Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
  • A61B5/6801—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
  • A61B5/6802—Sensor mounted on worn items
  • A61B5/681—Wristwatch-type devices
• • 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
  • A61B5/14535—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 for measuring haematocrit
• • 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
  • A61B5/14551—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 for measuring blood gases
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/41—Detecting, measuring or recording for evaluating the immune or lymphatic systems
  • A61B5/411—Detecting or monitoring allergy or intolerance reactions to an allergenic agent or substance
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
  • A61B5/6801—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
  • A61B5/6813—Specially adapted to be attached to a specific body part
  • A61B5/6825—Hand
  • A61B5/6826—Finger
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
  • A61B5/6801—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
  • A61B5/683—Means for maintaining contact with the body
  • A61B5/6838—Clamps or clips
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
  • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
  • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
  • G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
  • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
  • G01N21/47—Scattering, i.e. diffuse reflection
  • G01N21/49—Scattering, i.e. diffuse reflection within a body or fluid
  • G01N21/53—Scattering, i.e. diffuse reflection within a body or fluid within a flowing fluid, e.g. smoke
  • G01N21/532—Scattering, i.e. diffuse reflection within a body or fluid within a flowing fluid, e.g. smoke with measurement of scattering and transmission
• • 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
  • A61B5/14551—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 for measuring blood gases
  • A61B5/14557—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 for measuring blood gases specially adapted to extracorporeal circuits

Definitions

• the present invention relates to a non-invasive method for determination of blood characteristics including hemoglobin in a vessel containing a mixture of liquid and blood cells using the orientation effects of the red blood cells.
• the present invention also relates to an apparatus for performing the method.
• a method and an apparatus are disclosed in WO 97/15229 for determining hemoglobin concentration in blood.
• the method is used for detecting hemoglobin in the microvascular system beneath the mucosal membranes on the inside of the lip of a human by introducing a measuring tip into the mouth of the human.
• the measuring tip of the apparatus must have some kind of sterile shell before it may be placed in the mouth.
• This sterility of the measuring tip means that either the apparatus must be autoclaved before measuring or that a disposable plastic tip has to be used when performing the method.
• This method further uses the reflection of light for determining the concentration of hemoglobin.
• a new non-invasive method for determination of blood characteristics including hemoglobin from a mixture of liquid and blood cells contained in a light pervious vessel comprising the steps of: a) directing a first light beam and a second light beam of different wavelengths against the vessel; b) detecting the intensity of the light of the first and second light beam, respectively, reflected from the vessel; c) calculating a quotient of the detected intensities; and d) analyzing the quotient to determine the blood characteristics .
• the advantage is achieved that influences from pressure and flow, in particular pulsating flow, of the liquid mixture is compensated for, whereby the determined blood characteristics will be accurate.
• the quotient is analyzed by comparing it with previously obtained quotients for known values of the blood characteristic in question.
• an apparatus for determination of blood characteristics including hemoglobin from a mixture of liquid and blood cells contained in a light pervious vessel comprising a first light source and a second light source for directing a first light beam and a second light beam, respectively, against the vessel, the first and second light beams having different wavelengths; at least one detector for detecting the intensity of the light of the first and second light beam, respectively, reflected from the vessel; and a processor for calculating a quotient of the detected intensities and for analyzing the quotient to determine the blood characteristics.
• the apparatus may further comprise registration means for storing values of the determined blood characteristics, and/or means for visualization of the determined blood characteristics .
• light source is to be understood to encompass one or more light emitting elements, such as light diodes.
• blood characteristics is meant in the present application characteristics of blood such as concentration of blood components, e.g. hemoglobin, red blood cells, white blood cells, platelets, cholesterol, albumin, thrombocytes, lymphocytes, drugs and other substances, viscosity, blood pressure, blood flow, blood volume, blood cell illnesses, abnormal blood cell appearances, anemia, leukemia or lymphoma.
• concentration of blood components e.g. hemoglobin, red blood cells, white blood cells, platelets, cholesterol, albumin, thrombocytes, lymphocytes, drugs and other substances, viscosity, blood pressure, blood flow, blood volume, blood cell illnesses, abnormal blood cell appearances, anemia, leukemia or lymphoma.
• hemoglobin is meant in the present application total hemoglobin, oxyhemoglobin, reduced hemoglobin, carboxy hemoglobin, methemoglobin or sulphhem ⁇ globin.
• red blood cells also known as erythrocytes, is meant in the present application whole or partly lysed red blood cells which contain hemoglobin.
