Systems, methods, and apparatus for generating nitric oxide

Abstract

Disclosed herein is a console comprising: at least one air inlet; a first container configured to hold a first source of nitric oxide; a second container configured to accommodate a second source of nitric oxide; a controller configured to selectively couple the at least one air inlet to one of the first container or the second container to deliver nitric oxide from the first source or the second source; and an outlet coupled to the first container and / or the second container and configured to deliver nitric oxide to a subject.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 418,426, filed on October 21, 2022, and U.S. Provisional Application No. 63 / 418,430, filed on October 21, 2022, the contents of which are incorporated herein by reference in their entireties. Technical Field

[0003] Certain aspects described herein relate to a medical device and, more particularly, to systems and methods for generating and delivering a gas including nitric oxide. Background Art

[0004] Some aspects described herein relate to the generation of nitric oxide (NO), which is then typically delivered to a patient in a medical setting.

[0005] Nitric oxide is a vasodilator indicated for use in conjunction with ventilatory support to improve oxygenation and reduce the need for extracorporeal membrane oxygenation, particularly in term and near-term neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension. Low concentrations of inhaled nitric oxide can also prevent, reverse, or limit the progression of conditions that may include, but are not limited to, acute pulmonary vasoconstriction, traumatic injury, aspiration or inhalation injury, pulmonary fat embolism, acidosis, lung inflammation, adult respiratory distress syndrome, acute pulmonary edema, acute mountain sickness, acute postoperative pulmonary hypertension, persistent pulmonary hypertension of the newborn, perinatal aspiration syndrome, hyaline membrane disease, acute pulmonary thromboembolism, heparin-protamine reaction, sepsis, asthma, and status asthmaticus, or hypoxia. Nitric oxide can also be used to treat chronic pulmonary hypertension, bronchopulmonary dysplasia, chronic pulmonary thromboembolism, and idiopathic or primary pulmonary hypertension or chronic hypoxia.

[0006] Typically, nitric oxide can be inhaled or otherwise delivered to the lungs of an individual. Providing a therapeutic dose of nitric oxide can treat a patient suffering from a disease or physiological condition that can be alleviated by inhaling nitric oxide, or as a supplement to conventional treatment or to minimize the demand for conventional treatment in such disease or physiological condition. A major challenge for nitric oxide delivery is that, even if there is a trace amount of oxygen (O 2 ) in the gas containing nitric oxide, nitric oxide may also be oxidized to produce nitrogen dioxide (NO 2 ). Unlike nitric oxide, nitrogen dioxide (which forms nitric acid and nitrous acid in the lungs) is highly toxic at levels as low as parts per million. Therefore, aspects described herein relate to systems and methods for producing nitric oxide on demand that reduce the duration of nitric oxide exposure to oxygen.

[0007] To ensure continuous delivery, some known nitric oxide delivery devices require the user to follow a series of steps to switch nitric oxide delivery from a first delivery system to a second delivery system when the first delivery system is nearing depletion. Some aspects described herein describe systems and methods for improving the continuity of nitric oxide delivery.

[0008] Some known nitric oxide delivery devices are sensitive to orientation and may malfunction if moved or tilted. Thus, there is a need for systems and devices that are resistant to orientation-related malfunctions. This need, and all other needs, are at least partially addressed by the present disclosure. Summary of the Invention

[0009] The present disclosure relates to an operating table comprising: at least one air inlet; a first container configured to hold a first source of nitric oxide; a second container configured to hold a second source of nitric oxide; a controller configured to selectively couple the at least one air inlet to one of the first container or the second container to deliver nitric oxide from the first source or the second source; and an outlet coupled to the first container and / or the second container and configured to deliver the nitric oxide to a subject.

[0010] Also disclosed herein is a method comprising: routing air from at least one air inlet through a first cartridge that generates nitric oxide gas; detecting a fill status of the first cartridge; and wherein the fill status of the first cartridge is near or below a threshold, automatically rerouting the air from the at least one air inlet through a second cartridge that generates nitric oxide.

[0011] Still further disclosed herein is an apparatus comprising: a frangible vessel containing nitrogen tetroxide; a reservoir, the frangible vessel disposed within the reservoir, the reservoir being configured to contain the nitrogen tetroxide when the frangible vessel is ruptured; and an outlet disposed above a wall of the reservoir, the frangible vessel, the reservoir, and the outlet being collectively configured such that when the frangible vessel is ruptured, the level of nitrogen tetroxide in the reservoir does not reach the outlet, regardless of the orientation of the vessel.

[0012] Additional advantages will be set forth in part in the following description and, in part, will be obvious from the description, or may be learned by practice of the aspects described below. The advantages described below will be realized and attained by the chemical compositions, methods, and combinations thereof particularly pointed out in the appended claims. It should be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and do not limit the invention as claimed. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 is a schematic illustration of an operating station according to one aspect.

[0014] Figure 2 is a flow chart of a method for generating nitric oxide according to one aspect.

[0015] Figure 3 is a schematic illustration of a cassette according to one aspect.

[0016] Figure 4 is a perspective view of a box according to one aspect.

[0017] Figure 5 yes Figure 4 Cross-sectional view of the box shown in .

[0018] Figure 6 yes Figure 4 and Figure 5 A top view of the box shown in FIG.

[0019] Figure 7 is a perspective view of a liquid vessel assembly according to one aspect.

[0020] Figure 8 yes Figure 7 A cross-sectional view of the liquid vessel assembly shown in FIG.

[0021] Figure 9 yes Figure 7 Another cross-sectional view of the liquid vessel assembly shown in .

[0022] Figures 10A to 10G Based on one aspect Figure 7 Perspective views of the liquid container assembly shown in different orientations.

[0023] Figure 11A is an exploded view of a cartridge assembly according to one aspect.

[0024] Figure 11B yes Figure 11A A perspective view of the cartridge assembly.

[0025] Figure 12 Experimental data showing a positive correlation between cartridge media water content and nitrogen dioxide conversion capacity are depicted.

[0026] Figure 13A Depicted is an exemplary schematic diagram of a system according to one aspect.

[0027] Figure 13B A flow chart depicting exemplary system operation is shown.

[0028] Figure 14 An exemplary arrangement according to one aspect is depicted.

[0029] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several aspects described below. DETAILED DESCRIPTION

[0030] The present invention may be more readily understood by reference to the following detailed description, examples, drawings, and claims, as well as the descriptions preceding and following them. However, before disclosing and describing the articles, systems, and / or methods of the present invention, it should be understood that the present invention is not limited to the specific or exemplary methods of the disclosed articles, systems, and / or methods, unless otherwise indicated, and therefore may, of course, vary. It should also be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

[0031] The following description of the present invention is provided as a facilitating teaching of the present invention in its best, currently known aspects. To this end, those skilled in the relevant art will recognize and understand that many changes can be made to the various aspects of the present invention described herein while still obtaining the beneficial results of the present invention. It is also apparent that some of the desired benefits of the present invention can be obtained by selecting some features of the present invention without utilizing other features. Therefore, those of ordinary skill in the art will recognize that many modifications and adaptations of the present invention are possible, and in some cases can even be desired and are part of the present invention. Therefore, the following description is again provided as an illustration of the principles of the present invention and not as a limitation thereof.

[0032] definition

[0033] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0034] It will be appreciated that certain features of the disclosure described in the context of separate aspects for clarity may also be provided in combination in a single aspect. Conversely, various features of the disclosure described in the context of a single aspect for brevity may also be provided individually or in any suitable subcombination.

[0035] As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a box" includes not only one such box, but also two or more such boxes; and reference to "an operating station" includes not only one such operating station, but also two or more such operating stations, and so forth.

[0036] Throughout the description and claims of this specification, the word "comprise" and other forms of the word, such as "comprising" and "comprises" are open, non-limiting terms and mean "including but not limited to", and are not intended to exclude, for example, other additives, segments, integers or steps. Furthermore, it should be understood that the terms "comprise", "comprising" and "comprises" when they refer to various aspects, elements and features of the disclosed invention include the more limited aspects of "consisting essentially of" and "consisting of".

[0037] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.In this specification and the appended claims, reference will be made to a number of terms which shall be defined herein.

[0038] The terms "for example" and "such as" and their grammatical equivalents, unless expressly stated otherwise, should be understood as meaning the phrase "without limitation." It should be further understood that these phrases are used for illustrative purposes only. It should be further understood that the term "exemplary," as used herein, means "an example of," and is not intended to convey an indication of a preferred or ideal aspect.

[0039] As used herein, the expressions "ambient temperature" and "room temperature" are understood in the art and generally refer to a temperature of about 20°C to about 35°C.

[0040] Although the numerical ranges and parameters setting forth the broad scope of the present disclosure are approximate, the numerical values ​​set forth in the specific examples are reported as accurately as possible. However, any numerical value inherently contains certain errors caused by the standard deviation found in its corresponding test measurements. In addition, when setting forth numerical ranges of different scopes in this article, it is contemplated that any combination of these values ​​can be used, including the values ​​described. Further, ranges can be expressed in this article as from "about" a particular value and / or to "about" another particular value. When expressing such a range, on the other hand, it is included from a particular value and / or to another particular value.

[0041] Similarly, when values ​​are expressed as approximate values ​​by use of the antecedent "about," it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each range are significant both relative to the other endpoint and independently of the other endpoint. Unless otherwise indicated, the term "about" means within 5% (e.g., within 2% or 1%) of the particular value modified by "about."

[0042] Throughout this disclosure, various aspects of the invention may be presented in range format. It should be understood that the description in range format is for convenience and brevity only and should not be construed as a hard limit to the scope of the invention. Therefore, the description of a range should be considered to have specifically disclosed all possible subranges and individual values ​​within the range. For example, a description of a range such as from 1 to 6 should be considered to have explicitly disclosed subranges, such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc.; and individual numbers within the range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6, and any whole and partial increments therebetween. This applies regardless of the breadth of the range.

[0043] In yet a further aspect, when a particular value between two endpoints is disclosed, it will be understood that these endpoints may also be included.

[0044] In yet a further aspect, when a range is given and exemplary values ​​are provided, it should be understood that any range can be formed between any exemplary value in the broadest range.

[0045] References in the specification and the concluding claims to parts by weight of a particular element or component in a composition refer to the weight relationship between that element or component and any other elements or components in the composition or article, expressed as parts by weight. Thus, in a mixture containing 2 parts by weight of component X and 5 parts by weight of component Y, X and Y are present in a weight ratio of 2:5, and remain so regardless of whether additional components are present in the mixture.

[0046] Unless specifically stated to the contrary, the weight percent (wt. %) of a component is based on the total weight of the formulation or composition in which it is included.

[0047] It should be understood that when an element is referred to as being “connected” or “coupled” to another element, it can be directly connected or coupled to the other element, or intervening elements may be present. In contrast, when an element is referred to as being “directly connected” or “directly coupled” to another element, there are no intervening elements. Other words used to describe the relationship between elements or layers should be interpreted in a similar manner (e.g., “between” versus “directly between,” “adjacent” versus “directly adjacent,” “on” versus “directly on”).

