Liver function testing apparatus

A liver function testing apparatus measures n-times the values .DELTA.logT.sub.1 and .DELTA.logT.sub.2 corresponding to pulse wave signals obtained upon passage through a prescribed optical path in vital tissue. A sensor (30) having first and second light sources (3, 4) and a light receiving element (6) is attached to a testee (5) before injection of a specific dye. A value .alpha..sub.0 is calculated by using a statistical computation with two variables as to n .DELTA.logT.sub.1 and .DELTA.logT.sub.2 on the basis of an equation of .DELTA.logT.sub.1 =.alpha..sub.0..DELTA.logT.sub.2..DELTA.logT.sub.1 and .DELTA.logT.sub.2 corresponding to pulse wave signals are measured in response to intensity levels of first light and second light passing through the vital tissue during a prescribed time following an injection on the basis of decision outputs representing levels of the first light and the second light from the light sources after the specific dye is injected. A value Cg corresponding to a specific dye concentration in the blood is calculated from .alpha..sub.0 , .DELTA.logT.sub.1 and .DELTA.logT.sub.2. A simulation curve as a function of time changes of the result of the measurements is calculated by the application of the least squares method, thereby to obtain a blood plasma disappearance rate K and a T-minute retention rate R % of the specific dye on the basis of the simulation curve.

FIELD OF THE INVENTION 
The present invention relates to a liver function testing apparatus. More 
specifically, the invention relates to a liver function testing apparatus 
for automatically performing measurements for testing and diagnosing the 
function of a liver by injecting a specific dye, which is selectively 
taken in and removed only by the liver. The dye is injected into a 
person's blood and a blood plasma disappearance rate and a plasma 
retention rate are measured. 
BACKGROUND INFORMATION 
In general, the blood plasma disappearance rate and the retention rate have 
been measured by a known method of blood sampling through use of 
indocyanine green (hereinafter referred to as ICG) serving as a specific 
dye. 
According to said known method, a tester intravenously injects ICG into an 
elbow vein of a person to be tested. Blood samples are taken from the 
testee three times after 5, 10 and 15 minutes have elapsed counted from 
the injection. Upon coagulation of blood clots in the blood samples, the 
blood serum is separated and the absorbance is measured at a wavelength of 
805 nm by a spectrophotometer to obtain ICG concentration values in the 
blood serum after 5, 10 and 15 minutes have elapsed. The measured values 
are compared to a previously obtained calibration curve plotted as the ICG 
concentration in the blood as a function of the absorbance. The blood 
plasma disappearance rate and the retention rate are calculated from 
changes of the concentration values. ICG is dissolved in a physiological 
salt solution or the like. The repeated taking of blood samples subjects 
the patient to mental and physical burdens which are undesirable. Japanese 
Patent Publication Gazette No. 58649/1985 discloses a method of applying 
light through the body surface of an organism and measuring quantities of 
light of a wavelength having a high ICG absorption sensitivity and that of 
a wavelength substantially having no such a sensitivity, whereby the blood 
plasma disappearance rate and the retention rate are obtained from changes 
occurring with the passage of time as shown in a dye disappearance curve, 
without performing blood sampling. 
An R.sub.MAX measuring method for evaluating the blood plasma disappearance 
rate requires performing measurements several times with changes in the 
ICG dosages. Such a method has been widely employed in recent years, even 
though blood samples must be taken ten or more times, which further 
increase the burdens on the testee. 
In the aforementioned method of performing measurements without blood 
sampling, which is disclosed in Japanese Patent Publication Gazette No. 
58649/1985 or Japanese Patent Laying-Open Gazette No. 162934/1986, the 
output of a sensor actually attached to an organism, fluctuates due to 
such influences as a blood flow disturbance caused by compressing a blood 
vessel, vibration of the organism, which is the object of measurement, 
pulsation in the organism, changes of the blood volume in the organism, 
and the like. The blood volume is changed, for example, by merely 
vertically moving an arm. As a result, a correct dye disappearance curve 
cannot be obtained. Thus, the blood plasma disappearance rate and the 
retention rate obtained by the curve cannot be recognized as being 
correct. 
