Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
  • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
  • A61B5/1459—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters invasive, e.g. introduced into the body by a catheter

Definitions

• the invention relates to a device for determining the concentration of substances in the blood, in particular for determining the hemoglobin, oxyhemoglobin and / or diagnostic dye concentration according to the preamble of claim 1.
• Such a device is used in particular to determine the oxygen saturation of the blood, ie the ratio between the oxyhemoglobin and the total hemoglobin concentration in the blood, the total hemoglobin concentration in the blood and / or the concentration of a diagnostic dye in the blood, which is used, for example, in thermo-dye Procedure for determining the Cardiac output is used, the concentration can be determined in vivo or in vitro.
• the light from the light source is radiated into a blood sample and the proportion of the light transmitted from the blood by transmission or reflection is determined.
• the wavelength of the incident light and the transmitted light used for the measurement is the same.
• the values for the oxyhemoglobin, the hemoglobin and the diagnostic dye concentration are determined from the ratio of the intensities of the incident and transmitted or reflected light.
• the measurement is carried out either in vitro using special measuring cuvettes or using a light guide directly in the blood vessels, i.e. in vivo.
• the light is preferably irradiated in a pulsating manner, ie measurements are carried out repeatedly at short time intervals. Since the measurement results are influenced by the path of the light through the blood samples, light is preferably defined for several different ones Wavelengths measured.
• the device known from DE-PS 2741 981 works according to the reflection measurement method at three wavelengths with a catheter with two light guides and the device known from US Pat. No. 4,776,340 likewise works according to the reflection measurement method at two wavelengths and with a catheter with three light guides.
• the disadvantage of these known devices consists in the fact that measurements in vitro can practically only be carried out at longer intervals because of the work involved, and because devices with optical in vitro measurement methods determine the transmission of the hemolyzed blood sample, in order to achieve the necessary measurement accuracy, and the determination of the oxygen partial pressure and the electrolyte concentration of the blood plasma in blood analysis devices would be disturbed by hemolysis, optical measurement methods are usually not integrated in blood analysis devices and therefore two measurements with to determine the oxygen saturation of the blood cells and the oxygen partial pressure of the blood plasma separate samples on different devices are required.
• the transmission and the reflection of other substances are influenced.
• the measurements influenced in this way can only be recognized as incorrect measurements in extreme cases, so that very precise placement of the catheter in the blood vessel and regular recalibration by comparison with laboratory measurements are required. This is associated with a very high outlay.
• the hemoglobin determination by means of the device known from US Pat. No. 4,776,340 has such large tolerances that the measured value is only used to correct cross-sensitivities of other measured values.
• the Reflection and transmission measurement are also strongly influenced by diagnostic dyes, for example by the dye indocyanine green, which is frequently used in medicine, with an absorption maximum at 800 nm.
• diagnostic dyes for example by the dye indocyanine green, which is frequently used in medicine, with an absorption maximum at 800 nm.
• the simultaneous determination of the concentration of diagnostic dyes and the oxygen saturation, ie the oxyhemoglobin concentration and hemoglobin concentration is not possible.
• the catheters implanted in medicine are used only once. Due to the high cost of conventional fiber optic catheters with two or three light guides, the possible uses are clearly limited, the catheters for the reflection and transmission measurements also having a large diameter due to the two or three required light guides, which makes them suitable for small blood vessels does not allow.
• the unavoidable crosstalk from the optical transmission to the reception light guide has a significant influence on the result.
• care must be taken when manufacturing the catheters that they all have the same optical behavior. Since separate light guides for transmitting and receiving are necessary because of the back reflections for light transmission occurring at the interfaces, these must still be positioned exactly at the catheter tip, which means that in a device according to US Pat. No. 4,776,340 for hematocrit correction, three inches Precisely defined distances between optical fibers are necessary. The associated manufacturing costs are extremely high.
• the reason why the measured intensity of the fluorescent light is evaluated with a reference signal in the form of a reflection signal is that although the fluorescence generally depends only on the concentration of the fluorescent substance and on the excitation light intensity, in a measurement in Whole blood, however, both the excitation light and the fluorescent light can be influenced in a complex manner by absorption and scattering.
• the absorption and the scattering depend on the composition of the blood, in particular on the hemoglobin content.
• the measured fluorescence intensities are therefore non-linearly dependent on the dominant parameters and strongly dependent on the hemoglobin content.
• the fluorescence intensities are also influenced to a lesser extent by the concentration of the other substances in the blood.
