Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
  • A61B5/0071—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by measuring fluorescence emission
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
  • A61B5/0075—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy
• • 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 or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
  • A61B5/14546—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue for measuring analytes not otherwise provided for, e.g. ions, cytochromes
• • 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 or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
  • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/72—Signal processing specially adapted for physiological signals or for diagnostic purposes
  • A61B5/7271—Specific aspects of physiological measurement analysis
  • A61B5/7282—Event detection, e.g. detecting unique waveforms indicative of a medical condition

Definitions

• the present invention relates to a method and a device for the transcutaneous measurement of bilirubin.
• Bilirubin is produced when the heme portion of hemoglobin is broken down in the liver and spleen and is found in the blood serum and tissues of all people. When bilirubin levels are significantly elevated, this is critical because high levels of bilirubin are toxic. For the layperson, an excessively high bilirubin concentration can be recognized as so-called jaundice by the well-known yellowish skin colouration, which often occurs in newborns, but also in adults.
• Bilirubin can exist in different forms in the human body. In this way, bilirubin is modified in the liver and converted into its water-soluble form, bilirubin di-glucuronide. Since this form of bilirubin can be excreted directly, it is also referred to as “direct” bilirubin, in contrast to so-called “indirect” bilirubin, which does not refer to a single molecule, but to non-metabolized forms of bilirubin, whose main entity is the Z,Z isomer, which is not water soluble and therefore cannot be cleared directly from the body, which is why the term "indirect” is used.
• bilirubin In the human body, the majority of bilirubin is non-covalently bound to a protein (albumin) (so-called “indirect bilirubin” or “indirectly reacting bilirubin”). In addition, there is water-soluble, i.e. glucuronidated (di- and monoglucuronidated) bilirubin and delta bilirubin bound (covalently) to albumin (so-called “direct bilirubin”, “directly reacting bilirubin” or “free bilirubin”). A distinction can therefore be made between free bilirubin, bilirubin bound to albumin and bilirubin conjugated in the liver. Nevertheless, as a rule, in simplified terms, reference is only made to a single bilirubin concentration.
• bilirubin is an important diagnostic marker that is used, for example, in clinical studies to assess the liver toxicity of drugs, especially in the development of new drugs. However, it also plays a major role in the diagnosis of various diseases such as jaundice in newborns.
• Elevated direct (glucuronidated) bilirubin indicates a bile duct problem or a problem in the gut, in which the liver is capable of glucuronidation, but is unable to pass on the direct bilirubin to the intestine.
• elevated levels of indirect bilirubin can indicate liver damage.
• an increase in unconjugated bilirubin can also be due to larger hematomas, a disruption in the uptake of bilirubin into the liver cells due to physiological jaundice in the newborn or polycythemia, hormones, hypothyroidism, medication, or Gilbert-Meulengracht disease, for example Disorder of glucuronidation in the immature liver of a preterm infant, known as Crigler-Najjar syndrome.
• An increase in conjugated (directly reacting) bilirubin is attributed to diseases of the liver such as hepatitis, autoimmune hepatitis, a metabolic defect or toxic liver damage, certain medications and parenteral nutrition, or diseases of the bile ducts such as intrahepatic bile duct dysfunction, extrahepatic bile duct atresia, choledocholithiasis , choledochal cyst, cholangitis or the so-called Rotor syndrome or Dubin-Johnson syndrome.
• diseases of the liver such as hepatitis, autoimmune hepatitis, a metabolic defect or toxic liver damage, certain medications and parenteral nutrition, or diseases of the bile ducts such as intrahepatic bile duct dysfunction, extrahepatic bile duct atresia, choledocholithiasis , choledochal cyst, cholangitis or the so-called Rotor syndrome or Dubin-Johnson syndrome.
• Non-invasive measurement methods that allow fast and precise measurement would be particularly desirable.
• bilirubin can be measured transcutaneously for therapies by applying light to a vital tissue section as part of an exposure step. radiates and at least part of the light emerging from this tissue section is detected and then the intensity and wavelength are taken into account in a system of equations with which the concentration of bilirubin is determined. Concentrations of hemoglobin and skin tissue are taken into account by determining absorbance values of hemoglobin at wavelengths of 452nm and 500nm, since these are those at the so-called "isosbestic" wavelengths at which the absorbance of hemoglobin does not change due to its oxygenation/deoxygenation.
• a therapy method is known from DE 10 2017 008 631 A1, in which a sensor device connected to a vital tissue area of the patient comprises a light source and a detection device, with which light emerging from the vital tissue area of the patient is detected. Signals are generated via the detection device which enable conclusions to be drawn about the bilirubin concentration in the vital tissue region, which allows the arrangement to be operated taking into account the determined bilirubin concentration and a gradual drop in the bilirubin concentration to be observed.
