Perfusion systems and methods for controlling tissue oxygenation at select vascular pressures

Abstract

Perfusion systems and methods are provided for enhancing perfusion to the vasculature of a patient suffering from reduced blood flow. For example, the system can increase peripheral blood flow to reduce limb ischemia, in which an extracorporeal pump having a controller, and catheter / tubing set, employed alone or in conjunction with an interventional or circulatory assist device, withdraws blood from a patient's vasculature and reintroduces that blood at another location within the patient's vasculature at a controlled local pressure or flow rate, without interfering with operation of the interventional or circulatory assist device or surgical intervention.

Description

225914-021001PERFUSION SYSTEMS AND METHODS FOR CONTROLLING TISSUE OXYGENATION AT SELECT VASCULAR PRESSURESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Appl. No. 63 / 738,936, filed December 26, 2024, U.S. Provisional Patent Appl. No. 63 / 682,275, filed August 12, 2024, and to EP Patent Appl. No. 24306347.6, filed August 9, 2024, the entire contents of each of which are incorporated herein by reference.TECHNICAL FIELD

[0002] The present technology relates generally to systems and methods for monitoring tissue oxygenation and reducing ischemia by providing enhanced perfusion to a patient’s extremities. In particular, the inventive system and methods may be employed for the treatment of any condition that induces limb ischemia including thrombotic or thromboembolic vascular occlusion or during medical procedures that involve use of devices that impede vascular blood flow (e.g., heart or vascular surgery, coronary or cardiac catheterization, insertion of cardiac support devices and / or following treatment to address peripheral artery disease and / or surgeries or interventions requiring tourniquets) or other causes of acute limb ischemia, in patients with shock or trauma, or in patients with existing peripheral arterial disease.BACKGROUND

[0003] Decreased blood flow to and / or pressure within a patient’s extremities, e.g., legs and arms, may arise from any of a number of causes, resulting in an acute or chronic ischemia of the limbs. During an interventional procedure, such as a percutaneous cardiac intervention, such as stenting, cardiac valve repair, or coronary or cardiac catheterization, a catheter may be placed in a patient’s vasculature that obstructs flow in that vessel. Similarly, placement of a circulatory support device in a vessel, such as a percutaneous ventricular assist device (pVAD), intra-aortic- 1 -713664833v3225914-021001 balloon pump (IABP), or cannula for an extracorporeal membrane oxygenator system (ECMO) may occlude downstream flow in the vicinity of the entry point of the circulatory support device.

[0004] Decreased flow to the extremities also may arise due to cardiogenic shock, for example, caused by myocardial infarction, myocarditis, pulmonary embolism, venous occlusion, rupture of a heart valve or heart muscle, and many other disease states, many of which manifest as an inability of the patient’s heart to pump sufficient oxygenated blood to body organs. Reduced circulation due to cardiogenic shock may lead to chronic ischemia of the patient’s extremities, which in turn may require amputation. Reduced peripheral circulation also may result from existing peripheral artery disease, and as side effect of a peripheral vascular intervention.

[0005] In addition, limb ischemia may also occur with use of medical tourniquets, which are commonly used in conditions of vascular trauma or during operations such as knee surgery to reduce bleeding in the operative field. Tourniquets will reduce both arterial and venous blood flow and if used for a prolonged period of time may induce limb ischemia. In these cases, the technology may enable arterial and venous blood flow using two bypass circuits for each respectively, thereby preserving limb perfusion with tourniquet(s) in place.

[0006] One approach for increasing blood flow to the extremities in patients suffering from poor peripheral circulation due to obstruction caused by placement of an interventional device (e.g., catheter shaft or cannula) or circulatory assist device (pVAD or IABP) in an iliac, femoral or axillary artery is to use tubing to create an extracorporeal shunt from a location upstream of the obstruction to a cannula inserted at a remote location, downstream of the obstructions, in the patient’s arterial system. Cardiopulmonary bypass (CPB) systems are primarily used to provide intraoperative perfusion. During cardiac or pulmonary surgical procedures, a heart-lung bypass machine provides the necessary perfusion for a limited number of hours while the organs need to remain immobilized. These procedures may include coronary artery bypass grafting (CABG), heart valve surgery, heart surgery, heart transplant, aortic surgery, or lung transplant. Full-body perfusion systems rely on pumps, either peristaltic (e.g., roller pumps) or centrifugal, to create the necessary flow to sustain circulation. Combined with reservoirs, heat exchangers, oxygenators, filters, and various tubing and cannulae, these systems form a circuit to bypass the- 2 -713664833v3225914-021001 patient’s heart and lungs. To effectively circulate the blood for full-body CPB in adults, these machines pump blood in the range of 4-6 L / min. As the patient is weaned off bypass, the flow rate is reduced to as low as 1.5 L / min. To achieve the necessary flow rates with the volume of blood required, these systems are large, freestanding units developed to contain all the necessary components.

[0007] Current blood pumps are utilized for full-body perfusion but may also be used for regional perfusion. Regional perfusion differs from full-body CPB in that only a single organ or vessel bed requires bypass and perfusion, requiring flow of generally less than 1.5 L / min. Specifically, in procedures performed outside of the heart and lungs, complete bypass is not necessary and regional perfusion may be employed to better match arterial pressure localized to the procedure. For example, regional perfusion is currently employed in situations including left heart bypass (LHB), visceral flow bypass, and occlusion of lower extremities.

[0008] During thoracoabdominal aortic aneurysm repair (TAAA), perfusion to the distal organs must be temporarily stopped while the aneurysm is repaired. LHB is one of the most common surgical techniques for providing appropriate circulatory support to the distal organs (as well as reducing the afterload of the heart) to prevent fatal damage of these organs during this procedure. LHB involves the withdrawal of oxygenated blood from the left side of the circulation (e.g., left chambers of heart) and reinfusion to the distal circulation below the location of the aneurysm repair. An important safety concern during LHB is excessive bleeding at the site of cannula insertions. As blood is withdrawn from the heart, less blood is available for “upper body” perfusion (including the heart itself and the brain). As a result, small changes in pump flow rate can result in a meaningful change (both increases and decreases) in mean arterial pressure and in circulatory support. Management of this interaction is critical to protecting the various vital organs of the patient during LHB.

[0009] As described above, the typical CPB system has a very large footprint and thus a challenge to fit in the tight spaces of an invasive surgical procedure of this nature given all of the other systems also required to manage the patient and the procedure. Additionally, the CPB system is being utilized simply for providing flow (at far lower flow rates than is typical), so a lot of space is taken up unnecessarily given the various other functionalities (e.g., heating,- 3 -713664833v3225914-021001 cooling, oxygenation) are not required. Further, multiple pump and adjunctive systems (including CPB) may be needed / utilized for supporting perfusion to the heart and brain in addition to the distal organs and lower extremities, thereby creating a complex procedural environment. There is a clear clinical need to address these challenges to further support a safer LHB procedural environment as well as improve the safety and efficacy of the procedure itself.

[0010] In addition, one of the key risk factors of TAAA procedures (described above) is organ damage, with Acute Renal Failure (ARF) being the most significant. In order to address this risk, clinicians developed a technique of visceral flow bypass whereby flow from the CPB machine originates in the left atrium (like as described with LHB above), but then the flow is divided into a number of smaller tubes to selectively perfuse various regions of the body including the celiac trunk, superior mesenteric artery, and the renal arteries. During visceral flow bypass, there is a specific focus on the perfusion to the renal arteries / kidneys whereby flow is potentially warmed or cooled before reinfusion into various locations. Clinical efforts to focus on adequate perfusion pressure and volume during visceral flow bypass procedures have highlighted the ability to adequately support renal function to prevent ARF. The current approach creates a number of challenges which are similar to the LHB procedure described above such as bleeding site complication risk, real-time management of the flow / pressure relationship as it relates to circulatory support and organ perfusion, and the footprint and complexity of managing a CPB system in this environment. Therefore, there is a clear clinical need to address these issues to support a safer visceral perfusion procedure and overall operating environment.

[0011] Due to increased developments in recent years of trans-catheter tools to support various cardiovascular ailments (e.g., Trans-catheter Aortic Valve Repair, Trans-catheter Edge- to-Edge Repair, and Mechanical Circulatory Support), the use of large bore sheaths and catheters in these procedures can inadvertently occlude circulation to the lower extremities. In order to address these situations, techniques have been developed by clinicians for creating temporary bypass circuits to the lower limb of patients with these occlusive sheaths or catheters in their femoral artery. For example, with an external contralateral bypass circuit, a connection is made between the contralateral common femoral artery to provide perfusion to the superficial femoral artery, with an external ipsilateral bypass circuit, a connection is made between the large bore- 4 -713664833v3225914-021001 occlusive sheath to provide perfusion to the ipsilateral superficial femoral artery, and with an internal contralateral femoral to ipsilateral profundal femoris bypass circuit, a connection is made between the internal contralateral femoral artery to provide perfusion to the ipsilateral profundal femoris artery.

[0012] Despite these temporary bypass circuit techniques, there are still very high rates of acute limb ischemia during these procedures. Additionally, even in situations where an approach to support limb perfusion during a potentially occlusive procedure is pre-prescribed, such as in the ECLS-SHOCK trial, high rates (11%) of peripheral vascular complications were still reported. The increase in acute limb ischemia is correlated with increased rates of amputation and mortality. Regarding safety, there is currently no way to measure the amount of flow (or pressure) in these passive bypass circuits so the safety (e.g., air bubbles in lines, kinking of lines, clotting over time) are serious issues that are difficult to manage, particularly in a busy and crowded operating environment. Regarding effectiveness, there is no standardized approach to these passive bypass circuits leading clinicians to create their own circuits which can be ineffective in providing appropriate flow to the occluded area given the variability of flow and pressure over time and the inability to measure it in any way. Therefore, there is a strong clinical need for a standardized solution to supporting perfusion to the lower extremities during these procedures. Specifically, in terms of safety, there is a need for a system that could actively provide a consistent method of perfusion that allows for the real-time assessment of air detection, kinking, and clotting would be of critical importance, and in terms of effectiveness, there is a need for a system that would actively provide a standardized approach to perfusion that allows for the management of flow and pressure could address the limitations of the current techniques.

[0013] Accordingly, it would be desirable to provide a dedicated, low flow pump to better perfuse the region of interest in the body rather than splitting up the higher flow systems or relying on passive bypasses on their own. Full-body CPB systems provide higher flow rates (e.g., in the range of 4-6 L / min) than are necessary for regional perfusion and thus are not designed to operate consistently at the lower flow rates needed for regional perfusion. Too high a flow rate can lead to shear stress on blood components; whereas, too low a flow rate can result in inadequate tissue perfusion. Accordingly, balancing the flow rate is crucial to ensure optimal oxygenation and prevent adverse effects.- 5 -713664833v3225914-021001

[0014] Regarding regional perfusion, flow rate is even more important as individual organs and vessel beds are more susceptible to flow rate complications. For example, the kidneys function at a hemodynamic flow rate around 1 L / min and the liver at 0.8-1.2 L / min, 20%-50% lower than the usual flow rate of CPB machines. Flow in the lower extremities, particularly distal to the superficial femoral artery (SFA), is multiples lower than that (e.g., <100ml / min).

[0015] As described above, current CPB systems are quite large in size, requiring larger pumps to provide high rates of flow, including blood oxygenation systems, and utilizing blood reservoirs to allow for sufficient volume, thereby creating additional challenges in their utilization in the operating room when only a certain part of the body requires perfusion without all of the other features of these large systems. Other methods of providing regional perfusion through passive bypass techniques utilizing standard cannulation tools and techniques lack appropriate methods to ensure safety and effectiveness. U.S. Patent No. 9,782,279 to Kassab is one example of such a passive perfusion system. It has been observed, however, that such proposed solutions are ineffective in reducing limb ischemia, require ad hoc set up, and are associated with very high incidence of adverse outcomes, including prolonged hospital stay, limb amputation and increased mortality.

[0016] Further, quite apart from limb ischemia, medical complications may arise due to rapid and catastrophic blood accumulation in the pericardium that impede heart function, thereby reducing systemic circulation. One approach to reduce blood accumulation in the pericardium is to manually and repeatedly aspirate blood from the pericardium. This is done until the patient can be transported to an operating room, which can take between one and four hours.

[0017] In view of the foregoing, it would be desirable to provide systems and methods for monitoring tissue oxygenation and / or increasing blood pressure and flow to the extremities of a patient undergoing an interventional procedure or on a circulatory assist device, wherein an interventional device, circulatory assist device, tourniquet or other natural cause (i.e., thrombosis) creates an obstruction in any artery or vein (i.e., iliac, femoral, axillary, brachial artery or vein) and that overcomes the drawbacks of previously known solutions. In particular, it would be desirable to provide apparatus and methods for enhancing blood flow and maintaining blood pressure in the peripheral vasculature sufficiently to save the limb.- 6 -713664833v3225914-021001

[0018] It further would be desirable to provide apparatus and methods for enhancing peripheral blood flow that reduce blood stagnation, particularly adjacent to a catheter or cannula insertion site, thereby reducing the risk of thrombus formation.

[0019] It still further would be desirable to provide apparatus and methods for increasing peripheral blood flow in patients undergoing vascular interventions or other surgical procedures including the use of tourniquets, and patients recovering from peripheral vascular interventions, that are designed to reduce a risk of blood leakage at a device insertion site.

[0020] Additionally, there is a clinical need for a lower profile system focused on providing regional and arterial perfusion that provides the user a standardized approach with the necessary tools and information to ensure appropriate levels of safety and effectiveness of the procedure.SUMMARY

[0021] Embodiments of this technology are directed to exemplary systems and methods for monitoring tissue oxygenation, vascular or local pressure, and / or increasing peripheral blood flow and vascular pressure to reduce limb ischemia in patients with arterial or venous obstruction due to disease conditions or due to cardiac or vascular interventions, where the interventional device or tourniquet causes at least a partial obstruction of downstream blood flow. In accordance with one aspect, the inventive devices comprise an extracorporeal pump and cannula / tubing set that may be used alone or in conjunction with any procedure or device that obstructs blood flow, to withdraw oxygenated blood from a patient’s vasculature or anatomic compartment (i.e., pericardium) and to reintroduce that blood at another location within the patient’s vasculature at an independently controlled vasculature pressure or flow rate. In this manner, the blood flow rate or blood pressure may be independently controlled in the patient’s extremities, without interfering with placement or operation of an interventional device or circulatory assist device. In a preferred embodiment, the flow rate may be adjusted in order to achieve a target vessel pressure to increase oxygenation of the tissue in the limb(s) experiencing, or at risk of experiencing, ischemia. Output from a near-infrared spectroscopy (NIRS) sensor, or other oxygen-sensing device applied to the affected limb may also be utilized as an input into the present inventive device to regulate the perfusion flow or pressure. Inlet suction pressure may also be used as a determinant of bypass flow.- 7 -713664833v3225914-021001

[0022] In accordance with one aspect, a system for providing extracorporeal circulation of blood for perfusion of a target region of a patient to support circulation is provided. The system may comprise: an inlet cannula having an inlet configured to be coupled to a source of blood, and an outlet; a return cannula comprising a first lumen and a second lumen, the first lumen extending between a first inlet configured to be fluidically coupled to the outlet of the inlet cannula, and a first outlet configured to be placed in a target area of the patient’s vasculature, the second lumen extending between a second inlet configured to be operatively coupled to a pressure transducer, and a second outlet disposed within the return cannula adjacent to the first outlet, the second outlet configured to fluidically couple the first lumen and the second lumen; a pressure sensor configured to measure an outlet pressure within the first lumen at the second outlet, the outlet pressure indicative of a local blood pressure associated with the target area of the patient’s vasculature; and a controller operatively coupled to the pressure transducer. The controller may be configured to, in a local pressure control mode, cause blood received from the source of blood via the inlet of the inlet cannula to be delivered through the first outlet of the return cannula to perfuse the target area of the patient’s vasculature at a selected local pressure.

[0023] For example, the pressure sensor may comprise one or more strain gauges embedded within the second outlet of the return cannula. In addition, the return cannula may comprise an occlusion balloon disposed proximal to the first outlet of the return cannula, the occlusion balloon configured to be inflated to at least partially occlude blood flow within the patient’s vasculature to direct blood flow in an antegrade direction within the patient’s vasculature. The system further may comprise an extracorporeal pump operatively coupled to the controller, the extracorporeal pump fluidically coupled to the outlet of the inlet cannula and the first inlet of the return cannula. Accordingly, the controller may be configured to cause the extracorporeal pump to draw blood through the inlet of the inlet cannula and to deliver blood through the first outlet of the return cannula. For example, the controller may be configured to cause the extracorporeal pump to generate pulsatile flow. Additionally, or alternatively, the controller may be configured to cause the extracorporeal pump to operate at an unsteady RPM to generate consistent flow. Moreover, the controller may be configured to adjust a speed of rotation of one or more rotors of the extracorporeal pump within a revolution to generate the consistent flow. In addition, the controller may be configured to regulate a flow rate of the extracorporeal pump to maintain the selected local pressure.- 8 -713664833v3225914-021001

[0024] The controller further may be configured to cause the extracorporeal pump to transition between the local pressure control mode and a flow mode, and wherein, in the flow mode, the controller is configured to cause the extracorporeal pump to pump at a set flow rate to perfuse the target region of the patient. The extracorporeal pump may be selected from amongst a vane pump, a centrifugal pump, a roller pump, an axial flow pump, a diaphragm pump, and a piston pump. In some embodiments, the source of blood may comprise a source of transfusion blood configured to supply transfusion blood to the extracorporeal pump, and the inlet of the return cannula may be fluidically coupled to an oxygenator of an extracorporeal membrane oxygenator (ECMO) circuit. The oxygenator may be fluidically coupled to the extracorporeal pump and configured to oxygenate blood. Accordingly, the controller may be configured to cause the extracorporeal pump to draw transfusion blood from the source of transfusion blood and pump the transfusion blood through the oxygenator to deliver oxygenated transfusion blood through the first outlet of the return cannula.

