Device for measuring performance parameters of substance and energy exchange modules

ES 2 227 754 T3 description

Procedure for measuring performance parameters of energy and substance exchange modules.

Hemodialysis has become in the last 30 years a life-saving facility for hundreds of thousands of patients around the world.

As it is a chronic treatment, during this period the expenses for the national economy have increased considerably.

To guarantee the treatment of an increasing number of patients in industrial countries and make it possible in developing countries, it is necessary to optimize the quality of the procedure and, on the other hand, reduce costs. On the other hand, the optimization of the procedure is an essential cost factor, since a well-treated patient is less morbid and, therefore, requires less care

Within the framework of the NCDS (National Cooperative Dialysis Study), the morbidity of a large group of patients has been investigated in the USA according to the “dialysis dose”. Gotch and Sargent (KIdney International 28,526-534,1985) have found a simple explanation for the results obtained: morbidity falls from a high value to a constant lower value when the Kt / V value increases from 0.8 to> = 1, formula in which K is the effective Clearance for urea, t is the treatment time and V is the total water in the body.

The hypothesis that morbidity and mortality depend on the parameters for urea described by Kt / V, has been confirmed in the US uniform treatment market; but not the interpretation of the Sargent and Gotch NCDS data. New data indicate that mortality continues to decline to a Kt / V of 1.5. Furthermore, reliable data are lacking for a sufficient number of patients (See: Parker Thomas F. Short-term dialysis should only be used with great caution. Seminars on Dialysis 1993: 6: 164-167. Hakim RM, Breyer J. Ismail N, Schulman F. Effects of dialysis dose on morbidity and mortality. In J. Kidney Dis. 1994; 23; 6619, Parker TF, Husni L, Lew N, Lowrie EG, Survival of hemodialysis patients in the US improves with large amounts of dialysis. In J. Kidney Dis. 1994; 23: 670-80 and others).

This knowledge has led to the conclusion that the USA standards (DOQI Guidelines) establish a minimum dose of Kf / V = ​​1.2 or 1.4 for diabetics. These standards have been considered relevant by the inspection authorities; but the maintenance of the minimum requirements must be confirmed by means of adequate procedures.

To this end, one possibility lies in determining the effective Clearance, the treatment time and the total body water. The treatment period can be determined trivially and the corporeal water can be determined by known methods such as, for example, the bio-impedance technique or by using the urea model. The effective Clearance is difficult to determine with conventional methods, although the inventor of DE 3938662 cites a procedure for the "in vitro" determination of the effective electrolytic dialysis which, within the scope of measurement precision, is equivalent to the effective Clearance for urea. Subsequently, "in vitro" and "In vivo" experiments have shown that this procedure is feasible in practice, being recommended in assemblies such as the 1997 EDTA Congress in Geneva and the 1997 ASN Congress in San Antonio, by the industry.

The hypothesis suggested that electrolyte dialysance is approximately equal to urea clearance, is only true when the electrolyte is a mixture generally referred to as "acid concentrate" and is essentially made up of chlorides. When, for example, the concentration of total dialysate or only the bicarbonate components varies, the coincidence is less.

