Systems and methods for controlling oxygen enrichment therapy based on microvascular resistance feedback - Patents.com

Abstract

The present disclosure provides systems and methods for controlling gas-enrichment, e.g., oxygen-enrichment, therapy. One or more sensors and / or one or more imaging systems may be used to measure or determine one or more physiological parameters of a patient. Feedback regarding the one or more physiological parameters or microvascular resistance may be provided to titrate or control the gas-enrichment therapy.

Description

[Technical field]

[0001] [Priority claim] This application claims priority under 35 U.S.C. §119(e) to U.S. patent application Ser. No. 63 / 319,174, filed March 11, 2022, the entire contents of which are hereby incorporated by reference.

[0002] The present disclosure relates to systems and methods for the delivery of gas-enriched liquids or blood to a patient. [Background technology]

[0003] Gas-enriched liquids are desirable in a wide variety of applications. However, the relatively low solubility of many gases, such as oxygen or nitrogen, in liquids, such as water, at atmospheric pressure results in a relatively low concentration of dissolved gas in the liquid. One method of obtaining increased gas concentration levels without a significant increase in liquid volume involves the injection and mixing of a gas-enriched liquid into the liquid of interest. Liquids can be gas-enriched at high pressure.

[0004] Conventional methods for delivering oxygenated blood or oxygen-enriched liquids to tissues and bodily fluids involve the use of extracorporeal circuits for blood oxygenation, which require drawing blood from a patient, circulating the blood through an oxygenator to increase the blood oxygen concentration, and then delivering the blood back to the patient. Summary of the Invention

[0005] This document describes a gas-enriched system configured to deliver gas-enriched blood intravenously to a patient. The system for delivering gas-enriched blood within a patient's vasculature (hereinafter, the delivery system) is configured to connect to a catheter device to deliver gas-enriched blood to the patient. The delivery system comprises a blood circuit having an inlet line and a return line. The inlet line and the return line are configured to connect to a catheter. Blood is drawn from the patient through the inlet line. The blood is mixed with a gas-enriched liquid, or an oxygen-enriched liquid, e.g., a supersaturated oxygen (SSO2)-enriched liquid, to create gas-enriched blood or supersaturated oxygen-enriched blood. The gas-enriched blood is delivered back to the patient through the catheter by the return line, e.g., to provide localized delivery of gas-enriched blood to ischemic tissue in the patient. For example, SSO2 therapy may deliver gas-enriched arterial blood directly to ischemic or at-risk myocardial tissue, increasing oxygen diffusion to the ischemic zone, thereby reducing endothelial swelling and microvascular resistance in the microvasculature and restoring microvascular blood flow.

[0006] The present disclosure provides systems and methods for monitoring, analyzing, delivering and / or controlling gas-enriched therapy or supersaturated oxygen or gas therapy. One or more sensors may be used to measure one or more physiological parameters of a patient, such as blood or tissue parameters, such as pressure and / or flow. A processor may be used to estimate the microvascular resistance in the vasculature of the patient based on the measured parameters, and generate an alert or control signal to titrate or control the gas-enriched blood delivered to the patient based on the microvascular resistance in the vasculature of the patient. According to a first example, a system for monitoring, analyzing, delivering and / or controlling gas-enriched therapy is disclosed. The system comprises a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and mix the gas-enriched liquid with blood, such as arterial blood, whereby gas-enriched blood may be formed. The system may comprise a plurality of fluid conduits fluidly coupled to the gas-enrichment system. At least one of the plurality of fluid conduits is configured for flow of the blood from the patient to the gas-enrichment system, and at least one of the plurality of conduits is configured for flow of gas-enriched blood from the gas-enrichment system to the patient. The system includes a blood pump coupled to at least one of the plurality of fluid conduits for pumping blood between the gas-enrichment system and the patient. The system includes at least one sensor configured to measure one or more physiological parameters. The system may include a user interface configured to receive user input and emit at least one of a visual alert and an audible alert, and a controller. The controller has a processor, memory, and associated circuitry communicatively coupled to the at least one sensor and the user interface.The controller or processor is configured to perform the steps of receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor, estimating the microvascular resistance in the vasculature of the patient based on the measured parameters, and generating an alert or control signal to titrate or control the gas-enriched blood delivered to the patient based on the microvascular resistance in the vasculature of the patient.

[0007] In a particular implementation, a delivery system for controlling gas-enriched therapy in a patient comprises a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and deliver the gas-enriched liquid to the patient's vasculature, where gas-enriched blood is formed in the patient's vasculature. At least one conduit is fluidly coupled to the gas-enrichment system, the at least one conduit configured for flow of the gas-enriched liquid from the gas-enrichment system to the patient. A pump is coupled to the at least one conduit, the pump configured to pump the gas-enriched liquid from the gas-enrichment system to the patient. The system comprises at least one sensor configured to measure one or more physiological parameters indicative of microvascular resistance in the patient's vasculature. The system comprises a processor, memory, and associated circuitry communicatively coupled to the at least one sensor. The processor is configured to perform the steps of receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor; estimating the microvascular resistance in the patient's vasculature based on the measured values; and generating an alert or control signal for titrating or controlling the gas-enriched liquid delivered to the patient based on the microvascular resistance in the patient's vasculature.

[0008] The systems and methods described herein provide one or more advantages. The delivery system enables a closed-loop feedback system to apply a gas-enriched therapy, e.g., SSO2 therapy, to a patient. The delivery system enables real-time or near-real-time measurement of partial myocardial blood flow and / or estimation of microvascular resistance in the patient. The measurement and / or estimation enables the delivery system to determine the patient's response to the gas-enriched therapy and to modify, e.g., stop or change, the therapy during the treatment without pausing the treatment. For example, the delivery system can estimate whether the gas-enriched therapy is reducing microvascular resistance or improving microvascular blood flow, e.g., partially or locally in the patient's vasculature, e.g., in the microvasculature of the left main coronary artery (LMC), in real-time or near-real-time, and provide real-time or near-real-time feedback to optimize the gas-enriched therapy.

[0009] The feedback allows the user to accurately determine when to terminate gas-enriched delivery or continue gas-enriched therapy. The delivery system provides data to the user to enable the user (e.g., a physician) to determine how long to provide gas-enriched therapy and whether the gas-enriched therapy is successful. In some implementations, the feedback allows the delivery system to provide an automated alert or trigger one or more automated actions, such as sending data to a remote device, displaying information to the user, or modifying the gas-enriched treatment. For example, the alert can be sent to the user device or displayed on a user interface. In some implementations, a treatment log can be generated that indicates how the gas-enriched therapy affected the patient.

[0010] Precise customized control over the duration, amount, or concentration of gas-enriched therapy provides increased efficiency of care for patients and reduces waste of time or other resource overhead. For example, if a microvascular resistance-based gas-enriched therapy can determine when or to what extent microvascular blood flow is restored, then depending on the patient's microvascular resistance (e.g., IMR value), gas-enriched therapy can be reduced or continued for a particular patient (e.g., for a time period less than 60 minutes). This can improve patient comfort and reduce the use of caregiver resources. In some implementations, the quality of gas-enriched therapy is improved even if the overall duration is comparable to a treatment without feedback. In some implementations, the delivery system allows for non-invasive confirmation of whether gas-enriched therapy is effective or not.

[0011] In certain implementations, an index of microcirculatory resistance (IMR) can be estimated or estimated, and control of gas-enriched therapy can be adjusted based on the IMR value. IMR is a quantitative and reproducible index that is independent of epicardial coronary artery disease, intrinsic to the microcirculation, and can be relatively easily measured during ST Elevation Myocardial Infarction (STEMI). A heart attack with a completely blocked coronary artery is called a STEMI. In some implementations, IMR includes a pressure / temperature sensor guidewire-based measurement of the minimum microcirculatory resistance in the target coronary artery region, performed during cardiac catheterization. In some implementations, IMR may be estimated from imaging data, such as angiograms or magnetic resonance imaging (MRI).

[0012] One or more of the advantages described herein may be enabled by one or more of the following embodiments.

[0013] In a general aspect, a system for controlling gas-enriched therapy in a patient is provided. The system includes a gas-enriched system configured to enrich a liquid with a gas to form a gas-enriched liquid and mix the gas-enriched liquid with blood to form gas-enriched blood. The system includes a plurality of fluid conduits fluidly coupled to the gas-enriched system, a first of the plurality of fluid conduits configured for flow of the blood from the patient to the gas-enriched system. The system includes a second of the plurality of conduits configured for flow of the gas-enriched blood from the gas-enriched system to the patient. The system includes a pump coupled to at least one of the plurality of fluid conduits. The pump is configured to pump blood between the gas-enriched system and the patient. The system includes at least one sensor configured to measure one or more physiological parameters indicative of microvascular resistance in the patient's vasculature. The system includes a controller having a processor, memory, and associated circuitry communicatively coupled to the at least one sensor. The processor is configured to perform operations including: receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor; estimating microvascular resistance in the patient's vasculature based on the measured values; and generating an alert or control signal for controlling the amount of the gas-enriched blood delivered to the patient based on the estimated microvascular resistance in the patient's vasculature.

[0014] In some implementations, the operations may include determining a change in the microvascular resistance of the patient's vasculature and generating an alert or control signal for controlling an amount of the gas-enriched blood delivered to the patient based on the determined change in microvascular resistance.

[0015] In some implementations, the at least one sensor includes a flow sensor. The one or more physiological parameters may include a flow rate of blood in the vascular system of the patient.

[0016] In some implementations, the at least one sensor may include a pressure sensor, and the one or more physiological parameters may include a pressure of blood in the vascular system of the patient.

[0017] In some implementations, the operations may include transmitting the control signal to the pump during operation of the pump for delivery of the gas-enriched blood to the patient, and may include causing the pump to increase or decrease a pump speed based on the transmitting control signal to increase or decrease the amount of the gas-enriched blood delivered to the patient.

[0018] In some implementations, controlling the amount of the gas-enriched blood delivered to the patient may include determining that a change in the value of the one or more physiological parameters is indicative of reduced microvascular resistance in the vasculature of the patient. Controlling the amount of the gas-enriched blood delivered to the patient may include generating the control signal in response to determining that the change in value is indicative of the reduced microvascular resistance, the control signal being configured to cause a reduction in the amount of the gas-enriched blood delivered to the patient.

[0019] In some implementations, controlling the amount of the gas-enriched blood delivered to the patient may include determining that a change in the value of the one or more physiological parameters is indicative of increased microvascular resistance in the vasculature of the patient. Controlling the amount of the gas-enriched blood delivered to the patient may include generating the control signal in response to determining that the change in value is indicative of the increased microvascular resistance, the control signal being configured to cause an increase in the amount of the gas-enriched blood delivered to the patient.

[0020] In some implementations, the at least one sensor may include a flow sensor and a pressure sensor. The physiological parameters may include a flow rate of the blood in the vasculature of the patient and a blood pressure in the vasculature of the patient. The operations may further include estimating a change in microvascular resistance in the patient based on a ratio of the blood pressure and the flow rate. The operations may further include generating the control signal based on the estimated microvascular resistance.

[0021] In some implementations, generating the control signal may be performed in real-time or near real-time during delivery of the gas-enriched blood to the patient. The delivery of the gas-enriched blood to the patient may not be paused during measurement of the one or more physiological parameters. The measurement of the one or more physiological parameters may represent a contemporaneous status of the patient with respect to the delivery of the gas-enriched blood to the patient.

[0022] In some implementations, real-time or near real-time may include processing, by the controller, the data received from one or more sensors as soon as the data is available to the controller, and generating the control signals based on the processing.

[0023] In some implementations, receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor may include receiving a series of measured values ​​of the one or more physiological parameters from the at least one sensor. The series of measured values ​​may correspond to a period of time during delivery of the gas-enriched blood to the patient. The operations may further include determining whether the value of the one or more physiological parameters is increasing or decreasing over time based on the series of measured values, optionally corresponding to the period of time. The operations may optionally include generating the control signal configured to increase or decrease the amount of the gas-enriched blood delivered to the patient based on determining that the value of the one or more physiological parameters is increasing or decreasing over time.

[0024] In some implementations, the operations may further include receiving angiography data representative of the patient for a period of time concurrent with delivery of the gas-enriched blood to the patient. The operations may include determining an IMR from the angiography data. The operations may include generating the control signal configured to increase or decrease the amount of the gas-enriched blood delivered to the patient based on the angiography data and the determined IMR or a change in IMR.

[0025] In some implementations, the system may include a catheter configured to deliver the gas-enriched blood to the patient. The system may include a wire coupled to the catheter. The wire may include the at least one sensor. The at least one sensor may be a pressure sensor. The pressure sensor may be configured to obtain pressure data in the vasculature of the patient. The operations may further include receiving the pressure data from the pressure sensor. The operations may include determining an index of microcirculatory resistance (IMR) value in the vasculature of the patient based on the pressure data. The operations may include generating the control signal configured to increase or decrease the amount of the gas-enriched blood delivered to the patient, optionally based on the IMR value or a change in IMR value.

[0026] In some implementations, the system may include at least one sensor including a plurality of sensors. The plurality of sensors may include a plurality of electrodes that may be configured for placement external to the patient. The operations may include measuring impedance values ​​from a tissue area between one or more pairs of the plurality of electrodes. The operations may include generating an impedance tomographic map based at least in part on the measured impedance values. The operations may include estimating the microvascular resistance of a region of the patient's vasculature based at least in part on an impedance distribution of the impedance tomographic map.

[0027] In some implementations, the region of the vasculature is a cardiac region.

[0028] In some implementations, the region of vasculature is a region of muscle tissue.

[0029] In some implementations, the estimating procedure is based at least in part on a mean impedance of the impedance distribution.

[0030] In some implementations, the estimating procedure is based at least in part on the product of the local impedance and the volume of the impedance distribution.

[0031] In some implementations, the gas enrichment system is configured to enrich a liquid with oxygen to form an oxygen-enriched liquid that is to be mixed with the blood.

[0032] In some implementations, the gas enrichment system comprises a cartridge.

[0033] In some implementations, the cartridge has three chambers.

[0034] In some implementations, the physiological parameter includes electrical activity of the patient's heart, as measured by an electrocardiogram (ECG) sensor.

[0035] In some implementations, the estimating step includes estimating microvascular resistance in a localized or partial area of ​​the patient's vasculature.

[0036] In some implementations, controlling includes titrating the amount of the gas-enriched blood delivered to the patient.

[0037] In a general aspect, a system for controlling gas-enriched therapy in a patient is provided, the system comprising: a gas-enriched system configured to enrich a liquid with a gas to form a gas-enriched liquid and mix the gas-enriched liquid with arterial blood to form gas-enriched blood; a plurality of fluid conduits fluidly coupled to the gas-enriched system, a first of the plurality of fluid conduits configured for flow of the blood from the patient to the gas-enriched system and a second of the plurality of conduits configured for flow of the gas-enriched blood from the gas-enriched system to the patient; a pump coupled to at least one of the plurality of fluid conduits, the pump configured to pump blood between the gas-enriched system and the patient; and a pump coupled to one or more of the plurality of fluid conduits. the patient, the patient being configured to deliver the gas-enriched blood from the gas-enrichment system to the patient based on operation of the pump; a wire coupled to the catheter or a separate probe, the wire configured to extend along the catheter or probe to a distal tip of the catheter or probe; a pressure sensor coupled to the wire at the distal tip of the catheter or probe, the pressure sensor configured to measure blood pressure in the patient's vasculature; and a controller having a processor, memory, and associated circuitry communicatively coupled to the pressure sensor, the processor configured to perform operations including determining a change in blood pressure in the patient's vasculature based on the measured blood pressure; determining blood flow in the patient's vasculature; estimating a microvascular resistance in the patient's vasculature based on a ratio of the blood pressure change and blood flow in the patient's vasculature; and generating an alert or control signal to control the amount of the gas-enriched blood delivered to the patient based on the microvascular resistance in the patient's vasculature.

[0038] In some implementations, the estimating step includes estimating microvascular resistance in a localized or partial area of ​​the patient's vasculature.

[0039] In some implementations, the controlling step includes titrating the amount of the gas-enriched blood delivered to the patient.

[0040] In a general aspect, a process is provided for controlling gas-enriched therapy in a patient, the process comprising: providing a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and mixing the gas-enriched liquid with blood to form gas-enriched blood; delivering the gas-enriched blood to the patient; receiving, at a controller coupled to a sensor configured to measure one or more physiological parameters indicative of a microvascular resistance of the patient's vasculature, one or more signals corresponding to measured values ​​of the one or more physiological parameters from the sensor; estimating the microvascular resistance in the patient's vasculature based on the measured values; and generating an alert or control signal to control an amount of the gas-enriched blood delivered to the patient based on the microvascular resistance in the patient's vasculature.

[0041] In some implementations, the control signal may be configured to control a pump configured to pump the gas-enriched blood for delivery to the patient. The process may include causing the pump to pump blood between the gas-enriched system and the patient based on sending the control signal to the pump.

[0042] In some implementations, the sensor may include a flow sensor. The one or more physiological parameters may include a flow rate of blood in the vascular system of the patient.

[0043] In some implementations, the sensor may include a pressure sensor, and the one or more physiological parameters may include a pressure of blood in the vascular system of the patient.

[0044] In some implementations, the process may include transmitting, by the controller, the control signal to a pump configured to pump the gas-enriched blood for delivery to the patient. The process may optionally include causing the pump to increase or decrease a pump speed based on transmitting the control signal to increase or decrease the amount of the gas-enriched blood delivered to the patient.

[0045] In some implementations, reducing the amount of the gas-enriched blood delivered to the patient may include determining that a change in the value of the one or more physiological parameters is indicative of reduced microvascular resistance in the vasculature of the patient. Reducing the amount of the gas-enriched blood delivered to the patient may optionally include generating the control signal in response to determining that the change in value is indicative of the reduced microvascular resistance, the control signal being configured to cause a reduction in the amount of the gas-enriched blood delivered to the patient.

[0046] In some implementations, increasing the amount of the gas-enriched blood delivered to the patient may include determining that a change in the value of the one or more physiological parameters is indicative of increased microvascular resistance in the vasculature of the patient. Increasing the amount of the gas-enriched blood delivered to the patient may include generating the control signal configured to cause an increase in the amount of the gas-enriched blood delivered to the patient in response to determining that the change in value is indicative of the increased microvascular resistance.

[0047] In some implementations, the sensors may include a flow sensor and a pressure sensor, and the physiological parameters include a flow rate of the blood in the vasculature of the patient and a blood pressure in the vasculature of the patient. The process may include estimating a microvascular resistance in the patient based on a ratio of the flow rate and the blood pressure. The process may include generating the control signal based on the estimated microvascular resistance.

[0048] In some implementations, generating the control signal may be performed in real-time or near real-time during delivery of the gas-enriched blood to the patient. The delivery of the gas-enriched blood to the patient may not be paused during measurement of the one or more physiological parameters. The measurement of the one or more physiological parameters may represent a contemporaneous status of the patient with respect to the delivery of the gas-enriched blood to the patient.

[0049] In some implementations, receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the sensor may include receiving a series of measured values ​​of the one or more physiological parameters from the sensor. The series of measured values ​​may correspond to a period of time during delivery of the gas-enriched blood to the patient. The process may include determining whether the value of the one or more physiological parameters is increasing or decreasing over time based on the series of measured values, optionally corresponding to the period of time. The process may optionally include generating the control signal configured to increase or decrease the amount of the gas-enriched blood delivered to the patient based on determining that the value of the one or more physiological parameters is increasing or decreasing over time.

[0050] In some implementations, the process may include receiving angiography data representative of the patient for a period of time concurrent with delivery of the gas-enriched blood to the patient. The process may include determining an IMR from the angiography data. The process may optionally include generating the control signal configured to increase or decrease the amount of the gas-enriched blood delivered to the patient based on the angiography data and the determined IMR or a change in IMR.

[0051] In some implementations, the process may optionally include receiving, by the controller, pressure data from a pressure sensor coupled to a wire supported at a distal end of a catheter in the patient's vasculature. The process may optionally include determining, by the controller, an index of microcirculatory resistance (IMR) value in the patient's vasculature based on the pressure data. The process may optionally include generating, by the controller, the control signal configured to increase or decrease the amount of the gas-enriched blood delivered to the patient based on the IMR value or a change in IMR value.

[0052] In some implementations, the process may optionally include measuring, by the controller, impedance values ​​from a tissue area between one or more pairs of a plurality of external electrodes configured for placement external to the patient. The process may optionally include generating, by the controller, an impedance tomographic map based at least in part on the measured impedance values. The process may optionally include estimating the microvascular resistance of a region of the patient's vasculature based at least in part on an impedance distribution in the impedance tomographic map.

[0053] In some implementations, the region of the vasculature is a cardiac region.

[0054] In some implementations, the region of vasculature is a region of muscle tissue.

[0055] In some implementations, the estimating step is based at least in part on a mean impedance of the impedance distribution.

[0056] In some implementations, the estimating step is based at least in part on a product of a local impedance and a volume of the impedance distribution.

[0057] In some implementations, the controlling step includes titrating the amount of the gas-enriched blood delivered to the patient.

[0058] In a general aspect, a system for controlling gas-enriched therapy in a patient is provided, the system comprising: a gas-enriched system configured to enrich a liquid with a gas to form a gas-enriched liquid and deliver the gas-enriched liquid to the patient's vasculature to form gas-enriched blood; at least one conduit fluidly coupled to the gas-enriched system, the at least one conduit configured for flow of the gas-enriched liquid from the gas-enriched system to the patient; a pump coupled to the at least one conduit, the pump configured to pump the gas-enriched liquid from the gas-enriched system to the patient; at least one sensor configured to measure one or more physiological parameters indicative of microvascular resistance in the patient's vasculature; and a controller having a processor, memory, and associated circuitry communicatively coupled to the at least one sensor. The processor is configured to perform operations. The operations include receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor; estimating the microvascular resistance in the patient's vasculature based on the measured values; and generating an alert or control signal for titrating or controlling the gas-enriched liquid delivered to the patient based on the microvascular resistance in the patient's vasculature.

[0059] In some implementations, the operations may include determining a change in the microvascular resistance of the patient's vasculature and generating an alert or control signal for titrating or controlling the gas-enriched liquid delivered to the patient based on the determined change in microvascular resistance.

[0060] In some implementations, the at least one sensor may include a flow sensor, and the one or more physiological parameters may include a flow rate of blood in the vascular system of the patient.

[0061] In some implementations, the at least one sensor may include a pressure sensor, and the one or more physiological parameters may include a pressure of blood in the vascular system of the patient.

[0062] In some implementations, the operations may include transmitting the control signal to the pump during operation of the pump for delivery of the gas-enriched liquid to the patient, and may include causing the pump to increase or decrease a pump speed based on the transmitting control signal to increase or decrease the amount of the gas-enriched liquid delivered to the patient.

[0063] In some implementations, controlling the amount of the gas-enriched blood delivered to the patient may include determining that a change in the value of the one or more physiological parameters is indicative of reduced microvascular resistance in the vasculature of the patient. Controlling the amount of the gas-enriched blood delivered to the patient may include generating the control signal in response to determining that the change in value is indicative of reduced microvascular resistance, the control signal being configured to cause a reduction in the amount of the gas-enriched liquid delivered to the patient.

[0064] In some implementations, controlling the amount of the gas-enriched liquid delivered to the patient may include determining that a change in the value of the one or more physiological parameters is indicative of increased microvascular resistance in the vasculature of the patient. Controlling the amount of the gas-enriched blood delivered to the patient may optionally include generating the control signal in response to determining that the change in value is indicative of the increased microvascular resistance, the control signal being configured to cause an increase in the amount of the gas-enriched liquid delivered to the patient.

[0065] In some implementations, the at least one sensor may include a flow sensor and a pressure sensor. The physiological parameters may include a flow rate of the blood in the vasculature of the patient and a blood pressure in the vasculature of the patient. The operations may include estimating a change in microvascular resistance in the patient based on a ratio of the blood pressure and the flow rate. The operations may include generating the control signal or alert based on the estimated microvascular resistance.

[0066] In some implementations, the procedure for generating the control signal or alert may be performed in real-time or near real-time during delivery of the gas-enriched liquid to the patient. The delivery of the gas-enriched liquid to the patient may not be paused during measurement of the one or more physiological parameters. The measurement of the one or more physiological parameters may represent the patient's contemporaneous status of the delivery of the gas-enriched liquid to the patient.

[0067] In some implementations, real-time or near real-time may include processing, optionally by the controller, the data received from the one or more sensors as soon as the data is available to the controller, and generating the control signal or alert based on the processing.

