Methods and systems for treatment, reduction, or prevention of reperfusion injury after ischemia

Abstract

Devices, methods, and systems for providing interacting components for deoxygenating blood for use in treating or preventing reperfusion injury, including features to enhance likelihood that deoxygenated blood has an ionized calcium concentration of less than 05mmol / L. System components may include one or more syringe pumps operatively communicating with various features via a controller / processor, including: a canula, a pump communicating with the cannula; a heat exchanger; a device for generating / producing a flow of a fluid; one or more infusion ports; mixing port; device hub; and catheter hub; which may be selectively connected to a subject optionally having one or monitoring and / or other leads / devices attached thereto. The leads / devices may include sensors and / or other devices attachable / connectable to the subject to provide health indicators, such as temperature sensors, electrodes for monitoring the electrical activity of the heart, and / or an SpO2 or other sensor for monitoring patient blood oxygen saturation levels.

Description

METHODS AND SYSTEMS FOR TREATMENT, REDUCTION, OR PREVENTION OF REPERFUSION INJURY AFTER ISCHEMIACROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is based upon and claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 437,304, filed January 5, 2023, the entire contents of which are incorporated herein by reference.FIELD

[0002] Aspects of the present disclosure relate to methods and systems for the reduction of reperfusion injury in post-ischemic tissue care, such as by modification of reperfused fluid parameters.BACKGROUND AND SUMMARY

[0003] Stroke is a very serious condition where the blood supply to part of the brain may be cut off or significantly reduced, such that cell death may occur and lead to irreversible tissue damage. A stroke may be caused, for example, when a weakened blood vessel ruptures (known as a hemorrhagic stroke) or when a blood vessel is obstructed (known as an ischemic stroke). Stroke is a major, worldwide health problem.

[0004] An ischemic stroke may be categorised as a thrombotic stroke or an embolic stroke. Thrombotic strokes may be caused by the formation of a thrombus (blood clot), typically around atherosclerotic plaques. An embolic stroke may occur when there is a blockage of an artery (e.g. an arterial embolism) by an embolus, a travelling particle or debris that originates from elsewhere. The embolus is commonly a thrombus, but it can also one of several other substances, such as fat, clumps of bacteria, cancer cells or air.

[0005] One of way of treating ischem ic stroke patients in the existing art is to perform a thrombectomy, which involves the mechanical removal of clots that are too large to be broken down by clot-busting drugs. Thrombectomy is typically most effective the faster it is used after a stroke. In fact, it is well accepted in the existing art that thetime that cells are deprived of oxygen is critical to positive stroke outcomes. The expression “time is brain” is commonly used to describe this phenomenon.

[0006] Once the obstruction has been removed from the blood vessel, blood is reintroduced into the tissues that have been starved of oxygen. When cells are deprived of oxygen, they typically enter a type of resting state with slow metabolism and low activity. This is a protective state to prolong tissue life while waiting for oxygen restoration. Counterintuitively, the uncontrolled restoration of blood flow and oxygen may lead to massive cellular damage. This effect may occur because the cells are restored from their resting state into what may be an unsuitable environment. Thus, when blood flow is restored, the ischemic injury may stop and reperfusion injury may begin. Thus, reperfusion injury may occur after ischemia.

[0007] While existing therapies, such as thrombectomy, can sometimes be very successful at removing the cause of a stroke, they often do not address reperfusion injury. There remains in the existing art an unmet clinical need for therapies, as well as systems and methods relating thereto, that reduce or prevent reperfusion injury following an ischemic stroke.

[0008] While exact clinical mechanisms of reperfusion are not completely understood, such aspects may involve Calcium Ion overload, Metabolic Tissue Rate, and / or Inflammatory Responses. Carbon Dioxide Gas Concentration and Oxygen Gas concentration of the blood are known to potentially influence the damage caused to cells following restoration of blood to a post ischemic tissue.

[0009] The reduction of Calcium ions may be achieved by the use of Chelation Agents (Such as EDTA or Ethylene diamine tetra acetic acid or Sodium Citrate), and the ratio of addition of the chelation agents may be influenced or controlled volumetrically and measured. The chelation of calcium ions may reduce their bioavailability in reperfused tissue and, for example, may prevent the edema and “no reflow” phenomenon in conjunction with other treatments of the tissue.