[0048] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0049] It should be understood that although the terms "first," "second," etc. may be used herein to describe various elements, components, regions, layers, and / or sections, these elements, components, regions, layers, and / or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer, or section from another element, component, region, layer, or section. Thus, a first element, component, region, layer, or section discussed below may be referred to as a second element, component, region, layer, or section without departing from the teachings of the exemplary aspects.

[0050] As used herein, the term "substantially" means that the subsequently described event or circumstance completely occurs or that the subsequently described event or circumstance generally, typically, or approximately occurs.

[0051] Still further, in some aspects, the term "substantially" can refer to at least about 90%, at least about 95%, at least about 99%, or about 100% of a stated property, component, composition, or other condition (substantially used to characterize or otherwise quantify the amount thereof).

[0052] In other aspects, as used herein, the term "substantially free," when used in the context of the substantial absence of a composition or component of a composition, is intended to refer to an amount of the recited material that is less than about 1 wt %, e.g., less than about 0.5 wt %, less than about 0.1 wt %, less than about 0.05 wt %, or less than about 0.01 wt %, based on the total weight of the composition.

[0053] For ease of description, spatially relative terms such as "below," "beneath," "lower," "above," "upper," "bottom," "top," etc. may be used herein to describe the relationship of one element or feature to another element or feature as shown in the accompanying drawings. It will be understood that, in addition to the orientation depicted in the accompanying drawings, spatially relative terms are intended to cover different orientations of the device when in use or in operation. For example, if the device in the accompanying drawings is turned over, elements described as being "below" or "below" other elements or features will be oriented "above" these other elements or features. Thus, the term "below" can cover both above and below orientations. The device can be oriented in other ways (rotated 90 degrees or in other orientations) and the spatially relative descriptors used herein are interpreted accordingly.

[0054] Some aspects described herein relate to methods. It should be understood that such methods can be computer-implemented. That is, when methods or other events are described herein, it should be understood that they can be performed by a computing device having a processor and memory. The memory of a computing device is also referred to as non-transitory computer-readable media, which may include instructions or computer code for performing various computer-implemented operations. Computer-readable media (or processor-readable media) is non-transitory in the sense that it does not itself include transient propagating signals (e.g., propagating electromagnetic waves that carry information on a transmission medium such as space or a cable). The media and computer code (also referred to as code) can be media and computer code designed and constructed for a specific purpose or use. Examples of non-transitory computer-readable media include, but are not limited to, magnetic storage media such as hard disks, floppy disks, and magnetic tapes; optical storage media such as compact discs / digital video discs (CD / DVDs), compact disc read-only memories (CD-ROMs), and holographic devices; magneto-optical storage media such as optical discs; carrier signal processing modules, read-only memories (ROMs), random access memories (RAMs), and the like. One or more processors may be communicatively coupled to storage and operable to execute code stored on a non-transitory processor-readable medium. Examples of processors include general-purpose processors (e.g., CPUs), graphics processing units, field programmable gate arrays (FPGAs), application-specific integrated circuits (ASICs), digital signal processors (DSPs), programmable logic devices (PLDs), and the like. Examples of computer code include, but are not limited to, microcode or microinstructions, machine instructions (such as those generated by a compiler), code for generating network services, and files containing higher-level instructions executed by a computer using an interpreter. For example, various aspects may be implemented using imperative programming languages ​​(e.g., C, Fortran, etc.), functional programming languages ​​(Haskell, Erlang, etc.), logic programming languages ​​(e.g., Prolog), object-oriented programming languages ​​(e.g., Java, C++, etc.), or other suitable programming languages ​​and / or development tools. Additional examples of computer code include, but are not limited to, control signals, encryption codes, and compression codes.

[0055] Although aspects of the invention may be described and claimed in particular statutory categories, such as the system statutory category, this is for convenience only, and one of ordinary skill in the art will understand that each aspect of the invention may be described and claimed in any statutory category. Unless expressly stated otherwise, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a particular order. Therefore, in any aspect, where a method claim does not specifically state in the claim or specification that the steps are limited to a particular order, no order is intended to be inferred. This applies to any possible non-express basis for interpretation, including matters regarding the logic of the arrangement of steps or operational flow, ordinary meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0056] The present invention may be understood more readily by reference to the following detailed description of its various aspects and examples included therein and by reference to the accompanying drawings and their preceding and following descriptions.

[0057] Device

[0058] In certain aspects, a console is disclosed herein. It should be understood that the console disclosed herein can be used for medical purposes, and more specifically, for delivering nitric oxide to a subject. In aspects disclosed herein, the console can include various compartments and components configured to deliver a desired amount of nitric oxide to a subject.

[0059] In one aspect, disclosed herein is a workstation comprising: at least one air inlet; a first container configured to contain a first source of nitric oxide; and a second container configured to contain a second source of nitric oxide. In other words, the workstation disclosed herein is configured to contain at least two sources capable of providing a desired amount of nitric oxide.

[0060] In a further aspect, the console includes a controller configured to selectively couple at least one air inlet to one of the first container or the second container to deliver nitric oxide from the first source or the second source. In a further aspect, the console includes an outlet coupled to the first container and / or the second container and configured to deliver nitric oxide to the subject.

[0061] It should be understood that the nitric oxide source can be any source known in the art. For example, the nitric oxide source can be pressurized nitric oxide in a canister. In such aspects, the container can be adapted to house the canister itself or a nitric oxide delivery element that communicates with the canister and provides the desired amount of nitric oxide as needed.

[0062] However, in yet further aspects, nitric oxide can be formed in situ. In such aspects, if desired, the first and second sources can comprise materials configured to form nitric oxide. For example and without limitation, the first and second sources of nitric oxide can comprise air or a nitrite solution and an electrical arrangement that allows nitric oxide to be formed by a spark.

[0063] In some aspects, the first source and the second source of nitric oxide can comprise nitrogen dioxide. However, in other exemplary and non-limiting aspects, the first source and the second source of nitric oxide can comprise liquid nitrogen tetroxide. In this exemplary aspect, liquid nitrogen tetroxide can be accommodated in a reservoir (for example, the first reservoir and the second reservoir for the first source and the second source of nitric oxide respectively). Reservoir can be positioned in box. Liquid nitrogen dioxide can be the source of gaseous nitrogen dioxide, which can be converted into nitric oxide in box. In further aspects, the first source of nitric oxide comprises the first box configured to form nitric oxide, and / or wherein the second source of nitric oxide comprises the second box configured to generate nitric oxide. In further aspects, when at least one air inlet is coupled to the first container and the first source of nitric oxide is substantially exhausted, controller is configured to automatically switch the connection of at least one air inlet to the second container from the first container, thereby delivering nitric oxide from the second source.

[0064] In a still further aspect, the controller is configured to monitor a fill status of the first nitric oxide source and / or the second nitric oxide source.

[0065] exist Figure 1 An exemplary and non-limiting operating station is shown in FIG. Figure 1 is a schematic illustration of an operating station 50 according to aspects of the present invention. The operating station 50 is an on-demand delivery system for nitric oxide. Figure 1 As shown in FIG, the operating station 50 includes a controller 60, one or more air inlets 70, an air outlet 80, and one or more receptacles 90 configured to receive the cartridges 100.

[0066] The controller 60 in the console 50 can be operable to deliver nitric oxide at a controlled flow rate and / or concentration. In such aspects, the controller disclosed herein is configured to control the rate of nitric oxide delivered to the subject. Yet in yet further aspects, the controller is further configured to deliver nitric oxide at a desired concentration.

[0067] For example, the controller 60 can include one or more processors, memory, and / or control circuitry operable to, for example, selectively activate individual cartridges 100 and / or control the flow rate through the console 50. In such aspects, the controller is configured to control the rate of nitric oxide generation in the first cartridge and / or the second cartridge. For example, the controller 60 can be operable to control one or more pumps to draw air through one or more air inlets 70, selectively control the flow rate through one or more cartridges 100, control the temperature of liquid nitrogen tetroxide within the cartridge 100, control the rate of nitrogen dioxide generation within the cartridge 100, control the rate of nitric oxide generation within the cartridge 100, control the concentration and / or flow rate of nitric oxide exiting the cartridge 100, control the concentration and / or flow rate of nitric oxide exiting the console 50 (e.g., through one or more air outlets 80) for delivery to the patient, and / or the like. Controller 60 may include one or more user interfaces or controls to enable on-demand delivery of nitric oxide and / or to enable a user to interact with controller 60 to select, for example, a flow rate and / or nitric oxide flow concentration.

[0068] The cartridge 100 can be configured to be inserted into each of the one or more containers 90 and to generate nitric oxide upon activation. Each cartridge 100 can be a single-use, disposable component that stores liquid nitrogen tetroxide (N2O4). The N2O4 can be converted into gaseous nitrogen dioxide (NO2), and each cartridge can be activated to convert the NO2 into nitric oxide (NO).

[0069] In some aspects, the operation station 50 can be designed and / or configured to include more than one container 90 and more than one box 100. Each container 90 is configured to receive one box 100. When the first box is close to being exhausted, the controller 60 can automatically change from the first container / box to the second container / box. In other words, the controller 60 can be operable to selectively deliver nitric oxide from any box 100, monitor the fill status of each box 100, and / or, for example, when the first box is close to being empty, switch from obtaining nitrogen dioxide from the first box to the second box. This simplifies the usability of the delivery operation station 50 by eliminating the operator steps required to control the switch between two separate operation stations when the first box is close to being exhausted, and extends the time of nitric oxide delivery.

[0070] In some aspects, the operating station 50 can be designed and / or configured to include only one air inlet 70. When the operating station 50 includes more than one container 90 and more than one cartridge 100, the controller 60 can selectively couple the air inlet 70 to one of the containers 90 so that the operating station 50 can automatically switch from generating nitric oxide using one of the cartridges 100. For example, when the first cartridge is nearing depletion, the controller 60 can automatically change from coupling the air inlet 70 to a first container / cartridge to coupling the air inlet 70 to a second container / cartridge.

[0071] In some aspects, the operating station 50 can be designed and / or configured to include more than one air inlet 70. For example, the operating station can include two or more air inlets, such that the first container and the second container are each coupled to at least one air inlet.

[0072] In such aspects, each air inlet 70 is respectively coupled to one of more than one container 90 and one of more than one box 100. The controller 60 can selectively activate the air inlet 70 coupled to one of the containers and one of the boxes so that the console 50 can automatically switch from a state in which nitric oxide is produced using one of the boxes 100. For example, when the first box is nearing exhaustion, the controller 60 can automatically change from activating the first air inlet 70 coupled to the first container / box to activating the second air inlet 70 coupled to the second container / box. In other words, the controller is configured to selectively activate at least one air inlet in the first container or the second container based on the filling state of the first nitric oxide source and / or the second nitric oxide source. In exemplary aspects disclosed herein, the controller is configured to detect the filling state of the liquid nitrogen tetroxide used as the nitric oxide source.

[0073] Figure 2 is a flow chart of a method for generating nitric oxide according to exemplary aspects disclosed herein. Figure 2 The method 200 may be used, for example, Figure 1 It is implemented by the controller 60 of the operating console 50.

