Blood treatment equipment

Description of equivalent WO 2004022135 A1

Control apparatus and control method for a blood treatment equipment.

FIELD OF INVENTION

This invention relates to a control apparatus and control method for a blood

treatment equipment. The present invention relates also to a blood treatment

equipment comprising said control apparatus.

More particularly, the invention is concerned with an apparatus, such as a

programmable computer, capable of operating on a blood treatment equipment

such as an hemodialysis or other blood treatment equipment; the programmable

controller is adapted to receive entries of prescribed and measured information and

to generate one or more output signals in response thereto. In general the output

signals are employed to control a variable operation performed by the blood treatment equipment and hence automatically perform treatment procedure control

methods.

BACKGROUND OF THE INVENTION

It is known in the art of hemodialysis and other blood treatment machines using

measured values of certain parameters in order to control the working of the

machine.

For instance, EP097366 and US 4508622 both disclose a device provided with two conductivity cells 32,50 on the dialysis liquid side; one cell operates upstream the

dialyzer and the other downstream the dialyzer. The two cells are able to measure

conductivity of the dialysis liquid or sodium concentration. The measured data of

- l - detectors are compared and eventually used to control the composition of the dialysis solution.

In Gambro EP0330892, it is of advantage to employ measured values of a patient's conditional values to control functional aspects of hemodialysis equipments. In this fashion, the hemodialysis equipment may be controlled dependently of specific treatment requirements of a patient. In particular, this reference teaches to determine the concentration for a certain solute in patient's blood and other important parameters as actual clearance (indicated herein as K in ml/min) or dialysance values (expressed herein as D in ml/min). If for instance the system of EP0330892 is adapted for determining sodium concentration or conductivity of patient's blood, the dialysis liquid concentration can be controlled in order to bring about an equilibrium between the conductivities of blood and dialysis liquid, thereby obtaining a control adapted to the individual which should provide comfort for the patient. It is also known from EP0532433 a blood treatment device able to detect actual sodium dialysance and then derive urea clearance by extrapolation. Such a calculated urea clearance is then compared with a desired urea clearance value and in case of need the flow rate of the dialysis pump or of the blood pump, or the treatment time are changed. In case treatment time is changed also the UF rate of the ultrafiltration pump is modified.

On the other hand during the last twenty years a specific index, the KT/V index, has been regarded as particularly indicative of the dialysis treatment. More in detail Keshaviah and Collins (Keshaviah P, Collins A: Rapid high-efficency bicarbonate hemodialysis, Trans Am Soc Artif Intern Organs 32: 17, 1986) reported in a well documented and well designed study on short dialysis, using the KT/V index as a parameter of dialysis adequacy. This index, introduced in 1985 by Gotch and Sargent (Gotch F, Sargent JA: A mechanistic analysis of the National Cooperative Dialysis Study (NCDS). Kidney Int. 28: 526, 1985) is calculated as the product of the urea clearance (K, ml/min) of the dialyser and duration of the dialysis session (T, min), divided by the distribution volume of urea (V ml). Gotch and Sargent analysed the data of the large scale National Cooperative Dialysis Study (NCDS) in the US and determined that a KT/V value of 0.9-1.0 constitutes adequate dialysis therapy. Values less than 0.8 are associated with a high probability of therapy failure. Keshaviah and Collins (Keshaviah P, Collins A: Rapid high-efficency bicarbonate hemodialysis, Trans Am Soc Artif Intern Organs 32: 17, 1986) also demonstrated that short and rapid dialysis treatment is well tolerated when acetate is replaced by bicarbonate and is not associated with increased mortality and morbidity if therapy is prescribed keeping KT/V greater than 1. In view of the above works, the value D or K for a certain solute (Notice again that Durea=Kurea) have been employed to determine value K*Tj , herein indicated as dialysis dose achieved after time Tj.

The approach presently followed in the blood treatment machines available on the marketplace is to obtain a measure of and to provide information related to a total dialysis dosage K*T value delivered as time progresses during a hemodialysis treatment procedure. This measure and the information provided is essentially based on parameters including: a prescribed duration of the treatment procedure, the blood flow rate, the choice of the hemodialyser A combination of above parameters is employed to obtain a measure of the total dialysis dosage value K*T_t delivered as an integral of mean measured instantaneous clearance values measured after determined time increments, the dialysance of the chosen dialyser (which is an in vitro clearance value) and the effective treatment time. The effective treatment time is the time during which diffusive (and generally also convective) transfer of blood solutes across a semi- permeable membrane of a hemodialyser takes place. The above procedure basically enables a measure to be made of the K*T value delivered to a patient during a hemodialysis treatment procedure.

At the end of the treatment which normally lasts a prefixed total time T_tot, the machine provides the user with the value of K*Ttot and with the value K*Ttot/ V. This procedure, however, suffers from a number of drawbacks. Specifically, such factors as blood flow rate and effective treatment time, which are relevant to clearance, are prone to change or are difficult to follow during a hemodialysis treatment procedure. Furthermore, the dialysance or clearance capacity of hemodialyser products can change significantly during a hemodialysis treatment procedure time. Present day hemodialysis monitoring equipment and hemodialysis procedure methods may comprise means for assessing or measuring dialysis dosages delivered to a patient over determined time increments, but no means are available for controlling the dialysis dosage value actually delivered to the patient, on an ongoing bases during treatment, and for carrying out actions on the dialysis machine working parameters as a function of the detected dialysis dosage delivered to the patient. It is an overall objective of the present invention to secure an ongoing control over the actual total dialysis dosage delivered to a patient.

It is another object of the invention to control some parameters of a blood treatment machine as a function of the values of the dialysis dose measured in the course of the treatment.