[0010] The pH of blood may have an effect on the progression of reperfusion injury and the addition of acids, bases or buffering molecules may reduce the progression of reperfusion injury. Carbon dioxide gas may act to alter the pH of blood when used in the sweep gas stream of an oxygenator.

[0011] The no-reflow phenomenon may occur when swelling in tissue prevents flow through the capillaries in the tissue. This effect may be one of the leading causes of damage following stroke and may prevent or inhibit the administration of various therapies. In healthy subjects, pulsatile flow may be achieved via the ventricular output, and flow having the waveform of pulsatile flow is known to efficiently allow flow through capillaries. In the case of non-pulsatile flow, such as that achieved when unmodified peristaltic pumps and centrifugal pumps are used, the bloodflow through capillary beds may be less efficient, and clinical issues, such as “pump head” are known to may occur. These issues may be more pronounced in reperfusion injury where edema may inhibit flow through capillaries, for example.

[0012] The metabolic rate of tissue is dependent on the temperature of the tissue, and it is known that reduction in the temperature of reperfused tissue may reduce the damage that is expected at normothermic conditions. The timeliness of this temperature reduction may often be critical, and diminished value may be expected as the reperfusion injury progresses.

[0013] Osmolality is the moles of solute per liter of solvent. In membrane science, such as is found across cell membranes, osmosis acts to form equilibrium between areas of low and high osmolarity. Modification of the osmolality of reperfused fluids may therefore act to control the diffusion of such solutes across cell membranes and may have a neuroprotective effect.

[0014] The administration of Neuroprotective infusions and pharmaceutical agents with specific cellular action has previously been found to have failed to be of benefit in “real world” applications to treat reperfusion injury. This result may be in part due, for example, to the overwhelming damaging effects of arterial blood on reperfused tissues, and the ability to reduce the damaging effect of arterial blood during reperfusion may enable pharmaceutical interventions that were previously impossible or difficult to carry out.

[0015] Immune involvement in reperfusion may lead to the triggering of inflammatory pathways when the contents of cells are detected by the circulating immune system. The ability to reduce the damage caused by such an inflammatory immune responsemay be effected by pharmaceutical means or alternatively by the elimination of the circulating immune cells by means of specialised filtration, for example.

[0016] Many existing perfusion systems are scaled for systemic flow in the region of 4000mls / min to >7000mls / min, which is unsuitable for use with single organ reperfusion owing to the mis-alignment between the size and surface are of the contact surfaces and the internal volume of the device and the required blood flow for a single organ. Having too great of a gas exchange surface area for a given bloodflow may lead to the introduction of additional oxygen species and subsequent free radical damage in reperfused tissues.

[0017] Oftentimes single organ preservations circuits, for the preservation of ex-vivo organs for transplantation, are produced, which may lack the safety features necessary to be used in a living subject, for example, owing to the lack of concern with damage to other organs. The ability to prevent, detect or eliminate microbubbles and thrombus from the fluid may be critical where the fluid is to be returned to vascular circulation

[0018] The reliance on the introduction of an insulating or sensor catheter is known in the art for the reintroduction of cooling fluids; however, such designs are limited by, for example: (1 ) the necessity for dimensional compatibility with existing catheters on the market (e.g. balloon guide catheters) or (2) if they are to be delivered following the removal of a inline catheter, then there is a likelihood that calcium rich, normothermic arterial blood will reach the tissue prior to interventional reperfusion and that damage can occur. The ability to interface with the standard Luers on existing catheters is advantageous as it prevents both of these issues.

[0019] The mechanisms that lead to Reperfusion Injury are complex and are known to follow a time ordered sequence with the damaging species leading to injury at different times depending on their rate of injury. For example, the diffusion of Calcium Ions across the cell membranes happens much faster than the longer term activation of immune responses to cellular damage. The control of blood parameters to reduce reperfusion injury therefore relies on the control of the profile of the therapeutic parameters of the blood in a timely manner.

[0020] Reperfusion Injury occurs in all tissues that are deprived of oxygen for protracted periods of time. Other clinically significant examples are in chronic Total Occlusions, Myocardial Infarction, and Limb Ischemia

[0021] Aspects of the present disclosure provide devices, methods, and systems for addressing the above identified problems of the existing art, as well as others, via use of various interacting components for deoxygenating blood for use in treating or preventing reperfusion injury, including, for example, features to enhance likelihood that deoxygenated blood has an ionized calcium concentration of less than 0.5mmol / L.

