Methods and systems for the treatment, mitigation, or prevention of post-ischemia reperfusion injury

Abstract

A device comprising interconnected components for deoxygenating blood used in the treatment and prevention of reperfusion injury, including a configuration to reduce the ionized calcium concentration of the deoxygenated blood to less than 0.5 mmol / L. The components may include a syringe pump operably communicating with various configurations via a control unit / processor, a cannula, a pump communicating with the cannula, a heat exchanger, a device for generating / creating fluid flow, an infusion port, a mixing port, a device hub, and a catheter hub. These components are selectively connected to a subject, and monitoring and / or other lead wires / devices may be attached to the subject. The lead wires / devices may include sensors and other devices that can be attached to / connected to the subject, providing health indicators, such as a temperature sensor, electrodes for monitoring cardiac electrical activity, and an oxygen saturation (SpO2) sensor for monitoring the patient's blood oxygen saturation.

Description

Technical Field

[0001] Cross-reference of related applications This application claims priority based on U.S. Provisional Patent Application No. 63437304, filed on January 5, 2023, the entire content of which is incorporated herein by reference.

[0002] Aspects of the present disclosure relate to methods and systems for reducing reperfusion injury in the treatment of post-ischemic tissue, for example, by adjusting parameters of the reperfusion fluid.

Background Art

[0003] A stroke is a very serious condition in which blood flow to a part of the brain is blocked or severely reduced, resulting in cell death and potentially irreversible tissue damage. A stroke can be caused, for example, when a fragile blood vessel ruptures (known as a hemorrhagic stroke) or when a blood vessel becomes blocked (known as an ischemic stroke). Stroke is a serious global health problem.

[0004] Ischemic stroke can be classified as thrombotic stroke or embolic stroke. Thrombotic stroke is usually caused by the formation of a thrombus (blood clot) around an atherosclerotic plaque. Embolic stroke can occur when an artery is blocked by an embolus, such as a particle or tissue fragment that has migrated from another site (for example, arterial embolism). An embolus is usually a thrombus, but can also be one of other substances, such as fat, a bacterial mass, cancer cells, or air.

[0005] One conventional method of treating ischemic stroke patients is thrombectomy, a procedure that mechanically removes blood clots that are too large to be dissolved by thrombolytic agents. Generally, thrombectomy is more effective the earlier it is performed after the onset of a stroke. In fact, it is widely accepted in conventional medicine that the time during which cells are deprived of oxygen is crucial for a good prognosis in stroke. The phrase "time is brain" is commonly used to describe this phenomenon.

[0006] Once the blockage is removed from the blood vessel, blood is reintroduced to the oxygen-deficient tissue. When cells are deprived of oxygen, they usually enter a kind of dormant state, with reduced metabolism and activity. This is a protective state to prolong survival until oxygen supply is restored. Counterintuitively, if blood flow and oxygen supply are restored without control, it can lead to severe damage to the cells. This can occur because cells recover from dormancy and are placed in an unsuitable environment. Therefore, once blood flow is restored, ischemic injury subsides, but reperfusion injury may occur. Thus, reperfusion injury can develop after ischemia.

[0007] While existing treatments such as thrombectomy can be very effective in removing the cause of stroke, they often fail to address reperfusion injury. The clinical need for treatments, as well as related systems and methods, to mitigate or prevent reperfusion injury after ischemic stroke remains unmet by conventional technologies.

[0008] The precise clinical mechanisms of reperfusion are not fully understood, but calcium ion overload, tissue metabolic rate, and / or inflammatory responses may be involved. Blood carbon dioxide and oxygen concentrations are known to influence cytotoxicity that occurs during the restoration of blood flow to post-ischemic tissues.

[0009] The reduction of calcium ions can be achieved by using chelating agents (such as EDTA (ethylenediaminetetraacetic acid) and sodium citrate). The addition ratio of chelating agents can be influenced, controlled, and measured volutatively. Chelation of calcium ions can reduce the bioavailability of calcium ions in reperfused tissue. For example, when used in combination with other treatments for reperfused tissue, it can be expected to prevent edema and the "no-reflow" phenomenon.

[0010] Blood pH is thought to influence the progression of reperfusion injury, and the addition of acids, bases, or buffer molecules may potentially suppress its progression. When carbon dioxide is used in the sweep gas flow of an oxygen supply system, that carbon dioxide can alter the blood pH.