[0025] Alternatively, the source of blood may comprise a first area of the patient’s vasculature such that the inlet of the inlet cannula may be configured to be placed in the first area of the patient’s vasculature. Accordingly, the system further may comprise an admixing chamber fluidically coupled to the extracorporeal pump and the outlet of the inlet cannula, and a second inlet cannula having a second inlet configured to be placed in an artery of the patient and a second outlet fluidically coupled to the admixing chamber. Moreover, the inlet of the inlet cannula may be configured to be placed in a vein of the patient comprising the first area of the patient’s vasculature, and the controller may be configured to: cause venous blood to be drawn through the inlet of the inlet cannula into the admixing chamber; selectively cause arterial blood to be drawn through the second inlet of the second inlet cannula into the admixing chamber to form a mixture of arterial and venous blood having a target oxygenation level; and cause the extracorporeal pump to deliver the mixture of arterial and venous blood having the target oxygenation level through the first outlet of the return cannula.

[0026] In addition, the controller may be configured to: cause the extracorporeal pump to deliver only venous blood through the first outlet of the return cannula for a first time period; selectively increase an amount of arterial blood drawn through the second inlet of the second inlet cannula into the admixing chamber to form a mixture of arterial and venous blood having a- 9 -713664833v3225914-021001 first target oxygenation level; and cause the extracorporeal pump to deliver the mixture of arterial and venous blood having the first target oxygenation level through the first outlet of the return cannula for a second time period. The controller further may be configured to: selectively increase the amount of arterial blood drawn through the second inlet of the second inlet cannula into the admixing chamber to form a mixture of arterial and venous blood having a second target oxygenation level; and cause the extracorporeal pump to deliver the mixture of arterial and venous blood having the second target oxygenation level through the first outlet of the return cannula for a third time period. In addition, a proximal end of the inlet cannula may comprise a hemostatic port configured to permit an interventional or circulatory assist device to be inserted therethrough. The inlet cannula further may comprise an occlusion balloon configured to at least partially occlude flow within the patient’s vasculature antegrade to the inlet of the inlet cannula. Additionally, the inlet cannula may comprise a sealing balloon configured to seal an insertion site of the inlet lumen into the first area of patient’s vasculature to prevent leakage.

[0027] The system further may comprise a second return cannula having an inlet fluidically coupled to the extracorporeal pump and an outlet configured to be placed in a second target area of the patient’s vasculature, and a second pressure sensor configured to measure local blood pressure associated with the second target area of the patient’s vasculature. Accordingly, the controller may be configured to cause the extracorporeal pump to, in the local pressure control mode, deliver blood through the outlet of the second return cannula to perfuse the second target area of the patient’s vasculature at a second selected local pressure. A proximal region of the return cannula may comprise a side arm having an outlet fluidically coupled to the first inlet of the return cannula, and the inlet of the second return cannula may be fluidically coupled to the outlet of the sidearm. Moreover, the system may further comprise an actuatable valve operatively coupled to the controller. The actuatable valve may be fluidically coupled to the second return cannula and configured to be actuated to selectively adjust a flow rate of blood flow through the second return cannula. Accordingly, the controller may be configured to, in the local pressure control mode, actuate the actuatable valve to selectively adjust the flow rate of blood flow through the second return cannula to deliver blood through the outlet of the second return cannula to perfuse the second target area of the patient’s vasculature at the second selected local pressure.- 10 -713664833v3225914-021001

[0028] The controller further may be configured to: periodically stop, at predefined intervals, flow through the extracorporeal pump for a short predetermined time period, such that the flow rate of blood at the first outlet of the return cannula is substantially zero; and measure the outlet pressure sensed by the pressure sensor during the short predetermined time period. In addition, the controller may be configured to: receive an input indicative of the patient’s mean arterial pressure (MAP); compute a distal limb perfusion index (DLPI) value as a ratio of the local blood pressure and the patient’s MAP; and automatically set the selected local pressure as the patient’s MAP if the DLPI value is within a predetermined threshold range. Moreover, the controller may be configured to adjust, if the DLPI value falls below a predetermined threshold, at least one parameter of the extracorporeal pump to maintain the patient’s MAP within a predetermined pressure threshold range.

[0029] The system further may comprise an actuatable valve operatively coupled to the controller. The actuatable valve may be fluidically coupled to the return cannula and configured to be actuated to selectively adjust a flow rate of blood flow through the return cannula. Accordingly, the controller may be configured to, in the local pressure control mode, actuate the actuatable valve to selectively adjust the flow rate of blood flow through the return cannula to deliver blood through the first outlet of the return cannula to perfuse the target area of the patient’s vasculature at the selected local pressure. For example, the actuatable valve may comprise a pinch slider operatively coupled to the return cannula, and a motor operatively coupled to the controller and configured to be actuated to cause the pinch slider to transition between an unactuated state where blood flow is permitted through the return cannula and an actuated state where blood flow is restricted through the return cannula. In addition, the inlet of the return cannula may be fluidically coupled to a main return cannula of an ECMO circuit. For example, the inlet of the return cannula may be fluidically coupled to the main return cannula of the ECMO circuit via a Y or T shaped connector.

[0030] In some embodiments, the system further may comprise an input line sensor configured to measure pressure in the inlet cannula, and an output line sensor configured to measure pressure in the first lumen of the return cannula, such that the controller may be configured to modify, if the pressure in the inlet cannula or in the first lumen of the return cannula reaches a predetermined input pressure safety limit or a predetermined output pressure- 11 -713664833v3225914-021001 safety limit, respectively, a flow rate of the extracorporeal pump to maintain the pressure in the inlet cannula and in the first lumen of the return cannula within the respective predetermined input and output pressure safety limits. For example, the input line sensor may be disposed adjacent to an inlet port of the extracorporeal pump, and the output line sensor may be disposed adjacent to an outlet port of the extracorporeal pump. Accordingly, in the local pressure control mode, the controller may be configured to, if the pressure in the inlet cannula or in the first lumen of the return cannula reaches the respective predetermined input and output pressure safety limits, decrease the flow rate of the extracorporeal pump and then gradually increase the flow rate of the extracorporeal pump to increase the local blood pressure towards the selected local pressure while maintaining the pressure in the inlet cannula and in the first lumen of the return cannula within the respective predetermined input and output pressure safety limits.

[0031] Additionally, the controller may be configured to cause the extracorporeal pump to transition between the local pressure control mode and a flow mode where the controller causes the extracorporeal pump to pump at a set flow rate to perfuse the target region of the patient. Accordingly, in the flow mode, the controller may be configured to, if the pressure in the inlet cannula or in the first lumen of the return cannula reaches the respective predetermined input and output pressure safety limits, decrease the flow rate of the extracorporeal pump and then gradually increase the flow rate of the extracorporeal pump towards the set flow rate while maintaining the pressure in the inlet cannula and in the first lumen of the return cannula within the respective predetermined input and output pressure safety limits. The predetermined input and output pressure safety limits may be a predetermined percentage of a predetermined input pressure safety value and a predetermined output pressure safety value, respectively. The system further may comprise a user interface associated with the controller. The user interface may be configured to receive input indicative of the selected local pressure. In addition, the system may comprise an input line sensor configured to measure pressure in the inlet cannula, and an output line sensor configured to measure pressure in the first lumen of the return cannula, such that the controller may be configured to monitor pressure in the inlet cannula and in the first lumen of the return cannula and generate an alert if the pressure in at least one of the inlet cannula or the first lumen of the return cannula deviates from a predetermined pressure range.- 12 -713664833v3225914-021001

[0032] In some embodiments, the return cannula further may comprise a third lumen extending between a third inlet configured to be fluidically coupled to a source of a drug, and a third outlet configured to be placed in the target area of the patient’s vasculature. Accordingly, the third lumen may be configured to deliver the drug from the source of the drug through the third outlet to the target area of the patient’s vasculature. For example, the drug may comprise at least one of a vasoactive drug configured to relax the target area of the patient’s vasculature and reduce the local blood pressure associated with the target area of the patient’s vasculature, a vasoactive drug configured to constrict the target area of the patient’s vasculature and increase pressure the local blood pressure associated with the target area of the patient’s vasculature, a thrombolytic drug configured to dissolve a clot within the target area of the patient’s vasculature, or an anti-perfusion drug configured to prevent reperfusion of the target area of the patient’s vasculature after a treatment. Moreover, the second inlet of the return cannula may be less than 1 cm from the first outlet of the return cannula.

[0033] In accordance with another aspect, a return cannula for providing perfusion of a target region of a patient’s vasulcaure to support circulation is provided. The return cannula may comprise a first lumen extending between a first inlet configured to be fluidically coupled to a source of blood, and a first outlet configured to be placed in a target area of the patient’s vasculature; a second lumen comprising a second inlet configured to be operatively coupled to a pressure transducer, and a second outlet disposed within the return cannula adjacent to the first outlet, the second outlet configured to fluidically couple the first lumen and the second lumen; and a pressure sensor operatively coupled to the pressure transducer. The pressure sensor may be configured to measure an outlet pressure within the first lumen at the second outlet, the outlet pressure indicative of a local blood pressure associated with the target area of the patient’s vasculature. The second inlet may be less than 1 cm from the outlet of the return cannula. Additionally, the return cannula may comprise a plug disposed within the second lumen between the second outlet and a distal end of the return cannula to thereby prevent stasis within the second lumen distal to the second outlet.

[0034] In accordance with another aspect, a system for providing extracorporeal circulation of blood for perfusion of a target region of a patient to support circulation is provided. The system may comprise an inlet cannula having an inlet configured to be coupled to a source of- 13 -713664833v3225914-021001 blood, and an outlet; a return cannula having an inlet fluidically coupled to the outlet of the inlet cannula, and an outlet configured to be placed in a target area of the patient’s vasculature; a pressure sensor configured to measure local blood pressure associated with the target area of the patient’s vasculature; an extracorporeal pump fluidically coupled to the outlet of the inlet cannula and the inlet of the return cannula; and a controller operatively coupled to the pressure sensor and the extracorporeal pump. The controller may be configured to: receive an input indicative of the patient’s mean arterial pressure (MAP); compute a distal limb perfusion index (DLPI) value as a ratio of the local blood pressure and the patient’s MAP; and cause, in a local pressure control mode, the extracorporeal pump to draw blood through the inlet of the inlet cannula and to deliver blood through the outlet of the return cannula to perfuse the target area of the patient’s vasculature at a selected local pressure. The controller may be configured to automatically set the selected local pressure as the patient’s MAP if the DLPI value is within a predetermined threshold range. Moreover, the controller may be configured to adjust, if the DLPI value falls below a predetermined threshold, at least one parameter of the extracorporeal pump to maintain the patient’s MAP within a predetermined pressure threshold range.

[0035] The return cannula may comprise a first lumen extending between the inlet and outlet of the return cannula and configured to deliver blood received from the source of blood through the outlet of the return cannula to perfuse the target area of the patient’s vasculature; and a second lumen comprising a second inlet configured to be operatively coupled to a pressure transducer operatively coupled to the pressure sensor, and a second outlet disposed within the return cannula adjacent to the outlet of the return cannula, the second outlet configured to fluidically couple the first lumen and the second lumen. Accordingly, the pressure sensor may be configured to measure an outlet pressure within the first lumen at the second outlet, the outlet pressure indicative of the local blood pressure associated with the target area of the patient’s vasculature. In some embodiments, the pressure sensor may comprise one or more strain gauges embedded within a wall of the return cannula. Alternatively, the pressure sensor may comprise a pump clamp disposed around the return cannula. The pump clamp may be configured to measure a degree of expansion of the return cannula, the degree of expansion proportional to the local blood pressure. In some embodiments, the pressure sensor may comprise a pair of plates configured to move up and down responsive to intravascular pressure, a position of the pair of plates proportional to the local blood pressure.- 14 -713664833v3225914-021001

[0036] In accordance with another aspect, a system for providing extracorporeal circulation of blood for perfusion of a target region of a patient to support circulation is provided. The system may comprise an inlet cannula having an inlet configured to be coupled to a source of blood, and an outlet; a return cannula having an inlet fluidically coupled to the outlet of the inlet cannula, and an outlet configured to be placed in a target area of the patient’s vasculature; a drug delivery port configured to deliver a drug to the target area of the patient’s vasculature; a pressure sensor configured to measure local blood pressure associated with the target area of the patient’s vasculature; and a controller operatively coupled to the pressure sensor. The controller may be configured to, in a local pressure control mode, cause blood received from the source of blood via the inlet of the inlet cannula to be delivered through the outlet of the return cannula to perfuse the target area of the patient’s vasculature at a selected local pressure and to support delivery of the drug to the target area of the patient’s vasculature. The drug delivery port may be coupled to the return cannula such that the drug and the blood are delivered through the outlet of the return cannula to the target area of the patient’s vasculature. The drug may comprise at least one of a vasoactive drug configured to relax the target area of the patient’s vasculature and reduce the local blood pressure associated with the target area of the patient’s vasculature, a vasoactive drug configured to constrict the target area of the patient’s vasculature and increase pressure the local blood pressure associated with the target area of the patient’s vasculature, a thrombolytic drug configured to dissolve a clot within the target area of the patient’s vasculature, or an anti-perfusion drug configured to prevent reperfusion of the target area of the patient’s vasculature after a treatment.BRIEF DESCRIPTION OF THE DRAWINGS

[0037] FIG. 1A is a schematic of a perfusion system constructed in accordance with some embodiments, in which an extracorporeal pump is connected between an inlet catheter, through which interventional or circulatory assist device may be placed, and a return catheter.

[0038] FIG. IB illustrates an exemplary extracorporal pump system of the perfusion system of FIG. 1A constructed in accordance with some embodiments.

[0039] FIG. 1C is a schematic of the perfusion system of FIG. 1A having an intravascular pressure sensor in accordance with some embodiments.- 15 -713664833v3225914-021001

[0040] FIG. ID illustrates an exemplary wearable perfusion system constructed in accordance with some embodiments.

[0041] FIGS. 2A and 2B are, respectively, a schematic of an alternative embodiment of the perfusion system in which features of the inlet and return catheters of the embodiment of FIG. 1A are integrated into a double lumen catheter, and a cross-section of the double lumen catheter.

[0042] FIGS. 3A and 3B are, respectively, a further embodiment similar to the embodiment of FIGS. 2, but further including an occlusion balloon for partially or fully occluding antegrade flow through the vessel and a sealing balloon for preventing excessive blood loss through the opening through which the perfusion cannula is inserted into the vessel.

[0043] FIGS. 4A and 4B are, respectively, a side view of an embodiment in which the inlet catheter includes a concave occlusion balloon to direct reperfused blood, and a side view of another alternative embodiment in which a perforated material is disposed over the skive of the return lumen to more evenly distribute blood reperfused into an vessel.

[0044] FIGS. 5A and 5B, are, respectively, an embodiment in which the occlusion balloon and skive of FIG. 3 are replaced by a balloon having a distal portion that occludes antegrade flow and a perforated proximal portion through blood is returned to the vessel; and an alternative embodiment wherein the distal and proximal faces of the balloon are inclined, relative to the axis of the cannula to form distal funnel and an enlarged proximal area for dispersing blood delivered by the extracorporeal pump.

[0045] FIG. 6 is another alternative embodiment of the perfusion cannula of FIG. 4, in which the occlusion balloon is expanded with blood delivered by the extracorporeal pump to occlude, partially or fully, antegrade flow while a perforated proximal face of the balloon disperses blood delivered by the extracorporeal pump to provide an antegrade flow with controlled volume and pressure.

[0046] FIG. 7 is a schematic view of an exemplary perfusion system wherein coaxial inlet and return catheters are coupled to an extracorporeal pump.- 16 -713664833v3225914-021001

[0047] FIG. 8 is an exemplary roller-type pump for providing pulsatile flow, suitable for use in the perfusion system.

[0048] FIGS. 9A, 9B, and 9C are schematic views of the operation of a piston-style pump for generating pulsatile flow, suitable for use in the perfusion system.

[0049] FIGS. 10A and 10B are, respectively, a schematic block diagram of extracorporeal pump and software for use in an exemplary controller for controlling operation of an extracorporeal pump employed in the perfusion system.

[0050] FIG. 11 is another alternative embodiment of the perfusion system of FIG. 1 A, in which the return cannula includes an actuatable sidearm for perfusion of the patient’s distal extremities during ECMO.

[0051] FIG. 12 is another alternative embodiment of the perfusion system of FIG. 1A, in which the extracorporeal pump is fed by two inlet cannulas and returns blood through one return cannula.

[0052] FIG. 13 is another alternative embodiment of the perfusion system of FIG. 1A, in which the extracorporeal pump supplies an oxygenator of an ECMO circuit with transfusion blood for perfusion of the patient’s distal extremities during ECMO.

[0053] FIG. 14 is another alternative embodiment of the perfusion system of FIG. 1A, in which the extracorporeal pump is selectively fed an admixture of varying degrees of oxygenated blood and returns blood through a single return cannula.

[0054] FIGS. 15A and 15B illustrate an exemplary valve actuation mechanism of an actuatable valve constructed in accordance with some embodiments.

[0055] FIG. 16 illsutrates an exemplary perfusion system without an extracorporeal pump, in which an actuatable valve regulates return of ECMO blood to the patient.

[0056] FIG. 17A illustrates an exemplary return cannula comprising an integrated intravascular pressure sensor constructed in accordance with some embodiments.- 17 -713664833v3225914-021001

[0057] FIG. 17B illustrates an alternative exemplary return cannula comprising an integrated intravascular pressure sensor and drug delivery port constructed in accordance with some embodiments.

[0058] FIGS. 18A to 18E illustrate exemplary method steps for manufacturing the return cannula of FIG. 17 in accordance with some embodiments.

[0059] FIG. 19 is screenshot of a display showing the results of near-infrared spectroscopic monitoring of limb oxygenation in an animal test, wherein a left limb of the animal is perfused by an embodiment of the present technology and the right limb is passively perfused.

[0060] FIGS. 20 A and 20B are graphs depicting tissue oxygenation and arterial blood gas values for a different animal test, demonstrating differences between active perfusion and passive perfusion.

[0061] FIG. 21 A is a graph depicting tissue oxygenation for a patient coupled to a passive bypass system, and FIG. 2 IB is a graph depicting tissue oxygenation for a patient coupled to the exemplary perfusion system.

[0062] FIGS. 22 A and 22B are graphs depicting pressure versus flow plots from a feasibility animal study.

[0063] FIGS. 23 A to 23D are graphs depicting conditional changes in Distal Limb Pressure Index (DLPI) and mean arterial pressure from a feasibility study.

[0064] FIGS. 24 A to 24C are graphs depicting superior distal limb perfusion compared to passive bypass in a preclinical model of acute limb ischemia.