[0068] In some implementations, receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor may include receiving a series of measured values ​​of the one or more physiological parameters from the at least one sensor. The series of measured values ​​may correspond to a period of time during delivery of gas-enriched liquid to the patient. The operations may include determining whether the value of the one or more physiological parameters is increasing or decreasing over time based on the series of measured values, optionally corresponding to the period of time. The operations may include generating the control signal or alert to increase or decrease the amount of the gas-enriched liquid delivered to the patient based on determining that the value of the one or more physiological parameters is increasing or decreasing over time.

[0069] In some implementations, the operations may include receiving angiographic data representative of the patient for a period of time contemporaneous with delivery of the gas-enriched liquid to the patient. The operations may include determining an IMR from the angiographic data. The operations may include generating the control signal or alert, optionally to increase or decrease the amount of the gas-enriched liquid delivered to the patient, based on the angiographic data and the determined IMR or a change in IMR.

[0070] In some implementations, the at least one sensor may include a plurality of sensors. The plurality of sensors may include a plurality of electrodes configured for placement external to the patient. The operations may include measuring impedance values ​​from a tissue area between one or more pairs of the plurality of electrodes. The operations may include generating an impedance tomographic map based at least in part on the measured impedance values. The operations may include estimating the microvascular resistance of a region of the patient's vasculature based at least in part on an impedance distribution in the impedance tomographic map.

[0071] In some implementations, the region of the vasculature is a cardiac region.

[0072] In some implementations, the region of vasculature is a region of muscle tissue.

[0073] In some implementations, the estimating step is based at least in part on a mean impedance of the impedance distribution.

[0074] In some implementations, the estimating procedure is based at least in part on a product of a local impedance and a volume of the impedance distribution.

[0075] In some implementations, the gas enrichment system is configured to enrich a liquid with oxygen to form an oxygen-enriched liquid that is to be mixed with the blood.

[0076] In some implementations, the gas enrichment system comprises a cartridge.

[0077] In some implementations, the cartridge has three chambers.

[0078] In some implementations, the controlling step includes titrating the amount of the gas-enriched blood delivered to the patient.

[0079] In a general aspect, a system for controlling gas-enriched therapy is provided. The system may include a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and optionally mix the gas-enriched liquid with blood to form gas-enriched blood. The system may include at least one conduit fluidly coupled to the gas-enrichment system. The at least one conduit may include a conduit configurable for flow of the gas-enriched blood or gas-enriched liquid from the gas-enrichment system to the patient. The at least one conduit may include a conduit configured for flow of the blood from the patient to the gas-enrichment system. The system may include a pump coupled to at least one of the plurality of fluid conduits. The pump may be configurable to pump blood from the patient to the gas-enrichment system. The pump may be configurable to pump blood from the gas-enrichment system to the patient. The pump may be configurable to pump gas-enriched liquid or gas-enriched blood from the gas-enrichment system to the patient. The system may include at least one sensor configurable to measure one or more physiological parameters indicative of microvascular resistance in the patient's vasculature. The system may include a controller configurable to perform operations including one or more of the following: receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor; estimating the microvascular resistance in the patient's vasculature based on the measured values; and generating an alert or control signal for titrating or controlling the gas-enriched blood or gas-enriched liquid delivered to the patient based on the microvascular resistance in the patient's vasculature.

[0080] In a general aspect, a system is provided that includes a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid; a pump configured to pump a fluid from the gas-enrichment system to the patient, the fluid including the gas-enriched liquid; at least one sensor configured to measure one or more physiological parameters indicative of microvascular resistance in the patient's vasculature; and a controller configured to perform operations including receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor; estimating microvascular resistance in the patient's vasculature based on the measured values; and generating an alert or control signal to titrate or control the fluid delivered to the patient based on the estimated microvascular resistance in the patient's vasculature. The gas-enrichment system may be configured to mix the gas-enriched liquid with blood to form the gas-enriched blood. The fluid may be gas-enriched liquid or gas-enriched blood.

[0081] In a general aspect, a system for controlling gas-enriched therapy in a patient is provided, the system comprising: a gas-enriched system configured to enrich a liquid with a gas to form a gas-enriched liquid and deliver the gas-enriched liquid to the patient's vasculature to form gas-enriched blood; at least one conduit fluidly coupled to the gas-enriched system, the at least one conduit configured for flow of the gas-enriched liquid from the gas-enriched system to the patient; a pump coupled to the at least one conduit, the pump configured to pump the gas-enriched liquid from the gas-enriched system to the patient; at least one sensor configured to measure one or more physiological parameters in the patient's vasculature; and one or more controllers having a processor, a memory, the one or more controllers configured to perform operations including receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor.

[0082] receiving imaging data representative of the patient's vasculature; estimating the microvascular resistance in the patient's vasculature based on the imaging data and the one or more signals corresponding to measured values ​​of the one or more physiological parameters; and generating an alert or control signal for titrating or controlling the gas-enriched liquid delivered to the patient based on the microvascular resistance in the patient's vasculature.

[0083] In some implementations, estimating the microvascular resistance includes determining an IMR value. In some implementations, the imaging data is one or more angiographic images. In some implementations, the sensor is a pressure sensor.

[0084] In some implementations, the operations further include receiving the imaging data in the form of angiography data representative of the patient, the angiography data being generated after delivery of the gas-enriched blood to the patient; determining an IMR from the angiography data; and generating an alert or control signal configured to increase or decrease the amount of the gas-enriched blood delivered to the patient based on the angiography data and the determined IMR or a change in IMR.

[0085] In some implementations, the at least one sensor is communicatively coupled to the controller and configured to measure one or more physiological parameters indicative of microvascular resistance in the patient's vasculature.

[0086] In some implementations, the at least one sensor is configured to transmit one or more signals corresponding to measured values ​​of the one or more physiological parameters. In some implementations, the at least one or more signals corresponding to measured values ​​of the one or more physiological parameters correspond to pressure or flow values.

[0087] In some implementations, the control signal increases or decreases the amount of the gas-enriched blood delivered to the patient without pausing the delivery of the gas-enriched blood to the patient.

[0088] In a general aspect, a system for controlling oxygen-enriched therapy in a patient is provided, the system comprising: an oxygen-enriched system configured to enrich a liquid with a gas to form a gas-enriched liquid and mix the oxygen-enriched liquid with blood to form oxygen-enriched blood; a plurality of fluid conduits fluidly coupled to the oxygen-enriched system, a first of the plurality of fluid conduits configured for flow of the blood from the patient to the oxygen-enriched system and a second of the plurality of conduits configured for flow of the oxygen-enriched blood from the oxygen-enriched system to the patient; a pump coupled to at least one of the plurality of fluid conduits, the pump configured to pump blood between the oxygen-enriched system and the patient; and one or more controllers having a processor, memory, and associated circuitry, the one or more controllers configured to perform operations. The operations include the steps of delivering oxygen-enriched blood to the patient; pausing the delivery of the oxygen-enriched blood to the patient after a predetermined period of time; capturing one or more angiographic images representative of the patient's vasculature; estimating a microvascular resistance index in the patient's vasculature based on the one or more angiographic images; generating an alert or instruction to control the delivery of the gas-enriched blood to the patient based on the estimated microvascular resistance index in the patient's vasculature; and controlling the delivery of the gas-enriched blood to the patient based on the alert or instruction.

[0089] In some implementations, the system includes at least one sensor configured to measure a pressure or flow in the patient's vasculature, and the one or more controllers are configured to receive one or more signals corresponding to a measured value of the pressure or flow from the at least one sensor, and estimate the microvascular resistance in the patient's vasculature based on the imaging data and the one or more signals corresponding to the measured value of the pressure or flow.

[0090] In some implementations, the gas-enrichment system is configured to form oxygen-enriched blood. In some implementations, the gas-enrichment system is configured to form oxygen-enriched liquid.

[0091] In a general aspect, a system for controlling gas-enrichment therapy in a patient is provided, the system comprising: a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and mix the gas-enriched liquid with blood to form gas-enriched blood; a plurality of fluid conduits fluidly coupled to the gas-enrichment system, a first of the plurality of fluid conduits configured for flow of the blood from the patient to the gas-enrichment system and a second of the plurality of conduits configured for flow of the gas-enriched blood from the gas-enrichment system to the patient; a pump coupled to at least one of the plurality of fluid conduits, the pump configured to pump blood between the gas-enrichment system and the patient; at least one sensor configured to measure one or more physiological parameters indicative of microvascular dysfunction in the patient's vasculature; and one or more controllers having a processor, memory, and associated circuitry, the processor configured to perform operations. The operations include receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor; estimating microvascular dysfunction in the patient's vasculature based on the measured values; and generating an alert or control signal for controlling the amount of the gas-enriched blood delivered to the patient based on the estimated microvascular dysfunction in the patient's vasculature.

[0092] In some implementations, the one or more signals correspond to measured values ​​of blood pressure from at least one pressure sensor, microvascular dysfunction in the patient's vasculature is estimated based on the measured pressure values, and an alert or control signal is generated based on the estimated microvascular dysfunction.

[0093] In some implementations, the one or more signals correspond to measured values ​​of blood flow from at least one flow sensor, microvascular dysfunction in the patient's vasculature is estimated based on the measured flow values, and an alert or control signal is generated based on the estimated microvascular dysfunction.

[0094] In some implementations, the microvascular dysfunction is microvascular obstruction.

[0095] In some implementations, the microvascular dysfunction is microvascular resistance.

[0096] In a general aspect, a system for controlling gas-enrichment therapy in a patient is provided, the system comprising: a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and deliver the gas-enriched liquid to a vasculature of the patient to form gas-enriched blood; at least one conduit fluidly coupled to the gas-enrichment system, the at least one conduit configured for flow of the gas-enriched liquid from the gas-enrichment system to the patient; a pump coupled to the at least one conduit, the pump configured to pump the gas-enriched liquid from the gas-enrichment system to the patient; at least one sensor configured to measure one or more physiological parameters indicative of microvascular dysfunction in the vasculature of the patient; and one or more controllers having a processor, memory, and associated circuitry, the processor configured to perform operations. The operations include receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor; estimating the microvascular dysfunction in the patient's vasculature based on the measured values; and generating an alert or control signal for titrating or controlling the gas-enriched liquid delivered to the patient based on the microvascular dysfunction in the patient's vasculature.

[0097] In some implementations, the one or more signals correspond to measured values ​​of blood pressure from at least one pressure sensor, microvascular dysfunction in the patient's vasculature is estimated based on the measured pressure values, and an alert or control signal is generated based on the estimated microvascular dysfunction.

[0098] In some implementations, the one or more signals correspond to measured values ​​of blood flow from at least one flow sensor, microvascular dysfunction in the patient's vasculature is estimated based on the measured flow values, and an alert or control signal is generated based on the estimated microvascular dysfunction.

[0099] In some implementations, the microvascular dysfunction is microvascular obstruction.

[0100] In some implementations, the microvascular dysfunction is microvascular resistance.

[0101] In a general aspect, a system for controlling gas-enrichment therapy in a patient is provided, the system comprising: a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and mix the gas-enriched liquid with blood to form gas-enriched blood; a plurality of fluid conduits fluidly coupled to the gas-enrichment system, a first of the plurality of fluid conduits configured for flow of the blood from the patient to the gas-enrichment system and a second of the plurality of conduits configured for flow of the gas-enriched blood from the gas-enrichment system to the patient; a pump coupled to at least one of the plurality of fluid conduits, the pump configured to pump blood between the gas-enrichment system and the patient; at least one sensor configured to measure blood flow through the patient's vasculature; and one or more controllers having a processor, memory, and associated circuitry, where the processor is configured to perform operations. The operations include receiving one or more signals corresponding to a measured value of the blood flow from the at least one sensor; and generating an alert or control signal for controlling the amount of the gas-enriched blood delivered to the patient based on the measured value of the blood flow.

[0102] In a general aspect, a system for controlling gas-enriched therapy in a patient is provided, the system comprising: a gas-enriched system configured to enrich a liquid with a gas to form a gas-enriched liquid and deliver the gas-enriched liquid to the patient's vasculature to form gas-enriched blood; at least one conduit fluidly coupled to the gas-enriched system, the at least one conduit configured for flow of the gas-enriched liquid from the gas-enriched system to the patient; a pump coupled to the at least one conduit, the pump configured to pump the gas-enriched liquid from the gas-enriched system to the patient; at least one sensor configured to measure blood flow in the patient's vasculature; and one or more controllers having a processor, memory, and associated circuitry, the processor configured to perform operations including receiving one or more signals from the at least one sensor corresponding to a measured value of the blood flow; and generating an alert or control signal to titrate or control the gas-enriched liquid delivered to the patient based on the blood flow measurement.

[0103] In a general aspect, a computer program is provided, which may be stored in a memory or on a non-transitory processor-readable medium, and which is configured to cause at least one processor to perform one or more of the operations described with reference to any preceding aspect.

[0104] In a general aspect, the operations performed by the systems described herein may be performed as a process by a system, a device, or multiple devices.

[0105] In general, an implementation described with respect to one aspect may be provided in combination with another aspect. The details of one or more embodiments are set forth in the accompanying drawings and description. Other features and advantages will be apparent from the description and drawings, and from the claims. [Brief description of the drawings]

[0106] [Figure 1A] FIG. 1 is a diagram of an exemplary gas-enrichment system for delivering gas-enriched blood within a patient's vasculature.

[0107] [Figure 1B] 1 is a diagram of an exemplary catheter in the vasculature of a patient, the catheter including a sensor for measuring a physiological parameter value.

[0108] [Diagram 2] FIG. 2 is a diagram of a portion of the system of FIGS. 1A-B, including a cartridge.

[0109] [Diagram 3] FIG. 3 is a perspective view of the system of FIGS. 1A, 1B, and 2.

[0110] [Figure 4] FIG. 4 is a schematic diagram of a system having an impedance tomography sensor for use with the systems of FIGS. 1A-3.

[0111] [Diagram 5] FIG. 1 is a flow diagram of an example process for controlling delivery of oxygen-enriched blood to a patient based on measurements from a physiological parameter sensor.

[0112] [Figure 6] FIG. 1 is a diagram of an exemplary gas-enrichment system for delivering gas-enriched liquid within a patient's vascular system.

[0113] [Figure 7] 1 is a graph containing example data.

[0114] [Figure 8] FIG. 2 is a flow diagram of an exemplary process for controlling delivery of oxygen-enriched blood to a patient.

[0115] [Figure 9]FIG. 1 illustrates an example computer system.

[0116] The drawings are primarily for illustrative purposes and are not intended to limit the scope of the inventive subject matter described herein. The drawings are not necessarily to scale; in some instances, various aspects of the inventive subject matter disclosed herein may be shown exaggerated or enlarged in the drawings to facilitate an understanding of different features. In the drawings, like reference numbers generally refer to like features (e.g., functionally similar and / or structurally similar elements). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0117] The following disclosure describes systems and methods related to gas-enrichment therapy or supersaturated oxygen or gas therapy systems, methods and components, and exemplary embodiments thereof. The system allows for gas-enrichment therapy, e.g., supersaturated oxygen (SSO2) therapy, to be provided to a patient and controlled based on analysis of one or more physiological parameters. SSO2 therapy refers to a minimally invasive procedure for enriching the oxygen content of blood through catheter-facilitated infusion of a physiological fluid (e.g., blood) enriched with supersaturated oxygen, or infusion of a supersaturated oxygen-enriched liquid, such as saline, directly into the patient's blood vessels. These procedures are generally intended to treat patients who have suffered an acute myocardial infarction (AMI), but can be used for other conditions as well, including, but not limited to, peripheral arterial disease. There is a need for improved control of SSO2 therapy based on feedback regarding changes in microvascular resistance, blood perfusion, tissue ischemia, and infarct size in response to SSO2 therapy. The various feedback mechanisms described herein provide improved control of SSO2 therapy, allowing caregivers and / or the system to optimize SSO2 therapy for improved patient outcomes.

[0118] The delivery system described herein is configured to perform measurements of one or more physiological parameters to estimate microvascular resistance in the patient. The delivery system uses the estimate of microvascular resistance to determine how to adjust the control of the delivery of gas-enriched blood to the patient. For example, the delivery system uses the estimate of microvascular resistance to determine how to titrate or control the gas-enriched therapy. Control of gas-enriched therapy may refer to the process of adjusting the delivery of gas-enriched blood or liquid either to increase the amount delivered over a period of time (e.g., seconds to minutes), or to decrease the amount delivered, or to increase or decrease the time of delivery, or to stop or start the delivery of gas-enriched blood or liquid, or to increase or decrease the amount of gas dissolved in the liquid that is subsequently mixed with the blood in a precisely controlled manner. For example, controlling the delivery of gas-enriched blood or liquid may include titrating the delivery of gas-enriched blood or liquid. The delivery system is configured to measure the physiological parameter during the delivery of the gas-enriched blood. The delivery system may be configured for real-time or near real-time control (e.g., real-time control loop) of the delivery of the gas-enriched blood or liquid to titrate or control the delivery of the gas-enriched blood or liquid to the patient based on measured or estimated parameters. Real-time in this context refers to instantaneous or near-instantaneous generation of control signals in response to receiving data from one or more sensors in communication with a controller of the delivery system. The control signals are generated with minimal delay, allowing for handling latencies and / or communication latencies inherent in measuring physiological parameter values ​​and processing the measured data. Thus, real-time refers to processing measured parameter values ​​as the data is received in a processor, rather than storing the measured values ​​for use in processing at a later time. For example, the delivery system may continuously update values ​​in a sensor buffer that represent the most recent measurements of the physiological parameters that are available to the controller for processing.

[0119] FIG. 1A is a diagram of an exemplary gas-enrichment and delivery system 100 for delivering gas-enriched blood within a patient's vasculature. The delivery system 100 can enable bodily fluids (e.g., blood) to be enriched with dissolved gas or gas-enriched liquid. As an example, the delivery system 100 creates gas-enriched blood by enriching the patient's blood with a gas-enriched liquid, e.g., oxygen-enriched liquid, in an extracorporeal gas-enrichment and control system comprising a controller 102 and a cartridge 200. The gas-enriched blood, e.g., oxygen-enriched blood or supersaturated oxygen (SSO2)-enriched blood, is delivered to a patient 144, e.g., a target or localized area in the patient, thereby increasing oxygen in the patient's blood and diffusing oxygen to the tissue to treat ischemic (oxygen-deficient) tissue, e.g., in the heart of a patient having a myocardial infarction. In some implementations, one or more objects described herein may be optional. 1A may be optional (including, but not limited to, one or more of bubble trap 120, intake line flow control mechanism 122, and / or pressure transducer 138b). For example, objects represented by dashed lines may be included in system 100 as options.

[0120] In certain implementations, the oxygen-enriched liquid or solution, e.g., supersaturated oxygen liquid or solution, may include a liquid having a dissolved O2 concentration (e.g., without clinically significant gas embolism) of 0.1 ml O2 / ml liquid (STP) or higher, or 0.1-6 ml O2 / ml liquid (STP), or 0.2-3 ml O2 / ml liquid (STP). When such a supersaturated oxygen liquid or solution is mixed with blood, the resulting blood may be referred to as supersaturated oxygen-enriched blood. In certain implementations, the system 100 may provide an infusion of supersaturated oxygen-enriched blood with an elevated pO2 in a target range of 400 mmHg or higher, or 600-1500 mmHg, or 760-1200 mmHg, or approximately 1000 mmHg.

[0121] In one example, supersaturated oxygen-enriched blood may have a pO2 of 760-1500 mmHg when the source blood delivered to the gas-enriched system for mixing with the supersaturated oxygen liquid or solution has a minimum pO2 of 80 mmHg, the blood flow rate is 50-150 mL / min, the SSO2 saline flow rate is 2-5 mL / min, and the dissolved O2 concentration in the saline is 0.2-3 ml O2 / ml saline (STP).

[0122] In another example, if the source blood is below 80 mmHg, the treatment goal may be to boost the blood pO2 to above 80 mmHg, so the system 100 may deliver an infusion of supersaturated oxygen-enriched blood having a pO2 level of 80 mmHg or higher, or between 80 and 760 mmHg.

[0123] The delivery system 100 is configured to perform real-time or quasi-real-time measurements of regional myocardial blood pressure and / or blood flow and provide feedback using those measurements to optimize the gas-enriched therapy, for example by titrating or controlling the delivery of gas-enriched blood. The delivery system includes one or more sensors for measuring physiological parameters, for example, pressure and / or flow. The measured physiological parameters are used to estimate microvascular resistance in the patient, as described in connection with FIG. 1B. For example, a decrease in microvascular resistance indicates a decrease in microvascular obstruction, which may result in a decrease in the size of an infarct, for example, in the heart. In some implementations, the delivery system 100 estimates microvascular resistance by using an index of microcirculatory resistance (IMR) to determine how to adjust the delivery of gas-enriched blood in real-time or quasi-real-time. The IMR may include a pressure / temperature sensor guidewire-based measurement of minimum microcirculatory resistance in a targeted or localized microvasculature region, for example, near a coronary artery, performed during a cardiac catheterization procedure. In general, IMR correlates with microvascular obstruction (MVO), vascular blood flow, wall motion abnormalities, left ventricular ejection fraction (LVEF), and myocardial viability.

[0124] The delivery of gas-enriched blood to a patient can result in a decrease in microcirculatory resistance, which results in a decrease in MVO, which results in improved perfusion in the microvasculature and tissue. The effect of the delivery of gas-enriched blood and the resulting decrease in IMR and MVO can include a decrease in infarct size. An infarct comprises a small, localized area of ​​necrotic tissue resulting from a failure of blood supply in the patient's vasculature. Thus, a decrease in IMR and the resulting increase in perfusion and blood supply to the infarcted area can indicate a decrease in infarct size.

[0125] As mentioned above, the delivery system 100 is configured to control gas-enriched therapy in a patient by enriching a liquid with a gas to form a gas-enriched liquid and mixing the gas-enriched liquid with blood to form gas-enriched blood. A pump 118, described in more detail below, is configured to pump blood between the gas-enriched system and the patient through a number of fluid conduits fluidly coupled to the gas-enriched system. At least one sensor (e.g., described in connection with FIG. 1B) is configured to measure one or more physiological parameters indicative of microvascular resistance in the patient's vasculature.

[0126] A controller 102, including a processor, memory, and associated circuitry, is communicatively coupled to at least one sensor. The processor is configured to receive one or more signals corresponding to measured values ​​of one or more physiological parameters from the at least one sensor. The processor of the controller 102 is configured to estimate a microvascular resistance in the patient's vasculature based on the measured values. The estimated microvascular resistance may include an estimate or determination of whether the microvascular resistance is increasing or decreasing, rather than an absolute value. However, an absolute value of the microvascular resistance may be estimated. The controller 102 is configured to generate an alert to alert a caregiver to take some action, or a control signal to send to the pump 118 to titrate or control the amount of gas-enriched blood delivered to the patient or the duration of delivery, based on the estimated microvascular resistance in the patient's vasculature. The process for titrating or controlling the amount of gas-enriched blood is described in more detail below.

[0127] The blood circuit includes a blood mixing chamber of the cartridge that receives blood from the patient 144, where enrichment of the blood with a gas-enriched liquid takes place. The blood circuit may include an air trap 120 or a bubble trap chamber. The blood mixing chamber and / or the bubble trap 120 may include one or more level sensors 160, e.g., ultrasonic sensors, to detect the presence or absence of liquid in the respective chamber or trap. These sensors 160 may send signals to control the flow control mechanism depending on the presence or absence of liquid. The blood circuit also includes tubing between these chambers. The blood circuit of the delivery system 100 is connected to an intravenous catheter 136 that is insertable into the vascular system of the patient 144 to complete the blood circuit. Blood is removed from the patient 144, drawn into the cartridge of the delivery system 100, mixed with a gas-enriched liquid, e.g., oxygen-enriched saline, in the blood mixing chamber, and returned to the patient. The chambers of the blood circuit may include one or more chambers of the cartridge 200 and the bubble trap 120. An air bubble detector 126 may be provided to detect air bubbles in the blood circuit.

[0128] In certain implementations, the delivery system 100 may include a console controller 102, a cartridge housing 104, a user interface 132, a pump 118, a power source 114, and an oxygen valve 108 and associated oxygen supply connector 110. The delivery system is configured to connect to several consumables used as part of the delivery system 100, including an oxygen bottle 112, a fluid source 106 (or saline bag 106), a cartridge 200, and a catheter 136.

[0129] The delivery system 100 further includes an inlet line 124 for drawing blood from the catheter 136 through a connector 138a. The inlet line 124 may include a bubble trap chamber 120 and may be configured to interface with the pump 118 and may be configured to interface with a first flow control mechanism, e.g., the inlet line flow control mechanism 122 of the delivery system 100. Pressure transducers 138a-b may be located on either side of the pump 118 to measure the pressure of blood flowing through the blood circuit, such as through the inlet line 124, through the return line 130, or through each of the inlet and return lines.

