SE512183C2 - Measuring concn. of urea etc. in composite fluid e.g. dialysis fluid - Google Patents

Abstract

The concn. of urea (or a similar substance) is measured in a composite soln. by a catalytic reaction with urease in a reactor column (10). The differential conductivity between reacted and unreacted soln. is measured to provide an indication of the urea concn. in the soln.. Carbon dioxide is added to the soln. which contains hydrogen carbonate ions, upstream of the column. An appts. for carrying out the process is also claimed.

Description

German Patent Specification DE-Cl-39 OO 119 describes a urea sensor of a similar type. A capillary is located in a conduit through which blood passes. By means of the capillary, plasma is sucked out of the blood and allowed to pass through a urease column. The difference in conductivity before and after the urease column is measured, and the difference is correlated to the urea content. To keep the temperature constant in the measuring device, dialysis fluid is passed in a circuit around the urease column and the two conductivity measuring cells.

Japanese publication JP-60-165551 discloses a similar device in which an ion exchange column is used to remove electrolytes, by anion-cation exchange. As a result, the measured values are considerably improved because the relative change in conductivity becomes larger because the initial conductivity is lower or almost zero. In addition, a buffer is added.

U.S. Pat. No. 3,930,957 discloses a urea sensor in which an organic buffer solution is added. An example is a solution of 0.05M Tris (hydroxymethyl) aminomethane, which has been adjusted to a pH of about 7 by the addition of glycine.

SUMMARY OF THE INVENTION According to the present invention, there is provided a method and apparatus for measuring the concentration of one or more substances in a composite solution. The substance or substances are broken down via heterogeneous catalyst, into products that are easy to measure. By adding other substances which take part in the catalyzed reaction, the chemical conditions can be changed so that the yield of the substance to be determined is optimal.

In a preferred embodiment, urea is broken down by the enzyme (catalyst) urease. This degradation depends on the pH value and by adding a suitable buffer the chemical conditions can be selected so that only one product is obtained. The method and device have the features set forth in the following claims, to which reference is made.

BRIEF DESCRIPTION OF THE DRAWINGS The invention is described in more detail below with reference to the accompanying drawings.

Fig. 1 is a schematic diagram of a sensor of the type to which the present invention relates.

Fig. 2 is a schematic cross-sectional view through a reactor column used in a preferred embodiment of the invention.

Fig. 3 is a schematic view showing the use of two parallel conductivity meters.

Fig. 4 is a schematic view showing a bypass line past the reactor column.

Fig. 5 is a schematic view showing alternating connection of one and the same measuring cell before and after the reactor column, respectively.

Fig. 6 is a valve diagram showing the coupling sequences of the valves of Fig. 5.

Fig. 7 is a schematic view showing the introduction of carbon dioxide gas into a test line.

Fig. 8 is a schematic view showing a preferred embodiment of the invention.

Fig. 9 is a schematic view of an alternative embodiment of the invention.

Fig. 10 is a schematic view of an alternative embodiment with double input of carbon dioxide.

Fig. 11 is a schematic view showing an alternative method of eliminating bubbles of carbon dioxide gas.

DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION Fig. 1 shows a sensor or meter of the type to which the present invention relates. 10 15 20 25 30 'J Ûll 512 183 In a line l passes the liquid or solution on which measurement is to be performed. This solution can be a dialysis solution that comes directly or indirectly from a dialyzer.

A sampling device 3 takes a subset of the solution from the line 1 and transfers it to an inlet line 2. The sampling device is exemplified in Fig. 1 by a pump.

An auxiliary device 4 is connected to the inlet line 2 for the addition of one or more substances, such as a buffer. The additive is controlled in Fig. 1 by a pump 5.

The sample thus obtained is fed to a reactor column 6 and allowed to pass through it. The reactor column may contain urease to catalyze the conversion of urea to ammonium ions.

From the reactor column 6, the sample is discharged to a measuring device 7, which measures the product converted in the reactor column. The measuring device 7 can be a conductivity cell, which measures the change in conductivity before and after the reactor column 6, respectively.

In order to obtain an initial value of the conductivity, there is a shunt line 9, which bypasses the reactor column 6. From the measuring device 7, the sample is discharged to a discharge device 8.

The general type of sensor shown in Fig. 1 is shown in, for example, US-A-3,930,957.

SOLUTION The composite solution, which is found in line 1 and where the content of a substance is to be measured, is a solution of a medical or biological type.

In a preferred embodiment, the solution is a dialysis solution, the urea concentration of which is to be determined. A dialysis solution contains electrolytes in a specific combination, for example Na *, K *, Cab, Mgpj Cl ", HCO§, CH3COO 'in predetermined concentrations and possibly additional substances such as glucose.

When the dialysis solution passes through a dialyzer, a low molecular weight substance is exchanged between blood on one side of the membrane of the dialyzer and dialysis solution on the other side of the membrane. Thereby, various substances from the blood pass into the dialysis solution, such as urea, creatinine, etc. At the same time, certain substances from the dialysis solution pass into the blood, especially bicarbonate HCO {.

Other types of solutions in which the present invention can be used are blood, where preferably high molecular weight substances are first separated, for example with a membrane, after which the ultrafiltrate, ie blood plasma, is analyzed.

Other types of solutions that can be used in accordance with the present invention are dialysis solution used in peritoneal dialysis, in which the outgoing PD solution is analyzed.

Still other solutions that can be analyzed are urine, sweat, tear fluid, saliva, or extracellular fluid, which is aspirated through the skin or otherwise extracted.

The solution in the tube 1 can also be a fresh dialysis solution or infusion solution where the concentration of a particular substance is to be determined, for example glucose or penicillin.

The substances whose concentration is to be measured in the solution are preferably those substances which require catalytic decomposition in order to be able to be measured, especially those which require that the pH value is within a narrow range, ie require the presence of a buffer system. Examples of such substances are: urea, L-glutamine, L-citrulin, N-acylamino acid, penicillin, L-asparagine, cholesterol, glucose. These substances can be caused to decompose or react under enzymatic action in the reactor column 6 via known corresponding enzymes. For further determination of suitable combinations, reference is made to EP-A2-0 437 789 and US-A-4 311 789.

The invention is described below with reference to urea and urease, but is applicable to the above-mentioned substances and other similar substances. 10 15 20 25 30 512 185 SAMPLING DEVICE From the solution in line 1, a sample is taken by means of the sampling device 3. In a preferred embodiment, the sampling device is a pump which is driven so that a constant small flow is taken from line 1. The sample flow can be between about 0 1-10 ml / min, preferably about 0.5-5 ml / min, such as for example 1 ml / min.