[0065] FIG. 25 is a graph depicting venous lactate levels during distal limb perfusion compared with arterial lactate levels during occlusion only.DETAILED DESCRIPTION

[0066] The present technology is directed to a perfusion system for monitoring tissue oxygenation and / or enhancing perfusion to the extremities of a patient suffering from reduced- 18 -713664833v3225914-021001 blood flow to the extremities from any of a number of causes. Causes of such reduced blood flow may include placement of a percutaneous interventional device or circulatory assist device in an artery or vein that results in partial or complete occlusion of downstream blood flow in that vessel, or as an after effect of cardiogenic shock or peripheral artery disease, or as a result of any procedure requiring cessation of blood flow using tourniquets or other methods to stop blood flow to an area. In accordance with one aspect, the perfusion system draws arterial blood from a location upstream of the obstruction or reduced-flow region, and delivers the blood back into the vessel, or an adjacent or contralateral vessel, with a controlled vasculature pressure or flow rate volume, thereby reducing a risk of limb ischemia. Further, the flow to the limb through the pump may be regulated by physiologic feedback such as target vessel pressure and / or tissue oxygen levels.

[0067] It is expected that acute and / or chronic limb ischemia that occurs in patients during vascular intervention is due to partial or complete obstruction of downstream arterial or venous flow created by the presence of a blood clot, traumatic injury, tourniquet, or a catheter of an interventional device, or circulatory assist device. Other potential causes may include compromised cardiac output, arteriosclerosis, and / or generalized increased vascular hydraulic resistance in the limbs, all which may contribute to less flow in the extremities at lower localized pressure. Reduced peripheral flow and / or blood pressure in turn may contribute to increased thrombus formation, worsening limb ischemia, and increased risk of myocardial infarction, pulmonary embolism and stroke. Accordingly, to address these issues, the systems and methods described herein are designed to direct a portion of the blood flowing towards the extremities to an extracorporeal blood pump, which returns the flow to the same or another vessel at a controlled pressure or flow rate sufficient to reduce ischemia.

[0068] Other patients experience complications of interventional procedures such as coronary perforation, cardiac rupture, right heart free wall puncture due to biopsies, or rupture of the aorta or other valves during valve replacement may develop rapid and catastrophic blood accumulation in the pericardium, thereby impeding function of the native heart. As excess blood is removed from the pericardium, the patient may require a transfusion to replace the aspirated blood. The systems and methods described herein further are designed to direct a portion of- 19 -713664833v3225914-021001 accumulated blood to an extracorporeal blood pump, which returns the blood to systemic circulation.

[0069] As mentioned in the Background, some surgeons and interventional clinicians have sought to augment flow to a patient’s extremities by using a tubing set to passively transfer blood from a higher pressure / flow region, e.g., an artery close to the heart, to a remote arterial location, e.g., in a femoral artery. Due to a number of factors, such attempts have not proven satisfactory due to the slow flow rates and low pressure inherent in such a passive system, as well as hydraulic resistance encountered in the tubing sets. Applicants hypothesize that even in the presence of substantial blood flow, the existence of low vasculature pressure in the limbs may drive insufficient oxygen absorption in the capillaries. It is the applicants’ insight that by providing an extracorporeal blood pump, blood flow rates and vasculature pressures supplied to the patient’s extremities may be better controlled to perfuse the extremities and reduce the risk of ischemia. In addition, provision of one or more separate extracorporeal pumps allows perfusion of the limbs to be controlled independently of operation of any vascular device or circulatory assist device that may create an obstruction. The systems and methods described herein further enable the clinician to monitor perfusion in the patient’s extremities, and to adjust the flow to achieve a targeted pressure in the perfused vessel in real time. It should be known that when describing various embodiments, the terms “vessel pressure,” “vascular pressure,” “local pressure,” “blood pressure,” or some combination of these terms refers to the fluidic pressure within a patient’s blood vessels and / or cappilaries.

[0070] Referring now to FIG. 1A, exemplary perfusion system 10 arranged in accordance with the principles of the present disclosure is described. System 10 may be based on the systems described in U.S. Patent No. 12,029,889 to Karas et al., the entire contents of which are incorporated herein by reference. System 10 includes inlet cannula 12, return cannula 14, and extracorporeal pump 16 coupled by tubing 18. Inlet cannula 12 is drainage cannula configured for placement in a femoral, iliac or axillary artery or vein and includes proximal end 20 having outlet port 22 and hemostatic port 24 through which an interventional device or circulatory assist device may be inserted to perform an interventional procedure or to assist cardiac function.Distal end 28 of inlet cannula 12 is configured to be placed in an antegrade direction in the vessel to assist in positioning of the interventional or circulatory assist device. Inlet cannula 12 has a- 20 -713664833v3225914-021001 sufficiently large diameter, e.g., 16-22 Fr, such that annulus 30 is formed by the exterior surface of the device inserted therethrough and the interior surface of inlet cannula 12, such that blood flow will pass to outlet port 22 and to inlet 32 of pump 16.

[0071] In an alternative or additional option, the inlet cannula may be a pigtail catheter that is inserted into the pericardium in the event of blood accumulation in the pericardium. The accumulated blood is then drained from the pericardium and auto-transfused into a vascular sheath through the return lumen. Such an embodiment would enable two life-saving treatments: 1) to drain the pericardium so blood does not build up and impede function of the heart; and 2) auto-transfuse patients so they do not require excess blood products.

[0072] In one embodiment, return cannula 14 may be configured to be placed in the patient’s iliac, femoral or axillary artery or vein with outlet end 34 facing in a retrograde direction. In this orientation, blood delivered from outlet 36 of pump 16 through lumen 38 of return cannula 14 is directed against inlet cannula 12 to cause wash out of any stagnation zones created where inlet cannula 12 enters the vessel. In some embodiments, return cannula 14 may be placed in the target vasculature such that outlet end 34 face in the antegrade direction. In such an embodiment, system 10 further may include an occlusion balloon disposed on a distal region of return cannula 14, e.g., proximal to outlet end 34, for directing blood flow into the target perfusion area. For example, occlusion balloon may be constructed similar to occlusion balloon 118, described in further detail below with regard to FIG. 3 A. Accordingly, the occlusion blood may be configured to be inflated to partially or completely block retrograde flow through the vessel and direct blood flow in the antegrade direction towards the target perfusion area.

[0073] Referring again to FIG. 1 A, return cannula 14 also may include valve 40 at its proximal end. At least a portion of blood exiting outlet end 34 of return cannula 14 thus flows in a retrograde direction before flowing in an antegrade direction to the patient’s extremities. Return cannula 14 also may have an infusion port to allow the pump circuit to be used simultaneously for blood transfusions and / or one or more delivery ports for the delivery of reperfusion protection agents or therapeutic agents to reduce or eliminate reperfusion injury. Such reperfusion protection or therapeutic agents may include, but are not limited to, anticoagulants and thrombolytics.- 21 -713664833v3225914-021001

[0074] In alternative embodiments, the return cannula may be configured to be placed at a more distal location in the peripheral circulation, spaced apart from the insertion site of the occlusive sheath. For example, the return cannula may be placed in a vein or artery near the ankle when treating ischemia in a leg or placed in a vein or artery near the wrist when treating ischemia in an arm even though the ankle or wrist are not near the occlusion. In some embodiments, the return cannula may include a sidearm configured to extend from and direct blood flow from the return cannula to the patient’s distal extremities simultaneously as the return cannula delivers blood to the target vessel, as described in further detail below with regard to FIG. 11.

[0075] Muscle perfusion requires not only an increase in blood flow, but also an increase in pressure. Applicant’s animal studies have shown that upon occlusion of an artery, near- infrared spectroscopy (NIRS) drops from around 50 to the teens (e.g., 10-19), and when pumping from artery-to-artery, NIRS returns to pre-occlusion levels, e.g., 50. In contrast, when pumping from artery -to-vein post-occlusion of the artery, NIRS only increases to about 30. Specifically, when delivering blood to a perfused vein, the pressure increase is achieved when going from the groin to the foot. However, when going from the foot to the groin, the perfused vein may need to be at least partially occluded and / or manually compressed to achieve the desired pressure increase.

[0076] FIG. IB illustrates an exemplary extracorporeal pump system including pump controller 45 operatively coupled to extracorporeal pump 16 and display panel 17.Extracorporeal pump 16 may be a conventional, commercially available blood pump capable of either continuous or pulsatile flow that uses any number of known pumping technologies, such as a vane pump, diaphragm pump, gear pump, roller pump, centrifugal pump, axial flow pump, balloon-mounted pump or piston pump. For example, extracorporeal pump 16 may be designed to pump blood through the circulatory system using the principle of peristalsis, which mimics the natural rhythmic contractions of the muscles in the digestive tract. Preferably, extracorporeal pump 16 pumps blood at a max flow rate of 1.5 L / min. In a preferred embodiment, extracorporeal pump 16 is driven by one or more electric motors, which may be powered by an internal battery, and operatively coupled to controller 45 that permits the vessel pressure or flow rate to be adjusted. Additionally, or alternatively, the exemplary extracorporeal pump system may be configured to accept line power. As shown in FIG. IB, the extracorporeal pump system- 22 -713664833v3225914-021001 further may include bubble trap 43 configured to trap air in the line and bubble sensor 47 configured to sense whether any extraneous bubbles exist in the blood, such that corrective action may be taken by the user before infusing the blood into the patient.

[0077] Accordingly, during operation, controller 45 may monitor the pressures in the input line and output line for safety, as well as the intravascular pressure, which may be used as input to control the pump speed. This parameter (e.g., the intravascular pressure in real time) will be used to drive the pump to deliver a target pressure in the vasculature within the physiologic range of 80 mmHg to 110 mmHg. Moreover, the pressures in the input and / or output lines also may be used to control the pump speed, for example, when the input and / or output line pressures approach respective predetermined safety thresholds, e.g., within a predetermined percentage thereof, as described in further detail below. Display panel 17 may be a touchscreen device that enables the user to select the target intravascular pressure setpoint, start and stop the pump, adjust operation of the pump, set and silence the alarm, and / or download recorded data. In addition, display panel 17 may display the output of sensors of the system, e.g., the input and output line pressure sensors disposed on the cannulas, the intravascular pressure sensor, etc. For example, in accordance with one aspect, extracorporeal pump 16 may include, or be in communication with, pressure sensors that sense blood pressure within inlet cannula 12 (“input line pressure”), e.g., input line sensor 37, and within return cannula 14 (“output line pressure”), e.g., output line sensor 39, as well as measure flow rate through the pump, and sense the presence of obstructions.

[0078] In such an embodiment where pump controller 45 is in communication with pressure sensors located within the vein or artery of the limb, it may be desirable to have the pressure sensors measure the local blood pressure through a lumen separate from any inlet or return lumen, such as a lumen described below in FIGS. 2 and 3. Use of a separate lumen may allow the local pressure to be transduced or measured independent of the flowing blood. Preferably, pressure sensors may also be located at inlet port 32 (e.g., input line sensor 37) and outlet port 36 (e.g., output line sensor 39), as shown in FIG. 1C. However, in such an embodiment with pressure sensors at the inlet and outlet ports, it may be desired to account for the drop in pressure caused by the friction in the pump circuit. Such a pressure drop may be accounted for by using a higher target pressure than the ideal target vessel pressure, reducing the friction in the pump- 23 -713664833v3225914-021001 circuit, or a combination of the two. For example, to reduce friction in the pump circuit, it may be desirable to coat the inner surface of the cannulas with a layer of polytetrafluoroethylene, such as TeflonTM. Additionally, or alternatively, pump controller 45 may be in communication with pressure sensors located at distal end 28 of inlet cannula 12 and outlet end 34 of return cannula 14 for sensing blood pressure within inlet cannula 12 and return cannula 14, respectively.

[0079] Further in accordance with the disclosure, controller 45 may include a processor programmed to drive extracorporeal pump 16, monitor the output from the pressure sensors, control user interface 17, and store required safety features. Moreover, the processor may be programmed to sense vascular resistance at outlet port 36. In addition, as described above, the processor may be programmed to sense input pressure at inlet port 32 via input line sensor 37 and output pressure at outlet port 36 via output line sensor 39. Accordingly, controller 45 further may be programmed to automatically adjust the outlet pressure and / or flow rate to maximize limb perfusion while avoiding the use of excessive pressure, which might cause extravascular leakage and edema. For example, the input pressure sensed at inlet port 32 may vary from normal pressure conditions, e.g., when flow through the inlet catheter is slow, to large negative pressures, e.g., when flow through the inlet catheter is high, which may be due to restrictions of the tubing / connections before the pump, and the output pressure sensed at outlet port 36 may increase significantly, e.g., when flow through the return cannula is slow, due to restrictions of the tubing / connections beyond the pump. Moreover, operation of the pump at around 1000 cc / min may result in high output pressure in the range of 800 mmHg or more, and high negative input pressure in the range of -500 mmHg or more. Consequently, high negative pressure at inlet port 32, e.g., around -500 mmHg, during operation of the pump may cause the inlet catheter to collapse, resulting in an inefficient pump that pumps an insufficient amount of blood.

[0080] Thus, to limit the magnitude of the input and output pressures, controller 45 further may be programmed with predetermined input and output pressure limits, such that if the sensed input or output pressure reaches the predetermined input or output pressure limit, respectively, controller 45 may modify the speed of extracorporeal pump 16 to thereby maximize flow across the system while maintaining the input and output pressures within the respective safety limits. For example, when the predetermined input and / or output pressure limits are reached, controller 45 may slow down the speed of extracorporeal pump 16 to thereby modulate flow through the- 24 -713664833v3225914-021001 pump to maintain the input and output pressures within the respective safety limits. Moreover, when the sensed input and output pressures are within acceptable ranges below the respective safety limits, controller 45 may gradually increase the speed of extracorporeal pump 16 while monitoring the input and output pressures and to ensure that the input and output pressures remain within the respective safety limits until the target flow rate (e.g., in flow mode) or the target vascular pressure (e.g., in local pressure control mode) is achieved, as described in further detail below, thereby maximizing limb perfusion while avoiding excessive input and output pressures.

[0081] The predetermined input pressure limit may be, e.g., between -200 mmHg to -400 mmHg, or preferably around -250 mmHg, and the predetermined output pressure limit may be, e.g., between 300 mmHg to 500 mmHg, or preferably around 400 mmHg. In some embodiments, controller 45 may slow down the speed of extracorporeal pump 16 when the sensed input or output pressure reaches a predetermined percentage of the respective safety limits, e.g., when the sensed input or output pressure is within 10% of the predetermined input and output pressure limit, respectively. Accordingly, by slowing down the pump when the respective safety limits are reached followed by gradually and continuously increasing the speed of the pump to achieve the desired flow rather than cutting off operation of the pump when the respective safety limits are reached, e.g., reducing the speed of the pump to zero, the desired flow at the outlet of the return cannula may be achieved while preserving pump efficiency, tubing / connection integrity, and blood safety.

[0082] In addition, extracorporeal pump 16 may be configured to generate a pulsatile flow at outlet 34 of return cannula 14 that mimics the pressure fluctuations of a normal cardiac cycle and thus reduces the risk of thrombus formation. As a further option, the pump may be synchronized with an ECG output or pressure wave sensor to eject blood during diastole, thereby reducing afterload on the heart. In some embodiments, controller 45 may be programmed to speed up and slow down pump 16 in one revolution of pump 16 to thereby modulate flow through the pump to avoid pressure spikes from the roller pump and address pulsatility, as well as provide consistent flow. Accordingly, controller 45 may cause pump 16 to operate at an unsteady RPM.- 25 -713664833v3225914-021001

[0083] In accordance with another aspect of the disclosure, the extracorporeal pump may be configured to maintain perfusion pressure at physiologic levels (e.g., <110 mmHg), rather than a selected output flow, e.g., “local pressure control mode” discussed in further detail below. For example, the extracorporeal pump may deliver blood so that the mean perfusion pressure in the limb, e.g., leg or arm, is maintained by continually varying the flow rate, preferably with a max flow rate of 1.5 L / min. In addition, the supply of blood delivered to the pump may be from other parts of the body, e.g., arm or other leg, and not simply upstream of the vessel in which blood is reperfused. Further, the controller of the pump may be in communication with sensors that measure the oxygenation of the blood and / or tissue in the limb being reperfused. Such sensors may use various measurement standards such as, for example, measuring levels of blood-oxygen saturation (SpO2), arterial blood gas (PaO2), Near Infrared Spectroscopy (NIRS) to measure absolute tissue saturation (StO2), pH levels, or lactate levels. For example, return cannula 14 may include integrated NIRS sensor 35 proximate to its distal end for measuring tissue oxygenation levels of the tissue surrounding the cannula at the reperfusion site. An example of an integrated NIRS sensor suitable for such use is described in the article by K.D. Hakkel et al., entitled “Integrated near-infrared spectral sensing,” Nature Communications, 13:103 (2022), available at https: / / doi.org / 10.1038 / s41467-021-27662-l. In this case, the controller of the extracorporeal pump may provide on display 17 a readout of the flow rate, local blood pressure in the perfused vessel, and level(s) of tissue oxygenation. The controller also may be programmed, e.g., via display panel 17, to permit an operator to select a combination of cycle length and outflow pressure that provides the highest flow at the target vessel pressure to achieve or maintain a target tissue oxygenation level.

[0084] Preferably, the controller of the extracorporeal pump has multiple operating modes. In each operating mode, the feedback loop controlling the pump is based on a different measured variable. In flow mode the operator will manually set the flow rate at which the pump will perfuse the extremity. In vascular or local pressure control mode, the system will perfuse the leg at a specific vascular pressure and this target pressure will be either manually or automatically determined. For example, in the local pressure control mode, the controller may primarily use the input from the intravascular pressure sensor to modulate flow provided by the pump to achieve and maintain a target vascular pressure within the target vessel. In some embodiments, the controller also may use the input from the inline and outlet pressure sensors indicative of - 26 -713664833v3225914-021001 input and output pressures to modulate flow provided by the pump to achieve the target vascular pressure while maintaining the input and output pressures within safety limits, as described in further detail below. As will be understood by a person skilled in the art, the controller may use a simple proportional, proportional-integral (PI), or proportion-integeral-derivative (PID) control algorithm to achieve the set vascular pressure.