[0130] The delivery system may include a flow sensor 146, for example, on or near the blood circuit (e.g., on the return line 130) to measure the flow rate of the blood circulation in the blood circuit. For example, the flow sensor 146 may measure the number of milliliters per minute (mL / min) of gas-enriched blood delivered to the patient 144. In some implementations, the flow sensor 146 is positioned near the pump 118. In some implementations, the flow sensor is positioned near the return line 130.

[0131] The delivery system 100 includes a return line 130 for returning the gas-enriched blood to a catheter 136 in the patient 144. The return line 130 may be connected through the air bubble detector 126 and connected to the catheter via a connector 138b. The return line may be configured to interface with a second flow control mechanism, for example, the return line flow control mechanism 128. As mentioned above, an inlet clamp or valve may be used to perform the function of the inlet flow control mechanism 122, and a return clamp or valve may be used to perform the function of the return flow control mechanism 128. In some implementations, another mechanism for controlling or regulating the flow of blood in the blood circuit (e.g., to prevent blood flow and / or flow of room air or air bubbles) may be used to perform the function of the inlet flow control mechanism 122 or the return flow control mechanism 128.

[0132] The catheter 136 can be connected to the delivery system 100. For example, the catheter 136 is a single-use consumable device that is used once before being discarded. The catheter includes a lumen for delivering gas-enriched blood to the patient 144. In the blood circuit, the draw line 124 can be connected (e.g., by connector 138a) to a sheath inserted into the patient 144 to draw blood from the patient 144. The return line 130 can be connected (e.g., by connector 138b) to the catheter 136 to return blood to the patient 144. In some implementations, a catheter including a lumen for delivery of gas-enriched blood to the patient can be inserted through a sheath 142 positioned in the patient's vascular system. In this example, the return line 130 is connected to the catheter 136. The sheath includes a lumen for drawing blood from the patient 144, and the draw line 124 is connected to the sheath. Alternatively, the catheter may include a second lumen for drawing blood from the patient 144 such that the sheath 142 is not used, and thus the catheter is configured for drawing blood as well as returning it to the patient 144. In this example, the draw line 124 and the return line 130 are connected to the catheter 136. The delivery system 100 is configured to be used with different types of catheters. In another example, the sheath 142 includes a first lumen for connecting to the draw line 124 for drawing blood from the patient 144 and a second lumen for connecting to the return line 130 for returning the blood to the patient.

[0133] To deliver gas-enriched blood to the patient 144, the delivery system 100 operates as follows: The console 102 of the delivery system 100 is connected to each of the other components of the delivery system. For example, the cartridge 200 is inserted into the cartridge housing 104 of the console 102. Tubes (e.g., inlet and return lines) extending from the cartridge and connecting the cartridge 200 to the catheter 136 are interfaced with the inlet flow control mechanism 122 and / or return flow control mechanism 128 of the console, and the pump 118. The cartridge and inlet and return lines 124, 130 may be configured such that upon insertion of the cartridge into the cartridge housing, the tubes automatically self-align with the inlet flow control mechanism 122 and / or return flow control mechanism 128, and the pump. For example, the cartridge may have return and inlet lines that have a predefined orientation and shape that match a corresponding shape or design in the cartridge housing and / or on the console. The predefined orientation and shape are such that upon insertion of the cartridge into the cartridge housing, the inlet and return lines automatically align and interface with the inlet and / or return flow control mechanisms 122, 128 and pump 118. The power supply 114 is connected to an external power source for providing power to the console 102. The oxygen supply 110 receptacle is provided with an oxygen bottle 112 for providing a source of oxygen to the cartridge 200. The user interface 132 can indicate whether any of these consumables are running low from the delivery system 100 before or when delivery of enriched blood to the patient has begun.

[0134] 1B, a diagram of an exemplary delivery catheter 136 for delivery of gas-enriched therapy is shown in a patient's vasculature 300 including sensors 308, 310 for measuring physiological parameter values ​​to estimate microvascular resistance in the patient. In the example of FIG. 1B, the vasculature 300 can include an epicardial vessel 304 and a microvasculature 306. Infarct areas 312a-b can be present in the epicardial vessel 304. Infarct areas 314a-b can be present in the microvasculature 306.

[0135] The catheter 136 includes a wire 316 extending from a distal end 318 of the catheter 136 into the patient's vasculature 300. The wire 316 supports sensors 308 and 310. The sensors 308, 310 can be instances of the same type of sensor or different types of sensors. In one example, the sensors 308, 310 each include a pressure sensor configured to measure blood pressure in the patient's vasculature 300. The two pressure sensors 308, 310 can provide a pressure difference (Δp) value for a region 304 of the vasculature surrounding the infarct areas 312a-b, for example, the sensors may record a blood pressure drop across the infarct areas 312a-b. In some implementations, the sensors 308, 310 are configured to measure a relative difference in blood flow in the patient's myocardium. When using wire-based IMR to estimate microvascular resistance, blood flow data is derived via thermodilution. Temperature sensors (e.g., thermistors) located at the proximal and distal ends of the wire may be utilized to measure changes in temperature of the cold saline solution. For example, a pressure sensor on the distal end of the wire can act as a distal thermistor, while a pressure sensor on the proximal shaft of the wire functions as a proximal thermistor. Accordingly, the mean transit time (T mn ) can be determined from the thermodilution curve. Using known thermodilution techniques, T mn Reciprocal of (1 / Tmn ) and absolute coronary blood flow are shown.

number

[0136] In a specific implementation, the IMR (index of microcirculatory resistance) is calculated by multiplying the mean distal coronary pressure P d and 1 / T mn may be calculated using the myocardial blood flow (T) mn is the mean transit time. The minimum achievable resistance is calculated by taking measurements during maximal hyperemia. Accordingly, at maximal hyperemia, IMR=Pd / (1 / Tmn) or Pd*Tmn. IMR can provide qualitative information about the resistance to flow in the vasculature (e.g., partial microvasculature) after inducing hyperemia. The change in IMR over time in the direction of the standard IMR will be the desired outcome and measurable effect of gas-enriched or SSO2 treatment.

[0137] In some implementations, the sensors 308, 310 include flow sensors configured to measure blood flow directly in the patient. The flow sensors may include electromagnetic, mechanical, or ultrasonic flow sensors.

[0138] The sensors 308, 310 may transmit pressure measurements (or measurements of another physiological parameter) to the controller 102 to estimate microvascular resistance in the microvascular region 306. The estimation may include determining a ratio of a change in pressure to a flow rate. In some implementations, at least one of the sensors 308, 310 includes a pressure sensor. The physiological parameter includes a pressure or pressure change of blood in the patient's vasculature 300. In some implementations, at least one of the sensors 308, 310 includes a flow sensor. Thus, the physiological parameter includes a flow rate of blood in the patient's vasculature.

[0139] In some implementations, the wire 316 is positioned on or near the distal end 318 of the delivery catheter 136. In some implementations, the one or more sensors 308, 310 are positioned directly on the body of the catheter 136. The wire 316 can extend through the lumen of the catheter 136 until it exits the distal end 318 of the catheter. In some implementations, the wire 316 extends along the shaft of the catheter 136 outside of the catheter lumen.

[0140] In some implementations, the wire 318 is positioned on a separate probe that is not directly attached to the delivery catheter 136. In some implementations, a second, separate catheter is used to support one or more sensors 308, 310. In such instances, the catheter 136 is not the delivery catheter, and the second, different catheter and the delivery catheter are not shown.

[0141] The one or more sensors 308, 310 are configured to transmit data to the controller 102, which can display feedback on the user interface 132 in response to receiving data from the sensors. The feedback displayed on the user interface 132 can include an indication of blood pressure values, flow rate values, an estimate of microvascular resistance, an estimate of the change in microvascular resistance in the vasculature 300 over time, the rate (e.g., titration) of delivery of gas-enriched blood, the rate of delivery of gas-enriched liquid, e.g., saline, pump speed and direction, and the like. As will be described in more detail below, the feedback displayed by the user interface 132 can include a time series showing a sequence of measurements. In some implementations, the feedback can include a chart or graph that is updated continuously or intermittently as new data is acquired and the estimate of microvascular resistance is updated. For example, the estimate of microvascular resistance can be graphed over time.

[0142] Data from the sensors 308, 310 is sent to the controller either automatically, directly, or through a user action. For example, in the case of non-invasive imaging modalities (described later), feedback may be entered by a user into a user interface. In some implementations, tomographic measurement signals may be sent directly to the controller 102. In some implementations, data is sent from the sensors 308, 310 to the controller 102 via wires 316, which are connected either directly to the wires 316 or indirectly to the wires through a catheter hub.

[0143] Data generated from the sensors 308, 310 is used to control the delivery of gas-enriched blood or liquid to the patient's vasculature. In some implementations, SSO2 delivery includes direct injection of gas-enriched liquid into blood in the patient's vasculature. In some implementations, SSO2 delivery includes mixing the patient's blood with the gas-enriched liquid in a mixing chamber external to the patient and delivering the gas-enriched blood to the patient using the catheter 136.

[0144] The delivery system 100 is configured to control the delivery of gas-enriched therapy based on feedback from the sensors 308, 310. In some implementations, the delivery system 100 is configured to enhance blood flow. In some implementations, the delivery system 100 is configured to increase the concentration of oxygen in the gas-enriched liquid / blood delivered to the patient. In some implementations, the delivery system 100 increases or decreases the amount of gas-enriched blood / liquid to the patient, either by increasing or decreasing the flow rate of the gas-enriched blood delivery, or by increasing or decreasing the duration of the gas-enriched blood delivery.

[0145] Generally, the controller 102 is configured to adjust the gas-enriched liquid or blood delivery based on a target value. The target value generally includes a target estimate for microvascular resistance. However, the target value may include a target amount of gas-enriched liquid or blood to be delivered, where an estimate of microvascular resistance is used as a value from which the target amount of liquid or blood to be delivered is determined. Generally, a physician (or other user) may set the target value and control the operation of the delivery system 100.

[0146] In some implementations, the delivery system 100 is configured to display the coronary flow reserve (CFR), which includes the maximum increase in blood flow through the coronary artery above the normal resting volume, which is the total flow rate. The delivery system 100 measures the normal flow and the hyperemic vasodilatory flow in the vessel and finds the ratio of these values. In some implementations, the delivery system 100 determines the epicardial fractional coronary flow reserve (FFR), which is measured by a pressure probe (e.g., sensors 308, 310) that enters the coronary artery 304. The pressure drop between the proximal and distal ends of the artery 304 is determined. These values ​​can be displayed on the user interface 134 along with any other operational values ​​of the delivery system 100 described herein.

[0147] The controller 102 of the delivery system is configured to determine a change in the microvascular resistance of the patient's vasculature 300 over time. In response to this determination, the controller generates an alert or control signal to titrate or control the gas-enriched blood delivered to the patient. The controller 102 is configured to send a control signal to the pump 118 during operation of the pump for delivery of the gas-enriched blood to the patient. Based on sending the control signal, the controller 102 causes the pump 118 to increase or decrease the pump speed to increase or decrease the amount of gas-enriched blood delivered to the patient. In some implementations, titrating or controlling the amount of gas-enriched blood delivered to the patient includes the controller 102 determining that a change in the pressure or flow rate value from the sensors 308, 310 represents a decreased microvascular resistance in the patient's vasculature. In certain implementations, the controller may estimate the microvascular resistance by determining the IMR over a period of time and take into account the decrease in the IMR over that period of time. If the IMR is still decreasing, it may indicate that more gas-enriched or SSO2 therapy is needed. If the IMR has reached a plateau, it may indicate that the maximum benefit of the treatment has been reached and the treatment can be stopped.

[0148] In response to determining that the IMR has reached a plateau or a change in value represents reduced microvascular resistance, the controller 102 can generate a control signal configured to cause a reduction in the amount of gas-enriched blood delivered to the patient or a reduction in the amount of oxygen dissolved in the liquid that is mixed with the blood to form the gas-enriched blood. Alternatively, the controller may in response generate an alert to inform a caregiver to take the necessary action to reduce the amount of gas-enriched blood delivered to the patient or the amount of oxygen dissolved in the liquid.

[0149] In some implementations, titrating or controlling the amount of gas-enriched blood delivered to the patient includes determining, by the controller 102, that a change in the flow rate or pressure change value represents increased microvascular resistance in the patient's vasculature 300. In certain implementations, the controller may estimate microvascular resistance by determining the IMR over a period of time and take into account an increase in the IMR over that period of time. If the IMR is still increasing, it may indicate that more gas-enriched or SSO2 therapy is needed. If the IMR has reached a plateau, it may indicate that the maximum benefit of the therapy has been reached and the therapy may be stopped.

[0150] In response to determining that the IMR is increasing or that a change in value represents increased microvascular resistance, the controller 102 can generate a control signal configured to cause an increase in the amount of gas-enriched blood delivered to the patient or an increase in the amount of oxygen dissolved in the liquid that is mixed with the blood to form the gas-enriched blood. Alternatively, the controller may in response generate an alert that tells a caregiver to take the necessary action to increase the amount of gas-enriched blood delivered to the patient or increase the amount of oxygen dissolved in the liquid.

[0151] The control of the gas-enriched blood delivery is performed in real-time or near real-time. The delivery of the gas-enriched blood to the patient is not paused during the measurement of the one or more physiological parameters. The measurement of the one or more physiological parameters represents the patient's contemporaneous status of the delivery of the gas-enriched blood to the patient. Generally, real-time or near real-time includes processing, by the controller, data received from the one or more sensors as soon as the data is available to the controller, and generating control signals or alerts based on the processing, as described above to titrate or control the gas-enriched therapy based on the feedback.

[0152] The controller 102 is configured to control the gas-enriched blood delivery over time. The controller 102 receives one or more signals corresponding to measured values ​​of one or more physiological parameters from the sensors 308, 310. The controller 102 may receive a series of measured values ​​of pressure or flow values ​​from the sensors 308, 310 over time. The series of measured values ​​corresponds to a period during the delivery of the gas-enriched blood to the patient. The controller 102 determines whether the pressure or flow (or microvascular resistance) value is increasing or decreasing over time based on the series of measured values. The controller 102 generates a control signal configured to increase or decrease the amount of gas-enriched blood delivered to the patient based on the time series of values. For example, if the pressure value is increasing over time, the controller may titrate the gas-enriched blood delivery to increase to deliver more oxygen to the vasculature 300. For example, if the pressure value is decreasing over time, the controller may titrate the gas-enriched blood delivery to decrease to deliver less oxygen to the vasculature 300.

[0153] The controller 102 can titrate or control the gas-enriched blood delivery based on other data in addition to or instead of the data from the sensors 308, 310. For example, the controller 102 is configured to receive angiography data representative of the patient during one or more time periods concurrent with the delivery of gas-enriched blood to the patient. The angiography data can include images of the patient's vasculature 300 showing signs of infarct regions 312a-b, 314a-b. The infarct regions 312a-b, 314a-b include blockages in the vasculature. Generally, the infarct size expressed as a percentage is determined by dividing the sum of the infarct areas from all sections by the sum of the vessel cross-sectional areas from all sections of the vasculature. The images provide additional context to the pressure and / or flow data from the sensors 308, 310 to estimate microvascular resistance. In certain implementations, the angio-IMR flow can be derived / estimated from the TIMI frame count of the angiogram. In certain implementations, angio-IMR may be estimated or calculated from angiography data, for example, using FlashAngio™ software by Rainmed™.

[0154] The controller 102 is configured to generate control signals or alerts to increase, decrease or stop (e.g., titrate or control) the amount of gas-enriched blood delivered to the patient based on the angiographic data and / or the microvascular resistance or IMR estimated from the angiographic data. In certain implementations, the control signals or alerts may be generated in real-time or near real-time.

[0155] In certain implementations, the system 100 may receive imaging data, e.g., angiographic imaging data, representing the patient's vasculature, and estimate a microvascular resistance, e.g., IMR, in the patient's vasculature based on the imaging data and / or measured values ​​of the sensor to provide feedback for controlling the amount of gas-enriched therapy.

[0156] 1A , once each of the delivery system components are connected, including cartridge 200, pump 118, air bubble detector 126, return flow control mechanism 128, and catheter 136, and optionally inlet flow control mechanism 122 and bubble trap 120, delivery system 100 is ready for use. The blood circuit is shown with arrows representing the direction of blood flow during operation of delivery system 100, where blood is drawn from catheter 136, through the inlet line, through the cartridge and blood mixing chamber where it mixes with gas-enriched liquid, and the resulting gas-enriched blood is returned to the catheter via the return line.

[0157] Prior to operation, a priming process is performed, which ensures that the blood circuit is filled or substantially filled with blood to a threshold level such that there is no room air and / or air bubbles in the blood circuit that can migrate to the patient 144. For example, the inlet line 124 and the return line 130 are filled with blood. For example, the bubble trap 120 and the pump 118, as well as the tubing connecting the various elements of the blood circuit, are filled with blood. The blood mixing chamber of the cartridge 200 is filled with blood, for example to a threshold level.

[0158] Room air and / or air bubbles from each of the blood circuit elements are vented from the respective elements as described below. The air bubble detector 126 is configured to detect any air bubbles present in the blood circuit during operation of the delivery system 100 and can send a signal that causes the return flow control mechanism 128 to close if room air and / or air bubbles are detected in the blood circuit. This prevents air bubbles from reaching the patient 144 in the catheter 136. The air bubble detector 126 can include an ultrasonic sensor, an infrared (IR) sensor (e.g., a photogate), or other such mechanism for detecting air or air bubbles in the line. For example, the air bubble detector 126 can include an IR sensor that senses an IR beam transmitted through the fluid of the blood circuit. Air bubbles in the fluid distort the beam, which can be detected by the IR sensor.

[0159] The delivery system 100 may be configured to control the oxygen level in the blood and / or tissues of the patient 144 by controlling the oxygen level in the supersaturated oxygen liquid or solution (e.g., a dissolved O2 concentration in saline of 0.1 ml O2 / ml liquid (STP) or higher or 0.1-6 ml O2 / ml liquid (STP) or 0.2-3 ml O2 / ml liquid (STP) and / or targeting the flow rate of the supersaturated oxygen-enriched blood delivered to the patient 144 by controlling the speed of the pump to achieve a target blood flow rate of, for example, 10-500 mL / min, 30-300 mL / min or 50-150 mL / min). The system 100 may be configured to titrate oxygen into a liquid, e.g., saline, that is mixed with the blood to adjust the oxygen level and / or blood flow rate. The concentration of delivered oxygen and / or blood flow rate may be modulated during treatment based on feedback from one or more sensors measuring one or more physiological parameters indicative of microvascular resistance in the patient's vasculature, and an estimation of the microvascular resistance based on the measured physiological parameters.

[0160] As discussed herein, one or more blood pressure sensors may be used to measure blood pressure values ​​in blood from a patient undergoing gas-enriched therapy. A processor of the controller may receive signals corresponding to measured values ​​of blood pressure and changes in blood pressure from the blood pressure sensor. The processor may compare the measured blood pressure to a target range of blood pressure, e.g., the blood pressure of a healthy individual. The processor may generate an alert, e.g., through a user interface, indicating the blood pressure or changes in blood pressure. The measured blood pressure or changes in blood pressure may indicate microvascular resistance in the patient's vasculature. The processor may control the gas-enriched system by modifying one or more saline or blood parameters in the gas-enriched system to optimize therapy based on blood pressure feedback.

[0161] The change in blood pressure may indicate a change in blood flow in the myocardial tissue in response to the gas-enriched therapy. Gas-enriched therapy, for example SSO2 therapy, provides a high concentration gradient of O2 that allows for improved diffusive transport to ischemic areas of the myocardium. This diffusive transport of O2 to areas of greatest need is not dependent on blood flow, and therefore O2 can easily access the endothelial cells of capillaries undergoing edema (swelling). SSO2 therapy can reverse this edema response in the microvasculature and restore flow, so that oxygenated blood nourishes the surrounding cardiac tissue.

[0162] In addition to the wire with pressure sensor discussed above, another exemplary sensor for measuring the arterial pressure of the patient's blood includes a pressure sensor positioned on or coupled to a catheter. The catheter may be connected to a fluid-filled system or pressure tube, which is connected to an electronic pressure transducer and / or pressure monitor. The detected change in blood pressure may indicate improved perfusion and / or restored flow in the ischemic tissue as a result of the SSO2 therapy. The therapy may result in improved cardiac function. In certain implementations, the processor may control the delivery of the SSO2 therapy based on the arterial pressure feedback.

[0163] In certain implementations, the feedback may be based on a measured blood pressure waveform. Changes in the waveform reflection pattern may be detected. In one example, changes in the reflection pattern of a normal pulsatile waveform of the patient's blood pressure may be detected or measured. In another example, a pulsatile flow may be created (for finer adjustment) and changes in the reflection pattern of the created pulsatile waveform of the patient's blood pressure may be detected or measured. In either example, the pulsatile waveform may be analyzed for information such as the relative magnitude and timing of secondary peaks identified in the waveform.

[0164] The user interface 132 is configured to display operational and / or patient data on the user interface in a configuration that allows a user to determine a status for the SSO2 liquid and gas-enriched blood delivery to the patient 144. The user interface 132 indicates the current operational status of the delivery system 100.

[0165] These values ​​can be stored as a time sequence of data entries or log entries in an operational log. The user interface can include a visual representation of the operational log, which includes operational data specifying how the delivery system 100 is performing during delivery of the enriched blood to the patient. For example, the delivery system 100 logs sensor readings and IMR during delivery and generates alerts or reports indicating whether the delivery of the gas-enriched blood should be titrated or controlled. In some implementations, the delivery system 100 can transmit the logged data to a remote network-attached storage (e.g., in cloud storage) for access from one or more network-attached devices.

[0166] In some implementations, various data elements are logged during the delivery process. For example, the duration of the delivery can be logged. Each time a checkpoint is reached, a timestamp associated with the checkpoint is saved. The checkpoints can include completion of the delivery process, an indication of the titration of the delivery of gas-enriched blood, an indication of the value of one or more physiological parameters such as pressure or flow rate, a visualization of an estimate of the microvascular resistance, or any other data of interest during the delivery process. Values ​​of sensors such as level sensors, pressure sensors, and temperature sensors can be stored at a given moment. Operational values ​​of devices on the blood circuit, such as how fast the pump is running, the blood level in the blood mixing chamber or bubble trap when one or more flow control mechanisms 122, 128 are activated, etc., can be monitored. These data provide information to determine whether a problem is occurring during the delivery of the gas-enriched blood.

[0167] In some implementations, the delivery system 100 may include a processor, memory, and associated circuitry coupled to one or more sensors for detecting physiological data. The physiological data is collected and / or stored within the system for retrospective, current, or other review. The delivery system 100 is configured to generate log entries for the operational data (e.g., delivery data). The log entries may be displayed on the user interface 132. In certain implementations, the log entries may each be structured messages that contain specific values ​​associated with the operation of the delivery system 100 generated from data messages. In some implementations, the data messages (also referred to as log messages) represent instantaneous snapshots of the operational data. For example, the data messages may include treatment data or current pressure, flow rate, or microvascular resistance values ​​at a given point in time (e.g., associated with a timestamp). In some implementations, the data messages may include data representing the treatment duration or system mode of the gas-enriched liquid treatment for the patient 144 in the structured log entries. The data messages are stored in a digital format that allows streaming of the data messages to a remote system. The remote system is configured to rapidly extract values ​​representative of patient data and operational data of the delivery system 100 and display representations of these data on a local or remote user interface. For example, the data messages can be formatted for streaming from a hospital room to an operator or nurse's station. In some implementations, the data messages can include warnings or alerts that prompt intervention from a user of the remote system. In some implementations, the data messages can be stored in a structured format that facilitates searching and retrieval of operational data about the patient 144 for operation of the delivery system 100 during SSO2 delivery.

[0168] In some implementations, the log entries may each be a structured message that includes specific values ​​associated with the operation of the delivery system 100, generated from a data message. For example, the data message may indicate a current snapshot of the operation of the delivery system 100. In this case, the values ​​of the data message include a list of operational and / or physiological values. The operational and / or physiological values ​​may be parsed from the data message (e.g., by a remote device) and used to populate a screen or display of a remote computing system. For example, the delivery system 100 may transmit a stream of data that includes the data message to a remote system for remote monitoring of the operation of the delivery system 100. In some implementations, the processor is configured to stream digital output data having the patient data and the operational data to a remote server. In some implementations, the operational and patient data may be transmitted or streamed in real time or near real time via a wired RS-232 streaming output on the system console to a remote processor or computer, such as an EMR data hub or hospital hub. In some implementations, operational and patient data may be transmitted or streamed in real-time or near real-time via WiFi communication, Bluetooth, cellular, USB or other wireless connections or links.

