System and method for reducing gaseous microemboli using venous blood bypass with filter

Abstract

To provide a system and method capable of inhibiting the bubble formation in the blood while reducing the number and size of bubbles during extracorporeal circulation.SOLUTION: Provided are a system and method for reducing gas bubbles, including gaseous microemboli (GME) during cardiopulmonary bypass (CPB) by the use of an oxygenator with venous blood bypass and a filter in the venous blood bypass.SELECTED DRAWING: Figure 3

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 369,262, filed August 1, 2016, the contents of which are incorporated herein by reference in their entirety. [Technical Field]

[0002] The present disclosure relates to systems and methods for cardiopulmonary bypass, and more particularly to systems and methods for reducing gaseous microemboli (GME) using an oxygenator with a venous bypass and a filter. [Background technology]

[0003] During cardiac surgery, it is necessary to replace cardiac and pulmonary function by artificial means. Also, in more chronic conditions, such as during more severe pulmonary, cardiac, or renal failure, various artificial means can be used to support life until an organ for transplant becomes available. Many clinical situations require an extracorporeal circuit incorporating an artificial organ.

[0004] Gas bubbles readily form in blood and are extruded into the circulation of living organisms during extracorporeal circulation. Gas bubbles form from many sources, including cavitation, temperature gradients, and differences in the amount of dissolved gas between the subject's own blood and the incoming blood, as well as the inadvertent physical introduction of gas bubbles into the blood by caregivers during surgical procedures or parenteral administration of fluids. In cardiac surgery, the extracorporeal circuit includes a gas exchange device, e.g., an oxygenator, used for oxygenation and carbon dioxide removal. The close contact between the blood and gas within the oxygenator poses a significant risk of inadvertent introduction of gas bubbles into the circulating blood.

[0005] Currently, to avoid bubble formation during cardiac surgery, membrane oxygenators are used instead of bubble oxygenators, avoiding high temperature gradients and controlling the use of suction in the surgical field. Heart-lung machines include bubble sensors that alert the person controlling the heart-lung machine to the appearance of small bubbles and immediately stop the main pump if larger bubbles appear. Typically, bubble sensors can identify bubbles with a diameter of approximately 0.3 millimeters (mm) or larger and stop the main pump if bubbles with a diameter of 3 to 5 mm are recognized.

[0006] Cardiac surgery is often complicated by postoperative neurocognitive impairment, which increases healthcare costs and reduces functional capacity and quality of life. Multifactorial contributors to this significant public health problem likely include gaseous microemboli (GME). Despite the use of membrane oxygenation and arterial filters, during cardiopulmonary bypass (CPB), the arterial circulation receives thousands of GME particles measuring 10–40 micrometers (μm) in diameter. Vaso-occlusive GME causes tissue ischemia in the brain and other end organs, denuding the endothelium and resulting in vasodilation, increased permeability, activation of platelets and the coagulation cascade, and recruitment of complement and cellular mediators of inflammation.

[0007] Current perfusion methods aim for mildly hyperoxic blood gas during CPB by reducing the oxygen tension in the oxygenator sweep gas through air dilution, but this has the unwanted side effect of dissolving nitrogen in the blood. Blood saturated with dissolved gases in this way is largely unable to dissolve gases present in the form of bubbles, such as in GME.

[0008] Nevertheless, there remains a need to prevent or reduce the formation of gas bubbles, for example, during cardiac surgery. In blood bubbles, a layer of lipoproteins, approximately 40-100 angstroms (Å) (4-10 nanometers), is present at the liquid-air interface, which is denatured upon direct contact with a foreign substance, such as gas. Hagemann factor is then activated, initiating clotting and the concomitant undesirable consumption of factors promoting clotting used to prevent bleeding from surgical wounds.

[0009] Therefore, there is a need for a system and method that can reduce the number and size of bubbles in extracorporeal circulation and suppress bubble formation in the blood. Summary of the Invention

[0010] Disclosed herein are systems and methods for reducing bubbles, including gaseous microemboli (GME), during cardiopulmonary bypass (CPB). This approach reduces the number and size of GME, which helps reduce postoperative complications, including neurocognitive impairment during CPB and other surgeries. The systems and methods can be used for both in vitro and in vivo approaches. The systems and methods can be used under both hypobaric and normobaric conditions.

[0011] 10. A system for reducing gaseous microemboli, the system comprising: a fluid source; a flow diverter fluidly connected to the fluid source, the flow diverter configured to remove a portion of fluid from the fluid source; an inlet flow controller fluidly connected to the fluid source, the inlet flow controller configured to control a flow rate of fluid from the fluid source to the flow diverter; a bypass line fluidly connected to the flow diverter; a bypass flow controller fluidly connected to the bypass line, the bypass flow controller configured to control a flow rate of fluid from the bypass line; a filter fluidly connected to the bypass line, the filter removing gaseous microemboli having a defined pore size, preferably 15-50 μm, or larger; an oxygenator fluidly connected to the fluid source, the oxygenator configured to oxygenate fluid from the fluid source; an outlet fluidly connected to the oxygenator and the bypass line; and a controller configured to control the inlet flow controller, the bypass flow controller, the outlet flow controller, or a combination comprising at least one or more of the foregoing.

[0012] 1. A method for reducing gaseous microemboli, comprising: providing an oxygenator configured to oxygenate a fluid, the oxygenator having a venous inlet, an arterial outlet, and a venous bypass line fluidly connected to the venous inlet and the arterial outlet, the venous bypass line including a filter configured to remove gaseous microemboli having a defined pore size, preferably 15-50 μm, and larger diameters, the venous bypass line configured to remove a portion of the fluid from the venous inlet; introducing the fluid into the oxygenator; oxygenating the fluid passing through the oxygenator; and mixing the fluids from the venous bypass line and the arterial outlet to form a combined fluid, wherein the combined fluid has a partial pressure of dissolved oxygen of 100-700 millimeters of mercury (mmHg), preferably 150-250 mmHg. [Brief explanation of the drawings]

[0013] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate several aspects of the present disclosure and, together with the description, serve to explain the principles of the disclosure.

[0014] [Figure 1] FIG. 1 is a schematic diagram of an embodiment of a CPB system using a venous bypass with a filter.

[0015] [Figure 2] 1 is a schematic diagram of an oxygenator that can be used.

[0016] [Figure 3] 1 shows the cardiopulmonary bypass circuit used to obtain the data presented herein.

[0017] [Figure 4] 1 shows experimental data showing the percentage of total flow that moves through the shunt limb over a wide range of total flow rates.