[0011] No-reflow can occur when tissue swelling obstructs blood flow in the capillaries within the tissue. This phenomenon is considered one of the major causes of post-stroke complications and can hinder or make various treatments inapplicable. In healthy individuals, pulsatile flow is produced by ventricular ejection, and it is known that such pulsatile flow flows efficiently through the capillaries. Non-pulsatile flow, such as that obtained with unmodified peristaltic or centrifugal pumps, is known to reduce the efficiency of blood flow through the capillary bed and can lead to clinical problems such as "pump head" issues. These problems can be more pronounced, for example, in reperfusion injury, where edema can obstruct capillary flow.

[0012] The metabolic rate of tissues depends on tissue temperature, and it is known that lowering the temperature of reperfusion tissue can sometimes mitigate the damage that would be expected at normal temperatures. The timing of this temperature reduction is often extremely important, and its effectiveness may decrease as reperfusion injury progresses.

[0013] Osmolality by weight is expressed as the number of moles of solute per liter of solvent. In membrane science, osmosis, such as that observed between cell membranes, acts to create an equilibrium between low and high osmolality regions. Therefore, regulating the osmolality of the reperfusion solution may control the diffusion of such solutes between cell membranes and have a neuroprotective effect.

[0014] The administration of neuroprotective injectors and drugs with specific cellular effects has been shown to be ineffective in "real-world" applications for the treatment of reperfusion injury. One reason for this is, for example, the severe damaging effect of arterial blood on reperfused tissue. By mitigating the damaging effect of arterial blood during reperfusion, drug administration that was previously impossible or difficult becomes possible.

[0015] During reperfusion, the immune system is involved, and when the circulating immune system detects cellular contents, an inflammatory pathway may be triggered. Mitigation of damage caused by such inflammatory immune responses can be achieved, for example, by pharmaceutical means or by removing circulating immune cells through specialized filtration.

[0016] Many existing perfusion systems are designed for systemic perfusion flow rates of 4000 ml / min to 7000 ml / min or higher, and are not suitable for reperfusion of individual organs. This is because the size and area of ​​the contact surface and the internal volume of the device do not match the blood flow rate required for a single organ. If the gas exchange surface area is excessive for a given blood flow rate, an overabundance of oxygen species may be introduced, potentially leading to free radical damage in the reperfused tissue.

[0017] While single-organ storage circuits are often manufactured for preserving extracorporeal organs for transplantation, these may lack the necessary safety features for use in living organisms. For example, they may not take into account the risk of damage to other organs. Preventing, detecting, and removing microbubbles and thrombi in the perfusion fluid can be extremely important when returning the perfusion fluid to the vascular circulation.

[0018] It is known in the art that the introduction of an insulating catheter or sensor catheter is necessary for reperfusion of cooled perfusion fluid. However, such configurations are constrained by factors such as: (1) the need for dimensional compatibility with existing commercially available catheters (such as balloon-guided catheters), or (2) the risk of injury if these are administered after removal of an inline catheter, as calcium-rich, ambient-temperature arterial blood may reach the tissue prior to reperfusion therapy intervention. Connectability to the standard Luer connector of existing catheters has the advantage of avoiding these two problems.

[0019] The mechanisms causing reperfusion injury are complex and known to progress over time, with each damaging factor inducing injury at different times depending on the rate at which it triggers the injury. For example, the diffusion of calcium ions across the cell membrane occurs much faster than the time it takes for the immune response to cell damage to be activated. Therefore, controlling blood parameters to mitigate reperfusion injury depends on appropriately controlling the profile of therapeutic parameters in the blood.

[0020] Reperfusion injury occurs in any tissue that has been deprived of oxygen for an extended period. Other clinically important examples include chronic total occlusion, myocardial infarction, and limb ischemia. [Overview of the Initiative]

[0021] According to aspects of this disclosure, apparatuses, methods, and systems are provided that address the above-mentioned and other problems of the prior art by utilizing various interconnected components for deoxygenating blood used in the treatment or prevention of reperfusion injury. For example, a configuration is included for ensuring that the ionized calcium concentration of the deoxygenated blood is less than 0.5 mmol / L.

[0022] Some additional advantages and novel features of these aspects will become apparent in the following description, and some will become even more apparent to those skilled in the art by considering the following description or practicing the present disclosure.