[0074] like Figure 2 As shown in FIG, method 200 begins at 201 by introducing air into at least one air inlet (e.g., Figure 1 The air inlet 70 in the embodiment is routed through a first cartridge (e.g., Figure 1 For example, a controller (e.g., Figure 1 The controller 60 in FIG. 1 may control the air inlet (eg, Figure 1 ) to route air through the first cartridge (e.g., Figure 1The controller may further be operable to control the rate at which nitric oxide is generated by the cartridge, e.g., by controlling the temperature of the reservoir containing nitrogen tetroxide and / or the concentration of nitric oxide delivered, e.g., by controlling the flow rate of the carrier gas from the air inlet to the air outlet.

[0075] At 202, the method continues by detecting the nitrogen tetroxide filling status of the first cartridge. A controller (e.g., Figure 1 The controller 60 in the first box) monitors and detects the first box (e.g., Figure 1 The nitrogen tetroxide filling state of the box 100 in the embodiment of the present invention can be used to determine the appropriate time when the first box is close to exhaustion, to stop using the first box for administration, and start using the second box for administration. This method improves the utilization rate of the box nitrogen tetroxide source material, to reduce the remaining material (e.g., nitrogen tetroxide, nitrogen dioxide) at the end of each box administration, while maintaining continuous nitric oxide dosage delivery. The nitrogen tetroxide filling state can be detected by, for example, monitoring the temperature and / or pressure of the liquid vessel assembly (e.g., the liquid vessel assembly 3000 discussed in further detail below). As the amount of nitrogen tetroxide in the liquid vessel assembly decreases (i.e., close to exhaustion), the temperature required to reach the internal pressure of nitric oxide producing a given amount / concentration may increase. The feedback control mechanism can measure the amount / concentration of nitric oxide produced by the box, and adjust the temperature set point of the liquid vessel assembly to maintain a set level and / or produce a target amount / concentration. The controller can determine whether the box is close to exhaustion based on the temperature and / or pressure in the liquid vessel assembly and / or the rate at which the box produces nitric oxide.

[0076] At 203, the method continues to automatically introduce air from at least one air inlet (e.g., Figure 1 The air inlet 70 in the rerouting is sent through the second box (e.g., Figure 1 For example, when a controller (e.g., Figure 1 The controller 60 in the embodiment detects that the first cartridge (eg, Figure 1 When the filling state of the cartridge 100 in the cartridge 100 is lower than a predetermined threshold, the controller automatically draws air from the air inlet (eg, Figure 1 The air inlet 70 in the re-route is conveyed through the second box (e.g., Figure 1 The first cartridge is different from the second cartridge. In some cases, at 203, the method may further include activating the second cartridge, for example, by breaking or rupturing a vessel (e.g., an ampoule) containing liquid nitrogen tetroxide.

[0077] The control algorithm for producing nitric oxide can also be switched from controlling the first box to controlling the second box. In some aspects, switching can be stepwise. In further aspects, the controller is configured to, while still delivering nitric oxide from the first source, gradually increase the concentration of nitric oxide from the second source. For example, the second box can be promoted (for example, by increasing the temperature of the liquid vessel in the second box to produce the nitric oxide of the target level), and the first box keeps the responsibility of supplying nitric oxide via the air outlet. During the promotion phase, the nitric oxide produced by the second box can be discharged into the room air or inerted. Once the second box has reached the target level, the valve can disconnect the first box from the air outlet, and the second box is connected to the air outlet. Any residual nitric oxide produced by the disconnected first box can be discharged into the room air and / or inerted. In other aspects, the switching from the first box to the second box can be gradual.

[0078] For example, the control algorithm can gradually increase the concentration of nitric oxide produced by the second cartridge (e.g., by increasing the temperature of the second cartridge's liquid container) while simultaneously decreasing the concentration of nitric oxide produced by the first cartridge (e.g., by decreasing the temperature of the first cartridge's liquid container). During the transition period, both the first and second cartridges can be coupled to the air outlet and contribute to the supply of nitric oxide. In other words, aspects are also disclosed in which, at least once, at least one air inlet is simultaneously coupled to the first container and the second container.

[0079] In some aspects, for example, the system includes only one air inlet (e.g., Figure 1 70 in the air inlet), while the system includes more than one box (e.g., Figure 1 100 in the box). The controller (e.g., Figure 1 The controller 60 in FIG. 1 is capable of routing air from the air inlet through a first cartridge (e.g., Figure 1 The cartridge 100 in FIG. 1 generates nitric oxide gas by coupling an air inlet to a first cartridge. A controller may monitor and detect a fill level of the first cartridge while the first cartridge generates nitric oxide gas. When the controller detects that the fill level of the first cartridge is below a threshold, the controller may automatically reroute air from the air inlet through a second cartridge (e.g., Figure 1 The second box generates nitric oxide gas by coupling the air inlet to the second box to ensure the continuity of the air flow.

[0080] For example, in some aspects, the system includes more than one air inlet (e.g., Figure 1 70 in the air inlet), while the system includes more than one box (e.g., Figure 1Each air inlet is connected to one of the more than one boxes. A controller (e.g., Figure 1 The controller 60 in FIG. 1 is capable of directing air from the first air inlet (eg, Figure 1 The air inlet 70 in the first box is routed through the first box (e.g., Figure 1 The first cartridge generates nitric oxide gas by activating the first air inlet. The controller can monitor and detect the fill level of the first cartridge while the first cartridge generates nitric oxide gas. When the controller detects that the fill level of the first cartridge is below a threshold, the controller can automatically reroute air from the second air inlet through the second cartridge (e.g., Figure 1 The second cartridge 100) generates nitric oxide gas by switching to and activating the second air inlet to ensure continuity of the air flow.

[0081] Figure 3 1 is a schematic diagram of a box 100 according to one aspect. U.S. Patent No. 8,887,720 (the disclosure of which is hereby incorporated by reference in its entirety) describes a known reservoir assembly and cartridge suitable for box 100. Box 100 includes a cartridge assembly 200 and a liquid vessel (LV) assembly 300. LV assembly 300 includes a reservoir 310, a flow restrictor 320, and a heater 330. Reservoir 310 can hold liquid nitrogen tetroxide. After activation (e.g., by operating station 50), heater 330 increases the temperature of liquid nitrogen tetroxide, which produces nitrogen dioxide. Nitrogen dioxide can leave reservoir 310 through flow restrictor 320. Heater 330 and flow restrictor 320 together can provide a controlled release of nitrogen dioxide. After passing through the flow restrictor, nitrogen dioxide can flow to cartridge assembly 200, which can be operable to, for example, convert nitrogen dioxide into nitric oxide by a chemical reaction. For example, the chemical reaction can be a reaction of nitrogen dioxide with an antioxidant coated on a surface active material that retains moisture. In some embodiments, the antioxidant can be ascorbic acid, and the surface active material can be silica gel. However, in other aspects, nitric oxide can be formed from nitrogen dioxide in the presence of a certain amount of water and in the absence of other antioxidants. The generated nitric oxide is then delivered to the patient via the operating table 50.

[0082] Figure 41 is a perspective view of a cartridge 1000 according to aspects. The cartridge 1000 includes a cartridge assembly 2000 and a liquid vessel (LV) assembly 3000. The LV assembly 3000 can contain liquid nitrogen tetroxide. Upon activation, the liquid nitrogen tetroxide can be heated to produce nitrogen dioxide. The nitrogen dioxide can flow into the cartridge assembly 2000 for further conversion. The cartridge assembly 2000 can be operable to convert the nitrogen dioxide into nitric oxide, for example, by a chemical reaction. The chemical reaction can be a reaction of the nitrogen dioxide with an antioxidant coated on a surface-active material that retains moisture. In some embodiments, the antioxidant can be ascorbic acid, and the surface-active material can be silica gel.

[0083] In other aspects, the antioxidant can be water.The generated nitric oxide is then delivered to the patient via the operating table. Figure 5 yes Figure 4 A cross-sectional view of box 1000 is shown in FIG. Figure 6 yes Figure 4 and Figure 5 A top view of the box 1000 is shown in FIG. Figure 5 As shown in , cartridge assembly 2000 comprises cartridge housing 2100, cartridge inlet sieve plate 2110, cartridge medium 2200, cartridge edge connector 2500, compression plug 2300, cartridge outlet sieve plate 2120, cartridge housing cover 2400 and output gas port 2600. Cartridge assembly 2000 is configured to convert nitrogen dioxide into nitric oxide by chemical reaction. This chemical reaction can be the reaction of nitrogen dioxide and the antioxidant coated on the surface active material that retains moisture. The cartridge medium 2200 accommodated in cartridge assembly 2000 can be the antioxidant coated on the surface active material. In some embodiments, the antioxidant can be ascorbic acid, and the surface active material can be silica gel. However, it should be understood that water can also be used as an antioxidant. In still further aspects, other known antioxidants can be used, such as vitamin C, vitamin E, alpha-tocopherol, gamma-tocopherol or its any combination.

[0084] Tube inlet sieve plate 2110 and tube outlet sieve plate 2120 are configured to tube medium 2200 is remained in the tube housing 2100, and provide the uniform air flow that flows into and flows out of tube by sieve plate.Compression plug 2300 is configured to be remained in the tube housing 2100 by compression tube medium 2200.Compression plug 2300 can be made by elastomeric material or other suitable materials, and this material allows compression plug 2300 to meet tube housing 2100 and / or compression tube medium 2200.Compression plug 2300 can not chemically react with tube medium 2200, antioxidant, nitrogen dioxide and / or nitric oxide.Tube housing cover 2400 is configured to seal and close tube housing 2100, makes that the tube medium 2200 that is accommodated in the tube housing 2100 can be protected and isolated with room air.Output gas port 2600 is configured to output the nitric oxide that is produced with controlled flow velocity, to be delivered to the patient.

[0085] Cartridge edge connector 2500 is configured to electrically and / or communicatively connect cartridge 1000 to a control unit capable of controlling the delivery of nitric oxide. Figure 6 As shown in , the control unit can be a cartridge PCB assembly 4000. In some embodiments, the cartridge PCB assembly 4000 can be operable to control one or more pumps to draw air through the air gas port 3700, selectively control the flow through one or more cartridges 1000, control the temperature of liquid nitrogen tetroxide within the cartridge 1000, control the rate at which nitrogen dioxide is produced within the cartridge 1000, control the rate at which nitric oxide is produced within the cartridge 1000, control the concentration and / or flow rate of nitric oxide leaving the cartridge 1000 through the output gas port 2600, and / or the like. In some embodiments, the cartridge PCB assembly 4000 can be connected to a single heater element and configured to control the temperature of the nitrogen tetroxide within the cartridge 1000. Upon activation, the cartridge PCB assembly 4000 can control the single heater element to heat the temperature to an elevated level. The liquid vessel heater 3510 can be a single cartridge heater, such as Figure 6 The liquid vessel heater 3510 can be provided by the restrictor body 3210 (eg, Figure 6 ) is thermally coupled to the reservoir. In some embodiments, multiple heaters may be used in the liquid vessel assembly 3000 to increase and / or control the temperature of the nitrogen tetroxide.

