APPARATUS FOR EXTRACORPOREAL BLOOD TREATMENT

TECHNICAL FIELD

The present invention relates to an apparatus for extracorporeal blood treatment and a method for controlling the extracorporeal blood treatment apparatus.

In particular, the invention may be used for regulating the conductivity of a dialysis liquid during a hemodialysis or hemodiafiltration treatment.

In more detail, the apparatus and the method are particularly adapted for properly regulating the concentration of sodium in the dialysis liquid, particularly to run an isotonic or an isonatremic or an isonatrikalemic dialysis treatment.

BACKGROUND OF THE INVENTION

The kidneys fulfil many functions, including the removal of water, the excretion of catabolites (or waste from the metabolism, for example urea and creatinine), the regulation of the concentration of the electrolytes in the blood (e.g. sodium, potassium, magnesium, calcium, bicarbonates, phosphates, chlorides) and the regulation of the acid/base equilibrium within the body, which is obtained in particular by the removal of weak acids and by the production of ammonium salts.

In individuals who have lost the use of their kidneys, since these excretion and regulation mechanisms no longer work, the body accumulates water and waste from the metabolism and exhibits an excess of electrolytes, as well as, in general, acidosis, the pH of the blood plasma shifting downwards, below 7.35 (the blood pH normally varies within narrow limits of between 7.35 and 7.45).

In order to overcome renal dysfunction, resort is conventionally made to a blood treatment involving extracorporeal circulation through an exchanger having a semipermeable membrane (dialyzer) in which the patient's blood is circulated on one side of the membrane and a dialysis liquid, comprising the main electrolytes of the blood in concentrations close to those in the blood of a healthy subject, is circulated on the other side.

Furthermore, a pressure difference is created between the two compartments of the dialyzer which are delimited by the semipermeable membrane, so that a fraction of the plasma fluid passes by ultrafiltration through the membrane into the compartment containing the dialysis liquid.

The blood treatment which takes place in a dialyzer as regards waste from the metabolism and electrolytes results from two mechanisms of molecular transport through the membrane.

On the one hand, the molecules migrate from the liquid where their concentration is higher to the liquid where their concentration is lower. This is diffusive transport.

On the other hand, certain catabolites and certain electrolytes are entrained by the plasma fluid which filters through the membrane under the effect of the pressure difference created between the two compartments of the exchanger. This is convective transport.

Three of the abovementioned functions of the kidney, namely the removal of water, the excretion of catabolites and the regulation of the electrolytic concentration of the blood, are therefore performed in a conventional blood treatment device by the combination of dialysis and blood filtration (this combination is referred to as hemodialysis).

As regards the regulation of the acid/base equilibrium inside the body, the approach adopted to overcome renal deficiency is to act on a mechanism by which the acid/base equilibrium inside the body is regulated, this mechanism consisting of the buffer systems of the blood, the main one of which comprises carbonic acid, as a weak acid, associated with its alkali salt, bicarbonate. This is why, in order to correct acidosis in a patient suffering from renal insufficiency, he is administered with bicarbonate via the vascular route, directly or indirectly, during a hemodialysis session.

Moreover, it must be underlined that sodium is the main ionic solute of extracellular volume. From literature search and according to the main opinion leaders in the dialysis field, the determination of dialysis fluid sodium concentration to be used during the dialysis treatment appears as one of the major challenges of dialysis prescription.

The dialysis fluid sodium concentration significantly affects the sodium balance and the intracellular hydration of the patient with implications on hemodialysis tolerance and also long term patient survival.

Hypertonic dialysis fluid sodium prescription will result in a positive sodium balance followed by a water shift from the intracellular to extracellular compartment. The intracellular dehydration increases vasopressin release and provokes thirst with the consequence of a greater inter-dialytic weight gain and hypertension.

On the contrary, a dialysis fluid sodium concentration that is too low (i.e., hypotonic) will provoke a negative sodium gradient with a water shift in the intracellular compartment, which is responsible for intra-dialytic cramps, headache, hypovolemia and risk of hypotension.

One of current opinions is the idea that sodium balance should be maintained null during a dialysis treatment: this is based on the so-called “sodium set point” theory, according to which both healthy subjects and dialysis patients tend to maintain a stable extra-cellular sodium concentration.

As above mentioned, sodium is removed during dialysis through convection and diffusion. The main sodium removal process during dialysis is convective. If we assume that the ultrafiltrate fluid is basically isotonic, convection does not change the tonicity of the extracellular fluid.

There is a need to help the physician to prescribe a “physiological” dialysis fluid composition to treat the patient.

Moreover, a second need is to have a bio-sensing-based therapy which is easy to use and designed also for operators not very skilled or working in crowded and very busy dialysis rooms.

To at least partly solve the above mentioned drawbacks, document U.S. Pat. No. 4,508,622 teaches a dialysis device in which the electrolyte composition of the untreated and treated fluids routed through the dialyzer may be determined and the composition of the dialysis solution adapted to the patient's requirements.

A first electrolyte detector (conductivity cell) is provided upstream of the dialyzer and a second electrolyte detector (conductivity cell) is provided downstream of the dialyzer. Each detector is coupled to a readout element through which both of the values of the dialysis solution may be observed and eventually controlled. In more detail, the apparatus according to U.S. Pat. No. 4,508,622 consists essentially of a unit for production of the dialysis solution and a dialyzer connected to the unit and followed downstream by a pump to produce a vacuum in the dialyzer on the side of the dialysis fluid. The detector mounted upstream of the dialyzer, and connected with a control unit, measures the conductivity of the total dialysis solution.

A second detector is mounted downstream of dialyzer and is connected with a comparator which is, in turn, connected to a differentiation unit. A control signal is provided by the differentiation unit to control unit if there is a difference in the differentiation unit that deviates from the predetermined nominal value.

During dialysis fluid circulation, if detector generates a signal to the evaluation unit and subsequently to the differentiation unit which deviates by a certain amount from the signal generated by detector, i.e., a difference in value appears which deviates from the predetermined value for differentiation unit, the difference unit activates the control unit, which in turn switches concentrate pump on or off as a function of the higher or lower concentration in the dialysis solution to be produced. A treatment in which the dialysis fluid has the same conductivity of the blood and of the spent dialysis fluid, is one of the described implementations.

However, the dialysis fluid and the blood reach the same conductivity after a certain time lapse which clearly affects the pre-dialytic plasma sodium content. Therefore, the method described in U.S. Pat. No. 4,508,622 in not properly an ‘isoconductive’ dialysis treatment.

In any case, ‘isoconductive’ dialysis has been shown to lead to undesired sodium loading in the patient.

Moreover, the prior art devices include dialysis apparatus wherein the conductivity of dialysis fluid is controlled in order to reach a desired post-dialysis plasmatic conductivity, i.e. conductivity (or sodium concentration) of the patient's blood at the end of the dialysis treatment.

It is known, for example from EP 1389475, a dialysis apparatus provided with a conductivity system that computes the dialysis fluid conductivity (corresponding to the dialysis fluid sodium concentration) from periodic measurements of the sodium blood concentration allowing the sodium level of the patient to reach a prescribed end-of-session value.

This dialysis apparatus includes a bag and a pump for infusing a patient with an infusion solution containing sodium at a determined and known concentration.

A structure for determining the sodium concentration [Na⁺]_dialof the dialysis liquid is also provided so that the patient's body tends towards a desired sodium concentration [Na⁺]_des, as a function of the dialysance D for sodium of the dialyser, of the desired sodium concentration [Na⁺]_desinside the patient's body, of the infusion flow rate and of the sodium concentration [Na⁺]_solof the infusion solution.

A control unit drives the pump for regulating the sodium concentration of the dialysis liquid such that this concentration is equal (tends towards) to the determined concentration [Na⁺]_dial.

As previously mentioned, one of the problems of the dialysis apparatus of the discussed prior art is presently the choice of the appropriate post-dialysis plasmatic conductivity target.

EP 2377563 discloses a dialysis apparatus comprising a blood treatment unit with an online preparation device for preparing a dialysis fluid containing sodium and comprising a dialysis preparation section for regulating the concentration of sodium in the dialysis fluid. The blood circuit is configured to circulate extracorporeal blood through the blood chamber; control means determines a value representative of the sodium concentration in the blood and are programmed for driving the dialysis preparation section as a function of the determined plasma sodium value, such that the substance concentration in the dialysis fluid tends towards the substance concentration in the blood.

The plasma sodium content is determined by measuring the inlet and outlet conductivities of the dialysis fluid upstream and downstream the dialyzer, by then changing the conductivity upstream the filter by a prefixed step and measuring a second time the inlet and outlet conductivities of the dialysis fluid upstream and downstream the dialyzer with the modified conductivity value.

With the methods described, for example in EP 547025 or in EP 920877, it is possible to determine the plasma conductivity and thereby to properly regulate the dialysis fluid preparation section.

The described system however changes the blood conductivity and tonicity since the dialysis fluid enters into contact and exchange significantly with blood before a plasma conductivity calculation; the effect on plasma conductivity is in an amount proportional to the difference between blood and dialysis fluid conductivities.

Finally, document U.S. Pat. No. 8,182,692 describes a dialysis apparatus providing a treatment in which a dialysis fluid having a sodium concentration substantially equal to the estimated current sodium concentration in the patient's blood is performed by placing the dialysis fluid in communication with the patient's blood across the semi-permeable membrane to perform a dialysis treatment on the patient's blood without substantially altering the sodium concentration of the patient's blood during the performance of the dialysis treatment.

In more detail, a solution supply device, containing a conductivity-testing solution, is selectively placed in communication with dialyzer and the blood flowing therein.

According to this patent, any subject, including hemodialysis patients, has a set level of sodium in his body, referred to as the “set point.” The set point of a subject tends to remain relatively constant, and sodium levels deviating too far from the set point may cause discomfort to the subject. Given the above, the method of the prior art includes causing blood to flow through blood conduit of the dialyzer and flowing the conductivity-testing solution in the opposite direction through the dialyzer.

Conductivity detectors measure the conductivity of conductivity-testing solution as the solution enters and exits dialyzer. Conductivity-testing solution is formulated such that electrically conductive solutes other than sodium in the patient's blood have little or no effect on the conductivity measurements of conductivity-testing solution.

According to U.S. Pat. No. 8,182,692, due to the closely matched concentrations of electrically conductive solutes, such as phosphate, sulfate, bicarbonate, potassium, calcium, and magnesium, in conductivity-testing solution and in the patient's blood, little diffusion of those electrically conductive solutes occurs across membrane. Consequently, the conductivity measurements of conductivity-testing solution is closely correlated with the level of sodium in the patient's blood.

Therefore, conductivity-testing solution is exclusively used to accurately determine the level of sodium in the patient's blood as a function of the change in conductivity across dialyzer of the conductivity-testing solution.

Control unit then determines the level of sodium in the patient's blood as a function of the measured conductivity values.

After determining the concentration of sodium in the patient's blood, dialysis fluid may be prepared to include a concentration of sodium that is substantially equal to the concentration of sodium determined to exist in the patient's blood.

Moreover, US2012/018379 discloses an apparatus and a method for the determination and regulation of the concentration of one dissolved substance (e.g. sodium) in a dialysis fluid circuit of a hemodialysis machine.

The user presets the sodium regulation range before the start of the dialysis using an estimated value for the dialysis fluid sodium required to achieve the isonatremic state or a lab measurement of the patient sodium or a value determined by the regulation from earlier treatments. In addition, the distribution volume of the patient is input for the application of the model for the correction of the diffusive balance. Furthermore, the initial concentrations of bicarbonate and potassium in the patient are set. They come from an analysis by means of a blood gas analyzer before the start of the dialysis treatment.

After the start of the treatment, the dialysis fluid flow and the conductivity are determined upstream and downstream of the dialyzer and a calculation of the updated current bicarbonate and potassium concentration in the patient takes place with it being assumed that the potassium clearance corresponds to the sodium clearance and that the bicarbonate clearance corresponds to 70% of the sodium clearance. The sodium clearance from the blood flow is estimated until the presence of the first clearance measurement.

The calculation of the conductivity balance and of the correction term for the ion exchange and thus for the sodium balance then takes place from these data.

The conductivity of fluids measured upstream and downstream, the sodium balance and the correction term for the dialysis fluid conductivity downstream of the dialyzer are then the input values for the sodium regulation. The desired conductivity thus determined is finally converted into a desired value for the dialysate sodium while taking account of the composition of the dialysis concentrate and this preset value is transmitted to a metering unit for dialysis fluid preparation.

SUMMARY

An aim of the present invention is providing an extracorporeal blood treatment apparatus able to automatically perform a proper setting of the dialysis fluid content of a substance, particularly an ionic substance, present in the blood as well.

In detail it is an aim of the present invention to provide an extracorporeal blood treatment apparatus with a proper tool helping the physician to prescribe a “physiological” dialysis fluid composition, particularly to run an isotonic, isonatremic or isonatrikalemic dialysis treatment.

A further aim of the invention is to make available an extracorporeal blood treatment apparatus provided with a selectable biosensing-based therapy which is easy to use and designed for not skilled operators or users working in crowded and busy dialysis rooms.

It is an aim of the invention to provide an extracorporeal blood treatment machine configured to automatically perform a proper automatic setting of the dialysis fluid conductivity.

A further aim of the invention is to make available a dialysis apparatus able to provide an automated delivery and control of the dialysis prescription, particularly in order to restore at each dialysis session the proper sodium-water equilibrium to the patient.

At least one of the above-indicated aims is attained by an apparatus and a corresponding method as in one or more of the appended claims, taken singly or in any combination.

According to a first independent aspect of the invention an extracorporeal blood treatment device is provided including

- a filtration unit (2) having a primary chamber (3) and a secondary chamber (4) separated by a semi-permeable membrane (5);
- a blood withdrawal line (6) connected to an inlet of the primary chamber (3),
- a blood return line (7) connected to an outlet of the primary chamber (3), said blood lines being configured for connection to a patient cardiovascular system;
- a dialysis supply line (8) connected to an inlet of the secondary chamber (4);
- a dialysis effluent line (13) connected to an outlet of the secondary chamber (4);
- a preparation device (9) for preparing a dialysis fluid connected to said dialysis supply line (8) and comprising regulating means (10) for regulating the composition of the dialysis fluid,
- a sensor (11) for measuring a parameter value of the dialysate in the dialysis effluent line (13), said parameter of the dialysate being at least one chosen in a group consisting of conductivity of the dialysate, a conductivity-related parameter of the dialysate, concentration of at least a substance in the dialysate and a concentration-related parameter of at least a substance in the dialysate;
- a control unit (12) connected to the sensor (11) for receiving said parameter value of the dialysate, said control unit (12) being also connected to the regulating means (10) and programmed for calculating a value representative of the plasma conductivity, wherein said control unit (12) is configured for:
  - setting a parameter value for the dialysis fluid in the dialysis supply line (8) at an initial set point, said parameter of the dialysis fluid being at least one chosen in a group consisting of conductivity of the dialysis fluid, a conductivity-related parameter of the dialysis fluid, concentration of at least a substance in the dialysis fluid and a concentration-related parameter of at least a substance in the dialysis fluid;
  - after setting the dialysis fluid parameter value at the initial set point, circulating the dialysis fluid through the secondary chamber (4) of the filtration unit (2) so as to exchange with blood;
  - circulating blood through the primary chamber (3) of the filtration unit (2);
  - measuring at least an initial value of said parameter of the dialysate downstream of said secondary chamber (4) at the beginning of the treatment,
  - calculating, based on the measured initial parameter value of the dialysate and on the corresponding parameter value of the dialysis fluid in the supply line (8), the value of the initial plasma conductivity, said circulating the dialysis fluid through the secondary chamber (4) up to measuring the initial value of said parameter of the dialysate downstream of said secondary chamber used for the calculating of the initial plasma conductivity being performed maintaining the dialysis fluid parameter value substantially constant.

According to a further independent aspect of the invention a method for setting the parameters in an apparatus for extracorporeal blood treatment is provided, the apparatus comprising:

- a filtration unit (2) having a primary chamber (3) and a secondary chamber (4) separated by a semi-permeable membrane (5);
- a blood withdrawal line (6) connected to an inlet of the primary chamber (3),
- a blood return line (7) connected to an outlet of the primary chamber (3), said blood lines being configured for connection to a patient cardiovascular system;
- a dialysis supply line (8) connected to an inlet of the secondary chamber (4);
- a dialysis effluent line (13) connected to an outlet of the secondary chamber (4);
- a preparation device (9) for preparing a dialysis fluid connected to said supply line (2) and comprising regulating means (10) for regulating the composition of the dialysis fluid,
- a sensor (11) for measuring a parameter value of the dialysate in the dialysis effluent line (13), said parameter of the dialysate being at least one chosen in a group consisting of conductivity of the dialysate, a conductivity-related parameter of the dialysate, concentration of at least a substance in the dialysate and a concentration-related parameter of at least a substance in the dialysate;
- a control unit (12) connected to the sensor (11) for receiving said parameter value of the dialysate, said control unit (12) being also connected to the regulating means (10) and programmed for calculating a value representative of the plasma conductivity of the blood in said blood lines (6, 7), the method comprising the following steps performed by the control unit:
  - setting a parameter value for the dialysis fluid in the dialysis supply line (8) at an initial set point, said parameter of the dialysis fluid being at least one chosen in a group consisting of conductivity of the dialysis fluid, a conductivity-related parameter of the dialysis fluid, concentration of at least a substance in the dialysis fluid and a concentration-related parameter of at least a substance in the dialysis fluid;
  - after setting the dialysis fluid parameter value at the initial set point, circulating the dialysis fluid through the secondary chamber (4) of the filtration unit (2) so as to exchange with blood;
  - circulating blood trough the primary chamber (3) of the filtration unit (2);
  - measuring at least an initial value of said parameter of the dialysate downstream of said secondary chamber (4) at the beginning of the treatment,
- calculating, based on the measured initial parameter value of the dialysate and on the corresponding parameter value of the dialysis fluid in the dialysis supply line (8), the value of the initial plasma conductivity, said circulating the dialysis fluid through the secondary chamber (4) up to measuring the initial value of said parameter of the dialysate downstream of said secondary chamber used for the calculating of the initial plasma conductivity being performed maintaining the dialysis fluid parameter value substantially constant.