The sampling device can also be operated intermittently so that a sample is taken per unit of time, for example at intervals in the order of 5-60 minutes, for example 30 minutes. The sample size can then be between about 1-100 ml / sample, preferably about 5-50 ml / sample, such as for example 10 ml / sample.

In an alternative embodiment, the pump in the sampling device 3 is driven so that the sampling flow to the inlet line 2 is proportional to the flow in the solution line 1 with a determined proportionality constant. If, for example, the solution in line 1 is dialysis solution, which passes at 500 ml / min, one-fifth is taken via the sampling device 3, ie about 1 ml / min. If the flow in the line 1 varies, the flow in the inlet line also varies. The advantage of this embodiment is that the present invention can then be combined with the invention which appears from European patent application EP 94.102383.0, filed on 17 February 1994. In this embodiment, the pump of the sampling device 3 can also be operated intermittently, but each time so, that the sampled stream taken is a fixed subset of the solution stream in line 1.

The pump can be a ceramic pump with constant displacement per revolution and of the same type used in the GAMBRO AK 100 monitor. This ceramic pump has a very constant displacement. Thus, a very accurately metered amount can be taken from line 1. Alternatively, a peristaltic pump of known type or other similar pumps can be used. In the case that the contents of line 1 are blood, the same technique can be used as described in DE-Cl-39 00 119 where a fiber of the same type used in a fiber dialyzer is used for sampling. The required negative pressure for extraction of the ultrafiltrate, ie plasma, is generated by the pump.

It is also possible to carry out the sampling from a container with a solution to be analyzed. The container then replaces the line 1.

ADDITIONAL DEVICE The sample taken by means of the sampling device 3 is fed to the inlet line 2. An additive may be added to this line. In some cases it is desirable to adjust the pH of the solution so that the desired reaction is obtained in the reactor column 6.

In the preferred embodiment, the solution to be analyzed is dialysis solution, which contains urea and whose pH is usually about 7.4. The degradation of urea to ammonium ions causes an increase in the pH value.

US-A-3,930,957 discloses the addition of an organic buffer.

An alternative buffer system that can be used is a so-called phosphate buffer, consisting of H¿P0 [/ HPOf ', which has a pH approximately equal to 7.

However, the disadvantage of a liquid buffer is that it dilutes the solution and thus lowers its conductivity before the reaction in the reactor column.

According to a preferred embodiment of the present invention, a buffer in gaseous form, namely carbon dioxide (CO 2), is used, which cooperates with the bicarbonate buffer present in the dialysis solution. In this case, carbon dioxide in gaseous form is supplied from the additive device 4 via the pump 5 to the inlet line 2.

This is described in more detail below. 3 15 20 25 3C 512 183 The use of carbon dioxide gas as an additive in dialysis solution containing bicarbonate and in the use of conductivity measurement provides at least two advantages relative to liquid buffer, namely that the addition of carbon dioxide does not give any volume change and thus no dilution of the solution , partly that carbon dioxide has no conductivity.

By using a buffer system in connection with dialysis solution containing urea, especially carbon dioxide gas, the pH value can be checked so that optimal effect is obtained from urease.

At the same time, precipitation of calcium carbonate is avoided.

It is also possible to use a solid buffer where the buffer is immobilized on a suitable support.

REACTOR COLUMN In a preferred embodiment, the reactor column 6 is shown in Fig. 2, a cylindrical container containing the enzyme required. In the preferred embodiment, column 10 contains urease II, which is immobilized by means of alumina grains 12. At the inlet and outlet there are fine mesh filters 13, 14. The filters prevent urease and alumina from passing out of column 10. Furthermore, the filters prevent that larger particles can enter the column.

The cylindrical container 10 must have such a large volume that the substance to be converted has time to come into contact with or adjacent to the corresponding enzyme so long that a conversion reaction is catalyzed. Preferably, the column is arranged so that the sample solution containing the substance to at least 99% comes in activating proximity of the enzyme as long as the corresponding reaction is catalyzed.

It is preferred to feed the solution from below via an inlet 15 and to dispense the reacted solution at the upper end of the column via an outlet 16. Furthermore, there is a filter 17, which separates an upper part of the column 10, which contains only alumina 18, ie without urease. It will be appreciated that column 10 may have different configurations depending on the substance to be analyzed and the enzyme used. Thus, the column can also be horizontal or the flow can be reversed and pass from top to bottom. Furthermore, in the case of intermittent operation, it may be possible to introduce the sample into column 10 and allow it to remain in the column as long as a reaction is obtained, after which the sample is discharged for analysis and measurement.

It may also be possible to perform the analysis already in column 10 by measuring the conversion rate or the like.

In a preferred embodiment, the solution to be analyzed is dialysis solution containing urea and the enzyme is urease. Furthermore, the sample passes through the urease column 10 at a rate of about 1 ml / min and the column has a volume of about 4 ml, with a diameter of about 10 mm and a height of about 50 mm.

In the above-mentioned preferred embodiment, it occurs that protein and fat accompany the dialysis solution. It is desirable to separate protein and fat before or after the column, wherein either or both of the filters 13 or 14 may be a double filter, where one half of the filter has the task of filtering the incoming or outgoing solution and retaining the urease while the other half of the filter consists of a cellulose filter impregnated with activated carbon. In such a filter, organic molecules are practically completely absorbed.

MEASURING DEVICE The measuring device 7 depends on the substance to be analyzed in the solution. In connection with the preferred embodiment where urea is to be analyzed, the measuring device 7 can be an ammonium ion-sensitive electrode, which determines the ammonium ion content in the solution after the reactor column 6. Such a measuring device appears from WO 94 / O8641 and US-A-4 686 479 The measuring device can also be a pH meter or a meter for gas that is separated, such as ammonia, see WO 93/22668.

According to a preferred embodiment, however, the measuring device is a device for measuring the difference in conductivity of the solution before and after the urease column 10. Such an embodiment is shown in Fig. 4 (see also Fig. 9).

The reactor column 6 is preceded by a three-way valve 20, with which the inlet flow can be redirected to a shunt line 9 and a second three-way valve 23 past the reactor column 6. When the three-way valves 20 and 23 are in the position shown in Fig. 4, the dialysis solution passes the column 6 via the shunt line 9 directly to the measuring cell 7 for measuring the initial conductivity of the dialysis solution, ie without the decomposition of urea. Thereafter, the three-way valves 20 and 23 are adjusted to their other positions so that the solution is allowed to pass through the reactor column 6 and further to the measuring cell 7 and a reaction conductivity value is measured.