[0086] In some embodiments, the cassette printed circuit board assembly 4000 can be removed from a workstation (e.g., Figure 1The operating station 50 in the cartridge 1000 receives / sends signals and executes instructions received from the operating station. For example, the cartridge printed circuit board assembly 4000 can respond to instructions received from the operating station and / or send signals from the thermistor 3500 back to the operating station to activate the liquid vessel heater 3510 on the liquid vessel assembly (3000), so that the operating station can monitor the temperature in the cartridge 1000. In such embodiments, the operating station can control one or more pumps that draw air through the air gas port 3700 and flow through one or more cartridges 1000.

[0087] like Figure 6 As shown in FIG, temperature is monitored and / or controlled using a single thermistor 3500. Figure 6 , the thermistor 3500 is attached to the top surface of the liquid vessel assembly 3000 via a spade-shaped tab hole connection portion fixed with a screw (not shown). Compared with the wire heater coil heating element, the single heater element liquid vessel heater 3510 has improved mechanical strength and durability, which reduces the possibility of wire / coil breakage failure. The process of fixing the liquid vessel heater 3510 and the thermistor 3500 to the liquid vessel assembly 3000 is greatly simplified compared to the process of fixing the wire heater coil heating element as implemented in some known boxes. In some embodiments, a plurality of thermistors can be used and attached to the liquid vessel assembly 3000 to monitor and / or control temperature.

[0088] like Figure 5 As shown in FIG, the input air conduit 3600 and the input air port 3700 are configured to guide the input air into the box 1000. Figure 6 As shown in FIG, the nitrogen dioxide containing gas conduit 3800 is configured to direct the generated nitrogen dioxide into the cartridge assembly 2000 for further conversion to nitric oxide. The activation pin opening 3415 contains a pin for activating the cartridge 1000, which will be Figure 8 The following is a detailed description of the Figure 6 As shown in FIG, the tee connector 3416 is coupled to a flow restrictor (e.g., Figure 9 The capillary restrictor conduit 3211 shown in FIG 32 is configured to introduce nitrogen dioxide generated in the liquid vessel assembly into a carrier gas (e.g., air) that flows from the input air gas port 3700, through the input air conduit 3600, and onto the nitrogen dioxide-containing gas conduit 3800 and cartridge assembly 2000.

[0089] like Figure 54400 is discharged into the inerting chamber 4100. The inerting chamber 4100 is configured to enclose the liquid vessel assembly 3000 to prevent nitrogen dioxide and / or dinitrogen tetroxide from accidentally releasing the chamber in the box 1000. The inerting chamber top gasket and fixture 4200 and inerting chamber bottom gasket 4300 are configured to be connected to the inerting chamber 4100 with the liquid vessel assembly 3000. The inerting chamber top gasket and fixture 4200 and inerting chamber bottom gasket 4300 can be made of elastic material. If the ampoule 3150 is not used to rupture when the box 1000 generates nitric oxide (for example, in transportation, if it falls etc.), the dinitrogen tetroxide and / or nitrogen dioxide contained in the box 1000 can be discharged into the inerting chamber 4100 by the inerting discharge path 4400. The color indicator 4500 can change color to warn the user that nitrogen dioxide has been discharged into the inerting chamber 4100.

[0090] Figure 7 is a perspective view of a liquid vessel assembly 3000 according to aspects. Figure 8 yes Figure 7 A cross-sectional view of the liquid vessel assembly 3000 is shown in FIG. Figure 9 yes Figure 7 1. Another cross-sectional view of the liquid vessel assembly 3000 is shown in FIG. As described above, the liquid vessel (LV) assembly 3000 is configured to store liquid nitrogen tetroxide. The liquid nitrogen tetroxide can be heated to produce nitrogen dioxide.

[0091] Still further disclosed herein is an apparatus comprising: a frangible vessel containing nitrogen tetroxide; a reservoir, the frangible vessel disposed within the reservoir, the reservoir being configured to contain the nitrogen tetroxide when the frangible vessel is ruptured; and an outlet disposed above a wall of the reservoir, the frangible vessel, the reservoir, and the outlet being collectively configured such that when the frangible vessel is ruptured, the level of nitrogen tetroxide in the reservoir does not reach the outlet, regardless of the orientation of the vessel.

[0092] exist Figure 8 Such exemplary aspects are also shown in FIG. Figure 8 As shown in FIG, LV assembly 3000 includes an ampoule 3150 (e.g., a breakable container). Ampoule 3150 is configured to store liquid nitrogen tetroxide. LV assembly 3000 includes an activation mechanism that ruptures ampoule 3150 to release the liquid nitrogen tetroxide into a reservoir within LV assembly 3000. The activation mechanism includes an activation wedge 3121, an activation wedge spring 3122, an activation sleeve 3123, an ePTFE pad 3124, an activation sleeve (bottom) 3414, an activation pin 4313, an activation pin O-ring 3412, an activation pin spring 3411, and LV housing 3400.

[0093] Prior to activation / rupturing, the ampoule 3150 is laterally secured in place with an expanded PTFE foam pad (ePTFE pad 3124) beneath the bottom end of the ampoule 3150 and a low contact force conical spring (activation wedge spring 3122) at the activated top end of the ampoule 3150. The ePTFE pad 3124 and activation wedge spring 3122 cushion mechanical shocks on the end of the ampoule 3150. The ampoule 3150 is also supported around its circumference in the lower half of its length using an aluminum sleeve (activation sleeve 3123) that has minimal clearance between the inner diameter of the activation sleeve 3123 and the outer diameter of the ampoule 3150 to minimize potential shock from side impacts. These features improve the mechanical durability of the ampoule 3150.

[0094] Fracturing / activation of the ampoule 3150 is achieved using an activation wedge 3121. When the ampoule contacts during actuation, the leading edge of the activation wedge 3121 applies a lateral force to the unsupported, free end of the ampoule 3150. This lateral force causes the ampoule 3150 to bend against the cylindrical activation sleeve 3123, which holds the ampoule 3150 in concentric alignment with the LVM housing 3400 and supports the ampoule 3150 for approximately half its length. The lateral bending force creates strain on the wall of the ampoule 3150 at the midpoint of its length, causing it to rupture. During activation and prior to rupture, the larger diameter of the interior of the LVM housing 3400 forms a gas seal with the U-cup seal 3410. The activation pin 3413 is in a retracted position before and after use. In the retracted position, the smaller diameter portion of the interior of the LVM housing 3400 is located within the interior of the LV assembly 3000 and the inerting chamber 4100 (e.g., Figure 5 ) maintains an open exhaust gas path between Figure 5 4. Inerting chamber 4100 may contain an absorbent medium, such as a soda lime chemical absorbent medium, which may be suitable for neutralizing nitrogen tetroxide and / or nitrogen dioxide, preventing the release of toxic gases from the LV assembly.

[0095] The activation sleeve (bottom) 3414, the activation pin 3413, the activation pin O-ring 3412 and the activation pin spring 3411 are also part of the activation mechanism. The activation sleeve 3414 is configured to protect the activation pin 3413 and hold the activation pin 3413 in place before or after activation. Figure 5 As shown in FIG, activation pin 3413 and activation pin spring 3411 are disposed in activation pin opening 3415. Activation pin 3413 and activation pin spring 3411 are configured to activate LV assembly 3000 by applying a constant force to activation wedge 3121 and activation wedge spring 3122. Activation pin O-ring 3412 is configured to seal LV assembly 3000 and prevent liquid / gas leakage.

[0096] Upon activation, liquid nitrogen tetroxide is released from the ampoule 3100 and into the reservoir. Further, activation may seal the inerting exhaust path 4400. The reservoir may be heated by a heater to produce nitrogen dioxide and control the pressure within the reservoir. The nitrogen dioxide may exit the LV assembly 3000 through a flow restrictor. By controlling the pressure, which is a function of temperature, the nitrogen dioxide may be released at a controlled rate through the flow restrictor. After passing through the flow restrictor, the nitrogen dioxide may flow along with a carrier gas supplied by the operating station to the cartridge assembly 2000, which may be operable to convert the nitrogen dioxide into nitric oxide. Figure 8 and Figure 9 As shown in FIG, the LV assembly 3000 includes a restrictor body 3210 and a capillary restrictor tube 3211. Figure 6 3211) is loaded into a hole in the restrictor body 3210 near the capillary restrictor tube 3211 for heating liquid nitrogen tetroxide to produce nitrogen dioxide. The proximity of the liquid vessel heater 3510 to the capillary restrictor tube 3211 is positioned to maintain an elevated temperature in the restrictor body 3210 relative to the temperature of the LV assembly 3000, which reduces the likelihood of liquid condensation and clogging of the capillary restrictor tube 3211. In some embodiments, multiple heaters may be used in the LV assembly 3000 to heat the nitrogen tetroxide.

[0097] The main body of liquid vessel assembly 3000 can be made of aluminum, which reduces manufacturing cost and material cost. In fact, for the same reason, most of the components of LV assembly 3000 can be made of aluminum. Aluminum provides high thermal conductivity and heat transfer for the heat generated at the restrictor body 3210 end portions of LV assembly 3000. It may be desirable that restrictor body 3210 be made of a material (such as stainless steel) with higher heat capacity than the main body of liquid vessel assembly 3000, which can provide relatively better heat retention during cooling (for example, during the time period when cartridge heater is closed), which can keep capillary restrictor conduit 3211 hotter than reservoir, further suppressing condensation.

[0098] As described above, a single thermistor 3500 can be used to monitor and / or control temperature, and the single thermistor is attached to the top surface of the flow restrictor body 3210 via a spade-shaped tab hole connection secured with a screw. The single thermistor 3500 has improved mechanical strength and durability, which reduces the possibility of wire breakage failure. In some embodiments, multiple thermistors can be used and attached to the liquid vessel assembly 3000 to monitor temperature.

[0099] The LV assembly 3000 also includes an insulating polymer sleeve 3110 for insulating the LV assembly 3000 and reducing heat loss. During assembly, the insulating sleeve 3110 is applied around the outer surface of the LV assembly 3000. The insulating sleeve 3110 creates a small air gap (e.g., a slit) between the outer surface of the LV assembly 3000 and the surrounding absorbent medium in the inerting chamber 4100. Figure 5 This air gap provides a thermal barrier that reduces the rate of heat loss to the surrounding medium and reduces the time to heat up to the target temperature by a factor of approximately 2 compared to heating with the same input power and without the insulating sleeve. Figure 6 3214 and is configured to introduce nitrogen dioxide generated in the reservoir into a carrier gas (e.g., air or oxygen). The ferrule seal 3213 and the vented set screw 3214 are configured to connect tubing (e.g., capillary restrictor tubing 3211 and tee fitting 3416) and allow the release of the nitric oxide flow.

