Abstract:
Methods and apparatus for measuring the concentration of decomposable substances, such as urea, are disclosed. The disclosed methods include adding a gaseous buffer, such as CO 2 , to the solution containing the decomposable compound, measuring the conductivity of the solution, decomposing the decomposable compound, measuring the conductivity of the thus-decomposed compound solution, and calculating the differential conductivities between the two measured solutions. The apparatus for carrying out these methods are also disclosed.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application is a divisional of U.S. Ser. No. 07/776,308, filed Apr. 17, 1997, Now U.S. Pat. No. 6,114,176, which was a national stage application of PCT/SE95/00888, filed Jul. 28, 1995. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to a method and a device for measuring the concentration of urea or a similar substance in a composite solution. The concentration of urea is difficult to measure directly, and therefore, urea is catalytically decomposed by urease and the differential conductivity is measured. 
     The solution is preferably a medical solution but can also be a biological solution such as plasma. The present invention relates particularly to the measurement of the concentration of urea in connection with dialysis. 
     BACKGROUND OF THE INVENTION 
     The present invention is based on the technique which is disclosed in European Patent No. 0,437,789. This patent discloses, for example, a system for measuring the urea concentration in a complex solution by decomposing urea into ammonium ions catalyzed by urease. It is difficult to measure the urea directly, and it must, therefore, first be converted into ammonium ions. The change in the conductivity due to the contribution of the ammonium ions is measured by means of a conductivity meter. 
     In German Patent No. 39 00 119 a urea sensor of a similar type is described. A capillary is positioned in a tube, through which blood passes. By means of the capillary, plasma is drawn out of the blood and is 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. In order to keep the temperature constant in the measuring apparatus the dialysis fluid is circulated in a closed loop around the urease column and the two conductivity measurement cells. 
     Japanese Patent No. 60-165551 discloses a similar arrangement, where an ion exchange column is used to remove electrolytes by means of anion-cation-exchange. In this way, the accuracy of the measured values are considerably improved, since the relative change in the conductivity becomes larger due to the fact that the initial conductivity is lower or almost zero. Furthermore, a buffer is added. 
     U.S. Pat. No. 3,930,957 describes a urea sensor, where an organic buffer solution is added. As an example a solution of 0.05M Tris(hydroxymethyl)aminomethane can be used, which is adjusted to a pH-value of about 6-7 by the addition of glycine. 
     SUMMARY OF THE INVENTION 
     In accordance with the present invention, a method and apparatus for measuring the concentration of urea or similar substance in composite solutions is provided. According to the method of the present invention, a method for measuring the concentration of a decomposable compound in a solution has been discovered, comprising adding a buffer in gaseous form to the solution, measuring the conductivity of the solution, decomposing the decomposable compound so as to produce a reacted solution, measuring the conductivity of the reacted solution, and calculating the differential conductivities between the solution and the reacted solution so as to provide a measure of the concentration of the decomposable compound in the solution. 
     In a preferred embodiment, the buffer in gaseous form comprises carbon dioxide. Preferably, the decomposable compound comprises urea. More preferably, the solution comprises biocarbonate ions. In a preferred embodiment, the decomposing of the decomposable compound comprises catalytically reacting the solution and preferably with urease. 
     In accordance with one embodiment of the method of the present invention, the adding of the carbon dioxide to the solution comprises diffusing the carbon dioxide through a silicon tube into the solution. 
     In accordance with another embodiment of the method of the present invention, calculating of the differential conductivities comprises increasing the pressure of the solution in order to increase the solubility of the carbon dioxide in the solution. Preferably, the pressure is increased to about 0.1 MPa. 
     In accordance with another embodiment of the method of the present invention, calculating of the differential conductivities comprises decreasing the temperature of the solution in order to increase the solubility of the carbon dioxide in the solution. Preferably, the temperature is decreased to about 25° C. 
     In accordance with another embodiment of the method of the present invention, measuring of the conductivity of the solution and measuring of the conductivity of the reacted solution is carried out by means of a single measurement cell. In a preferred embodiment, the method includes measuring the conductivity of the solution by connecting the single measurement cell at a location upstream of the decomposing step and measuring the conductivity of the reacted solution by connecting the single measurement cell at a location downstream of the decomposing step. 
     In accordance with another embodiment of the method of the present invention, the method includes measuring the conductivity of the solution by diverting a portion of the solution from the decomposing step. 
     In accordance with another embodiment of the method of the present invention, the method includes diverting a portion of the solution into a flow path separate from the decomposing step, measuring the conductivity of the solution by means of a first measurement cell in the separate flow path, and measuring the conductivity of the reacted solution by means of a second measurement cell downstream of the decomposing step. In a preferred embodiment, the method includes delaying the flow of the method through the separate flow path whereby the flow of the solution through the separate flow path to the first measurement cell and the flow of the reacted solution to the second measurement cell can take approximately the same amount of time. 
     In accordance with another embodiment of the method of the present invention, a method is provided for measuring the concentration of a decomposable compound in a solution comprising dividing the solution into a first portion and a second portion, decomposing the decomposable compound in the first portion of the solution so as to provide a first reacted solution, equalizing the temperatures of the first reacted solution and the second portion of the solution in a heat exchanger having a mean temperature, measuring the conductivities of the temperature equalized first reacted solution and second portion of the solution, and calculating the differential conductivity between the first reacted solution and the second portion of the solution, temperature compensating the differential conductivity by means of the mean temperature of a heat exchanger, and calculating the concentration of the decomposable compound from the compensated differential conductivity. Preferably, the decomposable compound comprises urea. In a preferred embodiment, decomposing of the decomposable compound comprising catalytically reacting the decomposable compound in the solution, and preferably catalytically reacting the solution comprises reaction with urease. 
     In accordance with another embodiment of the method of the present invention, the measuring of the conductivities comprises measuring the conductivity of the temperature equalized first reacted solution and the second portion of the solution with separate conductivity measurement cells. 
     In accordance with another embodiment of the method of the present invention, the heat exchanger comprises a heat exchange fluid in heat exchange communication with the first reacted solution and the second portion of the solution, and the method includes. providing the mean temperature of the heat exchanger by measuring the temperature of the heat exchange fluid. In a preferred embodiment, the method includes measuring the conductivity of the solution by diverting a portion of the solution from the decomposing step. 
     In accordance with the apparatus of the present invention, apparatus is provided for measuring the concentration of a decomposable compound in a solution comprising charging means for charging a buffer in gaseous form to the solution, a reactor for decomposing the decomposable compound whereby a reacted solution is formed, and measuring means for measuring the conductivities of the solution and the reacted solution whereby a differential conductivity can be calculated therefrom. In a preferred embodiment, the buffer in gaseous form comprises carbon dioxide. Preferably, the decomposable compound comprises urea, and the solution comprises bicarbonate ions. In another embodiment, the decomposing of the decomposable compound comprises catalytically reacting the solution, preferably reacting the solution with urease. 
     In accordance with one embodiment of the apparatus of the present invention, the apparatus is a silicon tube in contact with the solution whereby the carbon dioxide can be added to the solution by diffusion through the silicon tube. 
     In accordance with another embodiment of the apparatus of the present invention, the apparatus includes a bubble detector for detecting bubbles in the reacted solution. 
     In accordance with another embodiment of the apparatus of the present invention, the apparatus includes pressure increasing means for increasing the pressure of the solution in order to increase the solubility of the carbon dioxide in the solution. 
     In accordance with another embodiment of the apparatus of the present invention, the apparatus includes temperature decreasing means for decreasing the temperature of the solution in order to increase the solubility of the carbon dioxide in the solution during the measuring step. 
     In accordance with another embodiment of the apparatus of the present invention, the measuring means for measuring the conductivity of the solution and the reacted solution comprises a single measurement cell. 
     In accordance with another embodiment of the apparatus of the present invention, the apparatus comprises a first conduit path and a second conduit path, the first conduit path including the reactor, and wherein the measuring means for measuring the conductivities of the solution and the reacted solution comprises a first measuring means for measuring the conductivity of the solution and a second measuring means for measuring the conductivity of the reacted solution, the first measuring means be located in the second conduit path and the second measuring means being located in the first conduit path. In a preferred embodiment, the second conduit path is configured so that the flow of the solution through the first and second conduit paths to the first and second measurement cells takes approximately the same amount of time. 
     In accordance with another embodiment of the apparatus of the present invention, the heat exchanger is disposed for maintaining the temperatures of the solutions in the first and second conduit paths approximately equal. 