[0169] The data messages may include summary data. For example, the log entries may include data representing a summary of the operational and / or physiological data for a period of time (e.g., pre-titration data, titration data, and post-titration data). Each log entry may form all or a portion of an operational log, which provides an overall summary of the operation of the delivery system 100. The operational log allows a healthcare provider to quickly review a summary of the operation of the delivery system 100. The operational and physiological data, e.g., data messages, log entries, operational logs, and / or other data stored by a system processor or accessories to the system or data modules coupled to the system console, may be stored on volatile or non-volatile memory. The log entries may be visually represented on the user interface 132.

[0170] The data messages may provide instantaneous values ​​of operational and physiological data of the delivery system 100. The log entries may represent data collected over time and may be part of a system and / or patient profile. For example, the operational log and log entries may be stored in an electronic medical record (EMR).

[0171] In some implementations, the log entries of the operational log are sent to a remote device (such as a data hub at a hospital). The delivery system 100 sends data, including the log entries, to the remote device in one or more different ways. The delivery system 100 sends the log entry data to the remote device in response to a trigger. For example, the delivery system 100 can send a log entry to the remote device when titration or control of the delivery of gas-enriched blood is complete. In some implementations, the delivery system 100 sends the operational log data when the entire procedure is complete. For example, when the cartridge 200 is removed or the pump 118 is turned off, the controller 102 can determine that the procedure is complete and send the log entry data to the remote device.

[0172] In some implementations, the delivery system 100 transmits operational log data to a remote device upon detecting a fault, such as a failure of the bubble trap 120, a failure of the catheter 136, a patient's blood pressure or microvascular resistance dropping below a threshold, etc. The operational log data can be analyzed (e.g., by a user) to determine why the fault occurred and / or to determine whether operation of the delivery system 100 is adversely affected by the fault. This allows the user to take immediate corrective action (e.g., replace the bubble trap 120, repair a fluid leak, etc.) to ensure that treatment of the patient 144 is not compromised.

[0173] In some implementations, the delivery system 100 transmits the operational log data without a trigger. For example, the delivery system 100 can transmit the log entry data to the remote device periodically (e.g., once per minute, once per hour, etc.).

[0174] In one aspect, the delivery system 100 links log entries related to operations together in a structured format. For example, a key value can be stored with each log entry. The entire log of an operation of the delivery system 100 can be retrieved by referencing the key value.

[0175] The delivery system 100 can generate one or more alerts indicating the status of one or more components of the delivery system 100. The alerts can be generated based on operational log data or data in a data message. The alerts can be generated for presentation on a user interface 132 of the delivery system 100. The processor may send the alerts to one or more other computing devices, such as a computing device associated with a healthcare provider of the patient 144. In one aspect, the user interface is configured to communicate with the processor, and the data represents an alert indicating whether a fault has occurred, whether priming has started / completed, or any other relevant aspect of the operation of the delivery system 100 that satisfies a notification rule causes a notification to be displayed on the user interface. The user interface can be coupled to a console via wires or wirelessly (e.g., the user interface can be a portable tablet or a remote computing device).

[0176] The alert may indicate that there is a fault or error in the operation of the delivery system 100. The alert provides an indicator for a healthcare provider to investigate the operation of the delivery system 100, for example, whether any faults have occurred. The alert may indicate that titration of the delivery of gas-enriched blood is complete, that there is a pressure in the blood circuit above a value, that room air and / or air bubbles have been detected, etc.

[0177] In some implementations, the processor generates an alert that causes one or more devices to perform an action. For example, feedback such as an audio cue, a visual presentation, etc. can be presented to a healthcare provider. The alert can cause the device to contact the healthcare provider (e.g., phone call or page a doctor, nurse, etc.). The alert can cause the device to display certain data regarding the delivery process or execution of the system or data regarding the patient 144, such as a presentation of blood pressure or microvascular resistance over a given treatment period. The alert can cause the device to update a health record associated with the patient 144 or cause the device to retrieve a health record associated with the patient for further analysis. In certain implementations, the processor of the system can be configured to determine whether the alert is a real-time alert or one that has been recorded for retrospective review. If it is real-time, the processor determines whether to display the alert on a user interface, send the alert in the information chain, or send the alert data to a third-party monitor. An example route is to send the alert to a doctor's or nurse's cell phone.

[0178] The alert may open a mobile phone based application or an Internet based application. From either application, a doctor or nurse can view the alert and other associated data that may have been sent. The alert includes a hospital-specific patient identifier, but may be otherwise invisible to the identity of the patient 144 unless the doctor or hospital adds the patient's name to either the application on their phone or the Internet. The alert may include a non-patient-specific identifier, such as a bed number. In addition, the doctor will have the opportunity to take action in response to receiving the alert. This could include triggering a phone call to the ICU desk or marking that the doctor has seen the alert. Changing the duration or range of values ​​monitored will allow the user to set the duration so that transient spikes do not trigger an alert. If the time and / or duration of the alert is adjusted, such adjustment may only affect notifications for that particular person.

[0179] Dual alerts to nurses or doctors may have different alert scopes and actions. The features described may be fully controlled by a user, e.g., a doctor. For example, a first point of control may be at the bedside where the alert scope may be set. A second point of control may be at the receiving application or website where the user may adjust nominal settings for, e.g., "sound". Thus, two or more triggers may be established, the first being to "send" the alert to the network from the machine to the receiving device, and the second being the action the receiving device takes upon receiving the alert. A scheduling feature may be provided that allows data to be forwarded from one doctor whose shift is ending to another who is entering a shift. A response tree may be provided that requires an acknowledgement that the alert has been seen or forwarded from one doctor to another. For example, a first doctor is given five minutes to acknowledge the alert, and if there is no acknowledgement, the alert is sent to another doctor or nurse. In a particular implementation, one or more of the various alerts or alert parameters described herein may be customized by the user. Multiple options for alert delivery may be configured, e.g., device display, nurse's station, EMR, cell phone, etc. Alerts for the thermoregulatory activity of the patient 144 may include other formats. For example, a color scale or an audible alert may be output via a user interface to provide a value indicative of the patient's activity.

[0180] In some implementations, a healthcare provider can query the delivery system 100 to obtain operational data. The query can request specific data such as what the battery status is, determine whether the titration of gas-enriched blood was successful, etc.

[0181] In some implementations, the controller is configured to store digital output data representative of the delivery process in a data store. The controller is configured to detect that a trigger condition of the delivery process is met. For example, the trigger condition can include completion of all or a portion of the delivery process. In some implementations, the controller transmits the digital output data to a remote device in real time or near real time in response to detecting that the trigger condition is met, e.g., during or after delivery of the gas-enriched blood by the delivery system.

[0182] In some implementations, the digital output data includes a predefined format that allows the digital output data to be streamed to a remote device. The delivery system can include a transmitter configured to transmit the digital output data to the remote device. In some implementations, the predefined format is configured to allow the remote device, upon receiving the digital output data, to parse the digital output data to display the physiological data and / or the motion data. In some implementations, the process includes streaming the digital output data via WiFi communication, Bluetooth, cellular, or other wireless connection or link, or USB. In some implementations, the process includes transmitting the digital output data via a wired connection.

[0183] FIG. 2 is a diagram of an example of a portion of the system of FIG. 1A including a cartridge 200. In this example, the cartridge 200 includes a fluid supply chamber (piston device 202), a gas enrichment chamber (oxygenator 204), and a blood mixing chamber 206. In some implementations, the cartridge 200 may include a bubble trap 208 and at least a portion of the tubing of the inlet line 214 and the tubing of the return line 218. In FIG. 2, the pump 210 is similar to the pump 118, the inlet line 214 is similar to the inlet line 124, the return line 218 is similar to the return line 130, and the bubble trap 208 is similar to the bubble trap 120. The cartridge 200 is a consumable portion of the blood circuit that includes the portion of the blood circuit that contacts the patient's blood. The return inlet flow control mechanism 216, the pump 210, and the inlet flow control mechanism 212 are shown in dashed lines because they are part of the console system and are reusable. Similarly, return pressure sensor 238 and / or retract pressure sensor 240 may be reusable; whereas, in certain embodiments, return pressure sensor 238 and / or retract pressure sensor 240 may be part of a single-use consumable cartridge and tubing. In some implementations, one or more objects described herein in connection with FIG. 2 may be optional (including, but not limited to, bubble trap 208, clamp 212, vent 234, solenoid 236, or transducer 240, etc.). For example, objects represented by dashed lines may be included in cartridge 200 as options.

[0184] The cartridge 200 is configured to interface with components of the console 102 of the delivery system 100 during operation, priming, and treatment. A portion of the tubing of the cartridge 200, which may be referred to as the pump tubing, is configured to be disposed in the pump 210 of the console. The tubing of the inlet line 214 and the tubing of the return line 218 are oriented to be disposed inside the inlet flow control mechanism 212 and the return flow control mechanism 216, respectively. The flow control mechanisms 212, 216 are coupled to the console 102. When the cartridge 200 is installed, the flow control mechanisms 212, 216 align with the inlet and return lines 214, 218 to allow the flow control mechanisms to restrict fluid flow in the inlet and return lines 214, 218 (e.g., by clamping). The inlet flow control mechanism 212 and the return flow control mechanism 216 are actuated by control signals of a controller of the console 102. Similarly, the pump 210 is coupled to the console 102. The pump 210 is enabled by a control signal from the pump's console controller to pump in either the intake line direction or the return line direction as required.

[0185] The piston device 202 includes a mechanical device for drawing saline from a fluid source. Fluid from the IV source is drawn through a tube into the piston chamber. The piston moves vertically in the chamber based on a signal from a piston actuator. A load cell determines the force required to move the piston. A stepper motor controls the actuator's motion. An encoder reports the piston position based on the stepper motor rotor location. A piston top sensor and a piston bottom sensor can detect when the piston moves to the edge of the chamber. The position of the piston determines how much fluid from the saline bag is sent to the oxygenator.

[0186] The piston device 202 is configured to draw saline into the oxygenator 204. The oxygenator 204 is configured to add oxygen to the saline from the saline bag 106. An oxygen pressure line 220 adds oxygen to the oxygenator 204. The oxygenator 204 is coupled to an oxygen vent 226 and an oxygen vent solenoid 228 that controls operation of the vent 226. The oxygenator vent 226 is configured to vent excess air from the oxygenator if the oxygen pressure exceeds a threshold value.

[0187] The oxygenator 204 includes an oxygen chamber, an atomizer, and a valve manifold. The valve manifold includes several valves, such as a fill valve, a flush valve, and a supersaturated oxygen SSO2 flow valve (not shown). The fill valve, flush valve, and SSO2 flow valve are each controlled by a respective solenoid. The fill solenoid opens / closes the fill valve. The flush solenoid opens / closes the flush valve 406. The SSO2 flow solenoid opens / closes the flow valve. The SSO2 level sensor 400 indicates the level of gas-enriched liquid in the oxygenator.

[0188] The oxygen chamber is connected to an oxygen pressure line and an oxygen vent. The oxygenator releases excess oxygen through the oxygen vent 426 and receives additional oxygen through the oxygen pressure line. The oxygenator receives fluid from the piston chamber. The atomizer includes a central passage in which a one-way valve is located. When fluid pressure overcomes the force of the spring in the one-way valve and overcomes the pressure of the oxygen in the atomizer chamber, the fluid travels through the passage and exits through a nozzle at the end of the atomizer.

[0189] The nozzle forms droplets of fluid, and oxygen in the atomization chamber diffuses into the droplets as they move through the atomization chamber. This oxygen-enriched fluid is referred to as the SSO2 solution. The nozzle is preferably a simplex-type swirl pressurized atomizer nozzle that includes a fluid orifice of about 0.004 inches (0.1016 mm) diameter to 0.005 inches (0.127 mm) diameter. The oxygen-infused droplets fall into a pool at the bottom of the atomizer chamber. The pool level is controlled to ensure that the atomizer continues to function properly, since the atomizer will not atomize properly if the pool level rises above the nozzle level. Once the oxygen is dissolved in the saline using controlled pressure, the gas-enriched saline is sent to the blood mixing chamber 206 for mixing with the blood in the blood circuit.

[0190] The blood mixing chamber 206 is connected to the oxygenator 204. Thus, the blood mixing chamber 206 is part of the blood circuit. The blood mixing chamber 206 is positioned between the tubing of the pump 210 and the return line flow control mechanism 216 and the air bubble detector 126. The blood mixing chamber 230 is configured to vent any room air and / or air bubbles from the blood mixing chamber 230. The blood mixing chamber vent solenoid 232 controls the operation of the vent 230.

[0191] The blood mixing chamber 206 includes a volume configured to receive the gas-enriched saline from the oxygenator 204. The blood mixing chamber includes a low sensor and a high sensor. The low sensor is configured to detect when the blood mixing volume 502 is empty. The high sensor detects when the blood mixing volume is full.

[0192] The blood mixing volume vents from the blood circuit through a vent line to vent room air and / or air bubbles. The blood mixing chamber receives gas-enriched saline from the oxygenator. The blood mixing chamber receives blood from the pump 210 from the pump tubing during operation of the delivery system 100. The gas-enriched saline from the oxygenator 204 mixes with blood from the inlet line of the blood circuit. A return pressure sensor measures the pressure in the blood circuit on the return line side of the pump 210. Blood from the blood circuit passes through the blood mixing volume and mixes with the gas-enriched saline from the oxygenator 204. The return line draws blood out of the blood mixing volume to the air bubble detector 126.

[0193] The oxygenator and piston chamber of the blood mixing chamber 206 may be located in a single housing or separate from each other. The pump 210 is configured to interface with the pump tubing. The pump tubing connects the bubble trap 208 to the pump 210. The pump tubing connects the blood mixing chamber 210 to the pump on the opposite side of the pump 210 from the bubble trap 208. Thus, blood in an operational blood circuit of the delivery system 100 comes from the intake line 214 through the bubble trap, is pumped by the pump 210, passes through the blood mixing chamber 206, and then passes through or past the air bubble detector 126 in the return line 218.

[0194] A bubble trap 208 may be provided and configured to remove room air and / or air bubbles from the blood circuit. The bubble trap 208 has a bubble trap volume configured to receive blood from the inlet line. The bubble trap volume vents room air and / or air bubbles from the volume to a bubble trap vent. Air bubbles rise to the top of the volume and are vented. The bubble trap volume has a low sensor that detects when the bubble trap volume is empty. The bubble trap volume has a high sensor that detects when the bubble trap volume is full. When the volume is full of blood, the bubble trap 208 is primed.

[0195] FIG. 3 illustrates in more detail the system 100 of FIG. 1A for administering a gas-enriched therapy, e.g., an SSO2 therapy. The system 100 for administering an SSO2 therapy generally includes three component devices: a main control system, a gas-enriched system (e.g., an oxygenation cartridge), and an infusion device (e.g., an infusion catheter). These devices work together to create a highly oxygen-enriched saline solution called an SSO2 solution. Blood is mixed with the SSO2 solution to generate supersaturated oxygen-enriched blood. The supersaturated oxygen-enriched blood is delivered to the patient. The system 100 may have a modular design including three removable modules, such as a base module 340, a mid-section control module 342, and a display module 346. The system 100 also includes a sensing catheter or probe of an image or sensor system 338, which may be implemented via a catheter (e.g., catheter 136) according to a particular implementation. A gas tank receptacle 346 is provided on the back of the base module 340 to receive and accommodate a standard "E-bottle" USP oxygen tank 348. The oxygen tank 348 is attached to the system via a gas tank adapter. A suitable gas, such as oxygen, is delivered from the oxygen tank 348 to a second chamber in the oxygenator cartridge. Physiological liquid, e.g., saline, from the first chamber is pumped into the second chamber and atomized to create a supersaturated, oxygen-enriched physiological solution. This supersaturated, oxygen-enriched physiological solution is then delivered to a third chamber of the oxygenator cartridge along with blood from the patient. When the patient's blood mixes with the supersaturated, oxygen-enriched physiological solution, supersaturated, oxygen-enriched blood is created, which is then delivered via an infusion catheter to the target major epicardial artery, e.g., the left main coronary artery.

[0196] An imaging or IMR system 356 may be included to provide imaging or IMR data to the system 100 independent of the probe or catheter 136 collecting data from the patient's vasculature. For example, an angiographic imaging system 356 may be used in addition to the catheter or probe 136 to collect imaging data and estimate the patient's IMR. The imaging or IMR system 356 may transmit the estimated IMR value or imaging data to the controller 102 to control the delivery of the gas-enriched liquid to the patient. The imaging or IMR system 356 may use a separate port from the catheter or probe 136 (as shown in FIG. 3 ) to communicate with the controller 102 of the system 100. In some implementations, the imaging or IMR system 356 may use the same port as the catheter or probe 136 to communicate with the controller 102 of the system 100. In some implementations, the imaging or IMR system 356 is included as part of the delivery system console. In some implementations, the imaging or IMR system 356 may communicate with the controller 102 wirelessly.

[0197] Each of the three modules 340, 342, 344 of the system 100 may include doors or access panels to protect and access the various components housed therein. For example, the mid-section control module 342 includes a hinged door 336 to enclose the gas enrichment system (i.e., cartridges) and an access panel 350 to cover an access window to the interior space of the module. Safety switches (e.g., emergency stop switch 352) may be provided to allow a user to initiate a shutdown of the system in the same manner even when the system is operating within its defined boundaries.

[0198] In the particular embodiment described above, the body of the base module 340 is comprised of a tubular chassis that sits on a circular shaped platform 354. A number of wheels are attached to the bottom of the circular shaped platform to provide mobility for the system. The wheels have a locking mechanism to keep the wheels stationary. The base chassis houses certain electrical and mechanical components, including a battery (not shown), a power source (not shown), and connectors for connecting the base module 340 to the mid-section main module 342. The user interface 134 includes a screen 330, buttons 332, knobs 334, and other controls for interaction with the delivery system 100.

[0199] In another example, a delivery system 400 such as that shown in FIG. 4 including system 100 may execute a process for controlling the delivery of oxygen-enriched blood to a patient based on feedback from one or more sensors or electrodes 402 used to estimate microvascular resistance in the patient's vasculature.

[0200] The delivery system 400 is configured to generate a tomographic map of the measured impedance values ​​generated by the impedance tomography sensor system 402. Electrical impedance tomography (EIT) is a non-invasive type of medical imaging in which the conductivity, permittivity, and impedance of a portion of a body are inferred from surface electrode measurements and used to form a tomographic image of that tissue region. The delivery system 400 causes the delivery of gas-enriched blood produced by a gas-enrichment system to a patient to provide the patient with a treatment of supersaturated gas, e.g., oxygen. The delivery system 400 causes an electric current to be applied to the patient's tissue between a number of sensors in the form of external electrodes positioned on an external surface of the patient's body (e.g., on the patient's chest and back). The external electrodes may be coupled to a controller via one or more cables or other wired connections. The controller 104 of the system 400 receives a number of signals from the electrodes 402 among the number of external electrodes corresponding to the measured impedance values ​​from the tissue. The controller 102 generates an impedance tomographic map based at least in part on the measured impedance values. A microvascular resistance of a region of the patient's vasculature is estimated based at least in part on the impedance distribution of the impedance tomographic map. In certain implementations, estimating the microvascular resistance may be based at least in part on the average impedance of the impedance distribution. In other implementations, estimating the microvascular resistance may be based at least in part on the product of the local impedance and the volume of the impedance distribution. Microvascular resistance may be estimated in various regions of the vasculature, including, for example, cardiac regions or muscle regions.

[0201] In a particular implementation, a catheter (not shown) may be used, where the delivery system 400 causes a current to be applied to the patient's tissue between an electrode positioned on the catheter located in the vasculature, e.g., the left main (LM) coronary artery, and multiple external electrodes positioned on the external surface of the patient's body. The signal from the electrode 402 corresponds to a measured impedance value from the tissue between the catheter electrode and the multiple external electrodes.

[0202] The controller 102 generates a map of the measured impedance values ​​in the tissue area having the infarct and compares the tomographic map of the measured impedance values ​​in the tissue area to a baseline tomographic map of the measured impedance values ​​in the tissue area, which may be used to estimate changes in microvascular resistance or blood perfusion and / or changes in infarct size in the patient throughout the SSO2 treatment. The mapped area and any changes in microvascular resistance or blood perfusion and / or changes in infarct size may be stored by the controller 102 in the memory device 382 and tagged for future reference. The controller 102 correlates the mapped zones with low impedance values ​​to tissue zones with decreased microvascular resistance or increased blood perfusion and / or reduced infarct size. For ischemic tissue, higher impedance and greater microvascular resistance are expected because there will be less blood in the ischemic tissue compared to non-ischemic tissue or tissue with increased blood perfusion and reduced microvascular resistance. The controller 102 may overlay these mapped zones onto other mapped images of the same area or infarct zone, such as MRI or CT images, and spatially align them.

[0203] The delivery of oxygen-enriched blood to the patient may be controlled based on the tomographic map of the measured impedance values ​​and the estimated microvascular resistance. For example, the location of the delivery catheter may be adjusted, and / or the rate of delivery of oxygen-enriched blood (i.e., as controlled by the blood pump of the system) may be adjusted. In certain embodiments, if the tomographic map has an area that does not show a decrease in impedance below a predetermined threshold, e.g., 10%, or if the estimated infarct size based on the tomographic map has not decreased by more than some other predetermined threshold, e.g., 15%, the SO2 in the blood may be increased based on the tomographic map of the measured impedance values ​​and / or the estimated change in infarct size. The SO2 in the blood may be decreased or stopped based on exceeding a threshold in either the impedance or the estimated infarct size of the area of ​​the tomographic map. The tomographic data is used by the controller 102 to estimate the microvascular resistance in the mapped vasculature area, and to titrate or control the SSO2 delivery based on the tomographic data and the estimated microvascular resistance.

[0204] The electrodes may be any type of electrode suitable for external use on the subject's body, such as wet or dry self-adhesive medical electrodes typically used to measure electrical signals on the subject's body. Sheffield Mark3.5 and Enlight1800 are exemplary electrical impedance tomography technologies that may be implemented to provide imaging feedback useful for controlling the SSO2 therapy provided by the system 400.

[0205] The system 400 is configured with a plurality of electrodes 402 for placement external to the patient. The controller 102 measures impedance values ​​from a tissue area between one or more pairs of the plurality of electrodes, generates a tomographic map based on the measured impedance values, estimates blood perfusion in the tissue area based on the tomographic map, and estimates a change in value of one or more physiological parameters indicative of microvascular resistance of the patient's vasculature based on the blood perfusion.

[0206] FIG. 5 illustrates a flow diagram of a process 500 for controlling SSO2 delivery by one or more of the systems described herein, for example in relation to FIGS. 1A-4. In some implementations, the process 500 is performed by a controller (e.g., controller 102) of the delivery system 100. The process 500 for controlling gas-enriched therapy in a patient includes providing (502) a gas-enrichment system configured to enrich a liquid with gas to form a gas-enriched liquid and mix the gas-enriched liquid with blood to form gas-enriched blood. The process 500 includes delivering (504) the gas-enriched blood to the patient. The process 500 includes receiving (506) at a controller coupled to a sensor configured to measure one or more physiological parameters indicative of microvascular resistance of the patient's vasculature, one or more signals from the sensor corresponding to measured values ​​of the one or more physiological parameters. The process 500 includes estimating (508) microvascular resistance in the patient's vasculature based on the measured values. The process 500 includes generating (510) an alert or control signal to titrate or control the amount of gas-enriched blood delivered to the patient based on the microvascular resistance in the patient's vasculature.

[0207] In some implementations, the control signal is configured to control a pump configured to pump the gas-enriched blood for delivery to the patient. The process 500 includes causing the pump to pump blood between the gas-enriched system and the patient based on sending the control signal to the pump. The sensor can include a flow sensor. The one or more physiological parameters include a flow rate of the blood in the patient's vasculature. In some implementations, the sensor includes a pressure sensor. The one or more physiological parameters include a pressure of the blood in the patient's vasculature.

[0208] In some implementations, process 500 includes sending, by the controller, a control signal to a pump configured to pump the gas-enriched blood for delivery to the patient. Based on the sending of the control signal, process 500 includes causing the pump to increase or decrease a pump speed to increase or decrease the amount of gas-enriched blood delivered to the patient.