[0100] In yet a further aspect, the apparatus includes a separator disposed in the outlet and positioned above the nitrogen tetroxide regardless of the orientation of the vessel or external vibrations applied to the vessel. For example, the LV assembly 3000 includes a gas intake frit (or separator) 3212 coupled to a capillary restrictor conduit 3211 and a tee fitting 3416. The gas intake frit 3212, the capillary restrictor conduit 3211, and the tee fitting 3416 collectively define a flow path through which nitrogen dioxide exits the LV assembly 3000. As shown in Figure 9 and 10B As best seen in the figure, the inlet screen 3212 is disposed on a base that is coaxial with and within the LV assembly 3000. In this way, the inlet screen 3212 can be positioned above the liquid level of nitrogen tetroxide in the reservoir regardless of the orientation of the LV assembly 3000. This feature improves the performance of the LV assembly 3000 for a wider range of use conditions, for example, when the patient or cassette may be moved during use, such as in hospital transport or other outpatient / portable use applications. For example, the position of the inlet screen 3212 allows the liquid vessel assembly to be operated in any orientation without the liquid contacting the inlet screen 3212, which would block the gas path and inhibit nitrogen dioxide from leaving the liquid vessel assembly 3000. This can allow the cassette 1000 to be placed in a portable operating table or vehicle (such as an ambulance or helicopter). Such an operating table can be used without the risk of nitric oxide being disrupted due to changes in orientation or vibration.

[0101] Figures 10A to 10G yes Figure 7As described above, the inlet screen 3212 is positioned so that the liquid fill level does not reach the screen inlet position in any orientation of the LV assembly 3000. Figures 10A to 10E Several examples of liquid levels under extreme orientation conditions are shown in . Figure 10A and Figure 10B Liquid nitrogen tetroxide fill levels in an upright orientation at room temperature are shown. Figure 10C Liquid nitrogen tetroxide fill levels are shown in a 5 degree tilt orientation at room temperature. Figure 10D and Figure 10E Liquid nitrogen tetroxide fill levels are shown at room temperature in a 90 degree rotated orientation. Figure 10F and Figure 10G The liquid nitrogen tetroxide filling level in the inverted orientation at room temperature is shown. Figures 10A to 10G As shown in , under any extreme orientation conditions of the LV assembly 3000, the liquid fill level does not reach the screen inlet location, and thus prevents or reduces the possibility of liquid blocking the gas path in use or during transportation.

[0102] Figure 11B is a perspective view of a cartridge assembly 2000 according to an aspect. Figure 11A yes Figure 11A Exploded view of the cartridge assembly 2000. The cartridge assembly 2000 includes a cartridge housing 2100. The cartridge housing 2100 is filled with a porous medium 2200 moistened with an antioxidant. A plug 2300, which may be made of rubber or other suitable elastomeric material, may package and contain the porous medium 2200 and the antioxidant within the cartridge housing 2100 under compression. A cap 2400 may be coupled to the cartridge housing 2100 by threads or other means. Figure 4 and Figure 5 As best shown in FIG. 2 , the cartridge assembly 2100 may be disposed within the cartridge 1000 discussed above.

[0103] The cartridge assembly 2000 can be fluidly coupled to the liquid vessel assembly 3000 via the capillary restrictor tubing 3211, the tee fitting 3416, and the cartridge inlet frit 2110. The input air gas port 3700 can allow air or other suitable carrier gas (e.g., oxygen, nitrogen, etc.) to flow from outside the cartridge 1000 and into the tee fitting 3416. By controlling the temperature of the reservoir of the liquid vessel assembly 3000 containing nitrogen tetroxide, the rate at which nitrogen dioxide flows into the tee fitting 3416 can be controlled. By controlling the flow rate of the carrier gas, the concentration of nitrogen dioxide delivered to the cartridge assembly 2000 via the inlet frit 2110 can be controlled.

[0104] Cartridge media 2200 can be silica gel or other suitable high surface area wettable material. Cartridge media 2200 can be wetted with an antioxidant, such as an aqueous solution of ascorbic acid. In some aspects, cartridge media 2200 can be wetted with water. Nitric oxide can react with water bound to cartridge media 2200 to produce nitric oxide according to the following reaction: a. 6NO2 (gaseous) + 3H2O (liquid) → 3HNO3 (liquid) + 3HNO2 (liquid) Equation 1a

[0105] b. 3HNO2 (liquid) → HNO3 (liquid) + 2NO (gas) + H2O (liquid) Equation 1b

[0106] The ascorbic acid-moistened cartridge media 2200 (or other suitable antioxidant-containing cartridges) is functionally similar to the media described in U.S. Patent No. 8,607,785, the entire disclosure of which is hereby incorporated by reference. Cartridge assembly 2100 differs from known cartridges in that, in some aspects and excluding water and antioxidants, the cartridge media is essentially entirely (>95%) made of active derivatized silica gel. Similarly, the cartridge media can be substantially free (<5%) of inactive components, such as ultra-high molecular weight polyethylene binder materials, which are sintered with silica in some known cartridges to create solid media units. Such solid media units do not conform to known cartridge housings and therefore fail to maximize the space within the housing. In contrast, cartridge media 2200 is a flowable granular material. Plug 2300 can maintain the cartridge media 2200 in a compressed state, allowing it to conform to the cartridge housing 2100, maximizing the use of available volume, and eliminating the need for a binder to create a solid media unit. Furthermore, unlike known media units that require multiple coating and drying steps on various individual components and subcomponents, the cartridge media 2200 is more suitable for high-volume manufacturing because the cartridge media 2200 can be wetted with a large amount of antioxidant solution or water. The cartridge media 2200 can then be added to the cartridge housing from a bulk container in a process similar to an assembly line.

[0107] In some cases, cartridge 2100 may not include ascorbic acid or other antioxidants, which may degrade over time, but instead rely on stable water to improve shelf life. Additionally or alternatively, cartridge 2100 may be designed to reduce nitrogen dioxide with consideration of water availability, such that cartridge 2100 may be operable to generate nitric oxide based on a reaction with ascorbic acid (or other antioxidant) and / or water, which may improve the cartridge's ability to generate nitric oxide and / or shelf life.

[0108] Additionally, the cartridge media 2200 may have a higher density and / or a higher moisture content than known cartridges. For example, some known cartridges have cartridge media with a moisture content of 1%-10.6%. Figure 12As shown in , experimental data reveals a positive correlation between the water content of the cartridge media 2200 and the nitrogen dioxide conversion capacity. The increased NO2 conversion capacity is attributed to the reaction between NO2 and water to produce NO (as described above), which leads to increased NO2 conversion capacity. In some aspects, the cartridge media 2200 can have a water content of at least 20%. For example, the water content can be 20wt% to 60wt%, 20wt% to 40wt%, or 20wt% to 35wt%. Such high water concentrations, particularly water concentrations above 20wt%, are not feasible for known cartridges because the presence of inactive binder material reduces the relative proportion of surface active material available for absorbing water.

[0109] The cartridge medium 2200 can be moistened with a solution containing one or more suitable antioxidants. It is desirable that the cartridge medium 2200 and / or the material moistening it is nontoxic and / or food safe because the nitric oxide produced may be intended to be used for inhalation. Therefore, in such aspects, catalysts and / or antioxidants containing heavy metals or other materials that may contaminate nitric oxide may be unsuitable. A suitable antioxidant is ascorbic acid. The various aspects of the cartridge medium 2200 can be moistened with a solution containing the ascorbic acid between 0 and 32%, including the exemplary values ​​of 1wt%, 5wt%, 10wt%, 15wt%, 20wt%, 25wt% and 30wt%. It should be understood that ascorbic acid can exist with any amount falling between any two of the above-mentioned disclosed values, or it can exist with any scope that can be formed by any two values ​​falling within the widest range. For example, ascorbic acid can be present in an amount of 1 wt% to 32 wt%, or 5 wt% to 32 wt%, or 15 wt% to 32 wt%, 1 wt% to 15 wt%, or 10 wt% to 15 wt%, etc. It may be desirable to have an antioxidant concentration at or below the room temperature solubility limit because, at higher concentrations, the antioxidant may precipitate out before the cartridge media 2200 is evenly saturated, which may produce inconsistent nitric oxide conversion kinetics. However, it should be understood that the antioxidant concentration can be further increased by heating the antioxidant solution prior to wetting the cartridge media 2200.

[0110] system

[0111] Currently known control methods based on NO concentration (amount) have serious drawbacks. For example, control methods based on NO concentration may not be able to determine the optimal initial injection concentration at the start of drug administration because the initial NO concentration is zero and the flow rate supplied by the respiratory assistance device (such as a ventilator) is initially unknown. When entering the dose set point before starting drug administration, known systems typically require the user to provide a ventilator flow rate in the low, medium or high range. The ventilator flow information provided by the user is used to define the normal initial injection parameters and rate of change for feedback control information within the algorithm to maintain the dose without excessively exceeding the target dose and to optimize the time to reach the target dose.

[0112] Furthermore, the feedback control rate of the NO concentration-based control method may be limited by the time response of the NO gas sensor to changes in NO concentration and the time it takes for the initial NO injection control change to propagate from the source to the sampling system. Depending on the flow usage pattern of the respiratory assistance device (such as a ventilator), the feedback control time interval can vary from less than 30 seconds to more than 60 seconds. The rate at which the system parameters change is limited by the time it takes for the information to change. For this reason, the system responds more slowly to changes in ventilator system operation than systems that use more rapidly changing parameters to control dosage.

[0113] Other known nitric oxide delivery systems use the measured ventilator flow at the nitric oxide injection site as the primary input parameter to determine the injection flow from a delivery system with a fixed nitric oxide source concentration. This approach is particularly suitable for the speed of system control when the ventilator system flow varies. Furthermore, under normal operating conditions where all ventilator flow passes through the NO injector module at once, this control method achieves acceptable NO concentration accuracy (within + / - 20% of the dose).

[0114] In some important medical applications where the presence of nitric oxide needs to be tightly controlled, the accuracy of such systems may not be sufficient. The system disclosed herein allows this goal to be achieved.

[0115] In some aspects, a system for delivering nitric oxide to a subject is disclosed, wherein the system includes a nitric oxide infusion line configured to inject a first gas into a breathing tube containing a respiratory gas at an infusion point. In such exemplary and non-limiting aspects, the first gas contains a first amount of nitric oxide. It should be understood that the infusion point can be anywhere along the breathing tube. In some aspects, the infusion point is adjacent to a portion of the breathing tube near a respiratory assistance device. It should be understood that the respiratory assistance device can be any device that can provide a steady amount of respiratory gas to a patient at a desired rate and concentration. In some aspects, the respiratory assistance device is a ventilator. In further aspects, the ventilator can be a face mask ventilator. However, in other aspects, the ventilator can be a mechanical ventilator. In further aspects, the mechanical ventilator can be a negative pressure ventilator and / or a positive pressure ventilator. However, in other aspects, other types of ventilators can also be used to deliver respiratory gas to the patient. For example, other types of ventilators can include tracheostomy ventilators.

[0116] In a still further aspect, the breathing gas can include air and / or oxygen-enriched air.

