US 3848580 A
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.
Beschreibung (OCR-Text kann Fehler enthalten)
United States Patent 1191 ydn et'al.
APPARATUS FOR CONTROLLED SELECTIVE SEPARATION OF UNDESIRABLE CONSTITUENTS FROM BLOOD TO ACHIEVE A THERAPEUTIC EFFECT Inventors: Viktor I-Iolger Hyde'n,
Prastgardsgatan 2; Fritz Victor Hasselblad, Box 220, both of Goteborg, Sweden Filed: Dec. 10, 1971 Appl. No.: 206,812
Foreign Application Priority Data Dec. 11, 1970 Sweden 16781/70 US. Cl. 128/2 F, 73/422 TC, 128/2 G, 128/2 L, 356/40 Int. Cl A6lb 5/00 Field of Search 128/2 G, 2 E, 2 L, 2 P,
128/2 R, 2.05 D, 2.05 E, 2.05 F, 2.05 R, 2.1 E, 2.] R, 214 B, 214 C, 214 E; 356/39-41; 73/422 TC, 423 R Primary ExaminerWilliam E. Kamm Attorney, Agent, or Firm-Sherman & Shalloway [5 7 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.
10 Claims, 6 Drawing Figures PATENTEL MW 1 91974 3; 848 580 SHEET 10F 2 Fig. 2b
APPARATUS FOR CONTROLLED SELECTIVE SEPARATION OF UNDESIRABLE CONSTITUENTS FROM BLOOD TO ACHIEVE A THERAPEUTIC EFFECT 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 sidceffects 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 5 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 ones 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 donors 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 receivers 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 socalled 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 function 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 bypass 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 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 thereofbecomes 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 I 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 I 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 outletopening 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 l3 behind a window 14, and on the opposite side with a lightsensitive 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 l3 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 predetermined 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 l3 emits a beam 42 through the measuring cell 7. The photocell 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. 30) 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.
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 secondfilter to cause blood flow from said inlet tosaidoutlet 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.