[0209] In some implementations, reducing the amount of gas-enriched blood delivered to the patient includes determining that a change in value of the one or more physiological parameters is indicative of reduced microvascular resistance in the patient's vasculature. In response to determining that the change in value is indicative of reduced microvascular resistance, process 500 includes generating a control signal configured to cause a reduction in the amount of gas-enriched blood delivered to the patient.

[0210] In some implementations, increasing the amount of gas-enriched blood delivered to the patient includes determining that a change in value of the one or more physiological parameters is indicative of increased microvascular resistance in the patient's vasculature. In response to determining that the change in value is indicative of increased microvascular resistance, process 500 includes generating a control signal configured to cause an increase in the amount of gas-enriched blood delivered to the patient.

[0211] In some implementations, the sensors include a flow sensor and a pressure sensor, respectively, and the physiological parameters include a flow rate of blood in the patient's vascular system and a blood pressure in the patient's vascular system. The process 500 includes estimating a microvascular resistance in the patient based on a ratio of the flow rate and the blood pressure, and generating a control signal or alert based on the estimated microvascular resistance.

[0212] In some implementations, generating the control signal or alert is performed in real-time or near real-time during delivery of the gas-enriched blood to the patient. The delivery of the gas-enriched blood to the patient is not paused during the measurement of the one or more physiological parameters. The measurement of the one or more physiological parameters represents the patient's contemporaneous status of the delivery of the gas-enriched blood to the patient.

[0213] In some implementations, receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the sensor includes receiving a series of measured values ​​of the one or more physiological parameters from the sensor. The series of measured values ​​can correspond to a time period during delivery of the gas-enriched blood to the patient. The process 500 includes determining whether the value of the one or more physiological parameters is increasing or decreasing over time based on the series of measured values ​​corresponding to the time period. The process 500 includes generating a control signal or alert to increase or decrease the amount of gas-enriched blood delivered to the patient based on determining that the value of the one or more physiological parameters is increasing or decreasing over time.

[0214] In some implementations, process 500 includes receiving angiography data representative of a patient concurrently with or during a period of time following delivery of gas-enriched blood to the patient, and calculating or estimating an IMR based on the angiography data. Process 500 includes generating a control signal based on the angiography data that is configured to increase or decrease the amount of gas-enriched blood delivered to the patient.

[0215] In some implementations, process 500 includes receiving, by the controller, pressure data from a pressure sensor coupled to a wire supported at a distal end of the catheter in the patient's vasculature. Process 500 includes determining, by the controller, an index of microcirculatory resistance (IMR) value in the patient's vasculature based on receiving the pressure data. Process 500 includes generating, by the controller, an alert or control signal configured to increase or decrease an amount of gas-enriched blood delivered to the patient based on the IMR value.

[0216] In some implementations, the process 500 includes measuring, by the controller, impedance values ​​from the tissue area between one or more pairs of a plurality of external electrodes configured for placement external to the patient. The process 500 includes generating, by the controller, a tomographic map based on the measured impedance values. The process 500 includes estimating, by the controller, blood perfusion in the tissue area based on the tomographic map. The process 500 includes estimating, by the controller, a change in value of one or more physiological parameters indicative of microvascular resistance of the patient's vasculature based on the blood perfusion.

[0217] The entire disclosures of U.S. Patent No. 6,743,196, U.S. Patent No. 6,582,387, U.S. Patent No. 7,820,102 and U.S. Patent No. 8,246,564 are expressly incorporated herein by reference.

[0218] 6 illustrates an exemplary system 600 for enriching bodily fluids with dissolved gas or gas-enriched liquid inside an enclosed area of ​​the body. As an example, the system 600 can be used to enrich a patient's blood with supersaturated oxygen-enriched liquid or supersaturated liquid within the patient's vascular system, thereby delivering supersaturated oxygen (SSO2) therapy to the patient, increasing oxygen in the blood and diffusing oxygen to tissues. In certain implementations, the oxygen-enriched liquid or solution, e.g., the supersaturated oxygen-enriched liquid or solution, may include a liquid having a dissolved O2 concentration of 0.1 ml O2 / ml liquid (STP) or higher, or 0.1-6 ml O2 / ml liquid (STP) or 0.2-3 ml O2 / ml liquid (STP) (e.g., without clinically significant gas embolism).

[0219] 6, the system 600 includes a catheter 602, a gas-enriched liquid source 650, a pump 652, a sensor 654, and a sample extraction device 656. The catheter 602 is configured to be inserted into a patient's vascular system to facilitate delivery of gas-enriched liquid (e.g., from the gas-enriched liquid source 650) to the patient's vascular system via the pump 652. Additionally, the catheter 602 is configured to facilitate measurement of one or more characteristics of the patient's blood in the patient's vascular system (e.g., by providing access to the patient's vascular system for the sensor 654) and / or facilitate collection of a blood sample from the patient's vascular system (e.g., by providing access to the patient's vascular system for the sample extraction device 656). For example, the sensor 654 may be positioned on a distal (or first) end 608a of the catheter 602 or within a communicating lumen of the catheter 602. The sensor 654 can detect various blood parameters (e.g., partial pressure of oxygen in the patient's blood (pO2), oxygen saturation of the patient's blood (SO2), flow rate of the patient's blood, temperature of the patient's blood) during the procedure or after the procedure is paused or completed. In some implementations, the sensor or imaging device 654 is part of the catheter. In some implementations, the sensor or imaging device 654 is part of a system that includes the controller 102 or is separate from but in communication with the controller.

[0220] The catheter 602 includes an elongated catheter body 604 (e.g., extending through the center of the catheter body 604 along a longitudinal axis 606) having a proximal (or second) end 608b opposite a distal end 608a. In some implementations, the catheter can have a circular, elliptical, or oval cross-section along a portion or all of its length. In some implementations, the catheter body 604 can be flexible (e.g., such that it can bend or curve at one or more locations along its length). In some implementations, at least a portion of the catheter 602 and / or catheter body 604 can be constructed from polycarbonate, glass, ceramic, stainless steel, polyetheretherketone (PEEK), polyetherblockamide (PEBA) (e.g., PEBAX manufactured by Akrema SA of Colombes, France), acrylonitrile butadiene styrene (ABS), polyimide, and / or other suitable materials. In some implementations, the catheter body 604 can have an outer diameter in the range of 4F to 12F, or such as 4F to 6F (on the French scale, approximately 1.33 mm to 4 mm, or approximately 1.33 mm to 2 mm).

[0221] Additionally, the catheter 602 includes multiple lumens extending through the catheter body 604. In this example, the catheter 602 includes one or more communicating lumens 610a extending through the center of the catheter body 604 (e.g., along the longitudinal axis 606). At least two additional lumens 610b and 610c may extend through opposite sides of the catheter body 604 (e.g., parallel to the communicating lumen 610a). Each of the lumens 610a-c may have a circular, elliptical, or oval cross-section along a portion or the entirety of its length. In some implementations, the communicating lumen 610a may have an inner diameter in the range of 0.020 inches to 0.045 inches (about 0.5 mm to about 1.1 mm).

[0222] Each of the lumens 610a-610c includes a respective inflow opening and a respective outflow opening. For example, the communicating lumen 610a includes an inflow opening 612a on the first (or distal) end 608a of the catheter body 604 and an outflow opening 612b on the second (or proximal) end 608b of the catheter body 604. As another example, the lumen 610b includes an inflow opening 614a on the first end 608a of the catheter body 604 and an outflow opening 614b on the second end 608b of the catheter body 604. As another example, the lumen 610c includes an inflow opening 616a on the first end 608a of the catheter body 604 and an outflow opening 616b on the second end 608b of the catheter body 604.

[0223] Additionally, the catheter 602 includes a capillary tube 618a extending from and in fluid communication with the outflow opening 614b of the lumen 610b (e.g., allowing fluid to flow from the lumen 610b to the capillary tube 618a). The capillary tube 618a terminates at the outflow opening 620a. In some implementations, the capillary tube 618a can have an inner diameter between 40 microns and 100 microns. In some implementations, the capillary tube 618a can have an outer diameter between 140 microns and 160 microns. In some implementations, the capillary tube 618a can have a length in the range of 5 cm to 10 cm, or a length "I" substantially equal to the diameter of the catheter tip or distal end.

[0224] The catheter 602 also includes a capillary tube 618b that extends from and is in fluid communication with the outflow opening 616b of the lumen 610c (e.g., to allow fluid to flow from the lumen 610c to the capillary tube 618b). The capillary tube 618b terminates at an outflow opening 620b. In some implementations, the capillary tube 618b can have an inner diameter between 40 microns and 100 microns. In some implementations, the capillary tube 618b can have an outer diameter between 140 microns and 400 microns. In some implementations, the capillary tube 618b can have a length in the range of 5 cm to 10 cm, or a length "I" that is substantially equal to the diameter of the catheter tip or distal end.

[0225] In some implementations, the capillaries 618a and 618b may have inner and / or outer diameters of the same or different sizes. In some implementations, the capillaries 618a and 618b may have lengths of the same or different sizes.

[0226] During an exemplary use of the system 600, the gas-enriched liquid source 650 and the pump 652 are coupled to the catheter 602 such that the gas-enriched liquid source 650 and the pump 652 are in fluid communication with the inlet openings 614a and 616a of the lumens 610b and 610c, respectively. By way of example, one or more fluid-tight tubes may be used to transport the gas-enriched liquid from the gas-enriched liquid source 650 to the pump 652 and from the pump 652 to the inlet openings 614a and 616b. In some implementations, one or more fluid-tight tubes may be used to transport the gas-enriched liquid from the gas-enriched liquid source 650 to the inlet openings 614a and 616b, where at least a portion of the one or more fluid-tight tubes are coupled to or form part of a peristaltic pump that urges fluid from the gas-enriched liquid source to the inlet openings 614a and 616b. In some implementations, the tubes can be secured to the inlet openings 614a and 616b using fittings or connectors, such as high pressure luer fittings.

[0227] In some implementations, the gas-enriched liquid source 650 may include one or more storage tanks for storing the gas-enriched liquid. In some implementations, the gas-enriched liquid may be a supersaturated oxygen-enriched liquid or a supersaturated liquid, such as a liquid having a dissolved oxygen (O2) concentration of 0.2-3 ml O2 / ml solvent (which is an equivalent concentration of 100 psi (690 kPa)-1500 psi (10 MPa)). In some implementations, the gas-enriched liquid may include a liquid enriched with oxygen, ozone, inert gas, nitrogen, nitrous oxide, carbon dioxide, and / or air. In some implementations, the gas-enriched liquid source 650 may include an oxygenation device, which is operated by a console or hardware component that controls the operation of the oxygenation device, as described in U.S. Pat. No. 9,919,276, the entire disclosure of which is expressly incorporated herein by reference in its entirety. The console or hardware component may include a controller, a processor, a memory, and associated circuitry. The oxygenation device may include a fluid supply chamber for receiving a physiological liquid, e.g., saline from an IV bag, and an atomization chamber for receiving a suitable gas, e.g., oxygen from an oxygen tank. The saline is pumped into the oxygen pressurized atomization chamber and atomized to create a gas-enriched or supersaturated liquid, e.g., supersaturated oxygen-enriched saline or supersaturated saline. In certain implementations, the gas-enriched liquid may be an oxygen-enriched liquid or solution, e.g., a supersaturated oxygen-enriched liquid or solution may include a liquid having a dissolved O2 concentration (e.g., without clinically significant gas embolism) of 0.1 ml O2 / ml liquid (STP) or higher, or 0.1-6 ml O2 / ml liquid (STP) or 0.2-3 ml O2 / ml liquid (STP). In some implementations, the gas-enriched liquid can be a supersaturated oxygen-enriched liquid or solution (e.g., saline having a dissolved O2 concentration in saline of 0.1 ml O2 / ml saline (STP) or higher, or 0.1-6 ml O2 / ml saline (STP) or 0.2-3 ml O2 / ml saline (STP) (e.g., without clinically significant gas embolism).

[0228] Further, a portion of the catheter 602 is inserted into the patient, e.g., the second end 608b of the catheter body 604 is positioned within the patient's vascular system (e.g., a blood vessel 660, e.g., a vein or an artery). After the catheter 602 is inserted into the patient, the pump 652 is enabled such that it draws gas-enriched liquid from the gas-enriched liquid source 650 and pumps the gas-enriched liquid, e.g., supersaturated liquid, into each of the lumens 610b and 610c. The gas-enriched liquid flows through the lumens 610b and 610c into the capillaries 618a and 618b and exits from the outlet openings 620a and 620b as two respective streams 622a and 622b.

[0229] In some implementations, system 600 can be configured to output streams according to different flow rates and / or pressures. For example, system 600 can be configured to output streams at between 1 mL / min (e.g., at a pressure of 100 psi, about 690 kPa) and 3 mL / min (e.g., at a pressure of 300 psi, about 2 MPa).

[0230] The capillaries 618a and 618b are configured such that the streams 622a and 622b cross one another and mix at a mixing region 624 within the patient's vasculature. For example, the capillaries 618a and 618b can define respective paths that are angled relative to the longitudinal axis 606, such that the streams 622a and 622b exit the outlet openings 620a and 620b at respective angles relative to the longitudinal axis 606. In some implementations, the capillaries 620a and 620b can be configured such that the streams 622a and 622b cross at a point 626 beyond the tip of the catheter 602 (e.g., where the point 626 is on or around the longitudinal axis 606). For example, streams 622a and 622b may mix without or without significant bubble formation in a mixing region 624 a distance downstream from the outlet openings of capillaries 618a and 618b.

[0231] Additionally, the communication lumen 610a provides access to the patient's vascular system. For example, in some implementations, the sensor 654 can be at least partially inserted into the communication lumen 610a, such that it is in fluid communication with the patient's blood. In other implementations, the sensor can be located outside the communication lumen or on the catheter wall. The sensor 654 can obtain one or more sensor measurements on the blood and provide feedback regarding measured parameters adversely affected by the SSO2 treatment to optimize the SSO2 treatment. For example, the sensor 654 can measure the partial pressure of oxygen in the patient's blood, the oxygen concentration or SO2 in the patient's blood, the pressure of the patient's blood, e.g., arterial blood pressure, the flow rate of the patient's blood, and / or the temperature of the patient's blood.

[0232] Examples of such sensors include:

[0233] One example of a sensor for measuring the partial pressure of oxygen (pO2) or oxygen saturation SO2 in the patient's blood is a pulse oximeter. A pulse oximeter may be used to estimate arterial pO2 or SO2. Pulse oximetry estimates the percentage of oxygen bound to hemoglobin in the blood. A pulse oximeter uses a light-emitting diode and a photosensitive sensor to measure the absorption of red and infrared light. In another example, a sensor for measuring the partial pressure of oxygen includes an electrode, such as a Clark electrode for measuring pO2. A Clark electrode is an electrode that measures the ambient oxygen concentration in a liquid using a catalytic platinum surface according to the net reaction O2 + 4e- + 4H+ → 2H2O. These various sensors may be coupled to the system's controller via a cable or other wired connection or via a wireless connection.

[0234] The processor may receive signals from these sensors, which correspond to a measured value of pO2. The processor compares the measured pO2 to a target range for blood pO2, e.g., 760-1500 mmHg (approximately 100 kPa-200 kPa). The target range may be calculated based on a blood flow rate of 50-150 mL / min, a saline flow rate of 2-5 mL / min, and a dissolved O2 concentration in the saline of 0.2-3 ml O2 / ml saline (STP). The controller may adjust the saline flow rate and / or the dissolved O2 concentration in the saline based on the measured pO2 in the blood to achieve an arterial blood pO2 within the target range. The processor may generate an alert, e.g., an audible and / or visual alarm through a user interface indicating the level of pO2. The measured pO2 indicates the effectiveness of the supersaturated oxygen therapy and lets the caregiver know whether the pO2 in the blood is within a target range for optimizing the delivery of oxygen to the patient's ischemic tissue. In certain implementations, the processor may control the delivery of the supersaturated oxygen therapy by modifying one or more of the above-mentioned saline or oxygen parameters based on the signals received from the sensor.

[0235] Another example of a sensor is an O2 fluorescent probe. The fluorescent probe may be coupled to the controller of the system via a cable or other wired or wireless connection. A light source of the O2 fluorescent probe is illuminated. In a particular implementation, a fiber optic cable may be used to provide light to the light source, where the fiber optic cable is connected to the controller of the system. Fluorescence of a sensor molecule of the O2 fluorescent probe is measured. The sensor molecule may include a fluorescent molecule. A signal is received from the O2 fluorescent probe based on the fluorescence measurement by a processor. The fluorescence is measured by measuring the lifetime or decay of a fluorescence intensity signal from a sensor molecule (e.g., a fluorescent molecule) illuminated on the fluorescent probe. This signal decay is caused by the quenching effect of oxygen molecules in the blood or tissue on the fluorescence intensity signal of the sensor molecule. The processor can determine the oxygen concentration, SO2 or pO2, in the blood or tissue based on the quenching effect of oxygen on the fluorescence intensity signal of the fluorescent probe. The change in the amount of time required for the signal to decay due to oxygen quenching is indicative of the local oxygen concentration, SO2 or pO2, in the blood or tissue. The processor generates an alert, e.g., an audible and / or visual alarm through a user interface, based on the determined oxygen concentration, SO2 or pO2 in the blood or tissue. The alert may indicate the effectiveness of the supersaturated oxygen therapy. The determined oxygen concentration, SO2 or pO2 indicates the effectiveness of the supersaturated oxygen therapy, letting the caregiver know whether the oxygen concentration, SO2 or pO2 in the blood is within a predefined target range (e.g., an expected range for a healthy individual) to optimize the delivery of oxygen to the patient. In certain implementations, the processor may control the delivery of supersaturated oxygen therapy by modifying one or more of the saline or oxygen parameters, e.g., saline flow rate or dissolved O2 concentration in the saline, based on the determined oxygen concentration, SO2 or pO2 value.

[0236] Another example of a sensor is a temperature sensor located on or in the catheter. For example, a thermistor may be utilized to measure the patient's blood temperature. The processor may receive a signal from the thermistor, which corresponds to a measured value of the blood temperature. The processor may generate an alert, e.g., an audible and / or visual alarm through a user interface indicating the blood temperature, which may alert a caregiver to a hypothermic or hyperthermic, e.g., feverish, condition in the patient.

[0237] An exemplary sensor for measuring the arterial pressure of the patient's blood is a pressure sensor positioned or coupled to the communication lumen. The communication lumen may be used for direct measurement of arterial pressure. The communication lumen may be connected to a fluid-filled system, which is connected to an electronic pressure transducer. The detected change in blood pressure may indicate improved perfusion and / or restored flow in the ischemic tissue as a result of the SSO2 therapy. The therapy may result in improved cardiac function. In certain implementations, the processor may control the delivery of supersaturated oxygen therapy based on the arterial pressure feedback.

[0238] Exemplary sensors used to determine blood flow rate include temperature sensors, such as thermistors, thermocouples, or thermoanemometers. The temperature sensor may be located on the catheter tip, capillary tip, or within the communicating lumen. The temperature sensor may be heated such that the sensor temperature increases. As blood flows past the temperature sensor, the degree to which the temperature sensor cools indicates the flow rate past the temperature sensor. The determined blood flow rate may be fed back to the system and may indicate efficacy of SSO2 therapy, which results in improved perfusion and / or restored flow in the ischemic tissue. In certain implementations, the processor may control the delivery of supersaturated oxygen therapy based on the blood flow rate feedback.

[0239] If the sensor is a pressure sensor, the sensor may detect the pressure difference between the ambient pressure and the arterial pressure or the absolute value of the arterial pressure. The pressure sensor may be located anywhere in the communication lumen, but does not necessarily need to be positioned in the communication lumen, and may be located outside the lumen. One example of a pressure sensor is a strain gauge. In a catheter with multiple communication lumens, the pressure sensor may be located in a first communication lumen and provide a continuous pressure signal, while blood sampling may be performed through a second communication lumen at the same time. In another example, two pressure sensors may be used, a sensor located in the first communication lumen and a sensor located in the second communication lumen to provide redundancy of pressure readings.

[0240] As another example, in some implementations, a sample extraction device 656 can be used to obtain a sample of the patient's blood via the communicating lumen 610a. For example, the sample extraction device 656 can include one or more pumps or syringes to draw a sample of the patient's blood exiting the patient's body through the lumen 610a. The syringes can be coupled to the proximal end of the catheter for sampling. A valve or stopcock can be included at the proximal end of another lumen of the catheter to control sampling.

[0241] In some implementations, the communicating lumen 610a can also be used to guide the catheter 602 into the patient's body. For example, a guidewire can be inserted into the communicating lumen 610a and manipulated to control the shape and / or position of the catheter 602 within the patient's body. The sample extraction device 656 can, in some examples, be in communication with or controlled by the controller 102. In some implementations, the sample extraction device 656 is a separate device from the controller 102 and can be in communication with the controller (e.g., to transmit data representing samples or measurements to the controller 102).

[0242] Additionally, catheter 602 may be configured to eliminate or otherwise reduce the formation of air bubbles within the patient's vasculature. For example, streams 622a and 622b mix in a mixing region 624 away from any surfaces of catheter 602 or capillaries, thereby reducing, preventing, or reducing the likelihood of air bubble formation through nucleation on surfaces of catheter 602 or capillaries.

[0243] In some implementations, a controller (e.g., controller 102 of FIG. 1A) is connected to the sensor or imaging device 654. The sensor or imaging device 654 can be part of the system 100 including the controller 102. In some implementations, the sensor or imaging device 654 can be separate from the controller 102 and in communication with the controller. For example, an angiography imaging device can be controlled by a different controller and image data can be transmitted from the imaging device 654 to the controller 102. The sensor or imaging device 654 can include the sensors (e.g., 308, 310) and / or imaging devices (e.g., MRI angiography, etc.) of the delivery system 100 of FIG. 1A. The catheter 602 can be included in the delivery system 100 as the catheter 136. The controller of the delivery system 100 is configured to estimate a change in microvascular resistance of a partial or local area of ​​the patient's vasculature, e.g., the vasculature or microvasculature. In some implementations, titrating or controlling the amount of gas-enriched liquid delivered to the patient includes determining, by the controller 102, a change in a value of pressure and / or flow rate from the sensor or imaging device 654 indicative of decreased microvascular resistance in the patient's vasculature. In response to determining that the change in value is indicative of decreased microvascular resistance or that the IMR has reached a plateau, the controller 102 generates a control signal configured to cause a decrease in the amount of gas-enriched liquid delivered to the patient or to stop the therapy. In some implementations, titrating or controlling the amount of gas-enriched liquid delivered to the patient includes determining, by the controller 102, a change in a value of flow rate and / or pressure change indicative of increased microvascular resistance in the patient's vasculature. In response to determining that the change in value is indicative of increased microvascular resistance or that the IMR is increasing, the controller 102 generates a control signal configured to cause an increase in the amount of gas-enriched liquid delivered to the patient. In certain implementations, an alert may be generated, to which a caregiver responds by titrating or controlling therapy appropriately.

[0244] In certain implementations, the controller may estimate microvascular resistance by determining the IMR over a period of time and take into account the decline in the IMR over that period. If the IMR is still decreasing, it may indicate that more gas-enriched or SSO2 therapy is required. If the IMR has reached a plateau, it may indicate that the maximum benefit of the therapy has been reached and the therapy may be stopped.

[0245] In certain implementations, the controller may estimate microvascular resistance by determining the IMR over a period of time and take into account any increase in IMR over that period. If the IMR is still increasing, it may indicate that more gas-enriched or SSO2 therapy is required. If the IMR has reached a plateau, it may indicate that the maximum benefit of the therapy has been reached and the therapy may be stopped.

[0246] In particular implementations, the system 600 may receive imaging data, e.g., angiographic imaging data, representing the patient's vasculature, and estimate a microvascular resistance, e.g., IMR, in the patient's vasculature based on the imaging data and / or measured values ​​of the sensor to provide feedback for controlling the amount of gas-enriched therapy.

[0247] FIG. 7 is a graph 700 including example values ​​for IMR in a patient, where IMR is determined from an angiogram. Although this example is described in the context of an angiogram, other imaging techniques such as MRI can be used. The graph 700 includes a post-PCI IMR value 702 and a post-SSO2 IMR value 704 (IMR value after PCI and subsequent SSO2). The post-PCI IMR value occurs after a percutaneous coronary intervention (PCI) is performed on the patient. PCI refers to a procedure to open blocked coronary arteries on the patient. For example, these procedures can include balloon angioplasty, angioplasty with stents, rotational atherectomy, etc., as described herein. PCI is generally performed with a catheter near the heart, where a contrast agent is injected so that an angiogram can easily show narrowed areas of the blood vessels on an x-ray, as described herein.

