DE4201259C2 - Device for perfusion of the coronary arteries of an isolated heart - Google Patents

Description

The invention relates to a device for perfusing the coronary vessels of an iso lated heart according to the preamble of claim 1.

Such a perfusion device is described in the treatise "The isolated perfused warm-blooded heart according to Langendorff "by H.J. Döring and H. Dehnert (Biomeßtechnik-Verlag March GmbH, ISBN 3-924638-04-7, 1985). It consists in essentially from a reservoir, a pump and a holder for the iso grafted coronary heart. The pump transports the perfusate a supply line from the reservoir to the isolated heart. According to the Per fusion leaves the perfusate through a drain line. The perfusion of the Coronary vessels (coronary vessels) are reached using the Langendorff method. The perfusate is hereby cannulated into the ascending part of the Preparation remaining on the heart, aorta pressed. Here close due to the the aortic valves as they do for the heart do in situ during diastole. The perfusate is thereby in the coronary arteries pressed, passes through the coronary vasculature and leaves it at the sinus corona rius again. The cardiac cavities, i.e. atria and chambers, remain during this Perfusion empty.

An extension of the examinations on isolated hearts is the "Working Heart" - Method. Here, coronary perfusion is no longer carried out via a pump, but instead the perfusate is fed into the left atrium and passes through the mitral valve pen in the left ventricle. From there it gets into the aorta with every heartbeat pumped. The resulting pressure now ensures perfusion of the coronary vessels. The left side of the heart works as in situ.

As preparations such. B. Hearts of guinea pigs, rabbits and rats used. With the help of a heat exchanger and a heated reservoir can the perfusate at any temperature, usually in physiological loading  be kept rich. The flow rate through the coronary vasculature can be adjust the delivery rate of the pump. To the effective perfusion pressure too can measure, a manometer in the supply line, directly in front of the heart to be appropriate.

Such a device is used for the biomedical examination of warm-blooded animals hearts, which through constant perfusion with an oxygen-containing nutrient solution in almost physiological conditions with the most diverse experimental Methods can be examined in vitro. In particular, using one of the like device investigates drug effects and electrophysiological Experiments carried out.

The device described has various disadvantages.

The first disadvantage is that the course of the aortic pressure over time the pulsation of the heart cannot be influenced. The one in the experiment The setting pressure curve usually deviates from the curve measured in situ. Around To get meaningful results, the course should follow the physiological course be adapted as well as possible.

In addition, the device described above is only suitable for measurements under the so-called constant flow condition, since only the flow through the conveyor performance of the pump is adjustable. The resulting pressure depends on the characteristics of the heart and their changes during the measurement towards. During slow pressure readings on the pressure gauge still can be corrected manually via the delivery rate of the pump Pressure changes not possible.

To make it possible to work at constant pressure, many people use it Laboratories instead of the reservoir and the pump of high liquid columns. The columns serve as a reservoir and hydrostatic pressure generator at the same time. The liquid level an overflow keeps them at a constant level. Sol  Columns of liquid are very high and bulky and are difficult or impossible to remove do not adjust to a certain pressure. For example, a pressure of 100 To generate mmHg, a nutrient solution storage height of 135 cm must be set the. If a pressure of more than about 120 mmHg is required, a hole must be made the ceiling must be drilled so that the pipe system above the laboratory table is high enough can be.

Furthermore, EP 0 347 923 A1 describes a portable perfusion device for isolated hearts, which work pulsating. With this perfusion device a pump repeatedly presses a certain volume of perfusate into the Aorta of the isolated heart. The pulsating perfusion is, however, for laboratory workers unsuitable because laboratory tests are either continuous retrograde perfusion flow through the coronary vessels desired or - at the The "Working Heart" method described above - the coronary vessels through the we blood flow to the heart of the beating heart.

DE 37 12 200 A1 describes an apparatus for extracorporeal long-term perfusion sion of human or animal tissue and for extracorporeal regeneration tion of organs, preferably from the heart. This apparatus has a blood pump on, which is divided into two pumping units, the large and small circle Supply the run, the small circuit being equipped with an oxygenator. Both pump units are arranged in series, similar to the heart. The However, this publication cannot be seen as an isolated heart with the described apparatus is to be perfused, whether or not with this apparatus Wind boiler function can be realized.