• the expression "light pervious vessel” is meant in the present application a blood vessel in an animal, mammal or human, or a pipe, a tube or a tubing which is light pervious.
• the pipe, tube or tubing may be manufactured from acrylonitrile butadiene styrene (ABS) , polycarbonate or acrylic glass (polymethylmethacrylate; PMMA) which gives a non-flexible material or from polyvinyl chloride (PVC) or silicon rubber, plasticized PVC, e.g. PVC plasticized with dioctylphtalate, diethylhexylphtalate or trioctyltrimellitate, which gives a flexible material.
• PMMA is the most preferred non-flexible material . The elasticity of the material may be varied in a wide range .
• light refers generally to electromagnetic radiation at any wavelength, which includes the infrared, visible and ultraviolet portions of the spectrum.
• light of the portion of the spectrum such as visible and near-infrared light, that at least partly is capable of penetrating tissue, is of particular interest.
• the light may comprise non-polarized or polarized light, coherent or incoherent light and illumination of the vessel may be carried out by using steady pulses of light, amplitude modulated light or continuous light.
• the wavelength of the first light beam preferably is selected such that the light absorbance of the red blood cells, as the first light beam passes therethrough, is relatively insignificant, whereas the wavelength of the second light beam is selected such that the light absorbance of the red blood cells, as the second light beam passes therethrough, is relatively significant.
• the wavelength of each light beam may be selected, in the range of 200 nm to 2000 run, preferably 400 nm to 1500 run.
• the wavelength of the first light beam may be selected in the range of 770 nm to 950 nm, i.e. near infrared light (NIR) , preferably 770, 800, 850 or 940, 950 nm, .and the wavelength of the second light beam may be selected in the range of 480 to 590 nm, i.e. green light, preferably 500 nm.
• NIR near infrared light
• the first and second light beam, respectively is directed essentially perpendicular to the vessel, and the intensity of the reflected light of the first and second light beam, respectively, is detected on the vessel between the light beams .
• Step (a) and (b) of the new method may be performed while the mixture of liquid and blood cells is flowing in the vessel .
• the vessel comprises a blood vessel.
• the blood vessel should have a diameter greater than 0,1 mm, and should be a vein, an artery or arteriol .
• the blood vessel may suitably be in a wrist, toe or finger, preferably in a wrist or finger on the third phalanx.
• steps (a) and (b) may be performed while the mixture is standing still as is the case for a fluid medium in a blood bag assemby.
• Steps (a) and (b) may also be performed on a vessel of an extracorporeal equipment including e.g. dialysis apparatus, cell savers, dialysis monitors, slaughter house device or blood fractionation device, or on a vessel of a blood bag assembly.
• an extracorporeal equipment including e.g. dialysis apparatus, cell savers, dialysis monitors, slaughter house device or blood fractionation device, or on a vessel of a blood bag assembly.
• the value of the detected intensity of the reflected light of the first and second light beam, respectively, is preferably wirelessly transmitted to a means for performing steps (d) and (e) , suitably by using a Bluetooth TM standard based communication path.
• the first light source emits light of a wavelength which is essentially not absorbable by red blood cells
• the second light source emits light of a wavelength which is essentially absorbable by red bl'ood cells.
• Each light source should emit light having a wavelength in the range of 200 nm to 2000 nm, preferably 400 nm to 1500 nm.
• the wavelength of the light emitted by the first light source suitably is in the range of 770 nm to 950 nm, preferably 770, 800, 850 or 940, 950 nm
• the wavelength of the light emitted by the second light source suitably is in the range of 480 to 590 nm, preferably 500 nm.
• the detector suitably is positioned between the first and second light sources, for detecting the intensity of the reflected light of the first and second light beam, respectively, and the first and second light source, respectively, may direct the first and second light beam, respectively, essentially perpendicular to the vessel .
• the light sources and detector are assembled in a test device designed for non-invasive application over a blood vessel of a mammal, preferably a human being.
• the test: device may be shaped to fit a wrist, toe or finger.
• the test device may comprise a thimble-like shell to be applied on a finger or toe.
• the light sources and the detector may be arranged to direct the light beams and detect the light intensity within the shell .
• the shell may form a constriction on which the detector and at least one of the first and second light sources are positioned.
• Communication means may be provided for wireless communication between various components of the apparatus, including the light sources, detector and processor, and optionally the registration means and visualizing means.
• the communication means preferably comprises a separate module for transmitting and receiving signals, wherein the module is capable of sending and receiving signals by using a Bluetooth TM standard based communication path.
