System and method for blood oxygenation, passive oxygenation circuit, and neonatal extracorporeal circulatory support system

Abstract

A method for oxygenating the blood of a newborn infant includes receiving deoxygenated arterial blood from the newborn infant's umbilical cord in a non-pumped extracorporeal circuit, the extracorporeal circuit including a membrane oxygenator. The deoxygenated arterial blood is delivered at a blood flow rate R F The method comprises at least 2R F The method can include flowing a mixed sweep gas through the membrane oxygenator at a mixed sweep gas flow rate equal to or greater than 1000 ppm, wherein the mixed sweep gas comprises oxygen and at least about 1% by volume of carbon dioxide.

Description

[Technical Field]

[0001] Extracorporeal circulatory support devices have been proposed for both adults and neonates. These systems use an oxygenator to exchange carbon dioxide for oxygen in the patient's blood. Summary of the Invention [Means for solving the problem]

[0002] A method for oxygenating the blood of a newborn includes receiving deoxygenated arterial blood from the umbilical cord of the newborn in a non-pumped extracorporeal circuit, the extracorporeal circuit including a membrane oxygenator. The deoxygenated arterial blood is delivered at a blood flow rate R F The method comprises at least 2R F and flowing a mixed sweep gas through the membrane oxygenator at a mixed sweep gas flow rate equal to or greater than 1000 ppm, the mixed sweep gas having oxygen and at least about 1% by volume of carbon dioxide.

[0003] The mixed sweep gas may further comprise one or more selected from the group consisting of ambient air at sea level, nitrogen, and nitric oxide. The mixed sweep gas contains a carbon dioxide partial pressure sufficient to maintain normocapnia in the venous blood of the neonate. The mixed sweep gas flow rate is about 2 R F ~approx. 20R F The mixed sweep gas flow rate may be about 2 R F ~about 16R F In the method, the blood flow rate R F The mixed sweep gas flow rate may be about 120 mL / min to about 800 mL / min. The mixed sweep gas may contain about 3 vol % to about 6 vol % carbon dioxide. At least a portion of the carbon dioxide in the mixed sweep gas may be recovered from the exhaust gas of the membrane oxygenator.

[0004] The method includes receiving, by a gas mixing device, a first gas from a first source and a second gas from a second source, the first gas being different from the second gas, and mixing the first gas and the second gas to generate the mixed sweep gas. The first source may be a first gas tank and the second source may be a second gas tank. The first source may be a wall pipe and the second source may be at least one of a second wall pipe and a gas tank.

[0005] The pumpless oxygenation circuit includes a mixer adapted and configured to receive an oxygen-containing gas from an oxygen source, a carbon dioxide-containing gas from a carbon dioxide source, and output a mixed sweep gas having oxygen and at least about 1% carbon dioxide by volume. The pumpless oxygenation circuit includes a flow controller, a membrane oxygenator, and a blood flow sensor. The flow controller is fluidly connectable to an outlet of the mixer and configured to allow a predetermined mixed sweep gas flow rate for the mixed sweep gas passing through the flow controller. The membrane oxygenator is configured to connect to the flow controller and to an unpumped neonatal blood circuit. The blood flow sensor is positionable along the unpumped neonatal blood circuit and is configured to measure neonatal blood flow R. F The flow controller is adapted and configured to measure the mixed sweep gas flow rate by at least 2R. F Control is performed so that the above is achieved.

[0006] The pumpless oxygenation circuit includes a controller communicatively connected to the flow controller and the blood flow sensor. The pumpless oxygenation circuit includes a blood gas sensor disposed along the pumpless neonatal blood circuit and communicatively connected to the controller. The controller controls the mixer to titrate the composition of the mixed sweep gas to reflect the neonatal blood gas values ​​and to provide a carbon dioxide partial pressure sufficient to maintain normocapnia. The mixed sweep gas flow rate is approximately 2R.F ~approx. 20R F The mixed sweep gas flow rate may be about 2 R F ~about 16R F The mixed sweep gas flow rate may be about 120 mL / min to about 800 mL / min. The mixed sweep gas may contain about 3% by volume to about 6% by volume of carbon dioxide.

[0007] The neonatal extracorporeal circulatory support system includes a neonatal nursery, a neonatal blood system, and a non-pump oxygenation circuit. The neonatal nursery can be adapted and configured to maintain the neonate in saline. The neonatal blood system can be adapted and configured to connect to multiple blood vessels of the neonate. [Brief explanation of the drawings]

[0008] For a more complete understanding of the nature and desired objects of the present invention, reference is now made to the following detailed description taken in conjunction with the accompanying drawings, in which like reference numerals designate corresponding parts throughout the several views, and in which: [Figure 1] FIG. 1 shows a schematic diagram of an extracorporeal circulatory assist system according to one embodiment of the present disclosure. [Figure 2] FIG. 2 shows a schematic diagram of a portion of an extracorporeal circulatory assist system according to another embodiment of the present disclosure. [Figure 3] FIG. 3 shows an isometric view of a portion of an extracorporeal circulatory assist system according to yet another embodiment of the present disclosure. [Figure 4] FIG. 4 shows an isometric view of an oxygenation device according to one embodiment of the present disclosure. [Figure 5] FIG. 5 shows an isometric view of a portion of a gas exchanger according to one embodiment of the present disclosure. [Figure 6] FIG. 6 shows an isometric view of a gas exchanger according to another embodiment of the present disclosure. [Figure 7] FIG. 7 shows a front view of the gas exchanger of FIG. [Figure 8] FIG. 8 shows a side view of an oxygenation device according to one embodiment of the present disclosure. [Figure 9]FIG. 9 illustrates a method for oxygenating blood according to one embodiment of the present disclosure. [Figure 10] FIG. 10 illustrates a system for oxygenating blood according to one embodiment of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0009] definition The invention is most clearly understood by reference to the following definitions.

