US3427135A - Hematology apparatus - Google Patents

Hematology apparatus Download PDF

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US3427135A
US3427135A US564291A US3427135DA US3427135A US 3427135 A US3427135 A US 3427135A US 564291 A US564291 A US 564291A US 3427135D A US3427135D A US 3427135DA US 3427135 A US3427135 A US 3427135A
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stream
quotient
coupled
sample
treating
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Milton H Pelavin
William A Weschler
Kent M Negersmith
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Bayer Corp
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Technicon Instruments Corp
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    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/08Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a stream of discrete samples flowing along a tube system, e.g. flow injection analysis
    • G01N35/085Flow Injection Analysis
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/01Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials specially adapted for biological cells, e.g. blood cells
    • G01N2015/012Red blood cells
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/01Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials specially adapted for biological cells, e.g. blood cells
    • G01N2015/016White blood cells
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10Investigating individual particles
    • G01N2015/1024Counting particles by non-optical means
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10Investigating individual particles
    • G01N2015/1029Particle size
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10Investigating individual particles
    • G01N15/14Optical investigation techniques, e.g. flow cytometry
    • G01N2015/1486Counting the particles
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00Chemistry: analytical and immunological testing
    • Y10T436/11Automated chemical analysis
    • Y10T436/117497Automated chemical analysis with a continuously flowing sample or carrier stream
    • Y10T436/118339Automated chemical analysis with a continuously flowing sample or carrier stream with formation of a segmented stream

Definitions

  • This invention relates to the automatic analysis of a plurality of samples of body fluids, and particularly to the analysis of blood for the diagnosis of body disorders, such as, for example, anemias.
  • a feature of this invention is the provision of an apparatus for receiving a plurality of blood samples, for sequentially analyzing each sample for a plurality of characteristics and for recording these characteristics on a single document.
  • FIG. 1 is a flow diagram of a preferred embodiment of this invention
  • FIG. 2 is a block diagram of the components of the preferred embodiment.
  • FIG. 3 is an exemplary document on which the characteristics of a single blood sample are recorded.
  • each whole blood sample which may be an unmeasured volume of about 2 ml.
  • a liquid sample supply device 12 of the type shown in US. Patent No. 3,230,776 issued to Jack Isreeli et al. on Jan. 25, 1966.
  • the containers 10 are disposed in a circular row on a tumtable 14 which is intermittently rotated past an off-take tube 16, to sequentially present each container to the tube.
  • the inlet of the oil-take tube is disposed into each container for the aspiration therefrom of a measured volume of sample. Alternately, between successive samples, the inlet of the tube is disposed in a container 18 of wash liquid.
  • the outlet end of the off-take tube is coupled to the inlet leg of a junction 20 having four outlet legs 22, 24, 26 and 28. Each of the four outlet legs is coupled to a respective resiliently compressible pump tube 30, 32,
  • the quotient sample stream flowing through the pump tube 34 is used to determine the hematocrit and passes through a junction 40.
  • a pump tube 42 has an inlet open to the atmosphere, and an outlet coupled to the junction 40 to add additional segments of air to the quotient stream, or intra-sample segmentation, as taught in US. Patent No. 2,797,149 issued to Leonard T. Skeggs on June 25, 1957.
  • This intra-sample segmentized quotient stream then passes through a helical mixing coil 44 having a horizontal axis to ensure a homogeneous mixing of each intra-sample segment as taught in US. Patent No. 2,899,280 issued to Edwin C. Whitehead on Aug. 11, 1958.
  • the quotient stream then passes through a debubbling junction 45 having one leg coupled to a pump tube 46 which discharges to waste to remove the air bubbles from the quotient stream as taught in US. Patent No. 3,109,714 issued to Leonard T. Skeggs on Nov. 5, 1963.
  • the debubbled quotient stream is finally passed through a hematocrit flow cell 48 and discharges to waste.
  • the hematocrit flow cell has a central passageway 50 for the passage of the quotient stream and two spaced apart electrodes 52 and 54 which extend to the passageway for the continuous measurement of the electrical resistance of the increment of the quotient stream which is disposed between the two electrodes.
  • the electrodes are disposed in a bridge circuit 56 as taught in An Electric Method to Determine Hemotocrits by R. H. Okada et al., I.R.E. Transactions on Medical Electronics, volume ME-7, July 1960, pp. 188-192.
  • the electrical signal which is generated by the bridge circuit 56 is periodically examined and recorded as will be described subsequently with respect to FIG. 2.
  • the debubbling junction 45 is desirably made integral with the hematocrit flow cell to minimize the length of the flow path of the debubbled quotient stream prior to examination to minimize contamination of succeeding increments of the stream by preceding increments.
  • the quotient sample stream flowing through the pump tube 30 is used to determine the red blood cell count and passes through a junction 58.
  • a pump tube 60 whose inlet .is open to the atmosphere, and a pump tube 62 whose inlet is coupled to a source of saline diluent, have outlets which are coupled to a junction 64 whose outlet is coupled to an inlet of the junction 58.
  • the quotient stream is thus continuously added to an air segmentized saline stream at the junction 58 and is thereby diluted and intra-sample segmentized.
  • This stream is passed through a horizontal helical coil 65 for uniform mixing and thence to the inlet of a junction 66.
  • a pump tube 68 has its inlet coupled to one outlet of the junction 66 for withdrawing a fraction of the one-stage-diluted quotient stream, the remaining fraction of which is discharged to waste through the other outlet of this junction.
  • a pump tube 70 whose inlet is open to the atmosphere, and a pump tube 72 whose inlet is coupled to a source of saline diluent, have outlets which are coupled to a junction 74.
  • the outlet of the junction 74 and the outlet of the pump tube 68 are coupled to a junction 76 whose outlet is coupled to a horizontal mixing coil 78.
  • the one-stage-diluted and intra-sample segmentized quotient stream is thus continuously added to another air segmentized saline stream and is thereby further diluted and intro-sample segmentized.
  • the outlet of the mixing coil 78 is coupled to the inlet of a fiat helix 80 of compressible tubing.
  • the tubing may be compressed to reduce its cross-sectional areas to increase the velocity of the two-stage diluted, intra-sample segmentized quotient stream therethrough, as taught in U.S. patent application Ser. No. 529,366 of Jack Isreeli et al., filed Feb. 23, 1966, and assigned to a common assignee.
  • the outlet of the phasing helix 80 is coupled to one inlet of a debubbling junction 82 of a cell counter module 84, as taught in U.S. patent application Ser. No. 518,908 of Nelson G. Kling et al., filed Jan. 5, 1966, and assigned to a common assignee.
  • a fraction of the stream is passed through one passageway in a two position valve 86, thence in one direction through a flow cell 88 for red cell counting, thence through another passageway in the valve 86, and thence through a conduit 90 which is coupled to a pump tube 92 to waste.