• optical measurements of bilirubin in vital tissue are regularly strongly influenced by the optical properties of the skin, for example due to light absorption by hemoglobin or pigments such as melanin, whereby these influencing factors can not only have different effects from patient to patient, but also in one and differences may occur in the same patient depending on current perfusion, blood oxygen saturation and the specific area of vital tissue examined. It has been proposed to measure the thickness of an examined tissue area mechanically, see US 2013/00 23 742 A1, but this also falls far short of the mark, especially since the pincer-like mechanism proposed there for measuring thickness is suitable for many applications, at least for newborns is practical.
• the previously known methods for bilirubin measurement not only suffer from inaccuracies with regard to the measured values obtained due to skin pigmentation or blood circulation.
• the optical properties of the different bilirubin forms can also change due to various influencing factors such as the pH or the protein content of the solution. Effects such as the so-called Förster resonance come into play, through which the spectral properties of a molecule shift according to the type and concentration of other substances in the vicinity. It was shown in vitro that the protein content of a bilirubin solution influences the spectral properties. That at transcutaneous Measurement quantities such as the protein content are not known, makes the determination of bilirubin more difficult in general and makes it all the more difficult to distinguish between different forms of bilirubin.
• the object of the present invention is to provide something new for commercial use.
• a method for determining bilirubin in which light is irradiated into a vital tissue area with a wavelength that is suitable for the transformation of bilirubin, light from the irradiated vital tissue area is detected and a time series is determined according to the transformation of changing detection signals and bilirubin is determined in response to the time series, it is further provided that light is irradiated locally into the vital tissue area, the intensity of which is high enough to provide a faster phototransformable form of bilirubin, regardless of endogenous transport processes a slower phototransformable form of bilirubin compared to other tissue areas to deplete locally in a recognizable manner with the detection means used, and that differed from the detection signals of the time series recorded during the local depletion liche bilirubin forms can be quantified in the non-depleted state.
• the irradiation can easily be done from the outside, i.e. transcutaneously.
• a tissue area can be irradiated and its fluorescence can be determined outside the body.
• the detection of the light obtained from the tissue area with one or more detectors is preferably done at some distance from the light source, so that a sufficiently long light path through the vital tissue area is ensured and a direct irradiation of light from the light source into the detector is avoided;
• an absolute intensity can be recorded directly with an additional sensor, for example in order to standardize.
• fluorescence signals are to be detected, it should be pointed out that, regardless of this, permanent illumination is desired during the recording of the time series in order to bring about the progressive phototransformation, in particular of the more quickly phototransformable bilirubin. For this, enough light must be irradiated throughout the entire measurement, i.e. over the entire time series.
• a pulsed light source for this purpose, which radiates at least one or more light pulses onto the tissue during the measurement and in particular during or before each acquisition of an individual detection signal of the time series ;
• continuous operation of the light source during the recording of a series of measurements is structurally simpler and therefore preferred.
• the light radiated into a vital tissue area for the measurement is radiated in locally, ie over a small area compared to the entire skin area of the patient.
• the area of the local irradiation will typically be less than 5 cm 2 , preferably less than 3 cm 2 , in particular around or less than 1 cm 2 . This also allows the use of small and therefore permanently portable devices with which the method is implemented.
• a small irradiation area of less than 5 cm 2 , preferably less than 3 cm 2 , preferably around 1 cm 2 makes it possible to use comparatively high irradiation power densities by focusing with little design effort, which in turn allows the desired rapid bilirubin transformation.
• (blue) LEDs were used for lighting, which were operated with a power of 75mW to 150mW.
• the irradiation area is too small, small-scale pigment spots on the skin have too great an impact and that irradiated (capillary) vessels in the beam path between the light source and light detector may also have a stronger effect, which is undesirable.
• the method of the present invention should therefore not be confused with the repeated measurement of a bilirubin content during long-term, phototherapeutic irradiation, not even when bilirubin measurements are repeatedly carried out parallel to such phototherapeutic irradiation, possibly also by local irradiation of light , as may be known from the prior art.
• the time series recorded in the known phototherapy will at best record a gradual drop in the total bilirubin value, but without inferring the different bilirubin forms from a measuring radiation-induced local drop in bilirubin forms that can be transformed more quickly or distinguishing these different bilirubin forms from one another.
• the invention has recognized and implemented that the different photo decomposition in light of conjugated and unconjugated bilirubin can be used to quantify different forms of bilirubin, especially since it is possible to use blue light of a wavelength at which essentially the unconjugated, indirect bilirubin is degraded, in which the conjugated bilirubin is degraded at least less quickly and in which other molecules that otherwise interfere with spectral examinations, such as melanin or hemoglobin, are not significantly destroyed - at least with a reasonably limited intensity.