[0085] As shown in FIG. 1C, input line sensor 37 may be fluidically coupled to inlet cannula 12 to measure pressure in the input line in fluidic communication the source (e.g., artery or vein), and output line sensor 39 may be fluidically coupled to return cannula 14 to measure pressure in the output line in fluidic communication with the perfused vessel (e.g., artery or vein). For example, input line sensor 37 may be integrated with inlet cannula 12 and output line sensor 39 may be integrated with return cannula 14. In some embodiments, the input line and output line sensors may be pressure sensors made available by Utah Medical, Midvale, Utah. In addition, the system further may include intravascular pressure sensor 41 in fluid communication with the perfused vessel (e.g., artery or vein) for measuring the local intravascular vessel pressure.

[0086] Perferably, intravascular pressure sensor 41 is disposed in a position within the patient’s vasculature to measure intravascular pressure distal to the extracorporeal circuit within the treated vasculature, to thereby ensure that the vessel achieves intravascular pressure within the normal physiologic range. For example, intravascular pressure sensor 41 may be disposed on a catheter separate from return cannula 14 (e.g., vascular blood pressure sensor made available by Utah Medical, Midvale, Utah). Additionally, or alternatively, pressure sensor 41 may be disposed in a position within the patient’s vasculature to measure intravascular pressure proximal to the outlet end of return cannula 14, e.g., out of the path of blood flow exiting the outlet end of return cannula 14. For example, pressure sensor 41 may be embedded within a wall of return cannula 14, e.g., an indwelling pressure sensor, such that return cannula 14 is also a “tubing sensor.”

[0087] In some embodiments, indwelling pressure sensor 41 may be in fluidic communication with the blood flow path within return cannula 14 at the outlet of return cannula 14, and configured to sense pressure at the outlet of return cannula 14, which is disposed in the patient’s vasculature. Moreover, the controller may be programmed to periodically stop flow of- 27 -713664833v3225914-021001 the extracorporeal pump, e.g., in predefined intervals, for a short predetermined time period such that flow at the outlet of return cannula 14 is close to or essentially zero when the flow through the extracorporeal pump is stopped briefly, and to measure the pressure at the outlet of return cannula 14 sensed by indwelling pressure sensor 41 at the predefined intervals when the flow through the extracorporeal pump is close to or essentially zero, which, in accordance to Ohm’s law, will be equivalent to the intravascular pressure within the patient’s vasculature. Accordingly, rather than (or in addition to) using a sensor positioned within the patient’s vasculature to measure intravascular pressure, the intravascular pressure may be approximated by measuring pressure within return cannula 14, e.g., at the outlet of return cannula 14.

[0088] In some embodiments, pressure sensor 41 may be fluidically coupled to an external fluid column configured to measure intravascular pressure within the patient’s vasculature. Additionally, or alternatively, pressure sensor 41 may comprise a pump clamp disposed around return cannula 14, the pump clamp configured to measure the degree of expansion / contract! on of return cannula 14, which may be proportional to intravascular pressure within the patient’s vasculature. For example, the pump clamp may comprise a pair of plates configured to move up and down responsive to intravascular pressure, such that the position of the pair of plates are proportional to intravascular pressure within the patient’s vasculature. Alternatively, the pump clamp may comprise one or more strain gauges embedded within a wall of return cannula 14. Accordingly, pressure sensor 41 need not be in contact with blood within the patient’s vasculature in order to measure intravascular pressure. Additionally, or alternatively, the pressure sensor may be integrated with the return cannula, such that the pressure sensor is disposed within the return cannula adjacent the outlet of the return cannula and in fluidic communication with the blood flow path within the return cannula to thereby sense pressure at or adjacent to the outlet of return cannula, which may be effectively equal to the local pressure within the patient’s vasculature, as described in further detail with regard to FIG. 17A.

[0089] In addition, as shown in FIG. 1C, pressure sensor 41 may be in electrical communication with the controller of the extracorporeal pump, such that the controller may monitor the intravascular pressure based on electrical signals received from pressure sensor 41 to thereby prevent the overpressure of the vessel where the blood is being delivered and maintain the intravascular pressure within normal physiological pressure ranges (e.g., <110 mmHg). For- 28 -713664833v3225914-021001 example, the controller may monitor average intravascular pressure within the patient’s vasculature, such that the average intravascular pressure is the target intravascular pressure that is maintained in the local pressure control mode. Additionally, the controller may generate an alert if the intravascular pressure measured by intravascular pressure sensor 41 deviates from the target vessel pressure by at least a predetermined pressure value. For example, the controller may monitor peak pressure within the patient’s vasculature, and may generate an alert if the peak pressure exceeds a predetermined peak pressure level.

[0090] Moreover, as described above, input line sensor 37 and output line sensor 39 may be in electrical communication with the controller of the extracorporeal pump, such that the controller may monitor the input and output pressures, e.g., at the inlet and outlet ports of the pump, respectively, based on electrical signals received from input line sensor 37 and output line sensor 39 to thereby prevent excessively high negative pressure at the inlet port and excessive pressure at the outlet port while maximizing flow to achieve the target vascular pressure in local pressure control mode (or the target flow rate in flow mode). Accordingly, unlike flow-based systems, e.g., systems have safety flow limits, the system herein advantageously may maximize flow to achieve the target vascular pressure regardless of the state of vasodilation of the target vessel. For example, when the target vascular pressure in local pressure control mode is, e.g., 80 mmHg, and the target vessel is significantly dilated such that a large amount of flow at the outlet of the return cannula would be required to achieve the target vascular pressure, the preset safety flow limits of a flow-based system would typically prevent the system from providing the magnitude of flow necessary to achieve the target vascular pressure, e.g., the pump speed would be slowed down or shut off before the requisite flow can be achieved. In contrast, the system herein may maximize flow to achieve the target vascular pressure independent of flow at the outlet of the return cannula within the target vessel.

[0091] In addition, local pressure control mode may be used to support active drug delivery to the target vessel, and accordingly, associated tissue, e.g., an ischemic limb or other muscle. For example, it has been found that drug delivery via a passive bypass system does not salvage mitochondria, and the drug may not be properly absorbed into the target tissue. However, by providing pressurized perfusion of the target vasculature at a selected local pressure in the local pressure control mode, e.g., an active bypass approach, the local pressure may be selected to- 29 -713664833v3225914-021001 facilitate drug absorption by the target tissue while salvaging mitochondria, particularly in occluded and / or low pressure environments. For example, the drug delivered to the target vessel may be a vasoactive drug configured to relax the target vessel, and accordingly reduce the local pressure of the target vessel, or alteratively, a vasoactive drug configured to constrict the target vessel, and accordingly reduce flow / increase pressure of the target vessel. In some embodiments, the drug delivered to the target vessel may be a thrombolytic drug configured to dissolve a clot that may cause low flow within the target vessel. Accordingly, the thrombolytic drug may be delivered in a retrograde direction, e.g., towards the clot. In addition, the drug delivered to the target vessel may be an anti-perfusion drug configured to prevent reperfusion after treatment. In some embodiments, the drug may be delivered via a separate lumen of the return cannulas described herein, for example, as described in further detail below with regard to FIG. 17B. For example, the drug delivery lumen of the return cannula may extend between an inlet of the return cannula configured to be coupled to a source of the drug and an outlet at the distal region of the return cannula and configured to be disposed within the target vessel. Alternatively, the drug may be delivered to the target vessel via a separate drug delivery catheter.

[0092] Similarly, in tissue oxygen control mode, the system will perfuse the extremity to achieve a specific tissue oxygen level and this target oxygen level will be either manually or automatically determined. In any of these modes, the measured variable may be either manually entered or automatically determined by the artificial intelligence component. The software of the controller also may include an artificial intelligence component that prompts the controller to reassess this selected combination at various intervals of time to optimize settings that work best for a particular patient. Alternatively, the pump circuit may serve as a passive bypass circuit until the controller senses a drop in tissue oxygenation levels that may result in limb ischemia via sensor 35. Once the controller senses a drop in the tissue oxygenation level below a predetermined value, the controller may automatically activate the pump.

[0093] In some embodiments, the extracorporeal pump system described above may be configured to be worn by the patient, as shown in FIG. ID. The extracorporeal pump system of FIG. ID may be constructed similar to extracorporeal pump system of FIG. IB, with similar components having like-prime reference numerals. For example, controller 45', extracorporeal pump 16' having inlet port 32' fluidically coupled to inlet cannula 12' and outlet port 36'- 30 -713664833v3225914-021001 fluidically coupled to return cannula 14', and display panel 17' correspond with controller 45, extracorporeal pump 16 having inlet port 32 fluidically coupled to inlet cannula 12 and outlet port 36 fluidically coupled to return cannula 14, and display panel 17. The extracorporeal pump system of FIG. ID differs from the extracorporeal pump system of FIG. IB in that controller 45', extracorporeal pump 16', and display panel 17' may be configured to be worn by the patient, e.g., via straps 49, thereby providing a low-profile mobile system that improves patient comfort and mobility. In addition, the extracorporeal pump system of FIG. ID may comprise a micrpuncture kit to reduce access site complications.

[0094] In accordance with another aspect of the disclosure, the pump may have two or more return cannulas where each return cannula is supplying blood to a different limb, each return cannula is supplying blood to different areas or veins / arteries of the same limb, or each return cannula is supplying blood different areas of multiple limbs such as supplying blood to both an upper portion and a lower portion of a leg at the same time as supplying blood to an arm proximate to the shoulder and proximate to the wrist. In such an embodiment, it may be desirable to maintain either a constant flow rate or a constant vessel pressure for some or all limbs being reperfused. Otherwise, the use of pressure control or flow rate control valves may be desired to change the flow rate or pressure in one limb without changing the flow rate or pressure in another limb. The inlet cannula alternatively may be coupled to multiple pumps or a single pump having multiple stages, such that each pump or stage is employed to reperfuse a different limb. In such an embodiment, each limb may have their own, individual flow rates or vessel pressures maintained.

[0095] For example, referring to FIG. 11, an exemplary perfusion system having two return cannulas fluidically coupled to the extracorporeal pump is provided. Perfusion system 10' may be constructed similar to perfusion system 10 of FIG. 1A, with similar components having like- prime reference numerals. For example, inlet cannula 12' having annulus 30' and hemostatic port 24' for receiving an interventional device or circulatory assist device therethrough, and pump 16' having display 17' and fluidically coupld to inlet cannula 12' via outlet port 22' and inlet 32' of pump 16', correspond with inlet cannula 12 having annulus 30 and hemostatic port 24, and pump 16 having display 17. System 10' differs from system 10 in that return cannula 14' having lumen 38' is fluidically coupled to pump 16' via tubing 18' and outlet 36' of pump 16' via connector 400.- 31 -713664833v3225914-021001As shown in FIG. 11, connector 400, e.g., a Y-shaped connector, may be fluidically coupled to or otherwise integrated with valve 40' for fluidic communication with tubing 18', and further may have a first outlet fluidically coupled to an inlet of return cannula 14'. For example, return cannula 14' may be removeably coupled to connector 400, or alternatively, may be integrally formed with connector 400.

[0096] Moreover, connector 400 may inlude sidearm 402 in fluidic communication with tubing 18' and lumen 38' of return cannula 14'. Sidearm 402 may be fluidically coupled to a second return cannula, e.g., return cannula 406 having outlet end 410 configured to be inserted in another portion of the patient’s vasculature, e.g., at the patient’s distal extremities, and lumen 408 extending therethrough and in fluidic communication with connector 400, and accordingly, with tubing 18' and lumen 38'. In some embodiments, as shown in FIG. 11, sidearm 402 may include a flow regulator, e.g., actuatable valve 404, fluidically coupled to return cannula 406. For example, actuatable valve 404 may be operatively coupled to the controller, such that the controller may be programmed to actuate valve 404 to thereby permit, prohibit, or adjust blood flow across valve 404, and accordingly, from tubing 18' and sidearm 402 to lumen 408 of return cannula 406 for delivery to the patient’s distal extremities via outlet end 410. An exemplary valve actuation mechanism is described in further detail below with regard to FIGS. 15A and 15B.

[0097] Accordingly, controller may be programmed to actuate valve 404 based on, e.g., intravascular pressure measurements in the local pressure control mode, to thereby control the flow rate of blood across valve 404 and achieve the target intravascular pressure within the target vessel receiving blood via return cannula 406. Thus, system 10' further may include an intravascular pressure sensor associated with return cannula 406 and operatively coupled to the controller, which like intravascular pressure sensor 41, may be in fluid communication with the perfused vessel (e.g., artery or vein) for measuring the local intravascular vessel pressure at the patient’s distal extremities. Additionally, or alternatively, sidearm 402 may be a compressible tube configured to be clampable via an external clamping device to thereby stop flow therethrough. As will be understood by a person skilled in the art, return cannulas 14' and 406 may be inserted in different target vessels than is shown in FIG. 11. In some embodiments, the- 32 -713664833v3225914-021001 intravascular pressure sensor may be integrated with the return cannula, as described in further detail with regard to FIG. 17A.

[0098] As another alternative, there may be multiple inlet cannulas that each supply blood to the same or different pumps or motors. In such an embodiment, it may be desirable to have each inlet cannula inserted into a different vein or artery or a supply of transfusion blood. The blood reperfusion system may use any combination of the multiple return and inlet cannulas and single or multiple pumps or motors. These inlet cannulas may then either supply blood to the same pump, two different pumps, or one or both inlet cannulas may supply blood to more than one pump. When both inlet cannulas are supplying blood to the same pump, the pump may have one or more return cannulas. When the inlet cannulas are supplying blood to multiple pumps, each pump may have one or more return cannulas. When there is more than one return cannula, each return cannula may supply blood to different limbs, different areas of the same limb, different veins and / or arteries of the same limb, or some combination of the aforementioned.

[0099] For example, referring to FIG. 12, pump 376 may have two inlet cannulas and one return cannula. The first inlet cannula may be arterial inlet cannula 318 inserted into artery 332 of a limb while the second inlet cannula of pump 376 is oxygenated inlet cannula 316 that carries oxygenated blood from ECMO 320, e.g., an oxygenator of the ECMO circuit. ECMO 320 may be supplied by venous inlet cannula 314 and transfusion cannula 312 where the transfusion cannula supplies the ECMO with transfusion blood from a source of transfusion blood, e.g., source 310. The blood supplied to pump 376 by arterial inlet cannula 318 and oxygenated inlet cannula 316 is then mixed before being returned to vein or artery 334 through return cannula 322. One skilled in the art would understand that any number of other possible combinations exist. For example, the pump may have three inlets. One inlet for transfusion blood, one inlet for venous blood, and one inlet for arterial. In such an embodiment, the ECMO may be omitted or it may only oxygenate one of the transfusion blood, venous blood, or arterial blood. The pump also may have more than one return cannula where each return cannula returns blood to different areas of the limb or to different limbs. In such an embodiment, the pump may or may not mix the inlet blood before supplying it to the return cannulas. As a further option, the reperfusion system may have more than one pump or motor. For example, there may be a single- 33 -713664833v3225914-021001 pump or motor for each inlet and / or each return. In another example, there may be one pump or motor for venous inlet cannulas and one pump or motor for all arterial inlets cannulas.

[0100] In some embodiments, on the inlet side of pump 376, pump 376 may only be fluidically coupled to the ECMO circuit, e.g., oxygenator 320 of the ECMO circuit via oxygenated inlet cannula 316, as the source of blood, e.g., without venous inlet cannula 314 and arterial inlet cannula 318, such that pump 376 delivers only blood received from the ECMO circuit to the target vessel. Accordingly, transfusion blood may flow from source 310 into oxygenator 320 where it may be oxygenated to achieve a predetermined oxygenation level, and the oxygenated transfusion blood may be drawn into pump 376, e.g, via oxygenated inlet cannula 316, for delivery to the target vessel, e.g., vein or artery 334, via return cannula 322.

[0101] Alternatively, the extracorporeal pump may be fluidically coupled to the source of transfusion blood of the ECMO circuit, such that the pump draws transfusion blood from the source of transfusion blood and pumps the transfusion blood into the oxygenator of the ECMO circuit for oxygenation before being delivered to the target vessel. For example, as shown in FIG. 13, pump 376' may be fluidically coupled to a source of transfusion blood of the ECMO circuit, e.g., source 310', via an inlet cannula, e.g., transfusion cannula 312', and fluidically coupled to an oxygenator of the ECMO circuit, e.g., oxygenator 320', via an outlet cannula, e.g., outlet cannula 378, and oxygenator 320' may be fluidically coupled to a return cannula, e.g., return cannula 322', having an outlet end disposed in the target vessel, e.g., vein or artery 334'. Accordingly, outlet cannula 378 may supply oxygenator 320' with transfusion blood that is drawn from source 310' by pump 376' via transfusion cannula 312', and oxygenator 320' may oxygenate the transfusion blood to achieve a predetermined oxygenation level. For example, pump 376' may provide prositive pressure to drive the transfusion blood through oxygenator 320' for oxygenation and for delivering oxygenated transfusion blood to vein or artery 334' via return cannula 322'. Moreover, while FIG. 13 illustrates a single return cannula, e.g., the system may include more than one return cannula fluidically coupled to pump 376' for selectively delivering the oxygenated transfusion blood to different target vessels, e.g., at respective selected local pressures in the local pressure control mode, simultaneously.- 34 -713664833v3225914-021001

[0102] In accordance with one aspect, the device may be used to provide flow to one or more vascular compartments. For example, using a single motor and single console or independent motors and consoles, two rotors can be used to bypass two arteries or an artery and a vein or two veins. This application is particularly useful when full occlusion of blood flow to and from an extremity has occurred or is required as in the case of a tourniquet. In this case, the device would provide antegrade arterial flow to the limb and retrograde venous flow from the leg. This will enable optimal limb perfusion. In another example, the multi-rotor device may provide arterial bypass to both legs or to a leg and an arm simultaneously.

[0103] In a still further addition, the pump may be configured to oxygenate blood flowing through the pump in the event increasing vessel pressure or flow rate is insufficient. One skilled in the art would recognize the possibility of splicing a separate extracorporeal membrane oxygenator system (ECMO) to the pump circuit. In an alternative option, one inlet cannula may supply the pump with arterial blood while venous and / or transfusion blood may be fed through an ECMO before being fed into the pump. The pump then supplies the combination of this arterial blood and the oxygenated venous and / or transfused blood through the return lumen. In another alternative option, one inlet cannula may supply the pump with deoxygenated venous blood while oxygenated arterial blood (and / or oxygenated transfusion blood from an ECMO circuit) may be selectively fed into the pump to form an admixture of varying degrees of oxygenated blood for return to the patient’s vasculature, to thereby prevent / reduce reperfusion injury caused by the rapid reperfusion of an ischemic limb with both high flow and high oxygen content.