[0117] In yet further aspects, the disclosed system includes a sampling line configured to sample a second gas. In such aspects, the second gas comprises a second amount of nitric oxide and respiratory gas. It should be understood that sampling of the second gas can be performed at any sampling location between the injection point of the first gas and the subject. In some aspects, the sampling location is closer to the subject than the injection point.

[0118] In yet further aspects, it should be understood that, in addition to a breathing tube configured to deliver fresh breathable gas to the subject, the respiratory assistance device may also include an expiratory tube configured to remove exhaled gas from the subject. In some aspects, the exhaled gas is exhausted to the surrounding atmosphere; in other aspects, the exhaled gas can be collected, purified to remove carbon dioxide and other harmful gases, and recirculated if necessary. In yet further aspects, the breathing tube and the expiratory tube can be attached to a mask or a tube inserted directly into the subject's body. In certain aspects, the sampling location can be at a distance of about 6 to about 12 inches from the location where the breathing tube and the expiratory tube are connected to the mask or breathing tube. In yet other aspects, the distance can be from about 6 inches to about 12 inches, including exemplary values ​​of about 7 inches, about 8 inches, about 9 inches, about 10 inches, and about 11 inches. It should be understood that the distance can be anywhere between two of the values ​​disclosed above. However, in yet further aspects, the sampling location can be located at a distance that can fall within any range formed by any of the above values. For example, and without limitation, the sample location may be located at a distance between approximately 6 inches and 10 inches, or between 6 inches and 11 inches, or between 7 inches and 12 inches, or between 7 inches and 10 inches, or between 6.5 inches and 11.8 inches, etc.

[0119] In still other aspects, the system may further include a feedback loop controller in communication with: (i) a nitric oxide setpoint controller configured to set a nitric oxide setpoint amount; (ii) a source configured to provide a third gas having a third amount of nitric oxide; and (iii) at least one sensor configured to measure a second amount of nitric oxide in the sampling line, wherein the third amount of nitric oxide is determined by the feedback loop controller based on the second amount of nitric oxide and the nitric oxide setpoint amount.

[0120] In such exemplary and non-limiting aspects, the source of the third gas configured to provide nitric oxide having a third amount is any source configured to provide or form nitric oxide. In certain aspects, any nitric oxide source disclosed herein can be utilized. In certain aspects, the nitric oxide source can be a nitric oxide tank. In other aspects, the nitric oxide source can be a system that allows nitric oxide to be formed by a spark. However, in other aspects, the nitric oxide source can be one or more cartridges that are configured to form nitric oxide by a chemical reaction, as described above.

[0121] In yet further aspects, the nitric oxide set point controller is configured to set a nitric oxide set point amount or target amount of nitric oxide that will be delivered to the subject. It should be understood that the terms "target amount" and "nitric oxide set point" are used interchangeably herein. The target amount (or set point amount) is determined based on the subject's medical condition and according to a doctor's prescription. In some aspects, the target amount can be manually set by a caregiver or the subject. It should be understood that the set point can be defined in any terms. For example, in some aspects, the nitric oxide set point is the flow rate of nitric oxide associated with the first amount of nitric oxide. However, in other aspects, the nitric oxide set point is the concentration of nitric oxide associated with the first amount of nitric oxide. It should be understood that in some aspects, the system may include a set point controller that may allow the target amount to be defined based on both the nitric oxide flow rate and the concentration of nitric oxide.

[0122] Should be understood that the concentration (or amount) of nitric oxide can be determined in ppm.Aspect further again, system disclosed herein can deliver the nitric oxide of any desired amount to the experimenter.In certain aspects, the amount of nitric oxide delivered to the experimenter can be greater than 0ppm to about 10,000ppm, including about 100ppb, about 200ppb, about 500ppb, about 1ppm, about 5ppm, about 10ppm, about 20ppm, about 40ppm, about 50ppm, about 100ppm, about 250ppm, about 500ppm, about 1,000ppm, about 1,250ppm, about 1,500ppm, about 1,750ppm, about 2,000ppm, about 2,250ppm, about 2,500ppm, about 2,750ppm, about 3,000ppm, about 3,250ppm, about 3,500ppm, about 3,750ppm and about 4,000ppm. It should be understood that the actual amount of nitric oxide delivered to a subject can have any value falling between any two of the disclosed values ​​above, or it can fall within any range formed by any value within the widest range. In some instances, the nitric oxide delivered to a subject can be in the range of about 0.1 ppm to 100 ppm, for example, for selective pulmonary vasodilation. In some instances, the nitric oxide delivered to a subject can be in the range of about 100 ppm to 300 ppm, for example, for antimicrobial applications.

[0123] However, in other aspects, the target value can be determined in flow rate units and can be from about 0.5 microliters / minute to about 2 milliliters / minute of NO.

[0124] In further aspect yet, the first gas being injected into the respiratory conduit can comprise a carrier gas. In such aspect, it should be understood that carrier gas is the gas that a certain amount of nitric oxide (in this case, the first amount) is transported to experimenter. In some aspects, carrier gas can flow through a nitric oxide source and collect nitric oxide, no matter how its method of forming or delivering nitric oxide is. But in other aspects, for example, if a nitric oxide source is a tank comprising nitric oxide, then such tank can also comprise a carrier gas. In some aspects, carrier gas can comprise a certain amount of inert gas (such as nitrogen), or it can comprise air or oxygen-enriched air.

[0125] In a still further aspect, the first gas can form a second gas after being injected into the respiratory gas together with the respiratory gas.The second gas can comprise a second amount of nitric oxide, the respiratory gas, and optionally a carrier gas.

[0126] exist Figure 13A , an exemplary system 5000 is shown in FIG. Respiratory assistance device 5100 has two conduits: respiratory conduit 5300 and expiratory conduit 5400. A user can establish a target amount of nitric oxide to be delivered in nitric oxide setpoint controller 5010, which communicates with feedback loop controller 5020, which in turn communicates with nitric oxide source 5030. The nitric oxide source can generate nitric oxide or deliver it in a third amount. It should be understood that at least once during the delivery of nitric oxide to the subject, the first amount of nitric oxide and the third amount of nitric oxide are the same. For example, during the first infusion, controller 5020 communicates with nitric oxide source 5030 to deliver a certain amount of nitric oxide to respiratory conduit 5600 at delivery point 5500, at which point the third amount of nitric oxide is equal to the first amount of nitric oxide.

[0127] Respiratory conduit 5300 delivers a second gas 5035 comprising a breathing gas and a second amount of nitric oxide. Expiratory conduit 5400 delivers gas exhaled by the subject. In some aspects, the exhaled gas is exhausted to the atmosphere. However, in other aspects, the exhaled gas is collected and purged of harmful gases such as carbon dioxide and recirculated back into the respiratory conduit.

[0128] In yet further aspects, sampling line 5055 can be operated by pump 5040. The sampling line samples the second amount of nitric oxide at location 5600, for example, on breathing tube 5300. It should be understood that this schematic diagram is merely exemplary and that the sampling location can be any location, as disclosed above. Sampling line 5055, operated by pump 5040, transports the second gas to at least one sensor 5060 via line 5065. In such aspects, the at least one sensor is a sensor configured to determine the second amount of nitric oxide in the second gas. It should be understood that any sensor capable of detecting nitric oxide can be utilized. NO sensor 5060 communicates with feedback loop controller 5020. Upon receiving information about the second amount of nitric oxide in the sampling line, feedback loop controller 5020 can communicate with nitric oxide setpoint controller 5010 to compare the second amount of nitric oxide with a target amount. In aspects where the second amount of nitric oxide is different than the nitric oxide set point amount, the feedback loop controller 5020 is configured to communicate with the source 5030 to adjust the third amount of nitric oxide to match the nitric oxide set point amount.

[0129] In a further aspect and as disclosed above, the nitric oxide can be formed in situ. It can be formed by a spark or a chemical reaction using liquid nitrogen tetroxide. In aspects where nitric oxide from liquid nitrogen tetroxide is used, the source can be any of those disclosed above. In a further aspect and as disclosed above, the amount of nitric oxide formed by the source can be controlled by the temperature and pressure applied to the source.

[0130] exist Figure 13B An exemplary and non-limiting flow chart 6000 illustrating the operation of the system disclosed herein is shown in FIG. First, a user can establish a target amount of NO at 6010; this target amount is communicated 1 to a feedback loop controller 6020. The feedback loop controller communicates 2 with a NO source 6030 and injects 3 a first amount 6040 of NO into a breathing tube (not shown). The sampling line measures 4 a second amount of NO 6050 and transmits 5 it back to the feedback loop controller 6020. If the target amount of NO at 6010 is different from the second amount 6050, the controller 6020 communicates with the source 6030 to form 9 a third amount of NO 6060 to correct the total amount of NO reaching the subject. This amount is injected into the system and measured again at 10. This loop can continue as long as the subject receives NO.

[0131] In yet further aspects, the system can further include one or more additional sensors 5070. In such aspects, the one or more additional sensors are in communication 5072 with the feedback loop controller. In yet further aspects, the one or more additional sensors include an oxygen sensor and / or a nitrogen dioxide sensor. In still other aspects, the oxygen sensor detects the amount of oxygen in the second gas, and / or the nitrogen dioxide sensor detects the amount of nitrogen dioxide in the second gas.

[0132] In yet further aspects, the system can further include an auxiliary sensor 5080 positioned proximate the injection point and configured to measure the flow rate of the breathing gas, and wherein the auxiliary sensor is in communication with the feedback loop controller 5095. In such aspects, the feedback loop controller corrects the flow rate of the third gas when the flow rate of the breathing gas differs from a flow rate associated with the nitric oxide set point amount.

[0133] For example, in such aspects, an auxiliary sensor (such as flow sensor 5080) is connected to the output of a respiratory assistance device (such as a ventilator). In such aspects, the sensor can provide a direct measurement of the ventilator dilution flow. If an auxiliary flow sensor is used, it provides ventilator flow information to the system, which is used together with the NO dose set point to define the target NO amount and the first (injected) amount of NO. In addition, the flow sensor can be further used to detect changes in ventilator flow, which allows the system to respond to changes in ventilator flow more quickly than when using only the NO concentration measured in the circuit.

[0134] When all ventilator flow cannot be delivered through NO infusion at once, a system that relies solely on a flow sensor without sampling the amount of nitric oxide near the subject may be insufficient. For example, if NO delivery to a subject is required during anesthesia, such a system may be problematic. Anesthesia can be an expensive procedure, and therefore, it is desirable to recirculate exhaled gas, and thereby recirculate anesthetic compounds back to the subject. Anesthetic gas machines typically recirculate exhaled gas to minimize the use of expensive anesthetics. When residual NO is present in the recirculated gas, the additional NO injection required to maintain the target concentration should be reduced compared to normal use without recirculation. Ventilator flow-based control methods assume a zero starting NO concentration in the patient's gas and do not account for residual NO in the recirculated gas. As a result, the amount of NO to be infused may be overestimated because the actual amount of NO in the respiratory catheter is higher than the target value. This situation may continue to increase over time, resulting in ventilator circuit NO and NO2 concentrations not meeting FDA guidelines when recirculation occurs. Consequently, NO delivery systems using ventilator flow-based control have not been validated for use with recirculating anesthesia delivery systems.

