U.S. patent number 3,848,580 [Application Number 05/206,812] was granted by the patent office on 1974-11-19 for apparatus for controlled selective separation of undesirable constituents from blood to achieve a therapeutic effect.
Invention is credited to Fritz Victor Hasselblad, Viktor Holger Hyden.
United States Patent |
3,848,580 |
Hyden , et al. |
November 19, 1974 |
APPARATUS FOR CONTROLLED SELECTIVE SEPARATION OF UNDESIRABLE
CONSTITUENTS FROM BLOOD TO ACHIEVE A THERAPEUTIC EFFECT
Abstract
Apparatus for controlled selective separation of undesirable
constituents from blood for therapeutic purposes including a device
having a plurality of active surfaces for separating predetermined
constituents of the blood, a measuring cell having a light source
at one end and a light detector at the other end to determine
concentration of substances in the blood after filtering, a
pressure control device, a sampling device and an alarm system
responsive to predetermined value levels of pressure and
concentration.
Inventors: |
Hyden; Viktor Holger (Goteborg,
SW), Hasselblad; Fritz Victor (Goteborg,
SW) |
Family
ID: |
20302742 |
Appl.
No.: |
05/206,812 |
Filed: |
December 10, 1971 |
Foreign Application Priority Data
|
|
|
|
|
Dec 11, 1970 [SW] |
|
|
16781/70 |
|
Current U.S.
Class: |
600/310; 600/573;
356/40 |
Current CPC
Class: |
A61M
1/3609 (20140204); G01N 33/491 (20130101); A61M
1/367 (20130101); G01N 21/85 (20130101); A61M
2202/0433 (20130101) |
Current International
Class: |
A61M
1/36 (20060101); G01N 33/49 (20060101); G01N
21/85 (20060101); A61b 005/00 () |
Field of
Search: |
;128/2G,2E,2L,2P,2R,2.5D,2.5E,2.5F,2.5R,2.1E,2.1R,214B,214C
;356/39-41 ;73/422TC,423R |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Kamm; William E.
Attorney, Agent or Firm: Sherman & Shalloway
Claims
We claim:
1. Therapeutic apparatus for controlled selective separation of
constituents of blood flowing from a donor comprising a passage
adapted to have blood flow therethrough a device communicating with
said passage including a plurality of active surface means
positioned to be contacted by the said flowing blood for separating
predetermined constituents of the blood, and detection means
communicating with the passage and said device for measuring
characteristics of the flowing blood and for emitting a signal in
response to a predetermined value of each such measured
characteristic whereby the occurrence of an abnormality in or
completion of said selective separation can be detected.
2. The therapeutic apparatus as recited in claim 1 wherein said
detection means includes conduit means forming a measuring cell and
having filter means defining a boundary of said cell to separate
blood plasma, a light source in said cell and a light detector in
said cell responsive to light directed from said light source
through the blood to provide an electrical signal corresponding to
the concentration of free haemoglobin in the blood and output means
for communicating, said electrical signal to an alarm means whereby
the occurrence of an abnormality in or completion of said selective
separation can be detected.
3. The therapeutic apparatus as recited in claim 2 wherein said
conduit means includes a conduit arranged parallel to said cell,
and said filter means includes a first filter disposed at an inlet
for said cell from said conduit and a second filter disposed at an
outlet from said cell to said conduit downstream from said first
filter.
4. The therapeutic apparatus as recited in claim 3 wherein said
conduit means includes a throttling obstruction in said conduit
adjacent said second filter to cause blood flow from said inlet to
said outlet through said measuring cell.
5. The therapeutic apparatus as recited in claim 2 wherein said
conduit means includes a conduit for through flow of blood past
said measuring cell, and said measuring cell includes an inlet
communicating with said conduit through said filter means and an
outlet for communicating with a pressure lower than the pressure of
blood in said conduit.
6. The therapeutic apparatus as recited in claim 2 wherein said
detection means includes alarm means responsive to an electrical
signal from said light detector to provide an alarm when the
concentration of the free haemoglobin is above a predetermined
value.
7. The therapeutic apparatus as recited in claim 6 wherein said
detection means includes pressure sensing means for supplying an
electrical signal to said alarm means to provide an alarm when the
pressure of blood in said conduit means drops below a predetermined
value.