Furthermore, it an object of the invention to provide a control apparatus and a blood treatment equipment able to coordinate achievement of the prescribed dialysis dose with substantially contemporaneous achievement of other prescription(s).

A further object is to provide a system for synchronizing achievement of a prescribed dialysis dose, of a prescribed weight loss and of a further prescribed prescription, such as concentration of a certain substance in patient's blood.

Another object of the invention is to offer a system, which is adapted to reduce, if possible, the treatment time while achieving the requested prescribed results at the end of the treatment. Moreover it is an object of the invention to provide a controller and an equipment using said controller able to display updated values for a number of parameters, on ongoing basis at regular intervals during treatment.

SUMMARY OF THE INVENTION The above and other objects are reached by a controller, by a control method and by an equipment according to one or more of the appended claims. T h e c o n t ro l l e r a c c o rd i n g to th e i n ve n t i o n i s adapted to receive one or more entries of measured information measured during the course of a treatment procedure, calculate from said measured information at least a significant parameter indicative of the progress of an extracorporeal blood treatment carried out by the equipment, compare said calculated significant parameter to at least a prescribed reference value for the same parameter, and to generate at least one output control signal responsive to said comparison for automatically controlling one or more operations performed by the equipment. The significant parameter can be one chosen in the group comprising:

- the actual dialysance D or clearance K-π of a blood treatment unit associated with the equipment for a specific solute after a time Tj elapsed from the beginning of the treatment; - the concentration of a substance in the blood of a patient undergoing a treatment or the patient's plasmatic conductivity Cp-π achieved at the elapsed time Tf,

- the dialysis dose K*Tτι achieved at the elapsed time T;

- the weight loss WL-η achieved at the elapsed time T,; - a parameter proportional or known function of one or more of the above

parameters.

The controller is adapted for receiving measured information from a conductivity sensor operating downstream the treatment unit or from a concentration sensor, again operating downstream the treatment unit, calculates at regular time intervals the achieved value of dialysis dosage and regulates the removal rate from the second compartment in order to have achievement, at the end of the treatment, of both the total prescribed dialysis dosage value KT_P and the prescribed total weight

<img file="WO2004022135A1_D0001.tif" /> The removal rate can be controlled by changing the speed of an ultrafiltration pump or if the equipment does not include a pump devoted to ultrafiltration only, by changing the speed of a pump associated to the waste line at the output of the second compartment. The controller can be programmed for estimating at regular time intervals the remaining treatment procedure time Tt_r or the total treatment time T_tot necessary for achieving the prescriptions.

The controller can also be programmed for keeping said rate of fluid removal UF-π at time T, substantially equal to the product of a factor R, determined by the ratio between WLp and KT_P, by the instantaneous clearance K-n or instantaneous dialysance value D_Tι measured at treatment time Tj. In this case the controller synchronizes two prescriptions and ends the treatment at the prescribed values are reached with no need of calculating the remaining treatment time or the treatment time at each interval. Safety measures may be provided to avoid that the treatment time or the fluid removal from the second compartment fall outside prescribed ranges. Note that the prescribed reference value may comprise a patient blood conductivity or concentration target Cp_end: in this case the controller is programmed for controlling the conductivity or concentration of the treatment liquid entering the second compartment as a function of a blood conductivity or concentration target Cp_en_d. in order to have blood conductivity or concentration for a substance reaching said conductivity or concentration target Cp_end on or before said estimated total treatment time Tt_ot- Alternatively the controller is programmed for controlling the conductivity or concentration of the treatment liquid entering the second compartment for reaching said conductivity or concentration target Cp_end When another prescription is reached (for instance total prescribed weight loss or total prescribed dialysis dose), with no need of calculation of a remaining treatment time.

According to a further aspect, the controller is associated with a display screen adapted to display at the time intervals Tj one or more of the values of the group comprising:

- remaining time Tt_r ,

- total treatment time Ttot,

- clearance of dialysance measurements at the elapsed time T_it

- achieved dialysis dosage KT-π after Tj time,

- achieved weight loss WL-n after T| time,

- achieved patient's conductivity after Tj time, - prescribed value for more of the significant parameters,

- a value proportional to one or more of the above values. The invention also relates to a control method.

The invention furthermore concerns program storage means including a program for a programmable controller, the program when run by the controller programming the controller to carry out the steps disclosed in the claims.

An important difference between the invention as described above and approaches followed in the past is that the treatment procedure time involved in the present invention need not be a prescribed time but may be a time which is dependent on achievement of a prescribed value. Thus, in accordance with the invention, the treatment time may be controlled by measured information which can be related to a measure of an effective clearance value of a substance

(usually urea is the reference substance) measured after a determined time increment during a hemodialysis treatment procedure.

Notice that clearance values are influenced by ultrafiltration, which leads to convective transfer of solutes in blood plasma across a semi-permeable

membrane of a hemodialyser product into dialysis fluid. In practically all

hemodialysis treatment procedures, ultrafiltration to achieve loss of excess fluid in the patient is required. The controller is therefore adapted to include or

account for the convective clearance, which follows from ultrafiltration. Most preferably, therefore, the controller should be adapted to provide output

information related to both the diffusive and convective clearance values or

conveniently an integrated measure of these two values.

DESCRIPTION OF THE DRAWINGS

The invention will be described with reference to the accompanying exemplary

drawing tables, wherein:

Fig 1 is a schematic drawing of hemodialysis equipment associated

with a controller according to the invention;

Fig 2 is a flow diagram showing the working principle of a controller

according to a first embodiment of the invention; Fig 3 is a flow diagram showing the working principle of a controller

according to a second embodiment of the invention; Fig 4 is a flow diagram showing the working principle of a controller according to a third embodiment of the invention; Fig 5 is a flow diagram showing the working principle of a controller according to a fourth embodiment of the invention; Fig 6 and 7 are flow diagrams of routines, which can be executed by the controller of the invention as part of its working principle. Fig 8 schematically shows a display screen that would be associated with the controller and equipment of the invention.

