Device for delivering gas-air mixture for artificial blood circulation devices

Abstract

This utility model relates to medicine, specifically to a device for delivering nitric oxide from a nitric oxide therapy device, an oxygenator, and an artificial blood circulation and assisted circulation (extracorporeal membrane oxygenation) apparatus. The device is intended for use in an operating room or hospital setting. The device comprises two short lines no longer than 100 mm and a section of a common line no longer than 1000 mm.

Description

[0001] Application area

[0002] The utility model relates to medicine, namely to a device for delivering nitric oxide from a nitric oxide therapy apparatus, an oxygenator and an artificial blood circulation and assisted circulation (extracorporeal membrane oxygenation) apparatus of a gas-air mixture to a patient, and is intended for use in an operating room or hospital setting.

[0003] Prior Art

[0004] Currently, a significant portion of cardiac surgeries are performed under artificial circulation (AC). The operation of the artificial circulation machine (ACM) is accompanied by adverse side effects - mechanical damage to erythrocytes by roller pumps and the development of hemolysis [Chumakova S. P., Shipulin V. M., Urazova O. I. et al. The influence of mechanical resistance of erythrocytes on the severity of hemolysis after surgery with artificial circulation. Pathology of blood circulation and cardiac surgery. 2012; 1:65-69; Billings F. T., Ball S. K., Roberts L. J. et al. Postoperative acute kidney injury is associated with hemoglobinemia and an enhanced oxidative stress response. Free Radical Biology and Medicine. 2011; 50:1480-1487]. When the red blood cell membrane is destroyed, biologically active substances, especially free hemoglobin (Hbf), are released into the plasma. The negative effects of Hbf can significantly worsen the outcomes of heart surgery.It has been proven that Hbf contributes to the development of renal dysfunction, hemostasis disorders, and damage to other systems and organs. The mechanism of pathological action of Hbf includes direct cytotoxicity and prooxidant effects on tissues, binding of endogenous nitric oxide (NO) with subsequent microcirculation impairment, stimulation of leukocyte adhesion in the vascular bed, inflammation, and thrombosis [Rother RP, Bell L, Hillmen P, et al. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA. 2005; 293(13):1653-1662. DOI: 10.1001 / jama.293.13.1653; Vermeulen Windsant IC, de Wit NC, Sertorio JT et al. Hemolysis during cardiac surgery is associated with increased intravascular nitric oxide consumption and perioperative kidney and intestinal tissue damage. Frontiers in Physiology. 2014; 5:340. DOI: 10.3389 / fphys.2014.00340].These circumstances require a search for measures to reduce the concentration of Hbf and decrease its toxic manifestations [Vermeulen Windsant IC, Hanssen SJ, Buurman WA, et al. Cardiovascular surgery and organ damage: time to reconsider the role of hemolysis. J Thorac Cardiovasc Surg. 2011; 142(1):1-11. DOI:10.1016 / j.jtcvs.2011.02.012]. Extracorporeal membrane oxygenation (ECMO) is the most common option for circulatory support. This technology can replace the functions of the heart and lungs in cases of severe damage and save lives in various critical conditions (myocardial infarction, severe pneumonia, chest trauma). Intravascular hemolysis accompanies the work of ECMO systems due to the destruction of red blood cells by pumps and is an adverse side effect that significantly reduces potentially positive outcomes.Thus, the task of eliminating Hbf and reducing its toxic manifestations is also relevant for this method of assisted circulation.

[0005] It is currently known that nitric oxide can mitigate the adverse effects of this side effect of cardiopulmonary bypass. Experimental data suggest the possibility of reducing plasma free hemoglobin concentrations through the oxidative conversion of free oxyhemoglobin to a form that is eliminated more rapidly and exhibits less toxicity when blood comes into contact with NO. These effects are explained by mechanisms involving the reaction of hemoglobin and its oxidative protection in microcirculation, interaction with endogenous nitric oxide, and influence on inflammatory and thrombotic cascades. Given this, the proposal is based on the idea of ​​treating blood with nitric oxide under cardiopulmonary bypass and ECMO conditions to reduce the formation of free hemoglobin and mitigate its toxic effects, which may reduce the risk of renal dysfunction and vascular complications during cardiac surgery.This concept suggests the possibility of applying NO treatment directly into existing CPB / ECMO circuits, potentially improving outcomes and protecting tissues during hemolysis.

