DE202010017537U1 - Detection device for determining the urea content - Google Patents

Abstract

Detection device for the photometric determination of the urea content of a liquid, in particular in a dialysate as a control variable for a hemodialysis treatment, with - a UV-transparent radiation cuvette for receiving the liquid, - a UV radiation source aimed at the radiation cuvette for providing radiation at at least two predetermined wavelengths of which a first wavelength is in a first subrange between 280 nm and 300 nm and at least a second wavelength is in a second subrange between 250 nm and 270 nm, - a photodetector device which is sensitive at least at the first and second wavelengths for recording an absorption measurement signal from the radiation cuvette and - a signal processing device for correction or calibration processing of the photodetector signal at the first wavelength with the photodetector signal at the second wavelength and for calculating the urea content from the ko corrected or calibrated measurement result at the first wavelength.

Description

The invention relates to a device for the photometric determination of the urea content of a liquid, in particular in a dialysate as a control variable of a hemodialysis treatment.

Spectrophotometric methods for the quantitative determination of ingredients in compounds or mixtures have long been known, and especially in use for the analysis of the composition of body fluids or in contact with a living body brought fluids in medical laboratory use. Dialysis treatments assist the body of a human (or animal) with impaired or lost renal function in the removal of metabolic waste products from the blood, to the complete takeover of renal function by the dialysis system. Already years ago, it was recognized as desirable to control a dialysis treatment depending on its success - ie the time-dependent state of blood purification - on the one hand to ensure a sufficient effect of this cumbersome and cumbersome treatment for the patient and on the other hand the expenditure of unnecessary treatment time avoid. Model approaches for assessing the success of treatment during treatment were developed and parameters were found, the current value of which is sufficiently representative of the success of the treatment and which can be recorded during treatment.

Among other things, the urea content can be measured in the spent from the dialysis device, used dialysis fluid and used as a measure of the treatment success. However, this requires a sampling and laboratory evaluation and is therefore hardly "online" during the treatment process used. In addition, a monitoring method using conductivity sensors has been developed which detect enzymatically induced changes in the conductivity of the discharged dialysis fluid caused by the hydrolysis of urea (or other relevant molecules) in the dialysis fluid. In this method, however, practical problems have occurred in the calibration of the sensors and the compensation of a (occasionally differing) basic conductivity.

In the WO 99/62574 Therefore, a method for determining the content of degradation products in the dialysis fluid during a dialysis treatment is proposed, which makes use of the spectrophotometric analysis of the dialysis fluid. In the WO 2008/000433 A1 Also proposed are a spectroscopic detector and a method with similar application, which are specifically designed for the detection of blood and biological markers in liquids - such as in dialysis fluid - are provided. A corresponding blood detector is used in dialysis systems, in particular for rapid detection of patient-critical conditions as a result of malfunction of the arrangement (such as a membrane rupture of the membrane filter, the interchanging of terminals or hemolysis). The latter document also contains a number of references for further prior art.

Furthermore, a small and easily applicable "dialysis adequacy monitor" (DIAMON) is known, which consists of a light source (UV LED - with maximum radiation of 280 ± 5 nm), an optical cuvette, a detector (GaNi-UV photodiode ) and a pressure plate. The monitor is connected to the dialysate drainage of the dialyzer, in the cuvette is a partial absorption of UV radiation, depending on the concentration of waste products in the dialysate, and the absorption is determined by the photodiode, which sends a corresponding signal for data processing. For the statements of this device see. I. Fridolin et al. "Accurate On-line Estimation of Delivered Dialysis Dose by Dialysis Adequacy Monitor (DIAMON)", (2007) ,

The basics of this simple and compact realizable measuring principle are pointed to US 6,666,841 B1 and the WO 2009/071102 A1 teaching a method and apparatus for the determination of metabolic products in a dialysate or for determining the concentration of uric acid in biological fluids. In particular, the latter method can be used to determine uric acid concentration in dialysate. The method itself and its modifications are based on the measurement of spectral transmission of the dialysate in the UV range, for. In the range of 270-330 nm, in a flow cell located at the end of the dialyzer, an application of the Savitzky-Golay algorithm for spectrum smoothing and the application of correlation regression analysis to determine uric acid concentration.

The object of the present invention is to provide an improved detection device, which in particular should provide more accurate results and enable more reliable statements.