• the light sources may comprise light emitting diodes, wherein the distance between each diode and the detector is from 4 to 12 mm, preferably 8 to 9 mm, when referring from the centres of the diode and detector.
• the light diodes may be incorporated in the same shell, e.g. a chip, and be positioned on one common side of the measured object. These light diodes may when used together in a chip be lightened alternately.
• the processor is adapted to perform steps (a) to (d) of the new method.
• the processor may be adapted to convert the detected intensity values to a concentration value of a determined blood characteristic.
• light sources for use in the method and apparatus of the invention may be light emitting diodes (LEDs) or laser diodes, such as vertical cavity surface emitting laser (VCEL) . Preferably less expensive LEDs are used. Today there are also new strong light emitting diodes which may be used. Flash lamps, quartz halogen lamps or tungsten lamps may also be used as light sources.
• the light sources may further be capable of emitting monochromatic light, i.e. monochromators.
• the spot on the vessel to be measured may be directly illuminated or indirectly illuminated by guiding the light through optical fibres.
• Detectors suitable for use in the method and apparatus of the invention are phototransistors, photodiodes, photomultipliers, photocells, photodetectors, optical power meters, amplifiers, CCD arrays and the like.
• the mixture of liquid and blood cells may comprise plasma or any other liquid as e.g. water or dialysis liquids.
• the plasma is preferably in or from a mammal.
• the liquid may as well be any other fluid comprising blood cells which may be obtained during or after the processing of blood.
• the light pervious vessel preferably a tube or pipe, should have a diameter greater than 0,1 mm.
• steps (a) and (b) of the new method may be performed on tubings, bags, filters or any other component that may be used in association with blood bag assemblies which may contain whole blood or buffy coat i.e. concentrates of white blood cells (leukocytes) .
• the new method may be usef l when recovering blood from slaughter animals and when further processing that blood to give whole blood for use directly in food or fractionate it to obtain the blood components albumin, immunoglobulins and so on.
• the new method may also be used when counting blood cells i.e. a process when you count red and white blood cells. This may be done in an apparatus such as a blood cell counter e.g. a Coulter counter manufactured by Coulter Diagnostics of Miami Florida.
• the new method may be used in association with blood analysing, blood typing or blood gas analysing.
• the new method may be used when fractionating human blood in a blood fractionating unit. It may be desirable to use the new method when plasma is obtained from donors . The new method may also be useful when obtaining buffy coats from a donor or when these buffy- coats are further processed for producing e.g. cytokines such as interferon alpha. Finally, the new method may be useful to determine how the lysis of the RBC:s are performing during the purification of white blood cells which subsequently after one or more steps involving RBC lysis with e.g. ammonium chloride, are exposed to virus e.g. Sendai virus during incubation in a suitable medium e.g. Eagles Minimal Essential Medium, EMEM.
• a suitable medium e.g. Eagles Minimal Essential Medium, EMEM.
• At least six light beams are directed against the vessel from six light sources, of which three emit near infrared light and the other three emit- green light .
• the intensity of the reflected infrared and green light from the vessel is performed by at least one detector, preferably by only one detector.
• the cable free communication may allow for internet-billing, patient information follow up and statistics, software package updates and service.
• the user may by ordering via a mode get the necessary codes to perform a certain number of tests much in the same way as with cellular phones.
• BluetoothTM has opened the opportunity for cable-free equipment in the hospital environment .
• BluetoothTM technology enables electronic devices to communicate with one another without cables.
• BluetoothTM modules comprising a transmitter and receiver may replace cables in many applications.
• Figure 13 shows a system including a computer and a blood characteristics-detector where there is no need for cables between them when using the BluetoothTM technology.
• BluetoothTM technology developed by L M Ericsson, ' may use the ISM band 2.45 Ghz and may ensure interruption-free communication.
• the system may work with quick frequency hopping of 1,600 hops per second.
• the output power from the transmitter may be low and may be adapted to work at a maximum distance of 10 meters.
• the distance between the wireless communicable components in the apparatus of the present invention may however be variable from 1 cm up to 10000000 miles.
• the components i) and ii) may form an own entity, e.g. a handcuff or thimble which is further described below.
• the handcuff or thimble may then have a transmitter incorporated which may transmit signals to a receiver for further processing the signals .
• Components of the new apparatus including light diodes and detector may be housed in a shell comprising: a) a first part in close proximity to the components i.e. diodes and detector, which preferably houses the components in a flexible way by using a flexible material, preferably a polymeric material, most preferred silicon rubber, and b) an optional second part also comprising a flexible material, preferably a polymeric material, most preferred silicon rubber.