Brief Description of Drawings

[0023] [Figure 1] FIG. 1 is a diagram showing an example of various components according to an embodiment of a system for deoxygenating blood used for the treatment or prevention of reperfusion injury, and having a function to make the ionized calcium concentration of the processed blood less than 0.5 mmol / L. [Figure 2] FIG. 2 is a diagram showing a representative flowchart of functions related to the control, monitoring, and / or regulation of blood flow, including functions related to venous blood extracted in circulation or extracorporeally, processed venous blood, and the overall blood supply, according to an aspect of the present disclosure. [Figure 3] FIG. 3 is a representative flowchart of functions related to various coordinated inputs and operation controls related to blood flow control according to an aspect of the present disclosure. [Figure 4] FIG. 4 is a representative flowchart of functions related to various coordinated inputs and operation controls related to chelation rate control according to an aspect of the present disclosure. [Figure 5] FIG. 5 shows a representative flowchart of functions related to various coordinated inputs and operation controls related to temperature control according to an aspect of the present disclosure. [Figure 6] FIG. 6 is a representative flowchart of functions related to various coordinated inputs and operation controls related to gas control according to an aspect of the present disclosure. [Figure 7] FIG. 7 is a representative diagram showing various components of a computer system capable of executing the functions described in an embodiment according to an aspect of the present disclosure. [Figure 8] FIG. 8 is a representative block diagram showing an example of various system / network components that can be used in accordance with the content described in an embodiment according to an aspect of the present disclosure. [Figure 9A] FIG. 9A is a cross-sectional view showing various cross-sectional shapes / features of an example of a mixing port that can be used according to an aspect of the present disclosure. [Figure 9B] FIG. 9B is a cross-sectional view showing various cross-sectional shapes / features of an example of a mixing port that can be used according to an aspect of the present disclosure together with FIG. 9A.

MODE FOR CARRYING OUT THE INVENTION

[0024] According to an aspect of the present disclosure, there are provided an apparatus, a method, and a system for addressing the above problems and other problems in the prior art.

[0025] FIGS. 1 to 9B show various features of an apparatus, a method, and a system for addressing such problems, including features and methods for deoxygenation of blood used for treatment or prevention of reperfusion injury. Among a plurality of advantages, in particular, the ionized calcium concentration of the deoxygenated blood is less than 0.5 mmol / L. Such deoxygenated blood may be venous blood. Note that the normal level of oxygen in the blood is about 100 mmHg. If it contains an oxygen carrier group such as red blood cells or synthetic or biotechnologically produced heme molecules, such a blood preparation can also be used instead of or in combination with deoxygenated venous blood.

[0026] The altered blood may be selectively administered intra-arterially or intra-venously, or may be administered at a predetermined appropriate temperature. This blood may be selectively administered, for example, to a patient suffering from ischemic stroke, and this blood may be taken from the patient. For example, this blood may be administered during reperfusion after thrombectomy (in some cases, preferably after thrombectomy). The reperfusion event may be, for example, reperfusion injury in ischemic stroke or may include such an injury. Administration of the altered blood may preferably, but not limited to, be performed according to an event such as reperfusion injury due to ischemic stroke in the neurovascular system.

[0027] Deoxygenated blood may be selectively administered in combination with anticoagulants.

[0028] Deoxygenated blood may selectively include, for example, the administration of contrast agents used in radiography.

[0029] Figure 1 shows various configurations relating to an example of a system embodiment that addresses the above-mentioned problems and other problems. As shown in Figure 1, the system 100 may comprise one or more of the following configurations: 1) one or more syringe pumps 105 operably connected to the various configurations of the system 100; 2) a cannula 110; 3) a pump 115 communicating with the cannula 110; 4) a heat exchanger (HEX 120); 5) an oxygen supply device and / or other device 130, which is a device for generating / generating a fluid flow containing one or more of oxygen, hydrogen, nitrogen, nitrous oxide and / or carbon dioxide; 6) one or more injection ports 135; 7) a mixing port 140; 8) a device hub 145; 9) a catheter hub 150; and 10) a patient 155 selectively connected thereto, the patient 155 may optionally be fitted with one or more monitoring and / or other lead wires / devices. The lead wires / devices may include various sensors and / or other devices that can be attached to or otherwise connected to the patient and used to obtain health indicators. Examples include one or more temperature sensors, multiple electrodes or electrode connectors configured to be selectively attached to electrodes for monitoring the electrical activity of the heart, and / or oxygen saturation (SpO2) sensors or other sensors for monitoring the patient's blood oxygen saturation.