[0022] Additional advantages and novel features of these aspects will be set forth in part in the description that follows, and in part will become more apparent to those skilled in the art upon examination of the following or upon learning by practice of the disclosure.BRIEF DESCRIPTION OF THE FIGURES

[0023] In the drawings:

[0024] FIG. 1 is an example representative diagram illustrating various example components involved in one example implementation of a system for deoxygenating blood for use in treating or preventing reperfusion injury, in accordance with aspects of the present disclosure, including features to enhance likelihood that modified blood has an ionized calcium concentration of less than 0.5mmol / L.

[0025] FIG. 2 shows a representative flow chart of example functions for controlling, monitoring, and / or modifying blood flow that includes functions relating to circulating or abstracted venous blood, modified venous blood, and systemic blood supply, in accordance with aspects of the present disclosure.

[0026] FIG. 3 presents a representative flow chart of example functions for various interoperative inputs and operational controls relating to blood flow rate control, in accordance with aspects of present disclosure.

[0027] FIG. 4 contains a representative flow chart of example functions for various interoperative inputs and operational controls relating to chelation rate control, in accordance with aspects of present disclosure.

[0028] FIG. 5 shows a representative flow chart of example functions for various interoperative inputs and operational controls relating to temperature control, in accordance with aspects of present disclosure.

[0029] FIG. 6 presents a representative flow chart of example functions for various interoperative inputs and operational controls relating to gas control, in accordance with aspects of present disclosure.

[0030] FIG. 7 show a representative diagram of various aspects of an example computer system capable of carrying out functionality described in example implementations, in accordance with aspects of the present disclosure.

[0031] Fig. 8 is a representative block diagram of various example system / network components, capable of being used along the lines as described in example implementations, in accordance with aspects of the present disclosure.

[0032] Figs. 9A and 9B show cross-sectional images of various sectional shapes / features of example mixing ports usable in accordance with aspects of the present disclosure.DETAILED DESCRIPTION

[0033] Aspects of the present disclosure provide devices, methods, and systems for addressing the above identified problems of the existing art, as well as others.

[0034] FIGs. 1 -9B show various features of devices, methods, and systems for addressing such issues, including features and methods for deoxygenating blood for use in treating or preventing reperfusion injury, such that, among other advantages, the deoxygenated blood has an ionized calcium concentration of less than 0.5mmol / L. Such deoxygenated blood may be venous blood. It is noted that a normal level of oxygen in blood is about l OOmmhg. It is also possible that blood products may be used in lieu of or in conjunction with deoxygenated venous blood, so long as such blood products contain red blood cells, or oxygen carrier groups, such as synthetic or biologically engineered Heme molecules.

[0035] The degenerated blood may be selectively administered intra-arterially or intravenously and may be administered at a determined proper temperature. The blood may be selectively administered to a subject suffering from an ischemic stroke, for example, and the blood may be from that subject. For example, the blood may beadministered during reperfusion, such as after (and in some cases preferably after) a thrombectomy has been performed. The reperfusion incident may be or include a ischemic stroke reperfusion injury, for example, and the administration of the degenerated blood may preferably occur in response to an event such as, but not limited to, neurovascular ischemic stroke reperfusion injury.

[0036] The deoxygenated blood may be administered selectively in combination with a blood anti-coagulant.

[0037] The deoxygenated blood may selectively include administration of a contrast medium, such as for use in radiography.

[0038] FIG. 1 shows various features of one example implementation of a system for addressing the above identified aspects, as well as others. As shown in FIG. 1 , the system 100 may include one or more of the following features: 1 ) one or more syringe pumps 105 operatively communicating with various features of the system 100; 2) a canula 110, 3) a pump 115 communicating with the cannula 110; 4) a heat exchanger (HEX 120); 5) an oxygenator and / or other device for generating / producing a flow of a fluid, such fluid including, but not limited to one or more of oxygen, hydrogen, nitrogen, nitrous oxide, and / or carbon dioxide 130, 6) one or more infusion ports 135, 7) a mixing port 140; 8) a device hub 145, and 9) a catheter hub 150; selectively connected to 10) a patient 155, with such patient optionally having one or monitoring and / or other leads / devices attached thereto. The leads / devices may include a variety of sensors and / or other devices that are attachable or otherwise connectable to patient to provide health indicators, such as one or more temperature sensors, a plurality of electrodes or electrode connectors configured to selectively mount to electrodes for monitoring the electrical activity of the heart, and / or an SpO2 or other sensor for monitoring patient blood oxygen saturation levels.