[0135] Some ventilator systems, such as intrapulmonary percussive ventilation (IPV) systems, introduce respiratory gas downstream of the first gas injection. For this reason, the respiratory gas flow measurement at the NO injection point does not represent the complete respiratory gas flow to the patient. If the first amount of NO (which is being infused) is determined based on the flow measurement at the injection point, it may result in the subject receiving a lower NO concentration than the desired set dose.

[0136] In bidirectional flow delivery mode, if flow in both directions is included in the dose control, the accuracy of the ventilator circuit flow measurement is also reduced. This form of error in bidirectional flow devices leads to overdelivery of NO and ventilator circuit NO concentration, which is not in compliance with FDA guidance.

[0137] The system disclosed herein, which is configured to measure a second amount of NO to be delivered to a subject and, if necessary, correct the second amount by measuring the flow rate of the respiratory gas, can allow accurate delivery of NO amounts in anesthetic gas delivery systems, bidirectional flow systems (e.g., BiPAP, Phasitron), systems that introduce additional flow after the infusion module (e.g., intrapulmonary percussive ventilators), and the like.

[0138] In yet further aspects and as disclosed above, the systems described herein can be used to deliver additional pharmaceutically active compounds, such as anesthetic materials.In such exemplary and non-limiting aspects, the respiratory gas can contain a first amount of a pharmaceutically active ingredient.

[0139] In yet further aspects, the system can also measure gas exhaled by the subject. In some aspects, the expiratory conduit contains a fourth gas exhaled by the subject, wherein the fourth gas is exhausted to the surrounding environment. Yet in yet further aspects, the expiratory conduit can contain a fourth gas exhaled by the subject, and wherein the system is configured to recirculate at least a portion of the fourth gas into the respiratory conduit, wherein at least a portion of the fourth gas is substantially free of carbon dioxide. It should be understood that the fourth gas can be processed to remove carbon dioxide before being recycled back into the respiratory conduit.

[0140] In aspects where the fourth gas is recirculated, such gas can include a fourth amount of nitric oxide. The fourth gas enters the breathing conduit along with the respiratory gas and the first gas to form a second gas that can be sampled at the sampling point. In such aspects, the second gas can include at least a portion of the fourth gas. It should be understood that in such exemplary and non-limiting aspects, the second amount of nitric oxide includes at least the first amount and the fourth amount of nitric oxide.

[0141] If the respiratory gas contains a first amount of the pharmaceutically active ingredient, and if exhaled gas is collected, the exhaled gas (or fourth gas) may contain a second amount of the pharmaceutically active ingredient. It should be understood that in such aspects, the second amount of the pharmaceutically active ingredient is less than the first amount of the pharmaceutically active ingredient.

[0142] If the system is used for anesthesia, the active pharmaceutical ingredient includes an anesthetic drug.

[0143] In yet further aspects, the systems disclosed herein are configured to deliver from about 0.1 L / min to about 200 L / min of breathing gas, including exemplary values ​​of about 0.5 L / min, about 1 L / min, about 1.5 L / min, about 2 L / min, about 5 L / min, about 10 L / min, about 25 L / min, about 50 L / min, about 75 L / min, about 100 L / min, about 125 L / min, about 150 L / min, and about 175 L / min. It should be further understood that the system can deliver any amount of breathing gas that falls between any two of the aforementioned values ​​or any range that can be formed by any two of the aforementioned values. For example, the system can deliver breathing gas in an amount of about 0.1 L / min to about 195 L / min, or about 0.1 L / min to about 140 L / min, or about 0.5 L / min to about 100 L / min, or about 0.1 L / min to about 50 L / min, or about 0.1 L / min to about 100 L / min, or about 10 L / min to about 20 L / min, and so on.

[0144] Also disclosed herein is a device comprising any of the disclosed systems integrated with a ventilator, an anesthetic gas delivery system, a bidirectional flow system, an intrapulmonary percussive ventilator system, a high flow oxygen delivery system, or any combination thereof.

[0145] Figure 14 An exemplary and non-limiting schematic diagram of an apparatus disclosed herein in one aspect is shown.

[0146] method

[0147] Still further disclosed herein is a method of delivering nitric oxide to a subject. In such aspects, the method comprises: routing air from at least one air inlet through a first cartridge that generates nitric oxide gas; detecting a fill level of the first cartridge; and wherein the fill level of the first cartridge is near or below a threshold, automatically rerouting the air from the at least one air inlet through a second cartridge that generates nitric oxide.

[0148] Any of the cartridges disclosed above can be used in the method. In some aspects, the first cartridge is disposed in a first container, and the second cartridge is disposed in a second, separate container. In yet other aspects, the first cartridge and the second cartridge are electrically connected to a controller. Likewise, it should be understood that any of the controllers disclosed above can be used in the described method.

[0149] In yet further aspects, the controller is configured to automatically reroute the air. In yet further aspects, the controller is configured to simultaneously connect both containers to the air inlet when needed. In yet further aspects and as disclosed above, the controller used in the described method is configured to control the rate of generation of nitric oxide gas in the first cartridge and / or the second cartridge.

[0150] Although various aspects have been described above, it should be understood that these aspects are presented by way of example and not limitation. In addition, although various aspects have been described as having specific features and / or combinations of components, other aspects may have any combination of features and / or components from any aspect, as well as additional features and / or components.

[0151] Where the methods described above indicate that certain events occur in a certain order, the order of certain events may be modified. Additionally, when possible, certain events may be performed simultaneously in parallel processes, as well as sequentially as described above. Although various aspects have been described as having specific features and / or combinations of components, other aspects may have any combination of features and / or components from any aspect where appropriate.

[0152] Exemplary Aspects

[0153] Example 1. An operating table comprising: at least one air inlet; a first container configured to hold a first source of nitric oxide; a second container configured to hold a second source of nitric oxide; a controller configured to selectively couple the at least one air inlet to one of the first container or the second container to deliver nitric oxide from the first source or the second source; and an outlet coupled to the first container and / or the second container and configured to deliver nitric oxide to a subject.

[0154] Example 2. An operating station according to any of the examples herein (particularly Example 1), wherein the first source of nitric oxide comprises a first box configured to form nitric oxide, and / or wherein the second source of nitric oxide comprises a second box configured to generate nitric oxide.

[0155] Example 3. An operating station according to any of the examples herein (particularly Example 1 or 2), wherein when the at least one air inlet is connected to the first container and the first source of nitric oxide is substantially exhausted, the controller is configured to automatically switch the connection of the at least one air inlet from the first container to the second container, thereby delivering nitric oxide from the second source.

[0156] Example 4. The operating station according to any one of the examples herein, in particular examples 1 to 3, wherein at least once, the at least one air inlet is coupled to both the first container and the second container.

[0157] Example 5. An operating station according to any one of the examples herein, in particular examples 1 to 4, wherein the controller is configured to monitor the filling status of the first nitric oxide source and / or the second nitric oxide source.

[0158] Example 6. The operating station according to any one of the examples herein, particularly examples 1 to 5, wherein the operating station comprises two or more air inlets, such that the first container and the second container are each coupled to at least one air inlet.

[0159] Example 7. An operating station according to any of the examples herein (particularly Example 6), wherein the controller is configured to selectively activate at least one air inlet in the first container or the second container based on the filling state of the first nitric oxide source and / or the second nitric oxide source.

[0160] Example 8. The operating station of any one of the examples herein, particularly examples 1 to 7, wherein the controller is configured to control the rate of nitric oxide delivered to the subject.

[0161] Example 9. The operating station of any one of the examples herein (particularly examples 2 to 8), wherein the controller is configured to control the rate of nitric oxide generation in the first cartridge and / or the second cartridge.

[0162] Example 10. An operating station according to any one of the examples herein (particularly Examples 2 to 9), wherein the first box and / or the second box respectively comprise a first reservoir and a second reservoir, wherein the first reservoir and the second reservoir contain dinitrogen tetroxide, and wherein the first box and / or the second box are configured to convert dinitrogen tetroxide into nitrogen oxides.

[0163] Example 11. An operating station according to any one of the examples herein, in particular Example 10, wherein the controller is configured to control a filling state of nitrogen tetroxide.

[0164] Example 12. An operating station according to any of the examples herein, particularly examples 3 to 11, wherein the controller is configured to gradually increase the concentration of nitric oxide from the second source while still delivering nitric oxide from the first source.

[0165] Example 13. The operating station according to any of the examples herein, in particular examples 3 to 12, wherein after switching the at least one air inlet to the second container, the remaining nitric oxide in the first source of nitric oxide is exhausted.

[0166] Example 14. A method comprising: routing air from at least one air inlet through a first cartridge that generates nitric oxide gas; detecting a fill state of the first cartridge; and wherein the fill state of the first cartridge is near or below a threshold, automatically rerouting the air from the at least one air inlet through a second cartridge that generates nitric oxide.

[0167] Example 15. The method of any one of the examples herein, in particular Example 14, wherein the first cartridge is provided in a first container and the second cartridge is provided in a second, separate container.

[0168] Example 16. A method according to any of the examples herein, particularly examples 14 or 15, wherein the first and second boxes are in electrical communication with a controller.

[0169] Example 17. The method of any one of the examples herein, in particular Example 16, wherein the controller is configured to automatically reroute the air.

[0170] Example 18. The method according to any of the examples herein (particularly examples 16 or 17), wherein the controller is configured to control the rate of generation of nitric oxide gas in the first cartridge and / or the second cartridge.

[0171] Example 19. The method of any one of the examples herein, particularly examples 14 to 18, wherein the rerouting is gradual or immediate.

[0172] Example 20. An apparatus comprising: a frangible vessel containing nitrogen tetroxide; a reservoir, the frangible vessel disposed within the reservoir, the reservoir being configured to contain the nitrogen tetroxide when the frangible vessel is broken; and an outlet disposed above a wall of the reservoir, the frangible vessel, the reservoir, and the outlet being collectively configured such that when the frangible vessel is broken, the level of nitrogen tetroxide in the reservoir does not reach the outlet, regardless of the orientation of the vessel.

[0173] Example 21. An apparatus according to any of the examples herein (particularly Example 20), wherein the apparatus includes a separator disposed in the outlet and positioned above the nitrogen tetroxide regardless of the orientation of the vessel or external vibrations applied to the vessel.

[0174] Example 22. The apparatus of example 19 or 20, wherein the reservoir is configured to be heated to form nitrogen dioxide from dinitrogen tetroxide.

[0175] Example 23. The apparatus according to any of the examples herein, in particular Example 22, wherein the apparatus is further configured to convert nitrogen dioxide into nitric oxide.

[0176] Example 24. The apparatus of any one of the examples herein, particularly examples 20 to 23, wherein the apparatus is thermally insulated.

[0177] Example 25. An apparatus according to any one of the examples herein (particularly examples 20 to 24), wherein the apparatus comprises an activation mechanism comprising an activation wedge configured to break the frangible vessel.

