipped with a topical anticoagulant source 10, such as at least a secondary fluid container or bag for supplying to the solidification line 51; In the illustrated example comprising an anticoagulant pump 54, for example a peristaltic pump, directly connected to the blood draw line 6 to introduce topical anticoagulant directly into the blood, by using the corresponding actuator(s) for transporting the fluid. By doing so, it is possible to control the fluid flow in the line. Defines the direction 200 of circulation of fluid (blood) from the blood withdrawal line 6 towards the filtration unit 2 and from the latter through the blood return line 7 towards the patient P (during normal use of the device) After that, a known blood pressure sensor 48 is placed immediately downstream of the anticoagulant line 51, which will not be described in more detail. The blood circuit 17 comprises actuator(s) for transporting the fluid, ie at least a blood pump 21 for controlling and managing, in this particular case, the proper blood flow Q _b in the circuit. Also, the blood pump 21 is generally a peristaltic pump acting on a blood withdrawal line (eg as shown in Figure 1) or a blood return line. The operator can input a set value for the blood fluid flow rate Q _b via the user interface 15, and the control unit 12 is configured to control the blood pump based on the set blood fluid flow rate during treatment. . Alternatively, it should be noted that the blood pump 21 may be controlled automatically without the need for user input/prescription: in this case the control unit 12 may have a predetermined flow rate or (as will be seen in the following description) ) to control the blood pump 21 at a flow rate calculated based on other parameters, such as, for example, other flow rates and limits set by the medical operator. Additionally or alternatively, the blood pump may also be controlled based on pressure; If the blood pump 21 is controlled based on the pressure signal detected upstream of the blood pump, in this case the pressure sensor 48 is present in the tube of the blood line upstream of the blood pump 21: For example, the control unit ( 12) may be designed to drive the blood pump in such a way as to keep the pressure detected by the pressure sensor 48 within a predetermined range or below a predetermined threshold.

Depending on the direction of blood circulation, a gas exchanger 46 for removing CO ₂ from circulating blood may be connected to the blood circuit. Gas exchanger 46 is in fluid communication with blood circuit 17 to receive extracorporeal blood, remove CO ₂ from the blood, and return the blood to the blood circuit at a downstream point. 1 shows a gas exchanger 46 arranged upstream of the filtration unit 2; However, the gas exchanger may alternatively be located downstream of the filtration unit along the direction of blood circulation. As mentioned, the direction of blood circulation during normal use of the device is indicated in FIG. 1 by an arrow 200 which also indicates the direction of blood flow rate (Q _b ) during treatment. A gas exchanger 46 is connected in series with the filtration unit 2 and is located downstream of the injection point 50 where the topical anticoagulant solution is delivered to the extracorporeal blood. The gas exchanger 46 has a blood chamber and a gas chamber separated by a membrane permeable to gas, particularly CO ₂ ; A gas exchanger is in fluid communication with a gas inlet that can be connected to a gas source, such as a hospital medical gas supply system, for example, to receive compressed air or oxygen, and a gas chamber to expel exhaust gas that has removed CO ₂ from extracorporeal blood. It includes a gas outlet that The blood inlet and blood outlet bring the extracorporeal blood circuit 17 into fluid communication with the gas exchanger blood chamber.

The blood then passes through another pressure sensor 49 which controls the correct flow within the blood circuit. After passing through the primary chamber 3 of the filtration unit 2, where proper exchange of substances, molecules, and fluids takes place by means of a semi-permeable membrane, the treated blood enters the blood return line 7, first commonly referred to as a "bubble trap" ”, which is designed to ensure the detection and removal of air bubbles present in the blood. The treated blood coming out of the air separator 19, before being returned to the patient P, passes through the air bubble sensor 55, so that there are no such dangerous formations in the treated blood that need to be reintroduced into the patient's blood circulation. Check the Immediately downstream of the bubble sensor 55, a safety valve 20 (or venous clamp) may be placed to shut off blood flow to the patient when an alarm sounds. In particular, if the bubble sensor 55 detects the presence of an abnormality in the blood flow, the safety valve 20 will allow the machine to immediately block the passage of blood to avoid any consequences for the patient. A corresponding safety valve 27 (or arterial clamp) is present on the blood withdrawal line to close the patient's access to the blood vessel in order to completely isolate the patient from the extracorporeal blood circuit if necessary. Downstream of the safety valve 20 , the treated blood is then conveyed back to the patient P undergoing therapy. The extracorporeal blood treatment device of FIG. 1 has a dialysis fluid circuit 32 , which also has at least a dialysis supply line 8 leading to the filtration unit 2 and an effluent (or dialysate) line from the filtration unit. (13) is provided. At least a primary fluid container defining the dialysis liquid source 14 is designed to supply the supply line 8 of the dialysis fluid circuit 32 (usually the primary fluid container is one or more bags containing suitable dialysis liquid). will consist of). The supply line 8 comprises at least a dialysis fluid pump 25 (in the embodiment of FIG. 1 a peristaltic pump) for controlling the flow rate of dialysis fluid Q _dial from the bag and defining the direction 200 of the dialysis fluid circulation and and actuator(s) for transporting the same fluid. Downstream from the dialysis fluid pump 25 in the circulation direction 200 there is a branch 56 dividing the dialysis supply line 8 into a suction branch 57 and an infusion branch 58 . In particular, the infusion branch 58 is connected to the blood return line 7 of the blood circuit 17 . In other words, by means of the infusion branch 58, it is possible to obtain post-infusion directly into the blood line 17 using the contents of the primary fluid container. Conversely, the suction branch 57 conveys the fluid directly to the filtration unit 2, in particular to the secondary chamber of said unit. The dialysis fluid circuit 32 is further equipped with a selector 59 for determining the percentage of fluid flow in the infusion branch 58 and the suction branch 57. In general, the selector 59, which is generally arranged near the branch portion 56, has at least a first operating condition allowing passage of the fluid in the suction branch 57 and blocking the passage in the injection branch 58; It may be located between a second operating condition allowing passage of fluid at branch 58 and blocking passage at suction branch 57 . In other words, the selector 59 may consist of a valve element that operates in the dialysis fluid circuit 32 by alternately blocking the passage of fluid in either branch. A suitable selector can alternatively be provided which can establish a priori the amount of liquid that must pass simultaneously through the two branches. It is also possible to change the percentage of fluid in either branch as a function of time and a pre-established regimen. The dialysis liquid through the suction branch 57 enters the secondary chamber 4 of the filtration unit 2 . In particular, the primary chamber 3 through which the blood flow passes is separated from the secondary chamber 4 through which the dialysis liquid passes from the blood into the dialysis liquid mainly through convection and diffusion processes. and through a semi-permeable membrane 5 which ensures proper passage of fluid and also ensures passage of substances/molecules from the dialysis fluid towards the blood through the same principle. The dialysis fluid then enters the effluent line 13 and passes through an appropriate effluent pressure sensor 60 . An actuator such as, for example, a dialysate pump 26 controlling the flow rate Q _eff in the effluent line 13 in the fluid circuit 32 is provided to transfer the fluid. Also, the pump will generally be a peristaltic pump. The fluid to be removed then passes through the blood detector 61 and is conveyed to a collection container or bag 62 . The hydraulic circuit of the device according to FIG. 1 comprises at least another infusion line 63 for supplying fluid to the blood return line 7 of the blood circuit 17 . In particular, the infusion fluid is taken from at least an auxiliary vessel 64 and an actuator(s) to transfer the fluid, typically an infusion pump 65 (in this example a peristaltic pump) controlling the flow rate Q _rep - the total replacement flow rate ) to the blood return line 7 of the blood circuit 17. In particular, the injection liquid can be introduced directly into the air separator 19 . As may also be inferred, the infusion branch 58 and the infusion line 63 of the dialysis fluid circuit 32 have a common end length 66 allowing fluid to enter the blood circuit 17 . The suction end length 66 is disposed downstream from the injection pump 65 with respect to the injection direction and carries the fluid directly to the air separator 19 . Referring also to the diagram of FIG. 1 , the infusion line 63 includes at least a pre-infusion branch 67 connected to the blood withdrawal line 6 of the blood circuit 17 . More specifically, downstream from the injection pump 65 with respect to the injection direction, there is an injection branch 68 dividing the injection line 63 into a pre-injection branch 67 and a post-injection branch 69 . The pre-injection branch 67 carries in particular the fluid taken from the bag 64 to the blood withdrawal line 6 of the blood circuit 17 downstream from the blood pump 21 and downstream from the gas exchanger 46 with respect to the direction of blood circulation. do. Conversely, the post-injection branch 69 is directly connected to the common end length 66. The injection line 63 further includes a selector 70 for determining the percentage of liquid flow to be directed to the post-injection branch 69 and the pre-injection branch 67 . The selector 70 arranged near the branch portion 68 provides at least a first operating condition for permitting passage of fluid in the pre-injection branch 67 and blocking passage in the post-injection branch 69, and in the post-injection branch ( It is possible to switch between at least a second operating condition allowing passage of fluid at 69 and blocking passage at pre-injection branch 67 . Obviously, as in the case of the selector 59 present on the dialysis fluid circuit 32, also the other selector 70 can determine the percentage of fluid that must pass through each of the two branches and time according to the planned regimen. You can change this accordingly. Also, selector 59 and other selectors 70 will generally, but not necessarily, have the same properties. In particular, the flow rate through the pre-injection branch/line 67 may be determined by appropriate control of the injection pump 65 and other selectors 70; The control unit 12 receives the pre-injection ratio (PRE) (value between 0 and 1) of the replacement fluid flow and, based on the pre-injection ratio (PRE) and the total replacement flow rate (Q _rep ), the total injection flow rate (Q _{rep. pre} ) can be determined. In particular, Q _rep.pre = PRE·Q _rep . Alternatively, the post-injection ratio is used symmetrically, or the ratio between the pre- and post-injection rates can also be used (R ₃ = Q _re.pre /Q _rep.post ).

The device is equipped with means 71 for at least determining the weight of the primary fluid container 14 and/or auxiliary fluid container 64 and/or regional anticoagulant container 10 and/or collection container 62. . In particular, said means 71 comprises a weight sensor, for example each scale A, B, C, D and E (eg at least an independent sensor for each fluid bag associated with the machine). . In particular, there will be at least 4 of these scales, each pair being independent of the other, each one measuring the respective weight of the bag. In this case, a pressure sensor 48 which is (at least) active in the blood circuit 17 and in particular for reading the pressure value, a blood pump 21, a gas exchanger 46, another pressure sensor 49, and a bubble 55 ), and a control unit or CPU 12 which is activated at each safety valve 20, 27. The control unit 12 must also control the dialysis fluid circuit 32, in particular with respect to the weight of the bag 14 and the data detected by the scales A, B, C, D and (possibly) E. Scale A, which must be input and act on the pump 25, the selector 59, the pressure sensor 60, and then the dialysate pump 26, which eventually functions to determine the weight of the collection container 62 The data detected by should be received. The control unit 12 must act on the infusion line 63 which checks the weight of the auxiliary container 64 (ascertained by the scale C) and controls both the infusion pump 65 and the other selector 70. You will be able to. The control unit 12 also acts on the anticoagulant line 51 to detect the weight of the anticoagulant fluid container 10 by means of the scale B and to set the anticoagulant pump 54 according to the treatment to be performed as detailed below. appropriately control. As is evident, a topical anticoagulation system is implemented in the device 1 of FIG. 1 to provide limited anticoagulation to the extracorporeal blood circuit 17 . Topical anticoagulation systems are described in detail in their respective descriptive paragraphs. However, the device of FIG. 1 may alternatively (or additionally) be provided with a systemic anticoagulant system, such as a syringe pump 9 for injecting heparin downstream of the blood pump 21 . Indeed, the algorithms of embodiments of the present invention, as described in the detailed description below, work in both CRRT treatment configurations with RCA and CRRT treatment configurations with (or without) systemic anticoagulation without RCA.

Control unit 12 is also connected to memory 16 and to a user interface 15, for example a graphical user interface that receives operator input and displays device output. For example, graphical user interface 15 may include a touch screen, display screen, and/or hard keys for inputting user input, or a combination thereof.

topical anticoagulant system

The topical anticoagulant system comprises a source of topical anticoagulant 10, eg a container or bag comprising a substance having at least an anticoagulant effect. For example, citrate in the form of pure sodium citrate (Na ₃ citrate) or a mixture of sodium citrate and citric acid is used for blood anticoagulant purposes. Alternatively, pure citric acid can be used as an anticoagulant. Indeed, citrate has a high affinity for calcium when forming complexes, and several steps in the coagulation cascade depend on blood (ionized) calcium. Appropriate reduction of ionized calcium concentration in the presence of citrate inactivates the coagulation cascade.

Normal plasma contains about 1.1 to 1.3 mmol/l ionized calcium, 0.1 to 0.2 mmol/l complex calcium, and 0.9 to 1.2 mmol/l protein bound calcium. To achieve an adequate anticoagulant effect, a general guideline is to adjust the citrate amount/dose to reach an ionized calcium concentration of 0.20 to 0.35 mmol/l in the extracorporeal blood circuit after citrate infusion. Plasma spiked with citrate for anticoagulant purposes contains (on average) about 0.3 mmol/l ionized calcium, 1.8 mmol/l complex calcium (mainly Ca ₃ citrate ₂ ) and 0.2 mmol/l protein-bound calcium. . During RCA, the anticoagulant strength can be adjusted through the amount of citrate injected. The unit ionized calcium concentration after filtration is usually used as the key parameter (target in the range of 0.20 to 0.35 mmol/l) and is measured, for example, with a blood gas analyzer.

The local anticoagulant system is arranged to deliver a topical anticoagulant at a delivery point 50 of the extracorporeal blood circuit 17 . The citrate infusion is preferably administered close to the approach end of the blood withdrawal line (6) to obtain complete anticoagulation of the extracorporeal blood circuit (17). Generally, the delivery point 50 is located upstream of the blood pump 21; However, it is not excluded that the delivery point 50 is located in the blood draw line 6 downstream of the blood pump. Alternatively or in combination, the delivery point 50 for the citrate may be the inlet of the filtration unit 2 . In this latter configuration, the dialysis fluid includes an amount of citrate sufficient to achieve an ionized calcium level of about 0.25 to 0.35 mmol/l in the blood circuit downstream of the dialyser. If the dialysis fluid is prepared on-line, as in current devices for chronic treatment, citrate may be added to the treatment fluid flowing along the supply line 8 using a corresponding thickening bag/container. Alternatively, particularly in the case of a CRRT device, the source 14 for dialysis liquid is a container/bag containing an appropriate citrate concentration or amount.

Commercial citrate solutions are generally packaged in individual plastic bags (source 10) and can be divided into physiological solutions and concentrated solutions. Physiological citrate solutions have a sodium concentration of about 140 mmol/l, such as Baxter PrismoCitrate 10/2 (with 10 mmol/l Nacitrate and 2 mmol/l Citric Acid) and Baxter RegioCit 18/0 (with 18 mmol/l Nacitrate). it is a solution Concentrated citrate solutions include, for example, Anticoagulant Citrate Dextrose Solution (ACD-A) from Biomet: a mixture of sodium citrate (75 mmol/l), citric acid (38 mmol/l) and glucose; and 4% citrate from Fresenius: 136 mmol/l citrate.

When citrate is injected into the blood withdrawal line (6) close to the patient's vascular access, the blood pump speed is automatically adjusted to take the blood flow rate set by the operator from the access site (blood pump speed = k*(Q _b + Q _cit ), where Q _b is the established (or calculated) blood flow rate minus that required at the access site and Q _cit is the citrate infusion flow rate).

The amount of citrate is prescribed through the 'citrate dose' parameter (D _citrate ), which is the amount of citrate per liter of blood treated (mmol/l blood). In particular, the citrate dose does not match the citrate concentration of the diluted blood reaching the filtration unit. The concept is rather to provide the amount of citrate in proportion to the amount of calcium to be chelated. The set of citrate pumps 54 are as follows:

(식 1)

(Equation 1)

here

Q _cit is the citrate injection flow rate;

Q _b is the set blood flow rate;

D _cit is the citrate dose; and

C _{cit_pbp} is the citrate concentration of the anticoagulant source. This is the citrate flow rate stored in the memory 16 of the control unit 12 and used to determine the citrate injection rate Q _cit given the citrate concentration in the anticoagulant source 10 and the citrate dose D _cit as inputs. It is a mathematical relationship. The blood flow may be an input value (prescription parameter) or a calculated value (operating parameter) that the control unit determines based on system configuration and prescription parameters (see detailed description below).

The citrate infusion is delivered at a dose to maintain the level of ionized calcium in the blood circuit downstream of the dialyzer at about 0.25 to 0.35 mmol/l. Generally, citrate doses fall in the range of 1.5 to 6.0 mmol/l of blood. The most common range is 2 to 4 mmol/l blood. A citrate dosage guideline of 3.0 mmol/l blood-l is followed worldwide.

The ionized calcium and citrate complex is a rather small molecule that readily passes through the filtration unit (2). The loss rate basically depends on the flow rate, the filter efficiency for small molecules, and the solute concentration. About half of the total calcium is unavailable for mass transfer during standard anticoagulation (because it is protein bound), but about 90% of the total calcium can be made available during citrate anticoagulation. Thus, citrate topical anticoagulation combined with calcium-free dialysis and/or use of replacement fluids implies a significant loss of calcium to the dialysate. In extracorporeal blood therapy involving RCA, calcium infusion is required to balance calcium loss to the dialysate. During RCA, calcium infusion is adjusted to maintain the patient's systemic ionized calcium in the normal range (eg, 1.0 to 1.2 mmol/l).