• the first part may also be made of a black plastic material, most preferred epoxy plastic or PMMA.
• the shell may be cast in industrial scale or may be hand-made according to methods known to a person skilled in the art. When silicon rubber is cast to make the first and optionally the second part, preferably a colour powder (dye) is added to the rubber.
• the dye is black to minimize disturbances from other light sources.
• the shell may be fixed in a position on e.g. a finger, toe or wrist by holding the first and second part together, preferably by linking them together by gluing, or by sticking the parts together in any other way. Further the shell may form an inward bend, an internal constriction, preferably the first part of the shell, where the finger, toe or .wrist may be positioned during the measuring.
• the shell may have an arbitrary shape which surrounds said inward bend or constriction.
• the finger, toe or wrist may be "squeezed" so that a blood vessel is easily accessible for performing the method of the invention.
• This squeezing may be acheived by mechanical means or by just pressing by hand.
• a clamping device which may comprise e.g. a rubber band together with a clamping ring , or a strap device, it may also be possible to fix the thimble or handcuff and squeeze the measuring object.
• the flexible material in the first part of the shell may also be made of natural rubber or any pure flexible polymer or any co-polymer. Alternatively, the flexible material may comprise one or more polymers.
• the materials in both parts do preferably not contain allergenic substances and thus the thimble is preferably well tolerable to the skin of a mammal.
• the shell allows for a finger, toe or wrist of a subject to be '"squeezed" so that preferably a blood vessel is easily accessible for performing the method of the invention.
• the blood vessel is preferably an artery, vein or arteriol .
• the detection is preferably performed on a wrist or finger on the third phalanx.
• the handcuff according to one embodiment of the present invention may preferably be present as a flexible plastic patch anchored to a strap for fastening to the wrist, wherein the strap in turn may be locked, using a locking device, during the measurement, thus squeezing the wrist.
• This embodiment ' can be seen in figure 10 and 11.
• the components may preferably be arranged, as an "H", in the corner of a flexible essentially rectangular patch.
• the patch may preferably have rounded corners and a size of 51 x 35 ' mm.
• the patch may additionally preferably have an elevated side, to be in touch with the measuring area e.g. skin of a human, where the light sources and the detector appear.
• the patch may preferably have a size of 51 x 35 mm and the elevation 31 x 47 mm, leaving a margin of 2 mm to the outer size.
• the components, when arranged as an "H", may preferably be fixed in a corner of the smaller of the smaller rectangle, i.e. 31 x 47 mm, as can be seen in the figure 11.
• the "H” is preferably tilted approximately 90° during the measurement on e.g. a wrist when looking from the direction of the arm or the blood vessel.
• the new apparatus may comprise at least four light emitting diodes, preferably at least six light emitting diodes, and one detector which together form an "H" with the detector in the centre, fixed on a patch which in turn is making part of a handcuff construction suitable for wrist measurements, wherein the distance between the light sources and the detector preferably is from 4 to 12 mm when referring from the centres of respective component, most preferred said distance is approximately from 8 to 9 mm.
• the light sources and the detector may be fixed at the edge of the patch, which may house a finger, a toe or wrist.
• the patch is a flexible plastic patch anchored to a strap for fastening to the wrist wherein the strap has a locking device.
• the apparatus may have the light sources and detector incorporated in the patch whereby the electric components are fixed on one side of a printed circuit card covered with black-coloured silicone and the optical components are fixed on the other side covered with transparent silicone, which ensures electrical isolation, reduction of stray light and the possibility for sterilization.
• the patch may preferably be rectangular with a size of 51 x 35 mm, and the light sources and detector may be arranged as an "H" fixed in a corner of said patch.
• the vessel in which the blood characteristics is to be monitored may be identified by proper choice of the separation between the light sources and the detector.
• the theoretical analysis and experimental verification of this optical technique has been presented by I. Fridolin, K. Hansson and L.- G. Lindberg in two papers which have been accepted and are to be published in Physics in Medicine and Biology (Optical non- invasive technique for vessel imaging I and II, Department of Biomedical Engineering, Link ⁇ ping University, Sweden) .
• the following is a summary of their analysis and experimental verifications .
• Light reflection from human tissue depends on many parameters, such as optical wavelength, source-detector separation, size and aperture of the light source and detector and optical properties of the blood and tissues .
• the separation between the light source and the detector fibre was varied between five centre-to-centre distances: 2, 3, 4, 5 and 6 mm.