Further, there is disclosed a method of measuring the ICG concentration in 
blood by employing the widths between peaks of changes in the quantities 
of light beams of two wavelengths caused by pulse waves through an optical 
blood measuring apparatus described in Japanese Patent Laying-Open Gazette 
No. 128387/1975 or an oximeter described in Japanese Patent Laying-Open 
Gazette No. 88778/1978 as another method of performing measurements 
without blood sampling. However, such widths of changes in the light 
quantities cannot be correctly measured due to vibration of the organism, 
etc., and it has been impossible to obtain a correct dye disappearance 
curve. 
SUMMARY OF THE INVENTION 
Accordingly, it is a principal object of the present invention to provide a 
liver function testing apparatus which remains uninfluenced by such 
factors, as blood flow disturbance, vibration of an organism, pulsation in 
the organism and changes of the blood volume in the organism caused while 
a sensor is attached to the organism, to enable a correct measurement. 
Briefly stated, a sensor comprising light sources and a light receiving 
element, is attached to a testee before the testee receives an injection 
of a specific dye. The sensor measures values .DELTA.log T.sub.1 and 
.DELTA.log T.sub.2 corresponding to pulse wave signals obtained when the 
testee's blood passes through a prescribed optical path in the vital 
tissue to which the sensor is attached. The measurements are made n-times. 
Prior to a dye injection a value .alpha..sub.0 is calculated by 
statistical computation using two variables, namely n values of .DELTA.log 
T.sub.1 and n values of .DELTA.log T.sub.2 and further using the following 
operation expression: 
EQU .DELTA.log T.sub.1 =.alpha..sub.0..DELTA.log T.sub.2 .fwdarw..alpha..sub.0 
=.DELTA.log T.sub.1 /.DELTA.log T.sub.2. 
The computations are made in response to decision outputs of levels of 
respective light beams emitted by the light sources. The values .DELTA.log 
T.sub.1 and .DELTA.log T.sub.2 corresponding to the pulse wave signals are 
measured on the basis of light intensity levels of first light and second 
light reflected by the vital tissue. The measurements are made during a 
time span beginning when the injection is completed and ending when a 
prescribed length of time after the specific dye injection has elapsed. A 
value Cg corresponding to a specific dye concentration in the blood, is 
derived or calculated from .alpha..sub.0, .DELTA.log T.sub.1 and 
.DELTA.log T.sub.2. Additionally, a function or a simulation curve 
representing calculation results changing with time is calculated by the 
least squares method for fitting output calculation results of a blood 
plasma disappearance rate K and a T-minute retention rate R % of the 
specific dye to the simulation curve or function. 
According to the present invention, therefore, the time management of a 
correct specific dye disappearance curve becomes possible, whereby correct 
data can be obtained. Further, the blood plasma disappearance rate K and 
the T-minute retention rate R % can be obtained, not from several samples 
taken according to the conventional blood sampling method, but from a 
large number of plasma disappearance curve data, thereby improving the 
reliability of the data. In addition, the present method can be further 
simplified as compared with the conventional testing method of obtaining 
the blood plasma disappearance rate K and the T-minute retention rate R %, 
by performing the measurements three times with changes of the ICG 
dosages. Further, the problematic influences such as blood flow 
disturbance, vibration of an organism, pulsation in the organism and 
changes of the blood volume in the organism caused upon attachment of a 
sensor to the organism, can be avoided to enable a correct measurement. 
Thus, the present invention is effectively applicable to the general field 
of measuring a dye in an organism without any invasion of the organism for 
taking blood samples. 
In a preferred embodiment of the present invention .DELTA.log T.sub.1 and 
.DELTA.log T.sub.2 are measured n times as operation values Cg(T), 
assuming that .DELTA.log T.sub.1 and .DELTA.log T.sub.2 represent values 
corresponding to pulse wave signals of intensity levels of a first light 
and a second light passing through a prescribed optical path in a vital 
tissue, and that a value .alpha.(t) is evaluated as n.times.2 by a 
statistical computation with two variables according to .DELTA.log T.sub.1 
=.alpha.(t). .DELTA.log T.sub.2, to obtain 
Cg(t)=.beta.(.alpha.(t)-.alpha..sub.0) wherein B is a constant. 