[0018] [Figure 5] Experimental data showing the partial pressure of dissolved CO2 or O2 under three different conditions are presented.

[0019] [Figure 6] 1 shows experimental data showing the reduction of GME at two locations within a CPB system.

[0020] [Figure 7] Figure 1 shows experimental data demonstrating reduced GME delivery through the shunt limb in the presence of arterial filters at three locations within the CPB bypass circuit.

[0021] [Figure 8] The total partial pressure as a function of the shunt ratio is shown. DETAILED DESCRIPTION OF THE INVENTION

[0022] The following disclosure details certain exemplary embodiments that provide methods and systems for reducing GME in CPB systems. An overview of the mechanisms and methods used herein is provided.

[0023] In one embodiment, the inventors have unexpectedly solved the practical problem of shunting GME around an oxygenator by using an arterial filter in the shunt limb.

[0024] This disclosure relates to the reduction of GME during CPB and other treatments, including extracorporeal membrane oxygenation (ECMO), including veno-arterial ECMO and veno-venous ECMO, by using a venous bypass and an oxygenator with a filter within the bypass. The described systems and methods can also be used in extracorporeal circulation systems, including dialysis, continuous veno-venous hemofiltration (CVVH), and ventricular assist devices (VADs). The venous bypass takes a portion of blood from the venous system or other deoxygenated blood source, bypasses the oxygenator, and introduces the bypassed venous blood into the blood coming from the oxygenator. Mixing the oxygenated and deoxygenated blood reduces the oxygen concentration in the blood coming from the oxygenator and promotes the removal of microbubbles from the blood. This approach allows the oxygenator to operate using a pure oxygen, nitrogen-free sweep gas, thereby avoiding both hyperoxemia, which can be damaging to the patient, and dissolved nitrogen, which can interfere with the dissolution and removal of microbubbles.

[0025] Although applicants are not bound by any theory presented herein, the mechanism for reducing GME described herein involves reducing the total partial pressure of dissolved gases in the arterial blood returning to the patient, thereby allowing gas from the bubbles to be reabsorbed into the blood phase.

[0026] In one embodiment, the gas profile in the mixed arterial blood traveling to the patient is approximately 150-250 mmHg of dissolved oxygen (normal for a healthy individual is approximately 100 mmHg) + approximately 40 mmHg of dissolved CO2, for a total partial pressure of dissolved gases of 190-290 mmHg, a low pressure compared to atmospheric pressure of approximately 760 mmHg.

[0027] In one embodiment, all gas emboli, large or small, are removed within the filtered circuit. In one embodiment, emboli with diameters larger than a specified filter pore size, e.g., between 15 and 50 μm, such as larger than 15 μm, 20 μm, 28 μm, 32 μm, 37 μm, or 40 μm, are removed, while particles with diameters smaller than the specified pore size pass through. In one embodiment, emboli with diameters larger than 50 μm, preferably larger than 40 μm, and preferably larger than 28 μm, are removed from the filtered circuit. Emboli in this size range are considered large enough to block capillaries but small enough to pass through an arterial filter.

[0028] As used herein, "fluid" and "blood" are used interchangeably unless otherwise noted. It is understood that the present systems and methods can be used with blood or other fluids such as blood substitutes, blood artificials, blood products such as plasma, albumin, platelets, plasma concentrates, saline, Ringer's lactate, crystalloids such as normosol, plasmalyte, hetastarch, or combinations comprising at least one of the foregoing.

[0029] The fluid source can be from a subject, such as an animal, e.g., a human, or other mammal. The fluid source can be from the subject using a cannula inserted into the subject's venous or arterial system, a cardiac or body cavity, from a fluid reservoir, or from a source external to the subject. The subject can be a patient undergoing treatment or evaluation.

[0030] The filter acts as a resistance to flow and can therefore be used to regulate or control the flow in the bypass line.

[0031] The flow diverter is used to divert a portion of the blood and may be any suitable device used to remove a portion of the fluid from a fluid source, such as a T-tube, or a separate non-gas exchange shunt channel through a pump, or an oxygenator.

[0032] The use of a separate non-gas exchange shunt channel through the oxygenator can be achieved using either: 1) a filtered or unfiltered shunt channel within the oxygenator, the flow through which can be adjustable or user-determined; or 2) a means of selectively directing sweep gas through only a small portion of the sweep gas microtubules within the oxygenator fiber bundle, thereby creating non-gas exchange shunting within the oxygenator without, for example, compromising the oxygenator's filtering function. 2a) This approach can use adjustable flaps or devices made of rubber, gel, polymer, foam, wax, plastic, metal, or other suitable material or reversible occlusion devices to prevent gas flow through portions of the fiber bundle near the sweep gas inlet or in the sweep gas inlet manifold, near the sweep gas outlet or in the sweep gas outlet manifold, or both, or anywhere along the sweep gas flow path. More than one occlusion device may be used within the device, and a user or controller may engage them in any desired combination to create the desired amount of non-gas exchange shunting. Occlusion may also be achieved using a fluid or other suitable substance, such as water, oil, polymer, foam, or wax, injected into the sweep gas inlet manifold, or the sweep gas outlet manifold, or both. 2b) This approach can also prevent flow through some of the sweep gas microtubules of the fiber bundle using a fluid or other suitable substance, such as water, saline, crystalloid, colloid, blood product, oil, gel, polymer, foam, or wax, permanently or reversibly injected into the sweep gas inlet manifold or the sealed or non-sealed sweep gas outlet manifold, or both. Additional ports in the dependent or non-dependent portions of the sweep gas inlet manifold or the sweep gas outlet manifold, or both, may be required to allow injection and removal of substances to adjust the sweep gas flow within the fiber bundle.Positive pressure relief valves in the sweep gas inlet manifold or the sweep gas outlet manifold, or both, may be required to relieve the positive pressure resulting from restricting the sweep gas flow to a portion of the fiber bundle. 2c) Non-gas exchange shunt channels through the oxygenator can also be implemented by dividing the oxygenator into compartments or by using multiple oxygenators, where each compartment or oxygenator receives blood flow, but the user can decide whether to allow sweep gas in and how much sweep gas to flow to some compartments or oxygenators to achieve the desired level of non-gas exchange shunt.

[0033] 3) In the case of an oxygenator using multiple compartments, or during use of multiple oxygenators, the same desired effect on dissolved gases in the blood and GME removal can be achieved in the absence of a non-gas exchange shunt by directing blood and sweep gas flow to the minimum number of compartments or oxygenators necessary to achieve a user-defined oxygenation target. The amount and flow characteristics, e.g., flow rate, flow volume, and other characteristics, of fluid coming from the fluid source and entering the flow diverter can be controlled by an inflow controller, such as a needle valve, mass flow controller, pump, or partial occlusion clamp. As further described herein, the inflow controller can be independently controlled or can be controlled by a controller configured to control other components of the system.