     An object of the present invention is to provide a method and a device for measuring the concentration of urea in a composite solution by heterogenous catalytic reaction of urea with urease in a reactor column for decomposing thereof, and measuring the differencial conductivity between reacted solution and unreacted solution for providing an indication of the concentration of urea in said solution. According to the invention, carbon dioxide is added to the solution, which comprises hydrogen carbonate ions, before the reaction in the reactor column. The carbon dioxide, together with the hydrogen carbonate ions, form a buffer maintaining the pH-value of the solution within predetermined limits. At the same time, the carbon dioxide contributes to making the relationship between the differential conductivity and the concentration of urea linear over a large range. The addition of carbon dioxide also results in each urea molecule being decomposed into four ions, each contributing to the increase in conductivity. 
     The carbon dioxide is added in the form of a gas, and preferably in such an amount that the solution is substantially saturated with carbon dioxide. In order to further increase the solubility of carbon dioxide gas in the solution, the pressure of the solution can be raised and/or the temperature of the solution can be lowered. In this way it is assured that a sufficient amount of carbon dioxide is dissolved in the solution for making the relationship linear over as large a range as possible. 
     The differential conductivity between reacted and unreacted solution can be measured by a single conductivity cell. The unreacted and reacted solutions can be switched to the single conductivity cell in sequence. In this way the two measurements are as equal as possible, independent of the construction of the conductivity cell. 
     It is also possible to measure the two conductivities with two separate conductivity cells, a first of which is positioned in a first branch including the reactor column and a second of which is positioned in a branch passing the reactor column. Since the measurement of conductivity is highly dependent on temperature, the measurement values must be corrected for temperature or the two different solutions must have the same temperature. 
     By placing the two conductivity cells in close proximity to each other and passing the two solutions through heat exchanging coils in a heat exchanger, the two solutions attain the same temperature. 
     Other features, properties and advantages appear from the appended claims. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     The invention will now be described in more detail below with reference to the accompanying drawings in which: 
     FIG. 1 is an elevational, schematic representation of a urea sensor of the type envisaged by the present invention; 
     FIG. 2 is a schematic representation similar to FIG. 1, showing the use of two parallel conductivity meters; 
     FIG. 3 is a schematic representation showing valves switching one and the same measurement cell before and after the reactor column, respectively; 
     FIG. 4 is a valve diagram which shows the coupling sequence for the valves according to FIG. 3; 
     FIG. 5 is a schematic representation of a portion of the device shown in FIG. 1, showing the supply of carbon dioxide gas into a sample conduit; 
     FIG. 6 is a schematic representation of a portion of the device shown in FIG. 1, showing an alternative method of eliminating bubbles of carbon dioxide gas; 
     FIG. 7 is a schematic representation of a device similar to the device shown in FIG. 1, showing the use of two conductivity meters; 
     FIG. 8 is a schematic representation of a device similar to the device shown in FIG. 1, showing the use of a heat exchanger; 
     FIG. 9 is a detailed schematic representation of a preferred embodiment of the urea sensor according to the present invention; 
     FIG. 10 is an elevational, cross-sectional view through the heat exchanger included in the urea sensor according to FIG. 9; 
     FIG. 11 is a perspective exploded view of a double conductivity cell positioned at the bottom of the heat exchanger according to FIG. 10; 
     FIG. 12 is a schematic representation of a device similar to the device shown in FIG. 9, showing the urea sensor during disinfection; and 
     FIG. 13 is a schematic representation of a device similar to the device shown in FIG. 9, showing the urea sensor during disinfection. 
    
    
     DETAILED DESCRIPTION 
     FIG. 1 shows a urea sensor or meter of the type to which the present invention relates. 
     A fluid or solution on which the measurement is to be carried out passes through a conduit  1 . This solution can be a dialysis solution which comes either directly or indirectly from a dialyser. 
     A sampling device  3  removes a partial quantity of the solution from the conduit  1  and transports this sample to an inlet conduit  2 . The sampling device is exemplified in FIG. 1 by a pump  6 . 
     A charging device  4  is connected to the inlet conduit  2  for the addition of one or more substances. The addition is controlled by a pump  5  in FIG.  1 . 
     The sample solution is supplied to a reactor column  10  and is allowed to pass therethrough. The reactor column can contain urease for catalyzing the decomposition of urea into ammonium ions and bicarbonate ions. 
     The sample is fed from the reactor column  10  to a measuring device  7  which measures the decomposed product in the reactor column. The measurement device  7  can be a differential conductivity cell which measures the change in conductivity before and after the reactor column  10  respectively. 
     The sample is fed from the measuring device  7  to an outlet arrangement  8 . 
     An ion exchanger can be included in the inlet conduit in order to lower the content of undesirable ions, in order to improve the accuracy of the measuring device. 
     The invention primarily relates to the measurement of urea, and the reaction in the reactor column is linearised by the addition of carbon dioxide. 
     The solubility of carbon dioxide is improved by a high pressure and at least the conductivity measurement can take place at increased pressure. 
     By lowering the temperature, the solubility of carbon dioxide increases, which also can be used with advantage in the present invention. 
     Solution 
     The composite solution which is present in conduit  1 , and where the content of a substance is to be measured, is a solution of a medical and/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 comprises electrolytes with for example Na + , K + , Ca 2+ , Mg 2+ , Cl − , HCO 3   − , CH 3 COO −  in predetermined concentrations and combinations, as well as possibly further substances such as glycose. When the dialysis solution passes through a dialyser an exchange of low-molecular-weight substances occurs between blood on one side of the membrane of the dialyser and the dialysis solution on the other side of the membrane. Various substances thereby pass from the blood into the dialysis solution, such as urea, creatinine, etc. At the same time certain substances pass from the dialysis solution into the blood, such as bicarbonate ions (HCO 3   − ). 
     Other types of solutions to which the present invention can be applied are blood, in which high-molecular-weight substances are preferably first separated, for example by means of a membrane, after which the ultrafiltrate, i.e. blood plasma, is analyzed. 
     Other types of solutions which can be used according to the present invention are dialysis solutions which are used for peritoneal dialysis, whereby the out-going PD-solution is analyzed. 
     Additional solutions which can be analyzed are urine, sweat, tear fluid, saliva or other extra-cellular fluids which are sucked out through the skin or withdrawn in another way. 
     The solution in the conduit  1  can also be a fresh dialysis solution or infusion solution where the concentration of a particular substance is to be determined, for example glycose or penicillin. 
     The substances of which the concentration is to be measured in the solution are preferably such substances which require catalytic decomposition in order to be measured, and particularly those which require a pH-value lying within a small range, i.e. requiring the presence of a buffer system. Examples of such substances are: urea, L-glutamine, L-citrulline, N-acylaminoacid, penicillin, L-asparagine, cholesterol, and glycose. These substances can be made to decompose or to react during enzymatic influence in the reactor column  10  via known corresponding enzymes. For a more detailed determination of suitable combinations reference is made to European Patent No. 0 437 789 and U.S. Pat. No. 4,311,789. 
     The invention is described below with reference to urea and urease, but is also applicable to the afore-mentioned substances and other similar substances. 
     Sampling Devive 
     A sample is taken from the solution in conduit  1  by means of the sampling device  3 . In a preferred embodiment, the sampling device is a pump  6  which is driven so that a constant small flow is taken from the conduit  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 driven intermittently so that a sample is taken per unit of time, for example at an interval in the region of 5-60 minutes, for example 30 minutes. The volume of the sample can thereby be between about 1-100 ml/sample, preferably about 5-50 ml/sample, such as for example 10 ml/sample. 
     In one embodiment, the pump is driven in the sampling device  3  so that the sampling flow to. the inlet conduit  2  is proportional to the flow in the solution conduit  1  with a particular proportionality constant. If, for example, the solution in the conduit  1  is a dialysis solution which passes at about 500 ml/min, a five-hundredth part is taken out via the sample device  3 , i.e. about 1 ml/min. If the flow in the conduit  1  varies, the flow in the inlet conduit  2  also varies. The advantage with this embodiment is that the present invention can thereby be combined with the invention which is disclosed in European patent application EP 94.102383.0. The pump of the sampling device  3  can also be driven intermittently but each time so that the extracted sample flow is a particular proportion of the solution flow in the conduit  1 . 
     The pump  6  can be a ceramic pump with constant displacement per revolution and can be of the same type which is used in the monitor GAMBRO AK 100. Thus a very accurate metered amount can be taken out from the conduit  1 . Alternatively a peristaltic pump of known type can be used, or other similar pumps. 