DETAILED DESCRIPTION

Specific embodiments of a controller and of a blood treatment equipment, associated with or comprising a controller according to the invention, are described below. For the purpose of this description reference is made to a specific blood treatment equipment, namely a dialysis equipment. However the invention is not limited to such equipment and can be used in conjunction to other kinds of blood treatment machines. With reference to specification, including the accompanying schematic drawings and the claims, the symbols below will have the meanings identified as follows: T_ot = total treatment time

T|= elapsed treatment time, i.e. effective treatment time elapsed from the beginning of the treatment session T_tr= remaining treatment time m_ax= maximum treatment time T_mιn= minimum treatment time

D_a= average dialysance

D_T|= actual dialysance at time T,

K_a= average clearance Kχι= actual clearance at time T

KT= dialysis dosage value

KT_P= prescribed dialysis dosage value

KTτ,= integrated dialysis dosage value at time T,

WL= weight loss WL_P= prescribed weight loss

WLτ,= weight loss at time T,

UF= fluid removal rate from the second compartment of the treatment unit

UFτ_ι= fluid removal rate from the second compartment of the treatment unit at time T,

Referring now to Figure 1 schematic drawing, reference numeral 1 refers generally to a blood treatment equipment, such as for instance hemodialysis equipment, comprising or associated with a controller 2, for instance a programmable controller. The equipment as shown is connected to a blood treatment unit 3, such as a hemodialyser, comprising a first or blood compartment 4 and a second or dialysate compartment 5 divided by a semi- permeable membrane 6. A blood pump 7 is provided upstream of the hemodialyzer for pumping blood from a patient along blood arterial line 8 into the blood compartment and out from the blood compartment along blood venous line 9 to drip chamber 10 and back to the patient (not shown). Of course the position and number of blood pumps and the specific treatment unit indicated in the embodiment of fig.1 are for exemplifying purpose only and are not intended to limit the scope of the invention. Dialysate, coming for instance from a dialysate preparation section 16, is conveyed into the dialysate compartment 5 along dialysate inlet line 11 and out from the dialysate compartment along dialysate outlet line 12 in a direction counter-current to blood flow in the hemodialyzer. A fluid balancing system is responsible of controlling the amount of fluid entering the second compartment and the amount of fluid exiting the second compartment so as to create a desired weight loss rate during treatment. For instance, the balancing system may be associated to a variable speed ultrafiltration pump 13 operating on an ultrafiltration line 13a branching off line 12 and provided for pumping ultrafiltrate from blood compartment across the semi-permeable membrane into the dialysate chamber and out from the dialysate outlet line 12. The balancing system can comprise conventional means, e.g. flow meters 14, 15 located upstream and downstream of the hemodialyzer product 3 in the way shown in figure 1. The flow meters are connected to controller 2 so that the controller is able to act at least on the ultrafiltration pump and on the waste pump 12a to keep the flow rate of the fresh dialysis liquid measured by flow meter 14 equal to the used liquid flow rate measured by flow meter 15. As the ultrafiltration pump 13 branching off conduit 12 operates upstream the flowmeter 15, such pump 13 flow rate defines the weight loss rate. Other balancing systems may comprise controlling volumes and/or weights of dialysate delivered to and withdrawn from the dialysate compartment. An infusion line may also be provided with (not shown in the appended drawing tables) for injecting replacement fluid in the arterial and/or in the venous line 8, 9. The infusion line flow rate can be obtained by variable speed pumps, which can be controlled by flow meters or volumeters or weight meters associated to the infusion line. In case of use of one or more infusion lines, also the flow rate of any infusion liquid needs to be accurately controlled during treatment, in order to control the overall balance of liquid. In this respect, notice that flow rate sensors or volumetric sensors are generally used when the dialysis or the infusion line are generated online or come from a continuous source of liquid, while weight sensors are typical of embodiments wherein the liquids are withdrawn from or conveyed to containers. For instance in case of a hemodialysis circuit using a fresh dialysate bag and a waste container, it is known to use one or two separate scales associated to the containers in order to provide a controller with an information concerning the overall weight difference between the fluid entering the second compartment of the dialyzer and the fluid exiting the second compartment. It is clear for those skilled in the art that the present invention can be used in any kind of blood treatment machine, independently from the specific balancing system. Going now back to the detailed description of the embodiment of figure 1 , the equipment 10 can be adapted to perform different treatments such as: conventional hemodialysis, HD, where no infusion is present and dialysis liquid circulates in the second compartment of the dialyzer (fig 1 ); hemofiltration, HF, where no dialysis liquid is present while solutes and plasma water are pumped through line 12 and substitution fluid (not shown) is infused in the extracorporeal circuit or directly into the patient; - hemodiafiltration, HDF, which is a combination of HD and HF; other blood treatments in case the treatment unit is correspondingly modified. After the above description of the general structure of equipment 1 , here below a more detailed analysis of the controller 2 will be provided. Controller 2 comprises at least a programmable microprocessor with associated memories and interfaces suitable to communicate with the components of equipment 1. Of course the present invention controller could also comprise an analogical type calculator, though this embodiment is not felt to be the most appropriate in term of costs and flexibility. The controller 2 is adapted to receive one or more entries of measured information measured during the course of a treatment procedure. In the embodiments shown the measured information comprises the conductivity of the dialysis liquid or the concentration of the dialysis liquid for at least a substance, measured downstream the dialyzer 3, i.e. on line 12. As shown in figure 1 the controller is connected with measuring means 18 for measuring the conductivity of the treatment liquid downstream the treatment unit. Alternatively the controller may be connected to means for measuring the concentration of a substance in the treatment liquid downstream the treatment unit. Since the measured information may also comprise the conductivity of the dialysis liquid or the concentration of the dialysis liquid for at least a substance, measured upstream the dialyzer 3, i.e. on line 11 , the equipment 1 of figure 1 also includes measuring means 17 for measuring at least one of the conductivity of the treatment liquid upstream the treatment unit, or of the concentration of a substance in the treatment liquid upstream the treatment unit. The measurements carried out by the measuring means 17 operating upstream the treatment unit could be substituted by set or known values of conductivity or concentration. Notice that if the measured information is the urea concentration, it is not even necessary to carry out a measurement upstream as urea is absent from fresh dialysis liquid. In case the measuring means are devoted to measure conductivity, then each measuring means 17, 18 comprises at least a conductivity cell. If the measuring means are devoted to measure an ion's concentration then said means comprises an ion selective sensor or a urea sensor (notice again that in case of measure of a quantity absent in fresh dialysis liquid -as urea - then there is no need to use a sensor on line 11 ).