• indirect bilirubin such as the Z,Z isomer by exposure to light from the blue to green range
• the isomers produced by exposure to light have a higher water solubility than indirect bilirubin , so that the bilirubin can also be excreted without prior metabolization in the liver, which leads to the achievement of the therapeutically desired reduction in bilirubin.
• the most important degradation products are lumirubin and the isomers Z, E and IXa-bilirubin.
• the fluorescence spectra are also comparable; However, the breakdown of bilirubin leads to a decrease in the fluorescence during the time series, because a clearly noticeable breakdown of bilirubin takes place due to the lack of transport of unirradiated body fluid to the site of local irradiation. In a time series recorded with sufficient time resolution, the degradation of the rapidly degradable bilirubin is thus reflected in a rapid decrease in fluorescence; accordingly, the presence of more or less unconjugated, indirect bilirubin can be inferred from the decrease in fluorescence. It should be noted that the fluorescence will not fall completely to zero, but it will be sufficiently strong Decrease is achievable with acceptable irradiation intensities and irradiation power densities.
• the quantification does not necessarily have to be absolute, i.e. it does not necessarily have to deliver an absolute value in mg/dl. It is often diagnostically helpful to be able to indicate a particularly high or particularly low proportion of unconjugated bilirubin in the total bilirubin.
• a total bilirubin value can be determined from the total fluorescence itself, for example at the beginning of the measurement, or from the mean total fluorescence over a specific measurement time.
• the measurement duration for recording a time series is less than 15 minutes, preferably less than 10 minutes, particularly preferably less than 5 minutes, and very particularly preferably less than 2 minutes. If the measuring time is too long, typically irradiated vital tissue areas, which can be located on the forehead, a finger or the arm and are generally well supplied with blood, will result in the body's own transport processes, which interfere with the actual measurement, due to diffusion processes and the like Gain meaning. It will be clear that these endogenous transport processes have a greater effect on tissue areas that are particularly well supplied with blood. These effects will have less of an impact if the measurement duration is shorter. In addition, it is generally desirable for patients and possibly also for medical personnel not to have to wait too long for a result.
• Measurement times of less than 2 minutes, for example 1 minute, are therefore particularly preferred.
• a time series with a sufficient number of detection signals must be recorded, which, moreover, should not be excessively affected by noise.
• the evaluated time series includes at least 5, preferably at least 10, detection signals.
• the pulse may have a disruptive effect because the optical properties of the tissue per se change with the pulse even without bilirubin degradation. Sufficiently long measurement periods with a sufficient number of detection signals in a time series are therefore clearly preferred.
• the measurement duration for recording a time series is greater than 15 seconds, preferably at least 30 seconds and particularly preferably at least 50 seconds, better at least 1 minute.
• the integration duration per detection signal of the time series is at least 100 ms, preferably at least 500 s, in particular at least 1 second.
• the integration duration per detection signal of the time series is at least 100 ms, preferably at least 500 s, in particular at least 1 second.
• the integration time for each detection signal should not be too long, because otherwise too few measured values can be recorded in a time series during the meaningful, available measurement time, i.e. before transport processes cause a further measurable change in the detection signal, such as a noticeable decrease in the fluorescence signal due to a breakdown of faster phototransformable bilirubin and counteract disruptively.
• the method is therefore carried out in such a way that the time resolution of the time series is better than 10 seconds, preferably better than 5 seconds, particularly preferably better than 2 seconds and particularly preferably about 1 second. For example, in a practical implementation, a series of 30 fluorescence intensity measurements, each 1 second long, were taken over a measurement period of 30 seconds, with good results.
• a repeated measurement of bilirubin is carried out, with a time of at least 5 minutes, better 10 minutes, preferably at least 15 minutes being waited between the recording of two time series and the light intensity of the local light irradiation being reduced during this waiting time, preferably the intensity of the light with which the faster phototransformable bilirubin form is locally depleted compared to other tissue areas is less than 20% of the light intensity used for the measurement, preferably less than 10% of the local light irradiation and particularly preferably a local light irradiation light source does not shine on the vital tissue area during the waiting period.
• Such a repeated measurement can be particularly advantageous where phototherapy is carried out in which the patient is irradiated extensively and not only locally, as in the present measurement, with bilirubin-degrading radiation, and in which the therapeutically achieved bilirubin degradation is recorded should.
