Device and method to control blood flow and oxygen content in the body

Abstract

A circulatory device for maintenance of tissue oxygen levels in a subject includes a first conduit for fluid to flow into the device, a second conduit for fluid to flow out of the device. an oxygenator device, an oxygenator control unit, at least one fluid flow sensor, a flow control unit which provides input to the flow control element, and a flow control element configured to accept a variable input to modify the rate of fluid flow into and out of the device, and at least one tissue oxygen sensor. The device is affixed removably to the body of an individual.

Description

2102463-0005451DEVICE AND METHOD TO CONTROL BLOOD FLOW AND OXYGEN CONTENT IN THE BODYThis Application is related to and claims the benefit of priority of U.S. Provisional Application No. 63 / 685,011, entitled Device and Method to Control Blood Flow and Oxygen Content in the Body, filed on August 20, 2024, the contents of which are incorporated herein by reference in their entirety for all purposes.BACKGROUNDField

[0001] Embodiments relate to a device, method and a system to control blood flow and oxygen content in the body, and particularly to non-invasive cerebral monitoring and cerebral metric-based guidance for medical purposes.Background

[0002] Currently in the field there is a critical need for brain-directed management of blood flow and oxygen content in the blood flow of a subject in need thereof. Typically, measurement of certain vital sign parameters— including, e.g ., blood pressure, pulse rate, blood oxygen saturation, and respiratory rate— is a basic requirement in determining the health of a subject. These measurements are vital in situations requiring cardiopulmonary resuscitation (CPR) and / or potentially extracorporeal life support (ECLS).

[0003] Cardiac arrest, or the abrupt loss of heart function, is one of the leading causes of death in the United States, having nearly 535,000 incidents annually and accounting for about 20% of all deaths annually. While many patients do not initially survive the event, there are a number of mechanisms and procedures currently in place to increase the chances of survival and hospital discharge without long-term effects. For example, patient blood flow and oxygen content may be assisted by an extracorporeal membrane oxygenation, or ECMO, which is an artificial heart-lung machine.

[0004] ECMO machines are a life support "bridge" therapy, and are used in 5-27% of in-hospital cardiac arrest. Currently, ECMO is shown to improve survival and neurological outcomes as opposed to conventional CPR. Despite an approximately lOx increase in pediatric ECMO-assisted cardiopulmonary resuscitation (ECPR), hospital survival rates are relatively stagnant. One contributing factor is that, currently, there is no optimal way to guide or control ECLS or the effectiveness of ECMO in patients who are suffering from, or recovering from, a cardiac event.2102463-0005452

[0005] Therefore, there exists a need to reduce or eliminate neurologic impairment resulting from cardiac arrest via a novel brain-directed management of venoarterial extracorporeal oxygenation based on real-time feedback from non-invasive diffuse optical neuromonitoring.SUMMARY OF THE INVENTION

[0006] In one embodiment, this disclosure provides a circulatory device for maintenance of oxygen levels. The device includes a plurality of conduits for fluid flow into and out of the device. The device also includes an oxygenator device which may work in connection with an oxygenator control unit. Additionally is at least one fluid flow sensor which may provide input to a flow control unit, which thereafter may provie input to a flow control element. The flow control element may accept a variable input to modify the rate of fluid flow into and out of the device. The device may additionally include at least one tissue oxygen sensor.

[0007] In another embodiment, a device to control tissue oxygen content is disclosed. The device includes elements of the circulatory device recited above and may additionally include a user interface to display data parameter values, a means for storing said data and a processor. The user interface may accept input for desired tissue oxygen values, fluid sources, and / or oxygen sources and may input said data to alter a processor algorithm. The data storage device may work with the device to receive input values, measurement data, and / or input data. The storage device may also store values of inputs, tissue oxygen sensor measurements, desired tissue oxygen values, fluid sources, and oxygen sources.