The controller 1 is then programmed to calculate from the measured information (for instance from the value of the conductivity upstream and downstream the treatment unit) a value of at least a significant parameter indicative of the progress of an extracorporeal blood treatment carried out by the equipment. According to the invention the significant parameter is one chosen in the group comprising:

- the actual dialysance D-n or clearance K-n of a blood treatment unit associated with the equipment for a specific solute after a time Tj elapsed from the beginning of the treatment; - the concentration of a substance in the blood of a patient undergoing a treatment or the patient's plasmatic conductivity Cp-π achieved at the elapsed time TJ;

- the dialysis dose K^*T_Tj achieved at the elapsed time T; - the weight loss WL-π achieved at the elapsed time T;

- a parameter proportional or known function of one or more of the above parameters.

Finally, the controller is adapted to compare said calculated significant parameter to at least a prescribed reference value for the same parameter, and to generate at least one output control signal responsive to said comparison for automatically controlling one or more operations performed by the equipment. For instance, the controller 1 after having compared the calculated value of one or more significant parameters with the corresponding reference value for the same parameter may generate the output control signal responsive to said comparison for automatically controlling a fluid removal rate from said second compartment. Note that the measurement of the measured information, the calculation of the significant parameter(s), and the comparison with the respective reference value are done during the treatment (or at least during an effective portion of the treatment) on an ongoing basis, at regular time intervals, as it will be described in detail here below with reference to the embodiments shown in the drawing tables. The way that is felt to be the easiest for implementing the invention provides that the time intervals are indeed constant and prefixed, for instance equal to 15 minutes each. However, the invention can be implemented also using regular but not constant time intervals: i.e. time intervals following a specified rule or rules, which the controller should know or made aware of.

In a first embodiment, the controller 2 is programmed to carry out the steps shown in figure 2.

After having started the treatment, the controller waits for a prefixed time, for instance 10 or 15 minutes, and then carries for the first time the loop shown in figure 2, loop cycle 20, which is then repeated at each successive time interval. More in detail, according to this embodiment, the controller is programmed for determining the estimated remaining treatment procedure time T_tr and/or the estimated total treatment time T_Totas a function of a calculated value of a significant parameter at time Tj. In other words the controller is able to modify the duration of the treatment if certain actual values of parameters deemed to be significant change during treatment. In particular, the controller according to the first embodiment receives (as a first step 21 of the loop cycle 20) the prescribed values for the dialysis dosage KTp and for the total weight loss WL_P to be achieved at the end of the treatment. Then, as second step 22, determines the instantaneous clearance K-π or dialysance value D_Tj corresponding to the conductivity or concentration measurements at treatment time Tj. Then, the controller calculates the effective dialysis dosage KTJI achieved at time Tj (step 23). Once calculated KTjj, the controller proceeds with step 24 for estimating the remaining treatment procedure time Tt_r as a function of said total dialysis dosage value KT_P, of the effective total dialysis dosage KTji achieved by time T, and of the instantaneous clearance Kη or dialysance value D-π measured at treatment time Tj. As an alternative or in conjunction with the determination of the estimated remaining treatment time, the controller 2 is programmed for determining the estimated value of the total treatment time T_tot. The estimated value of the total treatment time can be calculated for instance as a function of said total dialysis dosage value KT_P, of the effective total dialysis dosage KTj achieved by time Tj, and of the elapsed treatment time Tj. Alternatively said controller can calculate the estimated total treatment time Tt_ot as sum of the elapsed treatment time T| and of the estimated value of the remaining treatment procedure time T_tr. Once the estimated remaining treatment time or the estimated total treatment time are know at the instant Tj, the controller proceeds with step 25 determining an actual measured total weight loss WL-π achieved by time Tj, and setting the fluid removal rate UF from said second compartment for achieving the prescribed total weight loss WL_Pι substantially at the same time as the prescribed total dialysis dosage value KT_P is achieved.

Notice that the control on the fluid rate removal can also be done in such a way as to achieve the prescribed total weight loss some minutes before the estimated total treatment time, which as explained derives from the calculation of the actual dialysis dosage achieved at time Tj. Once corrected, if necessary (there might be the case where the flow rate extracted from the second compartment is already well tuned), the loop ends and the controller repeats the loop starting from step 21 or from step 22 at the successive time interval, i.e. after a time which can be prefixed or calculated by the controller. In the case of figure 2 the time interval is equal to15 minutes.