• a first measurement will result in a local depletion of the faster phototransformable bilirubin, typically the unconjugated, indirect bilirubin, which leads to a characteristic change over time of the detection signals of a first time series, which are assigned to the first measurement.
• the local intense light source which may have irradiated locally particularly intense light in addition to the phototherapeutic large-area irradiation, can be switched off, whereupon the body's own transport mechanisms gradually restore the distribution of different bilirubin forms at the site of irradiation that was not for the locally irradiated areas of comparable tissue are characteristic.
• the rate of recovery of the bilirubin forms at the irradiation site to the globally observed distribution will depend on the efficiency of the transport mechanisms and thus may vary from patient to patient.
• the specified waiting times between 2 time series of at least 5 minutes, better 10 minutes and preferably at least 15 minutes take this into account.
• bilirubin measurements can be carried out repeatedly with the present method, not only obtaining a measure of the gradually decreasing bilirubin values during the phototherapy irradiated over a large area of the patient, but also of the different current bilirubin forms can be re-quantified.
• the measurement is strongly affected by pigmentation of the skin, for example due to melanin present in the skin, since melanin not only has similar spectral properties to bilirubin and thus interferes with the measurements per se, but also with the entry of light blocked into the skin, so dark skin allows less blue light to penetrate to the tissue, which obviously impairs bilirubin transformations.
• melanin not only has similar spectral properties to bilirubin and thus interferes with the measurements per se, but also with the entry of light blocked into the skin, so dark skin allows less blue light to penetrate to the tissue, which obviously impairs bilirubin transformations.
• Precisely where multispectral measurements are carried out with suitable sensors however, such a basic pigmentation of the skin can be determined by illuminating with light from one or more bilirubin non-transforming (or only very little) wavelengths and detecting the corresponding sensor signals.
• the light source is able to emit one or more colors in addition to the blue light used for bilirubin transformation, which is readily possible with suitable multicolor LEDs.
• Detection signals can then be recorded at the multispectral detectors with such an illumination, which allows conclusions to be drawn about the skin pigmentation and thus a correction of the bilirubin values to be determined with regard to the pigmentation.
• Such a correction measurement can take place immediately before a first bilirubin measurement or afterwards, or during a waiting period until the next measurement.
• the light radiated in for the bilirubin transformation will have a wavelength of 400 to 450 nm, in particular 400 nm.
• the wavelength or the wavelength distribution should be chosen so that on the one hand light can be generated with a cheap and energy-saving light source and on the other hand the light radiated into the tissue can bring about an efficient bilirubin transformation of one of the bilirubin forms.
• light of a plurality of distinguishable wavelengths it is possible and preferable for light of a plurality of distinguishable wavelengths to be detected from the irradiated vital tissue region, with light of the irradiation wavelength preferably being detected as well as, distinguishable therefrom, longer-wavelength light.
• the detection of light of the irradiation wavelength first makes it possible to estimate how much light is irradiated into the tissue and reaches a detector through it. This is important because, for example, both the attachment of an arrangement to the patient's body and, for example, his pigmentation can have a significant influence on how much of the light generated by a light source is actually available for the phototransformation of bilirubin. It is thus possible to standardize approximately the fluorescence intensity.
• light is detected in at least two distinguishable wavelength ranges, which do not include the incident light and preferably include one of the wavelengths within an FWHM range, which is selected from the (Central) wavelengths 500+-20nm, 550+-10nm, 570+-10nm, 600+-20nm and 650+-20nm.
• FWHM range which is selected from the (Central) wavelengths 500+-20nm, 550+-10nm, 570+-10nm, 600+-20nm and 650+-20nm.
• light of the irradiation wavelength can be recorded, eg at 450+-10nm, so that the recorded intensities can be standardized. It should be mentioned that different time profiles of the fluorescence curves can result in different wavelength ranges, for example because the photolysis products generated during a phototransformation fluoresce to different degrees when irradiated with the scattered light.
• a measurement in several wavelength ranges requires at most a negligible additional structural effort, because there are detector components that have a large number of separate photodetectors, for example photodiodes, each with a different upstream wavelength filter.
• An example is the AS7262 module from AMS for recording 6 different spectral channels, which was used in a practical embodiment, with the central wavelengths of the respective spectral channels being 500 nm, 550 nm, 570 nm, 600 nm and 650 nm with an accuracy of plus or minus 5 nm and an FWHM bandwidth of 40 nm per channel have been implemented.
• the evaluation of the detection signals recorded on several of these channels makes it possible to increase the accuracy of the bilirubin measurements.
• the absolute bilirubin concentration can be recorded more precisely than is possible when only a single channel is observed.
• irradiation with blue light as bilirubin-transforming radiation is not mandatory.