     In the case where the content in the conduit  1  consists of blood, the same technique can be used as described in German Patent No. 39 00 119 where a hollow fiber of the same type as used in a hollow fiber dialyser is used for the sampling. The required under-pressure for taking out the ultrafiltrate, i.e. plasma, is created by the pump. 
     It is also possible to perform the sampling from a container comprising the solution to be analyzed. In this way the container replaces the conduit  1 . 
     Charging Device 
     The sample which is taken out by means of the sampling device  3  is fed to the inlet conduit  2 . An additive may possibly be added in this conduit. In certain cases it is desirable to adjust the pH-value for the solution so that the desired reaction is obtained in the reactor column  10 . 
     In the preferred embodiment the solution which is to be analyzed is a dialysis solution which contains urea and has a pH-value normally of around 7.4. The decomposition of the urea to ammonium ions brings about an increase in that pH-value. 
     U.S. Pat. No. 3,930,957 describes the addition of an organic buffer in liquid form. An alternative liquid buffer system which can be used is a so-called phosphate buffer consisting of H 2 PO 4   − /HPO 4   2−  which has a pH approximately equal to 7. 
     One disadvantage with a buffer in liquid form is, however, that it dilutes the solution and adds ions and thus alters the conductivity of the solution before the reaction in the reactor column. 
     According to a preferred embodiment of the present invention a buffer in gas form is used, namely carbon dioxide (Co 2 ), which cooperates with the bicarbonate buffer already present in the dialysis solution. In this connection carbon dioxide is supplied in gas form from the charging device  4  via the pump  5  to the inlet conduit  2 . This is described in more detail below. 
     The use of carbon dioxide gas as an additive for the dialysis solution comprising bicarbonate and for application to measuring the conductivity gives at least two advantages relative to a buffer in liquid form, namely that the additive of carbon dioxide does not produce any volume change and thus no dilution of the solution, and also that the dissolved carbon dioxide has no inherent conductivity. 
     By use of a buffer system in connection with a dialysis solution containing urea, in particular carbon dioxide gas, the pH-value can be controlled so that optimal effect is obtained from the urease. At the same time precipitation of calcium carbonate is avoided. 
     Reactor Column 
     An embodiment of the reactor column  10  is shown in FIG.  7  and comprises a cylindrical container which contains the enzyme which is required. In a preferred embodiment the column  10  comprises urease  11  which is immobilized by means of aluminium oxide  12  granules. Closely-meshed filters  13  and  14  are arranged at the inlet and the outlet. The filters prevent the urease and aluminium oxide, if released, from passing out of the column  10 . The filters furthermore prevent larger particles from entering the column. 
     The cylindrical container  10  has to have a sufficiently large volume such that the substance which is to be transformed is able to come into contact with, or close to, the corresponding enzyme for the length of time that a decomposition reaction is catalyzed. The column is preferably arranged so that the sample solution comprising the substance reaches the activation proximity of the enzyme to at least 99% for as long as the corresponding reaction is catalyzed. 
     It is preferred to feed the solution in from below by means of an inlet  15  and to feed out the reacted solution at the upper end of the column by means of an outlet  16 . Additionally, a filter  17  is provided which separates an upper part of the column  10 , which only contains aluminium oxide  18 , i.e. without urease. 
     It is clear that the column  10  can have various constructions depending on which substance is to be analyzed and which enzyme is used. Thus, the column may also be horizontal or the flow can be reversed and pass from the top downwardly. Additionally, it is possible with intermittent functioning to introduce the sample in the column  10  and to let this remain in the column for as long a time as a reaction is obtained, after which the sample is fed out for analysis and measurement. 
     In such a preferred embodiment protein and fat are included with the dialysis solution. It is desirable to separate protein and fat before or after the column, whereby one or both of the filters  13  or  14  may constitute 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 constitutes a cellulose filter impregnated with active carbon. In such a filter organic molecules are absorbed, practically speaking, completely. Other filter designs can also be used. 
     Measuring Device 
     The measuring device  7  is dependent on the substance which is 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  10 . Such a measuring device is disclosed in PCT Application No. WO 94/08641 and U.S. Pat. No. 4,686,479. 
     The measuring device can also be a pH-meter or a meter for gas which is released, such as ammonia, see PCT Application No. WO 93/22668. 
     According to a preferred embodiment the measuring device is an arrangement for measuring the difference in conductivity of the solution before and after the urease column  10 . 
     With reference to FIG. 1, the reactor column  10  is preceded by a three-way valve  20 , by means of which the inlet flow can be diverted to a shunt conduit  9  and a second three-way valve  23  past the reactor column  10 . When the three-way valves  20  and  23  are in the positions opposite as shown in FIG. 1 the dialysis solution passes beyond the column  10  via shunt conduit  9  directly to the measurement cell  7  for measurement of the initial or unreacted conductivity of the dialysis solution, i.e. without decomposing the urea. Then the three-way valves  20  and  23  are switched to their other position shown in FIG. 1 so that the solution can pass through the reactor column  10  and further to the measurement cell  7  and a reaction conductivity value is measured. By this embodiment, the same measurement cell  7  is used for measuring both unreacted and reacted conductivity values, which is beneficial. 
     In order to carry out the measurement even more reliably it may be suitable to introduce a delay conduit  22  in the shunt conduit  21  with the same volume as the reactor column  10 , which is shown in FIG.  2 . The delay conduit  22  preferably comprises the same amount of aluminium oxide as the urease-column  10  so that account is taken of the contribution of aluminium oxide to the conductivity. In the embodiment of FIG. 2, two different conductivity cells are used, which however can be calibrated as discussed below. 
     A further method for determining the conductivity before and after the reactor column is to arrange a measurement cell before and a measurement cell after the column, respectively, which is shown in FIG.  7 . 
     A preferred measurement method is disclosed in FIG.  8  and involves the sample solution being divided into two parallel flows and measurements being carried out on respective flows with separate measurement cells in order to simultaneously determine the initial conductivity and the reaction conductivity. It will suitably take approximately the same time for the sample solution to reach the respective measurement cell so that the two measurements are carried out on approximately the same sample. 
     A further way is to use the same measurement cell for measuring the conductivity on the same specific sample not only before but also after the reactor column  10 . FIG. 3 shows the reactor column  10  and a measurement cell  7  coupled together with a plurality of valves  31   a ,  31   b ,  32   a ,  32   b ,  33 ,  34 ,  35  and  36 . The valves are operated according to the valve scheme in FIG. 4, where O defines open valve and C defines closed valve. The switching scheme has twelve steps denoted T 1 -T 12 . After this the same cycle is adopted again. 
     At time T 1  the valves  31   a ,  32   a ,  33  and  34  are open and the flow first occurs through the measurement device  7  and thereafter through the reactor column  10 . This position is maintained during a relatively long time period so that the reactor column  10  and the conduits are filled with a sample and an initial conductivity is measured. 
     At time T 7  the valves have been switched so that the valves  31   b ,  32   b ,  35  and  36  are open. In this position the sample which earlier passed the measurement device  7  into the reactor column  10  flows through the same measurement device  7 . Also this position, T 7 , is maintained during a sufficiently long time so that a reliable measured value of the reaction conductivity can be obtained from the measurement device  7 . 
     In this way the same sample or amount of fluid passes through the measurement device  7  twice (although in different directions) and inbetween has passed the reactor column  10 . A particularly accurate measurement can be obtained in this way. 
     The different switching steps T 2 -T 6  as well as T 8 -T 12  have the task of removing pressure pulses in connection with the switching due to the fact that the measurement device  7  is coupled in parallel with shunt conduits  37 ,  38  during the switching process. It is of course possible that other valve schemes can be used than that shown in FIG.  4 . Similarly the discrete valves  31 - 36  may be replaced by three-way valves which perform similar functions. It will be clear to a skilled man how such valves should be connected with the guidance provided by FIG.  3  and FIG.  4 . 
     In a preferred embodiment the measurement device  7  is is a conductivity measurement cell which measures the conductivity of the solution which passes the measurement device. 
     The conductivity measurement cell can be of so-called four-pole type where the electric voltage is supplied to two feed electrodes positioned at a distance from one another. Two detector electrodes are positioned therebetween. The voltage over the detector electrodes is measured and the voltage which is supplied to the feed electrodes is regulated so that the measured voltage is constant. The resultant current is measured and is proportional to the conductivity of the solution. By means of four-pole measurement it is avoided that transition resistances between the supply electrodes and the solution affect the result. The feed voltage is an alternating voltage. 
     A conductivity measurement cell has a relatively large temperature dependence, for which reason it is necessary to maintain the temperature constant and/or correct for temperature variations as described in more detail below. 