• the analysis agreed with the earlier conclusion that to increase the influence from deeper tissue on the measured signal, a larger light source-detector separation should be selected.
• FIG. 9 is a schematic diagram of photon migration at two different source-detector separations and for different FL ( ⁇ ) (FL(0) and FL( ⁇ /2)) .
• FL fibre pair position relative the Lining of the vein. Two positions of the light source and the photodetector fibres relative to the lining of the vein were considered. An angle ⁇ is defined to characterize different positions.
• the abbreviation FL(0) means that the light source and the photodetector are positioned in parallel and FL( ⁇ /2) that the light source and the photodetector are positioned perpendicular to the vessel.
• Monte Carlo simulations have shown that for human tissues in the near infrared region photons penetrate approximately 2 mm before being detected if the separation is about 2 mm between the source and the detector.
• Blood vessels in terms of veins may be determined at three vascular levels in combination with a fixed fibre diameter (lmm) and according to;
• a superficial vascular level (approximately 1 mm) . This may be sufficient to set the minimal distance between the illuminating and detecting fibre (2 mm during the above experiments .
• the minimal distance between the illuminating and detecting fibre may preferably be 2 - 3 mm
• the distance between the illuminating and detecting fibre may preferably be greater than 3 mm.
• the present invention may have light sources and detecto (s) on different distances as set out above depending on which measuring area is to be monitored, which enables reaching the aimed vessel and thus the detection of the blood characteristics including Hb.
• the distance between detector (s) and light source (s) may, as set out above, thus be from 1 to 20 mm depending on the measuring area.
• Equation 32 in this paper provides a general solution in which equation ⁇ a and ⁇ s describes the influence of the optical coefficients and H and B (or Z) the influence on pulsatile variations in vessel diameter during the cardiac pulse.
• the light sources are connected by cords to any power source, which may be an oscillator.
• the oscillator may be connected to amplifiers and LED-Drivers . These drivers may be connected to one or more LEDs.
• Detectors e.g. photodiodes for reflection are connected to at least one current/voltage converter, which in turn may be connected to the amplifiers.
• the signals may then pass to Band pass Filters and subsequently to analog outputs or to a ⁇ -controller which is connected to a Read out unit .
• the apparatus of the invention may further comprise big matrix probes including several light sources (more than six) and detectors (more than one) which may have the form of a ring, plate, cube, sphere.
• the processor of the new apparatus may be capable of searching for the optimal measuring spot on the vessel, especially when using a matrix comprising several light sources and detectors. Furthermore, the processor may be used for controlling/verifying reliable strength of ' the signal, for performing algorithm calculations, for evaluating data against stored standard curves, and for displaying (and storing) the results together with patient data and relevant quality criteria.
• the output of the results from the practise of the present invention may be accomplished on a connected printer device, optionally connected via the visualization means.
• a calibration curve may be used.
• This calibration curve stored in a memory of a processor which preferably is part of a computer, allows the readily conversion from the quotient reflection light intensity/reflection light intensity %, which may be stated: AC R /AC R or DC a /DC E , obtained when directing the light beams against the vessel and subsequently detecting the reflection/reflection, to a hemoglobin value in mmol/1.
• the calibration curve may preferably be obtained by analysing in parallel with the method according to the present invention, drawn blood samples from volontary healthy persons and patients on a Hemocue apparatus or blood gas analyser.
• a spectrophotometric absorption curve in reflection mode or recording curve in reflection mode may also be used in conjunction with the method above.
• the PPG-signal is consisting of two parts, a constant signal and a pulsating signal superposed on the constant signal, first maximum and minimum points are calculated.
• the maximum points are calculated through sweeping a window over the curve.
• the size of the window is adjusted according to the frequency of the AC-signal (the pulse) to approximately 60% of the period time, divided equally to the right and to the left. If no value within the window is higher than the value in the middle, this value is designated a maximum point, whereafter the window is moved by leaps half of the window length in order to avoid that a plateau formed curve is registrated as many maximum points. If any value within the window exceeds the value in the middle, the window is moved only one step. In a corresponding way the minimum points are calculated.
• Step d) in the summary of the invention above may preferably comprise the following steps :
• the value is designated a maximum point whereupon the window is moved by leap half of the window length, or if a value exceeds the middle value the window is moved only one step;
• the height of the AC-signal is obtained by subtracting from a value on a connection line involving two maximum points, the vertically laying value of an in between laying minimum point;
• step IV) repeating step IV) at least 8 times, and summarize the values from IV) and dividing the sum with number of observations, thus obtaining a median AC-value
• VI) optionally obtaining the DC-signal by adding the total height of the minimum point in IV) to the median AC-signal of step V) .