[0006] A method for reducing Hbf levels by delivering NO to the body by inhalation is known [Bautin A.E., Chomakhashvili I.G., Radovsky A.M. et al. The effect of nitric oxide (II) inhalation on the concentration of free hemoglobin in blood plasma during hemolysis. Experimental study / / Translational medicine. 2024. Vol. 11. No. 2. - P. 181-190]. Intravascular hemolysis was modeled in experimental animals (pigs) after induction of anesthesia and transfer to artificial ventilation (ALV) by administering 4 g of Hbf. After this, the animals of the experimental group (n=5) were given NO inhalation at a dosage of 80 ppm. Animals from the control group (n=5) did not receive NO. The dynamics of Hbf were assessed over 6 hours.The Hbf level in the experimental group was statistically significantly lower compared to the control group 30 minutes (1.2 (1; 1.3) vs. 1.7 (1.6; 1.9), p=0.047), 60 minutes (0.9 (0.9; 1) vs. 1.24 (1.2; 1.5), p=0.046) and 90 minutes (0.7 (0.7; 0.8) vs. 0.94 (0.9; 1.2), p=0.035) after Hbf administration. The authors concluded that NO inhalation at a dosage of 80 ppm reduces Hbf levels. Unlike the one proposed by us, the above-mentioned method can be used only after the completion of artificial circulation, when it becomes possible to restore the patient's breathing and effective NO inhalation. This method cannot be fully implemented during CPB due to the lack of effective lung ventilation during this period. It's important to consider that Hbf is produced throughout the entire duration of CPB. Therefore, with the inhalation method discussed, Hbf elimination begins delayed, after CPB has ended, reducing its effectiveness.

[0007] The closest analogue of the proposed device is the device according to patent RU 234110, published on 05 / 20 / 2025. The claimed device for artificial blood circulation and assisted blood circulation includes an oxygenator having a membrane made of hollow fibers, characterized in that it contains a gas analyzer for determining the content of NO and NO2 and connected by tubes: a segment for insufflation of NO, containing a generator synthesizing NO from atmospheric air, an adsorber with soda lime for absorbing NO2 before feeding the gas mixture into the oxygenator and a hydrophobic filter connected to the line for delivering the gas-air mixture to the oxygenator, a segment for monitoring NO and NO2, including first and second taps, and a segment for monitoring the evacuated gases from the oxygenator, including an absorber for cleaning the gas mixture from NO2 after leaving the oxygenator, connected by two tubes to the second tap, wherein the oxygenator is connected to the segment for insufflation of NO and the segment for monitoring NO and NO2,The NO and NO2 monitoring segment includes a line that is connected via the first three-way valve to the NO insufflation segment, and via the second three-way valve via two mistrals to the oxygenator gas evacuation monitoring segment. The technical result of this device is to improve the safety and effectiveness of cardiac surgery performed under artificial circulation and assisted circulation procedures in critically ill patients by reducing the severity of the side effect of CPB and ECMO—hemolysis with the formation of Hbf.

[0008] However, this device includes three-way valves and a rather complex connection scheme for long pipelines.

[0009] In this case, it is quite problematic to ensure timely and sterile delivery of the gas-air mixture to a patient on ECMO, on a heart-lung machine.

[0010] Based on the above, a need has been identified for a delivery device containing short lines and ensuring rapid and safe delivery of the gas-air mixture. Thus, the technical result of the proposed utility model is the creation of a delivery device with a reduced risk of side effects due to the device's safety and sterility during operations performed under artificial circulation and assisted circulation procedures in critically ill patients by reducing the severity of the side effect of CPB and ECMO—hemolysis with the formation of Hbf.

[0011] The technical result is achieved by using the described device for delivering a gas-air mixture from an artificial blood circulation apparatus through a line of a certain configuration (design), shown in Fig. 1.

[0012] Description of figures

[0013] Fig. 1 - Device for artificial circulation, fragment of the line.

[0014] List of items:

[0015] 1 - connector protective cover.

[0016] 2 - Luer connector for connecting the NO supply line to the nitrogen oxide supply device.

[0017] 3 - NO supply line up to 100 mm long.

[0018] 4 - Luer connector for connecting the NO supply line to the hydrophobic filter.