[0010] As used herein, the singular forms "a," "an," and "the" include the plural forms unless the context clearly indicates otherwise.

[0011] Unless otherwise specified or clear from the context, the term "about" as used herein is understood to mean within a normal range of tolerance in the art, for example, within 2 standard deviations of the mean. "About" can be understood to mean within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values ​​described herein are modified by the term "about."

[0012] As used in this specification and the claims, the terms "comprises," "comprising," "containing," "having," and the like, shall have the meaning defined in U.S. Patent Law and may mean "includes," "including," and the like.

[0013] As used herein, unless expressly stated otherwise or clear from context, the term "or" is understood to be inclusive.

[0014] The terms "proximal" and "distal" may refer to the location of one portion of a given device relative to the remainder or opposite end of that device as illustrated by the drawings. The proximal end is used to refer to the end that is manipulated by the user. The distal end is used to refer to the end that is inserted and advanced and is furthest from the user. As one skilled in the art will appreciate, proximal and distal may be used differently in other contexts, such as when proximal and distal are used in an anatomical context relative to the patient or when the point of insertion is distal from the user.

[0015] Ranges provided herein are understood to be shorthand notations for all values ​​within that range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 (including fractions thereof unless the context clearly indicates otherwise).

[0016] Aspects of the present invention provide methods and systems for blood oxygenation that utilize high flow rates of carbon dioxide-rich sweep gas, thereby avoiding the technical challenges of flow control when the low blood flow rate of neonates results in low flow rates of oxygen-rich sweep gas.

[0017] Referring now to FIG. 1, one embodiment of the present invention provides an extracorporeal circulatory assist system that is particularly useful in neonates.

[0018] 1-3, system 10 is configured to provide extracorporeal circulatory support to a neonate. According to one aspect of the present disclosure, system 10 can be configured to provide a system environment similar to the environment a neonate would experience in utero. Survival rates of neonates placed outside the utero environment (e.g., due to preterm birth), for example, between about 22 and about 28 weeks of gestation, may be improved by placing the neonate in the system environment.

[0019] According to one aspect of the invention, the system environment can be configured to achieve one or more of the following objectives: (1) limit the neonate's exposure to light, (2) limit the neonate's exposure to sound, (3) maintain the neonate in a liquid environment, (4) maintain the neonate within a desired temperature range, (5) accommodate the neonate's growth, and (6) control the level of oxygenation in the neonate's bloodstream. The system also allows for neonate activities necessary for organ growth and development (e.g., neonate breathing, neonate swallowing of fluids).

[0020] The system 10 can be configured to treat neonates (e.g., those with an estimated gestational age of less than 37 weeks, particularly those with an estimated gestational age of about 28 weeks to about 32 weeks) or extremely preterm neonates (e.g., those with an estimated gestational age of about 22 weeks to about 28 weeks). While the gestational ages are intended for humans, other preterm animal counterparts can also be used. In certain embodiments, the neonates are free of underlying congenital disorders. Full-term or preterm neonates may have limited pulmonary gas exchange capacity due to congenital anomalies affecting lung development, such as pulmonary hypoplasia or congenital diaphragmatic hernia. In certain aspects, the subject may be a preterm or full-term neonate awaiting lung transplant due to a congenital lung disease (e.g., bronchoalveolar dysplasia, surfactant protein B deficiency, etc.). Such transplant procedures are currently rarely performed in the United States. However, the more robust lung support methods provided by the present invention may potentially increase the number of transplant procedures. The newborn 5 may be a candidate for ex utero intrapartum treatment (EXIT), including patients with severe airway disease and a prolonged course of curative resection. The newborn 5 may also be a candidate for neonatal surgery or fetoscopic procedures, particularly following preterm birth due to early labor. According to one aspect of the present disclosure, the system 10 may be configured to maintain the newborn 5 within the system 10 for a selected period of time (e.g., days, weeks, or months until the newborn 5 is able to survive without the assistance of the system 10). The system 10 should be operable to maintain the newborn 5 for at least 7 days, 14 days, at least 21 days, at least 28 days, at least 35 days, at least 42 days, at least 49 days, or at least 56 days.

[0021] The system 10 includes a neonatal room 100 configured to accommodate a neonate 5, a physiological saline solution (PSS) circuit configured to provide a flow (e.g., a constant flow rate) of physiological saline solution (PSS) through the neonatal room 100, and an oxygenation circuit 400 configured to remove carbon dioxide from the neonate's blood and provide oxygen to the neonate's blood.

[0022] The system 10 is configured to maintain the newborn infant 5 in a nursery 100 immersed in physiological saline (PSS). The system 10 is further configured to provide sufficient gas exchange to sustain the life of the newborn infant 5 via an oxygenation circuit 400. In this configuration, the system 10 provides an environment similar to that in utero to promote the continued growth and development of the newborn infant 5. The system 10 may also include a cart or similar device (not shown) to facilitate monitoring, care, and transportation of the newborn infant 5 within the medical facility.

[0023] According to one aspect of the present disclosure, the system 10 may be as described in pending U.S. Patent Application Publication No. 2019 / 0380900 (U.S. Patent Application No. 16 / 469,192).

[0024] The oxygenation circuit 400 can be venously / venously connected to the neonate 5. Alternatively, the oxygenation circuit 400 can be arterially / venously connected to the neonate 5. The circulatory system of the neonate 5 can be connected to the oxygenator 500 by inserting a cannula into the neonate's 5 large neck vessels (e.g., carotid artery, jugular vein). Placement in the large neck vessels avoids problems such as vasospasm and instability of the cannula within the umbilical vessels. The outer portion of the cannula may be sleeved (e.g., to increase tension on the stabilizing sutures). The sleeve may be made of silicone and may be, for example, about 1 cm to about 10 cm in length, or particularly about 3 cm to about 5 cm in length. The cannula can be sutured to the neonate 5 (e.g., via the attached sleeve) to secure it to the neonate's neck.