[0034] The bypass line can be any suitable material, such as medical tubing or other material known to one of ordinary skill in the art without undue experimentation. The diameter, length, and composition of the bypass line are readily determined by one of ordinary skill in the art without undue experimentation.

[0035] The flow of fluid in the bypass line can be further controlled, for example, to achieve desired fluid characteristics at the outlet. Sensors can be used at any desired or useful location in the system to determine, for example, the actual or approximate number and size of GMEs or other particles, the concentration of anticoagulants, anesthetics, or other medications, the concentration of gases such as oxygen, nitrogen, or carbon dioxide, the oxygen saturation of blood hemoglobin, or flow rate. Flow and oxygen saturation sensors are mounted on the outside of the tubing and are standard. Blood samples are frequently, or in some cases continuously, removed for more detailed blood gas and anticoagulant analysis. The composition or other characteristics of the fluid in the bypass line can be modified from those of the fluid in the fluid source. For example, agents such as anticoagulants or other medications, or gases such as oxygen, nitrogen, carbon dioxide, or air, can be added or removed to achieve desired levels of gases and other constituents.

[0036] In embodiments, the sensor is installed at a location in the bypass line before the filter, at a location in the bypass line after the filter, or a combination including one or more of the foregoing, to obtain desired levels of oxygen and other substances in the fluid in the bypass line.

[0037] A filter is inserted into the bypass line, which may be a so-called "arterial filter," as known in the art, designed to remove air bubbles (GME), lipids, and other debris having a diameter larger than a specified pore size, for example, larger than 15 μm, larger than 20 μm, larger than 28 μm, larger than 32 μm, larger than 37 μm, or larger than 40 μm, for example, and to allow particles having a diameter smaller than the specified pore size to pass through.

[0038] The filter pore size must be small enough to remove air bubbles, but not so small as to prevent desired blood flow at reasonable pressures known to those skilled in the art or to cause damage or filtration of cellular elements. The filter may also be a hemoconcentrator, bubble trap, or oxygenator, any of which may be operated under vacuum. The filter may be made of any suitable material, such as polyester.

[0039] The oxygenator can be any of several devices, such as a membrane oxygenator, a diffusion membrane oxygenator, or a hollow fiber microporous membrane oxygenator. In one embodiment, the oxygenator is a microporous membrane oxygenator with a sealed housing, or preferably without a sealed housing. In one embodiment, the oxygenator is a microporous membrane oxygenator without a sealed housing. Connections between fluids and the oxygenator, between fluids and the bypass line, and other connections are known to those of skill in the art without undue experimentation. Operation of the oxygenator is known to those of skill in the art without undue experimentation.

[0040] The flow rate and volume of the fluid at any point in the system, as well as other desired characteristics, can be controlled by a flow controller or other suitable device, which can be a needle valve, a mass flow controller, a pump, a clamp, or a partial occlusion clamp.

[0041] The outlet is fluidly connected to the oxygenator and the bypass line. The outlet can be a point where fluid from the bypass line and the oxygenator join. A sensor can be used to measure a desired property of the fluid at the outlet, such as the concentration of an anticoagulant or other drug, the concentration of a gas such as oxygen, nitrogen, carbon dioxide, or air, or blood oxygen saturation.

[0042] After the fluid has passed through the oxygenator and mixed with fluid from the venous bypass, the fluid can be, for example, stored or reinfused into the subject or patient.

[0043] The parameters of the system can be controlled by a controller configured to control an inlet flow controller, a bypass flow controller, an outlet flow controller, or a combination comprising at least one or more of these. Each parameter of the system can also be controlled independently, such as by use of manual valves.

[0044] In one embodiment, 0 to 50 percent of the total volume of blood entering the CPB system from the patient is diverted to the venous bypass. In one embodiment, 0 to 40 percent of the total volume of blood entering the CPB system from the patient is diverted to the venous bypass. In one embodiment, 0 to 30 percent of the total volume of blood entering the CPB system from the patient is diverted to the venous bypass. In one embodiment, 0 to 20 percent of the total volume of blood entering the CPB system from the patient is diverted to the venous bypass. In one embodiment, 0 to 10 percent of the total volume of blood entering the CPB system from the patient is diverted to the venous bypass. In one embodiment, 0 to 5 percent of the total volume of blood entering the CPB system from the patient is diverted to the venous bypass. The blood entering the venous bypass can be filtered, cooled, warmed, strengthened, or otherwise treated with various drugs or gases. In one embodiment, the oxygen partial pressure at the outlet is 50 to 800 mmHg. In one embodiment, the oxygen partial pressure at the outlet is 100 to 700 mmHg. In one embodiment, the oxygen partial pressure at the outlet is 75 to 650 mmHg. In one embodiment, the nitrogen partial pressure at the outlet is zero. In one embodiment, the nitrogen partial pressure at the outlet is minimized. In one embodiment, the nitrogen partial pressure at the outlet is a non-zero level up to about 600 mmHg.

[0045] The desired parameters / composition of the blood or fluid at the outlet (the mixing point between blood from the oxygenator and blood from the shunt) depend on the surgical team and the perfusionist's goals for the patient. Often, perfusionists target an oxygen tension or partial pressure of 150–250 mmHg, a CO2 tension or partial pressure of 40 mmHg, and an overall flow rate that produces an appropriate blood pressure in the patient's vasculature that reasonably approximates the patient's predicted normal cardiac output. In a typical scenario, the perfusionist might infuse a total flow rate of 5 L / min, consisting of 1.5 L / min flow through the shunt limb and 3.5 L / min flow through the oxygenator. The perfusionist can adjust pO2 by increasing or decreasing the shunt rate, pCO2 by increasing or decreasing the sweep gas flow rate, or blood pressure by increasing or decreasing the flow rate.

[0046] In one embodiment, the filter acts to remove gaseous microemboli and also acts as a flow restrictor for the venous bypass, which can be used, for example, to control the oxygen level of blood returning to the patient. This method can be used under both normal atmospheric and low-pressure conditions. In one embodiment, the oxygenator is configured to have a low-atmospheric pressure and can have a pressure of 0.4 to 1 atmospheres absolute. The described shunt can be used in conjunction with operating the oxygenator at low-atmospheric pressure. In one embodiment, the system includes a vacuum regulator fluidly connected to the oxygenator and configured to provide the low-atmospheric pressure. In one embodiment, the oxygenator is configured to have atmospheric pressure.