[0008] Additionally provided by this disclosure is a method of maintaining tissue oxygen values in a subject in need thereof. In one embodiment, the method includes monitoring the physiological data of a subject with one or more devices, analyzing said data with a processor, assessing tissue oxygen values based on tissue oxygen measurements, and determining the effectiveness of a cardiopulmonary resuscitation procedure. The method may include displaying the tissue oxygen level of the subject on a user interface. The device used herein may have a plurality of conduits for fluid flow into and / or out of the device, an oxygenator device, an oxygen control unit, a plurality of fluid flow sensors, a flow control unit and a flow control element. The device may be removably and non-permanently attached to an individual in need of monitoring. The method may use a combination of oxygen flow rate and vasoactive medication titration to achieve desired results.

[0009] The disclosure herein additionally provides for a system. The system includes a circulatory device, a flow control unit, a device to measure tissue blood flow values, a2102463-0005453 data storage device which may save physiological data, and a processor in communication with the devices and / or sensors. The processor may assess effectiveness of treatment by comparing values of tissue blood flow sensors, desired tissue blood flow value, and values of inputs to flow control elements. The processor may then determine whether input values to flow control elements should be maintained or altered by interfacing with the flow control unit to alter necessary inputs.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Other features and advantages of the processes and compositions disclosed herein will be apparent to those skilled in the art reading the following detailed description in conjugation with the exemplary embodiments illustrated in the drawings, wherein:

[0011] FIG. 1 shows a graphic of the general system according to an embodiment of the invention;

[0012] FIG. 2 shows a schematic of the input flow to the processor and the outputs available according to aspects of the present invention; and

[0013] FIG. 3 shows a more detailed schematic of the input flow to the processor and the decision process used in the algorithm according to aspects of the present invention.

[0014] FIG. 4 shows results of tissue oxygenation monitoring of Oxygen Extraction Fraction (OEF) values measured in the brain in swine that underwent a model of cardiac arrest and ECMO-assisted cardiopulmonary resuscitation. At 1 hour into ECMO support, animals began brain-directed treatment to maintain OEF at a desired OEF targets of 0.6, 0.7, or 0.8. The measured OEF as a function of hours of ECMO support are summarized across animals that were designated to a desired OEF target of 0.6 (blue), 0.7 (green) or 0.8 (orange). The median of the target group is represented by bold lines, with the interquartile ranges shaded;

[0015] FIG. 5 shows results of tissue oxygenation monitoring of OEF levels in swine that underwent a model of cardiac arrest and ECMO-assisted cardiopulmonary resuscitation in a non-brain directed management trial, where OEF values vary widely during ECMO treatment;

[0016] FIG. 6 shows a series of graphs illustrating the linear correlation of mean ECMO values versus brain health outcome, measured as the respiratory control ratio of the convergent maximal oxidative phosphorylation through Complex I and II in cortical mitochondria (Cortical OXPHOSci+cn). Tissue oxygenation monitoring of OEF in the brain is significantly associated with brain health, but standard clinical parameters which are used to manage ECMO (e.g., ECMO Flow Rate, Mean Arterial pressure) are not significantly associated;2102463-0005454

[0017] FIG. 7A shows fibrinogen staining in the cortex of an animal that underwent ECMO; and

[0018] FIG. 7B shows the percentage of animals that had extravascular fibrinogen present in certain brain regions following a model of cardiac arrest and ECMO-assisted cardiopulmonary resuscitation.DESCRIPTION

[0019] The following description is of exemplary embodiments and methods of use that are presently contemplated for carrying out the present invention. This description is not to be taken in a limiting sense, but is made merely for the purpose of describing the general principles and features of various aspects of the present invention. The scope of the present invention is not limited by this description.

[0020] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. Specific methods, devices, and materials are described, although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention.

[0021] As used herein, "oxygen extraction fraction" (OEF) relates to a measure of how efficiently tissue uses oxygen from blood flow to maintain its function and structure. The OEF value is calculated by comparing the difference in oxygen concentration between arterial and venous blood. It can be used to assess the balance between oxygen delivery and consumption, and can provide indication of cell stress or death. OEF may be measured using, e.g., near-infrared spectroscopy (NIRS), positron emission tomography (PET) or magnetic resonance imaging (MRI).