In a second aspect, according to the previous aspects, the regulating means (10) modify the dialysis fluid composition by changing conductivity of the dialysis fluid and/or by changing the concentration of at least one substance in the dialysis fluid.

In a 3^rdaspect, according to the previous aspects, the preparation device (9) prepares a dialysis fluid containing at least a substance, said substance being present in the blood too, said regulating means (10) regulating the concentration of at least said substance in the dialysis fluid.

In a 4^thaspect according to the previous aspects, said substance is an ionic substance, in particular said substance being sodium.

In a 5^thaspect according to anyone of the previous aspects, the control unit is configured to set the parameter value for the dialysis fluid at the initial set point so that a dialysis fluid conductivity matches a first estimate of the plasma conductivity of the blood.

In a 6^thaspect according to anyone of the previous aspects, the parameter value is a concentration value of at least a substance of the dialysis fluid, in particular said substance being sodium.

In a 7^thaspect according to anyone of the previous aspects, the control unit (12) is configured for calculating the initial set point of a substance concentration in the dialysis fluid, a regulation of the dialysis fluid conductivity in the supply line (8) deriving from said calculated set point of said substance.

In an 8^thaspect according to the 7^thaspect, the control unit is configured to calculate the initial set point of the substance concentration to be set in the dialysis fluid as a function of the difference in concentration of at least a further substance in the dialysis fluid and the same further substance in the plasma, the substance, whose concentration is to be set, being different from the further substance.

In a 9^thaspect according to the 7^thor 8^thaspects, the control unit is configured to calculate the initial set point of the substance in the dialysis fluid as a function of the concentration of at least a further substance in the dialysis fluid, the substance, whose concentration is to be set, being different from the further substance, optionally the further substance being chosen in the group including bicarbonate, potassium, calcium, magnesium, acetate, lactate, citrate, phosphate and sulphate, in particular as a function of the concentration of at least two of said substances, optionally as a function of the concentration of bicarbonate, potassium, acetate, and/or citrate, in the dialysis fluid.

In a 10^thaspect according to anyone of the previous aspects from the 7^thto the 9^th, the control unit is configured to calculate the initial set point of the substance in the dialysis fluid as a function of the difference in concentration of at least a further substance in the dialysis fluid and in the plasma, the substance, whose concentration is to be set, being different from the further substance, said further substance being chosen in the group including bicarbonate, potassium, calcium, magnesium, acetate, lactate, phosphate, sulphate, and citrate, in particular as a function of the difference, in particular a weighted difference, in concentration of at least two of said substances, optionally as a function of the difference, in particular a weighted difference, in concentration of bicarbonate, potassium, citrate, and/or acetate in the dialysis fluid and plasma.

In an 11^thaspect according to anyone of the previous aspects from the 7^thto the 10^th, the control unit is configured to calculate the initial set point of the substance in the dialysis fluid as a function of the molar conductivities of at least a substance in the dialysis fluid chosen in the group including acids and salts of bicarbonate (HCO₃⁻), chloride (Cl⁻), acetate (CH₃COO⁻), lactate (C₃H₅O₃⁻), citrate, phosphate (PO₄³⁻), and sulphate (SO₄²⁻), wherein the salts are formed with sodium, potassium, calcium, or magnesium, in particular as a function of the molar conductivities of at least two of said substances, in more detail as a function of the molar conductivities of at least three of said substances, optionally as a function of the molar conductivities of the four of said substances, for example sodium bicarbonate (NaHCO₃), sodium chloride (NaCl), sodium acetate (NaCH₃COO), and potassium chloride (KCl), or sodium bicarbonate (NaHCO₃), sodium chloride (NaCl), trisodium citrate (Na₃C₆H₅O₇), and potassium chloride (KCl).

In a 12^thaspect according to anyone of the previous aspects from the 7^thto the 11^th, the control unit is configured to calculate the initial set point of the substance in the dialysis fluid as a function of an estimated plasma concentration of at least a substance chosen in the group including sodium, bicarbonate, potassium, acetate, and citrate, in particular as a function of the estimated plasma concentration of at least two of said substances, in more detail as a function of the estimated plasma concentration of at least three of said substances, optionally as a function of the estimated plasma concentration of at least four of said substances included in the group consisting of sodium, potassium, calcium, magnesium, bicarbonate, acetate, lactate, citrate, phosphate, and sulphate.

In a 13^thaspect according to the 12^thaspect, the estimated plasma concentration of at least a substance chosen in the group including sodium, bicarbonate, potassium, acetate, lactate, and citrate is the mean pre-dialysis values of the corresponding substance for large patient populations, or historical data of the corresponding substance for the individual patient or theoretical values of the corresponding substance or measured values of the corresponding substance.

In a 14^thaspect according to anyone of the previous aspects from the 7^thto the 13^th, the control unit is configured to calculate the initial set point of the substance in the dialysis fluid as a function of at least one flow rate, in particular the dialysate flow rate at the outlet of the secondary chamber (4).

In a 15^thaspect according to anyone of the previous aspects from the 7^thto the 14^th, the control unit is configured to calculate the initial set point of the substance in the dialysis fluid as a function of at least an efficiency parameter of the filtration unit (2), in particular a clearance of the filtration unit (2), optionally the urea clearance and/or the citrate clearance.

In a 16^thaspect according to anyone of the previous aspects from the 7^thto the 15^th, the control unit is configured to calculate the initial set point of sodium concentration in the dialysis fluid using the following relationship:

$\begin{matrix} c_{di, Na, start} = α * c_{pw, Na} + \frac{1}{M_{κ_{NaCl}}} (M_{κ_{{NaHCO}_{3}}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, {HCO}_{3}} - c_{di, {HCO}_{3}}) ++ \frac{1}{M_{κ_{NaCl}}} (M_{κ_{NaAc}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, Ac} - c_{di, Ac}) + \frac{M_{κ_{KCl}}}{M_{κ_{NaCl}}} (α * c_{pw, K} - c_{di, K}) ++ \frac{1}{M_{κ_{NaCl}}} \frac{Q_{do}}{K_{u}} κ_{rest 3} & (I) \end{matrix}$

wherein:

M _κ_NaHCO3
Is the molar conductivity of sodium bicarbonate (NaHCO₃)

M _κ_NaCl
Is the molar conductivity of sodium chloride (NaCl)

M _κ_NaAc
Is the molar conductivity of sodium acetate (NaCH₃COO)

M _κ_KCl
Is the molar conductivity of potassium chloride (KCl)

□_rest3
Is the conductivity contribution from lesser solutes 3

c_di,HCO3
Is the dialysis fluid concentration of bicarbonate

c_di,K
Is the dialysis fluid concentration of potassium

c_di,Ac
Is the dialysis fluid concentration of acetate

c_pw,Na
Is the estimated or measured pre-dialysis

concentration of sodium ions

(Na⁺) in plasma water

c_pw,HCO3
Is the estimated or measured pre-dialysis

concentration of bicarbonate

anions (HCO₃⁻) in plasma water

c_pw,Ac
Is the estimated or measured pre-dialysis

concentration of acetate anions

(CH₃COO⁻) in plasma water

c_pw,K
Is the estimated or measured pre-dialysis

concentration of potassium ions

(K⁺) in plasma water

Qdo
Is the dialysate flow rate at dialyzer outlet

Ku
Is the dialyzer clearance for urea

α
Is the Donnan factor

In a 17^thaspect according to anyone of the previous aspects from the 7^thto the 15^th, the control unit is configured to calculate the initial set point of sodium concentration in the dialysis fluid using the following relationship:

$\begin{matrix} c_{di, Na, start} = α \cdot c_{{pw}_{{Na}^{+}}} ++ \frac{1}{M_{κ_{NaCl}}} (M_{κ_{{NaHCO}_{3}}} - M_{κ_{NaCl}}) \cdot (α^{- 1} \cdot c_{{pw}_{{HCO}_{3^{-}}}} - c_{d_{{HCO}_{3^{-}}}}) ++ M_{κ_{KCl}} \cdot (α \cdot c_{{pw}_{K^{+}}} - c_{d_{K^{+}}}) ++ (M_{κ_{NaAc}} - M_{κ_{NaCl}}) \cdot (α^{- 1} \cdot c_{{pw}_{{Ac}^{-}}} - c_{d_{{Ac}^{-}}}) ++ \frac{K_{b_{Cit}}}{K_{b}} \cdot (M_{κ_{{Na}_{3} Cit}} - 3 M_{κ_{NaCl}}) \cdot ((0.167 α^{- 3} + 0.125 α^{- 2} + 0.706 α^{- 1}) \cdot c_{{pw}_{{Na}_{3} Cit}} - c_{d_{{Na}_{3} Cit}}) ++ \frac{Q_{do}}{K_{b}} \cdot κ_{rest 3}) & (II) \end{matrix}$

wherein:

M _κ_NaHCO3
Is the molar conductivity of sodium bicarbonate (NaHCO₃)

M _κ_NaCl
Is the molar conductivity of sodium chloride (NaCl)

M _κ_NaAc
Is the molar conductivity of sodium acetate (NaCH₃COO)

M _κ_KCl
Is the molar conductivity of potassium chloride (KCl)

M _Na₃_Cit
Is the molar conductivity of trisodium citrate (Na₃C₆H₅O₇)

□_rest3
Is the conductivity contribution from lesser solutes 3

c_di,HCO3
Is the dialysis fluid concentration of bicarbonate

c_di,K
Is the dialysis fluid concentration of potassium

c_di,Ac
Is the dialysis fluid concentration of acetate

c_di,Na₃_Cit
Is the dialysis fluid concentration of total citrate

c_pw,Na
Is the estimated or measured pre-dialysis

concentration of sodium ions

(Na⁺) in plasma water

c_pw,HCO3
Is the estimated or measured pre-dialysis

concentration of bicarbonate

anions (HCOO⁻) in plasma water

c_pw,Ac
Is the estimated or measured pre-dialysis

concentration of acetate anions

(CH₃CO₃⁻) in plasma water

c_pw,K
Is the estimated or measured pre-dialysis

concentration of potassium ions

(K⁺) in plasma water

c_pw,Na₃_Cit
Is the estimated or measured pre-dialysis

concentration of total citrate in

plasma water

Qdo
Is the dialysate flow rate at dialyzer outlet

Ku
Is the dialyzer clearance for urea

K_b_Cit
Is the dialyzer clearance for citrate

α
Is the Donnan factor

In a 18^thaspect according to anyone of the previous aspects, the sensor (11) is configured to measure a conductivity of the dialysate.

In an 19^thaspect according to anyone of the previous aspects, the control unit is configured to estimate at least the initial value of the parameter value of the dialysate representative of the conditions prevailing after the exchange process has reached stable conditions, said estimate being based on at least one measurement of the parameter value in the dialysate.

In a 20^thaspect according to anyone of the previous aspects, the control unit (12) is configured to measure at least the initial value of the parameter value of the dialysate in the dialysis effluent line (13) downstream of the secondary chamber (4) as soon as the exchange process in the filtration unit (2) reaches stable conditions.

In a 21^staspect according to the previous aspect, the control unit (12) is configured to determine reaching of stable conditions for the exchange process in case one or more of the following conditions occurs:

- a first derivative of the median or of the average value of the conductivity of the dialysate is lower in size than a first threshold for a specified time window;
- a first derivative of the value of conductivity of the dialysate is lower in size than a first threshold for a specified time window;
- a first derivative of the filtered value of conductivity of the dialysate is lower in size than a first threshold for a specified time window, the filtered value being a value filtered either by a median filter or a linear filter, either a finite impulse response filter, or an infinite impulse response filter;
- a second derivative of the median value of the conductivity of the dialysate is lower in size than a second threshold for a specified time window;
- a second derivative of the value of conductivity of the dialysate is lower in size than a first threshold for a specified time window;
- a second derivative of the filtered value of conductivity of the dialysate is lower in size than a first threshold for a specified time window;
- a change or a relative change of the value of conductivity of the dialysate or a filtered version of the value of the conductivity since a fixed previous point in time is below a first threshold;
- a change or the relative change of the value of conductivity of the dialysate or a filtered version of the value of the conductivity since a fixed time interval backwards is below a first threshold;
- a prefixed time has lapsed after starting circulation of both blood and dialysis fluid in the filtration unit, in particular said pre-fixed time being not more than 15 minutes;
- a variable time has lapsed after starting circulation of both blood and dialysis fluid in the filtration unit, said variable time being function of at least a parameter of the apparatus.

In a 22^ndaspect according to the previous aspect, the at least one parameter is chosen in the group including a volume of the secondary chamber (4) of the filtration unit (2), dialysis fluid flow rate, blood flow rate, filtration unit permeability.

In a 23^rdaspect according to the previous 21^stor 22^ndaspects, during the step of determining reaching of stable conditions, the control unit (12) is configured to prevent changes in the dialysis fluid flow rate, particularly the control unit (12) is also configured to prevent changes in the blood flow rate and/or in the ultrafiltration rate.

In a 24^thaspect according to anyone of the previous aspects, the control unit (12) is configured to measure a conductivity value of the dialysate and to compensate the measured initial conductivity value of the dialysate for the effect of the electrically neutral substance, in particular said electrically neutral substances include urea and glucose.

In a 25^thaspect according to the previous aspect, the control unit (12) is configured to compensate the measured initial conductivity value of the dialysate as a function of the concentration of at least a substance in the dialysis fluid, said substance being particularly glucose.

In a 26^thaspect according to the previous 24^thor 25^thaspects, the control unit is configured to compensate the measured initial conductivity value of the dialysate as a function of at least one flow rate, in particular the dialysate flow rate at the outlet of the secondary chamber (4).

In a 27^thaspect according to anyone of the previous aspects from the 24^thto the 26^th, the control unit is configured to compensate the measured initial conductivity value of the dialysate as a function of at least an efficiency parameter of the filtration unit (2), in particular a clearance of the filtration unit (2), optionally the urea clearance.

In a 28^thaspect according to anyone of the previous aspects from the 24^thto the 27^th, the control unit is configured to compensate the measured initial conductivity value of the dialysate as a function of an estimated plasma concentration of at least a substance chosen in the group including glucose and urea, in particular as a function of the estimated plasma concentration of both glucose and urea.

In a 29^thaspect according to anyone of the previous aspects from the 24^thto the 28^th, the control unit is configured to compensate the measured initial conductivity value of the dialysate using the following formula (III):

$\begin{matrix} κ_{0, d o} = \frac{κ_{d o}}{\begin{matrix} (1 - γ_{g} (c_{d i, g} + \frac{f_{g, K_{B}} K_{u}}{Q_{d o}} (\frac{c_{p, g}}{f_{p w}} - c_{di, g})) \\ (1 - γ_{u} \frac{K_{u}}{Q_{d o}} \frac{c_{p, u}}{f_{p w}}) \end{matrix}} & (III) \end{matrix}$

wherein:

κ_do
Dialysate conductivity after filtration unit;

Q_do
Dialysate flow rate at the filtration unit outlet;

K_u
Filtration unit clearance for urea;

c_di,g
Dialysis fluid concentration of glucose;

c_p,g
Pre-dialysis concentration of glucose in plasma;

c_p,u
Pre-dialysis concentration of urea in plasma;

f_pw
Plasma water fraction, i.e. the part of

plasma that is pure water;

f_g,KB
Glucose clearance fraction, i.e. the relative

glucose clearance compared to urea

clearance;

□_0,do
Dialysate fluid conductivity at the filtration

unit outlet for a pure electrolyte

solution (with conductivity compensated for

the influence of glucose and urea);

□_g
Conductivity correction term for glucose;

□_u
Conductivity correction term for urea;

In a 30^thaspect according to anyone of the previous aspects, the control unit (12) is configured to compensate an initial conductivity of the dialysis fluid for the effect of the electrically neutral substances, in particular said electrically neutral substances include glucose.

In a 31^staspect according to the previous aspect, the control unit (12) is configured to compensate the initial conductivity of the dialysis fluid as a function of the concentration of at least a substance in the dialysis fluid, said substance being particularly glucose.