     For calibration purposes or for taring, a shunt conduit  24  is shown in FIG. 2, said shunt conduit connecting the inlet of the two conductivity cells  7   a  and  7   b  with each other. By coupling-in this conduit the conductivity cells can be balanced to give the same measured value. If the conduit  24  is double the conductivity cells can be cross-connected for comparison of the measured values. 
     Outlet Arrangement 
     The sample is fed from the measurement device  7  to an outlet arrangement  8 , which in FIG. 1 is shown in the form of a collection vessel. 
     Alternatively, the sample solution can be sent to a drain or be fed back to the conduit  1  downstream of the sampling device  3 . 
     If the present invention is to be combined with the invention according to European Patent Application No. 94.102383.0 as mentioned above, an extra three-way valve  25  is used, said valve being positioned in the shunt conduit  9  (see FIG.  1 ), or after the conductivity cell  7   b  in the corresponding conduit in FIG. 2 to the left where the solution has not passed the urease-column. In order to ensure that a certain proportion of the dialysis solution in the conduit  1  passes through the shunt conduit, a separate pump  26  is used (see FIG.  2 ). The solution is led from the three-way valve  25  to a separate collection bag  27 . The volume of solution in the collection bag  27  thus has a predetermined relationship to the amount of solution which has passed through conduit  1 , for example 1:500. Furthermore the concentration of the substances included in the collection bag is the same as the average in the conduit  1 . By integrating the measured values for the urea sensor over the dialysis time, a total value of the urea is obtained which can be compared with the concentration in the collecting bag (which is analyzed in a different way). In this manner the function of the urea sensor can be monitored and double safety is achieved. Since the urea has been decomposed in the right branch, the solution which has passed along this route cannot be used for this purpose. 
     Ion Exchanger 
     In certain cases it is desirable to remove electrolytes from the sample solution before it is fed into the reactor column  10  and the measuring device  7 . It is the difference between the conductivity before and after the reactor column  10 , which is measured. If the measured value before the reactor column  10  is low or zero, a better accuracy is obtained. For this reason an ion exchanger can be incorporated into the inlet conduit  2  before the reactor column  10 , as shown in FIG. 1 with dashed lines at  21 . 
     Such an ion exchanger can be of conventional construction, where the ions are exchanged with corresponding hydrogen ions or hydroxide ions which form water. Such ion exchangers can be very effective but usually require a large amount of space. 
     Other methods can also be used in order to minimize or eliminate the electrolytes in the solution before the reactor column  10 . One example is to use an electrostatic method, where the solution in the inlet conduit  2  is made to pass charged electrode surfaces and where the charged ions are attracted by the electrodes&#39; surfaces whilst the uncharged substances, such as urea, are unaffected. 
     Additional 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 dialyser. The urea concentration in this dialysis solution is related to the urea content in the blood which is cleaned by the dialyser. 
     Urea is often used as an indicator for whether an 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 respectively in order to determine whether the required dialysis has been obtained, is not the subject matter of this invention and will not be described further. There are a large number of literature articles which discuss these questions and attention is directed to European Patent No. 0 547 025 as well as PCT Application No. WO 94/08641. 
     As concerns measurement of the urea concentration, this cannot be measured directly in an easy manner. As described above the solution which comprises urea must pass a reactor column  10  which comprises urease. Urease is an enzyme which catalyzes the transformation of urea to ammonium ions according to the reaction (1) below:                      (     NH   2     )     2                   CO     +     2                   H   2        O                       →                urease                                    NH   4   +     +     NH   3     +     HCO   3   -               (   1   )                                
     Thus ammonium ions and ammonia are formed as well as hydrogen carbonate ions (bicarbonate). The yield is practically 100% if the contact between the urea and the urease is sufficiently effective. 
     On the other hand ammonia is decomposed into ammonium ions in dependence on the pH-value of the solution, according to the equilibrium reaction (2) below: 
     
       
         NH 3 +H 2 O=NH 4   + +OH −   (2) 
       
     
     If the solution comprises a buffer system such as the phosphate buffer mentioned above, this equilibrium (2) will be replaced at sufficiently low pH-value, for example at pH=7, by the following reaction (3): 
     
       
         NH 3 +H 2 PO 4   − →NH 4   + +HPO 4   2−   (3) 
       
     
     With the aforementioned phosphate buffer the pH-value can be adjusted to approximately 7 and the amount of buffer regulated so that this pH-value is shifted only a very tiny amount. In this way, by suitable choice of the pH-value, practically all the ammonia can be transformed into ammonium ions. Other buffer systems can also be used such as disclosed in U.S. Pat. No. 3,930,957. 
     The disadvantage with using a buffer of the phosphate buffer type is that it dilutes the solution and contributes to the conductivity before transformation in the reactor column, which makes the measurement of the differential conductivity additionally difficult.. This problem is treated in U.S. Pat. No. 3,930,957 which proposes buffered organic carrier solutions which in themselves have very low electric conductivity and which do not react with the enzyme used. 
     Carbon Dioxide 
     In a preferred embodiment according to the present invention it is proposed that a buffer system consisting of carbon dioxide and hydrogen carbonate (bicarbonate) ions be used. Particularly with the measurement of the urea concentration in a dialysis solution, great advantages can be obtained. The dialysis solution normally comprises bicarbonate which together with carbon dioxide forms said buffer system. 
     Carbon dioxide reacts with ammonia according to the following reaction (4): 
     
       
         NH 3 +CO 2 +H 2 O→NH 4   + +HCO 3   −   (4) 
       
     
     The reaction upon which the present invention is based is the sum of reaction (1) and reaction (4), which results in the following reaction (5): 
     
       
         (NH 2 ) 2 CO+CO 2 +3H 2 O→2NH 4   + +2HCO 3   −   (5) 
       
     
     As is clear from the reaction (5) two ammonium ions and two hydrogen carbonate ions are obtained from each urea molecule, all four of which ions contribute to the increase in conductivity. Since carbon dioxide is added in excess, reaction (5) is displaced to the right so that the exchange becomes practically 100%. By addition of surplus carbon dioxide it is further obtained that the pH-value for the solution will be relatively low, which will prevent the precipitation of calcium carbonate. 
     If the pH-value is under about 7.35, the exchange in the above reaction is larger than about 99.5%. Additionally, the activity of urease is largest within the pH-range of about 6 to about 8. If at the same time the residence time for the solution in the urease column is sufficiently long, a total exchange in excess of 99% is obtained. Thus a pH-value for the solution after the urease-column lying between about 6 and about 8 is preferred, preferably between 6.2 and 7.4. 
     The carbon dioxide is added by means of the charging device  4 . A method for adding carbon dioxide gas to the sample solution in the conduit  2  is shown in more detail in FIG.  5 . 
     The charging device comprises a source of carbon dioxide under pressure  41  as well as a pressure reduction valve  42 . Carbon dioxide gas is fed from this source with a predetermined pressure to a conduit  43 . The conduit  43  is provided at its lower end with a connector  44  which passes through the wall in the conduit  2  into the sample solution. 
     A silicon tube  45  or other gas-permeable tube is connected to the coupling  44 , said tube being positioned in the conduit  2  substantially concentrically therewith along a predetermined length. The silicon has the property that carbon dioxide gas present within the tube  45  can be diffused through the silicon material and emitted to the solution in the conduit  2 . 
     The regulation of the pressure regulator  42  is is controlled by two pressure meters  46 ,  47 , which detect the pressure difference over the tube  45 . These two pressure meters can of course be combined into one differential pressure meter. 
     The diffusion speed is dependent on the differential pressure across the tube  45 . By adapting the length of the tube as well as the pressure difference, the desired amount of carbon dioxide can be fed into the sample solution in the conduit  2 . Preferably as much carbon dioxide is added so as to make the sample solution substantially saturated. In this context there is normally a sufficient amount of carbon dioxide which can be used in reaction (5) in order to decompose all the urea to ammonium ions. 
     At high urea concentrations it is difficult to add a sufficient amount of carbon dioxide gas which will dissolve in the sample solution. In this case a surplus of carbon dioxide gas can be added, said gas being included with the sample solution in the form of micro-bubbles or more or less large bubbles. This gas dissolves partially in the sample solution during transport to the urease column and the remaining amount of carbon dioxide gas is used during the reaction in the urease column. 
     FIG. 7 shows a further method of supplying carbon dioxide gas to the sample solution in the conduit  2 . As in FIG. 5, a source  41  of carbon dioxide gas under pressure is provided. Additionally two valves  49  and  50  are provided, between which a container  48  with predetermined volume is placed. The valve  49  connects the container  48  with the source  41  and the valve  50  connects the container  48  with the conduit  2 . Two pressure meters  51   a  and  51   b  are arranged across the valve  50 . 