  • the passage of both red and white cells through the flow cell is detected and is counted in a counter module 84 as taught in U.S. patent application Ser. No. 347,769 of Seymour Rosin, filed Feb. 27, 1964, and assigned to a common assignee.
  • the error provided by counting the relatively few white cells, when counting red cells is substantially insignificant.
  • the quotient sample stream flowing through the pump tube 36 is used to determine the white blood cell count and passes through a junction 96.
  • a pump tube 98 whose inlet is open to the atmosphere, and a pump tube 100 whose inlet is coupled to a source of acetic acid and tergitol, have outlets which are coupled to a junction 102 whose outlet is coupled to an inlet of the junction 96.
  • the function of the acetic acid is to lyse the red cells, leaving only the white cells as discrete particles to be counted.
  • the quotient stream is thus continually added to an air segmentized red cell lysing stream at the junction 96 and is thereby diluted and intra-sample segmentized.
  • This stream is passed through a horizontal helical coil 102 for uniform mixing and thence through a phasing helix 104.
  • the outlet of the phasing helix is coupled to an inlet of a debubbling junction 106 of the cell counter module 84.
  • a fraction of the stream is passed through said other passageway in the two position valve 86, thence in the opposite direction through the flow cell 88 for white cell counting, thence through said one passageway in the valve, and thence through said conduit 90 and pump tube 92 to waste.
  • the counter module 84 counts the passage of white cells through the flow cell.
  • the quotient sample stream flowing through the pump tube 32 is used to determine the hemoglobin concentration and passes through a junction 107.
  • a pump tube 108 whose inlet is open to the atmosphere, and a pump tube 110 which is coupled to a source of distilled water, have outlets which are coupled to a junction 112 whose outlet is coupled to an inlet of the junction 107.
  • the function of the distilled water is to lyse the red cells.
  • the quotient stream is thus continually added to an air segmentized hemolyzing stream at the junction 107 and is thereby hemolyzed, diluted and intra-sample segmentized.
  • This stream is passed through a first horizontal helical mixing coil 114, thence through a junction 116, and thence a second horizontal helical mixing coil 118.
  • a pump tube has an inlet coupled to a source of ferricyanide-cyanide reagent and an outlet coupled to an inlet of the junction 116.
  • the reagent is added to the hemolyzed, diluted and intra-sample segmentized quotient stream to produce a color in the stream whose optical density is responsive to the hemoglobin concentration.
  • the hemoglobin is oxidized to methemoglobin by potassium ferricyanide which is subsequently converted to cyanemethemoglobin by potassium cyanide.
  • the outlet of the second mixing coil is coupled to the inlet of a helical phasing coil 121 whose outlet is coupled to the inlet of a heated, vertical, helical time delay coil 122.
  • the outlet of the time delay coil is coupled to a debubbling junction 124 having a lower outlet transmitting a fraction of the colored quotient stream through a fiow cell 126 and thence through a pump tube 128 to discharge to waste.
  • the flow cell is disposed in a colorimeter 130, which may be of the type shown in U.S. Patent No. 3,031,917 issued to Milton H. Pelavin on May 1, 1962. This colorimeter has two photocells, one of which provides a percent transmittance signal, the other of which provides a reference signal.
  • the characteristics of interest of each whole blood sample are recorded on a single document, in correlation, by a single pen recorder 132.
  • the time interval determined between the start of the flow of one sample up the offtake tube and the start of the next successive sample up the tube may be considered to be one cycle of operation of the system.
  • all of the characteristics of interest of a respective sample must be recorded by the recorder.
  • the initial sample stream is divided into four quotient streams, which quotient streams are processed in parallel, i.e. concurrently, until the examination and readout stage which is conducted serially in each cycle.
  • a programmer 134 has a motor 136 which rotates a plurality of snap-action switch controlling cams at 1 rpm.
  • a programmer cam 138 controls the operation of the sampler 12 to start a fresh sample of blood up the offtake tube every minute.
  • the sample is divided into four fractions by the junction 20 and the pump tubes 22, 24, 26 and 28.
  • the time of arrival of each fraction from the sample at its respective analysis device is determined by the length of the respective conduit from the junction 20 to such device. This length, and thereby the phasing between fractions may be nicely adjusted by the phasing coils 80, 121 and 104.
  • the hematocrit flow cell receives its sample fraction firstly, the cell counting module with its valve and counter in their white cell counting postures receives its white sample fraction secondly, the colorimeter receives its sample fraction thirdly, and the cell counting module with its valve and counter in their red cell counting postures receives its red sample fraction fourthly.
  • the hematocrit flow cell 48 is continuously coupled into the hematocrit bridge circuit 56 which continuously provides an analogue voltage which is responsive to the internal impedance of the flow cell 48 which is responsive to the percent hematocrit of the increment of blood in the flow cell.
  • the colorimeter 130 is continuously coupled to a logratio single-ended output amplifier 140 to continuously provide thereto an analogue voltage which is responsive to the percent transmittance of the increment of blood in the flow cell 126 which is responsive to its hemoglobin concentration, and an analogue reference voltage.
  • the logratio amplifier continuously provides an analogue voltage which is directly proportional to the hemoglobin concentration.
  • the cell counter 84 is continuously coupled to a two configuration filter network 142 of the type taught in US. patent application Ser. No. 554,083, by Edwin C. Whitehead et al., filed May 31, 1966, and assigned to a common assignee.
  • a valve cam 144 controls the disposition of the flow cell valve 86 and, if necessary, the counter for red or white cell counting in the alternative.
  • the counter 84 provides to the filter network 142 an analogue voltage which is alternatively proportional to the red or white cell count of the blood flowing through the flow cell 86.
  • a prebias cam 146 when the counter 84 is doing the red cell count, initially disposes the filter network 142 in its first configuration wherein the network has a low time constant and the charge on a capacitor in the network rapidly follows the voltage provided by the counter 84 and subsequently, during the interval when the signal is to be coupled to the recorder 132, disposes the network on its second configuration wherein the network has a high time constant and heavily filters the signal from the counter.
  • the cam 146 similarly switches the network 142 through its two configurations.
  • a calibration module 148 has seven biasing circuits as taught in Us. 3,241,432, supra, to adjust the travel of the stylus of the recorder 132 to conform to the respective scales printed on the recorder paper. These scales may be calibrated to indicate the characteristics of interest in direct units or coefficients.
  • the recorder 132 is provided with a retransmitting slidewire as taught in US. Patent No. 2,960,910 issued to Milton Pelavin on Nov. 20, 1960.
  • the moving contact of this slidewire provides an analogue voltage which is directly proportional to the movement of the stylus of the recorder.
  • a signal conditioner 150 has seven biasing circuits to modify the respective analogue voltages provided by the recorder retransmitting slidewire to be directly proportional to the characteristic of interest.