In a 32^ndaspect according to anyone of the previous 30^thor 31^staspects, the control unit is configured to compensate the initial conductivity of the dialysis fluid using the following formula (IV):

$\begin{matrix} κ_{0, d i} = \frac{κ_{d i}}{1 - γ_{g} c_{di, g}} & (IV) \end{matrix}$

wherein:

κ_di
Dialysis fluid conductivity upstream the filtration unit;

c_di,g
Dialysis fluid concentration of glucose;

□_0,di
Dialysis fluid conductivity at the filtration

unit inlet for a pure electrolyte

solution (with conductivity compensated for

the influence of glucose, if

present);

□_g
Conductivity correction term for glucose;

In a 33^rdaspect according to anyone of the previous aspects, once the diffusion process in the filtration unit (2) reaches stable conditions, the control unit (12) is configured to determine at least an initial conductivity of the dialysis fluid upstream said secondary chamber (4), said determining being executed either by receiving the dialysis fluid conductivity set value or by receiving a signal from a sensor for measuring a conductivity-related value of the dialysis fluid in the dialysis fluid supply line (8).

In a 34^thaspect according to the previous aspect, the control unit (12) is configured to determine the initial conductivity of the dialysis fluid and the initial conductivity of the dialysate substantially at the same time.

In a 35^thaspect according to anyone of the previous aspects, the control unit is configured to calculate the plasma conductivity as a function of at least one flow rate, in particular said flow rate being chosen in the group including the dialysate flow rate at the outlet of the secondary chamber (4) and the blood flow rate in the blood lines (6, 7).

In a 36^thaspect according to the previous aspect, the control unit is configured to calculate the plasma conductivity as a function of the dialysate flow rate at the outlet of the secondary chamber (4) and the blood flow rate in the blood lines (6, 7).

In a 37^thaspect according to anyone of the previous aspects, the control unit is configured to calculate the plasma conductivity as a function of at least an efficiency parameter of the filtration unit (2), in particular a clearance of the filtration unit (2), optionally the urea clearance.

In a 38^thaspect according to anyone of the previous aspects from the 24^thto 29^th, the control unit is configured to calculate the plasma conductivity as a function of at least a compensated initial conductivity of the dialysate.

In a 39^thaspect according to anyone of the previous aspects from the 30^thto 32^nd, the control unit is configured to calculate the plasma conductivity as a function of at least a compensated conductivity of the dialysis fluid in the dialysis supply line (8).

In a 40^thaspect according to anyone of the previous aspects, the control unit is configured to calculate the plasma conductivity according to the following formula (V):

$\begin{matrix} κ_{p, 1}^{'} = κ_{0, d o} + \frac{Q_{d o}}{Q_{Bset}} (κ_{0, d o} - κ_{0, d i}) & (V) \end{matrix}$

wherein:

κ_p,l
Plasma conductivity first estimate;

Q_do
Dialysate flow rate at the filtration unit outlet;

Q_bset
Set blood flow rate at the filtration unit inlet;

□_0,di
Dialysis fluid conductivity at the filtration

unit inlet for a pure electrolyte

solution;

□_0,do
Dialysate conductivity at the filtration unit

outlet for a pure electrolyte solution;

In a 41^staspect according to anyone of the previous aspects, the control unit is configured to calculate the plasma conductivity according to the following formula (VI):

$\begin{matrix} κ_{p, 1}^{″} = κ_{0, d o} + \frac{Q_{d o}}{K_{u}} (κ_{0, d o} - κ_{0, d i}) & (VI) \end{matrix}$

wherein:

κ_p,l
Plasma conductivity first estimate;

Q_do
Dialysate fluid flow rate at the filtration unit outlet;

K_u
Filtration unit clearance for urea;

□_0,di
Dialysis fluid conductivity at the filtration

unit inlet for a pure electrolyte

solution;

□_0,do
Dialysate conductivity at the filtration unit

outlet for a pure electrolyte solution;

In a 42^ndaspect according to anyone of the 37^thor 41^staspect, the control unit is configured to calculate the urea clearance as a function of at least one flow rate chosen in the group including the blood water flow rate, the blood flow rate, and the dialysis fluid flow rate at the inlet of the secondary chamber (4).

In a 43^rdaspect according to the previous aspect, the control unit is configured to calculate the urea clearance according to the following formula (VII):

$\begin{matrix} K_{u} = Q_{b w} Q_{d i} \frac{1 - e^{KoA (\frac{1}{Q_{d i}} \frac{1}{Q_{b w}})}}{Q_{d i} - Q_{b w} e^{KoA (\frac{1}{Q_{d i}} \frac{1}{Q_{b w}})}} & (VII) \end{matrix}$

wherein:

Q_di
Dialysis fluid flow rate at the filtration unit inlet;

Q_bw
Real blood water flow rate at the filtration unit inlet;

K_u
Filtration unit clearance for urea;

K_oA
Urea mass transfer coefficient of the filtration unit;

In a 44^thaspect according to anyone of the previous aspects, after calculating the initial plasma conductivity, the control unit is configured to drive the regulating means (10) to change the composition of the dialysis fluid to reach a dialysis fluid conductivity substantially equal to the calculated initial plasma conductivity.

In a 45^thaspect according to anyone of the previous aspects, immediately after calculating the initial plasma conductivity, the control unit is configured to drive the regulating means (10) to change the composition of the dialysis fluid and to set the dialysis fluid conductivity substantially equal to the calculated plasma conductivity.

In a 46^thaspect according to the previous aspect, after setting the dialysis fluid conductivity substantially equal to the calculated plasma conductivity, the control unit is configured to execute a second calculating step, based on a second determined initial conductivity of the dialysate and on a second corresponding conductivity of the dialysis fluid in the supply line (8), of a second estimate of the initial plasma conductivity, said calculating the second estimate being performed maintaining the dialysis fluid conductivity substantially constant and substantially equal to the calculated plasma conductivity.

In a 47^thaspect according to anyone of the previous aspects, after calculating the second estimate of the initial plasma conductivity, the control unit is configured to drive the regulating means (10) to change the composition of the dialysis fluid and to set the dialysis fluid conductivity substantially equal to said second estimate.

In a 48^thaspect according to anyone of the previous 46^thor 47^thaspects, the calculation of the second estimate of the plasma conductivity is executed according to anyone of the aspects from the 35^thto 43^rd.

In a 49^thaspect according to anyone of the previous aspects, the control unit is configured to drive the regulating means as a function of the calculated plasma conductivity to change the dialysis fluid conductivity.

In a 50^thaspect according to anyone of the previous aspects, the control unit is programmed to allow selection of at least one treatment mode chosen in the group including isotonic dialysis, isonatremic dialysis, and isonatrikalemic dialysis, the control unit is configured to drive the regulating means as a function of the calculated plasma conductivity and of the chosen treatment mode to set either a desired dialysis fluid inlet conductivity or a desired dialysis fluid inlet substance concentration, in particular said substance being sodium.

In a 51^staspect according to the previous aspect, the control unit is programmed to keep the desired dialysis fluid inlet conductivity substantially constant throughout the remainder of the treatment.

In a 52^ndaspect according to the 5^thaspect, the parameter value is a conductivity value of the dialysis fluid.

In a 53^rdaspect according to anyone of the previous aspects, the setting of the parameter value in the dialysis fluid includes the sub-step of calculating the parameter value as a function of a main contribution term based on a blood parameter and as a function of an adjustment contribution term based on a concentration of at least a substance in the dialysis fluid chosen in the group including bicarbonate, potassium, acetate, lactate, citrate, magnesium, calcium, and phosphate, said blood parameter being the plasma conductivity or a plasma conductivity-related of the blood in the extracorporeal blood circuit.

In a 54^thaspect according to the previous aspect, the control unit is configured to calculate the adjustment contribution term based on the concentration of two or more substances in the dialysis fluid chosen in the group including bicarbonate, potassium, acetate, lactate, citrate, in particular as a function of the concentration of at least three of said substances, optionally as a function of the concentration of bicarbonate, potassium, and acetate in the dialysis fluid.

In a 55^thaspect according to the 53^rdor 54^thaspect, the control unit is configured to calculate the adjustment contribution term as a function of the difference in concentration of at least a substance in the dialysis fluid and the same substance in the blood plasma.

In a 56^thaspect according to anyone of the previous aspects from the 53^rdto the 55^th, the control unit is configured to calculate the adjustment contribution term as a function of the difference in concentration of at least a substance in the dialysis fluid and the same substance in the plasma, said substance being chosen in the group including bicarbonate, potassium, acetate, lactate, and citrate, in particular as a function of the difference in concentration of at least two of said substances, optionally as a function of the difference in concentration of bicarbonate, potassium, citrate, and acetate in the dialysis fluid and plasma.

In a 57^thaspect according to anyone of the previous aspects from the 53^rdto the 56^th, the blood parameter is the plasma conductivity, or the concentration of at least a substance in the blood, said substance being in particular sodium.

In a 58^thaspect according to anyone of the previous aspects from the 53^rdto the 57^th, the parameter of the dialysis fluid is the conductivity of the dialysis fluid, or the concentration of at least a substance in the dialysis fluid, said substance being in particular sodium.

In a 59^thaspect according to anyone of the previous aspects from the 53^rdto the 58^th, the blood parameter is the plasma conductivity and the parameter of the dialysis fluid is the conductivity of the dialysis fluid.

In a 60^thaspect according to anyone of the previous aspects from the 53^rdto 59^th, the blood parameter is the concentration of at least a substance in the blood, said substance being in particular sodium, and the parameter of the dialysis fluid is the concentration of at least a substance in the dialysis fluid, said substance being in particular sodium.

In a 61^staspect according to anyone of the previous aspects from the 53^stto the 60^th, the blood parameter is the concentration of at least a substance in the blood, and the parameter of the dialysis fluid is the concentration of at least the same substance in the dialysis fluid.

In a 62^ndaspect according to anyone of the previous aspects from the 53^rdto the 61^st, the main contribution term is dimensionally a concentration of a substance in a fluid.

In a 63^staspect according to anyone of the previous aspects from the 53^stto the 62^nd, the main contribution term is a dialysis fluid concentration of sodium at an isoconductive state, i.e. when the dialysis fluid conductivity substantially matches the plasma conductivity.

In a 64^thaspect according to anyone of the previous aspects from the 53^rdto the 63^rd, the main contribution term affects the dialysis fluid parameter value for at least 80% of the parameter value, the adjustment contribution term contributes to the dialysis fluid parameter value for less than 15% of the parameter value.

In a 65^thaspect according to anyone of the previous aspects from the 53^rdto the 64^th, the sub-step of calculating the parameter value as a function of the main contribution term and the adjustment contribution term is a sub-step of calculating an algebraic sum of at least the main contribution term and the adjustment contribution term and particularly the adjustment contribution term is dimensionally a concentration of a substance in a fluid.

In a 66^thaspect according to anyone of the previous aspects from the 53^rdto the 65^th, the adjustment contribution term is the sodium concentration set point adjustment relative to an isoconductive state to provide a treatment chosen in the group including isotonic dialysis, isonatremic dialysis, and isonatrikalemic dialysis.

In a 67^thaspect according to anyone of the previous aspects from the 53^stto the 66^th, the main contribution term affects (contributes to) the dialysis fluid parameter value for at least 90% of the parameter value, the adjustment contribution term contributing to the dialysis fluid parameter value for less than 10% of the parameter value.

In a 68^thaspect according to anyone of the previous aspects from the 53^rdto the 67^th, the control unit drives the regulating means (10) for regulating the conductivity or the concentration of at least a substance in the dialysis fluid, the control unit setting the parameter value for the dialysis fluid in the dialysis supply line (8) at the calculated set point.

In a 69^thaspect according to anyone of the previous aspects from the 53^rdto the 68^th, the regulating means (10) regulates the concentration of at least a substance in the dialysis fluid, in particular an ionic substance, such as sodium.

In a 70^thaspect according to anyone of the previous aspects from the 53^stto the 69^th, the control unit drives the regulating means (10) for regulating the sodium concentration in the dialysis fluid to set the parameter value for the dialysis fluid in the dialysis supply line (8) at the calculated set point.

In a 71^staspect according to anyone of the previous aspects from the 53^rdto the 70^th, the control unit is configured to calculate the adjustment contribution term as a function of the molar conductivities of at least a substance in the dialysis fluid chosen in the group including sodium bicarbonate (NaHCO₃), sodium chloride (NaCl), sodium acetate (NaCH₃COO), potassium chloride (KCl), lactate, and trisodium citrate (Na₃C₆H₅O₇), in particular as a function of the molar conductivities of at least two of said substances, in more detail as a function of the molar conductivities of at least three of said substances, optionally as a function of the molar conductivities of sodium bicarbonate (NaHCO₃), sodium chloride (NaCl), sodium acetate (NaCH₃COO), trisodium citrate (Na₃C₆H₅O₇), and potassium chloride (KCl).

In a 72^ndaspect according to anyone of the previous aspects from the 53^rdto the 71^st, the control unit is configured to calculate the adjustment contribution term as a function of a difference between two molar conductivities.

In a 73^staspect according to anyone of the previous aspects from the 53^rdto the 72^nd, the control unit is configured to calculate the adjustment contribution term as a function of a difference between a first molar conductivity of a substance chosen in the group including sodium bicarbonate (NaHCO₃), sodium acetate (NaCH₃COO), trisodium citrate (Na₃C₆H₅O₇), and potassium chloride (KCl), and a molar conductivity of sodium chloride (NaCl).

In a 74^thaspect according to anyone of the previous aspects from the 53^stto the 73^rd, the control unit is configured to calculate the adjustment contribution term as a function of a difference between a molar conductivity of sodium bicarbonate (NaHCO₃), and a molar conductivity of sodium chloride (NaCl).

In a 75^thaspect according to anyone of the previous aspects from the 53^stto the 74^th, the control unit is configured to calculate the adjustment contribution term as a function of a difference between a molar conductivity of sodium acetate (NaCH₃COO), and a molar conductivity of sodium chloride (NaCl).

In a 76^thaspect according to anyone of the previous aspects from the 53^rdto the 75^th, the control unit is configured to calculate the adjustment contribution term as a function of a difference between a molar conductivity of trisodium citrate (Na₃C₆H₅O₇), and a molar conductivity of sodium chloride (NaCl).

In a 77^thaspect according to anyone of the previous aspects from the 53^stto the 76^th, the control unit is configured to calculate the adjustment contribution term as a function of a difference between a molar conductivity of potassium chloride (KCl), and a molar conductivity of sodium chloride (NaCl).

In a 78^thaspect according to anyone of the previous aspects from the 53^rdto the 77^th, the control unit is configured to calculate the adjustment contribution term as a function of an estimated plasma water concentration of at least a substance chosen in the group including bicarbonate, potassium, acetate, lactate, and citrate, in particular as a function of the estimated plasma water concentration of at least two of said substances, in more detail as a function of the estimated plasma water concentration of at least three of said substances, optionally as a function of the estimated plasma water concentration of bicarbonate, potassium, citrate, and acetate.

In a 79^thaspect according to anyone of the previous aspects from the 53^rdto the 78^th, the estimated plasma water concentration of at least a substance chosen in the group including bicarbonate, potassium, citrate, and acetate is the mean pre-dialysis values of the corresponding substance for large patient populations or historical data of the corresponding substance for the individual patient or theoretical values of the corresponding substance or measured values of the corresponding substance.

In a 80^thaspect according to the 78^thor 79^thaspects, the estimated plasma water concentration is adjusted by a respective, preferably fixed, adjusting factor taking account of the Donnan effect.

In a 81^staspect according to anyone of the previous aspects from the 53^stto the 80^th, the control unit is configured to calculate the adjustment contribution term as an algebraic sum of at least two components, a first component being function of the difference, in particular weighted difference, in concentration of at least a substance in the dialysis fluid and the same substance in the blood plasma, the second component being function of the difference, in particular weighted difference, in concentration of at least a second substance in the dialysis fluid and the same second substance in the blood plasma.

In an 82^ndaspect according to anyone of the previous aspects from the 53^stto the 81^st, the control unit is configured to calculate the adjustment contribution term as an algebraic sum of at least three components, a first component being function of the difference, in particular weighted difference, in concentration of at least a substance in the dialysis fluid and the same substance in the blood plasma, the second component being function of the difference, in particular weighted difference, in concentration of at least a second substance in the dialysis fluid and the same second substance in the blood plasma, the third component being function of the difference, in particular weighted difference, in concentration of at least a third substance in the dialysis fluid and the same third substance in the blood plasma.

In an 83^staspect according to anyone of the previous aspects from the 53^stto the 82^nd, the control unit is configured to calculate the adjustment contribution term as an algebraic sum of at least two components, a first component being function of a concentration of at least a substance in the dialysis fluid and/or in the blood plasma, a second component being function of a concentration of at least a second substance in the dialysis fluid and/or in the blood plasma.

In an 84^thaspect according to anyone of the previous aspects from the 53^rdto the 83^rd, the control unit is configured to calculate the adjustment contribution term as an algebraic sum of at least three components, a first component being function of a concentration of at least a substance in the dialysis fluid and/or in the blood plasma, a second component being function of a concentration of at least a second substance in the dialysis fluid and/or in the blood plasma, a third component being function of a concentration of at least a third substance in the dialysis fluid and/or in the blood plasma.

In an 85^thaspect according to anyone of the previous aspects from the 81^stto the 84^th, said substance is chosen in the group including bicarbonate anions (HCO₃⁻), acetate anions (CH₃COO⁻), citrate, and potassium ions (K⁺).