     The function of the charging device according to FIG. 7 is according to the following. The valve  49  is opened and carbon dioxide is fed from the source  41  to the container  48  until the pressure meter  51   a  detects a predetermined pressure. The valve  49  is then closed and the valve  50  opened, whereby the contents in container  48  is supplied to conduit  2 . 
     When the pressure meter  51   a  or  51   b  detects a low pressure, the valve  50  is closed and the valve  49  is opened for a renewed filling of container  48 . 
     Since the volume of the container  48  and the pressure difference are known, the supplied amount of carbon dioxide in the conduit  2  can be determined. 
     The valve  50 , in the open condition, can perform a certain throttling so that supply of carbon dioxide gas occurs with a relatively even speed. By regulating the degree of throttling in the valve  50  during its open time, the amount of gas supplied per unit of time can be regulated. 
     It is also possible to operate the valve  50  so that a large bubble of carbon dioxide gas is fed into the sample conduit  2  so that the bubble fills up the complete cross-section of the conduit  2 . During the following transport towards the reactor column, the bubble of carbon dioxide gas dissolves partially in the sample solution next to it so that this becomes substantially saturated with carbon dioxide. The remaining amount of carbon dioxide gas is finally dispersed by the filter  13  in the reactor column  10  (see FIG. 2) so that the carbon dioxide gas is evenly distributed in the sample solution. The inlet conduit  15  should thereby be conically shaped so that the sample solution is divided over the whole cross-section of the reactor column  10 . During passage through the reactor column  10 , the carbon dioxide is used in reaction (5), whereby the surplus of carbon dioxide is used up. 
     In order to ensure that no carbon dioxide in gas form remains in the solution which leaves the reactor column  10 , which would disturb the following conductivity measurements, the outlet conduit  16  (see FIG. 7) may be provided with a bubble detector  52 , for example an ultra-sound detector. The output signal from one such bubble detector can be used in many ways. It can be used to indicate feasibly erroneous measurement values and/or to regulate the supply of carbon dioxide gas. In the latter case it should be observed that the time delay from supply to detection is relatively long, for example four minutes. If the concentration of urea does not change too quickly, an efficient and optimal regulation caN however be obtained. 
     In connection with the bubble detector  52  a gas separator  62  (see FIG. 6) may be present, separating any possible gas in free form from the solution in outlet  16 . 
     The carbon dioxide gas source  41  is preferably formed by a pressure container with carbon dioxide gas in condensed form, which immediately vaporizes upon release and corresponding reduction of pressure. Such carbon dioxide cartridges are available in different sizes. The consumption of carbon dioxide gas is ever so small that such a carbon dioxide cartridge of small dimension will suffice for very long periods of operation. 
     An alternative source of carbon dioxide gas can be the production of carbon dioxide gas in-situ. One way is to heat sodium bicarbonate powder (NaHCO 3 ) to a high temperature, for example over 50° C. In this way the sodium bicarbonate is decomposed and carbon dioxide gas is given off. The bicarbonate can be provided in a small container which is placed on a heating element. When the apparatus is to be used, the heating source is activated and the carbon dioxide gas is given off after a short time. The cartridge is of course replaceable. Other methods are known in the art. The exact method of manufacturing carbon dioxide gas does not form part of the subject matter of the present invention, but reference is made to European Patent No. 0 481 257 where a method for production of carbon dioxide gas is described. 
     During the reaction in the urease column  10  the pH-value of the solution rises, particularly if the urea concentration is high and the content of carbon dioxide gas is too low. If the pH-value rises above about 7.4 there is a risk for precipitation of calcium carbonate and magnesium carbonate (calcium ions and magnesium ions are normally part of the dialysis solution). If such precipitation occurs in the measurement cell  7 , this can very soon lead to erroneous measured values and the measurement device must be cleaned. 
     In order to obtain a sufficiently low pH-value in the solution which passes the measurement cell  7 , it can be desirable to add carbon dioxide gas also at the outlet from the urease-column  10 , i.e. at the outlet  16 . 
     It is also possible to provide the column  10  with a second inlet for carbon dioxide approximately at the filter  17  (see FIG. 7) or in other places, whereby it is ensured that the pH-value is always sufficiently low to avoid precipitation of calcium carbonate in the conductivity measurement cell. 
     Preferred pH-values (at a position after or inside the conductivity cell) are between 5.5 and 8.5, preferably between 6 and 8. With use of carbon dioxide and bicarbonate as the buffer, it is preferred that the pH-value lies between about 6.2 and about 7.7, preferably between 6.3 and 7.4. 
     Pressure 
     It is known that the solubility of carbon dioxide gas in water is essentially proportional to the pressure in the water. This fact is used in the embodiment shown in FIG.  7 . 
     An adjustable throttle valve  53  is arranged after the outlet  16  of the urease column. The throttle valve  53  functions together with the pump  6  in order to raise the pressure in the conduit  2  and the urease column as well as the measurement device  7   a  if bubbles are detected by the bubble detector  52 . The carbon dioxide gas then dissolves due to the increase solubility. The pressure is suitably re-adjusted to normal pressure as soon as the supply of carbon dioxide has been reduced so that no bubbles remain. 
     In another embodiment the throttle valve  53  is used together with the measurement device  7   a  in order to detect the occurrence of bubbles in the sample solution which upsets the measurement in the measurement device  7   a , like a replacement for, or complement to, the bubble detector  52 . At predetermined intervals, where it is desirable to check whether the measured results are reliable, the pressure is raised momentarily by activating the throttle valve  53 . The pressure increase can be monitored by the pressure meter  51   b  or a separate pressure meter. If the pressure rise results in a change in the measured value in the measurement device  7   a , this is a sign that the sample solution contains gas bubbles which disturb the measuring. This information can be used in order to reduce the supply of carbon dioxide gas, after which a new test is carried out after a certain time in order to verify that the change has given the desired effect. 
     The pressure meter  51   b  can also be used in order to ensure that the sample solution  2  is always at approximately the same pressure, for example atmospheric pressure. If the sampling occurs at the outlet from a dialysis machine, the pressure before the pump  6  can vary considerably. If the discharging device  8  is formed by a return conduit to conduit  1 , the whole of the sample conduit  2  will be at that pressure which is present in the conduit  1 . By manoeuvring the throttle valve  53  and the pump  6 , which is monitored by means of the pressure meter  51   b , the desired pressure in the sample conduit  2  as well as the measuring device  7   a  can be set, for example at somewhat above atmospheric pressure. 
     The aforementioned pressure increase only effects the measured result in the measurement device  7   a  to a very small extent in normal cases if the measurement device  7   a  is a conductivity cell. With the use of other types of measurement devices, one has to correct for the pressure-dependence of these measurement devices when applying the aforementioned method with pressure increase. 
     As an alternative to the method described above a local pressure increase in only the measurement device  7   a  can be used. For this an extra pump arranged before the measurement device  7   a  and a throttle valve arranged after the measurement device  7   a  are used. The extra pump and throttle device  53  are controlled so that the pressure in the reactor column  10  is not affected. Apart from this the function is the same as described above. 
     It is also possible to use a permanent pressure increased. The pressure increase could be in the range 0.03-0.3 MPa, preferably about 0.1 MPa. In this way a sufficient amount of carbon dioxide gas can dissolve in the solution in order to satisfy the reaction (5) and at the same time to ensure an outlet pH-value below about 7.4 up to a urea concentration of about 35 mM, without extra addition of carbon dioxide gas. 
     Temperature 
     It is known that the logarithm of the solubility of carbon dioxide gas in the sample solution in the conduit  2  is inversely proportional to the temperature. Normally the temperature of the used dialysis solution is about 36-37° C. 
     In order to avoid dependence on the temperature in the incoming dialysis fluid, the sample solution can be heated up, by means of a heating element, to a fixed temperature which lies at a value between about 38 and about 45° C., preferably about 40°. The reason that: the temperature is chosen to be so high is that it is higher than all expected incoming temperatures, for which reason no cooling is required and consistent measurements are obtained independent 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  10  and the measurement device  7 . At least the temperature of the reactor column should be constant in order to obtain uniform activity. However the temperature should not be raised (at least not too much) before the conductivity measurement cell in order to avoid possible bubble formation due to surplus carbon dioxide. 