To make the measurement even more reliable, it may be convenient to insert a delay line 22 in the shunt line 21 with the same volume as the reactor column 6 as shown in Fig. 3. Preferably, the delay line 22 contains the same amount of alumina as the urea column 10, so that the alumina is taken into account. contribution to conductivity.

A further method of determining the conductivity before and after the reactor column, respectively, is to arrange a measuring cell before and a measuring cell after the column, respectively, as shown in Fig. 9.

A preferred method is shown in Fig. 8 and means that the sample solution is divided into two parallel flows and measurements are performed on each flow with separate measuring cells to determine initial conductivity and reaction conductivity.

Preferably, it takes approximately the same time for the sample solution to reach the respective measurement cell so that the two measurements are performed on approximately the same sample. Yet another way is to use the same measuring cell for measurement both before and after the reactor column 6. Fig. 5 shows the reactor column 6 and a measuring cell 7 connected to several valves 31a, 3lb, 32a, 32b, 33 , 34, 35 and 36. The valves are operated according to the valve diagram in Fig. 6, where 0 indicates open valve (open) and C indicates closed valve (closed). The switching scheme has twelve steps denoted by T1-T12. Then the same cycle takes place, etc. At time T1 the valves 3la, 32a, 33 and 34 are open and the flow takes place first through the measuring device 7 and then through the reactor column 6. This position is maintained for a relatively long period of time so that the reactor column 6 and the lines are filled with a sample and an initial conductivity are measured. At time T7, the valves have rearranged so that the valves 3lb, 32b, 35 and 36 are open. In this position the sample which has previously passed the measuring device 7 flows into the reactor column 6 again through the measuring device 7 at the same time as a fresh sample is fed into the reactor column 6 via a shunt line 37. This position, T7, is also maintained for such a long time that a - reliable measured value of the final conductivity is obtained by the measuring device 7. In this way the same sample or liquid quantity passes through the measuring device 7 twice (but in different directions) and has in between passed the reactor column 6. A particularly accurate measurement can be obtained on this way. The task of the various switching stages T2-T6 and T8-T12 is to eliminate pressure surges in connection with the switching by connecting the measuring device 7 in parallel with shunt lines 37, 38 during the switching process. It will be appreciated that different valve diagrams may be used than those shown in Fig. 6.

Likewise, the discrete valves 31-36 can be replaced by three-way valves that perform similar functions. One skilled in the art will appreciate how such valves should be connected on the basis of Fig. 5 and Fig. 6. In a preferred embodiment, the measuring device 7 is a conductivity measuring cell which measures the conductivity of the solution passing through the measuring device. Preferably, the conductivity measuring cell is of the so-called four-pole type where electrical voltage is applied to two supply electrodes located at a distance from each other. Two sensing electrodes are located in between.

The voltage across the measuring electrodes is measured and the voltage applied to the supply electrodes is regulated so that the measuring voltage becomes constant. The current generated is measured and is proportional to the conductivity of the solution. Four-pole measurement avoids that the transition resistance between the supply electrodes and the solution affects the result. The supply voltage consists of an alternating voltage.

Such a conductivity measuring cell has a relatively large temperature dependence, so it becomes necessary to keep the temperature constant and / or correct for temperature deviations, as described in more detail below.

For calibration purposes or for tarring, there is a shunt line 24 in Fig. 3, which connects the inlets of the two conductivity cells 7a and 7b to each other. By connecting this line, the conductivity cells can be balanced to give the same measured value. If the line 24 is double, the conductivity cells can be cross-connected for comparison of the measured values.

DISCHARGE DEVICE From the measuring device 7, the sample is fed to a discharge device 8, which is shown in Fig. 1 in the form of a collecting vessel.

Alternatively, the sample solution may be discharged to a drain or returned to line 1 downstream of the sampling device 3. If the present invention is to be combined with the invention according to EP 94, 1032383.0 as mentioned above, an additional three-way valve is used Located in the shunt line 9 (see Fig. 4) (or after the conductivity cell 7 in Fig. 4) or the corresponding line in Fig. 3 on the left where the solution has not passed the urease column. To ensure that a certain proportion of the dialysis solution in the line 1 passes through the shunt line, for example a separate pump 26 is used, see Fig. 3. From the three-way valve 25 the solution is led to a special collection bag 27. The volume of solution in the collection bag 27 thus has a predetermined ratio to the amount of solution that has passed line 1, for example 1: 500. Furthermore, the concentration of the substances contained in the collection bag is equal to the average in line 1. By integrating the measured values for the urea sensor over the dialysis time, a total value of urea is obtained, which can be compared with the concentration in the collection bag (which is analyzed otherwise). In this way, the function of the urea sensor can be monitored and double safety is achieved. Since urea has decomposed in the right branch, the solution that has passed that way cannot be used for this purpose.

ION EXCHANGER In some cases it may be desirable to remove electrolytes from the sample solution before it is fed into the reactor column 6 and the measuring device 7.

In the preferred embodiment, the difference between the conductivity before and after the reactor column 6 is measured.

If the measured value before the reactor column 6 is low or zero, better accuracy is obtained. Therefore, an ion exchanger can be incorporated in the inlet line 2 before the reactor column 6, as shown in Fig. 4 in broken lines at 21.

Such an ion exchanger may be of conventional construction, where ions are exchanged for corresponding hydrogen ions or hydroxide ions, which form water. Such ion exchangers can be very efficient, but are usually space consuming. Other methods can also be used to reduce or eliminate the electrolytes in the solution before the reactor column 6.

An example is to use an electrostatic method where the solution in the inlet line 2 is made to pass past charged electrode surfaces and where the charged ions are attracted by the electrode surfaces while the uncharged substances, such as urea, continue straight ahead. Optionally, such electrostatic electrodes may consist of sponge-like structures where the ions can migrate into the electrode surface during a phase. Thereafter, the potential is reversed and corresponding ions are delivered to the solution for regeneration of the electrodes in a second phase, whereby this solution is discarded.

Still other known ion exchange techniques can be used.

UREA The present invention is particularly intended for measuring the urea concentration in a dialysis solution after a dialyzer. The urea concentration in this dialysis solution is related to the urea content of the blood purified by the dialyzer.