In an 86^thaspect according to anyone of the previous aspects from the 53^rdto the 85^th, the control unit is configured to calculate the adjustment contribution term as a function of at least one flow rate, in particular the spent dialysis fluid flow rate at the outlet of the secondary chamber (4).

In an 87^thaspect according to anyone of the previous aspects from the 53^stto the 86^th, the control unit is configured to calculate the adjustment contribution term as a function of at least an efficiency parameter of the filtration unit (2), in particular a clearance of the filtration unit (2), optionally the urea clearance and/or the citrate clearance.

In an 88^thaspect according to anyone of the previous aspects from the 53^stto the 87^th, the control unit is configured to calculate the adjustment contribution term as a function of at least a ratio between one flow rate, in particular the spent dialysis fluid flow rate at the outlet of the secondary chamber (4), and an efficiency parameter of the filtration unit (2), in particular a clearance of the filtration unit (2), optionally the urea clearance and/or the citrate clearance.

In an 89^thaspect according to anyone of the previous aspects from the 53^rdto the 88^th, the control unit is configured to calculate the adjustment contribution term as an algebraic sum of at least two, and particularly three or four or five, components, one component being a function of at least a ratio between one flow rate, in particular the spent dialysis fluid flow rate at the outlet of the secondary chamber (4), and an efficiency parameter of the filtration unit (2), in particular a clearance of the filtration unit (2), optionally the urea clearance and/or the citrate clearance.

In a 90^thaspect according to anyone of the previous aspects from the 53^stto the 89^th, the control unit (12) is programmed for calculating the blood parameter.

In a 91^staspect according to anyone of the previous aspects from the 53^rdto the 90^th, the control unit (12) is programmed for receiving as an input the blood parameter.

In a 92^ndaspect according to anyone of the previous aspects from the 53^stto the 91^st, the control unit (12) is programmed for storing in a memory said value representative of the parameter of the blood in said blood lines, said value representative of the parameter of the blood being not calculated by the control unit.

In a 93^rdaspect according to anyone of the previous aspects from the 53^rdto the 92^nd, the adjustment contribution term has a negative value.

In a 94^thaspect according to anyone of the previous aspects from the 53^stto the 93^rd, the adjustment contribution term is:

$\begin{matrix} c_{di, Na, isotonic, adj} = - \frac{1}{M_{κ_{NaCl}}} ((M_{κ_{{NaHCO}_{3}}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, Ac} - c_{di, Ac}) ++ (M_{κ_{KCl}} - M_{κ_{NaCl}}) (α * c_{pw, K} - c_{di, K}) + \frac{Q_{do}}{K_{u}} (κ_{rest 1} + κ_{rest 2})) & (VIII) \end{matrix}$

wherein:

C_{di,Na,isotonic,adj}
Sodium concentration set point

adjustment (relative to isoconductive

state) required to provide isotonic dialysis

M _κ_NaHCO3
Is the molar conductivity of sodium

bicarbonate (NaHCO₃)

M _κ_NaCl
Is the molar conductivity of sodium chloride (NaCl)

M _κ_NaAc
Is the molar conductivity of sodium

acetate (NaCH₃COO)

M _κ_KCl
Is the molar conductivity of potassium chloride (KCl)

□_rest1
Is the conductivity contribution from lesser solutes 1

□_rest2
Is the conductivity contribution from lesser solutes 2

c_di,HCO3
Is the dialysis fluid concentration of bicarbonate

c_di,K
Is the dialysis fluid concentration of potassium

c_di,Ac
Is the dialysis fluid concentration of acetate

c_pw,HCO3
Is the estimated or measured pre-dialysis

concentration of bicarbonate

anions (HCO₃⁻) in plasma water

c_pw,Ac
Is the estimated or measured pre-dialysis

concentration of acetate anions

(CH₃COO⁻) in plasma water

c_pw,K
Is the estimated or measured pre-dialysis

concentration of potassium ions

(K⁺) in plasma water

Qdo
Is the dialysate flow rate at dialyzer outlet

Ku
Is the dialyzer clearance for urea

α
Is the Donnan factor

In a 95^thaspect according to anyone of the previous aspects from the 53^stto the 93^st, the adjustment contribution term is:

$\begin{matrix} c_{di, Na, isoNa, adj} = - \frac{1}{M_{κ_{NaCl}}} ((M_{κ_{{NaHCO}_{3}}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, {HCO}_{3}} - c_{di, {HCO}_{3}}) + (M_{κ_{NaAc}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, Ac} - c_{di, Ac}) ++ M_{κ_{KCl}} (α * c_{pw, K} - c_{di, K}) + \frac{Q_{do}}{K_{u}} κ_{rest 3}) & (IX) \end{matrix}$

wherein:

C_{di,Na,isoNa,adj}
Sodium concentration set point

adjustment (relative to isoconductive

state) required to provide isonatremic dialysis

M _κ_NaHCO3
Is the molar conductivity of sodium bicarbonate (NaHCO₃)

M _κ_NaCl
Is the molar conductivity of sodium chloride (NaCl)

M _κ_NaAc
Is the molar conductivity of sodium acetate (NaCH₃COO)

M _κ_KCl
Is the molar conductivity of potassium chloride (KCl)

□_rest3
Is the conductivity contribution from lesser solutes 3

c_di,HCO3
Is the dialysis fluid concentration of

bicarbonate anions (HCO₃⁻)

c_di,K
Is the dialysis fluid concentration of potassium ions (K⁺)

c_di,Ac
Is the dialysis fluid concentration

of acetate anions (CH₃COO⁻)

c_pw,HCO3
Is the estimated or measured pre-dialysis

concentration of bicarbonate

anions (HCO₃⁻) in plasma water

c_pw,Ac
Is the estimated or measured pre-dialysis

concentration of acetate anions

(CH₃COO⁻) in plasma water

c_pw,K
Is the estimated or measured pre-dialysis

concentration of potassium ions

(K⁺) in plasma water

Qdo
Is the dialysate flow rate at dialyzer outlet

Ku
Is the dialyzer clearance for urea

α
Is the Donnan factor

In a 96^thaspect according to anyone of the previous aspects from the 53^rdto the 93^rd, the adjustment contribution term is:

$\begin{matrix} c_{di, Na, isoNa + K, adj} = - \frac{1}{M_{κ_{NaC1}}} ((M_{κ_{{NaHCO}_{3}}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, {HCO}_{3}} - c_{di, {HCO}_{3}}) + (M_{κ_{NaAc}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, Ac} - c_{di, Ac}) ++ (M_{κ_{KCl}} - M_{κ_{NaCl}}) (α * c_{pw, K} - c_{di, K}) + \frac{Q_{do}}{K_{u}} κ_{rest 3}) & (X) \end{matrix}$

wherein:

C_{di,Na,isoNa+K,adj}
Sodium concentration set point

adjustment (relative to isoconductive

state) required to provide isonatrikalemic dialysis

M _κ_NaHCO3
Is the molar conductivity of sodium

bicarbonate (NaHCO₃)

M _κ_NaCl
Is the molar conductivity of sodium chloride (NaCl)

M _κ_NaAc
Is the molar conductivity of sodium

acetate (NaCH₃COO)

M _κ_KCl
Is the molar conductivity of potassium chloride (KCl)

□_rest3
Is the conductivity contribution from lesser solutes 3

c_di,HCO3
Is the dialysis fluid concentration of

bicarbonate anions (HCO₃⁻)

c_di,K
Is the dialysis fluid concentration of

potassium ions (K⁺)

c_di,Ac
Is the dialysis fluid concentration of acetate

anions (CH₃COO⁻)

c_pw,HCO3
Is the estimated or measured pre-dialysis

concentration of bicarbonate

anions (HCO₃⁻) in plasma water

c_pw,Ac
Is the estimated or measured pre-dialysis

concentration of acetate anions

(CH₃COO⁻) in plasma water

c_pw,K
Is the estimated or measured pre-dialysis

concentration of potassium ions

(K⁺) in plasma water

Qdo
Is the dialysate flow rate at dialyzer outlet

Ku
Is the dialyzer clearance for urea

α
Is the Donnan factor

In a 97^thaspect according to anyone of the previous aspects from the 53^rdto the 93^rd, the adjustment contribution term is:

$\begin{matrix} c_{di, Na, isotonic, adj} = - \frac{1}{M_{κ_{NaC1}}} ((M_{κ_{{NaHCO}_{3}}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, {HCO}_{3}} - c_{di, {HCO}_{3}}) + (M_{κ_{NaAc}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, Ac} - c_{di, Ac}) ++ (M_{κ_{KCl}} - M_{κ_{NaCl}}) (α * c_{pw, K} - c_{di, K}) ++ \frac{K_{b_{Cit}}}{K_{u}} (M_{{Na}_{3} Cit} - 3 M_{κ_{NaCl}}) ((0.167 α^{- 3} + 0.125 α^{- 2} + 0.706 α^{- 1}) * c_{pw, {Na}_{3} Cit} - c_{di, {Na}_{3} Cit}) ++ \frac{Q_{do}}{K_{u}} (κ_{res 1} + κ_{rest 2})) & (XI) \end{matrix}$

wherein:

C_{di,Na,isotonic,adj}
Sodium concentration set point

adjustment (relative to isoconductive

state) required to provide isotonic dialysis

M _κ_NaHCO3
Is the molar conductivity of sodium

bicarbonate (NaHCO₃)

M _κ_NaCl
Is the molar conductivity of sodium chloride (NaCl)

M _κ_NaAc
Is the molar conductivity of sodium

acetate (NaCH₃COO)

M _κ_KCl
Is the molar conductivity of potassium chloride (KCl)

M _Na₃_Cit
Is the molar conductivity of trisodium

citrate (Na₃C₆H₅O₇)

□_rest1
Is the conductivity contribution from lesser solutes 1

□_rest2
Is the conductivity contribution from lesser solutes 2

c_di,HCO3
Is the dialysis fluid concentration of

bicarbonate anions (HCO₃⁻)

c_di,K
Is the dialysis fluid concentration of potassium ions (K⁺)

c_di,Ac
Is the dialysis fluid concentration of acetate

anions (CH₃COO⁻)

c_di,Na₃_Cit
Is the dialysis fluid concentration of total citrate

c_pw,HCO3
Is the estimated or measured pre-dialysis

concentration of bicarbonate

anions (HCO₃⁻) in plasma water

c_pw,Ac
Is the estimated or measured pre-dialysis

concentration of acetate anions

(CH₃COO⁻) in plasma water

c_pw,K
Is the estimated or measured pre-dialysis

concentration of potassium

ions (K⁺) in plasma water

c_pw,Na₃_Cit
Is the estimated or measured pre-dialysis

concentration of total citrate in

plasma water

Qdo
Is the dialysate flow rate at dialyzer outlet

Ku
Is the dialyzer clearance for urea

K_b_Cit
Is the dialyzer clearance for citrate

α
Is the Donnan factor

In a 98^thaspect according to anyone of the previous aspects from the 53^rdto the 93^rd, the adjustment contribution term is:

$\begin{matrix} c_{di, Na, isoNa, adj} = - \frac{1}{M_{κ_{NaC1}}} ((M_{κ_{{NaHCO}_{3}}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, {HCO}_{3}} - c_{di, {HCO}_{3}}) + (M_{κ_{NaAc}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, Ac} - c_{di, Ac}) ++ \frac{K_{b_{Cit}}}{K_{u}} (M_{{Na}_{3} Cit} - 3 M_{κ_{NaCl}}) ((0.167 α^{- 3} + 0.125 α^{- 2} + 0.706 α^{- 1}) * c_{pw, {Na}_{3} Cit} - c_{di, {Na}_{3} Cit}) ++ M_{κ_{KCl}} (α * c_{pw, K} - c_{di, K}) + \frac{Q_{do}}{K_{u}} κ_{rest 3}) & (XII) \end{matrix}$

wherein:

C_{di,Na,isoNa,adj}
Sodium concentration set point adjustment

(relative to isoconductive

state) required to provide isonatremic dialysis

M _κ_NaHCO3
Is the molar conductivity of sodium bicarbonate (NaHCO₃)

M _κ_NaCl
Is the molar conductivity of sodium chloride (NaCl)

M _κ_NaAc
Is the molar conductivity of sodium acetate (NaCH₃COO)

M _κ_KCl
Is the molar conductivity of potassium chloride (KCl)

M _Na₃_Cit
Is the molar conductivity of trisodium citrate (Na₃C₆H₅O₇)

□_rest3
Is the conductivity contribution from lesser solutes 3

c_di,HCO3
Is the dialysis fluid concentration of

bicarbonate anions (HCO₃⁻)

c_di,K
Is the dialysis fluid concentration of potassium ions (K⁺)

c_di,Ac
Is the dialysis fluid concentration of

acetate anions (CH₃COO⁻)

c_di,Na₃_Cit
Is the dialysis fluid concentration of total citrate

c_pw,HCO3
Is the estimated or measured pre-dialysis

concentration of bicarbonate

anions (HCO₃⁻) in plasma water

c_pw,Ac
Is the estimated or measured pre-dialysis

concentration of acetate anions

(CH₃COO⁻) in plasma water

c_pw,K
Is the estimated or measured pre-dialysis

concentration of potassium ions

(K⁺) in plasma water

c_pw,Na₃_Cit
Is the estimated or measured pre-dialysis

concentration of total citrate in

plasma water

Qdo
Is the dialysate flow rate at dialyzer outlet

Ku
Is the dialyzer clearance for urea

K_b_Cit
Is the dialyzer clearance for citrate

α
Is the Donnan factor

In a 99^thaspect according to anyone of the previous aspects from the 53^stto the 93^rd, the adjustment contribution term is:

$\begin{matrix} c_{di, Na, isoNa + K, adj} = - \frac{1}{M_{κ_{NaC1}}} ((M_{κ_{{NaHCO}_{3}}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, {HCO}_{3}} - c_{di, {HCO}_{3}}) + (M_{κ_{NaAc}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, Ac} - c_{di, Ac}) ++ \frac{K_{b_{Cit}}}{K_{u}} (M_{{Na}_{3} Cit} - 3 M_{κ_{NaCl}}) ((0.167 α^{- 3} + 0.125 α^{- 2} + 0.706 α^{- 1}) * c_{pw, {Na}_{3} Cit} - c_{di, {Na}_{3} Cit}) ++ (M_{κ_{KCl}} - M_{κ_{NaCl}}) (α * c_{pw, K} - c_{di, K}) + \frac{Q_{do}}{K_{u}} κ_{rest 3}) & (XIII) \end{matrix}$

wherein:

C_{di,Na,isoNa+K,adj}
Sodium concentration set point

adjustment (relative to isoconductive

state) required to provide isonatrikalemic dialysis

M _κ_NaHCO3
Is the molar conductivity of sodium

bicarbonate (NaHCO₃)

M _κ_NaCl
Is the molar conductivity of sodium chloride (NaCl)

M _κ_NaAc
Is the molar conductivity of sodium

acetate (NaCH₃COO)

M _κ_KCl
Is the molar conductivity of potassium chloride (KCl)

M _Na₃_Cit
Is the molar conductivity of trisodium

citrate (Na₃C₆H₅O₇)

□_rest3
Is the conductivity contribution from lesser solutes 3

c_di,HCO3
Is the dialysis fluid concentration of

bicarbonate anions (HCO₃⁻)

c_di,K
Is the dialysis fluid concentration of

potassium ions (K⁺)

C_di,Ac
Is the dialysis fluid concentration of

acetate anions (CH₃COO⁻)

c_di,Na₃_Cit
Is the dialysis fluid concentration of total citrate

c_pw,HCO3
Is the estimated or measured pre-dialysis

concentration of bicarbonate

anions (HCO₃⁻) in plasma water

c_pw,Ac
Is the estimated or measured pre-dialysis

concentration of acetate anions

(CH₃COO⁻) in plasma water

c_pw,K
Is the estimated or measured pre-dialysis

concentration of potassium ions

(K⁺)in plasma water

c_pw,Na₃_Cit
Is the estimated or measured pre-dialysis

concentration of total citrate in

plasma water

Qdo
Is the dialysate flow rate at dialyzer outlet

Ku
Is the dialyzer clearance for urea

K_b_Cit
Is the dialyzer clearance for citrate

α
Is the Donnan factor

In a 100^thaspect according to the previous aspects, the setting of the second parameter value in the dialysis fluid includes the sub-step of calculating the parameter value as a function of the main contribution term, the adjustment contribution term and a compensation contribution term.

In a 101^staspect according to the previous aspect, the compensation contribution term is dimensionally a concentration of a substance in a fluid.

In a 102^ndaspect according to the previous two aspects, the sub-step of calculating the parameter value as a function of the main contribution term, the adjustment contribution term and the compensation contribution term is a sub-step of calculating an algebraic sum of at least the main contribution term, the adjustment contribution term, and the compensation contribution term.

In a 103^staspect according to the previous three aspects, the compensation contribution term is a sodium compensation term to compensate for occurred unintended sodium transfers during treatment.

In a 104^thaspect according to the previous four aspects, the compensation contribution term is a sodium compensation term to compensate for unintended sodium transfers occurred during calculation of said value representative of the parameter of the blood in said blood lines, particularly at the start of the treatment.