[0047] The system can include one or more sensors configured to measure one or more of flow rate, fluid composition, oxygen saturation, carbon dioxide content, nitrogen content, temperature, hematocrit, or a combination comprising one or more of these, and the sensors are fluidly connected to a fluid source, a bypass line, an outlet, or a combination comprising one or more of these. The sensors can be any of several common sensors known to those skilled in the art.

[0048] In one embodiment, the controller includes a processor and software instructions executed by the processor.

[0049] The fluid source may be a blender or mixer configured to combine one or more fluids.

[0050] The system can be used with many different fluids, such as blood or blood products such as blood substitutes, blood artificials, plasma, albumin, platelets, plasma concentrates, etc., saline, crystalloids such as Ringer's lactate, Normosol, Plasmalyte, hetastarch, or other fluids, or combinations comprising one or more of these.

[0051] Also provided is a method for reducing gaseous microemboli. The method includes providing an oxygenator configured to oxygenate a fluid. The oxygenator has a venous inlet, an arterial outlet, and a venous bypass line fluidly connected to the venous inlet and the arterial outlet, the venous bypass line including a filter configured to remove gaseous microemboli with diameters greater than a defined pore size, typically 15-50 μm or 28-40 μm, and the venous bypass line configured to remove a portion of the fluid from the venous inlet. The method also includes introducing a fluid into the oxygenator, oxygenating the fluid passing through the oxygenator, typically using a pure oxygen sweep gas, and mixing the fluids from the venous bypass line and the arterial outlet to form a combined fluid. In this case, the combined fluid has an oxygen concentration of 75-800 mmHg, preferably 100-700 mmHg, preferably 100-650 mmHg, and preferably 150-250 mmHg. The oxygenator may be any suitable device capable of introducing oxygen into a fluid and removing carbon dioxide from the fluid. The method may further include introducing a drug or gas into the fluid. The method may further include measuring the concentration of oxygen, nitrogen, carbon dioxide, anesthesia, medication, oxygen saturation, or other substances at any point, including the blood and gas at the sweep gas outlet. The measurements may be made using any suitable measurement device or sampling technique, such as using an in-line dual-wavelength oximeter or using a sampling technique that removes a portion of the fluid for analysis. The method may further include monitoring or controlling the temperature of the fluid at any point.

[0052] The system and method may also include a non-gas exchange shunt channel through the oxygenator instead of or in addition to a shunt limb. In one embodiment, either a non-gas exchange shunt channel or a shunt limb through the oxygenator is used. In one embodiment, a non-gas exchange shunt channel through the oxygenator is used. The non-gas exchange shunt channel may be a filtered shunt flow channel within the oxygenator, and the flow rate through the filtered shunt flow channel may be optionally adjustable. In one embodiment, the oxygenator may be fluidly connected to a sweep gas reservoir or source via a sweep gas inlet and a sweep gas outlet. In this case, the oxygenator includes fiber bundle sweep gas microtubules, and the non-gas exchange shunt channel includes a means for selectively flowing the sweep gas through a portion of the fiber bundle sweep gas microtubules of the oxygenator. In this case, non-gas exchange shunting occurs within the oxygenator. In one embodiment, the oxygenator is fluidly connected to a sweep gas reservoir via a sweep gas inlet and a sweep gas outlet, and the means for selectively flowing sweep gas through a portion of the sweep gas microtubules in the oxygenator fiber bundle includes a variable flow flap or occlusion device that prevents gas flow through a portion of the fiber bundle near the sweep gas inlet, near the sweep gas outlet, or both, or anywhere along the fluid flow path from the fluid source. In one embodiment, the oxygenator includes two or more compartments, and the flow of sweep gas in each compartment is independently adjustable. In embodiments where the system includes two or more oxygenators, each oxygenator can be fluidly connected to the sweep gas reservoir via a sweep gas inlet and a sweep gas outlet, each oxygenator can receive fluid from the fluid source, and the flow of sweep gas to each oxygenator is independently adjustable. In embodiments where the oxygenator includes two or more compartments, the blood flow to each compartment is independently adjustable, and blood flow to some compartments can be throttled back to use only as much oxygenation capacity as necessary to achieve a target level of dissolved oxygen.In embodiments where multiple oxygenators are used, the blood flow to each oxygenator can be adjusted independently, allowing blood flow to some oxygenators to be throttled back to use only the oxygenation capacity necessary to achieve a target level of dissolved oxygen. In one embodiment, the nitrogen partial pressure at the outlet is reduced or minimized compared to standard oxygenation strategies incorporating air.

[0053] The present systems and methods can be used with any CPB system or circuit, including, for example, the systems described in WO 2015 / 047927, which is incorporated herein by reference in its entirety.

[0054] Example The following examples are non-limiting: Reference will now be made to the drawings, wherein like reference numerals are used to refer to like elements throughout this disclosure.

[0055] FIG. 1 shows a schematic diagram of an exemplary embodiment of a system for reducing GME using a venous bypass with a filter. Fluid from a fluid source 10 (which may be a gas, liquid, dissolved gas, or a combination including one or more of these) enters an optional inlet flow controller 20. This optional inlet flow controller 20 controls the flow rate, volume, and other characteristics of the fluid entering the fluid source 10 into a flow diverter 30. The optional inlet flow controller 20 may be a pump in a CPB circuit. Bypass and outlet flow controllers, i.e., elements 60 and 70, are also optional. An optional controller 90 may control the inlet flow controller 20, the bypass flow controller 60, and / or the outlet flow controller 70. The flow diverter 30 may be any of several suitable embodiments, such as a tee, a valve, or other suitable device for dividing fluid flow into two or more paths. Fluid from the flow diverter 30 enters an oxygenator 40 and a bypass line 100. The proportion of fluid from the fluid source 10 entering the oxygenator 40 and the bypass line 100 can vary depending on several factors, including the amount of desired substances, such as oxygen or other substances, in the outlet 80, the desired fluid volume at the outlet 80, or other factors. The oxygenator 40 can be any of several devices or systems useful for adding oxygen to a fluid and removing carbon dioxide. The bypass line 100 includes a filter 50. The filter 50 can be a so-called "arterial filter," typically used in CPB to reduce the number and size of GMEs. The filter 50 can be a screen filter, as described elsewhere herein, that uses a filter medium with a desired pore size to remove particles larger than the pore size of the filter medium. The filter 50 can be a depth filter, with a thickness that allows larger particles to be trapped in the surface layer, while smaller particles are trapped by subsequent layers. The desired pore size or filter thickness can be varied to remove or reduce the number of particles of a selected size.As an example, a screen filter with a filter media having a pore size of 50 μm, 40 μm, 25 μm, 15 μm, or other size can be used that removes GME but does not filter (remove) white blood cells or other desired blood components or restrict flow so that the necessary or desired flow rate cannot be achieved. In one embodiment, the filter is compatible with the appropriate flow rate. The volume, flow rate, or other parameters of the fluid from the filter 50 can be controlled by a bypass flow controller 60. The volume, flow rate, or other parameters from the oxygenator 40 can be controlled by an output flow controller 70. The fluids from the bypass line 100 and the oxygenator 40 combine at an outlet 80.