[0022] Multiple embodiments of a circulatory device and accompanying methods which provide the ability to control blood flow, or to control oxygen in an individual using physiologic measurements are provided herein. The measurements may include parameters regarding one or both of blood flow or oxygen in the body. The device may use sensors such as optical sensors on the brain or on the body to inform alterations to the device flow rate, hemodilution, medication delivery, and oxygen delivery. Additional sensors for measuring other physiologic characteristics may also be used with the disclosed embodiments as would be appreciated by one of ordinary skill in the art. Likewise, it is further contemplated that the inventive circulatory device and methods for using thereof may be used in connection with other monitoring and / or imaging devices such as electrocardiograms, ultrasound, etc.

[0023] In one preferred embodiment, the circulatory device may be removably or non- permanently attached to a body. The body may be of a human or animal.2102463-0005455

[0024] The device may contain a conduit for fluild flow into the device. The fluid flow may originate from a body or an external fluid source. Fluid originating from the body may be venous blood, and external fluid may be from a bag of crystalloid, donor blood, or of fluid medications.

[0025] The device additionally may contain a conduit for fluid flow out of the device. The fluid would necessarily then flow from the device to an external source, such as the body of the human or animal.

[0026] In some embodiments, the device contains a flow control element. The flow control element may be a peristaltic pump or centrifugal pump, which is capable of accepting a variable input to modify the fluid flow rate into the device. Alternatively or additionally, the device may contain a flow control element such as a peristaltic pump or centrifugal pump which is capable of accepting a variable input to modify the rate of fluid flow into the body.

[0027] In other preferred embodiments, the device contains a flow control unit. The flow control unit may interface with the circulatory device to provide a single or a plurality of inputs to the flow control elements. The input may be mechanical force or electrical potnetials. The flow control unit input may increase or decrease the rate of fluid flow into the circulatory device, and / or may increase or decrease the rate of fluid from to the body from the circulatory device.

[0028] The flow control components may include a tissue blood flow sensor, which provides measurement of body parameters. The measurement rate may be rapid, and may occur at a rate greater than 0.0016Hz. The measurement of, for example tissue oxygenation or blood volume, may be correlated with blood flow in the tissue of a body (such as the brain or the leg) whereby an increase in the parameter value reflects an increase in blood flow, and a decrease in the parameter value reflects a decrease in blood flow. The parameter value may alternatively be a linear transform of the parameter value, such as negation. The tissue blood flow sensor may provide measurements at a single or at multiple locations on the body, and measurements may be taken and provided simultaneously.

[0029] In certain embodiments, the device to control body blood flow may have a user interface, a data storage means, and a decision making unit or processor.

[0030] The user interface of the device to control body blood flow may display current tissue blood flow measurement values as single or multiple values depending upon the number of measurement locations on the body. The user interface may accept input for desired tissue blood flow values, where the input may be a mechanical dial or a number keypad entry. It may also or alternatively accept a single input or multiple input for2102463-0005456 multiple body locations corresponding to where the blood flor measurements are being acquired from the body.

[0031] The user interface may accept inputs which identify the fluid source of the circulatory device. These inputs may include molecular composition, concentrations, or available volume. The user interface may also or alternatively accept input to select or alter the algorithm used for the decision-making unit, or processor. This input may be, for example, PID loop parameters.

[0032] In other embodiments, the circulatory device contains a data storage medium. One of ordinary skill in the art will understand that data storage may be accomplished through any number of internal and / or external medium including, for example one or more of memory (e.g., random-access memory, read-only memory, or any other suitable memory), hard drives, solid state drives, optical drives, any other suitable fixed or removable storage devices (e.g., DVD recorder, CD recorder, or other suitable recording device), or cloud-based storage. The data storage medium may be local or remote to the circulatory device. The data storage medium may interface with the flow control device to receive input values for controlling flow elements, interface with the tissue blood flow sensor to receive parameter measurement data, interface with the user interface to receive inputted data, store current and / or previous values of inputs to flow control elements, store current and / or previous values of the tissue blood flow sensor measurement parameters, store the desired tissue bloow flow values, and / or store available information regarding fluid sources of the circulatory device.

