JP2786271B2 - Protective device against diseases related to blood, especially thrombosis, embolism, bleeding, blood disease and the presence of abnormalities in blood - Google Patents

Description

The present invention relates to a method for automatically analyzing the biological and chemical composition of blood and / or circulatory factors of blood, and detecting abnormalities when abnormalities are found. The present invention relates to a device and an analytical method which can be selectively treated in humans and other mammals, and an analytical method, and a processing method used therefor.

In particular, the present invention relates to an implant device for preventing blood-related disorders.

Prior art Conventional methods of preventing thrombosis, arterial embolism and venous embolism are not very effective, costly and often have side effects.

Traditionally, thrombosis prevention measures are based on medical treatment, especially when a certain amount of a chemical or biochemical anticoagulant is used during a prolonged period of hemostasis or during a surgical recovery procedure.
In addition, when thrombosis and embolism suddenly occur, a thrombolytic agent such as streptokinase, urokinase, a derivative thereof, tissue plasminogen activator (TPA) and a derivative thereof is preferably used immediately at the site, preferably at a blood coagulation site. This is done when the drug is administered in the vicinity.

This endovascular treatment must be performed as quickly as possible in order to reduce the required dose of the drug and to be more efficient in preparation for the risk of bleeding.

SUMMARY OF THE INVENTION One object of the present invention is to provide a device for protecting against thrombosis, embolism and atheromatous or infectious stenosis (constriction) of blood vessels and vascular lumens, in particular of the arteries of the myocardium or brain. Is to provide.

Another object of the present invention is to suppress vascular bleeding due to blood coagulation disorders, excessive hypertension, or abnormal permeability of small blood vessels and capillaries.

Yet another object of the present invention is to selectively monitor certain compounds present in blood vessels and chemical, biochemical and ionic molecules to enable early detection and early treatment. At the same time, to count blood cells and monitor blood composition to continuously manage blood disorders, including those that occur spontaneously.

It is still another object of the present invention to provide a method for examining the presence or absence of a certain cancer and treating the same by monitoring the change in the concentration of a predetermined existing molecule or the appearance of a new molecule. is there.

It is yet another object of the present invention to protect against air, water and food contamination by automatically monitoring molecules in blood and bone marrow resulting from contaminant compounds, hematopoietic agents, blood cell counts and blood composition analysis. It is in.

In addition, the present invention has improved and completed the heart protection device that is the subject of the French Zacouto patent (patent application No. 2,082,703) and its additional US patent applications 3,857,399 and 4,052,991. Things.

SUMMARY OF THE INVENTION One object of the present invention is to provide an immediate, rapid, efficient and selective treatment of pre-existing or developing thrombosis and vascular embolism. So that there is in the protection device.

Another subject of the present invention is that if physiological pathological changes due to blood development occur for several days, preventative measures can be taken promptly and automatically, if necessary, and The prevention device has a low risk of side effects.

Yet another object of the present invention is to provide thrombosis of an artery, especially a coronary artery and a carotid artery or a cerebral artery, at an early stage, especially during the progression stage of pulmonary thrombosis or embolism, preferably in the body. Therefore, the present invention is directed to a device capable of treating and preventing the occurrence of thrombosis. This device is
In particular, reocclusion after an aortic annular bypass of the intima of the annular artery, carotid artery or cerebral artery or after angioplasty can be prevented.

Yet another subject of the invention is a debilitating coagulation disorder (CIV
D) to provide a protective device.

Yet another subject of the invention is such a device that prevents bleeding and adjusts treatment with anticoagulants in response to spontaneous changes in blood development.

The protection device of the present invention for the above-mentioned blood disease comprises: (1) a permanent or periodic measurement of at least one biochemical parameter which is or is likely to be accompanied by a blood disease or the occurrence of a blood disease; An implanting means, (2) an implanting means for determining one or more threshold values to be compared with the measured parameter values, and (3) an alert outside the patient's body in response to exceeding said threshold value. Automatically transmit signals and / or thrombolytics, anticoagulants, vasodilators, beta-blockers,
Transplant means for administering a suitable amount of one or more therapeutic agents such as diuretics, calcium suppressants and / or prostaglandins IG2 and PG12 and / or clotting factors into the circulation.

The above measurement parameters are general parameters, that is,
Factors that change relatively quickly after the onset of thrombosis (eg, coronary, carotid or cerebral artery thrombosis) or embolism (eg, pulmonary embolism) or general circulatory disease, embolism, thrombosis, It is a parameter related to general factors that appear as a result of bleeding or hematological disorders. The above general parameters include, for example, blood clotting ability, the occurrence of arterial hypertension or hypotension, furthermore, catecholamines, hypoxia, hypercapnia, ionic imbalance and pH and excess milky granules, glucose, creatinine, There are factors that affect the state of the circulatory system, such as blood volume.

Furthermore, the respiratory rhythm and amplitude can be detected according to known methods, in particular by measuring the electrical impedance of the chest.

The device according to the invention can be modified to detect general parameters at any point in the circulatory system,
It is desirable to place the measuring device in the heart cavity, which is particularly disturbed or in need of consultation, or in the blood vessels, lymphatic vessels, bones or immediately adjacent to the blood vessels of the heart.

According to another aspect of the invention, the measurement parameter may be a local parameter and the measurement means is located near or in the affected blood or lymph vessel or branch. These parameters reflect, for example, local abnormalities resulting from the imminent onset or onset of embolism or thrombosis in the monitored area. These parameters are
For example, ionic concentrations or concentrations of other components related to tissue ischemia, or electrical abnormalities, including the generation, propagation or absorption of naturally or artificially measurable currents associated with the fear or onset of such ischemia, Alternatively, other parameters that reflect the effects of ischemia in the tissue, such as tissue hypoxia, changes in myocardial sound, slight changes in local temperature, and increased transaminases.

In addition, to detect electrical parameters relating to rhythm disorders that cause a decrease in the flow of the heart and coronary arteries, in particular cardiac rhythm disorders such as atrial fibrillation, ventricular premature contraction or ventricular tachycardia, rapid heartbeat due to ventricular fibrillation. Alternatively, an electrocardiogram measurement can be used. Means for detecting such faults are described, for example, in Zacoto, U.S. Pat. No. 3,857,399. U.S. Pat. No. 4,052,991 also discloses that in addition to the automatic electrotherapy described above, anticoagulants and / or fibrinolytics are administered to cause thrombosis, which often causes rhythm disorders or exacerbates them. The risk of the disease can be reduced or eliminated.

However, the device according to the invention can be carried out in a direct or indirect detection method, for example, by controlling the properties of perfusion, such as peak, average or minimum velocity, flow rate, geometric deformation, active perfusion or vasoconstriction pressure. It is desirable to have sensitive detection and measurement means for sensing. Desirable parameters are
The electrical impedance representing these features, but other parameters such as pressure, geometric deformation, flow measurements, light absorption (spectroscopy), resonance frequency for arterial dendrites, arterial pulse wave Speed and the like can also be used.

For the prevention of embolism, it is desirable to measure local parameters that lead to an imminent or onset of blood clotting, for example, in particularly suitable arteries, such as the atria or ventricular cavities.

The device according to the invention is a means for grasping the rhythms associated with hemodynamics, in particular the rhythm of the heart and the rhythm of the respiration, such as electrocardiograms, changes in electrical impedance, volume curves,
It is desirable to have a voice curve, a mechanical curve and the like at the same time. This detection method determines and interprets periodically changing parameter measurements (eg, impedance, pressure, geometric deformation or light absorption) and analyzes the measurement results according to the detected cardiovascular cycle. It can be used to modify thresholds or suppress functions.

In a preferred embodiment, the device of the invention is provided with means capable of measuring the electrical, acoustic or optical impedance or conductivity at one or more critical areas of the blood vessel to be protected.

Further, an endoscopic type having a known type of quartz fiber having a predetermined viewing angle capable of changing its direction in or at the end of the blood circulation system or outside the blood circulation system (for example, into the bone marrow of the sternum). It is also possible to install an optical device and transmit the color image to a small image analyzer. In this miniature image analyzer, the images are analyzed, digitized, commanded,
Stored in memory. The entire device can be contained, for example, in an implant housing containing other means of the device according to the invention. The detected image is compared with a typical image of a blood cell or a cell having an abnormal shape, content or number stored in a memory, for example, by a known electronic comparison means, and externally transmitted as necessary by high-frequency transmission. Is transmitted to This device, for example, activates an external alarm with a high frequency to notify that an abnormal image has been recognized. Also,
If the dosage is programmed for this purpose, the appropriate amount of the appropriate drug is automatically administered. Puncture samples can be made by percutaneous needle and optical irrigation by irrigation according to known methods.