This object is achieved by a detection device having the features of claim 1. Advantageous developments of the inventive concept are the subject of the dependent claims.

One aspect of the invention is that the liquid is irradiated with UV radiation at at least two wavelengths in the wavelength range between 250 nm and 300 nm and the radiation absorption in the liquid is measured at the predetermined wavelengths, of which a first in a first partial range between 280 nm and 300 nm and at least a second in a second subregion between 250 nm and 270 nm. The measurement result at the first wavelength is corrected or calibrated using the measurement result or the measurement results at the second and possibly further wavelengths in the second subrange. The urea content and optionally the content of other ingredients is calculated from the corrected or calibrated measurement result.

In one embodiment of the invention, the first wavelength is 285 nm and the second wavelength is 260 nm. One embodiment provides that the UV radiation is irradiated discretely at the predetermined wavelengths, in particular at 285 nm and 260 nm. Alternatively, the analytically relevant wavelengths can be filtered out of a continuous spectrum or band spectrum of another type of radiation generator and selectively radiated into the sample, or a broadband absorption signal can be appropriately filtered before reaching the detector.

In a further embodiment, it is basically provided that the processing of the measurement results is an input of the respective specific 1st and 2nd order spectral absorption indices of urea and a second liquid component, namely an intermediate product of the nucleic acid metabolism, and the correction or calibration thereof Processing in a system of equations includes 2nd order. If simplified assumptions can be made with regard to the 2nd order, the signal processing can be limited to the 1st order; For details, see below.

In a specific application of the invention, in the course of a hemodialysis treatment, a plurality of measurements and calculations are carried out at predetermined times or at predetermined intervals and the respectively calculated values of the urea content are subjected to a threshold discrimination for deriving a control signal. It can thus be discreetly triggered in response to the achievement of a predetermined urea level, a control process in dialysis. An alternative embodiment provides that a curve is formed from the calculated values of the urea content, from which a control signal is derived. A corresponding progression curve is well suited for an accompanying graphical representation to facilitate medical monitoring and allows the consideration of different assumptions about measurement errors, the course of treatment etc. in the control of the treatment on the basis of the measurement results.

• – eine UV-transparente Durchstrahlungsküvette zur Aufnahme der Flüssigkeit,
• – eine auf die Durchstrahlungsküvette gerichtete UV-Strahlenquelle zur Bereitstellung von Strahlung bei mindestens zwei vorbestimmten Wellenlängen, von denen eine erste Wellenlänge in einem ersten Teilbereich zwischen 280 nm und 300 nm und mindestens eine zweite Wellenlänge in einem zweiten Teilbereich zwischen 250 nm und 270 nm liegt,
• – eine mindestens bei der ersten und zweiten Wellenlänge empfindliche Photodetektoreinrichtung zur Aufnahme eines Absorptions-Messsignals aus der Durchstrahlungsküvette und
• – eine Signalverarbeitungseinrichtung zur Korrektur- bzw. Kalibrierungs-Verarbeitung des Photodetektorsignals bei der ersten Wellenlänge mit dem Photodetektorsignal bei der zweiten Wellenlänge und zur Berechnung des Urea-Gehalts aus dem korrigierten bzw. kalibrierten Messergebnis bei der ersten Wellenlänge.

The proposed detection device thus comprises

• A UV-transparent radiographic cuvette for receiving the liquid,
• A UV radiation source directed onto the radiation cuvette for providing radiation at at least two predetermined wavelengths, of which a first wavelength lies in a first partial range between 280 nm and 300 nm and at least a second wavelength in a second partial range between 250 nm and 270 nm .
• - A sensitive at least at the first and second wavelength photodetector device for receiving an absorption measurement signal from the transmission cuvette and
• Signal processing means for correcting the photodetector signal at the first wavelength with the photodetector signal at the second wavelength and calculating the urea content from the corrected or calibrated measurement result at the first wavelength.

In one embodiment of the device, the UV radiation source has at least one first light-emitting diode emitting at the first wavelength, in particular at 285 nm, and a second light-emitting diode emitting at the second wavelength, in particular at 265 nm. As already noted above with regard to method aspects, it is also possible to provide a broadband UV radiation source with a filter for filtering out the required wavelengths either on the irradiation side or on the detection side.