[0019] 5 - hydrophobic filter on the supply line NO.

[0020] 6 - T-shaped tee for connecting a hydrophobic filter to the oxygenator gas-air mixture delivery line.

[0021] 7 - fragment of the gas-air mixture delivery line oxygenator.

[0022] 8 - T-shaped tee for connecting a hydrophobic filter to the oxygenator gas-air mixture delivery line.

[0023] 9 - hydrophobic filter on the sampling line for gas analysis.

[0024] 10 - Luer connector for connecting the NO supply sampling line to the hydrophobic filter.

[0025] 11 - 100mm gas analysis sampling line.

[0026] 12 - Luer connector for connecting the gas analyzer sampling line to the gas analyzer monitor.

[0027] Description of the utility model

[0028] A device for delivering a gas-air mixture containing nitrogen oxide NO for artificial blood circulation devices is proposed, comprising in series a luer connector for connecting the NO supply line to the nitric oxide supply device, a NO supply line up to 100 mm long, a luer connector for connecting the NO supply line to a hydrophobic filter, a hydrophobic filter on the NO supply line, a T-shaped tee for connecting the hydrophobic filter to the oxygenator gas-air mixture delivery line, a fragment of the oxygenator gas-air mixture delivery line no more than 100 mm long, a T-shaped tee for connecting the hydrophobic filter to the oxygenator gas-air mixture delivery line, a hydrophobic filter on the gas analysis sampling line, a luer connector for connecting the NO supply sampling line to the hydrophobic filter, a gas analysis sampling line no more than 100 mm long, a luer connector for connecting the gas analyzer sampling line to the monitor gas analysis,in this case, the total length of the line from the oxygenator to the connection to the artificial blood circulation apparatus or further to another apparatus, including connections to the line, is no more than 1000 mm.

[0029] The proposed delivery device consists of a section of line 7, which is designed to deliver the gas-air mixture to the oxygenator.

[0030] The common line also includes a supply line for the NO generator, an oxygenator, and a discharge line for gas analysis.

[0031] Connectors 2 and 4, 10 and 12, the NO supply line and the gas analysis sampling line 10 form a single system with a fragment of the common line 7. In Fig. 1, all the elements are shown separately, however, it should be borne in mind that they represent a common system and are inseparable components of the system.

[0032] The device includes a section of the gas-air mixture delivery line to the oxygenator, e.g., ¼ or ½ inch in diameter and 1000 mm in total length, with NO supply lines from the nitric oxide therapy device and gas analysis sampling lines (at a distance of no more than 100 mm from the NO supply line) connected to it (e.g., 100 mm before the oxygenator). The total length of the line is no more than 1000 mm, including tees for connecting the lines.

[0033] This tube is a line connected to a device that delivers a gas-air mixture, such as a nitric oxide therapy device or a generator that synthesizes NO. Lines are tubes or hoses made of medical plastic that can be sterilized with ethylene oxide or radiation methods. Typically, the tubes are made of polyvinyl chloride, and the lines have a diameter of 1.2 mm and a total length of no more than 1000 mm, including 100 mm between tees 6 and 8, as well as the tees themselves, when measured from the oxygenator outlet.

[0034] Nitrogen monoxide supply line 3 and gas analysis sampling line 11 may also be made of medical plastic with the ability to be sterilized with ethylene oxide and radiation methods. Supply line 3 is connected to a section of the gas-air mixture delivery line 7 into the oxygenator through tee 8. The gas analysis sampling line is also connected to a section of the delivery line 7. In this case, the length of the tube between the connections of lines 3 and 1 is no more than 100 mm, and the length of section of line 7, including the connections of lines 3 and 1, from the oxygenator to the connection to the artificial circulation apparatus or further, to another device, is no more than 1000 mm.

[0035] The system also includes two hydrophobic filters. The hydrophobic filter is a waterproof filter element that allows gases to pass through but repels water, dust, and aerosols. It is used to protect sensitive equipment components, such as gas analyzers or aspirators, from moisture and contaminants, ensuring measurement accuracy and extending the device's service life. The hydrophobic filter is compact and integrated into the NO supply and sample lines.