The electrical impedance measurement can be performed simultaneously at at least two different frequencies to improve the accuracy of the measurement and make the selected changes in the conductivity of the tissue or liquid environment under examination more appropriate. Devices for impedance measurement by means of transmission frequency adjustment over at least one frequency variation range, or over a plurality of frequency ranges, use the same transmission and reception electrodes or, for example, limit several electrodes, especially geometrical aspects It can be operated with electrodes arranged on two geometric axes. In the above geometric plane, it is desirable that the axes are perpendicular to each other so as to determine the impedance vector of this plane. In addition, to obtain a three-dimensional vectorogram of impedance, it is desirable to perform the measurements simultaneously on an axis located outside the plane, preferably perpendicular to the plane. The measurement current can be transmitted, for example, as a scan pulse at a frequency that is simultaneous or delayed from one measurement axis to another.

A time delay of a predetermined portion of the electrical impedance spectrum can also be used.

These means include electrodes placed around the blood vessel to be protected, e.g., the coronary artery, or in the blood vessel, especially in the atria or arteries, which are connected to the means for receiving electricity during the electrical impedance measurement. You.

A local electrode for impedance measurement can also be inserted into the myocardium, particularly the tip tissue, septum tissue or wall tissue, to measure the local impedance of the portion of the myocardium monitored by the electrode. The distance between the electrodes may be, for example, several mm.

In this way, the impedance or simultaneously the value of the conductivity can be measured intermittently or continuously.

Furthermore, the maximum difference between the electrical impedances that reflects, for example, changes in blood volume in the blood vessel under examination, or for example, for each cardiac cycle, changes in capillary circulation and / or muscle contraction of the myocardium. You can also.

In addition, for each cardiac cycle, the pattern, shape, peaks, and other characteristics of the resulting impedance curve, including differentiation or integration, can be measured.

The current used for impedance measurement may be, for example, in a very small, fairly homogeneous area. For example, monomeric or polymeric fibrin or fibrin precursors, fibrinogen, fibrinopeptides (mixed or individual), or prothrombin mixed with prothrombinase to test for a propensity to produce thrombin, a fibrin forming factor When measuring impedance for an artificial or artificially derived thin film consisting of At the same time, it is desirable to consider the local accumulation of calcium or magnesium ions relative to the ions measured in the general circulation. To measure the impedance of the blood volume in a coronary artery or heart cavity, a relatively low frequency of, for example, about a few KHz can be used. For example, about 100 kHz to several hundred
It is desirable to use higher frequencies to measure tissue impedance in MHz.

Other biological parameters for arterial or cardiac cavity protection (either individually or in combination with impedance measurements) include changes in the electrocardiogram, especially in either the epicardium or simply in the cavity. Utilizing vector electrocardiographic changes detected at polar positions or by adding bipolar electrodes, preferably at a suitable set of electrodes in the space above the catheter for cardiac stimulants in the cavity Can be. In this way, significant and selective changes in the propagation of electrical signals emitted by the heart during polarization and repolarization can be detected.

Instead of or in addition to the aforementioned electrical parameter measurements, oxygen, CO ₂ , CO levels, pH, rH (redox coefficient) and / or sodium, chlorine or phosphorus ions for osmotic pressure measurements Or means for sensing phenomena related to ischemia of the tissue infiltrated by the arterial branch to be protected, in particular an ion change sensor such as potassium ions or H ⁺ in or near said area and / or in or near said area Oxygen level sensor, eg, wavelength
A 660 nm oxyhemoglobin or methemoglobin optical sensor can also be provided [Karl Stangle (Ka
rl Stangl et al., "A New Multisensor Pacing System", Pace, Vol. 11, June, 1988: pages 712-724].

Other documents include photodetectors, eg, red light detectors or hemoglobin in lymphatic vessels that drain lymph into the lymphatic flow path from the body or the cerebrum and / or other colored substances, eg, bilirubin The possibility of internal bleeding can also be detected by arranging another detector responsive to the wavelength absorbed by the device. Furthermore, in addition to the above-mentioned volume determining device which is sensitive to a small amount of hemoglobin in lymphatic vessels, at least one known type optical microcomputer for counting red blood cells or platelets can be added.
The computer makes quantitative measurements of blood flow in the lymph and, if appropriate, determines whether these factors are attributable to the brain. In this way, a tendency to bleed from hypocoagulability or vascular fragility due to poisoning, infection or excessive high arterial pressure is detected and, if necessary, Stuart factor and calcium ions or hypotensive drugs. By administering a recoagulant such as prothrombin so as to be balanced, the treatment is automatically performed. This re-coagulation perfusion is automatically interrupted as soon as a detector of trace blood in the lymph indicates a hemostasis or a blood quality factor meter indicates a tendency to onset of hypercoagulability.

It is also possible to detect intramyocardial or intramuscular hemorrhage using selective photodetectors that distinguish hemoglobin and its derivatives and myoglobin. Such an optical cell, for example, an endoscope type cell with quartz fiber, allows for the analysis of local images and the observation of ischemia, and its progress can be monitored at rest and operating positions. This cell can be located in the intramyocardial portion of the probe connected to the heart stimulator.

By using an optical cell with quartz fibers (eg, placed in a catheter in the right heart cavity), the blood concentration of red blood cells, platelets, or white blood cells, hematocrit that decreases during bleeding, or related or related to bleeding No red blood cell or platelet loss can be measured.

In addition, means can be used that emit light in the appropriate direction by IR or UV to respond to light radiation reflected or absorbed by the blood and / or myocardium or blood vessel walls.
This light may be monochromatic or coherent, and may be continuous light or pulsed light (for example, using a very thin light guide such as a quartz fiber having a diameter of 1 mm or less), and the color of blood or blood at the end of the optical system. Identify the color of the myocardium where it is located. Means with such a fiber are arranged for analyzing the spectrum of light which, for example, individually reflects blood or tissue oxygenation or other metabolic parameters.

As another parameter, deformation of a blood vessel or a heart cavity (for example, using a stress meter), or ultrasonic transit time [for example, Triton Technolog, San Diego, California, USA
y, Inc.) with two crystals 2 mm in diameter-
Using a device such as a sonomicrometer or SL5-2.

One or several piezoelectric sensors can also be used to detect changes in sound or ultrasound propagation or reflection. Alternatively, for example, a change in sound or ultrasound resonance, or sound and / or ultrasound absorption, preferably with respect to the cycle of the heart, may be determined. It is also possible to detect the quality and level of sound produced by the myocardium, hemodynamics and / or heart valves using sensors such as microphones.

According to a variant, such sensors transmit sound or ultrasound into the blood and / or myocardium to detect any general or local malfunctions that may be caused by stenosis, occlusion or excessive arterial hypertension. You can also. According to a variant, the ultrasound waves can be modulated by one or more sound frequencies. At the same time, the modulation of this sound wave can be started in connection with the detected phonogram. Sound waves or ultrasound waves are transmitted with a rapidly changing frequency to scan the programmed spectrum to provide resonance and / or sound of arterial or venous blood clots or myocardium, depending on the location and orientation of the communication pickup. Or it is desirable to detect absorption. The transmission of such sound waves can be permanent or at very short intervals so that the entire cardiac cycle can be scanned. By combining each transmission and reception cycle to produce one or more fixed duration sounds of the heart cycle, the heart cavity,
The transmission and subsequent measurement of the pressure and volume of the vein or artery column or myocardium can also be made at important moments. Specifically, the event of the selected sound wave, for example,
The transmission and measurement can be adjusted according to the closing of the heart valve and the sound associated with the movement of the myocardium.

In addition, transmission and measurement may optionally be, for example,
Measuring the resonance and absorption of arterial or venous blood dendrites, when performed with a sensor transmitter positioned in the cavity by a probe and directed towards the venous or arterial blood dendrites Can also. This provides an immediate indication of blood volume pressure and arterial wall stiffness. For each of the maximal and diastolic blood pressures, there is a corresponding resonance frequency for each task. This allows the device to administer the appropriate amount of drug immediately after detecting, for example, the appearance or reduction of hypertension that may promote thrombosis, embolism or vascular bleeding. Furthermore, by appropriately selecting the measurement time, the position and the orientation of the transmitting sensor, it is also possible to remotely detect and measure any blood volume, especially after contraction or dilated ventricle. As an example, measurements of arterial dendritic resonance can be made with ultrasound or sound transmission sensors located in or near the left ventricular cavity, with a transseptal catheter from the right ventricle.

According to a variant, several frequencies spread over the desired spectrum can be transmitted simultaneously by time scanning at a predetermined sound or ultrasonic frequency, for example by adjusting the amplitude of the higher ultrasonic frequency during transmission. . The previously described acoustic or ultrasonic transmitting and receiving devices can also be placed in peripheral blood vessels, for example, the radial arteries of the arm or wrist. By implanting this device, it is possible to set the corresponding arterial column at the resonance vibration from this peripheral position and detect the spectrum of the sound that can be formed at a location at a predetermined distance from the transmitter. According to a variant of the invention, the measurement of special substances, for example noxious substances, in the blood is achieved by remote control from outside the implanted, programmed or programmable means. The device adjusts measuring means, for example, molecular optics, to be sensitive to the harmful substances. After detecting a toxic compound, such as a toxic compound, for one item of food, its concentration in food, water or air is detected and information is transmitted to the implanted device by remote control so that the device is responsive to this substance. On its return, it informs an external device or user of the concentration of this toxic compound in the body and informs about the resistance to additional introduction of this resonance compound. Still further, for example, radiation or a radioisotope detector can be implanted in the bone marrow.