[0056] Fluid parameters such as the concentration of oxygen, nitrogen, carbon dioxide, anesthetic agents, drugs, or other substances can be measured and adjusted at any time as described herein.

[0057] Figure 2 shows an exemplary oxygenator that can be used. In Figure 2, the oxygenator includes a housing, a blood inlet and outlet, a sweep gas inlet and outlet, and sweep gas inlet and outlet manifolds (including vent openings). The oxygenator has a fiber bundle. A water connector for heat exchange is also shown. The oxygenator can use any suitable membrane, such as polypropylene. A gas vent can be used to control the oxygenator pressure.

[0058] Figure 3 shows the cardiopulmonary bypass circuit used for the data presented herein, with an emboli detection classification (EDAC) and a CPB bypass circuit with venous air entrainment (500 mL / min).

[0059] Figure 4 shows experimental data demonstrating that the addition of a filter (Terumo AF125x) to the shunt limb (e.g., "Shunt Limb Device" in Figure 3) effectively limits the shunt rate to a safe level, and that this level is stable over a wide range of CPB flow rates.

[0060] Figure 5 provides experimental data demonstrating that a filtered shunt in a cardiopulmonary bypass reduces dissolved oxygen (O2) in arterial blood to a safe, mildly hyperoxic level targeted by perfusionists during CPB. Because the sweep gas did not contain nitrogen, the demonstrated levels of dissolved O2 and CO2 represent the only dissolved gases in the blood. Figure 5 provides data for three conditions: measurements of pCO2 and pO2 in venous blood from a patient simulator (condition 1); measurements of pCO2 and pO2 in arterial blood from a cardiopulmonary bypass with a filtered shunt in place (condition 2); and measurements of pCO2 and pO2 in arterial blood from a cardiopulmonary bypass without a shunt (condition 3). In Figure 5, the Y-axis is the partial pressure of dissolved CO2 or O2 (units: mmHg). The X-axis in Figure 5 represents the above conditions.

[0061] Figure 6 provides experimental data showing the reduction in GME before (top graph titled "Before Arterial Line Filter") and after (bottom graph titled "After Arterial Line Filter") the arterial line filter when using a filtered shunt compared to a control or control group (no shunt). The reduction in GME after the arterial line filter is measured downstream of the oxygenator / filtered shunt in question and on its way to the patient. In Figure 6, control = no shunt, filtered = filtered shunt, the y-axis is emboli per minute, and the x-axis is emboli diameter (μm).

[0062] Figure 7 provides experimental data showing GME at three locations within the CPB bypass circuit: post-pump, post-oxygenator, and the shunt limb end (referred to as "post-shunt limb" in Figure 3). In Figure 7, control = unfiltered shunt, filtered = filtered shunt, the y-axis represents emboli per minute, and the x-axis represents emboli diameter.

[0063] FIG. 8 shows a mathematical model of the total partial pressure as a function of shunt ratio.

[0064] The addition of a filter to the shunt limb reduces the shunting of GME through the shunt limb, which is useful for providing GME reduction strategies.

[0065] Embodiment The present methods and systems are further illustrated by the following non-limiting embodiments.

[0066] Embodiment 1: A system for reducing gaseous microemboli, the system comprising: a fluid source; a flow diverter fluidly connected to the fluid source and configured to remove a portion of fluid from the fluid source; an inlet flow controller fluidly connected to the fluid source and configured to control a flow rate of fluid from the fluid source to the flow diverter; a bypass line fluidly connected to the flow diverter; a bypass flow controller fluidly connected to the bypass line and configured to control a flow rate of fluid from the bypass line; a filter fluidly connected to the bypass line and configured to remove gaseous microemboli having a defined pore size, preferably 15-50 μm, or larger diameter; an oxygenator fluidly connected to the fluid source and configured to oxygenate fluid from the fluid source; an outlet fluidly connected to the oxygenator and the bypass line; and a controller configured to control the inlet flow controller, the bypass flow controller, the outlet flow controller, or a combination comprising at least one or more of these.

[0067] Embodiment 2: The system of embodiment 1, wherein the oxygenator is configured to have a sub-atmospheric pressure.

[0068] Embodiment 3: The system of any of embodiments 1 or 2, further comprising a vacuum regulator fluidly connected to the oxygenator and configured to provide a sub-atmospheric pressure.

[0069] Embodiment 4: The system of any of embodiments 1 to 3, wherein the oxygenator is configured to have atmospheric pressure.

[0070] Embodiment 5: The system of any of embodiments 1-4, further comprising a sensor configured to measure one or more of flow rate, fluid composition, blood oxygen saturation, oxygen tension, carbon tension fraction, nitrogen tension, hematocrit, or a combination comprising one or more of these, wherein the sensor is fluidly connected to the fluid source, the bypass line, the outlet, or a combination comprising one or more of these.

[0071] Embodiment 6: The system of any of embodiments 1 to 5, wherein the controller includes a processor and software instructions executed by the processor.

[0072] Embodiment 7: The system of any one of embodiments 1 to 6, wherein the oxygenator is a membrane oxygenator, a diffusion membrane oxygenator, or a hollow fiber microporous membrane oxygenator.

[0073] Embodiment 8: The system of embodiment 7, wherein the oxygenator is a microporous membrane oxygenator having a sealed housing.

[0074] Embodiment 9: The system of any of embodiments 1 to 8, wherein the fluid is blood or a blood product such as a blood substitute, an artificial blood, plasma, albumin, platelets, or a plasma concentrate; a crystalloid solution such as saline, lactated Ringer's solution, Normosol, or Plasmalyte; hetastarch; or a combination comprising at least one of these.

[0075] Embodiment 10: The system of any of embodiments 1-9, wherein the fluid source is a blender configured to combine one or more fluids.

[0076] Embodiment 11: The system of any of embodiments 1 to 10, wherein blood flows through the system.