[0025] In some aspects, the oxygenation circuit 400 may be connected to the neonate 5 via the neonate's umbilical cord. In such a configuration, a cannula may be connected by suturing or connecting methods and / or devices to the veins and arteries of the umbilical cord. It is understood that other connection configurations are also available. In one particular embodiment, a sutureless device or cannula is described in U.S. Patent Application Publication No. 2021 / 0338270. In this or other embodiments, the neonate 5 is connected to the oxygenation circuit 400 using a cannula that connects one vein and two arteries of the umbilical cord.

[0026] The oxygenation circuit 400 can include an oxygenation device 500 (shown in FIG. 1 as an extracorporeal membrane oxygenation (ECMO) device) for providing gas exchange, particularly for oxygenating and removing carbon dioxide from the neonate 5. One contemplated oxygenation device is described in PCT International Application No. ____, filed September 14, 2022, entitled "Oxygenating and Neonatal Extracorporeal Support Devices and Systems," the disclosure of which is incorporated herein by reference in its entirety. The oxygenation device 500 can be removably connected to the neonate 5 and, optionally, to other components of the oxygenation circuit 400 and system 10. The oxygenation device 500 is connected to the neonate 5 via two or more fluid lines, including at least an exhaust line 440 and an inlet line 445. Blood flows from the neonate 5 through an exhaust line 440 into the oxygenator 500. The system 10 may include a drug supply line 114 that introduces a drug into the neonate's blood in the exhaust line 440. A sensor 120 may analyze the blood flow through the exhaust line. The sensor 120 may also perform gas analysis of the sweep gas that returns to the oxygenator 500 through the exhaust line 440. The drug supply line 114 may also introduce a drug into the neonate's blood in the inlet line 445. A drug may also be introduced into the oxygenator 500 through the drug supply line 114.

[0027] The blood then flows through the oxygenator 500 and returns to the neonate 5 via the inlet line 445. The oxygenation levels of the blood exiting the oxygenator and the blood entering the inlet line 445 are substantially equivalent. In certain embodiments, the blood oxygenation level is measured using a gas analyzer 110, such as the AD Instruments ML206 Gas Analyzer, which uses an infrared sensor and optical or visible spectrum absorption to measure the levels of carbon dioxide (CO2) and oxygen (O2), respectively, in the blood. The first gas analyzer 110 can analyze the sweep gas entering the oxygenator 500. The second gas analyzer 110 can analyze the oxygenation level in the blood. The sampler 112 can sample the flow rate of the sweep gas. In this or another embodiment, the sampled pump flow rate ranges from about 35 to about 200 milliliters per minute (ml / min). The residual gas in the blood is nitrogen (N2).

[0028] In some embodiments, while the oxygenation circuit 400 is in operation, the oxygenator 500 can be configured to be disconnected and replaced with another oxygenator 500. If the oxygenator 500 is damaged or exceeds its expected lifespan (typically 8 hours or other period(s) based on regulatory approval), the oxygenation circuit 400 can be configured to temporarily bypass the oxygenator 500, thereby allowing the oxygenator 500 to be disconnected from the oxygenation circuit 400 and a new, primed oxygenator 500 to be connected in its place without interrupting blood flow.

[0029] 4-8 , the oxygenation device 500 includes a housing 502 defining a cavity 540 therein. The housing 502 may include multiple ports extending through the housing 502 into the cavity 540. Blood from the neonate 5 enters the oxygenation device 500 through a blood inlet port 504 located on the housing 502 and in fluid communication with the cavity 540 and a blood outlet port 508. The housing 502 has an interior volume that houses a gas exchanger 550. In some embodiments, the multiple blood inlet ports 504 may be configured to alternately or simultaneously receive blood from the neonate 5. The blood inlet ports 504 are connected to an exhaust line 440 through which blood travels from the neonate 5 to the oxygenation device 500.

[0030] One or more additional ports, such as a pressure transducer 524, can be located on or adjacent to the blood inlet port 504, or in-line with the exhaust line 440. The pressure transducer 524 can measure the pressure of the neonate's 5 blood entering the oxygenation device 500 at the blood inlet port 504. In some embodiments, a sampling port (not shown) can be located on or adjacent to the blood inlet port 504 or the exhaust line 440 to allow a portion of the blood entering the oxygenation device 500 to be extracted from the oxygenation circuit 400 for analysis or testing. The sampling port can also be used to infuse medications or nutrients, such as total perinatal nutrition (TPN), directly into the blood. These one or more additional ports can include any suitable connection means, such as a Luer connector.

[0031] A blood outlet port 508 is provided on the housing 502 through which blood exits the oxygenator 500 and returns to the neonate 5. The blood outlet port 508 is connected to the inlet line 445 through which blood travels from the oxygenator 500 to the neonate 5. The number of blood outlet ports 508 may be the same as or different from the number of blood inlet ports 504.

[0032] One or more additional ports, such as a pressure transducer 528, can be located on or adjacent to the blood outlet port 508, 504, or in-line with the inlet line 445. The pressure transducer 528 can measure the pressure of the blood exiting the oxygenator 500. In some embodiments, a sampling port (not shown) can be located on or adjacent to the blood outlet port 508 to allow a portion of the blood exiting the oxygenator 500 to be extracted from the oxygenation circuit 400 for analysis or testing. A sampling port at the outlet of the oxygenator 500 (e.g., located on a line extending from the outlet port 508 or on the same line as the pressure transducer 528 (preferably a port located upstream from the transducer 528)) can be used to inject medications or nutrients directly into the blood. These one or more additional ports can have any suitable connection means, such as a Luer connector.