[0033] In some embodiments, the circulatory device additionally may have a decisionmaking unit, or processor 120. Processor 120 may intake current and previous values of the tissue blood flow sensors, the desired tissue blood flow value, and / or current or previous values of inputs to flow control elements 110. Processor 120 may then use a computational algorithm 100 which determines if current input values 115 to the flow control elements should be maintained or altered to achieve a desired tissue blood flow value. The processor may interface with flow control components via processor outputs 125 to alter necessary inputs to flow control elements 130 or 140 to modify tissue blood flow as dictated by the algorithm 100, as shown in at least FIGS. 2 and 3.

[0034] Described in more detail in FIG. 3, algorithm 100 achieves optimal oxygen extraction fraction (OEF) targets during neurometabolic optical monitoring (NOM)-guided E-CFR. A pump flow range of between 60 - 120ml / min / kg was utilized, with a mean arterial pressure (MAP) range of 45-100mmHg and Het of 30-35. Need for additional OEF intervention may be assessed at regular or irregular time intervals, including, e.g., every 5 minutes.2102463-0005457

[0035] Similar to the description of algorithm 100 in FIG. 2, tissue blood flow values, which may include current and previous values of the tissue blood flow sensors, the desired tissue blood flow value, and / or current or previous values to flow control elements 110, are received by processor 120. Processor 120 then determines whether the desired tissue blood flow values 110 have been met based on predetermined or user input values 150. In accordance with, algorithm 100, processor 120 may direct drug administration 160 and / or modifying pump flow 170.MEANS OF INCREASING OEF

[0036] Algorithm 100 may increase OEF by reducing pump flow (e.g., by 10ml / min / kg for 60 min). If MAP is less than a predetermined value (e.g., less than 45 mmHg), medication may be administered as well. The medication may be epinephrine administered at therapeutically effective increments of, e.g., 0.1, 0.2, 0.5, 1, and 2 mcg / kg / min.

[0037] One of ordinary skill in the art will appreciate that there are various ways to increase OEF by undertaking of clinical interventions. Reducing rate of fluid flow to the brain, thus increasing OEF, can be accomplished by known methods such as compression or dissection of a vessel which delivers blood to the brain, or diversion of blood flow from the brain by, for example, adding additional routes that aid in diverting a portion of the blood that travels to the brain. Another method is to reduce oxygen content of blood by 1) reducing the volume of blood; 2) reducing the oxygen carrying capacity of blood by, for example, reducing the concentration of red blood cells; or 3) reducing the exposure of blood to oxygen. Lastly, it is possible to increase OEF by increasing the metabolic demand of the brain. This can be accomplished by increasing tissue temperature, stimulating brain activity, or decreasing sedation in the individual.MEANS OF DECREASING OEF

[0038] Algorithm 100 may decrease OEF through one or more of several avenues. For example, OEF may be decreased by increasing pump flow (e,g, pump flow may be increased by lOml / min / kg for 120min). If MAP is greater than 100, medication may be administered. In one embodiment, the medication may be nicardipine administered at increments of 0.5 mcg / kg / min or nitroglycerin administered at increments of 5 mcg / kg / min.

[0039] Algorithm 100 may decrease OEF by increasing FiO2. In certain embodiments, the rate of FiO2 may be downtitrated if the SvO2 parameter is less than a predetermined value (e.g., 60%).

[0040] Algorithm 100 may decrease OEF by increasing MAP. For example, if MAP is less than 100 and no vasodilators have been administered, MAP may be increased2102463-0005458 through the administration of known medicaments (e.g., epinephrine at 0.1- 0.5mc / kg / min or phenyl at O.lmg / kg / min).

[0041] Algorithm 100 may decrease OEF by administering nitroglycerin at 5mcg / kg / min if MAP is greater than 60 and no vasopressors are administered.

[0042] In other embodiments, the circulatory device also contemplates an oxygenator device. The oxygenator device interfaces with the circulatory device and has a plurality of conduits. A first conduit may allow oxygen to enter the device and come into contact with the fluid of the circulatory device, which may flow into the fluid prior to entry into the body. The oxygenator may draw from a single or several oxygen sources, for example, dissolved oxygen in a fluid, or an oxygen gas canister, among others.

[0043] The oxygenator device may additionally have a rate control element which is capable of accepting a variable input to modify the rate that the fluid in the circulatory device is exposed to oxygen. The rate control element may be any suitable gas control means, such as a gas valve.