In the method described in DE 3938662, the electrolyte transfer is measured at two (or more) input electrolyte concentrations and the dialysis is calculated from this. For this purpose, the inlet and outlet concentration must be kept constant for a period of approximately 1 to 5 minutes, since the variations give rise to error based on the time constant of the measurement. The time constant is generated by the fill volume of the dialyzer and causes a skip function at the inlet to slow the outlet concentration and adjust slowly. Such a curve is found in the work of the inventors Polaschegg HD, Levin NW, Hemodialysis machines and monitors., Jacobs C, Kjellstrand CM, Koch KM, Winchester JF, editors. Replacement of kidney function by dialysis, 4^to edition, Kluwer Academic Publishers, 1996: 333-79. The book cited here also contains all the information necessary to understand these statements from the point of view of the current technique. The modification of the electrolyte concentration is carried out, as a rule, automatically, by varying the mixing ratio between the concentrate and the water in the dialysis apparatus. Since the setting of a new dialysis fluid concentration is subject to a time constant, the total measurement takes several minutes and requires considerable electrolyte transmission, which must subsequently be compensated for by a regulated input or output. Consequently, the method is only indicated in practice for newly built apparatuses, the retrofitting of existing apparatuses is expensive and not indicated. Because of the relatively long measurement time with this procedure, only the effective clearance can be measured, not the dialyser clearance. The two values ​​are distinguished by the influence of the recycling in the blood input or in the circulatory system, parameters that are interesting in themselves. Finally, the procedure, provided that the modification of the dialysis fluid concentration is carried out by the mixing system of the dialysis fluid, is only indicated for

ES 2 227 754 T3 single-seat dialysis machines; but not for centrally supplied dialysis machines.

Consequently, the following limitations or drawbacks are deduced for the procedure described by the inventor and already in application:

The measurement is relatively long and is linked to a transmission of electrolyte that should not be neglected. The procedure is not indicated for measuring substances not contained in dialysate (eg creatinine, phosphate) and cannot distinguish between dialyser clearance and effective clearance.

The purpose of the present invention is to reduce these drawbacks and, furthermore, to offer an installation that can be easily adapted to existing devices without the need to alter the electronic control and that is also suitable for other substances. In the invented installation, a predetermined quantity of substance is added to the cycle of the dialysate upstream of the dialyzer, the quantity that comes out of the dialyzer down-current is determined and, based on it, the dialysance or "clearance" of the dialyser is calculated. the supplied substance.

The addition of substance can be carried out in different ways and even, instead of an addition, a dilution can be carried out. Thus, upstream of the dialyzer, a liquid concentrate of a single substance (eg, NaCl or creatinine) can be injected or, alternatively, simply water can be added. Injection can be done manually with a syringe or semi-automatically with a spring loaded syringe or automatically with the aid of a pump. Similarly, the concentrate drive pump installed in the dialysis apparatus may be momentarily actuated at a higher rate to generate a bolus of electrolyte. As an alternative to adding a predetermined quantity of substance, an unknown quantity can be added, although this must be determined with a sensor installed upstream in the dialyzer. Furthermore, an amount not exactly known, but repeatable, can be calibrated by means of a first bolus injection, taking the measurement itself with a second injection. In this regard, the calibrator injection can be carried out in favor or against the current of the sensor or the dialysate cycle can be connected to a “bypass” and carry out the calibrator injection in the same place against the current of the dialyzer as the injection for the measurement. proper.

Instead of injecting a liquid substance, the addition of a quantity of substance can be effected by momentarily passing the dialysis liquid through a cartridge or powder bag.

The invention is explained in detail below on the basis of a mathematical derivative and representations of various embodiments.

Fig. 1 shows a section of the liquid cycle in a conventional dialysis machine. 10 is the dialysate inlet from a source not shown in more detail. In this regard, it may be a mixing system of a single-seat dialysis machine or a central dialysate supply. In this line, an injection point or supply connection 170 has been added through which the substance for clearance measurement can flow. A first sensor for measuring clearance 172 follows, which is optional, as well as a first valve for dialysate 124. 200 is the dialyser which is separated on the one hand for blood and the other for dialysate by means of a membrane. semipermeable (not shown). The consumed dialysis liquid leaves the dialyzer through line 144, first passes through the second dialysate valve 125, a pressure sensor 126 and a blood loss detector 128 and finally reaches the second sensor for clearance measurement. 174 and continues on line 12 to an exit not shown. From line 10 a "bypass" line with valve 122 is bypassed to line 144. The injection point 170 is preferably located; but not necessarily upstream of the "bypass" valve, while the second sensor is preferably positioned downstream of the "bypass" valve in the drain line. Sensor 174 and discretionary sensor 172 are linked with an evaluator 190.