[0030] Each of the above components / patients 105-155 may be operably connected to a device 160 comprising a control unit, inputs / outputs, and a processor (which may include, for example, one or more processors and / or one or more networks and / or other configurations, as further described in relation to Figures 7 and 8, and such a processor device is also referred to herein as the “control unit”). One of its functions may be to selectively control the infusion of deoxygenated blood into patent 155 by selectively receiving data and / or other inputs from each of these components 105-155 and selectively providing data / outputs to each of these components 105-155. Alternatively, or in addition, the control unit 160 may be configured to access information relating to one or more components 105-155 to enable bidirectional monitoring and control of various system functions (for example, via data stored in a local or remote data repository, the remote data being accessible, for example, via a network). For example, such accessible data may include profile information of commercially available catheters, and the control unit 160 may utilize stored profile information corresponding to the catheters used in the system 100 to easily adjust flow parameters to supply pulsatile flow to each vessel in sync with the patient's heartbeat. In one embodiment, for example, a user (such as a clinician) can select or confirm the type information / catheter information to be used in the system to provide the necessary supply. The system 100 may then automatically or otherwise adjust the parameters of the pulsatile flow pump and / or other system parameters so that the necessary supply is provided, for example, in response to a detected heartbeat.

[0031] In one embodiment of the present disclosure, venous blood (or, for example, suitable patient-derived blood or blood substitute fluid) may be collected from the venous system via, for example, a venous cannula (such as a Medtronic Bio-Medicus cannula from Medtronic, Irvine, California) (110), passed through a pulsatile flow pump (such as a Harvard Apparatus 1423 pulsatile from Harvard Apparatus, Holliston, Massachusetts) (115), and sent to a heat exchanger (such as a CAPIOXR myocardial protection heat exchanger from Thermocorticoids, Ann Arbor, Michigan) (120). Flow rate and blood temperature may be used to control the temperature within the heat exchanger (120). Sensors may detect blood temperature and flow rate and transmit this information to a control unit (160), which may adjust the mixing of sweep gases via an oxygen supply or other fluid generation / flow supply device (130). The flow rate on the output side of the fluid generation / flow supply device (130) may be measured and transmitted to the control unit (160), and the syringe pump (105) may be operated to adjust the rate at which the chelating agent is added through the infusion port (135). To ensure that the chelating agent is uniformly dispersed in the reperfusion fluid flow, blood may be passed through the mixing port (140) (see Figures 9A and 9B, which include cross-sectional views showing various cross-sectional shapes / features relating to an example of a mixing port usable according to an aspect of this disclosure). For example, blood may be introduced into the device hub (145) attached to the catheter hub (150) of the guide catheter. The control unit (160) may change the target parameters to adjust the temperature, gas, and chelating gradients as required by the patient's therapeutic needs, and may further add adjunctive therapies such as calcium ions or magnesium ions, anticoagulants, radiodetectable compounds, and / or neuroprotective agents through the infusion port.

[0032] Figures 2-6 show typical flowcharts relating to various functions related to the provision of deoxygenated blood and / or other related inputs / outputs / controls, such as one or more functions related to the configuration illustrated in Figure 1, in accordance with aspects of the present disclosure.

[0033] Figure 2 is a diagram showing a typical flowchart of functions related to the control, monitoring, and / or regulation of blood flow, including functions related to circulating or extracorporeally extracted venous blood, processed venous blood, and systemic blood supply, according to aspects of this disclosure.

[0034] Figure 3 is a typical flowchart of various interconnected input and motion control functions related to blood flow control, according to the embodiments of this disclosure.

[0035] Figure 4 is a typical flowchart of various interconnected input and operation control functions related to chelation rate control, according to an aspect of this disclosure.

[0036] Figure 5 shows a typical flowchart of various interconnected inputs and operation control functions related to temperature control, according to an aspect of this disclosure.

[0037] Figure 6 is a typical flowchart of various interconnected input and operation control functions related to gas control, according to an aspect of this disclosure.

[0038] The embodiments of this disclosure may be implemented by hardware, software, or a combination thereof, and may be implemented in one or more computer systems or other processing systems. One embodiment of this disclosure is configured for one or more computer systems capable of performing the functions described in the specification. Various embodiments of such a computer system 1900 are shown in Figure 7.