In the preferred embodiment, further, the function Cg of the calculated 
simulation curve is: 
EQU Cg=A.e.sup.Bt 
where 
Cg: the calculated value 
t: elapsed time (min.) after injection of the specific dye 
A, B: constants 
The blood plasma disappearance rate K and the T-minute retention rate R % 
are obtained from: 
EQU K=-B 
EQU R %=e.sup.Bt 
assuming that the elapsed time after injection, which characteristically 
expresses intake of the specific dye in the liver, is T expressed in 
minutes. 
These and other objects, features, aspects and advantages of the present 
invention will become more apparent from the following detailed 
description of the present invention when taken in conjunction with the 
accompanying drawings.

DESCRIPTION OF THE PREFERRED EMBODIMENT 
FIG. 2 illustrates incident light I.sub.in which is applied to vital tissue 
and transmitted light I.sub.t, FIG. 3 illustrates changes in the quantity 
of transmitted light corresponding to a pulse wave, and FIG. 4 illustrates 
changes of .DELTA.log T.sub.1 and .DELTA.log T.sub.2 expressed on x and y 
coordinates. 
With reference to FIGS. 2 to 4, the principle of the present invention will 
now be described. When incident light I.sub.in is applied to an organism 
as shown in FIG. 2, the absorbance A is expressed as log I.sub.t 
/I.sub.in, assuming that It represents the quantity of transmitted light. 
The organism is formed by a tissue layer and a blood layer as shown in 
FIG. 2, and the blood layer is formed by an arterial layer and a venous 
layer. The thickness of the arterial layer is changed by .DELTA.D in 
response to pulsation (pulse wave) caused by the heart. The quantity 
I.sub.t of the transmitted light varies with this change. Therefore, the 
absorbance A is similarly changed by .DELTA.A. Hence, 
EQU .DELTA.A=.DELTA.log I.sub.t (1) 
Assuming that .DELTA.A.sub.1 and .DELTA.A.sub.2 represent changes of 
absorption quantities caused by pulse waves of a wavelength .lambda..sub.1 
largely absorbed by a specific dye and an unabsorbed wavelength 
.lambda..sub.2, .DELTA.A.sub.1 and .DELTA.A.sub.2 are expressed as: (after 
dye injection) 
EQU .DELTA.A.sub.1 =(E.sub..beta..sup.1.C.sub..beta. 
+E.sub.g.sup.1.c.sub.g)..DELTA.D and (2) 
EQU .DELTA.A.sub.2 =E.sub..beta..sup.2.C.sub..beta...DELTA.D, (3), 
where 
E.sub..beta..sup.1 : is the absorption coefficient of blood at light 
wavelength .lambda..sub.1, 
E.sub..beta..sup.2 : is the absorption coefficient of blood at light 
wavelength .lambda..sub.2, 
E.sub.g.sup.1 : is the absorption coefficient of ICG at light wavelength 
.lambda..sub.1 
C.sub..beta. : is the blood concentration 
C.sub.g : is the specific dye concentration, and 
.DELTA.D : is the change in thickness of the blood layer. 
However, before dye injection the addend in equation (2) is zero. 
Therefore, equation (2) may be expressed as follows: 
EQU .DELTA.A.sub.1 =E.sub..beta..sup.1.C.sub..beta...DELTA.D. (4) 
Additionally, the degree of oxygen saturation during testing of the blood 
is assumed to be constant. Therefore, and because the above defined value 
.alpha..sub.0 correslates .DELTA.A.sub.1 and .DELTA.A.sub.2 we can write 
equation (5) 
EQU E.sub..beta..sup.1.C.sub..beta...DELTA.D=.alpha..sub.0 
(E.sub..beta..sup.2.C.sub..beta...DELTA.D) (5) 
based on equations (3) and (4). Solving equation (5) for .alpha..sub.0 or 
E.sub..beta..sup.1 we obtain: 
##EQU1## 
Inserting equation (6) into equation (4), we obtain for 
EQU .DELTA.A.sub.1 =.alpha..sub.0 E.sub..beta..sup.3 C.sub..beta...DELTA.D (7). 
According to equation (3) the factor 
E.sub..beta..sup.2.C.sub..beta...DELTA.D equals .DELTA.A.sub.2. Hence, 
inserting .DELTA.A.sub.2 into equation (7), we obtain, before dye 
injection: 
EQU .DELTA.A.sub.1 =.alpha..sub.0 .DELTA.A.sub.2 (8). 