- u Going in further detail, notice that the controller, which is programmed for controlling, on an ongoing basis, the fluid removal rate as a function of the estimated remaining treatment procedure time Tt_r or of estimated total treatment time T_tot, sets the fluid removal rate UF-r, at time T, equal to the prescribed total weight loss WL_P less the measured weight loss WLη at time T,, divided by the estimated remaining treatment time T_tr, according to the formula:

<img file="WO2004022135A1_D0002.tif" />

Ttr

Alternatively, the controller can be programmed for setting of the fluid removal rate UFT_I at time T, equal to the prescribed total weight loss WL_P less the measured weight loss WL_T! at time T,, divided by a difference between the estimated total treatment time Tt_ot and the elapsed treatment time Tt according to the formula: UFτ, = WL₀ -WL^

Ttot - T, As explained, the controller is programmed for recalculating and updating at regular time intervals during treatment the estimated total treatment time Tt_ot and/or the estimated remaining treatment time T_tr, on the basis of the value of instantaneous clearance K_τ, or dialysance DT_I measured at the time Tj. As an alternative for determining the estimated total treatment time T_tot and/or the estimated remaining treatment time T_tr, at instant Ti, the controller could be programmed for using recent values of clearance K-n-_k or dialysance D-n-_k (i.e. values determined at one or more time intervals before Tι) .

In order to calculate dialysance and or clearance values during treatment any known method could be suitable. A know method provides that the instantaneous clearance value K_Tι or instantaneous dialysance value D_Tj is determined at treatment time Tj, by means of the following sub-steps:

- sending at least a first liquid through the second compartment of the treatment unit, - sending at least a second liquid through the second compartment of the treatment unit, the second liquid having conductivity or concentration for at least a solute different from that of the first liquid

- measuring the conductivity or concentration values of said substance in the treatment liquid downstream the treatment unit at least for both said first and for said second liquid,

- calculating the instantaneous clearance K-π or instantaneous dialysance value DTJ at least as a function of said measured conductivity or concentration values.

Further details of the above method and variants thereof are described in detail in the following publications, which are incorporated herein by reference: EP patent n.0547025 EP patent n.0658352 EP patent n.0920887

Each of the above references describes an alternative way for in vivo determination of the actual dialysance, blood sodium concentration and dialysis dose. Note that any method able to determine one or more of the above significant parameters can be used for the purpose of the present invention. Referring by way of non-limiting example to a first known method for determining the concentration of a substance in blood and/or the actual dialysance for said substance (described in detail in EP 0547025B1 ), at least two liquids differing for their respective concentration of said specific substance are sequentially circulated through the dialysate compartment 5. The first liquid can be the dialysis liquid at its normal prescribed value of concentration for the substance and the second liquid can be obtained by introducing a step or a change in the concentration of said substance at the dialyzer inlet. The step or the change has to be in someway known or measurable. Then the conductivity or concentration of the substance are measured for the first ad second liquid both upstream and downstream of the dialyzer. Note that the upstream measurements can be substituted by set reference values. Notice in this respect that if the substance is a ionic substance, then the concentration of the substance influences the conductivity of the dialysis liquid; in particular considering that conductivity is largely influenced by the concentration of sodium ions, than measure/calculation of conductivity values gives an indication of sodium concentration in blood and in the dialysis liquid. As conductivity sensors are much more convenient and easy to use than ion selective sensors for directly detecting the concentration of an electrolyte in a liquid flow, conductivity measurements are preferably used. Then by applying the following formula cited in EP 0547025B1 for the two dialysis liquids it is possible to determine the unknowns D and Cbj_n (no ultrafiltration and neglecting the so-called Donnan effect):

DTt Cdout = Cdjn + — - (Cbjn - Cd_in)

Qd

Wherein: Cdout is the conductivity or concentration of sodium in used dialysis liquid

Cdjn is the conductivity or concentration of sodium in fresh dialysis liquid C b j n i s t h e co n c e n t rat i o n of so d i u m i n u n t re ate d b l o o d

Qd is the dialysis liquid flow

D-rt is the dialysance of the membrane for the solute sodium at time T_t

(or urea clearance: notice that the size of the urea molecule being the same as the size of the sodium molecule, the capacity for these two molecules to pass through the same predetermined membrane is consequently the same. Therefore we can establish for a same membrane, the following equation: D_sodium = K_urea^; so detection of sodium dialysance gives clearance). Referring to the embodiment of figure 1 , conductivity or sensors 17 and 18 are provided which are respectively located for measuring the conductivity of dialysate flowing to dialysate compartment 5 along dialysate inlet line 11. In detail, conductivity sensor 17 provides upstream dialysate conductivity measures Cun, C₂j_n relating to the conductivity of the first and second liquid upstream the dialyzer, while conductivity sensor 18 measures the conductivities Cι_out, C_2out of the first and second dialysis liquid flowing from dialysate compartment 5 along dialysate outlet line 12. The measures of conductivity (as intermittently influenced by intermittently introducing small boluses of higher or lower concentration dialysate solutions into the dialysate inlet line) are employed to determine with the above formula instantaneous sodium dialysance values (and therefore instantaneous urea clearance values K_T!) at any point in time T, during a hemodialysis treatment procedure or after determined time increments so that a dialysis dosage K T-n, delivered at time T may be determined. The above equation can be written for the two dialysis liquids circulated through the dialyzer so that the two unknowns D-r, and Cbin, can be determined. Referring again to the drawings, the periodically measured conductivity values Cd _ιn , Cd_2m and Cdι_out , Cd_2out (1 and 2 referring to the first and second liquid respectively) are entered into the controller via lines 17a and 18a.

As mentioned the total dialysis dosage delivered up to a certain time interval is calculated and updated at each interval as function of K- , or D_tj values determined with any suitable method. In detail notice that the controller can be programmed to determine the effective total dialysis dosage KT-r, value, which has been delivered at the determined effective treatment time T,, as an integration over time of effective instantaneous clearance K_Tι or instantaneous dialysance D-r, values determined at the various regular time intervals T,. Alternatively, the effective total dialysis dosage KT value, which has been delivered at the effective treatment time T,, could be calculated as the product of the treatment time T, by a mean value of effective instantaneous clearance K-n or of instantaneous dialysance D_τ, values determined at the various regular time intervals T,. Of course other suitable methods could be devised. Figure 3 shows the steps, which a second embodiment of the controller 2 is programmed to carry out.