[0039] The computer system 1900 comprises one or more processors, including a processor 1904. The processor 1904 may be connected to a communication infrastructure 1906 (for example, a communication bus, crossover bar, or network). Various software configurations will be described based on this computer system example. By reading the description herein, those skilled in the art will understand how to implement configurations of this disclosure using other computer systems and / or architectures.

[0040] The computer system 1900 may include a display interface 1902 for transferring images, text, and other data from a communication infrastructure 1906 (or a frame buffer, not shown) for display on a display device 1930. The computer system 1900 may also include a main memory 1908, such as random access memory (RAM), and may further include an auxiliary storage device 1910. The auxiliary storage device 1910 may include, for example, a hard disk drive 1912 and / or a removable storage drive 1914. Examples of removable storage drives 1914 include floppy disk drives, magnetic tape drives, optical disk drives, etc. The removable storage drive 1914 may read from and / or write to the removable storage device 1918 by known methods. The removable storage device 1918 may be represented by a floppy disk, magnetic tape, optical disk, etc., and may be read from and written to by the removable storage drive 1914. As will be understood by those skilled in the art, the removable storage device 1918 may include a storage medium usable by a computer on which computer software and / or data is stored.

[0041] In other embodiments, the system may include an auxiliary storage device 1910, and other similar devices for loading computer programs and other instructions into the computer system 1900. Such devices may include, for example, a removable storage device 1918 and an interface 1920. Examples of such devices include a program cartridge and its cartridge interface (for example, as found in video game consoles), a removable memory chip (for example, an erasable programmable read-only memory (EPROM) or programmable read-only memory (PROM)) and a corresponding socket, and other removable storage devices 1922 and interfaces 1920. These enable the transfer of software and data from the removable storage device 1914 to the computer system 1900.

[0042] The computer system 1900 may further include a communication interface 1924. The communication interface 1924 may enable the transfer of software and data between the computer system 1900 and external devices. Examples of the communication interface 1924 include a modem, a network interface (such as an Ethernet card), a communication port, and PCMCIA standard slots and cards. The software and data transferred via the communication interface 1924 may be in the form of signals 1928, which may be or include electronic signals, electromagnetic signals, optical signals, or other signals receivable by the communication interface 1924. These signals 1928 may be supplied to the communication interface 1924 via a communication path (e.g., a channel) 1926. The communication path 1926 may transmit the signals 1928 and may be implemented using wires or cables, optical fibers, telephone lines, cellular links, radio frequency (RF) links, and / or other communication channels. In this specification, the terms “computer program medium” and “computer-usable medium” typically refer to media such as a removable storage drive 1914, a hard disk contained within a hard disk drive 1912, and / or a signal 1928. These computer program products may supply software to the computer system 1900. Aspects of this disclosure relate to such computer program products.

[0043] The computer program (also called computer control logic) may be stored in the main memory 1908 and / or the auxiliary memory 1910. The computer program may be received via the communication interface 1924. By executing such a computer program, the computer system 1900 may be made capable of performing functions according to the various embodiments described herein. In particular, by executing the computer program, the processor 1904 may be made capable of performing functions according to the embodiments of this disclosure. Thus, such a computer program can be considered to represent the controller of the computer system 1900.

[0044] Aspects of this disclosure may be implemented using software, which may be stored in a computer program product and loaded into a computer system 1900 using a removable storage drive 1914, a hard drive 1912, or a communication interface 1924. The control logic (software), when executed by a processor 1904, may cause the processor 1904 to perform the functions described herein. In other aspects of this disclosure, the system may be implemented primarily in hardware, using hardware components such as, for example, an ASIC. Implementation of a hardware state machine for performing the functions described herein will be obvious to those skilled in the art.

[0045] Further modifications may show that aspects of this disclosure may be implemented by a combination of hardware and software.