US 4,902,277 describes a device for perfusing a knee joint. Of the However, the accumulator described there only represents a drip chamber, the Liquid level kept constant with the help of a sensor and a pump in order to keep the perfusion pressure of the knee constant. The accumulator does not have the effect of a wind boiler because the amount of gas does not  is adjustable, and is therefore not suitable for perfusion of a heart.

Finally, WO 91/12034 A1 describes a method and an apparatus for Perfusion of the eye during eye surgery. This is the one in the infusion bottle pressurized gas space above the perfusion liquid, whereby the discharge rate of the perfusion liquid is adjustable. This method and this device is not suitable for the perfusion of the coronary vessels of isolated hearts since there is no wind boiler function. To do this, the gas-filled containers switched into the supply line leading to the heart his. Furthermore, there is none with this method and with this device independent adjustment of pressure and perfusion rate possible.

Based on the subject matter of Döring and Dehnert therefore has the task of developing a perfusion device in such a way that that the time course of the aortic pressure is adjustable.

This object is achieved by the characterizing features of claim 1. Advantageous refinements can be found in the subclaims.

The characterizing features of claims 2 and 3 also solve the Task that both constant flow and constant pressure measurements in each pressure range of physiological interest are possible, the apparatus being small and should be compact. The characteristic features of claim 25 also solve the task of switching to the "Working Heart" method can be done without damage to the heart.

Two embodiments of the invention are described below with reference to the drawing nations explained in more detail. The same reference numbers refer to the same parts.

It shows

Figure 1 is a schematic representation of the perfusion device for perfusion according to the Langendorff method.

FIG. 2 shows a detail from FIG. 1;

Fig. 3 is a cross section through a slightly modified component (Aortenblock) of FIGS. 1 and 2;

FIG. 4 shows an expanded embodiment of the perfusion device from FIG. 1 for perfusion according to the "working heart" method.

The perfusion device shown in FIG. 1 consists of a reservoir 14 which contains the perfusate and can be heated via a liquid passage. The heating fluid enters the hollow wall 24 of the reservoir 14 via an opening 23 and leaves it again via an opening 25 . Hoses are connected to the openings 23 and 25 , which lead to a pump with a temperature controller (not shown). The reservoir 14 also has a gassing device 26 for gassing the perfusate, e.g. B. with oxygen. The perfusate is aspirated by the peristaltic pump 16 via the suction line 16 a from the reservoir 14 and supplied via the supply line 16 b to the so-called aortic block 30 , which is shown enlarged in FIG. 2 and will be described. After leaving the aortic block 30 , the supply line 16 b leads to the isolated heart 1 . It is connected to it via the ascending aorta. Due to the perfusion pressure applied, the aortic valves close as described in the introduction and the perfusate is pressed through the coronary arteries into the coronary arteries (Langendorff method). It passes through the coronary vasculature and leaves it again at the coronary sinus. A drain line 27 is attached here, through which the perfusate leaves the system after flowing through the heart 1 and flows into the thermostatted heart receiving chamber 19 . At a branch of the drain line 27 thermostatic transducers 80 are connected, which are flowed through with a peristaltic pump 81 with a constant flow. The outputs of these sensors 80 lead to display devices 82 . The partial pressures of hydrogen, carbon dioxide and oxygen of the perfusate are measured here.

The aortic block 30 enlarged in FIG. 2 and shown in cross section in FIG. 3 essentially consists of three functional components: the actual pressure vessel 31 , the artificial flow resistance 32 and the membrane vibration damper 33 . It should be noted that the cross section of the aortic block 30 shown in Fig. 3 is a slightly different embodiment of the aortic block 30 shown in Fig. 2. In the aortic block 30 according to FIG. 2, the artificial flow resistance 32 lies opposite the diaphragm vibration damper 33 , while in the aortic block 30 according to FIG. 3 these two components lie on adjacent sides.