[0033] A fluid flow meter 116 (FIG. 1) is installed in-line in the inlet line 445 to monitor the blood flow returning to the neonate 5 or leaving the oxygenator 500 .

[0034] A gas inlet port 512 is located on the housing 502 for introducing a sweep gas into the oxygenator 500. The sweep gas can flow from the gas inlet port 512 toward a gas outlet 516 along a direction 518. The sweep gas can include a single gas or a combination of various gases, such as oxygen and other ambient gases. It is understood that the sweep gas can include various ratios of gases that can be adjusted to achieve a desired gas combination and ratio for use in the system 10. In some embodiments, the sweep gas has a flow rate ranging from about 25 mL / min to about 300 mL / min, from about 25 mL / min to about 200 mL / min, from about 50 mL / min to about 175 mL / min, or from about 75 mL / min to about 150 mL / min. In some embodiments, the sweep gas flow rate is about 100 mL / min. An additional port (not shown) may be provided on or adjacent to the gas inlet port 512 to extract a portion of the sweep gas entering the oxygenator 500 for analysis or testing. The additional port may have any suitable connection means, such as a Luer connector. The flow rate from the inlet at 524 to the outlet at 528 is adjusted by narrowing the inner diameter of the tubing (or reducing the diameter of the tubing) to increase resistance and slow the flow of fluid through the tubing. In this or another embodiment, the resistance in the oxygenator essentially controls the gas flow rate. The neonate can adjust the gas flow rate by increasing their heart rate, which can be sensed by a sensor. In some embodiments, the sensor is a pressure sensor. In another embodiment, the sensor is a flow rate sensor, a volumetric flow meter, or a mass flow meter.

[0035] A gas exhaust port 516 is located on the housing 502 for exhausting the sweep gas from the oxygenator 500. An additional port (not shown) may be provided on or adjacent to the gas exhaust port 516 to extract a portion of the sweep gas exhausted from the oxygenator 500 for analysis or testing. The additional port may include any suitable connection means, such as a luer connector.

[0036] A gas bleed port 520 is located on the housing 502 to remove excess gas when the oxygenator is filling with liquid. If the pressure within the oxygenator 500 is too high, the flow of blood into the oxygenator 500 may be blocked, reduced, or stagnated, which may result in blood clotting or poor circulation in the newborn 5. Additionally, unnecessary pressure buildup within the oxygenator 500 may increase the pressure on the blood leaving the oxygenator 500 and entering the newborn 5. This may result in increased blood flow, which may damage the blood (e.g., blood cells in the blood), leading to the formation of undesirable blood clots and poor blood quality.

[0037] In some embodiments, oxygenation circuit 400 is configured so that blood flows through the circuit without the operation of an external pump (e.g., a mechanical pump). Instead, blood is circulated through outlet line 440, oxygenator 500, inlet line 445, and other components by the neonate's heart. That is, oxygenation circuit 400 is a passive or pumpless circuit.

[0038] Therefore, minimizing pressure and resistance within the oxygenation circuit 400, and particularly within the oxygenator 500, is advantageous for allowing blood to flow through the oxygenation circuit 400 without excessive obstruction. Using a non-pumping system avoids exposing the neonatal heart to the excessive preload that occurs in circuits using non-pulsatile pumps. A non-pumping system also allows for hemodynamics that are specific to neonatal circulation. Preferably, the oxygenator 500 has at least one or more of the following characteristics to provide efficient gas exchange: very low resistance, low priming volume, and low transmembrane pressure drop. As described above, unnecessary pressure buildup within the oxygenator 500 requires additional force to move blood through the oxygenator 500, which can strain the neonatal heart and cause health problems. If the heart cannot overcome the additional force, blood flow may stagnate or be significantly reduced, potentially resulting in cessation of circulation or a reduction in the neonatal blood volume.

[0039] In some embodiments, the oxygenator 500 may have a fluid pressure drop measured across the oxygenator inlet 504 and outlet 508 of less than about 50 mmHg, less than about 40 mmHg, or less than about 30 mmHg at a blood flow rate of 1.5 L / min. For neonates, a fluid pressure drop of 10 mmHg or less is required to achieve a flow rate in the range of about 50 mL to 200 mL. That is, it is important that the oxygenator have low resistance. In some embodiments, neonatal blood pressure ranges from about 20 mmHg to about 40 mmHg. The priming volume of the oxygenator 500 may range from about 20 mL to about 200 mL, from about 30 mL to about 100 mL, from about 40 mL to about 85 mL, or from about 50 mL to about 75 mL, and may be less than about 200 mL, less than about 100 mL, less than about 85 mL, less than about 75 mL, less than about 50 mL, less than about 40 mL, or less than about 30 mL. In some embodiments, the priming volume is preferably in the range of about 20 mL to about 50 mL, about 20 mL to about 40 mL, or about 25 mL to about 30 mL. Such small priming volumes are advantageous because they reduce dilution of the neonatal blood by the priming substance. In some embodiments, the blood flow rate of the oxygenator 500 may be at least about 1.5 L / min, preferably about 1.5 to 2.8 L / min, about 2.0 L / min, or about 1.5 L / min to about 2.5 L / min, or in the range of 1.5 L / min to about 2.8 L / min, or even greater than these ranges. In certain embodiments, the gas transfer rate through the oxygenator 500 may be in the range of about 30 to about 180 mL / min, about 25 to about 50 mL / min, about 50 to about 75 mL / min, about 75 to about 100 mL / min, about 100 to about 150 mL / min, about 150 to about 180 mL / min, or a range exceeding these ranges for a sweep gas containing oxygen gas (O). However, the gas transfer rate is not limited to these ranges. In these or other embodiments, the gas transfer rate may be the gas transfer rate in the blood of a newborn. In some embodiments, the composition of the gas may affect the gas transfer rate. The blood flow rate through the oxygenator may also affect the gas transfer rate.In some embodiments, higher blood flow may increase the rate of gas transfer.