Accordingly, the local anticoagulant system of the device 1 comprises an ion balancing solution source 11, which is reinfused into the blood, in particular in the return line 7 close to the venous vascular access, or directly into the patient P ( injection into the recommended central catheter). The ion balancing solution 11 is contained in a container, for example a syringe, container or bag; The local anticoagulation system of device 1 includes an ion replacement implantation line 74 and a corresponding ion replacement pump 75 to drive delivery of an appropriate ion replacement implantation rate Q _ca . Figure 1 shows a line 74 that injects directly into the blood return line 7, possibly close to the venous access. Of course, line 74 could alternatively be injected directly into patient P. In the example of Figure 1, the syringe pump 9 commonly used to deliver heparin may alternatively be used to deliver the ion balancing solution directly to the patient or alternatively in the blood return line. The ion balancing solution contains ionized (concentrated) calcium, and an infusion is performed to restore the patient's systemic ionized calcium to normal levels. In particular, the ion balancing solution may also contain ionized magnesium, and infusion is performed to restore the patient's systemic ionized magnesium to normal levels because magnesium removal from the dialysate is increased during RCA. The ion replacement infusion rate (Q _ca ) can be adjusted according to the determined concentration of ionized calcium in the patient's blood, or an automatic control can be implemented as described in patent publication US8668825B2 (this application is incorporated herein by reference).

In one implementation, the ion balancing solution flow rate is maintained in proportion to the expected rate of calcium loss in the dialysate. For example, it is calculated by the device control unit via a formula (calcium flow rate mathematical relationship).

(식 2)

(Equation 2)

where CaComp is the calcium compensation parameter, Q _ca is the ion balancing solution flow rate (ml/h), Jca is the expected rate of calcium loss in the dialysate (mmol/h), and C _ca is the calcium concentration in the ion balancing solution (mmol/l). , Q _rep.post is the post-dilution replacement flow rate (ml/h), C _{ca_rep.post} is the post-dilution replacement solution's calcium concentration (mmol/l), and Q _HCO3 is the post-dilution bicarbonate inlet line (23). is the fluid flow rate in ml/h, and C _{ca_HCO3} is the calcium concentration in the bicarbonate vessel. Calcium compensation is a user controllable setting, which can typically be set by the operator in the range of 5% to 200%.

In particular, consider not only bicarbonate infusions containing calcium as above, but also solutions after replacement containing calcium. If there is no calcium in the solution after replacement (or if no replacement solution is used), the second term of the equation must be ignored (equal to zero). If there is no calcium in the bicarbonate replacement solution (or if no bicarbonate solution is used), the third term of the equation must be neglected (equal to zero).

The mathematical relationship of the calcium flow rate is also used by the control unit 12 to determine the ion re-establishment flow rate (Q _ca ) based on the known (input) calcium concentrations of the various post-injection solutions. It is also assumed that no calcium is injected upstream of the filtration unit 2 to avoid undesirable coagulant effects (in this regard the anticoagulant solution does not contain any calcium, there is no pre-dilution injection line 67 or no pre-dilution injection line 67). no calcium in the injected replacement solution). In addition, ion compensation parameters are also part of the prescription. The post-injection flow rates, ie Q _rep.post and Q _HCO3 are operating parameters, and the control unit 12 determines them based on the prescription parameters and device configuration. Also, Jca is assumed as disclosed for example in the referenced US8668825B2 application.

Alternatively, the 'calcium dose' D _ca can be given by the medical staff as the calcium concentration in the effluent (mmol/l). The ion balancing solution flow rate (Q _ca ) is calculated based on the set calcium capacity taking into account the calcium concentration of the ion balancing solution, the calcium concentration of the replacement solution, and the expected calcium concentration in the blood at the outlet of the filtration unit (2).

Indeed, as for dialysis fluids (and replacement solutions), they are generally free of calcium to prevent ionized calcium from migrating into the blood. Additionally, the dialysis and/or replacement fluid may have an adapted buffer content due to citrate metabolism and sodium adapted if concentrated citrate solutions (hypertonic) are used.

Regarding the buffering agent, since RCA has a complex effect on the acid-base balance equilibrium due to the return of significant amounts of citrate to the patient (citrate is metabolized to bicarbonate), when assisting the prescription, the control unit 12 achieves will require the input of a steady-state acid-base balance target to be Indeed, the blood returned to the patient contains significant concentrations of citrate-calcium complex. This complex is (rapidly) metabolized by the liver, skeletal muscle, and kidneys releasing calcium into the bloodstream, preventing systemic anticoagulation from developing; Citrate metabolism produces bicarbonate (3 mol HCO ₃ ^- to 1 mol citrate).

In this regard, the dialysis fluid may not include a buffering agent, such as bicarbonate. The buffer from the source/container/bag 64 can be injected into the blood return line 7 via suitable buffer supply lines 63, 69, 66 and a corresponding buffer pump 65. Alternatively or in combination, device 1 may also set a dialysis fluid (lower) buffer concentration and/or a different buffer concentration, for example between 15 and 25 mmol for bicarbonate, to allow for further control of the acid-balance. Designed to change the buffer balance of the extracorporeal blood circuit in an easy and controlled manner with the possibility of using source bags (14, 64) in the range of /l (and up to 40 mmol/l and/or up to 0 mmol/l) It can be. As described, specially designed bicarbonate solutions can be post-injected to allow further control of the acid-base balance (see, eg, FIGS. 4-6).

As mentioned, a patient's citrate accumulation can be correlated with hypocalcemia, metabolic acidosis (low bicarbonate production due to poor metabolism) or metabolic alkalosis (excessive bicarbonate production due to high citrate load). Since citrate measurements are not commonly seen in the hospital, the ratio of total calcium to ionized calcium is used as an indicator, i.e., values less than 2.5 are considered normal (normal values less than 2.0), and values greater than 2.5 are associated with total calcium. ionized calcium, possibly due to the presence of significant systemic concentrations of citrate. However, such monitoring is considered an insufficient measure in CRRT treatments, which include an associated risk of acid/base imbalance, especially in RCA with 'large' flow rates, such as certain SCUF treatments.

specific embodiment

The embodiment of FIGS. 2 and 3 depicts a different configuration of the device 1 shown in FIG. 1 , where the same components described for the embodiment of FIG. 1 are also present and identified with the same reference numbers, again again. not explained in detail.

The example in Figure 2 shows a CRRT configuration with no systemic anticoagulant or with systemic anticoagulant. In particular, when a systemic anticoagulant is used, a heparin container (e.g., syringe 9) is generally passed downstream of the blood pump 21 via an infusion heparin line 22 to an outgoing line 6 to a ball of anticoagulant. Used to inject loose. This embodiment includes a pre-blood pump (PBP) line 52 for infusion of a replacement solution (without citrate) contained in a PBP container 18 into a PBP pump 53 that produces a pre-blood pump infusion flow rate Q _PBP . includes There is also a post-injection line for post-injection of the replacement solution contained in the auxiliary container 64. A dialysis liquid source 14 is also included to provide a dialysis fluid flow rate Q _dial to the second chamber 4 of the filtration unit 2; The effluent fluid flow rate Q _eff is conducted by the dialysate pump 26 to the collection vessel 62 . Comparing the embodiment of FIGS. 1 and 2 , the embodiment of FIG. 2 does not have any ion balancing infusion line 74 (no topical anticoagulant is provided) and fluid from the liquid source 14 is directed to the dialyzer. (selector 59 is configured to prevent any fluid from going to post-injection), and replacement liquid from auxiliary vessel 64 is sent only to post-dilution (additional selector 70 is configured to prevent any fluid from going post-dilution). configured to prevent going to pre-injection).

The embodiment of FIG. 3 differs from the embodiment of FIG. 2 because it refers to a CRRT configuration using a topical anticoagulant. Heparin syringes (9) are not used. Container 10 is a source of topical anticoagulant (citrate), and anticoagulant pump 54 produces a citrate infusion rate Q _cit . A corresponding ion balancing injection line 74 and ion balancing pump 75 are included for injecting the calcium enriched solution from the ion balancing solution source 11 at a calcium injection rate Q _ca .

The embodiment of FIG. 4 includes the same dialysis fluid circuit of Examples 2 and 3. As already shown in Example 2, the example of Figure 4 shows a CRRT configuration with no systemic anticoagulant and systemic anticoagulant. Alternatively, a pre-infusion line downstream of the blood pump 21 is included for infusion of the pre-diluted replacement solution. The pre-injection line may be the infusion line 63 of FIG. 1 , wherein another selector 70 is configured to direct all replacement fluid coming from the pre-diluted secondary vessel 63 through the pre-injection branch 67 . Alternatively, a pre-dilution infusion line 29 is provided which delivers a replacement fluid contained in the replacement source 30 . The infusion pump 31 produces a total infusion replacement flow Q _rep.pre . Additionally, a post-diluted bicarbonate inlet line 23 for concentrated bicarbonate solutions is also included. The bicarbonate pump 24 injects the bicarbonate concentrated solution from the bicarbonate container 28 at a bicarbonate concentrated postinjection flow rate (Q _HCO3 ).

The embodiment of Figure 5 shows a CRRT configuration using a topical anticoagulant. Heparin syringes (9) are not used. Container 10 is a source of topical anticoagulant (citrate), and anticoagulant pump 54 produces a citrate infusion rate Q _cit . A corresponding ion balancing injection line 74 and ion balancing pump 75 are included for injecting the calcium enriched solution from the ion balancing solution source 11 at a calcium injection rate Q _ca . There is also a post-injection line 63 for post-injection of the replacement solution contained in the auxiliary container 64. Additionally, a post-injection line 23 for the concentrated bicarbonate solution is also included. The bicarbonate pump 24 injects the bicarbonate concentrated solution from the bicarbonate container 28 at a bicarbonate concentrated postinjection flow rate (Q _HCO3 ).

Figure 6 is another embodiment, wherein the device comprises all possible infusion lines, namely two separate infusion lines before the blood pump: one anticoagulant line for citrate infusion (flow rate: Q _cit ), and before the blood pump. One PBP injection line 52 (flow rate: Q _PBP ) for replacement fluid injection, injecting replacement fluids from replacement sources 30 (eg prepackaged containers) by respective pre-infusion pumps 31 One pre-dilution injection line 29 (flow rate: Q _rep.pre ), one post-dilution injection line 63 (flow rate: Q _rep.post ) for injection from the auxiliary container 64 containing the replacement solution, One post-dilution bicarbonate infusion line 23 (flow rate: Q _HCO3 ), one ion balancing infusion line 74 (flow rate: Q _ca ) for infusion of calcium concentrated solution, one for directing fresh dialysis fluid to the filtration unit. It includes a dialysis supply line 8 (flow rate: Q _dial ) and one effluent line 13 (flow rate: Q _eff ) for directing spent dialysis fluid to a collection container 62 . In the embodiment of Figure 6, the pre-infusion blood pump post-infusion line 29 and post-infusion line 63 are shown as separate and independent lines; Alternatively, the two lines 29 and 63 may be merged together as in the embodiment of Figure 1, where one single bag 64 provides the same replacement fluid to two branches, one for the former. One guides the dilution fluid and the other guides the postdilution fluid. Each infusion fluid flow rate Q _rep.post and Q _rep.pre is obtained by appropriately driving the infusion pump 65 and selector 70: the flow from a single pump 65 depends on the selector 70 over time. ) is selectively guided through pre-injection or post-injection; Controlling the time spent in each of the two states controls the splitting of the flow between pre-injection and post-injection. The desired flow value is obtained as an average value over a certain period of time, which of course must be sufficiently long, ie at least several minutes.

Additionally, the two infusion lines 51 and 52 that inject fluid prior to the blood pump can be replaced with a single line, used for citrate in case of local anticoagulation, or in place of PBP if no systemic anticoagulant or systemic anticoagulant is present. used for fluids.

Finally, it should be noted that if any line is missing from a particular circuit configuration, the corresponding flow rate may be omitted from any of the following formulas/mathematical relationships (or values set to zero):

Expression for flow

The following equations for flow rates express the relationship between flow rates used in the detailed description. These equations are stored in the memory 16 of the device. If necessary, control unit 12 uses the following equations to determine operating parameters (as described in the next section).

Plasma water flux is a function of blood flux as follows:

(식 3)

(Equation 3)

Plasma water flux is a function of blood flux as follows:

(식 4)

(Equation 4)

The plasma water flow rate at the filter inlet is:

(Equation 5)

Blood water flow rate is a function of blood flow rate as follows:

(식 6)

(Equation 6)

The blood water flow rate at the filter inlet is:

(Equation 7)

The ultrafiltration rate of the filtration unit is:

(Equation 8)

If one single infusion line 63 (as in FIG. 1 ) is used, the full injection rate of the replacement fluid is the (total) replacement flow rate delivered by the injection pump 65 (Q _rep ) times the fluid flow before replacement. It can be calculated based on the coefficient PRE:

(식 9)

(Equation 9)

The effluent flow rate is:

(Equation 10)

clinical prescription parameters

The clinical prescription parameter is a parameter requested from a medical staff when the CRRT device starts or updates a treatment prescription for a specific patient. The device may request the physician to enter prescription parameters or provide suggested values to be verified or updated. The prescription parameters to be checked/updated can be read from a patient card or similar support.

The purpose of the 'Support Prescribing' process is to operate on prescribing parameters that are fully meaningful from a clinical point of view; Selected prescription parameters of interest are listed in the following table.

Although not all of the clinical regimen parameters mentioned above are necessary/required, their relevance will depend on the treatment option chosen and physician preference.

For example, the blood flow rate listed in the table may be used as a prescription parameter (set by the medical staff) or operating parameter (set by the system algorithm) according to the customer's preference, as described below.

Citrate dose and calcium compensation are relevant in the case of local anticoagulant therapy and are not required in the absence of systemic anticoagulant therapy or in the presence of systemic anticoagulant therapy.

The patient fluid removal rate may be entered into the prescription or, alternatively, calculated by the control unit.

In general, the CRRT dose is a 'running' dose that should be derived from a clinical target (20 to 25 ml/kg/h according to KDIGO guidelines) corrected for system downtime; This leads to a recommended running capacity in the range of 25 to 30 ml/kg/h. CRRT capacities are detailed in the following paragraphs.

As pointed out earlier, citrate dose modulates the intensity of anticoagulation; This should be adjusted to lower the ionized calcium concentration in the extracorporeal blood circuit to the range of 0.2 to 0.35 mM. At the same time, calcium compensation controls the balancing level of calcium loss relative to the calculated default loss rate; Instead of percentage, calcium balancing can be prescribed as the concentration of calcium in the effluent (calcium dose (D _ca )).

Steady-state acid-base balance targets were defined as steady-state patient bicarbonate concentrations (requiring assumptions for nNBL), or normalized net buffer loading (requiring assumptions for bicarbonate concentrations). Generally, the second option is preferred. In steady state, nNBL is expected to balance the rate of proton (H+) production from the patient's metabolism. Steady-state acid-base balance targets are discussed further in the next paragraph.

The patient fluid removal regimen is derived directly from an analysis of the patient's fluid balance, taking into account all patient's fluid inputs and outputs, and the desired correction of the patient's fluid condition. It is clear that it may be desirable to set the patient fluid removal rate; However, setting other fluid flow rates can result in determining the patient fluid removal rate (eg, using Equation 10 with knowledge of the effluent flow rate setting and the infusion flow rate and the dialysis flow rate).

Blood flow rate is not expected to have any strong clinical background except for some technical considerations for the patient's vascular access. When selected as a prescription parameter, the medical prescription may provide a desired set value or may simply define a lower and/or upper limit(s) of the blood flow setting range.

CRRT capacity definition

In this specification, CRRT capacity primarily refers to a flow rate or a combination of flow rates (hereafter expressed in ml/h). However, it should be noted that a further definition of therapeutic dose in CRRT is expressed in ml/kg/h, which means normalization of the flow rate (or combination of flow rates) to the patient's body weight (BW). Especially for infants, literature CRRT doses also refer to therapeutic doses normalized to patient body surface area (BSA).

Volume (excluding 'normalization' for patient size) can be defined as a combination of flow rates in the most general way, as in the following examples.

- Effluent capacity (D _eff ): Q _eff , as a perfect typical (and simple) example from field practice.

- convective capacity (D _conv ): sum of all infusion flows into the blood circuit or patient + patient fluid removal rate;

- Diffusion capacity (D _dial ): Dialysis flow rate (Q _dial ),

- All of the above volumes corrected for blood (or plasma) predilution upstream of the filter

- Urea capacity (D _urea ): Estimated urea clearance,

- Clearance capacity (D _sol ): Any capacity calculated based on the estimated clearance of a given solute (=> function to express all flow settings and dialyzer/filter related parameters).

Formula for CRRT dialysis dose

All dose expressions below are not normalized to patient size (weight (BW) or patient surface area (PA)); The expression of the normalized capacity (NDose) can be directly expressed as:

NDose = capacity/BW; or

NDose = dose/BSA x 1.73 (patient with 1.73 m² surface area - when normalized to body surface area; see pediatric literature)

For example, one of the following sizes may be used as a dose:

Effluent capacity (D _eff ): flow rate across the effluent line, ie D _eff =Q _eff ;

Convective capacity (D _conv ): the sum of the flow rate through the infusion line or lines connected directly to the patient or to the blood circuit and the patient fluid removal rate, i.e.

Of course, if one or more lines are missing, either the corresponding flow term(s) is not in the definition or the value is set to zero;

· Diffusion capacity (D _dial ): The flow rate of the fluid supplied to the secondary chamber of the filtration unit, ie D _dial =Q _dial .

· Urea dose (D _urea ): estimated urea clearance (K _urea ); It should be noted that under the CRRT condition, the first approximation expression assumes that the filter urea clearance is more or less equal to the effluent flow rate (Q _eff ); In a further alternative, a more accurate urea clearance estimate than Q _eff , especially when operating with large flow rates or small filters (pediatric conditions), can be given by the equation:

a) For pure diffusion mode (no injection of replacement fluid and zero or substantially zero patient fluid removal rate) and counter-Courant flow configuration (fluid in the chamber of filtration unit 2 is countercurrent):

(Equation 11)

Where: S (effective filter surface area) depends on the hemodialysis machine in use (ie filtration unit 2); RT is the total mass transfer resistance, which depends on the hemodialysis machine in use (membrane properties, filter design) and the solute of interest, in this case urea; It should be noted that S/RT is also the mass transfer characteristic of the filtration unit, ie K0.A (ml/min), and Qbw _inlet is the blood flow rate at the inlet of the filtration unit (2).

b) If both dialysis fluid flow (Q _dial ) and one or more fluid infusions are present:

(Equation 12)

where: S (effective filter surface area) depends on the hemodialysis machine in use; RT is the total mass transfer resistance, which depends on the hemodialysis machine in use (membrane properties, filter design) and the solute of interest, in this case urea; Q _fil is the ultrafiltration rate of the CRRT filter; and Q _bw inlet is the blood water flow rate at the inlet of the filtration unit (2). SC _urea is the sieving factor for urea (depending on the selected filtration unit).