Another biological parameter in a preferred embodiment is at least one blood quality parameter measured in a blood vessel or lymph vessel, desirably upstream of a ganglion or heart cavity, especially an atrium or ventricle. This is, for example,
The use of one or several sensors of one or several clotting factors or, more generally, the clotting ability of blood or the liquefaction of a clotting agent, for example, due to the tendency to sediment viscous or fibrin. This can be done by measuring the connected parameters. For example, proton bin, plasminogen, prothrombinase, plasmin, fibrinopeptide, protein C, endothelin, serotonin, catecholamine, neuropeptide Y, fibrinogen, plasminogen activator, LACI (lipoprotein-containing anticoagulant, EPI (intrinsic pathway) Inhibitors), the concentration of at least one of the substances such as factor VIII in the blood can be measured.

For this purpose, it is also advantageous to utilize artificial representations of one or several clotting factors or their precursors used in clotting induction tests. This permanent or regular expression is
In particular, it can be carried out in the following manner: (1) the substance is permanently immobilized on an insoluble and immutable substrate in the blood, and the active sites of the factors are brought into contact with the blood, freeing their activity, This can be done by allowing the site to locally attract the corresponding factor in the blood composition. This fixation can be carried out by any known method, for example, adsorption on a substrate with a usual crosslinking agent, for example, usual chemical adhesion with an avidin-biotin type substrate, or the like. As the substrate, a substrate known in the art, for example, a polymer, cellulose acetate, nitrocellulose, or the like can be used. Further, a detection method on the surface of the field effect transistor can be used. In this case, the molecule is immobilized on the surface of the semiconductor, and the molecule is activated to be bound to another molecule reactive with the ion or molecule to be detected. To form a durable membrane [Langmuir Blod film by M. Sugi (Langmuir Blod
dgett films) ", J. of Molec. Electron. 1,3 (1985),
"Ultra-thin organics (Conduct) by A. Barrand
eurs organiques ultraminces) "Clef CEA, 6, 42, 1
987).

(2) For example, slow diffusion through a porous membrane substrate.

(3) Local microperfusion at about a few mm ³ / hour, for example, refilling the subcutaneous storage container every six months.

According to a variant of the invention, at least two biological agents forming equal amounts of the opposite substance in the blood composition can be monitored in this way simultaneously or sequentially. Here, the two factors are, for example, a clotting factor for fibrin formation and / or clot formation and an anticoagulation factor such as a plasmin activator, a plasminogen or a derivative of heparin.
For example, in the case of DIVC (reduced intravascular clotting), diagnosis is possible if thrombin detection is inadequate in relation to reduced fibrinogen levels.

These sensors or analysis means can be implemented, for example, by a catheter. For example, a thin membrane or thin thread of fibrin, deposited on a catheter and in a container, preferably surrounded by a protective grid or stopper, or a porous membrane or filter or on the outer wall of the catheter, or on a small autograft vein segment. Using a tube, the tendency of fibrin to settle can be measured. Such measurements may be made by optical means (eg, sensitive to color and / or molecular absorption and / or fibrin thickness) or other means, eg, depending on the mass of the precipitated fibrin or detectable molecular weight. By measuring different sounds or ultrasound resonances, or by measuring at least one dimension of the fibrin membrane by, for example, A-mode ultrasound diagnosis. In addition, it is possible to measure the electrical impedance, for example the ohmic impedance and / or the absorption of alternating current with a constant or variable frequency, or the absorption of ultrasound via macromolecular resonances associated with coagulation or thrombolysis. The container or relief is V-shaped or tapered to minimize fibrin precipitation and is usually controlled by blood flow and spontaneous fibrinolysis, the dimensions of which depend on blood composition. It can be surrounded by a barrier or lattice to prevent passage of the formed blood clot and diffusion of the fibrin membrane.

By way of example, the device may comprise a short tubular member having a diameter of about 2-3 mm disposed parallel to the side of the catheter on the catheter. The axis of the tubular member is substantially parallel to the catheter so that the blood flow traverses it. The catheter is provided with a sensor for detecting substances such as fibrin or fibrinopeptide, fibrin monomer, prothrombin and prothrombinase, inside or in the cavity of the tubular member. The sensor comprises a first wall integral with the catheter and a thin slit or opening or spacing located between the second wall also integral with the catheter. The distance between these two walls is
For blood of normal blood composition, it can be determined empirically by determining the thickness that causes slight fibrin precipitation. The end of the optical fiber reaches one of these two walls, where it is connected to a light source, and the tip of the second optical fiber reaches the other opposite wall. The two optical fibers return to the catheter, the first fiber reaching the light source, or the second fiber reaching the light sensor. The whole of these walls or reliefs is surrounded by a lattice or stopper to prevent the passage and clumping of the formed blood clot and to prevent the fibrinous components from escaping. In this sensor, for example, around the whole of the two walls,
If necessary, means are provided for injecting a thrombolytic agent that dissolves any fibrin accumulated on the sensor. When a thin precipitate of fibrin or its precursors forms between the two optical fiber ends of the wall, the light transmission changes and the received light intensity decreases. In addition, the color changes,
The means responsive to light reception can determine that a fibrinous membrane has been formed when a predetermined threshold is exceeded.
The device may also be sensitive to the rate or direction of fibrin membrane changes by indicating changes in the light signal over time.

At a point at a predetermined distance from the downstream, or on a single part for indicating the trend, on the catheter and in the tubular member,
It would be advantageous to have a detector for components that promote blood lysis, such as heparin, plasminogen, protein C, protein S, and the like.

Furthermore, particles, microparticles or molecules, in particular substances or factors related to blood composition (some of which have already been described, but in particular soluble fibrin or its precursors, or other proteins, in particular fibrinogen, plasminogen, prothrombin Etc.) can be detected as well as the presence and concentration of the utility present in blood, and even its dimensions. This is performed by means of a microprocessor program, for example a rotating prism or a multiple reflecting prism system, and / or a light source whose wavelength can be changed by means of known optical networks and / or multiple monochromatic or tunable laser sources. be able to. Detection of the absorption spectrum of the molecule to be determined
For example, it can be implemented by micro-thermocouples and / or very sensitive photovoltaic cells and / or field-effect transistors (FETs), or other means that operate with thermistor or operate like a local charge detector. . It is also possible to examine their absorption and interference analysis by detection using a laser or maser. The detection and study of interference allows the transmission frequency to be fixed and determined depending on the factors to be determined.
Alternatively, for example, components such as fibrin or factors or fibrin precursors or thrombin formation can be changed by scanning a range of predetermined frequencies.

In particular, on thin fibrin or thrombin precursors, on the one hand, and on thin, solid or semi-solid membranes of heparin and plasminogen, on the other hand, without performing measurement tests to determine the coagulable and noncoagulable state of blood. Often, procoagulant and / or anticoagulant substances can be measured by their relative liquid concentrations of the substance near the receptor. These receptors are
It may be either a solid containing the insolubilized substance on the substrate or one consisting of the liquid diffusion liquid already described. In this way, induction of fibrin precipitation is prevented and the need for a protective grate or stopper is eliminated. According to a variant, the clotting and anticoagulant factors are attached to the insoluble material on one side of the rod, for example in a small tube, which reduces the flow rate of the local blood circulation, resulting in calcium, magnesium,
Alternatively, the blood composition is automatically evaluated based on the detection ratio of H ⁺ ions in the entire local body.

According to a variant of the invention, an ultrasonic transmitter or other means, a pulsed laser or other laser, can be used to break or move dangerous aggregates formed on the sensor in the protected volume. Such aggregates are broken by the administered fibrinolytic agent.

In addition, spherical aggregates, in particular platelets, can also be used as a parameter, for example by means of a suitable detection means of the optical type.

The means for measuring hemoglobin and / or red blood cells in a volume of a few mm ³ can be used to determine hematocrit and hemoglobin per liter. Such an analysis allows for the detection and monitoring of bleeding, erythrocytosis, and abnormalities in blood volume. Sensors of this type are known and can be miniaturized.

When the measured parameter exceeds a predetermined threshold, the device automatically, regularly or periodically dispenses a reduced amount of fibrinolysis or anticoagulant or antibleeding agent or other into the blood from the implanted pump and container. , For example, dropwise.

Conversely, if the parameter falls below a predetermined threshold during the measurement, administration of the fibrinolytic or anticoagulant is discontinued. The frequency at which the device makes measurements depends on the characteristics of the therapeutic agent and its effect, such as the speed and duration of the effect, its half-life,
In addition, it is adapted to the patient's unique constitution. By way of example, the intervals between successive measurements may range from a fraction of a second to several hours, and the measurements may be continuous or at least intermittent.