• the object on which the invention is based is to provide a device according to the preamble of claim 1, with which it is possible to determine the concentration of substances in the blood with high accuracy and low sensitivity to interference.
• the device according to the invention it should in particular be possible to carry out continuous determinations of the hemoglobin and oxyhemoglobin content and of the diagnostic dye concentration in the blood, wherein measurement errors due to the diagnostic dyes present in the blood are to be avoided, so that the use of diagnostic dyes as an indicator in the blood system is not restricted.
• At least a second fluorescent light signal is used to correct the dependence of the fluorescence signal on other substances in the blood, in particular the hemoglobin dependency has sufficiently different behavior with regard to the concentration of the substance to be measured than the fluorescence signal corresponding to the substance to be measured. If the fluorescence signals also have different behavior with respect to the hemoglobin concentration, this can also be determined.
• Another advantage of measuring and evaluating only fluorescent light is the difference in the wavelength of the excitation light, i.e. of the light which is radiated into the blood and of the measurement, i.e. Fluorescence light.
• Second or third optical fibers are therefore unnecessary, so that the costs for their exact positioning are also eliminated.
• the device according to the invention thus has the further advantage that inexpensive catheters with very small catheter diameters can be used.
• the measuring cell and thus the required sample volume can be selected to be very small. Since the blood sample is not changed by the measurement, the measuring device can be connected upstream of an ordinary blood gas analyzer. This is the most important Blood parameters possible with a blood sample and in one measurement.
• FIG. 1 shows the block diagram of the exemplary embodiment of the device according to the invention
• FIG. 2 shows a sectional view of the catheter tip of a catheter with two light guides for the exemplary embodiment shown in FIG. 1,
• FIG. 3 shows a sectional view of the catheter tip of a catheter with a light guide for the exemplary embodiment shown in FIG. 1,
• FIG. 4 shows a view of a simple catheter with an optical fiber and a plug
• FIG. 5 shows a sectional top view of the optical part of the exemplary embodiment of the device according to the invention
• FIG. 6 shows a sectional side view of the optical part of the exemplary embodiment of the device according to the invention
• Fig. 10 is a graphical representation of the intensity of the fluorescent light versus its wavelength in blood with and without the diagnostic dye indocyanine green and
• 11 is a graphical representation of the intensity of the Fluorescent light versus the concentration of indocyanine green in the blood in oxygenated and deoxygenated blood.
• the embodiment of the device according to the invention shown in a block diagram in FIG. 1 essentially comprises a sequence control 11 for controlling the entire measurement sequence.
• the sequence controller 11 controls a flash lamp driver 12, which is connected to a flash lamp unit 30, the output light of which lies on an optical fiber coupler unit 50 via an excitation filter unit 40.
• the flash lamp driver 12, the flash lamp unit 30 and the excitation filter unit 40 form a light source which emits light in the range of at least one specific wavelength, which is determined by the range of the filter unit 40.
• the light from the coupler unit 50 passes through the optical waveguide of a catheter 20 into the blood sample to be measured, and the light transmitted from the blood sample is detected via the coupler unit 50 and an emission filter unit 60 by a light detector unit 70, the output signal of which at a programmable amplifier 13 and via dual slope integrators 14 and time counter 15 on an evaluation unit 16.
• the dual slope integrators 14 and the evaluation unit 16 are also controlled by the sequence control 11, while the programmable amplifier 13 is controlled by the evaluation unit 16.
• the excitation filter unit 40 and the emission filter unit 60 are each selected so that the detector unit 70 detects light with a wavelength which corresponds to the wavelength of the fluorescent light of the substance whose concentration is to be determined, which by the excitation filter unit 40 defined range of the wavelength of the excitation light is spectrally separated from the range of the wavelength of the fluorescent light.
• the fluorescence of the blood at 485 nm and at 640 nm can be used to determine the hemoglobin and oxyhemoglobin content.
• the wavelength of the excitation light is then, for example, 370 nm. There is practically no influence on the fluorescence measurement by the dye indocyanine green.
• the fluorescence of the diagnostic dye at 830 nm can be used, the excitation light then having a wavelength at, for example, 740 nm.
• two light guides 21, 22 are provided for the excitation light and the emission or fluorescent light.
• the light guides 21, 22 are arranged in the catheter envelope tube 25 via an adhesive bond 24.
• the excitation light from the light guide 21 falls, for example, on a fluorescent erythrocyte 26, the fluorescent light of which is fed via the light guide 22, the coupler unit 50 and the filter unit 60 to the detector unit 70 for measurement and evaluation.