After having started the treatment, the controller waits for a prefixed time, for instance 10 or 15 minutes, and then carries out for the first time the loop cycle 30 shown in figure 3; loop cycle 30 is then repeated at each successive time interval. More in detail, according to this embodiment, the controller is not programmed for determining the estimated remaining treatment procedure time T_tr and/or the estimated total treatment time T-r₀t , and as a matter of fact could be unaware of the actual duration of the treatment. The aim of the controller according to this second embodiment is to receive the prescribed parameters, i.e. the total clearance dosage value KTp to be achieved at the end of the treatment (step 31 ), and a prescribed total weight loss WL_P to be achieved at the end of the treatment (step 31 ), and to synchronize achievement of both said parameters. In detail the controller is programmed for determining a prescribed rate R by dividing said total weight loss WL_P to be achieved at the end of the treatment by said total dialysis dose value KT_P to be achieved at the end of the treatment, as shown in step 32.

Then, in steps 33 and 34, the controller controls the rate of fluid removal from the second compartment of the blood treatment, said controlling comprising keeping said rate of fluid removal UF_T, at time T, substantially equal to the product of said prescribed rate R by the instantaneous clearance K_T) or instantaneous dialysance value DT, measured at treatment time T,. The loop is then concluded and the controller, as for the embodiment of figure 2, waits a time interval before stating again loop 30 from the step 31 or directly from step 32, if no new prescribed values shall be considered.

Notice that the instantaneous clearance Kτ_ι or instantaneous dialysance value D_T| measured at treatment time Tj can be determined as for the embodiment of figure 2.

In figure 4 a further embodiment of the program steps to be followed by a controller 2 according to the present invention is shown. The philosophy of the control loop 40 of figure 4 is similar to the one of figure 20 with some further features added.

After having started the treatment, the controller waits for a prefixed time, for instance 10 or 15 minutes, and then carries out for the first time the loop shown in figure 4, loop cycle 40, which is then repeated at each successive time interval. More in detail, according to this embodiment, the controller is programmed for determining the estimated remaining treatment procedure time T_tr and/or the estimated total treatment time T-r_0tas a function of a calculated value of a significant parameter at time Tj. In other words the controller is able to modify the duration of the treatment if certain actual values of parameters deemed to be significant change during treatment.

In particular, the controller according to the first embodiment receives (as a first step 41 of the loop cycle 40) the prescribed values for the dialysis dosage KT_P and for the total weight loss WL_P to be achieved at the end of the treatment, as well as prescribed values for a minimum acceptable treatment time Tmin and for a maximum acceptable treatment time Tm_ax.

Then, as second step 42, determines the instantaneous clearance K_Tj or dialysance value D-n corresponding to the conductivity or concentration measurements at treatment time Tj. Then, the controller calculates the effective dialysis dosage KTπ achieved at time Tj (step 43). Once calculated KT-π, the controller proceeds with step 44 for estimating the remaining treatment procedure time Tt_r as a function of said total dialysis dosage value KT_P, of the effective total dialysis dosage KTTJ achieved by time T, and of the instantaneous clearance K-π or dialysance value DTI measured at treatment time Tj. As an alternative or in conjunction with the determination of the estimated remaining treatment time, the controller 2 is programmed for determining the estimated value of the total treatment time Ttot- The estimated value of the total treatment time can be calculated for instance as a function of said total dialysis dosage value KT_P, of the effective total dialysis dosage KT, achieved by time Tι, and of the elapsed treatment time T_\.

Alternatively said controller can calculate the estimated total treatment time T_tot as sum of the elapsed treatment time T_\ and of the estimated value of the remaining treatment procedure time Tt_r. The controller is then programmed to carry out a sequence of operations globally indicated with 45 in figure 4 and aiming to check whether or not the estimated values of Tt_r or of Ttot are within the prescribed ranges.

In detail, said controller, at each time interval, is programmed for executing the following sub-steps of step 45: - sub-step 46: comparing the sum T-, + T_&amp;- with a minimum treatment time Tmj_n and with a maximum treatment time T_max

- sub-step 47: setting a total treatment time Tt_ot equal to the minimum treatment time T_mjn , if said sum is less then the minimum treatment time

- sub-step 48: setting a total treatment time T_tot equal to the maximum treatment time Tm_ax , if said sum is more then the minimum treatment time

- sub-step 49: setting a total treatment time T_tot equal to said sum if the sum is neither less then the minimum treatment time T_mi_n nor more then the minimum treatment time T_max Once the total treatment time is known at the instant Tj, the controller proceeds with step 45 determining an actual measured total weight loss WLγi achieved by time Tj, and setting the fluid removal rate UF from said second compartment for achieving the prescribed total weight loss WL_Pι substantially at the end of said treatment time T_ot. Notice that if the controller determines in step 46 that the remaining treatment time is such that a superior time limit for the whole treatment T_max cannot be fulfilled, the controller can activate an alarm procedure 52 and ask for intervention of an operator. If vice versa the remaining treatment time is acceptable, notice that the control on the fluid rate removal can also be done in such a way as to achieve the prescribed total weight loss some minutes before the estimated total treatment time, which as explained derives from the calculation of the actual dialysis dosage achieved at Once corrected the fluid removal rate from the second compartment, if necessary (there might be the case where the flow rate extracted from the second compartment is already tuned), the loop ends and the controller repeats the loop starting from step 41 or from step 42 at the successive time interval, i.e. after a time which can be prefixed or calculated by the controller .In the case of figure 4 the time interval is equal to15 minutes.