• current phototherapy lamps, with which a bilirubin transformation is also achieved through radiation work primarily at 450 to 470 nm, it is also being considered whether light with a longer wavelength of 490 to 510 nm (i.e. light of the colors turquoise or green) is better for Bilirubin degradation could be suitable, see Hendrik J.
• the method is carried out in such a way that light of the irradiation wavelength and longer-wave light is detected, the intensity of each detection signal of the detected longer-wave light is related to the intensity of the detected light of the irradiation wavelength, and from the time series thus obtained, the intensity of the longer-wave light or The intensity of the detected light of the irradiation wavelength is used to determine the non-depleted ratio of different bilirubin forms. In other words, for each wavelength at which fluorescence is to be detected, the incident light intensity is standardized before the different bilirubin forms are quantified.
• the respective intensities are related to the intensity of the detected light of the irradiation wavelength and then from the at least two irradiation intensity-corrected time series values together to the non-depleted ratio of different bilirubin forms is closed.
• Such a procedure makes sense insofar as the different bilirubin forms can first be inferred separately for each of the wavelengths and then a variable that takes the corresponding quantifications jointly into account can be calculated.
• the detection signals are preferably normalized to the incident light intensity.
• the normalization of the detection signals it is also possible, in particular, to normalize the total amount of light irradiated up to a detection signal of a time series during a time series, i.e. the irradiation intensity integrated over time, and/or both the time integral of the irradiation intensity and the current one Irradiation intensity at the time of the fluorescence has to be taken into account if the irradiation intensity fluctuates strongly over the time of the time series.
• ratios of the intensities obtained at different wavelengths are determined. For example - when irradiated with light with a wavelength of 400 nm (blue), the ratio of the detection signals obtained with orange (600 nm) and red (650 nm) can be determined, the ratio of the detection signals obtained with green (550 nm) and yellow (570 nm) or the ratio of the detection signals obtained at 450nm and 550nm can be determined. In this way, a large number of estimates of the total bilirubin can be obtained with one and the same time series based on the values recorded at different points of the spectrum.
• the proposed simultaneous consideration of individual total bilirubin values determined with different spectral pairings and the determination of a multispectrally determined total bilirubin value derived from the individual total bilirubin values, for example by averaging offers an advantage insofar as the different pairings determine the respective influencing variables partly overestimate and partly underestimate, so that with suitable averaging from the combination of the total bilirubin values obtained for several color pairs to a multispectral total bilirubin value, a quantity can be determined that correlates very well with total bilirubin values obtained from blood analyzes in the laboratory, although each value associated with a single color pair is quite imprecise on its own.
• the total bilirubin value can be determined even more precisely if at least the layer thicknesses are estimated from the detection signals, which is possible with multispectral evaluation. Since in the end only extinction coefficients and layer thickness are required as unknown variables in order to take into account the Lambert-Beer laws when determining total bilirubin, it is in principle possible to determine these two variables from detection signals determined for several colors using suitable mathematical methods. Thus, the thickness of the layer up to which the incident light intensity penetrates and through which fluorescent light passes, will be the same for all colors; this allows the path length to be determined using suitable mathematical methods such as the Gaussian method.
• Protection is also claimed for a device for measuring bilirubin, in particular according to a measuring method as described above, with a light source for irradiating a vital tissue area with light that has a wavelength that is suitable for transforming bilirubin, and the one Has an intensity that is so great that a more rapidly phototransformable form of bilirubin is locally depleted relative to other tissue regions, regardless of endogenous transport processes, compared to a more slowly phototransformable form of bilirubin; a detection arrangement for generating a time series of detection signals, which relate to the detection of light from the irradiated vital tissue area, and an evaluation unit for evaluating a time series of the detection s signals in such a way that from the detection signals of the time series recorded during the local depletion non-depleted ratio of different bilirubin forms is closed.
• the described structure of a claimed device shows that it is possible to provide diagnostically particularly valuable information about different bilirubin forms with only very little structural effort. It can be seen from the representation of the preferred embodiments of the method that neither the light source nor the detection arrangement have to be particularly complex.
• the signal conditioning of the detection signals is also possible in a simple manner and with little structural effort.
• the detection signals are digitized, optionally after suitable bandpass filtering, impedance matching and amplification. In view of the low time resolution of the time series, this digitization does not place any special demands on an analog-digital converter and the subsequent evaluation of the data can also be carried out on very inexpensive hardware, since only a few measured values have to be processed over long periods of time.
• the detection arrangement in the device for measuring bilirubin has a spectral filter means in order to be able to distinguish received light of different wavelengths from one another.
• a spectral filter means in order to be able to distinguish received light of different wavelengths from one another.