Urea is often used as a marker for whether adequate dialysis has been obtained. Exactly how the urea measurement on the dialysis side is related to the urea concentration in blood and how this is interpreted to assess whether the required dialysis has been obtained does not constitute an object of the present invention and is not described in more detail. There are a large number of references that discuss these issues and special reference is made to EP-A1-0 547 025 and WO 94/08641.

When it comes to measuring the urea concentration, this can not easily be measured directly. As described above, the solution containing urea is passed through a reactor column 10 containing urease. Ureas is an enzyme that catalyzes the conversion of urea to ammonium ions according to the following reaction (1): UFEBS (Naga co + 2 rgo ~ NH; + NH: + fl co¿ (1) 10 15 20 25 30 512185 15 Thus ammonium ions and ammonia are formed and hydrogen carbonate ions (bicarbonate) The yield is practically 100%, if the contact between urea and urease is sufficiently effective.On the other hand, ammonia decomposes into ammonium ions depending on the pH value of the solution according to the equilibrium below (2) = NH, + Hzo - my * + on '(2) If the solution contains a buffer system, such as the above mentioned phosphate buffer, this equilibrium (2) is replaced at a sufficiently low pH value, for example at pH = 7 of the following reaction (3): mas + Hzpoó '- my * + HPof' (3) With the above-mentioned phosphate buffer, the pH value can be adjusted to about 7 and the amount of buffer can be adjusted so that this pH value is shifted very little, in this way by suitable selection of the pH value practically all ammonia is converted to ammonium ions, other buffer systems can also a The disadvantage of using a phosphate buffer-type buffer is that it dilutes the solution and contributes to the conductivity before the conversion in the reactor column, which further complicates the measurement of the conductivity. This problem is addressed in US-A-3 930 957 which proposes buffered organic carrier solutions (carrier solution) which in themselves have very low electrical conductivity and which do not react with the enzyme used. According to the present invention, in a preferred embodiment, it is proposed to use a buffer system consisting of carbon dioxide and bicarbonate ions. Especially when measuring the urea concentration in a dialysis solution, great advantages are obtained. The dialysis solution usually contains bicarbonate, which together with carbon dioxide forms the said buffer system.

Carbon dioxide reacts with ammonia according to the following reaction (4): NH; + co? + H 2 O - NH; + Hcos' (4) The reaction on which the present invention is based is the sum of reaction (1) and reaction (4), which becomes the following reaction (5): (una), co + coz +: H 2 O - zrm; + 2Hco3 '(s) As shown in reaction (5), for each urea molecule two ammonium ions and two bicarbonate ions are obtained, both of which contribute to an increase in the conductivity. By adding carbon dioxide in excess, reaction (5) is shifted to the right so that the yield is practically 100%. By adding excess carbon dioxide it is further obtained that the pH value of the solution will be quite low.

If the pH value is below about 7.35, the yield in the above reaction is greater than about 99.5%. Furthermore, the activity of urease is greatest in the pH range about 6 to about 8. If at the same time the residence time of the solution in the urease column is sufficiently large, a total yield exceeding 99% is obtained. Thus, it is preferred that the pH of the solution after the urease column is between about 6 and about 8, preferably between 6.2 and 7.4.

The carbon dioxide is added by means of the additive device 4.

A method of adding carbon dioxide gas to the sample solution in line 2 is shown in Fig. 7. The auxiliary device consists of a source of carbon dioxide gas under pressure 41 and a pressure reducing valve 42. From this source carbon dioxide gas is discharged at a predetermined pressure to a conduit 43. The conduit 43 is provided at its lower end with a coupling 44, which passes through the wall of the conduit 2 into the sample solution.

Connected to the coupling 44 is a silicone hose 45 or other gas-permeable hose, which is located in the line 2 substantially concentrically therewith over a predetermined distance.

Silicone has the property that carbon dioxide gas located inside the hose 45 can diffuse through the silicone material and be delivered to the solution in the line 2.

The control of the pressure regulator 42 is controlled by two pressure gauges 46,47, which sense the pressure difference across the hose 45.

Of course, these two pressure gauges can be combined into one differential pressure gauge.

The diffusion rate depends on the differential pressure across the hose 45. By adjusting the length of the hose and the pressure difference, the desired amount of carbon dioxide gas can be introduced into the sample solution in line 2. Preferably, so much carbon dioxide gas is added that the sample solution becomes substantially saturated. There is normally a sufficient amount of carbon dioxide, which can be used in reaction (5) to convert all urea to ammonium ions.

At high urea concentrations, it is difficult to supply a sufficient amount of carbon dioxide gas that dissolves in the sample solution. An excess of carbon dioxide gas can be added which accompanies the sample solution in the form of microbubbles or more or less large bubbles. This gas partially dissolves in the sample solution during transport to the urease column and the rest of the carbon dioxide gas is consumed during the reaction in the urease column.

Fig. 9 shows another method of supplying carbon dioxide gas to the sample solution in line 2. As in Fig. 7, there is a source 41 for carbon dioxide gas under pressure. There are also two valves 49 and 50, between which there is a container 48 with a predetermined volume. the valve 49 connects the container 48 to the source 41 and the valve 50 connects the container 48 to the line 2. Over the valve 50 two pressure gauges 51a and S1b are arranged. The function of the attachment device according to Fig. 9 is as follows. the valve 49 is opened and carbon dioxide is supplied from the source 41 to the container 48 until the pressure gauge 51a senses a predetermined pressure. Then the valve 49 is closed and the valve 50 is opened, the contents of the container 48 being discharged to the line 2.

When the pressure gauge 51a or 51b senses a minimum pressure, the valve 50 is closed and the valve 49 is opened for a new filling of the container 48.

Because the volume of the container 48 and the pressure difference are known, the amount of carbon dioxide gas fed into the line 2 can be determined.

In the open state, the valve 50 can constitute a certain throttling so that carbon dioxide gas is discharged at a relatively even speed. By controlling the degree of throttling in the valve 50 during its opening time, the amount of gas supplied per unit time can be regulated.

It is also possible to drive the valve 50 so that a large bubble of carbon dioxide gas is fed into the test line 2 so that the bubble fills the entire cross section of the line 2. During the continued transport to the reactor column, the bubble of carbon dioxide gas partially dissolves in adjacent sample solution so that it is substantially saturated. carbon dioxide. The remaining amount of carbon dioxide gas is atomized by the filter 13 in the reactor column 10 (see Fig. 2) so that the carbon dioxide gas is evenly dispersed in the sample solution. The inlet line 15 should then be designed conically so that the sample solution is distributed over the entire cross section of the reactor column 10.