· Clearance capacity: estimated clearance for a given solute; A first approximation expression for a particular solute assumes that the filter solute clearance is more or less equal to the effluent flow rate (Q _eff ); Alternatively, solute clearance can be estimated as a function of all flow settings and dialyzer/filter related parameters; Alternatively, a suitable sensor may be placed to measure the conductivity or concentration and thereby measure the conductivity or concentration accordingly, for example using one of the methods described in EP Patent No. 0547025 or EP Patent No. 0658352 or EP Patent No. 0920887, incorporated herein by reference. , one can calculate the actual clearance for a given solute (eg sodium). In a further alternative, the equations in paragraphs a) and b) above as described for urea clearance may be used with RT(K0.A) and SC _xxx adjusted to account for the specific solute 'xxx'.

In the course of the description below, reference will be made to the dose definitions above in relation to doses not normalized to patient weight (BW) or patient surface area (BSA). Of course, the same principles and formulas described below can be normalized for body weight or patient surface area by dividing the dose value by body weight (BW) or surface area (BSA). Examples at the end of the description include normalized CRRT doses and patient weights.

Also, when a fluid replacement line is present upstream of the treatment unit, such as lines 51 and 67 in the attached figures, the above defined capacity can be corrected to account for pre-dilution effects. Each dose defined above can be corrected by multiplying the dose value by the dilution factor (F _dilution ):

Dose _{corr_xxx} = F _dilution D _xxx (xxx = eff, conv, dial, etc.);

The dilution factor (F _dilution ) can be defined according to one of the following:

(식 13)Blood dilution factor:

(Equation 13)

(식 14)Plasma dilution factor:

(Equation 14)

(식 15)Plasma number dilution factor:

(Equation 15)

(식 15')Blood water dilution factor:

(Equation 15')

Here, in the above equation, if Q _cit and / or Q _PBP and / or Q _rep.pre and / or Q _syr do not exist or can be ignored, the corresponding terms can be canceled (or set to 0). In the entire application, whenever a term in a formula is negligible (generally this applies to syringe flow rate, but not exclusively, but not exclusively), that term is negligible, i.e. its value is considered zero. or the term is removed.

In practice, the effluent volume corrected for predilution effects is: Dose _{corr_eff} = F _dilution x D _eff .

The F _dilution factor should be selected according to the distribution of solutes and their ability to migrate across the erythrocyte membrane (eg: creatinine diffuses slowly through erythrocytes => plasma dilution factor).

For example, if we assume that the urea dose (D _urea ) is more or less equal to the effluent flow rate, the correction factor to be considered for predilution should refer to whole blood, since urea is distributed in whole blood and can move rapidly through the red blood cell membrane. do. thus:

(Equation 16)

More sophisticated equations can provide a more accurate estimate of urea clearance (K _urea ) than Q _eff (as previously shown in equations 11 and 12), especially when operating with large flow rates or small filters (pediatric conditions).

Buffer load definition

Net buffer loading during extracorporeal therapy is defined as a combination of (one or more) of the following:

Bicarbonate resulting from the metabolism of citrate infused into the patient (J _{met_cit} ) and/or bicarbonate resulting from the metabolism of lactate injected into the patient (J _{met_lact} ) - more generally resulting from the metabolism of all bicarbonate precursors;

Bicarbonate balance from extracorporeal blood therapy (J _{HCO3_bal} ), which may match a net loss or net benefit to the patient;

· Where applicable, acid injection (J _H+ ), eg from the citric acid content of the anticoagulant solution.

From a mathematical point of view, the general definition of net buffer load is:

(식 17)

(Equation 17)

Typically, the net buffer load is positive if the extracorporeal blood therapy provides a net buffer/bicarbonate gain to the patient and negative if buffer loss.

From a physiological point of view, extracorporeal blood therapy is expected to provide a net buffer benefit to the patient to balance the metabolic production of protons (protein metabolism). However, net buffer loss may be desirable in scenarios in which the patient initiates therapy in the context of (severe) metabolic alkalosis.

Buffer balance parameters are derived from modeling one or more of the following:

the rate of citrate infusion to the patient (citrate load);

balance of bicarbonate and other buffers (e.g. lactate);

Assumptions on citrate metabolism (1 mole of citrate is metabolized to 3 moles of bicarbonate);

· Assumptions on patient systemic concentrations for citrate, bicarbonate and other buffers (either fixed values or may be calculated from other sub-models).

The established buffer balance target is not consistent with the current buffer balance of the CRRT running regimen (requiring specific knowledge of current patient levels for citrate and bicarbonate), and is not expected in steady state where patient bicarbonate is stabilized at eg 25 mM ( normalized) to the net buffer load.

Acid-base steady state is established slowly, and measurable changes usually appear after 24 hours; 2 days appears to be a reasonable minimum considering that the acid-base state is reaching a steady state with respect to CRRT.

In the framework of the buffer balance analysis introduced here, acid-base balance steady state is reached when:

- the patient's systemic citrate concentration is stabilized across all body compartments, leading to a constant citrate load and bicarbonate production;

- The patient's bicarbonate concentrations stabilized across all body compartments as a result of net buffer loading balancing the rate of metabolic proton production (G _H+ ).

citrate load

Citrate load is defined as the net infusion rate of citrate to the patient, which corresponds to the difference between the rate of citrate infusion from the anticoagulant circuit before the blood pump (J _{cit_PBP} ) and the rate of citrate removal into the dialysate (J _{cit_dial} ), i.e., the blood circuit are consistent with differences in citrate infusion and citrate loss via dialyser/dialysate.

From a mathematical point of view, the equations below relate to the calculation of the amount of citrate returned to the patient (citrate load) associated with an acid-base balancing regimen during RCA.

The definition of patient citrate load is as follows:

(식 18)

(Equation 18)

Calculation of citrate infusion can be expressed in two ways depending on the definition of citrate dose (D _cit ).

From a mathematical point of view, the definition of the citrate infusion rate is:

(식 19)

(Equation 19)

Citric acid and citrate forms are considered in the same way in this approach.

The rate of citrate removal into the dialysate is expressed from the definition of the filter clearance for citrate-calcium complex (K _cit ) and the citrate concentration (in plasma water) at the filter inlet.

From a mathematical point of view, the definition of citrate removal to the effluent is:

(식 20)

(Equation 20)

Citrate load (major strain)

In the hypotheses for modeling citrate mass transport in the extracorporeal blood circuit, citrate is distributed in plasma (not erythrocytes), CRRT filter citrate clearance is calculated based on the citrate concentration in plasma water for mass transport calculations, and patient's Non-zero steady-state citrate concentrations are considered for citrate metabolism and blood access, and the assumption that the patient's citrate clearance is proportional to body weight is included.

The definition of the plasma water flow rate at the filter inlet is:

(Equation 5)

Here (and in the following), it is assumed that there is no other pre-blood pump infusion line other than the (citrate) anticoagulant line 51, and that no heparin is used/infused since the RCA is provided (i.e., PBP replacement fluid and Syringe flow rate not taken into account - terms are included in parentheses for reasons explained).

The equation for calculating citrate clearance in CRRT using non-zero dialysis fluid and filtration flow rate (Equation 21) is:

(식 21)

(Equation 21)

It should be noted that the citrate mass transfer parameters used in the calculation of the above removal rates are known and are constant values depending on the dialyzer selected.

For example, the following table reports the values of some used Baxter Prismaflex sets.

A simpler formula can be used with less precision. For example, it can be assumed that K _cit is equal to the effluent flow rate (Q _eff ).

The plasma water citrate concentration at the filter inlet (Cpw _{cit_inlet} ) can be defined taking into account whether the patient's citrate concentration is increased.

A simple, rough estimate would take into account that patient citrate concentrations are maintained at negligible levels throughout therapy (see next paragraph), but a more accurate approach would be to estimate patient systemic citrate concentrations (K _{cit_met} ) through an estimate of patient citrate metabolic clearance ( It is necessary to estimate an increase in Cp _{cit_pat} ) (see below). Indeed, during RCA treatment, the citrate concentration upon blood access is never zero as some citrate accumulates in the patient. This accumulation (if neglected) should be taken into account to avoid a bias of about 10%. Knowledge of the rate of citrate metabolism in the liver and muscle of the patient (K _{cit_met} ) is required, which can vary widely and can significantly bias the final estimate. However, it may be appropriate to consider 'minimal' accumulation that occurs in patients with 'normal' citrate metabolism. In this regard, assuming (from the literature) a typical metabolic clearance value of (approximately) 700 ml/min, patient citrate concentrations at steady state are calculated. Although not described in the literature, it is assumed that the patient's citrate clearance is proportional to body weight.

The expression of the patient's systemic citrate concentration at steady state is as follows:

(식 22)

(Equation 22)

According to the above, an estimate of the patient's citrate metabolic clearance (ml/min) is as follows:

(식 23)

(Equation 23)

The expression of the citrate plasma number concentration at the filter inlet is:

(식 24)

(Equation 24)

The combination of Equation 18, Equation 20, Equation 22, and Equation 24 above eliminates the citrate concentration parameter and allows the patient citrate load to be expressed as a function of flow rate and clearance.

(Equation 25)

The above citrate loading mathematical relationship is based on the buffer loading parameters (depending on citrate loading): citrate capacity, blood flow, metabolic clearance and citrate clearance (depending on respective flow rate), as well as plasma flow rate and plasma water flow rate at the filtration unit inlet. Also used in the context of this application to relate to.

Citrate loading (simplified variant)

According to the main transformation described previously, an increase in the patient's systemic citrate concentration (Cp _{cit_pat} ) following citrate anticoagulation is taken into account and estimated through Eqs 22 and 23. This choice leads to Equation 25 reported above for citrate loading.

A simpler alternative to this formula is to ignore changes in the patient's systemic citrate concentration and take it as a constant, eg zero. Equations 22 and 23 are consequently not used according to this alternative. Assuming a patient systemic citrate concentration of zero (Cp _{cit_pat} =0), Eqs 24 and 25 are converted into the following Eqs 24' and 25':

(식 24')

(Equation 24')

(식 25')

(Equation 25')

Bicarbonate balance in the extracorporeal blood circuit

Bicarbonate balance is defined as the rate of net infusion or loss of bicarbonate in extracorporeal blood therapy; This is consistent with the difference between the rate of infusion from dialysis and/or any replacement fluid (J _{HCO3_inf} ) and the rate of removal of bicarbonate into the effluent (J _{HCO3_eff} l).

The definition of the bicarbonate balance rate is as follows:

(식 26)

(Equation 26)

The hypotheses for modeling bicarbonate mass transport in the extracorporeal blood circuit assume that bicarbonate is distributed in both plasma and red blood cells, and that the bicarbonate concentration (Cp _{HCO3_pat} 0) is fixed (e.g., 25 mM) upon blood access. included; Of course, different (fixed) values for bicarbonate concentration in blood access can be used.

Another assumption is that there is no bicarbonate in the citrate solution and no other pre-pump infusions containing bicarbonate are present (conversely, the bicarbonate content/concentration is in the bicarbonate balance, i.e., Q _cit C _{HCO3 cit} and/or Q _PBP C should be considered in _HCO3PBP ), CRRT filtration unit bicarbonate clearance equals urea clearance, and bicarbonate removal from dialysate is calculated according to an equation similar to citrate, including taking into account the bicarbonate concentration in plasma water for mass transfer calculations. .

Calculation of the bicarbonate injection rate is based on knowledge of the fluid composition (ie known bicarbonate concentration).

(Equation 27)

If bicarbonate is present in the calcium replacement infusion line 74 (not likely due to potential precipitation risk), then the term Q _ca · C _{HCO 3 ca} is added to Equation 27. The fluid composition (i.e., bicarbonate concentration and/or replacement fluid prescription) can be entered by a physician (on request of the dialysis machine) or read through a reader of the dialysis machine, for example by associating a product name with a bicarbonate content/concentration. .

The expression for bicarbonate removal into the dialysate is very similar to that for citrate removal; However, they differ in the fact that bicarbonate is present in the dialysis fluid, the mass transfer parameter K ₀ A has different values and a fixed value for the patient's systemic bicarbonate is considered. Clearly, when citrate is present in the dialysis fluid, the corresponding citrate load/balance can account for this dialysis fluid citrate concentration in the same way as shown below for bicarbonate in the corresponding equations for citrate.

The definition of bicarbonate removal into the dialysate is as follows:

(Equation 28)

Contrary to citrate, bicarbonate is readily transported between red blood cells and plasma; Thus, whole blood moisture is taken into account in the calculation of mass transfer into the dialysate. Also, the CRRT filter diffusion mass transfer coefficient of bicarbonate is considered equal to that of urea based on their respective molecular weights (61 vs. 60 g/mole). The constitution factor is considered to be 1.

A constant physiological value of bicarbonate is considered for blood access.

The definition of the blood water flow rate at the filter inlet is:

(Equation 7)

The equation for calculating bicarbonate clearance in CRRT using non-zero dialysis fluid and filtration rate is similar to that for citrate; However, for the reasons mentioned above, the mass transfer coefficients (SC and K ₀ A) are different, and the flow rate considered in the blood circuit is the whole blood water flow (Q bw ) and not the plasma water flow ( _Qpw ). Indeed, bicarbonate is distributed in both plasma and erythrocytes, and assuming that transport is unimpeded, consider total blood water flux for clearance estimation. The equation for calculating citrate clearance in CRRT using non-zero dialysis fluid and filtration rate (Equation 29) is:

(Equation 29)

It should be noted that the bicarbonate mass transfer parameters used in the calculation of the above removal rates are known and constant values depending on the dialyzer selected.

For example, the following table reports values for some used Baxter Prismaflex sets:

As an alternative to the complexity of the above equation (Equation 29), a reasonable approximation of the bicarbonate clearance in most circumstances is given by the equation below for a simplified estimate of the filter bicarbonate clearance:

(식 30)

(Equation 30)

The plasma water concentration at the filter inlet is derived from the set of equations 31 below, i.e.:

(Equation 31)

From the equations above, the expression for the concentration of bicarbonate plasma water at the filter inlet is:

(Equation 32)

Lactate balance in the extracorporeal blood circuit (optional)

Lactate balance is defined as the rate of net infusion or loss of lactate in extracorporeal blood therapy; This corresponds to the difference between the rate of infusion from the dialysate and/or replacement fluid (J _{lact_inf} ) and the rate of lactate removal into the dialysate (J _{lact_dial} ).

Lactate can be used as an alternative buffer to bicarbonate with the advantage of obtaining a more stable solution. Lactate-based dialysis fluids are well known in dialysis; This is used, for example, in the home dialysis version of NxStage's System One device. Lactate is also present in certain numbers of bicarbonate solutions in the form of lactic acid to control pH and solution stability. This is the case for the Baxter Hemosol/PrismaSol CRRT solution range with 3 mM lactate. Similar to citrate, lactate is rapidly metabolized to bicarbonate when infused into a patient, with a mole-per-mole conversion. Lactate can be modeled in much the same way as bicarbonate, assuming a patient's steady-state plasma lactate concentration is about 1.5 mM.

Lactate clearance can be assumed to be the same as urea clearance, even though the lactate molecular weight is about twice that of urea (112 vs. 60 g/mole). However, clearance estimation errors are minimized in CRRT situations where flow rate is the main limiting factor. Of course, more accurate estimates can be used, for example using the power dependence of _K0A on solute molecular weight (it is possible to derive _{K0A_lactate} from known _K0A from urea, creatinine, vitamin B12, inulin). meaning).

Hypotheses for modeling lactate mass transport in the extracorporeal blood circuit include the assumption that lactate is distributed in plasma and red blood cells, and that lactate clearance in the CRRT filtration unit is equal to urea clearance. In addition, it is assumed that the patient's steady-state plasma lactate concentration at the time of blood access is fixed at 1.5 mM; Obviously, other fixed values may be assumed and used. The balance of lactate substances in the extracorporeal blood circuit is calculated in a similar way to bicarbonate by considering the metabolism of a lactate load leading to one mole of bicarbonate per mole of lactate.

The mass transfer equation for lactate is: The definition of the lactate balance rate is as follows:

(식 33)

(Equation 33)

Calculation of the lactate injection rate is based on knowledge of fluid composition (i.e., known lactate concentration); Here, it is assumed that no bicarbonate concentrated solution is injected/lactate is not present in the bicarbonate concentrated solution (otherwise the Q _HCO3 ·C _lact.HCO3 term is considered); The same is true for infusion before the blood pump.

(Equation 34)

The fluid composition (ie, lactate concentration and/or replacement fluid regimen) may be entered by a physician or read, for example, via a reader in the dialysis machine.

The definition of lactate removal into the dialysate is as follows:

(Equation 35)

Lactate is readily transported between red blood cells and plasma; Thus, whole blood moisture is taken into account in the calculation of mass transfer into the dialysate. Also, the CRRT filter diffusion mass transfer coefficient of bicarbonate is taken to be the same as that of urea. The constitution factor is considered to be 1.