Obviously, when the device administers several compounds, for example complementary or antagonistic compounds, or independent compounds, one or several different parameters will be added together with one or several different thresholds corresponding to each detection. May be included.

Particularly preferably, the device comprises one or several pickups capable of measuring at least one, preferably several, of the following parameters:

(1) As the increase in mass corresponds to the tendency of hypercoagulability, whereas the decrease in mass corresponds to the tendency of thrombolysis,
For example, small membranes or clumps of fibrin on a substrate properly placed in the blood circulation, such as in the atrium or ventricle, or changes in small membranes or clumps containing fibrin or one or more of its precursors. Appearance. Whereas existing methods require discontinuous extracorporeal sampling, which is time consuming to interpret, the present invention allows for rapid monitoring of changes in blood composition. Selectively applying a low voltage to the membrane; (2) measuring the concentration of calcium and / or magnesium ions in or immediately adjacent to the membrane or film by a sensor based on a known calcium ion selective membrane; Another sensor can immediately monitor changes in local calcium ion concentration as compared to the total calcium ion concentration measured elsewhere in the blood. This change in calcium ion concentration is related to the degree of coagulation of blood.

For example, the small membrane described above can be supported on a catheter and formed on a surface, such as an etched glass known per se, to which a predetermined negative voltage is applied, which forms a prothrombin that activates the complex. It causes local formation and a tendency to clot.

The value of this negative voltage depends on the time or place, the surface, or the continuum of such a surface. Thus, the measuring means takes into account the value of the voltage corresponding to the fastest precipitation increase.

Optionally, the surface is insolubilized, affecting the formation of fibrin or precursors, or being, for example, a precursor attached by suitable means on a negatively charged surface. Or other factors may be present.

The means for determining the threshold to which the measured values of the parameters are compared allows a human adjustment and preferably an automatic adjustment of the threshold. It is desirable that these means be remotely controlled from outside the organ and visually displayed on an external monitor, such as a remote control device for a heart simulator.

The apparatus includes, in association with the threshold determining means, logic or analogy comparing means, which compares the measured value with a programmed threshold and, if the threshold is exceeded, preferably the pathology of this excess. Alternatively, after obtaining permission from a means for controlling metabolic importance, an appropriate amount of a drug is administered into the circulation.

These dosing means include one or several implanted pumps and reservoirs containing the substance to be administered and capable of administering a programmed amount of the substance through at least one intracardiac or intracorporeal tube. It would be advantageous if.

Determination of the dosage can be made by a physician according to conventional methods, taking into account the usual factors for the selected drug, such as activity, clearance, half-life and the like. For this purpose, the implanted pump is equipped with conventional dose control devices, remote control means, for example, electromagnetic means, which allow the physician to adjust the control by radio control or other means from outside the organ. It is desirable to install.

These means can be connected, for example, to the general blood, vein, or arterial system, or to a local, predetermined vessel, such as the coronary or carotid arteries.

When the present invention is applied to a device for protecting a coronary artery, it is desirable that the tube from the drug container reach into the coronary artery for natural treatment. At this time, the tube is desirably a tube included in or associated with the intracavity catheter. For example, the tube may connect to the coronary artery of interest after traversing the myocardium at its tip and passing through the epicardium. However, it is also possible to administer the substance into another blood vessel or heart cavity, atrium, ventricle or tissue.

Similarly, in such an embodiment, it is preferred that the conductor connected to the coronary impedance measurement electrode pass through the myocardium and desirably join the catheter of the heart stimulator in the right ventricular cavity.

According to an important refinement of the device according to the invention, the device can be provided with means sensitive to the heart and / or pulse period of the arterial system to be monitored. These responsive means control the parameter measuring means and enable measurements at scheduled or known points in the cycle.

According to a particularly preferred aspect of the present invention, the means for responsive to the cardiac cycle comprises, for example, means for responsive to organs of the cardiac cycle. It can also include the origin and propagation of the electrical activation to determine this, thus assessing the pathological or non-pathological properties of this function if the threshold is exceeded, and automatically You can decide whether or not to intervene.

This detection is used to modify the threshold and / or the treatment method according to a predetermined program.

For peripheral arteries, an implanted pulse detector or intra-arterial or peripheral pressure sensor or other known device can be used.

For protection against blood diseases such as leukemia, an optical cell associated with the means for measuring and / or calculating red blood cells provided in the means for analysis of the detected image or the optical end of a fiberscope endoscope can be arranged. . Optical elements for data collection are located, for example, within the lymph ganglia or bone marrow in the sternum. Electrodes in or around the bone can also be used as electrodes for electrocardiography or for measuring changes in electrical impedance.

For protection of the heart and / or coronary arteries of the heart, see, for example, Zact U.S. Pat.
No. 399 and 4,052,991, the duration of at least one preceding cardiac cycle, or several earlier cycles, and more preferably also the quality of propagation of electrical activation. It is particularly beneficial to have a means of responding.

In this way, for example, for an extrasystole, a threshold based on the early onset of the extrasystole and the potential for extrasystole obtained from the mechanical and myocardial metabolic parameters can be automatically modified.

For example, for tachycardia, there is no thrombosis, but reduced amplitude and metabolic changes in mechanical phenomena that would cause a sudden phenomenon of coronary flow, if coronary thrombosis is detected simultaneously by another means With the exception of, it is not considered a justification for administering a given amount of pure thrombolytic or coronary vasodilator.

Further, in an embodiment desirable for the protection of the heart or its coronary arteries, at least one of the electrocardiograms and / or the pressure sensitive and / or the volumetric change of the heart cavity is sensitive to changes in the volume of the heart cavity.
Providing means for data collection of the electrical phenomena of the heart, such as three sensors, and performing measurements at predetermined or known times of the cycle, in particular systolic or diastolic, by controlling the measuring means. Can be.

In such devices, differences or changes in parameters such as electrical impedance during diastole and systole are compared to a threshold or critical bifurcation. It should be noted that such a threshold value and a limit branch point can be fixed, or
In particular, it can be adjusted automatically in response to the heart frequency and / or arterial pressure and, for example, in response to the level of detection of catecholamines in the blood or in the heart muscle.

In addition, it is desirable to detect electrocardiograms, blood pressure and clotting tendency (by detecting changes in at least one factor of the clotting system). The device is preferably operated as follows.

(1) If an ischemic change in the electrocardiogram and a substantial increase in the propensity to coagulate are detected simultaneously, the device assumes that coronary thrombosis is present and administers a predetermined amount of anticoagulant into the bloodstream. .

(2) If the electrocardiogram is normal and the tendency of clotting is substantially increased, it is determined that extracardiac thrombosis or blood loss has occurred. If the intracardiac pressure is gradually decreasing, do not administer the anticoagulant. If the pressure does not decrease or decreases rapidly, the device will dispense a predetermined amount of anticoagulant. In a variant, the ultrasound detection of the arterial tree is activated to detect arterial (including cerebral) thrombosis, in which case an anticoagulant is injected.

In another variation, the device emits a warning light or sound signal to activate the external control to the patient or physician. The external controller instructs the implant device to administer a predetermined amount of thrombolytic agent or tells the patient to take the oral anticoagulant.

External controls and monitoring devices are connected to the implant device to allow manual setting or interruption of the clotting procedure, monitor information from the sensors, generate warning signals, and allow the physician to modify the implant device threshold. Is desirable.

EXAMPLES As can be seen from FIG. 1, the device of the present invention is completely implanted in an organ in the body. The device has an implantable housing (1) similar to an implantable heart stimulator (heart pacemaker). The configuration of this housing (1) will be described in detail below. The composite venous catheter (2) emerging from the housing (1) extends to the right ventricle (3). A predetermined number of detection electrodes and respective stimulation electrodes are provided in the ventricle, especially in the atrium, and these electrodes are connected to the heart contained in the housing (1) through the lead wires in the catheter (2). Connected to stimulator. The catheter (2) extends further from the stimulation electrode (4) as a tube (5). This tube reaches the myocardial surface via the transmyocardial tract (6), and its tip ends in a cannula (7) inserted into the coronary artery (9).

The tube (5) is preferably covered with a sheath (outer sheath). A predetermined number of wires (1
0) and (11) are embedded, and the distal end of each conductive wire is exposed from the sheath and connected to the electrodes (14) and (15). These electrodes (14), (15) are supported inside two rings, preferably elastic rings (16), (17), which have been placed around the coronary artery by thoracotomy.
The inner diameter of each ring (16), (17) with electrodes should be large enough so as not to compress the coronary artery or cause stenosis. The cannula (7) is inserted into the coronary artery (9) during the above operation.

The composite catheter (2) comprises all the electrodes and conductors for a catheter known in the art, which stimulate the heart via the right heart tract and detect its signal, and the conductors leading to the electrodes (14), (15). And a tube (5) with The end of the tube (5) is connected via a suitable microvalve to a small pump capable of administering a predetermined amount of a drug, for example, urokinase, hirudin, tpA (tissue plasminogen activator).