• these above steps are accomplished by using a computer program for obtaining said AC-signal and optionally said DC-signal.
• the computer program is stored on a data carrier for performing the above steps I) to VI) .
• the data carrier is part of the processor (or central processing unit, CPU) designated iv) of the Summary of invention part above or a separate floppy disc to be inserted and used by the processor.
• the processor may preferably comprise a computer program for performing the method according to the present invention, as e.g. set forth in the summary of the invention, and/or the above steps I to VI .
• the present invention also provides a computer program stored on a data carrier for performing the new method, as e.g. set forth in the summary of the invention.
• the equation looks similar except that the light may be reduced depending on the absorption of light and the light scattering in the tissue.
• the intensity may be compensated at different blood flows when performing the present invention.
• the reflex light detection is preferably performed over a large blood vessel, e.g. on the wrist or on the finger of the third phalanx.
• the blood vessel must however contain a blood volume which significantly differs from the blood volume in the surroundings (which may comprise capillaries) .
• the method and apparatus according to the present invention may preferably be used for measuring the central blood characteristics as represented in larger vessels such as arteries .
• the effect used in the present method and apparatus according to the present invention may also be used for measuring the change in blood characteristics in one individual or in an extracorporeal system when the blood hemoglobin value is constant.
• a further feature of the present invention is that the method and apparatus may in a very simple way be adapted to detect oxygen, as 97-98 % of all oxygen in the blood of a human being is transported by hemoglobin molecules in the blood.
• the method may also be used for detecting red cells themselves as hemoglobin is normally incorporated in the red blood cells, unless they are lysed.
• the viscosity of blood corresponds to the amount of red blood cells in the blood, the method may also be used for detection of viscosity as .well.
• the method and apparatus of the invention may also be used to determine the hematocrit (Hct) .
• hemoglobin which is the grams of hemoglobin per volume of blood
• hematocrit which is the volume of blood cells per volume of blood
• Hct hematocrit or erythrocyte Hct RBCxMCV
• MCV erythrocyte volume, abr. MCV EVF/RBC mean corpuscular volume
• MCH weight of haemoglobin MCH Hb/RBC in erythrocytes , abr. mean corpuscular haemolglobin
• MCHC concentration of haemoglobin MCHC Hb/ ⁇ VF in erythrocytes, abr. mean corpuscular haemoglobin concentration
• human blood is made up of formed elements and plasma.
• red blood cells contain hemoglobin that carries oxygen from the lungs to the tissues of the body. Normally the hemoglobin concentration varies between 132 - 163 gram/litre in men, and 116 - 148 gram/litre in women.
• the hematocrit (Hct) normally varies between 39 - 49 % (EVF 0.39 - 0.49) in men, and 37 - 44 % (EVF 0.37 - 0.44) in women.
• White blood cells are of approximately the same size as red blood cells, but they do not contain hemoglobin.
• a normal healthy individual has approximately 5,000,000 red blood cells per cubic millimeter of blood (the human body contains approximately 5 litres of blood), and approximately 7,500 white blood cells per cubic millimeter of blood. Therefore, a normal healthy individual will have approximately one white blood cell (leukocyte) for every 670 red blood cells circulating in the vascular system.
• the white blood cells are responsible for the immune system in a mammal, preferably a human being. E.g. certain WBCs engulf intruder agents .
• Platelets they are the smallest of the formed blood cell components, being typically less than 1 ⁇ m in diameter. Platelets are less abundant than red cells, but more abundant than white blood cells . A normal healthy individual has approximately one platelet for every 17 red blood cells circulating in the vascular system for a total of about two trillion.
• the method and apparatus according to the present invention may be used to determine various characteristics of the vascular system through the use of known relationships between parameters, as for the cases when determining indirectly the amount of white blood cells and/or platelets.
• the factor is 1/670 of the red blood cells and for platelets it is 1/17
• the blood characteristics in steps e) and iv) in the method and apparatus, respectively, according to the invention also include white blood cells and/or platelets.
• Cholesterol and albumin concentration may also be determined when using the known hemoglobin concentration in connection with the method described in GB 2 329 015, hereby incorporated by reference. The above method refers to non-invasive measurement of blood component concentrations .
• the method and apparatus of the invention also enables diagnosing of irregularites or diseases in a mammal e.g. anemia where there is a shortage of red blood cells .