An important embodiment variant provides that the detection device is a continuation of a dialysis system, the transmission cuvette is a measuring cuvette or a section of a fluid line through which the spent dialysis fluid removed from the dialysis system flows. Specifically, in this case, the signal processing device of the detection device with an input of a control device connected to the dialysis device such that the operation of the dialysis device is controllable due to the control variable detected by the detection device.

Incidentally, advantages and expediencies of the invention will become apparent from the following description of exemplary embodiments and aspects with reference to the FIGURE. This shows a schematic overall representation of a dialysis device with a detection device according to the invention.

The apparatus for measuring uric acid concentration in the dialysate during a dialysis according to 1 includes a light source module 1 with two (not separately shown) light sources with emission wavelengths of 285 nm and 260 nm; a light source power supply 2 ; an optic 3 for beam shaping; a quartz flow cell 4 , Light sensors 5 for recording the LED radiation passing through the cuvette; a recording and processing module 6 for electrical signals, including AD / converters and amplifiers; a data acquisition and processing module 7 ; a computer connection module 8th and a computer 9 with installed special software. This detection device is in a dialysis arrangement 10 integrated, which is an extracorporeal blood circulation 11 , a dialyzer 12 and a dialysate processing module 13 includes.

The apparatus enables automated measurement of the dialysate transmission coefficient in the course of the dialyzer at wavelengths of 260 nm and 285 nm at precisely defined times, calculation of uric acid concentration and an unknown component taking into account the individual spectral absorption characteristics of the patient, generation of time charts / Concentration and the amount of uric acid withdrawn from the patient's body during treatment, a display of the results on a computer screen and their storage in a database.

The working principle of in 1 The arrangement shown is as follows: The light from the light source module 1 is using the beam shaping optics 3 to the working area of the quartz flow cell connected to the drainage tube of the dialysis machine 4 steered, and the transmitted light is on the light sensors 5 focused. Using the recording module 6 are amplified and digitized by each light sensor electrical signals. The data acquisition and processing module 7 is for setting the recording mode in the module 6 , the reference signal recording, determination of the dialysis transmission coefficient, data buffering and data transmission to the computer connection module 8th responsible.

Immediately before dialysis treatment, when a patient P is not yet connected to the dialysis machine, the extracorporeal circulation 11 and the dialyzer 12 filled with physiological saline. At this time, flows out of the dialysate processing module 13 through the drainage tube of the dialysis machine 10 clean dialysate, which contains no substances measured during monitoring and is used as a reference. At this time, the working mode is set using the electric signal recording and processing module, and signals at the light sensors are referred to as 100% transmission. After the patient is connected to the dialyzer, signals at the light sensors are measured over equal time intervals, and the transmission coefficient is calculated by the data acquisition and processing module for each channel (at 260 nm and 285 nm). The received data is cached and retrieved by the computer connection module 8th to the computer 9 transfer.

The settings of the monitoring mode (duration, measuring interval) and calculation parameters (specific absorption coefficients, dialysate flow, patient code), the measurement of controlled parameters in the dialysate, the production of a uric acid concentration over time and the total value withdrawn urea on time charts and saving the results are made by the special software on the computer 9 expires. The calculation of the concentration of the components studied is done using the algorithm implemented by the claimed method.

worin k_d(λ₁), k_d(λ₂) die spektrale Absorption des Dialysats (untersuchtes Fluid) bei den angegebenen Wellenlängen ist; Tλ1, Tλ2 das spektrale Transmissionsmaß des Dialysats bei den ausgewählten Wellenlängen ist;

jeweils die Spektralabsorption von Harnsäure bei den Wellenlängen λ₁, λ₂ ist,

jeweils die spektrale Absorption des zweiten Bestandteils bei den Wellenlängen λ₁, λ₂ ist,

der spezifische spektrale Absorptionsindex für Harnsäure bei den Wellenlängen λ₁, λ₂ ist,

der spezifische spektrale Absorptionsindex für den zweiten Bestandteil bei den Wellenlängen λ₁, λ₂ ist,

der spezifische spektrale Absorptionskoeffizient zweiter Ordnung für Harnsäure bei den Wellenlängen λ₁, λ₂ ist,

der spezifische spektrale Absorptionskoeffizient zweiter Ordnung für den zweiten Bestandteil bei den Wellenlängen λ₁, λ₂ ist, C₁ die Harnstoffkonzentration im Dialysat ist, und C₂ die Harnstoffkonzentration des zweiten Bestandteils im Dialysat ist.The proposed method for measurement of uric acid concentration in a dialysate during a dialysis treatment is based on the Beer-Lambert law and the Additivitätsprinzip, according to the absorption index kd (λ) for a mixture of two non-interacting constituents in a uniformly thick layer at wavelengths λ1 and λ2 as follows can be shown in writing:

where k _d (λ ₁ ), k _d (λ ₂ ) is the spectral absorption of the dialysate (fluid under investigation) at the indicated wavelengths; Tλ1, Tλ2 is the spectral transmission of the dialysate at the selected wavelengths;

in each case the spectral absorption of uric acid at the wavelengths λ ₁ , λ ₂ ,

in each case the spectral absorption of the second constituent at the wavelengths λ ₁ , λ ₂ ,

the specific spectral absorption index for uric acid at the wavelengths λ ₁ , λ ₂ ,

is the specific spectral absorption index for the second constituent at the wavelengths λ ₁ , λ ₂ ,

is the second order spectral absorption coefficient for uric acid at the wavelengths λ ₁ , λ ₂ ,

the second-order specific spectral absorption coefficient for the second constituent at the wavelengths λ ₁ , λ ₂ , C _{1 is} the urea concentration in the dialysate, and C _{2 is} the urea concentration of the second constituent in the dialysate.

The concentration of the uric acid and optionally the second component is derived by solving the simultaneous equation (1) for C ₁ and C ₂ .

The substances that make a major contribution to the spectral absorption of the dialysate in the UV range, are low molecular weight components such as uric acid, creatinine, phosphates, low molecular weight proteins (albumins) u. like.

worin ε_λ der spezifische Absorptionskoeffizient erster Ordnung und ε (2) / λ der spezifische Absorptionskoeffizient zweiter Ordnung ist.At the beginning of the dialysis session, the concentration of the components may reach significant levels and may decrease (possibly several times) during treatment, forcing a possible nonlinearity in the dependency of spectral absorption on the concentration to be considered. It is possible to use the Taylor series to exponentiate the absorption function kλ (C) = f (C). If restricted by the second order, the following is obtained:

where ε _{λ is} the specific absorption coefficient of first order and ε (2) / λ is the second order specific absorption coefficient.

The sign of the second term defines the nature of the dependence of the absorption coefficient on the concentration.

If ε (2) / λ = 0 is, the linear Beer-Lambert law is observed;
if ε (2) / λ> 0 is, there is a superlinear dependence;
if ε (2) / λ <0 is, there is a sublinear dependence.

In order to take into account a possible non-linearity of the spectral absorption dependence of the dialysate on the concentration, the second-order specific absorption coefficients are included in the simultaneous equations (1).

In the spectral range of 200-300 nm, a close ratio (p ≥ 0.9) between the spectral dialysate absorption and the concentration of potential low-molecular-weight uremic toxins (urea, creatinine and uric acid) removed from the body is observed.

A differentiation of the spectral absorbance spectra of the dialysate in the range of 250-300 nm can be estimated by the ratio of integer absorption values in ranges of 250-270 nm and 280 to 300 nm. A quantitative experimental distribution of patient numbers by a dialysate absorption spectrum form in the range of 250-300 nm is described by the normal law of distribution.

The individuality of the spectral dialysate absorption in the range of 250-300 nm, which is described by a ratio of integer absorption values in the ranges of 250-270 nm and 280-300 nm, can be explained by the presence of two constituents in the dialysate - both metabolites of nucleic acids ,

Uric acid - metabolic end product of nucleic acids, longwave part of absorbance in dialysate in the range of 280 nm - shortwave part of dialysate absorption in the range of 250-270 nm, bound to the absorption of NK - as yet unidentified metabolic intermediate of nucleic acids, possibly adenosine, uracil, etc.

In the proposed method, the uric acid and optionally the concentration of an unknown constituent in the dialysate are calculated by measuring the light transmission at two wavelengths, each settling in one of the spectral regions responsible for spectrum individuality. Recommended values are λ1 = 260 nm - maximum value for the absorption of the component NK, and λ2 = 285 - maximum value for the uric acid absorption.