The pressure vessel 31 of the aortic block 30 is essentially cuboid and has a cylindrical interior 34 . In the lower area of this inner space 34, the supply line 16 opens from the pump 16 b Coming. For this purpose, the wall of the pressure vessel 31 has a bore 35 . In the interior of the aortic block 30 also ends a measuring line 66 of a pressure transducer 67 , with which the pressure inside the pressure vessel 31 (aortic pressure) can be measured. At the lowest end of the pressure vessel 31 , the last part of the supply line 16 c leading to the isolated heart 1 is flanged. For this purpose, the pressure vessel 31 has a bore 36 . Approximately half the height of the cylindrical interior 34 of the pressure vessel 31 the desired liquid level 37 is of the perfusate. One side of the wall of the pressure vessel 31 has two through bores 38 and 39 , which are necessary for operating the artificial flow resistance 32 . At least one of these bores ( 38 ) must lie below the liquid level 37 of the perfusate. From the other bore 39 , a line 40 runs to a further wall of the pressure vessel 31 and ends there in a cavity 41 . In the embodiment shown in FIG. 2, this cavity 41 is formed outside the wall of the pressure vessel 31 ; in the embodiment according to FIG. 3, which will be discussed below, it is realized as a recess in the outer wall of the pressure vessel 31 . This recess is flush with an elastic membrane 42 and forms the cavity 41 with it. A further bore 44 leads to the cavity 41 , to which a return line 45 is connected, which leads back to the reservoir 14 .

A component 63 is attached to the side of the membrane 42 opposite the cavity 41 , that is to say on the outside of the pressure vessel 31 . This component 63 has a recess which, together with the membrane 42, forms a chamber 43 . In this chamber 43 , a needle valve can be attached to the bore 64 , via which the vibration damping behavior can be adjusted.

In the area of its upper side, the pressure vessel 31 of the aortic block 30 has two white holes 46 and 47 . At the bore 46 a Ma nometer 49 is connected via a line 48 , on which the pressure in the interior 34 of the pressure vessel 31 can be read. Furthermore, a syringe 50 is connected to a line 49 branching off from the line 48 , with which the amount of gas in the cavity 34 can be changed. The bore 47 contains an insertion screw 65 for a so-called micro-tip pressure transducer, which can be inserted through the bore 47 into the aortic block 30 and extends axially into the sem through a guide tube 51 , leaves it again through the bore 36 and via the to the heart 1 leading line 16 b can be inserted into a heart chamber.

The structure of the artificial flow resistance 32 will be explained below with reference to FIG. 3. The bores 38 and 39 are covered with a membrane 52 , which is sealingly connected along its edge to the outer wall of the pressure vessel 31 . The membrane 52 is preferably made of rubber. Behind the membrane 52 is a component 53 with a recess facing the membrane 52 . Together with the membrane 52 , this recess forms a chamber 54 . This chamber 54 is accessible to pressurization via a line 55 , which can be partially incorporated in the component 53 .

The line 55 leads, as shown in FIG. 2, to a spindle syringe 56 , which essentially consists of a cylinder 57 and a piston 58 . The piston 58 can be screwed into the cylinder 57 via a threaded rod 59 running in a thread of the cover and a setting wheel 60 attached thereto, as a result of which the pressure within the cylinder 57 , the line 55 and thus the cavity 54 can be changed. To the cylinder 57 a pressure gauge 61 is also connected, to which the pressure can be read within the cylinder 57th The interior of the cylinder 57 can be connected to the environment for pressure equalization via a valve 62 .

Since the isolated heart 1 , as described in the introduction, works essentially empty in the "Langendorff method", a balloon 69 is provided in the left ventricle of the isolated heart 1 , which is connected via a line 70 to a spindle syringe 71 and a pressure sensor 72 connected is. By actuating the syringe 71 , the internal pressure of the balloon 69 , and thus a preload in the left ventricle, can be set and read off at the outlet 73 of the pressure sensor 72 , for example with the aid of an oscilloscope or a measuring device. Finally, a possibility of measuring the coronary flow is provided. For this purpose, a flow sensor 74 is attached to the supply line 16 c, the output 75 of which can be fed to a measuring device and from whose signal output to an oscilloscope.