[0039] Each of the above components / patient 105-155 may be operatively coupled to a controller, input / output, processer device 160 (which may, for example, include one or more processors and / or one or more network, and / or other features, as further shown and discussed in relation to FIGs. 7 and 8 below; such processor device also interchangeably referred to herein as a “controller”), which may selectively receive data and / or other input from, and selectively provide data / output to, each of such components 105-155, so as to selectively control the input of deoxygenated blood to the patent 155, among other functions. Alternatively or in addition, the controller 160may be configured to access (e.g., via stored data in a local or remote data repository, such remote data being accessible via a network, for example) information relating to the one or more components 105-155 to enable interactive monitoring and control of various system functions. For example, such accessible data may include profile information for commercially available catheters, such that the controller 160 may utilize the corresponding stored profile information for the catheters utilized in the system 100 to readily adjust flow parameters so as to synchronizably deliver pulsatile flow within each vessel for the patient’s heartbeat. In one example implementation, for instance, a user (e.g., clinician) is able to select or confirm the model / catheter information used within the system for needed delivery, and the system 100 may then automatically or otherwise adjust, for example, the pulsatile pump parameters and / or other system parameters to match the needed delivery for the detected heartbeat.

[0040] In one example implementation in accordance with aspects of the present disclosure, venous blood (or, for example, blood from a matching patient or blood substitute fluid) may be withdrawn from the venous system via, for example, the venous cannula (for example, the Medtronic Bio-Medicus™ cannula made by Medtronic of Irvine, CA)(110) and passed through the Pulsatile Pump (for example Harvard Apparatus 1423 pulsatile made by Harvard Apparatus of Holliston, MA) (115) to the heat exchanger (for example, a CAPIOX® Cardioplegia heat exchanger made by Terumo Cardiovascular of Ann Arbor, MI)(120). The flow rate and blood temperature may be used to control the temperature within the heat exchanger (120). Sensors may read the blood temperature and flow rate to inform the controller (160) to adjust the mixing of the sweep gas through the Oxygenator or other fluid generation / flow delivery device (130). The flow rate on the outlet side of the fluid generation / flow delivery device (130) may be measured and sent to the controller (160) to adjust the rate of addition of the Chelation agent through the infusion port (135) by adjusting the syringe pump (105). The blood may be passed through a mixing port (140 (e.g., see FIGs. 9A and 9B, containing cross-sectional images of various sectional shapes / features of example mixing ports usable in accordance with aspects of the present disclosure) to ensure the chelation agents are homogenously distributed in the reperfused fluid stream. The blood may enter into the device hub (145), which, for example, may be attached to the catheter hub (150) of a guide catheter. The Controller (160) may adjust the target parameters based on the therapeutic needs ofthe patients to adjust temperature, gas and chelation gradients and may add additional therapies through the infusion ports, such as calcium or magnesium ions, anticoagulants, radiodetectable compounds, and / or neuroprotective drugs.

[0041] FIGs. 2-6 show representative flow charts of various functions relating to providing deoxygenated blood and / or providing other input / output / controls relating thereto, such as with regard to one or more functions associated with the example features of FIG. 1 , in accordance with aspects of the present disclosure.

[0042] FIG. 2 shows a representative flow chart of example functions for controlling, monitoring, and / or modifying blood flow that includes functions relating to circulating or abstracted venous blood, modified venous blood, and systemic blood supply, in accordance with aspects of the present disclosure.

[0043] FIG. 3 presents a representative flow chart of example functions for various interoperative inputs and operational controls relating to blood flow rate control, in accordance with aspects of present disclosure.

[0044] FIG. 4 contains a representative flow chart of example functions for various interoperative inputs and operational controls relating to chelation rate control, in accordance with aspects of present disclosure.

[0045] FIG. 5 shows a representative flow chart of example functions for various interoperative inputs and operational controls relating to temperature control, in accordance with aspects of present disclosure.

[0046] FIG. 6 presents a representative flow chart of example functions for various interoperative inputs and operational controls relating to gas control, in accordance with aspects of present disclosure.