Since lactate clearance (K _lact ) is considered equal to bicarbonate clearance (K _HCO3 ), the control unit calculates it in the same way using the same equation given previously. The expression for lactate plasma water concentration at the filter inlet is:

(식 36)

(Equation 36)

Cyclic buffer load

Circular patient buffer load is defined in terms of the rate of citrate infusion to the patient (i.e., citrate load) and bicarbonate production. To achieve this goal, the hypotheses for citrate metabolism include the following assumptions: Metabolism of citrate load leads to 3 moles of bicarbonate per mole of citrate, and the net buffer load (NBL) is reduced by the acid injection rate, such as citric acid. can be reduced The expression for the rate of bicarbonate production from citrate metabolism (at steady state) is:

(식 37)

(Equation 37)

The expression for the rate of acid injection is:

(식 38)

(Equation 38)

The combination of Equations 17, Equations 37, and Equations 38 leads to an expression for net buffer loading as a function of citrate loading and bicarbonate balance:

(식 39)

(Equation 39)

that the expression of J _{citrate_load} is given in Equation 25 (or simplified Equation 25'), and the full expression of J _{HCO3_bal} is derived from Equations 26, 27, 28, Equation 29 (or simplified Equation 30) and Equation 32 pay attention to J _{citric_acid} is derived from Equation 38.

From a therapy point of view, the net buffer loading should be positive to neutralize the rate of proton (H+) production from metabolism (G _H+ ). The literature reports typical G _H+ values of about 1 mmol/day/kg or 0.04 mmol/h/kg. However, the generation of protons from metabolism is highly dependent on protein catabolism.

If lactate is considered (optional), the expression for the net buffer load as a function of citrate load, lactate balance and bicarbonate balance becomes:

(식 40)

(Equation 40)

In this case, in addition to the equations mentioned for J _{citrate_load} , J _{HCO3_bal} and J _{citric_acid} , the equations for J _{lact_bal} , i.e. Eqs 33, Equations 34, Equations 35, Equations 29 − Lactate clearance (K _lact ) corresponds to bicarbonate clearance (K _HCO3 -) (or the corresponding expression for lactate clearance, or simplification K _lact =Q _eff ) and Equation 36 are required.

Steady-state acid-base balance prescription

The device control unit is configured to receive a steady-state acid-base balance target, i.e., a steady-state acid-base balance prescription set value, prior to initiation of treatment. These additional prescription values affect the various flow rates determined by the control unit 12 . In practice, the definition of the steady-state acid-base balance target depends on almost all operational parameters (not just system configuration) and other prescription parameters.

As previously pointed out, the steady state acid-base balance regimen can be specified as one of the following:

A) Steady-state patient bicarbonate concentration (requires assumptions about nNBL, i.e., nNBL0), or

B) Normalized net buffer load or nNBL (requires assumptions on bicarbonate concentration, i.e., (Cp _{HCO3_pat} 0)).

In steady state, nNBL is expected to balance the rate of proton (H+) production from the patient's metabolism.

nNBL

The control unit 12 of the device for extracorporeal blood therapy allows the operator to enter a parameter (J _{buffer_load} /BW) representing the steady-state acid-base (or buffer) balance in the blood of a patient subject to CRRT blood therapy. . This parameter defines quantitative information about the intensity of therapy in terms of net patient buffer (bicarbonate) gain or loss. This parameter is high in complex cases of citrate anticoagulation and of particular interest, but is still relevant for any extracorporeal dialysis regimen (with or without systemic anticoagulation). More specifically, the control unit 12 receives the net buffer load at device setup (ie, before the CRRT treatment begins).

The definition of normalized net buffer load (nNBL) is as follows:

(식 41)

(Equation 41)

nNBL was chosen as an indicator parameter of the level of acid-base balance at steady state, expressed as the amount of buffer infused (mmol/h/kg) per unit of time and per kg of patient.

In this regard, it should be noted that J _{buffer_load} is linked to several different flow rates through the previously shown equations. In practice, J _{buffer_load} and consequently NBL or nNBL are expressed by Eq 17, Eq 26, Eq 27, Eq 28 (or a combination of Eq 26, Eq 27 and Eq 28 Eq 26'), Eq 29 (or Eq 30), Eq 32, It is defined based on Eq. 38; When lactate is present, the definition is additionally based on Eqs 29 (or 30), 33, 34, 35 and 36. All of these equations are functions of one or more other flow rates of the CRRT device configuration. Thus, imposing a set point for a steady state acid-base balance regimen creates a limit between the various fluid flow rates and consequently affects the operating flow rate of the device. Solving the aforementioned equations, the device control unit 12 is able to derive the corresponding flow rate of operating parameters consistent with the prescription (as will be apparent from the detailed description that follows).

In particular, a review of published clinical data on CRRT with RCA in steady-state showed good correlations of this nNBL parameter with both bicarbonate and base excess in steady-state patients. Thus, instead of using the (normalized) net buffer load as defined above, the buffer balance parameter can be expressed in steady state bicarbonate concentration, assuming a 'default' value for the normalized net buffer load (nNBL). can; Reference is made to the additional paragraphs in this regard.

In the previously described embodiment, nNBL matches the value of the buffer balance when the patient reaches the hypothesized bicarbonate level (eg, 25 mM) => nNBL ₂₅ . If nNBL ₂₅ matches the proton production rate (G), in this case steady state is reached and the patient will stabilize at the hypothesized HCO3 level (25 mM). Alternatively, if nNBL ₂₅ is greater than the proton generation rate, the patient's bicarbonate will increase to a Ceq equal to the nNBL _Ceq matching the (current) proton generation rate. If nNBL ₂₅ is less than G _H+ , then the patient's bicarbonate will stabilize at a value lower than the assumed level.

Although a parameter representative of the steady state acid-base (or buffer) balance in a patient's blood has been described as being normalized to the patient's weight, it is also possible to normalize the parameter to the patient's surface or other patient related variables. Of course, and even if this is not considered the best approach, the control unit 12 may receive the net buffer load (mmol/h) without any normalization.

Variant with Steady State HCO3 Indicator - Cp _{HCO3_pat}

Patient bicarbonate concentration (Cp _{HCO3_pat} ) can alternatively be taken as an indicator parameter of steady-state acid-base equilibrium if the (desired/targeted) nNBL level is chosen. In this scenario, the previous equations can be rearranged to express the patient steady-state bicarbonate concentration as a function of a predefined nNBL level (eg, nNBL0 = 0.1 mmol/h/kg). The citrate formulas, ie, formulas 18-25, formulas 24' and formulas 25' remain unchanged.

Otherwise, bicarbonate formulas require some rearrangement. More specifically, the expression for steady-state patient bicarbonate (rearrangement of Equation 31) is:

(Equation 42)

The expression of plasma water bicarbonate concentration at the filter inlet (rearrangement of Equation 28) is:

(Equation 43)

Combining Equations 42 and 43 gives the following equation for steady-state patient bicarbonate:

(Equation 42')

The expression for bicarbonate loss to the effluent (from Equations 17 and 26) is:

(Equation 44)

The relationship between selected/set nNBL0 and J _{buffer_load} is as follows:

(식 45)

(Equation 45)

Thus, Equation 44 can be expressed as:

(식 44')

(Equation 44')

J _{buffer_load} from Equation 45, J _H+ from Equation 38, Equation 37 and Equation 25 or J _{met_cit} from Equation 25' and J _{HCO3_inf} from Equation 27 are input into Equation 44; The latter is then combined with Equation 43 so that all terms of this combined expression are known. Cpw _{HCO3_inlet} is finally introduced into Equation 42 to derive the expression of the variable defining steady-state patient bicarbonate value, a parameter that must be set by the clinician that affects almost all fluid flow rates that must be set.

As should be clear, this solution uses an alternative parameter, i.e., the steady-state patient bicarbonate concentration relative to the normalized buffer loading parameter, which in turn is a parameter representing the steady-state acid-base balance in the blood of a patient undergoing CRRT blood therapy. provided, so that the medical staff can set an appropriate value and the control unit 12 can maintain an appropriate acid-base balance during CRRT treatment.

Therapy configuration parameters

The regimen configuration parameters are user settings that can be set in the system to configure the CRRT modalities according to local protocols and/or some customer preferences. Although it is possible to set therapy configuration parameters as needed, typically these user settings are set only once at a particular customer location and are thereafter used for all treated patients.

Other default regimen configuration parameters may result from system technology limitations and/or manufacturer choice. These limits are built into the system and cannot be selected by the user. Examples of such parameters are the flow operating range of a fluid circuit (e.g., calcium infusion of an RCA), or the necessary relationship between certain flow rates related to safety or technical considerations (e.g., maximum PBP or citrate flow rate versus blood flow rate). ).

Treatment configuration parameters

A treatment composition parameter is a variable specific to the patient to be treated and the composition of the prescribed fluid (which is also part of the medical prescription).

In particular, hematocrit can alternatively be measured directly by the device and monitored online.

A number of default treatment configuration parameters such as flow operating range and/or mass transfer coefficient(s) may be provided together from the filter type. These are not user selectable and are provided by the manufacturer. Of course, instead of providing the filter type to the device (either by reading the filtration unit code with a reader or by entering/selecting the filtration unit used on the user interface), the relevant parameter values could be entered manually. As will be seen from the following discussion, in the simplest approach where the clearance of small solutes is estimated equal to the effluent flow rate, identification of the filter is not required. This type of approach becomes imprecise in scenarios where dialysate and blood flow become similar, such as in pediatric applications or high-dose CRRT.

operating parameters

The operating parameters are functions of

- prescription parameters

- therapy configuration parameters

- CRRT monitor treatment parameters calculated by a supporting prescription algorithm (exemplified here below) as a function of treatment configuration parameters.

All operating parameters are flow rates. The list of operating parameters is specific to the anticoagulation method and CRRT system capability and configuration.

In certain embodiments, calcium infusion may not be directly controlled by the CRRT system during RCA, and infusion may be performed by a separate infusion pump. In such a situation, the calculated prescribed value must be input to the external ion balancing infusion pump 75, and the control unit 12 may not verify or ensure compliance with the assisted prescription. The same applies to anticoagulant infusion during systemic anticoagulation (usually a syringe bolus infusion).

The CRRT system can have a variable number of pumps that can be used for fluid injection at different locations along the extracorporeal blood circuit. Reference is made to the examples of FIGS. 2-6 with different numbers of infusion lines and/or pumps.

The following table identifies operating parameters (associated with each pump) to be considered in the examples. This list shows up to 7 pumps (including blood pumps), but systems with more pumps and infusion lines are also contemplated.

PBP and citrate flow rates are both shown in the table, but are generally delivered by the same pump in alternative configurations. PBP flux is specific to regimens without citrate anticoagulants. Note that the embodiment of FIG. 6 provides two different pre-blood pump infusion lines: an anticoagulant (citrate) infusion line 51 and a separate PBP infusion line 52 .

Prescribing support with/without systemic anticoagulants

With regard to systemic anticoagulants, a concentrated anticoagulant solution is infused into the extracorporeal blood circuit. Although this regimen is clinically important, since the (heparin) infusion flow rate is very low, heparin infusion is not particularly relevant with respect to the CRRT regimen and flow calculation, and is typically 5 ml, which corresponds to approximately 0.1% of all fluid infusion rates. /h, it does not significantly affect the CRRT dose and the anticoagulant used does not disturb the acid-base equilibrium. Because of these characteristics, the anticoagulant regimen in systemic anticoagulants during RRT can be considered completely independent of the RRT regimen itself and is not covered in the next section, so both systemic anticoagulant and systemic anticoagulant regimens can be addressed simultaneously.

If systemic anticoagulants are not used or if systemic anticoagulants are used, the CRRT prescription can be drawn up from:

1. CRRT capacity;

2. The steady-state acid-base equilibrium target;

3. Patient Fluid Removal Rate (PFR);

4. Optionally, blood flow rate.

Anticoagulant regimens may also be listed in the case of systemic anticoagulation; However, it does not cause measurable interference with any of the other prescription parameters and can be CRRT processed independently.

In a system with three fluid infusion pumps and one outflow pump, four fluid flow rates are defined from the above three first prescription parameters. Thus, there is one degree of freedom to consider one additional setting from the regimen configuration in the definition of operational flow parameters. If one additional infusion pump is added, in this case two degrees of freedom are available and two additional settings can be selected so that the control unit can suggest corresponding flow rates matching the prescription and settings. With one infusion pump or less, the three first prescription parameters are sufficient to define the fluid flow rate for a regimen configuration.

Qualitative dependence of operating parameters

The following table provides an indication of the interdependencies between operating parameters and regimen parameters in the absence of systemic anticoagulation therapy or in the absence of systemic anticoagulation therapy; In particular, this dependence is conditional according to the definition/selection given to CRRT capacity.

X1: The contribution of flow rate to CRRT capacity depends on the definition given to it (see previous paragraph). Most relevant definitions use all flow rates (Q _eff or whatever simply refers to the estimated clearance).

X2: The contribution of blood velocity to CRRT dose also depends on the dose definition chosen. Blood flow is appropriate as soon as predilution effects are taken into account (not simply when effluent flow rate is referred to as CRRT capacity).

X3: All infusion fluids or dialysis fluids contribute to the acid-base balance depending on the fluid composition associated with each infusion solution. Blood flow affects the predilution and concentration of buffer solutes at the CRRT filter inlet.

X4: The patient fluid removal rate regimen is directly controlled by the definition of the effluent flow rate versus all other infusion rates of the dialysis system, including the anticoagulant flow rate if relevant.

X5: When blood flow is defined as one prescription parameter, there is a loss of one degree of freedom in the definition of operational flow rate, which means fewer restrictions from regimen configuration parameters can be used. The number of degrees of freedom is defined as the difference between the number of operating flow rates to be calculated minus the number of prescription parameters.

Control unit and supporting prescription algorithm

The control unit 12 is connected to various sensors, actuators for regulating flow rates through various lines (in the above examples these actuators include pumps operating on lines and switch valves) and a user interface. Control unit 12 may include a digital processor (CPU) and the necessary memory (or memories) such as memory 16, analog type circuitry, or a combination thereof. In the course of this description, a control unit is referred to as being “configured” or “programmed” to perform a particular step: this may in fact be accomplished by any means capable of configuring or programming the control unit. For example, in the case of a control unit that includes one or more CPUs, the program may be stored in an appropriate memory containing instructions that, when executed by the control unit, cause the control unit to execute the steps described herein. Alternatively, if the control unit is of an analog type, then the circuitry of the control unit may be designed to include circuitry configured to carry out the steps disclosed herein during use. The steps of method aspects are generally performed by a control unit unless otherwise indicated by the circumstances.

In the examples of FIGS. 1-6 , control unit 12 is configured to execute a flow rate setup procedure as described below. Starting from the example of Figure 2, five pumps must be set up, defining (or generating) a total of five flow rates; The flow rate must be received by the medical staff or calculated by the control unit 12 .

This flow rate setup procedure includes initially setting up (or accepting or maintaining) a regimen configuration. In practice, control unit 12 is configured to enable a user to select one or more regimen configurations. Available therapy configurations are illustratively disclosed in the previous paragraphs of this specification. The CRRT dialysis dose should be chosen among the described (or additional) possibilities. For example, the CRRT capacity can be selected as the effluent capacity (D _eff ); Alternatively, a urea dose (D _urea ) or any other dose type may be selected. The acid-base balance parameter is selected between, for example, (normalized) net buffer load (n)NBL or patient systemic bicarbonate plasma concentration. Blood flow rate can be determined as either a prescription parameter or an operating parameter. Finally, according to the number of degrees of freedom (i.e., the number of flow rates set by the control unit 12 minus the prescription parameter), as a further constraint, among the convective diffusion relationship, the blood predilution relationship, and the before-after relationship None may be selected, and one, two or more of them may be selected (see step 100 of FIG. 7).

After setting/accepting the regimen configuration, the necessary treatment configurations must be provided. Please refer to step 101 of FIG. 7 . In particular, patient specific values and device or disposable or solution specific values should be provided. In general, the patient's body weight (BW) (or equivalent in the case of CRRT dose - body surface area (BSA) according to parameter normalization) needs to be provided. This is required if any one of the patient prescriptions is normalized for patient weight according to the example at the end of this disclosure. Depending on the device configuration, hematocrit (Hct) is required. Where specific device configurations and mathematical relationships are required to calculate operational parameters, the concentration of the specific solute contained in the relevant bag must also be provided. In particular, all solutes that contribute to acid-base balance must be given concentrations and specific locations. For example, all bicarbonate solutions, and various bags of citrate and calcium concentrations are generally required; Other bicarbonate precursors such as lactate and acetate may also be required. Finally, filtration unit data such as the K0.A of one or more solutes may be required. As already pointed out, the data can be entered manually or acquired automatically, for example via a reader. For example, the device memory may include data associated with a product code (eg, solution bag code or filtration unit code). Of course, the device input system (graphical user interface) prompts for input of only the necessary values/parameters, or, alternatively, requests all data and then the control unit 12 uses the necessary ones exclusively.

After the above steps, the device is ready to receive prescription parameters whose values are entered by an operator (see step 102 of Fig. 7). Once obtained, the control unit 12 uses one or more of the previously mentioned mathematical relationships in conjunction with the entered treatment configuration data and prescription parameters to determine operational parameters configured for the various requested flow rates. In this regard, the control unit 12 uses the mathematical relationships linking the treatment configuration data, prescription parameters and operational parameters as a system of formulas that, once solved, provide all relevant flow rates to be suggested or set. At the end of step 103, control unit 12 stores the calculated operating parameters in memory 16 and provides the calculated values to the user interface for display to the user. In general, the control unit 12 waits for acceptance of the proposed values before driving the corresponding actuators (pumps) and achieving the calculated flow rate in the respective line. In another embodiment, control unit 12 automatically sets the pumps to achieve the flow rates in each line once flow rates become available.

A warning is provided to the user if the imposed conditions conflict, i.e. there is no solution for the flow system given the regimens and treatment configurations, imposed limitations and existing limitations and prescription parameters. Possibly, one or more solutions may be presented to the user via a user interface in terms of a suggested operating flow rate that approximates the imposed condition. For example, additional mathematical relationships (convection-diffusion relationships, blood predilution relationships, and pre-post relationships) are given lower priority over other key mathematical relationships linking input prescription parameters. In addition, rankings may be assigned to the convection-diffusion relationship, the blood pre-dilution relationship, and the before-after relationship. Alternatively, if blood flow rate is selected as the prescription parameter, blood flow, instead of being received, is moved to an operating parameter and its value is calculated. In other words, the control unit 12 may be configured to manage conflicting situations with different intervention protocols. Optionally, two or more sets of solutions for operating flow are provided for user selection.