• the fact that lenses and possibly other optical elements are required in the beam path between the (LED) illuminant for generating the light to be irradiated and the skin as well as in the beam path between the skin at the exit point and the detectors should also be mentioned, as well as the fact that these other required elements do not require excessive structural effort.
• the irradiation point is at a distance from the detection arrangement, with a distance of at least 3 mm preferably between the irradiation point and one or each light-sensitive detector surface, preferably at least 4mm, in particular at least 5mm. It will be appreciated that such spacing ensures that both the short wavelength light input for excitation and the longer wavelength light detected in response thereto Light traverses a sufficiently long distance of tissue that usefully strong signal detection signals can be acquired.
• the light source should be aligned in such a way that it radiates away from a light source carrier such as a printed circuit board as a carrier of a light source LED, and in fact steep enough so that the light irradiated penetrates sufficiently deeply into the tissue. At the same time, however, it should also radiate in the direction of the detectors, as this means that more light is radiated into tissue areas closer to the detectors. If this is observed, excessively large distances from detectors and light sources would lead to irradiation that is too flat, which impairs the penetration of light into sufficiently deep tissue layers. It should also be mentioned that the detector can be mounted at an angle if necessary or that a suitable lens can be placed in front of it so that it receives more light from the irradiated area.
• the corresponding objection also ensures that within an arrangement the detector arrangement can be adequately protected against scattered light propagating within the device from the light source to the detector arrangement.
• a distance between the detector array and the light source of 0.5 cm has proven to be sufficient, which allows using SMD components to achieve an overall size of a practical implementation of less than 3 cm.
• a light source with a discrete spectrum is used, in particular a semiconductor light source.
• a semiconductor light source is particularly worth mentioning.
• the light source and the detection arrangement are arranged together on a carrier with which the device can be held in the area of the local vital tissue, in particular directly on the skin of a patient.
• the light source and the detection arrangement can be arranged on a printed circuit board as a carrier. Straps, for example, can be arranged on the carrier or on a housing surrounding it, in order to strap the arrangement around the patient or put it around like a cuff; alternatively, the arrangement can also be attached to the skin with a larger piece of medical adhesive tape or plaster.
• the arrangement will thus preferably be in direct contact with the skin.
• this entails corresponding requirements in terms of skin compatibility and thus the carrier material or housing material used.
• the device claims have a communication interface for the wireless transmission of detected signals and/or data generated in response thereto.
• the arrangement can not only be structurally simple, but also has an extremely low energy requirement, so that it allows measurements over a longer period of time even with commercially available small batteries.
• the wireless transmission of detected signals or the data generated in response thereto enables considerable additional convenience compared to wired solutions, especially for long-term measurements.
• the invention is described below only by way of example with reference to the drawing. This is represented by:
• FIG. 1 shows a device for measuring bilirubin according to the present invention
• FIG. 2 shows a fluorescence curve recorded with a device according to FIG. 1, from which a decrease in the detected fluorescence intensity over time can be seen;
• FIG. 4 shows a fluorescence profile for light from the wavelength range around 570 nm recorded with a device according to FIG. 1;
• FIG. 1 shows a device 1 with which a method for determining bilirubin can be carried out in a simple manner, in which light is radiated into a vital tissue region with a wavelength suitable for the transformation of bilirubin, light from the radiated vital Tissue area is detected and a time series corresponding to the transformation of changing detection signals is obtained and bilirubin is determined in response to the time series, and in which the vital tissue area is locally irradiated with light whose intensity is large enough regardless of a faster phototransformable bilirubin form endogenous transport processes to locally deplete a slower phototransformable bilirubin form compared to other tissue areas, and that different bilirubin forms in the non-depleted state are quantified from the detection signals of the time series recorded during the depletion the.
• the device 1 shown in FIG. 1 and generally designated 1 for measuring bilirubin has a light source 101 for radiating light into a vital tissue region vG, the light radiated into the vital tissue region vG having a wavelength lambda 1 that is suitable for the transformation of bilirubin, and which further has an intensity that is so great that a more rapidly phototransformable form of bilirubin is locally depleted, regardless of endogenous transport processes, compared to a slower phototransformable form of bilirubin compared to other tissue areas.
• the device 1 also has a detector arrangement 103 for generating a time series of detection signals which are related to the detection of light from the irradiated vital tissue region, the detector arrangement having a plurality of, in this case separate, detectors 103a, 103b for light of different wavelengths, in this case represented by the arrows lambda 1 and lambda 2, as well as an evaluation unit (not shown) for evaluating a time series of the detection signals in such a way that the non-depleted ratio of different bilirubin forms can be inferred from the detection signals of the time series recorded during the local depletion.