• Bulimia patients often suffer from anemia.
• congestive heart failure and cardiac arythmies may be detected using the method and apparatus according to . the invention.
• the method and the apparatus gives an indirect possibility of measuring platelet diseases such as thrombocytopeni . This could be indicative for problems of menostasis and coagulation.
• An elevated level of certain white blood cells is further indicative of a viral infection.
• Leukocytosis and leukopenia are also thinkable indications which may be possible to detect indirectly.
• Other diseases of the phagocytic and Immune Systems may also be detectable.
• Neonatal monitoring is another application area for the present invention.
• Operative monitoring is also a conceivable application.
• the apparatus may be set to a "zero-level" at the start of an operation, in order to compensate for stable interactive effects (skin colour, lipids and so on) and thus a readily monitoring of blood characteristics including hemoglobin may be acheived.
• the present invention also enables an accurate measurement of patient's blood, without any risks associated with drawing blood (e.g. AIDS, hepatitis A, B and C etc).
• Drawing blood by using injection needles is also a painful method, especially for individuals requiring many blood samples to be drawn. These drawbacks may be eliminated by using the method and apparatus according to the present invention. Further the method and apparatus according to the present invention is especially suitable for measurements on children.
• Figure 1 shows schematically a flow model for detection of light reflection.
• Figure 2 shows the orientation of red blood cells at an intermediate level of shear rate .
• Figure 3 shows light absorption in blood due to different absorbing matter.
• Figure 4 shows light scattering due to red blood cells .
• Figure 5 shows the relative change in transmitted light versus blood flow for two different types of red blood cells.
• Figure 6 shows the relative change in transmitted light intensity versus blood flow for two types of blood cells .
• Figure 7 shows essentially the experimental setup of an example (example 2) .
• Figure 8 shows the results from the relative pressure being monitored as in example 4.
• Figure 9 shows at larger separation values the photons forming maximum photon paths and detected by the photodetector originate from deeper layer than for short separation values.
• Figure 10 shows a probe of the apparatus of the invention placed over the radial artery of the wrist of a subject.
• Figure 11 shows the probe comprising a patch made of flexible material .
• Figure 12 shows three diagrams illustrating saline injected in the flow direction close to the probe in figure 10 and 11. Only the intensity of the reflected light was recorded and the change in signal corresponded to the dilution effect in the blood.
• the two diagrams in the bottom of figure 12 shows a recording on a patient with atrial fibrillation, i.e. the PPG and ECG signals.
• Figure 13 illustrates an apparatus of the invention for determining blood characteristics including cable-free BluetoothTM equipment for wireless communication of data between separate elements of the apparatus .
• Figure 14 shows the PPG-signal with DC-signal, AC-signal, minimum points and maximum points.
• Detection was performed using the following equipment: -A tube of acrylic glass (PMMA) with an inside diameter of 3 mm -Two optical fibres with a diameter of 0.094 mm. One fibre was for transmission of light (light source) and the other for receiving reflection of light (photo detector) . -A glass tube with an outside diameter of 0.210 . mm for housing the optical fibres placed in parallel with " each other. -Whole blood from volonteers, which was pumped through the tube made up of PMMA.
• PMMA acrylic glass
• One fibre was for transmission of light (light source) and the other for receiving reflection of light (photo detector) .
• -A glass tube with an outside diameter of 0.210 . mm for housing the optical fibres placed in parallel with " each other. -Whole blood from volonteers, which was pumped through the tube made up of PMMA.
• Figure 1 shows schematically the flow model for detection of light reflection.
• Figure 2 shows the orientation of red blood cells at an intermediate level of shear rate.
• Figure 3 shows light absorption in blood due to different absorbing matter.
• Figure 4 shows light scattering due to red blood cells.
• the results from this experiment suggest that the light is spread in a special way when hitting the red blood cells in the tube. This probably depends on the shape of the blood cells, i- concave disc, which forces the cells to orientate in different way as they move in the circular tube.
• This is demonstrated with optical technique through placing two optical fibres in a small catheter, where one of the fibres works as a light source and the other as photodetector as set out above . The fibre pair is moved from one periphery to the other in a cross-section of a circular tube.
• Figures 5 and 6 are summaries of experimental results.
• the experimental setup was the same as in the above mentioned experiments.
• Figure 5 shows the relative change in transmitted light versus blood flow for two different types of red blood cells.
• the "stiff cells” are red blood cells, which were treated with glutaraldehyde in order to make them stiff i.e. they had lost their ability to change shape with the stress created by the flow.