Moving to the example of Figure 2, only the PBP infusion line and the post-dilution infusion line are used as replacement fluids. There are five flow rates to be set, namely blood flow rate (Q _b ), dialysis fluid flow rate (Q _dial ), PBP flow rate (Q _PBP ), postdilution flow rate (Q _rep.post ) and effluent flow rate (Q _eff ). am. As pointed out above, once the therapy configuration is received, the treatment configuration must be provided. Assuming that the effluent volume is chosen from the available volume types (meaning that blood predilution does not affect the CRRT dialysis volume) and that the filtration unit clearance for small solutes can be taken sufficiently equal to the effluent flow rate, the filter No data required. Body weight, hematocrit and bicarbonate concentration must be entered into memory through the user interface. The control unit then receives the prescribed volume value (D _set ), the prescribed value for the rate of fluid removal from the patient (Q _pfr ), the steady-state acid-base balance parameter target, and the setting for the blood flow rate (Q _b ). wait to do so (see step 102 of FIG. 7).

A memory 16 associated with or coupled to the control unit 12 stores a plurality of mathematical relationships that correlate fluid flow rates Q _PBP , Q _rep.post , Q _eff , Q _b , Q _PFR and Q _dial . Since 4 prescription parameters and 5 flow rates have to be set, additional restrictions can be selected. In this regard, there is an additional mathematical relation stored in the memory, which may be:

- a convection-diffusion relationship relating the total fluid flow rate through the infusion line + patient fluid removal rate (Q _PBP + Q _rep.post + Q _PFR ) to the fluid flow rate through the dialysis fluid line (Q _dial ); The convection-diffusion relationship may in fact define a first ratio R ₁ = (Q _PBP + Q _rep.post + Q _PFR )/(Q _dial );

- a blood pre-dilution relationship relating the flow rate of blood or plasma (Q _b or Q _p ) to the flow rate of the fluid injected into the blood withdrawal line via the pre-dilution infusion line 52 (Q _PBP ); The blood predilution relationship may define a second ratio R ₂ =Q _b /(Q _PBP ) or R ₂ =Q _p /(Q _PBP );

- a before-after relationship relating the fluid flow rate through the pre-dilution injection line (Q _PBP ) to the fluid flow rate through the post-dilution injection line (Q _rep.post ); The before-after relationship can actually define a third ratio R ₃ = (Q _PBP )/(Q _rep.post ).

The control unit 12 may allow the user to select one of the above relationships, for example via the user interface 12, and then to the set value of the dose (D _set ), the steady state acid-base balance. Target values for , the set blood flow rate (Q _b ), and the operator-entered set values of the fluid removal rate (Q _pfr ), the previously discussed mathematical relationships linking the steady-state acid-base balance parameters to the various flow rates, and to the user The above additional mathematical relationship identified and selected by (and the fluid balance equation that must be satisfied to maintain fluid balance according to prescription: Q _PBP + Q _rep.post + Q _dial + Q _pfr = Q _eff ; FBE - fluid balance equation ), it is possible to calculate the set values of all flow rates (Q _PBP , Q _rep.post , Q _eff and Q _dial ) (step 103 of FIG. 7 ).

If a syringe pump is also present/considered for injecting an auxiliary fluid, eg heparin, into the blood draw line, then the above equation can be modified accordingly to take into account the syringe flow rate.

A preset value for each one of the first, second and third ratios (R ₁ , R ₂ , R ₃ ) may be pre-stored in a memory, or the control unit may use the user interface 12 for example. It should be noted that input by an operator of a set value or set range for each of the first, second and third ratios (R ₁ , R ₂ , R ₃ ) may be allowed.

In one alternative, the memory 16 of the device of FIG. 1 may (additionally) store a plurality of optimization criteria, which the control unit 12 may use to determine the ratio (R ₁ , R ₂ , R ₃ ), or in combination with them, a setpoint for the relevant operating flow rate can be calculated.

For example, the optimization criterion stored in the memory 16 may determine that the emptying time of at least one of the containers of fresh fluid 14, 64, 10, 11 and/or the filling time of the waste container 62 is the value of fresh fluid. and a first optimization criterion that is substantially equal to, a multiple of, or proportional to the emptying time of one or more of the other containers. A second optimization criterion stored in memory 16 may impose such that fluid consumption through the fluid lines is minimized. A third optimization criterion stored in the memory 16 may be imposed such that the lifetime of the filtration unit 2 is maximized. A fourth optimization criterion stored in memory 16 may be imposed such that the urea clearance or dialisance of a given solute is maximized.

Indeed, if the optimization criterion is stored in the memory 16, the control unit 12 may be configured to allow the user, for example via the user interface 12, to select the criterion he wishes to satisfy (step ( 100)), to calculate the setpoint for the relevant operating flow rate based on the previously discussed mathematical relationship linking the steady-state acid-base balance parameters to the various flow rates and selected optimization criteria and the fluid balance equation (FBE) mentioned above. can be further configured.

If the selected mathematical relationship (and finally selected criterion) is compatible, then the set flow rate is calculated based on the selected mathematical relationship (and finally the optimization criterion). On the other hand, if the selected mathematical relationship (and/or selected criterion) conflicts, control unit 12 may be configured to execute one or more of the following sub-steps:

- notifying the user; The user then has the right to re-enter compatible choices;

- assigning a priority order to mathematical relationships (and/or selected criteria); The order of priority may be predetermined or adjusted by the user: in any case, the control unit is configured to disregard the criterion or mathematical relation as soon as the flow rate is calculated from the criterion/mathematical relation to which the priority is assigned;

- Defining a compromise between conflicting mathematical relationships and/or criteria using pre-established rules.

According to a variant, the control unit may use a flow rate setup procedure to initially calculate the flow rate setpoints through the various lines and control the actuators to adjust using the calculated setpoints during the first interval of treatment. . Then, after a period of time or when user input is detected, the control unit adjusts the flow rate through the various lines based entirely on one or more different prescription values and/or additional mathematical relationships that have been chosen differently (or values have been modified). A set value for may be recalculated, and the newly calculated set value is applied for a second period following the first period. For example, a flow rate setup procedure may allow setting the flow rate such that a specific delivery capacity is achieved. On the other hand, if at a certain point in time the user wants bag emptying synchronizing authority, he may choose to impose a first optimization criterion so that the control unit can recalculate the set value of the flow rate which allows synchronizing the emptying of the fluid bag as much as possible.

Figure 3 shows another configuration of a CRRT device in which a local anticoagulation protocol is used. In this second example, there are six flow rates to be set: Q _cit , Q _rep.post , Q _eff , Q _b , Q _ca and Q _dial . However, topical anticoagulants should provide citrate dose and calcium compensation parameters as patient prescription parameters. Accordingly, the CRRT device control unit 12 requires the medical staff to input CRRT dialysis dose, acid-base balance parameters, patient fluid removal rate, citrate dose and calcium compensation parameters. Once blood flow rate is chosen as the prescription parameter, there are no more degrees of freedom. Thus, when the physician enters the requested information, no additional equations can be selected. The control unit 12 calculates the operating parameters through an equation system of related mathematical relationships. Of course, based on different system configurations (i.e., additional post-injection of calcium) and different contents of bags used (e.g., citrate in bag 10), the relevant mathematical relationships used by control unit 12 are (here 2) as is evident from the detailed examples reported below in . Eq systems define some limitations primarily due to citrate injection and the need to maintain imposed acid-base parameter targets that can lead to systems with no solutions for flow rates. Again, one or more of the approaches defined above may be taken in this situation. Again, a detailed example makes this situation clear.

The configuration of Figure 4 provides an HDF configuration in which a pre-dilution line and a bicarbonate post-dilution line are used. Specifically, the postdilution line injects a replacement solution with a high bicarbonate concentration. This configuration allows more freedom in controlling the acid-base balance. Also in this configuration, the control unit 12 uses the relevant mathematical relationship based on the CRRT device design, the determined prescription parameter type/characteristic, the treatment configuration parameter, the imposed value for the prescription parameter, and the corresponding related mathematical relationship.

Figure 5 relates to another embodiment of a CRRT device: HDF configuration with a topical anticoagulant comprising a post-diluted replacement solution and a post-diluted bicarbonate solution, in addition to a calcium reinfusion line. There are seven flow rates to be set, and there are generally six prescription parameters: blood flow rate, acid-base balance target, CRRT dialysis volume, citrate volume and calcium reinfusion parameter values. Thus, once again, the user can additionally select one of the convective/diffusion split, the pre-dilution ratio and the pre-post implantation ratio. The configuration of FIG. 5 requires control unit 12 to utilize a number of mathematical relationships to properly account for the interactions of the various fluids, especially with respect to acid-base balance.

yes

In this section, several examples are provided to better explain the operation of CRRT devices.

Regarding CRRT with or without systemic anticoagulants, there appears to be limited potential for adjusting the steady-state acid-base balance equilibrium when using fluids with all similar bicarbonate contents. There are several possibilities when simultaneously using one fluid with a low bicarbonate content (eg less than 25 mM) and one fluid with a higher bicarbonate content (eg greater than 40 mM).

2 where four fluid pumps (dialysis fluid pump 25, effluent pump 26, PBP infusion pump 53, and postdilution infusion pump 65) are provided to implement HDF therapy. Please refer to the same device.

The following examples S1-S5 (where S stands for systemic anticoagulant or no anticoagulant) are based on the above circuit configuration and FIG. 2 .

Example S1

Since the effluent volume is chosen as the CRRT volume, blood predilution does not affect the volume and the equation is simpler to solve. In the context of this simplistic approach, the filter clearance of small solutes (such as bicarbonate) is also considered equal to the effluent flow rate; As a result, information about filter type/performance is not required.

In addition, steady-state bicarbonate is selected as an acid-base balance regimen parameter (when selecting steady-state bicarbonate, the device control unit assumes that nNBL0 is equal to 0.1 mmol/h/kg); Blood flow rate is also selected among prescription parameters (with reduced freedom of configuration). Five pumps are available and four prescription values are entered. Thus, the system has one degree of freedom, and one additional regime configuration constraint can be selected to obtain calculation of all operating flow parameters.

Among the regimen configurations, any of convective/diffusion splitting, pre-dilution ratio and pre-infusion/post-infusion ratio can be selected. Predefined (modifiable) values for these relationships are also included in memory and presented to the user.

In addition, the necessary treatment configuration values are also input by the operator or obtained by the control unit 12 .

Assume that the following prescription is entered by the user via the user interface 12:

- Patient: BW (weight) = 75 kg

- HCT (%) = 32

- CRRT dose D _eff = 28 ml/kg/h, where dose is 'effluent volume' per kg.

- steady-state bicarbonate target value: Cp _{HCO3_pat} = 25 mmol/l

- Patient fluid removal rate: Q _PFR = 120 ml/h

- blood flow: Q _b = 200 ml/min

A number of additional restrictions are stored in memory 16, in particular with respect to minimum/maximum flow rates; For example: dialysate flow rate (Q _dial ): 0 to 6000 ml/h and replacement flow rate (Q _rep.post ): 0 to 4000 ml/h.

The operator selects (or previously configured):

- Diffusion/convection split: 50-50, i.e. ratio: R ₁ = 1.0

The control unit 12 then calculates the operating parameters, namely the various flow rates, as follows:

especially:

The effluent flow rate is determined from the CRRT dialysis volume and body weight as: Q _eff = 28 x 75 = 2100 ml/h,

- Q _dial , Q _PBP , Q _rep.post and Q _eff are defined via the set of equations below and are explicitly indicated:

With the above two equations, the Q _dial can be directly calculated and set to 990 ml/h; Additionally Q _PBP + Q _rep.post is 990 ml/h.

In this case, Q _PBP is - arbitrarily - chosen as the remaining unknown parameter to be calculated in the following steps.

Q _fil is calculated based on Equation 8, which relates it to the PBP flow rate, the postdilution flow rate, and the patient fluid removal rate:

Then, the patient's _steady -state bicarbonate concentration (Cpw _{HCO3_pat} ) is determined by the following _mathematical relationship relating the various flow rates to produce additional fluid flow restriction: 30) (in the equations below, terms referring to missing fluid lines have been removed from the general formulas provided in equations 42 and 43):

All terms of the above two equations can be computed or expressed as a function of Q _PBP as indicated below.

Q _bw and Q _{bw_inlet} are determined using equations 6 and 7:

J _{HCO3_eff} is determined based on Equation 44:

J _{buffer_load} is determined based on equation 45 (assuming nNBL0 = 0.1):

J _{HCO3_inf} is determined based on Equation 27, see J _{HCO3_inf} (mmol/h) and Q _PBP (ml/h):

Using the expression for the bicarbonate ratio above, the following expression for the plasma water concentration of bicarbonate at the filter inlet can be derived:

Thus, the expression for steady-state patient plasma bicarbonate is:

One single solution to the above equation is positive, consistent with the expected PBP flow rate:

In this case, the flow rate after substitution is easily derived as:

Flow values are finally rounded up.

Example S2

Similar to the previous example S1, the effluent volume is chosen as the CRRT volume (blood predilution does not affect the volume), and the filter clearance of small solutes (such as bicarbonate) is also considered equal to the effluent flow rate.

Conversely, the normalized net buffer load (nNBL) is selected as an acid-base balance regimen (when nNBL, the device control unit assumes that Cp _{HCO3_pat} 0 is equal to 25 mM); The blood flow rate is also selected among prescription parameters (with reduced freedom of configuration). As in the previous example, 5 pumps are available and 4 prescription values are entered. Thus, the system has one degree of freedom and one additional regime configuration constraint can be selected to obtain calculation of all operating flow parameters.

Among the regimen configurations, any of convective/diffusion splitting, pre-dilution ratio and pre-infusion/post-infusion ratio can be selected. Predefined (modifiable) values for these relationships are also included in memory and presented to the user.

In addition, the necessary treatment configuration values are also input by the operator or obtained by the control unit 12 . Changed values are identified by a different background shade.

It should be noted that the acid-base balance regimen is converted to nNBL, and solutions with low or high bicarbonate concentrations are used to provide some potential for adjustment of the acid-base balance.

Assume that the following prescription is entered by the user via the user interface 12:

- Patient: BW (weight) = 75 kg

- HCT (%) = 32

- CRRT dose D _eff = 28 ml/kg/h, where dose is 'effluent volume' per kg.

- normalized net buffer load nNBL target value: nNBL = 0.15 mmol/h/kg

- Patient fluid removal rate: Q _PFR = 120 ml/h

- blood flow: Q _b = 200 ml/min

This time, the operator selects:

- a pre-injection/post-infusion ratio between 33% and 67%, i.e. the ratio: R ₂ = 0.5

The control unit 12 then calculates the operating parameters, namely the various flow rates, as follows:

especially:

The effluent flow rate is determined as follows: Q _eff = 28 x 75 = 2100 ml/h,

- Q _dial , Q _PBP , Q _rep.post and Q _eff are defined through the set of expressions below explicitly indicated:

Then, the normalized net buffer balance (nNBL) is defined in the following mathematical relations that relate the various flow rates to produce an additional fluid flow limit: Equation 41, Equation 26, Equation 27, Equation 28 (missing fluid line (terms related to ) have been removed from the relevant equations):

According to the assumption, K _HCO3 is approximated as the effluent flow rate (see Equation 30):

Q _fil is calculated based on Equation 8:

Cpw _{HCO3_inlet} is determined based on Equation 32, assuming that the patient's patient plasma bicarbonate concentration is imposed at 25 mM:

Q _bw and Q _{bw_inlet} are determined using equations 6 and 7:

Q _dial = 600 ml/h, Q _rep.post = 920 ml/h, followed by Q _PBP = 460 ml/h.

Example S3

Similar to the previous example S2, the effluent volume is chosen as the CRRT volume, the filter clearance of small solutes (such as bicarbonate) is considered equal to the effluent flow rate, and the normalized net buffer load (nNBL) is also the acid-base It is selected as a balanced regimen (for nNBL, the device control unit assumes that Cp _{HCO3_pat} is equal to 25 mM).

Conversely, the blood flow rate is removed from the prescription parameters (configurational freedom is increased). Now, 5 pumps are available, and 3 prescription values are entered. Thus, the system has two degrees of freedom, and two additional regime configuration constraints can be selected to obtain calculations of all operating flow parameters.

Among the regimen configurations, any of convective/diffusion splitting, pre-dilution ratio and pre-infusion/post-infusion ratio can be selected. Predefined (modifiable) values for these relationships are also included in memory and presented to the user.

In addition, the necessary treatment configuration values are also input by the operator or obtained by the control unit 12 . Changed values are identified by a different background shade.

It should be noted that the acid-base balance regimen is converted to nNBL, and solutions with low or high bicarbonate concentrations are used to provide some potential for adjustment of the acid-base balance.

Assume that the following prescription is entered by the user via the user interface 12:

- Patient: BW (weight) = 75 kg

- HCT (%) = 32

- CRRT dose D _eff = 28 ml/kg/h, where dose is 'effluent volume' per kg.

- normalized net buffer load (nNBL) target value: nNBL = 0.15 mmol/h/kg

- Patient fluid removal rate: Q _PFR = 120 ml/h

The operator chooses:

- Diffusion/convection split: 50-50, i.e. ratio: R ₁ = 1.0

- a pre-injection/post-injection ratio of 33 to 67, i.e. the ratio: R ₂ = 0.5

Since Q _b is an operating parameter to be calculated, the mathematical relationship of convective diffusion addition is added to the previous equation/mathematical relationship used for example in S2.

Control unit 12 then attempts to calculate operating parameters, ie various flow rates. The additional degree of freedom provided by the blood flow settings left to the control unit calculations allows for the selection of additional equations that impose pre-infusion/post-infusion ratios. The other equations used are the same as those used in the previous example S2; However, in this case, the expression system has no solution for the imposed setting.