8. The therapeutic apparatus as recited in claim 7 wherein said
detection means includes sampling apparatus including a conduit
having a plurality of apertures therein and a plurality of sample
cylinders sealably received in said apertures.
9. The therapeutic apparatus as recited in claim 1 wherein said
detection means includes sampling apparatus including a conduit
having a plurality of apertures therein and a plurality of sample
cylinders sealably received in said apertures.
10. The therapeutic apparatus as recited in claim 1 wherein said
detection means includes pressure sensing means for providing an
alarm when the pressure of blood in said passage drops below a
predetermined value.
Description
The present invention relates to an apparatus for selectively
separating amino acids and proteins from blood according to the
Swedish Pat. No. 320,155. The invention, more precisely, relates to
an improvement of such separating apparatus in, that it is provided
with control means operating to indicate directly and/or,
indirectly the manner in which the separation of the undesirable
substance or substances proceeds and to indicate by alarm when
sideeffects occur.
The construction of the control means allows control not only for
the original application of the separating apparatus, i.e., for the
separation of amino acids and defined proteins, but also for the
separation of, for example, free haemoglobin, antibodies and
antigens, thus widening the application of such separating
apparatus.
The control means comprises a sampling part, which is connected in
series with the separating apparatus and includes removable samples
of the active surface utilized in the apparatus, and a spectrometer
connected in series with the separating apparatus and filled with
blood serum subsequent to the separation of the red corpuscles by a
suitable filter means. The blood serum may then in known manner be
examined with respect to the presence of, for example, free
haemoglobin. The spectrometer operates intermittently in order to
preserve the current source and is controlled by an electronic
coupling device including an alarm device, which provides an alarm
when the presence of the substance to be separated falls below a
predetermined concentration, or when the presence of a detrimental
substance approaches a critical value.
The separating apparatus to the Swedish Pat. No. 320,155 comprises
in principle a closed system through which the blood of the patient
passes. During the treatment, the apparatus is connected into a
by-pass conduit between a vein and an artery. The internal part of
the apparatus which during the treatment is filled with blood, is
provided with special surfaces, which have been made active so as
to render possible a selective separation of amino acids and
defined proteins. The active surface may be an integrated portion
of the apparatus, for example the interior of a hose, or it may be
a special insert, mounted exchangeably in the apparatus.
Carriers of the active substances, as mentioned in said
specification, includes prepared collagen as well as polymers and
copolymers. The active substance, which is an enzyme specific for
the separation in question, and heparine are fixed on the carrier
by known methods. The object of the heparine is to render the blood
non-thrombogenous. The amino acid or defined protein to be
separated from the blood is degraded enzymatically upon contact of
the blood with the active surface.
According to later discoveries, special qualities of glass may also
be used as carriers for the active substances. The possibility of
applying a material which s inorganic, deformation resistant,
resistant to ageing and chemically inactive, such as glass,
provides a considerable advantage.
It was subsequently found that substances other than enzymes can be
fixed on the aforementioned carriers and that these substances are
adapted for selectively separating other undesirable substances in
the blood. In these cases the enzymatic degradation is replaced by
catching the substance in question. As examples of the latter type
of active substances are antibodies for catching corresponding
antigens and, vice versa, antigens for catching corresponding
antibodies.
It is possible to fix three different types of active substances on
the aforedescribed carriers, in addition to the heparine which is
fixed on the carriers in all cases. The three types are as
follows.
A. enzymes for selectively separating amino acids and defined
proteins.
B. antigens for selectively separating corresponding
antibodies.
C. antibodies for selectively separating corresponding
antigens.
Selective separation according to A above is the original
application field of known separating apparatus. This field has
been widened substantially by the introduction of the methods
according to B and C above. It can be assumed that by future
research it will be possible to fix in a similar way other
biologically active substances. Thereby the range of application of
the known apparatus will be widened still more.
The diseases to which the apparatus will be applied in order to
selectively separate undesirable constituents from the blood of the
patient and thereby to achieve a therapeutical effect, are
exemplified below in a concise manner, reference being made to A-C
above.
Enzymatic degradation of amino acids and defined proteins according
to A above is applied to the treatment of tumors, the growth of
which requires normal concentration in the blood of a specific
amino acid or of several such amino acids.