[0104] For example, referring to FIG. 14, pump 350 may be fluidically coupled to two inlet cannulas, e.g., venous inlet cannula 342 inserted into vein 360 of a limb and arterial inlet cannula 344 inerted into artery 362 of a limb, via admixing chamber 346 fluidically coupled to pump 350 via inlet cannula 348. Accordingly, venous inlet cannula 342 may carry deoxygenated blood from vein 360 into chamber 346, and arterial inlet cannula 344 may carry oxygenated blood from artery 362 into chamber 346. Moreover, chamber 346 may include one or more motorized pumps configured to selectively draw blood from artery 362 into chamber 346 via arterial inlet cannula 344. In some embodiments, pump 350 and admixing chamber 346 may be integrated in a single unit, e.g., without requiring inlet cannula 348 to fluidically couple pump 350 and- 35 -713664833v3225914-021001 admixing chamber 346. Accordingly, the integrated unit may include a pump operatively coupled to venous inlet cannula 342 for drawing venous blood into the admixing chamber and another pump operatively coupled to arterial inlet cannula 344 for drawing arterial blood into the admixing chamber. As shown in FIG. 14, pump 350 may have a single return cannula, e.g., return cannula 352, inserted into a target vessel (e.g., vein or artery 364). For example, the controller may be programmed to initially only cause pump 350 to draw deoxygenated blood from vein 360 via venous inlet cannula 343, chamber 346, and inlet cannula 348, and deliver only the deoxygenated blood to target vessel 364 for a first time period.

[0105] The controller may then be programmed to simultaneously cause a predetermined amount of oxygenated arterial blood to be drawn from artery 362 into chamber 346 via arterial inlet cannula 344 to mix with the venous blood drawn from vein 360 to thereby form a first admixture of venous / arterial blood having first predetermined oxygenation level, e.g., predominantly low-oxygen blood, and cause pump 350 to deliver the first admixture to target vessel 364 via return cannula 352 for a second time period. The controller may be programmed to incrementally draw more arterial blood from artery 362 via arterial inlet cannula 344 into chamber 346 to form additional admixtures of venous / arterial blood, each having incrementally higher predetermined oxygenation levels, and to cause pump 350 to deliver the additional admixtures to target vessel 364 over additional time periods. Accordingly, the system may prevent reperfusion injury by initially reperfusing the limb with predominantly low-oxygen venous blood, and then incrementally, over time, increasing the oxygen content by mixing in more arterial blood.

[0106] As will be understood by a person skilled in the art, instead of or in addition to oxygenated arterial blood from artery 362, chamber 346 may further be fluidically coupled to an ECMO circuit, e.g., via an ECMO inlet cannula in fluidic communication with the ECMO circum, for receiving oxygenated transfused blood from the ECMO circuit to form the admixtures of blood having varying predetermined oxygenation levels for delivery to target vessel 364. Moreover, while FIG. 14 illustrates a single return cannula, e.g., return cannula 352, the system may include more than one return cannula fluidically coupled to pump 350 for selectively delivering the admixtures of oxygenated blood to different target vessels simultaneously. In such an embodiment, the system may include more than one admixing- 36 -713664833v3225914-021001 chamber, such that the controller may be programmed to selectively form admixtures having different oxygenation levels within each admixing chamber for selective delivery to the respective target vessels via the pump.

[0107] Turning now to FIGS. 2A and 2B, an alternative embodiment of a perfusion system constructed in accordance with the principles of the present disclosure is described. Perfusion system 50 is designed to provide similar functionality to system 10 of FIG. 1A, but employs double lumen cannula 52 instead of separate inlet and return cannulas. Cannula 52 includes distal end 54 having inlet 55, proximal end 56 having valved inlet port 58 and outlet port 60, and hemostatic valve 62 through which interventional or circulatory assist device 64 may be inserted. As depicted in FIG. 2B, cannula 52 has inlet lumen 66 and outlet lumen 68, which opens to skive 70 at a location proximal of distal end 54. NIRS sensor 69 may be located downstream of skive 70 to sense tissue oxygenation in the reperfused region. Inlet lumen 66 is sufficiently large that annulus 72 forms around shaft 74 of device 64, so that extracorporeal pump 76 may draw blood from the vessel through inlet 55 of distal end 54, annulus 72, and inlet port 58. Extracorporeal pump 76 is coupled to inlet port 58 and outlet port 60 of cannula 52 via tubing 78, so that blood exiting pump 76 passes through outlet port 60, lumen 68, and skive 70. Pump 76 may include built-in display panel 77 that serves as both an input device and display screen.

[0108] Extracorporeal pump 76 may be configured as described for the embodiment of FIG. 1A, and preferably includes pressure and flow sensors for monitoring flow characteristics, such as local blood pressure and flow rates, at the distal ends of the inlet and return cannulas. In addition, pump 76 may be configured to provide pulsatile flow to skive 70 to perfuse the extremities at controlled pressures or flow rates. It is expected that although skive 70 is opposed to the vessel wall, flow through lumen 68 will be sufficient to locally move cannula 52 away from the vessel wall to permit blood to freely flow in an antegrade direction.

[0109] Referring now to FIGS. 3A and 3B, a further alternative embodiment of a perfusion system of the present disclosure is described. System 80 includes multi-lumen cannula 82 coupled to extracorporeal pump 84 via tubing 86. Extracorporeal pump 84 suitable for use with cannula 82 may have any of the features for the embodiments described for the perfusion systems of FIGS. 1 and 2A. Cannula 82 is similar in design to cannula 52 of the embodiment of- 37 -713664833v3225914-021001FIGS. 2A and 2B, except that it further includes an occlusion balloon and an optional sealing balloon.

[0110] More specifically, cannula 82 includes distal end 88 having inlet 89, proximal end 90 having valved inlet port 92 and outlet port 94, balloon inflation ports 96 and 98, and hemostatic valve 100 through which interventional or circulatory assist device 102 may be inserted. As shown in FIG. 3B, cannula 82 has inlet lumen 104, balloon inflation lumens 106 and 108, and outlet lumen 110, which opens to skive 112 at a location proximal of distal end 88. Inlet lumen 104 is sufficiently large that annulus 114 forms around shaft 116 of device 102, so that extracorporeal pump 84 may draw blood from the vessel through inlet 89 of distal end 88, annulus 114, and inlet port 92. Extracorporeal pump 84 is coupled to inlet port 92 and outlet port 94 of cannula 82 via tubing 86, so that blood exiting pump 84 passes through outlet port 94, lumen 110, and skive 112.

[0111] Still referring to FIGS. 3 A and 3B, cannula 82 further includes occlusion balloon 118 disposed between distal end 88 and skive 112 to partially or completely block antegrade flow through the vessel, and optional elongated sealing balloon 120 disposed proximal of skive 112 to reduce blood leakage around cannula 82 where it enters the vessel. Occlusion balloon 118 is in fluid communication with inflation port 96 via inflation lumen 106, and aperture 122, which opens to the interior of occlusion balloon 118. Likewise, sealing balloon 120 is in fluid communication with inflation port 98 via inflation lumen 108 and aperture 124, which opens to the interior of sealing balloon 120. Occlusion balloon 118 preferably comprises a semi- compliant material, such as nylon, or compliant material such as polyurethane, which enables the balloon to conform to the diameter of the vessel to occlude, partially or fully, antegrade flow. Sealing balloon 120 preferably comprises a more rigid material, such as polyethylene terephthalate, which holds its shape during expansion, to provide tight approximation to the entry wound through which cannula 82 is inserted into the vessel. In particular, sealing balloon 120, if provided, may be inflated via inflation port 98 if, during operation of pump 84, the insertion site begins to bleed, thus stopping the bleeding and directing the blood exiting from skive 112 toward the patient’s extremities.- 38 -713664833v3225914-021001

[0112] Referring to FIGS. 4A and 4B, alternative structures for more evenly distributing blood exiting from skive 70 of cannula 52 of FIGS. 2A and 2B or skive 112 of cannula 82 of FIGS. 3 A and 3B are now described. In FIG. 4A, a portion of cannula 82 of FIGS. 3 A and 3B is depicted having multiple skives 112' and occlusion balloon 118' disposed distal to skives 112'. When inflated, occlusion balloon 118' assumes concave shape 125, such that blood exiting skives 112' impinges of the proximal surface of the balloon and is redirected in an antegrade direction. Occlusion balloon 118' may be molded to assume concave shape 125 during manufacture. In this manner, blood reperfused into the vessel from the extracorporeal pump may be more evenly redistributed and directed in an antegrade direction within the vessel without directly impinging upon the vessel wall.

[0113] FIG. 4B shows an alternative structure that may be used to distribute flow returned through skive 70 of cannula 52 or skive 112 of cannula 82. Diffuser 130 comprises a thin- walled layer of shrink tubing 132 that includes a multiplicity of holes 134, and is affixed to the cannula over the skive 70 of cannula 52, or skive 112 of cannula 82, to more evenly distribute blood returned from the extracorporeal pump. In particular, diffuser 130 may be bonded to the cannula using a heat weld or suitable biocompatible glue along lines 136. Diffuser 130 reduces the risk that blood returned to the vessel through the skive will jet against the vessel wall at high velocity. In addition, diffuser 130 may be readily flushed with saline prior to use without causing the cannula to become bulky or impede insertion. In such embodiments of FIGS. 3 A and 3B, it may be desirable to place the local blood pressure sensor in the vessel downstream of diffuser 130.

[0114] FIGS. 5 A and 5B depict additional modifications that may be made to cannula 82 of the embodiment of FIGS. 3 A and 3B. FIGS. 5 A and 5B depict the distal end of the perfusion cannula (e.g., cannula 82), and omits the interventional or circulatory assist device, which may extend through the inlet lumen of the cannula and distal end. In the embodiment of FIG. 5 A, occlusion balloon 118 and skive 112 are combined into dual layer balloon 140. Balloon 140 may be formed of a semi-compliant material, such as nylon, or compliant material such as polyurethane, and includes upper compartment 142 separated from lower compartment 144 by fluid impermeable membrane 145. Sealed upper compartment 142 is configured to expand into contact with the vessel wall when filled with saline through aperture 122. Lower compartment- 39 -713664833v3225914-021001144 is in fluid communication with skive 112, and includes lower surface 146 having a multiplicity of perforations 146.

[0115] In the arrangement of FIG. 5 A, upper compartment 142 of balloon 140 serves to partially or fully occlude the vessel, while lower compartment 144 delivers blood to the distal vessel. Optionally, separate balloons could be used instead of dual layer balloon 140, although the dual layer construction of balloon 140, more preferably disk-shaped, may be desirable to shorten the balloon so it may be readily inserted into a highly atherosclerotic vessel. In addition, the multiplicity of perforations 148 will ensure that blood is reperfused into the vessel away from the vessel wall. FIG. 5B depicts an alternative embodiment of a dual-layer balloon having sealed and perforated compartments similar to the design of FIG. 5 A. Dual-layer balloon 150 differs from balloon 140 principally in that the top surface of balloon 150 forms funnel shape 152, while perforated lower surface 154 of the balloon also may be inclined relative to the vessel wall, to further distribute blood reperfused into the vessel. In such embodiments of FIGS. 5A and 5B, it may be desirable to place the vessel pressure sensor within the vessel downstream of perforated lower surface 154.

[0116] Referring now to FIG. 6, a further alternative embodiment of a perfusion system of the present disclosure is described. In FIG. 6, elements of the system that are common to the embodiments of FIG. 2A and FIG. 3 A are omitted for clarity. Cannula 160 is a dual lumen cannula as described above with respect to FIG. 2A. Balloon 162 is affixed to the cannula so that the interior of balloon 162 communicates with skive 164, through which blood is delivered by the extracorporeal pump (e.g., pump 76 of FIG. 2A) into the vessel. Balloon 162 includes a multiplicity of perforations 166 in its lower surface. In this manner, balloon 162 expands at least partially to occlude the vessel when blood from the extracorporeal pump is delivered into the interior of balloon 162. The blood then exits balloon 162 through a multiplicity of perforations 166 and flows in an antegrade fashion to the patient’s extremities. In such embodiments of FIG. 6, it may be desirable to place the vessel pressure sensor within the vessel downstream of balloon 162.

[0117] FIG. 7 depicts a further alternative embodiment of a perfusion system constructed in accordance with the principles of the present disclosure. System 170 differs from the preceding- 40 -713664833v3225914-021001 embodiments in that its inlet catheter may be employed to perform an interventional procedure, e.g., to treat peripheral artery disease, and thereafter used as part of a perfusion system to reduce the risk of limb ischemia. As depicted in FIG. 7, system 170 includes inlet cannula 172 and return catheter 174 coupled to extracorporeal pump 176 by tubing 178. Extracorporeal pump 176 may be any of the pumps described throughout this specification.

[0118] Inlet cannula 172 has distal end 180 having inlet 182, proximal end 184 including outlet port 186 and hemostatic port 188, and inlet lumen 190 extending between distal end 180 and proximal end 184 and also in fluid communication with outlet port 186. Inlet cannula 172 is configured to be placed in an antegrade manner in a limb, such as an arm or leg, for performing an interventional procedure. Once that treatment is completed, inlet cannula 172 may be left in place and employed as part of the perfusion system, as described below.

[0119] Return cannula 174 has proximal end 192 including inlet port 194, outlet 196, and lumen 198 extending therebetween. Return cannula 174 preferably is longer than inlet cannula 172, and has a diameter selected so that, when inserted through inlet cannula 172, annulus 200 is created in inlet lumen 190 to permit blood to be drawn through inlet 182, annulus 200, and outlet port 186 to extracorporeal pump 176. Return catheter 174 is inserted through hemostatic port 188. The inlet and outlet cannulas then may be coupled to extracorporeal pump 176 by tubing 178. In operation, pump 176 draws blood through inlet 182, annulus 200, and outlet port 186 to the pump, and then expels the blood through inlet port 194, lumen 198, and outlet 196 of return cannula 174 in an antegrade direction into the vessel, at a controlled pressure or flow rate determined by pump 176 based on user input, or as determined by the pump controller.Alternatively, return cannula 174 may be placed in the patient’s contralateral arm or leg, as may be required to reduce the risk of limb ischemia.

[0120] In a yet further embodiment, an inlet cannula may be inserted in more than one artery or vein, and blood delivered by the extracorporeal pump may be reperfused to more than one extremity. For example, an extracorporeal pump may include two or more inlets, such that one inlet may be connected to a cannula located in an artery and a second inlet may be coupled to a cannula placed in a vein of a limb. Blood delivered by the extracorporeal pump may be reperfused into the artery downstream of an obstruction, while venous blood may be drawn from- 41 -713664833v3225914-021001 the limb, thereby creating a further gradient to enhance perfusion of the limb. Alternatively, an extracorporeal system may be configured to have a single inlet but multiple outlets, so that oxygenated blood directed to the pump may be reperfused in multiple limbs. In another alternative embodiment, the return cannula may deliver the blood to afferent lymph vessels of the lymphatic system to reduce or prevent venous thrombosis, peripheral edema or lymphedema.

[0121] Referring now to FIG. 8, exemplary mechanism 210 for a roller-type pump suitable for use as the extracorporeal pump of the perfusion system is provided. As will be understood by persons of skill in the art of pump design, mechanism 210 may include rotor 212 that carries a plurality of rollers 214, e.g., two or more rollers. Rollers 214 contact plastic tubing 216, which tubing connected to inlet port 218 and outlet port 220 of the pump. Rotor 212 is mounted on axle 222 that is coupled to an electric motor (not shown) either directly or via a suitable gear train, so that rotation of the rotor causes rollers 214 to ride along plastic tubing 216 to propel blood within the tubing from the inlet port 218 to outlet port 220. U.S. Patent No. 3,963,023 to Hankinson, incorporated herein by reference, provides additional details for roller pumps of the type depicted in FIG. 8. A suitable alternative blood pump design capable of generating pulsatile flow is described in U.S. Patent No. 9,295,767 to Schmid, also incorporated herein by reference. U.S. Patent No. 4,468,177 to Strimling describes a diaphragm type pump suitable for use as the extracorporeal pump of the inventive perfusion system, and is also incorporated herein by reference.

[0122] Referring now to FIGS. 9A, 9B, and 9C, a piston-type mechanism for use as the extracorporeal pump of the inventive system is described. Pump 230 includes piston 232 arranged to reciprocate within chamber 234, which communicates with inlet 236 and outlet 238. As will be understood by one of skill in the art of pump design, piston 232 is coupled to an electric motor via a gear system (not shown) that cyclically advances and retracts the piston head within chamber 234. One-way valve 240, e.g., a butterfly valve or flap valve, is located distal of inlet 236 and another one-way valve 242 is located proximal of outlet 238. Pressure sensor 244 monitors pressure within the conduit distal to outlet 238. In FIG. 9A, pump 230 is shown in an equipoise condition, in which blood is not being drawn into or expelled from chamber 234. In the event pressure sensor 244 detects a high pressure within the conduit while the vessel pressure sensor detects a low pressure, it may indicate that the tubing is blocked, clotted, or kinked. The- 42 -713664833v3225914-021001 controller may signal an alarm based on detection of a pressure differential exceeding a predetermined threshold.

[0123] FIG. 9B depicts an intake stroke of pump 230, during which inlet valve 240 opens to permit blood to be drawn into chamber 234 during retraction of piston 232. During this phase of operation, one-way valve 242 is closed and pressure sensor 244 registers a negative pressure.Once the piston reaches its minimum stroke, it reverses direction, causing one-way valve 240 to close and one-way valve 242 to open, and thus permit blood to flow through outlet 238, as shown in FIG. 9C. During this phase of operation, pressure sensor 244 registers a positive pressure. When piston 232 reaches its maximum stroke, it begins to reverse direction, thereby causing one-way valve 242 to close and one-way valve 240 again to open. In this manner, depending upon the speed at which the electric motor and gear train drives piston 232, a specified blood flow rate or pressure may be obtained at outlet 238. U.S. Patent No. 4,221,548 to Child, incorporated by reference herein, describes an alternative embodiment of a piston pump suitable for use in the perfusion system described herein.