  • Three track and hold circuits are provided, one 152 for hematocrit, one 154 for hemoglobin, and one 156 for red blood cell count.
  • Each of these circuits comprises a network including an operational amplifier having a feedback capacitor. This capacitor is initially switched into a short time constant configuration to rapidly follow the voltage provided by the signal conditioner, which will be the peak value for each characteristic, and is subsequently switched into a long time constant configuration to store this peak value.
  • Three log ratio amplifiers are provided, one 158 for mean corpuscular hemoglobin, one 160 for mean corpuscular volume, and one for mean corpuscular hemoglobin concentration.
  • the MCH equals hemoglobin/ red cell count; the MCV equals percent hematocrit/ red cell count; and the MCHC equals hemoglobin/percent hematocrit.
  • These amplifiers are coupled to respective pairs of the peak detector and hold circuits as indicated to provide analogue voltages responsive to the ratios of the voltages stored by the respective pairs of hold circuits.
  • Three antilog amplifiers are provided, one 164 for MCH, one 166 for MCV, and one 168 for MCHC. These amplifiers transform the output log to ratio signals of the log ratio amplifiers to respective analogue voltages which are directly proportional to the respective ratios.
  • An analysis cam 170 pulses a counter and relay driver 172 or a stepping switch which drives an input selector module 174 having seven input channels and a single output channel.
  • the seven input channels are coupled to receive the hemoglobin signal from the log-ratio amplifier '140, the white blood cell count signal and the red blood cell count signal from the filter network 142, the percent hematocrit signal from the bridge circuit 56 and to receive the MCH signal from the amplifier 164, the MCV signal from the amplifier 1'66 and the MCHC signal from the amplifier 168.
  • One input channel at a time is gated open in conjunction with a respective biasing circuit in the calibration module 148 and this signal is provided to the recorder for recording, on a single document 175.
  • the hematocrit sample which is not diluted, has the highest rate of contamination of successive samples by preceding samples, and, therefore, it is desirable that the length of the conduit that this sample travels be minimized. For this reason the hematocrit conduit is made the shortest of the four conduits, and will be the first sample analyzed in any cycle. It is also desirable that the valve of the flow cell counter module spend one half of the cycle in one position and one half of the cycle in the other position for maximum cleansing of the flow passageway. Since the red cell count is a prerequisite to determining the ratios of MCH, MCV and MCHC, it should occur before the ratios and the white cell count. The hemoglobin concentration is also a prerequisite to determining the ratios and should occur before the ratios.
  • the following phasing is most advantageous: (1) Hematocrit, (2) Red Cell Count, (3) Hemoglobin, (4-5- 6) MCH, MCV and MCHC in any order, and (7) White Cell Count.
  • the four direct tests may be recorded initially, and the three ratio tests subsequently for each sample. If the ratios are omitted in a four test system the following phasing is advantageous: (l) Hematocrit, (2) either RBC or WBC, (3) Hemoglobin, and (4) either WBC or RBC.
  • a meter 176 may be provided to directly indicate the four directly read concentrations of constituents of interest.
  • the meter 176 may be fed by a meter calibration module 178 which has four biasing networks and which also receives signals from the amplifier 140, the filter network 142, and the bridge circuit 56, and is driven by the driver 172 to pass one calibrated signal at a time to the meter.
  • suitable digital date logging equipment having a suitable analogue to digital converting input channel may be provided to receive signals from the conditioner 158, the data logger being under the control of a data logger cam 180.
  • Apparatus for the analysis of a plurality of blood samples with respect to a given number of characteristics of blood comprising: supply means for providing the blood samples sequentially to form an initial stream or" sequential samples wherein each sample is in sequence with the preceding and succeeding samples; dividing means coupled to said supply means for receiving the initial stream of sequential samples and for dividing such initial stream into a plurality, equal to the given number of characteristics, of quotient streams, each sequential increment in each of such quotient streams being a fractional portion of a respective sequential sample in the initial stream; means coupled to said dividing means, for receiving and for treating one of the quotient streams for red blood cell counting; means coupled to said red blood cell counting treating means, for receiving and examining the treated quotient stream to determine the red blood cell count of each sequential increment thereof and for providing a signal responsive to such determination; means, coupled to said dividing means, for receiving and for treating one of the quotient streams for hematocrit analysis; means, coupled to said hematocrit treating means, for receiving and
  • Apparatus according to claim 1 further including: means, coupled to said dividing means, for receiving and for treating one of the quotient streams for hemoglobin concentration; and means, coupled to said hemoglobin treating means, for receiving and examining the treated quotient stream to determine the hemoglobin concentration of each sequential increment thereof and for providing a signal responsive to such determination; said recording means being additionally coupled to said hemoglobin concentration determining means for receiving the respective signals therefrom and for recording such signals in correlation with the other signals as aforesaid.
  • Apparatus according to claim 2 further including: means, coupled to said dividing means, for receiving and for treating one of the quotient streams for white blood cell counting; and means, coupled to said white blood cell counting treating means, for receiving and examining the treated quotient stream to determine the White blood cell count of each sequential increment thereof and for providing a signal responsive to such determination; said recording means being additionally coupled to said white blood cell count determining means for receiving the respective signals therefrom and for recording such signals in correlation with the other signals a aforesaid.
  • Apparatus according to claim 1 further including: means for receiving signals respectively responsive to the hematocrit and the red blood cell count of the respective sequential increments from a common sample of the initial stream, for providing an additional signal responsive to the ratio thereof which is responsive to the mean corpuscular volume; said recording means being additionally coupled to said mean corpuscular volume signal providing means for receiving the respective signals therefrom and for recording such signals in correlation with the other signals as aforesaid.
  • Apparatus according to claim 2 further including: means for receiving signals respectively responsive to the hemoglobin and the red cell count of the respective sequential increments from a common sample of the initial stream, for providing an additional signal responsive to the ratio thereof which is responsive to the mean corpuscular hemoglobin; said recording means being additionally coupled to said mean corpuscular hemoglobin signal providing means for receiving the respective signals therefrom and for recording such signals in correlation with the other signals as aforesaid.
  • Apparatus according to claim 2 further including: means for receiving signals respectively responsive to the hemoglobin and the hematocrit of the respective sequential increments from a common sample of the initial stream, for providing an additional signal responsive to the ratio thereof Which is responsive to the mean corpuscular hemoglobin concentration; said recording means being additionally coupled to said mean corpuscular hemoglobin concentration signal providing means for receiving the respective signals therefrom and for recording such signals in correlation with the other signals as aforesaid.