In a 105^thaspect according to the previous aspect, the compensation contribution term has generally a negative value.

In a 106^thaspect according to the previous six aspects, the control unit (12) is further configured, during a monitoring phase, to re-determine the blood parameter, the monitoring phase occurring a predetermined number of times during the treatment, at each monitoring phase an unintended net transfer of a substance, e.g. sodium, occurs through the semipermeable membrane (5), the compensation contribution term is a sodium compensation term to compensate for occurred unintended sodium transfers during the monitoring phase.

In a 107^thaspect according to the previous seven aspects, the compensation contribution term for the unintended substance transfer is calculated for distributing a compensation for the substance during the remaining treatment time.

In a 108^thaspect according to the previous eight aspects, the compensation contribution term is a function of the remaining treatment time, i.e. total treatment time (T) minus elapsed treatment time (t_i), in particular is a function of 1/(T−t_i).

In a 109^thaspect according to the previous nine aspects, the compensation contribution term is a function of the difference between the calculated substance, e.g. sodium, set point (c_{di,Na,set,isotonic}; c_{di,Na,set,isoNa}; c_{di,Na,set,isoNa+K}) and the actual dialysis fluid same substance, e.g. sodium, concentration set point (c_{di,Na,set,actual}) used during treatment.

In a 110^thaspect according to the previous ten aspects, the compensation contribution term is calculated according to the following formula:

$\begin{matrix} \sum_{i} \frac{1}{T - t_{i}} \int_{t_{i}}^{t_{i} + Δ t_{i}} (c_{di, Na, set} - c_{di, Na, actual, i}) dt & (XIV) \end{matrix}$

wherein

c_{di,Na,set,actual}is the actual dialysis fluid sodium concentration set point used during the treatment;

c_di,Na,set, is the calculated sodium set point which may correspond to either dialysis fluid concentration of sodium ions (Na⁺) to provide isotonic dialysis c_{di,Na,set,isotonic}or dialysis fluid concentration of sodium ions (Na⁺) to provide isonatremic dialysis c_{di,Na,set,isoNa}or dialysis fluid concentration of sodium ions (Na⁺) to provide isonatrikalemic dialysis c_{di,Na,set,isoNa+K};

T is the total treatment time; and

t_iis the elapsed treatment time.

In a 111^thaspect according to the previous eleven aspects, the second parameter value in the dialysis fluid is calculated according to the following relation:

$\begin{matrix} c_{di, Na, set, compensated} = c_{di, Na, set} + \sum_{i} \frac{1}{T - t_{i}} \int_{t_{i}}^{t_{i} Δ t_{i}} (c_{di, Na, set} - c_{di, Na, actual, i}) dt & (XV) \end{matrix}$

wherein

c_{di,Na,set,actual}is the actual dialysis fluid sodium concentration set point used during the treatment;

T is the total treatment time; and

t_iis the elapsed treatment time.

Further characteristics and advantages of the present invention will better emerge from the detailed description that follows of at least an embodiment of the invention, illustrated by way of non-limiting example in the accompanying figures of the drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The description will now follow, with reference to the appended figures, provided by way of non-limiting example, in which:

FIG. 1 schematically represents an extracorporeal blood treatment apparatus made according to an illustrating embodiment;

FIG. 2 is a schematic representing the main steps of the method of the present description;

FIG. 3 is a diagram showing dialysis fluid and dialysate conductivity values at the start of the treatment when performing a calculation according to an embodiment of the invention;

FIG. 4 is a diagram showing dialysis fluid and dialysate conductivity values after adjusting sodium concentration in dialysis fluid to run an isotonic dialysis treatment.

DETAILED DESCRIPTION

FIG. 1 illustrates an extracorporeal blood treatment apparatus 1 in an embodiment of the invention.

An example of a hydraulic circuit 100 is schematically illustrated, but it is to be noted that the specific structure of the hydraulic circuit 100 is not relevant for the purposes of the present invention and therefore other and different circuits to those specifically shown in FIG. 1 might be used in consequence of the functional and design needs of each single medical apparatus.

The hydraulic circuit 100 exhibits a dialysis fluid circuit 32 presenting at least one dialysis supply line 8, destined to transport a dialysis liquid from at least one source 14 towards a treatment station 15 where one or more filtration units 2, or dialyzers, operate.

The dialysis fluid circuit 32 further comprises at least one dialysis effluent line 13, destined for the transport of a dialysate liquid (spent dialysate and liquid ultrafiltered from the blood through a semipermeable membrane 5) from the treatment station 15 towards an evacuation zone, schematically denoted by 16 in FIG. 1.

The hydraulic circuit cooperates with a blood circuit 17, also schematically represented in FIG. 1 in its basic component parts. The specific structure of the blood circuit is also not fundamental, with reference to the present invention. Thus, with reference to FIG. 1, a brief description of a possible embodiment of a blood circuit is made, which is however provided purely by way of non-limiting example.

The blood circuit 17 of FIG. 1 comprises a blood withdrawal line 6 designed to remove blood from a vascular access 18 and a blood return line 7 designed to return the treated blood to the vascular access 18.

The blood circuit 17 of FIG. 1 further comprises a primary chamber 3, or blood chamber, of the blood filtration unit 2, the secondary chamber 4 of which is connected to the hydraulic circuit 100.

In greater detail, the blood withdrawal line 6 is connected at the inlet of the primary chamber 3, while the blood return line 7 is connected at the outlet of the primary chamber 3.

In turn, the dialysis supply line 8 is connected at the inlet of the secondary chamber 4, while the dialysis effluent line 13 is connected at the outlet of the secondary chamber 4.

The filtration unit 2, for example a dialyzer or a plasma filter or a hemofilter or a hemodiafilter, comprises, as mentioned, the two chambers 3 and 4 which are separated by a semipermeable membrane 5, for example of the hollow-fibre type or plate type.

The blood circuit 17 may also comprise one or more air separators 19: in the example of FIG. 1 a separator 19 is included at the blood return line 7, upstream of a safety valve 20.

Of course other air separators may be present in the blood circuit, such as positioned along the blood withdrawal line 6.

The safety valve 20 may be activated to close the blood return line 7 when, for example, for security reasons the blood return to the vascular access 18 has to be halted.

The extracorporeal blood treatment apparatus 1 may also comprise one or more blood pumps 21, for example positive displacement pumps such as peristaltic pumps; in the example of FIG. 1, a blood pump 21 is included on the blood withdrawal line 6.

The apparatus of above-described embodiment may also comprise a user interface 22 (e.g. a graphic user interface or GUI) and a control unit 12, i.e. a programmed/programmable control unit, connected to the user interface.

The control unit 12 may, for example, comprise one or more digital microprocessor units or one or more analog units or other combinations of analog units and digital units. Relating by way of example to a microprocessor unit, once the unit has performed a special program (for example a program coming from outside or directly integrated on the microprocessor card), the unit is programmed, defining a plurality of functional blocks which constitute means each designed to perform respective operations as better described in the following description.

In combination with one or more of the above characteristics, the medical apparatus may also comprise a closing device operating, for example, in the blood circuit 17 and/or in the dialysis fluid circuit 32 and commandable between one first operating condition, in which the closing device allows a liquid to flow towards the filtration unit 2, and a second operative position, in which the closing device blocks the passage of liquid towards the filtration unit 2.

In this case, the control unit 12 may be connected to the closing device and programmed to drive the closing device to pass from the first to the second operative condition, should an alarm condition have been detected.

In FIG. 1 the closing device includes the safety valve 20 (e.g. a solenoid valve) controlled by the unit 12 as described above. Obviously a valve of another nature, either an occlusive pump or a further member configured to selectively prevent and enable fluid passage may be used.

Alternatively or additionally to the safety valve 20, the closing device may also comprise a bypass line 23 which connects the dialysis fluid supply line 8 and the dialysate effluent line 13 bypassing the dialyzer, and one or more fluid check members 24 connected to the control unit 12 for selectively opening and closing the bypass line 23. The components (bypass line 23 and fluid check members 24), which may be alternative or additional to the presence of the safety valve 20 are represented by a broken line in FIG. 1.

The check members 24 on command of the control unit close the fluid passage towards the treatment zone and connect the source 14 directly with the dialysis effluent line 13 through the bypass line 23.

Again with the aim of controlling the fluid passage towards the filtration unit 2, a dialysis fluid pump 25 and a dialysate pump 26 may be included, located respectively on the dialysis fluid supply line 8 and on the dialysate effluent line 13 and also operatively connected to the control unit 12.

The apparatus also comprises a dialysis fluid preparation device 9 which may be of any known type, for example including one or more concentrate sources 27, 28 and respective concentrate pumps 29, 30 for the delivery, as well as at least a conductivity sensor 35.

Of course other kinds of dialysis fluid preparation devices 9 might be equivalently used, having a single or further concentrate sources and/or a single or more pumps.

Since the dialysis apparatus may comprise various liquid sources 14 (for example one or more water sources, one or more concentrate sources 27, 28, one or more sources 33 of disinfectant liquids) connected to the dialysis supply line 8 with respective delivery lines 36, 37 and 38, the apparatus may exhibit, at each delivery line, a respective check member (not all are shown) and, for example, comprising a valve member 31 and 34 and/or an occlusive pump.

The preparation device 9 may be any known system configured for on-line preparing dialysis fluid from water and concentrates.

The dialysis supply line 8 fluidly connects the preparation device 9 for preparing dialysis fluid to the filtration unit 2. The preparation device 9 may be, for example, the one described in the U.S. Pat. No. 6,123,847 the content of which is herein incorporated by reference.

As shown, the dialysis supply line 8 connects the preparation device 9 for preparing dialysis fluid to the filtration unit 2 and comprises a main line 40 whose upstream end is intended to be connected to a source 14 of running water.

Delivery line/s 36/37 is/are connected to this main line 40, the free end of which delivery line/s is/are intended to be in fluid communication (for example immersed) in a container/s 27, 28 for a concentrated saline solution each containing sodium chloride and/or calcium chloride and/or magnesium chloride and/or potassium chloride.

Concentrate pump/s 29, 30 is/are arranged in the delivery line/s 36/37 in order to allow the metered mixing of water and concentrated solution in the main line 40. The concentrate pump/s 29, 30 is/are driven on the basis of the comparison between 1) a target conductivity value for the mixture of liquids formed where the main line 40 joins the delivery line/s 36/37, and 2) the value of the conductivity of this mixture measured by means of a conductivity sensor 35 arranged in the main line 40 immediately downstream of the junction between the main line 40 and the delivery line/s 36/37.

Therefore, as mentioned, the dialysis fluid may contain, for example, ions of sodium, calcium, magnesium, and potassium and the preparation device 9 may be configured to prepare the dialysis fluid on the basis of a comparison between a target conductivity value and an actual conductivity value of the dialysis fluid measured by the conductivity sensor 35 of the device 9.

The preparation device 9 comprises regulating means 10, of a known type (i.e. concentrate pump/s 29, 30), which is configured to regulate the concentration of a specific substance, in particular an ionic substance, in the dialysis liquid. Generally it is advantageous to control the sodium concentration of the dialysis fluid.

The dialysis supply line 8 forms an extension of the main line 40 of the preparation device 9 for preparing dialysis fluid. Arranged in this dialysis supply line, in the direction in which the liquid circulates, there are the first flow meter 41 and the dialysis fluid pump 25.

The dialysis effluent line 13 may be provided with a dialysate pump 26 and a second flow meter 42. The first and second flow meters 41, 42 may be used to control (in a known manner) the fluid balance of a patient connected to the blood circuit 17 during a dialysis session.

A sensor 11 is provided on the dialysis effluent line 13, immediately downstream the filtration unit 2, to measure a parameter value of the dialysate in the dialysate effluent line.

In detail, the parameter of the dialysate, which is measured by the sensor 11 is at least one chosen in the group consisting of conductivity of the dialysate, a conductivity-related parameter of the dialysate, concentration of at least a substance in the dialysate and a concentration-related parameter of at least a substance in the dialysate.

In detail the sensor 11 is a conductivity sensor, which is connected to the dialysis effluent line 13, and is configured to detect conductivity values of the dialysate downstream of the filtration unit 2.

Alternatively (or in combination) sensor 11 may include a concentration sensor configured for measuring the concentration of at least one substance in the dialysate, such as sodium concentration.

Correspondingly, sensor 35 on the dialysis fluid supply line may be not a conductivity sensor and, differently, may include a concentration sensor configured for measuring the concentration of at least one substance in the dialysis fluid, such as sodium concentration.

The control unit 12 of the dialysis apparatus represented in FIG. 1 may be connected to a (graphic) user interface 22 through which it may receive instructions, for example target values, such as blood flow rate Q_b, dialysis fluid flow rate Q_di, infusion liquid flow rate Q_inf(where appropriate), patient weight loss WL. The control unit 12 furthermore may receive detected values by the sensors of the apparatus, such as the aforementioned flow meters 41, 42, the (e.g. conductivity) sensor 35 of the preparation device 9 and the (e.g. conductivity) sensor 11 in the dialysis effluent line 13. On the basis of the instructions received and the operating modes and algorithms which have been programmed, the control unit 12 drives the actuators of the apparatus, such as the blood pump 21, the aforementioned dialysis fluid and dialysate pumps 25, 26, and the preparation device 9.

As already mentioned, the described embodiments are intended to be non-limiting examples. In particular the circuits of FIG. 1 should not be interpreted as defining or limiting, as an apparatus such as in the invention may comprise other additional or alternative components to those described.

For example an ultrafiltration line may be included, with at least one respective pump connected to the dialysis effluent line 13.

One or more infusion lines 39 may also be included, with respective infusion pumps 43 or flow regulation valves, the infusion lines being connected up to the blood return line 7 and/or the blood withdrawal line 6 and/or directly to the patient. The liquid sources for the infusion lines may be pre-packaged bags 44 and/or liquids prepared by the apparatus itself.

In the example of FIG. 1, an infusion line 39 is shown directly connected to the blood return line 7, in particular to the air separator 19. The infusion line 39 may either receive infusion liquid from a pre-packaged bag 44 (solid line 45a) or from an online preparation trough branch 45b (dotted line).

Of course a pre-infusion line may be alternatively or additionally provided receiving the infusion liquid from a bag or from an online preparation device.

The blood circuit of FIG. 1 is intended for double needle treatments; however, this is a non-limiting example of the blood set.

Indeed, the apparatus may be configured to perform single needle treatments, i.e. the patient is connected to the extracorporeal blood circuit by way of a single needle and the extracorporeal line from the patient is then split into a withdrawal line and a return line, using, for example, an ‘Y’ connector. During single needle treatment, a blood withdrawal phase removing blood from patient is alternated to a blood return phase in which blood is restituted to the patient.

Furthermore one or more devices for measuring specific substance concentrations might be implemented either (or both) in the dialysis fluid side or (and) in the blood side of the hydraulic circuit. Concentration of calcium, potassium, magnesium, bicarbonate, and/or sodium might be desired to be known.

Finally, the above-cited one or more pumps and all the other necessary temperature, pressure, and concentration sensors may operate either on the dialysis supply line 8 and/or on the dialysis effluent line 13, in order to adequately monitor the preparation and movement of the liquid in the hydraulic circuit.

Given the above description of a possible embodiment of extracorporeal blood treatment apparatus, thereafter the specific working of the apparatus and the algorithm programming the control unit are described.

Definitions

We define the “dialysis fluid” as the fluid prepared and introduced to the second chamber (4) of the filtration unit (2), the dialyzer. The dialysis fluid may also be denoted “fresh dialysis fluid”.

We define the “dialysate” as the fluid from the outlet from the second chamber (4) of the filtration unit (2), the dialyzer. Dialysate is the spent dialysis fluid, comprising the uremic toxins removed from the blood.

We define ‘isonatremic dialysis’ as a treatment where the sodium concentration of the dialysis fluid does not change pre- to post-filtration unit 2.

We define ‘isotonic dialysis’, as a dialysis where the tonicity of the dialysis fluid does not change pre- to post-filtration unit 2.

We define an ‘isonatrikalemic dialysis’, as a treatment where the sum of sodium and potassium concentrations of the dialysis fluid does not change pre- to post-filtration unit 2.

We define ‘isoconductive dialysis’, as a dialysis treatment where the conductivity of the dialysis fluid does not change pre- to post-filtration unit 2, □_di=□□_do.

We define ‘plasma conductivity’ (PC, □_p) as the conductivity of the dialysis fluid in an isoconductive dialysis.

In this application, when “isotonic treatment” word is used alone, this actually implies isotonic, isonatremic or isonatrikalemic dialyses.

In this application the term “citrate” means that the component is in form of a salt of citric acid, such as sodium, magnesium, calcium, or potassium salt thereof. The citric acid (denoted C₆H₈O₇) is deprotonated stepwise, therefore the “citrate” include all the different forms, citrate (denoted C₆H₅O₇³⁻), hydrogen citrate (denoted C₆H₆O₇²⁻), and dihydrogen citrate (denoted C₆H₇O⁷⁻).

The term “citrate” or “total citrate” means the total amount of citric acid and any salts thereof, such as its sodium, magnesium, calcium, or potassium salt thereof.

In other terms, “total citrate” is the sum of free citrate ions and citrate containing complexes and ion pairs.