*Q _b : 100 ml/min is assumed as minimum acceptable value

In examples S1 and S2, not only CRRT flow configuration constraints can be found, but also operational parameters that exactly match all prescription parameters. In example S3, using one additional degree of freedom (blood flow), it is not possible to simultaneously satisfy all prescription parameters for the two CRRT flow configuration constraints; In this case, the system must select one of the two flow configuration limits (possibly in predefined priority order) to provide an operating flow rate that meets all prescription parameters, but does not select the second limit.

In the same Example S3, considering only one of the two therapy flow configuration constraints, multiple solutions exist. The system may report the solution closest to the 'dropped' flow limit (in example S3, a parameter set with Q _b = 100 ml/min, where the convective diffusion split is 66% to 34% instead of 67% to 33%). ), or provide several options to the operator. In this example, in addition to the closest solution, an operating parameter with one larger blood flow rate (Q _b = 200 ml/min) is proposed.

***

The following examples S4 and S5 include the same system configuration as considered in the previous series of examples; Also, Examples S4 and S5 are identical to Examples S1 and S2 except for the selected definition of CRRT capability; In examples S4 and S5 below, the CRRT dose means urea clearance, so the predilution effect is taken into account.

In this context, a more complex formula is used to estimate the clearance of urea (CRRT dose - see Eq. 12) and bicarbonate (acid-base balance assay); The mass transfer characteristics (K0.A) of the filter must be known.

Yes S4

This example is the same as Example S1, but the CRRT capacity definition taken is different.

Using the above prescription data and selected limits, the control unit can suggest the following operating flow parameters to the user:

Yes S5

This example is the same as example S2, but the selected CRRT capacity definition is different.

Using the above prescription data and selected limits, the control unit can suggest the following operating flow parameters to the user:

The K0.A parameter specifies the diffusive mass transfer performance for either bicarbonate or urea, which is related to the type of CRRT filter in use and is assumed to be the same in these examples; This assumption relies on similar molecular weights for the two species (60 g/mole for urea and 61 g/mole for HCO ₃ ⁻ ).

As expected with the use of CRRT capacity incorporating the effect of predilution, higher effluent flow rates are calculated for Examples S4 and S5 when compared to Examples S1 and S2.

Prescribing support including citrate anticoagulants

As previously described with respect to citrate anticoagulants, the citrate solution is injected next to the patient's vascular access in the access line of the extracorporeal circuit, particularly upstream of the blood pump. At the same time, a calcium solution to re-establish the ionic content in the blood is injected directly into the patient or into the return line of the circuit to balance calcium (and possibly other ion) losses to the effluent.

The flow rates of the two infusions are related to the anticoagulant regimen (amount of citrate titrated to reach a constant level of ionized calcium in the extracorporeal blood circuit) and the CRRT dose regimen (for calcium loss), as well as the respective citrate and calcium It is also related to the concentration of the solution.

Even in the context of 'concentrated' solutions (e.g., 110-140 mM citrate, >500 mM calcium), the combined flux of citrate and calcium infusions make a measurable contribution to CRRT capacity (5-10% range).

In addition, some of the infused citrate is returned to the patient and metabolized to release calcium and produce bicarbonate, which affects the acid-base balance equilibrium.

Thus, in contrast to systemic anticoagulants, citrate anticoagulant regimens have complex interactions with both CRRT dose and acid-base balance management. These interactions introduce a significant level of complexity to the prescription of CRRT with citrate anticoagulants.

Prescription

When using citrate anticoagulants, a CRRT patient prescription may consist of the following clinical prescription parameters, all of which have clear implications for the clinician dealing with CRRT therapy.

1. CRRT capacity;

2. The steady-state acid-base equilibrium target;

3. Anticoagulant (citrate) dose,

4. ion (calcium) balancing,

5. Patient Fluid Removal Rate (PFR);

6. Optionally, blood flow rate.

In a system with 4 fluid pumps (dialysis + infusion pump) and 1 effluent pump, 5 fluid flow rates are defined from the above 5 primary prescription parameters. Thus, there are no degrees of freedom left, and no option to consider additional settings from the therapy configuration (unless blood flow is defined as an operating parameter).

Qualitative dependence of operating parameters

The following table provides the interdependencies between operating parameters and prescription parameters; Importantly, this dependence may be conditional on the definition given for CRRT capacity.

X1: The contribution of flow rate to CRRT capacity depends on the definition given to it (see previous paragraph). Most relevant definitions use all flow rates (Q _eff or whatever simply refers to the estimated clearance).

X2: The contribution of blood velocity to CRRT dose depends on the dose definition chosen. In the context of RCA, where citrate infusion is proportional to blood flow, blood flow rate will substantially prevent almost any representation of the CRRT dose used.

X3: All fluid infusions or dialysis fluids contribute to the acid-base balance according to the fluid composition associated with them. The effect of blood flux is more significant than without or with systemic anticoagulants because it defines, in addition to the predilution effect, the amount of citrate returned to the patient - and the associated bicarbonate production -. The contribution of calcium infusion is negligible when associated with very low infusion rates (< 20 ml/h).

X4: The patient fluid removal rate regimen is directly controlled by the definition of the effluent flow rate versus all other infusion rates of the dialysis system, including the anticoagulant flow rate if relevant.

X5: When blood flow is defined as a prescription parameter, there is a loss of one degree of freedom in the definition of operational flow rate, which means fewer restrictions from regimen configuration parameters can be used. In CRRT systems, which currently include most RCAs, there is no degree of freedom left when selecting blood flow as a prescription parameter and intending to prescribe acid-base balance equilibrium.

X6: In RCA, the citrate infusion rate is usually prescribed proportional to the blood flow, via the prescribed citrate dose factor. The resulting flow rate is usually infused prior to the blood pump and matches the PBP flow rate of the systemic anticoagulant.

X7: Calcium injection is defined in terms of the expected loss of effluent. This loss depends on the clearance of the citrate-calcium complex, and therefore on all operating flow rates, and also on the filter mass transfer characteristics. The basic system can assume a calcium loss proportional to the effluent flow rate.

yes

Although a simplified expression can be considered, the complexity of the interaction between the mass transport of citrate complex and bicarbonate in a CRRT filter justifies the use of a more accurate estimate of the filter clearance, which provides access to the mass transport properties of the filter in use. need In this context, all examples will include these parameters.

Examples will illustrate the use of 'concentrated' or 'diluted' citrate solutions, as commonly used in clinical practice.

In all of the following examples, the calcium concentrations of the citrate and dialysate solutions are assumed to be zero. The presence of calcium in the post-injection fluid will be considered in some instances.

All flow rates are rounded to the next 10, except where less than 100 ml/h.

The system configuration used throughout the following examples is similar to the system configuration considered in Examples S1-S5, but with the addition of one pump for calcium injection. Of course, the infusion line before the blood pump injects citrate, not the replacement solution as in the previous examples S1 to S5. The infusion line before the blood pump may be physically identical to that used in the previous examples (see Figure 1), but the notation 'cit' is used to identify the respective flow rate and vessel concentration of citrate, and different reference numbers are used. (See FIG. 3 vs. FIG. 2). The system for RCA includes 5 fluid pumps and a blood pump.

CRRT system definitions for Examples C1-C6 are shown in the following table.

The following examples C1 to C5 are based on the above circuit configuration and FIG. 3 .

Example with effluent volume as CRRT volume

In this first series of examples, the CRRT dose represents the effluent rate without correction for predilution.

In the successive examples in this section, the changed parameters are identified by color cells.

Example C1

A first reference example is built using the normalized net buffer load as an acid-base balance regimen, diluted citrate solution and blood flow rate as clinical regimen parameters.

The regimen composition is established according to the following table. Treatment configuration data is requested and entered according to Table 2 below as reported.

As indicated, the following clinical prescription parameters are entered by the medical staff:

The prescription parameters provide six limits, so there is no degree of freedom to further set up additional regimen configurations.

With the above device set up, the control unit determines the operating flow rate as follows (Q _b is indicated, but it is already a prescription parameter set to 130 ml/min).

In particular, the effluent flow rate (Q _eff ) is determined based on the CRRT dose and patient weight:

The anticoagulant flux (Q _cit ) is related to the blood flux by the citrate flux mathematical relationship (Equation 1):

Given the blood flow rate (Q _b ) and citrate dose (D _cit ) and knowing the citrate concentration, Q _cit is derived directly from the equation above.

Calcium flux is derived from the calcium flux mathematical relationship (Equation 2); Missing flow rates and zero equivalent or negligible terms have been removed from the general formula of this description:

As indicated in the previous examples, the effluent flow rate should follow the fluid balance (see Equation 10):

A final but more complex constraint is based on the normalized net buffer loading parameter target (nNBL) due to the interaction with all flow rates and buffer balancing effects from bicarbonate and bicarbonate precursors, i.e., citrate.

The net buffer load mathematical relationship links the parameters to citrate load and bicarbonate balance (Equations 40 and 41):

Citrate load is determined based on the citrate load mathematical relationship (Equation 25) that takes into account citrate metabolic clearance:

Citrate clearance (K _cit ) is derived from Equation 21 (with SC _cit =1):

where the plasma water flow rate at the filtration unit inlet (Qpw _inlet ) comes from Equation 5:

And the plasma water flux (Qpw) is calculated from Equation 4:

The ultrafiltration flow rate through the filtration unit 2 is (Equation 8):

Metabolic clearance for citrate is estimated by Equation 22:

Conversely, the second term of the net buffer load, i.e., the bicarbonate balance (J _{HCO3_bal} ), is derived for example from Equation 26':

Bicarbonate clearance is more accurately estimated through the bicarbonate clearance mathematical relationship (Equation 29); SC _HCO3 =1:

The blood moisture flow rate at the filtration unit inlet (Qbw _inlet ) is given in FIG. 7:

The blood water flow rate is derived from Equation 6:

Finally, the required plasma water bicarbonate concentration at the filter inlet (Cpw _{HCO3_inlet} ) in Equation 32 is:

Here, it is assumed that the bicarbonate concentration in the patient's plasma at steady state is fixed and constant (eg, 25 mM).

Using all of the above mathematical relationships, the control unit 12 determines all of the surgical prescription parameters.

Example C2

The second example uses the previous example C1 as a reference, and changes in flow rate required in addition to changes in citrate dose regimen that may be necessary to maintain blood circuit ionized calcium within recommended levels (eg, in the range of 0.25 to 0.35 mM). exemplify

The regimen composition is established according to the following table. Treatment configuration data is requested and entered according to Table 2 below as reported.

The prescription parameters provide six limits, so there is no degree of freedom to further set up additional regimen configurations.

With the above device set up, the control unit determines the operating flow rate as follows (Q _b is indicated, but this is a prescription parameter already set to 130 ml/min). As can be seen, all operational flow rates are strongly affected by the citrate dose change, except for the effluent flow rate.

Example C3

As a continuation of the previous two examples, Example C3 illustrates the changes required to further increase the citrate dose.

The regimen composition is established according to the following table. Treatment configuration data is requested and entered according to Table 2 below as reported.

The prescription parameters provide six limits, so there is no degree of freedom to further set up additional regimen configurations.

With the above device set up, the control unit attempts to determine the operating flow rate (in column 2, Q _b is indicated, but this is already a prescription parameter set to 130 ml/min). As can be seen, there is no solution to a dietary system that is compatible with prescriptions.

All operational flow rates are greatly affected by the citrate volume change, but, with the exception of the effluent flow rate, the desired target cannot be achieved. The third column provides a proposed solution by considering Q _b as an operating parameter (which may vary within prescribed limits).

Example C4

Example C4 is based on reference C1 in which the diluted citrate solution is replaced by a 'concentrated' solution; The calcium solution is also changed to a less concentrated solution.

The highlighted changes are those related to the C1 example.

The regimen composition is established according to the following table. Treatment configuration data is requested and entered according to Table 2 below as reported.

The prescription parameters provide six limits, so there is no degree of freedom to further set up additional regimen configurations.

With the above device set up, the control unit attempts to determine the operating flow rate (in column 2, Q _b is indicated, but this is already a prescription parameter set to 130 ml/min). As can be seen, there is no solution to a dietary system that is compatible with prescriptions.

All operational flow rates are greatly affected by the citrate volume change, but, with the exception of the effluent flow rate, the desired target cannot be achieved. The third column provides a proposed solution by considering Q _b as an operating parameter (which may vary within prescribed limits).

Examples C1 to C4 above illustrate the importance of blood flow rate during citrate anticoagulation for the definition of proper acid-base balance when the bicarbonate composition of the fluid is fixed.

Example using urea clearance dose as CRRT dose

Similar to the series of examples given with and without systemic anticoagulant, the following example is provided in the context of RCA, where the CRRT dose includes a factor for predilution when referring to eg urea clearance dose.

The same system configuration is the same as that used in Examples C1-C4 (see FIG. 3). The mathematical relationship used is essentially the same as that used for example C1, but the CRRT dialysis dose is determined using Equation 12.

Example C5

This example was prepared with reference to Example C1, replacing the effluent CRRT capacity with the urea clearance capacity (see related paragraph). Changes are highlighted with respect to Example C1.

The regimen composition is established according to the following table. Treatment configuration data is requested and entered according to Table 2 below as reported.

The prescription parameters provide six limits, so there is no degree of freedom to further set up additional regimen configurations.

With the above device set up, the control unit determines the operating flow rate as follows (Q _b is indicated, but this is a prescription parameter already set to 130 ml/min).

Example C6

Simulations similar to those performed between examples C2 and C1 are repeated here between examples C6 and C5.

Changes between Examples C6 and C5 are highlighted in the following table.

The regimen composition is established according to the following table. Treatment configuration data is requested and entered according to Table 2 below as reported.

The prescription parameters provide six limits, so there is no degree of freedom to further set up additional regimen configurations.

With the above device set up, the control unit determines the operating flow rate as follows (Q _b is indicated, but this is a prescription parameter already set to 130 ml/min).

Examples C5 and C6 show the main effect of blood predilution when using 'diluted' citrate solution and referring to CRRT dose incorporating the effect of predilution such as urea clearance dose. The effluent flow rate increased significantly between Examples C5-C6 and Examples C1-C2 (about 400-500 ml/h).

At the same time, these examples demonstrate the major adjustments in dialysate and post-replacement flow rates required to maintain the desired acid-base balance while increasing CRRT capacity.

Bicarbonate post-injection system configuration

This section provides support prescription examples in the context of a system in which concentrated bicarbonate solutions are infused after filters (through all fluids including dialysate) and contribute to a major portion of all bicarbonate infusion through CRRT therapy. Ideally, this major fraction is greater than 50% and may reach 100%; In the latter case, this means that all fluids are bicarbonate-free, except for the concentrated bicarbonate injection.

The purpose of the system configuration is to separate the acid-base balance regimen as much as possible from the CRRT dose and/or citrate dose regimen, giving more freedom to independently alter these parameters.

All examples provided in this section are built using CRRT capacity based on urea clearance, thus taking into account the effect of predilution.

Cases with or without systemic anticoagulant

The system configuration used throughout the following examples is similar to the system configuration considered in Examples S1-S5 for the number of fluid pumps (n=4) and the presence of one injection circuit for pre-dilution and one for post-dilution; However, several changes are included as reported in the following table.

The CRRT system definitions referred to in Examples BS1 to BS2 (BS indicates bicarbonate + systemic or no anticoagulation) are shown in the following table and are also shown in FIG. 4 .

Yes BS1

This example is similar to example S5, but the composition of the fluid and regimen configuration parameters are different.

The regimen composition is established according to the following table. Treatment configuration data is requested and entered according to Table 2 below as reported.

Since one degree of freedom is possible, one additional constraint can be chosen, in this example the convective-diffusion split (or ratio) is selected and set to 50%-50% or R ₁ =1.

Given the above clinical prescription parameters and further user selection of regimen configurations, the control unit 12 determines the following operating parameters (Q _b being part of the prescription):

Yes BS2

This example is similar to the previous one, and targets a much higher net buffer load. Changes from the previous example BS1 are highlighted with a cell with a background.

The regimen composition is established according to the following table. Treatment configuration data is requested and entered according to Table 2 below as reported.

The clinical prescription parameters are the same as in the previous example BS1, but the nNBL was changed from 0.15 to 0.25 with a noticeably higher value.

The calculated flow rates for the remaining operating parameters are (Q _b is still part of the prescription):

In the context of a system with only bicarbonate infusion as postinfusion, it is not relevant/possible to include a regimen parameter such as preinfusion ratio, since the postinfusion rate is determined by the acid-base balance regimen. That is, selecting a pre-postinjection ratio prevents the control unit from returning a solution to the equation system. Thus, the choice of convection/diffusion ratio appears to be an exclusively rational choice among the regimen's additional constraints.

A comparison of Example BS1 and Example BS2 illustrates the strong and direct dependence of the acid-base balance equilibrium on the bicarbonate post-injection rate, in a configuration where more than 80% of the total bicarbonate injection comes from a single source.

In particular, the 'high' nNBL level regimen of Example BS2, unless extremely high CRRT regimen dialysis doses (e.g., approximately 50 ml/kg/h) are used, are not sufficient for the existing systems and bicarbonate fluid configurations of Examples S4-S5. cannot be provided in

Examples of citrate anticoagulants

The concept of bicarbonate infusion is further elaborated in the context of citrate anticoagulants (RCAs).

The selected system configuration is similar to that of Examples C1-C6 with the addition of a bicarbonate post-infusion pump. Thus, this system includes six fluid pumps and one blood pump (see example in FIG. 5 ).

The CRRT system definitions for Examples BC1-BC3 (BC stands for bicarbonate + citrate anticoagulant) are shown in the following table:

Refer to FIG. 5 for reference to the circuit configuration used.

Yes BC1

This example is similar to the previous example C5, but with the addition of bicarbonate postinfusion and the use of unbuffered dialysate.

The regimen composition is established according to the following table. Treatment configuration data is requested and entered according to Table 2 below as reported.