[0248] IMR is a hemodynamic marker for microvascular dysfunction. IMR provides data for assessment of coronary microvascular status immediately after an interventional procedure. As explained above, IMR can be determined using a wire-based system (wire-IMR). IMR may also be determined by model-based analysis of angiographic films (angio-IMR). In certain implementations, model-based analysis of angiographic films may be paired with blood pressure data.

[0249] The data in graph 700 shows a contrast between a value 702 for angio-IMR after PCI where no SSO2 therapy is performed (e.g., before SSO2 injection and after PCI) and a data value 704 for angio-IMR after PCI where SSO2 therapy is performed (e.g., immediately after SSO2 injection). As shown in graph 700, the angio-IMR value 704 drops significantly after SSO2 therapy is performed.

[0250] The data values ​​702, 704 of the graph 700 show a significant decrease in the median angio-IMR value by about 9.05 after SSO2 therapy injection in patients with a post-PCI IMR value above 40. Patients with a post-PCI angio-IMR value above 40 treated with SSO2 therapy showed a steep decrease in microvascular resistance. The IMR value of 40 is selected as a representative threshold value at which a negative outcome is more likely for patients after PCI. Thus, in a population that may have a poor outcome, SSO2 therapy has been shown to cause a significant improvement to the angio-IMR value.

[0251] To generate the value 704, an SSO2 treatment system such as the system described above with reference to FIGS. 1A-4 can be used. In general, a PCI is performed. An angiogram is generated after a period (e.g., within minutes) of the PCI. The system then performs an SSO2 delivery. The SSO2 treatment is paused and a second angiogram is performed after a period (e.g., within minutes) of the treatment. Blood pressure values ​​are collected after the PCI and after the SSO2 delivery. An IMR value is determined based on an analysis of the angiographic film. For example, an angiographic projection is captured and the controller generates a 3D mesh reconstruction of the vascular pathway from the entrance of the coronary artery and / or coronary artery tree to the most distal location. A mean aortic pressure (MAP) is calculated by averaging pressure waves in successive cardiac cycles. The controller is configured to calculate diastolic flow velocity (e.g., using a thrombolysis in myocardial infarction (TIMI) frame counting method or a similar method). A steady-state laminar flow simulation through a 10-30 stenotic vessel is generated.

[0252] As described in connection with FIG. 8, SSO2 therapy can be provided non-concurrently with the collection of IMR data, for example, through angio-IMR. In other implementations, SSO2 therapy can be provided consecutively or concurrently with the collection of IMR data (e.g., through other forms of imaging, etc.). In some implementations, other IMR data collection techniques that allow for consecutive and / or concurrent SSO2 therapy can be used. In some implementations, SSO2 injection is paused during IMR data collection and / or IMR determination.

[0253] 8 is a flow diagram of an example process 800 for controlling delivery of gas-enriched blood, e.g., oxygen-enriched blood, or gas-enriched liquid, e.g., oxygen-enriched liquid, to a patient based on an IMR value determined from vasculature imaging data. In one example, process 800 can be used to generate values ​​704 of graph 700 described in connection with FIG. 7. Process 800 can be used to control oxygen-enriched therapy delivery to a patient, such as SSO2 therapy delivery, by one or more of the systems described herein, such as in connection with FIGs. 1A-4.

[0254] Processes 500, 800 may be performed by a single system (such as delivery system 100 or any of the systems described in connection with FIGS. 1A-4) or by multiple systems or devices. In some implementations, process 800 is performed by a controller (e.g., controller 102) of delivery system 100. For example, a first system or device may generate angiographic images, calculate IMR values, and transmit them to a second device (e.g., a processor or controller of the delivery system or another system) to perform gas-enriched therapy based on the calculated IMR values.

[0255] A process 800 for controlling gas-enriched therapy, e.g., oxygen-enriched therapy or SSO2 therapy, in a patient includes providing (802) a gas-enrichment system configured to enrich a liquid with gas to form a gas-enriched liquid and mix the gas-enriched liquid with blood to form gas-enriched blood. Process 800 includes delivering (804) the gas-enriched blood to the patient. Alternatively, in certain implementations, the gas-enriched liquid may be delivered directly to the patient's vascular system and mixed with the blood to form gas-enriched blood within the patient's vascular system.

[0256] In step 806, the process includes determining whether the gas-enriched therapy should be paused to collect imaging and IMR data, or should not be paused and run continuously while the imaging and IMR data are generated. In one example, for angio-IMR-based data collection, the gas-enriched therapy may be paused. For another imaging-based data collection, the gas-enriched therapy may not be paused.

[0257] The IMR can be calculated based on the angiogram as described herein. As described above, the IMR value represents blood flow velocity, which can be indicated by distal pressure. Proximal can be the beginning of the left anterior descending artery, and distal can be approximately 75 mm below proximal. In one example, the controller or other processor of the system is configured to generate a three-dimensional (3D) model of the patient's coronary vasculature from the angiogram data. The 3D model includes the vasculature up to a threshold length. The threshold length can be approximately 72 or 75 millimeters. In some implementations, other threshold lengths are possible (e.g., less than 90 mm, 60-90 mm, etc.). The processor or controller of the system processes the blood pressure data, including both systolic and diastolic data. The processor or controller can estimate a mean arterial pressure (MAP) based on the processed blood pressure data. The MAP includes the proximal pressure in the coronary vasculature at a length equal to 0 (origin). The controller or other processor processes the angiographic data to calculate the coronary blood flow velocity (V) occurring during diastole. Based on each of the MAP value and the coronary blood flow velocity value V, the processor or controller is configured to estimate the distal pressure. The controller executes a fluid model to perform this calculation. The controller or processor determines a value for IMR based on the distal pressure and the coronary blood flow velocity value V. The relationship between the distal pressure V and the IMR value is based on a constant value K. The controller uses the constant value K (e.g., 2.1) to estimate the hyperemic flow and thus the IMR value. The controller determines the IMR in this manner in a post-PCI scenario before SSO2 is performed. This procedure can be repeated by the controller or processor to determine the IMR value for the patient after post-SSO2 is performed using updated angiographic data.

[0258] In some implementations, the system determines that the gas-enriched therapy should be paused, for example, in response to determining which type of imaging is to be used for the IMR value estimation. For example, if angio-based IMR is being performed, the system pauses the gas-enriched injection (808). As mentioned above, the gas-enriched therapy can be paused after a predetermined period of time has elapsed, for example, 30-60 minutes. Contrast fluid is inserted (810) to perform an angiogram. Angiographic image data is captured (812). Angiographic imaging data representative of the patient's vasculature is then received (814) at a controller of the gas-enriched system or other remote system. The IMR in the patient's vasculature is then estimated based on the angiographic imaging data. The system is configured to generate an alert or control signal to control the amount of gas-enriched blood delivered to the patient based on the IMR in the patient's vasculature. Depending on the patient's IMR value, the system may resume or stop the gas-enriched therapy. In some implementations, the system is configured to resume (820) gas-enriched therapy once angiographic imaging data is acquired, in parallel with determining the IMR value.

[0259] In some implementations, the system determines that the gas-enriched therapy can continue continuously while still acquiring an IMR value (806). In this example, while the gas-enriched therapy is being performed, the system captures MRI or other images of the patient's vasculature from which an IMR value can be estimated (822). While the gas-enriched therapy is being performed, MRI or other imaging data representative of the patient's vasculature is then received at a controller of the gas-enriched system or other remote system (816), and the IMR in the patient's vasculature is estimated based on the imaging data. The gas-enriched therapy can be controlled in response to determining the IMR value. Specifically, the IMR can be determined while the patient is still receiving the gas-enriched therapy, and the therapy can be adjusted accordingly. In general, steps 806, 820, 822, and 824 can be optional, and the delivery system can be configured to automatically pause the gas-enriched therapy to perform imaging and estimate the IMR value or determine blood flow in the patient's vasculature.

[0260] In some implementations, PCI is performed and an angiogram is obtained as a representation of the baseline IMR value. The gas-enrichment therapy is performed for a predetermined amount of minutes (e.g., 45 or 60 minutes). The therapy can be either continued or paused while a subsequent angiogram is performed and the IMR value is determined, as indicated above.

[0261] In certain implementations, a controller (e.g., controller 102 of FIG. 1A or the controller of FIG. 6) may be coupled to and / or receive signals generated by one or more sensors. The sensors may include flow and / or pressure sensors as described herein. In some implementations, titrating or controlling the amount of gas-enriched blood or gas-enriched liquid delivered to the patient may be based on detected blood flow and / or blood pressure in the patient's vasculature or microvasculature.

[0262] In certain implementations, in a system for controlling gas-enriched therapy, one or more controllers having a processor, memory, and associated circuitry communicatively coupled to at least one sensor may receive one or more signals corresponding to measured values ​​of one or more physiological parameters from one or more sensors (e.g., flow or pressure sensors). Based on the measured values, an alert or control signal may be generated to control the amount of gas-enriched blood or gas-enriched liquid delivered to the patient, and control or titration of the therapy may be achieved. In certain implementations, based on the measured values, a value representative of microvascular dysfunction in the patient's vasculature may be estimated, and based on the estimated microvascular dysfunction in the patient's vasculature, an alert or control signal may be generated to control the amount of gas-enriched blood or gas-enriched liquid delivered to the patient. As a result, control or titration of the therapy may be achieved. In certain implementations, the estimated microvascular dysfunction may include a value representative of microvascular obstruction or microvascular resistance.

[0263] Some implementations of the subject matter and operations described herein (e.g., processes 500, 800) can be implemented in digital electronic circuitry, including structures disclosed herein and their structural equivalents, or in computer software, firmware, or hardware, or in a combination of one or more of them. For example, in some implementations, a processor of a delivery system (e.g., delivery system 100) can be implemented using digital electronic circuitry, or in computer software, firmware, or hardware, or in a combination of one or more of them.

[0264] In one aspect, a system for controlling gas-enrichment therapy in a patient (such as system 100 described above) can include: The system includes a gas-enrichment system configured to enrich a liquid with gas to form a gas-enriched liquid and mix the gas-enriched liquid with blood to form gas-enriched blood. The system includes a plurality of fluid conduits fluidly coupled to the gas-enrichment system, a first of the plurality of fluid conduits configured for flow of blood from the patient to the gas-enrichment system, and a second of the plurality of conduits configured for flow of gas-enriched blood from the gas-enrichment system to the patient. The system includes a pump coupled to at least one of the plurality of fluid conduits. The pump is configured to pump blood between the gas-enrichment system and the patient. The system includes at least one sensor configured to measure one or more physiological parameters indicative of microvascular dysfunction in the patient's vasculature. The system includes one or more controllers having a processor, memory, and associated circuitry, the processor configured to perform the operations. The operations include receiving one or more signals corresponding to measured values ​​of one or more physiological parameters from at least one sensor. The operations include estimating a microvascular dysfunction in the patient's vasculature based on the measured values. The operations include generating an alert or control signal for controlling an amount of gas-enriched blood delivered to the patient based on the estimated microvascular dysfunction in the patient's vasculature.

[0265] In some implementations, the one or more signals correspond to a measured value of blood pressure from at least one pressure sensor, a microvascular dysfunction in the patient's vasculature is estimated based on the measured pressure values, and an alert or control signal is generated based on the estimated microvascular dysfunction. In some implementations, the one or more signals correspond to a measured value of blood flow from at least one flow sensor, a microvascular dysfunction in the patient's vasculature is estimated based on the measured flow values, and an alert or control signal is generated based on the estimated microvascular dysfunction. In some implementations, the microvascular dysfunction is a microvascular obstruction. In some implementations, the microvascular dysfunction is a microvascular resistance.

[0266] In one aspect, a system for controlling gas-enrichment therapy in a patient (such as system 100 described above) may include: The system for controlling gas-enrichment therapy in a patient includes a gas-enrichment system configured to enrich a liquid with gas to form a gas-enriched liquid and deliver the gas-enriched liquid to the patient's vasculature to form gas-enriched blood. The system includes at least one conduit fluidly coupled to the gas-enrichment system, the at least one conduit configured for flow of the gas-enriched liquid from the gas-enrichment system to the patient. The system includes a pump coupled to the at least one conduit, the pump configured to pump the gas-enriched liquid from the gas-enrichment system to the patient. The system includes at least one sensor configured to measure one or more physiological parameters indicative of microvascular dysfunction in the patient's vasculature. The system includes one or more controllers having a processor, memory, and associated circuitry, the processor configured to perform operations. The operations include receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor. The operations include estimating microvascular dysfunction in the patient's vasculature based on the measured values. The operations include generating an alert or control signal to titrate or control the gas-enriched liquid delivered to the patient based on the microvascular dysfunction in the patient's vasculature.

[0267] In some implementations, the one or more signals correspond to measured values ​​of blood pressure from at least one pressure sensor, microvascular dysfunction in the patient's vasculature is estimated based on the measured pressure values, and an alert or control signal is generated based on the estimated microvascular dysfunction.

[0268] In some implementations, the one or more signals correspond to measured values ​​of blood flow from at least one flow sensor, microvascular dysfunction in the patient's vasculature is estimated based on the measured flow values, and an alert or control signal is generated based on the estimated microvascular dysfunction.

[0269] In some implementations, the microvascular dysfunction comprises microvascular obstruction.

[0270] In some implementations, the microvascular dysfunction comprises microvascular resistance.

[0271] In some implementations, a system for controlling gas-enriched therapy in a patient includes a gas-enriched system configured to enrich a liquid with a gas to form a gas-enriched liquid and mix the gas-enriched liquid with blood to form gas-enriched blood. A plurality of fluid conduits are fluidly coupled to the gas-enriched system, a first of the plurality of fluid conduits configured for flow of blood from the patient to the gas-enriched system, and a second of the plurality of conduits configured for flow of gas-enriched blood from the gas-enriched system to the patient. A pump is coupled to at least one of the plurality of fluid conduits, the pump configured to pump blood between the gas-enriched system and the patient, and the at least one sensor configured to measure blood flow or blood pressure for the patient's vasculature. One or more controllers having a processor, memory, and associated circuitry are included, where the processor is configured to: receive one or more signals corresponding to a measured value of blood flow from the at least one sensor; and generate an alert or control signal for controlling an amount of gas-enriched blood delivered to the patient based on the measured value of blood flow or blood pressure.

[0272] In some implementations, a system for controlling gas-enriched therapy in a patient includes a gas-enriched system configured to enrich a liquid with a gas to form a gas-enriched liquid and deliver the gas-enriched liquid to the patient's vasculature to form gas-enriched blood. At least one conduit is fluidly coupled to the gas-enriched system, the at least one conduit configured for flow of the gas-enriched liquid from the gas-enriched system to the patient. A pump is coupled to the at least one conduit, the pump configured to pump the gas-enriched liquid from the gas-enriched system to the patient, and the at least one sensor is configured to measure blood flow or blood pressure in the patient's vasculature. One or more controllers having a processor, memory, and associated circuitry are included, where the processor is configured to: receive one or more signals corresponding to a measured value of blood flow or blood pressure from the at least one sensor; and generate an alert or control signal to titrate or control the gas-enriched liquid delivered to the patient based on the blood flow or blood pressure measurement.

[0273] Some implementations described herein (such as, for example, the processor of the delivery system) can be implemented as one or more groups or modules of digital electronic circuitry, computer software, firmware, or hardware, or in a combination of one or more of these. Although different modules can be used, each module need not be unique, and multiple modules can be implemented on the same digital electronic circuitry, computer software, firmware, or hardware, or in a combination thereof.

[0274] Some implementations described herein can be implemented as one or more computer programs, i.e., one or more modules of computer program instructions encoded on a computer storage medium for execution by or to control the operation of a data processing apparatus. A computer storage medium can be or be included in a computer readable storage device, a computer readable storage substrate, a random or serial access memory array or device, or a combination of one or more of these. Moreover, a computer storage medium is not a propagating signal, but a computer storage medium can be a source or destination of computer program instructions encoded in an artificially generated propagating signal. A computer storage medium can also be or be included in one or more separate physical components or media (e.g., multiple CDs, disks, or other storage devices).

[0275] The term "data processing apparatus" encompasses all kinds of apparatus, devices, and machines for processing data, including, by way of example, a programmable processor, a computer, a system on a chip, or a combination or combinations of the foregoing. An apparatus may include special purpose logic circuitry, such as a field programmable gate array (FPGA) or an application specific integrated circuit (ASIC). In addition to hardware, an apparatus may also include code that creates an execution environment for a given computer program, such as code that constitutes a processor firmware, a protocol stack, a database management system, an operating system, a cross-platform runtime environment, a virtual machine, or a combination of one or more of these. The apparatus and execution environment may implement a variety of different computing model infrastructures, such as web services, distributed computing, and grid computing infrastructures.

[0276] A computer program (also known as a program, software, software application, script, or code) can be written in any form of programming language, including compiled or interpreted languages, declarative or procedural languages. A computer program may, but need not, correspond to a file in a file system. A program can be stored in a portion of a file that holds other programs or data (e.g., one or more scripts stored in a markup language document), in a single file dedicated to that program, or in multiple associated files (e.g., files that store one or more modules, subprograms, or portions of code). A computer program can be deployed to be executed on one computer or on multiple computers that are located at one site or distributed across multiple sites and interconnected by a communications network.

[0277] Some of the processes and logic flows described herein may be performed by one or more programmable processors executing one or more computer programs to perform actions by operating on input data and generating output. The processes and logic flows may also be performed by, and an apparatus may be implemented as, special purpose logic circuitry, for example, an FPGA (field programmable gate array) or an ASIC (application specific integrated circuit).

[0278] Processors suitable for executing computer programs include, by way of example, both general purpose and special purpose microprocessors, and processors of any kind of digital computer. Typically, a processor receives instructions and data from a read-only memory or a random access memory, or both. A computer includes a processor for performing actions in accordance with the instructions, and one or more memory devices for storing instructions and data. A computer may include one or more mass storage devices, such as magnetic, magneto-optical, or optical disks, for storing data, or may be operatively coupled to receive data therefrom or transfer data thereto, or both. However, a computer need not have such devices. Devices suitable for storing computer program instructions and data include all types of non-volatile memory, media, and memory devices, including, by way of example, semiconductor memory devices (e.g., EPROM, EEPROM, flash memory devices, etc.), magnetic disks (e.g., internal hard disks, removable disks, etc.), magneto-optical disks, and CD-ROM and DVD-ROM disks. The processor and memory may be supplemented by, or incorporated in, special purpose logic circuitry.

[0279] To provide interaction with a user, the operations can be implemented on a computer having a display device (e.g., a monitor or another type of display device) for displaying information to the user, and a keyboard and pointing device (e.g., a mouse, trackball, tablet, touch-sensitive screen, or another type of pointing device) by which the user can provide input to the computer. Other types of devices can be used to provide interaction with the user as well, for example, feedback provided to the user can be any form of sensory feedback, e.g., visual feedback, auditory feedback, or tactile feedback; input from the user can be received in any form, including acoustic, speech, or tactile input. Additionally, the computer can interact with the user by sending documents to and receiving documents from devices used by the user; for example, by sending web pages to a web browser on the user's client device in response to requests received from that web browser.

[0280] A computer system may include a single computing device or multiple computers operating nearby or generally remotely from each other and typically interact through a communications network. Examples of communications networks include local area networks ("LANs") and wide area networks ("WANs"), internetworks (e.g., the Internet), networks including satellite links, and peer-to-peer networks (e.g., ad hoc peer-to-peer networks). The relationship of client and server may arise by virtue of computer programs running on the respective computers and having a client-server relationship to each other.

[0281] 9 illustrates an example computer system 900 including a processor 900, a memory 920, a storage device 930, and an input / output device 940. Each of the components 900, 920, 930, and 940 may be interconnected, for example, by a system bus 950. The processor 900 may process instructions for execution within the system 900. In some implementations, the processor 900 may be a single-threaded processor, a multi-threaded processor, or another type of processor. The processor 900 may process instructions stored in the memory 920 or on the storage device 930. The memory 920 and the storage device 930 may store information within the system 900.

[0282] The input / output devices 940 provide input / output operations for the system 900. In some implementations, the input / output devices 940 may include one or more of a network interface device, e.g., an Ethernet card, a serial communication device, e.g., an RS-232 port, and / or a wireless interface device, e.g., an 802.11 card, a 3G wireless modem, a 4G wireless modem, a 5G wireless modem, etc. In some implementations, the input / output devices may include driver devices configured to receive input data and send output data to other input / output devices, e.g., keyboards, printers, and display devices 960. In some implementations, mobile computing devices, mobile communication devices, and other devices may be used.

[0283] While this specification contains many details, these should not be construed as limiting the scope of what may be claimed, but rather as descriptions of features specific to particular examples. Certain features that are described in this specification in the context of separate implementations can also be combined. Conversely, various features that are described in the context of a single implementation can also be implemented in multiple embodiments separately or in any suitable subcombination.

[0284] Several embodiments have been described. For example, the detailed description and the accompanying drawings to which it refers are intended to describe some, but not necessarily all, examples or embodiments of the system. The described embodiments are to be considered in all respects only as illustrative and not restrictive. Nevertheless, various modifications may be made without departing from the scope of the data processing system described herein. Accordingly, other embodiments are within the scope of the following claims.

[0285] Substantial modifications may be made according to particular requirements. For example, customized hardware might be used and / or particular elements might be implemented in hardware, software (including portable software, such as applets, etc.), or both. Further, connection to other computing devices, such as network input / output devices, might be employed.

[0286] Information and signals may be represented using any of a variety of different technologies and techniques. For example, the data, instructions, commands, information, signals, and symbols that may be referenced throughout the above description may be represented by voltages, currents, electromagnetic waves, magnetic fields or particles, optical fields or particles, or any combination thereof.

[0287] The methods, systems, and devices discussed above are examples. Various alternative configurations may omit, substitute, or add various procedures or components as appropriate. The configurations may be described as processes shown as flow diagrams or block diagrams. While each may describe operations as a sequential process, many of the operations may be performed in parallel or simultaneously. In addition, the order of operations may be rearranged. The process may have additional stages not included in the figures. Specific details are given in the description to provide a thorough understanding of the example configurations (including implementations). However, the configurations may be practiced without these specific details. For example, well-known circuits, processes, algorithms, structures, and techniques have been shown without unnecessary details to avoid obscuring the configurations. This description only provides an example configuration and does not limit the scope, applicability, or configuration of the claims. Rather, the preceding description of the configurations provides a person skilled in the art with an enabling description to implement the described techniques. Various changes may be made in the function and arrangement of elements without departing from the scope of the present disclosure.

[0288] Also, the configurations may be described as processes that are shown as flow diagrams or block diagrams. While each operation may be described as a sequential process, many of the operations may be performed in parallel or simultaneously. Additionally, the order of operations may be rearranged. A process may have additional stages or functions not included in the figures. Furthermore, example methods may be implemented by hardware, software, firmware, middleware, microcode, hardware description languages, or any combination thereof. If implemented in software, firmware, middleware, or microcode, program code or code segments for performing tasks may be stored in a non-transitory processor-readable medium, such as a storage medium. A processor may perform the tasks described.

[0289] Functional or other components illustrated in the figures and / or discussed herein as connecting or communicating with each other are communicatively coupled, i.e., they may be directly or indirectly connected to enable communication therebetween.

[0290] As used in this specification, including the claims, "and" as used in a list of items followed by "at least one of" indicates a disjunctive list, for example, the list "at least one of A, B, and C" is meant to mean A or B or C or AB or AC or BC or ABC (i.e., A and B and C), or combinations having more than one feature (e.g., AA, AAB, ABBC, etc.). As used in this specification, including the claims, unless otherwise stated, a reference to a function or operation being "based on" an item or condition means that the function or operation is based on the item or condition mentioned, and may be based on one or more items and / or conditions in addition to the item or condition mentioned.

[0291] Although several example configurations have been described, various modifications, alternative configurations, and equivalents may be used without departing from the disclosure. For example, the above elements may be components of a larger system, and other rules may take precedence over or otherwise modify the application of the present invention. Also, multiple operations may be undertaken before, during, or after the above elements are considered. Also, technology advances, and many of the elements are examples and do not limit the scope of the disclosure or the claims. Thus, the above description does not limit the scope of the claims. Moreover, more than one invention may be disclosed.

[0292] Other embodiments are within the scope of the invention. For example, due to the nature of software, the functionality described above may be implemented using software, hardware, firmware, hardwiring, or any combination thereof. The features that implement the functionality may be physically located in various locations, including being distributed such that portions of the functionality are implemented in different physical locations.