[0077] Embodiment 12: The system of any of embodiments 1 to 11, wherein the oxygen concentration at the outlet is 75 to 800 mmHg, preferably 100 to 700 mmHg, preferably 100 to 650 mmHg, preferably 150 to 250 mmHg.

[0078] Embodiment 13: The system of any of embodiments 1-12, wherein the nitrogen partial pressure at the outlet is reduced or minimized compared to standard oxygenation strategies incorporating air.

[0079] Embodiment 14: A method for reducing gaseous microemboli, comprising: providing an oxygenator configured to oxygenate a fluid, the oxygenator having a venous inlet, an arterial outlet, and a venous bypass line fluidly connected to the venous inlet and the arterial outlet, the venous bypass line including a filter configured to remove gaseous microemboli having a defined pore size, preferably 15-50 μm, and larger diameters, the venous bypass line configured to remove a portion of the fluid from the venous inlet; introducing the fluid into the oxygenator; oxygenating the fluid passing through the oxygenator; and mixing the fluids from the venous bypass line and the arterial outlet to form a combined fluid, wherein the combined fluid has an oxygen concentration of 100-700 mmHg, preferably 150-250 mmHg.

[0080] Embodiment 15: The method of embodiment 14, comprising diverting a portion of the flow through a non-gas exchange shunt channel that is a filtered shunt flow channel in the oxygenator.

[0081] Embodiment 16: The method of embodiment 14 or 15, wherein the flow rate through the filtered shunt flow channel is optionally adjustable.

[0082] Embodiment 17: The method of any of embodiments 14-16, further comprising restricting fluid flow through the oxygenator.

[0083] Embodiment 18: The system of any of embodiments 1 to 13, further comprising a non-gas exchange shunt channel through the oxygenator.

[0084] Embodiment 19: The system of any of embodiments 1-13 or 18, wherein the non-gas exchange shunt channel is a filtered shunt flow channel within the oxygenator, and the flow rate through the filtered shunt flow channel is optionally adjustable.

[0085] Embodiment 20: The system of any of embodiments 1-13 or 18-19, wherein the oxygenator is fluidly connected to a sweep gas reservoir or source via a sweep gas inlet and a sweep gas outlet, the oxygenator includes sweep gas microtubules in a fiber bundle, and the non-gas exchange shunt channel includes means for selectively flowing sweep gas to a portion of the sweep gas microtubules in the oxygenator fiber bundle, and the non-gas exchange shunt occurs within the oxygenator.

[0086] Embodiment 21: The system of any of embodiments 1-13 or 18-20, wherein the oxygenator is fluidly connected to a sweep gas reservoir via a sweep gas inlet and a sweep gas outlet, and the means for selectively flowing sweep gas through a portion of the sweep gas microtubules in the oxygenator fiber bundle includes a variable flow flap or occlusion device, which prevents gas flow through a portion of the fiber bundle near the sweep gas inlet, near the sweep gas outlet, or both, or anywhere along the fluid flow path from the fluid source.

[0087] Embodiment 22: The system of any of embodiments 1-13 or 18-21, wherein the oxygenator is fluidly connected to the sweep gas reservoir via a sweep gas inlet and a sweep gas outlet, and wherein the means for selectively flowing sweep gas through a portion of the sweep gas microtubules in the oxygenator fiber bundle comprises a fluid or other suitable substance, such as water, saline, crystalloid, colloid, blood product, oil, gel, polymer, foam, or wax, permanently or reversibly injected into the sweep gas inlet manifold or the sealed or non-sealed sweep gas outlet manifold, or both, to prevent flow through a portion of the sweep gas microtubules of the fiber bundle.

[0088] Embodiment 22: The system of any of embodiments 1-13 or 18-21, wherein the oxygenator housing includes additional ports in the depending or non-depending portions of the sweep gas inlet manifold or the sweep gas outlet manifold, or both, to allow for the injection and removal of substances to adjust the sweep gas flow within the fiber bundle.

[0089] Embodiment 23: The system of any of embodiments 1-13 or 18-22, wherein the oxygenator housing includes a positive pressure relief valve in the sweep gas inlet manifold or the sweep gas outlet manifold, or both, to relieve positive pressure resulting from restricting the sweep gas flow to a portion of the fiber bundle.

[0090] Embodiment 24: The system of any of embodiments 1-13 or 18-23, wherein the oxygenator comprises two or more compartments, and the flow of sweep gas in each compartment is independently adjustable.

[0091] Embodiment 25: The system of any of embodiments 1-13 or 18-24, wherein the oxygenator comprises two or more compartments, and the flow of blood in each compartment is independently adjustable.

[0092] Embodiment 26: The system of any of embodiments 1-13 or 18-25, wherein the system includes two or more oxygenators, each fluidly connected to a sweep gas reservoir via a sweep gas inlet and a sweep gas outlet, each oxygenator receiving fluid from a fluid source, and the flow of sweep gas to each oxygenator being independently adjustable.

[0093] Embodiment 27: The system of any of embodiments 1-13 or 18-26, wherein the system includes two or more oxygenators, each fluidly connected to a blood reservoir or blood source via a blood inlet and a blood outlet, each oxygenator receiving fluid from the fluid source, and the flow of blood to each oxygenator being independently adjustable.

[0094] Embodiment 28: The system of any of embodiments 1-13 or 18-27, wherein the nitrogen partial pressure at the outlet is reduced or minimized compared to standard oxygenation strategies incorporating air.

[0095] Also disclosed is a system for reducing gaseous microemboli, comprising: a fluid source; a flow diverter fluidly connected to the fluid source and configured to remove a portion of fluid from the fluid source; an inlet flow controller fluidly connected to the fluid source and configured to control a flow rate of fluid from the fluid source to the flow diverter; a bypass line fluidly connected to the flow diverter; a bypass flow controller fluidly connected to the bypass line and configured to control a flow rate of fluid from the bypass line; a filter fluidly connected to the bypass line and configured to remove gaseous microemboli having a defined pore size, preferably 15-50 μm, or larger; an oxygenator fluidly connected to the fluid source and configured to oxygenate fluid from the fluid source; an outlet fluidly connected to the oxygenator and the bypass line; and a controller configured to control the inlet flow controller, the bypass flow controller, the outlet flow controller, or a combination comprising at least one or more of these.