As indicated below, Q _b is still a prescription parameter in addition to the prescribed dialysis volume to be delivered (D _set - urea clearance), normalized net buffer load, patient fluid removal rate (Q _PFR ) and RCA prescription:

One degree of freedom remains based on the six prescription parameters and the seven flow rates to be determined. However, the selected convection-diffusion split is unattainable given the system configuration and clinical regimen parameters:

The control unit 12 provides a solution related to the flow rate for the operating parameters closest to the selected convective diffusion ratio. In this case, the convective diffusion ratio is 57% to 43% (R ₁ =1,33). As an alternative, _Qb is moved from a prescription parameter to an operating parameter, and the convective diffusion ratio is maintained at 50%-50% as originally set. The resulting blood flow rate is reduced to 100 ml/min.

Yes BC2

Example BC2 is similar to BC1 where the citrate solution is changed to a higher concentration. Changes from BC1 are highlighted.

The regimen composition is established according to the following table. Treatment configuration data is requested and entered according to Table 2 below as reported.

Clinical regimen parameters are unchanged for Example BC1:

Depending on the change (increase) of the anticoagulant bag concentration to citrate, the control unit 12 finds a solution to the operating flow rate without the need to change the set blood flow rate and/or without the need to change the convection/diffusion split:

Yes BC3

BC3 shows the change in flow rate when changing the citrate dose regimen given in example BC2.

Changes from BC2 are highlighted.

The regimen composition is established according to the following table. Treatment configuration data is requested and entered according to Table 2 below as reported.

As shown below, the citrate dose is raised from 3.1 to 3.5 mmol/L:

The calculated operational parameters are as follows (blood flow rate is a prescription parameter):

The addition of a bicarbonate post-infusion pump adds one degree of freedom and allows one regimen configuration restriction to be considered in example BC1 (compared to example C5). However, using a 'diluted' citrate solution drives significant convective flow, making it difficult to achieve HDF formulations with equal convective and diffusive flow rates.

Example BC2 documents the benefit of a more concentrated citrate solution when targeting a CRRT regimen configuration that has a significant dialysis/diffusion contribution and further reduces the citrate solution flow rate (which contributes to convective fluid exchange).

Example BC3 shows that changes in citrate dose (for the purpose of adjusting anticoagulant strength) can be easily balanced through adjustment of bicarbonate postinfusion rate to maintain the same acid-base equilibrium target.

Compatibility with other system features

There is a high degree of interaction between supporting prescription features and optional features and advanced CRRT systems.

Blood Flow Management: In a configuration where the system is equipped with a module that automatically optimizes the blood pump rate as a function of vascular access performance, the system must operate with defined blood flow as an operating parameter and not as a prescription parameter. However, the maximum blood flow value should be provided as an operator-settable limit. Under these conditions, the control unit should automatically recalculate the various flow settings whenever the blood flow rate is adjusted by the 'blood pump management' module.

TMP Monitoring/Convection: In configurations where the system is equipped with a module that automatically optimizes the convective flow rate as a function of TMP (or other pressure parameter), the assist prescription system, i.e. the control unit, monitors the various flow settings whenever the convective flow rate is adjusted. It should automatically recalculate.

Dose Control: A support prescription module provides calculation of flow settings, while the dose control system monitors 'immediate' CRRT dose requirements along with therapy to achieve full CRRT dose clinical goals over several days of treatment. The support prescription enhancements provided, including acid-base balance prescription parameters, allow the dose control system to be applied to citrate anticoagulation in a safe and practical manner.

mathematical relationship

In the following, the main mathematical relationships used by control unit 12 to link patient prescription parameters, treatment configuration parameters and operating parameters are reported. The mathematical relationship has already been described in detail in previous sections of this application. Upon receipt of the required and/or selected patient prescription parameters and treatment configuration parameters, the control unit 12 is configured to calculate a set flow rate of fluid in the lines for the operating parameters using the relevant mathematical equations.

Then, the control unit 12 can output the set and calculated flow rate to the user for approval, and after approval, can drive various actuators (pumps) to obtain the set and calculated flow rate in the relevant lines. . Alternatively, the control unit 12 may automatically set the actuator to achieve the set and calculated flow rate.

Equation 1 - Citrate flow rate mathematical relationship

Equation 2 - Calcium flux mathematical relationship

Equation 3 - Plasma flow rate mathematical relationship

Equation 4 - Mathematical Relation to Plasma Water Flow Rate

Equation 5 - Mathematical relationship of plasma water flow rate at the inlet of the filtration unit

Equation 6 - Blood Moisture Flow Rate Mathematical Relation

Equation 7 - Mathematical relationship of blood water flow rate at the inlet of the filtration unit

Equation 8 - Mathematical relationship of ultrafiltration flow rate

Equation 9 - Before-After Split

Equation 10 - Effluent flow rate mathematical relationship

Equation 11 - Urea clearance (pure diffusion mode)

Equation 12 - Urea clearance (diffusion and/or convective mode)

Equation 13/14/15/15' - Dilution factor

Equation 16 - Urea capacity (corrected for pre-dilution)

Equation 17 - Net buffer load mathematical relationship

Equation 18/19/20 - Citrate loading mathematical relationship

Equation 21/22/23/24/24' - Citrate clearance and inlet concentration mathematical relationship

Equation 25/25' - citrate load mathematical relationship

Equation 26/26' - bicarbonate balance mathematical relationship

Equation 27 - Bicarbonate Injection Mathematical Relationship

Equation 28 - Bicarbonate Removal Mathematical Relationship

Equation 29/30 - Bicarbonate Clearance Mathematical Relationship

Equation 31 - Plasma Water Bicarbonate Concentration Equation

Equation 32 - Mathematical relationship of plasma water bicarbonate concentration at filter inlet

Equation 33/34/35/36 - mathematical relationship to lactate

Formula 37 - Patient Citrate Metabolic Clearance

EQUATION 38 - ACID INJECTION Equation

Equation 39/40/41 - Net Buffer Load Mathematical Relation

Equation 42/43/44/45/42'/44' - steady-state acid-base balance indicator mathematical relationship

Claims (25)

As a Continuous Renal Replacement Therapy (CRRT) device,
a filtration unit (2) having a primary chamber (3) and a secondary chamber (4) separated by a semipermeable membrane (5);
An extracorporeal blood circuit (17) having a blood withdrawal line (6) connected to the inlet of the primary chamber (3) and a blood return line (7) connected to the outlet of the primary chamber (3), wherein the extracorporeal blood circuit ( 17) is an extracorporeal blood circuit 17 configured to be connected to the patient's cardiovascular system;
a blood pump (21) configured to control the flow of blood through the extracorporeal blood circuit (17);
an effluent fluid line (13) connected to the outlet of the secondary chamber (4);
As one or more of the additional fluid lines,
A pre-dilution infusion line 29 having one end connected to the blood withdrawal line 6;
A post-dilution infusion line 63 having one end connected to the blood return line 7;
A post-diluted bicarbonate infusion line 23 having one end connected to the blood return line 7;
an ion balancing infusion line 74 having one end connected to the blood return line 7 or the patient catheter;
a dialysis liquid supply line (8) connected at one end to the inlet of the secondary chamber (4);
A pre-blood pump - PBP - infusion line 52 having one end connected to the blood withdrawal line in the region of the blood withdrawal line located upstream of the blood pump 21 in use;
In use, an anticoagulant infusion line 51 having one end connected to the blood withdrawal line in the region of the blood withdrawal line located upstream of the blood pump 21, and
A syringe fluid line (22) connected at one end to the blood withdrawal line.
At least one of the additional fluid lines selected from the group comprising;
an actuator for regulating the flow of fluid (24, 25, 26, 31, 53, 54, 65, 75) through the fluid line (23, 8, 13, 29, 52, 51, 63, 74);
memory 16 for storing one or more mathematical relationships; and
a control unit 12 coupled to the memory 16 and the actuator;
including,
The control unit is configured to execute a flow rate setup procedure, the flow rate setup procedure comprising:
- receiving a patient prescription comprising clinical prescription parameters, said receiving step comprising:
o Allowing input of a target value for a parameter (nNBL; Cp _{HCO3_pat} ) representing the steady state acid-base balance in the blood of a patient who needs CRRT blood treatment
A step comprising
- determining one or more operating parameters using the one or more mathematical relationships, wherein determining the operating parameters comprises:
Fluid flow rate (Q _cit ) through the anticoagulant infusion line 51,
Fluid flow rate through the PBP injection line 52 (Q _PBP );
Fluid flow rate (Q _rep.pre ) through the pre-dilution injection line 29 ,
Fluid flow rate (Q _rep.post ) through the post-dilution injection line 63,
Fluid flow rate (Q _HCO3 ) through the post-diluted bicarbonate injection line (23);
the fluid flow rate (Q _ca ) through the ion balancing implant line 74;
blood fluid flow rate (Q _b ) through the extracorporeal blood circuit (17);
Fluid flow rate through the syringe fluid line 22 (Q _syr ),
Fluid flow rate (Q _dial ) through the dialysis liquid supply line 8, and
Fluid flow rate through the effluent fluid line 13 (Q _eff )
Comprising the step of calculating the set value of one or more fluid flow rates selected from the group containing
including,
wherein the step of calculating the set value of one or more fluid flow rates is based on the target value for the parameter (nNBL; Cp _{HCO3_pat} ) representing at least a steady-state acid-base balance in blood. According to claim 1,
Receiving the patient prescription includes accepting input of a set value (D _set ) for the prescribed dialysis dose to be delivered, and determining one or more operating parameters comprises determining at least two operating parameters. wherein the step of determining the operating parameters comprises calculating set values of at least two fluid flow rates selected from the group, and calculating the set values of at least two fluid flow rates selected from at least the prescribed dialysis treatment based on the set value of capacity (D _set ) and the target value for the parameter (nNBL; Cp _{HCO3_pat} ) representing steady-state acid-base balance in blood. According to claim 2,
The step of calculating the set values of the at least two fluid flow rates includes at least the set values of the prescribed dialysis volume (D _set ) and the parameter (nNBL; Cp _{HCO3_pat} ) representing the steady-state acid-base balance in the blood. The step of calculating each set value of the at least two fluid flow rates based on all of the target values, the CRRT device. According to any one of claims 1 to 3,
The parameter (nNBL) representing the steady-state acid-base balance in the blood of a patient undergoing CRRT treatment is a parameter function of the expected patient's net buffer load (NBL) at steady state, wherein the net buffer load is , bicarbonate precursor metabolism such as citrate metabolism or lactate metabolism, bicarbonate balance of the extracorporeal blood circuit 17 and/or bicarbonate due to acid infusion of the extracorporeal blood circuit 17 such as bicarbonate infusion and/or citric acid infusion to the patient. is the sum of the productions,
In particular, the net buffer load is the normalized net buffer load (nNBL) load of a patient expected at steady state, in particular normalized to the patient's body weight (BW), and more particularly, the steady state acid in the blood of a patient undergoing CRRT treatment. - the parameter (nNBL) representing the base balance is the net buffer load (NBL) or the normalized net buffer load (nNBL),

, which is a CRRT device. According to any one of claims 1 to 4,
The parameter nNBL, representing the steady-state acid-base balance in the patient's blood, is
• an estimate of the amount per unit time of bicarbonate resulting from the metabolism of the bicarbonate precursors, particularly citrate (J _{met_cit} ) and/or lactate (J _{met_lact} ), injected into the patient;
• bicarbonate balance from the CRRT blood treatment to be delivered in amount per unit time (J _{HCO3_bal} );
· Lactate balance from the CRRT blood treatment to be delivered in amount per unit time (J _{lact_bal} );
Acid injection from citric acid contained in the fluid source in quantity per unit time (J _H+ )
CRRT device based on one or more, in particular four, of According to claim 5,
The parameter representing the steady-state acid-base balance in the patient's blood (nNBL) is the estimate of bicarbonate form precursor metabolism (J _{met_cit} ; J _lact ), the bicarbonate balance (J _{HCO3_bal} ), and the acid infusion (J _H+ ) is an algebraic sum of , in particular the acid infusion (J _H+ ) is the negative term giving the loss of patient buffer,
Specifically, the parameter (nNBL) representing the steady-state acid-base balance in the patient's blood is

is defined as,
Alternatively, if lactate balance is also considered, the parameter (nNBL) representing the steady-state acid-base balance in the patient's blood is:

Which is defined as, CRRT device. According to any one of claims 1 to 6,
wherein at least a plurality of the one or more mathematical relationships correlates the parameter (nNBL; Cp _{HCO3_pat} ) indicative of a steady-state acid-base balance in the blood of a patient subject to CRRT blood therapy with at least two fluid flow rates selected from the group. , CRRT devices. According to any one of claims 1 to 7,
The step of calculating the set value of the fluid flow rate Q _cit through the anticoagulant infusion line 51 is, in particular, the set value for the blood fluid flow rate Q _b through the extracorporeal blood circuit 17 The setting of the prescribed dialysis dose and/or the target value for at least the parameter (nNBL; Cp _{HCO3_pat} ) indicative of the steady-state acid-base balance in the blood, if determined by the control unit 12 as an operating parameter. Based on the value (D _set ),
In particular, the control unit 12 calculates the set value of the fluid flow rate Q _cit through the anticoagulant infusion line 51 using the mathematical relationship; and/or
Calculating the set value of the fluid flow rate (Q _PBP ) through the PBP infusion line (52) includes at least the target value for the parameter (nNBL; Cp _{HCO3_pat} ) representing the steady-state acid-base balance in blood and /or based on the set value (D _set ) of the prescribed dialysis dose, in particular the control unit ( 12 ) determines the rate of the fluid flow rate (Q _PBP ) through the PBP infusion line (52) using the mathematical relationship. calculate the set value; and/or
Calculating the set value of the fluid flow rate (Q _rep.pre ) through the pre-dilution infusion line ( 29 ) is based on the parameter (nNBL; Cp _{HCO3_pat} ) representing the steady-state acid-base balance in the blood at least. Based on the target value and/or the set value D _set of the prescribed dialysis dose, in particular the control unit 12 uses the mathematical relationship to determine the fluid flow rate through the pre-dilution infusion line 29 ( Calculate the set value of Q _rep.pre ); and/or
Calculating the set value of the fluid flow rate (Q _rep.post ) through the postdilution infusion line (63 ) is based on at least the above parameter (nNBL; Cp _{HCO3_pat} ) representing the steady-state acid-base balance in the blood. Based on the target value and/or the set value D _set of the prescribed dialysis dose, in particular, the control unit 12 uses the mathematical relationship to determine the fluid flow rate through the post-dilution infusion line 63 ( Calculate the set value of Q _rep.post ); and/or
Calculating the set value of the fluid flow rate (Q _HCO3 ) through the post-dilution bicarbonate infusion line (23) includes at least the target for the parameter (nNBL; Cp _{HCO3_pat} ) representative of the steady-state acid-base balance in the blood. value and/or the set value D _set of the prescribed dialysis dose, in particular the control unit 12 uses the mathematical relationship to determine the fluid flow rate through the post-diluted bicarbonate infusion line 23 ( Calculate the set value of Q _HCO3 ); and/or
Calculating the set value of the fluid flow rate (Q _ca ) through the ion balancing infusion line (74) is at least the target value for the parameter (nNBL; Cp _{HCO3_pat} ) representing the steady-state acid-base balance in the blood. and/or based on the set value (D _set ) of the prescribed dialysis dose, in particular the control unit (12) uses the mathematical relationship to determine the fluid flow rate (Q _ca ) through the ion balancing infusion line (74). ) calculates the set value of; and/or
Calculating the set value of the blood fluid flow rate (Q _b ) through the extracorporeal blood circuit (17) includes at least the target value for the parameter (nNBL; Cp _{HCO3_pat} ) representing the steady-state acid-base balance in the blood. and/or based on the set value (D _set ) of the prescribed dialysis dose; in particular, the control unit (12) uses the mathematical relationship to determine the fluid flow rate (Q _b ) through the extracorporeal blood circuit (17). Calculate the set value of ; and/or
Calculating the set value of the fluid flow rate (Q _dial ) through the dialysis liquid supply line (8) includes at least the target value for the parameter (nNBL; Cp _{HCO3_pat} ) representing the steady-state acid-base balance in the blood. and/or based on the set value (D _set ) of the prescribed dialysis dose, in particular, the control unit (12) uses the mathematical relationship to determine the fluid flow rate (Q _dial ) through the dialysis liquid supply line (8). ) calculates the set value of; and/or
Calculating the set value of the fluid flow rate (Q _eff ) through the effluent fluid line ( 13 ) includes at least the target value for the parameter (nNBL; Cp _{HCO3_pat} ) representing the steady-state acid-base balance in the blood. and/or based on the set value (D _set ) of the prescribed dialysis dose, in particular the control unit ( 12 ) determines the fluid flow rate (Q _eff ) through the effluent fluid line ( 13 ) using the mathematical relationship. ), which calculates the set value of the CRRT device. According to any one of claims 1 to 8,
The one or more mathematical relationships determine the parameter (nNBL; Cp _{HCO3_pat} ) representing the steady-state acid-base balance in blood,
o bicarbonate balance (J _{HCO3_bal} );
o In particular, bicarbonate produced from the metabolism of citrate (J met_cit ), or citrate load (J _{cit_load} ), where metabolism of citrate _load leads to 3 moles of bicarbonate per mole of citrate at steady state, i.e. J _{met_cit} = 3 J _{cit_load} ;
o In particular, the metabolism of lactate is bicarbonate resulting from the metabolism of lactate (J _{met_lact} ), or lactate balance (J _{lact_bal} ), which leads to 1 mole of bicarbonate per mole of lactate at steady state, i.e., J _{met_lact} = J _{lact_bal} ;
o Acid injection (J _H+ )
a net buffer load mathematical relation linking at least one, and in particular all, of the
Optionally the net buffer load mathematical relationship is

ego,
Here, the meaning of the symbol marks is given in the glossary, and if any of the mass transfer rates are missing, the corresponding mass transfer term is omitted from the mathematical relationship, or the corresponding value is set to zero. . According to any one of claims 1 to 9,
The one or more mathematical relations comprises a bicarbonate balance mathematical relation based on the bicarbonate balance (J _{HCO3_bal} ) from the CRRT blood treatment to be delivered in an amount per unit time, in particular the bicarbonate balance (J _{HCO3_bal} ) is based on the is the difference between the bicarbonate infusion rate from the dialysis liquid supply line 8 and/or the infusion line (J _{HCO3_inf} ) and the bicarbonate removal into the dialysate (J _{HCO3_eff} ), in particular the bicarbonate balance mathematical relationship