  • Apparatus for the analysis of a plurality of blood samples with respect to a given number of characteristics of blood comprising: supply means for providing the blood samples sequentially to form an initial stream of sequential samples wherein each sample is in sequence with the preceding and succeeding samples; dividing means coupled to said supply means for receiving the initial stream of sequential samples and for dividing such initial stream into a plurality, equal to the given number of characteristics, of quotient streams, each sequential increment in each of such quotient streams being a fractional portion of a respective sequential sample in the initial stream; means coupled to said dividing means, for receiving and for treating one of the quotient streams for hemoglobin concentration; means coupled to said hemoglobin concentration treating means, for receiving and examining the treated quotient stream to determine the hemoglobin concentration of each sequential increment thereof and for providing a signal responsive to such determination; means, coupled to said dividing means, for receiving and for treating one of the quotient streams for hematocrit analysis; means, coupled to said hematocrit treating means, for receiving and examining
  • Apparatus for the analysis of a plurality of blood samples with respect to a given number of characteristics of blood comprising: supply means for providing the blood samples sequentially to form an initial stream of sequential samples wherein each sample is in sequence with the preceding and succeeding samples; dividing means coupled to said supply means for receiving the initial stream of sequential samples and for dividing such initial stream into a plurality, equal to the given 7 number of characteristics, of quotient streams, each sequential increment in each of such quotient streams being a fractional portion of a respective sequential sample in the initial stream; means coupled to said dividing means, for receiving and for treating one of the quotient streams for hematocrit analysis; means, coupled to said hematocrit treating means, for initially in phase receiving and examining the treated quotient stream to determine the hematocrit of each sequential increment thereof and for providing a signal responsive to such determination; means coupled to said dividing means, for receiving and for treating one of the quotient streams for red blood cell counting; means coupled to said red blood cell counting treating means, for

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Abstract

1,192,192. Determining blood characteristics. TECHNICON CORP. 22 June, 1967 [11 July, 1966], No. 28851/67. Heading B1X. Apparatus for determining blood characteristics comprises supply means 12 for providing an initial stream of the samples to be tested; means 30, 32, 34, 36 coupled to junction 20 for providing a plurality of quotient streams, each containing a fractional portion of each of the samples in the initial stream; first treating means coupled to tube 34 for treating one quotient stream for HCT analysis, first determining means for measuring the HCT for example by continuous measurement of the resistance of the stream by means of electrodes 54 and for providing a signal responsive to the HCT measurement; second treating means for treating another of the quotient streams for analysis and second determining means for making the appropriate measurement and providing a signal responsive to it; and recording means 132 for receiving the signals and recording in correlation the signals obtained by measurements on the fractional portions of a common sample of the initial stream. The quotient stream in tube 30 may be twice diluted with saline (at junctions 58 and 76) then passed through phaser coil 80 (see 1,183,631) to counter module 84 for RBC determination. The quotient stream in tube 32 may be lysed with water added at 107, mixed with ferricyanide-cyanide reagent at 116 to convert the haemoglobin to cyanomethaemoglobin and passed through phaser coil 121 to colorimeter 130 for HGB measurement. The quotient stream in tube 36 may be lysed with acetic acid and a surfactant added at 96, and passed through phaser coil 104 to counter module 84 for WBC determination. MCH, MCV and MCHC are calculated from the measured characteristics and all seven characteristics of the sample are printed out on a single document (Fig. 3 not shown). The circuit (Fig. 2 not shown) permits display of the measured characteristics in turn on a meter.

Description

Feb. 11, 1969 M. H. PELAVIN ETAL HEMATOLOGY APPARATUS Arrow/5r V w United States Patent 8 Claims This invention relates to the automatic analysis of a plurality of samples of body fluids, and particularly to the analysis of blood for the diagnosis of body disorders, such as, for example, anemias.
It has been well known to perform analyses of a blood sample for diagnostic purposes. Such analyses have been performed independently of each other and then the results must be correlated. Certain characteristics are not conveniently obtainable directly from the blood, but must be calculated from directly obtained characteristics. Characteristics which are directly obtainable are hemoglobin weight concentration of whole blood volume, red blood cell count of whole blood volume, white blood cell count of whole blood volume, and hematocrit or volume percent of red blood cells in whole blood volume. The red blood cell or erythrocyte constants, which provide significant insight into the anemias, can most rapidly be obtained indirectly; these are: means corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration.
It is an object of this invention to provide an apparatus which will automatically process a plurality of whole blood samples, and which will provide on a respective single document the various characteristics of each blood sample.
A feature of this invention is the provision of an apparatus for receiving a plurality of blood samples, for sequentially analyzing each sample for a plurality of characteristics and for recording these characteristics on a single document.
These and other objects, features and advantages of this invention will be apparent from the following specification of this invention, taken in conjunction with the accompanying drawing in which:
FIG. 1 is a flow diagram of a preferred embodiment of this invention;
FIG. 2 is a block diagram of the components of the preferred embodiment; and
FIG. 3 is an exemplary document on which the characteristics of a single blood sample are recorded.
Turning to FIG. 1, each whole blood sample, which may be an unmeasured volume of about 2 ml., is disposed in a respective sample container in a liquid sample supply device 12, of the type shown in US. Patent No. 3,230,776 issued to Jack Isreeli et al. on Jan. 25, 1966. The containers 10 are disposed in a circular row on a tumtable 14 which is intermittently rotated past an off-take tube 16, to sequentially present each container to the tube. The inlet of the oil-take tube is disposed into each container for the aspiration therefrom of a measured volume of sample. Alternately, between successive samples, the inlet of the tube is disposed in a container 18 of wash liquid. The outlet end of the off-take tube is coupled to the inlet leg of a junction 20 having four outlet legs 22, 24, 26 and 28. Each of the four outlet legs is coupled to a respective resiliently compressible pump tube 30, 32,
3,427,135 Patented Feb. 11, 1969 "ice 3-4 and 36, which are disposed in a proportioning pump 38, such as the peristaltic pump shown in US. Patent No. 2,935,028 issued to Andres Ferrari, Jr. et al. on May 3, 1960. These and other pump tubes are disposed on a platen and are concurrently progressively occluded along their lengths by a plurality of rollers to advance fluid through the tubes. The volumetric flow rates are determined by the internal cross-sectional areas of the tube. It will be appreciated that the samples flow successively, interspaced by segments of wash liquid and air, through the off-take tube 16 as an initial stream which is divided into four concurrent quotient streams of sample, wash liquid and air segments. Each of these quotient streams is analyzed for a particular characteristic of interest, in a manner which is akin to that taught in US. Patent No. 3,241,432 issued to Leonard T. Skeggs et al. on Mar. 22, 1966.