[0047] Aspects of the present disclosure may be implemented using hardware, software, or a combination thereof and may be implemented in one or more computer systems or other processing systems. In an aspect of the present disclosure, features are directed toward one or more computer systems capable of carrying out the functionality described herein. Various aspects of an example of such a computer system 1900 are shown in FIG. 7.

[0048] Computer system 1900 includes one or more processors, such as processor 1904. The processor 1904 may be coupled to a communication infrastructure 1906 (e.g., a communications bus, cross-over bar, or network). Various software aspectsare described in terms of this example computer system. After reading this description, it will become apparent to a person skilled in the relevant art(s) how to implement aspects hereof using other computer systems and / or architectures.

[0049] Computer system 1900 may include a display interface 1902 that forwards graphics, text, and other data from the communication infrastructure 1906 (or from a frame buffer not shown) for display on a display unit 1930. Computer system 1900 may include a main memory 1908, such as random-access memory (RAM), and may also include a secondary memory 1910. The secondary memory 1910 may include, for example, a hard disk drive 1912 and / or a removable storage drive 1914, representing a floppy disk drive, a magnetic tape drive, an optical disk drive, etc. The removable storage drive 1914 may read from and / or write to a removable storage unit 1918 in a well-known manner. Removable storage unit 1918, represents a floppy disk, magnetic tape, optical disk, etc., which may be read by and written to removable storage drive 1914. As will be appreciated, the removable storage unit 1918 may include a computer usable storage medium having stored therein computer software and / or data.

[0050] Alternative aspects may include secondary memory 1910 and may include other similar devices for allowing computer programs or other instructions to be loaded into computer system 1900. Such devices may include, for example, a removable storage unit 1918 and an interface 1920. Examples of such may include a program cartridge and cartridge interface (such as that found in video game devices), a removable memory chip (such as an erasable programmable read only memory (EPROM), or programmable read only memory (PROM)) and associated socket, and other removable storage units 1922 and interfaces 1920, which allow software and data to be transferred from the removable storage unit 1914 to computer system 1900.

[0051] Computer system 1900 may also include a communications interface 1924. Communications interface 1924 may allow software and data to be transferred among computer system 1900 and external devices. Examples of communications interface 1924 may include a modem, a network interface (such as an Ethernet card), a communications port, a Personal Computer Memory Card International Association (PCMCIA) slot and card, etc. Software and data transferred via communications interface 1924 may be in the form of signals 1928, which may be or include electronic,electromagnetic, optical or other signals capable of being received by communications interface 1924. These signals 1928 may be provided to communications interface 1924 via a communications path (e.g., channel) 1926. This path 1926 may carry signals 1928 and may be implemented using wire or cable, fiber optics, a telephone line, a cellular link, a radio frequency (RF) link and / or other communications channels. As used herein, the terms “computer program medium” and “computer usable medium” refer generally to media such as a removable storage drive 1914, a hard disk installed in hard disk drive 1912, and / or signals 1928. These computer program products may provide software to the computer system 1900. Aspects of the present disclosure are directed to such computer program products.

[0052] Computer programs (also referred to as computer control logic) may be stored in main memory 1908 and / or secondary memory 1910. Computer programs may also be received via communications interface 1924. Such computer programs, when executed, may enable the computer system 1900 to perform the features in accordance with various aspects discussed herein. In particular, the computer programs, when executed, may enable the processor 1904 to perform the features in accordance with aspects of the present disclosure. Accordingly, such computer programs may represent controllers of the computer system 1900.

[0053] Where aspects of the present disclosure may be implemented using software, the software may be stored in a computer program product and loaded into computer system 1900 using removable storage drive 1914, hard drive 1912, or communications interface 1924. The control logic (software), when executed by the processor 1904, may cause the processor 1904 to perform the functions described herein. In another aspect of the present disclosure, the system may be implemented primarily in hardware using, for example, hardware components, such as application specific integrated circuits (ASICs). Implementation of the hardware state machine so as to perform the functions described herein will be apparent to persons skilled in the relevant art(s).

[0054] In yet another variation, aspects of the present disclosure may be implemented using a combination of both hardware and software.