For a measurement of the concentration of constituents by the proposed method, the absorption coefficient ελ for each constituent must be calculated at the selected wavelengths. For uric acid, this object can be achieved by measuring absorption spectra of the solutions of known concentration, whereby spectral properties of the second constituent can only be estimated indirectly by correlating differently shaped dilatation absorption spectra and then modeled.

aus den simultanen Gleichungen (1) ausgeschlossen werden, was die Konzentrationsberechnung vereinfacht.It should be noted that the contribution of uric acid to nonlinearity at 260 nm is not significant because the maximum absorption of uric acid is far from this range. Thus, the term

be excluded from the simultaneous equations (1), which simplifies the concentration calculation.

The computation of the concentration C2 of the unknown substance was done in arbitrary units because the absolute value of the concentration of this constituent is unknown and therefore it is reasonable to exclude the specific second order spectral absorption coefficient for that constituent from the simultaneous equation (1).

With these simplifications, the simultaneous equation (1) takes the following form:

• – Echtzeitberechnung der Harnsäurekonzentration im Dialysat während der Hämodialyse
• – Bestimmung der spektralen Dialysatabsorption bei zwei Wellenlängen
• – Online-Überwachung der Dialyse
• – Im Ergebnis quantitative Schätzung von Harnsäurekonzentrationsveränderungen im Dialysat
• – Bestimmung der aus dem Organismus des Patienten während einer Dialysesitzung entzogenen Harnsäuremenge in Echtzeit.

Using the invention to calculate the concentration of constituents present in a dialysate during hemodialysis using flow cells, the following objectives are achieved:

• - Real-time calculation of uric acid concentration in dialysate during hemodialysis
• - Determination of spectral dialysate absorption at two wavelengths
• - Online monitoring of dialysis
• - As a result, quantitative estimation of uric acid concentration changes in the dialysate
• Determination of the amount of uric acid withdrawn from the patient's body during a dialysis session in real time.

The use of the proposed device makes it possible to carry out a calculation of the uric acid concentration in the dialysate by measuring transmission coefficients at two wavelengths with an accuracy of ± 10%.

The use of flow cells allows a uric acid concentration calculation using the proposed method in on-line operation during treatment and a time-chart of uric acid concentration changes during the dialysis session.

If the dialysate stream is known, the proposed method can be used to calculate the total amount of uric acid removed during the dialysis session.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• WO 99/62574 [0004]
• WO 2008/000433 A1 [0004]
• US 6666841 B1 [0006]
• WO 2009/071102 A1 [0006]

Cited non-patent literature

• I. Fridolin et al. "Accurate On-line Estimation of Delivered Dialysis Dose by Dialysis Adequacy Monitor (DIAMON)", (2007) [0005]

Claims (6)

Detection device for the photometric determination of the urea content of a liquid, in particular in a dialysate as a control variable of a hemodialysis treatment, with A UV-transparent radiographic cuvette for receiving the liquid, A UV radiation source directed onto the radiation cuvette for providing radiation at at least two predetermined wavelengths, of which a first wavelength is in a first partial region between 280 nm and 300 nm and at least one second wavelength lies in a second subrange between 250 nm and 270 nm, - A sensitive at least at the first and second wavelength photodetector device for receiving an absorption measurement signal from the transmission cuvette and Signal processing means for correcting the photodetector signal at the first wavelength with the photodetector signal at the second wavelength and calculating the urea content from the corrected or calibrated measurement result at the first wavelength. Detection device according to claim 1, wherein the UV radiation source has at least one first, at the first wavelength, in particular at 285 nm, emitting light emitting diode and a second, at the second wavelength, in particular at 265 nm, emitting light emitting diode. Apparatus according to claim 1 or 2, comprising means for inputting the respective 1st and 2nd order specific spectral absorption indices of urea and a second liquid component, namely an intermediate product of the nucleic acid metabolism, and means for correcting or calibrating their processing in a system of equations of the second order. Apparatus according to any one of the preceding claims, including processing means for approximating the urea level C ₁ by means of the equation

where:

spectral absorption of the liquid at the first and second wavelength,

specific spectral absorption index of urea at the first or second wavelength,

specific spectral absorption index of a second liquid component, namely a product of the nucleic acid metabolism, at the first and second wavelength, respectively. Dialysis device with a detection device according to one of the preceding claims, wherein the transmission cuvette is a measuring cuvette or a portion of a fluid line, which is flowed through by discharged from the dialysis device, spent dialysis fluid. The dialysis device according to claim 5, wherein the signal processing device of the detection device is connected to an input of a control device of the dialysis device such that the operation of the dialysis device can be controlled on the basis of the control variable detected by the detection device.

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