In another variation of the invention, the device is simply inserted into an artery without requiring cardiac surgery. In this case, the tube (5) and the rings (16) and (17) are omitted, and the catheter (4) is replaced with a conventional stimulation catheter.
Then, in one or several sites of the selected coronary artery,
Through an arterial catheter, for example, through the femoral artery,
Insert the intracoronary prosthesis according to known methods,
The prosthesis is pressed against the inner wall of the coronary artery. The prosthesis may be, for example, circular or tubular and have at least two prostheses.
There is a conductive element forming one of the electrodes so that the blood impedance at the arterial portion between the two electrodes can be measured. In some cases, two or more electrodes can be placed along an artery to measure blood impedance at multiple arterial segments along the artery. The electrodes positioned as above on the intracoronary prosthesis are connected via very thin, flexible leads (preferably grouped together) extending along the arterial segment, such as outlets, e.g. It is extended to the outlet of the femoral artery and implanted subcutaneously, where it is connected and at the same time connected to the electronic means housed in the housing (1).

In a preferred variant, the arterial electrodes as in (14) and (15) above are powered by a spontaneous energy source or by radio frequency or Hertz transmission, for example from an internal transmitter housed in the housing of the heart stimulator. You. Similarly, the impedance measurement is sent to the internal receiver in a known manner.

FIG. 2 is a conceptual view of a part of the device housed in the housing (1). This device has an automatic rhythm type anti-tachycardia stimulator (20). This antitachycardia stimulator (2
0) is U.S. Patent Application Nos. 3,857,399 and 4,
The type described in 052,991 is preferred.
If desired, the stimulator can be equipped with a fully automatic defibrillator. An example of this defibrillator is Zact's French Patent 1,237,702 (1
(July 11, 953) and the implantable ones described in Zact's French Patent No. 74/01383.

The housing (1) further has means for periodically transcutaneous transmission of energy for recharging a power supply, for example a lithium battery and / or a battery, a capacitor or a capacitor. State-of-the-art batteries used in implantable stimulators have a long enough life so that the patient does not need to recharge or replace it when the power consumption is quite high, for example when operating an ultrasound transmitter have.
Further, a known nuclear (isotope) battery that can be transplanted can also be used.

The stimulator (20) is connected in a known manner to a logic device, such as a microprocessor, connected to the detector and the stimulator in the manner described in the aforementioned U.S. Patent. In particular, the logic device assists in taking an electrocardiogram with the right intracardiac electrode and an extracardiac electrode, for example, an electrode on the housing (1). The ECG (EC
One of the features of G) is that the instantaneous rhythm of the electrocardiogram, that is, the time to separate the two QRS complex waves, is obtained.

The stimulator (20) includes an automatic antiarrhythmic means as described in the Zact patent and detects the rhythm disturbance by detecting the frequency of the rhythm disturbance, preferably the shape of a spontaneous electrical signal taken from at least one cavity or heart wall. Respond. When a known danger signal is sensed, the stimulation device (20) automatically sends the electrical stimulation described in the above patent, in particular the electrical stimulation that increases the rhythm of the stimulation.

In the present invention, the catheter (2), the outer tube (5) and the conductors attached thereto (conductors provided for the electrodes adjacent to or inside the coronary artery) are described in U.S. Pat. No. 4,754,753. The means described in the above patent can be provided with a structure similar to that of the catheter and capable of producing a vector electrocardiogram at each pulsation of the heart inside the housing (1).

As shown in the conceptual diagram of FIG. 2, the device housed in the housing (1) further comprises a square wave pulse, a sine wave pulse or other pulse generator or source (30).
Alternatively, a continuous current supply capable of sending a continuous square wave pulse to a circuit consisting of a pair of conductors (10), (11) is provided. The duration of the pulse train is, for example, 30 ms, the frequency is 5 to 25 MHz, and the current is 10 to 30 μA. An impedance (or conductance) measurement circuit (40) is electrically connected to a pair of conductors from a pair of coronary electrodes (14), (15) and
Measure the impedance while the current pulse is sent from 0). The measurement circuit (40) is tuned to the corresponding frequency.

The pulse generator (30) and the impedance measurement circuit (40) can be controlled via the heart stimulator (20) as a function of the frequency of the electrocardiogram.

The impedance measuring circuit (40) can be constituted by means using a microprocessor. The microprocessor calculates the difference between the maximum impedance and the minimum impedance in one cycle and sends the measurement result to the comparison means (50). This comparing means can be constituted by a microprocessor or a comparator. This means of comparison (5
The second input value of 0), that is, the threshold value, is given by a potentiometer (51). The threshold of this potentiometer (51) is adjustable.
The output of the comparison means (50) is sent to a pump control circuit (60). The pump control circuit (60) activates the motor of the pump housed in the housing (1) when a pulse is sent from the comparator (50) to activate the motor in the coronary artery (sic) in question. A predetermined amount of the drug is administered via the tube (5).

Hereinafter, the operation during the normal operation will be described with reference to FIG.

The pulse generator sends pulses to the electrodes (14) and (15)
The corresponding impedance measurement circuit (40) is the electrode (14),
Measure the impedance difference between (15). As a result, a curve C indicating the impedance change pattern is obtained.
The impedance measurement circuit (40) is responsive to the electrical cycle of the heart detected by the heart stimulator. This cycle is in the form of a series of QRS complex waves on the electrocardiogram, which is sent to the impedance measurement circuit (40) in the form converted to pulse I by the stimulator. The impedance measurement circuit (40) further detects a difference i between the maximum impedance and the minimum impedance measured during one cycle. The difference i between these two impedance values during the same cycle is sent to the comparison means (50), where the difference i is compared with a programmed threshold, and if the threshold is exceeded, a circuit (60) controlling the pump. ) Is activated.

The threshold value compared to the impedance difference i may be a fixed value, but may also be programmed to take into account the duration and starting point of one or more previous cycles. Conversely, if a certain threshold is maintained, for example, if the previous cycle is abnormally short, a blocking circuit that blocks the drive of the pump control circuit (60) independent of the cycle is provided. It is preferred to provide.

That is, for example, when the detector of the stimulator detects a tachycardia exceeding a certain frequency threshold, for example, 150 pm,
The microprocessor of the stimulator suppresses the circuit controlling the pump (60), which allows the pump to provide the drug as programmed, even if the difference between the maximum impedance and the minimum impedance per stroke is below the threshold. Is not administered.

Similarly, these blocking means may cause the device to be blocked during normal cycles following short and / or ectopic heartbeat cycles.

In an improved variant, the device according to the invention can be modified so that the motor control circuit (60) is not activated if it is first detected that the difference i has become smaller than the threshold value. Further, the motor control circuit (60) may be operated only when it is detected that the difference i becomes smaller than the threshold value in one or more consecutive cycles.

Instead of getting the data of each cycle from ECG,
It can also be obtained from other means, such as a pressure sensor in the cavity and / or a myocardial pressure sensor and / or an arterial pressure sensor.

The device doses each time the physician detects that the threshold has been exceeded in the above blocking condition (this can be treated immediately,
It has the advantage of being able to administer the drug in a rapid manner, or is administered after a predetermined number of consecutive detections of a decrease below the threshold (only when the coronary flow rate has an almost constant degree of abnormality). (They have the advantage of administering).

In another embodiment of the present invention, a small piezoelectric (piezoelectronic) sensor is preferably used in the coronary artery in combination with the above embodiment. That is, at least one
One sensor, preferably several sensors, is placed, for example, on a ring-shaped electrode, possibly distributed along the coronary artery. By doing so, a pressure curve at one or more sites of the coronary artery can be obtained in each cycle, which is combined with the impedance measurement to represent the product of impedance and pressure as a flow / pressure ratio. Strength (magnitude) can be obtained.

The pressure curve in the coronary artery can be analyzed by a microprocessor similar to an impedance curve. In particular, the device of the present invention can detect the intersection of the pressure curve of the blood flow in the coronary artery and the reflux curve, in addition to the pattern change of the pressure curve or the time delay of the pattern of the pressure curve compared to the electrical cycle. it can.

FIG. 4 shows another embodiment of the present invention. In this embodiment, the parts of the device housed in the housing (1) are substantially the same as those described above, but the catheter (2) is passed through the myocardium to one or more other coronary arteries. The tube reached is not extended.

The distal end (101) of this catheter (2) is inserted some distance into the myocardium at the base of the right ventricle towards the top of the heart. The insertion distance is, for example, 4 to 8 mm. A pressure sensor (102) and two electrodes (103) and (104) on both sides of the catheter are sequentially attached to the distal end (101) from the distal end. The two electrodes (103), (104) are slightly separated in the myocardium to form a V-shaped anchor point. The catheter is further equipped with potassium and H ⁺ ion sensors (105) and (106), followed by two electrodes (107) and (108) that open and anchor in a V-shape. .

The catheter in the ventricle contains other electrodes and other sensors (11
0), (111), (112), for example, pressure for detecting potassium and H ⁺ ions in the blood, as well as at least one parameter relating to clotting ability, in particular blood plasma and / or blood formation. Preferably, a sensor (109) is provided.