During the passage through the reactor column 10, carbon dioxide is consumed in reaction (5), whereby the excess carbon dioxide is consumed.

To ensure that no gaseous carbon dioxide remains in the solution leaving the reactor column 10, the outlet line 16 (see Fig. 9) can be provided with a bubble detector 52, for example an ultrasonic detector. The output signal from such a bubble detector can be used in several ways. It can be used to indicate a possible incorrect measured value and / or to regulate the input of carbon dioxide gas. In the latter case, it should be noted that the time delay from the input to the sensing is relatively long, for example four minutes. If the concentration of urea does not change too quickly, however, effective and optimal regulation can be obtained.

In connection with the bubble detector 52 there may be a gas trap 62 (see Fig. 10), which separates any gas in free form from the solution in the outlet 16. This gas can optionally be reused by return to the test line 2 via a line 63.

The source of carbon dioxide gas 41 is suitably constituted by a pressure vessel with carbon dioxide gas in liquid form, which evaporates immediately upon delivery and associated lowering of the pressure. Such carbon dioxide cartridges are available in different sizes. The consumption of the carbon dioxide gas is extremely small, so such a carbon dioxide cartridge of the smallest size is sufficient for very long operation.

An alternative source of carbon dioxide gas can be the production of carbon dioxide gas on site. One way is to heat bicarbonate powder (NaHCO3) to a high temperature, for example above 50 ° C. The bicarbonate is decomposed and carbon dioxide gas is emitted. The bicarbonate may be located in a small container, which is placed on a heating element. When the appliance is to be used, the heat source is activated and carbon dioxide gas is emitted after a short time.

The cartridge is of course replaceable. Another method of producing carbon dioxide gas on site is to add an acid and water to a dry powder of bicarbonate. Carbon dioxide gas is released in proportion to the amount of liquid added until the bicarbonate powder is consumed. Also in this case a cartridge containing necessary ingredients can be used, for example bicarbonate powder and citric acid in powder form. When carbon dioxide gas is to be generated, water (or other liquid) is added to the bicarbonate powder so that the appropriate pressure develops inside the carbon dioxide gas cartridge. The exact method of producing carbon dioxide gas is not the subject of the present invention, but reference is made to EP-A1-0 481 257 where methods for producing carbon dioxide gas are described. 10 15 20 25 30 35 20 DOUBLE FEED OF CARBON DIOXIDE During the reaction in the urease column 10, the pH value rises, especially if the urea concentration is high and the carbon dioxide gas content is too small. If the pH value rises above about 7.4, there is a risk of precipitation of calcium carbonate and magnesium carbonate (calcium and magnesium ions are normally included in the dialysis solution). If such precipitation takes place in the measuring cell 7, this quickly leads to incorrect measurement values and the measuring cell must be cleaned.

In order to obtain a sufficiently low p fl value of the solution passing the measuring cell 7, it may be desirable to add carbon dioxide gas also at the outlet from the urease column 10, i.e. at the outlet 16. Such an embodiment is shown in Fig. 10.

The carbon dioxide source 41 is in this case connected to the test line 2 via a valve 60, which may be of the same construction as in Fig. 9, i.e. the elements 48 to 51. Alternatively, the valve 60 may be a high-frequency valve of known type, which regulates the amount of carbon dioxide gas fed into the test line. 2. There is also a second valve 61 which connects the carbon dioxide source 41 to the outlet 16 from the urease column 10. Then there is a bubble detector 52 and optionally said bubble separator 62, which via the line 63 returns separated carbon dioxide gas to the test line 2 (or discharged to the atmosphere or line 1 or otherwise).

If the measuring device 7 senses a high concentration of urea above a predetermined value, the valve 61 is opened and carbon dioxide gas is supplied to the outlet 16. The valve 61 can be controlled directly by the bubble detector 52 as these are close to each other and there is no major time delay. In this way it is ensured that the pH value is lowered to safe values before the solution enters the measuring cell. Any ammonia passing out of the urease column 10 due to all the carbon dioxide consumed in the urease column 10 may react with the added carbon dioxide according to reaction (4) (see above). However, there is still a risk that the upper part of the urease column will precipitate calcium carbonate. 10 15 20 25 30 512 185 21 Simultaneously with the supply of carbon dioxide gas via the valve 61, the supply of carbon dioxide gas via the valve 60 can be increased so that the supply via the valve 61 can decrease after a certain time delay and possibly finally cease completely.

As an alternative, only a certain maximum amount is supplied via the valve 60, which can always be dissolved in the test line 2, after which additional any necessary gas is added via the valve 61.

In this case, it may be appropriate to provide a post-reaction chamber after the inlet of gas via the valve 61 to allow the equilibrium of reaction 4 to move to the right. It may also be possible to provide the column 10 with a carbon dioxide inlet approximately at the filter 17 (see Fig. 2), the space 18 acting as a post-reaction chamber.

In this embodiment, it is ensured that the pH value is always low enough to avoid precipitation of calcium carbonate in the conductivity measuring cell. Preferred pH values (at a position after the conductivity cell) are between 5.5 and 8.5, preferably between 6 and 8. When using carbon dioxide and bicarbonate as buffer, it is preferred that the pH value is between about 6.2 and c : a 7.7, preferably between 6.3 and 7.4.

PRESSURE It is known that the solubility of carbon dioxide gas in water is mainly proportional to the pressure in the solution. In the event that the bubble detector detects bubbles in the sample solution after the outlet 16, it takes a long time before the supply of carbon dioxide gas is reduced via the valve 60 in Fig. 10 or the valve 48-si in Fig. 9.

In order to avoid such bubbles affecting the measuring result, as can be seen in Fig. 9, a controllable throttle valve 53 can be arranged after the outlet 16 of the urease column. Since such bubbles mainly interfere with the measurement in the measuring device, the adjustable throttle valve should be arranged after this measuring device 7. The throttle valve 53 works together with the pump 3 to increase the pressure in the line 2 and the urease column as well as the measuring device 7 if bubbles are sensed by the bubble detector 52. The carbon dioxide gas dissolves due to the increased solubility. Suitably 10 15 20 25 30 512 185 22 the pressure is restored to normal pressure as soon as the carbon dioxide supply has been reduced so that no bubbles remain.

In another embodiment, the throttle valve 53 is used together with the measuring device 7 to detect the presence of bubbles in the sample solution as the large measurement in the measuring device 7 as a replacement for or complement to the bubble detector 52.