[0040] The oxygenator 500 includes a gas exchanger 550 disposed within the cavity 540. Blood entering the cavity 540 through the blood inlet port 504 contacts and flows through the gas exchanger 550. The blood then exits the cavity 540 through a blood outlet port 508 on the housing 502. The gas exchanger 550 includes elements configured to diffuse at least oxygen and carbon dioxide gases between the gas exchanger 550 and the blood flowing through the oxygenator 500. The gas exchanger 550 includes a plurality of hollow fibers 554 arranged in a predetermined pattern such that the blood contacts and / or passes near, but not through, at least a portion of the hollow fibers 554. Diffusion of gas occurs as the blood contacts and / or passes near, the hollow fibers 554. It is understood that the diffusion rate may be predetermined and controlled by at least one or more of the following variables: sweep gas composition, blood flow rate, sweep gas flow rate, quantity of hollow fibers 554, size and shape of hollow fibers 554, relative spacing of hollow fibers 554 within oxygenator 500 or chamber 502, blood flow path within oxygenator 500, sweep gas flow path within oxygenator 500, and / or other factors that may affect the above variables.

[0041] As shown in FIG. 1 , two or more gases can be mixed in a gas mixer 104 to generate a sweep gas. In one embodiment, these gases consist of oxygen and ambient air. The gas mixer can take a variety of forms, including a simple Y-type fitting. A mass flow controller located upstream of the gas mixer can control the ratio of gases included in the sweep gas. The two or more gases can be supplied from a first supply 102. The first supply 102 can be a bulk gas storage source, such as wall piping connected to a central gas supply configured to supply gas to the storage source. The composition of such gases will vary depending on the public supply and configuration of the healthcare facility. Alternatively, the two or more gases can be supplied from a second supply 106. The second supply 106 can be a gas storage source. In one embodiment, the second supply 106 includes a portable oxygen tank and a portable air tank, or other gas storage vessel. It will be understood that a variety of suitable gases can be used. In some embodiments, oxygen gas and nitrogen gas can be mixed to achieve a desired oxygen concentration. The oxygen concentration can range from 0% to 100% of the mixed gas.

[0042] In some aspects, such as the embodiment shown in FIG. 5, hollow fibers 554 comprise polymethylpentene (PMP) due to its excellent gas permeability properties. Other suitable gas permeable materials, such as, but not limited to, silicone sheet membranes or polypropylene hollow fibers, may also be used. Each hollow fiber 554 has a receiving end 558 through which the sweep gas enters and a discharge end 562 through which the sweep gas exits. A flow passage 566 extends between receiving end 558 and discharge end 562 and is configured to transport the sweep gas through hollow fiber 554.

[0043] The hollow fibers 554 can be arranged in a specific pattern to form the gas exchanger 550. Referring to FIG. 8 , in some embodiments, the gas exchanger 550 can be substantially cylindrical. Each hollow fiber 554 can extend between opposing upper and lower planar ends of the cylinder so that all of the hollow fibers 554 are arranged parallel to one another. In such an arrangement, the flow direction of the sweep gas is preferably opposite to the direction of blood flow. Referring to FIG. 8 , for example, the sweep gas inlet can be located at one of the opposing planar ends of the cylinder (e.g., the upper end shown in FIG. 8 ), and the sweep gas outlet can be located at the other of the opposing planar ends of the cylinder (e.g., the lower end shown in FIG. 8 ). In this case, the sweep gas flows from the top to the bottom of the cylinder in the direction D2. The blood inlet port 504 can be located at the lower end shown in Fig. 8, and the blood outlet port 508 can be located at the upper end opposite the lower end shown in Fig. 8, in which case blood flows from the bottom to the top of the illustrated cylindrical portion in the direction D1 opposite to the flow direction of the sweep gas. This embodiment is advantageous because it allows for better and more efficient gas exchange between the blood and the gas exchange hollow fibers 554.

[0044] Referring to Figures 5-7, in another embodiment of the present disclosure, the plurality of hollow fibers 554 can be arranged in a crisscross pattern or a grid. The plurality of hollow fibers 554 can be arranged substantially parallel to one another in a single plane. A gas exchanger 550 can be constructed by combining multiple such arrangements, and the orientation of each planar arrangement can be the same as, the same as, or different from the other planar arrangements. Referring again to Figures 5-7, a portion of an exemplary gas exchanger 550 is shown having a first plane 570 containing a plurality of hollow fibers and a second plane 572 adjacent to the first plane 570. Plane 570 and plane 572 are substantially identical, except that the hollow fibers 554 in the second plane 572 are at a predetermined angle relative to the hollow fibers 554 in the first plane 570. The second plane 572 is rotated 90 degrees relative to the first plane or is positioned substantially perpendicular, although it is understood that other relative angles between the planes of adjacent fibers are possible. Any number of planes 570, 572 can be arranged to configure the gas exchanger 550.

[0045] The fibers 554 are arranged to form spaces 576 through which blood can pass between adjacent fibers. The size of the spaces 576 depends on one or more of the following parameters: quantity of fibers, density of fibers, blood flow rate, sweep gas flow rate, desired resistance in the oxygenator, and / or other parameters that may affect gas exchange in the blood.