The quotient sample stream flowing through the pump tube 34 is used to determine the hematocrit and passes through a junction 40. A pump tube 42 has an inlet open to the atmosphere, and an outlet coupled to the junction 40 to add additional segments of air to the quotient stream, or intra-sample segmentation, as taught in US. Patent No. 2,797,149 issued to Leonard T. Skeggs on June 25, 1957. This intra-sample segmentized quotient stream then passes through a helical mixing coil 44 having a horizontal axis to ensure a homogeneous mixing of each intra-sample segment as taught in US. Patent No. 2,899,280 issued to Edwin C. Whitehead on Aug. 11, 1959. The quotient stream then passes through a debubbling junction 45 having one leg coupled to a pump tube 46 which discharges to waste to remove the air bubbles from the quotient stream as taught in US. Patent No. 3,109,714 issued to Leonard T. Skeggs on Nov. 5, 1963. The debubbled quotient stream is finally passed through a hematocrit flow cell 48 and discharges to waste. The hematocrit flow cell has a central passageway 50 for the passage of the quotient stream and two spaced apart electrodes 52 and 54 which extend to the passageway for the continuous measurement of the electrical resistance of the increment of the quotient stream which is disposed between the two electrodes. The electrodes are disposed in a bridge circuit 56 as taught in An Electric Method to Determine Hemotocrits by R. H. Okada et al., I.R.E. Transactions on Medical Electronics, volume ME-7, July 1960, pp. 188-192. The electrical signal which is generated by the bridge circuit 56 is periodically examined and recorded as will be described subsequently with respect to FIG. 2. It should be noted that the debubbling junction 45 is desirably made integral with the hematocrit flow cell to minimize the length of the flow path of the debubbled quotient stream prior to examination to minimize contamination of succeeding increments of the stream by preceding increments.
It has been established by Okada et al., supra, that the electrical conductance of whole blood is a reliable index of its hematocrit. Erythrocytes do not conduct an electric current, whereas plasma does. The lower the red cell volume, the higher the conductance, and vice versa.
The quotient sample stream flowing through the pump tube 30 is used to determine the red blood cell count and passes through a junction 58. A pump tube 60 whose inlet .is open to the atmosphere, and a pump tube 62 whose inlet is coupled to a source of saline diluent, have outlets which are coupled to a junction 64 whose outlet is coupled to an inlet of the junction 58. The quotient stream is thus continuously added to an air segmentized saline stream at the junction 58 and is thereby diluted and intra-sample segmentized. This stream is passed through a horizontal helical coil 65 for uniform mixing and thence to the inlet of a junction 66. A pump tube 68 has its inlet coupled to one outlet of the junction 66 for withdrawing a fraction of the one-stage-diluted quotient stream, the remaining fraction of which is discharged to waste through the other outlet of this junction. A pump tube 70 whose inlet is open to the atmosphere, and a pump tube 72 whose inlet is coupled to a source of saline diluent, have outlets which are coupled to a junction 74. The outlet of the junction 74 and the outlet of the pump tube 68 are coupled to a junction 76 whose outlet is coupled to a horizontal mixing coil 78. The one-stage-diluted and intra-sample segmentized quotient stream is thus continuously added to another air segmentized saline stream and is thereby further diluted and intro-sample segmentized. The outlet of the mixing coil 78 is coupled to the inlet of a fiat helix 80 of compressible tubing. The tubing may be compressed to reduce its cross-sectional areas to increase the velocity of the two-stage diluted, intra-sample segmentized quotient stream therethrough, as taught in U.S. patent application Ser. No. 529,366 of Jack Isreeli et al., filed Feb. 23, 1966, and assigned to a common assignee. The outlet of the phasing helix 80 is coupled to one inlet of a debubbling junction 82 of a cell counter module 84, as taught in U.S. patent application Ser. No. 518,908 of Nelson G. Kling et al., filed Jan. 5, 1966, and assigned to a common assignee. A fraction of the stream is passed through one passageway in a two position valve 86, thence in one direction through a flow cell 88 for red cell counting, thence through another passageway in the valve 86, and thence through a conduit 90 which is coupled to a pump tube 92 to waste. The passage of both red and white cells through the flow cell is detected and is counted in a counter module 84 as taught in U.S. patent application Ser. No. 347,769 of Seymour Rosin, filed Feb. 27, 1964, and assigned to a common assignee. The error provided by counting the relatively few white cells, when counting red cells, is substantially insignificant.
The quotient sample stream flowing through the pump tube 36 is used to determine the white blood cell count and passes through a junction 96. A pump tube 98 whose inlet is open to the atmosphere, and a pump tube 100 whose inlet is coupled to a source of acetic acid and tergitol, have outlets which are coupled to a junction 102 whose outlet is coupled to an inlet of the junction 96. The function of the acetic acid is to lyse the red cells, leaving only the white cells as discrete particles to be counted. The quotient stream is thus continually added to an air segmentized red cell lysing stream at the junction 96 and is thereby diluted and intra-sample segmentized. This stream is passed through a horizontal helical coil 102 for uniform mixing and thence through a phasing helix 104. The outlet of the phasing helix is coupled to an inlet of a debubbling junction 106 of the cell counter module 84. A fraction of the stream is passed through said other passageway in the two position valve 86, thence in the opposite direction through the flow cell 88 for white cell counting, thence through said one passageway in the valve, and thence through said conduit 90 and pump tube 92 to waste. The counter module 84 counts the passage of white cells through the flow cell.
The quotient sample stream flowing through the pump tube 32 is used to determine the hemoglobin concentration and passes through a junction 107. A pump tube 108 whose inlet is open to the atmosphere, and a pump tube 110 which is coupled to a source of distilled water, have outlets which are coupled to a junction 112 whose outlet is coupled to an inlet of the junction 107. The function of the distilled water is to lyse the red cells. The quotient stream is thus continually added to an air segmentized hemolyzing stream at the junction 107 and is thereby hemolyzed, diluted and intra-sample segmentized. This stream is passed through a first horizontal helical mixing coil 114, thence through a junction 116, and thence a second horizontal helical mixing coil 118. A pump tube has an inlet coupled to a source of ferricyanide-cyanide reagent and an outlet coupled to an inlet of the junction 116. The reagent is added to the hemolyzed, diluted and intra-sample segmentized quotient stream to produce a color in the stream whose optical density is responsive to the hemoglobin concentration. Specifically the hemoglobin is oxidized to methemoglobin by potassium ferricyanide which is subsequently converted to cyanemethemoglobin by potassium cyanide. The outlet of the second mixing coil is coupled to the inlet of a helical phasing coil 121 whose outlet is coupled to the inlet of a heated, vertical, helical time delay coil 122. The outlet of the time delay coil is coupled to a debubbling junction 124 having a lower outlet transmitting a fraction of the colored quotient stream through a fiow cell 126 and thence through a pump tube 128 to discharge to waste. The flow cell is disposed in a colorimeter 130, which may be of the type shown in U.S. Patent No. 3,031,917 issued to Milton H. Pelavin on May 1, 1962. This colorimeter has two photocells, one of which provides a percent transmittance signal, the other of which provides a reference signal.