After dye injection, the addend of equation (2) must be added to equation 
(8), thus: 
EQU .DELTA.A.sub.1 =.alpha..sub.0 .DELTA.A.sub.2 +E.sub.g.sup.1.Cg..DELTA.D 
(9). 
Dividing both sides of equation (9) by .DELTA.A.sub.2, having regard to 
equation (3), we obtain: 
##EQU2## 
Solving equation (10) for Cg, we obtain: 
##EQU3## 
Since E.sub..beta..sup.1 and E.sub.g.sup.1 in equation (11) are known 
physical values, and C.sub..beta. is assumed to be constant, the 
expression E.sub..beta..sup.2 C.sub..beta. /E.sub.g.sup.1 is also a 
constant value which is the above mentioned .beta.. 
Hence, the specific dye concentration C.sub.g in the blood can be 
calculated by obtaining .DELTA.A.sub.1 /.DELTA.A.sub.2 after injection of 
the specific dye. 
Assuming that T.sub.1 and T.sub.2 represent quantities of transmitted light 
having the wavelength .lambda..sub.1 and the wavelength .lambda..sub.2 
respectively, while .DELTA.T.sub.1 and .DELTA.T.sub.2 represent changes 
thereof caused by .DELTA.D, the following equations result from the 
expression (1) for .alpha..sub.0 and .alpha.: 
EQU .alpha..sub.0 =.DELTA.log T.sub.1 /.DELTA.log T.sub.2 =, prior to dye 
injection, (12) 
EQU and .alpha.=.DELTA.A.sub.1 /.DELTA.A.sub.2 =.DELTA.log T.sub.1 
(i)/.DELTA.log T.sub.2 (i), after dye injection (13), 
as will be explained in more detail below. 
Hence, the expression (8) is solved to obtain .alpha..sub.0 before 
injection of the specific dye and the expression (13) is solved to obtain 
.alpha. after injection of the specific dye. Cg is calculated from the 
expression (11). In the oximeter described in the aforementioned Japanese 
Patent Laying-Open Gazette No. 88778/1978 etc., the difference between 
peaks of changes in quantity of light corresponding to a pulse wave, has 
been regarded as .DELTA.log T.sub.1, as shown in FIG. 3. However, this 
method can only prepare a sample corresponding to the cardiac cycle, and 
the above .DELTA.log T.sub.1 has been obtained by performing the 
measurement several times and averaging the results in the actual 
circumstances. 
According to the present invention, the difference between the peaks of 
curves c and d in FIG. 4 is not obtained, rather .DELTA.log T.sub.1 is 
plotted on the y-axis and .DELTA.log T.sub.2 is plotted on the x-axis as 
shown in FIG. 4. Curve "c" represents values obtained through a light 
sensor element 6 prior to dye injection. Curve "d" represents values 
obtained through light sensor element 6 after dye injection. Changes in 
the measured values are as shown in FIG. 4, whereby a straight line "a" 
has an inclination .alpha..sub.0 before injection of the specific dye. 
.alpha..sub.0 is used in the above expression (6). Then, when the specific 
dye has been injected, the absorbance of .lambda..sub.1 is changed as 
shown by the pulse waveform d and the inclination is changed as 
represented by a straight line b having an inclination 
.alpha.=.DELTA.A.sub.1 /.DELTA.A.sub.2 as shown in the above expression 
(6). 
Hence, inclination .alpha.(t) can be accurately calculated by increasing 
the number of measurement samples of .DELTA.log T.sub.1 and .DELTA.log 
T.sub.2 for understanding the concentration changes of the specific dye at 
a high speed without depending on the cardiac cycle. 
A testing apparatus for operating according to this method, will now be 
described. 
FIG. 1 is a schematic block diagram showing an embodiment of the present 
invention. Referring to FIG. 1, a liver function testing apparatus 
comprises a sensor section 30 and a measurement processing section 31. The 
sensor section 30 includes a first light source 3, a second light source 4 
and a light receiving sensor element 6. The first light source 3 generates 
optical pulses of the wavelength .lambda..sub.1 having a large absorbance 
with respect to the specific dye. The second light source 4 generates 
optical pulses of the wavelength .lambda..sub.2 having no such absorbance. 