[0046] Gas exchanger 550 can include a variety of shapes and configurations, such as a cylindrical shape, a cubic shape, or a parallelepiped shape. Referring to Figures 6-7, the gas exchanger 550 can be configured as a cylinder with two opposing flat ends, with adjacent flat surfaces (e.g., flat surface 570 and flat surface 572 positioned at a 90-degree angle relative to flat surface 570). Blood enters gas exchanger 550 at one flat end, passes through gas exchanger 550, and exits at the opposite flat end. Sweep gas enters gas exchanger 550 at one point on the curved wall of the cylinder and exits at another point on the curved wall.

[0047] Referring again to FIG. 5 , in some embodiments, as discussed above, it is advantageous to configure the gas exchanger 550 to have multiple planes 570, 572 that form a cylindrical shape. Such a gas exchanger has a circular cross-section perpendicular to the direction of blood flow D1. The circular cross-section eliminates corners, reducing areas of severe turbulence and stagnant flow, and also helps maintain a predetermined flow pattern (e.g., a constant flow rate) throughout the gas exchanger 550. This reduces the potential for damage to blood cells and reduces clot formation. Such a configuration may also be advantageous because it reduces pressure within the oxygenator 500 and reduces blood flow resistance. As discussed above, because the system 10 is non-pump / passive, it is important to keep blood flow resistance as low as possible to prevent cessation or significant reduction in blood flow and excessive strain on the neonatal heart as it pumps blood through the oxygenation circuit 400. If the resistance of the blood circuit is too low, it is possible to non-invasively restrict blood flow in the umbilical cord (440 in Figure 1) before entering the oxygenator (between P1 and the oxygenator) if necessary to avoid starving the newborn's blood circulation.

[0048] In some embodiments, the gas exchanger 550, housing 502, or any port disclosed herein may be coated or lined with one or more anticoagulant, antithrombotic, and / or non-thrombotic materials, such as, but not limited to, immobilized polypeptides and heparin.

[0049] System 10 may include a heating element 600 disposed therein and configured to heat oxygenation circuit 400. Heating element 600 is not part of oxygenator 500 itself. Heating element 600 heats and maintains desired temperatures for neonate 5, the neonate's environment, the housing of oxygenation circuit 400, and other components of system 10. Referring to FIG. 2, an exemplary arrangement is shown in which heating element 600 is separate from oxygenator 500 and in contact with oxygenation circuit 400. FIG. 2 is an exemplary schematic diagram illustrating one embodiment of such an arrangement, and it is understood that heating element 600 may be located elsewhere, either directly adjacent to or in indirect contact with oxygenation circuit 400.

[0050] Maintaining the entire oxygenation circuit 400 within a desired temperature eliminates the need for additional heating of the blood, particularly as it flows toward and through the oxygenator 500. The desired temperature can range from about 36°C to about 39°C. Therefore, a heating element 600 is not necessary or desirable within the oxygenator 500. Eliminating the heating element 600 from the oxygenator 500 allows for a more compact oxygenator 500, reducing the amount of hollow fibers required, blood flow resistance, and the amount of priming material required for operation. It is important to note that oxygenators in extracorporeal circuits typically require a heating element to maintain the proper temperature of the blood passing through them. Failure to install a heating element can result in blood damage, shock to the patient, or other health hazards. The systems described throughout this application eliminate these drawbacks by using a heating element 600 to heat the entire system 10, or at least the oxygenation circuit 400. This allows the removal of heating devices from the oxygenator 500 itself while maintaining the required temperature for the blood and sweep gas moving between the neonate 5 and the oxygenator 500.

[0051] As mentioned above, removing the heating device typically required from the oxygenator 500 allows for a smaller gas exchanger 550 and cavity 540, thereby reducing the priming volume required to operate the oxygenator 500. To begin the oxygenation process, the oxygenator 500 must be primed with an appropriate priming material. The larger the oxygenator 500, the greater the minimum amount of priming material required. In some embodiments, the priming material used when the neonate 5 is connected to the oxygenation circuit 400 is comprised of adult blood (e.g., maternal blood or blood from a blood bank). Because adult blood has different properties than neonate blood, it is desirable to minimize the effects of these differences. Priming the oxygenator 500 with adult blood results in hemodilution of the neonate's blood (i.e., the neonate's blood mixes with the adult blood used for priming). The greater the amount of priming material, the greater the hemodilution. Minimizing hemodilution of the neonate 5 may be advantageous. By removing the heating device from the oxygenator 500 (instead of the heating element 600 in the system 10 or oxygenation circuit 400), the total volume of the oxygenator 500 is reduced, and therefore the required priming volume is correspondingly reduced.

[0052] Additionally, reducing the overall size and volume of the oxygenator 500 also reduces the transit time for blood moving through the oxygenator 500. Longer transit times can lead to thrombosis and clot formation, and reducing the size of the oxygenator 500 reduces the transit time for blood flowing therethrough, reducing the likelihood of clot formation. The blood flow rate through the oxygenator 500 depends on the age and size of the newborn 5. For example, in some embodiments, a newborn weighing approximately 500 grams may have a blood flow rate ranging from about 40 mL / min to about 60 mL / min. In some embodiments, a 24-week-old newborn may have a blood flow rate ranging from about 60 mL / min to about 90 mL / min. Larger, more developed newborns may require increased blood flow, which depends in part on the weight of the newborn. An appropriate blood flow rate ranges from about 75 mL / kg / min to about 175 mL / kg / min.

[0053] 9 and 10, another embodiment of the present invention provides a system and method for controlling the flow rate and / or composition of a sweep gas.