The characteristics of interest of each whole blood sample are recorded on a single document, in correlation, by a single pen recorder 132. The time interval determined between the start of the flow of one sample up the offtake tube and the start of the next successive sample up the tube may be considered to be one cycle of operation of the system. During each such cycle all of the characteristics of interest of a respective sample must be recorded by the recorder. To accomplish this, the initial sample stream is divided into four quotient streams, which quotient streams are processed in parallel, i.e. concurrently, until the examination and readout stage which is conducted serially in each cycle. To accomplish this in, for example, a one minute cycle, a programmer 134 has a motor 136 which rotates a plurality of snap-action switch controlling cams at 1 rpm.
A programmer cam 138 controls the operation of the sampler 12 to start a fresh sample of blood up the offtake tube every minute. The sample is divided into four fractions by the junction 20 and the pump tubes 22, 24, 26 and 28. The time of arrival of each fraction from the sample at its respective analysis device is determined by the length of the respective conduit from the junction 20 to such device. This length, and thereby the phasing between fractions may be nicely adjusted by the phasing coils 80, 121 and 104. The hematocrit flow cell receives its sample fraction firstly, the cell counting module with its valve and counter in their white cell counting postures receives its white sample fraction secondly, the colorimeter receives its sample fraction thirdly, and the cell counting module with its valve and counter in their red cell counting postures receives its red sample fraction fourthly.
The hematocrit flow cell 48 is continuously coupled into the hematocrit bridge circuit 56 which continuously provides an analogue voltage which is responsive to the internal impedance of the flow cell 48 which is responsive to the percent hematocrit of the increment of blood in the flow cell.
The colorimeter 130 is continuously coupled to a logratio single-ended output amplifier 140 to continuously provide thereto an analogue voltage which is responsive to the percent transmittance of the increment of blood in the flow cell 126 which is responsive to its hemoglobin concentration, and an analogue reference voltage. The logratio amplifier continuously provides an analogue voltage which is directly proportional to the hemoglobin concentration. Such amplifiers are described in A Circuit With Logarithmic Transfer Response Over Nine Decades by J. F. Gibbons et al., I.E.E.E. Transactions of the Circuit Theory Group, volume CT-l 1, September 1964, pp. 378
384, and are manufactured by Philbrick Researchers, Inc.; among others.
The cell counter 84 is continuously coupled to a two configuration filter network 142 of the type taught in US. patent application Ser. No. 554,083, by Edwin C. Whitehead et al., filed May 31, 1966, and assigned to a common assignee. A valve cam 144 controls the disposition of the flow cell valve 86 and, if necessary, the counter for red or white cell counting in the alternative. The counter 84 provides to the filter network 142 an analogue voltage which is alternatively proportional to the red or white cell count of the blood flowing through the flow cell 86. A prebias cam 146, when the counter 84 is doing the red cell count, initially disposes the filter network 142 in its first configuration wherein the network has a low time constant and the charge on a capacitor in the network rapidly follows the voltage provided by the counter 84 and subsequently, during the interval when the signal is to be coupled to the recorder 132, disposes the network on its second configuration wherein the network has a high time constant and heavily filters the signal from the counter. When the counter 84 is doing the white cell count, the cam 146 similarly switches the network 142 through its two configurations.
A calibration module 148 has seven biasing circuits as taught in Us. 3,241,432, supra, to adjust the travel of the stylus of the recorder 132 to conform to the respective scales printed on the recorder paper. These scales may be calibrated to indicate the characteristics of interest in direct units or coefficients.
The recorder 132 is provided with a retransmitting slidewire as taught in US. Patent No. 2,960,910 issued to Milton Pelavin on Nov. 20, 1960. The moving contact of this slidewire provides an analogue voltage which is directly proportional to the movement of the stylus of the recorder.
A signal conditioner 150 has seven biasing circuits to modify the respective analogue voltages provided by the recorder retransmitting slidewire to be directly proportional to the characteristic of interest.
Three track and hold circuits are provided, one 152 for hematocrit, one 154 for hemoglobin, and one 156 for red blood cell count. Each of these circuits comprises a network including an operational amplifier having a feedback capacitor. This capacitor is initially switched into a short time constant configuration to rapidly follow the voltage provided by the signal conditioner, which will be the peak value for each characteristic, and is subsequently switched into a long time constant configuration to store this peak value.
Three log ratio amplifiers are provided, one 158 for mean corpuscular hemoglobin, one 160 for mean corpuscular volume, and one for mean corpuscular hemoglobin concentration. The MCH equals hemoglobin/ red cell count; the MCV equals percent hematocrit/ red cell count; and the MCHC equals hemoglobin/percent hematocrit. These amplifiers are coupled to respective pairs of the peak detector and hold circuits as indicated to provide analogue voltages responsive to the ratios of the voltages stored by the respective pairs of hold circuits.
Three antilog amplifiers are provided, one 164 for MCH, one 166 for MCV, and one 168 for MCHC. These amplifiers transform the output log to ratio signals of the log ratio amplifiers to respective analogue voltages which are directly proportional to the respective ratios.
An analysis cam 170 pulses a counter and relay driver 172 or a stepping switch which drives an input selector module 174 having seven input channels and a single output channel. The seven input channels are coupled to receive the hemoglobin signal from the log-ratio amplifier '140, the white blood cell count signal and the red blood cell count signal from the filter network 142, the percent hematocrit signal from the bridge circuit 56 and to receive the MCH signal from the amplifier 164, the MCV signal from the amplifier 1'66 and the MCHC signal from the amplifier 168. One input channel at a time is gated open in conjunction with a respective biasing circuit in the calibration module 148 and this signal is provided to the recorder for recording, on a single document 175. The hematocrit sample, which is not diluted, has the highest rate of contamination of successive samples by preceding samples, and, therefore, it is desirable that the length of the conduit that this sample travels be minimized. For this reason the hematocrit conduit is made the shortest of the four conduits, and will be the first sample analyzed in any cycle. It is also desirable that the valve of the flow cell counter module spend one half of the cycle in one position and one half of the cycle in the other position for maximum cleansing of the flow passageway. Since the red cell count is a prerequisite to determining the ratios of MCH, MCV and MCHC, it should occur before the ratios and the white cell count. The hemoglobin concentration is also a prerequisite to determining the ratios and should occur before the ratios. Therefore, for the seven test system the following phasing is most advantageous: (1) Hematocrit, (2) Red Cell Count, (3) Hemoglobin, (4-5- 6) MCH, MCV and MCHC in any order, and (7) White Cell Count. However, it will be appreciated that if desired, the four direct tests may be recorded initially, and the three ratio tests subsequently for each sample. If the ratios are omitted in a four test system the following phasing is advantageous: (l) Hematocrit, (2) either RBC or WBC, (3) Hemoglobin, and (4) either WBC or RBC.