[0046] Figure 8 is a block diagram of various examples of system components used in accordance with aspects of this disclosure. Figure 8 shows a communication system 2000 that can be used in accordance with aspects of this disclosure. The communication system 2000 shown in Figure 4 includes one or more accessors 2060 (also referred to herein as one or more “users”) and one or more terminals 2042. In one embodiment, data used in accordance with aspects of this disclosure is input and / or accessed by accessors 2060, for example, via terminals 2042. Examples of terminals 2042 include personal computers (PCs), command issuing devices with graphical user interfaces (GUIs), minicomputers, mainframe computers, microcomputers, telephone equipment, and wireless devices connected to server 2043, such as personal digital assistants (PDAs), smartphones, and other handheld wireless devices. Examples of server 2043 include PCs, minicomputers, mainframe computers, microcomputers, or other devices. The other devices include a processor, have a data repository, and / or are connected to the data repository via a network 2044 such as the Internet or an intranet and couplings 2045, 2046, and 2047. Examples of couplings 2045, 2046, and 2047 include wired links, wireless links, or fiber optic links. In one example, an aspect of the control unit / system 2070 related to reperfusion failure may be connected to the network 2044 via coupling 2047, thereby enabling it to receive and transmit input data from a user server 2043 and a user 2060. For example, a user can monitor and / or input information regarding the operation of the control unit / system. In other modifications, the methods and systems according to aspects of the present disclosure may operate in a standalone environment, such as operating on a single terminal.

[0047] The following numbered sections indicate the aspects of this disclosure:

[0048] Paragraph 1: A method for selectively administering treated blood or blood substitute for use in the treatment or prevention of reperfusion injury, the method comprising a step of selectively treating circulating blood or extracorporeal blood or blood substitute, the selective treatment step of adjusting the circulating blood or extracorporeal blood or blood substitute to control its temperature; The regulated circulating blood, extracorporeal blood, or blood substitute is passed through a fluid generation / flow supply device to control dissolved gases; Adjust the circulating blood, extracorporeal blood, or blood substitute by performing at least one selected from the following: changing the amount of gas in the circulating blood, extracorporeal blood, or blood substitute; reducing the amount of ionized calcium in the circulating blood, extracorporeal blood, or blood substitute; and lowering the pH of the circulating blood, extracorporeal blood, or blood substitute; and This includes monitoring the supply of the aforementioned circulating blood, extracorporeal blood, or blood substitute. A method for administering the adjusted and passed circulating blood, extracorporeal blood, or blood substitute to a subject when the ionized calcium concentration of the selectively treated circulating blood, extracorporeal blood, or blood substitute is less than 0.5 mmol / L.

[0049] Paragraph 2 The method according to Paragraph 1, wherein the processed blood or blood substitute is venous blood.

[0050] Paragraph 3: The method according to Paragraph 1, wherein the processed blood or blood substitute is administered intra-arterial or intravenously.

[0051] Paragraph 4 The method according to Paragraph 1, wherein the processed blood or blood substitute is administered to a subject suffering from ischemic stroke, and the prepared blood or blood substitute is derived from the subject.

[0052] Paragraph 5 The prepared blood or blood substitute described above is administered during reperfusion as described in paragraph 1.

[0053] Paragraph 6: The prepared blood or blood substitute described above is administered after thrombectomy according to the method described in paragraph 5.

[0054] Paragraph 7 The method according to paragraph 1, wherein the prepared blood or blood substitute is administered in combination with an anticoagulant.

[0055] Paragraph 8 The method described in Paragraph 1, wherein the reperfusion injury is reperfusion injury due to ischemic stroke.

[0056] Paragraph 9: The method according to Paragraph 8, wherein the ischemic stroke or reperfusion injury is reperfusion injury of an ischemic stroke in the neurovascular system.

[0057] Paragraph 10 The method according to paragraph 1, wherein the prepared and passed circulating blood or extracorporeal blood or blood substitute contains a contrast agent used for radiography.

[0058] Paragraph 11 The method according to paragraph 1, wherein the prepared and passed circulating blood or extracorporeal blood, or blood substitute, is administered in combination with a contrast agent used for radiography.

[0059] Paragraph 12 A composition for use in the treatment or prevention of reperfusion injury in a subject, the composition comprising controlled and passed circulating blood or extracorporeal blood or blood substitute, and further comprising at least one selected from an anticoagulant and a contrast agent used for radiography.