     According to one embodiment of the present invention the temperature is instead lowered on the incoming sample solution by means of cooling. Such cooling can occur in many different ways, but since the amount of solution which is to be cooled is relatively small, Peltier-elements can be used where the electric current is directly converted into cooling. The sample solution is made to pass a Peltier-element  55  and current is supplied so that the required temperature drop is obtained as shown with dashed lines in FIG. 6, which is detected by a temperature sensor  56  positioned downstream of the Peltier-element  55 . A suitable temperature in this alternative embodiment is about 25° C. 
     The temperatures used should lie in the range of about 20° C. to about 50° C. The reason for this is that below about 20° C. the urease-enzyme has low effectiveness, which means that the transformation from urea to ammonium ions takes too long time. Above about 50° C. the urease-enzyme is decomposed, which of course is undesirable. A temperature between about 25° C. and about 45° C. is therefore preferred. 
     By using lowering of temperature with Peltier-elements, it is ensured that a sufficient amount of carbon dioxide gas can always dissolve in the sample solution in the conduit  2 . 
     A lowering of the temperature in connection with the measurement cell can be used in order to detect the presence of carbon dioxide gas which upsets the measuring, analogous with the aforementioned pressure increase. With lowering of the temperature in the measurement cell the solubility of carbon dioxide increases and carbon dioxide gas in bubble form will possibly dissolve. In order to compare conductivity values before and after such a temperature reduction, temperature compensation of the measured values is however required which can be difficult to achieve with desired accuracy. 
     FIG. 6 shows a gas trap  62  in the form of a gas-permeable tube  57  of silicon. Outside the tube there is a solution with a low content of carbon dioxide, for example dialysis solution, such as the content in the heat exchanger as described in connection with the preferred embodiment in FIG. 8 (see below). The surplus of carbon dioxide gas inside the tube  57  may possibly be given off to the fluid outside the tube  57 , particularly if a pressure difference is present. Other types of gas separators can also be used. 
     Priming 
     The urease-column  10  contains a dry powder which has to be moistened before use. This can take place by allowing a physiological sodium chloride solution to pass through the urease-column and the measurement device  7 . 
     Alternatively one can use the dialysis solution which is used by the dialysis machine during its start-up period in order to moisten the urease column and put this into an operation-suitable condition. The dialysis machine carries out a start-up procedure called “priming”, whereby the dialysis solution is circulated through the dialysis machine&#39;s system without the dialyser which is shunted. This solution can also be used for priming the urea-sensor. 
     Disinfection 
     Normally no particular cleaning of the urea-sensor is required. It is however recommended to flush out the urea-sensor after completed use, for example by allowing a physiological sodium chloride solution to pass through the urea-sensor for a predetermined time. A disinfection with raised temperature is normally not required. However the disinfection of the dialysis monitor and the urea sensor can be coordinated so that the disinfection solution may also pass through the urea sensor. In this case a heat disinfection is preferred, but also disinfection using citric acid etc. may be used (CleanCart). 
     In certain cases the dialysis solution contains glycose which can cause problems. By flushing after use such problems are however avoided. 
     The urea sensor according to the invention can be used completely separate from a dialysis monitor. In this case the urea sensor is connected to the outlet tube of the monitor. Of course the urea-sensor can be fixed to the casing of the apparatus and connected at a different location, for example immediately after the dialyser. It is also possible to completely 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 preferable to establish that everything is working satisfactorily. To this end, a small amount of solution containing urea at a particular known concentration is supplied to the conduit  2  and may pass the urea sensor. If the measurement device  7  does not produce an expected measured value it has to be exchanged and sent for repair/service. 
     Such a quality control can be carried out in a relatively simple way in that the urease column  10  comprises a small amount of urea in powder form at its inlet  15 . As soon as the physiological sodium chloride solution or other solution is supplied for priming, the urea powder is dissolved and transformed by the urease column  10  into ammonium ions which give a reading on the measurement device  7 . In this way only one exchangeable and disposable unit is required, namely the urease column  10  containing said urea powder. 
     The urease column  10  consists of a cartridge which is exchangeable. Before a dialysis treatment a new cartridge is put into place and priming occurs as described above. 
     With the case of manufacturing carbon dioxide gas in-situ, a second cartridge containing the necessary ingredients can be used. These two cartridges can form a unit by being built together in a suitable manner. The unit is exchanged in connection with each measurement and is dimensioned to allow measuring during a normal dialysis treatment, which can be about four hours with haemodialysis. 
     Preferred Embodiment 
     FIG. 8 shows a preferred embodiment of the invention. A sampling pump  6  extracts a sample solution from the content in the conduit  1 . This sample solution is divided into two parallel branches with approximately equal amounts in each branch. The first branch (to the right in FIG. 8) contains the urease-column  10  as well as the supply of carbon dioxide from a carbon dioxide source  41  via a dosage valve  60 . The second branch contains a delay conduit or a delay vessel  22  which contains the same quantity of aluminium oxide as the urease-column  10  and additionally has the same flow resistance as the urease-column  10 , but has no urease. 
     The contents of the urease-column  10  and the delay conduit  22  are supplied to heat exchanger coils  71 ,  72  of a heat exchanger  70 , which contains a large amount of fluid. The content of each branch,  71  and  72 , is transferred to each conductivity cell  7   a  and  7   b , respectively. After the conductivity cells the two branches are combined to a single outlet conduit  73 , in which a variable throttle device  53  is arranged and finally the sample solution is given off to a collection container  8  (or to conduit  1 ). 
     The inside of the heat exchanger is filled with a fluid which is kept at a very constant temperature. This fluid can be the dialysis fluid which passes in the conduit  1  or it can be another fluid which is heated to a desired constant temperature. In order to regulate the temperature there is a heating element  74  in an inlet  75  to the heat exchanger and a temperature sensor  76  in an outlet  77  from the heat exchanger. Additional temperature sensors can be placed in strategic positions in the heat exchanger  70 . The heat exchanger is insulated from the surroundings to an extent which is suitable practically. 
     The conductivity cells  7   a  and  7   b  are connected to an electronic device  78  which provides the required voltages and measuring devices in order to carry out the conductivity measurement. The electronic device  78  further comprises a subtraction circuit in order to arrive at a difference between the measured values from the cells  7   a  and  7   b  as well as further possible arrangements for compensating the measured values for temperature. These functions are preferably carried out with the help of a microcomputer. The microcomputer also converts the measured values directly into the urea concentration in the sample solution. 
     The measured values may be corrected with respect to the prevailing temperature according to known techniques. The temperature of the solution in each sensor  7   a  and  7   b  is measured by temperature sensors  79  and  80 . Since however the flow at the measurement points is very low, it is difficult to obtain reliable temperature measurements. 
     In order to obtain a sufficient accuracy in the determination of the urea concentration, it is necessary that the temperature difference between the solutions in the cells  7   a  and  7   b  is kept very small, in the order of magnitude of less than ±0.01° C. We have found that if the tubes  71  and  72  are sufficiently long. and the temperature in the heat exchanger  70  is constant, sufficiently accurate measured values can be obtained. 
     In this case it is not necessary to temperature compensate each conductivity value before subtracting them, but the temperature compensation can be made on the differential conductivity. Then, a temperature value which is the mean value of the two solutions can be used. 
     As the mean value can be used the temperature of the heat exchanging fluid in the heat exchanger but outside the coils  71 ,  72 . This temperature can be obtained by a temperature sensor, such as temperature sensor  110 , shown in FIG.  9 . The accuracy of the mean temperature need not be as high as mentioned above, but can be ±0.4° C. 
     The fluid which is present within the heat exchanger  70  is preferably dialysis fluid from the conduit  1 . In this way a relatively large flow can pass through the heat exchanger  70 , which ensures that the temperature is substantially constant. 
     Alternatively a closed system can be used which is shown with dashed lines in FIG. 8, where a pump  81  circulates the fluid in an outer closed circuit  82 . 
     The preferred embodiment according to FIG. 8 can be additionally complemented by a drainage device  25 ,  27  according to FIG. 1 in the left branch, which thereby contains a separate valve arrangement or pump. 
     In another alternative the arrangement according to FIG. 8 is provided with a cross-coupling which connects the urease column  10  with the tube  72  and the delay conduit  22  with the tube  71 . In this way the measurement cells  7   a  and  7   b  respectively can be used alternately for the urease-column  10  and the delay conduit  22 , whereby a reliable calibration can be obtained. 
     By using the throttle device  53  and the pump  6 , an overpressure can be achieved in the urea-sensor in the order of magnitude of 0.1 MPa, whereby a sufficiently high solubility for the carbon dioxide is obtained before the urease column  10  for the intended linear measurement range up to 35 mM urea concentration. The reason for this linearity is above all that the conversion is based on reaction (5), which is heavily displaced to the right due to the catalysis by urease and the surplus of carbon dioxide as well as a low pH-value. 