At predetermined intervals, when it is desired to check whether the measurement results are reliable, the pressure is momentarily raised by activating the throttle valve 53. The pressure increase can be monitored with the pressure gauge 51b or a special pressure gauge. If the increase in pressure gives rise to a change in the measured value in the measuring device 7, this is a sign that the sample solution contains gas bubbles which interfere with the measurement. This can be used to reduce the supply of carbon dioxide gas, after which a new test is performed after a certain time to verify that the change has given the desired effect.

The pressure gauge Slb can also be used to ensure that the sample solution 2 is always at approximately the same pressure, for example atmospheric pressure. If the sampling takes place at the outlet of a dialysis machine, the pressure before the pump 3 can vary considerably. If the discharge device 8 consists of a return line to the line 1, the entire test line 2 will be at the pressure present in the line 1. By operating the throttle valve 53 and the pump 3, which is monitored by the pressure gauge 51b, the desired pressure in the test line 2 and the measuring device 7 can is set, which may be slightly above atmospheric pressure, for example.

The above-mentioned pressure increase affects the measurement result in the measuring device 7 very little in normal cases if the measuring device 7 is a conductivity cell. When using other types of measuring devices, one must correct for the pressure dependence of these measuring devices when using the above-described method of pressure increase.

As an alternative to the method described above, a local pressure increase can only be used in the measuring device 7. In this case an additional pump arranged before the measuring device 7 and a throttle valve arranged after the measuring device 7. The additional pump and the throttling device 53 are controlled so that the pressure in the reactor column 6 does not 15 20 25 30 35 512185 23 is affected. Otherwise, the function is the same as described above.

In a preferred embodiment of the invention, a permanent pressure increase is used. The pressure increase should be in the range 0.03 - 0.3 MPa, preferably 0.1 MPa. In this case, a sufficient amount of carbon dioxide gas can dissolve in the solution to satisfy the reaction (5) and at the same time ensure an outgoing pH value of about 7.4 up to a urea concentration of about 35 mM, without additional addition of carbon dioxide gas.

THE TEMPERATURE It is known that the solubility of the carbon dioxide gas in the sample solution in line 2 is inversely proportional to the temperature. Usually the temperature of the dialysis solution used is about 36-37 ° C.

To avoid dependence on the temperature of the incoming dialysis fluid, the sample solution can be heated by means of a heating element to a fixed temperature, which is between about 38 and about 42 ° C, preferably about 40 °. The reason why the temperature is chosen is so high that it is higher than all expected incoming temperatures, so no cooling is required and consistent measurements are obtained regardless of the incoming temperature.

It is desirable to maintain the temperature substantially constant during the passage of the sample solution through the device, i.e. from the sampling device 3 through the reactor column 6 and the measuring device 7. At least the temperature of the reactor column should be constant to obtain uniform activity. However, the temperature should not be raised (at least not too much) before the conductivity measuring cell to avoid bubble formation in the event of excess carbon dioxide.

According to an alternative embodiment of the present invention, the temperature of the incoming sample solution is instead lowered by cooling. Such cooling can take place in many different ways, but since the amount of solution to be cooled is relatively small, Peltier elements can be used, where electric current is directly converted to cooling. The sample solution is passed through a Peltier element 55 and current is applied so that the required temperature drop is obtained as shown by broken lines in Fig. 11, which is sensed by a temperature sensor 56 located downstream of the Peltier element 55. A suitable temperature in this alternative embodiment is about 25 ° C.

The temperatures used should be in the range of about 20 ° C to about 50 ° C. The reason that below about 20 ° C the urease enzyme has low efficiency, which means that the conversion from urea to ammonium ions takes too long. Above about 50 ° C, the urease enzyme is broken down, which is of course not desirable. Therefore, a temperature between about 25 ° C and about 45 ° C is preferred.

By using lowering the temperature with Peltier elements, it can be ensured that a sufficient amount of carbon dioxide gas can always dissolve in the sample solution in line 2, whereby the additional supply of carbon dioxide gas according to Fig. 10, valve 61, is not required. Of course, extra supplies can still be used as an extra safety measure.

A lowering of the temperature in connection with the measuring cell can be used to detect the presence of carbon dioxide gas which interferes with the measurement, analogous to the pressure increase described above. By lowering the temperature in the measuring cell, the solubility for carbon dioxide increases and any carbon dioxide gas dissolves. However, in order to compare the conductivity values before and after such a temperature reduction, temperature compensation of the measured values and thus accurate temperature measurement is required, which can, however, be difficult to achieve.

Fig. 11 shows a gas trap 62 in the form of a gas-permeable hose 57 of silicone. Outside the hose there is a solution with a low content of carbon dioxide, for example dialysis solution, such as the contents of the heat exchanger described in connection with the preferred embodiment in Fig. 8, see below. Any excess carbon dioxide gas inside the hose 57 is delivered to the liquid outside the hose 57, especially if there is a pressure difference. 10 15 20 25 512 183 25 PREFERRED EMBODIMENT Fig. 8 shows the presently preferred embodiment of the invention. A sampling pump 3 is used which takes out approximately 1 ml / minute of sample solution from the contents of line 1. This sample solution is divided into two parallel branches with approximately the same amount in each branch. The first branch (right in Fig. 8) contains the urease column 6 and the supply of carbon dioxide from a carbon dioxide source 41 via a metering valve 60. The second branch contains a delay line or a delay vessel 22, which contains as much alumina as the urease column 6 and has the same resistance as the urease column 6 but lacks urease.

The contents of the urease column 6 and the delay line 22 are fed to a heat exchanger 70, which contains a large amount of liquid. The contents of the two branches are allowed to pass through a long narrow tube for each branch, 71 and 72, to the respective conductivity cells 7a and 7b, respectively. After the conductivity cells, the two branches are combined into a common outlet line 73, in which a variable throttling device 53 is arranged, and finally the sample solution is delivered to a collecting container 8.

The interior of the heat exchanger is filled with a liquid, which is kept at a very constant temperature. This liquid may be the dialysis liquid passing in the line 1 or may be another liquid heated to a predetermined temperature. To control the temperature, there is a heating element 74 in an inlet 75 of the heat exchanger and a temperature sensor 76 in an outlet 77 of the heat exchanger. Additional temperature sensors may be located at strategic positions in the heat exchanger 70. The heat exchanger is isolated from the environment to an extent that is practically suitable. The conductivity cells 7a and 7b are connected to an electronic device 78, which provides the necessary voltages and measuring devices for performing the conductivity measurement. Furthermore, the electronic device 78 contains a subtraction circuit for forming the difference between the measured values from the cells 7a and 7b and possibly further devices for compensating the measured values for temperature. These functions are preferably performed by means of a microcomputer. The microcomputer also converts the measured values directly to the urea concentration in the sample solution.