The light receiving sensor element 6 receives light beams, which are 
applied by the light sources 3 and 4 to vital tissue 5 to pass through a 
prescribed optical path. The light sources 3 and 4 are controlled by a 
timing circuit 2 on the basis of a command from a CPU 1 which is provided 
in the measurement processing section 31, to alternately generate the 
light beams in a pulse operation. 
The CPU 1 included in the measurement processing section 31 serves as 
arithmetic means. As hereinabove described, the CPU 1 supplies prescribed 
pulses to the light sources 3 and 4 through the timing circuit 2. The 
light beams emitted by the first and second light sources 3 and 4 pass 
through the prescribed optical path in the vital tissue 5 to be incident 
upon the light receiving sensor element 6. A current generated from the 
light receiving sensor element 6 is subjected to a current-voltage 
conversion and amplified by an amplifier 7. The amplified signal is 
supplied to a logarithmic converter 8 for a logarithmic conversion, and 
supplied to a sample-and-hold circuit 9, for separating the signals in 
accordance with the wavelengths .lambda..sub.1 and .lambda..sub.2 The 
separated respective signals of the wavelengths .lambda..sub.1 and 
.lambda..sub.2 are supplied to high-pass filters 10 and 11. These signals 
include pulse wave components and blood volume changes such as those in 
the venous blood represented by large fluctuating or undulating components 
log T.sub.1, log T.sub.2 shown in FIG. 7. Therefore, the high-pass filters 
10 and 11 remove these undulating components to output only pulsating 
components, which in turn are supplied to an A-D converter 14 through 
amplifiers 12 and 13. The amplifiers 12 and 13 are so controlled that the 
amplification factors thereof are changed in response to control signals 
from the CPU 1. The A-D converter 14 converts the inputted signals into 
digital signals and supplies the same to the CPU 1. The CPU 1 stores the 
digital signals in a RAM 16. 
The CPU 1 is connected with a ROM 15, the RAM 16, a display section 17, a 
printing section 18 and a manipulation section 19. The ROM 15 stores 
programs based on flow charts shown in FIGS. 5 and 6 as hereinafter 
described. The manipulation section 19 includes a start key 20 and a print 
key 21. The start key 20 is adapted to command starting of a measurement 
mode, and the print key 21 is adapted to supply a command for printing out 
test results in the printing section 18. 
FIGS. 5 and 6 are flow charts for illustrating an actual operation of the 
embodiment of the present invention, FIG. 7 is a waveform diagram showing 
voltages corresponding to pulse waves, and FIG. 8 illustrates an exemplary 
ICG disappearance curve obtained when ICG is used as the specific dye. 
With reference to FIGS. 1 and 5 to 8, an actual operation of the embodiment 
of the present invention will now be described whereby ICG is used as the 
specific dye. At a step SP1 shown in FIG. 5, power is applied to the 
apparatus and then the light quantities are adjusted. That is, the CPU 1 
supplies a command to the timing circuit 2 for adjusting the driving 
currents for the light sources 3 and 4 respectively, while adjusting the 
light receiving element 6 so that its output reaches a prescribed level. 
Light beams emitted by the light sources 3 and 4 pass through a prescribed 
optical path in the vital tissue 5 to be incident upon the light receiving 
element 6, and a current generated by the light receiving element 6 is 
subjected to a current-voltage conversion and amplified by the amplifier 
7, to provide an output V.sub.PD shown in FIG. 7. This signal is supplied 
to the logarithmic converter 8 for a logarithmic conversion, and separated 
into signals of the waveforms .lambda..sub.1 and .lambda..sub.2 by the 
sample-and-hold circuit 9. These signals are expressed as log T.sub.1 and 
log T.sub.2 in FIG. 7 respectively. These signals contain components 
caused by pulse waves and by blood volume changes such as those in venous 
blood etc. These components fluctuate or undulate substantially and the 
fluctuations are removed by the high-pass filters 10 and 11 so that only 
pulsating components such as .DELTA.log T.sub.1 and .DELTA.log T.sub.2 
shown in FIG. 7 are extracted. 
At a step SP2, the CPU 1 controls the amplification factors of the 
amplifiers 12 and 13 for amplifying the signals until the widths between 
peaks of the pulse wave corresponding voltages of .DELTA.log T.sub.1 and 
.DELTA.log T.sub.2 shown in FIG. 7 reach certain levels. Then, the CPU 1 
calculates .alpha..sub.0 at a step SP3 using the above relationship 
.alpha..sub.0 =.DELTA.log T.sub.1 /.DELTA.log T.sub.2 prior to a dye 
injection. 