[0055] FIG. 8 is a block diagram of various example system components, for use in accordance with aspects of the present disclosure. FIG. 8 shows a communication system 2000 usable in accordance with aspects hereof. The communication system 2000 shown in FIG. 4 includes one or more accessors 2060 (also referred to interchangeably herein as one or more “users”) and one or more terminals 2042. In one aspect, data for use in accordance with aspects of the present disclosure is, for example, input and / or accessed by accessor 2060 via terminal 2042, such as personal computers (PCs), command issuing devices including Graphical User Interfaces (GUIs), minicomputers, mainframe computers, microcomputers, telephonic devices, or wireless devices, such as personal digital assistants (PDAs), smart phones, or other hand-held wireless devices coupled to a server 2043, such as a PC, minicomputer, mainframe computer, microcomputer, or other device having a processor and a repository for data and / or connection to a repository for data, via, for example, a network 2044, such as the Internet or an intranet, and couplings 2045, 2046, 2047. The couplings 2045, 2046, 2047 may include, for example, wired, wireless, or fiber optic links. In one example, aspects of a reperfusion injury related controller / system 2070 may be coupled to network 2044 via coupling 2047 and be therefore able to receive input data from and output data to user server 2043 and user 2060, such that the user may be able to monitor and / or input information relatint to controller / system operation, for example. In another variation, the method and system in accordance with aspects of the present disclosure may operate in a stand-alone environment, such as on a single terminal.

[0056] The following numbered clauses identify aspects of the disclosure:

[0057] Clause 1. A method for selectively administering treated blood or blood substitute for use in treating or preventing reperfusion injury, the method comprising: selectively treating circulating or abstracted blood or blood substitute, wherein the selectively treating includes: modifying the circulated or abstracted blood or blood substitute to control the temperature of the circulated or abstracted blood or blood substitute; passing the modified circulated or abstracted blood or blood substitute to a fluid generation / flow delivery device to control dissolved gasses; modifying the passed circulated or abstracted blood or blood substitute, wherein modifying the passed circulated or abstracted blood or blood substitute includes at least one selected fromthe group consisting of changing gas levels in the circulating or abstracted blood or blood substitute, reducing ionized calcium levels in the circulating or abstracted blood or blood substitute, and reducing the pH levels in the circulating or abstracted blood or blood substitute; and monitoring supply of the circulated or abstracted blood or blood substitute; and passing the modified and passed circulated or abstracted blood or blood substitute to a subject when the selectively treated circulating or abstracted blood or blood substitute comprises an ionized calcium concentration of less than 0.5mmol / L.

[0058] Clause 2. The method of claim 1 , wherein the treated blood or blood substitute is venous blood.

[0059] Clause 3. The method of claim 1 , wherein the treated blood or blood substitute is administered intra-arterially or intravenously.

[0060] Clause 4. The method of claim 1 , wherein the treated blood or blood substitute is administered to a subject suffering from an ischemic stroke, and wherein the modified blood or blood substitute originates from the subject.

[0061] Clause s. The method of claim 1 , wherein the modified blood or blood substitute is administered during reperfusion.

[0062] Clause s. The method of claim 5, wherein the modified blood or blood substitute is administered after a thrombectomy.

[0063] Clause ?. The method of claim 1 , wherein the modified blood or blood substitute is administered in combination with a blood anticoagulant.

[0064] Clause 8. The method of claim 1 , wherein the reperfusion injury is ischemic stroke reperfusion injury.

[0065] Clause 9. The method of claim 8, wherein the ischemic stroke or reperfusion injury is a neurovascular ischemic stroke reperfusion injury.

[0066] Clause 10. The method of claim 1 , wherein the modified and passed circulated or abstracted blood or blood substitute comprises a contrast medium for use in radiography.

[0067] Clause 11 . The method of claim 1 , wherein the modified and passed circulated or abstracted blood is administered in combination with a contrast medium for use in radiography.

[0068] Clause 12. A composition for use in treating or preventing reperfusion injury in a subject, wherein the composition comprises modified and passed circulated or abstracted blood or blood substitute, and at least one selected from a group consisting of a blood anticoagulant and a contrast medium for use in radiography.