[0124] FIGS. 10A and 10B are, respectively, an exemplary schematic of an extracorporeal pump and software for operating the system. More particularly, FIG. 10A is a schematic depicting the functional blocks of extracorporeal pump 250 for use in a perfusion system and includes processor 252 coupled to non-volatile memory 254, such as flash memory, electrically erasable programmable read only memory and / or a hard disk, and volatile memory 256 via data buses. Processor 252 is electrically coupled to electric motor 258, a plurality of sensors 260, user interface 262, and valve controller 264. Motor 258 may include a separate dedicated controller, which interprets and actuates motor 258 responsive to commands from processor 252.

[0125] Processor 252 executes programming, described with respect to FIG. 10B, stored in non-volatile memory 254 that controls operation of motor 258 responsive to signals generated by sensors 260 and input from user interface 262. Processor 252 is configured to monitor operation of motor 258 (and any associated motor controller) and sensors 260, as described below, and to store data reflecting operation of the pump, including event logs and alarms. Non-volatile memory 254 preferably comprises flash memory, EEPROM or a solid state or hard disk, and stores a unique device identifier for the pump, and firmware and programming to be executed by- 43 -713664833v3225914-021001 processor 252, configuration set point data relating to operation of the pump. Volatile memory 256 is coupled to and supports operation of processor 252, and stores data and event log information gathered during operation of pump 250.

[0126] Motor 258 is of a type selected to drive the pumping mechanism of the extracorporeal pump such as described above. User interface 262 may include an input device, e.g., corresponding to display panels 17 and 77 described above, or include input keys and a display for displaying input pump operational parameters, pump status, and sensed data. Sensors 260 may include pressure sensors at the inlet port and outlet port of the pump, pressure sensors in the artery or vein upstream of the inlet of the inlet cannula(s) and downstream of the outlet of the return cannula(s) for measuring intravascular blood pressure, blood and / or tissue oxygenation sensors such as NIRS, pH and / or lactate level sensors, as well as a flow sensor to determine the rate of flow of blood through the pump. Sensors 260 may be monitored by processor 252 to determine inlet and outlet blood pressures, local intravascular blood pressure, tissue oxygenation, and the occurrence of obstructions within the blood circuit.

[0127] Processor 252 may be in communication with valve controller 264; alternatively, valve controller 264 may be part of the functionality of processor 252. Valve controller 264 controls the actuation of any valves that may be used to control the flow of blood from the inlet port to the outlet port. Valve controller 264 also may coordinate the actuation of one-way valves in the embodiment of FIGS. 9A to 9C, e.g., one-way valves 240 and 242.

[0128] Turning now to FIG. 10B, software 270 for operating extracorporeal pump 250 of FIG. 10A is described. It will be understood that software 270 is implemented as programming that is run by processor 252 to control, inter alia, operation of motor 258 of the extracorporeal pump. Software 270 comprises a number of functional blocks, including main block 272, sensor block 274, alarm detection block 276, event logging block 278, user interface block 280, configuration setup block 282, and Al module 284. In one embodiment, the software is configured to run on top of a Microsoft Windows® (a registered trademark of Microsoft Corporation, Redmond, Wash.) or Unix-based operating system.

[0129] Main block 272 preferably consists of a main software routine that executes on processor 252, and controls overall operation of the other functional blocks. Main block 272- 44 -713664833v3225914-021001 enables the operator to input operational data for the pump via User Interface 280 and User Interface 262, as well as to display operational and status data for the pump, including pump outlet pressure and / or flow rate, local blood pressure, tissue oxygenation levels, and alarm limit data. Main block 272 also controls operation of motor 258 and monitoring of sensors via Sensor block 274.

[0130] Alarm Detection block 276 may include a routine for evaluating the data received from sensors 260 to determine the occurrence of abnormal conditions for the operator’s attention. For example, Alarm Detection block 276 may be configured to alert the operator to a departure of the sensor data from the preset values, or to identify potential occlusions in effecting the pump operation, or displacement of the catheter from the vessel lumen. Alarm detection block 276 also may be configured to detect an increase in vascular resistance and / or pressure in the patient’s extremities, as well as potentially slow flow conditions that could lead to limb ischemia. Further, alarm detection block 276 may be configured to detect a decrease limb tissue oxygenation. Such alarms may be communicated to the operator via a display of User Interface 262. This information may be stored by Event Log block 278 in non-volatile memory 254 to create a record of the pump operational data, including pump operating times, and pressure / flow data.

[0131] User interface block 280 handles receipt of data input by the operator, as well as display of information about the pump operational status in an intuitive, easily understood format for operator review. Configuration Setup block 282 is a routine that configures the parameters stored within non-volatile memory 254 that control operation of pump 250, including the required pump output pressure, local blood pressure, flow rate, tissue oxygenation, and any limit values used to assess the occurrence of alarm conditions. Block 282 also may configure parameters stored within non-volatile memory 254 of relating to control of operation of processor 252 and motor 258.

[0132] Al Module block 284 may include programming that permits the extracorporeal pump automatically to optimize the local blood pressure and tissue oxygenation levels for a specific patient to reduce the risk of limb ischemia. In particular, Al Module 284 may include programming that initiates pump operation at a pressure and / or tissue oxygenation level initially- 45 -713664833v3225914-021001 set by a human operator. Then, based on monitored pressure data from the limb and / or monitored tissue oxygenation levels, the Al module may step through a series of pump speeds to adjust the flow rate while also monitoring the pressure in the patient’s extremities. In one embodiment, Al Module 282 then may continue further operation of the pump by selecting the pump speed that produces the highest monitored flow rate at the lowest pressure.

[0133] In an alternative embodiment, Al Module 282 may be configured to activate a built in or inline ECMO system if it is determined that increased flow rate or local blood pressure is not enough to maintain a target level of oxygenation in the tissue of the extremities. In a further embodiment, Al Module 282 may activate the ECMO to cause hyperbaric oxygenation of the blood to further increase tissue oxygenation. In yet another embodiment, the pump circuit may act as a passive bypass until sensors 260 detect tissue oxygenation levels that drop below a target value. When it is detected the tissue oxygenation levels drop below a target value, Al Module 282 then may activate the pump to increase local blood pressure in the reperfused region.

[0134] Referring now to FIGS. 15 A and 15B, an exemplary valve actuation mechanism of the flow regulators described herein, e.g., actuatable valve 404, is provided. FIG. 15A illustrates actuatable valve 404 in an unactuated state where blood flow through the return cannula is permitted, e.g., return cannula 406, and FIG. 15B illustrates actuatable valve 404 in an actuated state wherein blood flow is prevented / restricted through the return cannula 406. As shown in FIGS. 15A and 15B, actuatable valve 404 may include pinch slider 405 operatively coupled to return cannula 406, and motor 403 operatively coupled to the system controller and configured to actuate pinch slider 405. For example, motor 403 may be actuated to cause pinch slider 405 move between the unactuated state, as shown in FIG. 15A, where pinch slider 405 is not engaged with return cannula 406, and the actuated state, as shown in FIG. 15B. wherein pinch slider 405 is engaged with return cannula 406 to thereby prevent blood flow therethrough. In some embodiments, actuatable valve 404 may be selectively actuated such that motor 403 may cause pinch slider 405 to restrict blood flow through return cannula 406 by a predetermined amount, to thereby selectively control / adjust the blood flow rate through the return canniula, e.g., to deliver blood to the target vessel at a selected local pressure in the local pressure control mode by dynamically adjusting the blood flow rate to achieve and maintain the selected local pressure- 46 -713664833v3225914-021001 and / or to deliver blood to the target vessel at a predetermined set flow rate in the flow mode, as described above.

[0135] Referring now to FIG. 16, exemplary perfusion system 500 for selectively controlling the return of ECMO blood to the patient, e.g., without requiring an extracorporeal pump, is provided. As shown in FIG. 16, system 500 may include connector 504, e.g., a T orY shaped connector, fluidically coupled to the main return cannula of an ECMO circuit, e.g., main return cannula 502 configured to deliver ECMO blood to a first target region of the patient’s vasculature for perfusion thereof. Connector 504 may be configured to direct at least some ECMO blood from main return cannula 502 through lower return cannula 506 to a second target region of the patient’s vasculature, e.g., an artery or vein of the patient’s distal extremities, for perfusion thereof. As shown in FIG. 16, system 500 may include a flow regulator, e.g., actuatable valve 510, fludicially coupled to lower return cannula 506. Acutatable valve 510 may be constructed similar to actuatable valve 404 described above. Accordingly, actuatable valve 510 may be selectively actuated to control high pressure blood flow from the ECMO circuit through lower return cannula 506, e.g., to deliver blood to the target vessel at a selected local pressure in the local pressure control mode.

[0136] For example, as shown in FIG. 16, system 500 may include ECMO pressure sensor 508, e.g., a pressure transducer configured to measure pressure of the ECMO circuit upstream of actuatable valve 510. ECMO pressure sensor 508 may be operatively coupled to actuatable valve 510 to thereby transmit feedback signals indicative of the sensed ECMO pressure to actuatable valve 510. In addition, system 500 may include intravascular pressure sensor 512 in fluid communication with the second target region of the patient’s vasculature for measuring the local intravascular vessel pressure at the patient’s distal extremities. Intravascular pressure sensor 512 may constructed similar to intravascular pressure sensor 41 described above, and may be operatively coupled to actuatable valve 510 to thereby transmit feedback signals indicative of the sensed local intravascular vessel pressure to actuatable valve 510. Accordingly, based on the sensed ECMO pressure and the sensed local intravascular vessel pressure, the controller of system 500 operatively coupled to actuatable valve 510 may selectively actuate actuatable valve 510 to regulate blood flow through lower return cannula 506 to thereby perfuse the second target region of the patient’s vasculature at the selected local pressure in the local pressure control- 47 -713664833v3225914-021001 mode. Additionally, or alternatively, the intravascular pressure sensor may be integrated with the lower return cannula, as described in further detail with regard to FIG. 17A.

[0137] Referring now to FIG. 17A, an exemplary return cannula comprising an integrated intravascular pressure sensor is provided. Return cannula 600 may be configured for insertion within a patient’s vasculature for perfusion of the patient’s distal extremities, and to measure pressure within the return cannula at or adjacent the outlet of the return cannula, which is effectively equal to the local intravascular pressure. As shown in FIG. 17A, return cannula 600 may include cannula body 601 comprising an internal wall, e.g., septum 606, extending within the lumen of cannula body 601 between proximal portion 602 and distal portion 604, to thereby define a first lumen, e.g., flow lumen 610, and a second lumen, e.g., pressure sensing lumen 614, separated via septum 606. Flow lumen 610 may fluidically couple tubing 611 at proximal portion 602 to outlet 612 of return cannula 600 at distal portion 604, to thereby permit blood flow from tubing 611 through flow lumen 610 and out outlet 612 for perfusion of the target vasculature, e.g., at the selected local pressure in the local pressure control mode or the target flow rate in the flow mode. Accordingly, tubing 611 may be fluidically coupled to the outlet of an extracorporeal pump, as described above.

[0138] Return cannula 600 may include an opening, e.g., skive 608, extending through septum 606 at distal portion 604 at a location close to or adjacent outlet 612 of return cannula 600 to fluidically couple flow lumen 610 and pressure sensing lumen 614. Skive 608 may be sized and shaped to permit sensing of pressure within flow lumen 610 at or adjacent outlet 612 of flow lumen 610, which has been observed to be essentially and effectively equal to the local intravascular pressure of the blood vessel within which distal portion 604 is disposed. For example, as shown in Table 1 below, in a test setup to compare intravascular pressure measured directly within a vessel via a pressure transducer with pressure measured within the flow lumen adjacent the outlet of the flow lumen within the vessel, e.g., via a prototype of return cannula 600, the Applicant of the instant application observed that the pressure values measured via return cannula 600 (“Pressure Lumen Transducer”) were either identical to or very close to the pressure values measured via the pressure transducer (“Vessel Transducer”) across a range of predefined flow rates (e.g., in the flow mode) within the vessel, e.g., from 0 - 700 cc / min, as all- 48 -713664833v3225914-021001 of the pressure drop in the system has occurred. A restriction clamp was used to obtain five sample pressures at each predefined flow rate.Table 1

[0139] Preferably, skive 608 comprises a single opening extending across septum 606 between flow lumen 610 and pressure sensing lumen 614. Alternatively, in some embodiments, skive 608 may comprise more than one opening extending across septum 606 at distal portion 604. As shown in FIG. 17A, pressure sensing lumen 614 may fluidically couple tubing 615 at proximal portion 602 to skive 608 at distal portion 604, to thereby permit sensing of pressure - 49 -713664833v3225914-021001 within flow lumen 610 via skive 608. For example, tubing 615 may be fluidically coupled to a pressure tranducer configured to generate one or more signals indicative of pressure within flow lumen 610 sensed at skive 608. Alternatively, in some embodiments, the pressure within flow lumen 610 at distal portion 604 may be sensed via an inward facing solid state or fiber optic sensor at skive 608. As shown in FIG. 17A, return cannula 600 further may comprise plug 616 disposed within pressure sensing lumen 614 distal to skive 608. Plug 616 may be sized and shaped to fill the space within pressure sensing lumen 614 between skive 608 and the distal end of cannula body 601, to thereby prevent stasis and clot formation and propagation within the space.

[0140] Unlike traditional pressure sensing catheters with outward facing skives that contact blood within a vessel for measuring intravascular pressure within the vessel, which may press against and be blocked by the vessel wall and are prone to clot off with thrombus, by having skive 608 disposed within cannula body 601 (“inward looking”), the risk of the pressure sensing capability of skive 608 being blocked by the vessel wall is eliminated. Moreover, as skive 608 is in fluidic communication with a high flow region of flow lumen 610, e.g., at distal portion 604 of return cannula 600, and contained within cannula body 601, a continuous drip through pressure sensing lumen 614, which is generally required for all pressure sensing catheters with open lumens, may not be required due to the high flow rate of fluid past skive 608. By eliminating the need of a continuous drip, e.g., 3 cc / hour, return cannula 600 allows for low cost, traditional fluid column pressure sensing via the external pressure transducer. Additionally, the high flow rate of fluid past skive 608 may also prevent thrombus formation at skive 608 and, thus, skive 608 may be less prone to clot off with thrombus. In some embodiments where a continuous drip, e.g., 3 cc / hour, may be needed, rather than delivering the drip via a big pressure bag and / or a bag of saline, the systems described herein may deliver the drip via a spring-loaded syringe, e.g., a spring-load 30cc syringe configured to provide drip for 10 hours.

[0141] As described above, the return cannulas described herein may comprise a drug delivery port configured to deliver a drug to the target vessel during pressurized perfusion, which may facilitate drug absorption by the target tissue. For example, FIG. 17B illustrates an alternative exemplary return cannula comprising an integrated intravascular pressure sensor and drug delivery port. Return cannula 600' may be constructed similar to return cannula 600, with- 50 -713664833v3225914-021001 similar components having like-prime reference numerals. For example, cannula body 601' comprising septum 606' extending between proximal portion 602' and distal portion 604' and having skive 608', flow lumen 610' having outlet 612' and fluidically coupled to tubing 611', pressure sensing lumen 614' having plug 616' and fluidically coupled to pressure transducer tubing 615' correspond with cannula body 601 comprising septum 606 extending between proximal portion 602 and distal portion 604 and having skive 608, flow lumen 610 having outlet 612 and fluidically coupled to tubing 611, pressure sensing lumen 614 having plug 616 and fluidically coupled to pressure transducer tubing 615.

[0142] Return cannula 600' differs from return cannula 600 in that return cannula 600' may comprise an additional lumen, e.g., drug delivery lumen 618, extending between proximal portion 602' and distal portion 604' and sized and shaped to deliver a drug to the target area of the patient’s vasculature. As shown in FIG. 17B, drug delivery lumen 618 may fluidically couple tubing 619 at proximal portion 602' to outlet 620 of return cannula 600' at distal portion 604', to thereby permit delivery of a drug from tubing 619 through drug delivery lumen 618 and out outlet 620 to the target area of the patient’s vasculature. Accordingly, tubing 619 may be fluidically coupled to a source of a drug, as described above. Moreover, as described above, outlet 620 may be positioned to deliver the drug in a retrograde direction, e.g., towards a clot within the patient’s vasculature. Accordingly, while FIG. 17B illustrates outlet 620 facing in the distal direction of return cannula 600', in some embodiments, outlet 620 may be disposed on a lateral outer surface of cannula body 601', and further may be angled to direct flow of the drug in a desired direction.

[0143] Referring now to FIGS. 18A to 18E, an exemplary method for manufacturing return cannula 600 is provided. As shown in FIG. 18A, return cannula 600 may be formed from an off- the-shelf, commercially available dual lumen catheter such as an Arrow 12 Fr, 16 cm, 2 lumen catheter (made available by Teleflex, Wayne, Pennsylvania) having dual lumen cannula body 601 fluidically coupled to flow tubing 611 and pressure transducer tubing 615, as described above, and one or more outward facing skives at the distal region of cannula body 601. As shown in FIG. 18B, the distal region of cannula body 601 may be cut, e.g., at a location just proximal to the one or more outward facing skives, thereby forming outlet 612 at distal portion 604 of return cannula 600 and exposing flow lumen 610 and pressure sensing lumen 614,- 51 -713664833v3225914-021001 separated via septum 606, as shown in FIG. 18C. Next, a cut may be made lengthwise from the distal end of cannula body 601 along the portion of cannula body 601 that defines flow lumen 610, e.g., along a plane extending perdicular to the plane of septum 606 and intersecting the central longitudinal axis of septum 606. The cut may comprise a predetermined length, e.g., 1 cm, such that the skive may be created at a location within 1 cm from the distal end of cannula body 601.