The two electrodes (103) and (107) separated from each other by several mm are connected to a pulse generator (30) and an impedance measuring circuit (40) between the electrodes (103) and (107). The above electrode (104)
And (108) detect between them a local electrocardiogram in this region of the myocardium. In this way, a local electrical impedance, an electrocardiogram, and a myocardial pressure mechanogram are obtained.

A selective photodetector that distinguishes hemoglobin from myoglobin for detecting possible bleeding can be placed on the catheter section inserted into the myocardium.

As described above, the device of the present invention provides a local bipolar ECG and / or its corresponding impedance curve and / or impedance peaks or minimum and maximum impedances during one cardiac cycle as determined by the minimum time delay. The difference can be compared to a programmed threshold. The apparatus of the present invention further stores a threshold value and compares the threshold value with the maximum and minimum values of pressure during one cardiac cycle, the shape of the pressure curve and any displacement of peak pressure or minimum pressure with respect to the cardiac cycle. Can be.

In addition, abnormal potassium ion diffusion or abnormal pH
You can respond to change.

In the present invention, of course, the number of variables can be set.
In particular, the means for detecting the passage or stagnation of blood flow in the coronary or sub-coronary arteries may be different from each other.

The electrical impedance can be measured using intra-arterial electrodes instead of measuring the electrodes around the artery. This intra-arterial electrode, for example, when performing a coronary bypass using an arterial intima probe, for example,
It can be a simple wire inserted into the artery.

When an artificial heart is transplanted (which was first successfully transplanted into an animal by the present inventors in 1953), an artery,
In particular, it is particularly important to protect the carotid and cerebral arteries. However, tests for detecting clotting ability or lack of clotting ability, as well as vascular bleeding tests and blood composition tests, are limited by the device.

It is also possible to use an electric means for detecting the blood flow rate other than the impedance measurement. For example, an ultrasonic transmitter and receiver operating based on the Doppler effect, or an optical sensor for a light source can be used. However, it is not limited to these.

Further, instead of using a blood flow detector in the body, using a means of detecting a vector electrocardiogram as described in U.S. Pat.No.4,754,753, a starting point and a factor of electric propagation between depolarization and repolarization are determined. Can also be collected. By examining these vector changes,
The myocardial region where ischemia has occurred can be determined at least approximately. If the vector change in this region exceeds a certain threshold, the device according to the invention is connected to the circulatory system in the cavity or directly into the blood vessels of the coronary arteries, or to selectively administer the medicament. A predetermined amount of drug is administered into three main coronary arteries.

With reference to FIGS. 5 and 6, one embodiment of a sensor (112) for optically measuring changes in the deposition thickness of fibrin (fibrin) may be seen. This sensor (112) is located in the cavity of the catheter (2).
In the drawing, the catheter (2) is approximately 4 mm in diameter.
The appropriately shaped cavity (150) is covered on the outside by a steel grid, which is provided with holes, eg 3/10, with a mesh diameter of 1/10 mm or more. At 1-2m
m or less. Preferred dimensions are, for example, about
0.8 mm. The grid is periodically irradiated with ultrasonic waves to remove blood components that tend to clot the blood. At the center of the cavity (150) is an arm (152) containing a bundle of optical fibers. This bundle of optical fibers is directed to conventional optics, the tip of which terminates in a bundle of fibers (153) along the length of the catheter. Opposite to this is provided an optical means (155) which leads via a space (154) to a bundle of fibers housed in an arm (156). This bundle of optical fibers re-joins an oblique section (153) connected to a light source capable of transmitting light radiation into space (154) through arm arm (152). The light is sensed by optical means (155) and retransmitted through a bundle of optical fibers (156) to the measuring means. Space (15
In (4), a grating (157) is provided between the optical means (153) and (155). This grid is preferably an electric conductor, and is capable of periodically removing coagulation components by ultrasonic vibration. The grid is supported in this space by arms (158). A field effect transistor (159) is provided below the lattice (157),
Preferably, a small electrode (not shown) to which a negative voltage is applied is provided. The entire grid and transistor (159) are housed in a very fine grid (160) with 3 μm mesh openings. This lattice can be made of, for example, a fiber thread such as carbon fiber having a diameter of 1 to 3 μm.

When the catheter is placed in the blood, the blood flow passes through the grid (151) and circulates somewhat through the cavity (150). Blood enters the space (154) through a fine grill, but the blood mass cannot enter the space due to the small diameter of the grid (160). In some cases, a negative potential can be applied to the grid (160) to repel the formed mass. Desirably, the formed fibrin is deposited on a grid (157). For this purpose, the lattice (157) is coated with a fibrin membrane in advance, or fibrin and a substance capable of inducing fibrin formation, such as a specific precursor or factor, which are insolubilized on the lattice. It can be coated with the combination. Light passing through the space (154) is reduced in intensity, and its spectrum changes depending on the presence or absence of fibrin on the grid (157) and the thickness of the fibrin membrane. The transistor (159) is sensitive to calcium ion concentration. By applying a negative potential below the lattice (160) that promotes the formation of fibrin, it is advantageous to observe a deposit that decreases in thickness towards the tip. This spatial change in thickness can also be analyzed by analyzing each pixel received on each fiber of the fiber bundle (156). In addition, one or several tubes are provided in the arm (158), and a predetermined amount of a fibrin melting agent, for example, plasminogen, heparin, or the like is supplied into the space (154) as necessary, and the space is supplied to the space. The amount of fibrin formed can also be limited. If the lattice (160) is broken, the fibrin of a dangerous size is prevented from entering the circulatory system by the lattice (151).

Various means for measuring parameters for measuring electrical impedance, for example, a laser or maser modulated as necessary, ultrasound, sound wave transmitter and / or receiver, etc. Preferably, the spatial position can be controlled by remote control from outside the body. Also, the energy required for the mechanical movement of these means can be provided by remote transmission, for example by high frequency. The energy source of the device according to the invention may be, for example, a nuclear battery or a conventional battery, or an implantable receiver receiving external energy, which allows the special operation of the device and the excess The energy required for low power consumption and all or part of the power supply can be recharged.

That is, for example, a movable or rotatable transmission-reception head monitored by a remote control is attached to an ultrasonic transmitter / detector implanted in or near the heart,
An echocardiogram or a mediastinal echocardiogram of the ultrasonic wave of the oscillation source can be recorded in the memory of the implanted device, and can be retransmitted to the outside by remote control.

To examine and direct the structure of bone or cells,
Optical means using an endoscope can also be used.

The catheter 2 shown in FIG. 7 has a reinforcing member 113 surrounded by a porous membrane. This porous membrane
Membrane used in plasmapheresis, for example, 0.5
The membrane can be a polyamide or polytetrafluoroethylene membrane having μ pores and a pore / total surface area ratio of about 60%. Instead of this porous membrane, a filter having a similar porosity, in particular a filter of ceramic or pyrolytic carbon, can be used. Plasma molecules and plasma proteins can easily pass through the porous membrane 114 and enter the reinforcing member 113, but platelets, red blood cells and other cells cannot enter the space 113 through this membrane. For comparative measurements, a second assembly with a membrane at least partially permeable to platelets can also be provided. The catheter is provided with a number of known miniature ultrasonic transmitters in contact with the porous membrane. These transmitters are activated periodically to remove platelets, fibrin, and other sediment from the porous membrane 114 that may clog the membrane. In addition, by applying a variable voltage to the porous membrane, the selective permeability can be adjusted.

At the center of the reinforcing member 113, the vertical arm 1
16 are growing. This vertical arm 116 is fixed to the catheter, at its end, for example, a small block 11 of thin fibrin having a thin base in the form of a parallelepiped with a square base.
7 are supported. The upper square face of this block 117 faces the optical end of the light carrier 118. For example, this light carrier is composed of 30,000 fibers having a total diameter of 1 m.
It is an endoscope configured to be bundled so as to be m. The other end of 10% of these fibers is connected to a light source such as a laser or other light emitting diode to direct light to the fibrin block 117. The remaining fibers also serve to receive the reflected light and guide it to detection or analysis means for sensing the intensity or quality of the reflected light and / or the outer contour of the fibrin block 117.

As a modification, light returning through the light transmitting body 118,
In some cases, by spectroscopically measuring the attenuated light,
Means for measuring light density or absorption can also be provided.

The end of the photoconductor 118 may be provided with a known type of optical head with a viewing angle of 50 ° and a depth of a few tenths of a millimeter.

As the blood has a greater tendency to coagulate, fibrin precipitates on the fibrin block 117 and its thickness increases. When the thickness increases to a thickness corresponding to one or several molecular layers, it can be known by the detection / analysis means. Similarly, increasing fibrin accumulation at the periphery of the square can be seen by the light transmitter,
This information is sent to the analysis means.

In the device of the present invention, if there is an excess of fibrinolytic factor in the blood, on the contrary, the thickness of the fibrin sample and / or
Alternatively, it detects that the size is reduced.