[0054] In one embodiment shown in FIGS. 9 and 10, a method for controlling the composition, gas flow rate, or combination thereof of a sweep gas containing oxygen (O), nitrogen (N), and carbon dioxide (CO) is shown, comprising receiving deoxygenated arterial blood from a neonate in an oxygenation device; flowing a mixed carbon dioxide (CO)-enriched sweep gas (above atmospheric pressure) containing 0% to about 10% or about 2% to about 5% more carbon dioxide (CO) by volume than the deoxygenated arterial blood; at least one sensor (shown in FIG. 10) in electrical communication with a controller 1012 and a flow controller 1004 for adjusting the amount of oxygen (O), nitrogen (N), carbon dioxide (CO), and other components in the sweep gas via a gas mixer 1002; optionally separating excess carbon dioxide (CO) using a carbon dioxide (CO) separator; and delivering the oxygenated blood to a neonate 5 in a neonate nursery 100.

[0055] The sweep gas can be controlled (e.g., by gas mixer 1002) to have a carbon dioxide (CO2) content ranging from about 0 to about 10% or from about 2 to about 5% and can be controlled (e.g., by flow controller 1004) to have a neonatal blood flow rate R F Alternatively, the sweep gas may be controlled to have a high flow rate to the deoxygenated arterial blood. The sweep gas may further include carbon dioxide (CO), oxygen (O), nitrogen (N), nitric oxide (NO), and other gases.

[0056] Neonatal blood flow R F can be measured using a flow sensor 1006 in communication with a blood flow circuit 1008 that runs from the newborn 5 in the nursery 100, through the oxygenator, and back to the newborn 5. The blood flow circuit 1008 and oxygenator 500 can be pump-free, i.e., the newborn's heart alone can generate the blood flow.

[0057] The neonate's blood flow can be measured in real time or periodically using a flow sensor 1006, such as an ultrasonic flow sensor that can be clamped to a component of the blood flow circuit, such as tubing. Suitable sensors 1006 are available from Spectrum Medical, Gloucester, UK.

[0058] Applicant has discovered that maintaining normocapnia during extracorporeal circulatory support in neonates is particularly challenging. Without wishing to be bound by theory, it is believed that the low blood flow rate of neonates (compared to adults) makes it difficult to control the composition and flow rate of the sweep gas (e.g., at very low blood flow rates). Embodiments of the present invention overcome these challenges by "oversweeping," i.e., by providing a higher ratio of sweep gas to blood flow than is typically required to remove the desired amount of carbon dioxide (CO2) and by better controlling the flow rate of the sweep gas (e.g., using more accurate and / or less expensive flow control devices). To prevent a high ratio of sweep gas from excessively removing carbon dioxide (CO2) from the neonate's blood (which could cause hypocapnia), the sweep gas contains a higher ratio of carbon dioxide than typically used in extracorporeal circulatory support, thereby maintaining normocapnia. Here, the composition of the sweep gas can be adjusted by varying the carbon dioxide (CO2) level of the sweep gas, thereby maintaining the desired normocapnia. The initial CO2 level of the sweep gas can initially be equal to the desired CO2 level in the neonate's blood, and the CO2 level of the sweep gas can then be adjusted based on the CO2 level detected in the neonate's blood.

[0059] For example, some embodiments of the sweep gas contain about 1% to about 6% carbon dioxide (CO2) by volume, based on 100%. More preferably, the sweep gas contains about 3% to about 6% carbon dioxide (CO2), e.g., about 3.0% to about 3.5%, about 3.5% to about 4.0%, about 4.0% to about 4.5%, about 4.5% to about 5.0%, about 5.0% to about 5.5%, or about 5.5% to about 6.0% by volume. Without being bound by theory, applicants believe that the carbon dioxide (CO2) content in the sweep gas according to embodiments of the present invention is two orders of magnitude greater than the proportion typically used in extracorporeal circulation assist devices, which typically mix pure oxygen with medical air. For comparison, dry air contains 0.04% carbon dioxide (CO2). In some embodiments, the sweep gas comprises about 0% to about 10%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, or about 40% to about 50% carbon dioxide (CO2).

[0060] The flow rate and carbon dioxide (CO2) composition of a particular sweep gas can be adjusted based on the surface area, permeability, and other characteristics of the hollow fibers of the oxygenator 500 and / or sensor readings (e.g., blood sensor 1006 and / or sweep gas sensors described and shown in connection with FIGS. 1-8) to achieve and maintain desired blood oxygen and carbon dioxide levels. For example, controller 1012 is communicatively coupled to each sensor (e.g., 1006), gas mixer 1002, and flow controller. The principles of using feedback (e.g., from blood oxygen and carbon dioxide sensors) to adjust component operation are described, for example, in Karl Johan Astrom & Richard M. Murray, Feedback Systems: An Introduction for Scientists & Engineers (2008). For example, the concentration of carbon dioxide (CO2) in the sweep gas entering the oxygenator 500 may change over time (e.g., via feedback-based or non-feedback-based models) to reflect oxygenator "wear-out," neonatal growth, etc.

[0061] Without being bound by theory, Applicant believes that oversweeping with a high flow of carbon dioxide (CO2)-rich sweep gas advantageously avoids the need to increase gas flow to clear condensation from the oxygenator, thereby causing the oxygenator to periodically "sigh" during extracorporeal membrane oxygenation (ECMO). While such sighs are tolerable in adults on ECMO, a small percentage of neonates cannot tolerate such increased gas flow and inevitably develop hypocapnia.

[0062] 10, another aspect of the present invention provides systems and methods for capturing carbon dioxide (CO) for use in generating a carbon dioxide (CO)-rich sweep gas. In one embodiment, a carbon dioxide (CO) separation device (e.g., a carbon dioxide (CO)-selective membrane such as a glassy polymer membrane, a metal-organic framework (MOF), a zeolitic-imidazolate framework (ZIF), and a cryogenic distillation device) is provided between the outlet of the oxygenator and the carbon dioxide (CO) inlet of the gas mixer 1002, and the separated carbon dioxide (CO) is recycled as input to the gas mixer 1002.