Fig. 2 shows the dialyzer 200 with blood, as well as the dialysate inlet and outlet lines and the designations used in the mathematical derivative, with QB being blood flow and QD being dialysate flow. cBi is the concentration of blood at the inlet, cBo the concentration of blood at the outlet of the blood section of the dialyzer. In this regard, cDi is the concentration at the dialysate inlet and cDo the concentration at the outlet.

The following derivative is expressly mentioned, in relation to the level of the technique, in the aforementioned patent DE938662, as well as in the inventor's publication “Polaschegg HD. Non-invasive automatic measurement of intradialytic clearance ”. Int. J. Artif. Organs 1993; 16; 185-181 ".

Dialysis D can be calculated from the QD dialysate flow, the Cdi and Cdo dialysate concentrations, and the cBi blood concentration, as follows:

D = QD *

CDi - CDo

CBi - CDi (1)

The concentrations before the addition of substance are designated with the index 0 and the concentration during the substance bolus, with the index 1. For the simplified derivative that follows, it is further accepted that the flow of dialysate and dialysis (and therefore therefore, also the blood flow), they remain constant during the measurement and there is no

ES 2 227 754 T3 some ultra-filtered. However, the current procedure is also usable with simultaneous ultra-filtering. Thus, it applies that:

D⁰ = D¹ = D und QD⁰ = QD¹ = QD (2)

In addition, another hypothesis is made, which is applied to the measurement method of the invention; but not to that described in DE3938662, accepting that during the measurement, the concentration in the blood inlet does not vary cBi⁰ = cBi¹ (3)

1, 2 and 3 can vary as follows for both indices:

D * CBi - D * cDi⁰ - QD * (cDi⁰ - cDo⁰) (4)

D * CBi - D * cDi¹ = QD * (cDi *¹ - cDo¹)

The lower formula of 4 is used to substitute D * CBi in the upper formula, thus eliminating the unknown quantity cBi. Thus, it turns out:

D * (cDi¹ - cDi⁰) = QD * (cDi¹ - cDi⁰) - QD * (cDo¹ - cDo⁰) (5) and, finally, you get:

_D _ QD * (cDi¹ - cDi⁰) - QD * (cDo¹ - cDo⁰) _ Cdi¹ - cDi⁰⁽⁶⁾

Both sides are divided by QD:

D _ QD * (cDi¹ - cDi⁰) - QD * (cDo¹ - cDo⁰)

QD _ QD * (cDi¹ - CDi⁰)(7)

Assuming the concentration of flowing dialysate does not vary, cDi 'can be considered as superposition of a constant concentration cDio and a bolus concentration DcDi, as graphically represented in FIG. 2b.

Cdi¹ _ cDi⁰ + dcDi, cDo¹ _ cdo⁰ + dcDo (8)

With 7 and 8 you also get

D _ QD * (dcDi) - QD * (dcDo) QD _ QD * (dcDi) (9)

Now, the integration over dcDi or dcDo over time multiplied by QD yields the amount of substance that circulates and leaves the dialyzer against the current and with the current:

ΔΜ1 _ QD * f dcDi * dt, ΔΜ2 _ QD * f dcDo * dt (10)

The integration interval should be chosen until the output bolus has decreased to a negligible rate.

Thus, it is obtained with 9 and 10:

D _ QD *

ΔΜί - ΔΜ <>

ΔΜϊ (11)

ES 2 227 754 T3

Since the amount of substance Mi is predetermined, only the concentration at the outlet is measured as a function of time and, furthermore, after deducting the base, the integral is formed. In practice, this is done either by continuously calculating an average value of the output concentration in a continuous manner or immediately prior to measurement. When starting the substance addition, the integration program is started in the evaluator 190 either automatically or by means of a delivery system not shown. This evaluator receives from the control unit of the dialysis apparatus a signal proportional to the dialysate flow and, via another delivery unit, information on the quantity of substance. The measurement constants for the conversion of the sensor signal into a concentration signal are stored in the evaluator 190 or can be transmitted by means of a transmitter. These transmitter units conform to the state of the art and will not be described in more detail. Digital and analog transmissions and, to some extent, computer transmissions are also possible.