[0060] Paragraph 13 A system for selectively administering treated blood or blood substitute for the treatment or prevention of reperfusion injury, the system comprising a conduit and; A flow control device that selectively operates with the conduit to allow deoxygenated blood or blood substitute to flow through the conduit; A heat exchanger that works in cooperation with the conduit or flow control device to regulate the temperature of the blood or blood substitute; A fluid generation / flow supply device for selectively supplying oxygen, hydrogen, nitrous oxide, nitrogen, or carbon dioxide to the blood or blood substitute; At least one injection port communicating with the aforementioned conduit; A mixing port communicating with the aforementioned conduit; A device hub communicating with the aforementioned conduit; A catheter hub communicating with the aforementioned conduit; The system comprises the conduit, the flow rate control device, the heat exchanger, the fluid generation / flow supply device, and a control device for selective processing of circulating blood or extracorporeal blood or blood substitute, which is actuariably connected to at least one of the injection port, the mixing port, the device hub, and the catheter, wherein the selective processing of the blood or blood substitute regulates the circulating blood or extracorporeal blood or blood substitute to control its temperature; The regulated circulating blood or extracorporeal blood, or blood substitute, is passed through the fluid generation / flow supply device to control dissolved gases; Adjust the circulating blood, extracorporeal blood, or blood substitute by performing at least one of the following: changing the amount of gas in the circulating blood, extracorporeal blood, or blood substitute; reducing the amount of ionized calcium in the circulating blood, extracorporeal blood, or blood substitute; and lowering the pH of the circulating blood, extracorporeal blood, or blood substitute; and A system comprising monitoring the supply of the circulating blood, extracorporeal blood, or blood substitute, and administering the regulated and passed circulating blood, extracorporeal blood, or blood substitute to a subject when the ionized calcium concentration of the selectively processed circulating blood, extracorporeal blood, or blood substitute is less than 0.5 mmol / L.

[0061] Paragraph 14 The system according to paragraph 13, wherein the conduit comprises a cannula or a pump.

[0062] The system according to paragraph 13, wherein the conduit, the flow control device, the heat exchanger, the fluid generation / flow supply device, at least one of the injection port, the mixing port, or the catheter is a sensor.

[0063] While the embodiments described herein, along with the exemplary embodiments outlined above, various alternatives, modifications, variations, improvements, and / or substantially equivalents, whether known or not currently foreseeable, may become apparent to those skilled in the art. Therefore, the exemplary embodiments described above are intended as examples only, and not as limitations. Various modifications may be made without departing from the spirit and scope of this disclosure. For this reason, this disclosure is intended to encompass all known or subsequently developed alternatives, modifications, variations, improvements, and / or substantially equivalents.

[0064] Accordingly, the claims of this application are not intended to be limited to the embodiments shown herein, but rather the entire scope consistent with the language of the claims should be recognized, and where an element is referred to in the singular, it means "one or more" and not "one" unless otherwise specified. All structural and functional equivalents of elements in various embodiments described throughout this disclosure, known or to those skilled in the art, are intended to be expressly incorporated by means of and included in the claims. Furthermore, nothing disclosed herein is intended to be made available to the public, whether such disclosure is expressly stated in the claims or not. Also, elements of the claims should not be interpreted as means-plus-function unless expressly stated using the expression "means for".

[0065] Furthermore, the term “example” in this specification means “something that functions as an example, illustration or diagram.” An embodiment described as “example” in this specification is not necessarily construed to be preferable or advantageous to other embodiments. Unless otherwise stated, the term “some” means one or more. Also, combinations such as “at least one of A, B, or C,” “at least one of A, B, and C,” and “any combination of A, B, C, or thereafter” include any combination of A, B, and / or C, and may further include multiple A, multiple B, or multiple C. Specifically, combinations such as “at least one of A, B, or C,” “at least one of A, B, and C,” and “any combination of A, B, C, or thereafter” may include only A, only B, only C, A and B, A and C, B and C, or combinations of A, B, and C, and these combinations may include one or more of A, B, and C. Nothing disclosed herein, whether expressly stated in a claim or not, is intended to be made available to the public.

[0066] As used in this disclosure, the term “comprises” has an open meaning and may include other characteristics not defined herein. This term encompasses, but is not limited to, the semi-closed term “consisting essentially of” and the closed term “consisting of.” Unless the context specifically indicates otherwise, “comprises” may be replaced with “consisting essentially of” or “consists of.” Furthermore, “consisting essentially of” may be used interchangeably with “consists of.”