[0069] Clause 13. A system for selectively administering treated blood or blood substitute for use in treating or preventing reperfusion injury, the system comprising: a conduit; a flow control device selectively operable with conduit to induce flow of deoxygenated blood or blood substitute via the conduit; a heat exchanger interoperable with the conduit or flow control device for modifying the temperature of the blood or blood substitute; a fluid generation / flow delivery device for selectively administering oxygen, hydrogen, nitrous oxide, nitrogen, or carbon dioxide to the blood or blood substitute; at least one infusion port communicating with the conduit; a mixing port communicating with the conduit; a device hub communicating with the conduit; a catheter hub communicating with the conduit; and a controller device operably or communicatively coupled to at least one of the conduit, the flow control device, the heat exchanger, the fluid generation / flow delivery device, the at least one infusion port, the mixing port, the device hub and the catheter for selective treating of circulating or abstracted blood or blood substitute, wherein the selective treating of blood or blood substitute includes: modifying the circulated or abstracted blood or blood substitute to control the temperature of the circulated or abstracted blood or blood substitute; passing the modified circulated or abstracted blood or blood substitute to the fluid generation / flow delivery device to control dissolved gasses; modifying the passed circulated or abstracted blood or blood substitute, wherein modifying the passed circulated or abstracted blood or blood substitute includes at least one selected from the group consisting of changing gas levels in the circulating or abstracted blood or blood substitute, reducing ionized calcium levels in the circulating or abstracted blood or blood substitute, and reducing the pH levels in the circulating or abstracted blood or blood substitute; and monitoring supply of the circulated or abstracted blood or blood substitute; and passing the modified and passed circulated or abstracted bloodor blood substitute to a subject when the selectively treated circulating or abstracted blood or blood substitute comprises an ionized calcium concentration of less than 0.5 mmol / L.

[0070] Clause 14. The system of claim 13, wherein the conduit comprises a cannula or a pump.

[0071] Clause 15. The system of claim 13, wherein at least one of the conduit, the flow control device, the heat exchanger, the fluid generation / flow delivery device, the at least one infusion port, the mixing port, or the catheter comprises a sensor.

[0072] While the aspects described herein have been described in conjunction with the example aspects outlined above, various alternatives, modifications, variations, improvements, and / or substantial equivalents, whether known or that are or may be presently unforeseen, may become apparent to those having at least ordinary skill in the art. Accordingly, the example aspects, as set forth above, are intended to be illustrative, not limiting. Various changes may be made without departing from the spirit and scope of the disclosure. Therefore, the disclosure is intended to embrace all known or later-developed alternatives, modifications, variations, improvements, and / or substantial equivalents.

[0073] Thus, the claims are not intended to be limited to the aspects shown herein, but are to be accorded the full scope consistent with the language of the claims, wherein reference to an element in the singular is not intended to mean “one and only one” unless specifically so stated, but rather “one or more.” All structural and functional equivalents to the elements of the various aspects described throughout this disclosure that are known or later come to be known to those of ordinary skill in the art are expressly incorporated herein by reference and are intended to be encompassed by the claims. Moreover, nothing disclosed herein is intended to be dedicated to the public regardless of whether such disclosure is explicitly recited in the claims. No claim element is to be construed as a means plus function unless the element is expressly recited using the phrase “means for.”

[0074] Further, the word “example” is used herein to mean “serving as an example, instance, or illustration.” Any aspect described herein as “example” is not necessarily to be construed as preferred or advantageous over other aspects. Unless specificallystated otherwise, the term “some” refers to one or more. Combinations such as “at least one of A, B, or C,” “at least one of A, B, and C,” and “A, B, C, or any combination thereof” include any combination of A, B, and / or C, and may include multiples of A, multiples of B, or multiples of C. Specifically, combinations such as “at least one of A, B, or C,” “at least one of A, B, and C,” and “A, B, C, or any combination thereof” may be A only, B only, C only, A and B, A and C, B and C, or A and B and C, where any such combinations may contain one or more member or members of A, B, or C. Nothing disclosed herein is intended to be dedicated to the public regardless of whether such disclosure is explicitly recited in the claims.

[0075] As used in the present disclosure, the term “comprises” has an open meaning, which allows other, unspecified features to be present. This term embraces, but is not limited to, the semi-closed term “consisting essentially of” and the closed term “consisting of”. Unless the context indicates otherwise, the term “comprises” may be replaced with either “consisting essentially of” or “consists of”. The term “consisting essentially of” may also be interchangeably used with regard to “consists of”.