The utilization of antigens for selectively catching and thereby
separating corresponding antibodies according to B above can be
applied within a very wide range as shown by examples below.
For autoimmune diseases in general, the tolerance to one's own
cellbound antigens is lost. A special clone of immunopotent cells
can then be activated and form antibodies to antigens having been
released from tissues and cells by disease processes or damage. In
all these cases, separation and catching of antibodies is extremely
valuable, particularly when the antibody titre is high, as in the
case of panencephalitis after measles and for a high antibody titre
against cow milk in children, which causes lung complications and
intestinal bleeding with resulting loss of iron.
For allergic diseases a high antibody titre in the blood is found,
for example for allergies caused by organic threshing dust and the
like, in which case a separation of the antibodies according to B
above is of value.
A further field of particular interest which also is associated
with B above, and for which the apparatus according to the
invention is of great importance, is the reduction of the risk of
rejection for transplanted organs. The apparatus is applied in such
cases in principle as follows.
Prior to the transplantation, antigen from the donor's tissues
and/or organs is prepared in such a manner that the antigen is
fixed on the active surface of the apparatus. Subsequent to the
transplantation of the organ to the receiver, the apparatus is
connected to the receiver's blood channel in the aforedescribed way
where it removes antibodies formed by the receiver against the
foreign antigens of the transplanted organ. The apparatus may
remain connected as long as there is a risk that the organ in
question is rejected.
Antibodies according to C above for catching and separating
antigens can be utilized in cases where antibodies and antigens
form a free antibody-antigen complex in the blood. Such
antibody-antigen complexes are present in the blood of patients
suffering from lupus erytematodes and serum nephrites and can bring
about severe disturbances and, therefore, their removal is of
value.
Haemolysis, which means that free haemoglobin and/or its
derivatives subsequent to reaction is present in the blood and may
damage internal organs, occurs when antibodies are formed against
special blood groups and further as a side-effect at dialysis with
a so-called artificial kidney. Free haemoglobin can be caught from
the blood when its amboceptor, haptoglobin, is insolubilized on the
active surface in the separating apparatus.
The known separating apparatus includes a manometer for controlling
the blood pressure, but it does not include any control and
inspection means for the selective separation. The absence of such
equipment is a substantial shortcoming. The need of control has two
aspects: Firstly, it is desirable to observe the selective
separation as a functin of the treatment time and, secondly, it is
desirable, for safety reasons, to be able to interrupt the
treatment if and when the blood includes any constituent indicating
that the treatment has brought about detrimental side-effects or if
the apparatus is clogged by coagulated blood. The selective
separation as well as the possible occurrence of detrimental
side-effects take place after smoothly proceeding without points of
sudden changes. There is, therefore, no need of continuous
indication and/or registration during the process of the treatment.
It is, however, of great interest to obtain a series of point by
point values at time intervals adjusted to the separation in
question.
According to the invention, therefore, necessary control means are
provided on or after the separating apparatus which now covers a
wider application range including selective separation according to
B and C above. The control means of the present invention comprises
a photometer with associated electronic circuits and a plurality of
small sample plates of the same kind as the active surface of the
apparatus, which plates are inserted into a correspondingly
adjusted sampling part from which they can be removed one by one.
The photometer, the sampling part and the apparatus for selective
separation are connected in series in such a manner that the
sampling part is to be placed on the pressure side of the treating
part.
The photometer operates in accordance with known principles, the
blood plasma, being passed through a measuring cell, at the ends of
which are provided a lamp and a light-sensitive means, for example
a photo resistor. For restricting the light to the wave length
range in question, for example to that of haemoglobin or its
degradation products, a filter adjusted thereto is placed in the
path of rays. The circuits associated with the photometer are
described below. For effecting blood plasma to flow through the
measuring cell, the red corpuscles in the blood must be prevented
from flowing into the measuring cell. For this reason, filters are
mounted before the inlet and outlet of the measuring cell, the pore
size of the filters being selected such that only the plasma
portion of the blood can pass therethrough. The measuring cell is
arranged as a by-pass to the conduit for the blood flowing through
the apparatus. A throttling placed in the photometer portion
through which blood flows causes a pressure difference between the
openings of the measuring cell, thereby delivering the desired flow
of blood plasma through the cell.