• a detector arrangement 103 for generating a time series of detection signals which are related to the detection of light from the irradiated vital tissue region, the detector arrangement having a plurality of, in this case separate, detectors 103a, 103b for light of different wavelengths, in this case represented by the arrows lambda 1 and lambda 2, as well as an evaluation unit (not shown) for evaluating a time
• the light source and the detectors are arranged at a distance from one another on a printed circuit board 105 serving as a carrier, which also contains the evaluation unit and a associated power supply, such as a replaceable battery, and circuits assigned to the detectors, with which electrical light detection signals generated by the detectors are amplified, impedance-matched and digitized so that they can be processed digitally as digital data by the evaluation unit.
• the distance between the light source and detector is 5 mm in the exemplary embodiment shown, which on the one hand allows adequate shielding against light passing directly from the light source to the detector and on the other hand enables the light source and detector to be oriented in such a way that light penetrates sufficiently far and deep into the vital tissue can.
• the light source radiates light obliquely into the vital tissue due to mounting and/or the associated optics, namely with an inclination in the direction of the detector.
• the light source and the detectors are arranged in such a way that their entry and exit optics can be pressed directly against the vital tissue.
• the irradiation area is smaller than 1 cm 2 .
• the carrier can be embedded in a plastic mass or provided with a housing in such a way that it can be fixed at a selected local location, for example by means of elastic or Velcro straps.
• a fingertip is shown as the area of vital tissue, but this is not mandatory. Rather, other skin areas can also be selected, with areas close to the wrist (where wristwatches are typically worn) being advantageous for long-term monitoring; other areas can offer advantages if the body's own transport processes run slower there due to a somewhat weaker blood flow and a fluorescence curve drop can therefore be monitored over a longer period of time.
• the light source has a wavelength of 450 nm, ie a wavelength which is well known to enable efficient transformation, in particular of unconjugated bilirubin, to be effected and which can be produced well with LEDs available on the application date.
• a wavelength of 450 nm ie a wavelength which is well known to enable efficient transformation, in particular of unconjugated bilirubin, to be effected and which can be produced well with LEDs available on the application date.
• other wavelength ranges can be used for bilirubin transformation.
• the detector is an integrated multispectral detector component with separate sensors for the central wavelengths of 450 nm, 500 nm, 550 nm, 570 nm, 600 nm and 650 nm.
• the different spectral sensitivity of the respective sensors is achieved by upstream optical bandpass filters . It should be pointed out that even modern photo sensors with Bayer filters or similar pixels have different spectral sensitivities and, assuming a sufficiently high sensitivity, could possibly be used, so that it is conceivable in principle to use smartphone cameras as detectors, especially if these are close enough to a suitable light source.
• the evaluation unit is designed not only to process the digitized sensor signals in such a way that initially, as is preferred and possible, equidistant times of 1 sec. the detection signals of all separate sensors integrated over a period of one second are recorded and stored until a time series of 60 values per spectral channel has been recorded, but also to control the light source in such a way that the light source continuously emits light during the recording of the time series and after the end of the time series the light emission is also stopped.
• the evaluation unit can further do this be configured to record another time series after a certain period of time, such as 15 minutes.
• the above-mentioned equidistant times of 1 second, the integration time of 1 second, the number of 60 values per spectral channel in a time series and the specified waiting time until a new time series is recorded are not mandatory, but other values may also be can be selected, in particular adjustable values.
• there is a wireless interface for example for communication via Bluetooth, in order, among other things, to make such settings and to transmit measured values.
• the detection signals can preferably be evaluated locally and then only a current total bilirubin measured value determined therefrom and the distribution of unconjugated to conjugated bilirubin can be transmitted, which is preferred in clinical practice; alternatively, the individual detection signals can also be transmitted for checking the device, for example by a service technician.
• a wired interface and/or a display can be provided in addition to or instead of a wireless interface, on which information such as a current total bilirubin measurement value or the distribution of unconjugated to conjugated bilirubin can be displayed.
• the device is placed in direct contact with the skin of a human patient, and then the light source is activated so that the vital tissue near the skin is locally irradiated with light having an intensity and wavelength suitable for transforming a significant amount of bilirubin therein.
• the vital tissue near the skin is locally irradiated with light having an intensity and wavelength suitable for transforming a significant amount of bilirubin therein.
• more light-sensitive forms of bilirubin, particularly unconjugated bilirubin are degraded more rapidly than other forms such as conjugated bilirubin.
• a measurement series of digitized detection signals is then recorded during a one-minute measurement period, while the light source continues to shine continuously with a constant (nominal) intensity.