     FIG. 9 shows a more detailed flow scheme of the preferred embodiment of the urea sensor. The solution, enters from a dialysis machine via an inlet line  111  and enters a heater  112  and flows therefrom to a bubble separator  113 . From there, the dialysate is conducted further on to a heat exchanger  114  and via an outlet line  115  to an outlet as shown by arrow  116 . 
     The heater  112  comprises a heater rod  117  and a temperature sensor  118 . Another temperature sensor  119  is positioned in the inlet line  111  immediately before the heater  112  and measures the temperature of the inlet dialysate. Moreover, there is a power measuring device  120  for measuring supplied power to the heater rod  117  via a suitable current source  121 . 
     The inlet temperature of the dialysate in the line  111  is usually between about 20-37° C., for example about 34° C. The heater rod  117  is adapted to rise the temperature to for example about 42° C., which is sensed by a temperature sensor  110  positioned at heat exchanger  114 . 
     By measuring the temperature difference between temperature sensor  110  and temperature sensor  119  and supplied power from the current source  121  by the power meter  120 , the mass flow of dialysate through line  111  can be determined (a so-called thermal flow meter). Since the dialysate has an essentially constant composition, its specific heat capacitivity and density is approximately constant and the amount of dialysate., which is heated by the heater rod  117 , can be determined as to its mass and/or volume. 
     Since the rise in temperature by means of the heater rod  117  is relatively slight, the accuracy of such a thermal flow meter will be low. The flow meter can be used for sensing that the inlet fluid flow via the inlet line  111  are within predetermined limits. Further possibilities of use appears from the description below. 
     The bubble separator  113  comprises a chamber having relatively large cross section so that :the flow velocity is low through the chamber from an inlet  122  at the lower end of the chamber to an outlet  123  at the upper end of the chamber. The bubble separator  113  is provided with a partition wall  124  and a second outlet  125  is adapted behind the partition wall  124  in relation to the inlet  122  in order to protect the outlet from turbulence. From outlet  125  a small partial quantity of the dialysate is taken out, a so-called sample solution of for example about 1% or less, which partial amount constitutes the fluid which is analyzed as to the contents of urea (or any other substance of interest). Thus, the sample solution taken out via outlet  25  will be comparatively free from gas bubbles. 
     The sample solution taken out passes from outlet  125  via a line  126  to a branch point  127 . Line  126  comprises an inlet coupling  128  for a bag  129  enclosing a test solution, and a ground connection  130  for grounding the fluid in line  126 . Moreover, there is an airation valve  131 . Furthermore, line  126  may be winded a few revolutions around the dialysate line  115  as shown at  132  for equalizing possible temperature differences between the fluids in the lines. 
     Coupling  128  is intended for cooperation with a connector  133 . When connector  133  is inserted in the coupling  128 , a valve  134  in line  126  before coupling  128  is closed so that the contents of the bag  129  passes through line  126  to the branch point  127  instead of the sample solution. 
     The bag  129  including test solution may comprise about 50-100 ml test solution, which comprises urea in a known concentration. The test solution can be colder than the temperature of the dialysate of the sample solution, and that is why the heat exchanger  132  heats the sample solution to a certain degree. A volume of about 55 ml is sufficient for about 20 minutes use of the test solution. 
     At the branch point  127 , the sample solution from line  126  is divided into three branches. The first branch goes via a line  135  to a pump  136  of peristaltic type. The second branch goes via a dummy volume  137  to a second pump  138  of peristaltic type. The third branch goes via a line  139  to a third pump  140  of peristaltic type. 
     From pump  136 , the sample solution passes further on via a line  142  to a urease column  141  in the nature of a disposable article. The column comprises a sufficient amount of urease and further material required for transforming the urea contents of the sample solution to ammonium ions and bicarbonate ions as described above. The column  141  is shaped as a cartridge having a specific shape and with connections so that it easily be connected to the urea sensor. 
     Before the urease column  141  there is supplied carbon dioxide gas to the line  142 , for example in a T-coupling  143 . The pressure of the supplied gas is measured by a pressure meter  144 . The amount of gas supplied is controlled by a valve arrangement as closer described below. 
     In the urease column  141 , the urea contents of the solution is decomposed into ammonium ions and bicarbonate ions. The transformed solution is passed via a line  145  to a bubble separator  146 . From the outlet connection of the bubble separator, the solution passes further on via a valve  147  (closer described below) via a line  148  to a fourth pump  149 . 
     All pumps  136 ,  138 ,  140 ,  149  are driven by a common motor  150  via a common shaft or via any suitable transmission. The pumps are preferably so-called peristaltic pumps. The pump  136  has preferably a slightly larger capacity than the other pumps, which mutually have the same capacity, which can be about 0.6 ml/min for the pumps  138 ,  140 ,  149  and about 20% more for the pump  136 . The pump  140  can have a different and/or separate capacity. 
     During normal operation, a closed system prevails between the first pump  136 , line  142 , urease column  141 , line  145 , bubble separator  146 , via valve  147 , line  148  and pump  139 . Thus, the difference in capacity (about 20%) between pumps  136  and  149  must be given off via the second line  151  of the bubble separator for separated gases. Thus, the inlet solution via line  145  to the bubble separator  146  is divided in two flows, 20% via line  151  and 80% via line  148 . The major portion of the gas contents of the inlet line  145  passes out via the upper outlet to line  151 . 
     The solution which passes out through line  148  to pump  149  is thus more or less completely free from gases. This solution is conducted further on via a line  152  to a conductivity measurement cell  153  (below named condcell). 
     From the branch point  127  a partial amount of the sample solution is passed via the volume  137  and the pump  138  and via a line  154  to a second condcell  155 . In this way there is obtained a time delay of said partial amount passing the volume  137 , which is approximately equally large as the time delay for the partial amount which passes the urease column. 
     Before the solutions in the lines  152  and  154  reaches each respective condcell  153 ,  155 , the solution passes through tubes, for example in the shape of heat exchanger coils  156 ,  157  positioned in the heat exchanger  114  and thus surrounded by dialysis solution of relatively constant temperature. The conditions are such that the solutions in the two coils  156 ,  157  have passed through approximately the same volumes and lengthes of lines at their way to the coils  156 ,  157 . Moreover, the coils are positioned very tight adjacent to each other in the heat exchanger, which means that the temperature of the two solutions are equal or very similar, typically less than a difference of 0.01° C. 
     The difference in conductivity between the two solutions depends on the contents of ammonium ions and bicarbonate ions in the catalytically decomposed solution, which thus can be measured and correlated to the urea contents. 
     Due to the supply of carbon dioxide, the relationship between the amount of urea and ammonium ions is linear over a large area sufficient for the measurement of the present invention. Thus, no calibrations are required for corrections for possible deviations from a linear relationship. 
     From the two condcells  153 ,  155 , the solution passes further on via a common line  158  to a pressure equalizing device  159 . In line  158  there is further placed a ground connection  160  in order to ensure that no electric disturbances enter via the solution from the surroundings. 
     The pressure equalization device  159  comprises a container  161  having an inlet connection from line  158  and an outlet connection to an outlet line  162  both preferably in the bottom  161 . In the upper end of the container there is a connection to a line  163 , which terminates with a pressure meter  165 . The signal from the pressure meter  165  controls the opening degree of a valve  164  positioned in outlet line  162 . 
     When solution enters the container  161  via line  158 , the container is filled and air passes out via line  163  and influences upon the pressure meter  165 . When a certain predetermined pressure prevails in the container  161 , valve  164  is opened and allows the solution to pass out via line  162  and valve  164 . Thus, a certain predetermined pressure is maintained in container  161  and controlled via the remaining amount of air in container  161  and the valve  164 . 
     The remaining amount of air in container  164  operates as an air cushion which damps possible pressure oscillations which may have a tendence of occuring during for example a pump stroke. By means of device  159 , an overpressure is obtained in the lines between the pumps and up to device  159 . This overpressure means that possible remaining carbon dioxide in the solution which passes via line  152  and other possible remaining gas bubbles in the solutions reaching the condcells will dissolve in the liquid. In this way problems in connection with the measuring in the condcells are avoided. It is known that gas bubbles considerably disturb the measurement in the condcells. 
     It is also possible to change the pressure of device  159  by closing valve  164  so that the pressure increases temporary or intermittent. A change of the conductivity value (especially an increase) at increased pressure indicates error in the condcells, as described above. 