The blood enters the photometer at a pressure of about 100 mm Hg
when it has been taken from an artery. The corresponding pressure
in a vein is lower, but of the same order of magnitude, so that the
difference in pressure between the inlet and outlet of the
apparatus is of a moderate size. The pressure difference between
the inlet and outlet of the photometer, due to the throttling,
therefore amounts only to a few mm Hg. This is a small difference
when considering the resistance in the filters for the red
corpuscles, but it nevertheless is sufficient when good filters
with a low flow resistance are chosen. An alternative embodiment of
the photometer, however, with a substantially higher pressure
difference has been provided for. For the alternative embodiment,
the throttling and the outlet from the measuring cell to the blood
stream passing therethrough are abolished, and another similar
outlet is provided in the measuring cell. From the outlet, the
blood plasma having passed through the measuring cell flows either
back to the patient via a separate connection or flows to a
collecting vessel without counterpressure. If the plasma is desired
to flow back to the patient, which may be necessary for a treatment
of long duration, the separate connection preferably is connected
to a vein with low pressure, whereby the desired higher pressure
difference is obtained. In cases with a relatively short treatment
time, the small plasma quantity flowing through the photometer can
be neglected and, consequently, the separate return line to the
patient can be abolished.
The photometer described above renders it possible to measure the
presence of colored compounds in the blood plasma, among which free
haemoglobin and its degradation products are of greatest interest.
When it is desired, on the other hand, to measure the presence of,
for example, a water-soluble uncolored amino acid the photometer
described above cannot be applied. Provision is, therefore, made to
replace for this purpose the photometer by a fluorescence
photometer of a kind known per se, for which the supply of blood
and blood plasma is arranged in the same manner as with the
aforedescribed photometer.
On the outlet side of the photometer a pressure control device is
placed to signal when the pressure in the blood stream falls below
a critical value, which may be caused, for example, by coagulated
blood clogging the photometer. The pressure control device
comprises a movable spring-loaded piston actuated by the pressure
in the conduit and via a pressure rod actuating a switch connected
to the electronic circuits of the photometer.
The electronic circuits for the photometer and pressure control
device are applications of conventional coupling principles. For
rendering the apparatus according to the invention easy to move and
independent of mains supply, a separate current source, for example
a battery, is provided for operating the circuits. The current
source can be chosen relatively small, in view of the fact that it
is used for intermittent measuring.
The measuring principle of the photometer is as follows. A pulsator
comprising a multivibrator emits a pulse in the form of a square
wave, for example one pulse every third minute with a duration of
about half a second. This pulse is supplied directly to a
discriminator, viz. one and, in a more or less attenuated form, to
the discriminator via the photometer. The discriminator compares
the amplitudes of the two signal portions of the pulse. The
difference in amplitude is a measure of the occurrence of that
substance in the blood to which the measurement in question is
directed. The discriminator is coupled such as to actuate an alarm
device of optical and/or acoustic type, either when the
concentration of the substance in question reaches a pre-determined
highest level or when the concentration falls below a
pre-determined lowest level. When the photometer, for example, is
intended to measure the content of free haemoglobin in the blood,
the first mentioned alternative is used for signalling the
occurrence of haemolysis, and the second alternative is used for
signalling at the selective separation of free haemoglobin when the
treatment can be finished. The alarm device actuated by the
discriminator further is connected with the pressure control device
in such a manner that an alarm is given provided when the blood
pressure in the conduit falls below a predetermined safety value.
The different circuits and their construction relative to one
another are described in greater detail below by way of an example
of their application.
The sampling part for examining the active, selectively separating
surface of the apparatus comprises in principle a relatively
thick-walled portion of the through conduit for the blood stream,
in which portion are arranged a plurality of pull-out plugs
containing samples of the active surface in question stored in the
blood stream. By pulling out such a plug a certain distance, but
not entirely so as to cause leakage, the sample stored within the
plug or a break-away portion thereof becomes accessible and can be
removed for analysis. Only a moderate number of such samples of the
active surface, normally about three to five samples, are required.
Samples taken out at intervals of one or some hours provide
sufficient reference points for controlling the way the separation
proceeds.