The perfusion apparatus can be used both under constant flow conditions and under constant pressure conditions. For measurements at constant flow, the pressure in the interior of the cylinder 57 and thus in the cavity 54 is set somewhat higher by screwing in the piston 58 than the perfusion pressure to be expected during the test may be physiologically. This leads to a permanent closure of the through hole 38 as long as the perfusion pressure remains in the physiological range. The desired flow can now be set on the pump 16 . If, for example due to incorrect setting of the pump 16 , the perfusion pressure and thus the pressure in the bore 38 becomes greater than the pressure in the cavity 54 , the membrane 52 dodges and opens the way to the bore 39 and thus to the return line 45 . This effectively protects the coronary vascular system against impermissibly high perfusion pressure.

The pump 16 sucks perfusate via the suction line 16 a from the reservoir 14 and pumps it via the supply line 16 b to the bore 35 in the wall of the pressure vessel 31 . Since its other bores ( 46 , 47 , 38 ) are tightly sealed, a defined liquid level 37 is reached when a certain, dependent on the isolated heart 1 is dependent, internal pressure, and the isolated heart 1 becomes with the constant flow set on the pump 16 with coronary flow. This can be checked by looking at the signal from the output 75 of the flow sensor 74 . The aortic pressure is detected via the pressure sensor 67 , the output signal 68 of which is viewed in a time-resolved manner on an oscilloscope. Since the isolated heart 1 beats, the pressure is not constant over time, but pulsates. The pulsation of this pressure can now be influenced by changing the volume in the interior 34 of the pressure vessel 31 . This interior 34 takes over here the natural wind boiler function of the aorta. Based on the shape of the pressure curve of the aortic pressure detected by the oscilloscope, the degree of filling of the air chamber (interior space 34 ) can now be changed with the aid of the syringe 50 until an approximately "physiological" curve shape of the pulsation is reached. The valve in line 49 is then closed and the experiments can be started.

To work at constant pressure, which is usually physiologically cheaper, the pump 16 is switched to a sufficiently high delivery rate and the pressure in the cylinder 57 is brought to the desired perfusion pressure by unscrewing the piston 58 via the threaded rod 59 and turning handle 60 . This can be read on the manometer 61 . As soon as a higher than the set pressure is present in the pressure vessel 31 , the membrane 52 recedes into the cavity 54 , whereby the bore 38 is connected to the bore 39 , and thus to the line 40 . Excess perfusate is fed via line 40 to the membrane vibration damper 33 , which compensates for 42 pressure peaks by the yielding of its elastic membrane. The elasticity of the membrane 42 and thus its pressure compensation behavior can be adjusted by varying the pressure compensation speed in the chamber 43 behind the membrane 42 . For this purpose, this chamber has a needle valve in the bore 64 . After leaving the diaphragm vibration damper 33 through the bore 44 , the perfusate flows through the return line 45 back into the reservoir 3 . The function of the wind chamber and the other functions of the perfusion device correspond to the description of the constant flow condition.

In the exemplary embodiment of an experimental apparatus "Ar working heart" shown in FIG. 4, an atrial head 83 is additionally provided, in which all parts are integrated which must be present close to the atrial cannula 84 for the functional connection of the left atrium of the isolated heart 1 . Because of the preparation-related atrium of the isolated heart 1 , the wind chamber 85 in the atrial head 83 is particularly important so that a satisfactory filling of the ventricle is ensured. Furthermore, the wind boiler 85 should intercept possibly washed-in air or gas bubbles. It is located near the exit hole to the cannula cone in the atrial head 83 . In operation, the wind chamber 85 should be about half full of perfusate. This level can be adjusted with the injection syringe 86 . A line 87 connects to the atrial head 83 for the supply of the perfusate. This line 87 leads to a preload vessel 88 , which serves to provide the perfusate flowing into the atrium. The height difference between the liquid level 89 in the preload vessel 88 and the atrium results in a hydrostatic pressure which corresponds to the filling pressure of the atrium. This pressure is illustrated in Figure 4 by "X".