If desired, a meter 176 may be provided to directly indicate the four directly read concentrations of constituents of interest. The meter 176 may be fed by a meter calibration module 178 which has four biasing networks and which also receives signals from the amplifier 140, the filter network 142, and the bridge circuit 56, and is driven by the driver 172 to pass one calibrated signal at a time to the meter.
If desired, suitable digital date logging equipment, having a suitable analogue to digital converting input channel may be provided to receive signals from the conditioner 158, the data logger being under the control of a data logger cam 180.
While there has been shown and described the preferred embodiment of the invention, it will be understood that the invention may be embodied otherwise than as herein specifically illustrated or described, and that certain changes in the form and arrangement of parts and in the specific manner of practicing the invention may be made without departing from the underlying idea or principles of this invention within the scope of the appended claims- What is claimed is:
1. Apparatus for the analysis of a plurality of blood samples with respect to a given number of characteristics of blood, said apparatus comprising: supply means for providing the blood samples sequentially to form an initial stream or" sequential samples wherein each sample is in sequence with the preceding and succeeding samples; dividing means coupled to said supply means for receiving the initial stream of sequential samples and for dividing such initial stream into a plurality, equal to the given number of characteristics, of quotient streams, each sequential increment in each of such quotient streams being a fractional portion of a respective sequential sample in the initial stream; means coupled to said dividing means, for receiving and for treating one of the quotient streams for red blood cell counting; means coupled to said red blood cell counting treating means, for receiving and examining the treated quotient stream to determine the red blood cell count of each sequential increment thereof and for providing a signal responsive to such determination; means, coupled to said dividing means, for receiving and for treating one of the quotient streams for hematocrit analysis; means, coupled to said hematocrit treating means, for receiving and examining the treated quotient stream to determine the hematocrit of each sequential increment thereof and for providing a signal responsive to such determination; and recording means coupled to said red blood cell count determining means and to said hematocrit determining means for receiving the respective signals therefrom and for recording the signals with respect to the increments from a common sample of the initial stream in correlation.
2. Apparatus according to claim 1 further including: means, coupled to said dividing means, for receiving and for treating one of the quotient streams for hemoglobin concentration; and means, coupled to said hemoglobin treating means, for receiving and examining the treated quotient stream to determine the hemoglobin concentration of each sequential increment thereof and for providing a signal responsive to such determination; said recording means being additionally coupled to said hemoglobin concentration determining means for receiving the respective signals therefrom and for recording such signals in correlation with the other signals as aforesaid.
3. Apparatus according to claim 2 further including: means, coupled to said dividing means, for receiving and for treating one of the quotient streams for white blood cell counting; and means, coupled to said white blood cell counting treating means, for receiving and examining the treated quotient stream to determine the White blood cell count of each sequential increment thereof and for providing a signal responsive to such determination; said recording means being additionally coupled to said white blood cell count determining means for receiving the respective signals therefrom and for recording such signals in correlation with the other signals a aforesaid.
4. Apparatus according to claim 1 further including: means for receiving signals respectively responsive to the hematocrit and the red blood cell count of the respective sequential increments from a common sample of the initial stream, for providing an additional signal responsive to the ratio thereof which is responsive to the mean corpuscular volume; said recording means being additionally coupled to said mean corpuscular volume signal providing means for receiving the respective signals therefrom and for recording such signals in correlation with the other signals as aforesaid.
5. Apparatus according to claim 2 further including: means for receiving signals respectively responsive to the hemoglobin and the red cell count of the respective sequential increments from a common sample of the initial stream, for providing an additional signal responsive to the ratio thereof which is responsive to the mean corpuscular hemoglobin; said recording means being additionally coupled to said mean corpuscular hemoglobin signal providing means for receiving the respective signals therefrom and for recording such signals in correlation with the other signals as aforesaid.
6. Apparatus according to claim 2 further including: means for receiving signals respectively responsive to the hemoglobin and the hematocrit of the respective sequential increments from a common sample of the initial stream, for providing an additional signal responsive to the ratio thereof Which is responsive to the mean corpuscular hemoglobin concentration; said recording means being additionally coupled to said mean corpuscular hemoglobin concentration signal providing means for receiving the respective signals therefrom and for recording such signals in correlation with the other signals as aforesaid.
7. Apparatus for the analysis of a plurality of blood samples with respect to a given number of characteristics of blood, said apparatus comprising: supply means for providing the blood samples sequentially to form an initial stream of sequential samples wherein each sample is in sequence with the preceding and succeeding samples; dividing means coupled to said supply means for receiving the initial stream of sequential samples and for dividing such initial stream into a plurality, equal to the given number of characteristics, of quotient streams, each sequential increment in each of such quotient streams being a fractional portion of a respective sequential sample in the initial stream; means coupled to said dividing means, for receiving and for treating one of the quotient streams for hemoglobin concentration; means coupled to said hemoglobin concentration treating means, for receiving and examining the treated quotient stream to determine the hemoglobin concentration of each sequential increment thereof and for providing a signal responsive to such determination; means, coupled to said dividing means, for receiving and for treating one of the quotient streams for hematocrit analysis; means, coupled to said hematocrit treating means, for receiving and examining the treated quotient stream to determine the hematocrit of each sequential increment thereof and for providing a signal responsive to such determination; and recording means coupled to said hemoglobin concentration determining means and to said hematocrit determining means for receiving the respective signals therefrom and for recording the signals with respect to the increments from a common sample of the initial stream in correlation.
8. Apparatus for the analysis of a plurality of blood samples with respect to a given number of characteristics of blood, said apparatus comprising: supply means for providing the blood samples sequentially to form an initial stream of sequential samples wherein each sample is in sequence with the preceding and succeeding samples; dividing means coupled to said supply means for receiving the initial stream of sequential samples and for dividing such initial stream into a plurality, equal to the given 7 number of characteristics, of quotient streams, each sequential increment in each of such quotient streams being a fractional portion of a respective sequential sample in the initial stream; means coupled to said dividing means, for receiving and for treating one of the quotient streams for hematocrit analysis; means, coupled to said hematocrit treating means, for initially in phase receiving and examining the treated quotient stream to determine the hematocrit of each sequential increment thereof and for providing a signal responsive to such determination; means coupled to said dividing means, for receiving and for treating one of the quotient streams for red blood cell counting; means coupled to said red blood cell counting treating means, for secondly in phase receiving and examining the treated quotient stream to determine the red blood cell count of each sequential increment thereof and for providing a signal responsive to such determina tion; means, coupled to said dividing means, for receiving and for treating one of the quotient streams for hemoglobin concentration analysis; means, coupled to said hemoglobin treating means for thirdly in phase receiving and examining the treated quotient stream to determine the hemoglobin concentration of each sequential increment thereof and for providing a signal responsive to such determination; first means coupled to said hemoglobin determining mean-s, and said red cell count determining means, for receiving the respective signals therefrom with respect to the increments from a common sample of the initial stream and for providing a signal responsive to the ratio of these signals; second means coupled to said hematocrit determining means and said red cell count determining means, for receiving the respective signals therefrom with respect to the increments from a common sample of the initial stream and for providing a signal responsive to the ratio of these signals; third means coupled to said hemoglobin determining means and said hematocrit determining means for receiving the respective signals therefrom with respect to the increments from a common sample of the initial stream and for providing a signal responsive to the ratio of these signals; means, coupled to said dividing means, for receiving and for treating one of the quotient streams for white blood cell counting; means coupled to said white blood cell counting treating means for fourthly in phase receiving and examining the treated quotient stream to determine the white blood cell count of each sequential increment thereof and for providing a signal responsive to such determination; said red cell examining means and said white cell examining means having at least a flow cell in common through which the respective treated quotient streams pass for counting, and valve means for alternatively coupling said flow cell to said red cell treating means and to said White cell treating means; and recording means coupled to said seven signal providing means in the order first mentioned for recording the respective signals with respect to the increments from a common sample of the initial stream in correlation.