[0063] While preferred embodiments of the invention have been described using specific language, it is to be understood that such description is for purposes of example only and that changes and modifications are possible without departing from the spirit or scope of the following claims.

[0064] The entire contents of all patents, published patent applications, and other publications cited herein are hereby incorporated by reference.

[0065] U.S. Pat. No. 10,864,131, U.S. Pat. No. 10,751,238, and U.S. Patent Application Publication No. 2019 / 0380900 further describe extracorporeal circulation systems, and WO 2020 / 210275 describes oxygenation devices, each suitable for combination with the systems and methods described herein.

Claims

1. A method of operating a pumpless extracorporeal circulation circuit in a medical system, comprising: (a) operating the non-pumping extracorporeal circuit to receive deoxygenated arterial blood from the umbilical cord of a newborn infant; the non-pumped extracorporeal circuit includes a membrane oxygenator; The deoxygenated arterial blood has a blood flow rate R Ｆ and operating the non-pumping extracorporeal circuit to receive the deoxygenated arterial blood; (b) operating the non-pumped extracorporeal circuit so that a mixed sweep gas flows through the membrane oxygenator at a mixed sweep gas flow rate of at least 2 RF; and The mixed sweep gas comprises oxygen and at least about 1% by volume of carbon dioxide. How it works.

2. An operating method according to claim 1, wherein a blood flow sensor of the pumpless extracorporeal circulation circuit measures the blood flow rate R F , and a flow control device controls the mixed sweep gas flow rate passing through the membrane oxygenation device to be at least 2R F in response to a signal from the blood flow sensor.

3. 10. The method of claim 1, wherein the mixed sweep gas further comprises one or more selected from the group consisting of ambient air at sea level, nitrogen, and nitric oxide.

4. 10. The method of claim 1, wherein the mixed sweep gas has a carbon dioxide partial pressure sufficient to maintain normocapnia in the venous blood of the neonate.

5. 2. The method of claim 1, wherein the mixed sweep gas flow rate is about 2 R Ｆ ~ Approx. 20R Ｆ That's how it works.

6. 2. The method of claim 1, wherein the mixed sweep gas flow rate is about 2 R Ｆ ~About 16R Ｆ That's how it works.

7. 10. The method of claim 1 further comprising: (a') The blood flow rate R Ｆ A method of operation comprising the step of measuring

8. The method of claim 1 , wherein the mixed sweep gas flow rate is between about 120 mL / min and about 800 mL / min.

9. The method of claim 1 , wherein the mixed sweep gas comprises about 3% to about 6% carbon dioxide by volume.

10. 10. The method of claim 1, wherein at least a portion of the carbon dioxide in the mixed sweep gas is recovered from the exhaust gas of the membrane oxygenator.

11. 10. The method of claim 1, further comprising the steps of receiving, by a gas mixing device, a first gas from a first source and a second gas from a second source, the first gas being different from the second gas; mixing the first gas and the second gas to generate the mixed sweep gas; The method of operation comprises:

12. 12. The method of claim 11, wherein the first source is a first gas tank and the second source is a second gas tank.

13. 12. The method of claim 11, wherein the first supply source is a wall pipe and the second supply source is at least one of a second wall pipe and a gas tank.

14. 1. A pumpless oxygenation circuit comprising:

1. A mixing device comprising: receiving an oxygen-containing gas from an oxygen source; receiving a carbon dioxide-containing gas from a carbon dioxide source; and outputting a mixed sweep gas having oxygen and at least about 1% by volume of carbon dioxide. the mixing device adapted and configured to a flow control device fluidly connected to the mixer outlet, the flow control device configured to allow a predetermined mixed sweep gas flow rate for the mixed sweep gas passing through the flow control device; a membrane oxygenator configured to connect to the flow control device and the non-pumped neonatal blood circuit; A pump-free neonatal blood circuit is disposed along the neonatal blood flow rate R Ｆ a blood flow sensor adapted and configured to measure and The flow rate control device controls the mixed sweep gas flow rate by at least 2R Ｆ The control is performed so that the above Pump-free oxygenation circuit.

15. 15. The pumpless oxygenation circuit of claim 14, further comprising: A pumpless oxygenation circuit having a controller communicatively connected to the flow control device and the blood flow sensor.

16. 16. The pumpless oxygenation circuit of claim 15, further comprising: a blood gas sensor disposed along the non-pumped neonatal blood circuit and communicatively connected to the controller; the controller controls the mixer to titrate the composition of the mixed sweep gas to reflect the neonate's blood gas values ​​and to provide a carbon dioxide partial pressure sufficient to maintain normocapnia. Pump-free oxygenation circuit.

17. 15. The pumpless oxygenation circuit of claim 14, wherein the mixed sweep gas flow rate is about 2 R Ｆ ~ Approx. 20R Ｆ This is a pumpless oxygenation circuit.

18. 15. The pumpless oxygenation circuit of claim 14, wherein the mixed sweep gas flow rate is about 2 R Ｆ ~About 16R Ｆ This is a pumpless oxygenation circuit.

19. 15. The pumpless oxygenation circuit of claim 14, wherein the mixed sweep gas flow rate is between about 120 mL / min and about 800 mL / min.

20. 15. The pumpless oxygenation circuit of claim 14, wherein the mixed sweep gas has about 3% to about 6% carbon dioxide by volume.

21. 1. A neonatal extracorporeal circulatory support system, comprising: a neonatal nursery adapted and configured to maintain a neonate in saline; a neonatal blood system adapted and configured to couple to a plurality of blood vessels of a neonate; A pumpless oxygenation circuit according to any one of claims 14 to 20. A neonatal extracorporeal circulatory support system comprising:

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