[0044] In another embodiment, the circulatory device may have an oxygen control unit which interfaces with the oxygenator device to provide one or multiple inputs ot the oxygen rate control elements. The inputs may be mechanical force or electrical potential. The oxygen control unit uses said inputs to increase or decrease the rate that fluid in the circulatory device is exposed to oxygen.

[0045] Additionally contemplated herein is a tissue oxygen sensor used with the circulatory device. The tissue oxygen sensor provides parameter measurements of the body at a rapid rate. The measurements may occur, for example, at a rate faster than 0.0016 Hz. The measurement may be of tissue blood flow or blood volume, for example, and is then correlated with oxygen content in the body's tissue where said measurement was obtained (for example, the brain or the leg). An increase in the parameter value reflects an increase in tissue oxygen content, and a decrease in the parameter value reflects a decrease in tissue oxygen content.

[0046] In further embodiments, the circulatory device may include a device to control tissue oxygen content in the body, which includes a user interface, data storage device, and a decision making unit / processor.

[0047] The user interface of the device to control body blood flow may display current tissue blood flow measurement values as single or multiple values depending upon the number of measurement locations on the body. The user interface may accept input for desired tissue blood flow values, where the input may be a mechanical dial or a number keypad entry. It may also or alternatively accept a single input or multiple input for2102463-0005459 multiple body locations corresponding to where the blood flor measurements are being acquired from the body.

[0048] The user interface may accept inputs which identify the fluid source of the circulatory device. These inputs may include molecular composition, concentrations, or available volume. The user interface may also or alternatively accept input to select or alter the algorithm used for the decision-making unit, or processor. This input may be, for example, PID loop parameters.

[0049] The data storage medium may interface with the flow control device to receive input values for controlling flow elements, interface with the tissue blood flow sensor to receive parameter measurement data, interface with the user interface to receive inputted data, store current and / or previous values of inputs to flow control elements, store current and / or previous values of the tissue blood flow sensor measurement parameters, store the desired tissue bloow flow values, and / or store available information regarding fluid sources of the circulatory device. Data may be stored on any type of recording medium, such as physical material that holds information, or other data storage devices such as RAM, solid state drives, hard drives, disk storage, external storage, among others.

[0050] The decision making unit (e.g., processor) may receive as inputs current and previous values of the tissue blood flow sensors, the desired tissue blood flow value, and / or current or previous values of inputs to flow control elements. The processor may then use a computational algorithm which determines if current input values to the flow control elements should be maintained or altered to achieve a desired tissue blood flow value. The processor may interface with flow control components to alter necessary inputs to flow control elemnts to modify tissue blood flow as dictated by the algorithm.

[0051] In further embodiments, the disclosure relates to a method to determine the appropriate fluid flow rate changes of circulatory device to achieve desired blood flow rates in the body based on tissue blood flow measurements from the body location.

[0052] The method includes monitoring the physiological data of a subject with one or more devices, analyzing said data with a processor, assessing tissue oxygen values based on the tissue oxygen measurements and displaying the tissue oxygen level of the subjet on a user interface. The device may include a plurality of conduits for fluid flow into / out of the device, an oxygenator unit, an oxygen control unit, at least one fluid flow sensor, a flow control unit and a flow control element. The device may be removably attached to the body of an individual.

[0053] The method may include analyzing the physiological data to determine appropriate fluid flow rate within the device to achieve a desired tissue oxygen value in2102463-00054510 a subject. The desired fluid flow rate may be achieved from measurements of the fluid flow sensor as explained above.

[0054] The desired fluid flow rate may be iteratively modified to achieve a desired tissue oxygen value based on tissue oxygen measurements. The physiological data may then be analyzed using the algorithm, which may be the algorithm described above, to determine the appropriate fluid flow rate and oxygenator device exposure rate within at least one device to achieve a desired tissue oxygen value in the subject.

[0055] The method may additionally include modifying the desired fluid flow rate in an iterative manner to achieve the desired tissue oxygen value based on tissue oxygen measurements.

[0056] In other embodiments, the disclosure relates to a method for determining the appropriate fluid flow rate changes of the circulatory device and oxygen exposure rate of the oxygenator to achieve a desired tissue oxygen content on the body based on tissue oxygen measurements from the corresponding body location.