Going in further detail, notice that the controller, which is programmed for controlling, on an ongoing basis, the fluid removal rate as a function of the estimated remaining treatment procedure time T_tr or of estimated total treatment time Tt_ot, sets the fluid removal rate UF-r, at time T, equal to the prescribed total weight loss WL_P less the measured weight loss WL-n at time T,, divided by the estimated remaining treatment time T_tr, according to the formula:

<img file="WO2004022135A1_D0003.tif" /> Alternatively, the controller can be programmed for setting of the fluid removal rate UFT_I at time T, equal to the prescribed total weight loss WL_P less the measured weight loss WL-n at time T divided by a difference between the estimated total treatment time T_tot and the elapsed treatment time T_t according to the formula:

<img file="WO2004022135A1_D0004.tif" /> Ttot- T,

As explained, the controller is programmed for recalculating and updating at regular time intervals during treatment the estimated total treatment time Tt_ot and/or the estimated remaining treatment time T_tr, on the basis of the value of instantaneous clearance K-n or dialysance D_Tι measured at the time Ti. As an alternative for determining the estimated total treatment time T_tot and/or the estimated remaining treatment time Ttr, at instant Ti, the controller could be programmed for using recent values of clearance Kn-k or dialysance D -_k (i.e. values determined at one or more time intervals before Tj) . In order to calculate dialysance and or clearance values during treatment any known method could be suitable as for the embodiment of figure 2. As mentioned the total dialysis dosage delivered up to a certain time interval is calculated and updated at each interval as a function of KTi or Dti values. In detail notice that the controller can be programmed to determine the effective total dialysis dosage KT-π value, which has been delivered at the determined effective treatment time T, as an integration over time of effective instantaneous clearance KTI or instantaneous dialysance D-n values determined at the various regular time intervals Tj. Alternatively, the effective total dialysis dosage KTj value, which has been delivered at the effective treatment time Tj, could be calculated as the product of the treatment time Tj by a mean value of effective instantaneous clearance K-π or of instantaneous dialysance D_Tj values determined at the various regular time intervals Tj. Of course other suitable methods could be devised.

In figure 5 a variant program loop is shown, which the controller 2 can be programmed to execute. Control loop 40 of figure 5 is almost identical to the loop 40 of figure 4 and will not be described again in detail: the same reference numerals being used to identify corresponding features or steps. As in the embodiment of figure 4, after having started the treatment, the controller waits for a prefixed time, for instance 10 or 15 minutes, and then carries out for the first time the loop shown in figure 5, which is then repeated at each successive time interval.

More in detail, according to this embodiment, the controller is programmed for determining the estimated remaining treatment procedure time T_tr and/or the estimated total treatment time T_Tot as a function of a calculated value of a significant parameter at time Tj. In other words the controller is able to modify the duration of the treatment if certain actual values of parameters deemed to be significant change during treatment.

Differently from the embodiment of figure 4, the controller programmed to execute the steps of figure 5 receives (as a first step 41 of the loop cycle 40):

- the prescribed values for the dialysis dosage KT_P and for the total weight loss WL_P to be achieved at the end of the treatment,

- prescribed values for a minimum acceptable treatment time T_mj_n and for a maximum acceptable treatment time T_max, - a patient blood conductivity or concentration target Cp_end,

- the urea distribution volume V₀ for the patient.

As it will appear clear the controller 2 of this embodiment is programmed not only for achieving the aims of the controller programmed according to figure 4 steps, but also for controlling the conductivity or concentration of the treatment liquid entering the second compartment as a function of said blood conductivity or concentration

target Cp_end.

Indeed, in accordance with the embodiment of figure 5, the controller executes the same identical steps 42, 43,44, 45, 46, 47, 48, 49, 50, 51 ,52 above described with reference to figure 4 and then, after step 51 , is programmed for changing, if necessary, at each time interval, the conductivity or concentration of the treatment liquid entering the second compartment in order to have blood conductivity or concentration for a substance reaching said conductivity or concentration target Cpend on or before said estimated total treatment time T_tot (step 53 in figure 5). Notice that step 53 can equivalently be carried out before steps 50, 51 , as soon as the controller has estimated a remaining treatment time or a total treatment time at time interval Tj.

The step 53 of modifying of treatment liquid conductivity or concentration Cd comprises the following sub-steps: i. Determining a calculated value C_di of the conductivity or concentration for a substance C_d as a function of the interval target C_Pj and of the measured instantaneous dialysance or clearance Dj or Kj for time Ti, ii. Bringing the conductivity or concentration for a substance C_d of treatment liquid entering the second compartment to said calculated value C_di In detail the determining step uses one of the following formulas wherein Vo represents the urea distribution volume for the patient:

<img file="WO2004022135A1_D0005.tif" /> In the above formulas the interval target blood conductivity or concentration Cpj for the patient's blood relating to a time interval tj, according to the following steps:

- evaluating if the elapsed treatment time Ti is more or less of a prescribed value Tp,

- assigning as interval target blood Cpi = Cp_end + A, wherein A is a positive value, if Ti less than Tp

- assigning as interval target blood Cpi = Cp_end, if Ti more than or equal to Tp. In the embodiment shown, the prescribed value Tp is less than Ttot an equal to T_tot reduced by one hour.

After the detailed description concerning the embodiments of figures 2,3,4 and 5, here below are disclosed further features of the invention which can be employed in any of the embodiments wherein an estimated total treatment time or an estimated remaining treatment time are being calculated in use by the controller 2. In detail, as shown in figure 6, the controller is programmed to carry out an end treatment test 60 to check if the remaining treatment time T_tr is less than a prescribed value, for instance 15 minutes. In the negative the cycle continues with no changes while in the affirmative the removal rate at time Tj is calculated and set for the last time (blocks 25, 26; 50, 51 ) and an output signal is sent to an output device, such as display unit 19.