Glossary

The following terms are consistently used throughout the equations provided in the following description of the detailed working of the extracorporeal blood treatment apparatus.

Name
Description
Unit

κ_d,pre= κ_di
Dialysis fluid conductivity
mS/cm

upstream the filtration unit

(corresponding to final conductivity

of the dialysis fluid);

κ_d,post= κ_do
Dialysate conductivity
mS/cm

downstream the filtration unit;

PC = κ_p
Plasma conductivity;
mS/cm

Q_di
Dialysis fluid flow rate at
mL/min

filtration unit inlet;

Q_uf
Ultrafiltration flow rate;
mL/min

Q_do
Dialysate flow rate at filtration
mL/min

unit outlet (i.e., Q_di+ Q_uf);

Q_bset
Set blood flow rate at filtration
mL/min

unit inlet;

Q_b
Real blood flow rate at filtration
mL/min

unit inlet (set blood flow

compensated for arterial pressure);

Q_bw
Real blood water flow rate
mL/min

at filtration unit inlet;

K_u
Filtration unit clearance for urea;
mL/min

K_b_Cit
bot Filtration unit clearance
mL/min

for citrate;

KoA
Urea mass transfer coefficient
mL/min

of filtration unit (average of

normally used dialyzers);

c_di,Na,start
Dialysis fluid concentration of
mmol/L

sodium ions (Na⁺) at the start

of treatment, automatically

calculated and set by the machine

before the start of the treatment;

c_{di,Na,□p,pre}
Dialysis fluid concentration
mmol/L

of sodium ions (Na⁺) at

isoconductive dialysis, i.e.,

when the dialysis fluid

conductivity κ_dimatches the

estimated pre-dialysis plasma

conductivity κ_p,pre;

c_di,Na,set
Dialysis fluid concentration of
mmol/L

sodium ions (Na⁺) to provide

isotonic or isonatremic or

isonatrikalemic dialysis;

c_{di,Na,set,isotonic}
Dialysis fluid concentration
mmol/L

of sodium ions (Na⁺) to provide

isotonic dialysis;

c_{di,Na,isotonic,adj}
Sodium set point adjustment
mmol/L

(relative to isoconductive state)

required to provide isotonic

dialysis;

c_{di,Na,set,isoNa}
Dialysis fluid concentration
mmol/L

of sodium to provide

isonatremic dialysis;

c_{di,Na,isoNa,adj}
Sodium set point adjustment
mmol/L

(relative to isoconductive state)

required to provide

isonatremic dialysis;

c_{di,Na,set,isoNa+K}
Dialysis fluid concentration
mmol/L

of sodium to provide

isonatrikalemic dialysis;

c_{di,Na,isoNa+K,adj}
Sodium set point adjustment
mmol/L

(relative to isoconductive state)

required to provide

isonatrikalemic dialysis;

c_di,Na,set,
Sodium concentration set point
mmol/L

_compensated

to compensate unintended

sodium transfers;

c_{di,Na,set,actual}
Actual dialysis fluid sodium
mmol/L

concentration set point during

the treatment at the time an

additional compensation is to be

applied for

c_di,HCO3
Dialysis fluid concentration
mmol/L

of bicarbonate as set by the

operator;

c_di,K
Dialysis fluid concentration
mmol/L

of potassium ions (K⁺) as

determined by the used

concentrate;

c_di,Ac
Dialysis fluid concentration
mmol/L

of acetate as determined by the

used concentrate;

c_di,Na₃_Cit
Dialysis fluid concentration of
mmol/L

total citrate as determined by

the used concentrate;

c_di,g
Dialysis fluid concentration of
mmol/L

glucose as determined by the

used concentrate;

c_pw,Na
Estimated or measured pre-dialysis
mmol/L

concentration of sodium

ions (Na⁻) in plasma water;

c_pw,HCO3
Estimated or measured
mmol/L

pre-dialysis concentration of

bicarbonate anions (HCO₃⁻)

in plasma water;

c_pw,Ac
Estimated or measured
mmol/L

pre-dialysis concentration of acetate

anions (CH₃COO⁻) in plasma water;

c_pw,K
Estimated or measured
mmol/L

pre-dialysis concentration of

potassium ions (K⁺) in plasma water;

c_pw,Na₃_Cit
Estimated or measured or known
mmol/L

pre-dialysis concentration

of total citrate in plasma water

c_p,g
Estimated or measured pre-dialysis
mmol/L

concentration of glucose

in plasma;

c_p,u
Estimated or measured pre-dialysis
mmol/L

concentration of urea in

plasma;

f_bw
Apparent blood water fraction,
dimensionless

i.e., the part of whole blood

that appears as pure water for urea;

f_pw
Plasma water fraction, i.e., the
dimensionless

part of plasma that is pure

water;

f_g,KB
Glucose clearance fraction,
dimensionless

i.e., the relative glucose

clearance compared to

urea clearance;

□_0,di
Dialysis fluid conductivity at
mS/cm

filtration unit inlet for a pure

electrolyte solution (i.e. without

glucose, either because the

actual solution does not contain

glucose, or because the

conductivity has been compensated

for the influence of

glucose);

□_0,do
Dialysate conductivity at filtration
mS/cm

unit outlet for a pure

electrolyte solution (i.e. without

glucose and urea, because

the conductivity has been

compensated for the influence of

glucose and urea);

□_{p,1 and}□_p,2
1st and 2nd estimate of
mS/cm

plasma conductivity;

□_p,pre
Estimate of plasma conductivity
mS/cm

at beginning of treatment

(representing a pre-dialysis value);

□_isotonic
Conductivity offset between
mS/cm

□_doand □_dito provide isotonic

dialysis (correspondent

to c_{di,Na,isotonic,adj});

□_isoNa
Conductivity offset between
mS/cm

□_doand □_dito provide

isonatremic dialysis

(correspondent to C_{di,Na,isoNa,adj});

□_isoNa+K
Conductivity offset between
mS/cm

□_doand □_dito provide

isonatrikalemic dialysis

(correspondent to c_{di,Na,isoNa+K,adj});

□_rest1
Conductivity contribution
mS/cm

from lesser solutes 1;

□_rest2
Conductivity contribution
mS/cm

from lesser solutes 2;

□_rest3
Conductivity contribution
mS/cm

from lesser solutes 3;

□_g
Conductivity correction
M-1 = L/mol

term for glucose;

□_u
Conductivity correction
M-1 = L/mol

term for urea;

M _κ_NaHCO3
Molar conductivity of sodium
L · mS/mol · cm

bicarbonate (NaHCO₃) at

ionic strength 150 mM;

M _κ_NaCl
Molar conductivity of sodium
L · mS/mol · cm

chloride (NaCl) at ionic

strength 150 mM;

M _κ_NaAc
Molar conductivity of sodium
L · mS/mol · cm

acetate (NaCH₃COO) at ionic

strength 150 mM;

M _κ_KCl
Molar conductivity of potassium
L · mS/mol · cm

chloride (KCl) at ionic

strength 150 mM;

M _Na₃_Cit
Molar conductivity of trisodium
L · mS/mol · cm

citrate (Na₃C₆H₅O₇) at ionic

strength 150 mM;

T
Set total treatment time;
min

T
Elapsed time into treatment;
min

A
Donnan factor

The Donnan factor indicates a value of electroneutrality to be kept over the membrane. For estimating the Donnan factor reference is made to Trans Am Soc Artif Intern Organs, 1983; 29; 684-7, “Sodium Fluxes during hemodialysis”, Lauer A., Belledonne M., Saccaggi A., Glabman S., Bosch J.

Solution Proposal

The technical solution here described consists of three main parts:

- Estimating PC at the beginning of the treatment (i.e., □_p,pre);
- Setting the dialysis fluid sodium concentration such that the dialysis fluid tonicity (or sodium or sodium+potassium) is not changed during its passage through the filtration unit;
- Maintaining the dialysis fluid composition throughout the whole treatment.

The various steps of the proposed method described below are intended to be performed by the control unit 12 of the extracorporeal blood treatment device 1, even if not explicitly stated.

In particular a treatment session is started, preferably, but not necessarily, as a double needle hemodialysis treatment.

The user shall input the prescription values through the user interface 22. For example the set values for total weight loss WL and total treatment time T are provided, as well as the blood flow rate Q_band the fresh dialysis flow rate Q_di.

Other parameters may be entered through the user interface, such as bag type, sodium user limits, etc.

The operator has to further input the ‘bicarbonate’ set before starting the treatment.

The control unit 12 calculates either the initial dialysis liquid conductivity or the initial concentration of at least one solute, e.g. sodium, in the dialysis liquid in order to start with a dialysis fluid conductivity as close as possible to the expected patient pre-dialytic plasma conductivity.

In order to not disturb the tonicity of the patient, it is necessary to set the fluid composition as quickly as possible so that the patient initial plasma conductivity is not inadvertently changed. Thus, estimating of the plasma conductivity has to be done as rapidly as possible when treatment starts; moreover, since the estimation is preferably performed only once, this measure should be as reliable as possible.

In this respect it is worth to note that, in the following detailed description, reference is made to regulating means controlling concentration of an ionic substance, in detail sodium concentration, in the preparation of the dialysis fluid so as to obtain a desired conductivity of the dialysis fluid.

However, regulating means directly regulating the overall dialysis fluid conductivity is also included in the spirit of the present description or, alternatively, regulating means modifying the concentration of a different ionic substance is included in the present description, too.

Given the above, the control unit 12 sets a parameter value for the dialysis fluid in the dialysis fluid supply line 8 at an initial set point; in general the parameter of the dialysis fluid is either the conductivity of the dialysis fluid, or a conductivity-related parameter of the dialysis fluid, or concentration of at least a substance (in particular an ionic substance and in more detail sodium) in the dialysis fluid, or a concentration-related parameter of at least a substance (e.g. sodium) in the dialysis fluid.

In detail, the control unit 12 is configured to set the parameter value for the dialysis fluid at the initial set point so that a dialysis fluid conductivity matches a first estimate of the plasma conductivity of the blood.

In the specific, the control unit 12 calculates the initial set point of the substance concentration and drives the regulating means 10 acting on the sodium concentration in the dialysis liquid.

The set point is calculated before starting the blood circulation (i.e. before starting the treatment).

In order to calculate the dialysis composition initial set point alternative ways might be used, e.g. determine a certain sodium concentration (see below), or using an average plasma conductivity from a large population, or using an average plasma conductivity from a large population corrected for the composition of the dialysis fluid, or calculate based on historic patient data.

In any case, the initial set point for the dialysis liquid is calculated by the control unit 12 so that the expected plasma conductivity is the best guess of plasma conductivity that may be calculated, without prior knowledge of the individual patient.

In general terms, the control unit is configured to calculate the initial set point of the substance concentration to be set (e.g. sodium) in the dialysis fluid as a function of the difference in concentration of at least one (and in detail several) further substance in the dialysis fluid and the same further substance in the plasma.

The calculation is based on average pre-dialysis concentrations of at least one (and preferably all) substance chosen between sodium, potassium, acetate, citrate, and bicarbonate (as well as other solutes) in a large patient population, plus the contribution related to dialysis fluid of bicarbonate, potassium, acetate, and citrate resulting from the prescription and from the chosen concentrate combination.

The control unit 12 calculates the initial set point also as a function of the concentration of at least one, in particular two, and precisely all the substances in the dialysis fluid included in the group comprising bicarbonate, potassium, acetate, and citrate.

Furthermore, the control unit 12 calculates the initial set point of the substance (i.e. sodium) in the dialysis fluid also as a function of the difference in concentration of one or more further substances in the dialysis fluid different from sodium; in particular these substances include bicarbonate, potassium, acetate, and citrate and two, and precisely all, the differences, in particular weighted differences, in concentration value of the mentioned substances in the dialysis fluid and in the plasma are taken into account.

The control unit 12 calculates the initial set point of the substance in the dialysis fluid also as a function of the molar conductivities of one or more substances, such as one, two, three, or all of the following substances in the dialysis fluid which are sodium bicarbonate (NaHCO₃), sodium chloride (NaCl), sodium acetate (NaCH₃COO), trisodium citrate (Na₃C₆H₅O₇), potassium chloride (KCl), and sodium lactate (Na₃C₃H₅O₃).

The control unit 12 calculates the initial set point of the substance in the dialysis fluid as a function of an estimated plasma water concentration of at least sodium, and/or bicarbonate, and/or potassium and/or acetate and/or citrate. The estimated plasma water concentration of sodium, bicarbonate, potassium, acetate, and citrate, is, for example, the mean pre-dialysis values of the corresponding substance for large patient populations, or historical document for a particular patient.

The initial set point may also be a function of one or more flow rates, in particular of the dialysate flow rate at the outlet of the secondary chamber 4.

Also an efficiency parameter of the filtration unit 2 plays a role in the initial set point calculation of sodium. In particular a clearance of the filtration unit 2 may be used (e.g. the urea clearance).

Specifically, the control unit 12 is configured to calculate the initial set point of sodium concentration to be set in the dialysis fluid before the start of the treatment using the following relationship:

wherein the used symbols meaning is clarified in the glossary section.

In case also citrate has to be taken into consideration, the control unit 12 may alternatively use the following relationship:

$\begin{matrix} c_{di, Na, start} = α * c_{pw, Na} + \frac{1}{M_{κ_{NaCl}}} (M_{κ_{{NaHCO}_{3}}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, {HCO}_{3}} - c_{di, {HCO}_{3}}) ++ \frac{1}{M_{κ_{NaCl}}} (M_{κ_{NaAc}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, Ac} - c_{di, Ac}) + \frac{M_{κ_{KCl}}}{M_{κ_{NaCl}}} (α * c_{pw, K} - c_{di, K}) ++ \frac{K_{b_{Cit}}}{K_{u}} (M_{{Na}_{3} Cit} - 3 M_{κ_{NaCl}}) ((0.167 α^{- 3} + 0.125 α^{- 2} + 0.706 α^{- 1}) * c_{pw, {Na}_{3} Cit} - c_{di, {Na}_{3} Cit}) ++ \frac{1}{M_{κ_{NaCl}}} \frac{Q_{do}}{K_{u}} κ_{rest 3} & (1 a) \end{matrix}$

wherein the used symbols meaning is clarified in the glossary section.

Since K_umay not be known at dialysis start, a fixed value equal to Q_di/2 may be possibly used, or of formula (6) below with K_oA as mean value of used type of filtration unit or the value for the actual filtration unit. K_b_Citis the approximated clearance value for citrate (for calculation/estimation see below description).

Of course, different mathematical relationships may be used taking into account exclusively some of the considered substances and/or exclusively some of the conductivities and/or molar differences.

Once the sodium initial set point has been calculated and a corresponding dialysis fluid has been prepared by the control unit 12 driving the regulating means 10, the treatment may start.

The dialysis fluid is circulated through the dialysis fluid circuit 32 and the secondary chamber 4 of the filtration unit 2 so as to exchange with blood.

Correspondingly, blood is withdrawn from the patient and circulated in the extracorporeal blood circuit 17 and particularly is circulated through the primary chamber 3 of the filtration unit 2.

At least one, and in general a plurality, of consecutive initial values of the parameter (in the specific example, the conductivity) of the dialysate downstream of the secondary chamber 4 are measured at the beginning of the treatment through sensor 11.

The control unit 12 is configured to validate and further process the measurement of an initial value of the conductivity of the dialysate as soon as the diffusion process in the filtration unit 2 reaches stable conditions.

Indeed, a transient exists when dialysis fluid and blood start exchanging during which the dialyzer outlet conductivity is not stable; during the transient period the measured outlet conductivity values should be disregarded.

Stable conditions for the diffusion process may be determined in case one or more of the following conditions occurs:

- a first derivative of the median or of the average value of the conductivity of the dialysate is lower in size than a first threshold;
- a first derivative of the value of conductivity of the dialysate is lower in size than a first threshold for a specified time window;
- a first derivative of the filtered value of conductivity of the dialysate is lower in size than a first threshold for a specified time window, the filtered value being a value filtered either by a median filter (which picks out the median) or a linear filter, either a finite impulse response filter (which is equal to a weighted average), or an infinite impulse response filter (which is standard, but has the form yf(t)=−a1*yf(t−1)− . . . −an*yf(t−n)+b1*y(t−k−1)+ . . . +bm*y(t−k−m), where yf(t) is the filtered value at time t, y(t) is the measured value at time t, n and m are the number of parameters a and b (the order) of the filter and k is the number of pure time delays);
- a second derivative of the median value of the conductivity of the dialysate is lower in size than a second threshold;
- a second derivative of the filtered value of conductivity of the dialysate is lower in size than a first threshold for a specified time window;
- a change or a relative change of the value itself or a filtered version of the value of the conductivity since a fixed previous point in time is below a first threshold (an expanding window);
- a change or the relative change of the value itself or a filtered version of the value of the conductivity since a fixed time interval backwards is below a first threshold (a sliding window, constant in length);
- a prefixed time has lapsed after starting circulation of both blood and fresh dialysis fluid in the filtration unit, in particular said pre-fixed time being not more than 15 minutes;
- a variable time has lapsed after starting circulation of both blood and dialysis fluid in the filtration unit, said variable time being function of at least one parameter, such as the volume of the secondary chamber 4 of the filtration unit 2; in particular the variable time may be a function of further parameters such as dialysis fluid flow rate, blood flow rate, filtration unit permeability, etc.