An embodiment of the invention is described below in greater
detail, with reference to the accompanying drawings, in which
FIG. 1 is a schematic and perspective view of the invention,
FIG. 2a is a longitudinal section through a photometer and a
pressure control device, FIG. 2b is a longitudinal section through
a variant of the photometer shown in FIG. 2a,
FIG. 3a is a longitudinal section through a sampling part for the
active surface of the apparatus,
FIG. 3b is on an enlarged elevation of a sample plug for the
sampling part according to FIG. 3a, seen in the blood flow
direction, and
FIG. 4 is a block diagram of the electronic circuitry of the
apparatus.
The apparatus according to the invention, FIG. 1, comprises a
treatment part 1 known per se for selectively separating
undesirable constituents from the blood. The treatment part is
connected in series with a photometer 2, a pressure control device
3 and a sampling part 4 including samples on the selectively
separating surface. For the sake of clarity, the control and
inspection means 2, 3 and 4 are shown in FIG. 1 on a scale
exaggerated relative to the treatment part 1. Blood flows through
apparatus by means of a by-pass conduit placed between two blood
vessels of a patient having sufficient pressure difference
therebetween. The flow direction through the apparatus is per se of
no importance, but the pressure control device 3 is to be placed
for safety reasons after the photometer 2 such that the blood, as
shown in the embodiment according to FIG. 1, enters the apparatus
through an inlet 5 and leaves it through an outlet 6.
The treatment part 1, FIG. 1, includes a known active surface 43
for the selective separation, for example in the form of a set of
glass plates arranged in parallel with and somewhat spaced from
each other so that the plane of the glass plate set is located in
the flow direction. On the glass plates the active substances are
fixed in a known manner. The selective separation takes place
either as an enzymatic degradation or as a catching of the
undesirable constituent or constituents in the blood upon its
contact with the active surface.
Blood plasma flows through measuring cell 7 of the photometer 2,
FIG. 2a, after having been separated from the blood stream 8
flowing through the apparatus by a filter means 9 with prevents the
red corpuscles from passing therethrough. The blood plasma leaves
the measuring cell 7 through a second filter means 10, the object
of which is to prevent red corpuscles from entering the measuring
cell 7 downstream. For practical reasons, the filter means 9, 10
are manufactured in one piece, as shown in FIG. 2a. For obtaining
the desired flow of blood plasma through the measuring cell 7, a
throttling or bulge 11 is provided in the through blood stream 8
thereby producing a pressure difference above the measuring cell 7.
In those cases when the pressure difference above the measuring
cell 7 is too small for maintaining a sufficient blood plasma flow
through the measuring cell, an alternative embodiment of the
photometer 2 (FIG. 2b) is utilized. In this embodiment, the filter
10 and throttling or bulge 11 (FIG. 2a) are replaced by a separate
outlet opening 12 (FIG. 2b) which is covered by a filter and opens
either into the open air or into a blood vessel with a pressure
lower than that prevailing in the blood vessel in which the blood
is returned to the patient.
The measuring cell 7 of the photometer 2 (FIGS. 2a and 2b) is
provided on one side with a lamp 13 behind a window 14, and on the
opposite side with a light-sensitive means, for example a
photoresistor or photocell 15 behind an exchangeable light filter
16. The wave length of light filter 16 is adjusted to the substance
to be measured in the blood plasma, for example free haemoglobin.
The lamp 13 and photoresistor 15 are connected to electronic
circuits of the apparatus which are described below.
The pressure control device 3 (FIG. 2a) is arranged as a side pipe
18 to the conduit for the blood stream 8. Within side pipe 18 is
placed a piston 17 actuated by the blood pressure and provided with
an associated sealing ring 19. Piston 17 includes a cone 20 adapted
to project out through the free end of the pipe 18 which inwardly
is provided with a shoulder 21. Between piston 17 and shoulder 21
are arranged a compression spring 22 and a washer 23 resting
against the shoulder 21. The cone 20 controls a pressure switch 24
mounted on the side pipe 18 and connected to an electronic alarm
circuit of the apparatus. The length of cone 20 is chosen such that
the pressure switch 24 is kept open as long as the blood pressure
on the piston 17 compresses the spring 22 so much that it reaches
outside of the side pipe 18. When the blood pressure falls below
the pre-determined safety value, the cone 20 disengages from the
pressure switch, which thereby closes the circuit and provides an
alarm.