The control unit calculates, from the constants received and the quantity of substance measured leaving the dialyzer, calculates the dialysis D according to equation 11 and transmits it to an indicator or transmits the information to an external computer or stores it.

It should be noted that the formulas are derived from the amounts of substance or from the concentrations. Generally, a substance concentration is measured indirectly, for example through conductivity. If the dependence between the concentration or quantity of the substance and the physically measured parameters in the relevant area is not linear, this circumstance must be taken into account. This is the case when conductivity is used for measurement and another conductivity scale is used. The corresponding transfer functions can advantageously be sent to the evaluator 190 or, alternatively, the signals can be transmitted directly to an external computer by making the correction with a suitable program.

The optional sensor can be used against the dialyzer current to determine the input quantity when it is not easily determinable because, for example, the quantity cannot be determined with sufficient accuracy.

Water injection: In a special embodiment of the invention, simply water is injected. In this way, the dialysis of a discretionary substance cannot be determined, but only the dialysis of one or more substances contained in the fresh dialysate. As the amount of the input substance Mi, the volume of the added amount of water is chosen. The amount of exit substance Mo is calculated from the integral of the negative exit bolus relative to the basic concentration. When injecting the water, the amount should be measured in such a way that the osmolarity of the dialysis fluid does not fall below the limit for hemolysis.

By means of a suitable semi-permeable membrane, for example a reverse osmosis membrane, water can also be momentarily removed. This case can be treated as adding a concentrate.

Disturbing influences: By injecting a quantity of substance, the flow of dialysis fluid is momentarily increased. Preferably, the point of delivery should be far enough away from the dialyzer for the bolus of substance to reach the dialyzer when the flow has normalized. In so-called volumetrically balanced dialysis systems, the injected amount cannot expel an equal amount of dialysis fluid in evacuation since it is a closed system. On the contrary, this amount is re-filtered in the patients or, in the case of a long-lasting ultra-filtration, it is reduced for the duration of the bolus. This can lead to a slight alteration of the output quantities and, as a consequence, to a violation of the hypotheses 6 and 6. This influence, which can be calculated or determined experimentally, can be sent to the evaluator as a correction quantity. Alternatively, simultaneously with the injection of the substance, an equal amount of liquid can be withdrawn upstream or downstream of the dialyzer. This operation can be carried out manually or automatically with a syringe or a pump or also automatically by means of a momentary increase in the ultrafiltration ratio. Alternatively, an expansion chamber or bag can be integrated into the dialysis fluid cycle to avoid pressure shocks due to addition.

If the dialysance of the electrolyte solution is determined and it is accepted that the concentrations have not increased by more than 10% at most, a momentary increase in flow of 3 to 5% occurs when concentrates with a molar concentration of 3 to 5 are used. Generally, this increase in flow is negligible.

Influence of re-circulation: The formulas are obtained from a constant input concentration on the blood side. Correspondingly, the clearance of the dialyzer is determined. The amount of substance delivered per bolus is partially transferred into the blood with the concentration increasing there on the outlet side. This bolus on the blood side passes to the blood inlet and, in the event of recirculation in this area, a part of this bolus returns to the blood inlet side of the dialyzer. If at this time, the measurement process is not yet finished, this circumstance influences the result by increasing the dialysis output bolus, thereby reducing the clearance calculated according to 6 with respect to the clearance of the dialyzer. This value is called effective clearance. The aforementioned blood concentration bolus passes through the human blood circulation, part of it recirculates and, after 1 to 2 minutes, reaches the blood access again. This re-circulation is called cardiopulmonary and its influence can be taken into consideration after a suitably long integration.