10 References Cited UNITED STATES PATENTS 2/1963 Jones et al. 3/1966 Skeggs et a1 23--230XR MORRIS O. WOLK, Primary Examiner.
R. M. REESE, Assistant Examiner.
US. Cl. X.R.

Claims (1)

1. APPARATUS FOR THE ANALYSIS OF A PLURALITY OF BLOOD SAMPLES WITH RESPECT TO A GIVEN NUMBER OF CHARACTERISTICS OF BLOOD, SAID APPARATUS COMPRISING: SUPPLY MEANS FOR PROVIDING THE BLOOD SAMPLES SEQUENTIALLY TO FORM AN INITIAL STREAM OF SEQUENTIAL SAMPLES WHEREIN EACH SAMPLE IS IN SEQUENCE WITH THE PRECEDING AND SUCCEEDING SAMPLES; DIVIDING MEANS COUPLED TO SAID SUPPLY MEANS FOR RECEIVING THE INITIAL STREAM OF SEQUENTIAL SAMPLES AND FOR DIVIDING SUCH INITIAL STREAM INTO A PLURALITY, EQUAL TO THE GIVEN NUMBER OF CHARACTERISTICS, OF QUOTIENT STREAMS, EACH SEQUENTIAL INCREMENT IN EACH OF SUCH QUOTIENT STREAMS BEING A FRACTIONAL PORTIONOF A RESPECTIVE SEQUENTIAL SAMPLE IN THE INITIAL STREAM; MEANS COUPLED TO SAID DIVIDING MEANS, FOR RECEIVING AND FOR TREATING ONE OF THE QUOTIENT STREAMS FOR RED BLOOD CELL COUNTING; MENAS COUPLED TO SAID RED BLOOD CELL COUNTING TREATING MEANS, FOR RECEIVING AND EXAMINING THE TREATED QUOTIENT STREAM TO DETERMINE THE RED BLOOD CELL COUNT OF EACH SEQUENTIAL INCREMENT THEREOF AND FOR PROVIDING A SIGNAL RESPONSIVE TO SUCH DETERMINATION; MEANS, COUPLED TO SAID DIVIDING MEANS, FOR RECEIVING AND FOR TREATING ONE OF THE QUOTIENT STREAMS FOR HEMATOCRIT ANALYSIS; MEANS COUPLED TO SAID HEMATOCRIT TREATING MEANS, FOR RECEIVING AND EXAMINING THE TREATED QUOTIENT STREAM TO DETERMINE THE HEMATOCRIT OF EACH SEQUENTIAL INCREMENT THEREOF AND FOR PROVIDING A SIGNAL RESPONSIVE TO SUCH DETERMINATION; AND RECORDING MEANS COUPLED TO SAID RED BLOOD CELL COUNT DETERMINING MEANS AND TO SAID HEMATOCRIT DETERMINING MEANS FOR RECEIVING THE RESPECTIVE SIGNALS THEREFROM AND FOR RECORDING THE SIGNALS WITH RESPEECT TO THE INCREMENTS FROM A COMMON SAMPLE OF THE INITIAL STREAM IN CORRELATION.
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US3635680A (en) * 1969-09-22 1972-01-18 Technicon Corp Automatic method and apparatus for the sequential typing of blood samples
US3663175A (en) * 1970-10-05 1972-05-16 Bio Dynamics Inc Method of determining hemoglobin in blood
FR2113336A5 (en) * 1970-10-30 1972-06-23 Mount Sinai Research Fou
US3948605A (en) * 1974-08-22 1976-04-06 The Perkin-Elmer Corporation Diluter for a kinetic analysis apparatus
US3948607A (en) * 1974-08-22 1976-04-06 The Perkin-Elmer Corporation Transfer system for use in analysis apparatus
US4000973A (en) * 1974-09-09 1977-01-04 Beckman Instruments, Inc. Sample residue cleaning system for biological analyzers
US4000974A (en) * 1974-09-09 1977-01-04 Beckman Instruments, Inc. Sample residue cleaning system for biological analyzers
US4022575A (en) * 1974-09-16 1977-05-10 Block Engineering, Inc. Automatic chemical analyzer
DE2740570A1 (en) * 1976-09-15 1978-03-16 Bifok Ab AUTOMATIC ANALYSIS OF ALKALINE METALS, HALOGENIDES AND THE LIKE THROUGH THE USE OF ION-SELECTIVE ELECTRODES
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US4097237A (en) * 1977-03-04 1978-06-27 Technicon Instruments Corporation Determination of cells in blood
US4243883A (en) * 1979-01-19 1981-01-06 Midwest Cardiovascular Institute Foundation Blood hematocrit monitoring system
US4798803A (en) * 1985-07-10 1989-01-17 The Dow Chemical Company Method for titration flow injection analysis
US5139956A (en) * 1986-09-02 1992-08-18 Fiatron-Eppendorf, Inc. Method and system for determining peroxide content
EP2690446A1 (en) * 2012-07-26 2014-01-29 Mettler-Toledo AG Sample divider
CN103575586A (en) * 2012-07-26 2014-02-12 梅特勒-托利多公开股份有限公司 Sample divider
US9194770B2 (en) 2012-07-26 2015-11-24 Mettler-Toledo Ag Sample splitter
CN103575586B (en) * 2012-07-26 2018-11-30 梅特勒-托莱多有限公司 Sample splitter

Also Published As

Publication number Publication date
SE340190B (en) 1971-11-08
DE1673146A1 (en) 1972-02-24
DE1673146B2 (en) 1974-07-11
CH475558A (en) 1969-07-15
BE701133A (en) 1968-01-10
JPS512839B1 (en) 1976-01-29
FR1529316A (en) 1968-06-14
GB1192192A (en) 1970-05-20
DE1673146C3 (en) 1975-02-27

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