     The present invention uses double gas separators, a first separator  122  for taking out a sample from the dialysis solution which is essentially free from bubbles, and a second separator  146 , which separates a possible excess of supplied carbon dioxide gas. Moreover, the extra safety measure of an increased pressure is used. The solubility of gas in a liquid decreases with increased temperature, but the temperature is relatively constant in the present invention. 
     From valve  164 , the solution passes out to the outlet line  115  for dialysate solution and is delivered to a waste etc. 
     The third pump  140  is connected to the branch point  127  via line  139  and takes out a test sample with constant flow speed, for example about 0,6 ml/min. From pump  140  this sample solution passes via a line  166  to an outlet  167  and via a valve  171  to the outlet line  115 . In the outlet  167  can be inserted a connector  170  which via a line  169  is connected to a collection bag  168 . When the connector  170  is inserted in the outlet  167 , valve  171  is closed and all the solution in line  166  must pass to the collection vessel  168 . 
     Preferably pump  150  is driven with constant speed in order to take out a constant partial amount of the dialysate solution passing through the entire urea sensor. Alternatively, pump  150  can be driven with a speed which is proportional to the amount of dialysate solution passing in outlet line  115 , for example with a proportion constant of 1:500 and is used for the purpose stated in European patent application 94.102383.0. In this case, motor  150  which drives pumps  136 ,  138 ,  140 ,  149  is controlled by a signal obtained from the dialysis machine so that said proportionality constant is obtained. Alternatively, it is possible to use the measurement of the dialysis flow achieved via the heater rod  117  and corresponding temperature sensors  110 ,  119 . 
     Carbon dioxide gas is supplied via the T-connection  143  to the sample solution as described above. The carbon dioxide gas is obtained from a suitable source  132  for carbon dioxide gas, which can be a carbon dioxide cartridge or a device for generating carbon dioxide gas in situ. 
     The pressure from the source of carbon dioxide gas is controlled with a regulator  173  of known construction and the outlet pressure is monitored by a pressure sensor. 
     Two valves  175 ,  176  are adapted in a line  177  leading from the pressure regulator  173  to said T-coupling  143 . Valves  175 ,  176  are controlled so that when one is open the other is closed. By controlling the frequency for opening and closing of said valves, the amount of carbon dioxide gas passing valves  175 ,  176  is controlled if the pressure difference across the valves is known. The pressure difference is measured by the pressure sensors  174  and  144 . 
     The amount of carbon dioxide gas introduced in the branch point  143  is controlled so that a sufficient amount of carbon dioxide gas is introduced while a too large excess is avoided. 
     Line  177  comprises a valve  178  connecting line  177  with container  159  under certain operation conditions such as disinfection of the system. 
     There is a bypass-line  179  bypassing the urease column  141  when it is taken out from its holder. 
     Heat exchanger  114  comprises a cylindrical or rectangular container  180  having a relatively large volume, for example 2 dl. The dialysate surrounds the heat coils  156  and  157  so that they obtain the same temperature as the dialysate and mutually the same temperature to a very large accuracy. 
     The condcells  153 ,  155  are positioned in the bottom of the container at the outside of the container  180  as more closely appears from FIG.  10 . The heat coils  156 ,  157  terminate in two openings  181  and  182  through the relatively thick bottom  183  of the container. At the outside of the bottom  183  (or in a recess in the bottom plate), the two condcells  153 ,  155  are integrated to a single unit on the same substrate. Thus, it is assured that they adopt the same temperature. By having both cells in close thermal prixmity, the accuracy required for the temperature sensor is reduced. 
     As shown in FIG. 11, the condcells comprise two plates  184 ,  185 , which are made for example of sapphir and comprise each a longitudinal concave recess  187 ,  188 , respectively. The plates are entirely symmetrical and are faced against each other and connected against each other with spring loaded attachment means (not shown in FIG. 11) so that a sealing  186  between the sapphir plates is always loaded. The sealing  186  can be made very thin and is made of a plastic material, which is inert in relation to the dialysate, such as polypropylene. 
     Opposite the corresponding recess  187 ,  188  there are several gold electrodes  189 ,  190 , which extend out to the sides of the plate. Each electrode cooperates with a corresponding contact  191 , only one of which is shown in FIG.  11 . There are in principal six equal electrodes  189 , positioned symmetrically around a common electrode  190 . 
     Between the two outer electrodes  189  and the electrode  190  there is applied an electric current via a current generator. The voltage over the two next following electrodes on each side is measured and gives two measurement signals which in principal should be equally large (possibly after correction due to different distances). 
     The gold electrodes  189 ,  190  can be applied by means of known techniques, such as plating or by means of ion assists or ion implant. Other known methods can also be used. 
     Since the plates are made of sapphire having a good thermal conductivity, only small temperature differences occur internally in the condcell. Of course, also other conventional materials can be used. 
     The sample solution enters through holes  181 ,  182 , respectively, to each recess  187 ,  188  and passes in the same direction to outlet holes  192 ,  193  in order to obtain similar temperature conditions. It is alternatively possible that the flow through the recesses takes place in opposite directions. 
     In an alternative embodiment, each plate has two recesses and the plates are so positioned that each recess faces a corresponding recess in the other plate. A further alternative is to provide one plate with two recesses while the other plate is plain and provided with the electrodes. 
     In all other respects, the operation is identical to the embodiment described above. 
     The plates  184 ,  185  are maintained against each other by means of spring loaded attachment means  194  as shown in FIG.  10 . There can be many such attachment means distributed over the periphery of the plates in order to give a uniform pressure distribution on the plates  184 ,  185  and the sealing  86  interposed therebetween. Also the contacts  191  contribute to keeping the plates together. 
     The urea sensor described above requires cleaning and disinfection with regular intervalls in order to maintain a high accuracy. Disinfection with heat can be performed at the same time as the dialysis machine which the urea sensor is connected to. Disinfection can take place after each treatment or each day. 
     When the dialysis machine is disinfected, dialysate having increased temperature passes through the urea sensor, which is sensed by the temperature sensors  119  and  110 . Then, the operation of the urea sensor is also switched over to heat disinfection and the heater rod  117  heats the inlet dialysate further to a temperature of about 95° C. The urease column  141  has to be disconnected and the bypass line  179  is activated since the urease material does not withstand high temperatures. In this way an effective heat disinfection of the urea sensor is obtained. The urea sensor can also be cleaned by chemical means. 
     At disinfection (chemical and/or with heat) the valves are placed in certain positions as shown in FIG.  12  and FIG.  13 . FIG. 12 shows disinfection, phase one. Then, fluid passes from inlet  125  via line  126 , valve  131 , coil  132  to point  127 . From point  127 , the fluid passes further on via pump  138 , line  154 , coil  157 , cell  155 , line  158 , vessel  161  and valve  164  to the outlet  116 . Moreover, the solution passes from point  127  via line  139 , pump  140 , line  166 , connector  167  to valve  171 . 
     Valve  180 , which connects valve  171  to the outlet is, however, closed as is shown by the cross  181  in FIG.  12 . Thus, the solution in line  166  must pass via valve  171  and backwards in line  151  to the bubble separator  146  and then via valve  147 , line  148 , pump  149 , line  152 , coil  156 , cell  153  to the line  158  and further on to the outlet. 
     At the same time the solution passes from point  127  via line  135  and pump  136  to the line  142 . Due to the flow conditions, the pressure at point  143  and the pressure at the inlet to the bubble chamber  146  are approximately equal and that is why the solution does not pass through the bypass line  179  via line  145  to the bubble separator  146  but instead passes from the branch point  143  and backwards in line  177  (where it is normally only carbon dioxide) and then via valve  178  and line  182  to the upper end of the chamber  159 . In this first phase the main part of the system is disinfected except for valve  180  and line  145  and bypass line  179 . 
     In the second phase of the cleaning as shown in FIG. 13, valve  180  is switched over so that it is open and valve  147  is switched for connecting line  148  with a line  183  and to block the connection between the bubble separator  146  and the line  148 . By this measure, the line  145  and the bypass line  179  are disinfected with a large flow, which gives a high heating (at heat disinfection). Moreover, valve  164  is closed which means that the flow in line  182  changes direction and goes from chamber  159  to valve  178  and the point  143 . 
     The present invention has above been described with reference to several embodiments shown on the drawings. The invention can however be varied and modified in many manners within the scope of the invention. The different single features shown in one or the other drawings can be combined in manners different from those shown on the drawings. Such modifications, which are obvious to a skilled person reading this specification, is intended to be within the scope of the invention. The invention is only limited by the appended patent claims.