[0036] In this case, the lines are permanently connected to ensure a leak-proof seal during operation and storage. Luers are permanently connected to the lines and secured to them during initial assembly. This feature is crucial for the operation of the device, as it prevents dust, infection, or other contamination, and ensures the sterility and safety of the lines. This device is sterilized before use and stored in sterile packaging. Before use, the device is removed from its packaging and immediately connected to the CPB or ECMO machine in the operating room. This ensures reliable and safe operation of the nitric oxide therapy and artificial circulation device.

[0037] In this case, the arrangement of components is also significant, as it ensures the functional purpose and technical result are realized. The lines are permanently connected to prevent misplacement of components and assembly errors, ensuring proper connection and operation of the device. Therefore, the device includes components in a specific order, with lines that are firmly connected and ensure proper operation for optimal performance.

[0038] Example of device operation.

[0039] During cardiac surgery under artificial circulation, a nitric oxide therapy machine is used to reduce the severity of side effects. Nitric oxide at a dose of 100 ppm is delivered to the oxygenator to treat the blood.

[0040] The device also monitors the NO dose at the oxygenator inlet and outlet. The effectiveness of free hemoglobin removal is assessed by measuring its content in arterial blood using the hemoglobin cyanide method followed by photometry. Nitric oxide treatment continues throughout the entire period of artificial circulation and ceases when the artificial circulation is disconnected.

[0041] This device can also be used to provide ECMO for critically ill patients and during cardiac surgery. The difference lies in the device's ability to be used for several days of ECMO until Hbf levels are sustainably reduced to less than 0.2 g / L. In these cases, plasma Hbf levels are monitored every 6 hours.

[0042] The device is used as follows.

[0043] During cardiac surgery, before initiating artificial circulation, prepare the device for operation. Connect the therapy device to the described device (lines). The NO supply line is connected to the nitric oxide therapy device for NO delivery. The section of the gas-air mixture delivery line is connected to the oxygenator via tee 8. After initiating artificial circulation, the gas-air mixture readings are adjusted to ensure nitrogen monoxide saturation corresponds to the therapy regimen. After verifying that the gas analyzer is functioning properly and detects NO and NO2 levels within 0-0.5 ppm, turn on the nitric oxide therapy device. Gradually increasing the device's output, the NO concentration in the gas-air mixture supply line is increased to the required level. Subsequently, throughout the artificial circulation period, the specified NO concentration is maintained by adjusting the device's output.During operation of the device, the NO2 content is monitored and should not exceed it. 2 ppm. If NO2 concentrations exceed the specified level, reduce generator output and NO concentration. Nitric oxide and nitric oxide levels and concentrations are monitored every 30 minutes. Arterial blood Hbf concentrations are also monitored every 30 minutes. Maintaining Hbf levels below 0.4 g / L indicates effective device operation.

[0044] When using circulatory support to treat life-threatening conditions, prepare the device before starting the ECMO procedure. Connect line 3 to the nitric oxide therapy device, and connect line 7 to the oxygenator outlet with tee 8. Next, connect line 11 to collect samples through a gas analyzer for monitoring NO and NO2 levels. After ensuring that the gas analyzer is functioning properly and detects NO and NO2 levels within 0-0.5 ppm, turn on the NO generator. By gradually increasing the generator output, increase the NO concentration in the gas-air mixture supply line to the required level (e.g., 100 ppm). Then, maintain the specified NO concentration by adjusting the nitric oxide therapy device output. During device operation, monitor the NO2 content, which should not exceed 2 ppm. If the NO2 concentration increases above the specified level, reduce the generator output and the NO concentration.NO2 levels should not exceed 0.5 ppm. Arterial blood Hbf concentrations are monitored every 4 hours. Maintaining Hbf levels below 0.4 g / L indicates the device is working effectively.

[0045] The operation of the device is also shown in the following examples.

[0046] The study of the effectiveness of the proposed device was conducted in an experiment on pigs that underwent circulatory support procedures with the connection of the ECMO system.