[0144] As shown in FIG. 18D, spacer S may be temporarily positioned within the distal region of flow lumen 610 to thereby separate the halves of cannula body 601 along the cut line and provide access to septum 606 for the creation of skive 608. Accordingly, skive 608 may be created in septum 606, e.g., via drilling or the like, at a target location from the distal end of cannula body 601, e.g., 0.5 to 1 cm from the distal end of cannula body 601, and preferably 0.8 cm from the distal end of cannula body 601. Preferably, skive 608 may comprise a 1 mm opening extending through septum 608. As will be understood by a person having ordinary skill in the art, skive 608 may be sized and shaped to permit accurate pressure sensing of flow within flow lumen 610 and, thus, may be smaller or larger than 1 mm. As shown in FIG. 18E, the distal region of pressure sensing lumen 614 may be filled with, e.g., epoxy, to form plug 616, and the cut may be sealed via an adhesive to thereby define outlet 612 at the distal end of flow lumen 610. For example, a plug may be inserted through skive 608 and temporarily positioned within pressure sensing lumen 614, e.g., to temporarily block fluid flow within pressure sensing leumn 614 beyond the plug, such that the epoxy may be injected into the distal region of pressure sensing lumen 614 to fill the space between the distal end of cannula body 601 and the plug. The epoxy may then be cured to form plug 616, the tempory plug removed from skive 608, and the cut line of cannula body 601 sealed.

[0145] Alternatively, a well fit plug having a predefined geometry corresponding to the geometry of pressure sensing lumen 614 and having a length corresponding to the distance between skive 608 and the distal end of cannula body 601 may be inserted into pressure sensing lumen 614 through the distal end of cannula body 601 and adhered therein to form plug 616. For example, the well fit plug may be pre-cut with a ramp having a geometry that mimics the shape of pressure sensing lumen 614 to create a well fit coverage of pressure sensing lumen 614 distal to skive 608. As will be understood by a person having ordinary skill in the art, skive 608 may- 52 -713664833v3225914-021001 instead be formed by cutting along the portion of cannula body 601 that defines pressure sensing lumen 614, which may be sealed prior to insterion of plug 616 within pressure sensing lumen 614 distal to skive 608, as described above.Preliminary Experimental Observations

[0146] Initial testing of the proposed reperfusion pump system and methods of the present disclosure has been conducted in a porcine model. The results of that testing demonstrated unexpected, beneficial results as described below.Vascular Pressure Controlled Pump vs Passive Bypass

[0147] FIG. 19 is a screenshot of a display depicting vascular blood pressure and oxygen saturation in the legs of a pig. In this experiment, the inventive pump circuit was used to create a blood circuit from the carotid artery to the left leg (top graph), while a passive circuit was created by tubing inserted at one end into the other carotid artery and at the other into the right leg (bottom graph). In both legs, continuous NIRS measurements were taken to determine absolute tissue saturation (StCh) levels through various stages of the reperfusion process, with the digital readouts to the right of the graphs showing the StCh levels at the end of the experiment. The top line of each graph, indicates the reference values of non-occluded regions of the animal (81% for the right leg; 73% for the left leg). The lower line in the top graph (indicated as 77% StCh) corresponds to NIRS measurements of the StCh levels in the left leg (with the inventive pump circuit) after occlusion of that leg. The lower line of the lower graph (indicated as 55% StCh) corresponds to NIRS measurements of the StCh levels in the right leg with just passive bypass. At the initiation of the NIRS measurements, both legs were occluded with no form of reperfusion to reduce the StCh levels in each leg. Once quasi-static levels were reached, the NIRS measurements were recorded for five minutes before reperfusion was initiated. At the five minute mark, as noted by the asterisk (*), both the passive bypass and the inventive pump system were activated. In the left leg (top graph) it can be seen that vascular pressure controlled perfusion resulted in higher perfusion of the leg tissue as indicated by the steep curve ending at 77% StO2. The right leg (bottom graph) shows that the passive bypass has little reperfusion value as indicated by the flat curve ending at 55% StO2. The experiment demonstrates that a- 53 -713664833v3225914-021001 passive system does not oxygenate the tissue as much as the inventive pump circuit in which vascular blood pressure is controlled.Absolute Tissue Saturation (StCh) and the Blood’s Partial Pressure of Oxygen (PaO2)

[0148] FIGS. 20 A and 20B show the results of a second experiment, in which flow was occluded (the iliac artery closed off) to cause ischemia in one leg of a pig, followed by passive bypass reperfusion and then vascular controlled pressure reperfusion with the inventive pump system. FIG. 20A depicts StO2 levels during five sequential intervals, while FIG. 20B depicts the PaO2 levels at the same five intervals. Point 1 represents a base level of StO2 and PaO2 that was measured before occlusion occurred. Point 2 corresponds to occlusion of the leg for twenty minutes to induce ischemia, as shown by the drastic drop in both levels. Point 3 corresponds to provision of passive bypass for about fifteen minutes, ending at Point 4. Notably, during passive bypass, the blood oxygenation level rises substantially (to 246.9), although tissue oxygenation, as determined by the NIRS measurement, shows virtually no increase, from 27% StCh to only 28% StCh. At Point 4 in FIGS. 20A and 20B, the passive bypass was terminated for about 90 seconds to return the limb to an ischemic state. Then, from points 4 to 5, the described vascular pressure- controlled system described herein was activated. After one minute, the blood oxygenation level returned to normal, from 128.8 Path to 315.5 PaCh. Importantly, however, tissue oxygenation as measured by the NIRS sensor also rose significantly, from 15% StCh to 41% StCh. The foregoing preliminary results demonstrate that reperfusing an ischemic limb at a controlled vascular pressure provides much higher oxygen uptake than simply flowing physiologic flow rates. Applicants hypothesize that vascular blood pressure causes higher oxygen exchange in the capillary beds of the limb than can be achieved merely by providing physiologic flow rates to the reperfused vessel.% Tissue Oxygenation for Vascular Pressure Controlled Pump vs Passive Bypass

[0149] In the clinical situation around the occlusion of the lower extremities, initial animal research has demonstrated that the passive bypass circuit does not increase tissue perfusion in an animal model where there is total occlusion of the vasculature of the animal’s leg; however, including a pump in the circuit in accordance with the principles of the present disclosure was shown to increase tissue perfusion. FIGS. 21 A and 21B are graphs illustrating the results of two- 54 -713664833v3225914-021001 animal tests where the vessels of both legs of the animals were occluded. The y-axis is the “% Tissue Oxygenation” as measured by a Near-Infrared System (NIRS) where >50% indicates normal perfusion, and the x-axis is time. In the first animal test shown in FIG. 21 A, after 60 minutes of total occlusion where there is an expected drop in perfusion to the legs as measured by the NIRS system, a passive bypass circuit was created in both legs. The passive bypass circuit was left open for 180 minutes in both legs (orange and blue curves) and as shown in FIG. 21 A, there was no improvement in the perfusion of the leg as measured by the NIRS system.

[0150] In the second animal test shown in FIG. 2 IB, similar to the first animal of FIG. 21 A, both legs of the animal were occluded for 60 min and then bypasses were created in the legs of the animal. In one of the legs (orange curve) a vascular pressure controlled pump operating in the local pressure control mode described herein was placed and turned on for 120 min. In the other leg (blue curve), the passive bypass circuit was left open for the same 120 minutes. During the time when the vascular pressure controlled pump was pumping, the perfusion pressure increased to normal values as shown by the orange curve in FIG. 21B while the leg with just a passive bypass circuit did not show any improvement in perfusion as shown by the blue curve.

[0151] Lastly, in the second animal, after 120 minutes of pumping with the vascular pressure controlled pump (orange) and the passive bypass circuit (blue), the vascular pressure controlled pump was switched to the leg which was passively perfused (blue) and immediately the perfusion pressure in the leg normalized. In addition, the leg that was pumped by the vascular pressure controlled pump was subsequently allowed to be perfused only passively and its perfusion pressure decreased, as shown in FIG. 21B.Pressure versus Flow Plots from Feasibility Animal Study

[0152] To test the concept of using the feedback from the pressure transducers to control the flow rate of the peristaltic pump to maintain a constant intravascular pressure, a prototype vascular pressure controlled pump system was developed. This system was evaluated during several feasibility animal studies in which other systems were also evaluated in addition to the prototype vascular pressure controlled pump system. The prototype system tested the overall concept of flow control to a set pressure, and the prototype pump used off-the-shelf components and a custom designed interface and control software / circuit to allow for the modulation of flow- 55 -713664833v3225914-021001 to maintain the desired intravascular pressure setpoint. This prototype pump was used in two animals to start to develop the algorithms needed to safely control the flow to the desired pressure. FIGS. 22A and 22B are graphs illustrating pressure (green curve) and flow rate of the pump (blue curve) when used to pump blood to the extremities of a pig.

[0153] As shown in FIG. 22A, the flow (blue curve) started off low but then had to increase over time to maintain the set intravascular pressure of 80 mmHg (green curve). As shown in FIG. 22B, the flow required was high at the beginning but then was reduced to maintain the 80 mmHg intravascular pressure setpoint. In FIGS. 22 A and 22B, the green pressure plot was able to remain constant while the blue flow rate plot showed variations because the flow variations were a result of different feedback loop methods and other aspects of the animal studies, including the use of different vasodilators.Conditional Changes in Distal Limb Pressure Index (DLPI) and Mean Arterial Pressure (MAP)

[0154] FIGS. 23 A to 23D are graphs depicting conditional changes in Distal Limb Pressure Index (DLPI) and mean arterial pressure (MAP) from a feasibility study. DPLI is a novel index defined herein as the ratio of distal limb pressure, e.g., local pressure within the target vasculature of the patient’s ischemic extremity such as the patient’s superficial femoral artery (SFA), and the patient’s MAP, which may be measured anywhere in the patient’s body such as the patient’s radial artery. The distal limb pressure measured within the SFA may be the mean arterial pressure within the SFA (e.g., SFA-MAP). Accordingly, a low DLPI value may indicated a large reduction in blood flow to the patient’s distal limb, e.g., the patient’s leg. The DLPI values pre- and post- active bypass using the systems described herein may be a strong indicator of the viability of the patient’s distal limb, e.g., leg. Alternatively, as the SFA has pulsatile flow, the distal limb pressure measured within the SFA for computing the DLPI value may be the systolic pressure or the diastolic pressure within the SFA.

[0155] FIGS. 23 A and 23B are graphs illustrating clinical data for six patients requiring peripheral VA-ECMO for cardiogenic shock, where the distal limb pressure within the SFA was measured via pressure wires, and limb tissue oxygenation was measure using near infrared spectroscopy (NIRS). The data was collected before arterial cannula insertion (“Pre-ECMO: no cannula”), after arterial cannula insertion within the SFA (“Pre-ECMO: with cannula”), after- 56 -713664833v3225914-021001 passive bypass without VA-ECMO activation (“Passive Bypass”), and then during active bypass ten minutes after VA-ECMO initiation (“Active Bypass”) whereby distal limb pressure was measured within the SFA and the patient’s MAP was measured within the patient’s radial artery. Passive bypass was performed by supplying blood to the SFA from the contralateral limb via a distal perfusion catheter, and active bypass was performed by coupling a distal perfusion catheter to the VA-ECMO circuit to pressurize blood flow to the SFA.

[0156] As shown in FIG. 23 A, during “Pre-ECMO: no cannula,” the patient’s distal limb pressure (e.g., SFA-MAP) was 62 mmHg and the patient’s MAP was 78 mmHg, such that the DLPI for “Pre-ECMO, without arterial cannula” is approximately 0.80, as shown in FIG. 23B. Moreover, as shown in FIGS. 23A and 23B, during “Pre-ECMO: with cannula,” the patient’s distal limb pressure was 37 mmHg and the patient’s MAP was 77 mmHg, such that the DLPI is approximately 0.49; during “Passive Bypass,” the patient’s distal limb pressure was 45 mmHg and the patient’s MAP was 75 mmHg, such that the DLPI is approximately 0.60; and during “Active Bypass,” the patient’s distal limb pressure was 65 mmHg and the patient’s MAP was 78 mmHg, such that the DLPI is approximately 0.89. Thus, as shown in FIGS. 23 A and 23B, when active flow is initiated in the extracorporeal blood pump for perfusion of the patient’s SFA, the patient’s distal limb pressure increased to 65 mmHg, thereby increasing the DLPI to 0.89, which is close to normal, e.g., “normal” DLPI is 1; whereas, when passive bypass was initiated to perfuse the patient’s SFA, the patient’s distal limb pressure only increased to 45 mmHg, such that the DLPI was 0.60. NIRS values were unchanged across conditions. Moreover, arterial cannula insertion significantly reduced SFA-MAP (p<0.01) and the DLPI (p=0.02), and passive bypass before VA-ECMO activation failed to raise SFA-MAP (p=0.72) or DLPI (p=0.46); whereas, active bypass significantly increased SFA-MAP (p=0.02) and DLPI (p<0.01) after cannula insertion and provided superior increases in SFA-MAP (p=0.03) and DLPI (p=0.001) compared to passive bypass.

[0157] FIGS. 23 C and 23D are graphs illustrating clinical data from another study where data was collected before arterial cannula insertion (“Pre-ECMO, without arterial cannula”), after arterial cannula insertion within the SFA (“Pre-ECMO, with arterial cannula”), after passive bypass without VA-ECMO activation (“Passive Bypass, off ECMO”), after passive bypass with VA-ECMO activation (“Passive Bypass, on ECMO”), and then during active bypass after VA-- 57 -713664833v3225914-021001ECMO initiation (“Active Bypass”), whereby distal limb pressure was measured within the SFA and the patient’s MAP was measured within the patient’s radial artery. Passive bypass was performed by supplying blood to the SFA from the contralateral limb via a distal perfusion catheter before and after VA-ECMO activation, such that after VA-ECMO activation, the patient’s distal limb was perfused by the patient’s systemic pressure, which was supported by the ECMO circuit. Active bypass was performed by coupling a distal perfusion catheter to the VA- ECMO circuit to pressurize blood flow to the SFA.

[0158] As shown in FIG. 23C, during “Pre-ECMO, without arterial cannula,” the patient’s distal limb pressure was 30 mmHg and the patient’s MAP was 77 mmHg, such that the DLPI for “Pre-ECMO, without arterial cannula” is approximately 0.39, as shown in FIG. 23D. Moreover, as shown in FIGS. 23C and 23D, during “Pre-ECMO, with arterial cannula,” the patient’s distal limb pressure was 23 mmHg and the patient’s MAP was 82 mmHg, such that the DLPI is approximately 0.28; during “Passive Bypass, off ECMO,” the patient’s distal limb pressure was 35 mmHg and the patient’s MAP was 81 mmHg, such that the DLPI is approximately 0.44; during “Passive Bypass, on ECMO,” the patient’s distal limb pressure was 37 mmHg and the patient’s MAP was 97 mmHg, such that the DLPI is approximately 0.38; and during “Active Bypass,” the patient’s distal limb pressure was 64 mmHg and the patient’s MAP was 77 mmHg, such that the DLPI is approximately 0.84. Thus, as shown in FIGS. 23C and 23D, when active flow was initiated in the extracorporeal blood pump for perfusion of the patient’s SFA, the patient’s distal limb pressure increased to 64 mmHg, thereby increasing the DLPI to 0.84, which is close to normal, as described above; whereas, when passive bypass was initiated to perfuse the patient’s SFA, the patient’s distal limb pressure only increased to 35 mmHg, such that the DLPI was 0.44, and when VA-ECMO was initiated during passive bypass, the patient’s distal limb pressure only increased to 37 mmHg, such that the DLPI was 0.38.

[0159] Accordingly, in local pressure mode, the patient’s DLPI value may be used to select the target local pressure, which ideally would be equal to the patient’s MAP. For example, if the patient’s distal limb pressure within the target vasculature for perfusion, e.g., the SFA, is low, e.g., around 70 mmHg, this would generally indicate unusually low blood flow to the patient’s limb. However, if the patient’s MAP is also low, e.g., around 70 mmHg, the patient’s DLPI value would be around 1, thereby indicating normal conditions for the patient. Thus, the- 58 -713664833v3225914-021001 controller of the system may be programmed to compute the patient’s DLPI based on the patient’s distal limb pressure and MAP as described above, and automatically set the target local pressure, e.g., as equal to the MAP, if the DLPI falls within a predetermined threshold.Moreover, the controller may be programmed to continuously monitor the patient’s MAP and adjust the pump parameters to maintain the patient’s DLPI value within a predetermined range, e.g., close to 1, such that the patient’s MAP does not get too high, e.g., indicating the patient is hypertensive, or too low, e.g., indicating the patient is hypotensive.

[0160] Additionally or alternatively, the controller of the system may be programmed to compute the patient’s Ankle-Brachial Index (ABI), e.g., a ratio of the blood pressure within the patient’s ankle and the blood pressure within the patient’s arm, which may be indicative of narrowed or blocked arteries in the patient’s distal extremities, and automatically set the target local pressure, e.g., as equal to the blood pressure within the patient’s ankle, if the ABI falls within a predetermined threshold. Similarly, the controller may be further programmed to continuously monitor the blood pressure within the patient’s arm and adjust the pump parameters to maintain the patient’s ABI value within a predetermined range, such that the blood pressure within the patient’s arm does not get too high, e.g., indicating the patient is hypertensive, or too low, e.g., indicating the patient is hypotensive.

[0161] FIGS. 24 A to 24C are graphs depicting superior distal limb perfusion via active bypass compared to passive bypass in a preclinical model of acute limb ischemia. In the study, adult swine were subjected to aortic occlusion balloon and ligation of both common iliac arteries, e.g., acute limb ischemia, for six hours, followed by 90 minutes of passive bypass with a 12 Fr carotid donor sheath and a 7 Fr superficial femoral arterial distal perfusion catheter (n=4 / group). Subsequently, the system described herein was used to provide pressurized perfusion to the distal ischemic limb, e.g., active bypass, by connecting the distal perfusion catheter to the bypass circuit for 90 minutes. The contralateral leg did not receive either passive bypass or active bypass. Carotid and tibial mean arterial pressures (MAP) and tissue oxygenation of the abdomen and ischemic calf were measured via near infrared spectroscopy (NIRS), and comparisons were tested using paired Student’s T-tests. As shown in FIGS. 24A and 24B, six hours of aortic occlusion reduced systemic blood pressure, active bypass increased tissue oxygenation (NIRS) back to abdominal levels and increased tibial MAP back to carotid levels, and passive bypass- 59 -713664833v3225914-021001 increased tissue oxygenation only after 90 minutes, but failed to normalize tissue oxygenation at any point, and increased tibial MAP, but all values were lower than active bypass and carotid levels. As shown in FIG. 24C, tissue oxygenation (NIRS) correlated directly with MAP during active bypass and passive bypass, but not during occlusion alone.