• only a single combined light guide 23 is provided, which guides the excitation light and the emission light.
• the light guide catheter 20 is provided with a fixed catch 28 on the light guide plug 27, as shown in FIG. 4, which is connected to a plug receptacle 76 of the optical part of the device shown in FIGS. 5 and 6.
• the optical part comprises the flash lamp unit 30 with a Flash lamp 31 and a reflector 33 for the excitation light with a wavelength of 370 nm and a flash lamp 32 and a reflector 34 for the excitation light with a wavelength of 740 nm.
• an optical seal 35 and the flash lamps ⁇ unit 30 is enclosed by a housing 36 and a cover 37.
• the excitation filter unit 40 comprises a filter 41 for excitation light with a wavelength of 370 nm and a filter 42 for the excitation light with a wavelength of 740 nm.
• the light coming through the filters 41 and 42 lies on the optical fiber coupler unit 50 with an optical fiber 51 for the catheter connection, an optical fiber coupling 52, an optical fiber 53 for the excitation light with a wavelength of 740 nm, an optical fiber 54 for the excitation light with a wavelength of 370 nm, a light guide 55 for the emission light with a wavelength of 485 nm, a light guide 56 for the emission light with a wavelength of 640 nm and a light guide 57 for the emission light with a wavelength of 830 nm.
• the coupler unit 50 is of a housing 58 and a lid 59 enclosed.
• the emission filter unit 60 comprises a filter 61 for the emission light with a wavelength of 485 nm, a filter 62 for the emission light with a wavelength of 640 nm and a filter 63 for the emission light with a wavelength of 830 nm.
• the detector unit 70 comprises a detector 71 for the emission light with a wavelength of 485 nm, a detector 72 for the emission light with a wavelength of 640 nm and a detector 73 for the emission light with a wavelength of 830 nm.
• the detectors and plugs are in housed in a housing 74, between the detector unit 70 and an optical seal 75 is provided to the coupler unit 50. With 77 a resilient catch is designated and with 78 the bonding of the detectors in the housing is designated.
• optical grids for filtering monofiber catheters, duofiber catheters, measuring cuvettes or other light sources can be provided.
• the light guide catheter 20 is placed in the blood as usual and, after a position check, for example via an image converter, is connected with its light guide plug 27 to the connector receptacle 76 of the optical part of the device.
• a light pulse emitted by one of the flash lamps 31 or 32 is focused on the corresponding light guide 54 or 53 by the associated reflector or elliptical mirror 33 or 34.
• the filter 41 or 42 limits the spectrum of the emitted light to the wavelength range of the excitation light around 370 nm or 740 nm, respectively.
• the light pulse is transmitted from the light guide coupler 52 to the blood via the light guide for the catheter connection 51 and the light guide 21 or 23 of the catheter 20.
• the excitation light radiated into the blood generates fluorescent light around the wavelengths 485 nm, 640 nm and 830 nm, the intensity of which depends on the hemoglobin, oxyhemoglobin and diagnostic dye content, ie the concentration of these substances.
• These light signals go through the light guides 22, 23 and 51 to the light guide coupler 52 and are distributed from there to the light guides 55 to 57.
• the emission filters 61, 62 and 63 separate the excitation light, the ambient light and other fluorescent light signals from the fluorescent light signal to be measured from.
• the filtered light signals (filter 61: 480 to 530 nm, filter 62: 620 to 680 nm, filter 63: 830 nm) are converted by the light detectors 71, 72 and 73 into electrical signals and after amplification by the amplifier 13 and digital conversion supplied to the evaluation unit 16.
• the oxyhemoglobin content or the oxygen saturation, the hemoglobin content and the dye concentration of the blood are determined there using calibration curves or corresponding algorithms.
• the changeover between the excitation wavelengths required for this is effected by the sequence control 11.
• FIG. 7 showing the fluorescent light for oxygenated and deoxygenated blood when excited with a light wavelength of 370 nm
• FIG. 10 showing that Fluorescent light from blood with and without the diagnostic dye indocyanine green shows when excited with light of a wavelength of 740 nm
• 8 and 9 show the fluorescence of blood occurring at 485 nm and 640 nm when excited with light having a wavelength of 370 nm for different hemoglobin concentrations as a function of the oxygen saturation.