[0096] Also disclosed is a method for reducing gaseous microemboli, comprising providing an oxygenator configured to oxygenate a fluid, the oxygenator having a venous inlet, an arterial outlet, and a venous bypass line fluidly connected to the venous inlet and the arterial outlet, the venous bypass line including a filter configured to remove gaseous microemboli having a defined pore size, preferably 15-50 μm, and larger diameters, the venous bypass line configured to remove a portion of the fluid from the venous inlet; introducing the fluid into the oxygenator; oxygenating the fluid passing through the oxygenator; and mixing the fluids from the venous bypass line and the arterial outlet to form a combined fluid, wherein the combined fluid has an oxygen concentration of 100-700 mmHg, preferably 150-250 mmHg.

[0097] In any of the foregoing embodiments, the oxygenator is configured to have a sub-atmospheric pressure, and / or further includes a vacuum regulator fluidly connected to the oxygenator and configured to provide the sub-atmospheric pressure, and / or the oxygenator is configured to have an atmospheric pressure, and / or further includes a sensor configured to measure one or more of flow rate, fluid composition, blood oxygen saturation, oxygen tension, carbon tension rate, nitrogen tension, hematocrit, or a combination comprising one or more of these, wherein the sensor is connected to the fluid source, the bypass line, the outlet, or one or more of these. and / or the controller includes a processor and software instructions executed by the processor, and / or the oxygenator is a membrane oxygenator, a diffusion membrane oxygenator, or a hollow fiber microporous membrane oxygenator, and / or the oxygenator is a microporous membrane oxygenator having a sealed housing, and / or the fluid is blood or a blood product such as a blood substitute, an artificial blood, plasma, albumin, platelets, or plasma concentrate, saline, a crystalloid solution such as lactated Ringer's solution, Normosol, or Plasmalyte, hetastarch, or A combination comprising at least one of these, and / or the fluid source is a blender configured to combine one or more fluids, and / or blood flows through the system, and / or the oxygen concentration at the outlet is 75-800 mmHg, preferably 100-700 mmHg, preferably 100-650 mmHg, preferably 150-250 mmHg, and / or further comprising a non-gas exchange shunt channel through the oxygenator, and / or the non-gas exchange shunt channel is a filtered shunt flow channel in the oxygenator. and wherein the flow rate through the filtered shunt flow channel is optionally adjustable, and / or the oxygenator is fluidly connected to a sweep gas reservoir or source via a sweep gas inlet and a sweep gas outlet, the oxygenator including sweep gas microtubules in a fiber bundle, the non-gas exchange shunt channel including means for selectively flowing the sweep gas through a portion of the sweep gas microtubules in the oxygenator fiber bundle, and the non-gas exchange shunt occurs within the oxygenator, and / or the oxygenator is fluidly connected to a sweep gas reservoir via a sweep gas inlet and a sweep gas outlet,The means for selectively flowing sweep gas through a portion of the sweep gas microtubules in the oxygenator fiber bundle includes a variable flow flap or occlusion device that prevents gas flow through the portion of the fiber bundle near the sweep gas inlet, near the sweep gas outlet, or both, or anywhere along the fluid flow path from the fluid source, and / or the oxygenator is fluidly connected to a sweep gas reservoir via the sweep gas inlet and the sweep gas outlet, and the means for selectively flowing sweep gas through a portion of the sweep gas microtubules in the oxygenator fiber bundle includes a variable flow flap or occlusion device that prevents gas flow through the portion of the fiber bundle near the sweep gas inlet, near the sweep gas outlet, or both, or anywhere along the fluid flow path from the fluid source, and / or the oxygenator is fluidly connected to a sweep gas reservoir via the sweep gas inlet and the sweep gas outlet, and , a fluid or other suitable substance, such as water, saline, crystalloid, colloid, blood product, oil, gel, polymer, foam, or wax, permanently or reversibly injected into the sweep gas inlet manifold or the sealed or non-sealed sweep gas outlet manifold, or both, to prevent flow through a portion of the sweep gas microtubules of the fiber bundle, and / or the oxygenator housing includes additional ports in the depending or non-depending portions of the sweep gas inlet manifold or the sweep gas outlet manifold, or both. and / or the oxygenator housing includes a positive pressure relief valve in the sweep gas inlet manifold or the sweep gas outlet manifold, or both, to relieve positive pressure resulting from restricting the sweep gas flow to a portion of the fiber bundle, and / or the oxygenator includes two or more compartments, the flow of sweep gas in each compartment being independently adjustable, and / or the oxygenator includes two or more compartments, the flow of blood in each compartment being independently adjustable. and / or the system includes two or more oxygenators, each fluidly connected to a sweep gas reservoir via a sweep gas inlet and a sweep gas outlet, each oxygenator receiving fluid from a fluid source, and the flow of sweep gas to each oxygenator being independently adjustable; and / or the system includes two or more oxygenators, each fluidly connected to a blood reservoir or source via a blood inlet and a blood outlet, each oxygenator receiving fluid from a fluid source, and the flow of blood to each oxygenator being independently adjustable; and / or the nitrogen partial pressure at the outlet isThe oxygenation strategy may further include diverting a portion of the flow through a non-gas exchange shunt channel, which is a filtered shunt flow channel within the oxygenator, and / or the flow rate through the filtered shunt flow channel is optionally adjustable, and / or restricting fluid flow through the oxygenator.

[0098] All references cited herein, including publications, patent applications, and patents, are herein incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference, and are hereby incorporated by reference in their entireties.

[0099] The use of the terms "a," "an," "the," and similar referents in the context of describing the present invention (particularly in the context of the claims below) is to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context, except as follows. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to"), unless otherwise noted. The recitation of ranges of values herein is intended to serve merely as a shorthand method of individually referring to each separate value falling within the range, unless otherwise specified herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. Any and all examples provided herein, or the use of exemplary language (e.g., "such as"), are merely intended to better clarify the invention and do not limit the scope of the invention unless specifically claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0100] Illustrative embodiments of the invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of these embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as they see fit, and the inventors intend to practice the invention otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or clearly contradicted by context.

Claims

1. 1. A system for reducing gaseous microemboli, comprising: a fluid source; a flow diverter fluidly connected to the fluid source and configured to remove a portion of fluid from the fluid source; an input flow controller fluidly connected to the fluid source and configured to control a flow rate of fluid from the fluid source to the flow diverter; a bypass line fluidly connected to the flow diverter; a bypass flow controller fluidly connected to the bypass line and configured to control the flow rate of fluid from the bypass line; a filter fluidly connected to the bypass line, the filter removing gaseous microemboli having a defined pore size, preferably 15-50 μm, but larger than the diameter of the filter; an oxygenator fluidly connected to the fluid source and configured to oxygenate fluid from the fluid source; an outlet flow controller fluidly connected to the oxygenator and configured to control the flow of fluid from the oxygenator; an outlet fluidly connected to the oxygenator and the bypass line; a controller configured to control the inlet flow controller, the bypass flow controller, the outlet flow controller, or a combination comprising at least one or more of the foregoing; A system with.