[0047] Eight animals were placed under general combined anesthesia with isoflurane using the endotracheal technique and were connected to a central ECMO system via a veno-arterial circuit. A venous cannula was inserted into the right atrium, and an arterial cannula was inserted into the ascending thoracic aorta. An Ex-Stream device (Biosoft-M, Russia) was used for the ECMO procedure. Eurosets polymethylpentene oxygenators (Eurosets, Italy) were used. The volumetric perfusion rate was 2.5 l / min / m 2 The initial gas flow was 2 L / min, with subsequent adjustments based on blood gas assessment. The perfusion volume was adjusted based on hemodynamic needs. To prevent thrombosis of the ECMO circuit components, heparin was administered intravenously at a dose of 100 U / kg before cannulation. 5000 U of heparin were also added to the primary ECMO circuit fill volume during the preparatory phase. The heparin dosage was then determined based on the activated clotting time (target value 180-220 s). The duration of ECMO support was 16 hours.

[0048] Given the inherent mechanical resistance of erythrocytes in pigs and the low incidence of hemolysis during artificial and assisted circulation, an osmotic hemolysis model was used. The goal of this model was to increase Hbf levels to levels typical of ECMO and ECMO procedures in humans—approximately 1 g / L. To achieve this, 60 minutes after the start of the ECMO procedure, 4 g of free hemoglobin, previously obtained from the animal's blood using osmotic hemolysis, was administered intravenously.

[0049] Hbf concentration was determined using a HemoCue Plasma / Low Hb analyzer (HemoCue AB, Sweden). Plasma Hbf levels were measured initially before ECMO was connected, before the administration of 4 g of Hbf, 15 minutes after the administration of Hbf, and then every 30 minutes up to and including the 300th minute. The hemolysis model was run twice in each animal. Thus, 16 cases of hemolysis were studied in 8 pigs. The animals included in the study were randomly divided into two groups. In 4 pigs in the main group, a device was connected to reduce the severity of the side effects of circulatory support, while in 4 animals in the control group, ECMO was performed without the use of a device.

[0050] The dynamics of Hbf content in animals of the main and control groups over a five-hour period after the administration of 4 g of Hbf are presented in Table 1. More rapid elimination of Hbf was observed when the device was connected and the method was implemented. In animals of the control group, a slow decrease in Hbf concentration was noted. These features were characteristic of the first 3.5 hours after the induction of hemolysis, and the intergroup differences during this period were statistically significant (Table 1). When using the device and implementing the method, a safe Hbf concentration (less than 0.4 g / L) was achieved 3.5 hours after the induction of hemolysis, while in animals of the control group, even after 5 hours, the median Hbf content exceeded 0.4 g / L.

[0051] Using the nonparametric Wilcoxon signed-rank test for pairwise comparisons in related samples, no differences from baseline Hbf values ​​after hemolysis induction in the control group were detected until 270 minutes. When using the device and method, due to the more rapid elimination of Hbf, no differences from baseline Hbf levels were observed as early as 150 minutes after hemolysis induction.

[0052] Example 2

[0053] Device sterilization

[0054] The device was assembled from components as shown in Fig. 1. Sterilization was performed using radiation. The length of line 7 with tees 6 and 8 was no more than 1000 mm. This length ensures sterility.

[0055] The claimed device, made of PVC, was treated with ionizing radiation—gamma radiation from a cobalt-60 isotope source. The process took place in a sterilization chamber, where the gamma rays penetrated the tubing material, killing microorganisms without significantly increasing the temperature. The radiation dose for sterilization typically ranged from 15-20 kGy, ensuring the effective and rapid destruction of all viable forms of microorganisms, including spores.

[0056] For quality control after sterilization, the appearance, tightness, mechanical properties of the tubes, and the absence of residual microbial activity were checked using direct inoculation. A sample of the swab from the lines was applied to a nutrient medium (agar medium), rinsed with sterile saline, incubated, and observed for microbial growth. The absence of growth indicated successful sterilization; in 10 out of 10 cases, no microbial growth was observed on the nutrient medium immediately after sterilization and after one year of storage.

[0057] For comparison, a device was used as shown in Fig. 1, but with a length of lines 3 and 11 of at least 100 mm each, a distance between tees 6 and 8, essentially a line 7-200 mm, and a total length of more than 1000 mm.

[0058] The microbiological purity test result was 8 out of 10 units. Therefore, 2 units were insufficiently sterilized under the same conditions. Furthermore, as the length of line 7 increased, a decrease in the number of sterile devices was observed. For example, with line 7 exceeding 300 mm in length and the total line length exceeding 1500 mm, only 50% of the devices submitted for sterilization were sterile. Therefore, maximum sterility can only be ensured for a specific product length.

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