[0057] This disclosure also relates to a system 200 comprising a circulatory device 220, flow control unit, a device to measure tissue blood flow values, a data storage device which may communicate with said measurement devices and / or sensors to obtain physiological data, and a processor with or without a user interface 210 which communicates with said measurement devices, sensors, and / or storage devices to analyze physiological data and assess effectiveness of treatment by comparing current and previous values of the parameters obtained from sensors to make a determination of current input values and to alter necessary inputs to flow control elements for modification of tissue blood flow. As seen in FIG. 1, the system utilizes data detected from a body using an E-CPR or ECMO machine, allowing the data to be viewed on a user interface 210, and implements interventions based upon user inputs and a predetermined algorithm 100 to maintain preferred tissue blood oxygen levels.

[0058] EXAMPLES

[0059] Presented is a demonstration according to aspects of the present invention of brain-directed management of veno-arterial extracorporeal membrane oxygenation (VA- ECMO) based on real-time feedback from non-invasive neurometabolic optical monitoring (NOM). VA-ECMO provides life-sustaining oxygenation and circulatory support. It is known that the brain is vulnerable to hypoxic-ischemic injury if oxygen delivery to the brain is insufficient to meet metabolic demands. NOM enables continuous quantification of cerebral blood flow, oxygen extraction fraction (OEF), and oxygen metabolism within a compact non-invasive forehead sensor. Elevated cerebral OEF > 0.85 has been associated with ischemic injury. Maintaining cerebral OEF below this threshold holds2102463-00054511 promise to prevent injury. The feasibility of achieving and maintaining cerebral OEF levels of 0.8, 0.7, and 0.6 during VA-ECMO support was assessed following prolonged cardiac arrest in swine.

[0060] Continuous optical monitoring of cerebral OEF was performed in a swine model of ECMO-assisted cardiopulmonary resuscitation (CPR). Following 8 minutes of untreated ventricular fibrillation, animals underwent 30 minutes of low-flow ECMO (20 ml / kg / min) with administration of epinephrine (0.02 mg / kg) boluses every four minutes to simulate prolonged CPR. Subsequently, the ECMO flow rate was increased to 70-100 ml / kg / min to reflect clinical initiation of VA-ECMO. After 1 hour of full-flow ECMO, animals were randomized to a cerebral OEF target of 0.8 (n = ll), 0.7 (n = 12), or 0.6 (n=12) and brain- directed management was performed for 7 hours. Cerebral OEF was re-assessed every 5 minutes and ECMO flow was adjusted between 50-120 ml / kg / min to meet the individual subject's cerebral physiology. If the target was not achieved (±0.05 of target) with ECMO flow, vasoactive infusions were administered. Blood gas, electrolyte, and hematocrit levels, anticoagulation, and anesthesia were otherwise standardized across all subjects.

[0061] As shown in FIG. 1, 71% (n=25 / 35) of animals achieved their cerebral OEF target within 1 hour of initiating brain-directed ECMO management according to the present invention. Targets were maintained for 79% [57, 93] of the 7-hour period (median [IQR] across animals).

[0062] FIG. 2 shows trial results of OEF levels measured during ECMO procedure without extra use of brain-directed management. The graph shows that the OEF levels vary widely.

[0063] FIG.3 shows specific results of mean ECMO values versus brain health outcomes. The first chart shows optical measurements of OEF during brain-directed OEF ECMO management, where higher cortical OXPHOS respiratory control ratios are indicative of increased brain health. NOM monitoring of OEF in the brain is significantly associated with brain health, but standard clinical parameters which are used to manage ECMO (e.g., ECMO Flow Rate, Mean Arterial pressure) are not significantly associated.

[0064] The results demonstrate precision of real-time optimization of oxygen delivery to the brain based on NOM feedback for an individual. This represents a shift in VA-ECMO management and presents new opportunities for early intervention to prevent neurological injury.

[0065] The results in the swine models shown in FIGS. 1-3 were determinative of positive neurological outcomes for NOM guided OEF target monitoring. These values were used to determine appropriate upper and lower values within the algorithm to create a circulatory device, method, and system which can react and measure tissue blood flow2102463-000545- 12 - values and moderate response to maintain the most desirable OEF values as discovered herein.