The stability condition is preferably determined by observing, on a 1-minute window, the first derivative of □_doand checking when it is lower in size than a fixed threshold. Once this stability criterion is fulfilled, □_dois taken as the median value on the 1-minute window. The first derivative is used to avoid the presence of possible drifts in the outlet conductivity. Extracting the median and/or the average value of □_doallows discharging possible outliers of the outlet conductivity signal from the average calculation.

In order to minimize the time needed to reach stability conditions, changes in dialysis fluid flow rate and in bicarbonate prescription may be prevented during this preliminary isotonic sodium identification phase.

Changes in blood flow, ultrafiltration flow rate or bypass are vice versa generally allowed, but they will delay stability. Moreover, it is not possible to change the concentrate combination type after the treatment is started.

Alternatively, it might be possible to just estimate the initial value of the conductivity of the dialysate fluid representative of the conditions prevailing after the diffusion process has reached stable conditions; the estimate is based on one or more conductivity measurements in the dialysate before reaching the stable conditions and using proper estimate algorithms.

Glucose and urea, the main electrically neutral substances in dialysis fluid, reduce the conductivity of the dialysis fluid. The effect is small but noticeable and leads to a plasma conductivity underestimation and thus to an underestimation of the plasma sodium. Hence, a compensation for urea and glucose contribution may also be applied to the measured conductivities □_diand ≡_do: the resulting conductivities for pure ion solutions (□_0,diand □_0,do) may alternatively be used in all the calculations using conductivities reported below.

The control unit 12 may compensate the measured initial conductivity value of the dialysate as a function of the concentration of at least glucose.

Moreover, the control unit may compensate the measured initial conductivity value of the dialysate as a function of a flow rate, such as the dialysate flow rate at the outlet.

The control unit 12 may compensate the measured initial conductivity value of the dialysate as a function of an efficiency parameter of the filtration unit 2, (e.g. a clearance of the filtration unit 2, in detail the urea clearance).

Furthermore, the control unit 12 may compensate the measured initial conductivity value of the dialysate as a function of an estimated plasma concentration of glucose and/or urea.

The specific formula to compensate the measured initial conductivity value of the dialysate is the following:

$\begin{matrix} κ_{0, d o} = \frac{κ_{d o}}{(1 - γ_{g} (c_{d i, g} + \frac{f_{g, K_{B}} K_{u}}{Q_{d o}} (\frac{c_{p, g}}{f_{p w}} - c_{d i, g})) (1 - γ_{u} \frac{K_{u}}{Q_{d o}} \frac{c_{p, u}}{f_{p w}})} & (2) \end{matrix}$

The significance of the denotations and constants above is given in the Glossary.

The control unit 12 may be configured to compensate the initial conductivity of the dialysis fluid as a function of the concentration of glucose, if glucose is present in the dialysis liquid.

The control unit 12 is specifically configured to compensate the initial conductivity of the fresh dialysis fluid using the following formula:

$\begin{matrix} κ_{0, di} = \frac{κ_{di}}{1 - γ_{g} c_{di, g}} & (3) \end{matrix}$

The significance of the denotations and constants above is given in the Glossary.

It is worth to note that the initial conductivity of the fresh dialysis fluid upstream the secondary chamber 4 may be either measured or taken as the set value for dialysis conductivity.

In general, it is preferred to measure the initial conductivity of the dialysis fluid through the sensor 35, too.

It is important to underline that the initial setting of the sodium concentration calculated or determined as above stated to be as close as possible to the expected plasma conductivity (eq. 1) may be optional, meaning that the method for estimating the initial plasma conductivity may be performed even if the sodium content of the dialysis conductivity is initially simply set by the operator.

Also correction based on main electrically neutral substances is optional and may be used or not to increase accuracy.

The compensation for the main electrically neutral substances (e.g. urea and glucose) may be alternatively applied to the final adjustment contribution terms.

Vice versa, it is relevant to measure at least the conductivity downstream the filtration unit (and preferably also the conductivity upstream the filtration unit) as soon as possible, i.e. as soon as stable conditions are reached or as soon as an estimate of such conductivity in stable conditions may be performed.

This is due to the need of matching as much as possible the patient initial plasma conductivity which is clearly affected/changed by the different conductivity of the dialysis fluid circulating during the treatment.

In order to make a first estimate of the plasma conductivity based on measured values, two embodiments are provided, which may be used together or alternatively.

Firstly, the control unit 12 calculates the value of the initial plasma conductivity, based on the measured initial parameter value of the dialysate (i.e. based on conductivity or concentration measurement of dialysate on the filtration unit outlet) and on the corresponding parameter value of the dialysis fluid in the dialysis fluid supply line 8 e.g. conductivity or concentration). During the start of the treatment and particularly during circulating the dialysis fluid through the secondary chamber 4 up to measuring the initial value of the parameter of the dialysate downstream of the secondary chamber used for the calculating of the initial plasma conductivity, the dialysis fluid conductivity (or concentration) is kept substantially constant.

In other words, the calculation of the initial plasma conductivity is performed with no conductivity step as it was normally made in the prior art devices.

Indeed, both the two embodiments allowing plasma conductivity estimation do not require to change the dialysis conductivity or the sodium content in the dialysis liquid and to take measures at the inlet and at the outlet of the dialyzer in both conditions.

In this respect the term ‘substantially constant’ means that the conductivity of the dialysis fluid is not changed by the machine or by the operator, but it may not be exactly constant due to small oscillations on the measured value caused by noise, tolerances in the concentrate dosing system or tolerances in the conductivity measurements. Generally these small variations around the set value are less than 0.2 mS/cm.

Just a single reliable measurement at the inlet and at the outlet of the dialyzer may be sufficient to have a preliminary (to be made more accurate) or an already final estimation of the PC.

From a general point of view, the control unit 12 is further configured to calculate the plasma conductivity as a function of at least one or more flow rates.

The flow rates include the dialysate flow rate at the outlet of the secondary chamber 4; in addition, the flow rates may include the blood flow rate in the blood lines too.

Also an efficiency parameter of the filtration unit 2, in particular a clearance of the filtration unit 2 (e.g. the urea clearance) is used for plasma conductivity. Of course, a nominal clearance and/or a calculated clearance may be used; the calculated clearance may be both an estimated clearance as well as a compensated clearance.

Moreover, the plasma conductivity depends on an (possibly compensated) initial conductivity of the dialysate and on a (possibly compensated) conductivity of the dialysis fluid in the dialysis supply line 8.

According to a first embodiment, the control unit 12 is programmed to calculate the initial plasma conductivity based on the sum of at least the initial conductivity of the dialysate plus a difference between inlet and outlet conductivity at the filtration unit, or dialyzer, weighted by a factor of the dialysate flow rate. In more detail the difference between inlet and outlet conductivity at the dialyzer is weighted by a factor of the blood flow rate in the blood lines too.

Specifically, according to the first embodiment, the control unit 12 is configured to calculate the plasma conductivity using the following formula:

$\begin{matrix} κ_{p, 1}^{'} = κ_{0, do} + \frac{Q_{do}}{Q_{Bset}} (κ_{0, do} - κ_{0, di}) & (4) \end{matrix}$

The significance of the denotations above is given in the Glossary.

It is worth to underline that during the above described calculation of the initial plasma conductivity (formula (4)), the dialysis fluid circulates through the secondary chamber 4 maintaining the dialysis fluid parameter value substantially constant.

In the second embodiment, the control unit 12 is programmed to calculate the initial plasma conductivity based on the sum of at least the initial conductivity of the fresh dialysis fluid plus a difference between inlet and outlet conductivity at the dialyzer weighted by a factor of the dialysate flow rate. In more detail the difference between inlet and outlet conductivity at the filtration unit, or dialyzer, is weighted by a factor of the dialyzer clearance too.

Specifically, according to the second embodiment, the control unit 12 is configured to calculate the plasma conductivity using the following formula:

$\begin{matrix} κ_{p, 1}^{″} = κ_{0, di} + \frac{Q_{do}}{K_{u}} (κ_{0, do} - κ_{0, di}) & (5) \end{matrix}$

The significance of the denotations and constants above is given in the Glossary.

It is worth to underline that during the above described calculation of the initial plasma conductivity (formula (5)), the dialysis fluid circulates through the secondary chamber 4 maintaining the dialysis fluid parameter value substantially constant.

In more detail, in the formulas above:

- k_0,diis the set/measured-by-sensor 35 value for conductivity of the dialysis fluid, corrected for glucose (see previous equation);
- k_0,dois the mean value of outlet conductivity on the stability 1-minute window, corrected for glucose and urea;
- Q_diis the set value for dialysis fluid flow rate;
- Q_bsetand Q_doare the mean values, respectively, of blood flow rate set and of dialysate flow rate at the filtration unit, or dialyzer, outlet, on the stability window;
- K_uis the dialyzer diffusive clearance for urea. Since Ku may not be known at this time, different estimates may be used.

K_umay be approximated as Q_di/2.

Alternatively, K_umay be calculated as follows:

$\begin{matrix} K_{u} = Q_{bw} Q_{di} = \frac{1 - e^{KoA (\frac{1}{Q_{di}} - \frac{1}{Q_{bw}})}}{Q_{di} - Q_{bw} e^{KoA (\frac{1}{Q_{di}} - \frac{1}{Q_{bw}})}} & (6) \end{matrix}$

where

- KoA is either a known value if the control unit has information about the dialyzer used. In case the control unit has no information on the used dialyzer, a standard dialyzer value with a KoA=1100 ml/min as a fixed value is used.
- Q_bwis the blood water flow, for example, calculated as:

Q
_bw
=f
_bw
·Q
_b=0.89·Q_b (7)

where Q_bis real blood flow rate and f_bwis the apparent blood water fraction for urea, where a hematocrit of 30% has been assumed.

According to first estimate, k_p,1may be found after approx. 6 to 10 minutes after treatment start.

Of course, both formulas (4) and (5) for estimation of plasma conductivity may be iteratively applied, meaning that the newly calculated estimate of PC (k_p,1) is imposed to the dialysis fluid and a new estimate again calculated after taking measures of the conductivity at the inlet and outlet of the filter as soon as stable conditions are reached.

Of course, in case of iteration of anyone of the above calculations according to formulas (4) or (5), after the first plasma conductivity estimation, the dialysis fluid parameter value is changed since the newly calculated estimate of PC (k_p,1) is imposed to the dialysis fluid, meaning that the conductivity of the dialysis fluid is changed. This however does not impact on the fact that the first calculation according to formulas (4) and (5) is made without a change in the conductivity of the dialysis fluid.

In one way of exploiting the method, the first formula (4) or the second formula (5) is applied only once and the estimated PC (k_p,1) is considered already a good estimation of initial plasma conductivity.

In another way, the first formula (4) is applied twice.

In a further way, the second formula (5) is applied twice; in this case, the dialysis fluid sodium concentration correspondent to k_p,1″ is iteratively calculated and applied. k_d0is measured again as soon as stable conditions are reached: the stability criteria are the same as previously described. A second estimation of PC (k_p,2) according to formula (5) is done and k_p,2is used as k_p,pre.

In this second case k_p,2should be found after approx. 11-17 minutes after treatment start.

A further way, the second formula (5) is applied twice.

The above mentioned steps according to one of the described embodiment are schematically shown in FIG. 3.

It is relevant to note that in equations (4) and (5), k_doand k_dimay be used instead of k_0,doand k_0,di.

A timeout may be provided for each of k_p,1and k_p,2estimation phases (due to e.g. a change in some parameters). At the end of either one of these timeouts (e.g., if the stability has not been reached), an alarm shall be triggered to de-activate the isotonic treatment procedure. In general it does not make sense to apply isotonic dialysis too late into the treatment.

The dialysis fluid sodium concentration correspondent to k_p,preis then determined.

The resulting dialysis fluid sodium concentration applied, c_di,Na,kp,pre, would correspond to implement an isoconductive dialysis.

However, since an isotonic or isonatremic or isonatrikalemic dialysis is to be applied, this sodium value may be adjusted with a proper adjustment factor (depending on the choice to apply isotonic, isonatremic or isonatrikalemic dialysis).

In respect to the above mentioned treatments, it is relevant to note the following.

An isonatremic dialysis may in general terms be considered as a treatment where the sodium concentration in the extracellular fluid of the patient is maintained stable or undergoes reduced variations throughout treatment.

It is however worth noting that tonicity is determined by the particles that are osmotically active.

Actually, the dialysis fluid (and the plasma) contains a multitude of substances that influence tonicity/osmolality, not just sodium, even if this is the main determinant of serum osmolality.

Hence, an isotonic dialysis may be considered as a dialysis where the tonicity of the fluids in the patient is maintained stable or undergoes reduced variations throughout dialysis treatment. This would be achieved by maintaining the tonicity of the dialysis fluid substantially equal to the tonicity of the extracellular fluid throughout treatment. In this case, the tonicity of the dialysis fluid does not change pre- to post-filtration unit 2.

An isonatrikalemic dialysis, may in general terms be considered as a treatment where the sum of sodium and potassium concentrations in the patient extracellular fluid is maintained stable or undergoes reduced variations throughout dialysis treatment (in this case, the sum of sodium and potassium concentrations of the dialysis fluid does not change pre- to post-filtration unit 2).

Considering that a patient shall lose a certain amount of potassium during treatment, the isonatrikalemic condition may be maintained with a proportional increase in serum sodium concentration.

An isoconductive dialysis may in general terms be considered as a dialysis treatment maintaining the conductivity of the dialysis fluid equal to the conductivity of the extracellular fluid, which in this case is represented by the plasma conductivity.

The plasma conductivity (PC, □_p) is the conductivity at which the dialysis fluid conductivity is not changed during its passage through the dialyzer. Then the conductivities upstream and downstream the filtration unit 2 are equal: □_di=□□_do.

In case of an isotonic or isonatremic or isonatrikalemic treatment is to be performed, the mentioned adjustment factor is calculated based on molar conductivities, dialysis fluid composition, and the best estimate of plasma water composition as will better emerge from the following description. The best estimate of plasma water composition may be derived from literature, or may be based on statistical prepared values, or test of patient, or obtained with direct lab measurements made before the treatment.

According to an innovative aspect, the control unit 12 receives a value representative of a parameter of the blood in said blood lines 6, 7. The blood parameter may be the plasma conductivity or a plasma conductivity-related parameter.

In particular, the control unit 12 may be programmed for calculating the plasma conductivity, for example executing the method previously disclosed or, alternatively using known methods such as those described in EP 2377563.

Alternatively, the control unit 12 directly receives as an input the plasma conductivity. For example, the physician or the nurse may receive a lab analysis and may provide the datum to the machine through the user interface of the dialysis monitor; the control unit 12 is programmed for storing in a memory the plasma conductivity to be used for the following dialysis fluid parameter regulation.

Finally, the plasma conductivity may be directly measured in vivo by the monitor before starting the treatment session using a proper plasma conductivity sensor.

The control unit 12 is generally configured for setting a parameter value for the dialysis fluid in the dialysis supply line 8 at a set point.

The parameter of the dialysis fluid is chosen between a conductivity of the dialysis fluid, a conductivity-related parameter of the dialysis fluid, a concentration of a substance in the dialysis fluid and a concentration-related parameter of a substance in the dialysis fluid.

Depending on the specific dialysis monitor, the sodium content (or the content of more than one electrolyte) may be regulated in the dialysis line. Alternatively, the control parameter may be the overall conductivity of the dialysis fluid.

The setting of the parameter value in the dialysis fluid (which is hereinafter identified as sodium concentration set point in the dialysis fluid with no limiting effect) includes the sub-step of calculating the sodium concentration set point (at least) as a function of a main contribution term based on/function of the plasma conductivity and as a function of an adjustment contribution term, i.e. a term which takes into account the transport driving gradient of certain specific substances. Additionally, compensation for unintended sodium transfer may be applied as explained in detail in the last paragraphs of the present description.

The main contribution term may affect (may contribute to) the dialysis fluid sodium concentration set point for at least 80% of the same parameter value (and in particular for at least 90% of the parameter value), i.e. the general value of the sodium concentration mainly depend on plasma conductivity.

In more detail, the adjustment contribution term may contribute to the dialysis fluid sodium concentration set point for less than 15% of the same parameter value (and in particular for less than 10% of the parameter value).

The calculation is an algebraic sum of at least the main contribution term (c_di,Na,κ_p,pre) and the adjustment contribution term (c_di,Na,adj) according to the following general formula:

c
_di,Na,set
=c
_di,Na,κ
_p,pre
+c
_di,Na,adj

In order to obtain a dialysis fluid sodium implementing a certain kind of dialysis, i.e. C_di,Na,set, an adjustment factor C_di,Na,adjneeds to be applied to make the dialysis fluid matching a certain specific concentration of the plasma.

(c_di,Na,κ_p,pre) is the dialysis fluid concentration of sodium at isoconductive state, i.e. when the dialysis fluid conductivity □_dimatches the estimated pre-dialysis plasma conductivity □_p,pre.

Though not essential since a calculation may be made based on conductivities too, the main contribution term and the adjustment contribution term are dimensionally concentrations of a substance (e.g. sodium) in a fluid.