By means of an ideal conception of the volumes of the extrapolar system and of the dialysis fluid cycle and with

With the aid of shorter injectable boluses, the influence of re-circulation can be determined, at least approximately, not only integrally, but also separately.

Other embodiments: Another preferred embodiment is represented in fig. 3. 180, 182 and 184 are valves and 186 is a reservoir that can contain a liquid or powder concentrate, granular or solid (tablet). To produce a bolus of substance, the dialysate flow is momentarily passed through reservoir 186, closing valve 184 and opening valves 180 and 182. During this process the flow of dialysate is not altered, not registering any alteration as mentioned before. Valve 180 can be designed as a passive spring-loaded valve that opens at a certain overpressure, for example 0.2 bar. Valve 182 can be implemented as a passive check valve. When valve 184 closes, the pressure therein increases and valve 180 opens. When valve 184 opens, valve 180 closes again.

The reservoir 186 can contain a liquid concentrate that is entrained when the valve 184 is closed, thus obtaining a bolus of extremely short duration. Since quantity versus volume can be easily determined, a dialyzer 172 counter current sensor is not required for this procedure. If the reservoir 186 is filled with solid concentrate that does not completely dissolve in the dialysis fluid, as a general rule, the amount dissolved cannot be predetermined. The advantage of such an embodiment is that the measurement process can be repeated several times without recharging the tank. Obviously, the reservoir can be filled with a powder that dissolves completely with the passage of dialysate. This embodiment is analogous to filling with liquid concentrate.

Sensors: As sensors, all sensors that directly or indirectly measure the concentration of a substance and have sufficient time segregation are indicated. For electrolyte, this is advantageously a conductivity sensor. If a pure substance is added upstream, such as NaCl or NaHCO3, the dialysance for this substance can be determined even though the conductivity sensor is not specific for the substance. Thus, for example, the dialysance of sodium bicarbonate can be determined, which, as a consequence of the size of the molecules, is smaller than that of urea, a circumstance that is not normally taken into account. If several specific downstream sensors are available, by adding a mixture of countercurrent substance, the dialysance of several substances can be simultaneously determined. Ion sensitive electrodes are indicated for measuring electrolytes.

To determine the dialysance of non-conductive substances, optical sensors such as light spin sensors can be used to determine the glucose concentration. The dialysance of creatinine and urea as well as different amino acids can be measured by optical extinction in the ultraviolet zone. Generally, the flow of dialysis fluid is known exactly in dialysis machines. If the device of the invention is installed in a further apparatus, a flow sensor can advantageously be provided, the signal of which is sent to the flow sensor. In another embodiment, the signal can also be sent to the ultrafiltrate pump, suitably correcting the dialysance by known approximate formulas against the influence of the ultrafiltrate.

Calibration: For sensor calibration or, in the event that the amount of substance to be added is not sufficiently known, an initial bolus addition can be made immediately before the sensor. This operation can be performed manually or automatically by opening the "bypass" valve 122 and simultaneously closing the dialyzer valves 124 and 125. In the case of automatic control of the dialysis apparatus, the dialysis liquid cycle will first be connected to the "bypass" and then a first bolus will be generated; then, the “bypass” will be closed again, it will wait for a stable state to be reached and a new bolus will be produced. During this process only good reproducibility is necessary; but not a precise addition of a quantity of substance or a sensor upstream of the dialyzer.

Other applications: The device of the invention can work in principle "in vivo" by injection on the blood side; but this does not represent an advantage due to the risk of bacterial contamination by the injection. Checking the dialysate side can be done as indicated. Checking on the blood side is usually more difficult because normally, for economic reasons, non-invasive sensors have to be used and optical procedures are altered by hemoglobin as well as plasma protein.