[0178] Example 26. An apparatus according to any of the examples herein (particularly Examples 24 or 25), wherein the activation mechanism further comprises at least one activation sleeve, wherein the at least one activation sleeve is configured to maintain the position of the fragile vessel.

[0179] Example 27. A system for delivering nitric oxide to a subject, wherein the system comprises: (a) a nitric oxide infusion line configured to inject a first gas into a breathing conduit containing a breathing gas at an injection point, wherein the first gas contains a first amount of nitric oxide; (b) a sampling line configured to sample a second gas containing a second amount of nitric oxide and the breathing gas at a sampling location located between the injection point of the first gas and the subject; and (c) a feedback loop controller that communicates with: (i) a nitric oxide set point controller configured to set a nitric oxide set point amount; (ii) a source configured to provide a third gas having a third amount of nitric oxide; and (iii) at least one sensor configured to measure the second amount of nitric oxide in the sampling line; wherein the third amount of nitric oxide is determined by the feedback loop controller based on the second amount of nitric oxide and the nitric oxide set point amount.

[0180] Example 28. A system according to any of the examples herein, in particular Example 27, wherein the sampling location is located at a distance of about 6 inches to about 12 inches from the point at which the respiratory and expiratory conduits connect to the mask or breathing tube.

[0181] Example 29. The system of any of the examples herein, particularly examples 27 or 28, wherein the sampling line is operated by a pump and is configured to deliver a predetermined amount of the second gas to the at least one sensor.

[0182] Example 30. A system according to any one of the examples herein (particularly examples 27 to 29), wherein the breathing gas is delivered by a respiratory assistance device.

[0183] Example 31. A system according to any of the examples herein (particularly Examples 27 to 30), wherein the breathing gas comprises air and / or oxygen-enriched air.

[0184] Example 32. The system of any one of the examples herein, particularly examples 27 to 31, wherein the first gas further comprises a carrier gas.

[0185] Example 33. A system according to any of the examples herein, particularly Example 32, wherein the second gas further comprises a carrier gas.

[0186] Example 34. A system according to any of the examples herein, particularly examples 27 to 33, wherein the at least one sensor is a NO sensor.

[0187] Example 35. A system according to any of the examples herein, particularly examples 27 to 34, wherein the feedback loop controller further communicates with one or more additional sensors.

[0188] Example 36. A system according to any of the examples herein, in particular Example 35, wherein the additional sensor or sensors include an oxygen sensor and / or a nitrogen dioxide sensor.

[0189] Example 37. A system according to any of the examples herein, in particular Example 36, wherein the oxygen sensor detects the amount of oxygen in the second gas and / or the nitrogen dioxide sensor detects the amount of nitrogen dioxide in the second gas.

[0190] Example 38. A system according to any one of the examples herein, particularly examples 27 to 37, wherein the nitric oxide set point amount is a therapeutic target amount.

[0191] Example 39. A system according to any of the examples herein, particularly examples 27 to 37, wherein the nitric oxide set point is a flow rate of nitric oxide associated with the first amount of nitric oxide.

[0192] Example 40. A system according to any of the examples herein, particularly Examples 27 to 39, wherein the nitric oxide set point is a nitric oxide concentration associated with the first amount of nitric oxide.

[0193] Example 41. A system according to any of the examples herein (particularly Examples 27 to 40), wherein when the second amount of nitric oxide is different from the nitric oxide set point amount, the feedback loop controller is configured to communicate with the source to adjust the third amount of nitric oxide to match the nitric oxide set point amount.

[0194] Example 42. A system according to any of the examples herein, particularly examples 27 to 41, wherein at least once during delivery of nitric oxide to the subject, the first amount of nitric oxide is the same as the third amount of nitric oxide.

[0195] Example 43. A system according to any of the examples herein, particularly Examples 27 to 42, wherein the source is configured to generate nitric oxide in situ.

[0196] Example 44. A system according to any of the examples herein, in particular Example 43, wherein the third amount is controlled by the temperature and pressure supplied to the source.

[0197] Example 45. A system according to any of the examples herein (particularly Examples 27 to 44), wherein the system includes an auxiliary sensor positioned adjacent to an injection point and configured to measure the flow rate of the respiratory gas, and wherein the auxiliary sensor communicates with the feedback loop controller.

[0198] Example 46. A system according to any of the examples herein, in particular Example 45, wherein the feedback loop controller corrects the flow of the third gas when the flow rate of the breathing gas differs from the flow rate associated with the nitric oxide set point amount.

[0199] Example 47. A system according to any of the examples herein (particularly examples 27 to 46), wherein the respiratory gas further comprises a first amount of a pharmaceutically active ingredient.

[0200] Example 48. A system according to any of the examples herein (particularly examples 27 to 47), wherein the expiratory conduit contains a fourth gas exhaled by the subject, and wherein the fourth gas is exhausted to the surrounding environment.

[0201] Example 49. A system according to any of the examples herein (particularly Examples 27 to 48), wherein the expiratory conduit contains a fourth gas exhaled by the subject, and wherein the system is configured to recirculate at least a portion of the fourth gas into the respiratory conduit, wherein the at least a portion of the fourth gas is substantially free of carbon dioxide.

[0202] Example 50. A system according to any of the examples herein, particularly Example 49, wherein the fourth gas comprises a fourth amount of nitric oxide.

[0203] Example 51. A system according to any of the examples herein, particularly Examples 49 or 50, wherein the second gas comprises at least a portion of the fourth gas.

[0204] Example 52. A system according to any of the examples herein, in particular Example 51, wherein the second amount of nitric oxide comprises at least the first amount of nitric oxide and the fourth amount of nitric oxide.

[0205] Example 53. A system according to any of the examples herein (particularly Examples 49 to 52), wherein the fourth gas contains a second amount of a pharmaceutically active ingredient, wherein the second amount of the pharmaceutically active ingredient is less than the first amount of the pharmaceutically active ingredient.

[0206] Example 54. A system according to any one of the examples herein (particularly Examples 49 to 53), wherein the pharmaceutically active ingredient comprises an anesthetic.

[0207] Example 55. A system according to any of the examples herein (particularly examples 27 to 24), wherein the system is configured to deliver 0.1 L / min to 200 L / min of respiratory gas.

[0208] Example 56. A device comprising a system according to any of the examples herein (particularly Examples 27 to 55), integrated with a ventilator, an anesthetic gas delivery system, a bidirectional flow system, an intrapulmonary shock ventilator system, a high flow oxygen delivery system, or any combination thereof.

Claims

1. An operating table, comprising: at least one air inlet; a first container configured to house a first source of nitric oxide; a second container configured to house a second source of nitric oxide; a controller configured to selectively couple the at least one air inlet to one of the first container or the second container to deliver nitric oxide from the first source or the second source; as well as An outlet is coupled to the first container and / or the second container and configured to deliver nitric oxide to a subject.

2. The operating station of claim 1, wherein the first source of nitric oxide comprises a first cartridge configured to form nitric oxide, and / or wherein the second source of nitric oxide comprises a second cartridge configured to generate nitric oxide.

3. The operating station of claim 1 or 2, wherein when the at least one air inlet is coupled to the first container and the first source of nitric oxide is substantially depleted, the controller is configured to automatically switch the coupling of the at least one air inlet from the first container to the second container, thereby delivering nitric oxide from the second source.

4. The operating station according to any one of claims 1 to 3, wherein the at least one air inlet is coupled to both the first container and the second container.

5. The operating station according to any one of claims 1 to 4, wherein the controller is configured to monitor the filling status of the first nitric oxide source and / or the second nitric oxide source. 6 . The operating station according to claim 1 , wherein the operating station comprises two or more air inlets, such that the first container and the second container are respectively coupled to at least one air inlet.

7. The operating station of claim 6, wherein the controller is configured to selectively activate the at least one air inlet in the first container or the second container based on a fill state of the first nitric oxide source and / or the second nitric oxide source.

8. The operating station of any one of claims 1 to 7, wherein the controller is configured to control the rate of nitric oxide delivered to the subject.

9. The operating station of any one of claims 2 to 8, wherein the controller is configured to control the rate of nitric oxide generation in the first cartridge and / or the second cartridge.

10. The operating station according to any one of claims 2 to 9, wherein the first cartridge and / or the second cartridge comprises a first reservoir and a second reservoir, respectively, wherein the first reservoir and the second reservoir contain dinitrogen tetroxide, and wherein the first cartridge and / or the second cartridge is configured to convert the dinitrogen tetroxide into nitrogen oxides. The operating station according to claim 10 , wherein the controller is configured to control a filling state of the nitrogen tetroxide.

12. The operating station of any one of claims 3 to 11, wherein the controller is configured to gradually increase the concentration of nitric oxide from the second source while still delivering nitric oxide from the first source.

13. The operating station according to any one of claims 3 to 12, wherein after switching the at least one air inlet to the second container, the remaining nitric oxide in the first source of nitric oxide is exhausted.

14. A method comprising: routing air from the at least one air inlet through the first cartridge that generates nitric oxide gas; detecting a filling status of the first cartridge; as well as Wherein when the filling state of the first cartridge approaches or falls below a threshold value, air is automatically re-routed from the at least one air inlet through a second cartridge that produces nitric oxide.

15. The method of claim 14, wherein the first cartridge is disposed in a first container and the second cartridge is disposed in a second, separate container.

16. The method of claim 14 or 15, wherein the first and second cartridges are in electrical communication with a controller.

17. The method of claim 16, wherein the controller is configured to automatically reroute the air.

18. The method according to claim 16 or 17, wherein the controller is configured to control the generation rate of nitric oxide gas in the first cartridge and / or the second cartridge.

19. The method of any one of claims 14 to 18, wherein the rerouting is gradual or immediate.

20. A device comprising: a fragile container containing nitrogen tetroxide; a reservoir, the frangible vessel being disposed within the reservoir, the reservoir being configured to contain the nitrogen tetroxide upon rupture of the frangible vessel; as well as an outlet disposed above a wall of the reservoir, The frangible vessel, the reservoir, and the outlet are collectively configured such that when the frangible vessel is ruptured, the level of nitrogen tetroxide in the reservoir does not reach the outlet, regardless of the orientation of the vessel.

21. The apparatus of claim 20, wherein the apparatus comprises a separator disposed in the outlet and positioned above the nitrogen tetroxide regardless of the orientation of the vessel or external vibrations applied to the vessel.

22. Apparatus according to claim 20 or 21, wherein the reservoir is configured to be heated to form nitrogen dioxide from dinitrogen tetroxide.

23. The apparatus of claim 22, wherein the apparatus is further configured to convert nitrogen dioxide into nitric oxide.

24. Apparatus according to any one of claims 20 to 23, wherein the apparatus is thermally insulated.

25. The apparatus of any one of claims 20 to 24, wherein the apparatus comprises an activation mechanism comprising an activation wedge configured to rupture the frangible vessel.

26. The apparatus of claim 24 or 25, wherein the activation mechanism further comprises at least one activation sleeve, wherein the at least one activation sleeve is configured to maintain the position of the frangible vessel.

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