For the atrial supply, a two-channel peristaltic pump 90 is also provided, which serves to provide the perfusate in the preload vessel 88 at a constant level 89 . The content of the preload vessel 88 can be gassed via a Begasungsein device 26 a. The perfusate is provided via the line 91 in excess, ie more and more perfusate is pumped into the preload vessel 88 than is required by the isolated heart 1 . The excess pumped volume is sucked off via line 92 of the second pump channel and pumped back into the reservoir 14 . For this purpose, the line 92 ends at the level of the desired liquid level 89 in the preload vessel 88 .

In the line 87 for the supply of the perfusate to the atrial head 8 , a tap block 93 with flow sensor 94 and shut-off valve 95 is installed. The flow sensor 94 is used to record the atrial flow or its mean value. With the stopcock 95 , the atrial flow can be adjusted according to the requirements of the respective operating state. A pressure sensor 96 for detecting the atrial filling pressure is also connected to the atrial block 83 . Its output leads to a pressure measuring amplifier, not shown, whereupon the signal can be observed on a measuring device or an oscilloscope. The atrial head 83 finally also has a connection for an injection syringe 97 , from which any substance can be continuously admixed.

The pump 16 is inoperative in this method. The heart is operated in Langendorff mode during the preparation phase. The supply takes place via the aortic block 30 from the pump 16 . As soon as the atrial cannula 84 is integrated, the stopcock 95 is opened. The perfusate now flows from the preload vessel 88 into the left ventricle and is pumped from the heart into the aorta. If the heart has reached a sufficient delivery rate, the pump 16 can be switched off. The heart is now self-sufficient, you are in "Working Heart" mode. The aortic block now takes over the function of aorta and vascular resistance.

Claims (32)