When the fibrin is completely eliminated, the fibrin is not present on the surface of the arm 116 serving to fix the fibrin, for example, on the surface of a porous ceramic or glass having fine grooves (the above-described light emission). After the optical detection (using the transmission body 118 or the dedicated fiber group 126), the cleaning ultrasonic transmitter 127 is operated to automatically perform cleaning.

Generally, new fibrin spontaneously deposits on the surface cleaned as described above. However, it is also possible to supply fibrinogen or proteron pins near this surface. These fibrinogens or proteron pins are, for example, a medium in a small container provided slightly away from the surface or in a porous container having micropores provided near the arm 116 (the medium includes fibrinogen and And / or bacteria or cells produced by cell fusion of proterone pins are cultured).

Instead of placing a fibrin block on the arm opposite the end of the optical fiber, deposit a very small fibrin sample at the end of the light transmitter, e.g., at the center of the end of the light transmitter. Can also. In this case, the light transmitter makes it possible to know the thickness change of the sample, ie the variation in the reflected light and the increase in the number of samples (this is expressed as the difference between the number of blocked optical fibers). .

In some cases, an ultrasonic transmitter may be placed around the end of the light transmitter to perform ultrasonic cleaning when the thickness of the fibrinous layer exceeds a predetermined value or completely disappears. .

In a modification using known means, the porous membrane 114 is omitted, the end of the light carrier is inserted into a short cylindrical portion of a hollow porous fiber, and one end of this cylindrical portion is closed with the fiber end. Alternatively, the other end can be closed with a stopper. In this case, since the volume inside the hollow fiber is observed from the light transmitter, the fibrin sample placed inside the hollow fiber can be analyzed by the change in the internal volume.

In another embodiment, the device of the present invention is provided with a pump or other means for rapid administration of the medicament (preferably via a tube in a blood vessel or heart cavity). This measure is such that in the event of a seizure, the patient can activate an external remote control to immediately administer the appropriate amount of drug, especially a thrombolytic and / or vasodilator and coronary antispasmodic. It can be operated remotely from outside, in particular by the patient himself. The dose may be about 5-20% of the usual dose. Instead of a pump, an implanted retractable storage container or a flexible or elastic storage container can also be used. These reservoirs are covered by the surgeon with a section cut off from the muscle, e.g., the chest or back muscle, i.e., the remaining muscle section connected to the vascular-nervous pedicle, and this muscle section is implanted into the muscle and implanted. The muscles are stimulated by electrodes that transmit electrical impulses provided by the applied power. If necessary, the deformable storage container may be provided with a metering means of a known type for dispensing a predetermined amount of medicine during muscle contraction.

In a preferred embodiment, the implantable device of the present invention can be provided with a known container for storing a liquid medicament. This container is implanted under the skin, for example under the skin at the pectoral muscle, so that the medicament can be filled with a needle using a known subcutaneous injection method. The container also has an elastic wall that expands when the medicament is refilled and applies pressure to the liquid therein. The outlet of the container is connected to a flexible tubing via an elastic microvalve which extends to the extracardiac portion of the pacemaker catheter and is intracardiac, preferably of the atrial appendage, as is known. It opens through the branch of the catheter. The tube opens into the atrial appendage via a check valve inside the catheter. This check valve is
The drug can be supplied, but the blood in the atrial appendage is prevented from flowing into the tube. The valve is electrically driven by means located in the implanted pacemaker housing, and when the valve is opened, a liquid medicament under pressure is delivered from the container into the atrial appendage and mixed with the blood. The dose of the medicament can be adjusted by the opening time of the valve. If necessary, a small auxiliary container, for example a few milliliter auxiliary container supplied separately from the medicament from the main container, can be mounted on the catheter in the atrial appendage. The auxiliary container is supplied with the medicine slowly from the main container, and the medicine in the inside can be quickly administered.

For certain therapeutic agents, it is also possible to irreversibly immobilize the therapeutic agent on a solid support instead of using the pump to administer the therapeutic agent. The support is placed, for example, on a blood vessel or lymph barrier in a tissue that exchanges with lymph or blood. The support itself is made of nitrocellulose, silica or siloxane, and the immobilization of the active molecule can be carried out by known means, for example, the means used in immunoassays or affinity chromatography. The support can be, for example, in the form of a band or a net. Drugs that can be irreversibly immobilized on a support include, in particular, certain proteases, heparin sulfate, human reuserbin II, dermatan sulfate, anti-vitamin K, protein C or S, factor ATIII, thrombo-
Anticoagulants such as globulin, specific anti-inhibitors of protein C and / or natural plasminogen tissues such as protein C, molecule TpA, antiplasmin alpha-2-antiplasmin A2-AP, factor XIIa and kallikrein Fibrinolytic agents which stimulate the release of the activator can be mentioned. Ultrasound can also be used to prevent precipitation of substances such as fibrin on the support. Also, activated plasminogen can be immobilized on a support. If necessary, a means for supplying the living body with the active surface on the support only when there is an automatic bilot instruction based on the detection result may be provided. This means can be provided with a mechanical shutter or an electrostatic grid, for example, that spontaneously activates the reaction and attracts or rejects ions such as Ca ⁺⁺ or Mg ⁺⁺ . further,
A support having a surface that can contract or expand between a rest position where the molecule is not delivered to the living body and a deployed position where the molecule is delivered to the lymph or blood circulation, for example, at the vena cava or at the auricle of the heart You can also set up your body.

Preferably, the device is adapted to exert and / or inhibit blood coagulation on a support such as a small band. This small band is in the blood or lymph after being covered with a molecular membrane (eg, obtained by the Langmuir-Blodgett method). Various molecular blood coagulation molecules (prothrombin, thrombin, fibrinogen having a Ca ⁺⁺ crosslink, fibrin monomer, serpent virus, etc.) and anticoagulant molecules (heparin sulfate, plasminogen activator, plasmin,
Protein C, AVK, hirudin, acetic acid-salicylic acid, etc.) are adhered in a linear or dot form. These molecules immobilized and distributed on the support attract certain molecules that tend to complete the functional chains of the molecule in question and certain molecules that tend to inhibit the activity of these molecules. Local accumulations or microprecipitates formed in the blood can be identified quantitatively and qualitatively by optical means, for example by optical fibers placed opposite the molecules to be detected. For example, two molecules of different clotting systems, such as antagonists, are preferably placed at two geometrically opposite points at a small distance, preferably less than 1 mm. Different antagonists or complementary agents can also be arranged stepwise along the catheter.
The opposite ends of a group of antagonists or complementers can be provided on the photoreceptor such that light builds up from one point to the other by accumulations formed therebetween. Therefore,
Abnormal or deficient molecules or chains in the clotting abnormalities can be instantly represented. By way of example, forming a Langmuir-Projected layer with attached fibrin monomers,
This layer is covered with a second protective layer of an inert molecule (siloxane), and a hole of about 100 angstroms is formed in the protective layer with a laser or an electron gun to form dots in each group, thereby altering the quality of the active molecule. Prevents reaction with this molecule while preventing it [J. Sagiv, Israel's Waisman Institute (I
nstitut WEIZSMANN)]. The second point in each group is thrombin,
It forms a layer activated by prothrombin, heparin, TPA, plasminogen, plasmin, protein C and the like. The thrombolytic device can automatically correct the clotting defect by administering a thrombolytic agent or an anticoagulant, or notify the patient of a blood disorder by a remote control signal, as needed, to the patient. Means may be provided for ingesting the appropriate medication.

A particularly advantageous improvement of the invention is that the active substance or drug is genetically modified in a bacterial, yeast or animal or plant cell line placed in a microporous body container placed in an organ, for example a blood vessel or tissue. It can be manufactured by the method. This porous container is a microporous membrane with a pore size that allows the passage of metabolites, ions and proteins of the genetically modified cells, but does not allow these cells to exit the container. Is preferred. Bacteria which can survive in a liquid chamber of a living body, particularly Klebsiella and Pasteurella, can be used as the recombinant cells. In eukaryotic cells,
Human cell lines that become the active substance by genetic modification are preferred.

In a variant, the microporous body container does not contain any bacteria or cells, but rather a mixture of nucleotides, genes, enzymes and ribosomes, as well as the respective ADNs and ARNs required to express in vivo known per se. Can be replaced by These can be made, for example, from organelles made of fungi or cells. In any case, the amino acids necessary to express the recombinant protein, oxygen, and the necessary substances from plasma enter the container through the microporous membrane and the catabolic waste is discarded through this membrane .

In some cases, the membrane of the container can be an electrically controlled membrane with variable diameter holes. Note that this film can be mechanically controlled.