• this series of measurements on the one hand, for normalization to the intensity of the light of the irradiated light wavelength, light of the irradiation wavelength length and, on the other hand, light of all other wavelengths of the multispectral detector, with each measurement being integrated over a measurement period of 1 second.
• Time series are obtained as shown in FIG. 3 for yellow light, or as shown in FIG. 2 for the total intensity over all fluorescence channels for a somewhat longer section of the time series.
• FIGS. 2 and 3 clearly show that the fluorescence decreases during the recording of the time series, which can be attributed to the degradation of the bilirubin forms by phototransformation.
• the values shown in FIG. 2 are subject to periodic fluctuations, which can be attributed, among other things, to the patient's pulse and the associated changes at the measurement location. Nevertheless, both the total bilirubin value and the ratio of different bilirubin forms, i. H. present from conjugated and unconjugated bilirubin, can be concluded with high accuracy.
• the individual measured values are first normalized to the irradiation intensity.
• the ratios of different spectral pairs of the measured values obtained at the beginning of the measurement are preferably formed—and it should be emphasized that this is considered to be inventive in and of itself and also claimable separately in divisional applications—to determine a total bilirubin value; that this type of determination of the total bilirubin value is also advantageous, although not mandatory, in connection with the differentiation of different forms of bilirubin by considering the time series, in particular the decrease in fluorescence.
• a quotient can be calculated for several pairs of wavelengths that are apart and an associated total bilirubin value can be determined for this quotient. This determination of a total bilirubin value for a respective quotient can refer to a previous calibration by laboratory measurements.
• a corresponding comparison curve is shown, for example, in Figure 4 for the ratio of the detection signals at 550 nm/450 nm, where a measurement was used there in which 450 nm was also irradiated, i.e. the detection signals recorded at 550 nm were essentially normalized to the irradiation intensity became.
• an averaging can then be carried out, which in the simplest case can be unweighted, but even then still an averaging offers high accuracy.
• the proportion of unconjugated bilirubin can then be deduced from the incident light intensity and the speed of the fluorescence decrease, which is recorded in the time series. It should be mentioned that the detected detection signals are also influenced by the degradation products and that this can lead to measurable effects that improve the measured values.
• transcutaneous measurement refers to a non-invasive measurement that is carried out through the skin without injuring the skin and that "body fluids" in which bilirubin occurs can be understood to mean blood in particular, in particular the Blood plasma portion, although it should be mentioned that bilirubin is also found in tissue fluids. It should be mentioned that when considering phototransformation, a reference to other tissue fluids is more likely, because in these the exchange by endogenous transport processes takes place more slowly than in blood, which is why a decrease in certain bilirubin forms is more likely to be observed in tissue fluids.
• a part of the human body can be referred to as a “vital tissue area” that primarily has skin that has normal blood supply, as well as any layers just below it, it should be mentioned, although this definition is not mandatory either.
• a vitamin tissue area that primarily has skin that has normal blood supply, as well as any layers just below it.
• these factors including, for example, the density of the vital tissue area (vG) and slice thickness of the vital tissue area (vG). . These factors depend on the one hand on the body part of the measurement, on the other hand they are very individual by the patient himself.
• step e) comprises the substeps el) calculating the Ite content of bilirubin to en) calculating the nth content of bilirubin, further comprising the step f) detecting the temporal variation in the intensity of light emitted by bilirubin in the body fluids at a second wavelength lambda2 based on the Ite to nth levels of bilirubin and correlating with the level of indirect bilirubin.
• the second wavelength lambda2 in the fluorescence spectrum of bilirubin is used in a second wavelength range between 500 nm and 600 nm in the range of yellow light, in particular at 550 nm. It should also be mentioned that it can be preferred that the first wavelength is lambdal in the range of blue light, in particular at 450 nm. It should also be mentioned that in a preferred variant of the above method, for which the applicant also withholds protection, the light source has a discrete spectrum.
• a device for transcutaneously measuring the level of bilirubin in body fluids comprising a light source that is designed to emit light with a first wavelength lambdal in the wavelength range between 400 nm and 500 nm with a known intensity and radiate onto a vital tissue area, -a detector that is designed to separate light with a second wavelength lambda2 in the wavelength range between 500 nm and 600 nm with a first sensor and light with the first wavelength lambdal with a second sensor from each other, with the light being sent back from the vital tissue area in each case, - a mounting element in which the light source and the detector are arranged at a predetermined angle and a predetermined distance from one another and from the vital tissue area, a computing unit.
• a light source that is designed to emit light with a first wavelength lambdal in the wavelength range between 400 nm and 500 nm with a known intensity and radiate onto a vital tissue area
• -a detector that is designed to separate light with a second wavelength lambda2 in

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• 2021
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