The electronic circuits of the apparatus are applications of
circuits known per se. In the block diagram (FIG. 4) a power
source, for example a battery 25, feeds the circuits. A pulse
generator 26 comprising a multivibrator emits at suitable
intervals, for example three minutes, a signal of short duration,
for example half a second. The signal is of square wave shape and
is supplied along two paths one unattenuated and one attenuated, to
a discriminator 27. The signal from the pulse generator 26 is
supplied first to an electronic gate 28 where it is divided such
that one portion lights the lamp 13 of the photometer and one
portion is supplied to a delay unit 29. Delay unit 29 has as its
object to delay the unattenuated portion of the signal prior to
supply to the discriminator 27 so much, that the lamp 13 is given
the necessary time for lighting up and assuming a stable intensity,
which takes milliseconds. The lamp 13 emits a beam 42 through the
measuring cell 7. The photocell 15 thereby assumes a resistance
corresponding to the light intensity received. The signal from the
photocell 15 is supplied to the discriminator 27 in an attenuated
state, dependent on the concentration of the substance in the blood
plasma to be measured by the photometer 2. A second electronic
measuring gate 30, which passes the unattenuated signal on its way
from the delay unit 29 to the discriminator 27, also emits a
measuring impulse to the measuring circuit of the photocell 15 in
such a manner that the discriminator 27 receives the unattenuated
and the attenuated signals at the same time. The discriminator 27
compares the difference in amplitude between the two signals, which
difference is a measure of the concentration of the substance in
the blood plasma to be measured by the photometer 2. The difference
in amplitude is transferred as a signal to an alarm gate 31. When
the amplitude difference is too great or alternatively too small in
relation to a present value depending on whether the apparatus is
set for providing an alarm when the concentration of the substance
in question in the blood plasma has exceeded a preset safety value
or when it has fallen to a preset minimum value at which the
treatment can be finished, alarm gate 31 emits an impulse to an
alarm device 32. Alarm device 32, which may be optical and/or
acoustic, is thereby activated. If the critical amplitude
difference has not been reached, the discriminator 27 does not emit
a signal and, therefore, no alarm will be given. To alarm gate 31
further is connected the pressure control device 3 in such a manner
that the alarm device 32 is activated when the blood pressure falls
to a value at which the pressure switch 24 closes.
The sampling part 4 (FIG. 3a) comprises in principle a plurality of
sample plugs 33 inserted into a thickened portion 34 of the conduit
for the blood stream. For each of sample plugs 33 a softly rounded
hollow or cup 35 is provided in the conduit for the blood stream 8.
The sample plugs 33 (FIGS. 3a and 3b) are fitted into holes with
sealing rings 36 located directly opposite hollow or cup 35 in the
conduit for the blood stream 8. In the sample plugs, which are of
cylindric shape and provided with handle portions 37 (FIG. 3b),
apertures 38 are arranged on the same level as the conduit for the
blood stream 8 apertures 38 are lined with a plastic lining 39, for
example a plastic hose piece. Samples 40 of the same quality as the
plates 43 with active surface disposed in the treatment part 1 are
inserted into apertures 38 and retained there by a slight pressure
of the slightly deformed lining 39. At their insertion, the sample
plugs 33 are oriented such that the apertures 38 extend in parallel
with the conduit for the blood stream 8, whereby the blood flows
all around the samples 40. The orientation is facilitated by arrows
41 on the upper surface of the handle portions 37 (FIG. 1), but may
also be guided positively, for example by a dog (not shown) on the
handle portion 37 which is fitted into corresponding recesses made
in the seats of the plugs in the conduit. For sampling, the sample
plugs 33 are pulled out carefully (see the center plug in FIG. 3a)
such a distance that the aperture 38 is exposed, whereafter the
sample 40 is taken out to be analyzed. The empty sample plug may
then suitably remain in its pulled-out position and thereby
indicate its empty state. A stop member (not shown) is provided to
prevent the sample plugs from unintentionally being pulled out
entirely. Such a stop member may, for example, be a detachable
protective yoke placed at a suitable height above the handle
portions 37.
* * * * *