In order to obtain a sufficient accuracy in the determination of the urea concentration, it is required that the temperature difference between the solutions in cells 7a and 7b is kept very small, in the order of 1 0.01 ° C. We have found that if the pipes 71 and 72 are sufficiently long and the temperature in the heat exchanger 70 is constant, sufficiently accurate measured values can be obtained.

The measured values may be corrected with respect to the current temperature according to known technology. This is most easily done by calibration. Therefore, it is necessary to know the temperature of the solution in the sensors 7a and 7b, which takes place by means of temperature sensors 79 and 80. However, since the flow at the measuring points is very small, it is difficult to obtain reliable temperature measurements. However, it turns out to be sufficient if the temperature can be measured with an accuracy of about 0.4 ° C, which is possible.

The liquid located inside the heat exchanger 70 is preferably dialysis liquid from the line 1. In this case, a relatively large flow can be passed through the heat exchanger 70, which ensures that the temperature is substantially constant.

Alternatively, a closed system, shown in broken lines in Fig. 8, may be used, where a pump 81 circulates the liquid in an external circuit 82. The preferred embodiment of Fig. 8 may be further supplemented with a draining device 25. , 27 according to Fig. 3 in the left branch, which thereby contains a separate throttling device or pump.

In another alternative, the device according to Fig. 8 is provided with a cross-connection connecting the urease column 6 with the tube 72 and the delay line 22 with the tube 71. In this way the measuring cells 7a and 7b can be used alternately for the urease column 6 and the delay line 22, whereby a safe calibration can be obtained.

By using the throttling device 53 and the pump 3, an overpressure in the urea sensor of the order of 0.1 MPa is achieved, which proves to be suitable for obtaining sufficient solubility for carbon dioxide before the urease column 6 for the intended measuring range up to 35 mM urea concentration.

The urea sensor according to Fig. 8 essentially only requires calibration during manufacture. The calibration then changes very little over time and recalibration of the urea sensor can take place with relatively long time intervals, for example a few times a year or once a year.

It has been found that the urea sensor according to Fig. 8 shows very good linearity within the intended measuring range up to about 35 mM. The reason for this linearity is above all that the conversion is based on reaction (5), which is strongly shifted to the right due to the catalysis by urease and excess carbon dioxide as well as low pH value.

The PRIMING Ureas column 10 contains a dry powder, which must be wetted before use. This can be done by passing a physiological saline solution through the urease column and the measuring device 7. Alternatively, the dialysis solution used by the dialysis machine during its start-up process can be used to wet the urease column and put it into operable condition. The dialysis machine performs a starting process called "priming", wherein dialysis solution is circulated through the dialysis machine's system excluding the dialyzer, which is shunted. This solution can also be used for priming the urea sensor.

DISINFECTION No special cleaning of the urea sensor is usually required. However, it is recommended to rinse out the urea sensor after use, for example by letting physiological saline solution pass the urea sensor for a predetermined time. No disinfection with elevated temperature is normally required. However, the disinfection of the dialysis monitor can be coordinated with the urea sensor, so that the disinfection solution can also pass the urea sensor. In this case, heat disinfection is preferred, but disinfection with citric acid, etc. can also be used (CleanCart).

In some cases, the dialysis solution contains glucose, which is somewhat sticky and can cause problems. However, rinsing after use avoids such problems.

The urea sensor according to the invention can be used completely separately from a dialysis monitor. The urea sensor is then connected to the monitor outlet. Of course, the urea sensor can be attached to the housing of the device and connected in another place, for example immediately after the dialyzer. It is also possible to fully integrate the urea sensor into the dialysis machine and / or provide the urea sensor with an electronic interface to the dialysis machine.

QUALITY TEST Before using the urea sensor, it is advisable to check that it works satisfactorily. For this purpose, a small amount of solution containing urea with a certain concentration is added to the line 2 and allowed to pass the urea sensor. If the measuring device 7 does not give an expected measuring value, the measuring device must be replaced and left for repair / service. Such a quality control can be performed in a relatively simple manner in that the urease column 10 at its inlet 15 contains a small amount of urea in powder form. As soon as physiological saline solution or other solution is added for priming, the urea powder is dissolved and converted by the urease column 10 to ammonium ions which give rise to the measuring device 7. In this way only a replaceable unit is required, namely the urease column 10 containing said urea powder. .

The Ureas column 10 consists of a cartridge, which is replaceable. Before a dialysis treatment, a new cartridge is inserted and priming takes place as mentioned above. However, the contents of a urease column are sufficient for more than one dialysis treatment. The Ureas column can thus be used for several treatments during the same day, for example three treatments with different people and can possibly also be used over several days, for example 2-3 days.

Of course, it is safer to change the urease column after each treatment.

In the case of on-site carbon dioxide production, a second cartridge containing the necessary ingredients can be used. These two cartridges can form a unit by assembling in a suitable manner. The unit is changed in connection with each measurement and is dimensioned to enable measurement during a normal dialysis treatment, which can be about four hours during hemodialysis.

The invention has been described above in connection with several different embodiments. It is understood that the various included alternatives can be combined in various suitable ways. Furthermore, other alternatives can be used, which are offered to a person skilled in the art who reads this description. Such professional modifications are, of course, within the scope of the invention. The invention is limited only by the following claims.

Claims (40)