[0162] FIG. 25 is a graph depicting venous lactate levels during distal limb perfusion compared with venous lactate levels during occlusion only. As shown in FIG. 25, upon initiation of distal limb perfusion via passive bypass, venous lactate levels increased significantly compared with pre-bypass (e.g., occlusion only) venous lactate levels; whereas, upon initiation of distal limb perfusion via active bypass, as described herein, venous lactate levels remained generally stable and / or decreased compared with pre-bypass (e.g., occlusion only) venous lactate levels.

[0163] While various illustrative embodiments of the invention are described above, it will be apparent to one skilled in the art that various changes and modifications may be made therein without departing from the invention.- 60 -713664833v3

Claims

225914-021001WHAT IS CLAIMED IS:

1. A system for providing extracorporeal circulation of blood for perfusion of a target region of a patient to support circulation, the system comprising: an inlet cannula having an inlet configured to be coupled to a source of blood, and an outlet; a return cannula comprising a first lumen and a second lumen, the first lumen extending between a first inlet configured to be fluidically coupled to the outlet of the inlet cannula, and a first outlet configured to be placed in a target area of the patient’s vasculature, the second lumen extending between a second inlet configured to be operatively coupled to a pressure transducer, and a second outlet disposed within the return cannula adjacent to the first outlet, the second outlet configured to fluidically couple the first lumen and the second lumen; a pressure sensor configured to measure an outlet pressure within the first lumen at the second outlet, the outlet pressure indicative of a local blood pressure associated with the target area of the patient’s vasculature; and a controller operatively coupled to the pressure transducer and configured to, in a local pressure control mode, cause blood received from the source of blood via the inlet of the inlet cannula to be delivered through the first outlet of the return cannula to perfuse the target area of the patient’s vasculature at a selected local pressure.

2. The system of claim 1, wherein the pressure sensor comprises one or more strain gauges embedded within the second outlet of the return cannula.

3. The system of claim 1, wherein the return cannula comprises an occlusion balloon disposed proximal to the first outlet of the return cannula, the occlusion balloon configured to be inflated to at least partially occlude blood flow within the patient’s vasculature to direct blood flow in an antegrade direction within the patient’s vasculature.

4. The system of claim 1, further comprising: an extracorporeal pump operatively coupled to the controller, the extracorporeal pump fluidically coupled to the outlet of the inlet cannula and the first inlet of the return cannula,- 61 -713664833v3225914-021001 wherein the controller is configured to cause the extracorporeal pump to draw blood through the inlet of the inlet cannula and to deliver blood through the first outlet of the return cannula.

5. The system of claim 4, wherein the controller is configured to cause the extracorporeal pump to generate pulsatile flow.

6. The system of claim 4, wherein the controller is configured to cause the extracorporeal pump to operate at an unsteady RPM to generate consistent flow.

7. The system of claim 6, wherein the controller is configured to adjust a speed of rotation of one or more rotors of the extracorporeal pump within a revolution to generate the consistent flow.

8. The system of claim 4, wherein the controller is configured to regulate a flow rate of the extracorporeal pump to maintain the selected local pressure.

9. The system of claim 4, wherein the controller is configured to cause the extracorporeal pump to transition between the local pressure control mode and a flow mode, and wherein, in the flow mode, the controller is configured to cause the extracorporeal pump to pump at a set flow rate to perfuse the target region of the patient.

10. The system of claim 4, wherein the extracorporeal pump is selected from amongst a vane pump, a centrifugal pump, a roller pump, an axial flow pump, a diaphragm pump, and a piston pump.

11. The system of claim 4, wherein the source of blood comprises a source of transfusion blood configured to supply transfusion blood to the extracorporeal pump, wherein the inlet of the return cannula is fluidically coupled to an oxygenator of an extracorporeal membrane oxygenator (ECMO) circuit, the oxygenator fluidically coupled to the extracorporeal pump and configured to oxygenate blood,- 62 -713664833v3225914-021001 wherein the controller is configured to cause the extracorporeal pump to draw transfusion blood from the source of transfusion blood and pump the transfusion blood through the oxygenator to deliver oxygenated transfusion blood through the first outlet of the return cannula.

12. The system of claim 4, wherein the source of blood comprises a first area of the patient’s vasculature such that the inlet of the inlet cannula is configured to be placed in the first area of the patient’s vasculature.

13. The system of claim 12, further comprising: an admixing chamber fluidically coupled to the extracorporeal pump and the outlet of the inlet cannula; and a second inlet cannula having a second inlet configured to be placed in an artery of the patient and a second outlet fluidically coupled to the admixing chamber, wherein the inlet of the inlet cannula is configured to be placed in a vein of the patient comprising the first area of the patient’s vasculature, and wherein the controller is configured to: cause venous blood to be drawn through the inlet of the inlet cannula into the admixing chamber; selectively cause arterial blood to be drawn through the second inlet of the second inlet cannula into the admixing chamber to form a mixture of arterial and venous blood having a target oxygenation level; and cause the extracorporeal pump to deliver the mixture of arterial and venous blood having the target oxygenation level through the first outlet of the return cannula.

14. The system of claim 13, wherein the controller is configured to: cause the extracorporeal pump to deliver only venous blood through the first outlet of the return cannula for a first time period; selectively increase an amount of arterial blood drawn through the second inlet of the second inlet cannula into the admixing chamber to form a mixture of arterial and venous blood having a first target oxygenation level; and- 63 -713664833v3225914-021001 cause the extracorporeal pump to deliver the mixture of arterial and venous blood having the first target oxygenation level through the first outlet of the return cannula for a second time period.

15. The system of claim 14, wherein the controller is configured to: selectively increase the amount of arterial blood drawn through the second inlet of the second inlet cannula into the admixing chamber to form a mixture of arterial and venous blood having a second target oxygenation level; and cause the extracorporeal pump to deliver the mixture of arterial and venous blood having the second target oxygenation level through the first outlet of the return cannula for a third time period.

16. The system of claim 12, wherein a proximal end of the inlet cannula comprises a hemostatic port configured to permit an interventional or circulatory assist device to be inserted therethrough.

17. The system of claim 12, wherein the inlet cannula further comprises an occlusion balloon configured to at least partially occlude flow within the patient’s vasculature antegrade to the inlet of the inlet cannula.

18. The system of claim 12, wherein the inlet cannula further comprises a sealing balloon configured to seal an insertion site of the inlet lumen into the first area of patient’s vasculature to prevent leakage.

19. The system of claim 4, further comprising: a second return cannula having an inlet fluidically coupled to the extracorporeal pump and an outlet configured to be placed in a second target area of the patient’s vasculature; and a second pressure sensor configured to measure local blood pressure associated with the second target area of the patient’s vasculature,- 64 -713664833v3225914-021001 wherein the controller is configured to cause the extracorporeal pump to, in the local pressure control mode, deliver blood through the outlet of the second return cannula to perfuse the second target area of the patient’s vasculature at a second selected local pressure.

20. The system of claim 19, wherein a proximal region of the return cannula comprises a side arm having an outlet fluidically coupled to the first inlet of the return cannula, and wherein the inlet of the second return cannula is fluidically coupled to the outlet of the sidearm.

21. The system of claim 20, further comprising: an actuatable valve operatively coupled to the controller, the actuatable valve fluidically coupled to the second return cannula and configured to be actuated to selectively adjust a flow rate of blood flow through the second return cannula, wherein the controller is configured to, in the local pressure control mode, actuate the actuatable valve to selectively adjust the flow rate of blood flow through the second return cannula to deliver blood through the outlet of the second return cannula to perfuse the second target area of the patient’s vasculature at the second selected local pressure.

22. The system of claim 4, wherein the controller is configured to: periodically stop, at predefined intervals, flow through the extracorporeal pump for a short predetermined time period, such that the flow rate of blood at the first outlet of the return cannula is substantially zero; and measure the outlet pressure sensed by the pressure sensor during the short predetermined time period.

23. The system of claim 4, wherein the controller is configured to: receive an input indicative of the patient’s mean arterial pressure (MAP); compute a distal limb perfusion index (DLPI) value as a ratio of the local blood pressure and the patient’s MAP; and- 65 -713664833v3225914-021001 automatically set the selected local pressure as the patient’s MAP if the DLPI value is within a predetermined threshold range.

24. The system of claim 23, wherein the controller is configured to adjust, if the DLPI value falls below a predetermined threshold, at least one parameter of the extracorporeal pump to maintain the patient’s MAP within a predetermined pressure threshold range.

25. The system of claim 1, further comprising: an actuatable valve operatively coupled to the controller, the actuatable valve fluidically coupled to the return cannula and configured to be actuated to selectively adjust a flow rate of blood flow through the return cannula, wherein the controller is configured to, in the local pressure control mode, actuate the actuatable valve to selectively adjust the flow rate of blood flow through the return cannula to deliver blood through the first outlet of the return cannula to perfuse the target area of the patient’s vasculature at the selected local pressure.

26. The system of claim 25, wherein the actuatable valve comprises: a pinch slider operatively coupled to the return cannula; and a motor operatively coupled to the controller and configured to be actuated to cause the pinch slider to transition between an unactuated state where blood flow is permitted through the return cannula and an actuated state where blood flow is restricted through the return cannula.

27. The system of claim 25, wherein the inlet of the return cannula is fluidically coupled to a main return cannula of an ECMO circuit.

28. The system of claim 27, further comprising: a pressure sensor operatively coupled to the controller and configured to measure a pressure of the ECMO circuit, wherein the controller is configured to, in the local pressure control mode, actuate the actuatable valve to adjust the flow rate of blood flow through the return cannula to deliver blood- 66 -713664833v3225914-021001 through the first outlet of the return cannula to perfuse the target area of the patient’s vasculature at the selected local pressure based at least partially on the pressure of the ECMO circuit.

29. The system of claim 27, wherein the first inlet of the return cannula is fluidically coupled to the main return cannula of the ECMO circuit via a Y or T shaped connector.

30. The system of claim 4, further comprising: an input line sensor configured to measure pressure in the inlet cannula; and an output line sensor configured to measure pressure in the first lumen of the return cannula, wherein the controller is configured to modify, if the pressure in the inlet cannula or in the first lumen of the return cannula reaches a predetermined input pressure safety limit or a predetermined output pressure safety limit, respectively, a flow rate of the extracorporeal pump to maintain the pressure in the inlet cannula and in the first lumen of the return cannula within the respective predetermined input and output pressure safety limits.

31. The system of claim 30, wherein, in the local pressure control mode, the controller is configured to, if the pressure in the inlet cannula or in the first lumen of the return cannula reaches the respective predetermined input and output pressure safety limits, decrease the flow rate of the extracorporeal pump and then gradually increase the flow rate of the extracorporeal pump to increase the local blood pressure towards the selected local pressure while maintaining the pressure in the inlet cannula and in the first lumen of the return cannula within the respective predetermined input and output pressure safety limits.

32. The system of claim 30, wherein the controller is configured to cause the extracorporeal pump to transition between the local pressure control mode and a flow mode where the controller causes the extracorporeal pump to pump at a set flow rate to perfuse the target region of the patient, and wherein, in the flow mode, the controller is configured to, if the pressure in the inlet cannula or in the first lumen of the return cannula reaches the respective predetermined input and output pressure safety limits, decrease the flow rate of the extracorporeal pump and then- 67 -713664833v3225914-021001 gradually increase the flow rate of the extracorporeal pump towards the set flow rate while maintaining the pressure in the inlet cannula and in the first lumen of the return cannula within the respective predetermined input and output pressure safety limits.

33. The system of claim 30, wherein the predetermined input and output pressure safety limits are a predetermined percentage of a predetermined input pressure safety value and a predetermined output pressure safety value, respectively.

34. The system of claim 30, wherein the input line sensor is disposed adjacent to an inlet port of the extracorporeal pump, and wherein the output line sensor is disposed adjacent to an outlet port of the extracorporeal pump.

35. The system of claim 1, further comprising a user interface associated with the controller, the user interface configured to receive input indicative of the selected local pressure.

36. The system of claim 1, further comprising: an input line sensor configured to measure pressure in the inlet cannula; and an output line sensor configured to measure pressure in the first lumen of the return cannula, wherein the controller is configured to monitor pressure in the inlet cannula and in the first lumen of the return cannula and generate an alert if the pressure in at least one of the inlet cannula or the first lumen of the return cannula deviates from a predetermined pressure range.

37. The system of claim 1, wherein the return cannula comprises a third lumen extending between a third inlet configured to be fluidically coupled to a source of a drug, and a third outlet configured to be placed in the target area of the patient’s vasculature, the third lumen configured to deliver the drug from the source of the drug through the third outlet to the target area of the patient’s vasculature.

38. The system of claim 37, wherein the drug comprises at least one of a vasoactive drug configured to relax the target area of the patient’s vasculature and reduce the local blood- 68 -713664833v3225914-021001 pressure associated with the target area of the patient’s vasculature, a vasoactive drug configured to constrict the target area of the patient’s vasculature and increase pressure the local blood pressure associated with the target area of the patient’s vasculature, a thrombolytic drug configured to dissolve a clot within the target area of the patient’s vasculature, or an antiperfusion drug configured to prevent reperfusion of the target area of the patient’s vasculature after a treatment.

39. The system of claim 1, wherein the second inlet of the return cannula is less than 1 cm from the first outlet of the return cannula.

40. A return cannula for providing perfusion of a target region of a patient’s vasulcaure to support circulation, the return cannula comprising: a first lumen extending between a first inlet configured to be fluidically coupled to a source of blood, and a first outlet configured to be placed in a target area of the patient’s vasculature; a second lumen comprising a second inlet configured to be operatively coupled to a pressure transducer, and a second outlet disposed within the return cannula adjacent to the first outlet, the second outlet configured to fluidically couple the first lumen and the second lumen; and a pressure sensor operatively coupled to the pressure transducer, the pressure sensor configured to measure an outlet pressure within the first lumen at the second outlet, the outlet pressure indicative of a local blood pressure associated with the target area of the patient’s vasculature.

41. The return cannula of claim 40, wherein the second inlet is less than 1 cm from the outlet of the return cannula.

42. The return cannula of claim 40, further comprising a plug disposed within the second lumen between the second outlet and a distal end of the return cannula to thereby prevent stasis within the second lumen distal to the second outlet.- 69 -713664833v3225914-02100143. A system for providing extracorporeal circulation of blood for perfusion of a target region of a patient to support circulation, the system comprising: an inlet cannula having an inlet configured to be coupled to a source of blood, and an outlet; a return cannula having an inlet fluidically coupled to the outlet of the inlet cannula, and an outlet configured to be placed in a target area of the patient’s vasculature; a pressure sensor configured to measure local blood pressure associated with the target area of the patient’s vasculature; an extracorporeal pump fluidically coupled to the outlet of the inlet cannula and the inlet of the return cannula; and a controller operatively coupled to the pressure sensor and the extracorporeal pump, the controller configured to: receive an input indicative of the patient’s mean arterial pressure (MAP); compute a distal limb perfusion index (DLPI) value as a ratio of the local blood pressure and the patient’s MAP; and cause, in a local pressure control mode, the extracorporeal pump to draw blood through the inlet of the inlet cannula and to deliver blood through the outlet of the return cannula to perfuse the target area of the patient’s vasculature at a selected local pressure, wherein the controller is configured to automatically set the selected local pressure as the patient’s MAP if the DLPI value is within a predetermined threshold range.

44. The system of claim 43, wherein the controller is configured to adjust, if the DLPI value falls below a predetermined threshold, at least one parameter of the extracorporeal pump to maintain the patient’s MAP within a predetermined pressure threshold range.

45. The system of claim 43, wherein the return cannula comprises: a first lumen extending between the inlet and outlet of the return cannula and configured to deliver blood received from the source of blood through the outlet of the return cannula to perfuse the target area of the patient’s vasculature; and- 70 -713664833v3225914-021001 a second lumen comprising a second inlet configured to be operatively coupled to a pressure transducer operatively coupled to the pressure sensor, and a second outlet disposed within the return cannula adjacent to the outlet of the return cannula, the second outlet configured to fluidically couple the first lumen and the second lumen, and wherein the pressure sensor is configured to measure an outlet pressure within the first lumen at the second outlet, the outlet pressure indicative of the local blood pressure associated with the target area of the patient’s vasculature.

46. The system of claim 43, wherein the pressure sensor comprises one or more strain gauges embedded within a wall of the return cannula.

47. The system of claim 43, wherein the pressure sensor comprises a pump clamp disposed around the return cannula, the pump clamp configured to measure a degree of expansion of the return cannula, the degree of expansion proportional to the local blood pressure.

48. The system of claim 43, wherein the pressure sensor comprises a pair of plates configured to move up and down responsive to intravascular pressure, a position of the pair of plates proportional to the local blood pressure.

49. A system for providing extracorporeal circulation of blood for perfusion of a target region of a patient to support circulation, the system comprising: an inlet cannula having an inlet configured to be coupled to a source of blood, and an outlet; a return cannula having an inlet fluidically coupled to the outlet of the inlet cannula, and an outlet configured to be placed in a target area of the patient’s vasculature; a drug delivery port configured to deliver a drug to the target area of the patient’s vasculature; a pressure sensor configured to measure local blood pressure associated with the target area of the patient’s vasculature; and a controller operatively coupled to the pressure sensor and configured to, in a local pressure control mode, cause blood received from the source of blood via the inlet of the inlet- 71 -713664833v3225914-021001 cannula to be delivered through the outlet of the return cannula to perfuse the target area of the patient’s vasculature at a selected local pressure and to support delivery of the drug to the target area of the patient’s vasculature.

50. The system of claim 49, wherein the drug delivery port is coupled to the return cannula such that the drug and the blood are delivered through the outlet of the return cannula to the target area of the patient’s vasculature.

51. The system of claim 49, wherein the drug comprises at least one of a vasoactive drug configured to relax the target area of the patient’s vasculature and reduce the local blood pressure associated with the target area of the patient’s vasculature, a vasoactive drug configured to constrict the target area of the patient’s vasculature and increase pressure the local blood pressure associated with the target area of the patient’s vasculature, a thrombolytic drug configured to dissolve a clot within the target area of the patient’s vasculature, or an antiperfusion drug configured to prevent reperfusion of the target area of the patient’s vasculature after a treatment.- 72 -713664833v3

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