Then, the CPU 1 displays an indication such as "inject ICG", for example, 
on the display section 17 at a step SP4. Thus, the operator prepares to 
inject ICG into the vein of the organism, and turns on the start key 20 of 
the manipulation section 19 simultaneously with the ICG injection. 
After the dye injection has been completed, CPU 1 also calculates .alpha. 
by sampling the signals of .DELTA.log T.sub.1 and .DELTA.log T.sub.2 
n-times at a step SP31 as shown in FIG. 6 and by then performing a 
regression analysis as to i=1 to n by using 2.times.n data in a 
calculation of .alpha. from .DELTA.log T.sub.1 (i)=.alpha...DELTA.log 
T.sub.2 (i) at a step SP32. The calculated value of .alpha. is then stored 
in the RAM 16 in the same way as .alpha..sub.0. 
During step SP5 the CPU 1 waits for the operation of the start key 20. When 
the start key has been operated the CPU 1 calculates the T-minute ICG 
concentration Cg in the blood at step SP6. More specifically, .alpha. at a 
certain time t following a dye injection is evaluated in accordance with 
the aforementioned flow chart shown in FIG. 6, thereby to obtain Cg from 
the above expression (11), supposing that .alpha. is .DELTA.A.sub.1 
/.DELTA.A.sub.2. The data of Cg provide an ICG disappearance curve as 
shown in FIG. 8, for example, and within the data, constants A and B are 
evaluated in accordance with the least squares method with a simulation 
curve of: 
EQU Cg(I)=Ae.sup.Bt 
EQU t=T.sub.S /(n-1) (min.) 
with respect to data between times T.sub.1 and T.sub.2 (0&lt;T.sub.1 &lt;T.sub.2 
&lt;T), whereby T.sub.s =T.sub.2 -T.sub.1. 
Then, the CPU 1 calculates a blood plasma disappearance rate K=-B and a 
T-minute retention rate R %=e.sup.Bt at a step SP7, to evaluate K and R. 
Then, the CPU 1 displays the disappearance curve shown in FIG. 8 and the 
values K and R on the display section 17, and outputs the same to the 
printing section 18 to print out the same at a step SP8. 
The present invention can be also applied to an apparatus for measuring 
R.sub.MAX by evaluating/calculating values K of various ICG dosages. 
According to the present invention, as hereinabove described, optical 
pulses of a wavelength largely absorbed by a specific dye and optical 
pulses of a wavelength not absorbed by the same, are applied to vital 
tissue at prescribed levels to detect optical pulses passing through a 
prescribed optical path in the vital tissue, and after the specific dye is 
injected on the basis of the outputs, a blood plasma disappearance rate 
and a retention rate of the specific dye are obtained on the basis of 
light receiving outputs from the injection during a prescribed lapse of 
time in accordance with a prescribed equation. Thus, time management of a 
correct specific dye disappearance curve is enabled and correct data are 
obtained. 
Further, the blood plasma disappearance rate and the retention rate are 
obtained without taking any blood samples as are used by the conventional 
blood sampling method, rather the invention uses a large number of 
disappearance curve data, whereby the reliability of the data is improved. 
In addition, the present method of measurement can be further simplified as 
compared with the conventional testing method of obtaining the blood 
plasma disappearance rate and the retention rate by performing the 
measurements several times with changes in the ICG dosages. 
Further, problematic or undesirable influences such as blood flow 
disturbances, vibration of an organism, pulsation in the organism and 
changes of the blood volume in the organism caused by the attachment of a 
sensor to the organism, are eliminated for obtaining correct measurements. 
Thus, the present invention is effectively applicable to the general field 
of measuring a dye in an organism without any invasion of the organism. 
The present invention is applicable not only to a liver function testing 
apparatus but to an apparatus, such as a pulse oximeter, for example, for 
measuring changes in the concentration of a dye in an organism through 
pulse waves. 
Although the present invention has been described and illustrated in 
detail, it is clearly understood that the same is by way of illustration 
and example only and is not to be taken by way of limitation, the spirit 
and scope of the present invention being limited only by the terms of the 
appended claims.