1. Device for perfusion of the coronary arteries of an isolated heart, comprising at least one reservoir for the perfusate and a pump which pumps the perfusate out of the reservoir via a supply line into the aorta of the isolated heart, characterized in that the supply line ( 16 b , 16 c) is interrupted by a closed container ( 31 ), partly filled with the perfusate and partly with gas, and the amount of gas in this container ( 31 ) is adjustable. 2. Apparatus according to claim 1, characterized in that the container ( 31 ) in the perfusate filling has a first through hole ( 38 ), against the outlet opening sealingly presses a closure member with a defined force and this closure member when a certain pressure is exceeded in Container ( 31 ) withdraws and thus allows perfusate to escape from the container ( 31 ). 3. Apparatus according to claim 2, characterized in that the perfusate emerging from the container ( 31 ) is returned via a return line ( 45 ) into the re servoir ( 14 ). 4. Apparatus according to claim 2 or 3, characterized in that the opening from the first through hole ( 38 ) is covered by an elastic membrane forming the closure part ( 52 ) and on the side facing away from the opening of the membrane ( 52 ) first chamber ( 54 ) is located, the internal pressure of which generates the defined force on the membrane ( 52 ). 5. Apparatus according to claim 3 or 4, characterized in that the membrane ( 52 ) is sealingly connected along its edge to a plate which has a second through hole ( 39 ) which is connected to the return line ( 45 ) and the opening thereof is covered by the elastic membrane ( 52 ) and when a certain pressure in the container ( 31 ) is exceeded, a connection between the container ( 31 ) and the return line ( 45 ) is formed. 6. Apparatus according to claim 4 or 5, characterized in that the first chamber ( 54 ) is connected via a line ( 55 ) to a cylinder ( 57 ) whose internal pressure is adjustable with a displaceable piston ( 58 ). 7. The device according to claim 6, characterized in that the cylinder / piston system ( 57, 58 ) is part of a spindle syringe ( 56 ). 8. Device according to one of claims 4 to 7, characterized in that a manometer ( 61 ) for displaying the pressure in the first chamber ( 54 ) is present. 9. Device according to one of claims 4 to 8, characterized in that the membrane ( 52 ) consists of rubber. 10. Device according to one of claims 5 to 9, characterized in that the plate is identical to the wall of the container ( 31 ). 11. Device according to one of claims 3 to 10, characterized in that the return line leads before reaching the reservoir ( 14 ) to a cavity ( 41 ), of which at least one wall for the purpose of vibration damping by a second, elastic membrane ( 42nd ) is formed. 12. The apparatus according to claim 11, characterized in that on the side of the second membrane ( 42 ) facing away from the cavity ( 41 ) there is a second chamber ( 43 ), the internal pressure properties of which also determine the elastic behavior of the second membrane ( 42 ). 13. The apparatus according to claim 12, characterized in that the wall of the second chamber ( 43 ) contains a needle valve. 14. Device according to one of claims 11 to 13, characterized in that the cavity ( 41 ) is formed by a recess in the outer wall of the container ( 31 ) which is covered with the second membrane ( 42 ). 15. Device according to one of the preceding claims, characterized in that the amount of gas in the container interior ( 34 ) by means of a syringe ( 50 ) connected to it is adjustable. 16. Device according to one of the preceding claims, characterized in that a manometer ( 49 ) for displaying the pressure in the container interior ( 34 ) is present. 17. Device according to one of the preceding claims, characterized in that a heat exchanger is built into the supply line ( 16 b) and / or the reservoir ( 14 ) is temperature-controlled. 18. Device according to one of the preceding claims, characterized in that the reservoir ( 14 ) has a gassing device ( 26 ) for the fusate. 19. Device according to one of the preceding claims, characterized in that a pressure probe catheter for detecting the pressure profile in the left ventricle of the isolated heart ( 1 ) is present. 20. The apparatus according to claim 19, characterized in that the pressure catheter is guided through a guide tube ( 51 ) in the container ( 31 ) to the left ventricle. 21. Device according to one of claims 3 to 20, characterized in that the return line ( 45 ) or the last part of the supply line ( 16 c) contains a flow sensor ( 74 ) for detecting the aortic flow. 22. Device according to one of the preceding claims, characterized in that a balloon ( 69 ) is provided for insertion into the left ventricle of the isolated heart ( 1 ), the internal pressure of which can be changed and can be displayed via a pressure sensor ( 72 ). 23. Device according to one of the preceding claims, characterized in that the drain line ( 27 ) contains a flow sensor for detecting the coronary flow and / or from the drain line ( 27 ) branches off a measuring line into which flow and / or gas partial pressure measuring devices or transducers ( 80 , 82 ) are integrated. 24. Device according to one of the preceding claims, characterized in that a pressure sensor ( 67 ) for measuring the pressure in the interior ( 34 ) of the container ( 31 ) is present. 25. Device according to one of the preceding claims, characterized in that it comprises an atrial head ( 83 ) which via a connec tion cone ( 84 ) with the left atrium of the isolated heart ( 1 ) and via a line ( 87 ) with a preload vessel ( 88 ) is connected and this forecourt head is partly filled with the perfusate and partly with gas, the gas filling forming a wind kettle ( 85 ). 26. The apparatus according to claim 25, characterized in that the amount of gas in the air vessel ( 85 ) by an injection syringe ( 86 ) is adjustable. 27. The apparatus of claim 25 or 26, characterized in that the liquid level ( 89 ) in the preload vessel ( 88 ) can be kept constant and the height difference (X) between the liquid level ( 89 ) and the atrium of the isolated heart ( 1 ) to the hydrostatic pressure Atrial filling created. 28. The apparatus according to claim 27, characterized in that the liquid speed mirror ( 89 ) by means of a two-channel peristaltic pump ( 90 ) can be kept constant, which perfusate in abundance from the reservoir ( 14 ) via a Lei device ( 91 ) in the preload vessel ( 88 ) promotes and excess perfusate via a line ( 92 ) back into the reservoir ( 14 ). 29. Device according to one of claims 25 to 28, characterized in that the preload vessel ( 88 ) has a gassing device ( 26 a) for the perfusate. 30. Device according to one of claims 25 to 29, characterized in that a pressure sensor ( 96 ) for detecting the atrial filling pressure is connected to the atrial head ( 83 ). 31. The device according to one of claims 25 to 30, characterized in that the connecting line ( 87 ) between the atrial head ( 83 ) and the front load vessel ( 88 ) contains a flow sensor ( 94 ) and / or a shut-off valve ( 95 ). 32. Device according to one of claims 25 to 31, characterized in that a further injection syringe ( 97 ) or infusion pump is connected to the atrial head ( 83 ) via a line from which the perfusate in the atrial head ( 83 ) can be admixed with a substance.