[0066] FIG. 7A shows an image of fibrinogen staining in the cortex of an animal that underwent ECMO. In normal healthy brain, fibrinogen is constrained within the lumen of blood vessels (designated in the image with a "V"). Extravascular fibrinogen is a highly specific indication of blood-brain barrier breakdown, a form of neurological injury, which can be observed in two vessels imaged.

[0067] FIG. 7B shows the percentage of animals that had extravascular fibrinogen present in the cortex, hippocampus, and thalamus, as summarized for four experimental groups of animals that underwent a model of cardiac arrest and ECMO-assisted cardiopulmonary resuscitation and were supported on ECMO for eight hours prior to fibrinogen analysis. The experimental groups include standard-of-care (SOC) bloodpressure directed ECMO management or brain-directed ECMO management targeting an OEF of 0.6, 0.7 or 0.8. The presence of blood-brain barrier breakdown in the cortex decreases with decreasing OEF target. The OEF 0.8 group demonstrates the least injury overall providing another indication that brain physiology and brain injury can be modulated by altering OEF.

Claims

2102463-00054513What is Claimed :

1. A circulatory device for maintenance of tissue oxygen levels in a subject in need thereof, comprising a first conduit for fluid to flow into the device; a second conduit for fluid to flow out of the device; an oxygenator device; an oxygenator control unit; at least one fluid flow sensor; a flow control unit which provides input to the flow control element; and a flow control element, wherein the flow control element accepts a variable input to modify the rate of fluid flow into and out of the device; an at least one tissue oxygen sensor; wherein the device is attached to the body of an individual.

2. The device of claim 1, wherein the device is configured to maintain predetermined tissue oxygen levels.

3. The device of claim 1, wherein the predetermined tissue oxygen levels comprise oxygen extraction fraction (OEF) levels in the range of 0.6 to 0.8.

4. The device of claim 1, wherein the fluid may comprise venous blood, a bag of crystalloid, donor blood, or intravenous medications.

5. The device of claim 1, wherein the flow control element comprises a peristaltic pump or a centrifugal pump.

6. The device of claim 5, wherein the flow control element modifies the rate of fluid flow into the device via variable inputs.

7. The device of claim 1, wherein the input provided by flow control unit is mechanical or electrical and increases or decreases the rate of fluid flow into or out of the device.

8. The flow control element of claim 1, wherein the tissue fluid flow sensor is configured to provide rapid measurements of fluid parameters, whereby an increase in said parameter value reflects an increase in fluid flow, and a decrease in parameter value reflects a decrease in fluid flow.

9. The device of claim 1, further comprising a user interface, wherein the user interface is configured to: display a plurality of fluid measurement values; accept input for desired fluid flow values; accept input regarding fluid source; accept inputs to alter decision-making unit of a processor.

10. The device of claim 9, further comprising a data storage element to:2102463-00054514 interface with said flow control unit; interface with said fluid flow sensor to receive measurement data; interfaces with said user interface to receive input data; store values of inputs to flow control elements and fluid flow sensors; stores desired fluid flow values; and stores information regarding fluid sources of the device.

11. The device of claim 1, further comprising a processor wherein said processor: receives physiological data from said sensors and units; analyzes said data with a predetermined algorithm to determine whether to maintain or alter current input values; and interfaces with the flow control unit and flow control elements to alter said inputs as dictated by the algorithm.

12. The device of claim 1, wherein the oxygenator device comprises: a conduit for oxygen to enter; an interface for oxygen to contact the fluid; and, a rate control element.

13. The device of claim 12, wherein the rate control element comprises a mechanical or electrical means such as a gas valve.

14. A device to control tissue oxygen comprising the elements of claim 1, and further comprising : a user interface which displays current tissue oxygen measurement values; a means for data storage; and a processor; wherein the user interface accepts inputs for desired tissue oxygen values, fluid sources, oxygen source, and inputs to alter a processor algorithm; wherein the data storage interfaces with the device to receive input values, measurement data, and / or input data; wherein the data storage device stores values of inputs, tissue oxygen sensor measurements, desired tissue oxygen values, fluid sources, and oxygen sources.