The device can be used advantageously "in vitro" as regards quality assurance. For this purpose, water can circulate on both sides of the membrane and the bolus on the side of the dialysis fluid; but, as an alternative, it can also be added on the blood side, since in these measurements the bacterial contamination is negligible. Also, checking is possible on either side. To obtain information on measurement errors, sensors can be arranged downwind in both circuits. In this case, the added quantity must be equal to the sum of the measurements in both outputs.

As a single measurement process lasts only a few minutes, by means of manual or automatic injection of the substances independently, a series of measurements can be quickly established, for example, for all conductive substances including sodium phosphate. Instead of water, a lowered solution can also be used in the case where the dialysance of a weak electrolyte is to be measured. By means of pH sensors the dialysance of acids can be measured.

Heat exchanger: Heat exchangers are described with the same formulas as dialyzers. Actually, the equations for dialyzers have been derived in the same way as the old formulas for dialyzers.

ES 2 227 754 T3 heat exchangers. By injecting hot or cold water on one side and measuring the temperature on the other side, the heat transfer coefficient can be determined analogously to how it is done to determine dialysis.

Implementation of the point of application: The device for supplying the amount of substance against the flow of the dialyzer can be realized as a point of application with separation or as a valve. Sampling valves that can be opened manually or automatically by installing an injection connector are also suitable.

Amount of substance provided: The volume of the solution with which the substance is applied should be as small as possible so that the alterations are scarce when the flow of dialysis fluid is varied. Correspondingly, the concentration should be as low as possible. The amount of absolute substance shall be adjusted to the sensor spacing and, in any case, shall not exceed the physiological limits. Furthermore, the resulting maximum concentration should not be higher or lower than the physiological limits. For the electrolyte, the following estimate applies: The normal electrolyte concentration in the dialysate is 150 mmol / l, and concentrates up to 5 mol can be obtained. For a bolus of 10% over the normal concentration and a duration of 1 minute, a quantity of substance of 7.5 mmol is required with a dialysate flow of 500 ml / min., Which corresponds to a volume of 7.5 mmol / 5000 mmol / l = 1.5 ml. If water is injected, to reduce the concentration by 10%, about 50 ml should be injected over 1 minute; but the injection process can be faster. The bolus is distributed based on the irregular current in the dialyzer, consequently reducing the maximum concentration.

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ES 2 227 754 T3

List of designations

<td>Ref No.</td><td>Designation</td>

<td> 10</td><td>Dialysate inlet from a dialysis fluid source not shown in more detail</td>

<td> 12</td><td>Dialysate bypass</td>

<td> 122</td><td>Bypass valve</td>

<td> 124</td><td>First dialyzer valve, dialyzer inlet valve</td>

<td> 125</td><td>Second dialyzer valve, dialyzer outlet valve.</td>

<td> 126</td><td>Dialysate pressure sensor</td>

<td> 128</td><td>Blood loss detector</td>

<td> 144</td><td>Dialysate outlet line from dialyzer to evacuation line 12</td>

<td> 170</td><td>Application point for clearance measurement</td>

<td> 172</td><td>First sensor for clearance measurement</td>

<td> 174</td><td>Second sensor for clearance measurement</td>

<td> 180</td><td>First bypass valve (electromagnetic valve or constant pressure valve)</td>

<td> 182</td><td>Second bypass valve (electromagnetic or reverse valve)</td>

<td> 184</td><td>Third bypass valve (electromagnetic)</td>

<td> 186</td><td>Cartridge for powder or liquid concentrate</td>

<td> 190</td><td>Evaluation unit</td>

<td> 200</td><td>Dialyzer</td>

<td> 220</td><td>Blood pump</td>

<td> 230</td><td>Arterial blood duct system</td>

<td> 242</td><td>Venous blood duct system</td>

<td> 244</td><td>Venous drip chamber</td>

<td> 246</td><td>Infusion connection in the venous drip chamber</td>

<td> 248</td><td>Connector to infusion connection</td>

<td> 312</td><td>Flowmeter</td>