2. The system of claim 1 , wherein the oxygenator is configured to have a sub-atmospheric pressure.

3. 3. The system of claim 1 or 2, further comprising a vacuum regulator fluidly connected to the oxygenator and configured to provide a sub-atmospheric pressure.

4. The system of any one of claims 1 to 3, wherein the oxygenator is configured to have atmospheric pressure.

5. 5. The system of claim 1, further comprising a sensor configured to measure one or more of flow rate, fluid composition, blood oxygen saturation, oxygen tension, carbon tension rate, nitrogen tension, hematocrit, or a combination comprising one or more of these, wherein the sensor is fluidly connected to the fluid source, the bypass line, the outlet, or a combination comprising one or more of these.

6. The system of any one of claims 1 to 5, wherein the controller includes a processor and software instructions executed by the processor.

7. The system according to any one of claims 1 to 6, wherein the oxygenator is a membrane oxygenator, a diffusion membrane oxygenator, or a hollow fiber microporous membrane oxygenator.

8. The system according to any one of claims 1 to 7, wherein the oxygenator is a microporous membrane oxygenator having a sealed housing.

9. 9. The system of claim 1, wherein the fluid is blood or a blood product such as a blood substitute, an artificial blood, plasma, albumin, platelets, or a plasma concentrate; a crystalloid solution such as saline, lactated Ringer's solution, Normosol, or Plasmalyte; hetastarch; or a combination comprising at least one of the foregoing.

10. The system of any one of claims 1 to 9, wherein the fluid source is a blender configured to combine one or more fluids.

11. The system of any one of claims 1 to 10, wherein blood flows through the system.

12. A system according to any one of the preceding claims, wherein the oxygen concentration at the outlet is between 75 and 800 mmHg, preferably between 100 and 700 mmHg, preferably between 100 and 650 mmHg, preferably between 150 and 250 mmHg.

13. The system of any one of claims 1 to 12, further comprising a non-gas exchange shunt channel through the oxygenator.

14. 14. The system of claim 13, wherein the non-gas exchange shunt channel is a filtered shunt flow channel within the oxygenator, and wherein the flow rate through the filtered shunt flow channel is optionally adjustable.

15. 15. The system of claim 1, wherein the oxygenator is fluidly connected to a sweep gas reservoir or source via a sweep gas inlet and a sweep gas outlet, the oxygenator includes sweep gas microtubules in a fiber bundle, and the non-gas-exchange shunt channel includes means for selectively flowing sweep gas to a portion of the sweep gas microtubules in the fiber bundle of the oxygenator, and non-gas-exchange shunting occurs within the oxygenator.

16. 16. The system of claim 1, wherein the oxygenator is fluidly connected to a sweep gas reservoir or source via a sweep gas inlet and a sweep gas outlet, and wherein the means for selectively flowing sweep gas through a portion of the sweep gas microtubules in the fiber bundle of the oxygenator comprises a variable flow flap or occlusion device that prevents gas flow through the portion of the fiber bundle near the sweep gas inlet, near the sweep gas outlet, or both, or anywhere along the fluid flow path from the fluid source.

17. 17. The system of any one of claims 1 to 16, wherein the oxygenator is fluidly connected to a sweep gas reservoir or source via a sweep gas inlet and a sweep gas outlet, and wherein the means for selectively flowing sweep gas through a portion of the sweep gas microtubules in the fiber bundle of the oxygenator comprises a fluid or other suitable substance, such as water, saline, crystalloid, colloid, blood product, oil, gel, polymer, foam, or wax, permanently or reversibly injected into a sweep gas inlet manifold or a sealed or non-sealed sweep gas outlet manifold, or both, to prevent flow through a portion of the sweep gas microtubules in the fiber bundle.

18. 18. The system of any one of claims 1 to 17, wherein the oxygenator housing includes additional ports in the depending or non-depending portions of the sweep gas inlet manifold and / or the sweep gas outlet manifold to allow for injection and removal of substances to adjust the sweep gas flow within the fiber bundle.

19. 19. The system of any one of claims 1 to 18, wherein the oxygenator housing includes a positive pressure relief valve in the sweep gas inlet manifold or the sweep gas outlet manifold, or both, to relieve positive pressure resulting from restricting sweep gas flow to a portion of the fiber bundle.

20. the oxygenator comprises two or more compartments; A system according to any preceding claim, wherein the flow of sweep gas in each compartment is independently adjustable.

21. the oxygenator comprises two or more compartments; The system of any one of claims 1 to 20, wherein the flow of blood in each compartment is independently adjustable.

22. the system includes two or more oxygenators; Each oxygenator is fluidly connected to a sweep gas reservoir via a sweep gas inlet and a sweep gas outlet; 22. The system of any one of claims 1 to 21, wherein each oxygenator receives fluid from the fluid source, and the flow of sweep gas to each oxygenator is independently adjustable.

23. the system includes two or more oxygenators; Each oxygenator is fluidly connected to a blood reservoir or source via a blood inlet and a blood outlet; 23. The system of any one of claims 1 to 22, wherein each oxygenator receives fluid from the fluid source, and the flow of blood to each oxygenator is independently adjustable.

24. 24. A system according to any one of claims 1 to 23, wherein the nitrogen partial pressure at the outlet is reduced or minimized compared to standard oxygenation strategies incorporating air.

25. 1. A method for reducing gaseous microemboli, comprising: providing an oxygenator configured to oxygenate a fluid, the oxygenator having a venous inlet, an arterial outlet, and a venous bypass line fluidly connected to the venous inlet and the arterial outlet, the venous bypass line including a filter configured to remove gaseous microemboli having a defined pore size, preferably 15-50 μm, and larger diameters, the venous bypass line configured to remove a portion of the fluid from the venous inlet; introducing a fluid into the oxygenator; oxygenating the fluid passing through the oxygenator; mixing fluids from the venous bypass line and the arterial outlet to form a composite fluid; wherein the oxygen concentration in the composite fluid is 100 to 700 mmHg, preferably 150 to 250 mmHg.

26. 26. The method of claim 25, comprising shunting a portion of the flow through a non-gas exchange shunt channel that is a filtered shunt flow channel in the oxygenator.

27. 27. The method of claim 25 or 26, wherein the flow rate through the filtered shunt flow channel is optionally adjustable.

28. 28. The method of any one of claims 25 to 27, further comprising restricting fluid flow through the oxygenator.

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