15. A method of maintaining tissue oxygen values in a subject in need thereof, the method comprising: monitoring, with one or more devices, physiological data of a subject; analyzing the physiological data with a processor; assessing tissue oxygen values based on tissue oxygen measurements to determine effectiveness of a cardiopulmonary resuscitation procedure; and,2102463-00054515 displaying on a user interface the tissue oxygen level of the subject; wherein an at least one device comprises: a first conduit for fluid to flow into the device; a second conduit for fluid to flow out of the device; an oxygenator device; an oxygen control unit; at least one fluid flow sensor; a flow control unit which provides input to the flow control element; and a flow control element, wherein the flow control element accepts a variable input to modify the rate of fluid flow into and out of the device; wherein the device is attached to the body of an individual.

16. The method of claim 15, wherein the physiological data is analyzed to determine appropriate fluid flow rate within the at least one device to achieve the desired tissue oxygen value in the subject.

17. The method of claim 16, wherein the desired fluid flow rate is achieved from measurements by the fluid flow sensor.

18. The method of claim 17, wherein the desired fluid flow rate is iteratively modified to achieve the desired tissue oxygen value based on tissue oxygen measurements.

19. The method of claim 15, wherein the physiological data is analyzed to determine appropriate fluid flow rate and oxygenator device exposure rate within the at least one device to achieve the desired tissue oxygen value in the subject.

20. The method of claim 19, wherein the desired fluid flow rate is achieved from measurements from the fluid flow sensor.

21. The method of claim 20, wherein the desired fluid flow rate is iteratively modified to achieve the desired tissue oxygen value based on tissue oxygen measurements.

22. The method of claim 19, wherein the oxygenator device exposure rate is iteratively modified to achieve the desired tissue oxygen value based on tissue oxygen measurements.

23. A system comprising : a circulatory device; a flow control unit; a device to measure tissue blood flow values; a data storage device in communication with said devices and / or sensors to obtain physiological data; and,2102463-00054516 a processor in communication with said devices and / or sensors to analyze the physiological data, assess effectiveness by comparing current and previous values of the tissue blood flow sensors, the desired tissue blood flow value, and current and previous values of inputs to flow control elements to then determine whether current input values to flow control elements should be maintained or altered; wherein the processor interfaces with the flow control unit to alter necessary inputs to flow control elements to modify tissue blood flow.

24. The system of claim 23, additionally comprising : an oxygenator device; an oxygenator control unit; a processor in communication with said devices and / or sensors to analyze the physiological data, assess effectiveness by comparing current and previous values of the tissue blood flow sensors, the desired tissue blood flow value, and current and previous values of inputs to flow control elements and oxygenator control elements to then determine whether current input values to flow control elements and oxygenator control elements should be maintained or altered; wherein the processor interfaces with the flow control unit and oxygenator control unit to alter necessary inputs to flow control elements and oxygenator control elements to modify tissue blood flow.

25. A system comprising : a circulatory device; a flow control unit; a device to measure tissue oxygen values; a data storage device in communication with said devices and / or sensors to obtain physiological data; and, a processor in communication with said devices and / or sensors to analyze the physiological data, assess effectiveness by comparing current and previous values of the tissue oxygen sensors, the desired tissue oxygen value, and current and previous values of inputs to flow control elements to then determine whether current input values to flow control elements should be maintained or altered; wherein the processor interfaces with the flow control unit to alter necessary inputs to flow control elements to modify tissue oxygen values.

26. The system of claim 25, additionally comprising : an oxygenator device; an oxygenator control unit; a processor in communication with said devices and / or sensors to analyze the physiological data, assess effectiveness by comparing current and previous values of2102463-000545- 17 - the tissue oxygen sensors, the desired tissue oxygen value, and current and previous values of inputs to flow control elements and oxygenator control elements to then determine whether current input values to flow control elements and oxygenator control elements should be maintained or altered; wherein the processor interfaces with the flow control unit and oxygenator control unit to alter necessary inputs to flow control elements and oxygenator control elements to modify tissue oxygen.

Images