In figure 7 an alarm procedure is shown, which could be activated in case the estimated treatment time is greater than the maximum acceptable treatment time. Indeed as shown in figure 4 the controller could either assign as total treatment time the maximum treatment time and then warn the operator that the prescribed dialysis dose will not be fulfilled or put the machine in bypass mode and ask for intervention of an operator. Notice that in some circumstances the presence of bubbles in the dialysis line or other factors degrade the performances of the treatment unit, which can recover however its normal properties upon appropriate corrections are carried out. If the operator action is positive then the calculation of the estimated remaining or total treatment time is repeated. If again the problem persists no further intervention is requested, the machine is put in permanent bypass mode (lines 11 and 12 connected bypassing second compartment 5) and an alarm given. Please also notice that in the embodiments shown the controller is programmed to generate a control signal (arrow ^!s' in figure 1 ) to automatically control the fluid removal rate from said second compartment by controlling the variable speed ultrafiltration pump 13. However the fluid removal rate from the second compartment could be controlled in a different way depending upon the hydraulic structure and configuration of the dialysis circuit.

The controller is also associated to display unit 19 which can operate as alert device, and which can be activated if the expected treatment procedure time or remaining hemodialysis treatment time are not within a prefixed range. The display 19 is also adapted to display at the time intervals Ti one or more of the values of the group comprising:

- remaining time Tt_r ,

- total treatment time Ttot,

- clearance of dialysance measurements at the elapsed time Tj,

- achieved dialysis dosage KTTJ after T time, - achieved weight loss WL-π after Tj time,

- achieved patient's conductivity after Tj time,

- prescribed value for more of the significant parameters,

- a value proportional to one or more of the above values. In figure 8 an embodiment of a display unit 19 is shown. The display unit comprises three fields 100, 101 , 102 each of a respective colour which are controlled by controller 2 to flash when specific events occur. First field can be for instance green and flashes when the prescribed value for one or more relevant parameter is or are reached. The second field can be for instance orange and controlled to flash when the patient is close to the treatment end (block 61 ).

The third field, for instance red, can be controlled to flash in case of an alarm condition, for instance when the prescribed value KTp cannot be reached within a maximum acceptable treatment time (block 52). The display unit can also comprise an area 105 including pictograms 103, 104 which can be activated to signal the two bypass modes above described, and various additional fields for displaying alphanumerical strings 106 relating to the above prescribed and achieved significant parameters.

In addition to what already described it is also convenient to shortly underline some further possible variants to the above-described embodiments. As already mentioned, the total treatment time T_tot or remaining treatment time Tt_r at time T is regularly recalculated and updated at regular, for instance identical, time intervals during treatment, on the basis of the last or most recent instantaneous measured clearance or dialysance value DTI. As an alternative the remaining treatment time and therefore also the fluid removal rate from the second compartment at time Ti can be calculated as known functions of more then one measured clearance or dialysance values. Thus, any such changes in parameters which take place during a hemodialysis treatment procedure which may influence the dialysance or clearance of a hemodialyser product, such as blood flow rate, dialysis fluid flow rate, alterations in the permeability of the semi- permeable membrane of the hemodialyser product, will automatically be accounted for each time the treatment time is recalculated. This procedure of the invention accordingly provides a reliable means for securing a measure of the treatment time required to secure the prescribed dialysis dosage value KT_P.

It should also be borne in mind that it is one objective of the present invention to secure control over the actual total dialysis dosage delivered to a patient; this control can for example be achieved, in accordance with the invention, by computing a hemodialysis treatment procedure time as a function of calculated values related to one or more of the above identified significant parameters (such as an effective clearance or dialysis dosage value reached after at treatment time Ti); a basic component of such computation would comprise a determination of a treatment time as a function of such one or more calculated values. Thus, in this example, a computed total effective treatment time would need to be a function of one or more values KTti, KT^, KTt3,— , KT_tn, calculated in vivo using any known method after determined time increments Δt = say 5 min. For practical reasons it may only be possible to obtain a first measured value after about say 15 min of effective treatment time. Presuming this to be the case, a reasonably accurate assessment of an initial clearance or dosage value KT_tj, which has been achieved during said 15 min initial treatment time can be obtained by assuming that the measured clearance value or dosage delivered, for example after a 5 min interval, will substantially equate with the clearance value delivered over the same time period before the first measurement is made. Successive measurements of clearance values would generally be at least fractionally different from one another in that these values are dependent on changes (usually lowering) of the clearance capacity of the dialyser product during a treatment procedure, changes of blood rate, possible recirculation of treated blood, presence of bubbles in the dialysis liquid, dialysis liquid flow rate, ultrafiltration rate and other changes.

Also notice that measurements of clearance values would only be made during effective treatment times, i.e. while blood and dialysis liquid are flowing through the hemodialyser product. The controller is accordingly programmed to initiate measurements only during effective treatment times and similarly only compute or integrate effective treatment times to arrive at a computed hemodialysis treatment procedure time during effective treatment times. It would be possible to compute a hemodialysis treatment procedure time as a function of measured values in various fashions, e.g. by reference of the difference between successive total dialysis dosage values to a reference difference value and to compute an increase or decrease in the treatment time proportional to deviations from the reference difference value. Such a procedure could for example be realised more readily if a standardised total clearance or dialysis dosage value is to be achieved. Finally, it is to be noted that the invention relates also to program storage means including a program for the programmable controller 2; the program when executed by the controller programs the controller to perform the steps disclosed above and shown in the attached drawings. The program storage may comprise an optical data carrier and/or a magnetic data carrier and or a volatile memory support, which can be read or associated or put into communication with the controller for programming this latter.