[0293] The claims should not be read as limited to the described order or elements unless stated to that effect. It should be understood that various changes in form and details may be made by those skilled in the art without departing from the spirit and scope of the appended claims. All implementations that come within the spirit and scope of the following claims and equivalents thereof are claimed. (Other possible items) (Item 1) 1. A system for controlling gas-enriched therapy in a patient, the system comprising: a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and mix the gas-enriched liquid with blood to form gas-enriched blood; a plurality of fluid conduits fluidly coupled to the gas-enrichment system, a first of the plurality of fluid conduits configured for flow of the blood from the patient to the gas-enrichment system and a second of the plurality of conduits configured for flow of the gas-enriched blood from the gas-enrichment system to the patient; a pump coupled to at least one of the plurality of fluid conduits, the pump configured to pump blood between the gas enrichment system and the patient; at least one sensor configured to measure one or more physiological parameters indicative of microvascular resistance in the patient's vasculature; and a controller having a processor, memory, and associated circuitry communicatively coupled to the at least one sensor, the processor comprising: receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor; estimating microvascular resistance in the vasculature of the patient based on the measured values; and generating an alert or control signal for controlling the amount of the gas-enriched blood delivered to the patient based on the estimated microvascular resistance in the vasculature of the patient. configured to perform operations including: A system comprising: (Item 2) The operation includes: determining a change in the microvascular resistance of the vasculature of the patient; and generating an alert or control signal for controlling the amount of the gas-enriched blood delivered to the patient based on the determined change in microvascular resistance. 2. The system of claim 1, further comprising: (Item 3) 2. The system of claim 1, wherein the at least one sensor includes a flow sensor and the one or more physiological parameters include a flow rate of blood in the patient's vascular system. (Item 4) 2. The system of claim 1, wherein the at least one sensor includes a pressure sensor and the one or more physiological parameters include a pressure of blood in the patient's vascular system. (Item 5) The operation includes: transmitting the control signal to the pump during operation of the pump for delivery of the gas-enriched blood to the patient; and and causing the pump to increase or decrease a pumping speed based on the sending of the control signal to increase or decrease the amount of the gas-enriched blood delivered to the patient. 2. The system of claim 1, further comprising: (Item 6) The step of controlling the amount of the gas-enriched blood delivered to the patient comprises: determining that a change in the value of the one or more physiological parameters is indicative of decreased microvascular resistance in the vasculature of the patient; and generating the control signal configured to cause a decrease in the amount of the gas-enriched blood delivered to the patient in response to determining that the change in value is indicative of the decreased microvascular resistance. 2. The system according to item 1, comprising: (Item 7) The step of controlling the amount of the gas-enriched blood delivered to the patient comprises: determining that the change in the value of the one or more physiological parameters is indicative of increased microvascular resistance in the vasculature of the patient; and generating the control signal configured to cause an increase in the amount of the gas-enriched blood delivered to the patient in response to determining that the change in value is indicative of the increased microvascular resistance. 2. The system according to item 1, comprising: (Item 8) The at least one sensor includes a flow sensor and a pressure sensor, the physiological parameters include a flow rate of the blood in the vascular system of the patient and a blood pressure in the vascular system of the patient, and the operation includes: estimating a change in microvascular resistance in the patient based on the ratio of the blood pressure and the flow rate; and generating said control signal based on said estimated microvascular resistance; 2. The system of claim 1, further comprising: (Item 9) 2. The system of claim 1, wherein the procedure for generating the control signal is performed in real time or quasi-real time during delivery of the gas-enriched blood to the patient, the delivery of the gas-enriched blood to the patient is not paused during measurement of the one or more physiological parameters, and the measurement of the one or more physiological parameters represents the patient's status with respect to the delivery of the gas-enriched blood to the patient. (Item 10) 10. The system of claim 9, wherein real-time or near real-time includes processing, by the controller, the data received from the one or more sensors as soon as data is available to the controller, and generating the control signal based on the processing. (Item 11) The step of receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor includes receiving a series of measured values ​​of the one or more physiological parameters from the at least one sensor, the series of measured values ​​corresponding to a period during delivery of the gas-enriched blood to the patient, and the operations include: determining whether the value of the one or more physiological parameters is increasing or decreasing over time based on the series of measured values ​​corresponding to the period of time; and generating the control signal configured to increase or decrease the amount of the gas-enriched blood delivered to the patient based on determining that the value of the one or more physiological parameters is increasing or decreasing over time. 2. The system of claim 1, further comprising: (Item 12) The operation includes: receiving angiographic data representative of the patient for a period of time concurrent with delivery of the gas-enriched blood to the patient; determining an IMR from the angiographic data; and generating the control signal configured to increase or decrease the amount of the gas-enriched blood delivered to the patient based on the angiographic data and the determined IMR or change in IMR. 2. The system of claim 1, further comprising: (Item 13) a catheter configured to deliver the gas-enriched blood to the patient; and a wire coupled to the catheter, the wire having the at least one sensor, the at least one sensor being a pressure sensor configured to obtain pressure data in the vascular system of the patient; Further comprising: The operation includes: receiving the pressure data from the pressure sensor; determining an index of microcirculatory resistance (IMR) value in the vasculature of the patient based on the pressure data; and generating the control signal configured to increase or decrease the amount of the gas-enriched blood delivered to the patient based on the IMR value or a change in the IMR value. 2. The system of claim 1, further comprising: (Item 14) the at least one sensor includes a plurality of sensors, the plurality of sensors including a plurality of electrodes configured for placement external to the patient; The operation includes: measuring an impedance value from a tissue area between one or more pairs of said plurality of electrodes; generating an impedance tomographic map based at least in part on the measured impedance values; and estimating the microvascular resistance of a region of the patient's vasculature based at least in part on an impedance distribution of the impedance tomographic map. 2. The system of claim 1, further comprising: (Item 15) 15. The system of claim 14, wherein the region of the vascular system is a cardiac region. (Item 16) 15. The system of claim 14, wherein the region of vasculature is a region of muscle tissue. (Item 17) Item 15. The system of item 14, wherein the estimating step is based at least in part on a mean impedance of the impedance distribution. (Item 18) Item 15. The system of item 14, wherein the estimating step is based at least in part on a product of a local impedance and a volume of the impedance distribution. (Item 19) Item 1 , the system of item 1 , wherein the gas enrichment system is configured to enrich a liquid with oxygen to form an oxygen-enriched liquid to be mixed with blood. (Item 20) Item 1, wherein the gas enrichment system comprises a cartridge. (Item 21) 21. The system of claim 20, wherein the cartridge has three chambers. (Item 22) 2. The system of claim 1, wherein the physiological parameter comprises electrical activity of the patient's heart measured by an electrocardiogram (ECG) sensor. (Item 23) 2. The system of claim 1, wherein the estimating step comprises estimating microvascular resistance in a localized or partial area of ​​the patient's vasculature. (Item 24) 2. The system of claim 1, wherein the controlling step comprises titrating the amount of the gas-enriched blood delivered to the patient. (Item 25) 1. A system for controlling gas-enriched therapy in a patient, the system comprising: a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and mix the gas-enriched liquid with arterial blood to form gas-enriched blood; a plurality of fluid conduits fluidly coupled to the gas-enrichment system, a first of the plurality of fluid conduits configured for flow of the blood from the patient to the gas-enrichment system and a second of the plurality of conduits configured for flow of the gas-enriched blood from the gas-enrichment system to the patient; a pump coupled to at least one of the plurality of fluid conduits, the pump configured to pump blood between the gas enrichment system and the patient; a catheter coupled to one or more of the plurality of fluid conduits and configured to deliver the gas-enriched blood from the gas-enrichment system to the patient based on operation of the pump; a wire coupled to the catheter or separate probe, the wire configured to extend along the catheter or probe to a distal tip of the catheter or probe; a pressure sensor coupled to the wire at the distal tip of the catheter or probe, the pressure sensor configured to measure blood pressure in the patient's vascular system; and a controller having a processor, memory, and associated circuitry communicatively coupled to the pressure sensor, the processor comprising: determining a change in blood pressure in the vascular system of the patient based on the measured blood pressure; determining blood flow in the vascular system of the patient; estimating microvascular resistance in the patient's vasculature based on the ratio of blood pressure change and blood flow in the patient's vasculature; and generating an alert or control signal for controlling the amount of the gas-enriched blood delivered to the patient based on the microvascular resistance in the vasculature of the patient. configured to perform operations including: A system comprising: (Item 26) 26. The system of claim 25, wherein the estimating step comprises estimating microvascular resistance in a localized or partial area of ​​the patient's vasculature. (Item 27) 26. The system of claim 25, wherein the controlling step comprises titrating the amount of the gas-enriched blood delivered to the patient. (Item 28) 1. A method for controlling gas-enrichment therapy in a patient, the method comprising: providing a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and to mix the gas-enriched liquid with blood to form gas-enriched blood; delivering said gas-enriched blood to said patient; receiving, at a controller coupled to a sensor configured to measure one or more physiological parameters indicative of microvascular resistance of the patient's vasculature, from the sensor, one or more signals corresponding to measured values ​​of the one or more physiological parameters; estimating the microvascular resistance in the vasculature of the patient based on the measured values; and generating an alert or control signal for controlling the amount of the gas-enriched blood delivered to the patient based on the microvascular resistance in the vasculature of the patient. A method comprising: (Item 29) The control signal is configured to control a pump configured to pump the gas-enriched blood for delivery to the patient, the method comprising: causing the pump to pump blood between the gas-enrichment system and the patient based on the step of transmitting the control signal to the pump. 29. The method of claim 28, further comprising: (Item 30) 30. The method of claim 28, wherein the sensor comprises a flow sensor and the one or more physiological parameters comprise a flow rate of blood in the patient's vascular system. (Item 31) 30. The method of claim 28, wherein the sensor comprises a pressure sensor and the one or more physiological parameters comprise a pressure of blood in the vascular system of the patient. (Item 32) transmitting, by the controller, the control signal to a pump configured to pump the gas-enriched blood for delivery to the patient; and causing the pump to increase or decrease a pump speed based on the sending of the control signal to increase or decrease the amount of the gas-enriched blood delivered to the patient. 29. The method of claim 28, further comprising: (Item 33) Reducing the amount of the gas-enriched blood delivered to the patient comprises: determining that the change in the value of the one or more physiological parameters is indicative of decreased microvascular resistance in the vasculature of the patient; and generating the control signal configured to cause a decrease in the amount of the gas-enriched blood delivered to the patient in response to determining that the change in value is indicative of the decreased microvascular resistance. 29. The method according to item 28, comprising: (Item 34) Increasing the amount of the gas-enriched blood delivered to the patient comprises: determining that the change in the value of the one or more physiological parameters is indicative of increased microvascular resistance in the vasculature of the patient; and generating the control signal configured to cause an increase in the amount of the gas-enriched blood delivered to the patient in response to determining that the change in value is indicative of the increased microvascular resistance. 29. The method according to item 28, comprising: (Item 35) The sensors include a flow sensor and a pressure sensor, and the physiological parameters include a flow rate of the blood in the vascular system of the patient and a blood pressure in the vascular system of the patient, and the method further comprises: estimating microvascular resistance in the patient based on the ratio of the flow rate and the blood pressure; and generating the control signal based on the estimated microvascular resistance; 29. The method of claim 28, further comprising: (Item 36) 29. The method of claim 28, wherein generating the control signal is performed in real time or quasi-real time during delivery of the gas-enriched blood to the patient, the delivery of the gas-enriched blood to the patient is not paused during measurement of the one or more physiological parameters, and the measurement of the one or more physiological parameters represents a contemporaneous status of the patient with respect to the delivery of the gas-enriched blood to the patient. (Item 37) Receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the sensor comprises receiving a series of measured values ​​of the one or more physiological parameters from the sensor, the series of measured values ​​corresponding to a period during delivery of the gas-enriched blood to the patient, the method comprising: determining whether the value of the one or more physiological parameters is increasing or decreasing over time based on the series of measured values ​​corresponding to the period of time; and generating the control signal configured to increase or decrease the amount of the gas-enriched blood delivered to the patient based on determining that the value of the one or more physiological parameters is increasing or decreasing over time. 29. The method of claim 28, further comprising: (Item 38) The method comprises: receiving angiography data representative of the patient during a period concurrent with delivery of the gas-enriched blood to the patient; determining an IMR from the angiographic data; and generating the control signal configured to increase or decrease the amount of the gas-enriched blood delivered to the patient based on the angiographic data and the determined IMR or change in IMR. 29. The method of claim 28, further comprising: (Item 39) receiving, by the controller, pressure data from a pressure sensor coupled to a wire supported at a distal end of a catheter in the vasculature of the patient; determining, by the controller, a value of an index of microcirculatory resistance (IMR) in the vasculature of the patient based on the pressure data; and generating, by the controller, the control signal configured to increase or decrease the amount of the gas-enriched blood delivered to the patient based on the IMR value or a change in the IMR value. 29. The method of claim 28, further comprising: (Item 40) measuring, by the controller, an impedance value from a tissue area between one or more pairs of a plurality of external electrodes configured for placement external to the patient; generating, by the controller, an impedance tomographic map based at least in part on the measured impedance values; and estimating the microvascular resistance of a region of the patient's vasculature based at least in part on an impedance distribution of the impedance tomographic map. 29. The method of claim 28, further comprising: (Item 41) 41. The method of claim 40, wherein the region of the vascular system is the cardiac region. (Item 42) 41. The method of claim 40, wherein the region of the vasculature is a region of muscle tissue. (Item 43) 41. The method of claim 40, wherein the estimating step is based at least in part on a mean impedance of the impedance distribution. (Item 44) 41. The method of claim 40, wherein the estimating step is based at least in part on a product of a local impedance and a volume of the impedance distribution. (Item 45) 26. The system of claim 25, wherein the controlling step comprises titrating the amount of the gas-enriched blood delivered to the patient. (Item 46) 1. A system for controlling gas-enriched therapy in a patient, the system comprising: a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and deliver the gas-enriched liquid to a vascular system of the patient to form gas-enriched blood; at least one conduit fluidly coupled to the gas-enrichment system, the at least one conduit configured for flow of the gas-enriched liquid from the gas-enrichment system to the patient; a pump coupled to the at least one conduit, the pump configured to pump gas-enriched liquid from the gas-enrichment system to the patient; at least one sensor configured to measure one or more physiological parameters indicative of microvascular resistance in the patient's vasculature; and a controller having a processor, memory, and associated circuitry communicatively coupled to the at least one sensor, the processor comprising: receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor; estimating the microvascular resistance in the vasculature of the patient based on the measured values; and generating an alert or control signal to titrate or control the gas-enriched liquid delivered to the patient based on the microvascular resistance in the vasculature of the patient. configured to perform operations including: A system comprising: (Item 47) The operation includes: determining a change in the microvascular resistance of the vasculature of the patient; and generating an alert or control signal to titrate or control the gas-enriched liquid delivered to the patient based on the determined change in microvascular resistance. Item 47. The system of item 46, further comprising: (Item 48) 47. The system of claim 46, wherein the at least one sensor includes a flow sensor and the one or more physiological parameters include a flow rate of blood in the patient's vascular system. (Item 49) 47. The system of claim 46, wherein the at least one sensor includes a pressure sensor and the one or more physiological parameters include a pressure of blood in the patient's vascular system. (Item 50) The operation includes: transmitting the control signal to the pump during operation of the pump for delivery of the gas-enriched liquid to the patient; and and causing the pump to increase or decrease a pump speed based on the sending of the control signal to increase or decrease the amount of the gas-enriched liquid delivered to the patient. Item 47. The system of item 46, further comprising: (Item 51) The step of controlling the amount of the gas-enriched blood delivered to the patient comprises: determining that a change in the value of the one or more physiological parameters is indicative of decreased microvascular resistance in the vasculature of the patient; and generating the control signal configured to cause a decrease in the amount of the gas-enriched liquid delivered to the patient in response to determining that the change in value is indicative of the decreased microvascular resistance. Item 47. The system according to item 46, comprising: (Item 52) The step of controlling the amount of the gas-enriched liquid delivered to the patient comprises: determining that the change in the value of the one or more physiological parameters is indicative of increased microvascular resistance in the vasculature of the patient; and generating the control signal configured to cause an increase in the amount of the gas-enriched liquid delivered to the patient in response to determining that the change in value is indicative of the increased microvascular resistance. Item 47. The system according to item 46, comprising: (Item 53) The at least one sensor includes a flow sensor and a pressure sensor, the physiological parameters include a flow rate of the blood in the vascular system of the patient and a blood pressure in the vascular system of the patient, and the operation includes: estimating a change in microvascular resistance in the patient based on the ratio of the blood pressure and the flow rate; and generating said control signal or alert based on said estimated microvascular resistance; Item 47. The system of item 46, further comprising: (Item 54) 47. The system of claim 46, wherein the procedure for generating the control signal or alert is performed in real time or quasi-real time during delivery of the gas-enriched liquid to the patient, the delivery of the gas-enriched liquid to the patient is not paused during measurement of the one or more physiological parameters, and the measurement of the one or more physiological parameters represents the patient's contemporaneous status with respect to the delivery of the gas-enriched liquid to the patient. (Item 55) Item 55. The system of item 54, wherein real-time or near real-time includes processing, by the controller, the data received from the one or more sensors as soon as the data is available to the controller, and generating the control signal or alert based on the processing. (Item 56) The step of receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor includes receiving a series of measured values ​​of the one or more physiological parameters from the at least one sensor, the series of measured values ​​corresponding to a period during delivery of the gas-enriched liquid to the patient, and the operations include: determining whether the value of the one or more physiological parameters is increasing or decreasing over time based on the series of measured values ​​corresponding to the period of time; and generating the control signal or alert to increase or decrease the amount of the gas-enriched liquid delivered to the patient based on determining that the value of the one or more physiological parameters is increasing or decreasing over time. Item 47. The system of item 46, further comprising: (Item 57) The operation includes: receiving angiographic data representative of the patient for a period of time concurrent with delivery of the gas-enriched liquid to the patient; determining an IMR from the angiographic data; and generating the control signal or alert to increase or decrease the amount of the gas-enriched liquid delivered to the patient based on the angiographic data and the determined IMR or change in IMR. Item 47. The system of item 46, further comprising: (Item 58) the at least one sensor includes a plurality of sensors, the plurality of sensors including a plurality of electrodes configured for placement external to the patient; The operation includes: measuring an impedance value from a tissue area between one or more pairs of said plurality of electrodes; generating an impedance tomographic map based at least in part on the measured impedance values; and estimating the microvascular resistance of a region of the patient's vasculature based at least in part on an impedance distribution of the impedance tomographic map. Item 47. The system of item 46, further comprising: (Item 59) 47. The system of claim 46, wherein the region of the vascular system is a cardiac region. (Item 60) 47. The system of claim 46, wherein the region of vasculature is a region of muscle tissue. (Item 61) Item 47. The system of item 46, wherein the estimating step is based at least in part on an average impedance of the impedance distribution. (Item 62) Item 47. The system of item 46, wherein the estimating step is based at least in part on a product of a local impedance and a volume of the impedance distribution. (Item 63) Item 47. The system of item 46, wherein the gas enrichment system is configured to enrich a liquid with oxygen to form an oxygen-enriched liquid to be mixed with blood. (Item 64) Item 47. The system of item 46, wherein the gas enrichment system comprises a cartridge. (Item 65) Item 48. The system of item 47, wherein the cartridge has three chambers. (Item 66) 47. The system of claim 46, wherein the controlling step comprises titrating the amount of the gas-enriched blood delivered to the patient. (Item 67) 1. A system for controlling gas-enriched therapy in a patient, the system comprising: a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and mix the gas-enriched liquid with blood to form gas-enriched blood; a plurality of fluid conduits fluidly coupled to the gas-enrichment system, a first of the plurality of fluid conduits configured for flow of the blood from the patient to the gas-enrichment system and a second of the plurality of conduits configured for flow of the gas-enriched blood from the gas-enrichment system to the patient; a pump coupled to at least one of the plurality of fluid conduits, the pump configured to pump blood between the gas-enrichment system and the patient; and at least one sensor configured to measure one or more physiological parameters in the patient's vasculature; and One or more controllers having a processor, memory, and associated circuitry, wherein the one or more controllers: receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor; receiving imaging data representative of the vasculature of the patient; estimating microvascular resistance in the vasculature of the patient based on the imaging data and the measured values ​​of the one or more physiological parameters; and generating an alert or control signal for controlling the amount of the gas-enriched blood delivered to the patient based on the estimated microvascular resistance in the vasculature of the patient. configured to perform operations including: A system comprising: (Item 68) 70. The system of claim 67, wherein the step of estimating microvascular resistance includes a step of determining an IMR value. (Item 69) Item 68. The system of item 67, wherein the imaging data is one or more angiographic images. (Item 70) Item 68. The system of item 67, wherein the sensor is a pressure sensor. (Item 71) The operation includes: receiving the imaging data in the form of angiographic data representative of the patient, the angiographic data being generated following delivery of the gas-enriched blood to the patient; determining an IMR from the angiographic data; and generating an alert or control signal configured to increase or decrease the amount of the gas-enriched blood delivered to the patient based on the angiographic data and the determined IMR or change in IMR. Item 68. The system of item 67, further comprising: (Item 72) Item 68. The system of item 67, wherein the at least one sensor is communicatively coupled to the controller and configured to measure one or more physiological parameters indicative of microvascular resistance in the patient's vasculature. (Item 73) Item 68. The system of item 67, wherein the at least one sensor is configured to transmit one or more signals corresponding to measured values ​​of the one or more physiological parameters. (Item 74) Item 74. The system of item 73, wherein the at least one or more signals corresponding to measured values ​​of the one or more physiological parameters correspond to pressure or flow values. (Item 75) 70. The system of claim 67, wherein the control signal increases or decreases the amount of gas-enriched blood delivered to the patient without pausing delivery of the gas-enriched blood to the patient. (Item 76) 1. A system for controlling gas-enriched therapy in a patient, the system comprising: a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and deliver the gas-enriched liquid to a vascular system of the patient to form gas-enriched blood; at least one conduit fluidly coupled to the gas-enrichment system, the at least one conduit configured for flow of the gas-enriched liquid from the gas-enrichment system to the patient; a pump coupled to the at least one conduit, the pump configured to pump gas-enriched liquid from the gas-enrichment system to the patient; at least one sensor configured to measure one or more physiological parameters in the patient's vasculature; and one or more controllers having a processor, a memory, the one or more controllers receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor; receiving imaging data representative of the vasculature of the patient; estimating the microvascular resistance in the vasculature of the patient based on the imaging data and the one or more signals corresponding to measured values ​​of the one or more physiological parameters; and generating an alert or control signal to titrate or control the gas-enriched liquid delivered to the patient based on the microvascular resistance in the vasculature of the patient. configured to perform operations including: A system comprising: (Item 77) 77. The system of claim 76, wherein the step of estimating microvascular resistance includes a step of determining an IMR value. (Item 78) Item 77. The system of item 76, wherein the imaging data is one or more angiographic images. (Item 79) Item 77. The system of item 76, wherein the sensor is a pressure sensor. (Item 80) The operation includes: receiving the imaging data in the form of angiographic data representative of the patient, the angiographic data being generated following delivery of the gas-enriched blood to the patient; determining an IMR from the angiographic data; and generating an alert or control signal configured to increase or decrease the amount of the gas-enriched blood delivered to the patient based on the angiographic data and the determined IMR or change in IMR. 77. The system of claim 76, further comprising: (Item 81) 8. The system of claim 76, wherein the at least one sensor is communicatively coupled to the controller and configured to measure one or more physiological parameters indicative of microvascular resistance in the patient's vasculature. (Item 82) Item 77. The system of item 76, wherein the at least one sensor is configured to transmit one or more signals corresponding to measured values ​​of the one or more physiological parameters. (Item 83) Item 83. The system of item 82, wherein the at least one or more signals corresponding to measured values ​​of the one or more physiological parameters correspond to pressure or flow values. (Item 84) 77. The system of claim 76, wherein the control signal increases or decreases the amount of the gas-enriched blood delivered to the patient without pausing delivery of the gas-enriched blood to the patient. (Item 85) 1. A system for controlling oxygen enrichment therapy in a patient, the system comprising: an oxygen enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and mix the oxygen-enriched liquid with blood to form oxygen-enriched blood; a plurality of fluid conduits fluidly coupled to the oxygen-enriched system, a first of the plurality of fluid conduits configured for flow of the blood from the patient to the oxygen-enriched system and a second of the plurality of conduits configured for flow of the oxygen-enriched blood from the oxygen-enriched system to the patient; a pump coupled to at least one of the plurality of fluid conduits, the pump configured to pump blood between the oxygen enrichment system and the patient; and One or more controllers having a processor, memory, and associated circuitry, wherein the one or more controllers: delivering oxygen-enriched blood to said patient; suspending delivery of said oxygen-enriched blood to said patient after a predetermined period of time; capturing one or more angiographic images representative of the patient's vasculature; estimating a microvascular resistance index in the vasculature of the patient based on the one or more angiographic images; generating an alert or command to control delivery of the gas-enriched blood to the patient based on the estimated microvascular resistance index in the vasculature of the patient; and controlling the delivery of gas-enriched blood to the patient based on the alert or command. configured to perform operations including: A system comprising: (Item 86) Item 86. The system of item 85, further comprising at least one sensor configured to measure a pressure or flow in the patient's vasculature, wherein the one or more controllers are configured to perform the steps of receiving one or more signals corresponding to the measured values ​​of the pressure or flow from the at least one sensor, and estimating the microvascular resistance in the patient's vasculature based on the imaging data and the one or more signals corresponding to the measured values ​​of pressure or flow. (Item 87) Item 86. The system of item 85, wherein the gas-enrichment system is configured to form oxygen-enriched blood. (Item 88) Item 86. The system of item 85, wherein the gas enrichment system is configured to form an oxygen-enriched liquid. (Item 89) 1. A system for controlling gas-enriched therapy in a patient, the system comprising: a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and mix the gas-enriched liquid with blood to form gas-enriched blood; a plurality of fluid conduits fluidly coupled to the gas-enrichment system, a first of the plurality of fluid conduits configured for flow of the blood from the patient to the gas-enrichment system and a second of the plurality of conduits configured for flow of the gas-enriched blood from the gas-enrichment system to the patient; a pump coupled to at least one of the plurality of fluid conduits, the pump configured to pump blood between the gas enrichment system and the patient; at least one sensor configured to measure one or more physiological parameters indicative of microvascular dysfunction in the patient's vasculature; and One or more controllers having a processor, memory, and associated circuitry, wherein the processor: receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor; estimating microvascular dysfunction in the vasculature of the patient based on the measured values; and generating an alert or control signal for controlling the amount of the gas-enriched blood delivered to the patient based on the estimated microvascular dysfunction in the vasculature of the patient. configured to perform operations including: A system comprising: (Item 90) 90. The system of claim 89, wherein the one or more signals correspond to measured values ​​of blood pressure from at least one pressure sensor, microvascular dysfunction in the patient's vasculature is estimated based on the measured pressure values, and an alert or control signal is generated based on the estimated microvascular dysfunction. (Item 91) 90. The system of claim 89, wherein the one or more signals correspond to measured values ​​of blood flow from at least one flow sensor, microvascular dysfunction in the patient's vasculature is estimated based on the measured flow values, and an alert or control signal is generated based on the estimated microvascular dysfunction. (Item 92) 92. The system of claim 91, wherein the microvascular dysfunction is microvascular obstruction. (Item 93) 92. The system of claim 91, wherein the microvascular dysfunction is microvascular resistance. (Item 94) 1. A system for controlling gas-enriched therapy in a patient, the system comprising: a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and deliver the gas-enriched liquid to a vascular system of the patient to form gas-enriched blood; at least one conduit fluidly coupled to the gas-enrichment system, the at least one conduit configured for flow of the gas-enriched liquid from the gas-enrichment system to the patient; a pump coupled to the at least one conduit, the pump configured to pump gas-enriched liquid from the gas-enrichment system to the patient; at least one sensor configured to measure one or more physiological parameters indicative of microvascular dysfunction in the patient's vasculature; and One or more controllers having a processor, memory, and associated circuitry, wherein the processor: receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor; estimating the microvascular dysfunction in the vasculature of the patient based on the measured values; and generating an alert or control signal to titrate or control the gas-enriched liquid delivered to the patient based on the microvascular dysfunction in the vasculature of the patient. configured to perform operations including: A system comprising: (Item 95) 95. The system of claim 94, wherein the one or more signals correspond to measured values ​​of blood pressure from at least one pressure sensor, microvascular dysfunction in the patient's vasculature is estimated based on the measured pressure values, and an alert or control signal is generated based on the estimated microvascular dysfunction. (Item 96) 95. The system of claim 94, wherein the one or more signals correspond to measured values ​​of blood flow from at least one flow sensor, microvascular dysfunction in the patient's vasculature is estimated based on the measured flow values, and an alert or control signal is generated based on the estimated microvascular dysfunction. (Item 97) 95. The system of item 94, wherein the microvascular dysfunction is microvascular obstruction. (Item 98) 95. The system of item 94, wherein the microvascular dysfunction is microvascular resistance. (Item 99) 1. A system for controlling gas-enriched therapy in a patient, the system comprising: a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and mix the gas-enriched liquid with blood to form gas-enriched blood; a plurality of fluid conduits fluidly coupled to the gas-enrichment system, a first of the plurality of fluid conduits configured for flow of the blood from the patient to the gas-enrichment system and a second of the plurality of conduits configured for flow of the gas-enriched blood from the gas-enrichment system to the patient; a pump coupled to at least one of the plurality of fluid conduits, the pump configured to pump blood between the gas enrichment system and the patient; at least one sensor configured to measure blood flow through the patient's vasculature; and One or more controllers having a processor, memory, and associated circuitry, wherein the processor: receiving one or more signals corresponding to a measured value of the blood flow from the at least one sensor; and generating an alert or control signal for controlling the amount of the gas-enriched blood delivered to the patient based on the measured value of the blood flow. configured to perform operations including: A system comprising: (Item 100) 1. A system for controlling gas-enriched therapy in a patient, the system comprising: a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and deliver the gas-enriched liquid to a vascular system of the patient to form gas-enriched blood; at least one conduit fluidly coupled to the gas-enrichment system, the at least one conduit configured for flow of the gas-enriched liquid from the gas-enrichment system to the patient; a pump coupled to the at least one conduit, the pump configured to pump gas-enriched liquid from the gas-enrichment system to the patient; at least one sensor configured to measure blood flow in the patient's vasculature; and One or more controllers having a processor, memory, and associated circuitry, wherein the processor: receiving one or more signals corresponding to a measured value of the blood flow from the at least one sensor; generating an alert or control signal to titrate or control the gas-enriched liquid delivered to the patient based on the blood flow measurements. configured to perform operations including: A system comprising: (Item 101) 1. A method for controlling gas-enrichment therapy in a patient, the method comprising: receiving one or more signals corresponding to measured values ​​of one or more physiological parameters indicative of microvascular resistance in the patient's vasculature from at least one sensor configured to measure the one or more physiological parameters; estimating the microvascular resistance in the vasculature of the patient based on the measured values; and generating an alert or control signal based on the microvascular resistance in the vasculature of the patient to titrate or control a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and deliver the gas-enriched liquid to the vasculature of the patient to form gas-enriched blood. A method comprising: (Item 102) 1. A method for controlling gas-enrichment therapy in a patient, the method comprising: receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from at least one sensor configured to measure the one or more physiological parameters in the patient's vasculature; receiving imaging data representative of the vasculature of the patient; estimating microvascular resistance in the vasculature of the patient based on the imaging data and the measured values ​​of the one or more physiological parameters; and generating an alert or control signal based on the estimated microvascular resistance in the vasculature of the patient to control an amount of the gas-enriched blood delivered to the patient by a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and mix the gas-enriched liquid with blood to form gas-enriched blood. A method comprising: (Item 103) 1. A method for controlling gas-enrichment therapy in a patient, the method comprising: receiving one or more signals corresponding to measured values ​​of one or more physiological parameters from at least one sensor configured to measure the one or more physiological parameters in the patient's vasculature; receiving imaging data representative of the vasculature of the patient; estimating the microvascular resistance in the vasculature of the patient based on the imaging data and the one or more signals corresponding to the measured values ​​of the one or more physiological parameters; and generating an alert or control signal based on the microvascular resistance in the patient's vasculature to titrate or control an amount of the gas-enriched liquid delivered to the patient by a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and deliver the gas-enriched liquid to the patient's vasculature to form gas-enriched blood. A method comprising: (Item 104) 1. A method for controlling oxygen enrichment therapy in a patient, the method comprising: configuring an oxygen enrichment system to enrich a liquid with a gas to form a gas-enriched liquid and to mix the oxygen-enriched liquid with blood to form oxygen-enriched blood; delivering oxygen-enriched blood to said patient; suspending delivery of said oxygen-enriched blood to said patient after a predetermined period of time; capturing one or more angiographic images representative of the patient's vasculature; estimating a microvascular resistance index in the vasculature of the patient based on the one or more angiographic images; and generating an alert or command to control delivery of the gas-enriched blood to the patient based on the estimated microvascular resistance index in the vasculature of the patient; and controlling the delivery of gas-enriched blood to the patient based on the alert or command. A method comprising: (Item 105) 1. A method for controlling gas-enrichment therapy in a patient, the method comprising: receiving, from at least one sensor configured to measure one or more physiological parameters indicative of microvascular dysfunction in the patient's vasculature, one or more signals corresponding to measured values ​​of the one or more physiological parameters; estimating microvascular dysfunction in the vasculature of the patient based on the measured values; and generating an alert or control signal based on the estimated microvascular dysfunction in the vasculature of the patient to control an amount of the gas-enriched blood delivered to the patient by a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and mix the gas-enriched liquid with blood to form gas-enriched blood. A method comprising: (Item 106) 1. A method for controlling gas-enrichment therapy in a patient, the method comprising: receiving, from at least one sensor configured to measure one or more physiological parameters indicative of microvascular dysfunction in the patient's vasculature, one or more signals corresponding to measured values ​​of the one or more physiological parameters; estimating the microvascular dysfunction in the vasculature of the patient based on the measured values; and generating an alert or control signal to titrate or control a gas-enriched liquid delivered to the patient based on the microvascular dysfunction in the vasculature of the patient. A method comprising: (Item 107) 1. A method for controlling gas-enrichment therapy in a patient, the method comprising: receiving one or more signals corresponding to a measured value of blood flow from at least one sensor configured to measure blood flow about the patient's vasculature; and generating an alert or control signal based on the measured value of the blood flow to control an amount of the gas-enriched blood delivered to the patient by a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and mix the gas-enriched liquid with blood to form gas-enriched blood. A method comprising: (Item 108) 1. A method for controlling gas-enrichment therapy in a patient, the method comprising: receiving one or more signals corresponding to a measured value of blood flow from at least one sensor configured to measure blood flow in the patient's vasculature; generating an alert or control signal based on the blood flow measurements to titrate or control an amount of gas-enriched liquid delivered to the patient by a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and deliver the gas-enriched liquid to the patient's vascular system to form gas-enriched blood. A method comprising:

Claims

1. 1. A system for controlling gas-enrichment therapy in a patient, the system comprising: a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and mix the gas-enriched liquid with blood to form gas-enriched blood; a plurality of fluid conduits fluidly coupled to the gas-enrichment system, a first of the plurality of fluid conduits configured for flow of the blood from the patient to the gas-enrichment system, and a second of the plurality of fluid conduits configured for flow of the gas-enriched blood from the gas-enrichment system to the patient; a pump coupled to at least one of the plurality of fluid conduits, the pump configured to pump blood between the gas-enrichment system and the patient; a wire configured to extend into the patient's vasculature and comprising at least one sensor configured to measure one or more physiological parameters indicative of microvascular resistance in the patient's vasculature; and a controller communicatively coupled to the at least one sensor, the controller having a processor, memory, and associated circuitry, wherein the processor: receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor; estimating microvascular resistance in the vasculature of the patient based on the measured values; and generating an alert or control signal for controlling the amount of the gas-enriched blood delivered to the patient based on the estimated microvascular resistance in the patient's vasculature. configured to perform operations including: wherein the at least one sensor comprises a pressure sensor, and the one or more physiological parameters comprise a pressure of blood in the patient's vasculature, the pressure of blood being indicative of microvascular resistance in the patient's vasculature.

2. The operation is determining a change in the microvascular resistance of the vasculature of the patient; and generating an alert or control signal for controlling the amount of the gas-enriched blood delivered to the patient based on the determined change in microvascular resistance. The system of claim 1 further comprising:

3. 2. The system of claim 1, wherein the at least one sensor includes a flow sensor, the one or more physiological parameters include a flow rate of blood in the patient's vasculature, and the estimate of microvascular resistance in the patient's vasculature is based on the flow rate.

4. The operation is transmitting the control signal to the pump during operation of the pump for delivery of the gas-enriched blood to the patient; and and causing the pump to increase or decrease a pumping speed based on the sending of the control signal to increase or decrease the amount of the gas-enriched blood delivered to the patient. The system of claim 1 further comprising:

5. The step of controlling the amount of gas-enriched blood delivered to the patient comprises: determining that the change in the value of the one or more physiological parameters is indicative of decreased microvascular resistance in the vasculature of the patient; and generating the control signal configured to cause a decrease in the amount of the gas-enriched blood delivered to the patient in response to determining that the change in the value is indicative of the decreased microvascular resistance. The system of claim 1 , comprising:

6. The step of controlling the amount of gas-enriched blood delivered to the patient comprises: determining that the change in the value of the one or more physiological parameters is indicative of increased microvascular resistance in the vasculature of the patient; and generating the control signal configured to cause an increase in the amount of the gas-enriched blood delivered to the patient in response to determining that the change in the value represents the increased microvascular resistance. The system of claim 1 , comprising:

7. the at least one sensor includes a flow sensor and a pressure sensor, the one or more physiological parameters include a flow rate of the blood in the vascular system of the patient and a blood pressure in the vascular system of the patient, and the operation includes: estimating a change in microvascular resistance in the patient based on the ratio of the blood pressure and the flow rate; and generating the control signal based on the estimated microvascular resistance; The system of claim 1 further comprising:

8. 2. The system of claim 1, wherein the procedure for generating the control signal is performed in real time or near real time during delivery of the gas-enriched blood to the patient, the delivery of the gas-enriched blood to the patient is not paused during measurement of the one or more physiological parameters, and the measurement of the one or more physiological parameters represents the patient's status with respect to the delivery of the gas-enriched blood to the patient.

9. 9. The system of claim 8, wherein real-time or near real-time includes processing, by the controller, the data received from the one or more sensors as soon as the data is available to the controller, and generating the control signal based on the processing.

10. The step of receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor includes receiving a series of measured values ​​of the one or more physiological parameters from the at least one sensor, the series of measured values ​​corresponding to a period during delivery of the gas-enriched blood to the patient, and the operations include: determining whether the value of the one or more physiological parameters is increasing or decreasing over time based on the series of measured values ​​corresponding to a period during the delivery; and generating the control signal configured to increase or decrease the amount of the gas-enriched blood delivered to the patient based on determining that the value of the one or more physiological parameters is increasing or decreasing over time. The system of claim 1 further comprising:

11. The operation is receiving, from an imaging device in communication with the controller, angiography data representative of the patient for a period concurrent with delivery of the gas-enriched blood to the patient; determining an index of microcirculatory resistance (IMR) value from the angiographic data; and generating the control signal configured to increase or decrease the amount of the gas-enriched blood delivered to the patient based on the angiographic data and the determined IMR value or change in IMR value. The system of claim 1 further comprising:

12. 1. A system for controlling gas-enrichment therapy in a patient, the system comprising: a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and mix the gas-enriched liquid with arterial blood to form gas-enriched blood; a plurality of fluid conduits fluidly coupled to the gas-enrichment system, a first of the plurality of fluid conduits configured for the flow of blood from the patient to the gas-enrichment system, and a second of the plurality of fluid conduits configured for the flow of the gas-enriched blood from the gas-enrichment system to the patient; a pump coupled to at least one of the plurality of fluid conduits, the pump configured to pump blood between the gas-enrichment system and the patient; a catheter coupled to one or more of the plurality of fluid conduits and configured to deliver the gas-enriched blood from the gas-enrichment system to the patient based on operation of the pump; a wire coupled to the catheter or separate probe, the wire configured to extend along the catheter or probe to the distal tip of the catheter or probe; a pressure sensor coupled to the wire at the distal tip of the catheter or probe, the pressure sensor configured to measure blood pressure in the patient's vascular system; and a controller communicatively coupled to the pressure sensor, the controller having a processor, memory, and associated circuitry, the processor comprising: determining a change in blood pressure in the vascular system of the patient based on the measured blood pressure; determining blood flow in the vascular system of the patient; estimating microvascular resistance in the patient's vasculature based on the ratio of the change in blood pressure and blood flow in the patient's vasculature; and generating an alert or control signal for controlling the amount of the gas-enriched blood delivered to the patient based on the microvascular resistance in the vasculature of the patient. configured to perform operations including: A system comprising:

13. The system of claim 12 , wherein estimating comprises estimating microvascular resistance in a localized or partial area of ​​the patient's vasculature.

14. The system of claim 12 , wherein the controlling step comprises titrating the amount of the gas-enriched blood delivered to the patient.

15. The system of claim 12 , wherein the controlling step comprises titrating the amount of the gas-enriched blood delivered to the patient.

16. 1. A system for controlling gas-enrichment therapy in a patient, the system comprising: a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and deliver the gas-enriched liquid to the patient's vascular system to form gas-enriched blood; at least one conduit fluidly coupled to the gas-enrichment system, the at least one conduit configured for flow of the gas-enriched liquid from the gas-enrichment system to the patient; a pump coupled to the at least one conduit, the pump configured to pump gas-enriched liquid from the gas-enrichment system to the patient; a wire configured to extend into the patient's vasculature and comprising at least one sensor configured to measure one or more physiological parameters indicative of microvascular resistance in the patient's vasculature; and a controller communicatively coupled to the at least one sensor, the controller having a processor, memory, and associated circuitry, wherein the processor: receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor; estimating the microvascular resistance in the vasculature of the patient based on the measured values; and generating an alert or control signal to titrate or control the gas-enriched liquid delivered to the patient based on the microvascular resistance in the vasculature of the patient. configured to perform operations including: wherein the at least one sensor comprises a pressure sensor, and the one or more physiological parameters comprise a pressure of blood in the patient's vasculature, the pressure of blood being indicative of microvascular resistance in the patient's vasculature.

17. The operation is determining a change in the microvascular resistance of the vasculature of the patient; and generating an alert or control signal to titrate or control the gas-enriched liquid delivered to the patient based on the determined change in microvascular resistance. The system of claim 16 further comprising:

18. 17. The system of claim 16, wherein the at least one sensor includes a flow sensor, the one or more physiological parameters include a flow rate of blood in the patient's vasculature, and the estimate of microvascular resistance in the patient's vasculature is based on the flow rate.

19. The operation is transmitting the control signal to the pump during operation of the pump for delivery of the gas-enriched liquid to the patient; and and causing the pump to increase or decrease a pumping speed based on the sending of the control signal to increase or decrease the amount of the gas-enriched liquid delivered to the patient. The system of claim 16 further comprising:

20. The method of controlling the amount of gas-enriched blood delivered to the patient comprises: determining that the change in the value of the one or more physiological parameters is indicative of decreased microvascular resistance in the vasculature of the patient; and generating the control signal configured to cause a decrease in the amount of the gas-enriched liquid delivered to the patient in response to determining that the change in the value is indicative of the decreased microvascular resistance.

17. The system of claim 16, comprising:

21. The step of controlling the amount of the gas-enriched liquid delivered to the patient comprises: determining that the change in the value of the one or more physiological parameters is indicative of increased microvascular resistance in the vasculature of the patient; and generating the control signal configured to cause an increase in the amount of the gas-enriched liquid delivered to the patient in response to determining that the change in the value represents the increased microvascular resistance.

17. The system of claim 16, comprising:

22. the at least one sensor includes a flow sensor and a pressure sensor, the one or more physiological parameters include a flow rate of blood in the vascular system of the patient and a blood pressure in the vascular system of the patient, and the operation includes: estimating a change in microvascular resistance in the patient based on the ratio of the blood pressure and the flow rate; and generating the control signal or alert based on the estimated microvascular resistance; The system of claim 16 further comprising:

23. 17. The system of claim 16, wherein the procedure for generating the control signal or alert is performed in real time or near real time during delivery of the gas-enriched liquid to the patient, the delivery of the gas-enriched liquid to the patient is not paused during measurement of the one or more physiological parameters, and the measurement of the one or more physiological parameters represents the patient's concurrent status regarding the delivery of the gas-enriched liquid to the patient.

24. 24. The system of claim 23, wherein real-time or near real-time includes processing, by the controller, the data received from the one or more sensors as soon as the data is available to the controller, and generating the control signal or alert based on the processing.

25. The step of receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor includes receiving a series of measured values ​​of the one or more physiological parameters from the at least one sensor, the series of measured values ​​corresponding to a period during delivery of the gas-enriched liquid to the patient, and the operations include: determining whether the value of the one or more physiological parameters is increasing or decreasing over time based on the series of measured values ​​corresponding to a period during the delivery; and generating the control signal or alert to increase or decrease the amount of the gas-enriched liquid delivered to the patient based on determining that the value of the one or more physiological parameters is increasing or decreasing over time; The system of claim 16 further comprising:

26. The operation is receiving, from an imaging device in communication with the controller, angiographic data representative of the patient for a period concurrent with delivery of the gas-enriched liquid to the patient; determining an index of microcirculatory resistance (IMR) value from the angiographic data; and generating the control signal or alert to increase or decrease the amount of the gas-enriched liquid delivered to the patient based on the angiographic data and the determined IMR value or change in IMR value. The system of claim 16 further comprising:

27. 1. A system for controlling gas-enrichment therapy in a patient, the system comprising: a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and mix the gas-enriched liquid with blood to form gas-enriched blood; a plurality of fluid conduits fluidly coupled to the gas-enrichment system, a first of the plurality of fluid conduits configured for flow of the blood from the patient to the gas-enrichment system, and a second of the plurality of fluid conduits configured for flow of the gas-enriched blood from the gas-enrichment system to the patient; a pump coupled to at least one of the plurality of fluid conduits, the pump configured to pump blood between the gas-enrichment system and the patient; and at least one sensor configured to measure one or more physiological parameters in the patient's vasculature; and one or more controllers having a processor, memory, and associated circuitry, wherein the one or more controllers: receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor; receiving imaging data representative of the vasculature of the patient; estimating microvascular resistance in the patient's vasculature based on the imaging data and the measured values ​​of the one or more physiological parameters; and generating an alert or control signal for controlling the amount of the gas-enriched blood delivered to the patient based on the estimated microvascular resistance in the patient's vasculature. configured to perform operations including: A system comprising:

28. 1. A system for controlling gas-enrichment therapy in a patient, the system comprising: a gas-enrichment system configured to enrich a liquid with a gas to form a gas-enriched liquid and deliver the gas-enriched liquid to the patient's vascular system to form gas-enriched blood; at least one conduit fluidly coupled to the gas-enrichment system, the at least one conduit configured for flow of the gas-enriched liquid from the gas-enrichment system to the patient; a pump coupled to the at least one conduit, the pump configured to pump gas-enriched liquid from the gas-enrichment system to the patient; at least one sensor configured to measure one or more physiological parameters in the patient's vasculature; and a processor, one or more controllers having a memory, wherein the one or more controllers: receiving one or more signals corresponding to measured values ​​of the one or more physiological parameters from the at least one sensor; receiving imaging data representative of the vasculature of the patient; estimating microvascular resistance in the vasculature of the patient based on the imaging data and the one or more signals corresponding to measured values ​​of the one or more physiological parameters; and generating an alert or control signal to titrate or control the gas-enriched liquid delivered to the patient based on the microvascular resistance in the vasculature of the patient. configured to perform operations including: A system comprising:

29. 29. The system of claim 27 or 28, wherein the step of estimating microvascular resistance comprises determining an IMR value.

30. 29. The system of claim 27 or 28, wherein the imaging data is one or more angiographic images.

31. 29. The system of claim 27 or 28, wherein the sensor is a pressure sensor.

32. The operation is receiving the imaging data in the form of angiographic data representative of the patient, the angiographic data being generated after delivery of the gas-enriched blood to the patient; determining IMR from the angiographic data; and generating an alert or control signal configured to increase or decrease the amount of gas-enriched blood delivered to the patient based on the angiographic data and the determined IMR or change in IMR.

29. The system of claim 27 or 28, further comprising:

33. 29. The system of claim 27 or 28, wherein the at least one sensor is communicatively coupled to the one or more controllers and configured to measure one or more physiological parameters indicative of microvascular resistance in the patient's vasculature.

34. 29. The system of claim 27 or 28, wherein the at least one sensor is configured to transmit one or more signals corresponding to measured values ​​of the one or more physiological parameters.

35. 35. The system of claim 34, wherein the at least one or more signals corresponding to measured values ​​of the one or more physiological parameters correspond to pressure or flow values.

36. 29. The system of claim 27 or 28, wherein the control signal increases or decreases the amount of gas-enriched blood delivered to the patient without pausing delivery of the gas-enriched blood to the patient.

Images