Claims

CLAIMS1 . A method for selectively administering treated blood or blood substitute for use in treating or preventing reperfusion injury, the method comprising: selectively treating circulating or abstracted blood or blood substitute, wherein the selectively treating includes: modifying the circulated or abstracted blood or blood substitute to control temperature of the circulated or abstracted blood or blood substitute; passing the modified circulated or abstracted blood or blood substitute to a fluid generation / flow delivery device to control dissolved gasses; modifying the passed circulated or abstracted blood or blood substitute, wherein modifying the passed circulated or abstracted blood or blood substitute includes at least one selected from the group consisting of changing gas levels in the circulating or abstracted blood or blood substitute, reducing ionized calcium levels in the circulating or abstracted blood or blood substitute, and reducing pH levels in the circulating or abstracted blood or blood substitute; and monitoring supply of the circulated or abstracted blood or blood substitute; and passing the modified and passed circulated or abstracted blood or blood substitute to a subject when the selectively treated circulating or abstracted blood or blood substitute comprises an ionized calcium concentration of less than 0.5mmol / L.

2. The method of claim 1 , wherein the treated blood or blood substitute is venous blood.

3. The method of claim 1 , wherein the treated blood or blood substitute is administered intra-arterially or intravenously.

4. The method of claim 1 , wherein the treated blood or blood substitute is administered to a subject suffering from an ischemic stroke, and wherein the modified blood or blood substitute originates from the subject.

5. The method of claim 1 , wherein the modified blood or blood substitute is administered during reperfusion.

6. The method of claim 5, wherein the modified blood or blood substitute is administered after a thrombectomy.

7. The method of claim 1 , wherein the modified blood or blood substitute is administered in combination with a blood anticoagulant.

8. The method of claim 1 , wherein the reperfusion injury is ischemic stroke reperfusion injury.

9. The method of claim 8, wherein the ischemic stroke or reperfusion injury is a neurovascular ischemic stroke reperfusion injury.

10. The method of claim 1 , wherein the modified and passed circulated or abstracted blood or blood substitute comprises a contrast medium for use in radiography.11 . The method of claim 1 , wherein the modified and passed circulated or abstracted blood is administered in combination with a contrast medium for use in radiography.

12. A composition for use in treating or preventing reperfusion injury in a subject, wherein the composition comprises modified and passed circulated or abstracted blood or blood substitute, and at least one selected from a group consisting of a blood anticoagulant and a contrast medium for use in radiography.

13. A system for selectively administering treated blood or blood substitute for use in treating or preventing reperfusion injury, the system comprising: a conduit; a flow control device selectively operable with conduit to induce flow of deoxygenated blood or blood substitute via the conduit; a heat exchanger interoperable with the conduit or flow control device for modifying temperature of the blood or blood substitute; a fluid generation / flow delivery device for selectively administering oxygen, hydrogen, Nitrous Oxide, Nitrogen, or carbon dioxide to the blood or blood substitute; at least one infusion port communicating with the conduit; a mixing port communicating with the conduit; a device hub communicating with the conduit; a catheter hub communicating with the conduit; and a controller device operably or communicatively coupled to at least one of the conduit, the flow control device, the heat exchanger, the fluid generation / flow delivery device, the at least one infusion port, the mixing port, the device hub and the catheter for selective treating of circulating or abstracted blood or blood substitute, wherein the selective treating of blood or blood substitute includes: modifying the circulated or abstracted blood or blood substitute to control the temperature of the circulated or abstracted blood or blood substitute; passing the modified circulated or abstracted blood or blood substitute to the fluid generation / flow delivery device to control dissolved gasses; modifying the passed circulated or abstracted blood or blood substitute, wherein modifying the passed circulated or abstracted blood or blood substitute includes at least one selected from the group consisting of changing gas levels in the circulating or abstracted blood or blood substitute, reducing ionized calcium levels in the circulating or abstracted blood or blood substitute, and reducing pH levels in the circulating or abstracted blood or blood substitute; andmonitoring supply of the circulated or abstracted blood or blood substitute; and passing the modified and passed circulated or abstracted blood or blood substitute to a subject when the selectively treated circulating or abstracted blood or blood substitute comprises an ionized calcium concentration of less than 0.5 mmol / L.

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

15. The system of claim 13, wherein at least one of the conduit, the flow control device, the heat exchanger, the fluid generation / flow delivery device, the at least one infusion port, the mixing port, or the catheter comprises a sensor.

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