• 11 shows the fluorescence of diagnostic dye indocyanine green occurring in the blood at 830 nm when excited with light of a wavelength of 740 nm for oxygenated and deoxygenated blood depending on the dye concentration in each case.
• the filter units 40 and 60 preferably limit the frequency range very steeply.
• inter- reference bandpass filter used.
• optical gratings can also be used, but the filters can also be replaced or supplemented by a light source or a detector with a suitably limited spectral range (laser). The measured value detection largely suppresses disturbances due to the integrating behavior.
• a flash lamp driver 12, a flash lamp 30 and an excitation filter 40 are provided for each wavelength of the excitation light.
• an emission filter 60, a detector 70, a programmable amplifier 13, an integrator 14 and a time counter 15 are provided.
• the integrators 14 are first reset to zero potential.
• the amplified signals from the detectors 71 to 73 are integrated downwards for a short time (for example 1 ms) without excitation.
• the first flash lamp 31 is ignited and the detector signals are integrated with excitation upwards for an equally long time. Afterwards, integration takes place downwards again with a constant reference voltage.
• the time counters 15 determine the times required until the zero potential is reached.
• the second excitation i.e. move with the excitation light of the second excitation light wavelength.
• the fluorescent light intensities at 485 nm, 640 nm and 830 nm are present in digital form in the evaluation unit 16.
• the reflection intensity at 640 nm can also be determined.
• the above measurement cycle is e.g. repeated every 100 ms.
• a comparison value Fv 485, Fv 640, Fv 830 determined and stored.
• the sample can be a standardized blood sample, but for reasons of hygiene, a calibration device with suitable synthetic substances that have a fluorescence behavior similar to blood is preferred.
• the actual measured values Fm 485, Fm 640 and Fm 830 are determined and converted into relative intensities by division by the associated comparison values.
• the value F485 formed here is mainly influenced by the hemoglobin concentration
• the value F640 formed here is mainly influenced by the oxygen saturation
• the value F830 formed is mainly influenced by the diagnostic dye concentration.
• the measurement value formed in this way for the substance whose concentration is to be determined is processed together with the value formed in this way of at least one further substance in the blood, for example the value influenced by the hemoglobin concentration, by these values according to a Function related to each other, which is determined empirically.
• Impurities with a constant concentration can also be eliminated by the calibration.
• the desired function according to which the value for the substance whose concentration is to be measured is related to the value of at least one further substance in the blood, can be determined empirically by measurements on samples with a known concentration.
• a polynomial approach is suitable for this, in which the parameter sought, ie the concentration value sought, is calculated in a multi-dimensional power series with, for example, powers up to second order from the relative intensities:
• Y stands for the hemoglobin concentration, the oxygen saturation or the diagnostic dye concentration.
• the constants a to k are different for each parameter and must be determined once for each combination of device type, catheter type and calibration device. To improve the measurement accuracy, higher order power series can also be used.
• the relative fluorescence signals F485 at 485 nm and F640 at 640 nm are determined in the manner described above.
• the oxygen saturation SO and the hemoglobin concentration Hb are determined using other known measurement methods. Both fluorescence signals are dependent both on the hemoglobin concentration Hb and on the oxygen saturation SO.
• Fig. 7 shows an increasing with increasing oxygen saturation Fluorescence signal at 640 nm and a falling fluorescence signal at 485 nm.
• FIGS. 8 and 9 show a falling fluorescence signal with increasing hemoglobin concentration.
• a second option which requires more effort but is more accurate, is to determine a large number of data records in the desired measuring range and to calculate the constants that best match using the method of least squares.
• the function according to which the determined relative fluorescence signals have to be related to one another in order to obtain the concentration of the substance to be determined is determined, ie when the constants a, b, c and d or a to k given above are given the use of a third Fluorescence signal are determined, then the measured values of the subsequent measurements can be evaluated using this function.
• the above embodiment concerned a device for measurement in vivo.
• the light from the light source can be directly, i.e. without a light guide, are irradiated into a blood sample and received by the blood sample through a light detector.
• a measuring cell is arranged at the location of the coupler unit 50.

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• 1993
  • 1993-07-29 DE DE19934325529 patent/DE4325529C2/de not_active Expired - Fee Related
• 1994
  • 1994-07-28 EP EP94925412A patent/EP0711124A1/de not_active Withdrawn
  • 1994-07-28 WO PCT/EP1994/002507 patent/WO1995003736A1/de not_active Application Discontinuation
  • 1994-07-28 JP JP7505567A patent/JPH09503856A/ja active Pending

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