ego,
Here, the meaning of the symbol marks is given in the glossary, and if any of the mass transfer rates are missing, the corresponding mass transfer term is omitted from the mathematical relationship, or the corresponding value is set to zero,
Optionally, the bicarbonate infusion rate (J _{HCO3_inf} ) from the dialysis liquid supply line (8) is dependent on the fluid flow rate (Q _dial ) through the dialysis liquid supply line (8) and the dialysis fluid flowing in the dialysis liquid supply line (8). bicarbonate concentration in the fluid (C _HCO3dial ), in particular as a function of the fluid flow rate (Q _dial ) times the bicarbonate concentration (C _HCO3dial ); and/or
The bicarbonate injection rate from the injection line (J _{HCO3_inf} ) is a function of the fluid flow rate (Q _rep.pre ; Q _rep.post ; Q _cit ; Q _PBP ; Q _HCO3 ; Q _ca ) and the corresponding bicarbonate concentration (C _HCO3rep.pre ; C _HCO3rep.post ; _CHCO3cit ; _CHCO3PBP ; _CHCO3HCO3 ; _CHCO3ca ), in particular the fluid flow rate (Q _rep.pre ; Q _rep.post ; Q _cit ; Q _PBP ; Q _HCO3 ; Q _ca ) x the corresponding bicarbonate concentration (C _HCO3rep.pre ; C _HCO3rep.post ; C _HCO3cit ; C _HCO3PBP ; C _HCO3HCO3 ; C _HCO3ca ). According to claim 10,
The bicarbonate removal (J _{HCO3_eff} ) into spent dialysate in the effluent line (13) is associated with the fluid flow rate (Q _dial ) through the dialysis liquid supply line (8) and the flow in the dialysis liquid supply line (8). the bicarbonate concentration of the dialysis fluid (C _HCO3dial ), in particular as a function of the fluid flow rate (Q _dial ) times the bicarbonate concentration (C _HCO3dial ); and/or
The bicarbonate removal into the spent dialysate in the effluent line 13 (J _{HCO3_eff} ) is a function of the bicarbonate concentration of the dialysis fluid (C _HCO3dial ), in particular the bicarbonate plasma water concentration at the filter inlet (Cpw _{HCO3_inlet} ) and the is a function of the difference between bicarbonate concentrations (C _HCO3dial ) in the dialysis fluid; and/or
The bicarbonate removal (J _{HCO3_eff} ) from the effluent line (13) into the used dialysate is dependent on the ultrafiltration flow rate (Q _fil ) of the filtration unit (2) and the dialysis fluid flowing in the dialysis liquid supply line (8). bicarbonate concentration (C _HCO3dial ), in particular the ultrafiltration flow rate (Q _fil ) times a function of the bicarbonate concentration (C _HCO3dial ); and/or
The bicarbonate removal (J _{HCO3_eff} ) into the spent dialysate in the effluent line (13) is a function of the bicarbonate clearance (K _HCO3 ); and/or
The bicarbonate removal (J _{HCO3_eff} ) into the spent dialysate in the effluent line 13 is a function of the fluid flow rate (Q _eff ) through the effluent fluid line 13, in particular the bicarbonate clearance (K _HCO3 ) is estimated equal to the effluent fluid flow rate (Q _eff ); and/or
The bicarbonate removal (J _{HCO3_eff} ) into the spent dialysate in the effluent line (13) is a function _{of the bicarbonate clearance (K HCO3 )} , which is in particular via the dialysis liquid supply line (8). CRRT device, which is a function of one or more flow rates including one or more of the fluid flow rate (Q _dial ), the ultrafiltration rate (Q _fil ) of the filtration unit (2), and the blood water flow rate (Qbw _inlet ). According to any one of claims 1 to 11,
The one or more mathematical relationships include a bicarbonate balance mathematical relationship based on the bicarbonate balance (J _{HCO3_bal} ) from the CRRT blood treatment to be delivered in amount per unit time, in particular the bicarbonate balance mathematical relationship:

ego,
Here, the meaning of the symbol marks is given in the glossary, and if any of the infusion line or the dialysis liquid supply line is missing, the corresponding flow rate is dropped from the mathematical relationship, or the corresponding flow rate is set to zero. Phosphorus, a CRRT device. According to any one of claims 1 to 12,
The one or more mathematical relations comprises a citrate load mathematical relation based on a citrate load (J _{cit_load} ) for the patient in amount per unit time, in particular, the citrate load (J _{cit_load} ) is the anticoagulant infusion line (51 ) is the difference between the rate of citrate injection (J _{cit_PBP} ) and the rate of citrate removal into the effluent from the eluent line (13) (J _{cit_dial} ), in particular the citrate loading mathematical relationship

ego,
Here, the meaning of the symbol marks is given in the glossary, and if any of the mass transfer rates are missing, the corresponding mass transfer term is omitted from the mathematical relationship, or the corresponding value is set to zero. . According to any one of claims 1 to 13,
The citrate load (J _{cit_load} ) is alternatively a function of the citrate dose (D _cit ) and the blood flow (Q _b ), ie according to D _cit Q _b , or the citrate flow rate (Q _cit ) and the total citrate concentration (C _{cit_pbp} ), that is, a function according to Q _cit ·C _citPBP , a CRRT device. According to any one of claims 1 to 14,
Said one or more mathematical relationships relate citrate load (J _{cit_load} ) to citrate capacity (D _cit ) and/or blood flow rate (Q _b ) and/or citrate clearance (K _cit ) and/or at the inlet of said filtration unit (2). and a citrate load mathematical relationship linking it to the plasma water flow rate (Q _{pw_inlet} ), in particular the citrate load mathematical relationship:

or:

ego,
A CRRT device, wherein the meaning of the symbol marks is given in the glossary. According to any one of claims 1 to 15,
The control unit 12 is further configured to calculate the set values of the at least two fluid flow rates by applying the clinical prescription parameters to the mathematical relationship, wherein the clinical prescription parameters correspond to the fluid removal from the patient with respect to the mathematical relationship. A parameter representing the rate (Q _pfr ), the blood flow rate (Q _b ) in the extracorporeal blood circuit 17, the prescribed dialysis volume (D _set ) and the steady-state acid-base balance in the patient's blood (nNBL; Cp _{HCO3_pat} ) , a local anticoagulant dose (D _cit ) and an ion re-establishment solution parameter (CaComp; D _ca ). According to any one of claims 1 to 16,
wherein the parameter (Cp _{HCO3_pat} ) indicative of the steady-state bicarbonate concentration in the patient's blood is based on an estimated net buffer load (J _{buffer_load} /BW) indicative of the steady-state acid-base balance in the patient's blood. According to any one of claims 1 to 17,
The one or more mathematical relations include a steady state bicarbonate indicator mathematical relation, wherein the steady state bicarbonate indicator mathematical relation determines the parameter (Cp _{HCO3_pat} ) representing a steady state bicarbonate concentration in the blood of the patient. wherein the CRRT device is associated with said at least two flow rates of a group. According to any one of claims 1 to 18,
The one or more mathematical relationships include a steady-state bicarbonate indicator mathematical relationship, wherein the steady-state bicarbonate indicator mathematical relationship converts the parameter (Cp _{HCO3_pat} ) indicative of the steady-state bicarbonate concentration in the patient's blood to the pre-dilution infusion line (29). The fluid flow rate (Q _rep.pre ) through the dialysis liquid supply line (8), the fluid flow rate (Q _dial ) through the anticoagulant infusion line (51 ), the fluid flow rate (Q _cit ) through the PBP injection Connect one or more of the fluid flow rates (Q _PBP ) through line 52 , in particular the parameter (Cp _{HCO3_pat} ) to the fluid flow rates (Q _rep.pre ; Q _dial ; Q _{cit )} of the fluid flowing in each of the lines; Q _PBP ) x the corresponding bicarbonate concentration (C _HCO3rep.pre ; C _HCO3dial ; C _HCO3cit ; C _HCO3PBP ). According to any one of claims 1 to 19,
The one or more mathematical relationships include a steady-state bicarbonate indicator mathematical relationship, wherein the steady-state bicarbonate indicator mathematical relationship determines the parameter (Cp _{HCO3_pat} ) representing the steady-state bicarbonate concentration in the patient's blood;
• the blood flow rate (Q _b ), in particular the blood moisture flow rate (Q _bw ) and/or the blood moisture flow rate at the inlet of the filtration unit 2 (Q _{bw_inlet} ); and/or
• the bicarbonate concentration of the fluid flowing in the dialysis liquid supply line 8 (C _HCO3dial ) and/or the bicarbonate clearance of the filtration unit 2 (K _HCO3 ); and/or
• bicarbonate plasma water concentration at the filtration unit inlet (Cpw _{HCO3_inlet} ); and/or
• the ultrafiltration flow rate of the filtration unit 2 (Q _fil ), in particular the ultrafiltration flow rate (Q _fil ) x the bicarbonate concentration of the fluid flowing in the dialysis liquid supply line 8 (C _HCO3dial ); and/or
Removal of bicarbonate into spent dialysate flowing in the effluent line 13 (J _eff )
A CRRT device, which is to be connected with. The method of any one of claims 1 to 20,
wherein the one or more mathematical relationships include a steady state bicarbonate indicator mathematical relationship, wherein the steady state bicarbonate indicator mathematical relationship is:

Here, the meaning of the symbol marks is given in the glossary, and if any of the infusion line or the dialysis liquid supply line is missing, the corresponding flow rate is dropped from the mathematical relationship, or the corresponding flow rate is set to zero. Phosphorus, a CRRT device. As a continuous renal replacement therapy (CRRT) device,
a filtration unit (2) having a primary chamber (3) and a secondary chamber (4) separated by a semipermeable membrane (5);
An extracorporeal blood circuit (17) having a blood withdrawal line (6) connected to the inlet of the primary chamber (3) and a blood return line (7) connected to the outlet of the primary chamber (3), wherein the extracorporeal blood circuit ( 17) is an extracorporeal blood circuit 17 configured to be connected to the patient's cardiovascular system;
a blood pump (21) configured to control the flow of blood through the extracorporeal blood circuit (17);
an effluent fluid line (13) connected to the outlet of the secondary chamber (4);
As one or more of the additional fluid lines,
A pre-dilution infusion line 29 having one end connected to the blood withdrawal line 6;
A post-dilution infusion line 63 having one end connected to the blood return line 7;
A post-diluted bicarbonate infusion line 23 having one end connected to the blood return line 7;
an ion balancing infusion line 74 having one end connected to the blood return line 7 or the patient catheter;
A dialysis liquid supply line (8), one end of which is connected to the inlet of the secondary chamber (4);
A pre-blood pump - PBP - infusion line 52 connected at one end to the blood draw line in the region of the blood draw line located upstream of the blood pump 21 in use;
In use, an anticoagulant infusion line 51 having one end connected to the blood withdrawal line in the region of the blood withdrawal line located upstream of the blood pump 21, and
A syringe fluid line (22) connected at one end to the blood withdrawal line.
At least one of the additional fluid lines selected from the group comprising;
an actuator for regulating the flow of fluid (24, 25, 26, 31, 53, 54, 65, 75) through the fluid line (23, 8, 13, 29, 52, 51, 63, 74);
memory 16 for storing one or more mathematical relationships; and
a control unit 12 coupled to the memory 16 and the actuator;
including,
The control unit is configured to execute a flow rate setup procedure, the flow rate setup procedure comprising:
- receiving a patient prescription comprising clinical prescription parameters, said receiving step comprising:
o Allowing input of a target value for a parameter (nNBL; Cp _{HCO3_pat} ) representing the steady-state acid-base balance in the blood of a patient who needs CRRT blood treatment
A step comprising
- determining one or more operating parameters using the one or more mathematical relationships, wherein determining the operating parameters comprises:
Fluid flow rate (Q _cit ) through the anticoagulant infusion line 51,
Fluid flow rate through the PBP injection line 52 (Q _PBP );
Fluid flow rate (Q _rep.pre ) through the pre-dilution injection line 29 ,
Fluid flow rate (Q _rep.post ) through the post-dilution injection line 63,
Fluid flow rate (Q _HCO3 ) through the post-diluted bicarbonate injection line (23);
the fluid flow rate (Q _ca ) through the ion balancing implant line 74;
blood fluid flow rate (Q _b ) through the extracorporeal blood circuit (17);
Fluid flow rate through the syringe fluid line 22 (Q _syr ),
Fluid flow rate (Q _dial ) through the dialysis liquid supply line 8, and
Fluid flow rate through the effluent fluid line 13 (Q _eff )
Comprising the step of calculating the set value of one or more fluid flow rates selected from the group containing
including,
calculating said set value of one or more fluid flow rates is based on said target value for said parameter representing at least a steady-state acid-base balance in blood;
The parameter representing the steady-state acid-base balance in the blood of a patient undergoing CRRT treatment is a parameter function of the expected patient's net buffer load (NBL) at steady state, which is the bicarbonate precursor metabolism, the extracorporeal blood circuit The bicarbonate balance of (17) is the sum of bicarbonate production from bicarbonate infusion into the patient and acid infusion of the extracorporeal blood circuit (17). As a continuous renal replacement therapy (CRRT) device,
a filtration unit (2) having a primary chamber (3) and a secondary chamber (4) separated by a semipermeable membrane (5);
An extracorporeal blood circuit (17) having a blood withdrawal line (6) connected to the inlet of the primary chamber (3) and a blood return line (7) connected to the outlet of the primary chamber (3), wherein the extracorporeal blood circuit ( 17) is an extracorporeal blood circuit 17 configured to be connected to the patient's cardiovascular system;
a blood pump (21) configured to control the flow of blood through the extracorporeal blood circuit (17);
an effluent fluid line (13) connected to the outlet of the secondary chamber (4);
As one or more of the additional fluid lines,
A pre-dilution infusion line 29 having one end connected to the blood withdrawal line 6;
A post-dilution infusion line 63 having one end connected to the blood return line 7;
A post-diluted bicarbonate infusion line 23 having one end connected to the blood return line 7;
an ion balancing infusion line 74 having one end connected to the blood return line 7 or the patient catheter;
A dialysis liquid supply line (8), one end of which is connected to the inlet of the secondary chamber (4);
A pre-blood pump - PBP - infusion line 52 connected at one end to the blood draw line in the region of the blood draw line located upstream of the blood pump 21 in use;
In use, an anticoagulant infusion line 51 having one end connected to the blood withdrawal line in the region of the blood withdrawal line located upstream of the blood pump 21, and
A syringe fluid line (22) connected at one end to the blood withdrawal line.
At least one of the additional fluid lines selected from the group comprising;
an actuator for regulating the flow of fluid (24, 25, 26, 31, 53, 54, 65, 75) through the fluid line (23, 8, 13, 29, 52, 51, 63, 74);
memory 16 for storing one or more mathematical relationships; and
a control unit 12 coupled to the memory 16 and the actuator;
including,
The control unit is configured to execute a flow rate setup procedure, the flow rate setup procedure comprising:
- receiving a patient prescription comprising clinical prescription parameters, said receiving step comprising:
o Allowing input of a target value for a parameter (nNBL; Cp _{HCO3_pat} ) representing the steady-state acid-base balance in the blood of a patient who needs CRRT blood treatment
A step comprising
- determining one or more operating parameters using the one or more mathematical relationships, wherein determining the operating parameters comprises:
Fluid flow rate (Q _cit ) through the anticoagulant infusion line 51,
Fluid flow rate through the PBP injection line 52 (Q _PBP );
Fluid flow rate (Q _rep.pre ) through the pre-dilution injection line 29 ,
Fluid flow rate (Q _rep.post ) through the post-dilution injection line 63,
Fluid flow rate (Q _HCO3 ) through the post-diluted bicarbonate injection line (23);
the fluid flow rate (Q _ca ) through the ion balancing implant line 74;
blood fluid flow rate (Q _b ) through the extracorporeal blood circuit (17);
Fluid flow rate through the syringe fluid line 22 (Q _syr ),
Fluid flow rate (Q _dial ) through the dialysis liquid supply line 8, and
Fluid flow rate through the effluent fluid line 13 (Q _eff )
Comprising the step of calculating the set value of one or more fluid flow rates selected from the group containing
including,
calculating said set value of one or more fluid flow rates is based on said target value for said parameter (Cp _{HCO3_pat} ) representing at least a steady-state acid-base balance in blood;
Said parameter representing the steady-state bicarbonate concentration in the patient's blood (Cp _{HCO3_pat} ) is defined to impose a constant value on the normalized net buffer load (NBL) for the patient at steady-state, said constant value being, for example, NBL = nNBL0 BW = 0,1 mmol / h / kg, which is a CRRT device. According to claim 23,
The one or more mathematical relationships include a steady-state bicarbonate indicator mathematical relationship, wherein the steady-state bicarbonate indicator mathematical relationship sets the parameter (Cp _{HCO3_pat} ) indicative of the steady-state bicarbonate concentration in the patient's blood to the flow rate of the one or more fluids of the group. The CRRT device, which is to connect. According to claim 24,
The steady-state bicarbonate indicator mathematical relationship is based on the parameter (Cp _{HCO3_pat} ) representing the steady-state bicarbonate concentration in the patient's blood, the fluid flow rate (Q _rep.pre ) through the predilution infusion line 29, the dialysis fluid supply at least one of the fluid flow rate (Q _dial ) through line (8), the fluid flow rate (Q _cit ) through the anticoagulant infusion line (51 ), and the fluid flow rate (Q _PBP ) through the PBP infusion line (52). In particular, the fluid flow rate of the fluid flowing in each of the lines (Q _rep.pre ; Q _dial ; Q _cit ; _{Q PBP} ) x the corresponding bicarbonate concentration (C _HCO3rep.pre ; C _HCO3dial ; C _HCO3cit ; C _HCO3PBP ), the CRRT device.

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