FIG. 8 is a conceptual diagram of the above-mentioned part of the present invention. This part comprises a container 119, the membrane 12 of which is located on the body fluid side.
0 is provided. In addition, means for expressing a protein such as a bacterium or a recombinant cell is contained in the inside 121 of the container. The outlet of the container 119 is provided with a second membrane for holding bacteria or cells inside the container, and is connected to a check valve 122 and a large-capacity hard or flexible storage bag 123. This storage bag 1
All or a part of the contents of 23 is discharged through a discharge tube 124 by means not shown. Discharge tube 1
24 leads to the intracardiac catheter, enters the heart cavity via a check valve or anti-reflux device 125, and discharge tube 124
Is open into the right ventricle. This implantation site is formed by the inlet formed by the membrane 120 and the end of the drainage tube 124, during diastole, where there is a natural slight pressure difference between the location of the membrane 120 and the right ventricle. Select a place where a slow circulation can be made between the exit and the exit. Therefore, the drug or active substance represented by the cells in the container 121 gradually enters the storage bag 123 and stays in the bag, and a small amount of the small amount is gradually removed by the same flow rate through the discharge tube 124. Get out of. Conversely, during systole, the catheter provides a dosing opening or drain tube.
Backflow from the end of 124 to the flexible bag 123 is a backflow prevention device
Blocked by 125.

In the apparatus of the present invention, when a predetermined parameter exceeds a predetermined threshold, the storage bag 123 is contracted by means not shown, so that part or all of the contents of the storage bag 123 can be quickly discharged from the discharge tube 124. They are released to release large amounts of genetically modified substances into the circulation.

In another variant of the invention, the antithrombin III and / or
Alternatively, it is preferable to previously contain a bacterium or a recombinant cell capable of expressing and releasing an anticoagulant such as heparin in blood. Preferably, the cells are cardiovascular fused endothelial cells, which are fused monolayers formed on a support of a known synthetic material (polytetrafluoroethylene).
For this purpose, an arterial-venous shunt is formed. For example,
At the abdominal apical artery and vein, the arteries are branched so that blood is pumped into one or more cavities containing a fused monolayer of the cardiovascular fused endothelial cells.
The cavities have, for example, fibrin attached to a support, and the cavities open to the arterial bifurcation. Also, a porous membrane, eg, a 0.25 micron membrane, is provided at the exit of the cavity to keep the fused endothelial cells from entering the arteries-veins. This membrane is not required if the fused cells are obtained from the patient itself and fused with an expression vector having heparin or antithrombin III. Further, it is preferable to control the discharge amount by a variable cross-sectional obstruction member or the like for increasing or decreasing the amount of blood passing through the extraction part as a function of the required amount of heparin or antithrombin III.

Further, the device of the present invention is preferably provided with a detector for measuring blood viscosity to check the concentration of fibrinogen. This measurement of blood viscosity can be performed very easily, for example, by sonicating or ultrasonically oscillating a flake or membrane on a catheter in a blood vessel, stopping the drive motor, and then contacting the flake or membrane with blood. It can be easily determined by measuring the curve at which the vibration of the is damped. Furthermore, the blood viscosity can be measured optically by a known method. That is, it can be determined by counting the flow rate of blood particles, eg, blood, and the number of red blood cells and comparing it to a calibration curve. The method using this calibration curve can also detect the degree of agglutination of red blood cells, and then examine the increase in the degree of blood clotting.

[Brief description of the drawings]

FIG. 1 is a conceptual diagram of the device of the present invention, FIG. 2 is a diagram of a measuring / comparing means of the device implanted, and FIG. 3 is a measurement curve of an electrocardiogram and an electric impedance measured by the device. FIG. 4 is a diagram of a means for measuring myocardial parameters, FIGS. 5 and 6 are a cross-sectional view and an axial cross-sectional view of a blood composition sensor, and FIG. 7 is a modification of the blood composition sensor. FIG. 8 is a sectional view in the axial direction, and FIG. 8 is a conceptual diagram of one embodiment of a supply system for supplying an active substance. (Main reference numbers) 1 ... Housing, 2 ... Vein catheter, 3 ... Right ventricle, 4 ... Electrode, 5 ... Tube, 6 ... Transmyocardial tract, 7 ... Cannula, 9 ... Coronary artery , 10,11 ... conductor, 14,15 ... electrode, 16,17 ... ring,

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int.Cl. ⁶ , DB name) A61B 10/00 A61B 5/00

Claims (27)

(57) [Claims] 1. A method for treating blood coagulation including at least thrombosis, arterial embolism, abnormal coagulation, bleeding, blood disease, and abnormal cell elements in blood, characterized by the following (a) to (c): A device for protecting the patient from related diseases: (a) for contacting surrounding blood vessels or lymphatic vessels with stimulating means for dynamically and continuously causing local biochemical reactions of blood coagulation-related factors; Abutment means mounted in or on a blood vessel, lymphatic vessel or body cavity, and sensing means disposed in proximity to the abutment means responsive to a local biochemical reaction of a factor stimulated by the abutment means A first transplantation means (4, 14, 15, 103-109) for continuously or periodically measuring at least one biochemical parameter associated with blood coagulation or imminent blood coagulation or its precursors, comprising: (B) Pa A second transplantation means (40, 50, 51) for determining one or more threshold values to be compared with the measured values of the parameters; A third transplantation means for automatically administering a therapeutic agent into the circulatory system. 2. The sensing means of the first implant means has at least two pressure sensors arranged along a blood vessel or a cardiovascular vessel, the second implant means having a pressure value sensed by the pressure sensor and / or 2. The apparatus according to claim 1, further comprising means for detecting a time delay before the pressure sensor reaches a predetermined predetermined pressure. 3. The method of claim 1, wherein the sensing means of the first implant means comprises oxygen, CO ₂ ,
Sensing one concentration selected from the group consisting of hemoglobin or a derivative thereof, myoglobin, myosin,
The device of claim 1, wherein the sensing means is mounted in a blood vessel or lymph vessel or body cavity near the diseased site. 4. The apparatus according to claim 1, wherein the sensing means of the first implant means senses calcium and / or H ⁺ ions. 5. The apparatus according to claim 4, wherein the stimulating means of the abutting means includes surrounding blood, lymph, or at least one factor influencing blood coagulation in contact with these vessel walls. 6. The device according to claim 5, wherein the plurality of abutment means are arranged at a short distance from each other. 7. The apparatus of claim 1, wherein the sensing means of the first implantation means includes optical sensing means for sensing an optical change in at least one factor of blood coagulation. 8. The method of claim 5, wherein the sensing means of the first implant means includes means for detecting fibrin or a precursor thereof deposited on or near the abutment means and deposited on the abutment means. apparatus. 9. The sensing means of the first implantation means, wherein the heart and / or
2. The apparatus according to claim 1, further comprising means for detecting a motion cycle of a blood vessel. 10. The device according to claim 1, wherein the third implantation means comprises a heart stimulator and / or a defibrillator. 11. The device according to claim 10, wherein the heart stimulator comprises anti-tachycardia means. 12. The apparatus according to claim 1, wherein said sensing means comprises optical sensing means sensitive to the wavelength of a colored component of blood located within the blood vessel or lymph vessel. 13. The apparatus according to claim 1, wherein the sensing means comprises optical sensing means sensitive to the concentration of red blood cells and / or platelets and / or white blood cells. 14. The apparatus according to claim 1, wherein said sensing means comprises optical sensing means sensitive to blood coagulation factors. 15. Apparatus according to claim 1, further comprising means for detecting a cardiac and / or vascular cycle and taking measurements at predetermined times of the cycle to control the first implantation means. 16. The apparatus of claim 1, wherein the first implanting means further comprises means for measuring local factor variations associated with different electric fields or currents. 17. Apparatus according to claim 1, wherein the sensing means comprises optical sensing means responsive to the concentration of red blood cells and / or platelets and / or white blood cells for measuring the size of the fibrin sheet disposed on the abutment means. . 18. The apparatus according to claim 1, wherein the stimulating means includes factors affecting blood coagulation in contact with surrounding blood, lymph, or these vessel walls. 19. The apparatus of claim 1, wherein the sensing means includes a power supply and electrical means coupled to the power supply for measuring impedance at a frequency between a few KHz and a few MHz. 20. The electrical means includes at least two electrodes spaced apart from each other at a distance from the heart muscle to form a single measurement axis, and wherein the sensing means comprises an electrical source of the heart. 20. The apparatus of claim 19, wherein the impedance is sensed by a vector of change. 21. The device according to claim 1, further comprising at least one pressure sensor for sensing blood pressure or myocardial pressure. 22. The apparatus according to claim 1, wherein the pressure sensor detects a geometric deformation of the heart or blood vessel. 23. The apparatus according to claim 22, wherein the pressure sensor detects a geometric deformation of the heart or blood vessel. 24. The apparatus of claim 1, wherein the sensing means senses the electrocardiogram, and wherein the second implant means compares the electrocardiographic abnormality to an electrocardiographic threshold. 25. The apparatus of claim 1, wherein the sensing means comprises means for producing a sound in the heart and means for detecting the propagation or absorption of the sound. 26. The apparatus according to claim 1, wherein said sensing means comprises ultrasonic wave generating means and means for detecting ultrasonic resonance corresponding to blood factors. 27. The apparatus according to claim 1, wherein the sensing means comprises optical means for taking the color or image of the circulating blood or the wall or bone marrow of the heart or blood vessel.