Claims

1. A method for selectively administering treated blood or blood substitute used for the treatment or prevention of reperfusion injury, wherein the method is: The process includes a step of selectively processing circulating blood, extracorporeal blood, or blood substitute, and the selective processing step is: The circulating blood, extracorporeal blood, or blood substitute is regulated to control its temperature; The regulated circulating blood, extracorporeal blood, or blood substitute is passed through a fluid generation / flow supply device to control dissolved gases; Adjust the circulating blood, extracorporeal blood, or blood substitute by performing at least one selected from the following: changing the amount of gas in the circulating blood, extracorporeal blood, or blood substitute; reducing the amount of ionized calcium in the circulating blood, extracorporeal blood, or blood substitute; and lowering the pH of the circulating blood, extracorporeal blood, or blood substitute; and This includes monitoring the supply of the aforementioned circulating blood, extracorporeal blood, or blood substitute. A method for administering the adjusted and passed circulating blood, extracorporeal blood, or blood substitute to a subject when the ionized calcium concentration of the selectively treated circulating blood, extracorporeal blood, or blood substitute is less than 0.5 mmol / L.

2. The method according to claim 1, wherein the processed blood or blood substitute is venous blood.

3. The method according to claim 1, wherein the processed blood or blood substitute is administered intraarterially or intravenously.

4. The method according to claim 1, wherein the processed blood or blood substitute is administered to a subject suffering from ischemic stroke, and the prepared blood or blood substitute originates from the subject.

5. The method according to claim 1, wherein the adjusted blood or blood substitute is administered during reperfusion.

6. The method according to claim 5, wherein the prepared blood or blood substitute is administered after thrombectomy.

7. The method according to claim 1, wherein the prepared blood or blood substitute is administered in combination with an anticoagulant.

8. The method according to claim 1, wherein the reperfusion injury is reperfusion injury due to ischemic stroke.

9. The method according to claim 8, wherein the ischemic stroke or reperfusion injury is reperfusion injury of an ischemic stroke in the neurovascular system.

10. The method according to claim 1, wherein the regulated and passed circulating blood or extracorporeal blood, or blood substitute, contains a contrast agent used for radiography.

11. The method according to claim 1, wherein the regulated and passed circulating blood or extracorporeal blood, or blood substitute, is administered in combination with a contrast agent used for radiography.

12. A composition for use in the treatment or prevention of reperfusion injury in a subject, wherein the composition comprises controlled and passed circulating blood or extracorporeal blood, or blood substitute, and further comprises at least one selected from an anticoagulant and a contrast agent used for radiography.

13. A system for selectively administering treated blood or blood substitute for the treatment or prevention of reperfusion injury, wherein the system is: Conduits and; A flow control device that selectively operates with the conduit to allow deoxygenated blood or blood substitute to flow through the conduit; A heat exchanger that works in cooperation with the conduit or flow control device to regulate the temperature of the blood or blood substitute; A fluid generation / flow supply device for selectively supplying oxygen, hydrogen, nitrous oxide, nitrogen, or carbon dioxide to the blood or blood substitute; At least one injection port communicating with the aforementioned conduit; A mixing port communicating with the aforementioned conduit; A device hub communicating with the aforementioned conduit; A catheter hub communicating with the aforementioned conduit; The system comprises the conduit, the flow rate control device, the heat exchanger, the fluid generation / flow supply device, and a control device for selective processing of circulating blood or extracorporeal blood or blood substitute, which is operably or transmissibly connected to at least one of the injection port, the mixing port, the device hub, and the catheter, wherein the selective processing of the blood or blood substitute is The circulating blood, extracorporeal blood, or blood substitute is regulated to control its temperature; The regulated circulating blood or extracorporeal blood, or blood substitute, is passed through the fluid generation / flow supply device to control dissolved gases; Adjust the circulating blood, extracorporeal blood, or blood substitute by performing at least one of the following: changing the amount of gas in the circulating blood, extracorporeal blood, or blood substitute; reducing the amount of ionized calcium in the circulating blood, extracorporeal blood, or blood substitute; and lowering the pH of the circulating blood, extracorporeal blood, or blood substitute; and This includes monitoring the supply of the circulating blood, extracorporeal blood, or blood substitute. A system for administering the adjusted and passed circulating blood, extracorporeal blood, or blood substitute to a subject when the ionized calcium concentration of the selectively treated circulating blood, extracorporeal blood, or blood substitute is less than 0.5 mmol / L.

14. The system according to claim 13, wherein the conduit comprises a cannula or a pump.

15. The system according to claim 13, comprising the conduit, the flow rate control device, the heat exchanger, the fluid generation / flow supply device, at least one of the injection port, the mixing port, or the catheter, which is a sensor.

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