10 15 20 25 30 35 512 185 30 PATENT REQUIREMENTS A process for measuring the concentration of a substance in a composite solution by catalytic reaction under the action of a catalyst in a reactor column for decomposing the substance and measuring the difference in conductivity between reacted solution and unreacted solution to provide an indication of the concentration of the substance in the solution, characterized by the addition of carbon dioxide to the solution before the reaction in the reactor column, the solution containing bicarbonate ions and said substance being urea and said catalyst being urease. Process according to Claim 1, characterized in that carbon dioxide is added to the solution in gaseous form before the reactor column and in such an amount that the solution becomes substantially saturated. Process according to Claim 2, characterized in that carbon dioxide is added to the solution in gaseous form even immediately after the reactor column in such an amount that no gas bubbles remain during the measurement. Method according to claim 2 or 3, characterized by sensing residual gas bubbles in the solution in connection with the measurement. Process according to Claim 4, characterized in that the addition of carbon dioxide is regulated in dependence on the detection of residual gas bubbles so that no gas bubbles remain. Method according to one of the preceding claims, characterized by regulating the addition of carbon dioxide in dependence on the measured value obtained during the measurement. Process according to any one of the preceding claims, characterized in that carbon dioxide is added to the solution in gaseous form by using a silicone hose containing carbon dioxide gas on one side and the solution on the other side, wherein carbon dioxide gas diffuses through the silicone hose to the solution, preferably a pressure difference formed over the silicone hose to increase the diffusion of carbon dioxide gas through the silicone layer. 10 15 20 25 30 35 31 512 183 Process according to one of the preceding claims, characterized in that carbon dioxide is supplied from a source of carbon dioxide gas, for example a carbon dioxide cartridge, alternatively by producing carbon dioxide gas on site, for example by reacting bicarbonate. Method according to one of the preceding claims, characterized in that the measurement is carried out under elevated pressure, for example an overpressure of approximately 0.1 MPa, in order to increase the solubility of carbon dioxide gas in the solution, and / or at reduced temperature, for example at about 25 ° C, to increase the solubility of carbon dioxide gas in the solution. 10. lO. Process according to one of the preceding claims, characterized in that the reaction is carried out under elevated pressure, for example an overpressure of cza 0.1 MPa, in order to increase the solubility of carbon dioxide gas in the solution, and / or at reduced temperature, for example at cza 25 ° C, to increase the solubility of carbon dioxide gas in the solution. 11. ll. Method according to one of the preceding claims, characterized in that the same measuring cell is used for both measurements. Method according to Claim 11, characterized in that the measuring cell is first switched on before the reactor column for measuring the initial conductivity and then after the reactor column for measuring the reaction conductivity, by means of valves (Fig. 5). Method according to claim 11, characterized in that the solution passes past the reactor column via a shunz line for measuring the initial conductivity. Method according to one of Claims 1 to 10, characterized in that two measuring cells are used to supply the initial conductivity and the reaction conductivity. A method according to claim 14, characterized in that the sample solution is divided into two branches, wherein the first branch passes the reactor column and a first measuring cell and the second branch passes a second measuring cell. 10 15 20 25 30 35 512 185 Al Method according to claim 15, characterized in that the second branch contains a delay line so that the passage through the two branches to the respective measuring cell takes approximately the same length of time. Method according to Claim 15 or 16, characterized in that the temperature of the solutions in the two branches is kept as close to one another as possible. Method according to Claim 17, characterized in that the measured values are corrected with regard to the temperature of the respective measuring cell. Process according to one of Claims 15 to 18, characterized in that carbon dioxide gas is added only to the first branch before and / or after the reactor column. Process according to any one of the preceding claims, characterized in that the pH of the solution after the reaction in the reactor column is between about 6 and about 8, preferably lower than about 7.4, and that the catalyzed reaction is: ( N flfl z CO + CO2 + 3H $) - + ZNHX + 2HCO { Apparatus for measuring the concentration of a substance in a composite solution by catalytic reaction under the action of a catalyst, in a reactor column (6) for decomposition of the substance comprising a conductivity measuring device (7) for measuring the difference in conductivity between reacted solution and unreacted solution to give an indication of the concentrations of the substance in the solution, characterized by an additive device (4) for adding carbon dioxide to said solution before the reactor column (6), the solution containing bicarbonate ions and said substance being urea and said catalyst being urease . Device according to claim 21, characterized in that the additive device (4) is arranged to add carbon dioxide to the solution in gaseous form. Device according to Claim 21 or 22, characterized by an additive device (41,61) for adding carbon dioxide to the gaseous solution even immediately after the reactor column. 10 15 20 25 30 35 512 183 Device according to claim 21, 22 or 23, characterized by a bubble detector (52) for sensing residual gas bubbles in the solution in connection with the measuring device (7). Device according to one of Claims 21 to 24, characterized by a control device for regulating the addition of carbon dioxide in dependence on the measured value obtained during the measurement. Device according to any one of claims 21-25, characterized by a silicone hose (45) for adding carbon dioxide to the solution, wherein the silicone hose contains carbon dioxide gas on one side and the solution on the other side, and the carbon dioxide gas diffuses through the silicone hose to the solution. Device according to one of Claims 21 to 26, characterized by a source of carbon dioxide gas, for example a carbon dioxide cartridge, or alternatively a device for the production of carbon dioxide gas on site, for example by reaction of bicarbonate. Device according to any one of claims 21-27, characterized by a device (53,3) for producing an elevated pressure during the reaction and / or the measurement, for example an overpressure of about 0.1 MPa, in order to increase the solubility of carbon dioxide gas in the solution. Device according to one of Claims 21 to 27, characterized by a device (55, 56) for lowering the temperature, for example to about 25 ° C, in order to increase the solubility of carbon dioxide gas in the solution. Device according to one of Claims 21 to 29, characterized by a single measuring cell (7) for measuring the difference in conductivity before and after the reactor column (6), respectively. Device according to claim 30, characterized in that a valve device (31-36) is arranged to first connect the measuring cell (7) before the reactor column for measuring the initial conductivity and then after the reactor column for measuring the reaction conductivity (Fig. 5). Device according to claim 30, characterized by a shunt line (9) through which the solution passes by the reactor column for measuring the initial conductivity. 10 15 20 25 30 BH 512 185 Device according to one of Claims 21 to 29, characterized by a first measuring cell (7a) for measuring the reaction conductivity and a second measuring cell (7b) for measuring the initial conductivity, respectively. Device according to claim 33, characterized by two branches for the sample solution, wherein the first branch contains the reactor column (6) and the first measuring cell (7a) while the second branch contains the second measuring cell (7b). Device according to claim 34, characterized in that the second branch contains a delay line (22) so that the passage through the two branches to the respective measuring cell takes approximately the same length of time. Device according to claim 34 or 35, characterized by a heat exchanger (70-77) arranged to keep the temperature of the solutions in the two branches almost equal. Device according to Claim 36, characterized in that a device (78-80) for correcting the measured values with regard to the temperature of the respective measuring cell. Device according to one of Claims 34 to 37, characterized by a device (41, 60) for adding carbon dioxide gas only to the first branch before and / or after the reactor column. Device according to any one of claims 21-38, characterized in that the pH value of the solution is between cza 6 and cza 8, preferably below cza 7.4. Device according to any one of claims 21-39, characterized in that said solution is a dialysis solution containing at least bicarbonate ions; and that the catalyzed reaction is: (Nfmz co + coz + 3H2O -> 2NH4 * + 2Hco3 '