• Figure 6 shows the relative change in transmitted light intensity versus blood flow for two types of blood cells .
• the "spherical cells” are red blood cells treated with non-isotonic buffer solution. This makes the cells loose their bi-concave disc shape. This results in a close contact and orientation with increasing flow as demonstrated by the reduced transmission intensity with increasing flow. Red blood cells with spherical shape exhibit less shear stress with increasing flow and show little or no orientation effect with flow as measured light transmission changes .
• a second experimental setup consisted essentially of the following. There were essentially three main parts:
• the setup is essentially shown in figure 7, but it lacks one photodetector, as both transmission and reflection was measured.
• a waveform generator regulated the roller pump, which produced a continuous blood flow.
• a pressure transducer was also part of the circuit for the blood flow.
• a gas mixture was lead into the reservoir and mixed with the blood.
• the gas exchange was simulated by a disc oxygenator and the gas mixture consisted of 19% oxygen and 5.6 % carbon dioxide in nitrogen.
• the oxygen saturation was maintained at 98-99%, and the blood gas parameters (p0 2 , pC0 2 and pH) were assumed not to deviate from normal physiological values.
• Laminar flow-through model was used in order to minimize hemolysis of the red blood cells.
• the wavelength that was used was 800 nm, an isobestic point where a minimal absorbance of light take place on the red blood cells .
• the measurements were performed on a tube made of acrylic glass with an inner diameter of 3.0 mm.
• a handcuff-like 1 test device comprising a shell which is one preferred embodiment of the present invention shown in Figure 10 was used.
• the handcuff comprises a patch of flexible material and a strap.
• the flexible material comprises silicon rubber with black dye (ceramic pigment which is non-conducting) .
• the flexible material may form a bend for e.g. a wrist, a finger or a toe.
• the PPG sensor was especially designed to be used on the wrist.
• the optical geometry of the sensor was optimized in order to make it possible to monitor blood characteristics, preferably blood flow, deep in the tissue from the radial artery where it passes over the flat portion of the radius bone.
• the center to center distance between the LEDs and the photodetector is approximately 8-9 mm.
• All components are incorporated in the sensor with the electronics on one side of the printed circuit card covered with black-coloured silicone and the optical components on the other side covered with transparent silicone. This ensures electrical isolation, reduction of stray light and the possibility for sterilization.
• FIG. 10 How the handcuff is connected to a power source, a battery eliminator, is shown in Figure 10 through a block diagram illustrating this schematically.
• the handcuff is further connected to a laptop computer where all measured signals were stored.
• Measurement were performed by using the above probe fastened on the wrist (see figure 12) of a subject.
• the probe was placed on the wrist over the radial artery.
• Saline was injected in the flow direction close to the probe.
• the artery needle was inserted 10 cm from the hand into the radial artery with the needle in the flow direction.
• the distance between the sensor and the tip of the needle was approximately 5 cm.
• Physiological saline was injected during 1-5 seconds at different volumes. The PPG signal was recorded in order to confirm the monitoring depth.
• the PPG signal was recorded in heart failure patients simultaneously with ECG recording. Only the intensity of the reflected light was recorded and the change in signal corresponded to the dilution effect in the blood.
• the result i.e. the PPG signal which consists of two components namely a pulsatile component (AC) synchronous with the heart rate and a slowly varying component (DC)
• AC pulsatile component
• DC slowly varying component
• FIG 12 shows a recording on a patient with atrial fibrillation.
• the AC PPG signal (upper curve) is in accordance with the irregular appearance of the QRS complex in the electrocardiogram.
• the DC component reflects total blood volume changes of different physiological features in the circulation, e.g. vasomotion, temperature regulation and respiration.
• the apparatus according to the present invention thus is useful for e.g. central related blood flow monitoring on the wrist.
• Signal variations in amplitude, curve form and frequency content may further reflect different pathological events in the body corresponding to congestive heart failure and cardiac arythmies .
• Other telemetrical applications in telemedicine are thinkable for the apparatus and the method according to the present invention.
• the apparatus according to the present invention is susceptible to patient arm movement.
• An artefact reducing loop may further be incorporated in the apparatus.
• the apparatus means for monitoring blood pressure, heart rate, respiratory rate and oxygen saturation.
• the relative pressure was monitored and the results can be seen in figure 8.
• the diagram in figure 8 shows the intensity of the reflected pulsative light versus increasing systolic pressure.
• the diastolic pressure was kept constant.

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