The adjustment contribution term is the sodium concentration set point adjustment relative to an isoconductive state to provide a specific treatment which may be, for example, chosen in the group including isotonic dialysis, isonatremic dialysis, and isonatrikalemic dialysis.

The Applicant has understood that certain specific substances, namely bicarbonate, potassium, acetate, and citrate have a major effect which should be taken into account when it is desired to run an isotonic, or isonatric, or isonatrikalemic dialysis treatment. Indeed, an isoconductive dialysis (i.e. a dialysis maintaining the conductivity of the dialysis fluid equal to the conductivity of the extracellular fluid, which in this case is represented by the plasma conductivity—as defined, plasma conductivity (PC, □_p) as the conductivity at which the dialysis fluid conductivity is not changed during its passage through the dialyzer so that the pre-dialyzer and the post-dialyzer conductivities are equal: □_di=□_do) causes an overload of sodium in the patient.

To avoid overloading at least the effect of the above substances must be taken into duly consideration. Of course other substances play a role, such as lactate, magnesium, and calcium.

Furthermore, the difference in concentration between same substances in the blood and in the dialysis fluid influences, as well, the sodium overload in case of isoconductive treatments.

Given the above, the Applicant also realized that in calculating the adjustment contribution term, certain parameters having a weight in determining the overload of sodium are known and depends on the machine dressing (e.g. used concentrates) or on the prescription for the patient (e.g. dialysate flow rate). Other parameters depend on the patient undergoing the treatment and therefore may be either directly measured (e.g. lab analysis) or estimated (e.g. based on large population numbers or patient history).

Since isoconductive dialysis causes sodium overload, the adjustment contribution term generally assumes a negative value, i.e. reduces the set point concentration of sodium in the dialysis fluid calculated for isoconductive treatment.

In more detail, the control unit is configured to calculate the adjustment contribution term based on a concentration of at least a substance in the dialysis fluid chosen in the group including bicarbonate, potassium, acetate, lactate, and citrate; in particular calculation is made as a function of the concentration of at least two of said substances, and in further detail as a function of the concentration of bicarbonate, potassium, acetate, and/or citrate, and lactate in the dialysis fluid.

As mentioned, the control unit is configured to calculate the adjustment contribution term as a function of the difference, in particular weighted difference, in concentration of at least one of the above cited substances in the dialysis fluid and the same substances in the blood plasma.

Additionally, the control unit calculates the adjustment contribution term as a function of the molar conductivities of at least a substance in the dialysis fluid; in detail the substance may be chosen from the group including acids or salts of bicarbonate, chloride, acetate, phosphate, and sulphate, wherein the salt is formed with sodium, potassium, calcium, or magnesium.

In more detail, the calculations take into account the molar conductivities of at least two of said substances, specifically of at least three and particularly of sodium bicarbonate (NaHCO₃), sodium chloride (NaCl), sodium acetate (NaCH₃COO), trisodium citrate (Na₃C₆H₅O₇), and potassium chloride (KCl).

Again, the adjustment contribution term is a function of the differences between two molar conductivities, a first molar conductivity of a substance chosen in the group including sodium bicarbonate (NaHCO₃), sodium acetate (NaCH₃COO), trisodium citrate (Na₃C₆H₅O₇), and potassium chloride (KCl), and a molar conductivity of sodium chloride (NaCl).

Alternatively, the adjustment contribution term is a function of the differences between two molar conductivities, a first molar conductivity of a substance chosen in the group including sodium bicarbonate (NaHCO₃), trisodium citrate (Na₃C₆H₅O₇), and potassium chloride (KCl), and a molar conductivity of sodium chloride (NaCl).

The control unit is also configured to calculate the adjustment contribution term as a function of an estimated plasma water concentration of at least a substance chosen in the group including bicarbonate, potassium, acetate, lactate, and citrate; in particular the calculation is made based on the estimated plasma water concentration of at least two, three or four of said substances; in the specific example of the present description the adjustment contribution term is a function of the estimated plasma water concentration of bicarbonate, potassium, and acetate or is a function of the estimated plasma water concentration of bicarbonate, potassium, citrate, and acetate.

The estimated plasma water concentration of bicarbonate, potassium, citrate, and acetate is the mean pre-dialysis values of the corresponding substance for large patient populations. As previously mentioned, the estimated plasma water concentration of bicarbonate, potassium, and acetate may alternatively be based on other statistical prepared values, or historical values for the specific patient, or direct measurements made before the treatment.

Note that, in the specific formula, the estimated plasma water concentration is adjusted by a respective (preferably fixed) adjusting factor. Numerical values can be, e.g. 0.95 or 1.05, but other values may be used (generally depending on the protein content, or charge of ions).

The adjustment contribution term is an algebraic sum of a plurality of components, a first component being function of the difference, in particular weighted difference, in concentration of at least a substance in the dialysis fluid and the same substance in the blood plasma, the second component being function of the difference, in particular weighted difference, in concentration of at least a second substance in the dialysis fluid and the same second substance in the blood plasma, the third component being function of the difference, in particular weighted difference, in concentration of at least a third substance in the dialysis fluid and the same third substance in the blood plasma, optionally the fourth component being function of the difference, in particular a weighted difference, in concentration of at least a fourth substance in the dialysis fluid and the same fourth substance in the blood plasma, the fifth component depends on at least a ratio between one flow rate, in particular the dialysate flow rate at the outlet of the secondary chamber 4, and an efficiency parameter of the filtration unit 2, in particular a clearance of the filtration unit 2, optionally the urea clearance.

The substance may be chosen in the group including bicarbonate anions (HCO₃⁻), acetate anions (CH₃COO⁻), citrate, and potassium ions (K⁺), but additionally also lactate.

The above general consideration is reflected in specific and non limiting implementing formulas which allow, when the plasma conductivity is known, to determine the precise set point for sodium concentration in the dialysis fluid for running an isotonic, isonatremic or isonatrikalemic treatment.

Of course, different formulas including one or more of the general principles/substances above stated may be alternatively used.

In order to obtain a dialysis fluid sodium implementing isotonic dialysis, i.e. c_{di,Na,set,isotonic}, an adjustment factor c_{di,Na,isotonic,adj}needs to be applied to make the dialysis fluid matching the tonicity of the plasma:

c
_{di,Na,set,isotonic}
=c
_di,Na,κ
_p,pre
+c
_{di,Na,isotonic,adj} (8)

where:

or where the adjustment factor also takes care of citrate according to the following relationship:

$\begin{matrix} c_{di, Na, isotonic, adj} = - \frac{1}{M_{κ_{NaCl}}} ((M_{κ_{{NaHCO}_{3}}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, {HCO}_{3}} - c_{di, {HCO}_{3}}) + (M_{κ_{NaAc}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, Ac} - c_{di, Ac}) ++ (M_{κ_{KCl}} - M_{κ_{NaCl}}) (α * c_{pw, K} - c_{di, K}) ++ \frac{K_{b_{Cit}}}{K_{u}} (M_{{Na}_{3} Cit} - 3 M_{κ_{NaCl}}) ((0.167 α^{- 3} + 0.125 α^{- 2} + 0.706 α^{- 1}) * c_{pw, {Na}_{3} Cit} - c_{di, {Na}_{3} Cit}) ++ \frac{Q_{do}}{K_{u}} (κ_{rest 1} + κ_{rest 2})) & (9 a) \end{matrix}$

K_b_Citis the approximated clearance value for citrate. This clearance is calculated for the actual flow rates using a mass transfer value of K₀A_Cit=0,212*K₀A_Ureain the corresponding K_uformula.

FIG. 4 shows the conductivity values upstream and downstream the dialyzer after setting the fresh dialysis fluid sodium concentration for running an isotonic dialysis treatment.

It is worth to mention that the plasma conductivity might be also measured using conductivity steps and applying the methods described in publications n. EP 547025 and/or in EP 920877. This alternative or additional estimation of plasma conductivity may further improve the plasma conductivity estimation made with the previously described technique.

Factor k (namely, k_rest1, k_rest2, and k_rest3—see also the following formulas (10) and (11)) defines the effect on the conductivity due to other components in the dialysis fluid different from the components already treated and included in the respective formula. Thus, the effect of salts containing calcium, magnesium, lactate, phosphate, and sulphate may have upon the conductivity. The effect created by these components is most often small, and does not vary considerably between the dialysis treatments.

In order to obtain a dialysis fluid sodium implementing isonatremic dialysis, i.e. c_{di,Na,set,isoNa}, a adjustment factor c_{di,Na,isoNa,adj}needs to be applied to make the sodium concentration of dialysate out from the dialyzer matching the sodium concentration of dialysis fluid at the inlet of the dialyzer:

c
_{di,Naset,isoNa}
=c
_di,Na,κ
_p,pre+_{cdi,Na,isoNa,adj} (10)

where:

$\begin{matrix} c_{di, Na, isoNa, adj} = - \frac{1}{M_{κ_{NaCl}}} ((M_{κ_{{NaHCO}_{3}}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, {HCO}_{3}} - c_{di, {HCO}_{3}}) + (M_{κ_{NaAc}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, Ac} - c_{di, Ac}) ++ M_{κ_{KCl}} (α * c_{pw, K} - c_{di, K}) + \frac{Q_{do}}{K_{u}} κ_{rest 3}) & (11) \end{matrix}$

or where the adjustment factor also takes care of citrate according to the following relationship:

$\begin{matrix} c_{di, Na, isoNa, adj} = - \frac{1}{M_{κ_{NaCl}}} ((M_{κ_{{NaHCO}_{3}}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, {HCO}_{3}} - c_{di, {HCO}_{3}}) + (M_{κ_{NaAc}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, Ac} - c_{di, Ac}) ++ \frac{K_{b_{Cit}}}{K_{u}} (M_{{Na}_{3} Cit} - 3 M_{κ_{NaCl}}) ((0.167 α^{- 3} + 0.125 α^{- 2} + 0.706 α^{- 1}) * c_{pw, {Na}_{3} Cit} - c_{di, {Na}_{3} Cit}) ++ M_{κ_{KCl}} (α * c_{pw, K} - c_{di, K}) + \frac{Q_{do}}{K_{u}} κ_{rest 3}) & (11 a) \end{matrix}$

For K_b_Citcalculation see above.

In order to obtain a dialysis fluid sodium implementing isonatrikalemic dialysis, i.e. C_{di,Na,set,isoNa+K}, an adjustment factor c_{di,Na,isoNa+K.adj}needs to be applied to make the sum of sodium and potassium concentrations of dialysate out from the dialyzer matching the corresponding sum of concentrations of dialysis fluid at the inlet of the dialyzer:

c
_{di,Na,set,isoNa+K}
=c
_di,Na,κ
_p,pre
+c
_{di,Na,isoNa+K,adj} (12)

where:

$\begin{matrix} c_{di, Na, isoNa + K, adj} = - \frac{1}{M_{κ_{NaCl}}} ((M_{κ_{{NaHCO}_{3}}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, {HCO}_{3}} - c_{di, {HCO}_{3}}) + (M_{κ_{NaAc}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, Ac} - c_{di, Ac}) ++ (M_{κ_{KCl}} - M_{κ_{NaCl}}) (α * c_{pw, K} - c_{di, K}) + \frac{Q_{do}}{K_{u}} κ_{rest 3}) & (13) \end{matrix}$

or where the adjustment factor also takes care of citrate according to the following relationship:

$\begin{matrix} c_{di, Na, isoNa + K, adj} = - \frac{1}{M_{κ_{NaCl}}} ((M_{κ_{{NaHCO}_{3}}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, {HCO}_{3}} - c_{di, {HCO}_{3}}) + (M_{κ_{NaAc}} - M_{κ_{NaCl}}) (\frac{1}{α} * c_{pw, Ac} - c_{di, Ac}) ++ \frac{K_{b_{Cit}}}{K_{u}} (M_{{Na}_{3} Cit} - 3 M_{κ_{NaCl}}) ((0.167 α^{- 3} + 0.125 α^{- 2} + 0.706 α^{- 1}) * c_{pw, {Na}_{3} Cit} - c_{di, {Na}_{3} Cit}) ++ (M_{κ_{KCl}} - M_{κ_{NaCl}}) (α * c_{pw, K} - c_{di, k}) + \frac{Q_{do}}{K_{u}} κ_{rest 3}) & (13 a) \end{matrix}$

For K_b_Citcalculation see above.

Once the set point for sodium is calculated, the control unit drives the regulating means 10 for regulating the conductivity or the concentration of the substance in the fresh dialysis fluid and sets the parameter value for the dialysis fluid in the dialysis fluid supply line 8 at the calculated set point.

With respect to all the above sodium concentrations set for the isotonic, isonatremic, and isonatrikalemic dialysis treatments, it is worth to note that the calculated and proposed concentration shall be within the isotonic sodium set user limits.

These limits may be chosen by the operator before isotonic dialysis start, within the following limits:

- For instance, the absolute safety range (e.g. 120±160 mmol/l);
- the sodium range corresponding to the conductivity allowed range of the machine (e.g. 12÷16 mS/cm), given the used bag and the prescribed bicarbonate.

Generally, if the calculated sodium concentration value for the set falls outside the user range, the isotonic dialysis should be de-activated and/or at least a warning is given to the operator.

Hence, the output of the described task is a new value for sodium concentration in the dialysis fluid, which is used as sodium set value for the regulating means (i.e. concentrate dosing system) when isotonic dialysis is active.

Advantageously, the changes to sodium set value will not affect the bicarbonate set value, which remains the one set by the operator.

In order to have a further degree of freedom for sodium set adjustment, before applying it to the remainder of the treatment, an additional offset may also be applied. This additional offset can be different depending on the isotonic dialysis type.

After the application of sodium adjustments above described, the inlet conductivity correspondent to the fresh dialysis fluid sodium concentration determined with Eq. 8, 10, or 12 shall then be kept constant throughout the remainder of the treatment.

After the setting of the sodium set point for the isotonic treatment, the plasma conductivity may be further calculated/monitored using common procedures, such as those described in patents EP 547025 or in EP 920877 to monitor PC throughout the treatment.

During the identification phase (i.e. plasma conductivity initial estimate), the sodium setting is likely to be too high, leading to unintended sodium load. The time for this estimation may slightly vary, but as an average is about 15 minutes; accordingly, the magnitude of the error is in the range of 5 mmol/l (of course varying with how well the expected plasma conductivity matches the actual plasma conductivity, as well as the magnitude of the isotonic adjustment).

To maintain the patient's sodium balance during the dialysis treatment, the calculated sodium set value must be adjusted to compensate for any additional unwanted sodium load to the patient.

Moreover, if common procedures such as those described in patents EP 547025 or in EP 920877 to monitor plasma conductivity throughout the treatment are used (e.g. Diascan measurements), a sodium transfer will result from the conductivity steps (10 mmol/L for 120 s for example). This sodium transfer can be either in the positive or negative direction.

Such unintended transfers may need to be compensated for in order to maintain the desired sodium balance during the treatment.

In order to make the treatment truly isotonic (or better, to minimize the tonicity gradient between the dialysis fluid and the blood), such unintended transfers need to be compensated for as a whole.

In order to manage multiple deviations e.g. from Diascan measurements, the compensation may be implemented by integrating some, or possibly any deviation from the intended sodium set point (i.e. the sodium concentration that is set after the measurement of the isoconductivity, c_di,Na,set) and then compensate for this over the remaining time of treatment (T−t, where T is the total treatment time and t is the elapsed treatment time).

The applied compensated sodium concentration set point may be calculated according to the following formula:

$c_{di, Na, set, compensated} = c_{di, Na, set} + \sum_{i} \frac{1}{T - t_{i}} \overset{t_{i} + Δ t_{i}}{\int_{t_{i}}} (c_{di, Na, set} - c_{di, Na, actual, i}) dt$

where c_di,Na,set, is the sodium setpoint calculated by the described algorithm (in other terms c_di,Na,setmay be c_{di,Na,set,isotonic}, c_{di,Na,set,isoNa}, c_{di,Na,set,isoNa+K}; cf. formulas the actual 8, 10, and 12), c_di,Na,actualis the actual dialysis fluid sodium concentration set point used during the treatment at the time an additional compensation is to be applied for (note that c_di,Na,actualmay deviate from c_di,Na,set, due to both the initial estimation of isoconductivity and/or the plasma conductivity monitoring procedures, e.g. Diascan steps).

The compensation may be or may be not activated once c_di,Na,sethas been calculated (for example about 15 minutes after treatment start, i.e. at the end of the identification phase), and may (or may not) take the past history into account so that any sodium transfer during the isoconductivity identification phase is also compensated.

The compensation may be applied after every sodium i-th deviation, i.e., when sodium is equal to c_{di,Na,actual,i}for a duration of Δt_i. Hence, also aborted Diascan measures may be taken into account (in this case, Δt may be lower than the forecast conductivity step).

Instead of applying a single compensation factor for each deviation, a potential alternative is to apply an integral controller, which, on the basis of the current error on applied sodium set vs. isotonic/isonatremic/isonatrikalemic set found and on the time still available, applies automatically a corrected set.

	Number	Date	Country
Parent	15574956	Nov 2017	US
Child	16849456		US

APPARATUS FOR EXTRACORPOREAL BLOOD TREATMENT

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